Annual estimates of the burden of seasonal influenza in the United States: A tool for strengthening influenza surveillance and preparedness

Background Estimates of influenza disease burden are broadly useful for public health, helping national and local authorities monitor epidemiologic trends, plan and allocate resources, and promote influenza vaccination. Historically, estimates of the burden of seasonal influenza in the United States, focused mainly on influenza‐related mortality and hospitalization, were generated every few years. Since the 2010‐2011 influenza season, annual US influenza burden estimates have been generated and expanded to include estimates of influenza‐related outpatient medical visits and symptomatic illness in the community. Methods We used routinely collected surveillance data, outbreak field investigations, and proportions of people seeking health care from survey results to estimate the number of illnesses, medical visits, hospitalizations, and deaths due to influenza during six influenza seasons (2010‐2011 through 2015‐2016). Results We estimate that the number of influenza‐related illnesses that have occurred during influenza season has ranged from 9.2 million to 35.6 million, including 140 000 to 710 000 influenza‐related hospitalizations. Discussion These annual efforts have strengthened public health communications products and supported timely assessment of the impact of vaccination through estimates of illness and hospitalizations averted. Additionally, annual estimates of influenza burden have highlighted areas where disease surveillance needs improvement to better support public health decision making for seasonal influenza epidemics as well as future pandemics.


| INTRODUCTION
Estimates of the burden of seasonal influenza are broadly useful for public health, helping national and local authorities monitor epidemiologic trends, plan and allocate resources, demonstrate the impact of vaccine programs as well as other public health and clinical interventions, and inform the public, clinicians, and policymakers about the importance of influenza and influenza prevention.
Estimates of the burden of seasonal influenza in the United States have evolved over time. First, estimates focused on the number of deaths due to influenza in the 1960s. 1 With better access to hospital records, estimates were expanded to include influenza-related hospitalizations. 2,3 During the 2009 H1N1 pandemic, there was a need to describe the burden of less severe outcomes, which further expanded the burden estimation to include outpatient medical visits and illness in the community. 4 Changes were also made to the methods used to generate estimate of influenza burden. Statistical models were initially used to estimate excess deaths and hospitalizations, those that occur above what is predicted based on historical trends. 1,5,6 During the 2009 H1N1 pandemic, there was a move toward using a multiplier that could extrapolate rates of hospitalization to rates of less severe disease.
Historically, new estimates of influenza-related mortality or hospitalization over multiple influenza seasons were published periodically, as new data became available. [5][6][7] However, a hallmark of influenza is its variability from one season to the next and periodic assessments of the burden of influenza fail to capture the full extent of seasonal variation. For this reason, the Centers for Disease Control and Prevention (CDC) has transitioned from providing periodic estimates to reporting annual estimates of influenza burden in the United States. Annual estimates of disease burden, in combination with annual assessments of influenza vaccine coverage and vaccine effectiveness in preventing disease, allow for timely evaluation of influenza prevention and control efforts.

| GENERATING ANNUAL ESTIMATES OF INFLUENZA BURDEN
Data from the 2010-2011 through 2015-2016 influenza seasons (October through April) have been used on an annual basis to estimate the burden of seasonal influenza and the disease burden averted by influenza vaccination in the United States. [8][9][10][11][12][13] The methods have previously been described in detail (Fig. S1). 7,9,[11][12][13][14] Briefly, rates of hospitalization with laboratory-confirmed influenza were obtained from the Influenza Hospitalization Surveillance Network (FluSurv-NET), a population-based surveillance conducted in 14 geographically distributed states. 15 Hospitalization rates were generated by age group (0-4, 5-17, 18-49, 50-64, and ≥65 years). Rates were adjusted for influenza testing practices and test sensitivity and then applied to the US population to obtain estimates of the number of influenza-associated hospitalizations that occurred each season.
Estimates of excess deaths related to influenza were based on a statistical model of the weekly number of deaths obtained from the National Center for Health Statistics. 16 The model accounts for seasonal trends in mortality and weekly circulation of influenza and respiratory syncytial virus, obtained from national virologic surveillance. 16,17 The model was fitted using Markov chain Monte Carlo methods, yielding "point estimates" (mean or median of the empirical posterior distribution) and "confidence intervals" (95% credible intervals) for the number of deaths attributable to influenza. Data on deaths with pneumonia or influenza listed as a cause of death were used in the statistical model because they are available in near real time. However, most influenza-related deaths are likely not due directly to influenza virus infection but may be due to secondary bacterial infection or worsening of underlying chronic health conditions, such as chronic heart or lung disease. Even when influenza likely contributed to the events leading to a death, it may not be recognized and is rarely listed on the death certificate. From prior analyses, the number of deaths associated with influenza may be two to four times higher than the number of deaths related to influenza that have pneumonia or influenza listed on the death certificate. 7,18 Deaths with any respiratory or circulatory causes listed on the death certificate are likely more inclusive of deaths related to influenza than deaths with pneumonia or influenza causes; therefore, additional statistical models were created using death from respiratory or circulatory causes. Data on respiratory and circulatory Estimates of the numbers of influenza-associated illnesses, outpatient medical visits, hospitalizations, and deaths prevented by influenza vaccination were derived from burden estimates, influenza vaccination coverage, and vaccine effectiveness, as previously described. 9 Briefly, estimates of monthly influenza vaccine coverage by age group

| ESTIMATED INFLUENZA-ASSOCIATED DISEASE BURDEN PREVENTED THROUGH INFLUENZA VACCINATION
Given the estimates of seasonal incidence of influenza, the associated burden of severe disease, and estimates of influenza vaccine effectiveness and coverage in the United States, we estimate that influenza vaccination has prevented between 1.6 million and 6.7 million illnesses, 790 000-3.1 million outpatient medical visits, 39 000-87 000 hospitalizations, and 3000-10 000 respiratory and circulatory deaths related to influenza each season ( Table 2).
Surveys in the US population suggest that overall vaccination coverage was 42%-47% over the past six influenza seasons, although coverage varies considerably by age. 22   In addition to being reported annually, CDC estimates of influenza disease burden were expanded to include outpatient medical visits and symptomatic community illness. Estimates focused on influenza-related mortality and hospitalizations reinforce the potentially serious nature of influenza, but are a small fraction of the total burden of influenza and can be biased, as they are highly influenced by patterns and policies for hospital admission, influenza testing, and reporting. 11 On the other hand, estimates of the number of symptomatic community illnesses, for which medical care is not sought but may still result in missed school or work, and outpatient medical visits due to influenza underscore the frequency of influenza illness and its widespread societal impact. We estimate that for every influenza-related hospitalization, between 11 and 365 more non-hospitalized cases occur in the community, depending on the age group. 4,8 Generating annual estimates of influenza burden helped CDC recognize gaps in influenza surveillance activities. For example, there were no means to directly estimate medically-attended and community illness during the 2009 pandemic. Instead, these portions of influenza burden were indirectly estimated using the rates of influenza-associated hospitalization and field-validated multipliers of healthcare utilization and case-to-hospitalization ratios from the 2009 H1N1 pandemic. In an effort to fill these gaps, there are now several ongoing efforts and collaborations to gather data that can directly estimate the burden of medically-attended illness related to influenza as well as symptomatic community illness on a routine basis. [25][26][27] Not only are these improvements to surveillance helpful during seasonal epidemics, but the creation and optimization of surveillance activities that are routine, robust, and near real time will be helpful when a pandemic occurs. 16,28 The methods and estimates of seasonal influenza burden are not