Kawasaki Disease, Multisystem Inflammatory Syndrome in Children: Antibody-Induced Mast Cell Activation Hypothesis

Abstract

Multisystem Inflammatory Syndrome in Children (MIS-C) is appearing in infants, children, and young adults in association with COVID-19 (coronavirus disease 2019) infections of SARS-CoV-2. Kawasaki Disease (KD) is one of the most common vasculitides of childhood. KD presents with similar symptoms to MIS-C especially in severe forms such as Kawasaki Disease Shock Syndrome (KDSS). The observed symptoms for MIS-C and KD are consistent with Mast Cell Activation Syndrome (MCAS) characterized by inflammatory molecules released from activated mast cells. Based on the associations of KD with multiple viral and bacterial pathogens, we put forward the hypothesis that KD and MIS-C result from antibody activation of mast cells by Fc receptorbound pathogen antibodies causing a hyperinflammatory response upon second pathogen exposure. Within this hypothesis, MIS-C may be atypical KD or a KD-like disease associated with SARS-CoV-2. We extend the mast cell hypothesis that increased histamine levels are inducing contraction of effector cells with impeded blood flow through cardiac capillaries. In some patients, pressure from impeded blood flow, within cardiac capillaries, may result in increased coronary artery blood pressure leading to aneurysms, a well-known complication in KD.Multisystem Inflammatory Syndrome in Children (MIS-C, previously designated as Pediatric Multisystem Inflammatory Syndrome -PMIS) is appearing in infants, children, and young adults in association with COVID-19 (coronavirus disease 2019) infections [1][2][3][4][5][6][7][8][9][10][11] . Kawasaki Disease (KD, previously called mucocutaneous lymph node syndrome) is one of the most common vasculitides of childhood 12 . KD presents with similar symptoms to MIS-C especially in severe forms such as Kawasaki Disease Shock Syndrome (KDSS). The cause of KD is currently unknown; KD has features similar to those associated with a viral infection. The leading hypothesis is that a ubiquitous infectious agent can induce KD in a genetically susceptible patient 13 . This hypothesis is supported by the presence of IgA plasma cells identified in inflamed tissues and coronary arteries of KD patients 14 . Associations between KD and multiple pathogens have been reported, including adenovirus 15,16 , human bocavirus 17 , coronavirus 16 , human coronavirus 229E 18 , human coronavirus (HCoV-NH) NL63 19 , cytomegalovirus 20 , dengue 21,22 , enterovirus 16,23 , Epstein-Barr virus 24 , human herpesvirus 6 25 , human lymphotropic virus 26 , human rhinovirus 16 , influenza 27 , measles 28 , parvovirus B19 29,30 , parainfluenza virus type 2 31 , respiratory syncytial virus (RSV) 32 , rotavirus 33 , varicella zoster (chicken pox) 34,35 , torque teno virus 36 , Staphylococcus aureus 37 , and Streptococcus 24,38 . Postinfluenza vaccination KD has also been

Two Different Antibody-Dependent Enhancement (ADE) Risks for SARS-CoV-2 Antibodies

“…Multisystem inflammatory syndrome in children (MIS-C) and adults (MIS-A) associated with COVID-19 has appeared in areas following SARS-CoV-2 outbreaks. A model of MIS-C has been proposed where activation and degranulation of mast cells with Fc receptor-bound SARS-CoV-2 antibodies leads to increased histamine levels (26). This model is consistent with MIS-C in infants with maternally transferred antibodies (matAbs) (37-40) to SARS-CoV-2.…”

“…Elevated PGE 2 may be driving hyper-activated mast cells as an alternative mechanism driving increased histamine levels in older children and adults. These increased histamine levels are predicted to impede blood flow through cardiac capillaries due to constricted pericytes with increased risk for cardiac pathology due to cell death by anoxia and coronary artery aneurysms due to increased blood pressure (26). An instance of a 12 years old child with a previous asymptomatic COVID-19 infection developing MIS-C on likely second infection has been reported (72).…”

“…Increased risk for antibodydependent enhancement (ADE) from antibodies targeting SARS-CoV-2, SARS-CoV-1, and MERS-CoV exposed residues is indicated by observed ADE in animal models and the antibody facilitated infection of phagocytic immune cells by coronaviruses (9,25). In addition, SARS-CoV-2 antibodies bound to mast cells may also be involved in ADE for some MIS-C and MIS-A patients (26).…”

Immune response to SARS‐CoV‐2 in children: A review of the current knowledge

“… 116 Degranulation of mast cells with Fc receptor‐bound SARS‐CoV‐2 antibodies leads to an hyperinflammatory response, which results in increased histamine levels, upregulated prostaglandin E2 (PGE2), leading to increased risks of coronary artery aneurysms. 116 …”

Interacciones entre SARS-CoV-2 y el sistema de defensas del aparato respiratorio: consideraciones para la prevención y el manejo de las infecciones

“…La respuesta inmune adaptativa y específica contra SARS-CoV-2 puede resultar en procesos inflamatorios severos cuando los individuos se enfrentan de nuevo al virus en etapas posteriores a la fase aguda de la infección inicial. Se ha propuesto que el síndrome multisistémico inflamatorio en niños y jóvenes (MIS-C), que se inicia con síntomas leves de COVID-19 alrededor de 25 días después del inicio de la enfermedad, es causado por el fenómeno ADE, con la participación de anticuerpos IgG anti-SARS-CoV-2, neutrófilos y mastocitos que responden a una exposición secundaria al virus (Ricke et al, 2020). Es también posible que la ADE se inicie por anticuerpos inespecíficos producidos previamente por infecciones debidas a uno de los coronavirus estacionales (Berard et al, 2020) o por la inmunización pasiva (Dzik, 2020;Sullivan & Roback, 2020).…”