Influenza is a serious respiratory virus in terms of global morbidity and mortality. Patients hospitalized with influenza generally have comorbidities contributing to their disease severity and are most at risk for further severe influenza-related outcomes. Despite the importance of this group, there are few studies investigating interventions in populations of patients hospitalized due to influenza. Specifically, robust evaluation is needed of the two most used interventions against severe influenza, vaccination and neuraminidase inhibitors. The best available protection against influenza illness is vaccination, which is recommended annually in the United States and in many other countries worldwide. Treatment with neuraminidase inhibitors has been shown to prevent severe influenza outcomes and reduce symptomatic illness; antiviral treatment is recommended for all hospitalized patients with suspected or confirmed influenza in the United States. This dissertation examines two components of prevention of severe influenza: vaccine effectiveness against hospitalization, and the prevention of severity in individuals at high risk for severe influenza outcomes. Influenza vaccine effectiveness against hospitalization of Israeli children who are fully or partially vaccinated was determined through use of medical record data over three influenza seasons in chapter 2. Vaccination was found to be effective for fully, but not partially, vaccinated children over all three seasons. This result supports guidelines by the Advisory Committee on Immunization Practices in the United States and the Israeli Ministry of Health, which recommend two inoculations in the first season of vaccination for children under nine years of age.In chapter 3 we focused on the methodological validity of the test negative design in the inpatient setting. We tested specimens previously collected for vaccine effectiveness estimation against hospitalization in adults participating in the HAIVEN study for a variety of respiratory viruses. We calculated VE in three ways: using the traditional influenza-negative control group, using an influenza negative but other virus positive control group, and using a pan-negative control group, in order to evaluate whether inclusion of individuals without a true ARI in the influenza-negative control group biases VE estimates in the hospital. We did not find consistent differences in VE by control group, suggesting that this bias is not a persistent problem when estimating vaccine effectiveness against hospitalization. In the next two chapters, we focused on characterization of influenza severity and risk factors for severe influenza. In chapter 4 we studied adults hospitalized with influenza over two seasons. Using inverse probability weighted logistic and linear models, we found that rapid antiviral treatment was associated with reduced odds of lower pulmonary disease and that obese patients were treated more rapidly with antiviral medication than non-obese patients, making antiviral treatment timing a potential confounder of the relationship between obesity and severe influenza. In chapter 5, we evaluated predictors of ICU admission, 30-day readmission, and extended length of stay among hospitalized adults over two seasons of the HAIVEN study.Frailty and lack of prior year health care visits were associated with reduced influenza and acute respiratory infection severity. Through linear models stratified by vaccination status, we found that antiviral treatment was associated with reduced hospital length of stay in vaccinated, but not unvaccinated patients. Ongoing research to measure the underlying disease severity in these groups at presentation to the hospital will aid in further interpretation of this result.
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Acute Respiratory Infection Among Hospitalized Individuals: Prediction and Prevention of Severe Influenza
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