Background Children and young people (CYP) may experience prolonged symptoms following COVID-19, commonly termed "Long-COVID". The nature of this in CYP is unclear, as are the sequalae of acute COVID-19. We aimed to systematically synthesise evidence of the long-term outcomes of COVID-19 in CYP. Methods 13 databases were searched until January 2022. Inclusion criteria: Observational studies reporting outcomes occurring four-weeks or more after COVID-19 in children <18 years old. Exclusion criteria: Outcomes of Paediatric Inflammatory Multisystem Syndrome. Title, abstract and full text screening were conducted independently by two reviewers. Data extraction and risk of bias assessment was by one reviewer with independent verification. Critical appraisal tools appropriate for study type were employed. Results were narratively synthesised with meta-analysis to generate summary estimates of risk of prolonged symptoms in CYP. Findings 94 studies were included. 66 recruited from hospital settings, 8 recruited solely from community settings. >100 symptoms were reported, the most common being fatigue, headache and cognitive symptoms. Summary estimates of risk of prolonged symptoms were higher for hospital samples (31.2%, 95% CI 20.3% to 43.2%) than for community samples (4.6%, 95% CI 3.4% to 5.8). Sequalae including stroke, type-1 diabetes, Guillan-Barre syndrome, and persistent radiological or blood test abnormalities have been reported in CYP following COVID-19. Most studies reporting these are case reports / case series and quality of evidence is low. Interpretation Prolonged symptoms following COVID-19 in children are variable and multi-system. Rates in community samples are lower than hospital. There is limited data on other sequalae in CYP. Heterogeneity in diagnosis of COVID-19, symptom classification, assessment method and duration of follow-up made synthesis less secure. Funding HT, CB and GS have National Institute for Health and Care Research fellowships. RB, CM and VW are supported by the NIHR West Midlands Applied Research Collaboration. CM Is supported by the NIHR School for Primary Care Research Research in context panel Evidence before this study At the time of writing and to the best of our knowledge, the protocol for this systematic review was a novel endeavour to summarise the longer-term effects of COVID-19 in children and young people (CYP). At least three systematic reviews have since been published, summarising the symptom profile and prevalence of Long-COVID in CYP, but prevalence estimates vary widely and the evidence base remains uncertain. In addition, there is very limited information on other sequalae of COVID-19 in this population group. We searched thirteen electronic databases (MEDLINE, EMBASE, AMED, HMIC, CINAHLPlus, PsycINFO, Web of Science (Science Citation and Social Science Citation indicies), ASSIA, WHO COVID-19: Global literature on coronavirus disease, Cochrane COVID-19 study register, ProQuest Coronavirus research database, NDLTD and OpenGrey) up to January 2022 for any empirical study including search terms pertaining to longer term symptoms of COVID-19 in CYP (<18 years old). The quality of the studies was mixed. Results were analysed narratively for each objective, and random effects meta-analyses conducted to estimate risk of prolonged symptoms in CYP who have had COVID-19. Added value of this study This review adds to the evidence of the heterogeneity of prolonged symptoms following COVID-19 in CYP but importantly, stratifies risk of this by recruitment setting. We also synthesise evidence on broader sequalae of the acute infection in this CYP and longer-term effects in CYP with pre-existing conditions, which have not been considered in previous reviews. We purposefully included case studies and case series, to capture emerging patterns of outcomes, which may well be important in a novel condition with a rapidly increasing volume of publications. To our knowledge, this systematic review and meta-analysis is the most comprehensive to date. Implications of all the available evidence This review adds to the evidence that a substantial proportion of CYP do experience effects of COVID-19 that last longer than four-weeks, with the most frequently reported prolonged symptoms being fatigue, headache and cognitive symptoms. The proportion of CYP developing prolonged symptoms in children recruited from community setting was low, although this may translate to a large number of affected CYP at population level. There is a paucity of controlled studies and this limits confidence that prolonged symptoms are attributable to COVID-19. Sequalae including stroke, type-1 diabetes, Guillan-Barre syndrome, and persistent radiological or blood test abnormalities have been reported in CYP following COVID-19 but most studies reporting these are case reports / case series and quality of evidence is low. To develop treatment plans and interventions for affected CYP, further studies are needed to better characterise this condition and understand its impact on the lives of CYP and their families and communities. These should ideally recruit from community settings, include population-based control groups and consider using standardised definitions and outcome measures where possible.

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Long-term outcomes of COVID-19 infection in children and young people: a systematic review and meta-analysis

We present a case of a 17-year-old boy with X-linked agammaglobulinemia who had mild disease when initially infected with SARS-CoV-2 but after recovering from acute infection developed fevers and a raised erythrocyte sedimentation rate that persisted for several weeks without any ongoing respiratory symptoms. Multiple nasopharyngeal swabs were found to be negative for SARS-CoV-2 during the febrile period, but typical changes of COVID-19 on high resolution CT chest scan led to the detection of SARS-CoV-2 on RT-PCR in a sample from a bronchoalveolar lavage. His fevers completely resolved after a 5-day course of remdesivir.

Andres Fernando Almario-Hernandez

Papers

SARS-CoV-2 Infection in an Adolescent With X-linked Agammaglobulinemia.