Kawasaki Disease Treatment & Management

Updated: Jul 30, 2018
  • Author: Tina K Sosa, MD; Chief Editor: Russell W Steele, MD  more...
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Treatment

Approach Considerations

The principal goal of treatment for KD is to prevent coronary artery aneurysms and other cardiac complications. The mainstays of treatment for KD are IVIG and aspirin. [5, 8, 9]  All patients with KD should be admitted to the hospital for administration of IVIG, echocardiography, initiation of aspirin, and for observation until fevers have resolved.

 

 

 

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Intravenous Immunoglobulin

IVIG relieves acute inflammation and has been shown to reduce the rate of CAAs from approximately 25% in untreated patients to 3-5% in treated patients. [91]  Maximal benefits are seen when IVIG is given within the first 10 days after the onset of fever. 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 single high doses are more effective. In current practice, the dose is 2 g/kg intravenously over 10-12 hours. [17]

10-15% of patients will fail initial treatment with IVIG; treatment failure is defined as a fever occurring 36 hours or longer after IVIG is administered. In many of these cases, 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 (see Treatment/Treatment of IVIG-Resistant Disease).

A study in an ethnically diverse population in San Diego, California, found that patients with IVIG resistance tended to have higher percent bands, CRP, alanine aminotransferase, and gamma-glutamyl transferase, as well as lower platelet counts and age-adjusted hemoglobin concentrations. They were also more likely to have CAAs. 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 KD was delayed, and giant aneurysms developed. Patients with a high ESR were at an increased risk of IVIG-resistant Kawasaki disease. Patients with IVIG-resistant KD had a higher prevalence of coronary artery lesions at the acute phase and 2 months after onset. [86]

It is important to note that the American Academy of Pediatrics Red Book states that live vaccinations are contraindicated for 11 months after administration of IVIG for KD.

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Treatment of IVIG-Resistant Disease

Treatment of patients in which IVIG fails after the first and/or second dose remains controversial and is variable across institutions and providers. Guidelines from the AHA recommend a second dose of IVIG, methylprednisolone, a longer tapering course of prednisolone or prednisone plus IVIG, or infliximab be considered for patients resistant to IVIG. [91]  Infliximab (Remicade) is a chimeric mouse-human monoclonal antibody directed against soluble and membrane bound tumor necrosis factor-alpha. [17] Several studies have found infliximab at a dose of 5 mg/kg to be useful in treating KD 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]  In another study, 43 patients with KD who were initially resistant to IVIG were randomized to receive either a first does infliximab (n=11) or second dose of IVIG (n=32). IVIG retreatment gave 65.6% of patients a response while infliximab gave 90.9% of 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]

The AHA recommends that cyclosporine and other cytotoxic agents, immunomodulatory monoclonal antibody therapy, and plasma exchange be reserved for exceptional patients with particularly refractory KD.

In the future, by identifying a genetic signature for this group, more aggressive and targeted therapies may be used to reduce the risk of coronary complications. [43, 33]

 

 

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Aspirin

Aspirin has long been a standard part of therapy for KD. However, its use has been called into question, as it does not impact the development of CAAs. [104]  Although some authors have suggested that aspirin is no longer needed, most experts use medium- to high-dose aspirin for a variable period, followed by lower-dose aspirin.

Medium- (30-50 mg/kg/day) to high- (80-100 mg/kg/day) dose aspirin divided four times daily is typically 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 often 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 is commonly continued until the aneurysm resolves or is continued indefinitely.

Randomized controlled trial outcomes are insufficient to indicate whether children with this disorder should continue to receive aspirin 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 or refute the use of aspirin in children with KD as part of their treatment regimen. [93]

Patients who remain on long-term, low-dose aspirin should receive an annual influenza vaccine and be vaccinated against varicella. Additionally, the risks of developing Reye syndrome during an active infection with influenza or varicella should be addressed. 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]  Patients on prolonged aspirin therapy must also be instructed that concomitant use of ibuprofen antagonizes the irreversible effect of platelet inhibition by aspirin and should be avoided during therapy.

The pediatrician or cardiologist who provides the long-term care should monitor aspirin therapy and decide whether to use additional anticoagulative medications, including warfarin or heparin.

 

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Other Adjunctive Agents

In addition to their use in treatment of IVIG-resistant KD, 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, CRP levels, and initial treatment failure. [94]  The RAISE trial, conducted in Japan, also had similar findings. [105]

  • 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]

Statins are another class of medications that have been used variably in the setting of KD, due to their cholesterol-lowering and immunomodulatory properties. Further research is necessary to determine the impact of statins in the early phase of KD as well as the potential to lower the risk for atherosclerosis in the long term.

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 KD and giant aneurysms.

Clinical Trials

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

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Consultations

A cardiologist should be consulted for the following:

  • Assistance with determining the appropriate timing of initial and/or subsequent echocardiographic studies

  • Management of patients with electrocardiogram or echocardiogram abnormalities

  • Anticoagulation management

  • To determine whether other studies to assess cardiac function (including coronary artery angiography) are required

  • Long term follow up and monitoring of patient with confirmed or suspected KD

Other consulting services may be of value depending on the patient's clinical presentations and the differential diagnosis. These may include infectious disease specialists, rheumatologists, and dermatologists.

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Long-Term Monitoring

Long-term management begins at the end of the acute illness, typically 5-6 weeks after fever onset. This is typically when coronary artery involvement has reached its maximal extent and luminal dimensions. Thromboprophylaxis and careful echocardiographic surveillance for coronary artery stenoses and obstructions, as well as myocardial ischemia, are the pillars of management. Patients with severe cardiac complications may require catheterization, coronary artery bypass surgery, or even cardiac transplantation. Successful long-term management requires effective and collaborative programs between pediatric and adult cardiologists. [91]

Frequency of follow up, medication use, and imaging evaluations are highly dependent on the disease severity. For patients with no evidence of cardiac involvement during the acute phase, they are often discharged from cardiology care at 4-6 weeks after the onset of symptoms without any chronic follow up required. Patients with cardiac disease are treated and monitored regularly by cardiologists with the exact medications used and follow up frequency determined by their provider. [91]

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