Case 2 -

Histoplasmosis Complicating Treatment with Anti-tumor Necrosis Factor-α Elizabeth A. Montgomery Johns Hopkins Hospital Baltimore, Maryland

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Clinical History This specimen was from a 51 year old man with a history of Crohn's disease diagnosed in 1991. The patient lived in Richmond, Virginia. He had had erythema nodosum in 1997 and a history of ileal strictures (1997). The patient developed steroid-induced diabetes when treatment with steroids was used. He subsequently failed therapy with Cipro, Flagyl, Imuran, and 6-Mercapto Purine. In 12/01, he began methotrexate 25 mg IM qwk and Remicade (infliximab, anti-tumor necrosis factor-α) 5mg/kg (12/01). Remicade was increased to 10mg/kg q16 wks (6/02), to 10mg/kg q8 wks (8/04), and to 10mg/kg q6 wks (2/05). The patient developed progressive low-grade fevers, chills, anorexia, and dry cough (5/05) and was admitted to The Johns Hopkins Hospital (JHH) Gastroenterology service with jejunoileitis. An abdominal abdominal CT showed marked bowel thickening and focal narrowing consistent with Crohn's disease with a possible fistula (5/05). The patient was discharged to home (06/05). Remicade was effective for symptomatic control for 4 wks when the patient developed abdominal pain and cramps. Despite increasing Remicade, the patient was readmitted to the JHH for continued fevers and chills. Despite aggressive treatment and bowel rest with total parenteral nutrition, he underwent an emergency resection of a segment of jejunum containing a fistula. Case 2 - Figure 1 - Low magnification of the resected segment of small bowel showing transmural inflammation Case 2 - Figure 2 - A focus of pyloric metaplasia seen in the small intestinal mucosa. Case 2 - Figure 3 - Note the presence of granulomatous inflammation. Case 2 - Figure 4 - Higher magnification of one of the necrotizing granulomas from this small bowel resection. Case 2 - Figure 5 - High magnification of one of the granulomas. Macrophages are laden with organisms; the diagnosis can be suggested on the routine H&E preparation. Case 2 - Figure 6 - Vascular spaces are plugged with macrophages containing organisms (H&E). Case 2 - Figure 7 - Gomori methenamine silver displaying numerous organisms compatible with Histoplasma capsulatum. Case 2 - Figure 8 - This view shows budding forms of Histoplasma capsulatum. Diagnosis Histoplasmosis Complicating Treatment with Anti-tumor Necrosis Factor-α The sections of small bowel show mucosa with active chronic enteritis with pyloric metaplasia. There is transmural inflammation and many granulomas are seen. At first glance this looks like classic Crohn's disease but the process differs by having granulomas that are "too good to be true" for Crohn's disease and indeed that is the case. The granulomas display necrosis. On careful examination, organisms in keeping with histoplasmosis are apparent in macrophages in the granulomas on routine staining, an impression confirmed by additional staining with Gomori methenamine silver. The patient probably had underlying Crohn's disease. Treatment with Remicade provided relief for a time, but the ensuing immunosupression resulted in an unusual but well-described complication of this opportunistic infection [1, 2] . Unfortunately the patient died with widely disseminated histoplasmosis. Histoplasmosis is the most prevalent endemic infection in the US and a common opportunistic infection [3]. Immunosuppressed individuals are at high risk for severe infection. Murine models have shown that cell-mediated immunity, including that mediated by tumor necrosis factor-α, is critical for host defense against Histoplasma capsulatum [4]. Remicade is a monoclonal (IgG) antibody targeting soluble and cellular tumor necrosis factor-α. It has been used to treat a host of inflammatory disorders including psoriasis, rheumatoid arthritis, and Crohn's disease. Since it results in immune modulation, reported associated opportinustic infections have included aspergillosis, tuberculosis, and histoplasmosis [1, 2, 5, 6] . The latter is a dimorphic fungus endemic to the Central and Eastern United States, where it is found in bat and bird droppings. Histoplasmosis encompasses a wide spectrum of presentations, ranging from indolent pulmonary infections to fatal disseminated cases. Disseminated cases may present, like this one, with fever, malaise, and cough with dyspnea. In a large Mayo Clinic study of 500 patients treated with Remicade, 8.2% (48 patients) had associated infections. Twenty patients had life-threatening infections, including one with histoplasmosis [7]. Other authors have reported about a dozen cases. In general, these patients had severe infections, were undergoing simultaneous treatment with other immune modulators in addition to Remicade, and lived in endemic areas. Gastrointestinal histoplasmosis is not exclusively a disease of the immunodeficient but can also mimic Crohn's disease in immunocompetent individuals, a phenomenon to which Lamps et al called attention [8] They evaluated 56 specimens from 52 patients with H&E and silver stains. The presentation was with gastrointestinal rather than pulmonary disease in 43% of their patients. Gross gastrointestinal features included ulcers (49% of patients), nodules (21%), hemorrhage (13%), obstructive masses (6%) and normal mucosa (23%). Microscopic gastrointestinal findings included diffuse lymphohistiocytic infiltration (83%), ulceration (45%), lymphohistiocytic nodules (25%), or minimal inflammatory reaction (15%) but only rare well-formed granulomas (8.5%). The most common hepatic finding was portal lymphohistiocytic inflammation; discrete hepatic granulomas were seen in less than 20% of involved livers. In their series about half of patients were immunocompetent, underscoring the need to consider this possibility before making a new diagnosis of Crohn's disease. The differential diagnosis of granulomatous enterocolitis includes enterocolitis from the range of processes that result in granuloma formation elsewhere in the body but some infections are relatively specific to the GI tract. These processes include primarily yersiniosis (either with Y. enterocolitica or pseudotuberculosis) and some examples of salmonellosis. The granulomatous process in yersiniosis is centered around Peyer's patches and there may be histologic features of chronicity in specimens, although features of acute self-limiting entercolotis may similarly accompany yersiniosis [9, 10] . Yersinia genetic material has been detected from specimens from patients with Crohn's disease where it may better reflect an accomplice than a perpetrator [10]. Of course tuberculosis also sometimes affects the GI tract. Malakoplakia is also a possibility. Several forms of immunodeficiency disease can also result in granulomatous enterocolitis. Chronic granulomatous disease is an inherited disorder manifesting as immune deficiency caused by mutations in any of the genes which encode the various subunits of the superoxide-generating phagocyte NADPH oxidase system responsible for the respiratory burst involved in organism killing. This disease affects around 1 in 250000 children and is associated with significant morbidity and mortality, with the predicted life expectancy reduced to around 25–30years of age, with recurrent severe bacterial and fungal infections with granuloma formation. Treatment usually involves the use of prophylactic and therapeutic antibiotics, and newer therapies have been developed such as interferon (IFN)-γ, bone marrow transplantation and gene therapy. Chronic granulomatous disease can affect the colon in about a third of patients [11, 12] , and displays prominent macrophages and eosinophils. Granulomas, if present, are often poorly-formed. Macrophages are often pigmented [13]. Occasional cases of common variable immunodeficiency also show granuloma formation [14] but of course the hallmark is the absence of lamina propria plasma cells and apoptosis. Once the remainder of other granulomatous lesions are considered and excluded, sarcoidosis can rarely be diagnosed in the lower GI tract. References Lee JH, Slifman NR, Gershon SK, et al. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis Rheum. 2002;46(10):2565-70. Wood KL, Hage CA, Knox KS, et al. Histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy. Am J Respir Crit Care Med. 2003;167(9):1279-82. Cano MV, Hajjeh RA. The epidemiology of histoplasmosis: a review. Semin Respir Infect. 2001;16(2):109-18. Allendoerfer R, Deepe GS, Jr. Blockade of endogenous TNF-alpha exacerbates primary and secondary pulmonary histoplasmosis by differential mechanisms. J Immunol. 1998;160(12):6072-82. Zhang Z, Correa H, Begue RE. Tuberculosis and treatment with infliximab. N Engl J Med . 2002;346(8):623-6. De Rosa FG, Shaz D, Campagna AC, Dellaripa PE, Khettry U, Craven DE. Invasive pulmonary aspergillosis soon after therapy with infliximab, a tumor necrosis factor-alpha-neutralizing antibody: a possible healthcare-associated case? Infect Control Hosp Epidemiol. 2003;24(7):477-82. Colombel JF, Loftus EV, Jr., Tremaine WJ, et al. The safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 500 patients. Gastroenterology. 2004;126(1):19-31. Lamps LW, Molina CP, West AB, Haggitt RC, Scott MA. The pathologic spectrum of gastrointestinal and hepatic histoplasmosis. Am J Clin Pathol. 2000;113(1):64-72. Lamps LW, Madhusudhan KT, Greenson JK, et al. The role of Yersinia enterocolitica and Yersinia pseudotuberculosis in granulomatous appendicitis: a histologic and molecular study. Am J Surg Pathol. 2001;25(4):508-15. Lamps LW, Madhusudhan KT, Havens JM, et al. Pathogenic Yersinia DNA is detected in bowel and mesenteric lymph nodes from patients with Crohn's disease. Am J Surg Pathol. 2003;27(2):220-7. Marciano BE, Rosenzweig SD, Kleiner DE, et al. Gastrointestinal involvement in chronic granulomatous disease. Pediatrics. 2004;114(2):462-8. Schappi MG, Klein NJ, Lindley KJ, et al. The nature of colitis in chronic granulomatous disease. J Pediatr Gastroenterol Nutr. 2003;36(5):623-31. Levine S, Smith VV, Malone M, Sebire NJ. Histopathological features of chronic granulomatous disease (CGD) in childhood. Histopathology. 2005;47(5):508-16. Washington K, Stenzel TT, Buckley RH, Gottfried MR. Gastrointestinal pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia. Am J Surg Pathol. 1996;20(10):1240-52.