Kawasaki disease: Pathogenesis, epidemiology, and etiology

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.

KD can cause a variety of cardiovascular complications, most commonly coronary artery aneurysms. Other less common cardiovascular manifestations include:

●Cardiomyopathy with depressed myocardial contractility and heart failure

●Myocardial infarction

●Arrhythmias

●Peripheral arterial occlusion

These complications may cause significant morbidity and mortality, and they occur most commonly in children who are inadequately treated or who have aggressive disease. The frequency of aneurysm development and mortality has dramatically decreased as a result of intravenous immune globulin therapy. Early diagnosis is critical to optimize outcomes for children with KD.

The pathogenesis, epidemiology, and etiology of KD are reviewed here. The clinical features, diagnosis, treatment, and cardiac sequelae are presented separately. (See "Kawasaki disease: Clinical features and diagnosis" and "Kawasaki disease: Initial treatment and prognosis" and "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation".)

PATHOLOGY — 

Kawasaki disease (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 [1], but long-term sequelae appear to occur only in the arteries.

In KD, inflammatory cells infiltrate the vascular tissues, damaging the blood vessels. An autopsy study described three phases of KD arteriopathy [2]:

●Necrotizing arteritis – The arteritis is driven by neutrophils, moving through the adventitia in the first two weeks of illness. The stimulus for this infiltration is unknown, but it is most profound in the coronary arteries.

●Subacute/chronic vasculitis – The vasculitis is driven by plasma cells, lymphocytes, and eosinophils. In severe cases, the inflammatory cells destroy the luminal endothelial cells, elastic lamina, and medial smooth muscle cells, leading to fusiform aneurysms.

●Luminal myofibroblast infiltration – The myofibroblasts create stenotic lesions in the arteries, which predisposes the vessels to in situ thrombosis.

EPIDEMIOLOGY — 

Kawasaki disease (KD) is second only to immunoglobulin A (IgA) vasculitis (formerly Henoch-Schönlein purpura) as the most common vasculitis of childhood and is the leading cause of acquired heart disease in children in developed nations [3,4].

Geographic variation — KD has been found worldwide, in all racial and ethnic groups [5]. However, 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 [6].

The incidence of KD is less well described in developing countries, but there is increasing literature on the incidence of KD in South America and Africa, although ascertainment remains imperfect [6-8]. KD is particularly difficult to diagnose in areas where measles is still prevalent, since the presentation is similar [9,10].

The following studies illustrate the geographic and ethnic variation in the incidence of KD:

●Japan – KD is a reportable disease in Japan. Almost 360,000 cases of KD have been registered there since its initial description by Tomisaku Kawasaki in 1967 [11,12]. Biennial nationwide surveys have been performed in Japan since 1970, providing robust epidemiologic data.

The incidence of KD among children younger than five years of age was approximately 359 per 100,000 per year in 2018 [13], with the incidence in boys aged 9 to 11 months reaching as high as 572 per 100,000 [14].

In Japan, KD is most prevalent in the winter, with a smaller peak evident in summer [14].

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 [14]. Furthermore, the incidence in 2018 was the highest recorded at 17,364.

●Korea – Similar to Japan, South Korea has documented a continuous increase in the incidence of KD from 2000 until the coronavirus disease 2019 (COVID-19) pandemic. (See 'Time-based trends' below.)

The cumulative incidence of KD from 2015 to 2017 among children younger than five years old was estimated at 196.9 per 100,000. The peak incidence in a single year occurred in 2015, when it was 202.2 per 100,000 children <5 years of age.

●Taiwan and China – Data from the Taiwan National Health Insurance Database indicate that the average annual incidence of KD among children younger than five years was 67.3 per 100,000 per year between 2000 and 2010 [15].

A hospital-based survey of KD in 50 hospitals in Shanghai reported an incidence in children younger than five years of age from 68.8- to 107.3 per 100,000 from 2013 to 2017 [16]. There was an increase in incidence over the first two years of the study period and stabilization over the last two. In general, the incidence of KD had increased since 1998, when these surveys were first administered.

●United States – From 2016 to 2018, among children younger than five years old, the incidence rate of KD ranged from 18.4 to 19.8 per 100,000 [17,18].

However, children in the United States of Asian/Pacific Islander ancestry have the highest hospitalization rates [8]. For example, in the National Inpatient Sample in 2017, the hospitalization rates per 100,000 children <5 years of age were as follows: [18]

•45 for Asian/Pacific Islander children

•19.5 for Black children

•16.4 for Hispanic children

•12.7 for White children

●Middle East – 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 from 2000 to 2004 [19]. For male infants under one year of age, the KD incidence rate doubled when comparing patients diagnosed between 1996 and 1998 with patients diagnosed between 1999 and 2009.

●Africa – KD is one of the most commonly reported forms of systemic vasculitis in Africa [20]. In 2016, among children less than five years old, the annualized incidence rate in Tunisia, Morocco, and Algeria was 0.95, 4.52, and 3.15 per 100,000, respectively [21].

Patients with KD have also been reported throughout sub-Saharan Africa [20]. For example, KD was one of the most frequent reasons for admission to a children’s hospital in Kenya [22].

●Europe – The overall annual incidence of KD in Europe among children younger than five years old has been 10 to 15 per 100,000, although there are regional variations [23]. For example, the annual incidence rate of KD among children younger than five years old is 1.6 per 100,000 in the Czech republic and 17.6 per 100,000 in Italy. As in other regions, the incidence of KD in Europe is higher among children of Asian descent.

Time-based trends

●From 2000 to 2020 – Many nations around the world demonstrated an increase in the number of children diagnosed with KD since the early to mid-2000s. It is not clear, however, whether this represented 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.

●Since 2020 – Notably, the incidence of KD significantly decreased worldwide during the COVID-19 pandemic [24-27].

•Japan – In Japan, there was a decrease in KD incidence of nearly 36 percent between 2020 and 2019. This decrease was not attributable to a lack of access to care in the setting of the pandemic. After initiation of social isolation, the incidence declined more quickly among children aged >24 months than among children <12 months of age upon initiation of mitigation measures. However, the incidence also rebounded more quickly among children aged >24 months after rescinding the mitigation measures [24].

•United States – In the United States, data from 28 centers participating in the KIDCARE trial demonstrated an almost 30 percent decrease in KD cases between 2020 and 2019, although distribution of the decline varied geographically [28].

Driving forces behind this remarkable epidemiologic phenomenon include public health measures such as masking, distancing, and school closures, all of which decreased children’s exposure to infectious agents.

Other risk factors

●Age – Eighty to 90 percent of cases occur in children younger than five years [29,30]. KD is relatively uncommon among children younger than six months, who account for approximately 10 percent of KD hospitalizations in the United States [31].

Occurrence beyond late childhood is rare [30,32], although older children can develop KD and may experience delays in diagnosis and higher rates of coronary artery disease [33,34]. KD is rarely reported in adults [35].

●First-degree relatives – In the biennial survey from centers in Japan covering the years 2017 and 2018, 2.2 percent of patients had a sibling and 1.3 percent had a parent with a history of KD [13]. In North America, there are case reports of families with multiple affected members, but data are insufficient to determine whether there is an increased familial risk for developing KD [36].

●Gender – Boys are more likely to be diagnosed with KD than girls, with a male to female ratio of 1.5 to 1 [5].

POSSIBLE ETIOLOGIC FACTORS — 

The etiology of Kawasaki disease (KD) remains unknown. There is an ongoing debate as to whether KD is caused by a single, heretofore unidentified agent [37] or an immunologic response to a variety of triggers [38].

A variety of theories have been proposed based upon pathologic, epidemiologic, and demographic data [39]. The epidemiologic data imply that KD is caused by one (or more) common infections or exposures, which results in KD among genetically predisposed individuals [38].

The dramatic decrease in the incidence of KD around the world during the COVID-19 pandemic provides strong evidence that infectious triggers play a key inciting role in the pathogenesis of KD in most cases. (See 'Time-based trends' above.)

Genetic factors — Genetic factors appear to contribute to the pathogenesis of this disorder. Susceptibility to KD demonstrates a non-Mendelian pattern of inheritance, as demonstrated by its increased frequency among patients of East Asian ancestry and among family members of an index case [3,4,40-43].

Several gene variants have been associated with an increased risk of KD among multiple racial and ethnic populations, including:

●Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) – The ITPKC gene on chromosome 19q13.2 has been associated with an increased susceptibility to KD and an increased risk of aneurysm formation [44-46]. ITPKC may act through one of two different mechanisms:

•Intracellular calcium regulation – ITPKC regulates intercellular calcium, which influences the expression of NLRP3, interleukin 1 (IL-1) beta, and IL-18 [47]. Higher levels of IL-1B and IL-18 are associated with treatment-resistance.

•T-cell activation – ITPKC also acts as a negative regulator of T-cell activation, which includes transcription of IL-2. The single nucleotide polymorphism (SNP) associated with KD susceptibility results in a weaker inhibitory effect upon T-cell activation [48]. Patients with this SNP may have a more vigorous T-cell response during an inflammatory disease, such as KD, compared with 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.

●Immunoglobulin G receptor gene (FCGR2A) – Genome-wide association studies have identified an association between KD and a functional polymorphism in FCGR2A [49-53].

Expression of FCGR2A by effector cells may mediate autoantibody-induced inflammation [54]. Increased expression of FCGR2A correlates with both an increased risk of developing KD and treatment resistance to IVIG [55].

●Caspase 3 (CASP3) – Genome-wide association studies of both Japanese and European populations have identified an association between CASP3 polymorphisms and KD risk [46].

CASP3 is a mediator of cellular apoptosis and may specifically target the coronary artery smooth muscle cells in patients with KD [56].

Other genes that have been implicated in the pathogenesis of KD include:

●Angiopoietin 1 (ANGPT1) and vascular endothelial growth factor A (VEGFA) genes [57-59]. Expression of angiopoietin 1 is upregulated and VEGF is 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 [60].

●The adenosine triphosphate (ATP) binding cassette, subfamily C, member 4 (ABCC4) gene. ABCC4 is a cyclic nucleotide transporter involved in migration of dendritic cells and cellular efflux of prostaglandin [61].

Some gene associations appear to be specific to certain populations, implying that there may not be a single set of gene variants responsible for an increased risk of KD among all patients [46].

Additionally, the genetic variants that determine the risk of coronary aneurysms may not be the same as the variants associated with an increased risk of KD. A genome-wide association study of 11 patients with KD who developed coronary artery aneurysms identified five genes (NEBL, TUBA3C, TRAF5, MDGA1/MDGA12) associated with an increased risk of aneurysm formation. These genes are related to cardiac muscles and vessels, rather than immune dysregulation [62]. Other genetic factors related to the development of coronary lesions in KD are discussed separately. (See "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation", section on 'Coronary artery abnormalities'.)

Infectious etiology — Many epidemiologic data suggest that KD is caused or triggered by a transmissible agent or agents. Support for this theory is derived from the following similarities between KD and other pediatric infectious conditions [3]:

●Mucocutaneous features – KD 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.

●Seasonality – There is a seasonal increase in the winter and summer in some areas of the world, but this is not a consistent finding [63,64].

●Sibling studies – 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 [65].

●Age association – The disease is common among children younger than five years but rare among infants, although children younger than six months have the most aggressive disease and worse outcomes.

The rarity of KD among infants may be explained by transfer of passive immunity to the relatively common infectious trigger(s) by transplacentally acquired maternal antibodies.

●IgA immunoglobulin – Plasma cells producing oligoclonal immunoglobulin A (IgA) antibodies are found in the arteries and respiratory tract of children with KD [37]. The presence of IgA antibodies implies a mucosal immune response to an infectious stimulus.

●Multisystem inflammatory syndrome in children – Multisystem inflammatory syndrome in children (MIS-C), caused by COVID-19, bears some similarities to KD, including the presence of mucocutaneous symptoms and an association with severe inflammation [66]. In a percentage of such cases, coronary artery dilatation may develop. However, these are more transient than the coronary artery involvement seen in KD. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

●COVID-19 – The incidence of KD declined during the COVID-19 pandemic, which may have been the result of public health measures such as masking and social distancing. (See 'Time-based trends' above.)

●Potential causative agent – Synthetic antibodies created from plasmablasts derived from a fatal case of KD were used to identify a specific peptide epitope; this epitope indicates that a Hepacivirus may cause most cases of KD [67,68]. However, other studies have failed to identify a single causative agent:

•A retrospective review of 129 consecutive patients diagnosed during a 24-month period from 1997 to 1998 at a single tertiary-care hospital found that 33 percent of children with typical KD had at least one confirmed infection at KD diagnosis [69]. However, a wide variety of different bacterial and viral infections were identified.

•Screening of patients with "universal" prokaryotic and eukaryotic primers has not identified a single infectious agent as the cause.

•In a study that utilized high-throughput phage immunoprecipitation that covered the complete reference protein sequences of known viruses with human tropism, there were no differences in antibody profiles between patients with KD and matched febrile controls [70].

Environmental factors — Environmental factors have also been proposed as the triggers of KD:

●An analysis of seasonal variations in epidemics of KD suggest that cases are linked to large-scale wind currents from Central Asia, potentially carrying an airborne antigenic trigger in the troposphere [71].

●A study that included sites from around the United States as well as Japan, South Korea, Italy, and New Zealand described clustering of cases that was more pronounced than would be expected if random, suggesting that large-range environmental influences may impact exposure to KD triggers [64].

●Particulate matter – Some studies have linked air pollution to KD [72].

Immunologic response — KD likely involves activation of both the innate and adaptive immune systems. The innate immune system may be responsible for the initial inflammatory response, while the adaptive immune system may be responsible for damage to the coronary arteries [73].

●Innate immunity – A comparison of acute versus convalescent samples from patients with KD demonstrates activation of multiple pathways associated with innate immunity (eg, IL-1, IL-10, NLRP3 inflammasome) [74]. Transcriptome analysis indicates activation of both neutrophils and monocytes, which are innate immunity effector cells [75].

●Adaptive immunity – In the coronary artery tissue of patients with convalescent KD, adaptive immune cells (eg, B cells, CD8+ T cells) were significantly increased, although these same cells were depressed in the circulation. This discrepancy suggests that adaptive immune cells may be recruited selectively into the coronary arteries in patients with KD [73].

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Kawasaki disease (The Basics)")

SUMMARY

●Pathology – Kawasaki disease (KD) is a systemic, inflammatory illness that is associated with damage to the coronary arteries. Inflammation of the coronary arteries may lead to fusiform aneurysms and thrombosis. (See 'Pathology' above.)

●Epidemiology – KD is one of the most common vasculitides of childhood. KD is found worldwide. However, 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. Other risk factors include male sex, age between six months and five years, and family history of KD. The incidence of KD increased worldwide from 2000 to 2020 but has declined during the COVID-19 pandemic. (See 'Epidemiology' above.)

●Etiology and pathogenesis – The etiology of KD remains unknown, but several etiologic factors have been postulated:

•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. A number of gene polymorphisms are associated with an increased susceptibility to KD, including inositol 1,4,5-triphosphate 3-kinase C (ITPKC), immunoglobulin G receptor gene (FCGR2A), and caspase 3 (CASP3). Other gene polymorphisms may be important for specific patient populations. (See 'Genetic factors' above.)

•Infectious etiology – The similarities between KD and other pediatric infectious conditions suggest that KD is caused by a transmissible agent. Some studies have implicated a Hepacivirus as the causative agent. (See 'Infectious etiology' above.)

•Environmental factors – Temporal and spacial clustering of cases may imply an environmental trigger for some patients with KD. (See 'Environmental factors' above.)

•Immunologic response – KD likely involves activation of both the innate and adaptive immune systems, which are responsible for causing both systemic inflammation and vascular damage. (See 'Immunologic response' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Robert Sundel, MD, who contributed to earlier versions of this topic review.