Histoplasma capsulatum is a thermally dimorphic fungus that grows as a mold in soil enriched with bat or bird guano and converts to a yeast form at human body temperature. People acquire infection by inhaling microconidia—tiny airborne spores—released when contaminated soil is disturbed, whether in caves, poultry farms, or construction sites. In most immunologically healthy people, inhaled spores are contained by the lungs’ innate defenses and produce either no symptoms or a self-limited pulmonary illness. The fungus is endemic to the Mississippi and Ohio River valleys of North America, with additional foci across Central and South America, parts of Africa, and regions of Asia including the Indian subcontinent. In a subset of patients, however, the infection escapes pulmonary containment and spreads throughout the body as progressive disseminated histoplasmosis, a condition classically seen in people with defective cellular immunity such as those with HIV/AIDS, transplant recipients on immunosuppressive drugs, or patients receiving biologic agents.

That is precisely why this case is so unsettling. The young man had no history of corticosteroid use, diabetes, substance abuse, or high-risk sexual behavior. He denied fever, night sweats, and cough. When HIV serology came back negative, and when his morning cortisol and adrenocorticotropic hormone levels proved normal—ruling out the adrenal insufficiency that clinicians had considered given his persistent hyponatremia—he was, by all standard measures, immunocompetent. Disseminated histoplasmosis in such individuals is recognized but rare, generally attributed to overwhelming inoculum exposure or subtle, often undocumented, defects in innate immune signaling. The one telling detail in his history was a recent exploration of caves in hilly terrain. Bat guano accumulated in cave environments serves as the primary ecological niche for the fungus’s mycelial growth, and heavy exposure to cave aerosols can flood the lungs with organisms in quantities sufficient to overwhelm even intact immune defenses, seeding systemic dissemination.

The diagnostic odyssey began long before his hospital admission. An outside colonoscopy had already suggested either intestinal tuberculosis or inflammatory bowel disease, and given the region’s high tuberculosis burden and a strong family history of TB, his physicians had reasonably started empirical four-drug anti-tubercular therapy. He complied fully for 60 days and improved not at all. On admission, he was cachectic, pale, and profoundly ill, with bilateral digital clubbing, pitting pedal edema, a solitary ulcer on the hard palate, and firm, non-tender cervical lymph nodes. Laboratory work revealed microcytic hypochromic anemia with hemoglobin of 8.6 grams per deciliter, a C-reactive protein of 143.35 milligrams per liter, albumin of just 2 grams per deciliter, and serum sodium of 127 millimoles per liter. A chest radiograph showed mild bilateral pleural effusions.

Imaging then painted a deceptively clear picture. Magnetic resonance enterography demonstrated multi-segmental bowel wall thickening involving the distal jejunum and ileum without stricture formation, along with small reactive-appearing mesenteric lymph nodes, and the radiological impression favored Crohn’s disease. Fecal calprotectin—a protein released from neutrophils in inflamed intestinal mucosa—was markedly elevated at 1849.47 micrograms per gram, a level widely associated with active inflammatory bowel disease. Stool microscopy showed 8 to 12 pus cells per high-power field with mucus. Everything pointed toward a chronic inflammatory process of the gut. Yet as the case authors emphasize, fecal calprotectin is a marker of mucosal neutrophilic infiltration, not of any specific disease. It can be substantially elevated in infectious enteritis, including histoplasmosis, salmonellosis, and intestinal tuberculosis, and its dramatic rise should prompt a search for etiology rather than a reflexive diagnosis of IBD.

Endoscopic findings reinforced the mimicry. Upper endoscopy revealed a small benign-appearing duodenal ulcer, while colonoscopy demonstrated an ulcero-nodular lesion in the caecum studded with pseudopolyps distributed across the ascending, transverse, and descending colon. A repeat colonoscopy days later confirmed ulcero-nodular lesions with skip-pattern involvement of the distal ileum, ileocecal valve, and caecum—an appearance that overlaps almost perfectly with the colonoscopic spectrum of tuberculosis and Crohn’s disease. The ileocecal region is preferentially affected in all of these conditions, partly because the high density of Peyer’s patches in the terminal ileum facilitates reticuloendothelial seeding by pathogens, whether mycobacteria or fungi. GeneXpert MTB/RIF testing of tissue was negative for Mycobacterium tuberculosis, and a QuantiFERON-TB Gold Plus assay was non-reactive, a combination that carries a high negative predictive value for active mycobacterial disease.

The first biopsies were inconclusive, yielding only granulation tissue with acute and chronic inflammatory infiltration—no definitive granulomas, no malignancy, and no organisms. This pattern is well documented in gastrointestinal histoplasmosis, where superficial sampling frequently misses the intracellular yeasts lurking within lamina propria histiocytes. The breakthrough came from two directions. A repeat deep biopsy targeting the caecum and ileocecal valve revealed dense inflammatory infiltration rich in eosinophils and, crucially, multiple encapsulated, uniform, small oval yeast forms exhibiting narrow-based budding and eccentric nuclei, both within and outside histiocytes—morphological features diagnostic of Histoplasma capsulatum. The following day, fine-needle aspiration cytology of a cervical lymph node showed granulomatous inflammation teeming with intracellular and extracellular Histoplasma organisms, confirming that the infection was disseminated. Periodic acid-Schiff and Gomori methenamine silver stains are widely advocated to enhance fungal detection in tissue sections, particularly when organism burden is low, and the case authors argue that clinicians should maintain a low threshold for requesting such stains in unresolved ileocecal pathology, especially after anti-tubercular therapy fails.

Treatment began immediately. Oral itraconazole at 200 milligrams twice daily was started on the day of diagnosis, and systemic therapy was escalated to liposomal amphotericin B at 3 milligrams per kilogram per day the following day. It was too late. After just two doses of amphotericin, the patient suffered a massive lower gastrointestinal hemorrhage with acute hemodynamic collapse—his blood pressure became unrecordable and his oxygen saturation fell to 85 percent on 15 liters per minute of supplemental oxygen. Despite transfusion, intravenous fluid resuscitation, and vasopressor support, he was transferred to the intensive care unit and died roughly six hours later of refractory cardiorespiratory failure. Extensive mucosal ulceration, vascular erosion by the fungal inflammatory process, and consumptive coagulopathy from disseminated infection all predispose to this most feared complication, and antifungal therapy initiated a mere 72 hours earlier could not reverse tissue destruction that had already progressed past the threshold of reversibility.

The broader lessons are sobering. Published mortality rates for disseminated gastrointestinal histoplasmosis range from 20 to 50 percent, rising substantially when diagnosis is delayed beyond four weeks; this patient’s diagnosis lagged more than three months after symptom onset. In high-tuberculosis-burden settings, anchoring bias favors mycobacterial explanations for ileocecal pathology, weight loss, and lymphadenopathy, and failure of empirical anti-tubercular therapy is often the first signal that a different diagnosis deserves consideration. Equally hazardous is the temptation to treat a compelling Crohn’s-like phenotype—bowel wall thickening on enterography, skip lesions, pseudopolyps, and sky-high fecal calprotectin—with immunosuppressive therapy before infection has been histopathologically excluded, a step that could accelerate fungal dissemination with catastrophic consequences. In this case, the decision to defer immunosuppression pending tissue confirmation likely bought valuable time. The authors note that fungal culture and urine or serum Histoplasma antigen testing, which might have accelerated diagnosis, were unavailable, and formal immunological evaluation for rare innate immune defects such as STAT3 or IL-12 pathway mutations was not feasible in the acute setting. Their conclusion is unambiguous: when anti-tubercular therapy fails in ileocecal disease, fungi belong on the differential, deep colonoscopic biopsies with fungal stains are essential and may need repeating, and no patient should receive empirical immunosuppression for presumed inflammatory bowel disease until infection has been ruled out under the microscope.

Subject of Research: Disseminated gastrointestinal histoplasmosis mimicking intestinal tuberculosis and Crohn's disease in an immunocompetent host

Article Title: Gastrointestinal Histoplasmosis Mimicking Intestinal Tuberculosis and Crohn's Disease: Ileocecal Involvement in an Immunocompetent Host

Article References: Sazal, R. S., Esha, S. S., Faisal, A. A., Azad, M. A. K., Murshed, K. M., & Aftab, K. A. (2026). Gastrointestinal Histoplasmosis Mimicking Intestinal Tuberculosis and Crohn's Disease: Ileocecal Involvement in an Immunocompetent Host. Clinical Case Reports, 14(9), Article e73555. https://doi.org/10.1002/ccr3.73555

Image Credits: AI Generated

DOI: 10.1002/ccr3.73555

Keywords: histoplasmosis, Histoplasma capsulatum, gastrointestinal histoplasmosis, intestinal tuberculosis, Crohn's disease, ileocecal disease, fecal calprotectin, immunocompetent host, liposomal amphotericin B, diagnostic delay, colonoscopy biopsy, fungal infection