Genetic Prediction for Treatment Resistance in Kawasaki Disease

PROJECT SUMMARY Kawasaki Disease (KD) is systemic autoinflammatory vasculitis occurring in children and showing predilection for attacking the coronary arteries. Despite 60 years of research, the etiology and pathogenesis for KD still require elucidation. The predominant hypothesis regarding pathogenesis involves an unknown antigen, possibly microbial, or super-antigen induced hyperimmune response occurring in genetically susceptible individuals. Treatment includes inflammatory suppression with high dose immunoglobulin. However, response, defined as persistent of fever, or continuing coronary vasculitis characterized by dilation and aneurysm formation, is highly variable. The parent grant tests the hypothesis that treatment response depends on pharmacogenetics, which is currently being probed with whole genome sequencing. Disease severity, particularly formation of giant coronary aneurysms, could also depend on the pathogen signaling the immune response. Currently, the world faces a pandemic from the novel human corona virus SARS-COV-2 resulting in development of Covid-19 disease. This virus promotes a dramatic systemic inflammatory response, in some ways mirroring that occurring in KD. Thus, prior studies have explored and suggested a role for corona virus HCoV-NL63 in KD pathogenesis, although subject numbers displaying both KD and serological evidence for corona have been limited due to relatively low infectivity of corona virus overall. In contrast, SARS-COV-2 shows high human to human transmission, and modeling shows that millions of Americans will eventually be infected. This transmission alters the landscape for evaluating a potential role for corona viruses in pathogenesis of KD in children. Covid-19 is particularly intriguing for KD as the SARS-COV-2 spike protein binds to angiotensin converting enzyme2 (ACE2) as a receptor and promotes cellular entry of the virus. ACE2 enzymatically directs angiotensin2 to angiotensin (1-9), which promotes coronary arterial dilation, an important aspect of KD. SARS-COV-2 infection severity in children currently appears to be mild leading to low rates of testing (although we are now receiving reports of respiratory distress and even death in children and infants in the U.S and throughout the world). Thus, the relationship of SARS-COV-2 and autoinflammatory pediatric diseases such as KD remains unknown. This study will use existing grant infrastructure to determine relationships between SARS-COV-2 infection and KD. We will also use this opportunity to determine antibody response to SARS-COV-2 exposure in a febrile and afebrile Pediatric populations. The supplement scope will be supported by UAB investigators, who are at the forefront of developing serological testing for SARS-COV-2, as well as Seattle Children's located at the initial U.S epicenter for the pandemic.