Clinical, radiological and laboratory characteristics of central nervous system histoplasmosis: A systematic review of a severe disease

Background The knowledge of central nervous system (CNS) histoplasmosis is limited to case reports and series. Objectives Our objective was to synthesise clinical, radiological and laboratory characteristics of CNS histoplasmosis to improve our understanding of this rare disease. Methods We performed a systematic review using Pubmed/MEDLINE, Embase and LILACS databases accessed on March 2023 without publication date restrictions. Inclusion criteria comprised: (1) histopathological, microbiological, antigen or serological evidence of histoplasmosis; (2) CNS involvement based on cerebrospinal fluid pleocytosis or neuroimaging abnormalities. We classified the certainty of the diagnosis in proven (CNS microbiological and histopathological confirmation), probable (CNS serological and antigen confirmation) or possible (non‐CNS evidence of histoplasmosis). Metaproportion was used to provide a summary measure with 95% confidence intervals for the clinical, radiological and laboratory characteristics. Chi‐squared test was used to compare mortality between pairs of antifungal drugs. Results We included 108 studies with 298 patients. The median age was 31 years, predominantly male, and only 23% were immunocompromised (134/276, 95%CI: 3–71), mainly due to HIV infection. The most common CNS symptom was headache (130/236, 55%, 95%CI: 49–61), with a duration predominantly of weeks or months. Radiological presentation included histoplasmoma (79/185, 34%, 95%CI: 14–61), meningitis (29/185, 14%, 95%CI: 7–25), hydrocephalus (41/185, 37%, 95%CI: 7–83) and vasculitis (18/185, 6%, 95%CI: 1–22). There were 124 proven cases, 112 probable cases and 40 possible cases. The majority of patients presented positive results in CNS pathology (90%), serology (CSF: 72%; serum: 70%) or CSF antigen (74%). Mortality was high (28%, 56/198), but lower in patients who used liposomal amphotericin B and itraconazole. Relapse occurred in 13% (23/179), particularly in HIV patients, but less frequently in patients who used itraconazole. Conclusion Central nervous system histoplasmosis usually presents subacute‐to‐chronic symptoms in young adults. Neuroimaging patterns included not only focal lesions but also hydrocephalus, meningitis and vasculitis. Positive results were commonly found in CSF antigen and serology. Mortality was high, and treatment with liposomal amphotericin B followed by itraconazole may decrease mortality.