key: cord-1001121-ptckq3k9
authors: Grosso, Francesca; Castrofino, Ambra; Del Castillo, Gabriele; Galli, Cristina; Binda, Sandro; Pellegrinelli, Laura; Cereda, Danilo; Tirani, Marcello; Gramegna, Maria; Castaldi, Silvana; Pariani, Elena
title: A comparative study between the incidence and epidemiological features of Influenza-Like Illness and laboratory-confirmed COVID-19 cases in the Italian epicenter (Lombardy)
date: 2021-02-23
journal: J Infect Public Health
DOI: 10.1016/j.jiph.2021.02.003
sha: 8673b25c53bf2ef244e6ee3f9126cda219a371df
doc_id: 1001121
cord_uid: ptckq3k9

INTRODUCTION: In Lombardy, the influenza surveillance system relies on sentinel physicians that weekly report data on the number of influenza-like-illness (ILI) and a part of them also collect oropharyngeal samples for virologic analyses. This study aims at comparing the ILI incidence of 2019-2020 influenza season with the incidence of COVID-19 cases in order to better understand the current epidemic and to evaluate whether the implementation of ILI surveillance system could succeed in early detection and monitoring of COVID-19 diffusion. METHODS: The distribution of ILI cases in the seasons 2017-2018, 2018-2019 and 2019-2020 was taken in consideration and the curve trends were compared and analyzed according to geographical areas, age groups and time differences. RESULTS: The curve trends presented a similar pattern up to the 9(th) week; in fact, a reduction in the ILI incidence rate was observed in the 2017-2018 and 2018-2019 season but in the 2019-2020 an increase in the reported ILI emerged. The relation between the numbers reported by 2019-2020 ILI surveillance and those reported for COVID-19 is supported by the curve trends, the correspondence between age groups, the correspondence by geographical location, and also by the results of the nasopharyngeal swab tests performed. DISCUSSION: The influenza surveillance system is an effective tool for early detection of COVID-19. It may provide timely and high-quality data evaluating the SARS-CoV-2 burden among population with ILI. Implementation of the system has to be prioritized in order to identify any future novel respiratory pathogen with pandemic potential.

Following the first report of cases of acute respiratory syndrome in the Chinese Wuhan municipality at the end of December 2019 [1] , a pneumonia outbreak caused by human-to human transmission of a new coronavirus rapidly spread to become a global pandemic [2] . In February 2020, the World Health Organization (WHO) named the novel coronavirus SARS-CoV-2 and its associated spectrum of respiratory diseases COVID-19 [3] .

In Europe, the first positive COVID-19 case was found in France on the 24 th of January 2020 and a week later WHO declared COVID-19 as a "public health emergency of international concern [4] . On the 30 th of January the Italian Ministry of Health banned flights from and to China and implemented surveillance controls in the airports [5] . Despite these measures, Italy reported the first positive case of SARS-CoV-2 on February 20 th in the city of Codogno, in the province of Lodi (Northern-Italy), soon followed by an exponential growth of COVID-19 cases that initially involved almost exclusively the province of Lodi. This area was then referred to as "red zone" and restraint measures were applied to reduce the spread of the infection. Nevertheless, COVID-19 spread outside the "red-zone", reached all parts of Italy, and on March 8 th , the Italian Government implemented extraordinary measures to limit viral transmission, including a national lockdown to minimize the SARS-CoV-2 transmission.

Lombardy -a region in Northern Italy accounting for nearly 10 million inhabitants, equal to about 1/6 of the entire national population -has been, up to now, the core of coronavirus disease 2019 J o u r n a l P r e -p r o o f epidemic in Italy [6] . Since February 20 th , more than 239.410 people have been infected by SARS-CoV-2 in Italy, most of whom (38,95%) reside in the region of Lombardy, Italy's coronavirus epicenter [6] .

As of April 9 th , when COVID-19 had already taken on pandemic proportions and during the developing and drafting of this work, Italy recorded 136,110 positive cases, among which 19, 375 were hospitalized with respiratory symptom, 22.8% requiring admission at intensive care units (ICU) with a fatality rate of 12.2% [7] .

Since SARS-CoV-2 has never circulated among in humans in the past, we are all immunologically naïve to it and, thus potentially susceptible to it. As COVID-19 is an emerging, rapidly evolving situation, at the time of this manuscript's revision (January-2021), vaccine development was already on a fast track, including i) genetic, ii) viral vector, iii) protein-based and iv) whole-virus vaccines [8] . Up to now only two vaccines have been authorized and recommended by the Food and Drugs Administration (FDA) to prevent COVID-19: i) BNT162b2 mRNA Covid-19 Vaccine and ii) mRNA-1273 SARS-CoV-2 Vaccine, conferring respectively 95% and 94.1% efficacy in preventing COVID-19 illness, as shown by ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial. [9, 10] Both formulation are based on mRNA; BNT162b2 mRNA Covid- 19 Vaccine is a lipid nanoparticle-formulated, nucleoside-modified RNA (modRNA) encoding the SARS-CoV-2 fulllength spike, modified by two proline mutations to lock it in the prefusion conformation whereas mRNA-1273 SARS-CoV-2 Vaccine is a lipid-nanoparticle-encapsulated mRNA vaccine expressing the prefusion-stabilized spike glycoprotein and both formulation require two consecutive intramuscular injections to grant complete immunity against SARS-CoV-2. [9; 10] Given the worldwide limited supplies, a strategy of prioritization has been advocated and vaccines are firstly offered to those most at risk for SARS-CoV-2 or COVID-19 exposure and then to those that are progressively less at risk, following sequential prioritization steps, aiming at universal coverage [11] To current knowledge about COVID-19, the clinical outcome of symptomatic SARS-CoV-2 not only includes viral pneumonia, but also milder illness overlapping with influenza-like illness (ILI) [12] J o u r n a l P r e -p r o o f allowing the tracking of SARS-CoV-2 mild infection in the framework of influenza surveillance system [13, 14] .

InfluNet is the Italian national surveillance system for influenza. Coordinated by National Institute of Health (Istituto Superiore di Sanità) with the support of the Italian Ministry of Health, InfluNet is based on the voluntary participation of sentinel physicians who weekly report data on the number of ILI observed among their outpatients [15] and collect respiratory samples for virological analyses.

Epidemiological and virological data are collected at regional level and then centralized by the National Institute of Health (Istituto Superiore di Sanità) in the framework of Global Influenza Surveillance and Response System (GISRS) [16] .

This study aims at comparing the ILI incidence of routine 2017-2018, 2018-2019 and 2019-2020 influenza season with the incidence of COVID-19 cases in order to better understand the current epidemic and to evaluate whether the implementation of ILI surveillance system could succeed in early detecting and monitoring COVID-19 diffusion.

In Lombardy, influenza surveillance system relies on the voluntary participation of sentinel physicians (pediatricians and general practitioners) who survey about 2% of the general population seeking care in ambulatory facilities for ILI occurrence [15] .

Sentinel physicians weekly report data on the number of ILI according to the EU case definition : an abrupt onset of fever (>38 °C) or feverishness, one or more respiratory symptoms (cough, sore throat and/or shortness of breath) and one or more systemic symptoms (myalgia, headache and/or malaise) [17] . A number of sentinel physicians is also in charge of collecting respiratory samples (nasal/throat swabs) from their outpatients from November to April of each season (i.e. from week 46 to week 17 of the following year) for virological analyses.

Since the beginning of the COVID-19 epidemic in Lombardy (week 8 of 2020), "Integrated COVID-cases on inpatients (date of hospital admission, ICU admission, outcome), ii) laboratories, reporting confirmed diagnosis on nasopharyngeal swabs, iii) local health agencies, investigating individual cases and reporting epidemiologic characteristics (date of symptoms' onset, comorbidities, symptoms' severity, contacts), iv) and from regional registry, on general and health related information.

The 2017-2018, 2018-2019, 2019-2020 influenza seasons and laboratory-confirmed COVID-19 epidemic curves were compared and analyzed according to geographical areas, time distribution and age-groups. to carry out a more detailed analysis. From the 9 th to the 11 th week, the ILI incidence rate in the 15-24 age group was lower than those of the other two; ILI incidence rate in the 25-44 age group instead exceeded that of the 45-64 age group ( Table 2 . Trend of the incidence Rates of ILI cases per 1000 patients in each considered age group and in week 9 th ,10 th and 11 th during the 2019-2020 influenza season (Lombardy region). In bold the age group and the week with an increase in the ILI incidence rate.

The geographical distribution of reported ILI cases in Lombardy in the 2019/2020 season shows an increased incidence rate in four main areas: Bergamo, Brescia, Pavia and Mountain area (Figure4).

In particular: the incidence rate in Bergamo area reached a peak of 7.63 cases per 1000 patients at the 10 th week and then decreased to 1.45 at the 11 th week; the incidence rate in Brescia area was 2.97 cases per 1000 patients at the 10 th week and 3.94 at the 11 th week; Pavia area had an incidence rate 

The signs and symptoms of SARS-CoV-2 overlap with those of many other viral respiratory tract infections, including influenza viruses. Beside "Integrated COVID-19 surveillance" purposely establish to burden and track COVID-19, influenza surveillance may provide timely and high-quality data evaluating the SARS-CoV-2 burden among population with mild respiratory symptoms [18] .

Moreover, influenza surveillance can work as a global alert mechanism for the emergence of viruses with pandemic potential [16] . In Europe, influenza surveillance relies mainly on sentinel general J o u r n a l P r e -p r o o f practitioners in charge of recording the number of ILI cases per week and collecting respiratory specimens from their patients for laboratory tests [19] . In Italy, the influenza epidemiological and virological surveillance network (InfluNet) [15] consists surveys approximately 2% of the general population; epidemiological data are collected from week 42 to week 17 of the following year, while virological surveillance begins on week 46 and ends on week 17 of the following year.

Epidemiological and virological data are collected at a regional level and are aggregated subsequently prevented from going to their own general practitioner due to restrictive measures taken by the Government, or were accessing emergency care, and therefore the number of ILI cases reported by sentinel doctors decreased.

We have to consider that the reduction of the number of active sentinel doctors notifying ILI cases to the surveillance system in the 11 th week may concur to generate an inaccurate esteem of ILI incidence rates and that it has not been possible to collect complete information for every patient from "Integrated COVID-19 Surveillance"; in particular, the date of symptom onset was not available for 29% of the total population included in the analysis, that consisted of 15716 positive patients on March 15 th .

With the availability and introduction of SARS-CoV-2 vaccine, another parameter of ILI surveillance should be the assessment of SARS-CoV-2 vaccine effectiveness as referred to laboratory-confirmed cases, that may present due to the presence of circulating viral strains different from the one of the vaccine.

One of the limitations of this study was the limited number of sentinel physicians involved in the network, affecting the number of notified ILI during the SARS-CoV-2 epidemic; nevertheless, the influenza surveillance system in 2019-2020 enabled us to detect the introduction and distribution of COVID-19.

J o u r n a l P r e -p r o o f Implementation of the ILI surveillance system has to be prioritized in order to early identify viral respiratory outbreaks and any future novel respiratory pathogens with pandemic potential. To this end, sentinel physicians homogeneously allocated in the country should survey at least 4% instead of 2% of the general population seeking care in ambulatory facilities for ILI occurrence. This would empower this syndromic surveillance and strengthen the network. Furthermore, an increase in appointed doctors collecting respiratory swabs should also be endorsed to improve the virological surveillance. In fact, both individuals and health system take advantage from an early virological diagnosis: individuals with ILI can benefit from adequate treatments and can see reduced their

probability of viral-related complication, positively impacting the health system in reduce the ER and hospitals access, particularly during influenza seasons.

FUNDINGS. This research did not receive any specific grant from funding agencies in the public, commercial or not for profit sectors. 

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