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Association of SARS-CoV-2 Seropositivity With Myalgic Encephalomyelitis and/or Chronic Fatigue Syndrome Among Children and Adolescents in Germany

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Question  Is SARS-CoV-2 seropositivity associated with symptoms of myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) in children and adolescents?

Findings  This cross-sectional study of hospital-based SARS-CoV-2 seroprevalence surveys in Germany compared seropositive and seronegative children and adolescents and identified an excess of possible ME/CFS symptoms with serological evidence of preceding SARS-CoV-2 infection. This association almost disappeared with adjustment for confounders and restriction to children and adolescents unaware of preceding infection.

Meaning  These findings suggest that the risk of ME/CFS after SARS-CoV-2 infection in children and adolescents may be small and that recall bias may contribute to risk estimates.

Abstract

Importance  During the COVID-19 pandemic, a reduction in quality of life and physical and mental health among children and adolescents has been reported that may be associated with SARS-CoV-2 infection and/or containment measures.

Objective  To assess the association of SARS-CoV-2 seropositivity with symptoms that may be related to myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) among children and adolescents.

Design, Setting, and Participants  This substudy of the cross-sectional SARS-CoV-2 seroprevalence surveys in Germany (SARS-CoV-2 KIDS) was performed in 9 pediatric hospitals from May 1 to October 31, 2021. Pediatric patients were recruited during an inpatient or outpatient visit regardless of the purpose of the visit. Parental questionnaires and serum samples were collected during clinically indicated blood draws. The parental questionnaire on demographic and clinical information was extended by items according to the DePaul Symptom Questionnaire, a pediatric screening tool for ME/CFS in epidemiological studies in patients aged 5 to 17 years.

Exposures  Seropositivity was determined by SARS-CoV-2 IgG antibodies in serum samples using enzyme-linked immunosorbent assays.

Main Outcomes and Measures  Key symptoms of ME/CFS were evaluated separately or as clustered ME/CFS symptoms according to the DePaul Symptom Questionnaire, including fatigue.

Results  Among 634 participants (294 male [46.4%] and 340 female [53.6%]; median age, 11.5 [IQR, 8-14] years), 198 (31.2%) reported clustered ME/CFS symptoms, including 40 of 100 SARS-CoV-2–seropositive (40.0%) and 158 of 534 SARS-CoV-2–seronegative (29.6%) children and adolescents. After adjustment for sex, age group, and preexisting disease, the risk ratio for reporting clustered ME/CFS symptoms decreased from 1.35 (95% CI, 1.03-1.78) to 1.18 (95% CI, 0.90-1.53) and for substantial fatigue from 2.45 (95% CI, 1.24-4.84) to 2.08 (95% CI, 1.05-4.13). Confinement to children and adolescents with unknown previous SARS-CoV-2 infection status (n = 610) yielded lower adjusted risks for all symptoms except joint pain ME/CFS–related symptoms. The adjusted risk ratio was 1.08 (95% CI, 0.80-1.46) for reporting clustered ME/CFS symptoms and 1.43 (95% CI, 0.63-3.23) for fatigue.

Conclusions and Relevance  These findings suggest that the risk of ME/CFS in children and adolescents owing to SARS-CoV-2 infection may be very small. Recall bias may contribute to risk estimates of long COVID-19 symptoms in children. Extensive lockdowns must be considered as an alternative explanation for complex unspecific symptoms during the COVID-19 pandemic.

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Article Information

Accepted for Publication: August 4, 2022.

Published: September 27, 2022. doi:10.1001/jamanetworkopen.2022.33454

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Sorg AL et al. JAMA Network Open.

Corresponding Author: Anna-Lisa Sorg, MSc, Institute of Social Paediatrics and Adolescent Medicine, Division of Paediatric Epidemiology, Ludwig-Maximilians-University Munich, Haydnstraße 5, 80336 Munich (annalisa.sorg@med.uni-muenchen.de).

Author Contributions: Ms Sorg 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. Drs Drosten, Schroten, and von Kries contributed equally to this study.

Concept and design: Sorg, Becht, Jank, Behrends, Drosten, Schroten, von Kries.

Acquisition, analysis, or interpretation of data: Sorg, Becht, Jank, Armann, von Both, Hufnagel, Lander, Liese, Niehues, Verjans, Wetzke, Stojanov, Behrends, Schroten, von Kries.

Drafting of the manuscript: Sorg, Becht, Jank, Schroten, von Kries.

Critical revision of the manuscript for important intellectual content: Sorg, Jank, Armann, von Both, Hufnagel, Lander, Liese, Niehues, Verjans, Wetzke, Stojanov, Behrends, Drosten, Schroten.

Statistical analysis: Sorg, Becht, Stojanov.

Obtained funding: Drosten, Schroten.

Administrative, technical, or material support: Becht, Jank, von Both, Hufnagel, Liese, Verjans, Wetzke, Behrends, Drosten.

Supervision: Wetzke, Behrends, Drosten, Schroten, von Kries.

Conflict of Interest Disclosures: Dr Jank reported receiving grants from the German Federal Ministry of Education and Research (BMBF) during the conduct of the study. Dr Lander reported receiving grants from the BMBF during the conduct of the study. Dr Liese reported receiving grants from the BMBF during the conduct of the study and grants from GSK PLC, Janssen-Cilag AG, Pfizer Inc, Merck and Co, Inc, and Sanofi Pasteur outside the submitted work. Dr Verjans reported receiving grants from the BMBF for whole project during the conduct of the study. Dr Behrends reported grants from the BMBF during the conduct of the study; grants from Weidenhammer-Zoebele-Stiftung and Bavarian State Ministry of Health and Care outside the submitted work; and serving on the medical advisory board of the German Society for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Dr Drosten reported receiving grants from the German Federal Ministry of Research during the conduct of the study. Dr Schroten reported receiving grants from the BMBF during the conduct of the study. No other disclosures were reported.

Funding/Support: The work was supported by grant FKZ:01KI20131A from the BMBF.

Role of the Funder/Sponsor: The sponsor 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.

Additional Contributions: We thank all parents, legal caregivers, and patients for participation in the study. The following individuals participated at the study centers: Veronika Kaiser, [Degree], and Tamara Weindl, [Degree], for assistance with digitization and validation of questionnaires, support of study coordination, and communication (Institute of Social Paediatrics and Adolescent Medicine, Division of Paediatric Epidemiology, Ludwig- Maximilians-University Munich, Germany); Anna Görtz, [Degree], for study coordination, Giselle Decker, [Degree], and Andrea Hilpert, [Degree], for serum sample collection, and Claudia Fahandezh-Saadi, [Degree], for technical assistance (Paediatric Infectious Diseases, Department of Paediatrics, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany); Christiane Walther, [Degree], and Caty Ullmann, [Degree], for serum sample collection (Department of Paediatrics, University Hospital, and Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany); Laura Kolberg, MSc, for study coordination (Dr von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-University, Munich, Germany); and Ariane Leone, [Degree], and Kaja Michel, [Degree], for support in the selection and adaptation of the questionnaire, Sarah Hubmann, [Degree], Kaja Michel, [Degree], Laura Carlotta Peo, [Degree], and Katrin Gerrer, [Degree], for serum sample collection, and Lydia Cramer, [Degree], for technical assistance (Department of Paediatrics, Faculty of Medicine, Technical University Munich, Munich, Germany). None of these contributors received compensation for this work.

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