When Fevers Fade: The Lingering Shadows of Post-COVID Immune Dysregulation in Children

Nikos Papadopoulos¹, Eleni Kosta², Andreas Georgiou³, Maria Stamataki⁴

Abstract

Background:
While acute pediatric COVID-19 symptoms often resolve rapidly, a growing number of children experience chronic low-grade immune activation months after recovery, even in the absence of long COVID syndromes. The clinical impact of this phenomenon remains underexplored.

Objective:
To examine markers of immune dysregulation in children 3–9 months post-COVID-19 infection and evaluate associations with recurrent mild infections and fatigue syndromes.

Methods:
This multicenter prospective study enrolled 468 children aged 6–14 years from four pediatric clinics in Germany between May 2022 and January 2024. All participants had PCR-confirmed COVID-19 at least 3 months prior and no history of hospitalisation. Serum cytokine profiles (IL-6, IL-1β, TNF-α), lymphocyte subsets, and immunoglobulin levels were measured. Outcomes included the frequency of mild viral illnesses, fatigue score (PedsQL), and the number of missed school days.

Results:
Immune dysregulation markers (elevated IL-6 and TNF-α) were present in 39.1% of participants. These children had a 2.6-fold higher rate of recurrent mild respiratory infections, with a mean of 3.8 episodes per 6 months compared to 1.4 episodes (p < 0.001). They scored lower on fatigue-related quality-of-life metrics (PedsQL fatigue score: 61.3 vs 78.4, p = 0.002). Subtle B-cell dysregulation (IgM ↑, IgG ↓) was observed in 27.6%, especially in younger age groups (6–9 years).

Conclusion:
A subset of children experience persistent immune alterations post-COVID-19, even without overt long COVID symptoms. These changes may predispose to recurrent minor illnesses and functional fatigue. Early immune screening and fatigue monitoring could support timely pediatric intervention and reduce long-term functional impairment.