Immune-Metabolic Programs Drive Disease Trajectories in Paediatric Long COVID

While most children and adolescents recover uneventfully from SARS-CoV-2 infection, some develop persistent symptoms known as paediatric long COVID (LC). Paediatric LC presents with substantial, multisystem health impairment lasting months to years after SARS-CoV-2 infection^1,2. Despite its clinical burden, underpinnings of symptom persistence, heterogeneity, and recovery remain elusive^3,4. Here, we demonstrate that severe symptoms in paediatric LC remained stable over two-to-three years, despite unremarkable cardiopulmonary and routine assessments, and were underpinned by temporally shifting immune-metabolic responses. The first year of LC was marked by viral-associated and Th2-like cytokine responses, transitioning into Th17-like and innate responses over time. Neurofilament light chain, an indicator of neuro-axonal injury, rose with LC-severity, but common autoantibodies remained unchanged. Epstein-Barr virus (EBV) exposure emerged as a key modifier linked to broader immune dysfunction, whereas anti-DFS70 autoantibodies correlated with milder haematological alterations. In EBV-naïve LC cases, symptoms became more severe with altered blood viscosity, but less severe with higher IL-12p40, vitamin B1, and basophils, implicating them as protective. The identified LC subgroups displayed metabolically distinct signatures, supporting the existence of biologically coherent endotypes. These findings uncover immune-metabolic axes linked to resilience and persistence in paediatric LC and may provide a basis for biomarker-informed diagnosis and precision intervention.