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Etiology Model of Kawasaki Disease and Multisystem Inflammatory Syndromes: Mast Cell Activation
1Molecular BioInsights, 37 Pilgrim Drive, Winchester, MA 01890, USA.
Insights
Kawasaki disease (KD) and multisystem inflammatory syndrome (MIS) may share immune complex activation pathways. Vaccine safety signals for MIS and KD were identified, suggesting potential links to specific COVID-19 vaccines and other immunizations.
Area of Science:
- Pediatric immunology
- Vaccinology
- Infectious disease epidemiology
Background:
- Kawasaki disease (KD) is a primary cause of pediatric heart disease.
- Multisystem inflammatory syndrome (MIS) in children shares clinical similarities with KD.
- The etiologies of both KD and MIS remain largely unknown but are associated with pathogens and immunizations.
Purpose of the Study:
- To investigate potential etiological insights into Kawasaki disease (KD) and multisystem inflammatory syndrome (MIS).
- To examine vaccine safety signals associated with KD and MIS using the Vaccine Adverse Event Reporting System (VAERS).
Main Methods:
- Retrospective analysis of the Vaccine Adverse Event Reporting System (VAERS) database.
- Identification and evaluation of adverse event (AE) safety signals related to vaccines and MIS/KD.
Main Results:
- Statistically significant safety signals for MIS were observed with specific COVID-19 Pfizer-BioNTech vaccine lots across all age groups.
- Immediate-onset safety signals for KD were detected with specific vaccines and vaccine combinations in young infants, with some showing a male sex bias.
- Elevated AE MIS normalized frequencies were observed in children of all ages.
Conclusions:
- KD and MIS are hypothesized to involve two distinct immune activation pathways, potentially related to immune complexes and mast cell activation.
- Proposed models suggest KD and MIS could be novel mast cell activation syndromes (MCAS).
- MIS is hypothesized as KD associated with SARS-CoV-2 or its spike protein (MIS-V).
Background/Objectives:
Kawasaki's disease (KD) is a leading cause of heart disease in children. The multisystem inflammatory syndrome (MIS) associated with the SARS-CoV-2 virus is similar to KD. The etiologies of KD and MIS are unknown. Both diseases are associated with pathogens and immunizations.
Methods:
The Vaccine Adverse Event Reporting System (VAERS) was retrospectively examined for etiology insights into both KD and MIS.
Results:
Statistically significant, elevated AE MIS safety signals were observed for several COVID-19 Pfizer-BioNTech manufacturing lots. Elevated AE MIS normalized frequencies were observed in children of all ages. Immediate-onset AE KD safety signals were detected for specific vaccines and coadministered combinations of these vaccines (including specific live, attenuated virus vaccines and other specific vaccines) for young infants; a subset of these safety signals has a male sex bias, whereas others appear to be unbiased.
Conclusions:
Both KD and MIS are hypothesized to involve two activation pathways. The first pathway is hypothesized to involve high titers of immune complexes that activate Fc receptors on mast cells, platelets, and other immune cells. Immune complex titers higher than primary immune response levels are hypothesized to be required to activate low-affinity IgGFcγR2α receptors on immune cells and platelets. IVIG treatment is hypothesized to directly compete with immune complex binding to FcγR2α receptors. The second hypothesized pathway is proposed to directly activate mast cells and other immune cells without involving immune complexes and Fc receptors; lack of Fc receptor competition by immune complexes is hypothesized as a possible explanation for IVIG nonresponders for KD and MIS, worthy of future studies. The proposed etiology models for both KD and MIS may be consistent with being novel mast cell activation syndromes (MCAS). MIS is hypothesized to be KD-associated with the SARS-CoV-2 virus or the COVID-19 spike protein (MIS-V).
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