Disseminated Aspergillosis Following Infliximab Therapy in an Immunosuppressed Patient With Crohn's Disease and Chronic Hepatitis C: A Case Study and Review of the Literature

Joel W. Alderson, DO; Thomas G. Van Dinter, Jr., MD; Michael J. Opatowsky, MD; Elizabeth C. Burton, MD

Disclosures

September 21, 2005

Discussion

We report a fatal case of disseminated Aspergillus in a woman with Crohn's disease who was treated with a single infusion of infliximab. Aspergillosis is an opportunistic fungus that can cause severe, invasive infections in immunocompromised individuals. Aspergillus can colonize grain, leaves, soil, and water with the conidia easily dispersed into the air. Humans become infected by inhalation.[7] The conidia are ubiquitous in the environment and have posed a problem in immunocompromised hospitalized patients of whom hospital construction has occurred in the absence of laminar airflow or high-efficiency particulate air (HEPA) filtration, in particular, in close proximity to oncology and bone marrow transplant units.[8,9,10] Risk factors that predispose to IA include neutropenia, corticosteroid use, and cytotoxic and immunosuppressive therapy.[11] Emerging data also suggest that cirrhosis may be a host factor for IA.[12] The most common cause of invasive disease is A fumigatus, which in immunocompetent individuals causes a chronic granulomatous response. In immunocompromised individuals, it most often causes invasive pulmonary infections characterized by diffuse or localized necrotizing bronchopneumonia, hemorrhagic pulmonary infarctions, or abscesses.[7] In several series, the most common sites for IA include the lung, gastrointestinal tract, and central nervous system, followed by other sites, including the liver, kidneys, thyroid, spleen, and heart.[13,14]

Overall fungal infections involving the lower gastrointestinal tract are rare with a 1.6% incidence reported in one autopsy series.[15] However, in those patients with evidence of IA, gastrointestinal tract involvement is well documented. In one of the largest autopsy series of patients with aspergillosis, approximately one third of patients developed disseminated disease in which most had involvement of the gastrointestinal tract.[13,15] Symptoms of IA involving the gastrointestinal tract are usually vague, often including abdominal pain and fever[16]; however, patients can present with bowel ischemia and obstruction. Rarely bowel infarction may be the initial manifestation of disseminated aspergillosis, and bowel wall perforation is an uncommon complication.[17,18] Although rare, colonic ulcers with gastrointestinal bleeding have been reported to occur in cases of disseminated aspergillosis.[19] Once disseminated, aspergillosis is commonly fatal (mortality greater than 80%) even if promptly diagnosed and treated.[20,21]

Our patient had a history of Crohn's disease necessitating total proctocolectomy and an ileostomy that was complicated by recurrent stoma breakdown and pyoderma gangrenosum. Her medical therapy included prednisone, azathioprine, and more recently initiation of intravenous infliximab. She subsequently developed bilateral pulmonary infiltrates, and sputum cultures were positive for Aspergillus. Despite intensive antimicrobial, antifungal, and supportive therapy, she developed fatal IA. Immunosuppression, steroid use, cirrhosis, and recent initiation of infliximab therapy likely put this patient at risk for IA. A concomitant environmental exposure in this patient is unknown. The risk for acquisition of certain infections, including life-threatening opportunistic infections, following exposure to immunosuppressive regimens has been well demonstrated. Although threshold levels for steroid therapy have not been clearly delineated, one study of patients receiving corticosteroids after renal transplantation found that a daily dose of prednisone equal to or greater than 1.25 mg/kg was predictive of IA.[22] Similar to other reported cases,[4] our patient also had concurrent treatment with prednisone and azathioprine when infliximab was initiated. Because of the temporal relationship between initiation of infliximab therapy and IA in this patient, we propose that infliximab was a major contributing factor in the development of disseminated disease.

Infliximab is approved for the treatment of rheumatoid arthritis and Crohn's disease. It is a monoclonal chimeric antibody composed of a murine antigen-binding region joined to the human immunoglobulin (Ig)G1 constant region. Each molecule of infliximab can bind 2 molecules of TNF-alpha, and can bind either membrane-bound or membrane-soluble molecules. TNF-alpha is a proinflammatory cytokine involved in the activation and recruitment of inflammatory cells and amplification of other inflammatory cytokines. TNF-alpha overexpression has been implicated in many inflammatory diseases, including inflammatory bowel disease and rheumatoid arthritis. Binding of infliximab prevents soluble TNF-alpha from binding its natural receptors, thus blocking its biological activity. Binding to membrane-bound TNF-alpha causes lysis of TNF-alpha-producing cells.[23] Infliximab was approved for the treatment of Crohn's disease after 2 studies[24] showed dramatic improvement in remission from disease when compared with placebo[25] and improved healing of fistulas in patients with Crohn's disease.[26] Initial clinical trials of infliximab showed a good safety profile with limited serious adverse effects. Headache, nausea, and upper respiratory tract infections were most commonly reported.[27] Recent evidence suggests that anti-TNF compounds are involved in the recruitment of neutrophils into the lungs in response to pathogens, such as A fumigatus.[28] Antibody-mediated neutralization of TNF-alpha resulted in increased mortality in mice after intratracheal challenge with A fumigatus.[1] An association between the use of infliximab and unexpected infections has been shown to occur in clinical practice. A number of opportunistic infections have been described with a tendency to occur soon (as few as 5 days) after initiation of infliximab.[29,30,31]

Postmarketing reports of systemic fungal infections through January 31, 2001 included 23 cases of systemic fungal infections associated with infliximab.[4] A more recent update from the US Food and Drug Administration's adverse events reporting system reported 565 granulomatous infections, including 26 cases of aspergillosis associated with anti-TNF agents.[32] In addressing the risk of infection, in October 2001, a black box warning was issued regarding the risk for opportunistic infections, including invasive fungal infections.[33] Three cases of IA associated with infliximab have been described.[29,34,35] We believe that this is the fourth reported case of disseminated aspergillosis related to the use of infliximab and the first associated with bowel perforation. Warris and colleagues[29] reported a case of pulmonary aspergillosis associated with infliximab in a 25-year-old man with Crohn's disease who succumbed to septic shock with multiorgan failure. The patient had no other known risk factors for Aspergillus and was on no other immunosuppressive drugs 3 months prior to hospitalization. De Rosa and colleagues[34] reported a case of a 73-year-old woman receiving infliximab for rheumatoid arthritis who developed A fumigatus pulmonary infection. The patient was also receiving steroid therapy prior to admission, and the infection resolved after antifungal therapy. A third case[35] of pulmonary Aspergillus was reported in a 58-year-old woman receiving infliximab and methotrexate for rheumatoid arthritis. This patient also developed disseminated tuberculosis and cutaneous herpes simplex virus infection.

Another study on the use of infliximab for treatment of severe graft vs host disease showed an increased risk for invasive fungal infections in patients receiving infliximab compared with those who did not.[36] Infliximab has also been associated with disseminated or extrapulmonary tuberculosis,[3,35] other opportunisitic infections,[37,38,39] and invasive fungal infections by organisms other than Aspergillus. A case of cryptococcal pneumonia after initiation of infliximab in a patient with rheumatoid arthritis has been reported, with apparent transmission from a pet cockatiel.[40] Two cases of disseminated histoplasmosis following treatment with infliximab have also been reported.[41]

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