Severe COVID-19 Infection and Pediatric Comorbidities: A Systematic Review and Meta-Analysis

  • Boyan K. Tsankov
    Affiliations
    Department of Pediatrics, BC Children’s Hospital, Vancouver, BC, Canada

    Division of Gastroenterology, Hepatology and Nutrition, BC Children’s Hospital, Vancouver, BC, Canada

    BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada

    Department of Immunology, University of Toronto, Toronto, ON, Canada
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  • Joannie M. Allaire
    Affiliations
    Department of Pediatrics, BC Children’s Hospital, Vancouver, BC, Canada

    Division of Gastroenterology, Hepatology and Nutrition, BC Children’s Hospital, Vancouver, BC, Canada

    BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
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  • Michael A. Irvine
    Affiliations
    BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
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  • Alison A. Lopez
    Affiliations
    Department of Pediatrics, BC Children’s Hospital, Vancouver, BC, Canada

    Division of Infectious Diseases, BC Children’s Hospital, Vancouver, BC, Canada

    BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
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  • Laura J. Sauvé
    Affiliations
    Department of Pediatrics, BC Children’s Hospital, Vancouver, BC, Canada

    Division of Infectious Diseases, BC Children’s Hospital, Vancouver, BC, Canada

    BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
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  • Bruce A. Vallance
    Affiliations
    Department of Pediatrics, BC Children’s Hospital, Vancouver, BC, Canada

    Division of Gastroenterology, Hepatology and Nutrition, BC Children’s Hospital, Vancouver, BC, Canada

    BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
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  • Kevan Jacobson
    Correspondence
    Corresponding author at: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, BC Children’s Hospital, 4480 Oak Street, Vancouver, BC, V6H 3V4, Canada.
    Affiliations
    Department of Pediatrics, BC Children’s Hospital, Vancouver, BC, Canada

    Division of Gastroenterology, Hepatology and Nutrition, BC Children’s Hospital, Vancouver, BC, Canada

    BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada

    Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
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Open AccessPublished:November 20, 2020DOI:https://doi.org/10.1016/j.ijid.2020.11.163

      Highlights

      What is known
      • Adults with comorbidities are more likely to suffer from severe manifestations of COVID-19
      • Children with COVID-19 have less severe disease manifestations than adults
      • Children may experience multisystem inflammatory syndrome due to COVID-19
      What is new
      • Children with comorbidities may be at an increased risk for PICU admission and/or severe COVID-19
      • Children with comorbidities may be at an increased risk of mortality during COVID-19 infection
      • Childhood obesity likely contributes to more serious manifestations of COVID-19

      Abstract

      Objective

      There is limited information on the severity of COVID-19 infection in children with comorbidities. We investigated the effects of pediatric comorbidities on COVID-19 severity by means of a systematic review and meta-analysis of published literature.

      Methods

      PubMed, Embase, and Medline databases were searched for publications on pediatric COVID-19 infections published January 1st to October 5th, 2020. Articles describing at least one child with and without comorbidities, COVID-19 infection, and reported outcomes were included.

      Results

      42 studies containing 275,661 children without comorbidities and 9,353 children with comorbidities were included. Severe COVID-19 was present in 5.1% of children with comorbidities, and in 0.2% without comorbidities. Random-effects analysis revealed a higher risk of severe COVID-19 among children with comorbidities than for healthy children; relative risk ratio 1.79 (95% CI 1.27 – 2.51; I2 = 94%). Children with underlying conditions also had a higher risk of COVID-19-associated mortality; relative risk ratio 2.81 (95% CI 1.31 – 6.02; I2 = 82%). Children with obesity had a relative risk ratio of 2.87 (95% CI 1.16 – 7.07; I2 = 36%).

      Conclusions

      Children with comorbidities have a higher risk of severe COVID-19 and associated mortality than children without underlying disease. Additional studies are required to further evaluate this relationship.

      Keywords

      Introduction

      The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the human coronavirus disease 2019 (COVID-19) pandemic that officially began on March 11, 2020 (
      • Cucinotta D.
      • Vanelli M.
      WHO Declares COVID-19 a Pandemic.
      ). At the time of writing of this report —November 9th, 2020 — there had been 50,539,082 confirmed cases with an associated 1,258,321 deaths worldwide resulting from COVID-19 infection (
      • COVID-19 Map
      Johns Hopkins Coronavirus Resource Center n.d. https://coronavirus.jhu.edu/map.html (accessed August 17, 2020).
      ). The virus primarily affects the lower respiratory tract, and infected individuals primarily present with fever, cough, and dyspnea, however gastrointestinal (GI) manifestations can also occur (
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ,
      • Shi H.
      • Han X.
      • Jiang N.
      • Cao Y.
      • Alwalid O.
      • Gu J.
      • et al.
      Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study.
      ). Although the infection course is usually non-fatal, severe COVID-19 infection with life-threatening presentations of acute respiratory distress syndrome (ARDS) and multiple organ failure can occur (
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ,
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ). Risk factors for severe manifestations of SARS-CoV-2 illness and associated mortality include age greater than 65 years (
      • Du H.
      • Dong X.
      • Zhang J.
      • Cao Y.
      • Akdis M.
      • Huang P.
      • et al.
      Clinical characteristics of 182 pediatric COVID‐19 patients with different severities and allergic status.
      ;
      • Wu Z.
      • McGoogan J.M.
      Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese.
      ), and underlying comorbidities such as diabetes, hypertension, and obesity (
      • Caussy C.
      • Wallet F.
      • Laville M.
      • Disse E.
      Obesity is Associated with Severe Forms of COVID-19.
      ;
      • Du H.
      • Dong X.
      • Zhang J.
      • Cao Y.
      • Akdis M.
      • Huang P.
      • et al.
      Clinical characteristics of 182 pediatric COVID‐19 patients with different severities and allergic status.
      ;
      • Guan W.
      • Liang W.
      • Zhao Y.
      • Liang H.
      • Zi-sheng Chen
      • Li Y.
      • et al.
      Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis.
      ;
      • Wu Z.
      • McGoogan J.M.
      Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese.
      ).
      Multiple studies on COVID-19 infection in children have noted differences in infection rates, symptoms, and mortality as compared to adults (
      • Dong Y.
      • Mo X.
      • Hu Y.
      • Qi X.
      • Jiang F.
      • Jiang Z.
      • et al.
      Epidemiology of COVID-19 Among Children in China.
      ;
      • Wu Z.
      • McGoogan J.M.
      Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese.
      ). One of the most comprehensive early studies of pediatric patients with SARS-CoV-2 infection reported that children develop a relatively mild disease course with 83% of confirmed cases presenting with mild to moderate infection, with an additional 13% being asymptomatic, and only 3% presenting with severe and critical illness (
      • Dong Y.
      • Mo X.
      • Hu Y.
      • Qi X.
      • Jiang F.
      • Jiang Z.
      • et al.
      Epidemiology of COVID-19 Among Children in China.
      ). However, such early case series potentially suffer from decreased testing of mildly infected individuals thereby leading to a potentially low rate of documented asymptomatic infections. A recent outbreak in a children’s overnight camp in the United States reported an asymptomatic infection rate of 26% among COVID-19 infected children (
      • Szablewski C.M.
      SARS-CoV-2 Transmission and Infection Among Attendees of an Overnight Camp — Georgia, June 2020.
      ). Nonetheless, the disease course in children can be heterogenous in nature, with the most common clinical signs and symptoms including fever, headaches, and sore throat (
      • Szablewski C.M.
      SARS-CoV-2 Transmission and Infection Among Attendees of an Overnight Camp — Georgia, June 2020.
      ). Critical illness in children and adults alike typically manifests with severe pneumonia characterized by specific oxygen concentrations less than 92%, autoinflammatory shock, and respiratory distress (
      • Sankar J.
      • Dhochak N.
      • Kabra S.K.
      • Lodha R.
      COVID-19 in Children: Clinical Approach and Management.
      ). Such cases frequently require mechanical ventilation and treatment with antiviral and immunomodulating regimens (
      • Sankar J.
      • Dhochak N.
      • Kabra S.K.
      • Lodha R.
      COVID-19 in Children: Clinical Approach and Management.
      ,
      • Zimmermann P.
      • Curtis N.
      Coronavirus Infections in Children Including COVID-19: An Overview of the Epidemiology, Clinical Features, Diagnosis, Treatment and Prevention Options in Children.
      ).
      Even so, previous reports have indicated clusters of an inflammatory syndrome, called “Multisystem Inflammatory Syndrome associated with COVID-19 (MIS-C)” or “Paediatric inflammatory multisystem syndrome (PIMS)” Kawasaki-like disease, a potentially fatal vasculitis, occurring in children following COVID-19 infection (
      • Riollano‐Cruz M.
      • Akkoyun E.
      • Briceno‐Brito E.
      • Kowalsky S.
      • Reed J.
      • Posada R.
      • et al.
      Multisystem inflammatory syndrome in children related to COVID‐19: A New York City experience.
      ;
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • Martelli L.
      • Ruggeri M.
      • Ciuffreda M.
      • et al.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
      ). Such reports indicate the potential (albeit uncommon) for severe and potentially fatal COVID-19 in pediatric patients. Although previous studies have established pre-existing comorbidities as significant risk factors for severe SARS-CoV-2 infection in adults (
      • Du H.
      • Dong X.
      • Zhang J.
      • Cao Y.
      • Akdis M.
      • Huang P.
      • et al.
      Clinical characteristics of 182 pediatric COVID‐19 patients with different severities and allergic status.
      ,
      • Guan W.
      • Liang W.
      • Zhao Y.
      • Liang H.
      • Zi-sheng Chen
      • Li Y.
      • et al.
      Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis.
      ), questions remain regarding childhood comorbidities and associated COVID-19 outcomes. While systematic reviews and meta-analyses examining COVID-19 in pediatric patients have been published (
      • Ding Y.
      • Yan H.
      • Guo W.
      Clinical Characteristics of Children With COVID-19: A Meta-Analysis.
      ,
      • Hoang A.
      • Chorath K.
      • Axel Moreira
      • Evans M.
      • Burmeister-Morton F.
      • Burmeister F.
      • et al.
      COVID-19 in 7780 pediatric patients: A systematic review.
      ), these reports did not evaluate the risk of severe SARS-CoV-2 infection specifically in children with pre-existing conditions. Consequently, the objective of this systematic review and meta-analysis is to examine the relative risk of severe COVID-19 infection and associated mortality in children with comorbidities.

      Methods

       Search Strategy and Selection Criteria

      For this systematic review and meta-analysis PubMed, Medline, and Embase databases were queried for articles published from January 1st, 2020 until October 5th, 2020. The Medline and Embase searches were conducted via the Ovid interface. The search terms “COVID-19”, “SARS-nCoV-2”, “SARS-CoV-2”, “2019-nCoV”, “novel coronavirus”, and “coronavirus” were used to obtain articles relating to the novel coronavirus pandemic occurring in 2020. To obtain literature pertaining specifically to SARS-CoV-2 infection in pediatric patients, the terms “child*”, “pediatr*”, “paediatr*”, “teenage”, “adolescent”, “infant”, and “newborn” were queried in conjunction with the coronavirus search. For the full search queries, see Supplement S1. To capture articles potentially missed by our systematic search, Google Scholar was queried for articles pertaining to COVID-19 infection in pediatric patients. Further articles were obtained by examining the references of highly relevant systematically retrieved articles. Only articles in English were considered for inclusion. References were managed with Endnote (version X9.0) software which was also used for duplicate removal. The systematic literature search was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) recommendations (
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      • Group T.P.
      Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement.
      ).
      Following deduplication, the reference titles were reviewed by BKT. Titles that did not imply a subject matter relevant to COVID-19 in pediatric patients were excluded. Following title review, the full-text content of the remaining literature was thoroughly analyzed by the author BKT. The following exclusion criteria were applied to the full-text articles: articles not mentioning pediatric comorbidities; adult only studies; articles where the pediatric comorbidity data was indistinguishable from adult comorbidity data; pre-existing reviews, systematic-reviews, and meta-analyses; articles with patients without confirmed COVID-19 infections; basic science studies; clinical discussions, recommendations, and guidelines; articles without reported patient outcomes; and studies of other coronaviruses. Articles containing at least one paediatric patient with comorbidities, and one paediatric patient without comorbidities were included. Furthermore, we included articles for which the severity and outcomes of SARS-CoV-2 infection in the paediatric patients was clearly defined. Following full-text review, BKT and KJ graded the remaining studies using the National Institutes of Health (NIH) Quality Assessment Tool for Case Series and Studies (). Any disagreements in rating were handled via discussion by the two reviewers until a consensus was reached. For the literature grading see Supplement S2.

       Data Extraction and Case Definitions

      The study authors; design; country of origin; aims; pediatric sample size; COVID-19 infection counts; disease severity; comorbidity counts; pediatric intensive care unit (PICU) admittance counts; and mortality counts were extracted from the included literature. The extracted comorbidities were either defined by the studies or classified into representative broader categories by BKT and KJ. Comorbidities such as trisomy 21, prematurity, and undefined genetic abnormalities were deemed as “other” pre-existing conditions. Obesity was defined by the studies where available, or by the authors as a body mass index (BMI) at or greater than the 95th percentile for children of the same age and sex according to CDC definitions (). To operationalize severe COVID-19 infection across the different studies, severe infection was deemed as any SARS-CoV-2 infection requiring supplemental help to normal breathing and/or admission to a PICU unless otherwise explicitly stated in the literature. Finally, paediatric patients were defined as participants suffering from COVID-19 who were below 21 years of age.

       Statistical Analyses

      PICU admission and mortality outcomes were assessed using a random effects meta-analysis (
      • Schwarzer G.
      • Carpenter J.R.
      • Rücker G.
      Meta-Analysis with R.
      ). A random effects model was chosen due to the potential variation in sampled study populations leading to differences in outcomes by co-morbidities. Estimation of random-effects variance was conducted using the Sidik-Jonkman estimator with Hartung-Knapp adjustment (
      • IntHout J.
      • Ioannidis J.P.
      • Borm G.F.
      The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method.
      ). For individual trials with no events in one or both groups, a continuity correction of the opposite treatment arm size was added to each cell for each effect measure (
      • Sweeting M.J.
      • Sutton A.J.
      • Lambert P.C.
      What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data.
      ). Binary estimators including risk ratios, and risk difference were estimated using the Mantel-Haenszel method (
      • Mantel N.
      • Haenszel W.
      Statistical aspects of the analysis of data from retrospective studies of disease.
      ,
      • Robins J.
      • Breslow N.
      • Greenland S.
      Estimators of the Mantel-Haenszel Variance Consistent in Both Sparse Data and Large-Strata Limiting Models.
      ). All analyses and data visualization were conducted in R version 4.0.2 using the meta and tidyverse libraries (
      • Balduzzi S.
      • Rücker G.
      • Schwarzer G.
      How to perform a meta-analysis with R: a practical tutorial.
      ;
      • Team, R Core, and others
      “R: A Language and Environment for Statistical Computing.” Vienna, Austria.
      ;
      • Wickham H.
      • Averick M.
      • Bryan J.
      • Chang W.
      • McGowan L.D.
      • François R.
      • et al.
      Welcome to the Tidyverse.
      ).

      Role of the Funding Source

      This study did not receive any funding. The study design, data analysis, and writing of the manuscript was conceptualized only by the authors.

      Results

      There were 13310 studies identified from our systematic search across the three databases (Fig. 1). Following de-duplication, 8206 records were reviewed based on a title screen, of which 7398 were deemed irrelevant to the subject matter of this study. The full-texts of the remaining 808 articles were reviewed for the presence of pediatric study participants who had: 1) pre-existing comorbidities; and 2) COVID-19 infection, for which clear outcomes were reported. 98 articles then underwent literature grading, with 86 studies deemed fair for further analysis. Among these 86 articles, only 42 had pediatric case-control participants without comorbidities with either severe COVID-19 and/or COVID-19-associated mortality. Five studies (
      • Bellino S.
      • Punzo O.
      • Rota M.C.
      • Del Manso M.
      • Urdiales A.M.
      • Andrianou X.
      • et al.
      COVID-19 Disease Severity Risk Factors for Pediatric Patients in Italy.
      ;
      • Bixler D.
      • Miller A.D.
      • Mattison C.P.
      • Taylor B.
      • Komatsu K.
      • Peterson Pompa X.
      • et al.
      SARS-CoV-2-Associated Deaths Among Persons Aged <21 Years - United States, February 12-July 31, 2020.
      ;
      • Blumfield E.
      • Levin T.L.
      COVID-19 in pediatric patients: a case series from the Bronx.
      ;
      • Moraleda C.
      • Serna-Pascual M.
      • Soriano-Arandes A.
      • Simó S.
      • Epalza C.
      • Santos M.
      • et al.
      Multi-inflammatory Syndrome in Children Related to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Spain.
      ;
      • Otto W.R.
      • Geoghegan S.
      • Posch L.C.
      • Bell L.M.
      • Coffin S.E.
      • Sammons J.S.
      • et al.
      The Epidemiology of Severe Acute Respiratory Syndrome Coronavirus 2 in a Pediatric Healthcare Network in the United States.
      ) only examined children who died from COVID-19 and were therefore only included in the mortality analysis. These 42 studies were therefore the basis for our analysis examining the effects of comorbidities on severe and potentially fatal manifestations of pediatric SARS-CoV-2 infection. Among the 42 articles, 18 studies were from the USA (43%), and 4 studies were from China (10%), Italy (10%), and Spain (10%) respectively. Of the remaining studies, 3 were from France (7%), 2 were from the United Kingdom (5%), and Iran (5%), and 1 was from Austria (2%), Brazil (2%), India (2%), Turkey (2%), and Uruguay (2%) (Table 1).
      Fig. 1
      Fig. 1PRISMA flow diagram for the identification of studies pertaining to COVID-19 and children with comorbidities published between January 1 st, 2020 and October 5th, 2020.
      Table 1Summary and characteristics of the 42 studies included in this systematic review and meta-analysis.
      STUDYStudy typeCountryStudy AimCOVID-19 Infection (N = 285,004)With comorbidities and COVID-19

      (n = 9353)
      COmorbidities and Severe COVID-19A

      (n = 481)
      Comorbidities and mortality (N = 135)
      (
      • Abdel-Mannan O.
      • Eyre M.
      • Löbel U.
      • Bamford A.
      • Eltze C.
      • Hameed B.
      • et al.
      Neurologic and Radiographic Findings Associated With COVID-19 Infection in Children.
      )
      RetrospectiveU.KReport neurological manifestations of children with COVID-194110
      (
      • Anand P.
      • Yadav A.
      • Debata P.
      • Bachani S.
      • Gupta N.
      • Gera R.
      Clinical profile, viral load, management and outcome of neonates born to COVID 19 positive mothers: a tertiary care centre experience from India.
      )
      RetrospectiveIndiaDescribe the clinical profile of neonates born to mothers with COVID-197300
      (
      • Bellino S.
      • Punzo O.
      • Rota M.C.
      • Del Manso M.
      • Urdiales A.M.
      • Andrianou X.
      • et al.
      COVID-19 Disease Severity Risk Factors for Pediatric Patients in Italy.
      )
      RetrospectiveItalyDescribe characteristics of COVID-19 in pediatric patients38362064
      (
      • Belhadjer Zahra
      • Mathilde Méot
      • Fanny Bajolle
      • Diala Khraiche
      • Antoine Legendre
      • Samya Abakka
      • et al.
      Acute Heart Failure in Multisystem Inflammatory Syndrome in Children in the Context of Global SARS-CoV-2 Pandemic.
      )
      RetrospectiveFranceReport cases of acute heart failure associated with COVID-19 in children31440
      (
      • Bhumbra S.
      • Malin S.
      • Kirkpatrick L.
      • Khaitan A.
      • John C.C.
      • Rowan C.M.
      • et al.
      Clinical Features of Critical Coronavirus Disease 2019 in Children. Pediatric Critical Care Medicine.
      )
      RetrospectiveUSADescribe the infection course of children hospitalized with COVID-192483
      (
      • Biko D.M.
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      • Barrera C.A.
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      • Matsubara D.
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      • et al.
      Imaging of children with COVID-19: experience from a tertiary children’s hospital in the United States.
      )
      RetrospectiveUSADescribe imaging features, comorbidities, and outcomes of children with COVID-1931341170
      (
      • Bixler D.
      • Miller A.D.
      • Mattison C.P.
      • Taylor B.
      • Komatsu K.
      • Peterson Pompa X.
      • et al.
      SARS-CoV-2-Associated Deaths Among Persons Aged <21 Years - United States, February 12-July 31, 2020.
      )
      RetrospectiveUSAReport the SARS-CoV-2-associated deaths in children residing in the USA1219191
      (
      • Blumfield E.
      • Levin T.L.
      COVID-19 in pediatric patients: a case series from the Bronx.
      )
      RetrospectiveUSAReport the outcomes of critically-ill children with COVID-1918122
      (
      • Cai X.
      • Ma Y.
      • Li S.
      • Chen Y.
      • Rong Z.
      • Li W.
      Clinical Characteristics of 5 COVID-19 Cases With Non-respiratory Symptoms as the First Manifestation in Children.
      )
      Case-seriesChinaReport the outcomes and clinical characteristics of pediatric patients with COVID-19 that did not have respiratory symptoms as the first manifestation of infection5320
      (
      • Chao J.Y.
      • Derespina K.R.
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      • Goldman D.L.
      • Aldrich M.
      • Weingarten J.
      • et al.
      Clinical Characteristics and Outcomes of Hospitalized and Critically Ill Children and Adolescents with Coronavirus Disease 2019 at a Tertiary Care Medical Center in New York City.
      )
      RetrospectiveUSAReport the risk factors associated with severe COVID-19 in pediatric patients4631121
      (
      • de Farias E.C.F.
      • Pedro Piva J.
      • de Mello M.L.F.M.F.
      • do Nascimento L.M.P.P.
      • Costa C.C.
      • Machado M.M.M.
      • et al.
      Multisystem Inflammatory Syndrome Associated With Coronavirus Disease in Children: A Multi-centered Study in Belém, Pará, Brazil.
      )
      ProspectiveBrazilDescribe the characteristics of COVID-19-associated PIMS in 11 children11552
      (
      • DeBiasi R.L.
      • Song X.
      • Delaney M.
      • Bell M.
      • Smith K.
      • Pershad J.
      • et al.
      Severe Coronavirus Disease-2019 in Children and Young Adults in the Washington, DC, Metropolitan Region.
      )
      RetrospectiveUSAExamine the epidemiology of pediatric COVID-19 infection in Washington, DC1656950
      (
      • Derespina K.R.
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      • Plichta A.
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      • Bercow A.
      • Choi J.
      • et al.
      Clinical Manifestations and Outcomes of Critically Ill Children and Adolescents with Coronavirus Disease 2019 in New York City.
      )
      RetrospectiveUSADescribe outcomes of COVID-19 in children in New York City7052522
      (
      • Diorio C.
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      • Vella L.A.
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      • Chase J.
      • Burudpakdee C.
      • et al.
      Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS–CoV-2.
      )
      ProspectiveUSAReport the hematological differences between MIS-C and COVID-19 in children141392
      (
      • Du H.
      • Dong X.
      • Zhang J.
      • Cao Y.
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      • et al.
      Clinical characteristics of 182 pediatric COVID‐19 patients with different severities and allergic status.
      )
      RetrospectiveChinaReport the outcomes of and laboratory characteristics of COVID-19 among hospitalized pediatric patients with a focus on allergic patients1825920
      (
      • Eghbali A.
      • Shokrollahi S.
      • Mahdavi N.S.
      • Mahdavi N.S.A.
      • Dabbagh A.
      )
      Case-seriesIranDescribe 4 cases of pediatric COVID-19 in Iran4221
      (
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      • Montagnani C.
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      • Meini A.
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      • et al.
      Multicentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10 April 2020.
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      RetrospectiveItalyReport outcomes and disease characteristics of COVID-19 among multiple pediatric care centres in Italy1683320
      (
      • García-Salido A.
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      • Martínez de Azagra-Garde A.
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      • García-Teresa MÁ
      • et al.
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      ProspectiveSpainDescribe series of children admitted to a Spanish PICU due to COVID-197110
      (
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      RetrospectiveItalyDescribe the characteristics of severe vs non-severe COVID-19 in children1272060
      (
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      )
      RetrospectiveUruguayExamine the characteristics and

      outcomes of pediatric patients in PICUs due to COVID-19 infection
      1712121
      (
      • Götzinger F.
      • Santiago-García B.
      • Noguera-Julián A.
      • Lanaspa M.
      • Lancella L.
      • Calò Carducci F.I.
      • et al.
      COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.
      )
      Cross-sectionalAustriaExamine the characteristics and outcomes of children with COVID-19 across Europe582145252
      (
      • Kainth M.K.
      • Goenka P.K.
      • Williamson K.A.
      • Fishbein J.S.
      • Subramony A.
      • Barone S.
      • et al.
      Early Experience of COVID-19 in a US Children’s Hospital.
      )
      RetrospectiveUSADescribe the presentation, course, and severity of pediatric COVID-196530101
      (
      • Kaushik S.
      • Aydin S.I.
      • Derespina K.R.
      • Bansal P.B.
      • Kowalsky S.
      • Trachtman R.
      • et al.
      Multisystem Inflammatory Syndrome in Children Associated with Severe Acute Respiratory Syndrome Coronavirus 2 Infection (MIS-C): A Multi-institutional Study from New York City.
      )
      RetrospectiveUSAAssess the outcomes of COVID-19-associated MIS-C331616
      (
      • Leeb R.T.
      COVID-19 Trends Among School-Aged Children — United States, March 1–September 19, 2020.
      )
      RetrospectiveUSAExamine the epidemiology of COVID-19 among US children277,285773810914
      (
      • Lovinsky-Desir S.
      • Deshpande D.R.
      • De A.
      • Murray L.
      • Stingone J.A.
      • Chan A.
      • et al.
      Asthma among hospitalized patients with COVID-19 and related outcomes.
      )
      RetrospectiveUSAExamine the impact of asthma on COVID-19 severity552424
      (
      • Mannheim J.
      • Gretsch S.
      • Layden J.E.
      • Fricchione M.J.
      Characteristics of Hospitalized Pediatric Coronavirus Disease 2019 Cases in Chicago, Illinois, March–April 2020.
      )
      Case-seriesUSAReport the clinical characteristics of pediatric COVID-19 in Chicago64134
      (
      • Meslin P.
      • Guiomard C.
      • Chouakria M.
      • Porcher J.
      • Duquesne F.
      • Tiprez C.
      • et al.
      Coronavirus Disease 2019 in Newborns and Very Young Infants: a Series of Six Patients in France.
      )
      Case-seriesFrancePresent outcomes of 6 children with COVID-19 in France6200
      (
      • Moraleda C.
      • Serna-Pascual M.
      • Soriano-Arandes A.
      • Simó S.
      • Epalza C.
      • Santos M.
      • et al.
      Multi-inflammatory Syndrome in Children Related to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Spain.
      )
      Case-seriesSpainDescribe clinical features of MIS-C in Spain31102
      (
      • Moreno-Galarraga L.
      • Urretavizcaya-Martínez M.
      • Alegría Echauri J.
      • García Howard M.
      • Ruperez García E.
      • Aguilera-Albesa S.
      • et al.
      SARS-CoV-2 infection in children requiring hospitalization: the experience of Navarra, Spain.
      )
      RetrospectiveSpainDescribe the presentations of COVID-19 in Spain11400
      (
      • Otto W.R.
      • Geoghegan S.
      • Posch L.C.
      • Bell L.M.
      • Coffin S.E.
      • Sammons J.S.
      • et al.
      The Epidemiology of Severe Acute Respiratory Syndrome Coronavirus 2 in a Pediatric Healthcare Network in the United States.
      )
      RetrospectiveUSADescribe the outcomes and features of COVID-19 in children4242422
      (
      • Oualha M.
      • Bendavid M.
      • Berteloot L.
      • Corsia A.
      • Lesage F.
      • Vedrenne M.
      • et al.
      Severe and fatal forms of COVID-19 in children.
      )
      RetrospectiveFranceDescribe severe presentations of COVID-19 in children2719192
      (
      • Parri N.
      • Lenge M.
      • Cantoni B.
      • Arrighini A.
      • Romanengo M.
      • Urbino A.
      • et al.
      COVID-19 in 17 Italian Pediatric Emergency Departments.
      )
      RetrospectiveItalyExamine the diagnostic, clinical presentation, interventions and outcomes of pediatric patients with confirmed COVID-19 in Italy.1703860
      (
      • Riollano‐Cruz M.
      • Akkoyun E.
      • Briceno‐Brito E.
      • Kowalsky S.
      • Reed J.
      • Posada R.
      • et al.
      Multisystem inflammatory syndrome in children related to COVID‐19: A New York City experience.
      )
      RetrospectiveUSADescribe the first COVID-19 MIS-C associated cases in New York City15540
      (
      • Schwartz D.A.
      • Mohagheghi P.
      • Beigi B.
      • Zafaranloo N.
      • Moshfegh F.
      • Yazdani A.
      Spectrum of neonatal COVID-19 in Iran: 19 infants with SARS-CoV-2 perinatal infections with varying test results, clinical findings and outcomes.
      )
      Case-seriesIranDescribe the characteristics and outcomes of COVID-19 in neonates in Iran1915100
      (
      • Shekerdemian L.S.
      • Mahmood N.R.
      • Wolfe K.K.
      • Riggs B.J.
      • Ross C.E.
      • McKiernan C.A.
      • et al.
      Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units.
      )
      Cross-sectionalUSACharacterize COVID-19 infection in North American PICUs484040
      (
      • Sun D.
      • Li H.
      • Lu X.-X.
      • Xiao H.
      • Ren J.
      • Zhang F.-R.
      • et al.
      Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center’s observational study.
      )
      RetrospectiveChinaExamine the clinical characteristics of pediatric COVID-198110
      (
      • Swann O.V.
      • Holden K.A.
      • Turtle L.
      • Pollock L.
      • Fairfield C.J.
      • Drake T.M.
      • et al.
      Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study.
      )
      ProspectiveUKExplore the clinical characteristics of pediatric COVID-19 and MIS-C in the UK651276636
      (
      • Tagarro A.
      • Epalza C.
      • Santos M.
      • Sanz-Santaeufemia F.J.
      • Otheo E.
      • Moraleda C.
      • et al.
      Screening and Severity of Coronavirus Disease 2019 (COVID-19) in Children in Madrid, Spain.
      )
      RetrospectiveSpainDescribe the epidemiology and treatment of COVID-19 in Madrid411110
      (
      • Waltuch T.
      • Gill P.
      • Zinns L.E.
      • Whitney R.
      • Tokarski J.
      • Tsung J.W.
      • et al.
      Features of COVID-19 post-infectious cytokine release syndrome in children presenting to the emergency department.
      )
      Case seriesUSADescribe the characteristics and outcomes of 4 pediatric cases of COVID-194220
      (
      • Yayla B.C.C.
      Characteristics and Management of Children with COVID-19 in Turkey. Balkan Med J n.d.;37.
      )
      RetrospectiveTurkeyExamine characteristics of COVID-19 in children in Turkey2202120
      (
      • Zachariah P.
      • Johnson C.L.
      • Halabi K.C.
      • Ahn D.
      • Sen A.I.
      • Fischer A.
      • et al.
      Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York.
      )
      RetrospectiveUSACompare the features of pediatric COVID-19 disease between severe and mild infection50338
      (
      • Zheng F.
      • Liao C.
      • Fan Q.
      • Chen H.
      • Zhao X.
      • Xie Z.
      • et al.
      Clinical Characteristics of Children with Coronavirus Disease 2019 in Hubei, China.
      )
      RetrospectiveChinaDescribe the clinical characteristics of pediatric COVID-1925220
      Abbreviations: COVID-19 - coronavirus disease 2019; PICU - pediatric intensive care unit.
      A Defined by the studies, or PICU admission, or need for supplemental breathing aid during the course of infection.

       Study Patient Characteristics

      From the 42 articles, a total of 285,004 pediatric patients with laboratory-confirmed SARS-CoV-2 infection were identified. Among this cohort, 9,353 (3.3%) had at least one underlying comorbidity (Table 1). Gender demographic data was available for 280,999 COVID-19 infected children, of which 142,411 (50.7%) were female and 138,588 (49.3%) were male. We were able to extrapolate age-category data in 362 children. Of these, 138 (38%) were under 1 year of age, 82 (21%) 1 to 5 years of age, 31 (8%) 6 to 10, 22 (6%) 10 – 14, and 89 (23%) were older than 14 years of age. To the best of our ability, we have excluded any study participants that were over 21 years, such as those present in the study by DeBiasi and colleagues.

       Relative Risk of Pediatric Comorbidities on Severe COVID-19 Infection

      Among the 9,353 pediatric patients with SARS-CoV-2 infection and underlying comorbidities, 481 (5.1%) had severe COVID-19 and/or were admitted to a PICU (Table 1). In contrast, only 579 of the 275,661 (0.21%) pooled pediatric patients without comorbidities had a severe manifestation of COVID-19. Employing a random-effects model to examine the relative risk of severe COVID-19 and/or PICU admission among children with comorbidities, we obtained a total relative risk ratio of 1.79 (95% CI 1.27 – 2.51; χ 2 = 602.31 (P < 0.001); I2 = 94%) (Fig. 2). It is important to note that only 37 studies were included in this analysis as 5 studies only examined COVID-19-associated deaths (
      • Bellino S.
      • Punzo O.
      • Rota M.C.
      • Del Manso M.
      • Urdiales A.M.
      • Andrianou X.
      • et al.
      COVID-19 Disease Severity Risk Factors for Pediatric Patients in Italy.
      ;
      • Bixler D.
      • Miller A.D.
      • Mattison C.P.
      • Taylor B.
      • Komatsu K.
      • Peterson Pompa X.
      • et al.
      SARS-CoV-2-Associated Deaths Among Persons Aged <21 Years - United States, February 12-July 31, 2020.
      ;
      • Blumfield E.
      • Levin T.L.
      COVID-19 in pediatric patients: a case series from the Bronx.
      ;
      • Moraleda C.
      • Serna-Pascual M.
      • Soriano-Arandes A.
      • Simó S.
      • Epalza C.
      • Santos M.
      • et al.
      Multi-inflammatory Syndrome in Children Related to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Spain.
      ;
      • Otto W.R.
      • Geoghegan S.
      • Posch L.C.
      • Bell L.M.
      • Coffin S.E.
      • Sammons J.S.
      • et al.
      The Epidemiology of Severe Acute Respiratory Syndrome Coronavirus 2 in a Pediatric Healthcare Network in the United States.
      ). Nonetheless, 7 studies (
      • Anand P.
      • Yadav A.
      • Debata P.
      • Bachani S.
      • Gupta N.
      • Gera R.
      Clinical profile, viral load, management and outcome of neonates born to COVID 19 positive mothers: a tertiary care centre experience from India.
      ;
      • Kainth M.K.
      • Goenka P.K.
      • Williamson K.A.
      • Fishbein J.S.
      • Subramony A.
      • Barone S.
      • et al.
      Early Experience of COVID-19 in a US Children’s Hospital.
      ;
      • Meslin P.
      • Guiomard C.
      • Chouakria M.
      • Porcher J.
      • Duquesne F.
      • Tiprez C.
      • et al.
      Coronavirus Disease 2019 in Newborns and Very Young Infants: a Series of Six Patients in France.
      ;
      • Moreno-Galarraga L.
      • Urretavizcaya-Martínez M.
      • Alegría Echauri J.
      • García Howard M.
      • Ruperez García E.
      • Aguilera-Albesa S.
      • et al.
      SARS-CoV-2 infection in children requiring hospitalization: the experience of Navarra, Spain.
      ;
      • Riollano‐Cruz M.
      • Akkoyun E.
      • Briceno‐Brito E.
      • Kowalsky S.
      • Reed J.
      • Posada R.
      • et al.
      Multisystem inflammatory syndrome in children related to COVID‐19: A New York City experience.
      ;
      • Schwartz D.A.
      • Mohagheghi P.
      • Beigi B.
      • Zafaranloo N.
      • Moshfegh F.
      • Yazdani A.
      Spectrum of neonatal COVID-19 in Iran: 19 infants with SARS-CoV-2 perinatal infections with varying test results, clinical findings and outcomes.
      ;
      • Tagarro A.
      • Epalza C.
      • Santos M.
      • Sanz-Santaeufemia F.J.
      • Otheo E.
      • Moraleda C.
      • et al.
      Screening and Severity of Coronavirus Disease 2019 (COVID-19) in Children in Madrid, Spain.
      ) had a higher risk ratio of severe COVID-19 among pediatric patients without comorbidities than those with underlying conditions (Fig. 2). Furthermore, studies such as the CDC Mortality and Morbidity Weekly Report (
      • Leeb R.T.
      COVID-19 Trends Among School-Aged Children — United States, March 1–September 19, 2020.
      ) had noticeably larger participant cohort populations than other reports. To examine the potential preferential bias of these studies towards the overall relative risk ratio of our analysis, we individually excluded each of the 37 studies to determine the overall effect of each singular study on the net relative risk ratio. Notably, no article significantly influenced the risk ratio in either direction (Fig. 3).
      Fig. 2
      Fig. 2Pooled estimate of the relative risk of severe COVID-19 among pediatric patients with comorbidities.
      Fig. 3
      Fig. 3Sensitivity analysis of the influence of each included study on the overall relative risk of severe COVID-19 among children with comorbidities.

       Relative Risk of Pediatric Comorbidities on Mortality Associated with COVID-19 Infection

      Nineteen of the 42 articles included in this meta-analysis reported children who died while being infected with SARS-CoV-2 (Fig. 4). Across the 19 articles, of the 274,647 pediatric patients with COVID-19 infection without comorbidities, only 77 (0.03%) died across 8 studies (
      • Bixler D.
      • Miller A.D.
      • Mattison C.P.
      • Taylor B.
      • Komatsu K.
      • Peterson Pompa X.
      • et al.
      SARS-CoV-2-Associated Deaths Among Persons Aged <21 Years - United States, February 12-July 31, 2020.
      ;
      • Cai X.
      • Ma Y.
      • Li S.
      • Chen Y.
      • Rong Z.
      • Li W.
      Clinical Characteristics of 5 COVID-19 Cases With Non-respiratory Symptoms as the First Manifestation in Children.
      ;
      • Du H.
      • Dong X.
      • Zhang J.
      • Cao Y.
      • Akdis M.
      • Huang P.
      • et al.
      Clinical characteristics of 182 pediatric COVID‐19 patients with different severities and allergic status.
      ;
      • Götzinger F.
      • Santiago-García B.
      • Noguera-Julián A.
      • Lanaspa M.
      • Lancella L.
      • Calò Carducci F.I.
      • et al.
      COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.
      ;
      • Leeb R.T.
      COVID-19 Trends Among School-Aged Children — United States, March 1–September 19, 2020.
      ;
      • Oualha M.
      • Bendavid M.
      • Berteloot L.
      • Corsia A.
      • Lesage F.
      • Vedrenne M.
      • et al.
      Severe and fatal forms of COVID-19 in children.
      ;
      • Riollano‐Cruz M.
      • Akkoyun E.
      • Briceno‐Brito E.
      • Kowalsky S.
      • Reed J.
      • Posada R.
      • et al.
      Multisystem inflammatory syndrome in children related to COVID‐19: A New York City experience.
      ;
      • Yayla B.C.C.
      Characteristics and Management of Children with COVID-19 in Turkey. Balkan Med J n.d.;37.
      ). In contrast, 134 (1.5%) of the 8960 children with pre-existing conditions died during the course of their SARS-CoV-2 infection across 15 studies (
      • Bellino S.
      • Punzo O.
      • Rota M.C.
      • Del Manso M.
      • Urdiales A.M.
      • Andrianou X.
      • et al.
      COVID-19 Disease Severity Risk Factors for Pediatric Patients in Italy.
      ;
      • Bixler D.
      • Miller A.D.
      • Mattison C.P.
      • Taylor B.
      • Komatsu K.
      • Peterson Pompa X.
      • et al.
      SARS-CoV-2-Associated Deaths Among Persons Aged <21 Years - United States, February 12-July 31, 2020.
      ;
      • Blumfield E.
      • Levin T.L.
      COVID-19 in pediatric patients: a case series from the Bronx.
      ;
      • Chao J.Y.
      • Derespina K.R.
      • Herold B.C.
      • Goldman D.L.
      • Aldrich M.
      • Weingarten J.
      • et al.
      Clinical Characteristics and Outcomes of Hospitalized and Critically Ill Children and Adolescents with Coronavirus Disease 2019 at a Tertiary Care Medical Center in New York City.
      ;
      • Derespina K.R.
      • Kaushik S.
      • Plichta A.
      • Conway E.E.
      • Bercow A.
      • Choi J.
      • et al.
      Clinical Manifestations and Outcomes of Critically Ill Children and Adolescents with Coronavirus Disease 2019 in New York City.
      ;
      • Diorio C.
      • Henrickson S.E.
      • Vella L.A.
      • McNerney K.O.
      • Chase J.
      • Burudpakdee C.
      • et al.
      Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS–CoV-2.
      ;
      • Eghbali A.
      • Shokrollahi S.
      • Mahdavi N.S.
      • Mahdavi N.S.A.
      • Dabbagh A.
      ;
      • de Farias E.C.F.
      • Pedro Piva J.
      • de Mello M.L.F.M.F.
      • do Nascimento L.M.P.P.
      • Costa C.C.
      • Machado M.M.M.
      • et al.
      Multisystem Inflammatory Syndrome Associated With Coronavirus Disease in Children: A Multi-centered Study in Belém, Pará, Brazil.
      ;
      • Götzinger F.
      • Santiago-García B.
      • Noguera-Julián A.
      • Lanaspa M.
      • Lancella L.
      • Calò Carducci F.I.
      • et al.
      COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.
      ;
      • Kainth M.K.
      • Goenka P.K.
      • Williamson K.A.
      • Fishbein J.S.
      • Subramony A.
      • Barone S.
      • et al.
      Early Experience of COVID-19 in a US Children’s Hospital.
      ;
      • Leeb R.T.
      COVID-19 Trends Among School-Aged Children — United States, March 1–September 19, 2020.
      ;
      • Moraleda C.
      • Serna-Pascual M.
      • Soriano-Arandes A.
      • Simó S.
      • Epalza C.
      • Santos M.
      • et al.
      Multi-inflammatory Syndrome in Children Related to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Spain.
      ;
      • Otto W.R.
      • Geoghegan S.
      • Posch L.C.
      • Bell L.M.
      • Coffin S.E.
      • Sammons J.S.
      • et al.
      The Epidemiology of Severe Acute Respiratory Syndrome Coronavirus 2 in a Pediatric Healthcare Network in the United States.
      ;
      • Oualha M.
      • Bendavid M.
      • Berteloot L.
      • Corsia A.
      • Lesage F.
      • Vedrenne M.
      • et al.
      Severe and fatal forms of COVID-19 in children.
      ;
      • Swann O.V.
      • Holden K.A.
      • Turtle L.
      • Pollock L.
      • Fairfield C.J.
      • Drake T.M.
      • et al.
      Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study.
      ) (Table 1). The random effects model used to determine the risk of mortality among children with comorbidities and COVID-19 relative to pediatric patients without comorbidities revealed a total risk ratio of 2.81 (95% CI 1.31 – 6.02; χ 2 = 97.85 (P < 0.001); I2 = 82%) (Fig. 4). In only five of the studies (
      • Cai X.
      • Ma Y.
      • Li S.
      • Chen Y.
      • Rong Z.
      • Li W.
      Clinical Characteristics of 5 COVID-19 Cases With Non-respiratory Symptoms as the First Manifestation in Children.
      ;
      • Du H.
      • Dong X.
      • Zhang J.
      • Cao Y.
      • Akdis M.
      • Huang P.
      • et al.
      Clinical characteristics of 182 pediatric COVID‐19 patients with different severities and allergic status.
      ;
      • Oualha M.
      • Bendavid M.
      • Berteloot L.
      • Corsia A.
      • Lesage F.
      • Vedrenne M.
      • et al.
      Severe and fatal forms of COVID-19 in children.
      ;
      • Riollano‐Cruz M.
      • Akkoyun E.
      • Briceno‐Brito E.
      • Kowalsky S.
      • Reed J.
      • Posada R.
      • et al.
      Multisystem inflammatory syndrome in children related to COVID‐19: A New York City experience.
      ;
      • Yayla B.C.C.
      Characteristics and Management of Children with COVID-19 in Turkey. Balkan Med J n.d.;37.
      ) did children with comorbidities have a lower risk of mortality during the course of COVID-19 (Fig. 4). Notably, subsequent sensitivity analysis confirmed that no one article significantly affected the relative risk ratio of mortality among children with pre-existing conditions (Fig. 5).
      Fig. 4
      Fig. 4Pooled estimate of the relative risk of COVID-19-associated mortality among pediatric patients with comorbidities.
      Fig. 5
      Fig. 5Sensitivity analysis of the relative contributions of each study toward the relative risk of mortality during COVID-19 infection in pediatric patients with comorbidities.

       Relative Risks of Various Pediatric Comorbidities on Severe COVID-19 Manifestations

      Our previously presented analyses hinted at a higher risk of severe COVID-19 infection and associated mortality among pediatric patients with underlying comorbidities (Fig. 2, Fig. 4). We next sought to examine the potential impact of specific comorbidities on the risks of severe SARS-CoV-2 manifestations. For details on the underlying conditions represented among all 9,353 children with comorbidities regardless of COVID-19 severity, see Supplement S3. In the 42 studies included in this meta-analysis, we found that among children with severe COVID-19, 64 children were obese (
      • Abdel-Mannan O.
      • Eyre M.
      • Löbel U.
      • Bamford A.
      • Eltze C.
      • Hameed B.
      • et al.
      Neurologic and Radiographic Findings Associated With COVID-19 Infection in Children.
      ;
      • Chao J.Y.
      • Derespina K.R.
      • Herold B.C.
      • Goldman D.L.
      • Aldrich M.
      • Weingarten J.
      • et al.
      Clinical Characteristics and Outcomes of Hospitalized and Critically Ill Children and Adolescents with Coronavirus Disease 2019 at a Tertiary Care Medical Center in New York City.
      ;
      • DeBiasi R.L.
      • Song X.
      • Delaney M.
      • Bell M.
      • Smith K.
      • Pershad J.
      • et al.
      Severe Coronavirus Disease-2019 in Children and Young Adults in the Washington, DC, Metropolitan Region.
      ;
      • Derespina K.R.
      • Kaushik S.
      • Plichta A.
      • Conway E.E.
      • Bercow A.
      • Choi J.
      • et al.
      Clinical Manifestations and Outcomes of Critically Ill Children and Adolescents with Coronavirus Disease 2019 in New York City.
      ;
      • de Farias E.C.F.
      • Pedro Piva J.
      • de Mello M.L.F.M.F.
      • do Nascimento L.M.P.P.
      • Costa C.C.
      • Machado M.M.M.
      • et al.
      Multisystem Inflammatory Syndrome Associated With Coronavirus Disease in Children: A Multi-centered Study in Belém, Pará, Brazil.
      ;
      • Giacomet V.
      • Barcellini L.
      • Stracuzzi M.
      • Longoni E.
      • Folgori L.
      • Leone A.
      • et al.
      Gastrointestinal Symptoms in Severe COVID-19 Children.
      ;
      • González-Dambrauskas S.
      • Vásquez-Hoyos P.
      • Camporesi A.
      • Díaz-Rubio F.
      • Piñeres-Olave B.E.
      • Fernández-Sarmiento J.
      • et al.
      Pediatric Critical Care and COVID-19.
      ;
      • Kaushik S.
      • Aydin S.I.
      • Derespina K.R.
      • Bansal P.B.
      • Kowalsky S.
      • Trachtman R.
      • et al.
      Multisystem Inflammatory Syndrome in Children Associated with Severe Acute Respiratory Syndrome Coronavirus 2 Infection (MIS-C): A Multi-institutional Study from New York City.
      ;
      • Lovinsky-Desir S.
      • Deshpande D.R.
      • De A.
      • Murray L.
      • Stingone J.A.
      • Chan A.
      • et al.
      Asthma among hospitalized patients with COVID-19 and related outcomes.
      ;
      • Shekerdemian L.S.
      • Mahmood N.R.
      • Wolfe K.K.
      • Riggs B.J.
      • Ross C.E.
      • McKiernan C.A.
      • et al.
      Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units.
      ;
      • Swann O.V.
      • Holden K.A.
      • Turtle L.
      • Pollock L.
      • Fairfield C.J.
      • Drake T.M.
      • et al.
      Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study.
      ;
      • Waltuch T.
      • Gill P.
      • Zinns L.E.
      • Whitney R.
      • Tokarski J.
      • Tsung J.W.
      • et al.
      Features of COVID-19 post-infectious cytokine release syndrome in children presenting to the emergency department.
      ;
      • Zachariah P.
      • Johnson C.L.
      • Halabi K.C.
      • Ahn D.
      • Sen A.I.
      • Fischer A.
      • et al.
      Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York.
      ), 58 had chronic respiratory disease (
      • Belhadjer Zahra
      • Mathilde Méot
      • Fanny Bajolle
      • Diala Khraiche
      • Antoine Legendre
      • Samya Abakka
      • et al.
      Acute Heart Failure in Multisystem Inflammatory Syndrome in Children in the Context of Global SARS-CoV-2 Pandemic.
      ;
      • Chao J.Y.
      • Derespina K.R.
      • Herold B.C.
      • Goldman D.L.
      • Aldrich M.
      • Weingarten J.
      • et al.
      Clinical Characteristics and Outcomes of Hospitalized and Critically Ill Children and Adolescents with Coronavirus Disease 2019 at a Tertiary Care Medical Center in New York City.
      ;
      • DeBiasi R.L.
      • Song X.
      • Delaney M.
      • Bell M.
      • Smith K.
      • Pershad J.
      • et al.
      Severe Coronavirus Disease-2019 in Children and Young Adults in the Washington, DC, Metropolitan Region.
      ;
      • Diorio C.
      • Henrickson S.E.
      • Vella L.A.
      • McNerney K.O.
      • Chase J.
      • Burudpakdee C.
      • et al.
      Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS–CoV-2.
      ;
      • González-Dambrauskas S.
      • Vásquez-Hoyos P.
      • Camporesi A.
      • Díaz-Rubio F.
      • Piñeres-Olave B.E.
      • Fernández-Sarmiento J.
      • et al.
      Pediatric Critical Care and COVID-19.
      ;
      • Götzinger F.
      • Santiago-García B.
      • Noguera-Julián A.
      • Lanaspa M.
      • Lancella L.
      • Calò Carducci F.I.
      • et al.
      COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.
      ;
      • Kaushik S.
      • Aydin S.I.
      • Derespina K.R.
      • Bansal P.B.
      • Kowalsky S.
      • Trachtman R.
      • et al.
      Multisystem Inflammatory Syndrome in Children Associated with Severe Acute Respiratory Syndrome Coronavirus 2 Infection (MIS-C): A Multi-institutional Study from New York City.
      ;
      • Lovinsky-Desir S.
      • Deshpande D.R.
      • De A.
      • Murray L.
      • Stingone J.A.
      • Chan A.
      • et al.
      Asthma among hospitalized patients with COVID-19 and related outcomes.
      ;
      • Mannheim J.
      • Gretsch S.
      • Layden J.E.
      • Fricchione M.J.
      Characteristics of Hospitalized Pediatric Coronavirus Disease 2019 Cases in Chicago, Illinois, March–April 2020.
      ;
      • Riollano‐Cruz M.
      • Akkoyun E.
      • Briceno‐Brito E.
      • Kowalsky S.
      • Reed J.
      • Posada R.
      • et al.
      Multisystem inflammatory syndrome in children related to COVID‐19: A New York City experience.
      ;
      • Shekerdemian L.S.
      • Mahmood N.R.
      • Wolfe K.K.
      • Riggs B.J.
      • Ross C.E.
      • McKiernan C.A.
      • et al.
      Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units.
      ;
      • Swann O.V.
      • Holden K.A.
      • Turtle L.
      • Pollock L.
      • Fairfield C.J.
      • Drake T.M.
      • et al.
      Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study.
      ;
      • Waltuch T.
      • Gill P.
      • Zinns L.E.
      • Whitney R.
      • Tokarski J.
      • Tsung J.W.
      • et al.
      Features of COVID-19 post-infectious cytokine release syndrome in children presenting to the emergency department.
      ;
      • Yayla B.C.C.
      Characteristics and Management of Children with COVID-19 in Turkey. Balkan Med J n.d.;37.
      ;
      • Zachariah P.
      • Johnson C.L.
      • Halabi K.C.
      • Ahn D.
      • Sen A.I.
      • Fischer A.
      • et al.
      Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York.
      ), 45 had cardiovascular disease (
      • Chao J.Y.
      • Derespina K.R.
      • Herold B.C.
      • Goldman D.L.
      • Aldrich M.
      • Weingarten J.
      • et al.
      Clinical Characteristics and Outcomes of Hospitalized and Critically Ill Children and Adolescents with Coronavirus Disease 2019 at a Tertiary Care Medical Center in New York City.
      ;
      • DeBiasi R.L.
      • Song X.
      • Delaney M.
      • Bell M.
      • Smith K.
      • Pershad J.
      • et al.
      Severe Coronavirus Disease-2019 in Children and Young Adults in the Washington, DC, Metropolitan Region.
      ;
      • Derespina K.R.
      • Kaushik S.
      • Plichta A.
      • Conway E.E.
      • Bercow A.
      • Choi J.
      • et al.
      Clinical Manifestations and Outcomes of Critically Ill Children and Adolescents with Coronavirus Disease 2019 in New York City.
      ;
      • Diorio C.
      • Henrickson S.E.
      • Vella L.A.
      • McNerney K.O.
      • Chase J.
      • Burudpakdee C.
      • et al.
      Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS–CoV-2.
      ;
      • Eghbali A.
      • Shokrollahi S.
      • Mahdavi N.S.
      • Mahdavi N.S.A.
      • Dabbagh A.
      ;
      • Garazzino S.
      • Montagnani C.
      • Donà D.
      • Meini A.
      • Felici E.
      • Vergine G.
      • et al.
      Multicentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10 April 2020.
      ;
      • Giacomet V.
      • Barcellini L.
      • Stracuzzi M.
      • Longoni E.
      • Folgori L.
      • Leone A.
      • et al.
      Gastrointestinal Symptoms in Severe COVID-19 Children.
      ;
      • González-Dambrauskas S.
      • Vásquez-Hoyos P.
      • Camporesi A.
      • Díaz-Rubio F.
      • Piñeres-Olave B.E.
      • Fernández-Sarmiento J.
      • et al.
      Pediatric Critical Care and COVID-19.
      ;
      • Götzinger F.
      • Santiago-García B.
      • Noguera-Julián A.
      • Lanaspa M.
      • Lancella L.
      • Calò Carducci F.I.
      • et al.
      COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.
      ;
      • Kainth M.K.
      • Goenka P.K.
      • Williamson K.A.
      • Fishbein J.S.
      • Subramony A.
      • Barone S.
      • et al.
      Early Experience of COVID-19 in a US Children’s Hospital.
      ;
      • Kaushik S.
      • Aydin S.I.
      • Derespina K.R.
      • Bansal P.B.
      • Kowalsky S.
      • Trachtman R.
      • et al.
      Multisystem Inflammatory Syndrome in Children Associated with Severe Acute Respiratory Syndrome Coronavirus 2 Infection (MIS-C): A Multi-institutional Study from New York City.
      ;
      • Mannheim J.
      • Gretsch S.
      • Layden J.E.
      • Fricchione M.J.
      Characteristics of Hospitalized Pediatric Coronavirus Disease 2019 Cases in Chicago, Illinois, March–April 2020.
      ;
      • Schwartz D.A.
      • Mohagheghi P.
      • Beigi B.
      • Zafaranloo N.
      • Moshfegh F.
      • Yazdani A.
      Spectrum of neonatal COVID-19 in Iran: 19 infants with SARS-CoV-2 perinatal infections with varying test results, clinical findings and outcomes.
      ,
      • Shekerdemian L.S.
      • Mahmood N.R.
      • Wolfe K.K.
      • Riggs B.J.
      • Ross C.E.
      • McKiernan C.A.
      • et al.
      Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units.
      ,
      • Swann O.V.
      • Holden K.A.
      • Turtle L.
      • Pollock L.
      • Fairfield C.J.
      • Drake T.M.
      • et al.
      Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study.
      ,
      • Zachariah P.
      • Johnson C.L.
      • Halabi K.C.
      • Ahn D.
      • Sen A.I.
      • Fischer A.
      • et al.
      Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York.
      ,
      • Zheng F.
      • Liao C.
      • Fan Q.
      • Chen H.
      • Zhao X.
      • Xie Z.
      • et al.
      Clinical Characteristics of Children with Coronavirus Disease 2019 in Hubei, China.
      ), 33 had neurologic disorders (
      • Cai X.
      • Ma Y.
      • Li S.
      • Chen Y.
      • Rong Z.
      • Li W.
      Clinical Characteristics of 5 COVID-19 Cases With Non-respiratory Symptoms as the First Manifestation in Children.
      ,
      • Chao J.Y.
      • Derespina K.R.
      • Herold B.C.
      • Goldman D.L.
      • Aldrich M.
      • Weingarten J.
      • et al.
      Clinical Characteristics and Outcomes of Hospitalized and Critically Ill Children and Adolescents with Coronavirus Disease 2019 at a Tertiary Care Medical Center in New York City.
      ,
      • DeBiasi R.L.
      • Song X.
      • Delaney M.
      • Bell M.
      • Smith K.
      • Pershad J.
      • et al.
      Severe Coronavirus Disease-2019 in Children and Young Adults in the Washington, DC, Metropolitan Region.
      ,
      • Diorio C.
      • Henrickson S.E.
      • Vella L.A.
      • McNerney K.O.
      • Chase J.
      • Burudpakdee C.
      • et al.
      Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS–CoV-2.
      ,
      • Giacomet V.
      • Barcellini L.
      • Stracuzzi M.
      • Longoni E.
      • Folgori L.
      • Leone A.
      • et al.
      Gastrointestinal Symptoms in Severe COVID-19 Children.
      ,
      • González-Dambrauskas S.
      • Vásquez-Hoyos P.
      • Camporesi A.
      • Díaz-Rubio F.
      • Piñeres-Olave B.E.
      • Fernández-Sarmiento J.
      • et al.
      Pediatric Critical Care and COVID-19.
      ,
      • Götzinger F.
      • Santiago-García B.
      • Noguera-Julián A.
      • Lanaspa M.
      • Lancella L.
      • Calò Carducci F.I.
      • et al.
      COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.
      ,
      • Kainth M.K.
      • Goenka P.K.
      • Williamson K.A.
      • Fishbein J.S.
      • Subramony A.
      • Barone S.
      • et al.
      Early Experience of COVID-19 in a US Children’s Hospital.
      ,
      • Oualha M.
      • Bendavid M.
      • Berteloot L.
      • Corsia A.
      • Lesage F.
      • Vedrenne M.
      • et al.
      Severe and fatal forms of COVID-19 in children.
      ,
      • Shekerdemian L.S.
      • Mahmood N.R.
      • Wolfe K.K.
      • Riggs B.J.
      • Ross C.E.
      • McKiernan C.A.
      • et al.
      Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units.
      ,
      • Zachariah P.
      • Johnson C.L.
      • Halabi K.C.
      • Ahn D.
      • Sen A.I.
      • Fischer A.
      • et al.
      Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York.
      ), 26 had immune disorders (
      • Belhadjer Zahra
      • Mathilde Méot
      • Fanny Bajolle
      • Diala Khraiche
      • Antoine Legendre
      • Samya Abakka
      • et al.
      Acute Heart Failure in Multisystem Inflammatory Syndrome in Children in the Context of Global SARS-CoV-2 Pandemic.
      ,
      • Chao J.Y.
      • Derespina K.R.
      • Herold B.C.
      • Goldman D.L.
      • Aldrich M.
      • Weingarten J.
      • et al.
      Clinical Characteristics and Outcomes of Hospitalized and Critically Ill Children and Adolescents with Coronavirus Disease 2019 at a Tertiary Care Medical Center in New York City.
      ,
      • Kainth M.K.
      • Goenka P.K.
      • Williamson K.A.
      • Fishbein J.S.
      • Subramony A.
      • Barone S.
      • et al.
      Early Experience of COVID-19 in a US Children’s Hospital.
      ,
      • Mannheim J.
      • Gretsch S.
      • Layden J.E.
      • Fricchione M.J.
      Characteristics of Hospitalized Pediatric Coronavirus Disease 2019 Cases in Chicago, Illinois, March–April 2020.
      ,
      • Shekerdemian L.S.
      • Mahmood N.R.
      • Wolfe K.K.
      • Riggs B.J.
      • Ross C.E.
      • McKiernan C.A.
      • et al.
      Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units.
      ,
      • Swann O.V.
      • Holden K.A.
      • Turtle L.
      • Pollock L.
      • Fairfield C.J.
      • Drake T.M.
      • et al.
      Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study.
      ,
      • Zachariah P.
      • Johnson C.L.
      • Halabi K.C.
      • Ahn D.
      • Sen A.I.
      • Fischer A.
      • et al.
      Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York.
      ), and 19 had metabolic disease (
      • DeBiasi R.L.
      • Song X.
      • Delaney M.
      • Bell M.
      • Smith K.
      • Pershad J.
      • et al.
      Severe Coronavirus Disease-2019 in Children and Young Adults in the Washington, DC, Metropolitan Region.
      ,
      • Derespina K.R.
      • Kaushik S.
      • Plichta A.
      • Conway E.E.
      • Bercow A.
      • Choi J.
      • et al.
      Clinical Manifestations and Outcomes of Critically Ill Children and Adolescents with Coronavirus Disease 2019 in New York City.
      ,
      • Riollano‐Cruz M.
      • Akkoyun E.
      • Briceno‐Brito E.
      • Kowalsky S.
      • Reed J.
      • Posada R.
      • et al.
      Multisystem inflammatory syndrome in children related to COVID‐19: A New York City experience.
      ,
      • Shekerdemian L.S.
      • Mahmood N.R.
      • Wolfe K.K.
      • Riggs B.J.
      • Ross C.E.
      • McKiernan C.A.
      • et al.
      Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units.
      ,
      • Waltuch T.
      • Gill P.
      • Zinns L.E.
      • Whitney R.
      • Tokarski J.
      • Tsung J.W.
      • et al.
      Features of COVID-19 post-infectious cytokine release syndrome in children presenting to the emergency department.
      ,
      • Zachariah P.
      • Johnson C.L.
      • Halabi K.C.
      • Ahn D.
      • Sen A.I.
      • Fischer A.
      • et al.
      Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York.
      ,
      • Zheng F.
      • Liao C.
      • Fan Q.
      • Chen H.
      • Zhao X.
      • Xie Z.
      • et al.
      Clinical Characteristics of Children with Coronavirus Disease 2019 in Hubei, China.
      ). Additionally, 12 had hematologic disorders (
      • Eghbali A.
      • Shokrollahi S.
      • Mahdavi N.S.
      • Mahdavi N.S.A.
      • Dabbagh A.
      ,
      • García-Salido A.
      • Leoz-Gordillo I.
      • Martínez de Azagra-Garde A.
      • Nieto-Moro M.
      • Iglesias-Bouzas M.I.
      • García-Teresa MÁ
      • et al.
      Children in Critical Care Due to Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Experience in a Spanish Hospital.
      ,
      • Kaushik S.
      • Aydin S.I.
      • Derespina K.R.
      • Bansal P.B.
      • Kowalsky S.
      • Trachtman R.
      • et al.
      Multisystem Inflammatory Syndrome in Children Associated with Severe Acute Respiratory Syndrome Coronavirus 2 Infection (MIS-C): A Multi-institutional Study from New York City.
      ,
      • Oualha M.
      • Bendavid M.
      • Berteloot L.
      • Corsia A.
      • Lesage F.
      • Vedrenne M.
      • et al.
      Severe and fatal forms of COVID-19 in children.
      ,
      • Shekerdemian L.S.
      • Mahmood N.R.
      • Wolfe K.K.
      • Riggs B.J.
      • Ross C.E.
      • McKiernan C.A.
      • et al.
      Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units.
      ,
      • Yayla B.C.C.
      Characteristics and Management of Children with COVID-19 in Turkey. Balkan Med J n.d.;37.
      ,
      • Zachariah P.
      • Johnson C.L.
      • Halabi K.C.
      • Ahn D.
      • Sen A.I.
      • Fischer A.
      • et al.
      Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York.
      ), and 11 had cancer (
      • Chao J.Y.
      • Derespina K.R.
      • Herold B.C.
      • Goldman D.L.
      • Aldrich M.
      • Weingarten J.
      • et al.
      Clinical Characteristics and Outcomes of Hospitalized and Critically Ill Children and Adolescents with Coronavirus Disease 2019 at a Tertiary Care Medical Center in New York City.
      ,
      • Diorio C.
      • Henrickson S.E.
      • Vella L.A.
      • McNerney K.O.
      • Chase J.
      • Burudpakdee C.
      • et al.
      Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS–CoV-2.
      ,
      • Du H.
      • Dong X.
      • Zhang J.
      • Cao Y.
      • Akdis M.
      • Huang P.
      • et al.
      Clinical characteristics of 182 pediatric COVID‐19 patients with different severities and allergic status.
      ,
      • González-Dambrauskas S.
      • Vásquez-Hoyos P.
      • Camporesi A.
      • Díaz-Rubio F.
      • Piñeres-Olave B.E.
      • Fernández-Sarmiento J.
      • et al.
      Pediatric Critical Care and COVID-19.
      ,
      • Götzinger F.
      • Santiago-García B.
      • Noguera-Julián A.
      • Lanaspa M.
      • Lancella L.
      • Calò Carducci F.I.
      • et al.
      COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.
      ,
      • Kainth M.K.
      • Goenka P.K.
      • Williamson K.A.
      • Fishbein J.S.
      • Subramony A.
      • Barone S.
      • et al.
      Early Experience of COVID-19 in a US Children’s Hospital.
      ,
      • Sun D.
      • Li H.
      • Lu X.-X.
      • Xiao H.
      • Ren J.
      • Zhang F.-R.
      • et al.
      Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center’s observational study.
      ). Five children had renal disease (
      • Cai X.
      • Ma Y.
      • Li S.
      • Chen Y.
      • Rong Z.
      • Li W.
      Clinical Characteristics of 5 COVID-19 Cases With Non-respiratory Symptoms as the First Manifestation in Children.
      ,
      • Götzinger F.
      • Santiago-García B.
      • Noguera-Julián A.
      • Lanaspa M.
      • Lancella L.
      • Calò Carducci F.I.
      • et al.
      COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.
      ,
      • Oualha M.
      • Bendavid M.
      • Berteloot L.
      • Corsia A.
      • Lesage F.
      • Vedrenne M.
      • et al.
      Severe and fatal forms of COVID-19 in children.
      ), and 2 had GI comorbidities (
      • Giacomet V.
      • Barcellini L.
      • Stracuzzi M.
      • Longoni E.
      • Folgori L.
      • Leone A.
      • et al.
      Gastrointestinal Symptoms in Severe COVID-19 Children.
      ) respectively. Seventy-one children had other conditions (
      • Diorio C.
      • Henrickson S.E.
      • Vella L.A.
      • McNerney K.O.
      • Chase J.
      • Burudpakdee C.
      • et al.
      Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS–CoV-2.
      ,
      • Garazzino S.
      • Montagnani C.
      • Donà D.
      • Meini A.
      • Felici E.
      • Vergine G.
      • et al.
      Multicentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10 April 2020.
      ,
      • González-Dambrauskas S.
      • Vásquez-Hoyos P.
      • Camporesi A.
      • Díaz-Rubio F.
      • Piñeres-Olave B.E.
      • Fernández-Sarmiento J.
      • et al.
      Pediatric Critical Care and COVID-19.
      ,
      • Götzinger F.
      • Santiago-García B.
      • Noguera-Julián A.
      • Lanaspa M.
      • Lancella L.
      • Calò Carducci F.I.
      • et al.
      COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.
      ,
      • Kainth M.K.
      • Goenka P.K.
      • Williamson K.A.
      • Fishbein J.S.
      • Subramony A.
      • Barone S.
      • et al.
      Early Experience of COVID-19 in a US Children’s Hospital.
      ,
      • Kaushik S.
      • Aydin S.I.
      • Derespina K.R.
      • Bansal P.B.
      • Kowalsky S.
      • Trachtman R.
      • et al.
      Multisystem Inflammatory Syndrome in Children Associated with Severe Acute Respiratory Syndrome Coronavirus 2 Infection (MIS-C): A Multi-institutional Study from New York City.
      ,
      • Mannheim J.
      • Gretsch S.
      • Layden J.E.
      • Fricchione M.J.
      Characteristics of Hospitalized Pediatric Coronavirus Disease 2019 Cases in Chicago, Illinois, March–April 2020.
      ,
      • Schwartz D.A.
      • Mohagheghi P.
      • Beigi B.
      • Zafaranloo N.
      • Moshfegh F.
      • Yazdani A.
      Spectrum of neonatal COVID-19 in Iran: 19 infants with SARS-CoV-2 perinatal infections with varying test results, clinical findings and outcomes.
      ,
      • Shekerdemian L.S.
      • Mahmood N.R.
      • Wolfe K.K.
      • Riggs B.J.
      • Ross C.E.
      • McKiernan C.A.
      • et al.
      Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units.
      ,
      • Swann O.V.
      • Holden K.A.
      • Turtle L.
      • Pollock L.
      • Fairfield C.J.
      • Drake T.M.
      • et al.
      Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study.
      ,
      • Zachariah P.
      • Johnson C.L.
      • Halabi K.C.
      • Ahn D.
      • Sen A.I.
      • Fischer A.
      • et al.
      Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York.
      ) including prematurity, trisomy 21, or other genetic abnormalities. Finally, only 1 child presented with allergies (
      • Du H.
      • Dong X.
      • Zhang J.
      • Cao Y.
      • Akdis M.
      • Huang P.
      • et al.
      Clinical characteristics of 182 pediatric COVID‐19 patients with different severities and allergic status.
      ) and hepatobiliary disease (
      • Riollano‐Cruz M.
      • Akkoyun E.
      • Briceno‐Brito E.
      • Kowalsky S.
      • Reed J.
      • Posada R.
      • et al.
      Multisystem inflammatory syndrome in children related to COVID‐19: A New York City experience.
      ) respectively.
      We next analyzed the relative contribution of childhood obesity to pediatric COVID-19 severity. We chose to focus primarily on obesity as it has an easily definable metric (i.e. BMI) that can be compared across multiple studies. Although 64 pediatric patients with underlying obesity presented with severe COVID-19 across 13 studies (
      • Abdel-Mannan O.
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      • et al.
      Neurologic and Radiographic Findings Associated With COVID-19 Infection in Children.
      ,
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      ,
      • DeBiasi R.L.
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      • Bell M.
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      • Pershad J.
      • et al.
      Severe Coronavirus Disease-2019 in Children and Young Adults in the Washington, DC, Metropolitan Region.
      ,
      • Derespina K.R.
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      • Bercow A.
      • Choi J.
      • et al.
      Clinical Manifestations and Outcomes of Critically Ill Children and Adolescents with Coronavirus Disease 2019 in New York City.
      ,
      • de Farias E.C.F.
      • Pedro Piva J.
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      • do Nascimento L.M.P.P.
      • Costa C.C.
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      • et al.
      Multisystem Inflammatory Syndrome Associated With Coronavirus Disease in Children: A Multi-centered Study in Belém, Pará, Brazil.
      ,
      • Giacomet V.
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      Gastrointestinal Symptoms in Severe COVID-19 Children.
      ,
      • González-Dambrauskas S.
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      • et al.
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      ,
      • Kaushik S.
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      • Kowalsky S.
      • Trachtman R.
      • et al.
      Multisystem Inflammatory Syndrome in Children Associated with Severe Acute Respiratory Syndrome Coronavirus 2 Infection (MIS-C): A Multi-institutional Study from New York City.
      ,
      • Lovinsky-Desir S.
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      • De A.
      • Murray L.
      • Stingone J.A.
      • Chan A.
      • et al.
      Asthma among hospitalized patients with COVID-19 and related outcomes.
      ,
      • Shekerdemian L.S.
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      • Ross C.E.
      • McKiernan C.A.
      • et al.
      Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units.
      ,
      • Swann O.V.
      • Holden K.A.
      • Turtle L.
      • Pollock L.
      • Fairfield C.J.
      • Drake T.M.
      • et al.
      Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study.
      ,
      • Waltuch T.
      • Gill P.
      • Zinns L.E.
      • Whitney R.
      • Tokarski J.
      • Tsung J.W.
      • et al.
      Features of COVID-19 post-infectious cytokine release syndrome in children presenting to the emergency department.
      ,
      • Zachariah P.
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      • Halabi K.C.
      • Ahn D.
      • Sen A.I.
      • Fischer A.
      • et al.
      Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York.
      ), we chose to perform a meta-analysis only on the studies that included case-control participants (
      • Abdel-Mannan O.
      • Eyre M.
      • Löbel U.
      • Bamford A.
      • Eltze C.
      • Hameed B.
      • et al.
      Neurologic and Radiographic Findings Associated With COVID-19 Infection in Children.
      ,
      • Chao J.Y.
      • Derespina K.R.
      • Herold B.C.
      • Goldman D.L.
      • Aldrich M.
      • Weingarten J.
      • et al.
      Clinical Characteristics and Outcomes of Hospitalized and Critically Ill Children and Adolescents with Coronavirus Disease 2019 at a Tertiary Care Medical Center in New York City.
      ,
      • Giacomet V.
      • Barcellini L.
      • Stracuzzi M.
      • Longoni E.
      • Folgori L.
      • Leone A.
      • et al.
      Gastrointestinal Symptoms in Severe COVID-19 Children.
      ,
      • Moreno-Galarraga L.
      • Urretavizcaya-Martínez M.
      • Alegría Echauri J.
      • García Howard M.
      • Ruperez García E.
      • Aguilera-Albesa S.
      • et al.
      SARS-CoV-2 infection in children requiring hospitalization: the experience of Navarra, Spain.
      ,
      • Swann O.V.
      • Holden K.A.
      • Turtle L.
      • Pollock L.
      • Fairfield C.J.
      • Drake T.M.
      • et al.
      Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study.
      ,
      • Zachariah P.
      • Johnson C.L.
      • Halabi K.C.
      • Ahn D.
      • Sen A.I.
      • Fischer A.
      • et al.
      Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York.
      ). Examining the risk of obesity on COVID-19 severity in relation to children without comorbidities, we obtained a relative risk ratio of 2.87 (95% CI 1.16 – 7.07; χ 2 = 7.81 (P = 0.17); I2 = 36%) (Fig. 6). We also examined the relative risk of childhood cancer on severe COVID-19 (Supplement S4), from which we were not able to draw any conclusions due to the confidence interval of the relative risk ratio spanning a value of 1.0. Taken together, these results indicate that childhood obesity likely increases risk of severe COVID-19. However, more case-controlled, well-defined studies are needed to examine the effects that other childhood comorbidities such as cancer have on risk of severe manifestations of SARS-CoV-2.
      Fig. 6
      Fig. 6Relative risk of childhood obesity on severe manifestations of COVID-19

      Discussion

      Current meta-analyses of publications involving children with COVID-19 infection primarily examine the overall characteristics, symptoms, and outcomes of SARS-CoV-2 infection regardless of comorbidity status (
      • Ding Y.
      • Yan H.
      • Guo W.
      Clinical Characteristics of Children With COVID-19: A Meta-Analysis.
      ,
      • Hoang A.
      • Chorath K.
      • Axel Moreira
      • Evans M.
      • Burmeister-Morton F.
      • Burmeister F.
      • et al.
      COVID-19 in 7780 pediatric patients: A systematic review.
      ,
      • Ludvigsson J.F.
      Systematic review of COVID‐19 in children shows milder cases and a better prognosis than adults.
      ). Studies suggest that children typically have a milder infection course than adults, with an overall good prognosis. However, the effects of comorbidities on COVID-19 severity in children remain unclear. Although a previous correspondence suggested a worse SARS-CoV-2 infection course in children with comorbidities (
      • Harman K.
      • Verma A.
      • Cook J.
      • Radia T.
      • Zuckerman M.
      • Deep A.
      • et al.
      Ethnicity and COVID-19 in children with comorbidities.
      ), the small sample size precludes definitive conclusions. In this systematic review and meta-analysis of 42 articles, we report that children with comorbidities are at higher risk for severe manifestations of COVID-19 and associated mortality relative to previously healthy children. Furthermore, we also note that childhood obesity probably leads to a worse COVID-19 prognosis. To our knowledge, we are the first to report these findings.
      Early analyses in adults with COVID-19 indicated that older age (
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ) and comorbidities such as diabetes, hypertension, malignancies, chronic respiratory disease and obesity are significant risk factors for severe infection (
      • Caussy C.
      • Wallet F.
      • Laville M.
      • Disse E.
      Obesity is Associated with Severe Forms of COVID-19.
      ,
      • Guan W.
      • Liang W.
      • Zhao Y.
      • Liang H.
      • Zi-sheng Chen
      • Li Y.
      • et al.
      Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis.
      ,
      • Yang J.
      • Zheng Y.
      • Gou X.
      • Pu K.
      • Chen Z.
      • Guo Q.
      • et al.
      Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis.
      ). As such, the early lockdown measures implemented across the world in the spring of 2020 were aimed at protecting vulnerable populations (i.e., the elderly, and people with comorbid conditions) from COVID-19 infection, as well as preventing the overburdening of hospitals. In contrast, early epidemiological studies of pediatric populations (
      • Dong Y.
      • Mo X.
      • Hu Y.
      • Qi X.
      • Jiang F.
      • Jiang Z.
      • et al.
      Epidemiology of COVID-19 Among Children in China.
      ) cited high rates of mild and asymptomatic COVID-19 infection, with certain publications advocating for their return to school (
      • Munro A.P.S.
      • Faust S.N.
      Children are not COVID-19 super spreaders: time to go back to school.
      ,
      • van Bruwaene L.
      • Mustafa F.
      • Cloete J.
      • Goga A.
      • Green R.J.
      What are we doing to the children of South Africa under the guise of COVID-19 lockdown?.
      ). The results from our study suggest that children with specific comorbidities are a vulnerable population at risk for potentially life-threatening consequences of COVID-19 infection.
      We report that childhood obesity is likely associated with a worsened prognosis of COVID-19 infection. This is in keeping with several adult studies noting that patients who had a BMI greater than or equal to 35 kg/m2 required invasive mechanical ventilation due to SARS-CoV-2 infection more frequently than their leaner counterparts (
      • Caussy C.
      • Wallet F.
      • Laville M.
      • Disse E.
      Obesity is Associated with Severe Forms of COVID-19.
      ,
      • Simonnet A.
      • Chetboun M.
      • Poissy J.
      • Raverdy V.
      • Noulette J.
      • Duhamel A.
      • et al.
      High Prevalence of Obesity in Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Requiring Invasive Mechanical Ventilation.
      ). The effects of childhood obesity in potentiating severe COVID-19 are unsurprising. The high visceral adiposity present in obese individuals is known to induce higher levels of local and systemic inflammatory cytokines such as Interleukin-6 (IL-6), and C-reactive protein (CRP) (
      • Fontana L.
      • Eagon J.C.
      • Trujillo M.E.
      • Scherer P.E.
      • Klein S.
      Visceral Fat Adipokine Secretion Is Associated With Systemic Inflammation in Obese Humans.
      ). The increased baseline of these cytokines in obesity are also likely the result of increased pro-inflammatory macrophage populations that have been observed in this population (
      • Russo L.
      • Lumeng C.N.
      Properties and functions of adipose tissue macrophages in obesity.
      ). These cytokines have been positively correlated with COVID-19 severity (
      • Zeng F.
      • Huang Y.
      • Guo Y.
      • Yin M.
      • Chen X.
      • Xiao L.
      • et al.
      Association of inflammatory markers with the severity of COVID-19: A meta-analysis.
      ) and their higher levels in obese individuals may contribute to their increased susceptibility to severe infection. However, childhood obesity likely contributes to severe COVID-19 infection in additional ways.
      Unfortunately, we were unable to determine whether other comorbidities increase risk of severe COVID-19. This is in part due to the paucity of case-controlled literature examining the outcomes of children with COVID-19 who have well-defined comorbid conditions. Towards this aim, various international Surveillance Epidemiology of Coronavirus (COVID-19) Under Research Exclusion (SECURE) databases and registries are set up to prospectively collect data, and will be particularly helpful in defining risk of COVID-19 infection and severity in patients with comorbidities. However, to date the available data remain quite limited. Apart from a recent article (
      • Brenner E.J.
      • Ungaro R.C.
      • Gearry R.B.
      • Kaplan G.G.
      • Kissous-Hunt M.
      • Lewis J.D.
      • et al.
      Corticosteroids, But Not TNF Antagonists, Are Associated With Adverse COVID-19 Outcomes in Patients With Inflammatory Bowel Diseases: Results From an International Registry.
      ) and the SECURE-IBD database (
      • Brenner E.J.
      • Ungaro R.C.
      • Colombel J.F.
      • Kappelman M.D.
      SECURE-IBD Database Public Data Update.
      ), a multi-national database examining the outcomes of patients with IBD and COVID-19, limited literature examining the effects of GI diseases on COVID-19 outcomes in children has been published. Furthermore, although recent approaches have begun examining the effects of COVID-19 infection on diseases such as sickle-cell disease (SSD) (
      • McCloskey K.A.
      • Meenan J.
      • Hall R.
      • Tsitsikas D.A.
      COVID-19 infection and sickle cell disease: a UK centre experience.
      ,
      • Hussain F.A.
      • Njoku F.U.
      • Saraf S.L.
      • Molokie R.E.
      • Gordeuk V.R.
      • Han J.
      COVID-19 infection in patients with sickle cell disease.
      ), limited data exist for other systemic diseases. For example, for rheumatic diseases, apart from a retrospective report (
      • Zhong J.
      • Shen G.
      • Yang H.
      • Huang A.
      • Chen X.
      • Li Dong
      • et al.
      COVID-19 in patients with rheumatic disease in Hubei province, China: a multicentre retrospective observational study.
      ), only a speculative review on the topic has been published (
      • Licciardi F.
      • Giani T.
      • Baldini L.
      • Favalli E.G.
      • Caporali R.
      • Cimaz R.
      COVID-19 and what pediatric rheumatologists should know: a review from a highly affected country.
      ). With reports of MIS-C occurring in cohorts of children with COVID-19 infection (
      • Riphagen S.
      • Gomez X.
      • Gonzalez-Martinez C.
      • Wilkinson N.
      • Theocharis P.
      Hyperinflammatory shock in children during COVID-19 pandemic.
      ,
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • Martelli L.
      • Ruggeri M.
      • Ciuffreda M.
      • et al.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
      ) the dynamics and underlying characteristics of severe infection in the context of autoinflammatory comorbidities in children require further study.

       Study Strengths

      Our study has several important strengths. To our knowledge, this is the first systematic review and meta-analysis that examines the relative risk of severe COVID-19 and associated mortality among children with comorbidities. Furthermore, our study is the first to show that childhood obesity likely increases the risk of severe COVID-19 infection course. Lastly, our study has a relatively large sample size of 9,353 children with comorbidities among 42 articles. This relatively large sample size and study number allows for high statistical power, enabling accurate conclusions to be drawn from the study results.

       Study Limitations

      Our systematic review and meta-analysis have several potential limitations. Most importantly, there likely exists variations in PICU admission criteria across the studies, particularly regarding children with comorbidities and COVID-19 infection. We cannot ascertain whether admission to the PICU was primarily due to problems with underlying comorbidities in some children, with COVID-19 infection being subsequently discovered. Therefore, the increased risk of severe COVID-19 infection among children with comorbidities addressed in this meta-analysis could be the result of a selection bias of PICU admission in favor of children with underlying conditions. Furthermore, our study is subject to a high degree of study heterogeneity due to the small sample size in some of the included studies. In addition, based on the large body of rapidly-published literature surrounding COVID-19 infection, some studies may have used similar participants. Therefore, we cannot be certain that patients were not duplicated in our study. Our meta-analysis was also not able to capture the relative risk that comorbidities other than obesity contribute to severe SARS-CoV-2 viral infection. This is due to the sub-population heterogeneity of comorbidities that limits the ability to draw accurate comparisons between studies. Lastly, our meta-analysis amplifies the ascertainment bias of the primary literature. Asymptomatic COVID-19 infections among children with comorbidities do occur (
      • Poli P.
      • Timpano S.
      • Goffredo M.
      • Padoan R.
      • Badolato R.
      Asymptomatic case of Covid-19 in an infant with cystic fibrosis.
      ), however in most jurisdictions at this time, testing of asymptomatic or pauci-symptomatic children is very limited outside of outbreak settings. Consequently, such mild cases among children with comorbidities are likely less represented in the primary literature and therefore in our analysis. We therefore call for further availability of data on pediatric patients with comorbidities and COVID-19 outcomes, regardless of illness severity. Such broader representation within the literature would increase the accuracy of relative risk computation within this population by future meta-analyses.

      Conclusions

      To our knowledge, this is the first systematic review and meta-analysis examining the severity of COVID-19 infection among pediatric patients with comorbidities. We report that children with pre-existing conditions are at a greater risk of severe COVID-19 and associated mortality. In particular, childhood obesity is likely positively correlated with COVID-19 severity. However, further cross-sectional, case-controlled studies examining the effects of specific well-defined comorbidities are required to examine the effects that pediatric underlying conditions play in COVID-19 severity.

      Author Contributions

      BKT: study concept and design; literature review, acquisition of data; literature grading; analysis and interpretation of data; statistical analysis; drafting of the manuscript; approval of final manuscript.
      JMA: study concept and design; critical revision of the manuscript for important intellectual content; approval of final manuscript.
      MAI: statistical analysis, analysis and interpretation of data; critical revision of the manuscript for important intellectual content; approval of final manuscript.
      AAL: literature review; critical revision of the manuscript for important intellectual content; approval of final manuscript.
      LJS: critical revision of the manuscript for important intellectual content; approval of final manuscript.
      BAV: study concept and design; critical revision of the manuscript for important intellectual content; approval of final manuscript.
      KJ: study concept and design; literature grading; review and interpretation of data; drafting of the manuscript, critical revision of the manuscript for important intellectual content; approval of final manuscript.

      Ethics Approval

      No ethics approval was required for this publication.

      Potential competing interest

      None declared.

      Financial Support

      KJ has received research support from Janssen, AbbVie and adMare Bioinnovations (formerly the Center for Drug Research and development -CDRD). KJ has served on the advisory boards of Janssen, AbbVie, and Merck and participates in the speaker’s bureau for AbbVie and Janssen.
      The remaining authors disclose no conflicts of interest.

      Acknowledgements

      K.J. is a Senior Clinician Scientist supported by the Children with Intestinal and Liver Disorders (CHILD) Foundation and the BC Children’s Hospital Research Institute Clinician Scientists Award Program, University of British Columbia. B.A.V. holds the CHILD Foundation Chair in Pediatric Gastroenterology. B.K.T. was supported by a Natural Sciences and Engineering Research Council of Canada Undergraduate Student Research Award (NSERC-USRA). J.A. is supported by a Canadian Institute for Health Research (CIHR)/Canadian Association of Gastroenterology and Michael Smith Foundation for Health Research (MSFHR) research fellowships.

      Appendix A. Supplementary data

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