Dominguez, Samuel R.; Anderson, Marsha S.
It has been over 40 years since the first published cases series in Japan described Kawasaki disease in 1967 . Since that time, there has been considerable progress in the treatment of Kawasaki disease. The current standard of care for the treatment of children in the United States is a single dose of 2 g/kg intravenous immunoglobulin (IVIG) infused over 10–12 h accompanied by high-dose aspirin (80–100 mg/kg/day orally in four divided doses) [2,3]. The rationale for this therapy is based on several pivotal studies. First, in 1983, Japanese investigators reported that children with Kawasaki disease treated with IVIG had faster resolution of fever and developed fewer coronary artery abnormalities than historical controls . This observation was followed by a multicenter, open-label, randomized trial in the USA which demonstrated that children treated with IVIG and high-dose aspirin had significantly faster resolution of fever and other inflammatory markers and fewer coronary artery abnormalities (3 vs. 15%, 7 weeks after treatment) than children treated with aspirin alone . A subsequent randomized, controlled study established the efficacy and superiority of the now accepted dose of IVIG (one single infusion of 2 g/kg infusion vs. four infusions of 400 mg/kg over 4 days) . Recently, there has been interest in identifying effective adjunctive initial therapies for children with Kawasaki disease at higher risk for coronary artery abnormalities. There is also a need to establish effective second-line therapy for children with Kawasaki disease who fail initial IVIG therapy. This review focuses on the advances in these two areas of treatment.
The use of corticosteroids in the treatment of Kawasaki disease has a checkered history. Because Kawasaki disease is primarily an acute inflammatory vasculitis, and because other vasculitides and rheumatological diseases respond well to corticosteroids, the effectiveness of this treatment would be expected to be biologically plausible. However, in 1979, an initial published report suggested that the use of steroids might actually worsen coronary artery abnormalities if used as part of the initial therapy of children with Kawasaki disease . This study showed that children treated with steroids alone (2–3 mg/kg/day prednisolone for 2 weeks followed by 1–1.5 mg/kg/day for 2 weeks) had a statistically significantly higher incidence of coronary artery aneurysms (11 of 17, 65%), as evidenced by coronary angiography 1 month after the onset of illness, compared with children with Kawasaki disease who received either prednisolone plus aspirin (0 of 7, 0%), aspirin alone (4 of 36, 11%), or no therapy (5 of 25, 20%). Despite the limitations of this study (lack of randomization, dedicated use of particular protocols at individual centers, different doses and durations of aspirin and steroids compared with current regimens, and study conducted prior to the routine use of IVIG), this data led to the abandonment of steroids for use in Kawasaki disease therapy by many practitioners. Subsequently, some case series, retrospective studies, and prospective studies suggested that corticosteroids may be beneficial in preventing coronary artery aneurysms. In particular, two trials from Japan and one from the USA found benefit from corticosteroids [8–10]. Similarly, a meta-analysis concluded that the addition of steroids to initial therapy with IVIG and aspirin reduced the incidence of coronary artery aneurysms , and a later meta-analysis suggested that steroids reduced the incidence of IVIG failures but did not have an impact on coronary artery aneurysms . The results of a multicenter, randomized, double-blind, placebo-controlled study conducted in the USA provided a definitive answer to the utility of adjunctive steroids in the initial therapy of Kawasaki disease and has guided therapeutic decisions for the past 5 years . In this study, patients were randomly assigned to receive 30 mg/kg intravenous methylprednisolone (n = 101) or placebo (n = 98) in addition to 2 g/kg IVIG and high-dose aspirin. The two groups did not differ in the number of days hospitalized, the number of days of fever, the rates of retreatment with IVIG, or the incidence of coronary artery abnormalities.
Over the last year, there have been two important Japanese studies raising again the issue of corticosteroids as adjunctive initial therapy [14,15▪▪]. These researchers targeted a combination intervention of IVIG plus steroids to ‘high risk’ Kawasaki disease patients who, by various means, were predicted to have resistant disease, requiring a secondary therapy after their initial treatment with IVIG. The first study from a single center in Japan randomized 48 high-risk Kawasaki disease patients (Egami score ≥3 points, Table 1) to receive IVIG plus aspirin (ASA) (n = 26) or IVIG plus ASA plus 1 dose of 30 mg/kg intravenous methylprednisolone (n = 22) . The major endpoint of this study was treatment efficacy, defined as defervescence and remaining afebrile (<37.5°C) for at least 36 h after the completion of initial therapy. Echocardiograms (ECHOs) were read at 36 h and 1 month after treatment by cardiologists blinded to treatment assignment. Patient demographics, clinical characteristics, and laboratory findings were not significantly different at the time of enrollment between the treatment groups. Nineteen of the 22 (86%) patients in the IVIG plus steroids group responded to initial therapy, whereas only six of the 26 (23%) patients in the IVIG alone group defervesced (P < 0.001). Furthermore, two of 22 (9%) patients in the IVIG plus steroids group had coronary artery z-scores of at least 2.5 at 1 month after therapy compared with 10 of 26 (39%) patients in the IVIG alone group (P = 0.04).
This study was followed by the Randomized controlled trial to Assess Immunoglobulin plus Steroid Efficacy for Kawasaki Disease (RAISE) study [15▪▪]. The RAISE study was a multicenter, prospective, randomized, blinded, endpoints study conducted in 74 hospitals in Japan over a 2-year period from September 2008 to December 2010. In contrast to the previous study, these researchers enrolled all high-risk Kawasaki disease patients based upon a Kobayashi risk score of at least 5 points (Table 1). Patients (121 in each group) were randomly assigned to initial treatment with either IVIG (2 g/kg) plus ASA (30 mg/kg/day) or IVIG plus ASA plus prednisolone [2 mg/kg/day in three divided doses intravenously for 5 days, followed by an oral, 15-day taper once the patient was afebrile and the C-reactive protein (CRP) had normalized]. Patients were considered treatment failures and retreated if they had fever (≥37.5°C) lasting more than 24 h. ECHOs were performed and reviewed blinded at 1, 2, and 4 weeks after completion of therapy. Four (3%) patients in the IVIG plus steroids group compared with 28 (23%) patients in the IVIG alone group had coronary artery abnormalities (P < 0.0001). Additionally, patients in the steroid group had a lower incidence of needing second-line therapy (13 vs. 40%, P < 0.0001) and had significantly lower median z-scores for all coronary arteries measured at all three time points. In both Japanese studies, the incidence of serious adverse events was not higher in the groups using steroids than in the control groups.
Together these trials provide compelling evidence for the use of intensified primary therapy for high-risk Kawasaki disease patients with IVIG plus corticosteroids. The differences between these studies and the previous study conducted in the USA reflect the differences in patient selection (high risk vs. all patients) and treatment duration. Of note, a post-hoc subgroup analysis of high-risk patients who needed retreatment with IVIG because of persistence of fever in the US trial demonstrated better coronary artery outcomes in the steroids plus IVIG group compared with the IVIG alone group [13,16▪▪]. This suggests that using steroids in ‘high-risk’ US populations would most likely also be beneficial. Implementation of the use of steroids as adjunctive therapy into a broader population, however, faces several challenges. First, as most patients in North America with Kawasaki disease are discharged within 2–3 days of admission, differences in the healthcare systems between Japan and other developed countries might hamper the implementation of a 5-day course of intravenous corticosteroids because of logistical and financial burdens. The second challenge is the ability to identify those Kawasaki disease patients who are at high risk for coronary artery abnormalities. Several studies have attempted to define the risk factors for the development of coronary artery abnormalities in children with Kawasaki disease. Identified risk factors include incomplete presentation, delay in diagnosis and duration of fever prior to treatment, male sex, young and older age, and IVIG resistance [17–25]. IVIG resistance, as used in the Japanese studies, is the most commonly used target because it is known to be a strong risk factor for the development of coronary artery abnormalities. Furthermore, at least three different scoring systems for the development of IVIG resistance have been developed and validated exclusively in Japanese populations (Table 1) [26–28]. Although these models were helpful in the most recent studies, the overall predictive power of these models is modest at best, with positive predictive values ranging from only 32 to 59%. More importantly, attempts to reproduce these models or to create other predictive models in US populations have been unsuccessful [29,30].
The current challenge facing clinicians and investigators is the early identification of high-risk patients in all populations who would benefit from combined initial therapy of IVIG and steroids. We propose that one possible high-risk group of patients might be the subset of patients who present with coronary artery abnormalities at the time of diagnosis prior to initiation of therapy. We recently demonstrated that, at our institution, the majority (81%) of Kawasaki disease patients who developed coronary artery abnormalities (defined as presence of an aneurysm or a z-score ≥2.5) had abnormalities detected on their initial echocardiogram (mean day 7 of illness) [31▪]. Of those patients who had abnormal z-scores at presentation, 58% of them had persistent abnormalities 2 weeks later and 40% had continued abnormalities 6 weeks after their initial ECHO. These data mirror the findings in two previously published studies. In a study of 4811 acute Kawasaki disease patients from 27 US pediatric hospitals, 157 (3.3%) were noted to have coronary artery abnormalities (at some time from diagnosis to 6-week follow-up). Of those patients who developed abnormalities, 127 of 157 (81%) were coded as being present while hospitalized for the initial diagnosis of Kawasaki disease (median length of stay 3 days) . A second study published by the investigators in the Pediatric Heart Network described only 6% of Kawasaki disease patients with a normal ECHO on admission later developing coronary artery abnormalities. This suggests that the majority of abnormalities were detected on the ECHO done at diagnosis . These studies, combined with our findings, suggest that the majority of Kawasaki disease patients who develop coronary artery abnormalities have existing abnormalities early in their course, prior to diagnosis and treatment. This is important because it suggests that the majority of the ‘high-risk’ (i.e. those who develop coronary artery abnormalities) patients might be identifiable at the time of initiation of therapy by ECHO.
TUMOR NECROSIS FACTORα INHIBITORS
For patients with Kawasaki disease who fail initial treatment with IVIG (IVIG-resistant), many physicians opt to use a second dose of IVIG. For the minority of patients who do not respond to a second dose of IVIG, there are only case reports and small series in the medical literature to help guide therapeutic decisions. Many different immune-modulatory agents have been proposed and used. It is also unclear whether an agent other than IVIG might be a better second-line choice, as there are no large randomized trials comparing second-line therapies. The choice of second and third-line agents is an important consideration because patients with IVIG-resistant disease are at higher risk for developing coronary artery abnormalities, and so rapid shutting off of their inflammation is desired.
Currently, the most commonly used third-line agent is infliximab (Remicade). Infliximab is a chimeric murine and human immunoglobulin G1 monoclonal antibody that specifically binds to human tumor necrosis factor (TNF)-α-1 and blocks its function . Inhibition of TNFα was originally postulated to be potentially effective in the treatment of Kawasaki disease based upon the observation that serum levels of TNFα are very elevated in patients with Kawasaki disease and that higher levels of TNFα were correlated with the development of coronary artery abnormalities . This observation led to the trial and successful use of infliximab (5 mg/kg) as the third-line therapy in several case reports and small case series of Kawasaki disease patients with IVIG-resistant disease [34–38]. These reports were followed by a small US multicenter, randomized trial of second IVIG infusion vs. infliximab in 24 children with Kawasaki disease after failure with initial treatment with IVIG. Although this study was not powered to detect significant differences in outcomes between treatment groups, 11 of 12 (92%) patients in the infliximab group and 8 of 12 (67%) of patients in the IVIG group responded as indicated by the cessation of fever . There were no differences in adverse outcomes or coronary artery abnormalities between the two groups. This study demonstrated that infliximab was safe and well tolerated in Kawasaki disease patients and opened the door for further studies with this agent. Additional prospective case series from Korea and Japan have also demonstrated the efficacy of infliximab in 13 of 16 (81%) and 18 of 20 (90%) IVIG-resistant Kawasaki disease patients, respectively [40,41]. A recent, two-center, US retrospective review of IVIG-resistant patients treated with either second-line IVIG (n = 86) or infliximab (n = 20) demonstrated that patients treated with infliximab had statistically significantly fewer days of fever and shorter lengths of hospitalization, with similar coronary artery outcomes [42▪]. To further evaluate the role of infliximab in the treatment of Kawasaki disease, there is an ongoing multicenter study in the USA comparing IVIG plus ASA (standard therapy) with IVIG plus ASA plus infliximab as initial therapy for all patients with Kawasaki disease.
Etanercept (Enbrel) is another TNF-α inhibitor that has been studied in a small number of Kawasaki disease patients. Etanercept is a soluble TNF receptor and functions as a TNF antagonist with a proposed similar mechanism of action to infliximab in the treatment of Kawasaki disease. Similarly to infliximab, etanercept has been widely used in a wide array of autoimmune and inflammatory diseases. Etanercept (three doses at 0.8 mg/kg/dose weekly) was recently shown to be safe and well tolerated in a small study (n = 15) of children with Kawasaki disease as adjunctive initial therapy with IVIG . None of the patients treated in this study required retreatment. On the basis of these preliminary data, there is a proposed multicenter, double-blind, randomized, placebo-controlled trial looking at the efficacy of etanercept in addition to IVIG plus ASA for initial therapy at reducing the rate of IVIG-resistant disease .
An emerging therapy for IVIG-resistant disease is the use of the calcineurin inhibitor cyclosporine A (CSA). Large-scale genetic susceptibility studies of Kawasaki disease patients have demonstrated that a functional polymorphism of inositol 1,4,5-trisphospate 3-kinase C (ITPKC) is associated with susceptibility to Kawasaki disease, IVIG resistance, and risk of development of coronary artery abnormalities in both Asian and US children [45–51]. ITPKC acts as a negative regulator of T-cell activation through the calcineurin/nuclear factor of activated T cell (NFAT) pathway and the risk allele may result in increased signaling of this pathway leading to increased T-cell activation. Several studies have also suggested that T cells play an important role in the pathogenesis of Kawasaki disease [52–56]. These data together support a potential role for CSA, which is a potent inhibitor of T cells via inhibition of the NFAT pathway, in the treatment of children with IVIG-resistant disease.
Toward this end, two recent studies support the use of CSA in the treatment of Kawasaki disease. A prospective case series of IVIG-resistant Kawasaki disease patients in Japan demonstrated efficacy, as measured by defervescence and decreased CRP, using an oral regimen of 4–8 mg/kg/day in 18 of 28 (64%) patients . Similarly, a multicenter case series in the USA demonstrated the efficacy of using CSA in nine of nine (100%) patients with IVIG-resistant disease (a tenth patient was treated and responded to another calcineurin inhibitor, tacrolimus) [58▪]. On the basis of their experience, these researchers have proposed a detailed protocol for the use of CSA which recommends a dose of 3 mg/kg/day intravenously divided every 12 h followed by a switch to Neoral (oral CSA) once the patient is afebrile for 24 h. Their recommendations also include detailed administrating, monitoring, and drug tapering instructions (see paper for full protocol).
Several other therapies have been tried for IVIG-resistant disease. Two case series and a case report in Korea have documented success in using methotrexate (10 mg/body surface area weekly) in a total of 22 patients with IVIG-resistant disease [59–61]. Several case reports and one large retrospective case series (125 patients) in Japan have reported favorable outcomes for plasma exchange in IVIG-resistant disease [62–66]. Ulinastatin, a urinary trypsin inhibitor that protects tissues against neutrophil-mediated injury, has also regained some attention in the literature. Ulinastatin has been shown to be inferior to the use of IVIG in the treatment of Kawasaki disease , but a large, recent retrospective study in Japan suggests that it may have some utility as initial adjunctive therapy in combination with IVIG .
Although several promising second-line therapies have been studied in a limited number of patients, most clinicians currently use IVIG as the second-line therapy. Of other therapies in this review, infliximab and steroids have the most experience as alternative second and third-line therapies. Further studies are urgently needed to identify what optimal therapy is needed for high-risk Kawasaki disease patients.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 156–157).
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