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Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
Research Unit of Evidence-Based Evaluation and Guidelines, Chinese Academy of Medical Sciences (2021RU017), School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaEvidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaLanzhou University GRADE Center, Lanzhou, ChinaLanzhou University, An Affiliate of the Cochrane China Network, Lanzhou, China
# Luo Ren and Enmei Liu contributed equally to this study.
Luo Ren
Correspondence
Corresponding authors: Luo Ren, Department of Respiratory Medicine, Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China.
# Luo Ren and Enmei Liu contributed equally to this study.
Affiliations
Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, ChinaPediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, China
# Luo Ren and Enmei Liu contributed equally to this study.
Enmei Liu
Correspondence
Corresponding author: Dr. Enmei Liu, Department of Respiratory Medicine, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China.
# Luo Ren and Enmei Liu contributed equally to this study.
Affiliations
Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
We read with interest the study by Han et al., which identified changes in the detection rates of respiratory viruses among children during the coronavirus disease 2019 (COVID-19) pandemic in Hangzhou, China.
We congratulate Han et al. for their important work, however, the study was single-centered and focused on only four viruses. Therefore, we conducted a systematic review and meta-analysis to assess and compare the global prevalence of respiratory pathogens in children with acute respiratory tract infections (ARTIs) before and during the COVID-19 pandemic to examine how COVID-19 may have altered the spectrum of respiratory pathogens in children.
We searched PubMed, Web of Science, Embase, Cochrane library, China National Knowledge Infrastructure, Wanfang Data, and China Biology Medicine disk from inception to May 4, 2022 (Supplementary Material 1). We also searched preprint servers (medRxiv, bioRxiv and SSRN) and Google Scholar, as well as the reference lists of included studies. We included observational studies that reported the detection rate of one or more respiratory viruses (respiratory syncytial virus [RSV], influenza virus [IFV], human adenovirus [HAdV], human rhinovirus [HRV], parainfluenza virus [PIV], human bocavirus [HBoV], human metapneumovirus [HMPV], human coronavirus [HCoV]) or atypical pathogens (mycoplasma pneumoniae [MP], chlamydia pneumoniae [CP]) in children (aged <18 years old) with ARTIs. The included study either focused only on detection during the pandemic period, or compared rates before and during COVID-19. The definitions of before and during COVID-19 were adapted according to the authors’ description, which followed the local outbreak time.
Risk of bias assessment was performed using the Joanna Briggs Institute Prevalence Critical Appraisal Tool.
Freeman-Tukey double arcsine transformation and DerSimonian and Laird random-effects models were used to calculate the pooled prevalence for each pathogen and the Mann-Whitney test to compare the differences in prevalence before and during the COVID-19 pandemic.
Data before COVID-19 were extracted from studies that compared prevalence before and during COVID-19, and data during COVID-19 were extracted from studies that focused only on the COVID-19 period as well as studies that compared rates before and during COVID-19. Statistical analyses were performed using Stata 15.0 and SPSS 22.0 (Stata “meta‑prop” command to achieve pooled prevalence). We reported this review according to PRISMA guidelines.
The protocol was registered in PROSPERO (CRD42022315842).
A total of 42 studies with 589,074 children were included (Supplementary Material 2). Overall, the studies were carried out in 11 countries in four WHO regions, plus an additional study which was conducted in four countries in Latin America. Thirty-three studies were performed in low- and middle-income countries (LMIC). Twelve studies focused only during the COVID-19 pandemic, while 30 studies compared before and during COVID-19. The period before COVID-19 covered from September 2010 to February 2020, and the period during COVID-19 covered from January 2020 to December 2021. Thirty-five studies were rated as low risk of bias and the remaining seven had moderate risk of bias (Supplementary Material 3).
MP, HRV and RSV were the three most detected pathogens before and during COVID-19. HRV (23.4%, 95%CI 17.8–29.6) ranked first during the pandemic. The prevalence of most pathogens decreased compared with that before COVID-19, with statistically significant decreases in RSV, IFV, IFV-A, HAdV, and PIV. An increase in the prevalence was observed for HRV and HCoV, but the changes were not statistically significant (Fig. 1; Supplementary Material 4). Substantial heterogeneity was detected in overall prevalence. Sensitivity analysis found reductions of heterogeneity for HCoV and CP before COVID-19 when including studies with low risk of bias and studies with sample sizes of 101 to 10,000, respectively (Supplementary Material 5). Funnel plots and Egger's test suggested possible publication bias for RSV (p = 0.001) before COVID-19 (Supplementary Material 6–7).
Fig. 1Overview of the prevalence of respiratory pathogens in children with ARTIs before and during the COVID-19 pandemic. * p <0.05 after comparing the prevalence of each pathogen before and during the COVID-19 pandemic by Mann-Whitney test.
Subgroup analysis showed that the prevalence of most pathogens in high-income countries (HIC) was lower than that in LMIC during COVID-19, while the prevalence of HRV was as high as 43.3% (95%CI 19.1–69.3) in Europe, which may be related to economic and resource differences. In LMIC, the availability and implementation of non-pharmaceutical interventions (NPIs) and virus testing may be inadequate. Besides, differences in the prevalence of each pathogen existed among population sources, specimens, ARTIs types, and detection methods (Supplementary Material 8).
Our study suggests an overall downward epidemiological shift during COVID-19, and NPIs may be a major contributor to this phenomenon, especially for enveloped viruses, as they are known to be more sensitive to environmental determinants. Other explanations could be changes in care-seeking behavior, particularly for children with mild symptoms, as well as virus-virus interactions. Of note, HRV increased and became the most frequent pathogen during COVID-19. We believe that this is possibly the result of its absence of envelope, small diameter, tremendous genetic diversity (>160 serotypes), and epidemiological inverse correlation with IFV (virus interference).
In our study, we also noticed that the prevalence of most pathogens in China after September 2020 was higher than before September 2020, likely corresponding to the relaxation of NPIs. These phenomena may be related to what is known as “immunity debt”,
which reminds us the need to recognize NPIs as a double-edged sword, and highlights the importance of active and continuous epidemiological surveillance and timely adjustment of immunization strategies.
The limitations of this review include high level of heterogeneity among studies; inconsistent stratification of included studies, hence the analyses of some subgroups were not sufficiently detailed; the possible underestimation of the prevalence before COVID-19, as we extracted pre-COVID-19 data from studies that compared before and during COVID-19; and the pooled prevalence during the pandemic corresponds to a wide time range, hence some subtle changes such as initial suppression and subsequent resurgence may have been averaged out.
This study is the first to systematically summarize the changes in the etiology for childhood ARTIs during COVID-19. However, hopefully, with further containment of the pandemic, the prevalence may gradually return to the pre-COVID-19 patterns. Further research is needed to elucidate how different components and intensities of NPIs relate to pathogen transmission, as well as the mechanism of virus-virus interactions, to better prepare us for any future respiratory virus pandemics.
Contributors
EL and LR proposed the concept of the systematic review. YT and XD did the literature search, reviewed studies for inclusion, and extracted and checked the data, with assistance from LR. YT did the data analyses and wrote the first draft of the manuscript. YC, SLN, ML provided methodological advice. EL, LR, YC, and SLN critically reviewed the manuscript. All authors approved the final manuscript as submitted.
Declaration of Competing Interest
We declare no competing interests.
Acknowledgments
This work was supported by the National Key Research and Development Program of China (2022YFC2704900) and Innovation Program for Chongqing's Overseas Returnees (2021059).
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