Opportunistic Fungal Infection Risk and Mortality in Non-HIV, Non-Transplant U.S. Adults Receiving Systemic Glucocorticoids: An Observational Cohort Study

The dose-dependent risk of opportunistic fungal infections and associated mortality from systemic glucocorticoids remains poorly defined in non-HIV, non-transplant (NHNT) populations. This study evaluated the cumulative incidence of opportunistic fungal infections and the association between glucocorticoid dose, infection risk, and one-year mortality in NHNT adults. In this observational cohort study (NCT05707156), adults without HIV or solid organ transplant who received systemic glucocorticoids for ≥14 days between 2022 and 2024 were identified using the TriNetX research network. Glucocorticoid doses, standardized to prednisone equivalents (PEQ), were categorized as ≤10mg/day, 11–20mg/day, and >20mg/day based on clinically relevant thresholds from prior literature. Cumulative duration beyond the initial ≥14 days was unavailable. Multivariable logistic regression identified predictors of opportunistic fungal infections. Cox proportional hazards and Kaplan–Meier analyses evaluated associations between glucocorticoid dose and one-year all-cause mortality. Among 7,839 eligible patients, 6% developed opportunistic fungal infections, predominantly histoplasmosis (96%). Compared with ≤10 mg/day, neither 11–20 mg PEQ/day (OR 0.85, 95% CI 0.18–3.91) nor >20 mg/day (OR 0.89, 95% CI 0.24–3.33) was independently associated with infection risk. Crude one-year mortality was higher in the >20 mg group (1.1%) versus ≤10 mg (0.5%) and 11–20 mg (0.4%) groups (p=0.002), but glucocorticoid dose was not independently associated with mortality after adjustment. Increased mortality was associated with older age (HR 1.03/year), female sex (HR 1.96), and higher Charlson Comorbidity Index (HR 1.17 per point). Higher glucocorticoid doses did not independently predict opportunistic fungal infection risk or mortality, illustrating the limitations of dose-based risk stratification.