ARTICULO MEDICO: EPIEDEMIOLOGIA Y ETIOLOGIA DE LA ENFERMEDAD DE KAWASAKI

Kawasaki disease: Epidemiology and etiology
Author
Robert Sundel, MD
Section Editors
Marisa Klein-Gitelman, MD, MPH
Sheldon L Kaplan, MD
Deputy Editor
Elizabeth TePas, MD, MS
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: May 2013. | This topic last updated: may 2, 2012.

INTRODUCTION — Kawasaki disease (KD, previously called mucocutaneous lymph node syndrome) is one of the most common vasculitides of childhood, particularly in East Asia. It is typically a self-limited condition, with fever and other acute inflammatory manifestations lasting for an average of 12 days if not treated. The underlying etiology is unknown. Complications such as coronary artery aneurysm, cardiomyopathy with depressed myocardial contractility and heart failure, myocardial infarction, arrhythmias,
and peripheral arterial occlusion may develop. These complications may cause significant morbidity and mortality. The frequency of aneurysm development and mortality has  dramatically decreased as a result of intravenous immune globulin therapy. Early diagnosis is critical to achieve the optimal treatment result.
The epidemiology and etiology of Kawasaki disease are reviewed here. The clinical features, diagnosis, treatment, and cardiac sequelae are presented separately. Incomplete Kawasaki disease is also discussed separately. (See "Kawasaki disease: Clinical features and diagnosis" and "Kawasaki disease: Initial treatment and prognosis" and "Cardiovascular sequelae of Kawasaki disease" and "Incomplete (atypical) Kawasaki
disease".)

EPIDEMIOLOGY — Kawasaki disease (KD) is one of the most common vasculitides of childhood [1].
Geographic variation — The incidence of KD is greatest in children who live in East Asia  or are of Asian ancestry living in other parts of the world [2-4]. The incidence in underdeveloped countries is largely unknown and ascertainment may be incomplete. KD is particularly difficult to diagnose in areas where measles is still prevalent, since the presentation is similar [5,6]. Many nations around the world have demonstrated an increase in the number of children diagnosed with KD since the early to mid 2000s. It is not clear, however, whether this represents an actual increase in the incidence of the disease, increased awareness of the condition, or a greater tendency to classify children with incomplete clinical features as having KD.
The following studies illustrate the geographic and ethnic variation in the incidence of KD:
· Japan — KD is a reportable disease in Japan and almost 250,000 cases of KD have been registered there since its initial description by Tomisaku Kawasaki in 1967 [7,8]. The incidence among children younger than five years of age was about 215 per 100,000 per year in 2007 and 2008, with the incidence in boys aged 0 to 4 years reaching as high as 240 per 100,000 [8]. The highest incidence was among children aged 6 to 11 months. Thus, about 1 in 100 Japanese children develops KD by the age of 5, making KD a very common illness in Japan. Although epidemics of KD were observed in Japan in 1979, 1982, and 1986, there has not been an epidemic since that time. However, incidence rates now exceed the rates observed during the three previous epidemics [8]. In Japan, KD is most prevalent in the winter, with a smaller peak evident in summer [8].
· Taiwan and China — Data from the Taiwan National Health Insurance Database indicate that the incidence of KD among children younger than five years was 69 per 100,000 per year between 2003 and 2006 [9]. A hospital-based survey of KD in all 45 hospitals in Beijing reported an increase in the incidence in children younger than five years of age from 41 per 100,000 in 2000 to 51 per 100,000 in 2004 [10].
· United States — Studies of hospital discharge records by the United States Centers for Disease Control (CDC) estimated an overall annual incidence of 20 per 100,000 children younger than five years in the United States [11]. Annual incidence was highest among Asians and Pacific Islanders (30 per 100,000), intermediate among non-Hispanic African Americans (17 per 100,000) and Hispanics (16 per 100,000), and lowest among Caucasians (12 per 100,000) [11]. A winter-spring predominance of cases is characteristic, and the peak incidence of illness is at less than one year of age [11]. In contrast to Japan, surveillance in the United States is passive and many cases may be missed. The overall incidence was 22 per 100,000 children less than five years of age in San Diego County during a six-year period from 1998 to 2003 [3]. The rates based upon ethnicity were 15, 25, 20, and 46 per 100,000 children less than five years of age for non-Hispanic whites, non-Hispanic African Americans, Hispanics, and Asian/Pacific Islanders, respectively.
· England — In an analysis of national admissions data in England, the annual incidence of KD for children under five years of age averaged 8 per 100,000 from 1998 to 2003 [12]. The incidences were higher for children of Chinese ethnicity, and those who lived in areas of greatest urban density and with the greatest degree of poverty.
· Israel — A retrospective study using the Israel National Hospital Discharge Register indicated an increase in KD incidence in Israel from 5 per 100,000 children under five years of age from 1996 to 1999 to 7 per 100,000 in 2000 to 2004 [13]. For male infants under one year of age, the KD incidence rate doubled between 1996 to 1998 and 1999 to 2009.
Other risk factors — Boys are affected more commonly than girls [4,9,10,14,15]. Eighty to 90 percent of cases occur in children younger than five [9,16], although KD is relatively uncommon among children younger than six months (approximately 10 percent of KD hospitalizations in the US) [11]. Occurrence beyond late childhood is rare [16,17], although older children can develop KD and may experience delays in diagnosis and higher rates of coronary artery disease [18,19]. Fewer than 100 cases of classic KD in adults had been reported in the literature at the time of a 2010 case series and review [20].

The epidemiology of the illness is illustrated by an analysis of data from the Pediatric Health Information System (PHIS) that identified 4811 patients who were treated in 27 hospitals in the United States [4]. The median age at first admission was 3.4 years (range 1 month to 21.3 years), and 60 percent of the patients were between one and four years of age. Sixty percent of patients were male. Patients of Asian ancestry were overrepresented in the KD group compared to the overall patient group contained within the PHIS dataset (6.9 versus 1.6 percent).
In Japan, there is a reported 10-fold increased risk of KD for children with an affected sibling and a twofold increased risk for those with a previously affected parent [21,22]. In North America, there are case reports of families with multiple affected members, but data are lacking to determine whether there is an increased familial risk for developing KD [23].

POSSIBLE ETIOLOGIC FACTORS — The etiology of KD remains unknown. A variety of theories have been proposed based upon pathologic, epidemiologic, and demographic data [24]. Infection by one or more agents that usually cause an asymptomatic or nonvasculitic condition in most children, but results in KD in genetically predisposed individuals, fits the epidemiologic data well [25] . This theory explains the paucity of cases in very young infants (who may be protected by passive maternal antibody), the rarity of cases in adults (who would have already experienced asymptomatic infection), and the scarcity of data showing person-to-person transmission (since most individuals would be infected asymptomatically).

Immunologic response — KD is a systemic inflammatory illness that particularly affects medium-sized arteries, especially the coronary arteries. Pathologic studies indicate that multiple organs and tissues are involved [26], but long-term sequelae appear to occur only in the arteries. Blood vessel damage appears to result from inflammatory cell infiltration into vascular tissues. The stimulus for this infiltration is unknown, but it is most profound in the coronary arteries and can involve destruction of luminal endothelial cells, elastic lamina, and medial smooth muscle cells in severe cases. The destruction of elastin and collagen fibers and loss of structural integrity of the arterial wall leads to dilatation and aneurysm formation. Inflammatory cells infiltrating the coronary arteries can include neutrophils, T cells (particularly CD8 T cells), eosinophils, plasma cells (particularly IgAproducing), and/or macrophages.
A neutrophilic infiltrate is observed in the arterial wall in fatalities that occur within the first two weeks of fever onset and may represent an innate immune response [27]. A study of gene expression patterns in acute KD peripheral blood using DNA microarrays reflects the predominance of neutrophils early in the course of KD [28]. Expression of genes associated with neutrophils and inflammatory processes, including adrenomedullin, grancalcin, and granulin, was high during the acute phase of illness. Levels of these transcripts tended to decrease over time, while gene expression in CD8 T cells and natural killer (NK) cells increased as the illness evolved. CD8 T cells were prevalent in the arterial wall in fatalities that occur after two weeks in another study, consistent with the development of an acquired immune response [29]. Gene expression in the peripheral blood from individual patients tended to be more consistent over time than did clustering by day of illness, suggesting the possibility that DNA polymorphisms affected individuals’ gene
expression.
Plasma cells producing oligoclonal IgA antibodies are found in the arteries of children with KD [30]. The distribution of IgA plasma cells in respiratory tract and arteries suggests that an etiologic agent (not yet identified) enters via the respiratory tract and spreads through the bloodstream to targeted susceptible organs, such as the coronary arteries. A synthetic monoclonal antibody derived from prevalent IgA sequences in the KD arterial wall identified intracytoplasmic inclusion bodies consistent with aggregates of proteins and nucleic acids in 85 percent of KD cases, but not in infant control tissues [31,32]. Immune complexes are sometimes detected in the peripheral blood in KD, but they are not observed to form deposits in affected tissues and do not appear to correlate with the development of coronary artery disease [33,34].

Infectious etiology — Many epidemiologic data suggest that KD is caused by a transmissible agent. Support for this theory is derived from the following similarities between KD and other pediatric infectious conditions [1]:
· Kawasaki disease is characterized by a febrile exanthem with lymphadenitis and mucositis. These are features similar to those of contagious diseases such as adenovirus infection, measles, and scarlet fever.
· There is a seasonal increase in disease incidence in the winter and summer in many geographic areas [35].
· The disease often occurs in epidemics [35,36], and a geographic wave-like spread of illness during epidemics has been noted [36].
· Boys are more susceptible than girls. In general, the “set-point” of the immune system varies between genders, leading to an overall higher incidence and morbidity of a variety of infections in males (eg, meningitis [37], campylobacter enteritis [38]), and a higher incidence of autoimmune diseases in females [39].
· Siblings of children with KD in Japan are at increased risk for developing the disease, which usually occurs within one week of onset of the index case [36].
· The disease is common among children younger than five years, but rare in those younger than six months. The rarity in infants may be explained by transfer of passive immunity to the relatively common infectious trigger(s) by transplacentally acquired maternal antibodies.
· There is spatial and temporal clustering of cases [3].

The cause of KD remains unknown despite clinical and epidemiologic data suggesting an infectious etiologic agent. Screening of patients with “universal” prokaryotic and eukaryotic primers has not identified an infectious agent as the cause. Thus, the significance of findings such as the presence of aggregates of particles that share morphologic features with several RNA virus families in a small number of patients with KD remains unclear [40].

Genetic factors — Genetic factors appear to contribute to the pathogenesis of this disorder, as suggested by the increased frequency of the disease in Asian and Asian-American populations and among family members of an index case [1,21,41-43]. Variants or polymorphisms of the following genes are associated with an increased susceptibility to KD:
· Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 [44,45]. ITPKC acts as a negative regulator of T cell activation, which includes transcription of interleukin 2 (IL-2). The single nucleotide polymorphism (SNP) associated with KD susceptibility results in a weaker inhibitory effect upon T cell activation. Patients with this SNP may have a more vigorous T cell response during an inflammatory disease, such as KD, compared to those without this allelic change. However, this polymorphism is not common enough even in the Japanese population to explain the vast majority of cases of KD.
· Angiopoietin 1 (ANGPT1) and vascular endothelial growth factor A (VEGFA) genes [46-48]. Expression of angiopoietin 1 is upregulated, and VEGF downregulated, in patients with acute versus convalescent KD, suggesting disruption of vascular homeostasis.
· The genes encoding the chemokine receptor CCR5 and its major ligand CCL3L1 [49].
· The gene for ATP-binding cassette, subfamily C, member 4 (ABCC4), a cyclic nucleotide transporter involved in migration of dendritic cells and cellular efflux of prostaglandin [50].
· Genome-wide association studies have revealed other potential susceptibility loci, including a functional polymorphism in the immunoglobulin G receptor gene (FCGR2A) [51-55].
· In addition to being a putative susceptibility factor, ITPKC is associated with an increased risk of coronary artery aneurysms. Other genetic factors related to the development of coronary lesions in KD are discussed separately. (See "Cardiovascular sequelae of Kawasaki disease", section on 'Coronary artery
aneurysm'.)

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SUMMARY
· Kawasaki disease (KD) is one of the most common vasculitides of childhood. The incidence of KD is greatest in children who live in East Asia (eg, Japan, Korea, Taiwan) or are of Asian ancestry living in other parts of the world. Other risk factors include male gender, age between six months and five years, and family history of KD. (See 'Epidemiology' above.)
· The etiology of KD remains unknown. Inflammatory cell infiltration into KD vascular tissue leads to vascular damage, but the stimulus for this inflammatory infiltration has not been identified. (See 'Immunologic response' above.)
· The similarities between KD and other pediatric infectious conditions suggest that KD is caused by a transmissible agent. However, no studies have convincingly identified a specific virus, bacteria or bacterial toxin, or other pathogen associated with KD. The etiology may be a previously unidentified infectious agent. An alternative theory to a specific inciting agent is that KD represents a final common pathway of immune-mediated vascular inflammation following a variety of inciting infections. (See 'Infectious etiology' above.)
· Genetic factors appear to contribute to the pathogenesis of this disorder, as suggested by the increased frequency of the disease in Asian and Asian-American populations and among family members of an index case. A number of gene polymorphisms are associated with an increased susceptibility to KD, and some of
these variants are also associated with coronary artery lesions and aneurysm formation. (See 'Genetic factors' above.)