Clinical-Based Phenotypes in Children with Pediatric Post-COVID Condition

Background: Pediatric Post-COVID Condition (PPCC) is a heterogeneous syndrome, which can have a big impact on children’s daily life. The aim of this study was to identify clinically meaningful phenotypes within children with PPCC, to better characterize and treat this condition. Methods: Participants were children with physician-diagnosed PPCC, referred to the academic hospital Amsterdam UMC, the Netherlands (November 2021-March 2023). Demographic factors and information on post-COVID symptoms, comorbidities, and impact on daily life were collected. Clusters were identified using an unsupervised and unbiased approach for mixed data types. Findings: Analysis of 112 patients (aged 3-18) revealed 3 distinct clusters within PPCC. Cluster 1 (N=60, median age=15 years) consisted of predominantly girls (73∙3%). These patients suffered relatively more from exercise intolerance, dyspnea, and taste and smell disorders. Cluster 2 (N=33, median age=13) contained patients with an even gender distribution (48∙5% girls). They suffered from relatively more sleep problems, gastrointestinal symptoms, arthralgia, and myalgia. Cluster 3 (N=19, median age = 11) had a higher proportion of boys (63∙2%). They suffered relatively more from fever and had significantly fewer symptoms (median of 4 compared to 8 and 10 for clusters 1 and 2 respectively), and experienced a lower impact on daily life. Interpretation: This study identified three distinct clinical PPCC phenotypes, with variations in sex, age, symptom patterns, and impact on daily life. These findings highlight the need for further research to understand the potentially diverse underlying mechanisms contributing to post-COVID symptoms in children.Funding: The authors received no financial support for the research, authorship, and/or publication of this article.Declaration of Interest: L.C.E.N., J.M.B., C.R.L., M.A.H., G.B., M.I.A.-A., M.W.A., C.L.H.B., K.J.O., S.H. and S.W.J.T.-L. have nothing to declare. A.H.M.-Z. is the PI of a public private consortium (P4O2 (Precision Medicine for More Oxygen)) sponsored by Health Holland involving many private partners that contribute in cash and/or in kind (AbbVie. Boehringer Ingelheim, Breathomix, Clear, Fluidda, Ortec Logiqcare, Olive, Philips, Quantib-U, Smartfish, Clear, SODAQ, Thirona, Roche, TopMD, Novartis, RespiQ). She received unrestricted research grants from GSK and Boehringer Ingelheim and received the Vertex innovation award grant, and had honoraria paid to institution by GSK, Boehringer Ingelheim and Astra Zeneca. A.H.M.-Z. is also the chair of DSMB of a study on BPD in neonates and the president of FIGON (Federation Innovative drug research in the Netherlands). J.B.G. has received a grant from Danone Research and has a patent planned for amino acid composition of infant formulas. He is a member of the national health council (unpaid) and the director of the national Human Milk Bank (unpaid).Ethical Approval: The medical ethics committee of the Amsterdam UMC, location AMC, approved the study (METc 2021_126). All participants and/or caregivers provided oral and written informed consent.