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

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.

reported 39 . The seasonality and temporal clustering of KD 32,40 further support an infectious etiology. A mild cold may precede the onset of KD and up to one-third of patients have concurrent, confirmed infections at the time of KD diagnosis 41 . The aggregate of these pathogen associations with KD supports the rejection of the hypothesis that KD is caused by a single infectious agent. The alternative hypothesis is that KD is associated with multiple infectious agents. We hypothesize that MIS-C may be atypical KD or a KD-like disease associated with SARS-CoV-2 42 as a result of antibody-dependent enhancement activation of mast cells. We further hypothesize that KD and MIS-C may be induced in part by histamine and other inflammatory molecules released from activation of mast cells by Fc receptor-bound pathogen antibodies resulting in a hyperinflammatory response.
The diagnosis of classic KD is based on the presence of fever lasting five days or longer together with at least four of five additional clinical findings: bilateral conjunctivitis, oral mucosal changes, cervical lymphadenopathy, extremity changes, and a polymorphous rash. However, not all patients present with this complete clinical picture. Atypical KD occurs in patients with fever lasting five days or longer with two or three of the previously mentioned clinical features. MIS-C symptoms demonstrate remarkable overlap (Table 1) (Figure 1). We hypothesize that both COVID-19 patients and MIS-C patients may have the same impeded blood flow through capillaries likely due to increased histamine levels. Impeded blood flow in capillaries is likely the cause of myocarditis, valvulitis, necrotizing microvasculitis, edema of hands and feet, etc. 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 (Figure 1). We hypothesize that KD and MIS-C coronary artery aneurysms are initiated with a pathologic dilation injury caused by increased pressure in the artery; the injured cells use damage-associated molecular patterns (DAMPs) signaling that initiates the inflammation at the site of injury. In this model, inflammation is a secondary event not the primary event leading to aneurysms. This inflammation is a feedforward process contributing to further weakening of the arterial wall. Of all arteries, the coronary artery has the shortest distance to downstream capillaries. Hypertension has been implicated in the pathogenesis of arterial aneurysms 48,49 .
Pediatric patients with first COVID-19 infection generally have less severe clinical manifestations than adult patients 53 . The COVID-19 asymptomatic infection rate has been estimated in adults to be 46% 54  infections have been reported since late April, 2020 56 suggesting that MIS-C manifests more than one month after the peak of COVID-19 cases in an affected area 57 . The number of affected children is rising rapidly; within weeks of the publication of COVID-19 related MIS-C cases 2 , 93 children were diagnosed with up to five deaths in New York. As of May 29 th , 186 cases have been identified 58 . With an observed New York population infection rate of roughly 1.7% (337,055 infected 59 of 19,450,000 population), the timing is consistent with a possible second wave of pediatric SARS-CoV-2 infections (1.7% x 1.7% of 1.7 million New York children, or 491 possible second infections in New York children). With a rate of 306 cases per 100,000 under age 18 adjusted to 567 for asymptomatic children, the 1.7% infection rate of 1.7 million New York children predicts 169 possible second infections. The 186 cases identified by May 29 th represents between 110% of the lower estimate of 169 infections to 38% of the 491 that would be predicted in the second wave of infections. This second wave hypothesis is consistent with the lack of MIS-C patients in China and elsewhere that contained outbreaks in their regions consequently avoiding or minimizing the second wave of infections. With more than 250 cases of MIS-C reported in the United States by May 21, 2020 60 , MIS-C may reflect a subset of children initially infected with SARS-CoV-2 who sustained a subsequent exposure to the virus. MIS-C may be a manifestation of a delayed trigger from the antibody-dependent disease. Without an effective vaccine for COVID-19, the first exposure to COVID-19 may result in asymptomatic to mild disease for most children accompanied by risk for MIS-C/KD upon subsequent infection. Ricke and Malone 61 predict antibody-dependent enhancement disease risks associated with COVID-19 based on disease enhancements from animal model vaccine studies of severe acute respiratory syndrome, Middle East respiratory syndrome, and other coronaviruses. Extending this hypothesis to these children predicts that this postinfectious inflammatory process (MIS-C or KD) could be a direct result of antibody-dependent enhancement (ADE) of disease for children previously infected with SARS-CoV-2 or primary infected infants with either transplacental transferred antibodies (matAbs) or SARS-CoV-2 antibodies from breast milk. Children diagnosed with a postinfectious inflammatory process (MIS-C or KD) frequently test negative on PCR for SARS-CoV-2 1 , however, they test positive for antibodies of SARS-CoV-2 52,57 suggesting antibodies are required for disease manifestation.
The symptoms of MIS-C and KD are consistent with the activation of mast cells via antibodies as seen in Mast Cell Activation Syndromes (MCAS). We hypothesize that SARS-2 antibodies created after first infection bind mast cells, triggering histamine release. These antibodies may be recognizing low levels of SARS-CoV-2 from a re-emergent infection or a possible second exposure. Mast cell released histamine stimulates pericytes or effector cells causing capillary constriction, notably in cardiac tissue. The MIS-C/ KD symptoms of diarrhea and vomiting may be attributed to increased histamine levels and/or SARS-CoV-2 gastrointestinal infection akin to symptoms seen for the severe acute respiratory syndrome. Current KD and MIS-C treatments include intravenous gamma globulin (IVIG), corticosteroids, and high-dose aspirin 62 . IVIG can decrease, but not eliminate, this risk of developing coronary artery aneurysms. Corticosteroids as adjunctive therapy to IVIG may be helpful for lowering the risk of coronary artery aneurysms 62 . We hypothesize that IVIG dilutes the current infection pathogen antibodies bound to mast cells, reducing the level of mast cell activation. High doses of aspirin may help treat inflammation; aspirin can also decrease pain and reduce fever. While not appreciated for treating KD, aspirin is a known mast cell stabilizer. This ADE model for MIS-C and COVID-19 emphasizes the importance of developing safe T-cell vaccines and increases the importance of safety testing for any B-cell vaccines being developed. In addition to IVIG, famotidine 63 , famotidine+cetirizine 64 , montelukast 65 and other potential treatments have been identified by Malone et al. 66 to reduce the degranulation of mast cells. We suggest children presenting with evidence of MIS-C/KD should also be tested for antibodies for SARS-CoV-2 as PCR testing is frequently negative.

Conclusion
We must be cautious of inappropriately creating new clinical entities in the context of COVID-19 67 . It has been hypothesized before the advent of COVID-19 that KD could be induced by RNA viruses in genetically susceptible hosts. It is also possible we are seeing SARS-CoV-2 induced KD complicated by KDSS in MIS-C as a result of antibodydependent enhancement activation of mast cells.

Conflict of Interest
The authors have indicated they have no potential conflicts of interest to disclose. This material is based upon work supported under Air Force Contract No. FA8702-15-D-0001. Any opinions, findings, conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the U.S. Air Force.