International Pediatric COVID-19 Severity Over the Course of the Pandemic

Yanshan Zhu; Flávia Jacqueline Almeida; J Kenneth Baillie; Asha C Bowen; Philip N Britton; Martin Eduardo Brizuela; Danilo Buonsenso; David Burgner; Keng Yih Chew; Kulkanya Chokephaibulkit; Cheryl Cohen; Stephania A Cormier; Nigel Crawford; Nigel Curtis; Camila G A Farias; Charles F Gilks; Anne von Gottberg; Diana Hamer; Daniel Jarovsky; Waasila Jassat; Ana Rita Jesus; Lisa S Kemp; Benjawan Khumcha; Georgina McCallum; Jessica E Miller; Rosa Morello; Alasdair P S Munro; Peter J M Openshaw; Srivatsan Padmanabhan; Wanatpreeya Phongsamart; Gary Reubenson; Nicole Ritz; Fernanda Rodrigues; Supattra Rungmaitree; Fiona Russell; Marco A P Sáfadi; Christoph Saner; Malcolm G Semple; Daniella Gregória Bomfim Prado da Silva; Laíse Marine Moura de Sousa; Marília Diogo Moço Souza; Kirsten Spann; Sibongile Walaza; Nicole Wolter; Yao Xia; Daniel K Yeoh; Heather J Zar; Petra Zimmermann; Kirsty R Short

doi:10.1001/jamapediatrics.2023.3117

. 2023 Aug 21;177(10):1073–1084. doi: 10.1001/jamapediatrics.2023.3117

International Pediatric COVID-19 Severity Over the Course of the Pandemic

Yanshan Zhu ^1,², Flávia Jacqueline Almeida ^3,⁴, J Kenneth Baillie ^2,^5,^6,⁷, Asha C Bowen ^8,⁹, Philip N Britton ^10,¹¹, Martin Eduardo Brizuela ¹², Danilo Buonsenso ¹³, David Burgner ^14,^15,¹⁶, Keng Yih Chew ¹, Kulkanya Chokephaibulkit ¹⁷, Cheryl Cohen ^18,¹⁹, Stephania A Cormier ^20,²¹, Nigel Crawford ^14,¹⁶, Nigel Curtis ^14,^15,²², Camila G A Farias ⁴, Charles F Gilks ²³, Anne von Gottberg ^18,²⁴, Diana Hamer ²⁵, Daniel Jarovsky ⁴, Waasila Jassat ²⁶, Ana Rita Jesus ²⁷, Lisa S Kemp ²⁵, Benjawan Khumcha ¹⁷, Georgina McCallum ¹, Jessica E Miller ^14,¹⁵, Rosa Morello ¹³, Alasdair P S Munro ^28,²⁹, Peter J M Openshaw ^30,³¹, Srivatsan Padmanabhan ^32,³³, Wanatpreeya Phongsamart ¹⁷, Gary Reubenson ³⁴, Nicole Ritz ^15,^35,³⁶, Fernanda Rodrigues ^27,³⁷, Supattra Rungmaitree ¹⁷, Fiona Russell ^14,¹⁵, Marco A P Sáfadi ^3,⁴, Christoph Saner ^38,^39,⁴⁰, Malcolm G Semple ^41,⁴², Daniella Gregória Bomfim Prado da Silva ⁴, Laíse Marine Moura de Sousa ³, Marília Diogo Moço Souza ³, Kirsten Spann ⁴³, Sibongile Walaza ^18,¹⁹, Nicole Wolter ^18,²⁴, Yao Xia ⁴⁴, Daniel K Yeoh ^8,⁴⁵, Heather J Zar ⁴⁶, Petra Zimmermann ⁴⁷, Kirsty R Short ^1,^48,^✉, for the for the International Severe Acute Respiratory Infection Consortium (ISARIC4C) group; Pediatric Active Enhanced Disease Surveillance (PAEDS) Network group

¹School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia

²Baillie Gifford Pandemic Science Hub, Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

³Santa Casa de São Paulo School of Medical Sciences, São Paulo, Brazil

⁴Hospital Infantil Sabará, São Paulo, Brazil

⁵Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh, United Kingdom

⁶MRC Human Genetics Unit, Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom

⁷Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom

⁸Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia

⁹Department of Infectious Diseases, Perth Children’s Hospital, Perth, Western Australia, Australia

¹⁰Department of Infectious Diseases and Microbiology, the Children’s Hospital, Westmead, New South Wales, Australia

¹¹Sydney Medical School and Sydney Infectious Diseases, University of Sydney, Sydney, New South Wales, Australia

¹²Hospital General de Agudos Velez Sarsfield, Buenos Aires, Argentina

¹³Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy

¹⁴Infection and Immunity, Murdoch Children’s Research Institute, Parkville, Victoria, Australia

¹⁵Department of Pediatrics, The University of Melbourne, Parkville, Victoria, Australia

¹⁶Department of General Medicine, The Royal Children’s Hospital, Parkville, Victoria, Australia

¹⁷Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand

¹⁸Centre for Respiratory Disease and Meningitis, National Institute of Communicable Diseases, Johannesburg, South Africa

¹⁹School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

²⁰Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana

²¹Pennington Biomedical Research Center, Baton Rouge, Louisiana

²²Infectious Diseases, The Royal Children’s Hospital Melbourne, Parkville, Victoria, Australia

²³School of Public Health, The University of Queensland, Brisbane, Queensland, Australia

²⁴School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

²⁵Our Lady of the Lake Regional Medical Center, Baton Rouge, Louisiana

²⁶Division of the National Health Laboratory Services, National Institute of Communicable Diseases, Johannesburg, South Africa

²⁷Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal

²⁸NIHR Southampton Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom

²⁹Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, United Kingdom

³⁰National Heart and Lung Institute, Imperial College London, London, United Kingdom

³¹Imperial College Healthcare NHS Trust: London, London, United Kingdom

³²Elson S. Floyd College of Medicine, Washington State University, Tacoma, Washington

³³St Joseph Medical Center, Tacoma, Washington

³⁴Empilweni Service & Research Unit, Rahima Moosa Mother & Child Hospital, Department of Paediatrics & Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

³⁵Mycobacterial and Migrant Health Research Group, University of Basel Children’s Hospital Basel and Department of Clinical Research, University of Basel, Basel, Switzerland

³⁶Department of Pediatrics and Pediatric Infectious Diseases, Children’s Hospital Lucerne and Faculty of Health Science and Medicine, University of Lucerne, Lucerne, Switzerland

³⁷Faculty of Medicine, University of Coimbra, Coimbra, Portugal

³⁸Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville, Victoria, Australia

³⁹Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, University Hospital Inselspital, University of Bern, Bern, Switzerland

⁴⁰Department of Biomedical Research, University of Bern, Bern, Switzerland

⁴¹NIHR Health Protection Research Unit, Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom

⁴²Respiratory Medicine, Alder Hey Children’s Hospital, Institute in The Park, University of Liverpool, Alder Hey Children’s Hospital, Liverpool, United Kingdom

⁴³Centre for Immunology and Infection Control, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia

⁴⁴Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

⁴⁵Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia

⁴⁶Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, SA- MRC Unit on Child & Adolescent Health, University of Cape Town, Cape Town, South Africa

⁴⁷Department of Community Health, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland

⁴⁸Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia

Group Information: The members of the International Severe Acute Respiratory Infection Consortium (ISARIC4C) group and the Pediatric Active Enhanced Disease Surveillance (PAEDS) Network group appear in Supplement 2.

Accepted for Publication: June 21, 2023.

Published Online: August 21, 2023. doi:10.1001/jamapediatrics.2023.3117

^✉

Corresponding Author: Kirsty Short, PhD, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia (k.short@uq.edu.au).

Author Contributions: Dr Short had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Zhu, Almeida, Bowen, Burgner, Chew, Cohen, Cormier, Curtis, Farias, Gilks, Munro, Rodrigues, Russell, Sáfadi, Saner, Semple, Sousa, Spann, Zimmermann, Short.

Acquisition, analysis, or interpretation of data: Zhu, Almeida, Baillie, Britton, Brizuela, Buonsenso, Burgner, Chew, Chokephaibulkit, Cohen, Cormier, Crawford, Farias, Hamer, Jarovsky, Jassat, Jesus, Kemp, Khumcha, McCallum, Miller, Morello, Munro, Openshaw, Padmanabhan, Phongsamart, Reubenson, Ritz, Rodrigues, Rungmaitree, Russell, Sáfadi, Saner, Semple, Silva, Sousa, Souza, Spann, Walaza, Wolter, Xia, Yeoh, Zar, Zimmermann, Short.

Drafting of the manuscript: Zhu, Almeida, Buonsenso, Cormier, Farias, Khumcha, Saner, Silva, Sousa, Souza, Spann, Short.

Critical review of the manuscript for important intellectual content: Baillie, Kemp, Openshaw, Phongsamart, Semple.

Statistical analysis: Zhu, Brizuela, Farias, Miller, Padmanabhan, Ritz, Saner, Spann, Yeoh.

Obtained funding: Britton, Burgner, Cohen, Cormier, Crawford, Semple, Short.

Administrative, technical, or material support: Zhu, Almeida, Bowen, Britton, Buonsenso, Chew, Cormier, Farias, Gilks, Kemp, McCallum, Openshaw, Reubenson, Ritz, Rungmaitree, Sáfadi, Semple, Silva, Sousa, Souza, Spann, Xia, Zar, Zimmermann, Short.

Supervision: Baillie, Bowen, Buonsenso, Burgner, Chew, Cormier, Gilks, Semple, Spann, Short.

Other - data collect: Souza.

Conflict of Interest Disclosures: Dr Britton reported grants from Australian Commonwealth Department of Health and Aged Care PAEDS and the Royal Australasian College of Physicians Cottrell Research Establishment Fellowship during the conduct of the study. Dr Buonsenso reported personal fees from Pfizer during the conduct of the study. Dr Burgner reported grants from the National Health and Medical Research Council during the conduct of the study. Dr Cohen reported grants from US Centers for Disease Control and Prevention during the conduct of the study and grants from PATH, the South African Medical Research Council, and the Bill & Melinda Gates Foundation outside the submitted work. Dr Cormier reported grants from the National Institutes of Health (P42 ES013648) during the conduct of the study. Dr Crawford reported grants from the Royal Columbian Hospital Foundation and the Victorian State Government of Australia during the conduct of the study. Dr von Gottberg reported grants from the US Centers for Disease Control and Prevention, the World Health Organization, Africa Region, the US Centers for Disease Control and Prevention through African Field Epidemiology Network, Africa Centres for Disease Control and Prevention (Institute of Pathogen Genomics), Fleming Fund SeqAfrica, and African Medical Research Council during the conduct of the study. Dr Openshaw reported advisory board fees from GSK, Janssen, Seqirus, and Moderna outside the submitted work. Dr Rodrigues reported honoraria for participation in advisory boards and as speaker in scientific meetings from Pfizer, Merck, Sharp & Dohme, GSK, and Sanofi outside the submitted work. Dr Sáfadi reported grants and personal fees from Pfizer, Sanofi, and Abbott, and grants from GSK outside the submitted work. Dr Semple reported grants from the National Institute of Health Research UK, Medical Research Council UK, the Health Protection Research Unit in Emerging & Zoonotic Infections, and the University of Liverpool and UK Health Security Agency during the conduct of the study, nonfinancial support from Chiesi Farmaceutici S.p.A., being minority shareholder of Integrum Scientific, being an independent external and nonremunerated member of Pfizer’s External Data Monitoring Committee for their mRNA vaccine program, and being a member of HMG UK Scientific Advisory Group for Emergencies, COVID-19 Response from March 2020 to March 2022 outside the submitted work. Dr Walaza reported grants from the US Centers for Disease Control and Prevention, the National Department of Health, and the Bill and Melinda Gates Foundation outside the submitted work. Dr Wolter reported grants from US Centers for Disease Control and Prevention, the Bill and Melinda Gates Foundation, and Sanofi outside the submitted work. Dr Zimmermann reported grants from the Federal Office of Public Health Switzerland during the conduct of the study. Dr Short reported consulting fees from Sanofi, Novonodisk, and Roche outside the submitted work. No other disclosures were reported.

Funding/Support: Prof Short is supported by The Australia National Health and Medical Research Council I (2007919). Prof Bowen is supported by the Australia National Health and Medical Research Council Investigator Award (GNT1175509). Prof Burgner is supported by the Australia National Health and Medical Research Council Investigator Grant. Prof Nigel Curtis is supported by the Australia National Health and Medical Research Council Investigator Grant (GNT1197117). Prof Russell is supported by the National Health and Medical Research Council Investigator Grant (GNT1177245). Prof Zar is supported by the South African Medical Research Council. This work was supported by grants from the UK National Institutes of Health, Global Effort on Covid (GEC111), and Wellcome Trust Centre for Infectious Disease Research in Africa. Prof Ritz and Dr Zimmermann were supported by grants from the Swiss Federal Office of Public Health, the Swiss Society of Paediatrics, and the Paediatric Infectious Disease Group of Switzerland, The DATCOV national COVID-19 hospital surveillance system of South Africa, was initially funded by the National Institute for Communicable Diseases and the South African National Government, and subsequently supported by the US Agency for International Development (72067422F00001). The contents of this study are the sole responsibility of the National Institute For Communicable Diseases of South Africa and Navajo Department of Health and do not necessarily reflect the views of the US Agency for International Development or the US Government. The Pneumonia surveillance programme, South Africa was funded by the Wellcome Trust (221003/Z/20/Z) in collaboration with the Foreign, Commonwealth and Development Office, United Kingdom, the US Centers for Disease Control and Prevention (NU51IP000930 and U01IP001048); funds through the US Centers for Disease Control and Prevention under the terms of a subcontract with the African Field Epidemiology Network (AF-NICD-001/2021), the South African Medical Research Council (96838); the African Society of Laboratory Medicine and Africa Centers for Disease Control and Prevention through a subaward from the Bill and Melinda Gates Foundation grant (INV-018978), as well as the National Institute for Communicable Diseases, a division of the National Health Laboratory Service, South Africa. This work includes data provided by the COVID-19 Data Platform. The platform is hosted and led by the Infectious Diseases Data Observatory and the International Severe Acute Respiratory and emerging Infections Consortium. International Severe Acute Respiratory and emerging Infections Consortium is supported by grants from the National Institute for Health Research (CO-CIN-01), the Medical Research Council (MC_PC_19059), the National Institute for Health and Care Research Health Protection Research Unit in Emerging, and Zoonotic Infections at University of Liverpool in partnership with Public Health England, in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (200907), Wellcome Trust and Department for International Development (DID; 215091/Z/18/Z), and the Bill and Melinda Gates Foundation (OPP1209135).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the individuals listed below contributed the data to the COVID-19 Data Platform: Marcel van den Berge, ADRZ, MD, PhD, Amsterdam, Netherlands, Carolien van Netten, PhD, ADRZ, Goes, Netherlands, Christian Prebensen, MD, PhD, Akershus University Hospital, Nordbyhagen, Norway, Machteld van der Feltz, MD, Alrijne Hospital, Leiden, Netherlands, Maja Katherine Lingad, MD, Angeles University Foundation Medical Center, Angeles, Philippines, Soulichanya Phoutthavong, PhD, Attapeu Provincial Hospital, Attapeu, Laos, Anders Tveita, MD, PhD, Baerum Sykehus, Gjettum, Norway, Patrick Breen, MD, Beacon Hospital, Dublin, Ireland, Brenda Reeve, MD, Brantford General Hospital, Brantford, Canada, Rolando Claure-Del Granado, MD, Caja Nacional De Salud, Trinidad, Bolivia, Oscar Hoiting, MD, Canisius Wilhelmina Ziekenhuis, Nijmenjen, Netherlands, François Lamontagne, MD, MSc, Centre hospitalier Universitaire de Sherbrooke, Sherbrooke, Canada, Ana Marques, MD, Centro Hospital e Universitário de Coimbra, Coimbra, Portugal, Filipa Sequeira, MD, Centro Hospitalar de Leiria, Leiria, Portugal, Ana Isabel de Pinho Oliveira, MD, Centro Hospitalar de Tondela-Viseu, Viseu, Portugal, Andrea Dias, MD, Centro Hospitalar e Universitário de Coimbra-Hospital Pediátrico, Coimbra, Portugal, Irene Aragao, MD, Centro Hospitalar Universitário do Porto, Porto, Portugal, Kathy Brickell, MD, Children’s Health Ireland, Dublin, Ireland, Galway University Hospital, Dublin, Ireland, Our lady of Lourdes Drogheda, Drogheda, Ireland, St Vincents University Hospital, Dublin, Ireland, and Wexford General Hospital, Wexford, Ireland, Claire Roger, MD, MSc, CHU Carémeau, Nimes, France, Hernando Torres-Zevallos, MD, Clinica Internacional, Lima, Peru, Luis Felipe Reyes, MD, PhD, Clinica Universidad de La Sabana, Chia, Colombia, Alina Kalicinska, Consortium IMGEN, Piaseczno, Poland, Dorothy Breen, MD, Cork University Hospital, Cork, Ireland, Jolanta Popielska, MD, PhD, Department of Children's Infectious Diseases, Warsaw, Poland, Lars Heggelund, MD, PhD, Drammen Hospital, Drammen, Norway, Albert Groenendijk, PhD, Erasmus Medical Centre, Rotterdam, Netherlands, Evert-Jan Wils, MD, PhD, Franciscus Gasthuis and Vlietland, Rotterdam, Netherlands, Tjard Schermer, PhD, Gelre Hospitals, Zutphen, Netherlands, Patricia Patricio, MD, Hospital Beatriz Ângelo, Loures, Portugal, Bernardo Neves, MD, Hospital Da Luz, Lisbon, Portugal, Maisa Guimarã es de Castro, MD, Hospital de Amor, São Paulo, Brazil, Joan Gómez-Junyent, MD, Hospital del Mar, Barcelona, Spain, Nelson Cardoso, BScN, Hospital Espírito Santo de Évora, Évora, Portugal, Angel Asensio, MD, PhD, Hospital Puerta de Hierro Majadahonda, Madrid, Spain, Jordi Rello, MD, PhD, Hospital Universitario de Alava, Araba, Spain, Christelle Delmas, MD, PhD, INSERM, Paris, France, Adam Nowinski, MD, PhD, Institute of TB and Lung Diseases, Warsaw, Poland, Claudia Figueiredo-Mello, MD, Instituto de Infectologia Emílio Ribas, São Paulo, Brazil, Oksana Kruglova, MD, PhD, Kharkiv Regional Clinical Infectious Diseases Hospital, Kharkiv, Ukraine, and Lugansk State Medical University, Department of Internal Medicine No 2, Lugansk, Ukraine, Samuel Bernard Ekow Harrison, MD, Kintampo Health Research Centre, Kintampo, Ghana, Ben Morton, MD, Malawi-Liverpool Wellcome Trust, Lilongwe, Malawi, Volkan Korten, MD, Marmara University Hospital, Istanbul, Turkey, Brian Marsh, Mater Misericordia e University, Dublin, Ireland, Todd C. Lee, MD, MPH, McGill University Health Centre, Montreal, Canada, Marieke Haalboom, MSc, Medisch Spectrum Twente, Zutphen, Netherlands, Edmund Manning, PhD, Mercy Hospital, Cork, Ireland, Emanuele Durante-Mangoni, MD, PhD, Monaldi Hospital, Napoli, Italy, Jesse Gitaka, MD, PhD, Mount Kenya University, Thika, Kenya, Caroline Mudara, MSc, National Institute for Communicable Diseases, Johannesburg, South Africa, Fernando Augusto Bozza, PhD, National Institute of Infectious Disease Evandro Chagas, Rio de Janeiro, Brazil, Xin Ci Wong, MSc, National Institutes of Health, Ministry of Health Malaysia, Setia Alam, Malaysia, Stephanie Nonas, MD, Oregon Health & Science University, Portland, Oregon, Jan Cato Holter, MD, PhD, Oslo University Hospital, Oslo, Norway, Malcolm G. Semplre, PhD, Oxford University, Oxford, United Kingdom, Jacobien Ellerbroek, MD, PhD, Reinier de Graaf Gasthuis, Delft, Netherlands, Suzette Willems, PhD, Royal Columbian Hospital, Vancouver, Canada, Dwi Utomo Nusantara, PhD, RSUD Pasar Minggu, South Jakarta, Indonesia, Daniel Munblit, PhD, Sechenov University, Moscow, Russia, Bryan Whelan, MD, Sligo University Hospital, Sligo, Ireland. Maria Toki, MD, MSc, Sotiria General Hospital, Athens, Greece, Roberta Meta, MD, St Bernard’s Hospital, Gibraltar, Gibraltar, Michelle E. Kho, PhD, St. Joseph’s Healthcare Hamilton, Hamilton, Canada, Robert A. Fowler, MD, MS, Sunnybrook Health Sciences Centre, Toronto, Canada, Yock Ping Chow, PhD, Sunway Medical Centre, Selangor, Malaysia, Peter de Vries, MD, PhD, Tergooi Hospital, Hilversum, Netherlands, Daniel Glikman, PhD, The Baruch Padeh Medical Center Poriya, Tiberias, Israel, Anne-Marie Guerguerian, MD, The Hospital for Sick Children (SickKids), Toronto, Canada, Shirley Sarfo-Mensah, MPH, The Ottawa Hospital, Ottawa, Canada, Andriy Bal, PhD, Unidade Local de Saúde de Alto Minho, Viana Do Castelo, Portugal, Aquiles Henriquez, MD, Universidad de Las Américas, Quito, Ecuador, Jose Andres Calvache, MD, PhD, Universidad del Cauca, Cauca, Colombia, Pieter Depuydt, MD, Universitair Ziekenhuis, Gent, Belgium, Deepali Kumar, MD, MSc, University Health Network, Toronto, Canada, Niamh Feely, MD, PhD, University Hospital Kerry, Kerry, Ireland, Sheeba Hakak, PhD, University Hospital-Waterford, Waterford, Ireland, Malte Kohns Vasconcelos, MD, MSc, University Hospital Dusseldorf, Dusseldorf, Germany, Siobhan Egan, MSc, University Hospital Limerick, Limerick, Ireland, Anders Benjamin Kildal, MD, PhD, University Hospital of North Norway, Tromso, Norway, Matteo Puntoni, PhD, University Hospital of Parma, Parma, Italy, Hanna Renk, MD, University Hospital of Tubingen, Tubingen, Germany, Andrea Cortegiani, MD, PhD, University Hospital Policlinico Paolo Giaccone, Palermo, Italy, José Miguel Cisneros Herreros, MD, PhD, University Hospital Virgen del Rocío/Institute of Biomedicine of Seville, Seville, Spain, François Lellouche, MD, PhD, University Institute of Cardiology and Respirology, Quebec, Canada, Ymkje Stienstra, MD, PhD, University Medical Center Groningen, Groningen, Netherlands, Simone Piva, MD, University of Brescia, Brescia, Italy, Stella Huo, PhD, University of California-San Francisco, San Francisco, California, Jonathan Samuel Chávez Iñiguez, MD, University of Guadalajara Health Sciences Center, Guadalajara, Mexico, T. Eoin West, MD, MPH, University of Washington Medical Center-Northwest, Seattle, Washington, Doug Robb, MCom, University of Western Australia/Fiona Stanley Hospital, Murdoch, Australia, Alex Nagrebetsky, MD, MSc, the US National Heart, Lung, and Blood Institute PETAL Network, Boston, Massachusetts, and Catherine L. Hough, MD, MSc, the US National Heart, Lung, and Blood Institute PETAL Network, Boston, Massachusetts. We also want to acknowledge the colleagues of all the institutions caring for these children. Authors in Italy acknowledge the support of Piero Valentini, Ilaria Lazzareschi, Francesco Proli, Giulia Bersani, Rosa Morello.

^✉

Corresponding author.

PMCID: PMC10442787 PMID: 37603343

This study attempts to determine whether the dominant circulating SARS-CoV-2 variants of concern were associated with differences in COVID-19 severity among hospitalized children.

Key Points

Question

Were the dominant circulating SARS-CoV-2 variants of concern associated with differences in COVID-19 severity among hospitalized children?

Findings

This cohort study including 31 785 hospitalized children with SARS-CoV-2 infection suggested that while intensive care unit admission decreased over the course of the pandemic in all age groups, ventilatory and oxygen support did not decrease over time in children aged younger than 5 years.

Meaning

These study data can inform mechanistic and intervention research, as well as public health policy, which must be aware of the importance of considering different pediatric age groups when assessing the severity of disease in future SARS-CoV-2 waves.

Abstract

Importance

Multiple SARS-CoV-2 variants have emerged over the COVID-19 pandemic. The implications for COVID-19 severity in children worldwide are unclear.

Objective

To determine whether the dominant circulating SARS-CoV-2 variants of concern (VOCs) were associated with differences in COVID-19 severity among hospitalized children.

Design, Setting, and Participants

Clinical data from hospitalized children and adolescents (younger than 18 years) who were SARS-CoV-2 positive were obtained from 9 countries (Australia, Brazil, Italy, Portugal, South Africa, Switzerland, Thailand, UK, and the US) during 3 different time frames. Time frames 1 (T1), 2 (T2), and 3 (T3) were defined to represent periods of dominance by the ancestral virus, pre-Omicron VOCs, and Omicron, respectively. Age groups for analysis were younger than 6 months, 6 months to younger than 5 years, and 5 to younger than 18 years. Children with an incidental positive test result for SARS-CoV-2 were excluded.

Exposures

SARS-CoV-2 hospitalization during the stipulated time frame.

Main Outcomes and Measures

The severity of disease was assessed by admission to intensive care unit (ICU), the need for ventilatory support, or oxygen therapy.

Results

Among 31 785 hospitalized children and adolescents, the median age was 4 (IQR 1-12) years and 16 639 were male (52.3%). In children younger than 5 years, across successive SARS-CoV-2 waves, there was a reduction in ICU admission (T3 vs T1: risk ratio [RR], 0.56; 95% CI, 0.42-0.75 [younger than 6 months]; RR, 0.61, 95% CI; 0.47-0.79 [6 months to younger than 5 years]), but not ventilatory support or oxygen therapy. In contrast, ICU admission (T3 vs T1: RR, 0.39, 95% CI, 0.32-0.48), ventilatory support (T3 vs T1: RR, 0.37; 95% CI, 0.27-0.51), and oxygen therapy (T3 vs T1: RR, 0.47; 95% CI, 0.32-0.70) decreased across SARS-CoV-2 waves in children 5 years to younger than 18 years old. The results were consistent when data were restricted to unvaccinated children.

Conclusions and Relevance

This study provides valuable insights into the impact of SARS-CoV-2 VOCs on the severity of COVID-19 in hospitalized children across different age groups and countries, suggesting that while ICU admissions decreased across the pandemic in all age groups, ventilatory and oxygen support generally did not decrease over time in children aged younger than 5 years. These findings highlight the importance of considering different pediatric age groups when assessing disease severity in COVID-19.

Introduction

Since the emergence of SARS-CoV-2 in late 2019, there have been numerous studies characterizing disease severity in both adults and children.^1,2,3 Several distinct SARS-CoV-2 variants have since emerged with the most clinically significant known as variants of concern (VOCs). While differences have existed and still do exist regarding the dominant viral variant among countries, the COVID-19 pandemic globally can be broadly classified as being dominated by the ancestral strain, Alpha/Beta/Delta variant, and the Omicron variant.⁴

In adults, the emergence of VOCs, in particular the Omicron variant, has been associated with altered disease severity relative to the ancestral virus.⁵ Indeed, infections with the Omicron variant remained associated with reduced morbidity and mortality in adults compared with those with the Delta variant.^6,7,8 Importantly, while these data may reflect changes in the virus over time, they could also reflect the increased protection from vaccination that was increasingly available over the course of the pandemic, as well as increasing protection from prior SARS-CoV-2 infection.

The role of VOCs, particularly Omicron, in severe COVID-19 among children remains less well defined. For example, while some studies suggest that pediatric intensive care unit (ICU) admission rates during the Omicron wave peaked at approximately 3.5 times the peak rate during the Delta wave,^9,10 others found no difference or a reduction in ICU admission of children across COVID-19 waves.^11,12,13 Severe croup associated with SARS-CoV-2 infection was a new phenotype first observed in young children (younger than 5 years old) during the Omicron wave¹⁰ while the use of mechanical ventilation and the use of noninvasive ventilation were reduced.^12,14,15,16 It is difficult to discern if any of these differences are the result of functional changes in the virus or reflect changes in the host through increased immunity or changes in health care. This is complicated by the fact that, in children, vaccination was initially prioritized for children older than 12 years old, with younger children either not being vaccinated or vaccinated at a later point in the pandemic.

Understanding disease severity following VOC infection in children is further limited by the single-center design of most available studies. Moreover, pediatric studies have largely focused on only a subset of children or group all children younger than 18 years as a single cohort, precluding the analysis of age-specific differences in disease and vaccination status. Studies across the age spectrum in children are urgently needed to inform public health policies. Here, we review morbidity among pediatric hospitalized patients (separated by different age groups) among periods of dominance by different VOCs.

Methods

Study Design

This is a multicenter observational study using retrospective clinical data of hospitalized children and adolescents (younger than 18 years) who were SARS-CoV-2 positive. Deidentified data from hospitalized pediatric patients with were requested from the (Australia, Brazil, Italy, Portugal, South Africa, Switzerland, Thailand, the UK, and the US) between January 1, 2020, and March 31, 2022. Results were stratified by age to investigate potential age differences during the course of the COVID-19 pandemic. The age categories were defined as younger than 6 months, 6 months to younger than 5 years, and 5 years to younger than 18 years. The primary outcome was disease severity as defined by the need for ICU admission, ventilatory support, or oxygen therapy. The study was approved by the University of Queensland and local human research ethics committee. No further informed consent by participants was required. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.¹⁷

Data Source

A total of 10 databases (from 9 countries) provided data (eTable 1 in Supplement 1). To provide site-specific estimates for each research population, each site adhered to a standardized data collection and analysis process. All transfer of data to the University of Queensland was subject to a data transfer agreement.

Data Collection

We collected data on hospitalized pediatric patients younger than 18 years with polymerase chain reaction–confirmed SARS-CoV-2 infection from 10 sites across 9 countries (eTable 1 in Supplement 1). Data were requested from 3 time frames: time frame 1 (T1) was defined as the period in which ancestral SARS-CoV-2 was dominant, time frame 2 (T2) was defined as the period in which pre-Omicron VOCs were dominant, and time frame 3 (T3) was defined as the period in which Omicron-derived VOCs were dominant. The dates used to define T1, T2, and T3 in each participating site were derived from the corresponding national SARS-CoV-2 genome surveillance where a VOC was considered to be dominant in the community if it constituted more than 70% of the collected SARS-CoV-2 sequences.¹⁸ The specific time periods and date of pediatric COVID-19 vaccine roll out for each country are shown in eTable 2 and eTable 3 in Supplement 1. The data collection materials are described in the eMethods in Supplement 1.

Statistical Analysis

Descriptive statistics (number [%] or median [IQR]) were used for the characteristics of patients across the entirety of the study period and within each time frame and age category. To examine statistical differences of comparisons between different time frames, we used the χ² test for categorical variables, Fisher exact test for variables with small sample sizes (less than 5), and the t test or the Mann-Whitney U test for continuous variables as appropriate. A P value of less than .05 was used as the criterion for statistical significance. Adjusted estimates of 3 outcomes were calculated for each site and time frame (eMethods in Supplement 1). Each independent covariable included in the adjusted models were combined in a meta-analysis. Risk ratios (RRs) were summarized using fixed- and random-effects models with the random-effects estimates presented in the text. All analyses were performed with R software version 4.1.1 (The R Project).

Results

Characteristics of Patients Included in the Study

A total of 31 785 children and adolescents were included (eTable 4 in Supplement 1). The median age was 4 (IQR, 1-12) years and 16 639 patients were male (52.3%). When data were stratified by time frame, the study team identified 5438 children hospitalized during T1 (ancestral cohort [17.1%]), 15 205 in T2 (pre-Omicron cohort [47.8%]), and 11 142 in T3 (Omicron cohort [35.1%]). More boys than girls were admitted for COVID-19 in each time period. The median age was lower in T3 (3 [IQR 1-11] years) compared with T1 and T2 (5 [IQR 1-13] years).

Most hospitalizations were among children and adolescents not known to be vaccinated (more than 75%), regardless of the time frame. Only 64 of 14 841 of hospitalized adolescents were vaccinated in T2 (0.4%)—although this number rose to just over 72 of 8582 when Omicron infections first accelerated in T3 (0.8%). Across the 3 time periods, 2737 of hospitalized children were admitted to the ICU (8.6%), 5209 required oxygen support (16.4%), and 1125 required ventilatory support (3.5%). ICU admission was more frequent in patients during T1 (726 of 5392 [13.5%]) and T2 (1402 of 15 070 [9.3%]) compared with patients in T3 (609 of 11 055 [5.5%]). Ventilatory support and oxygen therapy were all more frequent during both T1 and T2, relative to T3. eTables 5, 6, 7, 8, 9, 10, 11, 12, and 13 in Supplement 1 show the distribution of pediatric cases for each site in 3 time periods by age, sex, symptoms at hospital admission, comorbidities, outcomes, and COVID-19 vaccination status. The most frequently reported symptoms in all sites were fever and cough during all time frames. When looking at the proportion of ICU admission, oxygen support, or ventilatory support across different ages, most outcome events across multiple sites were noted in children younger than 6 months (eFigure 1 in Supplement 1). In contrast, events appeared to be evenly distributed across other ages. Therefore, the study team elected to stratify the data according to 3 age groups: children younger than 6 months, children 6 months to younger than 5 years, and 5 years to younger than 18 years. Site-specific estimates of odds ratios for ICU admission, ventilation, and oxygen therapy using unadjusted and adjusted models are shown in eTable 14 in Supplement 1.

COVID-19 Severity Among Hospitalized Children Younger Than 6 Months

The association between study periods and COVID-19 severity among hospitalized children younger than 6 months is shown in Figure 1. The relative risk of ICU admission was significantly lower in T3 vs T1 (random-effects adjusted RR, 0.56; 95% CI, 0.42-0.75). No difference was noted in the proportion of oxygen therapy during the pandemic in this age group (Figure 1). Children younger than 6 months were less likely to be ventilated during T3 compared with T1 (RR, 0.57; 95% CI, 0.36-0.90). The I² statistic ranged from 0% to 68% across all the analyses, which suggested limited-modest heterogeneity across study sites.

Figure 1 shows that South African site 1 contributed the largest cases to the analysis of ICU admission, ventilatory support, and oxygen among children younger than 6 months who were hospitalized with COVID-19. To assess if this 1 site was influencing the observed results, a sensitivity analysis was performed excluding South African site 1. In the absence of South African site 1, the same patterns in ICU admission, ventilatory support, and oxygen therapy were observed. Namely, the proportion of ICU admission was significantly lower in T3 vs T1 (RR, 0.58; 95% CI, 0.34-0.99) (eFigure 2 in Supplement 1). However, the relative risk of ventilatory support and oxygen therapy did not change over the course of the pandemic in this age group.

COVID-19 Severity Among Hospitalized Children Aged 6 Months to Younger Than 5 years

The association between time frame and COVID-19 severity among hospitalized children aged 6 months to younger than 5 years is shown in Figure 2. In this age group, the relative risk of ICU admission was significantly lower in T2 vs T1 (RR, 0.78; 95% CI, 0.62-0.98). Similarly, children aged 6 months to younger than 5 years in T3 were approximately 24% less likely to be admitted to the ICU as were children aged 6 months to younger than 5 years in T2 (RR, 0.76; 95% CI, 0.62-0.93). The relative risk of ICU admission was also reduced in this age group in T3 vs T1 (RR, 0.61; 95% CI, 0.47-0.79). The reduced relative risk of ICU admission in T3 vs T1 was maintained if a sensitivity analysis was performed excluding South African site 1 (eFigure 3 in Supplement 1). No significant difference was noted in the relative risk of ventilatory support or oxygen therapy over the course of the pandemic in this age group (Figure 2). Findings did not change when the major contributing site, South African site 1, was excluded from the analysis (eFigure 3 in Supplement 1). In the aforementioned analyses, the I² statistic ranged from 0% to 67% indicating limited-modest heterogeneity across study sites.

COVID-19 Severity Among Hospitalized Children Aged 5 to Younger Than 18 Years

The association between time period and COVID-19 severity among hospitalized children older than 5 years is shown in Figure 3. In this age group, ICU admission rate decreased significantly over study time period, namely T2 vs T1 (RR, 0.75; 95% CI, 0.64-0.88), T3 vs T2 (RR, 0.53; 95% CI, 0.40-0.71), and T3 vs T1 (RR, 0.39; 95% CI, 0.32-0.48) (Figure 3); an observation which held true even if South African site 1 was excluded from the analysis (eFigure 4 in Supplement 1).

Although the RRs for oxygen therapy did not differ between T2 vs T1 in individuals aged 5 to younger than 18 years (RR, 1.08; 95% CI, 0.78-1.49) with a considerable heterogeneity between sites (I² value, 72%), significant reductions in the risk of oxygen therapy were seen in T3 compared with T1 (RR, 0.47; 95% CI, 0.32-0.70) and T3 compared with T2 (RR, 0.45; 95% CI, 0.40-0.50). This difference was maintained if South African site 1 was excluded from the analysis (eFigure 4 in Supplement 1).

In contrast to the analysis of children younger than 5 years (Figures 2 and 3), the risk ratio of ventilatory support decreased over the course of the pandemic in children 5 to younger than 18 years old (T3 vs T1 RR; 0.37; 95% CI, 0.27-0.51; Figure 3). When South African site 1 was excluded from the analysis, this remained true for the comparison of T3 vs T2 (RR, 0.51; 95% CI, 0.35-0.74) and the comparison of T3 vs T1 (RR, 0.41; 95% CI, 0.27-0.62) (eFigure 4 in Supplement 1).

Together, these data suggest that risk of ICU admission decreased over the course of the pandemic for all ages groups, but while risks for ventilatory support and oxygen therapy remained generally unchanged for children younger than 5 years of age, those risks also decreased over the course of the pandemic for ages 5 to younger than 18 years. To determine if these results were influenced by COVID-19 vaccination in children aged 5 to 18 years, a sensitivity analysis was performed where only unvaccinated children 5 to younger than 18 years were included. ICU admission, oxygen therapy, and ventilatory support still consistently decreased over the course of the pandemic in unvaccinated hospitalized children aged 5 to younger than18 years (Figure 4).

Figure 4. — Models were adjusted for sex (male/female), preexisting cardiovascular disease (yes/no), asthma (yes/no), neurological disorder (yes/no), childhood cancer (yes/no), immunological disease or immunosuppression (yes/no), diabetes (yes/no), HIV positive (yes/no), tuberculosis (yes/no), and prematurity (less than 37 weeks’ gestation [yes/no]), as appropriate. South Africa site 1 data were obtained from South Africa DATCOV and South Africa site 2 (SA_2) data were obtained from the National Institute for Communicable Diseases of South Africa. Data from the US (time frame 3 [T3]), Thailand (time frame 1 [T1]), and Australia (T1) were not included in this model because data were not available. NA indicates not applicable; T2, time frame 2.

Direct Comparison of COVID-19 Severity Between Different Pediatric Age Groups

Lastly, to understand age-dependent differences in the severity of COVID-19 in the 3 different time frames, the risk of ICU admission, oxygen support, and ventilatory support were compared directly between children younger than 6 months, children 6 months to younger than 5 years, and children 5 to younger than 18 years (eFigure 5 in Supplement 1). No notable differences were recorded in any of the 3 outcomes (in any time frame) between children younger than 6 months and children 6 months to younger than 5 years (eFigure 5 in Supplement 1). In contrast, compared with children 6 months to younger than 5 years, children aged 5 to younger than 18 years had a significantly higher risk of ICU admission (RR, 1.72; 95% CI, 1.38-2.14), ventilatory support (RR, 1.81; 95% CI, 1.30-2.51), and oxygen support during T1 (RR, 1.35; 95% CI, 1.12-1.63) (eFigure 5 in Supplement 1) compared with those aged 6 months to younger than 5 years. Together, these data suggest that within each of the selected time frames of the study, disease severity was equivalent between hospitalized children younger than 6 months and hospitalized children aged 6 months to younger than 5 years. In contrast, children 5 years and older had more severe disease compared with younger children in T1.

Discussion

This study found that hospitalized children younger than 5 years had a reduced proportion of COVID-19 ICU admissions with successive variants while proportions of ventilatory support only decreased in T3 vs T1 among children younger than 6 months and oxygen therapy did not change. In contrast, hospitalized children aged 5 to younger than 18 years had a lower proportion of ICU admission, ventilatory support, and oxygen support over the course of the entire COVID-19 pandemic. These same trends were observed among hospitalized children aged 5 to younger than 18 years who had not been vaccinated. Together, these data indicate that there were age-dependent differences in disease severity across the course of the COVID-19 pandemic among hospitalized children.

Recent studies of COVID-19 vaccination during pregnancy suggest the transplacental transfer of SARS-CoV-2–specific antibodies.¹⁹ Accordingly, maternal vaccination during pregnancy for COVID-19 has been associated with reduced hospitalization of children 6 months.²⁰ It may be that the reduced rate of ICU admission over the course of the COVID-19 pandemic in children younger than 6 months is reflective of maternal vaccination and/or infection (more likely to occur in T2 and T3). It is possible that this same effect was not seen in terms of ventilatory support and oxygen support because maternal vaccination may be most efficacious in protecting from more severe outcomes of SARS-CoV-2 infection (ie, ICU admission) and not more moderate outcomes (ie, ventilatory and oxygen support).

Children aged 6 months to younger than 5 years represent an important subgroup to understand disease severity in the absence of COVID-19 vaccination. It is widely accepted that at younger than 6 months of age transplacental antibodies have waned, although antibodies can be transferred via breastfeeding following maternal infection or vaccination.²¹ In the time period studied herein, vaccination was not licensed for children younger than 5 years. We found that children in this age group experienced a reduced ICU admission over the pandemic. This may reflect the protective effect of prior infection on the severe outcomes of disease, changes in clinical practice, case reporting or changes in the virulence of the virus over time. Indeed, these data are consistent with a US study documenting reduced ICU admissions in children younger than 5 years in the Omicron wave relative to the prior Delta wave.¹² It is interesting to note the same trend was not observed over time in terms of the ventilatory support and oxygen support in children aged 6 months to younger than 5 years. This could be affected by clinical threshold and/or availability of ventilation support, etc. Although, our study did not directly investigate the impact of multisystem inflammatory syndrome in children on ICU admissions, it is possible that differential incidences of multisystem inflammatory syndrome resulted in ICU admission in the absence of ventilation.²² Therefore, it is important to acknowledge that broad statements about disease severity over the course of the pandemic need to be carefully nuanced.

Children younger than 5 years experienced a reduction in ICU admission, ventilatory support, and oxygen therapy over the course of the pandemic. Noting that only a low number of hospitalized children in this study were vaccinated, these same trends were observed among unvaccinated children younger than 5 years. These data suggest that other factors, such as prior infection, changes in viral virulence, or changes in clinical practice, may have played a more significant role in the observed trends. Indeed, it is tempting to speculate that older children may have an immune response more akin to that of adults such that observed patterns of decreased virulence during the Omicron wave in adults^6,7,8 could be extrapolated to this age group.

In a direct comparison of disease severity between the different age groups, disease severity (in terms of ICU admission and ventilatory support) was elevated in older children in T1. These data are consistent with previous studies from the US, Canada, Iran, and Costa Rica showing that older children and adolescents had more severe illness when hospitalized with COVID-19 compared with younger children during the early stages of the pandemic.^23,24

Strengths and Limitations

This study has a number of strengths. Internationally, there has been considerable variation in the rate of SARS-CoV-2 infection, clinical practice, and medical capacity. It is, therefore, important, and albeit difficult, to consider global patterns in disease severity in both adult and pediatric populations. This speaks to the benefit of conducting a multicenter meta-analysis of disease severity. In the present study, while we did observe site-to-site variations in disease severity, most of the analyses showed low to moderate interstudy heterogeneity (mean/median I² value recorded 25/14%), confirming the robustness of our findings.

There are also important limitations of the present study. First, it is important to emphasize that the population studied herein were hospitalized children; therefore the rates of ICU admission, ventilatory support, and oxygen support cannot be generalized to children in the community. It is also important to acknowledge that these data were collected up until March 2022 and may not represent more recent evolution in SARS-CoV-2 variants. We acknowledge that the inability to collect reinfection status for all individuals limited a meaningful analysis of the impact of previous SARS-CoV-2 infection on COVID-19 severity.²⁵ In the present study, we used multiple imputation using chained equations²⁶ to address missing data from the South African and Australian sites where approximately 40% of individuals had random missing values in the comorbidities variable. While this may have induced bias, removing South African site 1 yielded similar results, providing reassurance about the findings’ robustness. Lastly, data were also limited to certain sites on different continents (eg, Brazil, South Africa, and Thailand), and might not be representative across the continent (eg, North America and Australia). Despite this limitation, this study represents, to our knowledge, the first multicenter analysis of COVID-19 severity in children over the course of the pandemic.

Conclusions

In conclusion, this study provides valuable insights into the impact of SARS-CoV-2 VOCs on the severity of COVID-19 in hospitalized children across different age groups and countries. The results suggest that while ICU admissions decreased over the course of the pandemic in all age groups, ventilatory and oxygen support did not decrease over time in children aged younger than 5 years. Moreover, the RRs of disease severity, including ICU admission, ventilatory support, and oxygen therapy, decreased across SARS-CoV-2 waves in those aged 5 to younger than 18 years old. These findings highlight the importance of considering different pediatric age groups when assessing disease severity in SARS-CoV-2.

Supplement 1.

eMethods. Data source, collection, capture, data quality assurance, and statistical analysis.

eTable 1. Data source and data of data collection from the study sites.

eTable 2. Site-specific time periods used for the present study.

eTable 3. Date of pediatric COVID-19 vaccine roll out for each country included in this study.

eTable 4. Characteristics of study population (based on three time frames).

eTable 5. Demographics, Clinical Presentation, Comorbidities and Clinical outcomes of the study population in the UK site.

eTable 6. Demographics, Clinical Presentation, Comorbidities and Clinical outcomes of the study population in the European site.

eTable 7. Demographics, Clinical Presentation, Comorbidities and Clinical outcomes of the study population in the Switzerland site.

eTable 8. Demographics, Clinical Presentation, Comorbidities and Clinical outcomes of the study population in the South Africa site 1.

eTable 9. Demographics, Clinical Presentation, Comorbidities and Clinical outcomes of the study population in the South Africa site 2.

eTable 10. Demographics, Clinical Presentation, Comorbidities and Clinical outcomes of the study population in the Brazil site.

eTable 11. Demographics, Clinical Presentation, Comorbidities and Clinical outcomes of the study population in the USA site.

eTable 12. Demographics, Clinical Presentation, Comorbidities and Clinical outcomes of the study population in the Thailand site.

eTable 13. Demographics, Clinical Presentation, Comorbidities and Clinical outcomes of the study population in the Australia site.

eTable 14. Site-Specific Odds Ratios for ICU admission, Ventilation and Oxygen therapy using Unadjusted and Adjusted Models, Stratified by Age Category.

eFigure 1. Summary of age distribution of children admitted to the ICU, ventilated or provided oxygen therapy.

eFigure 2. Meta-analysis risk ratios for ICU admission, noninvasive/invasive ventilatory support, oxygen therapy among pediatric patients under 6 months old excluding the South African site 1.

eFigure 3. Meta-analysis risk ratios for ICU admission, noninvasive/invasive ventilatory support, oxygen therapy among pediatric patients aged 6 months to < 5 years excluding the South African site 1.

eFigure 4. Meta-analysis risk ratios for ICU admission, noninvasive/invasive ventilatory support, oxygen therapy among pediatric patients aged 5 to <18 years old excluding the South African site 1.

eFigure 5. Direct comparison of COVID-19 severity between different pediatric age groups.

Click here for additional data file.^{(2.4MB, pdf)}

Supplement 2.

Group information

Click here for additional data file.^{(267.9KB, pdf)}

Supplement 3.

Data sharing statement

Click here for additional data file.^{(18.5KB, pdf)}

References

1.Preston LE, Chevinsky JR, Kompaniyets L, et al. Characteristics and disease severity of US children and adolescents diagnosed with COVID-19. JAMA Netw Open. 2021;4(4):e215298-e215298. doi: 10.1001/jamanetworkopen.2021.5298 [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Saito S, Asai Y, Matsunaga N, et al. First and second COVID-19 waves in Japan: a comparison of disease severity and characteristics. J Infect. 2021;82(4):84-123. doi: 10.1016/j.jinf.2020.10.033 [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Zachariah P, Johnson CL, Halabi KC, et al. ; Columbia Pediatric COVID-19 Management Group . 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. JAMA Pediatr. 2020;174(10):e202430-e202430. doi: 10.1001/jamapediatrics.2020.2430 [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Campbell F, Archer B, Laurenson-Schafer H, et al. Increased transmissibility and global spread of SARS-CoV-2 variants of concern as at June 2021. Euro Surveill. 2021;26(24):2100509. doi: 10.2807/1560-7917.ES.2021.26.24.2100509 [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Maslo C, Friedland R, Toubkin M, Laubscher A, Akaloo T, Kama B. Characteristics and outcomes of hospitalized patients in South Africa during the COVID-19 Omicron wave compared with previous waves. JAMA. 2022;327(6):583-584. doi: 10.1001/jama.2021.24868 [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Mayr FB, Talisa VB, Castro AD, Shaikh OS, Omer SB, Butt AA. COVID-19 disease severity in US Veterans infected during Omicron and Delta variant predominant periods. Nat Commun. 2022;13(1):3647. doi: 10.1038/s41467-022-31402-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Trobajo-Sanmartín C, Miqueleiz A, Guevara M, et al. Comparison of the risk of hospitalization and severe disease among co-circulating severe acute respiratory syndrome coronavirus 2 variants. J Infect Dis. 2022;227(3):332-338. doi: 10.1093/infdis/jiac385 [DOI] [PubMed] [Google Scholar]
8.Wrenn JO, Pakala SB, Vestal G, et al. COVID-19 severity from Omicron and Delta SARS-CoV-2 variants. Influenza Other Respir Viruses. 2022;16(5):832-836. doi: 10.1111/irv.12982 [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Marks KJ, Whitaker M, Agathis NT, et al. ; COVID-NET Surveillance Team . Hospitalization of infants and children aged 0-4 years with laboratory-confirmed COVID-19—COVID-NET, 14 states, March 2020-February 2022. MMWR Morb Mortal Wkly Rep. 2022;71(11):429-436. doi: 10.15585/mmwr.mm7111e2 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Tunç EM, Koid Jia Shin C, Usoro E, et al. Croup during the Coronavirus disease 2019 Omicron variant surge. J Pediatr. 2022;247:147-149. doi: 10.1016/j.jpeds.2022.05.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Lefchak B, Nickel A, Lammers S, Watson D, Hester GZ, Bergmann KR. Analysis of COVID-19-related croup and SARS-CoV-2 variant predominance in the US. JAMA Netw Open. 2022;5(7):e2220060-e2220060. doi: 10.1001/jamanetworkopen.2022.20060 [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Wang L, Berger NA, Kaelber DC, Davis PB, Volkow ND, Xu R. Incidence rates and clinical outcomes of SARS-CoV-2 infection with the Omicron and Delta variants in children younger than 5 years in the US. JAMA Pediatr. 2022;176(8):811-813. doi: 10.1001/jamapediatrics.2022.0945 [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Hamid S, Woodworth K, Pham H, et al. ; COVID-NET Surveillance Team . COVID-19-Associated Hospitalizations Among U.S. Infants Aged <6 Months—COVID-NET, 13 States, June 2021-August 2022. MMWR Morb Mortal Wkly Rep. 2022;71(45):1442-1448. doi: 10.15585/mmwr.mm7145a3 [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Torjesen I. Covid-19: Omicron variant is linked to steep rise in hospital admissions of very young children. BMJ. 2022;376:o110. doi: 10.1136/bmj.o110 [DOI] [PubMed] [Google Scholar]
15.Holm M, Espenhain L, Glenthøj J, et al. Risk and phenotype of multisystem inflammatory syndrome in vaccinated and unvaccinated Danish children before and during the Omicron wave. JAMA Pediatr. 2022;176(8):821-823. doi: 10.1001/jamapediatrics.2022.2206 [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Levy N, Koppel JH, Kaplan O, et al. Severity and incidence of multisystem inflammatory syndrome in children during 3 SARS-CoV-2 pandemic waves in Israel. JAMA. 2022;327(24):2452-2454. doi: 10.1001/jama.2022.8025 [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Vandenbroucke JP, von Elm E, Altman DG, et al. ; STROBE Initiative . Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. PLoS Med. 2007;4(10):e297. doi: 10.1371/journal.pmed.0040297 [DOI] [PMC free article] [PubMed] [Google Scholar]
18.CoVariants . Overview of variants in countries. Accessed July 13, 2023. https://covariants.org/per-country
19.Nir O, Schwartz A, Toussia-Cohen S, et al. Maternal-neonatal transfer of SARS-CoV-2 immunoglobulin G antibodies among parturient women treated with BNT162b2 messenger RNA vaccine during pregnancy. Am J Obstet Gynecol MFM. 2022;4(1):100492. doi: 10.1016/j.ajogmf.2021.100492 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Halasa NB, Olson SM, Staat MA, et al. ; Overcoming COVID-19 Investigators; Overcoming COVID-19 Network . Effectiveness of maternal vaccination with mRNA COVID-19 vaccine during pregnancy against COVID-19-associated hospitalization in infants aged <6 months—17 states, July 2021-January 2022. MMWR Morb Mortal Wkly Rep. 2022;71(7):264-270. doi: 10.15585/mmwr.mm7107e3 [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Perl SH, Uzan-Yulzari A, Klainer H, et al. SARS-CoV-2-specific antibodies in breast milk after COVID-19 vaccination of breastfeeding women. JAMA. 2021;325(19):2013-2014. doi: 10.1001/jama.2021.5782 [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Davies P, Evans C, Kanthimathinathan HK, et al. Intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study. Lancet Child Adolesc Health. 2020;4(9):669-677. doi: 10.1016/S2352-4642(20)30215-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Antoon JW, Grijalva CG, Thurm C, et al. Factors associated with COVID-19 disease severity in US children and adolescents. Journal of Hospital Medicine. 2021;16(10):603-610. doi: 10.12788/jhm.3689 [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Merckx J, Morris SK, Bitnun A, et al. Infants hospitalized for acute COVID-19: disease severity in a multicenter cohort study. Eur J Pediatr. 2022;181(6):2535-2539. doi: 10.1007/s00431-022-04422-x [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Medić S, Anastassopoulou C, Lozanov-Crvenković Z, et al. Incidence, risk, and severity of SARS-CoV-2 eeinfections in children and adolescents between March 2020 and July 2022 in Serbia. JAMA Netw Open. 2023;6(2):e2255779-e2255779. doi: 10.1001/jamanetworkopen.2022.55779 [DOI] [PMC free article] [PubMed] [Google Scholar]
26.van Buuren S, Groothuis-Oudshoorn K.. mice: Multivariate imputation by chained equations in R. Journal of Statistical Software. 2011;45(3):1-67. doi: 10.18637/jss.v045.i03 [DOI] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials