Incident Herpes Zoster and Risk of Dementia: A Population-Based Danish Cohort Study.

BACKGROUND AND OBJECTIVES: Herpes zoster is caused by reactivation of the neurotrophic varicella-zoster virus. Zoster may contribute to development of dementia through neuroinflammation, cerebral vasculopathy, or direct neural damage, but epidemiological evidence is limited. We used data from linked nationwide Danish registries to conduct a cohort study of the association between zoster and dementia during 1997 to 2017. As secondary aims, we examined if associations were more pronounced for zoster involving cranial nerves (mainly ophthalmic zoster) or the central nervous system and Alzheimer's disease as an outcome. METHODS: We included people aged ≥40 years with zoster and a general population comparison cohort matched 5:1 by sex and birth year. We identified zoster and dementia in the registries using prescription records in the community and hospital diagnoses. We used Cox regression to compute confounder-adjusted hazard ratios (HR) with 95% confidence intervals (CIs) for dementia associated with zoster during 0-1 year and 1-21 years of follow-up. We compared the cumulative incidence of dementia, inverse probability-weighted for confounders. RESULTS: The study included 247,305 people with zoster and 1,235,890 matched general population comparators (median age 64 years; 61% female). The HR of all-cause dementia was 0.98 (95% CI: 0.92-1.04) during the first year and 0.93 (95% CI: 0.90-0.95) thereafter in people with zoster versus matched comparators. Dementia was diagnosed in 9.7% of zoster patients and 10.3% of matched comparators by end of follow-up. We observed no increased long-term risk of dementia in subgroup analyses, except possibly in people with central nervous system infection (HR 1.94; 95% CI: 0.78-4.80). Analyses of Alzheimer's disease as a separate outcome showed similar results. DISCUSSION: Herpes zoster is not associated with increased risk of dementia, and contrary to expectation we found a small decrease in risk. The explanation for this finding is unclear, and systematic errors should be considered. Patients with central nervous system involvement had almost two-fold increased relative risk of dementia. The population attributable fraction of dementia due to this rare complication is estimated at 0.014%. Therefore, universal vaccination against varicella-zoster virus in the elderly is unlikely to reduce dementia risk.

Flecainide and risk of skin neoplasms: Results of a large nested case-control study in Spain and Denmark.

Background: A previous study in Denmark suggested an increased melanoma risk associated with the use of flecainide. Objective: To study the association between flecainide use and the risk of melanoma and non-melanoma skin cancer in Spain and Denmark. Methods: We conducted a multi-database case-control study in (database/study period) Spain (SIDIAP/2005-2017 and BIFAP/2007-2017) and Denmark (Danish registries/2001-2018). We included incident cases of melanoma or non-melanoma skin cancer (NMSC) aged ≥18 with ≥2 years of previous data (≥10 years for Denmark) before the skin cancer and matched them to controls (10:1 by age and sex). We excluded persons with immunosuppression or previous cancer. We defined ever-use as any prescription fill and high-use as a cumulative dose of at least 200 g (reference: never-use). We categorized a cumulative dose for a dose-response assessment. We used conditional logistic regression to compute ORs (95% CI) adjusted for photosensitizing, anti-neoplastic, disease-specific drugs and comorbidities. Results: The total numbers of melanoma/NMSC cases included were 7,809/64,230 in SIDIAP, 4,661/31,063 in BIFAP, and 27,978/152,821 in Denmark. In Denmark, high-use of flecainide was associated with increased adjusted ORs of skin cancer compared with never-use [melanoma: OR 1.97 (1.38-2.81); NMSC: OR 1.34 (1.15-1.56)]. In Spain, an association between high-use of flecainide and NMSC was also observed [BIFAP: OR 1.42 (1.04-1.93); SIDIAP: OR 1.19 (0.95-1.48)]. There was a non-significant dose-response pattern for melanoma in Denmark and no apparent dose-response pattern for NMSC in any of the three databases. We found similar results for ever-use of flecainide. Conclusion: Flecainide use was associated with an increased risk of melanoma (Denmark only) and NMSC (Denmark and Spain) but without substantial evidence of dose-response patterns. Further studies are needed to assess for possible unmeasured confounders.

Hydrochlorothiazide use and risk for Merkel cell carcinoma and malignant adnexal skin tumors: A nationwide case-control study.

BACKGROUND: Hydrochlorothiazide use has been associated with markedly increased risk for squamous cell carcinoma. No previous studies have investigated the association between hydrochlorothiazide use and the risk for Merkel cell carcinoma (MCC) and malignant adnexal skin tumors (MAST). OBJECTIVE: To examine the association between hydrochlorothiazide use and the risk for MCC and MAST. METHODS: Using Danish nationwide health registries, we identified all patients with incident MCC or MAST during 2004-2015 and matched the cases individually to cancer-free population controls by risk set sampling. Using conditional logistic regression, we estimated the odds ratios (ORs) and confidence intervals (CIs) associated with cumulative use of hydrochlorothiazide. RESULTS: The adjusted ORs for MCC and MAST associated with high use (≥50,000 mg) of hydrochlorothiazide was 2.3 (95% CI 1.1-4.8) and 3.6 (95% CI 1.9-7.0), respectively, which increased to 3.3 (95% CI 1.3-8.3) and 5.6 (95% CI 2.4-13.3), respectively, with highest use (≥100,000 mg). We found no increased risk for these tumors in analyses of drugs with similar indications as hydrochlorothiazide, except there was a tendency toward an increased risk for MCC associated with the use of furosemide (OR 1.9, 95% CI 0.9-4.0). LIMITATIONS: No data on sun exposure was available. CONCLUSION: Hydrochlorothiazide use is associated with an increased risk for MCC and MAST.

Human papillomavirus infection and lymphoma incidence using cervical conization as a surrogate marker: a Danish nationwide cohort study.

Persistent human papillomavirus (HPV) infection may promote carcinogenesis by hyperactivation of the immune system. We, therefore, explored the associations between HPV infection and risk of Hodgkin and non-Hodgkin lymphoma in a nationwide cohort study using conization as a surrogate marker. We identified all Danish women who underwent conization between 1978 and 2011. We computed standardized incidence ratios and 95% confidence intervals for Hodgkin and non-Hodgkin lymphoma based on national cancer incidence rates. Among 87 435 women who underwent conization, we noted an increased incidence of Hodgkin (standardized incidence ratio 1.48, 95% confidence interval 1.05-2.02) but only a slight increase for non-Hodgkin lymphoma (standardized incidence ratio 1.10, 95% confidence interval 0.97-1.25). As measured by conization, HPV infection is associated with an increased risk of lymphoma. This association may be attributable to a chronic immune activation induced by persistent HPV infection and/or failure of the immune system both to clear HPV infection and to control lymphoma development. Copyright © 2015 John Wiley & Sons, Ltd.