The burden of seasonal influenza in Italy: A systematic review of influenza‐related complications, hospitalizations, and mortality

Abstract Reliable country‐specific data on influenza burden play a crucial role in informing prevention and control measures. Our purpose was to provide a comprehensive summary of the available evidence on the burden of seasonal influenza in Italy. We performed a systematic literature review of articles published until July 31, 2020. PubMed, Embase, and Web of Science were searched using terms related to burden, influenza, and Italian population. We included studies investigating seasonal influenza‐related complications, hospitalizations, and/or mortality. Sixteen studies were included: eight (50%) analyzed influenza‐related complications, eight (50%) hospitalizations, and seven (43.8%) influenza‐related deaths. Only three studies (19.7%) concerned pediatric age. The synthesis of results showed that patients with chronic conditions have an increased risk for complications up to almost three times as compared with healthy people. Hospitalizations due to influenza can occur in as much as 5% of infected people depending on the study setting. Excess deaths rates were over sixfold higher in the elderly as compared with the rest of population. Although there are still gaps in existing data, there is evidence of the significant burden that influenza places each year especially on high‐risk groups. These data should be used to inform public health decision‐making.

The monitoring and surveillance of seasonal influenza is possible through data collection and sharing systems, such as FluView in the United States (www.cdc.gov/flu/weekly) and FluNews in Europe (www.flunewseurope.org), that systematically collect data on seasonal influenza and publish periodic reports to inform on epidemiological trends. InfluNet is the Italian nationwide sentinel surveillance system for influenza, coordinated by the Italian National Institute of Health. It collects epidemiological (InfluNet-Epi) and virological (InfluNet-Vir) data that are weekly published on FluNews-Italy (https://www. epicentro.iss.it/influenza/FluNews) reports and uploaded into the European database coordinated by the European Centre for Disease Prevention and Control (ECDC). FluNews-Italy also integrates findings from other surveillance systems, such as the monitoring system of severe and complicated laboratory-confirmed cases of influenza, daily mortality among the elderly and InfluWeb (a web-based surveillance system of influenza-like illness [ILI]). More information on influenza burden (e.g., complications and hospitalizations) can be gathered from other sources, such as Health for All database (https://www.istat.it/it/ archivio/14562) or published papers. However, the available evidence is still suboptimal. For instance, health technology assessment (HTA) projects of different preventive interventions against influenza have brought to light the need for more data. [10][11][12][13][14] In sum, reliable country-specific data on influenza burden play a crucial role in informing the planning of prevention and control measures to limit the spread of the disease and minimize associated costs. For this reason, in scientific literature, there are some country specific reviews aiming to assess influenza incidence and clinical and economic burden. The published reviews focus either on a specific geographical area, such as Latin America, sub-Saharan Africa, Japan, or West Europe, or on a specific age range, such as elderly or pediatric age. [15][16][17][18][19][20][21] To the best of our knowledge, no review has focused on Italy. Consequently, the present study aims to provide an overview of available data on the burden of seasonal influenza in Italy. Alongside the above-described Italian databases, this comprehensive review may be of aid for policy makers, health economists, public health practitioners, and other relevant stakeholders.

| MATERIALS AND METHODS
This systematic review of the literature (PROSPERO registration number: CRD42021272644) was conducted following the 2020 PRISMA guidelines (Appendix A).

| Identification of eligible studies
All studies quantifying the burden of seasonal influenza in Italy were potentially eligible, independently by initial influenza clinical presentation. The study outcome was the burden of influenza defined here as influenza-attributable complications, hospitalizations, or deaths. The study population was the entire Italian population, independently of age, health status, and any other variable affected by both laboratory-confirmed influenza and clinical proxies (e.g., ILI). No formal limits were established for study design. By contrast, the following exclusion criteria were applied: (i) studies evaluating the burden of pandemic influenza; (ii) case reports and case series with no possibility to establish the population burden of influenza; (iii) economic modeling with no original data; (iv) narrative reviews and other forms of the second-hand research; (v) original studies focusing only on epidemiological and/or virological surveillance of the laboratory-confirmed influenza and/or ILI.
The literature search was performed by consulting three databases, namely, PubMed, Web of Science (WoS), and Embase. The following search string was used on PubMed: "(epidemiology OR epidemiological OR virolog* OR surveillance OR incidence OR ("attack" AND rate) OR complicat* OR hospitalization OR (inpatient AND (admission OR care)) OR (outpatient AND (admission OR care)) OR (hospital AND (admission OR care OR discharge)) OR ambulatory OR mortality OR death OR sequelae OR visit) AND (influenza OR flu) AND (Italy OR italian)"; this spelling was then adapted to WoS and Embase. No search restrictions were applied. The search was updated to July 31, 2020.
After removing duplicates, papers were screened by title and abstract first. Clearly ineligible studies were discarded. The remaining records were assessed in the full-text modality.

| Data extraction and synthesis
From the articles definitively included in the literature review, the following information were extracted: bibliographic record, study location, study setting (i.e., outpatient, inpatient, institutionalized, and mixed), main demographic characteristics of the study population (e.g., sample size, age, and sex distribution); study period/influenza season, type of outcomes, and their occurrence. Moreover, if available, data were stratified by viral (sub)type and type of outcome.
A meta-analysis of data was not planned because of the expected heterogeneity in study populations and endpoints. Indeed, data were summarized in a narrative way.

| Quality assessment
The Newcastle-Ottawa Scale (NOS) was used for evaluating the quality of included studies. NOS adopts a star system, with a total score ranging from 0 to 9 and a score ≥7 indicating a high-quality study.
Two investigators separately performed the quality evaluation of each study, and disagreements were settled by a joint re-evaluation of the original article with a third author. No study was excluded based on quality criteria.

| RESULTS
The search of the three databases yielded a total of 9268 articles.
After duplicates removal, 6640 articles were screened for title and abstract and 28 were selected for full text screening. It was not possible to retrieve four articles. Twenty-four articles were then screened by full text, and eight studies were excluded with the following reasons: did not meet the inclusion criteria (n = 2), not related to the topic (n = 4), reviews (=2). Eventually, 16 articles 22-33 published from 2001 to 2020 were included in the qualitative synthesis. Details about the study selection process are shown in the flowchart (Figure 1).
The quality of studies varied in the range from 4 to 6 stars (median: 4; mean: 4.562) ( Table 2). All the studies were judged to have a representative exposed cohort and a follow up long enough for

T A B L E 2 Quality of included studies
Author, year Representativeness of the exposed cohort Selection of the unexposed cohort from the same community as the exposed outcomes to occur. The quality assessment was penalized by the absence of the non-exposed cohort that prevented assigning three stars for all the studies.

| Mortality
Four articles (25%) evaluated the number of deaths due to influenza in the study population. 22 37 Pneumonia affected a minor percentage of people but occurred in around 5% of individuals at risk. 26,33 As for the pediatric population, consistent with another systematic review on the topic, we found a lower probability of pneumonia in primary care-based studies as compared with hospital ones, but we were able to get a more precise estimation of the frequency of otitis media. 15 The findings of the papers included in this systematic review also showed a significant increased risk for complications among elderly (65+) and patients with at least one chronic condition. 29,37 This result is aligned with other systematic reviews on the topic. 17,21 Influenza-related hospitalizations were shown to be as low as less than 0.1% to more than 5% according to the study setting. Considering the amount of influenza cases occurring each year, we should keep in mind that these results could translate to tens of thousands of hospitalizations each year. Interestingly, hospitalizations were shown to occur in a similar percentage of cases also in the pediatric population.

| Viral strains contribution
Actually, the Italian Health For All database allows to ascertain that hospitalization rate for influenza and pneumonia in children less than 14 years old was the second highest after hospitalization rate of elderly across different age groups, and this was also confirmed in other countries. 21 Furthermore, another systematic review attributed 5%-16% of pediatric respiratory hospitalizations to influenza. 19 In respect to mortality, the findings of this systematic review suggests that influenza is responsible for a relevant excess in mortality rate. Excess death rates for elderly were estimated to be over six times higher than in general population with the most of influenzarelated deaths (65%-96%) occurring in persons 65+. 34,36 These data were also confirmed by other systematic reviews. 17,38 It is well-known that influenza is usually underreported on both death certificates and hospital discharge records either because secondary bacterial co-infections can develop or because influenza can make some chronic illnesses worse, and this information can be eventually registered as death cause in the place of influenza. Furthermore, it should be noted that patients with influenza-related complications are not always tested for influenza viruses, or they seek medical care late for influenza virus to be detected from respiratory samples. Indeed, both hospitalizations and deaths due to laboratoryconfirmed influenza can be underestimated.
As far as the contribution of type of viral strain is concerned, the findings of our systematic review seem to suggest a higher mortality due to virus A, but less conclusive results may be drawn about complications and hospitalizations.
Given this, although gaps in existing data still exist, there is evidence of the significant burden that influenza places each year on the Italian population across all age groups. This is even more important considering that a projected increase of more than 30% of cases of influenza has been estimated in a 30 years' time horizon in the US adult population aged 50 years and older. 39 Similarly, an increase in costs is forecasted and approximately 50% of productivity loss costs will be attributed to influenza-related mortality while 75% of direct costs will be due to hospitalized cases. Indeed, the prevention of influenza is of utmost importance in particular among people with higher risk for these two outcomes. Recommendations for vaccinating highrisk groups are already implemented in most countries and generally encompass elderly albeit with different age cut-off, 40 but attention should be paid also to children because mostly affected by the disease each year 41 and at risk of complications and hospitalizations. Nevertheless, more, and much standardized data would be worthwhile to inform the decision-making process at national level.
The findings of this systematic review should be interpreted considering the following limits. Because we restricted our review to published data available on three databases, it is not possible to exclude that we might have missed some articles. However, we believe that it is unlikely that additional relevant data could be found. Another limit is represented by the lack of pooled estimates that were not obtainable. Studies reported data across a range of seasons and settings and considered various endpoints; therefore, they used different methods for evaluating the burden of influenza. Considering this heterogeneity, a meta-analysis of data was not performed.
This prevents having a clear estimate of probabilities of different influenza-related complications and calls for further standardized and population-based research in the field. Nevertheless, to the best of our knowledge, this review represents the first attempts to collect and summarize italian data and could offer clues for further research.
In fact, a thorough and robust understanding of influenza-related burden is necessary to both make health systems prepared to manage influenza cases and better exploit the potential impact of control measures, such as vaccination.

| CONCLUSIONS
The evidence on influenza-related complications, hospitalizations, and mortality in the Italian population is fragmented because of heterogeneity in study populations, settings, and methods. Nonetheless, it shows the relevant burden that influence places each year, in particular among elderly, people with underlying conditions but also children.

FUNDING STATEMENT
This research received no external funding.

ETHICS APPROVAL STATEMENT
Not applicable.

PATIENT CONSENT STATEMENT
Not applicable.

SOURCES
Not applicable.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.12925.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Rationale 3
Describe the rationale for the review in the context of existing knowledge. 1.

Objectives 4
Provide an explicit statement of the objective(s) or question(s) the review addresses. 1.

Eligibility criteria 5
Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.

2.1
Information sources 6 Specify all databases, registers, websites, organizations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted.

2.1
Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used.

2.1
Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

2.1
Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process. Describe any methods used to explore possible causes of heterogeneity among study results (e.g., subgroup analysis, meta-regression).
N/A 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.

N/A
Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).

N/A
Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.

Study selection 16a
Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.

3.
16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded. 3.

Study characteristics 17
Cite each included study and present its characteristics.
3.1, Table 1 Risk of bias in studies 18 Present assessments of risk of bias for each included study. Table 2 Results of individual studies 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g., confidence/credible interval), ideally using structured tables or plots. Table 1, Table 3 Results of syntheses 20a For each synthesis, briefly summaries the characteristics and risk of bias among contributing studies.

3.2, 3.3 (Continues)
Item # Checklist item Reported (yes/no) TITLE Title 1 Identify the report as a systematic review. Yes

Objectives 2
Provide an explicit statement of the main objective(s) or question(s) the review addresses.

Eligibility criteria 3
Specify the inclusion and exclusion criteria for the review.

Yes
Information sources 4 Specify the information sources (e.g., databases, registers) used to identify studies and the date when each was last searched.

Yes
Risk of bias 5 Specify the methods used to assess risk of bias in the included studies.

Yes
Synthesis of results 6 Specify the methods used to present and synthesize results.

Included studies 7
Give the total number of included studies and participants and summaries relevant characteristics of studies.

Yes
Synthesis of results 8 Present results for main outcomes, preferably indicating the number of included studies and participants for each. If meta-analysis was done, report the summary estimate and confidence/ credible interval. If comparing groups, indicate the direction of the effect (i.e. which group is favored).

Limitations of evidence 9
Provide a brief summary of the limitations of the evidence included in the review (e.g., study risk of bias, inconsistency and imprecision).

Interpretation 10
Provide a general interpretation of the results and important implications.

Funding 11
Specify the primary source of funding for the review. Yes

Registration 12
Provide the register name and registration number. Yes