Diagnosis of histoplasmosis: current status and perspectives

Histoplasmosis is a worldwide-distributed systemic mycosis caused by the dimorphic fungus Histoplasma capsulatum. Its clinical manifestations range from subclinical or mild respiratory illness to progressive disseminated histoplasmosis (PDH), a life-threatening disease, whose accurate diagnosis is still challenging and limited in many countries, where this disease is highly endemic. In this regard, Histoplasma antigen testing is now included in the WHO Essential Diagnostics List. The final diagnosis of histoplasmosis is established by culture and/or visualization of the yeast cells by cytology or histopathology using specific stains. However, both procedures have limited sensitivity to detect the disease and cultures are time-consuming. Antibody detection assays are effective for the subacute and chronic clinical forms of histoplasmosis. However, their sensitivity is low in the immunocompromised host. Several molecular "in-house" tests were also developed and showed promising results, but none of these tests are commercially available and their standardization and validation are still pending. Antigen detection assays have high sensitivity in PDH cases and are of great value for the follow-up of patients with histoplasmosis; however, cross-reactivity with other related fungi are common. In addition, this assay is expensive and only performed in few laboratories. Novel protein antigen candidates have been recently identified and produced by DNA-recombinant techniques in order to obtain standardized and specific reagents for the diagnosis of histoplasmosis, as opposed to the unspecific antigens or crude extracts currently used. This review describes the currently available assays, highlighting their strengths and limitations and reports the latest approaches to achieve reliable and rapid diagnostic tests for histoplasmosis. KEY POINTS: • PDH causes thousands of deaths per year globally. • Rapid accurate diagnosis of PDH is unfeasible in many regions. • Fast, accurate, and low-cost diagnostic alternatives are currently under development.