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.