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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'.

LIPEMIA RETINALIS DURING CHEMOTHERAPY WITH ADJUNCTIVE GLUCOCORTICOID TREATMENT IN A PATIENT WITH COLON CARCINOMA. OBJECTIVE The purpose of this report is to describe a case of lipemia retinalis due to decompensating hyperlipidemia that occurred during chemotherapy in a patient with metastatic colon carcinoma. METHODS Retrospective case report. RESULTS A 55-year-old non-insulin-dependent diabetic man with well-controlled hyperlipidemia presented himself with temporarily blurred vision in both eyes occurring during chemotherapy. He was found to have lipemia retinalis in his both eyes. Blood tests revealed elevated cholesterol and triglyceride levels exceeding 8,200 mg/dL. He received six cycles of FOLFIRI/bevacizumab and accompanying dexamethasone because of colon cancer with pulmonary metastases. Lipemia retinalis had resolved after a 6-week follow-up when chemotherapy was finished, and the patients' triglyceride and glucose levels decreased to normal values. CONCLUSIONS Lipemia retinalis associated with visual impairment may occur during chemotherapy under accompanying treatment with dexamethasone. Even if patients with hyperlipidemia are metabolically well-controlled with oral medication, treatment with dexamethasone can potentially lead to decompensation of hyperlipidemia causing secondary lipemia retinalis. Hyperlipidemia is characterized by increased levels of serum concentrations of cholesterol or triglycerides and known as a major factor of premature vessel atherosclerosis. Lipemia retinalis is a rare retinal manifestation of hypertriglyceridemia. Retinal vessels appear creamy whitish colored due to the effect of light scattering by triglyceride-laden chylomicrons.1 In clinical practice, lipemia retinalis caused by chylomicronemia in hyperlipidemia is often observed in patients with metabolic syndrome. However, associations with primary hyperlipidemia or secondary factors causing high levels of triglycerides are also well-documented.2,3 Case Report A 55-year-old white man presented to our department with temporarily blurred vision in both eyes. Ocular history of the patient was unremarkable, and his best-corrected visual acuity was 100/100 in both eyes. Slit-lamp examination demonstrated normal anterior segments, and intraocular pressures were measured at 16 mmHg in both eyes. His medical history included metastatic colon cancer treated with surgery and chemotherapy, diabetes mellitus, and hyperlipidemia well-controlled with statins (atorvastatin 40 mg once per day). Dilated funduscopic examination revealed normal optic discs, white creamy retinal vessels, and arterial narrowing with arteriovenous crossing abnormalities but no signs of diabetic retinopathy. Furthermore, optical coherence tomography was unremarkable, and there was no evidence for diabetic macular edema. The clinical picture was consistent with lipemia retinalis (Figure 1, A and B). Fig. 1. Fundus photograph of right (A) and left (B) eye with signs of lipemia retinalis. Characteristic white creamy vessels are visible, making it difficult to distinguish the arteries from the veins. Before our ophthalmologic examination, the patient was treated with six cycles of chemotherapy with FOLFIRI/bevacizumab because of newly occurring pulmonary metastases. The chemotherapy consisted of bevacizumab, irinotecan, and 5-fluorouracil. In addition, he received intravenous therapy with dexamethasone (8 mg every 2 weeks) for treatment of the side effects of the chemotherapy. The patient was referred to the Department of Internal Medicine to perform further diagnosis and treatment; were laboratory evaluation revealed highly increased levels of cholesterol (681 mg/dL) and triglycerides (8,258 mg/dL). It seems the chemotherapy with concomitant treatment with dexamethasone led to metabolic decompensation in hyperlipidemia. The patient presented himself again to our department 6 weeks later, reporting that his visual problems had vanished. Fundus examination revealed reversion of the alterations of the retinal vessels due to lipemia (Figure 2, A and B). Metabolic control of the triglycerides was achieved (triglycerides were 605 mg/dL and cholesterol was 167 mg/dL on the day of examination) since he quitted chemotherapy and intravenous dexamethasone. In addition, his lipid-lowering therapy had been re-evaluated and changed to cholib 145/40 mg tablets once per day (combination of simvastatin and fenofibrate). Fig. 2. Fundus photograph of right (A) and left (B) eye, 6 weeks after initial presentation and under appropriate lipid-lowering medication. The lipemia retinalis had resolved, and the retinal vessels abnormalities returned to normal appearance. Discussion Lipemia retinalis is a rare ocular finding characterized by creamy white colored retinal blood vessels, which was first described in 1880 by Heyl.4 It is associated with elevated levels of plasma triglycerides and occurs in certain types of both primary and secondary hyperlipidemia. In early stages of lipemia retinalis (triglyceride levels of 2,500–3,499 mg/dL), only the peripheral retinal vessels appear creamy and thin. As triglyceride levels increase (3,500–5,000 mg/dL), lipemia spreads out to the posterior pole and the creamy color of the vessels extends toward the optic disc. With triglyceride levels exceeding 5,000 mg/dL, the retina becomes salmon-colored with creamy whitish arteries and veins distinguishable only by size.1,2 Although the exact correlation of the incidence of lipemia retinalis and the level of plasma triglycerides is not completely understood, the retinal changes are known as a direct consequence of the elevated levels of circulating chylomicrons in the retinal vessels. Chylomicrons are large lipoproteins, which serve to transport triglycerides in the circulatory system after intestinal absorption. The slightly smaller macromolecules very low-density lipoproteins also play an important role. These lipoproteins are involved in the process of transportation of fat in the metabolism but do not seem to contribute to the fundal appearance.5 However, it has been observed that not all patients with even highly elevated levels of chylomicrons and triglycerides present lipemia retinalis, suggesting that other factors, such as changes in hematocrit and difference in translucency of the retinal and choroidal vessels, have to be considered.5 Rayner et al1 assumed the light-scattering effect of chylomicrons is responsible for the clinical picture of lipemia retinalis in the fundi. Most lipemia retinalis cases are asymptomatic, but in fact, also patients with initially deteriorated visual acuity were reported.6 In general, only advanced and persistent lipemia is known to cause decrease in visual acuity or might even lead to complete loss of vision after massive irreversible lipid exsudation.1 Regarding current literature, several cases of lipemia retinalis caused by chylomicronemia in hyperlipidemia due to uncontrolled diabetes mellitus or due to primary hyperlipidemia or even caused by impairment of lipid metabolism during a viral illness were described.1,3 This is the first report to our knowledge of an association between symptomatic lipemia retinalis and decompensated hyperlipidemia related to treatment with chemotherapy and accompanying treatment with dexamethasone in a patient with metastatic colon cancer. The present data do not reveal any causal linkage between chemotherapy with FOLFOX/bevacizumab and secondary hyperlipidemia, so lipemia retinalis in our patient is believed to be a consequence of decompensated hyperlipidemia after chronic therapy with dexamethasone over a period of 5 months. Previously, Chahande et al described a case of a 14-year-old diabetic boy developing lipemia retinalis because of intravenous treatment with prednisolone (1 mg/kg for 5 days) for multiple intracranial neurocysticerci with perilesional edema. The authors also assume the lipemia in this case was caused by administration of steroids.7 Secondary hypertriglyceridemia is known as a result of the supply of glucocorticoids. Glucocorticoid substitution is associated with hypertriglyceridemia, elevated glucose, and higher non–high-density lipoprotein cholesterol levels and can lead to metabolic syndrome, which was proved in a study with GH- and glucocorticoid-replaced hypopituitary patients.8 Suggesting underlying mechanisms, studies reported that pharmacological doses of glucocorticoids lead to an increased endogenous glucose production in healthy people by stimulating hepatic gluconeogenic enzymes and augmenting supply of substrates to the liver for gluconeogenesis by peripheral lipolysis and proteolysis.9,10 Usually no treatment is required for lipemia retinalis. Once triglyceride levels return to normal, the retinal appearance of lipemia retinalis should quickly resolve without causing decrease in visual acuity or permanent retinal disease.11 However, lipemia retinalis is a very important sign of a potential life-threatening systemic metabolic disorder, and it is essential to recognize it as a sign of a profound lipid abnormality. We present the first documentation of lipemia retinalis associated with visual symptoms because of decompensating hyperlipidemia in a patient undergoing chemotherapy with concomitant treatment with dexamethasone, and we want to raise awareness of this probably often underdiagnosed retinal condition. Lipid-lowering therapy is believed to normalize fundal appearance and leads to restoration of visual acuity. It is important to adapt the lipid-lowering medication to obtain appropriate management of the lipid metabolism in patients receiving dexamethasone therapy. None of the authors has any financial/conflicting interests to disclose.

ATORVASTATIN, BEVACIZUMAB, DEXAMETHASONE, FLUOROURACIL, IRINOTECAN

DrugsGivenReaction

CC BY-NC-ND

30074937

2021-07-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lipaemia retinalis'.

LIPEMIA RETINALIS DURING CHEMOTHERAPY WITH ADJUNCTIVE GLUCOCORTICOID TREATMENT IN A PATIENT WITH COLON CARCINOMA. OBJECTIVE The purpose of this report is to describe a case of lipemia retinalis due to decompensating hyperlipidemia that occurred during chemotherapy in a patient with metastatic colon carcinoma. METHODS Retrospective case report. RESULTS A 55-year-old non-insulin-dependent diabetic man with well-controlled hyperlipidemia presented himself with temporarily blurred vision in both eyes occurring during chemotherapy. He was found to have lipemia retinalis in his both eyes. Blood tests revealed elevated cholesterol and triglyceride levels exceeding 8,200 mg/dL. He received six cycles of FOLFIRI/bevacizumab and accompanying dexamethasone because of colon cancer with pulmonary metastases. Lipemia retinalis had resolved after a 6-week follow-up when chemotherapy was finished, and the patients' triglyceride and glucose levels decreased to normal values. CONCLUSIONS Lipemia retinalis associated with visual impairment may occur during chemotherapy under accompanying treatment with dexamethasone. Even if patients with hyperlipidemia are metabolically well-controlled with oral medication, treatment with dexamethasone can potentially lead to decompensation of hyperlipidemia causing secondary lipemia retinalis. Hyperlipidemia is characterized by increased levels of serum concentrations of cholesterol or triglycerides and known as a major factor of premature vessel atherosclerosis. Lipemia retinalis is a rare retinal manifestation of hypertriglyceridemia. Retinal vessels appear creamy whitish colored due to the effect of light scattering by triglyceride-laden chylomicrons.1 In clinical practice, lipemia retinalis caused by chylomicronemia in hyperlipidemia is often observed in patients with metabolic syndrome. However, associations with primary hyperlipidemia or secondary factors causing high levels of triglycerides are also well-documented.2,3 Case Report A 55-year-old white man presented to our department with temporarily blurred vision in both eyes. Ocular history of the patient was unremarkable, and his best-corrected visual acuity was 100/100 in both eyes. Slit-lamp examination demonstrated normal anterior segments, and intraocular pressures were measured at 16 mmHg in both eyes. His medical history included metastatic colon cancer treated with surgery and chemotherapy, diabetes mellitus, and hyperlipidemia well-controlled with statins (atorvastatin 40 mg once per day). Dilated funduscopic examination revealed normal optic discs, white creamy retinal vessels, and arterial narrowing with arteriovenous crossing abnormalities but no signs of diabetic retinopathy. Furthermore, optical coherence tomography was unremarkable, and there was no evidence for diabetic macular edema. The clinical picture was consistent with lipemia retinalis (Figure 1, A and B). Fig. 1. Fundus photograph of right (A) and left (B) eye with signs of lipemia retinalis. Characteristic white creamy vessels are visible, making it difficult to distinguish the arteries from the veins. Before our ophthalmologic examination, the patient was treated with six cycles of chemotherapy with FOLFIRI/bevacizumab because of newly occurring pulmonary metastases. The chemotherapy consisted of bevacizumab, irinotecan, and 5-fluorouracil. In addition, he received intravenous therapy with dexamethasone (8 mg every 2 weeks) for treatment of the side effects of the chemotherapy. The patient was referred to the Department of Internal Medicine to perform further diagnosis and treatment; were laboratory evaluation revealed highly increased levels of cholesterol (681 mg/dL) and triglycerides (8,258 mg/dL). It seems the chemotherapy with concomitant treatment with dexamethasone led to metabolic decompensation in hyperlipidemia. The patient presented himself again to our department 6 weeks later, reporting that his visual problems had vanished. Fundus examination revealed reversion of the alterations of the retinal vessels due to lipemia (Figure 2, A and B). Metabolic control of the triglycerides was achieved (triglycerides were 605 mg/dL and cholesterol was 167 mg/dL on the day of examination) since he quitted chemotherapy and intravenous dexamethasone. In addition, his lipid-lowering therapy had been re-evaluated and changed to cholib 145/40 mg tablets once per day (combination of simvastatin and fenofibrate). Fig. 2. Fundus photograph of right (A) and left (B) eye, 6 weeks after initial presentation and under appropriate lipid-lowering medication. The lipemia retinalis had resolved, and the retinal vessels abnormalities returned to normal appearance. Discussion Lipemia retinalis is a rare ocular finding characterized by creamy white colored retinal blood vessels, which was first described in 1880 by Heyl.4 It is associated with elevated levels of plasma triglycerides and occurs in certain types of both primary and secondary hyperlipidemia. In early stages of lipemia retinalis (triglyceride levels of 2,500–3,499 mg/dL), only the peripheral retinal vessels appear creamy and thin. As triglyceride levels increase (3,500–5,000 mg/dL), lipemia spreads out to the posterior pole and the creamy color of the vessels extends toward the optic disc. With triglyceride levels exceeding 5,000 mg/dL, the retina becomes salmon-colored with creamy whitish arteries and veins distinguishable only by size.1,2 Although the exact correlation of the incidence of lipemia retinalis and the level of plasma triglycerides is not completely understood, the retinal changes are known as a direct consequence of the elevated levels of circulating chylomicrons in the retinal vessels. Chylomicrons are large lipoproteins, which serve to transport triglycerides in the circulatory system after intestinal absorption. The slightly smaller macromolecules very low-density lipoproteins also play an important role. These lipoproteins are involved in the process of transportation of fat in the metabolism but do not seem to contribute to the fundal appearance.5 However, it has been observed that not all patients with even highly elevated levels of chylomicrons and triglycerides present lipemia retinalis, suggesting that other factors, such as changes in hematocrit and difference in translucency of the retinal and choroidal vessels, have to be considered.5 Rayner et al1 assumed the light-scattering effect of chylomicrons is responsible for the clinical picture of lipemia retinalis in the fundi. Most lipemia retinalis cases are asymptomatic, but in fact, also patients with initially deteriorated visual acuity were reported.6 In general, only advanced and persistent lipemia is known to cause decrease in visual acuity or might even lead to complete loss of vision after massive irreversible lipid exsudation.1 Regarding current literature, several cases of lipemia retinalis caused by chylomicronemia in hyperlipidemia due to uncontrolled diabetes mellitus or due to primary hyperlipidemia or even caused by impairment of lipid metabolism during a viral illness were described.1,3 This is the first report to our knowledge of an association between symptomatic lipemia retinalis and decompensated hyperlipidemia related to treatment with chemotherapy and accompanying treatment with dexamethasone in a patient with metastatic colon cancer. The present data do not reveal any causal linkage between chemotherapy with FOLFOX/bevacizumab and secondary hyperlipidemia, so lipemia retinalis in our patient is believed to be a consequence of decompensated hyperlipidemia after chronic therapy with dexamethasone over a period of 5 months. Previously, Chahande et al described a case of a 14-year-old diabetic boy developing lipemia retinalis because of intravenous treatment with prednisolone (1 mg/kg for 5 days) for multiple intracranial neurocysticerci with perilesional edema. The authors also assume the lipemia in this case was caused by administration of steroids.7 Secondary hypertriglyceridemia is known as a result of the supply of glucocorticoids. Glucocorticoid substitution is associated with hypertriglyceridemia, elevated glucose, and higher non–high-density lipoprotein cholesterol levels and can lead to metabolic syndrome, which was proved in a study with GH- and glucocorticoid-replaced hypopituitary patients.8 Suggesting underlying mechanisms, studies reported that pharmacological doses of glucocorticoids lead to an increased endogenous glucose production in healthy people by stimulating hepatic gluconeogenic enzymes and augmenting supply of substrates to the liver for gluconeogenesis by peripheral lipolysis and proteolysis.9,10 Usually no treatment is required for lipemia retinalis. Once triglyceride levels return to normal, the retinal appearance of lipemia retinalis should quickly resolve without causing decrease in visual acuity or permanent retinal disease.11 However, lipemia retinalis is a very important sign of a potential life-threatening systemic metabolic disorder, and it is essential to recognize it as a sign of a profound lipid abnormality. We present the first documentation of lipemia retinalis associated with visual symptoms because of decompensating hyperlipidemia in a patient undergoing chemotherapy with concomitant treatment with dexamethasone, and we want to raise awareness of this probably often underdiagnosed retinal condition. Lipid-lowering therapy is believed to normalize fundal appearance and leads to restoration of visual acuity. It is important to adapt the lipid-lowering medication to obtain appropriate management of the lipid metabolism in patients receiving dexamethasone therapy. None of the authors has any financial/conflicting interests to disclose.

ATORVASTATIN, BEVACIZUMAB, DEXAMETHASONE, FLUOROURACIL, IRINOTECAN

DrugsGivenReaction

CC BY-NC-ND

30074937

2021-07-01

What was the administration route of drug 'DEXAMETHASONE'?

LIPEMIA RETINALIS DURING CHEMOTHERAPY WITH ADJUNCTIVE GLUCOCORTICOID TREATMENT IN A PATIENT WITH COLON CARCINOMA. OBJECTIVE The purpose of this report is to describe a case of lipemia retinalis due to decompensating hyperlipidemia that occurred during chemotherapy in a patient with metastatic colon carcinoma. METHODS Retrospective case report. RESULTS A 55-year-old non-insulin-dependent diabetic man with well-controlled hyperlipidemia presented himself with temporarily blurred vision in both eyes occurring during chemotherapy. He was found to have lipemia retinalis in his both eyes. Blood tests revealed elevated cholesterol and triglyceride levels exceeding 8,200 mg/dL. He received six cycles of FOLFIRI/bevacizumab and accompanying dexamethasone because of colon cancer with pulmonary metastases. Lipemia retinalis had resolved after a 6-week follow-up when chemotherapy was finished, and the patients' triglyceride and glucose levels decreased to normal values. CONCLUSIONS Lipemia retinalis associated with visual impairment may occur during chemotherapy under accompanying treatment with dexamethasone. Even if patients with hyperlipidemia are metabolically well-controlled with oral medication, treatment with dexamethasone can potentially lead to decompensation of hyperlipidemia causing secondary lipemia retinalis. Hyperlipidemia is characterized by increased levels of serum concentrations of cholesterol or triglycerides and known as a major factor of premature vessel atherosclerosis. Lipemia retinalis is a rare retinal manifestation of hypertriglyceridemia. Retinal vessels appear creamy whitish colored due to the effect of light scattering by triglyceride-laden chylomicrons.1 In clinical practice, lipemia retinalis caused by chylomicronemia in hyperlipidemia is often observed in patients with metabolic syndrome. However, associations with primary hyperlipidemia or secondary factors causing high levels of triglycerides are also well-documented.2,3 Case Report A 55-year-old white man presented to our department with temporarily blurred vision in both eyes. Ocular history of the patient was unremarkable, and his best-corrected visual acuity was 100/100 in both eyes. Slit-lamp examination demonstrated normal anterior segments, and intraocular pressures were measured at 16 mmHg in both eyes. His medical history included metastatic colon cancer treated with surgery and chemotherapy, diabetes mellitus, and hyperlipidemia well-controlled with statins (atorvastatin 40 mg once per day). Dilated funduscopic examination revealed normal optic discs, white creamy retinal vessels, and arterial narrowing with arteriovenous crossing abnormalities but no signs of diabetic retinopathy. Furthermore, optical coherence tomography was unremarkable, and there was no evidence for diabetic macular edema. The clinical picture was consistent with lipemia retinalis (Figure 1, A and B). Fig. 1. Fundus photograph of right (A) and left (B) eye with signs of lipemia retinalis. Characteristic white creamy vessels are visible, making it difficult to distinguish the arteries from the veins. Before our ophthalmologic examination, the patient was treated with six cycles of chemotherapy with FOLFIRI/bevacizumab because of newly occurring pulmonary metastases. The chemotherapy consisted of bevacizumab, irinotecan, and 5-fluorouracil. In addition, he received intravenous therapy with dexamethasone (8 mg every 2 weeks) for treatment of the side effects of the chemotherapy. The patient was referred to the Department of Internal Medicine to perform further diagnosis and treatment; were laboratory evaluation revealed highly increased levels of cholesterol (681 mg/dL) and triglycerides (8,258 mg/dL). It seems the chemotherapy with concomitant treatment with dexamethasone led to metabolic decompensation in hyperlipidemia. The patient presented himself again to our department 6 weeks later, reporting that his visual problems had vanished. Fundus examination revealed reversion of the alterations of the retinal vessels due to lipemia (Figure 2, A and B). Metabolic control of the triglycerides was achieved (triglycerides were 605 mg/dL and cholesterol was 167 mg/dL on the day of examination) since he quitted chemotherapy and intravenous dexamethasone. In addition, his lipid-lowering therapy had been re-evaluated and changed to cholib 145/40 mg tablets once per day (combination of simvastatin and fenofibrate). Fig. 2. Fundus photograph of right (A) and left (B) eye, 6 weeks after initial presentation and under appropriate lipid-lowering medication. The lipemia retinalis had resolved, and the retinal vessels abnormalities returned to normal appearance. Discussion Lipemia retinalis is a rare ocular finding characterized by creamy white colored retinal blood vessels, which was first described in 1880 by Heyl.4 It is associated with elevated levels of plasma triglycerides and occurs in certain types of both primary and secondary hyperlipidemia. In early stages of lipemia retinalis (triglyceride levels of 2,500–3,499 mg/dL), only the peripheral retinal vessels appear creamy and thin. As triglyceride levels increase (3,500–5,000 mg/dL), lipemia spreads out to the posterior pole and the creamy color of the vessels extends toward the optic disc. With triglyceride levels exceeding 5,000 mg/dL, the retina becomes salmon-colored with creamy whitish arteries and veins distinguishable only by size.1,2 Although the exact correlation of the incidence of lipemia retinalis and the level of plasma triglycerides is not completely understood, the retinal changes are known as a direct consequence of the elevated levels of circulating chylomicrons in the retinal vessels. Chylomicrons are large lipoproteins, which serve to transport triglycerides in the circulatory system after intestinal absorption. The slightly smaller macromolecules very low-density lipoproteins also play an important role. These lipoproteins are involved in the process of transportation of fat in the metabolism but do not seem to contribute to the fundal appearance.5 However, it has been observed that not all patients with even highly elevated levels of chylomicrons and triglycerides present lipemia retinalis, suggesting that other factors, such as changes in hematocrit and difference in translucency of the retinal and choroidal vessels, have to be considered.5 Rayner et al1 assumed the light-scattering effect of chylomicrons is responsible for the clinical picture of lipemia retinalis in the fundi. Most lipemia retinalis cases are asymptomatic, but in fact, also patients with initially deteriorated visual acuity were reported.6 In general, only advanced and persistent lipemia is known to cause decrease in visual acuity or might even lead to complete loss of vision after massive irreversible lipid exsudation.1 Regarding current literature, several cases of lipemia retinalis caused by chylomicronemia in hyperlipidemia due to uncontrolled diabetes mellitus or due to primary hyperlipidemia or even caused by impairment of lipid metabolism during a viral illness were described.1,3 This is the first report to our knowledge of an association between symptomatic lipemia retinalis and decompensated hyperlipidemia related to treatment with chemotherapy and accompanying treatment with dexamethasone in a patient with metastatic colon cancer. The present data do not reveal any causal linkage between chemotherapy with FOLFOX/bevacizumab and secondary hyperlipidemia, so lipemia retinalis in our patient is believed to be a consequence of decompensated hyperlipidemia after chronic therapy with dexamethasone over a period of 5 months. Previously, Chahande et al described a case of a 14-year-old diabetic boy developing lipemia retinalis because of intravenous treatment with prednisolone (1 mg/kg for 5 days) for multiple intracranial neurocysticerci with perilesional edema. The authors also assume the lipemia in this case was caused by administration of steroids.7 Secondary hypertriglyceridemia is known as a result of the supply of glucocorticoids. Glucocorticoid substitution is associated with hypertriglyceridemia, elevated glucose, and higher non–high-density lipoprotein cholesterol levels and can lead to metabolic syndrome, which was proved in a study with GH- and glucocorticoid-replaced hypopituitary patients.8 Suggesting underlying mechanisms, studies reported that pharmacological doses of glucocorticoids lead to an increased endogenous glucose production in healthy people by stimulating hepatic gluconeogenic enzymes and augmenting supply of substrates to the liver for gluconeogenesis by peripheral lipolysis and proteolysis.9,10 Usually no treatment is required for lipemia retinalis. Once triglyceride levels return to normal, the retinal appearance of lipemia retinalis should quickly resolve without causing decrease in visual acuity or permanent retinal disease.11 However, lipemia retinalis is a very important sign of a potential life-threatening systemic metabolic disorder, and it is essential to recognize it as a sign of a profound lipid abnormality. We present the first documentation of lipemia retinalis associated with visual symptoms because of decompensating hyperlipidemia in a patient undergoing chemotherapy with concomitant treatment with dexamethasone, and we want to raise awareness of this probably often underdiagnosed retinal condition. Lipid-lowering therapy is believed to normalize fundal appearance and leads to restoration of visual acuity. It is important to adapt the lipid-lowering medication to obtain appropriate management of the lipid metabolism in patients receiving dexamethasone therapy. None of the authors has any financial/conflicting interests to disclose.

Intravenous (not otherwise specified)

DrugAdministrationRoute

CC BY-NC-ND

30074937

2021-07-01

What was the dosage of drug 'ATORVASTATIN'?

LIPEMIA RETINALIS DURING CHEMOTHERAPY WITH ADJUNCTIVE GLUCOCORTICOID TREATMENT IN A PATIENT WITH COLON CARCINOMA. OBJECTIVE The purpose of this report is to describe a case of lipemia retinalis due to decompensating hyperlipidemia that occurred during chemotherapy in a patient with metastatic colon carcinoma. METHODS Retrospective case report. RESULTS A 55-year-old non-insulin-dependent diabetic man with well-controlled hyperlipidemia presented himself with temporarily blurred vision in both eyes occurring during chemotherapy. He was found to have lipemia retinalis in his both eyes. Blood tests revealed elevated cholesterol and triglyceride levels exceeding 8,200 mg/dL. He received six cycles of FOLFIRI/bevacizumab and accompanying dexamethasone because of colon cancer with pulmonary metastases. Lipemia retinalis had resolved after a 6-week follow-up when chemotherapy was finished, and the patients' triglyceride and glucose levels decreased to normal values. CONCLUSIONS Lipemia retinalis associated with visual impairment may occur during chemotherapy under accompanying treatment with dexamethasone. Even if patients with hyperlipidemia are metabolically well-controlled with oral medication, treatment with dexamethasone can potentially lead to decompensation of hyperlipidemia causing secondary lipemia retinalis. Hyperlipidemia is characterized by increased levels of serum concentrations of cholesterol or triglycerides and known as a major factor of premature vessel atherosclerosis. Lipemia retinalis is a rare retinal manifestation of hypertriglyceridemia. Retinal vessels appear creamy whitish colored due to the effect of light scattering by triglyceride-laden chylomicrons.1 In clinical practice, lipemia retinalis caused by chylomicronemia in hyperlipidemia is often observed in patients with metabolic syndrome. However, associations with primary hyperlipidemia or secondary factors causing high levels of triglycerides are also well-documented.2,3 Case Report A 55-year-old white man presented to our department with temporarily blurred vision in both eyes. Ocular history of the patient was unremarkable, and his best-corrected visual acuity was 100/100 in both eyes. Slit-lamp examination demonstrated normal anterior segments, and intraocular pressures were measured at 16 mmHg in both eyes. His medical history included metastatic colon cancer treated with surgery and chemotherapy, diabetes mellitus, and hyperlipidemia well-controlled with statins (atorvastatin 40 mg once per day). Dilated funduscopic examination revealed normal optic discs, white creamy retinal vessels, and arterial narrowing with arteriovenous crossing abnormalities but no signs of diabetic retinopathy. Furthermore, optical coherence tomography was unremarkable, and there was no evidence for diabetic macular edema. The clinical picture was consistent with lipemia retinalis (Figure 1, A and B). Fig. 1. Fundus photograph of right (A) and left (B) eye with signs of lipemia retinalis. Characteristic white creamy vessels are visible, making it difficult to distinguish the arteries from the veins. Before our ophthalmologic examination, the patient was treated with six cycles of chemotherapy with FOLFIRI/bevacizumab because of newly occurring pulmonary metastases. The chemotherapy consisted of bevacizumab, irinotecan, and 5-fluorouracil. In addition, he received intravenous therapy with dexamethasone (8 mg every 2 weeks) for treatment of the side effects of the chemotherapy. The patient was referred to the Department of Internal Medicine to perform further diagnosis and treatment; were laboratory evaluation revealed highly increased levels of cholesterol (681 mg/dL) and triglycerides (8,258 mg/dL). It seems the chemotherapy with concomitant treatment with dexamethasone led to metabolic decompensation in hyperlipidemia. The patient presented himself again to our department 6 weeks later, reporting that his visual problems had vanished. Fundus examination revealed reversion of the alterations of the retinal vessels due to lipemia (Figure 2, A and B). Metabolic control of the triglycerides was achieved (triglycerides were 605 mg/dL and cholesterol was 167 mg/dL on the day of examination) since he quitted chemotherapy and intravenous dexamethasone. In addition, his lipid-lowering therapy had been re-evaluated and changed to cholib 145/40 mg tablets once per day (combination of simvastatin and fenofibrate). Fig. 2. Fundus photograph of right (A) and left (B) eye, 6 weeks after initial presentation and under appropriate lipid-lowering medication. The lipemia retinalis had resolved, and the retinal vessels abnormalities returned to normal appearance. Discussion Lipemia retinalis is a rare ocular finding characterized by creamy white colored retinal blood vessels, which was first described in 1880 by Heyl.4 It is associated with elevated levels of plasma triglycerides and occurs in certain types of both primary and secondary hyperlipidemia. In early stages of lipemia retinalis (triglyceride levels of 2,500–3,499 mg/dL), only the peripheral retinal vessels appear creamy and thin. As triglyceride levels increase (3,500–5,000 mg/dL), lipemia spreads out to the posterior pole and the creamy color of the vessels extends toward the optic disc. With triglyceride levels exceeding 5,000 mg/dL, the retina becomes salmon-colored with creamy whitish arteries and veins distinguishable only by size.1,2 Although the exact correlation of the incidence of lipemia retinalis and the level of plasma triglycerides is not completely understood, the retinal changes are known as a direct consequence of the elevated levels of circulating chylomicrons in the retinal vessels. Chylomicrons are large lipoproteins, which serve to transport triglycerides in the circulatory system after intestinal absorption. The slightly smaller macromolecules very low-density lipoproteins also play an important role. These lipoproteins are involved in the process of transportation of fat in the metabolism but do not seem to contribute to the fundal appearance.5 However, it has been observed that not all patients with even highly elevated levels of chylomicrons and triglycerides present lipemia retinalis, suggesting that other factors, such as changes in hematocrit and difference in translucency of the retinal and choroidal vessels, have to be considered.5 Rayner et al1 assumed the light-scattering effect of chylomicrons is responsible for the clinical picture of lipemia retinalis in the fundi. Most lipemia retinalis cases are asymptomatic, but in fact, also patients with initially deteriorated visual acuity were reported.6 In general, only advanced and persistent lipemia is known to cause decrease in visual acuity or might even lead to complete loss of vision after massive irreversible lipid exsudation.1 Regarding current literature, several cases of lipemia retinalis caused by chylomicronemia in hyperlipidemia due to uncontrolled diabetes mellitus or due to primary hyperlipidemia or even caused by impairment of lipid metabolism during a viral illness were described.1,3 This is the first report to our knowledge of an association between symptomatic lipemia retinalis and decompensated hyperlipidemia related to treatment with chemotherapy and accompanying treatment with dexamethasone in a patient with metastatic colon cancer. The present data do not reveal any causal linkage between chemotherapy with FOLFOX/bevacizumab and secondary hyperlipidemia, so lipemia retinalis in our patient is believed to be a consequence of decompensated hyperlipidemia after chronic therapy with dexamethasone over a period of 5 months. Previously, Chahande et al described a case of a 14-year-old diabetic boy developing lipemia retinalis because of intravenous treatment with prednisolone (1 mg/kg for 5 days) for multiple intracranial neurocysticerci with perilesional edema. The authors also assume the lipemia in this case was caused by administration of steroids.7 Secondary hypertriglyceridemia is known as a result of the supply of glucocorticoids. Glucocorticoid substitution is associated with hypertriglyceridemia, elevated glucose, and higher non–high-density lipoprotein cholesterol levels and can lead to metabolic syndrome, which was proved in a study with GH- and glucocorticoid-replaced hypopituitary patients.8 Suggesting underlying mechanisms, studies reported that pharmacological doses of glucocorticoids lead to an increased endogenous glucose production in healthy people by stimulating hepatic gluconeogenic enzymes and augmenting supply of substrates to the liver for gluconeogenesis by peripheral lipolysis and proteolysis.9,10 Usually no treatment is required for lipemia retinalis. Once triglyceride levels return to normal, the retinal appearance of lipemia retinalis should quickly resolve without causing decrease in visual acuity or permanent retinal disease.11 However, lipemia retinalis is a very important sign of a potential life-threatening systemic metabolic disorder, and it is essential to recognize it as a sign of a profound lipid abnormality. We present the first documentation of lipemia retinalis associated with visual symptoms because of decompensating hyperlipidemia in a patient undergoing chemotherapy with concomitant treatment with dexamethasone, and we want to raise awareness of this probably often underdiagnosed retinal condition. Lipid-lowering therapy is believed to normalize fundal appearance and leads to restoration of visual acuity. It is important to adapt the lipid-lowering medication to obtain appropriate management of the lipid metabolism in patients receiving dexamethasone therapy. None of the authors has any financial/conflicting interests to disclose.

40 mg (milligrams).

DrugDosage

CC BY-NC-ND

30074937

2021-07-01

What was the dosage of drug 'BEVACIZUMAB'?

LIPEMIA RETINALIS DURING CHEMOTHERAPY WITH ADJUNCTIVE GLUCOCORTICOID TREATMENT IN A PATIENT WITH COLON CARCINOMA. OBJECTIVE The purpose of this report is to describe a case of lipemia retinalis due to decompensating hyperlipidemia that occurred during chemotherapy in a patient with metastatic colon carcinoma. METHODS Retrospective case report. RESULTS A 55-year-old non-insulin-dependent diabetic man with well-controlled hyperlipidemia presented himself with temporarily blurred vision in both eyes occurring during chemotherapy. He was found to have lipemia retinalis in his both eyes. Blood tests revealed elevated cholesterol and triglyceride levels exceeding 8,200 mg/dL. He received six cycles of FOLFIRI/bevacizumab and accompanying dexamethasone because of colon cancer with pulmonary metastases. Lipemia retinalis had resolved after a 6-week follow-up when chemotherapy was finished, and the patients' triglyceride and glucose levels decreased to normal values. CONCLUSIONS Lipemia retinalis associated with visual impairment may occur during chemotherapy under accompanying treatment with dexamethasone. Even if patients with hyperlipidemia are metabolically well-controlled with oral medication, treatment with dexamethasone can potentially lead to decompensation of hyperlipidemia causing secondary lipemia retinalis. Hyperlipidemia is characterized by increased levels of serum concentrations of cholesterol or triglycerides and known as a major factor of premature vessel atherosclerosis. Lipemia retinalis is a rare retinal manifestation of hypertriglyceridemia. Retinal vessels appear creamy whitish colored due to the effect of light scattering by triglyceride-laden chylomicrons.1 In clinical practice, lipemia retinalis caused by chylomicronemia in hyperlipidemia is often observed in patients with metabolic syndrome. However, associations with primary hyperlipidemia or secondary factors causing high levels of triglycerides are also well-documented.2,3 Case Report A 55-year-old white man presented to our department with temporarily blurred vision in both eyes. Ocular history of the patient was unremarkable, and his best-corrected visual acuity was 100/100 in both eyes. Slit-lamp examination demonstrated normal anterior segments, and intraocular pressures were measured at 16 mmHg in both eyes. His medical history included metastatic colon cancer treated with surgery and chemotherapy, diabetes mellitus, and hyperlipidemia well-controlled with statins (atorvastatin 40 mg once per day). Dilated funduscopic examination revealed normal optic discs, white creamy retinal vessels, and arterial narrowing with arteriovenous crossing abnormalities but no signs of diabetic retinopathy. Furthermore, optical coherence tomography was unremarkable, and there was no evidence for diabetic macular edema. The clinical picture was consistent with lipemia retinalis (Figure 1, A and B). Fig. 1. Fundus photograph of right (A) and left (B) eye with signs of lipemia retinalis. Characteristic white creamy vessels are visible, making it difficult to distinguish the arteries from the veins. Before our ophthalmologic examination, the patient was treated with six cycles of chemotherapy with FOLFIRI/bevacizumab because of newly occurring pulmonary metastases. The chemotherapy consisted of bevacizumab, irinotecan, and 5-fluorouracil. In addition, he received intravenous therapy with dexamethasone (8 mg every 2 weeks) for treatment of the side effects of the chemotherapy. The patient was referred to the Department of Internal Medicine to perform further diagnosis and treatment; were laboratory evaluation revealed highly increased levels of cholesterol (681 mg/dL) and triglycerides (8,258 mg/dL). It seems the chemotherapy with concomitant treatment with dexamethasone led to metabolic decompensation in hyperlipidemia. The patient presented himself again to our department 6 weeks later, reporting that his visual problems had vanished. Fundus examination revealed reversion of the alterations of the retinal vessels due to lipemia (Figure 2, A and B). Metabolic control of the triglycerides was achieved (triglycerides were 605 mg/dL and cholesterol was 167 mg/dL on the day of examination) since he quitted chemotherapy and intravenous dexamethasone. In addition, his lipid-lowering therapy had been re-evaluated and changed to cholib 145/40 mg tablets once per day (combination of simvastatin and fenofibrate). Fig. 2. Fundus photograph of right (A) and left (B) eye, 6 weeks after initial presentation and under appropriate lipid-lowering medication. The lipemia retinalis had resolved, and the retinal vessels abnormalities returned to normal appearance. Discussion Lipemia retinalis is a rare ocular finding characterized by creamy white colored retinal blood vessels, which was first described in 1880 by Heyl.4 It is associated with elevated levels of plasma triglycerides and occurs in certain types of both primary and secondary hyperlipidemia. In early stages of lipemia retinalis (triglyceride levels of 2,500–3,499 mg/dL), only the peripheral retinal vessels appear creamy and thin. As triglyceride levels increase (3,500–5,000 mg/dL), lipemia spreads out to the posterior pole and the creamy color of the vessels extends toward the optic disc. With triglyceride levels exceeding 5,000 mg/dL, the retina becomes salmon-colored with creamy whitish arteries and veins distinguishable only by size.1,2 Although the exact correlation of the incidence of lipemia retinalis and the level of plasma triglycerides is not completely understood, the retinal changes are known as a direct consequence of the elevated levels of circulating chylomicrons in the retinal vessels. Chylomicrons are large lipoproteins, which serve to transport triglycerides in the circulatory system after intestinal absorption. The slightly smaller macromolecules very low-density lipoproteins also play an important role. These lipoproteins are involved in the process of transportation of fat in the metabolism but do not seem to contribute to the fundal appearance.5 However, it has been observed that not all patients with even highly elevated levels of chylomicrons and triglycerides present lipemia retinalis, suggesting that other factors, such as changes in hematocrit and difference in translucency of the retinal and choroidal vessels, have to be considered.5 Rayner et al1 assumed the light-scattering effect of chylomicrons is responsible for the clinical picture of lipemia retinalis in the fundi. Most lipemia retinalis cases are asymptomatic, but in fact, also patients with initially deteriorated visual acuity were reported.6 In general, only advanced and persistent lipemia is known to cause decrease in visual acuity or might even lead to complete loss of vision after massive irreversible lipid exsudation.1 Regarding current literature, several cases of lipemia retinalis caused by chylomicronemia in hyperlipidemia due to uncontrolled diabetes mellitus or due to primary hyperlipidemia or even caused by impairment of lipid metabolism during a viral illness were described.1,3 This is the first report to our knowledge of an association between symptomatic lipemia retinalis and decompensated hyperlipidemia related to treatment with chemotherapy and accompanying treatment with dexamethasone in a patient with metastatic colon cancer. The present data do not reveal any causal linkage between chemotherapy with FOLFOX/bevacizumab and secondary hyperlipidemia, so lipemia retinalis in our patient is believed to be a consequence of decompensated hyperlipidemia after chronic therapy with dexamethasone over a period of 5 months. Previously, Chahande et al described a case of a 14-year-old diabetic boy developing lipemia retinalis because of intravenous treatment with prednisolone (1 mg/kg for 5 days) for multiple intracranial neurocysticerci with perilesional edema. The authors also assume the lipemia in this case was caused by administration of steroids.7 Secondary hypertriglyceridemia is known as a result of the supply of glucocorticoids. Glucocorticoid substitution is associated with hypertriglyceridemia, elevated glucose, and higher non–high-density lipoprotein cholesterol levels and can lead to metabolic syndrome, which was proved in a study with GH- and glucocorticoid-replaced hypopituitary patients.8 Suggesting underlying mechanisms, studies reported that pharmacological doses of glucocorticoids lead to an increased endogenous glucose production in healthy people by stimulating hepatic gluconeogenic enzymes and augmenting supply of substrates to the liver for gluconeogenesis by peripheral lipolysis and proteolysis.9,10 Usually no treatment is required for lipemia retinalis. Once triglyceride levels return to normal, the retinal appearance of lipemia retinalis should quickly resolve without causing decrease in visual acuity or permanent retinal disease.11 However, lipemia retinalis is a very important sign of a potential life-threatening systemic metabolic disorder, and it is essential to recognize it as a sign of a profound lipid abnormality. We present the first documentation of lipemia retinalis associated with visual symptoms because of decompensating hyperlipidemia in a patient undergoing chemotherapy with concomitant treatment with dexamethasone, and we want to raise awareness of this probably often underdiagnosed retinal condition. Lipid-lowering therapy is believed to normalize fundal appearance and leads to restoration of visual acuity. It is important to adapt the lipid-lowering medication to obtain appropriate management of the lipid metabolism in patients receiving dexamethasone therapy. None of the authors has any financial/conflicting interests to disclose.

SIX CYCLES

DrugDosageText

CC BY-NC-ND

30074937

2021-07-01

What was the dosage of drug 'FLUOROURACIL'?

LIPEMIA RETINALIS DURING CHEMOTHERAPY WITH ADJUNCTIVE GLUCOCORTICOID TREATMENT IN A PATIENT WITH COLON CARCINOMA. OBJECTIVE The purpose of this report is to describe a case of lipemia retinalis due to decompensating hyperlipidemia that occurred during chemotherapy in a patient with metastatic colon carcinoma. METHODS Retrospective case report. RESULTS A 55-year-old non-insulin-dependent diabetic man with well-controlled hyperlipidemia presented himself with temporarily blurred vision in both eyes occurring during chemotherapy. He was found to have lipemia retinalis in his both eyes. Blood tests revealed elevated cholesterol and triglyceride levels exceeding 8,200 mg/dL. He received six cycles of FOLFIRI/bevacizumab and accompanying dexamethasone because of colon cancer with pulmonary metastases. Lipemia retinalis had resolved after a 6-week follow-up when chemotherapy was finished, and the patients' triglyceride and glucose levels decreased to normal values. CONCLUSIONS Lipemia retinalis associated with visual impairment may occur during chemotherapy under accompanying treatment with dexamethasone. Even if patients with hyperlipidemia are metabolically well-controlled with oral medication, treatment with dexamethasone can potentially lead to decompensation of hyperlipidemia causing secondary lipemia retinalis. Hyperlipidemia is characterized by increased levels of serum concentrations of cholesterol or triglycerides and known as a major factor of premature vessel atherosclerosis. Lipemia retinalis is a rare retinal manifestation of hypertriglyceridemia. Retinal vessels appear creamy whitish colored due to the effect of light scattering by triglyceride-laden chylomicrons.1 In clinical practice, lipemia retinalis caused by chylomicronemia in hyperlipidemia is often observed in patients with metabolic syndrome. However, associations with primary hyperlipidemia or secondary factors causing high levels of triglycerides are also well-documented.2,3 Case Report A 55-year-old white man presented to our department with temporarily blurred vision in both eyes. Ocular history of the patient was unremarkable, and his best-corrected visual acuity was 100/100 in both eyes. Slit-lamp examination demonstrated normal anterior segments, and intraocular pressures were measured at 16 mmHg in both eyes. His medical history included metastatic colon cancer treated with surgery and chemotherapy, diabetes mellitus, and hyperlipidemia well-controlled with statins (atorvastatin 40 mg once per day). Dilated funduscopic examination revealed normal optic discs, white creamy retinal vessels, and arterial narrowing with arteriovenous crossing abnormalities but no signs of diabetic retinopathy. Furthermore, optical coherence tomography was unremarkable, and there was no evidence for diabetic macular edema. The clinical picture was consistent with lipemia retinalis (Figure 1, A and B). Fig. 1. Fundus photograph of right (A) and left (B) eye with signs of lipemia retinalis. Characteristic white creamy vessels are visible, making it difficult to distinguish the arteries from the veins. Before our ophthalmologic examination, the patient was treated with six cycles of chemotherapy with FOLFIRI/bevacizumab because of newly occurring pulmonary metastases. The chemotherapy consisted of bevacizumab, irinotecan, and 5-fluorouracil. In addition, he received intravenous therapy with dexamethasone (8 mg every 2 weeks) for treatment of the side effects of the chemotherapy. The patient was referred to the Department of Internal Medicine to perform further diagnosis and treatment; were laboratory evaluation revealed highly increased levels of cholesterol (681 mg/dL) and triglycerides (8,258 mg/dL). It seems the chemotherapy with concomitant treatment with dexamethasone led to metabolic decompensation in hyperlipidemia. The patient presented himself again to our department 6 weeks later, reporting that his visual problems had vanished. Fundus examination revealed reversion of the alterations of the retinal vessels due to lipemia (Figure 2, A and B). Metabolic control of the triglycerides was achieved (triglycerides were 605 mg/dL and cholesterol was 167 mg/dL on the day of examination) since he quitted chemotherapy and intravenous dexamethasone. In addition, his lipid-lowering therapy had been re-evaluated and changed to cholib 145/40 mg tablets once per day (combination of simvastatin and fenofibrate). Fig. 2. Fundus photograph of right (A) and left (B) eye, 6 weeks after initial presentation and under appropriate lipid-lowering medication. The lipemia retinalis had resolved, and the retinal vessels abnormalities returned to normal appearance. Discussion Lipemia retinalis is a rare ocular finding characterized by creamy white colored retinal blood vessels, which was first described in 1880 by Heyl.4 It is associated with elevated levels of plasma triglycerides and occurs in certain types of both primary and secondary hyperlipidemia. In early stages of lipemia retinalis (triglyceride levels of 2,500–3,499 mg/dL), only the peripheral retinal vessels appear creamy and thin. As triglyceride levels increase (3,500–5,000 mg/dL), lipemia spreads out to the posterior pole and the creamy color of the vessels extends toward the optic disc. With triglyceride levels exceeding 5,000 mg/dL, the retina becomes salmon-colored with creamy whitish arteries and veins distinguishable only by size.1,2 Although the exact correlation of the incidence of lipemia retinalis and the level of plasma triglycerides is not completely understood, the retinal changes are known as a direct consequence of the elevated levels of circulating chylomicrons in the retinal vessels. Chylomicrons are large lipoproteins, which serve to transport triglycerides in the circulatory system after intestinal absorption. The slightly smaller macromolecules very low-density lipoproteins also play an important role. These lipoproteins are involved in the process of transportation of fat in the metabolism but do not seem to contribute to the fundal appearance.5 However, it has been observed that not all patients with even highly elevated levels of chylomicrons and triglycerides present lipemia retinalis, suggesting that other factors, such as changes in hematocrit and difference in translucency of the retinal and choroidal vessels, have to be considered.5 Rayner et al1 assumed the light-scattering effect of chylomicrons is responsible for the clinical picture of lipemia retinalis in the fundi. Most lipemia retinalis cases are asymptomatic, but in fact, also patients with initially deteriorated visual acuity were reported.6 In general, only advanced and persistent lipemia is known to cause decrease in visual acuity or might even lead to complete loss of vision after massive irreversible lipid exsudation.1 Regarding current literature, several cases of lipemia retinalis caused by chylomicronemia in hyperlipidemia due to uncontrolled diabetes mellitus or due to primary hyperlipidemia or even caused by impairment of lipid metabolism during a viral illness were described.1,3 This is the first report to our knowledge of an association between symptomatic lipemia retinalis and decompensated hyperlipidemia related to treatment with chemotherapy and accompanying treatment with dexamethasone in a patient with metastatic colon cancer. The present data do not reveal any causal linkage between chemotherapy with FOLFOX/bevacizumab and secondary hyperlipidemia, so lipemia retinalis in our patient is believed to be a consequence of decompensated hyperlipidemia after chronic therapy with dexamethasone over a period of 5 months. Previously, Chahande et al described a case of a 14-year-old diabetic boy developing lipemia retinalis because of intravenous treatment with prednisolone (1 mg/kg for 5 days) for multiple intracranial neurocysticerci with perilesional edema. The authors also assume the lipemia in this case was caused by administration of steroids.7 Secondary hypertriglyceridemia is known as a result of the supply of glucocorticoids. Glucocorticoid substitution is associated with hypertriglyceridemia, elevated glucose, and higher non–high-density lipoprotein cholesterol levels and can lead to metabolic syndrome, which was proved in a study with GH- and glucocorticoid-replaced hypopituitary patients.8 Suggesting underlying mechanisms, studies reported that pharmacological doses of glucocorticoids lead to an increased endogenous glucose production in healthy people by stimulating hepatic gluconeogenic enzymes and augmenting supply of substrates to the liver for gluconeogenesis by peripheral lipolysis and proteolysis.9,10 Usually no treatment is required for lipemia retinalis. Once triglyceride levels return to normal, the retinal appearance of lipemia retinalis should quickly resolve without causing decrease in visual acuity or permanent retinal disease.11 However, lipemia retinalis is a very important sign of a potential life-threatening systemic metabolic disorder, and it is essential to recognize it as a sign of a profound lipid abnormality. We present the first documentation of lipemia retinalis associated with visual symptoms because of decompensating hyperlipidemia in a patient undergoing chemotherapy with concomitant treatment with dexamethasone, and we want to raise awareness of this probably often underdiagnosed retinal condition. Lipid-lowering therapy is believed to normalize fundal appearance and leads to restoration of visual acuity. It is important to adapt the lipid-lowering medication to obtain appropriate management of the lipid metabolism in patients receiving dexamethasone therapy. None of the authors has any financial/conflicting interests to disclose.

SIX CYCLES

DrugDosageText

CC BY-NC-ND

30074937

2021-07-01

What was the dosage of drug 'IRINOTECAN'?

LIPEMIA RETINALIS DURING CHEMOTHERAPY WITH ADJUNCTIVE GLUCOCORTICOID TREATMENT IN A PATIENT WITH COLON CARCINOMA. OBJECTIVE The purpose of this report is to describe a case of lipemia retinalis due to decompensating hyperlipidemia that occurred during chemotherapy in a patient with metastatic colon carcinoma. METHODS Retrospective case report. RESULTS A 55-year-old non-insulin-dependent diabetic man with well-controlled hyperlipidemia presented himself with temporarily blurred vision in both eyes occurring during chemotherapy. He was found to have lipemia retinalis in his both eyes. Blood tests revealed elevated cholesterol and triglyceride levels exceeding 8,200 mg/dL. He received six cycles of FOLFIRI/bevacizumab and accompanying dexamethasone because of colon cancer with pulmonary metastases. Lipemia retinalis had resolved after a 6-week follow-up when chemotherapy was finished, and the patients' triglyceride and glucose levels decreased to normal values. CONCLUSIONS Lipemia retinalis associated with visual impairment may occur during chemotherapy under accompanying treatment with dexamethasone. Even if patients with hyperlipidemia are metabolically well-controlled with oral medication, treatment with dexamethasone can potentially lead to decompensation of hyperlipidemia causing secondary lipemia retinalis. Hyperlipidemia is characterized by increased levels of serum concentrations of cholesterol or triglycerides and known as a major factor of premature vessel atherosclerosis. Lipemia retinalis is a rare retinal manifestation of hypertriglyceridemia. Retinal vessels appear creamy whitish colored due to the effect of light scattering by triglyceride-laden chylomicrons.1 In clinical practice, lipemia retinalis caused by chylomicronemia in hyperlipidemia is often observed in patients with metabolic syndrome. However, associations with primary hyperlipidemia or secondary factors causing high levels of triglycerides are also well-documented.2,3 Case Report A 55-year-old white man presented to our department with temporarily blurred vision in both eyes. Ocular history of the patient was unremarkable, and his best-corrected visual acuity was 100/100 in both eyes. Slit-lamp examination demonstrated normal anterior segments, and intraocular pressures were measured at 16 mmHg in both eyes. His medical history included metastatic colon cancer treated with surgery and chemotherapy, diabetes mellitus, and hyperlipidemia well-controlled with statins (atorvastatin 40 mg once per day). Dilated funduscopic examination revealed normal optic discs, white creamy retinal vessels, and arterial narrowing with arteriovenous crossing abnormalities but no signs of diabetic retinopathy. Furthermore, optical coherence tomography was unremarkable, and there was no evidence for diabetic macular edema. The clinical picture was consistent with lipemia retinalis (Figure 1, A and B). Fig. 1. Fundus photograph of right (A) and left (B) eye with signs of lipemia retinalis. Characteristic white creamy vessels are visible, making it difficult to distinguish the arteries from the veins. Before our ophthalmologic examination, the patient was treated with six cycles of chemotherapy with FOLFIRI/bevacizumab because of newly occurring pulmonary metastases. The chemotherapy consisted of bevacizumab, irinotecan, and 5-fluorouracil. In addition, he received intravenous therapy with dexamethasone (8 mg every 2 weeks) for treatment of the side effects of the chemotherapy. The patient was referred to the Department of Internal Medicine to perform further diagnosis and treatment; were laboratory evaluation revealed highly increased levels of cholesterol (681 mg/dL) and triglycerides (8,258 mg/dL). It seems the chemotherapy with concomitant treatment with dexamethasone led to metabolic decompensation in hyperlipidemia. The patient presented himself again to our department 6 weeks later, reporting that his visual problems had vanished. Fundus examination revealed reversion of the alterations of the retinal vessels due to lipemia (Figure 2, A and B). Metabolic control of the triglycerides was achieved (triglycerides were 605 mg/dL and cholesterol was 167 mg/dL on the day of examination) since he quitted chemotherapy and intravenous dexamethasone. In addition, his lipid-lowering therapy had been re-evaluated and changed to cholib 145/40 mg tablets once per day (combination of simvastatin and fenofibrate). Fig. 2. Fundus photograph of right (A) and left (B) eye, 6 weeks after initial presentation and under appropriate lipid-lowering medication. The lipemia retinalis had resolved, and the retinal vessels abnormalities returned to normal appearance. Discussion Lipemia retinalis is a rare ocular finding characterized by creamy white colored retinal blood vessels, which was first described in 1880 by Heyl.4 It is associated with elevated levels of plasma triglycerides and occurs in certain types of both primary and secondary hyperlipidemia. In early stages of lipemia retinalis (triglyceride levels of 2,500–3,499 mg/dL), only the peripheral retinal vessels appear creamy and thin. As triglyceride levels increase (3,500–5,000 mg/dL), lipemia spreads out to the posterior pole and the creamy color of the vessels extends toward the optic disc. With triglyceride levels exceeding 5,000 mg/dL, the retina becomes salmon-colored with creamy whitish arteries and veins distinguishable only by size.1,2 Although the exact correlation of the incidence of lipemia retinalis and the level of plasma triglycerides is not completely understood, the retinal changes are known as a direct consequence of the elevated levels of circulating chylomicrons in the retinal vessels. Chylomicrons are large lipoproteins, which serve to transport triglycerides in the circulatory system after intestinal absorption. The slightly smaller macromolecules very low-density lipoproteins also play an important role. These lipoproteins are involved in the process of transportation of fat in the metabolism but do not seem to contribute to the fundal appearance.5 However, it has been observed that not all patients with even highly elevated levels of chylomicrons and triglycerides present lipemia retinalis, suggesting that other factors, such as changes in hematocrit and difference in translucency of the retinal and choroidal vessels, have to be considered.5 Rayner et al1 assumed the light-scattering effect of chylomicrons is responsible for the clinical picture of lipemia retinalis in the fundi. Most lipemia retinalis cases are asymptomatic, but in fact, also patients with initially deteriorated visual acuity were reported.6 In general, only advanced and persistent lipemia is known to cause decrease in visual acuity or might even lead to complete loss of vision after massive irreversible lipid exsudation.1 Regarding current literature, several cases of lipemia retinalis caused by chylomicronemia in hyperlipidemia due to uncontrolled diabetes mellitus or due to primary hyperlipidemia or even caused by impairment of lipid metabolism during a viral illness were described.1,3 This is the first report to our knowledge of an association between symptomatic lipemia retinalis and decompensated hyperlipidemia related to treatment with chemotherapy and accompanying treatment with dexamethasone in a patient with metastatic colon cancer. The present data do not reveal any causal linkage between chemotherapy with FOLFOX/bevacizumab and secondary hyperlipidemia, so lipemia retinalis in our patient is believed to be a consequence of decompensated hyperlipidemia after chronic therapy with dexamethasone over a period of 5 months. Previously, Chahande et al described a case of a 14-year-old diabetic boy developing lipemia retinalis because of intravenous treatment with prednisolone (1 mg/kg for 5 days) for multiple intracranial neurocysticerci with perilesional edema. The authors also assume the lipemia in this case was caused by administration of steroids.7 Secondary hypertriglyceridemia is known as a result of the supply of glucocorticoids. Glucocorticoid substitution is associated with hypertriglyceridemia, elevated glucose, and higher non–high-density lipoprotein cholesterol levels and can lead to metabolic syndrome, which was proved in a study with GH- and glucocorticoid-replaced hypopituitary patients.8 Suggesting underlying mechanisms, studies reported that pharmacological doses of glucocorticoids lead to an increased endogenous glucose production in healthy people by stimulating hepatic gluconeogenic enzymes and augmenting supply of substrates to the liver for gluconeogenesis by peripheral lipolysis and proteolysis.9,10 Usually no treatment is required for lipemia retinalis. Once triglyceride levels return to normal, the retinal appearance of lipemia retinalis should quickly resolve without causing decrease in visual acuity or permanent retinal disease.11 However, lipemia retinalis is a very important sign of a potential life-threatening systemic metabolic disorder, and it is essential to recognize it as a sign of a profound lipid abnormality. We present the first documentation of lipemia retinalis associated with visual symptoms because of decompensating hyperlipidemia in a patient undergoing chemotherapy with concomitant treatment with dexamethasone, and we want to raise awareness of this probably often underdiagnosed retinal condition. Lipid-lowering therapy is believed to normalize fundal appearance and leads to restoration of visual acuity. It is important to adapt the lipid-lowering medication to obtain appropriate management of the lipid metabolism in patients receiving dexamethasone therapy. None of the authors has any financial/conflicting interests to disclose.

SIX CYCLES

DrugDosageText

CC BY-NC-ND

30074937

2021-07-01

What was the outcome of reaction 'Condition aggravated'?

LIPEMIA RETINALIS DURING CHEMOTHERAPY WITH ADJUNCTIVE GLUCOCORTICOID TREATMENT IN A PATIENT WITH COLON CARCINOMA. OBJECTIVE The purpose of this report is to describe a case of lipemia retinalis due to decompensating hyperlipidemia that occurred during chemotherapy in a patient with metastatic colon carcinoma. METHODS Retrospective case report. RESULTS A 55-year-old non-insulin-dependent diabetic man with well-controlled hyperlipidemia presented himself with temporarily blurred vision in both eyes occurring during chemotherapy. He was found to have lipemia retinalis in his both eyes. Blood tests revealed elevated cholesterol and triglyceride levels exceeding 8,200 mg/dL. He received six cycles of FOLFIRI/bevacizumab and accompanying dexamethasone because of colon cancer with pulmonary metastases. Lipemia retinalis had resolved after a 6-week follow-up when chemotherapy was finished, and the patients' triglyceride and glucose levels decreased to normal values. CONCLUSIONS Lipemia retinalis associated with visual impairment may occur during chemotherapy under accompanying treatment with dexamethasone. Even if patients with hyperlipidemia are metabolically well-controlled with oral medication, treatment with dexamethasone can potentially lead to decompensation of hyperlipidemia causing secondary lipemia retinalis. Hyperlipidemia is characterized by increased levels of serum concentrations of cholesterol or triglycerides and known as a major factor of premature vessel atherosclerosis. Lipemia retinalis is a rare retinal manifestation of hypertriglyceridemia. Retinal vessels appear creamy whitish colored due to the effect of light scattering by triglyceride-laden chylomicrons.1 In clinical practice, lipemia retinalis caused by chylomicronemia in hyperlipidemia is often observed in patients with metabolic syndrome. However, associations with primary hyperlipidemia or secondary factors causing high levels of triglycerides are also well-documented.2,3 Case Report A 55-year-old white man presented to our department with temporarily blurred vision in both eyes. Ocular history of the patient was unremarkable, and his best-corrected visual acuity was 100/100 in both eyes. Slit-lamp examination demonstrated normal anterior segments, and intraocular pressures were measured at 16 mmHg in both eyes. His medical history included metastatic colon cancer treated with surgery and chemotherapy, diabetes mellitus, and hyperlipidemia well-controlled with statins (atorvastatin 40 mg once per day). Dilated funduscopic examination revealed normal optic discs, white creamy retinal vessels, and arterial narrowing with arteriovenous crossing abnormalities but no signs of diabetic retinopathy. Furthermore, optical coherence tomography was unremarkable, and there was no evidence for diabetic macular edema. The clinical picture was consistent with lipemia retinalis (Figure 1, A and B). Fig. 1. Fundus photograph of right (A) and left (B) eye with signs of lipemia retinalis. Characteristic white creamy vessels are visible, making it difficult to distinguish the arteries from the veins. Before our ophthalmologic examination, the patient was treated with six cycles of chemotherapy with FOLFIRI/bevacizumab because of newly occurring pulmonary metastases. The chemotherapy consisted of bevacizumab, irinotecan, and 5-fluorouracil. In addition, he received intravenous therapy with dexamethasone (8 mg every 2 weeks) for treatment of the side effects of the chemotherapy. The patient was referred to the Department of Internal Medicine to perform further diagnosis and treatment; were laboratory evaluation revealed highly increased levels of cholesterol (681 mg/dL) and triglycerides (8,258 mg/dL). It seems the chemotherapy with concomitant treatment with dexamethasone led to metabolic decompensation in hyperlipidemia. The patient presented himself again to our department 6 weeks later, reporting that his visual problems had vanished. Fundus examination revealed reversion of the alterations of the retinal vessels due to lipemia (Figure 2, A and B). Metabolic control of the triglycerides was achieved (triglycerides were 605 mg/dL and cholesterol was 167 mg/dL on the day of examination) since he quitted chemotherapy and intravenous dexamethasone. In addition, his lipid-lowering therapy had been re-evaluated and changed to cholib 145/40 mg tablets once per day (combination of simvastatin and fenofibrate). Fig. 2. Fundus photograph of right (A) and left (B) eye, 6 weeks after initial presentation and under appropriate lipid-lowering medication. The lipemia retinalis had resolved, and the retinal vessels abnormalities returned to normal appearance. Discussion Lipemia retinalis is a rare ocular finding characterized by creamy white colored retinal blood vessels, which was first described in 1880 by Heyl.4 It is associated with elevated levels of plasma triglycerides and occurs in certain types of both primary and secondary hyperlipidemia. In early stages of lipemia retinalis (triglyceride levels of 2,500–3,499 mg/dL), only the peripheral retinal vessels appear creamy and thin. As triglyceride levels increase (3,500–5,000 mg/dL), lipemia spreads out to the posterior pole and the creamy color of the vessels extends toward the optic disc. With triglyceride levels exceeding 5,000 mg/dL, the retina becomes salmon-colored with creamy whitish arteries and veins distinguishable only by size.1,2 Although the exact correlation of the incidence of lipemia retinalis and the level of plasma triglycerides is not completely understood, the retinal changes are known as a direct consequence of the elevated levels of circulating chylomicrons in the retinal vessels. Chylomicrons are large lipoproteins, which serve to transport triglycerides in the circulatory system after intestinal absorption. The slightly smaller macromolecules very low-density lipoproteins also play an important role. These lipoproteins are involved in the process of transportation of fat in the metabolism but do not seem to contribute to the fundal appearance.5 However, it has been observed that not all patients with even highly elevated levels of chylomicrons and triglycerides present lipemia retinalis, suggesting that other factors, such as changes in hematocrit and difference in translucency of the retinal and choroidal vessels, have to be considered.5 Rayner et al1 assumed the light-scattering effect of chylomicrons is responsible for the clinical picture of lipemia retinalis in the fundi. Most lipemia retinalis cases are asymptomatic, but in fact, also patients with initially deteriorated visual acuity were reported.6 In general, only advanced and persistent lipemia is known to cause decrease in visual acuity or might even lead to complete loss of vision after massive irreversible lipid exsudation.1 Regarding current literature, several cases of lipemia retinalis caused by chylomicronemia in hyperlipidemia due to uncontrolled diabetes mellitus or due to primary hyperlipidemia or even caused by impairment of lipid metabolism during a viral illness were described.1,3 This is the first report to our knowledge of an association between symptomatic lipemia retinalis and decompensated hyperlipidemia related to treatment with chemotherapy and accompanying treatment with dexamethasone in a patient with metastatic colon cancer. The present data do not reveal any causal linkage between chemotherapy with FOLFOX/bevacizumab and secondary hyperlipidemia, so lipemia retinalis in our patient is believed to be a consequence of decompensated hyperlipidemia after chronic therapy with dexamethasone over a period of 5 months. Previously, Chahande et al described a case of a 14-year-old diabetic boy developing lipemia retinalis because of intravenous treatment with prednisolone (1 mg/kg for 5 days) for multiple intracranial neurocysticerci with perilesional edema. The authors also assume the lipemia in this case was caused by administration of steroids.7 Secondary hypertriglyceridemia is known as a result of the supply of glucocorticoids. Glucocorticoid substitution is associated with hypertriglyceridemia, elevated glucose, and higher non–high-density lipoprotein cholesterol levels and can lead to metabolic syndrome, which was proved in a study with GH- and glucocorticoid-replaced hypopituitary patients.8 Suggesting underlying mechanisms, studies reported that pharmacological doses of glucocorticoids lead to an increased endogenous glucose production in healthy people by stimulating hepatic gluconeogenic enzymes and augmenting supply of substrates to the liver for gluconeogenesis by peripheral lipolysis and proteolysis.9,10 Usually no treatment is required for lipemia retinalis. Once triglyceride levels return to normal, the retinal appearance of lipemia retinalis should quickly resolve without causing decrease in visual acuity or permanent retinal disease.11 However, lipemia retinalis is a very important sign of a potential life-threatening systemic metabolic disorder, and it is essential to recognize it as a sign of a profound lipid abnormality. We present the first documentation of lipemia retinalis associated with visual symptoms because of decompensating hyperlipidemia in a patient undergoing chemotherapy with concomitant treatment with dexamethasone, and we want to raise awareness of this probably often underdiagnosed retinal condition. Lipid-lowering therapy is believed to normalize fundal appearance and leads to restoration of visual acuity. It is important to adapt the lipid-lowering medication to obtain appropriate management of the lipid metabolism in patients receiving dexamethasone therapy. None of the authors has any financial/conflicting interests to disclose.

Recovered

ReactionOutcome

CC BY-NC-ND

30074937

2021-07-01

What was the outcome of reaction 'Hyperlipidaemia'?

LIPEMIA RETINALIS DURING CHEMOTHERAPY WITH ADJUNCTIVE GLUCOCORTICOID TREATMENT IN A PATIENT WITH COLON CARCINOMA. OBJECTIVE The purpose of this report is to describe a case of lipemia retinalis due to decompensating hyperlipidemia that occurred during chemotherapy in a patient with metastatic colon carcinoma. METHODS Retrospective case report. RESULTS A 55-year-old non-insulin-dependent diabetic man with well-controlled hyperlipidemia presented himself with temporarily blurred vision in both eyes occurring during chemotherapy. He was found to have lipemia retinalis in his both eyes. Blood tests revealed elevated cholesterol and triglyceride levels exceeding 8,200 mg/dL. He received six cycles of FOLFIRI/bevacizumab and accompanying dexamethasone because of colon cancer with pulmonary metastases. Lipemia retinalis had resolved after a 6-week follow-up when chemotherapy was finished, and the patients' triglyceride and glucose levels decreased to normal values. CONCLUSIONS Lipemia retinalis associated with visual impairment may occur during chemotherapy under accompanying treatment with dexamethasone. Even if patients with hyperlipidemia are metabolically well-controlled with oral medication, treatment with dexamethasone can potentially lead to decompensation of hyperlipidemia causing secondary lipemia retinalis. Hyperlipidemia is characterized by increased levels of serum concentrations of cholesterol or triglycerides and known as a major factor of premature vessel atherosclerosis. Lipemia retinalis is a rare retinal manifestation of hypertriglyceridemia. Retinal vessels appear creamy whitish colored due to the effect of light scattering by triglyceride-laden chylomicrons.1 In clinical practice, lipemia retinalis caused by chylomicronemia in hyperlipidemia is often observed in patients with metabolic syndrome. However, associations with primary hyperlipidemia or secondary factors causing high levels of triglycerides are also well-documented.2,3 Case Report A 55-year-old white man presented to our department with temporarily blurred vision in both eyes. Ocular history of the patient was unremarkable, and his best-corrected visual acuity was 100/100 in both eyes. Slit-lamp examination demonstrated normal anterior segments, and intraocular pressures were measured at 16 mmHg in both eyes. His medical history included metastatic colon cancer treated with surgery and chemotherapy, diabetes mellitus, and hyperlipidemia well-controlled with statins (atorvastatin 40 mg once per day). Dilated funduscopic examination revealed normal optic discs, white creamy retinal vessels, and arterial narrowing with arteriovenous crossing abnormalities but no signs of diabetic retinopathy. Furthermore, optical coherence tomography was unremarkable, and there was no evidence for diabetic macular edema. The clinical picture was consistent with lipemia retinalis (Figure 1, A and B). Fig. 1. Fundus photograph of right (A) and left (B) eye with signs of lipemia retinalis. Characteristic white creamy vessels are visible, making it difficult to distinguish the arteries from the veins. Before our ophthalmologic examination, the patient was treated with six cycles of chemotherapy with FOLFIRI/bevacizumab because of newly occurring pulmonary metastases. The chemotherapy consisted of bevacizumab, irinotecan, and 5-fluorouracil. In addition, he received intravenous therapy with dexamethasone (8 mg every 2 weeks) for treatment of the side effects of the chemotherapy. The patient was referred to the Department of Internal Medicine to perform further diagnosis and treatment; were laboratory evaluation revealed highly increased levels of cholesterol (681 mg/dL) and triglycerides (8,258 mg/dL). It seems the chemotherapy with concomitant treatment with dexamethasone led to metabolic decompensation in hyperlipidemia. The patient presented himself again to our department 6 weeks later, reporting that his visual problems had vanished. Fundus examination revealed reversion of the alterations of the retinal vessels due to lipemia (Figure 2, A and B). Metabolic control of the triglycerides was achieved (triglycerides were 605 mg/dL and cholesterol was 167 mg/dL on the day of examination) since he quitted chemotherapy and intravenous dexamethasone. In addition, his lipid-lowering therapy had been re-evaluated and changed to cholib 145/40 mg tablets once per day (combination of simvastatin and fenofibrate). Fig. 2. Fundus photograph of right (A) and left (B) eye, 6 weeks after initial presentation and under appropriate lipid-lowering medication. The lipemia retinalis had resolved, and the retinal vessels abnormalities returned to normal appearance. Discussion Lipemia retinalis is a rare ocular finding characterized by creamy white colored retinal blood vessels, which was first described in 1880 by Heyl.4 It is associated with elevated levels of plasma triglycerides and occurs in certain types of both primary and secondary hyperlipidemia. In early stages of lipemia retinalis (triglyceride levels of 2,500–3,499 mg/dL), only the peripheral retinal vessels appear creamy and thin. As triglyceride levels increase (3,500–5,000 mg/dL), lipemia spreads out to the posterior pole and the creamy color of the vessels extends toward the optic disc. With triglyceride levels exceeding 5,000 mg/dL, the retina becomes salmon-colored with creamy whitish arteries and veins distinguishable only by size.1,2 Although the exact correlation of the incidence of lipemia retinalis and the level of plasma triglycerides is not completely understood, the retinal changes are known as a direct consequence of the elevated levels of circulating chylomicrons in the retinal vessels. Chylomicrons are large lipoproteins, which serve to transport triglycerides in the circulatory system after intestinal absorption. The slightly smaller macromolecules very low-density lipoproteins also play an important role. These lipoproteins are involved in the process of transportation of fat in the metabolism but do not seem to contribute to the fundal appearance.5 However, it has been observed that not all patients with even highly elevated levels of chylomicrons and triglycerides present lipemia retinalis, suggesting that other factors, such as changes in hematocrit and difference in translucency of the retinal and choroidal vessels, have to be considered.5 Rayner et al1 assumed the light-scattering effect of chylomicrons is responsible for the clinical picture of lipemia retinalis in the fundi. Most lipemia retinalis cases are asymptomatic, but in fact, also patients with initially deteriorated visual acuity were reported.6 In general, only advanced and persistent lipemia is known to cause decrease in visual acuity or might even lead to complete loss of vision after massive irreversible lipid exsudation.1 Regarding current literature, several cases of lipemia retinalis caused by chylomicronemia in hyperlipidemia due to uncontrolled diabetes mellitus or due to primary hyperlipidemia or even caused by impairment of lipid metabolism during a viral illness were described.1,3 This is the first report to our knowledge of an association between symptomatic lipemia retinalis and decompensated hyperlipidemia related to treatment with chemotherapy and accompanying treatment with dexamethasone in a patient with metastatic colon cancer. The present data do not reveal any causal linkage between chemotherapy with FOLFOX/bevacizumab and secondary hyperlipidemia, so lipemia retinalis in our patient is believed to be a consequence of decompensated hyperlipidemia after chronic therapy with dexamethasone over a period of 5 months. Previously, Chahande et al described a case of a 14-year-old diabetic boy developing lipemia retinalis because of intravenous treatment with prednisolone (1 mg/kg for 5 days) for multiple intracranial neurocysticerci with perilesional edema. The authors also assume the lipemia in this case was caused by administration of steroids.7 Secondary hypertriglyceridemia is known as a result of the supply of glucocorticoids. Glucocorticoid substitution is associated with hypertriglyceridemia, elevated glucose, and higher non–high-density lipoprotein cholesterol levels and can lead to metabolic syndrome, which was proved in a study with GH- and glucocorticoid-replaced hypopituitary patients.8 Suggesting underlying mechanisms, studies reported that pharmacological doses of glucocorticoids lead to an increased endogenous glucose production in healthy people by stimulating hepatic gluconeogenic enzymes and augmenting supply of substrates to the liver for gluconeogenesis by peripheral lipolysis and proteolysis.9,10 Usually no treatment is required for lipemia retinalis. Once triglyceride levels return to normal, the retinal appearance of lipemia retinalis should quickly resolve without causing decrease in visual acuity or permanent retinal disease.11 However, lipemia retinalis is a very important sign of a potential life-threatening systemic metabolic disorder, and it is essential to recognize it as a sign of a profound lipid abnormality. We present the first documentation of lipemia retinalis associated with visual symptoms because of decompensating hyperlipidemia in a patient undergoing chemotherapy with concomitant treatment with dexamethasone, and we want to raise awareness of this probably often underdiagnosed retinal condition. Lipid-lowering therapy is believed to normalize fundal appearance and leads to restoration of visual acuity. It is important to adapt the lipid-lowering medication to obtain appropriate management of the lipid metabolism in patients receiving dexamethasone therapy. None of the authors has any financial/conflicting interests to disclose.

Recovered

ReactionOutcome

CC BY-NC-ND

30074937

2021-07-01

What was the outcome of reaction 'Lipaemia retinalis'?

LIPEMIA RETINALIS DURING CHEMOTHERAPY WITH ADJUNCTIVE GLUCOCORTICOID TREATMENT IN A PATIENT WITH COLON CARCINOMA. OBJECTIVE The purpose of this report is to describe a case of lipemia retinalis due to decompensating hyperlipidemia that occurred during chemotherapy in a patient with metastatic colon carcinoma. METHODS Retrospective case report. RESULTS A 55-year-old non-insulin-dependent diabetic man with well-controlled hyperlipidemia presented himself with temporarily blurred vision in both eyes occurring during chemotherapy. He was found to have lipemia retinalis in his both eyes. Blood tests revealed elevated cholesterol and triglyceride levels exceeding 8,200 mg/dL. He received six cycles of FOLFIRI/bevacizumab and accompanying dexamethasone because of colon cancer with pulmonary metastases. Lipemia retinalis had resolved after a 6-week follow-up when chemotherapy was finished, and the patients' triglyceride and glucose levels decreased to normal values. CONCLUSIONS Lipemia retinalis associated with visual impairment may occur during chemotherapy under accompanying treatment with dexamethasone. Even if patients with hyperlipidemia are metabolically well-controlled with oral medication, treatment with dexamethasone can potentially lead to decompensation of hyperlipidemia causing secondary lipemia retinalis. Hyperlipidemia is characterized by increased levels of serum concentrations of cholesterol or triglycerides and known as a major factor of premature vessel atherosclerosis. Lipemia retinalis is a rare retinal manifestation of hypertriglyceridemia. Retinal vessels appear creamy whitish colored due to the effect of light scattering by triglyceride-laden chylomicrons.1 In clinical practice, lipemia retinalis caused by chylomicronemia in hyperlipidemia is often observed in patients with metabolic syndrome. However, associations with primary hyperlipidemia or secondary factors causing high levels of triglycerides are also well-documented.2,3 Case Report A 55-year-old white man presented to our department with temporarily blurred vision in both eyes. Ocular history of the patient was unremarkable, and his best-corrected visual acuity was 100/100 in both eyes. Slit-lamp examination demonstrated normal anterior segments, and intraocular pressures were measured at 16 mmHg in both eyes. His medical history included metastatic colon cancer treated with surgery and chemotherapy, diabetes mellitus, and hyperlipidemia well-controlled with statins (atorvastatin 40 mg once per day). Dilated funduscopic examination revealed normal optic discs, white creamy retinal vessels, and arterial narrowing with arteriovenous crossing abnormalities but no signs of diabetic retinopathy. Furthermore, optical coherence tomography was unremarkable, and there was no evidence for diabetic macular edema. The clinical picture was consistent with lipemia retinalis (Figure 1, A and B). Fig. 1. Fundus photograph of right (A) and left (B) eye with signs of lipemia retinalis. Characteristic white creamy vessels are visible, making it difficult to distinguish the arteries from the veins. Before our ophthalmologic examination, the patient was treated with six cycles of chemotherapy with FOLFIRI/bevacizumab because of newly occurring pulmonary metastases. The chemotherapy consisted of bevacizumab, irinotecan, and 5-fluorouracil. In addition, he received intravenous therapy with dexamethasone (8 mg every 2 weeks) for treatment of the side effects of the chemotherapy. The patient was referred to the Department of Internal Medicine to perform further diagnosis and treatment; were laboratory evaluation revealed highly increased levels of cholesterol (681 mg/dL) and triglycerides (8,258 mg/dL). It seems the chemotherapy with concomitant treatment with dexamethasone led to metabolic decompensation in hyperlipidemia. The patient presented himself again to our department 6 weeks later, reporting that his visual problems had vanished. Fundus examination revealed reversion of the alterations of the retinal vessels due to lipemia (Figure 2, A and B). Metabolic control of the triglycerides was achieved (triglycerides were 605 mg/dL and cholesterol was 167 mg/dL on the day of examination) since he quitted chemotherapy and intravenous dexamethasone. In addition, his lipid-lowering therapy had been re-evaluated and changed to cholib 145/40 mg tablets once per day (combination of simvastatin and fenofibrate). Fig. 2. Fundus photograph of right (A) and left (B) eye, 6 weeks after initial presentation and under appropriate lipid-lowering medication. The lipemia retinalis had resolved, and the retinal vessels abnormalities returned to normal appearance. Discussion Lipemia retinalis is a rare ocular finding characterized by creamy white colored retinal blood vessels, which was first described in 1880 by Heyl.4 It is associated with elevated levels of plasma triglycerides and occurs in certain types of both primary and secondary hyperlipidemia. In early stages of lipemia retinalis (triglyceride levels of 2,500–3,499 mg/dL), only the peripheral retinal vessels appear creamy and thin. As triglyceride levels increase (3,500–5,000 mg/dL), lipemia spreads out to the posterior pole and the creamy color of the vessels extends toward the optic disc. With triglyceride levels exceeding 5,000 mg/dL, the retina becomes salmon-colored with creamy whitish arteries and veins distinguishable only by size.1,2 Although the exact correlation of the incidence of lipemia retinalis and the level of plasma triglycerides is not completely understood, the retinal changes are known as a direct consequence of the elevated levels of circulating chylomicrons in the retinal vessels. Chylomicrons are large lipoproteins, which serve to transport triglycerides in the circulatory system after intestinal absorption. The slightly smaller macromolecules very low-density lipoproteins also play an important role. These lipoproteins are involved in the process of transportation of fat in the metabolism but do not seem to contribute to the fundal appearance.5 However, it has been observed that not all patients with even highly elevated levels of chylomicrons and triglycerides present lipemia retinalis, suggesting that other factors, such as changes in hematocrit and difference in translucency of the retinal and choroidal vessels, have to be considered.5 Rayner et al1 assumed the light-scattering effect of chylomicrons is responsible for the clinical picture of lipemia retinalis in the fundi. Most lipemia retinalis cases are asymptomatic, but in fact, also patients with initially deteriorated visual acuity were reported.6 In general, only advanced and persistent lipemia is known to cause decrease in visual acuity or might even lead to complete loss of vision after massive irreversible lipid exsudation.1 Regarding current literature, several cases of lipemia retinalis caused by chylomicronemia in hyperlipidemia due to uncontrolled diabetes mellitus or due to primary hyperlipidemia or even caused by impairment of lipid metabolism during a viral illness were described.1,3 This is the first report to our knowledge of an association between symptomatic lipemia retinalis and decompensated hyperlipidemia related to treatment with chemotherapy and accompanying treatment with dexamethasone in a patient with metastatic colon cancer. The present data do not reveal any causal linkage between chemotherapy with FOLFOX/bevacizumab and secondary hyperlipidemia, so lipemia retinalis in our patient is believed to be a consequence of decompensated hyperlipidemia after chronic therapy with dexamethasone over a period of 5 months. Previously, Chahande et al described a case of a 14-year-old diabetic boy developing lipemia retinalis because of intravenous treatment with prednisolone (1 mg/kg for 5 days) for multiple intracranial neurocysticerci with perilesional edema. The authors also assume the lipemia in this case was caused by administration of steroids.7 Secondary hypertriglyceridemia is known as a result of the supply of glucocorticoids. Glucocorticoid substitution is associated with hypertriglyceridemia, elevated glucose, and higher non–high-density lipoprotein cholesterol levels and can lead to metabolic syndrome, which was proved in a study with GH- and glucocorticoid-replaced hypopituitary patients.8 Suggesting underlying mechanisms, studies reported that pharmacological doses of glucocorticoids lead to an increased endogenous glucose production in healthy people by stimulating hepatic gluconeogenic enzymes and augmenting supply of substrates to the liver for gluconeogenesis by peripheral lipolysis and proteolysis.9,10 Usually no treatment is required for lipemia retinalis. Once triglyceride levels return to normal, the retinal appearance of lipemia retinalis should quickly resolve without causing decrease in visual acuity or permanent retinal disease.11 However, lipemia retinalis is a very important sign of a potential life-threatening systemic metabolic disorder, and it is essential to recognize it as a sign of a profound lipid abnormality. We present the first documentation of lipemia retinalis associated with visual symptoms because of decompensating hyperlipidemia in a patient undergoing chemotherapy with concomitant treatment with dexamethasone, and we want to raise awareness of this probably often underdiagnosed retinal condition. Lipid-lowering therapy is believed to normalize fundal appearance and leads to restoration of visual acuity. It is important to adapt the lipid-lowering medication to obtain appropriate management of the lipid metabolism in patients receiving dexamethasone therapy. None of the authors has any financial/conflicting interests to disclose.

Recovered

ReactionOutcome

CC BY-NC-ND

30074937

2021-07-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'.

BULL'S EYE MACULOPATHY POSSIBLY DUE TO IRON OVERLOAD IN A CHILD WITH THALASSEMIA MAJOR: A CASE OF POSSIBLE "FERRITIN RETINOPATHY". OBJECTIVE To report a case of bull's eye maculopathy probably caused by iron overload in a child with thalassemia major. METHODS Case report. RESULTS A 6-year-old girl with thalassemia major who was on chronic multiple blood transfusions since 2 years of age presented with blurred vision in both eyes for 2 months. Blood reports showed very high serum ferritin levels in the range 400 to 2,250 ng/mL (checked every 3 months) since 4 years of age. She was on oral iron chelator deferasirox for 2 years, which was stopped a month ago. Fundus examination of both eyes showed a characteristic bull's eye macula with a purplish hue in the outer ring probably due to iron deposition. The center of the bull's eye had a beaten bronze appearance. CONCLUSIONS Careful history-taking is important in children with bull's eye maculopathy because all such retinopathies need not be hereditary fundus dystrophies. Further progression can be arrested by identifying and removing the cause vision loss. Bull's eye maculopathy is a term given to describe the appearance of the macula as a target or bull's eye. Degeneration of the retinal pigment epithelium (RPE) in the macular area causes alternating ring-like light and dark zones of pigmentation. This is the first case described to the best of our knowledge of bull's eye maculopathy probably caused due to serum iron overload in a child with thalassemia major. Case Report A 6-year-old girl of Indian origin, diagnosed to have beta thalassemia major at birth, presented with gradual decrease in vision in both eyes, especially for distance since 2 months. She had undergone multiple blood transfusions, and on repeated testing, her serum ferritin levels were between 400 ng/mL and 2,250 ng/mL checked every 3 months (normal range 7–140 ng/mL). She was using oral iron chelators deferasirox at 125 mg/day for 2 years, which was stopped a month back. Serum ferritin levels did not reach normal despite oral chelators. On examination, best-corrected visual acuity was 20/100, N18 in the right eye and 20/40p, N8 in the left eye. Anterior segment examination was unremarkable. Fundus examination of both eyes showed a bull's eye pattern in the macula with a ring of purplish hue outside a circular bronze-colored zone of possible RPE atrophy (Figures 1 and 2). Optical coherence tomography of both eyes showed foveal thinning, more in the right eye, photoreceptor atrophy, and increased RPE reflectivity (Figures 3 and 4). Electroretinography showed extinguished photopic response while scotopic response was minimally affected. Fig. 1. Fundus image of the right eye showing a purple-colored bull's eye maculopathy. Fig. 2. Fundus image of the left eye showing a purple-colored bull's eye maculopathy. Fig. 3. Optical coherence tomography of the right eye showing foveal and photoreceptor atrophy with underlying hyperreflectivity of the retinal pigment epithelium. Fig. 4. Optical coherence tomography of the left eye showing foveal thinning with underlying hyperreflectivity of the RPE. There was no history of family members affected with hereditary fundus dystrophies. Discussion Common causes of bull's eye maculopathy are progressive cone dystrophy, rod cone dystrophy, Stargardt dystrophy, benign concentric macular dystrophy, Batten disease, and drug-induced toxicity as in chloroquine and hydroxychloroquine retinopathy. In cone dystrophy, it is common to see a drop in visual acuity much earlier than fundus changes. Photophobia and loss of color vision are evident. With advancing age, visual acuity drops further with marked RPE atrophy in the fovea and temporal disk pallor. A bull's eye maculopathy in cone dystrophy presents as a lighter ring of RPE atrophy surrounding a dark center. In rod cone dystrophy, increased disk pallor, arteriolar attenuation, and pigmentary changes are seen in the retinal periphery, giving an appearance similar to that of retinitis pigmentosa. Night blindness occurs early in life. In Stargardt dystrophy, a beaten bronze–appearing fovea is seen with surrounding lighter RPE changes. This condition presents later in life and is rare in early childhood. Drug-induced toxicity is known to cause acquired bull's eye maculopathy. β-Thalassemia major is a hereditary haemolytic anemia that is treated with multiple blood transfusions.1 In this condition, blood transfusions, ineffective erythropoiesis, and increased gastrointestinal iron absorption lead to iron overload in the body. Iron overload can be determined by serum ferritin measurement. In these patients, iron deposition in parenchymal tissues begins within 1 year of starting the regular transfusions.2 Although blood transfusions are important for patients with anemia, chronic transfusions inevitably lead to iron overload because humans cannot actively remove excess iron. The cumulative effects of iron overload lead to significant morbidity and mortality, if untreated. A unit of erythrocytes transfused contains approximately 250 mg of iron, while the body cannot excrete more than 1 mg of iron per day. As iron loading progresses, the capacity of serum transferrin, the main transport protein of iron, to bind and detoxify iron may be exceeded. Thereafter, the non–transferrin-bound fraction of iron within plasma may promote generation of free hydroxyl radicals, propagators of oxygen-related damage. Excess iron is extremely toxic to all cells of the body and can cause serious and irreversible organic damage, such as cirrhosis, diabetes, heart disease, and hypogonadism.3 Normal values of serum ferritin for men and women are 12 to 300 ng/mL and 12 to 150 ng/mL, respectively. The distribution of iron and ferritin has been characterized in the adult rat retina.3 Proton-induced X-ray emission identified the largest amounts of heme and nonheme iron in the inner segments of photoreceptors, the RPE, the choroid, the inner nuclear layer, and the ganglion cell layer. Iron was present in somewhat lesser, but still significant amounts in the photoreceptor outer segments. Interestingly, immunohistochemistry studies have demonstrated a similar distribution pattern of retinal ferritin. The exception is that iron, but not much ferritin, is contained in the photoreceptor outer segment. Iron has an affinity for melanin in the RPE.4 Accumulation of iron in the RPE causes RPE atrophy and hence foveal and photoreceptor atrophy. The purplish hue in the outer ring of the bull's eye maculopathy seen in this child could possibly be due to iron accumulation. The center shows foveal atrophy, suggesting a loss of RPE due to previous iron accumulation. Our patient was using oral chelator deferasirox at a dose of 125 mg/day for 2 years before she presented to us. This drug is known to cause reversible retinopathy and improvement of vision on drug withdrawal.5 This drug did not help lower the ferritin levels, which were persistently high for 2 years. Our patient had stopped oral chelators a month ago and yet noticed progressive loss of vision in both eyes. Optical coherence tomography showed foveal and photoreceptor atrophy in our patient causing permanent vision loss. Although we do not have any conclusive evidence that suggests iron overload as the cause for the purplish hue and bull's eye appearance of the macula, we do believe this discoloration could be due to ferritin accumulation. We feel it is important to consider raised serum ferritin as a possible cause for vision loss as correcting this can prevent further visual loss. Conclusion Although bull's eye maculopathy in children and young adults points to a diagnosis of hereditary degenerations in most cases, a careful examination of the pattern of bull's eye in the macula and history-taking is essential. In this case, the outer zone of the bull's eye has a classic purple hue with a central bronze zone. A careful systemic history and history of drug intake are necessary. Although oral chelators may be harmful to the RPE, it is important to note that persistently raised serum ferritin may be more harmful. The author has no financial/conflicting interests to disclose.

DEFERASIROX

DrugsGivenReaction

CC BY-NC-ND

30395118

2021-07-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maculopathy'.

BULL'S EYE MACULOPATHY POSSIBLY DUE TO IRON OVERLOAD IN A CHILD WITH THALASSEMIA MAJOR: A CASE OF POSSIBLE "FERRITIN RETINOPATHY". OBJECTIVE To report a case of bull's eye maculopathy probably caused by iron overload in a child with thalassemia major. METHODS Case report. RESULTS A 6-year-old girl with thalassemia major who was on chronic multiple blood transfusions since 2 years of age presented with blurred vision in both eyes for 2 months. Blood reports showed very high serum ferritin levels in the range 400 to 2,250 ng/mL (checked every 3 months) since 4 years of age. She was on oral iron chelator deferasirox for 2 years, which was stopped a month ago. Fundus examination of both eyes showed a characteristic bull's eye macula with a purplish hue in the outer ring probably due to iron deposition. The center of the bull's eye had a beaten bronze appearance. CONCLUSIONS Careful history-taking is important in children with bull's eye maculopathy because all such retinopathies need not be hereditary fundus dystrophies. Further progression can be arrested by identifying and removing the cause vision loss. Bull's eye maculopathy is a term given to describe the appearance of the macula as a target or bull's eye. Degeneration of the retinal pigment epithelium (RPE) in the macular area causes alternating ring-like light and dark zones of pigmentation. This is the first case described to the best of our knowledge of bull's eye maculopathy probably caused due to serum iron overload in a child with thalassemia major. Case Report A 6-year-old girl of Indian origin, diagnosed to have beta thalassemia major at birth, presented with gradual decrease in vision in both eyes, especially for distance since 2 months. She had undergone multiple blood transfusions, and on repeated testing, her serum ferritin levels were between 400 ng/mL and 2,250 ng/mL checked every 3 months (normal range 7–140 ng/mL). She was using oral iron chelators deferasirox at 125 mg/day for 2 years, which was stopped a month back. Serum ferritin levels did not reach normal despite oral chelators. On examination, best-corrected visual acuity was 20/100, N18 in the right eye and 20/40p, N8 in the left eye. Anterior segment examination was unremarkable. Fundus examination of both eyes showed a bull's eye pattern in the macula with a ring of purplish hue outside a circular bronze-colored zone of possible RPE atrophy (Figures 1 and 2). Optical coherence tomography of both eyes showed foveal thinning, more in the right eye, photoreceptor atrophy, and increased RPE reflectivity (Figures 3 and 4). Electroretinography showed extinguished photopic response while scotopic response was minimally affected. Fig. 1. Fundus image of the right eye showing a purple-colored bull's eye maculopathy. Fig. 2. Fundus image of the left eye showing a purple-colored bull's eye maculopathy. Fig. 3. Optical coherence tomography of the right eye showing foveal and photoreceptor atrophy with underlying hyperreflectivity of the retinal pigment epithelium. Fig. 4. Optical coherence tomography of the left eye showing foveal thinning with underlying hyperreflectivity of the RPE. There was no history of family members affected with hereditary fundus dystrophies. Discussion Common causes of bull's eye maculopathy are progressive cone dystrophy, rod cone dystrophy, Stargardt dystrophy, benign concentric macular dystrophy, Batten disease, and drug-induced toxicity as in chloroquine and hydroxychloroquine retinopathy. In cone dystrophy, it is common to see a drop in visual acuity much earlier than fundus changes. Photophobia and loss of color vision are evident. With advancing age, visual acuity drops further with marked RPE atrophy in the fovea and temporal disk pallor. A bull's eye maculopathy in cone dystrophy presents as a lighter ring of RPE atrophy surrounding a dark center. In rod cone dystrophy, increased disk pallor, arteriolar attenuation, and pigmentary changes are seen in the retinal periphery, giving an appearance similar to that of retinitis pigmentosa. Night blindness occurs early in life. In Stargardt dystrophy, a beaten bronze–appearing fovea is seen with surrounding lighter RPE changes. This condition presents later in life and is rare in early childhood. Drug-induced toxicity is known to cause acquired bull's eye maculopathy. β-Thalassemia major is a hereditary haemolytic anemia that is treated with multiple blood transfusions.1 In this condition, blood transfusions, ineffective erythropoiesis, and increased gastrointestinal iron absorption lead to iron overload in the body. Iron overload can be determined by serum ferritin measurement. In these patients, iron deposition in parenchymal tissues begins within 1 year of starting the regular transfusions.2 Although blood transfusions are important for patients with anemia, chronic transfusions inevitably lead to iron overload because humans cannot actively remove excess iron. The cumulative effects of iron overload lead to significant morbidity and mortality, if untreated. A unit of erythrocytes transfused contains approximately 250 mg of iron, while the body cannot excrete more than 1 mg of iron per day. As iron loading progresses, the capacity of serum transferrin, the main transport protein of iron, to bind and detoxify iron may be exceeded. Thereafter, the non–transferrin-bound fraction of iron within plasma may promote generation of free hydroxyl radicals, propagators of oxygen-related damage. Excess iron is extremely toxic to all cells of the body and can cause serious and irreversible organic damage, such as cirrhosis, diabetes, heart disease, and hypogonadism.3 Normal values of serum ferritin for men and women are 12 to 300 ng/mL and 12 to 150 ng/mL, respectively. The distribution of iron and ferritin has been characterized in the adult rat retina.3 Proton-induced X-ray emission identified the largest amounts of heme and nonheme iron in the inner segments of photoreceptors, the RPE, the choroid, the inner nuclear layer, and the ganglion cell layer. Iron was present in somewhat lesser, but still significant amounts in the photoreceptor outer segments. Interestingly, immunohistochemistry studies have demonstrated a similar distribution pattern of retinal ferritin. The exception is that iron, but not much ferritin, is contained in the photoreceptor outer segment. Iron has an affinity for melanin in the RPE.4 Accumulation of iron in the RPE causes RPE atrophy and hence foveal and photoreceptor atrophy. The purplish hue in the outer ring of the bull's eye maculopathy seen in this child could possibly be due to iron accumulation. The center shows foveal atrophy, suggesting a loss of RPE due to previous iron accumulation. Our patient was using oral chelator deferasirox at a dose of 125 mg/day for 2 years before she presented to us. This drug is known to cause reversible retinopathy and improvement of vision on drug withdrawal.5 This drug did not help lower the ferritin levels, which were persistently high for 2 years. Our patient had stopped oral chelators a month ago and yet noticed progressive loss of vision in both eyes. Optical coherence tomography showed foveal and photoreceptor atrophy in our patient causing permanent vision loss. Although we do not have any conclusive evidence that suggests iron overload as the cause for the purplish hue and bull's eye appearance of the macula, we do believe this discoloration could be due to ferritin accumulation. We feel it is important to consider raised serum ferritin as a possible cause for vision loss as correcting this can prevent further visual loss. Conclusion Although bull's eye maculopathy in children and young adults points to a diagnosis of hereditary degenerations in most cases, a careful examination of the pattern of bull's eye in the macula and history-taking is essential. In this case, the outer zone of the bull's eye has a classic purple hue with a central bronze zone. A careful systemic history and history of drug intake are necessary. Although oral chelators may be harmful to the RPE, it is important to note that persistently raised serum ferritin may be more harmful. The author has no financial/conflicting interests to disclose.

DEFERASIROX

DrugsGivenReaction

CC BY-NC-ND

30395118

2021-07-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy non-responder'.

BULL'S EYE MACULOPATHY POSSIBLY DUE TO IRON OVERLOAD IN A CHILD WITH THALASSEMIA MAJOR: A CASE OF POSSIBLE "FERRITIN RETINOPATHY". OBJECTIVE To report a case of bull's eye maculopathy probably caused by iron overload in a child with thalassemia major. METHODS Case report. RESULTS A 6-year-old girl with thalassemia major who was on chronic multiple blood transfusions since 2 years of age presented with blurred vision in both eyes for 2 months. Blood reports showed very high serum ferritin levels in the range 400 to 2,250 ng/mL (checked every 3 months) since 4 years of age. She was on oral iron chelator deferasirox for 2 years, which was stopped a month ago. Fundus examination of both eyes showed a characteristic bull's eye macula with a purplish hue in the outer ring probably due to iron deposition. The center of the bull's eye had a beaten bronze appearance. CONCLUSIONS Careful history-taking is important in children with bull's eye maculopathy because all such retinopathies need not be hereditary fundus dystrophies. Further progression can be arrested by identifying and removing the cause vision loss. Bull's eye maculopathy is a term given to describe the appearance of the macula as a target or bull's eye. Degeneration of the retinal pigment epithelium (RPE) in the macular area causes alternating ring-like light and dark zones of pigmentation. This is the first case described to the best of our knowledge of bull's eye maculopathy probably caused due to serum iron overload in a child with thalassemia major. Case Report A 6-year-old girl of Indian origin, diagnosed to have beta thalassemia major at birth, presented with gradual decrease in vision in both eyes, especially for distance since 2 months. She had undergone multiple blood transfusions, and on repeated testing, her serum ferritin levels were between 400 ng/mL and 2,250 ng/mL checked every 3 months (normal range 7–140 ng/mL). She was using oral iron chelators deferasirox at 125 mg/day for 2 years, which was stopped a month back. Serum ferritin levels did not reach normal despite oral chelators. On examination, best-corrected visual acuity was 20/100, N18 in the right eye and 20/40p, N8 in the left eye. Anterior segment examination was unremarkable. Fundus examination of both eyes showed a bull's eye pattern in the macula with a ring of purplish hue outside a circular bronze-colored zone of possible RPE atrophy (Figures 1 and 2). Optical coherence tomography of both eyes showed foveal thinning, more in the right eye, photoreceptor atrophy, and increased RPE reflectivity (Figures 3 and 4). Electroretinography showed extinguished photopic response while scotopic response was minimally affected. Fig. 1. Fundus image of the right eye showing a purple-colored bull's eye maculopathy. Fig. 2. Fundus image of the left eye showing a purple-colored bull's eye maculopathy. Fig. 3. Optical coherence tomography of the right eye showing foveal and photoreceptor atrophy with underlying hyperreflectivity of the retinal pigment epithelium. Fig. 4. Optical coherence tomography of the left eye showing foveal thinning with underlying hyperreflectivity of the RPE. There was no history of family members affected with hereditary fundus dystrophies. Discussion Common causes of bull's eye maculopathy are progressive cone dystrophy, rod cone dystrophy, Stargardt dystrophy, benign concentric macular dystrophy, Batten disease, and drug-induced toxicity as in chloroquine and hydroxychloroquine retinopathy. In cone dystrophy, it is common to see a drop in visual acuity much earlier than fundus changes. Photophobia and loss of color vision are evident. With advancing age, visual acuity drops further with marked RPE atrophy in the fovea and temporal disk pallor. A bull's eye maculopathy in cone dystrophy presents as a lighter ring of RPE atrophy surrounding a dark center. In rod cone dystrophy, increased disk pallor, arteriolar attenuation, and pigmentary changes are seen in the retinal periphery, giving an appearance similar to that of retinitis pigmentosa. Night blindness occurs early in life. In Stargardt dystrophy, a beaten bronze–appearing fovea is seen with surrounding lighter RPE changes. This condition presents later in life and is rare in early childhood. Drug-induced toxicity is known to cause acquired bull's eye maculopathy. β-Thalassemia major is a hereditary haemolytic anemia that is treated with multiple blood transfusions.1 In this condition, blood transfusions, ineffective erythropoiesis, and increased gastrointestinal iron absorption lead to iron overload in the body. Iron overload can be determined by serum ferritin measurement. In these patients, iron deposition in parenchymal tissues begins within 1 year of starting the regular transfusions.2 Although blood transfusions are important for patients with anemia, chronic transfusions inevitably lead to iron overload because humans cannot actively remove excess iron. The cumulative effects of iron overload lead to significant morbidity and mortality, if untreated. A unit of erythrocytes transfused contains approximately 250 mg of iron, while the body cannot excrete more than 1 mg of iron per day. As iron loading progresses, the capacity of serum transferrin, the main transport protein of iron, to bind and detoxify iron may be exceeded. Thereafter, the non–transferrin-bound fraction of iron within plasma may promote generation of free hydroxyl radicals, propagators of oxygen-related damage. Excess iron is extremely toxic to all cells of the body and can cause serious and irreversible organic damage, such as cirrhosis, diabetes, heart disease, and hypogonadism.3 Normal values of serum ferritin for men and women are 12 to 300 ng/mL and 12 to 150 ng/mL, respectively. The distribution of iron and ferritin has been characterized in the adult rat retina.3 Proton-induced X-ray emission identified the largest amounts of heme and nonheme iron in the inner segments of photoreceptors, the RPE, the choroid, the inner nuclear layer, and the ganglion cell layer. Iron was present in somewhat lesser, but still significant amounts in the photoreceptor outer segments. Interestingly, immunohistochemistry studies have demonstrated a similar distribution pattern of retinal ferritin. The exception is that iron, but not much ferritin, is contained in the photoreceptor outer segment. Iron has an affinity for melanin in the RPE.4 Accumulation of iron in the RPE causes RPE atrophy and hence foveal and photoreceptor atrophy. The purplish hue in the outer ring of the bull's eye maculopathy seen in this child could possibly be due to iron accumulation. The center shows foveal atrophy, suggesting a loss of RPE due to previous iron accumulation. Our patient was using oral chelator deferasirox at a dose of 125 mg/day for 2 years before she presented to us. This drug is known to cause reversible retinopathy and improvement of vision on drug withdrawal.5 This drug did not help lower the ferritin levels, which were persistently high for 2 years. Our patient had stopped oral chelators a month ago and yet noticed progressive loss of vision in both eyes. Optical coherence tomography showed foveal and photoreceptor atrophy in our patient causing permanent vision loss. Although we do not have any conclusive evidence that suggests iron overload as the cause for the purplish hue and bull's eye appearance of the macula, we do believe this discoloration could be due to ferritin accumulation. We feel it is important to consider raised serum ferritin as a possible cause for vision loss as correcting this can prevent further visual loss. Conclusion Although bull's eye maculopathy in children and young adults points to a diagnosis of hereditary degenerations in most cases, a careful examination of the pattern of bull's eye in the macula and history-taking is essential. In this case, the outer zone of the bull's eye has a classic purple hue with a central bronze zone. A careful systemic history and history of drug intake are necessary. Although oral chelators may be harmful to the RPE, it is important to note that persistently raised serum ferritin may be more harmful. The author has no financial/conflicting interests to disclose.

DEFERASIROX

DrugsGivenReaction

CC BY-NC-ND

30395118

2021-07-01

What was the administration route of drug 'DEFERASIROX'?

BULL'S EYE MACULOPATHY POSSIBLY DUE TO IRON OVERLOAD IN A CHILD WITH THALASSEMIA MAJOR: A CASE OF POSSIBLE "FERRITIN RETINOPATHY". OBJECTIVE To report a case of bull's eye maculopathy probably caused by iron overload in a child with thalassemia major. METHODS Case report. RESULTS A 6-year-old girl with thalassemia major who was on chronic multiple blood transfusions since 2 years of age presented with blurred vision in both eyes for 2 months. Blood reports showed very high serum ferritin levels in the range 400 to 2,250 ng/mL (checked every 3 months) since 4 years of age. She was on oral iron chelator deferasirox for 2 years, which was stopped a month ago. Fundus examination of both eyes showed a characteristic bull's eye macula with a purplish hue in the outer ring probably due to iron deposition. The center of the bull's eye had a beaten bronze appearance. CONCLUSIONS Careful history-taking is important in children with bull's eye maculopathy because all such retinopathies need not be hereditary fundus dystrophies. Further progression can be arrested by identifying and removing the cause vision loss. Bull's eye maculopathy is a term given to describe the appearance of the macula as a target or bull's eye. Degeneration of the retinal pigment epithelium (RPE) in the macular area causes alternating ring-like light and dark zones of pigmentation. This is the first case described to the best of our knowledge of bull's eye maculopathy probably caused due to serum iron overload in a child with thalassemia major. Case Report A 6-year-old girl of Indian origin, diagnosed to have beta thalassemia major at birth, presented with gradual decrease in vision in both eyes, especially for distance since 2 months. She had undergone multiple blood transfusions, and on repeated testing, her serum ferritin levels were between 400 ng/mL and 2,250 ng/mL checked every 3 months (normal range 7–140 ng/mL). She was using oral iron chelators deferasirox at 125 mg/day for 2 years, which was stopped a month back. Serum ferritin levels did not reach normal despite oral chelators. On examination, best-corrected visual acuity was 20/100, N18 in the right eye and 20/40p, N8 in the left eye. Anterior segment examination was unremarkable. Fundus examination of both eyes showed a bull's eye pattern in the macula with a ring of purplish hue outside a circular bronze-colored zone of possible RPE atrophy (Figures 1 and 2). Optical coherence tomography of both eyes showed foveal thinning, more in the right eye, photoreceptor atrophy, and increased RPE reflectivity (Figures 3 and 4). Electroretinography showed extinguished photopic response while scotopic response was minimally affected. Fig. 1. Fundus image of the right eye showing a purple-colored bull's eye maculopathy. Fig. 2. Fundus image of the left eye showing a purple-colored bull's eye maculopathy. Fig. 3. Optical coherence tomography of the right eye showing foveal and photoreceptor atrophy with underlying hyperreflectivity of the retinal pigment epithelium. Fig. 4. Optical coherence tomography of the left eye showing foveal thinning with underlying hyperreflectivity of the RPE. There was no history of family members affected with hereditary fundus dystrophies. Discussion Common causes of bull's eye maculopathy are progressive cone dystrophy, rod cone dystrophy, Stargardt dystrophy, benign concentric macular dystrophy, Batten disease, and drug-induced toxicity as in chloroquine and hydroxychloroquine retinopathy. In cone dystrophy, it is common to see a drop in visual acuity much earlier than fundus changes. Photophobia and loss of color vision are evident. With advancing age, visual acuity drops further with marked RPE atrophy in the fovea and temporal disk pallor. A bull's eye maculopathy in cone dystrophy presents as a lighter ring of RPE atrophy surrounding a dark center. In rod cone dystrophy, increased disk pallor, arteriolar attenuation, and pigmentary changes are seen in the retinal periphery, giving an appearance similar to that of retinitis pigmentosa. Night blindness occurs early in life. In Stargardt dystrophy, a beaten bronze–appearing fovea is seen with surrounding lighter RPE changes. This condition presents later in life and is rare in early childhood. Drug-induced toxicity is known to cause acquired bull's eye maculopathy. β-Thalassemia major is a hereditary haemolytic anemia that is treated with multiple blood transfusions.1 In this condition, blood transfusions, ineffective erythropoiesis, and increased gastrointestinal iron absorption lead to iron overload in the body. Iron overload can be determined by serum ferritin measurement. In these patients, iron deposition in parenchymal tissues begins within 1 year of starting the regular transfusions.2 Although blood transfusions are important for patients with anemia, chronic transfusions inevitably lead to iron overload because humans cannot actively remove excess iron. The cumulative effects of iron overload lead to significant morbidity and mortality, if untreated. A unit of erythrocytes transfused contains approximately 250 mg of iron, while the body cannot excrete more than 1 mg of iron per day. As iron loading progresses, the capacity of serum transferrin, the main transport protein of iron, to bind and detoxify iron may be exceeded. Thereafter, the non–transferrin-bound fraction of iron within plasma may promote generation of free hydroxyl radicals, propagators of oxygen-related damage. Excess iron is extremely toxic to all cells of the body and can cause serious and irreversible organic damage, such as cirrhosis, diabetes, heart disease, and hypogonadism.3 Normal values of serum ferritin for men and women are 12 to 300 ng/mL and 12 to 150 ng/mL, respectively. The distribution of iron and ferritin has been characterized in the adult rat retina.3 Proton-induced X-ray emission identified the largest amounts of heme and nonheme iron in the inner segments of photoreceptors, the RPE, the choroid, the inner nuclear layer, and the ganglion cell layer. Iron was present in somewhat lesser, but still significant amounts in the photoreceptor outer segments. Interestingly, immunohistochemistry studies have demonstrated a similar distribution pattern of retinal ferritin. The exception is that iron, but not much ferritin, is contained in the photoreceptor outer segment. Iron has an affinity for melanin in the RPE.4 Accumulation of iron in the RPE causes RPE atrophy and hence foveal and photoreceptor atrophy. The purplish hue in the outer ring of the bull's eye maculopathy seen in this child could possibly be due to iron accumulation. The center shows foveal atrophy, suggesting a loss of RPE due to previous iron accumulation. Our patient was using oral chelator deferasirox at a dose of 125 mg/day for 2 years before she presented to us. This drug is known to cause reversible retinopathy and improvement of vision on drug withdrawal.5 This drug did not help lower the ferritin levels, which were persistently high for 2 years. Our patient had stopped oral chelators a month ago and yet noticed progressive loss of vision in both eyes. Optical coherence tomography showed foveal and photoreceptor atrophy in our patient causing permanent vision loss. Although we do not have any conclusive evidence that suggests iron overload as the cause for the purplish hue and bull's eye appearance of the macula, we do believe this discoloration could be due to ferritin accumulation. We feel it is important to consider raised serum ferritin as a possible cause for vision loss as correcting this can prevent further visual loss. Conclusion Although bull's eye maculopathy in children and young adults points to a diagnosis of hereditary degenerations in most cases, a careful examination of the pattern of bull's eye in the macula and history-taking is essential. In this case, the outer zone of the bull's eye has a classic purple hue with a central bronze zone. A careful systemic history and history of drug intake are necessary. Although oral chelators may be harmful to the RPE, it is important to note that persistently raised serum ferritin may be more harmful. The author has no financial/conflicting interests to disclose.

Oral

DrugAdministrationRoute

CC BY-NC-ND

30395118

2021-07-01

What was the outcome of reaction 'Maculopathy'?

BULL'S EYE MACULOPATHY POSSIBLY DUE TO IRON OVERLOAD IN A CHILD WITH THALASSEMIA MAJOR: A CASE OF POSSIBLE "FERRITIN RETINOPATHY". OBJECTIVE To report a case of bull's eye maculopathy probably caused by iron overload in a child with thalassemia major. METHODS Case report. RESULTS A 6-year-old girl with thalassemia major who was on chronic multiple blood transfusions since 2 years of age presented with blurred vision in both eyes for 2 months. Blood reports showed very high serum ferritin levels in the range 400 to 2,250 ng/mL (checked every 3 months) since 4 years of age. She was on oral iron chelator deferasirox for 2 years, which was stopped a month ago. Fundus examination of both eyes showed a characteristic bull's eye macula with a purplish hue in the outer ring probably due to iron deposition. The center of the bull's eye had a beaten bronze appearance. CONCLUSIONS Careful history-taking is important in children with bull's eye maculopathy because all such retinopathies need not be hereditary fundus dystrophies. Further progression can be arrested by identifying and removing the cause vision loss. Bull's eye maculopathy is a term given to describe the appearance of the macula as a target or bull's eye. Degeneration of the retinal pigment epithelium (RPE) in the macular area causes alternating ring-like light and dark zones of pigmentation. This is the first case described to the best of our knowledge of bull's eye maculopathy probably caused due to serum iron overload in a child with thalassemia major. Case Report A 6-year-old girl of Indian origin, diagnosed to have beta thalassemia major at birth, presented with gradual decrease in vision in both eyes, especially for distance since 2 months. She had undergone multiple blood transfusions, and on repeated testing, her serum ferritin levels were between 400 ng/mL and 2,250 ng/mL checked every 3 months (normal range 7–140 ng/mL). She was using oral iron chelators deferasirox at 125 mg/day for 2 years, which was stopped a month back. Serum ferritin levels did not reach normal despite oral chelators. On examination, best-corrected visual acuity was 20/100, N18 in the right eye and 20/40p, N8 in the left eye. Anterior segment examination was unremarkable. Fundus examination of both eyes showed a bull's eye pattern in the macula with a ring of purplish hue outside a circular bronze-colored zone of possible RPE atrophy (Figures 1 and 2). Optical coherence tomography of both eyes showed foveal thinning, more in the right eye, photoreceptor atrophy, and increased RPE reflectivity (Figures 3 and 4). Electroretinography showed extinguished photopic response while scotopic response was minimally affected. Fig. 1. Fundus image of the right eye showing a purple-colored bull's eye maculopathy. Fig. 2. Fundus image of the left eye showing a purple-colored bull's eye maculopathy. Fig. 3. Optical coherence tomography of the right eye showing foveal and photoreceptor atrophy with underlying hyperreflectivity of the retinal pigment epithelium. Fig. 4. Optical coherence tomography of the left eye showing foveal thinning with underlying hyperreflectivity of the RPE. There was no history of family members affected with hereditary fundus dystrophies. Discussion Common causes of bull's eye maculopathy are progressive cone dystrophy, rod cone dystrophy, Stargardt dystrophy, benign concentric macular dystrophy, Batten disease, and drug-induced toxicity as in chloroquine and hydroxychloroquine retinopathy. In cone dystrophy, it is common to see a drop in visual acuity much earlier than fundus changes. Photophobia and loss of color vision are evident. With advancing age, visual acuity drops further with marked RPE atrophy in the fovea and temporal disk pallor. A bull's eye maculopathy in cone dystrophy presents as a lighter ring of RPE atrophy surrounding a dark center. In rod cone dystrophy, increased disk pallor, arteriolar attenuation, and pigmentary changes are seen in the retinal periphery, giving an appearance similar to that of retinitis pigmentosa. Night blindness occurs early in life. In Stargardt dystrophy, a beaten bronze–appearing fovea is seen with surrounding lighter RPE changes. This condition presents later in life and is rare in early childhood. Drug-induced toxicity is known to cause acquired bull's eye maculopathy. β-Thalassemia major is a hereditary haemolytic anemia that is treated with multiple blood transfusions.1 In this condition, blood transfusions, ineffective erythropoiesis, and increased gastrointestinal iron absorption lead to iron overload in the body. Iron overload can be determined by serum ferritin measurement. In these patients, iron deposition in parenchymal tissues begins within 1 year of starting the regular transfusions.2 Although blood transfusions are important for patients with anemia, chronic transfusions inevitably lead to iron overload because humans cannot actively remove excess iron. The cumulative effects of iron overload lead to significant morbidity and mortality, if untreated. A unit of erythrocytes transfused contains approximately 250 mg of iron, while the body cannot excrete more than 1 mg of iron per day. As iron loading progresses, the capacity of serum transferrin, the main transport protein of iron, to bind and detoxify iron may be exceeded. Thereafter, the non–transferrin-bound fraction of iron within plasma may promote generation of free hydroxyl radicals, propagators of oxygen-related damage. Excess iron is extremely toxic to all cells of the body and can cause serious and irreversible organic damage, such as cirrhosis, diabetes, heart disease, and hypogonadism.3 Normal values of serum ferritin for men and women are 12 to 300 ng/mL and 12 to 150 ng/mL, respectively. The distribution of iron and ferritin has been characterized in the adult rat retina.3 Proton-induced X-ray emission identified the largest amounts of heme and nonheme iron in the inner segments of photoreceptors, the RPE, the choroid, the inner nuclear layer, and the ganglion cell layer. Iron was present in somewhat lesser, but still significant amounts in the photoreceptor outer segments. Interestingly, immunohistochemistry studies have demonstrated a similar distribution pattern of retinal ferritin. The exception is that iron, but not much ferritin, is contained in the photoreceptor outer segment. Iron has an affinity for melanin in the RPE.4 Accumulation of iron in the RPE causes RPE atrophy and hence foveal and photoreceptor atrophy. The purplish hue in the outer ring of the bull's eye maculopathy seen in this child could possibly be due to iron accumulation. The center shows foveal atrophy, suggesting a loss of RPE due to previous iron accumulation. Our patient was using oral chelator deferasirox at a dose of 125 mg/day for 2 years before she presented to us. This drug is known to cause reversible retinopathy and improvement of vision on drug withdrawal.5 This drug did not help lower the ferritin levels, which were persistently high for 2 years. Our patient had stopped oral chelators a month ago and yet noticed progressive loss of vision in both eyes. Optical coherence tomography showed foveal and photoreceptor atrophy in our patient causing permanent vision loss. Although we do not have any conclusive evidence that suggests iron overload as the cause for the purplish hue and bull's eye appearance of the macula, we do believe this discoloration could be due to ferritin accumulation. We feel it is important to consider raised serum ferritin as a possible cause for vision loss as correcting this can prevent further visual loss. Conclusion Although bull's eye maculopathy in children and young adults points to a diagnosis of hereditary degenerations in most cases, a careful examination of the pattern of bull's eye in the macula and history-taking is essential. In this case, the outer zone of the bull's eye has a classic purple hue with a central bronze zone. A careful systemic history and history of drug intake are necessary. Although oral chelators may be harmful to the RPE, it is important to note that persistently raised serum ferritin may be more harmful. The author has no financial/conflicting interests to disclose.

Not recovered

ReactionOutcome

CC BY-NC-ND

30395118

2021-07-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Idiopathic intracranial hypertension'.

CASE REPORT OF THE ROLE OF OPTICAL COHERENCE TOMOGRAPHY IN RECOMBINANT GROWTH HORMONE THERAPY. OBJECTIVE To report the correlation between recombinant growth hormone (rhGH) dosage and retinal nerve fiber layer (RNFL) thickness values measured by optical coherence tomography in a case of pseudotumor cerebri syndrome (PTCS) after rhGH. METHODS An 11-year-old girl was receiving rhGH for panhypopituitarism. The patient developed PTCS, and her rhGH dose was adjusted using optical coherence tomography RNFL thickness measurements. The linear correlation coefficient (r) and coefficient of determination (r2) were calculated to assess the relationship between RNFL thickness and rhGH dose. RESULTS As the rhGH dosage was increased, the RNFL thickness values also increased, especially when acetazolamide was excluded because of its confounding effect. (r = 0.64) In separate subgroup analysis, a higher acetazolamide dosage strongly correlated with reduced RNFL thickness (r = 0.77). CONCLUSIONS Although PTCS is a rare complication after rhGH therapy, its detrimental effects cannot be ignored. In our case report, we used optical coherence tomography RNFL values in addition to clinical findings to carefully titrate the rhGH dosage to prevent a flare-up of PTCS. Despite the obvious need for larger studies, our case report shows the value of RNFL thickness measured by optical coherence tomography and the valuable additional data it provides to refine rhGH therapy as an adjunct noninvasive method in PTCS. pmcPseudotumor cerebri syndrome (PTCS) after recombinant human growth hormone (rhGH) therapy is a rare but an important complication.1 Cessation of the therapy is often adequate for reversal of PTCS; however, this is complicated by the growth requirements of the patient.1 To the best of our knowledge, we report the first case of the prevention of flare-up of PTCS by titrating the rhGH dose based on retinal nerve fiber layer (RNFL) thickness values obtained by optical coherence tomography (OCT). Case Report An 11-year-old girl with a history of panhypopituitarism had been followed-up by the pediatric endocrinology (PE) team at University Hospitals Cleveland Medical Center since birth. She was referred to pediatric ophthalmology due to intermittent occipital headaches. A full ophthalmic examination was unremarkable except for the dilated fundus examination, which revealed +2 optic disc edema (ODE) in both eyes (Figure 1). The results of OCT of the optic discs revealed increased RNFL thickness in both eyes (Figure 2). Fig. 1. Fundus photography of the patient at the first visit revealing bilateral ODEs. Fig. 2. Optical coherence tomography RNFL changes. On November 13, 2013, the patient was receiving a 0.8 mg/kg rhGH dose, and her OCT RNFL values were greatly increased. Fifteen days later, upon stopping rhGH therapy totally, the OCT RNFL values started decreasing, and after 2 months, the values returned to normal. Magnetic resonance imaging showed pituitary hypoplasia in 2007, and treatment with hydrocortisone, levothyroxine, and somatropin (rhGH) was started. Other examinations were otherwise normal. The patient was born at 39 weeks of gestation with a birth weight of 3,517 g. No apparent reason was found for her hypopituitarism. Recombinant human growth hormone was stopped immediately, and magnetic resonance imaging and lumbar puncture were ordered to rule out PTCS. Visual acuity for both eyes was still 20/15, and ODE improved in the next follow-up after 2 weeks (Figure 2). Magnetic resonance imaging was negative, and lumbar puncture revealed high opening pressures, leading to confirmation of PTCS. Recombinant human growth hormone was started again, albeit on a lower dose at 0.3 mg/day reduced from 0.8 mg/day, and no ODE was noted in the next 2 months (Figure 2). However, the patient's growth rate halted because of inefficient rhGH. After communication among the medical providers, the rhGH dose was increased from 0.3 mg/day to 0.5 mg/day. Three-month follow-up revealed mild ODE, which was confirmed with increased RNFL OCT values (Figure 3A). After consultations with the PE team, the rhGH dose was reduced to 0.3 mg/day again. Dilated fundus examination revealed improved ODE, which was confirmed with RNFL OCT values (Figure 3B). To increase the growth rate further, the PE team decided to increase the rhGH dose to 0.8 mg/day incrementally. Subsequent visits revealed normal optic discs and stable OCT values up to 0.7 mg/day. However, after 3 months on 0.7 mg/day, OCT RNFL values increased, and the dose was adjusted to 0.4 mg/day (Figure 3C). In addition to decreasing the dose of rhGH, 250 mg/day acetazolamide was started. At the 2-month follow-up, OCT RNFL values returned to baseline (Figure 3D). The PE team again began to incrementally increase the dose to 0.8 mg/day. Two months later, OCT RNFL values again increased above baseline despite the acetazolamide therapy (Figure 4A). A second lumbar puncture revealed high opening pressures. However, because of the slow growth rate, declining percentiles, and episodes of hypoglycemia, rhGH was not stopped completely but was instead reduced to 0.4 mg/day with 250 mg acetazolamide. Optical coherence tomography RNFL values were then the same as those at baseline (Figure 4B). As the PE team was not satisfied with the growth rate, the dose was increased to 0.8 mg/day. Clinical examination showed mildly elevated optic nerve head with elevated RNFL values (Figure 4C). We decided to increase the acetazolamide dose to 500 mg without changing the dose of rhGH. At her next visit, the patient had slightly lower RNFL values, but they had not returned to baseline (Figure 4D). Therefore, we decided to further increase the acetazolamide dose to 750 mg. At the next visit, the PE team reported that the patient's growth had reached a normal rate but requested to further increase the dose. Subsequent visits showed the RNFL values returning to baseline with 750 mg acetazolamide; therefore, the rhGH dosage was increased to 0.9 mg/day (Figure 5). Fig. 3. A. OCT RNFL values with 0.5 mg/day rhGH. B. OCT RNFL values after decreasing the rhGH dose to 0.3 mg/dL. C. OCT RNFL values after increasing the rhGH dose to 0.7 mg/dL. D. OCT RNFL values after decreasing the rhGH dose to 0.4 mg/dL and starting 250 mg acetazolamide. Fig. 4. A. OCT RNFL values after rhGH was increased to 0.8 mg/dL with 250 mg acetazolamide. B. OCT RNFL values after rhGH was reduced to 0.4 mg/dL with 250 mg acetazolamide. C. OCT RNFL values after increasing the rhGH dose to 0.8 mg/dL. D. OCT RNFL values after increasing acetazolamide to 500 mg. Fig. 5. OCT RNFL values after increasing acetazolamide to 750 mg. Methods and Results The rhGH dose values were compared against the RNFL thickness values, and the Pearson's product moment correlation coefficient for sample statistic (r) and coefficient of determination (r2) were calculated to assess the relationship using Microsoft Excel. (Microsoft, Redmond, WA) We performed three different analyses to explore the relationship between the RNFL and rhGH dosage in this single-patient case study. In the first analysis, we looked at the relationship between all RNFL values and rhGH dosage. The correlation between average RNFL values and its relationship with rhGH dosage were relatively weak (r = 0.47 and r2 = 0.22) (Figure 6A). Calculating each quadrant separately also showed a relatively low correlation (Figure 6, B–E). In the second analysis, we removed the RNFL values under acetazolamide treatment and only compared nontreated RNFL values against the rhGH dosage. This time, the correlation for both the average values and quadrants separately was much higher (r = 0.64, r2 = 0.40) (Figure 7). For the third analysis, we only calculated acetazolamide's effect on RNFL under 0.8 mg/mL rhGH, which revealed a high negative correlation. Higher doses of the drug correlated strongly with lower (i.e., thinner) RNFL values (r = 0.77, r2 = 0.59) (Figure 8). Fig. 6. A. Average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values. Despite an overall positive correlation between rhGH dose and RNFL thickness was observed, it was not very strong (r = 0.47, r2 = 0.22). B–E. Superior, inferior, nasal, and temporal quadrant average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values. When the correlation was recalculated for each quadrant separately, the overall trend of positive but weak correlation between rhGH dose and RNFL thickness persisted. Fig. 7. Acetazolamide exclusion subgroup analysis. A. Average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values after RNFL values under acetazolamide treatment were excluded. Removing RNFL values under acetazolamide treated further strengthened the positive correlation between rhGH dose and RNFL thickness (r = 0.64, r2 = 0.40). B–E. Superior, inferior, nasal and temporal quadrant average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values after RNFL values under acetazolamide treatment were excluded. When the correlation was recalculated for each quadrant separately, the strengthened positive trend persisted with exception of the temporal quadrant. Fig. 8. Average RNFL values at 0.8 mg/dL with different acetazolamide doses, correlation graph with coefficient of correlation and determination values. Higher doses of acetazolamide resulted lower (i.e., thinner) RNFL values, indicating a very strong negative correlation (r = 0.77, r2 = 0.59). Discussion In recent years, OCT has started to be used in neuro-ophthalmology practices, especially for the follow-up of ODE.2 In a multicenter trial by the NORDIC Idiopathic Intracranial Hypertension Study Group, the OCT substudy committee showed that idiopathic intracranial hypertension therapy with acetazolamide and weight loss effectively improved RNFL thickness values.3 In part II of the study, the OCT measurements were shown to strongly correlate with the Frisen grading of papilledema.4 Although rhGH therapy is relatively safe and is associated with only few adverse effects,5 it is essential to perform ophthalmic examination to detect PTCS and its detrimental effects on the eye.5 In children, PTCS can be entirely asymptomatic and in early stages may present only with subtle papilledema.6 When diagnosed at relatively later stages, studies have shown permanent loss of vision and visual field defects in up to 10% and 17% of children, respectively.6 The pathogenesis of rhGH-induced PTCS remains relatively unknown. It is postulated to alter cerebrospinal fluid drainage across arachnoid villi.6 It is also theorized that rhGH might be increasing cerebrospinal fluid production by the way of IGF-1 receptors.7 Ophthalmoscopic examination of the fundus has been the gold standard for optic nerve evaluations.3 However, this technique is limited because assessment is subjective and based on the training and experience of the physician, especially for subtle changes. A noninvasive adjunct evaluation tool, such as OCT, might therefore be valuable in the evaluation and follow-up of patients, especially children. To the best of our knowledge, this is the first report in the literature that correlates OCT RNFL values with rhGH dose. As mentioned previously, there is a substantial amount of information in the literature showing the relationship between rhGH therapy and PTCS.5,6 The literature also shows that OCT is reliable for the follow-up of PTCS and related papilledema.2–4 Our case report combines these two pieces of information from the literature. We have found that the average RNFL values correlated well with rhGH, especially when acetazolamide's effect was not included in the calculations. When we studied each quadrant separately, all had a good correlation of RNFL values with rhGH dose. The correlation was higher in the superior and inferior quadrants compared with the nasal and temporal quadrants. This finding was consistent in both the general and acetazolamide exclusion groups. As reported in previous studies, we also found that higher doses of acetazolamide correlated with lower (thinner) RNFL values.3 Optical coherence tomography was used to measure RNFL thickness every 2 months or at each rhGH dose adjustment. In the case of PTCS after rhGH therapy, rhGH is usually stopped all together until resolution and restarted at a lower dose.5 By contrast, we were able to titrate the dose precisely to prevent a flare-up of PTCS but without stopping it totally. The OCT was easy to use and accurately demonstrated even minor changes in the RNFL thickness. In our case report, we observed a correlation between rhGH dose and RNFL thickness measured by OCT, especially when acetazolamide was excluded because of its confounding effect. If it can be verified in larger prospective and randomized trials, this finding could be an early sign of rhGH-induced PTCS. Early detection and careful management of patients who receive rhGH might be a preventative measure. The study was presented as a poster presentation in Research ShowCASE meeting at Case Western Reserve University, Cleveland, OH, 2016. None of the authors has any financial/conflicting interests to disclose.

HYDROCORTISONE, LEVOTHYROXINE, SOMATROPIN

DrugsGivenReaction

CC BY-NC-ND

31568222

2021-11-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'.

CASE REPORT OF THE ROLE OF OPTICAL COHERENCE TOMOGRAPHY IN RECOMBINANT GROWTH HORMONE THERAPY. OBJECTIVE To report the correlation between recombinant growth hormone (rhGH) dosage and retinal nerve fiber layer (RNFL) thickness values measured by optical coherence tomography in a case of pseudotumor cerebri syndrome (PTCS) after rhGH. METHODS An 11-year-old girl was receiving rhGH for panhypopituitarism. The patient developed PTCS, and her rhGH dose was adjusted using optical coherence tomography RNFL thickness measurements. The linear correlation coefficient (r) and coefficient of determination (r2) were calculated to assess the relationship between RNFL thickness and rhGH dose. RESULTS As the rhGH dosage was increased, the RNFL thickness values also increased, especially when acetazolamide was excluded because of its confounding effect. (r = 0.64) In separate subgroup analysis, a higher acetazolamide dosage strongly correlated with reduced RNFL thickness (r = 0.77). CONCLUSIONS Although PTCS is a rare complication after rhGH therapy, its detrimental effects cannot be ignored. In our case report, we used optical coherence tomography RNFL values in addition to clinical findings to carefully titrate the rhGH dosage to prevent a flare-up of PTCS. Despite the obvious need for larger studies, our case report shows the value of RNFL thickness measured by optical coherence tomography and the valuable additional data it provides to refine rhGH therapy as an adjunct noninvasive method in PTCS. pmcPseudotumor cerebri syndrome (PTCS) after recombinant human growth hormone (rhGH) therapy is a rare but an important complication.1 Cessation of the therapy is often adequate for reversal of PTCS; however, this is complicated by the growth requirements of the patient.1 To the best of our knowledge, we report the first case of the prevention of flare-up of PTCS by titrating the rhGH dose based on retinal nerve fiber layer (RNFL) thickness values obtained by optical coherence tomography (OCT). Case Report An 11-year-old girl with a history of panhypopituitarism had been followed-up by the pediatric endocrinology (PE) team at University Hospitals Cleveland Medical Center since birth. She was referred to pediatric ophthalmology due to intermittent occipital headaches. A full ophthalmic examination was unremarkable except for the dilated fundus examination, which revealed +2 optic disc edema (ODE) in both eyes (Figure 1). The results of OCT of the optic discs revealed increased RNFL thickness in both eyes (Figure 2). Fig. 1. Fundus photography of the patient at the first visit revealing bilateral ODEs. Fig. 2. Optical coherence tomography RNFL changes. On November 13, 2013, the patient was receiving a 0.8 mg/kg rhGH dose, and her OCT RNFL values were greatly increased. Fifteen days later, upon stopping rhGH therapy totally, the OCT RNFL values started decreasing, and after 2 months, the values returned to normal. Magnetic resonance imaging showed pituitary hypoplasia in 2007, and treatment with hydrocortisone, levothyroxine, and somatropin (rhGH) was started. Other examinations were otherwise normal. The patient was born at 39 weeks of gestation with a birth weight of 3,517 g. No apparent reason was found for her hypopituitarism. Recombinant human growth hormone was stopped immediately, and magnetic resonance imaging and lumbar puncture were ordered to rule out PTCS. Visual acuity for both eyes was still 20/15, and ODE improved in the next follow-up after 2 weeks (Figure 2). Magnetic resonance imaging was negative, and lumbar puncture revealed high opening pressures, leading to confirmation of PTCS. Recombinant human growth hormone was started again, albeit on a lower dose at 0.3 mg/day reduced from 0.8 mg/day, and no ODE was noted in the next 2 months (Figure 2). However, the patient's growth rate halted because of inefficient rhGH. After communication among the medical providers, the rhGH dose was increased from 0.3 mg/day to 0.5 mg/day. Three-month follow-up revealed mild ODE, which was confirmed with increased RNFL OCT values (Figure 3A). After consultations with the PE team, the rhGH dose was reduced to 0.3 mg/day again. Dilated fundus examination revealed improved ODE, which was confirmed with RNFL OCT values (Figure 3B). To increase the growth rate further, the PE team decided to increase the rhGH dose to 0.8 mg/day incrementally. Subsequent visits revealed normal optic discs and stable OCT values up to 0.7 mg/day. However, after 3 months on 0.7 mg/day, OCT RNFL values increased, and the dose was adjusted to 0.4 mg/day (Figure 3C). In addition to decreasing the dose of rhGH, 250 mg/day acetazolamide was started. At the 2-month follow-up, OCT RNFL values returned to baseline (Figure 3D). The PE team again began to incrementally increase the dose to 0.8 mg/day. Two months later, OCT RNFL values again increased above baseline despite the acetazolamide therapy (Figure 4A). A second lumbar puncture revealed high opening pressures. However, because of the slow growth rate, declining percentiles, and episodes of hypoglycemia, rhGH was not stopped completely but was instead reduced to 0.4 mg/day with 250 mg acetazolamide. Optical coherence tomography RNFL values were then the same as those at baseline (Figure 4B). As the PE team was not satisfied with the growth rate, the dose was increased to 0.8 mg/day. Clinical examination showed mildly elevated optic nerve head with elevated RNFL values (Figure 4C). We decided to increase the acetazolamide dose to 500 mg without changing the dose of rhGH. At her next visit, the patient had slightly lower RNFL values, but they had not returned to baseline (Figure 4D). Therefore, we decided to further increase the acetazolamide dose to 750 mg. At the next visit, the PE team reported that the patient's growth had reached a normal rate but requested to further increase the dose. Subsequent visits showed the RNFL values returning to baseline with 750 mg acetazolamide; therefore, the rhGH dosage was increased to 0.9 mg/day (Figure 5). Fig. 3. A. OCT RNFL values with 0.5 mg/day rhGH. B. OCT RNFL values after decreasing the rhGH dose to 0.3 mg/dL. C. OCT RNFL values after increasing the rhGH dose to 0.7 mg/dL. D. OCT RNFL values after decreasing the rhGH dose to 0.4 mg/dL and starting 250 mg acetazolamide. Fig. 4. A. OCT RNFL values after rhGH was increased to 0.8 mg/dL with 250 mg acetazolamide. B. OCT RNFL values after rhGH was reduced to 0.4 mg/dL with 250 mg acetazolamide. C. OCT RNFL values after increasing the rhGH dose to 0.8 mg/dL. D. OCT RNFL values after increasing acetazolamide to 500 mg. Fig. 5. OCT RNFL values after increasing acetazolamide to 750 mg. Methods and Results The rhGH dose values were compared against the RNFL thickness values, and the Pearson's product moment correlation coefficient for sample statistic (r) and coefficient of determination (r2) were calculated to assess the relationship using Microsoft Excel. (Microsoft, Redmond, WA) We performed three different analyses to explore the relationship between the RNFL and rhGH dosage in this single-patient case study. In the first analysis, we looked at the relationship between all RNFL values and rhGH dosage. The correlation between average RNFL values and its relationship with rhGH dosage were relatively weak (r = 0.47 and r2 = 0.22) (Figure 6A). Calculating each quadrant separately also showed a relatively low correlation (Figure 6, B–E). In the second analysis, we removed the RNFL values under acetazolamide treatment and only compared nontreated RNFL values against the rhGH dosage. This time, the correlation for both the average values and quadrants separately was much higher (r = 0.64, r2 = 0.40) (Figure 7). For the third analysis, we only calculated acetazolamide's effect on RNFL under 0.8 mg/mL rhGH, which revealed a high negative correlation. Higher doses of the drug correlated strongly with lower (i.e., thinner) RNFL values (r = 0.77, r2 = 0.59) (Figure 8). Fig. 6. A. Average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values. Despite an overall positive correlation between rhGH dose and RNFL thickness was observed, it was not very strong (r = 0.47, r2 = 0.22). B–E. Superior, inferior, nasal, and temporal quadrant average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values. When the correlation was recalculated for each quadrant separately, the overall trend of positive but weak correlation between rhGH dose and RNFL thickness persisted. Fig. 7. Acetazolamide exclusion subgroup analysis. A. Average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values after RNFL values under acetazolamide treatment were excluded. Removing RNFL values under acetazolamide treated further strengthened the positive correlation between rhGH dose and RNFL thickness (r = 0.64, r2 = 0.40). B–E. Superior, inferior, nasal and temporal quadrant average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values after RNFL values under acetazolamide treatment were excluded. When the correlation was recalculated for each quadrant separately, the strengthened positive trend persisted with exception of the temporal quadrant. Fig. 8. Average RNFL values at 0.8 mg/dL with different acetazolamide doses, correlation graph with coefficient of correlation and determination values. Higher doses of acetazolamide resulted lower (i.e., thinner) RNFL values, indicating a very strong negative correlation (r = 0.77, r2 = 0.59). Discussion In recent years, OCT has started to be used in neuro-ophthalmology practices, especially for the follow-up of ODE.2 In a multicenter trial by the NORDIC Idiopathic Intracranial Hypertension Study Group, the OCT substudy committee showed that idiopathic intracranial hypertension therapy with acetazolamide and weight loss effectively improved RNFL thickness values.3 In part II of the study, the OCT measurements were shown to strongly correlate with the Frisen grading of papilledema.4 Although rhGH therapy is relatively safe and is associated with only few adverse effects,5 it is essential to perform ophthalmic examination to detect PTCS and its detrimental effects on the eye.5 In children, PTCS can be entirely asymptomatic and in early stages may present only with subtle papilledema.6 When diagnosed at relatively later stages, studies have shown permanent loss of vision and visual field defects in up to 10% and 17% of children, respectively.6 The pathogenesis of rhGH-induced PTCS remains relatively unknown. It is postulated to alter cerebrospinal fluid drainage across arachnoid villi.6 It is also theorized that rhGH might be increasing cerebrospinal fluid production by the way of IGF-1 receptors.7 Ophthalmoscopic examination of the fundus has been the gold standard for optic nerve evaluations.3 However, this technique is limited because assessment is subjective and based on the training and experience of the physician, especially for subtle changes. A noninvasive adjunct evaluation tool, such as OCT, might therefore be valuable in the evaluation and follow-up of patients, especially children. To the best of our knowledge, this is the first report in the literature that correlates OCT RNFL values with rhGH dose. As mentioned previously, there is a substantial amount of information in the literature showing the relationship between rhGH therapy and PTCS.5,6 The literature also shows that OCT is reliable for the follow-up of PTCS and related papilledema.2–4 Our case report combines these two pieces of information from the literature. We have found that the average RNFL values correlated well with rhGH, especially when acetazolamide's effect was not included in the calculations. When we studied each quadrant separately, all had a good correlation of RNFL values with rhGH dose. The correlation was higher in the superior and inferior quadrants compared with the nasal and temporal quadrants. This finding was consistent in both the general and acetazolamide exclusion groups. As reported in previous studies, we also found that higher doses of acetazolamide correlated with lower (thinner) RNFL values.3 Optical coherence tomography was used to measure RNFL thickness every 2 months or at each rhGH dose adjustment. In the case of PTCS after rhGH therapy, rhGH is usually stopped all together until resolution and restarted at a lower dose.5 By contrast, we were able to titrate the dose precisely to prevent a flare-up of PTCS but without stopping it totally. The OCT was easy to use and accurately demonstrated even minor changes in the RNFL thickness. In our case report, we observed a correlation between rhGH dose and RNFL thickness measured by OCT, especially when acetazolamide was excluded because of its confounding effect. If it can be verified in larger prospective and randomized trials, this finding could be an early sign of rhGH-induced PTCS. Early detection and careful management of patients who receive rhGH might be a preventative measure. The study was presented as a poster presentation in Research ShowCASE meeting at Case Western Reserve University, Cleveland, OH, 2016. None of the authors has any financial/conflicting interests to disclose.

HYDROCORTISONE, LEVOTHYROXINE, SOMATROPIN

DrugsGivenReaction

CC BY-NC-ND

31568222

2021-11-01

What was the dosage of drug 'HYDROCORTISONE'?

CASE REPORT OF THE ROLE OF OPTICAL COHERENCE TOMOGRAPHY IN RECOMBINANT GROWTH HORMONE THERAPY. OBJECTIVE To report the correlation between recombinant growth hormone (rhGH) dosage and retinal nerve fiber layer (RNFL) thickness values measured by optical coherence tomography in a case of pseudotumor cerebri syndrome (PTCS) after rhGH. METHODS An 11-year-old girl was receiving rhGH for panhypopituitarism. The patient developed PTCS, and her rhGH dose was adjusted using optical coherence tomography RNFL thickness measurements. The linear correlation coefficient (r) and coefficient of determination (r2) were calculated to assess the relationship between RNFL thickness and rhGH dose. RESULTS As the rhGH dosage was increased, the RNFL thickness values also increased, especially when acetazolamide was excluded because of its confounding effect. (r = 0.64) In separate subgroup analysis, a higher acetazolamide dosage strongly correlated with reduced RNFL thickness (r = 0.77). CONCLUSIONS Although PTCS is a rare complication after rhGH therapy, its detrimental effects cannot be ignored. In our case report, we used optical coherence tomography RNFL values in addition to clinical findings to carefully titrate the rhGH dosage to prevent a flare-up of PTCS. Despite the obvious need for larger studies, our case report shows the value of RNFL thickness measured by optical coherence tomography and the valuable additional data it provides to refine rhGH therapy as an adjunct noninvasive method in PTCS. pmcPseudotumor cerebri syndrome (PTCS) after recombinant human growth hormone (rhGH) therapy is a rare but an important complication.1 Cessation of the therapy is often adequate for reversal of PTCS; however, this is complicated by the growth requirements of the patient.1 To the best of our knowledge, we report the first case of the prevention of flare-up of PTCS by titrating the rhGH dose based on retinal nerve fiber layer (RNFL) thickness values obtained by optical coherence tomography (OCT). Case Report An 11-year-old girl with a history of panhypopituitarism had been followed-up by the pediatric endocrinology (PE) team at University Hospitals Cleveland Medical Center since birth. She was referred to pediatric ophthalmology due to intermittent occipital headaches. A full ophthalmic examination was unremarkable except for the dilated fundus examination, which revealed +2 optic disc edema (ODE) in both eyes (Figure 1). The results of OCT of the optic discs revealed increased RNFL thickness in both eyes (Figure 2). Fig. 1. Fundus photography of the patient at the first visit revealing bilateral ODEs. Fig. 2. Optical coherence tomography RNFL changes. On November 13, 2013, the patient was receiving a 0.8 mg/kg rhGH dose, and her OCT RNFL values were greatly increased. Fifteen days later, upon stopping rhGH therapy totally, the OCT RNFL values started decreasing, and after 2 months, the values returned to normal. Magnetic resonance imaging showed pituitary hypoplasia in 2007, and treatment with hydrocortisone, levothyroxine, and somatropin (rhGH) was started. Other examinations were otherwise normal. The patient was born at 39 weeks of gestation with a birth weight of 3,517 g. No apparent reason was found for her hypopituitarism. Recombinant human growth hormone was stopped immediately, and magnetic resonance imaging and lumbar puncture were ordered to rule out PTCS. Visual acuity for both eyes was still 20/15, and ODE improved in the next follow-up after 2 weeks (Figure 2). Magnetic resonance imaging was negative, and lumbar puncture revealed high opening pressures, leading to confirmation of PTCS. Recombinant human growth hormone was started again, albeit on a lower dose at 0.3 mg/day reduced from 0.8 mg/day, and no ODE was noted in the next 2 months (Figure 2). However, the patient's growth rate halted because of inefficient rhGH. After communication among the medical providers, the rhGH dose was increased from 0.3 mg/day to 0.5 mg/day. Three-month follow-up revealed mild ODE, which was confirmed with increased RNFL OCT values (Figure 3A). After consultations with the PE team, the rhGH dose was reduced to 0.3 mg/day again. Dilated fundus examination revealed improved ODE, which was confirmed with RNFL OCT values (Figure 3B). To increase the growth rate further, the PE team decided to increase the rhGH dose to 0.8 mg/day incrementally. Subsequent visits revealed normal optic discs and stable OCT values up to 0.7 mg/day. However, after 3 months on 0.7 mg/day, OCT RNFL values increased, and the dose was adjusted to 0.4 mg/day (Figure 3C). In addition to decreasing the dose of rhGH, 250 mg/day acetazolamide was started. At the 2-month follow-up, OCT RNFL values returned to baseline (Figure 3D). The PE team again began to incrementally increase the dose to 0.8 mg/day. Two months later, OCT RNFL values again increased above baseline despite the acetazolamide therapy (Figure 4A). A second lumbar puncture revealed high opening pressures. However, because of the slow growth rate, declining percentiles, and episodes of hypoglycemia, rhGH was not stopped completely but was instead reduced to 0.4 mg/day with 250 mg acetazolamide. Optical coherence tomography RNFL values were then the same as those at baseline (Figure 4B). As the PE team was not satisfied with the growth rate, the dose was increased to 0.8 mg/day. Clinical examination showed mildly elevated optic nerve head with elevated RNFL values (Figure 4C). We decided to increase the acetazolamide dose to 500 mg without changing the dose of rhGH. At her next visit, the patient had slightly lower RNFL values, but they had not returned to baseline (Figure 4D). Therefore, we decided to further increase the acetazolamide dose to 750 mg. At the next visit, the PE team reported that the patient's growth had reached a normal rate but requested to further increase the dose. Subsequent visits showed the RNFL values returning to baseline with 750 mg acetazolamide; therefore, the rhGH dosage was increased to 0.9 mg/day (Figure 5). Fig. 3. A. OCT RNFL values with 0.5 mg/day rhGH. B. OCT RNFL values after decreasing the rhGH dose to 0.3 mg/dL. C. OCT RNFL values after increasing the rhGH dose to 0.7 mg/dL. D. OCT RNFL values after decreasing the rhGH dose to 0.4 mg/dL and starting 250 mg acetazolamide. Fig. 4. A. OCT RNFL values after rhGH was increased to 0.8 mg/dL with 250 mg acetazolamide. B. OCT RNFL values after rhGH was reduced to 0.4 mg/dL with 250 mg acetazolamide. C. OCT RNFL values after increasing the rhGH dose to 0.8 mg/dL. D. OCT RNFL values after increasing acetazolamide to 500 mg. Fig. 5. OCT RNFL values after increasing acetazolamide to 750 mg. Methods and Results The rhGH dose values were compared against the RNFL thickness values, and the Pearson's product moment correlation coefficient for sample statistic (r) and coefficient of determination (r2) were calculated to assess the relationship using Microsoft Excel. (Microsoft, Redmond, WA) We performed three different analyses to explore the relationship between the RNFL and rhGH dosage in this single-patient case study. In the first analysis, we looked at the relationship between all RNFL values and rhGH dosage. The correlation between average RNFL values and its relationship with rhGH dosage were relatively weak (r = 0.47 and r2 = 0.22) (Figure 6A). Calculating each quadrant separately also showed a relatively low correlation (Figure 6, B–E). In the second analysis, we removed the RNFL values under acetazolamide treatment and only compared nontreated RNFL values against the rhGH dosage. This time, the correlation for both the average values and quadrants separately was much higher (r = 0.64, r2 = 0.40) (Figure 7). For the third analysis, we only calculated acetazolamide's effect on RNFL under 0.8 mg/mL rhGH, which revealed a high negative correlation. Higher doses of the drug correlated strongly with lower (i.e., thinner) RNFL values (r = 0.77, r2 = 0.59) (Figure 8). Fig. 6. A. Average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values. Despite an overall positive correlation between rhGH dose and RNFL thickness was observed, it was not very strong (r = 0.47, r2 = 0.22). B–E. Superior, inferior, nasal, and temporal quadrant average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values. When the correlation was recalculated for each quadrant separately, the overall trend of positive but weak correlation between rhGH dose and RNFL thickness persisted. Fig. 7. Acetazolamide exclusion subgroup analysis. A. Average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values after RNFL values under acetazolamide treatment were excluded. Removing RNFL values under acetazolamide treated further strengthened the positive correlation between rhGH dose and RNFL thickness (r = 0.64, r2 = 0.40). B–E. Superior, inferior, nasal and temporal quadrant average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values after RNFL values under acetazolamide treatment were excluded. When the correlation was recalculated for each quadrant separately, the strengthened positive trend persisted with exception of the temporal quadrant. Fig. 8. Average RNFL values at 0.8 mg/dL with different acetazolamide doses, correlation graph with coefficient of correlation and determination values. Higher doses of acetazolamide resulted lower (i.e., thinner) RNFL values, indicating a very strong negative correlation (r = 0.77, r2 = 0.59). Discussion In recent years, OCT has started to be used in neuro-ophthalmology practices, especially for the follow-up of ODE.2 In a multicenter trial by the NORDIC Idiopathic Intracranial Hypertension Study Group, the OCT substudy committee showed that idiopathic intracranial hypertension therapy with acetazolamide and weight loss effectively improved RNFL thickness values.3 In part II of the study, the OCT measurements were shown to strongly correlate with the Frisen grading of papilledema.4 Although rhGH therapy is relatively safe and is associated with only few adverse effects,5 it is essential to perform ophthalmic examination to detect PTCS and its detrimental effects on the eye.5 In children, PTCS can be entirely asymptomatic and in early stages may present only with subtle papilledema.6 When diagnosed at relatively later stages, studies have shown permanent loss of vision and visual field defects in up to 10% and 17% of children, respectively.6 The pathogenesis of rhGH-induced PTCS remains relatively unknown. It is postulated to alter cerebrospinal fluid drainage across arachnoid villi.6 It is also theorized that rhGH might be increasing cerebrospinal fluid production by the way of IGF-1 receptors.7 Ophthalmoscopic examination of the fundus has been the gold standard for optic nerve evaluations.3 However, this technique is limited because assessment is subjective and based on the training and experience of the physician, especially for subtle changes. A noninvasive adjunct evaluation tool, such as OCT, might therefore be valuable in the evaluation and follow-up of patients, especially children. To the best of our knowledge, this is the first report in the literature that correlates OCT RNFL values with rhGH dose. As mentioned previously, there is a substantial amount of information in the literature showing the relationship between rhGH therapy and PTCS.5,6 The literature also shows that OCT is reliable for the follow-up of PTCS and related papilledema.2–4 Our case report combines these two pieces of information from the literature. We have found that the average RNFL values correlated well with rhGH, especially when acetazolamide's effect was not included in the calculations. When we studied each quadrant separately, all had a good correlation of RNFL values with rhGH dose. The correlation was higher in the superior and inferior quadrants compared with the nasal and temporal quadrants. This finding was consistent in both the general and acetazolamide exclusion groups. As reported in previous studies, we also found that higher doses of acetazolamide correlated with lower (thinner) RNFL values.3 Optical coherence tomography was used to measure RNFL thickness every 2 months or at each rhGH dose adjustment. In the case of PTCS after rhGH therapy, rhGH is usually stopped all together until resolution and restarted at a lower dose.5 By contrast, we were able to titrate the dose precisely to prevent a flare-up of PTCS but without stopping it totally. The OCT was easy to use and accurately demonstrated even minor changes in the RNFL thickness. In our case report, we observed a correlation between rhGH dose and RNFL thickness measured by OCT, especially when acetazolamide was excluded because of its confounding effect. If it can be verified in larger prospective and randomized trials, this finding could be an early sign of rhGH-induced PTCS. Early detection and careful management of patients who receive rhGH might be a preventative measure. The study was presented as a poster presentation in Research ShowCASE meeting at Case Western Reserve University, Cleveland, OH, 2016. None of the authors has any financial/conflicting interests to disclose.

UNK UNK, UNKNOWN

DrugDosageText

CC BY-NC-ND

31568222

2021-11-01

What was the dosage of drug 'LEVOTHYROXINE'?

CASE REPORT OF THE ROLE OF OPTICAL COHERENCE TOMOGRAPHY IN RECOMBINANT GROWTH HORMONE THERAPY. OBJECTIVE To report the correlation between recombinant growth hormone (rhGH) dosage and retinal nerve fiber layer (RNFL) thickness values measured by optical coherence tomography in a case of pseudotumor cerebri syndrome (PTCS) after rhGH. METHODS An 11-year-old girl was receiving rhGH for panhypopituitarism. The patient developed PTCS, and her rhGH dose was adjusted using optical coherence tomography RNFL thickness measurements. The linear correlation coefficient (r) and coefficient of determination (r2) were calculated to assess the relationship between RNFL thickness and rhGH dose. RESULTS As the rhGH dosage was increased, the RNFL thickness values also increased, especially when acetazolamide was excluded because of its confounding effect. (r = 0.64) In separate subgroup analysis, a higher acetazolamide dosage strongly correlated with reduced RNFL thickness (r = 0.77). CONCLUSIONS Although PTCS is a rare complication after rhGH therapy, its detrimental effects cannot be ignored. In our case report, we used optical coherence tomography RNFL values in addition to clinical findings to carefully titrate the rhGH dosage to prevent a flare-up of PTCS. Despite the obvious need for larger studies, our case report shows the value of RNFL thickness measured by optical coherence tomography and the valuable additional data it provides to refine rhGH therapy as an adjunct noninvasive method in PTCS. pmcPseudotumor cerebri syndrome (PTCS) after recombinant human growth hormone (rhGH) therapy is a rare but an important complication.1 Cessation of the therapy is often adequate for reversal of PTCS; however, this is complicated by the growth requirements of the patient.1 To the best of our knowledge, we report the first case of the prevention of flare-up of PTCS by titrating the rhGH dose based on retinal nerve fiber layer (RNFL) thickness values obtained by optical coherence tomography (OCT). Case Report An 11-year-old girl with a history of panhypopituitarism had been followed-up by the pediatric endocrinology (PE) team at University Hospitals Cleveland Medical Center since birth. She was referred to pediatric ophthalmology due to intermittent occipital headaches. A full ophthalmic examination was unremarkable except for the dilated fundus examination, which revealed +2 optic disc edema (ODE) in both eyes (Figure 1). The results of OCT of the optic discs revealed increased RNFL thickness in both eyes (Figure 2). Fig. 1. Fundus photography of the patient at the first visit revealing bilateral ODEs. Fig. 2. Optical coherence tomography RNFL changes. On November 13, 2013, the patient was receiving a 0.8 mg/kg rhGH dose, and her OCT RNFL values were greatly increased. Fifteen days later, upon stopping rhGH therapy totally, the OCT RNFL values started decreasing, and after 2 months, the values returned to normal. Magnetic resonance imaging showed pituitary hypoplasia in 2007, and treatment with hydrocortisone, levothyroxine, and somatropin (rhGH) was started. Other examinations were otherwise normal. The patient was born at 39 weeks of gestation with a birth weight of 3,517 g. No apparent reason was found for her hypopituitarism. Recombinant human growth hormone was stopped immediately, and magnetic resonance imaging and lumbar puncture were ordered to rule out PTCS. Visual acuity for both eyes was still 20/15, and ODE improved in the next follow-up after 2 weeks (Figure 2). Magnetic resonance imaging was negative, and lumbar puncture revealed high opening pressures, leading to confirmation of PTCS. Recombinant human growth hormone was started again, albeit on a lower dose at 0.3 mg/day reduced from 0.8 mg/day, and no ODE was noted in the next 2 months (Figure 2). However, the patient's growth rate halted because of inefficient rhGH. After communication among the medical providers, the rhGH dose was increased from 0.3 mg/day to 0.5 mg/day. Three-month follow-up revealed mild ODE, which was confirmed with increased RNFL OCT values (Figure 3A). After consultations with the PE team, the rhGH dose was reduced to 0.3 mg/day again. Dilated fundus examination revealed improved ODE, which was confirmed with RNFL OCT values (Figure 3B). To increase the growth rate further, the PE team decided to increase the rhGH dose to 0.8 mg/day incrementally. Subsequent visits revealed normal optic discs and stable OCT values up to 0.7 mg/day. However, after 3 months on 0.7 mg/day, OCT RNFL values increased, and the dose was adjusted to 0.4 mg/day (Figure 3C). In addition to decreasing the dose of rhGH, 250 mg/day acetazolamide was started. At the 2-month follow-up, OCT RNFL values returned to baseline (Figure 3D). The PE team again began to incrementally increase the dose to 0.8 mg/day. Two months later, OCT RNFL values again increased above baseline despite the acetazolamide therapy (Figure 4A). A second lumbar puncture revealed high opening pressures. However, because of the slow growth rate, declining percentiles, and episodes of hypoglycemia, rhGH was not stopped completely but was instead reduced to 0.4 mg/day with 250 mg acetazolamide. Optical coherence tomography RNFL values were then the same as those at baseline (Figure 4B). As the PE team was not satisfied with the growth rate, the dose was increased to 0.8 mg/day. Clinical examination showed mildly elevated optic nerve head with elevated RNFL values (Figure 4C). We decided to increase the acetazolamide dose to 500 mg without changing the dose of rhGH. At her next visit, the patient had slightly lower RNFL values, but they had not returned to baseline (Figure 4D). Therefore, we decided to further increase the acetazolamide dose to 750 mg. At the next visit, the PE team reported that the patient's growth had reached a normal rate but requested to further increase the dose. Subsequent visits showed the RNFL values returning to baseline with 750 mg acetazolamide; therefore, the rhGH dosage was increased to 0.9 mg/day (Figure 5). Fig. 3. A. OCT RNFL values with 0.5 mg/day rhGH. B. OCT RNFL values after decreasing the rhGH dose to 0.3 mg/dL. C. OCT RNFL values after increasing the rhGH dose to 0.7 mg/dL. D. OCT RNFL values after decreasing the rhGH dose to 0.4 mg/dL and starting 250 mg acetazolamide. Fig. 4. A. OCT RNFL values after rhGH was increased to 0.8 mg/dL with 250 mg acetazolamide. B. OCT RNFL values after rhGH was reduced to 0.4 mg/dL with 250 mg acetazolamide. C. OCT RNFL values after increasing the rhGH dose to 0.8 mg/dL. D. OCT RNFL values after increasing acetazolamide to 500 mg. Fig. 5. OCT RNFL values after increasing acetazolamide to 750 mg. Methods and Results The rhGH dose values were compared against the RNFL thickness values, and the Pearson's product moment correlation coefficient for sample statistic (r) and coefficient of determination (r2) were calculated to assess the relationship using Microsoft Excel. (Microsoft, Redmond, WA) We performed three different analyses to explore the relationship between the RNFL and rhGH dosage in this single-patient case study. In the first analysis, we looked at the relationship between all RNFL values and rhGH dosage. The correlation between average RNFL values and its relationship with rhGH dosage were relatively weak (r = 0.47 and r2 = 0.22) (Figure 6A). Calculating each quadrant separately also showed a relatively low correlation (Figure 6, B–E). In the second analysis, we removed the RNFL values under acetazolamide treatment and only compared nontreated RNFL values against the rhGH dosage. This time, the correlation for both the average values and quadrants separately was much higher (r = 0.64, r2 = 0.40) (Figure 7). For the third analysis, we only calculated acetazolamide's effect on RNFL under 0.8 mg/mL rhGH, which revealed a high negative correlation. Higher doses of the drug correlated strongly with lower (i.e., thinner) RNFL values (r = 0.77, r2 = 0.59) (Figure 8). Fig. 6. A. Average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values. Despite an overall positive correlation between rhGH dose and RNFL thickness was observed, it was not very strong (r = 0.47, r2 = 0.22). B–E. Superior, inferior, nasal, and temporal quadrant average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values. When the correlation was recalculated for each quadrant separately, the overall trend of positive but weak correlation between rhGH dose and RNFL thickness persisted. Fig. 7. Acetazolamide exclusion subgroup analysis. A. Average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values after RNFL values under acetazolamide treatment were excluded. Removing RNFL values under acetazolamide treated further strengthened the positive correlation between rhGH dose and RNFL thickness (r = 0.64, r2 = 0.40). B–E. Superior, inferior, nasal and temporal quadrant average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values after RNFL values under acetazolamide treatment were excluded. When the correlation was recalculated for each quadrant separately, the strengthened positive trend persisted with exception of the temporal quadrant. Fig. 8. Average RNFL values at 0.8 mg/dL with different acetazolamide doses, correlation graph with coefficient of correlation and determination values. Higher doses of acetazolamide resulted lower (i.e., thinner) RNFL values, indicating a very strong negative correlation (r = 0.77, r2 = 0.59). Discussion In recent years, OCT has started to be used in neuro-ophthalmology practices, especially for the follow-up of ODE.2 In a multicenter trial by the NORDIC Idiopathic Intracranial Hypertension Study Group, the OCT substudy committee showed that idiopathic intracranial hypertension therapy with acetazolamide and weight loss effectively improved RNFL thickness values.3 In part II of the study, the OCT measurements were shown to strongly correlate with the Frisen grading of papilledema.4 Although rhGH therapy is relatively safe and is associated with only few adverse effects,5 it is essential to perform ophthalmic examination to detect PTCS and its detrimental effects on the eye.5 In children, PTCS can be entirely asymptomatic and in early stages may present only with subtle papilledema.6 When diagnosed at relatively later stages, studies have shown permanent loss of vision and visual field defects in up to 10% and 17% of children, respectively.6 The pathogenesis of rhGH-induced PTCS remains relatively unknown. It is postulated to alter cerebrospinal fluid drainage across arachnoid villi.6 It is also theorized that rhGH might be increasing cerebrospinal fluid production by the way of IGF-1 receptors.7 Ophthalmoscopic examination of the fundus has been the gold standard for optic nerve evaluations.3 However, this technique is limited because assessment is subjective and based on the training and experience of the physician, especially for subtle changes. A noninvasive adjunct evaluation tool, such as OCT, might therefore be valuable in the evaluation and follow-up of patients, especially children. To the best of our knowledge, this is the first report in the literature that correlates OCT RNFL values with rhGH dose. As mentioned previously, there is a substantial amount of information in the literature showing the relationship between rhGH therapy and PTCS.5,6 The literature also shows that OCT is reliable for the follow-up of PTCS and related papilledema.2–4 Our case report combines these two pieces of information from the literature. We have found that the average RNFL values correlated well with rhGH, especially when acetazolamide's effect was not included in the calculations. When we studied each quadrant separately, all had a good correlation of RNFL values with rhGH dose. The correlation was higher in the superior and inferior quadrants compared with the nasal and temporal quadrants. This finding was consistent in both the general and acetazolamide exclusion groups. As reported in previous studies, we also found that higher doses of acetazolamide correlated with lower (thinner) RNFL values.3 Optical coherence tomography was used to measure RNFL thickness every 2 months or at each rhGH dose adjustment. In the case of PTCS after rhGH therapy, rhGH is usually stopped all together until resolution and restarted at a lower dose.5 By contrast, we were able to titrate the dose precisely to prevent a flare-up of PTCS but without stopping it totally. The OCT was easy to use and accurately demonstrated even minor changes in the RNFL thickness. In our case report, we observed a correlation between rhGH dose and RNFL thickness measured by OCT, especially when acetazolamide was excluded because of its confounding effect. If it can be verified in larger prospective and randomized trials, this finding could be an early sign of rhGH-induced PTCS. Early detection and careful management of patients who receive rhGH might be a preventative measure. The study was presented as a poster presentation in Research ShowCASE meeting at Case Western Reserve University, Cleveland, OH, 2016. None of the authors has any financial/conflicting interests to disclose.

UNK UNK, UNKNOWN

DrugDosageText

CC BY-NC-ND

31568222

2021-11-01

What was the outcome of reaction 'Idiopathic intracranial hypertension'?

CASE REPORT OF THE ROLE OF OPTICAL COHERENCE TOMOGRAPHY IN RECOMBINANT GROWTH HORMONE THERAPY. OBJECTIVE To report the correlation between recombinant growth hormone (rhGH) dosage and retinal nerve fiber layer (RNFL) thickness values measured by optical coherence tomography in a case of pseudotumor cerebri syndrome (PTCS) after rhGH. METHODS An 11-year-old girl was receiving rhGH for panhypopituitarism. The patient developed PTCS, and her rhGH dose was adjusted using optical coherence tomography RNFL thickness measurements. The linear correlation coefficient (r) and coefficient of determination (r2) were calculated to assess the relationship between RNFL thickness and rhGH dose. RESULTS As the rhGH dosage was increased, the RNFL thickness values also increased, especially when acetazolamide was excluded because of its confounding effect. (r = 0.64) In separate subgroup analysis, a higher acetazolamide dosage strongly correlated with reduced RNFL thickness (r = 0.77). CONCLUSIONS Although PTCS is a rare complication after rhGH therapy, its detrimental effects cannot be ignored. In our case report, we used optical coherence tomography RNFL values in addition to clinical findings to carefully titrate the rhGH dosage to prevent a flare-up of PTCS. Despite the obvious need for larger studies, our case report shows the value of RNFL thickness measured by optical coherence tomography and the valuable additional data it provides to refine rhGH therapy as an adjunct noninvasive method in PTCS. pmcPseudotumor cerebri syndrome (PTCS) after recombinant human growth hormone (rhGH) therapy is a rare but an important complication.1 Cessation of the therapy is often adequate for reversal of PTCS; however, this is complicated by the growth requirements of the patient.1 To the best of our knowledge, we report the first case of the prevention of flare-up of PTCS by titrating the rhGH dose based on retinal nerve fiber layer (RNFL) thickness values obtained by optical coherence tomography (OCT). Case Report An 11-year-old girl with a history of panhypopituitarism had been followed-up by the pediatric endocrinology (PE) team at University Hospitals Cleveland Medical Center since birth. She was referred to pediatric ophthalmology due to intermittent occipital headaches. A full ophthalmic examination was unremarkable except for the dilated fundus examination, which revealed +2 optic disc edema (ODE) in both eyes (Figure 1). The results of OCT of the optic discs revealed increased RNFL thickness in both eyes (Figure 2). Fig. 1. Fundus photography of the patient at the first visit revealing bilateral ODEs. Fig. 2. Optical coherence tomography RNFL changes. On November 13, 2013, the patient was receiving a 0.8 mg/kg rhGH dose, and her OCT RNFL values were greatly increased. Fifteen days later, upon stopping rhGH therapy totally, the OCT RNFL values started decreasing, and after 2 months, the values returned to normal. Magnetic resonance imaging showed pituitary hypoplasia in 2007, and treatment with hydrocortisone, levothyroxine, and somatropin (rhGH) was started. Other examinations were otherwise normal. The patient was born at 39 weeks of gestation with a birth weight of 3,517 g. No apparent reason was found for her hypopituitarism. Recombinant human growth hormone was stopped immediately, and magnetic resonance imaging and lumbar puncture were ordered to rule out PTCS. Visual acuity for both eyes was still 20/15, and ODE improved in the next follow-up after 2 weeks (Figure 2). Magnetic resonance imaging was negative, and lumbar puncture revealed high opening pressures, leading to confirmation of PTCS. Recombinant human growth hormone was started again, albeit on a lower dose at 0.3 mg/day reduced from 0.8 mg/day, and no ODE was noted in the next 2 months (Figure 2). However, the patient's growth rate halted because of inefficient rhGH. After communication among the medical providers, the rhGH dose was increased from 0.3 mg/day to 0.5 mg/day. Three-month follow-up revealed mild ODE, which was confirmed with increased RNFL OCT values (Figure 3A). After consultations with the PE team, the rhGH dose was reduced to 0.3 mg/day again. Dilated fundus examination revealed improved ODE, which was confirmed with RNFL OCT values (Figure 3B). To increase the growth rate further, the PE team decided to increase the rhGH dose to 0.8 mg/day incrementally. Subsequent visits revealed normal optic discs and stable OCT values up to 0.7 mg/day. However, after 3 months on 0.7 mg/day, OCT RNFL values increased, and the dose was adjusted to 0.4 mg/day (Figure 3C). In addition to decreasing the dose of rhGH, 250 mg/day acetazolamide was started. At the 2-month follow-up, OCT RNFL values returned to baseline (Figure 3D). The PE team again began to incrementally increase the dose to 0.8 mg/day. Two months later, OCT RNFL values again increased above baseline despite the acetazolamide therapy (Figure 4A). A second lumbar puncture revealed high opening pressures. However, because of the slow growth rate, declining percentiles, and episodes of hypoglycemia, rhGH was not stopped completely but was instead reduced to 0.4 mg/day with 250 mg acetazolamide. Optical coherence tomography RNFL values were then the same as those at baseline (Figure 4B). As the PE team was not satisfied with the growth rate, the dose was increased to 0.8 mg/day. Clinical examination showed mildly elevated optic nerve head with elevated RNFL values (Figure 4C). We decided to increase the acetazolamide dose to 500 mg without changing the dose of rhGH. At her next visit, the patient had slightly lower RNFL values, but they had not returned to baseline (Figure 4D). Therefore, we decided to further increase the acetazolamide dose to 750 mg. At the next visit, the PE team reported that the patient's growth had reached a normal rate but requested to further increase the dose. Subsequent visits showed the RNFL values returning to baseline with 750 mg acetazolamide; therefore, the rhGH dosage was increased to 0.9 mg/day (Figure 5). Fig. 3. A. OCT RNFL values with 0.5 mg/day rhGH. B. OCT RNFL values after decreasing the rhGH dose to 0.3 mg/dL. C. OCT RNFL values after increasing the rhGH dose to 0.7 mg/dL. D. OCT RNFL values after decreasing the rhGH dose to 0.4 mg/dL and starting 250 mg acetazolamide. Fig. 4. A. OCT RNFL values after rhGH was increased to 0.8 mg/dL with 250 mg acetazolamide. B. OCT RNFL values after rhGH was reduced to 0.4 mg/dL with 250 mg acetazolamide. C. OCT RNFL values after increasing the rhGH dose to 0.8 mg/dL. D. OCT RNFL values after increasing acetazolamide to 500 mg. Fig. 5. OCT RNFL values after increasing acetazolamide to 750 mg. Methods and Results The rhGH dose values were compared against the RNFL thickness values, and the Pearson's product moment correlation coefficient for sample statistic (r) and coefficient of determination (r2) were calculated to assess the relationship using Microsoft Excel. (Microsoft, Redmond, WA) We performed three different analyses to explore the relationship between the RNFL and rhGH dosage in this single-patient case study. In the first analysis, we looked at the relationship between all RNFL values and rhGH dosage. The correlation between average RNFL values and its relationship with rhGH dosage were relatively weak (r = 0.47 and r2 = 0.22) (Figure 6A). Calculating each quadrant separately also showed a relatively low correlation (Figure 6, B–E). In the second analysis, we removed the RNFL values under acetazolamide treatment and only compared nontreated RNFL values against the rhGH dosage. This time, the correlation for both the average values and quadrants separately was much higher (r = 0.64, r2 = 0.40) (Figure 7). For the third analysis, we only calculated acetazolamide's effect on RNFL under 0.8 mg/mL rhGH, which revealed a high negative correlation. Higher doses of the drug correlated strongly with lower (i.e., thinner) RNFL values (r = 0.77, r2 = 0.59) (Figure 8). Fig. 6. A. Average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values. Despite an overall positive correlation between rhGH dose and RNFL thickness was observed, it was not very strong (r = 0.47, r2 = 0.22). B–E. Superior, inferior, nasal, and temporal quadrant average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values. When the correlation was recalculated for each quadrant separately, the overall trend of positive but weak correlation between rhGH dose and RNFL thickness persisted. Fig. 7. Acetazolamide exclusion subgroup analysis. A. Average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values after RNFL values under acetazolamide treatment were excluded. Removing RNFL values under acetazolamide treated further strengthened the positive correlation between rhGH dose and RNFL thickness (r = 0.64, r2 = 0.40). B–E. Superior, inferior, nasal and temporal quadrant average RNFL values at different rhGH dosages, correlation graph with coefficient of correlation and determination values after RNFL values under acetazolamide treatment were excluded. When the correlation was recalculated for each quadrant separately, the strengthened positive trend persisted with exception of the temporal quadrant. Fig. 8. Average RNFL values at 0.8 mg/dL with different acetazolamide doses, correlation graph with coefficient of correlation and determination values. Higher doses of acetazolamide resulted lower (i.e., thinner) RNFL values, indicating a very strong negative correlation (r = 0.77, r2 = 0.59). Discussion In recent years, OCT has started to be used in neuro-ophthalmology practices, especially for the follow-up of ODE.2 In a multicenter trial by the NORDIC Idiopathic Intracranial Hypertension Study Group, the OCT substudy committee showed that idiopathic intracranial hypertension therapy with acetazolamide and weight loss effectively improved RNFL thickness values.3 In part II of the study, the OCT measurements were shown to strongly correlate with the Frisen grading of papilledema.4 Although rhGH therapy is relatively safe and is associated with only few adverse effects,5 it is essential to perform ophthalmic examination to detect PTCS and its detrimental effects on the eye.5 In children, PTCS can be entirely asymptomatic and in early stages may present only with subtle papilledema.6 When diagnosed at relatively later stages, studies have shown permanent loss of vision and visual field defects in up to 10% and 17% of children, respectively.6 The pathogenesis of rhGH-induced PTCS remains relatively unknown. It is postulated to alter cerebrospinal fluid drainage across arachnoid villi.6 It is also theorized that rhGH might be increasing cerebrospinal fluid production by the way of IGF-1 receptors.7 Ophthalmoscopic examination of the fundus has been the gold standard for optic nerve evaluations.3 However, this technique is limited because assessment is subjective and based on the training and experience of the physician, especially for subtle changes. A noninvasive adjunct evaluation tool, such as OCT, might therefore be valuable in the evaluation and follow-up of patients, especially children. To the best of our knowledge, this is the first report in the literature that correlates OCT RNFL values with rhGH dose. As mentioned previously, there is a substantial amount of information in the literature showing the relationship between rhGH therapy and PTCS.5,6 The literature also shows that OCT is reliable for the follow-up of PTCS and related papilledema.2–4 Our case report combines these two pieces of information from the literature. We have found that the average RNFL values correlated well with rhGH, especially when acetazolamide's effect was not included in the calculations. When we studied each quadrant separately, all had a good correlation of RNFL values with rhGH dose. The correlation was higher in the superior and inferior quadrants compared with the nasal and temporal quadrants. This finding was consistent in both the general and acetazolamide exclusion groups. As reported in previous studies, we also found that higher doses of acetazolamide correlated with lower (thinner) RNFL values.3 Optical coherence tomography was used to measure RNFL thickness every 2 months or at each rhGH dose adjustment. In the case of PTCS after rhGH therapy, rhGH is usually stopped all together until resolution and restarted at a lower dose.5 By contrast, we were able to titrate the dose precisely to prevent a flare-up of PTCS but without stopping it totally. The OCT was easy to use and accurately demonstrated even minor changes in the RNFL thickness. In our case report, we observed a correlation between rhGH dose and RNFL thickness measured by OCT, especially when acetazolamide was excluded because of its confounding effect. If it can be verified in larger prospective and randomized trials, this finding could be an early sign of rhGH-induced PTCS. Early detection and careful management of patients who receive rhGH might be a preventative measure. The study was presented as a poster presentation in Research ShowCASE meeting at Case Western Reserve University, Cleveland, OH, 2016. None of the authors has any financial/conflicting interests to disclose.

Recovering

ReactionOutcome

CC BY-NC-ND

31568222

2021-11-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cough'.

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature. A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH. There are 3 distinct classes of histiocyte disorders: Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) (and other rarer class II disorders), and malignant histiocytoses.1 LCH is characterized by the proliferation of infiltrative Langerhans cells into skin or bone; multisystem disease can also involve the lungs, liver, spleen, bone marrow, and central nervous system. Although historically thought of as a benign, reactive process, BRAF-V600E mutations have been found in 25% to 70% of LCH patients, with MAP2K1 positivity in 46% of BRAF-negative cases, raising the possibility that LCH is a malignancy.2–4 Many believe LCH may represent a myeloid-lineage neoplasm driven by ERK signaling.5,6 The treatment for LCH depends on the extent of disease and ranges from local and/or topical therapies to systemic chemotherapy.5,7 HLH is a disease of systemic, dysregulated immune activation and inflammation.8 HLH can be familial or secondary to infections, autoimmune processes, or malignancies.1 Treatment is with systemic dexamethasone and etoposide per the HLH94 protocol, with some patients, especially those with familial and/or reactivated HLH, ultimately requiring hematopoietic stem cell transplant for a cure.9 Recent studies suggest that targeted therapies such as emapalumab may also play a role, especially in refractory cases.10 Table 1 reviews LCH and HLH in respect to presentation, diagnostic criteria, and treatments. Though they are regarded as separate disease states, they can occur together within the same patient. Favara et al11 reviewed 30 pathology files of patients with coexisting LCH and macrophage activation; 7 of these met full diagnostic criteria for HLH. We report the case of a 20-month-old patient with multisystem LCH who developed HLH during treatment and summarize the literature for other case reports of HLH in LCH. TABLE 1 Comparison of LCH and HLH8,12 LCH HLH Pathophysiology Derived from clonal CD1a+ dendritic cells Lesions contain inflammatory infiltrates including high levels of T-cell regulatory molecules Defects in target cell killing by cytotoxic T cells Immune dysregulation with excessive proinflammatory cytokine production and macrophage response Uncontrolled systemic inflammation Can be primary or secondary to an infection, malignancy, autoimmune condition Molecular findings 38%-57% possess BRAF-V600E mutation Perforin MUNC 13-4, MUNC 18-2 Syntaxin 11 LYST, CHS1, Rab27A, AP3B1 SH2D1A, XIAP, BIRC4, SAP Presenting signs/symptoms Bone pain, swelling, fractures Chest pain, cough, dyspnea Rash, seborrhea, otitis externa Polyuria, polydipsia Fatigue, weight loss, fevers, lymphadenopathy Sepsis-like presentation Fever Cytopenias Hepatitis Splenomegaly Ataxia, seizures, abnormal MRI in 50% Diagnostic criteria Tissue biopsy containing CD207+, CD1a+ dendritic cells Characteristic morphology of Langerhans cells Requires 5/8 diagnostic criteria:  Fever  Splenomegaly  Cytopenias in ≥2 cell lines  Hyperferritinemia >500 mg/mL  sIL2 >2400 U/mL  Hypertriglyceridemia/hypofibrinogenemia  Hemophagocytosis in tissue biopsy  Low or absent NK cell activity Treatment Local therapy for unifocal bony disease Prednisone, vinblastine Cladribine, cytarabine, clofarabine for refractory/recurrent disease BMT for marrow/refractory disease Decadron, etoposide±cyclosporine Alemtuzumab for refractory cases Anti-INF-gamma antibodies for refractory cases BMT indicates bone marrow transplant; HLH, hemophagocytic lymphohistiocytosis; IL2, soluble interleukin-2; INF, interferon; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; NK, natural killer. RESULTS: CASE DESCRIPTION A 20-month-old male individual presented to his pediatrician with 6 months of progressive limp and unilateral leg pain, leading to a refusal to bear weight. He also had chronic drainage from bilateral ears. A radiograph showed a lucent, expansile lesion of the child’s femur and biopsy was performed, showing s100+, CD1a+ LCH. Further evaluation using skeletal survey and positron emission tomography-computed tomography (PET/CT) revealed multiple bony lytic lesions of the skull, axial skeleton and extremities, a scaling diffuse rash of the scalp, and hypermetabolic cervical lymphadenopathy. He had no involvement of the lungs, liver, spleen, or bone marrow, and had normal magnetic resonance imaging appearance of his pituitary after passing a water deprivation test. His blood counts at diagnosis were normal other than a mild microcytic iron deficiency anemia. Liver function tests and ferritin were within normal limits. He began therapy with daily prednisone and weekly vinblastine as per the LCH-III protocol. After his initial 6 weeks of induction therapy, PET/CT showed improved but continued hypermetabolic bony lesions. He went on to the second phase of induction therapy with further improvement in lesions and then began continuation with pulses of prednisone and vinblastine every 3 weeks. Within 3 months, a follow-up PET/CT showed worsening hypermetabolic bony lesions. He was treated with cladribine for 5 days every 28 days. Interval imaging after 2 cycles again showed worsening hypermetabolic bony lesions, worsening skin rash on scalp, continued bilateral ear drainage, leg pain, and intermittent fevers with cough and rhinorrhea. He was found to be respiratory syncytial virus (RSV) positive at that time. The child began monotherapy with clofarabine 25 mg/m2 daily for 5 days. Daily fevers continued for 2 weeks and he developed transaminitis with hypoalbuminemia and fluid overload. Blood cultures were negative, and he was empirically treated with broad-spectrum antibiotics secondary to neutropenia. CT scans done as part of fever evaluation revealed multiple new lytic skull lesions. Epstein-Barr virus (EBV) polymerase chain reaction was positive at 863 copies, which resolved without intervention over the next month. He met criteria for HLH with fevers, pancytopenia, ferritin >7500 ng/mL, triglycerides 526 mg/dL, soluble interleukin (IL)2 of 8191 U/mL, and hemophagocytosis in his bone marrow. Mutational analysis for PRF1, MUNC 13-4, XIAP and other common HLH-causing genes was normal. He thus began therapy via HLH94 with dexamethasone 10 mg/m2/d and etoposide. At the end of the standard 8-week treatment period, his HLH was felt to be well controlled with resolution of fevers and cytopenias, as well as normalization of liver function tests, triglycerides, soluble IL2, and improvement in ferritin. He went on to complete an additional 5 cycles of clofarabine 25 mg/m2 (6 total cycles), with end of therapy PET/CT showing no evidence of disease. He is now 3 years off therapy and doing very well. DISCUSSION Histiocytes or mononuclear phagocytes, the immune cells implicated in the pathogenesis of both LCH and HLH, serve many functions in the normal immune response. These include antigen presentation, activation of immune function through cytokine signaling, and phagocytosis.12 In both LCH and HLH, affected tissues express high levels of T-cell stimulatory molecules and secrete inflammatory cytokines such as IL-6, interferon, and tumor necrosis factor.8 Studies of LCH lesions suggest that chemokine receptors, including CCR6, maybe abnormally upregulated which contributes to tissue infiltration.13,14 Furthermore, the T cells found abundantly in LCH lesions show increased expression for genes involved in leukocyte chemotaxis, such as SPP1, IL8 and plasminogen activator, among others.15 A lesion with increased accumulation of histiocytes and T cells may thus be at increased risk of uncontrolled activation of these cells, resulting in hypercytokinemia and progressive organ dysfunction like that seen in HLH.12 HLH has a known association with malignancy, especially leukemias and lymphomas. If LCH indeed represents a malignant clonal process of early myeloid-lineage cells, this may also explain the potential association between the 2 entities. Alternatively, it could be that children with LCH who require multiagent or prolonged chemotherapy courses develop HLH secondary to immune dysregulation from the treatments rather than the underlying disease. HLH in LCH is thought to be a rare phenomenon and we aimed to summarize the available reports (Table 2). In our patient (patient 8), and in those reported throughout the literature, common findings included young age, multisystem LCH, history of systemic chemotherapy, and often concurrent infection. Our patient with multisystem LCH had received a prolonged course of multiagent chemotherapy secondary to his refractory disease and then developed RSV. He was also positive for EBV. Although we did not find any other reports of RSV-associated HLH, EBV is a well-known trigger of HLH, as are other viruses including influenza, parvovirus, etc. One evaluation of 182 pediatric patients with EBV who also met criteria for HLH, showed significant immune dysregulation. These patients had abnormal natural killer cell activity, as well as decreased CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells, resulting in increased T-cell activation and decreased inhibition. HLA-DR expression was elevated, indicating high levels of T-cell activation, and further downstream cytokines such as IL2 and interferon-gamma were also significantly elevated.16 Thus, viral infections including EBV can result in uncontrolled proliferation and activation of T cells, which may be further increased in patients with preexisting immune dysregulation from chemotherapy and/or the underlying disease state. We believe the combination of immunosuppression and infection may have led to HLH in our patients. Interestingly, like our patient, another reported patient with LCH also developed HLH while receiving clofarabine, a deoxyadenosine analog. Although this may be coincidence, clofarabine after multiple other immunosuppressive agents may have contributed to significant immune dysregulation and HLH in these patients. A recently published multicenter article reviewed 29 patients who met criteria for HLH and LCH. As in the patients reviewed in Table 2, about half of the patients met criteria for HLH at or around the diagnosis of LCH. Most had active LCH at diagnosis of HLH and were receiving treatments similar to those listed in Table 2. Overall, 31% had some kind of infection when HLH developed, including EBV. HLH was increased most in those with risk organ involvement, but also seen in young females without bony involvement. The combination of HLH and LCH was associated with a poor prognosis.17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment. TABLE 2 Reported Patients With LCH and HLH Patient 111 Patient 211 Patient 318 Patient 419 Patient 520 Patient 621 Patient 722 Patient 8 Age at HLH 10 mo 17 mo 3 y 2 y 10 mo 3 y 1 y 2 y Areas of LCH Colon, skin, ln, bone marrow Left mastoid Skin, bone, ln, bone marrow Skin, bone Skin, bone, ln, lungs Skin, bone, ln Skin, bone, ln, hepatomegaly Skin, bone Prior therapies None None 2CDA, ARAC×6 mo Prednisone, VBL, 6-MP, MTX×6 mo None Prednisone, VBL, 6-MP, MTX Prednisone, VCR, ARAC Prednisone, VBL, 2CDA Clinical course Presented with fever, diarrhea, HSM, LAD, and pulmonary disease Presented with fever, HSM, LAD, and bone lesion 2 cycles of clofarabine. Lesions improved but developed HLH Presented with HLH on 3 different occasions 2 to 6 mo apart in the setting of influenza, HSV, and adenovirus Presented with HLH and CMV. Diagnosed with HLH and LCH of skin 9 mo after therapy completed, the patient presented with HLH 3 wk into therapy for LCH, the patient developed HLH 7 d after beginning clofarabine therapy, developed HLH. EBV PCR+ HLH treatment Chemotherapy Prednisone, VBL, VCR Dexamethasone, etoposide Cessation of chemotherapy, antibiotics, antivirals, IVIG Prednisone, etoposide Dexamethasone, cyclo A Dexamethasone, etoposide, cyclo A, followed by flu, mel, ATG cytox, and UCBT Dexamethasone, etoposide Outcome Died 10 mo after diagnosis CR Continued disease progression, followed by death within 2 mo CR CR CR CR and engrafted Disease-free now 3 y off therapy ARAC indicates cytarabine; ATG, anti-thymocyte globulin; 2CDA, cladribine; CMV, cytomegalovirus; CR, complete remission; cytox, cyclophosphamide; EBV, Epstein-Barr virus; flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; IN, lymph node; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; LCH, Langerhans cell histiocytosis; mel, melphalan; MP, mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction; UCBT, unrelated cord blood transplant; VBL, vinblastine; VCR, vincristine. The authors declare no conflict of interest.

CLADRIBINE, CLOFARABINE, PREDNISOLONE, VINBLASTINE

DrugsGivenReaction

CC BY-NC-ND

31725543

2021-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'.

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature. A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH. There are 3 distinct classes of histiocyte disorders: Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) (and other rarer class II disorders), and malignant histiocytoses.1 LCH is characterized by the proliferation of infiltrative Langerhans cells into skin or bone; multisystem disease can also involve the lungs, liver, spleen, bone marrow, and central nervous system. Although historically thought of as a benign, reactive process, BRAF-V600E mutations have been found in 25% to 70% of LCH patients, with MAP2K1 positivity in 46% of BRAF-negative cases, raising the possibility that LCH is a malignancy.2–4 Many believe LCH may represent a myeloid-lineage neoplasm driven by ERK signaling.5,6 The treatment for LCH depends on the extent of disease and ranges from local and/or topical therapies to systemic chemotherapy.5,7 HLH is a disease of systemic, dysregulated immune activation and inflammation.8 HLH can be familial or secondary to infections, autoimmune processes, or malignancies.1 Treatment is with systemic dexamethasone and etoposide per the HLH94 protocol, with some patients, especially those with familial and/or reactivated HLH, ultimately requiring hematopoietic stem cell transplant for a cure.9 Recent studies suggest that targeted therapies such as emapalumab may also play a role, especially in refractory cases.10 Table 1 reviews LCH and HLH in respect to presentation, diagnostic criteria, and treatments. Though they are regarded as separate disease states, they can occur together within the same patient. Favara et al11 reviewed 30 pathology files of patients with coexisting LCH and macrophage activation; 7 of these met full diagnostic criteria for HLH. We report the case of a 20-month-old patient with multisystem LCH who developed HLH during treatment and summarize the literature for other case reports of HLH in LCH. TABLE 1 Comparison of LCH and HLH8,12 LCH HLH Pathophysiology Derived from clonal CD1a+ dendritic cells Lesions contain inflammatory infiltrates including high levels of T-cell regulatory molecules Defects in target cell killing by cytotoxic T cells Immune dysregulation with excessive proinflammatory cytokine production and macrophage response Uncontrolled systemic inflammation Can be primary or secondary to an infection, malignancy, autoimmune condition Molecular findings 38%-57% possess BRAF-V600E mutation Perforin MUNC 13-4, MUNC 18-2 Syntaxin 11 LYST, CHS1, Rab27A, AP3B1 SH2D1A, XIAP, BIRC4, SAP Presenting signs/symptoms Bone pain, swelling, fractures Chest pain, cough, dyspnea Rash, seborrhea, otitis externa Polyuria, polydipsia Fatigue, weight loss, fevers, lymphadenopathy Sepsis-like presentation Fever Cytopenias Hepatitis Splenomegaly Ataxia, seizures, abnormal MRI in 50% Diagnostic criteria Tissue biopsy containing CD207+, CD1a+ dendritic cells Characteristic morphology of Langerhans cells Requires 5/8 diagnostic criteria:  Fever  Splenomegaly  Cytopenias in ≥2 cell lines  Hyperferritinemia >500 mg/mL  sIL2 >2400 U/mL  Hypertriglyceridemia/hypofibrinogenemia  Hemophagocytosis in tissue biopsy  Low or absent NK cell activity Treatment Local therapy for unifocal bony disease Prednisone, vinblastine Cladribine, cytarabine, clofarabine for refractory/recurrent disease BMT for marrow/refractory disease Decadron, etoposide±cyclosporine Alemtuzumab for refractory cases Anti-INF-gamma antibodies for refractory cases BMT indicates bone marrow transplant; HLH, hemophagocytic lymphohistiocytosis; IL2, soluble interleukin-2; INF, interferon; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; NK, natural killer. RESULTS: CASE DESCRIPTION A 20-month-old male individual presented to his pediatrician with 6 months of progressive limp and unilateral leg pain, leading to a refusal to bear weight. He also had chronic drainage from bilateral ears. A radiograph showed a lucent, expansile lesion of the child’s femur and biopsy was performed, showing s100+, CD1a+ LCH. Further evaluation using skeletal survey and positron emission tomography-computed tomography (PET/CT) revealed multiple bony lytic lesions of the skull, axial skeleton and extremities, a scaling diffuse rash of the scalp, and hypermetabolic cervical lymphadenopathy. He had no involvement of the lungs, liver, spleen, or bone marrow, and had normal magnetic resonance imaging appearance of his pituitary after passing a water deprivation test. His blood counts at diagnosis were normal other than a mild microcytic iron deficiency anemia. Liver function tests and ferritin were within normal limits. He began therapy with daily prednisone and weekly vinblastine as per the LCH-III protocol. After his initial 6 weeks of induction therapy, PET/CT showed improved but continued hypermetabolic bony lesions. He went on to the second phase of induction therapy with further improvement in lesions and then began continuation with pulses of prednisone and vinblastine every 3 weeks. Within 3 months, a follow-up PET/CT showed worsening hypermetabolic bony lesions. He was treated with cladribine for 5 days every 28 days. Interval imaging after 2 cycles again showed worsening hypermetabolic bony lesions, worsening skin rash on scalp, continued bilateral ear drainage, leg pain, and intermittent fevers with cough and rhinorrhea. He was found to be respiratory syncytial virus (RSV) positive at that time. The child began monotherapy with clofarabine 25 mg/m2 daily for 5 days. Daily fevers continued for 2 weeks and he developed transaminitis with hypoalbuminemia and fluid overload. Blood cultures were negative, and he was empirically treated with broad-spectrum antibiotics secondary to neutropenia. CT scans done as part of fever evaluation revealed multiple new lytic skull lesions. Epstein-Barr virus (EBV) polymerase chain reaction was positive at 863 copies, which resolved without intervention over the next month. He met criteria for HLH with fevers, pancytopenia, ferritin >7500 ng/mL, triglycerides 526 mg/dL, soluble interleukin (IL)2 of 8191 U/mL, and hemophagocytosis in his bone marrow. Mutational analysis for PRF1, MUNC 13-4, XIAP and other common HLH-causing genes was normal. He thus began therapy via HLH94 with dexamethasone 10 mg/m2/d and etoposide. At the end of the standard 8-week treatment period, his HLH was felt to be well controlled with resolution of fevers and cytopenias, as well as normalization of liver function tests, triglycerides, soluble IL2, and improvement in ferritin. He went on to complete an additional 5 cycles of clofarabine 25 mg/m2 (6 total cycles), with end of therapy PET/CT showing no evidence of disease. He is now 3 years off therapy and doing very well. DISCUSSION Histiocytes or mononuclear phagocytes, the immune cells implicated in the pathogenesis of both LCH and HLH, serve many functions in the normal immune response. These include antigen presentation, activation of immune function through cytokine signaling, and phagocytosis.12 In both LCH and HLH, affected tissues express high levels of T-cell stimulatory molecules and secrete inflammatory cytokines such as IL-6, interferon, and tumor necrosis factor.8 Studies of LCH lesions suggest that chemokine receptors, including CCR6, maybe abnormally upregulated which contributes to tissue infiltration.13,14 Furthermore, the T cells found abundantly in LCH lesions show increased expression for genes involved in leukocyte chemotaxis, such as SPP1, IL8 and plasminogen activator, among others.15 A lesion with increased accumulation of histiocytes and T cells may thus be at increased risk of uncontrolled activation of these cells, resulting in hypercytokinemia and progressive organ dysfunction like that seen in HLH.12 HLH has a known association with malignancy, especially leukemias and lymphomas. If LCH indeed represents a malignant clonal process of early myeloid-lineage cells, this may also explain the potential association between the 2 entities. Alternatively, it could be that children with LCH who require multiagent or prolonged chemotherapy courses develop HLH secondary to immune dysregulation from the treatments rather than the underlying disease. HLH in LCH is thought to be a rare phenomenon and we aimed to summarize the available reports (Table 2). In our patient (patient 8), and in those reported throughout the literature, common findings included young age, multisystem LCH, history of systemic chemotherapy, and often concurrent infection. Our patient with multisystem LCH had received a prolonged course of multiagent chemotherapy secondary to his refractory disease and then developed RSV. He was also positive for EBV. Although we did not find any other reports of RSV-associated HLH, EBV is a well-known trigger of HLH, as are other viruses including influenza, parvovirus, etc. One evaluation of 182 pediatric patients with EBV who also met criteria for HLH, showed significant immune dysregulation. These patients had abnormal natural killer cell activity, as well as decreased CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells, resulting in increased T-cell activation and decreased inhibition. HLA-DR expression was elevated, indicating high levels of T-cell activation, and further downstream cytokines such as IL2 and interferon-gamma were also significantly elevated.16 Thus, viral infections including EBV can result in uncontrolled proliferation and activation of T cells, which may be further increased in patients with preexisting immune dysregulation from chemotherapy and/or the underlying disease state. We believe the combination of immunosuppression and infection may have led to HLH in our patients. Interestingly, like our patient, another reported patient with LCH also developed HLH while receiving clofarabine, a deoxyadenosine analog. Although this may be coincidence, clofarabine after multiple other immunosuppressive agents may have contributed to significant immune dysregulation and HLH in these patients. A recently published multicenter article reviewed 29 patients who met criteria for HLH and LCH. As in the patients reviewed in Table 2, about half of the patients met criteria for HLH at or around the diagnosis of LCH. Most had active LCH at diagnosis of HLH and were receiving treatments similar to those listed in Table 2. Overall, 31% had some kind of infection when HLH developed, including EBV. HLH was increased most in those with risk organ involvement, but also seen in young females without bony involvement. The combination of HLH and LCH was associated with a poor prognosis.17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment. TABLE 2 Reported Patients With LCH and HLH Patient 111 Patient 211 Patient 318 Patient 419 Patient 520 Patient 621 Patient 722 Patient 8 Age at HLH 10 mo 17 mo 3 y 2 y 10 mo 3 y 1 y 2 y Areas of LCH Colon, skin, ln, bone marrow Left mastoid Skin, bone, ln, bone marrow Skin, bone Skin, bone, ln, lungs Skin, bone, ln Skin, bone, ln, hepatomegaly Skin, bone Prior therapies None None 2CDA, ARAC×6 mo Prednisone, VBL, 6-MP, MTX×6 mo None Prednisone, VBL, 6-MP, MTX Prednisone, VCR, ARAC Prednisone, VBL, 2CDA Clinical course Presented with fever, diarrhea, HSM, LAD, and pulmonary disease Presented with fever, HSM, LAD, and bone lesion 2 cycles of clofarabine. Lesions improved but developed HLH Presented with HLH on 3 different occasions 2 to 6 mo apart in the setting of influenza, HSV, and adenovirus Presented with HLH and CMV. Diagnosed with HLH and LCH of skin 9 mo after therapy completed, the patient presented with HLH 3 wk into therapy for LCH, the patient developed HLH 7 d after beginning clofarabine therapy, developed HLH. EBV PCR+ HLH treatment Chemotherapy Prednisone, VBL, VCR Dexamethasone, etoposide Cessation of chemotherapy, antibiotics, antivirals, IVIG Prednisone, etoposide Dexamethasone, cyclo A Dexamethasone, etoposide, cyclo A, followed by flu, mel, ATG cytox, and UCBT Dexamethasone, etoposide Outcome Died 10 mo after diagnosis CR Continued disease progression, followed by death within 2 mo CR CR CR CR and engrafted Disease-free now 3 y off therapy ARAC indicates cytarabine; ATG, anti-thymocyte globulin; 2CDA, cladribine; CMV, cytomegalovirus; CR, complete remission; cytox, cyclophosphamide; EBV, Epstein-Barr virus; flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; IN, lymph node; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; LCH, Langerhans cell histiocytosis; mel, melphalan; MP, mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction; UCBT, unrelated cord blood transplant; VBL, vinblastine; VCR, vincristine. The authors declare no conflict of interest.

CLADRIBINE, CLOFARABINE, PREDNISOLONE, VINBLASTINE

DrugsGivenReaction

CC BY-NC-ND

31725543

2021-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'.

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature. A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH. There are 3 distinct classes of histiocyte disorders: Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) (and other rarer class II disorders), and malignant histiocytoses.1 LCH is characterized by the proliferation of infiltrative Langerhans cells into skin or bone; multisystem disease can also involve the lungs, liver, spleen, bone marrow, and central nervous system. Although historically thought of as a benign, reactive process, BRAF-V600E mutations have been found in 25% to 70% of LCH patients, with MAP2K1 positivity in 46% of BRAF-negative cases, raising the possibility that LCH is a malignancy.2–4 Many believe LCH may represent a myeloid-lineage neoplasm driven by ERK signaling.5,6 The treatment for LCH depends on the extent of disease and ranges from local and/or topical therapies to systemic chemotherapy.5,7 HLH is a disease of systemic, dysregulated immune activation and inflammation.8 HLH can be familial or secondary to infections, autoimmune processes, or malignancies.1 Treatment is with systemic dexamethasone and etoposide per the HLH94 protocol, with some patients, especially those with familial and/or reactivated HLH, ultimately requiring hematopoietic stem cell transplant for a cure.9 Recent studies suggest that targeted therapies such as emapalumab may also play a role, especially in refractory cases.10 Table 1 reviews LCH and HLH in respect to presentation, diagnostic criteria, and treatments. Though they are regarded as separate disease states, they can occur together within the same patient. Favara et al11 reviewed 30 pathology files of patients with coexisting LCH and macrophage activation; 7 of these met full diagnostic criteria for HLH. We report the case of a 20-month-old patient with multisystem LCH who developed HLH during treatment and summarize the literature for other case reports of HLH in LCH. TABLE 1 Comparison of LCH and HLH8,12 LCH HLH Pathophysiology Derived from clonal CD1a+ dendritic cells Lesions contain inflammatory infiltrates including high levels of T-cell regulatory molecules Defects in target cell killing by cytotoxic T cells Immune dysregulation with excessive proinflammatory cytokine production and macrophage response Uncontrolled systemic inflammation Can be primary or secondary to an infection, malignancy, autoimmune condition Molecular findings 38%-57% possess BRAF-V600E mutation Perforin MUNC 13-4, MUNC 18-2 Syntaxin 11 LYST, CHS1, Rab27A, AP3B1 SH2D1A, XIAP, BIRC4, SAP Presenting signs/symptoms Bone pain, swelling, fractures Chest pain, cough, dyspnea Rash, seborrhea, otitis externa Polyuria, polydipsia Fatigue, weight loss, fevers, lymphadenopathy Sepsis-like presentation Fever Cytopenias Hepatitis Splenomegaly Ataxia, seizures, abnormal MRI in 50% Diagnostic criteria Tissue biopsy containing CD207+, CD1a+ dendritic cells Characteristic morphology of Langerhans cells Requires 5/8 diagnostic criteria:  Fever  Splenomegaly  Cytopenias in ≥2 cell lines  Hyperferritinemia >500 mg/mL  sIL2 >2400 U/mL  Hypertriglyceridemia/hypofibrinogenemia  Hemophagocytosis in tissue biopsy  Low or absent NK cell activity Treatment Local therapy for unifocal bony disease Prednisone, vinblastine Cladribine, cytarabine, clofarabine for refractory/recurrent disease BMT for marrow/refractory disease Decadron, etoposide±cyclosporine Alemtuzumab for refractory cases Anti-INF-gamma antibodies for refractory cases BMT indicates bone marrow transplant; HLH, hemophagocytic lymphohistiocytosis; IL2, soluble interleukin-2; INF, interferon; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; NK, natural killer. RESULTS: CASE DESCRIPTION A 20-month-old male individual presented to his pediatrician with 6 months of progressive limp and unilateral leg pain, leading to a refusal to bear weight. He also had chronic drainage from bilateral ears. A radiograph showed a lucent, expansile lesion of the child’s femur and biopsy was performed, showing s100+, CD1a+ LCH. Further evaluation using skeletal survey and positron emission tomography-computed tomography (PET/CT) revealed multiple bony lytic lesions of the skull, axial skeleton and extremities, a scaling diffuse rash of the scalp, and hypermetabolic cervical lymphadenopathy. He had no involvement of the lungs, liver, spleen, or bone marrow, and had normal magnetic resonance imaging appearance of his pituitary after passing a water deprivation test. His blood counts at diagnosis were normal other than a mild microcytic iron deficiency anemia. Liver function tests and ferritin were within normal limits. He began therapy with daily prednisone and weekly vinblastine as per the LCH-III protocol. After his initial 6 weeks of induction therapy, PET/CT showed improved but continued hypermetabolic bony lesions. He went on to the second phase of induction therapy with further improvement in lesions and then began continuation with pulses of prednisone and vinblastine every 3 weeks. Within 3 months, a follow-up PET/CT showed worsening hypermetabolic bony lesions. He was treated with cladribine for 5 days every 28 days. Interval imaging after 2 cycles again showed worsening hypermetabolic bony lesions, worsening skin rash on scalp, continued bilateral ear drainage, leg pain, and intermittent fevers with cough and rhinorrhea. He was found to be respiratory syncytial virus (RSV) positive at that time. The child began monotherapy with clofarabine 25 mg/m2 daily for 5 days. Daily fevers continued for 2 weeks and he developed transaminitis with hypoalbuminemia and fluid overload. Blood cultures were negative, and he was empirically treated with broad-spectrum antibiotics secondary to neutropenia. CT scans done as part of fever evaluation revealed multiple new lytic skull lesions. Epstein-Barr virus (EBV) polymerase chain reaction was positive at 863 copies, which resolved without intervention over the next month. He met criteria for HLH with fevers, pancytopenia, ferritin >7500 ng/mL, triglycerides 526 mg/dL, soluble interleukin (IL)2 of 8191 U/mL, and hemophagocytosis in his bone marrow. Mutational analysis for PRF1, MUNC 13-4, XIAP and other common HLH-causing genes was normal. He thus began therapy via HLH94 with dexamethasone 10 mg/m2/d and etoposide. At the end of the standard 8-week treatment period, his HLH was felt to be well controlled with resolution of fevers and cytopenias, as well as normalization of liver function tests, triglycerides, soluble IL2, and improvement in ferritin. He went on to complete an additional 5 cycles of clofarabine 25 mg/m2 (6 total cycles), with end of therapy PET/CT showing no evidence of disease. He is now 3 years off therapy and doing very well. DISCUSSION Histiocytes or mononuclear phagocytes, the immune cells implicated in the pathogenesis of both LCH and HLH, serve many functions in the normal immune response. These include antigen presentation, activation of immune function through cytokine signaling, and phagocytosis.12 In both LCH and HLH, affected tissues express high levels of T-cell stimulatory molecules and secrete inflammatory cytokines such as IL-6, interferon, and tumor necrosis factor.8 Studies of LCH lesions suggest that chemokine receptors, including CCR6, maybe abnormally upregulated which contributes to tissue infiltration.13,14 Furthermore, the T cells found abundantly in LCH lesions show increased expression for genes involved in leukocyte chemotaxis, such as SPP1, IL8 and plasminogen activator, among others.15 A lesion with increased accumulation of histiocytes and T cells may thus be at increased risk of uncontrolled activation of these cells, resulting in hypercytokinemia and progressive organ dysfunction like that seen in HLH.12 HLH has a known association with malignancy, especially leukemias and lymphomas. If LCH indeed represents a malignant clonal process of early myeloid-lineage cells, this may also explain the potential association between the 2 entities. Alternatively, it could be that children with LCH who require multiagent or prolonged chemotherapy courses develop HLH secondary to immune dysregulation from the treatments rather than the underlying disease. HLH in LCH is thought to be a rare phenomenon and we aimed to summarize the available reports (Table 2). In our patient (patient 8), and in those reported throughout the literature, common findings included young age, multisystem LCH, history of systemic chemotherapy, and often concurrent infection. Our patient with multisystem LCH had received a prolonged course of multiagent chemotherapy secondary to his refractory disease and then developed RSV. He was also positive for EBV. Although we did not find any other reports of RSV-associated HLH, EBV is a well-known trigger of HLH, as are other viruses including influenza, parvovirus, etc. One evaluation of 182 pediatric patients with EBV who also met criteria for HLH, showed significant immune dysregulation. These patients had abnormal natural killer cell activity, as well as decreased CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells, resulting in increased T-cell activation and decreased inhibition. HLA-DR expression was elevated, indicating high levels of T-cell activation, and further downstream cytokines such as IL2 and interferon-gamma were also significantly elevated.16 Thus, viral infections including EBV can result in uncontrolled proliferation and activation of T cells, which may be further increased in patients with preexisting immune dysregulation from chemotherapy and/or the underlying disease state. We believe the combination of immunosuppression and infection may have led to HLH in our patients. Interestingly, like our patient, another reported patient with LCH also developed HLH while receiving clofarabine, a deoxyadenosine analog. Although this may be coincidence, clofarabine after multiple other immunosuppressive agents may have contributed to significant immune dysregulation and HLH in these patients. A recently published multicenter article reviewed 29 patients who met criteria for HLH and LCH. As in the patients reviewed in Table 2, about half of the patients met criteria for HLH at or around the diagnosis of LCH. Most had active LCH at diagnosis of HLH and were receiving treatments similar to those listed in Table 2. Overall, 31% had some kind of infection when HLH developed, including EBV. HLH was increased most in those with risk organ involvement, but also seen in young females without bony involvement. The combination of HLH and LCH was associated with a poor prognosis.17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment. TABLE 2 Reported Patients With LCH and HLH Patient 111 Patient 211 Patient 318 Patient 419 Patient 520 Patient 621 Patient 722 Patient 8 Age at HLH 10 mo 17 mo 3 y 2 y 10 mo 3 y 1 y 2 y Areas of LCH Colon, skin, ln, bone marrow Left mastoid Skin, bone, ln, bone marrow Skin, bone Skin, bone, ln, lungs Skin, bone, ln Skin, bone, ln, hepatomegaly Skin, bone Prior therapies None None 2CDA, ARAC×6 mo Prednisone, VBL, 6-MP, MTX×6 mo None Prednisone, VBL, 6-MP, MTX Prednisone, VCR, ARAC Prednisone, VBL, 2CDA Clinical course Presented with fever, diarrhea, HSM, LAD, and pulmonary disease Presented with fever, HSM, LAD, and bone lesion 2 cycles of clofarabine. Lesions improved but developed HLH Presented with HLH on 3 different occasions 2 to 6 mo apart in the setting of influenza, HSV, and adenovirus Presented with HLH and CMV. Diagnosed with HLH and LCH of skin 9 mo after therapy completed, the patient presented with HLH 3 wk into therapy for LCH, the patient developed HLH 7 d after beginning clofarabine therapy, developed HLH. EBV PCR+ HLH treatment Chemotherapy Prednisone, VBL, VCR Dexamethasone, etoposide Cessation of chemotherapy, antibiotics, antivirals, IVIG Prednisone, etoposide Dexamethasone, cyclo A Dexamethasone, etoposide, cyclo A, followed by flu, mel, ATG cytox, and UCBT Dexamethasone, etoposide Outcome Died 10 mo after diagnosis CR Continued disease progression, followed by death within 2 mo CR CR CR CR and engrafted Disease-free now 3 y off therapy ARAC indicates cytarabine; ATG, anti-thymocyte globulin; 2CDA, cladribine; CMV, cytomegalovirus; CR, complete remission; cytox, cyclophosphamide; EBV, Epstein-Barr virus; flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; IN, lymph node; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; LCH, Langerhans cell histiocytosis; mel, melphalan; MP, mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction; UCBT, unrelated cord blood transplant; VBL, vinblastine; VCR, vincristine. The authors declare no conflict of interest.

CLADRIBINE, CLOFARABINE, PREDNISOLONE, VINBLASTINE

DrugsGivenReaction

CC BY-NC-ND

31725543

2021-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Otorrhoea'.

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature. A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH. There are 3 distinct classes of histiocyte disorders: Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) (and other rarer class II disorders), and malignant histiocytoses.1 LCH is characterized by the proliferation of infiltrative Langerhans cells into skin or bone; multisystem disease can also involve the lungs, liver, spleen, bone marrow, and central nervous system. Although historically thought of as a benign, reactive process, BRAF-V600E mutations have been found in 25% to 70% of LCH patients, with MAP2K1 positivity in 46% of BRAF-negative cases, raising the possibility that LCH is a malignancy.2–4 Many believe LCH may represent a myeloid-lineage neoplasm driven by ERK signaling.5,6 The treatment for LCH depends on the extent of disease and ranges from local and/or topical therapies to systemic chemotherapy.5,7 HLH is a disease of systemic, dysregulated immune activation and inflammation.8 HLH can be familial or secondary to infections, autoimmune processes, or malignancies.1 Treatment is with systemic dexamethasone and etoposide per the HLH94 protocol, with some patients, especially those with familial and/or reactivated HLH, ultimately requiring hematopoietic stem cell transplant for a cure.9 Recent studies suggest that targeted therapies such as emapalumab may also play a role, especially in refractory cases.10 Table 1 reviews LCH and HLH in respect to presentation, diagnostic criteria, and treatments. Though they are regarded as separate disease states, they can occur together within the same patient. Favara et al11 reviewed 30 pathology files of patients with coexisting LCH and macrophage activation; 7 of these met full diagnostic criteria for HLH. We report the case of a 20-month-old patient with multisystem LCH who developed HLH during treatment and summarize the literature for other case reports of HLH in LCH. TABLE 1 Comparison of LCH and HLH8,12 LCH HLH Pathophysiology Derived from clonal CD1a+ dendritic cells Lesions contain inflammatory infiltrates including high levels of T-cell regulatory molecules Defects in target cell killing by cytotoxic T cells Immune dysregulation with excessive proinflammatory cytokine production and macrophage response Uncontrolled systemic inflammation Can be primary or secondary to an infection, malignancy, autoimmune condition Molecular findings 38%-57% possess BRAF-V600E mutation Perforin MUNC 13-4, MUNC 18-2 Syntaxin 11 LYST, CHS1, Rab27A, AP3B1 SH2D1A, XIAP, BIRC4, SAP Presenting signs/symptoms Bone pain, swelling, fractures Chest pain, cough, dyspnea Rash, seborrhea, otitis externa Polyuria, polydipsia Fatigue, weight loss, fevers, lymphadenopathy Sepsis-like presentation Fever Cytopenias Hepatitis Splenomegaly Ataxia, seizures, abnormal MRI in 50% Diagnostic criteria Tissue biopsy containing CD207+, CD1a+ dendritic cells Characteristic morphology of Langerhans cells Requires 5/8 diagnostic criteria:  Fever  Splenomegaly  Cytopenias in ≥2 cell lines  Hyperferritinemia >500 mg/mL  sIL2 >2400 U/mL  Hypertriglyceridemia/hypofibrinogenemia  Hemophagocytosis in tissue biopsy  Low or absent NK cell activity Treatment Local therapy for unifocal bony disease Prednisone, vinblastine Cladribine, cytarabine, clofarabine for refractory/recurrent disease BMT for marrow/refractory disease Decadron, etoposide±cyclosporine Alemtuzumab for refractory cases Anti-INF-gamma antibodies for refractory cases BMT indicates bone marrow transplant; HLH, hemophagocytic lymphohistiocytosis; IL2, soluble interleukin-2; INF, interferon; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; NK, natural killer. RESULTS: CASE DESCRIPTION A 20-month-old male individual presented to his pediatrician with 6 months of progressive limp and unilateral leg pain, leading to a refusal to bear weight. He also had chronic drainage from bilateral ears. A radiograph showed a lucent, expansile lesion of the child’s femur and biopsy was performed, showing s100+, CD1a+ LCH. Further evaluation using skeletal survey and positron emission tomography-computed tomography (PET/CT) revealed multiple bony lytic lesions of the skull, axial skeleton and extremities, a scaling diffuse rash of the scalp, and hypermetabolic cervical lymphadenopathy. He had no involvement of the lungs, liver, spleen, or bone marrow, and had normal magnetic resonance imaging appearance of his pituitary after passing a water deprivation test. His blood counts at diagnosis were normal other than a mild microcytic iron deficiency anemia. Liver function tests and ferritin were within normal limits. He began therapy with daily prednisone and weekly vinblastine as per the LCH-III protocol. After his initial 6 weeks of induction therapy, PET/CT showed improved but continued hypermetabolic bony lesions. He went on to the second phase of induction therapy with further improvement in lesions and then began continuation with pulses of prednisone and vinblastine every 3 weeks. Within 3 months, a follow-up PET/CT showed worsening hypermetabolic bony lesions. He was treated with cladribine for 5 days every 28 days. Interval imaging after 2 cycles again showed worsening hypermetabolic bony lesions, worsening skin rash on scalp, continued bilateral ear drainage, leg pain, and intermittent fevers with cough and rhinorrhea. He was found to be respiratory syncytial virus (RSV) positive at that time. The child began monotherapy with clofarabine 25 mg/m2 daily for 5 days. Daily fevers continued for 2 weeks and he developed transaminitis with hypoalbuminemia and fluid overload. Blood cultures were negative, and he was empirically treated with broad-spectrum antibiotics secondary to neutropenia. CT scans done as part of fever evaluation revealed multiple new lytic skull lesions. Epstein-Barr virus (EBV) polymerase chain reaction was positive at 863 copies, which resolved without intervention over the next month. He met criteria for HLH with fevers, pancytopenia, ferritin >7500 ng/mL, triglycerides 526 mg/dL, soluble interleukin (IL)2 of 8191 U/mL, and hemophagocytosis in his bone marrow. Mutational analysis for PRF1, MUNC 13-4, XIAP and other common HLH-causing genes was normal. He thus began therapy via HLH94 with dexamethasone 10 mg/m2/d and etoposide. At the end of the standard 8-week treatment period, his HLH was felt to be well controlled with resolution of fevers and cytopenias, as well as normalization of liver function tests, triglycerides, soluble IL2, and improvement in ferritin. He went on to complete an additional 5 cycles of clofarabine 25 mg/m2 (6 total cycles), with end of therapy PET/CT showing no evidence of disease. He is now 3 years off therapy and doing very well. DISCUSSION Histiocytes or mononuclear phagocytes, the immune cells implicated in the pathogenesis of both LCH and HLH, serve many functions in the normal immune response. These include antigen presentation, activation of immune function through cytokine signaling, and phagocytosis.12 In both LCH and HLH, affected tissues express high levels of T-cell stimulatory molecules and secrete inflammatory cytokines such as IL-6, interferon, and tumor necrosis factor.8 Studies of LCH lesions suggest that chemokine receptors, including CCR6, maybe abnormally upregulated which contributes to tissue infiltration.13,14 Furthermore, the T cells found abundantly in LCH lesions show increased expression for genes involved in leukocyte chemotaxis, such as SPP1, IL8 and plasminogen activator, among others.15 A lesion with increased accumulation of histiocytes and T cells may thus be at increased risk of uncontrolled activation of these cells, resulting in hypercytokinemia and progressive organ dysfunction like that seen in HLH.12 HLH has a known association with malignancy, especially leukemias and lymphomas. If LCH indeed represents a malignant clonal process of early myeloid-lineage cells, this may also explain the potential association between the 2 entities. Alternatively, it could be that children with LCH who require multiagent or prolonged chemotherapy courses develop HLH secondary to immune dysregulation from the treatments rather than the underlying disease. HLH in LCH is thought to be a rare phenomenon and we aimed to summarize the available reports (Table 2). In our patient (patient 8), and in those reported throughout the literature, common findings included young age, multisystem LCH, history of systemic chemotherapy, and often concurrent infection. Our patient with multisystem LCH had received a prolonged course of multiagent chemotherapy secondary to his refractory disease and then developed RSV. He was also positive for EBV. Although we did not find any other reports of RSV-associated HLH, EBV is a well-known trigger of HLH, as are other viruses including influenza, parvovirus, etc. One evaluation of 182 pediatric patients with EBV who also met criteria for HLH, showed significant immune dysregulation. These patients had abnormal natural killer cell activity, as well as decreased CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells, resulting in increased T-cell activation and decreased inhibition. HLA-DR expression was elevated, indicating high levels of T-cell activation, and further downstream cytokines such as IL2 and interferon-gamma were also significantly elevated.16 Thus, viral infections including EBV can result in uncontrolled proliferation and activation of T cells, which may be further increased in patients with preexisting immune dysregulation from chemotherapy and/or the underlying disease state. We believe the combination of immunosuppression and infection may have led to HLH in our patients. Interestingly, like our patient, another reported patient with LCH also developed HLH while receiving clofarabine, a deoxyadenosine analog. Although this may be coincidence, clofarabine after multiple other immunosuppressive agents may have contributed to significant immune dysregulation and HLH in these patients. A recently published multicenter article reviewed 29 patients who met criteria for HLH and LCH. As in the patients reviewed in Table 2, about half of the patients met criteria for HLH at or around the diagnosis of LCH. Most had active LCH at diagnosis of HLH and were receiving treatments similar to those listed in Table 2. Overall, 31% had some kind of infection when HLH developed, including EBV. HLH was increased most in those with risk organ involvement, but also seen in young females without bony involvement. The combination of HLH and LCH was associated with a poor prognosis.17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment. TABLE 2 Reported Patients With LCH and HLH Patient 111 Patient 211 Patient 318 Patient 419 Patient 520 Patient 621 Patient 722 Patient 8 Age at HLH 10 mo 17 mo 3 y 2 y 10 mo 3 y 1 y 2 y Areas of LCH Colon, skin, ln, bone marrow Left mastoid Skin, bone, ln, bone marrow Skin, bone Skin, bone, ln, lungs Skin, bone, ln Skin, bone, ln, hepatomegaly Skin, bone Prior therapies None None 2CDA, ARAC×6 mo Prednisone, VBL, 6-MP, MTX×6 mo None Prednisone, VBL, 6-MP, MTX Prednisone, VCR, ARAC Prednisone, VBL, 2CDA Clinical course Presented with fever, diarrhea, HSM, LAD, and pulmonary disease Presented with fever, HSM, LAD, and bone lesion 2 cycles of clofarabine. Lesions improved but developed HLH Presented with HLH on 3 different occasions 2 to 6 mo apart in the setting of influenza, HSV, and adenovirus Presented with HLH and CMV. Diagnosed with HLH and LCH of skin 9 mo after therapy completed, the patient presented with HLH 3 wk into therapy for LCH, the patient developed HLH 7 d after beginning clofarabine therapy, developed HLH. EBV PCR+ HLH treatment Chemotherapy Prednisone, VBL, VCR Dexamethasone, etoposide Cessation of chemotherapy, antibiotics, antivirals, IVIG Prednisone, etoposide Dexamethasone, cyclo A Dexamethasone, etoposide, cyclo A, followed by flu, mel, ATG cytox, and UCBT Dexamethasone, etoposide Outcome Died 10 mo after diagnosis CR Continued disease progression, followed by death within 2 mo CR CR CR CR and engrafted Disease-free now 3 y off therapy ARAC indicates cytarabine; ATG, anti-thymocyte globulin; 2CDA, cladribine; CMV, cytomegalovirus; CR, complete remission; cytox, cyclophosphamide; EBV, Epstein-Barr virus; flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; IN, lymph node; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; LCH, Langerhans cell histiocytosis; mel, melphalan; MP, mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction; UCBT, unrelated cord blood transplant; VBL, vinblastine; VCR, vincristine. The authors declare no conflict of interest.

CLADRIBINE, CLOFARABINE, PREDNISOLONE, VINBLASTINE

DrugsGivenReaction

CC BY-NC-ND

31725543

2021-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pancytopenia'.

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature. A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH. There are 3 distinct classes of histiocyte disorders: Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) (and other rarer class II disorders), and malignant histiocytoses.1 LCH is characterized by the proliferation of infiltrative Langerhans cells into skin or bone; multisystem disease can also involve the lungs, liver, spleen, bone marrow, and central nervous system. Although historically thought of as a benign, reactive process, BRAF-V600E mutations have been found in 25% to 70% of LCH patients, with MAP2K1 positivity in 46% of BRAF-negative cases, raising the possibility that LCH is a malignancy.2–4 Many believe LCH may represent a myeloid-lineage neoplasm driven by ERK signaling.5,6 The treatment for LCH depends on the extent of disease and ranges from local and/or topical therapies to systemic chemotherapy.5,7 HLH is a disease of systemic, dysregulated immune activation and inflammation.8 HLH can be familial or secondary to infections, autoimmune processes, or malignancies.1 Treatment is with systemic dexamethasone and etoposide per the HLH94 protocol, with some patients, especially those with familial and/or reactivated HLH, ultimately requiring hematopoietic stem cell transplant for a cure.9 Recent studies suggest that targeted therapies such as emapalumab may also play a role, especially in refractory cases.10 Table 1 reviews LCH and HLH in respect to presentation, diagnostic criteria, and treatments. Though they are regarded as separate disease states, they can occur together within the same patient. Favara et al11 reviewed 30 pathology files of patients with coexisting LCH and macrophage activation; 7 of these met full diagnostic criteria for HLH. We report the case of a 20-month-old patient with multisystem LCH who developed HLH during treatment and summarize the literature for other case reports of HLH in LCH. TABLE 1 Comparison of LCH and HLH8,12 LCH HLH Pathophysiology Derived from clonal CD1a+ dendritic cells Lesions contain inflammatory infiltrates including high levels of T-cell regulatory molecules Defects in target cell killing by cytotoxic T cells Immune dysregulation with excessive proinflammatory cytokine production and macrophage response Uncontrolled systemic inflammation Can be primary or secondary to an infection, malignancy, autoimmune condition Molecular findings 38%-57% possess BRAF-V600E mutation Perforin MUNC 13-4, MUNC 18-2 Syntaxin 11 LYST, CHS1, Rab27A, AP3B1 SH2D1A, XIAP, BIRC4, SAP Presenting signs/symptoms Bone pain, swelling, fractures Chest pain, cough, dyspnea Rash, seborrhea, otitis externa Polyuria, polydipsia Fatigue, weight loss, fevers, lymphadenopathy Sepsis-like presentation Fever Cytopenias Hepatitis Splenomegaly Ataxia, seizures, abnormal MRI in 50% Diagnostic criteria Tissue biopsy containing CD207+, CD1a+ dendritic cells Characteristic morphology of Langerhans cells Requires 5/8 diagnostic criteria:  Fever  Splenomegaly  Cytopenias in ≥2 cell lines  Hyperferritinemia >500 mg/mL  sIL2 >2400 U/mL  Hypertriglyceridemia/hypofibrinogenemia  Hemophagocytosis in tissue biopsy  Low or absent NK cell activity Treatment Local therapy for unifocal bony disease Prednisone, vinblastine Cladribine, cytarabine, clofarabine for refractory/recurrent disease BMT for marrow/refractory disease Decadron, etoposide±cyclosporine Alemtuzumab for refractory cases Anti-INF-gamma antibodies for refractory cases BMT indicates bone marrow transplant; HLH, hemophagocytic lymphohistiocytosis; IL2, soluble interleukin-2; INF, interferon; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; NK, natural killer. RESULTS: CASE DESCRIPTION A 20-month-old male individual presented to his pediatrician with 6 months of progressive limp and unilateral leg pain, leading to a refusal to bear weight. He also had chronic drainage from bilateral ears. A radiograph showed a lucent, expansile lesion of the child’s femur and biopsy was performed, showing s100+, CD1a+ LCH. Further evaluation using skeletal survey and positron emission tomography-computed tomography (PET/CT) revealed multiple bony lytic lesions of the skull, axial skeleton and extremities, a scaling diffuse rash of the scalp, and hypermetabolic cervical lymphadenopathy. He had no involvement of the lungs, liver, spleen, or bone marrow, and had normal magnetic resonance imaging appearance of his pituitary after passing a water deprivation test. His blood counts at diagnosis were normal other than a mild microcytic iron deficiency anemia. Liver function tests and ferritin were within normal limits. He began therapy with daily prednisone and weekly vinblastine as per the LCH-III protocol. After his initial 6 weeks of induction therapy, PET/CT showed improved but continued hypermetabolic bony lesions. He went on to the second phase of induction therapy with further improvement in lesions and then began continuation with pulses of prednisone and vinblastine every 3 weeks. Within 3 months, a follow-up PET/CT showed worsening hypermetabolic bony lesions. He was treated with cladribine for 5 days every 28 days. Interval imaging after 2 cycles again showed worsening hypermetabolic bony lesions, worsening skin rash on scalp, continued bilateral ear drainage, leg pain, and intermittent fevers with cough and rhinorrhea. He was found to be respiratory syncytial virus (RSV) positive at that time. The child began monotherapy with clofarabine 25 mg/m2 daily for 5 days. Daily fevers continued for 2 weeks and he developed transaminitis with hypoalbuminemia and fluid overload. Blood cultures were negative, and he was empirically treated with broad-spectrum antibiotics secondary to neutropenia. CT scans done as part of fever evaluation revealed multiple new lytic skull lesions. Epstein-Barr virus (EBV) polymerase chain reaction was positive at 863 copies, which resolved without intervention over the next month. He met criteria for HLH with fevers, pancytopenia, ferritin >7500 ng/mL, triglycerides 526 mg/dL, soluble interleukin (IL)2 of 8191 U/mL, and hemophagocytosis in his bone marrow. Mutational analysis for PRF1, MUNC 13-4, XIAP and other common HLH-causing genes was normal. He thus began therapy via HLH94 with dexamethasone 10 mg/m2/d and etoposide. At the end of the standard 8-week treatment period, his HLH was felt to be well controlled with resolution of fevers and cytopenias, as well as normalization of liver function tests, triglycerides, soluble IL2, and improvement in ferritin. He went on to complete an additional 5 cycles of clofarabine 25 mg/m2 (6 total cycles), with end of therapy PET/CT showing no evidence of disease. He is now 3 years off therapy and doing very well. DISCUSSION Histiocytes or mononuclear phagocytes, the immune cells implicated in the pathogenesis of both LCH and HLH, serve many functions in the normal immune response. These include antigen presentation, activation of immune function through cytokine signaling, and phagocytosis.12 In both LCH and HLH, affected tissues express high levels of T-cell stimulatory molecules and secrete inflammatory cytokines such as IL-6, interferon, and tumor necrosis factor.8 Studies of LCH lesions suggest that chemokine receptors, including CCR6, maybe abnormally upregulated which contributes to tissue infiltration.13,14 Furthermore, the T cells found abundantly in LCH lesions show increased expression for genes involved in leukocyte chemotaxis, such as SPP1, IL8 and plasminogen activator, among others.15 A lesion with increased accumulation of histiocytes and T cells may thus be at increased risk of uncontrolled activation of these cells, resulting in hypercytokinemia and progressive organ dysfunction like that seen in HLH.12 HLH has a known association with malignancy, especially leukemias and lymphomas. If LCH indeed represents a malignant clonal process of early myeloid-lineage cells, this may also explain the potential association between the 2 entities. Alternatively, it could be that children with LCH who require multiagent or prolonged chemotherapy courses develop HLH secondary to immune dysregulation from the treatments rather than the underlying disease. HLH in LCH is thought to be a rare phenomenon and we aimed to summarize the available reports (Table 2). In our patient (patient 8), and in those reported throughout the literature, common findings included young age, multisystem LCH, history of systemic chemotherapy, and often concurrent infection. Our patient with multisystem LCH had received a prolonged course of multiagent chemotherapy secondary to his refractory disease and then developed RSV. He was also positive for EBV. Although we did not find any other reports of RSV-associated HLH, EBV is a well-known trigger of HLH, as are other viruses including influenza, parvovirus, etc. One evaluation of 182 pediatric patients with EBV who also met criteria for HLH, showed significant immune dysregulation. These patients had abnormal natural killer cell activity, as well as decreased CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells, resulting in increased T-cell activation and decreased inhibition. HLA-DR expression was elevated, indicating high levels of T-cell activation, and further downstream cytokines such as IL2 and interferon-gamma were also significantly elevated.16 Thus, viral infections including EBV can result in uncontrolled proliferation and activation of T cells, which may be further increased in patients with preexisting immune dysregulation from chemotherapy and/or the underlying disease state. We believe the combination of immunosuppression and infection may have led to HLH in our patients. Interestingly, like our patient, another reported patient with LCH also developed HLH while receiving clofarabine, a deoxyadenosine analog. Although this may be coincidence, clofarabine after multiple other immunosuppressive agents may have contributed to significant immune dysregulation and HLH in these patients. A recently published multicenter article reviewed 29 patients who met criteria for HLH and LCH. As in the patients reviewed in Table 2, about half of the patients met criteria for HLH at or around the diagnosis of LCH. Most had active LCH at diagnosis of HLH and were receiving treatments similar to those listed in Table 2. Overall, 31% had some kind of infection when HLH developed, including EBV. HLH was increased most in those with risk organ involvement, but also seen in young females without bony involvement. The combination of HLH and LCH was associated with a poor prognosis.17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment. TABLE 2 Reported Patients With LCH and HLH Patient 111 Patient 211 Patient 318 Patient 419 Patient 520 Patient 621 Patient 722 Patient 8 Age at HLH 10 mo 17 mo 3 y 2 y 10 mo 3 y 1 y 2 y Areas of LCH Colon, skin, ln, bone marrow Left mastoid Skin, bone, ln, bone marrow Skin, bone Skin, bone, ln, lungs Skin, bone, ln Skin, bone, ln, hepatomegaly Skin, bone Prior therapies None None 2CDA, ARAC×6 mo Prednisone, VBL, 6-MP, MTX×6 mo None Prednisone, VBL, 6-MP, MTX Prednisone, VCR, ARAC Prednisone, VBL, 2CDA Clinical course Presented with fever, diarrhea, HSM, LAD, and pulmonary disease Presented with fever, HSM, LAD, and bone lesion 2 cycles of clofarabine. Lesions improved but developed HLH Presented with HLH on 3 different occasions 2 to 6 mo apart in the setting of influenza, HSV, and adenovirus Presented with HLH and CMV. Diagnosed with HLH and LCH of skin 9 mo after therapy completed, the patient presented with HLH 3 wk into therapy for LCH, the patient developed HLH 7 d after beginning clofarabine therapy, developed HLH. EBV PCR+ HLH treatment Chemotherapy Prednisone, VBL, VCR Dexamethasone, etoposide Cessation of chemotherapy, antibiotics, antivirals, IVIG Prednisone, etoposide Dexamethasone, cyclo A Dexamethasone, etoposide, cyclo A, followed by flu, mel, ATG cytox, and UCBT Dexamethasone, etoposide Outcome Died 10 mo after diagnosis CR Continued disease progression, followed by death within 2 mo CR CR CR CR and engrafted Disease-free now 3 y off therapy ARAC indicates cytarabine; ATG, anti-thymocyte globulin; 2CDA, cladribine; CMV, cytomegalovirus; CR, complete remission; cytox, cyclophosphamide; EBV, Epstein-Barr virus; flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; IN, lymph node; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; LCH, Langerhans cell histiocytosis; mel, melphalan; MP, mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction; UCBT, unrelated cord blood transplant; VBL, vinblastine; VCR, vincristine. The authors declare no conflict of interest.

CLADRIBINE, CLOFARABINE, PREDNISOLONE, VINBLASTINE

DrugsGivenReaction

CC BY-NC-ND

31725543

2021-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'.

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature. A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH. There are 3 distinct classes of histiocyte disorders: Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) (and other rarer class II disorders), and malignant histiocytoses.1 LCH is characterized by the proliferation of infiltrative Langerhans cells into skin or bone; multisystem disease can also involve the lungs, liver, spleen, bone marrow, and central nervous system. Although historically thought of as a benign, reactive process, BRAF-V600E mutations have been found in 25% to 70% of LCH patients, with MAP2K1 positivity in 46% of BRAF-negative cases, raising the possibility that LCH is a malignancy.2–4 Many believe LCH may represent a myeloid-lineage neoplasm driven by ERK signaling.5,6 The treatment for LCH depends on the extent of disease and ranges from local and/or topical therapies to systemic chemotherapy.5,7 HLH is a disease of systemic, dysregulated immune activation and inflammation.8 HLH can be familial or secondary to infections, autoimmune processes, or malignancies.1 Treatment is with systemic dexamethasone and etoposide per the HLH94 protocol, with some patients, especially those with familial and/or reactivated HLH, ultimately requiring hematopoietic stem cell transplant for a cure.9 Recent studies suggest that targeted therapies such as emapalumab may also play a role, especially in refractory cases.10 Table 1 reviews LCH and HLH in respect to presentation, diagnostic criteria, and treatments. Though they are regarded as separate disease states, they can occur together within the same patient. Favara et al11 reviewed 30 pathology files of patients with coexisting LCH and macrophage activation; 7 of these met full diagnostic criteria for HLH. We report the case of a 20-month-old patient with multisystem LCH who developed HLH during treatment and summarize the literature for other case reports of HLH in LCH. TABLE 1 Comparison of LCH and HLH8,12 LCH HLH Pathophysiology Derived from clonal CD1a+ dendritic cells Lesions contain inflammatory infiltrates including high levels of T-cell regulatory molecules Defects in target cell killing by cytotoxic T cells Immune dysregulation with excessive proinflammatory cytokine production and macrophage response Uncontrolled systemic inflammation Can be primary or secondary to an infection, malignancy, autoimmune condition Molecular findings 38%-57% possess BRAF-V600E mutation Perforin MUNC 13-4, MUNC 18-2 Syntaxin 11 LYST, CHS1, Rab27A, AP3B1 SH2D1A, XIAP, BIRC4, SAP Presenting signs/symptoms Bone pain, swelling, fractures Chest pain, cough, dyspnea Rash, seborrhea, otitis externa Polyuria, polydipsia Fatigue, weight loss, fevers, lymphadenopathy Sepsis-like presentation Fever Cytopenias Hepatitis Splenomegaly Ataxia, seizures, abnormal MRI in 50% Diagnostic criteria Tissue biopsy containing CD207+, CD1a+ dendritic cells Characteristic morphology of Langerhans cells Requires 5/8 diagnostic criteria:  Fever  Splenomegaly  Cytopenias in ≥2 cell lines  Hyperferritinemia >500 mg/mL  sIL2 >2400 U/mL  Hypertriglyceridemia/hypofibrinogenemia  Hemophagocytosis in tissue biopsy  Low or absent NK cell activity Treatment Local therapy for unifocal bony disease Prednisone, vinblastine Cladribine, cytarabine, clofarabine for refractory/recurrent disease BMT for marrow/refractory disease Decadron, etoposide±cyclosporine Alemtuzumab for refractory cases Anti-INF-gamma antibodies for refractory cases BMT indicates bone marrow transplant; HLH, hemophagocytic lymphohistiocytosis; IL2, soluble interleukin-2; INF, interferon; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; NK, natural killer. RESULTS: CASE DESCRIPTION A 20-month-old male individual presented to his pediatrician with 6 months of progressive limp and unilateral leg pain, leading to a refusal to bear weight. He also had chronic drainage from bilateral ears. A radiograph showed a lucent, expansile lesion of the child’s femur and biopsy was performed, showing s100+, CD1a+ LCH. Further evaluation using skeletal survey and positron emission tomography-computed tomography (PET/CT) revealed multiple bony lytic lesions of the skull, axial skeleton and extremities, a scaling diffuse rash of the scalp, and hypermetabolic cervical lymphadenopathy. He had no involvement of the lungs, liver, spleen, or bone marrow, and had normal magnetic resonance imaging appearance of his pituitary after passing a water deprivation test. His blood counts at diagnosis were normal other than a mild microcytic iron deficiency anemia. Liver function tests and ferritin were within normal limits. He began therapy with daily prednisone and weekly vinblastine as per the LCH-III protocol. After his initial 6 weeks of induction therapy, PET/CT showed improved but continued hypermetabolic bony lesions. He went on to the second phase of induction therapy with further improvement in lesions and then began continuation with pulses of prednisone and vinblastine every 3 weeks. Within 3 months, a follow-up PET/CT showed worsening hypermetabolic bony lesions. He was treated with cladribine for 5 days every 28 days. Interval imaging after 2 cycles again showed worsening hypermetabolic bony lesions, worsening skin rash on scalp, continued bilateral ear drainage, leg pain, and intermittent fevers with cough and rhinorrhea. He was found to be respiratory syncytial virus (RSV) positive at that time. The child began monotherapy with clofarabine 25 mg/m2 daily for 5 days. Daily fevers continued for 2 weeks and he developed transaminitis with hypoalbuminemia and fluid overload. Blood cultures were negative, and he was empirically treated with broad-spectrum antibiotics secondary to neutropenia. CT scans done as part of fever evaluation revealed multiple new lytic skull lesions. Epstein-Barr virus (EBV) polymerase chain reaction was positive at 863 copies, which resolved without intervention over the next month. He met criteria for HLH with fevers, pancytopenia, ferritin >7500 ng/mL, triglycerides 526 mg/dL, soluble interleukin (IL)2 of 8191 U/mL, and hemophagocytosis in his bone marrow. Mutational analysis for PRF1, MUNC 13-4, XIAP and other common HLH-causing genes was normal. He thus began therapy via HLH94 with dexamethasone 10 mg/m2/d and etoposide. At the end of the standard 8-week treatment period, his HLH was felt to be well controlled with resolution of fevers and cytopenias, as well as normalization of liver function tests, triglycerides, soluble IL2, and improvement in ferritin. He went on to complete an additional 5 cycles of clofarabine 25 mg/m2 (6 total cycles), with end of therapy PET/CT showing no evidence of disease. He is now 3 years off therapy and doing very well. DISCUSSION Histiocytes or mononuclear phagocytes, the immune cells implicated in the pathogenesis of both LCH and HLH, serve many functions in the normal immune response. These include antigen presentation, activation of immune function through cytokine signaling, and phagocytosis.12 In both LCH and HLH, affected tissues express high levels of T-cell stimulatory molecules and secrete inflammatory cytokines such as IL-6, interferon, and tumor necrosis factor.8 Studies of LCH lesions suggest that chemokine receptors, including CCR6, maybe abnormally upregulated which contributes to tissue infiltration.13,14 Furthermore, the T cells found abundantly in LCH lesions show increased expression for genes involved in leukocyte chemotaxis, such as SPP1, IL8 and plasminogen activator, among others.15 A lesion with increased accumulation of histiocytes and T cells may thus be at increased risk of uncontrolled activation of these cells, resulting in hypercytokinemia and progressive organ dysfunction like that seen in HLH.12 HLH has a known association with malignancy, especially leukemias and lymphomas. If LCH indeed represents a malignant clonal process of early myeloid-lineage cells, this may also explain the potential association between the 2 entities. Alternatively, it could be that children with LCH who require multiagent or prolonged chemotherapy courses develop HLH secondary to immune dysregulation from the treatments rather than the underlying disease. HLH in LCH is thought to be a rare phenomenon and we aimed to summarize the available reports (Table 2). In our patient (patient 8), and in those reported throughout the literature, common findings included young age, multisystem LCH, history of systemic chemotherapy, and often concurrent infection. Our patient with multisystem LCH had received a prolonged course of multiagent chemotherapy secondary to his refractory disease and then developed RSV. He was also positive for EBV. Although we did not find any other reports of RSV-associated HLH, EBV is a well-known trigger of HLH, as are other viruses including influenza, parvovirus, etc. One evaluation of 182 pediatric patients with EBV who also met criteria for HLH, showed significant immune dysregulation. These patients had abnormal natural killer cell activity, as well as decreased CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells, resulting in increased T-cell activation and decreased inhibition. HLA-DR expression was elevated, indicating high levels of T-cell activation, and further downstream cytokines such as IL2 and interferon-gamma were also significantly elevated.16 Thus, viral infections including EBV can result in uncontrolled proliferation and activation of T cells, which may be further increased in patients with preexisting immune dysregulation from chemotherapy and/or the underlying disease state. We believe the combination of immunosuppression and infection may have led to HLH in our patients. Interestingly, like our patient, another reported patient with LCH also developed HLH while receiving clofarabine, a deoxyadenosine analog. Although this may be coincidence, clofarabine after multiple other immunosuppressive agents may have contributed to significant immune dysregulation and HLH in these patients. A recently published multicenter article reviewed 29 patients who met criteria for HLH and LCH. As in the patients reviewed in Table 2, about half of the patients met criteria for HLH at or around the diagnosis of LCH. Most had active LCH at diagnosis of HLH and were receiving treatments similar to those listed in Table 2. Overall, 31% had some kind of infection when HLH developed, including EBV. HLH was increased most in those with risk organ involvement, but also seen in young females without bony involvement. The combination of HLH and LCH was associated with a poor prognosis.17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment. TABLE 2 Reported Patients With LCH and HLH Patient 111 Patient 211 Patient 318 Patient 419 Patient 520 Patient 621 Patient 722 Patient 8 Age at HLH 10 mo 17 mo 3 y 2 y 10 mo 3 y 1 y 2 y Areas of LCH Colon, skin, ln, bone marrow Left mastoid Skin, bone, ln, bone marrow Skin, bone Skin, bone, ln, lungs Skin, bone, ln Skin, bone, ln, hepatomegaly Skin, bone Prior therapies None None 2CDA, ARAC×6 mo Prednisone, VBL, 6-MP, MTX×6 mo None Prednisone, VBL, 6-MP, MTX Prednisone, VCR, ARAC Prednisone, VBL, 2CDA Clinical course Presented with fever, diarrhea, HSM, LAD, and pulmonary disease Presented with fever, HSM, LAD, and bone lesion 2 cycles of clofarabine. Lesions improved but developed HLH Presented with HLH on 3 different occasions 2 to 6 mo apart in the setting of influenza, HSV, and adenovirus Presented with HLH and CMV. Diagnosed with HLH and LCH of skin 9 mo after therapy completed, the patient presented with HLH 3 wk into therapy for LCH, the patient developed HLH 7 d after beginning clofarabine therapy, developed HLH. EBV PCR+ HLH treatment Chemotherapy Prednisone, VBL, VCR Dexamethasone, etoposide Cessation of chemotherapy, antibiotics, antivirals, IVIG Prednisone, etoposide Dexamethasone, cyclo A Dexamethasone, etoposide, cyclo A, followed by flu, mel, ATG cytox, and UCBT Dexamethasone, etoposide Outcome Died 10 mo after diagnosis CR Continued disease progression, followed by death within 2 mo CR CR CR CR and engrafted Disease-free now 3 y off therapy ARAC indicates cytarabine; ATG, anti-thymocyte globulin; 2CDA, cladribine; CMV, cytomegalovirus; CR, complete remission; cytox, cyclophosphamide; EBV, Epstein-Barr virus; flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; IN, lymph node; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; LCH, Langerhans cell histiocytosis; mel, melphalan; MP, mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction; UCBT, unrelated cord blood transplant; VBL, vinblastine; VCR, vincristine. The authors declare no conflict of interest.

CLADRIBINE, CLOFARABINE, PREDNISOLONE, VINBLASTINE

DrugsGivenReaction

CC BY-NC-ND

31725543

2021-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rhinorrhoea'.

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature. A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH. There are 3 distinct classes of histiocyte disorders: Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) (and other rarer class II disorders), and malignant histiocytoses.1 LCH is characterized by the proliferation of infiltrative Langerhans cells into skin or bone; multisystem disease can also involve the lungs, liver, spleen, bone marrow, and central nervous system. Although historically thought of as a benign, reactive process, BRAF-V600E mutations have been found in 25% to 70% of LCH patients, with MAP2K1 positivity in 46% of BRAF-negative cases, raising the possibility that LCH is a malignancy.2–4 Many believe LCH may represent a myeloid-lineage neoplasm driven by ERK signaling.5,6 The treatment for LCH depends on the extent of disease and ranges from local and/or topical therapies to systemic chemotherapy.5,7 HLH is a disease of systemic, dysregulated immune activation and inflammation.8 HLH can be familial or secondary to infections, autoimmune processes, or malignancies.1 Treatment is with systemic dexamethasone and etoposide per the HLH94 protocol, with some patients, especially those with familial and/or reactivated HLH, ultimately requiring hematopoietic stem cell transplant for a cure.9 Recent studies suggest that targeted therapies such as emapalumab may also play a role, especially in refractory cases.10 Table 1 reviews LCH and HLH in respect to presentation, diagnostic criteria, and treatments. Though they are regarded as separate disease states, they can occur together within the same patient. Favara et al11 reviewed 30 pathology files of patients with coexisting LCH and macrophage activation; 7 of these met full diagnostic criteria for HLH. We report the case of a 20-month-old patient with multisystem LCH who developed HLH during treatment and summarize the literature for other case reports of HLH in LCH. TABLE 1 Comparison of LCH and HLH8,12 LCH HLH Pathophysiology Derived from clonal CD1a+ dendritic cells Lesions contain inflammatory infiltrates including high levels of T-cell regulatory molecules Defects in target cell killing by cytotoxic T cells Immune dysregulation with excessive proinflammatory cytokine production and macrophage response Uncontrolled systemic inflammation Can be primary or secondary to an infection, malignancy, autoimmune condition Molecular findings 38%-57% possess BRAF-V600E mutation Perforin MUNC 13-4, MUNC 18-2 Syntaxin 11 LYST, CHS1, Rab27A, AP3B1 SH2D1A, XIAP, BIRC4, SAP Presenting signs/symptoms Bone pain, swelling, fractures Chest pain, cough, dyspnea Rash, seborrhea, otitis externa Polyuria, polydipsia Fatigue, weight loss, fevers, lymphadenopathy Sepsis-like presentation Fever Cytopenias Hepatitis Splenomegaly Ataxia, seizures, abnormal MRI in 50% Diagnostic criteria Tissue biopsy containing CD207+, CD1a+ dendritic cells Characteristic morphology of Langerhans cells Requires 5/8 diagnostic criteria:  Fever  Splenomegaly  Cytopenias in ≥2 cell lines  Hyperferritinemia >500 mg/mL  sIL2 >2400 U/mL  Hypertriglyceridemia/hypofibrinogenemia  Hemophagocytosis in tissue biopsy  Low or absent NK cell activity Treatment Local therapy for unifocal bony disease Prednisone, vinblastine Cladribine, cytarabine, clofarabine for refractory/recurrent disease BMT for marrow/refractory disease Decadron, etoposide±cyclosporine Alemtuzumab for refractory cases Anti-INF-gamma antibodies for refractory cases BMT indicates bone marrow transplant; HLH, hemophagocytic lymphohistiocytosis; IL2, soluble interleukin-2; INF, interferon; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; NK, natural killer. RESULTS: CASE DESCRIPTION A 20-month-old male individual presented to his pediatrician with 6 months of progressive limp and unilateral leg pain, leading to a refusal to bear weight. He also had chronic drainage from bilateral ears. A radiograph showed a lucent, expansile lesion of the child’s femur and biopsy was performed, showing s100+, CD1a+ LCH. Further evaluation using skeletal survey and positron emission tomography-computed tomography (PET/CT) revealed multiple bony lytic lesions of the skull, axial skeleton and extremities, a scaling diffuse rash of the scalp, and hypermetabolic cervical lymphadenopathy. He had no involvement of the lungs, liver, spleen, or bone marrow, and had normal magnetic resonance imaging appearance of his pituitary after passing a water deprivation test. His blood counts at diagnosis were normal other than a mild microcytic iron deficiency anemia. Liver function tests and ferritin were within normal limits. He began therapy with daily prednisone and weekly vinblastine as per the LCH-III protocol. After his initial 6 weeks of induction therapy, PET/CT showed improved but continued hypermetabolic bony lesions. He went on to the second phase of induction therapy with further improvement in lesions and then began continuation with pulses of prednisone and vinblastine every 3 weeks. Within 3 months, a follow-up PET/CT showed worsening hypermetabolic bony lesions. He was treated with cladribine for 5 days every 28 days. Interval imaging after 2 cycles again showed worsening hypermetabolic bony lesions, worsening skin rash on scalp, continued bilateral ear drainage, leg pain, and intermittent fevers with cough and rhinorrhea. He was found to be respiratory syncytial virus (RSV) positive at that time. The child began monotherapy with clofarabine 25 mg/m2 daily for 5 days. Daily fevers continued for 2 weeks and he developed transaminitis with hypoalbuminemia and fluid overload. Blood cultures were negative, and he was empirically treated with broad-spectrum antibiotics secondary to neutropenia. CT scans done as part of fever evaluation revealed multiple new lytic skull lesions. Epstein-Barr virus (EBV) polymerase chain reaction was positive at 863 copies, which resolved without intervention over the next month. He met criteria for HLH with fevers, pancytopenia, ferritin >7500 ng/mL, triglycerides 526 mg/dL, soluble interleukin (IL)2 of 8191 U/mL, and hemophagocytosis in his bone marrow. Mutational analysis for PRF1, MUNC 13-4, XIAP and other common HLH-causing genes was normal. He thus began therapy via HLH94 with dexamethasone 10 mg/m2/d and etoposide. At the end of the standard 8-week treatment period, his HLH was felt to be well controlled with resolution of fevers and cytopenias, as well as normalization of liver function tests, triglycerides, soluble IL2, and improvement in ferritin. He went on to complete an additional 5 cycles of clofarabine 25 mg/m2 (6 total cycles), with end of therapy PET/CT showing no evidence of disease. He is now 3 years off therapy and doing very well. DISCUSSION Histiocytes or mononuclear phagocytes, the immune cells implicated in the pathogenesis of both LCH and HLH, serve many functions in the normal immune response. These include antigen presentation, activation of immune function through cytokine signaling, and phagocytosis.12 In both LCH and HLH, affected tissues express high levels of T-cell stimulatory molecules and secrete inflammatory cytokines such as IL-6, interferon, and tumor necrosis factor.8 Studies of LCH lesions suggest that chemokine receptors, including CCR6, maybe abnormally upregulated which contributes to tissue infiltration.13,14 Furthermore, the T cells found abundantly in LCH lesions show increased expression for genes involved in leukocyte chemotaxis, such as SPP1, IL8 and plasminogen activator, among others.15 A lesion with increased accumulation of histiocytes and T cells may thus be at increased risk of uncontrolled activation of these cells, resulting in hypercytokinemia and progressive organ dysfunction like that seen in HLH.12 HLH has a known association with malignancy, especially leukemias and lymphomas. If LCH indeed represents a malignant clonal process of early myeloid-lineage cells, this may also explain the potential association between the 2 entities. Alternatively, it could be that children with LCH who require multiagent or prolonged chemotherapy courses develop HLH secondary to immune dysregulation from the treatments rather than the underlying disease. HLH in LCH is thought to be a rare phenomenon and we aimed to summarize the available reports (Table 2). In our patient (patient 8), and in those reported throughout the literature, common findings included young age, multisystem LCH, history of systemic chemotherapy, and often concurrent infection. Our patient with multisystem LCH had received a prolonged course of multiagent chemotherapy secondary to his refractory disease and then developed RSV. He was also positive for EBV. Although we did not find any other reports of RSV-associated HLH, EBV is a well-known trigger of HLH, as are other viruses including influenza, parvovirus, etc. One evaluation of 182 pediatric patients with EBV who also met criteria for HLH, showed significant immune dysregulation. These patients had abnormal natural killer cell activity, as well as decreased CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells, resulting in increased T-cell activation and decreased inhibition. HLA-DR expression was elevated, indicating high levels of T-cell activation, and further downstream cytokines such as IL2 and interferon-gamma were also significantly elevated.16 Thus, viral infections including EBV can result in uncontrolled proliferation and activation of T cells, which may be further increased in patients with preexisting immune dysregulation from chemotherapy and/or the underlying disease state. We believe the combination of immunosuppression and infection may have led to HLH in our patients. Interestingly, like our patient, another reported patient with LCH also developed HLH while receiving clofarabine, a deoxyadenosine analog. Although this may be coincidence, clofarabine after multiple other immunosuppressive agents may have contributed to significant immune dysregulation and HLH in these patients. A recently published multicenter article reviewed 29 patients who met criteria for HLH and LCH. As in the patients reviewed in Table 2, about half of the patients met criteria for HLH at or around the diagnosis of LCH. Most had active LCH at diagnosis of HLH and were receiving treatments similar to those listed in Table 2. Overall, 31% had some kind of infection when HLH developed, including EBV. HLH was increased most in those with risk organ involvement, but also seen in young females without bony involvement. The combination of HLH and LCH was associated with a poor prognosis.17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment. TABLE 2 Reported Patients With LCH and HLH Patient 111 Patient 211 Patient 318 Patient 419 Patient 520 Patient 621 Patient 722 Patient 8 Age at HLH 10 mo 17 mo 3 y 2 y 10 mo 3 y 1 y 2 y Areas of LCH Colon, skin, ln, bone marrow Left mastoid Skin, bone, ln, bone marrow Skin, bone Skin, bone, ln, lungs Skin, bone, ln Skin, bone, ln, hepatomegaly Skin, bone Prior therapies None None 2CDA, ARAC×6 mo Prednisone, VBL, 6-MP, MTX×6 mo None Prednisone, VBL, 6-MP, MTX Prednisone, VCR, ARAC Prednisone, VBL, 2CDA Clinical course Presented with fever, diarrhea, HSM, LAD, and pulmonary disease Presented with fever, HSM, LAD, and bone lesion 2 cycles of clofarabine. Lesions improved but developed HLH Presented with HLH on 3 different occasions 2 to 6 mo apart in the setting of influenza, HSV, and adenovirus Presented with HLH and CMV. Diagnosed with HLH and LCH of skin 9 mo after therapy completed, the patient presented with HLH 3 wk into therapy for LCH, the patient developed HLH 7 d after beginning clofarabine therapy, developed HLH. EBV PCR+ HLH treatment Chemotherapy Prednisone, VBL, VCR Dexamethasone, etoposide Cessation of chemotherapy, antibiotics, antivirals, IVIG Prednisone, etoposide Dexamethasone, cyclo A Dexamethasone, etoposide, cyclo A, followed by flu, mel, ATG cytox, and UCBT Dexamethasone, etoposide Outcome Died 10 mo after diagnosis CR Continued disease progression, followed by death within 2 mo CR CR CR CR and engrafted Disease-free now 3 y off therapy ARAC indicates cytarabine; ATG, anti-thymocyte globulin; 2CDA, cladribine; CMV, cytomegalovirus; CR, complete remission; cytox, cyclophosphamide; EBV, Epstein-Barr virus; flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; IN, lymph node; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; LCH, Langerhans cell histiocytosis; mel, melphalan; MP, mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction; UCBT, unrelated cord blood transplant; VBL, vinblastine; VCR, vincristine. The authors declare no conflict of interest.

CLADRIBINE, CLOFARABINE, PREDNISOLONE, VINBLASTINE

DrugsGivenReaction

CC BY-NC-ND

31725543

2021-01

What was the dosage of drug 'CLADRIBINE'?

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature. A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH. There are 3 distinct classes of histiocyte disorders: Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) (and other rarer class II disorders), and malignant histiocytoses.1 LCH is characterized by the proliferation of infiltrative Langerhans cells into skin or bone; multisystem disease can also involve the lungs, liver, spleen, bone marrow, and central nervous system. Although historically thought of as a benign, reactive process, BRAF-V600E mutations have been found in 25% to 70% of LCH patients, with MAP2K1 positivity in 46% of BRAF-negative cases, raising the possibility that LCH is a malignancy.2–4 Many believe LCH may represent a myeloid-lineage neoplasm driven by ERK signaling.5,6 The treatment for LCH depends on the extent of disease and ranges from local and/or topical therapies to systemic chemotherapy.5,7 HLH is a disease of systemic, dysregulated immune activation and inflammation.8 HLH can be familial or secondary to infections, autoimmune processes, or malignancies.1 Treatment is with systemic dexamethasone and etoposide per the HLH94 protocol, with some patients, especially those with familial and/or reactivated HLH, ultimately requiring hematopoietic stem cell transplant for a cure.9 Recent studies suggest that targeted therapies such as emapalumab may also play a role, especially in refractory cases.10 Table 1 reviews LCH and HLH in respect to presentation, diagnostic criteria, and treatments. Though they are regarded as separate disease states, they can occur together within the same patient. Favara et al11 reviewed 30 pathology files of patients with coexisting LCH and macrophage activation; 7 of these met full diagnostic criteria for HLH. We report the case of a 20-month-old patient with multisystem LCH who developed HLH during treatment and summarize the literature for other case reports of HLH in LCH. TABLE 1 Comparison of LCH and HLH8,12 LCH HLH Pathophysiology Derived from clonal CD1a+ dendritic cells Lesions contain inflammatory infiltrates including high levels of T-cell regulatory molecules Defects in target cell killing by cytotoxic T cells Immune dysregulation with excessive proinflammatory cytokine production and macrophage response Uncontrolled systemic inflammation Can be primary or secondary to an infection, malignancy, autoimmune condition Molecular findings 38%-57% possess BRAF-V600E mutation Perforin MUNC 13-4, MUNC 18-2 Syntaxin 11 LYST, CHS1, Rab27A, AP3B1 SH2D1A, XIAP, BIRC4, SAP Presenting signs/symptoms Bone pain, swelling, fractures Chest pain, cough, dyspnea Rash, seborrhea, otitis externa Polyuria, polydipsia Fatigue, weight loss, fevers, lymphadenopathy Sepsis-like presentation Fever Cytopenias Hepatitis Splenomegaly Ataxia, seizures, abnormal MRI in 50% Diagnostic criteria Tissue biopsy containing CD207+, CD1a+ dendritic cells Characteristic morphology of Langerhans cells Requires 5/8 diagnostic criteria:  Fever  Splenomegaly  Cytopenias in ≥2 cell lines  Hyperferritinemia >500 mg/mL  sIL2 >2400 U/mL  Hypertriglyceridemia/hypofibrinogenemia  Hemophagocytosis in tissue biopsy  Low or absent NK cell activity Treatment Local therapy for unifocal bony disease Prednisone, vinblastine Cladribine, cytarabine, clofarabine for refractory/recurrent disease BMT for marrow/refractory disease Decadron, etoposide±cyclosporine Alemtuzumab for refractory cases Anti-INF-gamma antibodies for refractory cases BMT indicates bone marrow transplant; HLH, hemophagocytic lymphohistiocytosis; IL2, soluble interleukin-2; INF, interferon; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; NK, natural killer. RESULTS: CASE DESCRIPTION A 20-month-old male individual presented to his pediatrician with 6 months of progressive limp and unilateral leg pain, leading to a refusal to bear weight. He also had chronic drainage from bilateral ears. A radiograph showed a lucent, expansile lesion of the child’s femur and biopsy was performed, showing s100+, CD1a+ LCH. Further evaluation using skeletal survey and positron emission tomography-computed tomography (PET/CT) revealed multiple bony lytic lesions of the skull, axial skeleton and extremities, a scaling diffuse rash of the scalp, and hypermetabolic cervical lymphadenopathy. He had no involvement of the lungs, liver, spleen, or bone marrow, and had normal magnetic resonance imaging appearance of his pituitary after passing a water deprivation test. His blood counts at diagnosis were normal other than a mild microcytic iron deficiency anemia. Liver function tests and ferritin were within normal limits. He began therapy with daily prednisone and weekly vinblastine as per the LCH-III protocol. After his initial 6 weeks of induction therapy, PET/CT showed improved but continued hypermetabolic bony lesions. He went on to the second phase of induction therapy with further improvement in lesions and then began continuation with pulses of prednisone and vinblastine every 3 weeks. Within 3 months, a follow-up PET/CT showed worsening hypermetabolic bony lesions. He was treated with cladribine for 5 days every 28 days. Interval imaging after 2 cycles again showed worsening hypermetabolic bony lesions, worsening skin rash on scalp, continued bilateral ear drainage, leg pain, and intermittent fevers with cough and rhinorrhea. He was found to be respiratory syncytial virus (RSV) positive at that time. The child began monotherapy with clofarabine 25 mg/m2 daily for 5 days. Daily fevers continued for 2 weeks and he developed transaminitis with hypoalbuminemia and fluid overload. Blood cultures were negative, and he was empirically treated with broad-spectrum antibiotics secondary to neutropenia. CT scans done as part of fever evaluation revealed multiple new lytic skull lesions. Epstein-Barr virus (EBV) polymerase chain reaction was positive at 863 copies, which resolved without intervention over the next month. He met criteria for HLH with fevers, pancytopenia, ferritin >7500 ng/mL, triglycerides 526 mg/dL, soluble interleukin (IL)2 of 8191 U/mL, and hemophagocytosis in his bone marrow. Mutational analysis for PRF1, MUNC 13-4, XIAP and other common HLH-causing genes was normal. He thus began therapy via HLH94 with dexamethasone 10 mg/m2/d and etoposide. At the end of the standard 8-week treatment period, his HLH was felt to be well controlled with resolution of fevers and cytopenias, as well as normalization of liver function tests, triglycerides, soluble IL2, and improvement in ferritin. He went on to complete an additional 5 cycles of clofarabine 25 mg/m2 (6 total cycles), with end of therapy PET/CT showing no evidence of disease. He is now 3 years off therapy and doing very well. DISCUSSION Histiocytes or mononuclear phagocytes, the immune cells implicated in the pathogenesis of both LCH and HLH, serve many functions in the normal immune response. These include antigen presentation, activation of immune function through cytokine signaling, and phagocytosis.12 In both LCH and HLH, affected tissues express high levels of T-cell stimulatory molecules and secrete inflammatory cytokines such as IL-6, interferon, and tumor necrosis factor.8 Studies of LCH lesions suggest that chemokine receptors, including CCR6, maybe abnormally upregulated which contributes to tissue infiltration.13,14 Furthermore, the T cells found abundantly in LCH lesions show increased expression for genes involved in leukocyte chemotaxis, such as SPP1, IL8 and plasminogen activator, among others.15 A lesion with increased accumulation of histiocytes and T cells may thus be at increased risk of uncontrolled activation of these cells, resulting in hypercytokinemia and progressive organ dysfunction like that seen in HLH.12 HLH has a known association with malignancy, especially leukemias and lymphomas. If LCH indeed represents a malignant clonal process of early myeloid-lineage cells, this may also explain the potential association between the 2 entities. Alternatively, it could be that children with LCH who require multiagent or prolonged chemotherapy courses develop HLH secondary to immune dysregulation from the treatments rather than the underlying disease. HLH in LCH is thought to be a rare phenomenon and we aimed to summarize the available reports (Table 2). In our patient (patient 8), and in those reported throughout the literature, common findings included young age, multisystem LCH, history of systemic chemotherapy, and often concurrent infection. Our patient with multisystem LCH had received a prolonged course of multiagent chemotherapy secondary to his refractory disease and then developed RSV. He was also positive for EBV. Although we did not find any other reports of RSV-associated HLH, EBV is a well-known trigger of HLH, as are other viruses including influenza, parvovirus, etc. One evaluation of 182 pediatric patients with EBV who also met criteria for HLH, showed significant immune dysregulation. These patients had abnormal natural killer cell activity, as well as decreased CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells, resulting in increased T-cell activation and decreased inhibition. HLA-DR expression was elevated, indicating high levels of T-cell activation, and further downstream cytokines such as IL2 and interferon-gamma were also significantly elevated.16 Thus, viral infections including EBV can result in uncontrolled proliferation and activation of T cells, which may be further increased in patients with preexisting immune dysregulation from chemotherapy and/or the underlying disease state. We believe the combination of immunosuppression and infection may have led to HLH in our patients. Interestingly, like our patient, another reported patient with LCH also developed HLH while receiving clofarabine, a deoxyadenosine analog. Although this may be coincidence, clofarabine after multiple other immunosuppressive agents may have contributed to significant immune dysregulation and HLH in these patients. A recently published multicenter article reviewed 29 patients who met criteria for HLH and LCH. As in the patients reviewed in Table 2, about half of the patients met criteria for HLH at or around the diagnosis of LCH. Most had active LCH at diagnosis of HLH and were receiving treatments similar to those listed in Table 2. Overall, 31% had some kind of infection when HLH developed, including EBV. HLH was increased most in those with risk organ involvement, but also seen in young females without bony involvement. The combination of HLH and LCH was associated with a poor prognosis.17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment. TABLE 2 Reported Patients With LCH and HLH Patient 111 Patient 211 Patient 318 Patient 419 Patient 520 Patient 621 Patient 722 Patient 8 Age at HLH 10 mo 17 mo 3 y 2 y 10 mo 3 y 1 y 2 y Areas of LCH Colon, skin, ln, bone marrow Left mastoid Skin, bone, ln, bone marrow Skin, bone Skin, bone, ln, lungs Skin, bone, ln Skin, bone, ln, hepatomegaly Skin, bone Prior therapies None None 2CDA, ARAC×6 mo Prednisone, VBL, 6-MP, MTX×6 mo None Prednisone, VBL, 6-MP, MTX Prednisone, VCR, ARAC Prednisone, VBL, 2CDA Clinical course Presented with fever, diarrhea, HSM, LAD, and pulmonary disease Presented with fever, HSM, LAD, and bone lesion 2 cycles of clofarabine. Lesions improved but developed HLH Presented with HLH on 3 different occasions 2 to 6 mo apart in the setting of influenza, HSV, and adenovirus Presented with HLH and CMV. Diagnosed with HLH and LCH of skin 9 mo after therapy completed, the patient presented with HLH 3 wk into therapy for LCH, the patient developed HLH 7 d after beginning clofarabine therapy, developed HLH. EBV PCR+ HLH treatment Chemotherapy Prednisone, VBL, VCR Dexamethasone, etoposide Cessation of chemotherapy, antibiotics, antivirals, IVIG Prednisone, etoposide Dexamethasone, cyclo A Dexamethasone, etoposide, cyclo A, followed by flu, mel, ATG cytox, and UCBT Dexamethasone, etoposide Outcome Died 10 mo after diagnosis CR Continued disease progression, followed by death within 2 mo CR CR CR CR and engrafted Disease-free now 3 y off therapy ARAC indicates cytarabine; ATG, anti-thymocyte globulin; 2CDA, cladribine; CMV, cytomegalovirus; CR, complete remission; cytox, cyclophosphamide; EBV, Epstein-Barr virus; flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; IN, lymph node; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; LCH, Langerhans cell histiocytosis; mel, melphalan; MP, mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction; UCBT, unrelated cord blood transplant; VBL, vinblastine; VCR, vincristine. The authors declare no conflict of interest.

EVERY 28 DAYS

DrugDosageText

CC BY-NC-ND

31725543

2021-01

What was the dosage of drug 'CLOFARABINE'?

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature. A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH. There are 3 distinct classes of histiocyte disorders: Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) (and other rarer class II disorders), and malignant histiocytoses.1 LCH is characterized by the proliferation of infiltrative Langerhans cells into skin or bone; multisystem disease can also involve the lungs, liver, spleen, bone marrow, and central nervous system. Although historically thought of as a benign, reactive process, BRAF-V600E mutations have been found in 25% to 70% of LCH patients, with MAP2K1 positivity in 46% of BRAF-negative cases, raising the possibility that LCH is a malignancy.2–4 Many believe LCH may represent a myeloid-lineage neoplasm driven by ERK signaling.5,6 The treatment for LCH depends on the extent of disease and ranges from local and/or topical therapies to systemic chemotherapy.5,7 HLH is a disease of systemic, dysregulated immune activation and inflammation.8 HLH can be familial or secondary to infections, autoimmune processes, or malignancies.1 Treatment is with systemic dexamethasone and etoposide per the HLH94 protocol, with some patients, especially those with familial and/or reactivated HLH, ultimately requiring hematopoietic stem cell transplant for a cure.9 Recent studies suggest that targeted therapies such as emapalumab may also play a role, especially in refractory cases.10 Table 1 reviews LCH and HLH in respect to presentation, diagnostic criteria, and treatments. Though they are regarded as separate disease states, they can occur together within the same patient. Favara et al11 reviewed 30 pathology files of patients with coexisting LCH and macrophage activation; 7 of these met full diagnostic criteria for HLH. We report the case of a 20-month-old patient with multisystem LCH who developed HLH during treatment and summarize the literature for other case reports of HLH in LCH. TABLE 1 Comparison of LCH and HLH8,12 LCH HLH Pathophysiology Derived from clonal CD1a+ dendritic cells Lesions contain inflammatory infiltrates including high levels of T-cell regulatory molecules Defects in target cell killing by cytotoxic T cells Immune dysregulation with excessive proinflammatory cytokine production and macrophage response Uncontrolled systemic inflammation Can be primary or secondary to an infection, malignancy, autoimmune condition Molecular findings 38%-57% possess BRAF-V600E mutation Perforin MUNC 13-4, MUNC 18-2 Syntaxin 11 LYST, CHS1, Rab27A, AP3B1 SH2D1A, XIAP, BIRC4, SAP Presenting signs/symptoms Bone pain, swelling, fractures Chest pain, cough, dyspnea Rash, seborrhea, otitis externa Polyuria, polydipsia Fatigue, weight loss, fevers, lymphadenopathy Sepsis-like presentation Fever Cytopenias Hepatitis Splenomegaly Ataxia, seizures, abnormal MRI in 50% Diagnostic criteria Tissue biopsy containing CD207+, CD1a+ dendritic cells Characteristic morphology of Langerhans cells Requires 5/8 diagnostic criteria:  Fever  Splenomegaly  Cytopenias in ≥2 cell lines  Hyperferritinemia >500 mg/mL  sIL2 >2400 U/mL  Hypertriglyceridemia/hypofibrinogenemia  Hemophagocytosis in tissue biopsy  Low or absent NK cell activity Treatment Local therapy for unifocal bony disease Prednisone, vinblastine Cladribine, cytarabine, clofarabine for refractory/recurrent disease BMT for marrow/refractory disease Decadron, etoposide±cyclosporine Alemtuzumab for refractory cases Anti-INF-gamma antibodies for refractory cases BMT indicates bone marrow transplant; HLH, hemophagocytic lymphohistiocytosis; IL2, soluble interleukin-2; INF, interferon; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; NK, natural killer. RESULTS: CASE DESCRIPTION A 20-month-old male individual presented to his pediatrician with 6 months of progressive limp and unilateral leg pain, leading to a refusal to bear weight. He also had chronic drainage from bilateral ears. A radiograph showed a lucent, expansile lesion of the child’s femur and biopsy was performed, showing s100+, CD1a+ LCH. Further evaluation using skeletal survey and positron emission tomography-computed tomography (PET/CT) revealed multiple bony lytic lesions of the skull, axial skeleton and extremities, a scaling diffuse rash of the scalp, and hypermetabolic cervical lymphadenopathy. He had no involvement of the lungs, liver, spleen, or bone marrow, and had normal magnetic resonance imaging appearance of his pituitary after passing a water deprivation test. His blood counts at diagnosis were normal other than a mild microcytic iron deficiency anemia. Liver function tests and ferritin were within normal limits. He began therapy with daily prednisone and weekly vinblastine as per the LCH-III protocol. After his initial 6 weeks of induction therapy, PET/CT showed improved but continued hypermetabolic bony lesions. He went on to the second phase of induction therapy with further improvement in lesions and then began continuation with pulses of prednisone and vinblastine every 3 weeks. Within 3 months, a follow-up PET/CT showed worsening hypermetabolic bony lesions. He was treated with cladribine for 5 days every 28 days. Interval imaging after 2 cycles again showed worsening hypermetabolic bony lesions, worsening skin rash on scalp, continued bilateral ear drainage, leg pain, and intermittent fevers with cough and rhinorrhea. He was found to be respiratory syncytial virus (RSV) positive at that time. The child began monotherapy with clofarabine 25 mg/m2 daily for 5 days. Daily fevers continued for 2 weeks and he developed transaminitis with hypoalbuminemia and fluid overload. Blood cultures were negative, and he was empirically treated with broad-spectrum antibiotics secondary to neutropenia. CT scans done as part of fever evaluation revealed multiple new lytic skull lesions. Epstein-Barr virus (EBV) polymerase chain reaction was positive at 863 copies, which resolved without intervention over the next month. He met criteria for HLH with fevers, pancytopenia, ferritin >7500 ng/mL, triglycerides 526 mg/dL, soluble interleukin (IL)2 of 8191 U/mL, and hemophagocytosis in his bone marrow. Mutational analysis for PRF1, MUNC 13-4, XIAP and other common HLH-causing genes was normal. He thus began therapy via HLH94 with dexamethasone 10 mg/m2/d and etoposide. At the end of the standard 8-week treatment period, his HLH was felt to be well controlled with resolution of fevers and cytopenias, as well as normalization of liver function tests, triglycerides, soluble IL2, and improvement in ferritin. He went on to complete an additional 5 cycles of clofarabine 25 mg/m2 (6 total cycles), with end of therapy PET/CT showing no evidence of disease. He is now 3 years off therapy and doing very well. DISCUSSION Histiocytes or mononuclear phagocytes, the immune cells implicated in the pathogenesis of both LCH and HLH, serve many functions in the normal immune response. These include antigen presentation, activation of immune function through cytokine signaling, and phagocytosis.12 In both LCH and HLH, affected tissues express high levels of T-cell stimulatory molecules and secrete inflammatory cytokines such as IL-6, interferon, and tumor necrosis factor.8 Studies of LCH lesions suggest that chemokine receptors, including CCR6, maybe abnormally upregulated which contributes to tissue infiltration.13,14 Furthermore, the T cells found abundantly in LCH lesions show increased expression for genes involved in leukocyte chemotaxis, such as SPP1, IL8 and plasminogen activator, among others.15 A lesion with increased accumulation of histiocytes and T cells may thus be at increased risk of uncontrolled activation of these cells, resulting in hypercytokinemia and progressive organ dysfunction like that seen in HLH.12 HLH has a known association with malignancy, especially leukemias and lymphomas. If LCH indeed represents a malignant clonal process of early myeloid-lineage cells, this may also explain the potential association between the 2 entities. Alternatively, it could be that children with LCH who require multiagent or prolonged chemotherapy courses develop HLH secondary to immune dysregulation from the treatments rather than the underlying disease. HLH in LCH is thought to be a rare phenomenon and we aimed to summarize the available reports (Table 2). In our patient (patient 8), and in those reported throughout the literature, common findings included young age, multisystem LCH, history of systemic chemotherapy, and often concurrent infection. Our patient with multisystem LCH had received a prolonged course of multiagent chemotherapy secondary to his refractory disease and then developed RSV. He was also positive for EBV. Although we did not find any other reports of RSV-associated HLH, EBV is a well-known trigger of HLH, as are other viruses including influenza, parvovirus, etc. One evaluation of 182 pediatric patients with EBV who also met criteria for HLH, showed significant immune dysregulation. These patients had abnormal natural killer cell activity, as well as decreased CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells, resulting in increased T-cell activation and decreased inhibition. HLA-DR expression was elevated, indicating high levels of T-cell activation, and further downstream cytokines such as IL2 and interferon-gamma were also significantly elevated.16 Thus, viral infections including EBV can result in uncontrolled proliferation and activation of T cells, which may be further increased in patients with preexisting immune dysregulation from chemotherapy and/or the underlying disease state. We believe the combination of immunosuppression and infection may have led to HLH in our patients. Interestingly, like our patient, another reported patient with LCH also developed HLH while receiving clofarabine, a deoxyadenosine analog. Although this may be coincidence, clofarabine after multiple other immunosuppressive agents may have contributed to significant immune dysregulation and HLH in these patients. A recently published multicenter article reviewed 29 patients who met criteria for HLH and LCH. As in the patients reviewed in Table 2, about half of the patients met criteria for HLH at or around the diagnosis of LCH. Most had active LCH at diagnosis of HLH and were receiving treatments similar to those listed in Table 2. Overall, 31% had some kind of infection when HLH developed, including EBV. HLH was increased most in those with risk organ involvement, but also seen in young females without bony involvement. The combination of HLH and LCH was associated with a poor prognosis.17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment. TABLE 2 Reported Patients With LCH and HLH Patient 111 Patient 211 Patient 318 Patient 419 Patient 520 Patient 621 Patient 722 Patient 8 Age at HLH 10 mo 17 mo 3 y 2 y 10 mo 3 y 1 y 2 y Areas of LCH Colon, skin, ln, bone marrow Left mastoid Skin, bone, ln, bone marrow Skin, bone Skin, bone, ln, lungs Skin, bone, ln Skin, bone, ln, hepatomegaly Skin, bone Prior therapies None None 2CDA, ARAC×6 mo Prednisone, VBL, 6-MP, MTX×6 mo None Prednisone, VBL, 6-MP, MTX Prednisone, VCR, ARAC Prednisone, VBL, 2CDA Clinical course Presented with fever, diarrhea, HSM, LAD, and pulmonary disease Presented with fever, HSM, LAD, and bone lesion 2 cycles of clofarabine. Lesions improved but developed HLH Presented with HLH on 3 different occasions 2 to 6 mo apart in the setting of influenza, HSV, and adenovirus Presented with HLH and CMV. Diagnosed with HLH and LCH of skin 9 mo after therapy completed, the patient presented with HLH 3 wk into therapy for LCH, the patient developed HLH 7 d after beginning clofarabine therapy, developed HLH. EBV PCR+ HLH treatment Chemotherapy Prednisone, VBL, VCR Dexamethasone, etoposide Cessation of chemotherapy, antibiotics, antivirals, IVIG Prednisone, etoposide Dexamethasone, cyclo A Dexamethasone, etoposide, cyclo A, followed by flu, mel, ATG cytox, and UCBT Dexamethasone, etoposide Outcome Died 10 mo after diagnosis CR Continued disease progression, followed by death within 2 mo CR CR CR CR and engrafted Disease-free now 3 y off therapy ARAC indicates cytarabine; ATG, anti-thymocyte globulin; 2CDA, cladribine; CMV, cytomegalovirus; CR, complete remission; cytox, cyclophosphamide; EBV, Epstein-Barr virus; flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; IN, lymph node; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; LCH, Langerhans cell histiocytosis; mel, melphalan; MP, mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction; UCBT, unrelated cord blood transplant; VBL, vinblastine; VCR, vincristine. The authors declare no conflict of interest.

25 MG/M2, QD

DrugDosageText

CC BY-NC-ND

31725543

2021-01

What was the dosage of drug 'PREDNISONE'?

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature. A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH. There are 3 distinct classes of histiocyte disorders: Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) (and other rarer class II disorders), and malignant histiocytoses.1 LCH is characterized by the proliferation of infiltrative Langerhans cells into skin or bone; multisystem disease can also involve the lungs, liver, spleen, bone marrow, and central nervous system. Although historically thought of as a benign, reactive process, BRAF-V600E mutations have been found in 25% to 70% of LCH patients, with MAP2K1 positivity in 46% of BRAF-negative cases, raising the possibility that LCH is a malignancy.2–4 Many believe LCH may represent a myeloid-lineage neoplasm driven by ERK signaling.5,6 The treatment for LCH depends on the extent of disease and ranges from local and/or topical therapies to systemic chemotherapy.5,7 HLH is a disease of systemic, dysregulated immune activation and inflammation.8 HLH can be familial or secondary to infections, autoimmune processes, or malignancies.1 Treatment is with systemic dexamethasone and etoposide per the HLH94 protocol, with some patients, especially those with familial and/or reactivated HLH, ultimately requiring hematopoietic stem cell transplant for a cure.9 Recent studies suggest that targeted therapies such as emapalumab may also play a role, especially in refractory cases.10 Table 1 reviews LCH and HLH in respect to presentation, diagnostic criteria, and treatments. Though they are regarded as separate disease states, they can occur together within the same patient. Favara et al11 reviewed 30 pathology files of patients with coexisting LCH and macrophage activation; 7 of these met full diagnostic criteria for HLH. We report the case of a 20-month-old patient with multisystem LCH who developed HLH during treatment and summarize the literature for other case reports of HLH in LCH. TABLE 1 Comparison of LCH and HLH8,12 LCH HLH Pathophysiology Derived from clonal CD1a+ dendritic cells Lesions contain inflammatory infiltrates including high levels of T-cell regulatory molecules Defects in target cell killing by cytotoxic T cells Immune dysregulation with excessive proinflammatory cytokine production and macrophage response Uncontrolled systemic inflammation Can be primary or secondary to an infection, malignancy, autoimmune condition Molecular findings 38%-57% possess BRAF-V600E mutation Perforin MUNC 13-4, MUNC 18-2 Syntaxin 11 LYST, CHS1, Rab27A, AP3B1 SH2D1A, XIAP, BIRC4, SAP Presenting signs/symptoms Bone pain, swelling, fractures Chest pain, cough, dyspnea Rash, seborrhea, otitis externa Polyuria, polydipsia Fatigue, weight loss, fevers, lymphadenopathy Sepsis-like presentation Fever Cytopenias Hepatitis Splenomegaly Ataxia, seizures, abnormal MRI in 50% Diagnostic criteria Tissue biopsy containing CD207+, CD1a+ dendritic cells Characteristic morphology of Langerhans cells Requires 5/8 diagnostic criteria:  Fever  Splenomegaly  Cytopenias in ≥2 cell lines  Hyperferritinemia >500 mg/mL  sIL2 >2400 U/mL  Hypertriglyceridemia/hypofibrinogenemia  Hemophagocytosis in tissue biopsy  Low or absent NK cell activity Treatment Local therapy for unifocal bony disease Prednisone, vinblastine Cladribine, cytarabine, clofarabine for refractory/recurrent disease BMT for marrow/refractory disease Decadron, etoposide±cyclosporine Alemtuzumab for refractory cases Anti-INF-gamma antibodies for refractory cases BMT indicates bone marrow transplant; HLH, hemophagocytic lymphohistiocytosis; IL2, soluble interleukin-2; INF, interferon; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; NK, natural killer. RESULTS: CASE DESCRIPTION A 20-month-old male individual presented to his pediatrician with 6 months of progressive limp and unilateral leg pain, leading to a refusal to bear weight. He also had chronic drainage from bilateral ears. A radiograph showed a lucent, expansile lesion of the child’s femur and biopsy was performed, showing s100+, CD1a+ LCH. Further evaluation using skeletal survey and positron emission tomography-computed tomography (PET/CT) revealed multiple bony lytic lesions of the skull, axial skeleton and extremities, a scaling diffuse rash of the scalp, and hypermetabolic cervical lymphadenopathy. He had no involvement of the lungs, liver, spleen, or bone marrow, and had normal magnetic resonance imaging appearance of his pituitary after passing a water deprivation test. His blood counts at diagnosis were normal other than a mild microcytic iron deficiency anemia. Liver function tests and ferritin were within normal limits. He began therapy with daily prednisone and weekly vinblastine as per the LCH-III protocol. After his initial 6 weeks of induction therapy, PET/CT showed improved but continued hypermetabolic bony lesions. He went on to the second phase of induction therapy with further improvement in lesions and then began continuation with pulses of prednisone and vinblastine every 3 weeks. Within 3 months, a follow-up PET/CT showed worsening hypermetabolic bony lesions. He was treated with cladribine for 5 days every 28 days. Interval imaging after 2 cycles again showed worsening hypermetabolic bony lesions, worsening skin rash on scalp, continued bilateral ear drainage, leg pain, and intermittent fevers with cough and rhinorrhea. He was found to be respiratory syncytial virus (RSV) positive at that time. The child began monotherapy with clofarabine 25 mg/m2 daily for 5 days. Daily fevers continued for 2 weeks and he developed transaminitis with hypoalbuminemia and fluid overload. Blood cultures were negative, and he was empirically treated with broad-spectrum antibiotics secondary to neutropenia. CT scans done as part of fever evaluation revealed multiple new lytic skull lesions. Epstein-Barr virus (EBV) polymerase chain reaction was positive at 863 copies, which resolved without intervention over the next month. He met criteria for HLH with fevers, pancytopenia, ferritin >7500 ng/mL, triglycerides 526 mg/dL, soluble interleukin (IL)2 of 8191 U/mL, and hemophagocytosis in his bone marrow. Mutational analysis for PRF1, MUNC 13-4, XIAP and other common HLH-causing genes was normal. He thus began therapy via HLH94 with dexamethasone 10 mg/m2/d and etoposide. At the end of the standard 8-week treatment period, his HLH was felt to be well controlled with resolution of fevers and cytopenias, as well as normalization of liver function tests, triglycerides, soluble IL2, and improvement in ferritin. He went on to complete an additional 5 cycles of clofarabine 25 mg/m2 (6 total cycles), with end of therapy PET/CT showing no evidence of disease. He is now 3 years off therapy and doing very well. DISCUSSION Histiocytes or mononuclear phagocytes, the immune cells implicated in the pathogenesis of both LCH and HLH, serve many functions in the normal immune response. These include antigen presentation, activation of immune function through cytokine signaling, and phagocytosis.12 In both LCH and HLH, affected tissues express high levels of T-cell stimulatory molecules and secrete inflammatory cytokines such as IL-6, interferon, and tumor necrosis factor.8 Studies of LCH lesions suggest that chemokine receptors, including CCR6, maybe abnormally upregulated which contributes to tissue infiltration.13,14 Furthermore, the T cells found abundantly in LCH lesions show increased expression for genes involved in leukocyte chemotaxis, such as SPP1, IL8 and plasminogen activator, among others.15 A lesion with increased accumulation of histiocytes and T cells may thus be at increased risk of uncontrolled activation of these cells, resulting in hypercytokinemia and progressive organ dysfunction like that seen in HLH.12 HLH has a known association with malignancy, especially leukemias and lymphomas. If LCH indeed represents a malignant clonal process of early myeloid-lineage cells, this may also explain the potential association between the 2 entities. Alternatively, it could be that children with LCH who require multiagent or prolonged chemotherapy courses develop HLH secondary to immune dysregulation from the treatments rather than the underlying disease. HLH in LCH is thought to be a rare phenomenon and we aimed to summarize the available reports (Table 2). In our patient (patient 8), and in those reported throughout the literature, common findings included young age, multisystem LCH, history of systemic chemotherapy, and often concurrent infection. Our patient with multisystem LCH had received a prolonged course of multiagent chemotherapy secondary to his refractory disease and then developed RSV. He was also positive for EBV. Although we did not find any other reports of RSV-associated HLH, EBV is a well-known trigger of HLH, as are other viruses including influenza, parvovirus, etc. One evaluation of 182 pediatric patients with EBV who also met criteria for HLH, showed significant immune dysregulation. These patients had abnormal natural killer cell activity, as well as decreased CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells, resulting in increased T-cell activation and decreased inhibition. HLA-DR expression was elevated, indicating high levels of T-cell activation, and further downstream cytokines such as IL2 and interferon-gamma were also significantly elevated.16 Thus, viral infections including EBV can result in uncontrolled proliferation and activation of T cells, which may be further increased in patients with preexisting immune dysregulation from chemotherapy and/or the underlying disease state. We believe the combination of immunosuppression and infection may have led to HLH in our patients. Interestingly, like our patient, another reported patient with LCH also developed HLH while receiving clofarabine, a deoxyadenosine analog. Although this may be coincidence, clofarabine after multiple other immunosuppressive agents may have contributed to significant immune dysregulation and HLH in these patients. A recently published multicenter article reviewed 29 patients who met criteria for HLH and LCH. As in the patients reviewed in Table 2, about half of the patients met criteria for HLH at or around the diagnosis of LCH. Most had active LCH at diagnosis of HLH and were receiving treatments similar to those listed in Table 2. Overall, 31% had some kind of infection when HLH developed, including EBV. HLH was increased most in those with risk organ involvement, but also seen in young females without bony involvement. The combination of HLH and LCH was associated with a poor prognosis.17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment. TABLE 2 Reported Patients With LCH and HLH Patient 111 Patient 211 Patient 318 Patient 419 Patient 520 Patient 621 Patient 722 Patient 8 Age at HLH 10 mo 17 mo 3 y 2 y 10 mo 3 y 1 y 2 y Areas of LCH Colon, skin, ln, bone marrow Left mastoid Skin, bone, ln, bone marrow Skin, bone Skin, bone, ln, lungs Skin, bone, ln Skin, bone, ln, hepatomegaly Skin, bone Prior therapies None None 2CDA, ARAC×6 mo Prednisone, VBL, 6-MP, MTX×6 mo None Prednisone, VBL, 6-MP, MTX Prednisone, VCR, ARAC Prednisone, VBL, 2CDA Clinical course Presented with fever, diarrhea, HSM, LAD, and pulmonary disease Presented with fever, HSM, LAD, and bone lesion 2 cycles of clofarabine. Lesions improved but developed HLH Presented with HLH on 3 different occasions 2 to 6 mo apart in the setting of influenza, HSV, and adenovirus Presented with HLH and CMV. Diagnosed with HLH and LCH of skin 9 mo after therapy completed, the patient presented with HLH 3 wk into therapy for LCH, the patient developed HLH 7 d after beginning clofarabine therapy, developed HLH. EBV PCR+ HLH treatment Chemotherapy Prednisone, VBL, VCR Dexamethasone, etoposide Cessation of chemotherapy, antibiotics, antivirals, IVIG Prednisone, etoposide Dexamethasone, cyclo A Dexamethasone, etoposide, cyclo A, followed by flu, mel, ATG cytox, and UCBT Dexamethasone, etoposide Outcome Died 10 mo after diagnosis CR Continued disease progression, followed by death within 2 mo CR CR CR CR and engrafted Disease-free now 3 y off therapy ARAC indicates cytarabine; ATG, anti-thymocyte globulin; 2CDA, cladribine; CMV, cytomegalovirus; CR, complete remission; cytox, cyclophosphamide; EBV, Epstein-Barr virus; flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; IN, lymph node; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; LCH, Langerhans cell histiocytosis; mel, melphalan; MP, mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction; UCBT, unrelated cord blood transplant; VBL, vinblastine; VCR, vincristine. The authors declare no conflict of interest.

UNKNOWN

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CC BY-NC-ND

31725543

2021-01

What was the outcome of reaction 'Epstein-Barr virus infection'?

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature. A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH. There are 3 distinct classes of histiocyte disorders: Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) (and other rarer class II disorders), and malignant histiocytoses.1 LCH is characterized by the proliferation of infiltrative Langerhans cells into skin or bone; multisystem disease can also involve the lungs, liver, spleen, bone marrow, and central nervous system. Although historically thought of as a benign, reactive process, BRAF-V600E mutations have been found in 25% to 70% of LCH patients, with MAP2K1 positivity in 46% of BRAF-negative cases, raising the possibility that LCH is a malignancy.2–4 Many believe LCH may represent a myeloid-lineage neoplasm driven by ERK signaling.5,6 The treatment for LCH depends on the extent of disease and ranges from local and/or topical therapies to systemic chemotherapy.5,7 HLH is a disease of systemic, dysregulated immune activation and inflammation.8 HLH can be familial or secondary to infections, autoimmune processes, or malignancies.1 Treatment is with systemic dexamethasone and etoposide per the HLH94 protocol, with some patients, especially those with familial and/or reactivated HLH, ultimately requiring hematopoietic stem cell transplant for a cure.9 Recent studies suggest that targeted therapies such as emapalumab may also play a role, especially in refractory cases.10 Table 1 reviews LCH and HLH in respect to presentation, diagnostic criteria, and treatments. Though they are regarded as separate disease states, they can occur together within the same patient. Favara et al11 reviewed 30 pathology files of patients with coexisting LCH and macrophage activation; 7 of these met full diagnostic criteria for HLH. We report the case of a 20-month-old patient with multisystem LCH who developed HLH during treatment and summarize the literature for other case reports of HLH in LCH. TABLE 1 Comparison of LCH and HLH8,12 LCH HLH Pathophysiology Derived from clonal CD1a+ dendritic cells Lesions contain inflammatory infiltrates including high levels of T-cell regulatory molecules Defects in target cell killing by cytotoxic T cells Immune dysregulation with excessive proinflammatory cytokine production and macrophage response Uncontrolled systemic inflammation Can be primary or secondary to an infection, malignancy, autoimmune condition Molecular findings 38%-57% possess BRAF-V600E mutation Perforin MUNC 13-4, MUNC 18-2 Syntaxin 11 LYST, CHS1, Rab27A, AP3B1 SH2D1A, XIAP, BIRC4, SAP Presenting signs/symptoms Bone pain, swelling, fractures Chest pain, cough, dyspnea Rash, seborrhea, otitis externa Polyuria, polydipsia Fatigue, weight loss, fevers, lymphadenopathy Sepsis-like presentation Fever Cytopenias Hepatitis Splenomegaly Ataxia, seizures, abnormal MRI in 50% Diagnostic criteria Tissue biopsy containing CD207+, CD1a+ dendritic cells Characteristic morphology of Langerhans cells Requires 5/8 diagnostic criteria:  Fever  Splenomegaly  Cytopenias in ≥2 cell lines  Hyperferritinemia >500 mg/mL  sIL2 >2400 U/mL  Hypertriglyceridemia/hypofibrinogenemia  Hemophagocytosis in tissue biopsy  Low or absent NK cell activity Treatment Local therapy for unifocal bony disease Prednisone, vinblastine Cladribine, cytarabine, clofarabine for refractory/recurrent disease BMT for marrow/refractory disease Decadron, etoposide±cyclosporine Alemtuzumab for refractory cases Anti-INF-gamma antibodies for refractory cases BMT indicates bone marrow transplant; HLH, hemophagocytic lymphohistiocytosis; IL2, soluble interleukin-2; INF, interferon; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; NK, natural killer. RESULTS: CASE DESCRIPTION A 20-month-old male individual presented to his pediatrician with 6 months of progressive limp and unilateral leg pain, leading to a refusal to bear weight. He also had chronic drainage from bilateral ears. A radiograph showed a lucent, expansile lesion of the child’s femur and biopsy was performed, showing s100+, CD1a+ LCH. Further evaluation using skeletal survey and positron emission tomography-computed tomography (PET/CT) revealed multiple bony lytic lesions of the skull, axial skeleton and extremities, a scaling diffuse rash of the scalp, and hypermetabolic cervical lymphadenopathy. He had no involvement of the lungs, liver, spleen, or bone marrow, and had normal magnetic resonance imaging appearance of his pituitary after passing a water deprivation test. His blood counts at diagnosis were normal other than a mild microcytic iron deficiency anemia. Liver function tests and ferritin were within normal limits. He began therapy with daily prednisone and weekly vinblastine as per the LCH-III protocol. After his initial 6 weeks of induction therapy, PET/CT showed improved but continued hypermetabolic bony lesions. He went on to the second phase of induction therapy with further improvement in lesions and then began continuation with pulses of prednisone and vinblastine every 3 weeks. Within 3 months, a follow-up PET/CT showed worsening hypermetabolic bony lesions. He was treated with cladribine for 5 days every 28 days. Interval imaging after 2 cycles again showed worsening hypermetabolic bony lesions, worsening skin rash on scalp, continued bilateral ear drainage, leg pain, and intermittent fevers with cough and rhinorrhea. He was found to be respiratory syncytial virus (RSV) positive at that time. The child began monotherapy with clofarabine 25 mg/m2 daily for 5 days. Daily fevers continued for 2 weeks and he developed transaminitis with hypoalbuminemia and fluid overload. Blood cultures were negative, and he was empirically treated with broad-spectrum antibiotics secondary to neutropenia. CT scans done as part of fever evaluation revealed multiple new lytic skull lesions. Epstein-Barr virus (EBV) polymerase chain reaction was positive at 863 copies, which resolved without intervention over the next month. He met criteria for HLH with fevers, pancytopenia, ferritin >7500 ng/mL, triglycerides 526 mg/dL, soluble interleukin (IL)2 of 8191 U/mL, and hemophagocytosis in his bone marrow. Mutational analysis for PRF1, MUNC 13-4, XIAP and other common HLH-causing genes was normal. He thus began therapy via HLH94 with dexamethasone 10 mg/m2/d and etoposide. At the end of the standard 8-week treatment period, his HLH was felt to be well controlled with resolution of fevers and cytopenias, as well as normalization of liver function tests, triglycerides, soluble IL2, and improvement in ferritin. He went on to complete an additional 5 cycles of clofarabine 25 mg/m2 (6 total cycles), with end of therapy PET/CT showing no evidence of disease. He is now 3 years off therapy and doing very well. DISCUSSION Histiocytes or mononuclear phagocytes, the immune cells implicated in the pathogenesis of both LCH and HLH, serve many functions in the normal immune response. These include antigen presentation, activation of immune function through cytokine signaling, and phagocytosis.12 In both LCH and HLH, affected tissues express high levels of T-cell stimulatory molecules and secrete inflammatory cytokines such as IL-6, interferon, and tumor necrosis factor.8 Studies of LCH lesions suggest that chemokine receptors, including CCR6, maybe abnormally upregulated which contributes to tissue infiltration.13,14 Furthermore, the T cells found abundantly in LCH lesions show increased expression for genes involved in leukocyte chemotaxis, such as SPP1, IL8 and plasminogen activator, among others.15 A lesion with increased accumulation of histiocytes and T cells may thus be at increased risk of uncontrolled activation of these cells, resulting in hypercytokinemia and progressive organ dysfunction like that seen in HLH.12 HLH has a known association with malignancy, especially leukemias and lymphomas. If LCH indeed represents a malignant clonal process of early myeloid-lineage cells, this may also explain the potential association between the 2 entities. Alternatively, it could be that children with LCH who require multiagent or prolonged chemotherapy courses develop HLH secondary to immune dysregulation from the treatments rather than the underlying disease. HLH in LCH is thought to be a rare phenomenon and we aimed to summarize the available reports (Table 2). In our patient (patient 8), and in those reported throughout the literature, common findings included young age, multisystem LCH, history of systemic chemotherapy, and often concurrent infection. Our patient with multisystem LCH had received a prolonged course of multiagent chemotherapy secondary to his refractory disease and then developed RSV. He was also positive for EBV. Although we did not find any other reports of RSV-associated HLH, EBV is a well-known trigger of HLH, as are other viruses including influenza, parvovirus, etc. One evaluation of 182 pediatric patients with EBV who also met criteria for HLH, showed significant immune dysregulation. These patients had abnormal natural killer cell activity, as well as decreased CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells, resulting in increased T-cell activation and decreased inhibition. HLA-DR expression was elevated, indicating high levels of T-cell activation, and further downstream cytokines such as IL2 and interferon-gamma were also significantly elevated.16 Thus, viral infections including EBV can result in uncontrolled proliferation and activation of T cells, which may be further increased in patients with preexisting immune dysregulation from chemotherapy and/or the underlying disease state. We believe the combination of immunosuppression and infection may have led to HLH in our patients. Interestingly, like our patient, another reported patient with LCH also developed HLH while receiving clofarabine, a deoxyadenosine analog. Although this may be coincidence, clofarabine after multiple other immunosuppressive agents may have contributed to significant immune dysregulation and HLH in these patients. A recently published multicenter article reviewed 29 patients who met criteria for HLH and LCH. As in the patients reviewed in Table 2, about half of the patients met criteria for HLH at or around the diagnosis of LCH. Most had active LCH at diagnosis of HLH and were receiving treatments similar to those listed in Table 2. Overall, 31% had some kind of infection when HLH developed, including EBV. HLH was increased most in those with risk organ involvement, but also seen in young females without bony involvement. The combination of HLH and LCH was associated with a poor prognosis.17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment. TABLE 2 Reported Patients With LCH and HLH Patient 111 Patient 211 Patient 318 Patient 419 Patient 520 Patient 621 Patient 722 Patient 8 Age at HLH 10 mo 17 mo 3 y 2 y 10 mo 3 y 1 y 2 y Areas of LCH Colon, skin, ln, bone marrow Left mastoid Skin, bone, ln, bone marrow Skin, bone Skin, bone, ln, lungs Skin, bone, ln Skin, bone, ln, hepatomegaly Skin, bone Prior therapies None None 2CDA, ARAC×6 mo Prednisone, VBL, 6-MP, MTX×6 mo None Prednisone, VBL, 6-MP, MTX Prednisone, VCR, ARAC Prednisone, VBL, 2CDA Clinical course Presented with fever, diarrhea, HSM, LAD, and pulmonary disease Presented with fever, HSM, LAD, and bone lesion 2 cycles of clofarabine. Lesions improved but developed HLH Presented with HLH on 3 different occasions 2 to 6 mo apart in the setting of influenza, HSV, and adenovirus Presented with HLH and CMV. Diagnosed with HLH and LCH of skin 9 mo after therapy completed, the patient presented with HLH 3 wk into therapy for LCH, the patient developed HLH 7 d after beginning clofarabine therapy, developed HLH. EBV PCR+ HLH treatment Chemotherapy Prednisone, VBL, VCR Dexamethasone, etoposide Cessation of chemotherapy, antibiotics, antivirals, IVIG Prednisone, etoposide Dexamethasone, cyclo A Dexamethasone, etoposide, cyclo A, followed by flu, mel, ATG cytox, and UCBT Dexamethasone, etoposide Outcome Died 10 mo after diagnosis CR Continued disease progression, followed by death within 2 mo CR CR CR CR and engrafted Disease-free now 3 y off therapy ARAC indicates cytarabine; ATG, anti-thymocyte globulin; 2CDA, cladribine; CMV, cytomegalovirus; CR, complete remission; cytox, cyclophosphamide; EBV, Epstein-Barr virus; flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; IN, lymph node; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; LCH, Langerhans cell histiocytosis; mel, melphalan; MP, mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction; UCBT, unrelated cord blood transplant; VBL, vinblastine; VCR, vincristine. The authors declare no conflict of interest.

Recovered

ReactionOutcome

CC BY-NC-ND

31725543

2021-01

What was the outcome of reaction 'Neutropenia'?

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature. A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH. There are 3 distinct classes of histiocyte disorders: Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) (and other rarer class II disorders), and malignant histiocytoses.1 LCH is characterized by the proliferation of infiltrative Langerhans cells into skin or bone; multisystem disease can also involve the lungs, liver, spleen, bone marrow, and central nervous system. Although historically thought of as a benign, reactive process, BRAF-V600E mutations have been found in 25% to 70% of LCH patients, with MAP2K1 positivity in 46% of BRAF-negative cases, raising the possibility that LCH is a malignancy.2–4 Many believe LCH may represent a myeloid-lineage neoplasm driven by ERK signaling.5,6 The treatment for LCH depends on the extent of disease and ranges from local and/or topical therapies to systemic chemotherapy.5,7 HLH is a disease of systemic, dysregulated immune activation and inflammation.8 HLH can be familial or secondary to infections, autoimmune processes, or malignancies.1 Treatment is with systemic dexamethasone and etoposide per the HLH94 protocol, with some patients, especially those with familial and/or reactivated HLH, ultimately requiring hematopoietic stem cell transplant for a cure.9 Recent studies suggest that targeted therapies such as emapalumab may also play a role, especially in refractory cases.10 Table 1 reviews LCH and HLH in respect to presentation, diagnostic criteria, and treatments. Though they are regarded as separate disease states, they can occur together within the same patient. Favara et al11 reviewed 30 pathology files of patients with coexisting LCH and macrophage activation; 7 of these met full diagnostic criteria for HLH. We report the case of a 20-month-old patient with multisystem LCH who developed HLH during treatment and summarize the literature for other case reports of HLH in LCH. TABLE 1 Comparison of LCH and HLH8,12 LCH HLH Pathophysiology Derived from clonal CD1a+ dendritic cells Lesions contain inflammatory infiltrates including high levels of T-cell regulatory molecules Defects in target cell killing by cytotoxic T cells Immune dysregulation with excessive proinflammatory cytokine production and macrophage response Uncontrolled systemic inflammation Can be primary or secondary to an infection, malignancy, autoimmune condition Molecular findings 38%-57% possess BRAF-V600E mutation Perforin MUNC 13-4, MUNC 18-2 Syntaxin 11 LYST, CHS1, Rab27A, AP3B1 SH2D1A, XIAP, BIRC4, SAP Presenting signs/symptoms Bone pain, swelling, fractures Chest pain, cough, dyspnea Rash, seborrhea, otitis externa Polyuria, polydipsia Fatigue, weight loss, fevers, lymphadenopathy Sepsis-like presentation Fever Cytopenias Hepatitis Splenomegaly Ataxia, seizures, abnormal MRI in 50% Diagnostic criteria Tissue biopsy containing CD207+, CD1a+ dendritic cells Characteristic morphology of Langerhans cells Requires 5/8 diagnostic criteria:  Fever  Splenomegaly  Cytopenias in ≥2 cell lines  Hyperferritinemia >500 mg/mL  sIL2 >2400 U/mL  Hypertriglyceridemia/hypofibrinogenemia  Hemophagocytosis in tissue biopsy  Low or absent NK cell activity Treatment Local therapy for unifocal bony disease Prednisone, vinblastine Cladribine, cytarabine, clofarabine for refractory/recurrent disease BMT for marrow/refractory disease Decadron, etoposide±cyclosporine Alemtuzumab for refractory cases Anti-INF-gamma antibodies for refractory cases BMT indicates bone marrow transplant; HLH, hemophagocytic lymphohistiocytosis; IL2, soluble interleukin-2; INF, interferon; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; NK, natural killer. RESULTS: CASE DESCRIPTION A 20-month-old male individual presented to his pediatrician with 6 months of progressive limp and unilateral leg pain, leading to a refusal to bear weight. He also had chronic drainage from bilateral ears. A radiograph showed a lucent, expansile lesion of the child’s femur and biopsy was performed, showing s100+, CD1a+ LCH. Further evaluation using skeletal survey and positron emission tomography-computed tomography (PET/CT) revealed multiple bony lytic lesions of the skull, axial skeleton and extremities, a scaling diffuse rash of the scalp, and hypermetabolic cervical lymphadenopathy. He had no involvement of the lungs, liver, spleen, or bone marrow, and had normal magnetic resonance imaging appearance of his pituitary after passing a water deprivation test. His blood counts at diagnosis were normal other than a mild microcytic iron deficiency anemia. Liver function tests and ferritin were within normal limits. He began therapy with daily prednisone and weekly vinblastine as per the LCH-III protocol. After his initial 6 weeks of induction therapy, PET/CT showed improved but continued hypermetabolic bony lesions. He went on to the second phase of induction therapy with further improvement in lesions and then began continuation with pulses of prednisone and vinblastine every 3 weeks. Within 3 months, a follow-up PET/CT showed worsening hypermetabolic bony lesions. He was treated with cladribine for 5 days every 28 days. Interval imaging after 2 cycles again showed worsening hypermetabolic bony lesions, worsening skin rash on scalp, continued bilateral ear drainage, leg pain, and intermittent fevers with cough and rhinorrhea. He was found to be respiratory syncytial virus (RSV) positive at that time. The child began monotherapy with clofarabine 25 mg/m2 daily for 5 days. Daily fevers continued for 2 weeks and he developed transaminitis with hypoalbuminemia and fluid overload. Blood cultures were negative, and he was empirically treated with broad-spectrum antibiotics secondary to neutropenia. CT scans done as part of fever evaluation revealed multiple new lytic skull lesions. Epstein-Barr virus (EBV) polymerase chain reaction was positive at 863 copies, which resolved without intervention over the next month. He met criteria for HLH with fevers, pancytopenia, ferritin >7500 ng/mL, triglycerides 526 mg/dL, soluble interleukin (IL)2 of 8191 U/mL, and hemophagocytosis in his bone marrow. Mutational analysis for PRF1, MUNC 13-4, XIAP and other common HLH-causing genes was normal. He thus began therapy via HLH94 with dexamethasone 10 mg/m2/d and etoposide. At the end of the standard 8-week treatment period, his HLH was felt to be well controlled with resolution of fevers and cytopenias, as well as normalization of liver function tests, triglycerides, soluble IL2, and improvement in ferritin. He went on to complete an additional 5 cycles of clofarabine 25 mg/m2 (6 total cycles), with end of therapy PET/CT showing no evidence of disease. He is now 3 years off therapy and doing very well. DISCUSSION Histiocytes or mononuclear phagocytes, the immune cells implicated in the pathogenesis of both LCH and HLH, serve many functions in the normal immune response. These include antigen presentation, activation of immune function through cytokine signaling, and phagocytosis.12 In both LCH and HLH, affected tissues express high levels of T-cell stimulatory molecules and secrete inflammatory cytokines such as IL-6, interferon, and tumor necrosis factor.8 Studies of LCH lesions suggest that chemokine receptors, including CCR6, maybe abnormally upregulated which contributes to tissue infiltration.13,14 Furthermore, the T cells found abundantly in LCH lesions show increased expression for genes involved in leukocyte chemotaxis, such as SPP1, IL8 and plasminogen activator, among others.15 A lesion with increased accumulation of histiocytes and T cells may thus be at increased risk of uncontrolled activation of these cells, resulting in hypercytokinemia and progressive organ dysfunction like that seen in HLH.12 HLH has a known association with malignancy, especially leukemias and lymphomas. If LCH indeed represents a malignant clonal process of early myeloid-lineage cells, this may also explain the potential association between the 2 entities. Alternatively, it could be that children with LCH who require multiagent or prolonged chemotherapy courses develop HLH secondary to immune dysregulation from the treatments rather than the underlying disease. HLH in LCH is thought to be a rare phenomenon and we aimed to summarize the available reports (Table 2). In our patient (patient 8), and in those reported throughout the literature, common findings included young age, multisystem LCH, history of systemic chemotherapy, and often concurrent infection. Our patient with multisystem LCH had received a prolonged course of multiagent chemotherapy secondary to his refractory disease and then developed RSV. He was also positive for EBV. Although we did not find any other reports of RSV-associated HLH, EBV is a well-known trigger of HLH, as are other viruses including influenza, parvovirus, etc. One evaluation of 182 pediatric patients with EBV who also met criteria for HLH, showed significant immune dysregulation. These patients had abnormal natural killer cell activity, as well as decreased CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells, resulting in increased T-cell activation and decreased inhibition. HLA-DR expression was elevated, indicating high levels of T-cell activation, and further downstream cytokines such as IL2 and interferon-gamma were also significantly elevated.16 Thus, viral infections including EBV can result in uncontrolled proliferation and activation of T cells, which may be further increased in patients with preexisting immune dysregulation from chemotherapy and/or the underlying disease state. We believe the combination of immunosuppression and infection may have led to HLH in our patients. Interestingly, like our patient, another reported patient with LCH also developed HLH while receiving clofarabine, a deoxyadenosine analog. Although this may be coincidence, clofarabine after multiple other immunosuppressive agents may have contributed to significant immune dysregulation and HLH in these patients. A recently published multicenter article reviewed 29 patients who met criteria for HLH and LCH. As in the patients reviewed in Table 2, about half of the patients met criteria for HLH at or around the diagnosis of LCH. Most had active LCH at diagnosis of HLH and were receiving treatments similar to those listed in Table 2. Overall, 31% had some kind of infection when HLH developed, including EBV. HLH was increased most in those with risk organ involvement, but also seen in young females without bony involvement. The combination of HLH and LCH was associated with a poor prognosis.17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment. TABLE 2 Reported Patients With LCH and HLH Patient 111 Patient 211 Patient 318 Patient 419 Patient 520 Patient 621 Patient 722 Patient 8 Age at HLH 10 mo 17 mo 3 y 2 y 10 mo 3 y 1 y 2 y Areas of LCH Colon, skin, ln, bone marrow Left mastoid Skin, bone, ln, bone marrow Skin, bone Skin, bone, ln, lungs Skin, bone, ln Skin, bone, ln, hepatomegaly Skin, bone Prior therapies None None 2CDA, ARAC×6 mo Prednisone, VBL, 6-MP, MTX×6 mo None Prednisone, VBL, 6-MP, MTX Prednisone, VCR, ARAC Prednisone, VBL, 2CDA Clinical course Presented with fever, diarrhea, HSM, LAD, and pulmonary disease Presented with fever, HSM, LAD, and bone lesion 2 cycles of clofarabine. Lesions improved but developed HLH Presented with HLH on 3 different occasions 2 to 6 mo apart in the setting of influenza, HSV, and adenovirus Presented with HLH and CMV. Diagnosed with HLH and LCH of skin 9 mo after therapy completed, the patient presented with HLH 3 wk into therapy for LCH, the patient developed HLH 7 d after beginning clofarabine therapy, developed HLH. EBV PCR+ HLH treatment Chemotherapy Prednisone, VBL, VCR Dexamethasone, etoposide Cessation of chemotherapy, antibiotics, antivirals, IVIG Prednisone, etoposide Dexamethasone, cyclo A Dexamethasone, etoposide, cyclo A, followed by flu, mel, ATG cytox, and UCBT Dexamethasone, etoposide Outcome Died 10 mo after diagnosis CR Continued disease progression, followed by death within 2 mo CR CR CR CR and engrafted Disease-free now 3 y off therapy ARAC indicates cytarabine; ATG, anti-thymocyte globulin; 2CDA, cladribine; CMV, cytomegalovirus; CR, complete remission; cytox, cyclophosphamide; EBV, Epstein-Barr virus; flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; IN, lymph node; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; LCH, Langerhans cell histiocytosis; mel, melphalan; MP, mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction; UCBT, unrelated cord blood transplant; VBL, vinblastine; VCR, vincristine. The authors declare no conflict of interest.

Recovered

ReactionOutcome

CC BY-NC-ND

31725543

2021-01

What was the outcome of reaction 'Pancytopenia'?

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature. A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH. There are 3 distinct classes of histiocyte disorders: Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) (and other rarer class II disorders), and malignant histiocytoses.1 LCH is characterized by the proliferation of infiltrative Langerhans cells into skin or bone; multisystem disease can also involve the lungs, liver, spleen, bone marrow, and central nervous system. Although historically thought of as a benign, reactive process, BRAF-V600E mutations have been found in 25% to 70% of LCH patients, with MAP2K1 positivity in 46% of BRAF-negative cases, raising the possibility that LCH is a malignancy.2–4 Many believe LCH may represent a myeloid-lineage neoplasm driven by ERK signaling.5,6 The treatment for LCH depends on the extent of disease and ranges from local and/or topical therapies to systemic chemotherapy.5,7 HLH is a disease of systemic, dysregulated immune activation and inflammation.8 HLH can be familial or secondary to infections, autoimmune processes, or malignancies.1 Treatment is with systemic dexamethasone and etoposide per the HLH94 protocol, with some patients, especially those with familial and/or reactivated HLH, ultimately requiring hematopoietic stem cell transplant for a cure.9 Recent studies suggest that targeted therapies such as emapalumab may also play a role, especially in refractory cases.10 Table 1 reviews LCH and HLH in respect to presentation, diagnostic criteria, and treatments. Though they are regarded as separate disease states, they can occur together within the same patient. Favara et al11 reviewed 30 pathology files of patients with coexisting LCH and macrophage activation; 7 of these met full diagnostic criteria for HLH. We report the case of a 20-month-old patient with multisystem LCH who developed HLH during treatment and summarize the literature for other case reports of HLH in LCH. TABLE 1 Comparison of LCH and HLH8,12 LCH HLH Pathophysiology Derived from clonal CD1a+ dendritic cells Lesions contain inflammatory infiltrates including high levels of T-cell regulatory molecules Defects in target cell killing by cytotoxic T cells Immune dysregulation with excessive proinflammatory cytokine production and macrophage response Uncontrolled systemic inflammation Can be primary or secondary to an infection, malignancy, autoimmune condition Molecular findings 38%-57% possess BRAF-V600E mutation Perforin MUNC 13-4, MUNC 18-2 Syntaxin 11 LYST, CHS1, Rab27A, AP3B1 SH2D1A, XIAP, BIRC4, SAP Presenting signs/symptoms Bone pain, swelling, fractures Chest pain, cough, dyspnea Rash, seborrhea, otitis externa Polyuria, polydipsia Fatigue, weight loss, fevers, lymphadenopathy Sepsis-like presentation Fever Cytopenias Hepatitis Splenomegaly Ataxia, seizures, abnormal MRI in 50% Diagnostic criteria Tissue biopsy containing CD207+, CD1a+ dendritic cells Characteristic morphology of Langerhans cells Requires 5/8 diagnostic criteria:  Fever  Splenomegaly  Cytopenias in ≥2 cell lines  Hyperferritinemia >500 mg/mL  sIL2 >2400 U/mL  Hypertriglyceridemia/hypofibrinogenemia  Hemophagocytosis in tissue biopsy  Low or absent NK cell activity Treatment Local therapy for unifocal bony disease Prednisone, vinblastine Cladribine, cytarabine, clofarabine for refractory/recurrent disease BMT for marrow/refractory disease Decadron, etoposide±cyclosporine Alemtuzumab for refractory cases Anti-INF-gamma antibodies for refractory cases BMT indicates bone marrow transplant; HLH, hemophagocytic lymphohistiocytosis; IL2, soluble interleukin-2; INF, interferon; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; NK, natural killer. RESULTS: CASE DESCRIPTION A 20-month-old male individual presented to his pediatrician with 6 months of progressive limp and unilateral leg pain, leading to a refusal to bear weight. He also had chronic drainage from bilateral ears. A radiograph showed a lucent, expansile lesion of the child’s femur and biopsy was performed, showing s100+, CD1a+ LCH. Further evaluation using skeletal survey and positron emission tomography-computed tomography (PET/CT) revealed multiple bony lytic lesions of the skull, axial skeleton and extremities, a scaling diffuse rash of the scalp, and hypermetabolic cervical lymphadenopathy. He had no involvement of the lungs, liver, spleen, or bone marrow, and had normal magnetic resonance imaging appearance of his pituitary after passing a water deprivation test. His blood counts at diagnosis were normal other than a mild microcytic iron deficiency anemia. Liver function tests and ferritin were within normal limits. He began therapy with daily prednisone and weekly vinblastine as per the LCH-III protocol. After his initial 6 weeks of induction therapy, PET/CT showed improved but continued hypermetabolic bony lesions. He went on to the second phase of induction therapy with further improvement in lesions and then began continuation with pulses of prednisone and vinblastine every 3 weeks. Within 3 months, a follow-up PET/CT showed worsening hypermetabolic bony lesions. He was treated with cladribine for 5 days every 28 days. Interval imaging after 2 cycles again showed worsening hypermetabolic bony lesions, worsening skin rash on scalp, continued bilateral ear drainage, leg pain, and intermittent fevers with cough and rhinorrhea. He was found to be respiratory syncytial virus (RSV) positive at that time. The child began monotherapy with clofarabine 25 mg/m2 daily for 5 days. Daily fevers continued for 2 weeks and he developed transaminitis with hypoalbuminemia and fluid overload. Blood cultures were negative, and he was empirically treated with broad-spectrum antibiotics secondary to neutropenia. CT scans done as part of fever evaluation revealed multiple new lytic skull lesions. Epstein-Barr virus (EBV) polymerase chain reaction was positive at 863 copies, which resolved without intervention over the next month. He met criteria for HLH with fevers, pancytopenia, ferritin >7500 ng/mL, triglycerides 526 mg/dL, soluble interleukin (IL)2 of 8191 U/mL, and hemophagocytosis in his bone marrow. Mutational analysis for PRF1, MUNC 13-4, XIAP and other common HLH-causing genes was normal. He thus began therapy via HLH94 with dexamethasone 10 mg/m2/d and etoposide. At the end of the standard 8-week treatment period, his HLH was felt to be well controlled with resolution of fevers and cytopenias, as well as normalization of liver function tests, triglycerides, soluble IL2, and improvement in ferritin. He went on to complete an additional 5 cycles of clofarabine 25 mg/m2 (6 total cycles), with end of therapy PET/CT showing no evidence of disease. He is now 3 years off therapy and doing very well. DISCUSSION Histiocytes or mononuclear phagocytes, the immune cells implicated in the pathogenesis of both LCH and HLH, serve many functions in the normal immune response. These include antigen presentation, activation of immune function through cytokine signaling, and phagocytosis.12 In both LCH and HLH, affected tissues express high levels of T-cell stimulatory molecules and secrete inflammatory cytokines such as IL-6, interferon, and tumor necrosis factor.8 Studies of LCH lesions suggest that chemokine receptors, including CCR6, maybe abnormally upregulated which contributes to tissue infiltration.13,14 Furthermore, the T cells found abundantly in LCH lesions show increased expression for genes involved in leukocyte chemotaxis, such as SPP1, IL8 and plasminogen activator, among others.15 A lesion with increased accumulation of histiocytes and T cells may thus be at increased risk of uncontrolled activation of these cells, resulting in hypercytokinemia and progressive organ dysfunction like that seen in HLH.12 HLH has a known association with malignancy, especially leukemias and lymphomas. If LCH indeed represents a malignant clonal process of early myeloid-lineage cells, this may also explain the potential association between the 2 entities. Alternatively, it could be that children with LCH who require multiagent or prolonged chemotherapy courses develop HLH secondary to immune dysregulation from the treatments rather than the underlying disease. HLH in LCH is thought to be a rare phenomenon and we aimed to summarize the available reports (Table 2). In our patient (patient 8), and in those reported throughout the literature, common findings included young age, multisystem LCH, history of systemic chemotherapy, and often concurrent infection. Our patient with multisystem LCH had received a prolonged course of multiagent chemotherapy secondary to his refractory disease and then developed RSV. He was also positive for EBV. Although we did not find any other reports of RSV-associated HLH, EBV is a well-known trigger of HLH, as are other viruses including influenza, parvovirus, etc. One evaluation of 182 pediatric patients with EBV who also met criteria for HLH, showed significant immune dysregulation. These patients had abnormal natural killer cell activity, as well as decreased CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells, resulting in increased T-cell activation and decreased inhibition. HLA-DR expression was elevated, indicating high levels of T-cell activation, and further downstream cytokines such as IL2 and interferon-gamma were also significantly elevated.16 Thus, viral infections including EBV can result in uncontrolled proliferation and activation of T cells, which may be further increased in patients with preexisting immune dysregulation from chemotherapy and/or the underlying disease state. We believe the combination of immunosuppression and infection may have led to HLH in our patients. Interestingly, like our patient, another reported patient with LCH also developed HLH while receiving clofarabine, a deoxyadenosine analog. Although this may be coincidence, clofarabine after multiple other immunosuppressive agents may have contributed to significant immune dysregulation and HLH in these patients. A recently published multicenter article reviewed 29 patients who met criteria for HLH and LCH. As in the patients reviewed in Table 2, about half of the patients met criteria for HLH at or around the diagnosis of LCH. Most had active LCH at diagnosis of HLH and were receiving treatments similar to those listed in Table 2. Overall, 31% had some kind of infection when HLH developed, including EBV. HLH was increased most in those with risk organ involvement, but also seen in young females without bony involvement. The combination of HLH and LCH was associated with a poor prognosis.17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment. TABLE 2 Reported Patients With LCH and HLH Patient 111 Patient 211 Patient 318 Patient 419 Patient 520 Patient 621 Patient 722 Patient 8 Age at HLH 10 mo 17 mo 3 y 2 y 10 mo 3 y 1 y 2 y Areas of LCH Colon, skin, ln, bone marrow Left mastoid Skin, bone, ln, bone marrow Skin, bone Skin, bone, ln, lungs Skin, bone, ln Skin, bone, ln, hepatomegaly Skin, bone Prior therapies None None 2CDA, ARAC×6 mo Prednisone, VBL, 6-MP, MTX×6 mo None Prednisone, VBL, 6-MP, MTX Prednisone, VCR, ARAC Prednisone, VBL, 2CDA Clinical course Presented with fever, diarrhea, HSM, LAD, and pulmonary disease Presented with fever, HSM, LAD, and bone lesion 2 cycles of clofarabine. Lesions improved but developed HLH Presented with HLH on 3 different occasions 2 to 6 mo apart in the setting of influenza, HSV, and adenovirus Presented with HLH and CMV. Diagnosed with HLH and LCH of skin 9 mo after therapy completed, the patient presented with HLH 3 wk into therapy for LCH, the patient developed HLH 7 d after beginning clofarabine therapy, developed HLH. EBV PCR+ HLH treatment Chemotherapy Prednisone, VBL, VCR Dexamethasone, etoposide Cessation of chemotherapy, antibiotics, antivirals, IVIG Prednisone, etoposide Dexamethasone, cyclo A Dexamethasone, etoposide, cyclo A, followed by flu, mel, ATG cytox, and UCBT Dexamethasone, etoposide Outcome Died 10 mo after diagnosis CR Continued disease progression, followed by death within 2 mo CR CR CR CR and engrafted Disease-free now 3 y off therapy ARAC indicates cytarabine; ATG, anti-thymocyte globulin; 2CDA, cladribine; CMV, cytomegalovirus; CR, complete remission; cytox, cyclophosphamide; EBV, Epstein-Barr virus; flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; IN, lymph node; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; LCH, Langerhans cell histiocytosis; mel, melphalan; MP, mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction; UCBT, unrelated cord blood transplant; VBL, vinblastine; VCR, vincristine. The authors declare no conflict of interest.

Recovered

ReactionOutcome

CC BY-NC-ND

31725543

2021-01

What was the outcome of reaction 'Pyrexia'?

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature. A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH. There are 3 distinct classes of histiocyte disorders: Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) (and other rarer class II disorders), and malignant histiocytoses.1 LCH is characterized by the proliferation of infiltrative Langerhans cells into skin or bone; multisystem disease can also involve the lungs, liver, spleen, bone marrow, and central nervous system. Although historically thought of as a benign, reactive process, BRAF-V600E mutations have been found in 25% to 70% of LCH patients, with MAP2K1 positivity in 46% of BRAF-negative cases, raising the possibility that LCH is a malignancy.2–4 Many believe LCH may represent a myeloid-lineage neoplasm driven by ERK signaling.5,6 The treatment for LCH depends on the extent of disease and ranges from local and/or topical therapies to systemic chemotherapy.5,7 HLH is a disease of systemic, dysregulated immune activation and inflammation.8 HLH can be familial or secondary to infections, autoimmune processes, or malignancies.1 Treatment is with systemic dexamethasone and etoposide per the HLH94 protocol, with some patients, especially those with familial and/or reactivated HLH, ultimately requiring hematopoietic stem cell transplant for a cure.9 Recent studies suggest that targeted therapies such as emapalumab may also play a role, especially in refractory cases.10 Table 1 reviews LCH and HLH in respect to presentation, diagnostic criteria, and treatments. Though they are regarded as separate disease states, they can occur together within the same patient. Favara et al11 reviewed 30 pathology files of patients with coexisting LCH and macrophage activation; 7 of these met full diagnostic criteria for HLH. We report the case of a 20-month-old patient with multisystem LCH who developed HLH during treatment and summarize the literature for other case reports of HLH in LCH. TABLE 1 Comparison of LCH and HLH8,12 LCH HLH Pathophysiology Derived from clonal CD1a+ dendritic cells Lesions contain inflammatory infiltrates including high levels of T-cell regulatory molecules Defects in target cell killing by cytotoxic T cells Immune dysregulation with excessive proinflammatory cytokine production and macrophage response Uncontrolled systemic inflammation Can be primary or secondary to an infection, malignancy, autoimmune condition Molecular findings 38%-57% possess BRAF-V600E mutation Perforin MUNC 13-4, MUNC 18-2 Syntaxin 11 LYST, CHS1, Rab27A, AP3B1 SH2D1A, XIAP, BIRC4, SAP Presenting signs/symptoms Bone pain, swelling, fractures Chest pain, cough, dyspnea Rash, seborrhea, otitis externa Polyuria, polydipsia Fatigue, weight loss, fevers, lymphadenopathy Sepsis-like presentation Fever Cytopenias Hepatitis Splenomegaly Ataxia, seizures, abnormal MRI in 50% Diagnostic criteria Tissue biopsy containing CD207+, CD1a+ dendritic cells Characteristic morphology of Langerhans cells Requires 5/8 diagnostic criteria:  Fever  Splenomegaly  Cytopenias in ≥2 cell lines  Hyperferritinemia >500 mg/mL  sIL2 >2400 U/mL  Hypertriglyceridemia/hypofibrinogenemia  Hemophagocytosis in tissue biopsy  Low or absent NK cell activity Treatment Local therapy for unifocal bony disease Prednisone, vinblastine Cladribine, cytarabine, clofarabine for refractory/recurrent disease BMT for marrow/refractory disease Decadron, etoposide±cyclosporine Alemtuzumab for refractory cases Anti-INF-gamma antibodies for refractory cases BMT indicates bone marrow transplant; HLH, hemophagocytic lymphohistiocytosis; IL2, soluble interleukin-2; INF, interferon; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; NK, natural killer. RESULTS: CASE DESCRIPTION A 20-month-old male individual presented to his pediatrician with 6 months of progressive limp and unilateral leg pain, leading to a refusal to bear weight. He also had chronic drainage from bilateral ears. A radiograph showed a lucent, expansile lesion of the child’s femur and biopsy was performed, showing s100+, CD1a+ LCH. Further evaluation using skeletal survey and positron emission tomography-computed tomography (PET/CT) revealed multiple bony lytic lesions of the skull, axial skeleton and extremities, a scaling diffuse rash of the scalp, and hypermetabolic cervical lymphadenopathy. He had no involvement of the lungs, liver, spleen, or bone marrow, and had normal magnetic resonance imaging appearance of his pituitary after passing a water deprivation test. His blood counts at diagnosis were normal other than a mild microcytic iron deficiency anemia. Liver function tests and ferritin were within normal limits. He began therapy with daily prednisone and weekly vinblastine as per the LCH-III protocol. After his initial 6 weeks of induction therapy, PET/CT showed improved but continued hypermetabolic bony lesions. He went on to the second phase of induction therapy with further improvement in lesions and then began continuation with pulses of prednisone and vinblastine every 3 weeks. Within 3 months, a follow-up PET/CT showed worsening hypermetabolic bony lesions. He was treated with cladribine for 5 days every 28 days. Interval imaging after 2 cycles again showed worsening hypermetabolic bony lesions, worsening skin rash on scalp, continued bilateral ear drainage, leg pain, and intermittent fevers with cough and rhinorrhea. He was found to be respiratory syncytial virus (RSV) positive at that time. The child began monotherapy with clofarabine 25 mg/m2 daily for 5 days. Daily fevers continued for 2 weeks and he developed transaminitis with hypoalbuminemia and fluid overload. Blood cultures were negative, and he was empirically treated with broad-spectrum antibiotics secondary to neutropenia. CT scans done as part of fever evaluation revealed multiple new lytic skull lesions. Epstein-Barr virus (EBV) polymerase chain reaction was positive at 863 copies, which resolved without intervention over the next month. He met criteria for HLH with fevers, pancytopenia, ferritin >7500 ng/mL, triglycerides 526 mg/dL, soluble interleukin (IL)2 of 8191 U/mL, and hemophagocytosis in his bone marrow. Mutational analysis for PRF1, MUNC 13-4, XIAP and other common HLH-causing genes was normal. He thus began therapy via HLH94 with dexamethasone 10 mg/m2/d and etoposide. At the end of the standard 8-week treatment period, his HLH was felt to be well controlled with resolution of fevers and cytopenias, as well as normalization of liver function tests, triglycerides, soluble IL2, and improvement in ferritin. He went on to complete an additional 5 cycles of clofarabine 25 mg/m2 (6 total cycles), with end of therapy PET/CT showing no evidence of disease. He is now 3 years off therapy and doing very well. DISCUSSION Histiocytes or mononuclear phagocytes, the immune cells implicated in the pathogenesis of both LCH and HLH, serve many functions in the normal immune response. These include antigen presentation, activation of immune function through cytokine signaling, and phagocytosis.12 In both LCH and HLH, affected tissues express high levels of T-cell stimulatory molecules and secrete inflammatory cytokines such as IL-6, interferon, and tumor necrosis factor.8 Studies of LCH lesions suggest that chemokine receptors, including CCR6, maybe abnormally upregulated which contributes to tissue infiltration.13,14 Furthermore, the T cells found abundantly in LCH lesions show increased expression for genes involved in leukocyte chemotaxis, such as SPP1, IL8 and plasminogen activator, among others.15 A lesion with increased accumulation of histiocytes and T cells may thus be at increased risk of uncontrolled activation of these cells, resulting in hypercytokinemia and progressive organ dysfunction like that seen in HLH.12 HLH has a known association with malignancy, especially leukemias and lymphomas. If LCH indeed represents a malignant clonal process of early myeloid-lineage cells, this may also explain the potential association between the 2 entities. Alternatively, it could be that children with LCH who require multiagent or prolonged chemotherapy courses develop HLH secondary to immune dysregulation from the treatments rather than the underlying disease. HLH in LCH is thought to be a rare phenomenon and we aimed to summarize the available reports (Table 2). In our patient (patient 8), and in those reported throughout the literature, common findings included young age, multisystem LCH, history of systemic chemotherapy, and often concurrent infection. Our patient with multisystem LCH had received a prolonged course of multiagent chemotherapy secondary to his refractory disease and then developed RSV. He was also positive for EBV. Although we did not find any other reports of RSV-associated HLH, EBV is a well-known trigger of HLH, as are other viruses including influenza, parvovirus, etc. One evaluation of 182 pediatric patients with EBV who also met criteria for HLH, showed significant immune dysregulation. These patients had abnormal natural killer cell activity, as well as decreased CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells, resulting in increased T-cell activation and decreased inhibition. HLA-DR expression was elevated, indicating high levels of T-cell activation, and further downstream cytokines such as IL2 and interferon-gamma were also significantly elevated.16 Thus, viral infections including EBV can result in uncontrolled proliferation and activation of T cells, which may be further increased in patients with preexisting immune dysregulation from chemotherapy and/or the underlying disease state. We believe the combination of immunosuppression and infection may have led to HLH in our patients. Interestingly, like our patient, another reported patient with LCH also developed HLH while receiving clofarabine, a deoxyadenosine analog. Although this may be coincidence, clofarabine after multiple other immunosuppressive agents may have contributed to significant immune dysregulation and HLH in these patients. A recently published multicenter article reviewed 29 patients who met criteria for HLH and LCH. As in the patients reviewed in Table 2, about half of the patients met criteria for HLH at or around the diagnosis of LCH. Most had active LCH at diagnosis of HLH and were receiving treatments similar to those listed in Table 2. Overall, 31% had some kind of infection when HLH developed, including EBV. HLH was increased most in those with risk organ involvement, but also seen in young females without bony involvement. The combination of HLH and LCH was associated with a poor prognosis.17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment. TABLE 2 Reported Patients With LCH and HLH Patient 111 Patient 211 Patient 318 Patient 419 Patient 520 Patient 621 Patient 722 Patient 8 Age at HLH 10 mo 17 mo 3 y 2 y 10 mo 3 y 1 y 2 y Areas of LCH Colon, skin, ln, bone marrow Left mastoid Skin, bone, ln, bone marrow Skin, bone Skin, bone, ln, lungs Skin, bone, ln Skin, bone, ln, hepatomegaly Skin, bone Prior therapies None None 2CDA, ARAC×6 mo Prednisone, VBL, 6-MP, MTX×6 mo None Prednisone, VBL, 6-MP, MTX Prednisone, VCR, ARAC Prednisone, VBL, 2CDA Clinical course Presented with fever, diarrhea, HSM, LAD, and pulmonary disease Presented with fever, HSM, LAD, and bone lesion 2 cycles of clofarabine. Lesions improved but developed HLH Presented with HLH on 3 different occasions 2 to 6 mo apart in the setting of influenza, HSV, and adenovirus Presented with HLH and CMV. Diagnosed with HLH and LCH of skin 9 mo after therapy completed, the patient presented with HLH 3 wk into therapy for LCH, the patient developed HLH 7 d after beginning clofarabine therapy, developed HLH. EBV PCR+ HLH treatment Chemotherapy Prednisone, VBL, VCR Dexamethasone, etoposide Cessation of chemotherapy, antibiotics, antivirals, IVIG Prednisone, etoposide Dexamethasone, cyclo A Dexamethasone, etoposide, cyclo A, followed by flu, mel, ATG cytox, and UCBT Dexamethasone, etoposide Outcome Died 10 mo after diagnosis CR Continued disease progression, followed by death within 2 mo CR CR CR CR and engrafted Disease-free now 3 y off therapy ARAC indicates cytarabine; ATG, anti-thymocyte globulin; 2CDA, cladribine; CMV, cytomegalovirus; CR, complete remission; cytox, cyclophosphamide; EBV, Epstein-Barr virus; flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; IN, lymph node; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; LCH, Langerhans cell histiocytosis; mel, melphalan; MP, mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction; UCBT, unrelated cord blood transplant; VBL, vinblastine; VCR, vincristine. The authors declare no conflict of interest.

Recovered

ReactionOutcome

CC BY-NC-ND

31725543

2021-01

What was the outcome of reaction 'Respiratory syncytial virus infection'?

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature. A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH. There are 3 distinct classes of histiocyte disorders: Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) (and other rarer class II disorders), and malignant histiocytoses.1 LCH is characterized by the proliferation of infiltrative Langerhans cells into skin or bone; multisystem disease can also involve the lungs, liver, spleen, bone marrow, and central nervous system. Although historically thought of as a benign, reactive process, BRAF-V600E mutations have been found in 25% to 70% of LCH patients, with MAP2K1 positivity in 46% of BRAF-negative cases, raising the possibility that LCH is a malignancy.2–4 Many believe LCH may represent a myeloid-lineage neoplasm driven by ERK signaling.5,6 The treatment for LCH depends on the extent of disease and ranges from local and/or topical therapies to systemic chemotherapy.5,7 HLH is a disease of systemic, dysregulated immune activation and inflammation.8 HLH can be familial or secondary to infections, autoimmune processes, or malignancies.1 Treatment is with systemic dexamethasone and etoposide per the HLH94 protocol, with some patients, especially those with familial and/or reactivated HLH, ultimately requiring hematopoietic stem cell transplant for a cure.9 Recent studies suggest that targeted therapies such as emapalumab may also play a role, especially in refractory cases.10 Table 1 reviews LCH and HLH in respect to presentation, diagnostic criteria, and treatments. Though they are regarded as separate disease states, they can occur together within the same patient. Favara et al11 reviewed 30 pathology files of patients with coexisting LCH and macrophage activation; 7 of these met full diagnostic criteria for HLH. We report the case of a 20-month-old patient with multisystem LCH who developed HLH during treatment and summarize the literature for other case reports of HLH in LCH. TABLE 1 Comparison of LCH and HLH8,12 LCH HLH Pathophysiology Derived from clonal CD1a+ dendritic cells Lesions contain inflammatory infiltrates including high levels of T-cell regulatory molecules Defects in target cell killing by cytotoxic T cells Immune dysregulation with excessive proinflammatory cytokine production and macrophage response Uncontrolled systemic inflammation Can be primary or secondary to an infection, malignancy, autoimmune condition Molecular findings 38%-57% possess BRAF-V600E mutation Perforin MUNC 13-4, MUNC 18-2 Syntaxin 11 LYST, CHS1, Rab27A, AP3B1 SH2D1A, XIAP, BIRC4, SAP Presenting signs/symptoms Bone pain, swelling, fractures Chest pain, cough, dyspnea Rash, seborrhea, otitis externa Polyuria, polydipsia Fatigue, weight loss, fevers, lymphadenopathy Sepsis-like presentation Fever Cytopenias Hepatitis Splenomegaly Ataxia, seizures, abnormal MRI in 50% Diagnostic criteria Tissue biopsy containing CD207+, CD1a+ dendritic cells Characteristic morphology of Langerhans cells Requires 5/8 diagnostic criteria:  Fever  Splenomegaly  Cytopenias in ≥2 cell lines  Hyperferritinemia >500 mg/mL  sIL2 >2400 U/mL  Hypertriglyceridemia/hypofibrinogenemia  Hemophagocytosis in tissue biopsy  Low or absent NK cell activity Treatment Local therapy for unifocal bony disease Prednisone, vinblastine Cladribine, cytarabine, clofarabine for refractory/recurrent disease BMT for marrow/refractory disease Decadron, etoposide±cyclosporine Alemtuzumab for refractory cases Anti-INF-gamma antibodies for refractory cases BMT indicates bone marrow transplant; HLH, hemophagocytic lymphohistiocytosis; IL2, soluble interleukin-2; INF, interferon; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; NK, natural killer. RESULTS: CASE DESCRIPTION A 20-month-old male individual presented to his pediatrician with 6 months of progressive limp and unilateral leg pain, leading to a refusal to bear weight. He also had chronic drainage from bilateral ears. A radiograph showed a lucent, expansile lesion of the child’s femur and biopsy was performed, showing s100+, CD1a+ LCH. Further evaluation using skeletal survey and positron emission tomography-computed tomography (PET/CT) revealed multiple bony lytic lesions of the skull, axial skeleton and extremities, a scaling diffuse rash of the scalp, and hypermetabolic cervical lymphadenopathy. He had no involvement of the lungs, liver, spleen, or bone marrow, and had normal magnetic resonance imaging appearance of his pituitary after passing a water deprivation test. His blood counts at diagnosis were normal other than a mild microcytic iron deficiency anemia. Liver function tests and ferritin were within normal limits. He began therapy with daily prednisone and weekly vinblastine as per the LCH-III protocol. After his initial 6 weeks of induction therapy, PET/CT showed improved but continued hypermetabolic bony lesions. He went on to the second phase of induction therapy with further improvement in lesions and then began continuation with pulses of prednisone and vinblastine every 3 weeks. Within 3 months, a follow-up PET/CT showed worsening hypermetabolic bony lesions. He was treated with cladribine for 5 days every 28 days. Interval imaging after 2 cycles again showed worsening hypermetabolic bony lesions, worsening skin rash on scalp, continued bilateral ear drainage, leg pain, and intermittent fevers with cough and rhinorrhea. He was found to be respiratory syncytial virus (RSV) positive at that time. The child began monotherapy with clofarabine 25 mg/m2 daily for 5 days. Daily fevers continued for 2 weeks and he developed transaminitis with hypoalbuminemia and fluid overload. Blood cultures were negative, and he was empirically treated with broad-spectrum antibiotics secondary to neutropenia. CT scans done as part of fever evaluation revealed multiple new lytic skull lesions. Epstein-Barr virus (EBV) polymerase chain reaction was positive at 863 copies, which resolved without intervention over the next month. He met criteria for HLH with fevers, pancytopenia, ferritin >7500 ng/mL, triglycerides 526 mg/dL, soluble interleukin (IL)2 of 8191 U/mL, and hemophagocytosis in his bone marrow. Mutational analysis for PRF1, MUNC 13-4, XIAP and other common HLH-causing genes was normal. He thus began therapy via HLH94 with dexamethasone 10 mg/m2/d and etoposide. At the end of the standard 8-week treatment period, his HLH was felt to be well controlled with resolution of fevers and cytopenias, as well as normalization of liver function tests, triglycerides, soluble IL2, and improvement in ferritin. He went on to complete an additional 5 cycles of clofarabine 25 mg/m2 (6 total cycles), with end of therapy PET/CT showing no evidence of disease. He is now 3 years off therapy and doing very well. DISCUSSION Histiocytes or mononuclear phagocytes, the immune cells implicated in the pathogenesis of both LCH and HLH, serve many functions in the normal immune response. These include antigen presentation, activation of immune function through cytokine signaling, and phagocytosis.12 In both LCH and HLH, affected tissues express high levels of T-cell stimulatory molecules and secrete inflammatory cytokines such as IL-6, interferon, and tumor necrosis factor.8 Studies of LCH lesions suggest that chemokine receptors, including CCR6, maybe abnormally upregulated which contributes to tissue infiltration.13,14 Furthermore, the T cells found abundantly in LCH lesions show increased expression for genes involved in leukocyte chemotaxis, such as SPP1, IL8 and plasminogen activator, among others.15 A lesion with increased accumulation of histiocytes and T cells may thus be at increased risk of uncontrolled activation of these cells, resulting in hypercytokinemia and progressive organ dysfunction like that seen in HLH.12 HLH has a known association with malignancy, especially leukemias and lymphomas. If LCH indeed represents a malignant clonal process of early myeloid-lineage cells, this may also explain the potential association between the 2 entities. Alternatively, it could be that children with LCH who require multiagent or prolonged chemotherapy courses develop HLH secondary to immune dysregulation from the treatments rather than the underlying disease. HLH in LCH is thought to be a rare phenomenon and we aimed to summarize the available reports (Table 2). In our patient (patient 8), and in those reported throughout the literature, common findings included young age, multisystem LCH, history of systemic chemotherapy, and often concurrent infection. Our patient with multisystem LCH had received a prolonged course of multiagent chemotherapy secondary to his refractory disease and then developed RSV. He was also positive for EBV. Although we did not find any other reports of RSV-associated HLH, EBV is a well-known trigger of HLH, as are other viruses including influenza, parvovirus, etc. One evaluation of 182 pediatric patients with EBV who also met criteria for HLH, showed significant immune dysregulation. These patients had abnormal natural killer cell activity, as well as decreased CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells, resulting in increased T-cell activation and decreased inhibition. HLA-DR expression was elevated, indicating high levels of T-cell activation, and further downstream cytokines such as IL2 and interferon-gamma were also significantly elevated.16 Thus, viral infections including EBV can result in uncontrolled proliferation and activation of T cells, which may be further increased in patients with preexisting immune dysregulation from chemotherapy and/or the underlying disease state. We believe the combination of immunosuppression and infection may have led to HLH in our patients. Interestingly, like our patient, another reported patient with LCH also developed HLH while receiving clofarabine, a deoxyadenosine analog. Although this may be coincidence, clofarabine after multiple other immunosuppressive agents may have contributed to significant immune dysregulation and HLH in these patients. A recently published multicenter article reviewed 29 patients who met criteria for HLH and LCH. As in the patients reviewed in Table 2, about half of the patients met criteria for HLH at or around the diagnosis of LCH. Most had active LCH at diagnosis of HLH and were receiving treatments similar to those listed in Table 2. Overall, 31% had some kind of infection when HLH developed, including EBV. HLH was increased most in those with risk organ involvement, but also seen in young females without bony involvement. The combination of HLH and LCH was associated with a poor prognosis.17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment. TABLE 2 Reported Patients With LCH and HLH Patient 111 Patient 211 Patient 318 Patient 419 Patient 520 Patient 621 Patient 722 Patient 8 Age at HLH 10 mo 17 mo 3 y 2 y 10 mo 3 y 1 y 2 y Areas of LCH Colon, skin, ln, bone marrow Left mastoid Skin, bone, ln, bone marrow Skin, bone Skin, bone, ln, lungs Skin, bone, ln Skin, bone, ln, hepatomegaly Skin, bone Prior therapies None None 2CDA, ARAC×6 mo Prednisone, VBL, 6-MP, MTX×6 mo None Prednisone, VBL, 6-MP, MTX Prednisone, VCR, ARAC Prednisone, VBL, 2CDA Clinical course Presented with fever, diarrhea, HSM, LAD, and pulmonary disease Presented with fever, HSM, LAD, and bone lesion 2 cycles of clofarabine. Lesions improved but developed HLH Presented with HLH on 3 different occasions 2 to 6 mo apart in the setting of influenza, HSV, and adenovirus Presented with HLH and CMV. Diagnosed with HLH and LCH of skin 9 mo after therapy completed, the patient presented with HLH 3 wk into therapy for LCH, the patient developed HLH 7 d after beginning clofarabine therapy, developed HLH. EBV PCR+ HLH treatment Chemotherapy Prednisone, VBL, VCR Dexamethasone, etoposide Cessation of chemotherapy, antibiotics, antivirals, IVIG Prednisone, etoposide Dexamethasone, cyclo A Dexamethasone, etoposide, cyclo A, followed by flu, mel, ATG cytox, and UCBT Dexamethasone, etoposide Outcome Died 10 mo after diagnosis CR Continued disease progression, followed by death within 2 mo CR CR CR CR and engrafted Disease-free now 3 y off therapy ARAC indicates cytarabine; ATG, anti-thymocyte globulin; 2CDA, cladribine; CMV, cytomegalovirus; CR, complete remission; cytox, cyclophosphamide; EBV, Epstein-Barr virus; flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; IN, lymph node; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; LCH, Langerhans cell histiocytosis; mel, melphalan; MP, mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction; UCBT, unrelated cord blood transplant; VBL, vinblastine; VCR, vincristine. The authors declare no conflict of interest.

Recovered

ReactionOutcome

CC BY-NC-ND

31725543

2021-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Autonomic dysreflexia'.

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

BACLOFEN, MORPHINE SULFATE

DrugsGivenReaction

CC BY-NC-ND

31815605

2021-07

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Catheter site cellulitis'.

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

BACLOFEN, MORPHINE SULFATE

DrugsGivenReaction

CC BY-NC-ND

31815605

2021-07

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug withdrawal syndrome'.

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

BACLOFEN, FENTANYL, FLUCLOXACILLIN, MORPHINE, VANCOMYCIN

DrugsGivenReaction

CC BY-NC-ND

31815605

2021-07

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypertensive crisis'.

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

BACLOFEN, FENTANYL, FLUCLOXACILLIN, MORPHINE, VANCOMYCIN

DrugsGivenReaction

CC BY-NC-ND

31815605

2021-07

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Implant site abscess'.

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

BACLOFEN, MORPHINE SULFATE

DrugsGivenReaction

CC BY-NC-ND

31815605

2021-07

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neuralgia'.

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

BACLOFEN, MORPHINE SULFATE

DrugsGivenReaction

CC BY-NC-ND

31815605

2021-07

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pseudomonas infection'.

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

BACLOFEN, FENTANYL, FLUCLOXACILLIN, MORPHINE, VANCOMYCIN

DrugsGivenReaction

CC BY-NC-ND

31815605

2021-07

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Staphylococcal infection'.

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

BACLOFEN, FENTANYL, FLUCLOXACILLIN, MORPHINE, VANCOMYCIN

DrugsGivenReaction

CC BY-NC-ND

31815605

2021-07

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'.

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

BACLOFEN, FENTANYL, FLUCLOXACILLIN, MORPHINE, VANCOMYCIN

DrugsGivenReaction

CC BY-NC-ND

31815605

2021-07

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Withdrawal syndrome'.

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

BACLOFEN, MORPHINE SULFATE

DrugsGivenReaction

CC BY-NC-ND

31815605

2021-07

What was the administration route of drug 'FENTANYL'?

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

Transdermal

DrugAdministrationRoute

CC BY-NC-ND

31815605

2021-07

What was the administration route of drug 'MORPHINE SULFATE'?

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

Intrathecal

DrugAdministrationRoute

CC BY-NC-ND

31815605

2021-07

What was the administration route of drug 'MORPHINE'?

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

Intrathecal

DrugAdministrationRoute

CC BY-NC-ND

31815605

2021-07

What was the dosage of drug 'FENTANYL'?

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

50 MCG

DrugDosageText

CC BY-NC-ND

31815605

2021-07

What was the dosage of drug 'VANCOMYCIN'?

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

2 G/DAY

DrugDosageText

CC BY-NC-ND

31815605

2021-07

What was the outcome of reaction 'Autonomic dysreflexia'?

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

Recovered

ReactionOutcome

CC BY-NC-ND

31815605

2021-07

What was the outcome of reaction 'Catheter site cellulitis'?

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

Recovered

ReactionOutcome

CC BY-NC-ND

31815605

2021-07

What was the outcome of reaction 'Drug withdrawal syndrome'?

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

Recovered

ReactionOutcome

CC BY-NC-ND

31815605

2021-07

What was the outcome of reaction 'Hypertensive crisis'?

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

Recovered

ReactionOutcome

CC BY-NC-ND

31815605

2021-07

What was the outcome of reaction 'Neuralgia'?

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

Recovered

ReactionOutcome

CC BY-NC-ND

31815605

2021-07

What was the outcome of reaction 'Posterior reversible encephalopathy syndrome'?

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

Recovered

ReactionOutcome

CC BY-NC-ND

31815605

2021-07

What was the outcome of reaction 'Pseudomonas infection'?

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

Recovered

ReactionOutcome

CC BY-NC-ND

31815605

2021-07

What was the outcome of reaction 'Staphylococcal infection'?

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

Recovered

ReactionOutcome

CC BY-NC-ND

31815605

2021-07

What was the outcome of reaction 'Subarachnoid haemorrhage'?

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

Recovered

ReactionOutcome

CC BY-NC-ND

31815605

2021-07

What was the outcome of reaction 'Therapeutic product effect incomplete'?

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

Recovered

ReactionOutcome

CC BY-NC-ND

31815605

2021-07

What was the outcome of reaction 'Withdrawal syndrome'?

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury. Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency. Introduction Episodic attacks of autonomic dysreflexia (AD) (“sympathetic storm”) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels (above the outflow to the splanchnic and renal vascular beds).1–5 Noxious or innocuous visceral or somatic stimuli below the SCI lesion such as bladder and bowel irritation1,3,6 can lead to a sudden excessive sympathetic response. Spasticity, pain, sexual activity, pregnancy, delivery, pressure sores, and iatrogenic medical procedures are also known to trigger AD.1,3,7 Loss of descending inhibition results in higher levels of norepinephrine release, which is responsible for cold, pale skin vasoconstriction below the level of injury.3,8 The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure.2,3,6 The AD syndrome varies from silent, mild forms with diaphoresis above the lesion and piloerection to a severe, life-threatening situation.2,7 These attacks can happen up to 40 times a day.4 The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death.1–3 Intrathecal baclofen (ITB) has been used to treat chronic AD.9,10 We report the application of ITB in an emergency case of acute intractable sympathetic storm. After the approval of the medical ethics committee of Erasmus Medical Center (MEC-2017-326), we retrospectively studied the case. The requirement to obtain informed consent was waived. Presentation of the case A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002. Initially this complaint was controlled with oral baclofen. Due to progression of spasticity, ITB was administered after two years. For fourteen years, the patient was treated with ITB using an implanted infusion system (SynchroMed II, Medtronic Inc., Minneapolis, MN, USA). During that time, a neuropathic pain developed below the level of the SCI and morphine was added to the ITB. Complaints were again under control with intrathecal morphine of 1.2 mg/day and ITB of 192 mcg/day. More recently, the patient developed a cellulitis at the orifice of his suprapubic catheter. Initially, we started with flucloxacillin 4 g/day. After the bacteriological culture revealed both Staphylococcus aureus and a Pseudomonas aeruginosa, the antibiotic treatment was changed to piperacillin/tazobactam 16/2 g/day, and vancomycin 2g/day. The local infection quickly subsided with the antibiotic treatment, but the development of erythema and swelling around the pump in the left abdominal wall indicated that the infection had spread to the device. We feared that the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days. Explantation of the pump was thus deemed necessary. To prevent a withdrawal syndrome, we reduced the medication in three steps by 25%. Concomitantly, as a cross titration we started with oral baclofen and transdermal fentanyl (50 mcg). As intrathecal baclofen was still administered, we started with a low oral baclofen dose of 40 mg, which was increased to 80 mg while concomitantly reducing the intrathecal administration. At day four we removed the entire device. We did not find any sign of an infection dorsally at the catheter insertion site, but we identified an abscess in the abdominal pump pocket. The day thereafter, the patient developed episodic a severe headache, excess perspiration and piloerection in the upper part of the body, and severely varying blood pressures (BP), and pulse rates (PR), without pain, fever, respiratory insufficiency, and with except for a C-reactive protein of 73 mg/ml and an alkaline phosphatase of 135 U/l all laboratory values were normal and remained unchanged in the following days (Fig. 1). Thereby was his spasticity under control with oral baclofen and intravenous clonazepam. With a diagnosis of AD, related with a withdrawal syndrome, the patient was admitted to the ICU and initially was successfully treated with a mixture of clonazepam, clonidine and urapidil. However, the next day the clinical situation was complicated by the patient’s diminished consciousness, later diagnosed as a posterior reversible encephalopathy syndrome (PRES).11 The severely fluctuating BP and PR returned, and the maximum tolerable oral and intravenous substitution was insufficient to compensate for the prior highly efficient route of administration of his baclofen. Figure 1 Autonomic Dysreflexia: Severe fluctuations in blood pressure (black arrow) and pulse rate (gray arrow). A distinct subarachnoid hemorrhage (SAH) in the left frontal lobe was identified with MRI (Fig. 2). To alleviate the AD, we inserted at L2-3 a temporary external catheter (Perifix 19G, B. Braun, Oss, The Netherlands) 30 cm intrathecal for reinitiating ITB. After a positive 50 mcg single bolus, we titrated ITB up to 240 mcg/day using a standard syringe pump. With this treatment, we could manage the AD and the spasticity symptoms. After one week, we removed the temporarily external catheter and replaced it with a definite intrathecal Ascenda catheter (Medtronic Inc., Minneapolis, MN, USA). In order to bridge the time until the pump pocket infection was cured, we temporarily connected the catheter to a subcutaneously implanted portal system (Porthales 4000, Tricumed Medizintechnik GmbH, Kiel, Germany) at the opposite site (costal 10–11 level). After a dose titration ITB up to 384 mcg/day using a CADD-Solis external pump (Smiths Medical ASD, Inc., St. Paul, MN, USA), we discharged the patient from the hospital. Ten weeks later, we removed the portal system and connected the catheter to a new pump in the lower right abdominal quadrant. The patient gradually recovered from the PRES. His spasticity and AD were brought under control with ITB of 384 mcg/day, and his pain by intrathecal morphine of 1.2 mg/day. Figure 2 The approach of the treatment of the infected pump pocket (A, red arrow) as a complication of cellulitis at the orifice of a suprapubic urine catheter (A, yellow arrow). The implanted port system (B, white arrow) connected with the hardly visible Ascenda intrathecal catheter percutaneously punctured with a 90° Huber needle (B, green arrow). Discussion To our review, emergency resumption of ITB as treatment of life-threatening withdrawal syndrome with AD that has not been reported before. The cyclic character, the excessive regional perspiration, piloerection in the absence of pain and missing symptom control by an additional administrated opioid, we assumed opioid withdrawal was not likely. To preempt or minimize a withdrawal syndrome,12 we performed a cross titration initially with only oral baclofen, and later with the addition of clonazepam; furthermore, to prevent an opioid withdrawal, we used transdermal fentanyl. In our practice, we wean the intrathecal medication arbitrarily in steps of 25% while concomitantly starting oral and transdermal treatment. This manner of weaning is the compromise to prevent a withdrawal syndrome versus the potential for development of meningitis. Based on our experience, we assume the same clinical aggravation would have emerged after a slower weaning protocol. Thereby, it should be taken into consideration that the fear the abscess would force the infection to spread along the catheter to the epidural and intrathecal space in a matter of days is the reason for other physicians deciding upon the immediate removal of the implanted infusion system, thus preferring to take the risk of a withdrawal syndrome instead of the development of severe meningitis. The symptomatology, in this case, differed from the regular ITB withdrawal syndrome, as his spasticity was under control with no signs without fever, respiratory insufficiency, or a multiorgan failure. Our patient was previously diagnosed with severe AD that was successfully suppressed with ITB. The patient exhibited intractable sympathetic storms as a result of a spasticity exacerbation. Possible confounding factors could be the cessation of intrathecal morphine and the presence of an infection, which itself could lead to an autonomic disturbance. However, AD did not occur in the previous cellulitis at the orifice of the suprapubic catheter period, but developed several days later. Per protocol, we explored the common causes of an autonomic disturbance, including bowel, bladder, and skin problems. Also, a physical examination and computed tomography did not reveal additional treatable disorders to remove the triggers. Also, to our best knowledge a relation between the presence of morphine in the ITB pump and the development of AD is unknown. A primary concern is the paucity of knowledge of the syndrome AD among caregivers8 and additionally the limited knowledge of ITB, in particular its value in preventing AD.9,10 We observed a protracted duration of the syndrome over hours, which is consistent with prior studies.13,14 The patient revealed an excessive fluctuating BP and PR. the patient’s varying systolic BP of 90 to 155 mmHg exceeds the norm of 150 mmHg5,7 as well as the sudden 20–40 mmHg elevation7,15 and should therefore also be considered excessive. Moreover, the associated HR of 149/min was extreme. Because we could not control the clinical situation with the applied medication, we were forced to reinitiate ITB. With no sign of a local dorsal infection, clear CSF, and a CSF Gram examination that had not revealed microorganisms at the removal of the implanted device, we decided upon a catheter insertion, although we were at that time not informed about the bacterial culture. We regarded the insertion of a foreign body such as the temporary intrathecal catheter into a potentially infected area as a calculated risk for the introduction of meningitis. We considered the development of PRES and SAH as a direct complication of the frequently repeated hypertensive crises. Based on this case, we propose that ITB infusion using a temporary intrathecal catheter during emergency situations could be possible in every hospital. In our experience, the higher ITB dose at the end after a catheter replacement is not uncommon. We are not aware of a clear explanation. A different intrathecal catheter tip level or other ventral/lateral/dorsal position could be an option. Also, it is not excluded that the clinical situation has worsened the spasticity and AD complication, resulting in the need for a higher dose. A limitation of this study is the retrospective design and the experience in only one patient. Conclusion/clinical relevance The premise of the case is the rapid reintroduction of ITB (as opposed to IV and oral antispasmodics) in the setting of ITB withdrawal in particular when associated with AD to prevent complications (in this case, PRES, SAH). Further in-depth study is necessary to validate our observation. Disclaimer statements Contributors None. Conflicts of Interest ED reports fees from Medtronic Inc.; FH reports grants and fees from Abbott, Grünenthal; all outside the submitted work.

Recovered

ReactionOutcome

CC BY-NC-ND

31815605

2021-07

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Atrial fibrillation'.

Surgery for Renal Hyperparathyroidism in the Era of Cinacalcet: A Single-Center Experience. There are only few data on the influence of cinacalcet on the outcome of parathyroidectomy in patients with renal hyperparathyroidism. Indication and timing of surgery have changed since its introduction, especially with regard to kidney transplantation. Therefore, we retrospectively analyzed patients undergoing parathyroidectomy for renal hyperparathyroidism in our institution. Between 2008 and 2015, 196 consecutive operations in 191 patients were analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet compared with 116 operations (59%) in patients without cinacalcet. Clinical data, preoperative medication, pre- and postoperative laboratory values, type and details of surgery including complications, as well as cardiovascular complications and kidney transplantation with graft function were recorded. Demographical data were similar in patients with or without cinacalcet treatment. A total of 54% of patients received a kidney graft before or after parathyroidectomy. Pre- and postoperative parathormone levels were similar in both groups (preoperatively 755 vs 742 ng/L, postoperatively 50 vs 46 ng/L, p > 0.10), whereas patients with cinacalcet showed significantly lower calcium levels preoperatively (2.28 vs 2.41 mmol/L, p = 0.0002). There was no difference in recurrence or persistence of hyperparathyroidism, duration of surgery, hospital stay, or complication rate. Creatinine levels in patients with tertiary hyperparathyroidism were similar after 1-year follow-up. Cinacalcet did not influence outcome of patients with parathyroidectomy for renal hyperparathyroidism and can be safely offered to patients not responding to medical treatment. Introduction Since the introduction of cinacalcet in the treatment of renal hyperparathyroidism (rHPT) in 2004, clinical practice for indication and timing of surgery has changed following the Kidney Disease Improving Global Outcomes (KDIGO) International guideline group (1). Overall, the number of parathyroidectomies (PTxs) has declined (2) and the timepoint of surgery is delayed in patients with end-stage renal disease (ESRD) developing rHPT (3). But especially the long-term benefit of cinacalcet on patient morbidity and mortality has not been shown so far (4). In addition, the cost-effectiveness of surgery is better than that of cinacalcet treatment after 7.25 months of therapy (5), and cinacalcet is only cost-effective in patients not eligible for surgery or receiving a kidney-graft beforehand (6). On the contrary, a large cohort study showed a rather high 30-day morbidity and mortality (7) as well as an increased morbidity and rehospitalization rate in the first year for patients after PTx not receiving a kidney graft (8). Yet, the overall risk of death for dialysis patients is lower after PTx compared with patients with medical therapy alone (9), and PTx shows a trend in improving cardiovascular morbidity and mortality (10). In 2015, Messa (11) highlighted the need for additional randomized controlled trials comparing conservative and surgical therapy. Another question of concern is the timing of surgery in relation to kidney transplantation (KTx). It is known that in more than 40% of patients, rHPT persists after KTx (12) and that especially long duration of dialysis prior to KTx negatively influences spontaneous normalization. Studies have shown that parathyroidectomy after KTx has no negative influence on overall graft survival (13), although a temporary decrease in glomerular filtration rate (GFR) was confirmed (14). On the contrary, a retrospective analysis reported that PTx before KTx was associated with a lower risk of graft failure (15). A very recent study documented that persistent hyperparathyroidism (pHPT) more than 1 year after KTx is a risk factor for graft failure (16). In addition, cinacalcet treatment in patients receiving a kidney graft was a risk factor for delayed graft function experimentally and in a single cohort study (17). While in Germany cinacalcet cannot usually be prescribed for patients after KTx, it has been shown that its use after KTx corrects hypercalciuria and hyperparathyroidism (HPT) (18). In 2015, a randomized study concluded that patients with persistent HPT at 6 months after KTx should undergo PTx for normalization of parathyroid hormone (PTH) because of beneficial effects on bone mineral density compared with continuing cinacalcet therapy (19). So far, there are only few data on the influence of cinacalcet on the short- and long-term outcome of parathyroidectomy in patients with rHPT. Therefore, we retrospectively analyzed all patients undergoing parathyroidectomy for rHPT from the introduction of cinacalcet into clinical practice up to 2015. Material and Methods Study Population All patients undergoing parathyroidectomy for rHPT are prospectively collected in our database and were retrospectively analyzed. Between January 2004 and December 2007, only six patients had been treated with cinacalcet and were not considered for this retrospective analysis. From January 2008 until January 2015, 191 consecutive patients were included. All patients were followed until 1 May 2015 or death or loss of follow-up with a mean follow-up of 48.35 ± 25.2 months. Data were collected from medical charts including standard demographical data and from the kidney transplant database of our institution/European transplantation database (T-base) as well as from referring physicians, especially dialysis centers. Data concerning duration of dialysis, type of kidney disease, preoperative medication, pre- and postoperative laboratory values (calcium, intact para-thyroid hormone (iPTH), phosphate, creatinine, alkaline phosphatase (AP)), type and details of surgery including complications, as well as cardiovascular complications and KTx with graft function were recorded. Five patients who required redo surgery for recurrent or persistent HPT were calculated twice, because both operations were performed at our hospital within the study period. Thus, 196 operations in 191 patients were finally analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet at the time of surgery (group A) compared with 116 operations (59%) in patients not receiving cinacalcet (group B). A total of 156 patients (82%) were treated with phosphate binders, and 164 (86%) with 1,25 (OH)-vitamin D. After 2008, there was an increasing number of patients with cinacalcet treatment with a maximum in 2011 (Table 1). Table 1 Patients undergoing PTx with (group A) or without (group B) cinacalcet treatment in respective year. Year Group A Group B Total 2008 5 31 36 2009 8 25 33 2010 7 11 18 2011 24 15 39 2012 7 8 15 2013 11 16 27 2014 18 10 28 Our standard surgical procedure is a bilateral cervical exploration with subtotal PTx leaving a small nodular-free cervical remnant. A total PTx was performed only in patients with a high risk of recurrent HPT who were not listed for KTx. Cervical thymectomy was not routinely performed but carried out if less than four cervical glands were found. Neuromonitoring of the recurrent laryngeal nerve was routinely performed in all patients. In case of suspicious thyroid nodules or parathyroid glands with close relation to or inside the thyroid capsule, simultaneous thyroid surgery was done. In all patients, parathyroid tissue was cryopreserved. Postoperatively, all patients had daily controls of calcium, starting on the first postoperative day (POD). In case of persistently high iPTH levels directly after operation, consecutive controls were carried out. In case of missing glands, intraoperative iPTH was measured. Calcium substitution was instituted orally with 1000 mg/day immediately after PTx and adjusted to individual needs including additional intravenous substitution of calcium gluconate and changes in dialysate composition by our in-house nephrologists, as needed. All patients received 0.5 µg calcitriol twice daily with adjustment if needed. Patients were discharged if they were asymptomatic and as soon as the calcium level was stable (at least 1.9 mmol/L) or rising on two consecutive days. For measuring iPTH, an electrochemiluminescence immunoassay was performed by our laboratory (normal range: 15–65 ng/L). Calcium (normal range: 2.15–2.5 mmol/L), AP (35–105 U/L), creatinine (0.5–0.9 mg/dL), and phosphate (0.87–1.45 mmol/L) were measured routinely by our in-house nephrologists or referring dialysis centers later on. In order to define persistent or recurrent HPT, both elevated iPTH and calcium may be used. For this analysis, iPTH > 100 ng/L and/or calcium > 2.5 mmol/L were defined as persistent or recurrent hyperparathyroidism. All patients had an indirect laryngoscopy by an ear, nose, and throat specialist before and after the operation. In case of recurrent laryngeal nerve palsy, logopedic training was prescribed and patients were followed until vocal recovery in our outpatient clinic. Statistical Analysis Data were analyzed using the Statistica software 7.0 (StatSoft Inc., USA). All numerical results are presented as mean ± standard deviation (SD) independent from normal distribution. Categorial variables are presented as percentages. For testing normality of numerical variables, the Kolmogorov–Smirnov test (KS test) was used. Normally distributed data were tested with the unpaired t-test after comparing variances with the Levin test. For nonparametric variables with continuous distribution, the KS test was used for independent groups. Chi-square test with Yates’ correction was applied for nominal variables. Nonparametric data in dependent groups were analyzed with the Wilcoxon matched pairs test. Statistical significance was defined by p < 0.05. Results Demographic Data and Kidney Disease The study population consisted of 191 patients with 196 operations distributed to group A (80 cases, 41%) and group B (116 cases, 59%). The mean age was comparable in both groups (group A: 51.2 ± 13.3 vs group B: 51.5 ± 12.7 years), and the male/female ratio was 50% for group A, whereas group B consisted of more male patients (66%). Most patients had chronic kidney disease stage V (CKD V; 91% vs 84%, respectively) at the time of parathyroidectomy, an overview of underlying diseases is given in Table 2. Table 2 Underlying diseases leading to renal failure of patients with renal hyperparathyroidism. Number % Diabetic nephropathy 30 16 Σ = 71% Polycystic kidney disease 25 13 Chronic glomerulonephritis 20 10 Focal segmental glomerulosclerosis 16 8 Hypertensive nephropathy 15 8 IgA nephropathy 11 6 Interstitial nephritis 9 5 Membranoproliferative glomerulonephritis 10 5 Other 56 29 IgA: immunoglobulin A. A small number of patients had a functioning kidney graft at the time of parathyroidectomy (group A: 6% vs group B: 11%). Rarely, patients with CKD III and IV were operated in preparation of a living donor KTx (3% vs 5%). All patients were presented with comorbidities, including arterial hypertension, diabetes mellitus, adipositas, and coronary artery disease. Follow-up for patients with cinacalcet (group A, 39.7 ± 22.6 months) was significantly shorter compared with patients without cinacalcet (group B, 54.4 ± 25.3 months, p < 0.001, KS test). Kidney Transplantation Altogether 53% of the patients (n = 101) underwent KTx before or after PTx (25 patients lost to follow-up). At the end of the follow-up period, more patients were transplanted in both groups (54% vs 64%), but graft function varied between the groups. About 90 patients had no KTx during the study period (Table 3). Table 3 Clinical features of patients undergoing parathyroidectomy with (group A) or without cinacalcet (group B) including consecutive or prior kidney transplantation, type of parathyroidectomy, duration of surgery and hospital stay as well as complications and outcome. Cinacalcet (group A) n = 80 Without cinacalcet (group B) n = 116 No data Total Kidney transplantation 37 54 10 101  KTx before PTx 21 22 4 47  KTx after PTx 16 32 6 54 Type of operation  Subtotal PTx 49 89 – 138  Total PTx 21 19 – 40  Re-operation 10 8 – 18 Duration of surgery (minutes) 126 136 – – Hospital stay (days) 7 7 – – Complications  RLNP 2 (1 permanent) 3 – 5  Bleeding 0 2 – 2  30-day mortality 0 0 – 0 i.v. Calcium postoperatively 14 16 – 30 Death during follow-up 12 (52 alive) 14 (72 alive) 41 26 Recurrence of HPT 2 3 – 5 Persistence of HPT 1 3 – 4 HPT: hyperparathyroidism; RLNP: recurrent laryngeal nerve palsy; KTx: kidney transplantation; PTx: parathyreoidectomy. Note: Significance of bold values in the table was not calculated due to low numbers. Of the 47 patients undergoing PTx after KTx for tertiary hyperparathyroidism (tHPT), 15 (32%) were on dialysis (CKD V) in group A, while 6 patients (13%) had functioning grafts (creatinine: 1.23 ± 0.41 mg/dL) at the end of follow-up. In group B, 11 patients (23%) had CKD V and 11 (23%) presented with functioning grafts (creatinine: 1.91 ± 1.02 mg/dL), while 4 patients had unknown graft function. KTx was performed at a mean of 93.5 ± 83.1 months before PTx for both groups. In 54 patients with rHPT receiving their KTx after PTx, 42 had functioning grafts (group A: n = 13 (24%) vs group B: n = 29 (54%)), while six patients (11%) were back on dialysis (three patients in each group) and six had unknown graft function. Mean follow-up for these patients was 15.6 ± 10 months. Six patients received more than one KTx, with the PTx taking place after loss of function of the first kidney graft. Four of these were retransplanted after PTx and presented with good graft function. Creatinine levels in patients with tHPT (i.e. those with a functioning kidney transplant, defined as CKD I-III, n = 22) were analyzed before PTx and 1 year after operation. There were no significant differences neither in the whole group (p = 0.11), nor in the subgroups related to cinacalcet therapy (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet; Fig. 1). Fig. 1. Creatinine levels (mg/dL) in patients with kidney graft and good graft function at the time of PTx and at 1-year follow-up related to cinacalcet preoperatively (yes/no). There was no significant difference in creatinine levels for both groups (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet). Perioperative Data Operative technique A majority of 78% of all primary operations (138/178) underwent subtotal PTx (49 vs 89 cases in both groups, respectively). In 40 patients, a total PTx without autotransplantation was done. About 18 operations were performed for recurrent HPT (Table 3). In 86 cases (48%), concomitant thyroid surgery was carried out. Indications for thyroid surgery were solitary autonomous adenoma (n = 1), diffuse autonomy (n = 2), multinodular goiter (n = 56), suspicious thyroid nodules (n = 18), or a missing parathyroid gland (n = 12). In seven patients, a differentiated thyroid carcinoma was histologically confirmed. There was no difference in operative time between the groups (126 ± 44 min vs 136 ± 39 min with/without cinacalcet, p = 0.11, t-test). Length of in-hospital stay did not differ between the groups with a mean of 7.0 versus 7.1 days, respectively (p > 0.1, KS test). There is a trend toward shorter in-hospital stay in recent years, yet no significant difference could be seen (Table 3). Complications A total of five unilateral vocal cord palsies occurred (1.28% of 392 nerves at risk), two with and three without cinacalcet treatment. Four were temporary, while one patient after recurrent PTx revealed permanent unilateral vocal cord palsy. There were three reoperations for hematoma (n = 2) and infection (n = 1). One patient developed paroxysmal atrial fibrillation, but there was no perioperative mortality and all patients were discharged from hospital (Table 3). Perioperative laboratory values Preoperatively, calcium was significantly lower in group A (2.28 ± 0.23 mmol/L vs 2.41 ± 0.23 mmol/L, p = 0.0002, t-test), while neither postoperatively (1.89 ± 0.30 mmol/L vs 1.92 ± 0.30 mmol/L, p = 0.40, t-test) nor at discharge (2.12 ± 0.30 mmol/L vs 2.12 ± 0.27 mmol/L, p = 0.90, t-test) a statistically significant difference could be observed. Lowest calcium levels measured postoperatively were 1.91 ± 0.30 mmol/L for all patients. The lowest postoperative serum Ca levels were not significantly different between the groups, 1.89 ± 0.30 versus 1.92 ± 0.30 (p = 0.40, t-test). Altogether 30 patients received i.v. calcium postoperatively due to symptoms of hypocalcemia and/or calcium levels below 1.7 mmol/L (14 vs 16 patients). Preoperative iPTH levels were comparable between the groups (755 ± 657 ng/L vs 742 ± 545 ng/L, p > 0.10, KS test). In both groups, there was a significant drop on POD 1 with no difference between the groups (50 ± 124 ng/L vs 46 ± 83 ng/L, p > 0.10, KS test). More than 1/3 (36%) of the patients after KTx presented with good graft function at the moment of PTx. These patients showed no deterioration of creatinine levels at 1-year follow-up (1.42 mg/dL perioperatively vs 1.38 mg/dL after 1 year, p = 0.11, Wilcoxon test), and there was no difference between patients with or without cinacalcet preoperatively. 1-year surveillance data Calcium levels 1 year after PTx were not significantly different between the groups (2.26 ± 0.25 mmol/L vs 2.24 ± 0.25 mmol/L, p = 0.67, t-test). Regarding iPTH levels, no significant difference could be detected between patients with or without cinacalcet preoperatively (26.9 vs 42.1 ng/L, p > 0.1, KS test). Seven patients had extremely high iPTH (>2000 ng/L, n = 7) preoperatively, but none of these presented with persisting or recurrent hyperparathyroidism. Only two of these patients had been on cinacalcet before PTx. All of them had normalized iPTH at discharge. About 1 year after PTx, four of the patients presented with normal iPTH levels, for three of the patients iPTH was not available, but none of them was re-operated for HPT. Five of the patients had been transplanted before (n = 2) or after PTx (n = 3) and four presented with good graft function until the end of follow-up or death (n = 1). After 1 year, four patients were presented with iPTH > 100 ng/L and calcium > 2.5 mmol/L, while five patients only had elevated iPTH with normal calcium. Five of these patients had recurrent HPT (two with cinacalcet, group A) and four persisting HPT (one with cinacalcet, group A). Looking more closely at type of operation (subtotal PTx, total PTx, and recurrent PTx), there was no difference between postoperative iPTH and iPTH at 1 year. Patients with second PTx for recurrent or persisting HPT displayed a mean higher iPTH both postoperatively (45 ng/L) as well as at 1 year (92 ng/L). Patients with subtotal and total parathyroidectomy showed low levels of PTH both at discharge (11 and 8 ng/L) and at 1 year (8 and 7 ng/L). There was no significant difference between patients with or without cinacalcet. Overall mortality and morbidity Considering long-term follow-up, a considerable number of patients were lost to follow-up. There was no difference in mortality rate between the groups (p = 0.68, χ² test). At the end of follow-up, 12 of 77 patients in group A had died (16%), 52 (68%) were alive (no data in 16%, n = 13). In group B, 14 of 114 had died (12%), whereas 72 (63%) were alive (no data in 25%, n = 28). The prevalence of cardiovascular events was not significantly different between the groups. Myocardial infarction occured in 13% (group A) versus 18% of patients (group B), and the need for coronary artery intervention or bypass occurred in 13% versus 22% of patients in both groups, respectively. Also the need for peripheral revascularization (9% vs 12%) and stroke was recorded with a similar prevalence (13% vs 10%) in patients after PTx with or without cinacalcet. Discussion This single-center study in patients undergoing parathyroidectomy for rHPT shows excellent outcome independent of pretreatment with cinacalcet. Since the introduction of cinacalcet as treatment modality for rHPT, decreasing numbers of patients are being referred to parathyroidectomy (20). Nevertheless, no reduction of all-cause or cardiovascular mortality compared with surgery has been shown for patients with ESRD (4). A substantial part of these conservatively treated patients presents with persistently elevated iPTH, aggravation of complications, and consecutive referral to surgery (3). In our center, the number of patients referred to surgery was decreasing after the introduction of cinacalcet but is increasing again since 2012. Timing of PTx From our referring nephrology and transplant unit, a majority of patients on the waiting list for KTx is referred to parathyroidectomy, especially those with very high iPTH levels. This is due to the fact that only up to 56% of patients normalize PTH after KTx, mostly those with shorter waiting time on the transplant list (13). A total of 53% of our patients underwent KTx, either before or after PTx. In those patients undergoing PTx before KTx for rHPT, a majority of 78% presents with functioning grafts during follow-up. While it is clear that pHPT after KTx impairs long-term graft survival (17), optimal therapy still is under debate. An interesting report by Torregrosa et al. (21) has shown no decline in graft function 1 year after KTx for patients with rHPT that were treated with cinacalcet and also stable graft function for patients on cinacalcet during long-term follow-up. This was underlined by a meta-analysis by Cohen et al. (22) reporting that cinacalcet treatment for pHPT after KTx was not associated with inferior graft survival. In our study, 55% of patients undergoing PTx after KTx were on dialysis at the end of follow-up, mostly for graft failure before PTx. But those patients undergoing PTx with functioning kidney grafts did not show deterioration of creatinine levels postoperatively or during 1-year follow-up, irrespective of cinacalcet treatment. Interestingly, six of the patients underwent second or even third KTx after PTx and presented with functioning grafts during follow-up. In contrast, 78% of patients with PTx and consecutive KTx showed functioning grafts, irrespective of treatment with cinacalcet prior to surgery. Overall, these results favor parathyroidectomy before KTx, yet prospective trials will be necessary to evaluate optimal treatment for tHPT after KTx. Cardiovascular Morbidity Treatment with cinacalcet only showed limited effects on cardiovascular morbidity or mortality of patients with ESRD in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial (23), which evaluated patients on hemodialysis. Both a Cochrane analysis (4) and a meta-analysis by Palmer et al. (24) demonstrated that for patients with ESRD treatment with cinacalcet only reduced the risk for surgery without positively influencing all-cause or cardiovascular mortality. A smaller trial by Trombetti et al. (25) showed that PTx, on the contrary, is associated with both reduced morbidity and mortality of these patients. In this cohort, 19 months after PTx, mortality of patients with ESRD was less than without PTx. In our study, morbidity and mortality during follow-up were not different between patients with or without cinacalcet treatment before surgery. Both small sample size and patients lost to follow-up reduce the statistic power of our cohort. Laboratory Values Overall, we could see no significant differences in laboratory values perioperatively between the groups, only preoperative calcium levels were significantly lower in patients with cinacalcet. At 1 year after surgery, no difference could be detected in iPTH between the groups. A study by Somnay et al. (26) focused on patients with tHPT and the effect of cinacalcet treatment on perioperative findings and outcome. Although they presented a small patient cohort with cinacalcet treatment, they interestingly had higher iPTH levels preoperatively in this cohort, while cure rate was not influenced by cinacalcet pretreatment. Compared with our analysis, patients without cinacalcet treatment had much lower preoperative iPTH levels in this study, possibly reflecting lower thresholds for PTx after KTx. Only seven patients with tHPT in our study received cinacalcet treatment with similar preoperative iPTH levels, as patients with rHPT. A very recent study by Baker et al. (27) examined influence of cinacalcet on outcome in patients with rHPT and found greater iPTH levels in the untreated group before surgery with similar outcome. Only the study of Wirowski et al. (28) demonstrated comparable laboratory findings in patients operated for rHPT. In their analysis, pre- and postoperative iPTH levels were equal in patients with or without cinacalcet and calcium was significantly lower in cinacalcet patients. This is in line with our findings, and they also concluded that cinacalcet did not alter perioperative course. Looking more closely on recurrent, or persisting rHPT, only four patients were diagnosed during follow-up with both elevated iPTH and hypercalcemia, while five were normocalcemic with elevated iPTH. For this analysis, relatively strict values were applied as cut-off values for recurrent HPT. When increasing the cut-off values for iPTH, only two patients of the cohort would have been identified with recurrence of HPT. There was no significant difference in iPTH levels at 1 year between subtotal or total parathyroidectomy and also no difference related to cinacalcet treatment preoperatively. So overall, surgical technique with mostly subtotal PTx in our cohort showed good results and low rates of recurrent or persisting rHPT, independent of preoperative treatment with cinacalcet. Several groups have shown that subtotal PTx or total PTx with autotransplantation of parathyroid tissue represent a good compromise between effective treatment of rHPT while avoiding unnecessary complications of hypocalcemia, adynamic bone disease, or reoperations (29). Complications Overall, the rate of surgical complications was low in both groups and no difference could be calculated for patients with or without cinacalcet treatment. There was no perioperative mortality in our group. Duration of surgery and hospital stay did not differ between the groups, and hospital-stay was reduced during the study period but similar in both groups. Conclusion Our study underlines the fact that PTx represents a safe and successful treatment option for patients with rHPT, even after KTx and irrespective of co-medication with cinacalcet. In view of the morbidity and mortality of long-term dialysis, patients will need individualized decisions taken by interdisciplinary transplant and tumor boards. Surgery should at least be offered to patients not responding to cinacalcet treatment and especially to those planned for KTx. This not only should reduce complications of pHPT but also improve patient morbidity in view of a successful KTx. Authors thank Prof. Dr. med. Peter E Goretzki for discussion and critical review of the manuscript. Author Contributions: M.T.M., T.S., N.R. contributed to the study conception and design, analysis, and interpretation of data and writing of the manuscript. N.M.O., E.T., C.B. participated in the acquisition and analysis of data. P.R., N.R., J.P. contributed to the analysis and interpretation of data, the study conception, and critical review of the manuscript. Compliance with Ethical Standards: This is a retrospective non-interventional study. All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical Approval: Ethical approval was given by the local ethics committee (EA4/086/19) Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD: M. T. Mogl https://orcid.org/0000-0002-3676-047X

CALCITRIOL, CALCIUM, CALCIUM GLUCONATE, CHOLECALCIFEROL, CINACALCET HYDROCHLORIDE, SODIUM PHOSPHATE

DrugsGivenReaction

CC BY-NC

31906794

2021-03

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'.

Surgery for Renal Hyperparathyroidism in the Era of Cinacalcet: A Single-Center Experience. There are only few data on the influence of cinacalcet on the outcome of parathyroidectomy in patients with renal hyperparathyroidism. Indication and timing of surgery have changed since its introduction, especially with regard to kidney transplantation. Therefore, we retrospectively analyzed patients undergoing parathyroidectomy for renal hyperparathyroidism in our institution. Between 2008 and 2015, 196 consecutive operations in 191 patients were analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet compared with 116 operations (59%) in patients without cinacalcet. Clinical data, preoperative medication, pre- and postoperative laboratory values, type and details of surgery including complications, as well as cardiovascular complications and kidney transplantation with graft function were recorded. Demographical data were similar in patients with or without cinacalcet treatment. A total of 54% of patients received a kidney graft before or after parathyroidectomy. Pre- and postoperative parathormone levels were similar in both groups (preoperatively 755 vs 742 ng/L, postoperatively 50 vs 46 ng/L, p > 0.10), whereas patients with cinacalcet showed significantly lower calcium levels preoperatively (2.28 vs 2.41 mmol/L, p = 0.0002). There was no difference in recurrence or persistence of hyperparathyroidism, duration of surgery, hospital stay, or complication rate. Creatinine levels in patients with tertiary hyperparathyroidism were similar after 1-year follow-up. Cinacalcet did not influence outcome of patients with parathyroidectomy for renal hyperparathyroidism and can be safely offered to patients not responding to medical treatment. Introduction Since the introduction of cinacalcet in the treatment of renal hyperparathyroidism (rHPT) in 2004, clinical practice for indication and timing of surgery has changed following the Kidney Disease Improving Global Outcomes (KDIGO) International guideline group (1). Overall, the number of parathyroidectomies (PTxs) has declined (2) and the timepoint of surgery is delayed in patients with end-stage renal disease (ESRD) developing rHPT (3). But especially the long-term benefit of cinacalcet on patient morbidity and mortality has not been shown so far (4). In addition, the cost-effectiveness of surgery is better than that of cinacalcet treatment after 7.25 months of therapy (5), and cinacalcet is only cost-effective in patients not eligible for surgery or receiving a kidney-graft beforehand (6). On the contrary, a large cohort study showed a rather high 30-day morbidity and mortality (7) as well as an increased morbidity and rehospitalization rate in the first year for patients after PTx not receiving a kidney graft (8). Yet, the overall risk of death for dialysis patients is lower after PTx compared with patients with medical therapy alone (9), and PTx shows a trend in improving cardiovascular morbidity and mortality (10). In 2015, Messa (11) highlighted the need for additional randomized controlled trials comparing conservative and surgical therapy. Another question of concern is the timing of surgery in relation to kidney transplantation (KTx). It is known that in more than 40% of patients, rHPT persists after KTx (12) and that especially long duration of dialysis prior to KTx negatively influences spontaneous normalization. Studies have shown that parathyroidectomy after KTx has no negative influence on overall graft survival (13), although a temporary decrease in glomerular filtration rate (GFR) was confirmed (14). On the contrary, a retrospective analysis reported that PTx before KTx was associated with a lower risk of graft failure (15). A very recent study documented that persistent hyperparathyroidism (pHPT) more than 1 year after KTx is a risk factor for graft failure (16). In addition, cinacalcet treatment in patients receiving a kidney graft was a risk factor for delayed graft function experimentally and in a single cohort study (17). While in Germany cinacalcet cannot usually be prescribed for patients after KTx, it has been shown that its use after KTx corrects hypercalciuria and hyperparathyroidism (HPT) (18). In 2015, a randomized study concluded that patients with persistent HPT at 6 months after KTx should undergo PTx for normalization of parathyroid hormone (PTH) because of beneficial effects on bone mineral density compared with continuing cinacalcet therapy (19). So far, there are only few data on the influence of cinacalcet on the short- and long-term outcome of parathyroidectomy in patients with rHPT. Therefore, we retrospectively analyzed all patients undergoing parathyroidectomy for rHPT from the introduction of cinacalcet into clinical practice up to 2015. Material and Methods Study Population All patients undergoing parathyroidectomy for rHPT are prospectively collected in our database and were retrospectively analyzed. Between January 2004 and December 2007, only six patients had been treated with cinacalcet and were not considered for this retrospective analysis. From January 2008 until January 2015, 191 consecutive patients were included. All patients were followed until 1 May 2015 or death or loss of follow-up with a mean follow-up of 48.35 ± 25.2 months. Data were collected from medical charts including standard demographical data and from the kidney transplant database of our institution/European transplantation database (T-base) as well as from referring physicians, especially dialysis centers. Data concerning duration of dialysis, type of kidney disease, preoperative medication, pre- and postoperative laboratory values (calcium, intact para-thyroid hormone (iPTH), phosphate, creatinine, alkaline phosphatase (AP)), type and details of surgery including complications, as well as cardiovascular complications and KTx with graft function were recorded. Five patients who required redo surgery for recurrent or persistent HPT were calculated twice, because both operations were performed at our hospital within the study period. Thus, 196 operations in 191 patients were finally analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet at the time of surgery (group A) compared with 116 operations (59%) in patients not receiving cinacalcet (group B). A total of 156 patients (82%) were treated with phosphate binders, and 164 (86%) with 1,25 (OH)-vitamin D. After 2008, there was an increasing number of patients with cinacalcet treatment with a maximum in 2011 (Table 1). Table 1 Patients undergoing PTx with (group A) or without (group B) cinacalcet treatment in respective year. Year Group A Group B Total 2008 5 31 36 2009 8 25 33 2010 7 11 18 2011 24 15 39 2012 7 8 15 2013 11 16 27 2014 18 10 28 Our standard surgical procedure is a bilateral cervical exploration with subtotal PTx leaving a small nodular-free cervical remnant. A total PTx was performed only in patients with a high risk of recurrent HPT who were not listed for KTx. Cervical thymectomy was not routinely performed but carried out if less than four cervical glands were found. Neuromonitoring of the recurrent laryngeal nerve was routinely performed in all patients. In case of suspicious thyroid nodules or parathyroid glands with close relation to or inside the thyroid capsule, simultaneous thyroid surgery was done. In all patients, parathyroid tissue was cryopreserved. Postoperatively, all patients had daily controls of calcium, starting on the first postoperative day (POD). In case of persistently high iPTH levels directly after operation, consecutive controls were carried out. In case of missing glands, intraoperative iPTH was measured. Calcium substitution was instituted orally with 1000 mg/day immediately after PTx and adjusted to individual needs including additional intravenous substitution of calcium gluconate and changes in dialysate composition by our in-house nephrologists, as needed. All patients received 0.5 µg calcitriol twice daily with adjustment if needed. Patients were discharged if they were asymptomatic and as soon as the calcium level was stable (at least 1.9 mmol/L) or rising on two consecutive days. For measuring iPTH, an electrochemiluminescence immunoassay was performed by our laboratory (normal range: 15–65 ng/L). Calcium (normal range: 2.15–2.5 mmol/L), AP (35–105 U/L), creatinine (0.5–0.9 mg/dL), and phosphate (0.87–1.45 mmol/L) were measured routinely by our in-house nephrologists or referring dialysis centers later on. In order to define persistent or recurrent HPT, both elevated iPTH and calcium may be used. For this analysis, iPTH > 100 ng/L and/or calcium > 2.5 mmol/L were defined as persistent or recurrent hyperparathyroidism. All patients had an indirect laryngoscopy by an ear, nose, and throat specialist before and after the operation. In case of recurrent laryngeal nerve palsy, logopedic training was prescribed and patients were followed until vocal recovery in our outpatient clinic. Statistical Analysis Data were analyzed using the Statistica software 7.0 (StatSoft Inc., USA). All numerical results are presented as mean ± standard deviation (SD) independent from normal distribution. Categorial variables are presented as percentages. For testing normality of numerical variables, the Kolmogorov–Smirnov test (KS test) was used. Normally distributed data were tested with the unpaired t-test after comparing variances with the Levin test. For nonparametric variables with continuous distribution, the KS test was used for independent groups. Chi-square test with Yates’ correction was applied for nominal variables. Nonparametric data in dependent groups were analyzed with the Wilcoxon matched pairs test. Statistical significance was defined by p < 0.05. Results Demographic Data and Kidney Disease The study population consisted of 191 patients with 196 operations distributed to group A (80 cases, 41%) and group B (116 cases, 59%). The mean age was comparable in both groups (group A: 51.2 ± 13.3 vs group B: 51.5 ± 12.7 years), and the male/female ratio was 50% for group A, whereas group B consisted of more male patients (66%). Most patients had chronic kidney disease stage V (CKD V; 91% vs 84%, respectively) at the time of parathyroidectomy, an overview of underlying diseases is given in Table 2. Table 2 Underlying diseases leading to renal failure of patients with renal hyperparathyroidism. Number % Diabetic nephropathy 30 16 Σ = 71% Polycystic kidney disease 25 13 Chronic glomerulonephritis 20 10 Focal segmental glomerulosclerosis 16 8 Hypertensive nephropathy 15 8 IgA nephropathy 11 6 Interstitial nephritis 9 5 Membranoproliferative glomerulonephritis 10 5 Other 56 29 IgA: immunoglobulin A. A small number of patients had a functioning kidney graft at the time of parathyroidectomy (group A: 6% vs group B: 11%). Rarely, patients with CKD III and IV were operated in preparation of a living donor KTx (3% vs 5%). All patients were presented with comorbidities, including arterial hypertension, diabetes mellitus, adipositas, and coronary artery disease. Follow-up for patients with cinacalcet (group A, 39.7 ± 22.6 months) was significantly shorter compared with patients without cinacalcet (group B, 54.4 ± 25.3 months, p < 0.001, KS test). Kidney Transplantation Altogether 53% of the patients (n = 101) underwent KTx before or after PTx (25 patients lost to follow-up). At the end of the follow-up period, more patients were transplanted in both groups (54% vs 64%), but graft function varied between the groups. About 90 patients had no KTx during the study period (Table 3). Table 3 Clinical features of patients undergoing parathyroidectomy with (group A) or without cinacalcet (group B) including consecutive or prior kidney transplantation, type of parathyroidectomy, duration of surgery and hospital stay as well as complications and outcome. Cinacalcet (group A) n = 80 Without cinacalcet (group B) n = 116 No data Total Kidney transplantation 37 54 10 101  KTx before PTx 21 22 4 47  KTx after PTx 16 32 6 54 Type of operation  Subtotal PTx 49 89 – 138  Total PTx 21 19 – 40  Re-operation 10 8 – 18 Duration of surgery (minutes) 126 136 – – Hospital stay (days) 7 7 – – Complications  RLNP 2 (1 permanent) 3 – 5  Bleeding 0 2 – 2  30-day mortality 0 0 – 0 i.v. Calcium postoperatively 14 16 – 30 Death during follow-up 12 (52 alive) 14 (72 alive) 41 26 Recurrence of HPT 2 3 – 5 Persistence of HPT 1 3 – 4 HPT: hyperparathyroidism; RLNP: recurrent laryngeal nerve palsy; KTx: kidney transplantation; PTx: parathyreoidectomy. Note: Significance of bold values in the table was not calculated due to low numbers. Of the 47 patients undergoing PTx after KTx for tertiary hyperparathyroidism (tHPT), 15 (32%) were on dialysis (CKD V) in group A, while 6 patients (13%) had functioning grafts (creatinine: 1.23 ± 0.41 mg/dL) at the end of follow-up. In group B, 11 patients (23%) had CKD V and 11 (23%) presented with functioning grafts (creatinine: 1.91 ± 1.02 mg/dL), while 4 patients had unknown graft function. KTx was performed at a mean of 93.5 ± 83.1 months before PTx for both groups. In 54 patients with rHPT receiving their KTx after PTx, 42 had functioning grafts (group A: n = 13 (24%) vs group B: n = 29 (54%)), while six patients (11%) were back on dialysis (three patients in each group) and six had unknown graft function. Mean follow-up for these patients was 15.6 ± 10 months. Six patients received more than one KTx, with the PTx taking place after loss of function of the first kidney graft. Four of these were retransplanted after PTx and presented with good graft function. Creatinine levels in patients with tHPT (i.e. those with a functioning kidney transplant, defined as CKD I-III, n = 22) were analyzed before PTx and 1 year after operation. There were no significant differences neither in the whole group (p = 0.11), nor in the subgroups related to cinacalcet therapy (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet; Fig. 1). Fig. 1. Creatinine levels (mg/dL) in patients with kidney graft and good graft function at the time of PTx and at 1-year follow-up related to cinacalcet preoperatively (yes/no). There was no significant difference in creatinine levels for both groups (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet). Perioperative Data Operative technique A majority of 78% of all primary operations (138/178) underwent subtotal PTx (49 vs 89 cases in both groups, respectively). In 40 patients, a total PTx without autotransplantation was done. About 18 operations were performed for recurrent HPT (Table 3). In 86 cases (48%), concomitant thyroid surgery was carried out. Indications for thyroid surgery were solitary autonomous adenoma (n = 1), diffuse autonomy (n = 2), multinodular goiter (n = 56), suspicious thyroid nodules (n = 18), or a missing parathyroid gland (n = 12). In seven patients, a differentiated thyroid carcinoma was histologically confirmed. There was no difference in operative time between the groups (126 ± 44 min vs 136 ± 39 min with/without cinacalcet, p = 0.11, t-test). Length of in-hospital stay did not differ between the groups with a mean of 7.0 versus 7.1 days, respectively (p > 0.1, KS test). There is a trend toward shorter in-hospital stay in recent years, yet no significant difference could be seen (Table 3). Complications A total of five unilateral vocal cord palsies occurred (1.28% of 392 nerves at risk), two with and three without cinacalcet treatment. Four were temporary, while one patient after recurrent PTx revealed permanent unilateral vocal cord palsy. There were three reoperations for hematoma (n = 2) and infection (n = 1). One patient developed paroxysmal atrial fibrillation, but there was no perioperative mortality and all patients were discharged from hospital (Table 3). Perioperative laboratory values Preoperatively, calcium was significantly lower in group A (2.28 ± 0.23 mmol/L vs 2.41 ± 0.23 mmol/L, p = 0.0002, t-test), while neither postoperatively (1.89 ± 0.30 mmol/L vs 1.92 ± 0.30 mmol/L, p = 0.40, t-test) nor at discharge (2.12 ± 0.30 mmol/L vs 2.12 ± 0.27 mmol/L, p = 0.90, t-test) a statistically significant difference could be observed. Lowest calcium levels measured postoperatively were 1.91 ± 0.30 mmol/L for all patients. The lowest postoperative serum Ca levels were not significantly different between the groups, 1.89 ± 0.30 versus 1.92 ± 0.30 (p = 0.40, t-test). Altogether 30 patients received i.v. calcium postoperatively due to symptoms of hypocalcemia and/or calcium levels below 1.7 mmol/L (14 vs 16 patients). Preoperative iPTH levels were comparable between the groups (755 ± 657 ng/L vs 742 ± 545 ng/L, p > 0.10, KS test). In both groups, there was a significant drop on POD 1 with no difference between the groups (50 ± 124 ng/L vs 46 ± 83 ng/L, p > 0.10, KS test). More than 1/3 (36%) of the patients after KTx presented with good graft function at the moment of PTx. These patients showed no deterioration of creatinine levels at 1-year follow-up (1.42 mg/dL perioperatively vs 1.38 mg/dL after 1 year, p = 0.11, Wilcoxon test), and there was no difference between patients with or without cinacalcet preoperatively. 1-year surveillance data Calcium levels 1 year after PTx were not significantly different between the groups (2.26 ± 0.25 mmol/L vs 2.24 ± 0.25 mmol/L, p = 0.67, t-test). Regarding iPTH levels, no significant difference could be detected between patients with or without cinacalcet preoperatively (26.9 vs 42.1 ng/L, p > 0.1, KS test). Seven patients had extremely high iPTH (>2000 ng/L, n = 7) preoperatively, but none of these presented with persisting or recurrent hyperparathyroidism. Only two of these patients had been on cinacalcet before PTx. All of them had normalized iPTH at discharge. About 1 year after PTx, four of the patients presented with normal iPTH levels, for three of the patients iPTH was not available, but none of them was re-operated for HPT. Five of the patients had been transplanted before (n = 2) or after PTx (n = 3) and four presented with good graft function until the end of follow-up or death (n = 1). After 1 year, four patients were presented with iPTH > 100 ng/L and calcium > 2.5 mmol/L, while five patients only had elevated iPTH with normal calcium. Five of these patients had recurrent HPT (two with cinacalcet, group A) and four persisting HPT (one with cinacalcet, group A). Looking more closely at type of operation (subtotal PTx, total PTx, and recurrent PTx), there was no difference between postoperative iPTH and iPTH at 1 year. Patients with second PTx for recurrent or persisting HPT displayed a mean higher iPTH both postoperatively (45 ng/L) as well as at 1 year (92 ng/L). Patients with subtotal and total parathyroidectomy showed low levels of PTH both at discharge (11 and 8 ng/L) and at 1 year (8 and 7 ng/L). There was no significant difference between patients with or without cinacalcet. Overall mortality and morbidity Considering long-term follow-up, a considerable number of patients were lost to follow-up. There was no difference in mortality rate between the groups (p = 0.68, χ² test). At the end of follow-up, 12 of 77 patients in group A had died (16%), 52 (68%) were alive (no data in 16%, n = 13). In group B, 14 of 114 had died (12%), whereas 72 (63%) were alive (no data in 25%, n = 28). The prevalence of cardiovascular events was not significantly different between the groups. Myocardial infarction occured in 13% (group A) versus 18% of patients (group B), and the need for coronary artery intervention or bypass occurred in 13% versus 22% of patients in both groups, respectively. Also the need for peripheral revascularization (9% vs 12%) and stroke was recorded with a similar prevalence (13% vs 10%) in patients after PTx with or without cinacalcet. Discussion This single-center study in patients undergoing parathyroidectomy for rHPT shows excellent outcome independent of pretreatment with cinacalcet. Since the introduction of cinacalcet as treatment modality for rHPT, decreasing numbers of patients are being referred to parathyroidectomy (20). Nevertheless, no reduction of all-cause or cardiovascular mortality compared with surgery has been shown for patients with ESRD (4). A substantial part of these conservatively treated patients presents with persistently elevated iPTH, aggravation of complications, and consecutive referral to surgery (3). In our center, the number of patients referred to surgery was decreasing after the introduction of cinacalcet but is increasing again since 2012. Timing of PTx From our referring nephrology and transplant unit, a majority of patients on the waiting list for KTx is referred to parathyroidectomy, especially those with very high iPTH levels. This is due to the fact that only up to 56% of patients normalize PTH after KTx, mostly those with shorter waiting time on the transplant list (13). A total of 53% of our patients underwent KTx, either before or after PTx. In those patients undergoing PTx before KTx for rHPT, a majority of 78% presents with functioning grafts during follow-up. While it is clear that pHPT after KTx impairs long-term graft survival (17), optimal therapy still is under debate. An interesting report by Torregrosa et al. (21) has shown no decline in graft function 1 year after KTx for patients with rHPT that were treated with cinacalcet and also stable graft function for patients on cinacalcet during long-term follow-up. This was underlined by a meta-analysis by Cohen et al. (22) reporting that cinacalcet treatment for pHPT after KTx was not associated with inferior graft survival. In our study, 55% of patients undergoing PTx after KTx were on dialysis at the end of follow-up, mostly for graft failure before PTx. But those patients undergoing PTx with functioning kidney grafts did not show deterioration of creatinine levels postoperatively or during 1-year follow-up, irrespective of cinacalcet treatment. Interestingly, six of the patients underwent second or even third KTx after PTx and presented with functioning grafts during follow-up. In contrast, 78% of patients with PTx and consecutive KTx showed functioning grafts, irrespective of treatment with cinacalcet prior to surgery. Overall, these results favor parathyroidectomy before KTx, yet prospective trials will be necessary to evaluate optimal treatment for tHPT after KTx. Cardiovascular Morbidity Treatment with cinacalcet only showed limited effects on cardiovascular morbidity or mortality of patients with ESRD in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial (23), which evaluated patients on hemodialysis. Both a Cochrane analysis (4) and a meta-analysis by Palmer et al. (24) demonstrated that for patients with ESRD treatment with cinacalcet only reduced the risk for surgery without positively influencing all-cause or cardiovascular mortality. A smaller trial by Trombetti et al. (25) showed that PTx, on the contrary, is associated with both reduced morbidity and mortality of these patients. In this cohort, 19 months after PTx, mortality of patients with ESRD was less than without PTx. In our study, morbidity and mortality during follow-up were not different between patients with or without cinacalcet treatment before surgery. Both small sample size and patients lost to follow-up reduce the statistic power of our cohort. Laboratory Values Overall, we could see no significant differences in laboratory values perioperatively between the groups, only preoperative calcium levels were significantly lower in patients with cinacalcet. At 1 year after surgery, no difference could be detected in iPTH between the groups. A study by Somnay et al. (26) focused on patients with tHPT and the effect of cinacalcet treatment on perioperative findings and outcome. Although they presented a small patient cohort with cinacalcet treatment, they interestingly had higher iPTH levels preoperatively in this cohort, while cure rate was not influenced by cinacalcet pretreatment. Compared with our analysis, patients without cinacalcet treatment had much lower preoperative iPTH levels in this study, possibly reflecting lower thresholds for PTx after KTx. Only seven patients with tHPT in our study received cinacalcet treatment with similar preoperative iPTH levels, as patients with rHPT. A very recent study by Baker et al. (27) examined influence of cinacalcet on outcome in patients with rHPT and found greater iPTH levels in the untreated group before surgery with similar outcome. Only the study of Wirowski et al. (28) demonstrated comparable laboratory findings in patients operated for rHPT. In their analysis, pre- and postoperative iPTH levels were equal in patients with or without cinacalcet and calcium was significantly lower in cinacalcet patients. This is in line with our findings, and they also concluded that cinacalcet did not alter perioperative course. Looking more closely on recurrent, or persisting rHPT, only four patients were diagnosed during follow-up with both elevated iPTH and hypercalcemia, while five were normocalcemic with elevated iPTH. For this analysis, relatively strict values were applied as cut-off values for recurrent HPT. When increasing the cut-off values for iPTH, only two patients of the cohort would have been identified with recurrence of HPT. There was no significant difference in iPTH levels at 1 year between subtotal or total parathyroidectomy and also no difference related to cinacalcet treatment preoperatively. So overall, surgical technique with mostly subtotal PTx in our cohort showed good results and low rates of recurrent or persisting rHPT, independent of preoperative treatment with cinacalcet. Several groups have shown that subtotal PTx or total PTx with autotransplantation of parathyroid tissue represent a good compromise between effective treatment of rHPT while avoiding unnecessary complications of hypocalcemia, adynamic bone disease, or reoperations (29). Complications Overall, the rate of surgical complications was low in both groups and no difference could be calculated for patients with or without cinacalcet treatment. There was no perioperative mortality in our group. Duration of surgery and hospital stay did not differ between the groups, and hospital-stay was reduced during the study period but similar in both groups. Conclusion Our study underlines the fact that PTx represents a safe and successful treatment option for patients with rHPT, even after KTx and irrespective of co-medication with cinacalcet. In view of the morbidity and mortality of long-term dialysis, patients will need individualized decisions taken by interdisciplinary transplant and tumor boards. Surgery should at least be offered to patients not responding to cinacalcet treatment and especially to those planned for KTx. This not only should reduce complications of pHPT but also improve patient morbidity in view of a successful KTx. Authors thank Prof. Dr. med. Peter E Goretzki for discussion and critical review of the manuscript. Author Contributions: M.T.M., T.S., N.R. contributed to the study conception and design, analysis, and interpretation of data and writing of the manuscript. N.M.O., E.T., C.B. participated in the acquisition and analysis of data. P.R., N.R., J.P. contributed to the analysis and interpretation of data, the study conception, and critical review of the manuscript. Compliance with Ethical Standards: This is a retrospective non-interventional study. All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical Approval: Ethical approval was given by the local ethics committee (EA4/086/19) Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD: M. T. Mogl https://orcid.org/0000-0002-3676-047X

CALCITRIOL, CALCIUM, CALCIUM GLUCONATE, CHOLECALCIFEROL, CINACALCET HYDROCHLORIDE, SODIUM PHOSPHATE

DrugsGivenReaction

CC BY-NC

31906794

2021-03

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haematoma'.

Surgery for Renal Hyperparathyroidism in the Era of Cinacalcet: A Single-Center Experience. There are only few data on the influence of cinacalcet on the outcome of parathyroidectomy in patients with renal hyperparathyroidism. Indication and timing of surgery have changed since its introduction, especially with regard to kidney transplantation. Therefore, we retrospectively analyzed patients undergoing parathyroidectomy for renal hyperparathyroidism in our institution. Between 2008 and 2015, 196 consecutive operations in 191 patients were analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet compared with 116 operations (59%) in patients without cinacalcet. Clinical data, preoperative medication, pre- and postoperative laboratory values, type and details of surgery including complications, as well as cardiovascular complications and kidney transplantation with graft function were recorded. Demographical data were similar in patients with or without cinacalcet treatment. A total of 54% of patients received a kidney graft before or after parathyroidectomy. Pre- and postoperative parathormone levels were similar in both groups (preoperatively 755 vs 742 ng/L, postoperatively 50 vs 46 ng/L, p > 0.10), whereas patients with cinacalcet showed significantly lower calcium levels preoperatively (2.28 vs 2.41 mmol/L, p = 0.0002). There was no difference in recurrence or persistence of hyperparathyroidism, duration of surgery, hospital stay, or complication rate. Creatinine levels in patients with tertiary hyperparathyroidism were similar after 1-year follow-up. Cinacalcet did not influence outcome of patients with parathyroidectomy for renal hyperparathyroidism and can be safely offered to patients not responding to medical treatment. Introduction Since the introduction of cinacalcet in the treatment of renal hyperparathyroidism (rHPT) in 2004, clinical practice for indication and timing of surgery has changed following the Kidney Disease Improving Global Outcomes (KDIGO) International guideline group (1). Overall, the number of parathyroidectomies (PTxs) has declined (2) and the timepoint of surgery is delayed in patients with end-stage renal disease (ESRD) developing rHPT (3). But especially the long-term benefit of cinacalcet on patient morbidity and mortality has not been shown so far (4). In addition, the cost-effectiveness of surgery is better than that of cinacalcet treatment after 7.25 months of therapy (5), and cinacalcet is only cost-effective in patients not eligible for surgery or receiving a kidney-graft beforehand (6). On the contrary, a large cohort study showed a rather high 30-day morbidity and mortality (7) as well as an increased morbidity and rehospitalization rate in the first year for patients after PTx not receiving a kidney graft (8). Yet, the overall risk of death for dialysis patients is lower after PTx compared with patients with medical therapy alone (9), and PTx shows a trend in improving cardiovascular morbidity and mortality (10). In 2015, Messa (11) highlighted the need for additional randomized controlled trials comparing conservative and surgical therapy. Another question of concern is the timing of surgery in relation to kidney transplantation (KTx). It is known that in more than 40% of patients, rHPT persists after KTx (12) and that especially long duration of dialysis prior to KTx negatively influences spontaneous normalization. Studies have shown that parathyroidectomy after KTx has no negative influence on overall graft survival (13), although a temporary decrease in glomerular filtration rate (GFR) was confirmed (14). On the contrary, a retrospective analysis reported that PTx before KTx was associated with a lower risk of graft failure (15). A very recent study documented that persistent hyperparathyroidism (pHPT) more than 1 year after KTx is a risk factor for graft failure (16). In addition, cinacalcet treatment in patients receiving a kidney graft was a risk factor for delayed graft function experimentally and in a single cohort study (17). While in Germany cinacalcet cannot usually be prescribed for patients after KTx, it has been shown that its use after KTx corrects hypercalciuria and hyperparathyroidism (HPT) (18). In 2015, a randomized study concluded that patients with persistent HPT at 6 months after KTx should undergo PTx for normalization of parathyroid hormone (PTH) because of beneficial effects on bone mineral density compared with continuing cinacalcet therapy (19). So far, there are only few data on the influence of cinacalcet on the short- and long-term outcome of parathyroidectomy in patients with rHPT. Therefore, we retrospectively analyzed all patients undergoing parathyroidectomy for rHPT from the introduction of cinacalcet into clinical practice up to 2015. Material and Methods Study Population All patients undergoing parathyroidectomy for rHPT are prospectively collected in our database and were retrospectively analyzed. Between January 2004 and December 2007, only six patients had been treated with cinacalcet and were not considered for this retrospective analysis. From January 2008 until January 2015, 191 consecutive patients were included. All patients were followed until 1 May 2015 or death or loss of follow-up with a mean follow-up of 48.35 ± 25.2 months. Data were collected from medical charts including standard demographical data and from the kidney transplant database of our institution/European transplantation database (T-base) as well as from referring physicians, especially dialysis centers. Data concerning duration of dialysis, type of kidney disease, preoperative medication, pre- and postoperative laboratory values (calcium, intact para-thyroid hormone (iPTH), phosphate, creatinine, alkaline phosphatase (AP)), type and details of surgery including complications, as well as cardiovascular complications and KTx with graft function were recorded. Five patients who required redo surgery for recurrent or persistent HPT were calculated twice, because both operations were performed at our hospital within the study period. Thus, 196 operations in 191 patients were finally analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet at the time of surgery (group A) compared with 116 operations (59%) in patients not receiving cinacalcet (group B). A total of 156 patients (82%) were treated with phosphate binders, and 164 (86%) with 1,25 (OH)-vitamin D. After 2008, there was an increasing number of patients with cinacalcet treatment with a maximum in 2011 (Table 1). Table 1 Patients undergoing PTx with (group A) or without (group B) cinacalcet treatment in respective year. Year Group A Group B Total 2008 5 31 36 2009 8 25 33 2010 7 11 18 2011 24 15 39 2012 7 8 15 2013 11 16 27 2014 18 10 28 Our standard surgical procedure is a bilateral cervical exploration with subtotal PTx leaving a small nodular-free cervical remnant. A total PTx was performed only in patients with a high risk of recurrent HPT who were not listed for KTx. Cervical thymectomy was not routinely performed but carried out if less than four cervical glands were found. Neuromonitoring of the recurrent laryngeal nerve was routinely performed in all patients. In case of suspicious thyroid nodules or parathyroid glands with close relation to or inside the thyroid capsule, simultaneous thyroid surgery was done. In all patients, parathyroid tissue was cryopreserved. Postoperatively, all patients had daily controls of calcium, starting on the first postoperative day (POD). In case of persistently high iPTH levels directly after operation, consecutive controls were carried out. In case of missing glands, intraoperative iPTH was measured. Calcium substitution was instituted orally with 1000 mg/day immediately after PTx and adjusted to individual needs including additional intravenous substitution of calcium gluconate and changes in dialysate composition by our in-house nephrologists, as needed. All patients received 0.5 µg calcitriol twice daily with adjustment if needed. Patients were discharged if they were asymptomatic and as soon as the calcium level was stable (at least 1.9 mmol/L) or rising on two consecutive days. For measuring iPTH, an electrochemiluminescence immunoassay was performed by our laboratory (normal range: 15–65 ng/L). Calcium (normal range: 2.15–2.5 mmol/L), AP (35–105 U/L), creatinine (0.5–0.9 mg/dL), and phosphate (0.87–1.45 mmol/L) were measured routinely by our in-house nephrologists or referring dialysis centers later on. In order to define persistent or recurrent HPT, both elevated iPTH and calcium may be used. For this analysis, iPTH > 100 ng/L and/or calcium > 2.5 mmol/L were defined as persistent or recurrent hyperparathyroidism. All patients had an indirect laryngoscopy by an ear, nose, and throat specialist before and after the operation. In case of recurrent laryngeal nerve palsy, logopedic training was prescribed and patients were followed until vocal recovery in our outpatient clinic. Statistical Analysis Data were analyzed using the Statistica software 7.0 (StatSoft Inc., USA). All numerical results are presented as mean ± standard deviation (SD) independent from normal distribution. Categorial variables are presented as percentages. For testing normality of numerical variables, the Kolmogorov–Smirnov test (KS test) was used. Normally distributed data were tested with the unpaired t-test after comparing variances with the Levin test. For nonparametric variables with continuous distribution, the KS test was used for independent groups. Chi-square test with Yates’ correction was applied for nominal variables. Nonparametric data in dependent groups were analyzed with the Wilcoxon matched pairs test. Statistical significance was defined by p < 0.05. Results Demographic Data and Kidney Disease The study population consisted of 191 patients with 196 operations distributed to group A (80 cases, 41%) and group B (116 cases, 59%). The mean age was comparable in both groups (group A: 51.2 ± 13.3 vs group B: 51.5 ± 12.7 years), and the male/female ratio was 50% for group A, whereas group B consisted of more male patients (66%). Most patients had chronic kidney disease stage V (CKD V; 91% vs 84%, respectively) at the time of parathyroidectomy, an overview of underlying diseases is given in Table 2. Table 2 Underlying diseases leading to renal failure of patients with renal hyperparathyroidism. Number % Diabetic nephropathy 30 16 Σ = 71% Polycystic kidney disease 25 13 Chronic glomerulonephritis 20 10 Focal segmental glomerulosclerosis 16 8 Hypertensive nephropathy 15 8 IgA nephropathy 11 6 Interstitial nephritis 9 5 Membranoproliferative glomerulonephritis 10 5 Other 56 29 IgA: immunoglobulin A. A small number of patients had a functioning kidney graft at the time of parathyroidectomy (group A: 6% vs group B: 11%). Rarely, patients with CKD III and IV were operated in preparation of a living donor KTx (3% vs 5%). All patients were presented with comorbidities, including arterial hypertension, diabetes mellitus, adipositas, and coronary artery disease. Follow-up for patients with cinacalcet (group A, 39.7 ± 22.6 months) was significantly shorter compared with patients without cinacalcet (group B, 54.4 ± 25.3 months, p < 0.001, KS test). Kidney Transplantation Altogether 53% of the patients (n = 101) underwent KTx before or after PTx (25 patients lost to follow-up). At the end of the follow-up period, more patients were transplanted in both groups (54% vs 64%), but graft function varied between the groups. About 90 patients had no KTx during the study period (Table 3). Table 3 Clinical features of patients undergoing parathyroidectomy with (group A) or without cinacalcet (group B) including consecutive or prior kidney transplantation, type of parathyroidectomy, duration of surgery and hospital stay as well as complications and outcome. Cinacalcet (group A) n = 80 Without cinacalcet (group B) n = 116 No data Total Kidney transplantation 37 54 10 101  KTx before PTx 21 22 4 47  KTx after PTx 16 32 6 54 Type of operation  Subtotal PTx 49 89 – 138  Total PTx 21 19 – 40  Re-operation 10 8 – 18 Duration of surgery (minutes) 126 136 – – Hospital stay (days) 7 7 – – Complications  RLNP 2 (1 permanent) 3 – 5  Bleeding 0 2 – 2  30-day mortality 0 0 – 0 i.v. Calcium postoperatively 14 16 – 30 Death during follow-up 12 (52 alive) 14 (72 alive) 41 26 Recurrence of HPT 2 3 – 5 Persistence of HPT 1 3 – 4 HPT: hyperparathyroidism; RLNP: recurrent laryngeal nerve palsy; KTx: kidney transplantation; PTx: parathyreoidectomy. Note: Significance of bold values in the table was not calculated due to low numbers. Of the 47 patients undergoing PTx after KTx for tertiary hyperparathyroidism (tHPT), 15 (32%) were on dialysis (CKD V) in group A, while 6 patients (13%) had functioning grafts (creatinine: 1.23 ± 0.41 mg/dL) at the end of follow-up. In group B, 11 patients (23%) had CKD V and 11 (23%) presented with functioning grafts (creatinine: 1.91 ± 1.02 mg/dL), while 4 patients had unknown graft function. KTx was performed at a mean of 93.5 ± 83.1 months before PTx for both groups. In 54 patients with rHPT receiving their KTx after PTx, 42 had functioning grafts (group A: n = 13 (24%) vs group B: n = 29 (54%)), while six patients (11%) were back on dialysis (three patients in each group) and six had unknown graft function. Mean follow-up for these patients was 15.6 ± 10 months. Six patients received more than one KTx, with the PTx taking place after loss of function of the first kidney graft. Four of these were retransplanted after PTx and presented with good graft function. Creatinine levels in patients with tHPT (i.e. those with a functioning kidney transplant, defined as CKD I-III, n = 22) were analyzed before PTx and 1 year after operation. There were no significant differences neither in the whole group (p = 0.11), nor in the subgroups related to cinacalcet therapy (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet; Fig. 1). Fig. 1. Creatinine levels (mg/dL) in patients with kidney graft and good graft function at the time of PTx and at 1-year follow-up related to cinacalcet preoperatively (yes/no). There was no significant difference in creatinine levels for both groups (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet). Perioperative Data Operative technique A majority of 78% of all primary operations (138/178) underwent subtotal PTx (49 vs 89 cases in both groups, respectively). In 40 patients, a total PTx without autotransplantation was done. About 18 operations were performed for recurrent HPT (Table 3). In 86 cases (48%), concomitant thyroid surgery was carried out. Indications for thyroid surgery were solitary autonomous adenoma (n = 1), diffuse autonomy (n = 2), multinodular goiter (n = 56), suspicious thyroid nodules (n = 18), or a missing parathyroid gland (n = 12). In seven patients, a differentiated thyroid carcinoma was histologically confirmed. There was no difference in operative time between the groups (126 ± 44 min vs 136 ± 39 min with/without cinacalcet, p = 0.11, t-test). Length of in-hospital stay did not differ between the groups with a mean of 7.0 versus 7.1 days, respectively (p > 0.1, KS test). There is a trend toward shorter in-hospital stay in recent years, yet no significant difference could be seen (Table 3). Complications A total of five unilateral vocal cord palsies occurred (1.28% of 392 nerves at risk), two with and three without cinacalcet treatment. Four were temporary, while one patient after recurrent PTx revealed permanent unilateral vocal cord palsy. There were three reoperations for hematoma (n = 2) and infection (n = 1). One patient developed paroxysmal atrial fibrillation, but there was no perioperative mortality and all patients were discharged from hospital (Table 3). Perioperative laboratory values Preoperatively, calcium was significantly lower in group A (2.28 ± 0.23 mmol/L vs 2.41 ± 0.23 mmol/L, p = 0.0002, t-test), while neither postoperatively (1.89 ± 0.30 mmol/L vs 1.92 ± 0.30 mmol/L, p = 0.40, t-test) nor at discharge (2.12 ± 0.30 mmol/L vs 2.12 ± 0.27 mmol/L, p = 0.90, t-test) a statistically significant difference could be observed. Lowest calcium levels measured postoperatively were 1.91 ± 0.30 mmol/L for all patients. The lowest postoperative serum Ca levels were not significantly different between the groups, 1.89 ± 0.30 versus 1.92 ± 0.30 (p = 0.40, t-test). Altogether 30 patients received i.v. calcium postoperatively due to symptoms of hypocalcemia and/or calcium levels below 1.7 mmol/L (14 vs 16 patients). Preoperative iPTH levels were comparable between the groups (755 ± 657 ng/L vs 742 ± 545 ng/L, p > 0.10, KS test). In both groups, there was a significant drop on POD 1 with no difference between the groups (50 ± 124 ng/L vs 46 ± 83 ng/L, p > 0.10, KS test). More than 1/3 (36%) of the patients after KTx presented with good graft function at the moment of PTx. These patients showed no deterioration of creatinine levels at 1-year follow-up (1.42 mg/dL perioperatively vs 1.38 mg/dL after 1 year, p = 0.11, Wilcoxon test), and there was no difference between patients with or without cinacalcet preoperatively. 1-year surveillance data Calcium levels 1 year after PTx were not significantly different between the groups (2.26 ± 0.25 mmol/L vs 2.24 ± 0.25 mmol/L, p = 0.67, t-test). Regarding iPTH levels, no significant difference could be detected between patients with or without cinacalcet preoperatively (26.9 vs 42.1 ng/L, p > 0.1, KS test). Seven patients had extremely high iPTH (>2000 ng/L, n = 7) preoperatively, but none of these presented with persisting or recurrent hyperparathyroidism. Only two of these patients had been on cinacalcet before PTx. All of them had normalized iPTH at discharge. About 1 year after PTx, four of the patients presented with normal iPTH levels, for three of the patients iPTH was not available, but none of them was re-operated for HPT. Five of the patients had been transplanted before (n = 2) or after PTx (n = 3) and four presented with good graft function until the end of follow-up or death (n = 1). After 1 year, four patients were presented with iPTH > 100 ng/L and calcium > 2.5 mmol/L, while five patients only had elevated iPTH with normal calcium. Five of these patients had recurrent HPT (two with cinacalcet, group A) and four persisting HPT (one with cinacalcet, group A). Looking more closely at type of operation (subtotal PTx, total PTx, and recurrent PTx), there was no difference between postoperative iPTH and iPTH at 1 year. Patients with second PTx for recurrent or persisting HPT displayed a mean higher iPTH both postoperatively (45 ng/L) as well as at 1 year (92 ng/L). Patients with subtotal and total parathyroidectomy showed low levels of PTH both at discharge (11 and 8 ng/L) and at 1 year (8 and 7 ng/L). There was no significant difference between patients with or without cinacalcet. Overall mortality and morbidity Considering long-term follow-up, a considerable number of patients were lost to follow-up. There was no difference in mortality rate between the groups (p = 0.68, χ² test). At the end of follow-up, 12 of 77 patients in group A had died (16%), 52 (68%) were alive (no data in 16%, n = 13). In group B, 14 of 114 had died (12%), whereas 72 (63%) were alive (no data in 25%, n = 28). The prevalence of cardiovascular events was not significantly different between the groups. Myocardial infarction occured in 13% (group A) versus 18% of patients (group B), and the need for coronary artery intervention or bypass occurred in 13% versus 22% of patients in both groups, respectively. Also the need for peripheral revascularization (9% vs 12%) and stroke was recorded with a similar prevalence (13% vs 10%) in patients after PTx with or without cinacalcet. Discussion This single-center study in patients undergoing parathyroidectomy for rHPT shows excellent outcome independent of pretreatment with cinacalcet. Since the introduction of cinacalcet as treatment modality for rHPT, decreasing numbers of patients are being referred to parathyroidectomy (20). Nevertheless, no reduction of all-cause or cardiovascular mortality compared with surgery has been shown for patients with ESRD (4). A substantial part of these conservatively treated patients presents with persistently elevated iPTH, aggravation of complications, and consecutive referral to surgery (3). In our center, the number of patients referred to surgery was decreasing after the introduction of cinacalcet but is increasing again since 2012. Timing of PTx From our referring nephrology and transplant unit, a majority of patients on the waiting list for KTx is referred to parathyroidectomy, especially those with very high iPTH levels. This is due to the fact that only up to 56% of patients normalize PTH after KTx, mostly those with shorter waiting time on the transplant list (13). A total of 53% of our patients underwent KTx, either before or after PTx. In those patients undergoing PTx before KTx for rHPT, a majority of 78% presents with functioning grafts during follow-up. While it is clear that pHPT after KTx impairs long-term graft survival (17), optimal therapy still is under debate. An interesting report by Torregrosa et al. (21) has shown no decline in graft function 1 year after KTx for patients with rHPT that were treated with cinacalcet and also stable graft function for patients on cinacalcet during long-term follow-up. This was underlined by a meta-analysis by Cohen et al. (22) reporting that cinacalcet treatment for pHPT after KTx was not associated with inferior graft survival. In our study, 55% of patients undergoing PTx after KTx were on dialysis at the end of follow-up, mostly for graft failure before PTx. But those patients undergoing PTx with functioning kidney grafts did not show deterioration of creatinine levels postoperatively or during 1-year follow-up, irrespective of cinacalcet treatment. Interestingly, six of the patients underwent second or even third KTx after PTx and presented with functioning grafts during follow-up. In contrast, 78% of patients with PTx and consecutive KTx showed functioning grafts, irrespective of treatment with cinacalcet prior to surgery. Overall, these results favor parathyroidectomy before KTx, yet prospective trials will be necessary to evaluate optimal treatment for tHPT after KTx. Cardiovascular Morbidity Treatment with cinacalcet only showed limited effects on cardiovascular morbidity or mortality of patients with ESRD in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial (23), which evaluated patients on hemodialysis. Both a Cochrane analysis (4) and a meta-analysis by Palmer et al. (24) demonstrated that for patients with ESRD treatment with cinacalcet only reduced the risk for surgery without positively influencing all-cause or cardiovascular mortality. A smaller trial by Trombetti et al. (25) showed that PTx, on the contrary, is associated with both reduced morbidity and mortality of these patients. In this cohort, 19 months after PTx, mortality of patients with ESRD was less than without PTx. In our study, morbidity and mortality during follow-up were not different between patients with or without cinacalcet treatment before surgery. Both small sample size and patients lost to follow-up reduce the statistic power of our cohort. Laboratory Values Overall, we could see no significant differences in laboratory values perioperatively between the groups, only preoperative calcium levels were significantly lower in patients with cinacalcet. At 1 year after surgery, no difference could be detected in iPTH between the groups. A study by Somnay et al. (26) focused on patients with tHPT and the effect of cinacalcet treatment on perioperative findings and outcome. Although they presented a small patient cohort with cinacalcet treatment, they interestingly had higher iPTH levels preoperatively in this cohort, while cure rate was not influenced by cinacalcet pretreatment. Compared with our analysis, patients without cinacalcet treatment had much lower preoperative iPTH levels in this study, possibly reflecting lower thresholds for PTx after KTx. Only seven patients with tHPT in our study received cinacalcet treatment with similar preoperative iPTH levels, as patients with rHPT. A very recent study by Baker et al. (27) examined influence of cinacalcet on outcome in patients with rHPT and found greater iPTH levels in the untreated group before surgery with similar outcome. Only the study of Wirowski et al. (28) demonstrated comparable laboratory findings in patients operated for rHPT. In their analysis, pre- and postoperative iPTH levels were equal in patients with or without cinacalcet and calcium was significantly lower in cinacalcet patients. This is in line with our findings, and they also concluded that cinacalcet did not alter perioperative course. Looking more closely on recurrent, or persisting rHPT, only four patients were diagnosed during follow-up with both elevated iPTH and hypercalcemia, while five were normocalcemic with elevated iPTH. For this analysis, relatively strict values were applied as cut-off values for recurrent HPT. When increasing the cut-off values for iPTH, only two patients of the cohort would have been identified with recurrence of HPT. There was no significant difference in iPTH levels at 1 year between subtotal or total parathyroidectomy and also no difference related to cinacalcet treatment preoperatively. So overall, surgical technique with mostly subtotal PTx in our cohort showed good results and low rates of recurrent or persisting rHPT, independent of preoperative treatment with cinacalcet. Several groups have shown that subtotal PTx or total PTx with autotransplantation of parathyroid tissue represent a good compromise between effective treatment of rHPT while avoiding unnecessary complications of hypocalcemia, adynamic bone disease, or reoperations (29). Complications Overall, the rate of surgical complications was low in both groups and no difference could be calculated for patients with or without cinacalcet treatment. There was no perioperative mortality in our group. Duration of surgery and hospital stay did not differ between the groups, and hospital-stay was reduced during the study period but similar in both groups. Conclusion Our study underlines the fact that PTx represents a safe and successful treatment option for patients with rHPT, even after KTx and irrespective of co-medication with cinacalcet. In view of the morbidity and mortality of long-term dialysis, patients will need individualized decisions taken by interdisciplinary transplant and tumor boards. Surgery should at least be offered to patients not responding to cinacalcet treatment and especially to those planned for KTx. This not only should reduce complications of pHPT but also improve patient morbidity in view of a successful KTx. Authors thank Prof. Dr. med. Peter E Goretzki for discussion and critical review of the manuscript. Author Contributions: M.T.M., T.S., N.R. contributed to the study conception and design, analysis, and interpretation of data and writing of the manuscript. N.M.O., E.T., C.B. participated in the acquisition and analysis of data. P.R., N.R., J.P. contributed to the analysis and interpretation of data, the study conception, and critical review of the manuscript. Compliance with Ethical Standards: This is a retrospective non-interventional study. All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical Approval: Ethical approval was given by the local ethics committee (EA4/086/19) Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD: M. T. Mogl https://orcid.org/0000-0002-3676-047X

CALCITRIOL, CALCIUM, CALCIUM GLUCONATE, CHOLECALCIFEROL, CINACALCET HYDROCHLORIDE, SODIUM PHOSPHATE

DrugsGivenReaction

CC BY-NC

31906794

2021-03

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperparathyroidism'.

Surgery for Renal Hyperparathyroidism in the Era of Cinacalcet: A Single-Center Experience. There are only few data on the influence of cinacalcet on the outcome of parathyroidectomy in patients with renal hyperparathyroidism. Indication and timing of surgery have changed since its introduction, especially with regard to kidney transplantation. Therefore, we retrospectively analyzed patients undergoing parathyroidectomy for renal hyperparathyroidism in our institution. Between 2008 and 2015, 196 consecutive operations in 191 patients were analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet compared with 116 operations (59%) in patients without cinacalcet. Clinical data, preoperative medication, pre- and postoperative laboratory values, type and details of surgery including complications, as well as cardiovascular complications and kidney transplantation with graft function were recorded. Demographical data were similar in patients with or without cinacalcet treatment. A total of 54% of patients received a kidney graft before or after parathyroidectomy. Pre- and postoperative parathormone levels were similar in both groups (preoperatively 755 vs 742 ng/L, postoperatively 50 vs 46 ng/L, p > 0.10), whereas patients with cinacalcet showed significantly lower calcium levels preoperatively (2.28 vs 2.41 mmol/L, p = 0.0002). There was no difference in recurrence or persistence of hyperparathyroidism, duration of surgery, hospital stay, or complication rate. Creatinine levels in patients with tertiary hyperparathyroidism were similar after 1-year follow-up. Cinacalcet did not influence outcome of patients with parathyroidectomy for renal hyperparathyroidism and can be safely offered to patients not responding to medical treatment. Introduction Since the introduction of cinacalcet in the treatment of renal hyperparathyroidism (rHPT) in 2004, clinical practice for indication and timing of surgery has changed following the Kidney Disease Improving Global Outcomes (KDIGO) International guideline group (1). Overall, the number of parathyroidectomies (PTxs) has declined (2) and the timepoint of surgery is delayed in patients with end-stage renal disease (ESRD) developing rHPT (3). But especially the long-term benefit of cinacalcet on patient morbidity and mortality has not been shown so far (4). In addition, the cost-effectiveness of surgery is better than that of cinacalcet treatment after 7.25 months of therapy (5), and cinacalcet is only cost-effective in patients not eligible for surgery or receiving a kidney-graft beforehand (6). On the contrary, a large cohort study showed a rather high 30-day morbidity and mortality (7) as well as an increased morbidity and rehospitalization rate in the first year for patients after PTx not receiving a kidney graft (8). Yet, the overall risk of death for dialysis patients is lower after PTx compared with patients with medical therapy alone (9), and PTx shows a trend in improving cardiovascular morbidity and mortality (10). In 2015, Messa (11) highlighted the need for additional randomized controlled trials comparing conservative and surgical therapy. Another question of concern is the timing of surgery in relation to kidney transplantation (KTx). It is known that in more than 40% of patients, rHPT persists after KTx (12) and that especially long duration of dialysis prior to KTx negatively influences spontaneous normalization. Studies have shown that parathyroidectomy after KTx has no negative influence on overall graft survival (13), although a temporary decrease in glomerular filtration rate (GFR) was confirmed (14). On the contrary, a retrospective analysis reported that PTx before KTx was associated with a lower risk of graft failure (15). A very recent study documented that persistent hyperparathyroidism (pHPT) more than 1 year after KTx is a risk factor for graft failure (16). In addition, cinacalcet treatment in patients receiving a kidney graft was a risk factor for delayed graft function experimentally and in a single cohort study (17). While in Germany cinacalcet cannot usually be prescribed for patients after KTx, it has been shown that its use after KTx corrects hypercalciuria and hyperparathyroidism (HPT) (18). In 2015, a randomized study concluded that patients with persistent HPT at 6 months after KTx should undergo PTx for normalization of parathyroid hormone (PTH) because of beneficial effects on bone mineral density compared with continuing cinacalcet therapy (19). So far, there are only few data on the influence of cinacalcet on the short- and long-term outcome of parathyroidectomy in patients with rHPT. Therefore, we retrospectively analyzed all patients undergoing parathyroidectomy for rHPT from the introduction of cinacalcet into clinical practice up to 2015. Material and Methods Study Population All patients undergoing parathyroidectomy for rHPT are prospectively collected in our database and were retrospectively analyzed. Between January 2004 and December 2007, only six patients had been treated with cinacalcet and were not considered for this retrospective analysis. From January 2008 until January 2015, 191 consecutive patients were included. All patients were followed until 1 May 2015 or death or loss of follow-up with a mean follow-up of 48.35 ± 25.2 months. Data were collected from medical charts including standard demographical data and from the kidney transplant database of our institution/European transplantation database (T-base) as well as from referring physicians, especially dialysis centers. Data concerning duration of dialysis, type of kidney disease, preoperative medication, pre- and postoperative laboratory values (calcium, intact para-thyroid hormone (iPTH), phosphate, creatinine, alkaline phosphatase (AP)), type and details of surgery including complications, as well as cardiovascular complications and KTx with graft function were recorded. Five patients who required redo surgery for recurrent or persistent HPT were calculated twice, because both operations were performed at our hospital within the study period. Thus, 196 operations in 191 patients were finally analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet at the time of surgery (group A) compared with 116 operations (59%) in patients not receiving cinacalcet (group B). A total of 156 patients (82%) were treated with phosphate binders, and 164 (86%) with 1,25 (OH)-vitamin D. After 2008, there was an increasing number of patients with cinacalcet treatment with a maximum in 2011 (Table 1). Table 1 Patients undergoing PTx with (group A) or without (group B) cinacalcet treatment in respective year. Year Group A Group B Total 2008 5 31 36 2009 8 25 33 2010 7 11 18 2011 24 15 39 2012 7 8 15 2013 11 16 27 2014 18 10 28 Our standard surgical procedure is a bilateral cervical exploration with subtotal PTx leaving a small nodular-free cervical remnant. A total PTx was performed only in patients with a high risk of recurrent HPT who were not listed for KTx. Cervical thymectomy was not routinely performed but carried out if less than four cervical glands were found. Neuromonitoring of the recurrent laryngeal nerve was routinely performed in all patients. In case of suspicious thyroid nodules or parathyroid glands with close relation to or inside the thyroid capsule, simultaneous thyroid surgery was done. In all patients, parathyroid tissue was cryopreserved. Postoperatively, all patients had daily controls of calcium, starting on the first postoperative day (POD). In case of persistently high iPTH levels directly after operation, consecutive controls were carried out. In case of missing glands, intraoperative iPTH was measured. Calcium substitution was instituted orally with 1000 mg/day immediately after PTx and adjusted to individual needs including additional intravenous substitution of calcium gluconate and changes in dialysate composition by our in-house nephrologists, as needed. All patients received 0.5 µg calcitriol twice daily with adjustment if needed. Patients were discharged if they were asymptomatic and as soon as the calcium level was stable (at least 1.9 mmol/L) or rising on two consecutive days. For measuring iPTH, an electrochemiluminescence immunoassay was performed by our laboratory (normal range: 15–65 ng/L). Calcium (normal range: 2.15–2.5 mmol/L), AP (35–105 U/L), creatinine (0.5–0.9 mg/dL), and phosphate (0.87–1.45 mmol/L) were measured routinely by our in-house nephrologists or referring dialysis centers later on. In order to define persistent or recurrent HPT, both elevated iPTH and calcium may be used. For this analysis, iPTH > 100 ng/L and/or calcium > 2.5 mmol/L were defined as persistent or recurrent hyperparathyroidism. All patients had an indirect laryngoscopy by an ear, nose, and throat specialist before and after the operation. In case of recurrent laryngeal nerve palsy, logopedic training was prescribed and patients were followed until vocal recovery in our outpatient clinic. Statistical Analysis Data were analyzed using the Statistica software 7.0 (StatSoft Inc., USA). All numerical results are presented as mean ± standard deviation (SD) independent from normal distribution. Categorial variables are presented as percentages. For testing normality of numerical variables, the Kolmogorov–Smirnov test (KS test) was used. Normally distributed data were tested with the unpaired t-test after comparing variances with the Levin test. For nonparametric variables with continuous distribution, the KS test was used for independent groups. Chi-square test with Yates’ correction was applied for nominal variables. Nonparametric data in dependent groups were analyzed with the Wilcoxon matched pairs test. Statistical significance was defined by p < 0.05. Results Demographic Data and Kidney Disease The study population consisted of 191 patients with 196 operations distributed to group A (80 cases, 41%) and group B (116 cases, 59%). The mean age was comparable in both groups (group A: 51.2 ± 13.3 vs group B: 51.5 ± 12.7 years), and the male/female ratio was 50% for group A, whereas group B consisted of more male patients (66%). Most patients had chronic kidney disease stage V (CKD V; 91% vs 84%, respectively) at the time of parathyroidectomy, an overview of underlying diseases is given in Table 2. Table 2 Underlying diseases leading to renal failure of patients with renal hyperparathyroidism. Number % Diabetic nephropathy 30 16 Σ = 71% Polycystic kidney disease 25 13 Chronic glomerulonephritis 20 10 Focal segmental glomerulosclerosis 16 8 Hypertensive nephropathy 15 8 IgA nephropathy 11 6 Interstitial nephritis 9 5 Membranoproliferative glomerulonephritis 10 5 Other 56 29 IgA: immunoglobulin A. A small number of patients had a functioning kidney graft at the time of parathyroidectomy (group A: 6% vs group B: 11%). Rarely, patients with CKD III and IV were operated in preparation of a living donor KTx (3% vs 5%). All patients were presented with comorbidities, including arterial hypertension, diabetes mellitus, adipositas, and coronary artery disease. Follow-up for patients with cinacalcet (group A, 39.7 ± 22.6 months) was significantly shorter compared with patients without cinacalcet (group B, 54.4 ± 25.3 months, p < 0.001, KS test). Kidney Transplantation Altogether 53% of the patients (n = 101) underwent KTx before or after PTx (25 patients lost to follow-up). At the end of the follow-up period, more patients were transplanted in both groups (54% vs 64%), but graft function varied between the groups. About 90 patients had no KTx during the study period (Table 3). Table 3 Clinical features of patients undergoing parathyroidectomy with (group A) or without cinacalcet (group B) including consecutive or prior kidney transplantation, type of parathyroidectomy, duration of surgery and hospital stay as well as complications and outcome. Cinacalcet (group A) n = 80 Without cinacalcet (group B) n = 116 No data Total Kidney transplantation 37 54 10 101  KTx before PTx 21 22 4 47  KTx after PTx 16 32 6 54 Type of operation  Subtotal PTx 49 89 – 138  Total PTx 21 19 – 40  Re-operation 10 8 – 18 Duration of surgery (minutes) 126 136 – – Hospital stay (days) 7 7 – – Complications  RLNP 2 (1 permanent) 3 – 5  Bleeding 0 2 – 2  30-day mortality 0 0 – 0 i.v. Calcium postoperatively 14 16 – 30 Death during follow-up 12 (52 alive) 14 (72 alive) 41 26 Recurrence of HPT 2 3 – 5 Persistence of HPT 1 3 – 4 HPT: hyperparathyroidism; RLNP: recurrent laryngeal nerve palsy; KTx: kidney transplantation; PTx: parathyreoidectomy. Note: Significance of bold values in the table was not calculated due to low numbers. Of the 47 patients undergoing PTx after KTx for tertiary hyperparathyroidism (tHPT), 15 (32%) were on dialysis (CKD V) in group A, while 6 patients (13%) had functioning grafts (creatinine: 1.23 ± 0.41 mg/dL) at the end of follow-up. In group B, 11 patients (23%) had CKD V and 11 (23%) presented with functioning grafts (creatinine: 1.91 ± 1.02 mg/dL), while 4 patients had unknown graft function. KTx was performed at a mean of 93.5 ± 83.1 months before PTx for both groups. In 54 patients with rHPT receiving their KTx after PTx, 42 had functioning grafts (group A: n = 13 (24%) vs group B: n = 29 (54%)), while six patients (11%) were back on dialysis (three patients in each group) and six had unknown graft function. Mean follow-up for these patients was 15.6 ± 10 months. Six patients received more than one KTx, with the PTx taking place after loss of function of the first kidney graft. Four of these were retransplanted after PTx and presented with good graft function. Creatinine levels in patients with tHPT (i.e. those with a functioning kidney transplant, defined as CKD I-III, n = 22) were analyzed before PTx and 1 year after operation. There were no significant differences neither in the whole group (p = 0.11), nor in the subgroups related to cinacalcet therapy (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet; Fig. 1). Fig. 1. Creatinine levels (mg/dL) in patients with kidney graft and good graft function at the time of PTx and at 1-year follow-up related to cinacalcet preoperatively (yes/no). There was no significant difference in creatinine levels for both groups (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet). Perioperative Data Operative technique A majority of 78% of all primary operations (138/178) underwent subtotal PTx (49 vs 89 cases in both groups, respectively). In 40 patients, a total PTx without autotransplantation was done. About 18 operations were performed for recurrent HPT (Table 3). In 86 cases (48%), concomitant thyroid surgery was carried out. Indications for thyroid surgery were solitary autonomous adenoma (n = 1), diffuse autonomy (n = 2), multinodular goiter (n = 56), suspicious thyroid nodules (n = 18), or a missing parathyroid gland (n = 12). In seven patients, a differentiated thyroid carcinoma was histologically confirmed. There was no difference in operative time between the groups (126 ± 44 min vs 136 ± 39 min with/without cinacalcet, p = 0.11, t-test). Length of in-hospital stay did not differ between the groups with a mean of 7.0 versus 7.1 days, respectively (p > 0.1, KS test). There is a trend toward shorter in-hospital stay in recent years, yet no significant difference could be seen (Table 3). Complications A total of five unilateral vocal cord palsies occurred (1.28% of 392 nerves at risk), two with and three without cinacalcet treatment. Four were temporary, while one patient after recurrent PTx revealed permanent unilateral vocal cord palsy. There were three reoperations for hematoma (n = 2) and infection (n = 1). One patient developed paroxysmal atrial fibrillation, but there was no perioperative mortality and all patients were discharged from hospital (Table 3). Perioperative laboratory values Preoperatively, calcium was significantly lower in group A (2.28 ± 0.23 mmol/L vs 2.41 ± 0.23 mmol/L, p = 0.0002, t-test), while neither postoperatively (1.89 ± 0.30 mmol/L vs 1.92 ± 0.30 mmol/L, p = 0.40, t-test) nor at discharge (2.12 ± 0.30 mmol/L vs 2.12 ± 0.27 mmol/L, p = 0.90, t-test) a statistically significant difference could be observed. Lowest calcium levels measured postoperatively were 1.91 ± 0.30 mmol/L for all patients. The lowest postoperative serum Ca levels were not significantly different between the groups, 1.89 ± 0.30 versus 1.92 ± 0.30 (p = 0.40, t-test). Altogether 30 patients received i.v. calcium postoperatively due to symptoms of hypocalcemia and/or calcium levels below 1.7 mmol/L (14 vs 16 patients). Preoperative iPTH levels were comparable between the groups (755 ± 657 ng/L vs 742 ± 545 ng/L, p > 0.10, KS test). In both groups, there was a significant drop on POD 1 with no difference between the groups (50 ± 124 ng/L vs 46 ± 83 ng/L, p > 0.10, KS test). More than 1/3 (36%) of the patients after KTx presented with good graft function at the moment of PTx. These patients showed no deterioration of creatinine levels at 1-year follow-up (1.42 mg/dL perioperatively vs 1.38 mg/dL after 1 year, p = 0.11, Wilcoxon test), and there was no difference between patients with or without cinacalcet preoperatively. 1-year surveillance data Calcium levels 1 year after PTx were not significantly different between the groups (2.26 ± 0.25 mmol/L vs 2.24 ± 0.25 mmol/L, p = 0.67, t-test). Regarding iPTH levels, no significant difference could be detected between patients with or without cinacalcet preoperatively (26.9 vs 42.1 ng/L, p > 0.1, KS test). Seven patients had extremely high iPTH (>2000 ng/L, n = 7) preoperatively, but none of these presented with persisting or recurrent hyperparathyroidism. Only two of these patients had been on cinacalcet before PTx. All of them had normalized iPTH at discharge. About 1 year after PTx, four of the patients presented with normal iPTH levels, for three of the patients iPTH was not available, but none of them was re-operated for HPT. Five of the patients had been transplanted before (n = 2) or after PTx (n = 3) and four presented with good graft function until the end of follow-up or death (n = 1). After 1 year, four patients were presented with iPTH > 100 ng/L and calcium > 2.5 mmol/L, while five patients only had elevated iPTH with normal calcium. Five of these patients had recurrent HPT (two with cinacalcet, group A) and four persisting HPT (one with cinacalcet, group A). Looking more closely at type of operation (subtotal PTx, total PTx, and recurrent PTx), there was no difference between postoperative iPTH and iPTH at 1 year. Patients with second PTx for recurrent or persisting HPT displayed a mean higher iPTH both postoperatively (45 ng/L) as well as at 1 year (92 ng/L). Patients with subtotal and total parathyroidectomy showed low levels of PTH both at discharge (11 and 8 ng/L) and at 1 year (8 and 7 ng/L). There was no significant difference between patients with or without cinacalcet. Overall mortality and morbidity Considering long-term follow-up, a considerable number of patients were lost to follow-up. There was no difference in mortality rate between the groups (p = 0.68, χ² test). At the end of follow-up, 12 of 77 patients in group A had died (16%), 52 (68%) were alive (no data in 16%, n = 13). In group B, 14 of 114 had died (12%), whereas 72 (63%) were alive (no data in 25%, n = 28). The prevalence of cardiovascular events was not significantly different between the groups. Myocardial infarction occured in 13% (group A) versus 18% of patients (group B), and the need for coronary artery intervention or bypass occurred in 13% versus 22% of patients in both groups, respectively. Also the need for peripheral revascularization (9% vs 12%) and stroke was recorded with a similar prevalence (13% vs 10%) in patients after PTx with or without cinacalcet. Discussion This single-center study in patients undergoing parathyroidectomy for rHPT shows excellent outcome independent of pretreatment with cinacalcet. Since the introduction of cinacalcet as treatment modality for rHPT, decreasing numbers of patients are being referred to parathyroidectomy (20). Nevertheless, no reduction of all-cause or cardiovascular mortality compared with surgery has been shown for patients with ESRD (4). A substantial part of these conservatively treated patients presents with persistently elevated iPTH, aggravation of complications, and consecutive referral to surgery (3). In our center, the number of patients referred to surgery was decreasing after the introduction of cinacalcet but is increasing again since 2012. Timing of PTx From our referring nephrology and transplant unit, a majority of patients on the waiting list for KTx is referred to parathyroidectomy, especially those with very high iPTH levels. This is due to the fact that only up to 56% of patients normalize PTH after KTx, mostly those with shorter waiting time on the transplant list (13). A total of 53% of our patients underwent KTx, either before or after PTx. In those patients undergoing PTx before KTx for rHPT, a majority of 78% presents with functioning grafts during follow-up. While it is clear that pHPT after KTx impairs long-term graft survival (17), optimal therapy still is under debate. An interesting report by Torregrosa et al. (21) has shown no decline in graft function 1 year after KTx for patients with rHPT that were treated with cinacalcet and also stable graft function for patients on cinacalcet during long-term follow-up. This was underlined by a meta-analysis by Cohen et al. (22) reporting that cinacalcet treatment for pHPT after KTx was not associated with inferior graft survival. In our study, 55% of patients undergoing PTx after KTx were on dialysis at the end of follow-up, mostly for graft failure before PTx. But those patients undergoing PTx with functioning kidney grafts did not show deterioration of creatinine levels postoperatively or during 1-year follow-up, irrespective of cinacalcet treatment. Interestingly, six of the patients underwent second or even third KTx after PTx and presented with functioning grafts during follow-up. In contrast, 78% of patients with PTx and consecutive KTx showed functioning grafts, irrespective of treatment with cinacalcet prior to surgery. Overall, these results favor parathyroidectomy before KTx, yet prospective trials will be necessary to evaluate optimal treatment for tHPT after KTx. Cardiovascular Morbidity Treatment with cinacalcet only showed limited effects on cardiovascular morbidity or mortality of patients with ESRD in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial (23), which evaluated patients on hemodialysis. Both a Cochrane analysis (4) and a meta-analysis by Palmer et al. (24) demonstrated that for patients with ESRD treatment with cinacalcet only reduced the risk for surgery without positively influencing all-cause or cardiovascular mortality. A smaller trial by Trombetti et al. (25) showed that PTx, on the contrary, is associated with both reduced morbidity and mortality of these patients. In this cohort, 19 months after PTx, mortality of patients with ESRD was less than without PTx. In our study, morbidity and mortality during follow-up were not different between patients with or without cinacalcet treatment before surgery. Both small sample size and patients lost to follow-up reduce the statistic power of our cohort. Laboratory Values Overall, we could see no significant differences in laboratory values perioperatively between the groups, only preoperative calcium levels were significantly lower in patients with cinacalcet. At 1 year after surgery, no difference could be detected in iPTH between the groups. A study by Somnay et al. (26) focused on patients with tHPT and the effect of cinacalcet treatment on perioperative findings and outcome. Although they presented a small patient cohort with cinacalcet treatment, they interestingly had higher iPTH levels preoperatively in this cohort, while cure rate was not influenced by cinacalcet pretreatment. Compared with our analysis, patients without cinacalcet treatment had much lower preoperative iPTH levels in this study, possibly reflecting lower thresholds for PTx after KTx. Only seven patients with tHPT in our study received cinacalcet treatment with similar preoperative iPTH levels, as patients with rHPT. A very recent study by Baker et al. (27) examined influence of cinacalcet on outcome in patients with rHPT and found greater iPTH levels in the untreated group before surgery with similar outcome. Only the study of Wirowski et al. (28) demonstrated comparable laboratory findings in patients operated for rHPT. In their analysis, pre- and postoperative iPTH levels were equal in patients with or without cinacalcet and calcium was significantly lower in cinacalcet patients. This is in line with our findings, and they also concluded that cinacalcet did not alter perioperative course. Looking more closely on recurrent, or persisting rHPT, only four patients were diagnosed during follow-up with both elevated iPTH and hypercalcemia, while five were normocalcemic with elevated iPTH. For this analysis, relatively strict values were applied as cut-off values for recurrent HPT. When increasing the cut-off values for iPTH, only two patients of the cohort would have been identified with recurrence of HPT. There was no significant difference in iPTH levels at 1 year between subtotal or total parathyroidectomy and also no difference related to cinacalcet treatment preoperatively. So overall, surgical technique with mostly subtotal PTx in our cohort showed good results and low rates of recurrent or persisting rHPT, independent of preoperative treatment with cinacalcet. Several groups have shown that subtotal PTx or total PTx with autotransplantation of parathyroid tissue represent a good compromise between effective treatment of rHPT while avoiding unnecessary complications of hypocalcemia, adynamic bone disease, or reoperations (29). Complications Overall, the rate of surgical complications was low in both groups and no difference could be calculated for patients with or without cinacalcet treatment. There was no perioperative mortality in our group. Duration of surgery and hospital stay did not differ between the groups, and hospital-stay was reduced during the study period but similar in both groups. Conclusion Our study underlines the fact that PTx represents a safe and successful treatment option for patients with rHPT, even after KTx and irrespective of co-medication with cinacalcet. In view of the morbidity and mortality of long-term dialysis, patients will need individualized decisions taken by interdisciplinary transplant and tumor boards. Surgery should at least be offered to patients not responding to cinacalcet treatment and especially to those planned for KTx. This not only should reduce complications of pHPT but also improve patient morbidity in view of a successful KTx. Authors thank Prof. Dr. med. Peter E Goretzki for discussion and critical review of the manuscript. Author Contributions: M.T.M., T.S., N.R. contributed to the study conception and design, analysis, and interpretation of data and writing of the manuscript. N.M.O., E.T., C.B. participated in the acquisition and analysis of data. P.R., N.R., J.P. contributed to the analysis and interpretation of data, the study conception, and critical review of the manuscript. Compliance with Ethical Standards: This is a retrospective non-interventional study. All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical Approval: Ethical approval was given by the local ethics committee (EA4/086/19) Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD: M. T. Mogl https://orcid.org/0000-0002-3676-047X

CALCITRIOL, CALCIUM, CALCIUM GLUCONATE, CHOLECALCIFEROL, CINACALCET HYDROCHLORIDE, SODIUM PHOSPHATE

DrugsGivenReaction

CC BY-NC

31906794

2021-03

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infection'.

Surgery for Renal Hyperparathyroidism in the Era of Cinacalcet: A Single-Center Experience. There are only few data on the influence of cinacalcet on the outcome of parathyroidectomy in patients with renal hyperparathyroidism. Indication and timing of surgery have changed since its introduction, especially with regard to kidney transplantation. Therefore, we retrospectively analyzed patients undergoing parathyroidectomy for renal hyperparathyroidism in our institution. Between 2008 and 2015, 196 consecutive operations in 191 patients were analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet compared with 116 operations (59%) in patients without cinacalcet. Clinical data, preoperative medication, pre- and postoperative laboratory values, type and details of surgery including complications, as well as cardiovascular complications and kidney transplantation with graft function were recorded. Demographical data were similar in patients with or without cinacalcet treatment. A total of 54% of patients received a kidney graft before or after parathyroidectomy. Pre- and postoperative parathormone levels were similar in both groups (preoperatively 755 vs 742 ng/L, postoperatively 50 vs 46 ng/L, p > 0.10), whereas patients with cinacalcet showed significantly lower calcium levels preoperatively (2.28 vs 2.41 mmol/L, p = 0.0002). There was no difference in recurrence or persistence of hyperparathyroidism, duration of surgery, hospital stay, or complication rate. Creatinine levels in patients with tertiary hyperparathyroidism were similar after 1-year follow-up. Cinacalcet did not influence outcome of patients with parathyroidectomy for renal hyperparathyroidism and can be safely offered to patients not responding to medical treatment. Introduction Since the introduction of cinacalcet in the treatment of renal hyperparathyroidism (rHPT) in 2004, clinical practice for indication and timing of surgery has changed following the Kidney Disease Improving Global Outcomes (KDIGO) International guideline group (1). Overall, the number of parathyroidectomies (PTxs) has declined (2) and the timepoint of surgery is delayed in patients with end-stage renal disease (ESRD) developing rHPT (3). But especially the long-term benefit of cinacalcet on patient morbidity and mortality has not been shown so far (4). In addition, the cost-effectiveness of surgery is better than that of cinacalcet treatment after 7.25 months of therapy (5), and cinacalcet is only cost-effective in patients not eligible for surgery or receiving a kidney-graft beforehand (6). On the contrary, a large cohort study showed a rather high 30-day morbidity and mortality (7) as well as an increased morbidity and rehospitalization rate in the first year for patients after PTx not receiving a kidney graft (8). Yet, the overall risk of death for dialysis patients is lower after PTx compared with patients with medical therapy alone (9), and PTx shows a trend in improving cardiovascular morbidity and mortality (10). In 2015, Messa (11) highlighted the need for additional randomized controlled trials comparing conservative and surgical therapy. Another question of concern is the timing of surgery in relation to kidney transplantation (KTx). It is known that in more than 40% of patients, rHPT persists after KTx (12) and that especially long duration of dialysis prior to KTx negatively influences spontaneous normalization. Studies have shown that parathyroidectomy after KTx has no negative influence on overall graft survival (13), although a temporary decrease in glomerular filtration rate (GFR) was confirmed (14). On the contrary, a retrospective analysis reported that PTx before KTx was associated with a lower risk of graft failure (15). A very recent study documented that persistent hyperparathyroidism (pHPT) more than 1 year after KTx is a risk factor for graft failure (16). In addition, cinacalcet treatment in patients receiving a kidney graft was a risk factor for delayed graft function experimentally and in a single cohort study (17). While in Germany cinacalcet cannot usually be prescribed for patients after KTx, it has been shown that its use after KTx corrects hypercalciuria and hyperparathyroidism (HPT) (18). In 2015, a randomized study concluded that patients with persistent HPT at 6 months after KTx should undergo PTx for normalization of parathyroid hormone (PTH) because of beneficial effects on bone mineral density compared with continuing cinacalcet therapy (19). So far, there are only few data on the influence of cinacalcet on the short- and long-term outcome of parathyroidectomy in patients with rHPT. Therefore, we retrospectively analyzed all patients undergoing parathyroidectomy for rHPT from the introduction of cinacalcet into clinical practice up to 2015. Material and Methods Study Population All patients undergoing parathyroidectomy for rHPT are prospectively collected in our database and were retrospectively analyzed. Between January 2004 and December 2007, only six patients had been treated with cinacalcet and were not considered for this retrospective analysis. From January 2008 until January 2015, 191 consecutive patients were included. All patients were followed until 1 May 2015 or death or loss of follow-up with a mean follow-up of 48.35 ± 25.2 months. Data were collected from medical charts including standard demographical data and from the kidney transplant database of our institution/European transplantation database (T-base) as well as from referring physicians, especially dialysis centers. Data concerning duration of dialysis, type of kidney disease, preoperative medication, pre- and postoperative laboratory values (calcium, intact para-thyroid hormone (iPTH), phosphate, creatinine, alkaline phosphatase (AP)), type and details of surgery including complications, as well as cardiovascular complications and KTx with graft function were recorded. Five patients who required redo surgery for recurrent or persistent HPT were calculated twice, because both operations were performed at our hospital within the study period. Thus, 196 operations in 191 patients were finally analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet at the time of surgery (group A) compared with 116 operations (59%) in patients not receiving cinacalcet (group B). A total of 156 patients (82%) were treated with phosphate binders, and 164 (86%) with 1,25 (OH)-vitamin D. After 2008, there was an increasing number of patients with cinacalcet treatment with a maximum in 2011 (Table 1). Table 1 Patients undergoing PTx with (group A) or without (group B) cinacalcet treatment in respective year. Year Group A Group B Total 2008 5 31 36 2009 8 25 33 2010 7 11 18 2011 24 15 39 2012 7 8 15 2013 11 16 27 2014 18 10 28 Our standard surgical procedure is a bilateral cervical exploration with subtotal PTx leaving a small nodular-free cervical remnant. A total PTx was performed only in patients with a high risk of recurrent HPT who were not listed for KTx. Cervical thymectomy was not routinely performed but carried out if less than four cervical glands were found. Neuromonitoring of the recurrent laryngeal nerve was routinely performed in all patients. In case of suspicious thyroid nodules or parathyroid glands with close relation to or inside the thyroid capsule, simultaneous thyroid surgery was done. In all patients, parathyroid tissue was cryopreserved. Postoperatively, all patients had daily controls of calcium, starting on the first postoperative day (POD). In case of persistently high iPTH levels directly after operation, consecutive controls were carried out. In case of missing glands, intraoperative iPTH was measured. Calcium substitution was instituted orally with 1000 mg/day immediately after PTx and adjusted to individual needs including additional intravenous substitution of calcium gluconate and changes in dialysate composition by our in-house nephrologists, as needed. All patients received 0.5 µg calcitriol twice daily with adjustment if needed. Patients were discharged if they were asymptomatic and as soon as the calcium level was stable (at least 1.9 mmol/L) or rising on two consecutive days. For measuring iPTH, an electrochemiluminescence immunoassay was performed by our laboratory (normal range: 15–65 ng/L). Calcium (normal range: 2.15–2.5 mmol/L), AP (35–105 U/L), creatinine (0.5–0.9 mg/dL), and phosphate (0.87–1.45 mmol/L) were measured routinely by our in-house nephrologists or referring dialysis centers later on. In order to define persistent or recurrent HPT, both elevated iPTH and calcium may be used. For this analysis, iPTH > 100 ng/L and/or calcium > 2.5 mmol/L were defined as persistent or recurrent hyperparathyroidism. All patients had an indirect laryngoscopy by an ear, nose, and throat specialist before and after the operation. In case of recurrent laryngeal nerve palsy, logopedic training was prescribed and patients were followed until vocal recovery in our outpatient clinic. Statistical Analysis Data were analyzed using the Statistica software 7.0 (StatSoft Inc., USA). All numerical results are presented as mean ± standard deviation (SD) independent from normal distribution. Categorial variables are presented as percentages. For testing normality of numerical variables, the Kolmogorov–Smirnov test (KS test) was used. Normally distributed data were tested with the unpaired t-test after comparing variances with the Levin test. For nonparametric variables with continuous distribution, the KS test was used for independent groups. Chi-square test with Yates’ correction was applied for nominal variables. Nonparametric data in dependent groups were analyzed with the Wilcoxon matched pairs test. Statistical significance was defined by p < 0.05. Results Demographic Data and Kidney Disease The study population consisted of 191 patients with 196 operations distributed to group A (80 cases, 41%) and group B (116 cases, 59%). The mean age was comparable in both groups (group A: 51.2 ± 13.3 vs group B: 51.5 ± 12.7 years), and the male/female ratio was 50% for group A, whereas group B consisted of more male patients (66%). Most patients had chronic kidney disease stage V (CKD V; 91% vs 84%, respectively) at the time of parathyroidectomy, an overview of underlying diseases is given in Table 2. Table 2 Underlying diseases leading to renal failure of patients with renal hyperparathyroidism. Number % Diabetic nephropathy 30 16 Σ = 71% Polycystic kidney disease 25 13 Chronic glomerulonephritis 20 10 Focal segmental glomerulosclerosis 16 8 Hypertensive nephropathy 15 8 IgA nephropathy 11 6 Interstitial nephritis 9 5 Membranoproliferative glomerulonephritis 10 5 Other 56 29 IgA: immunoglobulin A. A small number of patients had a functioning kidney graft at the time of parathyroidectomy (group A: 6% vs group B: 11%). Rarely, patients with CKD III and IV were operated in preparation of a living donor KTx (3% vs 5%). All patients were presented with comorbidities, including arterial hypertension, diabetes mellitus, adipositas, and coronary artery disease. Follow-up for patients with cinacalcet (group A, 39.7 ± 22.6 months) was significantly shorter compared with patients without cinacalcet (group B, 54.4 ± 25.3 months, p < 0.001, KS test). Kidney Transplantation Altogether 53% of the patients (n = 101) underwent KTx before or after PTx (25 patients lost to follow-up). At the end of the follow-up period, more patients were transplanted in both groups (54% vs 64%), but graft function varied between the groups. About 90 patients had no KTx during the study period (Table 3). Table 3 Clinical features of patients undergoing parathyroidectomy with (group A) or without cinacalcet (group B) including consecutive or prior kidney transplantation, type of parathyroidectomy, duration of surgery and hospital stay as well as complications and outcome. Cinacalcet (group A) n = 80 Without cinacalcet (group B) n = 116 No data Total Kidney transplantation 37 54 10 101  KTx before PTx 21 22 4 47  KTx after PTx 16 32 6 54 Type of operation  Subtotal PTx 49 89 – 138  Total PTx 21 19 – 40  Re-operation 10 8 – 18 Duration of surgery (minutes) 126 136 – – Hospital stay (days) 7 7 – – Complications  RLNP 2 (1 permanent) 3 – 5  Bleeding 0 2 – 2  30-day mortality 0 0 – 0 i.v. Calcium postoperatively 14 16 – 30 Death during follow-up 12 (52 alive) 14 (72 alive) 41 26 Recurrence of HPT 2 3 – 5 Persistence of HPT 1 3 – 4 HPT: hyperparathyroidism; RLNP: recurrent laryngeal nerve palsy; KTx: kidney transplantation; PTx: parathyreoidectomy. Note: Significance of bold values in the table was not calculated due to low numbers. Of the 47 patients undergoing PTx after KTx for tertiary hyperparathyroidism (tHPT), 15 (32%) were on dialysis (CKD V) in group A, while 6 patients (13%) had functioning grafts (creatinine: 1.23 ± 0.41 mg/dL) at the end of follow-up. In group B, 11 patients (23%) had CKD V and 11 (23%) presented with functioning grafts (creatinine: 1.91 ± 1.02 mg/dL), while 4 patients had unknown graft function. KTx was performed at a mean of 93.5 ± 83.1 months before PTx for both groups. In 54 patients with rHPT receiving their KTx after PTx, 42 had functioning grafts (group A: n = 13 (24%) vs group B: n = 29 (54%)), while six patients (11%) were back on dialysis (three patients in each group) and six had unknown graft function. Mean follow-up for these patients was 15.6 ± 10 months. Six patients received more than one KTx, with the PTx taking place after loss of function of the first kidney graft. Four of these were retransplanted after PTx and presented with good graft function. Creatinine levels in patients with tHPT (i.e. those with a functioning kidney transplant, defined as CKD I-III, n = 22) were analyzed before PTx and 1 year after operation. There were no significant differences neither in the whole group (p = 0.11), nor in the subgroups related to cinacalcet therapy (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet; Fig. 1). Fig. 1. Creatinine levels (mg/dL) in patients with kidney graft and good graft function at the time of PTx and at 1-year follow-up related to cinacalcet preoperatively (yes/no). There was no significant difference in creatinine levels for both groups (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet). Perioperative Data Operative technique A majority of 78% of all primary operations (138/178) underwent subtotal PTx (49 vs 89 cases in both groups, respectively). In 40 patients, a total PTx without autotransplantation was done. About 18 operations were performed for recurrent HPT (Table 3). In 86 cases (48%), concomitant thyroid surgery was carried out. Indications for thyroid surgery were solitary autonomous adenoma (n = 1), diffuse autonomy (n = 2), multinodular goiter (n = 56), suspicious thyroid nodules (n = 18), or a missing parathyroid gland (n = 12). In seven patients, a differentiated thyroid carcinoma was histologically confirmed. There was no difference in operative time between the groups (126 ± 44 min vs 136 ± 39 min with/without cinacalcet, p = 0.11, t-test). Length of in-hospital stay did not differ between the groups with a mean of 7.0 versus 7.1 days, respectively (p > 0.1, KS test). There is a trend toward shorter in-hospital stay in recent years, yet no significant difference could be seen (Table 3). Complications A total of five unilateral vocal cord palsies occurred (1.28% of 392 nerves at risk), two with and three without cinacalcet treatment. Four were temporary, while one patient after recurrent PTx revealed permanent unilateral vocal cord palsy. There were three reoperations for hematoma (n = 2) and infection (n = 1). One patient developed paroxysmal atrial fibrillation, but there was no perioperative mortality and all patients were discharged from hospital (Table 3). Perioperative laboratory values Preoperatively, calcium was significantly lower in group A (2.28 ± 0.23 mmol/L vs 2.41 ± 0.23 mmol/L, p = 0.0002, t-test), while neither postoperatively (1.89 ± 0.30 mmol/L vs 1.92 ± 0.30 mmol/L, p = 0.40, t-test) nor at discharge (2.12 ± 0.30 mmol/L vs 2.12 ± 0.27 mmol/L, p = 0.90, t-test) a statistically significant difference could be observed. Lowest calcium levels measured postoperatively were 1.91 ± 0.30 mmol/L for all patients. The lowest postoperative serum Ca levels were not significantly different between the groups, 1.89 ± 0.30 versus 1.92 ± 0.30 (p = 0.40, t-test). Altogether 30 patients received i.v. calcium postoperatively due to symptoms of hypocalcemia and/or calcium levels below 1.7 mmol/L (14 vs 16 patients). Preoperative iPTH levels were comparable between the groups (755 ± 657 ng/L vs 742 ± 545 ng/L, p > 0.10, KS test). In both groups, there was a significant drop on POD 1 with no difference between the groups (50 ± 124 ng/L vs 46 ± 83 ng/L, p > 0.10, KS test). More than 1/3 (36%) of the patients after KTx presented with good graft function at the moment of PTx. These patients showed no deterioration of creatinine levels at 1-year follow-up (1.42 mg/dL perioperatively vs 1.38 mg/dL after 1 year, p = 0.11, Wilcoxon test), and there was no difference between patients with or without cinacalcet preoperatively. 1-year surveillance data Calcium levels 1 year after PTx were not significantly different between the groups (2.26 ± 0.25 mmol/L vs 2.24 ± 0.25 mmol/L, p = 0.67, t-test). Regarding iPTH levels, no significant difference could be detected between patients with or without cinacalcet preoperatively (26.9 vs 42.1 ng/L, p > 0.1, KS test). Seven patients had extremely high iPTH (>2000 ng/L, n = 7) preoperatively, but none of these presented with persisting or recurrent hyperparathyroidism. Only two of these patients had been on cinacalcet before PTx. All of them had normalized iPTH at discharge. About 1 year after PTx, four of the patients presented with normal iPTH levels, for three of the patients iPTH was not available, but none of them was re-operated for HPT. Five of the patients had been transplanted before (n = 2) or after PTx (n = 3) and four presented with good graft function until the end of follow-up or death (n = 1). After 1 year, four patients were presented with iPTH > 100 ng/L and calcium > 2.5 mmol/L, while five patients only had elevated iPTH with normal calcium. Five of these patients had recurrent HPT (two with cinacalcet, group A) and four persisting HPT (one with cinacalcet, group A). Looking more closely at type of operation (subtotal PTx, total PTx, and recurrent PTx), there was no difference between postoperative iPTH and iPTH at 1 year. Patients with second PTx for recurrent or persisting HPT displayed a mean higher iPTH both postoperatively (45 ng/L) as well as at 1 year (92 ng/L). Patients with subtotal and total parathyroidectomy showed low levels of PTH both at discharge (11 and 8 ng/L) and at 1 year (8 and 7 ng/L). There was no significant difference between patients with or without cinacalcet. Overall mortality and morbidity Considering long-term follow-up, a considerable number of patients were lost to follow-up. There was no difference in mortality rate between the groups (p = 0.68, χ² test). At the end of follow-up, 12 of 77 patients in group A had died (16%), 52 (68%) were alive (no data in 16%, n = 13). In group B, 14 of 114 had died (12%), whereas 72 (63%) were alive (no data in 25%, n = 28). The prevalence of cardiovascular events was not significantly different between the groups. Myocardial infarction occured in 13% (group A) versus 18% of patients (group B), and the need for coronary artery intervention or bypass occurred in 13% versus 22% of patients in both groups, respectively. Also the need for peripheral revascularization (9% vs 12%) and stroke was recorded with a similar prevalence (13% vs 10%) in patients after PTx with or without cinacalcet. Discussion This single-center study in patients undergoing parathyroidectomy for rHPT shows excellent outcome independent of pretreatment with cinacalcet. Since the introduction of cinacalcet as treatment modality for rHPT, decreasing numbers of patients are being referred to parathyroidectomy (20). Nevertheless, no reduction of all-cause or cardiovascular mortality compared with surgery has been shown for patients with ESRD (4). A substantial part of these conservatively treated patients presents with persistently elevated iPTH, aggravation of complications, and consecutive referral to surgery (3). In our center, the number of patients referred to surgery was decreasing after the introduction of cinacalcet but is increasing again since 2012. Timing of PTx From our referring nephrology and transplant unit, a majority of patients on the waiting list for KTx is referred to parathyroidectomy, especially those with very high iPTH levels. This is due to the fact that only up to 56% of patients normalize PTH after KTx, mostly those with shorter waiting time on the transplant list (13). A total of 53% of our patients underwent KTx, either before or after PTx. In those patients undergoing PTx before KTx for rHPT, a majority of 78% presents with functioning grafts during follow-up. While it is clear that pHPT after KTx impairs long-term graft survival (17), optimal therapy still is under debate. An interesting report by Torregrosa et al. (21) has shown no decline in graft function 1 year after KTx for patients with rHPT that were treated with cinacalcet and also stable graft function for patients on cinacalcet during long-term follow-up. This was underlined by a meta-analysis by Cohen et al. (22) reporting that cinacalcet treatment for pHPT after KTx was not associated with inferior graft survival. In our study, 55% of patients undergoing PTx after KTx were on dialysis at the end of follow-up, mostly for graft failure before PTx. But those patients undergoing PTx with functioning kidney grafts did not show deterioration of creatinine levels postoperatively or during 1-year follow-up, irrespective of cinacalcet treatment. Interestingly, six of the patients underwent second or even third KTx after PTx and presented with functioning grafts during follow-up. In contrast, 78% of patients with PTx and consecutive KTx showed functioning grafts, irrespective of treatment with cinacalcet prior to surgery. Overall, these results favor parathyroidectomy before KTx, yet prospective trials will be necessary to evaluate optimal treatment for tHPT after KTx. Cardiovascular Morbidity Treatment with cinacalcet only showed limited effects on cardiovascular morbidity or mortality of patients with ESRD in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial (23), which evaluated patients on hemodialysis. Both a Cochrane analysis (4) and a meta-analysis by Palmer et al. (24) demonstrated that for patients with ESRD treatment with cinacalcet only reduced the risk for surgery without positively influencing all-cause or cardiovascular mortality. A smaller trial by Trombetti et al. (25) showed that PTx, on the contrary, is associated with both reduced morbidity and mortality of these patients. In this cohort, 19 months after PTx, mortality of patients with ESRD was less than without PTx. In our study, morbidity and mortality during follow-up were not different between patients with or without cinacalcet treatment before surgery. Both small sample size and patients lost to follow-up reduce the statistic power of our cohort. Laboratory Values Overall, we could see no significant differences in laboratory values perioperatively between the groups, only preoperative calcium levels were significantly lower in patients with cinacalcet. At 1 year after surgery, no difference could be detected in iPTH between the groups. A study by Somnay et al. (26) focused on patients with tHPT and the effect of cinacalcet treatment on perioperative findings and outcome. Although they presented a small patient cohort with cinacalcet treatment, they interestingly had higher iPTH levels preoperatively in this cohort, while cure rate was not influenced by cinacalcet pretreatment. Compared with our analysis, patients without cinacalcet treatment had much lower preoperative iPTH levels in this study, possibly reflecting lower thresholds for PTx after KTx. Only seven patients with tHPT in our study received cinacalcet treatment with similar preoperative iPTH levels, as patients with rHPT. A very recent study by Baker et al. (27) examined influence of cinacalcet on outcome in patients with rHPT and found greater iPTH levels in the untreated group before surgery with similar outcome. Only the study of Wirowski et al. (28) demonstrated comparable laboratory findings in patients operated for rHPT. In their analysis, pre- and postoperative iPTH levels were equal in patients with or without cinacalcet and calcium was significantly lower in cinacalcet patients. This is in line with our findings, and they also concluded that cinacalcet did not alter perioperative course. Looking more closely on recurrent, or persisting rHPT, only four patients were diagnosed during follow-up with both elevated iPTH and hypercalcemia, while five were normocalcemic with elevated iPTH. For this analysis, relatively strict values were applied as cut-off values for recurrent HPT. When increasing the cut-off values for iPTH, only two patients of the cohort would have been identified with recurrence of HPT. There was no significant difference in iPTH levels at 1 year between subtotal or total parathyroidectomy and also no difference related to cinacalcet treatment preoperatively. So overall, surgical technique with mostly subtotal PTx in our cohort showed good results and low rates of recurrent or persisting rHPT, independent of preoperative treatment with cinacalcet. Several groups have shown that subtotal PTx or total PTx with autotransplantation of parathyroid tissue represent a good compromise between effective treatment of rHPT while avoiding unnecessary complications of hypocalcemia, adynamic bone disease, or reoperations (29). Complications Overall, the rate of surgical complications was low in both groups and no difference could be calculated for patients with or without cinacalcet treatment. There was no perioperative mortality in our group. Duration of surgery and hospital stay did not differ between the groups, and hospital-stay was reduced during the study period but similar in both groups. Conclusion Our study underlines the fact that PTx represents a safe and successful treatment option for patients with rHPT, even after KTx and irrespective of co-medication with cinacalcet. In view of the morbidity and mortality of long-term dialysis, patients will need individualized decisions taken by interdisciplinary transplant and tumor boards. Surgery should at least be offered to patients not responding to cinacalcet treatment and especially to those planned for KTx. This not only should reduce complications of pHPT but also improve patient morbidity in view of a successful KTx. Authors thank Prof. Dr. med. Peter E Goretzki for discussion and critical review of the manuscript. Author Contributions: M.T.M., T.S., N.R. contributed to the study conception and design, analysis, and interpretation of data and writing of the manuscript. N.M.O., E.T., C.B. participated in the acquisition and analysis of data. P.R., N.R., J.P. contributed to the analysis and interpretation of data, the study conception, and critical review of the manuscript. Compliance with Ethical Standards: This is a retrospective non-interventional study. All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical Approval: Ethical approval was given by the local ethics committee (EA4/086/19) Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD: M. T. Mogl https://orcid.org/0000-0002-3676-047X

CALCITRIOL, CALCIUM, CALCIUM GLUCONATE, CHOLECALCIFEROL, CINACALCET HYDROCHLORIDE, SODIUM PHOSPHATE

DrugsGivenReaction

CC BY-NC

31906794

2021-03

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Paralysis recurrent laryngeal nerve'.

Surgery for Renal Hyperparathyroidism in the Era of Cinacalcet: A Single-Center Experience. There are only few data on the influence of cinacalcet on the outcome of parathyroidectomy in patients with renal hyperparathyroidism. Indication and timing of surgery have changed since its introduction, especially with regard to kidney transplantation. Therefore, we retrospectively analyzed patients undergoing parathyroidectomy for renal hyperparathyroidism in our institution. Between 2008 and 2015, 196 consecutive operations in 191 patients were analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet compared with 116 operations (59%) in patients without cinacalcet. Clinical data, preoperative medication, pre- and postoperative laboratory values, type and details of surgery including complications, as well as cardiovascular complications and kidney transplantation with graft function were recorded. Demographical data were similar in patients with or without cinacalcet treatment. A total of 54% of patients received a kidney graft before or after parathyroidectomy. Pre- and postoperative parathormone levels were similar in both groups (preoperatively 755 vs 742 ng/L, postoperatively 50 vs 46 ng/L, p > 0.10), whereas patients with cinacalcet showed significantly lower calcium levels preoperatively (2.28 vs 2.41 mmol/L, p = 0.0002). There was no difference in recurrence or persistence of hyperparathyroidism, duration of surgery, hospital stay, or complication rate. Creatinine levels in patients with tertiary hyperparathyroidism were similar after 1-year follow-up. Cinacalcet did not influence outcome of patients with parathyroidectomy for renal hyperparathyroidism and can be safely offered to patients not responding to medical treatment. Introduction Since the introduction of cinacalcet in the treatment of renal hyperparathyroidism (rHPT) in 2004, clinical practice for indication and timing of surgery has changed following the Kidney Disease Improving Global Outcomes (KDIGO) International guideline group (1). Overall, the number of parathyroidectomies (PTxs) has declined (2) and the timepoint of surgery is delayed in patients with end-stage renal disease (ESRD) developing rHPT (3). But especially the long-term benefit of cinacalcet on patient morbidity and mortality has not been shown so far (4). In addition, the cost-effectiveness of surgery is better than that of cinacalcet treatment after 7.25 months of therapy (5), and cinacalcet is only cost-effective in patients not eligible for surgery or receiving a kidney-graft beforehand (6). On the contrary, a large cohort study showed a rather high 30-day morbidity and mortality (7) as well as an increased morbidity and rehospitalization rate in the first year for patients after PTx not receiving a kidney graft (8). Yet, the overall risk of death for dialysis patients is lower after PTx compared with patients with medical therapy alone (9), and PTx shows a trend in improving cardiovascular morbidity and mortality (10). In 2015, Messa (11) highlighted the need for additional randomized controlled trials comparing conservative and surgical therapy. Another question of concern is the timing of surgery in relation to kidney transplantation (KTx). It is known that in more than 40% of patients, rHPT persists after KTx (12) and that especially long duration of dialysis prior to KTx negatively influences spontaneous normalization. Studies have shown that parathyroidectomy after KTx has no negative influence on overall graft survival (13), although a temporary decrease in glomerular filtration rate (GFR) was confirmed (14). On the contrary, a retrospective analysis reported that PTx before KTx was associated with a lower risk of graft failure (15). A very recent study documented that persistent hyperparathyroidism (pHPT) more than 1 year after KTx is a risk factor for graft failure (16). In addition, cinacalcet treatment in patients receiving a kidney graft was a risk factor for delayed graft function experimentally and in a single cohort study (17). While in Germany cinacalcet cannot usually be prescribed for patients after KTx, it has been shown that its use after KTx corrects hypercalciuria and hyperparathyroidism (HPT) (18). In 2015, a randomized study concluded that patients with persistent HPT at 6 months after KTx should undergo PTx for normalization of parathyroid hormone (PTH) because of beneficial effects on bone mineral density compared with continuing cinacalcet therapy (19). So far, there are only few data on the influence of cinacalcet on the short- and long-term outcome of parathyroidectomy in patients with rHPT. Therefore, we retrospectively analyzed all patients undergoing parathyroidectomy for rHPT from the introduction of cinacalcet into clinical practice up to 2015. Material and Methods Study Population All patients undergoing parathyroidectomy for rHPT are prospectively collected in our database and were retrospectively analyzed. Between January 2004 and December 2007, only six patients had been treated with cinacalcet and were not considered for this retrospective analysis. From January 2008 until January 2015, 191 consecutive patients were included. All patients were followed until 1 May 2015 or death or loss of follow-up with a mean follow-up of 48.35 ± 25.2 months. Data were collected from medical charts including standard demographical data and from the kidney transplant database of our institution/European transplantation database (T-base) as well as from referring physicians, especially dialysis centers. Data concerning duration of dialysis, type of kidney disease, preoperative medication, pre- and postoperative laboratory values (calcium, intact para-thyroid hormone (iPTH), phosphate, creatinine, alkaline phosphatase (AP)), type and details of surgery including complications, as well as cardiovascular complications and KTx with graft function were recorded. Five patients who required redo surgery for recurrent or persistent HPT were calculated twice, because both operations were performed at our hospital within the study period. Thus, 196 operations in 191 patients were finally analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet at the time of surgery (group A) compared with 116 operations (59%) in patients not receiving cinacalcet (group B). A total of 156 patients (82%) were treated with phosphate binders, and 164 (86%) with 1,25 (OH)-vitamin D. After 2008, there was an increasing number of patients with cinacalcet treatment with a maximum in 2011 (Table 1). Table 1 Patients undergoing PTx with (group A) or without (group B) cinacalcet treatment in respective year. Year Group A Group B Total 2008 5 31 36 2009 8 25 33 2010 7 11 18 2011 24 15 39 2012 7 8 15 2013 11 16 27 2014 18 10 28 Our standard surgical procedure is a bilateral cervical exploration with subtotal PTx leaving a small nodular-free cervical remnant. A total PTx was performed only in patients with a high risk of recurrent HPT who were not listed for KTx. Cervical thymectomy was not routinely performed but carried out if less than four cervical glands were found. Neuromonitoring of the recurrent laryngeal nerve was routinely performed in all patients. In case of suspicious thyroid nodules or parathyroid glands with close relation to or inside the thyroid capsule, simultaneous thyroid surgery was done. In all patients, parathyroid tissue was cryopreserved. Postoperatively, all patients had daily controls of calcium, starting on the first postoperative day (POD). In case of persistently high iPTH levels directly after operation, consecutive controls were carried out. In case of missing glands, intraoperative iPTH was measured. Calcium substitution was instituted orally with 1000 mg/day immediately after PTx and adjusted to individual needs including additional intravenous substitution of calcium gluconate and changes in dialysate composition by our in-house nephrologists, as needed. All patients received 0.5 µg calcitriol twice daily with adjustment if needed. Patients were discharged if they were asymptomatic and as soon as the calcium level was stable (at least 1.9 mmol/L) or rising on two consecutive days. For measuring iPTH, an electrochemiluminescence immunoassay was performed by our laboratory (normal range: 15–65 ng/L). Calcium (normal range: 2.15–2.5 mmol/L), AP (35–105 U/L), creatinine (0.5–0.9 mg/dL), and phosphate (0.87–1.45 mmol/L) were measured routinely by our in-house nephrologists or referring dialysis centers later on. In order to define persistent or recurrent HPT, both elevated iPTH and calcium may be used. For this analysis, iPTH > 100 ng/L and/or calcium > 2.5 mmol/L were defined as persistent or recurrent hyperparathyroidism. All patients had an indirect laryngoscopy by an ear, nose, and throat specialist before and after the operation. In case of recurrent laryngeal nerve palsy, logopedic training was prescribed and patients were followed until vocal recovery in our outpatient clinic. Statistical Analysis Data were analyzed using the Statistica software 7.0 (StatSoft Inc., USA). All numerical results are presented as mean ± standard deviation (SD) independent from normal distribution. Categorial variables are presented as percentages. For testing normality of numerical variables, the Kolmogorov–Smirnov test (KS test) was used. Normally distributed data were tested with the unpaired t-test after comparing variances with the Levin test. For nonparametric variables with continuous distribution, the KS test was used for independent groups. Chi-square test with Yates’ correction was applied for nominal variables. Nonparametric data in dependent groups were analyzed with the Wilcoxon matched pairs test. Statistical significance was defined by p < 0.05. Results Demographic Data and Kidney Disease The study population consisted of 191 patients with 196 operations distributed to group A (80 cases, 41%) and group B (116 cases, 59%). The mean age was comparable in both groups (group A: 51.2 ± 13.3 vs group B: 51.5 ± 12.7 years), and the male/female ratio was 50% for group A, whereas group B consisted of more male patients (66%). Most patients had chronic kidney disease stage V (CKD V; 91% vs 84%, respectively) at the time of parathyroidectomy, an overview of underlying diseases is given in Table 2. Table 2 Underlying diseases leading to renal failure of patients with renal hyperparathyroidism. Number % Diabetic nephropathy 30 16 Σ = 71% Polycystic kidney disease 25 13 Chronic glomerulonephritis 20 10 Focal segmental glomerulosclerosis 16 8 Hypertensive nephropathy 15 8 IgA nephropathy 11 6 Interstitial nephritis 9 5 Membranoproliferative glomerulonephritis 10 5 Other 56 29 IgA: immunoglobulin A. A small number of patients had a functioning kidney graft at the time of parathyroidectomy (group A: 6% vs group B: 11%). Rarely, patients with CKD III and IV were operated in preparation of a living donor KTx (3% vs 5%). All patients were presented with comorbidities, including arterial hypertension, diabetes mellitus, adipositas, and coronary artery disease. Follow-up for patients with cinacalcet (group A, 39.7 ± 22.6 months) was significantly shorter compared with patients without cinacalcet (group B, 54.4 ± 25.3 months, p < 0.001, KS test). Kidney Transplantation Altogether 53% of the patients (n = 101) underwent KTx before or after PTx (25 patients lost to follow-up). At the end of the follow-up period, more patients were transplanted in both groups (54% vs 64%), but graft function varied between the groups. About 90 patients had no KTx during the study period (Table 3). Table 3 Clinical features of patients undergoing parathyroidectomy with (group A) or without cinacalcet (group B) including consecutive or prior kidney transplantation, type of parathyroidectomy, duration of surgery and hospital stay as well as complications and outcome. Cinacalcet (group A) n = 80 Without cinacalcet (group B) n = 116 No data Total Kidney transplantation 37 54 10 101  KTx before PTx 21 22 4 47  KTx after PTx 16 32 6 54 Type of operation  Subtotal PTx 49 89 – 138  Total PTx 21 19 – 40  Re-operation 10 8 – 18 Duration of surgery (minutes) 126 136 – – Hospital stay (days) 7 7 – – Complications  RLNP 2 (1 permanent) 3 – 5  Bleeding 0 2 – 2  30-day mortality 0 0 – 0 i.v. Calcium postoperatively 14 16 – 30 Death during follow-up 12 (52 alive) 14 (72 alive) 41 26 Recurrence of HPT 2 3 – 5 Persistence of HPT 1 3 – 4 HPT: hyperparathyroidism; RLNP: recurrent laryngeal nerve palsy; KTx: kidney transplantation; PTx: parathyreoidectomy. Note: Significance of bold values in the table was not calculated due to low numbers. Of the 47 patients undergoing PTx after KTx for tertiary hyperparathyroidism (tHPT), 15 (32%) were on dialysis (CKD V) in group A, while 6 patients (13%) had functioning grafts (creatinine: 1.23 ± 0.41 mg/dL) at the end of follow-up. In group B, 11 patients (23%) had CKD V and 11 (23%) presented with functioning grafts (creatinine: 1.91 ± 1.02 mg/dL), while 4 patients had unknown graft function. KTx was performed at a mean of 93.5 ± 83.1 months before PTx for both groups. In 54 patients with rHPT receiving their KTx after PTx, 42 had functioning grafts (group A: n = 13 (24%) vs group B: n = 29 (54%)), while six patients (11%) were back on dialysis (three patients in each group) and six had unknown graft function. Mean follow-up for these patients was 15.6 ± 10 months. Six patients received more than one KTx, with the PTx taking place after loss of function of the first kidney graft. Four of these were retransplanted after PTx and presented with good graft function. Creatinine levels in patients with tHPT (i.e. those with a functioning kidney transplant, defined as CKD I-III, n = 22) were analyzed before PTx and 1 year after operation. There were no significant differences neither in the whole group (p = 0.11), nor in the subgroups related to cinacalcet therapy (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet; Fig. 1). Fig. 1. Creatinine levels (mg/dL) in patients with kidney graft and good graft function at the time of PTx and at 1-year follow-up related to cinacalcet preoperatively (yes/no). There was no significant difference in creatinine levels for both groups (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet). Perioperative Data Operative technique A majority of 78% of all primary operations (138/178) underwent subtotal PTx (49 vs 89 cases in both groups, respectively). In 40 patients, a total PTx without autotransplantation was done. About 18 operations were performed for recurrent HPT (Table 3). In 86 cases (48%), concomitant thyroid surgery was carried out. Indications for thyroid surgery were solitary autonomous adenoma (n = 1), diffuse autonomy (n = 2), multinodular goiter (n = 56), suspicious thyroid nodules (n = 18), or a missing parathyroid gland (n = 12). In seven patients, a differentiated thyroid carcinoma was histologically confirmed. There was no difference in operative time between the groups (126 ± 44 min vs 136 ± 39 min with/without cinacalcet, p = 0.11, t-test). Length of in-hospital stay did not differ between the groups with a mean of 7.0 versus 7.1 days, respectively (p > 0.1, KS test). There is a trend toward shorter in-hospital stay in recent years, yet no significant difference could be seen (Table 3). Complications A total of five unilateral vocal cord palsies occurred (1.28% of 392 nerves at risk), two with and three without cinacalcet treatment. Four were temporary, while one patient after recurrent PTx revealed permanent unilateral vocal cord palsy. There were three reoperations for hematoma (n = 2) and infection (n = 1). One patient developed paroxysmal atrial fibrillation, but there was no perioperative mortality and all patients were discharged from hospital (Table 3). Perioperative laboratory values Preoperatively, calcium was significantly lower in group A (2.28 ± 0.23 mmol/L vs 2.41 ± 0.23 mmol/L, p = 0.0002, t-test), while neither postoperatively (1.89 ± 0.30 mmol/L vs 1.92 ± 0.30 mmol/L, p = 0.40, t-test) nor at discharge (2.12 ± 0.30 mmol/L vs 2.12 ± 0.27 mmol/L, p = 0.90, t-test) a statistically significant difference could be observed. Lowest calcium levels measured postoperatively were 1.91 ± 0.30 mmol/L for all patients. The lowest postoperative serum Ca levels were not significantly different between the groups, 1.89 ± 0.30 versus 1.92 ± 0.30 (p = 0.40, t-test). Altogether 30 patients received i.v. calcium postoperatively due to symptoms of hypocalcemia and/or calcium levels below 1.7 mmol/L (14 vs 16 patients). Preoperative iPTH levels were comparable between the groups (755 ± 657 ng/L vs 742 ± 545 ng/L, p > 0.10, KS test). In both groups, there was a significant drop on POD 1 with no difference between the groups (50 ± 124 ng/L vs 46 ± 83 ng/L, p > 0.10, KS test). More than 1/3 (36%) of the patients after KTx presented with good graft function at the moment of PTx. These patients showed no deterioration of creatinine levels at 1-year follow-up (1.42 mg/dL perioperatively vs 1.38 mg/dL after 1 year, p = 0.11, Wilcoxon test), and there was no difference between patients with or without cinacalcet preoperatively. 1-year surveillance data Calcium levels 1 year after PTx were not significantly different between the groups (2.26 ± 0.25 mmol/L vs 2.24 ± 0.25 mmol/L, p = 0.67, t-test). Regarding iPTH levels, no significant difference could be detected between patients with or without cinacalcet preoperatively (26.9 vs 42.1 ng/L, p > 0.1, KS test). Seven patients had extremely high iPTH (>2000 ng/L, n = 7) preoperatively, but none of these presented with persisting or recurrent hyperparathyroidism. Only two of these patients had been on cinacalcet before PTx. All of them had normalized iPTH at discharge. About 1 year after PTx, four of the patients presented with normal iPTH levels, for three of the patients iPTH was not available, but none of them was re-operated for HPT. Five of the patients had been transplanted before (n = 2) or after PTx (n = 3) and four presented with good graft function until the end of follow-up or death (n = 1). After 1 year, four patients were presented with iPTH > 100 ng/L and calcium > 2.5 mmol/L, while five patients only had elevated iPTH with normal calcium. Five of these patients had recurrent HPT (two with cinacalcet, group A) and four persisting HPT (one with cinacalcet, group A). Looking more closely at type of operation (subtotal PTx, total PTx, and recurrent PTx), there was no difference between postoperative iPTH and iPTH at 1 year. Patients with second PTx for recurrent or persisting HPT displayed a mean higher iPTH both postoperatively (45 ng/L) as well as at 1 year (92 ng/L). Patients with subtotal and total parathyroidectomy showed low levels of PTH both at discharge (11 and 8 ng/L) and at 1 year (8 and 7 ng/L). There was no significant difference between patients with or without cinacalcet. Overall mortality and morbidity Considering long-term follow-up, a considerable number of patients were lost to follow-up. There was no difference in mortality rate between the groups (p = 0.68, χ² test). At the end of follow-up, 12 of 77 patients in group A had died (16%), 52 (68%) were alive (no data in 16%, n = 13). In group B, 14 of 114 had died (12%), whereas 72 (63%) were alive (no data in 25%, n = 28). The prevalence of cardiovascular events was not significantly different between the groups. Myocardial infarction occured in 13% (group A) versus 18% of patients (group B), and the need for coronary artery intervention or bypass occurred in 13% versus 22% of patients in both groups, respectively. Also the need for peripheral revascularization (9% vs 12%) and stroke was recorded with a similar prevalence (13% vs 10%) in patients after PTx with or without cinacalcet. Discussion This single-center study in patients undergoing parathyroidectomy for rHPT shows excellent outcome independent of pretreatment with cinacalcet. Since the introduction of cinacalcet as treatment modality for rHPT, decreasing numbers of patients are being referred to parathyroidectomy (20). Nevertheless, no reduction of all-cause or cardiovascular mortality compared with surgery has been shown for patients with ESRD (4). A substantial part of these conservatively treated patients presents with persistently elevated iPTH, aggravation of complications, and consecutive referral to surgery (3). In our center, the number of patients referred to surgery was decreasing after the introduction of cinacalcet but is increasing again since 2012. Timing of PTx From our referring nephrology and transplant unit, a majority of patients on the waiting list for KTx is referred to parathyroidectomy, especially those with very high iPTH levels. This is due to the fact that only up to 56% of patients normalize PTH after KTx, mostly those with shorter waiting time on the transplant list (13). A total of 53% of our patients underwent KTx, either before or after PTx. In those patients undergoing PTx before KTx for rHPT, a majority of 78% presents with functioning grafts during follow-up. While it is clear that pHPT after KTx impairs long-term graft survival (17), optimal therapy still is under debate. An interesting report by Torregrosa et al. (21) has shown no decline in graft function 1 year after KTx for patients with rHPT that were treated with cinacalcet and also stable graft function for patients on cinacalcet during long-term follow-up. This was underlined by a meta-analysis by Cohen et al. (22) reporting that cinacalcet treatment for pHPT after KTx was not associated with inferior graft survival. In our study, 55% of patients undergoing PTx after KTx were on dialysis at the end of follow-up, mostly for graft failure before PTx. But those patients undergoing PTx with functioning kidney grafts did not show deterioration of creatinine levels postoperatively or during 1-year follow-up, irrespective of cinacalcet treatment. Interestingly, six of the patients underwent second or even third KTx after PTx and presented with functioning grafts during follow-up. In contrast, 78% of patients with PTx and consecutive KTx showed functioning grafts, irrespective of treatment with cinacalcet prior to surgery. Overall, these results favor parathyroidectomy before KTx, yet prospective trials will be necessary to evaluate optimal treatment for tHPT after KTx. Cardiovascular Morbidity Treatment with cinacalcet only showed limited effects on cardiovascular morbidity or mortality of patients with ESRD in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial (23), which evaluated patients on hemodialysis. Both a Cochrane analysis (4) and a meta-analysis by Palmer et al. (24) demonstrated that for patients with ESRD treatment with cinacalcet only reduced the risk for surgery without positively influencing all-cause or cardiovascular mortality. A smaller trial by Trombetti et al. (25) showed that PTx, on the contrary, is associated with both reduced morbidity and mortality of these patients. In this cohort, 19 months after PTx, mortality of patients with ESRD was less than without PTx. In our study, morbidity and mortality during follow-up were not different between patients with or without cinacalcet treatment before surgery. Both small sample size and patients lost to follow-up reduce the statistic power of our cohort. Laboratory Values Overall, we could see no significant differences in laboratory values perioperatively between the groups, only preoperative calcium levels were significantly lower in patients with cinacalcet. At 1 year after surgery, no difference could be detected in iPTH between the groups. A study by Somnay et al. (26) focused on patients with tHPT and the effect of cinacalcet treatment on perioperative findings and outcome. Although they presented a small patient cohort with cinacalcet treatment, they interestingly had higher iPTH levels preoperatively in this cohort, while cure rate was not influenced by cinacalcet pretreatment. Compared with our analysis, patients without cinacalcet treatment had much lower preoperative iPTH levels in this study, possibly reflecting lower thresholds for PTx after KTx. Only seven patients with tHPT in our study received cinacalcet treatment with similar preoperative iPTH levels, as patients with rHPT. A very recent study by Baker et al. (27) examined influence of cinacalcet on outcome in patients with rHPT and found greater iPTH levels in the untreated group before surgery with similar outcome. Only the study of Wirowski et al. (28) demonstrated comparable laboratory findings in patients operated for rHPT. In their analysis, pre- and postoperative iPTH levels were equal in patients with or without cinacalcet and calcium was significantly lower in cinacalcet patients. This is in line with our findings, and they also concluded that cinacalcet did not alter perioperative course. Looking more closely on recurrent, or persisting rHPT, only four patients were diagnosed during follow-up with both elevated iPTH and hypercalcemia, while five were normocalcemic with elevated iPTH. For this analysis, relatively strict values were applied as cut-off values for recurrent HPT. When increasing the cut-off values for iPTH, only two patients of the cohort would have been identified with recurrence of HPT. There was no significant difference in iPTH levels at 1 year between subtotal or total parathyroidectomy and also no difference related to cinacalcet treatment preoperatively. So overall, surgical technique with mostly subtotal PTx in our cohort showed good results and low rates of recurrent or persisting rHPT, independent of preoperative treatment with cinacalcet. Several groups have shown that subtotal PTx or total PTx with autotransplantation of parathyroid tissue represent a good compromise between effective treatment of rHPT while avoiding unnecessary complications of hypocalcemia, adynamic bone disease, or reoperations (29). Complications Overall, the rate of surgical complications was low in both groups and no difference could be calculated for patients with or without cinacalcet treatment. There was no perioperative mortality in our group. Duration of surgery and hospital stay did not differ between the groups, and hospital-stay was reduced during the study period but similar in both groups. Conclusion Our study underlines the fact that PTx represents a safe and successful treatment option for patients with rHPT, even after KTx and irrespective of co-medication with cinacalcet. In view of the morbidity and mortality of long-term dialysis, patients will need individualized decisions taken by interdisciplinary transplant and tumor boards. Surgery should at least be offered to patients not responding to cinacalcet treatment and especially to those planned for KTx. This not only should reduce complications of pHPT but also improve patient morbidity in view of a successful KTx. Authors thank Prof. Dr. med. Peter E Goretzki for discussion and critical review of the manuscript. Author Contributions: M.T.M., T.S., N.R. contributed to the study conception and design, analysis, and interpretation of data and writing of the manuscript. N.M.O., E.T., C.B. participated in the acquisition and analysis of data. P.R., N.R., J.P. contributed to the analysis and interpretation of data, the study conception, and critical review of the manuscript. Compliance with Ethical Standards: This is a retrospective non-interventional study. All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical Approval: Ethical approval was given by the local ethics committee (EA4/086/19) Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD: M. T. Mogl https://orcid.org/0000-0002-3676-047X

CALCITRIOL, CALCIUM, CALCIUM GLUCONATE, CHOLECALCIFEROL, CINACALCET HYDROCHLORIDE, SODIUM PHOSPHATE

DrugsGivenReaction

CC BY-NC

31906794

2021-03

What was the administration route of drug 'CALCIUM GLUCONATE'?

Surgery for Renal Hyperparathyroidism in the Era of Cinacalcet: A Single-Center Experience. There are only few data on the influence of cinacalcet on the outcome of parathyroidectomy in patients with renal hyperparathyroidism. Indication and timing of surgery have changed since its introduction, especially with regard to kidney transplantation. Therefore, we retrospectively analyzed patients undergoing parathyroidectomy for renal hyperparathyroidism in our institution. Between 2008 and 2015, 196 consecutive operations in 191 patients were analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet compared with 116 operations (59%) in patients without cinacalcet. Clinical data, preoperative medication, pre- and postoperative laboratory values, type and details of surgery including complications, as well as cardiovascular complications and kidney transplantation with graft function were recorded. Demographical data were similar in patients with or without cinacalcet treatment. A total of 54% of patients received a kidney graft before or after parathyroidectomy. Pre- and postoperative parathormone levels were similar in both groups (preoperatively 755 vs 742 ng/L, postoperatively 50 vs 46 ng/L, p > 0.10), whereas patients with cinacalcet showed significantly lower calcium levels preoperatively (2.28 vs 2.41 mmol/L, p = 0.0002). There was no difference in recurrence or persistence of hyperparathyroidism, duration of surgery, hospital stay, or complication rate. Creatinine levels in patients with tertiary hyperparathyroidism were similar after 1-year follow-up. Cinacalcet did not influence outcome of patients with parathyroidectomy for renal hyperparathyroidism and can be safely offered to patients not responding to medical treatment. Introduction Since the introduction of cinacalcet in the treatment of renal hyperparathyroidism (rHPT) in 2004, clinical practice for indication and timing of surgery has changed following the Kidney Disease Improving Global Outcomes (KDIGO) International guideline group (1). Overall, the number of parathyroidectomies (PTxs) has declined (2) and the timepoint of surgery is delayed in patients with end-stage renal disease (ESRD) developing rHPT (3). But especially the long-term benefit of cinacalcet on patient morbidity and mortality has not been shown so far (4). In addition, the cost-effectiveness of surgery is better than that of cinacalcet treatment after 7.25 months of therapy (5), and cinacalcet is only cost-effective in patients not eligible for surgery or receiving a kidney-graft beforehand (6). On the contrary, a large cohort study showed a rather high 30-day morbidity and mortality (7) as well as an increased morbidity and rehospitalization rate in the first year for patients after PTx not receiving a kidney graft (8). Yet, the overall risk of death for dialysis patients is lower after PTx compared with patients with medical therapy alone (9), and PTx shows a trend in improving cardiovascular morbidity and mortality (10). In 2015, Messa (11) highlighted the need for additional randomized controlled trials comparing conservative and surgical therapy. Another question of concern is the timing of surgery in relation to kidney transplantation (KTx). It is known that in more than 40% of patients, rHPT persists after KTx (12) and that especially long duration of dialysis prior to KTx negatively influences spontaneous normalization. Studies have shown that parathyroidectomy after KTx has no negative influence on overall graft survival (13), although a temporary decrease in glomerular filtration rate (GFR) was confirmed (14). On the contrary, a retrospective analysis reported that PTx before KTx was associated with a lower risk of graft failure (15). A very recent study documented that persistent hyperparathyroidism (pHPT) more than 1 year after KTx is a risk factor for graft failure (16). In addition, cinacalcet treatment in patients receiving a kidney graft was a risk factor for delayed graft function experimentally and in a single cohort study (17). While in Germany cinacalcet cannot usually be prescribed for patients after KTx, it has been shown that its use after KTx corrects hypercalciuria and hyperparathyroidism (HPT) (18). In 2015, a randomized study concluded that patients with persistent HPT at 6 months after KTx should undergo PTx for normalization of parathyroid hormone (PTH) because of beneficial effects on bone mineral density compared with continuing cinacalcet therapy (19). So far, there are only few data on the influence of cinacalcet on the short- and long-term outcome of parathyroidectomy in patients with rHPT. Therefore, we retrospectively analyzed all patients undergoing parathyroidectomy for rHPT from the introduction of cinacalcet into clinical practice up to 2015. Material and Methods Study Population All patients undergoing parathyroidectomy for rHPT are prospectively collected in our database and were retrospectively analyzed. Between January 2004 and December 2007, only six patients had been treated with cinacalcet and were not considered for this retrospective analysis. From January 2008 until January 2015, 191 consecutive patients were included. All patients were followed until 1 May 2015 or death or loss of follow-up with a mean follow-up of 48.35 ± 25.2 months. Data were collected from medical charts including standard demographical data and from the kidney transplant database of our institution/European transplantation database (T-base) as well as from referring physicians, especially dialysis centers. Data concerning duration of dialysis, type of kidney disease, preoperative medication, pre- and postoperative laboratory values (calcium, intact para-thyroid hormone (iPTH), phosphate, creatinine, alkaline phosphatase (AP)), type and details of surgery including complications, as well as cardiovascular complications and KTx with graft function were recorded. Five patients who required redo surgery for recurrent or persistent HPT were calculated twice, because both operations were performed at our hospital within the study period. Thus, 196 operations in 191 patients were finally analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet at the time of surgery (group A) compared with 116 operations (59%) in patients not receiving cinacalcet (group B). A total of 156 patients (82%) were treated with phosphate binders, and 164 (86%) with 1,25 (OH)-vitamin D. After 2008, there was an increasing number of patients with cinacalcet treatment with a maximum in 2011 (Table 1). Table 1 Patients undergoing PTx with (group A) or without (group B) cinacalcet treatment in respective year. Year Group A Group B Total 2008 5 31 36 2009 8 25 33 2010 7 11 18 2011 24 15 39 2012 7 8 15 2013 11 16 27 2014 18 10 28 Our standard surgical procedure is a bilateral cervical exploration with subtotal PTx leaving a small nodular-free cervical remnant. A total PTx was performed only in patients with a high risk of recurrent HPT who were not listed for KTx. Cervical thymectomy was not routinely performed but carried out if less than four cervical glands were found. Neuromonitoring of the recurrent laryngeal nerve was routinely performed in all patients. In case of suspicious thyroid nodules or parathyroid glands with close relation to or inside the thyroid capsule, simultaneous thyroid surgery was done. In all patients, parathyroid tissue was cryopreserved. Postoperatively, all patients had daily controls of calcium, starting on the first postoperative day (POD). In case of persistently high iPTH levels directly after operation, consecutive controls were carried out. In case of missing glands, intraoperative iPTH was measured. Calcium substitution was instituted orally with 1000 mg/day immediately after PTx and adjusted to individual needs including additional intravenous substitution of calcium gluconate and changes in dialysate composition by our in-house nephrologists, as needed. All patients received 0.5 µg calcitriol twice daily with adjustment if needed. Patients were discharged if they were asymptomatic and as soon as the calcium level was stable (at least 1.9 mmol/L) or rising on two consecutive days. For measuring iPTH, an electrochemiluminescence immunoassay was performed by our laboratory (normal range: 15–65 ng/L). Calcium (normal range: 2.15–2.5 mmol/L), AP (35–105 U/L), creatinine (0.5–0.9 mg/dL), and phosphate (0.87–1.45 mmol/L) were measured routinely by our in-house nephrologists or referring dialysis centers later on. In order to define persistent or recurrent HPT, both elevated iPTH and calcium may be used. For this analysis, iPTH > 100 ng/L and/or calcium > 2.5 mmol/L were defined as persistent or recurrent hyperparathyroidism. All patients had an indirect laryngoscopy by an ear, nose, and throat specialist before and after the operation. In case of recurrent laryngeal nerve palsy, logopedic training was prescribed and patients were followed until vocal recovery in our outpatient clinic. Statistical Analysis Data were analyzed using the Statistica software 7.0 (StatSoft Inc., USA). All numerical results are presented as mean ± standard deviation (SD) independent from normal distribution. Categorial variables are presented as percentages. For testing normality of numerical variables, the Kolmogorov–Smirnov test (KS test) was used. Normally distributed data were tested with the unpaired t-test after comparing variances with the Levin test. For nonparametric variables with continuous distribution, the KS test was used for independent groups. Chi-square test with Yates’ correction was applied for nominal variables. Nonparametric data in dependent groups were analyzed with the Wilcoxon matched pairs test. Statistical significance was defined by p < 0.05. Results Demographic Data and Kidney Disease The study population consisted of 191 patients with 196 operations distributed to group A (80 cases, 41%) and group B (116 cases, 59%). The mean age was comparable in both groups (group A: 51.2 ± 13.3 vs group B: 51.5 ± 12.7 years), and the male/female ratio was 50% for group A, whereas group B consisted of more male patients (66%). Most patients had chronic kidney disease stage V (CKD V; 91% vs 84%, respectively) at the time of parathyroidectomy, an overview of underlying diseases is given in Table 2. Table 2 Underlying diseases leading to renal failure of patients with renal hyperparathyroidism. Number % Diabetic nephropathy 30 16 Σ = 71% Polycystic kidney disease 25 13 Chronic glomerulonephritis 20 10 Focal segmental glomerulosclerosis 16 8 Hypertensive nephropathy 15 8 IgA nephropathy 11 6 Interstitial nephritis 9 5 Membranoproliferative glomerulonephritis 10 5 Other 56 29 IgA: immunoglobulin A. A small number of patients had a functioning kidney graft at the time of parathyroidectomy (group A: 6% vs group B: 11%). Rarely, patients with CKD III and IV were operated in preparation of a living donor KTx (3% vs 5%). All patients were presented with comorbidities, including arterial hypertension, diabetes mellitus, adipositas, and coronary artery disease. Follow-up for patients with cinacalcet (group A, 39.7 ± 22.6 months) was significantly shorter compared with patients without cinacalcet (group B, 54.4 ± 25.3 months, p < 0.001, KS test). Kidney Transplantation Altogether 53% of the patients (n = 101) underwent KTx before or after PTx (25 patients lost to follow-up). At the end of the follow-up period, more patients were transplanted in both groups (54% vs 64%), but graft function varied between the groups. About 90 patients had no KTx during the study period (Table 3). Table 3 Clinical features of patients undergoing parathyroidectomy with (group A) or without cinacalcet (group B) including consecutive or prior kidney transplantation, type of parathyroidectomy, duration of surgery and hospital stay as well as complications and outcome. Cinacalcet (group A) n = 80 Without cinacalcet (group B) n = 116 No data Total Kidney transplantation 37 54 10 101  KTx before PTx 21 22 4 47  KTx after PTx 16 32 6 54 Type of operation  Subtotal PTx 49 89 – 138  Total PTx 21 19 – 40  Re-operation 10 8 – 18 Duration of surgery (minutes) 126 136 – – Hospital stay (days) 7 7 – – Complications  RLNP 2 (1 permanent) 3 – 5  Bleeding 0 2 – 2  30-day mortality 0 0 – 0 i.v. Calcium postoperatively 14 16 – 30 Death during follow-up 12 (52 alive) 14 (72 alive) 41 26 Recurrence of HPT 2 3 – 5 Persistence of HPT 1 3 – 4 HPT: hyperparathyroidism; RLNP: recurrent laryngeal nerve palsy; KTx: kidney transplantation; PTx: parathyreoidectomy. Note: Significance of bold values in the table was not calculated due to low numbers. Of the 47 patients undergoing PTx after KTx for tertiary hyperparathyroidism (tHPT), 15 (32%) were on dialysis (CKD V) in group A, while 6 patients (13%) had functioning grafts (creatinine: 1.23 ± 0.41 mg/dL) at the end of follow-up. In group B, 11 patients (23%) had CKD V and 11 (23%) presented with functioning grafts (creatinine: 1.91 ± 1.02 mg/dL), while 4 patients had unknown graft function. KTx was performed at a mean of 93.5 ± 83.1 months before PTx for both groups. In 54 patients with rHPT receiving their KTx after PTx, 42 had functioning grafts (group A: n = 13 (24%) vs group B: n = 29 (54%)), while six patients (11%) were back on dialysis (three patients in each group) and six had unknown graft function. Mean follow-up for these patients was 15.6 ± 10 months. Six patients received more than one KTx, with the PTx taking place after loss of function of the first kidney graft. Four of these were retransplanted after PTx and presented with good graft function. Creatinine levels in patients with tHPT (i.e. those with a functioning kidney transplant, defined as CKD I-III, n = 22) were analyzed before PTx and 1 year after operation. There were no significant differences neither in the whole group (p = 0.11), nor in the subgroups related to cinacalcet therapy (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet; Fig. 1). Fig. 1. Creatinine levels (mg/dL) in patients with kidney graft and good graft function at the time of PTx and at 1-year follow-up related to cinacalcet preoperatively (yes/no). There was no significant difference in creatinine levels for both groups (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet). Perioperative Data Operative technique A majority of 78% of all primary operations (138/178) underwent subtotal PTx (49 vs 89 cases in both groups, respectively). In 40 patients, a total PTx without autotransplantation was done. About 18 operations were performed for recurrent HPT (Table 3). In 86 cases (48%), concomitant thyroid surgery was carried out. Indications for thyroid surgery were solitary autonomous adenoma (n = 1), diffuse autonomy (n = 2), multinodular goiter (n = 56), suspicious thyroid nodules (n = 18), or a missing parathyroid gland (n = 12). In seven patients, a differentiated thyroid carcinoma was histologically confirmed. There was no difference in operative time between the groups (126 ± 44 min vs 136 ± 39 min with/without cinacalcet, p = 0.11, t-test). Length of in-hospital stay did not differ between the groups with a mean of 7.0 versus 7.1 days, respectively (p > 0.1, KS test). There is a trend toward shorter in-hospital stay in recent years, yet no significant difference could be seen (Table 3). Complications A total of five unilateral vocal cord palsies occurred (1.28% of 392 nerves at risk), two with and three without cinacalcet treatment. Four were temporary, while one patient after recurrent PTx revealed permanent unilateral vocal cord palsy. There were three reoperations for hematoma (n = 2) and infection (n = 1). One patient developed paroxysmal atrial fibrillation, but there was no perioperative mortality and all patients were discharged from hospital (Table 3). Perioperative laboratory values Preoperatively, calcium was significantly lower in group A (2.28 ± 0.23 mmol/L vs 2.41 ± 0.23 mmol/L, p = 0.0002, t-test), while neither postoperatively (1.89 ± 0.30 mmol/L vs 1.92 ± 0.30 mmol/L, p = 0.40, t-test) nor at discharge (2.12 ± 0.30 mmol/L vs 2.12 ± 0.27 mmol/L, p = 0.90, t-test) a statistically significant difference could be observed. Lowest calcium levels measured postoperatively were 1.91 ± 0.30 mmol/L for all patients. The lowest postoperative serum Ca levels were not significantly different between the groups, 1.89 ± 0.30 versus 1.92 ± 0.30 (p = 0.40, t-test). Altogether 30 patients received i.v. calcium postoperatively due to symptoms of hypocalcemia and/or calcium levels below 1.7 mmol/L (14 vs 16 patients). Preoperative iPTH levels were comparable between the groups (755 ± 657 ng/L vs 742 ± 545 ng/L, p > 0.10, KS test). In both groups, there was a significant drop on POD 1 with no difference between the groups (50 ± 124 ng/L vs 46 ± 83 ng/L, p > 0.10, KS test). More than 1/3 (36%) of the patients after KTx presented with good graft function at the moment of PTx. These patients showed no deterioration of creatinine levels at 1-year follow-up (1.42 mg/dL perioperatively vs 1.38 mg/dL after 1 year, p = 0.11, Wilcoxon test), and there was no difference between patients with or without cinacalcet preoperatively. 1-year surveillance data Calcium levels 1 year after PTx were not significantly different between the groups (2.26 ± 0.25 mmol/L vs 2.24 ± 0.25 mmol/L, p = 0.67, t-test). Regarding iPTH levels, no significant difference could be detected between patients with or without cinacalcet preoperatively (26.9 vs 42.1 ng/L, p > 0.1, KS test). Seven patients had extremely high iPTH (>2000 ng/L, n = 7) preoperatively, but none of these presented with persisting or recurrent hyperparathyroidism. Only two of these patients had been on cinacalcet before PTx. All of them had normalized iPTH at discharge. About 1 year after PTx, four of the patients presented with normal iPTH levels, for three of the patients iPTH was not available, but none of them was re-operated for HPT. Five of the patients had been transplanted before (n = 2) or after PTx (n = 3) and four presented with good graft function until the end of follow-up or death (n = 1). After 1 year, four patients were presented with iPTH > 100 ng/L and calcium > 2.5 mmol/L, while five patients only had elevated iPTH with normal calcium. Five of these patients had recurrent HPT (two with cinacalcet, group A) and four persisting HPT (one with cinacalcet, group A). Looking more closely at type of operation (subtotal PTx, total PTx, and recurrent PTx), there was no difference between postoperative iPTH and iPTH at 1 year. Patients with second PTx for recurrent or persisting HPT displayed a mean higher iPTH both postoperatively (45 ng/L) as well as at 1 year (92 ng/L). Patients with subtotal and total parathyroidectomy showed low levels of PTH both at discharge (11 and 8 ng/L) and at 1 year (8 and 7 ng/L). There was no significant difference between patients with or without cinacalcet. Overall mortality and morbidity Considering long-term follow-up, a considerable number of patients were lost to follow-up. There was no difference in mortality rate between the groups (p = 0.68, χ² test). At the end of follow-up, 12 of 77 patients in group A had died (16%), 52 (68%) were alive (no data in 16%, n = 13). In group B, 14 of 114 had died (12%), whereas 72 (63%) were alive (no data in 25%, n = 28). The prevalence of cardiovascular events was not significantly different between the groups. Myocardial infarction occured in 13% (group A) versus 18% of patients (group B), and the need for coronary artery intervention or bypass occurred in 13% versus 22% of patients in both groups, respectively. Also the need for peripheral revascularization (9% vs 12%) and stroke was recorded with a similar prevalence (13% vs 10%) in patients after PTx with or without cinacalcet. Discussion This single-center study in patients undergoing parathyroidectomy for rHPT shows excellent outcome independent of pretreatment with cinacalcet. Since the introduction of cinacalcet as treatment modality for rHPT, decreasing numbers of patients are being referred to parathyroidectomy (20). Nevertheless, no reduction of all-cause or cardiovascular mortality compared with surgery has been shown for patients with ESRD (4). A substantial part of these conservatively treated patients presents with persistently elevated iPTH, aggravation of complications, and consecutive referral to surgery (3). In our center, the number of patients referred to surgery was decreasing after the introduction of cinacalcet but is increasing again since 2012. Timing of PTx From our referring nephrology and transplant unit, a majority of patients on the waiting list for KTx is referred to parathyroidectomy, especially those with very high iPTH levels. This is due to the fact that only up to 56% of patients normalize PTH after KTx, mostly those with shorter waiting time on the transplant list (13). A total of 53% of our patients underwent KTx, either before or after PTx. In those patients undergoing PTx before KTx for rHPT, a majority of 78% presents with functioning grafts during follow-up. While it is clear that pHPT after KTx impairs long-term graft survival (17), optimal therapy still is under debate. An interesting report by Torregrosa et al. (21) has shown no decline in graft function 1 year after KTx for patients with rHPT that were treated with cinacalcet and also stable graft function for patients on cinacalcet during long-term follow-up. This was underlined by a meta-analysis by Cohen et al. (22) reporting that cinacalcet treatment for pHPT after KTx was not associated with inferior graft survival. In our study, 55% of patients undergoing PTx after KTx were on dialysis at the end of follow-up, mostly for graft failure before PTx. But those patients undergoing PTx with functioning kidney grafts did not show deterioration of creatinine levels postoperatively or during 1-year follow-up, irrespective of cinacalcet treatment. Interestingly, six of the patients underwent second or even third KTx after PTx and presented with functioning grafts during follow-up. In contrast, 78% of patients with PTx and consecutive KTx showed functioning grafts, irrespective of treatment with cinacalcet prior to surgery. Overall, these results favor parathyroidectomy before KTx, yet prospective trials will be necessary to evaluate optimal treatment for tHPT after KTx. Cardiovascular Morbidity Treatment with cinacalcet only showed limited effects on cardiovascular morbidity or mortality of patients with ESRD in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial (23), which evaluated patients on hemodialysis. Both a Cochrane analysis (4) and a meta-analysis by Palmer et al. (24) demonstrated that for patients with ESRD treatment with cinacalcet only reduced the risk for surgery without positively influencing all-cause or cardiovascular mortality. A smaller trial by Trombetti et al. (25) showed that PTx, on the contrary, is associated with both reduced morbidity and mortality of these patients. In this cohort, 19 months after PTx, mortality of patients with ESRD was less than without PTx. In our study, morbidity and mortality during follow-up were not different between patients with or without cinacalcet treatment before surgery. Both small sample size and patients lost to follow-up reduce the statistic power of our cohort. Laboratory Values Overall, we could see no significant differences in laboratory values perioperatively between the groups, only preoperative calcium levels were significantly lower in patients with cinacalcet. At 1 year after surgery, no difference could be detected in iPTH between the groups. A study by Somnay et al. (26) focused on patients with tHPT and the effect of cinacalcet treatment on perioperative findings and outcome. Although they presented a small patient cohort with cinacalcet treatment, they interestingly had higher iPTH levels preoperatively in this cohort, while cure rate was not influenced by cinacalcet pretreatment. Compared with our analysis, patients without cinacalcet treatment had much lower preoperative iPTH levels in this study, possibly reflecting lower thresholds for PTx after KTx. Only seven patients with tHPT in our study received cinacalcet treatment with similar preoperative iPTH levels, as patients with rHPT. A very recent study by Baker et al. (27) examined influence of cinacalcet on outcome in patients with rHPT and found greater iPTH levels in the untreated group before surgery with similar outcome. Only the study of Wirowski et al. (28) demonstrated comparable laboratory findings in patients operated for rHPT. In their analysis, pre- and postoperative iPTH levels were equal in patients with or without cinacalcet and calcium was significantly lower in cinacalcet patients. This is in line with our findings, and they also concluded that cinacalcet did not alter perioperative course. Looking more closely on recurrent, or persisting rHPT, only four patients were diagnosed during follow-up with both elevated iPTH and hypercalcemia, while five were normocalcemic with elevated iPTH. For this analysis, relatively strict values were applied as cut-off values for recurrent HPT. When increasing the cut-off values for iPTH, only two patients of the cohort would have been identified with recurrence of HPT. There was no significant difference in iPTH levels at 1 year between subtotal or total parathyroidectomy and also no difference related to cinacalcet treatment preoperatively. So overall, surgical technique with mostly subtotal PTx in our cohort showed good results and low rates of recurrent or persisting rHPT, independent of preoperative treatment with cinacalcet. Several groups have shown that subtotal PTx or total PTx with autotransplantation of parathyroid tissue represent a good compromise between effective treatment of rHPT while avoiding unnecessary complications of hypocalcemia, adynamic bone disease, or reoperations (29). Complications Overall, the rate of surgical complications was low in both groups and no difference could be calculated for patients with or without cinacalcet treatment. There was no perioperative mortality in our group. Duration of surgery and hospital stay did not differ between the groups, and hospital-stay was reduced during the study period but similar in both groups. Conclusion Our study underlines the fact that PTx represents a safe and successful treatment option for patients with rHPT, even after KTx and irrespective of co-medication with cinacalcet. In view of the morbidity and mortality of long-term dialysis, patients will need individualized decisions taken by interdisciplinary transplant and tumor boards. Surgery should at least be offered to patients not responding to cinacalcet treatment and especially to those planned for KTx. This not only should reduce complications of pHPT but also improve patient morbidity in view of a successful KTx. Authors thank Prof. Dr. med. Peter E Goretzki for discussion and critical review of the manuscript. Author Contributions: M.T.M., T.S., N.R. contributed to the study conception and design, analysis, and interpretation of data and writing of the manuscript. N.M.O., E.T., C.B. participated in the acquisition and analysis of data. P.R., N.R., J.P. contributed to the analysis and interpretation of data, the study conception, and critical review of the manuscript. Compliance with Ethical Standards: This is a retrospective non-interventional study. All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical Approval: Ethical approval was given by the local ethics committee (EA4/086/19) Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD: M. T. Mogl https://orcid.org/0000-0002-3676-047X

Intravenous (not otherwise specified)

DrugAdministrationRoute

CC BY-NC

31906794

2021-03

What was the administration route of drug 'CALCIUM'?

Surgery for Renal Hyperparathyroidism in the Era of Cinacalcet: A Single-Center Experience. There are only few data on the influence of cinacalcet on the outcome of parathyroidectomy in patients with renal hyperparathyroidism. Indication and timing of surgery have changed since its introduction, especially with regard to kidney transplantation. Therefore, we retrospectively analyzed patients undergoing parathyroidectomy for renal hyperparathyroidism in our institution. Between 2008 and 2015, 196 consecutive operations in 191 patients were analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet compared with 116 operations (59%) in patients without cinacalcet. Clinical data, preoperative medication, pre- and postoperative laboratory values, type and details of surgery including complications, as well as cardiovascular complications and kidney transplantation with graft function were recorded. Demographical data were similar in patients with or without cinacalcet treatment. A total of 54% of patients received a kidney graft before or after parathyroidectomy. Pre- and postoperative parathormone levels were similar in both groups (preoperatively 755 vs 742 ng/L, postoperatively 50 vs 46 ng/L, p > 0.10), whereas patients with cinacalcet showed significantly lower calcium levels preoperatively (2.28 vs 2.41 mmol/L, p = 0.0002). There was no difference in recurrence or persistence of hyperparathyroidism, duration of surgery, hospital stay, or complication rate. Creatinine levels in patients with tertiary hyperparathyroidism were similar after 1-year follow-up. Cinacalcet did not influence outcome of patients with parathyroidectomy for renal hyperparathyroidism and can be safely offered to patients not responding to medical treatment. Introduction Since the introduction of cinacalcet in the treatment of renal hyperparathyroidism (rHPT) in 2004, clinical practice for indication and timing of surgery has changed following the Kidney Disease Improving Global Outcomes (KDIGO) International guideline group (1). Overall, the number of parathyroidectomies (PTxs) has declined (2) and the timepoint of surgery is delayed in patients with end-stage renal disease (ESRD) developing rHPT (3). But especially the long-term benefit of cinacalcet on patient morbidity and mortality has not been shown so far (4). In addition, the cost-effectiveness of surgery is better than that of cinacalcet treatment after 7.25 months of therapy (5), and cinacalcet is only cost-effective in patients not eligible for surgery or receiving a kidney-graft beforehand (6). On the contrary, a large cohort study showed a rather high 30-day morbidity and mortality (7) as well as an increased morbidity and rehospitalization rate in the first year for patients after PTx not receiving a kidney graft (8). Yet, the overall risk of death for dialysis patients is lower after PTx compared with patients with medical therapy alone (9), and PTx shows a trend in improving cardiovascular morbidity and mortality (10). In 2015, Messa (11) highlighted the need for additional randomized controlled trials comparing conservative and surgical therapy. Another question of concern is the timing of surgery in relation to kidney transplantation (KTx). It is known that in more than 40% of patients, rHPT persists after KTx (12) and that especially long duration of dialysis prior to KTx negatively influences spontaneous normalization. Studies have shown that parathyroidectomy after KTx has no negative influence on overall graft survival (13), although a temporary decrease in glomerular filtration rate (GFR) was confirmed (14). On the contrary, a retrospective analysis reported that PTx before KTx was associated with a lower risk of graft failure (15). A very recent study documented that persistent hyperparathyroidism (pHPT) more than 1 year after KTx is a risk factor for graft failure (16). In addition, cinacalcet treatment in patients receiving a kidney graft was a risk factor for delayed graft function experimentally and in a single cohort study (17). While in Germany cinacalcet cannot usually be prescribed for patients after KTx, it has been shown that its use after KTx corrects hypercalciuria and hyperparathyroidism (HPT) (18). In 2015, a randomized study concluded that patients with persistent HPT at 6 months after KTx should undergo PTx for normalization of parathyroid hormone (PTH) because of beneficial effects on bone mineral density compared with continuing cinacalcet therapy (19). So far, there are only few data on the influence of cinacalcet on the short- and long-term outcome of parathyroidectomy in patients with rHPT. Therefore, we retrospectively analyzed all patients undergoing parathyroidectomy for rHPT from the introduction of cinacalcet into clinical practice up to 2015. Material and Methods Study Population All patients undergoing parathyroidectomy for rHPT are prospectively collected in our database and were retrospectively analyzed. Between January 2004 and December 2007, only six patients had been treated with cinacalcet and were not considered for this retrospective analysis. From January 2008 until January 2015, 191 consecutive patients were included. All patients were followed until 1 May 2015 or death or loss of follow-up with a mean follow-up of 48.35 ± 25.2 months. Data were collected from medical charts including standard demographical data and from the kidney transplant database of our institution/European transplantation database (T-base) as well as from referring physicians, especially dialysis centers. Data concerning duration of dialysis, type of kidney disease, preoperative medication, pre- and postoperative laboratory values (calcium, intact para-thyroid hormone (iPTH), phosphate, creatinine, alkaline phosphatase (AP)), type and details of surgery including complications, as well as cardiovascular complications and KTx with graft function were recorded. Five patients who required redo surgery for recurrent or persistent HPT were calculated twice, because both operations were performed at our hospital within the study period. Thus, 196 operations in 191 patients were finally analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet at the time of surgery (group A) compared with 116 operations (59%) in patients not receiving cinacalcet (group B). A total of 156 patients (82%) were treated with phosphate binders, and 164 (86%) with 1,25 (OH)-vitamin D. After 2008, there was an increasing number of patients with cinacalcet treatment with a maximum in 2011 (Table 1). Table 1 Patients undergoing PTx with (group A) or without (group B) cinacalcet treatment in respective year. Year Group A Group B Total 2008 5 31 36 2009 8 25 33 2010 7 11 18 2011 24 15 39 2012 7 8 15 2013 11 16 27 2014 18 10 28 Our standard surgical procedure is a bilateral cervical exploration with subtotal PTx leaving a small nodular-free cervical remnant. A total PTx was performed only in patients with a high risk of recurrent HPT who were not listed for KTx. Cervical thymectomy was not routinely performed but carried out if less than four cervical glands were found. Neuromonitoring of the recurrent laryngeal nerve was routinely performed in all patients. In case of suspicious thyroid nodules or parathyroid glands with close relation to or inside the thyroid capsule, simultaneous thyroid surgery was done. In all patients, parathyroid tissue was cryopreserved. Postoperatively, all patients had daily controls of calcium, starting on the first postoperative day (POD). In case of persistently high iPTH levels directly after operation, consecutive controls were carried out. In case of missing glands, intraoperative iPTH was measured. Calcium substitution was instituted orally with 1000 mg/day immediately after PTx and adjusted to individual needs including additional intravenous substitution of calcium gluconate and changes in dialysate composition by our in-house nephrologists, as needed. All patients received 0.5 µg calcitriol twice daily with adjustment if needed. Patients were discharged if they were asymptomatic and as soon as the calcium level was stable (at least 1.9 mmol/L) or rising on two consecutive days. For measuring iPTH, an electrochemiluminescence immunoassay was performed by our laboratory (normal range: 15–65 ng/L). Calcium (normal range: 2.15–2.5 mmol/L), AP (35–105 U/L), creatinine (0.5–0.9 mg/dL), and phosphate (0.87–1.45 mmol/L) were measured routinely by our in-house nephrologists or referring dialysis centers later on. In order to define persistent or recurrent HPT, both elevated iPTH and calcium may be used. For this analysis, iPTH > 100 ng/L and/or calcium > 2.5 mmol/L were defined as persistent or recurrent hyperparathyroidism. All patients had an indirect laryngoscopy by an ear, nose, and throat specialist before and after the operation. In case of recurrent laryngeal nerve palsy, logopedic training was prescribed and patients were followed until vocal recovery in our outpatient clinic. Statistical Analysis Data were analyzed using the Statistica software 7.0 (StatSoft Inc., USA). All numerical results are presented as mean ± standard deviation (SD) independent from normal distribution. Categorial variables are presented as percentages. For testing normality of numerical variables, the Kolmogorov–Smirnov test (KS test) was used. Normally distributed data were tested with the unpaired t-test after comparing variances with the Levin test. For nonparametric variables with continuous distribution, the KS test was used for independent groups. Chi-square test with Yates’ correction was applied for nominal variables. Nonparametric data in dependent groups were analyzed with the Wilcoxon matched pairs test. Statistical significance was defined by p < 0.05. Results Demographic Data and Kidney Disease The study population consisted of 191 patients with 196 operations distributed to group A (80 cases, 41%) and group B (116 cases, 59%). The mean age was comparable in both groups (group A: 51.2 ± 13.3 vs group B: 51.5 ± 12.7 years), and the male/female ratio was 50% for group A, whereas group B consisted of more male patients (66%). Most patients had chronic kidney disease stage V (CKD V; 91% vs 84%, respectively) at the time of parathyroidectomy, an overview of underlying diseases is given in Table 2. Table 2 Underlying diseases leading to renal failure of patients with renal hyperparathyroidism. Number % Diabetic nephropathy 30 16 Σ = 71% Polycystic kidney disease 25 13 Chronic glomerulonephritis 20 10 Focal segmental glomerulosclerosis 16 8 Hypertensive nephropathy 15 8 IgA nephropathy 11 6 Interstitial nephritis 9 5 Membranoproliferative glomerulonephritis 10 5 Other 56 29 IgA: immunoglobulin A. A small number of patients had a functioning kidney graft at the time of parathyroidectomy (group A: 6% vs group B: 11%). Rarely, patients with CKD III and IV were operated in preparation of a living donor KTx (3% vs 5%). All patients were presented with comorbidities, including arterial hypertension, diabetes mellitus, adipositas, and coronary artery disease. Follow-up for patients with cinacalcet (group A, 39.7 ± 22.6 months) was significantly shorter compared with patients without cinacalcet (group B, 54.4 ± 25.3 months, p < 0.001, KS test). Kidney Transplantation Altogether 53% of the patients (n = 101) underwent KTx before or after PTx (25 patients lost to follow-up). At the end of the follow-up period, more patients were transplanted in both groups (54% vs 64%), but graft function varied between the groups. About 90 patients had no KTx during the study period (Table 3). Table 3 Clinical features of patients undergoing parathyroidectomy with (group A) or without cinacalcet (group B) including consecutive or prior kidney transplantation, type of parathyroidectomy, duration of surgery and hospital stay as well as complications and outcome. Cinacalcet (group A) n = 80 Without cinacalcet (group B) n = 116 No data Total Kidney transplantation 37 54 10 101  KTx before PTx 21 22 4 47  KTx after PTx 16 32 6 54 Type of operation  Subtotal PTx 49 89 – 138  Total PTx 21 19 – 40  Re-operation 10 8 – 18 Duration of surgery (minutes) 126 136 – – Hospital stay (days) 7 7 – – Complications  RLNP 2 (1 permanent) 3 – 5  Bleeding 0 2 – 2  30-day mortality 0 0 – 0 i.v. Calcium postoperatively 14 16 – 30 Death during follow-up 12 (52 alive) 14 (72 alive) 41 26 Recurrence of HPT 2 3 – 5 Persistence of HPT 1 3 – 4 HPT: hyperparathyroidism; RLNP: recurrent laryngeal nerve palsy; KTx: kidney transplantation; PTx: parathyreoidectomy. Note: Significance of bold values in the table was not calculated due to low numbers. Of the 47 patients undergoing PTx after KTx for tertiary hyperparathyroidism (tHPT), 15 (32%) were on dialysis (CKD V) in group A, while 6 patients (13%) had functioning grafts (creatinine: 1.23 ± 0.41 mg/dL) at the end of follow-up. In group B, 11 patients (23%) had CKD V and 11 (23%) presented with functioning grafts (creatinine: 1.91 ± 1.02 mg/dL), while 4 patients had unknown graft function. KTx was performed at a mean of 93.5 ± 83.1 months before PTx for both groups. In 54 patients with rHPT receiving their KTx after PTx, 42 had functioning grafts (group A: n = 13 (24%) vs group B: n = 29 (54%)), while six patients (11%) were back on dialysis (three patients in each group) and six had unknown graft function. Mean follow-up for these patients was 15.6 ± 10 months. Six patients received more than one KTx, with the PTx taking place after loss of function of the first kidney graft. Four of these were retransplanted after PTx and presented with good graft function. Creatinine levels in patients with tHPT (i.e. those with a functioning kidney transplant, defined as CKD I-III, n = 22) were analyzed before PTx and 1 year after operation. There were no significant differences neither in the whole group (p = 0.11), nor in the subgroups related to cinacalcet therapy (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet; Fig. 1). Fig. 1. Creatinine levels (mg/dL) in patients with kidney graft and good graft function at the time of PTx and at 1-year follow-up related to cinacalcet preoperatively (yes/no). There was no significant difference in creatinine levels for both groups (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet). Perioperative Data Operative technique A majority of 78% of all primary operations (138/178) underwent subtotal PTx (49 vs 89 cases in both groups, respectively). In 40 patients, a total PTx without autotransplantation was done. About 18 operations were performed for recurrent HPT (Table 3). In 86 cases (48%), concomitant thyroid surgery was carried out. Indications for thyroid surgery were solitary autonomous adenoma (n = 1), diffuse autonomy (n = 2), multinodular goiter (n = 56), suspicious thyroid nodules (n = 18), or a missing parathyroid gland (n = 12). In seven patients, a differentiated thyroid carcinoma was histologically confirmed. There was no difference in operative time between the groups (126 ± 44 min vs 136 ± 39 min with/without cinacalcet, p = 0.11, t-test). Length of in-hospital stay did not differ between the groups with a mean of 7.0 versus 7.1 days, respectively (p > 0.1, KS test). There is a trend toward shorter in-hospital stay in recent years, yet no significant difference could be seen (Table 3). Complications A total of five unilateral vocal cord palsies occurred (1.28% of 392 nerves at risk), two with and three without cinacalcet treatment. Four were temporary, while one patient after recurrent PTx revealed permanent unilateral vocal cord palsy. There were three reoperations for hematoma (n = 2) and infection (n = 1). One patient developed paroxysmal atrial fibrillation, but there was no perioperative mortality and all patients were discharged from hospital (Table 3). Perioperative laboratory values Preoperatively, calcium was significantly lower in group A (2.28 ± 0.23 mmol/L vs 2.41 ± 0.23 mmol/L, p = 0.0002, t-test), while neither postoperatively (1.89 ± 0.30 mmol/L vs 1.92 ± 0.30 mmol/L, p = 0.40, t-test) nor at discharge (2.12 ± 0.30 mmol/L vs 2.12 ± 0.27 mmol/L, p = 0.90, t-test) a statistically significant difference could be observed. Lowest calcium levels measured postoperatively were 1.91 ± 0.30 mmol/L for all patients. The lowest postoperative serum Ca levels were not significantly different between the groups, 1.89 ± 0.30 versus 1.92 ± 0.30 (p = 0.40, t-test). Altogether 30 patients received i.v. calcium postoperatively due to symptoms of hypocalcemia and/or calcium levels below 1.7 mmol/L (14 vs 16 patients). Preoperative iPTH levels were comparable between the groups (755 ± 657 ng/L vs 742 ± 545 ng/L, p > 0.10, KS test). In both groups, there was a significant drop on POD 1 with no difference between the groups (50 ± 124 ng/L vs 46 ± 83 ng/L, p > 0.10, KS test). More than 1/3 (36%) of the patients after KTx presented with good graft function at the moment of PTx. These patients showed no deterioration of creatinine levels at 1-year follow-up (1.42 mg/dL perioperatively vs 1.38 mg/dL after 1 year, p = 0.11, Wilcoxon test), and there was no difference between patients with or without cinacalcet preoperatively. 1-year surveillance data Calcium levels 1 year after PTx were not significantly different between the groups (2.26 ± 0.25 mmol/L vs 2.24 ± 0.25 mmol/L, p = 0.67, t-test). Regarding iPTH levels, no significant difference could be detected between patients with or without cinacalcet preoperatively (26.9 vs 42.1 ng/L, p > 0.1, KS test). Seven patients had extremely high iPTH (>2000 ng/L, n = 7) preoperatively, but none of these presented with persisting or recurrent hyperparathyroidism. Only two of these patients had been on cinacalcet before PTx. All of them had normalized iPTH at discharge. About 1 year after PTx, four of the patients presented with normal iPTH levels, for three of the patients iPTH was not available, but none of them was re-operated for HPT. Five of the patients had been transplanted before (n = 2) or after PTx (n = 3) and four presented with good graft function until the end of follow-up or death (n = 1). After 1 year, four patients were presented with iPTH > 100 ng/L and calcium > 2.5 mmol/L, while five patients only had elevated iPTH with normal calcium. Five of these patients had recurrent HPT (two with cinacalcet, group A) and four persisting HPT (one with cinacalcet, group A). Looking more closely at type of operation (subtotal PTx, total PTx, and recurrent PTx), there was no difference between postoperative iPTH and iPTH at 1 year. Patients with second PTx for recurrent or persisting HPT displayed a mean higher iPTH both postoperatively (45 ng/L) as well as at 1 year (92 ng/L). Patients with subtotal and total parathyroidectomy showed low levels of PTH both at discharge (11 and 8 ng/L) and at 1 year (8 and 7 ng/L). There was no significant difference between patients with or without cinacalcet. Overall mortality and morbidity Considering long-term follow-up, a considerable number of patients were lost to follow-up. There was no difference in mortality rate between the groups (p = 0.68, χ² test). At the end of follow-up, 12 of 77 patients in group A had died (16%), 52 (68%) were alive (no data in 16%, n = 13). In group B, 14 of 114 had died (12%), whereas 72 (63%) were alive (no data in 25%, n = 28). The prevalence of cardiovascular events was not significantly different between the groups. Myocardial infarction occured in 13% (group A) versus 18% of patients (group B), and the need for coronary artery intervention or bypass occurred in 13% versus 22% of patients in both groups, respectively. Also the need for peripheral revascularization (9% vs 12%) and stroke was recorded with a similar prevalence (13% vs 10%) in patients after PTx with or without cinacalcet. Discussion This single-center study in patients undergoing parathyroidectomy for rHPT shows excellent outcome independent of pretreatment with cinacalcet. Since the introduction of cinacalcet as treatment modality for rHPT, decreasing numbers of patients are being referred to parathyroidectomy (20). Nevertheless, no reduction of all-cause or cardiovascular mortality compared with surgery has been shown for patients with ESRD (4). A substantial part of these conservatively treated patients presents with persistently elevated iPTH, aggravation of complications, and consecutive referral to surgery (3). In our center, the number of patients referred to surgery was decreasing after the introduction of cinacalcet but is increasing again since 2012. Timing of PTx From our referring nephrology and transplant unit, a majority of patients on the waiting list for KTx is referred to parathyroidectomy, especially those with very high iPTH levels. This is due to the fact that only up to 56% of patients normalize PTH after KTx, mostly those with shorter waiting time on the transplant list (13). A total of 53% of our patients underwent KTx, either before or after PTx. In those patients undergoing PTx before KTx for rHPT, a majority of 78% presents with functioning grafts during follow-up. While it is clear that pHPT after KTx impairs long-term graft survival (17), optimal therapy still is under debate. An interesting report by Torregrosa et al. (21) has shown no decline in graft function 1 year after KTx for patients with rHPT that were treated with cinacalcet and also stable graft function for patients on cinacalcet during long-term follow-up. This was underlined by a meta-analysis by Cohen et al. (22) reporting that cinacalcet treatment for pHPT after KTx was not associated with inferior graft survival. In our study, 55% of patients undergoing PTx after KTx were on dialysis at the end of follow-up, mostly for graft failure before PTx. But those patients undergoing PTx with functioning kidney grafts did not show deterioration of creatinine levels postoperatively or during 1-year follow-up, irrespective of cinacalcet treatment. Interestingly, six of the patients underwent second or even third KTx after PTx and presented with functioning grafts during follow-up. In contrast, 78% of patients with PTx and consecutive KTx showed functioning grafts, irrespective of treatment with cinacalcet prior to surgery. Overall, these results favor parathyroidectomy before KTx, yet prospective trials will be necessary to evaluate optimal treatment for tHPT after KTx. Cardiovascular Morbidity Treatment with cinacalcet only showed limited effects on cardiovascular morbidity or mortality of patients with ESRD in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial (23), which evaluated patients on hemodialysis. Both a Cochrane analysis (4) and a meta-analysis by Palmer et al. (24) demonstrated that for patients with ESRD treatment with cinacalcet only reduced the risk for surgery without positively influencing all-cause or cardiovascular mortality. A smaller trial by Trombetti et al. (25) showed that PTx, on the contrary, is associated with both reduced morbidity and mortality of these patients. In this cohort, 19 months after PTx, mortality of patients with ESRD was less than without PTx. In our study, morbidity and mortality during follow-up were not different between patients with or without cinacalcet treatment before surgery. Both small sample size and patients lost to follow-up reduce the statistic power of our cohort. Laboratory Values Overall, we could see no significant differences in laboratory values perioperatively between the groups, only preoperative calcium levels were significantly lower in patients with cinacalcet. At 1 year after surgery, no difference could be detected in iPTH between the groups. A study by Somnay et al. (26) focused on patients with tHPT and the effect of cinacalcet treatment on perioperative findings and outcome. Although they presented a small patient cohort with cinacalcet treatment, they interestingly had higher iPTH levels preoperatively in this cohort, while cure rate was not influenced by cinacalcet pretreatment. Compared with our analysis, patients without cinacalcet treatment had much lower preoperative iPTH levels in this study, possibly reflecting lower thresholds for PTx after KTx. Only seven patients with tHPT in our study received cinacalcet treatment with similar preoperative iPTH levels, as patients with rHPT. A very recent study by Baker et al. (27) examined influence of cinacalcet on outcome in patients with rHPT and found greater iPTH levels in the untreated group before surgery with similar outcome. Only the study of Wirowski et al. (28) demonstrated comparable laboratory findings in patients operated for rHPT. In their analysis, pre- and postoperative iPTH levels were equal in patients with or without cinacalcet and calcium was significantly lower in cinacalcet patients. This is in line with our findings, and they also concluded that cinacalcet did not alter perioperative course. Looking more closely on recurrent, or persisting rHPT, only four patients were diagnosed during follow-up with both elevated iPTH and hypercalcemia, while five were normocalcemic with elevated iPTH. For this analysis, relatively strict values were applied as cut-off values for recurrent HPT. When increasing the cut-off values for iPTH, only two patients of the cohort would have been identified with recurrence of HPT. There was no significant difference in iPTH levels at 1 year between subtotal or total parathyroidectomy and also no difference related to cinacalcet treatment preoperatively. So overall, surgical technique with mostly subtotal PTx in our cohort showed good results and low rates of recurrent or persisting rHPT, independent of preoperative treatment with cinacalcet. Several groups have shown that subtotal PTx or total PTx with autotransplantation of parathyroid tissue represent a good compromise between effective treatment of rHPT while avoiding unnecessary complications of hypocalcemia, adynamic bone disease, or reoperations (29). Complications Overall, the rate of surgical complications was low in both groups and no difference could be calculated for patients with or without cinacalcet treatment. There was no perioperative mortality in our group. Duration of surgery and hospital stay did not differ between the groups, and hospital-stay was reduced during the study period but similar in both groups. Conclusion Our study underlines the fact that PTx represents a safe and successful treatment option for patients with rHPT, even after KTx and irrespective of co-medication with cinacalcet. In view of the morbidity and mortality of long-term dialysis, patients will need individualized decisions taken by interdisciplinary transplant and tumor boards. Surgery should at least be offered to patients not responding to cinacalcet treatment and especially to those planned for KTx. This not only should reduce complications of pHPT but also improve patient morbidity in view of a successful KTx. Authors thank Prof. Dr. med. Peter E Goretzki for discussion and critical review of the manuscript. Author Contributions: M.T.M., T.S., N.R. contributed to the study conception and design, analysis, and interpretation of data and writing of the manuscript. N.M.O., E.T., C.B. participated in the acquisition and analysis of data. P.R., N.R., J.P. contributed to the analysis and interpretation of data, the study conception, and critical review of the manuscript. Compliance with Ethical Standards: This is a retrospective non-interventional study. All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical Approval: Ethical approval was given by the local ethics committee (EA4/086/19) Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD: M. T. Mogl https://orcid.org/0000-0002-3676-047X

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2021-03

What was the dosage of drug 'CALCIUM GLUCONATE'?

Surgery for Renal Hyperparathyroidism in the Era of Cinacalcet: A Single-Center Experience. There are only few data on the influence of cinacalcet on the outcome of parathyroidectomy in patients with renal hyperparathyroidism. Indication and timing of surgery have changed since its introduction, especially with regard to kidney transplantation. Therefore, we retrospectively analyzed patients undergoing parathyroidectomy for renal hyperparathyroidism in our institution. Between 2008 and 2015, 196 consecutive operations in 191 patients were analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet compared with 116 operations (59%) in patients without cinacalcet. Clinical data, preoperative medication, pre- and postoperative laboratory values, type and details of surgery including complications, as well as cardiovascular complications and kidney transplantation with graft function were recorded. Demographical data were similar in patients with or without cinacalcet treatment. A total of 54% of patients received a kidney graft before or after parathyroidectomy. Pre- and postoperative parathormone levels were similar in both groups (preoperatively 755 vs 742 ng/L, postoperatively 50 vs 46 ng/L, p > 0.10), whereas patients with cinacalcet showed significantly lower calcium levels preoperatively (2.28 vs 2.41 mmol/L, p = 0.0002). There was no difference in recurrence or persistence of hyperparathyroidism, duration of surgery, hospital stay, or complication rate. Creatinine levels in patients with tertiary hyperparathyroidism were similar after 1-year follow-up. Cinacalcet did not influence outcome of patients with parathyroidectomy for renal hyperparathyroidism and can be safely offered to patients not responding to medical treatment. Introduction Since the introduction of cinacalcet in the treatment of renal hyperparathyroidism (rHPT) in 2004, clinical practice for indication and timing of surgery has changed following the Kidney Disease Improving Global Outcomes (KDIGO) International guideline group (1). Overall, the number of parathyroidectomies (PTxs) has declined (2) and the timepoint of surgery is delayed in patients with end-stage renal disease (ESRD) developing rHPT (3). But especially the long-term benefit of cinacalcet on patient morbidity and mortality has not been shown so far (4). In addition, the cost-effectiveness of surgery is better than that of cinacalcet treatment after 7.25 months of therapy (5), and cinacalcet is only cost-effective in patients not eligible for surgery or receiving a kidney-graft beforehand (6). On the contrary, a large cohort study showed a rather high 30-day morbidity and mortality (7) as well as an increased morbidity and rehospitalization rate in the first year for patients after PTx not receiving a kidney graft (8). Yet, the overall risk of death for dialysis patients is lower after PTx compared with patients with medical therapy alone (9), and PTx shows a trend in improving cardiovascular morbidity and mortality (10). In 2015, Messa (11) highlighted the need for additional randomized controlled trials comparing conservative and surgical therapy. Another question of concern is the timing of surgery in relation to kidney transplantation (KTx). It is known that in more than 40% of patients, rHPT persists after KTx (12) and that especially long duration of dialysis prior to KTx negatively influences spontaneous normalization. Studies have shown that parathyroidectomy after KTx has no negative influence on overall graft survival (13), although a temporary decrease in glomerular filtration rate (GFR) was confirmed (14). On the contrary, a retrospective analysis reported that PTx before KTx was associated with a lower risk of graft failure (15). A very recent study documented that persistent hyperparathyroidism (pHPT) more than 1 year after KTx is a risk factor for graft failure (16). In addition, cinacalcet treatment in patients receiving a kidney graft was a risk factor for delayed graft function experimentally and in a single cohort study (17). While in Germany cinacalcet cannot usually be prescribed for patients after KTx, it has been shown that its use after KTx corrects hypercalciuria and hyperparathyroidism (HPT) (18). In 2015, a randomized study concluded that patients with persistent HPT at 6 months after KTx should undergo PTx for normalization of parathyroid hormone (PTH) because of beneficial effects on bone mineral density compared with continuing cinacalcet therapy (19). So far, there are only few data on the influence of cinacalcet on the short- and long-term outcome of parathyroidectomy in patients with rHPT. Therefore, we retrospectively analyzed all patients undergoing parathyroidectomy for rHPT from the introduction of cinacalcet into clinical practice up to 2015. Material and Methods Study Population All patients undergoing parathyroidectomy for rHPT are prospectively collected in our database and were retrospectively analyzed. Between January 2004 and December 2007, only six patients had been treated with cinacalcet and were not considered for this retrospective analysis. From January 2008 until January 2015, 191 consecutive patients were included. All patients were followed until 1 May 2015 or death or loss of follow-up with a mean follow-up of 48.35 ± 25.2 months. Data were collected from medical charts including standard demographical data and from the kidney transplant database of our institution/European transplantation database (T-base) as well as from referring physicians, especially dialysis centers. Data concerning duration of dialysis, type of kidney disease, preoperative medication, pre- and postoperative laboratory values (calcium, intact para-thyroid hormone (iPTH), phosphate, creatinine, alkaline phosphatase (AP)), type and details of surgery including complications, as well as cardiovascular complications and KTx with graft function were recorded. Five patients who required redo surgery for recurrent or persistent HPT were calculated twice, because both operations were performed at our hospital within the study period. Thus, 196 operations in 191 patients were finally analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet at the time of surgery (group A) compared with 116 operations (59%) in patients not receiving cinacalcet (group B). A total of 156 patients (82%) were treated with phosphate binders, and 164 (86%) with 1,25 (OH)-vitamin D. After 2008, there was an increasing number of patients with cinacalcet treatment with a maximum in 2011 (Table 1). Table 1 Patients undergoing PTx with (group A) or without (group B) cinacalcet treatment in respective year. Year Group A Group B Total 2008 5 31 36 2009 8 25 33 2010 7 11 18 2011 24 15 39 2012 7 8 15 2013 11 16 27 2014 18 10 28 Our standard surgical procedure is a bilateral cervical exploration with subtotal PTx leaving a small nodular-free cervical remnant. A total PTx was performed only in patients with a high risk of recurrent HPT who were not listed for KTx. Cervical thymectomy was not routinely performed but carried out if less than four cervical glands were found. Neuromonitoring of the recurrent laryngeal nerve was routinely performed in all patients. In case of suspicious thyroid nodules or parathyroid glands with close relation to or inside the thyroid capsule, simultaneous thyroid surgery was done. In all patients, parathyroid tissue was cryopreserved. Postoperatively, all patients had daily controls of calcium, starting on the first postoperative day (POD). In case of persistently high iPTH levels directly after operation, consecutive controls were carried out. In case of missing glands, intraoperative iPTH was measured. Calcium substitution was instituted orally with 1000 mg/day immediately after PTx and adjusted to individual needs including additional intravenous substitution of calcium gluconate and changes in dialysate composition by our in-house nephrologists, as needed. All patients received 0.5 µg calcitriol twice daily with adjustment if needed. Patients were discharged if they were asymptomatic and as soon as the calcium level was stable (at least 1.9 mmol/L) or rising on two consecutive days. For measuring iPTH, an electrochemiluminescence immunoassay was performed by our laboratory (normal range: 15–65 ng/L). Calcium (normal range: 2.15–2.5 mmol/L), AP (35–105 U/L), creatinine (0.5–0.9 mg/dL), and phosphate (0.87–1.45 mmol/L) were measured routinely by our in-house nephrologists or referring dialysis centers later on. In order to define persistent or recurrent HPT, both elevated iPTH and calcium may be used. For this analysis, iPTH > 100 ng/L and/or calcium > 2.5 mmol/L were defined as persistent or recurrent hyperparathyroidism. All patients had an indirect laryngoscopy by an ear, nose, and throat specialist before and after the operation. In case of recurrent laryngeal nerve palsy, logopedic training was prescribed and patients were followed until vocal recovery in our outpatient clinic. Statistical Analysis Data were analyzed using the Statistica software 7.0 (StatSoft Inc., USA). All numerical results are presented as mean ± standard deviation (SD) independent from normal distribution. Categorial variables are presented as percentages. For testing normality of numerical variables, the Kolmogorov–Smirnov test (KS test) was used. Normally distributed data were tested with the unpaired t-test after comparing variances with the Levin test. For nonparametric variables with continuous distribution, the KS test was used for independent groups. Chi-square test with Yates’ correction was applied for nominal variables. Nonparametric data in dependent groups were analyzed with the Wilcoxon matched pairs test. Statistical significance was defined by p < 0.05. Results Demographic Data and Kidney Disease The study population consisted of 191 patients with 196 operations distributed to group A (80 cases, 41%) and group B (116 cases, 59%). The mean age was comparable in both groups (group A: 51.2 ± 13.3 vs group B: 51.5 ± 12.7 years), and the male/female ratio was 50% for group A, whereas group B consisted of more male patients (66%). Most patients had chronic kidney disease stage V (CKD V; 91% vs 84%, respectively) at the time of parathyroidectomy, an overview of underlying diseases is given in Table 2. Table 2 Underlying diseases leading to renal failure of patients with renal hyperparathyroidism. Number % Diabetic nephropathy 30 16 Σ = 71% Polycystic kidney disease 25 13 Chronic glomerulonephritis 20 10 Focal segmental glomerulosclerosis 16 8 Hypertensive nephropathy 15 8 IgA nephropathy 11 6 Interstitial nephritis 9 5 Membranoproliferative glomerulonephritis 10 5 Other 56 29 IgA: immunoglobulin A. A small number of patients had a functioning kidney graft at the time of parathyroidectomy (group A: 6% vs group B: 11%). Rarely, patients with CKD III and IV were operated in preparation of a living donor KTx (3% vs 5%). All patients were presented with comorbidities, including arterial hypertension, diabetes mellitus, adipositas, and coronary artery disease. Follow-up for patients with cinacalcet (group A, 39.7 ± 22.6 months) was significantly shorter compared with patients without cinacalcet (group B, 54.4 ± 25.3 months, p < 0.001, KS test). Kidney Transplantation Altogether 53% of the patients (n = 101) underwent KTx before or after PTx (25 patients lost to follow-up). At the end of the follow-up period, more patients were transplanted in both groups (54% vs 64%), but graft function varied between the groups. About 90 patients had no KTx during the study period (Table 3). Table 3 Clinical features of patients undergoing parathyroidectomy with (group A) or without cinacalcet (group B) including consecutive or prior kidney transplantation, type of parathyroidectomy, duration of surgery and hospital stay as well as complications and outcome. Cinacalcet (group A) n = 80 Without cinacalcet (group B) n = 116 No data Total Kidney transplantation 37 54 10 101  KTx before PTx 21 22 4 47  KTx after PTx 16 32 6 54 Type of operation  Subtotal PTx 49 89 – 138  Total PTx 21 19 – 40  Re-operation 10 8 – 18 Duration of surgery (minutes) 126 136 – – Hospital stay (days) 7 7 – – Complications  RLNP 2 (1 permanent) 3 – 5  Bleeding 0 2 – 2  30-day mortality 0 0 – 0 i.v. Calcium postoperatively 14 16 – 30 Death during follow-up 12 (52 alive) 14 (72 alive) 41 26 Recurrence of HPT 2 3 – 5 Persistence of HPT 1 3 – 4 HPT: hyperparathyroidism; RLNP: recurrent laryngeal nerve palsy; KTx: kidney transplantation; PTx: parathyreoidectomy. Note: Significance of bold values in the table was not calculated due to low numbers. Of the 47 patients undergoing PTx after KTx for tertiary hyperparathyroidism (tHPT), 15 (32%) were on dialysis (CKD V) in group A, while 6 patients (13%) had functioning grafts (creatinine: 1.23 ± 0.41 mg/dL) at the end of follow-up. In group B, 11 patients (23%) had CKD V and 11 (23%) presented with functioning grafts (creatinine: 1.91 ± 1.02 mg/dL), while 4 patients had unknown graft function. KTx was performed at a mean of 93.5 ± 83.1 months before PTx for both groups. In 54 patients with rHPT receiving their KTx after PTx, 42 had functioning grafts (group A: n = 13 (24%) vs group B: n = 29 (54%)), while six patients (11%) were back on dialysis (three patients in each group) and six had unknown graft function. Mean follow-up for these patients was 15.6 ± 10 months. Six patients received more than one KTx, with the PTx taking place after loss of function of the first kidney graft. Four of these were retransplanted after PTx and presented with good graft function. Creatinine levels in patients with tHPT (i.e. those with a functioning kidney transplant, defined as CKD I-III, n = 22) were analyzed before PTx and 1 year after operation. There were no significant differences neither in the whole group (p = 0.11), nor in the subgroups related to cinacalcet therapy (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet; Fig. 1). Fig. 1. Creatinine levels (mg/dL) in patients with kidney graft and good graft function at the time of PTx and at 1-year follow-up related to cinacalcet preoperatively (yes/no). There was no significant difference in creatinine levels for both groups (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet). Perioperative Data Operative technique A majority of 78% of all primary operations (138/178) underwent subtotal PTx (49 vs 89 cases in both groups, respectively). In 40 patients, a total PTx without autotransplantation was done. About 18 operations were performed for recurrent HPT (Table 3). In 86 cases (48%), concomitant thyroid surgery was carried out. Indications for thyroid surgery were solitary autonomous adenoma (n = 1), diffuse autonomy (n = 2), multinodular goiter (n = 56), suspicious thyroid nodules (n = 18), or a missing parathyroid gland (n = 12). In seven patients, a differentiated thyroid carcinoma was histologically confirmed. There was no difference in operative time between the groups (126 ± 44 min vs 136 ± 39 min with/without cinacalcet, p = 0.11, t-test). Length of in-hospital stay did not differ between the groups with a mean of 7.0 versus 7.1 days, respectively (p > 0.1, KS test). There is a trend toward shorter in-hospital stay in recent years, yet no significant difference could be seen (Table 3). Complications A total of five unilateral vocal cord palsies occurred (1.28% of 392 nerves at risk), two with and three without cinacalcet treatment. Four were temporary, while one patient after recurrent PTx revealed permanent unilateral vocal cord palsy. There were three reoperations for hematoma (n = 2) and infection (n = 1). One patient developed paroxysmal atrial fibrillation, but there was no perioperative mortality and all patients were discharged from hospital (Table 3). Perioperative laboratory values Preoperatively, calcium was significantly lower in group A (2.28 ± 0.23 mmol/L vs 2.41 ± 0.23 mmol/L, p = 0.0002, t-test), while neither postoperatively (1.89 ± 0.30 mmol/L vs 1.92 ± 0.30 mmol/L, p = 0.40, t-test) nor at discharge (2.12 ± 0.30 mmol/L vs 2.12 ± 0.27 mmol/L, p = 0.90, t-test) a statistically significant difference could be observed. Lowest calcium levels measured postoperatively were 1.91 ± 0.30 mmol/L for all patients. The lowest postoperative serum Ca levels were not significantly different between the groups, 1.89 ± 0.30 versus 1.92 ± 0.30 (p = 0.40, t-test). Altogether 30 patients received i.v. calcium postoperatively due to symptoms of hypocalcemia and/or calcium levels below 1.7 mmol/L (14 vs 16 patients). Preoperative iPTH levels were comparable between the groups (755 ± 657 ng/L vs 742 ± 545 ng/L, p > 0.10, KS test). In both groups, there was a significant drop on POD 1 with no difference between the groups (50 ± 124 ng/L vs 46 ± 83 ng/L, p > 0.10, KS test). More than 1/3 (36%) of the patients after KTx presented with good graft function at the moment of PTx. These patients showed no deterioration of creatinine levels at 1-year follow-up (1.42 mg/dL perioperatively vs 1.38 mg/dL after 1 year, p = 0.11, Wilcoxon test), and there was no difference between patients with or without cinacalcet preoperatively. 1-year surveillance data Calcium levels 1 year after PTx were not significantly different between the groups (2.26 ± 0.25 mmol/L vs 2.24 ± 0.25 mmol/L, p = 0.67, t-test). Regarding iPTH levels, no significant difference could be detected between patients with or without cinacalcet preoperatively (26.9 vs 42.1 ng/L, p > 0.1, KS test). Seven patients had extremely high iPTH (>2000 ng/L, n = 7) preoperatively, but none of these presented with persisting or recurrent hyperparathyroidism. Only two of these patients had been on cinacalcet before PTx. All of them had normalized iPTH at discharge. About 1 year after PTx, four of the patients presented with normal iPTH levels, for three of the patients iPTH was not available, but none of them was re-operated for HPT. Five of the patients had been transplanted before (n = 2) or after PTx (n = 3) and four presented with good graft function until the end of follow-up or death (n = 1). After 1 year, four patients were presented with iPTH > 100 ng/L and calcium > 2.5 mmol/L, while five patients only had elevated iPTH with normal calcium. Five of these patients had recurrent HPT (two with cinacalcet, group A) and four persisting HPT (one with cinacalcet, group A). Looking more closely at type of operation (subtotal PTx, total PTx, and recurrent PTx), there was no difference between postoperative iPTH and iPTH at 1 year. Patients with second PTx for recurrent or persisting HPT displayed a mean higher iPTH both postoperatively (45 ng/L) as well as at 1 year (92 ng/L). Patients with subtotal and total parathyroidectomy showed low levels of PTH both at discharge (11 and 8 ng/L) and at 1 year (8 and 7 ng/L). There was no significant difference between patients with or without cinacalcet. Overall mortality and morbidity Considering long-term follow-up, a considerable number of patients were lost to follow-up. There was no difference in mortality rate between the groups (p = 0.68, χ² test). At the end of follow-up, 12 of 77 patients in group A had died (16%), 52 (68%) were alive (no data in 16%, n = 13). In group B, 14 of 114 had died (12%), whereas 72 (63%) were alive (no data in 25%, n = 28). The prevalence of cardiovascular events was not significantly different between the groups. Myocardial infarction occured in 13% (group A) versus 18% of patients (group B), and the need for coronary artery intervention or bypass occurred in 13% versus 22% of patients in both groups, respectively. Also the need for peripheral revascularization (9% vs 12%) and stroke was recorded with a similar prevalence (13% vs 10%) in patients after PTx with or without cinacalcet. Discussion This single-center study in patients undergoing parathyroidectomy for rHPT shows excellent outcome independent of pretreatment with cinacalcet. Since the introduction of cinacalcet as treatment modality for rHPT, decreasing numbers of patients are being referred to parathyroidectomy (20). Nevertheless, no reduction of all-cause or cardiovascular mortality compared with surgery has been shown for patients with ESRD (4). A substantial part of these conservatively treated patients presents with persistently elevated iPTH, aggravation of complications, and consecutive referral to surgery (3). In our center, the number of patients referred to surgery was decreasing after the introduction of cinacalcet but is increasing again since 2012. Timing of PTx From our referring nephrology and transplant unit, a majority of patients on the waiting list for KTx is referred to parathyroidectomy, especially those with very high iPTH levels. This is due to the fact that only up to 56% of patients normalize PTH after KTx, mostly those with shorter waiting time on the transplant list (13). A total of 53% of our patients underwent KTx, either before or after PTx. In those patients undergoing PTx before KTx for rHPT, a majority of 78% presents with functioning grafts during follow-up. While it is clear that pHPT after KTx impairs long-term graft survival (17), optimal therapy still is under debate. An interesting report by Torregrosa et al. (21) has shown no decline in graft function 1 year after KTx for patients with rHPT that were treated with cinacalcet and also stable graft function for patients on cinacalcet during long-term follow-up. This was underlined by a meta-analysis by Cohen et al. (22) reporting that cinacalcet treatment for pHPT after KTx was not associated with inferior graft survival. In our study, 55% of patients undergoing PTx after KTx were on dialysis at the end of follow-up, mostly for graft failure before PTx. But those patients undergoing PTx with functioning kidney grafts did not show deterioration of creatinine levels postoperatively or during 1-year follow-up, irrespective of cinacalcet treatment. Interestingly, six of the patients underwent second or even third KTx after PTx and presented with functioning grafts during follow-up. In contrast, 78% of patients with PTx and consecutive KTx showed functioning grafts, irrespective of treatment with cinacalcet prior to surgery. Overall, these results favor parathyroidectomy before KTx, yet prospective trials will be necessary to evaluate optimal treatment for tHPT after KTx. Cardiovascular Morbidity Treatment with cinacalcet only showed limited effects on cardiovascular morbidity or mortality of patients with ESRD in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial (23), which evaluated patients on hemodialysis. Both a Cochrane analysis (4) and a meta-analysis by Palmer et al. (24) demonstrated that for patients with ESRD treatment with cinacalcet only reduced the risk for surgery without positively influencing all-cause or cardiovascular mortality. A smaller trial by Trombetti et al. (25) showed that PTx, on the contrary, is associated with both reduced morbidity and mortality of these patients. In this cohort, 19 months after PTx, mortality of patients with ESRD was less than without PTx. In our study, morbidity and mortality during follow-up were not different between patients with or without cinacalcet treatment before surgery. Both small sample size and patients lost to follow-up reduce the statistic power of our cohort. Laboratory Values Overall, we could see no significant differences in laboratory values perioperatively between the groups, only preoperative calcium levels were significantly lower in patients with cinacalcet. At 1 year after surgery, no difference could be detected in iPTH between the groups. A study by Somnay et al. (26) focused on patients with tHPT and the effect of cinacalcet treatment on perioperative findings and outcome. Although they presented a small patient cohort with cinacalcet treatment, they interestingly had higher iPTH levels preoperatively in this cohort, while cure rate was not influenced by cinacalcet pretreatment. Compared with our analysis, patients without cinacalcet treatment had much lower preoperative iPTH levels in this study, possibly reflecting lower thresholds for PTx after KTx. Only seven patients with tHPT in our study received cinacalcet treatment with similar preoperative iPTH levels, as patients with rHPT. A very recent study by Baker et al. (27) examined influence of cinacalcet on outcome in patients with rHPT and found greater iPTH levels in the untreated group before surgery with similar outcome. Only the study of Wirowski et al. (28) demonstrated comparable laboratory findings in patients operated for rHPT. In their analysis, pre- and postoperative iPTH levels were equal in patients with or without cinacalcet and calcium was significantly lower in cinacalcet patients. This is in line with our findings, and they also concluded that cinacalcet did not alter perioperative course. Looking more closely on recurrent, or persisting rHPT, only four patients were diagnosed during follow-up with both elevated iPTH and hypercalcemia, while five were normocalcemic with elevated iPTH. For this analysis, relatively strict values were applied as cut-off values for recurrent HPT. When increasing the cut-off values for iPTH, only two patients of the cohort would have been identified with recurrence of HPT. There was no significant difference in iPTH levels at 1 year between subtotal or total parathyroidectomy and also no difference related to cinacalcet treatment preoperatively. So overall, surgical technique with mostly subtotal PTx in our cohort showed good results and low rates of recurrent or persisting rHPT, independent of preoperative treatment with cinacalcet. Several groups have shown that subtotal PTx or total PTx with autotransplantation of parathyroid tissue represent a good compromise between effective treatment of rHPT while avoiding unnecessary complications of hypocalcemia, adynamic bone disease, or reoperations (29). Complications Overall, the rate of surgical complications was low in both groups and no difference could be calculated for patients with or without cinacalcet treatment. There was no perioperative mortality in our group. Duration of surgery and hospital stay did not differ between the groups, and hospital-stay was reduced during the study period but similar in both groups. Conclusion Our study underlines the fact that PTx represents a safe and successful treatment option for patients with rHPT, even after KTx and irrespective of co-medication with cinacalcet. In view of the morbidity and mortality of long-term dialysis, patients will need individualized decisions taken by interdisciplinary transplant and tumor boards. Surgery should at least be offered to patients not responding to cinacalcet treatment and especially to those planned for KTx. This not only should reduce complications of pHPT but also improve patient morbidity in view of a successful KTx. Authors thank Prof. Dr. med. Peter E Goretzki for discussion and critical review of the manuscript. Author Contributions: M.T.M., T.S., N.R. contributed to the study conception and design, analysis, and interpretation of data and writing of the manuscript. N.M.O., E.T., C.B. participated in the acquisition and analysis of data. P.R., N.R., J.P. contributed to the analysis and interpretation of data, the study conception, and critical review of the manuscript. Compliance with Ethical Standards: This is a retrospective non-interventional study. All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical Approval: Ethical approval was given by the local ethics committee (EA4/086/19) Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD: M. T. Mogl https://orcid.org/0000-0002-3676-047X

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31906794

2021-03

What was the outcome of reaction 'Death'?

Surgery for Renal Hyperparathyroidism in the Era of Cinacalcet: A Single-Center Experience. There are only few data on the influence of cinacalcet on the outcome of parathyroidectomy in patients with renal hyperparathyroidism. Indication and timing of surgery have changed since its introduction, especially with regard to kidney transplantation. Therefore, we retrospectively analyzed patients undergoing parathyroidectomy for renal hyperparathyroidism in our institution. Between 2008 and 2015, 196 consecutive operations in 191 patients were analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet compared with 116 operations (59%) in patients without cinacalcet. Clinical data, preoperative medication, pre- and postoperative laboratory values, type and details of surgery including complications, as well as cardiovascular complications and kidney transplantation with graft function were recorded. Demographical data were similar in patients with or without cinacalcet treatment. A total of 54% of patients received a kidney graft before or after parathyroidectomy. Pre- and postoperative parathormone levels were similar in both groups (preoperatively 755 vs 742 ng/L, postoperatively 50 vs 46 ng/L, p > 0.10), whereas patients with cinacalcet showed significantly lower calcium levels preoperatively (2.28 vs 2.41 mmol/L, p = 0.0002). There was no difference in recurrence or persistence of hyperparathyroidism, duration of surgery, hospital stay, or complication rate. Creatinine levels in patients with tertiary hyperparathyroidism were similar after 1-year follow-up. Cinacalcet did not influence outcome of patients with parathyroidectomy for renal hyperparathyroidism and can be safely offered to patients not responding to medical treatment. Introduction Since the introduction of cinacalcet in the treatment of renal hyperparathyroidism (rHPT) in 2004, clinical practice for indication and timing of surgery has changed following the Kidney Disease Improving Global Outcomes (KDIGO) International guideline group (1). Overall, the number of parathyroidectomies (PTxs) has declined (2) and the timepoint of surgery is delayed in patients with end-stage renal disease (ESRD) developing rHPT (3). But especially the long-term benefit of cinacalcet on patient morbidity and mortality has not been shown so far (4). In addition, the cost-effectiveness of surgery is better than that of cinacalcet treatment after 7.25 months of therapy (5), and cinacalcet is only cost-effective in patients not eligible for surgery or receiving a kidney-graft beforehand (6). On the contrary, a large cohort study showed a rather high 30-day morbidity and mortality (7) as well as an increased morbidity and rehospitalization rate in the first year for patients after PTx not receiving a kidney graft (8). Yet, the overall risk of death for dialysis patients is lower after PTx compared with patients with medical therapy alone (9), and PTx shows a trend in improving cardiovascular morbidity and mortality (10). In 2015, Messa (11) highlighted the need for additional randomized controlled trials comparing conservative and surgical therapy. Another question of concern is the timing of surgery in relation to kidney transplantation (KTx). It is known that in more than 40% of patients, rHPT persists after KTx (12) and that especially long duration of dialysis prior to KTx negatively influences spontaneous normalization. Studies have shown that parathyroidectomy after KTx has no negative influence on overall graft survival (13), although a temporary decrease in glomerular filtration rate (GFR) was confirmed (14). On the contrary, a retrospective analysis reported that PTx before KTx was associated with a lower risk of graft failure (15). A very recent study documented that persistent hyperparathyroidism (pHPT) more than 1 year after KTx is a risk factor for graft failure (16). In addition, cinacalcet treatment in patients receiving a kidney graft was a risk factor for delayed graft function experimentally and in a single cohort study (17). While in Germany cinacalcet cannot usually be prescribed for patients after KTx, it has been shown that its use after KTx corrects hypercalciuria and hyperparathyroidism (HPT) (18). In 2015, a randomized study concluded that patients with persistent HPT at 6 months after KTx should undergo PTx for normalization of parathyroid hormone (PTH) because of beneficial effects on bone mineral density compared with continuing cinacalcet therapy (19). So far, there are only few data on the influence of cinacalcet on the short- and long-term outcome of parathyroidectomy in patients with rHPT. Therefore, we retrospectively analyzed all patients undergoing parathyroidectomy for rHPT from the introduction of cinacalcet into clinical practice up to 2015. Material and Methods Study Population All patients undergoing parathyroidectomy for rHPT are prospectively collected in our database and were retrospectively analyzed. Between January 2004 and December 2007, only six patients had been treated with cinacalcet and were not considered for this retrospective analysis. From January 2008 until January 2015, 191 consecutive patients were included. All patients were followed until 1 May 2015 or death or loss of follow-up with a mean follow-up of 48.35 ± 25.2 months. Data were collected from medical charts including standard demographical data and from the kidney transplant database of our institution/European transplantation database (T-base) as well as from referring physicians, especially dialysis centers. Data concerning duration of dialysis, type of kidney disease, preoperative medication, pre- and postoperative laboratory values (calcium, intact para-thyroid hormone (iPTH), phosphate, creatinine, alkaline phosphatase (AP)), type and details of surgery including complications, as well as cardiovascular complications and KTx with graft function were recorded. Five patients who required redo surgery for recurrent or persistent HPT were calculated twice, because both operations were performed at our hospital within the study period. Thus, 196 operations in 191 patients were finally analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet at the time of surgery (group A) compared with 116 operations (59%) in patients not receiving cinacalcet (group B). A total of 156 patients (82%) were treated with phosphate binders, and 164 (86%) with 1,25 (OH)-vitamin D. After 2008, there was an increasing number of patients with cinacalcet treatment with a maximum in 2011 (Table 1). Table 1 Patients undergoing PTx with (group A) or without (group B) cinacalcet treatment in respective year. Year Group A Group B Total 2008 5 31 36 2009 8 25 33 2010 7 11 18 2011 24 15 39 2012 7 8 15 2013 11 16 27 2014 18 10 28 Our standard surgical procedure is a bilateral cervical exploration with subtotal PTx leaving a small nodular-free cervical remnant. A total PTx was performed only in patients with a high risk of recurrent HPT who were not listed for KTx. Cervical thymectomy was not routinely performed but carried out if less than four cervical glands were found. Neuromonitoring of the recurrent laryngeal nerve was routinely performed in all patients. In case of suspicious thyroid nodules or parathyroid glands with close relation to or inside the thyroid capsule, simultaneous thyroid surgery was done. In all patients, parathyroid tissue was cryopreserved. Postoperatively, all patients had daily controls of calcium, starting on the first postoperative day (POD). In case of persistently high iPTH levels directly after operation, consecutive controls were carried out. In case of missing glands, intraoperative iPTH was measured. Calcium substitution was instituted orally with 1000 mg/day immediately after PTx and adjusted to individual needs including additional intravenous substitution of calcium gluconate and changes in dialysate composition by our in-house nephrologists, as needed. All patients received 0.5 µg calcitriol twice daily with adjustment if needed. Patients were discharged if they were asymptomatic and as soon as the calcium level was stable (at least 1.9 mmol/L) or rising on two consecutive days. For measuring iPTH, an electrochemiluminescence immunoassay was performed by our laboratory (normal range: 15–65 ng/L). Calcium (normal range: 2.15–2.5 mmol/L), AP (35–105 U/L), creatinine (0.5–0.9 mg/dL), and phosphate (0.87–1.45 mmol/L) were measured routinely by our in-house nephrologists or referring dialysis centers later on. In order to define persistent or recurrent HPT, both elevated iPTH and calcium may be used. For this analysis, iPTH > 100 ng/L and/or calcium > 2.5 mmol/L were defined as persistent or recurrent hyperparathyroidism. All patients had an indirect laryngoscopy by an ear, nose, and throat specialist before and after the operation. In case of recurrent laryngeal nerve palsy, logopedic training was prescribed and patients were followed until vocal recovery in our outpatient clinic. Statistical Analysis Data were analyzed using the Statistica software 7.0 (StatSoft Inc., USA). All numerical results are presented as mean ± standard deviation (SD) independent from normal distribution. Categorial variables are presented as percentages. For testing normality of numerical variables, the Kolmogorov–Smirnov test (KS test) was used. Normally distributed data were tested with the unpaired t-test after comparing variances with the Levin test. For nonparametric variables with continuous distribution, the KS test was used for independent groups. Chi-square test with Yates’ correction was applied for nominal variables. Nonparametric data in dependent groups were analyzed with the Wilcoxon matched pairs test. Statistical significance was defined by p < 0.05. Results Demographic Data and Kidney Disease The study population consisted of 191 patients with 196 operations distributed to group A (80 cases, 41%) and group B (116 cases, 59%). The mean age was comparable in both groups (group A: 51.2 ± 13.3 vs group B: 51.5 ± 12.7 years), and the male/female ratio was 50% for group A, whereas group B consisted of more male patients (66%). Most patients had chronic kidney disease stage V (CKD V; 91% vs 84%, respectively) at the time of parathyroidectomy, an overview of underlying diseases is given in Table 2. Table 2 Underlying diseases leading to renal failure of patients with renal hyperparathyroidism. Number % Diabetic nephropathy 30 16 Σ = 71% Polycystic kidney disease 25 13 Chronic glomerulonephritis 20 10 Focal segmental glomerulosclerosis 16 8 Hypertensive nephropathy 15 8 IgA nephropathy 11 6 Interstitial nephritis 9 5 Membranoproliferative glomerulonephritis 10 5 Other 56 29 IgA: immunoglobulin A. A small number of patients had a functioning kidney graft at the time of parathyroidectomy (group A: 6% vs group B: 11%). Rarely, patients with CKD III and IV were operated in preparation of a living donor KTx (3% vs 5%). All patients were presented with comorbidities, including arterial hypertension, diabetes mellitus, adipositas, and coronary artery disease. Follow-up for patients with cinacalcet (group A, 39.7 ± 22.6 months) was significantly shorter compared with patients without cinacalcet (group B, 54.4 ± 25.3 months, p < 0.001, KS test). Kidney Transplantation Altogether 53% of the patients (n = 101) underwent KTx before or after PTx (25 patients lost to follow-up). At the end of the follow-up period, more patients were transplanted in both groups (54% vs 64%), but graft function varied between the groups. About 90 patients had no KTx during the study period (Table 3). Table 3 Clinical features of patients undergoing parathyroidectomy with (group A) or without cinacalcet (group B) including consecutive or prior kidney transplantation, type of parathyroidectomy, duration of surgery and hospital stay as well as complications and outcome. Cinacalcet (group A) n = 80 Without cinacalcet (group B) n = 116 No data Total Kidney transplantation 37 54 10 101  KTx before PTx 21 22 4 47  KTx after PTx 16 32 6 54 Type of operation  Subtotal PTx 49 89 – 138  Total PTx 21 19 – 40  Re-operation 10 8 – 18 Duration of surgery (minutes) 126 136 – – Hospital stay (days) 7 7 – – Complications  RLNP 2 (1 permanent) 3 – 5  Bleeding 0 2 – 2  30-day mortality 0 0 – 0 i.v. Calcium postoperatively 14 16 – 30 Death during follow-up 12 (52 alive) 14 (72 alive) 41 26 Recurrence of HPT 2 3 – 5 Persistence of HPT 1 3 – 4 HPT: hyperparathyroidism; RLNP: recurrent laryngeal nerve palsy; KTx: kidney transplantation; PTx: parathyreoidectomy. Note: Significance of bold values in the table was not calculated due to low numbers. Of the 47 patients undergoing PTx after KTx for tertiary hyperparathyroidism (tHPT), 15 (32%) were on dialysis (CKD V) in group A, while 6 patients (13%) had functioning grafts (creatinine: 1.23 ± 0.41 mg/dL) at the end of follow-up. In group B, 11 patients (23%) had CKD V and 11 (23%) presented with functioning grafts (creatinine: 1.91 ± 1.02 mg/dL), while 4 patients had unknown graft function. KTx was performed at a mean of 93.5 ± 83.1 months before PTx for both groups. In 54 patients with rHPT receiving their KTx after PTx, 42 had functioning grafts (group A: n = 13 (24%) vs group B: n = 29 (54%)), while six patients (11%) were back on dialysis (three patients in each group) and six had unknown graft function. Mean follow-up for these patients was 15.6 ± 10 months. Six patients received more than one KTx, with the PTx taking place after loss of function of the first kidney graft. Four of these were retransplanted after PTx and presented with good graft function. Creatinine levels in patients with tHPT (i.e. those with a functioning kidney transplant, defined as CKD I-III, n = 22) were analyzed before PTx and 1 year after operation. There were no significant differences neither in the whole group (p = 0.11), nor in the subgroups related to cinacalcet therapy (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet; Fig. 1). Fig. 1. Creatinine levels (mg/dL) in patients with kidney graft and good graft function at the time of PTx and at 1-year follow-up related to cinacalcet preoperatively (yes/no). There was no significant difference in creatinine levels for both groups (p = 0.14 with cinacalcet, p = 0.33 without cinacalcet). Perioperative Data Operative technique A majority of 78% of all primary operations (138/178) underwent subtotal PTx (49 vs 89 cases in both groups, respectively). In 40 patients, a total PTx without autotransplantation was done. About 18 operations were performed for recurrent HPT (Table 3). In 86 cases (48%), concomitant thyroid surgery was carried out. Indications for thyroid surgery were solitary autonomous adenoma (n = 1), diffuse autonomy (n = 2), multinodular goiter (n = 56), suspicious thyroid nodules (n = 18), or a missing parathyroid gland (n = 12). In seven patients, a differentiated thyroid carcinoma was histologically confirmed. There was no difference in operative time between the groups (126 ± 44 min vs 136 ± 39 min with/without cinacalcet, p = 0.11, t-test). Length of in-hospital stay did not differ between the groups with a mean of 7.0 versus 7.1 days, respectively (p > 0.1, KS test). There is a trend toward shorter in-hospital stay in recent years, yet no significant difference could be seen (Table 3). Complications A total of five unilateral vocal cord palsies occurred (1.28% of 392 nerves at risk), two with and three without cinacalcet treatment. Four were temporary, while one patient after recurrent PTx revealed permanent unilateral vocal cord palsy. There were three reoperations for hematoma (n = 2) and infection (n = 1). One patient developed paroxysmal atrial fibrillation, but there was no perioperative mortality and all patients were discharged from hospital (Table 3). Perioperative laboratory values Preoperatively, calcium was significantly lower in group A (2.28 ± 0.23 mmol/L vs 2.41 ± 0.23 mmol/L, p = 0.0002, t-test), while neither postoperatively (1.89 ± 0.30 mmol/L vs 1.92 ± 0.30 mmol/L, p = 0.40, t-test) nor at discharge (2.12 ± 0.30 mmol/L vs 2.12 ± 0.27 mmol/L, p = 0.90, t-test) a statistically significant difference could be observed. Lowest calcium levels measured postoperatively were 1.91 ± 0.30 mmol/L for all patients. The lowest postoperative serum Ca levels were not significantly different between the groups, 1.89 ± 0.30 versus 1.92 ± 0.30 (p = 0.40, t-test). Altogether 30 patients received i.v. calcium postoperatively due to symptoms of hypocalcemia and/or calcium levels below 1.7 mmol/L (14 vs 16 patients). Preoperative iPTH levels were comparable between the groups (755 ± 657 ng/L vs 742 ± 545 ng/L, p > 0.10, KS test). In both groups, there was a significant drop on POD 1 with no difference between the groups (50 ± 124 ng/L vs 46 ± 83 ng/L, p > 0.10, KS test). More than 1/3 (36%) of the patients after KTx presented with good graft function at the moment of PTx. These patients showed no deterioration of creatinine levels at 1-year follow-up (1.42 mg/dL perioperatively vs 1.38 mg/dL after 1 year, p = 0.11, Wilcoxon test), and there was no difference between patients with or without cinacalcet preoperatively. 1-year surveillance data Calcium levels 1 year after PTx were not significantly different between the groups (2.26 ± 0.25 mmol/L vs 2.24 ± 0.25 mmol/L, p = 0.67, t-test). Regarding iPTH levels, no significant difference could be detected between patients with or without cinacalcet preoperatively (26.9 vs 42.1 ng/L, p > 0.1, KS test). Seven patients had extremely high iPTH (>2000 ng/L, n = 7) preoperatively, but none of these presented with persisting or recurrent hyperparathyroidism. Only two of these patients had been on cinacalcet before PTx. All of them had normalized iPTH at discharge. About 1 year after PTx, four of the patients presented with normal iPTH levels, for three of the patients iPTH was not available, but none of them was re-operated for HPT. Five of the patients had been transplanted before (n = 2) or after PTx (n = 3) and four presented with good graft function until the end of follow-up or death (n = 1). After 1 year, four patients were presented with iPTH > 100 ng/L and calcium > 2.5 mmol/L, while five patients only had elevated iPTH with normal calcium. Five of these patients had recurrent HPT (two with cinacalcet, group A) and four persisting HPT (one with cinacalcet, group A). Looking more closely at type of operation (subtotal PTx, total PTx, and recurrent PTx), there was no difference between postoperative iPTH and iPTH at 1 year. Patients with second PTx for recurrent or persisting HPT displayed a mean higher iPTH both postoperatively (45 ng/L) as well as at 1 year (92 ng/L). Patients with subtotal and total parathyroidectomy showed low levels of PTH both at discharge (11 and 8 ng/L) and at 1 year (8 and 7 ng/L). There was no significant difference between patients with or without cinacalcet. Overall mortality and morbidity Considering long-term follow-up, a considerable number of patients were lost to follow-up. There was no difference in mortality rate between the groups (p = 0.68, χ² test). At the end of follow-up, 12 of 77 patients in group A had died (16%), 52 (68%) were alive (no data in 16%, n = 13). In group B, 14 of 114 had died (12%), whereas 72 (63%) were alive (no data in 25%, n = 28). The prevalence of cardiovascular events was not significantly different between the groups. Myocardial infarction occured in 13% (group A) versus 18% of patients (group B), and the need for coronary artery intervention or bypass occurred in 13% versus 22% of patients in both groups, respectively. Also the need for peripheral revascularization (9% vs 12%) and stroke was recorded with a similar prevalence (13% vs 10%) in patients after PTx with or without cinacalcet. Discussion This single-center study in patients undergoing parathyroidectomy for rHPT shows excellent outcome independent of pretreatment with cinacalcet. Since the introduction of cinacalcet as treatment modality for rHPT, decreasing numbers of patients are being referred to parathyroidectomy (20). Nevertheless, no reduction of all-cause or cardiovascular mortality compared with surgery has been shown for patients with ESRD (4). A substantial part of these conservatively treated patients presents with persistently elevated iPTH, aggravation of complications, and consecutive referral to surgery (3). In our center, the number of patients referred to surgery was decreasing after the introduction of cinacalcet but is increasing again since 2012. Timing of PTx From our referring nephrology and transplant unit, a majority of patients on the waiting list for KTx is referred to parathyroidectomy, especially those with very high iPTH levels. This is due to the fact that only up to 56% of patients normalize PTH after KTx, mostly those with shorter waiting time on the transplant list (13). A total of 53% of our patients underwent KTx, either before or after PTx. In those patients undergoing PTx before KTx for rHPT, a majority of 78% presents with functioning grafts during follow-up. While it is clear that pHPT after KTx impairs long-term graft survival (17), optimal therapy still is under debate. An interesting report by Torregrosa et al. (21) has shown no decline in graft function 1 year after KTx for patients with rHPT that were treated with cinacalcet and also stable graft function for patients on cinacalcet during long-term follow-up. This was underlined by a meta-analysis by Cohen et al. (22) reporting that cinacalcet treatment for pHPT after KTx was not associated with inferior graft survival. In our study, 55% of patients undergoing PTx after KTx were on dialysis at the end of follow-up, mostly for graft failure before PTx. But those patients undergoing PTx with functioning kidney grafts did not show deterioration of creatinine levels postoperatively or during 1-year follow-up, irrespective of cinacalcet treatment. Interestingly, six of the patients underwent second or even third KTx after PTx and presented with functioning grafts during follow-up. In contrast, 78% of patients with PTx and consecutive KTx showed functioning grafts, irrespective of treatment with cinacalcet prior to surgery. Overall, these results favor parathyroidectomy before KTx, yet prospective trials will be necessary to evaluate optimal treatment for tHPT after KTx. Cardiovascular Morbidity Treatment with cinacalcet only showed limited effects on cardiovascular morbidity or mortality of patients with ESRD in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial (23), which evaluated patients on hemodialysis. Both a Cochrane analysis (4) and a meta-analysis by Palmer et al. (24) demonstrated that for patients with ESRD treatment with cinacalcet only reduced the risk for surgery without positively influencing all-cause or cardiovascular mortality. A smaller trial by Trombetti et al. (25) showed that PTx, on the contrary, is associated with both reduced morbidity and mortality of these patients. In this cohort, 19 months after PTx, mortality of patients with ESRD was less than without PTx. In our study, morbidity and mortality during follow-up were not different between patients with or without cinacalcet treatment before surgery. Both small sample size and patients lost to follow-up reduce the statistic power of our cohort. Laboratory Values Overall, we could see no significant differences in laboratory values perioperatively between the groups, only preoperative calcium levels were significantly lower in patients with cinacalcet. At 1 year after surgery, no difference could be detected in iPTH between the groups. A study by Somnay et al. (26) focused on patients with tHPT and the effect of cinacalcet treatment on perioperative findings and outcome. Although they presented a small patient cohort with cinacalcet treatment, they interestingly had higher iPTH levels preoperatively in this cohort, while cure rate was not influenced by cinacalcet pretreatment. Compared with our analysis, patients without cinacalcet treatment had much lower preoperative iPTH levels in this study, possibly reflecting lower thresholds for PTx after KTx. Only seven patients with tHPT in our study received cinacalcet treatment with similar preoperative iPTH levels, as patients with rHPT. A very recent study by Baker et al. (27) examined influence of cinacalcet on outcome in patients with rHPT and found greater iPTH levels in the untreated group before surgery with similar outcome. Only the study of Wirowski et al. (28) demonstrated comparable laboratory findings in patients operated for rHPT. In their analysis, pre- and postoperative iPTH levels were equal in patients with or without cinacalcet and calcium was significantly lower in cinacalcet patients. This is in line with our findings, and they also concluded that cinacalcet did not alter perioperative course. Looking more closely on recurrent, or persisting rHPT, only four patients were diagnosed during follow-up with both elevated iPTH and hypercalcemia, while five were normocalcemic with elevated iPTH. For this analysis, relatively strict values were applied as cut-off values for recurrent HPT. When increasing the cut-off values for iPTH, only two patients of the cohort would have been identified with recurrence of HPT. There was no significant difference in iPTH levels at 1 year between subtotal or total parathyroidectomy and also no difference related to cinacalcet treatment preoperatively. So overall, surgical technique with mostly subtotal PTx in our cohort showed good results and low rates of recurrent or persisting rHPT, independent of preoperative treatment with cinacalcet. Several groups have shown that subtotal PTx or total PTx with autotransplantation of parathyroid tissue represent a good compromise between effective treatment of rHPT while avoiding unnecessary complications of hypocalcemia, adynamic bone disease, or reoperations (29). Complications Overall, the rate of surgical complications was low in both groups and no difference could be calculated for patients with or without cinacalcet treatment. There was no perioperative mortality in our group. Duration of surgery and hospital stay did not differ between the groups, and hospital-stay was reduced during the study period but similar in both groups. Conclusion Our study underlines the fact that PTx represents a safe and successful treatment option for patients with rHPT, even after KTx and irrespective of co-medication with cinacalcet. In view of the morbidity and mortality of long-term dialysis, patients will need individualized decisions taken by interdisciplinary transplant and tumor boards. Surgery should at least be offered to patients not responding to cinacalcet treatment and especially to those planned for KTx. This not only should reduce complications of pHPT but also improve patient morbidity in view of a successful KTx. Authors thank Prof. Dr. med. Peter E Goretzki for discussion and critical review of the manuscript. Author Contributions: M.T.M., T.S., N.R. contributed to the study conception and design, analysis, and interpretation of data and writing of the manuscript. N.M.O., E.T., C.B. participated in the acquisition and analysis of data. P.R., N.R., J.P. contributed to the analysis and interpretation of data, the study conception, and critical review of the manuscript. Compliance with Ethical Standards: This is a retrospective non-interventional study. All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical Approval: Ethical approval was given by the local ethics committee (EA4/086/19) Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD: M. T. Mogl https://orcid.org/0000-0002-3676-047X

Fatal

ReactionOutcome

CC BY-NC

31906794

2021-03

What was the outcome of reaction 'Drug dependence'?

Buprenorphine-cannabis interaction in patients undergoing opioid maintenance therapy. Buprenorphine is a partial μ-opioid agonist widely used for opioid maintenance therapy (OMT). It is mainly metabolized to pharmacologically active norbuprenorphine by the cytochrome P450 (CYP) isozyme 3A4. This may give rise to drug-drug interactions under combinations with inhibitors or inducers of CYP3A4. Cannabis is a potential inhibitor of CYP3A4, and there is a large degree of concomitant cannabis use among OMT patients. We performed a retrospective analysis on liver healthy OMT patients substituted with buprenorphine, either with (n = 15) or without (n = 17) concomitant use of cannabis. Patients with additional illicit drugs or medications affecting CYP3A were excluded. Measured blood concentrations of buprenorphine and norbuprenorphine were compared between the two groups. Cannabis users and non-users received similar doses, but users had 2.7-fold higher concentrations of buprenorphine (p < 0.01) and 1.4-fold for norbuprenorphine (1.4-fold, p = 0.07). Moreover, the metabolite-to-parent drug ratio was 0.98 in non-users and 0.38 in users (p = 0.02). Female gender did not produce significant effects. These findings indicate that cannabis use decreases the formation of norbuprenorphine and elevates buprenorphine and norbuprenorphine concentrations in blood most probably by inhibition of CYP3A4. The pharmacokinetic interaction may give rise to enhanced or altered opioid activity and risk of intoxications. Physicians should inform patients about this risk and supervise cannabis users by regular control of buprenorphine blood levels, i.e., by therapeutic drug monitoring. Introduction In the past years, the prevalence of cannabis consumption has steadily increased with differential Δ9-tetrahydrocannabinol (THC) content in different preparations [1]. Patients undergoing opioid maintenance therapy (OMT) represent a traditional high-risk group for additional substance use and substance use disorders, [2] including cannabis. There is evidence that cannabinoids may interfere with the oxidative metabolism via the cytochrome P450 (CYP) isozymes and precipitate drug–drug interactions [3, 4]. The partial μ-opioid agonist buprenorphine is widely used for opioid maintenance therapy (OMT). Its long elimination half-life is subject to great inter-individual variation [5–7]. Elimination includes N-dealkylation to norbuprenorphine by CYP3A4, and to a lesser extent by CYP2C8, glucuronidation and biliary excretion [8]. Approximately 10–30% are excreted via the urinary tract [5, 7, 9]. As norbuprenorphine has a much longer elimination half-life than buprenorphine, patient adherence to the therapy regimen is associated with metabolite-to-parent drug concentration ratios greater than 1 in the presence of normal hepatic metabolism [10]. As norbuprenorphine is a much less potent analgesic drug than buprenorphine, sufficiently high buprenorphine plasma concentrations are required for the suppression of withdrawal symptoms and successful OMT [9]. Moreover, relapse prevention depends on sufficiently high drug concentrations [11–13]. To optimize efficacy and tolerability and to control buprenorphine’s susceptibility to critical drug–drug or food–drug interactions [9, 10, 14], therapeutic drug monitoring (TDM) should be applied [8]. Analysis of buprenorphine and norbuprenorphine in blood may support the clinician regarding the need for changes in drug dosage or administration patterns and enables detection of non-compliance. In particular, the drug concentration-to-dose ratio in conjunction with the metabolite-to-parent drug ratio presents a valid parameter for assessing compliance [15, 16]. To prevent intravenous abuse, sublingual formulations containing buprenorphine/naloxone combinations are available. However, there is still a large degree of illicit concomitant drug use in patients undergoing OMT. In a representative sample of 2694 German patients undergoing OMT, Wittchen and colleagues found concomitant use of at least one drug in 54% of patients [2]. Moreover, there is a high prevalence of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infection; in the Wittchen et al. cohort, 67% of patients tested positive for HCV and for 7.3% for HIV infection [2]. Hepatic inflammation, damage and impairment induced by HCV infection may interfere with the metabolism of various drugs, including buprenorphine; elevated levels of buprenorphine with decreased metabolism to norbuprenorphine in patients with hepatic impairment due to HCV infection have been reported [17]. Furthermore, the various antiviral medications used to treat HCV or HIV infection have been described to both inhibit and induce CYP enzymes, most notably CYP3A4. As a consequence, suboptimal levels of concurrent psychotropic medication have been found with a higher incidence in HIV/HCV-positive cohorts than in negative cohorts [18]. Wittchen and colleagues identified concomitant cannabis use in 30–46% in small and large OMT centers, respectively [2]. A study of the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) in 2015 revealed a one year prevalence of cannabis use of 5% in Europe and 10% in North America [19]. Significant psychiatric and somatic co-morbidity in patients suffering from addiction are a further complication in the management of these patients. Elevated buprenorphine levels were only found in patients with HCV infection plus moderate-to-severe liver impairment [20, 21]. Another risk factor is antiviral therapy with drugs known to cause interactions via the CYP isozymes [18, 22]. The CYP3A4-dependent metabolism of buprenorphine may be subject to interactions with both therapeutic and illicit drugs. This might put OMT patients at risk of altering their buprenorphine levels in a detrimental manner. Controlling the drug concentrations in blood by TDM can prevent buprenorphine-induced toxicity or relapse due to supra- or sub-therapeutic drug concentrations. To evaluate a possible interaction between cannabis use and buprenorphine OMT, we analyzed serum buprenorphine and norbuprenorphine levels in patients without HCV and HIV infections undergoing OMT and supervised by TDM by comparing drug and metabolite concentrations in blood of cannabis users and non-users. Methods Patients Patients undergoing OMT with either buprenorphine or buprenorphine/naloxone at the clinic for psychiatry and psychotherapy from 2012 to 2018 of the University Medical Center Göttingen (UMG) were included based on the following criteria: Patients had to be in buprenorphine OMT for at least 5 years and considered to be clinically stable by the treating physician. Stable buprenorphine dosage and take-home prescription constituted further inclusion criteria. Correct buprenorphine dosage was determined by clinical parameters (opioid withdrawal score, patient reporting well-being without feeling of “high”) with daily intake under supervision over a long time period before being approved for take-home prescription. Patients had to visit the clinic for supervised intake in the morning once a week. All patients with take-home prescription were instructed to take in the drug in the morning only. Patients acknowledged this as they required adequate buprenorphine dosing for their work. No consumption of any legal or illegal drugs except for cannabis for at least one year, no HIV infection, no active hepatitis with hepatic impairment and no medications with known CYP3A4 and CYP2C8 interactions constituted further inclusion criteria. All patients included in this work gave informed consent to TDM and scientific use of generated data. Laboratory measurements For recording of trough plasma levels of buprenorphine, the blood samples were withdrawn 30 min prior to ingesting the next dose under supervision. Viral status for HCV, HBV and HIV was evaluated serologically by immunoassay, while medications were assessed by anamnesis and gas chromatography with mass spectroscopy/MS (GC/MS) in urine. We excluded patients with renal impairment as measured by plasma creatinine elevation. Liver function For estimation of hepatic impairment or irritation, we used plasma transaminase activities (AST, ALT), γ-GT, INR and plasma albumin concentration to prevent falsely high buprenorphine concentrations due to HCV-induced liver damage or irritation. Transaminase and bilirubin elevations, INR prolongation and abnormal γ-GT constituted exclusion criteria. Drug, alcohol and medication use Patients with a history of alcohol misuse were routinely tested for relapse by monitoring urine ethyl glucuronate, ethyl sulfate and serum carbohydrate-deficient transferrin by immunoassay. All patients were screened for drug misuse, including ethanol using immunologic urine testing on a monthly basis (Diagnostik Nord GmbH, see Table 1 for cutoff values) with subsequent confirmation of positive results for amphetamine and/or detection of other psychoactive drugs, using gas chromatography–mass spectrometry (GC/MS) or liquid chromatography–mass spectrometry (LC/MS). Furthermore, toxicological serum analysis using GC/MS was used for drug and medication testing both initially and punctually if warranted by clinical indication.Table 1 Cutoff values for immunological drug screening in urine Drug Cutoff Amphetamine 500 ng/mL Cannabis (THC and metabolites) 50 ng/mL Opiates 300 ng/mL Cocaine 300 ng/mL Benzodiazepines 300 ng/mL Barbiturates 300 ng/mL Methadone 300 ng/mL Measurement of cannabis/cannabinoids The immunoassay (urine stick by Diagnostik Nord) qualitatively detects cannabis in urine on the base of THC and its metabolites. To assess possible dose-dependent effects of cannabis, an immunoassay was used to grossly determine urinary cannabinoid levels on the base of THC and the THC metabolites in a semiquantitative fashion, a CEDIA system (Microgenics, Freemont) in patients selected by clinical need. The test was sensitive for tetrahydrocannabinol (THC) and most of its known metabolites, intermediary for cannabinol but not for cannabidiol. This test did not differentiate between the different cannabinoids. The GC/MS method in urine qualitatively detects THC and metabolites, cannabinol and cannabidiol (CBD) or synthetic cannabinoids. Patients self-reporting once-daily cannabis smoking underwent punctual measurements of THC, 11-OH THC and 9-nor-carboxy-THC concentrations in serum using GC/MS to quantitatively estimate actual cannabinoid exposure in our patients. Serum buprenorphine measurements For quantification of buprenorphine and norbuprenorphine in serum, a DIN EN ISO/IEC 17,025 accredited ultra-performance liquid chromatography–mass spectrometry method (Waters Acquity UPLC connected to TQ-S detector, Waters GmbH, Eschborn, Germany) was applied. Sample preparation: 100 µL serum was fortified with 20 µL internal standard solution containing 25 ng/mL buprenorphine-D4 (LGC Standards, Wesel, Germany) and 25 ng/mL norbuprenorphine-D3 (LGC Standards) in methanol. The sample was then protein-precipitated with 450 µL acetonitrile and 50 µL ammonia solution (32% v/v) and subsequently salted out with 50 µL 10 M ammonium acetate. After centrifugation, the organic supernatant was evaporated to dryness at 45 °C and the residue dissolved in 25 µL methanol + 125 µL mobile phase A. Injection volume into the UPLC-MS/MS system was 10 µL. Separation was conducted within 9 min on waters 2.1 × 150 mm, 1.8 µm HSS T3 column kept at 50 °C at a flow rate of 0.35 mL/min. Mobile phase A consisted of 20 mM ammonium formate (pH 3), and mobile phase B was 0.1% formic acid in methanol. Gradient separation started at 95% A and ended at 10% A. Data were acquired with an ESI source operating in the positive ionization, SRM mode with three transitions monitored per analyte and two transitions monitored per internal standard. Capillary voltage was set to 3 kV, ion source temperature was 150 °C, and desolvation gas was heated to 650 °C and delivered at a flow rate of 650 L/h. Cone gas flow (N2) was 150 L/h, and the collision gas flow (Ar) was 0.22 mL/min. The following transitions were monitored: buprenorphine: 468.2 > 396.2 (target ion), 468.2 > 414.3 (qualifier 1 ion), 468.2 > 83.8 (qualifier 2 ion); buprenorphine-D4: 472.3 > 400.2, 472.3 > 414.9, 4; norbuprenorphine: 414.3 > 83.1, 414.3 > 101.2, 414.3 > 187.1; norbuprenorphine-D3: 417.2 > 83.1, 417.2 > 152.2. Matrix calibration in human serum was performed at 0.1, 0.2, 0.3, 0.4, 0.5, 0.75, 1.0, 2.5 and 10 ng/mL. Limits of quantification were determined according to GTFCh guidelines at 0.1 ng/mL for buprenorphine and 0.2 ng/mL for norbuprenorphine. A commercial human serum control (STM 1–13-A SE, ACQ Science, Rottenburg-Hailfingen, Germany) and human urine control sample (FDT -25% UR, ACQ Science) with target values for buprenorphine at 3.51 ng/mL and 0.78 ng/mL and norbuprenorphine at 12.1 ng/mL and 0.74 ng/mL revealed CVs of 6.8% to 15.9% (n = 27). Statistics Statistical analysis was conducted by Student’s t test to compare the cannabis and treatment group and assess possible gender effects with a significance level of α = 0.00625 as determined by Holm–Bonferroni method due to multiple testing. Eligible measurements were stratified for each patient. Mean dosage was calculated over the course of the years between 2012 and 2018. Mann–Whitney U tests, which does not require normal distribution, were performed. Multi-variant one-way ANOVA was employed due to evaluate possible effects of treatment duration. All statistical calculations were done using the Statistica Software version 13.3 for Windows by TIBCO Software Inc. (Palo Alto). Statistical values are reported as mean ± standard deviation unless specified otherwise. Graphical representations were created using Office Excel 2016 (Microsoft Corporation, Redmond). Drug interaction scoring The probability of a cannabis–buprenorphine interaction was assessed using the Drug Interaction Probability Scale [23]. This scale employs 10 items to assess the probability of a drug interaction, with higher scores indicating higher probability of a drug–drug interaction. Scores between 2 and 4 are considered to indicate a possible interaction, 5–8 a probable interaction, while scores higher than 8 indicate a highly probable drug–drug interaction. Results Patient characteristics After examining our patients for inclusion and exclusion criteria described above, we identified 32 eligible measurements out of a total of 79 serum buprenorphine measurements. Five patients with 17 measurements over a course of 5 years tested negative on toxicological screening for all drugs of abuse except nicotine, while 5 patients with 15 measurements, also over a course of 5 years, tested positive for cannabis only and were thus assigned to the cannabis group. A positive test for any cannabinoid measured by immunological test was considered a positive test for cannabis use. No patient reported cannabinoid prescription. In GC/MS analysis of urine, no intake of synthetic cannabinoid could be found in all patients. In all cases of cannabinoid detection by GC/MS, THC and metabolites were detected, seldom cannabinol, while CBD was never detected. All patients included were smokers. Three of the patients in the control group received buprenorphine/naloxone, while all patients in the cannabis group received buprenorphine-only preparations. Totally, 40% of our samples in the cannabis group came from female patients, while all samples from the control group came from male patients (Table 2). No difference in buprenorphine dosage was observed (Table 2). Mean age calculated as the arithmetic means of patient’s ages at the time the blood was drawn was 36.9 ± 9.9 years in the control group and 33.7 ± 3.3 years in the cannabis group. The last time of buprenorphine intake was documented for 53% of our patients and was 24.2 ± 2.1 h in the control group and 21.6 ± 5.1 h in the cannabis group. This difference was not significant (p = 0.18).Table 2 Serum concentrations and dose-related values of cannabis non-users (control) and users Control (n = 17) Cannabis (n = 15) p (Student’s t test) p (Mann–Whitney U test) Dose 8.8 ± 3.9 mg 8.6 ± 0.9 mg 0.831 0.748 Serum buprenorphine 2.00 ± 3.17 ng/mL 5.41 ± 2.27 ng/mL 0.00167* 0.000249* Serum norbuprenorphine 1.07 ± 0.82 ng/mL 1.76 ± 1.23 ng/mL 0.0694 0.08576 Active moiety 3.07 ± 3.53 ng/mL 7.17 ± 2.73 ng/mL 0.00103* 0.000632* Metabolite-to-parent drug ratio 0.98 ± 0.78 0.39 ± 0.44 0.016 0.009171* Concentration/dose ratio Buprenorphine 0.29 ± 0.36 ng/mL/mg 0.63 ± 0.26 ng/mL/mg 0.00519* 0.00223* Concentration/dose ratio Norbuprenorphine 0.117 ± 0.077 ng/mL/mg 0.206 ± 0.147 ng/mL/mg 0.0372 0.0518 Active moiety/dose ratio 0.33 ± 0.34 ng/mL/mg 0.83 ± 0.32 ng/mL/mg 0.000141** 0.000268* Serum cannabinoid concentrations Patients reported once-daily cannabis use at night had their serum cannabinoid levels measured, as outlined above. The concentrations of THC and its metabolites measured punctually were in the micromolar range: THC 14.29 ± 2.39 mg/L; THC-COOH 101.24 ± 56.32 mg/L; 11-OH-THC 1.97 ± 0.38 mg/L, N = 3. Considering the pharmakokinetics of smoked cannabis [24], these values indicate that we did not phlebotomize patients at the time of peak cannabinoid serum concentrations shortly after smoking. Overall, our observed concentrations are compatible with once-daily cannabis use by those patients. The urinary cannabinoid concentrations support frequent use of moderate amounts of cannabis. Dose and serum concentrations of buprenorphine and norbuprenorphine The mean dose of buprenorphine in the control group was 8.8 ± 3.9 mg per day, while patients in the cannabis group received an average of 8.6 ± 0.9 mg a day. This difference was not significant with both t and Mann–Whitney U test. There were wide ranges of buprenorphine dosage in both groups due to different levels of opioid tolerance among patients (range 2.4–16 mg in the control group; 2–10 mg in the cannabis group). Within the control group, buprenorphine/naloxone (Suboxone®) therapy was not associated with significantly altered serum buprenorphine (p = 0.522) or dose-related concentrations compared to buprenorphine alone (Subutex®) (p = 0.504). Despite overall similar buprenorphine dosage, we found a highly significant correlation between cannabis use and serum buprenorphine level (p = 0.000563). Patients in the cannabis group reached a mean concentration of 5.4 ± 2.3 ng/mL (range 2.0–10.0 ng/mL; interquartile range 3.7–7.2 ng/mL), with control group patients reaching a mean of 2.0 ± 3.2 ng/ml (range 0.2–12.6 ng/mL; interquartile range 0.4–1.4 ng/mL). Consistent with this, we found a significant correlation between cannabis use and the concentration/dose (C/D) ratio for buprenorphine. The C/D ratio for buprenorphine in the cannabis group was elevated (0.63 ± 0.54 vs 0.29 ± 0.36; p = 0.0019). The Mann–Whitney U test, which does not require normal distribution of data, confirmed the statistically significance of the Student’s test. On average, norbuprenorphine concentrations were higher in the cannabis group; however, this effect was not statistically significant. The metabolite-to-parent drug ratio was reduced in the cannabis group (0.98 ± 0.78 vs 0.39 ± 0.44; p = 0.016; see Table 3 for distribution). However, it was not significant.Table 3 Distribution of metabolite-to-parent drug ratio in the control and cannabis group Control Cannabis Mean 0.423 0.18 SD 0.41 0.2 Median 0.93 0.278 Interquartile range Q1–Q3 0.33–1.33 0.13–0.42 Total active moiety was elevated in the cannabis group with a mean of 7.2 ± 2.7 ng/mL and a mean of 3.07 ± 3.54 ng/mL in the control group (p = 0.00103). The dose-related active moiety differed significantly as well, reaching 0.83 ± 0.32 ng/mL/mg in the cannabis group and 0.33 ± 0.34 ng/mL/mg in the control group. In order to assess possible dose-dependent effects, we searched for a correlation of gross urinary cannabinoid concentrations as measured by immunoassay and serum buprenorphine levels and C/D ratios. We found a weak, but not significant positive correlation. However, in three of our patients not included in then original study due to HCV infection and co-medication who managed to permanently cease cannabis use with laboratory confirmation, serum buprenorphine, metabolic ratio and C/D ratios declined after cannabis cessation, supporting the idea of an interaction between cannabis use and buprenorphine metabolism. Gender effects As 40% of measurements in the cannabis group came from female patients while the control group consisted of male patients only, we compared men and women in the cannabis group by performing multiple t-tests to assess effects of gender on the sample. We did not find a significant effect (Table 4). However, mean serum buprenorphine levels, metabolite-to-parent ratio and dose-related buprenorphine concentrations were slightly higher in female patients which is consistent with the findings reported by other investigators [25].Table 4 Serum concentrations of buprenorphine, norbuprenorphine in male and female consumers of cannabis Male (n = 9) Female (n = 6) p (Student’s t test) p (Mann–Whitney U test) Dose 8.56 ± 1.0 mg 8.6 ± 0.81 mg 0.827 0.850 Serum buprenorphine 4.49 ± 1.97 ng/mL 6.80 ± 2.11 ng/mL 0.0495 0.0518 Serum norbuprenorphine 1.49 ± 1.54 ng/mL 2.17 ± 0.35 ng/mL 0.313 0.138 Metabolite-to-parent drug ratio 0.429 ± 0.58 0.34 ± 0.94 0.717 0.316 Active moiety 5.98 ± 2.4 ng/mL 8.97 ± 2.29 ng/mL 0.0316 0.0518 Concentration/dose ratio Buprenorphine 0.52 ± 0.21 ng/mL/mg 0.79 ± 0.26 ng/mL/mg 0.0421 0.0518 Concentration/dose ratio norbuprenorphine 0.17 ± 0.18 ng/mL/mg 0.25 ± 0.059 0.324 0.195 Dose-related active moiety 0.69 ± 0.26 ng/mL/mg 1.05 ± 0.30 ng/mL/mg 0.0308 0.0677 Treatment effects In order to rule out effects of the duration of OMT and cannabis use, we performed multiple variant one-way ANOVA. There was no significant interaction in neither control group (Wilken’s Λ = 0.266, p = 0.8923) nor the cannabis group (Wilken’s Λ = 0.006, p = 0.152) nor in a group of pooled patients from both groups (Wilken’s Λ = 0.292, p = 0.9312; see Fig. 1).Fig. 1 Mean serum buprenorphine of the cannabis group (N = 15), dose-related buprenorphine concentrations, serum norbuprenorphine concentrations and metabolite-to-parent drug ratios per years of measuring (error bars denote 95% confidence intervals) Case report One patient in long-term OMT who was followed in this study since 2012 being clinically stable and in long-term employment ever since presented with marked clinical decline. He had always been using cannabis while on OMT with no additional concomitant drug use and required gradual increases in buprenorphine dosage from 7 to 10 mg daily over a course of 6 years starting 2012. This was consistent with increasing physical requirements by his occupation. He did not require any medication except for a pregabalin prescription (300 mg/d) which is not known to interfere with buprenorphine or cannabis metabolism. At one presentation, he reported sleep disturbances, agitation and decreased motivation, drive, contemplation and overall mood. Affect lability was found to be increased, and a depressive episode was diagnosed. Furthermore, the patient reported he had quit cannabis use a month ago, and this was confirmed by immunologic urine analysis and serum GC/MS for THC and metabolites (serum THC < 0.5 ng/mL, THC-COOH < 2.5 ng/mL, 11-OH-THC < 0.5 ng/mL) compared to presentation 6 months earlier (THC 16.82 ng/mL, THC-COOH 28.46 ng/mL, 11-OH-THC 1.63 ng/mL). He reported improved feeling of somatic health but increasing psychological issues. Upon clinical observation, he appeared pale, sweaty and agitated, indicating a withdrawal syndrome. The patient reported severe buprenorphine craving; this prompted buprenorphine status evaluation. Indeed, both buprenorphine and norbuprenorphine levels were markedly decreased compared to presentation six months earlier (0.3 ng/mL vs 6.3 ng/mL for buprenorphine; 0.3 ng/mL vs 1.0 ng/mL for norbuprenorphine), metabolic ratio having increased (1.00 compared to 0.16 6 months earlier). The patient was started on supportive therapy for psychic instability, depressed mood and insomnia using valproic acid (600 mg ramp-up) and mirtazapine (30 mg) and buprenorphine dosage was increased to 12 mg daily. Upon re-evaluation 14 days later, his clinical condition stabilized, while buprenorphine craving and agitation were still increased, albeit greatly ameliorated. The patient did not appear pale anymore. Serum buprenorphine concentration and dose-related concentrations were increased (2.1 ng/mL and 0.2 ng/mL/mg for buprenorphine; 0.8 ng/mL and 0.1 ng/mL/mg for norbuprenorphine; metabolic ratio 0.38); however, both plasma levels and dose-related concentrations had not rebounded to levels prior to cannabis cessation. This effect was consistent with prior attempts of this patient to reduce cannabis use with reductions in dose-related buprenorphine concentrations occurring at those times. Drug interaction score In the evaluation using the Drug Interaction Probability Score (DIPS) proposed by Horn and co-workers, the interaction was rated as ‘probable’, as intra-individual comparison in three patients who managed to quit cannabis use altogether showed all a decline of buprenorphine levels after cannabis cessation. This is consistent with the findings of a fourth patient described above, giving rise to a drug interaction score of probable. Discussion This retrospective analysis of buprenorphine concentrations in blood of opioid-dependent patients found elevated buprenorphine levels and metabolite-to-parent drug ratios in the cannabis patients compared to the control group. This suggests a lowered metabolic rate possibly via CYP3A4, CYP2C8 and/or the UGT2B7 pathways. Since CYP3A4 is the most important enzyme responsible for N-dealkylation of buprenorphine [5, 8], CYP3A4 inhibition may be assumed. Intra-individual comparison in patients who managed to quit cannabis use showed a decline of buprenorphine levels after cannabis cessation, giving rise to a drug interaction score of probable. This is consistent with the literature findings: Damkier et al. described the case of a 27-year-old male undergoing warfarin therapy due to endocarditis with subsequent mechanic heart valve replacement with severe INR elevation after recreational cannabis administration [26]. Additional similar case reports exist [27]. These reports are in line with findings in our own patients, one report described above. This underlines that changes in pharmacokinetics precipitated by cannabis are to be reckoned with by the treating physician, as changes in cannabis consumption habits may necessitate changes in treatment. Considering increasing prevalence of cannabis use, this has implications beyond the scope of addiction medicine, being relevant for the treatment of psychoses, depression and cancer, to name a few. Cannabis is a heterogeneous substance with great variability in its active ingredients [1, 28]. In vitro data suggest an inhibitory effect of cannabidiol (CBD), but not THC on CYP3A4 (IC50 = 1 μM) (reviewed by [4]). Both CBD and cannabinol (CBN) as well as THC seem to inhibit CYP2C9 (IC50 = 0.95–9.88 µM for CBD, IC50 = 0.88–1.29 μM for CBN, IC50 = 0.94–1.50 μM for THC, respectively). Especially drug–drug interactions precipitated by CBD have gained interest as CBD is being employed in the treatment of refractory epilepsia [29, 30]. There is further evidence for CBDs efficacy as an antipsychotic [31–34] and its usefulness in the treatment of non-motor symptoms in Parkinson’s disease [35]. CYP3A4 inhibition by CBD may explain the increased buprenorphine levels observed. CYP2C8 inhibition may exacerbate this effect, as there are FDA caveats against CYP2C8 inhibition by CBD [36, 37]. As both CBD and buprenorphine are substrates of uridyl-glucuronosyl transferase 2B7 (UGT2B7), competition for this transporter may impair fecal buprenorphine excretion, further increasing plasma concentration. A virtually unlimited amount of cannabis strains is available on the black market, including strains with significant CBD content. In the past decades, overall content of psychoactive cannabinoids in the cannabis plant in both the USA and the European Union has increased, especially the content of THC [1]. Several medicinally available strains of cannabis contain high CBD levls. This poses a significant risk of patients reliant on any drug subject to CYP3A4-mediated metabolism, especially considering the increasing prevalence of both illicit and medical cannabis use, legalization and the fact that high CBD cannabis tends to be marketed as especially healthy. An interaction between clobazam and CBD has been reported [29, 38] by Geffrey, Pollack et al. in children being treated for refractory epilepsy; elevated clobazam and norclobazam levels were found, precipitating side effects requiring a dose reduction. Although the in vitro data favor the role of CBD but less of THC on buprenorphine plasma levels, our clinical in vivo data, underlined by the case report with quantitative measurement of THC and its metabolites, lead to the suspicion that THC may probably also have inhibitory effects on CYP3A4. The buprenorphine levels decreased with decreasing THC levels. However, we did not assess serum CBD levels. Further studies have to be conducted to clarify the role of different substances of cannabis on the CYP isozymes in vivo. To avoid interactions with other drugs, we eliminated confounding effects of co-medication by excluding patients under medications with known inhibitory or inducing potential on CYP3A4 or CYP2C. Most psychiatric patients, however, require several drugs which are substrates, inducers or inhibitors of the CYP isozymes including CYP3A4 and CYP2C9, both inhibited by CBD (quetiapine, fluoxetine, levomepromazine [10]), leading to unpredictable buprenorphine levels. Consumption of readily available CYP inducers or inhibitors like St. John’s Wort or excessive amounts of grapefruit juice, respectively, may exacerbate this issue. The same holds true for patients receiving cannabis for chronic pain, or for chemotherapy-induced nausea. The serum levels of THC, hydroxylated THC (11-OH-THC) and THC-carboxylic acid (THC-COOH) measured by us were comparable steady-state concentrations of frequent users of cannabis via smoking, inhalation and the oral route, including prescription drugs like Dronabinol® or Sativex® [24, 39]. Concordantly, these patients did not consume cannabis in extremely and uncommonly high amounts. Still, we only measured cannabinoid concentrations (THC and metabolites) in few patients; therefore, total cannabis exposure of other patients can only be estimated. Limitations While we selected the cannabis users and non-users as control group with great care in regard to confounding factors, our approach harbors several limitations: Most of the patients were men, possibly inferring bias. There is evidence for higher CYP3A4 activity in women [25], warranting increased vigilance in regard to interactions. We did not find significantly higher buprenorphine levels or metabolite-to-parent drug ratios in female patients of our study, but recognized a trend for higher buprenorphine levels. This could be due to increased sensitivity to CYP3A4 inhibition due to increased CYP3A4 activities, but this remains unknown. Drug consumption was closely evaluated using GC/MS; however, patients were followed over several years: Since cannabis contents vary widely among different “suppliers” in regard to cannabinoid composition and total cannabinoid concentration, significant changes in cannabinoid consumption in the presence of normal test findings cannot be ruled out. Duration of buprenorphine treatment but also of concomitant cannabis use did not influence buprenorphine levels in our study. In vitro data suggest highly divergent action of different cannabinoids on the cytochrome P450 system [4]; therefore, different batches of cannabis may have divergent effects on serum buprenorphine concentrations. However, the immunoassay used in this study did not differentiate between the cannabinoids and was not sensitive for CBD as all other usually available cannabis tests. Furthermore, in the functionally performed urine tests with GC/MS of the cannabis user, we did not find CBD assuming that the preparations of cannabis used by the patients tested probably contained rather low concentrations of CBD. A standardized approach with defined cannabinoid intake is necessary to assess these effects in detail. We only included patients from a single center of care, increasing risk of bias in regard to the composition of the illegal cannabis used by our patients. Nasser et al. reported buprenorphine levels to be higher in subjects with HCV seropositivity or hepatic impairment [20, 21]. Conclusion Overall, increased serum buprenorphine levels and concentration-to-dose ratios support a cannabis–buprenorphine interaction. A decreased metabolite-to-parent drug ratio indicates reduced N-dealkylation, suggesting that cannabis preparations consumed by our patients inhibited CYP3A4 activity in favor of other metabolic pathways. Competition for UGT2B7 may lead to less buprenorphine conjugation and thus retention, further decreasing metabolite-to-parent drug ratio. This is consistent with preliminary in vitro and in vivo data. It should be taken into consideration when trying to wean OMT patients from cannabis use as it may cause additional buprenorphine withdrawal symptoms and may require increased buprenorphine dosage to stabilize these patients. Considering increasing use of cannabinoids in oncology and pain management, caution should be advised when prescribing medical cannabis preparations since a drug interaction could cause serious complications in settings of psychiatric treatment, pain treatment, chemotherapy or anticoagulation. The increasing recreational use of cannabis presents additional issues; physicians should be aware of this interaction, enabling them to give advise to their patients in order to maximize treatment efficacy and minimize side effects and drug toxicity precipitated by concomitant cannabis use by the patients unknown to the treating physician. Therapeutic drug monitoring of opioids (here buprenorphine) seems to be a valuable methodological option for optimizing maintenance treatment in case of additional intake of interacting substances by reducing the risk of plasma-level-dependent toxicities and other undesirable effects. Acknowledgements This research received support from the Deutsche Forschungs Gesellschaft (DFG) via the Center of Nanoscale and Molecular Physiology of the Brain as part of the project C1 Havemann-Reinecke Stress, Cannabinoids and Psychic Diseases. Compliance with ethical standards Conflict of interest Christoph Hiemke has received speaker’s or consultancy fees from the following pharmaceutical companies: Janssen-Cilag, Otsuka, Lohmann Transdermale Systeme, Roche and Servier. He is the managing editor of PSIAC (www.psiac.de) which provides an internet-based drug–drug interaction program for psychopharmacotherapy. He reports no conflict of interest with this publication. Ursula Havemann-Reinecke has served on the advisory Board on opioid maintenance treatment of Sanofi and Indivior London. She has received speaker’s fee from Hexal. She reports no conflict of interest with this publication. Michael Böttcher and Christopher Vierke report no conflicts of interests.

Not recovered

ReactionOutcome

CC BY

31907614

2021-08

What was the outcome of reaction 'Drug interaction'?

Buprenorphine-cannabis interaction in patients undergoing opioid maintenance therapy. Buprenorphine is a partial μ-opioid agonist widely used for opioid maintenance therapy (OMT). It is mainly metabolized to pharmacologically active norbuprenorphine by the cytochrome P450 (CYP) isozyme 3A4. This may give rise to drug-drug interactions under combinations with inhibitors or inducers of CYP3A4. Cannabis is a potential inhibitor of CYP3A4, and there is a large degree of concomitant cannabis use among OMT patients. We performed a retrospective analysis on liver healthy OMT patients substituted with buprenorphine, either with (n = 15) or without (n = 17) concomitant use of cannabis. Patients with additional illicit drugs or medications affecting CYP3A were excluded. Measured blood concentrations of buprenorphine and norbuprenorphine were compared between the two groups. Cannabis users and non-users received similar doses, but users had 2.7-fold higher concentrations of buprenorphine (p < 0.01) and 1.4-fold for norbuprenorphine (1.4-fold, p = 0.07). Moreover, the metabolite-to-parent drug ratio was 0.98 in non-users and 0.38 in users (p = 0.02). Female gender did not produce significant effects. These findings indicate that cannabis use decreases the formation of norbuprenorphine and elevates buprenorphine and norbuprenorphine concentrations in blood most probably by inhibition of CYP3A4. The pharmacokinetic interaction may give rise to enhanced or altered opioid activity and risk of intoxications. Physicians should inform patients about this risk and supervise cannabis users by regular control of buprenorphine blood levels, i.e., by therapeutic drug monitoring. Introduction In the past years, the prevalence of cannabis consumption has steadily increased with differential Δ9-tetrahydrocannabinol (THC) content in different preparations [1]. Patients undergoing opioid maintenance therapy (OMT) represent a traditional high-risk group for additional substance use and substance use disorders, [2] including cannabis. There is evidence that cannabinoids may interfere with the oxidative metabolism via the cytochrome P450 (CYP) isozymes and precipitate drug–drug interactions [3, 4]. The partial μ-opioid agonist buprenorphine is widely used for opioid maintenance therapy (OMT). Its long elimination half-life is subject to great inter-individual variation [5–7]. Elimination includes N-dealkylation to norbuprenorphine by CYP3A4, and to a lesser extent by CYP2C8, glucuronidation and biliary excretion [8]. Approximately 10–30% are excreted via the urinary tract [5, 7, 9]. As norbuprenorphine has a much longer elimination half-life than buprenorphine, patient adherence to the therapy regimen is associated with metabolite-to-parent drug concentration ratios greater than 1 in the presence of normal hepatic metabolism [10]. As norbuprenorphine is a much less potent analgesic drug than buprenorphine, sufficiently high buprenorphine plasma concentrations are required for the suppression of withdrawal symptoms and successful OMT [9]. Moreover, relapse prevention depends on sufficiently high drug concentrations [11–13]. To optimize efficacy and tolerability and to control buprenorphine’s susceptibility to critical drug–drug or food–drug interactions [9, 10, 14], therapeutic drug monitoring (TDM) should be applied [8]. Analysis of buprenorphine and norbuprenorphine in blood may support the clinician regarding the need for changes in drug dosage or administration patterns and enables detection of non-compliance. In particular, the drug concentration-to-dose ratio in conjunction with the metabolite-to-parent drug ratio presents a valid parameter for assessing compliance [15, 16]. To prevent intravenous abuse, sublingual formulations containing buprenorphine/naloxone combinations are available. However, there is still a large degree of illicit concomitant drug use in patients undergoing OMT. In a representative sample of 2694 German patients undergoing OMT, Wittchen and colleagues found concomitant use of at least one drug in 54% of patients [2]. Moreover, there is a high prevalence of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infection; in the Wittchen et al. cohort, 67% of patients tested positive for HCV and for 7.3% for HIV infection [2]. Hepatic inflammation, damage and impairment induced by HCV infection may interfere with the metabolism of various drugs, including buprenorphine; elevated levels of buprenorphine with decreased metabolism to norbuprenorphine in patients with hepatic impairment due to HCV infection have been reported [17]. Furthermore, the various antiviral medications used to treat HCV or HIV infection have been described to both inhibit and induce CYP enzymes, most notably CYP3A4. As a consequence, suboptimal levels of concurrent psychotropic medication have been found with a higher incidence in HIV/HCV-positive cohorts than in negative cohorts [18]. Wittchen and colleagues identified concomitant cannabis use in 30–46% in small and large OMT centers, respectively [2]. A study of the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) in 2015 revealed a one year prevalence of cannabis use of 5% in Europe and 10% in North America [19]. Significant psychiatric and somatic co-morbidity in patients suffering from addiction are a further complication in the management of these patients. Elevated buprenorphine levels were only found in patients with HCV infection plus moderate-to-severe liver impairment [20, 21]. Another risk factor is antiviral therapy with drugs known to cause interactions via the CYP isozymes [18, 22]. The CYP3A4-dependent metabolism of buprenorphine may be subject to interactions with both therapeutic and illicit drugs. This might put OMT patients at risk of altering their buprenorphine levels in a detrimental manner. Controlling the drug concentrations in blood by TDM can prevent buprenorphine-induced toxicity or relapse due to supra- or sub-therapeutic drug concentrations. To evaluate a possible interaction between cannabis use and buprenorphine OMT, we analyzed serum buprenorphine and norbuprenorphine levels in patients without HCV and HIV infections undergoing OMT and supervised by TDM by comparing drug and metabolite concentrations in blood of cannabis users and non-users. Methods Patients Patients undergoing OMT with either buprenorphine or buprenorphine/naloxone at the clinic for psychiatry and psychotherapy from 2012 to 2018 of the University Medical Center Göttingen (UMG) were included based on the following criteria: Patients had to be in buprenorphine OMT for at least 5 years and considered to be clinically stable by the treating physician. Stable buprenorphine dosage and take-home prescription constituted further inclusion criteria. Correct buprenorphine dosage was determined by clinical parameters (opioid withdrawal score, patient reporting well-being without feeling of “high”) with daily intake under supervision over a long time period before being approved for take-home prescription. Patients had to visit the clinic for supervised intake in the morning once a week. All patients with take-home prescription were instructed to take in the drug in the morning only. Patients acknowledged this as they required adequate buprenorphine dosing for their work. No consumption of any legal or illegal drugs except for cannabis for at least one year, no HIV infection, no active hepatitis with hepatic impairment and no medications with known CYP3A4 and CYP2C8 interactions constituted further inclusion criteria. All patients included in this work gave informed consent to TDM and scientific use of generated data. Laboratory measurements For recording of trough plasma levels of buprenorphine, the blood samples were withdrawn 30 min prior to ingesting the next dose under supervision. Viral status for HCV, HBV and HIV was evaluated serologically by immunoassay, while medications were assessed by anamnesis and gas chromatography with mass spectroscopy/MS (GC/MS) in urine. We excluded patients with renal impairment as measured by plasma creatinine elevation. Liver function For estimation of hepatic impairment or irritation, we used plasma transaminase activities (AST, ALT), γ-GT, INR and plasma albumin concentration to prevent falsely high buprenorphine concentrations due to HCV-induced liver damage or irritation. Transaminase and bilirubin elevations, INR prolongation and abnormal γ-GT constituted exclusion criteria. Drug, alcohol and medication use Patients with a history of alcohol misuse were routinely tested for relapse by monitoring urine ethyl glucuronate, ethyl sulfate and serum carbohydrate-deficient transferrin by immunoassay. All patients were screened for drug misuse, including ethanol using immunologic urine testing on a monthly basis (Diagnostik Nord GmbH, see Table 1 for cutoff values) with subsequent confirmation of positive results for amphetamine and/or detection of other psychoactive drugs, using gas chromatography–mass spectrometry (GC/MS) or liquid chromatography–mass spectrometry (LC/MS). Furthermore, toxicological serum analysis using GC/MS was used for drug and medication testing both initially and punctually if warranted by clinical indication.Table 1 Cutoff values for immunological drug screening in urine Drug Cutoff Amphetamine 500 ng/mL Cannabis (THC and metabolites) 50 ng/mL Opiates 300 ng/mL Cocaine 300 ng/mL Benzodiazepines 300 ng/mL Barbiturates 300 ng/mL Methadone 300 ng/mL Measurement of cannabis/cannabinoids The immunoassay (urine stick by Diagnostik Nord) qualitatively detects cannabis in urine on the base of THC and its metabolites. To assess possible dose-dependent effects of cannabis, an immunoassay was used to grossly determine urinary cannabinoid levels on the base of THC and the THC metabolites in a semiquantitative fashion, a CEDIA system (Microgenics, Freemont) in patients selected by clinical need. The test was sensitive for tetrahydrocannabinol (THC) and most of its known metabolites, intermediary for cannabinol but not for cannabidiol. This test did not differentiate between the different cannabinoids. The GC/MS method in urine qualitatively detects THC and metabolites, cannabinol and cannabidiol (CBD) or synthetic cannabinoids. Patients self-reporting once-daily cannabis smoking underwent punctual measurements of THC, 11-OH THC and 9-nor-carboxy-THC concentrations in serum using GC/MS to quantitatively estimate actual cannabinoid exposure in our patients. Serum buprenorphine measurements For quantification of buprenorphine and norbuprenorphine in serum, a DIN EN ISO/IEC 17,025 accredited ultra-performance liquid chromatography–mass spectrometry method (Waters Acquity UPLC connected to TQ-S detector, Waters GmbH, Eschborn, Germany) was applied. Sample preparation: 100 µL serum was fortified with 20 µL internal standard solution containing 25 ng/mL buprenorphine-D4 (LGC Standards, Wesel, Germany) and 25 ng/mL norbuprenorphine-D3 (LGC Standards) in methanol. The sample was then protein-precipitated with 450 µL acetonitrile and 50 µL ammonia solution (32% v/v) and subsequently salted out with 50 µL 10 M ammonium acetate. After centrifugation, the organic supernatant was evaporated to dryness at 45 °C and the residue dissolved in 25 µL methanol + 125 µL mobile phase A. Injection volume into the UPLC-MS/MS system was 10 µL. Separation was conducted within 9 min on waters 2.1 × 150 mm, 1.8 µm HSS T3 column kept at 50 °C at a flow rate of 0.35 mL/min. Mobile phase A consisted of 20 mM ammonium formate (pH 3), and mobile phase B was 0.1% formic acid in methanol. Gradient separation started at 95% A and ended at 10% A. Data were acquired with an ESI source operating in the positive ionization, SRM mode with three transitions monitored per analyte and two transitions monitored per internal standard. Capillary voltage was set to 3 kV, ion source temperature was 150 °C, and desolvation gas was heated to 650 °C and delivered at a flow rate of 650 L/h. Cone gas flow (N2) was 150 L/h, and the collision gas flow (Ar) was 0.22 mL/min. The following transitions were monitored: buprenorphine: 468.2 > 396.2 (target ion), 468.2 > 414.3 (qualifier 1 ion), 468.2 > 83.8 (qualifier 2 ion); buprenorphine-D4: 472.3 > 400.2, 472.3 > 414.9, 4; norbuprenorphine: 414.3 > 83.1, 414.3 > 101.2, 414.3 > 187.1; norbuprenorphine-D3: 417.2 > 83.1, 417.2 > 152.2. Matrix calibration in human serum was performed at 0.1, 0.2, 0.3, 0.4, 0.5, 0.75, 1.0, 2.5 and 10 ng/mL. Limits of quantification were determined according to GTFCh guidelines at 0.1 ng/mL for buprenorphine and 0.2 ng/mL for norbuprenorphine. A commercial human serum control (STM 1–13-A SE, ACQ Science, Rottenburg-Hailfingen, Germany) and human urine control sample (FDT -25% UR, ACQ Science) with target values for buprenorphine at 3.51 ng/mL and 0.78 ng/mL and norbuprenorphine at 12.1 ng/mL and 0.74 ng/mL revealed CVs of 6.8% to 15.9% (n = 27). Statistics Statistical analysis was conducted by Student’s t test to compare the cannabis and treatment group and assess possible gender effects with a significance level of α = 0.00625 as determined by Holm–Bonferroni method due to multiple testing. Eligible measurements were stratified for each patient. Mean dosage was calculated over the course of the years between 2012 and 2018. Mann–Whitney U tests, which does not require normal distribution, were performed. Multi-variant one-way ANOVA was employed due to evaluate possible effects of treatment duration. All statistical calculations were done using the Statistica Software version 13.3 for Windows by TIBCO Software Inc. (Palo Alto). Statistical values are reported as mean ± standard deviation unless specified otherwise. Graphical representations were created using Office Excel 2016 (Microsoft Corporation, Redmond). Drug interaction scoring The probability of a cannabis–buprenorphine interaction was assessed using the Drug Interaction Probability Scale [23]. This scale employs 10 items to assess the probability of a drug interaction, with higher scores indicating higher probability of a drug–drug interaction. Scores between 2 and 4 are considered to indicate a possible interaction, 5–8 a probable interaction, while scores higher than 8 indicate a highly probable drug–drug interaction. Results Patient characteristics After examining our patients for inclusion and exclusion criteria described above, we identified 32 eligible measurements out of a total of 79 serum buprenorphine measurements. Five patients with 17 measurements over a course of 5 years tested negative on toxicological screening for all drugs of abuse except nicotine, while 5 patients with 15 measurements, also over a course of 5 years, tested positive for cannabis only and were thus assigned to the cannabis group. A positive test for any cannabinoid measured by immunological test was considered a positive test for cannabis use. No patient reported cannabinoid prescription. In GC/MS analysis of urine, no intake of synthetic cannabinoid could be found in all patients. In all cases of cannabinoid detection by GC/MS, THC and metabolites were detected, seldom cannabinol, while CBD was never detected. All patients included were smokers. Three of the patients in the control group received buprenorphine/naloxone, while all patients in the cannabis group received buprenorphine-only preparations. Totally, 40% of our samples in the cannabis group came from female patients, while all samples from the control group came from male patients (Table 2). No difference in buprenorphine dosage was observed (Table 2). Mean age calculated as the arithmetic means of patient’s ages at the time the blood was drawn was 36.9 ± 9.9 years in the control group and 33.7 ± 3.3 years in the cannabis group. The last time of buprenorphine intake was documented for 53% of our patients and was 24.2 ± 2.1 h in the control group and 21.6 ± 5.1 h in the cannabis group. This difference was not significant (p = 0.18).Table 2 Serum concentrations and dose-related values of cannabis non-users (control) and users Control (n = 17) Cannabis (n = 15) p (Student’s t test) p (Mann–Whitney U test) Dose 8.8 ± 3.9 mg 8.6 ± 0.9 mg 0.831 0.748 Serum buprenorphine 2.00 ± 3.17 ng/mL 5.41 ± 2.27 ng/mL 0.00167* 0.000249* Serum norbuprenorphine 1.07 ± 0.82 ng/mL 1.76 ± 1.23 ng/mL 0.0694 0.08576 Active moiety 3.07 ± 3.53 ng/mL 7.17 ± 2.73 ng/mL 0.00103* 0.000632* Metabolite-to-parent drug ratio 0.98 ± 0.78 0.39 ± 0.44 0.016 0.009171* Concentration/dose ratio Buprenorphine 0.29 ± 0.36 ng/mL/mg 0.63 ± 0.26 ng/mL/mg 0.00519* 0.00223* Concentration/dose ratio Norbuprenorphine 0.117 ± 0.077 ng/mL/mg 0.206 ± 0.147 ng/mL/mg 0.0372 0.0518 Active moiety/dose ratio 0.33 ± 0.34 ng/mL/mg 0.83 ± 0.32 ng/mL/mg 0.000141** 0.000268* Serum cannabinoid concentrations Patients reported once-daily cannabis use at night had their serum cannabinoid levels measured, as outlined above. The concentrations of THC and its metabolites measured punctually were in the micromolar range: THC 14.29 ± 2.39 mg/L; THC-COOH 101.24 ± 56.32 mg/L; 11-OH-THC 1.97 ± 0.38 mg/L, N = 3. Considering the pharmakokinetics of smoked cannabis [24], these values indicate that we did not phlebotomize patients at the time of peak cannabinoid serum concentrations shortly after smoking. Overall, our observed concentrations are compatible with once-daily cannabis use by those patients. The urinary cannabinoid concentrations support frequent use of moderate amounts of cannabis. Dose and serum concentrations of buprenorphine and norbuprenorphine The mean dose of buprenorphine in the control group was 8.8 ± 3.9 mg per day, while patients in the cannabis group received an average of 8.6 ± 0.9 mg a day. This difference was not significant with both t and Mann–Whitney U test. There were wide ranges of buprenorphine dosage in both groups due to different levels of opioid tolerance among patients (range 2.4–16 mg in the control group; 2–10 mg in the cannabis group). Within the control group, buprenorphine/naloxone (Suboxone®) therapy was not associated with significantly altered serum buprenorphine (p = 0.522) or dose-related concentrations compared to buprenorphine alone (Subutex®) (p = 0.504). Despite overall similar buprenorphine dosage, we found a highly significant correlation between cannabis use and serum buprenorphine level (p = 0.000563). Patients in the cannabis group reached a mean concentration of 5.4 ± 2.3 ng/mL (range 2.0–10.0 ng/mL; interquartile range 3.7–7.2 ng/mL), with control group patients reaching a mean of 2.0 ± 3.2 ng/ml (range 0.2–12.6 ng/mL; interquartile range 0.4–1.4 ng/mL). Consistent with this, we found a significant correlation between cannabis use and the concentration/dose (C/D) ratio for buprenorphine. The C/D ratio for buprenorphine in the cannabis group was elevated (0.63 ± 0.54 vs 0.29 ± 0.36; p = 0.0019). The Mann–Whitney U test, which does not require normal distribution of data, confirmed the statistically significance of the Student’s test. On average, norbuprenorphine concentrations were higher in the cannabis group; however, this effect was not statistically significant. The metabolite-to-parent drug ratio was reduced in the cannabis group (0.98 ± 0.78 vs 0.39 ± 0.44; p = 0.016; see Table 3 for distribution). However, it was not significant.Table 3 Distribution of metabolite-to-parent drug ratio in the control and cannabis group Control Cannabis Mean 0.423 0.18 SD 0.41 0.2 Median 0.93 0.278 Interquartile range Q1–Q3 0.33–1.33 0.13–0.42 Total active moiety was elevated in the cannabis group with a mean of 7.2 ± 2.7 ng/mL and a mean of 3.07 ± 3.54 ng/mL in the control group (p = 0.00103). The dose-related active moiety differed significantly as well, reaching 0.83 ± 0.32 ng/mL/mg in the cannabis group and 0.33 ± 0.34 ng/mL/mg in the control group. In order to assess possible dose-dependent effects, we searched for a correlation of gross urinary cannabinoid concentrations as measured by immunoassay and serum buprenorphine levels and C/D ratios. We found a weak, but not significant positive correlation. However, in three of our patients not included in then original study due to HCV infection and co-medication who managed to permanently cease cannabis use with laboratory confirmation, serum buprenorphine, metabolic ratio and C/D ratios declined after cannabis cessation, supporting the idea of an interaction between cannabis use and buprenorphine metabolism. Gender effects As 40% of measurements in the cannabis group came from female patients while the control group consisted of male patients only, we compared men and women in the cannabis group by performing multiple t-tests to assess effects of gender on the sample. We did not find a significant effect (Table 4). However, mean serum buprenorphine levels, metabolite-to-parent ratio and dose-related buprenorphine concentrations were slightly higher in female patients which is consistent with the findings reported by other investigators [25].Table 4 Serum concentrations of buprenorphine, norbuprenorphine in male and female consumers of cannabis Male (n = 9) Female (n = 6) p (Student’s t test) p (Mann–Whitney U test) Dose 8.56 ± 1.0 mg 8.6 ± 0.81 mg 0.827 0.850 Serum buprenorphine 4.49 ± 1.97 ng/mL 6.80 ± 2.11 ng/mL 0.0495 0.0518 Serum norbuprenorphine 1.49 ± 1.54 ng/mL 2.17 ± 0.35 ng/mL 0.313 0.138 Metabolite-to-parent drug ratio 0.429 ± 0.58 0.34 ± 0.94 0.717 0.316 Active moiety 5.98 ± 2.4 ng/mL 8.97 ± 2.29 ng/mL 0.0316 0.0518 Concentration/dose ratio Buprenorphine 0.52 ± 0.21 ng/mL/mg 0.79 ± 0.26 ng/mL/mg 0.0421 0.0518 Concentration/dose ratio norbuprenorphine 0.17 ± 0.18 ng/mL/mg 0.25 ± 0.059 0.324 0.195 Dose-related active moiety 0.69 ± 0.26 ng/mL/mg 1.05 ± 0.30 ng/mL/mg 0.0308 0.0677 Treatment effects In order to rule out effects of the duration of OMT and cannabis use, we performed multiple variant one-way ANOVA. There was no significant interaction in neither control group (Wilken’s Λ = 0.266, p = 0.8923) nor the cannabis group (Wilken’s Λ = 0.006, p = 0.152) nor in a group of pooled patients from both groups (Wilken’s Λ = 0.292, p = 0.9312; see Fig. 1).Fig. 1 Mean serum buprenorphine of the cannabis group (N = 15), dose-related buprenorphine concentrations, serum norbuprenorphine concentrations and metabolite-to-parent drug ratios per years of measuring (error bars denote 95% confidence intervals) Case report One patient in long-term OMT who was followed in this study since 2012 being clinically stable and in long-term employment ever since presented with marked clinical decline. He had always been using cannabis while on OMT with no additional concomitant drug use and required gradual increases in buprenorphine dosage from 7 to 10 mg daily over a course of 6 years starting 2012. This was consistent with increasing physical requirements by his occupation. He did not require any medication except for a pregabalin prescription (300 mg/d) which is not known to interfere with buprenorphine or cannabis metabolism. At one presentation, he reported sleep disturbances, agitation and decreased motivation, drive, contemplation and overall mood. Affect lability was found to be increased, and a depressive episode was diagnosed. Furthermore, the patient reported he had quit cannabis use a month ago, and this was confirmed by immunologic urine analysis and serum GC/MS for THC and metabolites (serum THC < 0.5 ng/mL, THC-COOH < 2.5 ng/mL, 11-OH-THC < 0.5 ng/mL) compared to presentation 6 months earlier (THC 16.82 ng/mL, THC-COOH 28.46 ng/mL, 11-OH-THC 1.63 ng/mL). He reported improved feeling of somatic health but increasing psychological issues. Upon clinical observation, he appeared pale, sweaty and agitated, indicating a withdrawal syndrome. The patient reported severe buprenorphine craving; this prompted buprenorphine status evaluation. Indeed, both buprenorphine and norbuprenorphine levels were markedly decreased compared to presentation six months earlier (0.3 ng/mL vs 6.3 ng/mL for buprenorphine; 0.3 ng/mL vs 1.0 ng/mL for norbuprenorphine), metabolic ratio having increased (1.00 compared to 0.16 6 months earlier). The patient was started on supportive therapy for psychic instability, depressed mood and insomnia using valproic acid (600 mg ramp-up) and mirtazapine (30 mg) and buprenorphine dosage was increased to 12 mg daily. Upon re-evaluation 14 days later, his clinical condition stabilized, while buprenorphine craving and agitation were still increased, albeit greatly ameliorated. The patient did not appear pale anymore. Serum buprenorphine concentration and dose-related concentrations were increased (2.1 ng/mL and 0.2 ng/mL/mg for buprenorphine; 0.8 ng/mL and 0.1 ng/mL/mg for norbuprenorphine; metabolic ratio 0.38); however, both plasma levels and dose-related concentrations had not rebounded to levels prior to cannabis cessation. This effect was consistent with prior attempts of this patient to reduce cannabis use with reductions in dose-related buprenorphine concentrations occurring at those times. Drug interaction score In the evaluation using the Drug Interaction Probability Score (DIPS) proposed by Horn and co-workers, the interaction was rated as ‘probable’, as intra-individual comparison in three patients who managed to quit cannabis use altogether showed all a decline of buprenorphine levels after cannabis cessation. This is consistent with the findings of a fourth patient described above, giving rise to a drug interaction score of probable. Discussion This retrospective analysis of buprenorphine concentrations in blood of opioid-dependent patients found elevated buprenorphine levels and metabolite-to-parent drug ratios in the cannabis patients compared to the control group. This suggests a lowered metabolic rate possibly via CYP3A4, CYP2C8 and/or the UGT2B7 pathways. Since CYP3A4 is the most important enzyme responsible for N-dealkylation of buprenorphine [5, 8], CYP3A4 inhibition may be assumed. Intra-individual comparison in patients who managed to quit cannabis use showed a decline of buprenorphine levels after cannabis cessation, giving rise to a drug interaction score of probable. This is consistent with the literature findings: Damkier et al. described the case of a 27-year-old male undergoing warfarin therapy due to endocarditis with subsequent mechanic heart valve replacement with severe INR elevation after recreational cannabis administration [26]. Additional similar case reports exist [27]. These reports are in line with findings in our own patients, one report described above. This underlines that changes in pharmacokinetics precipitated by cannabis are to be reckoned with by the treating physician, as changes in cannabis consumption habits may necessitate changes in treatment. Considering increasing prevalence of cannabis use, this has implications beyond the scope of addiction medicine, being relevant for the treatment of psychoses, depression and cancer, to name a few. Cannabis is a heterogeneous substance with great variability in its active ingredients [1, 28]. In vitro data suggest an inhibitory effect of cannabidiol (CBD), but not THC on CYP3A4 (IC50 = 1 μM) (reviewed by [4]). Both CBD and cannabinol (CBN) as well as THC seem to inhibit CYP2C9 (IC50 = 0.95–9.88 µM for CBD, IC50 = 0.88–1.29 μM for CBN, IC50 = 0.94–1.50 μM for THC, respectively). Especially drug–drug interactions precipitated by CBD have gained interest as CBD is being employed in the treatment of refractory epilepsia [29, 30]. There is further evidence for CBDs efficacy as an antipsychotic [31–34] and its usefulness in the treatment of non-motor symptoms in Parkinson’s disease [35]. CYP3A4 inhibition by CBD may explain the increased buprenorphine levels observed. CYP2C8 inhibition may exacerbate this effect, as there are FDA caveats against CYP2C8 inhibition by CBD [36, 37]. As both CBD and buprenorphine are substrates of uridyl-glucuronosyl transferase 2B7 (UGT2B7), competition for this transporter may impair fecal buprenorphine excretion, further increasing plasma concentration. A virtually unlimited amount of cannabis strains is available on the black market, including strains with significant CBD content. In the past decades, overall content of psychoactive cannabinoids in the cannabis plant in both the USA and the European Union has increased, especially the content of THC [1]. Several medicinally available strains of cannabis contain high CBD levls. This poses a significant risk of patients reliant on any drug subject to CYP3A4-mediated metabolism, especially considering the increasing prevalence of both illicit and medical cannabis use, legalization and the fact that high CBD cannabis tends to be marketed as especially healthy. An interaction between clobazam and CBD has been reported [29, 38] by Geffrey, Pollack et al. in children being treated for refractory epilepsy; elevated clobazam and norclobazam levels were found, precipitating side effects requiring a dose reduction. Although the in vitro data favor the role of CBD but less of THC on buprenorphine plasma levels, our clinical in vivo data, underlined by the case report with quantitative measurement of THC and its metabolites, lead to the suspicion that THC may probably also have inhibitory effects on CYP3A4. The buprenorphine levels decreased with decreasing THC levels. However, we did not assess serum CBD levels. Further studies have to be conducted to clarify the role of different substances of cannabis on the CYP isozymes in vivo. To avoid interactions with other drugs, we eliminated confounding effects of co-medication by excluding patients under medications with known inhibitory or inducing potential on CYP3A4 or CYP2C. Most psychiatric patients, however, require several drugs which are substrates, inducers or inhibitors of the CYP isozymes including CYP3A4 and CYP2C9, both inhibited by CBD (quetiapine, fluoxetine, levomepromazine [10]), leading to unpredictable buprenorphine levels. Consumption of readily available CYP inducers or inhibitors like St. John’s Wort or excessive amounts of grapefruit juice, respectively, may exacerbate this issue. The same holds true for patients receiving cannabis for chronic pain, or for chemotherapy-induced nausea. The serum levels of THC, hydroxylated THC (11-OH-THC) and THC-carboxylic acid (THC-COOH) measured by us were comparable steady-state concentrations of frequent users of cannabis via smoking, inhalation and the oral route, including prescription drugs like Dronabinol® or Sativex® [24, 39]. Concordantly, these patients did not consume cannabis in extremely and uncommonly high amounts. Still, we only measured cannabinoid concentrations (THC and metabolites) in few patients; therefore, total cannabis exposure of other patients can only be estimated. Limitations While we selected the cannabis users and non-users as control group with great care in regard to confounding factors, our approach harbors several limitations: Most of the patients were men, possibly inferring bias. There is evidence for higher CYP3A4 activity in women [25], warranting increased vigilance in regard to interactions. We did not find significantly higher buprenorphine levels or metabolite-to-parent drug ratios in female patients of our study, but recognized a trend for higher buprenorphine levels. This could be due to increased sensitivity to CYP3A4 inhibition due to increased CYP3A4 activities, but this remains unknown. Drug consumption was closely evaluated using GC/MS; however, patients were followed over several years: Since cannabis contents vary widely among different “suppliers” in regard to cannabinoid composition and total cannabinoid concentration, significant changes in cannabinoid consumption in the presence of normal test findings cannot be ruled out. Duration of buprenorphine treatment but also of concomitant cannabis use did not influence buprenorphine levels in our study. In vitro data suggest highly divergent action of different cannabinoids on the cytochrome P450 system [4]; therefore, different batches of cannabis may have divergent effects on serum buprenorphine concentrations. However, the immunoassay used in this study did not differentiate between the cannabinoids and was not sensitive for CBD as all other usually available cannabis tests. Furthermore, in the functionally performed urine tests with GC/MS of the cannabis user, we did not find CBD assuming that the preparations of cannabis used by the patients tested probably contained rather low concentrations of CBD. A standardized approach with defined cannabinoid intake is necessary to assess these effects in detail. We only included patients from a single center of care, increasing risk of bias in regard to the composition of the illegal cannabis used by our patients. Nasser et al. reported buprenorphine levels to be higher in subjects with HCV seropositivity or hepatic impairment [20, 21]. Conclusion Overall, increased serum buprenorphine levels and concentration-to-dose ratios support a cannabis–buprenorphine interaction. A decreased metabolite-to-parent drug ratio indicates reduced N-dealkylation, suggesting that cannabis preparations consumed by our patients inhibited CYP3A4 activity in favor of other metabolic pathways. Competition for UGT2B7 may lead to less buprenorphine conjugation and thus retention, further decreasing metabolite-to-parent drug ratio. This is consistent with preliminary in vitro and in vivo data. It should be taken into consideration when trying to wean OMT patients from cannabis use as it may cause additional buprenorphine withdrawal symptoms and may require increased buprenorphine dosage to stabilize these patients. Considering increasing use of cannabinoids in oncology and pain management, caution should be advised when prescribing medical cannabis preparations since a drug interaction could cause serious complications in settings of psychiatric treatment, pain treatment, chemotherapy or anticoagulation. The increasing recreational use of cannabis presents additional issues; physicians should be aware of this interaction, enabling them to give advise to their patients in order to maximize treatment efficacy and minimize side effects and drug toxicity precipitated by concomitant cannabis use by the patients unknown to the treating physician. Therapeutic drug monitoring of opioids (here buprenorphine) seems to be a valuable methodological option for optimizing maintenance treatment in case of additional intake of interacting substances by reducing the risk of plasma-level-dependent toxicities and other undesirable effects. Acknowledgements This research received support from the Deutsche Forschungs Gesellschaft (DFG) via the Center of Nanoscale and Molecular Physiology of the Brain as part of the project C1 Havemann-Reinecke Stress, Cannabinoids and Psychic Diseases. Compliance with ethical standards Conflict of interest Christoph Hiemke has received speaker’s or consultancy fees from the following pharmaceutical companies: Janssen-Cilag, Otsuka, Lohmann Transdermale Systeme, Roche and Servier. He is the managing editor of PSIAC (www.psiac.de) which provides an internet-based drug–drug interaction program for psychopharmacotherapy. He reports no conflict of interest with this publication. Ursula Havemann-Reinecke has served on the advisory Board on opioid maintenance treatment of Sanofi and Indivior London. She has received speaker’s fee from Hexal. She reports no conflict of interest with this publication. Michael Böttcher and Christopher Vierke report no conflicts of interests.

Recovering

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31907614

2021-08

What was the outcome of reaction 'Drug level increased'?

Buprenorphine-cannabis interaction in patients undergoing opioid maintenance therapy. Buprenorphine is a partial μ-opioid agonist widely used for opioid maintenance therapy (OMT). It is mainly metabolized to pharmacologically active norbuprenorphine by the cytochrome P450 (CYP) isozyme 3A4. This may give rise to drug-drug interactions under combinations with inhibitors or inducers of CYP3A4. Cannabis is a potential inhibitor of CYP3A4, and there is a large degree of concomitant cannabis use among OMT patients. We performed a retrospective analysis on liver healthy OMT patients substituted with buprenorphine, either with (n = 15) or without (n = 17) concomitant use of cannabis. Patients with additional illicit drugs or medications affecting CYP3A were excluded. Measured blood concentrations of buprenorphine and norbuprenorphine were compared between the two groups. Cannabis users and non-users received similar doses, but users had 2.7-fold higher concentrations of buprenorphine (p < 0.01) and 1.4-fold for norbuprenorphine (1.4-fold, p = 0.07). Moreover, the metabolite-to-parent drug ratio was 0.98 in non-users and 0.38 in users (p = 0.02). Female gender did not produce significant effects. These findings indicate that cannabis use decreases the formation of norbuprenorphine and elevates buprenorphine and norbuprenorphine concentrations in blood most probably by inhibition of CYP3A4. The pharmacokinetic interaction may give rise to enhanced or altered opioid activity and risk of intoxications. Physicians should inform patients about this risk and supervise cannabis users by regular control of buprenorphine blood levels, i.e., by therapeutic drug monitoring. Introduction In the past years, the prevalence of cannabis consumption has steadily increased with differential Δ9-tetrahydrocannabinol (THC) content in different preparations [1]. Patients undergoing opioid maintenance therapy (OMT) represent a traditional high-risk group for additional substance use and substance use disorders, [2] including cannabis. There is evidence that cannabinoids may interfere with the oxidative metabolism via the cytochrome P450 (CYP) isozymes and precipitate drug–drug interactions [3, 4]. The partial μ-opioid agonist buprenorphine is widely used for opioid maintenance therapy (OMT). Its long elimination half-life is subject to great inter-individual variation [5–7]. Elimination includes N-dealkylation to norbuprenorphine by CYP3A4, and to a lesser extent by CYP2C8, glucuronidation and biliary excretion [8]. Approximately 10–30% are excreted via the urinary tract [5, 7, 9]. As norbuprenorphine has a much longer elimination half-life than buprenorphine, patient adherence to the therapy regimen is associated with metabolite-to-parent drug concentration ratios greater than 1 in the presence of normal hepatic metabolism [10]. As norbuprenorphine is a much less potent analgesic drug than buprenorphine, sufficiently high buprenorphine plasma concentrations are required for the suppression of withdrawal symptoms and successful OMT [9]. Moreover, relapse prevention depends on sufficiently high drug concentrations [11–13]. To optimize efficacy and tolerability and to control buprenorphine’s susceptibility to critical drug–drug or food–drug interactions [9, 10, 14], therapeutic drug monitoring (TDM) should be applied [8]. Analysis of buprenorphine and norbuprenorphine in blood may support the clinician regarding the need for changes in drug dosage or administration patterns and enables detection of non-compliance. In particular, the drug concentration-to-dose ratio in conjunction with the metabolite-to-parent drug ratio presents a valid parameter for assessing compliance [15, 16]. To prevent intravenous abuse, sublingual formulations containing buprenorphine/naloxone combinations are available. However, there is still a large degree of illicit concomitant drug use in patients undergoing OMT. In a representative sample of 2694 German patients undergoing OMT, Wittchen and colleagues found concomitant use of at least one drug in 54% of patients [2]. Moreover, there is a high prevalence of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infection; in the Wittchen et al. cohort, 67% of patients tested positive for HCV and for 7.3% for HIV infection [2]. Hepatic inflammation, damage and impairment induced by HCV infection may interfere with the metabolism of various drugs, including buprenorphine; elevated levels of buprenorphine with decreased metabolism to norbuprenorphine in patients with hepatic impairment due to HCV infection have been reported [17]. Furthermore, the various antiviral medications used to treat HCV or HIV infection have been described to both inhibit and induce CYP enzymes, most notably CYP3A4. As a consequence, suboptimal levels of concurrent psychotropic medication have been found with a higher incidence in HIV/HCV-positive cohorts than in negative cohorts [18]. Wittchen and colleagues identified concomitant cannabis use in 30–46% in small and large OMT centers, respectively [2]. A study of the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) in 2015 revealed a one year prevalence of cannabis use of 5% in Europe and 10% in North America [19]. Significant psychiatric and somatic co-morbidity in patients suffering from addiction are a further complication in the management of these patients. Elevated buprenorphine levels were only found in patients with HCV infection plus moderate-to-severe liver impairment [20, 21]. Another risk factor is antiviral therapy with drugs known to cause interactions via the CYP isozymes [18, 22]. The CYP3A4-dependent metabolism of buprenorphine may be subject to interactions with both therapeutic and illicit drugs. This might put OMT patients at risk of altering their buprenorphine levels in a detrimental manner. Controlling the drug concentrations in blood by TDM can prevent buprenorphine-induced toxicity or relapse due to supra- or sub-therapeutic drug concentrations. To evaluate a possible interaction between cannabis use and buprenorphine OMT, we analyzed serum buprenorphine and norbuprenorphine levels in patients without HCV and HIV infections undergoing OMT and supervised by TDM by comparing drug and metabolite concentrations in blood of cannabis users and non-users. Methods Patients Patients undergoing OMT with either buprenorphine or buprenorphine/naloxone at the clinic for psychiatry and psychotherapy from 2012 to 2018 of the University Medical Center Göttingen (UMG) were included based on the following criteria: Patients had to be in buprenorphine OMT for at least 5 years and considered to be clinically stable by the treating physician. Stable buprenorphine dosage and take-home prescription constituted further inclusion criteria. Correct buprenorphine dosage was determined by clinical parameters (opioid withdrawal score, patient reporting well-being without feeling of “high”) with daily intake under supervision over a long time period before being approved for take-home prescription. Patients had to visit the clinic for supervised intake in the morning once a week. All patients with take-home prescription were instructed to take in the drug in the morning only. Patients acknowledged this as they required adequate buprenorphine dosing for their work. No consumption of any legal or illegal drugs except for cannabis for at least one year, no HIV infection, no active hepatitis with hepatic impairment and no medications with known CYP3A4 and CYP2C8 interactions constituted further inclusion criteria. All patients included in this work gave informed consent to TDM and scientific use of generated data. Laboratory measurements For recording of trough plasma levels of buprenorphine, the blood samples were withdrawn 30 min prior to ingesting the next dose under supervision. Viral status for HCV, HBV and HIV was evaluated serologically by immunoassay, while medications were assessed by anamnesis and gas chromatography with mass spectroscopy/MS (GC/MS) in urine. We excluded patients with renal impairment as measured by plasma creatinine elevation. Liver function For estimation of hepatic impairment or irritation, we used plasma transaminase activities (AST, ALT), γ-GT, INR and plasma albumin concentration to prevent falsely high buprenorphine concentrations due to HCV-induced liver damage or irritation. Transaminase and bilirubin elevations, INR prolongation and abnormal γ-GT constituted exclusion criteria. Drug, alcohol and medication use Patients with a history of alcohol misuse were routinely tested for relapse by monitoring urine ethyl glucuronate, ethyl sulfate and serum carbohydrate-deficient transferrin by immunoassay. All patients were screened for drug misuse, including ethanol using immunologic urine testing on a monthly basis (Diagnostik Nord GmbH, see Table 1 for cutoff values) with subsequent confirmation of positive results for amphetamine and/or detection of other psychoactive drugs, using gas chromatography–mass spectrometry (GC/MS) or liquid chromatography–mass spectrometry (LC/MS). Furthermore, toxicological serum analysis using GC/MS was used for drug and medication testing both initially and punctually if warranted by clinical indication.Table 1 Cutoff values for immunological drug screening in urine Drug Cutoff Amphetamine 500 ng/mL Cannabis (THC and metabolites) 50 ng/mL Opiates 300 ng/mL Cocaine 300 ng/mL Benzodiazepines 300 ng/mL Barbiturates 300 ng/mL Methadone 300 ng/mL Measurement of cannabis/cannabinoids The immunoassay (urine stick by Diagnostik Nord) qualitatively detects cannabis in urine on the base of THC and its metabolites. To assess possible dose-dependent effects of cannabis, an immunoassay was used to grossly determine urinary cannabinoid levels on the base of THC and the THC metabolites in a semiquantitative fashion, a CEDIA system (Microgenics, Freemont) in patients selected by clinical need. The test was sensitive for tetrahydrocannabinol (THC) and most of its known metabolites, intermediary for cannabinol but not for cannabidiol. This test did not differentiate between the different cannabinoids. The GC/MS method in urine qualitatively detects THC and metabolites, cannabinol and cannabidiol (CBD) or synthetic cannabinoids. Patients self-reporting once-daily cannabis smoking underwent punctual measurements of THC, 11-OH THC and 9-nor-carboxy-THC concentrations in serum using GC/MS to quantitatively estimate actual cannabinoid exposure in our patients. Serum buprenorphine measurements For quantification of buprenorphine and norbuprenorphine in serum, a DIN EN ISO/IEC 17,025 accredited ultra-performance liquid chromatography–mass spectrometry method (Waters Acquity UPLC connected to TQ-S detector, Waters GmbH, Eschborn, Germany) was applied. Sample preparation: 100 µL serum was fortified with 20 µL internal standard solution containing 25 ng/mL buprenorphine-D4 (LGC Standards, Wesel, Germany) and 25 ng/mL norbuprenorphine-D3 (LGC Standards) in methanol. The sample was then protein-precipitated with 450 µL acetonitrile and 50 µL ammonia solution (32% v/v) and subsequently salted out with 50 µL 10 M ammonium acetate. After centrifugation, the organic supernatant was evaporated to dryness at 45 °C and the residue dissolved in 25 µL methanol + 125 µL mobile phase A. Injection volume into the UPLC-MS/MS system was 10 µL. Separation was conducted within 9 min on waters 2.1 × 150 mm, 1.8 µm HSS T3 column kept at 50 °C at a flow rate of 0.35 mL/min. Mobile phase A consisted of 20 mM ammonium formate (pH 3), and mobile phase B was 0.1% formic acid in methanol. Gradient separation started at 95% A and ended at 10% A. Data were acquired with an ESI source operating in the positive ionization, SRM mode with three transitions monitored per analyte and two transitions monitored per internal standard. Capillary voltage was set to 3 kV, ion source temperature was 150 °C, and desolvation gas was heated to 650 °C and delivered at a flow rate of 650 L/h. Cone gas flow (N2) was 150 L/h, and the collision gas flow (Ar) was 0.22 mL/min. The following transitions were monitored: buprenorphine: 468.2 > 396.2 (target ion), 468.2 > 414.3 (qualifier 1 ion), 468.2 > 83.8 (qualifier 2 ion); buprenorphine-D4: 472.3 > 400.2, 472.3 > 414.9, 4; norbuprenorphine: 414.3 > 83.1, 414.3 > 101.2, 414.3 > 187.1; norbuprenorphine-D3: 417.2 > 83.1, 417.2 > 152.2. Matrix calibration in human serum was performed at 0.1, 0.2, 0.3, 0.4, 0.5, 0.75, 1.0, 2.5 and 10 ng/mL. Limits of quantification were determined according to GTFCh guidelines at 0.1 ng/mL for buprenorphine and 0.2 ng/mL for norbuprenorphine. A commercial human serum control (STM 1–13-A SE, ACQ Science, Rottenburg-Hailfingen, Germany) and human urine control sample (FDT -25% UR, ACQ Science) with target values for buprenorphine at 3.51 ng/mL and 0.78 ng/mL and norbuprenorphine at 12.1 ng/mL and 0.74 ng/mL revealed CVs of 6.8% to 15.9% (n = 27). Statistics Statistical analysis was conducted by Student’s t test to compare the cannabis and treatment group and assess possible gender effects with a significance level of α = 0.00625 as determined by Holm–Bonferroni method due to multiple testing. Eligible measurements were stratified for each patient. Mean dosage was calculated over the course of the years between 2012 and 2018. Mann–Whitney U tests, which does not require normal distribution, were performed. Multi-variant one-way ANOVA was employed due to evaluate possible effects of treatment duration. All statistical calculations were done using the Statistica Software version 13.3 for Windows by TIBCO Software Inc. (Palo Alto). Statistical values are reported as mean ± standard deviation unless specified otherwise. Graphical representations were created using Office Excel 2016 (Microsoft Corporation, Redmond). Drug interaction scoring The probability of a cannabis–buprenorphine interaction was assessed using the Drug Interaction Probability Scale [23]. This scale employs 10 items to assess the probability of a drug interaction, with higher scores indicating higher probability of a drug–drug interaction. Scores between 2 and 4 are considered to indicate a possible interaction, 5–8 a probable interaction, while scores higher than 8 indicate a highly probable drug–drug interaction. Results Patient characteristics After examining our patients for inclusion and exclusion criteria described above, we identified 32 eligible measurements out of a total of 79 serum buprenorphine measurements. Five patients with 17 measurements over a course of 5 years tested negative on toxicological screening for all drugs of abuse except nicotine, while 5 patients with 15 measurements, also over a course of 5 years, tested positive for cannabis only and were thus assigned to the cannabis group. A positive test for any cannabinoid measured by immunological test was considered a positive test for cannabis use. No patient reported cannabinoid prescription. In GC/MS analysis of urine, no intake of synthetic cannabinoid could be found in all patients. In all cases of cannabinoid detection by GC/MS, THC and metabolites were detected, seldom cannabinol, while CBD was never detected. All patients included were smokers. Three of the patients in the control group received buprenorphine/naloxone, while all patients in the cannabis group received buprenorphine-only preparations. Totally, 40% of our samples in the cannabis group came from female patients, while all samples from the control group came from male patients (Table 2). No difference in buprenorphine dosage was observed (Table 2). Mean age calculated as the arithmetic means of patient’s ages at the time the blood was drawn was 36.9 ± 9.9 years in the control group and 33.7 ± 3.3 years in the cannabis group. The last time of buprenorphine intake was documented for 53% of our patients and was 24.2 ± 2.1 h in the control group and 21.6 ± 5.1 h in the cannabis group. This difference was not significant (p = 0.18).Table 2 Serum concentrations and dose-related values of cannabis non-users (control) and users Control (n = 17) Cannabis (n = 15) p (Student’s t test) p (Mann–Whitney U test) Dose 8.8 ± 3.9 mg 8.6 ± 0.9 mg 0.831 0.748 Serum buprenorphine 2.00 ± 3.17 ng/mL 5.41 ± 2.27 ng/mL 0.00167* 0.000249* Serum norbuprenorphine 1.07 ± 0.82 ng/mL 1.76 ± 1.23 ng/mL 0.0694 0.08576 Active moiety 3.07 ± 3.53 ng/mL 7.17 ± 2.73 ng/mL 0.00103* 0.000632* Metabolite-to-parent drug ratio 0.98 ± 0.78 0.39 ± 0.44 0.016 0.009171* Concentration/dose ratio Buprenorphine 0.29 ± 0.36 ng/mL/mg 0.63 ± 0.26 ng/mL/mg 0.00519* 0.00223* Concentration/dose ratio Norbuprenorphine 0.117 ± 0.077 ng/mL/mg 0.206 ± 0.147 ng/mL/mg 0.0372 0.0518 Active moiety/dose ratio 0.33 ± 0.34 ng/mL/mg 0.83 ± 0.32 ng/mL/mg 0.000141** 0.000268* Serum cannabinoid concentrations Patients reported once-daily cannabis use at night had their serum cannabinoid levels measured, as outlined above. The concentrations of THC and its metabolites measured punctually were in the micromolar range: THC 14.29 ± 2.39 mg/L; THC-COOH 101.24 ± 56.32 mg/L; 11-OH-THC 1.97 ± 0.38 mg/L, N = 3. Considering the pharmakokinetics of smoked cannabis [24], these values indicate that we did not phlebotomize patients at the time of peak cannabinoid serum concentrations shortly after smoking. Overall, our observed concentrations are compatible with once-daily cannabis use by those patients. The urinary cannabinoid concentrations support frequent use of moderate amounts of cannabis. Dose and serum concentrations of buprenorphine and norbuprenorphine The mean dose of buprenorphine in the control group was 8.8 ± 3.9 mg per day, while patients in the cannabis group received an average of 8.6 ± 0.9 mg a day. This difference was not significant with both t and Mann–Whitney U test. There were wide ranges of buprenorphine dosage in both groups due to different levels of opioid tolerance among patients (range 2.4–16 mg in the control group; 2–10 mg in the cannabis group). Within the control group, buprenorphine/naloxone (Suboxone®) therapy was not associated with significantly altered serum buprenorphine (p = 0.522) or dose-related concentrations compared to buprenorphine alone (Subutex®) (p = 0.504). Despite overall similar buprenorphine dosage, we found a highly significant correlation between cannabis use and serum buprenorphine level (p = 0.000563). Patients in the cannabis group reached a mean concentration of 5.4 ± 2.3 ng/mL (range 2.0–10.0 ng/mL; interquartile range 3.7–7.2 ng/mL), with control group patients reaching a mean of 2.0 ± 3.2 ng/ml (range 0.2–12.6 ng/mL; interquartile range 0.4–1.4 ng/mL). Consistent with this, we found a significant correlation between cannabis use and the concentration/dose (C/D) ratio for buprenorphine. The C/D ratio for buprenorphine in the cannabis group was elevated (0.63 ± 0.54 vs 0.29 ± 0.36; p = 0.0019). The Mann–Whitney U test, which does not require normal distribution of data, confirmed the statistically significance of the Student’s test. On average, norbuprenorphine concentrations were higher in the cannabis group; however, this effect was not statistically significant. The metabolite-to-parent drug ratio was reduced in the cannabis group (0.98 ± 0.78 vs 0.39 ± 0.44; p = 0.016; see Table 3 for distribution). However, it was not significant.Table 3 Distribution of metabolite-to-parent drug ratio in the control and cannabis group Control Cannabis Mean 0.423 0.18 SD 0.41 0.2 Median 0.93 0.278 Interquartile range Q1–Q3 0.33–1.33 0.13–0.42 Total active moiety was elevated in the cannabis group with a mean of 7.2 ± 2.7 ng/mL and a mean of 3.07 ± 3.54 ng/mL in the control group (p = 0.00103). The dose-related active moiety differed significantly as well, reaching 0.83 ± 0.32 ng/mL/mg in the cannabis group and 0.33 ± 0.34 ng/mL/mg in the control group. In order to assess possible dose-dependent effects, we searched for a correlation of gross urinary cannabinoid concentrations as measured by immunoassay and serum buprenorphine levels and C/D ratios. We found a weak, but not significant positive correlation. However, in three of our patients not included in then original study due to HCV infection and co-medication who managed to permanently cease cannabis use with laboratory confirmation, serum buprenorphine, metabolic ratio and C/D ratios declined after cannabis cessation, supporting the idea of an interaction between cannabis use and buprenorphine metabolism. Gender effects As 40% of measurements in the cannabis group came from female patients while the control group consisted of male patients only, we compared men and women in the cannabis group by performing multiple t-tests to assess effects of gender on the sample. We did not find a significant effect (Table 4). However, mean serum buprenorphine levels, metabolite-to-parent ratio and dose-related buprenorphine concentrations were slightly higher in female patients which is consistent with the findings reported by other investigators [25].Table 4 Serum concentrations of buprenorphine, norbuprenorphine in male and female consumers of cannabis Male (n = 9) Female (n = 6) p (Student’s t test) p (Mann–Whitney U test) Dose 8.56 ± 1.0 mg 8.6 ± 0.81 mg 0.827 0.850 Serum buprenorphine 4.49 ± 1.97 ng/mL 6.80 ± 2.11 ng/mL 0.0495 0.0518 Serum norbuprenorphine 1.49 ± 1.54 ng/mL 2.17 ± 0.35 ng/mL 0.313 0.138 Metabolite-to-parent drug ratio 0.429 ± 0.58 0.34 ± 0.94 0.717 0.316 Active moiety 5.98 ± 2.4 ng/mL 8.97 ± 2.29 ng/mL 0.0316 0.0518 Concentration/dose ratio Buprenorphine 0.52 ± 0.21 ng/mL/mg 0.79 ± 0.26 ng/mL/mg 0.0421 0.0518 Concentration/dose ratio norbuprenorphine 0.17 ± 0.18 ng/mL/mg 0.25 ± 0.059 0.324 0.195 Dose-related active moiety 0.69 ± 0.26 ng/mL/mg 1.05 ± 0.30 ng/mL/mg 0.0308 0.0677 Treatment effects In order to rule out effects of the duration of OMT and cannabis use, we performed multiple variant one-way ANOVA. There was no significant interaction in neither control group (Wilken’s Λ = 0.266, p = 0.8923) nor the cannabis group (Wilken’s Λ = 0.006, p = 0.152) nor in a group of pooled patients from both groups (Wilken’s Λ = 0.292, p = 0.9312; see Fig. 1).Fig. 1 Mean serum buprenorphine of the cannabis group (N = 15), dose-related buprenorphine concentrations, serum norbuprenorphine concentrations and metabolite-to-parent drug ratios per years of measuring (error bars denote 95% confidence intervals) Case report One patient in long-term OMT who was followed in this study since 2012 being clinically stable and in long-term employment ever since presented with marked clinical decline. He had always been using cannabis while on OMT with no additional concomitant drug use and required gradual increases in buprenorphine dosage from 7 to 10 mg daily over a course of 6 years starting 2012. This was consistent with increasing physical requirements by his occupation. He did not require any medication except for a pregabalin prescription (300 mg/d) which is not known to interfere with buprenorphine or cannabis metabolism. At one presentation, he reported sleep disturbances, agitation and decreased motivation, drive, contemplation and overall mood. Affect lability was found to be increased, and a depressive episode was diagnosed. Furthermore, the patient reported he had quit cannabis use a month ago, and this was confirmed by immunologic urine analysis and serum GC/MS for THC and metabolites (serum THC < 0.5 ng/mL, THC-COOH < 2.5 ng/mL, 11-OH-THC < 0.5 ng/mL) compared to presentation 6 months earlier (THC 16.82 ng/mL, THC-COOH 28.46 ng/mL, 11-OH-THC 1.63 ng/mL). He reported improved feeling of somatic health but increasing psychological issues. Upon clinical observation, he appeared pale, sweaty and agitated, indicating a withdrawal syndrome. The patient reported severe buprenorphine craving; this prompted buprenorphine status evaluation. Indeed, both buprenorphine and norbuprenorphine levels were markedly decreased compared to presentation six months earlier (0.3 ng/mL vs 6.3 ng/mL for buprenorphine; 0.3 ng/mL vs 1.0 ng/mL for norbuprenorphine), metabolic ratio having increased (1.00 compared to 0.16 6 months earlier). The patient was started on supportive therapy for psychic instability, depressed mood and insomnia using valproic acid (600 mg ramp-up) and mirtazapine (30 mg) and buprenorphine dosage was increased to 12 mg daily. Upon re-evaluation 14 days later, his clinical condition stabilized, while buprenorphine craving and agitation were still increased, albeit greatly ameliorated. The patient did not appear pale anymore. Serum buprenorphine concentration and dose-related concentrations were increased (2.1 ng/mL and 0.2 ng/mL/mg for buprenorphine; 0.8 ng/mL and 0.1 ng/mL/mg for norbuprenorphine; metabolic ratio 0.38); however, both plasma levels and dose-related concentrations had not rebounded to levels prior to cannabis cessation. This effect was consistent with prior attempts of this patient to reduce cannabis use with reductions in dose-related buprenorphine concentrations occurring at those times. Drug interaction score In the evaluation using the Drug Interaction Probability Score (DIPS) proposed by Horn and co-workers, the interaction was rated as ‘probable’, as intra-individual comparison in three patients who managed to quit cannabis use altogether showed all a decline of buprenorphine levels after cannabis cessation. This is consistent with the findings of a fourth patient described above, giving rise to a drug interaction score of probable. Discussion This retrospective analysis of buprenorphine concentrations in blood of opioid-dependent patients found elevated buprenorphine levels and metabolite-to-parent drug ratios in the cannabis patients compared to the control group. This suggests a lowered metabolic rate possibly via CYP3A4, CYP2C8 and/or the UGT2B7 pathways. Since CYP3A4 is the most important enzyme responsible for N-dealkylation of buprenorphine [5, 8], CYP3A4 inhibition may be assumed. Intra-individual comparison in patients who managed to quit cannabis use showed a decline of buprenorphine levels after cannabis cessation, giving rise to a drug interaction score of probable. This is consistent with the literature findings: Damkier et al. described the case of a 27-year-old male undergoing warfarin therapy due to endocarditis with subsequent mechanic heart valve replacement with severe INR elevation after recreational cannabis administration [26]. Additional similar case reports exist [27]. These reports are in line with findings in our own patients, one report described above. This underlines that changes in pharmacokinetics precipitated by cannabis are to be reckoned with by the treating physician, as changes in cannabis consumption habits may necessitate changes in treatment. Considering increasing prevalence of cannabis use, this has implications beyond the scope of addiction medicine, being relevant for the treatment of psychoses, depression and cancer, to name a few. Cannabis is a heterogeneous substance with great variability in its active ingredients [1, 28]. In vitro data suggest an inhibitory effect of cannabidiol (CBD), but not THC on CYP3A4 (IC50 = 1 μM) (reviewed by [4]). Both CBD and cannabinol (CBN) as well as THC seem to inhibit CYP2C9 (IC50 = 0.95–9.88 µM for CBD, IC50 = 0.88–1.29 μM for CBN, IC50 = 0.94–1.50 μM for THC, respectively). Especially drug–drug interactions precipitated by CBD have gained interest as CBD is being employed in the treatment of refractory epilepsia [29, 30]. There is further evidence for CBDs efficacy as an antipsychotic [31–34] and its usefulness in the treatment of non-motor symptoms in Parkinson’s disease [35]. CYP3A4 inhibition by CBD may explain the increased buprenorphine levels observed. CYP2C8 inhibition may exacerbate this effect, as there are FDA caveats against CYP2C8 inhibition by CBD [36, 37]. As both CBD and buprenorphine are substrates of uridyl-glucuronosyl transferase 2B7 (UGT2B7), competition for this transporter may impair fecal buprenorphine excretion, further increasing plasma concentration. A virtually unlimited amount of cannabis strains is available on the black market, including strains with significant CBD content. In the past decades, overall content of psychoactive cannabinoids in the cannabis plant in both the USA and the European Union has increased, especially the content of THC [1]. Several medicinally available strains of cannabis contain high CBD levls. This poses a significant risk of patients reliant on any drug subject to CYP3A4-mediated metabolism, especially considering the increasing prevalence of both illicit and medical cannabis use, legalization and the fact that high CBD cannabis tends to be marketed as especially healthy. An interaction between clobazam and CBD has been reported [29, 38] by Geffrey, Pollack et al. in children being treated for refractory epilepsy; elevated clobazam and norclobazam levels were found, precipitating side effects requiring a dose reduction. Although the in vitro data favor the role of CBD but less of THC on buprenorphine plasma levels, our clinical in vivo data, underlined by the case report with quantitative measurement of THC and its metabolites, lead to the suspicion that THC may probably also have inhibitory effects on CYP3A4. The buprenorphine levels decreased with decreasing THC levels. However, we did not assess serum CBD levels. Further studies have to be conducted to clarify the role of different substances of cannabis on the CYP isozymes in vivo. To avoid interactions with other drugs, we eliminated confounding effects of co-medication by excluding patients under medications with known inhibitory or inducing potential on CYP3A4 or CYP2C. Most psychiatric patients, however, require several drugs which are substrates, inducers or inhibitors of the CYP isozymes including CYP3A4 and CYP2C9, both inhibited by CBD (quetiapine, fluoxetine, levomepromazine [10]), leading to unpredictable buprenorphine levels. Consumption of readily available CYP inducers or inhibitors like St. John’s Wort or excessive amounts of grapefruit juice, respectively, may exacerbate this issue. The same holds true for patients receiving cannabis for chronic pain, or for chemotherapy-induced nausea. The serum levels of THC, hydroxylated THC (11-OH-THC) and THC-carboxylic acid (THC-COOH) measured by us were comparable steady-state concentrations of frequent users of cannabis via smoking, inhalation and the oral route, including prescription drugs like Dronabinol® or Sativex® [24, 39]. Concordantly, these patients did not consume cannabis in extremely and uncommonly high amounts. Still, we only measured cannabinoid concentrations (THC and metabolites) in few patients; therefore, total cannabis exposure of other patients can only be estimated. Limitations While we selected the cannabis users and non-users as control group with great care in regard to confounding factors, our approach harbors several limitations: Most of the patients were men, possibly inferring bias. There is evidence for higher CYP3A4 activity in women [25], warranting increased vigilance in regard to interactions. We did not find significantly higher buprenorphine levels or metabolite-to-parent drug ratios in female patients of our study, but recognized a trend for higher buprenorphine levels. This could be due to increased sensitivity to CYP3A4 inhibition due to increased CYP3A4 activities, but this remains unknown. Drug consumption was closely evaluated using GC/MS; however, patients were followed over several years: Since cannabis contents vary widely among different “suppliers” in regard to cannabinoid composition and total cannabinoid concentration, significant changes in cannabinoid consumption in the presence of normal test findings cannot be ruled out. Duration of buprenorphine treatment but also of concomitant cannabis use did not influence buprenorphine levels in our study. In vitro data suggest highly divergent action of different cannabinoids on the cytochrome P450 system [4]; therefore, different batches of cannabis may have divergent effects on serum buprenorphine concentrations. However, the immunoassay used in this study did not differentiate between the cannabinoids and was not sensitive for CBD as all other usually available cannabis tests. Furthermore, in the functionally performed urine tests with GC/MS of the cannabis user, we did not find CBD assuming that the preparations of cannabis used by the patients tested probably contained rather low concentrations of CBD. A standardized approach with defined cannabinoid intake is necessary to assess these effects in detail. We only included patients from a single center of care, increasing risk of bias in regard to the composition of the illegal cannabis used by our patients. Nasser et al. reported buprenorphine levels to be higher in subjects with HCV seropositivity or hepatic impairment [20, 21]. Conclusion Overall, increased serum buprenorphine levels and concentration-to-dose ratios support a cannabis–buprenorphine interaction. A decreased metabolite-to-parent drug ratio indicates reduced N-dealkylation, suggesting that cannabis preparations consumed by our patients inhibited CYP3A4 activity in favor of other metabolic pathways. Competition for UGT2B7 may lead to less buprenorphine conjugation and thus retention, further decreasing metabolite-to-parent drug ratio. This is consistent with preliminary in vitro and in vivo data. It should be taken into consideration when trying to wean OMT patients from cannabis use as it may cause additional buprenorphine withdrawal symptoms and may require increased buprenorphine dosage to stabilize these patients. Considering increasing use of cannabinoids in oncology and pain management, caution should be advised when prescribing medical cannabis preparations since a drug interaction could cause serious complications in settings of psychiatric treatment, pain treatment, chemotherapy or anticoagulation. The increasing recreational use of cannabis presents additional issues; physicians should be aware of this interaction, enabling them to give advise to their patients in order to maximize treatment efficacy and minimize side effects and drug toxicity precipitated by concomitant cannabis use by the patients unknown to the treating physician. Therapeutic drug monitoring of opioids (here buprenorphine) seems to be a valuable methodological option for optimizing maintenance treatment in case of additional intake of interacting substances by reducing the risk of plasma-level-dependent toxicities and other undesirable effects. Acknowledgements This research received support from the Deutsche Forschungs Gesellschaft (DFG) via the Center of Nanoscale and Molecular Physiology of the Brain as part of the project C1 Havemann-Reinecke Stress, Cannabinoids and Psychic Diseases. Compliance with ethical standards Conflict of interest Christoph Hiemke has received speaker’s or consultancy fees from the following pharmaceutical companies: Janssen-Cilag, Otsuka, Lohmann Transdermale Systeme, Roche and Servier. He is the managing editor of PSIAC (www.psiac.de) which provides an internet-based drug–drug interaction program for psychopharmacotherapy. He reports no conflict of interest with this publication. Ursula Havemann-Reinecke has served on the advisory Board on opioid maintenance treatment of Sanofi and Indivior London. She has received speaker’s fee from Hexal. She reports no conflict of interest with this publication. Michael Böttcher and Christopher Vierke report no conflicts of interests.

Recovering

ReactionOutcome

CC BY

31907614

2021-08

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cytomegalovirus infection reactivation'.

Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party. Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124. Introduction Systemic sclerosis (SSc) is a rare systemic autoimmune connective tissue disease characterized by vasculopathy, immune dysregulation and progressive fibrosis, affecting primarily the skin, gastrointestinal tract, lungs, heart and kidneys.1 It is associated with high disease-related mortality2 and the main causes of death are related to cardiac, pulmonary and renal involvement.2-5 Mortality rates in patients with SSc have remained higher than those in the general population (standardized mortality ratio above 3.5) over the past decades, in contrast to reductions in mortality for other rheumatic diseases or cancer.6 After the diagnosis of non-Raynaud phenomenon, the following risk factors for higher mortality related to progressive disease have been identified:2 diffuse skin fibrosis measured by the modified Rodnan skin score (mRSS, range 0-51),7 elevated C-reactive protein levels, altered left or right ventricular ejection fraction, interstitial lung disease with reduced forced vital capacity (FVC) or diffusion capacity for carbon monoxide (DLCO) on lung function testing, proteinuria and male sex. Earlier studies had found that the presence of anti-topoisomerase II (Scl-70) auto-antibodies, reduced functional status - as measured by the Scleroderma Health Assessment Questionnaire (sHAQ, range from 0 to 3, with lower values indicating a better quality of life)8 - or pulmonary arterial hypertension adversely affect survival.3-5 Treatment with biologic or immunosuppressive drugs did not improve SSc survival.2,9,10 Following early phase I-II trials,11-13 three randomized controlled trials, namely ASSIST (American scleroderma stem cell versus immune suppression trial, phase II),14 ASTIS (Autologous stem cell transplantation international scleroderma trial, phase III)15 and SCOT (Scleroderma: cyclophosphamide or transplantation, phase II)16 demonstrated the superiority of autologous hematopoietic stem cell transplantation (HSCT) compared to the standard cyclophosphamide pulse treatment with regards to overall and event-free survival. In this context, autologous HSCT has become the best treatment option for patients with severe or rapidly progressive SSc, with a grade 1 level of evidence since 2012 according to the Autoimmune Disease Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT) recommendations. 17,18 After two decades of progress in HSCT for autoimmune diseases, the use of autologous HSCT for severe or rapidly progressive SSc has also been endorsed by the European League Against Rheumatism (EULAR)10 and the American Society for Blood and Marrow Transplantation10,17,19 and the demand for this therapeutic procedure is the fastest growing indication for HSCT in Europe.10,17,19,20 We therefore designed this ADWP-EBMT non-interventional study, NISSC1, to further evaluate the efficacy and safety of autologous HSCT for early, severe, progressive SSc, when performed in real-life practice, and to identify risk factors for early adverse events and transplant-related mortality, in order to make this approach safer. Methods Study design This study is a prospective, open, multicenter, non-interventional study. Data regarding patients included in this study were prospectively collected using a specific case report form, designed according to EBMT guidelines for HSCT in SSc.17 All EBMT participating centers agreed to report their consecutive patients aged 18 to 65 years with severe progressive SSc undergoing their first autologous HSCT between December 2012 and February 2016. Inclusion and exclusion criteria are detailed in the Online Supplementary Appendix. Participating centers followed their own local protocols for the transplant procedure as wells as the patients’ evaluation at baseline and during the 2-year follow-up. The study was approved by the EBMT board in 2012 and by local ethics committees in participating countries and registered at ClinicalTrials.gov (NCT02516124). All patients gave written informed consent to their participation in the study. Patients’ evaluation The SSc patients’ characteristics were assessed at baseline (within 3 months before autologous HSCT) and at 3, 6, 12, 18 and 24 months after transplantation (day 0 was defined as the time point of reinfusion of stem cells). Data collected included mRSS, erythrocyte sedimentation rate (in mm/h), creatine kinase levels, presence or absence of autoantibodies, left ventricular ejection fraction (LVEF in %) and systolic pulmonary arterial pressure (in mmHg) on echocardiography, resting and 24 h Holter-electrocardiograms, abnormal cardiac magnetic resonance imaging (MRI) or pulmonary arterial hypertension on right heart catheterization (RHC), FVC and DLCO (% of predicted values), high resolution computed tomography of the lungs and kidney function as well as immunosuppressive drugs given before transplantation. The sHAQ was used to evaluate patients’ quality of life. Autologous hematopoietic stem cell transplantation procedure Data collected included details on the mobilization process with or without CD34+-cell selection, type of conditioning regimen; total dose of CD34+ cells infused; number of days of hospitalization for mobilization and conditioning, use and duration of granulocyte colony-stimulating factor (G-CSF), and time to engraftment. Endpoints The primary endpoint was progression-free survival (PFS), defined as survival after autologous HSCT without death or evidence of progression of SSc (see Online Supplementary Appendix S1) The secondary endpoints were: (i) infectious or non-infectious adverse events during the first 100 days after autologous HSCT; (ii) engraftment, defined as 3 consecutive days of neutrophils >0.5x109/L and platelets >20x109/L; (iii) response to treatment, defined as a >25% improvement in mRSS and/or ≥10% improvement in FVC or DLCO as compared to baseline and without need of further immunosuppression; (iv) incidence of progression; (v) non-relapse mortality (NRM), defined as any death without progression; and (vi) overall survival. Statistical analysis Cumulative incidence functions were used to estimate response to treatment, NRM, and progression to accommodate for competing risks. Probabilities of overall survival and PFS were calculated using the Kaplan-Meier method. Univariate analyses were performed using the Gray test for cumulative incidence and the log rank test for overall survival and PFS. Multivariate analysis was performed using a Cox regression model including variables associated with the outcome with a P-value less than 0.10 in univariate analyses. Age was included as a continuous variable. A generalized linear model was used to analyze evolution over time of mRSS, FVC, DLCO and sHAQ. Results are expressed as a hazard ratio (HR) with 95% confidence interval (95% CI). Results Eighty patients (71.3% female), who had undergone a first autologous HSCT between December 2012 and February 2016 in 13 EBMT centers from six European countries and Brazil were included in this study. The centers are listed in Online Supplementary Appendix S2. The median (range) follow- up after transplantation was 24 (6-57) months. Table 1 summarizes the patients’ baseline characteristics. The median disease duration since the diagnosis of SSc was 23.8 (5.3-103.7) months. At baseline, all 80 patients had skin involvement, and mRSS was above 15 in 64 (80%) of them. Abnormal chest x-rays or abnormal high-resolution computed tomography was reported in 70 (87%) patients. Heart involvement with an abnormal 24 h electrocardiogram was reported in 12/60 (20%) or with abnormal cardiac MRI in 11/59 (19%) patients. Among the 11 patients with abnormal MRI at baseline, echocardiography showed normal LVEF in all cases and pericardial effusion in one patient, the resting ECG was abnormal in one patient and the 24 h ECG was abnormal in two patients; baseline RHC performed in six patients (with fluid challenge in 2 cases) was normal. Overall, 21 patients (26%) were transplanted without any prior cardiac MRI or RHC at baseline; among these, two had pericardial effusion and seven had a systolic pulmonary artery pressure above 25 mmHg on echocardiography, one had ventricular disturbances on resting ECG (n=20), and 2/8 had an abnormal 24 h ECG. Table 1. Baseline characteristics of the patients (n=80). Mobilization and conditioning procedures All patients were mobilized using cyclophosphamide with a median dose of 2 g/m2 (range, 1-4 g/m2) plus G-CSF. The median duration of hospitalization was 4 (1-30) days for mobilization with large variation according to centers. CD34+-cell selection was performed in 35 (44%) patients (Table 2). The median time from mobilization to the start of the conditioning regimen for autologous HSCT was 52 (22-254) days. The conditioning regimen included cyclophosphamide in all 80 patients, alone in 76 (95%) patients, with a median total dose of 200 (50-240) mg/kg. Four patients (5%) received thiotepa 10 mg/kg with a total cyclophosphamide dose of 100 mg/kg as a single-center treatment for patients with cardiac abnormalities at the pre-transplant evaluation. Additional rabbit antithymocyte globulin (ATG), with different doses according to the brand, was also included in the conditioning regimen for all patients and administered over 4 to 5 days. Sixty-seven patients (82%) received methylprednisolone during the ATG treatment. No patient received total body irradiation. A median number of 5.2 x 106/kg (2.53-23.31) CD34+ cells were reinfused at transplantation. Following autologous HSCT, G-CSF was administered to 34 (43%) patients for a median duration of 5 (1-13) days. Following autologous HSCT, the median time to neutrophil engraftment was 11 (8-24) days and the median time to platelet engraftment was 9 (1-25) days. In 13 (16.9%) patients, the platelet counts were never below 20x109/L. There was an inverse correlation between the number of CD34+ cells infused and the time to engraftment (Spearman: r2= -0.31; P<0.01), while the number of infused CD34+ cells and addition of G-CSF until recovery of aplasia were not associated with a reduced number of infectious complications (P=0.32). The median duration of inpatient hospitalization for conditioning, autologous peripheral blood stem cell re-infusion and subsequent supportive care until engraftment and discharge was 24 (8-128) days (Table 2). Efficacy At 1 and 2 years after autologous HSCT, the PFS rate was 87.5% (95% CI: 80.2-94.7) and 81.8% (95% CI: 73.1-90.5), respectively, and the rate of response to treatment was 75% (95% CI: 63.7-83.2) and 88.7% (95% CI: 79-94.1), respectively. At the 1- and 2-year time-points, the incidence of progression was 6.3% (95% CI: 2.3-13.1) and 11.9% (95% CI: 5.8-20.5), respectively, and the overall survival rate was 91.2% (95% CI: 85.1-97.4) and 90% (95% CI 83.4-96.6) at 1 and 2 years, respectively (Figure 1). Three of the four patients transplanted with thiotepa and a reduced-dose cyclophosphamide regimen responded; one with worsening skin and lung involvement at day 350 was then treated with prednisone, mycophenolate mofetil and rituximab. By multivariate analysis, mRSS >24 at baseline and older age at transplantation were significantly associated with a lower PFS with hazard ratios of 3.33 (95% CI: 1.04-10.62) and 1.77 (95% CI: 1.07-2.94), respectively. CD34+-cell selection was associated with a better response to therapy (HR: 0.46; 95% CI: 0.27-0.76). Table 2. Treatment regimen used for mobilization and conditioning. Figure 2 illustrates the evolution of the parameters over time. The mean mRSS decreased from 23.9 (standard deviation [SD] 9.7) at baseline to 14.2 (SD 9.2) at 1 year and 12.6 (SD 8.3) at 2 years (n=55, P<0.001). Regarding lung function, the mean FVC increased from 73.6% (SD 16.9) of predicted value at baseline to 79.5% (SD 16.9) at 1 year and 80.6% (SD 19.1) at 2 years (n=37, P<0.001); the mean DLCO was 60.2% (SD 19.3) at baseline, 59.7% (SD 17.7) at 1 year and 60.4% (SD 19.1) at 2 years (n=35). The sHAQ score was available in 15 patients and decreased significantly from 0.96 (SD 0.8) at baseline to 0.73 (SD 0.6) at 1 year and 0.70 (SD 0.6) at 2 years (P<0.001). The mean erythrocyte sedimentation rate decreased from 23.2 mm/h (SD 19.8) at baseline to 16.1 mm/h (SD 11.3) at 1 year and 18.7 mm/h (SD 23.6) at 2 years (n=38, P<0.001). Anti-Scl-70 and anti-centromere autoantibodies did not change after autologous HSCT. Safety The NRM rate at 100 days and 2 years was 6.25% (95% CI 2.3-13) (Figure 1). Four of the five deaths not due to relapse were related to a cardiac event, due to cyclophosphamide toxicity in three patients. A 35-year old female, who died from cardiac toxicity and multiorgan failure on day +61 after autologous HSCT, had normal resting ECG and LVEF (62%) on echocardiography, and abnormal LVEF on heart scintigraphy (47%); MRI and RHC were not performed at baseline. Three other patients died from cardiac toxicity at day +1 (n=2) and day +9 (n=1), with normal cardiac MRI and no RHC evaluation at baseline. A fifth patient (conditioning with thiotepa + reduced-dose cyclophosphamide) died from cytomegalovirus reactivation with viral copies detectable also in the lung, with bacterial (Pseudomonas) pneumonia and multiorgan failure at day +21. This patient had a normal resting ECG, with an abnormal 24 h ECG, abnormal MRI and a mean pulmonary artery pressure of 17 mmHg on RHC performed without fluid challenge at baseline. During the 24 months of follow-up, three additional patients died, all due to disease progression. Baseline characteristics of all patients who died during the follow-up and the respective causes of death are presented in Table 3. Figure 1. Kaplan-Meier curves of outcomes of patients undergoing autologous hematopoietic stem cell transplantation for severe systemic sclerosis. Overall survival (OS), progression-free survival (PFS), progression and non-relapse (treatment)- related mortality (NRM) over time. Figure 2. Boxplots of the four most important efficacy parameters in the 24 months following autologous hematopoietic stem cell transplantation for severe systemic sclerosis. (A) Improvement of the modified Rodnan skin score (mRSS) (n=55; P<0.001). (B) Improvement of forced vital capacity (FVC) (n=37; P=0.001. (C) Stabilization of diffusion capacity of carbon monoxide (DLCO) (n=35; P=0.01). (D) Improvement of Scleroderma Health Assessment Questionnaire (sHAQ) score (n=15, P=0.001). Table 3. Baseline characteristics and results from the pretransplant evaluation in patients who died during the follow-up. During the 100 days after transplantation, a total of 119 adverse events were reported among the 80 patients as detailed in Table 4. The percentage of infectious complications was not significantly different between the patients who did or did not receive CD34+-selected grafts (P=0.44), or according to the cyclophosphamide dose at the time of mobilization (2 g/m2 vs. 4 g/m2, P=0.16) or depending on whether they were or were not given G-CSF after their transplant (P=0.32) (Online Supplementary Table S3). Discussion The NISCC1 study is the largest prospective cohort today analyzing the efficacy and safety of autologous HSCT in 80 patients with severe SSc in a real-life setting. The PFS rate was 82% and significant improvements were observed in skin score, lung function and quality of life during the 2 years of follow-up, consistent with results of previous randomized controlled trials14-16 and earlier studies.11-13 Nevertheless, the NRM rate associated with auto logous HSCT was 6.25%, with most (4 out of 5) of the deaths being related to early cardiac events; this is similar to the 6% NRM rate reported retrospectively among 89 SSc patients transplanted between 2002 to 2011 in one USA and one Brazilian expert center using a non-myeloablative conditioning regimen.21 We used PFS as the primary endpoint to assess autologous HSCT efficacy rather than event-free survival, as previously used14,15 and which was defined as survival without respiratory, renal, or cardiac failure. PFS, which encompasses disease progression and toxic deaths, better reflects safety and efficacy of HSCT. In NISSC1, the incidence of progression was 6.3% and 11.9% at 1 and 2 years, respectively, highlighting the need to identify patients who may benefit from early maintenance therapy after autologous HSCT. Several mechanisms contribute to the resetting of the immunological response and disease control after autologous HSCT, and vary according to individual patients.12 We showed that the immune reconstitution profile and Tcell repertoire diversity together with a decrease in mRSS >25% and in FVC >10% at 1-2 years after transplantation could identify long-term responders and nonresponders/ relapsing patients at 4-5 years.22 The immune reconstitution process and the balance between reinduction of tolerance and sustained autoreactivity after transplantation will depend on the type of conditioning regimen used to ablate the original immune system, the effect of ATG or ex vivo CD34+-cell selection to further deplete/eliminate residual autoreactive cells and the use of post-transplant maintenance immunosuppression. 15,16,22-24 All patients in the NISCC1 study received a ‘non-myeloablative’ cyclophosphamide-based conditioning regimen, which included rabbit-derived ATG in all cases. The degree of T-cell depletion for each patient varied according to the type and total dose of ATG as well as timing of its administration in relation to the peripheral blood stem cell infusion, and whether the infused cells had undergone ex vivo CD34+ selection. In a previous retrospective EBMT analysis, we failed to demonstrate a benefit of ex vivo CD34+-cell selection23 in 138 SSc patients with similar baseline characteristics transplanted between 2000 and 2012. Surprisingly, the NISCC1 study showed a superior response to treatment in patients who received a CD34+- selected graft, with no increased rate of infectious complications, consistent with the recent findings of Ayano et al. in a retrospective analysis of 19 SSc patients.24 The reason for the difference in outcomes between these studies is unclear, but the population included in the NISCC1 prospective cohort was more homogenous in terms of conditioning, including in vivo T-cell depletion with rabbitderived ATG. All patients in the NISCC1 study received rabbit ATG formulations (although of different brands) while, in the EBMT retrospective study,23 64% of patients treated with ATG received a rabbit-derived product and 35% the horse-derived ATG formulation, which were shown to be associated with significantly different clinical outcomes in aplastic anemia.25 This important finding raises the question of whether a randomized, controlled trial should be performed to clarify whether more profound depletion of autoreactive cells from the peripheral blood stem cell graft by CD34+-cell selection may translate into sustained clinical benefit in SSc patients after autologous HSCT, without adversely affecting safety and cost-effectiveness. During the immune reconstitution process, the re-emergence of naïve T and B cells, the renewal of the immune repertoire and reinstatement of synergistic immunoregulatory mechanisms are expected. Therefore maintenance or rapid reintroduction of immunosuppression after autologous HSCT may improve patients’ outcome. The ongoing open-label trial (ClinicalTrials.gov identifier: NCT01413100) analyzing the addition of mycophenolate mofetil for 2 years after autologous HSCT and the next NISCC2 study (ClinicalTrials.gov identifier: NCT 03444805) analyzing posttransplantation management may clarify the potential benefit of post-transplant maintenance immunosuppression. A critical point for autologous HSCT in autoimmune diseases is safety. The risks of early transplant-related complications and mortality vary according to the type of disease, pre-existing internal organ involvement, the experience of the transplant center and the intensity of the conditioning regimen.12,26,27 Major cardiac adverse events and NRM after autologous HSCT in SSc are predominantly related to primary cardiac and lung involvement, which are underevaluated in the absence of systematic MRI and RHC at baseline.28,29 Our study revealed important variations in clinical practice in the pre-transplant cardio-pulmonary evaluation process. Although all patients who died during the first 100 days had normal resting ECG and LVEF on echocardiography at baseline, they were not all assessed by 24 h ECG (3/5), MRI (4/5) or RHC with fluid challenge (1/5). Overall, 24 h ECG was only used in 75% of the NISCC1 patients to detect subclinical rhythm or conduction disturbances at baseline, although it has been recommended since 2004.27 Similarly, cardiac MRI and RHC with fluid challenge were only performed in 74% and 21% of the patients, respectively, while their use has been advocated among expert centers since 2012 to minimize the risk of the transplant procedure.21,30,31 From 2013 to 2017, the EBMT and collaborative partners worked collectively to establish common standards for the use and interpretation of cardiac MRI results and RHC with fluid challenge for a rigorous cardio-pulmonary assessment of SSc patients, carefully defining eligibility and selection criteria for transplant referral.32 Table 4. Complications reported in the 100 days following autologous hematopoietic stem cell transplantation among the 80 patients treated for severe systemic sclerosis. Optimized treatment regimens are warranted to improve the safety of autologous HSCT, even in patients without cardiac involvement. Interestingly, the NRM rate in the NISCC1 study was similar to the 6% reported among 32 SSc patients transplanted between 2005 and 2011, using a ‘myeloablative’ conditioning regimen comprising total body irradiation (8 Gy), cyclophosphamide (120 mg/kg) and horse-derived ATG in the prospective SCOT randomized controlled trial.16 However, in the SCOT trial, NRM was primarily related to late fatal myelodysplastic syndromes, while no cyclophosphamide toxicity was reported. Within the follow-up period of the NISSC1 study, there were no reports of myelodysplastic syndrome or other myeloid malignancies. In addition, there were no reports of serious late infectious complications or secondary autoimmune phenomena that may occasionally present as long-term complications following autologous HSCT in autoimmune diseases. Although further follow-up is required, it is possible that there are long-term advantages, in terms of late effects, of the ‘non-myeloablative’ regimen used in the NISCC1 study. Early toxicity remains the principal challenge, including a NRM rate of 6%. To reduce toxicity and thus treatmentrelated mortality of the conditioning, a more individualized regimen with respect to heart, lung or kidney involvement might further improve patients’ safety, without excluding patients with organ manifestations. Two studies addressing patients with heart involvement are ongoing, both using a conditioning regimen with a reduced dose of cyclophosphamide and the addition of either thiotepa, as in four patients in our NISCC1 cohort (NCT01895244), or rituximab and fludarabine followed by reinfusion of autologous hematopoietic stem cells (NCT03593902), although the hematopoietic recovery from this reduced-dose regimen is prompt and reinfusion is not necessary in this setting. Because mobilization with G-CSF alone may exacerbate autoimmune diseases, there is a clinical rationale for combining G-CSF with cyclophosphamide. The use of 2 g/m2 cyclophosphamide for mobilization was as effective as 4 g/m2 at achieving the EBMT recommended minimum CD34+-cell yield, supporting dose reduction in the mobilization regimen to limit early toxicity as well as long-term risks associated with cumulative doses of cyclophosphamide. During the autologous HSCT procedures, inevitable infectious and non-infectious toxicity occurred especially following the high-dose cytotoxic conditioning and the cytopenic phase. A correlation between the number of infused CD34+ cells and a reduced duration of aplasia after autologous HSCT has been described previously, 33,34 which was confirmed in the NISCC1 study, although CD34+-cell dose and addition of G-CSF until recovery from aplasia were not associated with a reduced number of infectious complications. The NISCC1 study has several limitations. Since the study was a non-interventional trial, follow-up physical and laboratory evaluations, although recommended by EBMT guidelines,17 were not mandatory, and were not obtained at all time-points. The non-interventional study design was also the cause of significant variation in data collection practices by the 13 participating sites. Data were prospectively collected and checked for consistency by the EBMT study office; however, when some examinations were not performed, as may occur in routine clinical practice, data were classified as “missing”. The NISCC1 results showed significant variation in local practices when evaluating patients at baseline. Similarly, the number of reported days for mobilization varied largely according to centers; indeed, some patients were hospitalized for the whole duration of this procedure, whereas in other cases it was carried in part on an outpatient basis. We aimed to investigate the factors influencing the safety and efficacy of autologous HSCT. We used validated parameters to assess post-transplant outcome, such as mRSS or lung function tests despite their large intra- and inter-individual variability. The results enable deeper analysis of the benefits and risks of the transplant procedure in relation to both SSc-related factors, including the extent of heart, lung and kidney involvement at the time of patient referral, and transplant-related factors such as the conditioning regimen and graft manipulation. No international consensus has yet validated a unique activity score in SSc and further studies will be necessary in the post-transplant setting to investigate disease activity, the concept of drug-free remission and longer term outcomes, with or without post-transplant interventions. In conclusion, the NISSC1 is a large prospective real‐world data study of importance for patients, clinicians, and healthcare payers, given the poor prognosis and burden of disability of patients with severe SSc. It allowed us to assess multicenter adherence and compliance to good clinical practice and adds significantly to the evidence base supporting the delivery of autologous HSCT for severe SSc in routine clinical practice. Supplementary Material Disclosures and Contributions Supplementary Appendix

CYCLOPHOSPHAMIDE, LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN, THIOTEPA

DrugsGivenReaction

CC BY-NC

31949011

2021-02-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Multiple organ dysfunction syndrome'.

Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party. Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124. Introduction Systemic sclerosis (SSc) is a rare systemic autoimmune connective tissue disease characterized by vasculopathy, immune dysregulation and progressive fibrosis, affecting primarily the skin, gastrointestinal tract, lungs, heart and kidneys.1 It is associated with high disease-related mortality2 and the main causes of death are related to cardiac, pulmonary and renal involvement.2-5 Mortality rates in patients with SSc have remained higher than those in the general population (standardized mortality ratio above 3.5) over the past decades, in contrast to reductions in mortality for other rheumatic diseases or cancer.6 After the diagnosis of non-Raynaud phenomenon, the following risk factors for higher mortality related to progressive disease have been identified:2 diffuse skin fibrosis measured by the modified Rodnan skin score (mRSS, range 0-51),7 elevated C-reactive protein levels, altered left or right ventricular ejection fraction, interstitial lung disease with reduced forced vital capacity (FVC) or diffusion capacity for carbon monoxide (DLCO) on lung function testing, proteinuria and male sex. Earlier studies had found that the presence of anti-topoisomerase II (Scl-70) auto-antibodies, reduced functional status - as measured by the Scleroderma Health Assessment Questionnaire (sHAQ, range from 0 to 3, with lower values indicating a better quality of life)8 - or pulmonary arterial hypertension adversely affect survival.3-5 Treatment with biologic or immunosuppressive drugs did not improve SSc survival.2,9,10 Following early phase I-II trials,11-13 three randomized controlled trials, namely ASSIST (American scleroderma stem cell versus immune suppression trial, phase II),14 ASTIS (Autologous stem cell transplantation international scleroderma trial, phase III)15 and SCOT (Scleroderma: cyclophosphamide or transplantation, phase II)16 demonstrated the superiority of autologous hematopoietic stem cell transplantation (HSCT) compared to the standard cyclophosphamide pulse treatment with regards to overall and event-free survival. In this context, autologous HSCT has become the best treatment option for patients with severe or rapidly progressive SSc, with a grade 1 level of evidence since 2012 according to the Autoimmune Disease Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT) recommendations. 17,18 After two decades of progress in HSCT for autoimmune diseases, the use of autologous HSCT for severe or rapidly progressive SSc has also been endorsed by the European League Against Rheumatism (EULAR)10 and the American Society for Blood and Marrow Transplantation10,17,19 and the demand for this therapeutic procedure is the fastest growing indication for HSCT in Europe.10,17,19,20 We therefore designed this ADWP-EBMT non-interventional study, NISSC1, to further evaluate the efficacy and safety of autologous HSCT for early, severe, progressive SSc, when performed in real-life practice, and to identify risk factors for early adverse events and transplant-related mortality, in order to make this approach safer. Methods Study design This study is a prospective, open, multicenter, non-interventional study. Data regarding patients included in this study were prospectively collected using a specific case report form, designed according to EBMT guidelines for HSCT in SSc.17 All EBMT participating centers agreed to report their consecutive patients aged 18 to 65 years with severe progressive SSc undergoing their first autologous HSCT between December 2012 and February 2016. Inclusion and exclusion criteria are detailed in the Online Supplementary Appendix. Participating centers followed their own local protocols for the transplant procedure as wells as the patients’ evaluation at baseline and during the 2-year follow-up. The study was approved by the EBMT board in 2012 and by local ethics committees in participating countries and registered at ClinicalTrials.gov (NCT02516124). All patients gave written informed consent to their participation in the study. Patients’ evaluation The SSc patients’ characteristics were assessed at baseline (within 3 months before autologous HSCT) and at 3, 6, 12, 18 and 24 months after transplantation (day 0 was defined as the time point of reinfusion of stem cells). Data collected included mRSS, erythrocyte sedimentation rate (in mm/h), creatine kinase levels, presence or absence of autoantibodies, left ventricular ejection fraction (LVEF in %) and systolic pulmonary arterial pressure (in mmHg) on echocardiography, resting and 24 h Holter-electrocardiograms, abnormal cardiac magnetic resonance imaging (MRI) or pulmonary arterial hypertension on right heart catheterization (RHC), FVC and DLCO (% of predicted values), high resolution computed tomography of the lungs and kidney function as well as immunosuppressive drugs given before transplantation. The sHAQ was used to evaluate patients’ quality of life. Autologous hematopoietic stem cell transplantation procedure Data collected included details on the mobilization process with or without CD34+-cell selection, type of conditioning regimen; total dose of CD34+ cells infused; number of days of hospitalization for mobilization and conditioning, use and duration of granulocyte colony-stimulating factor (G-CSF), and time to engraftment. Endpoints The primary endpoint was progression-free survival (PFS), defined as survival after autologous HSCT without death or evidence of progression of SSc (see Online Supplementary Appendix S1) The secondary endpoints were: (i) infectious or non-infectious adverse events during the first 100 days after autologous HSCT; (ii) engraftment, defined as 3 consecutive days of neutrophils >0.5x109/L and platelets >20x109/L; (iii) response to treatment, defined as a >25% improvement in mRSS and/or ≥10% improvement in FVC or DLCO as compared to baseline and without need of further immunosuppression; (iv) incidence of progression; (v) non-relapse mortality (NRM), defined as any death without progression; and (vi) overall survival. Statistical analysis Cumulative incidence functions were used to estimate response to treatment, NRM, and progression to accommodate for competing risks. Probabilities of overall survival and PFS were calculated using the Kaplan-Meier method. Univariate analyses were performed using the Gray test for cumulative incidence and the log rank test for overall survival and PFS. Multivariate analysis was performed using a Cox regression model including variables associated with the outcome with a P-value less than 0.10 in univariate analyses. Age was included as a continuous variable. A generalized linear model was used to analyze evolution over time of mRSS, FVC, DLCO and sHAQ. Results are expressed as a hazard ratio (HR) with 95% confidence interval (95% CI). Results Eighty patients (71.3% female), who had undergone a first autologous HSCT between December 2012 and February 2016 in 13 EBMT centers from six European countries and Brazil were included in this study. The centers are listed in Online Supplementary Appendix S2. The median (range) follow- up after transplantation was 24 (6-57) months. Table 1 summarizes the patients’ baseline characteristics. The median disease duration since the diagnosis of SSc was 23.8 (5.3-103.7) months. At baseline, all 80 patients had skin involvement, and mRSS was above 15 in 64 (80%) of them. Abnormal chest x-rays or abnormal high-resolution computed tomography was reported in 70 (87%) patients. Heart involvement with an abnormal 24 h electrocardiogram was reported in 12/60 (20%) or with abnormal cardiac MRI in 11/59 (19%) patients. Among the 11 patients with abnormal MRI at baseline, echocardiography showed normal LVEF in all cases and pericardial effusion in one patient, the resting ECG was abnormal in one patient and the 24 h ECG was abnormal in two patients; baseline RHC performed in six patients (with fluid challenge in 2 cases) was normal. Overall, 21 patients (26%) were transplanted without any prior cardiac MRI or RHC at baseline; among these, two had pericardial effusion and seven had a systolic pulmonary artery pressure above 25 mmHg on echocardiography, one had ventricular disturbances on resting ECG (n=20), and 2/8 had an abnormal 24 h ECG. Table 1. Baseline characteristics of the patients (n=80). Mobilization and conditioning procedures All patients were mobilized using cyclophosphamide with a median dose of 2 g/m2 (range, 1-4 g/m2) plus G-CSF. The median duration of hospitalization was 4 (1-30) days for mobilization with large variation according to centers. CD34+-cell selection was performed in 35 (44%) patients (Table 2). The median time from mobilization to the start of the conditioning regimen for autologous HSCT was 52 (22-254) days. The conditioning regimen included cyclophosphamide in all 80 patients, alone in 76 (95%) patients, with a median total dose of 200 (50-240) mg/kg. Four patients (5%) received thiotepa 10 mg/kg with a total cyclophosphamide dose of 100 mg/kg as a single-center treatment for patients with cardiac abnormalities at the pre-transplant evaluation. Additional rabbit antithymocyte globulin (ATG), with different doses according to the brand, was also included in the conditioning regimen for all patients and administered over 4 to 5 days. Sixty-seven patients (82%) received methylprednisolone during the ATG treatment. No patient received total body irradiation. A median number of 5.2 x 106/kg (2.53-23.31) CD34+ cells were reinfused at transplantation. Following autologous HSCT, G-CSF was administered to 34 (43%) patients for a median duration of 5 (1-13) days. Following autologous HSCT, the median time to neutrophil engraftment was 11 (8-24) days and the median time to platelet engraftment was 9 (1-25) days. In 13 (16.9%) patients, the platelet counts were never below 20x109/L. There was an inverse correlation between the number of CD34+ cells infused and the time to engraftment (Spearman: r2= -0.31; P<0.01), while the number of infused CD34+ cells and addition of G-CSF until recovery of aplasia were not associated with a reduced number of infectious complications (P=0.32). The median duration of inpatient hospitalization for conditioning, autologous peripheral blood stem cell re-infusion and subsequent supportive care until engraftment and discharge was 24 (8-128) days (Table 2). Efficacy At 1 and 2 years after autologous HSCT, the PFS rate was 87.5% (95% CI: 80.2-94.7) and 81.8% (95% CI: 73.1-90.5), respectively, and the rate of response to treatment was 75% (95% CI: 63.7-83.2) and 88.7% (95% CI: 79-94.1), respectively. At the 1- and 2-year time-points, the incidence of progression was 6.3% (95% CI: 2.3-13.1) and 11.9% (95% CI: 5.8-20.5), respectively, and the overall survival rate was 91.2% (95% CI: 85.1-97.4) and 90% (95% CI 83.4-96.6) at 1 and 2 years, respectively (Figure 1). Three of the four patients transplanted with thiotepa and a reduced-dose cyclophosphamide regimen responded; one with worsening skin and lung involvement at day 350 was then treated with prednisone, mycophenolate mofetil and rituximab. By multivariate analysis, mRSS >24 at baseline and older age at transplantation were significantly associated with a lower PFS with hazard ratios of 3.33 (95% CI: 1.04-10.62) and 1.77 (95% CI: 1.07-2.94), respectively. CD34+-cell selection was associated with a better response to therapy (HR: 0.46; 95% CI: 0.27-0.76). Table 2. Treatment regimen used for mobilization and conditioning. Figure 2 illustrates the evolution of the parameters over time. The mean mRSS decreased from 23.9 (standard deviation [SD] 9.7) at baseline to 14.2 (SD 9.2) at 1 year and 12.6 (SD 8.3) at 2 years (n=55, P<0.001). Regarding lung function, the mean FVC increased from 73.6% (SD 16.9) of predicted value at baseline to 79.5% (SD 16.9) at 1 year and 80.6% (SD 19.1) at 2 years (n=37, P<0.001); the mean DLCO was 60.2% (SD 19.3) at baseline, 59.7% (SD 17.7) at 1 year and 60.4% (SD 19.1) at 2 years (n=35). The sHAQ score was available in 15 patients and decreased significantly from 0.96 (SD 0.8) at baseline to 0.73 (SD 0.6) at 1 year and 0.70 (SD 0.6) at 2 years (P<0.001). The mean erythrocyte sedimentation rate decreased from 23.2 mm/h (SD 19.8) at baseline to 16.1 mm/h (SD 11.3) at 1 year and 18.7 mm/h (SD 23.6) at 2 years (n=38, P<0.001). Anti-Scl-70 and anti-centromere autoantibodies did not change after autologous HSCT. Safety The NRM rate at 100 days and 2 years was 6.25% (95% CI 2.3-13) (Figure 1). Four of the five deaths not due to relapse were related to a cardiac event, due to cyclophosphamide toxicity in three patients. A 35-year old female, who died from cardiac toxicity and multiorgan failure on day +61 after autologous HSCT, had normal resting ECG and LVEF (62%) on echocardiography, and abnormal LVEF on heart scintigraphy (47%); MRI and RHC were not performed at baseline. Three other patients died from cardiac toxicity at day +1 (n=2) and day +9 (n=1), with normal cardiac MRI and no RHC evaluation at baseline. A fifth patient (conditioning with thiotepa + reduced-dose cyclophosphamide) died from cytomegalovirus reactivation with viral copies detectable also in the lung, with bacterial (Pseudomonas) pneumonia and multiorgan failure at day +21. This patient had a normal resting ECG, with an abnormal 24 h ECG, abnormal MRI and a mean pulmonary artery pressure of 17 mmHg on RHC performed without fluid challenge at baseline. During the 24 months of follow-up, three additional patients died, all due to disease progression. Baseline characteristics of all patients who died during the follow-up and the respective causes of death are presented in Table 3. Figure 1. Kaplan-Meier curves of outcomes of patients undergoing autologous hematopoietic stem cell transplantation for severe systemic sclerosis. Overall survival (OS), progression-free survival (PFS), progression and non-relapse (treatment)- related mortality (NRM) over time. Figure 2. Boxplots of the four most important efficacy parameters in the 24 months following autologous hematopoietic stem cell transplantation for severe systemic sclerosis. (A) Improvement of the modified Rodnan skin score (mRSS) (n=55; P<0.001). (B) Improvement of forced vital capacity (FVC) (n=37; P=0.001. (C) Stabilization of diffusion capacity of carbon monoxide (DLCO) (n=35; P=0.01). (D) Improvement of Scleroderma Health Assessment Questionnaire (sHAQ) score (n=15, P=0.001). Table 3. Baseline characteristics and results from the pretransplant evaluation in patients who died during the follow-up. During the 100 days after transplantation, a total of 119 adverse events were reported among the 80 patients as detailed in Table 4. The percentage of infectious complications was not significantly different between the patients who did or did not receive CD34+-selected grafts (P=0.44), or according to the cyclophosphamide dose at the time of mobilization (2 g/m2 vs. 4 g/m2, P=0.16) or depending on whether they were or were not given G-CSF after their transplant (P=0.32) (Online Supplementary Table S3). Discussion The NISCC1 study is the largest prospective cohort today analyzing the efficacy and safety of autologous HSCT in 80 patients with severe SSc in a real-life setting. The PFS rate was 82% and significant improvements were observed in skin score, lung function and quality of life during the 2 years of follow-up, consistent with results of previous randomized controlled trials14-16 and earlier studies.11-13 Nevertheless, the NRM rate associated with auto logous HSCT was 6.25%, with most (4 out of 5) of the deaths being related to early cardiac events; this is similar to the 6% NRM rate reported retrospectively among 89 SSc patients transplanted between 2002 to 2011 in one USA and one Brazilian expert center using a non-myeloablative conditioning regimen.21 We used PFS as the primary endpoint to assess autologous HSCT efficacy rather than event-free survival, as previously used14,15 and which was defined as survival without respiratory, renal, or cardiac failure. PFS, which encompasses disease progression and toxic deaths, better reflects safety and efficacy of HSCT. In NISSC1, the incidence of progression was 6.3% and 11.9% at 1 and 2 years, respectively, highlighting the need to identify patients who may benefit from early maintenance therapy after autologous HSCT. Several mechanisms contribute to the resetting of the immunological response and disease control after autologous HSCT, and vary according to individual patients.12 We showed that the immune reconstitution profile and Tcell repertoire diversity together with a decrease in mRSS >25% and in FVC >10% at 1-2 years after transplantation could identify long-term responders and nonresponders/ relapsing patients at 4-5 years.22 The immune reconstitution process and the balance between reinduction of tolerance and sustained autoreactivity after transplantation will depend on the type of conditioning regimen used to ablate the original immune system, the effect of ATG or ex vivo CD34+-cell selection to further deplete/eliminate residual autoreactive cells and the use of post-transplant maintenance immunosuppression. 15,16,22-24 All patients in the NISCC1 study received a ‘non-myeloablative’ cyclophosphamide-based conditioning regimen, which included rabbit-derived ATG in all cases. The degree of T-cell depletion for each patient varied according to the type and total dose of ATG as well as timing of its administration in relation to the peripheral blood stem cell infusion, and whether the infused cells had undergone ex vivo CD34+ selection. In a previous retrospective EBMT analysis, we failed to demonstrate a benefit of ex vivo CD34+-cell selection23 in 138 SSc patients with similar baseline characteristics transplanted between 2000 and 2012. Surprisingly, the NISCC1 study showed a superior response to treatment in patients who received a CD34+- selected graft, with no increased rate of infectious complications, consistent with the recent findings of Ayano et al. in a retrospective analysis of 19 SSc patients.24 The reason for the difference in outcomes between these studies is unclear, but the population included in the NISCC1 prospective cohort was more homogenous in terms of conditioning, including in vivo T-cell depletion with rabbitderived ATG. All patients in the NISCC1 study received rabbit ATG formulations (although of different brands) while, in the EBMT retrospective study,23 64% of patients treated with ATG received a rabbit-derived product and 35% the horse-derived ATG formulation, which were shown to be associated with significantly different clinical outcomes in aplastic anemia.25 This important finding raises the question of whether a randomized, controlled trial should be performed to clarify whether more profound depletion of autoreactive cells from the peripheral blood stem cell graft by CD34+-cell selection may translate into sustained clinical benefit in SSc patients after autologous HSCT, without adversely affecting safety and cost-effectiveness. During the immune reconstitution process, the re-emergence of naïve T and B cells, the renewal of the immune repertoire and reinstatement of synergistic immunoregulatory mechanisms are expected. Therefore maintenance or rapid reintroduction of immunosuppression after autologous HSCT may improve patients’ outcome. The ongoing open-label trial (ClinicalTrials.gov identifier: NCT01413100) analyzing the addition of mycophenolate mofetil for 2 years after autologous HSCT and the next NISCC2 study (ClinicalTrials.gov identifier: NCT 03444805) analyzing posttransplantation management may clarify the potential benefit of post-transplant maintenance immunosuppression. A critical point for autologous HSCT in autoimmune diseases is safety. The risks of early transplant-related complications and mortality vary according to the type of disease, pre-existing internal organ involvement, the experience of the transplant center and the intensity of the conditioning regimen.12,26,27 Major cardiac adverse events and NRM after autologous HSCT in SSc are predominantly related to primary cardiac and lung involvement, which are underevaluated in the absence of systematic MRI and RHC at baseline.28,29 Our study revealed important variations in clinical practice in the pre-transplant cardio-pulmonary evaluation process. Although all patients who died during the first 100 days had normal resting ECG and LVEF on echocardiography at baseline, they were not all assessed by 24 h ECG (3/5), MRI (4/5) or RHC with fluid challenge (1/5). Overall, 24 h ECG was only used in 75% of the NISCC1 patients to detect subclinical rhythm or conduction disturbances at baseline, although it has been recommended since 2004.27 Similarly, cardiac MRI and RHC with fluid challenge were only performed in 74% and 21% of the patients, respectively, while their use has been advocated among expert centers since 2012 to minimize the risk of the transplant procedure.21,30,31 From 2013 to 2017, the EBMT and collaborative partners worked collectively to establish common standards for the use and interpretation of cardiac MRI results and RHC with fluid challenge for a rigorous cardio-pulmonary assessment of SSc patients, carefully defining eligibility and selection criteria for transplant referral.32 Table 4. Complications reported in the 100 days following autologous hematopoietic stem cell transplantation among the 80 patients treated for severe systemic sclerosis. Optimized treatment regimens are warranted to improve the safety of autologous HSCT, even in patients without cardiac involvement. Interestingly, the NRM rate in the NISCC1 study was similar to the 6% reported among 32 SSc patients transplanted between 2005 and 2011, using a ‘myeloablative’ conditioning regimen comprising total body irradiation (8 Gy), cyclophosphamide (120 mg/kg) and horse-derived ATG in the prospective SCOT randomized controlled trial.16 However, in the SCOT trial, NRM was primarily related to late fatal myelodysplastic syndromes, while no cyclophosphamide toxicity was reported. Within the follow-up period of the NISSC1 study, there were no reports of myelodysplastic syndrome or other myeloid malignancies. In addition, there were no reports of serious late infectious complications or secondary autoimmune phenomena that may occasionally present as long-term complications following autologous HSCT in autoimmune diseases. Although further follow-up is required, it is possible that there are long-term advantages, in terms of late effects, of the ‘non-myeloablative’ regimen used in the NISCC1 study. Early toxicity remains the principal challenge, including a NRM rate of 6%. To reduce toxicity and thus treatmentrelated mortality of the conditioning, a more individualized regimen with respect to heart, lung or kidney involvement might further improve patients’ safety, without excluding patients with organ manifestations. Two studies addressing patients with heart involvement are ongoing, both using a conditioning regimen with a reduced dose of cyclophosphamide and the addition of either thiotepa, as in four patients in our NISCC1 cohort (NCT01895244), or rituximab and fludarabine followed by reinfusion of autologous hematopoietic stem cells (NCT03593902), although the hematopoietic recovery from this reduced-dose regimen is prompt and reinfusion is not necessary in this setting. Because mobilization with G-CSF alone may exacerbate autoimmune diseases, there is a clinical rationale for combining G-CSF with cyclophosphamide. The use of 2 g/m2 cyclophosphamide for mobilization was as effective as 4 g/m2 at achieving the EBMT recommended minimum CD34+-cell yield, supporting dose reduction in the mobilization regimen to limit early toxicity as well as long-term risks associated with cumulative doses of cyclophosphamide. During the autologous HSCT procedures, inevitable infectious and non-infectious toxicity occurred especially following the high-dose cytotoxic conditioning and the cytopenic phase. A correlation between the number of infused CD34+ cells and a reduced duration of aplasia after autologous HSCT has been described previously, 33,34 which was confirmed in the NISCC1 study, although CD34+-cell dose and addition of G-CSF until recovery from aplasia were not associated with a reduced number of infectious complications. The NISCC1 study has several limitations. Since the study was a non-interventional trial, follow-up physical and laboratory evaluations, although recommended by EBMT guidelines,17 were not mandatory, and were not obtained at all time-points. The non-interventional study design was also the cause of significant variation in data collection practices by the 13 participating sites. Data were prospectively collected and checked for consistency by the EBMT study office; however, when some examinations were not performed, as may occur in routine clinical practice, data were classified as “missing”. The NISCC1 results showed significant variation in local practices when evaluating patients at baseline. Similarly, the number of reported days for mobilization varied largely according to centers; indeed, some patients were hospitalized for the whole duration of this procedure, whereas in other cases it was carried in part on an outpatient basis. We aimed to investigate the factors influencing the safety and efficacy of autologous HSCT. We used validated parameters to assess post-transplant outcome, such as mRSS or lung function tests despite their large intra- and inter-individual variability. The results enable deeper analysis of the benefits and risks of the transplant procedure in relation to both SSc-related factors, including the extent of heart, lung and kidney involvement at the time of patient referral, and transplant-related factors such as the conditioning regimen and graft manipulation. No international consensus has yet validated a unique activity score in SSc and further studies will be necessary in the post-transplant setting to investigate disease activity, the concept of drug-free remission and longer term outcomes, with or without post-transplant interventions. In conclusion, the NISSC1 is a large prospective real‐world data study of importance for patients, clinicians, and healthcare payers, given the poor prognosis and burden of disability of patients with severe SSc. It allowed us to assess multicenter adherence and compliance to good clinical practice and adds significantly to the evidence base supporting the delivery of autologous HSCT for severe SSc in routine clinical practice. Supplementary Material Disclosures and Contributions Supplementary Appendix

CYCLOPHOSPHAMIDE, LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN, THIOTEPA

DrugsGivenReaction

CC BY-NC

31949011

2021-02-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia pseudomonal'.

Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party. Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124. Introduction Systemic sclerosis (SSc) is a rare systemic autoimmune connective tissue disease characterized by vasculopathy, immune dysregulation and progressive fibrosis, affecting primarily the skin, gastrointestinal tract, lungs, heart and kidneys.1 It is associated with high disease-related mortality2 and the main causes of death are related to cardiac, pulmonary and renal involvement.2-5 Mortality rates in patients with SSc have remained higher than those in the general population (standardized mortality ratio above 3.5) over the past decades, in contrast to reductions in mortality for other rheumatic diseases or cancer.6 After the diagnosis of non-Raynaud phenomenon, the following risk factors for higher mortality related to progressive disease have been identified:2 diffuse skin fibrosis measured by the modified Rodnan skin score (mRSS, range 0-51),7 elevated C-reactive protein levels, altered left or right ventricular ejection fraction, interstitial lung disease with reduced forced vital capacity (FVC) or diffusion capacity for carbon monoxide (DLCO) on lung function testing, proteinuria and male sex. Earlier studies had found that the presence of anti-topoisomerase II (Scl-70) auto-antibodies, reduced functional status - as measured by the Scleroderma Health Assessment Questionnaire (sHAQ, range from 0 to 3, with lower values indicating a better quality of life)8 - or pulmonary arterial hypertension adversely affect survival.3-5 Treatment with biologic or immunosuppressive drugs did not improve SSc survival.2,9,10 Following early phase I-II trials,11-13 three randomized controlled trials, namely ASSIST (American scleroderma stem cell versus immune suppression trial, phase II),14 ASTIS (Autologous stem cell transplantation international scleroderma trial, phase III)15 and SCOT (Scleroderma: cyclophosphamide or transplantation, phase II)16 demonstrated the superiority of autologous hematopoietic stem cell transplantation (HSCT) compared to the standard cyclophosphamide pulse treatment with regards to overall and event-free survival. In this context, autologous HSCT has become the best treatment option for patients with severe or rapidly progressive SSc, with a grade 1 level of evidence since 2012 according to the Autoimmune Disease Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT) recommendations. 17,18 After two decades of progress in HSCT for autoimmune diseases, the use of autologous HSCT for severe or rapidly progressive SSc has also been endorsed by the European League Against Rheumatism (EULAR)10 and the American Society for Blood and Marrow Transplantation10,17,19 and the demand for this therapeutic procedure is the fastest growing indication for HSCT in Europe.10,17,19,20 We therefore designed this ADWP-EBMT non-interventional study, NISSC1, to further evaluate the efficacy and safety of autologous HSCT for early, severe, progressive SSc, when performed in real-life practice, and to identify risk factors for early adverse events and transplant-related mortality, in order to make this approach safer. Methods Study design This study is a prospective, open, multicenter, non-interventional study. Data regarding patients included in this study were prospectively collected using a specific case report form, designed according to EBMT guidelines for HSCT in SSc.17 All EBMT participating centers agreed to report their consecutive patients aged 18 to 65 years with severe progressive SSc undergoing their first autologous HSCT between December 2012 and February 2016. Inclusion and exclusion criteria are detailed in the Online Supplementary Appendix. Participating centers followed their own local protocols for the transplant procedure as wells as the patients’ evaluation at baseline and during the 2-year follow-up. The study was approved by the EBMT board in 2012 and by local ethics committees in participating countries and registered at ClinicalTrials.gov (NCT02516124). All patients gave written informed consent to their participation in the study. Patients’ evaluation The SSc patients’ characteristics were assessed at baseline (within 3 months before autologous HSCT) and at 3, 6, 12, 18 and 24 months after transplantation (day 0 was defined as the time point of reinfusion of stem cells). Data collected included mRSS, erythrocyte sedimentation rate (in mm/h), creatine kinase levels, presence or absence of autoantibodies, left ventricular ejection fraction (LVEF in %) and systolic pulmonary arterial pressure (in mmHg) on echocardiography, resting and 24 h Holter-electrocardiograms, abnormal cardiac magnetic resonance imaging (MRI) or pulmonary arterial hypertension on right heart catheterization (RHC), FVC and DLCO (% of predicted values), high resolution computed tomography of the lungs and kidney function as well as immunosuppressive drugs given before transplantation. The sHAQ was used to evaluate patients’ quality of life. Autologous hematopoietic stem cell transplantation procedure Data collected included details on the mobilization process with or without CD34+-cell selection, type of conditioning regimen; total dose of CD34+ cells infused; number of days of hospitalization for mobilization and conditioning, use and duration of granulocyte colony-stimulating factor (G-CSF), and time to engraftment. Endpoints The primary endpoint was progression-free survival (PFS), defined as survival after autologous HSCT without death or evidence of progression of SSc (see Online Supplementary Appendix S1) The secondary endpoints were: (i) infectious or non-infectious adverse events during the first 100 days after autologous HSCT; (ii) engraftment, defined as 3 consecutive days of neutrophils >0.5x109/L and platelets >20x109/L; (iii) response to treatment, defined as a >25% improvement in mRSS and/or ≥10% improvement in FVC or DLCO as compared to baseline and without need of further immunosuppression; (iv) incidence of progression; (v) non-relapse mortality (NRM), defined as any death without progression; and (vi) overall survival. Statistical analysis Cumulative incidence functions were used to estimate response to treatment, NRM, and progression to accommodate for competing risks. Probabilities of overall survival and PFS were calculated using the Kaplan-Meier method. Univariate analyses were performed using the Gray test for cumulative incidence and the log rank test for overall survival and PFS. Multivariate analysis was performed using a Cox regression model including variables associated with the outcome with a P-value less than 0.10 in univariate analyses. Age was included as a continuous variable. A generalized linear model was used to analyze evolution over time of mRSS, FVC, DLCO and sHAQ. Results are expressed as a hazard ratio (HR) with 95% confidence interval (95% CI). Results Eighty patients (71.3% female), who had undergone a first autologous HSCT between December 2012 and February 2016 in 13 EBMT centers from six European countries and Brazil were included in this study. The centers are listed in Online Supplementary Appendix S2. The median (range) follow- up after transplantation was 24 (6-57) months. Table 1 summarizes the patients’ baseline characteristics. The median disease duration since the diagnosis of SSc was 23.8 (5.3-103.7) months. At baseline, all 80 patients had skin involvement, and mRSS was above 15 in 64 (80%) of them. Abnormal chest x-rays or abnormal high-resolution computed tomography was reported in 70 (87%) patients. Heart involvement with an abnormal 24 h electrocardiogram was reported in 12/60 (20%) or with abnormal cardiac MRI in 11/59 (19%) patients. Among the 11 patients with abnormal MRI at baseline, echocardiography showed normal LVEF in all cases and pericardial effusion in one patient, the resting ECG was abnormal in one patient and the 24 h ECG was abnormal in two patients; baseline RHC performed in six patients (with fluid challenge in 2 cases) was normal. Overall, 21 patients (26%) were transplanted without any prior cardiac MRI or RHC at baseline; among these, two had pericardial effusion and seven had a systolic pulmonary artery pressure above 25 mmHg on echocardiography, one had ventricular disturbances on resting ECG (n=20), and 2/8 had an abnormal 24 h ECG. Table 1. Baseline characteristics of the patients (n=80). Mobilization and conditioning procedures All patients were mobilized using cyclophosphamide with a median dose of 2 g/m2 (range, 1-4 g/m2) plus G-CSF. The median duration of hospitalization was 4 (1-30) days for mobilization with large variation according to centers. CD34+-cell selection was performed in 35 (44%) patients (Table 2). The median time from mobilization to the start of the conditioning regimen for autologous HSCT was 52 (22-254) days. The conditioning regimen included cyclophosphamide in all 80 patients, alone in 76 (95%) patients, with a median total dose of 200 (50-240) mg/kg. Four patients (5%) received thiotepa 10 mg/kg with a total cyclophosphamide dose of 100 mg/kg as a single-center treatment for patients with cardiac abnormalities at the pre-transplant evaluation. Additional rabbit antithymocyte globulin (ATG), with different doses according to the brand, was also included in the conditioning regimen for all patients and administered over 4 to 5 days. Sixty-seven patients (82%) received methylprednisolone during the ATG treatment. No patient received total body irradiation. A median number of 5.2 x 106/kg (2.53-23.31) CD34+ cells were reinfused at transplantation. Following autologous HSCT, G-CSF was administered to 34 (43%) patients for a median duration of 5 (1-13) days. Following autologous HSCT, the median time to neutrophil engraftment was 11 (8-24) days and the median time to platelet engraftment was 9 (1-25) days. In 13 (16.9%) patients, the platelet counts were never below 20x109/L. There was an inverse correlation between the number of CD34+ cells infused and the time to engraftment (Spearman: r2= -0.31; P<0.01), while the number of infused CD34+ cells and addition of G-CSF until recovery of aplasia were not associated with a reduced number of infectious complications (P=0.32). The median duration of inpatient hospitalization for conditioning, autologous peripheral blood stem cell re-infusion and subsequent supportive care until engraftment and discharge was 24 (8-128) days (Table 2). Efficacy At 1 and 2 years after autologous HSCT, the PFS rate was 87.5% (95% CI: 80.2-94.7) and 81.8% (95% CI: 73.1-90.5), respectively, and the rate of response to treatment was 75% (95% CI: 63.7-83.2) and 88.7% (95% CI: 79-94.1), respectively. At the 1- and 2-year time-points, the incidence of progression was 6.3% (95% CI: 2.3-13.1) and 11.9% (95% CI: 5.8-20.5), respectively, and the overall survival rate was 91.2% (95% CI: 85.1-97.4) and 90% (95% CI 83.4-96.6) at 1 and 2 years, respectively (Figure 1). Three of the four patients transplanted with thiotepa and a reduced-dose cyclophosphamide regimen responded; one with worsening skin and lung involvement at day 350 was then treated with prednisone, mycophenolate mofetil and rituximab. By multivariate analysis, mRSS >24 at baseline and older age at transplantation were significantly associated with a lower PFS with hazard ratios of 3.33 (95% CI: 1.04-10.62) and 1.77 (95% CI: 1.07-2.94), respectively. CD34+-cell selection was associated with a better response to therapy (HR: 0.46; 95% CI: 0.27-0.76). Table 2. Treatment regimen used for mobilization and conditioning. Figure 2 illustrates the evolution of the parameters over time. The mean mRSS decreased from 23.9 (standard deviation [SD] 9.7) at baseline to 14.2 (SD 9.2) at 1 year and 12.6 (SD 8.3) at 2 years (n=55, P<0.001). Regarding lung function, the mean FVC increased from 73.6% (SD 16.9) of predicted value at baseline to 79.5% (SD 16.9) at 1 year and 80.6% (SD 19.1) at 2 years (n=37, P<0.001); the mean DLCO was 60.2% (SD 19.3) at baseline, 59.7% (SD 17.7) at 1 year and 60.4% (SD 19.1) at 2 years (n=35). The sHAQ score was available in 15 patients and decreased significantly from 0.96 (SD 0.8) at baseline to 0.73 (SD 0.6) at 1 year and 0.70 (SD 0.6) at 2 years (P<0.001). The mean erythrocyte sedimentation rate decreased from 23.2 mm/h (SD 19.8) at baseline to 16.1 mm/h (SD 11.3) at 1 year and 18.7 mm/h (SD 23.6) at 2 years (n=38, P<0.001). Anti-Scl-70 and anti-centromere autoantibodies did not change after autologous HSCT. Safety The NRM rate at 100 days and 2 years was 6.25% (95% CI 2.3-13) (Figure 1). Four of the five deaths not due to relapse were related to a cardiac event, due to cyclophosphamide toxicity in three patients. A 35-year old female, who died from cardiac toxicity and multiorgan failure on day +61 after autologous HSCT, had normal resting ECG and LVEF (62%) on echocardiography, and abnormal LVEF on heart scintigraphy (47%); MRI and RHC were not performed at baseline. Three other patients died from cardiac toxicity at day +1 (n=2) and day +9 (n=1), with normal cardiac MRI and no RHC evaluation at baseline. A fifth patient (conditioning with thiotepa + reduced-dose cyclophosphamide) died from cytomegalovirus reactivation with viral copies detectable also in the lung, with bacterial (Pseudomonas) pneumonia and multiorgan failure at day +21. This patient had a normal resting ECG, with an abnormal 24 h ECG, abnormal MRI and a mean pulmonary artery pressure of 17 mmHg on RHC performed without fluid challenge at baseline. During the 24 months of follow-up, three additional patients died, all due to disease progression. Baseline characteristics of all patients who died during the follow-up and the respective causes of death are presented in Table 3. Figure 1. Kaplan-Meier curves of outcomes of patients undergoing autologous hematopoietic stem cell transplantation for severe systemic sclerosis. Overall survival (OS), progression-free survival (PFS), progression and non-relapse (treatment)- related mortality (NRM) over time. Figure 2. Boxplots of the four most important efficacy parameters in the 24 months following autologous hematopoietic stem cell transplantation for severe systemic sclerosis. (A) Improvement of the modified Rodnan skin score (mRSS) (n=55; P<0.001). (B) Improvement of forced vital capacity (FVC) (n=37; P=0.001. (C) Stabilization of diffusion capacity of carbon monoxide (DLCO) (n=35; P=0.01). (D) Improvement of Scleroderma Health Assessment Questionnaire (sHAQ) score (n=15, P=0.001). Table 3. Baseline characteristics and results from the pretransplant evaluation in patients who died during the follow-up. During the 100 days after transplantation, a total of 119 adverse events were reported among the 80 patients as detailed in Table 4. The percentage of infectious complications was not significantly different between the patients who did or did not receive CD34+-selected grafts (P=0.44), or according to the cyclophosphamide dose at the time of mobilization (2 g/m2 vs. 4 g/m2, P=0.16) or depending on whether they were or were not given G-CSF after their transplant (P=0.32) (Online Supplementary Table S3). Discussion The NISCC1 study is the largest prospective cohort today analyzing the efficacy and safety of autologous HSCT in 80 patients with severe SSc in a real-life setting. The PFS rate was 82% and significant improvements were observed in skin score, lung function and quality of life during the 2 years of follow-up, consistent with results of previous randomized controlled trials14-16 and earlier studies.11-13 Nevertheless, the NRM rate associated with auto logous HSCT was 6.25%, with most (4 out of 5) of the deaths being related to early cardiac events; this is similar to the 6% NRM rate reported retrospectively among 89 SSc patients transplanted between 2002 to 2011 in one USA and one Brazilian expert center using a non-myeloablative conditioning regimen.21 We used PFS as the primary endpoint to assess autologous HSCT efficacy rather than event-free survival, as previously used14,15 and which was defined as survival without respiratory, renal, or cardiac failure. PFS, which encompasses disease progression and toxic deaths, better reflects safety and efficacy of HSCT. In NISSC1, the incidence of progression was 6.3% and 11.9% at 1 and 2 years, respectively, highlighting the need to identify patients who may benefit from early maintenance therapy after autologous HSCT. Several mechanisms contribute to the resetting of the immunological response and disease control after autologous HSCT, and vary according to individual patients.12 We showed that the immune reconstitution profile and Tcell repertoire diversity together with a decrease in mRSS >25% and in FVC >10% at 1-2 years after transplantation could identify long-term responders and nonresponders/ relapsing patients at 4-5 years.22 The immune reconstitution process and the balance between reinduction of tolerance and sustained autoreactivity after transplantation will depend on the type of conditioning regimen used to ablate the original immune system, the effect of ATG or ex vivo CD34+-cell selection to further deplete/eliminate residual autoreactive cells and the use of post-transplant maintenance immunosuppression. 15,16,22-24 All patients in the NISCC1 study received a ‘non-myeloablative’ cyclophosphamide-based conditioning regimen, which included rabbit-derived ATG in all cases. The degree of T-cell depletion for each patient varied according to the type and total dose of ATG as well as timing of its administration in relation to the peripheral blood stem cell infusion, and whether the infused cells had undergone ex vivo CD34+ selection. In a previous retrospective EBMT analysis, we failed to demonstrate a benefit of ex vivo CD34+-cell selection23 in 138 SSc patients with similar baseline characteristics transplanted between 2000 and 2012. Surprisingly, the NISCC1 study showed a superior response to treatment in patients who received a CD34+- selected graft, with no increased rate of infectious complications, consistent with the recent findings of Ayano et al. in a retrospective analysis of 19 SSc patients.24 The reason for the difference in outcomes between these studies is unclear, but the population included in the NISCC1 prospective cohort was more homogenous in terms of conditioning, including in vivo T-cell depletion with rabbitderived ATG. All patients in the NISCC1 study received rabbit ATG formulations (although of different brands) while, in the EBMT retrospective study,23 64% of patients treated with ATG received a rabbit-derived product and 35% the horse-derived ATG formulation, which were shown to be associated with significantly different clinical outcomes in aplastic anemia.25 This important finding raises the question of whether a randomized, controlled trial should be performed to clarify whether more profound depletion of autoreactive cells from the peripheral blood stem cell graft by CD34+-cell selection may translate into sustained clinical benefit in SSc patients after autologous HSCT, without adversely affecting safety and cost-effectiveness. During the immune reconstitution process, the re-emergence of naïve T and B cells, the renewal of the immune repertoire and reinstatement of synergistic immunoregulatory mechanisms are expected. Therefore maintenance or rapid reintroduction of immunosuppression after autologous HSCT may improve patients’ outcome. The ongoing open-label trial (ClinicalTrials.gov identifier: NCT01413100) analyzing the addition of mycophenolate mofetil for 2 years after autologous HSCT and the next NISCC2 study (ClinicalTrials.gov identifier: NCT 03444805) analyzing posttransplantation management may clarify the potential benefit of post-transplant maintenance immunosuppression. A critical point for autologous HSCT in autoimmune diseases is safety. The risks of early transplant-related complications and mortality vary according to the type of disease, pre-existing internal organ involvement, the experience of the transplant center and the intensity of the conditioning regimen.12,26,27 Major cardiac adverse events and NRM after autologous HSCT in SSc are predominantly related to primary cardiac and lung involvement, which are underevaluated in the absence of systematic MRI and RHC at baseline.28,29 Our study revealed important variations in clinical practice in the pre-transplant cardio-pulmonary evaluation process. Although all patients who died during the first 100 days had normal resting ECG and LVEF on echocardiography at baseline, they were not all assessed by 24 h ECG (3/5), MRI (4/5) or RHC with fluid challenge (1/5). Overall, 24 h ECG was only used in 75% of the NISCC1 patients to detect subclinical rhythm or conduction disturbances at baseline, although it has been recommended since 2004.27 Similarly, cardiac MRI and RHC with fluid challenge were only performed in 74% and 21% of the patients, respectively, while their use has been advocated among expert centers since 2012 to minimize the risk of the transplant procedure.21,30,31 From 2013 to 2017, the EBMT and collaborative partners worked collectively to establish common standards for the use and interpretation of cardiac MRI results and RHC with fluid challenge for a rigorous cardio-pulmonary assessment of SSc patients, carefully defining eligibility and selection criteria for transplant referral.32 Table 4. Complications reported in the 100 days following autologous hematopoietic stem cell transplantation among the 80 patients treated for severe systemic sclerosis. Optimized treatment regimens are warranted to improve the safety of autologous HSCT, even in patients without cardiac involvement. Interestingly, the NRM rate in the NISCC1 study was similar to the 6% reported among 32 SSc patients transplanted between 2005 and 2011, using a ‘myeloablative’ conditioning regimen comprising total body irradiation (8 Gy), cyclophosphamide (120 mg/kg) and horse-derived ATG in the prospective SCOT randomized controlled trial.16 However, in the SCOT trial, NRM was primarily related to late fatal myelodysplastic syndromes, while no cyclophosphamide toxicity was reported. Within the follow-up period of the NISSC1 study, there were no reports of myelodysplastic syndrome or other myeloid malignancies. In addition, there were no reports of serious late infectious complications or secondary autoimmune phenomena that may occasionally present as long-term complications following autologous HSCT in autoimmune diseases. Although further follow-up is required, it is possible that there are long-term advantages, in terms of late effects, of the ‘non-myeloablative’ regimen used in the NISCC1 study. Early toxicity remains the principal challenge, including a NRM rate of 6%. To reduce toxicity and thus treatmentrelated mortality of the conditioning, a more individualized regimen with respect to heart, lung or kidney involvement might further improve patients’ safety, without excluding patients with organ manifestations. Two studies addressing patients with heart involvement are ongoing, both using a conditioning regimen with a reduced dose of cyclophosphamide and the addition of either thiotepa, as in four patients in our NISCC1 cohort (NCT01895244), or rituximab and fludarabine followed by reinfusion of autologous hematopoietic stem cells (NCT03593902), although the hematopoietic recovery from this reduced-dose regimen is prompt and reinfusion is not necessary in this setting. Because mobilization with G-CSF alone may exacerbate autoimmune diseases, there is a clinical rationale for combining G-CSF with cyclophosphamide. The use of 2 g/m2 cyclophosphamide for mobilization was as effective as 4 g/m2 at achieving the EBMT recommended minimum CD34+-cell yield, supporting dose reduction in the mobilization regimen to limit early toxicity as well as long-term risks associated with cumulative doses of cyclophosphamide. During the autologous HSCT procedures, inevitable infectious and non-infectious toxicity occurred especially following the high-dose cytotoxic conditioning and the cytopenic phase. A correlation between the number of infused CD34+ cells and a reduced duration of aplasia after autologous HSCT has been described previously, 33,34 which was confirmed in the NISCC1 study, although CD34+-cell dose and addition of G-CSF until recovery from aplasia were not associated with a reduced number of infectious complications. The NISCC1 study has several limitations. Since the study was a non-interventional trial, follow-up physical and laboratory evaluations, although recommended by EBMT guidelines,17 were not mandatory, and were not obtained at all time-points. The non-interventional study design was also the cause of significant variation in data collection practices by the 13 participating sites. Data were prospectively collected and checked for consistency by the EBMT study office; however, when some examinations were not performed, as may occur in routine clinical practice, data were classified as “missing”. The NISCC1 results showed significant variation in local practices when evaluating patients at baseline. Similarly, the number of reported days for mobilization varied largely according to centers; indeed, some patients were hospitalized for the whole duration of this procedure, whereas in other cases it was carried in part on an outpatient basis. We aimed to investigate the factors influencing the safety and efficacy of autologous HSCT. We used validated parameters to assess post-transplant outcome, such as mRSS or lung function tests despite their large intra- and inter-individual variability. The results enable deeper analysis of the benefits and risks of the transplant procedure in relation to both SSc-related factors, including the extent of heart, lung and kidney involvement at the time of patient referral, and transplant-related factors such as the conditioning regimen and graft manipulation. No international consensus has yet validated a unique activity score in SSc and further studies will be necessary in the post-transplant setting to investigate disease activity, the concept of drug-free remission and longer term outcomes, with or without post-transplant interventions. In conclusion, the NISSC1 is a large prospective real‐world data study of importance for patients, clinicians, and healthcare payers, given the poor prognosis and burden of disability of patients with severe SSc. It allowed us to assess multicenter adherence and compliance to good clinical practice and adds significantly to the evidence base supporting the delivery of autologous HSCT for severe SSc in routine clinical practice. Supplementary Material Disclosures and Contributions Supplementary Appendix

CYCLOPHOSPHAMIDE, LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN, THIOTEPA

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31949011

2021-02-01

What was the dosage of drug 'CYCLOPHOSPHAMIDE'?

Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party. Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124. Introduction Systemic sclerosis (SSc) is a rare systemic autoimmune connective tissue disease characterized by vasculopathy, immune dysregulation and progressive fibrosis, affecting primarily the skin, gastrointestinal tract, lungs, heart and kidneys.1 It is associated with high disease-related mortality2 and the main causes of death are related to cardiac, pulmonary and renal involvement.2-5 Mortality rates in patients with SSc have remained higher than those in the general population (standardized mortality ratio above 3.5) over the past decades, in contrast to reductions in mortality for other rheumatic diseases or cancer.6 After the diagnosis of non-Raynaud phenomenon, the following risk factors for higher mortality related to progressive disease have been identified:2 diffuse skin fibrosis measured by the modified Rodnan skin score (mRSS, range 0-51),7 elevated C-reactive protein levels, altered left or right ventricular ejection fraction, interstitial lung disease with reduced forced vital capacity (FVC) or diffusion capacity for carbon monoxide (DLCO) on lung function testing, proteinuria and male sex. Earlier studies had found that the presence of anti-topoisomerase II (Scl-70) auto-antibodies, reduced functional status - as measured by the Scleroderma Health Assessment Questionnaire (sHAQ, range from 0 to 3, with lower values indicating a better quality of life)8 - or pulmonary arterial hypertension adversely affect survival.3-5 Treatment with biologic or immunosuppressive drugs did not improve SSc survival.2,9,10 Following early phase I-II trials,11-13 three randomized controlled trials, namely ASSIST (American scleroderma stem cell versus immune suppression trial, phase II),14 ASTIS (Autologous stem cell transplantation international scleroderma trial, phase III)15 and SCOT (Scleroderma: cyclophosphamide or transplantation, phase II)16 demonstrated the superiority of autologous hematopoietic stem cell transplantation (HSCT) compared to the standard cyclophosphamide pulse treatment with regards to overall and event-free survival. In this context, autologous HSCT has become the best treatment option for patients with severe or rapidly progressive SSc, with a grade 1 level of evidence since 2012 according to the Autoimmune Disease Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT) recommendations. 17,18 After two decades of progress in HSCT for autoimmune diseases, the use of autologous HSCT for severe or rapidly progressive SSc has also been endorsed by the European League Against Rheumatism (EULAR)10 and the American Society for Blood and Marrow Transplantation10,17,19 and the demand for this therapeutic procedure is the fastest growing indication for HSCT in Europe.10,17,19,20 We therefore designed this ADWP-EBMT non-interventional study, NISSC1, to further evaluate the efficacy and safety of autologous HSCT for early, severe, progressive SSc, when performed in real-life practice, and to identify risk factors for early adverse events and transplant-related mortality, in order to make this approach safer. Methods Study design This study is a prospective, open, multicenter, non-interventional study. Data regarding patients included in this study were prospectively collected using a specific case report form, designed according to EBMT guidelines for HSCT in SSc.17 All EBMT participating centers agreed to report their consecutive patients aged 18 to 65 years with severe progressive SSc undergoing their first autologous HSCT between December 2012 and February 2016. Inclusion and exclusion criteria are detailed in the Online Supplementary Appendix. Participating centers followed their own local protocols for the transplant procedure as wells as the patients’ evaluation at baseline and during the 2-year follow-up. The study was approved by the EBMT board in 2012 and by local ethics committees in participating countries and registered at ClinicalTrials.gov (NCT02516124). All patients gave written informed consent to their participation in the study. Patients’ evaluation The SSc patients’ characteristics were assessed at baseline (within 3 months before autologous HSCT) and at 3, 6, 12, 18 and 24 months after transplantation (day 0 was defined as the time point of reinfusion of stem cells). Data collected included mRSS, erythrocyte sedimentation rate (in mm/h), creatine kinase levels, presence or absence of autoantibodies, left ventricular ejection fraction (LVEF in %) and systolic pulmonary arterial pressure (in mmHg) on echocardiography, resting and 24 h Holter-electrocardiograms, abnormal cardiac magnetic resonance imaging (MRI) or pulmonary arterial hypertension on right heart catheterization (RHC), FVC and DLCO (% of predicted values), high resolution computed tomography of the lungs and kidney function as well as immunosuppressive drugs given before transplantation. The sHAQ was used to evaluate patients’ quality of life. Autologous hematopoietic stem cell transplantation procedure Data collected included details on the mobilization process with or without CD34+-cell selection, type of conditioning regimen; total dose of CD34+ cells infused; number of days of hospitalization for mobilization and conditioning, use and duration of granulocyte colony-stimulating factor (G-CSF), and time to engraftment. Endpoints The primary endpoint was progression-free survival (PFS), defined as survival after autologous HSCT without death or evidence of progression of SSc (see Online Supplementary Appendix S1) The secondary endpoints were: (i) infectious or non-infectious adverse events during the first 100 days after autologous HSCT; (ii) engraftment, defined as 3 consecutive days of neutrophils >0.5x109/L and platelets >20x109/L; (iii) response to treatment, defined as a >25% improvement in mRSS and/or ≥10% improvement in FVC or DLCO as compared to baseline and without need of further immunosuppression; (iv) incidence of progression; (v) non-relapse mortality (NRM), defined as any death without progression; and (vi) overall survival. Statistical analysis Cumulative incidence functions were used to estimate response to treatment, NRM, and progression to accommodate for competing risks. Probabilities of overall survival and PFS were calculated using the Kaplan-Meier method. Univariate analyses were performed using the Gray test for cumulative incidence and the log rank test for overall survival and PFS. Multivariate analysis was performed using a Cox regression model including variables associated with the outcome with a P-value less than 0.10 in univariate analyses. Age was included as a continuous variable. A generalized linear model was used to analyze evolution over time of mRSS, FVC, DLCO and sHAQ. Results are expressed as a hazard ratio (HR) with 95% confidence interval (95% CI). Results Eighty patients (71.3% female), who had undergone a first autologous HSCT between December 2012 and February 2016 in 13 EBMT centers from six European countries and Brazil were included in this study. The centers are listed in Online Supplementary Appendix S2. The median (range) follow- up after transplantation was 24 (6-57) months. Table 1 summarizes the patients’ baseline characteristics. The median disease duration since the diagnosis of SSc was 23.8 (5.3-103.7) months. At baseline, all 80 patients had skin involvement, and mRSS was above 15 in 64 (80%) of them. Abnormal chest x-rays or abnormal high-resolution computed tomography was reported in 70 (87%) patients. Heart involvement with an abnormal 24 h electrocardiogram was reported in 12/60 (20%) or with abnormal cardiac MRI in 11/59 (19%) patients. Among the 11 patients with abnormal MRI at baseline, echocardiography showed normal LVEF in all cases and pericardial effusion in one patient, the resting ECG was abnormal in one patient and the 24 h ECG was abnormal in two patients; baseline RHC performed in six patients (with fluid challenge in 2 cases) was normal. Overall, 21 patients (26%) were transplanted without any prior cardiac MRI or RHC at baseline; among these, two had pericardial effusion and seven had a systolic pulmonary artery pressure above 25 mmHg on echocardiography, one had ventricular disturbances on resting ECG (n=20), and 2/8 had an abnormal 24 h ECG. Table 1. Baseline characteristics of the patients (n=80). Mobilization and conditioning procedures All patients were mobilized using cyclophosphamide with a median dose of 2 g/m2 (range, 1-4 g/m2) plus G-CSF. The median duration of hospitalization was 4 (1-30) days for mobilization with large variation according to centers. CD34+-cell selection was performed in 35 (44%) patients (Table 2). The median time from mobilization to the start of the conditioning regimen for autologous HSCT was 52 (22-254) days. The conditioning regimen included cyclophosphamide in all 80 patients, alone in 76 (95%) patients, with a median total dose of 200 (50-240) mg/kg. Four patients (5%) received thiotepa 10 mg/kg with a total cyclophosphamide dose of 100 mg/kg as a single-center treatment for patients with cardiac abnormalities at the pre-transplant evaluation. Additional rabbit antithymocyte globulin (ATG), with different doses according to the brand, was also included in the conditioning regimen for all patients and administered over 4 to 5 days. Sixty-seven patients (82%) received methylprednisolone during the ATG treatment. No patient received total body irradiation. A median number of 5.2 x 106/kg (2.53-23.31) CD34+ cells were reinfused at transplantation. Following autologous HSCT, G-CSF was administered to 34 (43%) patients for a median duration of 5 (1-13) days. Following autologous HSCT, the median time to neutrophil engraftment was 11 (8-24) days and the median time to platelet engraftment was 9 (1-25) days. In 13 (16.9%) patients, the platelet counts were never below 20x109/L. There was an inverse correlation between the number of CD34+ cells infused and the time to engraftment (Spearman: r2= -0.31; P<0.01), while the number of infused CD34+ cells and addition of G-CSF until recovery of aplasia were not associated with a reduced number of infectious complications (P=0.32). The median duration of inpatient hospitalization for conditioning, autologous peripheral blood stem cell re-infusion and subsequent supportive care until engraftment and discharge was 24 (8-128) days (Table 2). Efficacy At 1 and 2 years after autologous HSCT, the PFS rate was 87.5% (95% CI: 80.2-94.7) and 81.8% (95% CI: 73.1-90.5), respectively, and the rate of response to treatment was 75% (95% CI: 63.7-83.2) and 88.7% (95% CI: 79-94.1), respectively. At the 1- and 2-year time-points, the incidence of progression was 6.3% (95% CI: 2.3-13.1) and 11.9% (95% CI: 5.8-20.5), respectively, and the overall survival rate was 91.2% (95% CI: 85.1-97.4) and 90% (95% CI 83.4-96.6) at 1 and 2 years, respectively (Figure 1). Three of the four patients transplanted with thiotepa and a reduced-dose cyclophosphamide regimen responded; one with worsening skin and lung involvement at day 350 was then treated with prednisone, mycophenolate mofetil and rituximab. By multivariate analysis, mRSS >24 at baseline and older age at transplantation were significantly associated with a lower PFS with hazard ratios of 3.33 (95% CI: 1.04-10.62) and 1.77 (95% CI: 1.07-2.94), respectively. CD34+-cell selection was associated with a better response to therapy (HR: 0.46; 95% CI: 0.27-0.76). Table 2. Treatment regimen used for mobilization and conditioning. Figure 2 illustrates the evolution of the parameters over time. The mean mRSS decreased from 23.9 (standard deviation [SD] 9.7) at baseline to 14.2 (SD 9.2) at 1 year and 12.6 (SD 8.3) at 2 years (n=55, P<0.001). Regarding lung function, the mean FVC increased from 73.6% (SD 16.9) of predicted value at baseline to 79.5% (SD 16.9) at 1 year and 80.6% (SD 19.1) at 2 years (n=37, P<0.001); the mean DLCO was 60.2% (SD 19.3) at baseline, 59.7% (SD 17.7) at 1 year and 60.4% (SD 19.1) at 2 years (n=35). The sHAQ score was available in 15 patients and decreased significantly from 0.96 (SD 0.8) at baseline to 0.73 (SD 0.6) at 1 year and 0.70 (SD 0.6) at 2 years (P<0.001). The mean erythrocyte sedimentation rate decreased from 23.2 mm/h (SD 19.8) at baseline to 16.1 mm/h (SD 11.3) at 1 year and 18.7 mm/h (SD 23.6) at 2 years (n=38, P<0.001). Anti-Scl-70 and anti-centromere autoantibodies did not change after autologous HSCT. Safety The NRM rate at 100 days and 2 years was 6.25% (95% CI 2.3-13) (Figure 1). Four of the five deaths not due to relapse were related to a cardiac event, due to cyclophosphamide toxicity in three patients. A 35-year old female, who died from cardiac toxicity and multiorgan failure on day +61 after autologous HSCT, had normal resting ECG and LVEF (62%) on echocardiography, and abnormal LVEF on heart scintigraphy (47%); MRI and RHC were not performed at baseline. Three other patients died from cardiac toxicity at day +1 (n=2) and day +9 (n=1), with normal cardiac MRI and no RHC evaluation at baseline. A fifth patient (conditioning with thiotepa + reduced-dose cyclophosphamide) died from cytomegalovirus reactivation with viral copies detectable also in the lung, with bacterial (Pseudomonas) pneumonia and multiorgan failure at day +21. This patient had a normal resting ECG, with an abnormal 24 h ECG, abnormal MRI and a mean pulmonary artery pressure of 17 mmHg on RHC performed without fluid challenge at baseline. During the 24 months of follow-up, three additional patients died, all due to disease progression. Baseline characteristics of all patients who died during the follow-up and the respective causes of death are presented in Table 3. Figure 1. Kaplan-Meier curves of outcomes of patients undergoing autologous hematopoietic stem cell transplantation for severe systemic sclerosis. Overall survival (OS), progression-free survival (PFS), progression and non-relapse (treatment)- related mortality (NRM) over time. Figure 2. Boxplots of the four most important efficacy parameters in the 24 months following autologous hematopoietic stem cell transplantation for severe systemic sclerosis. (A) Improvement of the modified Rodnan skin score (mRSS) (n=55; P<0.001). (B) Improvement of forced vital capacity (FVC) (n=37; P=0.001. (C) Stabilization of diffusion capacity of carbon monoxide (DLCO) (n=35; P=0.01). (D) Improvement of Scleroderma Health Assessment Questionnaire (sHAQ) score (n=15, P=0.001). Table 3. Baseline characteristics and results from the pretransplant evaluation in patients who died during the follow-up. During the 100 days after transplantation, a total of 119 adverse events were reported among the 80 patients as detailed in Table 4. The percentage of infectious complications was not significantly different between the patients who did or did not receive CD34+-selected grafts (P=0.44), or according to the cyclophosphamide dose at the time of mobilization (2 g/m2 vs. 4 g/m2, P=0.16) or depending on whether they were or were not given G-CSF after their transplant (P=0.32) (Online Supplementary Table S3). Discussion The NISCC1 study is the largest prospective cohort today analyzing the efficacy and safety of autologous HSCT in 80 patients with severe SSc in a real-life setting. The PFS rate was 82% and significant improvements were observed in skin score, lung function and quality of life during the 2 years of follow-up, consistent with results of previous randomized controlled trials14-16 and earlier studies.11-13 Nevertheless, the NRM rate associated with auto logous HSCT was 6.25%, with most (4 out of 5) of the deaths being related to early cardiac events; this is similar to the 6% NRM rate reported retrospectively among 89 SSc patients transplanted between 2002 to 2011 in one USA and one Brazilian expert center using a non-myeloablative conditioning regimen.21 We used PFS as the primary endpoint to assess autologous HSCT efficacy rather than event-free survival, as previously used14,15 and which was defined as survival without respiratory, renal, or cardiac failure. PFS, which encompasses disease progression and toxic deaths, better reflects safety and efficacy of HSCT. In NISSC1, the incidence of progression was 6.3% and 11.9% at 1 and 2 years, respectively, highlighting the need to identify patients who may benefit from early maintenance therapy after autologous HSCT. Several mechanisms contribute to the resetting of the immunological response and disease control after autologous HSCT, and vary according to individual patients.12 We showed that the immune reconstitution profile and Tcell repertoire diversity together with a decrease in mRSS >25% and in FVC >10% at 1-2 years after transplantation could identify long-term responders and nonresponders/ relapsing patients at 4-5 years.22 The immune reconstitution process and the balance between reinduction of tolerance and sustained autoreactivity after transplantation will depend on the type of conditioning regimen used to ablate the original immune system, the effect of ATG or ex vivo CD34+-cell selection to further deplete/eliminate residual autoreactive cells and the use of post-transplant maintenance immunosuppression. 15,16,22-24 All patients in the NISCC1 study received a ‘non-myeloablative’ cyclophosphamide-based conditioning regimen, which included rabbit-derived ATG in all cases. The degree of T-cell depletion for each patient varied according to the type and total dose of ATG as well as timing of its administration in relation to the peripheral blood stem cell infusion, and whether the infused cells had undergone ex vivo CD34+ selection. In a previous retrospective EBMT analysis, we failed to demonstrate a benefit of ex vivo CD34+-cell selection23 in 138 SSc patients with similar baseline characteristics transplanted between 2000 and 2012. Surprisingly, the NISCC1 study showed a superior response to treatment in patients who received a CD34+- selected graft, with no increased rate of infectious complications, consistent with the recent findings of Ayano et al. in a retrospective analysis of 19 SSc patients.24 The reason for the difference in outcomes between these studies is unclear, but the population included in the NISCC1 prospective cohort was more homogenous in terms of conditioning, including in vivo T-cell depletion with rabbitderived ATG. All patients in the NISCC1 study received rabbit ATG formulations (although of different brands) while, in the EBMT retrospective study,23 64% of patients treated with ATG received a rabbit-derived product and 35% the horse-derived ATG formulation, which were shown to be associated with significantly different clinical outcomes in aplastic anemia.25 This important finding raises the question of whether a randomized, controlled trial should be performed to clarify whether more profound depletion of autoreactive cells from the peripheral blood stem cell graft by CD34+-cell selection may translate into sustained clinical benefit in SSc patients after autologous HSCT, without adversely affecting safety and cost-effectiveness. During the immune reconstitution process, the re-emergence of naïve T and B cells, the renewal of the immune repertoire and reinstatement of synergistic immunoregulatory mechanisms are expected. Therefore maintenance or rapid reintroduction of immunosuppression after autologous HSCT may improve patients’ outcome. The ongoing open-label trial (ClinicalTrials.gov identifier: NCT01413100) analyzing the addition of mycophenolate mofetil for 2 years after autologous HSCT and the next NISCC2 study (ClinicalTrials.gov identifier: NCT 03444805) analyzing posttransplantation management may clarify the potential benefit of post-transplant maintenance immunosuppression. A critical point for autologous HSCT in autoimmune diseases is safety. The risks of early transplant-related complications and mortality vary according to the type of disease, pre-existing internal organ involvement, the experience of the transplant center and the intensity of the conditioning regimen.12,26,27 Major cardiac adverse events and NRM after autologous HSCT in SSc are predominantly related to primary cardiac and lung involvement, which are underevaluated in the absence of systematic MRI and RHC at baseline.28,29 Our study revealed important variations in clinical practice in the pre-transplant cardio-pulmonary evaluation process. Although all patients who died during the first 100 days had normal resting ECG and LVEF on echocardiography at baseline, they were not all assessed by 24 h ECG (3/5), MRI (4/5) or RHC with fluid challenge (1/5). Overall, 24 h ECG was only used in 75% of the NISCC1 patients to detect subclinical rhythm or conduction disturbances at baseline, although it has been recommended since 2004.27 Similarly, cardiac MRI and RHC with fluid challenge were only performed in 74% and 21% of the patients, respectively, while their use has been advocated among expert centers since 2012 to minimize the risk of the transplant procedure.21,30,31 From 2013 to 2017, the EBMT and collaborative partners worked collectively to establish common standards for the use and interpretation of cardiac MRI results and RHC with fluid challenge for a rigorous cardio-pulmonary assessment of SSc patients, carefully defining eligibility and selection criteria for transplant referral.32 Table 4. Complications reported in the 100 days following autologous hematopoietic stem cell transplantation among the 80 patients treated for severe systemic sclerosis. Optimized treatment regimens are warranted to improve the safety of autologous HSCT, even in patients without cardiac involvement. Interestingly, the NRM rate in the NISCC1 study was similar to the 6% reported among 32 SSc patients transplanted between 2005 and 2011, using a ‘myeloablative’ conditioning regimen comprising total body irradiation (8 Gy), cyclophosphamide (120 mg/kg) and horse-derived ATG in the prospective SCOT randomized controlled trial.16 However, in the SCOT trial, NRM was primarily related to late fatal myelodysplastic syndromes, while no cyclophosphamide toxicity was reported. Within the follow-up period of the NISSC1 study, there were no reports of myelodysplastic syndrome or other myeloid malignancies. In addition, there were no reports of serious late infectious complications or secondary autoimmune phenomena that may occasionally present as long-term complications following autologous HSCT in autoimmune diseases. Although further follow-up is required, it is possible that there are long-term advantages, in terms of late effects, of the ‘non-myeloablative’ regimen used in the NISCC1 study. Early toxicity remains the principal challenge, including a NRM rate of 6%. To reduce toxicity and thus treatmentrelated mortality of the conditioning, a more individualized regimen with respect to heart, lung or kidney involvement might further improve patients’ safety, without excluding patients with organ manifestations. Two studies addressing patients with heart involvement are ongoing, both using a conditioning regimen with a reduced dose of cyclophosphamide and the addition of either thiotepa, as in four patients in our NISCC1 cohort (NCT01895244), or rituximab and fludarabine followed by reinfusion of autologous hematopoietic stem cells (NCT03593902), although the hematopoietic recovery from this reduced-dose regimen is prompt and reinfusion is not necessary in this setting. Because mobilization with G-CSF alone may exacerbate autoimmune diseases, there is a clinical rationale for combining G-CSF with cyclophosphamide. The use of 2 g/m2 cyclophosphamide for mobilization was as effective as 4 g/m2 at achieving the EBMT recommended minimum CD34+-cell yield, supporting dose reduction in the mobilization regimen to limit early toxicity as well as long-term risks associated with cumulative doses of cyclophosphamide. During the autologous HSCT procedures, inevitable infectious and non-infectious toxicity occurred especially following the high-dose cytotoxic conditioning and the cytopenic phase. A correlation between the number of infused CD34+ cells and a reduced duration of aplasia after autologous HSCT has been described previously, 33,34 which was confirmed in the NISCC1 study, although CD34+-cell dose and addition of G-CSF until recovery from aplasia were not associated with a reduced number of infectious complications. The NISCC1 study has several limitations. Since the study was a non-interventional trial, follow-up physical and laboratory evaluations, although recommended by EBMT guidelines,17 were not mandatory, and were not obtained at all time-points. The non-interventional study design was also the cause of significant variation in data collection practices by the 13 participating sites. Data were prospectively collected and checked for consistency by the EBMT study office; however, when some examinations were not performed, as may occur in routine clinical practice, data were classified as “missing”. The NISCC1 results showed significant variation in local practices when evaluating patients at baseline. Similarly, the number of reported days for mobilization varied largely according to centers; indeed, some patients were hospitalized for the whole duration of this procedure, whereas in other cases it was carried in part on an outpatient basis. We aimed to investigate the factors influencing the safety and efficacy of autologous HSCT. We used validated parameters to assess post-transplant outcome, such as mRSS or lung function tests despite their large intra- and inter-individual variability. The results enable deeper analysis of the benefits and risks of the transplant procedure in relation to both SSc-related factors, including the extent of heart, lung and kidney involvement at the time of patient referral, and transplant-related factors such as the conditioning regimen and graft manipulation. No international consensus has yet validated a unique activity score in SSc and further studies will be necessary in the post-transplant setting to investigate disease activity, the concept of drug-free remission and longer term outcomes, with or without post-transplant interventions. In conclusion, the NISSC1 is a large prospective real‐world data study of importance for patients, clinicians, and healthcare payers, given the poor prognosis and burden of disability of patients with severe SSc. It allowed us to assess multicenter adherence and compliance to good clinical practice and adds significantly to the evidence base supporting the delivery of autologous HSCT for severe SSc in routine clinical practice. Supplementary Material Disclosures and Contributions Supplementary Appendix

100 MG/KG

DrugDosageText

CC BY-NC

31949011

2021-02-01

What was the dosage of drug 'LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN'?

Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party. Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124. Introduction Systemic sclerosis (SSc) is a rare systemic autoimmune connective tissue disease characterized by vasculopathy, immune dysregulation and progressive fibrosis, affecting primarily the skin, gastrointestinal tract, lungs, heart and kidneys.1 It is associated with high disease-related mortality2 and the main causes of death are related to cardiac, pulmonary and renal involvement.2-5 Mortality rates in patients with SSc have remained higher than those in the general population (standardized mortality ratio above 3.5) over the past decades, in contrast to reductions in mortality for other rheumatic diseases or cancer.6 After the diagnosis of non-Raynaud phenomenon, the following risk factors for higher mortality related to progressive disease have been identified:2 diffuse skin fibrosis measured by the modified Rodnan skin score (mRSS, range 0-51),7 elevated C-reactive protein levels, altered left or right ventricular ejection fraction, interstitial lung disease with reduced forced vital capacity (FVC) or diffusion capacity for carbon monoxide (DLCO) on lung function testing, proteinuria and male sex. Earlier studies had found that the presence of anti-topoisomerase II (Scl-70) auto-antibodies, reduced functional status - as measured by the Scleroderma Health Assessment Questionnaire (sHAQ, range from 0 to 3, with lower values indicating a better quality of life)8 - or pulmonary arterial hypertension adversely affect survival.3-5 Treatment with biologic or immunosuppressive drugs did not improve SSc survival.2,9,10 Following early phase I-II trials,11-13 three randomized controlled trials, namely ASSIST (American scleroderma stem cell versus immune suppression trial, phase II),14 ASTIS (Autologous stem cell transplantation international scleroderma trial, phase III)15 and SCOT (Scleroderma: cyclophosphamide or transplantation, phase II)16 demonstrated the superiority of autologous hematopoietic stem cell transplantation (HSCT) compared to the standard cyclophosphamide pulse treatment with regards to overall and event-free survival. In this context, autologous HSCT has become the best treatment option for patients with severe or rapidly progressive SSc, with a grade 1 level of evidence since 2012 according to the Autoimmune Disease Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT) recommendations. 17,18 After two decades of progress in HSCT for autoimmune diseases, the use of autologous HSCT for severe or rapidly progressive SSc has also been endorsed by the European League Against Rheumatism (EULAR)10 and the American Society for Blood and Marrow Transplantation10,17,19 and the demand for this therapeutic procedure is the fastest growing indication for HSCT in Europe.10,17,19,20 We therefore designed this ADWP-EBMT non-interventional study, NISSC1, to further evaluate the efficacy and safety of autologous HSCT for early, severe, progressive SSc, when performed in real-life practice, and to identify risk factors for early adverse events and transplant-related mortality, in order to make this approach safer. Methods Study design This study is a prospective, open, multicenter, non-interventional study. Data regarding patients included in this study were prospectively collected using a specific case report form, designed according to EBMT guidelines for HSCT in SSc.17 All EBMT participating centers agreed to report their consecutive patients aged 18 to 65 years with severe progressive SSc undergoing their first autologous HSCT between December 2012 and February 2016. Inclusion and exclusion criteria are detailed in the Online Supplementary Appendix. Participating centers followed their own local protocols for the transplant procedure as wells as the patients’ evaluation at baseline and during the 2-year follow-up. The study was approved by the EBMT board in 2012 and by local ethics committees in participating countries and registered at ClinicalTrials.gov (NCT02516124). All patients gave written informed consent to their participation in the study. Patients’ evaluation The SSc patients’ characteristics were assessed at baseline (within 3 months before autologous HSCT) and at 3, 6, 12, 18 and 24 months after transplantation (day 0 was defined as the time point of reinfusion of stem cells). Data collected included mRSS, erythrocyte sedimentation rate (in mm/h), creatine kinase levels, presence or absence of autoantibodies, left ventricular ejection fraction (LVEF in %) and systolic pulmonary arterial pressure (in mmHg) on echocardiography, resting and 24 h Holter-electrocardiograms, abnormal cardiac magnetic resonance imaging (MRI) or pulmonary arterial hypertension on right heart catheterization (RHC), FVC and DLCO (% of predicted values), high resolution computed tomography of the lungs and kidney function as well as immunosuppressive drugs given before transplantation. The sHAQ was used to evaluate patients’ quality of life. Autologous hematopoietic stem cell transplantation procedure Data collected included details on the mobilization process with or without CD34+-cell selection, type of conditioning regimen; total dose of CD34+ cells infused; number of days of hospitalization for mobilization and conditioning, use and duration of granulocyte colony-stimulating factor (G-CSF), and time to engraftment. Endpoints The primary endpoint was progression-free survival (PFS), defined as survival after autologous HSCT without death or evidence of progression of SSc (see Online Supplementary Appendix S1) The secondary endpoints were: (i) infectious or non-infectious adverse events during the first 100 days after autologous HSCT; (ii) engraftment, defined as 3 consecutive days of neutrophils >0.5x109/L and platelets >20x109/L; (iii) response to treatment, defined as a >25% improvement in mRSS and/or ≥10% improvement in FVC or DLCO as compared to baseline and without need of further immunosuppression; (iv) incidence of progression; (v) non-relapse mortality (NRM), defined as any death without progression; and (vi) overall survival. Statistical analysis Cumulative incidence functions were used to estimate response to treatment, NRM, and progression to accommodate for competing risks. Probabilities of overall survival and PFS were calculated using the Kaplan-Meier method. Univariate analyses were performed using the Gray test for cumulative incidence and the log rank test for overall survival and PFS. Multivariate analysis was performed using a Cox regression model including variables associated with the outcome with a P-value less than 0.10 in univariate analyses. Age was included as a continuous variable. A generalized linear model was used to analyze evolution over time of mRSS, FVC, DLCO and sHAQ. Results are expressed as a hazard ratio (HR) with 95% confidence interval (95% CI). Results Eighty patients (71.3% female), who had undergone a first autologous HSCT between December 2012 and February 2016 in 13 EBMT centers from six European countries and Brazil were included in this study. The centers are listed in Online Supplementary Appendix S2. The median (range) follow- up after transplantation was 24 (6-57) months. Table 1 summarizes the patients’ baseline characteristics. The median disease duration since the diagnosis of SSc was 23.8 (5.3-103.7) months. At baseline, all 80 patients had skin involvement, and mRSS was above 15 in 64 (80%) of them. Abnormal chest x-rays or abnormal high-resolution computed tomography was reported in 70 (87%) patients. Heart involvement with an abnormal 24 h electrocardiogram was reported in 12/60 (20%) or with abnormal cardiac MRI in 11/59 (19%) patients. Among the 11 patients with abnormal MRI at baseline, echocardiography showed normal LVEF in all cases and pericardial effusion in one patient, the resting ECG was abnormal in one patient and the 24 h ECG was abnormal in two patients; baseline RHC performed in six patients (with fluid challenge in 2 cases) was normal. Overall, 21 patients (26%) were transplanted without any prior cardiac MRI or RHC at baseline; among these, two had pericardial effusion and seven had a systolic pulmonary artery pressure above 25 mmHg on echocardiography, one had ventricular disturbances on resting ECG (n=20), and 2/8 had an abnormal 24 h ECG. Table 1. Baseline characteristics of the patients (n=80). Mobilization and conditioning procedures All patients were mobilized using cyclophosphamide with a median dose of 2 g/m2 (range, 1-4 g/m2) plus G-CSF. The median duration of hospitalization was 4 (1-30) days for mobilization with large variation according to centers. CD34+-cell selection was performed in 35 (44%) patients (Table 2). The median time from mobilization to the start of the conditioning regimen for autologous HSCT was 52 (22-254) days. The conditioning regimen included cyclophosphamide in all 80 patients, alone in 76 (95%) patients, with a median total dose of 200 (50-240) mg/kg. Four patients (5%) received thiotepa 10 mg/kg with a total cyclophosphamide dose of 100 mg/kg as a single-center treatment for patients with cardiac abnormalities at the pre-transplant evaluation. Additional rabbit antithymocyte globulin (ATG), with different doses according to the brand, was also included in the conditioning regimen for all patients and administered over 4 to 5 days. Sixty-seven patients (82%) received methylprednisolone during the ATG treatment. No patient received total body irradiation. A median number of 5.2 x 106/kg (2.53-23.31) CD34+ cells were reinfused at transplantation. Following autologous HSCT, G-CSF was administered to 34 (43%) patients for a median duration of 5 (1-13) days. Following autologous HSCT, the median time to neutrophil engraftment was 11 (8-24) days and the median time to platelet engraftment was 9 (1-25) days. In 13 (16.9%) patients, the platelet counts were never below 20x109/L. There was an inverse correlation between the number of CD34+ cells infused and the time to engraftment (Spearman: r2= -0.31; P<0.01), while the number of infused CD34+ cells and addition of G-CSF until recovery of aplasia were not associated with a reduced number of infectious complications (P=0.32). The median duration of inpatient hospitalization for conditioning, autologous peripheral blood stem cell re-infusion and subsequent supportive care until engraftment and discharge was 24 (8-128) days (Table 2). Efficacy At 1 and 2 years after autologous HSCT, the PFS rate was 87.5% (95% CI: 80.2-94.7) and 81.8% (95% CI: 73.1-90.5), respectively, and the rate of response to treatment was 75% (95% CI: 63.7-83.2) and 88.7% (95% CI: 79-94.1), respectively. At the 1- and 2-year time-points, the incidence of progression was 6.3% (95% CI: 2.3-13.1) and 11.9% (95% CI: 5.8-20.5), respectively, and the overall survival rate was 91.2% (95% CI: 85.1-97.4) and 90% (95% CI 83.4-96.6) at 1 and 2 years, respectively (Figure 1). Three of the four patients transplanted with thiotepa and a reduced-dose cyclophosphamide regimen responded; one with worsening skin and lung involvement at day 350 was then treated with prednisone, mycophenolate mofetil and rituximab. By multivariate analysis, mRSS >24 at baseline and older age at transplantation were significantly associated with a lower PFS with hazard ratios of 3.33 (95% CI: 1.04-10.62) and 1.77 (95% CI: 1.07-2.94), respectively. CD34+-cell selection was associated with a better response to therapy (HR: 0.46; 95% CI: 0.27-0.76). Table 2. Treatment regimen used for mobilization and conditioning. Figure 2 illustrates the evolution of the parameters over time. The mean mRSS decreased from 23.9 (standard deviation [SD] 9.7) at baseline to 14.2 (SD 9.2) at 1 year and 12.6 (SD 8.3) at 2 years (n=55, P<0.001). Regarding lung function, the mean FVC increased from 73.6% (SD 16.9) of predicted value at baseline to 79.5% (SD 16.9) at 1 year and 80.6% (SD 19.1) at 2 years (n=37, P<0.001); the mean DLCO was 60.2% (SD 19.3) at baseline, 59.7% (SD 17.7) at 1 year and 60.4% (SD 19.1) at 2 years (n=35). The sHAQ score was available in 15 patients and decreased significantly from 0.96 (SD 0.8) at baseline to 0.73 (SD 0.6) at 1 year and 0.70 (SD 0.6) at 2 years (P<0.001). The mean erythrocyte sedimentation rate decreased from 23.2 mm/h (SD 19.8) at baseline to 16.1 mm/h (SD 11.3) at 1 year and 18.7 mm/h (SD 23.6) at 2 years (n=38, P<0.001). Anti-Scl-70 and anti-centromere autoantibodies did not change after autologous HSCT. Safety The NRM rate at 100 days and 2 years was 6.25% (95% CI 2.3-13) (Figure 1). Four of the five deaths not due to relapse were related to a cardiac event, due to cyclophosphamide toxicity in three patients. A 35-year old female, who died from cardiac toxicity and multiorgan failure on day +61 after autologous HSCT, had normal resting ECG and LVEF (62%) on echocardiography, and abnormal LVEF on heart scintigraphy (47%); MRI and RHC were not performed at baseline. Three other patients died from cardiac toxicity at day +1 (n=2) and day +9 (n=1), with normal cardiac MRI and no RHC evaluation at baseline. A fifth patient (conditioning with thiotepa + reduced-dose cyclophosphamide) died from cytomegalovirus reactivation with viral copies detectable also in the lung, with bacterial (Pseudomonas) pneumonia and multiorgan failure at day +21. This patient had a normal resting ECG, with an abnormal 24 h ECG, abnormal MRI and a mean pulmonary artery pressure of 17 mmHg on RHC performed without fluid challenge at baseline. During the 24 months of follow-up, three additional patients died, all due to disease progression. Baseline characteristics of all patients who died during the follow-up and the respective causes of death are presented in Table 3. Figure 1. Kaplan-Meier curves of outcomes of patients undergoing autologous hematopoietic stem cell transplantation for severe systemic sclerosis. Overall survival (OS), progression-free survival (PFS), progression and non-relapse (treatment)- related mortality (NRM) over time. Figure 2. Boxplots of the four most important efficacy parameters in the 24 months following autologous hematopoietic stem cell transplantation for severe systemic sclerosis. (A) Improvement of the modified Rodnan skin score (mRSS) (n=55; P<0.001). (B) Improvement of forced vital capacity (FVC) (n=37; P=0.001. (C) Stabilization of diffusion capacity of carbon monoxide (DLCO) (n=35; P=0.01). (D) Improvement of Scleroderma Health Assessment Questionnaire (sHAQ) score (n=15, P=0.001). Table 3. Baseline characteristics and results from the pretransplant evaluation in patients who died during the follow-up. During the 100 days after transplantation, a total of 119 adverse events were reported among the 80 patients as detailed in Table 4. The percentage of infectious complications was not significantly different between the patients who did or did not receive CD34+-selected grafts (P=0.44), or according to the cyclophosphamide dose at the time of mobilization (2 g/m2 vs. 4 g/m2, P=0.16) or depending on whether they were or were not given G-CSF after their transplant (P=0.32) (Online Supplementary Table S3). Discussion The NISCC1 study is the largest prospective cohort today analyzing the efficacy and safety of autologous HSCT in 80 patients with severe SSc in a real-life setting. The PFS rate was 82% and significant improvements were observed in skin score, lung function and quality of life during the 2 years of follow-up, consistent with results of previous randomized controlled trials14-16 and earlier studies.11-13 Nevertheless, the NRM rate associated with auto logous HSCT was 6.25%, with most (4 out of 5) of the deaths being related to early cardiac events; this is similar to the 6% NRM rate reported retrospectively among 89 SSc patients transplanted between 2002 to 2011 in one USA and one Brazilian expert center using a non-myeloablative conditioning regimen.21 We used PFS as the primary endpoint to assess autologous HSCT efficacy rather than event-free survival, as previously used14,15 and which was defined as survival without respiratory, renal, or cardiac failure. PFS, which encompasses disease progression and toxic deaths, better reflects safety and efficacy of HSCT. In NISSC1, the incidence of progression was 6.3% and 11.9% at 1 and 2 years, respectively, highlighting the need to identify patients who may benefit from early maintenance therapy after autologous HSCT. Several mechanisms contribute to the resetting of the immunological response and disease control after autologous HSCT, and vary according to individual patients.12 We showed that the immune reconstitution profile and Tcell repertoire diversity together with a decrease in mRSS >25% and in FVC >10% at 1-2 years after transplantation could identify long-term responders and nonresponders/ relapsing patients at 4-5 years.22 The immune reconstitution process and the balance between reinduction of tolerance and sustained autoreactivity after transplantation will depend on the type of conditioning regimen used to ablate the original immune system, the effect of ATG or ex vivo CD34+-cell selection to further deplete/eliminate residual autoreactive cells and the use of post-transplant maintenance immunosuppression. 15,16,22-24 All patients in the NISCC1 study received a ‘non-myeloablative’ cyclophosphamide-based conditioning regimen, which included rabbit-derived ATG in all cases. The degree of T-cell depletion for each patient varied according to the type and total dose of ATG as well as timing of its administration in relation to the peripheral blood stem cell infusion, and whether the infused cells had undergone ex vivo CD34+ selection. In a previous retrospective EBMT analysis, we failed to demonstrate a benefit of ex vivo CD34+-cell selection23 in 138 SSc patients with similar baseline characteristics transplanted between 2000 and 2012. Surprisingly, the NISCC1 study showed a superior response to treatment in patients who received a CD34+- selected graft, with no increased rate of infectious complications, consistent with the recent findings of Ayano et al. in a retrospective analysis of 19 SSc patients.24 The reason for the difference in outcomes between these studies is unclear, but the population included in the NISCC1 prospective cohort was more homogenous in terms of conditioning, including in vivo T-cell depletion with rabbitderived ATG. All patients in the NISCC1 study received rabbit ATG formulations (although of different brands) while, in the EBMT retrospective study,23 64% of patients treated with ATG received a rabbit-derived product and 35% the horse-derived ATG formulation, which were shown to be associated with significantly different clinical outcomes in aplastic anemia.25 This important finding raises the question of whether a randomized, controlled trial should be performed to clarify whether more profound depletion of autoreactive cells from the peripheral blood stem cell graft by CD34+-cell selection may translate into sustained clinical benefit in SSc patients after autologous HSCT, without adversely affecting safety and cost-effectiveness. During the immune reconstitution process, the re-emergence of naïve T and B cells, the renewal of the immune repertoire and reinstatement of synergistic immunoregulatory mechanisms are expected. Therefore maintenance or rapid reintroduction of immunosuppression after autologous HSCT may improve patients’ outcome. The ongoing open-label trial (ClinicalTrials.gov identifier: NCT01413100) analyzing the addition of mycophenolate mofetil for 2 years after autologous HSCT and the next NISCC2 study (ClinicalTrials.gov identifier: NCT 03444805) analyzing posttransplantation management may clarify the potential benefit of post-transplant maintenance immunosuppression. A critical point for autologous HSCT in autoimmune diseases is safety. The risks of early transplant-related complications and mortality vary according to the type of disease, pre-existing internal organ involvement, the experience of the transplant center and the intensity of the conditioning regimen.12,26,27 Major cardiac adverse events and NRM after autologous HSCT in SSc are predominantly related to primary cardiac and lung involvement, which are underevaluated in the absence of systematic MRI and RHC at baseline.28,29 Our study revealed important variations in clinical practice in the pre-transplant cardio-pulmonary evaluation process. Although all patients who died during the first 100 days had normal resting ECG and LVEF on echocardiography at baseline, they were not all assessed by 24 h ECG (3/5), MRI (4/5) or RHC with fluid challenge (1/5). Overall, 24 h ECG was only used in 75% of the NISCC1 patients to detect subclinical rhythm or conduction disturbances at baseline, although it has been recommended since 2004.27 Similarly, cardiac MRI and RHC with fluid challenge were only performed in 74% and 21% of the patients, respectively, while their use has been advocated among expert centers since 2012 to minimize the risk of the transplant procedure.21,30,31 From 2013 to 2017, the EBMT and collaborative partners worked collectively to establish common standards for the use and interpretation of cardiac MRI results and RHC with fluid challenge for a rigorous cardio-pulmonary assessment of SSc patients, carefully defining eligibility and selection criteria for transplant referral.32 Table 4. Complications reported in the 100 days following autologous hematopoietic stem cell transplantation among the 80 patients treated for severe systemic sclerosis. Optimized treatment regimens are warranted to improve the safety of autologous HSCT, even in patients without cardiac involvement. Interestingly, the NRM rate in the NISCC1 study was similar to the 6% reported among 32 SSc patients transplanted between 2005 and 2011, using a ‘myeloablative’ conditioning regimen comprising total body irradiation (8 Gy), cyclophosphamide (120 mg/kg) and horse-derived ATG in the prospective SCOT randomized controlled trial.16 However, in the SCOT trial, NRM was primarily related to late fatal myelodysplastic syndromes, while no cyclophosphamide toxicity was reported. Within the follow-up period of the NISSC1 study, there were no reports of myelodysplastic syndrome or other myeloid malignancies. In addition, there were no reports of serious late infectious complications or secondary autoimmune phenomena that may occasionally present as long-term complications following autologous HSCT in autoimmune diseases. Although further follow-up is required, it is possible that there are long-term advantages, in terms of late effects, of the ‘non-myeloablative’ regimen used in the NISCC1 study. Early toxicity remains the principal challenge, including a NRM rate of 6%. To reduce toxicity and thus treatmentrelated mortality of the conditioning, a more individualized regimen with respect to heart, lung or kidney involvement might further improve patients’ safety, without excluding patients with organ manifestations. Two studies addressing patients with heart involvement are ongoing, both using a conditioning regimen with a reduced dose of cyclophosphamide and the addition of either thiotepa, as in four patients in our NISCC1 cohort (NCT01895244), or rituximab and fludarabine followed by reinfusion of autologous hematopoietic stem cells (NCT03593902), although the hematopoietic recovery from this reduced-dose regimen is prompt and reinfusion is not necessary in this setting. Because mobilization with G-CSF alone may exacerbate autoimmune diseases, there is a clinical rationale for combining G-CSF with cyclophosphamide. The use of 2 g/m2 cyclophosphamide for mobilization was as effective as 4 g/m2 at achieving the EBMT recommended minimum CD34+-cell yield, supporting dose reduction in the mobilization regimen to limit early toxicity as well as long-term risks associated with cumulative doses of cyclophosphamide. During the autologous HSCT procedures, inevitable infectious and non-infectious toxicity occurred especially following the high-dose cytotoxic conditioning and the cytopenic phase. A correlation between the number of infused CD34+ cells and a reduced duration of aplasia after autologous HSCT has been described previously, 33,34 which was confirmed in the NISCC1 study, although CD34+-cell dose and addition of G-CSF until recovery from aplasia were not associated with a reduced number of infectious complications. The NISCC1 study has several limitations. Since the study was a non-interventional trial, follow-up physical and laboratory evaluations, although recommended by EBMT guidelines,17 were not mandatory, and were not obtained at all time-points. The non-interventional study design was also the cause of significant variation in data collection practices by the 13 participating sites. Data were prospectively collected and checked for consistency by the EBMT study office; however, when some examinations were not performed, as may occur in routine clinical practice, data were classified as “missing”. The NISCC1 results showed significant variation in local practices when evaluating patients at baseline. Similarly, the number of reported days for mobilization varied largely according to centers; indeed, some patients were hospitalized for the whole duration of this procedure, whereas in other cases it was carried in part on an outpatient basis. We aimed to investigate the factors influencing the safety and efficacy of autologous HSCT. We used validated parameters to assess post-transplant outcome, such as mRSS or lung function tests despite their large intra- and inter-individual variability. The results enable deeper analysis of the benefits and risks of the transplant procedure in relation to both SSc-related factors, including the extent of heart, lung and kidney involvement at the time of patient referral, and transplant-related factors such as the conditioning regimen and graft manipulation. No international consensus has yet validated a unique activity score in SSc and further studies will be necessary in the post-transplant setting to investigate disease activity, the concept of drug-free remission and longer term outcomes, with or without post-transplant interventions. In conclusion, the NISSC1 is a large prospective real‐world data study of importance for patients, clinicians, and healthcare payers, given the poor prognosis and burden of disability of patients with severe SSc. It allowed us to assess multicenter adherence and compliance to good clinical practice and adds significantly to the evidence base supporting the delivery of autologous HSCT for severe SSc in routine clinical practice. Supplementary Material Disclosures and Contributions Supplementary Appendix

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Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party. Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124. Introduction Systemic sclerosis (SSc) is a rare systemic autoimmune connective tissue disease characterized by vasculopathy, immune dysregulation and progressive fibrosis, affecting primarily the skin, gastrointestinal tract, lungs, heart and kidneys.1 It is associated with high disease-related mortality2 and the main causes of death are related to cardiac, pulmonary and renal involvement.2-5 Mortality rates in patients with SSc have remained higher than those in the general population (standardized mortality ratio above 3.5) over the past decades, in contrast to reductions in mortality for other rheumatic diseases or cancer.6 After the diagnosis of non-Raynaud phenomenon, the following risk factors for higher mortality related to progressive disease have been identified:2 diffuse skin fibrosis measured by the modified Rodnan skin score (mRSS, range 0-51),7 elevated C-reactive protein levels, altered left or right ventricular ejection fraction, interstitial lung disease with reduced forced vital capacity (FVC) or diffusion capacity for carbon monoxide (DLCO) on lung function testing, proteinuria and male sex. Earlier studies had found that the presence of anti-topoisomerase II (Scl-70) auto-antibodies, reduced functional status - as measured by the Scleroderma Health Assessment Questionnaire (sHAQ, range from 0 to 3, with lower values indicating a better quality of life)8 - or pulmonary arterial hypertension adversely affect survival.3-5 Treatment with biologic or immunosuppressive drugs did not improve SSc survival.2,9,10 Following early phase I-II trials,11-13 three randomized controlled trials, namely ASSIST (American scleroderma stem cell versus immune suppression trial, phase II),14 ASTIS (Autologous stem cell transplantation international scleroderma trial, phase III)15 and SCOT (Scleroderma: cyclophosphamide or transplantation, phase II)16 demonstrated the superiority of autologous hematopoietic stem cell transplantation (HSCT) compared to the standard cyclophosphamide pulse treatment with regards to overall and event-free survival. In this context, autologous HSCT has become the best treatment option for patients with severe or rapidly progressive SSc, with a grade 1 level of evidence since 2012 according to the Autoimmune Disease Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT) recommendations. 17,18 After two decades of progress in HSCT for autoimmune diseases, the use of autologous HSCT for severe or rapidly progressive SSc has also been endorsed by the European League Against Rheumatism (EULAR)10 and the American Society for Blood and Marrow Transplantation10,17,19 and the demand for this therapeutic procedure is the fastest growing indication for HSCT in Europe.10,17,19,20 We therefore designed this ADWP-EBMT non-interventional study, NISSC1, to further evaluate the efficacy and safety of autologous HSCT for early, severe, progressive SSc, when performed in real-life practice, and to identify risk factors for early adverse events and transplant-related mortality, in order to make this approach safer. Methods Study design This study is a prospective, open, multicenter, non-interventional study. Data regarding patients included in this study were prospectively collected using a specific case report form, designed according to EBMT guidelines for HSCT in SSc.17 All EBMT participating centers agreed to report their consecutive patients aged 18 to 65 years with severe progressive SSc undergoing their first autologous HSCT between December 2012 and February 2016. Inclusion and exclusion criteria are detailed in the Online Supplementary Appendix. Participating centers followed their own local protocols for the transplant procedure as wells as the patients’ evaluation at baseline and during the 2-year follow-up. The study was approved by the EBMT board in 2012 and by local ethics committees in participating countries and registered at ClinicalTrials.gov (NCT02516124). All patients gave written informed consent to their participation in the study. Patients’ evaluation The SSc patients’ characteristics were assessed at baseline (within 3 months before autologous HSCT) and at 3, 6, 12, 18 and 24 months after transplantation (day 0 was defined as the time point of reinfusion of stem cells). Data collected included mRSS, erythrocyte sedimentation rate (in mm/h), creatine kinase levels, presence or absence of autoantibodies, left ventricular ejection fraction (LVEF in %) and systolic pulmonary arterial pressure (in mmHg) on echocardiography, resting and 24 h Holter-electrocardiograms, abnormal cardiac magnetic resonance imaging (MRI) or pulmonary arterial hypertension on right heart catheterization (RHC), FVC and DLCO (% of predicted values), high resolution computed tomography of the lungs and kidney function as well as immunosuppressive drugs given before transplantation. The sHAQ was used to evaluate patients’ quality of life. Autologous hematopoietic stem cell transplantation procedure Data collected included details on the mobilization process with or without CD34+-cell selection, type of conditioning regimen; total dose of CD34+ cells infused; number of days of hospitalization for mobilization and conditioning, use and duration of granulocyte colony-stimulating factor (G-CSF), and time to engraftment. Endpoints The primary endpoint was progression-free survival (PFS), defined as survival after autologous HSCT without death or evidence of progression of SSc (see Online Supplementary Appendix S1) The secondary endpoints were: (i) infectious or non-infectious adverse events during the first 100 days after autologous HSCT; (ii) engraftment, defined as 3 consecutive days of neutrophils >0.5x109/L and platelets >20x109/L; (iii) response to treatment, defined as a >25% improvement in mRSS and/or ≥10% improvement in FVC or DLCO as compared to baseline and without need of further immunosuppression; (iv) incidence of progression; (v) non-relapse mortality (NRM), defined as any death without progression; and (vi) overall survival. Statistical analysis Cumulative incidence functions were used to estimate response to treatment, NRM, and progression to accommodate for competing risks. Probabilities of overall survival and PFS were calculated using the Kaplan-Meier method. Univariate analyses were performed using the Gray test for cumulative incidence and the log rank test for overall survival and PFS. Multivariate analysis was performed using a Cox regression model including variables associated with the outcome with a P-value less than 0.10 in univariate analyses. Age was included as a continuous variable. A generalized linear model was used to analyze evolution over time of mRSS, FVC, DLCO and sHAQ. Results are expressed as a hazard ratio (HR) with 95% confidence interval (95% CI). Results Eighty patients (71.3% female), who had undergone a first autologous HSCT between December 2012 and February 2016 in 13 EBMT centers from six European countries and Brazil were included in this study. The centers are listed in Online Supplementary Appendix S2. The median (range) follow- up after transplantation was 24 (6-57) months. Table 1 summarizes the patients’ baseline characteristics. The median disease duration since the diagnosis of SSc was 23.8 (5.3-103.7) months. At baseline, all 80 patients had skin involvement, and mRSS was above 15 in 64 (80%) of them. Abnormal chest x-rays or abnormal high-resolution computed tomography was reported in 70 (87%) patients. Heart involvement with an abnormal 24 h electrocardiogram was reported in 12/60 (20%) or with abnormal cardiac MRI in 11/59 (19%) patients. Among the 11 patients with abnormal MRI at baseline, echocardiography showed normal LVEF in all cases and pericardial effusion in one patient, the resting ECG was abnormal in one patient and the 24 h ECG was abnormal in two patients; baseline RHC performed in six patients (with fluid challenge in 2 cases) was normal. Overall, 21 patients (26%) were transplanted without any prior cardiac MRI or RHC at baseline; among these, two had pericardial effusion and seven had a systolic pulmonary artery pressure above 25 mmHg on echocardiography, one had ventricular disturbances on resting ECG (n=20), and 2/8 had an abnormal 24 h ECG. Table 1. Baseline characteristics of the patients (n=80). Mobilization and conditioning procedures All patients were mobilized using cyclophosphamide with a median dose of 2 g/m2 (range, 1-4 g/m2) plus G-CSF. The median duration of hospitalization was 4 (1-30) days for mobilization with large variation according to centers. CD34+-cell selection was performed in 35 (44%) patients (Table 2). The median time from mobilization to the start of the conditioning regimen for autologous HSCT was 52 (22-254) days. The conditioning regimen included cyclophosphamide in all 80 patients, alone in 76 (95%) patients, with a median total dose of 200 (50-240) mg/kg. Four patients (5%) received thiotepa 10 mg/kg with a total cyclophosphamide dose of 100 mg/kg as a single-center treatment for patients with cardiac abnormalities at the pre-transplant evaluation. Additional rabbit antithymocyte globulin (ATG), with different doses according to the brand, was also included in the conditioning regimen for all patients and administered over 4 to 5 days. Sixty-seven patients (82%) received methylprednisolone during the ATG treatment. No patient received total body irradiation. A median number of 5.2 x 106/kg (2.53-23.31) CD34+ cells were reinfused at transplantation. Following autologous HSCT, G-CSF was administered to 34 (43%) patients for a median duration of 5 (1-13) days. Following autologous HSCT, the median time to neutrophil engraftment was 11 (8-24) days and the median time to platelet engraftment was 9 (1-25) days. In 13 (16.9%) patients, the platelet counts were never below 20x109/L. There was an inverse correlation between the number of CD34+ cells infused and the time to engraftment (Spearman: r2= -0.31; P<0.01), while the number of infused CD34+ cells and addition of G-CSF until recovery of aplasia were not associated with a reduced number of infectious complications (P=0.32). The median duration of inpatient hospitalization for conditioning, autologous peripheral blood stem cell re-infusion and subsequent supportive care until engraftment and discharge was 24 (8-128) days (Table 2). Efficacy At 1 and 2 years after autologous HSCT, the PFS rate was 87.5% (95% CI: 80.2-94.7) and 81.8% (95% CI: 73.1-90.5), respectively, and the rate of response to treatment was 75% (95% CI: 63.7-83.2) and 88.7% (95% CI: 79-94.1), respectively. At the 1- and 2-year time-points, the incidence of progression was 6.3% (95% CI: 2.3-13.1) and 11.9% (95% CI: 5.8-20.5), respectively, and the overall survival rate was 91.2% (95% CI: 85.1-97.4) and 90% (95% CI 83.4-96.6) at 1 and 2 years, respectively (Figure 1). Three of the four patients transplanted with thiotepa and a reduced-dose cyclophosphamide regimen responded; one with worsening skin and lung involvement at day 350 was then treated with prednisone, mycophenolate mofetil and rituximab. By multivariate analysis, mRSS >24 at baseline and older age at transplantation were significantly associated with a lower PFS with hazard ratios of 3.33 (95% CI: 1.04-10.62) and 1.77 (95% CI: 1.07-2.94), respectively. CD34+-cell selection was associated with a better response to therapy (HR: 0.46; 95% CI: 0.27-0.76). Table 2. Treatment regimen used for mobilization and conditioning. Figure 2 illustrates the evolution of the parameters over time. The mean mRSS decreased from 23.9 (standard deviation [SD] 9.7) at baseline to 14.2 (SD 9.2) at 1 year and 12.6 (SD 8.3) at 2 years (n=55, P<0.001). Regarding lung function, the mean FVC increased from 73.6% (SD 16.9) of predicted value at baseline to 79.5% (SD 16.9) at 1 year and 80.6% (SD 19.1) at 2 years (n=37, P<0.001); the mean DLCO was 60.2% (SD 19.3) at baseline, 59.7% (SD 17.7) at 1 year and 60.4% (SD 19.1) at 2 years (n=35). The sHAQ score was available in 15 patients and decreased significantly from 0.96 (SD 0.8) at baseline to 0.73 (SD 0.6) at 1 year and 0.70 (SD 0.6) at 2 years (P<0.001). The mean erythrocyte sedimentation rate decreased from 23.2 mm/h (SD 19.8) at baseline to 16.1 mm/h (SD 11.3) at 1 year and 18.7 mm/h (SD 23.6) at 2 years (n=38, P<0.001). Anti-Scl-70 and anti-centromere autoantibodies did not change after autologous HSCT. Safety The NRM rate at 100 days and 2 years was 6.25% (95% CI 2.3-13) (Figure 1). Four of the five deaths not due to relapse were related to a cardiac event, due to cyclophosphamide toxicity in three patients. A 35-year old female, who died from cardiac toxicity and multiorgan failure on day +61 after autologous HSCT, had normal resting ECG and LVEF (62%) on echocardiography, and abnormal LVEF on heart scintigraphy (47%); MRI and RHC were not performed at baseline. Three other patients died from cardiac toxicity at day +1 (n=2) and day +9 (n=1), with normal cardiac MRI and no RHC evaluation at baseline. A fifth patient (conditioning with thiotepa + reduced-dose cyclophosphamide) died from cytomegalovirus reactivation with viral copies detectable also in the lung, with bacterial (Pseudomonas) pneumonia and multiorgan failure at day +21. This patient had a normal resting ECG, with an abnormal 24 h ECG, abnormal MRI and a mean pulmonary artery pressure of 17 mmHg on RHC performed without fluid challenge at baseline. During the 24 months of follow-up, three additional patients died, all due to disease progression. Baseline characteristics of all patients who died during the follow-up and the respective causes of death are presented in Table 3. Figure 1. Kaplan-Meier curves of outcomes of patients undergoing autologous hematopoietic stem cell transplantation for severe systemic sclerosis. Overall survival (OS), progression-free survival (PFS), progression and non-relapse (treatment)- related mortality (NRM) over time. Figure 2. Boxplots of the four most important efficacy parameters in the 24 months following autologous hematopoietic stem cell transplantation for severe systemic sclerosis. (A) Improvement of the modified Rodnan skin score (mRSS) (n=55; P<0.001). (B) Improvement of forced vital capacity (FVC) (n=37; P=0.001. (C) Stabilization of diffusion capacity of carbon monoxide (DLCO) (n=35; P=0.01). (D) Improvement of Scleroderma Health Assessment Questionnaire (sHAQ) score (n=15, P=0.001). Table 3. Baseline characteristics and results from the pretransplant evaluation in patients who died during the follow-up. During the 100 days after transplantation, a total of 119 adverse events were reported among the 80 patients as detailed in Table 4. The percentage of infectious complications was not significantly different between the patients who did or did not receive CD34+-selected grafts (P=0.44), or according to the cyclophosphamide dose at the time of mobilization (2 g/m2 vs. 4 g/m2, P=0.16) or depending on whether they were or were not given G-CSF after their transplant (P=0.32) (Online Supplementary Table S3). Discussion The NISCC1 study is the largest prospective cohort today analyzing the efficacy and safety of autologous HSCT in 80 patients with severe SSc in a real-life setting. The PFS rate was 82% and significant improvements were observed in skin score, lung function and quality of life during the 2 years of follow-up, consistent with results of previous randomized controlled trials14-16 and earlier studies.11-13 Nevertheless, the NRM rate associated with auto logous HSCT was 6.25%, with most (4 out of 5) of the deaths being related to early cardiac events; this is similar to the 6% NRM rate reported retrospectively among 89 SSc patients transplanted between 2002 to 2011 in one USA and one Brazilian expert center using a non-myeloablative conditioning regimen.21 We used PFS as the primary endpoint to assess autologous HSCT efficacy rather than event-free survival, as previously used14,15 and which was defined as survival without respiratory, renal, or cardiac failure. PFS, which encompasses disease progression and toxic deaths, better reflects safety and efficacy of HSCT. In NISSC1, the incidence of progression was 6.3% and 11.9% at 1 and 2 years, respectively, highlighting the need to identify patients who may benefit from early maintenance therapy after autologous HSCT. Several mechanisms contribute to the resetting of the immunological response and disease control after autologous HSCT, and vary according to individual patients.12 We showed that the immune reconstitution profile and Tcell repertoire diversity together with a decrease in mRSS >25% and in FVC >10% at 1-2 years after transplantation could identify long-term responders and nonresponders/ relapsing patients at 4-5 years.22 The immune reconstitution process and the balance between reinduction of tolerance and sustained autoreactivity after transplantation will depend on the type of conditioning regimen used to ablate the original immune system, the effect of ATG or ex vivo CD34+-cell selection to further deplete/eliminate residual autoreactive cells and the use of post-transplant maintenance immunosuppression. 15,16,22-24 All patients in the NISCC1 study received a ‘non-myeloablative’ cyclophosphamide-based conditioning regimen, which included rabbit-derived ATG in all cases. The degree of T-cell depletion for each patient varied according to the type and total dose of ATG as well as timing of its administration in relation to the peripheral blood stem cell infusion, and whether the infused cells had undergone ex vivo CD34+ selection. In a previous retrospective EBMT analysis, we failed to demonstrate a benefit of ex vivo CD34+-cell selection23 in 138 SSc patients with similar baseline characteristics transplanted between 2000 and 2012. Surprisingly, the NISCC1 study showed a superior response to treatment in patients who received a CD34+- selected graft, with no increased rate of infectious complications, consistent with the recent findings of Ayano et al. in a retrospective analysis of 19 SSc patients.24 The reason for the difference in outcomes between these studies is unclear, but the population included in the NISCC1 prospective cohort was more homogenous in terms of conditioning, including in vivo T-cell depletion with rabbitderived ATG. All patients in the NISCC1 study received rabbit ATG formulations (although of different brands) while, in the EBMT retrospective study,23 64% of patients treated with ATG received a rabbit-derived product and 35% the horse-derived ATG formulation, which were shown to be associated with significantly different clinical outcomes in aplastic anemia.25 This important finding raises the question of whether a randomized, controlled trial should be performed to clarify whether more profound depletion of autoreactive cells from the peripheral blood stem cell graft by CD34+-cell selection may translate into sustained clinical benefit in SSc patients after autologous HSCT, without adversely affecting safety and cost-effectiveness. During the immune reconstitution process, the re-emergence of naïve T and B cells, the renewal of the immune repertoire and reinstatement of synergistic immunoregulatory mechanisms are expected. Therefore maintenance or rapid reintroduction of immunosuppression after autologous HSCT may improve patients’ outcome. The ongoing open-label trial (ClinicalTrials.gov identifier: NCT01413100) analyzing the addition of mycophenolate mofetil for 2 years after autologous HSCT and the next NISCC2 study (ClinicalTrials.gov identifier: NCT 03444805) analyzing posttransplantation management may clarify the potential benefit of post-transplant maintenance immunosuppression. A critical point for autologous HSCT in autoimmune diseases is safety. The risks of early transplant-related complications and mortality vary according to the type of disease, pre-existing internal organ involvement, the experience of the transplant center and the intensity of the conditioning regimen.12,26,27 Major cardiac adverse events and NRM after autologous HSCT in SSc are predominantly related to primary cardiac and lung involvement, which are underevaluated in the absence of systematic MRI and RHC at baseline.28,29 Our study revealed important variations in clinical practice in the pre-transplant cardio-pulmonary evaluation process. Although all patients who died during the first 100 days had normal resting ECG and LVEF on echocardiography at baseline, they were not all assessed by 24 h ECG (3/5), MRI (4/5) or RHC with fluid challenge (1/5). Overall, 24 h ECG was only used in 75% of the NISCC1 patients to detect subclinical rhythm or conduction disturbances at baseline, although it has been recommended since 2004.27 Similarly, cardiac MRI and RHC with fluid challenge were only performed in 74% and 21% of the patients, respectively, while their use has been advocated among expert centers since 2012 to minimize the risk of the transplant procedure.21,30,31 From 2013 to 2017, the EBMT and collaborative partners worked collectively to establish common standards for the use and interpretation of cardiac MRI results and RHC with fluid challenge for a rigorous cardio-pulmonary assessment of SSc patients, carefully defining eligibility and selection criteria for transplant referral.32 Table 4. Complications reported in the 100 days following autologous hematopoietic stem cell transplantation among the 80 patients treated for severe systemic sclerosis. Optimized treatment regimens are warranted to improve the safety of autologous HSCT, even in patients without cardiac involvement. Interestingly, the NRM rate in the NISCC1 study was similar to the 6% reported among 32 SSc patients transplanted between 2005 and 2011, using a ‘myeloablative’ conditioning regimen comprising total body irradiation (8 Gy), cyclophosphamide (120 mg/kg) and horse-derived ATG in the prospective SCOT randomized controlled trial.16 However, in the SCOT trial, NRM was primarily related to late fatal myelodysplastic syndromes, while no cyclophosphamide toxicity was reported. Within the follow-up period of the NISSC1 study, there were no reports of myelodysplastic syndrome or other myeloid malignancies. In addition, there were no reports of serious late infectious complications or secondary autoimmune phenomena that may occasionally present as long-term complications following autologous HSCT in autoimmune diseases. Although further follow-up is required, it is possible that there are long-term advantages, in terms of late effects, of the ‘non-myeloablative’ regimen used in the NISCC1 study. Early toxicity remains the principal challenge, including a NRM rate of 6%. To reduce toxicity and thus treatmentrelated mortality of the conditioning, a more individualized regimen with respect to heart, lung or kidney involvement might further improve patients’ safety, without excluding patients with organ manifestations. Two studies addressing patients with heart involvement are ongoing, both using a conditioning regimen with a reduced dose of cyclophosphamide and the addition of either thiotepa, as in four patients in our NISCC1 cohort (NCT01895244), or rituximab and fludarabine followed by reinfusion of autologous hematopoietic stem cells (NCT03593902), although the hematopoietic recovery from this reduced-dose regimen is prompt and reinfusion is not necessary in this setting. Because mobilization with G-CSF alone may exacerbate autoimmune diseases, there is a clinical rationale for combining G-CSF with cyclophosphamide. The use of 2 g/m2 cyclophosphamide for mobilization was as effective as 4 g/m2 at achieving the EBMT recommended minimum CD34+-cell yield, supporting dose reduction in the mobilization regimen to limit early toxicity as well as long-term risks associated with cumulative doses of cyclophosphamide. During the autologous HSCT procedures, inevitable infectious and non-infectious toxicity occurred especially following the high-dose cytotoxic conditioning and the cytopenic phase. A correlation between the number of infused CD34+ cells and a reduced duration of aplasia after autologous HSCT has been described previously, 33,34 which was confirmed in the NISCC1 study, although CD34+-cell dose and addition of G-CSF until recovery from aplasia were not associated with a reduced number of infectious complications. The NISCC1 study has several limitations. Since the study was a non-interventional trial, follow-up physical and laboratory evaluations, although recommended by EBMT guidelines,17 were not mandatory, and were not obtained at all time-points. The non-interventional study design was also the cause of significant variation in data collection practices by the 13 participating sites. Data were prospectively collected and checked for consistency by the EBMT study office; however, when some examinations were not performed, as may occur in routine clinical practice, data were classified as “missing”. The NISCC1 results showed significant variation in local practices when evaluating patients at baseline. Similarly, the number of reported days for mobilization varied largely according to centers; indeed, some patients were hospitalized for the whole duration of this procedure, whereas in other cases it was carried in part on an outpatient basis. We aimed to investigate the factors influencing the safety and efficacy of autologous HSCT. We used validated parameters to assess post-transplant outcome, such as mRSS or lung function tests despite their large intra- and inter-individual variability. The results enable deeper analysis of the benefits and risks of the transplant procedure in relation to both SSc-related factors, including the extent of heart, lung and kidney involvement at the time of patient referral, and transplant-related factors such as the conditioning regimen and graft manipulation. No international consensus has yet validated a unique activity score in SSc and further studies will be necessary in the post-transplant setting to investigate disease activity, the concept of drug-free remission and longer term outcomes, with or without post-transplant interventions. In conclusion, the NISSC1 is a large prospective real‐world data study of importance for patients, clinicians, and healthcare payers, given the poor prognosis and burden of disability of patients with severe SSc. It allowed us to assess multicenter adherence and compliance to good clinical practice and adds significantly to the evidence base supporting the delivery of autologous HSCT for severe SSc in routine clinical practice. Supplementary Material Disclosures and Contributions Supplementary Appendix

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2021-02-01

What was the outcome of reaction 'Cytomegalovirus infection reactivation'?

Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party. Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124. Introduction Systemic sclerosis (SSc) is a rare systemic autoimmune connective tissue disease characterized by vasculopathy, immune dysregulation and progressive fibrosis, affecting primarily the skin, gastrointestinal tract, lungs, heart and kidneys.1 It is associated with high disease-related mortality2 and the main causes of death are related to cardiac, pulmonary and renal involvement.2-5 Mortality rates in patients with SSc have remained higher than those in the general population (standardized mortality ratio above 3.5) over the past decades, in contrast to reductions in mortality for other rheumatic diseases or cancer.6 After the diagnosis of non-Raynaud phenomenon, the following risk factors for higher mortality related to progressive disease have been identified:2 diffuse skin fibrosis measured by the modified Rodnan skin score (mRSS, range 0-51),7 elevated C-reactive protein levels, altered left or right ventricular ejection fraction, interstitial lung disease with reduced forced vital capacity (FVC) or diffusion capacity for carbon monoxide (DLCO) on lung function testing, proteinuria and male sex. Earlier studies had found that the presence of anti-topoisomerase II (Scl-70) auto-antibodies, reduced functional status - as measured by the Scleroderma Health Assessment Questionnaire (sHAQ, range from 0 to 3, with lower values indicating a better quality of life)8 - or pulmonary arterial hypertension adversely affect survival.3-5 Treatment with biologic or immunosuppressive drugs did not improve SSc survival.2,9,10 Following early phase I-II trials,11-13 three randomized controlled trials, namely ASSIST (American scleroderma stem cell versus immune suppression trial, phase II),14 ASTIS (Autologous stem cell transplantation international scleroderma trial, phase III)15 and SCOT (Scleroderma: cyclophosphamide or transplantation, phase II)16 demonstrated the superiority of autologous hematopoietic stem cell transplantation (HSCT) compared to the standard cyclophosphamide pulse treatment with regards to overall and event-free survival. In this context, autologous HSCT has become the best treatment option for patients with severe or rapidly progressive SSc, with a grade 1 level of evidence since 2012 according to the Autoimmune Disease Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT) recommendations. 17,18 After two decades of progress in HSCT for autoimmune diseases, the use of autologous HSCT for severe or rapidly progressive SSc has also been endorsed by the European League Against Rheumatism (EULAR)10 and the American Society for Blood and Marrow Transplantation10,17,19 and the demand for this therapeutic procedure is the fastest growing indication for HSCT in Europe.10,17,19,20 We therefore designed this ADWP-EBMT non-interventional study, NISSC1, to further evaluate the efficacy and safety of autologous HSCT for early, severe, progressive SSc, when performed in real-life practice, and to identify risk factors for early adverse events and transplant-related mortality, in order to make this approach safer. Methods Study design This study is a prospective, open, multicenter, non-interventional study. Data regarding patients included in this study were prospectively collected using a specific case report form, designed according to EBMT guidelines for HSCT in SSc.17 All EBMT participating centers agreed to report their consecutive patients aged 18 to 65 years with severe progressive SSc undergoing their first autologous HSCT between December 2012 and February 2016. Inclusion and exclusion criteria are detailed in the Online Supplementary Appendix. Participating centers followed their own local protocols for the transplant procedure as wells as the patients’ evaluation at baseline and during the 2-year follow-up. The study was approved by the EBMT board in 2012 and by local ethics committees in participating countries and registered at ClinicalTrials.gov (NCT02516124). All patients gave written informed consent to their participation in the study. Patients’ evaluation The SSc patients’ characteristics were assessed at baseline (within 3 months before autologous HSCT) and at 3, 6, 12, 18 and 24 months after transplantation (day 0 was defined as the time point of reinfusion of stem cells). Data collected included mRSS, erythrocyte sedimentation rate (in mm/h), creatine kinase levels, presence or absence of autoantibodies, left ventricular ejection fraction (LVEF in %) and systolic pulmonary arterial pressure (in mmHg) on echocardiography, resting and 24 h Holter-electrocardiograms, abnormal cardiac magnetic resonance imaging (MRI) or pulmonary arterial hypertension on right heart catheterization (RHC), FVC and DLCO (% of predicted values), high resolution computed tomography of the lungs and kidney function as well as immunosuppressive drugs given before transplantation. The sHAQ was used to evaluate patients’ quality of life. Autologous hematopoietic stem cell transplantation procedure Data collected included details on the mobilization process with or without CD34+-cell selection, type of conditioning regimen; total dose of CD34+ cells infused; number of days of hospitalization for mobilization and conditioning, use and duration of granulocyte colony-stimulating factor (G-CSF), and time to engraftment. Endpoints The primary endpoint was progression-free survival (PFS), defined as survival after autologous HSCT without death or evidence of progression of SSc (see Online Supplementary Appendix S1) The secondary endpoints were: (i) infectious or non-infectious adverse events during the first 100 days after autologous HSCT; (ii) engraftment, defined as 3 consecutive days of neutrophils >0.5x109/L and platelets >20x109/L; (iii) response to treatment, defined as a >25% improvement in mRSS and/or ≥10% improvement in FVC or DLCO as compared to baseline and without need of further immunosuppression; (iv) incidence of progression; (v) non-relapse mortality (NRM), defined as any death without progression; and (vi) overall survival. Statistical analysis Cumulative incidence functions were used to estimate response to treatment, NRM, and progression to accommodate for competing risks. Probabilities of overall survival and PFS were calculated using the Kaplan-Meier method. Univariate analyses were performed using the Gray test for cumulative incidence and the log rank test for overall survival and PFS. Multivariate analysis was performed using a Cox regression model including variables associated with the outcome with a P-value less than 0.10 in univariate analyses. Age was included as a continuous variable. A generalized linear model was used to analyze evolution over time of mRSS, FVC, DLCO and sHAQ. Results are expressed as a hazard ratio (HR) with 95% confidence interval (95% CI). Results Eighty patients (71.3% female), who had undergone a first autologous HSCT between December 2012 and February 2016 in 13 EBMT centers from six European countries and Brazil were included in this study. The centers are listed in Online Supplementary Appendix S2. The median (range) follow- up after transplantation was 24 (6-57) months. Table 1 summarizes the patients’ baseline characteristics. The median disease duration since the diagnosis of SSc was 23.8 (5.3-103.7) months. At baseline, all 80 patients had skin involvement, and mRSS was above 15 in 64 (80%) of them. Abnormal chest x-rays or abnormal high-resolution computed tomography was reported in 70 (87%) patients. Heart involvement with an abnormal 24 h electrocardiogram was reported in 12/60 (20%) or with abnormal cardiac MRI in 11/59 (19%) patients. Among the 11 patients with abnormal MRI at baseline, echocardiography showed normal LVEF in all cases and pericardial effusion in one patient, the resting ECG was abnormal in one patient and the 24 h ECG was abnormal in two patients; baseline RHC performed in six patients (with fluid challenge in 2 cases) was normal. Overall, 21 patients (26%) were transplanted without any prior cardiac MRI or RHC at baseline; among these, two had pericardial effusion and seven had a systolic pulmonary artery pressure above 25 mmHg on echocardiography, one had ventricular disturbances on resting ECG (n=20), and 2/8 had an abnormal 24 h ECG. Table 1. Baseline characteristics of the patients (n=80). Mobilization and conditioning procedures All patients were mobilized using cyclophosphamide with a median dose of 2 g/m2 (range, 1-4 g/m2) plus G-CSF. The median duration of hospitalization was 4 (1-30) days for mobilization with large variation according to centers. CD34+-cell selection was performed in 35 (44%) patients (Table 2). The median time from mobilization to the start of the conditioning regimen for autologous HSCT was 52 (22-254) days. The conditioning regimen included cyclophosphamide in all 80 patients, alone in 76 (95%) patients, with a median total dose of 200 (50-240) mg/kg. Four patients (5%) received thiotepa 10 mg/kg with a total cyclophosphamide dose of 100 mg/kg as a single-center treatment for patients with cardiac abnormalities at the pre-transplant evaluation. Additional rabbit antithymocyte globulin (ATG), with different doses according to the brand, was also included in the conditioning regimen for all patients and administered over 4 to 5 days. Sixty-seven patients (82%) received methylprednisolone during the ATG treatment. No patient received total body irradiation. A median number of 5.2 x 106/kg (2.53-23.31) CD34+ cells were reinfused at transplantation. Following autologous HSCT, G-CSF was administered to 34 (43%) patients for a median duration of 5 (1-13) days. Following autologous HSCT, the median time to neutrophil engraftment was 11 (8-24) days and the median time to platelet engraftment was 9 (1-25) days. In 13 (16.9%) patients, the platelet counts were never below 20x109/L. There was an inverse correlation between the number of CD34+ cells infused and the time to engraftment (Spearman: r2= -0.31; P<0.01), while the number of infused CD34+ cells and addition of G-CSF until recovery of aplasia were not associated with a reduced number of infectious complications (P=0.32). The median duration of inpatient hospitalization for conditioning, autologous peripheral blood stem cell re-infusion and subsequent supportive care until engraftment and discharge was 24 (8-128) days (Table 2). Efficacy At 1 and 2 years after autologous HSCT, the PFS rate was 87.5% (95% CI: 80.2-94.7) and 81.8% (95% CI: 73.1-90.5), respectively, and the rate of response to treatment was 75% (95% CI: 63.7-83.2) and 88.7% (95% CI: 79-94.1), respectively. At the 1- and 2-year time-points, the incidence of progression was 6.3% (95% CI: 2.3-13.1) and 11.9% (95% CI: 5.8-20.5), respectively, and the overall survival rate was 91.2% (95% CI: 85.1-97.4) and 90% (95% CI 83.4-96.6) at 1 and 2 years, respectively (Figure 1). Three of the four patients transplanted with thiotepa and a reduced-dose cyclophosphamide regimen responded; one with worsening skin and lung involvement at day 350 was then treated with prednisone, mycophenolate mofetil and rituximab. By multivariate analysis, mRSS >24 at baseline and older age at transplantation were significantly associated with a lower PFS with hazard ratios of 3.33 (95% CI: 1.04-10.62) and 1.77 (95% CI: 1.07-2.94), respectively. CD34+-cell selection was associated with a better response to therapy (HR: 0.46; 95% CI: 0.27-0.76). Table 2. Treatment regimen used for mobilization and conditioning. Figure 2 illustrates the evolution of the parameters over time. The mean mRSS decreased from 23.9 (standard deviation [SD] 9.7) at baseline to 14.2 (SD 9.2) at 1 year and 12.6 (SD 8.3) at 2 years (n=55, P<0.001). Regarding lung function, the mean FVC increased from 73.6% (SD 16.9) of predicted value at baseline to 79.5% (SD 16.9) at 1 year and 80.6% (SD 19.1) at 2 years (n=37, P<0.001); the mean DLCO was 60.2% (SD 19.3) at baseline, 59.7% (SD 17.7) at 1 year and 60.4% (SD 19.1) at 2 years (n=35). The sHAQ score was available in 15 patients and decreased significantly from 0.96 (SD 0.8) at baseline to 0.73 (SD 0.6) at 1 year and 0.70 (SD 0.6) at 2 years (P<0.001). The mean erythrocyte sedimentation rate decreased from 23.2 mm/h (SD 19.8) at baseline to 16.1 mm/h (SD 11.3) at 1 year and 18.7 mm/h (SD 23.6) at 2 years (n=38, P<0.001). Anti-Scl-70 and anti-centromere autoantibodies did not change after autologous HSCT. Safety The NRM rate at 100 days and 2 years was 6.25% (95% CI 2.3-13) (Figure 1). Four of the five deaths not due to relapse were related to a cardiac event, due to cyclophosphamide toxicity in three patients. A 35-year old female, who died from cardiac toxicity and multiorgan failure on day +61 after autologous HSCT, had normal resting ECG and LVEF (62%) on echocardiography, and abnormal LVEF on heart scintigraphy (47%); MRI and RHC were not performed at baseline. Three other patients died from cardiac toxicity at day +1 (n=2) and day +9 (n=1), with normal cardiac MRI and no RHC evaluation at baseline. A fifth patient (conditioning with thiotepa + reduced-dose cyclophosphamide) died from cytomegalovirus reactivation with viral copies detectable also in the lung, with bacterial (Pseudomonas) pneumonia and multiorgan failure at day +21. This patient had a normal resting ECG, with an abnormal 24 h ECG, abnormal MRI and a mean pulmonary artery pressure of 17 mmHg on RHC performed without fluid challenge at baseline. During the 24 months of follow-up, three additional patients died, all due to disease progression. Baseline characteristics of all patients who died during the follow-up and the respective causes of death are presented in Table 3. Figure 1. Kaplan-Meier curves of outcomes of patients undergoing autologous hematopoietic stem cell transplantation for severe systemic sclerosis. Overall survival (OS), progression-free survival (PFS), progression and non-relapse (treatment)- related mortality (NRM) over time. Figure 2. Boxplots of the four most important efficacy parameters in the 24 months following autologous hematopoietic stem cell transplantation for severe systemic sclerosis. (A) Improvement of the modified Rodnan skin score (mRSS) (n=55; P<0.001). (B) Improvement of forced vital capacity (FVC) (n=37; P=0.001. (C) Stabilization of diffusion capacity of carbon monoxide (DLCO) (n=35; P=0.01). (D) Improvement of Scleroderma Health Assessment Questionnaire (sHAQ) score (n=15, P=0.001). Table 3. Baseline characteristics and results from the pretransplant evaluation in patients who died during the follow-up. During the 100 days after transplantation, a total of 119 adverse events were reported among the 80 patients as detailed in Table 4. The percentage of infectious complications was not significantly different between the patients who did or did not receive CD34+-selected grafts (P=0.44), or according to the cyclophosphamide dose at the time of mobilization (2 g/m2 vs. 4 g/m2, P=0.16) or depending on whether they were or were not given G-CSF after their transplant (P=0.32) (Online Supplementary Table S3). Discussion The NISCC1 study is the largest prospective cohort today analyzing the efficacy and safety of autologous HSCT in 80 patients with severe SSc in a real-life setting. The PFS rate was 82% and significant improvements were observed in skin score, lung function and quality of life during the 2 years of follow-up, consistent with results of previous randomized controlled trials14-16 and earlier studies.11-13 Nevertheless, the NRM rate associated with auto logous HSCT was 6.25%, with most (4 out of 5) of the deaths being related to early cardiac events; this is similar to the 6% NRM rate reported retrospectively among 89 SSc patients transplanted between 2002 to 2011 in one USA and one Brazilian expert center using a non-myeloablative conditioning regimen.21 We used PFS as the primary endpoint to assess autologous HSCT efficacy rather than event-free survival, as previously used14,15 and which was defined as survival without respiratory, renal, or cardiac failure. PFS, which encompasses disease progression and toxic deaths, better reflects safety and efficacy of HSCT. In NISSC1, the incidence of progression was 6.3% and 11.9% at 1 and 2 years, respectively, highlighting the need to identify patients who may benefit from early maintenance therapy after autologous HSCT. Several mechanisms contribute to the resetting of the immunological response and disease control after autologous HSCT, and vary according to individual patients.12 We showed that the immune reconstitution profile and Tcell repertoire diversity together with a decrease in mRSS >25% and in FVC >10% at 1-2 years after transplantation could identify long-term responders and nonresponders/ relapsing patients at 4-5 years.22 The immune reconstitution process and the balance between reinduction of tolerance and sustained autoreactivity after transplantation will depend on the type of conditioning regimen used to ablate the original immune system, the effect of ATG or ex vivo CD34+-cell selection to further deplete/eliminate residual autoreactive cells and the use of post-transplant maintenance immunosuppression. 15,16,22-24 All patients in the NISCC1 study received a ‘non-myeloablative’ cyclophosphamide-based conditioning regimen, which included rabbit-derived ATG in all cases. The degree of T-cell depletion for each patient varied according to the type and total dose of ATG as well as timing of its administration in relation to the peripheral blood stem cell infusion, and whether the infused cells had undergone ex vivo CD34+ selection. In a previous retrospective EBMT analysis, we failed to demonstrate a benefit of ex vivo CD34+-cell selection23 in 138 SSc patients with similar baseline characteristics transplanted between 2000 and 2012. Surprisingly, the NISCC1 study showed a superior response to treatment in patients who received a CD34+- selected graft, with no increased rate of infectious complications, consistent with the recent findings of Ayano et al. in a retrospective analysis of 19 SSc patients.24 The reason for the difference in outcomes between these studies is unclear, but the population included in the NISCC1 prospective cohort was more homogenous in terms of conditioning, including in vivo T-cell depletion with rabbitderived ATG. All patients in the NISCC1 study received rabbit ATG formulations (although of different brands) while, in the EBMT retrospective study,23 64% of patients treated with ATG received a rabbit-derived product and 35% the horse-derived ATG formulation, which were shown to be associated with significantly different clinical outcomes in aplastic anemia.25 This important finding raises the question of whether a randomized, controlled trial should be performed to clarify whether more profound depletion of autoreactive cells from the peripheral blood stem cell graft by CD34+-cell selection may translate into sustained clinical benefit in SSc patients after autologous HSCT, without adversely affecting safety and cost-effectiveness. During the immune reconstitution process, the re-emergence of naïve T and B cells, the renewal of the immune repertoire and reinstatement of synergistic immunoregulatory mechanisms are expected. Therefore maintenance or rapid reintroduction of immunosuppression after autologous HSCT may improve patients’ outcome. The ongoing open-label trial (ClinicalTrials.gov identifier: NCT01413100) analyzing the addition of mycophenolate mofetil for 2 years after autologous HSCT and the next NISCC2 study (ClinicalTrials.gov identifier: NCT 03444805) analyzing posttransplantation management may clarify the potential benefit of post-transplant maintenance immunosuppression. A critical point for autologous HSCT in autoimmune diseases is safety. The risks of early transplant-related complications and mortality vary according to the type of disease, pre-existing internal organ involvement, the experience of the transplant center and the intensity of the conditioning regimen.12,26,27 Major cardiac adverse events and NRM after autologous HSCT in SSc are predominantly related to primary cardiac and lung involvement, which are underevaluated in the absence of systematic MRI and RHC at baseline.28,29 Our study revealed important variations in clinical practice in the pre-transplant cardio-pulmonary evaluation process. Although all patients who died during the first 100 days had normal resting ECG and LVEF on echocardiography at baseline, they were not all assessed by 24 h ECG (3/5), MRI (4/5) or RHC with fluid challenge (1/5). Overall, 24 h ECG was only used in 75% of the NISCC1 patients to detect subclinical rhythm or conduction disturbances at baseline, although it has been recommended since 2004.27 Similarly, cardiac MRI and RHC with fluid challenge were only performed in 74% and 21% of the patients, respectively, while their use has been advocated among expert centers since 2012 to minimize the risk of the transplant procedure.21,30,31 From 2013 to 2017, the EBMT and collaborative partners worked collectively to establish common standards for the use and interpretation of cardiac MRI results and RHC with fluid challenge for a rigorous cardio-pulmonary assessment of SSc patients, carefully defining eligibility and selection criteria for transplant referral.32 Table 4. Complications reported in the 100 days following autologous hematopoietic stem cell transplantation among the 80 patients treated for severe systemic sclerosis. Optimized treatment regimens are warranted to improve the safety of autologous HSCT, even in patients without cardiac involvement. Interestingly, the NRM rate in the NISCC1 study was similar to the 6% reported among 32 SSc patients transplanted between 2005 and 2011, using a ‘myeloablative’ conditioning regimen comprising total body irradiation (8 Gy), cyclophosphamide (120 mg/kg) and horse-derived ATG in the prospective SCOT randomized controlled trial.16 However, in the SCOT trial, NRM was primarily related to late fatal myelodysplastic syndromes, while no cyclophosphamide toxicity was reported. Within the follow-up period of the NISSC1 study, there were no reports of myelodysplastic syndrome or other myeloid malignancies. In addition, there were no reports of serious late infectious complications or secondary autoimmune phenomena that may occasionally present as long-term complications following autologous HSCT in autoimmune diseases. Although further follow-up is required, it is possible that there are long-term advantages, in terms of late effects, of the ‘non-myeloablative’ regimen used in the NISCC1 study. Early toxicity remains the principal challenge, including a NRM rate of 6%. To reduce toxicity and thus treatmentrelated mortality of the conditioning, a more individualized regimen with respect to heart, lung or kidney involvement might further improve patients’ safety, without excluding patients with organ manifestations. Two studies addressing patients with heart involvement are ongoing, both using a conditioning regimen with a reduced dose of cyclophosphamide and the addition of either thiotepa, as in four patients in our NISCC1 cohort (NCT01895244), or rituximab and fludarabine followed by reinfusion of autologous hematopoietic stem cells (NCT03593902), although the hematopoietic recovery from this reduced-dose regimen is prompt and reinfusion is not necessary in this setting. Because mobilization with G-CSF alone may exacerbate autoimmune diseases, there is a clinical rationale for combining G-CSF with cyclophosphamide. The use of 2 g/m2 cyclophosphamide for mobilization was as effective as 4 g/m2 at achieving the EBMT recommended minimum CD34+-cell yield, supporting dose reduction in the mobilization regimen to limit early toxicity as well as long-term risks associated with cumulative doses of cyclophosphamide. During the autologous HSCT procedures, inevitable infectious and non-infectious toxicity occurred especially following the high-dose cytotoxic conditioning and the cytopenic phase. A correlation between the number of infused CD34+ cells and a reduced duration of aplasia after autologous HSCT has been described previously, 33,34 which was confirmed in the NISCC1 study, although CD34+-cell dose and addition of G-CSF until recovery from aplasia were not associated with a reduced number of infectious complications. The NISCC1 study has several limitations. Since the study was a non-interventional trial, follow-up physical and laboratory evaluations, although recommended by EBMT guidelines,17 were not mandatory, and were not obtained at all time-points. The non-interventional study design was also the cause of significant variation in data collection practices by the 13 participating sites. Data were prospectively collected and checked for consistency by the EBMT study office; however, when some examinations were not performed, as may occur in routine clinical practice, data were classified as “missing”. The NISCC1 results showed significant variation in local practices when evaluating patients at baseline. Similarly, the number of reported days for mobilization varied largely according to centers; indeed, some patients were hospitalized for the whole duration of this procedure, whereas in other cases it was carried in part on an outpatient basis. We aimed to investigate the factors influencing the safety and efficacy of autologous HSCT. We used validated parameters to assess post-transplant outcome, such as mRSS or lung function tests despite their large intra- and inter-individual variability. The results enable deeper analysis of the benefits and risks of the transplant procedure in relation to both SSc-related factors, including the extent of heart, lung and kidney involvement at the time of patient referral, and transplant-related factors such as the conditioning regimen and graft manipulation. No international consensus has yet validated a unique activity score in SSc and further studies will be necessary in the post-transplant setting to investigate disease activity, the concept of drug-free remission and longer term outcomes, with or without post-transplant interventions. In conclusion, the NISSC1 is a large prospective real‐world data study of importance for patients, clinicians, and healthcare payers, given the poor prognosis and burden of disability of patients with severe SSc. It allowed us to assess multicenter adherence and compliance to good clinical practice and adds significantly to the evidence base supporting the delivery of autologous HSCT for severe SSc in routine clinical practice. Supplementary Material Disclosures and Contributions Supplementary Appendix

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2021-02-01

What was the outcome of reaction 'Multiple organ dysfunction syndrome'?

Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party. Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124. Introduction Systemic sclerosis (SSc) is a rare systemic autoimmune connective tissue disease characterized by vasculopathy, immune dysregulation and progressive fibrosis, affecting primarily the skin, gastrointestinal tract, lungs, heart and kidneys.1 It is associated with high disease-related mortality2 and the main causes of death are related to cardiac, pulmonary and renal involvement.2-5 Mortality rates in patients with SSc have remained higher than those in the general population (standardized mortality ratio above 3.5) over the past decades, in contrast to reductions in mortality for other rheumatic diseases or cancer.6 After the diagnosis of non-Raynaud phenomenon, the following risk factors for higher mortality related to progressive disease have been identified:2 diffuse skin fibrosis measured by the modified Rodnan skin score (mRSS, range 0-51),7 elevated C-reactive protein levels, altered left or right ventricular ejection fraction, interstitial lung disease with reduced forced vital capacity (FVC) or diffusion capacity for carbon monoxide (DLCO) on lung function testing, proteinuria and male sex. Earlier studies had found that the presence of anti-topoisomerase II (Scl-70) auto-antibodies, reduced functional status - as measured by the Scleroderma Health Assessment Questionnaire (sHAQ, range from 0 to 3, with lower values indicating a better quality of life)8 - or pulmonary arterial hypertension adversely affect survival.3-5 Treatment with biologic or immunosuppressive drugs did not improve SSc survival.2,9,10 Following early phase I-II trials,11-13 three randomized controlled trials, namely ASSIST (American scleroderma stem cell versus immune suppression trial, phase II),14 ASTIS (Autologous stem cell transplantation international scleroderma trial, phase III)15 and SCOT (Scleroderma: cyclophosphamide or transplantation, phase II)16 demonstrated the superiority of autologous hematopoietic stem cell transplantation (HSCT) compared to the standard cyclophosphamide pulse treatment with regards to overall and event-free survival. In this context, autologous HSCT has become the best treatment option for patients with severe or rapidly progressive SSc, with a grade 1 level of evidence since 2012 according to the Autoimmune Disease Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT) recommendations. 17,18 After two decades of progress in HSCT for autoimmune diseases, the use of autologous HSCT for severe or rapidly progressive SSc has also been endorsed by the European League Against Rheumatism (EULAR)10 and the American Society for Blood and Marrow Transplantation10,17,19 and the demand for this therapeutic procedure is the fastest growing indication for HSCT in Europe.10,17,19,20 We therefore designed this ADWP-EBMT non-interventional study, NISSC1, to further evaluate the efficacy and safety of autologous HSCT for early, severe, progressive SSc, when performed in real-life practice, and to identify risk factors for early adverse events and transplant-related mortality, in order to make this approach safer. Methods Study design This study is a prospective, open, multicenter, non-interventional study. Data regarding patients included in this study were prospectively collected using a specific case report form, designed according to EBMT guidelines for HSCT in SSc.17 All EBMT participating centers agreed to report their consecutive patients aged 18 to 65 years with severe progressive SSc undergoing their first autologous HSCT between December 2012 and February 2016. Inclusion and exclusion criteria are detailed in the Online Supplementary Appendix. Participating centers followed their own local protocols for the transplant procedure as wells as the patients’ evaluation at baseline and during the 2-year follow-up. The study was approved by the EBMT board in 2012 and by local ethics committees in participating countries and registered at ClinicalTrials.gov (NCT02516124). All patients gave written informed consent to their participation in the study. Patients’ evaluation The SSc patients’ characteristics were assessed at baseline (within 3 months before autologous HSCT) and at 3, 6, 12, 18 and 24 months after transplantation (day 0 was defined as the time point of reinfusion of stem cells). Data collected included mRSS, erythrocyte sedimentation rate (in mm/h), creatine kinase levels, presence or absence of autoantibodies, left ventricular ejection fraction (LVEF in %) and systolic pulmonary arterial pressure (in mmHg) on echocardiography, resting and 24 h Holter-electrocardiograms, abnormal cardiac magnetic resonance imaging (MRI) or pulmonary arterial hypertension on right heart catheterization (RHC), FVC and DLCO (% of predicted values), high resolution computed tomography of the lungs and kidney function as well as immunosuppressive drugs given before transplantation. The sHAQ was used to evaluate patients’ quality of life. Autologous hematopoietic stem cell transplantation procedure Data collected included details on the mobilization process with or without CD34+-cell selection, type of conditioning regimen; total dose of CD34+ cells infused; number of days of hospitalization for mobilization and conditioning, use and duration of granulocyte colony-stimulating factor (G-CSF), and time to engraftment. Endpoints The primary endpoint was progression-free survival (PFS), defined as survival after autologous HSCT without death or evidence of progression of SSc (see Online Supplementary Appendix S1) The secondary endpoints were: (i) infectious or non-infectious adverse events during the first 100 days after autologous HSCT; (ii) engraftment, defined as 3 consecutive days of neutrophils >0.5x109/L and platelets >20x109/L; (iii) response to treatment, defined as a >25% improvement in mRSS and/or ≥10% improvement in FVC or DLCO as compared to baseline and without need of further immunosuppression; (iv) incidence of progression; (v) non-relapse mortality (NRM), defined as any death without progression; and (vi) overall survival. Statistical analysis Cumulative incidence functions were used to estimate response to treatment, NRM, and progression to accommodate for competing risks. Probabilities of overall survival and PFS were calculated using the Kaplan-Meier method. Univariate analyses were performed using the Gray test for cumulative incidence and the log rank test for overall survival and PFS. Multivariate analysis was performed using a Cox regression model including variables associated with the outcome with a P-value less than 0.10 in univariate analyses. Age was included as a continuous variable. A generalized linear model was used to analyze evolution over time of mRSS, FVC, DLCO and sHAQ. Results are expressed as a hazard ratio (HR) with 95% confidence interval (95% CI). Results Eighty patients (71.3% female), who had undergone a first autologous HSCT between December 2012 and February 2016 in 13 EBMT centers from six European countries and Brazil were included in this study. The centers are listed in Online Supplementary Appendix S2. The median (range) follow- up after transplantation was 24 (6-57) months. Table 1 summarizes the patients’ baseline characteristics. The median disease duration since the diagnosis of SSc was 23.8 (5.3-103.7) months. At baseline, all 80 patients had skin involvement, and mRSS was above 15 in 64 (80%) of them. Abnormal chest x-rays or abnormal high-resolution computed tomography was reported in 70 (87%) patients. Heart involvement with an abnormal 24 h electrocardiogram was reported in 12/60 (20%) or with abnormal cardiac MRI in 11/59 (19%) patients. Among the 11 patients with abnormal MRI at baseline, echocardiography showed normal LVEF in all cases and pericardial effusion in one patient, the resting ECG was abnormal in one patient and the 24 h ECG was abnormal in two patients; baseline RHC performed in six patients (with fluid challenge in 2 cases) was normal. Overall, 21 patients (26%) were transplanted without any prior cardiac MRI or RHC at baseline; among these, two had pericardial effusion and seven had a systolic pulmonary artery pressure above 25 mmHg on echocardiography, one had ventricular disturbances on resting ECG (n=20), and 2/8 had an abnormal 24 h ECG. Table 1. Baseline characteristics of the patients (n=80). Mobilization and conditioning procedures All patients were mobilized using cyclophosphamide with a median dose of 2 g/m2 (range, 1-4 g/m2) plus G-CSF. The median duration of hospitalization was 4 (1-30) days for mobilization with large variation according to centers. CD34+-cell selection was performed in 35 (44%) patients (Table 2). The median time from mobilization to the start of the conditioning regimen for autologous HSCT was 52 (22-254) days. The conditioning regimen included cyclophosphamide in all 80 patients, alone in 76 (95%) patients, with a median total dose of 200 (50-240) mg/kg. Four patients (5%) received thiotepa 10 mg/kg with a total cyclophosphamide dose of 100 mg/kg as a single-center treatment for patients with cardiac abnormalities at the pre-transplant evaluation. Additional rabbit antithymocyte globulin (ATG), with different doses according to the brand, was also included in the conditioning regimen for all patients and administered over 4 to 5 days. Sixty-seven patients (82%) received methylprednisolone during the ATG treatment. No patient received total body irradiation. A median number of 5.2 x 106/kg (2.53-23.31) CD34+ cells were reinfused at transplantation. Following autologous HSCT, G-CSF was administered to 34 (43%) patients for a median duration of 5 (1-13) days. Following autologous HSCT, the median time to neutrophil engraftment was 11 (8-24) days and the median time to platelet engraftment was 9 (1-25) days. In 13 (16.9%) patients, the platelet counts were never below 20x109/L. There was an inverse correlation between the number of CD34+ cells infused and the time to engraftment (Spearman: r2= -0.31; P<0.01), while the number of infused CD34+ cells and addition of G-CSF until recovery of aplasia were not associated with a reduced number of infectious complications (P=0.32). The median duration of inpatient hospitalization for conditioning, autologous peripheral blood stem cell re-infusion and subsequent supportive care until engraftment and discharge was 24 (8-128) days (Table 2). Efficacy At 1 and 2 years after autologous HSCT, the PFS rate was 87.5% (95% CI: 80.2-94.7) and 81.8% (95% CI: 73.1-90.5), respectively, and the rate of response to treatment was 75% (95% CI: 63.7-83.2) and 88.7% (95% CI: 79-94.1), respectively. At the 1- and 2-year time-points, the incidence of progression was 6.3% (95% CI: 2.3-13.1) and 11.9% (95% CI: 5.8-20.5), respectively, and the overall survival rate was 91.2% (95% CI: 85.1-97.4) and 90% (95% CI 83.4-96.6) at 1 and 2 years, respectively (Figure 1). Three of the four patients transplanted with thiotepa and a reduced-dose cyclophosphamide regimen responded; one with worsening skin and lung involvement at day 350 was then treated with prednisone, mycophenolate mofetil and rituximab. By multivariate analysis, mRSS >24 at baseline and older age at transplantation were significantly associated with a lower PFS with hazard ratios of 3.33 (95% CI: 1.04-10.62) and 1.77 (95% CI: 1.07-2.94), respectively. CD34+-cell selection was associated with a better response to therapy (HR: 0.46; 95% CI: 0.27-0.76). Table 2. Treatment regimen used for mobilization and conditioning. Figure 2 illustrates the evolution of the parameters over time. The mean mRSS decreased from 23.9 (standard deviation [SD] 9.7) at baseline to 14.2 (SD 9.2) at 1 year and 12.6 (SD 8.3) at 2 years (n=55, P<0.001). Regarding lung function, the mean FVC increased from 73.6% (SD 16.9) of predicted value at baseline to 79.5% (SD 16.9) at 1 year and 80.6% (SD 19.1) at 2 years (n=37, P<0.001); the mean DLCO was 60.2% (SD 19.3) at baseline, 59.7% (SD 17.7) at 1 year and 60.4% (SD 19.1) at 2 years (n=35). The sHAQ score was available in 15 patients and decreased significantly from 0.96 (SD 0.8) at baseline to 0.73 (SD 0.6) at 1 year and 0.70 (SD 0.6) at 2 years (P<0.001). The mean erythrocyte sedimentation rate decreased from 23.2 mm/h (SD 19.8) at baseline to 16.1 mm/h (SD 11.3) at 1 year and 18.7 mm/h (SD 23.6) at 2 years (n=38, P<0.001). Anti-Scl-70 and anti-centromere autoantibodies did not change after autologous HSCT. Safety The NRM rate at 100 days and 2 years was 6.25% (95% CI 2.3-13) (Figure 1). Four of the five deaths not due to relapse were related to a cardiac event, due to cyclophosphamide toxicity in three patients. A 35-year old female, who died from cardiac toxicity and multiorgan failure on day +61 after autologous HSCT, had normal resting ECG and LVEF (62%) on echocardiography, and abnormal LVEF on heart scintigraphy (47%); MRI and RHC were not performed at baseline. Three other patients died from cardiac toxicity at day +1 (n=2) and day +9 (n=1), with normal cardiac MRI and no RHC evaluation at baseline. A fifth patient (conditioning with thiotepa + reduced-dose cyclophosphamide) died from cytomegalovirus reactivation with viral copies detectable also in the lung, with bacterial (Pseudomonas) pneumonia and multiorgan failure at day +21. This patient had a normal resting ECG, with an abnormal 24 h ECG, abnormal MRI and a mean pulmonary artery pressure of 17 mmHg on RHC performed without fluid challenge at baseline. During the 24 months of follow-up, three additional patients died, all due to disease progression. Baseline characteristics of all patients who died during the follow-up and the respective causes of death are presented in Table 3. Figure 1. Kaplan-Meier curves of outcomes of patients undergoing autologous hematopoietic stem cell transplantation for severe systemic sclerosis. Overall survival (OS), progression-free survival (PFS), progression and non-relapse (treatment)- related mortality (NRM) over time. Figure 2. Boxplots of the four most important efficacy parameters in the 24 months following autologous hematopoietic stem cell transplantation for severe systemic sclerosis. (A) Improvement of the modified Rodnan skin score (mRSS) (n=55; P<0.001). (B) Improvement of forced vital capacity (FVC) (n=37; P=0.001. (C) Stabilization of diffusion capacity of carbon monoxide (DLCO) (n=35; P=0.01). (D) Improvement of Scleroderma Health Assessment Questionnaire (sHAQ) score (n=15, P=0.001). Table 3. Baseline characteristics and results from the pretransplant evaluation in patients who died during the follow-up. During the 100 days after transplantation, a total of 119 adverse events were reported among the 80 patients as detailed in Table 4. The percentage of infectious complications was not significantly different between the patients who did or did not receive CD34+-selected grafts (P=0.44), or according to the cyclophosphamide dose at the time of mobilization (2 g/m2 vs. 4 g/m2, P=0.16) or depending on whether they were or were not given G-CSF after their transplant (P=0.32) (Online Supplementary Table S3). Discussion The NISCC1 study is the largest prospective cohort today analyzing the efficacy and safety of autologous HSCT in 80 patients with severe SSc in a real-life setting. The PFS rate was 82% and significant improvements were observed in skin score, lung function and quality of life during the 2 years of follow-up, consistent with results of previous randomized controlled trials14-16 and earlier studies.11-13 Nevertheless, the NRM rate associated with auto logous HSCT was 6.25%, with most (4 out of 5) of the deaths being related to early cardiac events; this is similar to the 6% NRM rate reported retrospectively among 89 SSc patients transplanted between 2002 to 2011 in one USA and one Brazilian expert center using a non-myeloablative conditioning regimen.21 We used PFS as the primary endpoint to assess autologous HSCT efficacy rather than event-free survival, as previously used14,15 and which was defined as survival without respiratory, renal, or cardiac failure. PFS, which encompasses disease progression and toxic deaths, better reflects safety and efficacy of HSCT. In NISSC1, the incidence of progression was 6.3% and 11.9% at 1 and 2 years, respectively, highlighting the need to identify patients who may benefit from early maintenance therapy after autologous HSCT. Several mechanisms contribute to the resetting of the immunological response and disease control after autologous HSCT, and vary according to individual patients.12 We showed that the immune reconstitution profile and Tcell repertoire diversity together with a decrease in mRSS >25% and in FVC >10% at 1-2 years after transplantation could identify long-term responders and nonresponders/ relapsing patients at 4-5 years.22 The immune reconstitution process and the balance between reinduction of tolerance and sustained autoreactivity after transplantation will depend on the type of conditioning regimen used to ablate the original immune system, the effect of ATG or ex vivo CD34+-cell selection to further deplete/eliminate residual autoreactive cells and the use of post-transplant maintenance immunosuppression. 15,16,22-24 All patients in the NISCC1 study received a ‘non-myeloablative’ cyclophosphamide-based conditioning regimen, which included rabbit-derived ATG in all cases. The degree of T-cell depletion for each patient varied according to the type and total dose of ATG as well as timing of its administration in relation to the peripheral blood stem cell infusion, and whether the infused cells had undergone ex vivo CD34+ selection. In a previous retrospective EBMT analysis, we failed to demonstrate a benefit of ex vivo CD34+-cell selection23 in 138 SSc patients with similar baseline characteristics transplanted between 2000 and 2012. Surprisingly, the NISCC1 study showed a superior response to treatment in patients who received a CD34+- selected graft, with no increased rate of infectious complications, consistent with the recent findings of Ayano et al. in a retrospective analysis of 19 SSc patients.24 The reason for the difference in outcomes between these studies is unclear, but the population included in the NISCC1 prospective cohort was more homogenous in terms of conditioning, including in vivo T-cell depletion with rabbitderived ATG. All patients in the NISCC1 study received rabbit ATG formulations (although of different brands) while, in the EBMT retrospective study,23 64% of patients treated with ATG received a rabbit-derived product and 35% the horse-derived ATG formulation, which were shown to be associated with significantly different clinical outcomes in aplastic anemia.25 This important finding raises the question of whether a randomized, controlled trial should be performed to clarify whether more profound depletion of autoreactive cells from the peripheral blood stem cell graft by CD34+-cell selection may translate into sustained clinical benefit in SSc patients after autologous HSCT, without adversely affecting safety and cost-effectiveness. During the immune reconstitution process, the re-emergence of naïve T and B cells, the renewal of the immune repertoire and reinstatement of synergistic immunoregulatory mechanisms are expected. Therefore maintenance or rapid reintroduction of immunosuppression after autologous HSCT may improve patients’ outcome. The ongoing open-label trial (ClinicalTrials.gov identifier: NCT01413100) analyzing the addition of mycophenolate mofetil for 2 years after autologous HSCT and the next NISCC2 study (ClinicalTrials.gov identifier: NCT 03444805) analyzing posttransplantation management may clarify the potential benefit of post-transplant maintenance immunosuppression. A critical point for autologous HSCT in autoimmune diseases is safety. The risks of early transplant-related complications and mortality vary according to the type of disease, pre-existing internal organ involvement, the experience of the transplant center and the intensity of the conditioning regimen.12,26,27 Major cardiac adverse events and NRM after autologous HSCT in SSc are predominantly related to primary cardiac and lung involvement, which are underevaluated in the absence of systematic MRI and RHC at baseline.28,29 Our study revealed important variations in clinical practice in the pre-transplant cardio-pulmonary evaluation process. Although all patients who died during the first 100 days had normal resting ECG and LVEF on echocardiography at baseline, they were not all assessed by 24 h ECG (3/5), MRI (4/5) or RHC with fluid challenge (1/5). Overall, 24 h ECG was only used in 75% of the NISCC1 patients to detect subclinical rhythm or conduction disturbances at baseline, although it has been recommended since 2004.27 Similarly, cardiac MRI and RHC with fluid challenge were only performed in 74% and 21% of the patients, respectively, while their use has been advocated among expert centers since 2012 to minimize the risk of the transplant procedure.21,30,31 From 2013 to 2017, the EBMT and collaborative partners worked collectively to establish common standards for the use and interpretation of cardiac MRI results and RHC with fluid challenge for a rigorous cardio-pulmonary assessment of SSc patients, carefully defining eligibility and selection criteria for transplant referral.32 Table 4. Complications reported in the 100 days following autologous hematopoietic stem cell transplantation among the 80 patients treated for severe systemic sclerosis. Optimized treatment regimens are warranted to improve the safety of autologous HSCT, even in patients without cardiac involvement. Interestingly, the NRM rate in the NISCC1 study was similar to the 6% reported among 32 SSc patients transplanted between 2005 and 2011, using a ‘myeloablative’ conditioning regimen comprising total body irradiation (8 Gy), cyclophosphamide (120 mg/kg) and horse-derived ATG in the prospective SCOT randomized controlled trial.16 However, in the SCOT trial, NRM was primarily related to late fatal myelodysplastic syndromes, while no cyclophosphamide toxicity was reported. Within the follow-up period of the NISSC1 study, there were no reports of myelodysplastic syndrome or other myeloid malignancies. In addition, there were no reports of serious late infectious complications or secondary autoimmune phenomena that may occasionally present as long-term complications following autologous HSCT in autoimmune diseases. Although further follow-up is required, it is possible that there are long-term advantages, in terms of late effects, of the ‘non-myeloablative’ regimen used in the NISCC1 study. Early toxicity remains the principal challenge, including a NRM rate of 6%. To reduce toxicity and thus treatmentrelated mortality of the conditioning, a more individualized regimen with respect to heart, lung or kidney involvement might further improve patients’ safety, without excluding patients with organ manifestations. Two studies addressing patients with heart involvement are ongoing, both using a conditioning regimen with a reduced dose of cyclophosphamide and the addition of either thiotepa, as in four patients in our NISCC1 cohort (NCT01895244), or rituximab and fludarabine followed by reinfusion of autologous hematopoietic stem cells (NCT03593902), although the hematopoietic recovery from this reduced-dose regimen is prompt and reinfusion is not necessary in this setting. Because mobilization with G-CSF alone may exacerbate autoimmune diseases, there is a clinical rationale for combining G-CSF with cyclophosphamide. The use of 2 g/m2 cyclophosphamide for mobilization was as effective as 4 g/m2 at achieving the EBMT recommended minimum CD34+-cell yield, supporting dose reduction in the mobilization regimen to limit early toxicity as well as long-term risks associated with cumulative doses of cyclophosphamide. During the autologous HSCT procedures, inevitable infectious and non-infectious toxicity occurred especially following the high-dose cytotoxic conditioning and the cytopenic phase. A correlation between the number of infused CD34+ cells and a reduced duration of aplasia after autologous HSCT has been described previously, 33,34 which was confirmed in the NISCC1 study, although CD34+-cell dose and addition of G-CSF until recovery from aplasia were not associated with a reduced number of infectious complications. The NISCC1 study has several limitations. Since the study was a non-interventional trial, follow-up physical and laboratory evaluations, although recommended by EBMT guidelines,17 were not mandatory, and were not obtained at all time-points. The non-interventional study design was also the cause of significant variation in data collection practices by the 13 participating sites. Data were prospectively collected and checked for consistency by the EBMT study office; however, when some examinations were not performed, as may occur in routine clinical practice, data were classified as “missing”. The NISCC1 results showed significant variation in local practices when evaluating patients at baseline. Similarly, the number of reported days for mobilization varied largely according to centers; indeed, some patients were hospitalized for the whole duration of this procedure, whereas in other cases it was carried in part on an outpatient basis. We aimed to investigate the factors influencing the safety and efficacy of autologous HSCT. We used validated parameters to assess post-transplant outcome, such as mRSS or lung function tests despite their large intra- and inter-individual variability. The results enable deeper analysis of the benefits and risks of the transplant procedure in relation to both SSc-related factors, including the extent of heart, lung and kidney involvement at the time of patient referral, and transplant-related factors such as the conditioning regimen and graft manipulation. No international consensus has yet validated a unique activity score in SSc and further studies will be necessary in the post-transplant setting to investigate disease activity, the concept of drug-free remission and longer term outcomes, with or without post-transplant interventions. In conclusion, the NISSC1 is a large prospective real‐world data study of importance for patients, clinicians, and healthcare payers, given the poor prognosis and burden of disability of patients with severe SSc. It allowed us to assess multicenter adherence and compliance to good clinical practice and adds significantly to the evidence base supporting the delivery of autologous HSCT for severe SSc in routine clinical practice. Supplementary Material Disclosures and Contributions Supplementary Appendix

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2021-02-01

What was the outcome of reaction 'Pneumonia pseudomonal'?

Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party. Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124. Introduction Systemic sclerosis (SSc) is a rare systemic autoimmune connective tissue disease characterized by vasculopathy, immune dysregulation and progressive fibrosis, affecting primarily the skin, gastrointestinal tract, lungs, heart and kidneys.1 It is associated with high disease-related mortality2 and the main causes of death are related to cardiac, pulmonary and renal involvement.2-5 Mortality rates in patients with SSc have remained higher than those in the general population (standardized mortality ratio above 3.5) over the past decades, in contrast to reductions in mortality for other rheumatic diseases or cancer.6 After the diagnosis of non-Raynaud phenomenon, the following risk factors for higher mortality related to progressive disease have been identified:2 diffuse skin fibrosis measured by the modified Rodnan skin score (mRSS, range 0-51),7 elevated C-reactive protein levels, altered left or right ventricular ejection fraction, interstitial lung disease with reduced forced vital capacity (FVC) or diffusion capacity for carbon monoxide (DLCO) on lung function testing, proteinuria and male sex. Earlier studies had found that the presence of anti-topoisomerase II (Scl-70) auto-antibodies, reduced functional status - as measured by the Scleroderma Health Assessment Questionnaire (sHAQ, range from 0 to 3, with lower values indicating a better quality of life)8 - or pulmonary arterial hypertension adversely affect survival.3-5 Treatment with biologic or immunosuppressive drugs did not improve SSc survival.2,9,10 Following early phase I-II trials,11-13 three randomized controlled trials, namely ASSIST (American scleroderma stem cell versus immune suppression trial, phase II),14 ASTIS (Autologous stem cell transplantation international scleroderma trial, phase III)15 and SCOT (Scleroderma: cyclophosphamide or transplantation, phase II)16 demonstrated the superiority of autologous hematopoietic stem cell transplantation (HSCT) compared to the standard cyclophosphamide pulse treatment with regards to overall and event-free survival. In this context, autologous HSCT has become the best treatment option for patients with severe or rapidly progressive SSc, with a grade 1 level of evidence since 2012 according to the Autoimmune Disease Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT) recommendations. 17,18 After two decades of progress in HSCT for autoimmune diseases, the use of autologous HSCT for severe or rapidly progressive SSc has also been endorsed by the European League Against Rheumatism (EULAR)10 and the American Society for Blood and Marrow Transplantation10,17,19 and the demand for this therapeutic procedure is the fastest growing indication for HSCT in Europe.10,17,19,20 We therefore designed this ADWP-EBMT non-interventional study, NISSC1, to further evaluate the efficacy and safety of autologous HSCT for early, severe, progressive SSc, when performed in real-life practice, and to identify risk factors for early adverse events and transplant-related mortality, in order to make this approach safer. Methods Study design This study is a prospective, open, multicenter, non-interventional study. Data regarding patients included in this study were prospectively collected using a specific case report form, designed according to EBMT guidelines for HSCT in SSc.17 All EBMT participating centers agreed to report their consecutive patients aged 18 to 65 years with severe progressive SSc undergoing their first autologous HSCT between December 2012 and February 2016. Inclusion and exclusion criteria are detailed in the Online Supplementary Appendix. Participating centers followed their own local protocols for the transplant procedure as wells as the patients’ evaluation at baseline and during the 2-year follow-up. The study was approved by the EBMT board in 2012 and by local ethics committees in participating countries and registered at ClinicalTrials.gov (NCT02516124). All patients gave written informed consent to their participation in the study. Patients’ evaluation The SSc patients’ characteristics were assessed at baseline (within 3 months before autologous HSCT) and at 3, 6, 12, 18 and 24 months after transplantation (day 0 was defined as the time point of reinfusion of stem cells). Data collected included mRSS, erythrocyte sedimentation rate (in mm/h), creatine kinase levels, presence or absence of autoantibodies, left ventricular ejection fraction (LVEF in %) and systolic pulmonary arterial pressure (in mmHg) on echocardiography, resting and 24 h Holter-electrocardiograms, abnormal cardiac magnetic resonance imaging (MRI) or pulmonary arterial hypertension on right heart catheterization (RHC), FVC and DLCO (% of predicted values), high resolution computed tomography of the lungs and kidney function as well as immunosuppressive drugs given before transplantation. The sHAQ was used to evaluate patients’ quality of life. Autologous hematopoietic stem cell transplantation procedure Data collected included details on the mobilization process with or without CD34+-cell selection, type of conditioning regimen; total dose of CD34+ cells infused; number of days of hospitalization for mobilization and conditioning, use and duration of granulocyte colony-stimulating factor (G-CSF), and time to engraftment. Endpoints The primary endpoint was progression-free survival (PFS), defined as survival after autologous HSCT without death or evidence of progression of SSc (see Online Supplementary Appendix S1) The secondary endpoints were: (i) infectious or non-infectious adverse events during the first 100 days after autologous HSCT; (ii) engraftment, defined as 3 consecutive days of neutrophils >0.5x109/L and platelets >20x109/L; (iii) response to treatment, defined as a >25% improvement in mRSS and/or ≥10% improvement in FVC or DLCO as compared to baseline and without need of further immunosuppression; (iv) incidence of progression; (v) non-relapse mortality (NRM), defined as any death without progression; and (vi) overall survival. Statistical analysis Cumulative incidence functions were used to estimate response to treatment, NRM, and progression to accommodate for competing risks. Probabilities of overall survival and PFS were calculated using the Kaplan-Meier method. Univariate analyses were performed using the Gray test for cumulative incidence and the log rank test for overall survival and PFS. Multivariate analysis was performed using a Cox regression model including variables associated with the outcome with a P-value less than 0.10 in univariate analyses. Age was included as a continuous variable. A generalized linear model was used to analyze evolution over time of mRSS, FVC, DLCO and sHAQ. Results are expressed as a hazard ratio (HR) with 95% confidence interval (95% CI). Results Eighty patients (71.3% female), who had undergone a first autologous HSCT between December 2012 and February 2016 in 13 EBMT centers from six European countries and Brazil were included in this study. The centers are listed in Online Supplementary Appendix S2. The median (range) follow- up after transplantation was 24 (6-57) months. Table 1 summarizes the patients’ baseline characteristics. The median disease duration since the diagnosis of SSc was 23.8 (5.3-103.7) months. At baseline, all 80 patients had skin involvement, and mRSS was above 15 in 64 (80%) of them. Abnormal chest x-rays or abnormal high-resolution computed tomography was reported in 70 (87%) patients. Heart involvement with an abnormal 24 h electrocardiogram was reported in 12/60 (20%) or with abnormal cardiac MRI in 11/59 (19%) patients. Among the 11 patients with abnormal MRI at baseline, echocardiography showed normal LVEF in all cases and pericardial effusion in one patient, the resting ECG was abnormal in one patient and the 24 h ECG was abnormal in two patients; baseline RHC performed in six patients (with fluid challenge in 2 cases) was normal. Overall, 21 patients (26%) were transplanted without any prior cardiac MRI or RHC at baseline; among these, two had pericardial effusion and seven had a systolic pulmonary artery pressure above 25 mmHg on echocardiography, one had ventricular disturbances on resting ECG (n=20), and 2/8 had an abnormal 24 h ECG. Table 1. Baseline characteristics of the patients (n=80). Mobilization and conditioning procedures All patients were mobilized using cyclophosphamide with a median dose of 2 g/m2 (range, 1-4 g/m2) plus G-CSF. The median duration of hospitalization was 4 (1-30) days for mobilization with large variation according to centers. CD34+-cell selection was performed in 35 (44%) patients (Table 2). The median time from mobilization to the start of the conditioning regimen for autologous HSCT was 52 (22-254) days. The conditioning regimen included cyclophosphamide in all 80 patients, alone in 76 (95%) patients, with a median total dose of 200 (50-240) mg/kg. Four patients (5%) received thiotepa 10 mg/kg with a total cyclophosphamide dose of 100 mg/kg as a single-center treatment for patients with cardiac abnormalities at the pre-transplant evaluation. Additional rabbit antithymocyte globulin (ATG), with different doses according to the brand, was also included in the conditioning regimen for all patients and administered over 4 to 5 days. Sixty-seven patients (82%) received methylprednisolone during the ATG treatment. No patient received total body irradiation. A median number of 5.2 x 106/kg (2.53-23.31) CD34+ cells were reinfused at transplantation. Following autologous HSCT, G-CSF was administered to 34 (43%) patients for a median duration of 5 (1-13) days. Following autologous HSCT, the median time to neutrophil engraftment was 11 (8-24) days and the median time to platelet engraftment was 9 (1-25) days. In 13 (16.9%) patients, the platelet counts were never below 20x109/L. There was an inverse correlation between the number of CD34+ cells infused and the time to engraftment (Spearman: r2= -0.31; P<0.01), while the number of infused CD34+ cells and addition of G-CSF until recovery of aplasia were not associated with a reduced number of infectious complications (P=0.32). The median duration of inpatient hospitalization for conditioning, autologous peripheral blood stem cell re-infusion and subsequent supportive care until engraftment and discharge was 24 (8-128) days (Table 2). Efficacy At 1 and 2 years after autologous HSCT, the PFS rate was 87.5% (95% CI: 80.2-94.7) and 81.8% (95% CI: 73.1-90.5), respectively, and the rate of response to treatment was 75% (95% CI: 63.7-83.2) and 88.7% (95% CI: 79-94.1), respectively. At the 1- and 2-year time-points, the incidence of progression was 6.3% (95% CI: 2.3-13.1) and 11.9% (95% CI: 5.8-20.5), respectively, and the overall survival rate was 91.2% (95% CI: 85.1-97.4) and 90% (95% CI 83.4-96.6) at 1 and 2 years, respectively (Figure 1). Three of the four patients transplanted with thiotepa and a reduced-dose cyclophosphamide regimen responded; one with worsening skin and lung involvement at day 350 was then treated with prednisone, mycophenolate mofetil and rituximab. By multivariate analysis, mRSS >24 at baseline and older age at transplantation were significantly associated with a lower PFS with hazard ratios of 3.33 (95% CI: 1.04-10.62) and 1.77 (95% CI: 1.07-2.94), respectively. CD34+-cell selection was associated with a better response to therapy (HR: 0.46; 95% CI: 0.27-0.76). Table 2. Treatment regimen used for mobilization and conditioning. Figure 2 illustrates the evolution of the parameters over time. The mean mRSS decreased from 23.9 (standard deviation [SD] 9.7) at baseline to 14.2 (SD 9.2) at 1 year and 12.6 (SD 8.3) at 2 years (n=55, P<0.001). Regarding lung function, the mean FVC increased from 73.6% (SD 16.9) of predicted value at baseline to 79.5% (SD 16.9) at 1 year and 80.6% (SD 19.1) at 2 years (n=37, P<0.001); the mean DLCO was 60.2% (SD 19.3) at baseline, 59.7% (SD 17.7) at 1 year and 60.4% (SD 19.1) at 2 years (n=35). The sHAQ score was available in 15 patients and decreased significantly from 0.96 (SD 0.8) at baseline to 0.73 (SD 0.6) at 1 year and 0.70 (SD 0.6) at 2 years (P<0.001). The mean erythrocyte sedimentation rate decreased from 23.2 mm/h (SD 19.8) at baseline to 16.1 mm/h (SD 11.3) at 1 year and 18.7 mm/h (SD 23.6) at 2 years (n=38, P<0.001). Anti-Scl-70 and anti-centromere autoantibodies did not change after autologous HSCT. Safety The NRM rate at 100 days and 2 years was 6.25% (95% CI 2.3-13) (Figure 1). Four of the five deaths not due to relapse were related to a cardiac event, due to cyclophosphamide toxicity in three patients. A 35-year old female, who died from cardiac toxicity and multiorgan failure on day +61 after autologous HSCT, had normal resting ECG and LVEF (62%) on echocardiography, and abnormal LVEF on heart scintigraphy (47%); MRI and RHC were not performed at baseline. Three other patients died from cardiac toxicity at day +1 (n=2) and day +9 (n=1), with normal cardiac MRI and no RHC evaluation at baseline. A fifth patient (conditioning with thiotepa + reduced-dose cyclophosphamide) died from cytomegalovirus reactivation with viral copies detectable also in the lung, with bacterial (Pseudomonas) pneumonia and multiorgan failure at day +21. This patient had a normal resting ECG, with an abnormal 24 h ECG, abnormal MRI and a mean pulmonary artery pressure of 17 mmHg on RHC performed without fluid challenge at baseline. During the 24 months of follow-up, three additional patients died, all due to disease progression. Baseline characteristics of all patients who died during the follow-up and the respective causes of death are presented in Table 3. Figure 1. Kaplan-Meier curves of outcomes of patients undergoing autologous hematopoietic stem cell transplantation for severe systemic sclerosis. Overall survival (OS), progression-free survival (PFS), progression and non-relapse (treatment)- related mortality (NRM) over time. Figure 2. Boxplots of the four most important efficacy parameters in the 24 months following autologous hematopoietic stem cell transplantation for severe systemic sclerosis. (A) Improvement of the modified Rodnan skin score (mRSS) (n=55; P<0.001). (B) Improvement of forced vital capacity (FVC) (n=37; P=0.001. (C) Stabilization of diffusion capacity of carbon monoxide (DLCO) (n=35; P=0.01). (D) Improvement of Scleroderma Health Assessment Questionnaire (sHAQ) score (n=15, P=0.001). Table 3. Baseline characteristics and results from the pretransplant evaluation in patients who died during the follow-up. During the 100 days after transplantation, a total of 119 adverse events were reported among the 80 patients as detailed in Table 4. The percentage of infectious complications was not significantly different between the patients who did or did not receive CD34+-selected grafts (P=0.44), or according to the cyclophosphamide dose at the time of mobilization (2 g/m2 vs. 4 g/m2, P=0.16) or depending on whether they were or were not given G-CSF after their transplant (P=0.32) (Online Supplementary Table S3). Discussion The NISCC1 study is the largest prospective cohort today analyzing the efficacy and safety of autologous HSCT in 80 patients with severe SSc in a real-life setting. The PFS rate was 82% and significant improvements were observed in skin score, lung function and quality of life during the 2 years of follow-up, consistent with results of previous randomized controlled trials14-16 and earlier studies.11-13 Nevertheless, the NRM rate associated with auto logous HSCT was 6.25%, with most (4 out of 5) of the deaths being related to early cardiac events; this is similar to the 6% NRM rate reported retrospectively among 89 SSc patients transplanted between 2002 to 2011 in one USA and one Brazilian expert center using a non-myeloablative conditioning regimen.21 We used PFS as the primary endpoint to assess autologous HSCT efficacy rather than event-free survival, as previously used14,15 and which was defined as survival without respiratory, renal, or cardiac failure. PFS, which encompasses disease progression and toxic deaths, better reflects safety and efficacy of HSCT. In NISSC1, the incidence of progression was 6.3% and 11.9% at 1 and 2 years, respectively, highlighting the need to identify patients who may benefit from early maintenance therapy after autologous HSCT. Several mechanisms contribute to the resetting of the immunological response and disease control after autologous HSCT, and vary according to individual patients.12 We showed that the immune reconstitution profile and Tcell repertoire diversity together with a decrease in mRSS >25% and in FVC >10% at 1-2 years after transplantation could identify long-term responders and nonresponders/ relapsing patients at 4-5 years.22 The immune reconstitution process and the balance between reinduction of tolerance and sustained autoreactivity after transplantation will depend on the type of conditioning regimen used to ablate the original immune system, the effect of ATG or ex vivo CD34+-cell selection to further deplete/eliminate residual autoreactive cells and the use of post-transplant maintenance immunosuppression. 15,16,22-24 All patients in the NISCC1 study received a ‘non-myeloablative’ cyclophosphamide-based conditioning regimen, which included rabbit-derived ATG in all cases. The degree of T-cell depletion for each patient varied according to the type and total dose of ATG as well as timing of its administration in relation to the peripheral blood stem cell infusion, and whether the infused cells had undergone ex vivo CD34+ selection. In a previous retrospective EBMT analysis, we failed to demonstrate a benefit of ex vivo CD34+-cell selection23 in 138 SSc patients with similar baseline characteristics transplanted between 2000 and 2012. Surprisingly, the NISCC1 study showed a superior response to treatment in patients who received a CD34+- selected graft, with no increased rate of infectious complications, consistent with the recent findings of Ayano et al. in a retrospective analysis of 19 SSc patients.24 The reason for the difference in outcomes between these studies is unclear, but the population included in the NISCC1 prospective cohort was more homogenous in terms of conditioning, including in vivo T-cell depletion with rabbitderived ATG. All patients in the NISCC1 study received rabbit ATG formulations (although of different brands) while, in the EBMT retrospective study,23 64% of patients treated with ATG received a rabbit-derived product and 35% the horse-derived ATG formulation, which were shown to be associated with significantly different clinical outcomes in aplastic anemia.25 This important finding raises the question of whether a randomized, controlled trial should be performed to clarify whether more profound depletion of autoreactive cells from the peripheral blood stem cell graft by CD34+-cell selection may translate into sustained clinical benefit in SSc patients after autologous HSCT, without adversely affecting safety and cost-effectiveness. During the immune reconstitution process, the re-emergence of naïve T and B cells, the renewal of the immune repertoire and reinstatement of synergistic immunoregulatory mechanisms are expected. Therefore maintenance or rapid reintroduction of immunosuppression after autologous HSCT may improve patients’ outcome. The ongoing open-label trial (ClinicalTrials.gov identifier: NCT01413100) analyzing the addition of mycophenolate mofetil for 2 years after autologous HSCT and the next NISCC2 study (ClinicalTrials.gov identifier: NCT 03444805) analyzing posttransplantation management may clarify the potential benefit of post-transplant maintenance immunosuppression. A critical point for autologous HSCT in autoimmune diseases is safety. The risks of early transplant-related complications and mortality vary according to the type of disease, pre-existing internal organ involvement, the experience of the transplant center and the intensity of the conditioning regimen.12,26,27 Major cardiac adverse events and NRM after autologous HSCT in SSc are predominantly related to primary cardiac and lung involvement, which are underevaluated in the absence of systematic MRI and RHC at baseline.28,29 Our study revealed important variations in clinical practice in the pre-transplant cardio-pulmonary evaluation process. Although all patients who died during the first 100 days had normal resting ECG and LVEF on echocardiography at baseline, they were not all assessed by 24 h ECG (3/5), MRI (4/5) or RHC with fluid challenge (1/5). Overall, 24 h ECG was only used in 75% of the NISCC1 patients to detect subclinical rhythm or conduction disturbances at baseline, although it has been recommended since 2004.27 Similarly, cardiac MRI and RHC with fluid challenge were only performed in 74% and 21% of the patients, respectively, while their use has been advocated among expert centers since 2012 to minimize the risk of the transplant procedure.21,30,31 From 2013 to 2017, the EBMT and collaborative partners worked collectively to establish common standards for the use and interpretation of cardiac MRI results and RHC with fluid challenge for a rigorous cardio-pulmonary assessment of SSc patients, carefully defining eligibility and selection criteria for transplant referral.32 Table 4. Complications reported in the 100 days following autologous hematopoietic stem cell transplantation among the 80 patients treated for severe systemic sclerosis. Optimized treatment regimens are warranted to improve the safety of autologous HSCT, even in patients without cardiac involvement. Interestingly, the NRM rate in the NISCC1 study was similar to the 6% reported among 32 SSc patients transplanted between 2005 and 2011, using a ‘myeloablative’ conditioning regimen comprising total body irradiation (8 Gy), cyclophosphamide (120 mg/kg) and horse-derived ATG in the prospective SCOT randomized controlled trial.16 However, in the SCOT trial, NRM was primarily related to late fatal myelodysplastic syndromes, while no cyclophosphamide toxicity was reported. Within the follow-up period of the NISSC1 study, there were no reports of myelodysplastic syndrome or other myeloid malignancies. In addition, there were no reports of serious late infectious complications or secondary autoimmune phenomena that may occasionally present as long-term complications following autologous HSCT in autoimmune diseases. Although further follow-up is required, it is possible that there are long-term advantages, in terms of late effects, of the ‘non-myeloablative’ regimen used in the NISCC1 study. Early toxicity remains the principal challenge, including a NRM rate of 6%. To reduce toxicity and thus treatmentrelated mortality of the conditioning, a more individualized regimen with respect to heart, lung or kidney involvement might further improve patients’ safety, without excluding patients with organ manifestations. Two studies addressing patients with heart involvement are ongoing, both using a conditioning regimen with a reduced dose of cyclophosphamide and the addition of either thiotepa, as in four patients in our NISCC1 cohort (NCT01895244), or rituximab and fludarabine followed by reinfusion of autologous hematopoietic stem cells (NCT03593902), although the hematopoietic recovery from this reduced-dose regimen is prompt and reinfusion is not necessary in this setting. Because mobilization with G-CSF alone may exacerbate autoimmune diseases, there is a clinical rationale for combining G-CSF with cyclophosphamide. The use of 2 g/m2 cyclophosphamide for mobilization was as effective as 4 g/m2 at achieving the EBMT recommended minimum CD34+-cell yield, supporting dose reduction in the mobilization regimen to limit early toxicity as well as long-term risks associated with cumulative doses of cyclophosphamide. During the autologous HSCT procedures, inevitable infectious and non-infectious toxicity occurred especially following the high-dose cytotoxic conditioning and the cytopenic phase. A correlation between the number of infused CD34+ cells and a reduced duration of aplasia after autologous HSCT has been described previously, 33,34 which was confirmed in the NISCC1 study, although CD34+-cell dose and addition of G-CSF until recovery from aplasia were not associated with a reduced number of infectious complications. The NISCC1 study has several limitations. Since the study was a non-interventional trial, follow-up physical and laboratory evaluations, although recommended by EBMT guidelines,17 were not mandatory, and were not obtained at all time-points. The non-interventional study design was also the cause of significant variation in data collection practices by the 13 participating sites. Data were prospectively collected and checked for consistency by the EBMT study office; however, when some examinations were not performed, as may occur in routine clinical practice, data were classified as “missing”. The NISCC1 results showed significant variation in local practices when evaluating patients at baseline. Similarly, the number of reported days for mobilization varied largely according to centers; indeed, some patients were hospitalized for the whole duration of this procedure, whereas in other cases it was carried in part on an outpatient basis. We aimed to investigate the factors influencing the safety and efficacy of autologous HSCT. We used validated parameters to assess post-transplant outcome, such as mRSS or lung function tests despite their large intra- and inter-individual variability. The results enable deeper analysis of the benefits and risks of the transplant procedure in relation to both SSc-related factors, including the extent of heart, lung and kidney involvement at the time of patient referral, and transplant-related factors such as the conditioning regimen and graft manipulation. No international consensus has yet validated a unique activity score in SSc and further studies will be necessary in the post-transplant setting to investigate disease activity, the concept of drug-free remission and longer term outcomes, with or without post-transplant interventions. In conclusion, the NISSC1 is a large prospective real‐world data study of importance for patients, clinicians, and healthcare payers, given the poor prognosis and burden of disability of patients with severe SSc. It allowed us to assess multicenter adherence and compliance to good clinical practice and adds significantly to the evidence base supporting the delivery of autologous HSCT for severe SSc in routine clinical practice. Supplementary Material Disclosures and Contributions Supplementary Appendix

Fatal

ReactionOutcome

CC BY-NC

31949011

2021-02-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Congenital umbilical hernia'.

Maternal and Infant Outcomes Among Pregnant Women Treated for Multidrug/Rifampicin-Resistant Tuberculosis in South Africa. Data on safety and efficacy of second-line tuberculosis drugs in pregnant women and their infants are severely limited due to exclusion from clinical trials and expanded access programs. Pregnant women starting treatment for multidrug/rifampicin-resistant (MDR/RR)-tuberculosis at King Dinuzulu Hospital in KwaZulu-Natal, South Africa, from 1 January 2013 to 31 December 2017, were included. We conducted a record review to describe maternal treatment and pregnancy outcomes, and a clinical assessment to describe infant outcomes. Of 108 pregnant women treated for MDR/RR-tuberculosis, 88 (81%) were living with human immunodeficiency virus.. Favorable MDR/RR-tuberculosis treatment outcomes were reported in 72 (67%) women. Ninety-nine (91%) of the 109 babies were born alive, but overall, 52 (48%) women had unfavorable pregnancy outcomes. Fifty-eight (54%) women received bedaquiline, and 49 (45%) babies were exposed to bedaquiline in utero. Low birth weight was reported in more babies exposed to bedaquiline compared to babies not exposed (45% vs 26%; P = .034). In multivariate analyses, bedaquiline and levofloxacin, drugs often used in combination, were both independently associated with increased risk of low birth weight. Of the 86 children evaluated at 12 months, 72 (84%) had favorable outcomes; 88% of babies exposed to bedaquiline were thriving and developing normally compared to 82% of the babies not exposed. MDR/RR-tuberculosis treatment outcomes among pregnant women were comparable to nonpregnant women. Although more babies exposed to bedaquiline were of low birth weight, over 80% had gained weight and were developing normally at 1 year. (See the Editorial Commentary by Marais on pages 1169–70.) Over a half million individuals were estimated to have multidrug/rifampicin-resistant (MDR/RR) tuberculosis globally in 2017, with the highest burden among women of reproductive age (15–45 years) [1]. In women of this age, tuberculosis is the leading cause of death from an infectious agent and a common nonobstetric cause of maternal mortality [1–4]. Worldwide in 2011, an estimated 216 500 pregnant women developed tuberculosis, with the greatest burden in Africa [5]. Not only do biological changes in pregnancy double the risk of pregnant women developing tuberculosis compared to nonpregnant women, but pregnancy complicates the treatment of tuberculosis, and if untreated, pregnancy-associated tuberculosis can be associated with mortality of up to 40% [2]. In women living with tuberculosis and human immunodeficiency virus (HIV), the risk of maternal mortality increases dramatically; neonates born to these women also have increased morbidity and mortality [2, 6]. As the safety of first-line tuberculosis drugs in pregnancy have been established and treatment has been shown to improve maternal and neonatal outcome, the World Health Organization (WHO) recommends that pregnant women with drug-susceptible tuberculosis should be treated in the same way as nonpregnant women [7–9]. The management of MDR/RR-tuberculosis in pregnant women is more complicated as little is known about the use of second-line tuberculosis drugs in pregnancy [10]. Presently, WHO recommends that pregnant women be offered individualized regimens, aiming to include ≥4 effective drugs with an established safety profile and low teratogenic risk [7]. However, as pregnant women have generally been excluded from the studies on which WHO recommendations were based, safety data of most second-line tuberculosis drugs in pregnancy are lacking [7, 10], with fewer than 15 case reports describing the safety and outcomes of second-line tuberculosis treatment during pregnancy. The largest report included 38 women [11]. The tuberculosis treatment landscape has changed with programmatic introduction of 2 novel drugs, delamanid and bedaquiline, and repurposing of older drugs, including linezolid and clofazimine. None of the studies evaluating these drugs have included pregnant women, and currently, due to a paucity of data, the use of new and repurposed drugs during pregnancy and breastfeeding is not widely recommended [7, 12–14]. In South Africa, where the rate of tuberculosis is estimated at 10.3 per 1000 pregnancies [5], pregnant women with MDR/RR-tuberculosis have had access to bedaquiline since 2015. Given the improved treatment success rates among MDR/RR-tuberculosis patients treated with bedaquiline [15], the drug became increasingly used as a substitute for injectable agents. In September 2018, the national Department of Health recommended an injectable-free, modified 9–12-month regimen for all patients diagnosed with MDR/RR-tuberculosis, including pregnant women. We report treatment, pregnancy, and infant outcomes in a cohort of pregnant women with MDR/RR-tuberculosis in KwaZulu-Natal, South Africa, with a focus on women and infants exposed to bedaquiline during pregnancy. METHODOLOGY Study Design and Patient Population In this observational cohort study, medical records of women attending King Dinuzulu Hospital (KDH) for MDR/RR-tuberculosis management between 1 January 2013 and 31 December 2017 were reviewed. KDH is the specialist referral hospital for RR-tuberculosis in KwaZulu-Natal province where all pregnant women with MDR/RR-tuberculosis are referred. Definitions of Presenting Characteristics Pulmonary tuberculosis was defined as disease affecting the lungs only. Cavitary/bilateral disease was defined as the presence of either cavities or disease in both left and right lung fields and was considered an indication of extensive disease. Patients on antiretroviral therapy (ART) before MDR/RR-tuberculosis treatment started were defined as those receiving ART for at least 30 days prior to MDR/RR-tuberculosis treatment initiation. Baseline CD4 count was defined as the date recorded in the clinical notes closest to the date of MDR/RR-tuberculosis treatment initiation. Gestational age was recorded from clinical notes; determined by ultrasound, dates, or both. Drug Resistance Definitions MDR/RR-tuberculosis was classified as tuberculosis caused by Mycobacterium tuberculosis with genotypic or phenotypic resistance to rifampicin. It included MDR-tuberculosis (resistance to both isoniazid and rifampicin), rifampicin monoresistant tuberculosis (susceptibility to isoniazid), and forms of disease where rifampicin resistance has been identified, but no result for isoniazid has been returned (increasingly common when testing with the GeneXpert MTB/RIF molecular assay). Extensively drug-resistant (XDR) tuberculosis was classified as MDR-tuberculosis with additional resistance to a fluoroquinolone and a second-line injectable agent. Pre-XDR-tuberculosis is MDR-tuberculosis with additional resistance to either a fluoroquinolone or an injectable agent but not both. Diagnosis and Treatment Drug susceptibility testing (DST) was performed on all sputum cultures positive for M. tuberculosis. From 2013 to 2015 DST included isoniazid, rifampicin, streptomycin, kanamycin, and ofloxacin. From 2015 to 2018 moxifloxacin and capreomycin were added. Given the complexity of treating pregnant women with MDR/RR-tuberculosis, most women were initially hospitalized and received individualized treatment. Women who had started a standardized regimen for MDR/RR-tuberculosis prior to becoming pregnant may have subsequently had treatment modified, depending on the stage of treatment. Between 2013 and 2015, national MDR/RR-tuberculosis treatment guidelines recommended a standardized 18–24 month regimen, unless resistance or intolerance to specific drugs required regimen modification, as per WHO 2011 treatment guidelines [16, 17]. The injectable phase of treatment (6–8 months) included kanamycin, moxifloxacin, ethionamide, terizidone, and pyrazinamide, followed by the continuation phase (12–18 months) comprising moxifloxacin, ethionamide, terizidone, and pyrazinamide [17]. In some cases ethambutol and higher doses of isoniazid were added. Standard treatment changed in early 2017 when the WHO 9–12 month regimen was introduced across South Africa, and, like other adults with MDR/RR-tuberculosis, pregnant women benefitted from the shorter regimen [7]. However, kanamycin/amikacin and ethionamide are contraindicated in pregnancy. In most pregnant women receiving MDR/RR-tuberculosis treatment, these drugs were either omitted, stopped, or substituted with alternative agents, such as capreomycin or para-aminosalicylic acid prior to 2015, or linezolid or bedaquiline as access to these newer agents increased [18]. In line with local guidelines, specific drugs in the treatment regimens were stopped or substituted if drug resistance patterns changed, toxicity developed, or drug: drug interactions occurred. During the study period it was standard of care for pregnant women living with HIV to receive antiretroviral therapy (ART). Patients who were ART-naive started on ART after 2 weeks of MDR/RR-TB treatment During the study period first-line ART comprised tenofovir, emtricitabine, and efavirenz. ART regimen changes were not comprehensively documented, but pregnant women receiving efavirenz switched to nevirapine prior to bedaquiline initiation. Outcome Definitions We defined 3 outcomes: maternal treatment outcomes, pregnancy outcomes, and infant outcomes. Each were considered favorable or unfavorable and are defined in Table 1. Table 1. Definition of Terms Treatment Outcomes [19, 20] Favorable treatment outcomes Cured Treatment completed as recommended by the national policy without evidence of failure, AND ≥3 consecutive cultures taken at least 30 days apart are negative after the intensive phase. Treatment completed Treatment completed as recommended by the national policy without evidence of failure, BUT no record that ≥3 consecutive cultures taken at least 30 days apart are negative after the intensive phase. Treatment success The sum of cured and treatment completed. Unfavorable treatment outcomes Treatment failed Treatment terminated or need for permanent regimen change of at least 2 antituberculosis drugs because of a lack of culture conversion by the end of the intensive phase; bacteriological culture reversion in the continuation phase after conversion to negative; evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs; ADRs. Died A patient who dies for any reason during treatment. Lost to follow-up A patient whose treatment was interrupted for ≥2 consecutive months. Treatment unsuccessful The sum of failed, died, lost to follow-up, and not evaluated. Pregnancy outcomes Favorable pregnancy outcomes—all the below features are required to classify a pregnancy outcome as favorable Full term Babies born ≥37 weeks of pregnancy. Normal birth weight Birth weight of ≥2500 grams according to the World Health Organization (WHO) [21]. Alive A baby born alive who lives for >28 days. Unfavorable pregnancy outcomes—any of the following classify a pregnancy as having an unfavourable outcome Preterm birth Babies born <37 weeks of pregnancy. Miscarriage Spontaneous loss of a pregnancy before the fetus has reached viability at 24 weeks. This includes all pregnancy losses from the time of conception until 23 completed weeks of gestation [22]. Stillbirth In South Africa, the legal definition of stillbirth is an infant born dead after “6 months of intrauterine life” (ie, 28 weeks since the start of the last period or 26 weeks since conception). If the gestational age is not known, a weight of 1000 g is used to legally define a stillbirth. Infants that are born dead before this time are legally regarded as miscarriages. Termination of pregnancy Termination of pregnancy is when a woman decides to end her pregnancy before the full term by medical means. The woman must be <13 weeks pregnant to end the pregnancy without giving reasons. If she is between 13 and 20 weeks pregnant, the pregnancy may be terminated only under specific conditions. If she is >20 weeks pregnant, it will be done only if her life or the fetus’ life is in danger, or there are likely to be serious birth defects [23]. Low birth weight A birth weight of <2500 g (up to and including 2499 g), as per the World Health Organization (WHO) [21]. Infant outcomes Development Child development refers to how a child becomes able to do more complex things as they get older. Developmental milestones are a set of functional skills or age-specific tasks that most children can do at a certain age range [24]. These skills include gross and fine motor, language, cognitive, and social skills. Lost to follow-up It was not possible to verify the status of the child at 12 months. Favorable infant outcomes—both of the following are required to state that an infant has a favorable outcome Thrive normally If a child gains weight following the normal trajectory according to the growth chart, the child is said to be thriving normally. Normal development A child is described as having normal development if they achieve the developmental milestones timeously. Unfavorable infant outcomes—any of the following classify the child as having an unfavorable outcome Failure to thrive The infant fails to maintain an established pattern of growth [25]. Delayed development The child reaches developmental milestones later than the average child. TB diagnosis Diagnosed with TB or RR-TB before 12 months of age. Neonatal death Death of a live born infant in the first 28 days of life. An early neonatal death is a death that occurs in the first week of life [26]. Infant death Infant dies before 12 months. Abbreviations: ADR, adverse drug reactions; RR-TB, rifampicin-resistant TB; TB, tuberculosis. Data Variables and Collection We reviewed maternal medical records to collect demographic, clinical, and laboratory data. Response to treatment was determined from medical records and the laboratory database. Pregnancy outcomes, birth weight, APGAR scores, and postdelivery screening were extracted from patient-held notes and road-to-health cards. Infants were seen at KDH 6–8 weeks after delivery and assessed clinically to determine if they were thriving and screened for symptoms and signs of tuberculosis disease. Infants were assessed again at 6 and 12 months. If any problems were detected, the child was referred to routine care for further evaluation and investigation. Data Management and Statistical Analyses Data were captured using an Excel spreadsheet and imported into STATA/SE version 15.0. for analysis. Baseline clinical characteristics and maternal treatment, pregnancy, and infant outcomes were presented using descriptive statistics. Missing data were noted, and each analysis reflects the sample size used. All clinical characteristics, individual tuberculosis drugs, and ART drugs were assessed as potential predictors of outcome using univariable logistic regression. Any drug use during the MDR/RR-tuberculosis treatment episode was included in evaluation of treatment outcome, but only drug use ≥14 days during pregnancy was included for the evaluations of pregnancy and infant outcomes, reflecting in utero exposure. Clinical characteristics, other tuberculosis drugs, ART drugs, and all 3 outcomes were compared between mothers receiving regimens with bedaquiline and without bedaquiline using the χ 2 or Fisher exact test for categorical variables, and the t test or Wilcoxon rank sum test for continuous variables. After observing an effect of bedaquiline on birth weight, further multivariable analysis was conducted. Due to the collinearity between individual tuberculosis drugs, separate multivariable regression models were fitted for each tuberculosis drug noted to have a significant association with birth weight. All clinical characteristics were considered as potential explanatory variables and confounders and included in the final models if their inclusion resulted in a ≥10% change in the model coefficient associated with the tuberculosis drug of interest in bivariate analyses. Multiple imputation was used to conduct sensitivity analysis for the effect of bedaquiline on infant outcomes for all live births. The mother’s age, drug resistance category, body mass index, HIV status, and the infants’ exposure to bedaquiline in utero were used in the imputation model for infant outcome. Ethics This study was approved by the South African Medical Research Council (SAMRC) Ethics Review Committee (EC017-6/2016) and the KwaZulu-Natal Health Research Committee. RESULTS Presenting Characteristics Between 1 January 2013 and 30 December 2017, 10 042 patients were treated for MDR/RR-tuberculosis at KDH hospital; 4720 (47%) of these were women, and 126 were reported to have been pregnant; 108 women exposed to second-line tuberculosis treatment for at least 2 weeks while pregnant were included in the study. Figure 1 details study enrollment and attrition during the study. Of the 108 women in the study cohort, 20 (18%) started MDR/RR-TB treatment prior to becoming pregnant, 19 (18%) during the first trimester and 42 (39%) and 28 (26%) in the second and third trimesters, respectively. This is represented in Supplementary Figure 1 in which women are divided into 2 groups: those starting MDR/RR-TB treatment before pregnancy and in the first trimester and those starting treatment after the first trimester. Figure 1. Schema of enrollment and attrition (1 January 2013–31 December 2018). Abbreviations: KDH, King Dinuzulu Hospital; MDR/RR-TB, multidrug/rifampicin-resistant tuberculosis. Baseline characteristics of women in the study are shown in Table 2. The frequency of tuberculosis resistance to individual drugs is shown in Figure 2. Only 76 (70%) women had tuberculosis samples tested for fluoroquinolone resistance. Figure 3 demonstrates the second-line tuberculosis drugs to which fetuses were exposed in utero for at least 14 days. Table 2. Baseline Clinical Characteristics of Pregnant Women With Multidrug/Rifampicin-Resistant Tuberculosis (n = 108) Clinical Characteristics No. (%) Age: years, mean; SD 28.0; 6.13 Hb, g/dl: mean; SD (n = 102) 10.4; 1.59 BMI, kg/m2: mean; SD (n = 106) 24.0; 4.85 TB characteristics Culture positive at treatment initiation 73 (68%) Previous TB or MDR/RR-TB 38/82 (46%) Site of TB: Pulmonary 108 (100%) Extensive disease pattern on chest radiograph 45/97 (46%) Resistance pattern  RR-TB/Rif-mono/MDR-TB 83 (77%)  Pre-XDR-TB/XDR-TB 25 (23%) HIV-characteristics HIV-positive 88 (81%) HIV-positive patients on ART before MDR/RR-TB treatment started (n = 88): 74 (83%) Baseline CD4 count, median cells/mm3 [IQR] (n = 88) 353 [165–511] Pregnancy characteristics Pregnant before MDR/RR-TB treatment started 89 (82%) Gestational age at treatment start: weeks, median [IQR] 22 [14–28] Foetal exposure to any second-line drugs: Days, median [IQR] 118 [70–208] Abbreviations: ART, antiretroviral therapy; BMI, body mass index; Hb, hemoglobin; HIV, human immunodeficiency virus; IQR, interquartile range; MDR/RR-TB, multidrug/rifampicin-resistant TB; Pre-XDR-TB, pre-extensively drug-resistant TB; Rif-mono, rifampicin monoresistant; RR-TB, rifampicin-resistant TB; SD, standard deviation; TB, tuberculosis; XDR-TB, extensively drug-resistant TB. aExtensive disease was classified as bilateral disease and/or cavities on chest radiograph. Figure 2. Mycobacterial drug susceptibility test pattern for pregnant women treated for multidrug/rifampicin-resistant tuberculosis. Fluoroquinolones: Resistance to any fluoroquinolone. (Some isolates were tested for resistance to levofloxacin, some to moxifloxacin, and in some, a genotypic result was provided that stated fluoroquinolone resistance without specifying individual drug). Injectables: Resistance to any second-line injectable drug. (Some isolates were tested for resistance to amikacin, some to kanamycin, some to capreomycin, and in some, a genotypic result was provided that stated injectable resistance without specifying individual drug). During the study period, no drug susceptibility testing was done for ethambutol, ethionamide, pyrazinamide, para-aminosalicylic acid, or terizidone. Figure 3. Individual drugs to which fetuses were exposed in utero. Abbreviations: AMK, amikacin; AUG, augmentin; BDQ, bedaquiline; CAP, capreomycin; CFZ, clofazimine; CLM, clarithromycin; EMB, ethambutol; ETH, ethionamide; INH, isoniazid; KAN, kanamycin; LVX, levofloxacin; LZD, linezolid; MXF, moxifloxacin; OFX, ofloxacin; PAS, para-aminosalicylic acid; PTH, prothionamide; PZA, pyrazinamide; RIF, rifampin; TRD, terizidone. RR-Tuberculosis Treatment Outcomes Favorable treatment outcomes were reported in 72 (67%) women (Table 3; Figure 4). Multivariate analyses identified lower maternal hemoglobin at baseline as a predictor of an unfavorable maternal treatment outcome (unadjusted hazard ratio [uHR] 0.67, P = .006; see Supplementary Table 1). Eight women died a median of 67 days (interquartile range [IQR]: 32–299) after childbirth, but all 8 infants survived. Four maternal deaths were related to tuberculosis disease: 1 woman with XDR-tuberculosis, and 1 with pre-XDR-tuberculosis succumbed despite good adherence to treatment, but 2 women (1 with XDR-tuberculosis and 1 with MDR/RR-tuberculosis) had been repeatedly interrupting treatment. Two maternal deaths were related to childbirth and occurred 2 days and 5 days after delivery. One woman died from a cerebrovascular accident a year after completion of MDR/RR-tuberculosis therapy when her child was 5 months old. The cause of the remaining death was unknown; the woman died in a rural district hospital 3 months after the birth of her child. No maternal deaths were considered related to tuberculosis medication. Table 3. Maternal Treatment, Pregnancy, and Infant Outcomes Study Outcomes No. (%) Maternal MDR/RR-tuberculosis treatment outcomes (n = 108) Favorable treatment outcomes 72 (67%)  Cured 58 (54%)  Treatment completion 14 (13%) Unfavorable treatment outcomes 36 (33%)  Died 8 (7%)  Treatment failed 3 (3%)  Lost to follow-up 25 (23%) Pregnancy outcomes (n = 108 women pregnant with n = 109 fetuses, including a set of twins) Newborn characteristics Live births 99 (91%)  Gestational age at delivery: weeks, mean; SDa 37.76; SD 3.10  Birth weight, grams, median [IQR]b 2800 [2430–3200] Fetal and neonatal deaths 10 (9%)  Stillbirth 6 (6%)  Miscarriagec 3 (3%)  Termination of pregnancy 1 (1%) Favorable pregnancy outcomes (out of 109 fetuses) 57 (52%)  ≥37 weeksa 71 (72%)  Birthweight ≥2500 gb 61 (65%) Unfavorable pregnancy outcomes (out of 109 fetuses) 52 (48%)  Fetal and neonatal deaths 10 (9%)  Preterm <37 weeksa 28 (28%)  Low birth weight <2500 gb 33 (35%) Infant outcomes (n = 109) No infant outcomes at 12 months (n = 23)  Fetal and neonatal deaths 10 (9%)  Lost to follow-up after birth 13 (12%) Infant outcomes at 12 months (n = 86) Favorable infant outcomes 72 (84%)  Thriving normally 73 (85%)  Normal development 77 (89%) Unfavorable infant outcomes 14 (16%)  Failure to thrive 9 (10%)  Delayed development 5 (6%)  Early neonatal death 1 (1%)  Infant death 1 (1%)  Diagnosed with tuberculosis disease in the 1st year of life 2 (2%) Abbreviations: IQR, interquartile range; MDR/RR, multidrug/rifampicin-resistant. aLive births only (n = 99). bLive births only and missing data for 5 neonates (n = 94). cOne miscarriage was a set of twins. Figure 4. Primary outcomes. Pregnancy Outcomes Ninety-nine (91%) of the 109 fetuses, including a set of twins, were born alive, with a mean gestational age of 38 weeks (standard deviation [SD] 3.10) and median birth weight of 2800 grams (IQR 2430–3200) (Table 3). Only 57 (52%) pregnancies had a favorable pregnancy outcome when applying our study criteria (Table 1). Women living with HIV had a higher risk of an unfavorable pregnancy outcome (uHR 3.35; P = .030). Four infants born alive had congenital anomalies; an umbilical hernia, a ventral septal defect, kyphoscoliosis, and 1 infant had Ehlers-Danlos syndrome. Four of the 109 fetuses were lost early in pregnancy, and of the 6 stillborn babies, 5 were delivered at a gestational age <37 weeks. In 9 of the 10 fetal deaths the mother was living with HIV. All HIV-exposed babies were given nevirapine at birth for 6 weeks, and all tested HIV-negative at 6 weeks. Infant Outcomes We report infant outcomes after 12 months for 86 of the 99 live infants (Table 3). In addition to the 10 pregnancies that did not result in a live birth, we were unable to follow-up 13 of the infants after birth (Figure 1) Favorable infant outcomes were documented in 72 (84%) of the liveborn infants (Table 3). No baseline maternal characteristics, tuberculosis drugs, or ART were associated with unfavorable infant outcomes, even after reanalysis using multiple imputation for the 13 missing infant outcomes. There was 1 early neonatal death, 7 days after birth, and 1 infant death at 3 months. In their first year of life, 11 infants developed signs and symptoms of tuberculosis disease:” weight loss, cough, or infiltrates on chest radiograph. Two of these 11 infants were diagnosed and treated for MDR/RR-tuberculosis. Four had microbiological investigations, which were culture-negative for M. tuberculosis. The remaining 5 infants were never treated for tuberculosis and at a subsequent visit were well. Bedaquiline As bedaquiline is central to most novel treatment regimens being studied in clinical trials, we evaluated the impact of bedaquiline on all outcomes. No significant differences in baseline characteristics were identified between women treated with bedaquiline, compared to those who were not treated with bedaquiline (Table 4). Table 5 shows study outcomes stratified by bedaquiline exposure. Of the 58 women who received bedaquiline, 41 (71%) had a favorable treatment outcome, compared to 31 (62%) of those who received treatment without bedaquiline (P = .349). There was no difference in pregnancy outcomes between women whose fetuses were exposed to bedaquiline in utero (49% favorable pregnancy outcome) compared to those unexposed (57% favorable outcome, P = .312). However, a higher proportion of newborns exposed to bedaquiline in utero had a birth weight <2500 grams (45% vs 24%; P = .034; Table 5). Of infants exposed to bedaquiline, 36 (88%) had a favorable infant outcome, compared to 36 (80%) infants not exposed (P = .136). This result remained after multiple imputation for the 13 missing infant outcomes (P = .160). Table 4. Baseline Clinical Characteristics of Pregnant Women With Multidrug/Rifampicin-Resistant Tuberculosis, Stratified by Bedaquiline Exposure Clinical Characteristics Bedaquiline in Regimen n = 58 No. (%) No Bedaquiline in Regimen n = 50 No. (%) P Value Age: years, mean; SD 28.7; 6.08 27.0; 6.01 .150 Hb, g/dl: mean; SD 10.4; 1.55 N = 46; 10.4; 1.65 .928 Body Mass Index (BMI): kg/m2 mean; SD 23.7; 4.70 N = 48; 24.2; 5.08 .543 TB characteristics Culture positive at treatment initiation 42 (72%) N = 31; (63%) .405 Previous tuberculosis or MDR/ RR-tuberculosis N = 35; 19 (54%) N = 47; 19 (40%) .265 Site of tuberculosis: pulmonary 57 (100%) 51 (100%) NA Chest radiograph .923  Extensive disease N = 51; 23 (45%) N = 46; 22 (48%) Resistance pattern: no (%) 1.000  RR-/Rif-mono/MDR-tuberculosis 45 (78%) 38 (76%)  Pre-XDR-/XDR-tuberculosis 13 (22%) 12 (24%) HIV characteristics HIV-positive, no. (%) 48 (83%) 40 (80%) .806 HIV-positive patients on ART before MDR/RR-tuberculosis treatment started N = 48; 37 (77%) N = 40; 37 (90%) .155 Baseline CD4 count, median cells/mm3 [IQR] N = 45; 335 [138–500] N = 36; 395 [219–540] .352 Pregnancy characteristics Pregnant before MDR/RR-tuberculosis treatment started 47 (81%) 42 (84%) .802 Gestational age at treatment start: weeks, median [IQR] 23 [13–28] 20.5 [15–28] .905 Foetal exposure to any second-line drugs: days, median [IQR] 110 [66–203] 141 [70–213] .562 Fetal exposure to bedaquiline: days, median [IQR] 77 [28–140] NA NA Abbreviations: ART, antiretroviral therapy; Hb, hemoglobin; HIV, human immunodeficiency virus; IQR, interquartile range; MDR/RR-TB, multidrug/rifampicin-resistant TB; NA, not applicable; Pre-XDR, pre-extensively drug-resistant; Rif-mono, rifampicin monoresistant; SD, standard deviation; TB, tuberculosis; XDR, extensively drug-resistant. aExtensive disease was classified as bilateral disease and/or cavities on chest radiograph. Table 5. Maternal Treatment, Pregnancy, and Infant Outcomes Stratified by Bedaquiline Exposure Maternal RR-TB Treatment Outcomes Bedaquiline in Regimen n = 58 No. (%) No Bedaquiline in Regimen n = 50 No. (%) P Value Maternal MDR/RR-TB treatment outcomes .349 Favorable treatment outcomes 41 (71%) 31 (62%)  Cured 34 (59%) 24 (48%)  Treatment completion 7 (12%) 7 (14%) Unfavorable treatment outcomes 17 (29%) 19 (38%)  Died 4 (7%) 4 (8%)  Treatment failed 2 (4%) 1 (2%)  Loss to follow-up 11 (19%) 14 (28%) Pregnancy outcomes Bedaquiline exposure in utero n = 49 No bedaquiline exposure in utero n = 60 Newborn characteristics Birth outcomes .741  Live births 45 (92%) 54 (90%)   Gestational age at delivery: weeks, mean; SDa 37·68; SD 2·93 37·82; SD 3·25 .830   Birth weight, grams, median [IQR]b 2690 [2380–3095] 2900 [2550–3270] .179  Fetal and neonatal deaths 4 (8%) 6 (10%)   Stillbirth 3 (5%) 3 (6%)   Miscarriage 0 3 (6%)c   Termination of pregnancy 1 (2%) 0 Pregnancy outcomes .312 Favorable pregnancy outcomes (out of 109 fetuses) 24 (49%) 34 (57%)  ≥37 weeksa 32 (71%) 39 (72%)  Birth weight ≥2500 gb 24 (55%) 37 (74%) Unfavourable pregnancy outcomes (out of 109 fetuses) 25 (51%) 26 (43%)  Fetal and neonatal deaths 4 (8%) 6 (10%)  Preterm <37 weeksa 13 (29%) 15 (28%) .903  Low birth weight <2500 gb 20 (45%) 13 (26%) .034 Infant outcomes Bedaquiline exposure in utero n = 49 No bedaquiline exposure in utero n = 60 No infant outcomes at 12 months 8 (16%) 15 (25%)  Fetal and neonatal deaths 4 (8%) 6 (10%)  Lost to follow-up after birth 4 (8%) 9 (15%) Infant outcomes n = 41 n = 45 .136 Favorable infant outcomes at 12 months 36 (88%) 36 (80%)  Thriving normally 36 (88%) 37 (82%) .914  Normal development 38 (93%) 39 (86%) .705 Unfavorable infant outcomes at 12 months 5 (12%) 9 (20%)  Failure to thrive 4 (10%) 5 (11%)  Delayed development 2 (5%) 3 (7%)  Early neonatal death 0 1 (2%)  Infant death 1 (2%) 0  Developed TB in the 1st year of life 0 2 (4%) .186 Abbreviations: IQR, interquartile range; MDR/RR-TB, multidrug/rifampicin-resistant TB; SD, standard deviation; TB, tuberculosis. aLive births only (n = 99). bLive births only and missing data for 5 neonates (n = 94). cOne miscarriage was a set of twins. We evaluated whether exposure to bedaquiline was associated with exposure to any other tuberculosis drug or ART. In Supplementary Table 2 we describe the use of all tuberculosis and ART drugs in pregnancy, and in Supplementary Table 3 we explore the relationship between in utero exposure to bedaquiline and other drugs. We observed a relationship between bedaquiline use and more frequent use of clofazimine, levofloxacin, and linezolid. We evaluated risk factors for low birth weight among women and newborns. In univariate analysis no baseline maternal characteristics were associated with low birth weight (Supplementary Table 4). Exposure to bedaquiline, clofazimine, and levofloxacin in utero were all associated with an increased risk of low birth weight. In a multivariate model, bedaquiline and levofloxacin remained significant predictors of low birth weight. DISCUSSION In this cohort of pregnant women treated for MDR/RR-tuberculosis in KwaZulu-Natal, South Africa, favorable treatment outcomes were reported for two thirds of the women. Twenty-three percent of the women in our cohort had MDR/RR-tuberculosis with known resistance to the fluoroquinolones, injectables or both, and a large, additional proportion had RR-tuberculosis in which the isolate was not tested for susceptibility to these second-line drugs. The favorable treatment outcomes we report are better than the 55–60% reported for nonpregnant women in our setting [27, 28], and the 61% in the cohort of 38 pregnant women treated for MDR/RR-tuberculosis in Peru between 1996 and 2005 [11]. Notably, only 8% of the Peruvian cohort were living with HIV, and rates of second-line drug resistance were low. Favorable pregnancy outcomes were reported in 52% of the cohort with 28% of the live births born preterm and 35% with documented measurements having low birth weight. These proportions are higher than the preterm delivery rate of 12% and low birth weight rate of 15% reported for South Africa [29, 30], and this is likely to, at least in some part, be due to the high HIV prevalence with associated ART use in our study. There is growing evidence of adverse pregnancy outcomes, including preterm birth and stillbirth, in women living with HIV [31, 32]. Given that drug-susceptible tuberculosis in pregnant women living with HIV is known to increase unfavorable pregnancy and infant outcomes [2, 33, 34], it is not surprising that in our study of women with MDR/RR-tuberculosis, most of whom were living with HIV, the rate of unfavorable pregnancy outcomes is higher than that of the average population. We used a conservative definition of unfavorable pregnancy outcome, as many babies of moderate prematurity and/or marginally low birth weight were considered as unfavorable outcomes, even if otherwise well. Pregnant women have been treated with bedaquiline in South Africa since 2015. In our study, over 90% of the fetuses exposed to bedaquiline in utero were born alive, with similar fetal and neonatal deaths compared to those not exposed. Although no difference in the proportion of babies born prematurely in those exposed to bedaquiline, compared to those not exposed, more of the babies exposed to bedaquiline had a low birth weight. We analyzed our data for other predictors of low birth weight. However, given the extensive collinearity between drugs used to treat MDR/RR-tuberculosis, it was not possible to exclude other second-line tuberculosis drugs and ART either individually or in combination as being implicated. Healthy children with normal growth and development were reported in over 80% of the infants that were followed up for 12 months. Although bedaquiline and levofloxacin use was associated with low birth weight, 88% of the infants exposed to bedaquiline and levofloxacin in utero, who were born alive and followed up for 12 months, had a favorable infant outcome, with 88% thriving and 93% developing normally. Although this is the largest study to our knowledge to date documenting treatment, pregnancy, and infant outcomes in a cohort of women treated for MDR/RR-tuberculosis during pregnancy, it remains limited by its small size. It was a pragmatic observational study conducted in the public sector with limited resources, using often incomplete data routinely collected by health workers. The poor quality of data on adverse events, drug: drug interactions, and reasons for changes in both drugs and drug dosages limited our analyses and findings. In this study we noted an association between bedaquiline use and low birth weight, but it is not possible to conclusively ascribe this effect to bedaquiline, and more investigation is required to explore this relationship. Our data suggest that the use of bedaquiline is safe in pregnant women and is associated with good treatment, pregnancy, and infant outcomes. Supplementary Data Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. ciaa189_suppl_Supplementary_tables Click here for additional data file. Notes Author Contributions. M. L., B. S., I. M., S. C., N. G., and J. S. conceptualized and led the study. M. L., B. S., I. M., S. C., N. G., S. H., and J. S. contributed to the development of the methods. M. L., B. S., I. M., S. C., N. G., and S. H. collected the data. M. L., T. R., J. H., and J. S. analyzed the data and drafted the initial manuscript. All authors reviewed and contributed to the interpretation and approved the final manuscript. Acknowledgments. The authors thank Dr Norbet Ndjeka and Ms Jacqueline Ngozo for the support of the national and provincial tuberculosis directorates respectively. Financial support. This work was supported by the South African Medical Research Council. The funder had no role in study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the paper for publication. All researchers were independent of funders and sponsors. Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

BEDAQUILINE, EFAVIRENZ, EMTRICITABINE\TENOFOVIR DISOPROXIL FUMARATE

DrugsGivenReaction

CC BY-NC-ND

32141495

2021-04-08

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ehlers-Danlos syndrome'.

Maternal and Infant Outcomes Among Pregnant Women Treated for Multidrug/Rifampicin-Resistant Tuberculosis in South Africa. Data on safety and efficacy of second-line tuberculosis drugs in pregnant women and their infants are severely limited due to exclusion from clinical trials and expanded access programs. Pregnant women starting treatment for multidrug/rifampicin-resistant (MDR/RR)-tuberculosis at King Dinuzulu Hospital in KwaZulu-Natal, South Africa, from 1 January 2013 to 31 December 2017, were included. We conducted a record review to describe maternal treatment and pregnancy outcomes, and a clinical assessment to describe infant outcomes. Of 108 pregnant women treated for MDR/RR-tuberculosis, 88 (81%) were living with human immunodeficiency virus.. Favorable MDR/RR-tuberculosis treatment outcomes were reported in 72 (67%) women. Ninety-nine (91%) of the 109 babies were born alive, but overall, 52 (48%) women had unfavorable pregnancy outcomes. Fifty-eight (54%) women received bedaquiline, and 49 (45%) babies were exposed to bedaquiline in utero. Low birth weight was reported in more babies exposed to bedaquiline compared to babies not exposed (45% vs 26%; P = .034). In multivariate analyses, bedaquiline and levofloxacin, drugs often used in combination, were both independently associated with increased risk of low birth weight. Of the 86 children evaluated at 12 months, 72 (84%) had favorable outcomes; 88% of babies exposed to bedaquiline were thriving and developing normally compared to 82% of the babies not exposed. MDR/RR-tuberculosis treatment outcomes among pregnant women were comparable to nonpregnant women. Although more babies exposed to bedaquiline were of low birth weight, over 80% had gained weight and were developing normally at 1 year. (See the Editorial Commentary by Marais on pages 1169–70.) Over a half million individuals were estimated to have multidrug/rifampicin-resistant (MDR/RR) tuberculosis globally in 2017, with the highest burden among women of reproductive age (15–45 years) [1]. In women of this age, tuberculosis is the leading cause of death from an infectious agent and a common nonobstetric cause of maternal mortality [1–4]. Worldwide in 2011, an estimated 216 500 pregnant women developed tuberculosis, with the greatest burden in Africa [5]. Not only do biological changes in pregnancy double the risk of pregnant women developing tuberculosis compared to nonpregnant women, but pregnancy complicates the treatment of tuberculosis, and if untreated, pregnancy-associated tuberculosis can be associated with mortality of up to 40% [2]. In women living with tuberculosis and human immunodeficiency virus (HIV), the risk of maternal mortality increases dramatically; neonates born to these women also have increased morbidity and mortality [2, 6]. As the safety of first-line tuberculosis drugs in pregnancy have been established and treatment has been shown to improve maternal and neonatal outcome, the World Health Organization (WHO) recommends that pregnant women with drug-susceptible tuberculosis should be treated in the same way as nonpregnant women [7–9]. The management of MDR/RR-tuberculosis in pregnant women is more complicated as little is known about the use of second-line tuberculosis drugs in pregnancy [10]. Presently, WHO recommends that pregnant women be offered individualized regimens, aiming to include ≥4 effective drugs with an established safety profile and low teratogenic risk [7]. However, as pregnant women have generally been excluded from the studies on which WHO recommendations were based, safety data of most second-line tuberculosis drugs in pregnancy are lacking [7, 10], with fewer than 15 case reports describing the safety and outcomes of second-line tuberculosis treatment during pregnancy. The largest report included 38 women [11]. The tuberculosis treatment landscape has changed with programmatic introduction of 2 novel drugs, delamanid and bedaquiline, and repurposing of older drugs, including linezolid and clofazimine. None of the studies evaluating these drugs have included pregnant women, and currently, due to a paucity of data, the use of new and repurposed drugs during pregnancy and breastfeeding is not widely recommended [7, 12–14]. In South Africa, where the rate of tuberculosis is estimated at 10.3 per 1000 pregnancies [5], pregnant women with MDR/RR-tuberculosis have had access to bedaquiline since 2015. Given the improved treatment success rates among MDR/RR-tuberculosis patients treated with bedaquiline [15], the drug became increasingly used as a substitute for injectable agents. In September 2018, the national Department of Health recommended an injectable-free, modified 9–12-month regimen for all patients diagnosed with MDR/RR-tuberculosis, including pregnant women. We report treatment, pregnancy, and infant outcomes in a cohort of pregnant women with MDR/RR-tuberculosis in KwaZulu-Natal, South Africa, with a focus on women and infants exposed to bedaquiline during pregnancy. METHODOLOGY Study Design and Patient Population In this observational cohort study, medical records of women attending King Dinuzulu Hospital (KDH) for MDR/RR-tuberculosis management between 1 January 2013 and 31 December 2017 were reviewed. KDH is the specialist referral hospital for RR-tuberculosis in KwaZulu-Natal province where all pregnant women with MDR/RR-tuberculosis are referred. Definitions of Presenting Characteristics Pulmonary tuberculosis was defined as disease affecting the lungs only. Cavitary/bilateral disease was defined as the presence of either cavities or disease in both left and right lung fields and was considered an indication of extensive disease. Patients on antiretroviral therapy (ART) before MDR/RR-tuberculosis treatment started were defined as those receiving ART for at least 30 days prior to MDR/RR-tuberculosis treatment initiation. Baseline CD4 count was defined as the date recorded in the clinical notes closest to the date of MDR/RR-tuberculosis treatment initiation. Gestational age was recorded from clinical notes; determined by ultrasound, dates, or both. Drug Resistance Definitions MDR/RR-tuberculosis was classified as tuberculosis caused by Mycobacterium tuberculosis with genotypic or phenotypic resistance to rifampicin. It included MDR-tuberculosis (resistance to both isoniazid and rifampicin), rifampicin monoresistant tuberculosis (susceptibility to isoniazid), and forms of disease where rifampicin resistance has been identified, but no result for isoniazid has been returned (increasingly common when testing with the GeneXpert MTB/RIF molecular assay). Extensively drug-resistant (XDR) tuberculosis was classified as MDR-tuberculosis with additional resistance to a fluoroquinolone and a second-line injectable agent. Pre-XDR-tuberculosis is MDR-tuberculosis with additional resistance to either a fluoroquinolone or an injectable agent but not both. Diagnosis and Treatment Drug susceptibility testing (DST) was performed on all sputum cultures positive for M. tuberculosis. From 2013 to 2015 DST included isoniazid, rifampicin, streptomycin, kanamycin, and ofloxacin. From 2015 to 2018 moxifloxacin and capreomycin were added. Given the complexity of treating pregnant women with MDR/RR-tuberculosis, most women were initially hospitalized and received individualized treatment. Women who had started a standardized regimen for MDR/RR-tuberculosis prior to becoming pregnant may have subsequently had treatment modified, depending on the stage of treatment. Between 2013 and 2015, national MDR/RR-tuberculosis treatment guidelines recommended a standardized 18–24 month regimen, unless resistance or intolerance to specific drugs required regimen modification, as per WHO 2011 treatment guidelines [16, 17]. The injectable phase of treatment (6–8 months) included kanamycin, moxifloxacin, ethionamide, terizidone, and pyrazinamide, followed by the continuation phase (12–18 months) comprising moxifloxacin, ethionamide, terizidone, and pyrazinamide [17]. In some cases ethambutol and higher doses of isoniazid were added. Standard treatment changed in early 2017 when the WHO 9–12 month regimen was introduced across South Africa, and, like other adults with MDR/RR-tuberculosis, pregnant women benefitted from the shorter regimen [7]. However, kanamycin/amikacin and ethionamide are contraindicated in pregnancy. In most pregnant women receiving MDR/RR-tuberculosis treatment, these drugs were either omitted, stopped, or substituted with alternative agents, such as capreomycin or para-aminosalicylic acid prior to 2015, or linezolid or bedaquiline as access to these newer agents increased [18]. In line with local guidelines, specific drugs in the treatment regimens were stopped or substituted if drug resistance patterns changed, toxicity developed, or drug: drug interactions occurred. During the study period it was standard of care for pregnant women living with HIV to receive antiretroviral therapy (ART). Patients who were ART-naive started on ART after 2 weeks of MDR/RR-TB treatment During the study period first-line ART comprised tenofovir, emtricitabine, and efavirenz. ART regimen changes were not comprehensively documented, but pregnant women receiving efavirenz switched to nevirapine prior to bedaquiline initiation. Outcome Definitions We defined 3 outcomes: maternal treatment outcomes, pregnancy outcomes, and infant outcomes. Each were considered favorable or unfavorable and are defined in Table 1. Table 1. Definition of Terms Treatment Outcomes [19, 20] Favorable treatment outcomes Cured Treatment completed as recommended by the national policy without evidence of failure, AND ≥3 consecutive cultures taken at least 30 days apart are negative after the intensive phase. Treatment completed Treatment completed as recommended by the national policy without evidence of failure, BUT no record that ≥3 consecutive cultures taken at least 30 days apart are negative after the intensive phase. Treatment success The sum of cured and treatment completed. Unfavorable treatment outcomes Treatment failed Treatment terminated or need for permanent regimen change of at least 2 antituberculosis drugs because of a lack of culture conversion by the end of the intensive phase; bacteriological culture reversion in the continuation phase after conversion to negative; evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs; ADRs. Died A patient who dies for any reason during treatment. Lost to follow-up A patient whose treatment was interrupted for ≥2 consecutive months. Treatment unsuccessful The sum of failed, died, lost to follow-up, and not evaluated. Pregnancy outcomes Favorable pregnancy outcomes—all the below features are required to classify a pregnancy outcome as favorable Full term Babies born ≥37 weeks of pregnancy. Normal birth weight Birth weight of ≥2500 grams according to the World Health Organization (WHO) [21]. Alive A baby born alive who lives for >28 days. Unfavorable pregnancy outcomes—any of the following classify a pregnancy as having an unfavourable outcome Preterm birth Babies born <37 weeks of pregnancy. Miscarriage Spontaneous loss of a pregnancy before the fetus has reached viability at 24 weeks. This includes all pregnancy losses from the time of conception until 23 completed weeks of gestation [22]. Stillbirth In South Africa, the legal definition of stillbirth is an infant born dead after “6 months of intrauterine life” (ie, 28 weeks since the start of the last period or 26 weeks since conception). If the gestational age is not known, a weight of 1000 g is used to legally define a stillbirth. Infants that are born dead before this time are legally regarded as miscarriages. Termination of pregnancy Termination of pregnancy is when a woman decides to end her pregnancy before the full term by medical means. The woman must be <13 weeks pregnant to end the pregnancy without giving reasons. If she is between 13 and 20 weeks pregnant, the pregnancy may be terminated only under specific conditions. If she is >20 weeks pregnant, it will be done only if her life or the fetus’ life is in danger, or there are likely to be serious birth defects [23]. Low birth weight A birth weight of <2500 g (up to and including 2499 g), as per the World Health Organization (WHO) [21]. Infant outcomes Development Child development refers to how a child becomes able to do more complex things as they get older. Developmental milestones are a set of functional skills or age-specific tasks that most children can do at a certain age range [24]. These skills include gross and fine motor, language, cognitive, and social skills. Lost to follow-up It was not possible to verify the status of the child at 12 months. Favorable infant outcomes—both of the following are required to state that an infant has a favorable outcome Thrive normally If a child gains weight following the normal trajectory according to the growth chart, the child is said to be thriving normally. Normal development A child is described as having normal development if they achieve the developmental milestones timeously. Unfavorable infant outcomes—any of the following classify the child as having an unfavorable outcome Failure to thrive The infant fails to maintain an established pattern of growth [25]. Delayed development The child reaches developmental milestones later than the average child. TB diagnosis Diagnosed with TB or RR-TB before 12 months of age. Neonatal death Death of a live born infant in the first 28 days of life. An early neonatal death is a death that occurs in the first week of life [26]. Infant death Infant dies before 12 months. Abbreviations: ADR, adverse drug reactions; RR-TB, rifampicin-resistant TB; TB, tuberculosis. Data Variables and Collection We reviewed maternal medical records to collect demographic, clinical, and laboratory data. Response to treatment was determined from medical records and the laboratory database. Pregnancy outcomes, birth weight, APGAR scores, and postdelivery screening were extracted from patient-held notes and road-to-health cards. Infants were seen at KDH 6–8 weeks after delivery and assessed clinically to determine if they were thriving and screened for symptoms and signs of tuberculosis disease. Infants were assessed again at 6 and 12 months. If any problems were detected, the child was referred to routine care for further evaluation and investigation. Data Management and Statistical Analyses Data were captured using an Excel spreadsheet and imported into STATA/SE version 15.0. for analysis. Baseline clinical characteristics and maternal treatment, pregnancy, and infant outcomes were presented using descriptive statistics. Missing data were noted, and each analysis reflects the sample size used. All clinical characteristics, individual tuberculosis drugs, and ART drugs were assessed as potential predictors of outcome using univariable logistic regression. Any drug use during the MDR/RR-tuberculosis treatment episode was included in evaluation of treatment outcome, but only drug use ≥14 days during pregnancy was included for the evaluations of pregnancy and infant outcomes, reflecting in utero exposure. Clinical characteristics, other tuberculosis drugs, ART drugs, and all 3 outcomes were compared between mothers receiving regimens with bedaquiline and without bedaquiline using the χ 2 or Fisher exact test for categorical variables, and the t test or Wilcoxon rank sum test for continuous variables. After observing an effect of bedaquiline on birth weight, further multivariable analysis was conducted. Due to the collinearity between individual tuberculosis drugs, separate multivariable regression models were fitted for each tuberculosis drug noted to have a significant association with birth weight. All clinical characteristics were considered as potential explanatory variables and confounders and included in the final models if their inclusion resulted in a ≥10% change in the model coefficient associated with the tuberculosis drug of interest in bivariate analyses. Multiple imputation was used to conduct sensitivity analysis for the effect of bedaquiline on infant outcomes for all live births. The mother’s age, drug resistance category, body mass index, HIV status, and the infants’ exposure to bedaquiline in utero were used in the imputation model for infant outcome. Ethics This study was approved by the South African Medical Research Council (SAMRC) Ethics Review Committee (EC017-6/2016) and the KwaZulu-Natal Health Research Committee. RESULTS Presenting Characteristics Between 1 January 2013 and 30 December 2017, 10 042 patients were treated for MDR/RR-tuberculosis at KDH hospital; 4720 (47%) of these were women, and 126 were reported to have been pregnant; 108 women exposed to second-line tuberculosis treatment for at least 2 weeks while pregnant were included in the study. Figure 1 details study enrollment and attrition during the study. Of the 108 women in the study cohort, 20 (18%) started MDR/RR-TB treatment prior to becoming pregnant, 19 (18%) during the first trimester and 42 (39%) and 28 (26%) in the second and third trimesters, respectively. This is represented in Supplementary Figure 1 in which women are divided into 2 groups: those starting MDR/RR-TB treatment before pregnancy and in the first trimester and those starting treatment after the first trimester. Figure 1. Schema of enrollment and attrition (1 January 2013–31 December 2018). Abbreviations: KDH, King Dinuzulu Hospital; MDR/RR-TB, multidrug/rifampicin-resistant tuberculosis. Baseline characteristics of women in the study are shown in Table 2. The frequency of tuberculosis resistance to individual drugs is shown in Figure 2. Only 76 (70%) women had tuberculosis samples tested for fluoroquinolone resistance. Figure 3 demonstrates the second-line tuberculosis drugs to which fetuses were exposed in utero for at least 14 days. Table 2. Baseline Clinical Characteristics of Pregnant Women With Multidrug/Rifampicin-Resistant Tuberculosis (n = 108) Clinical Characteristics No. (%) Age: years, mean; SD 28.0; 6.13 Hb, g/dl: mean; SD (n = 102) 10.4; 1.59 BMI, kg/m2: mean; SD (n = 106) 24.0; 4.85 TB characteristics Culture positive at treatment initiation 73 (68%) Previous TB or MDR/RR-TB 38/82 (46%) Site of TB: Pulmonary 108 (100%) Extensive disease pattern on chest radiograph 45/97 (46%) Resistance pattern  RR-TB/Rif-mono/MDR-TB 83 (77%)  Pre-XDR-TB/XDR-TB 25 (23%) HIV-characteristics HIV-positive 88 (81%) HIV-positive patients on ART before MDR/RR-TB treatment started (n = 88): 74 (83%) Baseline CD4 count, median cells/mm3 [IQR] (n = 88) 353 [165–511] Pregnancy characteristics Pregnant before MDR/RR-TB treatment started 89 (82%) Gestational age at treatment start: weeks, median [IQR] 22 [14–28] Foetal exposure to any second-line drugs: Days, median [IQR] 118 [70–208] Abbreviations: ART, antiretroviral therapy; BMI, body mass index; Hb, hemoglobin; HIV, human immunodeficiency virus; IQR, interquartile range; MDR/RR-TB, multidrug/rifampicin-resistant TB; Pre-XDR-TB, pre-extensively drug-resistant TB; Rif-mono, rifampicin monoresistant; RR-TB, rifampicin-resistant TB; SD, standard deviation; TB, tuberculosis; XDR-TB, extensively drug-resistant TB. aExtensive disease was classified as bilateral disease and/or cavities on chest radiograph. Figure 2. Mycobacterial drug susceptibility test pattern for pregnant women treated for multidrug/rifampicin-resistant tuberculosis. Fluoroquinolones: Resistance to any fluoroquinolone. (Some isolates were tested for resistance to levofloxacin, some to moxifloxacin, and in some, a genotypic result was provided that stated fluoroquinolone resistance without specifying individual drug). Injectables: Resistance to any second-line injectable drug. (Some isolates were tested for resistance to amikacin, some to kanamycin, some to capreomycin, and in some, a genotypic result was provided that stated injectable resistance without specifying individual drug). During the study period, no drug susceptibility testing was done for ethambutol, ethionamide, pyrazinamide, para-aminosalicylic acid, or terizidone. Figure 3. Individual drugs to which fetuses were exposed in utero. Abbreviations: AMK, amikacin; AUG, augmentin; BDQ, bedaquiline; CAP, capreomycin; CFZ, clofazimine; CLM, clarithromycin; EMB, ethambutol; ETH, ethionamide; INH, isoniazid; KAN, kanamycin; LVX, levofloxacin; LZD, linezolid; MXF, moxifloxacin; OFX, ofloxacin; PAS, para-aminosalicylic acid; PTH, prothionamide; PZA, pyrazinamide; RIF, rifampin; TRD, terizidone. RR-Tuberculosis Treatment Outcomes Favorable treatment outcomes were reported in 72 (67%) women (Table 3; Figure 4). Multivariate analyses identified lower maternal hemoglobin at baseline as a predictor of an unfavorable maternal treatment outcome (unadjusted hazard ratio [uHR] 0.67, P = .006; see Supplementary Table 1). Eight women died a median of 67 days (interquartile range [IQR]: 32–299) after childbirth, but all 8 infants survived. Four maternal deaths were related to tuberculosis disease: 1 woman with XDR-tuberculosis, and 1 with pre-XDR-tuberculosis succumbed despite good adherence to treatment, but 2 women (1 with XDR-tuberculosis and 1 with MDR/RR-tuberculosis) had been repeatedly interrupting treatment. Two maternal deaths were related to childbirth and occurred 2 days and 5 days after delivery. One woman died from a cerebrovascular accident a year after completion of MDR/RR-tuberculosis therapy when her child was 5 months old. The cause of the remaining death was unknown; the woman died in a rural district hospital 3 months after the birth of her child. No maternal deaths were considered related to tuberculosis medication. Table 3. Maternal Treatment, Pregnancy, and Infant Outcomes Study Outcomes No. (%) Maternal MDR/RR-tuberculosis treatment outcomes (n = 108) Favorable treatment outcomes 72 (67%)  Cured 58 (54%)  Treatment completion 14 (13%) Unfavorable treatment outcomes 36 (33%)  Died 8 (7%)  Treatment failed 3 (3%)  Lost to follow-up 25 (23%) Pregnancy outcomes (n = 108 women pregnant with n = 109 fetuses, including a set of twins) Newborn characteristics Live births 99 (91%)  Gestational age at delivery: weeks, mean; SDa 37.76; SD 3.10  Birth weight, grams, median [IQR]b 2800 [2430–3200] Fetal and neonatal deaths 10 (9%)  Stillbirth 6 (6%)  Miscarriagec 3 (3%)  Termination of pregnancy 1 (1%) Favorable pregnancy outcomes (out of 109 fetuses) 57 (52%)  ≥37 weeksa 71 (72%)  Birthweight ≥2500 gb 61 (65%) Unfavorable pregnancy outcomes (out of 109 fetuses) 52 (48%)  Fetal and neonatal deaths 10 (9%)  Preterm <37 weeksa 28 (28%)  Low birth weight <2500 gb 33 (35%) Infant outcomes (n = 109) No infant outcomes at 12 months (n = 23)  Fetal and neonatal deaths 10 (9%)  Lost to follow-up after birth 13 (12%) Infant outcomes at 12 months (n = 86) Favorable infant outcomes 72 (84%)  Thriving normally 73 (85%)  Normal development 77 (89%) Unfavorable infant outcomes 14 (16%)  Failure to thrive 9 (10%)  Delayed development 5 (6%)  Early neonatal death 1 (1%)  Infant death 1 (1%)  Diagnosed with tuberculosis disease in the 1st year of life 2 (2%) Abbreviations: IQR, interquartile range; MDR/RR, multidrug/rifampicin-resistant. aLive births only (n = 99). bLive births only and missing data for 5 neonates (n = 94). cOne miscarriage was a set of twins. Figure 4. Primary outcomes. Pregnancy Outcomes Ninety-nine (91%) of the 109 fetuses, including a set of twins, were born alive, with a mean gestational age of 38 weeks (standard deviation [SD] 3.10) and median birth weight of 2800 grams (IQR 2430–3200) (Table 3). Only 57 (52%) pregnancies had a favorable pregnancy outcome when applying our study criteria (Table 1). Women living with HIV had a higher risk of an unfavorable pregnancy outcome (uHR 3.35; P = .030). Four infants born alive had congenital anomalies; an umbilical hernia, a ventral septal defect, kyphoscoliosis, and 1 infant had Ehlers-Danlos syndrome. Four of the 109 fetuses were lost early in pregnancy, and of the 6 stillborn babies, 5 were delivered at a gestational age <37 weeks. In 9 of the 10 fetal deaths the mother was living with HIV. All HIV-exposed babies were given nevirapine at birth for 6 weeks, and all tested HIV-negative at 6 weeks. Infant Outcomes We report infant outcomes after 12 months for 86 of the 99 live infants (Table 3). In addition to the 10 pregnancies that did not result in a live birth, we were unable to follow-up 13 of the infants after birth (Figure 1) Favorable infant outcomes were documented in 72 (84%) of the liveborn infants (Table 3). No baseline maternal characteristics, tuberculosis drugs, or ART were associated with unfavorable infant outcomes, even after reanalysis using multiple imputation for the 13 missing infant outcomes. There was 1 early neonatal death, 7 days after birth, and 1 infant death at 3 months. In their first year of life, 11 infants developed signs and symptoms of tuberculosis disease:” weight loss, cough, or infiltrates on chest radiograph. Two of these 11 infants were diagnosed and treated for MDR/RR-tuberculosis. Four had microbiological investigations, which were culture-negative for M. tuberculosis. The remaining 5 infants were never treated for tuberculosis and at a subsequent visit were well. Bedaquiline As bedaquiline is central to most novel treatment regimens being studied in clinical trials, we evaluated the impact of bedaquiline on all outcomes. No significant differences in baseline characteristics were identified between women treated with bedaquiline, compared to those who were not treated with bedaquiline (Table 4). Table 5 shows study outcomes stratified by bedaquiline exposure. Of the 58 women who received bedaquiline, 41 (71%) had a favorable treatment outcome, compared to 31 (62%) of those who received treatment without bedaquiline (P = .349). There was no difference in pregnancy outcomes between women whose fetuses were exposed to bedaquiline in utero (49% favorable pregnancy outcome) compared to those unexposed (57% favorable outcome, P = .312). However, a higher proportion of newborns exposed to bedaquiline in utero had a birth weight <2500 grams (45% vs 24%; P = .034; Table 5). Of infants exposed to bedaquiline, 36 (88%) had a favorable infant outcome, compared to 36 (80%) infants not exposed (P = .136). This result remained after multiple imputation for the 13 missing infant outcomes (P = .160). Table 4. Baseline Clinical Characteristics of Pregnant Women With Multidrug/Rifampicin-Resistant Tuberculosis, Stratified by Bedaquiline Exposure Clinical Characteristics Bedaquiline in Regimen n = 58 No. (%) No Bedaquiline in Regimen n = 50 No. (%) P Value Age: years, mean; SD 28.7; 6.08 27.0; 6.01 .150 Hb, g/dl: mean; SD 10.4; 1.55 N = 46; 10.4; 1.65 .928 Body Mass Index (BMI): kg/m2 mean; SD 23.7; 4.70 N = 48; 24.2; 5.08 .543 TB characteristics Culture positive at treatment initiation 42 (72%) N = 31; (63%) .405 Previous tuberculosis or MDR/ RR-tuberculosis N = 35; 19 (54%) N = 47; 19 (40%) .265 Site of tuberculosis: pulmonary 57 (100%) 51 (100%) NA Chest radiograph .923  Extensive disease N = 51; 23 (45%) N = 46; 22 (48%) Resistance pattern: no (%) 1.000  RR-/Rif-mono/MDR-tuberculosis 45 (78%) 38 (76%)  Pre-XDR-/XDR-tuberculosis 13 (22%) 12 (24%) HIV characteristics HIV-positive, no. (%) 48 (83%) 40 (80%) .806 HIV-positive patients on ART before MDR/RR-tuberculosis treatment started N = 48; 37 (77%) N = 40; 37 (90%) .155 Baseline CD4 count, median cells/mm3 [IQR] N = 45; 335 [138–500] N = 36; 395 [219–540] .352 Pregnancy characteristics Pregnant before MDR/RR-tuberculosis treatment started 47 (81%) 42 (84%) .802 Gestational age at treatment start: weeks, median [IQR] 23 [13–28] 20.5 [15–28] .905 Foetal exposure to any second-line drugs: days, median [IQR] 110 [66–203] 141 [70–213] .562 Fetal exposure to bedaquiline: days, median [IQR] 77 [28–140] NA NA Abbreviations: ART, antiretroviral therapy; Hb, hemoglobin; HIV, human immunodeficiency virus; IQR, interquartile range; MDR/RR-TB, multidrug/rifampicin-resistant TB; NA, not applicable; Pre-XDR, pre-extensively drug-resistant; Rif-mono, rifampicin monoresistant; SD, standard deviation; TB, tuberculosis; XDR, extensively drug-resistant. aExtensive disease was classified as bilateral disease and/or cavities on chest radiograph. Table 5. Maternal Treatment, Pregnancy, and Infant Outcomes Stratified by Bedaquiline Exposure Maternal RR-TB Treatment Outcomes Bedaquiline in Regimen n = 58 No. (%) No Bedaquiline in Regimen n = 50 No. (%) P Value Maternal MDR/RR-TB treatment outcomes .349 Favorable treatment outcomes 41 (71%) 31 (62%)  Cured 34 (59%) 24 (48%)  Treatment completion 7 (12%) 7 (14%) Unfavorable treatment outcomes 17 (29%) 19 (38%)  Died 4 (7%) 4 (8%)  Treatment failed 2 (4%) 1 (2%)  Loss to follow-up 11 (19%) 14 (28%) Pregnancy outcomes Bedaquiline exposure in utero n = 49 No bedaquiline exposure in utero n = 60 Newborn characteristics Birth outcomes .741  Live births 45 (92%) 54 (90%)   Gestational age at delivery: weeks, mean; SDa 37·68; SD 2·93 37·82; SD 3·25 .830   Birth weight, grams, median [IQR]b 2690 [2380–3095] 2900 [2550–3270] .179  Fetal and neonatal deaths 4 (8%) 6 (10%)   Stillbirth 3 (5%) 3 (6%)   Miscarriage 0 3 (6%)c   Termination of pregnancy 1 (2%) 0 Pregnancy outcomes .312 Favorable pregnancy outcomes (out of 109 fetuses) 24 (49%) 34 (57%)  ≥37 weeksa 32 (71%) 39 (72%)  Birth weight ≥2500 gb 24 (55%) 37 (74%) Unfavourable pregnancy outcomes (out of 109 fetuses) 25 (51%) 26 (43%)  Fetal and neonatal deaths 4 (8%) 6 (10%)  Preterm <37 weeksa 13 (29%) 15 (28%) .903  Low birth weight <2500 gb 20 (45%) 13 (26%) .034 Infant outcomes Bedaquiline exposure in utero n = 49 No bedaquiline exposure in utero n = 60 No infant outcomes at 12 months 8 (16%) 15 (25%)  Fetal and neonatal deaths 4 (8%) 6 (10%)  Lost to follow-up after birth 4 (8%) 9 (15%) Infant outcomes n = 41 n = 45 .136 Favorable infant outcomes at 12 months 36 (88%) 36 (80%)  Thriving normally 36 (88%) 37 (82%) .914  Normal development 38 (93%) 39 (86%) .705 Unfavorable infant outcomes at 12 months 5 (12%) 9 (20%)  Failure to thrive 4 (10%) 5 (11%)  Delayed development 2 (5%) 3 (7%)  Early neonatal death 0 1 (2%)  Infant death 1 (2%) 0  Developed TB in the 1st year of life 0 2 (4%) .186 Abbreviations: IQR, interquartile range; MDR/RR-TB, multidrug/rifampicin-resistant TB; SD, standard deviation; TB, tuberculosis. aLive births only (n = 99). bLive births only and missing data for 5 neonates (n = 94). cOne miscarriage was a set of twins. We evaluated whether exposure to bedaquiline was associated with exposure to any other tuberculosis drug or ART. In Supplementary Table 2 we describe the use of all tuberculosis and ART drugs in pregnancy, and in Supplementary Table 3 we explore the relationship between in utero exposure to bedaquiline and other drugs. We observed a relationship between bedaquiline use and more frequent use of clofazimine, levofloxacin, and linezolid. We evaluated risk factors for low birth weight among women and newborns. In univariate analysis no baseline maternal characteristics were associated with low birth weight (Supplementary Table 4). Exposure to bedaquiline, clofazimine, and levofloxacin in utero were all associated with an increased risk of low birth weight. In a multivariate model, bedaquiline and levofloxacin remained significant predictors of low birth weight. DISCUSSION In this cohort of pregnant women treated for MDR/RR-tuberculosis in KwaZulu-Natal, South Africa, favorable treatment outcomes were reported for two thirds of the women. Twenty-three percent of the women in our cohort had MDR/RR-tuberculosis with known resistance to the fluoroquinolones, injectables or both, and a large, additional proportion had RR-tuberculosis in which the isolate was not tested for susceptibility to these second-line drugs. The favorable treatment outcomes we report are better than the 55–60% reported for nonpregnant women in our setting [27, 28], and the 61% in the cohort of 38 pregnant women treated for MDR/RR-tuberculosis in Peru between 1996 and 2005 [11]. Notably, only 8% of the Peruvian cohort were living with HIV, and rates of second-line drug resistance were low. Favorable pregnancy outcomes were reported in 52% of the cohort with 28% of the live births born preterm and 35% with documented measurements having low birth weight. These proportions are higher than the preterm delivery rate of 12% and low birth weight rate of 15% reported for South Africa [29, 30], and this is likely to, at least in some part, be due to the high HIV prevalence with associated ART use in our study. There is growing evidence of adverse pregnancy outcomes, including preterm birth and stillbirth, in women living with HIV [31, 32]. Given that drug-susceptible tuberculosis in pregnant women living with HIV is known to increase unfavorable pregnancy and infant outcomes [2, 33, 34], it is not surprising that in our study of women with MDR/RR-tuberculosis, most of whom were living with HIV, the rate of unfavorable pregnancy outcomes is higher than that of the average population. We used a conservative definition of unfavorable pregnancy outcome, as many babies of moderate prematurity and/or marginally low birth weight were considered as unfavorable outcomes, even if otherwise well. Pregnant women have been treated with bedaquiline in South Africa since 2015. In our study, over 90% of the fetuses exposed to bedaquiline in utero were born alive, with similar fetal and neonatal deaths compared to those not exposed. Although no difference in the proportion of babies born prematurely in those exposed to bedaquiline, compared to those not exposed, more of the babies exposed to bedaquiline had a low birth weight. We analyzed our data for other predictors of low birth weight. However, given the extensive collinearity between drugs used to treat MDR/RR-tuberculosis, it was not possible to exclude other second-line tuberculosis drugs and ART either individually or in combination as being implicated. Healthy children with normal growth and development were reported in over 80% of the infants that were followed up for 12 months. Although bedaquiline and levofloxacin use was associated with low birth weight, 88% of the infants exposed to bedaquiline and levofloxacin in utero, who were born alive and followed up for 12 months, had a favorable infant outcome, with 88% thriving and 93% developing normally. Although this is the largest study to our knowledge to date documenting treatment, pregnancy, and infant outcomes in a cohort of women treated for MDR/RR-tuberculosis during pregnancy, it remains limited by its small size. It was a pragmatic observational study conducted in the public sector with limited resources, using often incomplete data routinely collected by health workers. The poor quality of data on adverse events, drug: drug interactions, and reasons for changes in both drugs and drug dosages limited our analyses and findings. In this study we noted an association between bedaquiline use and low birth weight, but it is not possible to conclusively ascribe this effect to bedaquiline, and more investigation is required to explore this relationship. Our data suggest that the use of bedaquiline is safe in pregnant women and is associated with good treatment, pregnancy, and infant outcomes. Supplementary Data Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. ciaa189_suppl_Supplementary_tables Click here for additional data file. Notes Author Contributions. M. L., B. S., I. M., S. C., N. G., and J. S. conceptualized and led the study. M. L., B. S., I. M., S. C., N. G., S. H., and J. S. contributed to the development of the methods. M. L., B. S., I. M., S. C., N. G., and S. H. collected the data. M. L., T. R., J. H., and J. S. analyzed the data and drafted the initial manuscript. All authors reviewed and contributed to the interpretation and approved the final manuscript. Acknowledgments. The authors thank Dr Norbet Ndjeka and Ms Jacqueline Ngozo for the support of the national and provincial tuberculosis directorates respectively. Financial support. This work was supported by the South African Medical Research Council. The funder had no role in study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the paper for publication. All researchers were independent of funders and sponsors. Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

AMINOSALICYLIC ACID, BEDAQUILINE, CAPREOMYCIN, EFAVIRENZ, EMTRICITABINE\TENOFOVIR DISOPROXIL FUMARATE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, KANAMYCIN A SULFATE, PYRAZINAMIDE, TERIZIDONE

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Maternal and Infant Outcomes Among Pregnant Women Treated for Multidrug/Rifampicin-Resistant Tuberculosis in South Africa. Data on safety and efficacy of second-line tuberculosis drugs in pregnant women and their infants are severely limited due to exclusion from clinical trials and expanded access programs. Pregnant women starting treatment for multidrug/rifampicin-resistant (MDR/RR)-tuberculosis at King Dinuzulu Hospital in KwaZulu-Natal, South Africa, from 1 January 2013 to 31 December 2017, were included. We conducted a record review to describe maternal treatment and pregnancy outcomes, and a clinical assessment to describe infant outcomes. Of 108 pregnant women treated for MDR/RR-tuberculosis, 88 (81%) were living with human immunodeficiency virus.. Favorable MDR/RR-tuberculosis treatment outcomes were reported in 72 (67%) women. Ninety-nine (91%) of the 109 babies were born alive, but overall, 52 (48%) women had unfavorable pregnancy outcomes. Fifty-eight (54%) women received bedaquiline, and 49 (45%) babies were exposed to bedaquiline in utero. Low birth weight was reported in more babies exposed to bedaquiline compared to babies not exposed (45% vs 26%; P = .034). In multivariate analyses, bedaquiline and levofloxacin, drugs often used in combination, were both independently associated with increased risk of low birth weight. Of the 86 children evaluated at 12 months, 72 (84%) had favorable outcomes; 88% of babies exposed to bedaquiline were thriving and developing normally compared to 82% of the babies not exposed. MDR/RR-tuberculosis treatment outcomes among pregnant women were comparable to nonpregnant women. Although more babies exposed to bedaquiline were of low birth weight, over 80% had gained weight and were developing normally at 1 year. (See the Editorial Commentary by Marais on pages 1169–70.) Over a half million individuals were estimated to have multidrug/rifampicin-resistant (MDR/RR) tuberculosis globally in 2017, with the highest burden among women of reproductive age (15–45 years) [1]. In women of this age, tuberculosis is the leading cause of death from an infectious agent and a common nonobstetric cause of maternal mortality [1–4]. Worldwide in 2011, an estimated 216 500 pregnant women developed tuberculosis, with the greatest burden in Africa [5]. Not only do biological changes in pregnancy double the risk of pregnant women developing tuberculosis compared to nonpregnant women, but pregnancy complicates the treatment of tuberculosis, and if untreated, pregnancy-associated tuberculosis can be associated with mortality of up to 40% [2]. In women living with tuberculosis and human immunodeficiency virus (HIV), the risk of maternal mortality increases dramatically; neonates born to these women also have increased morbidity and mortality [2, 6]. As the safety of first-line tuberculosis drugs in pregnancy have been established and treatment has been shown to improve maternal and neonatal outcome, the World Health Organization (WHO) recommends that pregnant women with drug-susceptible tuberculosis should be treated in the same way as nonpregnant women [7–9]. The management of MDR/RR-tuberculosis in pregnant women is more complicated as little is known about the use of second-line tuberculosis drugs in pregnancy [10]. Presently, WHO recommends that pregnant women be offered individualized regimens, aiming to include ≥4 effective drugs with an established safety profile and low teratogenic risk [7]. However, as pregnant women have generally been excluded from the studies on which WHO recommendations were based, safety data of most second-line tuberculosis drugs in pregnancy are lacking [7, 10], with fewer than 15 case reports describing the safety and outcomes of second-line tuberculosis treatment during pregnancy. The largest report included 38 women [11]. The tuberculosis treatment landscape has changed with programmatic introduction of 2 novel drugs, delamanid and bedaquiline, and repurposing of older drugs, including linezolid and clofazimine. None of the studies evaluating these drugs have included pregnant women, and currently, due to a paucity of data, the use of new and repurposed drugs during pregnancy and breastfeeding is not widely recommended [7, 12–14]. In South Africa, where the rate of tuberculosis is estimated at 10.3 per 1000 pregnancies [5], pregnant women with MDR/RR-tuberculosis have had access to bedaquiline since 2015. Given the improved treatment success rates among MDR/RR-tuberculosis patients treated with bedaquiline [15], the drug became increasingly used as a substitute for injectable agents. In September 2018, the national Department of Health recommended an injectable-free, modified 9–12-month regimen for all patients diagnosed with MDR/RR-tuberculosis, including pregnant women. We report treatment, pregnancy, and infant outcomes in a cohort of pregnant women with MDR/RR-tuberculosis in KwaZulu-Natal, South Africa, with a focus on women and infants exposed to bedaquiline during pregnancy. METHODOLOGY Study Design and Patient Population In this observational cohort study, medical records of women attending King Dinuzulu Hospital (KDH) for MDR/RR-tuberculosis management between 1 January 2013 and 31 December 2017 were reviewed. KDH is the specialist referral hospital for RR-tuberculosis in KwaZulu-Natal province where all pregnant women with MDR/RR-tuberculosis are referred. Definitions of Presenting Characteristics Pulmonary tuberculosis was defined as disease affecting the lungs only. Cavitary/bilateral disease was defined as the presence of either cavities or disease in both left and right lung fields and was considered an indication of extensive disease. Patients on antiretroviral therapy (ART) before MDR/RR-tuberculosis treatment started were defined as those receiving ART for at least 30 days prior to MDR/RR-tuberculosis treatment initiation. Baseline CD4 count was defined as the date recorded in the clinical notes closest to the date of MDR/RR-tuberculosis treatment initiation. Gestational age was recorded from clinical notes; determined by ultrasound, dates, or both. Drug Resistance Definitions MDR/RR-tuberculosis was classified as tuberculosis caused by Mycobacterium tuberculosis with genotypic or phenotypic resistance to rifampicin. It included MDR-tuberculosis (resistance to both isoniazid and rifampicin), rifampicin monoresistant tuberculosis (susceptibility to isoniazid), and forms of disease where rifampicin resistance has been identified, but no result for isoniazid has been returned (increasingly common when testing with the GeneXpert MTB/RIF molecular assay). Extensively drug-resistant (XDR) tuberculosis was classified as MDR-tuberculosis with additional resistance to a fluoroquinolone and a second-line injectable agent. Pre-XDR-tuberculosis is MDR-tuberculosis with additional resistance to either a fluoroquinolone or an injectable agent but not both. Diagnosis and Treatment Drug susceptibility testing (DST) was performed on all sputum cultures positive for M. tuberculosis. From 2013 to 2015 DST included isoniazid, rifampicin, streptomycin, kanamycin, and ofloxacin. From 2015 to 2018 moxifloxacin and capreomycin were added. Given the complexity of treating pregnant women with MDR/RR-tuberculosis, most women were initially hospitalized and received individualized treatment. Women who had started a standardized regimen for MDR/RR-tuberculosis prior to becoming pregnant may have subsequently had treatment modified, depending on the stage of treatment. Between 2013 and 2015, national MDR/RR-tuberculosis treatment guidelines recommended a standardized 18–24 month regimen, unless resistance or intolerance to specific drugs required regimen modification, as per WHO 2011 treatment guidelines [16, 17]. The injectable phase of treatment (6–8 months) included kanamycin, moxifloxacin, ethionamide, terizidone, and pyrazinamide, followed by the continuation phase (12–18 months) comprising moxifloxacin, ethionamide, terizidone, and pyrazinamide [17]. In some cases ethambutol and higher doses of isoniazid were added. Standard treatment changed in early 2017 when the WHO 9–12 month regimen was introduced across South Africa, and, like other adults with MDR/RR-tuberculosis, pregnant women benefitted from the shorter regimen [7]. However, kanamycin/amikacin and ethionamide are contraindicated in pregnancy. In most pregnant women receiving MDR/RR-tuberculosis treatment, these drugs were either omitted, stopped, or substituted with alternative agents, such as capreomycin or para-aminosalicylic acid prior to 2015, or linezolid or bedaquiline as access to these newer agents increased [18]. In line with local guidelines, specific drugs in the treatment regimens were stopped or substituted if drug resistance patterns changed, toxicity developed, or drug: drug interactions occurred. During the study period it was standard of care for pregnant women living with HIV to receive antiretroviral therapy (ART). Patients who were ART-naive started on ART after 2 weeks of MDR/RR-TB treatment During the study period first-line ART comprised tenofovir, emtricitabine, and efavirenz. ART regimen changes were not comprehensively documented, but pregnant women receiving efavirenz switched to nevirapine prior to bedaquiline initiation. Outcome Definitions We defined 3 outcomes: maternal treatment outcomes, pregnancy outcomes, and infant outcomes. Each were considered favorable or unfavorable and are defined in Table 1. Table 1. Definition of Terms Treatment Outcomes [19, 20] Favorable treatment outcomes Cured Treatment completed as recommended by the national policy without evidence of failure, AND ≥3 consecutive cultures taken at least 30 days apart are negative after the intensive phase. Treatment completed Treatment completed as recommended by the national policy without evidence of failure, BUT no record that ≥3 consecutive cultures taken at least 30 days apart are negative after the intensive phase. Treatment success The sum of cured and treatment completed. Unfavorable treatment outcomes Treatment failed Treatment terminated or need for permanent regimen change of at least 2 antituberculosis drugs because of a lack of culture conversion by the end of the intensive phase; bacteriological culture reversion in the continuation phase after conversion to negative; evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs; ADRs. Died A patient who dies for any reason during treatment. Lost to follow-up A patient whose treatment was interrupted for ≥2 consecutive months. Treatment unsuccessful The sum of failed, died, lost to follow-up, and not evaluated. Pregnancy outcomes Favorable pregnancy outcomes—all the below features are required to classify a pregnancy outcome as favorable Full term Babies born ≥37 weeks of pregnancy. Normal birth weight Birth weight of ≥2500 grams according to the World Health Organization (WHO) [21]. Alive A baby born alive who lives for >28 days. Unfavorable pregnancy outcomes—any of the following classify a pregnancy as having an unfavourable outcome Preterm birth Babies born <37 weeks of pregnancy. Miscarriage Spontaneous loss of a pregnancy before the fetus has reached viability at 24 weeks. This includes all pregnancy losses from the time of conception until 23 completed weeks of gestation [22]. Stillbirth In South Africa, the legal definition of stillbirth is an infant born dead after “6 months of intrauterine life” (ie, 28 weeks since the start of the last period or 26 weeks since conception). If the gestational age is not known, a weight of 1000 g is used to legally define a stillbirth. Infants that are born dead before this time are legally regarded as miscarriages. Termination of pregnancy Termination of pregnancy is when a woman decides to end her pregnancy before the full term by medical means. The woman must be <13 weeks pregnant to end the pregnancy without giving reasons. If she is between 13 and 20 weeks pregnant, the pregnancy may be terminated only under specific conditions. If she is >20 weeks pregnant, it will be done only if her life or the fetus’ life is in danger, or there are likely to be serious birth defects [23]. Low birth weight A birth weight of <2500 g (up to and including 2499 g), as per the World Health Organization (WHO) [21]. Infant outcomes Development Child development refers to how a child becomes able to do more complex things as they get older. Developmental milestones are a set of functional skills or age-specific tasks that most children can do at a certain age range [24]. These skills include gross and fine motor, language, cognitive, and social skills. Lost to follow-up It was not possible to verify the status of the child at 12 months. Favorable infant outcomes—both of the following are required to state that an infant has a favorable outcome Thrive normally If a child gains weight following the normal trajectory according to the growth chart, the child is said to be thriving normally. Normal development A child is described as having normal development if they achieve the developmental milestones timeously. Unfavorable infant outcomes—any of the following classify the child as having an unfavorable outcome Failure to thrive The infant fails to maintain an established pattern of growth [25]. Delayed development The child reaches developmental milestones later than the average child. TB diagnosis Diagnosed with TB or RR-TB before 12 months of age. Neonatal death Death of a live born infant in the first 28 days of life. An early neonatal death is a death that occurs in the first week of life [26]. Infant death Infant dies before 12 months. Abbreviations: ADR, adverse drug reactions; RR-TB, rifampicin-resistant TB; TB, tuberculosis. Data Variables and Collection We reviewed maternal medical records to collect demographic, clinical, and laboratory data. Response to treatment was determined from medical records and the laboratory database. Pregnancy outcomes, birth weight, APGAR scores, and postdelivery screening were extracted from patient-held notes and road-to-health cards. Infants were seen at KDH 6–8 weeks after delivery and assessed clinically to determine if they were thriving and screened for symptoms and signs of tuberculosis disease. Infants were assessed again at 6 and 12 months. If any problems were detected, the child was referred to routine care for further evaluation and investigation. Data Management and Statistical Analyses Data were captured using an Excel spreadsheet and imported into STATA/SE version 15.0. for analysis. Baseline clinical characteristics and maternal treatment, pregnancy, and infant outcomes were presented using descriptive statistics. Missing data were noted, and each analysis reflects the sample size used. All clinical characteristics, individual tuberculosis drugs, and ART drugs were assessed as potential predictors of outcome using univariable logistic regression. Any drug use during the MDR/RR-tuberculosis treatment episode was included in evaluation of treatment outcome, but only drug use ≥14 days during pregnancy was included for the evaluations of pregnancy and infant outcomes, reflecting in utero exposure. Clinical characteristics, other tuberculosis drugs, ART drugs, and all 3 outcomes were compared between mothers receiving regimens with bedaquiline and without bedaquiline using the χ 2 or Fisher exact test for categorical variables, and the t test or Wilcoxon rank sum test for continuous variables. After observing an effect of bedaquiline on birth weight, further multivariable analysis was conducted. Due to the collinearity between individual tuberculosis drugs, separate multivariable regression models were fitted for each tuberculosis drug noted to have a significant association with birth weight. All clinical characteristics were considered as potential explanatory variables and confounders and included in the final models if their inclusion resulted in a ≥10% change in the model coefficient associated with the tuberculosis drug of interest in bivariate analyses. Multiple imputation was used to conduct sensitivity analysis for the effect of bedaquiline on infant outcomes for all live births. The mother’s age, drug resistance category, body mass index, HIV status, and the infants’ exposure to bedaquiline in utero were used in the imputation model for infant outcome. Ethics This study was approved by the South African Medical Research Council (SAMRC) Ethics Review Committee (EC017-6/2016) and the KwaZulu-Natal Health Research Committee. RESULTS Presenting Characteristics Between 1 January 2013 and 30 December 2017, 10 042 patients were treated for MDR/RR-tuberculosis at KDH hospital; 4720 (47%) of these were women, and 126 were reported to have been pregnant; 108 women exposed to second-line tuberculosis treatment for at least 2 weeks while pregnant were included in the study. Figure 1 details study enrollment and attrition during the study. Of the 108 women in the study cohort, 20 (18%) started MDR/RR-TB treatment prior to becoming pregnant, 19 (18%) during the first trimester and 42 (39%) and 28 (26%) in the second and third trimesters, respectively. This is represented in Supplementary Figure 1 in which women are divided into 2 groups: those starting MDR/RR-TB treatment before pregnancy and in the first trimester and those starting treatment after the first trimester. Figure 1. Schema of enrollment and attrition (1 January 2013–31 December 2018). Abbreviations: KDH, King Dinuzulu Hospital; MDR/RR-TB, multidrug/rifampicin-resistant tuberculosis. Baseline characteristics of women in the study are shown in Table 2. The frequency of tuberculosis resistance to individual drugs is shown in Figure 2. Only 76 (70%) women had tuberculosis samples tested for fluoroquinolone resistance. Figure 3 demonstrates the second-line tuberculosis drugs to which fetuses were exposed in utero for at least 14 days. Table 2. Baseline Clinical Characteristics of Pregnant Women With Multidrug/Rifampicin-Resistant Tuberculosis (n = 108) Clinical Characteristics No. (%) Age: years, mean; SD 28.0; 6.13 Hb, g/dl: mean; SD (n = 102) 10.4; 1.59 BMI, kg/m2: mean; SD (n = 106) 24.0; 4.85 TB characteristics Culture positive at treatment initiation 73 (68%) Previous TB or MDR/RR-TB 38/82 (46%) Site of TB: Pulmonary 108 (100%) Extensive disease pattern on chest radiograph 45/97 (46%) Resistance pattern  RR-TB/Rif-mono/MDR-TB 83 (77%)  Pre-XDR-TB/XDR-TB 25 (23%) HIV-characteristics HIV-positive 88 (81%) HIV-positive patients on ART before MDR/RR-TB treatment started (n = 88): 74 (83%) Baseline CD4 count, median cells/mm3 [IQR] (n = 88) 353 [165–511] Pregnancy characteristics Pregnant before MDR/RR-TB treatment started 89 (82%) Gestational age at treatment start: weeks, median [IQR] 22 [14–28] Foetal exposure to any second-line drugs: Days, median [IQR] 118 [70–208] Abbreviations: ART, antiretroviral therapy; BMI, body mass index; Hb, hemoglobin; HIV, human immunodeficiency virus; IQR, interquartile range; MDR/RR-TB, multidrug/rifampicin-resistant TB; Pre-XDR-TB, pre-extensively drug-resistant TB; Rif-mono, rifampicin monoresistant; RR-TB, rifampicin-resistant TB; SD, standard deviation; TB, tuberculosis; XDR-TB, extensively drug-resistant TB. aExtensive disease was classified as bilateral disease and/or cavities on chest radiograph. Figure 2. Mycobacterial drug susceptibility test pattern for pregnant women treated for multidrug/rifampicin-resistant tuberculosis. Fluoroquinolones: Resistance to any fluoroquinolone. (Some isolates were tested for resistance to levofloxacin, some to moxifloxacin, and in some, a genotypic result was provided that stated fluoroquinolone resistance without specifying individual drug). Injectables: Resistance to any second-line injectable drug. (Some isolates were tested for resistance to amikacin, some to kanamycin, some to capreomycin, and in some, a genotypic result was provided that stated injectable resistance without specifying individual drug). During the study period, no drug susceptibility testing was done for ethambutol, ethionamide, pyrazinamide, para-aminosalicylic acid, or terizidone. Figure 3. Individual drugs to which fetuses were exposed in utero. Abbreviations: AMK, amikacin; AUG, augmentin; BDQ, bedaquiline; CAP, capreomycin; CFZ, clofazimine; CLM, clarithromycin; EMB, ethambutol; ETH, ethionamide; INH, isoniazid; KAN, kanamycin; LVX, levofloxacin; LZD, linezolid; MXF, moxifloxacin; OFX, ofloxacin; PAS, para-aminosalicylic acid; PTH, prothionamide; PZA, pyrazinamide; RIF, rifampin; TRD, terizidone. RR-Tuberculosis Treatment Outcomes Favorable treatment outcomes were reported in 72 (67%) women (Table 3; Figure 4). Multivariate analyses identified lower maternal hemoglobin at baseline as a predictor of an unfavorable maternal treatment outcome (unadjusted hazard ratio [uHR] 0.67, P = .006; see Supplementary Table 1). Eight women died a median of 67 days (interquartile range [IQR]: 32–299) after childbirth, but all 8 infants survived. Four maternal deaths were related to tuberculosis disease: 1 woman with XDR-tuberculosis, and 1 with pre-XDR-tuberculosis succumbed despite good adherence to treatment, but 2 women (1 with XDR-tuberculosis and 1 with MDR/RR-tuberculosis) had been repeatedly interrupting treatment. Two maternal deaths were related to childbirth and occurred 2 days and 5 days after delivery. One woman died from a cerebrovascular accident a year after completion of MDR/RR-tuberculosis therapy when her child was 5 months old. The cause of the remaining death was unknown; the woman died in a rural district hospital 3 months after the birth of her child. No maternal deaths were considered related to tuberculosis medication. Table 3. Maternal Treatment, Pregnancy, and Infant Outcomes Study Outcomes No. (%) Maternal MDR/RR-tuberculosis treatment outcomes (n = 108) Favorable treatment outcomes 72 (67%)  Cured 58 (54%)  Treatment completion 14 (13%) Unfavorable treatment outcomes 36 (33%)  Died 8 (7%)  Treatment failed 3 (3%)  Lost to follow-up 25 (23%) Pregnancy outcomes (n = 108 women pregnant with n = 109 fetuses, including a set of twins) Newborn characteristics Live births 99 (91%)  Gestational age at delivery: weeks, mean; SDa 37.76; SD 3.10  Birth weight, grams, median [IQR]b 2800 [2430–3200] Fetal and neonatal deaths 10 (9%)  Stillbirth 6 (6%)  Miscarriagec 3 (3%)  Termination of pregnancy 1 (1%) Favorable pregnancy outcomes (out of 109 fetuses) 57 (52%)  ≥37 weeksa 71 (72%)  Birthweight ≥2500 gb 61 (65%) Unfavorable pregnancy outcomes (out of 109 fetuses) 52 (48%)  Fetal and neonatal deaths 10 (9%)  Preterm <37 weeksa 28 (28%)  Low birth weight <2500 gb 33 (35%) Infant outcomes (n = 109) No infant outcomes at 12 months (n = 23)  Fetal and neonatal deaths 10 (9%)  Lost to follow-up after birth 13 (12%) Infant outcomes at 12 months (n = 86) Favorable infant outcomes 72 (84%)  Thriving normally 73 (85%)  Normal development 77 (89%) Unfavorable infant outcomes 14 (16%)  Failure to thrive 9 (10%)  Delayed development 5 (6%)  Early neonatal death 1 (1%)  Infant death 1 (1%)  Diagnosed with tuberculosis disease in the 1st year of life 2 (2%) Abbreviations: IQR, interquartile range; MDR/RR, multidrug/rifampicin-resistant. aLive births only (n = 99). bLive births only and missing data for 5 neonates (n = 94). cOne miscarriage was a set of twins. Figure 4. Primary outcomes. Pregnancy Outcomes Ninety-nine (91%) of the 109 fetuses, including a set of twins, were born alive, with a mean gestational age of 38 weeks (standard deviation [SD] 3.10) and median birth weight of 2800 grams (IQR 2430–3200) (Table 3). Only 57 (52%) pregnancies had a favorable pregnancy outcome when applying our study criteria (Table 1). Women living with HIV had a higher risk of an unfavorable pregnancy outcome (uHR 3.35; P = .030). Four infants born alive had congenital anomalies; an umbilical hernia, a ventral septal defect, kyphoscoliosis, and 1 infant had Ehlers-Danlos syndrome. Four of the 109 fetuses were lost early in pregnancy, and of the 6 stillborn babies, 5 were delivered at a gestational age <37 weeks. In 9 of the 10 fetal deaths the mother was living with HIV. All HIV-exposed babies were given nevirapine at birth for 6 weeks, and all tested HIV-negative at 6 weeks. Infant Outcomes We report infant outcomes after 12 months for 86 of the 99 live infants (Table 3). In addition to the 10 pregnancies that did not result in a live birth, we were unable to follow-up 13 of the infants after birth (Figure 1) Favorable infant outcomes were documented in 72 (84%) of the liveborn infants (Table 3). No baseline maternal characteristics, tuberculosis drugs, or ART were associated with unfavorable infant outcomes, even after reanalysis using multiple imputation for the 13 missing infant outcomes. There was 1 early neonatal death, 7 days after birth, and 1 infant death at 3 months. In their first year of life, 11 infants developed signs and symptoms of tuberculosis disease:” weight loss, cough, or infiltrates on chest radiograph. Two of these 11 infants were diagnosed and treated for MDR/RR-tuberculosis. Four had microbiological investigations, which were culture-negative for M. tuberculosis. The remaining 5 infants were never treated for tuberculosis and at a subsequent visit were well. Bedaquiline As bedaquiline is central to most novel treatment regimens being studied in clinical trials, we evaluated the impact of bedaquiline on all outcomes. No significant differences in baseline characteristics were identified between women treated with bedaquiline, compared to those who were not treated with bedaquiline (Table 4). Table 5 shows study outcomes stratified by bedaquiline exposure. Of the 58 women who received bedaquiline, 41 (71%) had a favorable treatment outcome, compared to 31 (62%) of those who received treatment without bedaquiline (P = .349). There was no difference in pregnancy outcomes between women whose fetuses were exposed to bedaquiline in utero (49% favorable pregnancy outcome) compared to those unexposed (57% favorable outcome, P = .312). However, a higher proportion of newborns exposed to bedaquiline in utero had a birth weight <2500 grams (45% vs 24%; P = .034; Table 5). Of infants exposed to bedaquiline, 36 (88%) had a favorable infant outcome, compared to 36 (80%) infants not exposed (P = .136). This result remained after multiple imputation for the 13 missing infant outcomes (P = .160). Table 4. Baseline Clinical Characteristics of Pregnant Women With Multidrug/Rifampicin-Resistant Tuberculosis, Stratified by Bedaquiline Exposure Clinical Characteristics Bedaquiline in Regimen n = 58 No. (%) No Bedaquiline in Regimen n = 50 No. (%) P Value Age: years, mean; SD 28.7; 6.08 27.0; 6.01 .150 Hb, g/dl: mean; SD 10.4; 1.55 N = 46; 10.4; 1.65 .928 Body Mass Index (BMI): kg/m2 mean; SD 23.7; 4.70 N = 48; 24.2; 5.08 .543 TB characteristics Culture positive at treatment initiation 42 (72%) N = 31; (63%) .405 Previous tuberculosis or MDR/ RR-tuberculosis N = 35; 19 (54%) N = 47; 19 (40%) .265 Site of tuberculosis: pulmonary 57 (100%) 51 (100%) NA Chest radiograph .923  Extensive disease N = 51; 23 (45%) N = 46; 22 (48%) Resistance pattern: no (%) 1.000  RR-/Rif-mono/MDR-tuberculosis 45 (78%) 38 (76%)  Pre-XDR-/XDR-tuberculosis 13 (22%) 12 (24%) HIV characteristics HIV-positive, no. (%) 48 (83%) 40 (80%) .806 HIV-positive patients on ART before MDR/RR-tuberculosis treatment started N = 48; 37 (77%) N = 40; 37 (90%) .155 Baseline CD4 count, median cells/mm3 [IQR] N = 45; 335 [138–500] N = 36; 395 [219–540] .352 Pregnancy characteristics Pregnant before MDR/RR-tuberculosis treatment started 47 (81%) 42 (84%) .802 Gestational age at treatment start: weeks, median [IQR] 23 [13–28] 20.5 [15–28] .905 Foetal exposure to any second-line drugs: days, median [IQR] 110 [66–203] 141 [70–213] .562 Fetal exposure to bedaquiline: days, median [IQR] 77 [28–140] NA NA Abbreviations: ART, antiretroviral therapy; Hb, hemoglobin; HIV, human immunodeficiency virus; IQR, interquartile range; MDR/RR-TB, multidrug/rifampicin-resistant TB; NA, not applicable; Pre-XDR, pre-extensively drug-resistant; Rif-mono, rifampicin monoresistant; SD, standard deviation; TB, tuberculosis; XDR, extensively drug-resistant. aExtensive disease was classified as bilateral disease and/or cavities on chest radiograph. Table 5. Maternal Treatment, Pregnancy, and Infant Outcomes Stratified by Bedaquiline Exposure Maternal RR-TB Treatment Outcomes Bedaquiline in Regimen n = 58 No. (%) No Bedaquiline in Regimen n = 50 No. (%) P Value Maternal MDR/RR-TB treatment outcomes .349 Favorable treatment outcomes 41 (71%) 31 (62%)  Cured 34 (59%) 24 (48%)  Treatment completion 7 (12%) 7 (14%) Unfavorable treatment outcomes 17 (29%) 19 (38%)  Died 4 (7%) 4 (8%)  Treatment failed 2 (4%) 1 (2%)  Loss to follow-up 11 (19%) 14 (28%) Pregnancy outcomes Bedaquiline exposure in utero n = 49 No bedaquiline exposure in utero n = 60 Newborn characteristics Birth outcomes .741  Live births 45 (92%) 54 (90%)   Gestational age at delivery: weeks, mean; SDa 37·68; SD 2·93 37·82; SD 3·25 .830   Birth weight, grams, median [IQR]b 2690 [2380–3095] 2900 [2550–3270] .179  Fetal and neonatal deaths 4 (8%) 6 (10%)   Stillbirth 3 (5%) 3 (6%)   Miscarriage 0 3 (6%)c   Termination of pregnancy 1 (2%) 0 Pregnancy outcomes .312 Favorable pregnancy outcomes (out of 109 fetuses) 24 (49%) 34 (57%)  ≥37 weeksa 32 (71%) 39 (72%)  Birth weight ≥2500 gb 24 (55%) 37 (74%) Unfavourable pregnancy outcomes (out of 109 fetuses) 25 (51%) 26 (43%)  Fetal and neonatal deaths 4 (8%) 6 (10%)  Preterm <37 weeksa 13 (29%) 15 (28%) .903  Low birth weight <2500 gb 20 (45%) 13 (26%) .034 Infant outcomes Bedaquiline exposure in utero n = 49 No bedaquiline exposure in utero n = 60 No infant outcomes at 12 months 8 (16%) 15 (25%)  Fetal and neonatal deaths 4 (8%) 6 (10%)  Lost to follow-up after birth 4 (8%) 9 (15%) Infant outcomes n = 41 n = 45 .136 Favorable infant outcomes at 12 months 36 (88%) 36 (80%)  Thriving normally 36 (88%) 37 (82%) .914  Normal development 38 (93%) 39 (86%) .705 Unfavorable infant outcomes at 12 months 5 (12%) 9 (20%)  Failure to thrive 4 (10%) 5 (11%)  Delayed development 2 (5%) 3 (7%)  Early neonatal death 0 1 (2%)  Infant death 1 (2%) 0  Developed TB in the 1st year of life 0 2 (4%) .186 Abbreviations: IQR, interquartile range; MDR/RR-TB, multidrug/rifampicin-resistant TB; SD, standard deviation; TB, tuberculosis. aLive births only (n = 99). bLive births only and missing data for 5 neonates (n = 94). cOne miscarriage was a set of twins. We evaluated whether exposure to bedaquiline was associated with exposure to any other tuberculosis drug or ART. In Supplementary Table 2 we describe the use of all tuberculosis and ART drugs in pregnancy, and in Supplementary Table 3 we explore the relationship between in utero exposure to bedaquiline and other drugs. We observed a relationship between bedaquiline use and more frequent use of clofazimine, levofloxacin, and linezolid. We evaluated risk factors for low birth weight among women and newborns. In univariate analysis no baseline maternal characteristics were associated with low birth weight (Supplementary Table 4). Exposure to bedaquiline, clofazimine, and levofloxacin in utero were all associated with an increased risk of low birth weight. In a multivariate model, bedaquiline and levofloxacin remained significant predictors of low birth weight. DISCUSSION In this cohort of pregnant women treated for MDR/RR-tuberculosis in KwaZulu-Natal, South Africa, favorable treatment outcomes were reported for two thirds of the women. Twenty-three percent of the women in our cohort had MDR/RR-tuberculosis with known resistance to the fluoroquinolones, injectables or both, and a large, additional proportion had RR-tuberculosis in which the isolate was not tested for susceptibility to these second-line drugs. The favorable treatment outcomes we report are better than the 55–60% reported for nonpregnant women in our setting [27, 28], and the 61% in the cohort of 38 pregnant women treated for MDR/RR-tuberculosis in Peru between 1996 and 2005 [11]. Notably, only 8% of the Peruvian cohort were living with HIV, and rates of second-line drug resistance were low. Favorable pregnancy outcomes were reported in 52% of the cohort with 28% of the live births born preterm and 35% with documented measurements having low birth weight. These proportions are higher than the preterm delivery rate of 12% and low birth weight rate of 15% reported for South Africa [29, 30], and this is likely to, at least in some part, be due to the high HIV prevalence with associated ART use in our study. There is growing evidence of adverse pregnancy outcomes, including preterm birth and stillbirth, in women living with HIV [31, 32]. Given that drug-susceptible tuberculosis in pregnant women living with HIV is known to increase unfavorable pregnancy and infant outcomes [2, 33, 34], it is not surprising that in our study of women with MDR/RR-tuberculosis, most of whom were living with HIV, the rate of unfavorable pregnancy outcomes is higher than that of the average population. We used a conservative definition of unfavorable pregnancy outcome, as many babies of moderate prematurity and/or marginally low birth weight were considered as unfavorable outcomes, even if otherwise well. Pregnant women have been treated with bedaquiline in South Africa since 2015. In our study, over 90% of the fetuses exposed to bedaquiline in utero were born alive, with similar fetal and neonatal deaths compared to those not exposed. Although no difference in the proportion of babies born prematurely in those exposed to bedaquiline, compared to those not exposed, more of the babies exposed to bedaquiline had a low birth weight. We analyzed our data for other predictors of low birth weight. However, given the extensive collinearity between drugs used to treat MDR/RR-tuberculosis, it was not possible to exclude other second-line tuberculosis drugs and ART either individually or in combination as being implicated. Healthy children with normal growth and development were reported in over 80% of the infants that were followed up for 12 months. Although bedaquiline and levofloxacin use was associated with low birth weight, 88% of the infants exposed to bedaquiline and levofloxacin in utero, who were born alive and followed up for 12 months, had a favorable infant outcome, with 88% thriving and 93% developing normally. Although this is the largest study to our knowledge to date documenting treatment, pregnancy, and infant outcomes in a cohort of women treated for MDR/RR-tuberculosis during pregnancy, it remains limited by its small size. It was a pragmatic observational study conducted in the public sector with limited resources, using often incomplete data routinely collected by health workers. The poor quality of data on adverse events, drug: drug interactions, and reasons for changes in both drugs and drug dosages limited our analyses and findings. In this study we noted an association between bedaquiline use and low birth weight, but it is not possible to conclusively ascribe this effect to bedaquiline, and more investigation is required to explore this relationship. Our data suggest that the use of bedaquiline is safe in pregnant women and is associated with good treatment, pregnancy, and infant outcomes. Supplementary Data Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. ciaa189_suppl_Supplementary_tables Click here for additional data file. Notes Author Contributions. M. L., B. S., I. M., S. C., N. G., and J. S. conceptualized and led the study. M. L., B. S., I. M., S. C., N. G., S. H., and J. S. contributed to the development of the methods. M. L., B. S., I. M., S. C., N. G., and S. H. collected the data. M. L., T. R., J. H., and J. S. analyzed the data and drafted the initial manuscript. All authors reviewed and contributed to the interpretation and approved the final manuscript. Acknowledgments. The authors thank Dr Norbet Ndjeka and Ms Jacqueline Ngozo for the support of the national and provincial tuberculosis directorates respectively. Financial support. This work was supported by the South African Medical Research Council. The funder had no role in study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the paper for publication. All researchers were independent of funders and sponsors. Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

Transplacental

DrugAdministrationRoute

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32141495

2021-04-08

What was the outcome of reaction 'Foetal exposure during pregnancy'?

Maternal and Infant Outcomes Among Pregnant Women Treated for Multidrug/Rifampicin-Resistant Tuberculosis in South Africa. Data on safety and efficacy of second-line tuberculosis drugs in pregnant women and their infants are severely limited due to exclusion from clinical trials and expanded access programs. Pregnant women starting treatment for multidrug/rifampicin-resistant (MDR/RR)-tuberculosis at King Dinuzulu Hospital in KwaZulu-Natal, South Africa, from 1 January 2013 to 31 December 2017, were included. We conducted a record review to describe maternal treatment and pregnancy outcomes, and a clinical assessment to describe infant outcomes. Of 108 pregnant women treated for MDR/RR-tuberculosis, 88 (81%) were living with human immunodeficiency virus.. Favorable MDR/RR-tuberculosis treatment outcomes were reported in 72 (67%) women. Ninety-nine (91%) of the 109 babies were born alive, but overall, 52 (48%) women had unfavorable pregnancy outcomes. Fifty-eight (54%) women received bedaquiline, and 49 (45%) babies were exposed to bedaquiline in utero. Low birth weight was reported in more babies exposed to bedaquiline compared to babies not exposed (45% vs 26%; P = .034). In multivariate analyses, bedaquiline and levofloxacin, drugs often used in combination, were both independently associated with increased risk of low birth weight. Of the 86 children evaluated at 12 months, 72 (84%) had favorable outcomes; 88% of babies exposed to bedaquiline were thriving and developing normally compared to 82% of the babies not exposed. MDR/RR-tuberculosis treatment outcomes among pregnant women were comparable to nonpregnant women. Although more babies exposed to bedaquiline were of low birth weight, over 80% had gained weight and were developing normally at 1 year. (See the Editorial Commentary by Marais on pages 1169–70.) Over a half million individuals were estimated to have multidrug/rifampicin-resistant (MDR/RR) tuberculosis globally in 2017, with the highest burden among women of reproductive age (15–45 years) [1]. In women of this age, tuberculosis is the leading cause of death from an infectious agent and a common nonobstetric cause of maternal mortality [1–4]. Worldwide in 2011, an estimated 216 500 pregnant women developed tuberculosis, with the greatest burden in Africa [5]. Not only do biological changes in pregnancy double the risk of pregnant women developing tuberculosis compared to nonpregnant women, but pregnancy complicates the treatment of tuberculosis, and if untreated, pregnancy-associated tuberculosis can be associated with mortality of up to 40% [2]. In women living with tuberculosis and human immunodeficiency virus (HIV), the risk of maternal mortality increases dramatically; neonates born to these women also have increased morbidity and mortality [2, 6]. As the safety of first-line tuberculosis drugs in pregnancy have been established and treatment has been shown to improve maternal and neonatal outcome, the World Health Organization (WHO) recommends that pregnant women with drug-susceptible tuberculosis should be treated in the same way as nonpregnant women [7–9]. The management of MDR/RR-tuberculosis in pregnant women is more complicated as little is known about the use of second-line tuberculosis drugs in pregnancy [10]. Presently, WHO recommends that pregnant women be offered individualized regimens, aiming to include ≥4 effective drugs with an established safety profile and low teratogenic risk [7]. However, as pregnant women have generally been excluded from the studies on which WHO recommendations were based, safety data of most second-line tuberculosis drugs in pregnancy are lacking [7, 10], with fewer than 15 case reports describing the safety and outcomes of second-line tuberculosis treatment during pregnancy. The largest report included 38 women [11]. The tuberculosis treatment landscape has changed with programmatic introduction of 2 novel drugs, delamanid and bedaquiline, and repurposing of older drugs, including linezolid and clofazimine. None of the studies evaluating these drugs have included pregnant women, and currently, due to a paucity of data, the use of new and repurposed drugs during pregnancy and breastfeeding is not widely recommended [7, 12–14]. In South Africa, where the rate of tuberculosis is estimated at 10.3 per 1000 pregnancies [5], pregnant women with MDR/RR-tuberculosis have had access to bedaquiline since 2015. Given the improved treatment success rates among MDR/RR-tuberculosis patients treated with bedaquiline [15], the drug became increasingly used as a substitute for injectable agents. In September 2018, the national Department of Health recommended an injectable-free, modified 9–12-month regimen for all patients diagnosed with MDR/RR-tuberculosis, including pregnant women. We report treatment, pregnancy, and infant outcomes in a cohort of pregnant women with MDR/RR-tuberculosis in KwaZulu-Natal, South Africa, with a focus on women and infants exposed to bedaquiline during pregnancy. METHODOLOGY Study Design and Patient Population In this observational cohort study, medical records of women attending King Dinuzulu Hospital (KDH) for MDR/RR-tuberculosis management between 1 January 2013 and 31 December 2017 were reviewed. KDH is the specialist referral hospital for RR-tuberculosis in KwaZulu-Natal province where all pregnant women with MDR/RR-tuberculosis are referred. Definitions of Presenting Characteristics Pulmonary tuberculosis was defined as disease affecting the lungs only. Cavitary/bilateral disease was defined as the presence of either cavities or disease in both left and right lung fields and was considered an indication of extensive disease. Patients on antiretroviral therapy (ART) before MDR/RR-tuberculosis treatment started were defined as those receiving ART for at least 30 days prior to MDR/RR-tuberculosis treatment initiation. Baseline CD4 count was defined as the date recorded in the clinical notes closest to the date of MDR/RR-tuberculosis treatment initiation. Gestational age was recorded from clinical notes; determined by ultrasound, dates, or both. Drug Resistance Definitions MDR/RR-tuberculosis was classified as tuberculosis caused by Mycobacterium tuberculosis with genotypic or phenotypic resistance to rifampicin. It included MDR-tuberculosis (resistance to both isoniazid and rifampicin), rifampicin monoresistant tuberculosis (susceptibility to isoniazid), and forms of disease where rifampicin resistance has been identified, but no result for isoniazid has been returned (increasingly common when testing with the GeneXpert MTB/RIF molecular assay). Extensively drug-resistant (XDR) tuberculosis was classified as MDR-tuberculosis with additional resistance to a fluoroquinolone and a second-line injectable agent. Pre-XDR-tuberculosis is MDR-tuberculosis with additional resistance to either a fluoroquinolone or an injectable agent but not both. Diagnosis and Treatment Drug susceptibility testing (DST) was performed on all sputum cultures positive for M. tuberculosis. From 2013 to 2015 DST included isoniazid, rifampicin, streptomycin, kanamycin, and ofloxacin. From 2015 to 2018 moxifloxacin and capreomycin were added. Given the complexity of treating pregnant women with MDR/RR-tuberculosis, most women were initially hospitalized and received individualized treatment. Women who had started a standardized regimen for MDR/RR-tuberculosis prior to becoming pregnant may have subsequently had treatment modified, depending on the stage of treatment. Between 2013 and 2015, national MDR/RR-tuberculosis treatment guidelines recommended a standardized 18–24 month regimen, unless resistance or intolerance to specific drugs required regimen modification, as per WHO 2011 treatment guidelines [16, 17]. The injectable phase of treatment (6–8 months) included kanamycin, moxifloxacin, ethionamide, terizidone, and pyrazinamide, followed by the continuation phase (12–18 months) comprising moxifloxacin, ethionamide, terizidone, and pyrazinamide [17]. In some cases ethambutol and higher doses of isoniazid were added. Standard treatment changed in early 2017 when the WHO 9–12 month regimen was introduced across South Africa, and, like other adults with MDR/RR-tuberculosis, pregnant women benefitted from the shorter regimen [7]. However, kanamycin/amikacin and ethionamide are contraindicated in pregnancy. In most pregnant women receiving MDR/RR-tuberculosis treatment, these drugs were either omitted, stopped, or substituted with alternative agents, such as capreomycin or para-aminosalicylic acid prior to 2015, or linezolid or bedaquiline as access to these newer agents increased [18]. In line with local guidelines, specific drugs in the treatment regimens were stopped or substituted if drug resistance patterns changed, toxicity developed, or drug: drug interactions occurred. During the study period it was standard of care for pregnant women living with HIV to receive antiretroviral therapy (ART). Patients who were ART-naive started on ART after 2 weeks of MDR/RR-TB treatment During the study period first-line ART comprised tenofovir, emtricitabine, and efavirenz. ART regimen changes were not comprehensively documented, but pregnant women receiving efavirenz switched to nevirapine prior to bedaquiline initiation. Outcome Definitions We defined 3 outcomes: maternal treatment outcomes, pregnancy outcomes, and infant outcomes. Each were considered favorable or unfavorable and are defined in Table 1. Table 1. Definition of Terms Treatment Outcomes [19, 20] Favorable treatment outcomes Cured Treatment completed as recommended by the national policy without evidence of failure, AND ≥3 consecutive cultures taken at least 30 days apart are negative after the intensive phase. Treatment completed Treatment completed as recommended by the national policy without evidence of failure, BUT no record that ≥3 consecutive cultures taken at least 30 days apart are negative after the intensive phase. Treatment success The sum of cured and treatment completed. Unfavorable treatment outcomes Treatment failed Treatment terminated or need for permanent regimen change of at least 2 antituberculosis drugs because of a lack of culture conversion by the end of the intensive phase; bacteriological culture reversion in the continuation phase after conversion to negative; evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs; ADRs. Died A patient who dies for any reason during treatment. Lost to follow-up A patient whose treatment was interrupted for ≥2 consecutive months. Treatment unsuccessful The sum of failed, died, lost to follow-up, and not evaluated. Pregnancy outcomes Favorable pregnancy outcomes—all the below features are required to classify a pregnancy outcome as favorable Full term Babies born ≥37 weeks of pregnancy. Normal birth weight Birth weight of ≥2500 grams according to the World Health Organization (WHO) [21]. Alive A baby born alive who lives for >28 days. Unfavorable pregnancy outcomes—any of the following classify a pregnancy as having an unfavourable outcome Preterm birth Babies born <37 weeks of pregnancy. Miscarriage Spontaneous loss of a pregnancy before the fetus has reached viability at 24 weeks. This includes all pregnancy losses from the time of conception until 23 completed weeks of gestation [22]. Stillbirth In South Africa, the legal definition of stillbirth is an infant born dead after “6 months of intrauterine life” (ie, 28 weeks since the start of the last period or 26 weeks since conception). If the gestational age is not known, a weight of 1000 g is used to legally define a stillbirth. Infants that are born dead before this time are legally regarded as miscarriages. Termination of pregnancy Termination of pregnancy is when a woman decides to end her pregnancy before the full term by medical means. The woman must be <13 weeks pregnant to end the pregnancy without giving reasons. If she is between 13 and 20 weeks pregnant, the pregnancy may be terminated only under specific conditions. If she is >20 weeks pregnant, it will be done only if her life or the fetus’ life is in danger, or there are likely to be serious birth defects [23]. Low birth weight A birth weight of <2500 g (up to and including 2499 g), as per the World Health Organization (WHO) [21]. Infant outcomes Development Child development refers to how a child becomes able to do more complex things as they get older. Developmental milestones are a set of functional skills or age-specific tasks that most children can do at a certain age range [24]. These skills include gross and fine motor, language, cognitive, and social skills. Lost to follow-up It was not possible to verify the status of the child at 12 months. Favorable infant outcomes—both of the following are required to state that an infant has a favorable outcome Thrive normally If a child gains weight following the normal trajectory according to the growth chart, the child is said to be thriving normally. Normal development A child is described as having normal development if they achieve the developmental milestones timeously. Unfavorable infant outcomes—any of the following classify the child as having an unfavorable outcome Failure to thrive The infant fails to maintain an established pattern of growth [25]. Delayed development The child reaches developmental milestones later than the average child. TB diagnosis Diagnosed with TB or RR-TB before 12 months of age. Neonatal death Death of a live born infant in the first 28 days of life. An early neonatal death is a death that occurs in the first week of life [26]. Infant death Infant dies before 12 months. Abbreviations: ADR, adverse drug reactions; RR-TB, rifampicin-resistant TB; TB, tuberculosis. Data Variables and Collection We reviewed maternal medical records to collect demographic, clinical, and laboratory data. Response to treatment was determined from medical records and the laboratory database. Pregnancy outcomes, birth weight, APGAR scores, and postdelivery screening were extracted from patient-held notes and road-to-health cards. Infants were seen at KDH 6–8 weeks after delivery and assessed clinically to determine if they were thriving and screened for symptoms and signs of tuberculosis disease. Infants were assessed again at 6 and 12 months. If any problems were detected, the child was referred to routine care for further evaluation and investigation. Data Management and Statistical Analyses Data were captured using an Excel spreadsheet and imported into STATA/SE version 15.0. for analysis. Baseline clinical characteristics and maternal treatment, pregnancy, and infant outcomes were presented using descriptive statistics. Missing data were noted, and each analysis reflects the sample size used. All clinical characteristics, individual tuberculosis drugs, and ART drugs were assessed as potential predictors of outcome using univariable logistic regression. Any drug use during the MDR/RR-tuberculosis treatment episode was included in evaluation of treatment outcome, but only drug use ≥14 days during pregnancy was included for the evaluations of pregnancy and infant outcomes, reflecting in utero exposure. Clinical characteristics, other tuberculosis drugs, ART drugs, and all 3 outcomes were compared between mothers receiving regimens with bedaquiline and without bedaquiline using the χ 2 or Fisher exact test for categorical variables, and the t test or Wilcoxon rank sum test for continuous variables. After observing an effect of bedaquiline on birth weight, further multivariable analysis was conducted. Due to the collinearity between individual tuberculosis drugs, separate multivariable regression models were fitted for each tuberculosis drug noted to have a significant association with birth weight. All clinical characteristics were considered as potential explanatory variables and confounders and included in the final models if their inclusion resulted in a ≥10% change in the model coefficient associated with the tuberculosis drug of interest in bivariate analyses. Multiple imputation was used to conduct sensitivity analysis for the effect of bedaquiline on infant outcomes for all live births. The mother’s age, drug resistance category, body mass index, HIV status, and the infants’ exposure to bedaquiline in utero were used in the imputation model for infant outcome. Ethics This study was approved by the South African Medical Research Council (SAMRC) Ethics Review Committee (EC017-6/2016) and the KwaZulu-Natal Health Research Committee. RESULTS Presenting Characteristics Between 1 January 2013 and 30 December 2017, 10 042 patients were treated for MDR/RR-tuberculosis at KDH hospital; 4720 (47%) of these were women, and 126 were reported to have been pregnant; 108 women exposed to second-line tuberculosis treatment for at least 2 weeks while pregnant were included in the study. Figure 1 details study enrollment and attrition during the study. Of the 108 women in the study cohort, 20 (18%) started MDR/RR-TB treatment prior to becoming pregnant, 19 (18%) during the first trimester and 42 (39%) and 28 (26%) in the second and third trimesters, respectively. This is represented in Supplementary Figure 1 in which women are divided into 2 groups: those starting MDR/RR-TB treatment before pregnancy and in the first trimester and those starting treatment after the first trimester. Figure 1. Schema of enrollment and attrition (1 January 2013–31 December 2018). Abbreviations: KDH, King Dinuzulu Hospital; MDR/RR-TB, multidrug/rifampicin-resistant tuberculosis. Baseline characteristics of women in the study are shown in Table 2. The frequency of tuberculosis resistance to individual drugs is shown in Figure 2. Only 76 (70%) women had tuberculosis samples tested for fluoroquinolone resistance. Figure 3 demonstrates the second-line tuberculosis drugs to which fetuses were exposed in utero for at least 14 days. Table 2. Baseline Clinical Characteristics of Pregnant Women With Multidrug/Rifampicin-Resistant Tuberculosis (n = 108) Clinical Characteristics No. (%) Age: years, mean; SD 28.0; 6.13 Hb, g/dl: mean; SD (n = 102) 10.4; 1.59 BMI, kg/m2: mean; SD (n = 106) 24.0; 4.85 TB characteristics Culture positive at treatment initiation 73 (68%) Previous TB or MDR/RR-TB 38/82 (46%) Site of TB: Pulmonary 108 (100%) Extensive disease pattern on chest radiograph 45/97 (46%) Resistance pattern  RR-TB/Rif-mono/MDR-TB 83 (77%)  Pre-XDR-TB/XDR-TB 25 (23%) HIV-characteristics HIV-positive 88 (81%) HIV-positive patients on ART before MDR/RR-TB treatment started (n = 88): 74 (83%) Baseline CD4 count, median cells/mm3 [IQR] (n = 88) 353 [165–511] Pregnancy characteristics Pregnant before MDR/RR-TB treatment started 89 (82%) Gestational age at treatment start: weeks, median [IQR] 22 [14–28] Foetal exposure to any second-line drugs: Days, median [IQR] 118 [70–208] Abbreviations: ART, antiretroviral therapy; BMI, body mass index; Hb, hemoglobin; HIV, human immunodeficiency virus; IQR, interquartile range; MDR/RR-TB, multidrug/rifampicin-resistant TB; Pre-XDR-TB, pre-extensively drug-resistant TB; Rif-mono, rifampicin monoresistant; RR-TB, rifampicin-resistant TB; SD, standard deviation; TB, tuberculosis; XDR-TB, extensively drug-resistant TB. aExtensive disease was classified as bilateral disease and/or cavities on chest radiograph. Figure 2. Mycobacterial drug susceptibility test pattern for pregnant women treated for multidrug/rifampicin-resistant tuberculosis. Fluoroquinolones: Resistance to any fluoroquinolone. (Some isolates were tested for resistance to levofloxacin, some to moxifloxacin, and in some, a genotypic result was provided that stated fluoroquinolone resistance without specifying individual drug). Injectables: Resistance to any second-line injectable drug. (Some isolates were tested for resistance to amikacin, some to kanamycin, some to capreomycin, and in some, a genotypic result was provided that stated injectable resistance without specifying individual drug). During the study period, no drug susceptibility testing was done for ethambutol, ethionamide, pyrazinamide, para-aminosalicylic acid, or terizidone. Figure 3. Individual drugs to which fetuses were exposed in utero. Abbreviations: AMK, amikacin; AUG, augmentin; BDQ, bedaquiline; CAP, capreomycin; CFZ, clofazimine; CLM, clarithromycin; EMB, ethambutol; ETH, ethionamide; INH, isoniazid; KAN, kanamycin; LVX, levofloxacin; LZD, linezolid; MXF, moxifloxacin; OFX, ofloxacin; PAS, para-aminosalicylic acid; PTH, prothionamide; PZA, pyrazinamide; RIF, rifampin; TRD, terizidone. RR-Tuberculosis Treatment Outcomes Favorable treatment outcomes were reported in 72 (67%) women (Table 3; Figure 4). Multivariate analyses identified lower maternal hemoglobin at baseline as a predictor of an unfavorable maternal treatment outcome (unadjusted hazard ratio [uHR] 0.67, P = .006; see Supplementary Table 1). Eight women died a median of 67 days (interquartile range [IQR]: 32–299) after childbirth, but all 8 infants survived. Four maternal deaths were related to tuberculosis disease: 1 woman with XDR-tuberculosis, and 1 with pre-XDR-tuberculosis succumbed despite good adherence to treatment, but 2 women (1 with XDR-tuberculosis and 1 with MDR/RR-tuberculosis) had been repeatedly interrupting treatment. Two maternal deaths were related to childbirth and occurred 2 days and 5 days after delivery. One woman died from a cerebrovascular accident a year after completion of MDR/RR-tuberculosis therapy when her child was 5 months old. The cause of the remaining death was unknown; the woman died in a rural district hospital 3 months after the birth of her child. No maternal deaths were considered related to tuberculosis medication. Table 3. Maternal Treatment, Pregnancy, and Infant Outcomes Study Outcomes No. (%) Maternal MDR/RR-tuberculosis treatment outcomes (n = 108) Favorable treatment outcomes 72 (67%)  Cured 58 (54%)  Treatment completion 14 (13%) Unfavorable treatment outcomes 36 (33%)  Died 8 (7%)  Treatment failed 3 (3%)  Lost to follow-up 25 (23%) Pregnancy outcomes (n = 108 women pregnant with n = 109 fetuses, including a set of twins) Newborn characteristics Live births 99 (91%)  Gestational age at delivery: weeks, mean; SDa 37.76; SD 3.10  Birth weight, grams, median [IQR]b 2800 [2430–3200] Fetal and neonatal deaths 10 (9%)  Stillbirth 6 (6%)  Miscarriagec 3 (3%)  Termination of pregnancy 1 (1%) Favorable pregnancy outcomes (out of 109 fetuses) 57 (52%)  ≥37 weeksa 71 (72%)  Birthweight ≥2500 gb 61 (65%) Unfavorable pregnancy outcomes (out of 109 fetuses) 52 (48%)  Fetal and neonatal deaths 10 (9%)  Preterm <37 weeksa 28 (28%)  Low birth weight <2500 gb 33 (35%) Infant outcomes (n = 109) No infant outcomes at 12 months (n = 23)  Fetal and neonatal deaths 10 (9%)  Lost to follow-up after birth 13 (12%) Infant outcomes at 12 months (n = 86) Favorable infant outcomes 72 (84%)  Thriving normally 73 (85%)  Normal development 77 (89%) Unfavorable infant outcomes 14 (16%)  Failure to thrive 9 (10%)  Delayed development 5 (6%)  Early neonatal death 1 (1%)  Infant death 1 (1%)  Diagnosed with tuberculosis disease in the 1st year of life 2 (2%) Abbreviations: IQR, interquartile range; MDR/RR, multidrug/rifampicin-resistant. aLive births only (n = 99). bLive births only and missing data for 5 neonates (n = 94). cOne miscarriage was a set of twins. Figure 4. Primary outcomes. Pregnancy Outcomes Ninety-nine (91%) of the 109 fetuses, including a set of twins, were born alive, with a mean gestational age of 38 weeks (standard deviation [SD] 3.10) and median birth weight of 2800 grams (IQR 2430–3200) (Table 3). Only 57 (52%) pregnancies had a favorable pregnancy outcome when applying our study criteria (Table 1). Women living with HIV had a higher risk of an unfavorable pregnancy outcome (uHR 3.35; P = .030). Four infants born alive had congenital anomalies; an umbilical hernia, a ventral septal defect, kyphoscoliosis, and 1 infant had Ehlers-Danlos syndrome. Four of the 109 fetuses were lost early in pregnancy, and of the 6 stillborn babies, 5 were delivered at a gestational age <37 weeks. In 9 of the 10 fetal deaths the mother was living with HIV. All HIV-exposed babies were given nevirapine at birth for 6 weeks, and all tested HIV-negative at 6 weeks. Infant Outcomes We report infant outcomes after 12 months for 86 of the 99 live infants (Table 3). In addition to the 10 pregnancies that did not result in a live birth, we were unable to follow-up 13 of the infants after birth (Figure 1) Favorable infant outcomes were documented in 72 (84%) of the liveborn infants (Table 3). No baseline maternal characteristics, tuberculosis drugs, or ART were associated with unfavorable infant outcomes, even after reanalysis using multiple imputation for the 13 missing infant outcomes. There was 1 early neonatal death, 7 days after birth, and 1 infant death at 3 months. In their first year of life, 11 infants developed signs and symptoms of tuberculosis disease:” weight loss, cough, or infiltrates on chest radiograph. Two of these 11 infants were diagnosed and treated for MDR/RR-tuberculosis. Four had microbiological investigations, which were culture-negative for M. tuberculosis. The remaining 5 infants were never treated for tuberculosis and at a subsequent visit were well. Bedaquiline As bedaquiline is central to most novel treatment regimens being studied in clinical trials, we evaluated the impact of bedaquiline on all outcomes. No significant differences in baseline characteristics were identified between women treated with bedaquiline, compared to those who were not treated with bedaquiline (Table 4). Table 5 shows study outcomes stratified by bedaquiline exposure. Of the 58 women who received bedaquiline, 41 (71%) had a favorable treatment outcome, compared to 31 (62%) of those who received treatment without bedaquiline (P = .349). There was no difference in pregnancy outcomes between women whose fetuses were exposed to bedaquiline in utero (49% favorable pregnancy outcome) compared to those unexposed (57% favorable outcome, P = .312). However, a higher proportion of newborns exposed to bedaquiline in utero had a birth weight <2500 grams (45% vs 24%; P = .034; Table 5). Of infants exposed to bedaquiline, 36 (88%) had a favorable infant outcome, compared to 36 (80%) infants not exposed (P = .136). This result remained after multiple imputation for the 13 missing infant outcomes (P = .160). Table 4. Baseline Clinical Characteristics of Pregnant Women With Multidrug/Rifampicin-Resistant Tuberculosis, Stratified by Bedaquiline Exposure Clinical Characteristics Bedaquiline in Regimen n = 58 No. (%) No Bedaquiline in Regimen n = 50 No. (%) P Value Age: years, mean; SD 28.7; 6.08 27.0; 6.01 .150 Hb, g/dl: mean; SD 10.4; 1.55 N = 46; 10.4; 1.65 .928 Body Mass Index (BMI): kg/m2 mean; SD 23.7; 4.70 N = 48; 24.2; 5.08 .543 TB characteristics Culture positive at treatment initiation 42 (72%) N = 31; (63%) .405 Previous tuberculosis or MDR/ RR-tuberculosis N = 35; 19 (54%) N = 47; 19 (40%) .265 Site of tuberculosis: pulmonary 57 (100%) 51 (100%) NA Chest radiograph .923  Extensive disease N = 51; 23 (45%) N = 46; 22 (48%) Resistance pattern: no (%) 1.000  RR-/Rif-mono/MDR-tuberculosis 45 (78%) 38 (76%)  Pre-XDR-/XDR-tuberculosis 13 (22%) 12 (24%) HIV characteristics HIV-positive, no. (%) 48 (83%) 40 (80%) .806 HIV-positive patients on ART before MDR/RR-tuberculosis treatment started N = 48; 37 (77%) N = 40; 37 (90%) .155 Baseline CD4 count, median cells/mm3 [IQR] N = 45; 335 [138–500] N = 36; 395 [219–540] .352 Pregnancy characteristics Pregnant before MDR/RR-tuberculosis treatment started 47 (81%) 42 (84%) .802 Gestational age at treatment start: weeks, median [IQR] 23 [13–28] 20.5 [15–28] .905 Foetal exposure to any second-line drugs: days, median [IQR] 110 [66–203] 141 [70–213] .562 Fetal exposure to bedaquiline: days, median [IQR] 77 [28–140] NA NA Abbreviations: ART, antiretroviral therapy; Hb, hemoglobin; HIV, human immunodeficiency virus; IQR, interquartile range; MDR/RR-TB, multidrug/rifampicin-resistant TB; NA, not applicable; Pre-XDR, pre-extensively drug-resistant; Rif-mono, rifampicin monoresistant; SD, standard deviation; TB, tuberculosis; XDR, extensively drug-resistant. aExtensive disease was classified as bilateral disease and/or cavities on chest radiograph. Table 5. Maternal Treatment, Pregnancy, and Infant Outcomes Stratified by Bedaquiline Exposure Maternal RR-TB Treatment Outcomes Bedaquiline in Regimen n = 58 No. (%) No Bedaquiline in Regimen n = 50 No. (%) P Value Maternal MDR/RR-TB treatment outcomes .349 Favorable treatment outcomes 41 (71%) 31 (62%)  Cured 34 (59%) 24 (48%)  Treatment completion 7 (12%) 7 (14%) Unfavorable treatment outcomes 17 (29%) 19 (38%)  Died 4 (7%) 4 (8%)  Treatment failed 2 (4%) 1 (2%)  Loss to follow-up 11 (19%) 14 (28%) Pregnancy outcomes Bedaquiline exposure in utero n = 49 No bedaquiline exposure in utero n = 60 Newborn characteristics Birth outcomes .741  Live births 45 (92%) 54 (90%)   Gestational age at delivery: weeks, mean; SDa 37·68; SD 2·93 37·82; SD 3·25 .830   Birth weight, grams, median [IQR]b 2690 [2380–3095] 2900 [2550–3270] .179  Fetal and neonatal deaths 4 (8%) 6 (10%)   Stillbirth 3 (5%) 3 (6%)   Miscarriage 0 3 (6%)c   Termination of pregnancy 1 (2%) 0 Pregnancy outcomes .312 Favorable pregnancy outcomes (out of 109 fetuses) 24 (49%) 34 (57%)  ≥37 weeksa 32 (71%) 39 (72%)  Birth weight ≥2500 gb 24 (55%) 37 (74%) Unfavourable pregnancy outcomes (out of 109 fetuses) 25 (51%) 26 (43%)  Fetal and neonatal deaths 4 (8%) 6 (10%)  Preterm <37 weeksa 13 (29%) 15 (28%) .903  Low birth weight <2500 gb 20 (45%) 13 (26%) .034 Infant outcomes Bedaquiline exposure in utero n = 49 No bedaquiline exposure in utero n = 60 No infant outcomes at 12 months 8 (16%) 15 (25%)  Fetal and neonatal deaths 4 (8%) 6 (10%)  Lost to follow-up after birth 4 (8%) 9 (15%) Infant outcomes n = 41 n = 45 .136 Favorable infant outcomes at 12 months 36 (88%) 36 (80%)  Thriving normally 36 (88%) 37 (82%) .914  Normal development 38 (93%) 39 (86%) .705 Unfavorable infant outcomes at 12 months 5 (12%) 9 (20%)  Failure to thrive 4 (10%) 5 (11%)  Delayed development 2 (5%) 3 (7%)  Early neonatal death 0 1 (2%)  Infant death 1 (2%) 0  Developed TB in the 1st year of life 0 2 (4%) .186 Abbreviations: IQR, interquartile range; MDR/RR-TB, multidrug/rifampicin-resistant TB; SD, standard deviation; TB, tuberculosis. aLive births only (n = 99). bLive births only and missing data for 5 neonates (n = 94). cOne miscarriage was a set of twins. We evaluated whether exposure to bedaquiline was associated with exposure to any other tuberculosis drug or ART. In Supplementary Table 2 we describe the use of all tuberculosis and ART drugs in pregnancy, and in Supplementary Table 3 we explore the relationship between in utero exposure to bedaquiline and other drugs. We observed a relationship between bedaquiline use and more frequent use of clofazimine, levofloxacin, and linezolid. We evaluated risk factors for low birth weight among women and newborns. In univariate analysis no baseline maternal characteristics were associated with low birth weight (Supplementary Table 4). Exposure to bedaquiline, clofazimine, and levofloxacin in utero were all associated with an increased risk of low birth weight. In a multivariate model, bedaquiline and levofloxacin remained significant predictors of low birth weight. DISCUSSION In this cohort of pregnant women treated for MDR/RR-tuberculosis in KwaZulu-Natal, South Africa, favorable treatment outcomes were reported for two thirds of the women. Twenty-three percent of the women in our cohort had MDR/RR-tuberculosis with known resistance to the fluoroquinolones, injectables or both, and a large, additional proportion had RR-tuberculosis in which the isolate was not tested for susceptibility to these second-line drugs. The favorable treatment outcomes we report are better than the 55–60% reported for nonpregnant women in our setting [27, 28], and the 61% in the cohort of 38 pregnant women treated for MDR/RR-tuberculosis in Peru between 1996 and 2005 [11]. Notably, only 8% of the Peruvian cohort were living with HIV, and rates of second-line drug resistance were low. Favorable pregnancy outcomes were reported in 52% of the cohort with 28% of the live births born preterm and 35% with documented measurements having low birth weight. These proportions are higher than the preterm delivery rate of 12% and low birth weight rate of 15% reported for South Africa [29, 30], and this is likely to, at least in some part, be due to the high HIV prevalence with associated ART use in our study. There is growing evidence of adverse pregnancy outcomes, including preterm birth and stillbirth, in women living with HIV [31, 32]. Given that drug-susceptible tuberculosis in pregnant women living with HIV is known to increase unfavorable pregnancy and infant outcomes [2, 33, 34], it is not surprising that in our study of women with MDR/RR-tuberculosis, most of whom were living with HIV, the rate of unfavorable pregnancy outcomes is higher than that of the average population. We used a conservative definition of unfavorable pregnancy outcome, as many babies of moderate prematurity and/or marginally low birth weight were considered as unfavorable outcomes, even if otherwise well. Pregnant women have been treated with bedaquiline in South Africa since 2015. In our study, over 90% of the fetuses exposed to bedaquiline in utero were born alive, with similar fetal and neonatal deaths compared to those not exposed. Although no difference in the proportion of babies born prematurely in those exposed to bedaquiline, compared to those not exposed, more of the babies exposed to bedaquiline had a low birth weight. We analyzed our data for other predictors of low birth weight. However, given the extensive collinearity between drugs used to treat MDR/RR-tuberculosis, it was not possible to exclude other second-line tuberculosis drugs and ART either individually or in combination as being implicated. Healthy children with normal growth and development were reported in over 80% of the infants that were followed up for 12 months. Although bedaquiline and levofloxacin use was associated with low birth weight, 88% of the infants exposed to bedaquiline and levofloxacin in utero, who were born alive and followed up for 12 months, had a favorable infant outcome, with 88% thriving and 93% developing normally. Although this is the largest study to our knowledge to date documenting treatment, pregnancy, and infant outcomes in a cohort of women treated for MDR/RR-tuberculosis during pregnancy, it remains limited by its small size. It was a pragmatic observational study conducted in the public sector with limited resources, using often incomplete data routinely collected by health workers. The poor quality of data on adverse events, drug: drug interactions, and reasons for changes in both drugs and drug dosages limited our analyses and findings. In this study we noted an association between bedaquiline use and low birth weight, but it is not possible to conclusively ascribe this effect to bedaquiline, and more investigation is required to explore this relationship. Our data suggest that the use of bedaquiline is safe in pregnant women and is associated with good treatment, pregnancy, and infant outcomes. Supplementary Data Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. ciaa189_suppl_Supplementary_tables Click here for additional data file. Notes Author Contributions. M. L., B. S., I. M., S. C., N. G., and J. S. conceptualized and led the study. M. L., B. S., I. M., S. C., N. G., S. H., and J. S. contributed to the development of the methods. M. L., B. S., I. M., S. C., N. G., and S. H. collected the data. M. L., T. R., J. H., and J. S. analyzed the data and drafted the initial manuscript. All authors reviewed and contributed to the interpretation and approved the final manuscript. Acknowledgments. The authors thank Dr Norbet Ndjeka and Ms Jacqueline Ngozo for the support of the national and provincial tuberculosis directorates respectively. Financial support. This work was supported by the South African Medical Research Council. The funder had no role in study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the paper for publication. All researchers were independent of funders and sponsors. Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

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2021-04-08

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'.

Vertical Transmission of Gut Microbiome and Antimicrobial Resistance Genes in Infants Exposed to Antibiotics at Birth. Vertical transmission of maternal microbes is a major route for establishing the gut microbiome in newborns. The impact of perinatal antibiotics on vertical transmission of microbes and antimicrobial resistance is not well understood. Using a metagenomic approach, we analyzed the fecal samples from mothers and vaginally delivered infants from a control group (10 pairs) and a treatment group (10 pairs) receiving perinatal antibiotics. Antibiotic-usage had a significant impact on the main source of inoculum in the gut microbiome of newborns. The control group had significantly more species transmitted from mothers to infants (P = .03) than the antibiotic-treated group. Approximately 72% of the gut microbial population of infants at 3-7 days after birth in the control group was transmitted from their mothers, versus only 25% in the antibiotic-treated group. In conclusion, perinatal antibiotics markedly disturbed vertical transmission and changed the source of gut colonization towards horizontal transfer from the environment to the infants. pmcAntibiotics have revolutionized the treatment of infectious diseases and enabled safe and modern clinical medicine. However, the emergence of antimicrobial resistance (AMR) has become a global threat to this success [1]. Antimicrobials are widely used after birth. During vaginal delivery, 20%–30% of mothers in most developed countries receive antimicrobials to prevent early-onset group B streptococcal sepsis in newborn infants [2, 3], and 2%–5% of newborns are treated with antibiotics owing to suspected sepsis [4, 5]. Over the last 15 years, the scientific community has gained extensive knowledge on human microbiome communities at different body sites [6–9]. Based on metagenomic sequencing and strain-level analysis of human microbiota in mother-to-child transmission, the maternal gut has been found to be the largest source of colonizing bacteria in the gastrointestinal tract of healthy infants [10]. During the neonatal period, mother-to-child microbiome transmission occurs at a much higher frequency in vaginally delivered newborn infants than in those born by cesarean delivery [11]. Vertical transmission of specific strains from mothers to infants is less well understood. Dominant strains in the maternal gut microbiome, comprising >70% of a particular species, are often inherited from mothers to infants [12]. However, infants also acquire strains that are less abundant in the maternal microbiome [12]. Besides strain-level metagenomic profiling, a metatranscriptomic approach was also applied to confirm the activity of transmitted strains [13]. Perinatal antibiotics given during delivery or after birth rapidly changes the colonization process of the gut in both term and preterm infants [14–17]. There are limited data, however, on the impact of perinatal antibiotics on the vertical transmission of microbes and AMR genes from mothers to infants. Earlier, Tapiainen et al [15] reported the impact of perinatal antibiotics on the colonization of vaginally delivered infants in a prospective cohort. In the present study, we further investigate the impact of perinatal antibiotic on vertical microbe transmission from mother to infant using metagenomic analysis. MATERIALS AND METHODS Study Design and Study Population The details are described elsewhere [15]. Briefly, this prospective controlled cohort included 149 term, vaginally delivered infants followed up from birth to age 12 months. Participants included 4 groups: the control group (neither mother nor infant received antibiotics), the intrapartum antibiotic prophylaxis (IAP) group (mother received IAP, infant did not receive antibiotics), the “postnatal” group (mother did not receive antibiotics, infants received postnatal antibiotics), and the IAP + postnatal group (both mother and infant received antibiotics). The Regional Ethics Committee of the Northern Ostrobothnia Hospital District, Oulu University Hospital, Oulu, Finland, reviewed and approved the study plan. All experiments were performed according to relevant regulations and guidelines. We enrolled only newborn infants whose parents gave written informed consent. Sample Collection The details of sample collection are described elsewhere [15]. Daily fecal samples were collected from diapers for infants until discharge. Mothers provided a fecal sample for analysis after birth or soon after discharge. Infants exposed to postnatal antibiotics received Lactobacillus reuteri probiotic until discharge, according to local clinical policy. The present study investigated a subset of 56 samples from 10 mother-infant pairs in the IAP + postnatal group (the antibiotic-treated group) and 10 mother-infant pairs in the control group. The samples included 20 mothers’ samples collected after birth, 20 infants’ samples collected before discharge from the hospital (3–7 days after birth), and 16 children’s samples collected at 12 months (2 children dropped out per group). This study focused on the combined effects of antibiotics exposure from both mothers and infants. The IAP group and the postnatal group from the original cohort were not investigated. Metagenomic Sequencing For metagenomic sequencing, DNA was extracted from fecal samples using the MO BIO Powersoil DNA Extraction kit (MO BIO Laboratories). Paired-end bar-coded libraries were prepared from extracted DNA using the NexteraXT kit (Illumina) and sequenced on a NextSeq instrument (Illumina), generating approximately 1.78 GB of shotgun sequence data (150–base pair [bp] paired end reads) per sample (Supplementary Table 1). Metagenomic Sequence Analysis Raw reads were processed using Trimmomatic software [18] to remove low-quality bases and adapter sequences. High-quality reads longer than 100 bp were mapped to the human reference genome (hg38) with BWA-MEM version 0.7.12 [19] and removed if they mapped concordantly with an alignment score of ≥60. The remaining reads were mapped to a reference genome database, compiled and curated from the National Center for Biotechnology Information RefSeq genome database, consisting of genomes from viruses, bacteria, archaea, fungi, and other small microbial organisms. Mapping was performed with BWA-MEM. Top-scored (≥75), concordantly mapped alignments were used for taxonomic profiling, which calculated the relative species abundance at different taxonomic ranks using a voting scheme. High-quality nonhuman reads were assembled into scaffolds using metaSPAdes software version 3.11.0 [20]. Scaffolds shorter than 250 bp were removed. Protein-coding genes were predicted using Prodigal software version 2.6.3 [21]. Genes were annotated by comparison with an internally curated Kyoto Encyclopedia of Genes and Genomes (KEGG) [22] protein reference database using BLASTP+ version 2.7.1. Abundance of KEGG Ortholog clusters and pathways were calculated based on BLAST (Basic Local Alignment Search Tool) search. Protein-coding genes were processed using Resistance Gene Identifier software version 4.2.2 in “strict” mode to predict the antibiotic resistome of each metagenomic sample with the Comprehensive Antibiotic Resistance Database (CARD) database [23]. After metagenome assembly and gene prediction, the nucleotide sequences of all the genes from all samples were pooled and clustered using cd-hit-est version 4.8.1 [24, 25] at 100% sequence identity (command line parameters: -c 1.00 -n 10 -g 1 -G 0 -aS 0.8 -aL 0.8). The gene clusters that are only found in 2 different subjects (not >2) from the same species were considered exclusively shared genes (ESGs). The statistical analysis comparing the number of transmitted species and ESGs between different groups was performed with Wilcoxon rank sum tests, using the R package (R release 3.6.1). (All metagenomes were deposited and are available at the National Center for Biotechnology Information Sequence Read Archive under BioProject no. PRJNA543520.) RESULTS Metagenomic sequencing and analysis were performed on a subset of subjects from a previously reported study cohort [15], including 10 mother-infant pairs in the antibiotic-treated group (both mothers and infants received antibiotics) and 10 pairs in the control group (neither mothers nor infants received antibiotics). In the antibiotic-treated group, mothers received antimicrobial prophylaxis, mainly penicillin, during delivery, and infants received postnatal antibiotics, mainly a combination of penicillin and aminoglycoside started within 24 hours after birth because of suspected sepsis. Fifty-six stool samples were studied, including 20 samples from mothers that were collected immediately after birth, 20 newborn samples collected before discharge from the hospital (3–7 days after birth), and 16 infant samples collected at 12 months. Clinical background data for the samples are presented in Supplementary Table 1. Source of Microbiome Transmission After bioinformatic processing of each sample, the genes identified from all 56 samples were analyzed to identify the bacterial species and genes shared between samples (see Methods). ESGs, defined as genes that were found in only 2 individuals of all subjects, were compared. In this study, the nucleotide sequences of ESGs were required to be 100% identical. As such, ESGs are strong indicators of the transmission of species and genes from one subject to another. If a single species is found in 2 individuals (1 mother, 1 infant) who have ≥1 ESG that belongs to this species, the species is considered a transmitted species. Similarly, if 1 species and ≥1 ESG belonging to this species are found in a child’s samples at birth and at 12 months, the species is considered persistent. We found that by 3–7 days after birth, the number of transmitted species in mother-infant pairs was significantly higher in the control group, unexposed to antibiotics (mean, 26 species), than in the antibiotic-treated group (5 species; P = .03) (Table 1) or in unrelated woman-infant pairs in the control group (7 species; P = .005) or the antibiotic-treated group (1 species; P < .001) (Figure 1A). The number of ESGs in the mother-infant pairs in the control group (mean, 1091 ESGs) was also significantly higher than in the antibiotic-treated group (38 ESGs; P = .01) (Table 1) or in unrelated woman-infant pairs in the control group (49 ESGs; P = .002) or the antibiotic-treated group (9 ESGs; P = .001) (Figure 1B). This was also true for the transmitted species with AMR genes or the ESGs that are AMR genes (Table 1 and Figure 1C and 1D). None of the AMR genes in the infants in the antibiotic-treated group originated from their mother’s microbiome. Table 1. Numbers of Transmitted Species and Exclusively Shared Genes in Mother-Infant Pairs From Control and Antibiotic-Treated Groups Study ID (Control Group; Antibiotic Group) Transmitted Species or ESGs (AMR Genesa), No. Age 3–7 d Age 12 mo Control Group Antibiotic Group Control Group Antibiotic Group Transmitted Species ESGs Transmitted Species ESGs Transmitted Species ESGs Transmitted Species ESGs 13; 6 20 (1) 466 (2) 1 (0) 2 (0) 32 (1) 1656 (1) 59 (0) 298 (0) 26; 31 8 (1) 270 (2) 6 (0) 26 (0) 38 (1) 1297 (2) 42 (0) 221 (0) 35; 32 0 (0) 0 (0) 0 (0) 0 (0) NA NA 37; 70 37 (0) 495 (0) 10 (0) 74 (0) 36 (0) 125 (0) 68 (0) 873 (0) 43; 74 43 (1) 2114 (23) 0 (0) 0 (0) 69 (0) 1344 (0) 22 (0) 98 (0) 45; 88 18 (1) 1223 (2) 0 (0) 0 (0) NA 11 (0) 32 (0) 89; 95 24 (1) 1786 (11) 1 (0) 1 (0) 68 (0) 3144 (0) 40 (0) 257 (0) 93; 98 0 (0) 0 (0) 1 (0) 1 (0) 34 (0) 327 (0) 18 (0) 159 (0) 105; 136 58 (4) 2080 (14) 27 (0) 274 (0) 62 (2) 1278 (3) NA 123; 148 47 (2) 2471 (2) 0 (0) 0 (0) 40 (0) 552 (0) 62 (1) 585 (1) Mean; mean 26 (1) 1091 (5) 5 (0) 38 (0) 47 (1) 1215 (1) 40 (0) 315 (0) Abbreviations: AMR, antimicrobial-resistant; ESGs, exclusively shared genes; ID, identification number; NA, dropped out. aParenthetical numbers represent species with AMR genes or ESGs that are AMR genes. Figure 1. Transmitted species and exclusively shared genes of different adult/mother-infant groups. P values (Wilcoxon rank sum test) for unrelated woman-infant antibiotic-treated group, unrelated woman-infant control group, and paired mother-infant antibiotic-treated group all represent comparisons with the paired mother-infant/child control group. Abbreviations: ESGs, exclusively shared genes. For the infants at 12 months of age, there was no statistically significant difference between the control and the antibiotic-treated groups in terms of transmitted species in mother-infant pairs. However, our analysis showed that the number of ESGs in mother-infant pairs for infants at 12 months of age, was still significantly higher in the control group (mean, 1215 ESGs) than in the antibiotic-treated group (315 ESGs; P = .02) (Table 1) or in unrelated woman-infant pairs in the control group (20 ESGs; P < .001) or the antibiotic-treated group (26 ESGs; P < .001) (Figure 1E and 1F). Although a transmitted species is defined when a single ESG exists in a mother-infant pair, the actual detected transmitted species, as listed in Table 1, have multiple ESGs per species. On average, 1 transmitted species has 43 ESGs between the mother-infant pairs in the control group and 8 ESGs in the treatment group. Therefore, the identified transmitted species are supported by multiple ESGs. Microbial species composition profiles were calculated at different taxonomic ranks (Figure 2 and Supplementary Figures 1 and 2). The relative abundance data is also available in Supplementary Tables 2–4. For each individual sample from the infants, we identified which species were transmitted from their mother, and which from unknown sources, such as horizontally transferred from the environment or other people (Figure 3). By 3–7 days after birth, on average 72% (σ = 39%) of the species population in the infants’ samples in the control group were shared with their mothers’ samples, compared to only 25% (σ = 38%) in the infants in the antibiotic-treated group (P = .04). At 12 months, the relative abundance of total bacteria species in the fecal samples of infants transmitted from their mothers was 82% (σ = 7%) in the control group and 72% (σ = 21%) in the antibiotic-treated group (P = .38). Figure 2. Relative abundance at phylum level. Figure 3. Relative species abundance of children’s fecal samples. Infant samples obtained 3–7 days after birth are shown on the bottom, and samples obtained at 12 months on the top. Species on the left side of the x-axis are species transmitted from the maternal gut microbiome. Only species that with ≥5% relative abundance in any sample are shown. (Individual species and their abundances are available in Supplementary Table 5.) Transmitted Species and AMR Genes The species that were vertically transmitted were not always the species with a high abundance in the maternal microbiome. In about 75% of cases, the relative abundance of these transmitted species is <1% in the maternal samples. The mean relative abundance of the transmitted species in mothers is 1.3% (σ = 3.0%) (Supplementary Table 6). The most frequently transmitted species from mother to infants in the control group, including the species found in either infants’ stool samples at 3–7 days after birth or at 12 months of age, were Bacteroides sp. 3_1_33FAA (9 occurrences among 10 children), Bacteroides vulgatus (8 occurrences), and Bacteroides fragilis, Bacteroides ovatus, Bacteroides salanitronis, Bifidobacterium longum, and Parabacteroides distasonis (7 occurrences each) (Supplementary Table 7). In the antibiotic-treated group, the most frequently transmitted species were quite different and included Faecalibacterium prausnitzii (8 occurrences among 10 children), B. vulgatus (7 occurrences), and Eubacterium rectale, Anaerostipes hadrus, B. ovatus, Bacteroides sp. 2_1_22, Flavonifractor plautii, Roseburia hominis, Roseburia intestinalis, and Ruminococcus sp. 5_1_39BFAA (6 occurrences each) (Supplementary Table 7). In the control group, the most abundant species transmitted from mothers to infants at either 3–7 days after birth or at 12 months of age were Escherichia coli (mean relative abundance, 0.28), B. vulgatus (0.13), B. longum (0.10), Bifidobacterium bifidum (0.09), Bacteroides uniformis (0.08), B. fragilis (0.06), and Bacteroides. sp. 2_1_22 (0.05) (Supplementary Table 8). In the antibiotic-treated group, these species were E. coli (mean relative abundance, 0.15), Parabacteroides johnsonii (0.12), Bifidobacterium breve (0.10), Collinsella aerofaciens (0.08), B. longum (0.07), F. prausnitzii (0.07), Citrobacter sp. 30_2 (0.07), B. vulgatus (0.06), and Bacteroides sp. 2_1_22 (0.05) (Supplementary Table 8). Among the species that were not transmitted from the mother’s gut (Supplementary Table 9), the most commonly seen was Staphylococcus epidermidis. S. epidermidis, an ubiquitous skin colonizer [26], is among the antibiotic-resistant pathogens that cause healthcare-associated infections [27]. Our analysis, which lacks skin samples from mothers, could not confirm the source of S. epidermidis. However, it has been known that human skin and hospital room surfaces share common species [28] and contaminated surfaces in hospitals contribute to the transmission of nosocomial pathogens [29]. We found S. epidermidis in 5 and 4 infants in the antibiotic and the control groups, respectively, at 3–7 days after birth. The relative abundance of S. epidermidis in the antibiotic-treated group (41%) was higher than in the control group (10%; P = .1) (Supplementary Table 9). L. reuteri, which was administered to the infants in the antibiotic-treated group, was found in 4 infants from this group. Several species from the genus Klebsiella were found to be horizontally transmitted from the environment only in the antibiotic-treated group (Supplementary Table 9). No statistically significant difference was found in the abundance of total AMR genes in infants’ samples between the 2 groups (Figure 4). However, when we separated the AMR genes according to whether they were vertically transmitted from mothers’ gut microbiome, we saw clear differences between the 2 groups. In the antibiotic-treated group, except for an outlier (Sample ID: Birth-antibiotic-70), the main source of AMR genes was not the maternal gut microbiome, especially at 3–7 days after birth, while in the control group, most AMR genes were inherited from the species transmitted from mothers. Figure 4. Antimicrobial-resistant (AMR) gene abundance and source of AMR genes in infants’ gut microbiome. The unit of abundance unit is copies per million (the number of reads mapped to the AMR gene per million reads mapped to all genes in the sample). AMR genes in infants transmitted from mothers are not necessarily exclusively shared genes (as listed in Table 1); exclusively shared genes must exist in both mother and infant and must be 100% identical in full gene length. In this figure, an AMR gene in an infant’s sample is considered transmitted if the gene is from a species that can be traced back to the mother’s sample, even if the AMR gene was not found in the mother’s sequencing data. Persistence of Transmitted Species From Birth Until 12 Months At 12 months, the control group shared more species with their corresponding 3–7-day samples than the antibiotic-treated group. The control group had significantly higher numbers of persistent bacterial species (mean, 21 species) and ESGs (mean, 1128 species) between 3–7 days and 12 months than the antibiotic-treated group (2 persistent species [P = .02]) and 27 persistent ESGs [P = .02]) (Table 2). This suggests that, in the first week of life, healthy infants vertically inherit a maternal microbiome and AMR signatures, which largely persist at 12 months after birth. Table 2. Numbers of Persistent Species and Exclusively Shared Genes Between Samples Collected at 3–7 Days and 12 Months After Birth in the Same Child Study ID Transmitted Species or ESGs (AMR Genesa), No. Persistent Species ESGs Control group  13 20 (0) 473 (0)  26 7 (0) 443 (0)  37 11 (0) 1608 (0)  43 46 (0) 1187 (0)  89 27 (1) 2769 (0)  93 0 (0) 0 (0)  105 44 (0) 2219 (0)  123 16 (0) 324 (0)  Mean 21 (0) 1128 (0) Antibiotic group  6 4 (0) 170 (0)  31 2 (0) 2 (0)  70 10 (0) 40 (0)  74 0 (0) 0 (0)  88 0 (0) 0 (0)  95 0 (0) 0 (0)  98 0 (0) 0 (0)  148 0 (0) 0 (0)  Mean 2 (0) 27 (0) Abbreviations: AMR, antimicrobial-resistant; ESGs, exclusively shared genes; ID, identification number. aNumbers in parenthesis are species with AMR genes or ESGs that are AMR genes. Shift of Microbiome Composition From Birth to 12 Months Microbial species composition profiles were calculated at different taxonomic ranks, and the relative abundances are provided in Supplementary Tables 2–4. We used a nonmetric multidimensional scaling approach to visualize the similarities between all the samples, using Bray-Curtis distance on species relative abundance (Figure 5A). Infants in the antibiotic-treated group have gut taxonomic composition that is more dissimilar from their mothers (Figure 5A and 5B) at 3–7 days after birth then the control group. However, during the first 12 months, the gut microbiome of the infants in the antibiotic-treated group underwent a bigger shift and mostly returned to normal by age 12 months. Most stool samples from infants at 12 months, in both groups, had an almost adultlike taxonomic composition (Figure 5A). Figure 5. Nonmetric multidimensional scaling (MDS) plot of samples and taxonomic distance between groups. A, X-axis and y-axis are the two MDS dimensions. Each point is a sample. A dashed line connects a mother’s sample to an infant’s sample at 3–7 days after birth, then to that child’s sample at 12 months. The 2 overlapping ellipses cover the mothers’ samples in the control and the antibiotic-treated groups. B, Taxonomic distance (range, 0.0–1.0) between different groups. Both plots were based on Bray-Curtis distance on species relative abundance. DISCUSSION We show that widely used perinatal antibiotics resulted in a significantly decreased vertical transmission of microbes from mothers to infants at 3–7 days after birth. At the same time, infants in the antibiotic-treated group had an increased proportion of microbes deriving from other environmental sources. Furthermore, infants in the antibiotic-treated group obtained their AMR species from their environment instead from their mothers. This emphasizes the potential role of the hospital microbial environment in the spread of AMR in infants exposed to antibiotics at birth. The present study demonstrates the vertical transmission of AMR genes from mothers to infants. In an earlier systematic review of 4839 articles [30], only 5 studies about vertical transmission of AMR pathogens or genes were identified, including studies about the transmission of penicillin-resistant Streptococcus pneumoniae [31], antibiotic-resistant group B streptococcus [32], extended β-lactamase producing E. coli [33], ampicillin-resistant E. coli [34], and tetracycline resistance genes [35]. Our study extends the earlier findings and presents the magnitude of the vertical transmission process using metagenome sequencing in a controlled study. Our results of maternal gut microbiome as the source of infant gut microbiome are analogous to those of the previous studies. Ferretti et al [10] have shown that the maternal gut provides a larger contribution of colonizing bacteria in the gastrointestinal tract in young infants than the skin, oral cavity, or vagina. Although we did not collect skin, oral or vaginal samples from mothers, our study demonstrated that 82% and 72% of bacterial species in children’s samples at 12 months of age originated from the mother’s gut, indicating that the maternal gut microbiome is the major source for gut colonization in newborns. Several transmitted organisms identified in our study, such as species in the genera Bacteroides and Bifidobacterium and in E. coli, are in alignment with transmitted species observed in other studies [10, 11]. Similar to the observations by Yassour et al [12], showing that both primary strains and secondary strains are inherited from mothers to infants, our present study shows that infants acquire both abundant and less abundant species from their mother. Perinatal antibiotics led to an increased environmental source in the newborn colonization process, which has clinical implications. In classic studies in the 1980s [36], Tullus et al [36] showed that newborn infants treated in certain neonatal wards subsequently had a long-term increased risk of E. coli infections, most likely owing to the early acquisition of nosocomially spread E. coli clones in the gut microbiome. Exposure to perinatal antibiotics may thus result in an increased risk of infections due to strains acquired from the hospital environment instead of the maternal microbiome. Furthermore, prenatal consumption of probiotics has shown some promise in preventing long-term diseases in offspring [37, 38]. Prenatal interventions based on the vertical transmission of microbes from mothers to infants may fail, however, if perinatal antibiotics, interfering with the source of colonization, are used. Finally, nosocomial spread of AMR is a known threat in neonatal wards [39–41]. The nosocomial acquisition of AMR from a hospital environment seems to be more likely in newborn infants exposed to antibiotics owing to the changed colonization process. Our study is one of the first controlled studies that used metagenomic sequencing to investigate the impact of perinatal antibiotics on newborn microbiome transmission. One of its major strength is the controlled prospective cohort that was followed up for a year. Although our study cohort (n = 10 per group for each group) is not very large, it still enabled us to find significant differences in vertical microbiome transmission between the antibiotic-exposed group and the control group. Cohorts in other related studies, owing to different designs and configurations, are not as well suited to answer the question of how antibiotics affect vertical microbiome transmission, as we have been able to accomplish in our study. For example, although the large cohort by Shao et al [11] included 596 subjects, they only had fecal samples for 5 mother-infant pairs in which both mothers and infants received antibiotic treatment and multiple samples were collected from infants [11], [supplementary table 1]. The antibiotic and microbiome study by Korpela et al [42] included 236 children, but only 14 stool samples were sequenced using a metagenomic approach and no samples were collected from mother. In the study by Yassour et al [12], samples from mothers and infants in 44 mother-infant pairs were sequenced using metagenomic approaches, and multiple samples were collected for the infants until they were 3 month of age. Clear patterns in vertical microbiome transmission were observed in that study, but it did not track antibiotic usage and the cohort did not have an antibiotic usage group. In addition, the infants were followed up until only 3 months of age. The study by Ferretti et al [10] focused on vertical microbiome transmission of different body sites in healthy populations. Only 4 infants received antepartum or intrapartum antibiotic treatments in that cohort [10], [supplementary table 1]. Breastfeeding has been shown to result in marked and persistent differences in the infant gut microbiome [43]. Bacteria in maternal breast milk are likely to be an important source of the infant gut microbiome [44]. In the current study, perinatal antibiotics seemed to disturb the mother-to-infant colonization even in the presence of breastfeeding, because all vaginally delivered infants, including those exposed to perinatal antibiotics, received maternal breast milk. The differences between groups might thus have been even larger in settings with low breastfeeding rates in sick infants receiving antibiotics. Our cohort study does have some limitations, however. The results may not be generalizable to all infant populations, because the cohort was from a homogenic Finnish population with a rather low background prevalence of clinically significant AMR genes as compared to that in many other countries. We only recruited vaginally delivered infants, so the possible effects in infants born by cesarean delivery were not studied in this population. The relatively small cohort size did not allow comparison of different antibiotics or other factors on the outcome. Therefore, more studies with larger cohorts that include different populations and cesarean-delivered infants are needed to further investigate how antibiotic treatments affect vertical microbiome transmission. The identification of transmitted species and genes can be influenced by sequencing depth. It is expected that a higher sequencing depth will provide better genome coverage, enabling more transmitted genes to be found. The actual transmitted species and genes may be missed if the sequencing depth is too low for these species to be detected in samples from either mothers or infants. Mothers have more diverse microbiomes than infants. Therefore, the average per-species sequencing depth is much lower in mothers than in infants, so variations in the sequencing depths of samples from mothers have a bigger impact in the analysis of transmitted species or genes. Furthermore, the abundance of transmitted species in mothers’ samples can have a wide range and can be low (Supplementary Table 6). Therefore, in our data set, the number of ESGs is not correlated with the sequencing depth of samples from either mothers or infants. As in typical microbiome studies, the sequencing depths of the samples in this study have a wide range (Supplementary Table 1B). However, there is no significant difference in sequencing depth between control and antibiotic groups in mothers or infants (both P = .81; t test). Therefore, variation in sequencing depth will not affect the significant findings in this study. The method we developed based on clustering analysis of genes for the detection of transmitted species between microbiome is very effective and sensitive. Several computational tools that offer strain-level analysis on microbiome samples can be used to detect transmission of species. For example, StrainPhlAn [45] is a commonly used program for strain analysis. StrainPhlAn is now part of the MetaPhlAn2 package [46], which analyzes a set of conserved and unique species marker genes to obtain taxonomic profiles for metagenomic samples. StrainPhlAn uses the results from MetaPhlAn2 to detect single-nucleotide polymorphisms (SNPs) so that the SNPs can be compared to find strain-level differences between samples. Because only a limited set of marker genes are analyzed, StrainPhlAn may miss transmission SNPs on other genes. StrainEST is another program for bacteria strain analysis in microbiome samples [47]. It can perform full-length genome SNP calling, using 1 representative genome per species to build multiple genome alignment for multiple strains in a species before SNP calling. For species with very diverse strains (ie, those with a large pangenome), it is difficult for the single representative genome to cover the whole pangenome. Therefore, this method may fail to detect transmitted species or genes. MIDAS software is another method for strain level analysis [48]. Like MetaPhlAn2, MIDAS relies on a set of marker genes for taxonomy profiling. But like StrainEST, it performs genome-wide SNP calling. MIDAS was also used for tracking the transmission of species from mother to infant in its original publication [48]. In the publication of MIDAS [48], the transmission of species from mother to infant (healthy population) was studied and it was found that, on average, approximately 40 species were transmitted at birth and approximately 60 species were transmitted at age 12 months. This is very comparable to our findings in the control group at these time points (Table 1). Compared with the above methods, our method for detection of transmitted species and genes has several advantages. The above-mentioned methods usually require relatively high sequencing depth for SNP calling. Our method does not have this requirement and can work with low-abundance species. Because our method is based on the clustering analysis of all the genes from the pangenomes, it can detect transmission events based on information beyond a subset of marker genes or the representative genome used in the above-mentioned methods. In addition, our analysis is gene focused and can therefore track the transmission of genes and AMR genes, which is an important aspect of our study. In summary, this study demonstrated that antibiotic use markedly affected the vertical transmission of maternal microbes to infants during early colonization. Antibiotics changed the main source of colonization and led to more horizontally transmitted species from the environment, some of which are potentially pathogenic species common to hospital environments. Our study suggests that vertical transmission is a continuous process. Despite the initial interruption of vertical transmission at birth caused by antibiotics, the children in the antibiotic-treated group still reached adultlike microbiome composition at 12 months of age. However, at 12 months of age, there were still detectable differences between the antibiotic-treated group and the control group, showing the possible long-term effect due to antibiotic use at birth. Supplementary Data Supplementary materials are available at The Journal of Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. jiaa155_suppl_Supplement_Figure_S1 Click here for additional data file. jiaa155_suppl_Supplement_Figure_S2 Click here for additional data file. jiaa155_suppl_supplementary_Table_S1 Click here for additional data file. jiaa155_suppl_supplementary_Table_S2_S9 Click here for additional data file. Notes Acknowledgments. We would like to thank the study nurse, Leena Okkonen, Oulu University Hospital, and the study coordinator, Helena Moilanen, NordLab, Oulu, Finland. Author contributions. T. T., M. T., and J. S. planned the clinical study design and organized stool sample collection and clinical data collection. K. M. performed metagenomic sequencing. W. L. performed bioinformatic analysis. W. L., L. B., and H. A. L. analyzed the data. W. L., T. T., and K. E. N. wrote the manuscript. All authors approved the final version of the manuscript. Financial support. The work performed in Finland was supported by the Academy of Finland and Pediatric Research Foundation, Finland. The work performed at the J. Craig Venter Institute, in the United States, was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, US Department of Health and Human Services (grant U19AI110819 to H. A. L. and K. E. N.). Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

CEFUROXIME

DrugsGivenReaction

CC BY-NC-ND

32239170

2021-10-13

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metabolic acidosis'.

Intraoperative refractory status epilepticus caused by propofol -a case report. Status epilepticus, when continued despite the administration of two antiepileptic drugs, is called refractory status epilepticus (RSE). The seizure-like phenomenon due to propofol is widely reported in the literature. However, RSE caused by propofol is rare and is a diagnostic dilemma. A 44-year-old male patient presented with RSE during the intraoperative period and was under general anesthesia on propofol infusion. The seizure was resistant to benzodiazepines and phenytoin. Thereafter, the seizure subsided after the discontinuation of propofol infusion, and the patient was shifted to fentanyl and dexmedetomidine infusion for the maintenance of anesthesia. The postoperative follow-up was uneventful. This article focuses on the management of intractable intraoperative seizure and highlights the need for the exploration of seizure characteristics caused by propofol. Propofol is the most popular drug used for the induction and maintenance of anesthesia, but causes excitatory activities, such as myoclonus, opisthotonus, and rarely, generalized seizures [1]. Prolonged non-resolving seizure activity is termed status epilepticus (SE) and is a medical emergency with significant associated morbidity and mortality. Pharmacological management is done with benzodiazepines and antiepileptic drugs, along with prompt resuscitation and source control. SE, when continued despite the administration of two antiepileptic drugs, is called refractory status epilepticus (RSE). The management of RSE includes the induction of general anesthesia with propofol, thiopentone, midazolam, or ketamine. However, management becomes intricate when RSE is caused by propofol. We report here a case of intraoperative RSE caused by propofol. The patient has provided written informed consent for publication of this case report. This manuscript adheres to the applicable Enhancing the Quality and Transparency Of health Research (EQUATOR) guideline. Case Report A 44-year-old male patient (weight 60 kg) was posted for C2–C5 astrocytoma excision under general anesthesia. The surgery was performed at All India Institute of Medical Sciences Patna, India in 2019. The patient did not have any coexisting disease or history of seizure. Anesthesia was induced with injection of propofol, fentanyl, and vecuronium followed by tracheal intubation. The propofol infusion at a rate of 75–100 μg/kg/min was started for the maintenance of anesthesia as motor and somatosensory evoked potential monitoring was planned for the patient. The bispectral index (BIS), invasive blood pressure, and central venous pressure were also monitored in addition to standard monitoring. Furthermore, the patient was made prone for surgery. Thirty minutes after the start of propofol infusion, as the surgeon was dissecting the superficial muscular layers after skin incision, the patient developed generalized tonic–clonic seizure (GTCS) involving all four limbs and truncal muscles. A sudden increase in blood pressure, heart rate, end tidal CO2, and BIS were also noted. The injection of 2 mg midazolam was then immediately given intravenously (IV). Although the intensity of seizure decreased, GTCS continued, for which a repeat dose of midazolam was given, but in vain. As the seizure was not controlled, a loading dose of 15 mg/kg phenytoin was given IV over 20 minutes. Nonetheless, the seizure continued with a seizure-free interval of 5 minutes. The injection of 250 mg thiopentone was then administered IV as a last resort for treating SE, which successfully aborted the episode for approximately 20 minutes, only to reappear again. Meanwhile, investigations such as electrolytes and arterial blood gases (ABG) were done to rule out aggravating factors. ABG indicated metabolic acidosis with hyperlactatemia, and electrolytes were within the normal range. A provisional diagnosis of propofol-induced seizure was made, and propofol infusion was discontinued. Anesthesia was then maintained on fentanyl, dexmedetomidine infusion and isoflurane to maintain a minimum alveolar concentration of 0.5–0.8, and surgery was allowed to proceed. The rest of the intraoperative and postoperative periods were uneventful, and the postoperative computerized tomography of the brain and electroencephalogram were within normal limits. The patient was symptom-free after three months of follow-up. Discussion Propofol is widely used as an induction agent for general anesthesia, and its common side effects are hypotension, respiratory depression, and local intravascular pain at the injection site. Neurological complications caused by propofol are widely reported and include GTCS, focal motor seizures, increased tone with twitching and rhythmic movements, opisthotonus and involuntary movements, collectively termed as seizure-like phenomenon (SLP). The mechanism of SLP due to propofol is mostly unknown, but potentially due to the imbalance between the activity of excitatory and inhibitory neurons in the GABA pathway [2]. Propofol-induced SLP does not have any fixed pattern of occurrence with respect to timing, duration, clinical presentation, age group, and the health of the patient involved [1]. In addition, no clear consensus exists regarding the prevention and management of such adverse events. Walder et al. [1], in a systemic review, analyzed 81 cases of SLP of which one of the principal findings was the predominance of SLP during induction, emergence, or delay after anesthesia and sedation. Only two cases of its occurrence arose during maintenance [3,4]. The lower incidence of SLP during maintenance of anesthesia resulted from masking by neuromuscular blockage (NMB), a steady state level of propofol concentration, and less cerebral excitation [1]. Our case was unique as it occurred during the maintenance phase and was presented as SE, which was refractory to treatment by two antiepileptic drugs. Only a few reported cases of propofol-induced SE have been available, most of which emerged in the postoperative period. Additionally, a report from Japan stated that prolonged GTCS was initiated 10 minutes after propofol infusion after the brachial plexus block [5]. One case of propofol-induced RSE during general anesthesia has also been reported in a patient with benign epilepsy with centrotemporal spikes, which lasted for 14 hours [6]. RSE is a condition where SE continues despite the administration of two antiepileptic drugs (e.g., benzodiazepines and phenytoin) and is associated with a high risk of complications. Complications of RSE include excitotoxic CNS injury, hyperthermia, pulmonary edema, arrhythmias, cardiovascular collapse, metabolic derangement, acute kidney and liver injury, rhabdomyolysis, and fractures [7]. Moreover, RSE has a high-mortality rate, and less than one-third of patients return to their premorbid level of functioning [8]. Seizures in the intraoperative period are difficult to diagnose when NMB is used, but suggestive signs include tachycardia, hypertension, increased end tidal CO2, pupillary dilatation, increased oxygen consumption, and increased muscle tone [7]. Management includes the administration of antiepileptic drugs and the correction of precipitant factors. In our case, the seizure was apparent because we did not use NMB in the maintenance of anesthesia. The treatment of RSE includes administering general anesthesia with propofol, thiopentone, midazolam, or ketamine. However, our patient was already on high-dose propofol infusion when he developed RSE. As no precipitating factors were found, we opted to discontinue propofol and started dexmedetomidine and fentanyl for the maintenance of anesthesia, which stopped the seizure episodes. Apart from being used as an induction agent for general anesthesia, propofol is also widely utilized in the treatment of seizure due to its anticonvulsive properties. Nevertheless, rare case reports of the pro-convulsant effects of propofol [1–6] emphasize the need for the exploration of seizure characteristics caused by propofol. Conflict of Interest No potential conflict of interest relevant to this article was reported. Author Contributions Abhyuday Kumar (Conceptualization; Validation; Visualization; Writing – original draft) Amarjeet Kumar (Validation; Visualization; Writing – review & editing) Neeraj Kumar (Validation; Visualization; Writing – review & editing) Ajeet Kumar (Supervision; Visualization; Writing – review & editing)

FENTANYL, PROPOFOL, VECURONIUM BROMIDE

DrugsGivenReaction

CC BY-NC

32388939

2021-02

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Status epilepticus'.

Intraoperative refractory status epilepticus caused by propofol -a case report. Status epilepticus, when continued despite the administration of two antiepileptic drugs, is called refractory status epilepticus (RSE). The seizure-like phenomenon due to propofol is widely reported in the literature. However, RSE caused by propofol is rare and is a diagnostic dilemma. A 44-year-old male patient presented with RSE during the intraoperative period and was under general anesthesia on propofol infusion. The seizure was resistant to benzodiazepines and phenytoin. Thereafter, the seizure subsided after the discontinuation of propofol infusion, and the patient was shifted to fentanyl and dexmedetomidine infusion for the maintenance of anesthesia. The postoperative follow-up was uneventful. This article focuses on the management of intractable intraoperative seizure and highlights the need for the exploration of seizure characteristics caused by propofol. Propofol is the most popular drug used for the induction and maintenance of anesthesia, but causes excitatory activities, such as myoclonus, opisthotonus, and rarely, generalized seizures [1]. Prolonged non-resolving seizure activity is termed status epilepticus (SE) and is a medical emergency with significant associated morbidity and mortality. Pharmacological management is done with benzodiazepines and antiepileptic drugs, along with prompt resuscitation and source control. SE, when continued despite the administration of two antiepileptic drugs, is called refractory status epilepticus (RSE). The management of RSE includes the induction of general anesthesia with propofol, thiopentone, midazolam, or ketamine. However, management becomes intricate when RSE is caused by propofol. We report here a case of intraoperative RSE caused by propofol. The patient has provided written informed consent for publication of this case report. This manuscript adheres to the applicable Enhancing the Quality and Transparency Of health Research (EQUATOR) guideline. Case Report A 44-year-old male patient (weight 60 kg) was posted for C2–C5 astrocytoma excision under general anesthesia. The surgery was performed at All India Institute of Medical Sciences Patna, India in 2019. The patient did not have any coexisting disease or history of seizure. Anesthesia was induced with injection of propofol, fentanyl, and vecuronium followed by tracheal intubation. The propofol infusion at a rate of 75–100 μg/kg/min was started for the maintenance of anesthesia as motor and somatosensory evoked potential monitoring was planned for the patient. The bispectral index (BIS), invasive blood pressure, and central venous pressure were also monitored in addition to standard monitoring. Furthermore, the patient was made prone for surgery. Thirty minutes after the start of propofol infusion, as the surgeon was dissecting the superficial muscular layers after skin incision, the patient developed generalized tonic–clonic seizure (GTCS) involving all four limbs and truncal muscles. A sudden increase in blood pressure, heart rate, end tidal CO2, and BIS were also noted. The injection of 2 mg midazolam was then immediately given intravenously (IV). Although the intensity of seizure decreased, GTCS continued, for which a repeat dose of midazolam was given, but in vain. As the seizure was not controlled, a loading dose of 15 mg/kg phenytoin was given IV over 20 minutes. Nonetheless, the seizure continued with a seizure-free interval of 5 minutes. The injection of 250 mg thiopentone was then administered IV as a last resort for treating SE, which successfully aborted the episode for approximately 20 minutes, only to reappear again. Meanwhile, investigations such as electrolytes and arterial blood gases (ABG) were done to rule out aggravating factors. ABG indicated metabolic acidosis with hyperlactatemia, and electrolytes were within the normal range. A provisional diagnosis of propofol-induced seizure was made, and propofol infusion was discontinued. Anesthesia was then maintained on fentanyl, dexmedetomidine infusion and isoflurane to maintain a minimum alveolar concentration of 0.5–0.8, and surgery was allowed to proceed. The rest of the intraoperative and postoperative periods were uneventful, and the postoperative computerized tomography of the brain and electroencephalogram were within normal limits. The patient was symptom-free after three months of follow-up. Discussion Propofol is widely used as an induction agent for general anesthesia, and its common side effects are hypotension, respiratory depression, and local intravascular pain at the injection site. Neurological complications caused by propofol are widely reported and include GTCS, focal motor seizures, increased tone with twitching and rhythmic movements, opisthotonus and involuntary movements, collectively termed as seizure-like phenomenon (SLP). The mechanism of SLP due to propofol is mostly unknown, but potentially due to the imbalance between the activity of excitatory and inhibitory neurons in the GABA pathway [2]. Propofol-induced SLP does not have any fixed pattern of occurrence with respect to timing, duration, clinical presentation, age group, and the health of the patient involved [1]. In addition, no clear consensus exists regarding the prevention and management of such adverse events. Walder et al. [1], in a systemic review, analyzed 81 cases of SLP of which one of the principal findings was the predominance of SLP during induction, emergence, or delay after anesthesia and sedation. Only two cases of its occurrence arose during maintenance [3,4]. The lower incidence of SLP during maintenance of anesthesia resulted from masking by neuromuscular blockage (NMB), a steady state level of propofol concentration, and less cerebral excitation [1]. Our case was unique as it occurred during the maintenance phase and was presented as SE, which was refractory to treatment by two antiepileptic drugs. Only a few reported cases of propofol-induced SE have been available, most of which emerged in the postoperative period. Additionally, a report from Japan stated that prolonged GTCS was initiated 10 minutes after propofol infusion after the brachial plexus block [5]. One case of propofol-induced RSE during general anesthesia has also been reported in a patient with benign epilepsy with centrotemporal spikes, which lasted for 14 hours [6]. RSE is a condition where SE continues despite the administration of two antiepileptic drugs (e.g., benzodiazepines and phenytoin) and is associated with a high risk of complications. Complications of RSE include excitotoxic CNS injury, hyperthermia, pulmonary edema, arrhythmias, cardiovascular collapse, metabolic derangement, acute kidney and liver injury, rhabdomyolysis, and fractures [7]. Moreover, RSE has a high-mortality rate, and less than one-third of patients return to their premorbid level of functioning [8]. Seizures in the intraoperative period are difficult to diagnose when NMB is used, but suggestive signs include tachycardia, hypertension, increased end tidal CO2, pupillary dilatation, increased oxygen consumption, and increased muscle tone [7]. Management includes the administration of antiepileptic drugs and the correction of precipitant factors. In our case, the seizure was apparent because we did not use NMB in the maintenance of anesthesia. The treatment of RSE includes administering general anesthesia with propofol, thiopentone, midazolam, or ketamine. However, our patient was already on high-dose propofol infusion when he developed RSE. As no precipitating factors were found, we opted to discontinue propofol and started dexmedetomidine and fentanyl for the maintenance of anesthesia, which stopped the seizure episodes. Apart from being used as an induction agent for general anesthesia, propofol is also widely utilized in the treatment of seizure due to its anticonvulsive properties. Nevertheless, rare case reports of the pro-convulsant effects of propofol [1–6] emphasize the need for the exploration of seizure characteristics caused by propofol. Conflict of Interest No potential conflict of interest relevant to this article was reported. Author Contributions Abhyuday Kumar (Conceptualization; Validation; Visualization; Writing – original draft) Amarjeet Kumar (Validation; Visualization; Writing – review & editing) Neeraj Kumar (Validation; Visualization; Writing – review & editing) Ajeet Kumar (Supervision; Visualization; Writing – review & editing)

FENTANYL, PROPOFOL, VECURONIUM BROMIDE

DrugsGivenReaction

CC BY-NC

32388939

2021-02

What is the weight of the patient?

Intraoperative refractory status epilepticus caused by propofol -a case report. Status epilepticus, when continued despite the administration of two antiepileptic drugs, is called refractory status epilepticus (RSE). The seizure-like phenomenon due to propofol is widely reported in the literature. However, RSE caused by propofol is rare and is a diagnostic dilemma. A 44-year-old male patient presented with RSE during the intraoperative period and was under general anesthesia on propofol infusion. The seizure was resistant to benzodiazepines and phenytoin. Thereafter, the seizure subsided after the discontinuation of propofol infusion, and the patient was shifted to fentanyl and dexmedetomidine infusion for the maintenance of anesthesia. The postoperative follow-up was uneventful. This article focuses on the management of intractable intraoperative seizure and highlights the need for the exploration of seizure characteristics caused by propofol. Propofol is the most popular drug used for the induction and maintenance of anesthesia, but causes excitatory activities, such as myoclonus, opisthotonus, and rarely, generalized seizures [1]. Prolonged non-resolving seizure activity is termed status epilepticus (SE) and is a medical emergency with significant associated morbidity and mortality. Pharmacological management is done with benzodiazepines and antiepileptic drugs, along with prompt resuscitation and source control. SE, when continued despite the administration of two antiepileptic drugs, is called refractory status epilepticus (RSE). The management of RSE includes the induction of general anesthesia with propofol, thiopentone, midazolam, or ketamine. However, management becomes intricate when RSE is caused by propofol. We report here a case of intraoperative RSE caused by propofol. The patient has provided written informed consent for publication of this case report. This manuscript adheres to the applicable Enhancing the Quality and Transparency Of health Research (EQUATOR) guideline. Case Report A 44-year-old male patient (weight 60 kg) was posted for C2–C5 astrocytoma excision under general anesthesia. The surgery was performed at All India Institute of Medical Sciences Patna, India in 2019. The patient did not have any coexisting disease or history of seizure. Anesthesia was induced with injection of propofol, fentanyl, and vecuronium followed by tracheal intubation. The propofol infusion at a rate of 75–100 μg/kg/min was started for the maintenance of anesthesia as motor and somatosensory evoked potential monitoring was planned for the patient. The bispectral index (BIS), invasive blood pressure, and central venous pressure were also monitored in addition to standard monitoring. Furthermore, the patient was made prone for surgery. Thirty minutes after the start of propofol infusion, as the surgeon was dissecting the superficial muscular layers after skin incision, the patient developed generalized tonic–clonic seizure (GTCS) involving all four limbs and truncal muscles. A sudden increase in blood pressure, heart rate, end tidal CO2, and BIS were also noted. The injection of 2 mg midazolam was then immediately given intravenously (IV). Although the intensity of seizure decreased, GTCS continued, for which a repeat dose of midazolam was given, but in vain. As the seizure was not controlled, a loading dose of 15 mg/kg phenytoin was given IV over 20 minutes. Nonetheless, the seizure continued with a seizure-free interval of 5 minutes. The injection of 250 mg thiopentone was then administered IV as a last resort for treating SE, which successfully aborted the episode for approximately 20 minutes, only to reappear again. Meanwhile, investigations such as electrolytes and arterial blood gases (ABG) were done to rule out aggravating factors. ABG indicated metabolic acidosis with hyperlactatemia, and electrolytes were within the normal range. A provisional diagnosis of propofol-induced seizure was made, and propofol infusion was discontinued. Anesthesia was then maintained on fentanyl, dexmedetomidine infusion and isoflurane to maintain a minimum alveolar concentration of 0.5–0.8, and surgery was allowed to proceed. The rest of the intraoperative and postoperative periods were uneventful, and the postoperative computerized tomography of the brain and electroencephalogram were within normal limits. The patient was symptom-free after three months of follow-up. Discussion Propofol is widely used as an induction agent for general anesthesia, and its common side effects are hypotension, respiratory depression, and local intravascular pain at the injection site. Neurological complications caused by propofol are widely reported and include GTCS, focal motor seizures, increased tone with twitching and rhythmic movements, opisthotonus and involuntary movements, collectively termed as seizure-like phenomenon (SLP). The mechanism of SLP due to propofol is mostly unknown, but potentially due to the imbalance between the activity of excitatory and inhibitory neurons in the GABA pathway [2]. Propofol-induced SLP does not have any fixed pattern of occurrence with respect to timing, duration, clinical presentation, age group, and the health of the patient involved [1]. In addition, no clear consensus exists regarding the prevention and management of such adverse events. Walder et al. [1], in a systemic review, analyzed 81 cases of SLP of which one of the principal findings was the predominance of SLP during induction, emergence, or delay after anesthesia and sedation. Only two cases of its occurrence arose during maintenance [3,4]. The lower incidence of SLP during maintenance of anesthesia resulted from masking by neuromuscular blockage (NMB), a steady state level of propofol concentration, and less cerebral excitation [1]. Our case was unique as it occurred during the maintenance phase and was presented as SE, which was refractory to treatment by two antiepileptic drugs. Only a few reported cases of propofol-induced SE have been available, most of which emerged in the postoperative period. Additionally, a report from Japan stated that prolonged GTCS was initiated 10 minutes after propofol infusion after the brachial plexus block [5]. One case of propofol-induced RSE during general anesthesia has also been reported in a patient with benign epilepsy with centrotemporal spikes, which lasted for 14 hours [6]. RSE is a condition where SE continues despite the administration of two antiepileptic drugs (e.g., benzodiazepines and phenytoin) and is associated with a high risk of complications. Complications of RSE include excitotoxic CNS injury, hyperthermia, pulmonary edema, arrhythmias, cardiovascular collapse, metabolic derangement, acute kidney and liver injury, rhabdomyolysis, and fractures [7]. Moreover, RSE has a high-mortality rate, and less than one-third of patients return to their premorbid level of functioning [8]. Seizures in the intraoperative period are difficult to diagnose when NMB is used, but suggestive signs include tachycardia, hypertension, increased end tidal CO2, pupillary dilatation, increased oxygen consumption, and increased muscle tone [7]. Management includes the administration of antiepileptic drugs and the correction of precipitant factors. In our case, the seizure was apparent because we did not use NMB in the maintenance of anesthesia. The treatment of RSE includes administering general anesthesia with propofol, thiopentone, midazolam, or ketamine. However, our patient was already on high-dose propofol infusion when he developed RSE. As no precipitating factors were found, we opted to discontinue propofol and started dexmedetomidine and fentanyl for the maintenance of anesthesia, which stopped the seizure episodes. Apart from being used as an induction agent for general anesthesia, propofol is also widely utilized in the treatment of seizure due to its anticonvulsive properties. Nevertheless, rare case reports of the pro-convulsant effects of propofol [1–6] emphasize the need for the exploration of seizure characteristics caused by propofol. Conflict of Interest No potential conflict of interest relevant to this article was reported. Author Contributions Abhyuday Kumar (Conceptualization; Validation; Visualization; Writing – original draft) Amarjeet Kumar (Validation; Visualization; Writing – review & editing) Neeraj Kumar (Validation; Visualization; Writing – review & editing) Ajeet Kumar (Supervision; Visualization; Writing – review & editing)

60 kg.

Weight

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32388939

2021-02

What was the dosage of drug 'PROPOFOL'?

Intraoperative refractory status epilepticus caused by propofol -a case report. Status epilepticus, when continued despite the administration of two antiepileptic drugs, is called refractory status epilepticus (RSE). The seizure-like phenomenon due to propofol is widely reported in the literature. However, RSE caused by propofol is rare and is a diagnostic dilemma. A 44-year-old male patient presented with RSE during the intraoperative period and was under general anesthesia on propofol infusion. The seizure was resistant to benzodiazepines and phenytoin. Thereafter, the seizure subsided after the discontinuation of propofol infusion, and the patient was shifted to fentanyl and dexmedetomidine infusion for the maintenance of anesthesia. The postoperative follow-up was uneventful. This article focuses on the management of intractable intraoperative seizure and highlights the need for the exploration of seizure characteristics caused by propofol. Propofol is the most popular drug used for the induction and maintenance of anesthesia, but causes excitatory activities, such as myoclonus, opisthotonus, and rarely, generalized seizures [1]. Prolonged non-resolving seizure activity is termed status epilepticus (SE) and is a medical emergency with significant associated morbidity and mortality. Pharmacological management is done with benzodiazepines and antiepileptic drugs, along with prompt resuscitation and source control. SE, when continued despite the administration of two antiepileptic drugs, is called refractory status epilepticus (RSE). The management of RSE includes the induction of general anesthesia with propofol, thiopentone, midazolam, or ketamine. However, management becomes intricate when RSE is caused by propofol. We report here a case of intraoperative RSE caused by propofol. The patient has provided written informed consent for publication of this case report. This manuscript adheres to the applicable Enhancing the Quality and Transparency Of health Research (EQUATOR) guideline. Case Report A 44-year-old male patient (weight 60 kg) was posted for C2–C5 astrocytoma excision under general anesthesia. The surgery was performed at All India Institute of Medical Sciences Patna, India in 2019. The patient did not have any coexisting disease or history of seizure. Anesthesia was induced with injection of propofol, fentanyl, and vecuronium followed by tracheal intubation. The propofol infusion at a rate of 75–100 μg/kg/min was started for the maintenance of anesthesia as motor and somatosensory evoked potential monitoring was planned for the patient. The bispectral index (BIS), invasive blood pressure, and central venous pressure were also monitored in addition to standard monitoring. Furthermore, the patient was made prone for surgery. Thirty minutes after the start of propofol infusion, as the surgeon was dissecting the superficial muscular layers after skin incision, the patient developed generalized tonic–clonic seizure (GTCS) involving all four limbs and truncal muscles. A sudden increase in blood pressure, heart rate, end tidal CO2, and BIS were also noted. The injection of 2 mg midazolam was then immediately given intravenously (IV). Although the intensity of seizure decreased, GTCS continued, for which a repeat dose of midazolam was given, but in vain. As the seizure was not controlled, a loading dose of 15 mg/kg phenytoin was given IV over 20 minutes. Nonetheless, the seizure continued with a seizure-free interval of 5 minutes. The injection of 250 mg thiopentone was then administered IV as a last resort for treating SE, which successfully aborted the episode for approximately 20 minutes, only to reappear again. Meanwhile, investigations such as electrolytes and arterial blood gases (ABG) were done to rule out aggravating factors. ABG indicated metabolic acidosis with hyperlactatemia, and electrolytes were within the normal range. A provisional diagnosis of propofol-induced seizure was made, and propofol infusion was discontinued. Anesthesia was then maintained on fentanyl, dexmedetomidine infusion and isoflurane to maintain a minimum alveolar concentration of 0.5–0.8, and surgery was allowed to proceed. The rest of the intraoperative and postoperative periods were uneventful, and the postoperative computerized tomography of the brain and electroencephalogram were within normal limits. The patient was symptom-free after three months of follow-up. Discussion Propofol is widely used as an induction agent for general anesthesia, and its common side effects are hypotension, respiratory depression, and local intravascular pain at the injection site. Neurological complications caused by propofol are widely reported and include GTCS, focal motor seizures, increased tone with twitching and rhythmic movements, opisthotonus and involuntary movements, collectively termed as seizure-like phenomenon (SLP). The mechanism of SLP due to propofol is mostly unknown, but potentially due to the imbalance between the activity of excitatory and inhibitory neurons in the GABA pathway [2]. Propofol-induced SLP does not have any fixed pattern of occurrence with respect to timing, duration, clinical presentation, age group, and the health of the patient involved [1]. In addition, no clear consensus exists regarding the prevention and management of such adverse events. Walder et al. [1], in a systemic review, analyzed 81 cases of SLP of which one of the principal findings was the predominance of SLP during induction, emergence, or delay after anesthesia and sedation. Only two cases of its occurrence arose during maintenance [3,4]. The lower incidence of SLP during maintenance of anesthesia resulted from masking by neuromuscular blockage (NMB), a steady state level of propofol concentration, and less cerebral excitation [1]. Our case was unique as it occurred during the maintenance phase and was presented as SE, which was refractory to treatment by two antiepileptic drugs. Only a few reported cases of propofol-induced SE have been available, most of which emerged in the postoperative period. Additionally, a report from Japan stated that prolonged GTCS was initiated 10 minutes after propofol infusion after the brachial plexus block [5]. One case of propofol-induced RSE during general anesthesia has also been reported in a patient with benign epilepsy with centrotemporal spikes, which lasted for 14 hours [6]. RSE is a condition where SE continues despite the administration of two antiepileptic drugs (e.g., benzodiazepines and phenytoin) and is associated with a high risk of complications. Complications of RSE include excitotoxic CNS injury, hyperthermia, pulmonary edema, arrhythmias, cardiovascular collapse, metabolic derangement, acute kidney and liver injury, rhabdomyolysis, and fractures [7]. Moreover, RSE has a high-mortality rate, and less than one-third of patients return to their premorbid level of functioning [8]. Seizures in the intraoperative period are difficult to diagnose when NMB is used, but suggestive signs include tachycardia, hypertension, increased end tidal CO2, pupillary dilatation, increased oxygen consumption, and increased muscle tone [7]. Management includes the administration of antiepileptic drugs and the correction of precipitant factors. In our case, the seizure was apparent because we did not use NMB in the maintenance of anesthesia. The treatment of RSE includes administering general anesthesia with propofol, thiopentone, midazolam, or ketamine. However, our patient was already on high-dose propofol infusion when he developed RSE. As no precipitating factors were found, we opted to discontinue propofol and started dexmedetomidine and fentanyl for the maintenance of anesthesia, which stopped the seizure episodes. Apart from being used as an induction agent for general anesthesia, propofol is also widely utilized in the treatment of seizure due to its anticonvulsive properties. Nevertheless, rare case reports of the pro-convulsant effects of propofol [1–6] emphasize the need for the exploration of seizure characteristics caused by propofol. Conflict of Interest No potential conflict of interest relevant to this article was reported. Author Contributions Abhyuday Kumar (Conceptualization; Validation; Visualization; Writing – original draft) Amarjeet Kumar (Validation; Visualization; Writing – review & editing) Neeraj Kumar (Validation; Visualization; Writing – review & editing) Ajeet Kumar (Supervision; Visualization; Writing – review & editing)

75?100 MCG/KG/MIN

DrugDosageText

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32388939

2021-02

What was the outcome of reaction 'Status epilepticus'?

Intraoperative refractory status epilepticus caused by propofol -a case report. Status epilepticus, when continued despite the administration of two antiepileptic drugs, is called refractory status epilepticus (RSE). The seizure-like phenomenon due to propofol is widely reported in the literature. However, RSE caused by propofol is rare and is a diagnostic dilemma. A 44-year-old male patient presented with RSE during the intraoperative period and was under general anesthesia on propofol infusion. The seizure was resistant to benzodiazepines and phenytoin. Thereafter, the seizure subsided after the discontinuation of propofol infusion, and the patient was shifted to fentanyl and dexmedetomidine infusion for the maintenance of anesthesia. The postoperative follow-up was uneventful. This article focuses on the management of intractable intraoperative seizure and highlights the need for the exploration of seizure characteristics caused by propofol. Propofol is the most popular drug used for the induction and maintenance of anesthesia, but causes excitatory activities, such as myoclonus, opisthotonus, and rarely, generalized seizures [1]. Prolonged non-resolving seizure activity is termed status epilepticus (SE) and is a medical emergency with significant associated morbidity and mortality. Pharmacological management is done with benzodiazepines and antiepileptic drugs, along with prompt resuscitation and source control. SE, when continued despite the administration of two antiepileptic drugs, is called refractory status epilepticus (RSE). The management of RSE includes the induction of general anesthesia with propofol, thiopentone, midazolam, or ketamine. However, management becomes intricate when RSE is caused by propofol. We report here a case of intraoperative RSE caused by propofol. The patient has provided written informed consent for publication of this case report. This manuscript adheres to the applicable Enhancing the Quality and Transparency Of health Research (EQUATOR) guideline. Case Report A 44-year-old male patient (weight 60 kg) was posted for C2–C5 astrocytoma excision under general anesthesia. The surgery was performed at All India Institute of Medical Sciences Patna, India in 2019. The patient did not have any coexisting disease or history of seizure. Anesthesia was induced with injection of propofol, fentanyl, and vecuronium followed by tracheal intubation. The propofol infusion at a rate of 75–100 μg/kg/min was started for the maintenance of anesthesia as motor and somatosensory evoked potential monitoring was planned for the patient. The bispectral index (BIS), invasive blood pressure, and central venous pressure were also monitored in addition to standard monitoring. Furthermore, the patient was made prone for surgery. Thirty minutes after the start of propofol infusion, as the surgeon was dissecting the superficial muscular layers after skin incision, the patient developed generalized tonic–clonic seizure (GTCS) involving all four limbs and truncal muscles. A sudden increase in blood pressure, heart rate, end tidal CO2, and BIS were also noted. The injection of 2 mg midazolam was then immediately given intravenously (IV). Although the intensity of seizure decreased, GTCS continued, for which a repeat dose of midazolam was given, but in vain. As the seizure was not controlled, a loading dose of 15 mg/kg phenytoin was given IV over 20 minutes. Nonetheless, the seizure continued with a seizure-free interval of 5 minutes. The injection of 250 mg thiopentone was then administered IV as a last resort for treating SE, which successfully aborted the episode for approximately 20 minutes, only to reappear again. Meanwhile, investigations such as electrolytes and arterial blood gases (ABG) were done to rule out aggravating factors. ABG indicated metabolic acidosis with hyperlactatemia, and electrolytes were within the normal range. A provisional diagnosis of propofol-induced seizure was made, and propofol infusion was discontinued. Anesthesia was then maintained on fentanyl, dexmedetomidine infusion and isoflurane to maintain a minimum alveolar concentration of 0.5–0.8, and surgery was allowed to proceed. The rest of the intraoperative and postoperative periods were uneventful, and the postoperative computerized tomography of the brain and electroencephalogram were within normal limits. The patient was symptom-free after three months of follow-up. Discussion Propofol is widely used as an induction agent for general anesthesia, and its common side effects are hypotension, respiratory depression, and local intravascular pain at the injection site. Neurological complications caused by propofol are widely reported and include GTCS, focal motor seizures, increased tone with twitching and rhythmic movements, opisthotonus and involuntary movements, collectively termed as seizure-like phenomenon (SLP). The mechanism of SLP due to propofol is mostly unknown, but potentially due to the imbalance between the activity of excitatory and inhibitory neurons in the GABA pathway [2]. Propofol-induced SLP does not have any fixed pattern of occurrence with respect to timing, duration, clinical presentation, age group, and the health of the patient involved [1]. In addition, no clear consensus exists regarding the prevention and management of such adverse events. Walder et al. [1], in a systemic review, analyzed 81 cases of SLP of which one of the principal findings was the predominance of SLP during induction, emergence, or delay after anesthesia and sedation. Only two cases of its occurrence arose during maintenance [3,4]. The lower incidence of SLP during maintenance of anesthesia resulted from masking by neuromuscular blockage (NMB), a steady state level of propofol concentration, and less cerebral excitation [1]. Our case was unique as it occurred during the maintenance phase and was presented as SE, which was refractory to treatment by two antiepileptic drugs. Only a few reported cases of propofol-induced SE have been available, most of which emerged in the postoperative period. Additionally, a report from Japan stated that prolonged GTCS was initiated 10 minutes after propofol infusion after the brachial plexus block [5]. One case of propofol-induced RSE during general anesthesia has also been reported in a patient with benign epilepsy with centrotemporal spikes, which lasted for 14 hours [6]. RSE is a condition where SE continues despite the administration of two antiepileptic drugs (e.g., benzodiazepines and phenytoin) and is associated with a high risk of complications. Complications of RSE include excitotoxic CNS injury, hyperthermia, pulmonary edema, arrhythmias, cardiovascular collapse, metabolic derangement, acute kidney and liver injury, rhabdomyolysis, and fractures [7]. Moreover, RSE has a high-mortality rate, and less than one-third of patients return to their premorbid level of functioning [8]. Seizures in the intraoperative period are difficult to diagnose when NMB is used, but suggestive signs include tachycardia, hypertension, increased end tidal CO2, pupillary dilatation, increased oxygen consumption, and increased muscle tone [7]. Management includes the administration of antiepileptic drugs and the correction of precipitant factors. In our case, the seizure was apparent because we did not use NMB in the maintenance of anesthesia. The treatment of RSE includes administering general anesthesia with propofol, thiopentone, midazolam, or ketamine. However, our patient was already on high-dose propofol infusion when he developed RSE. As no precipitating factors were found, we opted to discontinue propofol and started dexmedetomidine and fentanyl for the maintenance of anesthesia, which stopped the seizure episodes. Apart from being used as an induction agent for general anesthesia, propofol is also widely utilized in the treatment of seizure due to its anticonvulsive properties. Nevertheless, rare case reports of the pro-convulsant effects of propofol [1–6] emphasize the need for the exploration of seizure characteristics caused by propofol. Conflict of Interest No potential conflict of interest relevant to this article was reported. Author Contributions Abhyuday Kumar (Conceptualization; Validation; Visualization; Writing – original draft) Amarjeet Kumar (Validation; Visualization; Writing – review & editing) Neeraj Kumar (Validation; Visualization; Writing – review & editing) Ajeet Kumar (Supervision; Visualization; Writing – review & editing)

Recovered

ReactionOutcome

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32388939

2021-02

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiomyopathy'.

Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas. We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850). Introduction Brentuximab vedotin (BV) is an immunoconjugate consisting of a CD30-directed antibody linked to the anti-microtubule agent auristatin.1 BV is highly active in relapsed and refractory (r/r) classical Hodgkin lymphoma and in CD30-expressing T-cell lymphomas.2,3 In the frontline setting, BV combined with chemotherapy has been recently approved for advanced classical Hodgkin lymphoma and CD30-positive (CD30+) T-cell lymphomas based on results of randomized trials showing benefit of the BV-containing arms.4,5 BV targets the cell membrane protein CD30 that is expressed not only by classical Hodgkin lymphoma and some T-cell lymphomas, but at various frequencies also by B-cell non-Hodgkin lymphomas including up to 80% of primary mediastinal B-cell lymphomas (PMBCL).6-9 PMBCL is a mature large B-cell lymphoma of thymic origin which usually presents with mediastinal masses. It occurs predominantly in young adults and represents about 5% of aggressive B-cell lymphomas.10 While previous classifications considered it as a subtype of diffuse large B-cell lymphoma (DLBCL), PMBCL is now thought of as a distinct clinicopathological entity with clinical features and also a molecular signature that share similarities with those of classical Hodgkin lymphoma.11 Recent efforts using gene expression profiling have aimed at better defining PMBCL at the molecular level and distinguishing it from other aggressive B-cell lymphomas with mediastinal presentation. In particular, the NanoString© based Lymph3Cx assay measures expression of 58 genes and allows precise identification of PMBCL cases.12 Presently, the optimal frontline management of patients with PMBCL remains controversial. Traditionally, PMBCL was included in clinical trials regarding aggressive B-cell lymphomas and regimens designed for DLBCL were found to be effective.13-17 Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) results in event-free survival rates of about 80% when followed by consolidative radiation therapy.14,16 In 2013, in a phase II trial by Dunleavy et al. including 51 PMBCL patients treated at the National Cancer Institute, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, plus rituximab (DA-EPOCH-R) without radiotherapy achieved an event-free survival of 93%.15 Many centers in the USA now use this dose-intense DA-EPOCH-R approach for frontline treatment of all PMBCL patients without considering any risk stratification. 15 Some patients with r/r PMBCL, can be salvaged by high-dose chemotherapy with autologous stem cell transplant or radiation, but outcomes tend to be poor.18,19 Recently, pembrolizumab and axicabtagene ciloleucel were approved for the treatment of r/r PMBCL.20-22 While the activity of BV as monotherapy in r/r PMBCL has been disappointing, results of a phase II trial using nivolumab in combination with BV are very encouraging.23,24 To test the tolerability and make a preliminary assessment of the efficacy of BV in frontline treatment of B-cell lymphomas, we designed a phase I/II trial using BV in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of CD30+ PMBCL, DLBCL, and gray zone lymphoma (GZL) in adult patients (ClinicalTrials.gov identifier: NCT01994850). Methods Study design and patient eligibility This multicenter, single arm, phase I/II study enrolled patients aged 18 years and over with untreated histologically confirmed CD30+ PMBCL, DLBCL, or GZL. Patients with any stage, measurable disease, and an Eastern Cooperative Oncology Group Performance Status of 3 or less were eligible. The diagnostic biopsy had to demonstrate at least 1% or higher expression of CD30 on the lymphoma B cells by immunohistochemistry and was assessed independently by two pathologists. Patients with active central nervous system involvement and uncontrolled systemic infections were excluded. Enrollment began in January 2014 and was completed in April 2017. The primary objective of the phase I portion was to determine the safety of the combination and the maximum tolerated dose of BV in combination with R-CHP using a de-escalation design. The primary objective of the phase II portion was the overall response rate at the end of systemic treatment as determined by investigator assessment using International Working Group response criteria for non-Hodgkin lymphoma.25 Secondary endpoints were 2-year progression-free survival and 2- year overall survival for all patients and by each lymphoma subtype (PMBCL, DLBCL, and GZL). With regard to the toxicity assessment, the study had 90% power to detect any unforeseen toxicity that occurred in 7% or more of patients. The number of patients required for the trial was determined based on the following assumptions for an optimal two-stage design in order to detect and minimize enrollment if the overall response rate was not greater than 50% but also to minimize the likelihood of failing to reject the null hypothesis if the overall response rate was at least 70%. Sample size calculations for the stopping rules were based upon a type I error rate of 10% and type II error rate of 20%. The number of subjects enrolled and evaluable in the phase I cohort was defined as at least six and a maximum of 12. For the phase II cohort, using the null hypothesis of a 50% overall response rate, the study required a sample size of 20 patients. Since the phase I subjects were recruited, treated, and followed in the same way as the phase II subjects, the phase I subjects accrued at the phase II dose were included in the efficacy analysis. Table 1. The study regimen: brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BV-R-CHP). The study was conducted in three academic centers in the USA and was run in accordance with the Declaration of Helsinki. Approval from the institutional review board of each center was obtained before initiating the study at each site. All patients signed a written informed consent form before enrollment into the trial. Treatment protocol and response assessment As shown in Table 1, the study treatment protocol consisted of six cycles of BV administered with the R-CHOP regimen without vincristine, including: rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 on day 1 and prednisone 100 mg (or equivalent) daily on days 1 through 5 of each 21-day cycle. For cycle 1, rituximab was split into two doses (100 mg/m2 on day 1 and 275 mg/m2 on day 2) to reduce risks of an infusion reaction to rituximab. We also aimed to separate the initial rituximab infusion from the first exposure to BV to avoid any potential confusion about attribution of infusion reactions. The rest of the agents were given on day 2 (cyclophosphamide, doxorubicin, BV). In cycles 2 through 6, rituximab was administered at a dose of 375 mg/m2 on day 1 together with the rest of the agents. For phase I, the starting dose of BV was 1.8 mg/kg (maximum dose of 180 mg) with a 3+3 de-escalation design to 1.2 mg/kg (maximum dose of 120 mg) should dose-limiting toxicities occur during the first 21-day cycle. A dose-limiting toxicity was defined as any grade 3 or 4 non-hematologic toxicity requiring a dose delay over 14 days from the planned day 1 of cycle 2 or any hematologic toxicity not returning to baseline or ≤ grade 2 by 21 days from the planned day 1 of cycle 2. By protocol, at least six patients had to be enrolled and complete one cycle of dosing at the final recommended BV dose in phase I prior to beginning enrollment of patient in phase II. Dose modifications during cycle 2 through 6 for treatment-associated toxicity were specified in the protocol and based on the grade using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The use of granulocyte-colony stimulating factor (G-CSF) was allowed as per institutional policy. Consolidative radiation therapy was permitted after completion of all systemic therapy and only after end-of-treatment imaging at the discretion of the treating physician. Figure 1. CONSORT diagram. GZL: gray zone lymphoma; cHL: classical Hodgkin lymphoma; EOT: end of treatment. Table 2. Patients’ characteristics. Treatment response was assessed by imaging with fluorodeoxyglucose- positron emission tomography/computed tomography (FDG-PET/CT) using the revised response criteria for malignant lymphoma described by Cheson et al.25 Computed tomography scans were performed after cycles 2 and 4 to monitor for interim response. End-of-treatment imaging was performed 3-5 weeks after completion of systemic therapy using FDG-PET/CT. Consolidative radiation following end-of-treatment response assessment was permissible at the discretion of the treating physician. Correlative studies CD30 expression was determined on the diagnostic tissue biopsies using immunohistochemistry though visual inspection by two independent pathologists. The gene expression analysis (Lymph3Cx) was performed on archival formalin-fixed, paraffinembedded tissue from pre-treatment biopsies. The tissue was examined by a hematopathologist for adequate tumor amount and nucleic acids were extracted from formalin-fixed paraffinembedded scrolls or unstained slides. The Lymph3Cx assay was previously described and validated to aid in the molecular distinction of PMBCL versus DLBCL.26 The gene expression assay on the diagnostic tissue was performed in a blinded fashion, and once the assignment of diagnosis by Lymph3Cx was made, a correlation with investigator-based diagnosis (PMBCL vs. DLBCL vs. GZL) was performed. Statistical analysis The overall response rate and complete response rate with a two-sided 95% exact confidence intervals (95% CI) were calculated using the Clopper-Pearson method. Two-year progression-free and overall survival rates were estimated using the Kaplan-Meier method. The median follow-up was estimated by the reverse Kaplan-Meier method.27 The data cut-off for analysis was January 1, 2019. Results Patients’ characteristics Thirty-three patients gave consent to enrollment in the trial (Figure 1). One of these patients was subsequently reclassified from having GZL to having classical Hodgkin lymphoma and was taken off the study before starting therapy. Thus, 32 patients were enrolled and received at least one cycle of therapy. One patient withdrew from the study after cycle 1 to receive R-CHOP therapy closer to home. The characteristics of the patients evaluable for toxicity (n=31) are presented in Table 2. The median age was 37 years (range, 18-76), 50% of the patients were female, 42% had stage III/IV disease and 17% were classified in high-intermediate or high International Prognostic Index (IPI) risk group.28 Using traditional clinicopathological criteria, 23 patients had a diagnosis of PMBCL, six were diagnosed as having DLBCL, and two as having GZL. For the PMBCL cohort, 91% of patients had large mediastinal masses over 7.5 cm in maximal transverse diameter and 35% had stage III/IV disease. Two patients were removed from the study (1 patient because of non-compliance and 1 in complete remission because of a regimen violation). Therefore, a total of 29 patients were evaluable for efficacy. Of those, 15 patients (52%) received consolidative radiation after completing BV-RCHP and final end-of-treatment response assessment. This number included 13 (59%) of 22 evaluable PMBCL patients. Of those, 8 patients received radiation using protons. Twenty-six patients had archival formalin-fixed paraffin-embedded diagnostic tissue available for Lymph3Cx gene expression analysis. Safety and feasibility Toxicities of this outpatient regimen are listed in Table 3A and B. There were no treatment-related or on-study deaths. Using a de-escalation design during the phase I portion of the trial, the first six patients were treated with the initial dose of 1.8 mg/kg (maximum 180 mg) in combination with standard dose R-CHP with plans to reduce BV to 1.2 mg/kg (maximum 120 mg) should there be dose-limiting toxicities. As there were no dose-limiting toxicities during phase I, the BV dose of 1.8 mg/kg (maximum 180 mg) was used as the phase II dose. Overall in all patients (combining phase I and phase II cohorts), any grade 3 or 4 toxicity occurred in 84% of study patients. Hematologic adverse events of any grade were recorded in the majority of patients and in 77% of patients with grade 3 or 4 toxicities. Of note, 16% of patients received no G-CSF and 6% had G-CSF support for only one or two of the six cycles. Non-hematologic grade 3 and 4 toxicities were seen in 32% of patients, including infections in 15% of patients (Table 3B). Toxicities occurring in over 10% of patients included peripheral sensory neuropathy in 19 patients (61%) which were either grade 1 (48%) or grade 2 (13%) (Table 3A). Three patients (10%) reported motor neuropathy, two with grade 1 (6%) and one with grade 2 (3%). One patient discontinued protocol treatment after cycle 4 because of sepsis and grade 3 cardiomyopathy. One patient discontinued BV after cycle 5 because of transient grade 2 pneumonitis which was deemed at least possibly related to BV. Only three patients required BV dose reductions to 1.2 mg/kg because of persistent grade 2 peripheral sensory neuropathy outside of the period of dose-limiting toxicities. In total, two patients enrolled on the study died in the follow- up period. One PMBCL patient developed acute myeloid leukemia 2 years after completion of study treatment and mediastinal radiation therapy and ultimately died of acute myeloid leukemia 39 months after completing study treatment. One patient died of progressive lymphoma 40 months after completing study treatment. Thromboembolic events were noted in eight patients (36%) in the PMBCL cohort. Pulmonary embolism was seen in three patients and upper extremity deep vein thrombosis in five patients. Of those, three events were diagnosed prior to initiating BV-R-CHP and five events were diagnosed while patients were on study treatment. Three of the five patients who had on-treatment events were asymptomatic and thrombosis was reported as an incidental finding on their first computed tomography with intravenous contrast (1 with pulmonary embolism and 1 with internal jugular vein thrombosis). Two of the five patients with on-treatment events had line-associated thromboses. Table 3A All adverse events at least possibly related to the BV-R-CHP regimen. Table 3B Grade 3 or 4 adverse events at least possibly related to the BV-R-CHP regimen. Efficacy In the combined phase I/II cohort with 29 evaluable patients, the overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving a complete response and 14% (95% CI: 4-32) achieving a partial response according to FDG-PET/CT imaging at the end of treatment. All four patients with a partial response had a diagnosis of PMBCL and had a low or low-intermediate IPI risk classification. Only two of the four patients with a partial response ultimately progressed. At a median follow-up of 30 months (95% CI: 26-46), four patients (14%) progressed: three with PMBCL and one with GZL. The 2-year progression-free survival rate was 85% (95% CI: 66-94) and the 2-year overall survival was 100% (Figure 2). Of three patients who were not evaluable per study criteria, two remain progression-free at last followup and the status of one patient is unknown. In the PMBCL cohort of 22 evaluable patients with a median follow-up of 30 months (95% CI: 23-46), the 2- year progression-free survival rate was 86% (95% CI: 62-95) with a 2-year overall survival of 100% (Figure 2). Of the three PMBCL patients who progressed, two had bulky advanced stage disease with expression of CD30 ≤10% and one had bulky stage I disease with CD30 expression of 1%. There was no statistically significant difference in progression-free survival between the PMBCL patients who received consolidative radiation therapy (n=13) and those who did not (n=9) (P=0.95). CD30 expression as determined by immunohistochemistry and response to therapy While all cases expressed CD30 in at least 1% of the lymphoma B cells in the tumor biopsy by immunohistochemistry, it was challenging to capture CD30 expression as a single metric since there was great heterogeneity of CD30 expression patterns, as depicted in Figure 3. Additionally, given the 100% overall response rate and low number of relapses, we could not make any conclusions about correlations between efficacy of the BV-containing regimen and CD30 expression as determined by immunohistochemistry. Gene expression analysis to improve diagnostic accuracy of primary mediastinal B-cell lymphoma Of 29 evaluable patients with CD30+ B-cell lymphoma, 26 had a pre-treatment biopsy available (11 excisional biopsies and 15 core needle biopsies). Of the 26 samples, five core needle biopsies did not have adequate tumor content or amounts of extractable RNA for the Lymph3Cx assay. The biopsies of the remaining 21 patients (11 excisional and 10 core needle biopsies) were tested. All three subtypes of CD30+ B-cell lymphomas as assessed by investigator assessment were tested in blinded fashion by the Lymph3Cx assay and comprised 14 cases of PMBCL, six of DLBCL, and one case of GZL. Of 14 patients with PMBCL by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9 which were consistent with a molecular diagnosis of PMBCL (mPMBCL) by gene expression; two patients scored in the indeterminate category (0.1 to 0.9); and one patient scored as having a molecular diagnosis of DLBCL (< 0.1) (Figure 4). None of the CD30+ B-cell lymphoma samples that were felt to be DLBCL by investigator assessment scored as having a molecular diagnosis of PMBCL by Lymph3Cx. Figure 2. Survival curves for patients who received the BV-R-CHP treatment regimen. (A, B) Progression-free survival (A) and overall survival (B) of all evaluable patients enrolled in the trial (n=29). (C, D) Progression-free survival (C) and overall survival (D) of evaluable patients with primary mediastinal B-cell lymphoma (PMBCL) (n=22). Figure 3. Examples of different CD30 staining patterns by immunohistochemistry in three representative patients with primary mediastinal B-cell lymphoma enrolled on the trial. (A) Heterogeneous staining pattern with strong and dim staining in different areas of the same tumor. (B) Focal staining in one area of the tumor. (C) Diffuse staining throughout the tumor. The antibodies used were CD20 (ready to use, DAKO) and CD30 (ready to use, Leica) and they were detected using a chromogenic substrate, diaminobenzene (Leica). An original magnification x200 was used for all images. H&E: hematoxylin & eosin. Discussion There is a strong rationale for replacing vincristine with BV in the standard R-CHOP regimen for the treatment of CD30+ aggressive B-cell lymphomas. BV specifically delivers the antimicrotubule agent auristatin to CD30-expressing cells, which could result in improved efficacy from BV and reduced toxicity due to the omission of vincristine. While BV displayed only limited clinical activity as monotherapy in aggressive r/r B-cell lymphomas, it has not been widely studied in the frontline setting or in combination with chemotherapy.24,29 In our phase I/II study, we showed that a frontline regimen using BV at a dose of 1.8 mg/kg in combination with R-CHP for patients with CD30+ B-cell lymphomas has an acceptable toxicity profile and is highly active. Our study included a heterogeneous group of B-cell lymphomas, but the majority of the patients had a clinicopathological diagnosis of PMBCL. For many reasons, this is a challenging population to study in a frontline setting. PMBCL is a rare and clinically heterogeneous lymphoma. Patients with this type of lymphoma often present with an acute onset of pulmonary symptoms necessitating urgent therapy which may lead to a selection bias in nonrandomized studies. While several frontline treatment approaches are effective in PMBCL, there are unique challenges in this population of patients. DA-EPOCH-R is a highly active dose-intense regimen, but it requires central venous access, use of growth factors, frequent blood testing, and inpatient admission at some institutions. RCHOP is easier to administer, but the excellent outcomes in PMBCL are achieved using consolidative radiation therapy, which may cause long-term toxicities.14,16,30,31 While a recently published phase III trial comparing R-CHOP versus DA-EPOCH-R in DLBCL included a small cohort of PMBCL cases (n=35), it was not statistically powered to detect the differences in this lymphoma subtype.17 We recognize that it is difficult to compare regimens across different trials, but outcomes within the PMBCL cohort in our study are comparable to previously published results for patients treated with R-CHOP with radiotherapy or dose-intense regimens such as DAEPOCH- R.14-16,19,30,32 For lymphoma subtypes other than PMBCL, the numbers of patients were too small to make any efficacy conclusions regarding BV-R-CHP. One of two patients with GZL relapsed after achieving a complete response and none of the five patients with CD30+ DLBCL relapsed, which is encouraging. Interestingly, preliminary results from another phase II trial (ClinicalTrial.gov identifier: NCT01925612) using BV-R-CHOP in DLBCL (without any requirement for CD30 staining) documented an overall response rate of 97% in the initial 30 evaluable patients. None of the CD30+ DLBCL patients in the preliminary report relapsed, but the median follow-up of 5 months was short.33 Regarding toxicity of the BV-R-CHP regimen, there were no study-related deaths. With the caveats about cross-trial comparisons of studies, the rate of grade 3 or 4 hematologic and non-hematologic toxicities was similar or lower compared to the rates reported for R-CHOP.17,34 When compared to the DA-EPOCH-R arm from the recently published randomized trial in DLBCL, there appears to be less toxicity with BV-R-CHP in our study.17 However, one limitation of this comparison is the younger median age of patients in our cohort. Neuropathy is of particular concern with a BV-containing regimen and was closely monitored in our study. While peripheral sensory neuropathy was reported in 61% of patients, no patient experienced grade 3 or 4 neuropathy. This lack of severe peripheral neuropathy may again relate to the young age of our patients and the fact that our BV-containing regimen did not contain additional vinca alkaloids, in contrast to some of the other BV-containing combinations used frontline.4,33 There were no unexpected opportunistic infections using the combination of rituximab and BV. The administration of G-CSF was not consistent across the participating institutions in our study, but over 20% of patients did not require G-CSF at all or its use was limited to one or two cycles. However, considering that 23% of patients experienced febrile neutropenia, empiric use of G-CSF should be considered in patients being treated with BV-R-CHP. With regard to long-term toxicities, one patient developed acute myeloid leukemia 2 years after completing the trial therapy and radiation. It is not possible to determine the association between the protocol treatment and her leukemia, but the fact that the patient’s mother died of acute myeloid leukemia and the patient had normal cytogenetics (rare in secondary leukemias) is suggestive of other contributing factors. Figure 4. Correlation of Lymph3Cx results with standard clinicopathological diagnoses made by the investigators. DLBCL: diffuse large B-cell lymphoma; GZL: gray zone lymphoma; PMBCL: primary mediastinal B-cell lymphoma. Patients who progressed are labeled by an arrow. Of 14 patients with PMBCL diagnosed by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9, which were consistent with a molecular diagnosis of PMBCL by gene expression analysis, two patients (14%) scored in the indeterminate category (0.1 to 0.9), and one patient (7%) scored as having DLBCL (< 0.1). The high rate of thrombosis in the PMBCL cohort is of special interest. Thromboses were found in over one third of PMBCL patients and approximately 50% were diagnosed prior to initiation of therapy. This high risk of thrombosis in PMBCL patients was described with similar frequency in retrospective studies and is not likely to be related to BV-R-CHP.19,35 This finding warrants further investigations about screening, the potential contribution of central lines to thrombosis, and any possible role for prophylactic anticoagulation in PMBCL patients. We also attempted to define clinical and pathological factors which would correlate with outcomes of patients receiving BV-R-CHP therapy for CD30+ B-cell lymphomas. IPI risk group, which is well-established as a prognostic factor for outcomes of frontline treatments in DLBCL, did not clearly correlate with complete response rate, progression-free survival or overall survival in our study. This could be due to the small number of patients in the high or high-intermediate IPI risk category. Furthermore, the majority of our patients had PMBCL and the utility of the IPI has some limitations as most patients are young and present with limited stage disease. For our ancillary studies, we planned an analysis of CD30 expression by immunohistochemistry and correlation with outcomes as there is controversy over the impact of CD30 status on the efficacy of BV.33,36,37 However, this proved difficult because of the very low number of relapses and heterogeneity of CD30 staining patterns in neoplastic cells (Figure 3). Additional studies beyond a simple determination of the percentage of CD30+ cells by immunohistochemistry and visual assessment will need to be applied and other groups have attempted this with some success.37,38 Among 21 patients who had pre-treatment tissue analyzed by LymphC3x, we found that there was discordance between the protocol-specified standard clinicopathological diagnosis of PMBCL and the gene expression- based method. These findings are thought-provoking since, in small trials of PMBCL, even a few misclassified patients may have a great impact on interpretation of the results. We believe that developing objective diagnostic criteria based on quantitative methods, such as gene expression signatures, will be an important step in designing treatment strategies for B-cell lymphoma patients with mediastinal lesions and for comparing results across PMBCL trials. This trial is limited by the small number of evaluable patients and diagnostic heterogeneity. However, the entities included are rare, and we involved three institutions to enroll 32 patients. One of the challenges when interpreting the clinical efficacy and progression-free/overall survival data of patients treated with the BV-R-CHP regimen is the fact that consolidative radiation was used in about 50% of all patients enrolled on this trial. The protocol was designed in 2011-2012 when R-CHOP followed by consolidative radiation therapy was utilized by most centers for PMBCL patients. Therefore, the protocol allowed investigators to use consolidative radiotherapy after completion of BV-R-CHP. It is important to note that the end-of-treatment response assessment was performed before radiation. Interestingly, there were no statistically significant differences in progression-free or overall survival between patients who received consolidative radiation and those who did not. There were no clear differences in patients’ characteristics between those who received consolidative radiotherapy and those who did not other than institutional practice differences. Of the four patients who did not achieve metabolic complete response on end-of-treatment imaging, two received consolidative radiation therapy and two did not. Longer follow-up will be necessary to determine whether there are any long-term toxicities of radiation in the study participants (with the majority of patients having received proton radiation). Of note, an ongoing randomized trial in patients with PMBCL may allow us to determine whether consolidative radiation therapy after frontline chemoimmunotherapy is necessary in patients who achieve metabolic complete response after systemic treatment (ClinicalTrial.gov identifier: NCT01599559). BV in combination with R-CHP with or without consolidative radiation therapy is a feasible and active frontline treatment in patients with CD30+ B-cell lymphomas. The safety profile of this regimen, ease of administration and preliminary efficacy data appear promising. The next generation of trials in CD30+ B-cell lymphomas and PMBCL should take into consideration the clinical and biological heterogeneity of these lymphomas. Ultimately, developing treatment regimens that will be tailored to unique tumor and patient characteristics will result in improved outcomes and will minimize treatment-related toxicities.

BRENTUXIMAB VEDOTIN, CYCLOPHOSPHAMIDE, DOXORUBICIN, PREDNISONE, RITUXIMAB

DrugsGivenReaction

CC BY-NC

32414850

2021-06-01

Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sepsis'.

Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas. We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850). Introduction Brentuximab vedotin (BV) is an immunoconjugate consisting of a CD30-directed antibody linked to the anti-microtubule agent auristatin.1 BV is highly active in relapsed and refractory (r/r) classical Hodgkin lymphoma and in CD30-expressing T-cell lymphomas.2,3 In the frontline setting, BV combined with chemotherapy has been recently approved for advanced classical Hodgkin lymphoma and CD30-positive (CD30+) T-cell lymphomas based on results of randomized trials showing benefit of the BV-containing arms.4,5 BV targets the cell membrane protein CD30 that is expressed not only by classical Hodgkin lymphoma and some T-cell lymphomas, but at various frequencies also by B-cell non-Hodgkin lymphomas including up to 80% of primary mediastinal B-cell lymphomas (PMBCL).6-9 PMBCL is a mature large B-cell lymphoma of thymic origin which usually presents with mediastinal masses. It occurs predominantly in young adults and represents about 5% of aggressive B-cell lymphomas.10 While previous classifications considered it as a subtype of diffuse large B-cell lymphoma (DLBCL), PMBCL is now thought of as a distinct clinicopathological entity with clinical features and also a molecular signature that share similarities with those of classical Hodgkin lymphoma.11 Recent efforts using gene expression profiling have aimed at better defining PMBCL at the molecular level and distinguishing it from other aggressive B-cell lymphomas with mediastinal presentation. In particular, the NanoString© based Lymph3Cx assay measures expression of 58 genes and allows precise identification of PMBCL cases.12 Presently, the optimal frontline management of patients with PMBCL remains controversial. Traditionally, PMBCL was included in clinical trials regarding aggressive B-cell lymphomas and regimens designed for DLBCL were found to be effective.13-17 Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) results in event-free survival rates of about 80% when followed by consolidative radiation therapy.14,16 In 2013, in a phase II trial by Dunleavy et al. including 51 PMBCL patients treated at the National Cancer Institute, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, plus rituximab (DA-EPOCH-R) without radiotherapy achieved an event-free survival of 93%.15 Many centers in the USA now use this dose-intense DA-EPOCH-R approach for frontline treatment of all PMBCL patients without considering any risk stratification. 15 Some patients with r/r PMBCL, can be salvaged by high-dose chemotherapy with autologous stem cell transplant or radiation, but outcomes tend to be poor.18,19 Recently, pembrolizumab and axicabtagene ciloleucel were approved for the treatment of r/r PMBCL.20-22 While the activity of BV as monotherapy in r/r PMBCL has been disappointing, results of a phase II trial using nivolumab in combination with BV are very encouraging.23,24 To test the tolerability and make a preliminary assessment of the efficacy of BV in frontline treatment of B-cell lymphomas, we designed a phase I/II trial using BV in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of CD30+ PMBCL, DLBCL, and gray zone lymphoma (GZL) in adult patients (ClinicalTrials.gov identifier: NCT01994850). Methods Study design and patient eligibility This multicenter, single arm, phase I/II study enrolled patients aged 18 years and over with untreated histologically confirmed CD30+ PMBCL, DLBCL, or GZL. Patients with any stage, measurable disease, and an Eastern Cooperative Oncology Group Performance Status of 3 or less were eligible. The diagnostic biopsy had to demonstrate at least 1% or higher expression of CD30 on the lymphoma B cells by immunohistochemistry and was assessed independently by two pathologists. Patients with active central nervous system involvement and uncontrolled systemic infections were excluded. Enrollment began in January 2014 and was completed in April 2017. The primary objective of the phase I portion was to determine the safety of the combination and the maximum tolerated dose of BV in combination with R-CHP using a de-escalation design. The primary objective of the phase II portion was the overall response rate at the end of systemic treatment as determined by investigator assessment using International Working Group response criteria for non-Hodgkin lymphoma.25 Secondary endpoints were 2-year progression-free survival and 2- year overall survival for all patients and by each lymphoma subtype (PMBCL, DLBCL, and GZL). With regard to the toxicity assessment, the study had 90% power to detect any unforeseen toxicity that occurred in 7% or more of patients. The number of patients required for the trial was determined based on the following assumptions for an optimal two-stage design in order to detect and minimize enrollment if the overall response rate was not greater than 50% but also to minimize the likelihood of failing to reject the null hypothesis if the overall response rate was at least 70%. Sample size calculations for the stopping rules were based upon a type I error rate of 10% and type II error rate of 20%. The number of subjects enrolled and evaluable in the phase I cohort was defined as at least six and a maximum of 12. For the phase II cohort, using the null hypothesis of a 50% overall response rate, the study required a sample size of 20 patients. Since the phase I subjects were recruited, treated, and followed in the same way as the phase II subjects, the phase I subjects accrued at the phase II dose were included in the efficacy analysis. Table 1. The study regimen: brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BV-R-CHP). The study was conducted in three academic centers in the USA and was run in accordance with the Declaration of Helsinki. Approval from the institutional review board of each center was obtained before initiating the study at each site. All patients signed a written informed consent form before enrollment into the trial. Treatment protocol and response assessment As shown in Table 1, the study treatment protocol consisted of six cycles of BV administered with the R-CHOP regimen without vincristine, including: rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 on day 1 and prednisone 100 mg (or equivalent) daily on days 1 through 5 of each 21-day cycle. For cycle 1, rituximab was split into two doses (100 mg/m2 on day 1 and 275 mg/m2 on day 2) to reduce risks of an infusion reaction to rituximab. We also aimed to separate the initial rituximab infusion from the first exposure to BV to avoid any potential confusion about attribution of infusion reactions. The rest of the agents were given on day 2 (cyclophosphamide, doxorubicin, BV). In cycles 2 through 6, rituximab was administered at a dose of 375 mg/m2 on day 1 together with the rest of the agents. For phase I, the starting dose of BV was 1.8 mg/kg (maximum dose of 180 mg) with a 3+3 de-escalation design to 1.2 mg/kg (maximum dose of 120 mg) should dose-limiting toxicities occur during the first 21-day cycle. A dose-limiting toxicity was defined as any grade 3 or 4 non-hematologic toxicity requiring a dose delay over 14 days from the planned day 1 of cycle 2 or any hematologic toxicity not returning to baseline or ≤ grade 2 by 21 days from the planned day 1 of cycle 2. By protocol, at least six patients had to be enrolled and complete one cycle of dosing at the final recommended BV dose in phase I prior to beginning enrollment of patient in phase II. Dose modifications during cycle 2 through 6 for treatment-associated toxicity were specified in the protocol and based on the grade using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The use of granulocyte-colony stimulating factor (G-CSF) was allowed as per institutional policy. Consolidative radiation therapy was permitted after completion of all systemic therapy and only after end-of-treatment imaging at the discretion of the treating physician. Figure 1. CONSORT diagram. GZL: gray zone lymphoma; cHL: classical Hodgkin lymphoma; EOT: end of treatment. Table 2. Patients’ characteristics. Treatment response was assessed by imaging with fluorodeoxyglucose- positron emission tomography/computed tomography (FDG-PET/CT) using the revised response criteria for malignant lymphoma described by Cheson et al.25 Computed tomography scans were performed after cycles 2 and 4 to monitor for interim response. End-of-treatment imaging was performed 3-5 weeks after completion of systemic therapy using FDG-PET/CT. Consolidative radiation following end-of-treatment response assessment was permissible at the discretion of the treating physician. Correlative studies CD30 expression was determined on the diagnostic tissue biopsies using immunohistochemistry though visual inspection by two independent pathologists. The gene expression analysis (Lymph3Cx) was performed on archival formalin-fixed, paraffinembedded tissue from pre-treatment biopsies. The tissue was examined by a hematopathologist for adequate tumor amount and nucleic acids were extracted from formalin-fixed paraffinembedded scrolls or unstained slides. The Lymph3Cx assay was previously described and validated to aid in the molecular distinction of PMBCL versus DLBCL.26 The gene expression assay on the diagnostic tissue was performed in a blinded fashion, and once the assignment of diagnosis by Lymph3Cx was made, a correlation with investigator-based diagnosis (PMBCL vs. DLBCL vs. GZL) was performed. Statistical analysis The overall response rate and complete response rate with a two-sided 95% exact confidence intervals (95% CI) were calculated using the Clopper-Pearson method. Two-year progression-free and overall survival rates were estimated using the Kaplan-Meier method. The median follow-up was estimated by the reverse Kaplan-Meier method.27 The data cut-off for analysis was January 1, 2019. Results Patients’ characteristics Thirty-three patients gave consent to enrollment in the trial (Figure 1). One of these patients was subsequently reclassified from having GZL to having classical Hodgkin lymphoma and was taken off the study before starting therapy. Thus, 32 patients were enrolled and received at least one cycle of therapy. One patient withdrew from the study after cycle 1 to receive R-CHOP therapy closer to home. The characteristics of the patients evaluable for toxicity (n=31) are presented in Table 2. The median age was 37 years (range, 18-76), 50% of the patients were female, 42% had stage III/IV disease and 17% were classified in high-intermediate or high International Prognostic Index (IPI) risk group.28 Using traditional clinicopathological criteria, 23 patients had a diagnosis of PMBCL, six were diagnosed as having DLBCL, and two as having GZL. For the PMBCL cohort, 91% of patients had large mediastinal masses over 7.5 cm in maximal transverse diameter and 35% had stage III/IV disease. Two patients were removed from the study (1 patient because of non-compliance and 1 in complete remission because of a regimen violation). Therefore, a total of 29 patients were evaluable for efficacy. Of those, 15 patients (52%) received consolidative radiation after completing BV-RCHP and final end-of-treatment response assessment. This number included 13 (59%) of 22 evaluable PMBCL patients. Of those, 8 patients received radiation using protons. Twenty-six patients had archival formalin-fixed paraffin-embedded diagnostic tissue available for Lymph3Cx gene expression analysis. Safety and feasibility Toxicities of this outpatient regimen are listed in Table 3A and B. There were no treatment-related or on-study deaths. Using a de-escalation design during the phase I portion of the trial, the first six patients were treated with the initial dose of 1.8 mg/kg (maximum 180 mg) in combination with standard dose R-CHP with plans to reduce BV to 1.2 mg/kg (maximum 120 mg) should there be dose-limiting toxicities. As there were no dose-limiting toxicities during phase I, the BV dose of 1.8 mg/kg (maximum 180 mg) was used as the phase II dose. Overall in all patients (combining phase I and phase II cohorts), any grade 3 or 4 toxicity occurred in 84% of study patients. Hematologic adverse events of any grade were recorded in the majority of patients and in 77% of patients with grade 3 or 4 toxicities. Of note, 16% of patients received no G-CSF and 6% had G-CSF support for only one or two of the six cycles. Non-hematologic grade 3 and 4 toxicities were seen in 32% of patients, including infections in 15% of patients (Table 3B). Toxicities occurring in over 10% of patients included peripheral sensory neuropathy in 19 patients (61%) which were either grade 1 (48%) or grade 2 (13%) (Table 3A). Three patients (10%) reported motor neuropathy, two with grade 1 (6%) and one with grade 2 (3%). One patient discontinued protocol treatment after cycle 4 because of sepsis and grade 3 cardiomyopathy. One patient discontinued BV after cycle 5 because of transient grade 2 pneumonitis which was deemed at least possibly related to BV. Only three patients required BV dose reductions to 1.2 mg/kg because of persistent grade 2 peripheral sensory neuropathy outside of the period of dose-limiting toxicities. In total, two patients enrolled on the study died in the follow- up period. One PMBCL patient developed acute myeloid leukemia 2 years after completion of study treatment and mediastinal radiation therapy and ultimately died of acute myeloid leukemia 39 months after completing study treatment. One patient died of progressive lymphoma 40 months after completing study treatment. Thromboembolic events were noted in eight patients (36%) in the PMBCL cohort. Pulmonary embolism was seen in three patients and upper extremity deep vein thrombosis in five patients. Of those, three events were diagnosed prior to initiating BV-R-CHP and five events were diagnosed while patients were on study treatment. Three of the five patients who had on-treatment events were asymptomatic and thrombosis was reported as an incidental finding on their first computed tomography with intravenous contrast (1 with pulmonary embolism and 1 with internal jugular vein thrombosis). Two of the five patients with on-treatment events had line-associated thromboses. Table 3A All adverse events at least possibly related to the BV-R-CHP regimen. Table 3B Grade 3 or 4 adverse events at least possibly related to the BV-R-CHP regimen. Efficacy In the combined phase I/II cohort with 29 evaluable patients, the overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving a complete response and 14% (95% CI: 4-32) achieving a partial response according to FDG-PET/CT imaging at the end of treatment. All four patients with a partial response had a diagnosis of PMBCL and had a low or low-intermediate IPI risk classification. Only two of the four patients with a partial response ultimately progressed. At a median follow-up of 30 months (95% CI: 26-46), four patients (14%) progressed: three with PMBCL and one with GZL. The 2-year progression-free survival rate was 85% (95% CI: 66-94) and the 2-year overall survival was 100% (Figure 2). Of three patients who were not evaluable per study criteria, two remain progression-free at last followup and the status of one patient is unknown. In the PMBCL cohort of 22 evaluable patients with a median follow-up of 30 months (95% CI: 23-46), the 2- year progression-free survival rate was 86% (95% CI: 62-95) with a 2-year overall survival of 100% (Figure 2). Of the three PMBCL patients who progressed, two had bulky advanced stage disease with expression of CD30 ≤10% and one had bulky stage I disease with CD30 expression of 1%. There was no statistically significant difference in progression-free survival between the PMBCL patients who received consolidative radiation therapy (n=13) and those who did not (n=9) (P=0.95). CD30 expression as determined by immunohistochemistry and response to therapy While all cases expressed CD30 in at least 1% of the lymphoma B cells in the tumor biopsy by immunohistochemistry, it was challenging to capture CD30 expression as a single metric since there was great heterogeneity of CD30 expression patterns, as depicted in Figure 3. Additionally, given the 100% overall response rate and low number of relapses, we could not make any conclusions about correlations between efficacy of the BV-containing regimen and CD30 expression as determined by immunohistochemistry. Gene expression analysis to improve diagnostic accuracy of primary mediastinal B-cell lymphoma Of 29 evaluable patients with CD30+ B-cell lymphoma, 26 had a pre-treatment biopsy available (11 excisional biopsies and 15 core needle biopsies). Of the 26 samples, five core needle biopsies did not have adequate tumor content or amounts of extractable RNA for the Lymph3Cx assay. The biopsies of the remaining 21 patients (11 excisional and 10 core needle biopsies) were tested. All three subtypes of CD30+ B-cell lymphomas as assessed by investigator assessment were tested in blinded fashion by the Lymph3Cx assay and comprised 14 cases of PMBCL, six of DLBCL, and one case of GZL. Of 14 patients with PMBCL by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9 which were consistent with a molecular diagnosis of PMBCL (mPMBCL) by gene expression; two patients scored in the indeterminate category (0.1 to 0.9); and one patient scored as having a molecular diagnosis of DLBCL (< 0.1) (Figure 4). None of the CD30+ B-cell lymphoma samples that were felt to be DLBCL by investigator assessment scored as having a molecular diagnosis of PMBCL by Lymph3Cx. Figure 2. Survival curves for patients who received the BV-R-CHP treatment regimen. (A, B) Progression-free survival (A) and overall survival (B) of all evaluable patients enrolled in the trial (n=29). (C, D) Progression-free survival (C) and overall survival (D) of evaluable patients with primary mediastinal B-cell lymphoma (PMBCL) (n=22). Figure 3. Examples of different CD30 staining patterns by immunohistochemistry in three representative patients with primary mediastinal B-cell lymphoma enrolled on the trial. (A) Heterogeneous staining pattern with strong and dim staining in different areas of the same tumor. (B) Focal staining in one area of the tumor. (C) Diffuse staining throughout the tumor. The antibodies used were CD20 (ready to use, DAKO) and CD30 (ready to use, Leica) and they were detected using a chromogenic substrate, diaminobenzene (Leica). An original magnification x200 was used for all images. H&E: hematoxylin & eosin. Discussion There is a strong rationale for replacing vincristine with BV in the standard R-CHOP regimen for the treatment of CD30+ aggressive B-cell lymphomas. BV specifically delivers the antimicrotubule agent auristatin to CD30-expressing cells, which could result in improved efficacy from BV and reduced toxicity due to the omission of vincristine. While BV displayed only limited clinical activity as monotherapy in aggressive r/r B-cell lymphomas, it has not been widely studied in the frontline setting or in combination with chemotherapy.24,29 In our phase I/II study, we showed that a frontline regimen using BV at a dose of 1.8 mg/kg in combination with R-CHP for patients with CD30+ B-cell lymphomas has an acceptable toxicity profile and is highly active. Our study included a heterogeneous group of B-cell lymphomas, but the majority of the patients had a clinicopathological diagnosis of PMBCL. For many reasons, this is a challenging population to study in a frontline setting. PMBCL is a rare and clinically heterogeneous lymphoma. Patients with this type of lymphoma often present with an acute onset of pulmonary symptoms necessitating urgent therapy which may lead to a selection bias in nonrandomized studies. While several frontline treatment approaches are effective in PMBCL, there are unique challenges in this population of patients. DA-EPOCH-R is a highly active dose-intense regimen, but it requires central venous access, use of growth factors, frequent blood testing, and inpatient admission at some institutions. RCHOP is easier to administer, but the excellent outcomes in PMBCL are achieved using consolidative radiation therapy, which may cause long-term toxicities.14,16,30,31 While a recently published phase III trial comparing R-CHOP versus DA-EPOCH-R in DLBCL included a small cohort of PMBCL cases (n=35), it was not statistically powered to detect the differences in this lymphoma subtype.17 We recognize that it is difficult to compare regimens across different trials, but outcomes within the PMBCL cohort in our study are comparable to previously published results for patients treated with R-CHOP with radiotherapy or dose-intense regimens such as DAEPOCH- R.14-16,19,30,32 For lymphoma subtypes other than PMBCL, the numbers of patients were too small to make any efficacy conclusions regarding BV-R-CHP. One of two patients with GZL relapsed after achieving a complete response and none of the five patients with CD30+ DLBCL relapsed, which is encouraging. Interestingly, preliminary results from another phase II trial (ClinicalTrial.gov identifier: NCT01925612) using BV-R-CHOP in DLBCL (without any requirement for CD30 staining) documented an overall response rate of 97% in the initial 30 evaluable patients. None of the CD30+ DLBCL patients in the preliminary report relapsed, but the median follow-up of 5 months was short.33 Regarding toxicity of the BV-R-CHP regimen, there were no study-related deaths. With the caveats about cross-trial comparisons of studies, the rate of grade 3 or 4 hematologic and non-hematologic toxicities was similar or lower compared to the rates reported for R-CHOP.17,34 When compared to the DA-EPOCH-R arm from the recently published randomized trial in DLBCL, there appears to be less toxicity with BV-R-CHP in our study.17 However, one limitation of this comparison is the younger median age of patients in our cohort. Neuropathy is of particular concern with a BV-containing regimen and was closely monitored in our study. While peripheral sensory neuropathy was reported in 61% of patients, no patient experienced grade 3 or 4 neuropathy. This lack of severe peripheral neuropathy may again relate to the young age of our patients and the fact that our BV-containing regimen did not contain additional vinca alkaloids, in contrast to some of the other BV-containing combinations used frontline.4,33 There were no unexpected opportunistic infections using the combination of rituximab and BV. The administration of G-CSF was not consistent across the participating institutions in our study, but over 20% of patients did not require G-CSF at all or its use was limited to one or two cycles. However, considering that 23% of patients experienced febrile neutropenia, empiric use of G-CSF should be considered in patients being treated with BV-R-CHP. With regard to long-term toxicities, one patient developed acute myeloid leukemia 2 years after completing the trial therapy and radiation. It is not possible to determine the association between the protocol treatment and her leukemia, but the fact that the patient’s mother died of acute myeloid leukemia and the patient had normal cytogenetics (rare in secondary leukemias) is suggestive of other contributing factors. Figure 4. Correlation of Lymph3Cx results with standard clinicopathological diagnoses made by the investigators. DLBCL: diffuse large B-cell lymphoma; GZL: gray zone lymphoma; PMBCL: primary mediastinal B-cell lymphoma. Patients who progressed are labeled by an arrow. Of 14 patients with PMBCL diagnosed by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9, which were consistent with a molecular diagnosis of PMBCL by gene expression analysis, two patients (14%) scored in the indeterminate category (0.1 to 0.9), and one patient (7%) scored as having DLBCL (< 0.1). The high rate of thrombosis in the PMBCL cohort is of special interest. Thromboses were found in over one third of PMBCL patients and approximately 50% were diagnosed prior to initiation of therapy. This high risk of thrombosis in PMBCL patients was described with similar frequency in retrospective studies and is not likely to be related to BV-R-CHP.19,35 This finding warrants further investigations about screening, the potential contribution of central lines to thrombosis, and any possible role for prophylactic anticoagulation in PMBCL patients. We also attempted to define clinical and pathological factors which would correlate with outcomes of patients receiving BV-R-CHP therapy for CD30+ B-cell lymphomas. IPI risk group, which is well-established as a prognostic factor for outcomes of frontline treatments in DLBCL, did not clearly correlate with complete response rate, progression-free survival or overall survival in our study. This could be due to the small number of patients in the high or high-intermediate IPI risk category. Furthermore, the majority of our patients had PMBCL and the utility of the IPI has some limitations as most patients are young and present with limited stage disease. For our ancillary studies, we planned an analysis of CD30 expression by immunohistochemistry and correlation with outcomes as there is controversy over the impact of CD30 status on the efficacy of BV.33,36,37 However, this proved difficult because of the very low number of relapses and heterogeneity of CD30 staining patterns in neoplastic cells (Figure 3). Additional studies beyond a simple determination of the percentage of CD30+ cells by immunohistochemistry and visual assessment will need to be applied and other groups have attempted this with some success.37,38 Among 21 patients who had pre-treatment tissue analyzed by LymphC3x, we found that there was discordance between the protocol-specified standard clinicopathological diagnosis of PMBCL and the gene expression- based method. These findings are thought-provoking since, in small trials of PMBCL, even a few misclassified patients may have a great impact on interpretation of the results. We believe that developing objective diagnostic criteria based on quantitative methods, such as gene expression signatures, will be an important step in designing treatment strategies for B-cell lymphoma patients with mediastinal lesions and for comparing results across PMBCL trials. This trial is limited by the small number of evaluable patients and diagnostic heterogeneity. However, the entities included are rare, and we involved three institutions to enroll 32 patients. One of the challenges when interpreting the clinical efficacy and progression-free/overall survival data of patients treated with the BV-R-CHP regimen is the fact that consolidative radiation was used in about 50% of all patients enrolled on this trial. The protocol was designed in 2011-2012 when R-CHOP followed by consolidative radiation therapy was utilized by most centers for PMBCL patients. Therefore, the protocol allowed investigators to use consolidative radiotherapy after completion of BV-R-CHP. It is important to note that the end-of-treatment response assessment was performed before radiation. Interestingly, there were no statistically significant differences in progression-free or overall survival between patients who received consolidative radiation and those who did not. There were no clear differences in patients’ characteristics between those who received consolidative radiotherapy and those who did not other than institutional practice differences. Of the four patients who did not achieve metabolic complete response on end-of-treatment imaging, two received consolidative radiation therapy and two did not. Longer follow-up will be necessary to determine whether there are any long-term toxicities of radiation in the study participants (with the majority of patients having received proton radiation). Of note, an ongoing randomized trial in patients with PMBCL may allow us to determine whether consolidative radiation therapy after frontline chemoimmunotherapy is necessary in patients who achieve metabolic complete response after systemic treatment (ClinicalTrial.gov identifier: NCT01599559). BV in combination with R-CHP with or without consolidative radiation therapy is a feasible and active frontline treatment in patients with CD30+ B-cell lymphomas. The safety profile of this regimen, ease of administration and preliminary efficacy data appear promising. The next generation of trials in CD30+ B-cell lymphomas and PMBCL should take into consideration the clinical and biological heterogeneity of these lymphomas. Ultimately, developing treatment regimens that will be tailored to unique tumor and patient characteristics will result in improved outcomes and will minimize treatment-related toxicities.

BRENTUXIMAB VEDOTIN, CYCLOPHOSPHAMIDE, DOXORUBICIN, PREDNISONE, RITUXIMAB

DrugsGivenReaction

CC BY-NC

32414850

2021-06-01

What was the administration route of drug 'BRENTUXIMAB VEDOTIN'?

Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas. We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850). Introduction Brentuximab vedotin (BV) is an immunoconjugate consisting of a CD30-directed antibody linked to the anti-microtubule agent auristatin.1 BV is highly active in relapsed and refractory (r/r) classical Hodgkin lymphoma and in CD30-expressing T-cell lymphomas.2,3 In the frontline setting, BV combined with chemotherapy has been recently approved for advanced classical Hodgkin lymphoma and CD30-positive (CD30+) T-cell lymphomas based on results of randomized trials showing benefit of the BV-containing arms.4,5 BV targets the cell membrane protein CD30 that is expressed not only by classical Hodgkin lymphoma and some T-cell lymphomas, but at various frequencies also by B-cell non-Hodgkin lymphomas including up to 80% of primary mediastinal B-cell lymphomas (PMBCL).6-9 PMBCL is a mature large B-cell lymphoma of thymic origin which usually presents with mediastinal masses. It occurs predominantly in young adults and represents about 5% of aggressive B-cell lymphomas.10 While previous classifications considered it as a subtype of diffuse large B-cell lymphoma (DLBCL), PMBCL is now thought of as a distinct clinicopathological entity with clinical features and also a molecular signature that share similarities with those of classical Hodgkin lymphoma.11 Recent efforts using gene expression profiling have aimed at better defining PMBCL at the molecular level and distinguishing it from other aggressive B-cell lymphomas with mediastinal presentation. In particular, the NanoString© based Lymph3Cx assay measures expression of 58 genes and allows precise identification of PMBCL cases.12 Presently, the optimal frontline management of patients with PMBCL remains controversial. Traditionally, PMBCL was included in clinical trials regarding aggressive B-cell lymphomas and regimens designed for DLBCL were found to be effective.13-17 Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) results in event-free survival rates of about 80% when followed by consolidative radiation therapy.14,16 In 2013, in a phase II trial by Dunleavy et al. including 51 PMBCL patients treated at the National Cancer Institute, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, plus rituximab (DA-EPOCH-R) without radiotherapy achieved an event-free survival of 93%.15 Many centers in the USA now use this dose-intense DA-EPOCH-R approach for frontline treatment of all PMBCL patients without considering any risk stratification. 15 Some patients with r/r PMBCL, can be salvaged by high-dose chemotherapy with autologous stem cell transplant or radiation, but outcomes tend to be poor.18,19 Recently, pembrolizumab and axicabtagene ciloleucel were approved for the treatment of r/r PMBCL.20-22 While the activity of BV as monotherapy in r/r PMBCL has been disappointing, results of a phase II trial using nivolumab in combination with BV are very encouraging.23,24 To test the tolerability and make a preliminary assessment of the efficacy of BV in frontline treatment of B-cell lymphomas, we designed a phase I/II trial using BV in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of CD30+ PMBCL, DLBCL, and gray zone lymphoma (GZL) in adult patients (ClinicalTrials.gov identifier: NCT01994850). Methods Study design and patient eligibility This multicenter, single arm, phase I/II study enrolled patients aged 18 years and over with untreated histologically confirmed CD30+ PMBCL, DLBCL, or GZL. Patients with any stage, measurable disease, and an Eastern Cooperative Oncology Group Performance Status of 3 or less were eligible. The diagnostic biopsy had to demonstrate at least 1% or higher expression of CD30 on the lymphoma B cells by immunohistochemistry and was assessed independently by two pathologists. Patients with active central nervous system involvement and uncontrolled systemic infections were excluded. Enrollment began in January 2014 and was completed in April 2017. The primary objective of the phase I portion was to determine the safety of the combination and the maximum tolerated dose of BV in combination with R-CHP using a de-escalation design. The primary objective of the phase II portion was the overall response rate at the end of systemic treatment as determined by investigator assessment using International Working Group response criteria for non-Hodgkin lymphoma.25 Secondary endpoints were 2-year progression-free survival and 2- year overall survival for all patients and by each lymphoma subtype (PMBCL, DLBCL, and GZL). With regard to the toxicity assessment, the study had 90% power to detect any unforeseen toxicity that occurred in 7% or more of patients. The number of patients required for the trial was determined based on the following assumptions for an optimal two-stage design in order to detect and minimize enrollment if the overall response rate was not greater than 50% but also to minimize the likelihood of failing to reject the null hypothesis if the overall response rate was at least 70%. Sample size calculations for the stopping rules were based upon a type I error rate of 10% and type II error rate of 20%. The number of subjects enrolled and evaluable in the phase I cohort was defined as at least six and a maximum of 12. For the phase II cohort, using the null hypothesis of a 50% overall response rate, the study required a sample size of 20 patients. Since the phase I subjects were recruited, treated, and followed in the same way as the phase II subjects, the phase I subjects accrued at the phase II dose were included in the efficacy analysis. Table 1. The study regimen: brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BV-R-CHP). The study was conducted in three academic centers in the USA and was run in accordance with the Declaration of Helsinki. Approval from the institutional review board of each center was obtained before initiating the study at each site. All patients signed a written informed consent form before enrollment into the trial. Treatment protocol and response assessment As shown in Table 1, the study treatment protocol consisted of six cycles of BV administered with the R-CHOP regimen without vincristine, including: rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 on day 1 and prednisone 100 mg (or equivalent) daily on days 1 through 5 of each 21-day cycle. For cycle 1, rituximab was split into two doses (100 mg/m2 on day 1 and 275 mg/m2 on day 2) to reduce risks of an infusion reaction to rituximab. We also aimed to separate the initial rituximab infusion from the first exposure to BV to avoid any potential confusion about attribution of infusion reactions. The rest of the agents were given on day 2 (cyclophosphamide, doxorubicin, BV). In cycles 2 through 6, rituximab was administered at a dose of 375 mg/m2 on day 1 together with the rest of the agents. For phase I, the starting dose of BV was 1.8 mg/kg (maximum dose of 180 mg) with a 3+3 de-escalation design to 1.2 mg/kg (maximum dose of 120 mg) should dose-limiting toxicities occur during the first 21-day cycle. A dose-limiting toxicity was defined as any grade 3 or 4 non-hematologic toxicity requiring a dose delay over 14 days from the planned day 1 of cycle 2 or any hematologic toxicity not returning to baseline or ≤ grade 2 by 21 days from the planned day 1 of cycle 2. By protocol, at least six patients had to be enrolled and complete one cycle of dosing at the final recommended BV dose in phase I prior to beginning enrollment of patient in phase II. Dose modifications during cycle 2 through 6 for treatment-associated toxicity were specified in the protocol and based on the grade using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The use of granulocyte-colony stimulating factor (G-CSF) was allowed as per institutional policy. Consolidative radiation therapy was permitted after completion of all systemic therapy and only after end-of-treatment imaging at the discretion of the treating physician. Figure 1. CONSORT diagram. GZL: gray zone lymphoma; cHL: classical Hodgkin lymphoma; EOT: end of treatment. Table 2. Patients’ characteristics. Treatment response was assessed by imaging with fluorodeoxyglucose- positron emission tomography/computed tomography (FDG-PET/CT) using the revised response criteria for malignant lymphoma described by Cheson et al.25 Computed tomography scans were performed after cycles 2 and 4 to monitor for interim response. End-of-treatment imaging was performed 3-5 weeks after completion of systemic therapy using FDG-PET/CT. Consolidative radiation following end-of-treatment response assessment was permissible at the discretion of the treating physician. Correlative studies CD30 expression was determined on the diagnostic tissue biopsies using immunohistochemistry though visual inspection by two independent pathologists. The gene expression analysis (Lymph3Cx) was performed on archival formalin-fixed, paraffinembedded tissue from pre-treatment biopsies. The tissue was examined by a hematopathologist for adequate tumor amount and nucleic acids were extracted from formalin-fixed paraffinembedded scrolls or unstained slides. The Lymph3Cx assay was previously described and validated to aid in the molecular distinction of PMBCL versus DLBCL.26 The gene expression assay on the diagnostic tissue was performed in a blinded fashion, and once the assignment of diagnosis by Lymph3Cx was made, a correlation with investigator-based diagnosis (PMBCL vs. DLBCL vs. GZL) was performed. Statistical analysis The overall response rate and complete response rate with a two-sided 95% exact confidence intervals (95% CI) were calculated using the Clopper-Pearson method. Two-year progression-free and overall survival rates were estimated using the Kaplan-Meier method. The median follow-up was estimated by the reverse Kaplan-Meier method.27 The data cut-off for analysis was January 1, 2019. Results Patients’ characteristics Thirty-three patients gave consent to enrollment in the trial (Figure 1). One of these patients was subsequently reclassified from having GZL to having classical Hodgkin lymphoma and was taken off the study before starting therapy. Thus, 32 patients were enrolled and received at least one cycle of therapy. One patient withdrew from the study after cycle 1 to receive R-CHOP therapy closer to home. The characteristics of the patients evaluable for toxicity (n=31) are presented in Table 2. The median age was 37 years (range, 18-76), 50% of the patients were female, 42% had stage III/IV disease and 17% were classified in high-intermediate or high International Prognostic Index (IPI) risk group.28 Using traditional clinicopathological criteria, 23 patients had a diagnosis of PMBCL, six were diagnosed as having DLBCL, and two as having GZL. For the PMBCL cohort, 91% of patients had large mediastinal masses over 7.5 cm in maximal transverse diameter and 35% had stage III/IV disease. Two patients were removed from the study (1 patient because of non-compliance and 1 in complete remission because of a regimen violation). Therefore, a total of 29 patients were evaluable for efficacy. Of those, 15 patients (52%) received consolidative radiation after completing BV-RCHP and final end-of-treatment response assessment. This number included 13 (59%) of 22 evaluable PMBCL patients. Of those, 8 patients received radiation using protons. Twenty-six patients had archival formalin-fixed paraffin-embedded diagnostic tissue available for Lymph3Cx gene expression analysis. Safety and feasibility Toxicities of this outpatient regimen are listed in Table 3A and B. There were no treatment-related or on-study deaths. Using a de-escalation design during the phase I portion of the trial, the first six patients were treated with the initial dose of 1.8 mg/kg (maximum 180 mg) in combination with standard dose R-CHP with plans to reduce BV to 1.2 mg/kg (maximum 120 mg) should there be dose-limiting toxicities. As there were no dose-limiting toxicities during phase I, the BV dose of 1.8 mg/kg (maximum 180 mg) was used as the phase II dose. Overall in all patients (combining phase I and phase II cohorts), any grade 3 or 4 toxicity occurred in 84% of study patients. Hematologic adverse events of any grade were recorded in the majority of patients and in 77% of patients with grade 3 or 4 toxicities. Of note, 16% of patients received no G-CSF and 6% had G-CSF support for only one or two of the six cycles. Non-hematologic grade 3 and 4 toxicities were seen in 32% of patients, including infections in 15% of patients (Table 3B). Toxicities occurring in over 10% of patients included peripheral sensory neuropathy in 19 patients (61%) which were either grade 1 (48%) or grade 2 (13%) (Table 3A). Three patients (10%) reported motor neuropathy, two with grade 1 (6%) and one with grade 2 (3%). One patient discontinued protocol treatment after cycle 4 because of sepsis and grade 3 cardiomyopathy. One patient discontinued BV after cycle 5 because of transient grade 2 pneumonitis which was deemed at least possibly related to BV. Only three patients required BV dose reductions to 1.2 mg/kg because of persistent grade 2 peripheral sensory neuropathy outside of the period of dose-limiting toxicities. In total, two patients enrolled on the study died in the follow- up period. One PMBCL patient developed acute myeloid leukemia 2 years after completion of study treatment and mediastinal radiation therapy and ultimately died of acute myeloid leukemia 39 months after completing study treatment. One patient died of progressive lymphoma 40 months after completing study treatment. Thromboembolic events were noted in eight patients (36%) in the PMBCL cohort. Pulmonary embolism was seen in three patients and upper extremity deep vein thrombosis in five patients. Of those, three events were diagnosed prior to initiating BV-R-CHP and five events were diagnosed while patients were on study treatment. Three of the five patients who had on-treatment events were asymptomatic and thrombosis was reported as an incidental finding on their first computed tomography with intravenous contrast (1 with pulmonary embolism and 1 with internal jugular vein thrombosis). Two of the five patients with on-treatment events had line-associated thromboses. Table 3A All adverse events at least possibly related to the BV-R-CHP regimen. Table 3B Grade 3 or 4 adverse events at least possibly related to the BV-R-CHP regimen. Efficacy In the combined phase I/II cohort with 29 evaluable patients, the overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving a complete response and 14% (95% CI: 4-32) achieving a partial response according to FDG-PET/CT imaging at the end of treatment. All four patients with a partial response had a diagnosis of PMBCL and had a low or low-intermediate IPI risk classification. Only two of the four patients with a partial response ultimately progressed. At a median follow-up of 30 months (95% CI: 26-46), four patients (14%) progressed: three with PMBCL and one with GZL. The 2-year progression-free survival rate was 85% (95% CI: 66-94) and the 2-year overall survival was 100% (Figure 2). Of three patients who were not evaluable per study criteria, two remain progression-free at last followup and the status of one patient is unknown. In the PMBCL cohort of 22 evaluable patients with a median follow-up of 30 months (95% CI: 23-46), the 2- year progression-free survival rate was 86% (95% CI: 62-95) with a 2-year overall survival of 100% (Figure 2). Of the three PMBCL patients who progressed, two had bulky advanced stage disease with expression of CD30 ≤10% and one had bulky stage I disease with CD30 expression of 1%. There was no statistically significant difference in progression-free survival between the PMBCL patients who received consolidative radiation therapy (n=13) and those who did not (n=9) (P=0.95). CD30 expression as determined by immunohistochemistry and response to therapy While all cases expressed CD30 in at least 1% of the lymphoma B cells in the tumor biopsy by immunohistochemistry, it was challenging to capture CD30 expression as a single metric since there was great heterogeneity of CD30 expression patterns, as depicted in Figure 3. Additionally, given the 100% overall response rate and low number of relapses, we could not make any conclusions about correlations between efficacy of the BV-containing regimen and CD30 expression as determined by immunohistochemistry. Gene expression analysis to improve diagnostic accuracy of primary mediastinal B-cell lymphoma Of 29 evaluable patients with CD30+ B-cell lymphoma, 26 had a pre-treatment biopsy available (11 excisional biopsies and 15 core needle biopsies). Of the 26 samples, five core needle biopsies did not have adequate tumor content or amounts of extractable RNA for the Lymph3Cx assay. The biopsies of the remaining 21 patients (11 excisional and 10 core needle biopsies) were tested. All three subtypes of CD30+ B-cell lymphomas as assessed by investigator assessment were tested in blinded fashion by the Lymph3Cx assay and comprised 14 cases of PMBCL, six of DLBCL, and one case of GZL. Of 14 patients with PMBCL by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9 which were consistent with a molecular diagnosis of PMBCL (mPMBCL) by gene expression; two patients scored in the indeterminate category (0.1 to 0.9); and one patient scored as having a molecular diagnosis of DLBCL (< 0.1) (Figure 4). None of the CD30+ B-cell lymphoma samples that were felt to be DLBCL by investigator assessment scored as having a molecular diagnosis of PMBCL by Lymph3Cx. Figure 2. Survival curves for patients who received the BV-R-CHP treatment regimen. (A, B) Progression-free survival (A) and overall survival (B) of all evaluable patients enrolled in the trial (n=29). (C, D) Progression-free survival (C) and overall survival (D) of evaluable patients with primary mediastinal B-cell lymphoma (PMBCL) (n=22). Figure 3. Examples of different CD30 staining patterns by immunohistochemistry in three representative patients with primary mediastinal B-cell lymphoma enrolled on the trial. (A) Heterogeneous staining pattern with strong and dim staining in different areas of the same tumor. (B) Focal staining in one area of the tumor. (C) Diffuse staining throughout the tumor. The antibodies used were CD20 (ready to use, DAKO) and CD30 (ready to use, Leica) and they were detected using a chromogenic substrate, diaminobenzene (Leica). An original magnification x200 was used for all images. H&E: hematoxylin & eosin. Discussion There is a strong rationale for replacing vincristine with BV in the standard R-CHOP regimen for the treatment of CD30+ aggressive B-cell lymphomas. BV specifically delivers the antimicrotubule agent auristatin to CD30-expressing cells, which could result in improved efficacy from BV and reduced toxicity due to the omission of vincristine. While BV displayed only limited clinical activity as monotherapy in aggressive r/r B-cell lymphomas, it has not been widely studied in the frontline setting or in combination with chemotherapy.24,29 In our phase I/II study, we showed that a frontline regimen using BV at a dose of 1.8 mg/kg in combination with R-CHP for patients with CD30+ B-cell lymphomas has an acceptable toxicity profile and is highly active. Our study included a heterogeneous group of B-cell lymphomas, but the majority of the patients had a clinicopathological diagnosis of PMBCL. For many reasons, this is a challenging population to study in a frontline setting. PMBCL is a rare and clinically heterogeneous lymphoma. Patients with this type of lymphoma often present with an acute onset of pulmonary symptoms necessitating urgent therapy which may lead to a selection bias in nonrandomized studies. While several frontline treatment approaches are effective in PMBCL, there are unique challenges in this population of patients. DA-EPOCH-R is a highly active dose-intense regimen, but it requires central venous access, use of growth factors, frequent blood testing, and inpatient admission at some institutions. RCHOP is easier to administer, but the excellent outcomes in PMBCL are achieved using consolidative radiation therapy, which may cause long-term toxicities.14,16,30,31 While a recently published phase III trial comparing R-CHOP versus DA-EPOCH-R in DLBCL included a small cohort of PMBCL cases (n=35), it was not statistically powered to detect the differences in this lymphoma subtype.17 We recognize that it is difficult to compare regimens across different trials, but outcomes within the PMBCL cohort in our study are comparable to previously published results for patients treated with R-CHOP with radiotherapy or dose-intense regimens such as DAEPOCH- R.14-16,19,30,32 For lymphoma subtypes other than PMBCL, the numbers of patients were too small to make any efficacy conclusions regarding BV-R-CHP. One of two patients with GZL relapsed after achieving a complete response and none of the five patients with CD30+ DLBCL relapsed, which is encouraging. Interestingly, preliminary results from another phase II trial (ClinicalTrial.gov identifier: NCT01925612) using BV-R-CHOP in DLBCL (without any requirement for CD30 staining) documented an overall response rate of 97% in the initial 30 evaluable patients. None of the CD30+ DLBCL patients in the preliminary report relapsed, but the median follow-up of 5 months was short.33 Regarding toxicity of the BV-R-CHP regimen, there were no study-related deaths. With the caveats about cross-trial comparisons of studies, the rate of grade 3 or 4 hematologic and non-hematologic toxicities was similar or lower compared to the rates reported for R-CHOP.17,34 When compared to the DA-EPOCH-R arm from the recently published randomized trial in DLBCL, there appears to be less toxicity with BV-R-CHP in our study.17 However, one limitation of this comparison is the younger median age of patients in our cohort. Neuropathy is of particular concern with a BV-containing regimen and was closely monitored in our study. While peripheral sensory neuropathy was reported in 61% of patients, no patient experienced grade 3 or 4 neuropathy. This lack of severe peripheral neuropathy may again relate to the young age of our patients and the fact that our BV-containing regimen did not contain additional vinca alkaloids, in contrast to some of the other BV-containing combinations used frontline.4,33 There were no unexpected opportunistic infections using the combination of rituximab and BV. The administration of G-CSF was not consistent across the participating institutions in our study, but over 20% of patients did not require G-CSF at all or its use was limited to one or two cycles. However, considering that 23% of patients experienced febrile neutropenia, empiric use of G-CSF should be considered in patients being treated with BV-R-CHP. With regard to long-term toxicities, one patient developed acute myeloid leukemia 2 years after completing the trial therapy and radiation. It is not possible to determine the association between the protocol treatment and her leukemia, but the fact that the patient’s mother died of acute myeloid leukemia and the patient had normal cytogenetics (rare in secondary leukemias) is suggestive of other contributing factors. Figure 4. Correlation of Lymph3Cx results with standard clinicopathological diagnoses made by the investigators. DLBCL: diffuse large B-cell lymphoma; GZL: gray zone lymphoma; PMBCL: primary mediastinal B-cell lymphoma. Patients who progressed are labeled by an arrow. Of 14 patients with PMBCL diagnosed by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9, which were consistent with a molecular diagnosis of PMBCL by gene expression analysis, two patients (14%) scored in the indeterminate category (0.1 to 0.9), and one patient (7%) scored as having DLBCL (< 0.1). The high rate of thrombosis in the PMBCL cohort is of special interest. Thromboses were found in over one third of PMBCL patients and approximately 50% were diagnosed prior to initiation of therapy. This high risk of thrombosis in PMBCL patients was described with similar frequency in retrospective studies and is not likely to be related to BV-R-CHP.19,35 This finding warrants further investigations about screening, the potential contribution of central lines to thrombosis, and any possible role for prophylactic anticoagulation in PMBCL patients. We also attempted to define clinical and pathological factors which would correlate with outcomes of patients receiving BV-R-CHP therapy for CD30+ B-cell lymphomas. IPI risk group, which is well-established as a prognostic factor for outcomes of frontline treatments in DLBCL, did not clearly correlate with complete response rate, progression-free survival or overall survival in our study. This could be due to the small number of patients in the high or high-intermediate IPI risk category. Furthermore, the majority of our patients had PMBCL and the utility of the IPI has some limitations as most patients are young and present with limited stage disease. For our ancillary studies, we planned an analysis of CD30 expression by immunohistochemistry and correlation with outcomes as there is controversy over the impact of CD30 status on the efficacy of BV.33,36,37 However, this proved difficult because of the very low number of relapses and heterogeneity of CD30 staining patterns in neoplastic cells (Figure 3). Additional studies beyond a simple determination of the percentage of CD30+ cells by immunohistochemistry and visual assessment will need to be applied and other groups have attempted this with some success.37,38 Among 21 patients who had pre-treatment tissue analyzed by LymphC3x, we found that there was discordance between the protocol-specified standard clinicopathological diagnosis of PMBCL and the gene expression- based method. These findings are thought-provoking since, in small trials of PMBCL, even a few misclassified patients may have a great impact on interpretation of the results. We believe that developing objective diagnostic criteria based on quantitative methods, such as gene expression signatures, will be an important step in designing treatment strategies for B-cell lymphoma patients with mediastinal lesions and for comparing results across PMBCL trials. This trial is limited by the small number of evaluable patients and diagnostic heterogeneity. However, the entities included are rare, and we involved three institutions to enroll 32 patients. One of the challenges when interpreting the clinical efficacy and progression-free/overall survival data of patients treated with the BV-R-CHP regimen is the fact that consolidative radiation was used in about 50% of all patients enrolled on this trial. The protocol was designed in 2011-2012 when R-CHOP followed by consolidative radiation therapy was utilized by most centers for PMBCL patients. Therefore, the protocol allowed investigators to use consolidative radiotherapy after completion of BV-R-CHP. It is important to note that the end-of-treatment response assessment was performed before radiation. Interestingly, there were no statistically significant differences in progression-free or overall survival between patients who received consolidative radiation and those who did not. There were no clear differences in patients’ characteristics between those who received consolidative radiotherapy and those who did not other than institutional practice differences. Of the four patients who did not achieve metabolic complete response on end-of-treatment imaging, two received consolidative radiation therapy and two did not. Longer follow-up will be necessary to determine whether there are any long-term toxicities of radiation in the study participants (with the majority of patients having received proton radiation). Of note, an ongoing randomized trial in patients with PMBCL may allow us to determine whether consolidative radiation therapy after frontline chemoimmunotherapy is necessary in patients who achieve metabolic complete response after systemic treatment (ClinicalTrial.gov identifier: NCT01599559). BV in combination with R-CHP with or without consolidative radiation therapy is a feasible and active frontline treatment in patients with CD30+ B-cell lymphomas. The safety profile of this regimen, ease of administration and preliminary efficacy data appear promising. The next generation of trials in CD30+ B-cell lymphomas and PMBCL should take into consideration the clinical and biological heterogeneity of these lymphomas. Ultimately, developing treatment regimens that will be tailored to unique tumor and patient characteristics will result in improved outcomes and will minimize treatment-related toxicities.

Intravenous (not otherwise specified)

DrugAdministrationRoute

CC BY-NC

32414850

2021-06-01

What was the administration route of drug 'CYCLOPHOSPHAMIDE'?

Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas. We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850). Introduction Brentuximab vedotin (BV) is an immunoconjugate consisting of a CD30-directed antibody linked to the anti-microtubule agent auristatin.1 BV is highly active in relapsed and refractory (r/r) classical Hodgkin lymphoma and in CD30-expressing T-cell lymphomas.2,3 In the frontline setting, BV combined with chemotherapy has been recently approved for advanced classical Hodgkin lymphoma and CD30-positive (CD30+) T-cell lymphomas based on results of randomized trials showing benefit of the BV-containing arms.4,5 BV targets the cell membrane protein CD30 that is expressed not only by classical Hodgkin lymphoma and some T-cell lymphomas, but at various frequencies also by B-cell non-Hodgkin lymphomas including up to 80% of primary mediastinal B-cell lymphomas (PMBCL).6-9 PMBCL is a mature large B-cell lymphoma of thymic origin which usually presents with mediastinal masses. It occurs predominantly in young adults and represents about 5% of aggressive B-cell lymphomas.10 While previous classifications considered it as a subtype of diffuse large B-cell lymphoma (DLBCL), PMBCL is now thought of as a distinct clinicopathological entity with clinical features and also a molecular signature that share similarities with those of classical Hodgkin lymphoma.11 Recent efforts using gene expression profiling have aimed at better defining PMBCL at the molecular level and distinguishing it from other aggressive B-cell lymphomas with mediastinal presentation. In particular, the NanoString© based Lymph3Cx assay measures expression of 58 genes and allows precise identification of PMBCL cases.12 Presently, the optimal frontline management of patients with PMBCL remains controversial. Traditionally, PMBCL was included in clinical trials regarding aggressive B-cell lymphomas and regimens designed for DLBCL were found to be effective.13-17 Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) results in event-free survival rates of about 80% when followed by consolidative radiation therapy.14,16 In 2013, in a phase II trial by Dunleavy et al. including 51 PMBCL patients treated at the National Cancer Institute, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, plus rituximab (DA-EPOCH-R) without radiotherapy achieved an event-free survival of 93%.15 Many centers in the USA now use this dose-intense DA-EPOCH-R approach for frontline treatment of all PMBCL patients without considering any risk stratification. 15 Some patients with r/r PMBCL, can be salvaged by high-dose chemotherapy with autologous stem cell transplant or radiation, but outcomes tend to be poor.18,19 Recently, pembrolizumab and axicabtagene ciloleucel were approved for the treatment of r/r PMBCL.20-22 While the activity of BV as monotherapy in r/r PMBCL has been disappointing, results of a phase II trial using nivolumab in combination with BV are very encouraging.23,24 To test the tolerability and make a preliminary assessment of the efficacy of BV in frontline treatment of B-cell lymphomas, we designed a phase I/II trial using BV in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of CD30+ PMBCL, DLBCL, and gray zone lymphoma (GZL) in adult patients (ClinicalTrials.gov identifier: NCT01994850). Methods Study design and patient eligibility This multicenter, single arm, phase I/II study enrolled patients aged 18 years and over with untreated histologically confirmed CD30+ PMBCL, DLBCL, or GZL. Patients with any stage, measurable disease, and an Eastern Cooperative Oncology Group Performance Status of 3 or less were eligible. The diagnostic biopsy had to demonstrate at least 1% or higher expression of CD30 on the lymphoma B cells by immunohistochemistry and was assessed independently by two pathologists. Patients with active central nervous system involvement and uncontrolled systemic infections were excluded. Enrollment began in January 2014 and was completed in April 2017. The primary objective of the phase I portion was to determine the safety of the combination and the maximum tolerated dose of BV in combination with R-CHP using a de-escalation design. The primary objective of the phase II portion was the overall response rate at the end of systemic treatment as determined by investigator assessment using International Working Group response criteria for non-Hodgkin lymphoma.25 Secondary endpoints were 2-year progression-free survival and 2- year overall survival for all patients and by each lymphoma subtype (PMBCL, DLBCL, and GZL). With regard to the toxicity assessment, the study had 90% power to detect any unforeseen toxicity that occurred in 7% or more of patients. The number of patients required for the trial was determined based on the following assumptions for an optimal two-stage design in order to detect and minimize enrollment if the overall response rate was not greater than 50% but also to minimize the likelihood of failing to reject the null hypothesis if the overall response rate was at least 70%. Sample size calculations for the stopping rules were based upon a type I error rate of 10% and type II error rate of 20%. The number of subjects enrolled and evaluable in the phase I cohort was defined as at least six and a maximum of 12. For the phase II cohort, using the null hypothesis of a 50% overall response rate, the study required a sample size of 20 patients. Since the phase I subjects were recruited, treated, and followed in the same way as the phase II subjects, the phase I subjects accrued at the phase II dose were included in the efficacy analysis. Table 1. The study regimen: brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BV-R-CHP). The study was conducted in three academic centers in the USA and was run in accordance with the Declaration of Helsinki. Approval from the institutional review board of each center was obtained before initiating the study at each site. All patients signed a written informed consent form before enrollment into the trial. Treatment protocol and response assessment As shown in Table 1, the study treatment protocol consisted of six cycles of BV administered with the R-CHOP regimen without vincristine, including: rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 on day 1 and prednisone 100 mg (or equivalent) daily on days 1 through 5 of each 21-day cycle. For cycle 1, rituximab was split into two doses (100 mg/m2 on day 1 and 275 mg/m2 on day 2) to reduce risks of an infusion reaction to rituximab. We also aimed to separate the initial rituximab infusion from the first exposure to BV to avoid any potential confusion about attribution of infusion reactions. The rest of the agents were given on day 2 (cyclophosphamide, doxorubicin, BV). In cycles 2 through 6, rituximab was administered at a dose of 375 mg/m2 on day 1 together with the rest of the agents. For phase I, the starting dose of BV was 1.8 mg/kg (maximum dose of 180 mg) with a 3+3 de-escalation design to 1.2 mg/kg (maximum dose of 120 mg) should dose-limiting toxicities occur during the first 21-day cycle. A dose-limiting toxicity was defined as any grade 3 or 4 non-hematologic toxicity requiring a dose delay over 14 days from the planned day 1 of cycle 2 or any hematologic toxicity not returning to baseline or ≤ grade 2 by 21 days from the planned day 1 of cycle 2. By protocol, at least six patients had to be enrolled and complete one cycle of dosing at the final recommended BV dose in phase I prior to beginning enrollment of patient in phase II. Dose modifications during cycle 2 through 6 for treatment-associated toxicity were specified in the protocol and based on the grade using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The use of granulocyte-colony stimulating factor (G-CSF) was allowed as per institutional policy. Consolidative radiation therapy was permitted after completion of all systemic therapy and only after end-of-treatment imaging at the discretion of the treating physician. Figure 1. CONSORT diagram. GZL: gray zone lymphoma; cHL: classical Hodgkin lymphoma; EOT: end of treatment. Table 2. Patients’ characteristics. Treatment response was assessed by imaging with fluorodeoxyglucose- positron emission tomography/computed tomography (FDG-PET/CT) using the revised response criteria for malignant lymphoma described by Cheson et al.25 Computed tomography scans were performed after cycles 2 and 4 to monitor for interim response. End-of-treatment imaging was performed 3-5 weeks after completion of systemic therapy using FDG-PET/CT. Consolidative radiation following end-of-treatment response assessment was permissible at the discretion of the treating physician. Correlative studies CD30 expression was determined on the diagnostic tissue biopsies using immunohistochemistry though visual inspection by two independent pathologists. The gene expression analysis (Lymph3Cx) was performed on archival formalin-fixed, paraffinembedded tissue from pre-treatment biopsies. The tissue was examined by a hematopathologist for adequate tumor amount and nucleic acids were extracted from formalin-fixed paraffinembedded scrolls or unstained slides. The Lymph3Cx assay was previously described and validated to aid in the molecular distinction of PMBCL versus DLBCL.26 The gene expression assay on the diagnostic tissue was performed in a blinded fashion, and once the assignment of diagnosis by Lymph3Cx was made, a correlation with investigator-based diagnosis (PMBCL vs. DLBCL vs. GZL) was performed. Statistical analysis The overall response rate and complete response rate with a two-sided 95% exact confidence intervals (95% CI) were calculated using the Clopper-Pearson method. Two-year progression-free and overall survival rates were estimated using the Kaplan-Meier method. The median follow-up was estimated by the reverse Kaplan-Meier method.27 The data cut-off for analysis was January 1, 2019. Results Patients’ characteristics Thirty-three patients gave consent to enrollment in the trial (Figure 1). One of these patients was subsequently reclassified from having GZL to having classical Hodgkin lymphoma and was taken off the study before starting therapy. Thus, 32 patients were enrolled and received at least one cycle of therapy. One patient withdrew from the study after cycle 1 to receive R-CHOP therapy closer to home. The characteristics of the patients evaluable for toxicity (n=31) are presented in Table 2. The median age was 37 years (range, 18-76), 50% of the patients were female, 42% had stage III/IV disease and 17% were classified in high-intermediate or high International Prognostic Index (IPI) risk group.28 Using traditional clinicopathological criteria, 23 patients had a diagnosis of PMBCL, six were diagnosed as having DLBCL, and two as having GZL. For the PMBCL cohort, 91% of patients had large mediastinal masses over 7.5 cm in maximal transverse diameter and 35% had stage III/IV disease. Two patients were removed from the study (1 patient because of non-compliance and 1 in complete remission because of a regimen violation). Therefore, a total of 29 patients were evaluable for efficacy. Of those, 15 patients (52%) received consolidative radiation after completing BV-RCHP and final end-of-treatment response assessment. This number included 13 (59%) of 22 evaluable PMBCL patients. Of those, 8 patients received radiation using protons. Twenty-six patients had archival formalin-fixed paraffin-embedded diagnostic tissue available for Lymph3Cx gene expression analysis. Safety and feasibility Toxicities of this outpatient regimen are listed in Table 3A and B. There were no treatment-related or on-study deaths. Using a de-escalation design during the phase I portion of the trial, the first six patients were treated with the initial dose of 1.8 mg/kg (maximum 180 mg) in combination with standard dose R-CHP with plans to reduce BV to 1.2 mg/kg (maximum 120 mg) should there be dose-limiting toxicities. As there were no dose-limiting toxicities during phase I, the BV dose of 1.8 mg/kg (maximum 180 mg) was used as the phase II dose. Overall in all patients (combining phase I and phase II cohorts), any grade 3 or 4 toxicity occurred in 84% of study patients. Hematologic adverse events of any grade were recorded in the majority of patients and in 77% of patients with grade 3 or 4 toxicities. Of note, 16% of patients received no G-CSF and 6% had G-CSF support for only one or two of the six cycles. Non-hematologic grade 3 and 4 toxicities were seen in 32% of patients, including infections in 15% of patients (Table 3B). Toxicities occurring in over 10% of patients included peripheral sensory neuropathy in 19 patients (61%) which were either grade 1 (48%) or grade 2 (13%) (Table 3A). Three patients (10%) reported motor neuropathy, two with grade 1 (6%) and one with grade 2 (3%). One patient discontinued protocol treatment after cycle 4 because of sepsis and grade 3 cardiomyopathy. One patient discontinued BV after cycle 5 because of transient grade 2 pneumonitis which was deemed at least possibly related to BV. Only three patients required BV dose reductions to 1.2 mg/kg because of persistent grade 2 peripheral sensory neuropathy outside of the period of dose-limiting toxicities. In total, two patients enrolled on the study died in the follow- up period. One PMBCL patient developed acute myeloid leukemia 2 years after completion of study treatment and mediastinal radiation therapy and ultimately died of acute myeloid leukemia 39 months after completing study treatment. One patient died of progressive lymphoma 40 months after completing study treatment. Thromboembolic events were noted in eight patients (36%) in the PMBCL cohort. Pulmonary embolism was seen in three patients and upper extremity deep vein thrombosis in five patients. Of those, three events were diagnosed prior to initiating BV-R-CHP and five events were diagnosed while patients were on study treatment. Three of the five patients who had on-treatment events were asymptomatic and thrombosis was reported as an incidental finding on their first computed tomography with intravenous contrast (1 with pulmonary embolism and 1 with internal jugular vein thrombosis). Two of the five patients with on-treatment events had line-associated thromboses. Table 3A All adverse events at least possibly related to the BV-R-CHP regimen. Table 3B Grade 3 or 4 adverse events at least possibly related to the BV-R-CHP regimen. Efficacy In the combined phase I/II cohort with 29 evaluable patients, the overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving a complete response and 14% (95% CI: 4-32) achieving a partial response according to FDG-PET/CT imaging at the end of treatment. All four patients with a partial response had a diagnosis of PMBCL and had a low or low-intermediate IPI risk classification. Only two of the four patients with a partial response ultimately progressed. At a median follow-up of 30 months (95% CI: 26-46), four patients (14%) progressed: three with PMBCL and one with GZL. The 2-year progression-free survival rate was 85% (95% CI: 66-94) and the 2-year overall survival was 100% (Figure 2). Of three patients who were not evaluable per study criteria, two remain progression-free at last followup and the status of one patient is unknown. In the PMBCL cohort of 22 evaluable patients with a median follow-up of 30 months (95% CI: 23-46), the 2- year progression-free survival rate was 86% (95% CI: 62-95) with a 2-year overall survival of 100% (Figure 2). Of the three PMBCL patients who progressed, two had bulky advanced stage disease with expression of CD30 ≤10% and one had bulky stage I disease with CD30 expression of 1%. There was no statistically significant difference in progression-free survival between the PMBCL patients who received consolidative radiation therapy (n=13) and those who did not (n=9) (P=0.95). CD30 expression as determined by immunohistochemistry and response to therapy While all cases expressed CD30 in at least 1% of the lymphoma B cells in the tumor biopsy by immunohistochemistry, it was challenging to capture CD30 expression as a single metric since there was great heterogeneity of CD30 expression patterns, as depicted in Figure 3. Additionally, given the 100% overall response rate and low number of relapses, we could not make any conclusions about correlations between efficacy of the BV-containing regimen and CD30 expression as determined by immunohistochemistry. Gene expression analysis to improve diagnostic accuracy of primary mediastinal B-cell lymphoma Of 29 evaluable patients with CD30+ B-cell lymphoma, 26 had a pre-treatment biopsy available (11 excisional biopsies and 15 core needle biopsies). Of the 26 samples, five core needle biopsies did not have adequate tumor content or amounts of extractable RNA for the Lymph3Cx assay. The biopsies of the remaining 21 patients (11 excisional and 10 core needle biopsies) were tested. All three subtypes of CD30+ B-cell lymphomas as assessed by investigator assessment were tested in blinded fashion by the Lymph3Cx assay and comprised 14 cases of PMBCL, six of DLBCL, and one case of GZL. Of 14 patients with PMBCL by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9 which were consistent with a molecular diagnosis of PMBCL (mPMBCL) by gene expression; two patients scored in the indeterminate category (0.1 to 0.9); and one patient scored as having a molecular diagnosis of DLBCL (< 0.1) (Figure 4). None of the CD30+ B-cell lymphoma samples that were felt to be DLBCL by investigator assessment scored as having a molecular diagnosis of PMBCL by Lymph3Cx. Figure 2. Survival curves for patients who received the BV-R-CHP treatment regimen. (A, B) Progression-free survival (A) and overall survival (B) of all evaluable patients enrolled in the trial (n=29). (C, D) Progression-free survival (C) and overall survival (D) of evaluable patients with primary mediastinal B-cell lymphoma (PMBCL) (n=22). Figure 3. Examples of different CD30 staining patterns by immunohistochemistry in three representative patients with primary mediastinal B-cell lymphoma enrolled on the trial. (A) Heterogeneous staining pattern with strong and dim staining in different areas of the same tumor. (B) Focal staining in one area of the tumor. (C) Diffuse staining throughout the tumor. The antibodies used were CD20 (ready to use, DAKO) and CD30 (ready to use, Leica) and they were detected using a chromogenic substrate, diaminobenzene (Leica). An original magnification x200 was used for all images. H&E: hematoxylin & eosin. Discussion There is a strong rationale for replacing vincristine with BV in the standard R-CHOP regimen for the treatment of CD30+ aggressive B-cell lymphomas. BV specifically delivers the antimicrotubule agent auristatin to CD30-expressing cells, which could result in improved efficacy from BV and reduced toxicity due to the omission of vincristine. While BV displayed only limited clinical activity as monotherapy in aggressive r/r B-cell lymphomas, it has not been widely studied in the frontline setting or in combination with chemotherapy.24,29 In our phase I/II study, we showed that a frontline regimen using BV at a dose of 1.8 mg/kg in combination with R-CHP for patients with CD30+ B-cell lymphomas has an acceptable toxicity profile and is highly active. Our study included a heterogeneous group of B-cell lymphomas, but the majority of the patients had a clinicopathological diagnosis of PMBCL. For many reasons, this is a challenging population to study in a frontline setting. PMBCL is a rare and clinically heterogeneous lymphoma. Patients with this type of lymphoma often present with an acute onset of pulmonary symptoms necessitating urgent therapy which may lead to a selection bias in nonrandomized studies. While several frontline treatment approaches are effective in PMBCL, there are unique challenges in this population of patients. DA-EPOCH-R is a highly active dose-intense regimen, but it requires central venous access, use of growth factors, frequent blood testing, and inpatient admission at some institutions. RCHOP is easier to administer, but the excellent outcomes in PMBCL are achieved using consolidative radiation therapy, which may cause long-term toxicities.14,16,30,31 While a recently published phase III trial comparing R-CHOP versus DA-EPOCH-R in DLBCL included a small cohort of PMBCL cases (n=35), it was not statistically powered to detect the differences in this lymphoma subtype.17 We recognize that it is difficult to compare regimens across different trials, but outcomes within the PMBCL cohort in our study are comparable to previously published results for patients treated with R-CHOP with radiotherapy or dose-intense regimens such as DAEPOCH- R.14-16,19,30,32 For lymphoma subtypes other than PMBCL, the numbers of patients were too small to make any efficacy conclusions regarding BV-R-CHP. One of two patients with GZL relapsed after achieving a complete response and none of the five patients with CD30+ DLBCL relapsed, which is encouraging. Interestingly, preliminary results from another phase II trial (ClinicalTrial.gov identifier: NCT01925612) using BV-R-CHOP in DLBCL (without any requirement for CD30 staining) documented an overall response rate of 97% in the initial 30 evaluable patients. None of the CD30+ DLBCL patients in the preliminary report relapsed, but the median follow-up of 5 months was short.33 Regarding toxicity of the BV-R-CHP regimen, there were no study-related deaths. With the caveats about cross-trial comparisons of studies, the rate of grade 3 or 4 hematologic and non-hematologic toxicities was similar or lower compared to the rates reported for R-CHOP.17,34 When compared to the DA-EPOCH-R arm from the recently published randomized trial in DLBCL, there appears to be less toxicity with BV-R-CHP in our study.17 However, one limitation of this comparison is the younger median age of patients in our cohort. Neuropathy is of particular concern with a BV-containing regimen and was closely monitored in our study. While peripheral sensory neuropathy was reported in 61% of patients, no patient experienced grade 3 or 4 neuropathy. This lack of severe peripheral neuropathy may again relate to the young age of our patients and the fact that our BV-containing regimen did not contain additional vinca alkaloids, in contrast to some of the other BV-containing combinations used frontline.4,33 There were no unexpected opportunistic infections using the combination of rituximab and BV. The administration of G-CSF was not consistent across the participating institutions in our study, but over 20% of patients did not require G-CSF at all or its use was limited to one or two cycles. However, considering that 23% of patients experienced febrile neutropenia, empiric use of G-CSF should be considered in patients being treated with BV-R-CHP. With regard to long-term toxicities, one patient developed acute myeloid leukemia 2 years after completing the trial therapy and radiation. It is not possible to determine the association between the protocol treatment and her leukemia, but the fact that the patient’s mother died of acute myeloid leukemia and the patient had normal cytogenetics (rare in secondary leukemias) is suggestive of other contributing factors. Figure 4. Correlation of Lymph3Cx results with standard clinicopathological diagnoses made by the investigators. DLBCL: diffuse large B-cell lymphoma; GZL: gray zone lymphoma; PMBCL: primary mediastinal B-cell lymphoma. Patients who progressed are labeled by an arrow. Of 14 patients with PMBCL diagnosed by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9, which were consistent with a molecular diagnosis of PMBCL by gene expression analysis, two patients (14%) scored in the indeterminate category (0.1 to 0.9), and one patient (7%) scored as having DLBCL (< 0.1). The high rate of thrombosis in the PMBCL cohort is of special interest. Thromboses were found in over one third of PMBCL patients and approximately 50% were diagnosed prior to initiation of therapy. This high risk of thrombosis in PMBCL patients was described with similar frequency in retrospective studies and is not likely to be related to BV-R-CHP.19,35 This finding warrants further investigations about screening, the potential contribution of central lines to thrombosis, and any possible role for prophylactic anticoagulation in PMBCL patients. We also attempted to define clinical and pathological factors which would correlate with outcomes of patients receiving BV-R-CHP therapy for CD30+ B-cell lymphomas. IPI risk group, which is well-established as a prognostic factor for outcomes of frontline treatments in DLBCL, did not clearly correlate with complete response rate, progression-free survival or overall survival in our study. This could be due to the small number of patients in the high or high-intermediate IPI risk category. Furthermore, the majority of our patients had PMBCL and the utility of the IPI has some limitations as most patients are young and present with limited stage disease. For our ancillary studies, we planned an analysis of CD30 expression by immunohistochemistry and correlation with outcomes as there is controversy over the impact of CD30 status on the efficacy of BV.33,36,37 However, this proved difficult because of the very low number of relapses and heterogeneity of CD30 staining patterns in neoplastic cells (Figure 3). Additional studies beyond a simple determination of the percentage of CD30+ cells by immunohistochemistry and visual assessment will need to be applied and other groups have attempted this with some success.37,38 Among 21 patients who had pre-treatment tissue analyzed by LymphC3x, we found that there was discordance between the protocol-specified standard clinicopathological diagnosis of PMBCL and the gene expression- based method. These findings are thought-provoking since, in small trials of PMBCL, even a few misclassified patients may have a great impact on interpretation of the results. We believe that developing objective diagnostic criteria based on quantitative methods, such as gene expression signatures, will be an important step in designing treatment strategies for B-cell lymphoma patients with mediastinal lesions and for comparing results across PMBCL trials. This trial is limited by the small number of evaluable patients and diagnostic heterogeneity. However, the entities included are rare, and we involved three institutions to enroll 32 patients. One of the challenges when interpreting the clinical efficacy and progression-free/overall survival data of patients treated with the BV-R-CHP regimen is the fact that consolidative radiation was used in about 50% of all patients enrolled on this trial. The protocol was designed in 2011-2012 when R-CHOP followed by consolidative radiation therapy was utilized by most centers for PMBCL patients. Therefore, the protocol allowed investigators to use consolidative radiotherapy after completion of BV-R-CHP. It is important to note that the end-of-treatment response assessment was performed before radiation. Interestingly, there were no statistically significant differences in progression-free or overall survival between patients who received consolidative radiation and those who did not. There were no clear differences in patients’ characteristics between those who received consolidative radiotherapy and those who did not other than institutional practice differences. Of the four patients who did not achieve metabolic complete response on end-of-treatment imaging, two received consolidative radiation therapy and two did not. Longer follow-up will be necessary to determine whether there are any long-term toxicities of radiation in the study participants (with the majority of patients having received proton radiation). Of note, an ongoing randomized trial in patients with PMBCL may allow us to determine whether consolidative radiation therapy after frontline chemoimmunotherapy is necessary in patients who achieve metabolic complete response after systemic treatment (ClinicalTrial.gov identifier: NCT01599559). BV in combination with R-CHP with or without consolidative radiation therapy is a feasible and active frontline treatment in patients with CD30+ B-cell lymphomas. The safety profile of this regimen, ease of administration and preliminary efficacy data appear promising. The next generation of trials in CD30+ B-cell lymphomas and PMBCL should take into consideration the clinical and biological heterogeneity of these lymphomas. Ultimately, developing treatment regimens that will be tailored to unique tumor and patient characteristics will result in improved outcomes and will minimize treatment-related toxicities.

Intravenous (not otherwise specified)

DrugAdministrationRoute

CC BY-NC

32414850

2021-06-01

What was the administration route of drug 'DOXORUBICIN'?

Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas. We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850). Introduction Brentuximab vedotin (BV) is an immunoconjugate consisting of a CD30-directed antibody linked to the anti-microtubule agent auristatin.1 BV is highly active in relapsed and refractory (r/r) classical Hodgkin lymphoma and in CD30-expressing T-cell lymphomas.2,3 In the frontline setting, BV combined with chemotherapy has been recently approved for advanced classical Hodgkin lymphoma and CD30-positive (CD30+) T-cell lymphomas based on results of randomized trials showing benefit of the BV-containing arms.4,5 BV targets the cell membrane protein CD30 that is expressed not only by classical Hodgkin lymphoma and some T-cell lymphomas, but at various frequencies also by B-cell non-Hodgkin lymphomas including up to 80% of primary mediastinal B-cell lymphomas (PMBCL).6-9 PMBCL is a mature large B-cell lymphoma of thymic origin which usually presents with mediastinal masses. It occurs predominantly in young adults and represents about 5% of aggressive B-cell lymphomas.10 While previous classifications considered it as a subtype of diffuse large B-cell lymphoma (DLBCL), PMBCL is now thought of as a distinct clinicopathological entity with clinical features and also a molecular signature that share similarities with those of classical Hodgkin lymphoma.11 Recent efforts using gene expression profiling have aimed at better defining PMBCL at the molecular level and distinguishing it from other aggressive B-cell lymphomas with mediastinal presentation. In particular, the NanoString© based Lymph3Cx assay measures expression of 58 genes and allows precise identification of PMBCL cases.12 Presently, the optimal frontline management of patients with PMBCL remains controversial. Traditionally, PMBCL was included in clinical trials regarding aggressive B-cell lymphomas and regimens designed for DLBCL were found to be effective.13-17 Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) results in event-free survival rates of about 80% when followed by consolidative radiation therapy.14,16 In 2013, in a phase II trial by Dunleavy et al. including 51 PMBCL patients treated at the National Cancer Institute, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, plus rituximab (DA-EPOCH-R) without radiotherapy achieved an event-free survival of 93%.15 Many centers in the USA now use this dose-intense DA-EPOCH-R approach for frontline treatment of all PMBCL patients without considering any risk stratification. 15 Some patients with r/r PMBCL, can be salvaged by high-dose chemotherapy with autologous stem cell transplant or radiation, but outcomes tend to be poor.18,19 Recently, pembrolizumab and axicabtagene ciloleucel were approved for the treatment of r/r PMBCL.20-22 While the activity of BV as monotherapy in r/r PMBCL has been disappointing, results of a phase II trial using nivolumab in combination with BV are very encouraging.23,24 To test the tolerability and make a preliminary assessment of the efficacy of BV in frontline treatment of B-cell lymphomas, we designed a phase I/II trial using BV in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of CD30+ PMBCL, DLBCL, and gray zone lymphoma (GZL) in adult patients (ClinicalTrials.gov identifier: NCT01994850). Methods Study design and patient eligibility This multicenter, single arm, phase I/II study enrolled patients aged 18 years and over with untreated histologically confirmed CD30+ PMBCL, DLBCL, or GZL. Patients with any stage, measurable disease, and an Eastern Cooperative Oncology Group Performance Status of 3 or less were eligible. The diagnostic biopsy had to demonstrate at least 1% or higher expression of CD30 on the lymphoma B cells by immunohistochemistry and was assessed independently by two pathologists. Patients with active central nervous system involvement and uncontrolled systemic infections were excluded. Enrollment began in January 2014 and was completed in April 2017. The primary objective of the phase I portion was to determine the safety of the combination and the maximum tolerated dose of BV in combination with R-CHP using a de-escalation design. The primary objective of the phase II portion was the overall response rate at the end of systemic treatment as determined by investigator assessment using International Working Group response criteria for non-Hodgkin lymphoma.25 Secondary endpoints were 2-year progression-free survival and 2- year overall survival for all patients and by each lymphoma subtype (PMBCL, DLBCL, and GZL). With regard to the toxicity assessment, the study had 90% power to detect any unforeseen toxicity that occurred in 7% or more of patients. The number of patients required for the trial was determined based on the following assumptions for an optimal two-stage design in order to detect and minimize enrollment if the overall response rate was not greater than 50% but also to minimize the likelihood of failing to reject the null hypothesis if the overall response rate was at least 70%. Sample size calculations for the stopping rules were based upon a type I error rate of 10% and type II error rate of 20%. The number of subjects enrolled and evaluable in the phase I cohort was defined as at least six and a maximum of 12. For the phase II cohort, using the null hypothesis of a 50% overall response rate, the study required a sample size of 20 patients. Since the phase I subjects were recruited, treated, and followed in the same way as the phase II subjects, the phase I subjects accrued at the phase II dose were included in the efficacy analysis. Table 1. The study regimen: brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BV-R-CHP). The study was conducted in three academic centers in the USA and was run in accordance with the Declaration of Helsinki. Approval from the institutional review board of each center was obtained before initiating the study at each site. All patients signed a written informed consent form before enrollment into the trial. Treatment protocol and response assessment As shown in Table 1, the study treatment protocol consisted of six cycles of BV administered with the R-CHOP regimen without vincristine, including: rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 on day 1 and prednisone 100 mg (or equivalent) daily on days 1 through 5 of each 21-day cycle. For cycle 1, rituximab was split into two doses (100 mg/m2 on day 1 and 275 mg/m2 on day 2) to reduce risks of an infusion reaction to rituximab. We also aimed to separate the initial rituximab infusion from the first exposure to BV to avoid any potential confusion about attribution of infusion reactions. The rest of the agents were given on day 2 (cyclophosphamide, doxorubicin, BV). In cycles 2 through 6, rituximab was administered at a dose of 375 mg/m2 on day 1 together with the rest of the agents. For phase I, the starting dose of BV was 1.8 mg/kg (maximum dose of 180 mg) with a 3+3 de-escalation design to 1.2 mg/kg (maximum dose of 120 mg) should dose-limiting toxicities occur during the first 21-day cycle. A dose-limiting toxicity was defined as any grade 3 or 4 non-hematologic toxicity requiring a dose delay over 14 days from the planned day 1 of cycle 2 or any hematologic toxicity not returning to baseline or ≤ grade 2 by 21 days from the planned day 1 of cycle 2. By protocol, at least six patients had to be enrolled and complete one cycle of dosing at the final recommended BV dose in phase I prior to beginning enrollment of patient in phase II. Dose modifications during cycle 2 through 6 for treatment-associated toxicity were specified in the protocol and based on the grade using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The use of granulocyte-colony stimulating factor (G-CSF) was allowed as per institutional policy. Consolidative radiation therapy was permitted after completion of all systemic therapy and only after end-of-treatment imaging at the discretion of the treating physician. Figure 1. CONSORT diagram. GZL: gray zone lymphoma; cHL: classical Hodgkin lymphoma; EOT: end of treatment. Table 2. Patients’ characteristics. Treatment response was assessed by imaging with fluorodeoxyglucose- positron emission tomography/computed tomography (FDG-PET/CT) using the revised response criteria for malignant lymphoma described by Cheson et al.25 Computed tomography scans were performed after cycles 2 and 4 to monitor for interim response. End-of-treatment imaging was performed 3-5 weeks after completion of systemic therapy using FDG-PET/CT. Consolidative radiation following end-of-treatment response assessment was permissible at the discretion of the treating physician. Correlative studies CD30 expression was determined on the diagnostic tissue biopsies using immunohistochemistry though visual inspection by two independent pathologists. The gene expression analysis (Lymph3Cx) was performed on archival formalin-fixed, paraffinembedded tissue from pre-treatment biopsies. The tissue was examined by a hematopathologist for adequate tumor amount and nucleic acids were extracted from formalin-fixed paraffinembedded scrolls or unstained slides. The Lymph3Cx assay was previously described and validated to aid in the molecular distinction of PMBCL versus DLBCL.26 The gene expression assay on the diagnostic tissue was performed in a blinded fashion, and once the assignment of diagnosis by Lymph3Cx was made, a correlation with investigator-based diagnosis (PMBCL vs. DLBCL vs. GZL) was performed. Statistical analysis The overall response rate and complete response rate with a two-sided 95% exact confidence intervals (95% CI) were calculated using the Clopper-Pearson method. Two-year progression-free and overall survival rates were estimated using the Kaplan-Meier method. The median follow-up was estimated by the reverse Kaplan-Meier method.27 The data cut-off for analysis was January 1, 2019. Results Patients’ characteristics Thirty-three patients gave consent to enrollment in the trial (Figure 1). One of these patients was subsequently reclassified from having GZL to having classical Hodgkin lymphoma and was taken off the study before starting therapy. Thus, 32 patients were enrolled and received at least one cycle of therapy. One patient withdrew from the study after cycle 1 to receive R-CHOP therapy closer to home. The characteristics of the patients evaluable for toxicity (n=31) are presented in Table 2. The median age was 37 years (range, 18-76), 50% of the patients were female, 42% had stage III/IV disease and 17% were classified in high-intermediate or high International Prognostic Index (IPI) risk group.28 Using traditional clinicopathological criteria, 23 patients had a diagnosis of PMBCL, six were diagnosed as having DLBCL, and two as having GZL. For the PMBCL cohort, 91% of patients had large mediastinal masses over 7.5 cm in maximal transverse diameter and 35% had stage III/IV disease. Two patients were removed from the study (1 patient because of non-compliance and 1 in complete remission because of a regimen violation). Therefore, a total of 29 patients were evaluable for efficacy. Of those, 15 patients (52%) received consolidative radiation after completing BV-RCHP and final end-of-treatment response assessment. This number included 13 (59%) of 22 evaluable PMBCL patients. Of those, 8 patients received radiation using protons. Twenty-six patients had archival formalin-fixed paraffin-embedded diagnostic tissue available for Lymph3Cx gene expression analysis. Safety and feasibility Toxicities of this outpatient regimen are listed in Table 3A and B. There were no treatment-related or on-study deaths. Using a de-escalation design during the phase I portion of the trial, the first six patients were treated with the initial dose of 1.8 mg/kg (maximum 180 mg) in combination with standard dose R-CHP with plans to reduce BV to 1.2 mg/kg (maximum 120 mg) should there be dose-limiting toxicities. As there were no dose-limiting toxicities during phase I, the BV dose of 1.8 mg/kg (maximum 180 mg) was used as the phase II dose. Overall in all patients (combining phase I and phase II cohorts), any grade 3 or 4 toxicity occurred in 84% of study patients. Hematologic adverse events of any grade were recorded in the majority of patients and in 77% of patients with grade 3 or 4 toxicities. Of note, 16% of patients received no G-CSF and 6% had G-CSF support for only one or two of the six cycles. Non-hematologic grade 3 and 4 toxicities were seen in 32% of patients, including infections in 15% of patients (Table 3B). Toxicities occurring in over 10% of patients included peripheral sensory neuropathy in 19 patients (61%) which were either grade 1 (48%) or grade 2 (13%) (Table 3A). Three patients (10%) reported motor neuropathy, two with grade 1 (6%) and one with grade 2 (3%). One patient discontinued protocol treatment after cycle 4 because of sepsis and grade 3 cardiomyopathy. One patient discontinued BV after cycle 5 because of transient grade 2 pneumonitis which was deemed at least possibly related to BV. Only three patients required BV dose reductions to 1.2 mg/kg because of persistent grade 2 peripheral sensory neuropathy outside of the period of dose-limiting toxicities. In total, two patients enrolled on the study died in the follow- up period. One PMBCL patient developed acute myeloid leukemia 2 years after completion of study treatment and mediastinal radiation therapy and ultimately died of acute myeloid leukemia 39 months after completing study treatment. One patient died of progressive lymphoma 40 months after completing study treatment. Thromboembolic events were noted in eight patients (36%) in the PMBCL cohort. Pulmonary embolism was seen in three patients and upper extremity deep vein thrombosis in five patients. Of those, three events were diagnosed prior to initiating BV-R-CHP and five events were diagnosed while patients were on study treatment. Three of the five patients who had on-treatment events were asymptomatic and thrombosis was reported as an incidental finding on their first computed tomography with intravenous contrast (1 with pulmonary embolism and 1 with internal jugular vein thrombosis). Two of the five patients with on-treatment events had line-associated thromboses. Table 3A All adverse events at least possibly related to the BV-R-CHP regimen. Table 3B Grade 3 or 4 adverse events at least possibly related to the BV-R-CHP regimen. Efficacy In the combined phase I/II cohort with 29 evaluable patients, the overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving a complete response and 14% (95% CI: 4-32) achieving a partial response according to FDG-PET/CT imaging at the end of treatment. All four patients with a partial response had a diagnosis of PMBCL and had a low or low-intermediate IPI risk classification. Only two of the four patients with a partial response ultimately progressed. At a median follow-up of 30 months (95% CI: 26-46), four patients (14%) progressed: three with PMBCL and one with GZL. The 2-year progression-free survival rate was 85% (95% CI: 66-94) and the 2-year overall survival was 100% (Figure 2). Of three patients who were not evaluable per study criteria, two remain progression-free at last followup and the status of one patient is unknown. In the PMBCL cohort of 22 evaluable patients with a median follow-up of 30 months (95% CI: 23-46), the 2- year progression-free survival rate was 86% (95% CI: 62-95) with a 2-year overall survival of 100% (Figure 2). Of the three PMBCL patients who progressed, two had bulky advanced stage disease with expression of CD30 ≤10% and one had bulky stage I disease with CD30 expression of 1%. There was no statistically significant difference in progression-free survival between the PMBCL patients who received consolidative radiation therapy (n=13) and those who did not (n=9) (P=0.95). CD30 expression as determined by immunohistochemistry and response to therapy While all cases expressed CD30 in at least 1% of the lymphoma B cells in the tumor biopsy by immunohistochemistry, it was challenging to capture CD30 expression as a single metric since there was great heterogeneity of CD30 expression patterns, as depicted in Figure 3. Additionally, given the 100% overall response rate and low number of relapses, we could not make any conclusions about correlations between efficacy of the BV-containing regimen and CD30 expression as determined by immunohistochemistry. Gene expression analysis to improve diagnostic accuracy of primary mediastinal B-cell lymphoma Of 29 evaluable patients with CD30+ B-cell lymphoma, 26 had a pre-treatment biopsy available (11 excisional biopsies and 15 core needle biopsies). Of the 26 samples, five core needle biopsies did not have adequate tumor content or amounts of extractable RNA for the Lymph3Cx assay. The biopsies of the remaining 21 patients (11 excisional and 10 core needle biopsies) were tested. All three subtypes of CD30+ B-cell lymphomas as assessed by investigator assessment were tested in blinded fashion by the Lymph3Cx assay and comprised 14 cases of PMBCL, six of DLBCL, and one case of GZL. Of 14 patients with PMBCL by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9 which were consistent with a molecular diagnosis of PMBCL (mPMBCL) by gene expression; two patients scored in the indeterminate category (0.1 to 0.9); and one patient scored as having a molecular diagnosis of DLBCL (< 0.1) (Figure 4). None of the CD30+ B-cell lymphoma samples that were felt to be DLBCL by investigator assessment scored as having a molecular diagnosis of PMBCL by Lymph3Cx. Figure 2. Survival curves for patients who received the BV-R-CHP treatment regimen. (A, B) Progression-free survival (A) and overall survival (B) of all evaluable patients enrolled in the trial (n=29). (C, D) Progression-free survival (C) and overall survival (D) of evaluable patients with primary mediastinal B-cell lymphoma (PMBCL) (n=22). Figure 3. Examples of different CD30 staining patterns by immunohistochemistry in three representative patients with primary mediastinal B-cell lymphoma enrolled on the trial. (A) Heterogeneous staining pattern with strong and dim staining in different areas of the same tumor. (B) Focal staining in one area of the tumor. (C) Diffuse staining throughout the tumor. The antibodies used were CD20 (ready to use, DAKO) and CD30 (ready to use, Leica) and they were detected using a chromogenic substrate, diaminobenzene (Leica). An original magnification x200 was used for all images. H&E: hematoxylin & eosin. Discussion There is a strong rationale for replacing vincristine with BV in the standard R-CHOP regimen for the treatment of CD30+ aggressive B-cell lymphomas. BV specifically delivers the antimicrotubule agent auristatin to CD30-expressing cells, which could result in improved efficacy from BV and reduced toxicity due to the omission of vincristine. While BV displayed only limited clinical activity as monotherapy in aggressive r/r B-cell lymphomas, it has not been widely studied in the frontline setting or in combination with chemotherapy.24,29 In our phase I/II study, we showed that a frontline regimen using BV at a dose of 1.8 mg/kg in combination with R-CHP for patients with CD30+ B-cell lymphomas has an acceptable toxicity profile and is highly active. Our study included a heterogeneous group of B-cell lymphomas, but the majority of the patients had a clinicopathological diagnosis of PMBCL. For many reasons, this is a challenging population to study in a frontline setting. PMBCL is a rare and clinically heterogeneous lymphoma. Patients with this type of lymphoma often present with an acute onset of pulmonary symptoms necessitating urgent therapy which may lead to a selection bias in nonrandomized studies. While several frontline treatment approaches are effective in PMBCL, there are unique challenges in this population of patients. DA-EPOCH-R is a highly active dose-intense regimen, but it requires central venous access, use of growth factors, frequent blood testing, and inpatient admission at some institutions. RCHOP is easier to administer, but the excellent outcomes in PMBCL are achieved using consolidative radiation therapy, which may cause long-term toxicities.14,16,30,31 While a recently published phase III trial comparing R-CHOP versus DA-EPOCH-R in DLBCL included a small cohort of PMBCL cases (n=35), it was not statistically powered to detect the differences in this lymphoma subtype.17 We recognize that it is difficult to compare regimens across different trials, but outcomes within the PMBCL cohort in our study are comparable to previously published results for patients treated with R-CHOP with radiotherapy or dose-intense regimens such as DAEPOCH- R.14-16,19,30,32 For lymphoma subtypes other than PMBCL, the numbers of patients were too small to make any efficacy conclusions regarding BV-R-CHP. One of two patients with GZL relapsed after achieving a complete response and none of the five patients with CD30+ DLBCL relapsed, which is encouraging. Interestingly, preliminary results from another phase II trial (ClinicalTrial.gov identifier: NCT01925612) using BV-R-CHOP in DLBCL (without any requirement for CD30 staining) documented an overall response rate of 97% in the initial 30 evaluable patients. None of the CD30+ DLBCL patients in the preliminary report relapsed, but the median follow-up of 5 months was short.33 Regarding toxicity of the BV-R-CHP regimen, there were no study-related deaths. With the caveats about cross-trial comparisons of studies, the rate of grade 3 or 4 hematologic and non-hematologic toxicities was similar or lower compared to the rates reported for R-CHOP.17,34 When compared to the DA-EPOCH-R arm from the recently published randomized trial in DLBCL, there appears to be less toxicity with BV-R-CHP in our study.17 However, one limitation of this comparison is the younger median age of patients in our cohort. Neuropathy is of particular concern with a BV-containing regimen and was closely monitored in our study. While peripheral sensory neuropathy was reported in 61% of patients, no patient experienced grade 3 or 4 neuropathy. This lack of severe peripheral neuropathy may again relate to the young age of our patients and the fact that our BV-containing regimen did not contain additional vinca alkaloids, in contrast to some of the other BV-containing combinations used frontline.4,33 There were no unexpected opportunistic infections using the combination of rituximab and BV. The administration of G-CSF was not consistent across the participating institutions in our study, but over 20% of patients did not require G-CSF at all or its use was limited to one or two cycles. However, considering that 23% of patients experienced febrile neutropenia, empiric use of G-CSF should be considered in patients being treated with BV-R-CHP. With regard to long-term toxicities, one patient developed acute myeloid leukemia 2 years after completing the trial therapy and radiation. It is not possible to determine the association between the protocol treatment and her leukemia, but the fact that the patient’s mother died of acute myeloid leukemia and the patient had normal cytogenetics (rare in secondary leukemias) is suggestive of other contributing factors. Figure 4. Correlation of Lymph3Cx results with standard clinicopathological diagnoses made by the investigators. DLBCL: diffuse large B-cell lymphoma; GZL: gray zone lymphoma; PMBCL: primary mediastinal B-cell lymphoma. Patients who progressed are labeled by an arrow. Of 14 patients with PMBCL diagnosed by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9, which were consistent with a molecular diagnosis of PMBCL by gene expression analysis, two patients (14%) scored in the indeterminate category (0.1 to 0.9), and one patient (7%) scored as having DLBCL (< 0.1). The high rate of thrombosis in the PMBCL cohort is of special interest. Thromboses were found in over one third of PMBCL patients and approximately 50% were diagnosed prior to initiation of therapy. This high risk of thrombosis in PMBCL patients was described with similar frequency in retrospective studies and is not likely to be related to BV-R-CHP.19,35 This finding warrants further investigations about screening, the potential contribution of central lines to thrombosis, and any possible role for prophylactic anticoagulation in PMBCL patients. We also attempted to define clinical and pathological factors which would correlate with outcomes of patients receiving BV-R-CHP therapy for CD30+ B-cell lymphomas. IPI risk group, which is well-established as a prognostic factor for outcomes of frontline treatments in DLBCL, did not clearly correlate with complete response rate, progression-free survival or overall survival in our study. This could be due to the small number of patients in the high or high-intermediate IPI risk category. Furthermore, the majority of our patients had PMBCL and the utility of the IPI has some limitations as most patients are young and present with limited stage disease. For our ancillary studies, we planned an analysis of CD30 expression by immunohistochemistry and correlation with outcomes as there is controversy over the impact of CD30 status on the efficacy of BV.33,36,37 However, this proved difficult because of the very low number of relapses and heterogeneity of CD30 staining patterns in neoplastic cells (Figure 3). Additional studies beyond a simple determination of the percentage of CD30+ cells by immunohistochemistry and visual assessment will need to be applied and other groups have attempted this with some success.37,38 Among 21 patients who had pre-treatment tissue analyzed by LymphC3x, we found that there was discordance between the protocol-specified standard clinicopathological diagnosis of PMBCL and the gene expression- based method. These findings are thought-provoking since, in small trials of PMBCL, even a few misclassified patients may have a great impact on interpretation of the results. We believe that developing objective diagnostic criteria based on quantitative methods, such as gene expression signatures, will be an important step in designing treatment strategies for B-cell lymphoma patients with mediastinal lesions and for comparing results across PMBCL trials. This trial is limited by the small number of evaluable patients and diagnostic heterogeneity. However, the entities included are rare, and we involved three institutions to enroll 32 patients. One of the challenges when interpreting the clinical efficacy and progression-free/overall survival data of patients treated with the BV-R-CHP regimen is the fact that consolidative radiation was used in about 50% of all patients enrolled on this trial. The protocol was designed in 2011-2012 when R-CHOP followed by consolidative radiation therapy was utilized by most centers for PMBCL patients. Therefore, the protocol allowed investigators to use consolidative radiotherapy after completion of BV-R-CHP. It is important to note that the end-of-treatment response assessment was performed before radiation. Interestingly, there were no statistically significant differences in progression-free or overall survival between patients who received consolidative radiation and those who did not. There were no clear differences in patients’ characteristics between those who received consolidative radiotherapy and those who did not other than institutional practice differences. Of the four patients who did not achieve metabolic complete response on end-of-treatment imaging, two received consolidative radiation therapy and two did not. Longer follow-up will be necessary to determine whether there are any long-term toxicities of radiation in the study participants (with the majority of patients having received proton radiation). Of note, an ongoing randomized trial in patients with PMBCL may allow us to determine whether consolidative radiation therapy after frontline chemoimmunotherapy is necessary in patients who achieve metabolic complete response after systemic treatment (ClinicalTrial.gov identifier: NCT01599559). BV in combination with R-CHP with or without consolidative radiation therapy is a feasible and active frontline treatment in patients with CD30+ B-cell lymphomas. The safety profile of this regimen, ease of administration and preliminary efficacy data appear promising. The next generation of trials in CD30+ B-cell lymphomas and PMBCL should take into consideration the clinical and biological heterogeneity of these lymphomas. Ultimately, developing treatment regimens that will be tailored to unique tumor and patient characteristics will result in improved outcomes and will minimize treatment-related toxicities.

Intravenous (not otherwise specified)

DrugAdministrationRoute

CC BY-NC

32414850

2021-06-01

What was the administration route of drug 'RITUXIMAB'?

Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas. We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850). Introduction Brentuximab vedotin (BV) is an immunoconjugate consisting of a CD30-directed antibody linked to the anti-microtubule agent auristatin.1 BV is highly active in relapsed and refractory (r/r) classical Hodgkin lymphoma and in CD30-expressing T-cell lymphomas.2,3 In the frontline setting, BV combined with chemotherapy has been recently approved for advanced classical Hodgkin lymphoma and CD30-positive (CD30+) T-cell lymphomas based on results of randomized trials showing benefit of the BV-containing arms.4,5 BV targets the cell membrane protein CD30 that is expressed not only by classical Hodgkin lymphoma and some T-cell lymphomas, but at various frequencies also by B-cell non-Hodgkin lymphomas including up to 80% of primary mediastinal B-cell lymphomas (PMBCL).6-9 PMBCL is a mature large B-cell lymphoma of thymic origin which usually presents with mediastinal masses. It occurs predominantly in young adults and represents about 5% of aggressive B-cell lymphomas.10 While previous classifications considered it as a subtype of diffuse large B-cell lymphoma (DLBCL), PMBCL is now thought of as a distinct clinicopathological entity with clinical features and also a molecular signature that share similarities with those of classical Hodgkin lymphoma.11 Recent efforts using gene expression profiling have aimed at better defining PMBCL at the molecular level and distinguishing it from other aggressive B-cell lymphomas with mediastinal presentation. In particular, the NanoString© based Lymph3Cx assay measures expression of 58 genes and allows precise identification of PMBCL cases.12 Presently, the optimal frontline management of patients with PMBCL remains controversial. Traditionally, PMBCL was included in clinical trials regarding aggressive B-cell lymphomas and regimens designed for DLBCL were found to be effective.13-17 Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) results in event-free survival rates of about 80% when followed by consolidative radiation therapy.14,16 In 2013, in a phase II trial by Dunleavy et al. including 51 PMBCL patients treated at the National Cancer Institute, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, plus rituximab (DA-EPOCH-R) without radiotherapy achieved an event-free survival of 93%.15 Many centers in the USA now use this dose-intense DA-EPOCH-R approach for frontline treatment of all PMBCL patients without considering any risk stratification. 15 Some patients with r/r PMBCL, can be salvaged by high-dose chemotherapy with autologous stem cell transplant or radiation, but outcomes tend to be poor.18,19 Recently, pembrolizumab and axicabtagene ciloleucel were approved for the treatment of r/r PMBCL.20-22 While the activity of BV as monotherapy in r/r PMBCL has been disappointing, results of a phase II trial using nivolumab in combination with BV are very encouraging.23,24 To test the tolerability and make a preliminary assessment of the efficacy of BV in frontline treatment of B-cell lymphomas, we designed a phase I/II trial using BV in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of CD30+ PMBCL, DLBCL, and gray zone lymphoma (GZL) in adult patients (ClinicalTrials.gov identifier: NCT01994850). Methods Study design and patient eligibility This multicenter, single arm, phase I/II study enrolled patients aged 18 years and over with untreated histologically confirmed CD30+ PMBCL, DLBCL, or GZL. Patients with any stage, measurable disease, and an Eastern Cooperative Oncology Group Performance Status of 3 or less were eligible. The diagnostic biopsy had to demonstrate at least 1% or higher expression of CD30 on the lymphoma B cells by immunohistochemistry and was assessed independently by two pathologists. Patients with active central nervous system involvement and uncontrolled systemic infections were excluded. Enrollment began in January 2014 and was completed in April 2017. The primary objective of the phase I portion was to determine the safety of the combination and the maximum tolerated dose of BV in combination with R-CHP using a de-escalation design. The primary objective of the phase II portion was the overall response rate at the end of systemic treatment as determined by investigator assessment using International Working Group response criteria for non-Hodgkin lymphoma.25 Secondary endpoints were 2-year progression-free survival and 2- year overall survival for all patients and by each lymphoma subtype (PMBCL, DLBCL, and GZL). With regard to the toxicity assessment, the study had 90% power to detect any unforeseen toxicity that occurred in 7% or more of patients. The number of patients required for the trial was determined based on the following assumptions for an optimal two-stage design in order to detect and minimize enrollment if the overall response rate was not greater than 50% but also to minimize the likelihood of failing to reject the null hypothesis if the overall response rate was at least 70%. Sample size calculations for the stopping rules were based upon a type I error rate of 10% and type II error rate of 20%. The number of subjects enrolled and evaluable in the phase I cohort was defined as at least six and a maximum of 12. For the phase II cohort, using the null hypothesis of a 50% overall response rate, the study required a sample size of 20 patients. Since the phase I subjects were recruited, treated, and followed in the same way as the phase II subjects, the phase I subjects accrued at the phase II dose were included in the efficacy analysis. Table 1. The study regimen: brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BV-R-CHP). The study was conducted in three academic centers in the USA and was run in accordance with the Declaration of Helsinki. Approval from the institutional review board of each center was obtained before initiating the study at each site. All patients signed a written informed consent form before enrollment into the trial. Treatment protocol and response assessment As shown in Table 1, the study treatment protocol consisted of six cycles of BV administered with the R-CHOP regimen without vincristine, including: rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 on day 1 and prednisone 100 mg (or equivalent) daily on days 1 through 5 of each 21-day cycle. For cycle 1, rituximab was split into two doses (100 mg/m2 on day 1 and 275 mg/m2 on day 2) to reduce risks of an infusion reaction to rituximab. We also aimed to separate the initial rituximab infusion from the first exposure to BV to avoid any potential confusion about attribution of infusion reactions. The rest of the agents were given on day 2 (cyclophosphamide, doxorubicin, BV). In cycles 2 through 6, rituximab was administered at a dose of 375 mg/m2 on day 1 together with the rest of the agents. For phase I, the starting dose of BV was 1.8 mg/kg (maximum dose of 180 mg) with a 3+3 de-escalation design to 1.2 mg/kg (maximum dose of 120 mg) should dose-limiting toxicities occur during the first 21-day cycle. A dose-limiting toxicity was defined as any grade 3 or 4 non-hematologic toxicity requiring a dose delay over 14 days from the planned day 1 of cycle 2 or any hematologic toxicity not returning to baseline or ≤ grade 2 by 21 days from the planned day 1 of cycle 2. By protocol, at least six patients had to be enrolled and complete one cycle of dosing at the final recommended BV dose in phase I prior to beginning enrollment of patient in phase II. Dose modifications during cycle 2 through 6 for treatment-associated toxicity were specified in the protocol and based on the grade using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The use of granulocyte-colony stimulating factor (G-CSF) was allowed as per institutional policy. Consolidative radiation therapy was permitted after completion of all systemic therapy and only after end-of-treatment imaging at the discretion of the treating physician. Figure 1. CONSORT diagram. GZL: gray zone lymphoma; cHL: classical Hodgkin lymphoma; EOT: end of treatment. Table 2. Patients’ characteristics. Treatment response was assessed by imaging with fluorodeoxyglucose- positron emission tomography/computed tomography (FDG-PET/CT) using the revised response criteria for malignant lymphoma described by Cheson et al.25 Computed tomography scans were performed after cycles 2 and 4 to monitor for interim response. End-of-treatment imaging was performed 3-5 weeks after completion of systemic therapy using FDG-PET/CT. Consolidative radiation following end-of-treatment response assessment was permissible at the discretion of the treating physician. Correlative studies CD30 expression was determined on the diagnostic tissue biopsies using immunohistochemistry though visual inspection by two independent pathologists. The gene expression analysis (Lymph3Cx) was performed on archival formalin-fixed, paraffinembedded tissue from pre-treatment biopsies. The tissue was examined by a hematopathologist for adequate tumor amount and nucleic acids were extracted from formalin-fixed paraffinembedded scrolls or unstained slides. The Lymph3Cx assay was previously described and validated to aid in the molecular distinction of PMBCL versus DLBCL.26 The gene expression assay on the diagnostic tissue was performed in a blinded fashion, and once the assignment of diagnosis by Lymph3Cx was made, a correlation with investigator-based diagnosis (PMBCL vs. DLBCL vs. GZL) was performed. Statistical analysis The overall response rate and complete response rate with a two-sided 95% exact confidence intervals (95% CI) were calculated using the Clopper-Pearson method. Two-year progression-free and overall survival rates were estimated using the Kaplan-Meier method. The median follow-up was estimated by the reverse Kaplan-Meier method.27 The data cut-off for analysis was January 1, 2019. Results Patients’ characteristics Thirty-three patients gave consent to enrollment in the trial (Figure 1). One of these patients was subsequently reclassified from having GZL to having classical Hodgkin lymphoma and was taken off the study before starting therapy. Thus, 32 patients were enrolled and received at least one cycle of therapy. One patient withdrew from the study after cycle 1 to receive R-CHOP therapy closer to home. The characteristics of the patients evaluable for toxicity (n=31) are presented in Table 2. The median age was 37 years (range, 18-76), 50% of the patients were female, 42% had stage III/IV disease and 17% were classified in high-intermediate or high International Prognostic Index (IPI) risk group.28 Using traditional clinicopathological criteria, 23 patients had a diagnosis of PMBCL, six were diagnosed as having DLBCL, and two as having GZL. For the PMBCL cohort, 91% of patients had large mediastinal masses over 7.5 cm in maximal transverse diameter and 35% had stage III/IV disease. Two patients were removed from the study (1 patient because of non-compliance and 1 in complete remission because of a regimen violation). Therefore, a total of 29 patients were evaluable for efficacy. Of those, 15 patients (52%) received consolidative radiation after completing BV-RCHP and final end-of-treatment response assessment. This number included 13 (59%) of 22 evaluable PMBCL patients. Of those, 8 patients received radiation using protons. Twenty-six patients had archival formalin-fixed paraffin-embedded diagnostic tissue available for Lymph3Cx gene expression analysis. Safety and feasibility Toxicities of this outpatient regimen are listed in Table 3A and B. There were no treatment-related or on-study deaths. Using a de-escalation design during the phase I portion of the trial, the first six patients were treated with the initial dose of 1.8 mg/kg (maximum 180 mg) in combination with standard dose R-CHP with plans to reduce BV to 1.2 mg/kg (maximum 120 mg) should there be dose-limiting toxicities. As there were no dose-limiting toxicities during phase I, the BV dose of 1.8 mg/kg (maximum 180 mg) was used as the phase II dose. Overall in all patients (combining phase I and phase II cohorts), any grade 3 or 4 toxicity occurred in 84% of study patients. Hematologic adverse events of any grade were recorded in the majority of patients and in 77% of patients with grade 3 or 4 toxicities. Of note, 16% of patients received no G-CSF and 6% had G-CSF support for only one or two of the six cycles. Non-hematologic grade 3 and 4 toxicities were seen in 32% of patients, including infections in 15% of patients (Table 3B). Toxicities occurring in over 10% of patients included peripheral sensory neuropathy in 19 patients (61%) which were either grade 1 (48%) or grade 2 (13%) (Table 3A). Three patients (10%) reported motor neuropathy, two with grade 1 (6%) and one with grade 2 (3%). One patient discontinued protocol treatment after cycle 4 because of sepsis and grade 3 cardiomyopathy. One patient discontinued BV after cycle 5 because of transient grade 2 pneumonitis which was deemed at least possibly related to BV. Only three patients required BV dose reductions to 1.2 mg/kg because of persistent grade 2 peripheral sensory neuropathy outside of the period of dose-limiting toxicities. In total, two patients enrolled on the study died in the follow- up period. One PMBCL patient developed acute myeloid leukemia 2 years after completion of study treatment and mediastinal radiation therapy and ultimately died of acute myeloid leukemia 39 months after completing study treatment. One patient died of progressive lymphoma 40 months after completing study treatment. Thromboembolic events were noted in eight patients (36%) in the PMBCL cohort. Pulmonary embolism was seen in three patients and upper extremity deep vein thrombosis in five patients. Of those, three events were diagnosed prior to initiating BV-R-CHP and five events were diagnosed while patients were on study treatment. Three of the five patients who had on-treatment events were asymptomatic and thrombosis was reported as an incidental finding on their first computed tomography with intravenous contrast (1 with pulmonary embolism and 1 with internal jugular vein thrombosis). Two of the five patients with on-treatment events had line-associated thromboses. Table 3A All adverse events at least possibly related to the BV-R-CHP regimen. Table 3B Grade 3 or 4 adverse events at least possibly related to the BV-R-CHP regimen. Efficacy In the combined phase I/II cohort with 29 evaluable patients, the overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving a complete response and 14% (95% CI: 4-32) achieving a partial response according to FDG-PET/CT imaging at the end of treatment. All four patients with a partial response had a diagnosis of PMBCL and had a low or low-intermediate IPI risk classification. Only two of the four patients with a partial response ultimately progressed. At a median follow-up of 30 months (95% CI: 26-46), four patients (14%) progressed: three with PMBCL and one with GZL. The 2-year progression-free survival rate was 85% (95% CI: 66-94) and the 2-year overall survival was 100% (Figure 2). Of three patients who were not evaluable per study criteria, two remain progression-free at last followup and the status of one patient is unknown. In the PMBCL cohort of 22 evaluable patients with a median follow-up of 30 months (95% CI: 23-46), the 2- year progression-free survival rate was 86% (95% CI: 62-95) with a 2-year overall survival of 100% (Figure 2). Of the three PMBCL patients who progressed, two had bulky advanced stage disease with expression of CD30 ≤10% and one had bulky stage I disease with CD30 expression of 1%. There was no statistically significant difference in progression-free survival between the PMBCL patients who received consolidative radiation therapy (n=13) and those who did not (n=9) (P=0.95). CD30 expression as determined by immunohistochemistry and response to therapy While all cases expressed CD30 in at least 1% of the lymphoma B cells in the tumor biopsy by immunohistochemistry, it was challenging to capture CD30 expression as a single metric since there was great heterogeneity of CD30 expression patterns, as depicted in Figure 3. Additionally, given the 100% overall response rate and low number of relapses, we could not make any conclusions about correlations between efficacy of the BV-containing regimen and CD30 expression as determined by immunohistochemistry. Gene expression analysis to improve diagnostic accuracy of primary mediastinal B-cell lymphoma Of 29 evaluable patients with CD30+ B-cell lymphoma, 26 had a pre-treatment biopsy available (11 excisional biopsies and 15 core needle biopsies). Of the 26 samples, five core needle biopsies did not have adequate tumor content or amounts of extractable RNA for the Lymph3Cx assay. The biopsies of the remaining 21 patients (11 excisional and 10 core needle biopsies) were tested. All three subtypes of CD30+ B-cell lymphomas as assessed by investigator assessment were tested in blinded fashion by the Lymph3Cx assay and comprised 14 cases of PMBCL, six of DLBCL, and one case of GZL. Of 14 patients with PMBCL by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9 which were consistent with a molecular diagnosis of PMBCL (mPMBCL) by gene expression; two patients scored in the indeterminate category (0.1 to 0.9); and one patient scored as having a molecular diagnosis of DLBCL (< 0.1) (Figure 4). None of the CD30+ B-cell lymphoma samples that were felt to be DLBCL by investigator assessment scored as having a molecular diagnosis of PMBCL by Lymph3Cx. Figure 2. Survival curves for patients who received the BV-R-CHP treatment regimen. (A, B) Progression-free survival (A) and overall survival (B) of all evaluable patients enrolled in the trial (n=29). (C, D) Progression-free survival (C) and overall survival (D) of evaluable patients with primary mediastinal B-cell lymphoma (PMBCL) (n=22). Figure 3. Examples of different CD30 staining patterns by immunohistochemistry in three representative patients with primary mediastinal B-cell lymphoma enrolled on the trial. (A) Heterogeneous staining pattern with strong and dim staining in different areas of the same tumor. (B) Focal staining in one area of the tumor. (C) Diffuse staining throughout the tumor. The antibodies used were CD20 (ready to use, DAKO) and CD30 (ready to use, Leica) and they were detected using a chromogenic substrate, diaminobenzene (Leica). An original magnification x200 was used for all images. H&E: hematoxylin & eosin. Discussion There is a strong rationale for replacing vincristine with BV in the standard R-CHOP regimen for the treatment of CD30+ aggressive B-cell lymphomas. BV specifically delivers the antimicrotubule agent auristatin to CD30-expressing cells, which could result in improved efficacy from BV and reduced toxicity due to the omission of vincristine. While BV displayed only limited clinical activity as monotherapy in aggressive r/r B-cell lymphomas, it has not been widely studied in the frontline setting or in combination with chemotherapy.24,29 In our phase I/II study, we showed that a frontline regimen using BV at a dose of 1.8 mg/kg in combination with R-CHP for patients with CD30+ B-cell lymphomas has an acceptable toxicity profile and is highly active. Our study included a heterogeneous group of B-cell lymphomas, but the majority of the patients had a clinicopathological diagnosis of PMBCL. For many reasons, this is a challenging population to study in a frontline setting. PMBCL is a rare and clinically heterogeneous lymphoma. Patients with this type of lymphoma often present with an acute onset of pulmonary symptoms necessitating urgent therapy which may lead to a selection bias in nonrandomized studies. While several frontline treatment approaches are effective in PMBCL, there are unique challenges in this population of patients. DA-EPOCH-R is a highly active dose-intense regimen, but it requires central venous access, use of growth factors, frequent blood testing, and inpatient admission at some institutions. RCHOP is easier to administer, but the excellent outcomes in PMBCL are achieved using consolidative radiation therapy, which may cause long-term toxicities.14,16,30,31 While a recently published phase III trial comparing R-CHOP versus DA-EPOCH-R in DLBCL included a small cohort of PMBCL cases (n=35), it was not statistically powered to detect the differences in this lymphoma subtype.17 We recognize that it is difficult to compare regimens across different trials, but outcomes within the PMBCL cohort in our study are comparable to previously published results for patients treated with R-CHOP with radiotherapy or dose-intense regimens such as DAEPOCH- R.14-16,19,30,32 For lymphoma subtypes other than PMBCL, the numbers of patients were too small to make any efficacy conclusions regarding BV-R-CHP. One of two patients with GZL relapsed after achieving a complete response and none of the five patients with CD30+ DLBCL relapsed, which is encouraging. Interestingly, preliminary results from another phase II trial (ClinicalTrial.gov identifier: NCT01925612) using BV-R-CHOP in DLBCL (without any requirement for CD30 staining) documented an overall response rate of 97% in the initial 30 evaluable patients. None of the CD30+ DLBCL patients in the preliminary report relapsed, but the median follow-up of 5 months was short.33 Regarding toxicity of the BV-R-CHP regimen, there were no study-related deaths. With the caveats about cross-trial comparisons of studies, the rate of grade 3 or 4 hematologic and non-hematologic toxicities was similar or lower compared to the rates reported for R-CHOP.17,34 When compared to the DA-EPOCH-R arm from the recently published randomized trial in DLBCL, there appears to be less toxicity with BV-R-CHP in our study.17 However, one limitation of this comparison is the younger median age of patients in our cohort. Neuropathy is of particular concern with a BV-containing regimen and was closely monitored in our study. While peripheral sensory neuropathy was reported in 61% of patients, no patient experienced grade 3 or 4 neuropathy. This lack of severe peripheral neuropathy may again relate to the young age of our patients and the fact that our BV-containing regimen did not contain additional vinca alkaloids, in contrast to some of the other BV-containing combinations used frontline.4,33 There were no unexpected opportunistic infections using the combination of rituximab and BV. The administration of G-CSF was not consistent across the participating institutions in our study, but over 20% of patients did not require G-CSF at all or its use was limited to one or two cycles. However, considering that 23% of patients experienced febrile neutropenia, empiric use of G-CSF should be considered in patients being treated with BV-R-CHP. With regard to long-term toxicities, one patient developed acute myeloid leukemia 2 years after completing the trial therapy and radiation. It is not possible to determine the association between the protocol treatment and her leukemia, but the fact that the patient’s mother died of acute myeloid leukemia and the patient had normal cytogenetics (rare in secondary leukemias) is suggestive of other contributing factors. Figure 4. Correlation of Lymph3Cx results with standard clinicopathological diagnoses made by the investigators. DLBCL: diffuse large B-cell lymphoma; GZL: gray zone lymphoma; PMBCL: primary mediastinal B-cell lymphoma. Patients who progressed are labeled by an arrow. Of 14 patients with PMBCL diagnosed by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9, which were consistent with a molecular diagnosis of PMBCL by gene expression analysis, two patients (14%) scored in the indeterminate category (0.1 to 0.9), and one patient (7%) scored as having DLBCL (< 0.1). The high rate of thrombosis in the PMBCL cohort is of special interest. Thromboses were found in over one third of PMBCL patients and approximately 50% were diagnosed prior to initiation of therapy. This high risk of thrombosis in PMBCL patients was described with similar frequency in retrospective studies and is not likely to be related to BV-R-CHP.19,35 This finding warrants further investigations about screening, the potential contribution of central lines to thrombosis, and any possible role for prophylactic anticoagulation in PMBCL patients. We also attempted to define clinical and pathological factors which would correlate with outcomes of patients receiving BV-R-CHP therapy for CD30+ B-cell lymphomas. IPI risk group, which is well-established as a prognostic factor for outcomes of frontline treatments in DLBCL, did not clearly correlate with complete response rate, progression-free survival or overall survival in our study. This could be due to the small number of patients in the high or high-intermediate IPI risk category. Furthermore, the majority of our patients had PMBCL and the utility of the IPI has some limitations as most patients are young and present with limited stage disease. For our ancillary studies, we planned an analysis of CD30 expression by immunohistochemistry and correlation with outcomes as there is controversy over the impact of CD30 status on the efficacy of BV.33,36,37 However, this proved difficult because of the very low number of relapses and heterogeneity of CD30 staining patterns in neoplastic cells (Figure 3). Additional studies beyond a simple determination of the percentage of CD30+ cells by immunohistochemistry and visual assessment will need to be applied and other groups have attempted this with some success.37,38 Among 21 patients who had pre-treatment tissue analyzed by LymphC3x, we found that there was discordance between the protocol-specified standard clinicopathological diagnosis of PMBCL and the gene expression- based method. These findings are thought-provoking since, in small trials of PMBCL, even a few misclassified patients may have a great impact on interpretation of the results. We believe that developing objective diagnostic criteria based on quantitative methods, such as gene expression signatures, will be an important step in designing treatment strategies for B-cell lymphoma patients with mediastinal lesions and for comparing results across PMBCL trials. This trial is limited by the small number of evaluable patients and diagnostic heterogeneity. However, the entities included are rare, and we involved three institutions to enroll 32 patients. One of the challenges when interpreting the clinical efficacy and progression-free/overall survival data of patients treated with the BV-R-CHP regimen is the fact that consolidative radiation was used in about 50% of all patients enrolled on this trial. The protocol was designed in 2011-2012 when R-CHOP followed by consolidative radiation therapy was utilized by most centers for PMBCL patients. Therefore, the protocol allowed investigators to use consolidative radiotherapy after completion of BV-R-CHP. It is important to note that the end-of-treatment response assessment was performed before radiation. Interestingly, there were no statistically significant differences in progression-free or overall survival between patients who received consolidative radiation and those who did not. There were no clear differences in patients’ characteristics between those who received consolidative radiotherapy and those who did not other than institutional practice differences. Of the four patients who did not achieve metabolic complete response on end-of-treatment imaging, two received consolidative radiation therapy and two did not. Longer follow-up will be necessary to determine whether there are any long-term toxicities of radiation in the study participants (with the majority of patients having received proton radiation). Of note, an ongoing randomized trial in patients with PMBCL may allow us to determine whether consolidative radiation therapy after frontline chemoimmunotherapy is necessary in patients who achieve metabolic complete response after systemic treatment (ClinicalTrial.gov identifier: NCT01599559). BV in combination with R-CHP with or without consolidative radiation therapy is a feasible and active frontline treatment in patients with CD30+ B-cell lymphomas. The safety profile of this regimen, ease of administration and preliminary efficacy data appear promising. The next generation of trials in CD30+ B-cell lymphomas and PMBCL should take into consideration the clinical and biological heterogeneity of these lymphomas. Ultimately, developing treatment regimens that will be tailored to unique tumor and patient characteristics will result in improved outcomes and will minimize treatment-related toxicities.

Intravenous (not otherwise specified)

DrugAdministrationRoute

CC BY-NC

32414850

2021-06-01

What was the dosage of drug 'BRENTUXIMAB VEDOTIN'?

Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas. We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850). Introduction Brentuximab vedotin (BV) is an immunoconjugate consisting of a CD30-directed antibody linked to the anti-microtubule agent auristatin.1 BV is highly active in relapsed and refractory (r/r) classical Hodgkin lymphoma and in CD30-expressing T-cell lymphomas.2,3 In the frontline setting, BV combined with chemotherapy has been recently approved for advanced classical Hodgkin lymphoma and CD30-positive (CD30+) T-cell lymphomas based on results of randomized trials showing benefit of the BV-containing arms.4,5 BV targets the cell membrane protein CD30 that is expressed not only by classical Hodgkin lymphoma and some T-cell lymphomas, but at various frequencies also by B-cell non-Hodgkin lymphomas including up to 80% of primary mediastinal B-cell lymphomas (PMBCL).6-9 PMBCL is a mature large B-cell lymphoma of thymic origin which usually presents with mediastinal masses. It occurs predominantly in young adults and represents about 5% of aggressive B-cell lymphomas.10 While previous classifications considered it as a subtype of diffuse large B-cell lymphoma (DLBCL), PMBCL is now thought of as a distinct clinicopathological entity with clinical features and also a molecular signature that share similarities with those of classical Hodgkin lymphoma.11 Recent efforts using gene expression profiling have aimed at better defining PMBCL at the molecular level and distinguishing it from other aggressive B-cell lymphomas with mediastinal presentation. In particular, the NanoString© based Lymph3Cx assay measures expression of 58 genes and allows precise identification of PMBCL cases.12 Presently, the optimal frontline management of patients with PMBCL remains controversial. Traditionally, PMBCL was included in clinical trials regarding aggressive B-cell lymphomas and regimens designed for DLBCL were found to be effective.13-17 Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) results in event-free survival rates of about 80% when followed by consolidative radiation therapy.14,16 In 2013, in a phase II trial by Dunleavy et al. including 51 PMBCL patients treated at the National Cancer Institute, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, plus rituximab (DA-EPOCH-R) without radiotherapy achieved an event-free survival of 93%.15 Many centers in the USA now use this dose-intense DA-EPOCH-R approach for frontline treatment of all PMBCL patients without considering any risk stratification. 15 Some patients with r/r PMBCL, can be salvaged by high-dose chemotherapy with autologous stem cell transplant or radiation, but outcomes tend to be poor.18,19 Recently, pembrolizumab and axicabtagene ciloleucel were approved for the treatment of r/r PMBCL.20-22 While the activity of BV as monotherapy in r/r PMBCL has been disappointing, results of a phase II trial using nivolumab in combination with BV are very encouraging.23,24 To test the tolerability and make a preliminary assessment of the efficacy of BV in frontline treatment of B-cell lymphomas, we designed a phase I/II trial using BV in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of CD30+ PMBCL, DLBCL, and gray zone lymphoma (GZL) in adult patients (ClinicalTrials.gov identifier: NCT01994850). Methods Study design and patient eligibility This multicenter, single arm, phase I/II study enrolled patients aged 18 years and over with untreated histologically confirmed CD30+ PMBCL, DLBCL, or GZL. Patients with any stage, measurable disease, and an Eastern Cooperative Oncology Group Performance Status of 3 or less were eligible. The diagnostic biopsy had to demonstrate at least 1% or higher expression of CD30 on the lymphoma B cells by immunohistochemistry and was assessed independently by two pathologists. Patients with active central nervous system involvement and uncontrolled systemic infections were excluded. Enrollment began in January 2014 and was completed in April 2017. The primary objective of the phase I portion was to determine the safety of the combination and the maximum tolerated dose of BV in combination with R-CHP using a de-escalation design. The primary objective of the phase II portion was the overall response rate at the end of systemic treatment as determined by investigator assessment using International Working Group response criteria for non-Hodgkin lymphoma.25 Secondary endpoints were 2-year progression-free survival and 2- year overall survival for all patients and by each lymphoma subtype (PMBCL, DLBCL, and GZL). With regard to the toxicity assessment, the study had 90% power to detect any unforeseen toxicity that occurred in 7% or more of patients. The number of patients required for the trial was determined based on the following assumptions for an optimal two-stage design in order to detect and minimize enrollment if the overall response rate was not greater than 50% but also to minimize the likelihood of failing to reject the null hypothesis if the overall response rate was at least 70%. Sample size calculations for the stopping rules were based upon a type I error rate of 10% and type II error rate of 20%. The number of subjects enrolled and evaluable in the phase I cohort was defined as at least six and a maximum of 12. For the phase II cohort, using the null hypothesis of a 50% overall response rate, the study required a sample size of 20 patients. Since the phase I subjects were recruited, treated, and followed in the same way as the phase II subjects, the phase I subjects accrued at the phase II dose were included in the efficacy analysis. Table 1. The study regimen: brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BV-R-CHP). The study was conducted in three academic centers in the USA and was run in accordance with the Declaration of Helsinki. Approval from the institutional review board of each center was obtained before initiating the study at each site. All patients signed a written informed consent form before enrollment into the trial. Treatment protocol and response assessment As shown in Table 1, the study treatment protocol consisted of six cycles of BV administered with the R-CHOP regimen without vincristine, including: rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 on day 1 and prednisone 100 mg (or equivalent) daily on days 1 through 5 of each 21-day cycle. For cycle 1, rituximab was split into two doses (100 mg/m2 on day 1 and 275 mg/m2 on day 2) to reduce risks of an infusion reaction to rituximab. We also aimed to separate the initial rituximab infusion from the first exposure to BV to avoid any potential confusion about attribution of infusion reactions. The rest of the agents were given on day 2 (cyclophosphamide, doxorubicin, BV). In cycles 2 through 6, rituximab was administered at a dose of 375 mg/m2 on day 1 together with the rest of the agents. For phase I, the starting dose of BV was 1.8 mg/kg (maximum dose of 180 mg) with a 3+3 de-escalation design to 1.2 mg/kg (maximum dose of 120 mg) should dose-limiting toxicities occur during the first 21-day cycle. A dose-limiting toxicity was defined as any grade 3 or 4 non-hematologic toxicity requiring a dose delay over 14 days from the planned day 1 of cycle 2 or any hematologic toxicity not returning to baseline or ≤ grade 2 by 21 days from the planned day 1 of cycle 2. By protocol, at least six patients had to be enrolled and complete one cycle of dosing at the final recommended BV dose in phase I prior to beginning enrollment of patient in phase II. Dose modifications during cycle 2 through 6 for treatment-associated toxicity were specified in the protocol and based on the grade using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The use of granulocyte-colony stimulating factor (G-CSF) was allowed as per institutional policy. Consolidative radiation therapy was permitted after completion of all systemic therapy and only after end-of-treatment imaging at the discretion of the treating physician. Figure 1. CONSORT diagram. GZL: gray zone lymphoma; cHL: classical Hodgkin lymphoma; EOT: end of treatment. Table 2. Patients’ characteristics. Treatment response was assessed by imaging with fluorodeoxyglucose- positron emission tomography/computed tomography (FDG-PET/CT) using the revised response criteria for malignant lymphoma described by Cheson et al.25 Computed tomography scans were performed after cycles 2 and 4 to monitor for interim response. End-of-treatment imaging was performed 3-5 weeks after completion of systemic therapy using FDG-PET/CT. Consolidative radiation following end-of-treatment response assessment was permissible at the discretion of the treating physician. Correlative studies CD30 expression was determined on the diagnostic tissue biopsies using immunohistochemistry though visual inspection by two independent pathologists. The gene expression analysis (Lymph3Cx) was performed on archival formalin-fixed, paraffinembedded tissue from pre-treatment biopsies. The tissue was examined by a hematopathologist for adequate tumor amount and nucleic acids were extracted from formalin-fixed paraffinembedded scrolls or unstained slides. The Lymph3Cx assay was previously described and validated to aid in the molecular distinction of PMBCL versus DLBCL.26 The gene expression assay on the diagnostic tissue was performed in a blinded fashion, and once the assignment of diagnosis by Lymph3Cx was made, a correlation with investigator-based diagnosis (PMBCL vs. DLBCL vs. GZL) was performed. Statistical analysis The overall response rate and complete response rate with a two-sided 95% exact confidence intervals (95% CI) were calculated using the Clopper-Pearson method. Two-year progression-free and overall survival rates were estimated using the Kaplan-Meier method. The median follow-up was estimated by the reverse Kaplan-Meier method.27 The data cut-off for analysis was January 1, 2019. Results Patients’ characteristics Thirty-three patients gave consent to enrollment in the trial (Figure 1). One of these patients was subsequently reclassified from having GZL to having classical Hodgkin lymphoma and was taken off the study before starting therapy. Thus, 32 patients were enrolled and received at least one cycle of therapy. One patient withdrew from the study after cycle 1 to receive R-CHOP therapy closer to home. The characteristics of the patients evaluable for toxicity (n=31) are presented in Table 2. The median age was 37 years (range, 18-76), 50% of the patients were female, 42% had stage III/IV disease and 17% were classified in high-intermediate or high International Prognostic Index (IPI) risk group.28 Using traditional clinicopathological criteria, 23 patients had a diagnosis of PMBCL, six were diagnosed as having DLBCL, and two as having GZL. For the PMBCL cohort, 91% of patients had large mediastinal masses over 7.5 cm in maximal transverse diameter and 35% had stage III/IV disease. Two patients were removed from the study (1 patient because of non-compliance and 1 in complete remission because of a regimen violation). Therefore, a total of 29 patients were evaluable for efficacy. Of those, 15 patients (52%) received consolidative radiation after completing BV-RCHP and final end-of-treatment response assessment. This number included 13 (59%) of 22 evaluable PMBCL patients. Of those, 8 patients received radiation using protons. Twenty-six patients had archival formalin-fixed paraffin-embedded diagnostic tissue available for Lymph3Cx gene expression analysis. Safety and feasibility Toxicities of this outpatient regimen are listed in Table 3A and B. There were no treatment-related or on-study deaths. Using a de-escalation design during the phase I portion of the trial, the first six patients were treated with the initial dose of 1.8 mg/kg (maximum 180 mg) in combination with standard dose R-CHP with plans to reduce BV to 1.2 mg/kg (maximum 120 mg) should there be dose-limiting toxicities. As there were no dose-limiting toxicities during phase I, the BV dose of 1.8 mg/kg (maximum 180 mg) was used as the phase II dose. Overall in all patients (combining phase I and phase II cohorts), any grade 3 or 4 toxicity occurred in 84% of study patients. Hematologic adverse events of any grade were recorded in the majority of patients and in 77% of patients with grade 3 or 4 toxicities. Of note, 16% of patients received no G-CSF and 6% had G-CSF support for only one or two of the six cycles. Non-hematologic grade 3 and 4 toxicities were seen in 32% of patients, including infections in 15% of patients (Table 3B). Toxicities occurring in over 10% of patients included peripheral sensory neuropathy in 19 patients (61%) which were either grade 1 (48%) or grade 2 (13%) (Table 3A). Three patients (10%) reported motor neuropathy, two with grade 1 (6%) and one with grade 2 (3%). One patient discontinued protocol treatment after cycle 4 because of sepsis and grade 3 cardiomyopathy. One patient discontinued BV after cycle 5 because of transient grade 2 pneumonitis which was deemed at least possibly related to BV. Only three patients required BV dose reductions to 1.2 mg/kg because of persistent grade 2 peripheral sensory neuropathy outside of the period of dose-limiting toxicities. In total, two patients enrolled on the study died in the follow- up period. One PMBCL patient developed acute myeloid leukemia 2 years after completion of study treatment and mediastinal radiation therapy and ultimately died of acute myeloid leukemia 39 months after completing study treatment. One patient died of progressive lymphoma 40 months after completing study treatment. Thromboembolic events were noted in eight patients (36%) in the PMBCL cohort. Pulmonary embolism was seen in three patients and upper extremity deep vein thrombosis in five patients. Of those, three events were diagnosed prior to initiating BV-R-CHP and five events were diagnosed while patients were on study treatment. Three of the five patients who had on-treatment events were asymptomatic and thrombosis was reported as an incidental finding on their first computed tomography with intravenous contrast (1 with pulmonary embolism and 1 with internal jugular vein thrombosis). Two of the five patients with on-treatment events had line-associated thromboses. Table 3A All adverse events at least possibly related to the BV-R-CHP regimen. Table 3B Grade 3 or 4 adverse events at least possibly related to the BV-R-CHP regimen. Efficacy In the combined phase I/II cohort with 29 evaluable patients, the overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving a complete response and 14% (95% CI: 4-32) achieving a partial response according to FDG-PET/CT imaging at the end of treatment. All four patients with a partial response had a diagnosis of PMBCL and had a low or low-intermediate IPI risk classification. Only two of the four patients with a partial response ultimately progressed. At a median follow-up of 30 months (95% CI: 26-46), four patients (14%) progressed: three with PMBCL and one with GZL. The 2-year progression-free survival rate was 85% (95% CI: 66-94) and the 2-year overall survival was 100% (Figure 2). Of three patients who were not evaluable per study criteria, two remain progression-free at last followup and the status of one patient is unknown. In the PMBCL cohort of 22 evaluable patients with a median follow-up of 30 months (95% CI: 23-46), the 2- year progression-free survival rate was 86% (95% CI: 62-95) with a 2-year overall survival of 100% (Figure 2). Of the three PMBCL patients who progressed, two had bulky advanced stage disease with expression of CD30 ≤10% and one had bulky stage I disease with CD30 expression of 1%. There was no statistically significant difference in progression-free survival between the PMBCL patients who received consolidative radiation therapy (n=13) and those who did not (n=9) (P=0.95). CD30 expression as determined by immunohistochemistry and response to therapy While all cases expressed CD30 in at least 1% of the lymphoma B cells in the tumor biopsy by immunohistochemistry, it was challenging to capture CD30 expression as a single metric since there was great heterogeneity of CD30 expression patterns, as depicted in Figure 3. Additionally, given the 100% overall response rate and low number of relapses, we could not make any conclusions about correlations between efficacy of the BV-containing regimen and CD30 expression as determined by immunohistochemistry. Gene expression analysis to improve diagnostic accuracy of primary mediastinal B-cell lymphoma Of 29 evaluable patients with CD30+ B-cell lymphoma, 26 had a pre-treatment biopsy available (11 excisional biopsies and 15 core needle biopsies). Of the 26 samples, five core needle biopsies did not have adequate tumor content or amounts of extractable RNA for the Lymph3Cx assay. The biopsies of the remaining 21 patients (11 excisional and 10 core needle biopsies) were tested. All three subtypes of CD30+ B-cell lymphomas as assessed by investigator assessment were tested in blinded fashion by the Lymph3Cx assay and comprised 14 cases of PMBCL, six of DLBCL, and one case of GZL. Of 14 patients with PMBCL by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9 which were consistent with a molecular diagnosis of PMBCL (mPMBCL) by gene expression; two patients scored in the indeterminate category (0.1 to 0.9); and one patient scored as having a molecular diagnosis of DLBCL (< 0.1) (Figure 4). None of the CD30+ B-cell lymphoma samples that were felt to be DLBCL by investigator assessment scored as having a molecular diagnosis of PMBCL by Lymph3Cx. Figure 2. Survival curves for patients who received the BV-R-CHP treatment regimen. (A, B) Progression-free survival (A) and overall survival (B) of all evaluable patients enrolled in the trial (n=29). (C, D) Progression-free survival (C) and overall survival (D) of evaluable patients with primary mediastinal B-cell lymphoma (PMBCL) (n=22). Figure 3. Examples of different CD30 staining patterns by immunohistochemistry in three representative patients with primary mediastinal B-cell lymphoma enrolled on the trial. (A) Heterogeneous staining pattern with strong and dim staining in different areas of the same tumor. (B) Focal staining in one area of the tumor. (C) Diffuse staining throughout the tumor. The antibodies used were CD20 (ready to use, DAKO) and CD30 (ready to use, Leica) and they were detected using a chromogenic substrate, diaminobenzene (Leica). An original magnification x200 was used for all images. H&E: hematoxylin & eosin. Discussion There is a strong rationale for replacing vincristine with BV in the standard R-CHOP regimen for the treatment of CD30+ aggressive B-cell lymphomas. BV specifically delivers the antimicrotubule agent auristatin to CD30-expressing cells, which could result in improved efficacy from BV and reduced toxicity due to the omission of vincristine. While BV displayed only limited clinical activity as monotherapy in aggressive r/r B-cell lymphomas, it has not been widely studied in the frontline setting or in combination with chemotherapy.24,29 In our phase I/II study, we showed that a frontline regimen using BV at a dose of 1.8 mg/kg in combination with R-CHP for patients with CD30+ B-cell lymphomas has an acceptable toxicity profile and is highly active. Our study included a heterogeneous group of B-cell lymphomas, but the majority of the patients had a clinicopathological diagnosis of PMBCL. For many reasons, this is a challenging population to study in a frontline setting. PMBCL is a rare and clinically heterogeneous lymphoma. Patients with this type of lymphoma often present with an acute onset of pulmonary symptoms necessitating urgent therapy which may lead to a selection bias in nonrandomized studies. While several frontline treatment approaches are effective in PMBCL, there are unique challenges in this population of patients. DA-EPOCH-R is a highly active dose-intense regimen, but it requires central venous access, use of growth factors, frequent blood testing, and inpatient admission at some institutions. RCHOP is easier to administer, but the excellent outcomes in PMBCL are achieved using consolidative radiation therapy, which may cause long-term toxicities.14,16,30,31 While a recently published phase III trial comparing R-CHOP versus DA-EPOCH-R in DLBCL included a small cohort of PMBCL cases (n=35), it was not statistically powered to detect the differences in this lymphoma subtype.17 We recognize that it is difficult to compare regimens across different trials, but outcomes within the PMBCL cohort in our study are comparable to previously published results for patients treated with R-CHOP with radiotherapy or dose-intense regimens such as DAEPOCH- R.14-16,19,30,32 For lymphoma subtypes other than PMBCL, the numbers of patients were too small to make any efficacy conclusions regarding BV-R-CHP. One of two patients with GZL relapsed after achieving a complete response and none of the five patients with CD30+ DLBCL relapsed, which is encouraging. Interestingly, preliminary results from another phase II trial (ClinicalTrial.gov identifier: NCT01925612) using BV-R-CHOP in DLBCL (without any requirement for CD30 staining) documented an overall response rate of 97% in the initial 30 evaluable patients. None of the CD30+ DLBCL patients in the preliminary report relapsed, but the median follow-up of 5 months was short.33 Regarding toxicity of the BV-R-CHP regimen, there were no study-related deaths. With the caveats about cross-trial comparisons of studies, the rate of grade 3 or 4 hematologic and non-hematologic toxicities was similar or lower compared to the rates reported for R-CHOP.17,34 When compared to the DA-EPOCH-R arm from the recently published randomized trial in DLBCL, there appears to be less toxicity with BV-R-CHP in our study.17 However, one limitation of this comparison is the younger median age of patients in our cohort. Neuropathy is of particular concern with a BV-containing regimen and was closely monitored in our study. While peripheral sensory neuropathy was reported in 61% of patients, no patient experienced grade 3 or 4 neuropathy. This lack of severe peripheral neuropathy may again relate to the young age of our patients and the fact that our BV-containing regimen did not contain additional vinca alkaloids, in contrast to some of the other BV-containing combinations used frontline.4,33 There were no unexpected opportunistic infections using the combination of rituximab and BV. The administration of G-CSF was not consistent across the participating institutions in our study, but over 20% of patients did not require G-CSF at all or its use was limited to one or two cycles. However, considering that 23% of patients experienced febrile neutropenia, empiric use of G-CSF should be considered in patients being treated with BV-R-CHP. With regard to long-term toxicities, one patient developed acute myeloid leukemia 2 years after completing the trial therapy and radiation. It is not possible to determine the association between the protocol treatment and her leukemia, but the fact that the patient’s mother died of acute myeloid leukemia and the patient had normal cytogenetics (rare in secondary leukemias) is suggestive of other contributing factors. Figure 4. Correlation of Lymph3Cx results with standard clinicopathological diagnoses made by the investigators. DLBCL: diffuse large B-cell lymphoma; GZL: gray zone lymphoma; PMBCL: primary mediastinal B-cell lymphoma. Patients who progressed are labeled by an arrow. Of 14 patients with PMBCL diagnosed by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9, which were consistent with a molecular diagnosis of PMBCL by gene expression analysis, two patients (14%) scored in the indeterminate category (0.1 to 0.9), and one patient (7%) scored as having DLBCL (< 0.1). The high rate of thrombosis in the PMBCL cohort is of special interest. Thromboses were found in over one third of PMBCL patients and approximately 50% were diagnosed prior to initiation of therapy. This high risk of thrombosis in PMBCL patients was described with similar frequency in retrospective studies and is not likely to be related to BV-R-CHP.19,35 This finding warrants further investigations about screening, the potential contribution of central lines to thrombosis, and any possible role for prophylactic anticoagulation in PMBCL patients. We also attempted to define clinical and pathological factors which would correlate with outcomes of patients receiving BV-R-CHP therapy for CD30+ B-cell lymphomas. IPI risk group, which is well-established as a prognostic factor for outcomes of frontline treatments in DLBCL, did not clearly correlate with complete response rate, progression-free survival or overall survival in our study. This could be due to the small number of patients in the high or high-intermediate IPI risk category. Furthermore, the majority of our patients had PMBCL and the utility of the IPI has some limitations as most patients are young and present with limited stage disease. For our ancillary studies, we planned an analysis of CD30 expression by immunohistochemistry and correlation with outcomes as there is controversy over the impact of CD30 status on the efficacy of BV.33,36,37 However, this proved difficult because of the very low number of relapses and heterogeneity of CD30 staining patterns in neoplastic cells (Figure 3). Additional studies beyond a simple determination of the percentage of CD30+ cells by immunohistochemistry and visual assessment will need to be applied and other groups have attempted this with some success.37,38 Among 21 patients who had pre-treatment tissue analyzed by LymphC3x, we found that there was discordance between the protocol-specified standard clinicopathological diagnosis of PMBCL and the gene expression- based method. These findings are thought-provoking since, in small trials of PMBCL, even a few misclassified patients may have a great impact on interpretation of the results. We believe that developing objective diagnostic criteria based on quantitative methods, such as gene expression signatures, will be an important step in designing treatment strategies for B-cell lymphoma patients with mediastinal lesions and for comparing results across PMBCL trials. This trial is limited by the small number of evaluable patients and diagnostic heterogeneity. However, the entities included are rare, and we involved three institutions to enroll 32 patients. One of the challenges when interpreting the clinical efficacy and progression-free/overall survival data of patients treated with the BV-R-CHP regimen is the fact that consolidative radiation was used in about 50% of all patients enrolled on this trial. The protocol was designed in 2011-2012 when R-CHOP followed by consolidative radiation therapy was utilized by most centers for PMBCL patients. Therefore, the protocol allowed investigators to use consolidative radiotherapy after completion of BV-R-CHP. It is important to note that the end-of-treatment response assessment was performed before radiation. Interestingly, there were no statistically significant differences in progression-free or overall survival between patients who received consolidative radiation and those who did not. There were no clear differences in patients’ characteristics between those who received consolidative radiotherapy and those who did not other than institutional practice differences. Of the four patients who did not achieve metabolic complete response on end-of-treatment imaging, two received consolidative radiation therapy and two did not. Longer follow-up will be necessary to determine whether there are any long-term toxicities of radiation in the study participants (with the majority of patients having received proton radiation). Of note, an ongoing randomized trial in patients with PMBCL may allow us to determine whether consolidative radiation therapy after frontline chemoimmunotherapy is necessary in patients who achieve metabolic complete response after systemic treatment (ClinicalTrial.gov identifier: NCT01599559). BV in combination with R-CHP with or without consolidative radiation therapy is a feasible and active frontline treatment in patients with CD30+ B-cell lymphomas. The safety profile of this regimen, ease of administration and preliminary efficacy data appear promising. The next generation of trials in CD30+ B-cell lymphomas and PMBCL should take into consideration the clinical and biological heterogeneity of these lymphomas. Ultimately, developing treatment regimens that will be tailored to unique tumor and patient characteristics will result in improved outcomes and will minimize treatment-related toxicities.

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