Evidence of bias in estimates of influenza vaccine effectiveness in seniors

Background Numerous observational studies have reported that seniors who receive influenza vaccine are at substantially lower risk of death and hospitalization during the influenza season than unvaccinated seniors. These estimates could be influenced by differences in underlying health status between the vaccinated and unvaccinated groups. Since a protective effect of vaccination should be specific to influenza season, evaluation of non-influenza periods could indicate the possible contribution of bias to the estimates observed during influenza season. Methods We evaluated a cohort of 72 527 persons 65 years of age and older followed during an 8 year period and assessed the risk of death from any cause, or hospitalization for pneumonia or influenza, in relation to influenza vaccination, in periods before, during, and after influenza seasons. Secondary models adjusted for covariates defined primarily by diagnosis codes assigned to medical encounters. Results The relative risk of death for vaccinated persons compared with unvaccinated persons was 0.39 [95% confidence interval (95% CI), 0.33-0.47] before influenza season, 0.56 (0.52-0.61) during influenza season, and 0.74 (0.67-0.80) after influenza season. The relative risk of pneumonia hospitalization was 0.72 (0.59-0.89) before, 0.82 (0.75-0.89) during, and 0.95 (0.85-1.07) after influenza season. Adjustment for diagnosis code variables resulted in estimates that were further from the null, in all time periods. Conclusions The reductions in risk before influenza season indicate preferential receipt of vaccine by relatively healthy seniors. Adjustment for diagnosis code variables did not control for this bias. In this study, the magnitude of the bias demonstrated by the associations before the influenza season was sufficient to account entirely for the associations observed during influenza season.