Histoplasmosis in Uganda: A fungal infection hidden behind tuberculosis, and a diagnostic pathway for a low-resource setting: A narrative review

Histoplasmosis is a fungal infection caused by the true pathogen Histoplasma capsulatum that closely resembles tuberculosis, can infect immunocompetent as well as immunocompromised people, and remains poorly characterised in Uganda. This narrative review, guided by SANRA, brings together the Ugandan evidence across ecology, epidemiology, clinical presentation, diagnosis and treatment, and identifies where the evidence is absent. Exposure has been documented in Uganda for more than five decades, from pre-HIV histoplasmin foci near the Nile and Lake Victoria to a documented outbreak among visitors to a Ugandan rainforest traced to a bat-infested tree, and to antigen-positive patients in recent Kampala cohorts. The most substantial national evidence, a prospective study of 332 persons with advanced HIV disease across nine facilities, found histoplasmosis in 2.4 percent, all probable cases, with relatively good survival among untreated patients but with five of eight cases entangled with current or prior tuberculosis. This review therefore does not claim a large hidden burden of disseminated disease in that population. It argues instead that the question has not been asked of the right patients with the right test. No Ugandan study has screened patients under investigation for tuberculosis, a population in which antigen prevalence elsewhere in Africa has reached 24 percent, and none has tested for chronic pulmonary histoplasmosis, the form most often misdiagnosed as tuberculosis, in the large Ugandan population with post-tuberculous lung damage, where chronic pulmonary aspergillosis is already established. Whether antigenuria in advanced HIV disease warrants antifungal therapy in the absence of symptoms remains contested. An unvalidated screening pathway is proposed, requiring prospective evaluation and set out as separate algorithms for people living with HIV and HIV-negative individuals, that reflexes antigen testing onto a urine specimen already collected, includes GeneXpert-positive patients because co-infection is common, offers Giemsa microscopy of skin and oronasal lesion smears and, where antigen assays are unavailable, of other specimens, reserves antibody testing for suspected chronic pulmonary disease, and treats symptomatic rather than incidental antigen positivity. Research priorities are set out against the ISHAM 2030 targets.