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.
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.
Papers of particular interest, published within the annual period of review, have been highlighted as:
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 156–157).
1. Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children [in Japanese]. Arerugi 1967; 16:178–222.
2. Burns JC, Glode MP. Kawasaki syndrome. Lancet 2004; 364:533–544.
3. Newburger JW, Takahashi M, Gerber MA, 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.
4. Furusho K, Kamiya T, Nakano H, et al. High-dose intravenous gammaglobulin for Kawasaki disease. Lancet 1984; 2:1055–1058.
5. Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 1986; 315:341–347.
6. Newburger JW, Takahashi M, Beiser AS, et al. A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med 1991; 324:1633–1639.
7. Kato H, Koike S, Yokoyama T. Kawasaki disease: effect of treatment on coronary artery involvement. Pediatrics 1979; 63:175–179.
8. Shinohara M, Sone K, Tomomasa T, et al. Corticosteroids in the treatment of the acute phase of Kawasaki disease. J Pediatr 1999; 135:465–469.
9. Inoue Y, Okada Y, Shinohara M, et al. A multicenter prospective randomized trial of corticosteroids in primary therapy for Kawasaki disease: clinical course and coronary artery outcome. J Pediatr 2006; 149:336–341.
10. Sundel RP, Baker AL, Fulton DR, et al. Corticosteroids in the initial treatment of Kawasaki disease: report of a randomized trial. J Pediatr 2003; 142:611–616.
11. Wooditch AC, Aronoff SC. Effect of initial corticosteroid therapy on coronary artery aneurysm formation in Kawasaki disease: a meta-analysis of 862 children. Pediatrics 2005; 116:989–995.
12. Athappan G, Gale S, Ponniah T. Corticosteroid therapy for primary treatment of Kawasaki disease – weight of evidence: a meta-analysis and systematic review of the literature. Cardiovasc J Afr 2009; 20:233–236.
13. Newburger JW, Sleeper LA, McCrindle BW, et al. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med 2007; 356:663–675.
14. Ogata S, Ogihara Y, Honda T, et al. Corticosteroid pulse combination therapy for refractory Kawasaki disease: a randomized trial. Pediatrics 2012; 129:e17–e23.
15▪▪. Kobayashi T, Saji T, Otani T, et al. Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial. Lancet 2012; 379:1613–1620.
This Japanese, multicenter, prospective, randomized, open-label trial assessed the efficacy of IVIG plus steroids compared with IVIG plus aspirin (n = 148) as initial therapy in patients in whom a scoring system indicated that they were at high risk for IVIG resistance. The IVIG plus steroids group had significantly less coronary artery abnormalities than the IVIG plus aspirin group. This study may precipitate interest in a similar study in a US population.
16▪▪. Son MB, Newburger JW. Management of Kawasaki disease: corticosteroids revisited. Lancet 2012; 379:1571–1572.
This article provides a succinct review of the use of steroids in the treatment of Kawasaki disease and highlights the challenges facing the implementation of steroid use in the United States.
17. Song D, Yeo Y, Ha K, et al. Risk factors for Kawasaki disease-associated coronary abnormalities differ depending on age. Eur J Pediatr 2009; 168:1315–1321.
18. Belay ED, Maddox RA, Holman RC, et al. Kawasaki syndrome and risk factors for coronary artery abnormalities: United States. Pediatr Infect Dis J 2006; 25:245–249.
19. Sudo D, Monobe Y, Yashiro M, et al. Case–control study of giant coronary aneurysms due to Kawasaki disease: the 19th nationwide survey. Pediatr Int 2010; 52:790–794.
20. Kim T, Choi W, Woo CW, et al. Predictive risk factors for coronary artery abnormalities in Kawasaki disease. Eur J Pediatr 2007; 166:421–425.
21. Son MB, Gauvreau K, Ma L, et al. Treatment of Kawasaki disease: analysis of 27 US pediatric hospitals from 2001 to 2006. Pediatrics 2009; 124:1–8.
22. Honkanen VE, McCrindle BW, Laxer RM, et al. Clinical relevance of the risk factors for coronary artery inflammation in Kawasaki disease. Pediatr Cardiol 2003; 24:122–126.
23. Sabharwal T, Manlhiot C, Benseler SM, et al. Comparison of factors associated with coronary artery dilation only versus coronary artery aneurysms in patients with Kawasaki disease. Am J Cardiol 2009; 104:1743–1747.
24. Beiser AS, Takahashi M, Baker AL, et al. A predictive instrument for coronary artery aneurysms in Kawasaki disease. US Multicenter Kawasaki Disease Study Group. Am J Cardiol 1998; 81:1116–1120.
25. McCrindle BW, Li JS, Minich LL, et al. Coronary artery involvement in children with Kawasaki disease: risk factors from analysis of serial normalized measurements. Circulation 2007; 116:174–179.
26. Kobayashi T, Inoue Y, Takeuchi K, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation 2006; 113:2606–2612.
27. Sano T, Kurotobi S, Matsuzaki K, et al. Prediction of nonresponsiveness to standard high-dose gamma-globulin therapy in patients with acute Kawasaki disease before starting initial treatment. Eur J Pediatr 2007; 166:131–137.
28. Egami K, Muta H, Ishii M, et al. Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediatr 2006; 149:237–240.
29. Sleeper LA, Minich LL, McCrindle BM, et al. Evaluation of Kawasaki disease risk-scoring systems for intravenous immunoglobulin resistance. J Pediatr 2011; 158:831.e3–835.e3.
30. Tremoulet AH, Best BM, Song S, et al. Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr 2008; 153:117–121.
31▪. Dominguez SR, Anderson MS, Eladawy M, et al.
Preventing coronary artery abnormalities: a need for earlier diagnosis and treatment of Kawasaki disease. Pediatr Infect Dis J 2012; 31:1217–1220.
This study demonstrated 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.
32. Knight DM, Trinh H, Le J, et al. Construction and initial characterization of a mouse–human chimeric anti-TNF antibody. Mol Immunol 1993; 30:1443–1453.
33. Matsubara T, Furukawa S, Yabuta K. Serum levels of tumor necrosis factor, interleukin 2 receptor, and interferon-gamma in Kawasaki disease involved coronary-artery lesions. Clin Immunol Immunopathol 1990; 56:29–36.
34. Burns JC, Mason WH, Hauger SB, et al. Infliximab treatment for refractory Kawasaki syndrome. J Pediatr 2005; 146:662–667.
35. Girish M, Subramaniam G. Infliximab treatment in refractory Kawasaki syndrome. Indian J Pediatr 2008; 75:521–522.
36. O’Connor MJ, Saulsbury FT. Incomplete and atypical Kawasaki disease in a young infant: severe, recalcitrant disease responsive to infliximab. Clin Pediatr (Phila) 2007; 46:345–348.
37. Oishi T, Fujieda M, Shiraishi T, et al. Infliximab treatment for refractory Kawasaki disease with coronary artery aneurysm. Circ J 2008; 72:850–852.
38. Weiss JE, Eberhard BA, Chowdhury D, et al. Infliximab as a novel therapy for refractory Kawasaki disease. J Rheumatol 2004; 31:808–810.
39. Burns JC, Best BM, Mejias A, et al. Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease. J Pediatr 2008; 153:833–838.
40. Song MS, Lee SB, Sohn S, et al. Infliximab treatment for refractory Kawasaki disease in korean children. Korean Circ J 2010; 40:334–338.
41. Mori M, Imagawa T, Hara R, et al. Efficacy and limitation of infliximab treatment for children with Kawasaki disease intractable to intravenous immunoglobulin therapy: report of an open-label case series. J Rheumatol 2012; 39:864–867.
42▪. Son MB, Gauvreau K, Burns JC, et al. Infliximab for intravenous immunoglobulin resistance in Kawasaki disease: a retrospective study. J Pediatr 2011; 158:644.e1–649.e1.
This two-center retrospective study (n = 106) compares the use of second-dose IVIG vs. infliximab. The infliximab group had 1.2 fewer days of fever and shorter hospitalizations (by 0.5 days). Treatment groups were not significantly different in coronary artery dimensions or adverse events.
43. Choueiter NF, Olson AK, Shen DD, et al. Prospective open-label trial of etanercept as adjunctive therapy for kawasaki disease. J Pediatr 2010; 157:960.e1–966.e1.
44. Portman MA, Olson A, Soriano B, et al. Etanercept as adjunctive treatment for acute Kawasaki disease: study design and rationale. Am Heart J 2011; 161:494–499.
45. Chi H, Huang FY, Chen MR, et al. ITPKC gene SNP rs28493229 and Kawasaki disease in Taiwanese children. Hum Mol Genet 2010; 19:1147–1151.
46. Kuo HC, Yang KD, Juo SH, et al. ITPKC single nucleotide polymorphism associated with the Kawasaki disease in a Taiwanese population. PLoS One 2011; 6:e17370.
47. Lin MT, Wang JK, Yeh JI, et al. Clinical implication of the C allele of the ITPKC gene SNP rs28493229 in Kawasaki disease: association with disease susceptibility and BCG scar reactivation. Pediatr Infect Dis J 2011; 30:148–152.
48. Onouchi Y, Gunji T, Burns JC, et al. ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nat Genet 2008; 40:35–42.
49. Onouchi Y, Suzuki Y, Suzuki H, et al.
ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease. Pharmacogenomics J 2011. doi: 10.1038/tpj.2011.45. [Epub ahead of print]
50. Peng Q, Chen C, Zhang Y, et al.
Single-nucleotide polymorphism rs2290692 in the 3′ UTR of ITPKC associated with susceptibility to Kawasaki disease in a Han Chinese population. Pediatr Cardiol 2012; 33:1046–1053.
51. Peng Q, Chen CH, Wu Q, et al. Association study of a functional SNP rs28493229 of ITPKC gene and Kawasaki disease in a Chinese population [in Chinese]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2011; 28:644–648.
52. Brogan PA, Shah V, Clarke LA, et al. T cell activation profiles in Kawasaki syndrome. Clin Exp Immunol 2008; 151:267–274.
53. Franco A, Shimizu C, Tremoulet AH, et al. Memory T-cells and characterization of peripheral T-cell clones in acute Kawasaki disease. Autoimmunity 2010; 43:317–324.
54. Suzuki H, Suenaga T, Takeuchi T, et al. Marker of T-cell activation is elevated in refractory Kawasaki disease. Pediatr Int 2010; 52:785–789.
55. De Inocencio J, Hirsch R. The role of T cells in Kawasaki disease. Crit Rev Immunol 1995; 15:349–357.
56. Brown TJ, Crawford SE, Cornwall ML, et al. CD8 T lymphocytes and macrophages infiltrate coronary artery aneurysms in acute Kawasaki disease. J Infect Dis 2001; 184:940–943.
57. Suzuki H, Terai M, Hamada H, et al. Cyclosporin A treatment for Kawasaki disease refractory to initial and additional intravenous immunoglobulin. Pediatr Infect Dis J 2011; 30:871–876.
58▪. Tremoulet AH, Pancoast P, Franco A, et al.
Calcineurin inhibitor treatment of intravenous immunoglobulin-resistant Kawasaki disease. J Pediatr 2012; 161:506–512.
This multicenter study provides a rationale and proposes a therapeutic regimen for the use of cyclosporine in the treatment of IVIG-resistant Kawasaki disease.
59. Ahn SY, Kim DS. Treatment of intravenous immunoglobulin-resistant Kawasaki disease with methotrexate. Scand J Rheumatol 2005; 34:136–139.
60. Lee MS, An SY, Jang GC, et al. A case of intravenous immunoglobulin-resistant Kawasaki disease treated with methotrexate. Yonsei Med J 2002; 43:527–532.
61. Lee TJ, Kim KH, Chun JK, et al. Low-dose methotrexate therapy for intravenous immunoglobulin-resistant Kawasaki disease. Yonsei Med J 2008; 49:714–718.
62. Harada T, Ito S, Shiga K, et al. A report of two cases of Kawasaki disease treated with plasma exchange. Ther Apher Dial 2008; 12:176–179.
63. Hokosaki T, Mori M, Nishizawa T, et al. Long-term efficacy of plasma exchange treatment for refractory Kawasaki disease. Pediatr Int 2012; 54:99–103.
64. Imagawa T, Mori M, Miyamae T, et al. Plasma exchange for refractory Kawasaki disease. Eur J Pediatr 2004; 163:263–264.
65. Kashiwagi Y, Kawashima H, Akamatsu N, et al. Efficacy of plasma exchange therapy for Kawasaki disease by cytokine profiling. Ther Apher Dial 2012; 16:281–283.
66. Mori M, Imagawa T, Katakura S, et al. Efficacy of plasma exchange therapy for Kawasaki disease intractable to intravenous gamma-globulin. Mod Rheumatol 2004; 14:43–47.
67. Iwashima S, Seguchi M, Matubayashi T, et al. Ulinastatin therapy in kawasaki disease. Clin Drug Investig 2007; 27:691–696.
68. Kanai T, Ishiwata T, Kobayashi T, et al. Ulinastatin, a urinary trypsin inhibitor, for the initial treatment of patients with Kawasaki disease: a retrospective study. Circulation 2011; 124:2822–2828.