Which children and young people are at higher risk of severe disease and death after SARS-CoV-2 infection: a systematic review and individual patient meta-analysis
Authors: Harwood Rachel , Tan Helen , Camara Nish Talawila Da , Smith Clare , Ward Joseph , Tudur-Smith Catrin , Linney Michael , Clark Matthew , Whittaker Elizabeth , Saatci Defne , Davis Peter , Luyt Karen , Draper Elizabeth , Kenny Simon , Fraser Lorna , Viner Russell 
Published: July 2021

Abstract
Background We aimed to use individual patient data to describe pre-existing factors associated with severe disease, primarily admission to critical care, and death secondary to SARS-CoV-2 infection in children and young people (CYP) in hospital.Methods We searched Pubmed, European PMC, Medline and Embase for case series and cohort studies that included all CYP admitted to hospital with 30 CYP with SARS-CoV-2 or 5 CYP with PIMS-TS or MIS-C. Eligible studies contained 1) details of age, sex, ethnicity or co-morbidities, and 2) an outcome which included admission to critical care, mechanical invasive ventilation, cardiovascular support, or death. Studies reporting outcomes in more restricted grouping of co-morbidities were eligible for narrative review. Authors of eligible studies were approached for individual patient data (IPD). We used random effects meta-analyses for aggregate study-level data and multilevel mixed effect models for IPD data to examine risk factors (age, sex, comorbidities) associated with admission to critical care and death. Data shown are odds ratios and 95% confidence intervals (CI).Findings 81 studies were included, 57 in the meta-analysis (of which 22 provided IPD) and 26 in the narrative synthesis. Most studies had an element of bias in their design or reporting. Sex was not associated with critical care or death. Compared with CYP aged 1-4 years, infants had increased odds of admission to critical care (OR 1.63 (95% CI 1.40-1.90)) and death (OR 2.08 (1.57-2.86)). Odds of death were increased amongst CYP over 10 years (10-14 years OR 2.15 (1.54-2.98); >14 years OR 2.15 (1.61-2.88)). Number of comorbid conditions was associated with increased odds of admission to critical care and death for COVID-19 in a dose-related fashion. For critical care admission odds ratios were: 1 comorbidity 1.49 (1.45-1.53); 2 comorbidities 2.58 (2.41-2.75); ≥3 comorbidities 2.97 (2.04-4.32), and for death: 1 comorbidity 2.15 (1.98-2.34); 2 comorbidities 4.63 (4.54-4.74); ≥3 co-morbidities 4.98 (3.78-6.65). Odds of admission to critical care were increased for all co-morbidities apart from asthma (0.92 (0.91-0.94)) and malignancy (0.85 (0.17-4.21)) with an increased odds of death in all co-morbidities considered apart from asthma. Neurological and cardiac comorbidities were associated with the greatest increase in odds of severe disease or death. Obesity increased the odds of severe disease and death independently of other comorbidities.Interpretation Hospitalised CYP at greatest vulnerability of severe disease or death from SARS-CoV-2 infection are infants, teenagers, those with cardiac or neurological conditions, or 2 or more comorbid conditions, and those who are obese. These groups should be considered higher priority for vaccination and for protective shielding when appropriate. Whilst odds ratios were high, the absolute increase in risk for most comorbidities was small compared to children without underlying conditions.