Fatal Disseminated Cytomegalovirus Infection Associated With Infliximab and 6-Mercaptopurine Therapy in a Child With Crohn Disease

Abstract

To the Editors: We present a fatal case of cytomegalovirus (CMV) colitis with dissemination in a child with sickle cell anemia and Crohn disease who was receiving infliximab and 6-mercaptopurine. A 9-year-old boy with sickle cell anemia (HbSS) and biopsy-proven Crohn disease, presented with fever, extremity pain, and bloody diarrhea. Treatment included infliximab infusions, the last of which was 5 weeks earlier, and 6-mercaptopurine. On presentation, he was febrile with icteric sclera. Laboratory evaluation was significant for hemoglobin, 6.6 g/dL; leukocyte count, 12,500/mm3; and normal differential and platelet count. Blood culture was negative. Intravenous hydration, vancomycin, and ticarcillin-clavulanate were initiated. His symptoms persisted and abdominal pain developed. Computerized tomography revealed thickening of the colon and a left lower lobe lung infiltrate. Bacterial stool culture and stool for Clostridium difficile toxin were negative. CMV IgM and IgG serologies were positive. CMV was isolated from his urine. Therapy with ganciclovir was initiated and 6-mercaptopurine discontinued. He continued to deteriorate, developing respiratory distress with bilateral pulmonary infiltrates and hypotension. Colonoscopy revealed highly friable mucosa, a biopsy of which showed florid cytopathic effects with typical CMV inclusions and CMV antigen on histoimmunochemical staining. Foscarnet, daily infusions of immune globulin, and antifungal therapy were added. Serologic tests for hepatitis A, B, and C, parvovirus B19, and Epstein-Barr virus were negative, as was an assay for CMV antigen in his peripheral blood leukocytes. He remained febrile, passed frank blood per rectum, developed respiratory and subsequently hepatic failure, and expired 4 weeks after hospitalization. Postmortem evaluation showed diffuse bronchopneumonia and giant cells in the lungs with a single focus positive for CMV antigen. There were acute and chronic inflammatory cells in the esophagus, stomach, pancreas, liver, and spleen. The bowel had extensive ulceration with cryptitis and crypt abscess formation. Lung culture for CMV was negative. Our patient's symptom complex was suggestive of an exacerbation of inflammatory or infectious colitis. CMV colitis was confirmed on pathologic evaluation of colon biopsy specimens. CMV infection was further documented by the detection of IgM and IgG antibodies and the isolation of the virus from urine. It is likely that CMV infection was disseminated because in addition to colitis, he had hepatitis, diffuse pneumonitis with giant cells and a focus with CMV antigen (despite several weeks of antiviral therapy), and clinical sepsis with multiple negative blood cultures. CMV antigen was not detected in peripheral leukocytes; this test was performed after 2 weeks of antiviral therapy. CMV colitis complicating inflammatory bowel disease (IBD) has been described in adults1 and children.2 Withdrawal of immunosuppression with or without antiviral therapy usually resulted in resolution of symptoms. Our patient developed disseminated disease and succumbed despite antiviral therapy, immune globulin infusions, and withdrawal of immunosuppression. We are aware of 1 other report of disseminated CMV infection following infliximab therapy in a person with IBD: a 63-year-old woman with Crohn disease receiving infliximab and corticosteroids, presented with fever, diarrhea, and skin lesions.3 Although our patient had the comorbid condition of sickle cell anemia we are unaware of cases of disseminated CMV disease in patients with sickle cell disease. Clinicians caring for patients with IBD who receive infliximab or other immunosuppressive medications should be vigilant for gastrointestinal CMV infection as well as disseminated CMV disease. Olufunke Pickering, MD Department of Pediatrics Schneider Children's Hospital New Hyde Park, NY Toba Weinstein, MD Division of Pediatric Gastroenterology Schneider Children’s Hospital New Hyde Park, NY Lorry G. Rubin, MD Pediatric Infectious Diseases Schneider Children’s Hospital New Hyde Park, NY