A Confusing Case Report About an Important Issue

Disseminated cytomegalovirus infection in Crohn's disease following anti-tumour necrosis factor therapy. D. Helbling, TH Breitbach, M Krause. Eur J Gastroenterol Hepatol 2002;14:1393–95. Summary: The case is of a 63-year-old woman with 10 years of stable Crohn disease controlled with “low-dose corticosteroids”. After 1 month of increasing diarrhea, a colonoscopy showed “inflammatory lesions in the colon and ileum compatible with Crohn disease” but also a few “large cells with CMV inclusion bodies”. The patient was treated with increased dose of corticosteroids and, for unexplained reasons, azathioprine and a single infusion of infliximab. After a “transient improvement” of undefined duration, she developed fever, diarrhea, painful cutaneous ulcerations, rash along a dermatome, and mental status changes. Based on the demonstration of diffuse inclusions typical of CMV in biopsies of the colon, upper gastrointestinal tract, and skin, a positive CMV PCR test on spinal fluid, and on detection of IgM (but not IgG) virus-specific antibodies, the diagnosis of disseminated CMV infection was made. The authors discuss the clinical features of the patient's disseminated CMV, which they believed was a complication of the use of infliximab. Comment: This is a case report with a misleading title, which lacks both detail and description of the author's clinical reasoning, and ends with a bland discussion. Despite these drawbacks, this report highlights several issues important to pediatric gastroenterologists. There were three decision points in this case that merit consideration: (1) the decision to perform the first colonoscopy, (2) the decision to treat for an exacerbation of Crohn disease despite finding evidence of CMV, and (3) the decision to use azathioprine and infliximab without evaluating the risks of adverse events from these agents. I will look at these three decisions in that order. First, how should we approach a patient with a stable chronic disease who presents with new symptoms? Considerations generally include whether one is dealing with a disease exacerbation, a new disease process, or a complication of the underlying disease or its therapy. I think most pediatric gastroenterologists in this situation would have obtained stool samples for bacterial pathogens, Clostridium difficile toxin, and parasites. If negative, a short burst of corticosteroids would have been used. Colonoscopy would have been reserved for failure of this initial approach. The second issue was the decision to treat for an exacerbation of Crohn disease despite known CMV inclusions in the colon. CMV is a recognized mimic of “resistant colitis” and continues to receive attention in the literature (Am J Gastroenterol 2002;97:1061–2). The authors do not present any information on the reasons behind their decision to treat. A test was performed, and showed two potential processes (Crohn inflammation and CMV), but the less-expected finding (CMV) was ignored. If the new information was to be ignored, why perform the colonoscopy at all? Third, there is the issue of how to minimize adverse events while treating patients with azathioprine and infliximab. Specifically, what is the role of TPMT testing in patients who are taking or who are potential candidates for therapy with azathioprine or 6-MP? Azathioprine and 6-MP have known side effects, primarily bone marrow suppression and hepatotoxicity, which now appear to relate to variations in TPMT, the enzyme responsible for the metabolism of these agents. Should all patients or only selected patients, be tested for TPMT status? Should patients be tested before or after the initiation of therapy? The cost-benefit ratio of such testing has not yet been evaluated in inflammatory bowel disease or in any prospective studies that I could find. However, a Canadian study of patients with rheumatologic conditions, suggests that pretreatment testing may be cost-effective (J Rheumatol 2002;29:2507–12). A number of infections have been reported in patients being treated with anti-TNF alpha agents, primarily infections caused by intra-cellular organisms. A quick review of PubMed using infliximab and sepsis or infection as the key words revealed 60 papers on infections associated with the use of infliximab. The infections reported included necrotizing fasciitis, listeriosis, histoplasmosis, pneumocystis, cryptococcosis, aspergillosis, and tuberculosis. Reactivation of multiple sclerosis and other inflammatory conditions has also been reported. Of note, a PubMed search using infliximab and CMV or cytomegalovirus as key words revealed only this article. Cases are accumulating that indicate that re-activation or acquisition of TB during infliximab use is a complication which occurs frequently enough that it should be considered in every treated patient (NEJM 2002;346:623–6). Testing for TB is now recommended before the use of infliximab. In practice, testing may be difficult and even inaccurate, as the pediatric gastroenterologist and staff may not have expertise in applying and reading TB tests and may not be reimbursed for the cost of supplies, training, administration, and interpretation of the tests. Indeed, reading of the test in many circumstances relies on reports from untrained staff in primary care offices. Furthermore, in very ill or immunosupressed patients with inflammatory bowel disease, false negative tests are an added complication to screening. I am unconvinced that infliximab contributed to the disseminated CMV in this case. Azathioprine seems much more likely to be the culprit. Two take-home messages may be derived from this article. First, be wary of believing the title of every case report. Second, like our colleagues in oncology, pediatric gastroenterologists are in critical need of guidelines for preventing, detecting, and treating the potential infections associated with the more wide spread use of powerful new immunosuppressant agents. Edward J. Hoffenberg Associate Professor of Pediatrics Section of Pediatric Gastroenterology, Hepatology and Nutrition University of Colorado Health Sciences Center and The Children's Hospital Denver, Colorado, U.S.A.

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