Gastrointestinal Histoplasmosis

Gastrointestinal histoplasmosis is infection of the gut by the dimorphic fungus Histoplasma capsulatum, usually as part of disseminated disease in immunocompromised patients. It causes ulcers, masses and obstruction, most often in the terminal ileum and colon.

Gastrointestinal involvement is found in 70% to 90% of patients with progressive disseminated histoplasmosis, but causes symptoms in only about 3% to 12%. It is endemic in the Ohio and Mississippi River valleys, Central and South America, Africa and parts of Asia. Risk groups are people with HIV (CD4 count under 150 cells/microlitre), transplant recipients and those on tumour necrosis factor inhibitors.

Pathophysiology.

Inhaled spores spread through macrophages to the reticuloendothelial system, including Peyer patches. Macrophage infiltration of the lamina propria causes ulceration, nodules, strictures and lymphadenopathy.

Fever, weight loss, night sweats, abdominal pain, diarrhoea, gastrointestinal bleeding, intestinal obstruction, perforation, hepatosplenomegaly, adrenal insufficiency, oral ulcers and skin lesions.

Red flags.

• Septic shock or multiorgan failure.
• Perforation or obstruction.
• Adrenal crisis.
• Central nervous system involvement.

Urine and serum Histoplasma antigen (the most sensitive test in disseminated disease), blood and bone marrow cultures, and biopsy of ulcers (Grocott methenamine silver and periodic acid-Schiff stains show small intracellular yeasts; culture and PCR). Colonoscopy shows ulcers, nodules or masses. CT shows hepatosplenomegaly, adrenal enlargement and nodes. Test for HIV and check cortisol. Antibody tests are less useful in immunosuppressed patients.

Differential diagnosis.

• Crohn disease.
• Intestinal tuberculosis.
• Lymphoma.
• Cytomegalovirus enteritis.
• Colorectal cancer.
• Other fungal infection (cryptococcosis, candidiasis).

Moderately severe to severe disseminated disease needs an induction phase of liposomal amphotericin B followed by itraconazole. Mild disease can be treated with itraconazole alone. Operate for perforation, obstruction or uncontrolled bleeding. Start antiretroviral treatment in HIV within 2 weeks of starting antifungal therapy.

• Liposomal amphotericin B: 3 mg/kg IV once daily for 1 to 2 weeks or until clinical improvement; maximum 5 mg/kg daily; monitor creatinine, potassium, magnesium and infusion reactions; adjust by extending the interval for renal impairment, and replace potassium and magnesium.
• Itraconazole: 200 mg orally three times daily for 3 days, then 200 mg twice daily for at least 12 months (and for life if immunosuppression cannot be reversed); maximum 400 mg daily after the loading phase; monitor serum levels (target over 1 microgram/mL at 2 weeks), liver tests and heart failure symptoms; avoid in heart failure and with proton pump inhibitors and other interacting drugs (take capsules with food and acid; use the solution fasting); reduce in hepatic impairment.
• Hydrocortisone (adrenal insufficiency): 15 to 25 mg orally daily in two to three divided doses, higher for adrenal crisis (100 mg IV then 50 mg IV every 6 hours); monitor blood pressure, sodium and potassium; adjust to symptoms and stop when adrenal function recovers.

Monitoring. Antigen levels every 3 months during treatment and for 12 months after; itraconazole levels, liver tests and clinical review every 1 to 3 months.

Referral and escalation. Infectious disease, gastroenterology and surgery for complications; endocrinology for adrenal disease.

Special groups. Pregnancy: liposomal amphotericin B is used and azoles are avoided. Children need weight based dosing (itraconazole 5 to 10 mg/kg daily in two divided doses).