Human papillomavirus infection and the risk of uveitis: a propensity-score-matched electronic health record study

Uveitis is a leading cause of preventable blindness in working-age adults. While herpesviruses are established causes, the potential contribution of human papillomavirus (HPV), a prevalent infection with immunomodulatory properties, remains unexplored. This study aims to investigate whether prior HPV infection is associated with an increased risk of developing uveitis using a large-scale, real-world dataset. In this multicenter, retrospective cohort study, adults aged ≥ 18 years from the TriNetX US Collaborative Network. A total of 460,932 HPV patients and 460,932 propensity score-matched controls without HPV were included after exclusions for malignancy, prior uveitis, or insufficient follow-up. HPV infection was identified by ICD-10-CM codes. Propensity score matching balanced demographics, comorbidities, socioeconomic and behavioral risk factors, and healthcare utilization. Patients were followed for up to 15 years for incident uveitis. Stratified analyses were conducted by age, sex, race, and comorbidities. Sensitivity analyses tested alternative HPV definitions, different washout periods, follow-up horizons, and matching approaches. Incident uveitis defined by ICD-10-CM codes, with hazard ratios (HRs) and 95% confidence intervals (CIs) estimated. HPV infection was associated with an elevated risk of uveitis (HR = 1.30; 95% CI: 1.19-1.42, p < 0.05). Risks persisted across sensitivity analyses, with HRs ranging from 1.23 (95% CI: 1.04-1.47) to 1.46 (95% CI: 1.34-1.59). Subtype analyses showed significant associations with iridocyclitis (HR = 1.27; 95% CI: 1.16-1.39) and unspecified chorioretinal inflammation (HR = 1.49; 95% CI: 1.06-2.09). Stratified analyses demonstrated higher risks among patients aged ≥ 65 years (HR = 1.44; 95% CI: 1.13-1.83), males (HR = 1.63; 95% CI: 1.40-1.89). In patients having both HPV and herpes zoster infection, risk of uveitis was 2.98-fold higher than controls (95% CI, 1.66-5.35). Prior HPV infection was associated with subsequent uveitis-related diagnoses in this large observational study. However, given the reliance on administrative coding, potential diagnostic heterogeneity, and residual confounding, these findings should be interpreted cautiously. Further prospective studies with clinically validated uveitis phenotypes are needed to clarify the nature and clinical relevance of this association.