Kawasaki Disease in India, Lessons Learnt Over the Last 20 Years.

Over the last 20 years, Kawasaki disease is being increasingly recognized in India and it may soon replace acute rheumatic fever to become the commonest cause of acquired heart disease amongst children. However, the vast majority of children with Kawasaki disease in India are still not being diagnosed. Diagnosis of Kawasaki disease is based on a constellation of clinical findings which have a typical temporal sequence. All pediatricians must we familiar with the nuances involved in arriving at a diagnosis of Kawasaki disease. With early diagnosis and prompt treatment, the risk of coronary artery abnormalities can be significantly reduced.

Variations in ORAI1 Gene Associated with Kawasaki Disease.

Kawasaki disease (KD; MIM#61175) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD suggest possible involvement of the Ca(2+)/NFAT pathway in the pathogenesis of KD. ORAI1 is a Ca(2+) release activated Ca(2+) (CRAC) channel mediating store-operated Ca(2+) entry (SOCE) on the plasma membrane. The gene for ORAI1 is located in chromosome 12q24 where a positive linkage signal was observed in our previous affected sib-pair study of KD. A common non-synonymous single nucleotide polymorphism located within exon 2 of ORAI1 (rs3741596) was significantly associated with KD (P = 0.028 in the discovery sample set (729 KD cases and 1,315 controls), P = 0.0056 in the replication sample set (1,813 KD cases vs. 1,097 controls) and P = 0.00041 in a meta-analysis by the Mantel-Haenszel method). Interestingly, frequency of the risk allele of rs3741596 is more than 20 times higher in Japanese compared to Europeans. We also found a rare 6 base-pair in-frame insertion variant associated with KD (rs141919534; 2,544 KD cases vs. 2,414 controls, P = 0.012). These data indicate that ORAI1 gene variations are associated with KD and may suggest the potential importance of the Ca(2+)/NFAT pathway in the pathogenesis of this disorder.

Cardiac lesions and initial laboratory data in Kawasaki disease: a nationwide survey in Japan.

BACKGROUND: Cardiac lesions, such as coronary dilatation, aneurysms, narrowing, myocardial infarction, and valvular lesions, sometimes occur in Kawasaki disease, but most studies have only evaluated cardiac lesions in the later phase of the disease. This study was undertaken to clarify the related factors between cardiac lesions and laboratory data in the initial phase of Kawasaki disease. METHODS: We conducted a cross-sectional study using data for 26 691 patients from the 22nd nationwide survey of Kawasaki disease in Japan, the observation period of which was from January 2011 through December 2012. We excluded patients with recurrent Kawasaki disease and who were more than seven days from the start of symptoms at admission. We analyzed 23 155 cases (13 353 boys; mean age: 923 ± 734 days) with available laboratory data for white blood cell count, platelet count, serum albumin, and C-reactive protein (CRP). RESULTS: Cardiac lesions were detected in 984 cases (656 boys and 328 girls); lesions were classified as coronary dilatation (764 cases), coronary aneurysm (40), giant coronary aneurysm (6), coronary narrowing (3), and valvular lesions (204). The significant related factors of initial coronary dilatation were male sex (odds ratio [OR] 1.73), older age (OR per 100 days increase 1.03), higher platelet count (OR per 10 000 cells/µL increase 1.006), lower albumin (OR per 1 g/dL increase 0.66), and higher CRP (OR per 1 mg/dL increase 1.02). The factors related to coronary aneurysm were higher platelet count (OR 1.01) and lower albumin (OR 0.34). No factors were significantly related to giant coronary aneurysm. The related factors of valvular lesions were age (OR 0.98), and higher CRP (OR 1.05). CONCLUSIONS: Clinicians should consider male sex, older age, higher platelet count, lower albumin levels, and higher CRP levels when assessing risk of cardiac lesions in the initial phase of Kawasaki disease.

History of Kawasaki disease.

We describe a short history of Kawasaki disease. In 1967, we published a paper entitled 'Infantile acute febrile mucocutaneous lymph node syndrome with specific desquamation of the fingers and toes. Clinical observation of 50 cases'; this was the first report on what is now called Kawasaki disease. Since then, many reports on cardiology, treatment, epidemiology, pathology and etiology of Kawasaki disease have been published. Furthermore, a recent Chapel Hill Consensus Statement on Kawasaki disease in the classification of vasculitis is given, along with a figure on the relationship and classification of childhood vasculitis by autopsy material.

Kawasaki disease and the emerging coronary artery disease epidemic in India: is there a correlation?

Although Kawasaki disease (KD) is now being increasingly reported from India, the vast majority of children with KD are still not being diagnosed and treated. A recent study from Chandigarh has shown that the incidence of KD is at least 4.54/100,000 children below 15 y of age. Extrapolations of this figure suggest that a minimum of 17,417 new cases of KD would be occurring every year in our country. A significant proportion of these children may develop coronary artery abnormalities. These children would then be at risk of developing myocardial ischemia as young adults. It is authors' contention that (undiagnosed) KD in childhood may be contributing to the growing pool of coronary artery disease (CAD) in India. Similarly, a missed diagnosis of KD in childhood should be considered as a possibility while evaluating adults with CAD, especially when there are no overt risk factors and no family history of the disease.

Sudden death as a late sequel of Kawasaki disease: postmortem CT demonstration of coronary artery aneurysm.

Kawasaki disease (KD) is an acute, self-limited vasculitis of unknown etiology that primarily affects the coronary artery (CA) and presents during childhood. The characteristic coronary arterial lesion of KD is an aneurysm. Ischemic heart disease derived from a CA aneurysm is experienced approximately two decades after the onset of acute KD. In recent years, the primary issue of concern has been asymptomatic adults with a CA aneurysm caused by undiagnosed KD. We present a case of sudden death as a late KD sequel in a young adult. A postmortem CT scan revealed a coarse calcification of a left anterior descending CA aneurysm, which was confirmed at the time of autopsy. A postmortem CT scan is useful in cases of sudden death where the detection of a calcified CA aneurysm would suggest to the forensic pathologist that the deceased suffered from a late sequel of KD. The use of screening postmortem CT scans for young people may detect cases of unsuspected CA aneurysms, raising the possibility of untreated KD.

Kawasaki disease in Mongolia: results from 2 nationwide retrospective surveys, 1996-2008.

BACKGROUND: Kawasaki disease (KD) has been reported in many countries. However, the incidence of KD in Mongolia is not known. This is the first report of incident cases of KD in Mongolia, which were identified using data from 2 nationwide surveys. METHODS: Two nationwide retrospective surveys were conducted: medical histories were collected from patients aged 0 to 16 years who were hospitalized countrywide between 1996 and 2008. Hospital records for these patients were also reviewed. Nationwide training seminars on KD were conducted before each survey. RESULTS: For the nationwide surveys, the participation rates among all hospitals with pediatric wards were 97% and 94%. Inpatient medical histories from 1996 through 2008 were reviewed, and, among children younger than 16 years, 9 patients with KD were investigated. The age of KD patients ranged from 1.4 to 14 years; 7 of 9 patients were male. Six (67%) patients fulfilled all 6 clinical diagnostic criteria; the other 3 (33%) were defined as having KD based on the presence of 5 such criteria. Fever persisting 5 or more days, bilateral conjunctival congestion, and changes of the lips and oral cavity were the most common symptoms, and cervical lymphadenopathy was the least common symptom. Cardiac sequelae developed in 5 of the patients, 4 of whom were older than 10 years. CONCLUSIONS: The results of these nationwide surveys reveal that KD cases do exist in Mongolia. However, knowledge of KD among Mongolian pediatricians is likely to be poor. Thus, there is a need to augment their understanding to improve management of KD patients. Further studies are crucial to clarify the epidemiologic characteristics of KD in Mongolia.

Common variants in CASP3 confer susceptibility to Kawasaki disease.

Kawasaki disease (KD; OMIM 611775) is an acute vasculitis syndrome which predominantly affects small- and medium-sized arteries of infants and children. Epidemiological data suggest that host genetics underlie the disease pathogenesis. Here we report that multiple variants in the caspase-3 gene (CASP3) that are in linkage disequilibrium confer susceptibility to KD in both Japanese and US subjects of European ancestry. We found that a G to A substitution of one commonly associated SNP located in the 5' untranslated region of CASP3 (rs72689236; P = 4.2 x 10(-8) in the Japanese and P = 3.7 x 10(-3) in the European Americans) abolished binding of nuclear factor of activated T cells to the DNA sequence surrounding the SNP. Our findings suggest that altered CASP3 expression in immune effecter cells influences susceptibility to KD.

Kawasaki disease - an Indian perspective.

Kawasaki disease (KD) was first reported from Japan in 1967 by a young pediatrician, Tomisaku Kawasaki, while working at the Red Cross Hospital in Tokyo. Soon therafter, Marian Melish independently reported children with a similar clinical profile from Hawaii in the United States. KD has now been reported from all parts of the world, including several centers in India. Based on the epidemiology and clinical features, an infectious etiology has been suspected for long but no definitive causative agent has been implicated so far. Like many other vasculitides, the diagnosis of this condition is based on the recognition of a temporal sequence of clinical features, none of which is pathognomonic in isolation. KD is believed to be the commonest vasculitic disorder of children. Incidence rates as high as 60-150 per 100,000 children below 5 years of age have been reported from several countries. In India (as also perhaps in many other developing countries), however, majority of children with KD continue to remain undiagnosed probably because of the lack of awareness amongst pediatricians. The clinical features of KD can be confused with other common conditions like scarlet fever and the Stevens Johnson syndrome, if the clinician is not careful. Development of coronary artery abnormalities (CAA) is the hallmark of KD and accounts for most of the morbidity and mortality associated with the disease. Prompt recognition of the disease and early initiation of treatment with intravenous immunoglobulin (IVIG) results in significant reduction in the occurrence of CAA. It is, therefore, imperative for the pediatrician to diagnose and treat KD expeditiously. KD should be considered in the differential diagnosis of all febrile illnesses in young children where the fever persists for more than 5-7 days.

[Recognition of KD].

Ten years after starting my pediatric career at the Japanese Red Cross Central Hospital (now Japanese Red Cross Medical Center) in Tokyo, I examined on January 5, 1961, a 4 year-3 month old boy, with curious clinical symptom-complex I had never experienced. This patient was a typical Kawasaki disease patient. But at that time I was unable to make a diagnosis. In February 1962, a case of suspected sepsis was referred to me from a neighboring doctor. After admitting the child into the hospital, the patient had a similar clinical course as the previous patient. I realized that there were 2 patients with similar unique clinical symptom complexes that did not exist in any medical reference book. From March to September 1962, I was able to see 5 patients who fell into the same category. In 1967, I published my original article entitled, "Infantile Acute febrile Muco-cutaneous lymph node syndrome: clinical observations of 50 cases".

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.

A genomewide linkage analysis of Kawasaki disease: evidence for linkage to chromosome 12.

Kawasaki disease (KD) is an acute systemic vasculitis syndrome that primarily affects infants and young children. The cause of KD is largely unknown, but its higher incidence in the Asian population and increased risk in patients' families suggests the existence of underlying genetic factors. To determine the loci of a susceptibility gene for KD, a genomewide linkage analysis with affected sib pairs was performed on 78 family samples collected from all over Japan. Multipoint linkage analysis using MAPMAKER/SIBS 2.0 identified evidence of linkage on 12q24 [maximum lod score (MLS) = 2.69]. Possible linkage (MLS > 1.0) was also found on 4q35, 5q34, 6q27, 7p15, 8q24, 18q23, 19q13, Xp22, and Xq27. This is the first large-scale study of the genetic susceptibility to KD, and our results, combined with the accumulated knowledge of the human genome, could greatly promote research on identification of the molecular pathogenesis of KD.

Epidemiologic pictures of Kawasaki disease in Shanghai from 1998 through 2002.

BACKGROUND: Epidemiologic features of Kawasaki disease in China is still not clear. METHODS: A questionnaire form and diagnostic guidelines for Kawasaki disease were sent to hospitals in Shanghai, which provided with pediatric medical care. All patients with Kawasaki disease diagnosed during January 1998 through December 2002 were recruited in this study. RESULTS: A total of 768 patients with Kawasaki disease were reported. The incidence rates of Kawasaki disease for each year were 16.79 (1998), 25.65 (1999), 28.16 (2000), 28.05 (2001), and 36.76 (2002) per 100,000 children under 5 years of age. The male/female ratio was 1.83:1. The age at onset ranged from 1 month to 18.8 years (median: 1.8 years). The disease occurred more frequently in spring and summer. Fever was the most common clinical symptom, followed by oral changes, extremities desquamate, rash, conjunctive congestion, lymphadenopathy, extremities swelling, and crissum desquamate. Cardiac abnormalities were found in 24.3% of patients. The most common cardiac abnormality was coronary artery lesions including dilatation (68%) and aneurysm (10%). The case-fatality rate at acute stage of the disease was 0.26%. A second onset of the disease occurred in 1.82% of patients. CONCLUSIONS: The incidence rate of Kawasaki disease in Shanghai is lower than that reported in Japan, but higher than those in western countries. The increasing trend in incidence, sex distribution and cardiac abnormalities are similar to those in previous reports. The seasonal distribution is similar to the report from Beijing and different from other reports.

Kawasaki disease.

Short history of Kawasaki disease, clinical features (principal symptoms and other significant symptoms or findings), diagnosis, cardiovascular involvement, epidemiology. Pathological features (lesion of vessels and lesion of organs exclusive of vessels), comparison between infantile periarteritis nodosa (IPN)/Kawasaki disease and classic periarteritis nodosa (CPN), etiology, treatment and management of Kawasaki disease are described.

Mortality among persons with a history of Kawasaki disease in Japan: can paediatricians safely discontinue follow-up of children with a history of the disease but without cardiac sequelae?

AIM: To clarify the question of whether patients with Kawasaki disease suffer a higher mortality rate after the incidence of the disease in comparison with age-matched healthy individuals. METHODS: Between July 1982 and December 1992, 52 collaborating hospitals collected data on all patients having a new, definite diagnosis of Kawasaki disease. Patients were followed up until 31 December 2001 or their death. The expected number of deaths was calculated from Japanese vital statistics data and compared with the observed number. RESULTS: Of 6576 patients enrolled, 29 (20 males and 9 females) died. The standardized mortality ratio (SMR: the observed number of deaths divided by the expected number of deaths based on the vital statistics in Japan) was 1.15 (95% CI: 0.77-1.66). In spite of the high SMRs during the acute phase, the mortality rate was not high after the acute phase for the entire group of patients. Although the SMR after the acute phase was 0.75 for those without cardiac sequelae, six males (but none of the females) with cardiac sequelae died during this period; and the SMR for the male group with cardiac sequelae was 1.95 (95% CI: 0.71-4.25). The mortality from congenital anomalies of the circulatory system was elevated, but no increase in cancer deaths was observed. CONCLUSION: Although it was not statistically significant, the mortality rate among males with cardiac sequelae due to Kawasaki disease appeared to be higher than in the general population. On the other hand, the mortality rates for females with the sequelae and both males and females without sequelae were not elevated.

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.

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.