Difficult question in which the correct answer could give rise to discussion. The patient is a 16-year-old male who is admitted for a fairly clear case of mononucleosis due to EBV infection that becomes complicated during admission. The data available to us are: - Pancytopenia. - Hepatopathy. - Coagulopathy. - Absence of infectious focus: negative blood cultures, negative urine cultures, normal X-ray, normal CSF. - CRP and Ferritin elevated / normal Procalcitonin. The possible complications that could have occurred (and that are considered in the answers) are sepsis or a bad evolution of mononucleosis. The clinical data could be consistent with a septic process, however, the main infectious foci have been reasonably ruled out and one of the most sensitive and specific markers of bacteremia (procalcitonin) is in the normal range, which should draw our attention. On the other hand, a complication of the EBV mononucleosis suffered by our patient should be evaluated, among the possible complications are hemolytic anemia, meningoecephalitis (normal CSF) or Guillain-Barré sd. Guillain-Barré syndrome, which are not very consistent with the clinical picture presented to us. Another possible complication of exceptional severity would be hemophagocytic syndrome; this is a rare entity that occurs in certain predisposed subjects and is characterized by an uncontrolled activation and proliferation of histiocytes and T lymphocytes, which produces a state of hypercytokinemia.  The diagnostic criteria, revised in 2004, include persistent high fever, hepatosplenomegaly, cytopenias, hypertriglyceridemia, hyperferritinemia, and hypofibrinogenemia. Hyperferritinemia >3000 in a suggestive clinical context necessitates treatment of the patient (mainly with immunosuppressants and corticosteroids) since mortality is very high and early treatment is essential. The definitive diagnosis is made by microscopic study of an OM biopsy.  Although in this question they do not quantify the value of ferritinemia, it is a remarkable data and given that the clinical picture is suggestive, meeting the diagnostic criteria, it seems to me that answer 5 would be the most accurate.

Difficult question in which the correct answer could give rise to discussion. The patient is a 16-year-old male who is admitted for a fairly clear case of mononucleosis due to EBV infection that becomes complicated during admission. The data available to us are: - Pancytopenia. - Hepatopathy. - Coagulopathy. - Absence of infectious focus: negative blood cultures, negative urine cultures, normal X-ray, normal CSF. - CRP and Ferritin elevated / normal Procalcitonin. The possible complications that could have occurred (and that are considered in the answers) are sepsis or a bad evolution of mononucleosis. The clinical data could be consistent with a septic process, however, the main infectious foci have been reasonably ruled out and one of the most sensitive and specific markers of bacteremia (procalcitonin) is in the normal range, which should draw our attention. On the other hand, a complication of the EBV mononucleosis suffered by our patient should be evaluated, among the possible complications are hemolytic anemia, meningoecephalitis (normal CSF) or Guillain-Barré sd. Guillain-Barré syndrome, which are not very consistent with the clinical picture presented to us. Another possible complication of exceptional severity would be hemophagocytic syndrome; this is a rare entity that occurs in certain predisposed subjects and is characterized by an uncontrolled activation and proliferation of histiocytes and T lymphocytes, which produces a state of hypercytokinemia.  The diagnostic criteria, revised in 2004, include persistent high fever, hepatosplenomegaly, cytopenias, hypertriglyceridemia, hyperferritinemia, and hypofibrinogenemia. Hyperferritinemia >3000 in a suggestive clinical context necessitates treatment of the patient (mainly with immunosuppressants and corticosteroids) since mortality is very high and early treatment is essential. The definitive diagnosis is made by microscopic study of an OM biopsy.  Although in this question they do not quantify the value of ferritinemia, it is a remarkable data and given that the clinical picture is suggestive, meeting the diagnostic criteria, it seems to me that [HIDDEN].

A 16-year-old boy consults for presenting with pustular tonsillitis, fever up to 38.5°C, painful cervical lymphadenopathy, non-pruritic macular rash on the chest and mild hepatosplenomegaly, of 4-5 days of evolution. Paul-Bunnell test and Ig M for Epstein-Barr virus are positive. During his admission he developed continuous fever up to 40ºC, pancytopenia, icteric hepatitis and coagulopathy of progressive intensity. One week after admission, he was transferred to the ICU due to confusion and respiratory failure. Blood cultures and a urine culture were negative, CSF was normal and the chest x-ray showed no infiltrates. Procalcitonin is normal, but CRP and ferritin are very elevated. Of the following statements, which would be the most correct diagnostic and therapeutic approach?

She has a bacterial sepsis of undetermined origin and should be given ceftriaxone and supportive care.

She has bacterial sepsis of undetermined origin and should be given vancomycin, ceftacidime and supportive care.

This is infectious mononucleosis with a severe course and glucocorticoids should be administered.

This is an infectious mononucleosis of severe course and treatment with Acyclovir should be initiated.

I would perform a bone marrow biopsy/aspirate and, if hemophagocytosis is confirmed, initiate treatment with immunosuppressants.

[Agranulocytosis as a complication of acute infectious mononucleosis].

Acute infections mononucleosis is the most common clinical manifestation of primary Epstein-Barr virus (EBV) infection occurring during adolescence. It is a benign lymphoproliferative, usually self-limiting disease. Complications are relatively rare, but they may occur, especially hematological. Most common are autoimmune hematolytic anemia and thrombocytopenia, and they respond to corticoid therapy. Deuteration of white blood cells is rather rare, whereas mild neutropenia is a normal finding during the course of acute disease. On the other hand, agranulocytosis is extremely rate, and almost every case has been reported in the literature. Filgrastim--the recombinant human granulocyte colony-stimulating factor (G-CSF) stimulates the activation, proliferation and maturation of progenitor granulocyte cells. This drug is usually applied in treatment of iatrogenic neutropenia, during chemotherapy of malignancies and in some idiopathic and cyclic neutopenias. A female patient, 18 years of age, has been hospitalized at the Clinic of Infectious Diseases in Novi Sad on two occasions. First because of severe acute infectious mononucleosis with acute hepatitis and jaundice 10 days after onset of symptoms. Physical examination revealed severe intoxication, dehydration, icteric skin, mucosis and massive hepatosplenomegaly. The diagnosis was confirmed by ELISA IgM, EBV VCA positive and ELISA IgG EBV VCA and IgG EBVNA negative results. The patient was discharged from hospital after 24 days without complaints and with normal physical and laboratory findings. For several days she felt well, but gradually severe fatigue and malaise occurred and she became febrile again. That was the reason why she was hospitalized again, two weeks later. This time she was febrile, extremely intoxicated with general lymphadenopathy, catarrhal gingivostomatitis and massive splenomegaly. The first laboratory findings showed severe neutropenia (absolute count of granulocytes was 0.156 x 10/l, with only 12% segmented neutrophils). Mild anemia--3.05 x 10/l was also registered, while the platelet count was normal. Other biochemical analyses were normal, the Coombs' test negative, while the serological response was also normal. Bone marrow puncture was performed and normocellular bone marrow was registered, somewhere hypercellular due to hyperplasia of granulocyte progenitor cells from promyelocytes to normal maturated cells. Anemia showed megaloblastoid proliferation, while megakaryocytes were normal. High doses of corticosteroids were applied (dexamethasone 160 mg daily) and filgrastim 5 micrograms every other day. From the very beginning of therapy the patient felt better, whereas granulocytes responded with elevation as soon as 48 hours after initiation of therapy. On the sixth day the treatment was stopped because the level of granulocytes was normal and the patient has completely recovered. She was discharged from hospital 4 weeks later with mild meteorism, but normal physical and laboratory findings and mild splenomegaly registered only by ultrasonography. During the last 10 years only several cases of severe leukopenia with acute infectious mononucleosis had been reported in literature. In all cases it was associated with some other hematological complications and it occurred in young adults without previously registered immunodeficiency. We have no knowledge about application of filgrastim in treatment of EBV-induced agranulocytosis, but the International Association for Studying Agranulocytosis and Aplastic Anemia reported that in 4% of patients Epstein-Barr virus can cause agranulocytosis even a year after the occurrence of acute disease.

[An autopsied case of chronic active Epstein-Barr virus (EBV) infection with various symptom].

A 19-year-old boy, who complained of fever and fatigue was hospitalized in November 1986. On physical examination, he had a temperature of 37 degrees C, cervical lymphadenopathy and hepatosplenomegaly. Serum transaminase was elevated moderately, while serum alkaline-phosphatase was elevated severely. Extremely elevated antibody titers to the EBV capsid antigen (IgG: 2560x, IgA: 160x), early antigen (IgG: 1280x, IgA: 160x) and nuclear antigen (160x) were noted. PPD and DNCB skin test were negative. Severe mobilization of Kupfer cells and mild proliferation of pseudoductule were seen in liver biopsied specimen. Cervical lymphnode biopsy showed necrotizing lymphadenitis associated with proliferation of histiocyte. In February 1987 his temperature was elevated to 40 degrees C and he had arthralgia and exanthema. Intravenous Acyclovir (500 mg every 8 hours) and Interferon alpha (6 million u/day) were administered together for 1 month. After that he improved for about a week. In March 1987 he had dyspnea. Arterial blood gas analysis in room air showed a PO2 of 51.8 mmHg, a PCO2 of 28.9 mmHg. A chest radiograph showed thickening of bilateral bronchial walls and obscurity of pulmonary vascular shadows. The effects of transfer factor and Interleukin-2 were unremarkable. High antibody titers to EBV, liver dysfunction and hypo-oxygenemia continued. He died of respiratory and heart failure on 24 October 1987. The most interesting finding of autopsied specimens was stenosis of pulmonary artery associated with interstitial pneumonitis. Hemophagocytosis was seen in liver, spleen and bone marrow.

[Mosquito bite allergies terminating as hemophagocytic histiocytosis: report of a case].

A 21-year-old woman had suffered from repeated vasculitis and panniculitis with fever and chills after following mosquito bites since age 7. These manifestations were confirmed with a direct mosquito bite test during her admission to another hospital at age 17. The patient presented to our hospital with progressive dyspnea, productive cough and intermittent fever for one week. In addition to the bilateral infiltrative lesions on chest roentgenography, hepatosplenomegaly with an abnormal liver function test, pancytopenia, and elevated IgE were also detected. Blood and sputum cultures grew no microorganisms. Epstein-Barr virus-IgM, Cytomegalovirus-IgM and Mycoplasma pneumonia antibodies were all negative. Bone marrow aspiration and biopsy revealed histiocytosis with hemophagocytosis. No atypical histiocyte was found. The patient was put on dexamethasone treatment with improvement. Unfortunately, symptoms relapsed two weeks later. A repeated bone marrow aspiration and biopsy revealed a picture similar to the previous one. Despite antibiotic administration and ventilator support, a rapidly deteriorated course terminated in the patient's death by respiratory failure. Mosquito bite allergies were reported to be associated with malignant histiocytosis in Japan. However, atypical histiocytes were not found in our case upon repeated bone marrow aspirations, biopsies and skin biopsies. Mature histiocytes with hemophagocytosis were prominent instead. Reactive histiocytosis was thus favored rather than malignant histiocytosis. Although opportunistic infection cannot be excluded, we propose that a mosquito bite allergy with consequent histiocytic activation by antigen, immune complex or IgE is the possible pathogenetic mechanism for hemophagocytic histiocytosis in this patient.

A Case of Severe Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis Successfully Treated With High Dose Steroids and Ganciclovir.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematological disorder characterized by immune dysregulation with multiple organ involvement and carries a poor prognosis. The occurrence of HLH can be familial or sporadic, which is triggered by causes like infection or malignancy. This case report is about a 47-year-old male who presented to the hospital with a fever, chills, night sweats, and unintentional weight loss. He was found to have severely elevated ferritin, and computed tomography showed cirrhosis, a normal sized spleen, and retroperitoneal lymphadenopathy. He underwent an extensive battery of tests to identify the etiology. Meanwhile, he had recurrent fevers with worsening transaminitis and septic shock, requiring admission to the ICU. Blood tests for Epstein-Barr virus (EBV) deoxyribonucleic acid (DNA) and immunoglobulin G (IgG) were positive. Due to high suspicion of HLH, he was started on intravenous methylprednisone 1000 mg daily for three days with clinical improvement. A bone marrow biopsy showed hemophagocytosis and he was diagnosed with EBV-associated HLH. He was continued on steroids with oral prednisone and continued to clinically improve. He was later tapered off steroids over the course of five months. HLH is a rapidly progressive and fatal condition that requires prompt treatment, and thus a high index of suspicion is needed to make a timely diagnosis.

A 7-Year-Old With Persistent Fever and Cough.

A previously healthy, fully immunized 7-year-old girl presented with a 7-week history of daily fevers and a worsening cough with persistently elevated inflammatory markers. Before admission, she had an unrevealing outpatient workup by infectious disease, rheumatology, pulmonology, and otorhinolaryngology for her fever and other symptoms. Multiple courses of antibiotics had no effect, but brief courses of steroids seemed to modestly alleviate her symptoms. At an outside hospital, a computed tomography neck and chest scan revealed mediastinal lymphadenopathy. She was subsequently transferred to the authors' institution. Her examination was notable for a febrile, tired-appearing girl in respiratory distress with a muffled voice and inspiratory stridor. Her laboratory tests revealed leukocytosis with left shift, microcytic anemia, and hypoalbuminemia, as well as elevated inflammatory markers, ferritin, and fecal calprotectin. Her peripheral smear, uric acid, and lactate dehydrogenase were all within normal limits. Infectious study results, including blood and urine cultures, cytomegalovirus serologies, and Bartonella serologies were negative. On the second read of her outside computed tomography imaging, her lymphadenopathy was felt to be nonpathologic. Based on a recommendation by rheumatology, an ophthalmologic examination was obtained, which revealed bilateral anterior uveitis; however, rheumatologic laboratory test results returned negative. Her fevers continued, and inflammatory markers remained elevated despite antibiotics. On day 6 of hospitalization, she developed worsening respiratory distress, necessitating intubation and transfer to the ICU. Repeat laryngoscopy and bronchoscopy revealed severe purulent tracheitis; however, throat cultures remained sterile. Her clinical deterioration without identification of an offending organism prompted additional evaluation for a systemic etiology.

Fever, rash, and leukopenia in a 32-year-old man · Dx?

A 32-year-old man was admitted to our hospital with fever, chills, malaise, leukopenia, and a rash. About 3 weeks earlier, he'd had oral maxillofacial surgery and started a 10-day course of prophylactic amoxicillin/clavulanic acid. Fifteen days after the surgery, he developed a fever (temperature, 103° F), chills, arthralgia, myalgia, cough, diarrhea, and malaise. He was seen by his physician, who obtained a chest x-ray showing a lingular infiltrate. The physician diagnosed influenza and pneumonia in this patient, and prescribed oseltamivir, azithromycin, and an additional course of amoxicillin/clavulanic acid. Upon admission to the hospital, laboratory tests revealed a white blood cell count (WBC) of 3.1 k/mcL (normal: 3.2-10.8 k/mcL). The patient's physical examination was notable for lip edema, white mucous membrane plaques, submandibular and inguinal lymphadenopathy, and a morbilliform rash across his chest. Broad-spectrum antibiotics were initiated for presumed sepsis. On hospital day (HD) 1, tests revealed a WBC count of 1.8 k/mcL, an erythrocyte sedimentation rate of 53 mm/hr (normal: 20-30 mm/hr for women, 15-20 mm/hr for men), and a C-reactive protein level of 6.7 mg/dL (normal: <0.5 mg/dL). A repeat chest x-ray and orofacial computerized tomography scan were normal. By HD 3, all bacterial cultures were negative, but the patient was positive for human herpesvirus-6 on viral cultures. His leukopenia persisted and he had elevated levels of alanine transaminase ranging from 40 to 73 U/L (normal: 6-43 U/L) and aspartate aminotransferase ranging from 66 to 108 U/L (normal range: 10-40 U/L), both downtrending during his hospitalization. He also had elevated levels of antinuclear antibodies and anti-Smith antibody titers. A posterior-auricular biopsy was consistent with lymphocytic perivasculitis. The rash continued to progress, involving his chest, abdomen, and face. Bacterial and viral cultures remained negative and on HD 4, broad-spectrum antibiotics were discontinued.

[Lemierre's post-tonsillitis sepsis with meningitis and intravascular consumption coagulopathy as complication of infectious mononucleosis with pansinusitis].

24 days after the onset of infectious mononucleosis, clinically and serologically confirmed, an otherwise healthy 18-year-old schoolboy developed a fulminant septicaemia with acute meningitis and loss of consciousness, consumptive coagulopathy and acute renal failure. Computed tomography demonstrated pansinusitis. Lumbar puncture produced purulent cerebrospinal fluid with 11,500 cells/microliters, predominantly granulocytes, protein 205 mg/dl, glucose 19 mg/dl, indicating bacterial meningitis. The suspected diagnosis of posttonsillitis septicaemia (Lemierre's syndrome) was confirmed by repeated demonstration of fusiform gram-negative bacteria in anaerobic blood cultures, identified as Fusobacterium necrophorum. Anaerobic CSF culture grew Prevotella bivia of the Bacteroidaceae family. Both the consumptive coagulopathy and the renal failure were successfully treated and the patient's condition stabilized. The sinuses were surgically drained under high doses of piperacillin/sulbactam and chloramphenicol. Despite the sensitivity of the cultured bacteria to the administered antibiotics the septic temperature continued, but disappeared within 4 days of metronidazole having been added. After 5 weeks of antibiotic treatment, three of them in an intensive care unit, the patient was discharged in good general condition. This case illustrates that severe septicaemia caused by rare bacteria may follow an attack of infectious mononucleosis which had taken an uncomplicated course.

[Retrospective evaluation of patients who were diagnosed as infectious mononucleosis between 1984-2005].

In this study, the clinical and laboratory features of 26 infectious mononucleosis (IMN) cases who have been diagnosed between the years of 1984-2005 were evaluated retrospectively. The mean age of the patients was 26+/-11 years, the rate of being hospitalized was 65%, and mean hospitalization period was 9.2+/-6 days. Fever (81%), weakness (50%), sore throat (50%), headache (50%) and swollen neck (35%) were the most common symptoms, while in the physical examination cervical lymphadenopathy (81%), splenomegaly (69%), hyperemic pharynx (65%), hepatomegaly (54%) and tonsillitis (50%) were observed. Laboratory results yielded leukocytosis in 21%, leucopenia in 12%, anemia in 44%, thrombocytopenia in 5% and elevated transaminase levels in 84% of the patients. Of the patients 15 (57.7%) had the history of using antibiotics before the diagnosis. Serological diagnosis was performed by Paul-Bunnel test and/or IgM positivity against Epstein-Barr virus (EBV) viral capsid antigen (VCA). Tonsillo-pharyngitis secondary to edema and respiratory distress due to lymphadenopathy pressure were detected in four patients, whereas pancytopenia was established only in one patient, as complications. This study emphasized that, although IMN is a self-limited infection, the diagnostic difficulties may arise when the clinical course is atypical, and rarely seen life-threatening complications may also develop during IMN course.

Tuberculosis Presenting as Acute Sepsis and Secondary Hemophagocytic Lymphohistiocytosis.

We report the case of a 61-year-old man admitted to our emergency department with fever. At admission, he was hypotensive and tachycardic. In the initial investigation, elevation of inflammatory parameters, acute kidney injury (Kidney Disease Improving Global Outcomes (KDIGO) 3), hyperbilirubinemia, and hepatic cytocholestasis were evident. Empirical antibiotic therapy was started, after sepsis was assumed without an identifiable cause. His condition took an unfavorable clinical course, with respiratory failure, hepatosplenomegaly, pancytopenia, hyperferritinemia and hypofibrinogenemia. Microbial culture studies and a general immunological study were negative and lymphoproliferative disease was therefore excluded. Bone marrow aspirate revealed hemophagocytosis without granulomas. A diagnosis of hemophagocytic lymphohistiocytosis was assumed and pulse methylprednisolone therapy initiated. As this resulted in only a transient improvement, immunoglobulin and rituximab were initiated as a second-line therapy. The patient sadly had an unfavorable outcome despite all measures undertaken. In the postmortem study, <iMycobacterium tuberculosis</i complex was isolated in the bone marrow aspirate, which led to the postmortem diagnosis of disseminated tuberculosis and angioinvasive pulmonary aspergillosis. The clinical presentation of disseminated tuberculosis is non-specific and hemophagocytic lymphohistiocytosis is one of its rare presentations. The mortality rate of hemophagocytic lymphohistiocytosis is high and increases with delayed diagnosis of the underlying condition and respective treatment. Hemophagocytic lymphohistiocytosis should be considered in patients presenting with fever, lymphadenopathy, splenomegaly, cytopenias, hyperferritinaemia and hypertriglyceridemia.Despite its rarity, tuberculosis should be considered as an etiology of hemophagocytic lymphohistiocytosis and, if suspected, antituberculosis therapy should be initiated early, even in the absence of a definite diagnosis.Immunosuppressant therapy increases the risk of opportunistic infections, which establishes the need for prophylactic antibiotic, antifungal, and antiviral drugs.

[Fulminate liver failure in a 39-year-old female patient with leukocytosis, unclear fever, and arthralgic pain].

Fulminate liver insufficiency can have many causes and is a challenge for differential diagnosis. A 39-year-old woman was admitted because of a nonitching macular-papular exanthema on both thighs with spreading to the trunk. In addition, the patient complained of dysphagia, symmetrical arthralgias, myalgias, fever of 38 degrees C, and night sweats. An outpatient treatment with nonsteroidal antirheumatics, antihistamines and penicillin was started for 3 days before admission. On admission, a neutrophilic leukocytosis (23.6 Gpt/l), an increase in C-reactive protein (185 mg/l), and a ferritin level of 1,740 microg/l were found. Liver enzymes were increased (alanine aminotransferase 1.03 micromol/l.s, aspartate aminotransferase 1.06 micromol/l.s, gamma-glutamyltransferase 2.73 micromol/l.s, and lactate dehydrogenase 12.48 micromol/l.s). Sonographic examination showed a mild hepatosplenomegaly, but otherwise normal findings. X-rays of the lungs, hands, and ankles were normal. An echocardiography was within normal limits. Extensive serologic investigations including assays for hepatitides A, B and C as well as repeated blood cultures were negative. Antibiotic therapy was continued without any improvement. In addition, acetaminophen (4 x 1,000 mg/day) and ibuprofen (3 x 600 mg/day) were given. Liver function worsened and an icterus developed. The patient was transferred to the authors' university hospital. Because of the clinical findings of fever episodes, a typical macular exanthema, lymphadenopathy, hepatosplenomegaly, arthralgias, myalgias, dysphagia, and the presence of neutrophilic leukocytosis, fever, an increase in ferritin, but negative serologic titers and no bacteremia, a working diagnosis of Still's disease was made. The patient was treated with high-dose methylprednisone (250 mg/day for 3 days, then 100 mg/day). Liver biopsy revealed subacute hepatitis with necrosis and accompanying cholangitis. The prednisone therapy induced a fast remission and improvement of liver function, liver transplantation was not necessary. The patient is, 16 months after the incident, without symptoms under prednisone 3 mg/day, and the liver function is normal. The etiology of Still's disease is unknown and the disease is characterized by fever episodes, a typical macular-papular exanthema, lymphadenopathy, hepatosplenomegaly, and arthralgias. A mild to moderate increase in liver enzymes is often found as part of this disease. Rarely, a fulminate liver failure has been described, particularly in the presence of co-administration of nonsteroidal antirheumatics or acetaminophen. Still's disease must be considered as part of the differential diagnosis of acute liver failure, because an early diagnosis and consequent therapy with prednisone may prevent the need for liver transplantation.

Hemophagocytic Lymphohistiocytosis in Renal Transplant Recipients: A 2-Case Report.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by an excessive immune activation. HLH can be triggered by a variety of events that disrupt immune homeostasis, such as infections and immunosuppression. HLH presents with heterogeneous clinical symptoms and laboratory findings such as pancytopenia, elevated liver enzymes, impaired renal function, and hyperferritinemia. Case 1. A 58-year-old man was admitted because of a high fever and diarrhea. Laboratory findings showed acute renal impairment, pancytopenia, Epstein-Barr virus (EBV) DNA seropositivity with a replication index of 2 million copies/mL, and hyperferritinemia. A diagnosis of HLH was confirmed by bone marrow aspiration. He was treated with etoposide, steroids, and rituximab with initial good response and good kidney function restoration. He was discharged after 31 days but eventually died after 44 days after a disease relapse. Case 2. A 51-year-old kidney transplant recipient was admitted because of a fever of unknown origin. A worsening renal function, pancytopenia, EBV DNA of 4,356,222 copies/mL on blood, D-Dimer 7505 ng/mL, ferritinemia 9180.9 ug/L, and triglycerides 1273 mg/dL were found. Bone marrow aspiration was negative for HLH; a few days later, a diagnosis of HLH was made after a positive bone marrow biopsy. Continuous renal replacement therapy was started in the intensive care unit because of severe lactic acidosis due to sepsis. She died few days later. EBV infection could be a trigger for HLH in a renal transplant patient. Hyperferritinemia is useful for differential diagnosis in a septic patient. The outcome is very poor even with prompt treatment.

[Successful use of etoposide in an elderly patient with chronic recurrent hemophagocytic syndrome].

A 66-year-old man was admitted to our hospital for fever on January 19, 1998. He began showing periodic high fever in June 1997 and an increased serum LDH in August 1997. His history included surgery for esophageal cancer in 1993. On admission, the patient's body temperature was 38.5 degrees C. Physical examination was negative for lymphadenopathy, hepatosplenomegaly, and skin rash. Peripheral blood revealed a hemoglobin level of 8.6 g/dl and a platelet count of 7.9 x 10(4)/microliter. Bone marrow examination showed hypocellularity with marked histiocytic hemophagocytosis. The various bacterial cultures were negative. Serum LDH was elevated to 1,606 IU/l, and ferritin was greater than 3,000 ng/ml. Antinuclear antibodies were negative. No significant elevation of viral antibody titers including that to Epstein-Barr virus was found. Hemophagocytic syndrome (HPS) was diagnosed, but no underlying diseases was identified. The patient's condition was complicated by interstitial pneumonia and pleural effusion. gamma-globulin and pulse methylprednisolone both proved ineffective for the HPS; however, complete remission was achieved with cyclic intravenous administration of etoposide (VP-16, 150 mg/day). Interestingly, the interstitial pneumonia resolved promptly with etoposide therapy. The patient relapsed, in July 2001, exhibiting high fever, cytopenia, and marrow hemophagocytosis. His condition was ameliorated by administration of etoposide. This was a rare case of chronic and recurrent HPS of unknown etiology accompanied by interstitial pneumonia. Etoposide should be considered as a primary therapy for HPS and its complications in cases such as our patients.

Intense myelofibrosis in a child: unusual result of EBV-associated hemophagocytic lymphohistiocytosis.

A previously healthy 12-year-old girl was admitted to the intensive care unit with severe pulmonary bleeding. Her history revealed that she had suffered from high fever, fatigue, sore throat, myalgia and generalized rash for two weeks. Physical examination revealed hepatosplenomegaly. Laboratory investigation showed pancytopenia associated with unusual high levels of serum ferritin, triglyceride and lactate dehydrogenase (LDH) and low fibrinogen levels. Apparent hemophagocytosis was seen in bone marrow aspiration. Bone marrow biopsy revealed myelofibrosis, and confirmed hemophagocytosis. IgM for Epstein-Barr virus (EBV) viral capsid antigen was found to be positive. She received chemotherapy for 10 days according to hemophagocytic lymphohistiocytosis (HLH)-2004 treatment protocol, since the symptoms persisted despite supportive therapy and intravenous immunoglobulin (IVIG) administration. However, the clinical status and laboratory findings did not respond to treatment and she died from severe pulmonary bleeding associated with prolonged ventilator support and sepsis. Intense myelofibrosis, which is reported rarely, particularly in patients with EBV-related HLH, contributed to this fatal prognosis.

Case of haemophagocytic lymphohistiocytosis following Epstein-Barr virus infection.

Haemophagocytic lymphohistiocytosis (HLH) is a rare diagnosis that carries a high degree of mortality. We present this case of a previously healthy 22-year-old woman, who was admitted acutely ill to the hospital. One week prior, she had been seen by her primary care physician for fatigue and malaise. At that time, she was noted to have anterior and posterior cervical lymphadenopathy. She was referred to the emergency room and was diagnosed with acute Epstein-Barr virus (EBV) mononucleosis based on her clinical symptoms and positive heterophile antibody test. She was discharged after an uneventful 48-hour stay on the wards. She represented 7 days after discharge with cough, fatigue, nausea, vomiting, epigastric abdominal pain, diarrhoea, weight loss and subjective fevers. She had also reported haematemesis, epistaxis and melaena. Vital signs included temperature 36.9°C, blood pressure 90/50 mm Hg, heart rate 130 beats per minute and respiratory rate 32 breaths per minute. Physical examination was notable for an acutely ill appearing woman with scleral icterus, hepatosplenomegaly and palpable cervical and axillary lymphadenopathy. Complete blood count showed pancytopaenia with haemoglobin 59 g/L (normal 120-160 g/L), white blood cell count 2.7×10<sup9</sup/L (normal 4-10.5×10<sup9</sup/L) and platelet count 50×10<sup9</sup/L (normal 150-450×10<sup9</sup/L). The white blood cell count differential included 58% neutrophils (normal 38%-77%) with immature neutrophils in band form elevated at 45% (normal <14%), 16% lymphocytes (normal 20%-48%), 7% monocytes (normal <12%) and no eosinophils (normal <6%). Blood smear revealed anisocytosis, poikilocytosis and hypochromia. Coagulation panel showed elevated levels of d-dimer level at 1.39 µg/mL (normal <0.45 µg/mL), prolonged prothrombin time at 34.4 s (normal 11-15 s), prolonged activated partial thromboplastin time of 55.6 s (normal 25-34 s), prolonged international normalised ratio at 3.31 (normal <1.1) and low fibrinogen 60 mg/dL (normal >200 mg/dL). Lipid panel showed cholesterol at 114 mg/dL (normal 125-200 mg/dL), triglycerides 207 mg/dL (normal 30-150 mg/dL), high-density lipoprotein cholesterol 10 mg/dL (normal 40-60 mg/dL) and low-density lipoprotein cholesterol 63 mg/dL (normal <100 mg/dL). Other lab abnormalities included elevated ferritin of 6513 ng/mL (normal 10-150 ng/mL) and elevated lactate dehydrogenase of 1071 unit/L (normal 95-240 unit/L). Soluble interleukin-2 receptor alpha level was elevated at 60 727 units/mL (normal 223-710 units/mL). Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed abnormal tracer localisation within the paratracheal, hilar, pelvic, abdominal and subcarinal lymph nodes, along with FDG-PET positive hepatosplenomegaly. A bone marrow biopsy showed hypercellular marrow (95% cellularity) with trilineage haematopoiesis, haemophagocytic cells, polytypic plasmacytosis and T-cell lymphocytosis, along with positive latent membrane protein-1 immunohistochemical staining for EBV. EBV quantitative DNA PCR showed >1 million copies. These findings were consistent with a diagnosis of HLH secondary to EBV infection. Despite intense therapy with the HLH-94 protocol, the patient expired from her illness after a prolonged hospital course.

Unusual manifestation of disseminated herpes simplex virus type 2 infection associated with pharyngotonsilitis, esophagitis, and hemophagocytic lymphohisitocytosis without genital involvement.

Herpes simplex virus (HSV) has various presentations, depending on the patient's immune status, age, and the route of transmission. In adults, HSV type 1 is found predominantly in the oral area, and HSV type 2 (HSV-2) is commonly found in the genital area. HSV-2 infection without genital lesions is uncommon. Herein we report a unique case of pharyngotonsillitis as an initial manifestation of disseminated HSV-2 infection without genital involvement. A 46-year-old male was admitted to our hospital with a 1-week history of fever and sore throat. His past medical history included hypereosinophilic syndrome diagnosed at age 45 years. Physical examination revealed throat congestion, bilaterally enlarged tonsils with exudates, tender cervical lymphadenopathy in the left posterior triangle, and mild epigastric tenderness. The laboratory data demonstrated bicytopenia, elevated liver enzyme levels, and hyperferritinemia. A bone marrow smear showed hypocellular marrow with histiocytes and hemophagocytosis. The diagnosis of HLH was confirmed, and the patient was treated with methylprednisolone pulse therapy on days 1-3. On day 5, despite initial improvement of the fever and sore throat, multiple, new, small bullae developed on the patient's face, trunk, and extremities. Additional testing showed that he was positive for HSV-specific immunoglobulin M and immunoglobulin G. Disseminated HSV infection was suspected, and intravenous acyclovir (10 mg/kg every 8 h) was begun. A subsequent direct antigen test of a bulla sample was positive for HSV-2. Moreover, tonsillar and esophageal biopsies revealed viral inclusion bodies. Immunohistochemical staining and a quantitative real-time polymerase chain reaction (PCR) assay confirmed the presence of HSV-2. Disseminated HSV-2 infection with multiple bullae, tonsillitis, esophagitis, and suspected hepatic involvement was diagnosed. After a 2-week course of intravenous acyclovir, his hematological status and liver function normalized, and his cutaneous skin lesions resolved. He was discharged on day 22 in good general health and continued taking oral valacyclovir for viral suppression due to his immunosuppressed status. Disseminated HSV-2 infection should be considered as one of the differential diagnoses in patients with pharyngotonsillitis and impaired liver function of unknown etiology even if there are no genital lesions.

An Unusual Presentation of Glandular Fever.

Epstein-Barr virus (EBV) is an ubiquitous DNA herpesvirus with >90% of adults >40 years of age showing a serological response. While in their youth, primary EBV infection may pass unnoticed, young adults have a high incidence of infectious mononucleosis (IM). This is characterized by a triad of pharyngitis, cervical lymphadenopathy, and fever because of a self-limiting lymphoproliferative disease. Common complications include but are not limited to hepatitis, splenomegaly, encephalitis, and haemophagocytic lymphohistiocytosis (HLH) with evidence that Caucasian males and smokers are more likely to suffer severe disease. Here we present a 21-year-old male who presented with a 2-week history of fever, dry cough, and a 4-week history of pharyngitis. He had no exposure to unwell contacts and denied any new sexual partners. Examination revealed general pallor with tender bilateral cervical lymphadenopathy and pharyngeal erythema. Admission bloods revealed pancytopenia (WCC 1.5 × 10<sup9</sup/L, Plt 84 × 10<sup9</sup/L, and Hb 82 g/L) with normal reticulocyte count and raised mean corpuscular volume (114 fL). Serum vitamin B12 and folate were low with serum ferritin raised (1027 <iµ</ig/L) suggesting a proinflammatory state. Admission liver function tests, coeliac serology, autoimmune panel (ANA, ANCA, and anti-dsDNA), hepatitic (hepatitis A, B, and E), human immunodeficiency virus (HIV), toxoplasmosis, parvovirus, and CMV serology were normal. The monospot test on day 1 of the presentation was negative. Ultrasound (US) of the abdomen on day 3 of the presentation revealed isolated splenomegaly (16.8 cm). Day 4 EBV serology (VCA IgM, VCA IgG, and EBNA IgG) was negative as such haematological investigations including JAK2, serum free light chains, and BCR-ABL were undertaken alongside cervical lymph node core biopsy. Repeat Monospot testing on day 7 came back positive. Repeat EBV serology now showed equivocal EBV VCA IgG (0.77 OD) and positive VCA IgM (9.04 OD) with concurrent new hepatitis. Histopathology of the core biopsy revealed Sternberg-reed cells and a mixed immunoblastic reaction in keeping with resolving IM. This case highlights the need for physicians to have a strong clinical suspicion of IM and understand the multiple ways in which IM may be present as well as the time lag to positivity in serological testing.

Mumps caused hemophagocytic syndrome: a rare case report.

Mumps-associated hemophagocytic syndrome (HPS) is exceptionally rare. Here, we report a fatal case of concurrent mumps and HPS. A previously healthy 21-year-old male patient was admitted to the Department of Infectious Diseases on October 18, 2011,with complaints of parotid gland pain for 30 days and persistent fever (38.3°C-40°C) for 15 days. Admission examinations showed severe pancytopenia, liver dysfunction, hyperferritinemia, fibrinopenia, elevated lactalase dehydrase, bilateral pulmonary inflammation and pleural effusion, abdominal lymphadenopathy, and splenomegaly. The patient was accordingly suspected to have mumps-associated HPS and received nutrition support and hormonal therapies as well as platelet transfusions. On hospitalization day 3, the fever stayed high, and painful swelling in the right testicle was reported. A bone marrow biopsy evaluation and serological tests were then performed. Histiocytic hyperplasia and hemophagocytic macrophage infiltration were demonstrated in the bone marrow and antimumps virus immunoglobulin M was detected positive, but bacteria, Epstein-Barr virus, cytomegalovirus, and herpes simplex virus were detected negative in the peripheral blood. The initial diagnosis of mumps-associated HPS was eventually confirmed. Treatments with high doses of methylprednisolone, intravenous immunoglobulin, and etoposide were continued. By hospitalization day 20, patient's condition was improved, his body temperature and blood counts were almost normal, and the pain and swelling in his parotid glands and right testicle subsided considerably. On hospitalization day 28, however, patient's condition deteriorated rapidly, and pancytopenia became evident again. On hospitalization day 33, the patient died of multiple organ dysfunction.

Human betaherpesvirus 5

CMV should be suspected if a person has symptoms of infectious mononucleosis but has negative test results for mononucleosis and Epstein–Barr virus, or if they show signs of hepatitis, but have negative test results for hepatitis A, B, and C. For best diagnostic results, laboratory tests for CMV antibody should be performed by using paired serum samples. One blood sample should be taken upon suspicion of CMV, and another one taken within 2 weeks. A virus culture can be performed any time the person is symptomatic. Laboratory testing for antibodies to CMV can be performed to determine if a woman has already had CMV infection. However, routine testing of all pregnant women is costly and the need for testing should therefore be evaluated on a case-by-case basis. Serologic testing

Recurrent fever of unknown origin (FUO): aseptic meningitis, hepatosplenomegaly, pericarditis and a double quotidian fever due to juvenile rheumatoid arthritis (JRA).

Fever of unknown origin (FUO) has been defined as a fever of ≥101°F that persists for 3 weeks or more. It is not readily diagnosed after 1 week of intensive in-hospital testing or after intensive outpatient or inpatient testing. Fevers of unknown origin may be caused by infectious diseases, malignancies, collagen vascular diseases, or a variety of miscellaneous disorders. The relative distribution of causes of FUOs is partly age-related. In the elderly, the preponderance of FUOs is attributable to neoplastic and infectious etiologies, whereas in children, collagen vascular diseases, neoplasms, and viral infectious disease predominate. The diagnostic approach to FUOs depends on a careful analysis of the history, physical findings, and laboratory tests. Most patients with FUOs exhibit localizing findings that should direct the diagnostic workup and limit diagnostic possibilities. The most perplexing causes of FUOs involve those without specific diagnostic tests, e.g., juvenile rheumatoid arthritis (JRA) or adult Still's disease. In a young adult with FUO, if all of the cardinal symptoms are present, JRA may present either a straightforward or an elusive diagnosis, if key findings are absent or if the diagnosis goes unsuspected. We present a 19-year-old man with a recurrent FUO. His illness began 3 years before admission and has recurred twice since. In the past, he did not manifest arthralgias, arthritis, or a truncal rash. On admission, he presented with an FUO with hepatosplenomegaly, aseptic meningitis, and pericarditis. An extensive diagnostic workup ruled out lymphoma and leukemia. Moreover, a further extensive workup eliminated infectious causes of FUO appropriate to his clinical presentation, ie, tuberculosis, histoplasmosis, brucellosis, Q fever, typhoid fever, Epstein-Barr virus, infectious mononucleosis, cytomegalovirus, human herpes virus (HHV)-6, babesiosis, ehrlichiosis, viral hepatitis, and Whipple's disease. The diagnosis of JRA was based on the exclusion of infectious and neoplastic disorders in a young adult with hepatosplenomegaly, aseptic meningitis, pericarditis, and a double quotidian fever. With JRA, tests for rheumatic diseases are negative, as they were in this case. The only laboratory abnormalities in this patient included elevated serum transaminases, a mildly elevated erythrocyte sedimentation rate, and a moderately elevated level of serum ferritin. Diagnostic fever curves are most helpful in cases where the diagnosis is most elusive, as was the case here. Relatively few disorders are associated with a double quotidian fever, ie, visceral leishmaniasis, mixed malarial infections, right-sided gonococcal acute bacterial endocarditis, and JRA. Because the patient received antipyretics during the first week of admission, fever was not present. After infectious disease consultation during week 2 of hospitalization, antipyretics were discontinued, and a double quotidian fever was present, which provided the key diagnostic clue in this case.

Sinister sinusitis.

Two previously well Caucasian teenage girls with no significant travel or family history were admitted with sinusitis refractory to treatment with antibiotics. Both had progressive symptoms despite broad-spectrum antibiotics and developed involvement of other systems, ultimately requiring admission to the paediatric intensive care unit (PICU). They were subsequently diagnosed with the same condition and made an excellent recovery.The first girl, 14 years old, originally presented to her general practitioner with a sore throat, nasal congestion, and fever. Despite multiple courses of antibiotics over the following month she presented again multiple times with progressive symptoms including epistaxis, widespread myalgia and arthralgia, difficulty in breathing, haemoptysis, fatigue, and weight loss. Examination on admission found minimal discharge from her right tympanic membrane, ulcerated inferior turbinates with dried blood and yellow mucus in both nasal cavities, swollen tonsils without exudate, and an isolated aphthous ulcer on the tip of her tongue. She had small bilateral cervical lymph nodes. Examination of the cardiovascular system was unremarkable but on respiratory examination there was reduced air entry on the right side. Her abdomen was generally tender but soft with no organomegaly. A week into her admission she developed an oxygen requirement and increased work of breathing requiring intubation and ventilation.The second girl, 13 years old, presented to her local hospital with a 1-day history of epistaxis, right ear pain, and pain and swelling to the right periorbital tissues. Again, despite multiple courses of antibiotics, she had persistent symptoms and subsequently developed fever, fatigue, haemoptysis, and had a syncopal episode. She was admitted to her local district general hospital and, despite initial treatment, deteriorated over the following 2 weeks with persistent fever, new oxygen requirement, deteriorating renal function, and anaemia. She was transferred to a tertiary centre for respiratory support which escalated from Optiflow, through continuous then biphasic positive airway pressure, intubation and ventilation, and ultimately VV-ECMO.The investigations for both patients prior to admission to PICU at our centre are shown in table 1.edpract;107/2/113/T1T1T1Table 1Investigations Case 1 Case 2 Haematology  Leucocyte peak (×10<sup9</sup/L) 18.3 19.0  Neutrophil peak (×10<sup9</sup/L) 15.2 13.7  Lymphocyte peak (×10<sup9</sup/L) 3.5 2.3  Eosinophil peak (×10<sup9</sup/L) 0.9 2.5  Platelets Normal Normal  Haemoglobin nadir (g/L) 79 74  ESR (mm/hour) 104 44 Biochemistry  Creatinine peak (umol/L) Normal 153  CRP peak (mg/l) 321 280  ALT (IU/L) 122 Normal Microbiology Nasal swab: <iMoraxella catarrhalis</i Ear swab: <iPseudomonas aeruginosa</i Sputum negative for acid-fast bacilli, PCR negative ASOT 1600 IU/ml No growth on blood or urine culture Negative viral throat swab and MCS throat swab No positive microbiology including Monospot, Mantoux and TSpot Urine dipstick On day of admission: 1+pro, 4+Hb, 2+leu, 2+ket One week into admission: 3+pro, 4+Hb, 2+leu, 2+ket Three days prior to admission: 2+Hb, otherwise normal Radiology Echocardiogram: normal CXR at admission: normal CXR after 1 week: see figure 1 CT head: pansinusitis Abdominal USS: mild hepatomegaly, diffusely echogenic kidneys Echocardiogram: normal CT chest at local hospital: see figure 2 CXR on admission to PICU: bilateral consolidation with rounded lucency in right lower zone suggestive of cavity formation ALT, alanine aminotransferase; ASOT, anti-streptolysin O titre; CRP, C-reactive protein; CT, computed tomography; CXR, chest X-ray; ESR, erythrocyte sedimentation rate; Hb, haemoglobin; leu, leucocytes; ket, ketones; MCS, microscopy, culture, and sensitivity; PICU, paediatric intensive care unit; pro, protein; TSpot, measures T lymphocytes primed to <iMycobacterium tuberculosis</i antigens; USS, ultrasound scan. QUESTIONS: Describe findings in figures 1 and 2.Which causes of sinusitis could explain the presentation of both cases?Acute sinusitis following viral upper respiratory tract infection.Bacterial infection.Allergic sinusitis secondary to mould.Underlying diagnosis of cystic fibrosis.Sarcoidosis.Tuberculosis.Granulomatosis with polyangiitis.Samter's triad.Ciliary dysfunction.Immunodeficiency.What investigations should be performed in a child presenting with symptoms of sinusitis?edpract;107/2/113/F1F1F1Figure 1The chest X-ray for case 1, 1 week into her hospital admission.edpract;107/2/113/F2F2F2Figure 2The chest CT for case 2 at her local hospital, prior to transfer. <i<bAnswers can be found on page XX.</b</i

[Clinical reasoning and decision making in practice. A 41-year old with periodic fever of unknown origin].

A 41-year-old man presented with unexplained bleeding from the right tonsil. He subsequently developed periodic fever, cervical lymphadenopathy and hepatosplenomegaly. Despite extensive bacteriological, serological and radiographic investigations for infectious disease, rheumatic disease and malignancy no diagnosis was made. Although the fever pattern was very suggestive of Pel-Ebstein fever--commonly associated with lymphoproliferative disease--multiple biopsies of lymph nodes, bone marrow, tonsils and liver all proved negative. Empirical glucocorticoid therapy gave some temporary improvement lasting for a month. Splenectomy or splenic biopsy was not carried out because of the risk of excessive bleeding. Eventually the patient died of multi-organ failure and sepsis. At autopsy, a T-cell lymphoma with an unusual phenotype and focal involvement of bone marrow, liver and spleen was found. Clinicians are sometimes faced with the dilemma of whether to perform multiple, invasive and possibly harmful diagnostic tests or to start empirical therapy. Empirical therapy may only be started if the diagnosis has been made on strong clinical grounds and, if this is not the case, only after further diagnostic tests. The question of whether a potentially harmful diagnostic test is justified depends on the clinical course, the sensitivity and specificity of the test and the therapeutic possibilities.

InternalMed_Harrison

Differential Diagnosis Whereas ~90% of cases of IM are due to EBV, 5–10% of cases are due to cytomegalovirus (CMV) (Chap. 219). CMV is the most common cause of heterophile-negative mononucleosis; less common causes of IM and differences from IM due to EBV are shown in Table 218-2. Therapy for IM consists of supportive measures, with rest and analgesia. Excessive physical activity during the first month should be avoided to reduce the possibility of splenic rupture, which often necessitates splenectomy. Glucocorticoid therapy is not indicated for uncomplicated IM and in fact may predispose to bacterial superinfection. Prednisone (40–60 mg/d for 2–3 days, with subsequent tapering of the dose over 1–2 weeks) has been used for the prevention of airway obstruction in patients with severe tonsillar hypertrophy, for Epstein-Barr Virus Infections, Including Infectious Mononucleosis Time of symptoms

Glandular fever and pulmonary artery thrombosis in a paraplegic patient, who had undergone splenectomy for splenic trauma sustained along with spinal cord injury: misdiagnosed initially as urine infection and later as lymphoma when CT scan revealed enlarged lymph nodes: a case report.

A 36-year-old male sustained fracture of first lumbar vertebra, splenic tear and paraplegia in a motorcycle accident in 2001; splenectomy was performed. In 2008, he presented with temperature and feeling rough. With a diagnosis of urine infection, he was prescribed ciprofloxacin, followed by trimethoprim, amoxicillin, and gentamicin, as temperature did not subside. White cell count was 21.2 x 109/L; lymphocytes were 13.05 x 109/L (1.00 - 4.00). Therefore, computerised tomography (CT) of chest and abdomen was performed. Thrombus was present in pulmonary arteries bilaterally involving the lobar and segmental branches. Enlarged lymph nodes were seen in axillae, chest, abdomen and inguinal regions. Radiological diagnosis was lymphoma. Cell marker showed an excess of large granular lymphocytes and activated lymphocytes. The Glandular Fever Slide Test was positive. Subsequently, Paul Bunnell test was also positive. Epstein Barr virus serology was consistent with recent Epstein Barr virus infection. Antibiotic was omitted; enoxaparin was prescribed for pulmonary artery thrombosis. Learning points from this case: (1) Although routine administration of antibiotic to a spinal cord injury patient with pyrexia may be acceptable in outpatient setting, other possibilities such as infection by multi-drug resistant organism, viral infection, venous or, arterial thrombosis should be considered if a patient does not respond promptly to antibacterial therapy. (2) When full blood count showed lymphocytosis (comprising > 50% of white blood cells) with atypical morphology, lymphocyte surface markers, Paul Bunnell test, and Epstein Barr virus serology should be performed. These tests would have led to a diagnosis of infectious mononucleosis, and abdominal imaging studies could have been avoided. (3) Lymphoid hyperplasia is the hallmark of infectious mononucleosis; therefore, we should have suspected glandular fever rather than lymphoma when CT scan revealed enlarged lymph nodes in abdomen, mediastinum, axillae and inguinal regions in this patient, who had lymphocytosis with atypical morphology. (4) A soft tissue mass, situated inferior to left hemidiaphragm in this asplenic patient, was misinterpreted as lymph nodes; review of CT led to the correct diagnosis of splenunculus. (5) Acute infection with Epstein Barr virus may lead to transient induction of anti-phospholipid antibodies, which can cause vascular thrombosis. (6) This case illustrates the value of reviewing test results and discussion with senior doctors, as these measures help to recognize medical errors and improve patient care.

What is that rash?

A healthy 15-month-old girl presented to the emergency department with a 24-hour history of fever and rash. The initial blanching rash developed into non-blanching areas with associated leg swelling. She had received no recent medications, had no known drug allergies and no unwell contacts.On examination, she was feverish at 38.6°C, capillary refill time was <2 s with warm peripheries, heart rate 169 bpm and blood pressure 94/59 mm Hg. A palpable purpuric rash was evident on all four limbs and face (figure 1) although the trunk was spared. Her legs were tense and oedematous to the knee.edpract;103/1/25/EDPRACT2016311782F1F1EDPRACT2016311782F1Figure 1Rash at presentation.Initial investigations: Haemoglobin level: 131 g/L, white cell count: 16.6×10<sup9</sup/L, neutrophils: 11.1×10<sup9</sup/L and platelets: 407×10<sup9</sup/LCoagulation screen: normalC reactive protein level: 20 mg/LLactate level: 1.7 mmol/LIntravenous ceftriaxone was commenced following blood culture and meningococcal PCR. The following day, while remaining systemically well, she developed a vesicular rash on her trunk and back (figure 2).edpract;103/1/25/EDPRACT2016311782F2F2EDPRACT2016311782F2Figure 2Vesicular rash. What is the diagnosis? Henoch-Schonlein purpura (HSP)Meningococcal septicaemiaAcute haemorrhagic oedema of infancy (AHOI)Vasculitic urticariaGianotti-Crosti syndromeWhat further investigation is required? Check viral serology including Epstein-Barr virus and hepatitis B virusComplement levels and autoimmune screenSkin biopsyLumbar puncture and audiologyNo further investigationHow should this child be managed? Complete 7 days of ceftriaxone treatmentOral aciclovirOral steroidsRegular follow-up with urinalysis and blood pressure monitoringStop antibiotics if cultures were negative at 48 hours and discharge<iAnswers are on page</i▪▪.

Epstein–Barr virus-associated lymphoproliferative diseases

Systemic EBV-positive T cell lymphoma of childhood (TCLC) is an extremely rare and aggressive T cell lymphoma that occurs almost exclusively in children, adolescents, and young adults. It occurs more frequently in Asians and Latin Americans. The disease develops as a complication or progression of either Epstein–Barr virus-positive infectious mononucleosis (EPV+ IM) or chronic active Epstein–Barr virus infection (CAEBV)., that is, as a worsening of the signs/symptoms some three weeks after the onset of an EBV+ IM-like disease or an any time during the course of CAEBV. It presents in these diseases as the onset of progressive enlargements of the liver and spleen, worsening liver dysfunction, new skin rashes, pancytopenia (i.e. falls in the blood levels of leukocytes, red blood cells, and platelets), hemophagocytosis (i.e. ingestion of blood cells by histiocytes) in bone marrow and spleen), a coagulopathy (poor blood clotting), sepsis, and/or one or multiple organ failures. Unlike the

[Clinical aspects of the diagnosis and treatment of infectious mononucleosis in primary care and in departments of infectious diseases].

Medical documentation of the 342 patients hospitalised for infectious mononucleosis at the departments of infectious diseases of two county hospital was retrospectively reviewed between 1990 and 1996 and the most important clinical data were recorded. In order to document the effect of control measures, which were taken for the improvement diagnosis and therapy, data of the 105 infectious mononucleosis patients at one of the mentioned departments were also recorded in 1997 and 1998. The length of the time before the hospital admission (avg. 10.3 days), the length of the hospital stay (avg. 9.2 days) and the respectable amount of antibiotics taken for this indication show that this disease has great cost effect. High rate of classical clinical signs (fever, pharyngitis, lymphadenopathy, atypical cells) indicates, that the majority of the patients consulting their doctors presented the well-known signs of the disease. Only 43.6% of the patients were diagnosed as infectious mononucleosis by the G. P. s. Majority of the cases were treated for tonsillitis. 90.7% of the patients were given antibiotics before the hospital admission (avg. 1.6 antibiotics/person). 43.3% of the patients left the hospital without serologic diagnosis. After drowning lesson from the first part of this study, there was significant decrease in the rate of lack of serologic diagnosis and in the amount of consumption of antibiotics for this indication in the hospital, but there was no change at the level of G. P. s. The results of this paper demonstrate that the daily routine diagnosis and treatment of a well-known diseases differs remarkably from optimal practice. The fact is, that even if the physician has knowledge of a certain disease, does not necessarily mean that he uses it in his routine work. In order to reduce this failure, authors propose introduction of protocols and regular review of the practice.

InternalMed_Harrison

Most lymphadenopathy patients do not require a biopsy, and at least half require no laboratory studies. If the patient’s history and physical findings point to a benign cause for lymphadenopathy, careful follow-up at a 2to 4-week interval can be used. The patient should be instructed to return for reevaluation if there is an increase in the size of the nodes. Antibiotics are not indicated for lymphadenopathy unless strong evidence of a bacterial infection is present. Glucocorticoids should not be used to treat lymphadenopathy because their lympholytic effect obscures some diagnoses (lymphoma, leukemia, Castleman’s disease), and they contribute to delayed healing or activation of underlying infections. An exception to this statement is the life-threatening pharyngeal obstruction by enlarged lymphoid tissue in Waldeyer’s ring that is occasionally seen in infectious mononucleosis. CHAPTER 79 Enlargement of Lymph Nodes and Spleen

Kawasaki disease with a concomitant primary Epstein - Barr virus infection.

Kwasaki disease (KD) is the leading cause of acquired heart disease in children in most developed countries. The cause of KD remains unknown. The presumed theory is that KD occurs due to one or more infectious agents who evoke an abnormal immunological response in susceptible individuals. Epstein - Barr virus (EBV) infection has been considered as a suspected causative agent because of the potential effect on the immune system. A previously healthy 19 month old boy presented with a 6 day history of fever accompanied by a diffuse macular erythematous rash that appeared 1 day after. The physical examination on admission revealed bilateral non-suppurative conjunctivitis, dry fissured and injected lips without "strawberry" tongue, diffuse macular rash on the trunk, face and limbs, swelling of the hands and feet, and right cervical lymphadenopathy (2 cm in diameter). Following fulfillment of all the clinical criteria, the diagnosis of KD was made and treatment with IVIG 2 g/Kg was administered along with oral aspirin (80 mg/ kg/day). However, despite the treatment, he remained febrile for an additional 2 days with persistent clinical manifestations. Therefore, he received a second 2 g/kg IVIG course with a favorable response. On the 14th day of illness the patient became febrile again and was readmitted. Blood examinations revealed remarkable leukocytosis up to 35.7 X 10<sup9</sup/L with 87.3% lymphocytes and the blood smear revealed atypical lymphocytes and monocytes. The liver enzymes were elevated. The serology for infectious mononucleosis from his first admission revealed: IgM CMV (+), IgG CMV (-); IgM VCA EBV (+) IgG VCA EBV (-), IgG EBNA (-). To confirm infectious mononucleosis following the administration of 2 doses of IVIG, serum EBV PCR was performed and was positive (1.6X 10<sup3</sup cp/ml). We describe here a case of KD with a concomitant primary EBV infection. To the best of our knowledge, this is the first case in western country that describes KD with acute EBV infection as confirmed by PCR. The case we described stands as a contribution in favor of the possible role of EBV in the development of KD.

[Clinical reasoning and decision-making in practice. A patient with fever and pancytopenia].

An 82-year-old man was admitted with a 1-week history of chilling fever and dry cough. Laboratory tests revealed pancytopenia and elevated levels of C-reactive protein and lactic dehydrogenase (LDH). Screening for infectious diseases was negative. A bone marrow biopsy showed aspecific findings. The combination of pancytopenia, persistent fever, elevated LDH and hepatomegaly (demonstrated by ultrasound examination of the abdomen) was suggestive of the haemophagocytic syndrome. This was confirmed by very high levels of ferritin and soluble interleukin-2 receptor in the blood. In addition, re-examination of the bone marrow showed several haemophagocytic histiocytes. A polymerase chain reaction for Epstein-Barr virus (EBV) revealed a very high viral load. Since the patient had a history of an increased level of anti-EBV immunoglobulin-G, this was explained by a reactivation of the EBV infection. On the sixth day in hospital the patient developed signs of bilateral pneumonia and subsequent multiple organ failure. Despite intensive treatment the patient died. Autopsy revealed no haematological or other malignancies, but did show haemophagocytosis in many organs. It was then concluded that the patient had a virus-associated haemophagocytic syndrome, due to a reactivation of EBV, for which no underlying cause was found.

[Pneumonia caused by Fusobacterium necrophorum: is Lemierre syndrome still current?].

Fusobacterium necrophorum is a non-spore-forming gram-negative anaerobic bacillus that may be the causative agent of localized or severe systemic infections. Systemic infections due to F.necrophorum are known as Lemierre's syndrome, postanginal sepsis or necrobacillosis. The most common clinical course of severe infections in humans is a progressive illness from tonsillitis to septicemia in previously healthy young adults. A septic thrombophlebitis arising from the tonsillar veins and extending into the internal jugular vein leads to septicemia and septic emboli contributing to the development of necrotic abscesses especially in lungs and other tissues such as liver, bone and joints. In this case report, a previously healthy man with pneumonia and empyema due to F.necrophorum has been presented. A 22 year-old man suffering from sore throat for seven days was admitted to emergency department with ongoing fever and dysphagia for three days. On admission he was already taking amoxicillin-clavulanic acid and his complaints were relieved with continuation of therapy to a total of 10 days. However, five days after the cessation of treatment he developed productive cough, fever and generalized myalgia. On physical examination, there were crackles on right lower lung, and chest X-ray revealed pulmonary consolidation on the right middle lobe. Levofloxacin therapy was started based on the diagnosis of pneumonia. While polymorphonuclear leucocytes and intracellular gram-negative bacilli were seen in Gram stained sputum smear, sputum culture was reported as normal flora. Although the patient's status had started to improve with treatment, his condition deteriorated with development of fever and dyspnea. Chest X-ray revealed consolidation, pulmonary infiltrates, pleural effusion and air-fluid level on the right. Meropenem, clarithromycin and linezolid were initiated and a chest tube was inserted with the preliminary diagnosis of necrotizing pneumonia, empyema and type-1 respiratory failure. While there was no growth on bronchoalveolar lavage fluid culture, thoracentesis material inoculated into thioglycolate broth revealed turbidity. Further inoculation onto Schaedler agar which was incubated under anaerobic conditions, yielded growth of catalase negative, indol positive, gram-negative anaerobic bacilli identified as F.necrophorum by BBL Crystal system (Becton Dickinson, USA). The detailed history of the patient revealed that fish bone had stuck in his throat a week ago. Clarithromycin and linezolid were discontinued and he was recovered within six weeks of meropenem treatment. F.necrophorum infection should be considered in the differential diagnosis of persistent head and neck infections with rapidly progressive metastatic necrotic lesions especially in healthy young adults and clindamycin or metranidazol should be added to the treatment protocols.

Infectious mononucleosis.

Infectious mononucleosis is a unique disease in its hematologic aspects; it is different from the frequently occurring acute microbial diseases in that it affects primarily the reticuloendothelial system; and it is interesting serologically because of the heterophil antibody reaction, as well as the multiplicity of antibodies which may be produced. The diagnosis should be suspected clinically before hematology is reported - by remembering the prototypes. In fact, a patient between 16 and 25 years old who complains of sore throat and fever is more likely to have infectious mononucleosis than another disease; and if - in addition - he is jaundiced, a diagnosis of infectious mononucleosis is almost certain. Finally, a negative result of treatment with corticosteroid has the diagnostic significance mentioned above. Positive effect of treatment has no diagnostic significance.

Mononucleosis and hepatic failure associated with diphenylhydantoin treatment in an infant.

Diphenylhydantoin-induced hepatitis and mononucleosis are uncommon in children. The occurrence of these two diseases in the same individual, with progression to hepatic failure is rare and has not been reported in infants. This report represents a 6-month-old male infant who developed an infectious mononucleosis-like syndrome and hepatic failure 16 days after diphenylhydantoin administration. He took this anticonvulsant for controlling seizures after a head injury. Fever, skin rash, hepatosplenomegaly, lymphadenopathy, and atypical lymphocytosis led to the initial diagnosis of infectious mononucleosis. However, negative heterophil antibody did not support the diagnosis. Jaundice ensued in the following course and became more and more profound. Meanwhile, physical examination showed shrinking in liver size. Negative virology studies, including Epstein-Barr virus, cytomegalovirus, and hepatitis B virus, excluded them as causative agents. The patient lapsed into a stage I hepatic coma, but gradually recovered clinically and biochemically after eight successive exchange transfusions and supportive care. Two liver biopsies were performed 20 and 50 days after the onset of disease, respectively. Remarkable hepatic parenchymal loss, cholestasis, and fatty change were found on histologic examination of the first biopsy specimen, and portal fibrosis was noted on the second.