Kawasaki Disease Treatment & Management

Updated: Aug 14, 2017
  • Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: Russell W Steele, MD  more...
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Treatment

Approach Considerations

The principal goal of treatment for Kawasaki disease is to prevent coronary artery disease and to relieve symptoms. Full doses of intravenous immunoglobulin (IVIG) are the mainstay of treatment. [5, 8, 9]

Admit all patients to the hospital for administration of IVIG and for observation until fever is controlled. Closely monitor cardiovascular function. Once the fever resolves, clinically significant heart failure or myocardial dysfunction is unlikely.

Aspirin has traditionally been part of the standard treatment of this disorder. Although some authors have suggested that aspirin is no longer needed, most experts use high-dose aspirin for a variable period, followed by lower-dose aspirin for its antiplatelet effects. Aspirin is used in patients with small coronary artery aneurysms (CAAs). Dipyridamole is indicated in patients with larger CAAs.

The appropriate treatment of patients who fail to respond to IVIG remains unclear. Severe Kawasaki disease that is resistant to IVIG may benefit from intravenous pulse corticosteroid therapy or infliximab infusion.

Transfer patients with suspected Kawasaki disease to a facility that has clinicians experienced in the care of these patients and a pediatric or adult cardiologist to evaluate the echocardiogram. Some authorities recommend transferring patients who have documented coronary artery aneurysms to a tertiary pediatric facility.

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Emergency Department Care

Any young child who presents to the emergency department (ED) with symptoms of early or acute-stage Kawasaki disease should be evaluated to rule out sepsis or meningitis. Although the diagnosis may seem obvious, other life-threatening diseases must be ruled out. The ED physician must consider the possibility that a child has an incomplete case and proceed with the evaluation listed above. Intravenous access and cardiac monitoring should be established.

Depending on the institution, anti-inflammatory therapy may need to begin in the ED. Arrangements for admission must take into consideration the potential for multiple problems. This is not a routine pediatric illness. Accordingly, transferring the patient to a pediatric referral center may be prudent.

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Intravenous Immunoglobulin

IVIG relieves acute inflammation and has been shown to reduce the rate of coronary aneurysms from greater than 25% in untreated patients to 1-5% in treated patients. Maximal benefits are seen when IVIG is given within the first 10 days of the illness. Some controversy exists about the ideal time to begin IVIG, but it is given most often from days 5-7.

In the past, IVIG was given as a lower dose over 4 days (400 mg/kg/day), but newer studies have shown that high single doses are more effective. In current practice, the dose is 2 g/kg intravenously over 10-12 hours. [17]

In patients in whom the standard treatment fails (approximately 10-15%) and who continue to have fever 36 hours after the initial dose of IVIG, a second treatment with IVIG at the original dose is recommended. [84] A small subgroup of patients fails to respond to a second dose of IVIG.

A study in an ethnically diverse population in San Diego, California, found that patients with IVIG resistance tended to have higher percent bands; higher concentrations of C-reactive protein, alanine aminotransferase, and gamma-glutamyl transferase; lower platelet counts; and lower age-adjusted hemoglobin concentrations. They were also more likely to have aneurysms. However, a proposed scoring system to predict IVIG resistance proved insufficiently accurate to be clinically useful. [85]

In a review from Singapore by Sittiwangkul et al, initial treatment with IVIG (2 g/kg) failed to elicit a response in 13% of patients. [86] The diagnosis in 2 patients with IVIG-resistant Kawasaki disease was delayed, and giant aneurysms developed. Patients with a high erythrocyte sedimentation rate (ESR) were at an increased risk of IVIG-resistant Kawasaki disease. Patients with IVIG-resistant Kawasaki disease had a higher prevalence of coronary artery lesions at the acute phase and 2 months after onset. [86]

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Treatment of IVIG-Resistant Disease

Patients in whom a second dose of IVIG therapy fails can be treated with corticosteroids. Intravenous pulse methylprednisolone may be given at 30 mg/kg for 2-3 hours administered once daily for 1-3 days.

An alternative treatment is infliximab (Remicade) at 5 mg/kg, which is a chimeric mouse-human monoclonal antibody directed against soluble and membrane bound tumor necrosis factor-alpha. [17] Several studies have found infliximab to be useful in treating Kawasaki disease that is refractory to IVIG. [87, 88] Burns et al reported that infliximab was as effective as a second dose of IVIG in patients who did not respond to a first dose of IVIG. [89]

43 patients with KD who were initially treatment resistant to intravenous immunoglobulin (IVIG) had researchers randomized the 43 to get either a first does infliximab (n=11) or second dose of IVIG (n=32).  IVIG retreatment gave 65.6% (21) patients a response while infliximab gave 90.9% (10) patients a response. Infliximab provided less days of hospitalization and a shorter duration of fever. Adverse events and coronary artery outcomes resembled each other in the two groups. [90]

Other alternative therapies for resistant cases include cyclophosphamide with and without methotrexate; however, the effectiveness of these latter treatments is still uncertain because they have been used in only a small number of cases. [17] The following are adjunctive therapies for patients who do not respond to conventional therapies.

Ulinastatin is a human trypsin inhibitor purified from human urine. It has been used only in Japan for refractory cases of Kawasaki disease and is believed to function by inhibiting neutrophil elastase and prostaglandin H2 synthase at the mRNA level.

In the future, by identifying a genetic signature for this group, more aggressive therapies, such as anticytokine therapy, plasmapheresis, or cyclosporin A, may be used to reduce the risk of coronary complications. [43, 33]

Guidelines from the American Heart Association recommend a second dose of IVIG, methylprednisolone, a longer tapering course of prednisolone or prednisone plus IVIG, infliximab, cyclosporine, immunomodulatory monoclonal antibody therapy (except TNF-α blockers), cytotoxic agents, or plasma exchange for patients resistant to IVIG. [91]

 

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Aspirin

Aspirin has a synergistic effect with IVIG and has long been a standard part of therapy for Kawasaki disease. However, its use has been called into question. Some studies suggest that high- or medium-dose aspirin may have no effect on the response rate to IVIG, duration of fever, or incidence of coronary artery aneurysms despite treatment before or after 5 days of therapy.

Randomized controlled trial outcomes are insufficient to indicate whether children with this disorder should continue to receive salicylate as part of the treatment regimen. [92] Baumer et al concluded that no randomized clinical trials of adequate quality have been performed and that current evidence is insufficient to support the use of salicylate in children with Kawasaki disease as part of their treatment regimen. [93]

Nevertheless, most experts use high-dose aspirin for a variable period, followed by lower-dose aspirin for its antiplatelet effects. High-dose aspirin (80-100 mg/kg/d orally in 4 divided doses) is given in the acute phase for its anti-inflammatory effects. It is continued until day 14 of the illness or until the patient has been afebrile for 48-72 hours.

Once the patient has remained afebrile for 48-72 hours, low-dose aspirin is initiated for its antiplatelet activity. The dose is 3-5 mg/kg/day for a total of 6-8 weeks as long as the patient shows no evidence of coronary abnormalities. For patients who have aneurysms, aspirin should be continued until the aneurysm resolves or should be continued indefinitely.

Patients who remain on long-term, low-dose aspirin should receive an annual influenza vaccine. Additionally, the risks of developing Reye syndrome during an active infection with influenza or varicella should be addressed.

The pediatrician or cardiologist who provides the long-term care monitors aspirin therapy and decides whether to use warfarin or heparin.

Patients on prolonged aspirin therapy must be instructed that concomitant use of ibuprofen antagonizes the irreversible effect of platelet inhibition by aspirin and should be avoided during therapy. Contact activities or high-impact sports should be avoided in patients on prolonged antiplatelet therapy.

Clopidogrel (Plavix) may be briefly substituted for aspirin in patients who develop influenza or varicella. This agent can also be used in patients allergic to aspirin. [17]

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Other Adjunctive Agents

In addition to their use in treatment of IVIG-resistant Kawasaki disease, corticosteroids have been proposed as part of primary therapy. This indication is controversial, however. Research results have been inconsistent, as follows:

  • In a multicenter prospective randomized trial in Japan, the combination of corticosteroids and IVIG significantly decreased coronary artery abnormalities, duration of fever, C-reactive protein levels, and initial treatment failure [94]
  • A randomized trial in the United States in which a single pulsed dose of methylprednisolone (30 mg/kg) was added to conventional therapy saw a reduction in the ESR at 1 week, but no difference in coronary artery abnormalities [95]
  • In a meta-analysis of 4 studies and 447 patients, Athappan et al concluded that the addition of steroids to standard therapy with IVIG and aspirin decreased the rate of re-treatment but did not decrease the incidence of coronary aneurysms or adverse events [96]
  • Chen et al reviewed 16 studies that included 2746 patients and found that the rate of coronary artery abnormalities was significantly lower in the corticosteroids plus IVIG group than in the IVIG therapy alone group. The benefit was only found in the group using corticosteroids plus IVIG for the prevention of coronary artery abnormality and not in the group using the treatment as rescue therapy. The greatest benefit was also seen in patients predicted to be at high risk of IVIG resistance. [97, 98]

The roles of other adjunctive therapies, including pentoxifylline and abciximab, have not yet been definitively determined. Pentoxifylline acts as an anti-inflammatory agent by inhibiting tumor necrosis factor-alpha and may reduce the incidence of aneurysms. Abciximab is a platelet glycoprotein IIb/IIIa receptor inhibitor and has been used in conjunction with standard therapies in patients with Kawasaki disease and giant aneurysms.

Clinical Trials

A selection of ongoing, recruiting, and completed clinical trials is as follows:

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Consultations

Consultation with a pediatric cardiologist may be required if coronary artery aneurysms are identified or if other cardiac complications develop. Consult a pediatric or adult cardiologist for the following:

  • Children or adults with clinically significant coronary artery disease
  • Determining the appropriate timing of subsequent echocardiographic studies
  • Anticoagulation in patients with large aneurysms
  • To determine whether other studies to assess cardiac function (eg, stress testing, coronary artery angiography) are required

Consult a pediatric or adult infectious disease specialist to rule out infectious disease as a cause of fever. Consult a pediatric or adult rheumatologist to rule out other causes of vasculitis and connective tissue diseases. Consult a pediatric dermatologist to rule out other conditions that can manifest with fever and a rash. Pediatric cardiothoracic surgery assistance may be needed in the pediatric ICU for those patients who need bypass surgery.

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Long-Term Monitoring

Reevaluate all patients within 1 week of hospital discharge. Schedule the patient for repeat echocardiography 21-28 days after the onset of fever. If baseline echocardiographic studies and those obtained at 3-4 weeks do not show any evidence of coronary aneurysms, further echocardiography is usually unnecessary, as are activity restrictions or medications beyond 3 months after the initial illness. However, a repeat echocardiogram at 1 year and a cardiovascular risk assessment at 5-year intervals are optimal.

Ensure that a patient with coronary artery aneurysms (CAAs) or other cardiac abnormalities receives further care, as dictated by a cardiologist. Although 55% of patients who have identified coronary lesions during the acute phase of the disease typically show regression or reduction in these lesions within 1-2 years, these patients may still be at an increased risk for future atherosclerotic lesions.

Patients who develop coronary aneurysms should remain on aspirin therapy at least until the abnormalities resolve. Depending on the severity of the aneurysm, the patient will need biannual echocardiography, a cardiac stress test, a risk assessment with lipid evaluation, and possibly an angiogram if noninvasive tests suggest ischemia.

Cardiac stress testing is typically performed 1-5 years after the illness resolves in patients who had CAAs. It is used to assess the existence and functional consequences of coronary artery disease, and helps determine recommendations for physical activity. [33]

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