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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 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. Intravenous immunoglobulin(IVIG) and aspirin are indicated in Kawasaki disease.

Historical Perspective

Kawasaki disease was first discovered 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.

Epidemiology

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. 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. The incidence in the USA is 9-20 per 100000.

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.

Genetics

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.

Natural History 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

(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 blood clots.