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Kawasaki Disease

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Diagnosis

The diagnosis can be made where there is fever plus at least four of the five features listed under early manifestations. One of the most serious complications is the delayed development of coronary artery aneurysms, which will develop in at least 20% of untreated patients.

Febrile infants less than a year old may present with less <4 characteristic features. The diagnosis of atypical Kawasaki disease can be made in this situation if coronary artery disease is present.

Patients require admission to hospital if Kawasaki Disease is diagnosed or strongly suspected.

Early Clinical Manifestations

Kawasaki Disease is a multisystem illness with fever and rash, which occurs mainly in children less than 5 years old. Within 3 days of the abrupt onset of fever, the other characteristic features usually appear:

  • Bulbar conjunctivitis (no exudate) 
  • Mucositis: red cracked lips, red mouth and throat, strawberry tongue 
  • Polymorphous generalized rash that can be morbilliform, maculopapular, scarlatiniform or may resemble erythema multiforme 
  • Induration of the hands and feet with red palms and soles 
  • Cervical lymphadenopathy (usually a solitary, unilateral node > 1.5 cm in size) 
  • BCG site reactivation (erythema around BCG scar, usually on left upper arm) 

Other Findings

Extreme irritability, severe abdominal pain, diarrhoea and vomiting are common. Other features may include:

  • Urethritis with sterile pyuria (70% of cases) 
  • Hepatic dysfunction (40% of cases) 
  • Arthritis or arthralgias (35%) 
  • Aseptic meningitis (25%) 
  • Pericardial effusion or arrhythmias (20%) 
  • Gallbladder hydrops (<10%) 
  • Carditis with congestive heart failure (< 5%). This can occur at any time in the first 3 weeks, and usually resolves by 6 to 8 weeks. 
  • Other arterial aneurysms (e.g. iliac, femoral, renal, axillary) may occur 

Incomplete Kawasaki Disease

Some patients with Kawasaki Disease do not meet all the diagnostic criteria. See algorithm below for a strategy to evaluate suspected incomplete cases (Pediatrics 2004;114 (6):1708).

Kawasaki disease


Supplementary Laboratory Information

  • Albumin < 30g/L
  • Anaemia for age
  • White cell count > 15 E+9/L
  • Platelets after 7 days >450 E + 9/L
  • Elevated ALT
  • Urine White Cells > 10 per high powered field

Positive Echocardiogram (any ONE of the following)

  • Z score of RCA or LAD >2.5
  • Japanese MOH criteria
  • Any 3 suggestive features:

    - Perivascular brightness
    - Lack of tapering of coronary arteries
    - Z score > 2.0
    - Pericardial effusion
    - Mitral regurgitation
    - Impaired LV function

Late Manifestations

  • The lips usually begin to dry, crack and fissure by day 6 of the illness
  • The skin of the fingertips, palms ± soles begins to peel in weeks two and three
  • Beau lines (transverse grooves in nailbeds) and temporary hair loss
  • With no treatment, the average length of fever is 12 days, and when the fever resolves the child may remain irritable for a further 2 to 3 weeks.

Coronary Aneurysms

Coronary aneurysms usually appear 2 to 4 weeks into the illness, but can be found as early as 3 days. Appearance later than 6 weeks is uncommon. In some children with mild coronary dilatation, the coronary artery size may return to baseline within 8 weeks of the onset of disease. In others, the arteries frequently return to normal size over 1 to 2 years. However, the lumen of the vessel may remain abnormal, or there may be coronary stenosis.

75% of fatalities occur within six weeks of the onset of symptoms, but myocardial infarction and sudden death can occur months to years after the acute episode.

Various clinical scoring systems exist to identify patients at high risk of poor coronary outcomes however these have not been validated in non-Japanese populations.

Risk factors include:

  • Fever for > 10days at presentation
  • Significant laboratory abnormalities - thrombocytopenia, hypoalbuminaemia, raised liver transaminases, anaemia
  • Persisting fever & inflammation after first dose of IVIG
  • Age <12months or older than 5 years
  • Asian ethnicity
  • Male sex
  • Clinical signs of cardiac involvement (arrhythmias, pericardial effusion)

Differential Diagnosis

  • Viral infections e.g. measles, adenovirus, enterovirus
  • Scarlet fever
  • Staphylococcal scalded skin syndrome
  • Toxic shock syndrome
  • Polyarteritis nodosa
  • Bacterial cervical lymphadenitis
  • Drug hypersensitivity reactions
  • Stevens-Johnson syndrome
  • Leptospirosis
  • Mercury hypersensitivity

Recurrence

Second episodes are rare in previously affected children.

Epidemiology

The peak age of occurrence in the United States is 18 to 24 months, with 80% of affected children being less than 5 years old. Children older than 8 years rarely have Kawasaki's disease. The incidence is higher in the Asian community.

There can be clinical overlap with polyarteritis nodosa and toxic shock syndrome.

Investigations

The ESR and CRP are usually raised during the first two weeks of the illness. Thrombocytosis (platelet count > 450) after day 10 of the illness is also common.

ECG and CXR are the initial cardiological investigations.

Inpatient pediatric cardiology review and echocardiogram are indicated if:

  • there are ECG changes suggestive of myocardial ischaemia
  • there is a murmur of mitral regurgitation
  • there are signs of congestive heart failure
  • the diagnosis is unclear
  • there is persistent fever > 48 hours after IV immunoglobulin
  • the child presents beyond 10 days of illness

Adequate visualization of the coronary arteries is difficult in young, irritable children. The timing and site of the echocardiogram, and the need for sedation, should be discussed with the Paediatric Cardiologist on a case-by-case basis.

There is no indication for early echocardiography in those who present early (< 10days), have no ischaemia on their ECG and respond to IVIG. This is supported by NZPSU surveillance data and report (the AHA recommend echo for all at presentation but this remains unproven).

Treatment

Treatment aims to rapidly "switch off" the inflammatory process and minimise the risk of coronary artery inflammation / aneurysm formation. Specific therapy must be given early to be most effective, so it should be given when the diagnosis is strongly suspected.

  • Intravenous immunoglobulin. If given with aspirin within 10 days of the onset of fever, IVIG relieves symptoms and reduces the risk of coronary aneurysm. The dose is 2 grams per kg, over 10 to 12 hours - Evidence level A. In about 10% of children, the fever may not respond to the first dose of IVIG within 48 to 72 hours, or may recur. In this situation, a second dose of IVIG may be given.
  • IVIG should still be given later than 10 days if there are signs of continuing inflammation (fever, high ESR) or evolving coronary artery disease
  • Aspirin. Give at a dose of 30-50 mg/kg/day in 4 divided doses, in the first week of the illness. There is no evidence that the dose of salicylate effects aneurysm formation. Level A evidence. Reduce the dose to 3 to 5 mg/kg/day (once daily) once the fever is under control. If the coronary arteries are normal at 6 weeks, stop the aspirin. If there are coronary artery aneurysms, continue low-dose aspirin (see below) with or without warfarin or other antiplatelet medication. Aspirin is available in 300mg soluble tablets and 650mg enteric-coated tablets. Use soluble tablets dissolved in water to administer part doses, and consider enteric coated tablets for older children.

Note: several children with Kawasaki disease have developed Reye syndrome while on high dose Aspirin. It is important therefore to change to low dose Aspirin as soon as possible, and to warn the parents to discontinue Aspirin if the child develops influenza or chickenpox.

Children should remain in hospital until afebrile for 24 hours

Refractory Disease & High Risk Patients

Evidence in this area is evolving. Patients may require individualised management - please discuss with cardiology, general paediatrics, ID or rheumatology, as appropriate.

Methylprednisolone pulsed 30mg/kg/day once daily for three days may be given if the child does not improve after 2x doses of IVIG, or in selected circumstances where the child is very unwell. Other treatment options for refractory Kawasaki Disease include a weaning course of oral prednisolone - starting at 2mg/kg/day and Infliximab (TNF alpha blocker) 5mg/kg as a single dose

Subsequent Immunisation

Measles and other live virus vaccines (i.e. varicella) should be deferred for 11 months following high-dose IVIG treatment. Alternatively, a child at high risk of measles could be vaccinated, then re-vaccinated at least 11months after the administration of IVIG. See Table 1.3: Suggested intervals between immunoglobulin (IG) product administration or blood transfusion and MMR or varicella vaccination (does not apply to rotavirus vaccine)

Other routine immunisations should not be interrupted.

Annual influenza vaccination is recommended for children with coronary aneurysms on aspirin

Follow-Up

48 hours after discharge
Paediatric review to exclude ongoing fever

4 - 6 weeks after presentation
Starship cardiology outpatient clinic/day stay for clinical review, ECG, echocardiogram

Further Follow-Up

Dependent on risk stratification:

  • No coronary changes. No follow-up required. Low dose aspirin can be discontinued
  • Mild coronary artery ectasia. Low dose ASA. Repeat echocardiogram at one year. Stop ASA if no change or improving at this time. Consider exercise stress echocardiography after 10 years of age
  • Small-to-medium single coronary artery aneurysm. Continue low dose ASA. Annual review with ECG ± echocardiogram. Consider angiography. Consider stress echocardiography after 10 years of age. Advise against highly competitive sporting activities.
  • Multiple small aneurysms or one or more giant aneurysms. Low dose ASA ± warfarin. Annual review with ECG and echocardiogram. Consider dobutamine stress testing < 10 years of age. Exercise stress echocardiography after 10 years of age. Advise against competitive sporting activities.
  • Coronary artery obstruction. Low dose ASA ± warfarin. Holter monitor. Consider angiography. Consider repeating angiography ± thrombolysis if new ischaemic symptoms or ECG changes develop. Annual review with stress echocardiography. Advise against competitive sporting activities. Consider Beta blockers

Information for Families

Kidshealth factsheet on Kawasaki Disease (http://www.kidshealth.org.nz/kawasaki-disease)

References

Newburger J et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Statement for Health Professionals From the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association; Pediatrics 2004;114;1708-1733.

Kato H et al. Long-term consequences of Kawasaki Disease. A 10-to 21-year follow up study of 594 patients. Circulation 1996;94:1379-1385

AAP Red Book 2012

Kobayashi T, Saji T, Takeuchi K, et al. Efficacy of Immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki Disease (RAISE study); a randomized , open-label, blinded endpoint study. Lancet 2012; 379:1613 0 20.

Tacke C, Burgner D, Kuijpers I, Kuijpers T. Mangement of Acute and Refractory Kawasaki Disease. Expert Rev. Anti Infect Ther 2012; 10(10) 1203 - 1215.

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Document Control

  • Date last published: 01 February 2015
  • Document type: Clinical Guideline
  • Services responsible: Paediatric Cardiology
  • Author(s): Rachel Webb, Ross Nicholson, Nigel Wilson
  • Editor: Greg Williams
  • Review frequency: 2 years

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