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Effects of COVID-19-targeted nonpharmaceutical interventions on children's respiratory admissions in China: a national multicenter time series study

  • Xinyu Wang
    Affiliations
    Big Data Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
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  • Hui Xu
    Affiliations
    Big Data Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
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  • Ping Chu
    Affiliations
    Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
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  • Yueping Zeng
    Affiliations
    Medical Record Management Office, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
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  • Jian Tian
    Affiliations
    Big Data Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
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  • Fei Song
    Affiliations
    Medical Record Management Office, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
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  • Yongli Guo
    Affiliations
    Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
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  • Xin Xu
    Affiliations
    Information Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
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  • Xin Ni
    Affiliations
    Big Data Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
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  • Guoshuang Feng
    Correspondence
    Corresponding author: Guoshuang Feng, Big Data Center, Beijing Children's Hospital, 56 Nanlishi Road, Xicheng District, Beijing 100046, China. Tel: +8601059617184.
    Affiliations
    Big Data Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
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Open AccessPublished:October 11, 2022DOI:https://doi.org/10.1016/j.ijid.2022.10.009

      Highlights

      • Our results suggest that nonpharmaceutical interventions (NPIs) reduce children's respiratory admissions significantly.
      • The effect of NPIs is most drastic for pneumonia among children of all ages.
      • The effect is most drastic for children aged 4-6 and 7-12 years.
      • NPIs may be used to further prevent admissions for children's respiratory infections.

      Abstract

      Objectives

      To estimate the impact of nonpharmaceutical interventions (NPIs) targeted at the COVID-19 pandemic on the admission number of respiratory diseases, including pneumonia, acute bronchitis & bronchiolitis, and acute upper respiratory infections (AURIs) for children in China.

      Methods

      Continuous hospitalization records aged 0-18 years from January 1, 2016, to December 31, 2020, were collected from 26 tertiary children's hospitals. Interrupted time series analysis with a quasi-Poisson model was conducted with the start time of the COVID-19 pandemic as the interrupted timepoint and the weekly admission numbers of all-cause respiratory disease, pneumonia, acute bronchitis & bronchiolitis, and AURI as the outcome measures. Hospitalizations of childhood neoplasms were analyzed as the reference group.

      Results

      The reduction in admission numbers following NPIs was -55.0% (-57.9 to -51.9%) for all-cause respiratory diseases, -62.7% (-65.7 to -59.5%) for pneumonia, -48.1% (-53.3 to -42.3%) for bronchitis & bronchiolitis, and -24.3% (-28.6 to -19.8%) for AURI. The effect estimates of NPIs on childhood neoplasms was -29.1% (-33.6 to -24.4%). Stratification analysis showed the reduction was most drastic for children at 4-6 and 7-12 years.

      Conclusion

      The admission number for respiratory diseases among children in China decreased drastically after the implementation of NPIs. NPIs with low socio-economic burdens should be suggested even outside the COVID-19 pandemic.

      Keywords

      Introduction

      COVID-19 has exerted a profound influence on everyday life and the healthcare system worldwide. Since the outburst of COVID-19 in Wuhan city, China, in January 2020, a series of nonpharmaceutical interventions (NPIs) have been conducted nationwide. The NPIs refer to the combination of mask-wearing, handwashing, and social distancing, such as closing schools and public places, quarantining infected patients and close contacts, and travel restrictions (
      • Fricke LM
      • Glöckner S
      • Dreier M
      • Lange B.
      Impact of non-pharmaceutical interventions targeted at COVID-19 pandemic on influenza burden - a systematic review.
      ;
      • Zhang Y
      • Quigley A
      • Wang Q
      • MacIntyre CR.
      Non-pharmaceutical interventions during the roll out of COVID-19 vaccines.
      ). These measures have effectively curbed the large-scale spread of the epidemic, keeping the number of people infected with COVID-19 in China under control (
      • Tang JL
      • Abbasi K.
      What can the world learn from China's response to COVID-19?.
      ).
      Since the COVID-19 pandemic, many countries have witnessed a sharp fall in non-COVID-19-related emergency visits, outpatients, and inpatients for children (
      • Angoulvant F
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      • Filser M
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      • Rybak A
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      Coronavirus disease 2019 pandemic: impact caused by school closure and national lockdown on pediatric visits and admissions for viral and nonviral infections-a time series analysis.
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      • et al.
      COVID-19 related reduction in pediatric emergency healthcare utilization - a concerning trend.
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      • O'Leary F
      • et al.
      The impact of the COVID-19 pandemic on paediatric health service use within one year after the first pandemic outbreak in New South Wales Australia - a time series analysis.
      ;
      • Isba R
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      Where have all the children gone? Decreases in paediatric emergency department attendances at the start of the COVID-19 pandemic of 2020.
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      Change in urban and non-urban pattern of ED use during the COVID-19 pandemic in 28 Michigan hospitals: an observational study.
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      The impact of the COVID-19 pandemic on pediatric clinical practice in Wenzhou, China: a retrospective study.
      ). The reduction in hospital admission numbers could be explained in two ways, one being the change in healthcare-seeking behaviors. The public awareness of the pandemic has brought parents the fear of attending hospitals with their sick children, and they may choose to postpone the visit or seek medical help online (
      • Lim E
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      • et al.
      How to recognize if your child is seriously ill" during COVID-19 lockdown: an evaluation of parents' confidence and health-seeking behaviors.
      ). In addition, the regional lockdown from time to time and the restriction of patient flow since the start of the pandemic also caused the inaccessibility of health care (
      • Angoulvant F
      • Ouldali N
      • Yang DD
      • Filser M
      • Gajdos V
      • Rybak A
      • et al.
      Coronavirus disease 2019 pandemic: impact caused by school closure and national lockdown on pediatric visits and admissions for viral and nonviral infections-a time series analysis.
      ). The other explanation is about the secondary benefit of COVID-19-targeted NPIs since these measures are not specific to COVID-19 and could reduce the transmission of other viruses as well (
      • Kadambari S
      • Goldacre R
      • Morris E
      • Goldacre MJ
      • Pollard AJ.
      Indirect effects of the COVID-19 pandemic on childhood infection in England: population based observational study.
      ).
      The NPIs have been reported to have the strongest effect on children's respiratory systems. Respiratory diseases, especially pneumonia, are major causes of hospitalization and death among children younger than 5 years. Recently, a dramatic decrease in pediatric respiratory infections, such as pneumonia, bronchiolitis, and influenza, has been observed worldwide and deemed as the result of the interruption of person-to-person viral or bacterial transmission attributed mainly to mask-wearing, social distancing, and school closure (
      • Cheng W
      • Yu Z
      • Liu S
      • Sun W
      • Ling F
      • Pan J
      • et al.
      Successful interruption of seasonal influenza transmission under the COVID-19 rapid response in Zhejiang Province.
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      • et al.
      Fall of community-acquired pneumonia in children following COVID-19 non-pharmaceutical Interventions: a time series analysis.
      ;
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      Bronchiolitis in COVID-19 times: a nearly absent disease?.
      ).
      Since the NPIs are continuing in China, this study aimed to investigate how much the admission numbers of respiratory diseases, including pneumonia, bronchitis/bronchiolitis, and acute upper respiratory infections (AURI), have decreased in Chinese children since the implementation of NPIs. We utilized data from 26 tertiary children's hospitals in China from January 2016 to December 2020 and conducted an interrupted time series analysis with weekly data. In addition, we roughly estimated the effect of healthcare-seeking behavior change caused either by virus panic or by restriction of patient flow, using weekly admission numbers of childhood neoplasms. The rationale for choosing childhood neoplasms as the reference group was based on the hypothesis that the reduction in their admission number, if there is any, would be mainly caused by the city or school lockdown, travel restrictions, and healthcare-seeking behavior change. We could therefore approximate the extent to which the reduction in respiratory admissions can be attributed to NPIs such as mask-wearing, handwashing, and social distancing.

      Methods

      Data source

      The data was collected from The FUTang Updating medical REcords (FUTURE) Database. The database was set up by the Futang Research Center of Pediatric Development (FRCPD), which was founded in 2013 and was the first research-based organization of children's hospitals in China. Until June 2022, FRCPD has included 47 members who are all tertiary children's hospitals and distributed mostly in the capital cities of the provinces in China. This children's hospital alliance represents the best quality of health care for the diagnosis and treatment of children's diseases in China. Among the FRCPD members, 26 hospitals have agreed and uploaded the summary reports of discharged patients to the FUTURE database annually. The distribution of the 26 hospitals is shown in Figure 1. Up to the time that the research was conducted, the database had over 6 million hospitalization records from 2016 to 2020. The data recorded the demographic characteristics of each patient (age, gender, personal identification, etc.) and clinical information (diagnosis, comorbidity, surgery, etc.). Until now, FUTURE is still the largest and most representative database for hospitalized children in China and can reflect the situation and change in the composition of children's illnesses. More details about the database have been presented in a previous publication (
      • Wang X
      • Zeng Y
      • Tian J
      • Xu H
      • Song F
      • Guo Y
      • et al.
      A brief introduction to the FUTang Updating medical REcords (FUTURE) database.
      ).
      Figure 1
      Figure 1The distribution of the 26 tertiary children's hospitals included in this study.

      Case selection and study outcome

      Based on the International Classification of Diseases and Related Health Problems (10th-revision, ICD-10), we extracted hospital admissions with the following codes: J00-J06 for AURI; J12-J18 for pneumonia; J20 and J21 for bronchitis & bronchiolitis; J00-J99 for all-cause respiratory diseases; and C00- D48 for childhood neoplasms as the reference group.
      The outcome variables were the weekly admission numbers of all-cause respiratory diseases, pneumonia, bronchitis & bronchiolitis, and AURI over time. The second outcome variables were the weekly admission numbers of the aforementioned diseases stratified by age. According to the physical development and education stages, children were grouped into five periods: less than 1 year old; 1-3 years old; 4-6 years old (kindergarten period); 7-12 years old (primary school period); and 13-18 years old (middle school period).

      Statistical analysis

      We adopted the interrupted time series design in this study. Outcome variables were analyzed by quasi-Poisson regression, accounting for secular trends before and after the implementation of NPIs, seasonality, and overdispersion of data. The time unit of outcome variables was determined to be 1 week to achieve optimal model precision. We take the lockdown time of Wuhan city, which was January 23, 2020, as the beginning of the nationwide implementation of NPIs. The intervention was included in the model as a dummy variable estimating the immediate post-intervention change. We hypothesized that the implementation of NPIs would have an impact on the outcome variables of the next unit time. Therefore, the pre-NPIs period was from January 4, 2016, to January 26, 2020 (212 weeks), and the post-NPIs period was from January 27, 2020, to December 27, 2020 (48 weeks). There were strong seasonal fluctuations for respiratory diseases, with a higher number recorded in winter than in summer. We accounted for the seasonality by including harmonic terms (sines and cosines) with 52-week periods. Using data from the pre-NPIs period to generate a quasi-Poisson model that fits the observed values of weekly admission numbers for respiratory diseases, we can predict the “counterfactual” values if there had been no COVID-19 and NPIs. The discrepancy between the fitted values and the counterfactual values reveals the impact of NPIs on the admission number of respiratory diseases. The crude weekly numbers rather than the number per 1000 admissions were analyzed because the NPIs, including the lockdown, had an impact on all kinds of diseases. The model validation was conducted by visual inspection of the correlograms (autocorrelation and partial autocorrelation functions) and the residuals analysis. Statistical tests with p <0.05 were considered significant. All statistical analyses were performed by R v4.1.2 (http://www.R-project.org).

      Results

      From 2016 to 2020, there were a total of 5,660,475 admissions in the 26 participating centers, of which 1,566,284 met the ICD-10 code for all-cause respiratory diseases. As is presented in Table 1, before the implementation of NPIs, the weekly admission number for all-cause respiratory diseases was 6611.4 for all children, and it was reduced to 3430.4 after the NPIs. The percentage of change is estimated to be -55.0% (95% CI: -57.9%, -51.9%) by the interrupted time series analysis with a quasi-Poisson regression model (Figure 2). The stratification analyses showed that NPIs had the greatest impact on children aged 4-6 years (-61.9% 95% CI: -65.7%, -59.5%), followed by children aged 7-12 years (-61.4% 95% CI: -65.6%, -56.7%), and had the least impact on children aged 13-18 years (-24.0% 95% CI: -32.7%, -14.2%) (Figure 3). For hospitalizations due to childhood neoplasms, which served as the reference group in this study, the effect of NPIs is estimated to be -29.1% (95% CI: -33.6%, -24.4%), much lower than that on respiratory diseases.
      Table 1The mean weekly admissions before and after the implementation of NPIs and the estimated changes.
      Before NPIsAfter NPIsPercentage of change (95% CI)P-value
      Childhood neoplasms
      738.8644.8-29.1 (-33.6; -24.4)<0.001
      Respiratory diseases
       Total6611.43430.4-55.0(-57.9; -51.9)<0.001
       <1 year1197.6699.4-41.0(-51.9; -27.6)<0.001
       1-3 years3455.31680.7-56.4(-60.4; -51.9)<0.001
       4-6 years1293.4639.9-61.9(-65.7; -57.7)<0.001
       7-12 years620.3359.5-61.4(-65.6; -56.7)<0.001
       13-18 years44.950.9-24.0(-32.7; -14.2)<0.001
      Pneumonia
       Total4038.51857.5-62.7(-65.7; -59.5)<0.001
       <1 year906.0537.9-43.3(-54.0; -30.2)<0.001
       1-3 years2197.4969.3-63.6(-67.6; -59.2)<0.001
       4-6 years629.9240.8-74.0(-77.6; -69.9)<0.001
       7-12 years288.498.1-80.1(-83.8; -75.4)<0.001
       13-18 years16.811.4-58.0(-64.8; -49.9)<0.001
      Bronchitis & bronchiolitis
       Total692.0417.2-48.1(-53.3; -42.3)<0.001
       <1 year116.583.3-33.0(-45.0; -18.4)<0.001
       1-3 years375.3228.8-47.0(-53.1; -40.1)<0.001
       4-6 years140.968.1-59.3(-66.2; -51.0)<0.001
       7-12 years54.631.0-60.0(-67.1; -51.4)<0.001
       13-18 years4.75.9-33.5(-48.0; -14.8)<0.001
      Acute upper respiratory infections
       Total646.2554.6-24.3(-28.6; -19.8)<0.001
       <1 year52.150.9-3.5(-16.9; 12.0)0.638
       1-3 years329.5331.2-11.4(-16.7; -5.6)<0.001
       4-6 years169.898.3-48.2(-53.4; -42.3)<0.001
       7-12 years87.361.9-44.0(-49.1; -38.3)<0.001
       13-18 years7.512.436.6(15.5; 61.5)<0.001
      Abbreviation: NPIs, nonpharmaceutical interventions.
      Figure 2
      Figure 2Impact of NPIs on weekly admission numbers for all-cause respiratory diseases, pneumonia, bronchitis and bronchiolitis, and AURI, from January 1, 2016, to December 31, 2020.
      The blue dots show the observed data. The red line shows the model estimates based on observed data using quasi-Poisson regression modeling. The dotted red line shows the expected values without COVID-19 and the following NPIs in the post-intervention period. The start of the NPIs is indicated by the vertical dotted black line.
      Abbreviations: AURI, acute upper respiratory infections; NPIs, nonpharmaceutical interventions.
      Figure 3
      Figure 3Impact of NPIs on weekly admission numbers for all-cause respiratory diseases, pneumonia, bronchitis & bronchiolitis, and AURI for different age groups, from January 1, 2016, to December 31, 2020.
      The blue dots show the observed data. The red line shows the model estimates based on observed data using quasi-Poisson regression modeling. The dotted red line shows the expected values without COVID-19 and the following NPIs in the post-intervention period. The start of the NPIs is indicated by the vertical dotted black line.
      Abbreviations: AURI, acute upper respiratory infections; NPIs, nonpharmaceutical interventions.
      Admissions with pneumonia accounted for most of the respiratory diseases, and the reduction in admission number is estimated to be -62.7% (95% CI: -65.7%, -59.5%), with the weekly admission number of 4038.5 before and 1857.5 after the implementation of NPIs (Table 1 and Figure 2). The impact of NPIs was found greatest among children aged 7-12 years (-80.1% 95% CI: -83.8%, -75.4%), followed by children aged 4-6 years (-74.0% 95% CI: -77.6%, -69.9%) (Figure 3).
      For bronchitis and bronchiolitis, the weekly admission number was much lower than for pneumonia, which was 692 before the NPIs and 417.2 thereafter. The reduction caused by NPIs was estimated to be -48.1% (95% CI: -53.3%, -42.3%) (Table 1 and Figure 2). The two age groups most affected by NPIs were still 7-12 years (-60.0% 95% CI: -67.1%; -51.4%) and 4-6 years (-59.3% 95% CI: -66.2%, -51.0%) (Figure 3).
      As to the AURI, the effect of NPIs was estimated to be -24.3% (95% CI: -28.6%, -19.8%) (Table 1 and Figure 2). The effect was greatest for children aged 4-6 years (-48.2% 95% CI: -53.4%; -42.3%), followed by children 7-12 years (-44.0% 95% CI: -49.1%, -38.3%). For children less than 1 year, the impact of NPIs was not statistically significant. It is worth noting that the impact of NPIs on the admission number of AURI for children aged 13-18 years was significantly upward, with an estimated increase of 36.6% (95% CI: 15.5%, 61.5%) (Figure 3).

      Discussion

      In this interrupted time series analysis with 1,566,284 respiratory hospitalization records among Chinese children, the numbers of admission following NPIs decreased by -55%, -62.7%, -48.1%, and -24.3% for all-cause respiratory diseases, pneumonia, bronchitis/bronchiolitis, and AURI, respectively. This is the first time in China to assess the impact of COVID-19-targeted NPIs on the admission numbers for children with data from 26 tertiary children's hospitals across 5 years. The unprecedented data volume and study period make the conclusions of this study representative and reliable and can provide scientific evidence for the following control and prevention policy of the pandemic.
      Compared to the effect of NPIs on childhood neoplasms, which was estimated to be -29.1%, NPIs were found to have an additional effect of -25.9% on all-cause respiratory admissions, -33.6% on pneumonia admissions, and -19% on bronchitis/bronchiolitis admissions. The additional effect might be mostly attributed to the effects of mask-wearing, handwashing, and social distancing on the interruption of person-to-person viral or bacterial transmission. Mask-wearing has been strongly recommended in the world since the COVID-19 pandemic. Up till now, it is still a mandatory health policy in China and people wearing no masks are not allowed in transportation, entertainment venues, or other public places. Masks play a vital role in controlling the transmission of infectious agents by preventing both droplets and aerosols (
      • Jones DS
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      ). As aerosol and droplets are also the route of transmission for viral respiratory diseases but not for nonrespiratory diseases, the additional decrease in pediatric respiratory admissions in the present study might be attributed to mask-wearing to a large extent. In addition, hand hygiene and hand cleansing awareness, which have been emphasized since the COVID-19 pandemic, could also help reduce pediatric respiratory diseases. It is reported that proper hand hygiene could decrease a proportion of the spread of transmissible disease and a meta-analysis quantitively demonstrated that improvements in hand hygiene resulted in reductions in 21% of respiratory illnesses (
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      The present study found that NPIs had the most significant impact of -62.7% on pneumonia admissions, which is in line with the results of another related study in France that reported the monthly number of hospitalized community-acquired pneumonia decreased by -63.0% after NPI implementation (
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      ). The reduction may be related to the drastic change in the distribution of causative pathogens of respiratory tract infections (
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      ). It is reported that among children infected with community-acquired pneumonia in Shanghai, China, the detection rate of eight of the most common respiratory viruses, which ranged from 16.9-26.9% from 2011 to 2019, dramatically decreased to 10.5% in 2020 (
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      ). Another microbiological study in Poland discovered a 99% drop in the respiratory syncytial virus among pediatric infections during the pandemic season until April 2021 compared to the pre-pandemic years (
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      A more interesting discovery is that the reduction in admission numbers was most drastic in children aged 4-6 years, who are mostly in kindergarten, then in children aged 7-12 years, who are mostly in primary school. The phenomenon could be explained that: firstly, children in primary school and kindergarten experienced longer school closures than children aged 13-18 years, who had a heavier course load. Therefore, they were less likely to be infected by classmates. Secondly, children in these two age groups are supposed to have higher compliance with wearing masks than children aged 1-3 years and younger. Thirdly, mask-wearing may play a stronger protective effect on younger children who have immature lungs with smaller airways and immature immune systems but longer outdoor time or more chance of exposure to pathogens related to respiratory disease (
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      • et al.
      Air pollution and noncommunicable diseases: a review by the Forum of International Respiratory Societies' Environmental Committee, Part 1: the damaging effects of air pollution.
      ). Just as shown in Table 1, among all children with respiratory disease, the proportion was highest in the 1-3 years old group than the 4-6 years old group but lowest in the 13-18 years old group. Thus, the preventive effect of mask-wearing for respiratory disease was more apparent among children 4-6 years old. These findings highlight the great significance of mask-wearing to prevent pediatric respiratory disease, in view of mask “slackers” rejecting public health advice and refusing to wear them in some regions worldwide. Considering the cost-effective and sustainable characteristics of mask-wearing and handwashing, these two interventions should be strongly suggested even after the pandemic.
      The most notable strength of this study relies on the multicenter design and long time duration. We included 26 tertiary children's hospitals accounting for more than 40% of all national public tertiary children's hospitals in this study. Among them, 20 were located in the capital of the province and had the most representative population of hospitalized children in that area. Therefore, the conclusions can reflect the national situation to a large extent regarding how much the NPIs affected children's respiratory admission numbers. There are also several limitations of this study, so the interpretation of the results should be treated with caution. Firstly, the NPIs refer to the combination of several interventions, but part of NPIs, such as the closure of schools, entertainment venues, and public places, and travel restrictions, was not implemented continuously, so the impact of NPIs on the admission number might fluctuate depending on the severity of the pandemic. Secondly, we did not exclude noninfectious respiratory diseases from all-cause respiratory diseases. Therefore, the effect of mask-wearing, social distancing, and handwashing on infectious respiratory disease, which was supposed to be reflected by the disparity between the reduction of respiratory admissions and that of childhood neoplasms, might have been underestimated. Thirdly, some of the avoided infections during NPIs were reported to have shown an outbreak after the NPIs had been lifted, especially for children, and the concept of immune debt has been raised and further explored (
      • Cohen PR
      • Rybak A
      • Werner A
      • Béchet S
      • Desandes R
      • Hassid F
      • et al.
      Trends in pediatric ambulatory community acquired infections before and during COVID-19 pandemic: a prospective multicentric surveillance study in France.
      ). Since this study ended in 2020, it could not evaluate the long-term effect of NPIs in China. Further analysis would be imperative when the database is complete with data for 2021.

      Conclusion

      In conclusion, the NPIs following the COVID-19 pandemic caused a drastic reduction in the admission number of pediatric respiratory diseases in China, and NPIs such as mask-wearing, handwashing, and social distancing played a significant role in preventing infectious respiratory disease. The reduction was most drastic for pneumonia and in children aged 4-6 and 7-12 years.

      Declaration of competing interest

      The authors have no competing interests to declare.

      Funding

      This study was supported by Beihang University & Capital Medical University Advanced Innovation Center for Big Data-Based Precision Medicine Plan [No. 201901], The Special Fund of the Pediatric Medical Coordinated Development Center of Beijing Hospitals Authority [No. XTCX201809], and Beijing Municipal Administration of Hospitals Incubating Program [No.PG2021023].

      Ethical approval

      Ethical approval to hold and analyze the dataset was obtained from the Ethics Committee of Beijing Children's Hospital, Capital Medical University (Approval number: 2020-k-10).

      Author contributions

      Concept and design: Xinyu Wang, Guoshuang Feng. Acquisition, analysis, or interpretation of data: Guoshuang Feng, Xinyu Wang, and Hui Xu. Drafting of the manuscript: Xinyu Wang. Critical revision of the manuscript for important intellectual content: Ping Chu, Yongli Guo, and Fei Song. Obtained funding: Guoshuang Feng. Administrative, technical, or material support: Xin Xu, Jian Tian, and Xin Ni. The manuscript has been read and approved by all the authors.

      Acknowledgments

      We thank Anhui Provincial Children's Hospital, Baoding Children's Hospital, Children's Hospital of Hebei Province, Children's Hospital of Nanjing Medical University, Children's Hospital of Soochow University, Children's Hospital of Shanxi, Dalian Women and Children's Medical Group, Fuzhou Children's Hospital of Fujian Province, Gansu Provincial Maternity and Child-Care Hospital, Guiyang Children's Hospital, Hangzhou Children's Hospital, Henan Children's Hospital, Hunan Children's Hospital, Inner Mongolia Maternity and Child Health Care Hospital, Kunming Children's Hospital, Liaocheng Children's Hospital, Liaoning Children's Hospital, Liuzhou Maternity and Child Healthcare Hospital, Qilu Children's Hospital of Shandong University, The Affiliated Children's Hospital of Nanchang University, Urumqi Children's Hospital, Women and Children's Hospital of Qinghai Province, Wuhan Children's Hospital of Huazhong University of Science & Technology, Xi'an Children's Hospital, and Shenzhen Children's Hospital for providing data on hospitalization records.

      Appendix. Supplementary materials

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