Kawasaki Disease 

Kawasaki disease (KD), or Kawasaki syndrome, is an acute febrile vasculitic syndrome of early childhood. The disorder has also been called mucocutaneous lymph node syndrome and infantile periarteritis nodosa. Kawasaki disease was first described in 1967 by Dr Tomisaku Kawasaki, who reported 50 cases of a distinctive illness in children seen at the Tokyo Red Cross Medical Center in Japan.^[1] These children presented with fever, rash, conjunctival injection, cervical lymphadenitis, inflammation of the lips and oral cavity, and erythema and edema of the hands and feet. The photographs below depict various manifestations of Kawasaki disease.

The illness was initially thought to be benign and self-limited. However, subsequent reports indicated that nearly 2% of patients with Kawasaki disease later died from the illness. Fatalities occurred among children younger than 2 years. These children died while they were improving or after they had seemingly recovered. Postmortem examinations revealed complete thrombotic occlusion of coronary artery aneurysms (CAAs), with myocardial infarction (MI) as the immediate cause of death.

In 1976, Melish et al first reported Kawasaki disease in the United States, in a group of 12 children from Honolulu examined from 1971-1973.^[2] Kawasaki disease is now recognized worldwide, although the greatest number of cases has been in Japan. It is the leading cause of acquired heart disease in children in the developed world and may be a risk factor for adult ischemic heart disease. In the United States, Kawasaki disease has surpassed acute rheumatic fever as the leading cause of acquired heart disease in children younger than 5 years.^[3]

Echocardiographic studies have shown that 20-25% of untreated children with Kawasaki disease develop cardiovascular sequelae ranging from asymptomatic coronary artery ectasis or aneurysm formation to giant CAAs with thrombosis, MI, and sudden death. The mortality rate is 0.1-2%. Early administration of intravenous immunoglobulin (IVIG) reduces the risk of developing cardiac involvement to 5%. Although inflammatory infiltrates have been shown in the pancreas, kidney, and biliary tract, no significant sequelae persist in those tissues.

Because no specific test can be performed for Kawasaki disease and no clinical feature is pathognomonic, the diagnosis of Kawasaki disease is based on the presence of a constellation of clinical findings. Classic cases demonstrate prolonged fever along with at least 4 of 5 major clinical features. (See Presentation.)

In so-called incomplete cases, febrile patients appear to have Kawasaki disease but do not meet diagnostic criteria and have no other identified cause of their illness. Laboratory testing supports the diagnosis in these cases (see Workup).

Although most patients recover with little to no physical activity limitations, a delay in diagnosis results in a greater likelihood of coronary lesions and complications thereof; therefore, a provider must be aware of the classic and atypical presentation of this disease to ensure an optimal patient outcome. Therapy should be started within 10 days, and ideally within 7 days, of fever onset.^[4]

IVIG and aspirin have constituted the mainstays of therapy for Kawasaki disease. However, the usefulness of aspirin has been called into question. Other agents, such as corticosteroids and infliximab, have been used in patients with disease refractory to IVIG.^[5] (See Treatment.)

Despite the prominent mucocutaneous clinical findings that define the illness, Kawasaki disease is best regarded as a generalized vasculitis that involves small- to medium-sized arteries. Although the vascular inflammation is most pronounced in the coronary vessels, vasculitis can also occur in veins, capillaries, small arterioles, and larger arteries.

In the earliest stages of the disease, the endothelial cells and the vascular media become edematous, but the internal elastic lamina remains intact. Then, approximately 7-9 days after the onset of fever, an influx of neutrophils occurs, which is quickly followed by a proliferation of CD8⁺ (cytotoxic) lymphocytes and immunoglobulin A–producing plasma cells.

The inflammatory cells secrete various cytokines (ie, tumor necrosis factor, vascular endothelial growth factor, monocyte chemotactic and activating factor), interleukins (ILs; ie, IL-1, IL-4, IL-6), and matrix metalloproteinases (MMPs; ie, primarily MMP3 and MMP9) that target the endothelial cells and result in a cascade of events that eventuates in fragmentation of the internal elastic lamina and vascular damage.^[6]

In severely affected vessels, the media develops inflammation with necrosis of smooth muscle cells. The internal and external elastic laminae can split, leading to aneurysms.

Over the next few weeks to months, the active inflammatory cells are replaced by fibroblasts and monocytes, and fibrous connective tissue begins to form within the vessel wall. The intima proliferates and thickens. The vessel wall eventually becomes narrowed or occluded owing to stenosis or a thrombus.^{[7, 8, 9, 10, 11]} Cardiovascular death may occur from a myocardial infarction secondary to thrombosis of a coronary aneurysm or from rupture of a large coronary aneurysm.

Most of the pathology of the disease is induced by a medium vessel arterial vasculitis. Initially, neutrophils are present in great numbers, but the infiltrate rapidly switches to mononuclear cells, T lymphocytes, and immunoglobulin A (IgA)–producing plasma cells. Inflammation involves all 3 layers of vessels. Eosinophils are preferentially accumulated in microvessels.

The period during of the greatest vascular damage is when a concomitant progressive increase in the serum platelet count occurs, and this is the point of the illness when the risk of death is most significant.

The etiology of Kawasaki disease remains unknown. At present, most of the epidemiologic and immunologic evidence indicates that the causative agent is probably infectious. However, autoimmune reactions and genetic predisposition have been suggested as possible etiologic factors.

In 2007, the US Food and Drug Administration (FDA) required the makers of RotaTeq rotavirus vaccine to report in the package insert that 9 cases of Kawasaki disease had occurred in children who had received the vaccine. However, most believe that there is no connection between the vaccine and the disease.^[12] One case report in the literature documents a 35-day-old infant who developed Kawasaki disease after his second hepatitis B vaccination.^[13]

Infection

Features of Kawasaki disease that are consistent with an infectious etiology include the occurrence of epidemics primarily in late winter and spring with 3-year intervals and the wavelike geographic spread of those epidemics; the self-limited nature of the disease; and the characteristic fever, adenopathy, and eye signs. Kawasaki disease is unusual in infants younger than 4 months, suggesting that maternal antibodies may provide passive immunity. Epidemiologic data suggest, however, that person-to-person transmission of the disease is unlikely.

Some authors have proposed a controversial association of Kawasaki disease with recent carpet shampooing, flooding, the use of a humidifier in the room of a child with an antecedent respiratory illness,^[14] and locations near bodies of water.^[15] These data have led to a waterborne vector hypothesis.

The overall clinical presentation of patients with Kawasaki disease is similar to that of patients with a viral or superantigenic disease. However, investigations have shown that the immune response in Kawasaki disease is oligoclonal, which is seen as a response to a conventional antigen, rather than polyclonal, as would be found in a superantigen-driven response.^{[16, 17]}

Over the years, multiple infectious agents have been implicated; however, to date, no single microbial agent has surfaced as the prevailing cause.^{[18, 19]} Suspected pathogens and infections have included the following:

• Parvovirus B19
• Meningococcal septicemia
• Bacterial toxin–mediated superantigens
• Mycoplasma pneumoniae
• Klebsiella pneumoniae bacteremia
• Adenovirus
• Cytomegalovirus^[20]
• Parainfluenza type 3 virus
• Rotavirus infection
• Measles
• Epstein-Barr virus
• Human lymphotropic virus infection
• Mite-associated bacteria
• Tick-borne diseases
• Rickettsia species
• Propionibacterium acnes

Using light and electron microscopy, researchers have identified cytoplasmic inclusion bodies containing RNA in 85% of acute- and late-stage Kawasaki disease fatalities and 25% of adult controls. Based on this finding, it is hypothesized that the Kawasaki disease infective agent is most likely a ubiquitous RNA virus that results in asymptomatic infection in most individuals but leads to Kawasaki disease in a subset of genetically predisposed individuals.

It is postulated that the virus enters via a respiratory route, activating both the innate and adaptive immune system and resulting in B lymphocytes switching to immunoglobulin A (IgA) lymphocytes. The identity of this virus or group of closely related viruses is still under investigation.^[6]

Genetic factors

A genetic predilection to Kawasaki disease has long been suspected.^{[21, 22]} Siblings of affected children have a 10-20 times higher probability of developing Kawasaki disease than the general population, and children in Japan whose parents had Kawasaki disease seem to have a more severe form of the disease and to be more susceptible to recurrence.^[23] This risk of 2 family members having Kawasaki disease is greatest in twins, for whom the rate is approximately 13%.^[24]

In 1978, Kato et al discovered that patients with Kawasaki disease are more likely to express HLA-Bw22J2, which is a major histocompatibility complex antigen seen predominantly in Japanese populations, thereby further implicating a genetic influence to the increased susceptibility to Kawasaki disease in Japanese patients.^{[25, 26]} A genome-wide linkage analysis of affected sibling pairs was performed in Japan, and a multipoint linkage analysis identified evidence of linkage on chromosome 12q24.^[27]

Dergun et al, Newburger et al, and Burns et al described families with multiple members affected with Kawasaki disease.^{[28, 3, 29]} In these families, Kawasaki disease occurred in 2 generations or in multiple siblings. No clear pattern of inheritance could be deduced from these pedigrees. Therefore, multiple polymorphic alleles likely influence Kawasaki disease susceptibility.

A functional polymorphism of the inositol 1,4,5-triphosphate 3-kinase C (ITPKC) gene on band 19q13.2 has been found to be significantly associated with an increased susceptibility to developing Kawasaki disease. In addition, this polymorphism was associated with an increased risk of coronary artery lesions in both Japanese and US children.^[30]

In a Dutch cohort, Breunis et al observed an association of Kawasaki disease with common genetic variants in the chemokine receptor gene-cluster CCR3-CCR2-CCR5.^[31] The association of CCR2-CCR5 haplotypes and CCL3L1 copy number with Kawasaki disease, coronary artery lesions, and responses to intravenous immunoglobulin have been reported in Japanese children and in other children.^[32]

A genomic study by Taniuchi et al found that genetic factors may influence the development of coronary artery lesions in Kawasaki disease.^[33] In this study, genomic DNA was extracted from whole blood collected from 56 patients with Kawasaki disease who received gamma globulin treatment, and the genotypes for Fcg RIIIb-NA(1,2), Fcg RIIa-H/R131, and Fcg RIIIa-F/V158 were determined.

About 23% of patients with the HH allele for the Fcg RIIa polymorphism developed coronary artery lesions, compared with 60% with the HR and RR alleles. HR and RR alleles may be a predictor of the progression of coronary lesions in Kawasaki disease before the start of gamma-globulin therapy. Furthermore, a polymorphism in plasma platelet-activating factor acetylhydrolase is involved in resistance to immunoglobulin treatment in Kawasaki disease.

United States statistics

Epidemics of Kawasaki disease primarily occur in the late winter and spring, at 2- to 3-year intervals. Approximately 3000 children with Kawasaki disease are hospitalized annually in the United States. The approximate annual race-specific incidence per 100,000 children younger than 5 years is 32.5 cases for Americans of Asian and Pacific Island descent, 16.9 cases for non-Hispanic African Americans, 11.1 cases for Hispanics, and 9.1 cases for whites.^[34]

A 2010 article retrospectively examined all hospitalizations of children younger than 18 years who have Kawasaki disease and found that the rate of hospitalization in the United Sates from 1997-2007 remained relatively stable, except for a slight increase in 2005. The hospitalization rate for children younger than 5 years (mean age, 1.6 years) was 20.8 cases per 100,000 children in 2006 and demonstrated a slight male predilection.^[35]

International statistics

Outside the United States, the disease is most frequently observed in Japan, Taiwan, and Korea. The prevalence of Kawasaki disease increased from 1967 to the mid-1980s and has leveled out at 5000-6000 cases per year. The highest incidence of Kawasaki disease has been reported in Japan, where the frequency of the disease is 10 to 20 times higher than in Western countries.^[30]

Approximately 5000-6000 cases are reported each year in Japan. The incidence in 2000 was 134.2 cases per 100,000 children younger than 5 years. Epidemics occurred in Japan during the years 1979, 1982, and 1985. No epidemics have occurred since that time.

Marked spatial and temporal patterns were noted in both the seasonality and deviations from the average number of Kawasaki disease cases in Japan. Seasonality was bimodal, with peaks in January and June and/or July and a nadir in October. This pattern was consistent throughout Japan during the entire 14-year period. Very high or low numbers of cases were reported in certain years, but the overall variability was consistent throughout the entire country. Temporal clustering of Kawasaki disease cases was detected with nationwide outbreaks.^[36]

A review by Yanagawa et al of the epidemiology of Kawasaki disease in Japan from 1999-2002 found that 18,604 boys and 13,662 girls with Kawasaki disease were reported. The average annual incidence was 137.7 cases per 100,000 children younger than 5 years.^[37] Most cases occurred in January.

Park et al noted the average annual rate of incidence of Kawasaki disease in South Korea was 105 cases per 100,000 in children younger than 5 years, which was the second highest reported rate in the world.^[38] On average, the approximate annual incidence of Kawasaki disease in various Asian populations per 100,000 children younger than 5 years is 54.9 cases for Taiwan, 25.4 cases for Hong Kong, 16.8-36.8 cases for Shanghai, and 18.2-30.6 cases for Beijing.

The annual incidence reported in white populations outside the United States is similar to that reported in the US population, with 11.3-14.7 cases per 100,000 children younger than 5 years in Canada and 3.6 cases per 100,000 children younger than 5 years in Australia.^{[39, 40]} From 1999-2000, the incidence in the United Kingdom was 8.1 cases per 100,000 children.^[41]

Ontario has the highest rate of Kawasaki disease outside of Asia, with a yearly incidence of 26.2 cases per 100,000 population younger than 5 years. The incidence significantly increased from 1995 to 2006, with more patients diagnosed with incomplete Kawasaki disease. A reduction in coronary abnormalities was also seen during this period and was attributed to better recognition and treatment of the disease.^[42]

Racial and sexual differences in incidence

Although Kawasaki disease has been reported in children of all ethnic origins, it occurs most commonly in Asian children, especially those of Japanese descent. Rates are intermediate among blacks, Polynesians, and Filipinos and are lowest among whites.

Kawasaki disease is slightly more common in males than in females. The male-to-female ratio ranges from 1.3-1.83:1 depending on the country from which the statistics are reported.^[35] Arthritis appears to be more common in girls than in boys. Death and serious complications are more common in boys than in girls.

Age-related differences in incidence

Approximately 85-90% of Kawasaki disease cases occur in children younger than 5 years^[20] ; 90-95% of cases occur in children younger than 10 years. In the United States, the incidence peaks in children aged 18-24 months. In Japan, the incidence peaks in children aged 6-12 months. The earliest reported case in Japan occurred in a 20-day-old newborn.

Kawasaki disease has rarely been reported in adolescents and adults, most of whom are between ages 18 and 30 years.^[42] Fewer than 60 adult patients have been described in the literature for various geographic locations, including 25 in Europe, 23 in North America, 5 in Asia, 2 in South America, and 2 in Africa.^[43]

Kawasaki-like syndromes have been reported in adults infected with human immunodeficiency virus (HIV). However, it is unclear whether this is a variant of Kawasaki disease or an unrelated entity in the immunocompromised population.^[44]

Pannaraj et al noted that Kawasaki disease may occur at the extremes of the typical age range (ie, infants younger than 6 months or children older than 5 years).^[45] Manlhiot et al suggest that children younger than 6 months and those older than 9 years, are more likely to have a suboptimal outcome.^[46]

The majority of "incomplete" cases (see below) occur in very young children.^[47] Infants aged 6 months or younger may have maternal antibody protection, but incomplete cases—and some of the poorest outcomes—have been reported in that age group.^[47]

With prompt treatment, the prognosis is good. Data are limited, but in the United States, death occurs in approximately 1% of affected children. In children younger than 1 year, the mortality rate may exceed 4%. In patients aged 1 year or older, the death rate is probably less than 1%. The average mortality rate in Japan is 0.1-0.3%. The peak mortality occurs 15-45 days after the onset of fever. To date, no deaths have been reported in adult cases of Kawasaki disease.^[43]

Kawasaki disease has surpassed rheumatic heart disease as the leading cause of acquired heart disease in the US in children under the age of 5 years. Cardiovascular complications include the following:

• Clinically significant heart failure or myocardial dysfunction (unlikely to occur once fever is resolved)
• Diffuse coronary artery ectasia and aneurysm formation, giant aneurysm (internal luminal diameter ≥8 mm)
• Myocardial infarction (MI)
• Myocarditis (common but rarely causes chronic heart failure)
• Valvulitis, usually mitral (only occurs in 1% of patients and rarely requires valve replacement)
• Pericarditis with small pericardial effusions (occurs in 25% of patients with acute illness)
• Systemic arterial aneurysms
• Rupture of coronary artery aneurysms with hemopericardium

Approximately 20-25% of untreated patients develop cardiac problems, including coronary artery aneurysms (CAAs). Aneurysms develop in less than 5-10% of patients treated with intravenous gamma globulin before the 10th day of illness.^[34]

Patients who do not develop CAAs recover fully. In those who do develop CAAs, the severity of aneurysms determines the prognosis. More than half of all aneurysms resolve by the 2-year mark. Endovascular ultrasonography has shown that, even when aneurysms resolve, marked intimal thickening is present in some. Vessel flow may be abnormal. These patients may have an increased risk of premature coronary atherosclerotic disease.^[48]

Coronary artery bypass grafting (CABG) has been required in some children with severe perfusion deficits. Follow-up of children and adolescents 20-25 years after CABG has shown a 95% survival rate, though some patients have required repeat CABG or percutaneous coronary intervention.^[49] Transplant has been performed in some children who had large aneurysms in vessels not amenable to bypass.

Arthritis persists in some children. Kawasaki disease appears to be a rare cause of adult cardiac dysfunction.

Risk factors for aneurysm include the following:

• Fever for more than 16 days
• Recurrence of fever after an afebrile period of at least 48 hours
• Male sex
• Cardiomegaly
• Age younger than 1 year

Laboratory values at presentation that may predict a greater likelihood of aneurysm development include the following:

• Hematocrit < 35%
• Thrombocytopenia (< 350,000/μL)
• Elevated C-reactive protein level
• Albumin < 3.5 g/dL
• White blood cell count >12,000/μL

Incomplete Kawasaki disease may also be an independent predictor of CAA development.^[50] The most important predictor is total duration of fever longer than 8 days.^[47] Wilder's group reported that delayed diagnosis contributes to the development of these aneurysms.^[51]

Studies have shown that even in children who do not form aneurysms, up to 50% show a decrease in ventricular function and/or mild valvular regurgitation on echocardiograms. The greatest risk of cardiac damage occurs in children younger than 1 year and in older children, which may be related to an atypical presentation often seen in this age group that leads to a delay in treatment.

Recurrence is unusual: the recurrence rate in Japan is 3% and approximately 1% in North America. Most relapses occur within 2 years from the initial episode. The highest incidence is in younger children and those who had cardiac sequelae from the initial episode. The incidence also appears to be slightly increased in cases within families, with approximately 2.1% of siblings affected within 10 days to 1 year from the first sibling's illness.

The fact that most cases resolve must be communicated to the patient and family, as well as the fact that Kawasaki disease can be fatal. Also educate patients about the possibility of recurrence. The recurrence rate is 4% in Japan but is less than 1% in North America.

Emphasize the need for continued care if cardiac problems are present, because Kawasaki disease is a potentially fatal illness. Advise the patient's family that aspirin therapy must be continued until discontinued by the physician.

Parents and other caregivers must understand the need for close pediatric and cardiology follow-up until the disease has fully resolved. Physicians should also make affected families aware of the potential increased risk of Kawasaki disease among family members.