The first case of infantile mucocutaneous lymph node syndrome was recognized in Japan in 1961, with the original paper published by Tomisaku Kawasaki in 1967 1. Cases of sudden death with coronary aneurysms and thrombosis were recognized in 1970 after the first Japanese nationwide survey 2. Coronary artery aneurysms have been documented using arteriography and two-dimensional echocardiography 3. Intravenous gammaglobulin was introduced as a treatment for the condition in 1983 4.

EPIDEMIOLOGY

In Japan there has been a nationwide survey of Kawasaki disease (KD) at 2-year intervals since 1970 conducted by the KD Research Committee. As of December 1988, 10 surveys had been conducted and the total number of cases reported was 94,330. As of December 1990, more than 100,000 cases had been reported. According to recent data, recurrent cases make up 3–5% of this total. Each survey has shown that the peak age of incidence is 1 year of age, with 80–85% of cases under 5 years of age. The male to female ratio is 1.5:1.

The fatality rate before 1974 was 1.0–2.6%, but this declined after 1975 and at present the rate is 0.08–0.1%. The total number of fatal cases as of 1988 was 363 (0.4%). The male to female ratio of those who died was about 3:1.

There is no difference between the number of cases reported from urban areas and rural areas. Although cases reported in the USA involve patients from the middle class and above, in Japan this is not the case and patients may come from any background. Similarly, there is no difference between breast-fed and formula-fed children.

In Japan there have been three nationwide epidemics of KD:

· December 1978 – June 1979;

· January 1982 – June 1982;

· November 1985 – May 1986.

The usual annual incidence of KD is 70–80 cases per 100,000 children below 5 years of age, but in those years including an epidemic the number of cases increase about six-fold.

In 1979, the epidemic began in southwest Japan and in 4 months moved across the country to the northernmost part. In the 1982 epidemic there was no such movement. The 1986 outbreak 5 started in the Tokyo metropolitan area, moved northward, and in 4 months had spread throughout the country. Nevertheless, there was no clear evidence of person-to-person transmission. Interestingly, however, investigation of sibling cases, which accounted for only 1–2% of the total, showed that 50% occurred 7 days after the first sibling was affected.

According to reports from Hawaii, KD can be seen in children of all racial descents but particularly affects children of Oriental origin, especially children of Japanese ancestry. The lowest rate of occurrence is seen in Caucasian children. The rate of occurrence in Black children, Hawaiian children, and children of mixed ancestry, falls midway between these extremes.

There have been reports of cases of KD from every continent in the world, but the disease is most prevalent in developed countries, with only rare reports of cases from the developing countries.

CLINICAL FEATURES

The symptoms of KD can be classified into two categories: principal symptoms (Fig. 21.1), and other significant symptoms or findings.

Principal Symptoms

In general, the onset of this disease is with abrupt high fever, with or without prodromal symptoms. Irrespective of whether aspirin or antibiotics are administered, there is usually remittent or continuous fever ranging from 38–40°C and lasting 1–2 weeks. Sometimes the fever lasts 3–4 weeks; fever lasting more than 4 weeks is rare, so if fever persists another disease should be suspected. If gammaglobulin treatment is given, the fever subsides within a few days. Steroid with aspirin is also often effective in helping the fever to subside.

Within 2–4 days of onset, conjunctival congestion occurs. This condition usually subsides within 1 week but occasionally continues for several. Bulbar conjunctivae are especially remarkable. Usually there is no discharge.

Changes in the lips and oral cavity occur 2–5 days after onset. There is dryness, redness and fissuring of lips, and in some cases bleeding and crust formation (Fig. 21.2). The membrane of the oral cavity and pharyngeal mucosa show diffuse reddening. There is no vesicle, aphtha or pseudomembrane formation. Frequently, the strawberry tongue seen in scarlet fever can also be seen in KD. These changes subside within 2 weeks, although the reddening of the lips will often continue for 3–4 weeks.

Painful cervical lymphadenopathy can be seen and may appear 1 day before or simultaneously with the onset of fever. The swelling is a firm, nonfluctuant mass more than 1.5cm in diameter. Bilateral swelling is often misdiagnosed as mumps.

Exanthema can be seen on the trunk and/or on the extremities within 1–5 days of onset (Fig. 21.3). The nature of the exanthema is polymorphous: morbilliform, urticarial, or erythema multiform-like lesions can be seen. Scarlatiniform exanthema should be differentiated from scarlet fever. The exanthema disappears when fever subsides.

At about the same time as the appearance of the other principal symptoms there is reddening of the palms and soles and indurative edema also occurs. Again, these symptoms disappear when the fever subsides. Membranous desquamation on the fingertips (Fig. 21.4), sometimes extending to the wrists, can be seen 10–15 days from onset.

Other Symptoms or Findings of Significance

The most significant complications of KD involve cardiovascular events. In the acute phase in more than 80% of cases there is mild or severe carditis. Severe cases can be recognized through heart murmur, gallop rhythm, and distant heart sounds with auscultation. The changes on ECG are prolonged PR-QT intervals, abnormal Q wave, low voltage ST-T changes and arrhythmias. Cardiomegaly (due to myocarditis or pericarditis) can be found on chest X-ray. Two-dimensional echocardiography frequently shows coronary artery changes such as dilatation or aneurysms. In cases of angina pectoris or myocardial infarction 6, coronary angiography 7,8 is necessary (see Fig. 21.5). In rare cases, peripheral arteries such as axillary, subclavicular and iliac arteries, show aneurysms. Also very rare is necrosis of fingers and toes.

Gastrointestinal complications in the acute phase include diarrhea and vomiting, and abdominal pain and mild jaundice occur due to hydrops of the gall bladder. Sometimes there is paralytic ileus and a slight increase of serum transaminase due to hepatitis. Neurologic symptoms are also manifest in the acute phase. Patient irritability is often seen. Spinal tap shows mild pleocytosis of mononuclear cells in 30–40% of cases, and sometimes there is febrile convulsion. In rare cases there is facial palsy and paralysis of the extremities. Loss of consciousness may occur due to encephalitis or encephalopathy. Acute changes in the blood are leukocytosis with shift to the left, increased ESR and positive C-reactive protein (CRP). Two to three weeks after onset, remarkable thrombocytosis appears. In severe cases there is hypoalbuminemia.

Other complications include:

· slight proteinuria and slight increase of leukocytes in urine sediment;

· occasional aseptic small pustules on the elbows, knees and/or buttocks;

· transverse furrows of the fingernails seen 2–3 months after onset;

· upper respiratory signs such as sneezing and coughing, though chest X-rays do not indicate pneumonia;

· arthritis in about 20–30% of cases, with involvement of small and large joints.

INVESTIGATIONS AND DIFFERENTIAL DIAGNOSIS

The differential diagnosis of KD is extensive and includes essentially all febrile illnesses associated with rash in the pediatric age population. The following laboratory findings are suggestive of KD:

· leukocytosis with shift to the left;

· increased ESR;

· positive CRP;

· thrombocytosis;

· negative ASO;

· negative throat culture and blood culture;

· pleocytosis in cerebrospinal fluid;

· slight increase of serum transaminase activity.

STRUCTURE AND FUNCTION

The primary changes in KD are systemic vasculitis, especially involving coronary arteries, or inflammation of organs such as carditis and hepatitis.

Pathologic Processes and Development of Coronary Artery Aneurysms in Kawasaki Disease

The most important element in the pathologic process of KD is systemic vasculitis, particularly the development of coronary artery changes including aneurysms 9 (Fig. 21.6). In the acute phase there is vasculitis in the medium-sized arteries, such as the main coronary arteries and the interlobular arteries of the kidneys. The angiitis of KD is characterized by an acute inflammation lasting about 7 weeks, with or without mild fibrinoid necrosis. The course of this angiitis may be classified into four stages 10.

In stage one, which occurs during the first 2 weeks following onset, there is perivasculitis of the microvessels (arterioles, capillaries and venules), small arteries and veins, and then inflammation of the intima, adventitia and perivascular areas of the medium-sized and large arteries, with edema and infiltration with leukocytes and lymphocytes.

The second stage begins around 2 weeks after onset of the disease and lasts for a further 2 weeks. It is marked by a decrease in the inflammation of the microvessels, small arteries and veins, together with focal panvasculitis. Aneurysms with thrombi and stenosis occur in the medium-sized arteries, especially the coronary arteries. Panvasculitis is rarely seen in the large arteries. There is edema, infiltration with monocytes, and cellular granulation with an increase of capillaries.

Stage three, lasting from the fourth to the seventh week following onset, comprises subsidence of inflammation in the microvessels, small arteries and veins, and granulation in the medium-sized arteries.

Beyond the seventh week there is a fourth stage involving scar formation and intimal thickening, with aneurysm, thrombi and stenosis in the medium-sized arteries. The angiitis can be seen most frequently in the medium-sized and large arteries to the heart and iliac organs. In autopsy cases 90% of coronary arteries and 17–38% of iliac arteries reveal aneurysms. Other arteries, such as those to mesenteric organs and those to the kidneys, also occasionally reveal them. The angiitis can also be seen in the internal arteries of the heart, skin, kidneys and tongue, as well as in the veins. Myocarditis involving the conduction system, pericarditis, endocarditis, cholecystitis, cholangitis, pancreatic ductitis, sialoadenitis, meningitis and lymphadenitis are often seen.

ETIOLOGY

The etiology of KD is unknown. Microorganisms may initially act as a trigger for abnormal immunologic activation and/or suppression. Various hypotheses have been proposed, some supporting an infectious and some a noninfectious etiology. A number of bacteria (e.g. Propioni bacterium acnes, Streptococcus sanguis), and several viruses (Epstein–Barr virus, retroviruses), have been suspected etiologic agents. The noninfectious etiological agents which have been proposed include detergents, mercury, and mites. However, none of them has been confirmed.

PATHOGENESIS

During the acute phase KD patients have a significant reduction in circulating CD8+ suppressor/cytotoxic T cells and increased numbers of Ia/DR-bearing CD4+ T cells 11. There is also a significantly elevated number of circulating B cells, spontaneously secreting IgG and IgM. Immunologic abnormalities can also be seen. However, evidence of autoimmunity has not been recognized.

The mechanism of vascular lesion in the acute phase of KD may be due to increased presence of antibodies, g-interferon and monokines such as interleukin-1 and tumor necrosis factor.

A current theory for the development of vasculitis is that in the acute phase of KD the immune system is activated. This results in an increased production of cytokines and antibodies. Cytokines stimulate endothelial cells, giving rise to neoantigens. The increased immunoglobulins include cytolytic antibodies, which combine with the neoantigens to produce endothelial cell damage, leading to vasculitis.

Intravenous gammaglobulin treatment suppresses the activated immune system and stops the development of vasculitis.

MANAGEMENT

Acute Phase

Two-dimensional echocardiography is employed to confirm coronary artery changes, and as soon as a diagnosis is made, high dose i.v. gammaglobulin treatment should be started 12. The standard procedure is 400mg/kg/day for 4 days. Usually, aspirin treatment is added at a dosage of 80–100mg/kg/day.

Coronary artery changes are monitored by weekly two-dimensional echocardiography which is continued for 4 weeks from onset. If coronary artery aneurysms are discovered low-dose aspirin (3–5mg/kg/day) treatment is continued until regression can be seen. If large or giant aneurysms are discovered, regression is difficult and there is the possibility of development of stenosis/and or obstruction. In this case, anticoagulant drugs, for example dipyridamole (5mg/kg), flurbiprofen (4mg/kg), or ticlopidin (5mg/kg), should also be administered.

Long-term management is not necessary in cases without coronary artery changes, but when these are present, not only two-dimensional echocardiography but also angiography should be performed. Depending on the case, angiography should be repeated at 1–2 year intervals. For cases with infarction, ECG and thallium scintigraphy should be carried out. Some cases may call for bypass surgery.

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