Incidence of acute respiratory infections in preschool children in an outpatient setting before and during Covid-19 pandemic in Lombardy Region, Italy

Acute respiratory tract infections (ARTIs) are the most common type of childhood disease [1]. Each year, these infections impose an enormous burden on the healthcare system (frequent medical consultations, hospitalizations, and antibiotic prescriptions) and on society in high income countries (parental absenteeism and loss of productivity) [1]. ARTIs, especially those involving the upper airways, are particularly common in preschool children [2]. Their incidence is often difficult to estimate because ARTIs are typically treated in outpatient settings and the majority of available epidemiological data are collected in hospital settings and are referred to as the most severe respiratory illness [3‐6].

Given the paucity of evidence, the burden of respiratory infections in a real-world setting remains unclear, largely unexplored in preschool children, and appears to be an intriguing field for an observational study. As a result, we conducted a longitudinal cohort study in September 2019, which aimed to describe the epidemiology of ARTIs in a cohort of preschool children in the Lombardy region (Italy) followed in an outpatient setting. After 6 months, in March 2020, Lombardy experienced one of the first and deadliest COVID-19 outbreaks in the world, forcing the Health Authorities to lock down the entire country, completely close all schools, and suspend all work and sports activities from March 9 to May 3, 2020 [7]. In high COVID-19 incidence area (the so called “red zone”) such as Lombardy schools remained closed until June 2020. Schools then reopened for the new scholastic year in September 2020 and remained open until March 2021, when schools of all grades were closed again to contain the spread of the SARS-coV-2 following the onset of the third pandemic wave [8]. The dramatic COVID-19 outbreak and the widespread adherence to social distancing, hand washing, wearing of face masks, and lockdown have undoubtedly had an impact on the epidemiology of ARTIs in children. According to reports from different parts of the world, ARTIs in children decreased during the pandemic as a result of the combination of the different measures adopted to combat the pandemic [9‐14].

In this “unique scenario”, the purpose of our prospective cohort study was to estimate the incidence of ARTIs in preschool children aged 0–5 years, who were monitored in an outpatient setting from October 2019 to March 2021, before and during the COVID-19 pandemic in Italy’s Lombardy Region.

Five hundred twenty-five children were assessed for eligibility between October 1st, 2019 and January 30th, 2020. 29 children did not meet the inclusion and exclusion criteria, and 10 refused to participate; hence, we enrolled 484 children with a mean age of 2.39 ± and a standard deviation (SD) of 1.68 years (Fig. 1). The flow of children during the follow-up period is reported in Additional file 1.

249 (51.8%) of the recruited children were male and 340 (72.8%) were born through vaginal delivery. Children who were exclusively breastfed make up 43.5% of the sample (n = 462), with a median duration of 6 months of breastfeeding. At the time of recruitment, almost all the cohort (n = 438; 97.8%) had been administered at least 1 dose of hexavalent vaccine and at least one dose of pneumococcal vaccine (n = 448; 91.5%). The vast majority of the children (n = 404; 85.8%) attended kindergarten (IQR 1.91). The mean age of enrollment into kindergarten was 1.89 ± 1.31 SD, while the median daily attendance was of 7 h/day (IQR 1.8). The majority of children (97.2%) eat lunch in the community, while about half (58.1%) remain for an afternoon rest. 61.8% of the children use or have used pacifiers in the past. The children’s demographic characteristics are reported in Table 1.

Table 2 illustrates the incidence estimates (cases/100 children × 30 days) and the 95% CIs of ARTIs in children by age and calendar month during the study period. The estimated mean incidence of ARTIs in children aged 0–5 years was 12.1/100 children × 30 days (95% CIs: 9.5–12.9). The estimated incidence of ARTIs was the highest in infants (24.9/100 children × 30 days; CI:s 17.6–28.9) over the entire observation period. During the COVID-19 pandemic, incidence estimates reached the lowest value in July 2020, when no episodes of ARTIs were reported in the entire cohort of children.

In Table 3, ARTIs are differentiated as URTIs or LRTIs based on their location, and incidence estimates are given by age and calendar months. The mean incidence estimates of URTIs were higher than those reported for LRTIs in children aged 0–5 years over the entire observation period (8.3/100 children × 30 days – CIs: 7.6–8.9 v. 3.8/100 children × 30 days – CIs: 3.4–4.3, respectively). The incidence estimates of URTIs were highest in infants (16.8/100 children/30 days; CIs: 13.9–20.2). Similarly, the incidence of LRTIs also peaked in children in their first year of life (8.1/100 children/30 days; CIs: 6.1–10.5).

Table 4 compares the incidence rates of ARTIs in the pre-pandemic winter (from November 2019 to February 2020) and the pandemic one (from November 2020 to February 2021). In comparison to the pre-pandemic winter months, the pandemic winter saw a relative reduction of 82.1% (− 82.1%, CIs: 77.8–85.7) in the incidence of ARTIs in children aged 0–5 years.

During the study period, 64 patients were screened for SARS-CoV-2 infection; 8 (12.5%) tested positive. They recovered fully and did not required hospitalizations.

In this study of 484 children aged 0–5 years, who were followed for 18 months in an outpatient setting by an FP, the mean incidence of ARTIs was 12.1/100 children × 30 days over the course of the entire study period, which included both the pre-pandemic and COVID-19 pandemic periods. The incidence of ARTIs varied among the 5 age groups analyzed, reaching the highest value in infants (24.9/100 children × 30 days) and gradually decreasing up to the age of 5 years (8.1/100 children × 30 days). There is considerable variation in the reported incidence of ARTIs in healthy children, which limits comparisons between studies. Recruitment sites (emergency departments, pediatric wards, or outpatient settings), the country, the children’s ages, ethnicity, exposure to different environmental factors, seasonality, and the outcomes of interest are all factors that make the comparison difficult to perform [24‐26]. We observed an age-dependent decrease in the incidence of ARTIs during the observation period, which is consistent with data reported by other authors worldwide [27]. This could be explained by the physiological postnatal maturation of both the innate and adaptive immune systems occurring during the first 6 years of a child’s life, as a result of repeated environmental exposure to microbes [28]. On analyzing infants of less than 1 year of age, which is the most affected age group in our population over the whole study period, we observed that they experienced the highest incidence estimates of ARTIs, which is consistent with what certain authors reported a few years ago [29, 30]. While we are aware that the incidence peak of ARTIs is usually seen when the child starts kindergarten, the mean age of daycare entry in our study group was 1.89 years [31, 32]. We can hypothesize on a number of potential factors influencing this result. Firstly, the role of the COVID-19 pandemic cannot be entirely ruled out. In fact, some authors have previously underlined that the pandemic had an affect on the circulation of respiratory viruses [14, 33‐35]. In consequence, the shift of the incidence peak of ARTIs in younger age groups could have been the result of this new and unexpected epidemiological scenario. Secondly, the highest incidence in infants could reflect the fact that parents of younger children could be more likely to contact an FP to schedule a medical visit than parents of older children.

Not surprisingly, our study showed a higher incidence of URTIs when compared to LRTIs. When examining the incidence of ARTIs by calendar month, we observed a dramatic reduction in estimates when lockdown started in March 2020. The incidence continued to fall, reaching the nadir in July 2020, in the middle of the summer season. After the reopening of schools in September 2020, we observed an increase in ARTIs estimates which, however, never reached pre-pandemic values. This trend was similar when the incidence of URTIs and LRTIs was considered separately.

We also compared the incidence of ARTIs, URTIs, and LRTIs between the pre-pandemic winter months (from November 2019 to February 2020) and the pandemic ones (from November 2020 to February 2021). We observed a relative reduction in incidence estimates of 82.1, 70.2, and 86.1%, respectively, across all ages. The decrease in the rate of ARTIs may have primarily been caused by the reduction in social and educational activities such as school, sports and extracurricular activities, or day care centers, which are known to be major sources of respiratory infections [32]. It is worth noting that, during the pandemic period, the population of children aged 0–5 years did not wear masks, in accordance with international recommendations [36]. Therefore, the sustained decline in ARTIs when schools and educational activities reopened in September 2020 may have been influenced by hygiene measures, social distancing, and the wearing of masks by the older children, adolescents, and adult population [37]. These measures were, therefore, essential to protect children from respiratory infections during the pandemic period, when the COVID-19 vaccination campaign was just getting started (COVID-19 vaccine coverage in Lombardy was less than 5% in March 2021) [38].

This study has some limitations. First, the study was designed to assess the incidence of ARTIs in preschool children in mid-2019, when the COVID-19 pandemic did not yet exist. Therefore, the sudden outbreak was not anticipated when the study was conceived. Second, the incidence estimates of ARTIs could have been underestimated during the COVID-19 pandemic because of parents’ reluctance to seek medical assistance, especially during the lockdown period. However, we are confident that at least 80% of ARTIs were detected by this study given that FPs were the first doctors to be contacted in the event of respiratory diseases during the pandemic. Third, ARTIs were classified according to the site of infection and no etiological diagnosis was made. For the purposes of the study, FPs had no access to viral/bacterial diagnostic testing for URTIs and LRTIs, except during the COVID-19 pandemic when molecular tests to detect SARS-CoV-2 became mandatory in the presence of COVID-19 signs and symptoms. Fourth, not all infections were confirmed radiologically or in a laboratory, but were diagnosed according to clinical practice (for example, pneumonia was usually a clinical diagnosis because FPs did not have on-site radiologic capacity). Fifth, unfortunately we did not assess the severity of ARTIs and their outcomes (eg: drug prescription, admissions to emergency room and hospitalizations). Therefore, we cannot give any interpretation about the potential impact of the COVID-19 pandemic, direct and indirect, on the clinical severity of respiratory symptoms in children 0–5 years.

Finally, the number of FPs was relatively small when compared to the number of FPs working in Lombardy region (approximately 1000 FPs). However, we decided to involve into this study only FPs who were highly motivated and compliant to study procedure.

This study’s main strength lies in the fact that it is the largest cohort study, which unexpectedly revealed data on the incidence of ARTIs in preschool children in a real-word setting, both before and during the COVID-19 pandemic, using rigorous criteria and procedures.

The aim of this study was to report the incidence of ARTIs in preschool children in an outpatient setting before and during the COVID-19 pandemic. Children in their first year of age are more likely to develop ARTIs than older children. The COVID-19 pandemic has altered the epidemiology of ARTIs in children aged 0–5 years. Further studies are needed to determine the long-term impact of COVID-19 measures on the epidemiology of ARTIs in children.