Patients
We enrolled patients between December 2014 and January 2019 at five centers in Japan. Patients aged < 15 years who were newly diagnosed with KD between 4 and 7 days of illness (day 1 was defined as the first day of fever) were enrolled. Eligible patients also had at least five of the six major symptoms according to the definition outlined in the Japanese diagnostic guidelines for KD [6]. The major exclusion criteria were: (1) patients without a fever at the time of enrollment, (2) patients with serious bacterial infections, (3) patients with CAAs at the time of enrollment, (4) patients who had received systemic steroids within the previous 4 weeks, and (5) patients with underlying diseases, such as chromosomal abnormalities. We performed a sample size calculation based on a preliminary study. The mean difference in C-reactive protein after IVIG administration between the 12-h infusion group and 24-h infusion groups was approximately 2. Assuming that the standard deviation is 3, α = 5%, and β = 20%, we calculated a required sample size of 35. The target sample size was set at 40 patients, taking into account cases dropout after enrollment.
All patients or their legal guardians received adequate information using an informed consent form, and written informed consent was obtained from all legal guardians of the patients before enrollment. This study was approved by the institutional review boards of all participating institutions (number CB13–49). This trial was registered with the University Hospital Medical Information Network (UMIN no. 000014665).
Study protocol
Participating patients were randomly allocated to either a 12 h (12H group) or 24 h (24H group) IVIG administration group, with stratification according to age and sex. All patients in both groups received initial IVIG treatment (Venilon-I, Teijin Pharma Limited, Tokyo, Japan) at a dosage of 2 g/kg, and aspirin 30 mg/kg per day. The patients allocated to the 12H group were treated with IVIG infusion over the course of 12 h, while those in the 24H group were treated over the course of 24 h. Aspirin was reduced to 5 mg/kg per day after defervescence for two consecutive days.
Patients’ axillary temperature was obtained every 6 h until 7 days after the initial IVIG treatment. Patients were regarded as afebrile when their axillary temperature dropped below 37.5 °C for at least 48 h, and the start point of 48 h was defined as the time of defervescence.
When a patient’ s axillary temperature was greater than 37.5 °C at 48 h after the initiation of the initial IVIG treatment, they were defined as IVIG resistant and an additional dose of IVIG 2 g/kg was administered as a second-line treatment at the same infusion speed as the initial IVIG. Relapse was defined in cases of recurrent fever, despite defervescence after the initial IVIG treatment. Patients who had persistent fever after the first and second IVIG treatments received a third-line treatment according to the treatment protocol of each institution.
The risk score of IVIG non-responders was calculated using the risk scoring system by Kobayashi et al., which consists of 11 points based on five blood examinations and two patient characteristics [7]. Laboratory testing (white blood cell count, percentage of neutrophils, platelet count, aspartate aminotransferase, sodium, C-reactive protein, and serum level of immunoglobulin G (IgG)) was performed at the time of enrollment (study day 0), 48 h after initial IVIG (day 2), and 7 days after initial IVIG (day 7). Echocardiograms were obtained at each institution on day 0 (before the initial treatment) and on days 2, 7, and 30 after the initial IVIG administration. The absolute diameters of the right coronary artery, left main coronary artery, left anterior descending artery, and left circumflex artery were measured. Patients were diagnosed with CAAs according to the Japanese Ministry of Health criteria, which is based on absolute values (> 3 mm in children < 5 years old and > 4 mm in children ≥5 years old) or relative increase (≥1.5 times greater than adjacent segments) of the internal diameter of the coronary arteries. Echocardiography was performed by pediatricians at each facility. Patients, treatment physicians, and echocardiography assessments were not blinded to the assignment. An adverse event was defined as any unintended clinical symptoms or abnormal laboratory values observed after initial IVIG administration: fever, headache, skin rash, nausea, vomiting, neutropenia, liver dysfunction, renal dysfunction, lung edema, heart failure, shock, meningitis, and thrombosis. A severe adverse event was defined as any requiring additional treatment or extension of hospital stay.
Outcomes
The primary outcomes were (1) the median duration of fever after the initiation of IVIG and (2) the cumulative risk of CAAs. The secondary outcomes were as follows: (1) the risk of additional IVIG treatment, total dose of IVIG treatment, and risk of third-line treatment; (2) laboratory data changes at days 0, 2, and 7; and (3) adverse events.
Statistical analysis
Statistical analyses were conducted using Fisher’s exact test or χ2 test (categorical data) and the Wilcoxon–Mann–Whitney test (continuous data). Repeated measures ANOVA were used to analyze changes in the laboratory data. A 2-sided P value < 0.05 was considered statistically significant. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R version 4.0.0 (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics [8].