Journal of Cardiology (2009) 53, 1519

ORIGINAL ARTICLE

The strategy of immune globulin resistant

Kawasaki disease: A comparative study of
additional immune globulin and
steroid pulse therapy
Shohei Ogata (MD) a, Yuki Bando (MD) a, Sumito Kimura (MD) a,
Hisashi Ando (MD) a, Yayoi Nakahata (MD) a, Yoshihito Ogihara (MD) b,
Tadahiro Kaneko (MD) b, Katsunori Minoura (MD) b, Miho Kaida (MD) c,
Yukifumi Yokota (MD) c, Shinsuke Furukawa (MD) a,
Masahiro Ishii (MD, FJCC) a,
a

Department of Pediatrics, Kitasato University, 1-15-1 Kitasato,

Sagamihara, Kanagawa 228, Japan
b Ebina General Hospital, Ebina, Kanagawa, Japan
c Sagamihara Kyodo Hospital, Sagamihara, Kanagawa, Japan
Received 19 May 2008 ; received in revised form 8 July 2008; accepted 23 July 2008
Available online 16 September 2008

KEYWORDS
Kawasaki disease;
Intravenous
immunoglobulin
treatment;
Steroid pulse therapy;
Re-treatment;
Coronary aneurysm;
Vasculitis

Summary
Background: We compared the clinical utility of additional intravenous immune globulin (IVIG) therapy with the clinical utility of steroid pulse therapy in patients with
IVIG-resistant Kawasaki disease.
Methods: We enrolled 164 patients with Kawasaki disease who were treated with a
single dose of IVIG (2 g/kg) and aspirin (30 mg/kg per day). Twenty-seven of these
patients (16%) were resistant to the initial IVIG treatment. We compared the effectiveness of treatment strategies for the initial IVIG-resistant 27 patients, 14 of these
patients were treated with additional IVIG therapy, and the other 13 patients were
treated with steroid pulse therapy (methylprednisolone 30 mg/kg per day for 3 days).
Results: Three patients in the group receiving additional IVIG treatment had coronary
artery aneurysms (21.4%), no patients had coronary artery aneurysm in the steroid
pulse therapy group; the difference in the incidence of coronary artery aneurysm
was not statistically signicant. The duration of high fever after additional treatment

Corresponding author. Tel.: +81 42 778 8829; fax: +81 42 778 8829.
E-mail address: ishiim@med.kitasato-u.ac.jp (M. Ishii).

0914-5087/$ see front matter 2008 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.jjcc.2008.08.002

16

S. Ogata et al.
in the steroid pulse therapy group (1 1.3 days) was signicantly shorter than that
in the additional IVIG treatment group (3 2.4 days; P < 0.05). The medical costs
were signicantly lower in the steroid pulse therapy group than in the additional IVIG
treatment group.
Conclusion: Steroid pulse therapy was useful to reduce the fever duration and medical
costs for patients with Kawasaki disease. Steroid pulse therapy and additional IVIG
treatment were not signicantly different in terms of preventing the development of
coronary artery aneurysm.
2008 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights
reserved.

Introduction

Initial treatment

Kawasaki disease (KD) is an acute febrile illness

characterized by mucosal inammation, skin rash,
and cervical lymphadenopathy, and is observed
most often in children younger than 4 years of
age [1]. This is an acute vasculitis syndrome of
unknown etiology that affects primarily small- and
medium-sized arteries, particularly the coronary
artery [2]. Treatment for KD has been the subject
of many studies [36]. Recently, the administration of high-dose intravenous immune globulin
(IVIG) has been observed to reduce both the
duration of fever and the incidence of coronary
artery aneurysms (CAA) when given within a few
days of disease onset [79]. Nonetheless, approximately 1020% of patients have persistent or
recurrent fever despite IVIG treatment [3,6,10,11].
The risk of CAA is increased in these patients,
and there have been few studies on the optimal management of such cases [3,6,10,11]. In
a recent small-randomized trial, Hashino et al.
compared the efcacy of additional IVIG treatment with the efcacy of steroid pulse therapy
for IVIG treatment-resistant KD patients [3]. The
aim of the present study was to compare the
effectiveness of additional IVIG treatment with
that of steroid pulse therapy for KD patients
who showed resistance to initial IVIG treatment.

All patients were initially treated with a single

dose of IVIG (2 g/kg per day) in a single infusion over a 24-h period and were administered
aspirin orally (30 mg/kg per day) within the rst 9
days of the onset of fever. We dened a responder as a patient who showed resolution of fever
(<37.5 C) and a fall in C-reactive protein (CRP)
of more than 50% within 3648 h after initial
IVIG treatment [3,1214]. These patients were
treated with steroid pulse therapy or additional
IVIG.

Methods
Patients
One hundred and sixty-four patients, ranging in
age from 2 months to 10 years, were included
in the study. They were treated at Kitasato University, Ebina General Hospital, and Sagamihara
Kyodo Hospital between April 2004 and May 2007.
The diagnosis of KD was made according to criteria established by the Japanese Kawasaki Disease
Research Committee [12].

Additional IVIG treatment and steroid pulse

therapy
Twenty-seven patients (16%) showed no clinical
response at 3648 h after initial IVIG treatment. Thirteen non-responders were treated at
Kitasato University Hospital, and these patients
were treated with steroid pulse therapy (group
1: methylprednisolone 30 mg/kg per day for 3
days). The remaining 14 patients were treated
at Ebina General Hospital and Sagamihara Kyoudo
Hospital with additional IVIG treatment (group
2). There were no signicant differences in gender, age, or duration of illness between the
2 groups (Table 1). During steroid pulse infusion and IVIG treatment patients underwent
continuous cardiac monitoring and their blood
pressure was determined every 30 min. Frequent
evaluations were made after the infusion until
vital signs were stable and within normal limits.

Calculation of medical cost

In calculation of medical cost the hospitalization
basic charge, clinical test (laboratory test, electro
cardiograph, echocardiography, etc.) costs, disposal costs, cost of procedures and cost of drugs
were included. The medical costs were calculated
from admission to discharge.

Steroid pulse therapy for immune globulin resistant Kawasaki disease

Table 1

17

Age, gender, and duration of illness on admission

Age
Gender (male:female)
Duration of illness

Group 1

Group 2

1 year 2 months 1 year 5 months

7:5
5 0.3 days

2 years 9 months 2 years 0 month

9:4
4 1.3 days

NS
NS
NS

Group 1, steroid pulse therapy group; group 2, IVIG treatment group.

Statistical analysis
All data are expressed as the median S.D.
MannWhitneys U-test was used for the two-way
comparison of data. Values were considered significantly different at P < 0.05.

Results
Results of treatment
One hundred and sixty-four sequential patients
were treated with IVIG (2 g/kg) immediately
after being diagnosed with KD. One hundred and
thirty-seven of these patients (84%) were clinical responders to the initial treatment, and
none of these patients showed coronary artery
abnormalities. However, the remaining 27 patients
(16%) showed no clinical response. These patients
were treated with either steroid pulse therapy (methylprednisolone 30 mg/kg per day for 3
days) or additional IVIG (2 g/kg). The 13 IVIGresistant patients at Kitasato University Hospital
were treated with steroid pulse therapy (group
1), and the 14 IVIG-resistant patients at Ebina
General Hospital and Sagamihara Kyodo Hospital
were treated with additional IVIG treatment (group
2) within 3648 h after initial IVIG treatment.
Although 2 patients developed bradycardia in the

Table 2

steroid pulse group, these cases improved spontaneously.

Incidence of CAA
CAA occurred in 3 patients (21.4%) in the additional
IVIG treatment group (group 2). One patient had a
giant coronary aneurysm, and the other 2 patients
had small aneurysms. No patients had CAA in the
steroid pulse therapy group (group 1). There was no
statistically signicant difference in the incidence
of CAA between the 2 groups.

Duration of fever
No signicant difference was found between the
2 groups with regard to illness days before additional treatment (Table 2). The duration of fever
(>37.5 C) after additional treatment in patients
treated with steroid pulse therapy (1 1.3 days)
was signicantly shorter than that in patients
treated with additional IVIG treatment (3 2.4
days; P < 0.05). A signicant difference was found
in the total duration of fever between the 2 groups
(8 2.1 days in group 1 versus 11 2.0 days in group
2; P < 0.05).

Laboratory data
Laboratory data on admission and after initial treatment are shown in Tables 2 and 3. Except for

Illness day and laboratory data on additional treatment

Group 1

Illness day
WBC (l)
Neutrophils (%)
Ht (%)
Platelets (104 )
CRP (mg/dl)
AST (IU)
ALT (IU)
Na (mequiv./l)
Albumin (mg/dl)

7
12,500
67
32
32
4.3
35
28
134
4

Group 2
1.3
1,029
10
2
15
1.7
16
60
2.5
2.4

8
10,700
64
33
50
5.9
34
26
133
3.9

P
2.4
3,769
16
2
15
4.0
21
44
2.6
0.4

NS
NS
NS
NS
<0.05
NS
NS
NS
NS
NS

Data are the mean S.D. WBC, white blood cells; Ht, hematocrit; CRP, C-reactive protein; AST, aspartate aminotransferase; ALT,
alanine aminotransferase.
Group 1, steroid pulse therapy group; group 2, IVIG treatment group.

18
Table 3

S. Ogata et al.
Laboratory data on admission
Group 1

WBC (l)
Neutrophils (%)
Ht (%)
Platelets (104 )
CRP (mg/dl)
AST (IU)
ALT (IU)
Na (mequiv./l)
Albumin (mg/dl)

14,200
77
32
31
7.3
40
26
133
3.8

Group 2
5,435
24
2
11
9.8
533
207
1.9
0.4

12,000
72
30
31
9.5
32.5
26
132
4.1

P
3,368
9
3
16
6.0
75
158
22.5
1.2

NS
<0.05
NS
NS
NS
NS
NS
NS
NS

Data are the mean S.D. WBC, white blood cells; Ht, hematocrit; CRP, C-reactive protein; AST, aspartate aminotransferase; ALT,
alanine aminotransferase. Group 1, steroid pulse therapy group; group 2, IVIG treatment group.

neutrophils, no signicant difference was found

between the 2 groups with regard to laboratory
data on admission (Table 3). In the 3648 h after
initial treatment, except for platelet count, no signicant difference was found in laboratory data
between the 2 groups (Table 2). However, 3648 h
after additional treatment, the CRP level in group
1 patients (0.6 1.4 mg/dl) was signicantly lower
than that in group 2 patients (1.7 4.9 mg/dl;
P < 0.05).

Medical cost and duration of hospital stays

The medical costs for the 2 therapies were calculated to be 290,610 57,477 yen (group 1) and
918,300 61,405 yen (group 2), respectively. The
medical costs of patients treated with steroid pulse
therapy were signicantly lower than those of
patients treated with additional IVIG treatment
(P < 0.05). There was no signicant difference in
hospital stay in patients treated with steroid pulse
therapy and that in patients treated with additional
IVIG (14.5 2.0 days group 1 versus 12 2.1 days
group 2).

Discussion
CAA
There was no statistically signicant difference in
the incidence of CAA between the 2 groups. In
the present study, 3 patients who were treated
with additional IVIG therapy developed a CAA. However, no patients treated with steroid pulse therapy
had a CAA. Steroid pulse therapy, which has various anti-inammatory effects, is widely used for
the clinical treatment of inammatory and autoimmune disorders [36,15,16]. Both IVIG treatment
and steroid pulse therapy may inhibit the production of cytokines that act in the reconstruction of
the inamed coronary artery wall. Makata et al.

previously reported that steroid therapy resulted

in a more wide inhibition of inammatory cells
compared with immunoglobulin treatment in cultured cells setting [17]. However, it remains unclear
whether steroid pulse therapy affects the coronary
artery wall, particularly in the long-term [1820].
The long-term effect of steroid pulse therapy on
the coronary arteries (i.e., the incidence of regression, the occurrence of stenosis or obstruction, the
development of aneurysms, and endothelial function) has not been claried. Further investigation
of the long-term outcome of the coronary arteries
in KD patients treated with steroid pulse therapy
and estimation of the endothelial function of coronary arteries in KD patients is needed. In addition,
prospective studies will be needed to assess the
long-term benets or disadvantages to patients who
receive steroid pulse therapy or additional IVIG
treatment.

Clinical implications
A previous meta-analysis reported on the effectiveness of steroids in KD treatment [21]. However,
Newburger et al. reported that the effectiveness
of steroid pulse therapy in initial treatment is
not recognized [22]. In the present study, we rst
demonstrated the clinical utility of steroid pulse
therapy as a second treatment in IVIG treatmentresistant KD patients. The duration of fever after
additional treatment in the steroid pulse therapy
group was signicantly shorter than that in the
additional IVIG treatment group. In addition, the
medical costs were lower in the steroid pulse therapy group. It should be noted, however, that this
study employed only a small number of patients and
was not randomized. In the future, a randomized
prospective study involving multiple treatment centers may be necessary to examine the clinical utility
of additional therapy for KD patients resistant to
initial IVIG treatment.

Steroid pulse therapy for immune globulin resistant Kawasaki disease

Conclusions
Steroid pulse therapy was useful to reduce the fever
duration and medical costs in KD patients. Steroid
pulse therapy may be as effective as additional IVIG
treatment to prevent the development of CAA.

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