Discussion
In this study, we performed an immune profiling of the cellular and humoral immune response in 17 pediatric patients with non-specific PASC. We demonstrate an increased SARS-CoV-2 CD4+ and CD8+ T cell response characterized by low avidity, TNFα and IFNγ production among PASC patients. These findings might indicate a possible role of SARS-CoV-2-specific cellular immunity that triggers inflammation as possible immune mechanism of pediatric PASC. While immunological data among pediatric PASC patients are scarce, accumulating data regarding the pathogenesis of PASC in adult cohorts indicate expansion of cytotoxic CD8+ T cells to be an important pathogenic component of PASC (15,27–30). Bacher et al have already demonstrated the relevance of low avidity S-reactive T cells in immunopathogenesis of acute SARS-CoV-2 infection(31), while our group recently demonstrated increased number of SARS-CoV-2 reactive CD8+ T cells with a low TCR avidity associated with adult PASC(32).
Although the clinical laboratory workout showed comparable creatinine and liver parameters between the studied cohorts, we found association between GOT, GPT and IFNγ producing reactive CD4 T cells as well as between creatinine and TNFα producing reactive CD4+ T cells. These results may suggest a possible role of SARS-CoV-2-reactive T cells producing inflammatory cytokines in the frame of pediatric PASC with hepatic and renal involvement. In agreement with these findings, post-COVID-19 cholangiopathy has been increasingly reported in adults(33,34), while Cooper et al described recently PASC liver manifestation in 5 pediatric patients(35).
Of interest, we demonstrated a strong positive correlation between CRP and IFNγ producing reactive CD8+ T cells. The inflammatory immune response and cytokine levels have been associated with both depression and fatigue in a large body of literature across different disorders(36–40). In the frame of adult PASC, elevated pro-inflammatory proteins in cerebrospinal fluid, microglia activation markers and persistent loss of oligodendrocytes and myelinated axons in PASC patients and mice with neurological PASC manifestation have been demonstrated (41,42), while Kiho et al showed TNF-α and C-reactive protein predicted strong association with PASC symptoms at 12 months (43).
The present study has limitations. The number of included patients was small so that we were unable to differentiate immune response according to symptom clusters. Rao et al in a large-scale exploratory study found that the burden of pediatric PASC on the health system was low(10). However, despite its phenomenal benignity in most of the cases, long-term psychological and somatic effects of pediatric PASC are currently unknown. Our study group underlined the risk for the development of restrictive eating disorders in children and adolescents with long-COVID-associated smell and taste dysfunction(20). Pediatric PASC is a public health and social issue requiring interdisciplinary vigilant attention.
Taken together, our results suggest that cellular inflammatory response triggered by SARS-CoV-2 may be responsible for the observed sequelae in pediatric PASC. These results may have implications on future therapeutic and prevention strategies.