Kawasaki disease

Kawasaki disease (also known as lymph node syndrome, Mucocutaneous lymph node syndrome, and Kawasaki syndrome) is a disease, largely of infants, which affects many organs, including the skin, mucous membranes, lymph nodes, and blood vessel walls, but the most serious effect is on the heart where it can cause severe aneurysmal dilations. Without treatment, mortality may approach 1%, usually within 6 weeks of onset. With treatment, the mortality rate is less than 0.01% in the U.S.[2] There is often a pre-existing viral infection that may play some role in pathogenesis. The conjunctival and oral mucosa, along with the epidermis (skin), become erythmatous (red and inflammed). Edema is often seen in the hands and feet and the cervical lymph nodes are often enlarged. Also, some degree of fever is often noted. It was first described in 1967 by Dr. Tomisaku Kawasaki in Japan.

Symptoms

Kawasaki disease often begins with a high and persistent fever that is not very responsive to normal disease of paracetamol (acetaminophen) or ibuprofen. The fever may persist steadily for up to two weeks and is normally accompanied by irritability. Affected children develop red eyes, red mucous membranes in the mouth, red cracked lips, a "strawberry tongue", iritis, keratic precipitates (detectable by an ophthalmologist but usually too small to be seen by the unaided eye), and swollen lymph nodes. Skin rashes occur early in the disease, and peeling of the skin in the genital area, hands, and feet (especially around the nails and on the palms and soles) may occur in later phases. Some of these symptoms may come and go during the course of the illness. If left untreated, the symptoms will eventually relent, but coronary artery aneurysms will not improve, resulting in a significant risk of death or disability due to myocardial infarction (heart attack). If treated in a timely fashion, this risk can be mostly avoided and the course of illness cut short.

• High-grade fever (greater than 39 °C or 102 °F; often as high as 40 °C or 104 °F) that normally lasts for more than 5 days if left untreated.
• Red eyes (conjunctivitis) without pus or drainage, also known as "conjunctival injection"
• Bright red, chapped, or cracked lips
• Red mucous membranes in the mouth
• Strawberry tongue, white coating on the tongue or prominent red bumps (papillae) on the back of the tongue
• Red palms of the hands and the soles of the feet
• Rash which may take many forms, but not vesicular (blister-like), on the trunk
• Swollen lymph nodes (frequently only one lymph node is swollen), particularly in the neck area
• Joint pain (arthralgia) and swelling, frequently symmetrical
• Irritability
• Tachycardia (rapid heart beat)
• Peeling (desquamation) palms and soles (later in the illness); peeling may begin around the nails
• Beau's lines (transverse grooves on nails)
• may find breathing difficult.

Complications

The cardiac complications are the most important aspect of the disease. Kawasaki disease can cause vasculitic changes (inflammation of blood vessels) in the coronary arteries and subsequent coronary artery aneurysms. These aneurysms can lead to myocardial infarction (heart attack) even in young children. Overall, about 10–18% of children with Kawasaki disease develop coronary artery aneurysms with much higher prevalence among patients who are not treated early in the course of illness. Kawasaki disease and rheumatic fever are the most common causes of acquired heart disease among children in the United States.

Causes

Like all autoimmune diseases, the cause of Kawasaki disease is presumably the interaction of genetic and environmental factors, possibly including an infection. The specific cause is unknown, but current theories center primarily on immunological causes for the disease. Evidence increasingly points to an infectious etiology, but debate continues on whether the cause is a conventional antigenic substance or a superantigen. Children's Hospital Boston reports that "[s]ome studies have found associations between the occurrence of Kawasaki disease and recent exposure to carpet cleaning or residence near a body of stagnant water; however, cause and effect have not been established."

An association has been identified with a SNP in the ITPKC gene, which codes an enzyme that negatively regulates T-cell activation. An additional factor that suggests genetic susceptibility is the fact that regardless of where they are living, Japanese children are more likely than other children to contract the disease. The HLA-B51 serotype has been found to be associated with endemic instances of the disease.

Diagnosis

Kawasaki disease can only be diagnosed clinically (ie. by medical signs and symptoms). There exists no specific laboratory test for this condition. It is difficult to establish the diagnosis, especially early in the course of the illness, and frequently children are not diagnosed until they have seen several health care providers. Many other serious illnesses can cause similar symptoms, and must be considered in the differential diagnosis, including scarlet fever, toxic shock syndrome, juvenile idiopathic arthritis, and childhood mercury poisoning (acrodynia).

Classically, five days of fever plus four of five diagnostic criteria must be met in order to establish the diagnosis. The criteria are: (1) erythema of the lips or oral cavity or cracking of the lips; (2) rash on the trunk; (3) swelling or erythema of the hands or feet; (4) red eyes (conjunctival injection) (5) swollen lymph node in the neck of at least 15 millimeters.

Many children, especially infants, eventually diagnosed with Kawasaki disease do not exhibit all of the above criteria. In fact, many experts now recommend treating for Kawasaki disease even if only three days of fever have passed and at least three diagnostic criteria are present, especially if other tests reveal abnormalities consistent with Kawasaki disease. In addition, the diagnosis can be made purely by the detection of coronary artery aneurysms in the proper clinical setting.

Investigations

A physical examination will demonstrate many of the features listed above.

Blood tests

• Complete blood count (CBC) may reveal normocytic anemia and eventually thrombocytosis
• Erythrocyte sedimentation rate (ESR) will be elevated
• C-reactive protein (CRP) will be elevated
• Liver function tests may show evidence of hepatic inflammation and low serum albumin

Other optional tests

• Electrocardiogram may show evidence of ventricular dysfunction or, occasionally, arrhythmia due to myocarditis
• Echocardiogram may show subtle coronary artery changes or, later, true aneurysms.
• Ultrasound or computerized tomography may show hydrops (enlargement) of the gallbladder
• Urinalysis may show white blood cells and protein in the urine (pyuria and proteinuria) without evidence of bacterial growth
• Lumbar puncture may show evidence of aseptic meningitis
• Angiography was historically used to detect coronary artery aneurysms and remains the gold standard for their detection, but is rarely used today unless coronary artery aneurysms have already been detected by echocardiography.

Treatment

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 and pediatric infectious disease specialists (although no specific infectious agent has been identified yet). It is imperative that treatment be started as soon as the diagnosis is made to prevent damage to the coronary arteries.

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. 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 Intravenous immunoglobulin. 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.

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.

There are also treatments for iritis and other eye symptoms. Other treatment may include the use of Infliximab (Remicade). Infliximab works by binding tumour necrosis factor alpha.

Epidemiology

By far the highest incidence of Kawasaki disease occurs in Japan (175 per 100,000), though 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. The disease affects boys more than girls. Kawasaki was extremely uncommon in caucasians until the last few decades. Approximately 2,000-4,000 cases are identified in the United States each year.

Prognosis

With early treatment, rapid recovery from the acute symptoms can be expected and the risk of coronary artery aneurysms 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. Patients who have had Kawasaki disease should have an echocardiogram initially every few weeks, and then every one or two years to screen for progression of cardiac involvement.

It is also not uncommon that a relapse of symptoms may occur soon after initial treatment with IVIG. This usually requires re-hospitalization and re-treatment. Treatment with IVIG can cause allergic and non-allergic 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 non-treatment.