Kawasaki Disease (KD) is an infectious disease of unknown cause that can be difficult to diagnose and treat and can lead to lifelong heart disease or death from coronary artery (CA) aneurysms in previously healthy children. Our long-term research goal is to identify the pathogenesis of KD, so that a diagnostic test can be developed and improved therapies based on the molecular pathogenesis be designed. A paradigm of KD arteriopathy has held that KD is a self-limited acute vasculitis lasting 2-3 months after onset, and that arterial occlusion in KD was the result of inactive, healed "scar". We recently performed an extensive light and electron microscopic pathologic study of coronary arteriopathy in 41 KD cases that significantly challenges this model. We identified 3 linked pathologic processes in KD arteriopathy: necrotizing arteritis (NA), subacute/chronic vasculitis (SA/C), and luminal myofibroblastic proliferation (LMP). NA was the only self-limited process and was complete by 2 weeks after fever onset. SA/C and LMP began in the first 2 weeks but could persist for years. LMP is a medial smooth muscle cell-derived myofibroblastic proliferative process that can lead to progressive arterial stenosis, and may represent aberrant wound healing.
Our specific aims propose paradigm shifts for KD research that have significant clinical implications for KD patients. Identification of dysregulated molecular pathways in KD arteriopathy can lead to target-directed rather than empiric therapies. Children with chronic KD arteriopathy can have persistent or even worsening CA disease over time. While the prior paradigm indicated that their vasculitis resolved at ~2 months after onset, we showed persistence of SA/C, and identifying the molecular basis of their dysregulated immune response could result in a new approach to treatment. The discovery that LMP is an active proliferative process instead of "scar" leads to the need to understand its pathogenesis and develop therapies to prevent or reduce this serious KD complication. Previous biomarker studies of KD have focused primarily on inflammatory molecules, but markers of cardiovascular stress would likely better distinguish KD patients from children with febrile illnesses in the differential diagnosis. In this proposal, we will: 1) identiy the molecular pathogenesis of acute KD arteriopathy;2) determine the molecular pathogenesis of immune dysregulation in chronic KD arteriopathy, and 3) identify cardiovascular damage/stress induced molecules that are elevated in the plasma of KD children with CA dilation compared with febrile control children. The results of these studies will provide insights into the molecula pathogenesis of KD arteriopathy and identify new diagnostic tools and therapeutic targets.

Public Health Relevance

Kawasaki Disease (KD) is an infectious disease of unknown cause that can be difficult to diagnose and treat and can lead to lifelong heart disease or death from coronary artery aneurysms in previously healthy children. In this proposal, we will study gene expression in coronary arteries of patients with acute KD to improve understanding of the pathogenesis and to identify new therapeutic targets, identify the molecular characteristics of the immune response in chronically inflamed KD coronary arteries to better determine if additional therapies are needed for these patients, and test plasma proteins and microRNA genes that are induced by cardiovascular injury as diagnostic biomarkers of KD. These studies have the goal of improving diagnosis and treatment of this potentially fatal illness of childhood.

Agency
National Institute of Health (NIH)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56AI106030-13A1
Application #
8911558
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Park, Eun-Chung
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60611