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Immune-metabolic trajectories delineate subgroups in paediatric long COVID

Daniel Vilser1,2, Irina Han3,4, Katrin Vogel3,4

  • 1Post-COVID Outpatient Clinic, Department of Paediatrics and Adolescent Medicine, Jena University Hospital, Jena, Germany.

Nature Communications
|May 4, 2026
PubMed

Insights

Paediatric long COVID (LC) involves persistent immune and metabolic alterations, even years after infection. Understanding these immune ontogeny changes is key to stratifying patients and developing targeted therapies for children with long COVID.

Area of Science:

  • Immunology
  • Paediatrics
  • Infectious Diseases

Background:

  • While most children recover from SARS-CoV-2, some develop paediatric long COVID (LC).
  • The influence of immune development on LC biology and its varied presentations is not well understood.
  • Characterizing the long-term immune and metabolic landscape of paediatric LC is crucial.

Purpose of the Study:

  • To deeply phenotype children and adolescents with severe paediatric LC up to 3.2 years post-infection.
  • To identify immune, metabolic, and haematological biomarkers associated with LC heterogeneity and functional status.
  • To explore the relationship between immune ontogeny, viral status, and LC manifestations.

Main Methods:

  • Deep phenotyping of a cohort with severe paediatric LC (n=74) and controls (n=27) over two visits.
  • Analysis included symptom burden, neurofilament light chain (NfL) levels, cardiopulmonary assessments, serology, autoantibody profiling, cytokine analysis, and metabolomics.
  • Statistical analysis correlated immune features, metabolites, and clinical outcomes.

Main Results:

  • Persistent high symptom burden in severe LC, with NfL levels inversely correlating with functional status.
  • Immune profiles showed a decline in SARS-CoV-2 mediators within a year, but persistent innate-weighted, Th2-skewed cytokines.
  • Metabolomics revealed subgroups linked to EBV serostatus, disease phase, and anti-DFS70 positivity, highlighting immune-metabolic and haematological axes of heterogeneity.

Conclusions:

  • Paediatric LC exhibits distinct immune-metabolic and haematological profiles that contribute to its heterogeneity.
  • Specific biomarkers like MCHC, IL-12p40, thiamine, and basophil counts correlate with functional outcomes in EBV-naïve LC patients.
  • These findings support biomarker-guided stratification for personalized paediatric long COVID management.

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