Discussion
influenza infection, infection, death
PRIMARY INFECTION, DISEASE, INFECTION, SECONDARY, EVENTS, INFLUENZA
In this secondary analysis of the INVESTED randomized clinical trial, ILI was temporally associated with CP and CV hospitalization but not with all-cause death in patients with high-risk CV disease. A higher dose of trivalent influenza vaccine compared with standard-dose quadrivalent influenza vaccine did not modify this association, even after restricting the analysis to months with typically higher influenza activity or weeks in which ILI activity was high. Warmer months in the US were associated with lower CV risk independent of local ILI activity.The primary end point of INVESTED was designed to capture CP events that occurred during the broad influenza season, but not necessarily during times of high influenza activity, because we hypothesized that if influenza infection led to CV and pulmonary events, the events might occur even several months after a primary infection. Nevertheless, we anticipated the possibility that modification of these events might be more temporally associated with influenza infection. This prespecified analysis was designed to assess whether high-dose influenza vaccine would provide greater benefit than standard-dose vaccine during times of high influenza activity. That we did not observe a benefit in this analysis suggests that in a high-risk population, the higher dose of vaccine was not associated with modification of events that were extremely likely. However, the benefit of any influenza vaccine compared with placebo in this population cannot be determined from this analysis. Based on other data comparing vaccination with placebo, it is likely that influenza vaccination with either dose would have more substantial benefits over placebo in patients with high risk.In patients with high-risk CV disease, ILI activity was temporally associated with CP and CV hospitalizations. Although a similar OR for pulmonary-related hospitalizations was present, there was no association with increased ILI activity, which may in part be attributed to the small number of events (n = 183) and underscores the relatively higher occurrence of CV (n = 1141) compared with pulmonary events in this sample. Furthermore, individual-level ILI or infection was not assessed in this sample, so the true incidence of influenza is not known. Nevertheless, the temporal association with CV events supported prior findings of emergency department visits in New York City of the association of ILI with CV mortality and in observational data in an older cohort of the association of ILI with MI and HF events.Although all participants received influenza vaccine, the temporal association between ILI activity and CV events remained. Additional analysis demonstrated that warmer months were associated with lower risk of CV events after accounting for ILI activity and vaccine dose, suggesting that other seasonal factors may also play a role in the seasonal variation in CV events. Vaccine effectiveness was not associated with a modification in the seasonality of ILI and CV events in another analysis of New York state data.