Kawasaki disease is an acute multisystem inflammatory disease of blood vessels (vasculitis) that most commonly affects infants and young children. The disease may be characterized by a high fever, inflammation of the mucous membranes of the mouth and throat, a reddish skin rash, and swelling of lymph nodes (lymphadenopathy). In addition, individuals with Kawasaki disease may develop inflammation of arteries that transport blood to heart muscle (coronary arteritis), associated widening or bulging (aneurysms) of the walls of affected coronary arteries, inflammation of heart muscle (myocarditis), and/or other symptoms and findings. Kawasaki disease is the primary cause of acquired heart disease in children in the United States. Although the cause of the disease is unknown, it is widely thought to be due to infection or an abnormal immune response to infection.
In many affected children, the initial symptom associated with Kawasaki disease is a high fever that typically rises and falls (remittent fever) and lasts for approximately one to two weeks without treatment. In some cases, fever may persist for up to about three to four weeks. Additional characteristic features include inflammation of the whites of the eyes (bilateral conjunctivitis); inflammation of mucous membranes of the mouth and throat, resulting in dry, red, cracked lips and a strawberry-red tongue; swelling of lymph nodes in the neck (cervical lymphadenopathy); redness and swelling of the hands and feet; and a reddish rash, typically affecting the trunk and often involving the groin area. By about the second or third week, skin tissue may peel (desquamate) from the tips of the fingers and toes and may progress to involve the hands and feet.
In many cases, affected children may have additional symptoms and findings, such as irritability, diarrhea, vomiting, coughing, and/or joint inflammation (arthritis), pain, and swelling. Other associated abnormalities may include enlargement of the liver and spleen (hepatosplenomegaly), inflammation of the protective membranes covering the brain (aseptic meningitis), inflammation of the middle ear (otitis media), and/or other findings.
Many individuals with Kawasaki disease may also have heart (cardiac) involvement. Up to 50 percent may develop inflammation of heart muscle (myocarditis), which may be associated with an abnormally increased heart rate (tachycardia), decreased ventricular (lower heart chamber) functioning, and, in severe cases, impaired ability of the heart to effectively pump blood to the lungs and the rest of the body (heart failure). In addition, in some cases, heart involvement may include inflammation of the membranous sac surrounding the heart (pericarditis), leakage of certain heart valves (aortic or mitral valve insufficiency), or other abnormalities.
The most serious cardiac complication is inflammation of arteries that provide oxygen-rich blood to heart muscle (coronary arteritis) and possible weakening, widening (dilation), and bulging (aneurysms) of affected arterial walls. Dilation and aneurysm formation occur in approximately three to 20 percent of patients. In severe cases, complications may include the development of blood clots in the ballooned area with obstruction of blood flow, bursting (rupture) of an aneurysm, or heart attack, leading to potentially life-threatening complications. Some cases have also been reported in which patients, particularly infants, have fever with fewer than four other features of the disease (see “Diagnosis” below) and subsequently develop coronary artery disease.
Although the exact cause of Kawasaki disease is not known, evidence indicates an infection or an inappropriate immune response to infection. However, despite much research in this area, a specific infectious cause has not been identified.
Recent evidence by Yale University investigators (2005) suggests that a newly discovered coronavirus may have a role in Kawasaki disease. Additional research is needed.
Some researchers suggest that the disease may be caused by certain toxic substances, called bacterial “superantigens,” that are produced by particular types of bacteria, such as streptococci or staphylococci. They indicate that such superantigens may trigger an exaggerated response of the immune system, resulting in infiltration of blood vessel walls with certain white blood cells, associated blood vessel inflammation (vasculitis), and cardiovascular damage. However, other researchers suggest that one or more conventional antigens may be involved in causing the inflammatory disease process. (An antigen is any substance that may trigger a particular immune response, such as foreign proteins, including microorganisms.) Further research is necessary to determine the role specific antigens or “superantigens” may play in causing Kawasaki disease.
Kawasaki disease most frequently affects children five years of age or younger. In extremely rare cases, Kawasaki disease may occur during adolescence or adulthood. First reported in Japanese children in the 1960s, the disease is now recognized worldwide and occurs in individuals in all racial and ethnic groups. However, Kawasaki disease appears to affect Asian children most frequently. Estimates indicate that at least 3,000 cases of Kawasaki disease are diagnosed each year in the United States. Males appear to be affected more frequently than females by a ratio of approximately 1.5 to 1.
Kawasaki disease is diagnosed based on a thorough clinical evaluation; a detailed patient history; and detection of characteristic features, including fever of at least five days and at least four of five characteristic signs (reddened eyes; changes of the lips and mouth; reddish, swollen extremities; rash; and swollen lymph nodes). Laboratory tests may reveal certain non-specific, though characteristic findings, including increased numbers of white blood cells (leukocytosis) and low levels of red blood cells (anemia) during early illness, with a rapidly rising blood platelet count by the second to third week after onset.
In addition, diagnostic tests should be conducted in all individuals with Kawasaki disease to detect possible heart involvement. Such testing may include echocardiography at diagnosis as well as at recommended intervals (e.g., at two to three weeks, six to eight weeks, and potentially six to 12 months after onset). During an echocardiogram, high-frequency sound waves are directed toward the heart, enabling physicians to study cardiac structure and function. Electrocardiograms (EKGs) are often performed along with echocardiograms. An EKG records the electrical activities of heart muscle. For children who develop coronary artery abnormalities, physicians may advise more frequent echocardiography and additional cardiac tests (e.g., stress testing, coronary angiography, and/or other tests). The recommended frequency and the specific tests used during long-term follow-up will be based on various factors, including clinical course, degree of coronary artery involvement, and patient age.
Experts indicate that children with Kawasaki disease should be treated by or in consultation with pediatricians who specialize in the diagnosis and treatment of heart disorders (pediatric cardiologists).
Research has shown that early diagnosis and treatment speeds the resolution of fever and other acute symptoms and significantly lowers the risk of heart damage. Treatment is started as soon as possible after diagnosis and may include high-dose intravenous immune globulin (IGIV) and high-dose aspirin therapy. Immune globulin is a special preparation containing antibodies obtained from the fluid portion of the blood. Evidence indicates that, when given within the first 10 days of onset, IGIV reduces the incidence of coronary artery abnormalities from about 20 percent in patients receiving aspirin alone to three to four percent.
In rare cases, patients may have an insufficient response to initial IGIV treatment and may require re-treatment.
The Food and Drug Administration (FDA) has approved the following IGIV products (immune globulin intravenous [human]) for the treatment of Kawasaki disease: Gammagard S/D, manufactured by Baxter Healthcare; Venoglobulin-S, manufactured by Alpha Therapeutic; Venoglobulin-I, manufactured by Alpha Therapeutic; and Iveegam, manufactured by Baxter Healthcare.
By the 14th day of illness or after resolution of fever, a lower dose of aspirin is typically given for its antiplatelet effect to help prevent blood clots from forming. Such therapy may be continued for up to eight weeks after onset in children without abnormalities detected by echocardiography. However, physicians may advise that aspirin therapy be continued indefinitely for those with coronary artery abnormalities. In some cases, individuals who have multiple or large coronary aneurysms may also receive therapy with anticlotting medications, such as dipyridamole or warfarin.
Due to a small risk of Reye syndrome during outbreaks of flu (influenza) and chickenpox, physicians may recommend annual influenza vaccination for children who require long-term aspirin therapy. (Reye syndrome is a rare disorder of childhood characterized by fatty changes of the liver and acute swelling of the brain. There appears to be an association between the onset of Reye syndrome and the use of aspirin-containing medications [salicylates] in children or adolescents with certain viral illnesses, particularly upper respiratory tract infections [e.g., influenza B] or, in some cases, chickenpox.. If affected children develop symptoms of flu or chickenpox, parents should immediately alert their child's physician, who may recommend temporary interruption of aspirin therapy or temporary substitution with dipyridamole.
In rare cases, coronary artery bypass surgery or heart transplantation may be recommended for individuals with severe heart involvement. Treatment with corticosteroid drugs is not recommended for children with Kawasaki disease. Other treatment for affected individuals is symptomatic and supportive.
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