Hospital-Treated Infectious Diseases, Infection Burden, and Risk of Lung Cancer: An Observational and Mendelian Randomization Study.

ABSTRACT

BACKGROUND: Although infections play a role in the development of lung cancer, the longitudinal association between infection and the risk of lung cancer is disputed, and data relating to pathogen types and infection sites are sparse. RESEARCH QUESTION How do infections affect subsequent lung cancer risk, and is the impact limited to specific microbes rather than infection burden? STUDY DESIGN AND METHODS: Data on > 900 infectious diseases were gathered from the UK Biobank study. Short- and long-term effects of infections were assessed by using time-varying Cox proportional hazards models. The analysis was repeated, excluding patients with concurrent multi-pathogen infections or outcomes within the 10 years following the initial hospitalization for the index infection. A life table approach was used to estimate years of life lost from lung cancer. Infection burden was defined as the sum of the number of infection episodes over time and co-occurring infections. The genome-wide association studies used in two-sample Mendelian randomization were obtained from mostly European ancestry. RESULTS: Hospital-treated infectious disease was associated with a greater risk of lung cancer (adjusted hazard ratio [aHR], 1.79; 95% CI, 1.74-1.83). aHRs for lung cancer ranged from 1.39 to 2.82 across pathogen types. The impact of lower respiratory tract infections (LRTIs) on lung cancer was the strongest, with an aHR of 3.22 (95% CI, 2.64-3.92); the aHR for extra-LRTIs was 1.29 (95% CI, 1.16-1.44). A dose-response association was observed between infection burden and lung cancer risk across different FEV1 percent predicted (Ptrend < .001). Multiple infections led to significant life lost from lung cancer at the age of 50 years. Mendelian randomization analysis reaffirmed the causal association. INTERPRETATION: Both observational and genetic analyses suggest that infectious diseases could increase the risk of lung cancer. The dual perspective on the LRTIs and extra-LRTIs impacts may inform lung cancer prevention strategies.