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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

SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We explore several plausible avenues of activity including antiviral and host-mediated actions. We propose that the principal famotidine mechanism of action for COVID-19 involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release.