Discussion
With the present study we show a remarkable excess death attributable to influenza in Italy during the winter seasons 2014/15 and 2016/17, which was independent from mean weekly extreme temperature variations. Our results show that during these two seasons, in Italy, a high proportion of deaths was observed among the elderly (96.1% and 77.7%, respectively). However, high rates were also observed in children 0–4 years old (1.05 and 1.54/100,000, respectively).
The pattern of excess deaths attributable to influenza in Italy is comparable to the pattern observed in Europe, as obtained from the EuroMOMO network (
Nielsen et al., 2018). The EuroMOMO network reported, in 2014/15 and 2016/17 seasons, a higher excess death for all causes, in all ages, compared to the previous season: 28.58/100,000 in 2014/15 and 25.65/100,000 in 2016/17. In the same seasons, the highest all-cause excess mortality was reported among people aged 65+. According to previous studies conducted at the European level, all-cause mortality is mainly attributable to seasonal variations in IA (
Nielsen et al., 2018).
We estimated influenza-associated mortality using two indicators of influenza activity. When using ILI as the IA, mortality may be overestimated. By using the Goldstein index as the IA, the dynamic of transmission is better represented and overestimation due to deaths by other pathogens is limited (
Nielsen et al., 2018). Both indicators show a similar pattern, but the estimation of mortality associated with influenza based on the Goldstein index seems to be the most reliable. We considered ILI as IA indicator mainly for comparisons with previous studies adopting the same approach.
In 2014/15, among people aged 65+, European pooled data (
EuroMOMO Network, 2015) showed an increased influenza-attributable mortality rate of 147.41/100,000 deaths, with ILI as IA indicator. Using the same model for Italy, we estimated a rate of 292.8/100,000 (CI 95% 279.7–306.0/100,000), perfectly comparable with the rate reported at the EU level. The 2014/15 season in Europe was, as in Italy, characterized by co-circulation of influenza A/H3N2 and influenza A/H1N1pdm09 viruses, but the A/H3N2 virus strain was more commonly detected compared to season 2013/14 (
Mølbak et al., 2015).
A similar pattern was reported in the elderly in EU during the 2016/17 season, with an excess influenza-attributable mortality rate of 129.9/100,000 deaths (
Vestergaard et al., 2017) Italian estimates (using the Goldstein index) showed a rate of 143.43/100,000 (CI 95% 130.09–152.72), slightly higher compared to the European rate.
Scarce data is available on influenza-attributable mortality estimates for single countries in the study period considered. However, some studies have been published that have reported influenza-attributable excess mortality rates in EU countries. In particular, Italy shows a higher influenza attributable excess mortality compared to Denmark in all ages, with highest levels reported in elderly, but for the 0–4 age group where Denmark reported higher rates compared to Italy in all seasons, except for the 2014/2015 season (0.52/100,000 vs 1.05/100,000) (
Nielsen et al., 2018). In Sweden, the 2016/17 season was characterized by the predominant circulation of A/H3N2. In this season, the reported influenza-attributable mortality in the elderly was higher compared to other age groups, and was the highest recorded, compared to previous A(H3N2) dominated seasons (
Public Health Agency of Sweden, 2017). In the UK, estimates of the annual number of deaths directly attributable to influenza range from 4 to 14,000 per year, with an average of around 8,000 per year (
Public Health England, 2014). Moreover, influenza-attributable excess deaths using the FluMomo method for UK were reported in 2014/15 (
Pebody et al., 2018). UK estimates, in terms of absolute numbers, were higher compared to Italian data, in all ages and in particular in the elderly (26,542 vs 19,475 respectively).
Plausible hypotheses regarding the determinants of the observed excess deaths attributable to influenza in Italy, especially in the old population (i.e. 65+), are: i) meteorological factors (low and high temperatures), ii) seasonal influenza circulating virus strains, and iii) the amplitude of the at risk population (pools of elderly).
Deviation from expected temperature may have a great impact on mortality (
Allen and Sheridan, 2018). Very low temperatures were registered at the beginning of 2017 in various European countries. Therefore, we decided to adjust our estimates of influenza-associated mortality for extreme temperatures. We found that the impact of extreme temperatures on mortality in Italy was quite limited, with the exception of the 2016/17 season. Despite this impact of extreme low temperatures, most of the excess death rate registered in 2016/17 is attributable to influenza, confirming other observations recorded in Europe (
Nielsen et al., 2019). Nevertheless, this is the first study reporting the effect of temperatures on mortality in Italy, and we acknowledge that this association has to be further investigated, also analyzing this factor at sub-national level.
As in other European countries, the excess mortality observed in Italy during the 2014/15 and 2016/17 seasons could be related to the circulation of an A/H3N2 influenza virus, which is known to be associated to a higher mortality in the elderly (
Nielsen et al., 2019). The A/H3N2 strain was strikingly prevalent in 2016/17 compared to previous seasons, with a mismatch between the circulating A/H3N2 virus and the virus included in the vaccine composition, which may have caused a low vaccine effectiveness (
Rizzo et al., 2016). This is confirmed by case control studies conducted in the elderly population at the EU level (
Kissling et al., 2016,
Valenciano et al., 2016), showing moderate to low influenza vaccine effectiveness estimates both in primary care and in hospital settings, especially for the A/H3N2 component of the vaccine.
The vaccine coverage in the elderly in both seasons was close to 50% (
Bonanni et al., 2018). In Italy, annual influenza vaccination is targeted to persons aged 65 years or above and for high risk persons aged more than 6 months (including pregnant women, individuals with chronic conditions, etc.). In the last 10 years the influenza vaccine coverage progressively declined until 2015, especially in those aged 65+ (68% in 2005/06 to 49% in 2014/15 season), which is well below the WHO minimum target (75%) (
Ministry of Health, 2018). One study, reporting an excess of mortality in 2015 in the Italian city of Bologna, showed that elderly individuals unvaccinated against influenza had an increased risk of all-cause and cause-specific mortality compared to vaccinated individuals (
Francia et al., 2018).
In terms of amplitude of the at risk population, in Italy there are 6.7 million of people aged 75+ (more than 10% of the population) that constitute a large group of fragile subjects, among which the annual death rate is naturally high, around 4% (
ISTAT, 2018b). Among them, a large variation in the absolute number of deaths causes small fluctuations in the mortality rate. Excess deaths constitute a serious public health issue that can be prevented coupling influenza vaccination with personal protection measures (
ECDC, 2019).
This study has several limitations. The influenza surveillance system in Italy is based on voluntary general practitioners reporting ILI cases, and the participating general practitioners are not selected with random criteria. Another important limitation in the surveillance system is related to virological surveillance because sampling of influenza testing may be biased towards more samples taken at hospitals, and therefore may overestimate the proportion of positive samples in the population. These limitations may introduce a potential bias due to the selection of subjects under surveillance.
Moreover, the study is based on census mortality data, while previous published studies (
Nielsen et al., 2019) were based on sample data and limited to regional data. However, the proposed model uses all-cause weekly mortality data, usually available quite in real time in many countries, and can therefore be a valuable tool for monitoring the seasonal impact of influenza.
The study should be validated using cause specific mortality data, which, however, was not available for the entire study period. Furthermore, it would be valuable to investigate also regional patterns, but such details on mortality were not available in the study period considered.
To evaluate whether the association of influenza activity with mortality varied with temperatures, an interaction term of influenza activity and temperatures should be added to model. The adopted statistical model did not include an interaction term between temperatures and IA. This “rigidity” of the model can be considered a limitation and should be overcome in future applications.
Finally, the pattern of the effect of temperature on mortality should be investigated further to be able to obtain more valid estimated of the impact of this effect, e.g. testing different cut-off values for the extreme temperature definition.
Assessment of winter mortality in Italy, during the 2014/15 and 2016/17 seasons, confirmed the hypothesis that influenza was likely to have been the main contributor to the excess mortality seen, especially in the elderly. Routine use of methods, such as FluMoMo can assist in rapidly assessing the impact of influenza in the overall mortality, which varies considerably by age group and type of circulating viruses. In conclusion, the unpredictability of the influenza virus circulating strains continues to present a major challenge to health professionals and policy makers. Nonetheless, vaccination remains the most effective means for reducing the burden of influenza, with a particular impact on the influenza attributable mortality. Moreover, the influenza vaccine, by reducing influenza complications, can indirectly reduce morbidity and mortality from all causes in the elderly (
Trucchi et al., 2015). An improved protective effect on the elderly population could be obtained also by reducing the circulation of the influenza viruses through vaccination strategies targeting healthy children, who represent a crucial reservoir of the virus (
Pebody et al., 2015,
Grijalva et al., 2010,
King et al., 2005,
King et al., 2010).