Tomisaku Kawasaki

ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms

Kawasaki disease is a pediatric systemic vasculitis of unknown etiology for which a genetic influence is suspected. We identified a functional SNP (itpkc_3) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 that is significantly associated with Kawasaki disease susceptibility and also with an increased risk of coronary artery lesions in both Japanese and US children. Transfection experiments showed that the C allele of itpkc_3 reduces splicing efficiency of the ITPKC mRNA. ITPKC acts as a negative regulator of T-cell activation through the Ca2+/NFAT signaling pathway, and the C allele may contribute to immune hyper-reactivity in Kawasaki disease. This finding provides new insights into the mechanisms of immune activation in Kawasaki disease and emphasizes the importance of activated T cells in the pathogenesis of this vasculitis.

Myocardial infarction in Kawasaki disease: Clinical analyses in 195 cases

We analyzed clinical data from 195 patients (141 boys) with myocardial infarction complicating Kawasaki disease, collected from 74 major hospitals in Japan. The myocardial infarction usually occurred within the first year of illness, but 27.2% of the patients had myocardial infarction more than 1 year later. In 63% of the patients it occurred during sleep or at rest. The main symptoms of acute myocardial infarction were shock, unrest, vomiting, abdominal pain, and chest pain; chest pain was much more frequently recognized in the survivors and in older patients. The myocardial infarctions were asymptomatic in 37% of the patients. Twenty-two percent of the patients died during the first attack. Sixteen percent of the survivors of a first attack had a second attack. Forty-three percent of all survivors of the first or subsequent attack are doing well; however, others have some type of cardiac dysfunction, such as mitral regurgitation, decreased ejection fraction of the left ventricle, or left ventricular aneurysm. Coronary angiographic studies indicate that in most of the fatal cases there was obstruction either in the main left coronary artery or in both the main right coronary artery and the anterior descending artery. In survivors, one-vessel obstruction was frequently recognized, particularly in the right coronary artery.

Sequelae of Kawasaki disease in adolescents and young adults

Kawasaki disease is an acute vasculitis of unknown etiology that predominantly affects children <5 years of age. Structural damage to the coronary arteries after the acute, self-limited illness is detected by echocardiography in approximately 25% of untreated patients. The long-term effects of the acute coronary arteritis are unknown. To define the spectrum of clinical disease in young adults that can be attributed to Kawasaki disease in childhood, we performed a retrospective survey of cases reported in the English and Japanese published data of adult coronary artery disease attributed to antecedent Kawasaki disease. The mean age at presentation with cardiac sequelae was 24.7 +/- 8.4 years (range 12 to 39) for the 74 patients identified with presumed late sequelae of Kawasaki disease. Symptoms at the time of presentation with cardiac sequelae included chest pain/myocardial infarction (60.8%), arrhythmia (10.8%) and sudden death (16.2%). These symptoms were precipitated by exercise in 82% of patients. One-third of the patients in whom a chest radiograph was taken had ring calcification. Angiographic findings included coronary artery occlusion (66.1%). Extensive development of collateral vessels was reported in 44.1% of patients. Autopsy findings included coronary artery aneurysms (100%) and coronary artery occlusion (72.2%). The acute vasculitis of Kawasaki disease can result in coronary artery damage and rheologic changes predisposing to thrombus formation or progressive atherosclerotic changes that may remain clinically silent for many years. Coronary artery aneurysms and calcification on chest radiography were unusual features in this group of patients. A history of antecedent Kawasaki disease should be sought in all young adults who present with acute myocardial infarction or sudden death.

Lymphocyte Subsets Identified by Monoclonal Antibodies in Healthy Children

ABSTRACT: The distributions of lymphocyte subsets and monocytes in the peripheral blood mononuclear leukocytes of 72 normal children from 2 months to 135/12 yr were examined using quantitative immunofluorescence analysis with monoclonal antibodies. Distinct decreases with age were found in the total leukocyte counts, the percentages and the absolute numbers of peripheral blood mononuclear leukocytes. The percentages of Leu-2a+ cells, Leu-7+ cells, and Leu-M3+ cells significantly increased with age, whereas the percentages of Leu-3a+ cells, Leu-4+ cells, and 2H7+ cells significantly decreased with age. As a result, ratios of Leu-3a+/Leu-2a+ decreased with age. No prominent differences with age were found in the proportions of Leu-10+ cells and HLA-DR+ cells.

Seasonality and Temporal Clustering of Kawasaki Syndrome

Background: The distribution of a syndrome in space and time may suggest clues to its etiology. The cause of Kawasaki syndrome, a systemic vasculitis of infants and children, is unknown, but an infectious etiology is suspected. Methods: Seasonality and clustering of Kawasaki syndrome cases were studied in Japanese children with Kawasaki syndrome reported in nationwide surveys in Japan. Excluding the years that contained the 3 major nationwide epidemics, 84,829 cases during a 14-year period (1987–2000) were analyzed. To assess seasonality, we calculated mean monthly incidence during the study period for eastern and western Japan and for each of the 47 prefectures. To assess clustering, we compared the number of cases per day (daily incidence) with a simulated distribution (Monte Carlo analysis). Results: Marked spatial and temporal patterns were noted in both the seasonality and deviations from the average number of Kawasaki syndrome cases in Japan. Seasonality was bimodal with peaks in January and June/July and a nadir in October. This pattern was consistent throughout Japan and during the entire 14-year period. Some years produced very high or low numbers of cases, but the overall variability was consistent throughout the entire country. Temporal clustering of Kawasaki syndrome cases was detected with nationwide outbreaks. Conclusions: Kawasaki syndrome has a pronounced seasonality in Japan that is consistent throughout the length of the Japanese archipelago. Temporal clustering of cases combined with marked seasonality suggests an environmental trigger for this clinical syndrome.

Detection of antigen in bronchial epithelium and macrophages in acute Kawasaki disease by use of synthetic antibody

BACKGROUND Kawasaki disease (KD) is the most common acquired cardiac disease in children in developed nations. The etiology is unknown, but a ubiquitous infectious agent appears to be likely. Immunoglobulin A plasma cells infiltrate inflamed tissues in acute KD, producing oligoclonal, antigen-driven antibodies. METHODS To identify antigens important in the pathogenesis of KD, oligoclonal KD antibodies were prepared in vitro and tested by immunohistochemistry experiments on tissues from patients with acute KD and from control subjects and were also tested for reactivity with human inflammatory proteins. RESULTS By use of synthetic antibody A, specific binding to a cytoplasmic antigen in proximal bronchial epithelium was observed in 10 of 13 patients with acute KD but in 0 of 9 control subjects (P=.001). A subset of macrophages was positive in at least 1 inflamed tissue from all 17 patients with acute KD. Antigen was detected in 9 of 12 acute KD coronary artery aneurysms but in 0 of 10 control coronary arteries (P<.001). The antigen is not immunoglobulin or any of 40 common inflammatory proteins. CONCLUSIONS We report the first demonstration of a KD-associated antigen in the tissues targeted by the disease. Our findings are consistent with the theory that KD is caused by a previously unidentified respiratory infectious agent with tropism for vascular tissue.

Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease

Over 35 years have elapsed since the first case of Kawasaki disease was described in 1967. 1 As they grow older, many patients with a history of Kawasaki disease are treated in departments of internal medicine rather than in pediatric departments. This disease has been extensively studied throughout the world, and many reports have been published on its etiology and cardiovascular sequelae. While the causes of Kawasaki disease unfortunately remain unknown, its cardiovascular sequelae have been intensively studied, contributing to the establishment of their pathology, natural history, diagnosis, and treatment. This provided the impetus for the Japanese Circulation Society to prepare a set of guidelines. The latest guidelines for the diagnosis of Kawasaki disease, as revised in 2002, are shown in Table 1. These are used to diagnose the disease in its acute phase. The diagnostic guidelines may be useful in adults with an unknown history of Kawasaki disease when the illness is suspected from the morphology of any coronary artery aneurysms. In preparing the present guidelines for the cardiovascular sequelae of Kawasaki disease, the first issue addressed was the classification of the size and severity of coronary artery aneurysms using standardized criteria. The consensus criteria shown in Table 2 were prepared according to the conventional classification and the opinions of specialists.

NATIONWIDE EPIDEMIC OF KAWASAKI DISEASE IN JAPAN DURING WINTER OF 1985-86

Surveillance data on Kawasaki disease from 148 representative hospitals throughout Japan revealed a third nationwide epidemic of Kawasaki disease in Japan in November, 1985. The peak number of cases was at least 4.5 times greater than that observed in the preceding year. This epidemic wave spread from central Japan to the entire nation within six months.

CD40 ligand gene and Kawasaki disease.

Kawasaki disease (KD) is an acute systemic vasculitis syndrome of infants and young children. Although its etiology is largely unknown, epidemiological findings suggest that genetic factors play a role in the pathogenesis of KD. To identify genetic factors, affected sib-pair analysis has been performed. One of the identified peaks was located on the Xq26 region. A recent report of elevated expression of CD40 ligand (CD40L), which maps to Xq26, during the acute-phase KD, and its relationship to the development of coronary artery lesions (CAL) prompted us to screen for polymorphism of CD40L and to study the association of the gene to KD. A newly identified SNP in intron 4 (IVS4+121 A>G) is marginally over-represented in KD patients as compared to controls (109/602, 18.1 vs 111/737, 15.1%). When male KD patients with CAL were analyzed as a patient group, the SNP was significantly more frequent than in controls (15/58, 25.9%, vs 111/737, 15.1%, OR=2.0, 95% CI=1.07–3.66; P=0.030). Interestingly, this variation was extremely rare in a control Caucasian population (1/145, 0.7%). Our results suggest a role of CD40L in the pathogenesis of CAL and might explain the excess of males affected with KD.

Mortality among Children with Kawasaki Disease in Japan

BACKGROUND AND METHODS It is not certain whether patients with Kawasaki disease have a higher death rate than the age-matched healthy population. We therefore undertook a study to investigate this question. Between July 1982 and December 1988, 53 collaborating treatment centers collected data on all patients who had an unequivocal new diagnosis of Kawasaki disease; patients who had recurrent disease or whose first visit to the treatment center occurred more than 14 days after the onset of symptoms were excluded. Patients were followed from the time of the first visit to the treatment center until December 31, 1989, or until death, whichever occurred first. The expected number of deaths was calculated from Japanese vital-statistics data and compared with the number observed. RESULTS Of 4676 patients who met the eligibility criteria, 4608 (98.5 percent) were followed through either the end of the study or the date of death. Thirteen patients (10 boys and 3 girls) died during the study period. The number of deaths expected was 7.61 (ratio of observed to expected deaths, 1.71; 95 percent confidence interval, 0.91 to 2.92). The ratio was 2.04 (95 percent confidence interval, 0.98 to 3.76) for boys and 1.11 (95 percent confidence interval, 0.23 to 3.23) for girls. During the acute phase of the disease (the first two months after onset), the ratios of observed to expected deaths were higher: 9.86 overall (95 percent confidence interval, 3.95 to 20.31), 13.33 for boys (95 percent confidence interval, 4.89 to 29.07), and 3.85 for girls (95 percent confidence interval, 0.10 to 21.42). After the acute phase, however, both sexes had ratios of observed to expected deaths that were lower than 1, and the difference from the control population was not statistically significant. CONCLUSIONS The mortality rate among boys with Kawasaki disease in Japan is twice that among healthy boys of the same age, and most deaths occur within two months of diagnosis. The mortality rate among girls with the disease appears similar to that among healthy girls, although the numbers are very small.