Long-term Risk of Parkinson Disease Following Influenza and Other Infections

Abstract

Importance: Influenza has been associated with the risk of developing Parkinson disease, but the association is controversial.

Objective: To examine whether prior influenza and other infections are associated with Parkinson disease more than 10 years after infection.

Design, setting, and participants: This case-control study used data from 1977 to 2016 from the Danish National Patient Registry. All individuals with Parkinson disease, excluding those with drug-induced parkinsonism, were included and matched to 5 population controls on sex, age, and date of Parkinson diagnosis. Data were analyzed from December 2019 to September 2021.

Exposures: Infections were ascertained between 1977 and 2016 and categorized by time from infection to Parkinson disease diagnosis. To increase specificity of influenza diagnoses, influenza exposure was restricted to months of peak influenza activity.

Main outcomes and measures: Parkinson disease diagnoses were identified between January 1, 2000, and December 31, 2016. Crude and adjusted odds ratios (ORs) and 95% CIs were calculated by conditional logistic regression overall and stratified by time between infection and Parkinson disease (5 years or less, more than 5 to 10 years, more than 10 years).

Results: Of 61 626 included individuals, 23 826 (38.7%) were female, and 53 202 (86.3%) were older than 60 years. A total of 10 271 individuals with Parkinson disease and 51 355 controls were identified. Influenza diagnosed at any time during a calendar year was associated with Parkinson disease more than 10 years later (OR, 1.73; 95% CI, 1.11-2.71). When influenza exposure was restricted to months of highest influenza activity, an elevated OR with a wider confidence interval was found (OR, 1.52; 95% CI, 0.80-2.89). There was no evidence of an association with any type of infection more than 10 years prior to Parkinson disease (OR, 1.04; 95% CI, 0.98-1.10). Several specific infections yielded increased odds of Parkinson disease within 5 years of infection, but results were null when exposure occurred more than 10 years prior.

Conclusions and relevance: In this case-control study, influenza was associated with diagnoses of Parkinson disease more than 10 years after infection. These observational data suggest a link between influenza and Parkinson disease but do not demonstrate causality. While other infections were associated with Parkinson disease diagnoses soon after infection, null associations after more than 10 years suggest these shorter-term associations are not causal.

Figure 1.. Counts of Influenza-Related Diagnoses in the Danish National Patient Registry by Year, 1977 to 2016

Counts of influenza-specific diagnosis codes from 1977 to 2016. Each bar represents a month. Orange indicates months of increased influenza activity, and blue indicates months when influenza activity was not increased. Diagnosis codes can be found in eAppendix 2 in the Supplement.

Figure 2.. Odds Ratios of the Association of Influenza With Parkinson Disease by Time Since Infection Among Individuals With Parkinson Disease Identified in Denmark, January 2000 to December 2016

Odds ratios and 95% CIs for the primary analysis and sensitivity analyses for influenza. A, For the primary analysis, we identified prior influenza at any time during a calendar year. B, For the sensitivity analysis, we identified prior influenza only during peaks of influenza activity.