BackgroundDespite children and young people (CYP) having a low risk for severe coronavirus disease 2019 (COVID-19) outcomes, there is still a degree of uncertainty related to their risk in the context of immunodeficiency or immunosuppression, primarily due to significant reporting bias in most studies, as CYP characteristically experience milder or asymptomatic COVID-19 infection and the severe outcomes tend to be overestimated.MethodsA comprehensive systematic review to identify globally relevant studies in immunosuppressed CYP and CYP in general population (defined as younger than 25 years of age) up to 31 October 2021 (to exclude vaccinated populations) was performed. Studies were included if they reported the two primary outcomes of our study, admission to intensive therapy unit (ITU) and mortality, while data on other outcomes, such as hospitalization and need for mechanical ventilation were also collected. A meta-analysis estimated the pooled proportion for each severe COVID-19 outcome, using the inverse variance method. Random effects models were used to account for interstudy heterogeneity.FindingsThe systematic review identified 30 eligible studies for each of the two populations investigated: immunosuppressed CYP (n = 793) and CYP in general population (n = 102,022). Our meta-analysis found higher estimated prevalence for hospitalization (46% vs. 16%), ITU admission (12% vs. 2%), mechanical ventilation (8% vs. 1%), and increased mortality due to severe COVID-19 infection (6.5% vs. 0.2%) in immunocompromised CYP compared with CYP in general population. This shows an overall trend for more severe outcomes of COVID-19 infection in immunocompromised CYP, similar to adult studies.InterpretationThis is the only up-to-date meta-analysis in immunocompromised CYP with high global relevance, which excluded reports from hospitalized cohorts alone and included 35% studies from low- and middle-income countries. Future research is required to characterize individual subgroups of immunocompromised patients, as well as impact of vaccination on severe COVID-19 outcomes.Systematic Review RegistrationPROSPERO identifier, CRD42021278598.