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• W2092245888 abstract "Azathioprine is efficacious in maintaining remission in Crohn disease (1). The drug generally is well tolerated but has reported side effects ranging in severity from mild to life threatening. The most common side effects are nausea and vomiting (2). Dose-independent complications include fever, rash, nausea, diarrhea, malaise, arthralgia, pancreatitis, and, rarely, a septic shock-like syndrome (3). Dose-related side effects include leukopenia, thrombocytopenia, and hepatitis. Most of these side effects remit after dose reduction, but in about 18% of pediatric and adolescent patients, side effects may necessitate discontinuation of medication use (4). Infection is a well known complication during use of immunosuppressive agents. Infection is seen in about 3% of pediatric patients with inflammatory bowel disease taking azathioprine or 6-mercaptopurine (4). Commonly reported infections are varicella and warts. Neutropenic sepsis is an uncommon complication. Viral-associated hemophagocytic syndrome has occurred in adults (VAHS) (5) receiving azathioprine. We report a case of cytomegalovirus (CMV)-associated hemophagocytic syndrome in a child with Crohn disease. CASE REPORT This 12-year-old boy had ileocecal Crohn disease. Remission was induced initially with oral corticosteroid. Relapse occurred when the medication was discontinued. Another course of oral corticosteroid was prescribed in conjunction with azathioprine. The corticosteroid therapy was successfully discontinued and his condition remained in remission for 2 years with a regimen of 75 mg/day of azathioprine (2 mg/kg/day). Results of hemogram and hepatic function tests were normal. He took no other medications. At presentation in our center, he had a 2-week history of high spiking fever, lethargy, and poor appetite. He had no other gastrointestinal symptoms. He had no history of travel or contact with infectious diseases. There was no family history of hematologic disorders or unexplained infant deaths with fever. Physical examination revealed a temperature of 38.9°C, heart rate of 90 beats/minute and blood pressure of 89/45 mm Hg. His weight was between the 10th and 25th percentiles and his height was between the 25th and 50th percentiles for age. He was pale but anicteric. There was no lymphadenopathy. Abdominal examination and perianal examination results were normal. During his hospitalization he subsequently experienced tender hepatomegaly. Eye examination results were unremarkable. Laboratory investigations at the time of presentation included a hemogram showing pancytopenia. Liver biochemistry revealed elevated activities of transaminase and lactate dehydrogenase with hypoalbuminemia. Serum bilirubin concentration was normal (Table 1). Serial blood cultures and stool cultures for bacterial pathogens were negative. Fecal clostridium difficile cytotoxin assay was negative. Upper gastrointestinal and small bowel barium contrast radiographs were normal, as was the chest radiograph. Ultrasound examination of the abdomen revealed an enlarged (2-cm) lymph node in the porta hepatis. Radionuclide gallium scan did not reveal any intraabdominal collection of contrast. Abdominal computed tomography scan was normal and was not suggestive of active Crohn disease. Colonoscopy examination was not performed because he had no gastrointestinal symptoms. C-reactive protein was 9.3 (<5 mg/L). Total immunoglobulin G was 14.60 g/L (range, 7.59–15.5 g/L) and IgM was 5.91 g/L (range, 0.35–2.39 g/L). Antinuclear antibody (ANA) titer was negative. Immunoglobulin (Ig) G antibodies against Epstein-Barr virus capsid antigen (VCA) were present, but IgM antibodies against viral capsid antigen (VCA IgM) were not. No Epstein-Barr virus was detected by polymerase chain reaction. IgG antibodies to parvovirus B19 were detected. IgM antibodies were not detected, but results of polymerase chain reaction examination of blood were negative. IgG and IgM antibodies against CMV were detected. The Nuclisens CMV PP67 (Biomerieux, Boxtel, Netherlands) qualitative assay for mRNA of CMV was also positive, suggesting active CMV infection. Urine cultures were negative for CMV.TABLE 1: Summary of laboratory investigationsFibrinogen, prothrombin time, and activated partial thromboplastin time were normal. Fasting triglyceride and ferritin levels were 5.10 mmol/L (range, 0.27–1.64 mmol/L) and 583 μmol/L (range, 29–84 μmol/L), respectively. These biochemical markers, especially the elevated triglyceride and ferritin with pancytopenia, suggested hemophagocytic syndrome. Bone marrow examination revealed a hypoplastic marrow. It also revealed hyperplasia of histiocytes and prominent hemophagocytosis (Fig. 1). There were no viral inclusions seen on histologic examination of bone marrow. Viral culture of bone marrow was not performed.FIG. 1.: Bone marrow showing phagocytosis of a neutrophil, platelet, and lymphocyte by an activated macrophage (May-Grunwald-Giemsa stain; original magnification, ×1,000).Azathioprine use was discontinued on hospital admission, and oral mesalamine (Salofalk) therapy was started. Antibiotic use was discontinued after cultures were negative. The patient’s fever subsided 12 days after admission. Repeated evaluations revealed normalization of blood counts, transaminase level, albumin, ferritin, and triglyceride levels (Table 1). Assay for CMV pp67 mRNA became negative. The child’s Crohn disease remains in remission, and he continues to be treated with mesalamine18 months after the spontaneous resolution of VAHS. DISCUSSION This case describes an unusual complication of azathioprine therapy in a pediatric patient with inflammatory bowel disease, namely cytomegalovirus-associated hemophagocytic syndrome. Hemophagocytosis is the hallmark of hemophagocytic syndrome, which is also known as macrophage activation syndrome. Hemophagocytic syndrome may involve phagocytosis of erythrocytes, leukocytes, platelets, and/or their precursors by activated macrophages. This multisystem disorder is pathologically characterized by a reversible histiocytic proliferation associated with hemophagocytosis. Overproduction of cytokines from activated T lymphocytes is responsible for activation of monocyte-macrophages (6). High levels of soluble interleukin 2 receptor, interferon-γ, tumor necrosis factor-α, interleukin-1, and interleukin-6 have been seen in this syndrome (6–9). The immunosuppressive activity of azathioprine is not only a decrease in cell-mediated immunity but also a blunting of humoral responses and a decrease in circulating monocytes and granulocytes (10). These effects put patients receiving azathioprine at risk for infections, including CMV. CMV infection can lead to immune dysregulation with paradoxical activation of humoral immunity (11). Thus, CMV infection in a patient receiving azathioprine may predispose to VAHS. VAHS usually is characterized at presentation by high-grade fever, hepatosplenomegaly, elevated triglyceride levels with or without hypofibrinogenemia, and pancytopenia. Other clinical features include constitutional symptoms, lymphadenopathy, skin rash, and pulmonary infiltrates. Elevated ferritin and transaminase levels also occur. Criteria for making this diagnosis have been published (12). Hemophagocytic syndromes include a primary familial form and a secondary form that is occasionally associated with infection, rheumatoid arthritis, and malignancy (13). There was no family history suggestive of inherited hemophagocytic syndrome in our patient. CMV infection is a recognized cause of VAHS. Viral-associated hemophagocytic syndrome was first characterized in 1979 by Risdall et al. (14) in a study in which 10 of 19 patients with viral-associated hemophagocytosis had evidence of CMV infection. All patients had undergone renal transplants with splenectomy and were receiving azathioprine and prednisone. In adult patients with inflammatory bowel disease and immunosuppressive therapy CMV-associated hemophagocytosis is rare. In one published report, an adult patient with Crohn disease in remission experienced CMV-associated hemophagocytosis (15). Our case also was in clinical remission. Neither the gallium scan nor the computed tomography scan of the abdomen showed active inflammatory bowel disease. The low albumin likely was secondary to the systemic inflammatory process. Positive IgM and CMV nucleic acid assays were suggestive of active CMV infection. Urine culture in our patient was negative for CMV. Although there are no data in the literature comparing the sensitivity and specificity of urine culture and CMV pp67 assay in detecting active CMV infection, we believe pp67 m-RNA assay is a more sensitive tool than culture for detecting CMV infection. Our patient had evidence of active CMV infection that was not associated with an exacerbation of Crohn disease. He did not require antiviral therapy or treatment for VAHS. The elimination of azathioprine therapy was associated with clinical improvement, improvement in blood counts, and resolution of the hemophagocytic syndrome. We suspect that it was the discontinuation of azathioprine use that was responsible for reversing immune suppression, termination of CMV infection, and resolution of the VAHS. It is possible that CMV infection spontaneously cleared with resolution of the VAHS. Mortality is high in VAHS, and early recognition of the condition is vital (5). Leukopenia can be seen in patients receiving azathioprine and mesalamine or sulfasalazine because of drug interactions (16). A hepatitis-like presentation has been described in adult patients with Crohn disease who are receiving azathioprine and who develop active CMV infection without VAHS (17). Fasting triglyceride, fibrinogen, and ferritin levels may help in early discrimination of this condition from other causes of fever and leukopenia. Our patient had normal fibrinogen levels. Frequently observed clinical signs in hemophagocytic syndrome are fever (60–100% of affected patients), splenomegaly (35–100% of affected patients), and hepatomegaly (39–97% of affected patients). Consistent laboratory abnormalities are anemia (89–100% of patients affected), thrombocytopenia (82–100%), and hypertriglyceridemia (59–100%). Hypofibrinogenemia is seen in only 19% to 85% of affected patients (18). It should be noted that elevation of triglyceride and ferritin levels may persist for several days after clinical improvement, as was observed in our case. Confirmation of hemophagocytosis is made on histologic analysis of bone marrow. Tissue diagnosis with lymph node biopsy is an alternative, in which the bone marrow examination results are negative. Severe cases have been successfully treated with high-dose steroid, gamma-globulin, and cyclosporine therapy (19–20). However, elimination of immunosuppression is all that may be required in children with milder form of VAHS. Acknowledgment: We acknowledge Dr. Louis Wadsworth for his help and support." @default.
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• W2092245888 title "Cytomegalovirus-Associated Hemophagocytic Syndrome in a Child With Crohn Disease Receiving Azathioprine" @default.
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