Estimating the burden of seasonal influenza in Spain from surveillance of mild and severe influenza disease, 2010‐2016

Background Estimating the national burden of influenza disease is challenging. We aimed to estimate the disease burden of seasonal influenza in Spain, at the primary care and hospital level, over the 6 influenza seasons after 2009 pandemic. Methods We used data from the Spanish Influenza Sentinel Surveillance System to estimate weekly influenza rates and the number of influenza‐like illness (ILI) and mild confirmed influenza cases (MCIC). From the surveillance of severe hospitalized confirmed influenza cases (SHCIC), we obtained hospitalization rates and total number of SHCIC, intensive care unit (ICU) admissions and deaths in influenza hospitalized patients. We estimated both mild and severe influenza cases, overall, and by age‐group (<5, 5‐14, 15‐64, and ≥65 years). Results The highest cumulative rates of MCIC were observed in <15 years (1395‐3155 cases/100 000 population in 5‐14 years) and the lowest in ≥65 years (141‐608 cases/100 000 population). SHCIC rates revealed a characteristic U‐shaped distribution, with annual average hospitalization rates of 16.5 and 18.9 SHCIC/100, 000 p in 0‐4 years, and ≥65 years, respectively. We estimated an annual average of 866 868 cases of ILI attended in primary care (55% were MCIC), 3616 SHCIC, 1232 ICU admissions, and 437 deaths in SHCIC. The percentage of ICU admission among SHCIC was highest at 15‐64 years (42%), while the hospitalization fatality rate ranged from 1% in 0‐4 years to 18% in ≥65 years. Conclusions The ongoing Spanish Influenza Surveillance System allowed obtaining crucial information regarding the impact of mild and severe influenza in Spain.


| INTRODUCTION
Seasonal influenza is an acute respiratory infection caused by worldwide circulating influenza viruses. The spectrum of disease severity ranges from mild forms of disease to those with severe complications, including death. The main aim of influenza immunization programs is the reduction of hospitalization and death occurring mainly among high-risk individuals. However, the burden of mild outpatient illness is also important because it accounts for a large proportion of absenteeism in both healthy adults and children. 1 *See Appendix for Spanish Influenza Surveillance System.
[Correction added on 25 January 2018, after first online publication: Funding information has been added.] The copyright line for this article was changed on 25 January 2018 after original online publication Current estimates indicate that, worldwide, the annual influenza epidemics affect 5%-10% of the world's population, resulting in about 3-5 million cases of severe illness, and about 250 000-500 000 deaths. 1 The European Center for Disease Prevention and Control (ECDC) estimates that nearly 40 000 people in the European Union die prematurely each year due to influenza-related causes. 2 To better assess and plan targeted public health interventions, national estimates of the burden of seasonal influenza are needed to compare between different influenza seasons and pandemics.
Estimating the national burden of influenza disease is however challenging. Recently, the WHO issued recommendations toward the use of influenza surveillance data to better estimate the burden of disease at the national level. 3 The Spanish Influenza Sentinel Surveillance System (SISSS) is a well-established and consolidated system that provides timely information on the activity of mild influenza disease in Spain at primary care level since 1996. 4,5 It is based on sentinel physicians reporting clinical influenza-like illness (ILI) cases and integrates virological data collected in the same population, 6 providing an opportunity to calculate the disease burden in primary care. Regarding influenza severity, the surveillance system for severe hospitalized confirmed influenza cases (SHCIC) was established in Spain after the influenza pandemic of 2009, including sentinel hospitals from all Spanish regions.
To date, estimates of influenza-associated disease burden in Spain have been focused on specific age-groups, 7 regional geographical areas, 8 or severe disease but have not considered mild influenza disease. 9 Our aim was to utilize data obtained by the SISSS and SHCIC on the surveillance of mild and severe disease at the primary and secondary care level to estimate the age related burden of seasonal influenza disease in Spain, in the post-2009 pandemic period.

| The Spanish Influenza Sentinel Surveillance System (SISSS)
The SISSS comprises 17 networks of sentinel physicians (general practitioners and pediatricians) in 17 of the 19 Spanish regions, as well as the network-affiliated laboratories, including the National Influenza Reference Laboratory (National Centre for Microbiology, World Health Organization National Influenza Centre in Madrid). More than 800 sentinel physicians participated each season covering a population under surveillance of around 1 million of physician's catchment area, giving an overall coverage of 2.2% of the total population of the 17 Spanish regions. All the networks complied with a series of requirements as to the minimum population covered (>1%) and representativeness in terms of age, sex, and degree of urbanization. 4,5 Sentinel physicians reported ILI cases detected in their reference populations on a weekly basis, following a definition based on the EU-ILI case definition. 10 For influenza surveillance, they systematically swabbed (nasal or nasopharyngeal) the first 2 ILI patients each week and sent the swabs to the network-affiliated laboratories for influenza virus detection. The information collected in the SISSS includes data on demographic, clinical and virological characteristics, seasonal vaccination status, chronic conditions, and pregnancy. Data are entered weekly by each regional sentinel network in a webbased application (http://vgripe.isciii.es/gripe) and analyzed by the National Centre of Epidemiology to provide timely information on the evolving influenza activity in Spanish regions and at the national level.
We used data provided by the SISSS for the 2010-2011 to 2015-2016 influenza seasons. We calculated the cumulative weekly ILI rates by season, for all ages and by age-group (0-4, 5-14, 15-64, and >64 years). By extrapolation to the Spanish population we estimated the number of ILI cases by age and season and by applying the corresponding weekly positivity rate, we estimated the number of mild confirmed influenza cases (MCIC). Point estimates and 95% confidence intervals (95% CI) were calculated.

| Surveillance of SHCIC
The number of hospitals participating in the surveillance of SHCIC who would be referred to those hospitals for any reason leading to hospitalization. As the Spanish secondary health system provides national public coverage to almost all the Spanish population, the catchment hospital population is completely generalizable nationwide.
The system is based on the notification of those laboratory confirmed influenza hospitalized cases in all wards who met the Spanish SHCIC case definition. This case definition includes several severity criteria: "Any case with clinical features compatible with influenza, requiring hospitalization for clinical severity: at least one of the following criteria: pneumonia, septic shock, acute respiratory distress syndrome, multiple organ dysfunction syndrome, or admission to ICU." Although it was recommended to swab all influenza cases needing to be hospitalized, in the clinical practice, the extent of respiratory swabbing might depend of the hospital physician's discretion. Following swabbing, only those cases that were influenza confirmed and meet the case definition were reported. Data on clinical, epidemiological, and virological information were collected, as well as the patient outcome.
In this way, one unique system provides information on all hospitalized patients with severe confirmed influenza infection, including the ICUadmitted and deceased.
We used data obtained from the surveillance of SHCIC for the same study period and age-groups as in primary care, to calculate the cumulative hospitalization rates as well as the cumulative rates of ICU admission for each season. We used as denominators the population under surveillance in the participating hospitals. These rates were applied to the total Spanish population to estimate the total number of SHCIC and ICU-admitted patients (including the 95% CI) for the whole country, by season and age-group. The number of deaths in SHCIC was also extrapolated to the Spanish population to estimate the number of deaths in influenza hospitalized patients in Spain.
We used as denominators the Spanish population of the first year of each season (total and by age-group), obtained from the Spanish National Statistics Institute. 11 All estimations were performed using version 14.1 of the statistical analysis software stata (Stata Corp., College Station, TX, USA).

| Seasonality of influenza activity in Spain through the Influenza Surveillance Systems in primary and secondary care
Influenza activity in sentinel primary care varied by studied season (Figure 1). The ILI rates at the epidemic peak ranged be- We provide here results at national level. Influenza activity observed at primary and secondary health care in Spain varied by Spanish region and season and was timely reported through the national weekly and annual influenza reports.

| ILI cases and MCIC in sentinel primary care
The highest cumulative MCIC rates were observed in children under 15, whereas the lowest in the elderly (65+ aged) ( Figure 3). The cumulative MCIC rates varied from 141 to 608 cases per 100 000 population in the elderly, depending on the season, and from 1395 to 3155 cases per 100 000 population in the 5-to 14-year age-group.
The number of ILI cases in Spain in the study period ranged be-    In the study period, there was an annual average of 3616 SHCIC (Table 2). On average, the estimated severe hospitalized rates were highest in children under 4 years of age (18.9 SHCIC/100 000 population) and in elderly (16.5 SHCIC/100 000 population). ICU admission rates were also highest in these age-groups, with 4.9 ICU admissions/100 000 population and 4.5 ICU admissions/100 000 population in children <4 years and in elderly, respectively. There was an annual average of 437 influenza hospitalized deaths. Annual influenza hospitalized rates were highest in the elderly (3 deaths in influenza hospitalized patients/100 000 population) ( Table 2).  Table 3).

| SHCIC, ICU admissions and influenza deaths in secondary care
Of the total estimated number of SHCIC and ICU admissions, 46% and 57%, respectively, were in the young adults group, followed by the elderly (39% and 31%). Only 23 deaths in hospitals were estimated for children less than 5 years old, while the majority of deaths occurred in the 65+ age-group (58%), followed by the 15-64 age-group (39%) ( Figure 5).  Table 4). Children 0-4 and 5-14 years old experienced a percentage of ICU admission of 31% and 26%, respectively, but the hospitalization fatality rate was very low (1%-3%) compared to the young adults and elderly (10% and 18%, respectively) ( Table 4).

| DISCUSSION
We estimated the burden of mild and severe seasonal influenza dur- Our results indicate that the seasonal influenza burden of both mild and severe influenza disease in Spain is virus-and age-specific, with significant seasonal variation. During the 6 studied influenza seasons, we found that, while children under the age of 15 years have the highest ILI and MCIC rates, the very young (0-4 years) and the elderly exhibit the highest rates of severe influenza-associated hospitalizations. This is consistent with previous studies showing that young children and adolescents have the highest rates of medically attended influenza, 7,12-14 while the highest hospitalization rates for influenza are observed among very young 15 and persons aged ≥65 years. 16 Previous exposure to influenza viruses, providing a partial immunity to the circulating viruses, and higher vaccine coverage than in other age-groups, 17,18 could account for the lower ILI rates at the primary F I G U R E 3 Primary care. Cumulative annual rates of mild confirmed influenza cases by age group, SISSS, Spain care level in the elderly population. In addition, as the elderly have also the highest prevalence of chronic conditions, they would be more prone to complications and hospitalizations, once acquiring the influenza infection, therefore yielding higher hospitalization rates in this population group. 19 General primary care practitioners in Spain attended about half a million ILI cases each season in young adults (15-  illness in this population previously reported by other authors in primary care during the same period. 21 25 We have estimated the burden of severe influenza during each influenza epidemic finding an average of 3616 SHCIC, 1232 ICU admissions, and 437 deaths in severe influenza hospitalized patients. The impact of severe influenza varied by age-group and across the 6 studied influenza seasons. As we mentioned above, the impact of severe influenza during the 6 studied influenza seasons, as measured by the cumulative hospitalization rate, was higher in Spain for children less than 5 years old and elderly. However, in terms of the number of severe influenza cases, young adults bore the largest burden of influenza hospitalization and ICU admission, followed by the elderly. These 2 groups accounted for 85% and almost 90% of the total number of SHCIC and patients admitted to ICU, respectively. Mortality was highest in the elderly with 58% of the deaths reported in influenza hospitalized patients, followed by 39% in young adults. Future studies are needed to explore if certain risk factors contribute to mortality in the young adults group (e.g, underlying conditions).
Overall, during the post-2009 influenza pandemic period, the proportion of severe influenza cases admitted to the UCI was highest in young adults 15-64 years old, consistent with other studies in the same period. 26 In addition, the number of patients in this age-group admitted to the ICU was higher in A(H1N1)pdm09 dominant seasons compared with other subtype seasons. 26,27 Children  Finally, direct comparisons with equivalent studies are difficult due to differences not only in the estimation methods, but also in the different case definitions used, surveillance protocols, sentinel physicians training, primary, and secondary healthcare systems characteristics, etc.
In conclusion, we report a considerable influenza disease burden in Spain, with significant seasonal and age variations. Children less than 15 years old yielded the highest influenza activity in primary care, while influenza hospitalization rates were highest among the very young children and the elderly. Nevertheless, the impact of influenza in the National Health System was mainly concentrated in young adults for mild influenza, and in young adults and elderly for severe influenza disease.
Estimates of mild and severe influenza disease burden in Spain will allow understanding the impact of the epidemics, including potential influenza pandemics, helping to guide decisions targeting influenza prevention and control. This information, periodically updated, will also be crucial to estimate the impact of influenza vaccination programs, contributing toward enhanced guidance for the development of long lasting and more efficient influenza vaccines.