Kawasaki disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]

For the heart in Kawasaki disease click here

Kawasaki disease, also known as lymph node syndrome, mucocutaneous node disease, infantile polyarteritis and Kawasaki syndrome, is a poorly understood self-limited vasculitis that affects many organs, including the skin and mucous membranes, lymph nodes, blood vessel walls, and the heart. It does not seem to be contagious. It was first described in 1967 by Dr. Tomisaku Kawasaki in Japan.

Epidemiology and Demographics

KS occurs worldwide, with the highest incidence in Japan, and it most often affects boys and younger children. KS may have a winter-spring seasonality, and community-wide outbreaks have been reported occasionally. In the continental United States, population-based and hospitalization studies have estimated an incidence of KS ranging from 9 to 19 per 100,000 children younger than 5 years of age. Approximately 4248 hospitalizations for KS, of which 3277 (77%) were for children under 5 years of age, were estimated among children younger than 18 years of age in the United States in the year 2000.

CDC uses hospital discharge data, a passive KS surveillance system, and special studies to describe the incidence and epidemiology of KS in the United States. The KS surveillance system has been maintained by CDC since 1976 and is based on voluntary reporting of KS cases by health care providers and local and state health authorities. A standardized case report form is used to collect information on patients.

For epidemiologic surveillance, CDC defines a case of KS as illness in a patient with fever of 5 or more days duration (or fever until the date of administration of intravenous immunoglobulin if it is given before the fifth day of fever), and the presence of at least 4 of the following 5 clinical signs:

• Rash
• Cervical lymphadenopathy (at least 1.5 cm in diameter)
• Bilateral conjuctival injection
• Oral mucosal changes
• Peripheral extremity changes.

Patients whose illness does not meet the above KS case definition but who have fever and coronary artery abnormalities are classified as having atypical or incomplete KS.

Incidence, causes, and risk factors

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 5 years of age. Additional risk factors in the United States include Asian race and male sex.

The causative agent of Kawasaki disease is still unknown. However, current etiological theories center primarily on immunological causes for the disease. Much research is being performed to discover a definitive toxin or antigenic substance, possibly a superantigen, that is the specific cause of the disease. An unknown virus may play a role as an inciting factor as well.

The cardiac complications are, by far, 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 is the most common cause of acquired heart disease among children in the United States.

Symptoms

Kawasaki disease often begins with a high and persistent fever that is not very responsive to normal doses of 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 a week 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
• Swollen hands and 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

Signs and tests

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 tests (may or may not be performed)

• 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.

Diagnosis

Kawasaki disease is diagnosed clinically (by medical signs and symptoms), and there exists no specific laboratory test that can tell if someone has it. It is normally difficult to establish the diagnosis, especially early in the course of illness, and frequently children are not diagnosed until they have seen their doctor several times, or visited a number of different 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, and juvenile idiopathic arthritis.

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.

Differentiating Kawasaki disease from other diseases

Different rash-like conditions may be misdiagnosed with Kawasaki disease, including:

• Insect bites - In an insect bite, the insect injects formic acid, which can cause an immediate skin reaction often resulting in a rash and swelling in the injured area, often with formation of vesicles.

• Measles - commonly presents with high fever, coryza and conjunctivitis, with observation of oral mucosal lesions (Koplik's spots), followed by widespread skin rash.

• Monkeypox - presentation is similar to smallpox, although it is often a milder form, with fever, headache, myalgia, back pain, swollen lymph nodes, a general feeling of discomfort, and exhaustion. Within 1 to 3 days (sometimes longer) after the appearance of fever, the patient develops a papular rash, often first on the face. The lesions usually develop through several stages before crusting and falling off.

• Rubella - commonly presents with a facial rash which then spreads to the trunk and limbs, fading after 3 days, low grade fever, swollen glands, joint pains, headache and conjunctivitis. The rash disappears after a few days with no staining or peeling of the skin. Forchheimer's sign occurs in 20% of cases, and is characterized by small, red papules on the area of the soft palate.

• Atypical measles - symptoms commonly begin about 7-14 days after infection and present as fever, cough, coryza and conjunctivitis. Observation of Koplik's spots is also a characteristic finding in measles.

• Coxsackievirus - the most commonly caused disease is the Coxsackie A disease, presenting as hand, foot and mouth disease. It may be asymptomatic or cause mild symptoms, or it may produce fever and painful blisters in the mouth (herpangina), on the palms and fingers of the hand, or on the soles of the feet. There can also be blisters in the throat or above the tonsils. Adults can also be affected. The rash, which can appear several days after high temperature and painful sore throat, can be itchy and painful, especially on the hands/fingers and bottom of feet.

• Acne - typical of teenagers, usually appears on the face and upper neck, but the chest, back and shoulders may have acne as well. The upper arms can also have acne, but lesions found there are often keratosis pilaris, not acne. The typical acne lesions are comedones and inflammatory papules, pustules, and nodules. Some of the large nodules were previously called "cysts"

• Syphilis - commonly presents with gneralized systemic symptoms such as malaise, fatigue, headache and fever. Skin eruptions may be subtle and asymptomatic Classically described as 1) non-pruritic bilateral symmetrical mucocutaneous rash; 2) non-tender regional lymphadenopathy; 3) condylomata lata; and 4) patchy alopecia.

• Molluscum contagiosum - lesions are commonly flesh-colored, dome-shaped, and pearly in appearance. They are often 1-5 millimeters in diameter, with a dimpled center. Generally not painful, but they may itch or become irritated. Picking or scratching the lesions may lead to further infection or scarring. In about 10% of the cases, eczema develops around the lesions. They may occasionally be complicated by secondary bacterial infections.

• Mononucleosis - Common symptoms include low-grade fever without chills, sore throat, white patches on tonsils and back of the throat, muscle weakness and sometime extreme fatigue, tender lymphadenopathy, petechial hemorrhage and skin rash.

• Toxic erythema - common rash in infants, with clustered and vesicular appearance.

• Rat-bite fever - commonly presents with fever, chills, open sore at the site of the bite and rash, which may show red or purple plaques.

• Parvovirus B19 - the rash of fifth disease is typically described as "slapped cheeks," with erythema across the cheeks and sparing the nasolabial folds, forehead, and mouth.

• Cytomegalovirus - common symptoms include sore throat, swollen lymph nodes, fever, headache, fatigue, weakness, muscle pain and loss of appetite.

• Scarlet fever - commonly includes fever, punctate red macules on the hard and soft palate and uvula (Forchheimer's spots), bright red tongue with a "strawberry" appearance, sore throat and headache and lymphadenopathy.

• Rocky Mountain spotted fever - symptoms may include maculopapular rash, petechial rash, abdominal pain and joint pain.

• Stevens-Johnson syndrome - symptoms may include fever, sore throat and fatigue. Commonly presents ulcers and other lesions in the mucous membranes, almost always in the mouth and lips but also in the genital and anal regions. Those in the mouth are usually extremely painful and reduce the patient's ability to eat or drink. Conjunctivitis of the eyes occurs in about 30% of children. A rash of round lesions about an inch across, may arise on the face, trunk, arms and legs, and soles of the feet, but usually not on the scalp.

• Varicella-zoster virus - commonly starts as a painful rash on one side of the face or body. The rash forms blisters that typically scab over in 7-10 days and clears up within 2-4 weeks.

• Chickenpox - commonly starts with conjunctival and catarrhal symptoms and then characteristic spots appearing in two or three waves, mainly on the body and head, rather than the hands, becoming itchy raw pox (small open sores which heal mostly without scarring). Touching the fluid from a chickenpox blister can also spread the disease.

• Meningococcemia - commonly presents with rash, petechiae, headache, confusion, and stiff neck, high fever, mental status changes, nausea and vomiting.

• Rickettsialpox - first symptom is commonly a bump formed by a mite-bite, eventually resulting in a black, crusty scab. Many of the symptoms are flu-like including fever, chills, weakness and muscle pain but the most distinctive symptom is the rash that breaks out, spanning the person's entire body.

• Meningitis - commonly presents with headache, nuchal rigidity, fever, petechiae and altered mental status.

• Impetigo - commonly presents with pimple-like lesions surrounded by erythematous skin. Lesions are pustules, filled with pus, which then break down over 4-6 days and form a thick crust. It's often associated with insect bites, cuts, and other forms of trauma to the skin.

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 infectious agent has been demonstrated. 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.

Salicylate therapy, particularly aspirin, remains an important part of the treatment 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. Except for Kawasaki disease and a couple of 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.

The are also treatments for iritis and other eye symptoms.

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 1–2 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 retreatment. Treatment with IVIG can cause allergic and non-allergic acute reactions, aseptic meningitis, fluid overload and, rarely, other serious reactions. Aspirin may increase the risk of bleeding from other causes and may be associated with Reye's syndrome. Overall, life-threatening complications resulting from therapy for Kawasaki disease are exceedingly rare, especially compared with the risk of non-treatment.

Media

Kawasaki disease was mentioned in the television programs Nip/Tuck and Without a Trace . In the episode All In of the TV series House, it was inexplicably mentioned as a possible diagnosis for a 6 year old boy that was admitted with bloody diarrhea and coordination problems, as well as an elderly woman with unexplained respiratory, cardiovascular and neural deficiencies. Maxie Jones, a fictional character on General Hospital suffers from it. According to John Travolta and Kelly Preston, their son Jett Travolta also suffers from the disease.

External links

• Kawasaki Disease Foundation
• Kawasaki Disease Forum
• Kawasaki Disease Canada
• Kawasaki Disease Research Program
• Kawasaki Disease information from Seattle Children's Hospital Heart Center
• Template:GPnotebook