{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:59:12Z","timestamp":1775804352115,"version":"3.50.1"},"reference-count":249,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Pediatric Post-COVID Condition (PPCC) represents a significant and complex long-term sequela of SARS-CoV-2 infection, affecting a subset of children and adolescents even after mild acute disease. While acute COVID-19 is generally milder in children due to a more robust innate immune response, the mechanisms driving the persistence of symptoms in PPCC remain incompletely understood and likely multifactorial. This narrative review synthesizes current epidemiological data and explores the \u201cperfect storm\u201d of immunological and pathophysiological alterations underpinning the condition. We examine critical hypotheses including a dysregulated immune response characterized by altered T-cell subsets, monocyte activation, and autoantibody production. We discuss the potential role of persistent SARS-CoV-2 viral reservoirs in \u201csanctuary sites\u201d like the gastrointestinal tract and the reactivation of latent viruses such as Epstein-Barr virus (EBV). Furthermore, the review details downstream pathogenic pathways, including vascular endothelial inflammation (thrombo-inflammation), neuroinflammation, and metabolic dysfunctions affecting the mitochondria and tryptophan-kynurenine pathway. Finally, we address the role of microbiome dysbiosis in perpetuating systemic inflammation and the gut-lung axis dysfunction. Given the heterogeneity of clinical presentations, we conclude that PPCC is likely a syndrome of overlapping biological phenotypes. Future research must prioritize identifying these specific biological endotypes to develop targeted diagnostic and therapeutic strategies for the pediatric population.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1794596","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:03:51Z","timestamp":1775801031000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A perfect storm: the immunological and pathophysiological landscape of pediatric post-COVID-19 condition"],"prefix":"10.3389","volume":"17","author":[{"given":"Coen R.","family":"Lap","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Spaarne Gasthuis","place":["Haarlem, Netherlands"]},{"name":"Department of Pediatric Pulmonology, Emma Kinderziekenhuis Amsterdam University Medical Center (UMC)","place":["Amsterdam, Netherlands"]},{"name":"Universiteit Utrecht Departement Infectieziekten en Immunologie","place":["Utrecht, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marlies","family":"van Houten","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Spaarne Gasthuis","place":["Haarlem, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debby","family":"Bogaert","sequence":"additional","affiliation":[{"name":"Universitair Medisch Centrum Utrecht - Locatie Wilhelmina Kinderziekenhuis","place":["Utrecht, Netherlands"]},{"name":"The University of Edinburgh Centre for Inflammation Research","place":["Edinburgh, United Kingdom"]},{"name":"Rijksinstituut voor Volksgezondheid en Milieu","place":["Bilthoven, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giske","family":"Biesbroek","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Emma Kinderziekenhuis Amsterdam University Medical Center (UMC)","place":["Amsterdam, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/scitranslmed.abe8120","article-title":"Immune responses to SARS-CoV-2 infection in hospitalized pediatric and adult patients","volume":"12","author":"Pierce","year":"2020","journal-title":"Sci Trans Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/s41590-020-00826-9","article-title":"Distinct antibody responses to SARS-CoV-2 in children and adults across the COVID-19 clinical spectrum","volume":"22","author":"Weisberg","year":"2020","journal-title":"Nat Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00846-2","article-title":"Long COVID: major findings, mechanisms and recommendations","volume":"21","author":"Davis","year":"2023","journal-title":"Nat Rev Microbiol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanepe.2021.100138","article-title":"Are low SARS-CoV-2 viral loads in infected children missed by RT-PCR testing","volume":"5","author":"Langeland","year":"2021","journal-title":"Lancet Reg Health \u2013 Eur"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1136\/archdischild-2020-320338","article-title":"Why is COVID-19 less severe in children? 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