Pathology of the Coronary Arteries and Myocardium in Kawasaki Disease.

Kawasaki disease (KD) is an acute systemic inflammatory illness that occurs predominately in children <5 years of age. The reported incidence varies widely depending on the ethnicity of the population and the method of case ascertainment. Recent reports would suggest the annual incidence is ≈20 to 25 per 100 000 children <5 years of age in North America, with the highest reported incidence of 188 being in Japan, where the disease was first described in 1967.1 The illness is self-limited and of unknown cause, but is complicated by a systemic vasculitis with a predilection for small- to medium-sized arteries, particularly the coronary arteries. The majority of patients will have either transient coronary artery dilation or no coronary artery luminal changes as noted on echocardiography. Long-term prognosis for these patients is considered to be excellent. Coronary artery aneurysms occur in 25% of patients, but the prevalence is reduced to ≈4% for patients treated with intravenous immunoglobulin infusion within 10 days of illness onset. Aneurysms are associated with an intense inflammatory cell infiltrate, destruction of the internal elastic lamina, and smooth muscle cell death. Coronary artery involvement is usually maximal within 6 to 8 weeks after the acute episode. Regression of aneurysms can occur primarily through myointimal proliferation, although the arterial structure and function remains abnormal,2 and there is an important ongoing risk of stenoses and occlusions.3 Long-term cardiology assessment and management is required, and some of these patients may require revascularization procedures or, rarely, cardiac transplantation. KD has become the most prevalent acquired cardiac disease in children in developed countries. Article see p 60 Although coronary artery complications are the predominant cause of morbidity and mortality, other cardiovascular abnormalities can occur. Valvulitis is a less prevalent complication, and there have been case reports of important long-term aortic and …

Thirty-six years ago, Tomisaku Kawasaki penned the first description of a quixotic illness that he called mucocutaneous lymph node syndrome.1 Today this illness has been described in almost every country of the world. In studies from North America, Japan, and Western Europe, Kawasaki syndrome has replaced rheumatic fever as the most common cause of acquired heart disease.2 Despite the importance of Kawasaki syndrome as a cause of disease in children, a surprising number of aspects of this syndrome remain ill-defined. Because the etiology remains incompletely understood, the diagnosis is based on history and physical examination. Because the symptoms of Kawasaki syndrome are not unique and diagnosis can be difficult, it is likely that many cases of incomplete or atypical Kawasaki syndrome, as well as some presentations of classic Kawasaki syndrome, remain undiagnosed and untreated, and the child remains at risk of undetected coronary artery disease. Therapy with intravenous immunoglobulin (IGIV) and aspirin, while effective, is nonspecific and is associated with the problems of gamma globulin infusions. These problems include the need for intravenous cannulation, risk of adverse reactions, concern for possible adventitious agents, interference with the immune response to live vaccines, expense, shortages, and the fact that 2% to 4%% of treated children still develop coronary artery disease. Furthermore, the long-term cardiac outcome of children who experience Kawasaki syndrome both for those with and those without detectable coronary artery involvement is not clear. After >3 decades of study, what is known about Kawasaki syndrome and why are there still so many unanswered questions? The study by Holman et al3 in this issue of Pediatrics supports previous estimates regarding certain epidemiologic aspects of Kawasaki syndrome and offers important new detail into others. Using hospital discharge data from the Kids’ Inpatient Database (22 participating states), the authors address a … Address correspondence to H. Cody Meissner, MD, Pediatric Infectious Diseases Division, Tufts-New England Medical Center, 750 Washington St, Boston, MA 02111. E-mail: cmeissner{at}tufts-nemc.org

Kawasaki Disease (KD), an acute febrile illness and systemic vasculitis of unknown etiology, is the leading cause of acquired heart disease among children. Recent experimental data from mouse models, as well as clinical, genetic and transcriptome evidence from KD patients suggest a key role of the NLRP3-IL-1β pathway in the pathogenesis of KD. NLRP3 can be activated by mitochondrial (mt) DNA released in the setting of defective autophagy/mitophagy, but a potential role for autophagy/mitophagy in KD cardiovascular inflammation has not been determined. In the Lactobacillus casei cell wall extract (LCWE) mouse model of KD vasculitis, LCWE injection in WT mice results in coronary arteritis, aortitis and myocarditis, mimicking human KD. We found that expression of the autophagy/mitophagy markers Parkin and p62 was significantly higher in whole lysate and mitochondrial fractions of heart tissue of LCWE-injected mice than controls, indicating impaired autophagic flux and mitophagy. Parkin -/- mice developed significantly more LCWE-induced cardiovascular lesions than control mice, and treatment of WT mice with a GLP-1 receptor agonist, known to activate Parkin, significantly reduced LCWE-induced inflammation. LCWE-induced cardiovascular lesions were amplified in mice deficient in OGG1, a base excision repair protein sensitive to mtDNA damage. Finally, inhibiting autophagy with chloroquine exacerbated LCWE-induced KD vasculitis, whereas inducing autophagy by intermittent fasting decreased cardiovascular inflammation in the model. Altogether, our data suggest that impaired autophagy/mitophagy exacerbates KD and supports a role for mtDNA damage in the disease. These findings enhance our understanding of KD pathogenesis and may provide novel therapeutic targets.

TNF-α is superior to conventional inflammatory mediators in forecasting IVIG nonresponse and coronary arteritis in Chinese children with Kawasaki disease

Giant Thrombotic Right Coronary Aneurysm in an Infant with Undiagnosed Incomplete Kawasaki Disease and Rapidly Progressive Cardiovascular Collapse

Management of Kawasaki disease in resource-limited settings.

The aetiology and pathogenesis of Kawasaki disease (KD) remain unknown. To investigate the pathogenesis of vasculitis in KD, we tested for the presence of auto-antibodies against a component of vascular smooth muscle cells in the sera of patients with KD. Sera from 48 patients with KD, as well as sera from 14 sick children and from 22 healthy children, were examined for reactivity to both coronary arterial wall tissues and cultured smooth muscle cells (CSMC) derived from human coronary artery, using immunofluorescence and Western immunoblot assay techniques. Sera from 16 of 48 patients with KD gave positive immunoreactions to the vascular walls of coronary artery with fluorescein isothiocyanate-labelled rabbit anti-human IgA antibodies. In Western immunoblot assays, the sera from 15 of 34 and 10 of 31 patients with KD showed positive reactions against a 70 kDa protein from CSMC with IgA and IgM antibodies, respectively. Positive immunoreactivity of sera from patients with KD, determined either by immunofluorescence studies or by Western immunoblotting, was detected more frequently ( P<0.05) and more intensely ( P<0.005) in patients with coronary arterial lesions (CAL) than in those without CAL. Positive immunoreactivity of sera was prominent before intravenous immunoglobulin therapy and decreased dramatically thereafter. these data suggest that auto-antibodies against a 70 kDa protein from vascular smooth muscle cells may cause coronary arteritis and systemic vasculitis in KD.

Background: Kawasaki disease (KD) is the most common cause of acquired cardiac disease among US children and causes coronary artery aneurysms (CAA) in 25% of untreated patients. CAAs can result in myocardial ischemia, infarction, and even death. Other long-term sequelae from KD include extensive remodeling of CAA leading to stenosis and endothelial (EC) dysfunction. Acute KD is also associated with myocarditis that can cause arrhythmias, which can be fatal and may lead to long-term myocardial dysfunction and fibrosis, areas of KD research that are severely neglected. These myocardial changes may persist for decades after the acute illness and closely correlate with long-term myocardial sequelae. Objective: To investigate long-term myocardial dysfunction, including myocardial fibrosis and coronary microvascular lesions in the KD vasculitis mouse model. Methods: Mice were injected with Lactobacillus casei cell wall extract (LCWE) to induce KD vasculitis, coronary arteritis, and myocarditis at 1 week. Five weeks later, control or KD mice were injected with isoproterenol (ISO), a beta agonist, for 10 consecutive days to induce pharmacologically mediated exercise, followed by sacrifice and analysis. Cardiac hypertrophy was measured by calculating heart weight normalized to tibia length. Myocardial fibrosis was determined by Masson’s trichrome staining of the myocardium and myocardial function was measured by serum BMP levels and ventricular ejection fraction by MRI. Results: KD significantly increased the risk of cardiac hypertrophy and increased myocardial fibrosis, diminished ejection fraction and increased BMP following prolonged pharmacologic exercise (ISO), compared with controls. Post KD pharmacologic exercise-induced myocardial fibrosis was associated with significant reduction in the expression of the EC marker CD31 in the myocardium. This KD induced myocardial fibrosis was IL-1-dependent as the IL-1R KO mice were protected. Conclusions: Pharmacologic stress (exercise) leads to cardiac hypertrophy and chronic myocardial fibrosis in the LCWE-induced acute KD vasculitis mouse model, a process that involves IL-1 signaling and diminished microvascular circulation in the myocardium. Supported by NIH grant AI 072726 to MA

Background: Kawasaki Disease (KD) is the leading cause of acquired heart disease in the US. We have demonstrated the critical role of innate immune responses via IL-1R/MyD88 signaling in the Lactobacillus casei cell wall extract (LCWE)-induced KD mouse model. The diversity and composition of microflora (both bacterial and fungal) have been associated with the regulation and alterations of immune responses and various pathologies. However, the role of gut microbiota in immunopathology of KD has not been investigated. Objective: To evaluate the role of gut microflora in development of coronary arteritis, and vascular abnormalities in KD mouse model. Methods and Results: We investigated the role of gut microflora in the LCWE-induced KD mouse model, using Specific-Pathogen Free (SPF) and Germ Free (GF) mice (C57BL/6). GF mice showed a significant decrease of KD lesions, including coronary arteritis compared with SPF mice. The development of LCWE-induced AAA, which we recently discovered in this mouse model, was also markedly diminished in GF mice. In addition to GF mice, we also investigated the specific role of commensal fungi, and determined whether altered fungal burden in this KD mouse model contributes to disease severity. To deplete fungi in the gut microflora, we exposed pregnant SPF mice and their offspring to fluconazole (antifungal) in their drinking water for 5 wks and induced KD. The fluconazole treated mice had significantly reduced coronary arteritis, and AAA compared to controls. Since Dectin-1 has emerged as a key receptor that recognizes β-1,3-glucans found in the cell wall of nearly all fungi, we next induced KD in Dectin-1 deficient mice. Dectin-1 deficient mice also had significantly reduced KD lesions such as coronary arteritis compared with WT mice. Conclusions: We demonstrate here that gut microflora play a critical role in the development of KD vasculitis in LCWE-induced mouse model. Our results suggest that fungi in the intestinal microbiota may specifically control the induction and severity of KD vasculitis, which may be mediated by Dectin-1. These findings provide a new perspective on the potential role of the microbiome in KD pathogenesis and may offer new diagnostic and therapeutic strategies for KD patients.

Guidelines for medical treatment of acute Kawasaki disease: report of the Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery (2012 revised version).

Increased plasma adrenomedullin levels in kawasaki disease with coronary artery involvement

1. Alexander K.C. Leung, MD* 2. Consolato Maria Sergi, MD† 3. Kin Fon Leong, MD‡ 4. Paul F. Kantor 5. MD§ 1. *Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada 2. †Departments of Pediatrics, Laboratory Medicine, and Pathology, University of Alberta, Edmonton, Alberta, Canada 3. ‡Pediatric Institute, Kuala Lumpur General Hospital, Kuala Lumpur, Malaysia 4. §Division of Cardiology, Department of Pediatrics, University of Southern California, Los Angeles, CA A 3-year-old Chinese boy presents with high spiking fevers of 5 days' duration despite treatment with acetaminophen. He has cracked red lips, a widespread maculopapular rash, and bilateral nonpurulent conjunctival injection. There is no history of joint pain, vomiting, abdominal pain, or diarrhea. The medical history is otherwise normal. On examination the child is irritable. His temperature is 103.6°F (39.8°C), heart rate is 102 beats/min, respiratory rate is 27 breaths/min, and blood pressure is 95/60 mm Hg. He has a generalized blanching polymorphous maculopapular rash (Fig 1). The lips are cracked and erythematous. The bulbar conjunctiva is injected bilaterally with sparing of the limbus and without exudate. The tongue is strawberrylike. Perianal erythema and desquamation are noted (Fig 2). Marked erythema is noted on the lateral aspect of the left upper arm surrounding a previous Bacillus Calmette-Guerin (BCG) inoculation site (Fig 3). The hands and feet are erythematous and edematous (Figs 4 and 5). A sharp demarcation with an abrupt change to normal skin is noted at the wrists and ankles (Figs 4 and 5). A tender, nonfluctuant, freely mobile lymph node measuring 2×3 cm is palpable in the left anterior cervical area. The remaining examination findings are normal. Figure 1. A maculopapular rash over the trunk. Also noted in the picture are cracked red lips. Figure 2. Characteristic perianal desquamation. Figure 3. Erythema is surrounding a Bacillus Calmette-Guerin inoculation site. Figure 4. Erythema and indurated edema of the right foot. Figure 5. Erythema and indurated edema of the left hand. Note the sharp demarcation with an abrupt change to healthy skin. Laboratory findings are as follows: white blood cell count, …

Kawasaki Disease (KD) affects young children less than five years old with severe blood vessel inflammation. Despite being treatable, the causes and mechanisms remain elusive. This study conducted a meta-analysis of RNA sequencing (RNA-seq) data from human and animal models to explore KD's transcriptomic profile and evaluate animal models. We retrieved bulk and single-cell RNA-seq data from Gene Expression Omnibus, with blood and coronary artery samples from KD patients, aorta samples from KD mouse models (Lactobacillus casei cell wall extract-injected mice), and their controls. Upon consistent quality control, we applied Fisher's exact test to assess differential gene expression, followed by an enrichment analysis of overlapping genes. These studies identified 400 differentially expressed genes in blood samples of KD patients compared to controls and 413 genes in coronary artery samples. The data from KD blood and KD coronary artery samples shared only 16 differentially expressed genes. Eighty-one genes overlapped between KD human coronary arteries and KD mouse aortas, and 67 of these 81 genes were regulated in parallel in both humans and mice: 30 genes were up-regulated, and 37 were down-regulated. These included previously identified KD-upregulated genes: CD74, SFRP4, ITGA4, and IKZF1. Gene enrichment analysis revealed significant alterations in the cardiomyopathy pathway. Single-cell RNAseq showed a few significant markers, with known KD markers like S100A9, S100A8, CD74, CD14, IFITM2, and IFITM3, being overexpressed in KD cohorts. Gene profiles obtained from KD human coronary artery are more compatible with data from aorta samples of KD mice than blood samples of KD humans, validating KD animal models for identifying therapeutic targets. Although blood samples can be utilized to discover novel biomarkers, more comprehensive single-cell sequencing is required to detail gene expression in different blood cell populations. This study identifies critical genes from human and mouse tissues to help develop new treatment strategies for KD.

Index of suspicion.

Background: Kawasaki disease (KD) is the most common cause of acute systemic vasculitis and acquired cardiac disease among US children. KD causes coronary artery aneurysms in up to 25% of untreated patients, and less frequently aneurysms in other systemic arteries including the abdominal aorta. Lactobacillus casei cell wall extract (LCWE)-induced KD mouse model mimics histopathologically the coronary artery lesions seen in KD patients. Objective: To evaluate the development of abdominal aorta dilatation and aneurysm in KD mouse model and investigate the role of IL-1 signaling. Methods and Results: We investigated the incidence and progression of abdominal aorta aneurysm (AAA) and dilatation in the KD model at 1, 2, 5 weeks. Over 80% of the mice developed significant dilation of abdominal aorta at 2 wks with progressively greater dilatation at 5 wks, with greater severity in males. KD mice showed fusiform and saccular AAA, which were always below the renal artery. Immunohistochemistry showed significant intimal proliferation, massive myofibroblastic proliferation that breaks the elastin layer, infiltration of large numbers of neutrophils and macrophages into the media and adventitia. IL-1R- or IL-1beta-deficient mice were completely protected from the KD associated abdominal aorta dilatation and AAA. IL-1R antagonist (Anakinra) significantly prevented the abdominal aorta dilatation and AAA (in addition to blocking coronary arteritis) in the KD mice. Conclusions: We report a new model of AAA and aortic dilatation in the LCWE-induced KD mouse model. These studies suggest that in children with KD the incidence of abdominal aortic dilatation and AAA maybe higher than currently appreciated, thus requiring prospective studies to determine the frequency of these vascular complications. Our findings also demonstrate that IL-1 plays an important role in development of LCWE-induced abdominal aortic lesions and blockade of IL-1 signaling may be a promising therapeutic target not only for KD vasculitis and coronary arteritis, but also for abdominal aorta dilatation and AAA associated with the disease.