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Three Part Question

Do [patients with Kawaski Disease] who receive [steroids in the acute phase] have a better [outcome]?

Clinical Scenario

A 3 year old boy is admitted to your general paediatric ward with clinical features consistent with a diagnosis of Kawasaki disease. His parents agree for him to receive the current standard primary therapy of intravenous immunoglobulin (IVIG) and high dose aspirin. Given that the key pathological finding of Kawasaki disease is a vasculitis, you wonder whether treatment with steroids in addition to the IVIG can improve outcome, in particular reduce his risk of developing coronary artery aneurysms?

Search Strategy

Search term used: "Kawasaki" AND (steroid OR corticosteroid OR prednisolone OR methylprednisolone OR hydrocortisone)
Medline filters "Human studies" "0-18 years"
Embase searched using terms "Kawasaki AND (prednisolone OR methylprednisolone)" and "Kawasaki AND (hydrocortisone OR glucocorticoid)
CINAHL searched using terms "Kawasaki AND (prednisolone OR methylprednisolone)" and "Kawasaki AND (hydrocortisone OR glucocorticoid)

Search Outcome

Medline: 180 articles, 9 relevant and 2 further articles identified by screening the references of the 9 relevant articles .
Cochrane library: One protocol registered in 2003, not completed.
CINAHL: 15 papers, 1 relevant article already identified by the Medline search
Embase: 522 papers, 9 relevant papers with 8 already identified by medline search. The remaining paper is in Japanese therefore not able to obtain the abstract or full article

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Kato H, Et al 1979 Japan	92 patients, allocated to 5 treatment regimens: 1) Prednisolone, 2) aspirin, 3) antibiotic, 4) Prednisolone AND aspirin, 5) Prednisolone and warfarin	Prospective	Coronary artery aneurysm on angiography at 1 or 2 months	64.7% of patients in steroid treated group	Small patient numbers No randomisation No blinding
Kijima Y et al Japan 1982	60 patients with KD, all with altered coronary artery echodensity, dilatation or aneurysms. 2 cohorts, with one group receiving steroid pulse therapy and a control group not receiving steroid.	Prospective cohort study	Regression of coronary artery abnormalities	62% of patients receiving pulsed steroids demonstrated improvement	ONLY ABSTRACT AVAILABLE Uncertain trial size, Uncertain randomisation Endpoints not clearly defined. No details as to corticosteroid regime used
			Regression of coronary abnormality in patients with aneurysm on initial echocardiogram	53% of pulsed steroid therapy group demonstrated improvement
Kan Z et al 1990 Japan	255 patients with acute KD treated with corticosteroids	Uncontrolled prospective study	Coronary aneurysms in acute phase	Incidence 17.6%	Only abstract available In Japanese No details as to corticosteroid regimen used.
			Coronary aneurysms in sub-acute phase	Incidence 6.3%
Shinohara M et al Japan 1996	71 patients with KD disease receiving high dose aspirin and 2mg/kg once daily prednisolone. 1g/kg intravenous immunoglobulin (IVIG) over 5 days added to treatment for a number of indications	Case Series	Coronary artery aneurysm	15.5% of patients developed mild coronary artery aneurysm	No control cohort Inconsistent inclusion of IVIG to treatment Adverse affects not documented
Shinohara M Et al 1999 Japan	299 patients with KD. Treated with 1 of 4 regimens: 1) Aspirin, dipyridamole and propranolol, 2) As 1 plus 2mg/kg prednisolone for 2 weeks, then 2 weeks tapering dose, 3) As 1 plus IVIG (200 or 400mg/kg/day for 5 days) and 4) 1 plus prednisolone and IVIG - ?doses	Retrospective case note review	Duration of fever	Regimen 1 2.9 +/- 3.6 Regimen 2 1.4 +/- 1.8 Regimen 3 3.3 +/- 5.7 Regimen 4 0.6 +/- 1.1 (p <0.05 against regimen 1 and 2)	No randomisation to treatment groups. Patients treated with regimens 2 and 4 more ill at presentation
			Coronary aneurysm development	Regimen 1 14.3% Regimen 2 10.0% Regimen 3 16.0% Regimen 4 1.6% P=0.03 for regimens with steroid 'v' non-steroid
Sundel RP et al 2003 North America	39 patients with diagnosed KD. All received single dose 2g/kg IVIG and aspirin. Patients block randomised to receive 30mg/kg intravenous methylprednisolone prior to IVIG. Control group did not receive	Prospective randomised trial	Median Duration of Fever	1.0 +/- 1.3 days 'v' 2.4 +/- 1.9 days p=0.012	Block randomisation No blinding Only 39 patients enrolled from possible 71 Small sample size
			Median Hospital stay	1.9 +/- 0.7 days 'v' 3.3 +/- 2.1 days p = 0.01
			Coronary Aneurysm (2 weeks)	4/16 (25%) 'v' 2/21 (10%) Not statistically significant
			Re-treatment with IVIG	2/18 (11%) 'v' 5/21 (24%)
Okada Y et al 2003 Japan	32 patients with diagnosed KD disease, randomised to receive 1. IVIG (1g/kg on 2 consecutive days) and high dose aspirin (30mg/kg/day) or 2. regimen 1 plus Prednisolone sodium succinate (2mg/kg/day) followed by a weaning regimen of oral prednisolone	Multicentre Randomised controlled trial	Average duration of fever	0.3 +/- 0.5 days in steroid group 'v' 2.9 +/- 2.4 days in IVIG alone	No blinding to treatment arm
			Coronary Artery disease	No disease detectable in either group
Jibiki et al 2004 Japan	46 patients receiving 0.3mg/kg dexamethasone on 3 consecutive days. Also received IV heparin and 2g/kg IVIG over 4-5 days Control group 46 patients, received 2g/kg IVIG over 4-5 days and high dose ASA instead of heparin	Prospective cohort study	Duration of fever, median (range)	Dexamathasone group 1 day (1-12 days) Control group 2 days (1-16 days), p=0.015	Control group retrospectively analysed No blinding to treatment IVIG given over 4-5 days Treatment group received intavenous heparin and not high dose aspirin
			Coronary Aneurysm	2/46 in each group
			Re-treatment with IVIG	6/46 in each group
Woodcroft AC, Aronoff SC 2005 North America	Meta-analysis of 862 patients 8 trials included Compared patients receiving corticosteroids and aspirin +/- IVIG 'v' no corticosteroids but aspirin +/- IVIG	Meta-analysis	Incidence of coronary aneurysms	Odds ratio 0.546 95% CI 0.371-0.921	Heterogeneous study inclusion Variation in use of aspirin Variety of IVIG regimens used No randomisation or blinding in a number of studies
Inoue Y et al 2006 Japan	178 patients diagnosed with KD, individual patients randomly assigned to receive IVIG +/- Prednisolone (2mg/kg/day IV in three doses, tapered over 15 days when CRP normalised. Patients all received dipyridamole in conjunction with aspirin	Prospective multi-centre RCT	Coronary Abnormality before one month	2/90 (2.2%) 'v' 10/88 (11.4%) (p=0.017)	Patients received 1g/kg IVIG over 2 days. Not blinded Poor enrolment with a further 389 eligible patients declining
			Coronary abnormality at 3 months	0/90 (0.0%) 'v' 3/88 (3.4%) p=0.119
			Re-treatment with IVIG	5/90 (5.6%) 'v' 16/88 (18.2%) p=0.01
			Duration of fever	0.6 +/- 0.5 days 'v' 1.5 +/- 1 days (p <0.001
Newburger et al 2007 North America	199 children with diagnosis of KD. Randomised to receive 2g/kg IVIG and high dose aspirin +/- single dose methylprednisolone 30mg/kg Included patients with baseline coronary abnormality	Multi-centre double-blind RCT	Coronary aneurysm week 1	30/99 (30.3%) 'v' 28/93 (30.1%) p-1.00	Low enrolment rate (199/313 eligible patients) Only one dose of methlyprednisolone given
			Coronary Aneurysm week 5	15/95 (15.5%) 'v' 6/66 (9.1%) p=0.31
			Time until discharge median (IQR)	3 days (2-3) 'v' 3 days (I3-4) p=0.05
			Re-Treatment with IVIG	12/101 (11.9%) 'v' 15/97 (15.5%) p=0.54

Comment(s)

A number of the articles identified by the initial literature search studied the use of corticosteroids following the failure of primary IVIG treatment, and so were not included in our review. The most recent guidelines from the Council for Cardiovascular Disease in the Young, American Heart Association, were published in 2004 (1). These guidelines did not support the use of corticosteroids in the primary treatment of Kawasaki disease. However, since the publication of these guidelines 2 large multicentre trial (2;3), and one meta-analysis of 862 patients have been published (4). Steroids are used as the primary treatment in a large number of vasculitic disorders. Prior to the development of IVIG therapies, corticosteroids were used in the initial therapy of Kawasaki disease. Concerns were raised following the study by Kato et al in 1979 (5). This study reported a high incidence of coronary artery abnormalities in patients treated with corticosteroids. However, non-randomisation of patients to the different treatment regimens and small patient numbers are limiting factors and the results have to be viewed with caution. A study by Miura et al (6) was abandoned due to a high incidence of adverse effects, principally bradycardia, in patients treated with methylprednisolone following failure of a single dose of IVIG. Only 11 patients in total received corticosteroids in this study though, and no other studies identified by our search report such adverse outcomes. Sundel et al reported a 25% incidence of coronary artery aneurysm in patients treated with pulsed methlyprednisolone in addition to IVIG and high dose aspirin, compared to a 10% incidence in patients treated with IVIG and high dose aspirin alone, however, this difference was not statistically significant . Published studies on the primary use of corticosteroids have been of varying quality, and have examined a range of steroid regimens. This consequently limits the conclusions that can be drawn from them. Additionally, a surprisingly low enrolment rate was seen in a number of these studies, e.g Sundel et al (7) reported 54.9% recruitment, Inoue et al 31% (3) and Newburger et al (2) 63.5%. Study endpoints included development of coronary artery aneurysm or abnormality, regression of established aneurysm, duration of hospital stay, duration of fever and need for re-treatment with IVIG. Wooditch et al (4) performed a meta-analysis including 8 published studies, concluding that corticosteroid therapy reduced the incidence of coronary artery aneurysm, with an odds ratio of 0.546 (95% CI 0.371-0.921). However, there was large variability in study design (particularly with respect to blinding and randomisation) in the included studies, with a variety of corticosteroid regimens as adjuvant therapies with differing regimens of IVIG and aspirin. Four studies demonstrated a significant reduction in duration of fever (7-10), and 2 studies demonstrated significant reduction in hospital stay (3;7). Of the 4 studies reporting the need for re-treatment with IVIG, 2 found reduced incidence of retreatment with IVIG in the group that received corticosteroid therapy (3;7). However, this reached statistical significance in only one study (3). The 2 most recent studies are both large multi-centre prospective trials. Inoue et al (3) randomised patients to receive IVIG and high dose aspirin +/- a 3 day course of IV prednisolone followed by a tapering course. They reported a significant reduction in coronary artery aneurysm at one month (2.2% versus 11.4%, p=0.0017) in the steroid treated group, however,this was not observed at 3 month follow up (0% versus 3.4%, p=0.119). they also observed a significant reduction in the need for re-treatment with IVIG (5.6% versus 18.2%, p=0.01) and a reduction in duration of fever. However, this study did not blind the randomisation groups and the IVIG regimen used of 1g/kg given over 2 days may not be optimal compared 2g/kg given as a single dose . Newburger et al (2) report a large multi-centre randomised double-blind placebo-controlled trial comparing 2g/kg IVIG and high dose aspirin +/- a single 30mg/kg dose of methylprednisolone. This study did not show any significant differences between the two groups except for a significantly lower duration of hospital stay for the group that received steroids. However, the steroid regimen used may be sub-optimal as the majority of other similar studies have used multiple doses of steroid. Multiple steroid doses would generally be used in the clinical setting for other steroid responsive conditions. Reference List (1) Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, 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 Dec;114(6):1708-33. (2) Newburger JW, Sleeper LA, McCrindle BW, Minich LL, Gersony W, Vetter VL, et al. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med 2007 Feb 15;356(7):663-75. (3) Inoue Y, Okada Y, Shinohara M, Kobayashi T, Kobayashi T, Tomomasa T, et al. A multicenter prospective randomized trial of corticosteroids in primary therapy for Kawasaki disease: clinical course and coronary artery outcome. J Pediatr 2006 Sep;149(3):336-41. (4) 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 Oct;116(4):989-95. (5) Kato H, Koike S, Yokoyama T. Kawasaki disease: effect of treatment on coronary artery involvement. Pediatrics 1979 Feb;63(2):175-9. (6) Miura M, Ohki H, Yoshiba S, Ueda H, Sugaya A, Satoh M, et al. Adverse effects of methylprednisolone pulse therapy in refractory Kawasaki disease. Arch Dis Child 2005 Oct;90(10):1096-7. (7) Sundel RP, Baker AL, Fulton DR, Newburger JW. Corticosteroids in the initial treatment of Kawasaki disease: report of a randomized trial. J Pediatr 2003 Jun;142(6):611-6. (8) Shinohara M, Sone K, Kobayashi T, Kobayashi T, Kosuda T, Okada Y. Treatment of Kawasaki disease with corticosteroid. J Pediatr 1996 Sep;129(3):483-4. (9) Jibiki T, Terai M, Kurosaki T, Nakajima H, Suzuki K, Inomata H, et al. Efficacy of intravenous immune globulin therapy combined with dexamethasone for the initial treatment of acute Kawasaki disease. Eur J Pediatr 2004 Apr;163(4-5):229-33. (10) Okada Y, Shinohara M, Kobayashi T, Inoue Y, Tomomasa T, Kobayashi T, et al. Effect of corticosteroids in addition to intravenous gamma globulin therapy on serum cytokine levels in the acute phase of Kawasaki disease in children. J Pediatr 2003 Sep;143(3):363-7. (11) Kijima Y, Kamiya T, Suzuki A, Hirose O, Manabe H. A trial procedure to prevent aneurysm formation of the coronary arteries by steroid pulse therapy in Kawasaki disease. Jpn Circ J 1982 Nov;46(11):1239-42. (12) Kan Z, Hashino K. Effectiveness of steroid-aspirin combined therapy for kawasaki disease. Journal of Paediatric Practise 1990;53:328-31. (13) Shinohara M, Sone K, Tomomasa T, Morikawa A. Corticosteroids in the treatment of the acute phase of Kawasaki disease. J Pediatr 1999 Oct;135(4):465-9.

Clinical Bottom Line

• The use of corticosteroids in the primary treatment of Kawasaki disease in addition to IVIG and aspirin appears to reduce the duration of fever and hospital stay of patients. • There is insufficient evidence to state with certainty that corticosteroids reduce either the incidence of coronary artery aneurysm or the need for re-treatment with IVIG. • The evidence suggests that the addition of steroids is not associated with a significant increase in adverse effects. • As the primary objective of the treatment of Kawasaki disease is to reduce/ prevent the occurrence of coronary artery abnormalities, before steroids can be recommended as primary treatment there would have to be sufficient evidence to support its role in preventing coronary artery abnormalities.

References

1. Kato H, Koike S, Yokoyama T Kawasaki disease: Effect of treatment on coronary artery involvement Pediatrics 1979 Feb;63(2):175-9
2. Kijima Y, Kamiya T, Suzuki A, Hirose O, Manabe H A trial procedure to prevent aneurysm formation of the coronary arteries by steroid pulse therapy in Kawasaki disease. Jpn Circ J 1982 Nov;46(11):1239-42
3. Kan Z, Hashino K Effectiveness of steroid-aspirin combined therapy for kawasaki disease Journal of Paediatric Practise 1990;53:328-31
4. Shinohara M, Sone K, Kobayashi T, Kobayashi T, Kosuda T, Okada Y Treatment of Kawasaki disease with corticosteroid. J Pediatr 1996 Sep;129(3):483-4
5. Shinohara M, Sone K, Tomomasa T, Morikawa A. Corticosteroids in the treatment of the acute phase of Kawasaki disease. J Pediatr 1999 Oct;135(4):465-9
6. Sundel RP, Baker AL, Fulton DR, Newburger JW Corticosteroids in the initial treatment of Kawasaki disease: report of a randomized trial. J Pediatr 2003 Jun;142(6):611-6
7. Okada Y, Shinohara M, Kobayashi T, Inoue Y, Tomomasa T, Kobayashi T, et al. Effect of corticosteroids in addition to intravenous gamma globulin therapy on serum cytokine levels in the acute phase of Kawasaki disease in children J Pediatr 2003 Sep;143(3):363-7
8. Jibiki T, Terai M, Kurosaki T, Nakajima H, Suzuki K, Inomata H, et al Efficacy of intravenous immune globulin therapy combined with dexamethasone for the initial treatment of acute Kawasaki disease Eur J Pediatr 2004 Apr;163(4-5):229-33.
9. 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 Oct;116(4):989-95.
10. Inoue Y, Okada Y, Shinohara M, Kobayashi T, Kobayashi T, Tomomasa T, et al A multicenter prospective randomized trial of corticosteroids in primary therapy for Kawasaki disease: clinical course and coronary artery outcome. J Pediatr 2006 Sep;149(3):336-41
11. Newburger JW, Sleeper LA, McCrindle BW, Minich LL, Gersony W, Vetter VL, et al Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease N Engl J Med 2007 Feb 15;356(7):663-75.