Topic Editor: Grant E. Fraser, M.D., FRACGP, FACRRM, ASTEM

Review Date: 01/22/2013

Definition

Kawasaki Disease (KD), also known as mucocutaneous lymph node syndrome, is an acute febrile vasculitic condition which predominately affects young children and infants. It is of unclear etiology, and has a genetic and ethnic based predisposition.
Most morbidity and mortality relates to effects on the coronary arteries, with aneurysm, thrombosis, ectasia, acute coronary syndrome, and myocardial infarction occurring in a substantial number of cases. Other small and medium sized arteries can also be affected.

Description

• Tomisaku Kawasaki, a Japanese pediatrician, was the first to identify the disease in1967 in Japanese children. The first case of the disease reported outside Japan occurred in Hawaii (1,4)
• Kawasaki Disease (KD) is a believed to be triggered by an activated immune system which consequently stimulates an inflammatory response resulting in cytokine-mediated endothelial cell damage and vasculitis predominately involving coronary, and other small to medium sized arteries
• AHA Case Definition for KD includes fever lasting for longer than 5 days and at least 4 of the following 5 items
• Changes in extremities: Acute: Erythema and edema of hands and feet Convalescent: Membranous desquamation of fingertips
• Polymorphous exanthema
• Bilateral, painless bulbar conjunctival injection without exudate
• Changes in lips and oral cavity: Erythema and cracking of lips, strawberry tongue, diffuse injection of oral and pharyngeal mucosae
• Cervical lymphadenopathy (=1.5 cm in diameter), usually unilateral
• It is important to note that some cases of KD fail to meet these criteria. In patients with unexplained fever for =5 days who have less than 4 of the principle criteria, more complex criteria are available to still make the diagnosis of atypical KD. It is important to make this diagnosis in a timely manner and initiate appropriate therapy in such cases. The guidelines for diagnosis of atypical KD are available at: http://circ.ahajournals.org/content/110/17/2747/F1.expansion.html
• 90-95% of cases occur in children less than 10 years of age, with 85% being in those less than 5 years of age. Adult cases do occur, but are rare
• Typical features of Kawasaki disease include persistent fever, bilateral conjunctivitis, erythema of the tongue and lips, uveitis, perianal erythema, cervical adenopathy (generally unilateral solitary node), and non-vesicular rash, which may progress to a desquamating of the palms and soles
• If untreated, 15-25% children develop coronary artery aneurysms which can progress to rupture or case cardiac ischemia with death occurring in approximately 2% of untreated patients. Some patients require cardiac interventions such as coronary artery bypass grafting due to coronary artery aneurysm formation
• The disease progresses in three stages (when left untreated)
• Acute phase: The phase typically lasts 3 weeks and is characterized by carditis, mucocutaneous changes, and polymorphous rash. Coronary artery aneurysm, and symmetric polyarticular arthralgia in large joints, may develop in this stage
• Subacute phase: Patients may experience symptoms of periungual and perineal desquamation, arthralgia, and myocardial disease over the 2-3 weeks following the acute phase
• Chronic or convalescent phase: This phase can persist for months or years, during which the erythrocyte sedimentation rate normalizes but cardiac manifestations remain. Long term follow-up is required until resolution of coronary artery abnormalities

Epidemiology

Incidence/prevalence

• The incidence of Kawasaki disease is highest in Japan (222.9/100,000 children aged 0-4 years in 2010); however, it has a worldwide occurrence, with incidence of 20.8/100,000 in the U.S. and 8.4/100,000 in the U.K..
• Asians and Pacific Islanders have the greatest incidence, African Americans have moderate incidence, and Caucasians and Hispanics having the least incidence
• In the U.S., Kawasaki disease has exceeded rheumatic fever as the leading cause of acquired heart disease in children. In 2009, 5447 children were hospitalized for Kawasaki disease, of which 4040 were aged <5 years
• One evaluation of prevalence examining both Taiwan and U.S. concluded the following about patients in Taiwan:
• Incidence Age <5 years: 67.3/100,000
• Incidence Age 5-10 years: 5.75/100,000
• Incidence Age 10-15 years: 0.79/100,000
• Incidence Age 15-20 years: 0.26/100,000
• Modeling of disease incidence-prevalence in the U.S. indicates that by 2030, there should be:
• 6,200 new cases annually
• 161,776 people living in the U.S. with history of Kawasaki Disease
• 1 person per 1,600 living in the U.S. will have a history of Kawasaki Disease
• This condition occurs more commonly during winter and early spring

• Kawasaki disease is primarily seen in children aged 6 months to <5 years with peak incidence between 6-24 months

Gender

• Incidence is higher among males vs females (1.3-1.7:1)

Race

• Children of Japanese descent have the highest incidence of Kawasaki disease
• Children of Asian or Pacific Island descent also have a high incidence
• African Americans have a moderate incidence, while Caucasians and Hispanics have the lowest incidence
• A strong genetic component rather than environmental factors appears present, as Japanese who have immigrated to Hawaii have similar incidence to those in Japan (210.5/100,000 children/year), whereas Caucasians in Hawaii have incidence similar to that of the U.S. mainland (13.7 per 100,000 children/year)

Genetics

• Inositol 1,4,5-triphosphate 3-kinase C (ITPKC) has been identified as a susceptibility gene
• Siblings of children with Kawasaki disease have a 10-fold higher risk vs the general population. Children of parents with the disease have twice the risk of developing the disease
• There appears to be an increased incidence of various human leukocyte antigens:
• Greater availability of HLA types B54, Bw15, Bw35, and Bw22 in the Japanese
• HLA types Bw51, B5, and B44 among US whites
• HLA type Bw51 in Israelis
• Additional findings, also on the human leukocyte antigen 6p21.3 and in the CD40 region are reported

Risk factors

• Children aged 6 months to 5 years
• Male gender
• Japanese, Asian, or Pacific Islander ethnicity
• Twins with Kawasaki Disease (occurrence in second twin is ~13%)
• Winter and spring seasons

Etiology

• The exact etiology of this disease is unknown. Both clinical and epidemiologic features indicate an infectious link may be present; to date, no primary agent has been identified
• Genetic factors, yet to be fully identified are likely predominant as some populations, purely based upon ethnicity, and not environment have 20 fold increased risk (Japanese versus Caucasian children)
• A recent theory is that the disease may be related to Streptococcal pyogenic exotoxin A or C (SPEA or SPEC) and Staphylococcal enterotoxin A or B (SEA or SEB) which activate the immune system by acting as super antigens
• Kawasaki disease was once thought to be associated with bacterial infections such as scarlet fever, rheumatic fever, leptospirosis, Rocky Mountain spotted fever, and toxic shock syndrome; however, this appears incorrect
• Multiple infectious agents, primarily viral, have been isolated from patients with Kawasaki Disease. It is unclear if the presence of such agents is incidental, or plays some role in activating the immune processes which occur in this condition. Infectious agents reported include:
• Adenovirus
• Chlamydia pneumoniae
• Epstein-Barr virus
• Herpes virus 6 (HHV6)
• Influenza virus
• Measles virus
• Parainfluenza virus
• Parvovirus
• Rotavirus

History

Symptoms in the ten days leading up to a diagnosis of Kawasaki Disease (not including the principle clinical criteria) include (with % of cases reporting in parenthesis):

• Irritability (50%)
• Vomiting (44%)
• Decreased food/fluid intake (37%)
• Cough (28%)
• Diarrhea (26%)
• Rhinorrhea (19%)
• Weakness (19%)
• Abdominal pain (18%)
• Arthralgias or arthritis (15%)

• Duration and height of fever
• Presence of swelling or rash or other changes to the extremities
• Presence of rash
• Presence of conjunctivitis - without discharge
• Presence of changes in lips or tongue
• Presence of swollen cervical lymph node(s)

Physical findings on examination

• Diagnosis is based on clinical findings and history. No highly specific and sensitive test is available
• AHA Case Definition for KD includes fever lasting for longer than 5 days and at least 4 of the following 5 items
• Changes in extremities: Acute: Erythema and edema of hands and feet Convalescent: Membranous desquamation of fingertips
• Polymorphous exanthema
• Bilateral, painless bulbar conjunctival injection without exudate
• Changes in lips and oral cavity: Erythema and cracking of lips, strawberry tongue, diffuse injection of oral and pharyngeal mucosae
• Cervical lymphadenopathy (=1.5 cm in diameter), usually unilateral
• It is important to note that some cases of KD fail to meet these criteria. In patients with unexplained fever for =5 days who have less than 4 of the principle criteria, more complex criteria are available to still make the diagnosis of atypical KD. It is important to make this diagnosis in a timely manner and initiate appropriate therapy in such cases. The guidelines for diagnosis of atypical KD are available at: http://circ.ahajournals.org/content/110/17/2747/F1.expansion.html
• Other clinical findings include
• Cardiac findings
• Cardiovascular manifestations are mainly seen during the acute phase of the disease
• Cardiac murmur of aortic and/or mitral regurgitation
• If pericardial effusion is present, may have distant heart sounds, low voltage on ECG, large heart on chest x-ray
• May have tachycardia
• Central nervous system findings
• Temporary sensorineural hearing loss (acute phase)
• Temporary unilateral peripheral facial nerve palsy
• Irritability
• Gastrointestinal system findings
• Hepatomegally (rare)
• Jaundice (usually mild)
• Genitourinary system findings include
• Testicular swelling (rare)
• Urethritis/meatitis
• Musculoskeletal system findings
• Arthralgia or arthritis of interphalangeal joints and large weight-bearing joints
• Other findings
• Beau's lines on fingernails (in convalescent phase)
• Desquamating erythematous, maculopapular rash in perineum (in sub-acute phase)
• Erythema and induration at the site of a previous vaccination with Bacille Calmette-Guérin (BCG), common in Japan
• Mild anterior uveitis (common)

Blood tests findings

Laboratory findings are useful for the diagnosis of atypical Kawasaki disease in patients (7)

• Complete blood count
• White blood cell (WBC) count is increased in ~50% of patients, generally with a left shift (neutrophilia/bandemia)
• Elevated levels of erythrocyte sedimentation rate (ESR and C-reactive protein are seen which generally return to baseline levels by 6 to 10 weeks after disease onset
• Platelet count increases markedly during the acute stage
• Low platelet count during the acute stage is indicative of increased risk for coronary aneurysms
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels are often mildly elevated during the initial phase of the disease then decline
• Serum cholesterol, High density lipoprotein, and apolipoprotein A levels are decreased during the initial phase, but increase as the inflamma¬tion progresses
• Hypoalbuminemia may be evident in a severe and prolonged acute disease condition
• Decreased serum sodium levels can be correlated with a higher risk of coronary artery aneurysms
• Troponin Iand Troponin T levels are often elevated during the acute phase of the KD
• Diagnosis for atypical Kawasaki disease
• Patients in whom the fever lasts for 5 days with 2 diagnostic signs of the disease must be further investigated for systemic inflammation
• Abnormal levels include C-reactive protein >3mg/dl , ESR >40 mm/h, albumin <3.0 g/dl, anemia for age, elevated ALT, platelets >45000/mm3, WBC count > 15000/mm3, and urine >10 WBC/ high-power field
• If 3 criteria are met, perform electrocardiography (ECG) and initiate treatment
• Full criteria for atypical KD available at: http://circ.ahajournals.org/content/110/17/2747/F1.expansion.html

Other laboratory test findings

• Urinalysis: Mild to moderate sterile pyuria is seen in about one-third of patients
• Lumbar puncture: Cerebrospinal fluid (CSF) analysis reveals aseptic meningitis and elevated mononuclear cells in nearly 50% of patients

Radiographic findings

• Abdominal ultrasound may find hydrops of gallbladder during the first 2 weeks of the disease
• Chest Xray may show an enlarged boot like cardiac silhouette in the event of pericardial effusion. Lung changes may be evident in rare cases of congestive heart failure
• CT angiography may be used in the evaluation for systemic aneurysms which can occur in KD. It is rare for such an assessment to be required, as most systemic aneurysms (apart from coronary artery aneurysms) do not result in complications and usually regress in the convalescent stage
• CT coronary angiography (ECG triggers, dual source) is an option with low radiation exposure and excellent image quality in infants and children
• Magnetic resonance angiography (MRA) is a non-invasive procedure with good sensitivity and specificity for detecting coronary artery and systemic aneurysms

Other diagnostic test findings

• ECG is recommended in all patients presenting with suspected Kawasaki disease, and may have abnormalities such as abnormal Q waves, prolonged PR and/or QT, low voltage (usually with pericardial effusion), ST-T wave changes, and ST elevation may be present in myocardial infarction
• Echocardiography
  • Echocardiography is essential as part of any evaluation of KD, including initially and at 1-2 weeks, then at 4-8 weeks to monitor for coronary artery aneurysms and other cardiac complications
  • In descending order of frequency, coronary artery aneurysms occur in:
  • Proximal left anterior descending artery
  • Proximal right coronary artery
  • Left main coronary artery
  • Left circumflex artery
  • Distal right coronary artery
  • Junction between the right coronary artery and the posterior descending coronary artery
  • In one series of 198 patients with acute phase KD
  • 20% had left ventricular systolic dysfunction
  • 27% had mitral regurgitation
  • 8% had aortic root dilation
  • Of these patients with non-coronary artery cardiac abnormalities, a higher rate of coronary artery dilation was also found at echocardiograms done at 1 and 5 weeks after diagnosis

• Cervical lymphadenitis
• Drug hypersensitivity reactions
• Epstein-Barr virus
• Juvenile rheumatoid arthritis
• Leptospirosis
• Lyme disease
• Mercury hypersensitivity reaction (acrodynia)
• Mycoplasma infection
• Other vasculitides
• Peritonsillar or retropharyngeal abscess
• Reiter syndrome
• Rheumatic fever
• Rocky Mountain spotted fever
• Scarlet fever
• Staphylococcal scalded skin syndrome
• Stevens-Johnson syndrome
• Streptococcal infection (Group A)
• Toxic shock syndrome
• Toxoplasmosis
• Viral infections (e.g., Adenovirus, Enterovirus, Epstein Barr Virus, Parvovirus, Measles, and others)

General treatment items

• Intravenous immunoglobulin (IVIG)
• IVIG remains the gold standard treatment for treating the disease in its acute phase
• A single high dose of IVIG is known to significantly lower the incidence of coronary artery lesions and results in resolution of fever within 36 hours. In those who fail to respond; a second full dose is usually given. If there is failure to respond, then therapy for IVIG resistant treatment need to be administered
• A single dose of IVIG, along with aspirin should be administered as soon as KD is diagnosed. It is important that this occur within the first 10 days of the onset of KD to decrease the rate of coronary artery aneurysms and other sequelae
• Children without an initial accurate diagnosis who present after the 10th day of illness with persistent fever, aneurysms and contined systemic inflammation, should also be treated with IVIG
• The EATAK trial is evaluating whether addition of etanercept to IVIG and aspirin is beneficial for cases of KD with routinely administering all 3 agents at diagnosis
• Intravenous immunoglobulin-resistant treatment
• Approximately 15-20% of children fail to respond to the initial therapy of IVIG and aspirin. Such patients are at high risk for developing coronary artery lesions and require treatment with other interventions for refractory Kawasaki disease
• Options, none FDA approved, include steroids, infliximab or etanercept
• High dose methylprednisolone is a common option when steroids are utilized
• More recent small trials have showed etanercept and infliximab to be well tolerated and effective
• One trial in which infliximab was utilized for non-responders had 10% failure rate (2 cases), with both of these patients responding to plasma exchange with 5% albumin
• Aspirin
• Use of aspirin in combination with IVIG is recommended for treating KD. The anti-inflammatory dose of aspirin remains an issue of debate
• In the U.S., a high dose of aspirin (80-100 mg/kg per day for 4 days) is widely used with IVIG during the acute phase. Many clinicians reduce the dose of aspirin after the child remains afebrile for 48-72 hrs, while some continue the high dose until the 14th day of the disease and =>48-72 hrs after the fever has subsided
• In Japan, clinicians prefer a moderate starting dose of aspirin, such as 30-50 mg/kg per day due to concern regarding hepatotoxicity
• After discontinuation of high dose aspirin, most patients continue on low dose aspirin, (3 to 5 mg/kg per day) until there is no evidence of coronary arterial disease on 6-8 weeks followup echocardiography
• Children who develop coronary abnormalities should continue on aspirin for a more prolong period
• Steroids
• Before introduction of the IVIG therapy, corticosteroids were commonly used to treat the disease
• The use of methylprednisolone and IVIG may be effective in treating high-risk patients, although studies have had mixed results
• Intravenous methylprednisolone (IVMP) pulse therapy may be effective in patients who are resistant to the initial IVIG treatment
• Most clinicians are presently favoring use of tumor necrosis factor-a receptor blockers in this setting due to tolerability and efficacy (for patients resistant to IVIG and aspirin)
• Antithrombotic therapy
• Depending upon the degree of coronary artery aneurysmal disease, antiplatelet therapy with aspirin alone or in combination with dipyridamole or clopidogrel is often recommended. Combination anticoagulant and antiplatelet therapy (eg, warfarin plus aspirin) has also been used in more severe cases
• Surgery/Catheterization
• Surgical removal or plication of the coronary artery aneurysms is generally avoided due to a high mortality risk
• The primary surgical intervention for KD in cases of recurrent myocardial infarction and/or severe left ventricular dysfunction is coronary artery bypass grafting (CABG)
• Catheterization techniques such as balloon angioplasty, rotational ablation, and stenting can be utilized in patients with ischemic symptoms, reversible ischemia, or a high degree of stenosis in the LAD (75%)
• A small proportion of children with severe permanent myocardial impairment and coronary lesions that cannot be resolved by catheterization or CABG may require cardiac transplantation
• Other treatments
• Monoclonal antibodies against tumor necrosis factor-a receptor blocker such as infliximab or etanercept have been shown to be efficacious in treating patients that are unresponsive to conventional treatment
• Although plasma exchange therapy has shown benefit, is not routinely indicated, but appears efficacious in cases of IVIG refractory disease which also fails to respond to a tumor necrosis factor-a receptor blocker

Medications indicated with specific doses

Immunoglobulins

• Immune globulin (human) (Gammagard S/D) [IV]
• Adult dosing
• Pediatric Dosing

Anti-inflammatory agents

• Aspirin
• Adult dosing
• Pediatric Dosing

Corticosteroids

• Methylprednisolone [Injectable]
• Adult Dosing
• Pediatric Dosing

Tumor necrosis factor-a receptor blockers

• Etanercept [SC]
• Pediatric Dosing
• Infliximab [IV]
• Adult Dosing
• Pediatric Dosing

Dietary or Activity restrictions

• Low-risk patients with no coronary artery changes or mild arterial dilation/ectasia do not require activity restrictions after 6-8 weeks
• The physical activity of the patient with evidence of aneurysms is based on the ability to tolerate stress as shown by annual stress tests with myocardial perfusion scanning. In patients with no stress-induced myocardial ischemia, sports activity may include noncontact dynamic or recreational sports
• Avoidance of collision or high-impact sports if anticoagulants are being taken

Disposition

Admission criteria

• All patients with suspected Kawasaki disease meeting the diagnostic criteria should be admitted to hospital, generally on a cardiac monitored bed during the acute phase
• Patients with coronary artery involvement may require intensive care admission
• Cases with concerns for cardiac ischemia and potential need for either catheter directed or cardiothoracic intervention require transfer to a center capable of such therapy
• Patients refractory to IVIG and aspirin are at higher risk of complications and generally require transfer to a tertiary pediatric center

Discharge criteria

• Absence of fever 24-48 hours following IVIG treatment and otherwise clinically well, with close follow-up arranged and appropriate precautions given for indications to return
• Nontoxic children not meeting the diagnostic criteria may also be discharged

Monitoring

• It is essential to monitor WBC count, platelet count, and ESR weekly or biweekly until normal levels are attained
• Patients should undergo echocardiography for evaluation of coronary artery aneurysm development at 2 weeks, and at 6-8 weeks from disease onset. Coronary artery catheterization, CT coronary angiography (dual source, ECG gated), or MRA imaging should be obtained if aneurysm are evident on echocardiography
• Patients who develop symptoms of cardiac insufficiency require assessment of myocardial function

Complications

• Coronary artery aneurysm is the most common and serious complication of the disease. In absence of treatment, coronary artery aneurysm develops in ~25% patients
• Coronary artery aneurysms should generally occur within 6-8 weeks from the onset of the illness and can be adequately ruled out on 6-8 week echocardiography
• Other cardiac complications seen are
• Arrhythmias
• Cardiac tamponade
• Congestive cardiac failure
• Coronary artery dissection
• Left ventricular failure
• Myocardial infarction
• Myocarditis
• Pericardial effusion
• Pericarditis
• Valvular insufficiency (mitral or aortic)
• Neurological complications, found in ~1%-33% of patients, include
• Aseptic meningitis
• Ataxia
• Cerebral aneurysm; including risk of rupture - (rare)
• Cerebral infarction (rare)
• Chorea
• Facial palsy (rare)
• Focal encephalopathy
• Hearing loss (sensorineural)
• Migraine (late manifestation)
• Seizures
• Transient hemiplegia
• Other complications
• Acute renal failure (rare)
• Acute surgical abdomen
• Aneurysms of other arteries (systemic, cerebral, aorta)
• Hemophagocytic syndrome
• Irritability
• Lethargy
• Necrotizing enterocolitis (late manifestation)
• Pulmonary dysfunction
• Raynaud's phenomenon (late manifestation)
• Rhabdomyolysis

Prevention

• Given that the etiology of this disease appears primarily genetic rather than environmental, there are no definitive preventive measures available

• Most patients with disease-related aneurysms are asymptomatic
• Aneurysmal size is a crucial predictor of myocardial infarction. Giant aneurysms tend to have an unfavorable prognosis and may lead to ischemic heart disease
• Coronary artery aneurysm thrombosis can occur at any time. Progressive localized stenosis at the entry or exit of the aneurysm in the left coronary artery may also develop, most commonly during the first year of KD
• Patients who have significant coronary arterial disease from KD appear at high risk for progression of atherosclerotic disease of the coronary arteries. Such patients need to be monitored as myocardial infarction with atherosclerotic changes may occur in young adults
• Regional stenosis, especially in the left anterior descending artery can be predominant in some patients; often 10-20 years after KD diagnosis
• Coronary artery aneurysms and stenoses may lead to sudden cardiac death due to MI
• The hospital mortality rate in the United states remains low at ~0.17%, with majority of death occurring within 15-45 days of disease onset
• Infants <6 months of age, especially boys, appear at high risk of sudden death, even with optimal therapy as compared to older infants and children with KD

Pregnancy/Pediatric effects on condition

• Pregnancy and parturition may be associated with a risk of myocardial ischemia or infarction during labor due to changes in cardiovascular physiology and increased cardiac work load

Synonyms/Abbreviations

• Kawasaki syndrome
• Mucocutaneous lymph node syndrome
• Infantile polyarteritis

ICD-9-CM

• 446.1 Acute febrile mucocutaneous lymph node syndrome (MCLS)

ICD-10

• M30.3 Mucocutaneous lymph node syndrome [Kawasaki]

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