Immune-metabolic trajectories delineate subgroups in paediatric long COVID.

Vilser, Daniel; Han, Irina; Vogel, Katrin; Jakobs, Pauline; Lorenz, Michael; Huppke, Peter; Newman, Lars; Paszkier, Michelle et al. · Nat Commun · 2026

prospective_cohort · Level II

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Abstract

Most children and adolescents recover rapidly from SARS-CoV-2 infection, yet a subset develops paediatric long COVID (LC). How immune ontogeny shapes LC biology and heterogeneity remains unclear. We deeply phenotype a two-visit cohort with severe LC (n = 74) and controls (n = 27) spanning up to 3.2 years post index infection. Symptom burden remains high and neurofilament light chain (NfL) percentiles inversely associate with functional status (Bell score; <math xmlns="http://www.w3.org/1998/Math/MathML"><mi>r</mi></math>  = -0.3536, P = 0.0060). Cardiopulmonary assessment and serology are unremarkable. Conventional autoantibodies are not enriched, whereas anti-DFS70 supports subgrouping. Immune features are temporally structured; SARS-CoV-2-associated mediators decline within 1 year, while innate-weighted, Th2-skewed cytokines persist. Metabolomics (43 metabolites) recapitulate the identified subgroups and align with EBV serostatus, disease phase (<1 year versus years 1-3.2), and anti-DFS70 positivity. In EBV-naïve LC, higher haemoglobin concentration (MCHC) tracks worse function, whereas higher IL-12p40, thiamine and basophils track milder impairment (all P ≤ 0.0170). These data delineate immune-metabolic and haematological axes of paediatric LC heterogeneity and support biomarker-guided stratification.

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