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. 2024 Aug 21;332(14):1174-1188.
doi: 10.1001/jama.2024.12747. Online ahead of print.

Characterizing Long COVID in Children and Adolescents

Rachel S Gross  1 , Tanayott Thaweethai  2   3 , Lawrence C Kleinman  4   5 , Jessica N Snowden  6 , Erika B Rosenzweig  7 , Joshua D Milner  8 , Kelan G Tantisira  9 , Kyung E Rhee  10 , Terry L Jernigan  11 , Patricia A Kinser  12 , Amy L Salisbury  12 , David Warburton  13 , Sindhu Mohandas  14 , John C Wood  15 , Jane W Newburger  16   17 , Dongngan T Truong  18 , Valerie J Flaherman  19 , Torri D Metz  20 , Elizabeth W Karlson  21   22 , Lori B Chibnik  23   24 , Deepti B Pant  2 , Aparna Krishnamoorthy  2 , Richard Gallagher  25 , Michelle F Lamendola-Essel  26 , Denise C Hasson  27 , Stuart D Katz  28 , Shonna Yin  1   29 , Benard P Dreyer  30 , Megan Carmilani  31   32 , K Coombs  31   33 , Megan L Fitzgerald  31   34 , Nick Güthe  31 , Mady Hornig  31   35 , Rebecca J Letts  31 , Aimee K Peddie  31 , Brittany D Taylor  31   36 , Venkataraman Balaraman  37 , Amanda Bogie  38 , Hulya Bukulmez  39 , Allen J Dozor  40 , Daniel Eckrich  41 , Amy J Elliott  42 , Danielle N Evans  43 , Jonathan S Farkas  44 , E Vincent S Faustino  45 , Laura Fischer  46 , Sunanda Gaur  47 , Ashraf S Harahsheh  48 , Uzma N Hasan  49 , Daniel S Hsia  50 , Gredia Huerta-Montañez  51 , Kathy D Hummel  43 , Matt P Kadish  52 , David C Kaelber  53 , Sankaran Krishnan  40 , Jessica S Kosut  37 , Jerry Larrabee  52 , Peter Paul C Lim  54 , Ian C Michelow  55 , Carlos R Oliveira  56 , Hengameh Raissy  57 , Zaira Rosario-Pabon  58 , Judith L Ross  59 , Alice I Sato  60 , Michelle D Stevenson  61 , Maria M Talavera-Barber  62 , Ronald J Teufel  63 , Kathryn E Weakley  64 , Emily Zimmerman  65 , Marie-Abele C Bind  66 , James Chan  2 , Zoe Guan  2 , Richard E Morse  2 , Harrison T Reeder  2 , Natascha Akshoomoff  67 , Judy L Aschner  68 , Rakesh Bhattacharjee  9 , Lesley A Cottrell  69 , Kelly Cowan  70 , Viren A D'Sa  71 , Alexander G Fiks  72 , Maria L Gennaro  73 , Katherine Irby  74 , Manaswitha Khare  75 , Jeremy Landeo Guttierrez  9 , Russell J McCulloh  76 , Shalu Narang  77 , Manette Ness-Cochinwala  78 , Sheila Nolan  79 , Paul Palumbo  80 , Julie Ryu  9 , Juan C Salazar  55 , Rangaraj Selvarangan  81 , Cheryl R Stein  82 , Alan Werzberger  83 , William T Zempsky  84 , Robin Aupperle  85 , Fiona C Baker  86 , Marie T Banich  87 , Deanna M Barch  88 , Arielle Baskin-Sommers  89 , James M Bjork  90 , Susan Y Bookheimer  91 , Sandra A Brown  92 , B J Casey  93 , Linda Chang  94 , Duncan B Clark  95 , Anders M Dale  96 , Mirella Dapretto  91 , Thomas M Ernst  94 , Damien A Fair  97 , Sarah W Feldstein Ewing  98 , John J Foxe  99 , Edward G Freedman  99 , Naomi P Friedman  100 , Hugh Garavan  101 , Dylan G Gee  89 , Raul Gonzalez  102 , Kevin M Gray  103 , Mary M Heitzeg  104 , Megan M Herting  105 , Joanna Jacobus  67 , Angela R Laird  106 , Christine L Larson  107 , Krista M Lisdahl  107 , Monica Luciana  108 , Beatriz Luna  95 , Pamela A F Madden  109 , Erin C McGlade  110 , Eva M Müller-Oehring  86 , Bonnie J Nagel  111 , Michael C Neale  112 , Martin P Paulus  85 , Alexandra S Potter  113 , Perry F Renshaw  110 , Elizabeth R Sowell  114 , Lindsay M Squeglia  103 , Susan Tapert  67 , Lucina Q Uddin  91 , Sylia Wilson  115 , Deborah A Yurgelun-Todd  110 , Andrea S Foulkes  66 , Melissa S Stockwell  116   117 ; RECOVER-Pediatrics Consortium; RECOVER-Pediatrics Group Authors
Collaborators, Affiliations

Characterizing Long COVID in Children and Adolescents

Rachel S Gross et al. JAMA. .

Abstract

Importance: Most research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment.

Objective: To identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC.

Design, setting, and participants: Multicenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history.

Exposure: SARS-CoV-2 infection.

Main outcomes and measures: PASC and 89 prolonged symptoms across 9 symptom domains.

Results: A total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents.

Conclusions and relevance: This study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Kleinman reported receiving grants from New York University via subcontract of NIH during the conduct of the study; owning shares in Amgen, Regeneron, Sanofi, and GLAXF; and being a member of the board of Dartnet Institute and member of the board of health of Borough of Metuchen, Quality Matters, Inc. Dr Snowden reported serving on a Pfizer COVID-19 advisory board, which ended in November 2023. Dr Milner reported serving on a scientific advisory board for Blueprint Medicine and receiving grants from Pharming. Dr Jernigan reported receiving grants from University of California San Diego OTA during the conduct of the study. Dr Salisbury reported receiving grants from NIH and HRSA and donated funds from Anthem outside the submitted work. Dr Newburger reported receiving grants from Pfizer for an observational study on COVID-19 associated myocarditis, serving on a data and safety monitoring committee for BMS, and serving on an independent events adjudication committee for pediatric apixiban study outside the submitted work. Dr Truong reported being co–principal investigator on a Pfizer-funded study to assess long-term sequalae of vaccine-associated myocarditis. Dr Metz reported being a site principal investigator for Pfizer studies of SARS-CoV-2 vaccination in pregnancy, RSV vaccination in pregnancy, and Paxlovid in pregnancy. Dr Dreyer reported receiving grants from NYU Grossman School of Medicine during the conduct of the study. Dr Aschner reported being a stockholder in Gilead Sciences. Dr Bhattacharjee reported serving on an advisory board for Jazz Pharmaceuticals. Dr Werzberger reported receiving funding from Merck for a hepatitis A vaccine immunology study. Dr Zempsky reported affiliations with OmmioHealth, Lundbeck Pharmacueticals, and Editas. Dr Banich reported receiving grants from University of Colorado Boulder during the conduct of the study. Dr Barch reported receiving grants from NIMH and NIDA during the conduct of the study. Dr Bhattacharjee reported consulting for Jazz Pharmaceuticals and Avadel Pharmaceuticals outside the submitted work. Dr Dale reported being a founder of and holding equity in CorTechs Labs, Inc; serving on a scientific advisory board for CorTechs Labs, Inc, Human Longevity, Inc, and the Mohn Medical Imaging and Visualization Centre; and receiving funding through a research agreement with General Electric Healthcare (GEHC). Dr Fair reported being a patent holder for the Framewise Integrated Real-Time Motion Monitoring (FIRMM) software and a cofounder of Turing Medical, Inc. Dr Fiks reported receiving personal fees from Rutgers and salary support from AAP during the conduct of the study; receiving support from American Medical Association for travel and honorarium from Atlantic Health Systems and Boston Medical Center, PCORI, and Emory University; and having a patent for decision support software known as Care Assistant pending. Dr Foulkes reported receiving grants from NIH/NHLBI during the conduct of the study. Dr Gray reported receiving grants from Aelis Farma and personal fees from Indivior and Jazz Pharmaceuticals outside the submitted work. Dr McCulloh reported receiving grants from University of Arkansas for Medical Sciences sub-awardee for the NIH RECOVER grant during the conduct of the study and grants from Merck Foundation for vaccine communication research through the Merck Investigator Studies Program outside the submitted work. Dr McGlade reported receiving salary support from Department of Veteran Affairs outside the submitted work. Dr Neale reported receiving grants from NIH/NIDA during the conduct of the study. Dr Palumbo reported being a member of a data and safety monitoring committee for Gilead and Janssen outside the submitted work. Dr Paulus reported receiving grants from National Institute on Drug Abuse during the conduct of the study, receiving royalties from an article on methamphetamine in UpToDate, and having compensated consulting agreement with Boehringer Ingelheim International GmbH. Dr Ross reported receiving grants from Nemours Children’s Health-DE NIH RECOVER STUDY during the conduct of the study. Dr Stockwell reported receiving grants from CDC to Trustees of Columbia related to SARS-CoV-2 infection and vaccination research and service agreement paid to trustees of Columbia for being associate director of pediatric research in office settings from American Academy of Pediatrics outside the submitted work. Dr Teufel reported receiving grants from HRSA and Duke outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participants With Each Prolonged Symptom, Adjusted Odds Ratios, and Adjusted Risk Differences Comparing Infected vs Uninfected School-Age Children and Adolescents
A symptom was included if at least 5% of infected or uninfected participants reported experiencing that symptom. Adjusted odds ratios and risk differences were estimated from models that included infection status as the exposure and the presence of each prolonged symptom as the outcome, with adjustment for sex assigned at birth and race and ethnicity (see eMethods in Supplement 3).
Figure 2.
Figure 2.. Development of the Postacute Sequelae of SARS-CoV-2 Infection (PASC) Research Index and Threshold for School-Age Children (6-11 Years)
A, Least absolute shrinkage and selection operator (LASSO) was used to fit a logistic regression model to identify which symptoms could be used to identify individuals likely to have PASC. Estimated log odds ratios were divided by 0.10 and rounded up to the nearest 0.5 to calculate symptom scores. An individual’s PASC research index is calculated by summing the scores for each prolonged symptom a participant reported (ie, the participant experienced the symptom for 4 weeks since the beginning of the pandemic and is currently experiencing it at the time of the survey). B, The optimal index threshold for PASC was selected using bootstrapping to estimate standard error bars. An approximation of the “elbow” method was used to identify the cutoff where the number of uninfected participants misclassified as PASC-probable stabilized (eMethods in Supplement 3). The threshold (index of at least 5.5) can be used to identify school-age children with PASC for research purposes. Using this threshold, the percentage of infected PASC-probable school-age children with each symptom was as follows: headache, 55%; trouble with memory or focusing, 45%; trouble sleeping, 44%; stomach pain, 43%; nausea or vomiting, 34%; back or neck pain, 30%; itchy skin or skin rash, 29%; fear about specific things, 26%; feeling lightheaded or dizzy, 26%; and refusing to go to school, 23%. C, Participant responses to 3 questions from the Patient-Reported Outcomes Measurement Information System (PROMIS) Global 10 survey, stratified into 7 groups: participants with a zero PASC research index and no prolonged symptoms, zero PASC research index but at least 1 prolonged symptom, and participants with nonzero PASC index, divided into quintiles. The dark vertical line indicates the index threshold for PASC. Each cell is shaded according to the frequency of each response within each column, ranging from 0% to 100%.
Figure 3.
Figure 3.. Development of the Postacute Sequelae of SARS-CoV-2 Infection (PASC) Research Index and Threshold for Adolescents (Ages 12 to 17 Years)
A, Least absolute shrinkage and selection operator (LASSO) was used to fit a logistic regression model to identify which symptoms could be used to identify individuals likely to have PASC. Estimated log odds ratios were divided by 0.10 and rounded up to the nearest 0.5 to calculate symptom scores. An individual’s PASC research index is calculated by summing the scores for each prolonged symptom a participant reported (ie, the participant experienced the symptom for 4 weeks since the beginning of the pandemic and is currently experiencing it at the time of the survey). B, The optimal index threshold for PASC was selected using 95% CIs to estimate error bars. An approximation of the “elbow” method was used to identify the cutoff where the number of uninfected participants misclassified as PASC-probable stabilized (eMethods in Supplement 3). The threshold (index of at least 5) can be used to identify adolescents with PASC for research purposes. Using this threshold, the percentage of infected PASC-probable adolescents with each symptom was as follows: daytime tiredness/sleepiness or low energy, 80%; body, muscle, or joint pain, 61%; headache, 56%; trouble with memory or focusing, 47%; tired after walking, 42%; back or neck pain, 40%; feeling lightheaded or dizzy, 39%; and change or loss in smell or taste, 34%. C, Participant responses to 3 questions from the Patient-Reported Outcomes Measurement Information System (PROMIS) Global 10 survey, stratified into 7 groups: participants with a zero PASC research index and no prolonged symptoms, zero PASC research index but at least 1 prolonged symptoms, and participants with nonzero PASC index, divided into quintiles. The dark vertical line indicates the index threshold for PASC (to the left is PASC-unspecified, to the right is PASC-probable). Each cell is shaded according to the frequency of each response within each column, ranging from 0% to 100%.
Figure 4.
Figure 4.. Frequency of Prolonged Symptoms Among School-Age Children and Adolescents Stratified by Infection and PASC Status
Symptoms, sorted from most to least common in the study population overall, are in the center column. Left columns correspond to school-age children in 3 groups: uninfected, infected and not meeting the PASC research index threshold (infected, PASC-unspecified), and infected and meeting the PASC research index threshold (infected, PASC-probable). The columns on the right correspond to adolescents with columns in the reverse order. Note that school-age children were not asked about panic attacks. Frequency of each prolonged symptom is indicated by shading, from 0% to 100%.
Figure 5.
Figure 5.. Defining Subgroups of Postacute Sequelae of SARS-CoV-2 Infection (PASC)–Probable Participants
A and B, Subgroups formed using consensus clustering to group participants with similar symptom profiles (based on prolonged symptoms contributing to the PASC research index only). Four clusters were identified in PASC-probable school-age children and 3 clusters among adolescents. C and D, Frequencies of each prolonged symptom are shown for each cluster, where shading indicates frequency from 0%-100%. Symptoms that contribute to the PASC research index are above the dark horizontal line, and those below do not contribute to the PASC research index, sorted in decreasing frequency among all PASC-probable participants. Symptoms present in <5% of participants in every cluster were omitted. The full set of symptoms is in eFigure 6 in Supplement 3.
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Comment in

  • doi: 10.1001/jama.2024.13551

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