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      Three Linked Vasculopathic Processes Characterize Kawasaki Disease: A Light and Transmission Electron Microscopic Study

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          Abstract

          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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          Most cited references82

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          A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome.

          Treatment of acute Kawasaki syndrome with a four-day course of intravenous gamma globulin, together with aspirin, has been demonstrated to be safe and effective in preventing coronary-artery lesions and reducing systemic inflammation. We hypothesized that therapy with a single, very high dose of gamma globulin would be at least as effective as the standard regimen. We conducted a multicenter, randomized, controlled trial involving 549 children with acute Kawasaki syndrome. The children were assigned to receive gamma globulin either as a single infusion of 2 g per kilogram of body weight over 10 hours or as daily infusions of 400 mg per kilogram for four consecutive days. Both treatment groups received aspirin (100 mg per kilogram per day through the 14th day of illness, then 3 to 5 mg per kilogram per day). The relative prevalence of coronary abnormalities, adjusted for age and sex, among patients treated with the four-day regimen, as compared with those treated with the single-infusion regimen, was 1.94 (95 percent confidence limits, 1.01 and 3.71) two weeks after enrollment and 1.84 (95 percent confidence limits, 0.89 and 3.82) seven weeks after enrollment. Children treated with the single-infusion regimen had lower mean temperatures while hospitalized (day 2, P less than 0.001; day 3, P = 0.004), as well as a shorter mean duration of fever (P = 0.028). Furthermore, in the single-infusion group the laboratory indexes of acute inflammation moved more rapidly toward normal, including the adjusted serum albumin level (P = 0.004), alpha 1-antitrypsin level (P = 0.007), and C-reactive protein level (P = 0.017). Lower IgG levels on day 4 were associated with a higher prevalence of coronary lesions (P = 0.005) and with a greater degree of systemic inflammation. The two groups had a similar incidence of adverse effects (including new or worsening congestive heart failure in nine children), which occurred in 2.7 percent of the children overall. All the adverse effects were transient. In children with acute Kawasaki disease, a single large dose of intravenous gamma globulin is more effective than the conventional regimen of four smaller daily doses and is equally safe.
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            Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction.

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              The myofibroblast: one function, multiple origins.

              The crucial role played by the myofibroblast in wound healing and pathological organ remodeling is well established; the general mechanisms of extracellular matrix synthesis and of tension production by this cell have been amply clarified. This review discusses the pattern of myofibroblast accumulation and fibrosis evolution during lung and liver fibrosis as well as during atheromatous plaque formation. Special attention is paid to the specific features characterizing each of these processes, including the spectrum of different myofibroblast precursors and the distinct pathways involved in the formation of differentiated myofibroblasts in each lesion. Thus, whereas in lung fibrosis it seems that most myofibroblasts derive from resident fibroblasts, hepatic stellate cells are the main contributor for liver fibrosis and media smooth muscle cells are the main contributor for the atheromatous plaque. A better knowledge of the molecular mechanisms conducive to the appearance of differentiated myofibroblasts in each pathological situation will be useful for the understanding of fibrosis development in different organs and for the planning of strategies aiming at their prevention and therapy.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                18 June 2012
                : 7
                : 6
                : e38998
                Affiliations
                [1 ]Department of Pathology, George Washington University School of Medicine, Washington, District of Columbia, United States of America
                [2 ]Department of Pediatrics, Feinberg School of Medicine, Northwestern University, The Children’s Memorial Hospital, Chicago, Illinois, United States of America
                [3 ]Department of Pathology, Feinberg School of Medicine, Northwestern University, The Children’s Memorial Hospital, Chicago, Illinois, United States of America
                [4 ]Department of Microbiology/Immunology, Feinberg School of Medicine, Northwestern University, The Children’s Memorial Hospital, Chicago, Illinois, United States of America
                [5 ]Department of Pathology, Stritch School of Medicine, Loyola University, Maywood, Illinois, United States of America
                [6 ]Department Microbiology/Immunology, Stritch School of Medicine, Loyola University, Maywood, Illinois, United States of America
                [7 ]Department of Pediatrics, School of Medicine, University of Southern California, Los Angeles Children’s Hospital, Los Angeles, California, United States of America
                [8 ]Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
                [9 ]Department of Pathology, Children’s Hospital Colorado, Aurora, Colorado, United States of America
                [10 ]Department of Pathology and Laboratory Medicine, College of Medicine, Drexel University, St. Christopher’s Hospital for Children, Philadelphia, Pennsylvania, United States of America
                [11 ]Department of Pathology and Laboratory Medicine, Alberta Children’s Hospital, Calgary, Alberta, Canada
                [12 ]Department of Pediatrics, Riley Hospital for Children at Indiana University Health, Indianapolis, Indiana, United States of America
                [13 ]Office of the Medical Examiner, Cook County Institute of Forensic Medicine, Chicago, Illinois, United States of America
                S.G.Battista Hospital, Italy
                Author notes

                Conceived and designed the experiments: JMO STS LMF SCB MT TRB PAR GWM JPC EJP CT ATR MBK AHR. Performed the experiments: JMO LMF EJP AHR. Analyzed the data: JMO STS LMF SCB MT TRB PAR GWM JPC EJP CT ATR MBK AHR. Contributed reagents/materials/analysis tools: JMO STS LMF SCB MT TRB PAR GWM JPC EJP CT ATR MBK AHR. Wrote the paper: JMO STS LMF SCB MT TRB PAR GWM JPC EJP CT ATR MBK AHR.

                Article
                PONE-D-12-01785
                10.1371/journal.pone.0038998
                3377625
                22723916
                09ef7b91-78e9-47e6-a72b-0cb1402e888a
                Orenstein et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 16 January 2012
                : 15 May 2012
                Page count
                Pages: 25
                Categories
                Research Article
                Biology
                Microbiology
                Emerging Infectious Diseases
                Medicine
                Cardiovascular
                Coronary Artery Disease
                Myocardial Infarction
                Clinical Immunology
                Autoimmune Diseases
                Kawasaki Disease
                Vasculitis
                Immunopathology
                Diagnostic Medicine
                Pathology
                Anatomical Pathology
                Autopsy Pathology
                Histopathology
                Pediatrics
                Rheumatology
                Vasculitis

                Uncategorized
                Uncategorized

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