Epidemiology and Clinical Features of SARS-CoV-2 Infection in Children and Adolescents in the Pre-Omicron Era: A Global Systematic Review and Meta-Analysis

Background: Data on paediatric SARS-CoV-2 infections are limited, especially from the early pandemic period. In addition, children are not considered to be at high risk for severe outcomes of COVID-19. This systematic review with meta-analysis estimated the SAR-CoV-2 positivity rate, identified risk factors, and described the severity and mortality outcomes of SARS-CoV-2 infections in children aged ≤18 years, until December 2021, prior to the Omicron era.Methods: We searched MEDLINE, Embase, Global Health, CINAHL, China National Knowledge Infrastructure, Wanfang, CQvip, and WHO COVID-19 global literature databases for primary studies recruiting children aged ≤18 years with a confirmed diagnosis of SARS-CoV-2 infection either by molecular or antigen tests. The Joanna Briggs Institute critical appraisal tools were used to appraise the study quality. Meta-analyses using the random effects model were conducted for all outcomes except for race/ ethnicity as risk factor of SARS-CoV-2 infection.Findings: This review included 237 studies, each reporting at least one of the study outcomes. Based on data from 117 studies, the pooled SARS-CoV-2 positivity rate was 9·3% (95% CI = 7·15% to 11·73%). Having a comorbidity was identified as a risk factor for SARS-CoV-2 infection (RR = 1·33; 95% CI = 1·04 to 1·71) based on data from 49 studies. Most cases in this review presented with mild disease (n = 50) [52.47% (95% CI = 44.03% to 60.84%)]. However, around 20.70% of paediatric SARS-CoV-2 infections were hospitalised (n = 67), and 7·19%, 4·26%, and 2·92% required oxygen support (n = 57), intensive care (n = 93), and assisted ventilation (n = 63), respectively. The case fatality ratio (n = 119) was 0·87% (95% CI = 0·54% to 1·28%).Interpretation: Although there was substantial heterogeneity across individual study estimates, our analyses showed that children were at-risk for SARS-CoV-2 infections and severe outcomes in the pre-Omicron era. These findings underscore the need for effective vaccination strategies for paediatric population to protect against the acute and long-term sequalae of COVID-19.Funding: Pfizer.Declaration of Interest: DK reports consulting fees from Pfizer, related to the submitted work and outside the submitted work. XW received research grants from GlaxoSmithKline, Wellcome Trust, and Nanjing Medical University, outside the submitted work, and consultancy fees from Pfizer, related to the submitted work. NFI is an employee of the Ministry of Health, Malaysia (Johor State, Communicable Disease Control Unit). AK, JS and MHK are employees of Pfizer. HN reports consulting fees from Pfizer, related to the submitted work; and grants from the Innovative Medicines Initiative, Pfizer, and Icosavax outside the submitted work; consulting fees from the WHO, Pfizer, Gates Foundation, and Sanofi; honoraria from AbbVie; support from Sanofi for attending meetings; and participation on advisory boards from GSK, Sanofi, Merck, WHO, Janssen, Novavax, Resvinet, Icosavax, and Pfizer outside the submitted work.