Malignancy Risk after Ophthalmic Herpes Infection within a Diverse United States Cohort

PURPOSE: We evaluated the risk of malignancy following herpes zoster ophthalmicus (HZO) and ophthalmic herpes simplex virus (HSV) in a large, diverse United States cohort. DESIGN: Matched, retrospective cohort study. PARTICIPANTS: Adults enrolled in the National Institutes of Health All of Us Research Program. METHODS: Participants with incident diagnoses of HZO or ophthalmic HSV were propensity score-matched (1:3) to controls based on sociodemographic characteristics and preexisting immune dysregulation (i.e., autoimmune disease or immunodeficient states). MAIN OUTCOME MEASURES: Stratified Cox proportional hazards models were applied to estimate relative hazards of incident malignancy within 1-, 2-, and 3-year intervals and over the entire follow-up period. Effect modification was investigated based on age, sex, and baseline immune dysregulation. RESULTS: The HZO cohort comprised 327 patients matched to 981 control participants (mean follow-up, 7.48 ± 5.33 years), and the ophthalmic HSV cohort included 292 patients matched to 876 control participants (mean follow-up, 8.66 ± 5.89 years). Incident malignancy risk did not differ between patients with HZO and matched control participants within 1 year or less (P = 1.00), 2 years or less (P = 0.36), 3 years or less (P = 0.27), or across the full follow-up period (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.76-1.36; P = 0.93). However, significant effect modification by immune dysregulation was observed, with HZO associated with an increased risk of malignancy among participants with autoimmune disease (HR, 2.91; 95% CI, 1.48-5.74; P < 0.01) or immunodeficient status (HR, 5.75; 95% CI, 2.16-15.35; P < 0.01). For ophthalmic HSV, no increased malignancy risk was observed within 1 year or less (P = 0.86), 2 years or less (P = 0.18), 3 years or less (P = 0.10), or across the full follow-up period (HR, 0.97; 95% CI, 0.72-1.32; P = 0.87), with no evidence of effect modification. CONCLUSIONS: Ophthalmic herpes infections were not associated with an increased risk of malignancy in the overall cohort. However, HZO was associated with a higher subsequent risk of cancer among individuals with preexisting immune dysregulation, potentially warranting heightened oncologic vigilance in this patient demographic. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.