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Three linked vasculopathic processes characterize Kawasaki disease: a light and transmission electron microscopic
Jan Marc Orenstein1, Stanford T Shulman, Linda M Fox
1Department of Pathology, George Washington University School of Medicine, Washington, District of Columbia, USA. jmo@gwu.edu
Insights
Kawasaki disease involves three distinct arterial processes: acute necrotizing arteritis (NA), subacute/chronic vasculitis (SA/C), and myofibroblastic proliferation (LMP). NA is self-limiting, while SA/C and LMP can cause long-term arterial damage and stenosis.
Area of Science:
- Pediatric Cardiology
- Vascular Pathology
- Infectious Disease
Background:
- Kawasaki disease is a leading cause of acquired pediatric heart disease.
- An infectious etiology is suspected, possibly originating in the respiratory tract.
- Existing pathological models do not fully explain the disease's complex vascular manifestations.
Purpose of the Study:
- To characterize the distinct pathological processes in arteries affected by Kawasaki disease.
- To differentiate the temporal and structural characteristics of these vasculopathic changes.
- To correlate pathological findings with clinical outcomes and disease progression.
Main Methods:
- Analysis of 41 specimens (32 autopsies, 8 cardiac transplants, 1 aneurysm) using light and electron microscopy.
- Identification and classification of three primary vasculopathic processes: necrotizing arteritis (NA), subacute/chronic vasculitis (SA/C), and luminal myofibroblastic proliferation (LMP).
Main Results:
- Three distinct vasculopathic processes identified: NA (acute, self-limited, neutrophilic, affecting endothelium to adventitia), SA/C (subacute/chronic, adventitia to lumen, causing aneurysms and myofibroblast transition), and LMP (luminal myofibroblastic proliferation).
- NA occurs within the first two weeks of fever, leading to saccular aneurysms, thrombosis, or rupture.
- SA/C can persist for months, causing stenosis via myofibroblast proliferation and smooth muscle cell transformation, and affects non-coronary arteries.
- Earliest death (day 10) showed SA/C vasculitis, SA/C-LMP, and myocarditis.
Conclusions:
- Necrotizing arteritis (NA) is the sole self-limiting process, responsible for early morbidity and mortality, consistent with viral infection.
- Subacute/chronic vasculitis (SA/C) and luminal myofibroblastic proliferation (LMP) can persist for months to years, leading to progressive arterial stenosis and thrombosis.
- LMP involves unique smooth muscle cell-derived myofibroblasts contributing to arterial narrowing.
Background:
Kawasaki disease is recognized as the most common cause of acquired heart disease in children in the developed world. Clinical, epidemiologic, and pathologic evidence supports an infectious agent, likely entering through the lung. Pathologic studies proposing an acute coronary arteritis followed by healing fail to account for the complex vasculopathy and clinical course.
Methodology/Principal Findings:
Specimens from 32 autopsies, 8 cardiac transplants, and an excised coronary aneurysm were studied by light (n=41) and transmission electron microscopy (n=7). Three characteristic vasculopathic processes were identified in coronary (CA) and non-coronary arteries: acute self-limited necrotizing arteritis (NA), subacute/chronic (SA/C) vasculitis, and luminal myofibroblastic proliferation (LMP). NA is a synchronous neutrophilic process of the endothelium, beginning and ending within the first two weeks of fever onset, and progressively destroying the wall into the adventitia causing saccular aneurysms, which can thrombose or rupture. SA/C vasculitis is an asynchronous process that can commence within the first two weeks onward, starting in the adventitia/perivascular tissue and variably inflaming/damaging the wall during progression to the lumen. Besides fusiform and saccular aneurysms that can thrombose, SA/C vasculitis likely causes the transition of medial and adventitial smooth muscle cells (SMC) into classic myofibroblasts, which combined with their matrix products and inflammation create progressive stenosing luminal lesions (SA/C-LMP). Remote LMP apparently results from circulating factors. Veins, pulmonary arteries, and aorta can develop subclinical SA/C vasculitis and SA/C-LMP, but not NA. The earliest death (day 10) had both CA SA/C vasculitis and SA/C-LMP, and an "eosinophilic-type" myocarditis.
Conclusions/Significance:
NA is the only self-limiting process of the three, is responsible for the earliest morbidity/mortality, and is consistent with acute viral infection. SA/C vasculitis can begin as early as NA, but can occur/persist for months to years; LMP causes progressive arterial stenosis and thrombosis and is composed of unique SMC-derived pathologic myofibroblasts.
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