Kawasaki disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2]

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. 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.

Kawasaki disease was first discovered by Dr. Tomisaku Kawasaki when he saw his first case of Kawasaki disease in Japan, in 1961. Later in 1967, Kawasaki published his first report on Kawasaki disease in Japanese. Dr Kawasaki also developed “Japan Kawasaki Disease Research Center” in 1990.

Patients whose illness does not meet the diagnostic criteria of Kawasaki disease, but who have fever and coronary artery abnormalities are classified as atypical or incomplete Kawasaki disease. For patients of atypical or incomplete Kawasaki disease, an evidence of coronary abnormalities or CAA’s must be shown on the echocardiogram.

The exact pathogenesis of Kawasaki disease is not fully understood. However, it is thought that Kawasaki disease is caused by either environmental, viral, or genetic causes. Kawasaki disease is defined as the systemic inflammation of the medium sized arteries and in multiple organs and tissues, which can lead to the associated conditions of hepatitis, interstitial pneumonitis, abdominal pain, vomiting, diarrhea, gallbladder hydrops, aseptic meningitis, irritability, myocarditis, pericarditis, valvulitis, pyuria, pancreatitis, and lymphadenopathy. On gross pathology, large or giant coronary artery aneurysms, thrombi containing aneurysms, decreases in luminal diameter, stenosis of the lumen and chronic inflamation are can be seen. On microscopic histopathological analysis of autopsied cases of Kawasaki disease, intracytoplasmic inclusion bodies are frequently observed in ciliated bronchial epithelial cells.

The exact cause of Kawasaki disease has not been identified. The current etiological theories center primarily on immunological causes for the disease, much research is being carried out to discover a definitive toxin or antigenic substance, possibly a superantigen, that is the specific cause of the disease. There are several hypothesis for the cause of Kawasaki disease, infectious agents thought to induce Kawasaki disease include, parvovirus B19, meningococcal septicemia, adenovirus, bacterial toxin–mediated, superantigens, cytomegalovirus, Epstein-Barr virus, human lymphotropic virus, klebsiella pneumoniae bacteremia, mycoplasma pneumoniae, mite-associated bacteria, measles, propionibacterium acnes, parainfluenza type 3 virus, rotavirus infection, rickettsia species and tick-borne diseases.

Kawasaki disease must be differentiated from other diseases that cause different rash-like conditions and can be confused with Kawasaki disease. The various conditions that should be differentiated from Kawasaki disease include; infantile polyarteritis nodosa, juvenile idiopathic arthritis, leptospirosis, lyme disease, measles, mercury toxicity, pediatric rocky mountain spotted fever, toxic epidermal necrolysis, staphylococcal scalded skin syndrome, rheumatic fever, impetigo, insect bites, monkey pox, rubella, atypical measles, coxsackie virus, acne, syphilis, molluscum contagiosum, toxic erythema, rat-bite fever, parvovirus B19, cytomegalovirus, scarlet fever, Stevens-Johnson syndrome, varicella-zoster virus, chicken pox, meningococcemia, rickettsial pox, meningitis, toxic shock syndrome, roseola infantum (exanthem subitum), erythema infectiosum (fifth disease), enterovirus, dengue fever, drug – induced rash, infectious mononucleosis, pharyngoconjunctival fever, herpangina, and primary herpetic gingivostomatitis.

Kawasaki disease (KD) occurs worldwide, with the highest incidence in Japan, and it most often affects boys and younger children. KD 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 KD ranging from 9 to 19 per 100,000 children younger than 5 years of age. Approximately 4248 hospitalizations for Kawasaki disease, 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.

Common risk factors in the development of Kawasaki disease are due to a combination of non-modifiable and modifiable risk factors, that include environmental, genetic, and viral factors.

There is insufficient evidence to recommend routine screening for Kawasaki disease.

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. If treated in a timely fashion, this risk can be mostly avoided and the course of illness cut short. Patients with Kawasaki disease may progress to develop long term cardiovascular illness such as coronary artery disease, and pre-mature atherosclerosis. Common complications of Kawasaki disease include vasculitis and coronary artery aneurysms. Prognosis is generally excellent and the mortality rate of patients with Kawasaki disease is approximately 2%.

Kawasaki disease is diagnosed clinically (by medical signs and symptoms), and there are no specific laboratory tests that can tell if someone has Kawasaki disease. 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 a physician several times. 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, and include, mucositis (erythema of the palatine mucosa), fissured erythematous lips, “strawberry tongue”, rash (polymorphus, usually urticarial erythematous rash mainly in external extremities. The rash can spread to trunk), extremities changes (edema of hands and feet, erythema of palms & soles, desquamation of fingertips, bilateral non-exudative conjuctival erythema), and cervical lymphadenopathy of at least 15 milimeters.

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 and rise steadily for up to two weeks and is normally accompanied by irritability. Affected children develop red eyes, mucous membranes, and lips, a “strawberry tongue“, iritis, keratic precipitates (detectable by an ophthalmologist but usually too small to be seen by the naked eye), and swollen lymph nodes. Skin rashes occur early in the disease, and peeling of the skin in the genital area, hands, and feet may occur in later phases. Some of these symptoms may come and go during the course of the illness.

Physical examination of patients with Kawasaki disease is usually remarkable for erythematous rash, irritability, and desquamation of skin and mucous membranes.

Kawasaki disease is diagnosed by clinical presentation, although the laboratory findings are non-specific for the diagnosis of Kawasaki disease – normocytic anemia, thrombocytosis, with platelets ≥ 450×10³/μL (after first week of acute disease), leucocytosis with white blood cell count ≥ 15,000/μL, elevated erythrocyte sedimentation rate, elevated liver enzyme levels, hypoalbuminemia with ≥ 3.0g/dL, elevated c-reactive protein, hyponatremia and sterile pyuria can be noted on laboratory investigations.

Electrocardiogram in Kawasaki disease may demonstrate evidence of ventricular dysfunction or, occasionally arrhythmia due to myocarditis. However, in acute disease the electrocardiogram may demonstrate prolonged PR interval, non-specific ST changes, T-wave changes and increased Q/R ratio, which are consistent with myocarditis.

Abnormal findings on chest x-ray may be found in Kawasaki disease, however, they are non-specific and may include; peribronchial cuffing, reticulogranular pattern, pleural effusion, atelectasis and air trapping. In rare circumstances, several years after resolution of the first episode within the elderly population, calcifications of the coronary artery will lead to coronary artery aneurysms. These aneurysms may be visualized using a plain radiograph. This presentation is described as an “Aunt Minnie” sequelae of Kawasaki disease.

An ECG may be helpful in the diagnosis of Kawasaki disease. Findings on an ECG suggestive of Kawasaki disease include coronary artery dilatations, stenosis or aneurysms. Ultrasound may show hydrops (enlargement) of the gallbladder.

CT angiography scan may be helpful in the diagnosis of Kawasaki disease. Findings on CT scan suggestive of Kawasaki disease include small coronary artery dilatations, aneurysms or stenoses. Angiography is the most sensitive and specific for assessment of the vessels.

There are no MRI findings associated with Kawasaki disease, however, magnetic resonance angiography can accurately define coronary artery aneurysms in patients with Kawasaki disease.  

There are no other imaging findings associated with Kawasaki disease.

Apart from the imaging studies already discussed previously, urinalysis, lumbar puncture, biomarkers and angiography may be helpful in the diagnosis of Kawasaki disease. Findings suggestive of Kawasaki disease include the presence of white blood cells, leukocytosis and coronary artery aneurysms, respectively.

Intravenous immunoglobulin (IVIG) and aspirin are indicated in the treatment of Kawasaki Disease. It is imperative that treatment be started as soon as the diagnosis is made to prevent damage to the coronary arteries. Kawasaki disease and a couple of other indications are an exception to the use of aspirin in children, aspirin is otherwise normally not recommended for children due to its association with Reye’s syndrome. Children with Kawasaki disease should be hospitalized.

Mechanical revascularization may be attempted in patients with coronary artery compromise.

Primary prevention for Kawasaki disease is not applicable. Complications of the disease, however, may be prevented through the use of medical prophylaxis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2]

Kawasaki disease was first discovered by Dr. Tomisaku Kawasaki when he saw his first case of Kawasaki disease in Japan, in 1961. Later in 1967, Kawasaki published his first report of Kawasaki disease in Japanese. Dr Kawasaki also established the “Japan Kawasaki Disease Research Center” in 1990.

The historical timeline on Kawasaki disease is described below:^{[1][2][3][4][5][6][7]}

• In 1961, Dr. Tomisaku Kawasaki saw his first case of Kawasaki disease.
• In 1967, Kawasaki published his first report of Kawasaki disease in Japanese.
• In the 1960s, pathologist Noboru Tanaka and pediatrician Takajiro Yamamoto disputed the early assertion of Kawasaki that Kawasaki disease was a self-limited illness with no sequelae.
• In 1970, the first Japanese nationwide survey of Kawasaki disease was conducted and 10 autopsy cases of sudden cardiac death after Kawasaki disease were documented.
• In 1973, at the University of Hawaii hospital, pathologist Eunice Larson, in collaboration with Benjamin Landing at the Los Angeles Children’s Hospital, retrospectively established a diagnosis of Kawasaki disease in a 1971 autopsy case.
• In 1974, Tomisaku Kawasaki published the first English language report of 50 patients with Kawasaki disease.
• By 1974, the link between Kawasaki disease and coronary artery vasculitis was definitively established.
• In 1976, the first cases of Kawasaki disease outside of Japan were reported in Hawaii.
• In 1988, the Committee on Infectious Diseases of the American Academy of Pediatrics declared IVIG treatment as the recommended therapy for Kawasaki disease.
• In 1990, Dr Kawasaki established the “Japan Kawasaki Disease Research Center”.

• In March 2006, Kawasaki disease was mentioned in the television programs Nip/Tuck and Without a Trace, and 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 suffered from the disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2]

Patients whose illness does not meet the diagnostic criteria of Kawasaki disease, but who have fever and coronary artery abnormalities, are classified as atypical or incomplete Kawasaki disease. For patients of atypical or incomplete Kawasaki disease, an evidence of coronary abnormalities or CAAs must be shown on the echocardiogram.

• Patients whose illness does not meet the diagnostic criteria of Kawasaki disease, but who have fever and coronary artery abnormalities, are classified as:^[1]
  • Atypical Kawasaki disease
  • Incomplete Kawasaki disease
• For the patients of atypical or incomplete Kawasaki disease, an evidence of coronary abnormalities or CAA’s must be shown on the echocardiogram.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2], Sabawoon Mirwais, M.B.B.S, M.D.[3]

The exact pathogenesis of Kawasaki disease is not fully understood. However, it is thought that Kawasaki disease is caused by either environmental, genetic, or viral causes. Kawasaki disease is defined as the systemic inflammation of the medium sized arteries and in multiple organs and tissues, which can lead to associated conditions such as hepatitis, interstitial pneumonitis, abdominal pain, vomiting, diarrhea, gallbladder hydrops, aseptic meningitis, irritability, myocarditis, pericarditis, valvulitis, pyuria, pancreatitis, and lymphadenopathy. On gross pathology, large or giant coronary artery aneurysms, thrombi containing aneurysms, decreases in luminal diameter, stenosis of the lumen and chronic inflamation are noted. On microscopic histopathological analysis of autopsied cases of Kawasaki disease, intracytoplasmic inclusion bodies are frequently observed in ciliated bronchial epithelial cells.

• The exact pathogenesis of Kawasaki disease is not fully understood.
• It is thought that Kawasaki disease is caused by either environmental, viral, or genetic mutations in FCGR2A, CASP3, HLAclass II, BLK, IPTKC and CD40.

In independent cohort studies, the genes which have been identified to lead to the development of Kawasaki disease include:^[1]

• Inflammation of the coronary arteries leads to the most important clinical outcomes.^[8][9]
• Kawasaki disease is defined by the systemic inflammation of the medium-sized arteries, multiple organs and tissues.
• The systemic inflammation of the medium-sized arteries, organs and tissues can lead to the following associated conditions:

• On gross pathology, large or giant coronary artery aneurysms, thrombi containing aneurysms, decreases luminal diameter, stenosis of the lumen and chronic inflammation are the usual findings of Kawasaki disease.^[10]
• Kawasaki disease mainly involves the muscular arteries and is characterized by the following processes:
  • Necrotizing arteritis
  • Subacute vasculitis
  • Chronic vasculitis
  • Luminal myofibroblastic proliferation

• On microscopic histopathological analysis of autopsied cases of Kawasaki disease, intracytoplasmic inclusion bodies are frequently observed in ciliated bronchial epithelial cells.^[14]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2]

The exact cause of Kawasaki disease has not been identified. The current etiological theories center primarily on immunological causes for the disease. Much research has been carried out to discover a definitive toxin or antigenic substance, possibly a superantigen, to be established as the specific cause of the disease. There are several hypotheses for the cause of Kawasaki disease – infectious agents which are thought to induce Kawasaki disease include parvovirus B19, meningococcal septicemia, adenovirus, bacterial toxin–mediated, superantigens, cytomegalovirus, Epstein-Barr virus, human lymphotropic virus, klebsiella pneumoniae, mycoplasma pneumoniae, mite-associated bacteria, measles, propionibacterium acnes, parainfluenza type 3 virus, rotavirus infection, rickettsia species, and tick-borne diseases.

• The exact cause of Kawasaki disease has not been identified.
• The current etiological theories center primarily on immunological causes for the disease.
• Studies have failed to discover a definitive toxin or antigenic substance to be the causative agent.
• An unknown virus may play a role as an inciting factor as well.
• There are several hypotheses regarding the causality of Kawasaki disease.
• Infectious agents which are thought to induce Kawasaki disease are:^[1][2][3]
  • Parvovirus B19
  • Meningococcal septicemia
  • Adenovirus
  • Bacterial toxin–mediated superantigens
  • Cytomegalovirus
  • Epstein-Barr virus
  • Human lymphotropic virus
  • Klebsiella pneumoniae
  • Mycoplasma pneumoniae
  • Mite-associated bacteria
  • Measles
  • Propionibacterium acnes
  • Parainfluenza type 3 virus
  • Rotavirus
  • Rickettsia species
  • Tick-borne diseases

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2];Eiman Ghaffarpasand, M.D. [3]

Kawasaki disease must be differentiated from other diseases that cause different rash-like conditions and can be confused with Kawasaki disease. The various conditions that should be differentiated from Kawasaki disease include; infantile polyarteritis nodosa, juvenile idiopathic arthritis, leptospirosis, lyme disease, measles, mercury toxicity, pediatric rocky mountain spotted fever, toxic epidermal necrolysis, staphylococcal scalded skin syndrome, rheumatic fever, impetigo, insect bites, monkey pox, rubella, atypical measles, coxsackie virus, acne, syphilis, molluscum contagiosum, toxic erythema, rat-bite fever, parvovirus B19, cytomegalovirus, scarlet fever, Stevens-Johnson syndrome, varicella-zoster virus, chicken pox, meningococcemia, rickettsial pox, meningitis, toxic shock syndrome, roseola infantum (exanthem subitum), erythema infectiosum (fifth disease), enterovirus, dengue fever, drug – induced rash, infectious mononucleosis, pharyngoconjunctival fever, herpangina, and primary herpetic gingivostomatitis.

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:^{[1][2][3][4][5][6][7]}

Abbreviations: ABG= Arterial blood gas, ANA= Antinuclear antibody, ANP= Atrial natriuretic peptide, ASO= Antistreptolysin O antibody, BNP= Brain natriuretic peptide, CBC= Complete blood count, COPD= Chronic obstructive pulmonary disease, CRP= C-reactive protein, CT= Computed tomography, CXR= Chest X-ray, DVT= Deep vein thrombosis, ESR= Erythrocyte sedimentation rate, HRCT= High Resolution CT, IgE= Immunoglobulin E, LDH= Lactate dehydrogenase, PCWP= Pulmonary capillary wedge pressure, PCR= Polymerase chain reaction, PFT= Pulmonary function test.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2], Sabawoon Mirwais, M.B.B.S, M.D.[3]

Kawasaki disease (Kawasaki syndrome or 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 Kawasaki disease, 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.

• The incidence of Kawasaki disease is approximately 175 per 100,000 individuals in Japan.^[1]
• In the continental United States, population-based and hospitalization studies estimate an incidence ranging from 9 to 19 per 100,000 children under 5 years of age.^[2]
• The occurrence incidence of Kawasaki disease in the US is between 17.5 and 20.8 per 100,000 children < 5 years.^[3]
• Below is the list of the countries with the corresponding incidence rates of Kawasaki disease:
  • Japan: 243.1 and 264.8 per 100,000 in children younger than 5 years in 2011 and 2012, respectively.
  • South Korea: 134.4 cases per 100,000 for children under 5 years of age.^[4]
  • Ireland: 15.2 per 100,000 children younger than 5 years.^[5]
  • Finland:11.4 per 100,000 children younger than 5 years.^[6]
  • Norway: 5.4 per 100,000 children younger than 5 years.
  • Sweden: 7.4 per 100,000 children younger than 5 years.

• In 1999, the prevalence of Kawasaki disease was estimated to be in range of 5000 to 6000 in Japan.^[7]

• Kawasaki disease commonly affects individuals younger than 5 years of age.^[7]
• 80% of patients with Kawasaki disease are younger than 5 years of age

• Kawasaki disease usually affects individuals of the Asian race.^[7]
• Pacific Islanders are also more commonly affected.

• Males are more commonly affected by Kawasaki disease than females.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2]

Common risk factors in the development of Kawasaki disease are a combination of non-modifiable and modifiable risk factors, that include environmental, genetic, and viral factors.

Common risk factors in the development of Kawasaki disease are a combination of non-modifiable and modifiable risk factors, that include environmental, genetic, and viral factors.^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2]

There is insufficient evidence to recommend routine screening for Kawasaki disease.

There is insufficient evidence to recommend routine screening for Kawasaki disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2]

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. If treated in a timely fashion, this risk can be mostly avoided and the course of illness cut short. Patients with Kawasaki disease may progress to develop long term cardiovascular illness such as coronary artery disease, and pre-mature atherosclerosis. Common complications of Kawasaki disease include vasculitis and coronary artery aneurysms. Prognosis is generally excellent and the mortality rate of patients with Kawasaki disease is approximately 2%.

• 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.
• If treated in a timely fashion, this risk can be mostly avoided and the course of illness cut short.
• Patients with Kawasaki disease may progress to develop long term cardiovascular illness such as coronary artery disease, and pre-mature atherosclerosis.^[1]

• The cardiac complications are, by far, the most important aspect of Kawasaki disease:^[2][3]
  • Vasculitic changes in the coronary arteries
  • Coronary artery aneurysms
    • These aneurysms can lead to myocardial infarction 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.

• Other complications associated with Kawasaki disease are: ^[4]

• 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, but the risk of coronary artery involvement is much greater.
• Patients who have had Kawasaki disease should have an echocardiogram initially every few weeks, and then every 1 – 2 years to screen for the progression of cardiac involvement.
• Overall, about 2% of the patients die from complications of coronary vasculitis.
• 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.

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