Supplemental Methods Final PPI Fungal

A retrospective cohort study was conducted using the TriNetX Global Collaborative Network, a federated database comprising de-identified electronic health records from 142 healthcare organizations (HCOs). The database was queried on March 13, 2025, to identify patients diagnosed with gastroesophageal reflux disease (GERD). Patients were stratified into two cohorts based on proton pump inhibitor (PPI) exposure. The GERD+PPI cohort included patients with a diagnosis of GERD (ICD-10: K21) who had ≥2 prescriptions for a PPI (omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, or rabeprazole) within 5 years prior to the index date. The GERD control cohort included GERD patients with no history of PPI use, defined as no recorded prescriptions for any listed PPIs at any time.
Patients were excluded in the risk analysis if they had a history of cutaneous fungal infections, including onychomycosis, tinea corporis, tinea pedis, tinea cruris, or cutaneous candidiasis. Additional exclusions included a history of systemic antifungal use (fluconazole, terbinafine, itraconazole) within 1 day prior to the index date or a history of immunodeficiency conditions, including HIV (ICD-10: B20), solid organ transplantation, or primary immunodeficiency disorders (ICD-10: D80-D84).
Cohorts were propensity score-matched (1:1) to minimize confounding, using variables including age, sex, race/ethnicity, diabetes, obesity, immunosuppression, and concurrent medication use. Standardized mean differences (SMDs) were used to assess balance between matched cohorts. The primary outcome was the incidence of cutaneous fungal infections following PPI use. Risk ratios (RR) with 95% confidence intervals (CIs) were calculated using logistic regression. A p-value <0.05 was considered statistically significant. All statistical analyses were conducted within the TriNetX platform.