Histoplasma capsulatum is a dimorphic fungus and the most common endemic fungal infection within the United States. It resides in bird and bat droppings, making inhalation risk highest during activities such as cave exploration, farm work, or excavation. Once inhaled, the spores are ingested by macrophages and transform into yeast. As cell-mediated immunity is developing, macrophages disseminate the organism through the reticuloendothelial system. After 10 to 14 days, T cells activate macrophages to kill the organism. Likelihood of symptomatic or severe disease increases in patients with poor cellular immunity, such as infants, those with AIDS, and patients taking immunosuppressive medications, such as the patient in this case.2 In fact, TNF-alpha inhibitors such as infliximab have been shown to decrease IFN-gamma, which is critical for Th1 response to Histoplasma capsulatum. After numerous case reports of severe fungal infections in those taking infliximab or etanercept, some of which resulted in death, the FDA has issued a black box warning on TNF-alpha inhibitors for risk of endemic fungal infections.3

Histoplasma infection is common, with 80% of young adults living in the Ohio and Mississippi river valleys having been infected at some point during their lives. However, over 99% of people are asymptomatic.2 For those patients who are symptomatic, there is a wide range of organ involvement and severity. The most common manifestation is pulmonary infection presenting as acute pneumonia, with patchy or nodular involvement and enlarged hilar and mediastinal lymph nodes. Pulmonary infection can also result in severe illness, such as acute respiratory distress syndrome, or can be a chronic illness, occurring in patients with preexisting pulmonary diseases such as COPD.2 Histologically, most cases show typical necrotizing granulomatous inflammation. In acute pulmonary disease, parenchymal and vascular necrosis with lymphohistiocytic vasculitis may be present, resembling lymphomatoid granulomatosis.4

Although pulmonary disease is the most well-known presentation of Histoplasma capsulatum infection, it can also cause disseminated disease. In these cases, gastrointestinal involvement is common, with mucosal ulceration seen in almost half of patients. In the absence of a gross lesion, histoplasmosis is identified microscopically in nearly a quarter of patients. Similarly, with liver involvement, discrete nodules are not often found, and less than half of patients have grossly visible liver enlargement. Microscopically, lymphohistiocytic inflammation is a more frequent finding than distinct granulomas.5

Urine antigen testing is a common component of histoplasmosis diagnosis. Interestingly, the patient in this case had a false negative urine antigen test, although PCR results performed on the tissue later returned positive for Histoplasma. The original urine antigen test developed by MiraVista diagnostics has a 95% sensitivity in immunocompromised patients with disseminated histoplasmosis.6 However, this test is not commercially available. Commercially available tests have an overall lower sensitivity, ranging from 62% to 92%.7,8 One study has shown that ultrafiltration of specimens can result in a positive urine antigen test for 73.8% of falsely negative specimens, meaning it may be an option for improving the sensitivity of this test.9 Volume status of the patient may be an additional consideration, as one study has suggested that urine antigen levels vary significantly based on urine concentration.10 Other diagnostic tests include culture, which is the gold standard but has lower sensitivity, antibody testing, which is less useful in acute histoplasmosis, and serum antigen, which is less sensitive than urine antigen.2

Treatment for severe disseminated histoplasmosis includes amphotericin B for one to two weeks followed by oral itraconazole for 12 months. Itraconazole and Histoplasma antigen levels should be measured during treatment. Patients may need lifelong suppressive therapy if they are chronically immunocompromised.11 In the case presented, the patient was started on amphotericin B prior to the return of a positive PCR based on histopathologic and clinical features suspicious for histoplasmosis.