Coronary artery outcomes among children with Kawasaki disease in the United States and Japan

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Abstract

Objective

It has been claimed that the aneurysm rate for Kawasaki disease (KD) patients in Japan is lower than in the U.S. However it has been difficult to compare coronary artery (CA) outcomes between the two countries because of different definitions for CA abnormalities. Therefore, we compared CA internal diameters between Japanese and U.S. KD patients using standard definitions and methods.

Study design

We retrospectively reviewed CA outcomes in 1082 KD patients from 2 centers in the U.S. and 3 centers in Japan and compared Z-max scores (maximum internal diameter for the left anterior descending or right coronary artery expressed as standard deviation units from the mean (Z-score) normalized for body surface area) obtained within 12 weeks after onset and calculated using two different regression equations from Canada (Dallaire) and Japan (Fuse). We defined a Z-max of < 2.5 as normal and a Z-max of ≥ 10 as giant aneurysm.

Result

The median Z-max for the U.S. and Japanese subjects was 1.9 and 2.3 SD units, respectively (p < 0.001). There was no significant difference in rates of patients with Z-max  5.0 between the countries. In a multivariable model adjusting for age, sex, and treatment response, being Japanese was still associated with a higher Z-max score.

Conclusion

Previously reported differences in aneurysm rates between Japan and the U.S. likely resulted from use of different definitions and nomenclature. Adoption of Z-scores as a standard for reporting CA internal diameters will allow meaningful comparisons among different countries and will facilitate international, collaborative clinical trials.

Introduction

In the era before the use of intravenous immunoglobulin (IVIG) to treat children with Kawasaki disease (KD), aneurysm rates of approximately 25% were noted both in Japan and the U.S. [1], [2], [3]. KD is now the most important cause of acquired heart disease in children in the developed world and more than 60 countries in Asia, the Middle East, the U.S., Africa, and Europe have reported KD cases [4], [5], [6]. Reported rates of coronary artery (CA) aneurysms vary widely among KD patients from different countries [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. Currently, studies from the U.S. report an aneurysm rate of approximately 4.0–5.0% [7], [17], while rates for Japan are reported to be on the order of 1.0% [9]. To clarify whether this is a problem of semantics (different definitions of aneurysms), a real difference stemming from different clinical practices (timing of echocardiograms or timing of IVIG administration), or differences in host genetics, we conducted a comparative study among two centers in the U.S. and three centers in Japan over the same time period and used the internal diameter of the coronary artery normalized for body surface area (Z-score) as a standardized assessment tool to compare outcomes.

Section snippets

Patient population

Patients with KD included in this study met the case definitions of the American Heart Association (AHA) for the U.S. sites (Rady Children's Hospital San Diego and Boston Children's Hospital) or the Japanese Circulation Society (JCS) for the Japanese sites (Toho University Omori Medical Center, Kitasato University Hospital, and Juntendo University Urayasu Hospital; Table 1) [18], [19]. The records of unselected, consecutive KD patients treated at the five participating centers during the 4-year

Study population characteristics

A total of 1082 subjects were included with 568 from the U.S. and 514 from Japan (Table 2). U.S. subjects were older, were treated on average one day later, and were more likely to be treated after Illness Day 10 as compared to Japanese subjects (p < 0.001 for all comparisons). Japanese subjects were more likely to be classified as clinically incomplete cases (p < 0.001) and were more likely to receive additional infusions of IVIG (p = 0.03).

CA outcomes

The median BSA calculated by either the Du Bois or Haycock

Discussion

This is the first study to directly compare CA outcomes in Japanese and American KD patients using standardized definitions across populations. The median Z-max was significantly higher for Japanese subjects using the Dallaire Z-score equation. When analyzed as a categorical variable, there was no difference in the rate of patients with Z-max scores  5.0 or ≥ 10.0 using this definition. A higher percentage of Japanese children were classified as having at least one coronary artery segment with a

Acknowledgment of grant support

This work supported in part by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute HL69413 and 108460 awarded to JCB and a Japan Foundation for Pediatric Research grant awarded to SO.

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