HPV and uveitis: New research points to a potential connection

Human papillomavirus (HPV) is known for its oncogenic potential, but its immunomodulatory properties have raised the question of whether it may also contribute to intraocular inflammation. A multicenter, retrospective cohort study published in Scientific Reports by Chang and colleagues at Chung Shan Medical University Hospital and collaborating institutions examines whether prior HPV infection is associated with an increased risk of incident uveitis, using propensity score–matched real-world data from the TriNetX US Collaborative Network.¹

Study design and methods

The study included adults aged 18 years and older drawn from the TriNetX US Collaborative Network, which aggregates de-identified electronic health records from more than 70 US medical institutions covering approximately 130 million patients. HPV infection was identified by ICD-10-CM codes, with the index date defined as the initial recorded HPV diagnosis between January 1, 2005, and December 31, 2018. Controls were patients without any HPV diagnosis whose index date was a general health examination during the same period. Both cohorts excluded patients with prior uveitis, malignancy, death records, or fewer than 2 clinical encounters during follow-up.¹

Propensity score matching was performed 1:1 using nearest-neighbor methodology with a caliper of 0.1, balancing demographics, comorbidities, socioeconomic factors, lifestyle variables, and healthcare utilization. After matching, each cohort comprised 460,932 individuals. The primary end point was incident uveitis, defined by ICD-10-CM codes and identified from 3 months after the index date to minimize reverse causality. Patients were followed for up to 15 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated, and multiple sensitivity analyses were conducted varying the HPV definition, washout periods (12, 24, and 36 months), follow-up horizons (5, 10, and 15 years), and matching algorithms.¹

Results: Overall uveitis risk

In the matched cohort, the mean age at index was 27.6 years and 35.8% were male. HPV infection was associated with a significantly elevated risk of incident uveitis (HR, 1.30; 95% CI, 1.19–1.42; P < .05).¹ The association persisted across all sensitivity analyses, with HRs ranging from 1.23 (95% CI, 1.04–1.47) to 1.46 (95% CI, 1.34–1.59). At 5-year follow-up, the HR was 1.42 (95% CI, 1.26–1.62), declining modestly at 10 years (HR, 1.36; 95% CI, 1.24–1.50) and 15 years (HR, 1.30; 95% CI, 1.19–1.42), indicating sustained risk over time.¹

Uveitis subtype and stratified analyses

By uveitis subtype, statistically significant associations were observed for iridocyclitis (HR, 1.27; 95% CI, 1.16–1.39) and unspecified chorioretinal inflammation (HR, 1.49; 95% CI, 1.06–2.09). Posterior cyclitis, retinal vasculitis, and panuveitis showed elevated point estimates that did not reach statistical significance, attributed by the authors to smaller subgroup sample sizes.¹

Stratified analyses by age showed elevated risk in both those aged 18 to 64 years (HR, 1.38; 95% CI, 1.26–1.52) and those aged 65 years and older (HR, 1.44; 95% CI, 1.13–1.83). Sex-based stratification demonstrated a higher risk in males (HR, 1.63; 95% CI, 1.40–1.89) than in females (HR, 1.36; 95% CI, 1.22–1.52). By race, significant associations were observed in White (HR, 1.48; 95% CI, 1.31–1.67), Black (HR, 1.42; 95% CI, 1.20–1.68), and Hispanic (HR, 1.58; 95% CI, 1.22–2.04) patients; the association was not significant in Asian patients (HR, 0.97; 95% CI, 0.59–1.58), attributed to smaller sample size.¹

Comorbidity-based stratification revealed amplified risks in several subgroups. Among patients with vitamin D deficiency, the HR was 1.72 (95% CI, 1.39–2.12); among those with major depressive disorder, 1.76 (95% CI, 1.31–2.35). The most pronounced elevation was observed in patients with concurrent herpes zoster infection, with a nearly 3-fold higher risk compared with controls (HR, 2.98; 95% CI, 1.66–5.35).¹

Discussion and limitations

The authors propose several biologically plausible mechanisms by which HPV could contribute to ocular inflammation. HPV infection is known to activate the NF-κB pathway through oncoproteins E5, E6, and E7, increasing proinflammatory cytokines including TNF-α — cytokines that also play a role in noninfectious uveitis pathogenesis. Th17 responses and macrophage dysfunction are features shared by persistent HPV infection and immune-mediated uveitis, supporting the possibility that HPV may act as an associated factor in susceptible individuals, initiating or amplifying ocular autoimmune pathways.¹

The authors identify several limitations. HPV status was determined by ICD codes, which may underrepresent asymptomatic or transient infections. Uveitis was similarly defined by codes rather than clinical adjudication, and categories such as unspecified chorioretinal inflammation represent heterogeneous groupings that may include non-uveitis inflammatory or retinal conditions. The inability to distinguish infectious from noninfectious uveitis introduces further heterogeneity. Differential healthcare utilization between HPV-coded and control patients may have introduced detection bias, though healthcare utilization indicators were included in propensity score matching. Residual confounding by unmeasured variables including HLA-B27 status, immunosuppressant use, sexual behavior, and HPV vaccination status cannot be excluded. The study also could not distinguish between high- and low-risk HPV genotypes or assess the role of vaccination.¹

The authors conclude that prior HPV infection was associated with subsequent uveitis-related diagnoses in this large observational study, but emphasize that a causal relationship cannot be established and that findings should be interpreted cautiously given the diagnostic limitations of claims-based outcome ascertainment. They call for prospective studies incorporating clinically validated uveitis phenotypes to clarify the nature and clinical relevance of this association.¹

The authors declare no competing interests. This study was funded by Chung Shan Medical University Hospital (CSH-2025-C-007).

Reference

1. Chang HC, Tu YF, Sung CY, et al. Human papillomavirus infection and the risk of uveitis: a propensity-score-matched electronic health record study. Sci Rep. 2026;16(1):17135. Published 2026 Jun 3. doi:10.1038/s41598-026-51328-x