Impact of COVID-19 and Nonpharmaceutical Interventions on Common Respiratory Viruses in Children: A 5-Year Study in Hangzhou, China Open Access

Acute respiratory infections are a major global health problem related to high morbidity and mortality [1]. Respiratory viruses include adenovirus (ADV), influenza A virus (Flu A), influenza B virus (Flu B), and respiratory syncytial virus (RSV) [2]. At the end of 2019, the 2019 coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was widely prevalent worldwide [3, 4]. To curb the spread of SARS-CoV-2, a series of nonpharmaceutical interventions (NPIs) have been adopted, including maintaining social distance, wearing masks, taking refuge in situ, restricting travel, closing schools, etc. [5]. These measures have effectively controlled the popularity of COVID-19. The common child respiratory virus and SARS-CoV-2 have similar transmission routes. These measures may also change the epidemiological changes of common respiratory viruses in children to some extent [6, 7].

Although related studies have reported the impact of the COVID-19 pandemic on the prevalence of respiratory viruses in children [6, 8‒10], few studies have paid attention to the changes in children’s respiratory virus epidemic before, during and after the COVID-19 epidemic and the influence of NPIs on the spread of common respiratory viruses in children of different age groups during the COVID-19 epidemic. Therefore, the purpose of this study was to analyze the overall changes, seasonal distribution, and age distribution of children’s common respiratory infection viruses in Hangzhou during the pre-COVID-19, pandemic, and late stages by collecting the medical records of children’s respiratory infection from January 2019 to December 2023 and to explore the impact of different measures against the COVID-19 epidemic on the epidemiological characteristics of children’s common respiratory infection viruses.

From January 2019 to December 2023, samples of patients who met the standards of respiratory tract infection were collected and tested. The inclusion criteria were (1) patients under 18 years old and (2) patients diagnosed with acute respiratory infection (showing one or more of the following symptoms: fever, cough, earache, stuffy nose, runny nose, sore throat, vomiting after coughing, wheezing, dyspnea, shortness, or shallowness). All enrolled children were divided into 5 age groups: <28 days, 1–12 months, 1–3 years old, 4–6 years old, and >7 years old. According to the epidemic prevention policy issued by the China Center for Disease Control and Prevention, the 5-year period is divided into 3 periods in this study: pre-COVID-19 (January 1, 2019 to December 31, 2019), the pandemic period of COVID-19 (January 1, 2020 to December 31, 2022), and post-COVID-19 (January 1, 2023 to December 31, 2023) [11‒13]. January 2023 was defined as “post-COVID-19 period” in accordance with the “General Plan on the Implementation to Manage COVID-19 with Measures against Class B Infectious Diseases” issued by the National Health Commission of the People’s Republic of China on December 26, 2022.

Detection kits (colloidal gold method) were produced by Hangzhou Innovation Biological Inspection and Control Technology Co., Ltd.: Diagnostic Kit for Adenovirus Antigen (Colloidal Gold), Diagnostic Kit for RSV (Colloidal Gold), and Influenza A and Influenza B Nucleoprotein Antigen Test Kit (Colloidal Gold).

Specimen collection, testing, and outcome readout were performed according to the instructions in the users’ manual. Samples were collected via oral throat swabs. Following collection, the swab was immersed in the sample extraction solution within the collection tube and thoroughly mixed. A volume of 100 μL (approximately three drops) of this prepared sample was added to the sample well of the test device. The results were interpreted after a 15-min incubation period. For result determination, observe the test and control zones and make judgments based on the presence and number of bands in these zones.

Classification variables are expressed as percentage counts. The chi-squared test or Fisher’s exact test was used to compare the proportions of classified variables. A value of p < 0.05 was considered statistically significant. Statistical analysis was carried out with R software.

In this study, no direct contact was made with the subjects. Only specimens from the sources of visits for respiratory testing were collected. The results of this study are solely for analytical exploration and should not be utilized for any other purposes. Since there is no risk to the subjects, an ethical exemption was obtained from the Hospital Ethics Committee.

From January 2019 to December 2023, a total of 684,413 samples were tested, including 369,620 males, accounting for 54.01%, and 314,793 females, accounting for 45.99%. A total of 213,443 positive samples (31.19%) were detected, including 40,484 ADV-positive samples (18.97%), 106,423 Flu A-positive samples (49.86%), 32,379 Flu B-positive samples (15.17%), 30,776 RSV-positive samples (14.42%), and 3,381 mixed infection samples (1.58%). The overall detection data of respiratory viruses collected in different years are shown in Table 1. A total of 70,813 single virus-positive samples were detected before the COVID-19 epidemic, with a positive rate of 33.20%; 61,159 positive samples were detected during the COVID-19 pandemic, with a positive rate of 24.54% (including 2020, 2021, and 2022); and 78,090 positive samples were detected in the later period of the COVID-19 epidemic, with a positive rate of 35.20%. Analysis of the common respiratory virus infections among children of different ages in the pre-epidemic, pandemic, and late stages of COVID-19 shows that the highest total detection rate of respiratory virus among children aged 4–6 years is 36.69% (69,258 positive samples), followed by 35.10% (54,020 positive samples) among children aged >7 years. Before the COVID-19 epidemic, the detection rates of respiratory viruses in children aged 4–6 and >7 years were 43.44% and 41.81%, but the detection rates of respiratory viruses in children aged 4–6 and >7 years began to decrease in the later period of the COVID-19 epidemic. The detection rate of respiratory virus in children less than 28 days in the three stages was the lowest (see Table 2). According to the analysis of different seasons, the number of children infected with respiratory viruses reached peaks in winter and spring. Combined with Figure 1, the detection rate of common respiratory viruses from 2019 to 2023 was analyzed. It was found that Flu A and ADV were the most detected before the COVID-19 epidemic, accounting for 70.50% (37.05% + 33.45%) of the positive samples in 2019. During the COVID-19 pandemic, Flu A and Flu B were the most detected in 2020, accounting for 62.08% (32.83% + 29.25%) of the positive samples, and RSV and Flu B were the most detected in 2021, accounting for 81.02% (49.63% + 31.39%) of the positive samples. Flu A and ADV were the most detected in 2022, accounting for 66.02% (45.21% + 20.81%) of the positive samples in 2022. Flu A was the most detected in the late period of the COVID-19 epidemic, accounting for 76.76% of the positive specimens in 2023.

Comparison of gender distribution of respiratory viruses-positive number and rate between the pre-COVID-19, COVID-19, and post-COVID-19 periods is summarized in Table 3. In the past 5 years, the total number of respiratory virus-positive boys and girls was 120,321 and 96,560, respectively, with a ratio of 1.25. Among them, the boy-girl ratio of ADV-, Flu A-, Flu B-, and RSV-positive children was 1.38, 1.21, 1.19, and 1.26, respectively. The number of infected boys was a little higher than girls. By further chi-squared test, only ADV- and RSV-positive numbers were statistically significant between boys and girls, p < 0.05. The p value of Flu A and Flu B between male and female distributions was greater than 0.05, indicating that the differences were not statistically significant.

We also studied the situation of mixed infection and found that before the COVID-19 epidemic in 2019, 2,542 samples (1.19%) were detected with two or more virus infections at the same time. During the COVID-19 pandemic, there were 551 cases (0.78%) in 2020, 36 cases (0.06%) in 2021, 75 cases (0.06%) in 2022, and 177 cases (0.08%) in the late COVID-19 epidemic in 2023. The mixed infection situation decreased after the COVID-19 epidemic.

As shown in Tables 4-7 and Figure 2, before the COVID-19 epidemic, ADV still occupied the majority in most age groups (38.67% for 1–3 years old, 41.54% for 4–6 years old, and 26.83% for >7 years old); the proportions of Flu A and Flu B increased with age (Flu A: 36.66% for 1- to 3-year-old, 36.40% for 4- to 6-year-old, and 46.26% for >7 years; Flu B: 9.02% for 1- to 3-year-old, 19.96% for 4- to 6-year-old, and 26.22% for >7 years); the proportion of RSV decreased with age, accounted for 76.11% of the viruses that caused acute respiratory diseases in infants younger than 28 days. During the COVID-19 pandemic, RSV was the most important virus that caused acute respiratory diseases in infants younger than 28 days and infants from January to December. Compared with before the COVID-19 epidemic, the proportion of Flu A decreased sharply during the COVID-19 pandemic. However, in the late period of the COVID-19 epidemic, the proportion of Flu An increased sharply, and Flu A was the most important respiratory virus among children of all ages.

Figure 3 shows that the infection rate of ADV in children of different age groups had the same trend before, during, and after the COVID-19 pandemic, and the infection rate of children aged 4–6 years was high. The age distribution of RSV is mainly young children (<28 days, 1–12 months old), and the percentage of RSV-positive samples decreases with age. The age distribution of Flu A-positive samples increased with age. In addition, in 2021, the number of children infected with Flu A was the lowest, and only 44 cases of single Flu A-positive samples were found.

We statistically analyzed the seasonal changes in respiratory viruses and described the time characteristics of common respiratory virus infections in children (Fig. 4; Tables 8-11). We observed that the positive sample size and the detection rate of ADV in 2019 before the COVID-19 epidemic were higher than those in other years (Table 8). During the COVID-19 epidemic, the number of people infected with ADV decreased obviously, which was manifested in the following aspects: from January to February 2020, the number of people infected with ADV decreased from 1,861 to 170, and then the number of people infected with ADV remained at a low level for a long time. In addition, even in the late period of the COVID-19 epidemic, the infection level remained low.

Flu A has an obvious seasonal distribution pattern. Before the COVID-19 epidemic, Flu infection peaked in February 2019 (Table 9). During the COVID-19 pandemic, the infection rate of Flu A was low, especially in 2021, and only 52 cases of Flu A-positive samples (including single and mixed infection) were found. In addition, in the late period of the COVID-19 epidemic, Flu A ushered in a new round of infection peaks in February and March 2023, and the positive rate of Flu A was higher than the COVID-19 epidemic in 2019.

The infection characteristics of influenza B exhibit certain similarities to those of influenza A; however, distinct differences also exist between them. Before the COVID-19 epidemic, Flu B infection peaked in April 2019 (Table 10). After the COVID-19 pandemic began, the number of people infected with Flu B decreased sharply, specifically from 5,592 in January 2020 to 178 in February. After a long time, the number of people infected with Flu B was low. In December 2021, the infection rate of Flu B increased. In addition, in the late period of COVID-19, the detection rate of Flu B was low, and the level was much lower than that of Flu A.

RSV is another respiratory virus with a seasonal distribution pattern (Table 11). RSV infections typically occur within the period from November to February, with a notably higher prevalence during the winter season.

Hao et al. [12] have shown that from 2018 to 2022, the positive rate of respiratory virus infections in males was higher than that in females. This indicates that boys are more susceptible to respiratory virus infections than girls before and after the COVID-19 pandemic. In addition, recent research also shown that in the postpandemic era, the gender-based differences in the positive rate were generally small, although some pathogens exhibit slight variations [13]. In our study, the results are consistent with those of previous studies. The total number of respiratory virus-positive boys and girls was 120,321 and 96,560, respectively, with a ratio of 1.25. Among them, the boy-girl ratio of ADV-, Flu A-, Flu B-, and RSV-positive children was 1.38, 1.21, 1.19, and 1.26, respectively. The number of infected boys was a little higher than girls. Overall, boys are more prone to respiratory virus infections than girls, but further research and analysis are needed regarding specific types of viruses. The positive rate of COVID-19 in these samples did not count in this study. The coinfection of these pathogens with SARS-CoV-2 in children deserves further study. It may become one of the directions of our work in the future.

After the outbreak of COVID-19, many strict public health measures have been taken around the world to control the pandemic, which has also greatly affected the spread of respiratory viruses [7]. At present, few studies have focused on the epidemic characteristics of common respiratory viruses in children in the prepandemic and late stages of COVID-19. Therefore, we studied and compared the changes in epidemic characteristics of common respiratory viruses in children before, during, and after the COVID-19 pandemic. The results showed that the detection rate of COVID-19 was 33.20% before the epidemic, 24.54% during the pandemic, and 35.20% in the late epidemic. Compared with that before the COVID-19 epidemic, the detection rate of common respiratory viruses in children decreased significantly during the COVID-19 epidemic and increased again after NPIs were canceled in the late period of the COVID-19 epidemic.

By analyzing the detection of common respiratory viruses in children in the pre-epidemic, pandemic, and late stages of COVID-19, it was found that before the epidemic of COVID-19, the viruses of Flu A and ADV dominated in 2019. The viruses of Flu A and Flu B dominated in 2020, RSV and Flu B dominated in 2021, Flu A and ADV dominated in 2022, and Flu A dominated in the late stage of COVID-19. The results show that the mainstream virus spectrum of children's common respiratory infections in Hangzhou changed significantly in three stages: before, during, and after COVID-19. In addition, the infection rate of influenza viruses (Flu A and Flu B) was positively correlated with age, and the infection rate increased with the growth of children’s age (Fig. 2). Studies have shown that global influenza virus infection is more common than other respiratory viruses, but with the implementation of NPIs in the early stage of the COVID-19 pandemic, global influenza virus activity has dropped significantly [2, 14]. A study in Austria showed that in the short time after the blockade in March 2020, compared with the previous seasons (each season), the cases of different respiratory virus infections decreased rapidly and statistically [15]. This is consistent with our research results. A study carried out in Central China showed that influenza activity decreased significantly in 2020–2021 [16]. This proves our research. Our results show that from January to February 2020, the number of people infected with Flu A decreased from 6,452 (18.68%) to 39 (1.56%), and the spread of influenza virus decreased. Du et al. [17] showed that the age group most susceptible to influenza virus infection is 3–14 years old, which is similar to our results. In the early stage of the COVID-19 pandemic, NPIs effectively reduced nonfamily social interaction, thus reducing virus transmission and cross-infection [18]. We believe that the low infection rate of respiratory viruses in 2020 is due to strict NPIs, which have prevented the spread of SARS-CoV-2 and other respiratory viruses to some extent. With the effective control of the epidemic, schools will resume classes, and cross-communication among families, communities, and schools may lead to a large-scale surge of epidemics [19, 20]. Children have increased the risk of respiratory virus infection in their daily school activities, and the respiratory infection rate has increased. The reasons for the increase may be caused by many factors. During the epidemic in COVID-19, people pay attention to personal protection and other measures and rarely contact external pathogens, but immunity needs to be established and maintained through repeated contact with pathogenic microorganisms. The resurgence of the influenza A virus could potentially be attributed to low-temperature and low-humidity conditions, which have been shown to facilitate the transmission of the influenza virus [13]. The implementation of NPIs has effectively curbed the spread of viruses, thereby substantially influencing the exposure of children to respiratory viruses. In the subsequent period when individuals remove their masks, the likelihood of being exposed to pathogens surges remarkably. Nevertheless, due to the prior insufficient exposure of children to these viruses, certain aspects of their immune function have not been adequately maintained. Consequently, they may be less capable of mounting an effective defense against pathogen invasion. A typical feature of COVID-19 infection is that the level of lymphocytes decreases. Therefore, once infected with COVID-19, the resistance may further decline, making it easier for respiratory viruses to enter. In this study, we found that there were two infection peaks of Flu A in July 2022 and March 2023. After the orderly resumption of classes in March 2022, 4- to 6-year-olds need to go to school to participate in group activities, which leads to the emergence of cross-infection, and the compliance of young children with masks is not as high as that of older children, which leads to an increase in the respiratory tract infection rate. In March 2023, the number of people at the peak of Flu A infection (21,250) was higher than that in January to March 2019 before the epidemic (19,162), and Flu A infection rebounded and exceeded the historical level (2019), which appeared after most NPIs were relaxed. Physical distancing and face mask use have been worldwide recognized as effective NPIs to mitigate the spread of COVID-19 [21]. Activities of respiratory viral infections were reduced substantially in the early phases of the COVID-19 pandemic, and massive NPIs were likely the main driver [22]. This may be because NPIs reduce the chance of contact with viruses, which leads to a decline in immunity [23]. Our results show that from January to February 2020, the number of people infected with RSV dropped sharply. During the COVID-19 epidemic, the number of RSV viruses detected in various places also decreased significantly, which was due to the implementation of protective measures against COVID-19 in various places [24‒26]. RSV is the most common cause of acute lower respiratory tract infection in children. Studies have shown that in 2015, there were 33.1 million cases of acute lower respiratory tract infection associated with RSV among children aged 0–60 months worldwide, resulting in 111,800 deaths [27, 28]. Since RSV is usually transmitted through children’s close contact at school, the implementation of NPIs has reduced the spread of RSV among children.

The mixed infection situation decreased after the COVID-19 epidemic; this may be due to an overall reduction in virus transmission. It was found that 2,542 cases (3.46%) were detected in 2019 before the COVID-19 epidemic, 551 cases (2.87%) in 2020, 36 cases (0.25%) in 2021, 75 cases (0.26%) in 2022, and 177 cases (0.23%) in 2023 (Fig. 1). This is consistent with other similar regional research conclusions [29, 30].

In addition, we also studied the seasonal distribution and age distribution characteristics of common respiratory viruses in children. RSV is the only respiratory virus with a seasonal distribution pattern. RSV infection often occurs from November to February every year, and the prevalence rate is high in winter. Flu A also has an obvious seasonal distribution pattern, with a high prevalence rate in winter. At the same time, we also found that the main infected viruses in different age groups are different. RSV is the virus that mainly causes acute respiratory diseases in infants less than 28 days old and young children (1–12 months), and the proportion of RSV infection decreases with age. The infection rates of Flu A and Flu B increased with age. The ADV infection rate of children aged 4–6 years is the highest, which is the same as that of previous studies [31].

In response to the COVID-19 epidemic, most countries have restricted the spread of the virus through NPIs, and the number of influenza virus activities has also decreased sharply [32]. Where early intervention measures were implemented, the spread of all respiratory viruses was more effectively controlled, and the number of emergency department visits, hospitalizations, and deaths from respiratory diseases decreased significantly [33]. However, after the epidemic was released, the detection rate of influenza virus began to increase. We believe that the development of children’s respiratory virus infection depends on children’s susceptibility to different virus infections and the contact mode between infected patients and exposed objects. During the COVID-19 pandemic, we have deeply realized the role of NPIs in reducing the spread of respiratory viruses. Personal protective measures can effectively reduce the risk of personal infection, but children are not well protected because of their poor self-resistance and poor compliance with wearing masks. In addition, the transmissibility and mode of transmission of different viruses are specific and may vary with virus variants and subvariants [34]. It has been reported that seasonal influenza A and B viruses can escape the key antibodies induced by previous infection, vaccination, or both through antigen drift, resulting in an annual influenza epidemic [35]. Four pathogens were tested for patients suspected respiratory virus infection in actual clinical work. We will expand other data if conditions are available in the future.

In summary, NPI measures can effectively reduce the spread of common respiratory viruses. Lifting of NPIs can lead children to an increase viral infection rate, particularly in Flu A.

All experiments were performed involving human participants were in accordance with the guidelines and regulations of World Association Declaration of Helsinki (2013 version). The requirement for written informed consent was waived because of the retrospective nature of the study. Medical Ethics Committee approved this study of the Children’s Hospital, Zhejiang University School of Medicine (2023-IRB-0278-P-01).

The authors declare that they have no conflicts of interest related to this manuscript.

The authors received no financial support for the research, authorship, and/or publication of this article.

Jianming Zhou, Yanhong Sun, and Qing Ye designed and drafted the manuscript and contributed to manuscript editing. Jianming Zhou, Hao Shen, Liuqiao Yang, and Zhiwen Zhu collected and analyzed the data from patients. Jianming Zhou and Hongmei Zhu designed, edited, and revised the final manuscript. All authors approved the final manuscript.

The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon reasonable request.