Case 2 -
Histoplasmosis Complicating Treatment with Anti-tumor Necrosis Factor-α
Elizabeth A. Montgomery
Johns Hopkins Hospital
Click on each slide thumbnail image for an enlarged view
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.
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
. Unfortunately the patient died with widely
Histoplasmosis is the most prevalent endemic infection in the US and a common
opportunistic infection . 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 .
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
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 . 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  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
. Yersinia genetic
material has been detected from specimens from patients with Crohn's disease where it may better reflect
an accomplice than a perpetrator . 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
, and displays prominent macrophages and eosinophils.
Granulomas, if present, are often poorly-formed. Macrophages are often pigmented . Occasional cases
of common variable immunodeficiency also show granuloma formation  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.
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