Key PointsQuestion
Is elevated body mass index (BMI) associated with an increased risk of developing post-acute sequelae of SARS-Cov-2 infection (PASC) among children and young adults?
Findings
In this cohort study of 172 136 children and young adults, elevated BMI was associated with significantly higher risk of PASC. Compared with peers with a healthy BMI, there was a 25.4% increased risk of PASC among those with obesity and a 42.1% increased risk of PASC among those with severe obesity.
Meaning
These findings suggest that overweight and obesity are important risk factors for pediatric PASC, highlighting the need for targeted care to prevent chronic conditions in at-risk children and young adults who are infected with SARS-CoV-2.
Importance
Obesity is associated with increased severity of COVID-19. Whether obesity is associated with an increased risk of post-acute sequelae of SARS-CoV-2 infection (PASC) among pediatric populations, independent of its association with acute infection severity, is unclear.
Objective
To quantify the association of body mass index (BMI) status before SARS-CoV-2 infection with pediatric PASC risk, controlling for acute infection severity.
Design, Setting, and Participants
This retrospective cohort study occurred at 26 US children’s hospitals from March 2020 to May 2023 with a minimum follow-up of 179 days. Eligible participants included children and young adults aged 5 to 20 years with SARS-CoV-2 infection. Data analysis was conducted from October 2023 to January 2024.
Exposures
BMI status assessed within 18 months before infection; the measure closest to the index date was selected. The BMI categories included healthy weight (≥5th to <85th percentile for those aged 5-19 years or ≥18.5 to <25 for those aged >19 years), overweight (≥85th to <95th percentile for those aged 5-19 years or ≥25 to <30 for for those aged >19 years), obesity (≥95th percentile to <120% of the 95th percentile for for those aged 5-19 years or ≥30 to <40 for those aged >19 years), and severe obesity (≥120% of the 95th percentile for those aged 5-19 years or ≥40 for those aged >19 years).
Main Outcomes And Measures
To identify PASC, a diagnostic code specific for post–COVID-19 conditions was used and a second approach used clusters of symptoms and conditions that constitute the PASC phenotype. Relative risk (RR) for the association of BMI with PASC was quantified by Poisson regression models, adjusting for sociodemographic, acute COVID severity, and other clinical factors.
Results
A total of 172 136 participants (mean [SD] age at BMI assessment 12.6 [4.4] years; mean [SD] age at cohort entry, 13.1 [4.4] years; 90 187 female [52.4%]) were included. Compared with participants with healthy weight, those with obesity had a 25.4% increased risk of PASC (RR, 1.25; 95% CI, 1.06-1.48) and those with severe obesity had a 42.1% increased risk of PASC (RR, 1.42; 95% CI, 1.25-1.61) when identified using the diagnostic code. Compared with those with healthy weight, there was an increased risk for any occurrences of PASC symptoms and conditions among those with obesity (RR, 1.11; 95% CI, 1.06-1.15) and severe obesity (RR, 1.17; 95% CI, 1.14-1.21), and the association held when assessing total incident occurrences among those with overweight (RR, 1.05; 95% CI, 1.00-1.11), obesity (RR, 1.13; 95% CI, 1.09-1.19), and severe obesity (RR, 1.18; 95% CI, 1.14-1.22).
Conclusions And Relevance
In this cohort study, elevated BMI was associated with a significantly increased PASC risk in a dose-dependent manner, highlighting the need for targeted care to prevent chronic conditions in at-risk children and young adults.
Postacute sequelae of SARS-CoV-2 infection (PASC) encompasses a broad and heterogeneous array of persistent, relapsing, or newly emerging symptoms persisting beyond at least 4 weeks after the acute phase of COVID-19.1-4 This condition exhibits multifaceted involvement across various organ systems.5-8 The prevalence of pediatric PASC with SARS-CoV-2 infection varies across studies, with reported rates ranging from 1.6% to 70%.9-12 PASC continues to pose a substantial threat to children, necessitating an urgent and deeper understanding of pediatric PASC causes. This research priority is underscored in the updated National Institute for Health and Care Excellence guideline.13 This need to unravel the complexities of pediatric PASC continues to be crucial even after the COVID-19 pandemic.
Obesity is now one of the most common chronic diseases in the US, impacting more than 40% of adults and approximately 20% of children.14,15 The association of obesity with severe adverse outcomes was seen again with the onset of the COVID-19 pandemic.16 The association of obesity with increased risk of PASC has been widely discussed, with a predominant focus on adults.17,18 Some studies have reported that overweight or obesity is associated with an elevated risk of PASC18,19 across different timelines, irrespective of whether the definition of PASC extends to 12 weeks18 or 4 months.19 However, the nuances of this association become apparent when considering the specific timeline for defining PASC. For example, Sudre et al20 observed that increasing body mass index (BMI) and obesity were associated with higher odds of PASC lasting for more than 4 weeks, but this association did not extend to PASC lasting for more than 12 weeks.
While some studies21-23 have examined PASC in pediatric populations, including obesity as a risk factor, the association of BMI with PASC among children remains less studied than in adults, especially regarding the potential dose-response association. This gap in research is crucial, giving potential long-term implications for children’s health. Our study addresses this gap by analyzing data from 26 US children’s hospitals or institutions, exploring the association of preinfection BMI with PASC outcomes. The findings may help inform preventive strategies and clinical management for at-risk pediatric patients.
This retrospective cohort study was approved with a waiver of informed consent due to the use of deidentified data by the Biomedical Research Alliance of New York institutional review board and follows the Strengthening the Reporting of Observational Studies in Epidemiology () reporting guideline.24 This study is part of the National Institutes of Health Researching COVID-19 to Enhance Recovery, which aims to understand, treat, and prevent PASC.25 Twenty-six institutions contributed to the data, including data from both hospitals and primary care or outpatient settings, ensuring a comprehensive analysis of pediatric COVID-19 outcomes (see eTable 1 in Supplement 1 for details).
This study derived electronic health record (EHR) data from March 2020 to May 2023 by including patients with a documented SARS-CoV-2 infection younger than 21 years, aligning with the American Academy of Pediatrics definition of the pediatric population,26 who had at least 1 visit within the baseline period of 18 months to 7 days prior to the index date and had at least 1 visit within the follow-up period of 28 days to 179 days after the index date. Documented SARS-CoV-2 infections were defined by SARS-CoV-2 polymerase chain reaction testing; antigen or serology positive testing; or diagnosis of COVID-19, PASC, or multisystem inflammatory syndrome. The index date was set as either the earliest date of positive tests or COVID-19 diagnoses or 28 days before PASC or multisystem inflammatory syndrome diagnosis. Data are described in the eMethods in Supplement 1.
Participants were excluded if they were younger than 5 years at the time of assessing BMI, due to their potential for more dramatic BMI variations during the baseline period, and if they had genetic syndromes associated with obesity or any conditions signaling a need for weight gain or a medical cause of altered weight tendencies during the baseline period (eTable 2 in Supplement 1). The participants selection process is summarized in the eFigure in Supplement 1.
When multiple BMI measures (calculated as weight in kilograms divided by height in meters squared) were available during the baseline period, we selected the measure closest to the index date. For participants aged 5 to 19 years, according to the age- and sex-specific BMI percentiles based on US Centers for Disease Control and Prevention growth charts, the BMI status was categorized into healthy weight (5th percentile to less than 85th percentile), overweight (85th percentile to less than 95th percentile), obesity (95th percentile to less than 120% of the 95th percentile), and severe obesity (120% of the 95th percentile or greater)27; for participants older than 19 years, these 4 categories were divided by BMI of 18.5 to less than 25, 25 to less than 30, 30 to less than 40, and 40 or more within the baseline period.28
The outcome was assessed within the follow-up period. We first used International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code U09.9, specific for post–COVID-19 condition, to indicate PASC. For this, we created a binary outcome, PASC (U09.9), which was defined as positive if anyone was identified as having PASC with a U09.9 diagnosis code.
Second, we used clusters of symptoms and health conditions previously shown to constitute the PASC phenotype based on experts’ suggestions,23 including abdominal pain, abnormal liver enzyme, acute kidney injury, acute respiratory distress syndrome, arrhythmias, cardiovascular signs and symptoms, changes in taste and smell, chest pain, cognitive dysfunction, fatigue and malaise, fever and chills, fluid and electrolyte imbalances, generalized pain, hair loss, headache, heart disease, mental health disorders, musculoskeletal pain, myocarditis, myositis, postural orthostatic tachycardia syndrome or dysautonomia, respiratory signs and symptoms, skin symptoms, thrombophlebitis, and thromboembolism. We assessed incident occurrences of these 24 PASC symptoms and conditions that occurred within the follow-up period but did not occur during the baseline period, and then a binary and a count outcome were created. The binary outcome was defined as positive if any of these conditions occurred, and the count outcome was defined as total incident occurrences of these conditions.
Age at BMI status assessment and age at cohort entry were collected. Other demographic characteristics included sex (male or female), and EHR-derived race and ethnicity (Asian American or Pacific Islander, Hispanic, non-Hispanic Black, non-Hispanic White). The predominating COVID-19 virus variant was categorized as pre-Alpha (March 1, 2020, to March 31, 2021), Alpha (April 1, 2021, to June 30, 2021), Delta (July 1, 2021, to December 31, 2021), and Omicron (January 1, 2022, to December 1, 2022).29 We used numbers of emergency department visits, outpatient department visits, inpatient department visits, medications or prescriptions, and negative COVID-19 tests up to 24 months before index date as health care utilization metrics, and the pediatric medical complexity algorithm (PMCA)30 index to address levels of medical complexity comorbidity (no condition, noncomplex condition, or complex chronic condition) for the participants. We also classified participants based on the acute COVID-19 severity as asymptomatic, mild, moderate, or severe.31 Doses of COVID-19 vaccine prior to infection and interval since the last COVID-19 vaccination date (no vaccine, <4 months, and ≥4 months), and type of insurance (private, public, or other) were also considered in the secondary analyses.
We first presented the demographic and clinical characteristics across different BMI statuses. Comparisons of PASC (U09.9) and potential PASC symptoms and conditions were then made by BMI status. For the count outcome, total incident occurrences of PASC symptoms and conditions, we used Poisson regression to assess its association with BMI status by estimating the relative risk (RR) and 95% CI, adjusting for demographic characteristics (age, sex, and race and ethnicity), predominant variant, health care utilization metrics prior to cohort entry, PMCA index, and acute COVID-19. For binary outcomes, PASC (U09.9) and any incident occurrences of PASC symptoms and conditions, modified Poisson regression32 was employed, accounting for possible variance overestimation and adjusting for the factors described previously. Orthogonal trend analysis was used for the linear trend test. Statistical methods are described in eAppendix in Supplement 1. All analyses were conducted using R version 4.1.2 (R Project for Statistical Computing). Statistical significance was set at P < .05 (2-tailed). Data analysis was conducted from October 2023 to January 2024.
Post Hoc Secondary Analysis
We conducted exploratory subgroup analyses based on age (<18 or ≥18 years) and PMCA index (no chronic condition vs noncomplex or complex chronic condition), and race and ethnicity, acknowledging disparities in children and young adult, the presence or severity of chronic conditions, and BMI status and COVID-19 severity by race and ethnicity to explore potential effect modification.
To validate our findings, we performed several post hoc sensitivity analyses. These included excluding participants with BMI assessed more than 6 months before cohort entry because pediatric BMI increased during the pandemic;33 those entering the study before the ICD-10-CM code U09.9 became effective on October 1, 2021; those who were included with the diagnosis of PASC alone; and those diagnosed solely by serology testing after November 2022 due to potential accuracy concerns during the Omicron wave.34,35 We also excluded participants with moderate or severe infection, those with diabetes,36,37 and those without diabetes but using weight-loss drugs. Additionally, we adjusted for vaccination status before infection,38,39 insurance type, and site index. Lastly, we assessed our findings in a primary care setting and used a negative control outcome (foreign body in ear) to evaluate residual bias.40,41
After excluding 221 participants who had underweight and 67 451 with missing BMI status, a total of 172 136 participants (mean [SD] age at BMI assessment 12.6 [4.4] years; mean [SD] age at cohort entry, 13.1 [4.4] years; 90 187 female [52.4%]; 42 982 Hispanic [25.0]; 33 065 non-Hispanic Black [19.2%]; 87 275 non-Hispanic White [50.7%]) were included in the analysis. Participants missing BMI status data were more likely to be younger, be male, be non-Hispanic Black or non-Hispanic White, be infected after the pre-Alpha wave, have fewer complex chronic conditions, utilize health care less, and were less likely to develop PASC (eTable 3 in Supplement 1). The median (IQR) time from BMI status assessment to COVID-19 infection was 4.1 (1.6-8.6) months. Of all the participants, 85 613 (49.7%) had obesity or severe obesity (Table 1).
During the follow-up period, 1402 participants (0.8%) received a diagnosis of PASC (U09.9), of which 751 (53.6%) had obesity or severe obesity, and 63 046 (26.4%) had at least 1 incident occurrence of PASC symptoms and conditions, of which 8792 (52.8%) had obesity or severe obesity. The median (IQR) time from index date to outcomes (ie, the diagnosis of U09.9 and the first incident occurrence of any of the 24 PASC symptoms and conditions) was 50 (28-111) days and 63 (38-105) days, respectively. The median (IQR) total number of incident occurrences of PASC symptoms and conditions was 0 (0-2), signifying that at least one-half of the participants in the cohort did not experience any incident occurrences of PASC symptoms and conditions. Incident occurrences of each PASC symptoms and conditions are in eTable 4 in Supplement 1.
Participants with overweight, obesity, or severe obesity exhibited an increased risk of PASC compared with those with healthy weight; however, not all estimates reached statistical significance. Specifically, in comparison with those with healthy weight, there was a higher risk of PASC (U09.9) among participants categorized as having obesity (RR, 1.25; 95% CI, 1.06-1.48) and severe obesity (RR, 1.42; 95% CI, 1.25-1.61). Similarly, compared with those with healthy weight, there was an increased likelihood of encountering any manifestation of potential PASC symptoms and conditions among those who had obesity (RR, 1.11; 95% CI, 1.06-1.15) and severe obesity (RR, 1.17; 95% CI, 1.14-1.21). The association became slightly more pronounced when assessing the cumulative occurrences of PASC symptoms and conditions among those who had overweight (RR, 1.05; 95% CI, 1.00-1.11), obesity (RR, 1.14; 95% CI, 1.09-1.19), and severe obesity (RR, 1.18; 95% CI, 1.14-1.22). There was a significant dose-response association of increasing BMI category with risk of PASC (Table 2).
Subgroup analyses by age and PMCA index showed associations like the main findings. Post hoc analysis of racial and ethnic subgroups revealed a consistent association of BMI with PASC (U09.9) or PASC symptoms for non-Hispanic White participants. However, no significant association of BMI with PASC (U09.9) was observed among non-Hispanic Black participants, nor for any PASC outcomes among Hispanic participants (Table 3). Analysis for Asian American and Pacific Islander participants was not conducted due to insufficient U09.9 diagnoses across BMI categories. Post hoc sensitivity analysis generally supported the dose-response association, with slight variations in the associations (eTables 5-17 in Supplement 1). Negative control outcome analysis showed no significant results, suggesting absence of residual bias (eTable 18 and eTable 19 in Supplement 1).
To our knowledge, this retrospective cohort study is the first and the largest to explore the association of BMI status with PASC among the pediatric population. Our findings consistently reveal an adverse dose-response association of preinfection BMI with PASC susceptibility, even after adjusting for sociodemographic and clinical factors. This pattern mirrors findings in adult populations,19 although the magnitudes of association vary. In exploratory secondary analyses, the association generally remained robust. However, post hoc subgroup analyses by race and ethnicity suggested potential effect size modification, warranting further investigation. An exploratory negative control outcome analysis revealed no substantial residual bias, lending additional support to the primary findings. These post hoc results, while intriguing, should be interpreted cautiously and considered hypothesis-generating for future research.
This research is important because it addresses critical gaps in understanding the long-term impacts of PASC in children, a demographic often overlooked in earlier studies. By identifying the association of elevated BMI with PASC, this study highlights potential risks for prolonged health issues in pediatric populations. The findings suggest that PASC may lead to poorer long-term quality of life, affecting physical health, educational achievement, and social development; this underscores the importance of early identification, prevention, and targeted interventions to mitigate these risks. The implications of this research are crucial for guiding public health strategies and informing clinical practices aimed at improving the long-term well-being of children affected by COVID-19.
A pivotal strength of our study lies in its extensive and representative sample. Covering 172 136 pediatric patients with COVID-19 infection from 26 US children’s hospitals, our study is distinguished by its scale, enabling us ample statistical power to rigorously evaluate the association of BMI with PASC, accounting for key sociodemographic and clinical risk factors. A noteworthy distinction from the previous research is our ICD-10-CM coded EHR phenotypes rather than self-reported PASC symptoms because the latter may be influenced by individual perceptions, interpretations, recall biases, lack of standardization, and participant compliance with reporting protocols. The inclusion of multiple PASC outcomes enhances the clarity in understanding the burden and risk of PASC and mitigates the potential for misclassification; this is particularly relevant given the recognized limitations associated with only using ICD-10-CM code U09.942 and acknowledging the likely divergence in clinical features of PASC between pediatric and adult populations.23 Moreover, a considerable portion of the existing studies primarily focused solely on hospitalized cohorts, while our cohort is characterized by its inclusivity, incorporating both outpatient and hospitalized participants.
Our study revealed a higher obesity rate (35.7%-49.7%) compared with the national average (19.7%),15 although rates from primary care sites were comparable (17.5%-22.4%). This disparity may reflect better health among primary care participants and increased health risks among those with overweight or obesity.43 Higher BMI has been associated with increased risk of hospitalization44 and severe illness45 in pediatric patients with COVID-19. Pandemic-related increases in pediatric BMI levels, particularly in the overweight33 and obesity46 categories, could explain the higher RRs observed in the sensitivity analysis.
The association of BMI with PASC remained consistent across outcome measures, with larger-magnitude associations for U09.9, possibly due to its specificity compared with PASC symptoms and conditions. We used both measures to enhance comprehensiveness and precision. To address implausible BMI values in EHR data, we employed the PEDSnet Data Coordinating Center algorithm,47 matching the closest height within 60 days of a recorded weight. While this method improves accuracy, it may not fully eliminate all inaccuracies inherent in EHR analysis.
The associations observed in our study may be explained by several plausible biological mechanisms, although they may not be pediatric-specific. First, obesity’s association with chronic inflammation48,49 and susceptibility to COVID-19 may involve macrophages pyroptosis,50 leading to prolonged systemic inflammation implicated in the genesis of PASC.51,52 Second, obesity is also associated with altered microbiota,53 and the impact of COVID-19 on the latter may influence PASC risk.54 Third, obesity is recognized for its propensity to dysregulate adaptive autoimmunity,55,56 a phenomenon documented in patients with PASC.57,58 This dysregulation in adaptive immune responses may be implicated in the protracted nature of observed symptoms. Furthermore, clotting and endothelial abnormalities associated with obesity could explain observed pathophysiological changes in patients with PASC.57,59-61
Our study has several limitations. The high obesity prevalence may indicate sample skewness, requiring caution in generalizing to the entire US pediatric population. The absence of information on modifiable risk factors like diet and physical activity, which may reduce PASC risk,19 limits our findings, warranting further investigations in future studies.
Potential for overclassification in pediatric PASC diagnosis due to a lack of standardized criteria is also a concern and could be mitigated by using both ICD-10-CM codes and PASC symptoms and conditions based on experts’ suggestions as outcomes, although this may not be comprehensive. Some symptoms we examined may overlap with those common in pediatric populations with obesity or other conditions, potentially inflating the observed associations. To address potential overlap between PASC symptoms and obesity-related conditions, we focused on new, incident cases during follow-up.
Selection bias is another concern, particularly if children with higher BMI are more likely to be hospitalized, potentially leading to an overrepresentation of severe cases. This is highlighted by literature suggesting that collider bias can distort disease risk and severity assessment.62 By incorporating primary care and outpatient data, we attempted to capture a broader spectrum of disease severity, although children managing COVID-19 or PASC at home might still be underrepresented.
Our study found a significant association of higher pre–COVID-19 BMI with increased PASC risk in pediatric patients, highlighting the need for vigilant monitoring and personized care for those with elevated BMI. This association underscores the importance of early identification and targeted interventions to prevent long-term consequences. Public health efforts should focus on raising awareness and promoting healthy lifestyle behaviors to reduce severe outcomes. Addressing obesity as a modifiable risk factor could alleviate the burden of PASC and improve pediatric health postpandemic. Further research is needed to explore specific PASC symptoms associated with BMI.
Accepted for Publication: August 29, 2024.
Published: October 28, 2024. doi:10.1001/jamanetworkopen.2024.41970
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2024 Zhou T et al. vlog Open.
Corresponding Author: Yong Chen, PhD, The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, 423 Guardian Dr, 602 Blockley, Philadelphia, PA 19104 (ychen123@pennmedicine.upenn.edu).
Author Contributions: Drs Zhou and Chen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Chen and Forrest: senior authors.
Concept and design: Zhou, B. Zhang, D. Zhang, Chrischilles, Hornig-Rohan, Lorman, Mosa, Suresh, Wang, Forrest, Y. Chen.
Acquisition, analysis, or interpretation of data: Zhou, B. Zhang, D. Zhang, Wu, J. Chen, Li, Lu, Becich, Blecker, Chilukuri, Chu, Corsino, Reynolds Geary, Hornig, Hornig-Rohan, Kim, Liebovitz, Luo, Morizono, Pajor, Rao, Razzaghi, Tedla, Vance Utset, Wang, Williams, Gage Witvliet, Mangarelli, Jhaveri, Forrest, Y. Chen.
Drafting of the manuscript: Zhou, Corsino, Hornig-Rohan, Wang, Forrest.
Critical review of the manuscript for important intellectual content: All authors.
Statistical analysis: Zhou, B. Zhang, D. Zhang, Wu, J. Chen, Li, Lu, Chu, Luo, Wang.
Obtained funding: Williams, Jhaveri, Forrest, Y. Chen.
Administrative, technical, or material support: Chrischilles, Corsino, Hornig-Rohan, Kim, Liebovitz, Lorman, Morizono, Mosa, Rao, Razzaghi, Tedla, Vance Utset, Williams, Mangarelli, Forrest, Y. Chen.
Supervision: Suresh, Williams, Jhaveri, Forrest, Y. Chen.
Conflict of Interest Disclosures: Dr Reynolds Geary reported receiving grants from the Global Task Force for Health Care outside the submitted work. Dr Pajor reported receiving grants from Janssen Pharmceuticals, Agency for Healthcare Research and Quality, and PEDSnet outside the submitted work. Dr Jhaveri reported receiving personal fees from the AstraZeneca scientific advisory board, Seqirus scientific advisory board, Sanofi scientific advisory board, and Gilead scientific advisory board; grants from GSK; and an editorial stipend from the Pediatric Infectious Diseases Society for serving as editor in chief of the Journal of the Pediatric Infectious Diseases Society outside the submitted work. No other disclosures were reported.
Funding/Support: This work was supported in part by National Institutes of Health (grant Nos. OT2HL161847-01, U01TR003709, U24MH136069, RF1AG077820, 1R01LM014344, 1R01AG077820, R01LM012607, R01AI130460, R01AG073435, R56AG074604, R01LM013519, R56AG069880, R21AI167418, and R21EY034179). This work was supported partially through Patient-Centered Outcomes Research Institute (PCORI) Project Program Awards (grant Nos. ME-2019C3-18315 and ME-2018C3-14899).
Role of the Funder/Sponsor: The sponsors 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.
Disclaimer: This content is solely the responsibility of the authors and does not necessarily represent the official views of the RECOVER Initiative of the National Institutes of Health. All statements in this report, including its findings and conclusions, are solely those of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI), its Board of Governors, or Methodology Committee.
Data Sharing Statement: See Supplement 2.
Additional Contributions: We would like to thank the National Community Engagement Group (NCEG), all patients, caregivers, and community Representatives, and all the participants enrolled in the RECOVER Initiative. We want to thank to Teresa Akintonwa, BA (RECOVER Patient, Caregiver, or Community Advocate Representative), and Etienne Carignan, BA (RECOVER Patient, Caregiver, or Community Advocate Representative), for their helpful suggestions on our manuscript; they received financial compensation for their participation as a part of their contractual agreements with RECOVER as patient representatives.
Additional Information: This study is part of the National Institutes of Health Researching COVID-19 to Enhance Recovery (RECOVER) Initiative, which seeks to understand, treat, and prevent the post-acute sequelae of SARS-CoV-2 infection (PASC).24
1.Venkatesan
P. NICE guideline on long COVID. Lancet Respir Med. 2021;9(2):129. doi:
2.Soriano
JB, Murthy
S, Marshall
JC, Relan
P, Diaz
JV; WHO Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022;22(4):e102-e107. doi:
3.Datta
SD, Talwar
A, Lee
JT. A proposed framework and timeline of the spectrum of disease due to SARS-CoV-2 infection: illness beyond acute infection and public health implications. Ѵ. 2020;324(22):2251-2252. doi:
4.Greenhalgh
T, Knight
M, A’Court
C, Buxton
M, Husain
L. Management of post-acute covid-19 in primary care. Ѵ. Published online August 11, 2020. doi:
5.Al-Aly
Z, Xie
Y, Bowe
B. High-dimensional characterization of post-acute sequelae of COVID-19. ٳܰ. 2021;594(7862):259-264. doi:
6.Nalbandian
A, Sehgal
K, Gupta
A,
et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27(4):601-615. doi:
7.Montani
D, Savale
L, Noel
N,
et al; COMEBAC Study Group. Post-acute COVID-19 syndrome. Eur Respir Rev. 2022;31(163):210185. doi:
8.Davis
HE, McCorkell
L, Vogel
JM, Topol
EJ. Author correction: long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(6):408. doi:
9.Morello
R, Mariani
F, Mastrantoni
L,
et al. Risk factors for post-COVID-19 condition (Long Covid) in children: a prospective cohort study. Ծѱ徱Ա. 2023;59:101961. doi:
10.Lopez-Leon
S, Wegman-Ostrosky
T, Ayuzo Del Valle
NC,
et al. Long-COVID in children and adolescents: a systematic review and meta-analyses. Sci Rep. 2022;12(1):9950. doi:
11.Jiang
L, Li
X, Nie
J, Tang
K, Bhutta
ZA. A systematic review of persistent clinical features after SARS-CoV-2 in the pediatric population. ʱ徱ٰ. 2023;152(2):e2022060351. doi:
12.Zheng
YB, Zeng
N, Yuan
K,
et al. Prevalence and risk factor for long COVID in children and adolescents: a meta-analysis and systematic review. J Infect Public Health. 2023;16(5):660-672. doi:
13.National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing the long-term effects of COVID-19. Published December 8, 2020. Updated January 25, 2024. Accessed September 18, 2024.
14.US Centers for Disease Control and Prevention. Adult obesity facts. Updated May 14, 2024. Accessed September 18, 2024.
15.US Centers for Disease Control and Prevention. Childhood obesity facts. Updated April 2, 2024. Accessed September 18, 2024.
16.Kompaniyets
L, Goodman
AB, Belay
B,
et al. Body mass index and risk for COVID-19-related hospitalization, intensive care unit admission, invasive mechanical ventilation, and death - United States, March-December 2020. MMWR Morb Mortal Wkly Rep. 2021;70(10):355-361. doi:
17.Thompson
EJ, Williams
DM, Walker
AJ,
et al; OpenSAFELY Collaborative. Long COVID burden and risk factors in 10 UK longitudinal studies and electronic health records. Nat Commun. 2022;13(1):3528. doi:
18.Subramanian
A, Nirantharakumar
K, Hughes
S,
et al. Symptoms and risk factors for long COVID in non-hospitalized adults. Nat Med. 2022;28(8):1706-1714. doi:
19.Wang
S, Li
Y, Yue
Y,
et al. Adherence to healthy lifestyle prior to infection and risk of post-COVID-19 condition. Ѵ Intern Med. 2023;183(3):232-241. doi:
20.Sudre
CH, Murray
B, Varsavsky
T,
et al. Attributes and predictors of long COVID. Nat Med. 2021;27(4):626-631. doi:
21.Osmanov
IM, Spiridonova
E, Bobkova
P,
et al; and the Sechenov StopCOVID Research Team. Risk factors for post-COVID-19 condition in previously hospitalised children using the ISARIC global follow-up protocol: a prospective cohort study. Eur Respir J. 2022;59(2):2101341. doi:
22.Kikkenborg Berg
S, Dam Nielsen
S, Nygaard
U,
et al. Long COVID symptoms in SARS-CoV-2-positive adolescents and matched controls (LongCOVIDKidsDK): a national, cross-sectional study. Lancet Child Adolesc Health. 2022;6(4):240-248. doi:
23.Rao
S, Lee
GM, Razzaghi
H,
et al. Clinical features and burden of postacute sequelae of SARS-CoV-2 infection in children and adolescents. Ѵ Pediatr. 2022;176(10):1000-1009. doi:
24.Ghaferi
AA, Schwartz
TA, Pawlik
TM. STROBE reporting guidelines for observational studies. Ѵ Surg. 2021;156(6):577-578. doi:
25.RECOVER. RECOVER: researching COVID to enhance recovery. Accessed August 24, 2023.
26.Hardin
AP, Hackell
JM; Committee on Practice and Ambulatory Medicine. Age limit of pediatrics. ʱ徱ٰ. 2017;140(3):e20172151. doi:
27.US Centers for Disease Control and Prevention. Child and teen BMI categories. Updated June 28, 2024. Accessed September 18, 2024.
28.US Centers for Disease Control and Prevention. Adult BMI categories. Updated March 19, 2024. Accessed September 18, 2024.
29.Our World in Data. SARS-CoV-2 variants in analyzed sequences, United States. Accessed November 13, 2023.
30.Simon
TD, Cawthon
ML, Stanford
S,
et al; Center of Excellence on Quality of Care Measures for Children with Complex Needs (COE4CCN) Medical Complexity Working Group. Pediatric medical complexity algorithm: a new method to stratify children by medical complexity. ʱ徱ٰ. 2014;133(6):e1647-e1654. doi:
31.Forrest
CB, Burrows
EK, Mejias
A,
et al. Severity of acute COVID-19 in children <18 years old March 2020 to December 2021. ʱ徱ٰ. 2022;149(4):e2021055765. doi:
32.Zou
G. A modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004;159(7):702-706. doi:
33.Knapp
EA, Dong
Y, Dunlop
AL,
et al; Environmental Influences on Child Health Outcomes. Changes in BMI during the COVID-19 pandemic. ʱ徱ٰ. 2022;150(3):e2022056552. doi:
34.Rössler
A, Knabl
L, Raschbichler
LM,
et al. Reduced sensitivity of antibody tests after omicron infection. Lancet Microbe. 2023;4(1):e10-e11. doi:
35.US Food and Drug Administration. SARS-CoV-2 viral mutations: impact on COVID-19 tests. Updated September 28, 2023. Accessed July 31, 2024.
36.Tsampasian
V, Elghazaly
H, Chattopadhyay
R,
et al. Risk factors associated with post-COVID-19 condition: a systematic review and meta-analysis. Ѵ Intern Med. 2023;183(6):566-580. doi:
37.Pfaff
ER, Girvin
AT, Bennett
TD,
et al; N3C Consortium. Identifying who has long COVID in the USA: a machine learning approach using N3C data. Lancet Digit Health. 2022;4(7):e532-e541. doi:
38.Ayoubkhani
D, Bermingham
C, Pouwels
KB,
et al. Trajectory of long covid symptoms after covid-19 vaccination: community based cohort study. Ѵ. 2022;377:e069676. doi:
39.Ceban
F, Kulzhabayeva
D, Rodrigues
NB,
et al. COVID-19 vaccination for the prevention and treatment of long COVID: a systematic review and meta-analysis. Brain Behav Immun. 2023;111:211-229. doi:
40.Schuemie
MJ, Hripcsak
G, Ryan
PB, Madigan
D, Suchard
MA. Empirical confidence interval calibration for population-level effect estimation studies in observational healthcare data. Proc Natl Acad Sci U S A. 2018;115(11):2571-2577. doi:
41.Schuemie
MJ, Ryan
PB, DuMouchel
W, Suchard
MA, Madigan
D. Interpreting observational studies: why empirical calibration is needed to correct P ܱ. Stat Med. 2014;33(2):209-218. doi:
42.Pfaff
ER, Madlock-Brown
C, Baratta
JM,
et al. Coding long COVID: characterizing a new disease through an ICD-10 lens. BMC Med. Published online February 16, 2023. doi:
43.US Centers for Disease Control and Prevention. How overweight and obesity impacts your health. Updated January 4, 2024. Accessed September 18, 2024.
44.Mohammad
S, Aziz
R, Al Mahri
S,
et al. Obesity and COVID-19: what makes obese host so vulnerable? Immun Ageing. 2021;18(1):1. doi:
45.Sawadogo
W, Tsegaye
M, Gizaw
A, Adera
T. Overweight and obesity as risk factors for COVID-19-associated hospitalisations and death: systematic review and meta-analysis. Ѵ Nutr Prev Health. 2022;5(1):10-18. doi:
46.Lartey
ST, Jayawardene
WP, Dickinson
SL, Chen
X, Gletsu-Miller
N, Lohrmann
DK. Evaluation of unintended consequences of COVID-19 pandemic restrictions and obesity prevalence among youths. Ѵ Netw Open. 2023;6(7):e2323596. doi:
47.PEDSnet. PEDSnet-derivation-BMI. July 30, 2023. Accessed July 31, 2024.
48.Korakas
E, Ikonomidis
I, Kousathana
F,
et al. Obesity and COVID-19: immune and metabolic derangement as a possible link to adverse clinical outcomes. Am J Physiol Endocrinol Metab. 2020;319(1):E105-E109. doi:
49.Hildebrandt
X, Ibrahim
M, Peltzer
N. death and inflammation during obesity: “Know my methods, WAT(son)”. Death Differ. 2023;30(2):279-292. doi:
50.López-Reyes
A, Martinez-Armenta
C, Espinosa-Velázquez
R,
et al. NLRP3 inflammasome: the stormy link between obesity and COVID-19. Front Immunol. 2020;11:570251. doi:
51.Crook
H, Raza
S, Nowell
J, Young
M, Edison
P. Long covid-mechanisms, risk factors, and management. Ѵ. Published online July 26, 2021. doi:
52.Woodruff
MC, Bonham
KS, Anam
FA,
et al. Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID. Nat Commun. 2023;14(1):4201. doi:
53.Zsálig
D, Berta
A, Tóth
V,
et al. A review of the relationship between gut microbiome and obesity. Appl Sci (Basel). 2023;13(1):610. doi:
54.Liu
Q, Mak
JWY, Su
Q,
et al. ҳܳ microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome. ҳܳ. 2022;71(3):544-552. doi:
55.Kwiat
VR, Reis
G, Valera
IC, Parvatiyar
K, Parvatiyar
MS. Autoimmunity as a sequela to obesity and systemic inflammation. Front Physiol. 2022;13:887702. doi:
56.Tsigalou
C, Vallianou
N, Dalamaga
M. Autoantibody production in obesity: is there evidence for a link between obesity and autoimmunity? Curr Obes Rep. 2020;9(3):245-254. doi:
57.Proal
AD, VanElzakker
MB. Long COVID or post-acute sequelae of COVID-19 (PASC): an overview of biological factors that may contribute to persistent symptoms. Front Microbiol. 2021;12:698169. doi:
58.Su
Y, Yuan
D, Chen
DG,
et al; ISB-Swedish COVID-19 Biobanking Unit. Multiple early factors anticipate post-acute COVID-19 sequelae. . 2022;185(5):881-895.e20. doi:
59.Blokhin
IO, Lentz
SR. Mechanisms of thrombosis in obesity. Curr Opin Hematol. 2013;20(5):437-444. doi:
60.Kwaifa
IK, Bahari
H, Yong
YK, Noor
SM. Endothelial dysfunction in obesity-induced inflammation: molecular mechanisms and clinical implications. dzDZܱ. 2020;10(2):291. doi:
61.Katsoularis
I, Fonseca-Rodríguez
O, Farrington
P,
et al. Risks of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19: nationwide self-controlled cases series and matched cohort study. Ѵ. 2022;377:e069590. doi:
62.Griffith
GJ, Morris
TT, Tudball
MJ,
et al. Collider bias undermines our understanding of COVID-19 disease risk and severity. Nat Commun. 2020;11(1):5749. doi: