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

Overview

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, mucous membranes, lymph nodes, blood vessel walls, and the heart. There is no evidence that Kawasaki disease is contagious. It was first described in 1967 by Dr. Tomisaku Kawasaki in Japan. 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 the Asian race and male sex. Kawasaki disease can cause vasculitic changes (inflammation of blood vessels) in the coronary arteries and subsequent coronary artery aneurysms( reported in about 25% of cases). Common symptoms of Kawasaki disease include high-grade fever, red eyes, bright red and 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 soles of the feet, swollen hands, and feet, and rash. Echocardiography can be used to detect coronary artery dilatations and aneurysms. Intravenous immunoglobulin(IVIG) and aspirin are used to treat Kawasaki disease.

Historical Perspective

The first case of Kawasaki disease was seen at a Red Cross Hospital in a suburb of Tokyo,Japan in 1961 by Tomisaku Kawasaki, a Japanese pediatrician. He published his first case report in 1967 in the Japanese language. He founded the Kawasaki Disease Research Center in 1990. He expired on 14 June 2020 at the age of 95.

Initially, it was thought to be a self-limiting disease without any long term side effects. In the late '60s, Dr Noboru Tanaka and Dr Takajiro Yamamoto contested against this assumption based on their own experiences. In 1970, the first Japanese Nationwide Survey of the disease was done and it included a question regarding the cardiac sequelae of KD. This helped in confirming the suspicions of Dr Tanaka and Dr Yamamoto.

The Committee on Infectious Diseases of the American Academy of Pediatrics recommended IVIG as a therapy for kids with KD in 1988. Since then it has become the standard of care for the disease.

Classification

Kawasaki Disease can be classified as typical and atypical.

Typical cases fulfill the clinical diagnostic criteria.

Atypical or Incomplete Kawasaki disease cases are the ones that do not completely fulfill the clinical diagnostic criteria but have atypical clinical findings such as renal impairment. These cases are more common in young infants rather than older children. This makes diagnosing such cases imperative.

Pathophysiology

The pathophysiology of Kawasaki disease is not well understood.

Most of the current theories are of immunological origin. It is primarily a necrotizing inflammation of the medium-sized blood vessels affecting multiple organ systems. This can lead to various complications such as pericarditis, pneumonitis, myocarditis, aseptic meningitis, coronary artery aneurysms, etc. It leads to chronic inflammation of blood vessels which can evolve into stenosis as well as aneurysms. On microscopic analysis, ciliated bronchial epithelial cells frequently show intracytoplasmic inclusion-bodies.

Some believe that infectious agents combined with genetic predisposition lead to the development of Kawasaki Disease. But, the research in this direction has been controversial.

Causes

The etiology of Kawasaki disease remains unclear. A number of theories have been proposed suggesting various bacteria, viruses, and environmental factors as the trigger for the immune response in genetically susceptible individuals. However, none of these theories have been proven to date. While genetic predisposition has been observed in Kawasaki disease, the pattern of inheritance is unclear. The children, as well as the siblings of Kawasaki disease patients, are at an increased risk of developing the disease. One of the genes implicated in the pathogenesis of Kawasaki disease is the ITPKC gene. It codes for the enzyme Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC), which is responsible for the negative regulation of T-cell activation. Polymorphisms of this gene lead to varying levels of potential for T-lymphocyte activation in different individuals.

Differentiating Kawasaki disease from other diseases

Different rash-like conditions can be confused with Kawasaki Disease and are thus included in its differential diagnosis. The various conditions that should be differentiated from Kawasaki Disease include:

Disease	Features
Impetigo	It 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.
Insect bites	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.
Kawasaki disease	Commonly presents with high and persistent fever, red mucous membranes in mouth, "strawberry tongue", swollen lymph nodes and skin rash in early disease, with peeling off of the skin of the hands, feet and genital area.
Measles	Commonly presents with high fever, coryza and conjunctivitis, with observation of oral mucosal lesions (Koplik's spots), followed by widespread skin rash.
Monkeypox	The 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	The 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	It is 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	It commonly presents with gneralized systemic symptoms such as malaise, fatigue, headache and fever. Skin eruptions may be subtle and asymptomatic It is classically described as: Non-pruritic bilateral symmetrical mucocutaneous rash Non-tender regional lymphadenopathy Condylomata lata and Patchy alopecia.
Molluscum contagiosum	The 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	It is a common rash in infants, with clustered and vesicular appearance.
Rat-bite fever	It 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	The common symptoms include sore throat, swollen lymph nodes, fever, headache, fatigue, weakness, muscle pain and loss of appetite.
Scarlet fever	It 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	The symptoms may include maculopapular rash, petechial rash, abdominal pain and joint pain.
Stevens-Johnson syndrome	The 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	It 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	It 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	It commonly presents with rash, petechiae, headache, confusion, and stiff neck, high fever, mental status changes, nausea and vomiting.
Rickettsial pox	The 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	It commonly presents with headache, nuchal rigidity, fever, petechiae and altered mental status.

Epidemiology and Demographics

Incidence Kawasaki disease is most commonly found in children under 5 years of age. It is a common cause of acquired childhood heart disease in the United States of America. The incidence in the USA is 9-20 per 100000. It has been reported in over 60 countries. It has the highest incidence in North-East Asia esp. Japan and South Korea. Japan has been conducting nationwide surveys to evaluate the incidence of Kawasaki disease every two years since 1970. The 24th nationwide survey was conducted in 2017 to evaluate the incidence of Kawasaki disease for the years 2015 and 2016. The incidence was found to be 240 per 100000 for girls and 330 per 100000 for boys.

Case mortality Up to 25% of untreated KD cases and 5% of cases treated with IVIG develop cardiac complications such as coronary artery aneurysms. These can be fatal.

Age incidence is highest in children <5 years old. Although rarely, KD can occur in adults too.

Race The Asians and South Koreans are most prone to developing KD.

Gender Males are 150% more likely than females to develop KD.

Regions KD can be found worldwide ,but Japan and South Korea have reported the highest incidence of KD.

Risk Factors

Several risk factors have been identified :

• Age- It is most common in children below 5 years of age.

• Sex- males are more at risk as compared to females.

• Ethnicity- Pacific Islanders and Asians (especially common in Japanese and South Koreans).

Screening

No specific tests exist to diagnose or screen Kawasaki disease.

Patients with Kawasaki disease need to be screened for coronary artery lesions using imaging techniques such as 2D-Echo.

Natural History, Complications and Prognosis

Kawasaki disease is a condition often found in children below five years of age. It has an excellent even when left untreated with a mortality of only 2%. It usually resolves on its own. The course of the disease consists of 3 phases-

• Acute Febrile Phase- It is characterized by high fever, desquamation of mucous membranes, edema of hand & feet, and other diagnostic criteria. It usually lasts 1-2 weeks and can include the development of other clinical features such as aseptic meningitis, joint pains, myocarditis, and hepatic dysfunction.
• Subacute Phase-Begins afters 1-2 weeks of the onset of disease and lasts about four weeks. Fever, cervical lymphadenopathy, and rash resolve. Irritability, conjunctival injection, and anorexia persist. Coronary artery aneurysms might develop if the disease is untreated. The risk of sudden death is highest in this phase. Certain children may also develop neurological symptoms such as cerebral infarcts, encephalopathy, facial nerve block, etc.
• Convalescent Phase- Its beginning is marked by the resolution of all clinical signs & symptoms. Normalization of ESR, which takes about 5-6 weeks from the onset of the disease, marks the end of the convalescent phase.

Diagnosis

The diagnosis of Kawasaki Disease is clinical. The making a diagnosis requires the presence of high-grade fever for five days and four out of five other diagnostic criteria -

• Desquamation of mucous membranes( strawberry tongue)
• Polymorphous rash of hand & feet which can spread towards the trunk
• Cervical lymphadenopathy (more than 15mm in size; often unilateral and unpainful)
• Conjunctivitis
• Edema of hand & feet

Image Courtesy of Kim DS. (A) Bilateral, non-exudative conjunctival injection with perilimbal sparing. (B) Strawberry tongue and bright red, swollen lips with vertical cracking and bleeding. (C) Erythematous rash involving perineum. (D) Erythema of the palms, which is often accompanied by painful, brawny edema of the dorsae of the hands. (E) Erythema of the soles, and swelling dorsa of the feet. (F) Desquamation of the fingers. (G) Erythema and induration at the site of a previous vaccination with Bacille Calmette-Gurin (BCG). (H) Perianal erythematous desquamation

Labs and Imaging

Laboratory findings-

• Erythrocyte Sedimentation Rate and C-Reactive Protein are often elevated
• CBC shows a picture of Normocytic Anaemia
• Liver function tests(LFTs) might be elevated and Serum Albumin low if Hepatic dysfunction is present

Imaging

• Echocardiography might show coronary artery aneurysms & cardiac ventricular dysfunction
• Ultrasonography might show gall bladder enlargement

Treatment

Intravascular Immunoglobulin (IVIG) along with high dose Aspirin is the standard treatment of Kawasaki disease. Once IVIG is administered, a dramatic improvement in the patient's condition is noted within 24 hours. Although it is most beneficial in the first seven days of the disease, it effectively decreases the chances of development of coronary artery aneurysms and cardiac abnormalities up to ten days of onset. This improves the already excellent prognosis of Kawasaki disease.

Kawasaki disease is one of the exceptions where high-dose Aspirin can be given in children without worrying about Reye syndrome. Although it can cause normocytic anaemia and many physicians disagree with its use, the current guidelines recommend its use. It should be started as soon as possible and can be continued up to two months after the resolution of the disease. It is started at a high dose and then continued at low-dose after the resolution of fever. Aspirin prevents the development of any complication from hypercoagubility of the blood.

Most of the cases respond well to combined therapy with IVIG & Aspirin. However, 15-20 % of the cases are resistant and show inadequate response to this treatment. In such cases, treatment with steroids can be tried. It has been found that steroids hasten the resolution of the disease; shorten the hospital stay and also help prevent coronary artery complications.