key: cord-0037028-laku458z
authors: Mason, Wilbert
title: Epidemiology and etiology of Kawasaki disease
date: 2007
journal: Pediatric Infectious Diseases Revisited
DOI: 10.1007/978-3-7643-8099-1_10
sha: 415d631abafb711b3943496cb7e2851338a184a7
doc_id: 37028
cord_uid: laku458z

Kawasaki disease was first reported in Japan in 1967 by Dr. Tomisaku Kawasaki. It has since been recognized worldwide, and in at the United States and Japan is the most important cause of acquired heart disease in children, surpassing other more recognized conditions such as rheumatic fever, endocarditis and myocarditis. It is primarily a disease of children less than 5 years of age but has been reported in older children and adults. Risk factors for the illness include Asian ancestry, male gender and certain familial predispositions. Observations such as similarity to certain exanthematous infectious diseases, temporal-geographic clustering of cases and seasonality in incidence favors an infectious etiology. Pathology and pathogenesis of the disease indicate that it is a medium-sized artery vasculitis that results from a dramatic immune activation that in most cases reversed by immune modulating agents such as intravenous immunoglobulin. Unfortunately, the etiology of the illness remains obscure, although recent studies favor a possible viral etiology.

Doctor Tomisaku Kawasaki first described Kawasaki disease (KD) in 1967 based on 50 cases he had observed over the preceding 6 years at the Tokyo Red Cross Hospital [1] . He termed the illness mucocutaneous lymph node syndrome because of characteristic changes of the mucous membranes and skin, which seemed to characterize the illness. During the first few years following its description, it appeared to be a self-limited disease without sequelae. However, following the first nationwide survey of the illness in Japan in 1970, sudden death due to coronary artery disease was firmly linked to the illness [2]. KD was independently described in the United States in 1974 by Melish and colleagues [3] , and following consultation with Dr. Kawasaki , there was agreement that the illnesses were clinically the same. Following the recognition of cardiac complications in both Japan and the United States, pathologists in both countries observed similarities between coronary artery lesions seen in KD patients and those in patients who had died of infantile periarteritis nodosa (IPN), a rare vasculitis of infancy [3] . The question arose as to whether the two were the same disease. The issue was resolved by Landing and Larson in 1976 [4] , who performed blinded evaluations of autopsy cases of children from both Japan and the United States who had died with a diagnosis of KD and IPN. They found that the two illnesses were pathologically indistinguishable.

In subsequent years KD has been recognized worldwide, and in all age groups, although 85% of cases occur in children < 5 years of age. It is now recognized as the most common cause of acquired heart disease in children in the United States.

We attempt here to describe the current understanding of the epidemiology of KD and the most recent findings regarding its pathogenesis and etiology.

The diagnostic criteria described by Dr. Kawasaki have been used, with some modification, since the original description of the disease [5] (Tab. 1). Children with four or more principal criteria and at least 4 days of fever can be diagnosed on day 4. If fewer than four principal criteria are observed, KD may be diagnosed with the appearance of coronary artery abnormalities (CAA). With increasing experience, it became apparent that a significant minority of infants and children were not identified by the classic diagnostic criteria. This was especially true for infants < 6 months of age who often presented with less than the required criteria in what became known as "atypical" or more properly "incomplete" KD. The most recent guidelines have included an algorithm for the evaluation of suspected incomplete KD that incorporates refined clinical assessment, laboratory tests and echocardiographic results into the diagnostic equation [5] (Fig. 1) .

Health, Labor and Welfare. Questionnaires were sent to hospitals with pediatric departments and a bed capacity of at least 100, or hospitals with a bed capacity of less than 100 beds but specializing in pediatrics. (3) Supplemental laboratory criteria include albumin 3.0 g/100 ml, anemia for age, elevation of alanine aminotransferase, platelets after 7 days 450 000/mm 3 , white blood cell count 15 000/mm 3 , and urine 10 white blood cells/high-power field. (4) Can treat before performing echocardiogram. (5) Typical peeling begins under nail bed of fingers and then toes. (6) Echocardiogram is considered positive for purposes of this algorithm if any of three conditions are met: z score of LAD or RCA 2.5, coronary arteries meet Japanese Ministry of Health criteria for aneurysms, or 3 other suggestive features exist, including perivascular brightness, lack of tapering, decreased LV function, mitral regurgitation, pericardial effusion, or z scores in LAD or RCA of 2-2.5. (7) If the echocardiogram is positive, treatment should be given to children within 10 d of fever onset and those beyond day 10 with clinical and laboratory signs (CRP, ESR) of ongoing inflammation. Taken from [5] . Copyright © 2004 American Heart Association.

During the most recent study period, 32 266 patients were reported with an annual incidence of 137.7 per 100 000 children < 5 years old in 1999 and 151.2 per 100 000 in 2002. The male to female ratio was 1.30 [6] . The annual incidence of KD in Japan has increased progressively from 1987 to 2002 from 73.8 to 151.2 per 100 000 < 5 years of age [6-10].

Over the 32-year period of surveillance, three nationwide epidemics of KD have been observed, in 1979, 1982 and 1986 [11] . The incidence rate in the last epidemic in 1986 was 176.8 per 100 000 children < 5 years of age. No national epidemic outbreaks have been reported since 1987 but regional outbreaks continue to occur.

Surveillance of KD in the United States is through passive reporting of cases to the Centers for Disease Control and Prevention, where a database has been maintained since 1984. Unfortunately, only a fraction of cases are identified through this system. More robust estimates of the incidence of KD has come from reports from regional investigators [12-14], surveys conducted by specialty societies and more recently through the use of administrative databases [15] of childhood hospitalizations.

Taubert [16] conducted surveys of 440 general hospitals with at least 400 beds that included a pediatric section and of 63 children's hospitals. The survey periods covered the years 1984-1987, 1988-1990 and 1991-1993 . During the latter period only the children's hospitals were surveyed. The surveys yielded rates of 7.6 cases per 100 000 children < 5 years of age and 9.2 cases per 100 000 for the first two periods. Following the third survey, the reported cases throughout the 10-year period were totaled and a minimum estimate of the annual rate for the period was calculated which was 8.9 cases per 100 000 children < 5 years of age. This rate was similar to rates found previously reported in regional studies [13, 14] .

More recently, investigators from the Centers for Disease Control and Prevention utilized data from a large inpatient database to determine incidence rates in the United States. The database was designed to generate robust national estimates of pediatric hospitalizations [15] . The rates were determined for the years 1997 and 2000, which were 17.6 per 100 000 < 5 years of age and 17.1 per 100 000 < 5 years, respectively. These rates were comparable to those determined from the regional studies using State health or health maintenance organization data [18] [19] [20] . Based on data from this study and others published previously during the decade, the authors concluded that incidence rate for KD in the United States had been stable.

A national epidemic of KD involving ten regions in the United States occurred between August 1984 and January 1985 [21] . Several other regional outbreaks have been reported over the years as well [16] . Similar incidence rates were reported from Canada based on a national health statistic data-base. From 1990-1991 to 1995-1996 the mean rates for children < 5 years across Canada were 13.8 per 100 000 children [22] .

KD has been reported from every continent and several island groups across the globe (Tab. 2). While the incidence rates in Japan remain the highest in the world, several other Asian nations have posted high rates as well. Several reports from China (Beijing [23] , Hong Kong [24] , Shanghai [25] ), Taiwan [26] and Korea [27] documented rates intermediate between those of Japan and North America (Tab. 3). All but Taiwan appeared to have increasing rates over the study periods.

Case reports or case series have been reported from many countries in Europe, Oceania, Africa and South Africa as well as other Asian countries (Tab. 2). Of those countries reporting incidence rates, only those from Ireland are comparable to those in North America [28] .

To summarize the global experience with KD, the highest incidence rates are found in Japan followed by Korea, China, North America and Europe. Local or regional outbreaks have been documented in both Japan and the United States, and national epidemics have been observed in both countries as well as Finland [29] . Incidence rates have trended upward in several countries and have remained stable in others. The effect of ascertainment bias on apparent increases in incidence is not known.

As suggest by higher incidence rates in Asian countries, KD occurs in higher frequency in Asian populations. Numerous studies from the Unites States have shown KD to be over-represented among Asian children [12, 14-16, 18, 19 ]. An interesting study of the epidemiology of KD in Hawaii dramatically demonstrated this predominance [30] . A retrospective analysis of the State Inpatient Database for Hawaii was performed for KD patients hospitalized during 1996 through 2001. Race classification provided by Census 2000 indicated race listed alone or in combination with other races. This race-specific numerators and denominators could be determined. The average annual incidence for KD was 45.2 per 100 000 children < 5 years of age, highest in the United States. Japanese-American children < 5 years had the highest incidence (197.7 per 100 000) followed by Native Hawaiian 

Most series from diverse geographic and racial populations have shown approximately 85% of children with KD are < 5 years of age [2]. Thus, incidences are expressed generally as a proportion of children < 5 years old. The most recent population-based study in the United States indicated 76% and 77% of patients were < 5 years of age in 1997 and 2000. The median age of KD patients in the United States is 2 years. In Japan, the peak age is 9-11 months and 88.9% of KD patients were < 5 years of age [6] .

KD is relatively uncommon in children < 6 months old and above 5 years of age [6, 15, [17] [18] [19] . Studies have suggested that CAA are more common in these two age groups possibly because the illness is less typical and thus diagnosis is delayed [6, [32] [33] [34] [35] [36] . While KD is overwhelmingly a disease of children, rare cases have been reported in adults [37] .

KD occurs in males more frequently than females [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] . Males are at greater risk of developing CAA as well [33] . In the United States the male: female ratio is 1.5:1 while in Japan it is 1.3:1.

In the United States, KD hospitalizations are more frequent in the winter months [16, 38] . The seasonality in Hawaii is less obvious, although fewer cases were seen during April through June [30] . In a 5-year period of active surveillance in San Diego County, California, KD incidence was inversely associated with average monthly temperature and positively associated with average monthly precipitation [39] . In Japan, excluding epidemic years, there appears to be a bimodal seasonal occurrence with peaks in January and early summer and a nadir in October [6, 40] . In China and Korea seasonal peaks appear to be more frequent in spring and summer [23, 26, 29] .

Temporal-geographic clustering has been frequently observed in both the United States [15, 32, 38, 41] and Japan [6, 40] . The Japanese experience has been especially well described with "hot spots" occurring in various prefectures on a rotating basis [6, 40] .

There appears to be an observable enhanced risk of KD within certain families. In Japan, there is a tenfold increased risk of the illness in siblings of an index case [42, 43] . Parents of children with KD are twice as likely to have had the disease as compared to the general population [42] . In families where parents had KD, sibling cases among children are significantly more common [44] . Similar findings have been reported from the United States [45] .

Recurrent cases of KD have been reported in both the United States and Japan [42, 46] . The estimated rate of recurrence in Japan is 3%, while that in the United States is < 1 to slightly over 1% [46, 47] .

KD patients in the United States come from families with a higher median household income and are more likely to have private insurance [15, 39] . An analysis of hospitalization costs for KD in the United States for children < 5 years of age showed that the median cost was $6189 [48] . The average annual total estimated cost associated with hospitalization for KD patients < 18 years of age was $38.6 million [48] .

Several other risk factors for KD have been reported in the past. An ante-cedent respiratory illness has been a significant association with KD patients as compared to controls in outbreak situations in the United States [32] .

Shampooing or spot-cleaning carpets within 30-45 days of onset of KD has been a risk factor in some studies but not others [49, 50] . Other factors associated with KD include use of a humidifier [49] , living near a body of water [38] and having preexisting eczema [51] .

KD is an acute self-limited illness of children that is characterized epidemiologically by seasonality and occurring in geographic clusters. It shares many clinical characteristics with known infectious diseases such as scarlet fever, toxic shock syndrome, measles and adenovirus infections. It has been associated with antecedent viral-like illnesses in some epidemic situations. All of these factors suggest an infectious etiological agent or agents as a cause. The relative rarity in the first 3 months of life (possibly due to maternal antibody) and peak occurrence early in childhood is another characteristic shared by many common childhood infections.

Host factors also appear to be important in the disease. Susceptibility to the disease is clearly influenced by ethnicity, familial risk factors and possibly preexisting conditions such as atopy. A genetic predisposition is suggested by these factors.

Finally, environmental influences cannot be ruled out as suggested by apparently recent emergence of the disease in the last half of the 20th century, a socioeconomic bias toward more affluent lifestyle, possibly climatic associations and less well established associations such as rug cleaning.

The exposure of a predisposed host to an infectious pathogen or pathogens with possible environmental contributing factors is a reasonable model to propose for KD.

Pathologically KD is a vasculitis of medium-sized vessels [52] . Studies from Japan have described four stages of pathology in the heart [53] (Tab. 4) . The classification was based on the careful evaluation of 20 hearts taken from patients who had died of KD. Stages were based on the duration of illness at the time of death. The pathological description is considered unique and is distinguished from other vasculitis in the "medium-sized vasculitis" group, polyarteritis nodosa, in that the arterial inflammation does not affect vessels smaller than arteries [52] . Prior to the introduction and the availability of intravenous immunoglobulin (IVIG) for treatment of KD, 20-25% of children developed coronary artery aneurysms as a sequela [2].

The vasculitis of KD is clearly immunologically mediated and a wide variety of immunoregulatory abnormalities have been documented during the acute phase [54] . In a study of 21 children in the acute phase of KD, Leung and colleagues [54, 55] demonstrated a significant reduction in circulatory T8-positive (T8 + ) suppressor-cytotoxic T cells, increased activated T4 + helper cells and a proliferation of circulating activated B cells spontaneously secreting IgG and IgM. Furukawa et al. [56] , in Japan, demonstrated activation of CD23 + monocytes/macrophages in the peripheral blood of patients with acute KD.

Immunopotent cellular activation is associated with a broad array of proinflammatory cytokines including TNF- [57, 58] , IL-1 [59] , IFN- [60] and IL-6 [61] . These mediators undoubtedly contribute to the high fever, discomfort and inflammatory changes during the acute phase but also facilitate the vascular injury. Table 4 . Pathology of the heart in KD [52] Stage I (0-9 days):

Acute perivasculitis and vasculitis of microvessels (arterioles, capillaries and vessels) and small arteries Acute perivasculitis and end-arteritis of the three major coronary arteries (MCAs)

Inflammation of the atrioventricular conductor system Vascular endothelial cells become activated by cytokine stimulation and may induce or increase expression of endothelial cell surface antigens that promote functional changes such as leukocyte adhesion and antigen presentation. These changes may make endothelial cells more vulnerable to attack by cytotoxic IgM antibodies present in acute phase serum of KD [62] . Further evidence of immunological injury to coronary arteries derives from immunohistochemical studies demonstrating transmural infiltration of artery walls with CD45RO T lymphocytes (activated/memory T cells) with CD8 lymphocytes predominating over CD4 T cells [63] . Remarkably, T cell activation, cytokine excretion and other immunological perturbations are reversed by IVIG [64] .

Numerous other immunoregulatory abnormalities have been observed during KD or have been suggested as possible contributors to the pathogenesis of the disease. Macrophage activation syndrome has been observed with KD [65] . CD25 + CD4 + regulatory T cells, which maintain immunological self tolerance and control immune responses to microbial invasion, have been shown to be reduced in acute KD patients more than normal controls, suggesting this might play a role in the disease [66] .

Wang et al. [67] proposed that CD40 ligand (CD40L) might play a role in the pathogenesis of KD because they found CD40L expression on CD4 + T lymphocytes in patients with the acute disease. CD40L is a potent activator of the immune system and might enhance endothelial cell inflammation and vascular damage [67] .

Several recent reports implicate vascular endothelial grown factor (VEGF) in the pathological findings associated with KD. VEGF is the primary growth factor for formation of blood vessels and is a vascular permeability factor. It may also be a driver of inflammation as it enhances monocyte chemotaxis in humans and increased the production of B cells in mice [68] . Several reports have documented significantly elevated levels of VEGF in the acute and subacute phases of KD [69] [70] [71] . VEGF induces expression of matrix metalloproteinases (MMP), which degrade extracellular matrix and basement membrane proteins such as collagen and elastin [68] . Gavin et al. [72] demonstrated MMP-2 and MMP-9 in the damaged arterial walls of children who died of KD. The same group subsequently demonstrated angiogenesis in acute KD aneurysms much earlier than previously reported, probably related to several angiogenesis factors including VEGF.

Thus, through such highly complex and intricate interactions of immunopotent cells, cytokines and other mediators, the inflammatory process results in vascular damage in KD.

Racial differences in incidence, families with multiple cases, and the apparent greater tendency for CAA to occur in some children but not in others are all observations that suggest there may be a genetic influence in the pathogenesis of KD. Many investigators are attempting to identify genetic factors that predispose to acquiring KD or its complications.

Many single-nucleotide polymorphisms (SNPs) have been identified that seem to be associated with susceptibility to KD or a risk factor for developing CAA. Table 5 lists 21 studies that identify polymorphisms or SNPs possibly associated with these or other risks. The numerous known or candidate SNPs identified on multiple separate gene locations suggest that the genetic influence on pathogenesis, like the inflammatory process itself is highly complex [68] . New genetic markers will undoubtedly be identified in the future.

After almost 40 years of investigation following description of KD, we know a great deal about the epidemiology, pathology, pathogenesis of the disease and there is a fairly effective, although less than elegant, therapy available in the form of IVIG. The etiology of KD, however, remains an enigma.

As discussed previously, clinical and epidemiological factors favor an infectious etiology, but, as yet, a single microbial pathogen has not been consistently associated with the disease. A very abridged list of microbial and environmental agents that have been proposed as causes for KD is found in Table 6 .

The two most heavily investigated areas in the last 10-15 years have been a bacterial toxin-mediated cause versus a viral pathogen etiology.

The possibility of a superantigen (SA) being implicated in the cause of KD was prompted by the observation that the illness is associated with marked activation of T lymphocytes and monocytes/macrophages. The differences between SA and conventional antigen are compared in Table 7 . Early studies showed significantly elevated levels of V 2 + and V 8.1 + T cells in patients with KD [95, 96] . Subsequently, Leung et al. [97] published a case control study on the presence of bacterial colonization with Staphylococcus aureus organisms capable of producing toxic shock syndrome toxin (TSST). They found a significant association between colonization with toxin secreting S. aureus and the KD patients. Subsequent studies seemed to confirm the association [95, 98, 99] . A prospective multicenter trial assessing KD patients and controls for SA-producing staphylococcal and streptococcal bacteria (TSST-1, staphylococcal enterotoxins B and C, and streptococcal pyrogenic exotoxins A and C) were undertaken. Overall, isolation rates of SA-producing bacteria between KD patients and controls were not different statistically. A subset of patients with organisms expressing superantigens that stimulate V 2 + T cell receptor families of T cells were found significantly more often in the KD group [100] . Other investigations have not confirmed the SA hypothesis, however [101] [102] [103] [104] . More recent serological studies suggest a role in the pathogenesis of KD for TSST-1 staphylococcal enterotoxin B and streptococcal pyrogenic exotoxins A and C [105] [106] [107] .

The role of SA in the etiology of KD remains controversial [108] .

An alternative hypothesis to the superantigen theory is that KD results from infection with an as yet unidentified viral pathogen. Central to this idea is that the immunological response is oligoclonal in response to a conventional antigen rather than a polyclonal response as seen with a challenge by SA. A series of studies have compiled evidence to support this proposition. An unexpected observation from an immunohistochemical study of coronary arteries taken from infants and young children who had died in the acute phase of KD initiated this line of investigation. [109, 110] . IgA-secreting plasma cells were found infiltrating the vascular wall, pancreatic ducts Interacts with the variable (V), joining (J) and diversity (D) portions of the and chains of the T cell receptor (TCR).

Binding restricted to the specificity of the variable regions of the chain (V ) of TCR.

Recognized by the few sensitized T-cells with receptors for the antigen resulting in a limited more specific immune response.

Activates a specific set of V families resulting in activation of a large portion of T-cells causing a much more intense immune response.

Adapted from: Curtis et al. [95] . and kidneys of 100% of KD patients compared to none of the age-matched control patients. This observation was intriguing in view of the relative immaturity of the systemic IgA response in infancy as compared to a fully developed and more robust secretory IgA response at this age. A polyclonal response to an SA might engender infant B cells to respond with a predominantly IgM reaction. A viral or other microbe presented to a mucosal site in a similar patient might stimulate vigorous IgA response [111] . Also observed was a heavy infiltration of IgA-secreting plasma cells in the upper respiratory tract of KD patients as compared to controls [112] . Subsequently, the same investigators demonstrated that the vascular IgA response was oligoclonal in nature and, therefore, probably resulted from stimulation by a conventional antigen, not a superantigen [112] . As a next step, the group developed synthetic antibody from prevalent IgA gene sequences found in acute-phase KD arterial tissue. They then exposed the tissues to the antibody and detected antigen in the respiratory epithelium of proximal bronchi from lungs and in subsets of invading macrophages from the myocardium of other inflamed tissues. The strength of the antigen signal paralleled the concentration of IgA plasma cell infiltration. These findings were not present in tissue from non-KD control patients [113] . Spheroid bodies were seen in the region between the nucleus and apical surface of ciliated epithelium of the proximal bronchi. Similar bodies were seen in the splenic and lymph node tissues. Evaluation of these tissues was undertaken using light microscopy (LM) and transmitting electron microscopy (TEM) focusing on areas containing the spheroid bodies [114] . LM revealed roundto-oval intracytoplasmic perinuclear inclusion bodies in medium-sized bronchi. They stained with both eosin and hematoxylin, suggesting they contained both protein and nucleic acid. TEM showed regular electron-dense inclusion bodies in the perinuclear region of ciliated bronchial epithelial cells resembling aggregates of viral proteins and nucleic acids that are found in respiratory tissues during infection with RNA viruses [114] .

A recent report of association between newly described human coronavirus [115, 116] and KD raised hope that the etiology of KD had finally been identified [117] . Unfortunately, a series of reports from Japan and Taiwan and the United States found no consistent association between the new RNA respiratory virus and KD [118] [119] [120] [121] .

Thus, the search for the etiology of KD continues. Hopefully, with the application of histochemical and molecular techniques described above, the cause will soon be identified, possibly among the many new viral agents being identified at an increasing rate [122, 123] . Yanagawa H, Nakamura 

Pediatric acute mucocutaneous lymph node syndrome: clinical observations of 50 cases

An evaluation of hospitalizations for Kawasaki syndrome in Georgia

The incidence of Kawasaki syndrome in West Coast health maintenance organizations

Multiple outbreaks of Kawasaki syndrome -United States

Recognition and management of Kawasaki disease

Epidemiologic picture of Kawasaki disease in Beijing from 1995 through 1999

Kawasaki Disease in Hong Kong

Epidemiologic pictures of Kawasaki disease in Shanghai from

Epidemiologic features of Kawasaki disease in Taiwan

Epidemiologic picture of Kawasaki disease in Korea

Kawasaki syndrome hospitalizations in Ireland

Outbreak of Kawasaki syndrome in Finland

Kawasaki syndrome in Hawaii

Kawasaki syndrome among American Indian and Alaskan native children

Kawasaki syndrome: description of two outbreaks in the United States

Kawasaki syndrome and risk factors for coronary artery abnormalities

Kawasaki disease in older children and adolescents

Failure to diagnose Kawasaki disease at the extremes of the pediatric age

Features of Kawasaki disease at the extremes of age

Adult Kawasaki disease: report of two cases and literature review

Kawasaki syndrome review of new epidemiologic and laboratory developments

Relationship of climate, ethnicity and socioeconomic class to Kawasaki disease in San Diego County

Seasonality and temporal clustering of Kawasaki syndrome

The epidemiology and etiology of Kawasaki disease

Incidence rate of recurrent Kawasaki disease and related risk factors from the results of nationwide surveys of Kawasaki disease in Japan

Kawasaki disease in families

Clinical features of patients with Kawasaki disease whose parents had the same disease

Familial occurrence of Kawasaki syndrome in North America

Recurrence of Kawasaki disease in a large urban cohort in the United States

National Surveillance of Kawasaki disease

Kawasaki syndrome hospitalizations and associated costs in the United States

Investigation of Kawasaki syndrome risk factors in Colorado

Kawasaki syndrome

Increased prevalence of atopic dermatitis in Kawasaki disease

Nomenclature of systemic vasculatides proposal of an international consensus conference

Pathology of the heart in Kawasaki disease

Immunologic aspects of Kawasaki syndrome

Immunoregulatory abnormalities in mucocutaneous lymph node syndrome

Expressions of Fc epsilon R2/CD23 on peripheral blood macrophages/monocytes in Kawasaki disease

Peripheral blood monocyte/macrophages and serum tumor necrosis factor in Kawasaki disease

Spontaneous tumor necrosis factor production in Kawasaki disease

Circulating interleukin-1 in patients with Kawasaki disease

Serum interferon concentrations and retroviral serology in Kawasaki syndrome

The acute phase nature of interleukin-6: studies in Kawasaki disease and other febrile illnesses

Immunoglobulin M antibodies present in the acute phase of Kawasaki serum lyse cultured vascular endothelial cells stimulated by gamma interferon

CD8 T-lymphocytes and macrophages infiltrate coronary artery aneurysms in acute Kawasaki disease

Reversal of lymphocyte activation in vivo in the Kawasaki syndrome by intravenous gamma globulin

Macrophage activating syndrome as the presenting manifestation of rheumatic diseases in childhood

CD25 + regulatory T-cells in patients with Kawasaki disease

Expression of CD40 ligand on CD 4 T-cells and platelets correlated to the coronary artery lesion and disease progress in Kawasaki disease

Contribution of angiogenic genes to the complex genetic train underlying Kawasaki disease

Vascular endothelial growth factor in acute Kawasaki disease

Increased serum levels of vascular endothelial growth factor in Kawasaki disease

Serum vascular growth factor: a new predictive indicator for occurrence of coronary artery lesions in Kawasaki disease

Systemic arterial expression of matrix metalloproteinases 2 and 9 in acute Kawasaki disease

Augiogenesis in fatal Kawasaki disease coronary artery and myocardium

HLA antigens in mucocutaneous lymph node syndrome

HLA antigens in Kawasaki disease

HLA antigens in mucocutaneous lymph node syndrome in New England

HLA Bw 51 is increased in mucocutaneous lymph node syndrome

Epidemic and endemic HLA-B and DR association in mucocutaneous lymph node syndrome

Analysis of tumor necrosis factor-production and polymorphisms of the tumor necrosis factorgene in individuals with a history of Kawasaki disease

Monocyte chemoattractant 1 gene regulatory region polymorphism and serum level of monocyte chemoattractant protein 1 in Japanese patients with Kawasaki disease

Increased frequency of alleles associated with tumor necrosis factor-levels in children with Kawasaki disease

Polymorphism of SLC 11A1 (Formerly NRAMP1) gene confers susceptibility to Kawasaki disease

Association of IL-1Ra gene polymorphism, but no association of IL-1 and IL-4 gene polymorphisms with Kawasaki disease

Insertion/deletion polymorphism of angiotensin converting enzyme gene in Kawasaki disease

Vascular endothelial growth factor gene haplotypes in Kawasaki disease

High incidence of angiotensin 1 converting enzyme genotype II in Kawasaki disease patients with coronary aneurysm

Polymorphism of transmembrane region of MICA gene and Kawasaki disease

Methylenetetrahydrofolate reductase polymorphism in Kawasaki disease

A polymorphism in the promotor or the CD14 gene (CS14/-159) is associated with the development of coronary artery lesions in patients with Kawasaki disease

CD40 ligand gene and Kawasaki disease

Association of vascular endothelial growth factor (VEGF) and VEGF receptor gene polymorphisms with coronary artery lesions of Kawasaki disease

Polymorphism of matrix metalloprotemase-3 promotor gene as a risk factor for coronary artery lesions in Kawasaki disease

Polymorphism of Fc RIIa may affect the efficacy of gamma-globulin therapy in Kawasaki disease

Polymorphisms in the mannose-bending lectin gene as determinants of age-defined risk or coronary artery lesions in Kawasaki disease

Evidence for a superantigen mediated process in Kawasaki disease

Selective expansion of T-cells expressing T-cell receptor variable regions V 2 and V 8 in Kawasaki disease

Toxic shock syndrome toxin secreting Staphylococcus aureus is Kawasaki syndrome

Selective increase V 2 + T-cells in the small intestinal mucosa in Kawasaki disease

Association of toxic shock syndrome toxin-secreting Staphylococcus aureus with Kawasaki syndrome complicated by coronary artery disease

Prevalence of superantigen-secreting bacterial patients with Kawasaki disease

Toxic shock syndrome toxin-secreting Staphylococcus aureus in Kawasaki syndrome

Superantigenic exotoxin production by isolates of Staphylococcus aureus from the Kawasaki syndrome patients and age-matched control children

TCR V family reparative and T-cell activation markers in Kawasaki disease

T-helper cells in patients with Kawasaki disease: preferential production of tumor necrosis factor-alpha (TNF alpha) by Y 2-or V 8-CD4 + T-helper cells

Maternal antibody against toxic syndrome toxin-1 may protect infants younger than 6 months of age from developing Kawasaki syndrome

Possible relationship between streptococcal pyrogenic exotoxin A and Kawasaki syndrome in patients older than 6 months of age

Development of serum IgM antibodies against superantigens of Staphylococcus aureus and Streptococcus pyogenes in Kawasaki disease

Kawasaki disease and toxic shock syndrome -at last the etiology is clear?

IgA PC in vascular tissue of patients with Kawasaki disease

IgA plasma cell infiltration of proximal respiratory tract, pancreas, kidney and coronary artery in acute Kawasaki syndrome

Comparative evaluation of immunization with live attenuated and enhanced-potency inactivated trivalent poliovirus vaccines in childhood: systemic and local immune responses

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

Oligoclonal IgA response in the vascular wall in acute Kawasaki disease

Cytoplasmic inclusion bodies are detected by synthetic antibody in ciliated bronchial epithelium during acute Kawasaki disease

Identification of a new human coronavirus

Evidence of a novel human coronavirus that is associated with respiratory tract disease in infants and young children

Association between a novel human coronavirus and Kawasaki disease

Lack of association between New Haven coronavirus and Kawasaki disease

Kawasaki disease and human coronavirus

Human coronavirus NL63 is not detected in the respiratory tract of children with acute Kawasaki disease

Lack of association between infection with a novel human coronavirus (HCoV), HCoV-NH, and Kawasaki disease in Taiwan

The widening scope of coronaviruses

Frequent detection of bocavirus DNA in German children with respiratory tract infections