Recent advances in the treatment of Kawasaki disease : Journal of the Chinese Medical Association

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Review Article

Recent advances in the treatment of Kawasaki disease

Weng, Ken-Pena, b; Ou, Shan- F.c; Lin, Chu-Chuana; Hsieh, Kai-Shenga, *

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Journal of the Chinese Medical Association: November 2011 - Volume 74 - Issue 11 - p 481-484
doi: 10.1016/j.jcma.2011.09.001


    1. Introduction

    Kawasaki disease (KD), an acute systemic vasculitis more prevalent in Asian races, occurs mainly in infants and children under 5 years of age.1 This multisystem vasculitis is characterized by prolonged fever, polymorphous skin rash, nonpurulent conjunctival injection, extremity changes, oral mucosal changes, and cervical lymphadenopathy. KD is liable to be complicated by coronary artery lesions (CALs), which develop in approximately 15–25% of untreated KD children2–4 and in approximately 5% of KD children after intravenous immunoglobulin (IVIG) therapy.5,6 The etiology of KD remains unknown and may be attributed to combined effects of infection, immune response, and genetic susceptibility.1 The annual incidence of KD in Taiwan is estimated to be 69/100,000 children, the third highest in the world after Japan and Korea.7–9 Many researchers have made great efforts to unravel the mystery of the disease. Evidence on the treatment of KD from randomized clinical trials is well established.5 The present review article covers previous important publications with a special focus on the treatment of KD.

    2. IVIG

    Treatment with a single high dose (2g/kg) of IVIG is effective in reducing the incidence of CALs.6,10,11 A study by Newburger et al11 contributed greatly in this regard, and a single high dose of IVIG is the gold standard therapy in the acute stage of KD. The mechanism of IVIG in reducing inflammation in KD is not clearly understood. Five possible mechanisms include Fc receptor blockade, neutralization of the causative agents or a toxin produced by an infectious agent, an immunomodulating effect, induction of suppressor activity, and modulation of the production of cytokines and cytokine antagonists.12 Takatsuki et al showed that IVIG reduced the activity of oxidative stress,13 which provokes vasculitis in KD. Using a murine model of KD, Lau et al demonstrated that at therapeutic concentrations, IVIG effectively reduced the immune response leading to tumor necrosis factor (TNF) expression (a prerequisite for coronary arteritis).14 However, 7.8–38.3% of children are unresponsive to initial IVIG treatment and at increased risk for CAL development.15–20 Additional IVIG,15 steroid,21 infliximab,22 or other treatments have been used for IVIG-resistant patients, but controversy remains as regards alternative treatments. Additional treatments after initial IVIG treatment failure may not be effective for reducing fever or preventing coronary artery injury.15,23 For IVIG-resistant patients, earlier and more effective primary therapy might not be emphasized enough for reducing the risk of CALs. Potentially effective initial treatments for high-risk patients might be IVIG plus corticosteroids or another new agent, such as infliximab.24,25 Additional studies of KD pathogenesis are warranted to determine the role of these therapies for IVIG nonresponders.

    3. Aspirin

    Anti-inflammatory doses of aspirin are recommended in conjunction with IVIG, but controversy remains regarding anti-inflammatory doses of aspirin.1 In North America, high-dose (80–100mg/kg per day) aspirin is most widely used during the acute phase.26 In Japan, concern about hepatic toxicity has led to the use of moderate-dose (30–50mg/kg per day) aspirin as a recommended standard therapy in the acute phase.27 In Taiwan, IVIG with concomitant aspirin is used during acute-stage KD in most hospitals except Kaohsiung Veterans General Hospital. The results of our previous study indicate that treatment without aspirin in acute-stage KD had no effect on the response rate of IVIG therapy, duration of fever, or CAL incidence.6 Using a murine model of KD, Lau et al showed that at therapeutic concentrations, IVIG effectively reduced the immune response leading to TNF-α, but pharmacologic doses of salicylate enhanced its production.14 This finding may partly support our treatment without aspirin in acute-stage KD. We suggest that it is unnecessary to expose children to high- or medium-dose aspirin therapy in acute KD when the available data show no appreciable benefit in preventing the failure of IVIG therapy or CAL formation or in shortening fever duration.

    4. Steroids

    Although corticosteroids are the treatment of choice in other forms of vasculitis, the usefulness of steroids in treatment of KD is not well established. Corticosteroids were used as the initial therapy for KD long before the first report of IVIG efficacy by Furusho et al.28 An early study by Kato et al29 suggested that steroids exerted a negative effect when used as the initial therapy for KD, but some recent studies have shown possible benefit. Okada et al reported that corticosteroid therapy combined with IVIG as the initial treatment rapidly ameliorated symptoms by reducing cytokine levels in children with KD.30 Okada et al also showed that methylprednisolone and IVIG was effective and safe as a primary treatment for high-risk KD patients.24 However, Newburger et al demonstrated that their data do not provide support for the addition of a single pulsed dose of intravenous methylprednisolone to IVIG for routine primary treatment of children with KD.31 Further multicenter controlled trials are required to elucidate the role of methylprednisolone in initial therapy for KD or treatment of IVIG-resistant patients.

    5. Other treatments

    A new class of therapies directed against specific cytokines has expanded treatment for KD. Infliximab is a monoclonal antibody to TNF-α and has been effective in the treatment of patients with refractory KD.32,33 Treatment with infliximab might also be an initial therapy for high-risk KD patients.25 Our previous study showed an effect of IL-1B polymorphism on the association with IVIG resistance in Taiwanese children with KD,34 which suggests the potential usefulness of monoclonal antibodies to IL-1, such as anakinra, for IVIG-resistant patients.35 Other immunosuppressive therapies, including cyclophosphamide,36 methotrexate,37 and plasma exchange,38 have been used in the treatment of refractory KD. No definite conclusions can be reached from these rare individual cases. Prospective clinical trials are warranted to determine the role of these therapies.

    6. Statins

    Therapeutic regimens in the chronic stage of KD depend on the severity of coronary artery involvement and include antiplatelet therapy with aspirin, with or without dipyridamole or clopidogrel, anticoagulant therapy with warfarin or low-molecular-weight heparin.1 Ongoing low-grade inflammation and endothelial dysfunction persist in patients with a history of KD.39 Some studies also demonstrated that subclinical atherosclerosis develops early in KD patients,40,41 which makes early initiation of therapy to improve chronic inflammation an important issue. Statins are well-known lipid-lowering agents, but have so-called pleiotropic, cholesterol-independent effects that are believed to include anti-proliferative, anti-inflammatory, and antioxidant actions; they also upregulate eNOS activity.42–44 Our pilot study has shown that statin therapy seems to significantly improve chronic vascular inflammation and endothelial dysfunction in children with coronary arterial abnormality in the chronic stage of KD.45 A recent animal study also demonstrated that atorvastatin can inhibit critical pathogenic steps in the development of coronary artery damage in KD.46 Further study is needed to determine the safety and efficacy of statins in children with KD.

    In conclusion, high-dose IVIG in the acute phase of KD is the accepted treatment guideline. Anti-inflammatory high doses of aspirin are recommended in conjunction with IVIG, but the efficacy of aspirin may be limited to its anticoagulant and antipyretic actions, which can be achieved at a low dose. Additional treatments after initial IVIG treatment failure, including corticosteriod therapy, are controversial. Management in the chronic stage of KD, especially for patients without evidence of CALs, is still an issue under debate. Future multicenter studies may help to define the optimal management for KD patients.


    Parts of this research were supported by the Kaohsiung Veterans General Hospital (VGHKS100-G01-2).


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    coronary artery lesions; intravenous immunoglobulin; Kawasaki disease

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