Kawasaki disease, also known as mucocutaneous lymph node syndrome, is a disease in which blood vessels throughout the body become inflamed. The most common symptoms include a fever that lasts for more than five days not affected by usual medications, large lymph nodes in the neck, a rash in the genital area, and red eyes, lips, palms or soles of the feet. Other symptoms include sore throat and diarrhea. Within three weeks of the onset of symptoms, the skin from the hands and feet may peel. Recovery then typically occurs. In some children, coronary artery aneurysms may form in the heart after 1–2 years.
The cause is unknown. It may be due to an infection triggering an autoimmune response in those who are genetically predisposed. It does not spread between people. Diagnosis is usually based on a person’s signs and symptoms. Other tests such as an ultrasound of the heart and blood tests may support the diagnosis. Other conditions that may present similarly include scarlet fever and juvenile rheumatoid arthritis.
Typically, initial treatment consists of high doses of aspirin and immunoglobulin. Usually, with treatment, fever resolves within 24 hours and there is a full recovery. If the coronary arteries are involved, ongoing treatment or surgery may occasionally be required. Without treatment, coronary artery aneurysms occur in up to 25% and about 1% die. With treatment, the risk of death is reduced to 0.17%.
Kawasaki disease is rare. It affects between 8 and 67 per 100,000 people under the age of five except in Japan where it affects 124 per 100,000. It is much less common after the age of five. Boys are more commonly affected than girls. The disorder was first described in 1967 by Tomisaku Kawasaki in Japan.
As the cause(s) of Kawasaki disease remain unknown, the illness is more accurately referred to as Kawasaki syndrome. Its cause is widely hypothesized to involve the interaction of genetic and environmental factors, possibly including an infection in combination with genetic predisposition to an autoimmune mechanism. The specific cause is unknown, but current theories center primarily on immunological causes. Evidence increasingly points to an infectious cause, but debate continues on whether the cause is a conventional antigenic substance or a superantigen.
Other data show a clear correlation between Kawasaki disease and tropospheric wind patterns; winds blowing from central Asia correlate with Kawasaki disease cases in Japan, Hawaii, and San Diego. This association with tropospheric winds has been shown to be modulated at seasonal and interannual timescales by the El Niño–Southern Oscillation phenomenon, further indicating the agent responsible for the disease is a wind-borne pathogen. Efforts are underway to identify the suspected pathogen in air-filters flown at altitude above Japan.
An association has been identified with an SNP in the ITPKC gene, which codes an enzyme that negatively regulates T-cell activation. The HLA-B51 serotype has been found to be associated with endemic instances of the disease.
Children with Kawasaki disease should be hospitalized and cared for by a physician who has experience with this disease. When in an academic medical center, care is often shared between pediatric cardiology, pediatric rheumatology, and pediatric infectious disease specialists (although no specific infectious agent has yet been identified). To prevent damage to the coronary arteries, treatment should be started as soon as the diagnosis is made.
Intravenous immunoglobulin (IVIG) is the standard treatment for Kawasaki disease and is administered in high doses with marked improvement usually noted within 24 hours. If the fever does not respond, an additional dose may have to be considered. In rare cases, a third dose may be given to the child. IVIG by itself is most useful within the first seven days of onset of fever, in terms of preventing coronary artery aneurysm.
Salicylate therapy, particularly aspirin, remains an important part of the treatment (though questioned by some) but salicylates alone are not as effective as IVIG. Aspirin therapy is started at high doses until the fever subsides, and then is continued at a low dose when the patient returns home, usually for two months to prevent blood clots from forming. Except for Kawasaki disease and a few other indications, aspirin is otherwise normally not recommended for children due to its association with Reye’s syndrome. Because children with Kawasaki disease will be taking aspirin for up to several months, vaccination against varicella and influenza is required, as these infections are most likely to cause Reye’s syndrome. High-dose aspirin is associated with anemia and does not confer benefit to disease outcomes.
Corticosteroids have also been used, especially when other treatments fail or symptoms recur, but in a randomized controlled trial, the addition of corticosteroid to immune globulin and aspirin did not improve outcome. Additionally, corticosteroid use in the setting of Kawasaki disease is associated with increased risk of coronary artery aneurysm, so its use is generally contraindicated in this setting. In cases of Kawasaki disease refractory to IVIG, cyclophosphamide and plasma exchange have been investigated as possible treatments, with variable outcomes.
With early treatment, rapid recovery from the acute symptoms can be expected, and the risk of coronary artery aneurysms is greatly reduced. Untreated, the acute symptoms of Kawasaki disease are self-limited (i.e. the patient will recover eventually), but the risk of coronary artery involvement is much greater. Overall, about 2% of patients die from complications of coronary vasculitis.
Laboratory evidence of increased inflammation combined with demographic features (male sex, age less than six months or greater than eight years) and incomplete response to IVIG therapy create a profile of a high-risk patient with Kawasaki disease. The likelihood that an aneurysm will resolve appears to be determined in large measure by its initial size, in which the smaller aneurysms have a greater likelihood of regression. Other factors are positively associated with the regression of aneurysms, including being younger than a year old at the onset of Kawasaki disease, fusiform rather than saccular aneurysm morphology, and an aneurysm location in a distal coronary segment. The highest rate of progression to stenosis occurs among those who develop large aneurysms. The worst prognosis occurs in children with giant aneurysms. This severe outcome may require further treatment such as percutaneous transluminal angioplasty, coronary artery stenting, bypass grafting, and even cardiac transplantation.
A relapse of symptoms may occur soon after initial treatment with IVIG. This usually requires rehospitalization and retreatment. Treatment with IVIG can cause allergic and nonallergic acute reactions, aseptic meningitis, fluid overload and, rarely, other serious reactions. Overall, life-threatening complications resulting from therapy for Kawasaki disease are exceedingly rare, especially compared with the risk of nontreatment. Also, evidence indicates Kawasaki disease produces altered lipid metabolism that persists beyond the clinical resolution of the disease.
Rarely, recurrence can occur in Kawasaki disease with or without treatment.
Kawasaki disease affects boys more than girls, with people of Asian ethnicity, particularly Japanese and Korean people, most susceptible, as well as people of Afro-Caribbean ethnicity. The disease was rare in Caucasians until the last few decades, and incidence rates fluctuate from country to country.
Currently, Kawasaki disease is the most commonly diagnosed pediatric vasculitis in the world. By far, the highest incidence of Kawasaki disease occurs in Japan, with the most recent study placing the attack rate at 218.6 per 100,000 children <5 years of age (about one in 450 children). At this present attack rate, more than one in 150 children in Japan will develop Kawasaki disease during their lifetimes. However, its incidence in the United States is increasing. Kawasaki disease is predominantly a disease of young children, with 80% of patients younger than five years of age. About 2,000-4,000 cases are identified in the U.S. each year (9 to 19 per 100,000 children younger than 5 years of age). In the United Kingdom, estimates of incidence rate vary because of the rarity of Kawasaki disease. However, it is believed to affect fewer than one in every 25,000 people. Incidence of the disease doubled from 1991 to 2000, however, with four cases per 100,000 children in 1991 compared with a rise of eight cases per 100,000 in 2000. In the continental United States, Kawasaki disease is more common during the winter and early spring, boys with the disease outnumber girls by ≈1.5–1.7:1, and 76% of affected children are <5 years of age.
The disease was first reported by Tomisaku Kawasaki in a four-year-old child with a rash and fever at the Red Cross Hospital in Tokyo in January 1961, and he later published a report on 50 similar cases. Later, Kawasaki and colleagues were persuaded of definite cardiac involvement when they studied and reported 23 cases, of which 11 (48%) patients had abnormalities detected by an electrocardiogram. In 1974, the first description of this disorder was published in the English-language literature. In 1976, Melish et al. described the same illness in 16 children in Hawaii. Melish and Kawasaki had independently developed the same diagnostic criteria for the disorder, which are still used today to make the diagnosis of classic Kawasaki disease.
A question was raised whether the disease only started during the period between 1960 and 1970, but later a preserved heart of a seven-year-old boy who died in 1870 was examined and showed three aneurysms of the coronary arteries with clots, as well as pathologic changes consistent with Kawasaki disease. Kawasaki disease is now recognized worldwide. In the United States and other developed nations, it appears to have replaced acute rheumatic fever as the most common cause of acquired heart disease in children.