Analysis of Age, Sex, Lack of Response to Intravenous Immunoglobulin, and Development of Coronary Artery Abnormalities in Children With Kawasaki Disease in Japan

Abstract

Importance: Initial intravenous immunoglobulin (IVIG)-refractory status and prolonged fever are established risk factors for the development of coronary artery abnormalities (CAAs) among patients with acute-phase Kawasaki disease (KD). However, whether different risk factors exist for initial unresponsiveness to IVIG and CAA development remains unclear.

Objective: To evaluate whether different risk factors exist for initial unresponsiveness to IVIG and CAA development among patients with KD (stratified by age at disease onset).

Design, setting, and participants: This retrospective cohort study included a consecutive sample of 2414 patients from a database of patients with KD from October 1, 1999, to September 30, 2019. The data were based on annual surveys (response rate, 100%) using hospital medical records across Wakayama Prefecture, Japan. Data were analyzed from March 6 to March 26, 2022.

Exposures: The patient's age and diagnosis of KD by board-certified pediatricians using the criteria established by the Japan KD Research Committee.

Main outcomes and measures: Initial unresponsiveness to IVIG, defined as treatment with optional or advanced therapies, and development of CAAs. Echocardiograms performed 1 month after KD onset using the Japanese Ministry of Health criteria evaluated the presence or absence of CAAs. Odds ratios (ORs) with 95% CIs of patient age at KD onset for unresponsiveness to IVIG and developing CAAs were calculated using multivariable logistic regression models.

Results: A total of 2414 patients (1403 male patients [58.1%]; median age at onset of KD, 25 months [range, 1-212 months]) were included in the study: 550 younger than 12 months, 1342 aged 12 to 47 months, and 522 older than 47 months. A total of 535 patients (22.2%) received optional or advanced treatment and 68 patients (2.8%) developed CAAs 1 month after disease onset. The sex-adjusted OR among patients younger than 12 months for unresponsiveness to IVIG was 0.77 (95% CI, 0.59-0.99) and for development of CAAs was 1.94 (95% CI, 1.07-3.52); among those older than 47 months, the OR for unresponsiveness to IVIG was 1.32 (95% CI, 1.05-1.67) and for development of CAAs was 2.47 (95% CI, 1.39-4.39). After adjusting for IVIG administration, ORs among boys older than 47 months for unresponsiveness to IVIG was 1.14 (95% CI, 0.84-1.56) and for development of CAAs was 2.15 (95% CI, 1.08-4.30); among girls younger than 12 months, the OR for unresponsiveness to IVIG was 1.02 (95% CI, 0.65-1.60) and for development of CAAs was 3.79 (95% CI, 1.21-11.90).

Conclusions and relevance: The results of this study suggest that risks of unresponsiveness to IVIG and the development of CAAs differ between infants with KD and older patients with KD. Residual risk factors for KD-related CAAs other than initial unresponsiveness to IVIG should be addressed, particularly in infants.

Figure 1.. Transition of the Initial Intravenous Immunoglobulin (IVIG) Therapy Regimen Among Patients With Kawasaki Disease (KD) During the Study Period (N = 2414)

The study period was divided into 3 categories (October 1999-September 2006, October 2006-September 2013, and October 2013-September 2019) from our annual surveys. In the present study, the initial IVIG therapy regimen converged to 2 g/kg/24 hours.

Figure 2.. Odds Ratios of Patient Age at the Onset of Kawasaki Disease for the Presence of Optional and Advanced Therapies and Developing Coronary Artery Abnormalities Adjusted for Potential Confounders (N = 2414)

The association between patient age group and the 2 outcomes included the following: the adjusted ORs of patient age for the presence of optional or advanced therapies were 0.77 (95% CI, 0.59-0.99) among patients younger than 12 months and 1.39 (95% CI, 1.09-1.77) among those older than 47 months (reference: 12- to 47-month age group), while the adjusted ORs of patient age for the presence of CAAs were 1.86 (95% CI, 1.02-3.39) among patients younger than 12 months and 2.57 (95% CI, 1.44-4.61) among those older than 47 months (reference: 12- to 47-month age group).