Clinical significance of different Histoplasma genotypes in human histoplasmosis: insights from a multicenter study from Québec comparing North American (NAm2) with Latin American (LAmA) isolates

Histoplasmosis is recognized as endemic in Québec; however, no molecular epidemiological studies have been conducted to date. The clinical significance of identifying Histoplasma capsulatum genotypes remains unclear. We performed a retrospective multicenter study of 67 culture-confirmed histoplasmosis cases from four major academic hospitals in Québec between 1988 and 2014. Multi-locus sequence typing (MLST) was performed on isolates, and clinical data were analyzed for genotype-specific associations with demographics, clinical presentations, and outcomes. Most isolates belonged to either the North American clade 2 (48.1%) or Latin American clade A (39.2%), highlighting both endemic and imported disease patterns in Québec. A novel NAm2 sequence type (ST81) was identified, which was unique to Québec and accounted for 61% of the NAm2 isolates, but was not associated with significantly different clinical outcomes compared with other NAm2 strains. In multivariate analysis, disseminated disease was independently associated with immunosuppression (OR 14.18, P = 0.001), male sex (OR 6.01, P = 0.035), and LAmA genotype (OR 5.02, P = 0.031). Severe outcomes (intensive care unit admission, intubation, death, or amphotericin B use) were associated with immunosuppression (OR 4.48, P = 0.023), with a non-significant trend with LAmA infections (OR 3.06, P = 0.069). This first molecular characterization of histoplasmosis infections in Québec suggests a dual epidemiology, with locally acquired NAm2 and LAmA infections more often associated with travel or origin from endemic regions outside Québec. Host factors were associated with disease severity, while the potential contribution of fungal genotype requires further study. These findings highlight the value of molecular characterization for understanding the epidemiology of histoplasmosis in endemic settings. IMPORTANCE Histoplasmosis is an important dimorphic fungal infection in North America. Although Québec is a recognized endemic region, its molecular epidemiology has not been previously characterized, and the clinical relevance of different Histoplasma genotypes remains uncertain. In this multicenter study, we performed multi-locus sequence typing with detailed clinical data from 67 culture-confirmed cases diagnosed between 1988 and 2014. This represents the first molecular characterization of clinical Histoplasma isolates from Québec and the largest Canadian cohort examining the association between molecular genotypes, clinical presentation, and outcomes. We identified both North American NAm2 ( Histoplasma ohiense ) and imported Latin American LAmA ( Histoplasma suramericanum ) lineages, suggestive of a combination of locally acquired and travel-associated infections. We also identified a novel NAm2 sequence type (ST81) that appears unique to Québec, suggesting possible regional circulation. The LAmA genotype was associated with disseminated histoplasmosis, whereas immunosuppression was the principal predictor of severe outcomes. Overall, host factors were associated with disease severity, while the potential contribution of fungal genotype warrants further study. These findings highlight the value of molecular characterization for understanding the epidemiology of histoplasmosis in endemic settings.