In a recent review published in Nature Reviews Rheumatology, researchers reviewed existing data on the multisystem inflammatory syndrome in children (or MIS-C).
MIS-C is characterized by acute hyperinflammation in multiple organ systems in the following weeks of a viral infection, which can be fatal. The clinical manifestations of the syndrome have been well-characterized; however, data on the immunological responses, pathophysiology, and outcomes of the syndrome are limited.
Moreover, the involvement of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S (spike) protein and the relationship between MIS-C and novel SARS-CoV-2 variants of concern (VOC) such as Omicron has not been extensively investigated.
About the review
In the present review, researchers reviewed MIS-C data in the context of the nature of the vascular injury, SARS-CoV-2 S contribution to MIS-C pathophysiology, and the association between MIS-C and Omicron.
Nature of vascular injury in MIS-C
Studies conducted during the initial COVID-19 period indicated vascular pathophysiology, with coronary artery dilation observed on ECG (echocardiography), with serological findings of thrombocytopenia or reduced platelet count and elevated D-dimer levels. The vascular findings were indicative of low-grade coagulation within the blood vessels. However, further assessments indicated that the coronary vessel damage was short-term.
A study conducted in 2022 evaluated CEC (circulating endothelial cell) levels among nine pediatric patients of Kawasaki disease and 20 MIS-C patients of similar age during the subacute and acute periods of illness.
Of interest, during the subacute period, the number of CECs was greater among children with Kawasaki disease compared to those with MIS-C (46 CECs/ml versus four CECs/ml). The findings indicated long-term endothelial injury among Kawasaki disease patients but not among those with MIS-C. Among MIS-C patients, the greatest CEC counts were reported during the acute period.
Studies have reported that the human cardiac endothelium expresses ACE2 (angiotensin-converting enzyme 2), the receptors required by SARS-CoV-2 for entry into host cells. However, the endothelial cells do not permit SARS-CoV-2 replication. The finding could justify the sparing effect of the coronary endothelium among MIS-C patients.
Role of SARS-CoV-2 S protein in immunopathological outcomes of MIS-C
During the initial coronavirus disease 2019 (COVID-19) period, computer modeling study findings indicated a SARS-CoV-2 S sequence with superantigen characteristics for binding to the TCRVβ (T-cell antigen receptor variable β) chain. Subsequent studies documented T cell receptor repertoire skewing among MIS-C children with elevated levels of the TCRVβ21.3-encoding TRBV11-2 (T cell receptor beta variable 11-2) gene.
However, a study conducted in 2022 showed the absence of such inherent superantigen activity in SARS-CoV-2 S by comparatively evaluating the expression of inflammatory cytokine substances by TCRVβ3-type Jurkat T lymphocytes and human cluster of differentiation 4+ (CD4+) lymphocyte and CD8+ lymphocyte production, on stimulation by SARS-CoV-2 S or staphylococcus-produced B enterotoxin (known superantigen).
Another study evaluated T lymphocyte responses to SARS-CoV-2 peptide pools among children during the subacute MIS-C period. Numerous Vβ21.3-possessing CD4+ lymphocytes and CD8+ lymphocytes were observed; however, the lymphocytes were not a part of the T lymphocyte population activated by SARS-CoV-2. The findings indicated that the T lymphocyte expansion occurs as a response to an antigen unrelated to SARS-CoV-2.
The authors suggest that the unknown stimulating antigen might originate from the inflamed gut of MIS-C patients. Several studies demonstrated persistent SARS-CoV-2 S during the acute period of MIS-C; however, T lymphocyte stimulation by SARS-CoV-2 S was not documented. Electro-chemiluminescent immunoassay findings indicated the short-term presence of SARS-CoV-2 in MIS-C.
Association of MIS-C with SARS-CoV-2 Omicron infections
Studies conducted across the globe have reported reduced MIS-C prevalence in relation to Omicron infections. One study conducted prospectively across 12 hospitals in Israel over 16.0 weeks during the predominance of SARS-CoV-2 VOCs such as the Alpha VOC, Delta VOC, and Omicron VOC reported cardiovascular outcomes of lower severity during Omicron predominance with fewer ICU (intensive care unit) admissions.
National-scale data of MIS-C incidence among Israeli individuals among every 100,000 pediatric individuals were 55, 49, and 4.0 during the Alpha, Delta, and Omicron waves, respectively. The lower MIS-C prevalence during Omicron predominance could be due to S protein mutations resulting in less severe pathophysiological outcomes coupled with immune protection conferred by previous SARS-CoV-2 infections and/or COVID-19 vaccinations.
To conclude, based on the review findings, MIS-C results in short-term coronary vessel dilation and disruption of the vascular wall architecture. SARS-CoV-2 S does not have superantigen activity for binding with the TCRVβ-chain. The skewed Vβ21.3 expression of T lymphocytes is likely to occur in response to a non-SARS-CoV-2-related antigen in MIS-C.
MIS-C prevalence and severity appear to be lower during Omicron predominance compared to previous COVID-19 waves; however, further research is required to determine the precise reasons for fewer MIS-C cases during the Omicron wave. Moreover, future studies need to be conducted to identify the antigen that stimulates T lymphocyte production in MIS-C to improve understanding of MIS-C pathophysiological mechanisms and develop tailored strategies to reduce the MIS-C burden.
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