RoopeshDuvvi/final_results
Updated
•
6
•
1
title
stringlengths 21
314
| abstract
stringlengths 24
4.47k
| fulltext
stringlengths 1.5k
115k
| target
stringlengths 60
1.33k
| pmid
stringlengths 7
8
| fulltext_license
stringclasses 7
values | title_normalized
stringlengths 20
311
| issue
stringlengths 0
13
| pages
stringlengths 0
16
| journal
stringlengths 3
176
| authors
stringlengths 12
3.12k
| pubdate
stringlengths 4
10
| doi
stringlengths 0
43
| affiliations
stringlengths 0
18.8k
| medline_ta
stringlengths 3
48
| nlm_unique_id
stringlengths 7
9
| issn_linking
stringlengths 0
9
| country
stringlengths 4
25
| mesh_terms
stringlengths 0
959
| publication_types
stringlengths 14
221
| chemical_list
stringlengths 0
738
| keywords
stringlengths 0
1.13k
| references
stringlengths 0
2.77k
| delete
bool 1
class | pmc
stringclasses 1
value | other_id
stringclasses 1
value | safetyreportid
int64 5.78M
21M
| fulltext_processed
stringlengths 638
92.6k
|
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
SARS-CoV-2-related ARDS in a maintenance hemodialysis patient: case report on tailored approach by daily hemodialysis, noninvasive ventilation, tocilizumab, anxiolytics, and point-of-care ultrasound. | Without rescue drugs approved, holistic approach by daily hemodialysis, noninvasive ventilation, anti-inflammatory medications, fluid assessment by bedside ultrasound, and anxiolytics improved outcomes of a maintenance hemodialysis patient affected by severe COVID-19. |
==== Front
Clin Case Rep
Clin Case Rep
10.1002/(ISSN)2050-0904
CCR3
Clinical Case Reports
2050-0904
John Wiley and Sons Inc. Hoboken
33362933
10.1002/ccr3.3623
CCR33623
Case Report
Case Reports
SARS‐CoV‐2–related ARDS in a maintenance hemodialysis patient: case report on tailored approach by daily hemodialysis, noninvasive ventilation, tocilizumab, anxiolytics, and point‐of‐care ultrasound
GALASSI et al.
Galassi Andrea https://orcid.org/0000-0001-7533-2876
1 [email protected]
Casanova Francesca 2
Gazzola Lidia 3
Rinaldo Rocco 4
Ceresa Marco 5
Restelli Elena 2
Giorgini Alessia 6
Birocchi Simone 2
Giovenzana Marco 7
Zoni Ulisse 2
Valli Federica 8
Massironi Laura 8
Belletti Sebastiano 8
Magagnoli Lorenza 1
Stucchi Andrea 1
Ippolito Michela 1
Carugo Stefano https://orcid.org/0000-0002-5166-0899
8
Parazzini Elena 4
Cozzolino Mario https://orcid.org/0000-0002-8494-6252
1 9
1 Renal & Dialysis Unit S. Paolo Hospital ASST Santi Paolo e Carlo Milan Italy
2 Internal Medicine Unit S. Paolo Hospital ASST Santi Paolo e Carlo Milan Italy
3 Department of Health Sciences Clinic of Infectious Disease “San Paolo” Hospital‐University of Milan Milan Italy
4 Respiratory Unit Department of Health Sciences University of Milan ASST Santi Paolo e Carlo Milan Italy
5 Palliative Care Unit S. Paolo Hospital ASST Santi Paolo e Carlo Milan Italy
6 Gastroenterology and Hepatology Unit S. Paolo Hospital ASST Santi Paolo e Carlo Milan Italy
7 Unit of Hepatobiliary, Pancreatic, and Digestive Surgery Department of Surgery S. Paolo Hospital University of Milan Milan Italy
8 Division of Cardiology S. Paolo Hospital University of Milan Milan Italy
9 Department of Health Sciences University of Milan Milan Italy
* Correspondence
Andrea Galassi, Renal & Dialysis Unit, S. Paolo Hospital, ASST Santi Paolo e Carlo, Milan, Italy.
Email: [email protected]
04 12 2020
2 2021
9 2 10.1002/ccr3.v9.2 694703
18 10 2020
16 11 2020
18 11 2020
© 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.
This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
Abstract
Without rescue drugs approved, holistic approach by daily hemodialysis, noninvasive ventilation, anti‐inflammatory medications, fluid assessment by bedside ultrasound, and anxiolytics improved outcomes of a maintenance hemodialysis patient affected by severe COVID‐19.
Without rescue drugs approved, holistic approach by daily hemodialysis, noninvasive ventilation, anti‐inflammatory medications, fluid assessment by bedside ultrasound, and anxiolytics improved outcomes of a maintenance hemodialysis patient affected by severe COVID‐19.
COVID‐19
expanded hemodialysis
hemodialysis
point‐of‐care ultrasound
suprahepatic veins venogram
tocilizumab
source-schema-version-number2.0
cover-dateFebruary 2021
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.7 mode:remove_FC converted:08.02.2021
Galassi A , Casanova F , Gazzola L , et al. SARS‐CoV‐2–related ARDS in a maintenance hemodialysis patient: case report on tailored approach by daily hemodialysis, noninvasive ventilation, tocilizumab, anxiolytics, and point‐of‐care ultrasound. Clin Case Rep.2021;9 :694–703. 10.1002/ccr3.3623
==== Body
1 INTRODUCTION
A 50‐year‐old man, on maintenance hemodialysis, was affected by SARS‐CoV‐2–related acute respiratory distress syndrome. Multipronged intervention included daily expanded hemodialysis, noninvasive ventilation, anti‐inflammatory medications, fluid assessment by point‐of‐care ultrasound, and anxiolytics. Individualized subintensive care improved outcomes of a maintenance hemodialysis (MHD) patient affected by severe SARS‐CoV‐2–associated disease.
SARS‐CoV‐2–related disease (COVID‐19) affected MHD patients, 1 , 2 , 3 leading to high rate of hospitalization (61%), 2 acute respiratory distress syndrome (ARDS) (79%), 2 and mortality (11%‐29%) in Europe. 2 , 3 Cardiovascular disease resulted a strong independent predictor of worse outcomes. 1 , 2
Suggestions were published on how to prevent interhuman transmission of SARS‐CoV‐2 within facilities 4 and treating COVID‐19 in HD patients. 5 , 6 Although a gold standard of care remains uncertain, without a single intervention capable of healing the disease has yet been identified, several clinical issues could be relevant for caring MHD patients affected by severe COVID‐19.
Tailored management of fluids represents a mainstay for treating COVID‐19 critical cases. 6 , 7 Point‐of‐care ultrasound (US) was suggested for improving therapy of patients, 7 , 8 , 9 at high risk of developing SARS‐CoV‐2–related ARDS and acute cardiovascular syndrome, precipitating in heart failure, fluid overload, and death. 10 , 11 , 12
Neurological involvement was described in SARS‐CoV‐2 infection, including high incidence of anxiety and delirium. 13 , 14 , 15 , 16 Although monitoring and treatment of anxiety in COVID‐19 were discussed in intensive care unit (ICU), 14 strategies tailored on MHD patients are unexplored.
Case reports on COVID‐19 MHD patients were reported. 17 , 18 , 19 , 20 , 21 We herein describe the case of a 50‐year‐old hemodialysis (HD) man, affected by COVID‐19–related ARDS, successfully treated in subintensive setting, who developed severe fluid overload, acute myocardial insufficiency, and anxiety, requiring daily dialysis, noninvasive ventilation, anxiolytics, tocilizumab, steroids, and fluid assessment by point‐of‐care US.
Clinical messages are summarized (Figures 1, 2, 3, 4, Figures S1‐S7, Table S1). Assessment of dynamic trend in suprahepatic veins (SHV) venogram is categorized and discussed as potential tool, for improving real‐time diagnosis of venous return and tailoring fluid management in critically ill dialysis patients (Figure 4).
FIGURE 1 Clinical issues suggested by the case, for treating COVID‐19 in critically ill MHD patients. AVF, arteriovenous fistula; BNP, brain natriuretic peptide; CPAP, continuous positive airway pressure; CRRT, continuous renal replacement therapy; ECG, electrocardiography; HD, hemodialysis; ICU, intensive care unit; IL‐6, interleukin‐6; Iv, intravenously; LVEF, ejection fraction; NGT, nasogastric tube; NIMV, noninvasive mechanical ventilation; PAPs, pulmonary arterial pressures; PEEP, positive end respiratory pressure; Po, per os; RASS, Richmond Agitation Sedation Scale; Sc, subcutaneously; TAPSE, tricuspid annular plane systolic excursion
FIGURE 2 Imaging follow‐up by CT scan and thorax X‐rays. Bilateral ground‐glass areas were present on CT scans at day 1, followed by rapid worsening of multifocal pneumonia and vascular congestion from day 4 to day 14. Partial improvement of both inflammatory infiltrates and fluid congestion was observed on days 21 and 31. Extended follow‐up to days 93 and 98 revealed almost complete resolution, excepting apical fibrotic lesions on left lung
FIGURE 3 Daily representation of HD, cardiologic medications, and noninvasive assessment of hemodynamic and fluid distribution. Bicarb HD, bicarbonate hemodialysis; DBP, diastolic blood pressure; ER, emergency room; Exp HD, expanded hemodialysis; HR, heart rate; Iv, intravenously; IVC, inferior vena cava; LV, left ventricular; R., Renal‐COVID‐Unit; SBP, systolic blood pressure; SHV, suprahepatic veins; UF, ultrafiltration
FIGURE 4 Hypothetical dynamic classification of suprahepatic veins venogram. A, Normal SHV pattern during a complete cardiac cycle is characterized by positive A wave (right atrial systole), negative S wave (right ventricular systole), and negative D wave (right ventricular diastole). 9 Small positive wave between S and D (positive V wave) may occasionally be observed. Based on the authors' unpublished data, hypothetically normal SHV pattern is herein classified as a middle range class (class 2) out of 4 classes (0‐4) (fig a). Classes 0‐1 are attributed to increased venous return. Classes 3‐4 are attributed to reduced venous return. Descriptively: class 0 is characterized by fusion of S and D waves, class 1 by initial fusion of S and D waves and initial increase in deceleration time of both. On the opposite: class 3 is characterized by reduced deceleration time of S and D waves, appearing with diamond shape, occasionally associated with Z wave appearance, class 4 is characterized by S wave inversion as previously associated to pulmonary hypertension. 9 Flow patterns of venous return are herein taken as makers of resistance to venous return, hypothetically proportional to real‐time cardiac filling pressures, influenced by both primary cardiac performance as by circulating volume. Thus, classes 0‐1 are taken as markers of progressively increased venous return, reduced resistance to venous return and reduced cardiac filling pressure (soft patterns). On the opposite, classes 3‐4 are taken as markers of progressively reduced venous return, increased resistance to venous return, and increased cardiac filling pressure (hard patterns). Based on the authors' unpublished data, SHV patterns are sensible to inspiration as described for the inferior vena cava (IVC) ultrasonographic interpretation. B, SHV patterns are subcategorized into morphologic patterns assessed during apnea (category A, classes 0‐4) and inspiration (category I, classes 0‐4) leading to 15 combined classes. Hypothetically, patterns during apnea are herein purposed as mainly representative of resistance to venous return, primarily influenced by cardiac performance per se, while patterns assessed during inspiration as more influenced by reduction of venous pressure, secondary to inspiratory weakened mediastinic pressure (volume sensitivity). Thus, class A2‐I2 will correspond to the normal comprehensive class, class A0‐I0 to lowest venous return, lowest resistance, lowest filling pressure, highest volume sensitivity or hypovolemia (soft, volume sensitive or hypovolemic pattern), class A4‐I4 as corresponding to lowest venous return, highest resistance, highest filling pressure, lowest volume sensitivity or hypervolemia (hard, volume insensitive, or hypervolemic pattern). Patterns of IVC will be additive for interpreting SHV pattern. For instance, class A3‐I3 in the presence of enlarged and noncollapsing IVC may correspond to high resistance to venous return and high cardiac filling pressure, associated with volume expansion and thus subjective to possible improvement after reduction of circulating volume, to be tested by UF or diuretic challenge (hard, full, potentially volume‐sensitive pattern). The same class, in the presence of normal or highly collapsing IVC, may represent high resistance to venous return and high cardiac filling pressure despite normal‐low circulating volumes, thus less improvable by circulating volume reduction and marker of impaired cardiac performance (hard, empty, volume insensitive pattern). Transition between classes may be taken as a continuum, responsive to real‐time variations of circulating volume and cardiorenal performance. Of note, hepatic stiffness (as in cirrhosis) can induce pattern A0‐I0 independently from circulating volume and cardiac performance. 39 Original iconographic reports of US were herein not available due to contact isolation precautions observed during COVID‐19 emergency. The aforementioned classification and interpretation of SHV venogram must be taken as hypothesis generating and still prone to verification by extended trials
2 CASE PRESENTATION
2.1 Admission to emergency room and preliminary care
On 17 March 2020, a 50‐year‐old Asian man was admitted to emergency room (ER) due to cough and fever (Figure S3). He was receiving thrice weekly HD by native arteriovenous fistula (AVF). Clinical history was suggestive for hypertensive cardiomyopathy and renal failure due to IgA nephropathy, previously treated by deceased donor kidney transplantation, followed by chronic allograft rejection, requiring HD resumption. Chronic medications included prednisolone 2.5 mg on alternate days. No renin‐angiotensin‐aldosterone inhibitors or other immunosuppressants were prescribed.
Vital signs at admission were not remarkable (Figure 3, Figures S2 and S3). SARS‐CoV‐2 infection was ascertained by positive nasopharyngeal swab. Thorax CT scan revealed multiple ground‐glass parenchymal thickening, without pleural effusion or wet lungs (Figure 2).
The day after he became febrile, low flow oxygen supplementation was initiated and bicarbonate HD (FX® 80 dialyzer [Fresenius]) was delivered by portable osmosis in a dedicated room at ER. On day 3, HD session was performed without ultrafiltration (UF) due to fever and spontaneous BW reduction in the absence of fluid overload at physical examination (Figure 3, Table S1).
2.2 Transfer to Renal‐COVID‐Unit and respiratory worsening
Patient was transferred to Renal‐COVID‐Unit. Intravenous (iv) hydration was started based on refractory fever, mild‐to moderate cardiac filling pressure at point‐of‐care US (inferior vena cava [IVC] diameter 10 mm, inspiratory collapse 100%, SHV class A2‐I0) and absence of extravascular overload (Figures 3 and 4; Figure S4). Within next 48 hours, systemic inflammation increased (Figure S3) and respiratory parameters worsened (Figure S2) in association with B lines appearance without significant pleural effusion (Figure S4). Serologic tests for Chlamydia, Mycoplasma, Legionella, and Pneumococcus were negative. Paracetamol and lysine acetylsalicylate were required for resistant fever, keeping steroid doses unchanged. Thorax X‐ray showed worsened multifocal pneumonia (Figure 2). Hydroxychloroquine, meropenem, and linezolid were started at renal adjusted dose (Figures S1 and S3), and patient was transferred to pneumology‐COVID‐Unit, initiating helmet continuous positive airway pressure (CPAP; Figures S1 and S2). Multidisciplinary team (internists, infectious disease specialists, nephrologists, pneumologists, palliative care experts) was involved.
2.3 Transfer to Pneumology‐COVID‐Unit: early fluid overload, point‐of‐care ultrasound, CPAP, and tocilizumab initiation
Up to day 8, iv hydration was continued due to recurrent fever (Figure 3; Figure S2). Bicarbonate HD was performed on days 5 and 7 with mild UF in the suspicion of persistent normotensive hypovolemia (Figure 3, Table S1). Bedside US was not performed, and patient was not weighted before HD sessions. Between days 7 and 8 agitation crisis occurred, with tachypnea and oxygen desaturation. Low dose morphine was started subcutaneously (sc; Figure S5). Tocilizumab 400 mg was administered after infectious disease consult. On day 9, patient was relayed on bed scale and point‐of‐care US examination was performed: 4 Kg BW increase compared with admission time and bilateral pleural effusion were detected, despite the absence of intravascular fluid overload with normal‐high venous return (IVC diameter 17 mm, IVC inspiratory collapse 70%, SHV pattern A2‐I0; Figures 3 and 4; Figure S4). Expanded HD session (TheraNova® 500 dialyzer [Baxter]) was performed with moderate UF in the suspect of unpredictable hemodynamic instability due cytokine storm (Table S1). Iv hydration was interrupted. D‐dimer increased up to 12.366 pg/mL (Figure S6): Ecocolor‐doppler excluded deep vein thrombosis and calcium heparin (5.000 IU bid) was initiated due to bedridden patient and emerging rationale for systemic anticoagulation in COVID‐19 at that time (Figure S3).
2.4 Anxiety, hypertensive crisis, heart failure, and steroid initiation
Refractory fever and anxious crisis appeared from day 10 (Figure 3; Figures S2 and S5). Anxiolytics were upgraded, by midazolam and inappropriate use of morphine Figure S5). Physical restraint was applied. Remarkable increase in body weight (9.4 Kg) was detected in association with diffuse peripheral edema, pleural effusions, hypervolemia (IVC 22 mm, collapse 30%, SHV A3‐I2), and heart failure with low ejection fraction (EF) in the absence of myocardial necrosis (Figures 3 and 4; Figure S4). On day 11, HD was initiated by EvoDial® 2.2 dialyzer (Baxter), due to hypothetic absorption of SARS‐CoV‐2 virus on heparan sulfate particles. HD was interrupted after 60 minutes due to suspected dialyzer reaction. Symptoms improved after hydrocortisone bolus and HD suspension. HD was restarted by Expanded HD still with mild UF (Table S1). Reduction of positive end expiratory pressure (PEEP) during UF was ineffective in improving respiratory as hemodynamic parameters, rather hampering alveolar recruitment.
On day 11, refractory agitation was treated by escalating morphine and midazolam boluses, followed by continuous infusion of both (Figure S5). Prednisone was upgraded to methylprednisolone 20 mg iv/daily. Calcium heparin dose was increased to 5.000 IU thrice daily (Figure S3).
2.5 Respiratory depression and severe fluid overload: anxiolytic remodulation, NIMV, and daily hemodialysis
Up to day 14 clinical condition worsened, despite resolution of fever and improved inflammatory markers with exception of IL‐6 rebound (Figure S3). Anxiety was treated by morphine and midazolam boluses (12 and 9.5 mg/d, respectively) on top of escalating infusion rates of both (Figure S5). Impaired respiratory drive ensued and generalized fluid overload worsened (IVC 14 mm, collapse 30%, SHV A3‐I1) (Figures 3 and 4; Figures S2 and S4). Thorax X‐ray revealed worsened multifocal pneumonia, overlapped on wet lungs (Figure 2). Negative fluid balance was planned by daily UF (Figure 3; Table S1), methylprednisolone was increased up to 40 mg iv daily, CPAP helmet was alternated with noninvasive mechanical ventilation (NIMV; Figure S2), and anxiolytics were adjusted (Figure S5). Morphine drip was downgraded and finally suspended. Morphine boluses were avoided in the absence of respiratory distress. Chlorpheniramine and midazolam drip plus low dose haloperidol sc at night were preferred as maintaining anxiolytics. Low dose midazolam boluses were taken as first choice against anxious crisis. Physical restraint was abandoned and not further required.
Daily dialysis was performed on days 14‐18. On days 15‐16, venous return improved (SHV A2‐I2), despite persisting indexes of intravascular overload (IVC diameter 16‐18 mm, collapse 0%) and unchanged predialysis BW (Figure 3; Table S1). Almost 9 Kg of BW reduction was achieved on day 18. Systemic improvement of fluid overload was characterized by reduction of both edema and venous congestion (IVC diameter 16 mm, collapse 30%, SHV A2‐I1), as by resolution of pleural effusions, despite persisting thorax B lines and elevated NT‐proBNP (Figures 3 and 4; Figure S4). Anxiety control and breathing stability were achieved from day 17 (Figures S2 and S5).
2.6 Improvement of pulmonary infiltrates and fluid overload: steroid tapering and hypereosinophilia
On day 21 patient was afebrile, pitting edema and B lines decreased, interdialytic weight gain was almost null, respiratory drive, and P/F normalized (Figures 3 and 4; Figures S2‐S5). NIMV was suspended on day 22, proceeding with CPAP helmet for alveolar recruitment. CPAP was thereafter delivered by Venturi mixer, allowing PEEP administration with low FiO2, minimizing arterial pO2 excess. CPAP was alternated to O2 mask and thereafter to ambient air from day 28.
Thorax X‐ray confirmed improvement of multifocal pneumonia (Figure 2). Methylprednisolone was tapered to prednisolone 10 mg q.d. (still ongoing at discharge). UF by Expanded HD was continued thrice weekly, achieving further 5.4 Kg predialytic BW reduction on day 28 (Figure S3). Pitting edema and circulating volume reduced, despite residual B lines (Figure S4) and unstable indexes of venous congestion (IVC diameter 11‐17 mm, collapse 100%‐70%, SHV class ranging from A3‐I0 to A2‐I1; Figure 3; Figure S4).
Eosinophil count increased from day 23, following initial eosinopenia and reaching hypereosinophilic plateau on day 30, associated with normal circulating levels of IgE and positive fecal antigen for Helicobacter Pylori. Eosinophil count thereafter normalized and diarrhea resolved (Figure S3) with negative results for common causes of diarrhea (Epstein‐Barr, Cytomegalovirus, Salmonella, Shigella, Campylobacter, Clostridium Difficile, Mycobacteria, and parasites).
2.7 Step down to Renal‐COVID‐Unit: weaning CPAP and dry weight reassessment
Patient was transferred to Renal‐COVID‐Unit on day 31. On day 32, trends of venous return (SHV A3‐I2), cardiac filling pressure, and lung congestion inverted, despite stable improvement of circulating volumes (IVC 10 mm, collapse 80%‐100%) in the absence of heart failure, edema, or pleural effusion (Figure 3; Figure S4). Thorax X‐ray performed on day 31 was unchanged (Figure 2).
Bilateral centimetric ulcers were detected at the traction site of the shoulder belts for CPAP helmet, which rapidly healed by local dressing. Cycling CPAP was withdrawn on day 35 due to stable normalization of gas exchange in ambient air. Thorax US was normal on day 38 (Figure S4). Sedation was tapered toward low dose bromazepam as monotherapy, without anxiety recrudescence (Figure S5). Starting from day 37 UF was increased to reduce DW, due to indirect signs of lean mass wasting and slow recovery from acute myocardiopathy, deserving lower circulating volume (SHV A3‐I2, IVC 18 mm, collapse 80%; Figure 3). Post‐HD 2.5 Kg reduction in BW and moderate improvement of NT‐proBNP were achieved at discharge without intra‐HD hypotension (Figure 3; Table S1). Cardiac US on day 45 showed improvement of left ventricle EF up to 44% (Figure 3).
2.8 Discharge and follow‐up
Patient was discharged at home on day 49 after double negative nasopharyngeal swabs for SARS‐CoV‐2 on days 47 and 48.
At 93‐ and 98‐day follow‐ups, despite normal gas exchange at rest and normalized thorax X‐ray, patient remained persisting dyspnea at moderate physical activity, associated with positive 6 minutes walking test, residual apical ground glass at CT scan (Figure 2) and unchanged EF.
3 DISCUSSION AND CONCLUSIONS
Although mortality risk in COVID‐19 MHD patients is higher than in general population, MHD should not represent an independent contraindication for admission to subintensive wards. The high rate of ARDS and heart failure, described in COVID‐19, requires hospital wards predisposed for noninvasive ventilation also for MHD patients. Eventual preconditioned impaired access to subintensive care for MHD patients during early as unpredictable phase of pandemic emergency should represent a matter of allocating healthcare resources, poorly sustained by clinical and ethical principles up to date. Due to peculiarities of end‐stage renal disease (ESRD) concerning prognostic evaluation and fluids management, nephrologist may be included in the acute care team of critically ill COVID‐19 dialysis patients admitted to subintensive units.
Intensive dialysis may be required in ESRD as well as in acute kidney injury patients affected by severe COVID‐19, due to cytokine storm and rapid precipitation of fluid overload observed in SARS‐CoV‐2 infection. Although CRRT represents the mainstay in such conditions, 6 it was unavailable outside of ICU at our Institution. Thus, dedicated rooms, for delivering intermittent HD (IHD) by portable osmosis, were predisposed at San Paolo Hospital (Milan, Italy) shortly after initiation of SARS‐CoV‐2 outbreak in Lombardy. Expanded HD could be considered as the modality of choice for IHD in COVID‐19‐infected patients due to its ascertained anti‐inflammatory properties. 5 , 22 Daily IHD herein was life‐saving during acute phase of SARS‐CoV‐2 infection.
Abrupt precipitation of respiratory and cardiac function in COVID‐19 alters fluid redistribution just as quickly. Fluid overload in anuric patients represents a common drawback of resuscitating therapies in the absence of UF. Bed scale resulted indispensable for daily assessment of mass balance in subintensive setting, being more accurate than mathematical computation of fluid balance. Real‐time assessment of fluid status by point‐of‐care US was adjuvant for guiding fluid and ventilatory management. Notably, ultrasound data guided negative fluid balance during last 20 days, in the absence of otherwise objective fluid excess. Dynamic variation in SHV venogram was reported and interpreted based on literature 23 , 24 , 25 and authors' unpublished data. Classification of SHV venogram patterns in 15 combined classes (apnea [A: 0‐4] combined with inspiration [I: 0‐4]) is herein purposed (Figure S4). SHV pattern may appear influenced by both circulating volume, indirectly estimable by IVC diameter and collapse, and cardiac performance.
In April 2020, when the patient's clinical trend was improving, the venous excess ultrasound score (VEXUS) was purposed for assessing venous congestion in cardiorenal syndrome, including US examination of IVC diameter and waveforms of hepatic, portal and renal veins, in patients admitted to ICU after cardiac surgery, excluding patients with critical illness, eGFR < 15 mL/min, or renal transplantation. 26 VEXUS score was associated with the risk of acute kidney injury, and subsequently adopted by Bhardwaj et al, 27 for tailoring fluid removal by diuretics and ultrafiltration in patients with cardiorenal syndrome associated with acute kidney injury stage 1 to 3. On May 2020 Tri‐POCUS approach, including bedside assessment of lungs, heart, and venous system, was suggested for critically ill patients with COVID‐19. 28
Although assessment of hepatic, portal, and renal veins waveforms can be more complete, the present case is hypothesis generating on how easier approach, limited to hepatic veins and IVC, could be suitable outside from ICU. Furthermore, the case first describes assessment of venous congestion in a COVID‐19 MHD patient, where renal veins waveform could be less informative for cardiorenal trend. A new pattern of hepatic vein venogram (fusion of S and D waves, scored as stage 0) is herein suggested, which may associate with extreme reduction of venous congestion, potentially informative against excessive fluid removal. Finally, variation of hepatic vein venogram in apnea and inspiration is herein purposed for the first time; this may be adjuvant in interpreting sensibility of venous congestion to circulating volumes independently from IVC parameters. However, the herein reported interpretation of SHV venogram remains hypothetical, deserving further studies to be verified.
Positive end expiratory pressure was reported as crucial for treating COVID‐19 ARDS. The present case confirms efficacy of PEEP delivered by CPAP helmet. Transitory reduction of PEEP during UF in the acute phase was associated with oxygenation worsening without benefits on anxiety or hemodynamic parameters. Slow weaning from PEEP, also beyond normalization of P/F, was considered reasonable, due to high risk of wet lung recrudescence in HD patient with residual myocardial impairment and pulmonary inflammation. Venturi mixer for helmet CPAP (Harol®) resulted adjuvant for delivering PEEP during recovery phase, with low FiO2 (down to 35%), in order to avoid patient's hyperoxygenation. Prolonged use of noninvasive ventilation requires precaution against cutaneous lesions induced by helmet, belts, or mask. Counterweight system may be considered, for limiting traction on axillary areas induced by helmet straps. 29
Acute cardiovascular syndrome was described in COVID‐19 and attributed to acute coronary syndrome, demand ischemia, microvascular ischemic injury, myocarditis, or cytokine storm. 10 Severe transitory myocardial insufficiency without myocardial necrosis was herein taken as consequent to cytokine storm and fluid overload, superimposed on chronic hypertensive‐ESRD cardiomyopathy. Assessment of EF, NT‐proBNP, and troponin‐I at admission could be reasonable to monitor COVID‐19 HD patients, commonly affected by chronic cardiovascular disease and elevated basal levels of both markers.
COVID‐19 has been associated with hypercoagulability and itself worsens the prognosis. 30 Although prophylactic anticoagulation is now advised, 30 heparin was started on day 9 due to uncertain knowledge about anticoagulation in COVID‐19 at admission.
Anti‐inflammatory drugs were reported for treating COVID‐19 dialysis patients. 5 , 31 Tocilizumab, in association with moderate steroids doses, was herein well tolerated and followed by resolution of fever and improvement of inflammatory markers within 4 days, with exception of IL‐6 rebound as previously observed. 26 Although hypertensive crises were attributed to adrenergic activation triggered by COVID‐19, hypertension induced by tocilizumab has been reported. 11 Hydroxychloroquine was herein adopted prior to international warning against its use in COVID‐19. Notably hydroxychloroquine is now contraindicated in COVID‐19‐infected patients due to uncertain efficacy and increased arrhythmic risk. 32 Antivirals were herein not prescribed. Although Remdesivir is now approved for treating COVID‐19, 33 it remains contraindicated in dialysis patients.
Agitation represented a relevant matter. Notably, morphine is not indicated in dialysis patients due to risk of life threatening accumulation. Furthermore, it is indicated for treating pain, respiratory distress, or palliative sedation, but not for treating anxiety. Distinguishing respiratory distress from anxiety and terminal phase is crucial in COVID‐19‐infected patients, where anxiety and delirium could be better treated by benzodiazepine and antihistamines or neuroleptics, respectively, rather than with morphine (Figure 1; Figures S5 and S7). Agitation sedation should be monitored by Richmond Agitation Sedation Scale (RASS). 34 Other opioids, as buprenorphine or fentanyl, could be cautiously preferred when indicated.
Persistent eosinopenia was observed until day 24, being thereafter followed by eosinophilia associated with diarrhea and rash, uncertainly attributed to allergic reaction to Olmesartan. Eosinopenia was described in acute phase of COVID‐19. 35 , 36 Further eosinophils increase was suggested as marker of disease improvement, 36 based on unknown mechanisms. 37 , 38 Significance of eosinophil trend in COVID‐19 requires further investigation.
Renal associations have mostly provided recommendations for preventing COVID‐19 outbreak within dialysis facilities, but data are still poor for recommending specific drugs for the care of severe COVID‐19 in MHD patients at the moment. Although clinical messages derived by this case remain opinion‐based and hypothesis generating, in the current scenario meticulous application of available anti‐inflammatory drugs, ventilation and dialysis techniques, close to accurate daily evaluation of fluid balance and neurological status, may be crucial for treating severe COVID‐19 in MHD patients.
In conclusion, the case supports efficacy of individualized subintensive care, delivered by multidisciplinary team, and the need to allocate health resources for achieving similar goals in the treatment of critically ill COVID‐19 MHD patients during second pandemic wave.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTION
AG: had major role in data collection, writing, and editing the manuscript. All authors: involved in the patient care. All authors: read and approved the final manuscript.
ETHICAL APPROVAL AND CONSENT TO PARTICIPATE
No ethical issue in reporting of this case.
Supporting information
Supplementary Material
Click here for additional data file.
ACKNOWLEDGMENTS
None. Consent statement: Published with written consent of the patient.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Para clinic data which are referred to in the case presentation are available on request from the corresponding author.
==== Refs
REFERENCES
1 Xiong F , Tang H , Liu L , et al. Clinical characteristics of and medical interventions for COVID‐19 in hemodialysis patients in Wuhan, China. J Am Soc Nephrol. 2020;32 (7 ):1387‐1397.
2 Alberici F , Delbarba E , Manenti C , et al. A report from the Brescia renal COVID task force on the clinical characteristics and short‐term outcome of hemodialysis patients with SARS‐CoV‐2 infection. Kideny Int. 2020;98 (1 ):20‐26.
3 Goicoechea M , Camara LAS , Macias N , et al. COVID‐19: clinical course and outcomes of 36 hemodialysis patients in Spain. Kidney Int. 2020;98 (1 ):27‐34.32437770
4 Basile C , Combe C , Pizzarelli F , et al. Recommendation for the prevention, mitigation, and containment of the emerging SARS‐CoV‐2 (COVID‐19) pandemic in hemodialysis centers. Nephrol Dial Transplant. 2020;35 (5 ):737‐741.32196116
5 Alberici F , Delbarba E , Manenti C , et al. Management of patients on dialysis and with kidney transplantation during the SARS‐CoV‐2 (COVID‐19) pandemic in Brescia, Italy. Kidney Int Rep. 2020;5 (5 ):580‐585.32292866
6 Ronco C , Reis T , Husain‐Syed F . Management of acute kidney injury in patients with COVID‐19. Lancet Respir Med. 2020;8 (7 ):738‐742.32416769
7 Kazory A , Ronco C , McCullough PA . SARS‐CoV‐2 (COVID‐19) and intravascular volume management strategies in the critically ill. Prc (Bayl Univ Med Cent). 2020;33 (3 ):370‐375. 10.1080/08998280.2020.1754700
8 Sofia S , Boccatonda A , Montanari M , et al. Thoracic ultrasound and SARS‐COVID‐19: a pictorial essay. J Ultrasound. 2020;2 :217‐221.
9 Vieira ALS , Pazeli Junior JM , Bastos MG . Role of point‐of‐care ultrasound during the COVID‐19 pandemic: our recommendations in the management of dialytic patients. Ultrasound J. 2020;12 (1 ):30 10.1186/s13089-020-00177-4 32488686
10 Hendren N , Drazner MH , Bozkur B , et al. Description and proposal management of the acute COVID‐19 cardiovascular syndrome. Circulation. 2020;141 (23 ):1903‐1914.32297796
11 Long B , Brady W , Koyfman A , et al. Cardiovascular complication in COVID‐19. Am J Emerg Med. 2020;38 (7 ):1504‐1507.32317203
12 Guzik T , Mohiddin AA , Dimarco A , et al. COVID‐19 and the cardiovascular system: implications for risk assessment, diagnosis and treatment options. Cardiovasc Res. 2020;116 (10 ):1666‐1687. 10.1093/cvr/cvaa106 32352535
13 Helms J , Kremer S , Merdji H , et al. Neurologiv features in severe SARS‐CoV‐2 infection. N Engl J Med. 2020;382 :2268‐2270.32294339
14 Kotfis K , Roberson SW , Wilson JE , et al. COVID‐19: ICU delirium management during SARS‐CoV‐2 pandemic. Crit Care. 2020;24 (1 ):176 10.1186/s13054-020-02882-x 32345343
15 Mao L , Wang JH , Chen S , et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77 (6 ):1‐9.
16 Singhania N , Bansal S , Singhania G . An atypical presentation of novel coronavirus disease 2019 (COVID‐19). Am J Med. 2020;133 (7 ):e365‐e366.32320693
17 Ke C , Wang Y , Zeng X , et al. 2019 novel coronavirus disease (COVID‐19) in hemodialysis patients: a report of two cases. Clin Biochem. 2020;81 :9‐12.32360479
18 Wang R , Liao C , He H , et al. COVID‐19 in hemodialysis patients: a report of 5 cases. Am J Kidney Dis. 2020;776 (1 ):141‐143.
19 Fu D , Yang B , Xu J , et al. COVID‐19 infection in a patient with end‐stage kidney disease. Nephron. 2020;44 :245‐247.
20 Ferrey A , Choi G , Hanna RH , et al. A case of novel coronavirus disease 19 in a chronic hemodialysis patient presenting with gastroenteritis and developing severe pulmonary disease. Am J Nephrol. 2020;52 :337‐342.
21 Delafosse M , Saint‐Jaques C , Petit‐Hoang C , et al. Steroids: a therapeutic option for COVID‐19 pneumonia patients with end stage renal disease? Kidney Int Rep. 2020;5 (8 ):1375 10.1016/j.ekir.2020.05.031 32775845
22 Cozzolino M , Magagnoli L , Ciceri P , et al. Effects of medium cut‐off (Theranova) dialyser on hemodialysis patients: a prospective cross‐over study. Clin Kidney J. 2019 10.1093/ckj/sfz155
23 Meola M , Nalesso F , Petrucci I , et al. Clinical scenarios in in acute kidney injury: hepatorenal syndrome. Contrib Nephrol. 2016;188 :33‐38.27169751
24 Beigel R , Cercek B , Luo H , et al. Non invasive evaluation of atrial pressure. J Am Soc Echocardiogr. 2013;26 :1033‐1042.23860098
25 Iida N , Seo Y , Sai S , et al. Clinical implication of intrarenal hemodynamic evaluation by doppler ultrasonography in heart failure. JACC Heart Fail. 2016;4 :674‐678.27179835
26 Beaubien‐Souligny W , Rola P , Haycock K , et al. Quantifying systemic congestion with point‐of‐care ultrasound: development of the venous excess ultrasound grading system. Ultrasound J. 2020;12 (1 ):16 10.1186/s13089-020-00163-w 32270297
27 Bhardwaj V , Vikneswaran G , Rola P , et al. Combination of inferior vena cava ciameter, hepatic venous flow, and portal vein pulsatility index: venous excess ultrasound score (VEXUS score) in predicting acute kidney injury in patients with cardiorenal syndrome: a prospective cohort study. Indian J Crit Care Med. 2020;24 (9 ):783‐789.33132560
28 Koratala A , Ronco C , Kazory A . Need for objective assessment of volume status in critically ill patients with COVID‐19: the Tri‐POCUS approach. Cardiorenal Med. 2020;10 (4 ):209‐216.32460302
29 Lucchini A , Giani M , Isgrò D , et al. The “helmet bundle” in COVID‐19 patients undergoing non invasive ventilation. Intensive Crit Care Nurse. 2020;58 :102859 10.1016/j.iccn.2020.102859
30 Singhania N , Bansal S , Nimmatoori DP , et al. Current overview on hypercoagulability in COVID‐19. Am J Cardiovasc Drugs. 2020;20 (5 ):393‐403.32748336
31 Bose S , Adapa S , Aeddula NR , et al. Medical management of COVID‐19: evidence and experience. J Clin Med Res. 2020;12 (6 ):329‐343.32587649
32 U.S. Food and Drug Administration . July 2020 https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or. Accessed 14 November 2020.
33 U.S. Food and Drug Administration . October 2020 https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19. Accessed 14 November 2020
34 Toniati P , Piva S , Cattalini M , et al. Tocilizumab for the treatment of severe COVID‐19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia, Italy. Autoimmun Rev. 2020;19 (7 ):102568 10.1016/j.autrev.2020.102568 32376398
35 Zhang JJ , Dong X , Cao YY , et al. Clinical characteristics of 140 patients infected with SARS‐CoV‐2 in Wuhan, China. Allergy. 2020;75 (7 ):1730‐1741.32077115
36 Liu F , Xu A , Zhang Y , et al. Patients of COVID‐19 may benefit from sustained Lopinavir‐combined regimen and the increase eosinophil may predict the outcome of COVID‐19 progression. Int J Infect Dis. 2020;95 :183‐191.32173576
37 Jesenak M , Banovcin P , Diamant Z . COVID‐19, chronic inflammation respiratory disease and eosinophils – observations from reported clinical series. Allergy. 2020;75 (7 ):1819‐1822.32369190
38 Lindsley A , Schwartz JT , Rothenberg MC . Eosinophil response during COVID‐19 infections and coronavirus vaccination. J Allergy Clin Immunol. 2020;146 :1‐7.32344056
39 Meola M . Analisi della curva spettrale delle vene sovraepatiche. Ecografia clinica in Nefrologia. Eureka Editore. 2015:470‐477.
| serious: 1
patientsex: 1
drugs: ACETAMINOPHEN, ASPIRIN DL-LYSINE, BROMAZEPAM, HALOPERIDOL, HEPARIN CALCIUM, HYDROCORTISONE, HYDROXYCHLOROQUINE, LINEZOLID, MEROPENEM, METHYLPREDNISOLONE, MIDAZOLAM, MORPHINE, OLMESARTAN MEDOXOMIL, OXYGEN, PREDNISOLONE, TOCILIZUMAB
reactions: Diarrhoea, Drug hypersensitivity, Rash
| 33362933 | CC BY-NC-ND | sars cov 2 related ards in a maintenance hemodialysis patient case report on tailored approach by daily hemodialysis noninvasive ventilation tocilizumab anxiolytics and point of care ultrasound | Clinical case reports | Galassi|Andrea|A|https://orcid.org/0000-0001-7533-2876;Casanova|Francesca|F|;Gazzola|Lidia|L|;Rinaldo|Rocco|R|;Ceresa|Marco|M|;Restelli|Elena|E|;Giorgini|Alessia|A|;Birocchi|Simone|S|;Giovenzana|Marco|M|;Zoni|Ulisse|U|;Valli|Federica|F|;Massironi|Laura|L|;Belletti|Sebastiano|S|;Magagnoli|Lorenza|L|;Stucchi|Andrea|A|;Ippolito|Michela|M|;Carugo|Stefano|S|https://orcid.org/0000-0002-5166-0899;Parazzini|Elena|E|;Cozzolino|Mario|M|https://orcid.org/0000-0002-8494-6252 | 2020-12-04 | 10.1002/ccr3.3623 | Renal & Dialysis Unit S. Paolo Hospital ASST Santi Paolo e Carlo Milan Italy.;Internal Medicine Unit S. Paolo Hospital ASST Santi Paolo e Carlo Milan Italy.;Department of Health Sciences Clinic of Infectious Disease "San Paolo" Hospital-University of Milan Milan Italy.;Respiratory Unit Department of Health Sciences University of Milan ASST Santi Paolo e Carlo Milan Italy.;Palliative Care Unit S. Paolo Hospital ASST Santi Paolo e Carlo Milan Italy.;Internal Medicine Unit S. Paolo Hospital ASST Santi Paolo e Carlo Milan Italy.;Gastroenterology and Hepatology Unit S. Paolo Hospital ASST Santi Paolo e Carlo Milan Italy.;Internal Medicine Unit S. Paolo Hospital ASST Santi Paolo e Carlo Milan Italy.;Unit of Hepatobiliary, Pancreatic, and Digestive Surgery Department of Surgery S. Paolo Hospital University of Milan Milan Italy.;Internal Medicine Unit S. Paolo Hospital ASST Santi Paolo e Carlo Milan Italy.;Division of Cardiology S. Paolo Hospital University of Milan Milan Italy.;Division of Cardiology S. Paolo Hospital University of Milan Milan Italy.;Division of Cardiology S. Paolo Hospital University of Milan Milan Italy.;Renal & Dialysis Unit S. Paolo Hospital ASST Santi Paolo e Carlo Milan Italy.;Renal & Dialysis Unit S. Paolo Hospital ASST Santi Paolo e Carlo Milan Italy.;Renal & Dialysis Unit S. Paolo Hospital ASST Santi Paolo e Carlo Milan Italy.;Division of Cardiology S. Paolo Hospital University of Milan Milan Italy.;Respiratory Unit Department of Health Sciences University of Milan ASST Santi Paolo e Carlo Milan Italy.;Renal & Dialysis Unit S. Paolo Hospital ASST Santi Paolo e Carlo Milan Italy. | Clin Case Rep | 101620385 | 2050-0904 | England | D002363:Case Reports | COVID‐19; expanded hemodialysis; hemodialysis; point‐of‐care ultrasound; suprahepatic veins venogram; tocilizumab | 32775845;32376398;32369190;33132560;32320693;32385130;32488686;32317203;32294339;32292866;33362933;32352535;32275288;32360479;32222713;32297796;23860098;32336959;32249028;32587649;32460302;32344056;32416769;32297175;27179835;32345343;27169751;32270297;32173576;32240718;32196116;32437768;32077115;32437770;32748336;32222703 | false | 20,080,815 | TITLE:
SARS-CoV-2-related ARDS in a maintenance hemodialysis patient: case report on tailored approach by daily hemodialysis, noninvasive ventilation, tocilizumab, anxiolytics, and point-of-care ultrasound.
ABSTRACT:
Without rescue drugs approved, holistic approach by daily hemodialysis, noninvasive ventilation, anti-inflammatory medications, fluid assessment by bedside ultrasound, and anxiolytics improved outcomes of a maintenance hemodialysis patient affected by severe COVID-19.
TEXT:
1 INTRODUCTION
A 50‐year‐old man, on maintenance hemodialysis, was affected by SARS‐CoV‐2–related acute respiratory distress syndrome. Multipronged intervention included daily expanded hemodialysis, noninvasive ventilation, anti‐inflammatory medications, fluid assessment by point‐of‐care ultrasound, and anxiolytics. Individualized subintensive care improved outcomes of a maintenance hemodialysis (MHD) patient affected by severe SARS‐CoV‐2–associated disease.
SARS‐CoV‐2–related disease (COVID‐19) affected MHD patients, 1 , 2 , 3 leading to high rate of hospitalization (61%), 2 acute respiratory distress syndrome (ARDS) (79%), 2 and mortality (11%‐29%) in Europe. 2 , 3 Cardiovascular disease resulted a strong independent predictor of worse outcomes. 1 , 2
Suggestions were published on how to prevent interhuman transmission of SARS‐CoV‐2 within facilities 4 and treating COVID‐19 in HD patients. 5 , 6 Although a gold standard of care remains uncertain, without a single intervention capable of healing the disease has yet been identified, several clinical issues could be relevant for caring MHD patients affected by severe COVID‐19.
Tailored management of fluids represents a mainstay for treating COVID‐19 critical cases. 6 , 7 Point‐of‐care ultrasound (US) was suggested for improving therapy of patients, 7 , 8 , 9 at high risk of developing SARS‐CoV‐2–related ARDS and acute cardiovascular syndrome, precipitating in heart failure, fluid overload, and death. 10 , 11 , 12
Neurological involvement was described in SARS‐CoV‐2 infection, including high incidence of anxiety and delirium. 13 , 14 , 15 , 16 Although monitoring and treatment of anxiety in COVID‐19 were discussed in intensive care unit (ICU), 14 strategies tailored on MHD patients are unexplored.
Case reports on COVID‐19 MHD patients were reported. 17 , 18 , 19 , 20 , 21 We herein describe the case of a 50‐year‐old hemodialysis (HD) man, affected by COVID‐19–related ARDS, successfully treated in subintensive setting, who developed severe fluid overload, acute myocardial insufficiency, and anxiety, requiring daily dialysis, noninvasive ventilation, anxiolytics, tocilizumab, steroids, and fluid assessment by point‐of‐care US.
Clinical messages are summarized (Figures 1, 2, 3, 4, Figures S1‐S7, Table S1). Assessment of dynamic trend in suprahepatic veins (SHV) venogram is categorized and discussed as potential tool, for improving real‐time diagnosis of venous return and tailoring fluid management in critically ill dialysis patients (Figure 4).
FIGURE 1 Clinical issues suggested by the case, for treating COVID‐19 in critically ill MHD patients. AVF, arteriovenous fistula; BNP, brain natriuretic peptide; CPAP, continuous positive airway pressure; CRRT, continuous renal replacement therapy; ECG, electrocardiography; HD, hemodialysis; ICU, intensive care unit; IL‐6, interleukin‐6; Iv, intravenously; LVEF, ejection fraction; NGT, nasogastric tube; NIMV, noninvasive mechanical ventilation; PAPs, pulmonary arterial pressures; PEEP, positive end respiratory pressure; Po, per os; RASS, Richmond Agitation Sedation Scale; Sc, subcutaneously; TAPSE, tricuspid annular plane systolic excursion
FIGURE 2 Imaging follow‐up by CT scan and thorax X‐rays. Bilateral ground‐glass areas were present on CT scans at day 1, followed by rapid worsening of multifocal pneumonia and vascular congestion from day 4 to day 14. Partial improvement of both inflammatory infiltrates and fluid congestion was observed on days 21 and 31. Extended follow‐up to days 93 and 98 revealed almost complete resolution, excepting apical fibrotic lesions on left lung
FIGURE 3 Daily representation of HD, cardiologic medications, and noninvasive assessment of hemodynamic and fluid distribution. Bicarb HD, bicarbonate hemodialysis; DBP, diastolic blood pressure; ER, emergency room; Exp HD, expanded hemodialysis; HR, heart rate; Iv, intravenously; IVC, inferior vena cava; LV, left ventricular; R., Renal‐COVID‐Unit; SBP, systolic blood pressure; SHV, suprahepatic veins; UF, ultrafiltration
FIGURE 4 Hypothetical dynamic classification of suprahepatic veins venogram. A, Normal SHV pattern during a complete cardiac cycle is characterized by positive A wave (right atrial systole), negative S wave (right ventricular systole), and negative D wave (right ventricular diastole). 9 Small positive wave between S and D (positive V wave) may occasionally be observed. Based on the authors' unpublished data, hypothetically normal SHV pattern is herein classified as a middle range class (class 2) out of 4 classes (0‐4) (fig a). Classes 0‐1 are attributed to increased venous return. Classes 3‐4 are attributed to reduced venous return. Descriptively: class 0 is characterized by fusion of S and D waves, class 1 by initial fusion of S and D waves and initial increase in deceleration time of both. On the opposite: class 3 is characterized by reduced deceleration time of S and D waves, appearing with diamond shape, occasionally associated with Z wave appearance, class 4 is characterized by S wave inversion as previously associated to pulmonary hypertension. 9 Flow patterns of venous return are herein taken as makers of resistance to venous return, hypothetically proportional to real‐time cardiac filling pressures, influenced by both primary cardiac performance as by circulating volume. Thus, classes 0‐1 are taken as markers of progressively increased venous return, reduced resistance to venous return and reduced cardiac filling pressure (soft patterns). On the opposite, classes 3‐4 are taken as markers of progressively reduced venous return, increased resistance to venous return, and increased cardiac filling pressure (hard patterns). Based on the authors' unpublished data, SHV patterns are sensible to inspiration as described for the inferior vena cava (IVC) ultrasonographic interpretation. B, SHV patterns are subcategorized into morphologic patterns assessed during apnea (category A, classes 0‐4) and inspiration (category I, classes 0‐4) leading to 15 combined classes. Hypothetically, patterns during apnea are herein purposed as mainly representative of resistance to venous return, primarily influenced by cardiac performance per se, while patterns assessed during inspiration as more influenced by reduction of venous pressure, secondary to inspiratory weakened mediastinic pressure (volume sensitivity). Thus, class A2‐I2 will correspond to the normal comprehensive class, class A0‐I0 to lowest venous return, lowest resistance, lowest filling pressure, highest volume sensitivity or hypovolemia (soft, volume sensitive or hypovolemic pattern), class A4‐I4 as corresponding to lowest venous return, highest resistance, highest filling pressure, lowest volume sensitivity or hypervolemia (hard, volume insensitive, or hypervolemic pattern). Patterns of IVC will be additive for interpreting SHV pattern. For instance, class A3‐I3 in the presence of enlarged and noncollapsing IVC may correspond to high resistance to venous return and high cardiac filling pressure, associated with volume expansion and thus subjective to possible improvement after reduction of circulating volume, to be tested by UF or diuretic challenge (hard, full, potentially volume‐sensitive pattern). The same class, in the presence of normal or highly collapsing IVC, may represent high resistance to venous return and high cardiac filling pressure despite normal‐low circulating volumes, thus less improvable by circulating volume reduction and marker of impaired cardiac performance (hard, empty, volume insensitive pattern). Transition between classes may be taken as a continuum, responsive to real‐time variations of circulating volume and cardiorenal performance. Of note, hepatic stiffness (as in cirrhosis) can induce pattern A0‐I0 independently from circulating volume and cardiac performance. 39 Original iconographic reports of US were herein not available due to contact isolation precautions observed during COVID‐19 emergency. The aforementioned classification and interpretation of SHV venogram must be taken as hypothesis generating and still prone to verification by extended trials
2 CASE PRESENTATION
2.1 Admission to emergency room and preliminary care
On 17 March 2020, a 50‐year‐old Asian man was admitted to emergency room (ER) due to cough and fever (Figure S3). He was receiving thrice weekly HD by native arteriovenous fistula (AVF). Clinical history was suggestive for hypertensive cardiomyopathy and renal failure due to IgA nephropathy, previously treated by deceased donor kidney transplantation, followed by chronic allograft rejection, requiring HD resumption. Chronic medications included prednisolone 2.5 mg on alternate days. No renin‐angiotensin‐aldosterone inhibitors or other immunosuppressants were prescribed.
Vital signs at admission were not remarkable (Figure 3, Figures S2 and S3). SARS‐CoV‐2 infection was ascertained by positive nasopharyngeal swab. Thorax CT scan revealed multiple ground‐glass parenchymal thickening, without pleural effusion or wet lungs (Figure 2).
The day after he became febrile, low flow oxygen supplementation was initiated and bicarbonate HD (FX® 80 dialyzer [Fresenius]) was delivered by portable osmosis in a dedicated room at ER. On day 3, HD session was performed without ultrafiltration (UF) due to fever and spontaneous BW reduction in the absence of fluid overload at physical examination (Figure 3, Table S1).
2.2 Transfer to Renal‐COVID‐Unit and respiratory worsening
Patient was transferred to Renal‐COVID‐Unit. Intravenous (iv) hydration was started based on refractory fever, mild‐to moderate cardiac filling pressure at point‐of‐care US (inferior vena cava [IVC] diameter 10 mm, inspiratory collapse 100%, SHV class A2‐I0) and absence of extravascular overload (Figures 3 and 4; Figure S4). Within next 48 hours, systemic inflammation increased (Figure S3) and respiratory parameters worsened (Figure S2) in association with B lines appearance without significant pleural effusion (Figure S4). Serologic tests for Chlamydia, Mycoplasma, Legionella, and Pneumococcus were negative. Paracetamol and lysine acetylsalicylate were required for resistant fever, keeping steroid doses unchanged. Thorax X‐ray showed worsened multifocal pneumonia (Figure 2). Hydroxychloroquine, meropenem, and linezolid were started at renal adjusted dose (Figures S1 and S3), and patient was transferred to pneumology‐COVID‐Unit, initiating helmet continuous positive airway pressure (CPAP; Figures S1 and S2). Multidisciplinary team (internists, infectious disease specialists, nephrologists, pneumologists, palliative care experts) was involved.
2.3 Transfer to Pneumology‐COVID‐Unit: early fluid overload, point‐of‐care ultrasound, CPAP, and tocilizumab initiation
Up to day 8, iv hydration was continued due to recurrent fever (Figure 3; Figure S2). Bicarbonate HD was performed on days 5 and 7 with mild UF in the suspicion of persistent normotensive hypovolemia (Figure 3, Table S1). Bedside US was not performed, and patient was not weighted before HD sessions. Between days 7 and 8 agitation crisis occurred, with tachypnea and oxygen desaturation. Low dose morphine was started subcutaneously (sc; Figure S5). Tocilizumab 400 mg was administered after infectious disease consult. On day 9, patient was relayed on bed scale and point‐of‐care US examination was performed: 4 Kg BW increase compared with admission time and bilateral pleural effusion were detected, despite the absence of intravascular fluid overload with normal‐high venous return (IVC diameter 17 mm, IVC inspiratory collapse 70%, SHV pattern A2‐I0; Figures 3 and 4; Figure S4). Expanded HD session (TheraNova® 500 dialyzer [Baxter]) was performed with moderate UF in the suspect of unpredictable hemodynamic instability due cytokine storm (Table S1). Iv hydration was interrupted. D‐dimer increased up to 12.366 pg/mL (Figure S6): Ecocolor‐doppler excluded deep vein thrombosis and calcium heparin (5.000 IU bid) was initiated due to bedridden patient and emerging rationale for systemic anticoagulation in COVID‐19 at that time (Figure S3).
2.4 Anxiety, hypertensive crisis, heart failure, and steroid initiation
Refractory fever and anxious crisis appeared from day 10 (Figure 3; Figures S2 and S5). Anxiolytics were upgraded, by midazolam and inappropriate use of morphine Figure S5). Physical restraint was applied. Remarkable increase in body weight (9.4 Kg) was detected in association with diffuse peripheral edema, pleural effusions, hypervolemia (IVC 22 mm, collapse 30%, SHV A3‐I2), and heart failure with low ejection fraction (EF) in the absence of myocardial necrosis (Figures 3 and 4; Figure S4). On day 11, HD was initiated by EvoDial® 2.2 dialyzer (Baxter), due to hypothetic absorption of SARS‐CoV‐2 virus on heparan sulfate particles. HD was interrupted after 60 minutes due to suspected dialyzer reaction. Symptoms improved after hydrocortisone bolus and HD suspension. HD was restarted by Expanded HD still with mild UF (Table S1). Reduction of positive end expiratory pressure (PEEP) during UF was ineffective in improving respiratory as hemodynamic parameters, rather hampering alveolar recruitment.
On day 11, refractory agitation was treated by escalating morphine and midazolam boluses, followed by continuous infusion of both (Figure S5). Prednisone was upgraded to methylprednisolone 20 mg iv/daily. Calcium heparin dose was increased to 5.000 IU thrice daily (Figure S3).
2.5 Respiratory depression and severe fluid overload: anxiolytic remodulation, NIMV, and daily hemodialysis
Up to day 14 clinical condition worsened, despite resolution of fever and improved inflammatory markers with exception of IL‐6 rebound (Figure S3). Anxiety was treated by morphine and midazolam boluses (12 and 9.5 mg/d, respectively) on top of escalating infusion rates of both (Figure S5). Impaired respiratory drive ensued and generalized fluid overload worsened (IVC 14 mm, collapse 30%, SHV A3‐I1) (Figures 3 and 4; Figures S2 and S4). Thorax X‐ray revealed worsened multifocal pneumonia, overlapped on wet lungs (Figure 2). Negative fluid balance was planned by daily UF (Figure 3; Table S1), methylprednisolone was increased up to 40 mg iv daily, CPAP helmet was alternated with noninvasive mechanical ventilation (NIMV; Figure S2), and anxiolytics were adjusted (Figure S5). Morphine drip was downgraded and finally suspended. Morphine boluses were avoided in the absence of respiratory distress. Chlorpheniramine and midazolam drip plus low dose haloperidol sc at night were preferred as maintaining anxiolytics. Low dose midazolam boluses were taken as first choice against anxious crisis. Physical restraint was abandoned and not further required.
Daily dialysis was performed on days 14‐18. On days 15‐16, venous return improved (SHV A2‐I2), despite persisting indexes of intravascular overload (IVC diameter 16‐18 mm, collapse 0%) and unchanged predialysis BW (Figure 3; Table S1). Almost 9 Kg of BW reduction was achieved on day 18. Systemic improvement of fluid overload was characterized by reduction of both edema and venous congestion (IVC diameter 16 mm, collapse 30%, SHV A2‐I1), as by resolution of pleural effusions, despite persisting thorax B lines and elevated NT‐proBNP (Figures 3 and 4; Figure S4). Anxiety control and breathing stability were achieved from day 17 (Figures S2 and S5).
2.6 Improvement of pulmonary infiltrates and fluid overload: steroid tapering and hypereosinophilia
On day 21 patient was afebrile, pitting edema and B lines decreased, interdialytic weight gain was almost null, respiratory drive, and P/F normalized (Figures 3 and 4; Figures S2‐S5). NIMV was suspended on day 22, proceeding with CPAP helmet for alveolar recruitment. CPAP was thereafter delivered by Venturi mixer, allowing PEEP administration with low FiO2, minimizing arterial pO2 excess. CPAP was alternated to O2 mask and thereafter to ambient air from day 28.
Thorax X‐ray confirmed improvement of multifocal pneumonia (Figure 2). Methylprednisolone was tapered to prednisolone 10 mg q.d. (still ongoing at discharge). UF by Expanded HD was continued thrice weekly, achieving further 5.4 Kg predialytic BW reduction on day 28 (Figure S3). Pitting edema and circulating volume reduced, despite residual B lines (Figure S4) and unstable indexes of venous congestion (IVC diameter 11‐17 mm, collapse 100%‐70%, SHV class ranging from A3‐I0 to A2‐I1; Figure 3; Figure S4).
Eosinophil count increased from day 23, following initial eosinopenia and reaching hypereosinophilic plateau on day 30, associated with normal circulating levels of IgE and positive fecal antigen for Helicobacter Pylori. Eosinophil count thereafter normalized and diarrhea resolved (Figure S3) with negative results for common causes of diarrhea (Epstein‐Barr, Cytomegalovirus, Salmonella, Shigella, Campylobacter, Clostridium Difficile, Mycobacteria, and parasites).
2.7 Step down to Renal‐COVID‐Unit: weaning CPAP and dry weight reassessment
Patient was transferred to Renal‐COVID‐Unit on day 31. On day 32, trends of venous return (SHV A3‐I2), cardiac filling pressure, and lung congestion inverted, despite stable improvement of circulating volumes (IVC 10 mm, collapse 80%‐100%) in the absence of heart failure, edema, or pleural effusion (Figure 3; Figure S4). Thorax X‐ray performed on day 31 was unchanged (Figure 2).
Bilateral centimetric ulcers were detected at the traction site of the shoulder belts for CPAP helmet, which rapidly healed by local dressing. Cycling CPAP was withdrawn on day 35 due to stable normalization of gas exchange in ambient air. Thorax US was normal on day 38 (Figure S4). Sedation was tapered toward low dose bromazepam as monotherapy, without anxiety recrudescence (Figure S5). Starting from day 37 UF was increased to reduce DW, due to indirect signs of lean mass wasting and slow recovery from acute myocardiopathy, deserving lower circulating volume (SHV A3‐I2, IVC 18 mm, collapse 80%; Figure 3). Post‐HD 2.5 Kg reduction in BW and moderate improvement of NT‐proBNP were achieved at discharge without intra‐HD hypotension (Figure 3; Table S1). Cardiac US on day 45 showed improvement of left ventricle EF up to 44% (Figure 3).
2.8 Discharge and follow‐up
Patient was discharged at home on day 49 after double negative nasopharyngeal swabs for SARS‐CoV‐2 on days 47 and 48.
At 93‐ and 98‐day follow‐ups, despite normal gas exchange at rest and normalized thorax X‐ray, patient remained persisting dyspnea at moderate physical activity, associated with positive 6 minutes walking test, residual apical ground glass at CT scan (Figure 2) and unchanged EF.
3 DISCUSSION AND CONCLUSIONS
Although mortality risk in COVID‐19 MHD patients is higher than in general population, MHD should not represent an independent contraindication for admission to subintensive wards. The high rate of ARDS and heart failure, described in COVID‐19, requires hospital wards predisposed for noninvasive ventilation also for MHD patients. Eventual preconditioned impaired access to subintensive care for MHD patients during early as unpredictable phase of pandemic emergency should represent a matter of allocating healthcare resources, poorly sustained by clinical and ethical principles up to date. Due to peculiarities of end‐stage renal disease (ESRD) concerning prognostic evaluation and fluids management, nephrologist may be included in the acute care team of critically ill COVID‐19 dialysis patients admitted to subintensive units.
Intensive dialysis may be required in ESRD as well as in acute kidney injury patients affected by severe COVID‐19, due to cytokine storm and rapid precipitation of fluid overload observed in SARS‐CoV‐2 infection. Although CRRT represents the mainstay in such conditions, 6 it was unavailable outside of ICU at our Institution. Thus, dedicated rooms, for delivering intermittent HD (IHD) by portable osmosis, were predisposed at San Paolo Hospital (Milan, Italy) shortly after initiation of SARS‐CoV‐2 outbreak in Lombardy. Expanded HD could be considered as the modality of choice for IHD in COVID‐19‐infected patients due to its ascertained anti‐inflammatory properties. 5 , 22 Daily IHD herein was life‐saving during acute phase of SARS‐CoV‐2 infection.
Abrupt precipitation of respiratory and cardiac function in COVID‐19 alters fluid redistribution just as quickly. Fluid overload in anuric patients represents a common drawback of resuscitating therapies in the absence of UF. Bed scale resulted indispensable for daily assessment of mass balance in subintensive setting, being more accurate than mathematical computation of fluid balance. Real‐time assessment of fluid status by point‐of‐care US was adjuvant for guiding fluid and ventilatory management. Notably, ultrasound data guided negative fluid balance during last 20 days, in the absence of otherwise objective fluid excess. Dynamic variation in SHV venogram was reported and interpreted based on literature 23 , 24 , 25 and authors' unpublished data. Classification of SHV venogram patterns in 15 combined classes (apnea [A: 0‐4] combined with inspiration [I: 0‐4]) is herein purposed (Figure S4). SHV pattern may appear influenced by both circulating volume, indirectly estimable by IVC diameter and collapse, and cardiac performance.
In April 2020, when the patient's clinical trend was improving, the venous excess ultrasound score (VEXUS) was purposed for assessing venous congestion in cardiorenal syndrome, including US examination of IVC diameter and waveforms of hepatic, portal and renal veins, in patients admitted to ICU after cardiac surgery, excluding patients with critical illness, eGFR < 15 mL/min, or renal transplantation. 26 VEXUS score was associated with the risk of acute kidney injury, and subsequently adopted by Bhardwaj et al, 27 for tailoring fluid removal by diuretics and ultrafiltration in patients with cardiorenal syndrome associated with acute kidney injury stage 1 to 3. On May 2020 Tri‐POCUS approach, including bedside assessment of lungs, heart, and venous system, was suggested for critically ill patients with COVID‐19. 28
Although assessment of hepatic, portal, and renal veins waveforms can be more complete, the present case is hypothesis generating on how easier approach, limited to hepatic veins and IVC, could be suitable outside from ICU. Furthermore, the case first describes assessment of venous congestion in a COVID‐19 MHD patient, where renal veins waveform could be less informative for cardiorenal trend. A new pattern of hepatic vein venogram (fusion of S and D waves, scored as stage 0) is herein suggested, which may associate with extreme reduction of venous congestion, potentially informative against excessive fluid removal. Finally, variation of hepatic vein venogram in apnea and inspiration is herein purposed for the first time; this may be adjuvant in interpreting sensibility of venous congestion to circulating volumes independently from IVC parameters. However, the herein reported interpretation of SHV venogram remains hypothetical, deserving further studies to be verified.
Positive end expiratory pressure was reported as crucial for treating COVID‐19 ARDS. The present case confirms efficacy of PEEP delivered by CPAP helmet. Transitory reduction of PEEP during UF in the acute phase was associated with oxygenation worsening without benefits on anxiety or hemodynamic parameters. Slow weaning from PEEP, also beyond normalization of P/F, was considered reasonable, due to high risk of wet lung recrudescence in HD patient with residual myocardial impairment and pulmonary inflammation. Venturi mixer for helmet CPAP (Harol®) resulted adjuvant for delivering PEEP during recovery phase, with low FiO2 (down to 35%), in order to avoid patient's hyperoxygenation. Prolonged use of noninvasive ventilation requires precaution against cutaneous lesions induced by helmet, belts, or mask. Counterweight system may be considered, for limiting traction on axillary areas induced by helmet straps. 29
Acute cardiovascular syndrome was described in COVID‐19 and attributed to acute coronary syndrome, demand ischemia, microvascular ischemic injury, myocarditis, or cytokine storm. 10 Severe transitory myocardial insufficiency without myocardial necrosis was herein taken as consequent to cytokine storm and fluid overload, superimposed on chronic hypertensive‐ESRD cardiomyopathy. Assessment of EF, NT‐proBNP, and troponin‐I at admission could be reasonable to monitor COVID‐19 HD patients, commonly affected by chronic cardiovascular disease and elevated basal levels of both markers.
COVID‐19 has been associated with hypercoagulability and itself worsens the prognosis. 30 Although prophylactic anticoagulation is now advised, 30 heparin was started on day 9 due to uncertain knowledge about anticoagulation in COVID‐19 at admission.
Anti‐inflammatory drugs were reported for treating COVID‐19 dialysis patients. 5 , 31 Tocilizumab, in association with moderate steroids doses, was herein well tolerated and followed by resolution of fever and improvement of inflammatory markers within 4 days, with exception of IL‐6 rebound as previously observed. 26 Although hypertensive crises were attributed to adrenergic activation triggered by COVID‐19, hypertension induced by tocilizumab has been reported. 11 Hydroxychloroquine was herein adopted prior to international warning against its use in COVID‐19. Notably hydroxychloroquine is now contraindicated in COVID‐19‐infected patients due to uncertain efficacy and increased arrhythmic risk. 32 Antivirals were herein not prescribed. Although Remdesivir is now approved for treating COVID‐19, 33 it remains contraindicated in dialysis patients.
Agitation represented a relevant matter. Notably, morphine is not indicated in dialysis patients due to risk of life threatening accumulation. Furthermore, it is indicated for treating pain, respiratory distress, or palliative sedation, but not for treating anxiety. Distinguishing respiratory distress from anxiety and terminal phase is crucial in COVID‐19‐infected patients, where anxiety and delirium could be better treated by benzodiazepine and antihistamines or neuroleptics, respectively, rather than with morphine (Figure 1; Figures S5 and S7). Agitation sedation should be monitored by Richmond Agitation Sedation Scale (RASS). 34 Other opioids, as buprenorphine or fentanyl, could be cautiously preferred when indicated.
Persistent eosinopenia was observed until day 24, being thereafter followed by eosinophilia associated with diarrhea and rash, uncertainly attributed to allergic reaction to Olmesartan. Eosinopenia was described in acute phase of COVID‐19. 35 , 36 Further eosinophils increase was suggested as marker of disease improvement, 36 based on unknown mechanisms. 37 , 38 Significance of eosinophil trend in COVID‐19 requires further investigation.
Renal associations have mostly provided recommendations for preventing COVID‐19 outbreak within dialysis facilities, but data are still poor for recommending specific drugs for the care of severe COVID‐19 in MHD patients at the moment. Although clinical messages derived by this case remain opinion‐based and hypothesis generating, in the current scenario meticulous application of available anti‐inflammatory drugs, ventilation and dialysis techniques, close to accurate daily evaluation of fluid balance and neurological status, may be crucial for treating severe COVID‐19 in MHD patients.
In conclusion, the case supports efficacy of individualized subintensive care, delivered by multidisciplinary team, and the need to allocate health resources for achieving similar goals in the treatment of critically ill COVID‐19 MHD patients during second pandemic wave.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTION
AG: had major role in data collection, writing, and editing the manuscript. All authors: involved in the patient care. All authors: read and approved the final manuscript.
ETHICAL APPROVAL AND CONSENT TO PARTICIPATE
No ethical issue in reporting of this case.
Supporting information
Supplementary Material
Click here for additional data file.
ACKNOWLEDGMENTS
None. Consent statement: Published with written consent of the patient.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Para clinic data which are referred to in the case presentation are available on request from the corresponding author. |
||||||
Corynebacterium propinquum: A Rare Cause of Prosthetic Valve Endocarditis. | Nondiphtheria Corynebacterium species are often dismissed as culture contaminants, but they have recently become increasingly recognized as pathologic organisms. We present the case of a 48-year-old male patient on chronic prednisone therapy for rheumatoid arthritis with a history of mitral valve replacement with prosthetic valve. He presented with fever, dizziness, dyspnea on exertion, intermittent chest pain, and palpitations. Transesophageal echocardiography revealed two medium-sized densities along the inner aspect of the sewing ring and one larger density along the atrial surface of the sewing ring consistent with vegetation. Two separate blood cultures grew Corynebacterium propinquum, which were sensitive to ceftriaxone but highly resistant to vancomycin and daptomycin. The patient completed a course of ceftriaxone and repeat TEE study and after 6 weeks demonstrated near complete resolution of the vegetation. To our knowledge, this case represents the first in the literature of Corynebacterium propinquum causing prosthetic valve endocarditis. The ability of these organisms to cause deep-seated systemic infections should be recognized, especially in immune-compromised patients. |
==== Front
Case Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2016/1391789Case Report
Corynebacterium propinquum: A Rare Cause of Prosthetic Valve Endocarditis http://orcid.org/0000-0003-1133-6784Jangda Umair
*
http://orcid.org/0000-0002-3451-1074Upadhyay Ankit Bagheri Farshad Patel Nilesh R. Mendelson Robert I. Jamaica Hospital Medical Center, Department of Medicine, Jamaica, NY 11418, USA*Umair Jangda: [email protected] Editor: Gerald S. Supinski
2016 7 11 2016 2016 139178929 8 2016 18 10 2016 Copyright © 2016 Umair Jangda et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Nondiphtheria Corynebacterium species are often dismissed as culture contaminants, but they have recently become increasingly recognized as pathologic organisms. We present the case of a 48-year-old male patient on chronic prednisone therapy for rheumatoid arthritis with a history of mitral valve replacement with prosthetic valve. He presented with fever, dizziness, dyspnea on exertion, intermittent chest pain, and palpitations. Transesophageal echocardiography revealed two medium-sized densities along the inner aspect of the sewing ring and one larger density along the atrial surface of the sewing ring consistent with vegetation. Two separate blood cultures grew Corynebacterium propinquum, which were sensitive to ceftriaxone but highly resistant to vancomycin and daptomycin. The patient completed a course of ceftriaxone and repeat TEE study and after 6 weeks demonstrated near complete resolution of the vegetation. To our knowledge, this case represents the first in the literature of Corynebacterium propinquum causing prosthetic valve endocarditis. The ability of these organisms to cause deep-seated systemic infections should be recognized, especially in immune-compromised patients.
==== Body
1. Introduction
Prosthetic valve endocarditis (PVE) remains a rare but very serious complication of valve replacement. The incidence of prosthetic valve endocarditis ranges from 1% to 6% of valve implantations [1]. The most commonly reported pathogens causing PVE are coagulase-negative staphylococci, Staphylococcus aureus, and Gram-negative bacilli [2]. Corynebacterium propinquum is primarily isolated from the human respiratory tract [3]. It has been shown to be the pathogenic organism in two cases of native valve infective endocarditis, one in an adult and one in a child with congenital heart disease [4, 5]. It was also shown to be the causative agent in a handful of respiratory tract infections worldwide [6–8]. We present the case of a 48-year-old male with late PVE caused by Corynebacterium propinquum. To our knowledge, this case represents the first in the literature of Corynebacterium propinquum causing prosthetic valve endocarditis.
2. Case Report
A 48-year-old male presented with five to six weeks of dizziness with episodes of subjective fever. Patient also reported having increasing dyspnea on exertion associated with intermittent sharp chest pain, unrelated to exertion, and palpitations lasting 20–30 seconds per episode. Additionally, he complained of paroxysmal nocturnal dyspnea but denied orthopnea, peripheral edema, recent dental work, surgical procedure, or intravenous drug use. He has a significant past medical history of hypertension, rheumatoid arthritis on chronic low dose prednisone therapy, and rheumatic heart disease not on antibiotic prophylaxis. The patient had a mitral valve replacement with a bioprosthetic valve 27 years priorly, which was subsequently replaced with a metallic valve 12 years ago. The patient had a pacemaker placed for symptomatic bradycardia 12 years ago.
On admission, the patient was an ill appearing male and was complaining of a dull aching chest pain 4/10 in intensity. Vital signs were significant for fever of 101.6°F (38.6°C). Physical examination revealed tactile fever, clear breath sounds, and metallic S1. Laboratory findings showed a hemoglobin of 8.3 g/dL, leukocytosis of 17,900/uL with 91% PMNs, INR of 6.1, Troponin-I of 0.534 ng/mL, ESR of 85, and C-reactive protein of 20.70 mg/dL. Patient also had an elevated creatinine of 1.8 mg/dL. Prosthetic valve endocarditis was suspected and the patient received broad-spectrum antibiotics including vancomycin, cefepime, and gentamicin. Vancomycin was changed to daptomycin due to worsening renal function. Transesophageal echocardiography revealed mild left ventricular dysfunction with an ejection fraction of 50%. It also showed a mechanical prosthesis in the mitral position with two medium-sized, strand-like, echogenic, highly mobile densities along the inner aspect of the sewing ring and one larger echogenic, spherical density, measuring 9 × 5 mm along the atrial surface of the sewing ring, consistent with vegetation as shown in Figure 1. Two separate blood cultures drawn four hours apart from different sites on the initial day of presentation grew Corynebacterium propinquum. Table 1 shows antimicrobial susceptibility of Corynebacterium propinquum.
At the recommendation of the infectious disease and cardiology services, the patient was discharged home with a peripherally inserted central catheter to complete two months of intravenous ceftriaxone. Follow-up transesophageal echocardiogram done six weeks later demonstrated near complete resolution of the vegetation shown in Figure 2. Repeat blood cultures drawn at six weeks after starting antibiotic treatment were negative for any growth.
3. Discussion
The genus Corynebacterium has more than 80 published species of which over 50 can cause occasional or rare infections in humans [9]. Corynebacterium species are normal colonizers of the skin and mucous membranes and are often dismissed as culture contaminants. It is thought that the incidence of nondiphtheria Corynebacterium is increasing, especially as a cause of nosocomial infections and infections in immunocompromised patients [3]. In our case, the patient was on prednisone, which could have contributed to development of infection with Corynebacterium. In recent literature, there have been an increasing number of reports of Corynebacterium species causing prosthetic valve endocarditis [10].
Corynebacterium propinquum is primarily isolated from the human respiratory tract [3]. It has been shown to be the pathogenic organism in two cases of native valve infective endocarditis, one in an adult and one in a child with congenital heart disease [4, 5]. It has also been reported as the causative agent in a handful of respiratory tract infections worldwide [6–8]. It has also been reported to cause acute nongonococcal urethritis in one patient from Iran [11]. To our knowledge, this is the first report of Corynebacterium propinquum causing prosthetic valve endocarditis. The susceptibility pattern for the strain of C. propinquum from our case showed high resistance to vancomycin and daptomycin, which is unusual for this species. As in other studies, it was susceptible to beta-lactams and an aminoglycoside as well as other antibiotics [4, 5]. Due to the rarity of infections caused by this bacteria, it would be premature to make assumptions regarding resistance patterns.
4. Conclusion
Corynebacterium species are becoming recognized as an increasing cause of opportunistic infections. In our case, the patient had risk factors of immune suppression as well as a prosthetic valve resulting in this very rare infection. C. propinquum has now been shown to be a cause of not only infective endocarditis but also prosthetic valve endocarditis and nosocomial infections. Physicians should be cognizant of potential serious infections caused by C. propinquum in the correct clinical context. Proper identification of Corynebacterium species and recognition of its ability to be pathologic is important in order to inform prompt and appropriate treatment.
Competing Interests
The authors declare that there are no competing interests regarding the publication of this paper.
Figure 1 Transesophageal echocardiogram showing prosthetic mitral valve with vegetation (arrow). LA: left atrium; LV: left ventricle.
Figure 2 Repeat transesophageal echocardiogram repeated after six weeks of antibiotic treatment showing resolution of the vegetation. LA: left atrium; LV: left ventricle.
Table 1 Minimum inhibitory concentration for Corynebacterium propinquum.
Antimicrobial agent MIC (μg/mL)
Ceftriaxone 0.094
Ciprofloxacin 0.016
Daptomycin >256
Imipenem 0.019
Tetracycline 0.125
Vancomycin 12
==== Refs
1 Palraj R. Knoll B. Baddour L. Wilson W. Bennett J. Dolin R. Blaser M. Prosthetic valve endocarditis Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases 2014 8th Philadelphia, Pa, USA Saunders p. 1029
2 Karchmer A. V. Mandell G. L. Bennett J. E. Dolin R. Infections of prosthetic valves Principles and Practice of Infectious Diseases 2000 1 5th Philadelphia, Pa, USA Churchill Livingstone 903 917
3 Kim Reboli A. Bennett J. Dolin R. Blaser M. Other coryneform bacteria and rhodococci Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases 2014 8th Philadelphia, Pa, USA Saunders 2373 2382
4 Kawasaki Y. Matsubara K. Ishihara H. Corynebacterium propinquum as the first cause of infective endocarditis in childhood Journal of Infection and Chemotherapy 2014 20 5 317 319 10.1016/j.jiac.2013.10.013 2-s2.0-84903614077 24486166 24486166
5 Petit P. Bok J. Thompson J. Buiting A. Coyle M. Native-valve endocarditis due to CDC coryneform group ANF-3: report of a case and review of corynebacterial endocarditis Clinical Infectious Diseases 1994 19 5 897 901 10.1093/clinids/19.5.897 2-s2.0-0027996781 7893876
6 Motomura K. Masaki H. Terada M. Three adult cases with Corynebacterium propinquum respiratory infections in a community hospital The Journal of the Japanese Association for Infectious Diseases 2004 78 3 277 282 2-s2.0-2542435033 15103912
7 Furumoto A. Masaki H. Onidzuka T. A case of community-acquired pneumonia caused by Corynebacterium propinquum
The Journal of the Japanese Association for Infectious Diseases 2003 77 6 456 460 2-s2.0-0041846736 12872696
8 Babay H. A. H. Pleural effusion due to Corynebacterium propinquum in a patient with squamous cell carcinoma Annals of Saudi Medicine 2001 21 5-6 337 339 2-s2.0-0035741245 17261942
9 Bernard K. The genus Corynebacterium and other medically relevant coryneform-like bacteria Journal of Clinical Microbiology 2012 50 10 3152 3158 10.1128/jcm.00796-12 2-s2.0-84866441833 22837327
10 Sewell D. L. Coyle M. B. Funke A. G. Prosthetic valve endocarditis caused by Corynebacterium afermentans subsp. lipophilum (CDC coryneform group ANF-1) Journal of Clinical Microbiology 1995 33 3 759 761 2-s2.0-0028836550 7751392 7751392
11 Abdolrasouli A. Roushan A. Corynebacterium propinquum associated with acute, Nongonococcal urethritis Sexually Transmitted Diseases 2013 40 10 829 831 10.1097/olq.0000000000000027 2-s2.0-84888390228 24275738
| serious: 1
patientsex: 1
drugs: CEFEPIME HYDROCHLORIDE, DAPTOMYCIN, GENTAMICIN, PREDNISONE, VANCOMYCIN
reactions: Drug resistance, Renal impairment
| 27891149 | CC BY | corynebacterium propinquum a rare cause of prosthetic valve endocarditis | 2016() | 1391789 | Case reports in medicine | Jangda|Umair|U|0000-0003-1133-6784;Upadhyay|Ankit|A|0000-0002-3451-1074;Bagheri|Farshad|F|;Patel|Nilesh R|NR|;Mendelson|Robert I|RI| | 2016 | 10.1155/2016/1391789 | Jamaica Hospital Medical Center, Department of Medicine, Jamaica, NY 11418, USA.;Jamaica Hospital Medical Center, Department of Medicine, Jamaica, NY 11418, USA.;Jamaica Hospital Medical Center, Department of Medicine, Jamaica, NY 11418, USA.;Jamaica Hospital Medical Center, Department of Medicine, Jamaica, NY 11418, USA.;Jamaica Hospital Medical Center, Department of Medicine, Jamaica, NY 11418, USA. | Case Rep Med | 101512910 | United States | D016428:Journal Article | 24275738;17261942;22837327;7893876;12872696;7751392;24486166;15103912 | false | 13,044,101 | TITLE:
Corynebacterium propinquum: A Rare Cause of Prosthetic Valve Endocarditis.
ABSTRACT:
Nondiphtheria Corynebacterium species are often dismissed as culture contaminants, but they have recently become increasingly recognized as pathologic organisms. We present the case of a 48-year-old male patient on chronic prednisone therapy for rheumatoid arthritis with a history of mitral valve replacement with prosthetic valve. He presented with fever, dizziness, dyspnea on exertion, intermittent chest pain, and palpitations. Transesophageal echocardiography revealed two medium-sized densities along the inner aspect of the sewing ring and one larger density along the atrial surface of the sewing ring consistent with vegetation. Two separate blood cultures grew Corynebacterium propinquum, which were sensitive to ceftriaxone but highly resistant to vancomycin and daptomycin. The patient completed a course of ceftriaxone and repeat TEE study and after 6 weeks demonstrated near complete resolution of the vegetation. To our knowledge, this case represents the first in the literature of Corynebacterium propinquum causing prosthetic valve endocarditis. The ability of these organisms to cause deep-seated systemic infections should be recognized, especially in immune-compromised patients.
TEXT:
1. Introduction
Prosthetic valve endocarditis (PVE) remains a rare but very serious complication of valve replacement. The incidence of prosthetic valve endocarditis ranges from 1% to 6% of valve implantations [1]. The most commonly reported pathogens causing PVE are coagulase-negative staphylococci, Staphylococcus aureus, and Gram-negative bacilli [2]. Corynebacterium propinquum is primarily isolated from the human respiratory tract [3]. It has been shown to be the pathogenic organism in two cases of native valve infective endocarditis, one in an adult and one in a child with congenital heart disease [4, 5]. It was also shown to be the causative agent in a handful of respiratory tract infections worldwide [6–8]. We present the case of a 48-year-old male with late PVE caused by Corynebacterium propinquum. To our knowledge, this case represents the first in the literature of Corynebacterium propinquum causing prosthetic valve endocarditis.
2. Case Report
A 48-year-old male presented with five to six weeks of dizziness with episodes of subjective fever. Patient also reported having increasing dyspnea on exertion associated with intermittent sharp chest pain, unrelated to exertion, and palpitations lasting 20–30 seconds per episode. Additionally, he complained of paroxysmal nocturnal dyspnea but denied orthopnea, peripheral edema, recent dental work, surgical procedure, or intravenous drug use. He has a significant past medical history of hypertension, rheumatoid arthritis on chronic low dose prednisone therapy, and rheumatic heart disease not on antibiotic prophylaxis. The patient had a mitral valve replacement with a bioprosthetic valve 27 years priorly, which was subsequently replaced with a metallic valve 12 years ago. The patient had a pacemaker placed for symptomatic bradycardia 12 years ago.
On admission, the patient was an ill appearing male and was complaining of a dull aching chest pain 4/10 in intensity. Vital signs were significant for fever of 101.6°F (38.6°C). Physical examination revealed tactile fever, clear breath sounds, and metallic S1. Laboratory findings showed a hemoglobin of 8.3 g/dL, leukocytosis of 17,900/uL with 91% PMNs, INR of 6.1, Troponin-I of 0.534 ng/mL, ESR of 85, and C-reactive protein of 20.70 mg/dL. Patient also had an elevated creatinine of 1.8 mg/dL. Prosthetic valve endocarditis was suspected and the patient received broad-spectrum antibiotics including vancomycin, cefepime, and gentamicin. Vancomycin was changed to daptomycin due to worsening renal function. Transesophageal echocardiography revealed mild left ventricular dysfunction with an ejection fraction of 50%. It also showed a mechanical prosthesis in the mitral position with two medium-sized, strand-like, echogenic, highly mobile densities along the inner aspect of the sewing ring and one larger echogenic, spherical density, measuring 9 × 5 mm along the atrial surface of the sewing ring, consistent with vegetation as shown in Figure 1. Two separate blood cultures drawn four hours apart from different sites on the initial day of presentation grew Corynebacterium propinquum. Table 1 shows antimicrobial susceptibility of Corynebacterium propinquum.
At the recommendation of the infectious disease and cardiology services, the patient was discharged home with a peripherally inserted central catheter to complete two months of intravenous ceftriaxone. Follow-up transesophageal echocardiogram done six weeks later demonstrated near complete resolution of the vegetation shown in Figure 2. Repeat blood cultures drawn at six weeks after starting antibiotic treatment were negative for any growth.
3. Discussion
The genus Corynebacterium has more than 80 published species of which over 50 can cause occasional or rare infections in humans [9]. Corynebacterium species are normal colonizers of the skin and mucous membranes and are often dismissed as culture contaminants. It is thought that the incidence of nondiphtheria Corynebacterium is increasing, especially as a cause of nosocomial infections and infections in immunocompromised patients [3]. In our case, the patient was on prednisone, which could have contributed to development of infection with Corynebacterium. In recent literature, there have been an increasing number of reports of Corynebacterium species causing prosthetic valve endocarditis [10].
Corynebacterium propinquum is primarily isolated from the human respiratory tract [3]. It has been shown to be the pathogenic organism in two cases of native valve infective endocarditis, one in an adult and one in a child with congenital heart disease [4, 5]. It has also been reported as the causative agent in a handful of respiratory tract infections worldwide [6–8]. It has also been reported to cause acute nongonococcal urethritis in one patient from Iran [11]. To our knowledge, this is the first report of Corynebacterium propinquum causing prosthetic valve endocarditis. The susceptibility pattern for the strain of C. propinquum from our case showed high resistance to vancomycin and daptomycin, which is unusual for this species. As in other studies, it was susceptible to beta-lactams and an aminoglycoside as well as other antibiotics [4, 5]. Due to the rarity of infections caused by this bacteria, it would be premature to make assumptions regarding resistance patterns.
4. Conclusion
Corynebacterium species are becoming recognized as an increasing cause of opportunistic infections. In our case, the patient had risk factors of immune suppression as well as a prosthetic valve resulting in this very rare infection. C. propinquum has now been shown to be a cause of not only infective endocarditis but also prosthetic valve endocarditis and nosocomial infections. Physicians should be cognizant of potential serious infections caused by C. propinquum in the correct clinical context. Proper identification of Corynebacterium species and recognition of its ability to be pathologic is important in order to inform prompt and appropriate treatment.
Competing Interests
The authors declare that there are no competing interests regarding the publication of this paper.
Figure 1 Transesophageal echocardiogram showing prosthetic mitral valve with vegetation (arrow). LA: left atrium; LV: left ventricle.
Figure 2 Repeat transesophageal echocardiogram repeated after six weeks of antibiotic treatment showing resolution of the vegetation. LA: left atrium; LV: left ventricle.
Table 1 Minimum inhibitory concentration for Corynebacterium propinquum.
Antimicrobial agent MIC (μg/mL)
Ceftriaxone 0.094
Ciprofloxacin 0.016
Daptomycin >256
Imipenem 0.019
Tetracycline 0.125
Vancomycin 12 |
||||||
A Case of Pancytopenia with Many Possible Causes: How Do You Tell Which is the Right One? | Systemic lupus erythematosus (SLE) often presents with cytopenia(s); however, pancytopenia is found less commonly, requiring the consideration of possible aetiologies other than the primary disease. The authors describe the case of a female patient with a recent diagnosis of SLE admitted through the Emergency Department with fever of unknown origin and severe pancytopenia. She was medicated with prednisolone, hydroxychloroquine, azathioprine, amlodipine and sildenafil. Extensive investigation suggested azathioprine-induced myelotoxicity. However, the patient was found to have a concomitant cytomegalovirus (CMV) infection, with oral lesions, positive CMV viral load as well as the previously described haematological findings. Pancytopenia is always a diagnostic challenge, with drug-induced myelotoxicity, especially secondary to azathioprine, being a rare aetiology. This report reiterates the importance of the differential diagnosis of pancytopenia, especially in immunosuppressed patients with increased risk for opportunistic infections.
The possibility of multiple aetiologies for pancytopenia in the same patient should be considered.Azathioprine-induced myelotoxicity is dose-dependent and pancytopenia is a rare form of presentation.Opportunistic infections should always be considered as a cause of cytopenias when immunosuppression is present. |
==== Front
Eur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2019_0010121012-1-6986-1-10-20190123ArticlesA Case of Pancytopenia with Many Possible Causes: How Do You Tell Which is the Right One? Diaz Priscila Vieira Mariana Abreu Carneiro António Fernandes Natália Department of Internal Medicine, Cascais Hospital, Cascais, Portugal.2019 30 1 2019 6 2 00101205 12 2018 17 12 2018 © EFIM 20192019This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseSystemic lupus erythematosus (SLE) often presents with cytopenia(s); however, pancytopenia is found less commonly, requiring the consideration of possible aetiologies other than the primary disease. The authors describe the case of a female patient with a recent diagnosis of SLE admitted through the Emergency Department with fever of unknown origin and severe pancytopenia. She was medicated with prednisolone, hydroxychloroquine, azathioprine, amlodipine and sildenafil. Extensive investigation suggested azathioprine-induced myelotoxicity. However, the patient was found to have a concomitant cytomegalovirus (CMV) infection, with oral lesions, positive CMV viral load as well as the previously described haematological findings. Pancytopenia is always a diagnostic challenge, with drug-induced myelotoxicity, especially secondary to azathioprine, being a rare aetiology. This report reiterates the importance of the differential diagnosis of pancytopenia, especially in immunosuppressed patients with increased risk for opportunistic infections.
LEARNING POINTS
The possibility of multiple aetiologies for pancytopenia in the same patient should be considered.
Azathioprine-induced myelotoxicity is dose-dependent and pancytopenia is a rare form of presentation.
Opportunistic infections should always be considered as a cause of cytopenias when immunosuppression is present.
Pancytopeniasystemic lupus erythematosusazathioprinecytomegalovirus
==== Body
INTRODUCTION
Systemic lupus erythematosus (SLE) is a chronic inflammatory disease affecting multiple organs and systems. Cytopenias are common, however pancytopenia is found less frequently, requiring the consideration of possible aetiologies other than the primary disease. Active disease and immunosuppressive treatment should be the first possible causes to be considered[1].
CASE DESCRIPTION
The authors report the case of a 40-year-old female patient, with Hashimoto hypothyroidism and recently diagnosed SLE, medicated with prednisolone 60 mg/daily, hydroxychloroquine 400 mg/daily and azathioprine 100 mg/daily. She was admitted through the Emergency Department reporting a 4-day course of fever (39ºC), odynophagia and multiple and painful oral ulcers. On examination, she was febrile (38ºC) with extensive leucoplakia.
The patient was found to have severe pancytopenia (normocytic normochromic anaemia with a haemoglobin of 6.3 g/dl, leukopenia 350×106/l with neutropenia 120×106/l, and thrombocytopaenia 110×109/l) and mildly elevated inflammatory markers (C-reactive protein 5.96 mg/dl). Blood smear showed moderate anisopoikilocytosis with platelet anisocytosis.
The patient was prescribed piperacillin/tazobactam and fluconazole as a diagnosis of pancytopenia with neutropenic fever syndrome and oropharyngeal candidiasis was made. Additionally, azathioprine was suspended, due to potential drug-induced myelotoxicity. After resolution of the oral leucoplakia, multiple ulcers became evident, suggestive of viral or pemphigoid aetiology (Figs. 1–4).
No clinical or biochemical signs of active SLE were found, with normal complement and anti-dsDNA antibody levels. Vitamin B12 and folic acid levels were within the normal range. The patient was found to have positive IgM and IgG cytomegalovirus (CMV) antibodies, with a viral load of 2,800 copies/ml; testing was negative for other viruses, such as EBV, parvovirus, herpes simplex 1/2 and HIV. Blood, urine and bone marrow cultures were negative. Bone marrow aspiration was compatible with drug-induced agranulocytosis. Thiopurine methyltransferase (TPMT) was 11.9 U/ml (normal >19 U/ml).
As previously stated, azathioprine was suspended, and the patient was prescribed valganciclovir 900 mg every 12 hours, with complete resolution of the oral ulcers and haematological improvement (Table 1).
DISCUSSION
Pancytopenia, defined as a reduction in all three peripheral blood lineages, can result from bone marrow infiltration, aplasia or increased cell destruction or sequestration. Disease severity is dependent on aetiology (for example, acute leukaemia) and clinical impact (for example, symptomatic anaemia or febrile neutropenia). It often represents a diagnostic challenge, mainly because patients are increasingly complex, often having multiple potential confounding (and contributing) comorbidities and medications.
In SLE patients, pancytopenia is often related to other causes, apart from the autoimmune condition, for example haemophagocytic lymphohistiocytosis, macrophage activation syndrome, septic or drug-induced myelotoxicity and haematological malignancies.
Azathioprine is often used as a steroid-sparing drug, interfering with purine and protein synthesis. TPMT is an important enzyme involved in azathioprine metabolization, with low blood activity being associated with increased risk for drug-related toxicity[2]. Azathioprine-induced myelotoxicity is dose-dependent and the most common effect is leukopenia (5–25%)[3]; pancytopenia is rare. SLE patients seem to be more susceptible to these adverse events[4], which tend to manifest in the first 3 weeks of treatment, and last for 3 weeks after drug suspension. Some patients may require colony-stimulating factors[5].
An additional remark regarding opportunistic infections and their contribution to myelosuppression is in order. CMV can remain latent after a primary infection and reactivate when allowed, especially in permissive immunological states, such as drug-induced immunosuppression. CMV infection can range from mild flu-like symptoms, to cytopenias, to severe acute (even life-threatening) syndromes, such as haemophagocytic lymphohistiocytosis. Recommended treatment is intravenous ganciclovir or oral valganciclovir.
CONCLUSION
This case report is extremely relevant since it illustrates the complexity of the differential diagnosis of pancytopenia, and how this disorder can result from a combination of multiple aetiologies (comorbidities, medication, acute infections) rather than just one: this patient had an autoimmune disease which often presents with cytopenias, she was medicated with a potentially myelotoxic drug and she had signs of ongoing CMV infection.
Conflicts of Interests: The Authors declare that there are no competing interests.
Figure 1 Tongue lesion (day 8)
Figure 2 Hard palate lesion (day 8)
Figure 3 Tongue lesion (day 16)
Figure 4 Hard palate lesion (day 16)
Table 1 Cytopenia progression throughout hospitalisation
Complete Blood Count Day 0 Day 6 Day 9 Day 14 Day 18
Haemoglobin (g/dl) 6.3 7.7 8.0 8.9 9.0
White blood cells (×109/l) 0.35 0.42 0.67 1.59 2.12
Neutrophils (×109/l) 0.12 0.05 0.14 0.85 1.37
Lymphocytes (×109/l) 0.21 0.35 0.25 0.57 0.69
Platelets (×109/l) 110 20 18 72 218
==== Refs
REFERENCES
1 Levine AB Erkan D Clinical assessment and management of cytopenias in lupus patients Curr Rheumatol Rep 2011 13 291 299 21503695
2 Neto MP Alves AN Fortina A Burattini M Sumita NM Srougi M Therapeutic drug monitoring of azathioprine: a review Bras Patol Med Lab 2008 44 161 167
3 Anstey A Lennard L Mayou SC Kirby JD Pancytopenia related to azathioprine – an enzyme deficiency caused by a common genetic polymorphism J Royal Soc Med 1992 85 752 756
4 Yeter KC Afkhami M Brynes RK Aplastic anemia secondary to azathioprine in systemic lupus erythematosus: report of a case with normal thiopurine S-methyltransferase enzyme activity and review of the literature Lupus 2013 22 1526 1528 24029750
5 Jensen CH Tiu J Catalanotti JS Azathioprine-induced pancytopenia with normal TPMT activity presenting with HSV oral ulcers BMJ Case Rep 2018 10.1136/bcr-2018-225209
| serious: 1
patientsex: 2
drugs: AMLODIPINE BESYLATE, AZATHIOPRINE, HYDROXYCHLOROQUINE, PREDNISOLONE, SILDENAFIL
reactions: Bone marrow toxicity, Cytomegalovirus infection, Cytomegalovirus mucocutaneous ulcer, Febrile neutropenia, Leukoplakia, Odynophagia, Oropharyngeal candidiasis, Pancytopenia, Product use issue, Red blood cell poikilocytes present, Vitamin D deficiency
| 30931264 | CC BY-NC | a case of pancytopenia with many possible causes how do you tell which is the right one | 6(2) | 001012 | European journal of case reports in internal medicine | Diaz|Priscila|P|;Vieira|Mariana Abreu|MA|;Carneiro|António|A|;Fernandes|Natália|N| | 2019 | 10.12890/2019_001012 | Department of Internal Medicine, Cascais Hospital, Cascais, Portugal.;Department of Internal Medicine, Cascais Hospital, Cascais, Portugal.;Department of Internal Medicine, Cascais Hospital, Cascais, Portugal.;Department of Internal Medicine, Cascais Hospital, Cascais, Portugal. | Eur J Case Rep Intern Med | 101648453 | 2284-2594 | Italy | D016428:Journal Article | Pancytopenia; azathioprine; cytomegalovirus; systemic lupus erythematosus | 1494166;21503695;24029750;30002211 | false | 16,540,115 | TITLE:
A Case of Pancytopenia with Many Possible Causes: How Do You Tell Which is the Right One?
ABSTRACT:
Systemic lupus erythematosus (SLE) often presents with cytopenia(s); however, pancytopenia is found less commonly, requiring the consideration of possible aetiologies other than the primary disease. The authors describe the case of a female patient with a recent diagnosis of SLE admitted through the Emergency Department with fever of unknown origin and severe pancytopenia. She was medicated with prednisolone, hydroxychloroquine, azathioprine, amlodipine and sildenafil. Extensive investigation suggested azathioprine-induced myelotoxicity. However, the patient was found to have a concomitant cytomegalovirus (CMV) infection, with oral lesions, positive CMV viral load as well as the previously described haematological findings. Pancytopenia is always a diagnostic challenge, with drug-induced myelotoxicity, especially secondary to azathioprine, being a rare aetiology. This report reiterates the importance of the differential diagnosis of pancytopenia, especially in immunosuppressed patients with increased risk for opportunistic infections.
The possibility of multiple aetiologies for pancytopenia in the same patient should be considered.Azathioprine-induced myelotoxicity is dose-dependent and pancytopenia is a rare form of presentation.Opportunistic infections should always be considered as a cause of cytopenias when immunosuppression is present.
TEXT:
INTRODUCTION
Systemic lupus erythematosus (SLE) is a chronic inflammatory disease affecting multiple organs and systems. Cytopenias are common, however pancytopenia is found less frequently, requiring the consideration of possible aetiologies other than the primary disease. Active disease and immunosuppressive treatment should be the first possible causes to be considered[1].
CASE DESCRIPTION
The authors report the case of a 40-year-old female patient, with Hashimoto hypothyroidism and recently diagnosed SLE, medicated with prednisolone 60 mg/daily, hydroxychloroquine 400 mg/daily and azathioprine 100 mg/daily. She was admitted through the Emergency Department reporting a 4-day course of fever (39ºC), odynophagia and multiple and painful oral ulcers. On examination, she was febrile (38ºC) with extensive leucoplakia.
The patient was found to have severe pancytopenia (normocytic normochromic anaemia with a haemoglobin of 6.3 g/dl, leukopenia 350×106/l with neutropenia 120×106/l, and thrombocytopaenia 110×109/l) and mildly elevated inflammatory markers (C-reactive protein 5.96 mg/dl). Blood smear showed moderate anisopoikilocytosis with platelet anisocytosis.
The patient was prescribed piperacillin/tazobactam and fluconazole as a diagnosis of pancytopenia with neutropenic fever syndrome and oropharyngeal candidiasis was made. Additionally, azathioprine was suspended, due to potential drug-induced myelotoxicity. After resolution of the oral leucoplakia, multiple ulcers became evident, suggestive of viral or pemphigoid aetiology (Figs. 1–4).
No clinical or biochemical signs of active SLE were found, with normal complement and anti-dsDNA antibody levels. Vitamin B12 and folic acid levels were within the normal range. The patient was found to have positive IgM and IgG cytomegalovirus (CMV) antibodies, with a viral load of 2,800 copies/ml; testing was negative for other viruses, such as EBV, parvovirus, herpes simplex 1/2 and HIV. Blood, urine and bone marrow cultures were negative. Bone marrow aspiration was compatible with drug-induced agranulocytosis. Thiopurine methyltransferase (TPMT) was 11.9 U/ml (normal >19 U/ml).
As previously stated, azathioprine was suspended, and the patient was prescribed valganciclovir 900 mg every 12 hours, with complete resolution of the oral ulcers and haematological improvement (Table 1).
DISCUSSION
Pancytopenia, defined as a reduction in all three peripheral blood lineages, can result from bone marrow infiltration, aplasia or increased cell destruction or sequestration. Disease severity is dependent on aetiology (for example, acute leukaemia) and clinical impact (for example, symptomatic anaemia or febrile neutropenia). It often represents a diagnostic challenge, mainly because patients are increasingly complex, often having multiple potential confounding (and contributing) comorbidities and medications.
In SLE patients, pancytopenia is often related to other causes, apart from the autoimmune condition, for example haemophagocytic lymphohistiocytosis, macrophage activation syndrome, septic or drug-induced myelotoxicity and haematological malignancies.
Azathioprine is often used as a steroid-sparing drug, interfering with purine and protein synthesis. TPMT is an important enzyme involved in azathioprine metabolization, with low blood activity being associated with increased risk for drug-related toxicity[2]. Azathioprine-induced myelotoxicity is dose-dependent and the most common effect is leukopenia (5–25%)[3]; pancytopenia is rare. SLE patients seem to be more susceptible to these adverse events[4], which tend to manifest in the first 3 weeks of treatment, and last for 3 weeks after drug suspension. Some patients may require colony-stimulating factors[5].
An additional remark regarding opportunistic infections and their contribution to myelosuppression is in order. CMV can remain latent after a primary infection and reactivate when allowed, especially in permissive immunological states, such as drug-induced immunosuppression. CMV infection can range from mild flu-like symptoms, to cytopenias, to severe acute (even life-threatening) syndromes, such as haemophagocytic lymphohistiocytosis. Recommended treatment is intravenous ganciclovir or oral valganciclovir.
CONCLUSION
This case report is extremely relevant since it illustrates the complexity of the differential diagnosis of pancytopenia, and how this disorder can result from a combination of multiple aetiologies (comorbidities, medication, acute infections) rather than just one: this patient had an autoimmune disease which often presents with cytopenias, she was medicated with a potentially myelotoxic drug and she had signs of ongoing CMV infection.
Conflicts of Interests: The Authors declare that there are no competing interests.
Figure 1 Tongue lesion (day 8)
Figure 2 Hard palate lesion (day 8)
Figure 3 Tongue lesion (day 16)
Figure 4 Hard palate lesion (day 16)
Table 1 Cytopenia progression throughout hospitalisation
Complete Blood Count Day 0 Day 6 Day 9 Day 14 Day 18
Haemoglobin (g/dl) 6.3 7.7 8.0 8.9 9.0
White blood cells (×109/l) 0.35 0.42 0.67 1.59 2.12
Neutrophils (×109/l) 0.12 0.05 0.14 0.85 1.37
Lymphocytes (×109/l) 0.21 0.35 0.25 0.57 0.69
Platelets (×109/l) 110 20 18 72 218 |
||||
Hepatic Lesions with Secondary Syphilis in an HIV-Infected Patient. | Syphilis among HIV-infected patients continues to be a public health concern, especially in men who have sex with men. The clinical manifestations of syphilis are protean; syphilitic hepatitis is an unusual complication that can occur at any stage of the disease. We report a case of an HIV-infected male who presented with systemic symptoms and liver lesions highly suggestive of lymphoma and was proven to have syphilitic hepatitis by liver biopsy. Our case reinforces the importance of recognizing syphilis as a possible cause of unexplained abnormal liver enzymes and/or hepatic lesions in HIV-infected patients. |
==== Front
Case Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2014/604794Case ReportHepatic Lesions with Secondary Syphilis in an HIV-Infected Patient Solari Paola R. Jones Christopher Wallace Mark R. *Orlando Health, 1414 Kuhl Avenue, Orlando, FL 32806, USA*Mark R. Wallace: [email protected] Editor: Bruno Megarbane
2014 2 10 2014 2014 60479431 7 2014 23 9 2014 Copyright © 2014 Paola R. Solari et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Syphilis among HIV-infected patients continues to be a public health concern, especially in men who have sex with men. The clinical manifestations of syphilis are protean; syphilitic hepatitis is an unusual complication that can occur at any stage of the disease. We report a case of an HIV-infected male who presented with systemic symptoms and liver lesions highly suggestive of lymphoma and was proven to have syphilitic hepatitis by liver biopsy. Our case reinforces the importance of recognizing syphilis as a possible cause of unexplained abnormal liver enzymes and/or hepatic lesions in HIV-infected patients.
==== Body
1. Introduction
Syphilis among HIV-infected patients continues to be a public health concern. Although liver involvement with early syphilis is an infrequently recognized complication, it is an especially challenging diagnosis in HIV-infected individuals who often have abnormal liver function tests from any one of multiple potential causes [1]. Coexisting conditions such us hepatitis C, hepatitis B, mycobacterial infection, and neoplastic diseases as lymphoma or Kaposi's sarcoma may cause liver enzymes abnormalities in this population, as well as medications, substance abuse, and fatty liver disease. Treponema pallidum is known to cause hepatitis, but relatively few case reports have been published of hepatic involvement in early syphilis in HIV-infected patients [1–4]. We present a case of an HIV positive male with hepatic lesions suggestive of lymphoma who was eventually diagnosed with syphilitic hepatitis after liver biopsy.
2. Case Presentation
A 59-year-old married male with well-controlled insulin dependent diabetes mellitus, tinea versicolor, and long term nonprogressive HIV infection presented to our clinic with five weeks of generalized muscle, joint and back pain, headache, and weight loss of about seven pounds over three weeks. Two months prior to this presentation, at his annual HIV restaging, his CD4 was 650 cells/μL and quantitative HIV load was 481 copies/mL. His CD4 counts and viral loads had been in this range for eighteen years without any antiretroviral therapy. At the same routine annual visit, his urine screening for chlamydia and gonorrhea was negative, a RPR was nonreactive, and a hepatitis panel showed immunity to hepatitis B without evidence of acute or chronic viral hepatitis. A chest radiograph was normal. His hemoglobin A1c was 7.7%.
On examination he was afebrile and had no palpable lymph nodes, hepatosplenomegaly, or neurologic deficits. He did have a hypopigmented, macular rash limited to his back consistent with tinea versicolor. Serologies for cytomegalovirus, parvovirus B-19, and Epstein-Barr virus were consistent with past infection. No specific therapy was given. He returned to clinic two months later with persistent symptoms of headache, myalgias, and back pain. He now reported, additionally, that he had developed fever, sweats, blurred vision in his left eye, alopecia, a moccasin-type erythrodermic rash on his feet, and additional 10 pound weight loss. He denied any sexual activity for greater than 5 years, including oral sex. He had seen an optometrist for his blurry vision and been diagnosed with a left cataract; another physician he visited had prescribed an antifungal for his foot rash without improvement. Abdominal examination revealed new tenderness in the right upper quadrant with hepatomegaly. Laboratory investigation showed CD4 of 369 cells/μL and HIV load of 1314 copies/mL. His alkaline phosphatase was elevated at 209 U/L (40–115), but his alanine aminotransferase (ALT) and bilirubin were normal; he denied alcohol use or hepatotoxic medications. Albumin was normal. An erythrocyte sedimentation rate was 67 mm/hr (0–20). Cryptococcal serum antigen, urine histoplasmosis antigen, Bartonella and Brucella serologies, and an interferon-gamma release assay for M. tuberculosis were all negative.
A computed tomography (CT) of the abdomen pelvis and chest showed a questionable liver abnormality. Magnetic resonance (MRI) of liver confirmed three lesions within the right lobe with mild splenomegaly; lymphoma was considered the most likely diagnosis (Figures 1 and 2). Fine needle liver biopsy demonstrated chronic inflammation and extensive sclerosis; numerous spirochetes were identified on immunohistochemistry (Figure 3). A repeat RPR was 1 : 256; it had been negative four months previously at his annual evaluation.
His visual complaints prompted an ophthalmology evaluation revealing panuveitis in both eyes without retinal involvement, consistent with syphilis. A lumbar puncture showed a lymphocytic pleocytosis with 18 WBC (92% lymphocytes), protein 118, glucose 76, and a reactive VDRL (1 : 1).
Due to his work, he found a continuous penicillin infusion very difficult to be compliant with; therefore, ceftriaxone 2 gram per day for 14 days was chosen for his syphilis therapy. Within hours of the initiation of antibiotic, he developed a Jarisch-Herxheimer reaction with fevers, chills, and tachycardia which resolved within one day. He had complete resolution of systemic symptoms by the end of the course of ceftriaxone with improved vision on the left. One day after discontinuation of ceftriaxone, his right vision worsened acutely. A follow-up evaluation two days after completion of ceftriaxone showed worsening of panuveitis in the right eye with new retinal involvement. A 14-day course of penicillin G (PCN G) 24 million units intravenously every 24 hr was immediately initiated. His right vision improved during his 10 days of high dose penicillin treatment. He was also given weekly benzathine penicillin times 3 doses after the intravenous penicillin, completing a total of 7 weeks of syphilis treatment. HIV treatment was again declined. A repeat CD4 count and HIV-l load at the end of his syphilis treatment were 785 CD4 cell/μL and 792 copies/mL, respectively. His liver function tests normalized after treatment. Nine months after presentation his RPR was 1 : 16 and he was completely well.
3. Discussion
Syphilis/HIV coinfection accounts for approximately 25% of the cases of primary and secondary syphilis reported in the United States [5]. In recent years the majority of US syphilis cases have been reported among younger men who have sex with men (MSM); these cases account for 67% of primary and secondary syphilis. These increasing rates of syphilis among young men have been characterized by high rates of HIV coinfection and high risk sexual behavior [6–12].
Syphilis may present with a variety of clinical manifestations, most commonly with a painless chancre at the inoculation site that represents primary syphilis. Approximately 25% of untreated infected individuals will develop a systemic illness or secondary syphilis characterized by a rash, fever, and lymphadenopathy caused by the dissemination and invasion of spirochetes to mucocutaneous and visceral sites. Primary and secondary syphilis can overlap in HIV-coinfected patients as well as in the general population [13, 14].
Though hepatic involvement with syphilis was described over 400 years ago by Paracelsus, Matthiolus, and Francois de la Boe Sylvius [1, 15], syphilitic hepatitis continues to be an under recognized manifestation of syphilis. It is usually defined as the presence of abnormal liver enzymes in the setting of early syphilis and in the absence of an alternative cause of hepatitis that resolves with syphilis treatment. An elevation in the alkaline phosphatase (ALP) during secondary syphilis is the classic presentation in both the general population and HIV-infected patients. While the cholestatic pattern is more common, some cases may present predominantly with hepatocellular damage. The difference in presentation may be dictated by disease stage as suggested by Manavi et al. [4] who found that ALT was higher in proportion to other liver function test values in early syphilis, suggesting that hepatocellular predominant liver injury may be seen with early syphilis and may progress into cholestasis at later stages if left untreated. Elevation of total bilirubin was rarely seen in this cohort and no significant relationship between RPR titer and various HIV factors was observed. Our patient had the classic cholestatic pattern with an abdominal CT as well as MRI revealing three low attenuation lesions in the right lower lobe. Only one case report of pseudohepatic tumor associated to secondary syphilis in an HIV positive patient has been previously described [2].
Liver biopsy in syphilis may be nonspecific, typically characterized by periportal lymphocytic infiltration with focal necrosis of hepatic cells around veins, portal, and lobules. Although the visualization of spirochetes in liver tissue is diagnostic, these are observed in about half of reported cases [1, 16, 17]. Our case showed chronic inflammation and extensive sclerosis with innumerable spirochetes by immunohistochemistry.
Though localized or generalized maculopapular rash is the most common physical finding in patients with syphilitic hepatitis and HIV coinfection, other findings have been described. Crum-Cianflone et al. [3], in a recent retrospective study of twelve HIV/syphilis coinfected patients, reported the most common symptoms included rash (67%), pharyngitis (33%), adenopathy (25%), fever (16%), fatigue (16%), ocular symptoms (16%), and arthralgias (8%).
Mullick et al. [1] reported the first case series of syphilitic hepatitis in seven HIV-infected patients, all men presenting with a rash consistent with secondary syphilis and markedly elevated ALP, which improved significantly after two-week course of intravenous beta-lactam antibiotics. In this study patients with higher CD4+ cell counts had higher RPR titers, suggesting that coinfected patient with a preserved immune response may be more likely to develop a robust periportal inflammation responsible for the clinical manifestations, although other studies have showed no correlation between RPR titers and CD4 cell counts or HIV viral load [3, 4].
Although the pathogenesis is unknown, anal intercourse among MSM has been proposed as a risk factor for secondary syphilitic hepatitis, as T. pallidum may enter the portal system by direct venous drainage from the rectal area [3, 17]. An anorectal ulcer was not detected in our patient and he denied any intercourse in several years.
The characteristics of HIV-infected patients do not seem to play a role in the occurrence of hepatitis with early syphilis, except for the duration of HIV infection, as reported by Crum-Cianflone et al. [3]. The CD4 cell count, HIV viral load, and use of HAART were not associated with hepatitis. The duration of HIV infection may be of relevance as patients with syphilitic hepatitis typically have a longer duration of infection, 10 versus 4 years (P = 0.04). The authors suggested that this association may be the result of an intensified inflammatory response to the treponemal periportal infiltration in the presence of possible subclinical liver disease from cumulative exposure over time. The nature of this relationship is unknown and further studies on the pathogenesis will be needed to confirm this potential association [3, 4].
The incidence and prevalence of syphilitic hepatitis in HIV-infected patients are unknown but it seems more prevalent in men, mostly MSM [3, 4]. The high incidence and prevalence among HIV coinfected MSM may be the result of the higher rates of syphilis among this group. Although anal sex has been proposed as a potential risk factor for syphilitic hepatitis, more research is needed to confirm this hypothesis as syphilitic hepatitis has also been well reported in heterosexual men [1, 17–20].
Most cases show complete clinical and laboratory recovery after syphilis treatment, with normalization of all liver test abnormalities within days or months [3, 4]. These data suggest that syphilitic hepatitis in HIV-infected patients may have the same favorable prognosis as the general population. Liver cirrhosis following hepatic syphilis has been rarely reported, as well as a severe acute and fulminant hepatitis requiring liver transplant, but no such cases have been reported among HIV-coinfected patients. Early recognition and treatment of this condition is needed to avoid potential detrimental health consequences including liver injury, as well as to prevent transmission to others [1, 3, 21–24].
Our case was most unusual in that this patient presented with liver lesions and systemic symptoms highly suggestive of malignancy. A recent RPR had been negative and he denied sexual activity in the preceding 5 years, including oral sex. Syphilis must be entertained as a potential cause of abnormal liver enzymes and/or hepatic lesions, especially in HIV-infected males.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
Figure 1 Magnetic resonance of abdomen showing two lesions within the right lobe of the liver along the peripheral surface (black arrows).
Figure 2 Magnetic resonance of abdomen showing two lesions within the right lobe of the liver along the peripheral surface (black arrows).
Figure 3 Histological findings: (a) IHC, 40X: scanning power view of liver core biopsy immunohistochemically stained for Treponema pallidum. Organisms are visible as red color and correspond to the fibrotic inflamed area seen on hematoxylin and eosin stain (H&E). T. pallidum, 40X. (b) IHC, 200X: intermediate power view shows spirochetes centered around blood vessels and infiltrating into sclerotic hepatic parenchyma. T. pallidum, 200X. (c) IHC, 600X: high power magnification of spirochete highlights the spiral morphology. T. pallidum, (black arrow) 600X.
==== Refs
1 Mullick CJ Liappis AP Benator DA Roberts AD Parenti DM Simon GL Syphilitic hepatitis in HIV-infected patients: a report of 7 cases and review of the literature Clinical Infectious Diseases 2004 39 10 e100 e105 2-s2.0-16844361969 15546070
2 Mahto M Mohammed F Wilkins E Mason J Haboubi NY Khan AN Pseudohepatic tumour associated with secondary syphilis in an HIV-positive male International Journal of STD and AIDS 2006 17 2 139 141 2-s2.0-33644548305 16464282
3 Crum-Cianflone N Weekes J Bavaro M Syphilitic hepatitis among HIV-infected patients International Journal of STD and AIDS 2009 20 4 278 284 2-s2.0-66349129406 19304979
4 Manavi K Dhasmana D Cramb R Prevalence of hepatitis in early syphilis among an HIV cohort International Journal of STD and AIDS 2012 23 8 e4 e6 2-s2.0-84865830669
5 Chesson HW Heffelfinger JD Voigt RF Collins D Estimates of primary and secondary syphilis rates in persons with HIV in the United States, 2002 Sexually Transmitted Diseases 2005 32 5 265 269 2-s2.0-17744395706 15849526
6 Heffelfinger JD Swint EB Berman SM Weinstock HS Trends in primary and secondary syphilis among men who have sex with men in the United States The American Journal of Public Health 2007 97 6 1076 1083 2-s2.0-34250796734 17463387
7 Centers for Disease Control and Prevention Resurgent bacterial sexually transmitted disease among men who have sex with men—King County, Washington, 1997–1999 Morbidity and Mortality Weekly Report 1999 48 35 773 777 11263546
8 Centers for Disease Control and Prevention Outbreak of syphilis among men who have sex with men—Southern California, 2000 Morbidity and Mortality Weekly Report 2001 50 117 120 11393490
9 Centers for Disease Control and Prevention Primary and secondary syphilis among men who have sex with men—New York City, 2001 MMWR. Morbidity and Mortality Weekly Report 2002 51 38 853 856 12363336
10 Chen SY Gibson S Katz MH Continuing increases in sexual risk behavior and sexually transmitted diseases among men who have sex with men: San Francisco, Calif, 1999–2001 The American Journal of Public Health 2002 92 9 1387 1388 2-s2.0-0036721803 12197957
11 D’Souza G Lee JH Paffel JM Outbreak of syphilis among men who have sex with men in Houston, Texas Sexually Transmitted Diseases 2003 30 12 872 873 2-s2.0-0344736788 14646631
12 Centers for Disease Control and Prevention Primary and secondary syphilis—United States, 2003-2004 Morbidity and Mortality Weekly Report 2006 55 269 273 16543880
13 Rompalo AM Joesoef MR O'Donnell JA Clinical manifestations of early syphilis by HIV status and gender: results of the syphilis and HIV study Sexually Transmitted Diseases 2001 28 3 158 165 2-s2.0-0035122911 11289198
14 Sparling PF Swartz MN Musher DM Healy BP Holmes KK Sparling PF Stamm WE Clinical manifestations of syphilis Sexually Transmitted Diseases 2008 4th edition New York, NY, USA McGraw-Hill 661 684
15 Schrager VL Clinical aspects of syphilis of the liver Journal of the American Medical Association 1912 58 10 681 684
16 Taniguchi Y Nakae Y Ikoma K Subclinical syphilitic hepatitis, which was markedly worsened by a Jarisch-Herxheimer reaction The American Journal of Gastroenterology 1999 94 6 1694 1696 2-s2.0-0032976129 10364050
17 Kim GH Kim BU Lee JH Cholestatic hepatitis and thrombocytosis in a secondary syphilis patient Journal of Korean Medical Science 2010 25 11 1661 1664 2-s2.0-78449268850 21060758
18 Le Clair RA Early syphilitic hepatitis. A possible case The British Journal of Venereal Diseases 1971 47 3, article 212 2-s2.0-0015074188
19 Ibáñez M Varela M Rodríguez-Peláez M Luetic hepatitis. An emerging entity Gastroenterologia y Hepatologia 2009 32 9 610 613 2-s2.0-70349267530 19625105
20 Albandea Moreno C Aguilar Urbano VM Rivera Irigoin R Syphilitic Hepatitis: case report Revista Espanola de Enfermedades Digestivas 2009 101 11 813 819 2-s2.0-77950348894 20001160
21 Sabbatani S Manfredi R Attard L Salfi N Chiodo F Secondary syphilis presenting with acute severe hepatic involvement in a patient with undiagnosed HIV disease AIDS Patient Care and STDs 2005 19 9 545 549 2-s2.0-25144471613 16164381
22 Karmi G Thirkettle JL Read AE The association of syphilis with hepatic cirrhosis: a report of six cases and a review of the literature Postgraduate Medical Journal 1969 45 528 675 679 2-s2.0-0014586279 5358385
23 Lo JO Harrison RA Hunter AJ Syphilitic hepatitis resulting in fulminant hepatic failure requiring liver transplantation Journal of Infection 2007 54 3 e115 e117 2-s2.0-33846960731 16939692
24 Noto P del Nonno F Licci S Chinello P Petrosillo N Early syphilitic hepatitis in an immunocompetent patient: really so uncommon? International Journal of STD and AIDS 2008 19 1 65 66 2-s2.0-42949113651 18275654
| serious: 2
patientsex: 1
drugs: CEFTRIAXONE
reactions: Jarisch-Herxheimer reaction
| 25349616 | CC BY | hepatic lesions with secondary syphilis in an hiv infected patient | 2014() | 604794 | Case reports in medicine | Solari|Paola R|PR|;Jones|Christopher|C|;Wallace|Mark R|MR| | 2014 | 10.1155/2014/604794 | Orlando Health, 1414 Kuhl Avenue, Orlando, FL 32806, USA.;Orlando Health, 1414 Kuhl Avenue, Orlando, FL 32806, USA.;Orlando Health, 1414 Kuhl Avenue, Orlando, FL 32806, USA. | Case Rep Med | 101512910 | United States | D016428:Journal Article | 10364050;16543880;16464282;19304979;11289198;16164381;11263546;5358385;17463387;21060758;15546070;14646631;16939692;15849526;22930309;11393490;5090749;12197957;20001160;18275654;19625105;12363336 | false | 11,618,581 | TITLE:
Hepatic Lesions with Secondary Syphilis in an HIV-Infected Patient.
ABSTRACT:
Syphilis among HIV-infected patients continues to be a public health concern, especially in men who have sex with men. The clinical manifestations of syphilis are protean; syphilitic hepatitis is an unusual complication that can occur at any stage of the disease. We report a case of an HIV-infected male who presented with systemic symptoms and liver lesions highly suggestive of lymphoma and was proven to have syphilitic hepatitis by liver biopsy. Our case reinforces the importance of recognizing syphilis as a possible cause of unexplained abnormal liver enzymes and/or hepatic lesions in HIV-infected patients.
TEXT:
1. Introduction
Syphilis among HIV-infected patients continues to be a public health concern. Although liver involvement with early syphilis is an infrequently recognized complication, it is an especially challenging diagnosis in HIV-infected individuals who often have abnormal liver function tests from any one of multiple potential causes [1]. Coexisting conditions such us hepatitis C, hepatitis B, mycobacterial infection, and neoplastic diseases as lymphoma or Kaposi's sarcoma may cause liver enzymes abnormalities in this population, as well as medications, substance abuse, and fatty liver disease. Treponema pallidum is known to cause hepatitis, but relatively few case reports have been published of hepatic involvement in early syphilis in HIV-infected patients [1–4]. We present a case of an HIV positive male with hepatic lesions suggestive of lymphoma who was eventually diagnosed with syphilitic hepatitis after liver biopsy.
2. Case Presentation
A 59-year-old married male with well-controlled insulin dependent diabetes mellitus, tinea versicolor, and long term nonprogressive HIV infection presented to our clinic with five weeks of generalized muscle, joint and back pain, headache, and weight loss of about seven pounds over three weeks. Two months prior to this presentation, at his annual HIV restaging, his CD4 was 650 cells/μL and quantitative HIV load was 481 copies/mL. His CD4 counts and viral loads had been in this range for eighteen years without any antiretroviral therapy. At the same routine annual visit, his urine screening for chlamydia and gonorrhea was negative, a RPR was nonreactive, and a hepatitis panel showed immunity to hepatitis B without evidence of acute or chronic viral hepatitis. A chest radiograph was normal. His hemoglobin A1c was 7.7%.
On examination he was afebrile and had no palpable lymph nodes, hepatosplenomegaly, or neurologic deficits. He did have a hypopigmented, macular rash limited to his back consistent with tinea versicolor. Serologies for cytomegalovirus, parvovirus B-19, and Epstein-Barr virus were consistent with past infection. No specific therapy was given. He returned to clinic two months later with persistent symptoms of headache, myalgias, and back pain. He now reported, additionally, that he had developed fever, sweats, blurred vision in his left eye, alopecia, a moccasin-type erythrodermic rash on his feet, and additional 10 pound weight loss. He denied any sexual activity for greater than 5 years, including oral sex. He had seen an optometrist for his blurry vision and been diagnosed with a left cataract; another physician he visited had prescribed an antifungal for his foot rash without improvement. Abdominal examination revealed new tenderness in the right upper quadrant with hepatomegaly. Laboratory investigation showed CD4 of 369 cells/μL and HIV load of 1314 copies/mL. His alkaline phosphatase was elevated at 209 U/L (40–115), but his alanine aminotransferase (ALT) and bilirubin were normal; he denied alcohol use or hepatotoxic medications. Albumin was normal. An erythrocyte sedimentation rate was 67 mm/hr (0–20). Cryptococcal serum antigen, urine histoplasmosis antigen, Bartonella and Brucella serologies, and an interferon-gamma release assay for M. tuberculosis were all negative.
A computed tomography (CT) of the abdomen pelvis and chest showed a questionable liver abnormality. Magnetic resonance (MRI) of liver confirmed three lesions within the right lobe with mild splenomegaly; lymphoma was considered the most likely diagnosis (Figures 1 and 2). Fine needle liver biopsy demonstrated chronic inflammation and extensive sclerosis; numerous spirochetes were identified on immunohistochemistry (Figure 3). A repeat RPR was 1 : 256; it had been negative four months previously at his annual evaluation.
His visual complaints prompted an ophthalmology evaluation revealing panuveitis in both eyes without retinal involvement, consistent with syphilis. A lumbar puncture showed a lymphocytic pleocytosis with 18 WBC (92% lymphocytes), protein 118, glucose 76, and a reactive VDRL (1 : 1).
Due to his work, he found a continuous penicillin infusion very difficult to be compliant with; therefore, ceftriaxone 2 gram per day for 14 days was chosen for his syphilis therapy. Within hours of the initiation of antibiotic, he developed a Jarisch-Herxheimer reaction with fevers, chills, and tachycardia which resolved within one day. He had complete resolution of systemic symptoms by the end of the course of ceftriaxone with improved vision on the left. One day after discontinuation of ceftriaxone, his right vision worsened acutely. A follow-up evaluation two days after completion of ceftriaxone showed worsening of panuveitis in the right eye with new retinal involvement. A 14-day course of penicillin G (PCN G) 24 million units intravenously every 24 hr was immediately initiated. His right vision improved during his 10 days of high dose penicillin treatment. He was also given weekly benzathine penicillin times 3 doses after the intravenous penicillin, completing a total of 7 weeks of syphilis treatment. HIV treatment was again declined. A repeat CD4 count and HIV-l load at the end of his syphilis treatment were 785 CD4 cell/μL and 792 copies/mL, respectively. His liver function tests normalized after treatment. Nine months after presentation his RPR was 1 : 16 and he was completely well.
3. Discussion
Syphilis/HIV coinfection accounts for approximately 25% of the cases of primary and secondary syphilis reported in the United States [5]. In recent years the majority of US syphilis cases have been reported among younger men who have sex with men (MSM); these cases account for 67% of primary and secondary syphilis. These increasing rates of syphilis among young men have been characterized by high rates of HIV coinfection and high risk sexual behavior [6–12].
Syphilis may present with a variety of clinical manifestations, most commonly with a painless chancre at the inoculation site that represents primary syphilis. Approximately 25% of untreated infected individuals will develop a systemic illness or secondary syphilis characterized by a rash, fever, and lymphadenopathy caused by the dissemination and invasion of spirochetes to mucocutaneous and visceral sites. Primary and secondary syphilis can overlap in HIV-coinfected patients as well as in the general population [13, 14].
Though hepatic involvement with syphilis was described over 400 years ago by Paracelsus, Matthiolus, and Francois de la Boe Sylvius [1, 15], syphilitic hepatitis continues to be an under recognized manifestation of syphilis. It is usually defined as the presence of abnormal liver enzymes in the setting of early syphilis and in the absence of an alternative cause of hepatitis that resolves with syphilis treatment. An elevation in the alkaline phosphatase (ALP) during secondary syphilis is the classic presentation in both the general population and HIV-infected patients. While the cholestatic pattern is more common, some cases may present predominantly with hepatocellular damage. The difference in presentation may be dictated by disease stage as suggested by Manavi et al. [4] who found that ALT was higher in proportion to other liver function test values in early syphilis, suggesting that hepatocellular predominant liver injury may be seen with early syphilis and may progress into cholestasis at later stages if left untreated. Elevation of total bilirubin was rarely seen in this cohort and no significant relationship between RPR titer and various HIV factors was observed. Our patient had the classic cholestatic pattern with an abdominal CT as well as MRI revealing three low attenuation lesions in the right lower lobe. Only one case report of pseudohepatic tumor associated to secondary syphilis in an HIV positive patient has been previously described [2].
Liver biopsy in syphilis may be nonspecific, typically characterized by periportal lymphocytic infiltration with focal necrosis of hepatic cells around veins, portal, and lobules. Although the visualization of spirochetes in liver tissue is diagnostic, these are observed in about half of reported cases [1, 16, 17]. Our case showed chronic inflammation and extensive sclerosis with innumerable spirochetes by immunohistochemistry.
Though localized or generalized maculopapular rash is the most common physical finding in patients with syphilitic hepatitis and HIV coinfection, other findings have been described. Crum-Cianflone et al. [3], in a recent retrospective study of twelve HIV/syphilis coinfected patients, reported the most common symptoms included rash (67%), pharyngitis (33%), adenopathy (25%), fever (16%), fatigue (16%), ocular symptoms (16%), and arthralgias (8%).
Mullick et al. [1] reported the first case series of syphilitic hepatitis in seven HIV-infected patients, all men presenting with a rash consistent with secondary syphilis and markedly elevated ALP, which improved significantly after two-week course of intravenous beta-lactam antibiotics. In this study patients with higher CD4+ cell counts had higher RPR titers, suggesting that coinfected patient with a preserved immune response may be more likely to develop a robust periportal inflammation responsible for the clinical manifestations, although other studies have showed no correlation between RPR titers and CD4 cell counts or HIV viral load [3, 4].
Although the pathogenesis is unknown, anal intercourse among MSM has been proposed as a risk factor for secondary syphilitic hepatitis, as T. pallidum may enter the portal system by direct venous drainage from the rectal area [3, 17]. An anorectal ulcer was not detected in our patient and he denied any intercourse in several years.
The characteristics of HIV-infected patients do not seem to play a role in the occurrence of hepatitis with early syphilis, except for the duration of HIV infection, as reported by Crum-Cianflone et al. [3]. The CD4 cell count, HIV viral load, and use of HAART were not associated with hepatitis. The duration of HIV infection may be of relevance as patients with syphilitic hepatitis typically have a longer duration of infection, 10 versus 4 years (P = 0.04). The authors suggested that this association may be the result of an intensified inflammatory response to the treponemal periportal infiltration in the presence of possible subclinical liver disease from cumulative exposure over time. The nature of this relationship is unknown and further studies on the pathogenesis will be needed to confirm this potential association [3, 4].
The incidence and prevalence of syphilitic hepatitis in HIV-infected patients are unknown but it seems more prevalent in men, mostly MSM [3, 4]. The high incidence and prevalence among HIV coinfected MSM may be the result of the higher rates of syphilis among this group. Although anal sex has been proposed as a potential risk factor for syphilitic hepatitis, more research is needed to confirm this hypothesis as syphilitic hepatitis has also been well reported in heterosexual men [1, 17–20].
Most cases show complete clinical and laboratory recovery after syphilis treatment, with normalization of all liver test abnormalities within days or months [3, 4]. These data suggest that syphilitic hepatitis in HIV-infected patients may have the same favorable prognosis as the general population. Liver cirrhosis following hepatic syphilis has been rarely reported, as well as a severe acute and fulminant hepatitis requiring liver transplant, but no such cases have been reported among HIV-coinfected patients. Early recognition and treatment of this condition is needed to avoid potential detrimental health consequences including liver injury, as well as to prevent transmission to others [1, 3, 21–24].
Our case was most unusual in that this patient presented with liver lesions and systemic symptoms highly suggestive of malignancy. A recent RPR had been negative and he denied sexual activity in the preceding 5 years, including oral sex. Syphilis must be entertained as a potential cause of abnormal liver enzymes and/or hepatic lesions, especially in HIV-infected males.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
Figure 1 Magnetic resonance of abdomen showing two lesions within the right lobe of the liver along the peripheral surface (black arrows).
Figure 2 Magnetic resonance of abdomen showing two lesions within the right lobe of the liver along the peripheral surface (black arrows).
Figure 3 Histological findings: (a) IHC, 40X: scanning power view of liver core biopsy immunohistochemically stained for Treponema pallidum. Organisms are visible as red color and correspond to the fibrotic inflamed area seen on hematoxylin and eosin stain (H&E). T. pallidum, 40X. (b) IHC, 200X: intermediate power view shows spirochetes centered around blood vessels and infiltrating into sclerotic hepatic parenchyma. T. pallidum, 200X. (c) IHC, 600X: high power magnification of spirochete highlights the spiral morphology. T. pallidum, (black arrow) 600X. |
||||||
"Managing Toe Walking, a Treatment Side Effect, in a Child With T-Cell Non-Hodgkin's Lymphoma: A Cas(...TRUNCATED) | "Background and Purpose: Children who have survived cancer are at risk of experiencing adverse effec(...TRUNCATED) | "\n==== Front\nFront PediatrFront PediatrFront. Pediatr.Frontiers in Pediatrics2296-2360Frontiers Me(...TRUNCATED) | "serious: 1\npatientsex: 2\ndrugs: MERCAPTOPURINE, METHOTREXATE, PREDNISONE\nreactions: Joint range (...TRUNCATED) | 31921717 | CC BY | "managing toe walking a treatment side effect in a child with t cell non hodgkin s lymphoma a case r(...TRUNCATED) | 7() | 502 | Frontiers in pediatrics | "Kiebzak|Wojciech|W|;Żurawski|Arkadiusz|A|;Zmyślna|Anna|A|;Pogorzelska|Justyna|J|;Domagalska-Szopa(...TRUNCATED) | 2019 | 10.3389/fped.2019.00502 | "Department of Physiotherapy, Faculty of Medicine and Health Sciences, Jan Kochanowski University, K(...TRUNCATED) | Front Pediatr | 101615492 | 2296-2360 | Switzerland | D002363:Case Reports | DIERS formetric 4D; childhood cancer; gait disorders; physiotherapy; toe walking | "15768476;1712837;22745035;17763466;11863096;17592410;23135792;12688340;14687990;25730588;23810569;2(...TRUNCATED) | false | 17,523,916 | "TITLE:\nManaging Toe Walking, a Treatment Side Effect, in a Child With T-Cell Non-Hodgkin's Lymphom(...TRUNCATED) |
||||
"Discordance between the Clinical Presentation and Morphology of Myocardial Infarction in a Patient (...TRUNCATED) | "While atherosclerotic plaque disruption remains the hallmark of type 1 myocardial infarction (T1MI)(...TRUNCATED) | "\n==== Front\nJ Tehran Heart Cent\nJ Tehran Heart Cent\nJTHC\nThe Journal of Tehran University Hear(...TRUNCATED) | "serious: 1\npatientsex: 1\ndrugs: ALLOPURINOL, ASPIRIN, ATORVASTATIN, BISOPROLOL, ENALAPRIL, METOPR(...TRUNCATED) | 33552210 | CC BY-NC | "discordance between the clinical presentation and morphology of myocardial infarction in a patient (...TRUNCATED) | 15(3) | 136-141 | The journal of Tehran Heart Center | Hoang|Truong Huy|TH|;Lazarev|Pavel V|PV|;Maiskov|Victor V|VV|;Meray|Imad|I|;Kobalava|Zhanna D|ZD| | 2020-07 | 10.18502/jthc.v15i3.4225 | "Department of Internal Diseases, Medical Institute, RUDN University, Moscow, Russia.;Department of (...TRUNCATED) | J Tehran Heart Cent | 101289255 | 1735-5370 | Iran | D002363:Case Reports | Acute coronary syndrome; Anemia; Coronary angiography; Myocardial infarction; Myocardial ischemia | "31027064;453020;26320110;27732721;28890871;28158518;15866259;26139008;15561328;30535801;16887404;30(...TRUNCATED) | false | 18,639,015 | "TITLE:\nDiscordance between the Clinical Presentation and Morphology of Myocardial Infarction in a (...TRUNCATED) |
||||
"Post-operative nonketotic hyperglycemic induced focal motor status epilepticus related to treatment(...TRUNCATED) | "•Complications from standard ATL are uncommon and the use of post-operative corticosteroids may r(...TRUNCATED) | "\n==== Front\nEpilepsy Behav Case RepEpilepsy Behav Case RepEpilepsy & Behavior Case Reports2213-32(...TRUNCATED) | "serious: 1\npatientsex: 2\ndrugs: DEXAMETHASONE, LACOSAMIDE, PERAMPANEL\nreactions: Hyperglycaemic (...TRUNCATED) | 30416961 | CC BY-NC-ND | "post operative nonketotic hyperglycemic induced focal motor status epilepticus related to treatment(...TRUNCATED) | 10() | 124-128 | Epilepsy & behavior case reports | "Zillgitt|Andrew|A|;Alshammaa|Abdullah|A|;Kahn|Muhammad Salim|MS|;Madani|Sarah|S|;Zahoor|Salman|S|;A(...TRUNCATED) | 2018 | 10.1016/j.ebcr.2018.09.001 | "Department of Neurology, Beaumont Health, Royal Oak, MI, USA.;Department of Neurology, Henry Ford H(...TRUNCATED) | Epilepsy Behav Case Rep | 101614202 | 2213-3232 | United States | D002363:Case Reports | "11906505;23027091;14038613;1564479;16083215;22964510;7013652;29238960;6775582;20558093;22396514;231(...TRUNCATED) | false | 15,660,778 | "TITLE:\nPost-operative nonketotic hyperglycemic induced focal motor status epilepticus related to t(...TRUNCATED) |
|||||
Patient with typical carcinoid initially diagnosed as high-grade neuroendocrine carcinoma. | "We report the case of a patient initially diagnosed with a high-grade neuroendocrine carcinoma, whi(...TRUNCATED) | "\n==== Front\nLung Cancer ManagLung Cancer ManagLMTLung Cancer Management1758-19661758-1974Future M(...TRUNCATED) | "serious: 2\npatientsex: 1\ndrugs: CAPECITABINE, DENOSUMAB, OCTREOTIDE ACETATE, TEMOZOLOMIDE\nreacti(...TRUNCATED) | 30643569 | CC BY-NC-ND | patient with typical carcinoid initially diagnosed as high grade neuroendocrine carcinoma | 6(2) | 41-45 | Lung cancer management | Warsch|Sean|S|;Jahanzeb|Mohammad|M| | 2017-11 | 10.2217/lmt-2017-0010 | "University of Miami, Jackson Memorial Hospital, 1611 NW 12th Avenue, Miami, FL 33136, USA.;Sylveste(...TRUNCATED) | Lung Cancer Manag | 101588392 | 1758-1966 | England | D002363:Case Reports | carcinoid; diagnosis; neuroendocrine tumors; small cell carcinoma; treatment | 15644774;20459535;23391110;26291007;26703889;26731013;28404761;9706973 | false | 14,293,007 | "TITLE:\nPatient with typical carcinoid initially diagnosed as high-grade neuroendocrine carcinoma.\(...TRUNCATED) |
||||
"Non-traumatic perforation of the jejunum in a human immunodeficiency virus-infected patient receivi(...TRUNCATED) | "BACKGROUND\nNon-traumatic bowel perforation caused by cytomegalovirus (CMV) and Mycobacterium avium(...TRUNCATED) | "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer (...TRUNCATED) | "serious: 1\npatientsex: 1\ndrugs: ABACAVIR SULFATE\\DOLUTEGRAVIR SODIUM\\LAMIVUDINE, AMIKACIN, CLAR(...TRUNCATED) | 31804330 | CC BY | "non traumatic perforation of the jejunum in a human immunodeficiency virus infected patient receivi(...TRUNCATED) | 98(49) | e18163 | Medicine | "Lee|Yi-Chien|YC|;Chiou|Chien-Chun|CC|;Wang|Jann-Tay|JT|;Yang|Yi-Chun|YC|;Tung|Shao-Hsien|SH|;Hsieh|(...TRUNCATED) | 2019-12 | 10.1097/MD.0000000000018163 | "Department of Internal Medicine, Fu Jen Catholic University Hospital.;Department of Dermatology, Di(...TRUNCATED) | Medicine (Baltimore) | 2985248R | 0025-7974 | United States | "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D023241:Antiretroviral Therapy, Highl(...TRUNCATED) | D002363:Case Reports; D016428:Journal Article | "15844689;20334848;24833682;12130890;24698485;22752438;20146693;17937815;16496064;16652323;10901982;(...TRUNCATED) | false | 17,209,945 | "TITLE:\nNon-traumatic perforation of the jejunum in a human immunodeficiency virus-infected patient(...TRUNCATED) |
||||
"Compatibility of Biosimilar Filgrastim with Cytotoxic Chemotherapy during the Treatment of Malignan(...TRUNCATED) | "Febrile neutropenia (FN) is a serious and frequent complication of cytotoxic chemotherapy. Biosimil(...TRUNCATED) | "\n==== Front\nAdv Ther\nAdv Ther\nAdvances in Therapy\n0741-238X\n1865-8652\nSpringer Healthcare Ch(...TRUNCATED) | "serious: 1\npatientsex: 2\ndrugs: CARBOPLATIN, CLINDAMYCIN, DEXAMETHASONE, ETOPOSIDE, FILGRASTIM, O(...TRUNCATED) | 27743353 | CC BY-NC | "compatibility of biosimilar filgrastim with cytotoxic chemotherapy during the treatment of malignan(...TRUNCATED) | 33(11) | 1983-2000 | Advances in therapy | Fruehauf|Stefan|S|;Otremba|Burkhard|B|;Stötzer|Oliver|O|;Rudolph|Christine|C| | 2016-11 | 10.1007/s12325-016-0419-1 | "Klinik Dr. Hancken, Hämatologie, Onkologie und Palliativmedizin, Stade, Germany. stefan_fruehauf@u(...TRUNCATED) | Adv Ther | 8611864 | 0741-238X | United States | "D000368:Aged; D000970:Antineoplastic Agents; D059451:Biosimilar Pharmaceuticals; D003603:Cytotoxins(...TRUNCATED) | D016428:Journal Article; D016448:Multicenter Study | "D000970:Antineoplastic Agents; D059451:Biosimilar Pharmaceuticals; D003603:Cytotoxins; D006401:Hema(...TRUNCATED) | "Biosimilar; Chemotherapy; Filgrastim; Granulocyte-colony stimulating factor; Hematology; Neutropeni(...TRUNCATED) | "20428872;18319047;19756004;11850858;16682719;26507190;25525436;7691119;20555091;20637652;23419039;1(...TRUNCATED) | false | 12,912,889 | "TITLE:\nCompatibility of Biosimilar Filgrastim with Cytotoxic Chemotherapy during the Treatment of (...TRUNCATED) |
End of preview. Expand
in Dataset Viewer.
- Downloads last month
- 120
Size of downloaded dataset files:
338 MB
Size of the auto-converted Parquet files:
338 MB
Number of rows:
15,659