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IVIG 1 g/kg for Kawasaki disease



Intravenous immunoglobulin 1 g/kg as the initial
treatment for Kawasaki disease
Hirohiko Shiraishi, Mayu Iino, Masaru Hoshina, Kou Ichihashi, Mariko Y Momoi
Tochigi, Japan


    Background: Coronary artery lesion (CAL) in                                appeared but regressed within 6 months after the onset.
Kawasaki disease (KD) is prevented by intravenous                                  Conclusion: Treatment of KD with IVIG at an initial
immunoglobulin (IVIG); however, the total amount of                            dose of 1 g/kg on the 5th to 7th day with additional IVIG




                                                                                                                                               Original article
IVIG should be reduced if the outcome is the same. Our                         for refractory patients can have the same effect as the
aim was to determine whether the treatment with IVIG                           standard protocol (IVIG of 2 g/kg).
at an initial dose of 1 g/kg on the 5th to 7th day of illness
with additional IVIG for refractory patients is effective                                               World J Pediatr 2007;3(3):195-199
for preventing CAL.                                                                Key words: coronary artery;
    Methods: A total of 107 KD patients were treated                                          echocardiography;
according to the days of illness and the Harada score                                         immunoglobulin;
within 7 days of illness. All the patients with Harada score                                  Kawasaki disease
4 or more were treated with IVIG at an initial dose of 1
g/kg, and the patients who were refractory to the initial
dose, additional IVIG at a dose of 1 g/kg up to 3 g/kg was                     Introduction

                                                                               K
infused. Echocardiography was performed to detect the                                   awasaki disease (KD) is associated with
incidence of CAL.                                                                       coronary artery aneurysm in 15% to 25% of
     Results: Seventy-eight patients (73%) were treated                                 patients.[1] Acute phase KD is treated with
with IVIG at an initial dose of 1 g/kg according to the                        aspirin and intravenous immunoglobulin (IVIG), and
Harada score and the duration of illness; IVIG was                             the incidence of coronary artery aneurysm has decreased
started when their Harada score became 4 or more and                           after the introduction of high-dose IVIG.[2,3] The standard
basically on the 5th day or later. Six critically ill patients                 care for children with acute phase KD is treatment with         195
were treated with IVIG at a dose of 1 g/kg starting from                       a single infusion of high-dose (2 g/kg) IVIG within
the 2nd or 4th day, and all of them were refractory to the                     the 10th day of illness and aspirin.[4] Although a dose-
initial dose of 1 g/kg and further treated with additional                     dependent effect is reported in the treatment of KD,[5] the
doses of 1 to 3 g/kg (CAL was not observed); whereas the                       total amount of IVIG should be reduced if the incidence
other 72 patients (of whom 42 were admitted by the 4th                         of coronary artery lesions (CALs) can be the same as
day and waited until the 5th day) were treated on the 5th                      that with the standard protocol. Also, it is reported that
to 7th day with IVIG at an initial dose of 1 g/kg. Of the                      early treatment of KD with IVIG (on the 1st to 4th day
78 patients, 57 responded to the initial dose of 1 g/kg, but
                                                                               of illness) is likely to require additional IVIG.[6,7] In the
the remaining 21 refractory patients required additional
                                                                               treatment of KD, we found that IVIG at a dose of 1 g/kg
IVIG (a total dose of IVIG up to 4 g/kg). Twenty-nine
                                                                               was effective in most patients when it was infused on
patients (27%) were treated without IVIG because their
                                                                               the 5th to 7th day of illness. Thus, we began to treat KD
Harada score was less than 4, and CAL was not observed.
                                                                               with this regimen from February 2002. The aim of this
In 4 (3.7%) of the 107 patients who had IVIG at 1 g/
kg (n=1) or additional IVIG up to 3 g/kg (n=3), CAL                            study was to assess the efficacy of IVIG at an initial dose
                                                                               of 1g/kg on the 5th to 7th day of KD with additional
                                                                               IVIG in refractory patients, and whether the total amount
                                                                               of IVIG is reduced when patients were selected by the
Author Affiliations: Department of Pediatrics, Jichi Medical University,       Harada score.
Tochigi, 329-0498, Japan (Shiraishi H, Iino M, Hoshina M, Ichihashi K,
Momoi MY)
Corresponding Author: Hirohiko Shiraishi, MD, Department of Pediatrics,
Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498,     Methods
Japan (Tel: +81-285-58-7366; Fax: +81-285-44-6123; Email: shiraish@jichi.
ac.jp)
                                                                               In this study, we retrospectively reviewed clinical
                                                                               records of consecutive 118 acute phase KD patients
©2007, World J Pediatr. All rights reserved.                                   who were admitted to our institute between February
                                                                             World J Pediatr, Vol 3 No 3 . August 15, 2007 . www.wjpch.com
World Journal of Pediatrics


                   2000 and April 2004. Our criteria for a diagnosis of             patient was asked to wait until the 5th day of illness
                   KD included fever (temperature exceeding 38 degrees              without IVIG, even if the patient's Harada score was ≥
                   Celcius) accompanied by the presence of at least 4 of            4. If the patient was critically ill and suspected of having
                   the following 5 findings: bilateral conjunctival injection,      meningitis or hyponatremia was present, IVIG at a dose
                   changes in the lips and oral cavity, nonpurulent cervical        of 1 g/kg was started on admission. On the 5th to 7th day
                   lymphadenopathy, polymorphous exanthema, and                     of illness, if the patient's Harada score was ≤3, no IVIG
                   changes in the extremities. These diagnostic criteria            was infused, and if their Harada score was ≥4, IVIG at 1
                   were consistent with the Diagnostic Guidelines for               g/kg was infused for over 10 hours in one day.
                   Kawasaki Disease (5th revision).[8] Incomplete KD was                 2) When the patient was admitted on the 5th to
                   defined as lacking sufficient clinical signs of the disease      7th day of illness and the patient's Harada score was ≤
                   to fulfill the above criteria.[4] The first day of the illness   3, no IVIG was infused. They were asked to wait until
                   was defined as the first day of fever. Fourteen patients         the end of the 7th day of illness, and once the Harada
                   who were admitted or treated beyond the 7th day of               score became ≥4, IVIG at 1 g/kg was started. When the
Original article




                   illness were excluded in this study. The total number of         patient's Harada score on admission was ≥4, IVIG at 1
                   KD patients who were admitted within the 7th day of              g/kg was infused.
                   illness was 104, among whom 3 patients had recurrent                  3) For those patients who were refractory to the
                   KD (there were 14, 18 and 34 months between the initial          initial IVIG, additional IVIG at 1 g/kg was infused;
                   and the second episode of KD, respectively) during this          for those who were refractory to the second IVIG, total
                   period. Thus, a total of 107 admissions were enrolled            IVIG up to 4 g/kg was infused. The patients who were
                   in this study. Ninety-six patients met the criteria of KD,       refractory to IVIG were defined as having fever (≥37.5
                   and 11 patients were diagnosed as having incomplete              degrees Celcius), increased white blood cell counts
                   KD. There were 74 male (two of them had recurrent KD)            (WBC), or poor CRP decrease (more than half of the
                   and 30 female patients (one of them had recurrent KD).           pre-treatment level) that was observed 36 to 48 hours
                   In this report, one admission for KD is counted as one           after the end of the initial IVIG. Those patients who
                   patient because the clinical data and CAL of each patient        fulfilled all the 3 parameters were considered to be
                   were not substantially different between the initial and         responders, and IVIG treatment was considered to be
                   the second admissions. The average age at the onset of           effective.
                   KD was 2.47 (range 0.16 to 8.85) years. In this study                 Several IVIG preparations were used for the treatment
                   there was no control group, and therefore no statistical         of KD in this study: polyethylene glycol-treated human
                   analysis was performed.                                          immunoglobulin (Venoglobulin IH®, Mitsubishi-
196                                                                                 Welpharma Ltd) in 46 patients, pH4 stabilized acid human
                   Laboratory data                                                  immunoglobulin (Poliglobin N®, Bayer Yakuhin Ltd)
                   Complete blood count, C-reactive protein (CRP),                  in 25 patients, and sulfonated human immunoglobulin
                   serum aspartate aminotransferase (AST), alanine                  (Venilon®, Teijin Ltd) in 7 patients. Basically, the same
                   aminotransferase (ALT), and albumin were examined                preparation was used for the additional IVIG, except for
                   at least on admission, at 36 to 48 hours after completion        1 patient who showed an allergic response to the second
                   of IVIG, and before discharge.                                   IVIG, and the third IVIG preparation was changed to
                                                                                    another preparation (from Poliglobin N® to Venoglobulin
                                                                                    IH®).
                   Treatment
                   Once the patients were diagnosed as having KD, they              Echocardiography
                   were treated with oral aspirin at 30 mg/kg per day, or
                                                                                    The initial echocardiography was performed before
                   dipyridamole at 5 mg/kg per day when the AST or ALT
                                                                                    IVIG treatment, and subsequent echocardiography was
                   level was above 100 mU/ml. Then, the medication was
                   changed to oral aspirin at 5 mg/kg per day when the
                   body temperature was reduced to below 37.5 degrees               Table. Harada score
                   Celcius and AST and ALT levels were reduced to ≤100              1) WBC count: equal to or more than 12 ×103/μl
                   mU/ml. The guidelines established by Harada (Harada              2) Platelet count: less than 35×104/μl
                   score) were used to select those KD patients who were            3) CRP: equal to or more than 4 mg/dl
                                                                                    4) Hematocrit: less than 35%
                   likely to develop CALs; IVIG was started when the
                                                                                    5) Serum albumin: less than 3.5 g/dl
                   patient had Harada score of 4 or more (Table).[9]                6) Gender: male
                       Our basic treatment strategy for KD was as follows           7) Age: equal to or less than 12 months
                   (Fig.).                                                          When the patient with KD satisfies 4 or more of the above 7 criteria
                       1) When admitted before the 5th day of illness, the          within the 9th day of illness, treatment with IVIG should be started.

                   World J Pediatr, Vol 3 No 3 . August 15, 2007 . www.wjpch.com
IVIG 1 g/kg for Kawasaki disease


performed after IVIG, before discharge, and 1 month                           the initial IVIG. One patient who had febrile convulsion
after the onset of KD. CAL was defined and classified                         on the second day of illness and was treated with
as follows: coronary artery ectasia, when the coronary                        dexamethasone, and who responded to the initial IVIG,
artery was dilated with a diameter ≤4 mm or when the                          was included. Nine patients, however, were refractory to
diameter was less than 1.5 times that of the adjacent                         the initial dose of IVIG at 1 g/kg and were treated with
artery diameter; and coronary artery aneurysm, when                           additional IVIG (1 g/kg in 6 patients, 1.6 g/kg in 1, 2
the coronary artery was dilated with a diameter >4 mm.                        g/kg in 1, and up to 3 g/kg in 1). CALs were observed in
Once CAL was observed, oral aspirin was continued                             3 of the 9 patients, who received total IVIG of 2 g/kg, 2.6
and follow-up echocardiography was performed until                            g/kg and 4 g/kg for coronary artery ectasia of 3.4 mm, 3.8
it disappeared. Coronary artery dilatation or aneurysm                        mm and 3.8 mm, respectively (Fig.).
observed within 1 month was defined as CAL in this                                 Forty-six patients were admitted on the 5th to 7th
study.                                                                        day of illness. Sixteen patients were treated with no
                                                                              IVIG because their Harada scores were ≤3, and became




                                                                                                                                                  Original article
                                                                              defervescent spontaneously, without CAL appearance.
Results                                                                       In the other 30 patients with Harada scores ≥4 and
A total of 107 KD patients were admitted and treated                          treated with IVIG at 1 g/kg on the 5th to 7th day of
within the 7th day of illness during the study period                         illness, 24 responded to the initial IVIG, including 1
(Fig.).                                                                       patient developed CAL (coronary artery ectasia of 3.8
     Sixty-one patients were admitted before the 5th day                      mm); 6 patients were refractory to the initial IVIG and
of illness. Among them, 6 patients were treated before                        treated with additional IVIG at 1 g/kg, but no CAL was
the 5th day of illness (2 to 4 days) and showed Harada                        observed (Fig.).
scores ≥4 before IVIG therapy. They were refractory to                             Eleven patients (10%) who were diagnosed as having
IVIG (5 of them had persistent fever, and all had poor                        incomplete KD because of lacking sufficient clinical
CRP decrease) and were treated with additional IVIG                           signs of the disease to fulfill the criteria were included
(1 g/kg in 2 patients, 2 g/kg in 3 patients and up to 3                       in this study. The average age at the onset of incomplete
g/kg in 1 patient), but no CAL was observed. Fifty-five                       KD was 2.14 (range 0.16 to 5.28) years. Eight of the 11
patients were asked to wait until the 5th to 7th day of                       patients were treated without IVIG and 3 were treated
illness. Among them, 13 patients were treated without                         with IVIG at 1 g/kg on the 6th day of illness, but no
IVIG because their Harada scores were ≤3, and no CAL                          CAL was observed.
was observed. In the other 42 patients treated with IVIG                           In the 78 patients (73%) who were treated with IVIG
at 1 g/kg on the 5th to 7th day of illness, 33 responded to                   at an initial dose of 1 g/kg, 6 were treated before the             197


                                                      Patients with acute phase KD (n=107)


                         Admitted on the 0-4th day (n=61)                             Admitted on the 5th-7th day (n=46)


                 Treated within the 4th Waited until the 5th-7th day (n=55)
                 day with IVIG 1 g/kg
                       Harada ≥4
                         (n=6)         Harada ≤3              Harada ≥4                                      Harada ≥4
                                                                                      Harada ≤3
                                        (n=13)                  (n=42)                                         (n=30)
                                                                                       (n=16)
                                                             Treated with                                   Treated with
                                                             IVIG 1 g/kg                                    IVIG 1 g/kg


                      Refractory                   Responder         Refractory                      Responder       Refractory



                  Add IVIG 1-3 g/kg    No IVIG No more IVIG Add IVIG 1-3 g/kg No IVIG              No more IVIG Add IVIG 1 g/kg
                        (n=6)           (n=13)    (n=33)          (n=9)        (n=16)                 (n=24)         (n=6)
                       CAL 0           CAL 0        CAL 0             CAL 3            CAL 0          CAL 1            CAL 0
                                                                      3.4 to 3.8 mm                   3.8 mm
Fig. IVIG treatment for KD according to the day of illness and Harada score. Patients were treated according to the duration of KD and Harada
score. Add IVIG: additional intravenous immunoglobulin; CAL: coronary artery lesion; Harada: Harada score; KD: Kawasaki disease; IVIG:
intravenous immunoglobulin; Refractory: patients who were refractory to the initial treatment; Responder: patients who responded to the initial
treatment.

                                                                         World J Pediatr, Vol 3 No 3 . August 15, 2007 . www.wjpch.com
World Journal of Pediatrics


                   4th day of illness, and 72 on the 5th to 7th day. Of these      additional IVIG. The high rate (100%) of additional
                   78 patients, 57 (73%) responded to a single infusion            IVIG in our 6 patients may be due to the shortage of
                   of IVIG at a dose of 1 g/kg, and 21 (27%) required re-          the initial dose of IVIG. Muta et al[7] reported that early
                   treatment or multiple infusions of IVIG (total IVIG up          treatment is likely to result in a greater requirement for
                   to 4 g/kg). CALs were observed in 4 patients who had            additional IVIG, which is supported by our results. In
                   been infused with total IVIG at a dose of 1 g/kg, 2 g/kg,       those critically ill patients who need to be treated on
                   2.6 g/kg and 4 g/kg, respectively. All CALs regressed           ≤ the 4th day of illness, an initial IVIG dose of 2 g/kg
                   spontaneously within 6 months after the onset of KD,            would be better than 1 g/kg.
                   as observed echocardiographically. In 29 patients (27%)               We treated the patients who were refractory to
                   whose Harada scores were ≤3 and were treated without            the initial dose of 1 g/kg with additional IVIG. The
                   IVIG, no CAL was observed.                                      patients with KD who were refractory to IVIG were
                       In this study, the total amount of IVIG used in the 78      treated with high-dose methylprednisolone,[12,13] low-
                   patients was 1275.5 g: IVIG 1 g/kg in 57 patients, 2 g/kg       dose methotrexate,[14,15] or ulinastatin.[16] Hashino et
Original article




                   in 14, 2.6 g/kg in 1, 3 g/kg in 3, and 4 g/kg in 3. Total       al[12] reported that steroid pulse therapy was given to
                   body weight of the 107 patients was 1325.5 kg. Side-            those who were resistant to IVIG, but its efficacy for
                   effect of IVIG was observed in 1 patient, whose second          preventing CAL was not superior to that of additional
                   infusion of IVIG was stopped midway (0.6 g/kg), and the         IVIG therapy. Low-dose methotrexate therapy or
                   patient was treated with another preparation on the next        ulinastatin might be promising, but only a few case
                   day (a total dose of IVIG was 2.6 g/kg). Total IVIG up to       reports have been published.[14,16] A randomized control
                   4 g/kg was infused in 3 patients, but no dose-related side      study will disclose the efficacy of these therapies. In KD
                   effects were observed.                                          patients who are refractory to IVIG, plasma exchange
                                                                                   therapy has been reported to be effective;[17] however,
                                                                                   plasma exchange requires a rather complicated system,
                                                                                   and cannot be easily utilized in general pediatric wards.
                   Discussion                                                      Infliximab treatment for those refractory to IVIG was
                   In this study, the IVIG therapy at an initial dose of 1
                                                                                   reported by Burns.[18] The total number of patients who
                   g/kg on the 5th to 7th day of illness and additional IVIG       were treated with this method is so small that the safety
                   for the refractory patients was effective. The incidence        of this method has not been studied completely. In our
                   of CAL was lower than that reported in a nationwide             series, the patients who were refractory to the initial
                   KD survey in which most of the patients were treated            IVIG were treated with additional IVIG (total IVIG up
198                with the standard protocol (IVIG of 2 g/kg).[4] The IVIG        to 4 g/kg), but no patients suffered from dose-related
                   therapy at an initial dose of 1 g/kg could reduce the total     side effects of IVIG, and no giant coronary aneurysms
                   amount of IVIG used in treating acute phase KD.                 were observed.
                        The use of a moderate dose of IVIG for KD has been               Treating KD with IVIG was based on the score
                   reported by Khowsathit et al.[10] They started to treat KD      established by Harada (Table).[9] In our series, 78 patients
                   patients with IVIG at a dose of 1 g/kg, and the response        were treated with IVIG, giving a rate of 73% close to that
                   rate (76%) was similar to that in our study. They treated       in Harada's report (73.4%).[9] The total amount of IVIG
                   KD patients with IVIG up to 3 g/kg; however, the                infused in our series was 1275 g: 1 g/kg in 57 patients, 2
                   efficacy of preventing CAL was lower than that of the           g/kg in 14, 2.6 g/kg in 1, 3 g/kg in 3, and 4 g/kg in 3. If
                   high-dose regimen (2 g/kg). In our series, the patients         IVIG at a dose of 2 g/kg was given to all the patients (total
                   who were refractory to the initial IVIG dose of 1 g/kg,         body weight of 107 patients was 1325.5 kg), the total
                   IVIG of 2 g/kg could be infused within the 9th day, and         amount of IVIG would be 2651 g without taking account
                   the dose up to 4 g/kg was infused. The incidence of CAL         of the additional IVIG. Accordingly, at least 1376 g of
                   at 1 month (4 in 107 patients; 3.7%) was the same as that       IVIG was saved in our protocol. Sato et al[19] reported the
                   in a nationwide KD survey, in which most of the patients        cost effectiveness of high-dose IVIG in selected patients
                   were treated with IVIG at a dose of 2 g/kg.[11]                 using the Harada score. In their study, IVIG at a dose of
                        Six patients who had KD for less than 4 days were          2 g/kg was superior to the 5-day 400 mg/kg therapy. In
                   treated with IVIG at 1 g/kg, but failed. They were              this study, the same scoring system (Harada score) was
                   successfully retreated with additional IVIG (a total dose       used, but IVIG at a dose of 1 g/kg resulted in much less
                   up to 4 g/kg). Early treatment of KD with IVIG at a dose        utilization of IVIG.
                   of 2 g/kg is reported to be associated with persistent/               In 11 patients (10%) who were diagnosed as having
                   recrudescent fever that required additional IVIG in 33%         incomplete KD, 8 patients were treated without IVIG
                   of the patients.[6] In our 6 patients, 5 had persistent fever   and 3 with IVIG at a dose of 1 g/kg on the 6th day of
                   and all had a poor CRP decrease, and were treated with          illness; no CAL was observed. Incomplete KD is more

                   World J Pediatr, Vol 3 No 3 . August 15, 2007 . www.wjpch.com
IVIG 1 g/kg for Kawasaki disease


common in young infants than in older children and the                4 	 Newburger JW, Takahashi M, Gerber MA, Gewitz MH,
rate of incomplete KD is about 10%.[4,8] Even in patients                 Tani LY, Burns JC, et al. Diagnosis, treatment, and long-
                                                                          term management of Kawasaki disease: a statement for
with incomplete KD, CAL can develop; however, in this
                                                                          health professionals from the Committee on Rheumatic
study the average age at the onset of incomplete KD was                   Fever, Endocarditis and Kawasaki Disease, Council on
2.14 (range 0.16 to 5.28) years, and CAL was prevented                    Cardiovascular Disease in the Young, American Heart
by a single infusion of IVIG at a dose of 1 g/kg on the                   Association. Circulation 2004;110:2747-2771.
6th day in 3 patients. This might be explained by the                 5 Terai M, Shulman ST. Prevalence of coronary artery
benign nature of the condition in the incomplete KD                       abnormalities in Kawasaki disease is highly dependent on
patients enrolled in our study.                                           gamma globulin dose but independent of salicylate dose. J
                                                                          Pediatr 1997;131:888-893.
     In our series, 4 patients (3.7%) had coronary
                                                                      6 	 Fong NC, Hui YW, Li CK, Chiu MC. Evaluation of the
artery ectasia at 1 month, which regressed within 6                       efficacy of treatment of Kawasaki disease before day 5 of
months after onset. The total percentage of patients                      illness. Pediatr Cardiol 2004;25:31-34.
with CALs in the same period was 4.4 % in Japan, of                   7 	 Muta H, Ishii M, Egami K, Furui J, Sugahara Y, Akagi T, et




                                                                                                                                          Original article
whom most patients (79.8%) received IVIG at a dose                        al. Early intravenous gamma-globulin treatment for Kawasaki
of 2 g/kg.[8] Thus, our protocol showed the same effect                   disease: the nationwide surveys in Japan. J Pediatr 2004;
on KD patients. This is a study that was performed in                     144:496-499.
                                                                      8	 Ayusawa M, Sonobe T, Uemura S, Ogawa S, Nakamura Y,
a single institute without controls, and a multicenter                    Kiyosawa N, et al. Revision of diagnostic guidelines for
prospective randomized study would clarify the efficacy                   Kawasaki disease (the 5th revised edition). Pediatr Int 2005;
of our treatment strategy. The regimen for KD with                        47:232-234.
IVIG at an initial dose of 1 g/kg on the 5th to 7th day               9 	 Harada K. Intravenous gamma-globulin treatment in
with additional IVIG for refractory patients can be as                    Kawasaki disease. Acta Paediatr Jpn 1991;33:805-810.
effective as the standard protocol (2 g/kg). Accordingly,             10 Khowsathit P, Hong-Hgam C, Khositseth A, Wanitkun S.
it can reduce the total amount of IVIG for KD patients                    Treatment of Kawasaki disease with a moderate dose (1 g/kg)
                                                                          of intravenous immunoglobulin. J Med Assoc Thai 2002;85
without increasing CALs.                                                  Suppl 4:S1121-1126.
     In conclusion, IVIG therapy for KD patients at an                11 Nakamura Y, Yashiro M, Uehara R, Yanagawa H. Results
initial dose of 1 g/kg on the 5th to 7th day of illness and               of the 17th nationwide survey on Kawasaki disease. Japan
additional IVIG for the refractory patients was effective                 Kawasaki Disease Research Committee. J Pediatr Prac 2004;
and the total amount of IVIG could be reduced when                        67:313-323 (in Japanese).
patients were selected by the Harada scoring system.                  12	 Hashino K, Ishii M, Iemura M, Akagi T, Kato H. Re-
                                                                          treatment for immune globulin-resistant Kawasaki disease: a
This method can be an alternative for the prevention of
                                                                          comparative study of additional immune globulin and steroid
CAL.                                                                                                                                      199
                                                                          pulse therapy. Pediatr Int 2001;43:211-217.
                                                                      13	 Wright DA, Newburger JW, Baker A, Sundel RP. Treatment
                                                                          of immune globulin-resistant Kawasaki disease with pulsed
Funding: None.                                                            doses of corticosteroids. J Pediatr 1996;128:146-149.
Ethical approval: Not needed.                                         14	 Ahn SY, Kim DS. Treatment of intravenous immunoglobulin-
Competing interest: None declared.                                        resistant Kawasaki disease with methotrexate. Scand J
Contributors: Shiraishi H proposed the study and wrote the first          Rheumatol 2005;34:136-139.
draft. Ichihashi K analyzed the data. All authors contributed to      15	 Lee MS, An SY, Jang GC, Kim DS. A case of intravenous
the design and interpretation of the study and to further drafts.         immunoglobulin-resistant Kawasaki disease treated with
Momoi MY is the guarantor.                                                methotrexate. Yonsei Med J 2002;43:527-532.
                                                                      16	 Iino M, Shiraishi H, Igarashi H, Honma Y, Momoi MY. Case
                                                                          of Kawasaki disease in NICU. Pediatr Int 2003;45:580-583.
                                                                      17	 Imagawa T, Mori M, Miyamae T, Ito S, Nakamura T, Yasui K,
References                                                                et al. Plasma exchange for refractory Kawasaki disease. Eur J
1	 Kato H, Sugimura T, Akagi T, Sato N, Hashino K, Maeno Y,               Pediatr 2004;163:263-264.
    et al. Long-term consequences of Kawasaki disease. A 10- to       18	 Burns JC, Mason WH, Hauger SB, Janai H, Bastian JF,
    21-year follow-up study of 594 patients. Circulation 1996;94:         Wohrley JD, et al. Infliximab treatment for refractory
    1379-1385.                                                            Kawasaki syndrome. J Pediatr 2005;146:662-667.
2 	 Furusho K, Kamiya T, Nakano H, Kiyosawa N, Shinomiya K,           19	 Sato N, Sugimura T, Akagi T, Yamakawa R, Hashino K, Eto
    Hayashidera T, et al. High-dose intravenous gammaglobulin             G, et al. Selective high dose gamma-globulin treatment in
    for Kawasaki disease. Lancet 1984;2:1055-1058.                        Kawasaki disease: assessment of clinical aspects and cost
3 	 Newburger JW, Takahashi M, Burns JC, Beiser AS, Chung                 effectiveness. Pediatr Int 1999;41:1-7.
    KJ, Duffy CE, et al. The treatment of Kawasaki syndrome
    with intravenous gamma globulin. N Engl J Med 1986;315:                                              Received February 26, 2007
    341-347.                                                                                     Accepted after revision June 12, 2007




                                                                    World J Pediatr, Vol 3 No 3 . August 15, 2007 . www.wjpch.com

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Revision dec dose

  • 1. IVIG 1 g/kg for Kawasaki disease Intravenous immunoglobulin 1 g/kg as the initial treatment for Kawasaki disease Hirohiko Shiraishi, Mayu Iino, Masaru Hoshina, Kou Ichihashi, Mariko Y Momoi Tochigi, Japan Background: Coronary artery lesion (CAL) in appeared but regressed within 6 months after the onset. Kawasaki disease (KD) is prevented by intravenous Conclusion: Treatment of KD with IVIG at an initial immunoglobulin (IVIG); however, the total amount of dose of 1 g/kg on the 5th to 7th day with additional IVIG Original article IVIG should be reduced if the outcome is the same. Our for refractory patients can have the same effect as the aim was to determine whether the treatment with IVIG standard protocol (IVIG of 2 g/kg). at an initial dose of 1 g/kg on the 5th to 7th day of illness with additional IVIG for refractory patients is effective World J Pediatr 2007;3(3):195-199 for preventing CAL. Key words: coronary artery; Methods: A total of 107 KD patients were treated echocardiography; according to the days of illness and the Harada score immunoglobulin; within 7 days of illness. All the patients with Harada score Kawasaki disease 4 or more were treated with IVIG at an initial dose of 1 g/kg, and the patients who were refractory to the initial dose, additional IVIG at a dose of 1 g/kg up to 3 g/kg was Introduction K infused. Echocardiography was performed to detect the awasaki disease (KD) is associated with incidence of CAL. coronary artery aneurysm in 15% to 25% of Results: Seventy-eight patients (73%) were treated patients.[1] Acute phase KD is treated with with IVIG at an initial dose of 1 g/kg according to the aspirin and intravenous immunoglobulin (IVIG), and Harada score and the duration of illness; IVIG was the incidence of coronary artery aneurysm has decreased started when their Harada score became 4 or more and after the introduction of high-dose IVIG.[2,3] The standard basically on the 5th day or later. Six critically ill patients care for children with acute phase KD is treatment with 195 were treated with IVIG at a dose of 1 g/kg starting from a single infusion of high-dose (2 g/kg) IVIG within the 2nd or 4th day, and all of them were refractory to the the 10th day of illness and aspirin.[4] Although a dose- initial dose of 1 g/kg and further treated with additional dependent effect is reported in the treatment of KD,[5] the doses of 1 to 3 g/kg (CAL was not observed); whereas the total amount of IVIG should be reduced if the incidence other 72 patients (of whom 42 were admitted by the 4th of coronary artery lesions (CALs) can be the same as day and waited until the 5th day) were treated on the 5th that with the standard protocol. Also, it is reported that to 7th day with IVIG at an initial dose of 1 g/kg. Of the early treatment of KD with IVIG (on the 1st to 4th day 78 patients, 57 responded to the initial dose of 1 g/kg, but of illness) is likely to require additional IVIG.[6,7] In the the remaining 21 refractory patients required additional treatment of KD, we found that IVIG at a dose of 1 g/kg IVIG (a total dose of IVIG up to 4 g/kg). Twenty-nine was effective in most patients when it was infused on patients (27%) were treated without IVIG because their the 5th to 7th day of illness. Thus, we began to treat KD Harada score was less than 4, and CAL was not observed. with this regimen from February 2002. The aim of this In 4 (3.7%) of the 107 patients who had IVIG at 1 g/ kg (n=1) or additional IVIG up to 3 g/kg (n=3), CAL study was to assess the efficacy of IVIG at an initial dose of 1g/kg on the 5th to 7th day of KD with additional IVIG in refractory patients, and whether the total amount of IVIG is reduced when patients were selected by the Author Affiliations: Department of Pediatrics, Jichi Medical University, Harada score. Tochigi, 329-0498, Japan (Shiraishi H, Iino M, Hoshina M, Ichihashi K, Momoi MY) Corresponding Author: Hirohiko Shiraishi, MD, Department of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Methods Japan (Tel: +81-285-58-7366; Fax: +81-285-44-6123; Email: shiraish@jichi. ac.jp) In this study, we retrospectively reviewed clinical records of consecutive 118 acute phase KD patients ©2007, World J Pediatr. All rights reserved. who were admitted to our institute between February World J Pediatr, Vol 3 No 3 . August 15, 2007 . www.wjpch.com
  • 2. World Journal of Pediatrics 2000 and April 2004. Our criteria for a diagnosis of patient was asked to wait until the 5th day of illness KD included fever (temperature exceeding 38 degrees without IVIG, even if the patient's Harada score was ≥ Celcius) accompanied by the presence of at least 4 of 4. If the patient was critically ill and suspected of having the following 5 findings: bilateral conjunctival injection, meningitis or hyponatremia was present, IVIG at a dose changes in the lips and oral cavity, nonpurulent cervical of 1 g/kg was started on admission. On the 5th to 7th day lymphadenopathy, polymorphous exanthema, and of illness, if the patient's Harada score was ≤3, no IVIG changes in the extremities. These diagnostic criteria was infused, and if their Harada score was ≥4, IVIG at 1 were consistent with the Diagnostic Guidelines for g/kg was infused for over 10 hours in one day. Kawasaki Disease (5th revision).[8] Incomplete KD was 2) When the patient was admitted on the 5th to defined as lacking sufficient clinical signs of the disease 7th day of illness and the patient's Harada score was ≤ to fulfill the above criteria.[4] The first day of the illness 3, no IVIG was infused. They were asked to wait until was defined as the first day of fever. Fourteen patients the end of the 7th day of illness, and once the Harada who were admitted or treated beyond the 7th day of score became ≥4, IVIG at 1 g/kg was started. When the Original article illness were excluded in this study. The total number of patient's Harada score on admission was ≥4, IVIG at 1 KD patients who were admitted within the 7th day of g/kg was infused. illness was 104, among whom 3 patients had recurrent 3) For those patients who were refractory to the KD (there were 14, 18 and 34 months between the initial initial IVIG, additional IVIG at 1 g/kg was infused; and the second episode of KD, respectively) during this for those who were refractory to the second IVIG, total period. Thus, a total of 107 admissions were enrolled IVIG up to 4 g/kg was infused. The patients who were in this study. Ninety-six patients met the criteria of KD, refractory to IVIG were defined as having fever (≥37.5 and 11 patients were diagnosed as having incomplete degrees Celcius), increased white blood cell counts KD. There were 74 male (two of them had recurrent KD) (WBC), or poor CRP decrease (more than half of the and 30 female patients (one of them had recurrent KD). pre-treatment level) that was observed 36 to 48 hours In this report, one admission for KD is counted as one after the end of the initial IVIG. Those patients who patient because the clinical data and CAL of each patient fulfilled all the 3 parameters were considered to be were not substantially different between the initial and responders, and IVIG treatment was considered to be the second admissions. The average age at the onset of effective. KD was 2.47 (range 0.16 to 8.85) years. In this study Several IVIG preparations were used for the treatment there was no control group, and therefore no statistical of KD in this study: polyethylene glycol-treated human analysis was performed. immunoglobulin (Venoglobulin IH®, Mitsubishi- 196 Welpharma Ltd) in 46 patients, pH4 stabilized acid human Laboratory data immunoglobulin (Poliglobin N®, Bayer Yakuhin Ltd) Complete blood count, C-reactive protein (CRP), in 25 patients, and sulfonated human immunoglobulin serum aspartate aminotransferase (AST), alanine (Venilon®, Teijin Ltd) in 7 patients. Basically, the same aminotransferase (ALT), and albumin were examined preparation was used for the additional IVIG, except for at least on admission, at 36 to 48 hours after completion 1 patient who showed an allergic response to the second of IVIG, and before discharge. IVIG, and the third IVIG preparation was changed to another preparation (from Poliglobin N® to Venoglobulin IH®). Treatment Once the patients were diagnosed as having KD, they Echocardiography were treated with oral aspirin at 30 mg/kg per day, or The initial echocardiography was performed before dipyridamole at 5 mg/kg per day when the AST or ALT IVIG treatment, and subsequent echocardiography was level was above 100 mU/ml. Then, the medication was changed to oral aspirin at 5 mg/kg per day when the body temperature was reduced to below 37.5 degrees Table. Harada score Celcius and AST and ALT levels were reduced to ≤100 1) WBC count: equal to or more than 12 ×103/μl mU/ml. The guidelines established by Harada (Harada 2) Platelet count: less than 35×104/μl score) were used to select those KD patients who were 3) CRP: equal to or more than 4 mg/dl 4) Hematocrit: less than 35% likely to develop CALs; IVIG was started when the 5) Serum albumin: less than 3.5 g/dl patient had Harada score of 4 or more (Table).[9] 6) Gender: male Our basic treatment strategy for KD was as follows 7) Age: equal to or less than 12 months (Fig.). When the patient with KD satisfies 4 or more of the above 7 criteria 1) When admitted before the 5th day of illness, the within the 9th day of illness, treatment with IVIG should be started. World J Pediatr, Vol 3 No 3 . August 15, 2007 . www.wjpch.com
  • 3. IVIG 1 g/kg for Kawasaki disease performed after IVIG, before discharge, and 1 month the initial IVIG. One patient who had febrile convulsion after the onset of KD. CAL was defined and classified on the second day of illness and was treated with as follows: coronary artery ectasia, when the coronary dexamethasone, and who responded to the initial IVIG, artery was dilated with a diameter ≤4 mm or when the was included. Nine patients, however, were refractory to diameter was less than 1.5 times that of the adjacent the initial dose of IVIG at 1 g/kg and were treated with artery diameter; and coronary artery aneurysm, when additional IVIG (1 g/kg in 6 patients, 1.6 g/kg in 1, 2 the coronary artery was dilated with a diameter >4 mm. g/kg in 1, and up to 3 g/kg in 1). CALs were observed in Once CAL was observed, oral aspirin was continued 3 of the 9 patients, who received total IVIG of 2 g/kg, 2.6 and follow-up echocardiography was performed until g/kg and 4 g/kg for coronary artery ectasia of 3.4 mm, 3.8 it disappeared. Coronary artery dilatation or aneurysm mm and 3.8 mm, respectively (Fig.). observed within 1 month was defined as CAL in this Forty-six patients were admitted on the 5th to 7th study. day of illness. Sixteen patients were treated with no IVIG because their Harada scores were ≤3, and became Original article defervescent spontaneously, without CAL appearance. Results In the other 30 patients with Harada scores ≥4 and A total of 107 KD patients were admitted and treated treated with IVIG at 1 g/kg on the 5th to 7th day of within the 7th day of illness during the study period illness, 24 responded to the initial IVIG, including 1 (Fig.). patient developed CAL (coronary artery ectasia of 3.8 Sixty-one patients were admitted before the 5th day mm); 6 patients were refractory to the initial IVIG and of illness. Among them, 6 patients were treated before treated with additional IVIG at 1 g/kg, but no CAL was the 5th day of illness (2 to 4 days) and showed Harada observed (Fig.). scores ≥4 before IVIG therapy. They were refractory to Eleven patients (10%) who were diagnosed as having IVIG (5 of them had persistent fever, and all had poor incomplete KD because of lacking sufficient clinical CRP decrease) and were treated with additional IVIG signs of the disease to fulfill the criteria were included (1 g/kg in 2 patients, 2 g/kg in 3 patients and up to 3 in this study. The average age at the onset of incomplete g/kg in 1 patient), but no CAL was observed. Fifty-five KD was 2.14 (range 0.16 to 5.28) years. Eight of the 11 patients were asked to wait until the 5th to 7th day of patients were treated without IVIG and 3 were treated illness. Among them, 13 patients were treated without with IVIG at 1 g/kg on the 6th day of illness, but no IVIG because their Harada scores were ≤3, and no CAL CAL was observed. was observed. In the other 42 patients treated with IVIG In the 78 patients (73%) who were treated with IVIG at 1 g/kg on the 5th to 7th day of illness, 33 responded to at an initial dose of 1 g/kg, 6 were treated before the 197 Patients with acute phase KD (n=107) Admitted on the 0-4th day (n=61) Admitted on the 5th-7th day (n=46) Treated within the 4th Waited until the 5th-7th day (n=55) day with IVIG 1 g/kg Harada ≥4 (n=6) Harada ≤3 Harada ≥4 Harada ≥4 Harada ≤3 (n=13) (n=42) (n=30) (n=16) Treated with Treated with IVIG 1 g/kg IVIG 1 g/kg Refractory Responder Refractory Responder Refractory Add IVIG 1-3 g/kg No IVIG No more IVIG Add IVIG 1-3 g/kg No IVIG No more IVIG Add IVIG 1 g/kg (n=6) (n=13) (n=33) (n=9) (n=16) (n=24) (n=6) CAL 0 CAL 0 CAL 0 CAL 3 CAL 0 CAL 1 CAL 0 3.4 to 3.8 mm 3.8 mm Fig. IVIG treatment for KD according to the day of illness and Harada score. Patients were treated according to the duration of KD and Harada score. Add IVIG: additional intravenous immunoglobulin; CAL: coronary artery lesion; Harada: Harada score; KD: Kawasaki disease; IVIG: intravenous immunoglobulin; Refractory: patients who were refractory to the initial treatment; Responder: patients who responded to the initial treatment. World J Pediatr, Vol 3 No 3 . August 15, 2007 . www.wjpch.com
  • 4. World Journal of Pediatrics 4th day of illness, and 72 on the 5th to 7th day. Of these additional IVIG. The high rate (100%) of additional 78 patients, 57 (73%) responded to a single infusion IVIG in our 6 patients may be due to the shortage of of IVIG at a dose of 1 g/kg, and 21 (27%) required re- the initial dose of IVIG. Muta et al[7] reported that early treatment or multiple infusions of IVIG (total IVIG up treatment is likely to result in a greater requirement for to 4 g/kg). CALs were observed in 4 patients who had additional IVIG, which is supported by our results. In been infused with total IVIG at a dose of 1 g/kg, 2 g/kg, those critically ill patients who need to be treated on 2.6 g/kg and 4 g/kg, respectively. All CALs regressed ≤ the 4th day of illness, an initial IVIG dose of 2 g/kg spontaneously within 6 months after the onset of KD, would be better than 1 g/kg. as observed echocardiographically. In 29 patients (27%) We treated the patients who were refractory to whose Harada scores were ≤3 and were treated without the initial dose of 1 g/kg with additional IVIG. The IVIG, no CAL was observed. patients with KD who were refractory to IVIG were In this study, the total amount of IVIG used in the 78 treated with high-dose methylprednisolone,[12,13] low- patients was 1275.5 g: IVIG 1 g/kg in 57 patients, 2 g/kg dose methotrexate,[14,15] or ulinastatin.[16] Hashino et Original article in 14, 2.6 g/kg in 1, 3 g/kg in 3, and 4 g/kg in 3. Total al[12] reported that steroid pulse therapy was given to body weight of the 107 patients was 1325.5 kg. Side- those who were resistant to IVIG, but its efficacy for effect of IVIG was observed in 1 patient, whose second preventing CAL was not superior to that of additional infusion of IVIG was stopped midway (0.6 g/kg), and the IVIG therapy. Low-dose methotrexate therapy or patient was treated with another preparation on the next ulinastatin might be promising, but only a few case day (a total dose of IVIG was 2.6 g/kg). Total IVIG up to reports have been published.[14,16] A randomized control 4 g/kg was infused in 3 patients, but no dose-related side study will disclose the efficacy of these therapies. In KD effects were observed. patients who are refractory to IVIG, plasma exchange therapy has been reported to be effective;[17] however, plasma exchange requires a rather complicated system, and cannot be easily utilized in general pediatric wards. Discussion Infliximab treatment for those refractory to IVIG was In this study, the IVIG therapy at an initial dose of 1 reported by Burns.[18] The total number of patients who g/kg on the 5th to 7th day of illness and additional IVIG were treated with this method is so small that the safety for the refractory patients was effective. The incidence of this method has not been studied completely. In our of CAL was lower than that reported in a nationwide series, the patients who were refractory to the initial KD survey in which most of the patients were treated IVIG were treated with additional IVIG (total IVIG up 198 with the standard protocol (IVIG of 2 g/kg).[4] The IVIG to 4 g/kg), but no patients suffered from dose-related therapy at an initial dose of 1 g/kg could reduce the total side effects of IVIG, and no giant coronary aneurysms amount of IVIG used in treating acute phase KD. were observed. The use of a moderate dose of IVIG for KD has been Treating KD with IVIG was based on the score reported by Khowsathit et al.[10] They started to treat KD established by Harada (Table).[9] In our series, 78 patients patients with IVIG at a dose of 1 g/kg, and the response were treated with IVIG, giving a rate of 73% close to that rate (76%) was similar to that in our study. They treated in Harada's report (73.4%).[9] The total amount of IVIG KD patients with IVIG up to 3 g/kg; however, the infused in our series was 1275 g: 1 g/kg in 57 patients, 2 efficacy of preventing CAL was lower than that of the g/kg in 14, 2.6 g/kg in 1, 3 g/kg in 3, and 4 g/kg in 3. If high-dose regimen (2 g/kg). In our series, the patients IVIG at a dose of 2 g/kg was given to all the patients (total who were refractory to the initial IVIG dose of 1 g/kg, body weight of 107 patients was 1325.5 kg), the total IVIG of 2 g/kg could be infused within the 9th day, and amount of IVIG would be 2651 g without taking account the dose up to 4 g/kg was infused. The incidence of CAL of the additional IVIG. Accordingly, at least 1376 g of at 1 month (4 in 107 patients; 3.7%) was the same as that IVIG was saved in our protocol. Sato et al[19] reported the in a nationwide KD survey, in which most of the patients cost effectiveness of high-dose IVIG in selected patients were treated with IVIG at a dose of 2 g/kg.[11] using the Harada score. In their study, IVIG at a dose of Six patients who had KD for less than 4 days were 2 g/kg was superior to the 5-day 400 mg/kg therapy. In treated with IVIG at 1 g/kg, but failed. They were this study, the same scoring system (Harada score) was successfully retreated with additional IVIG (a total dose used, but IVIG at a dose of 1 g/kg resulted in much less up to 4 g/kg). Early treatment of KD with IVIG at a dose utilization of IVIG. of 2 g/kg is reported to be associated with persistent/ In 11 patients (10%) who were diagnosed as having recrudescent fever that required additional IVIG in 33% incomplete KD, 8 patients were treated without IVIG of the patients.[6] In our 6 patients, 5 had persistent fever and 3 with IVIG at a dose of 1 g/kg on the 6th day of and all had a poor CRP decrease, and were treated with illness; no CAL was observed. Incomplete KD is more World J Pediatr, Vol 3 No 3 . August 15, 2007 . www.wjpch.com
  • 5. IVIG 1 g/kg for Kawasaki disease common in young infants than in older children and the 4 Newburger JW, Takahashi M, Gerber MA, Gewitz MH, rate of incomplete KD is about 10%.[4,8] Even in patients Tani LY, Burns JC, et al. Diagnosis, treatment, and long- term management of Kawasaki disease: a statement for with incomplete KD, CAL can develop; however, in this health professionals from the Committee on Rheumatic study the average age at the onset of incomplete KD was Fever, Endocarditis and Kawasaki Disease, Council on 2.14 (range 0.16 to 5.28) years, and CAL was prevented Cardiovascular Disease in the Young, American Heart by a single infusion of IVIG at a dose of 1 g/kg on the Association. Circulation 2004;110:2747-2771. 6th day in 3 patients. This might be explained by the 5 Terai M, Shulman ST. Prevalence of coronary artery benign nature of the condition in the incomplete KD abnormalities in Kawasaki disease is highly dependent on patients enrolled in our study. gamma globulin dose but independent of salicylate dose. J Pediatr 1997;131:888-893. In our series, 4 patients (3.7%) had coronary 6 Fong NC, Hui YW, Li CK, Chiu MC. Evaluation of the artery ectasia at 1 month, which regressed within 6 efficacy of treatment of Kawasaki disease before day 5 of months after onset. The total percentage of patients illness. Pediatr Cardiol 2004;25:31-34. with CALs in the same period was 4.4 % in Japan, of 7 Muta H, Ishii M, Egami K, Furui J, Sugahara Y, Akagi T, et Original article whom most patients (79.8%) received IVIG at a dose al. Early intravenous gamma-globulin treatment for Kawasaki of 2 g/kg.[8] Thus, our protocol showed the same effect disease: the nationwide surveys in Japan. J Pediatr 2004; on KD patients. This is a study that was performed in 144:496-499. 8 Ayusawa M, Sonobe T, Uemura S, Ogawa S, Nakamura Y, a single institute without controls, and a multicenter Kiyosawa N, et al. Revision of diagnostic guidelines for prospective randomized study would clarify the efficacy Kawasaki disease (the 5th revised edition). Pediatr Int 2005; of our treatment strategy. The regimen for KD with 47:232-234. IVIG at an initial dose of 1 g/kg on the 5th to 7th day 9 Harada K. Intravenous gamma-globulin treatment in with additional IVIG for refractory patients can be as Kawasaki disease. Acta Paediatr Jpn 1991;33:805-810. effective as the standard protocol (2 g/kg). Accordingly, 10 Khowsathit P, Hong-Hgam C, Khositseth A, Wanitkun S. it can reduce the total amount of IVIG for KD patients Treatment of Kawasaki disease with a moderate dose (1 g/kg) of intravenous immunoglobulin. J Med Assoc Thai 2002;85 without increasing CALs. Suppl 4:S1121-1126. In conclusion, IVIG therapy for KD patients at an 11 Nakamura Y, Yashiro M, Uehara R, Yanagawa H. Results initial dose of 1 g/kg on the 5th to 7th day of illness and of the 17th nationwide survey on Kawasaki disease. Japan additional IVIG for the refractory patients was effective Kawasaki Disease Research Committee. J Pediatr Prac 2004; and the total amount of IVIG could be reduced when 67:313-323 (in Japanese). patients were selected by the Harada scoring system. 12 Hashino K, Ishii M, Iemura M, Akagi T, Kato H. Re- treatment for immune globulin-resistant Kawasaki disease: a This method can be an alternative for the prevention of comparative study of additional immune globulin and steroid CAL. 199 pulse therapy. Pediatr Int 2001;43:211-217. 13 Wright DA, Newburger JW, Baker A, Sundel RP. Treatment of immune globulin-resistant Kawasaki disease with pulsed Funding: None. doses of corticosteroids. J Pediatr 1996;128:146-149. Ethical approval: Not needed. 14 Ahn SY, Kim DS. Treatment of intravenous immunoglobulin- Competing interest: None declared. resistant Kawasaki disease with methotrexate. Scand J Contributors: Shiraishi H proposed the study and wrote the first Rheumatol 2005;34:136-139. draft. Ichihashi K analyzed the data. All authors contributed to 15 Lee MS, An SY, Jang GC, Kim DS. A case of intravenous the design and interpretation of the study and to further drafts. immunoglobulin-resistant Kawasaki disease treated with Momoi MY is the guarantor. methotrexate. Yonsei Med J 2002;43:527-532. 16 Iino M, Shiraishi H, Igarashi H, Honma Y, Momoi MY. Case of Kawasaki disease in NICU. Pediatr Int 2003;45:580-583. 17 Imagawa T, Mori M, Miyamae T, Ito S, Nakamura T, Yasui K, References et al. Plasma exchange for refractory Kawasaki disease. Eur J 1 Kato H, Sugimura T, Akagi T, Sato N, Hashino K, Maeno Y, Pediatr 2004;163:263-264. et al. Long-term consequences of Kawasaki disease. A 10- to 18 Burns JC, Mason WH, Hauger SB, Janai H, Bastian JF, 21-year follow-up study of 594 patients. Circulation 1996;94: Wohrley JD, et al. Infliximab treatment for refractory 1379-1385. Kawasaki syndrome. J Pediatr 2005;146:662-667. 2 Furusho K, Kamiya T, Nakano H, Kiyosawa N, Shinomiya K, 19 Sato N, Sugimura T, Akagi T, Yamakawa R, Hashino K, Eto Hayashidera T, et al. High-dose intravenous gammaglobulin G, et al. Selective high dose gamma-globulin treatment in for Kawasaki disease. Lancet 1984;2:1055-1058. Kawasaki disease: assessment of clinical aspects and cost 3 Newburger JW, Takahashi M, Burns JC, Beiser AS, Chung effectiveness. Pediatr Int 1999;41:1-7. KJ, Duffy CE, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 1986;315: Received February 26, 2007 341-347. Accepted after revision June 12, 2007 World J Pediatr, Vol 3 No 3 . August 15, 2007 . www.wjpch.com