Systematic comparison of Kawasaki disease Z-score formulas: Enhancing diagnostic accuracy and clinical applicability across populations

Abstract

This study aims to evaluate the performance of six distinct Z-score formulas in diagnosing coronary artery dilation in Kawasaki disease (KD) patients, with a focus on their clinical applicability across diverse populations. A retrospective analysis was conducted using comparative statistical methods to assess the sensitivity and specificity of each formula. The Kobayashi and Dallaire formulas demonstrated the highest sensitivity in China, particularly in younger patients with prolonged fever duration. Our findings provide evidence-based recommendations for selecting Z-score formulas to optimize diagnostic precision in KD patients.

Key Words: Kawasaki disease; Early diagnosis; Z-score; Children

Core Tip: Kawasaki disease (KD) is a critical pediatric vasculitis, with coronary artery lesions (CALs) as its most severe complication. The coronary artery Z-score is a valuable metric for assessing coronary dilation in KD patients. This paper reviews six Z-score calculation formulas, with a focus on their clinical applicability in different populations. A retrospective study from Suzhou, China, shows that the Kobayashi and Dallaire formulas offer the best sensitivity and accuracy for Chinese children, leading to better diagnostic outcomes and improved management of CALs.

INTRODUCTION

Kawasaki disease (KD) is a rare, but potentially life-threatening, form of acute systemic vasculitis in children. First described in 1967 by the Japanese pediatrician Dr. Tomisaku Kawasaki, KD has become one of the leading causes of acquired heart disease in children[1,2]. The main complications of KD are coronary artery disease, particularly coronary artery dilation and aneurysm formation, which can results in myocardial infarction or sudden death. Early identification and management of coronary artery lesions (CALs) are essential for effective diagnosis and treatment of KD.

Despite advances in diagnostic methods, challenges remain in the early diagnosis of KD, particularly in the recognition of CALs. The coronary artery Z-score is a standardized metric used to assess whether the coronary artery diameter is within normal limits[3]. However, varying Z-score formulas can significantly affect the accuracy of KD diagnoses across diverse populations. Research has shown that certain formulas may not be suitable for non-Asian populations owing to differences in body size and demographics, leading to potential underdiagnosis or misdiagnosis of coronary artery dilatation (CAD) in those groups.

Previous studies have highlighted the limitations of existing Z-score formulas, emphasizing that they often fail to account for variations in age, body surface area (BSA), and ethnicity. For instance, the Kobayashi formula, which is effective in Japanese populations, may not yield reliable results in children of different ethnic backgrounds. This inconsistency underscores the need for a thorough comparative analysis of Z-score formulas to identify the most accurate and clinically applicable options for diagnosing KD in various patient populations (Table 1).

Table 1 Comparison of Kawasaki disease Z-score formulas.

Z-score formula	Mathematical formula	Advantages	Disadvantages
Kobayashi	Z = D−μ/σ	High sensitivity in Asian children; specific for KD-related dilation	Limited applicability to non-Asian populations; requires caution in larger children
Kurotobi	Z = D−μ/σ	Detailed assessment of coronary artery segments; early detection of mild dilation	Less applicable to non-Japanese populations; may not reflect normal ranges in larger children
de Zorzi	Z = D−μ/σ	Adjusts for body surface area; allows for earlier detection of lesions	Complexity limits routine clinical use; requires further validation in diverse populations
McCrindle	Z = D−μ/σ	Broad applicability; high accuracy across various populations	Complexity requires multiple calculations; needs clinical discretion for individual patient assessment
Olivieri	Z = D−μ/σ	Suitable for diverse backgrounds; easy interpretation for KD follow-up	Complex calculations may limit use; requires validation in specific ethnic groups
Dallaire	Z = D−μ/σ	High accuracy and applicability; ideal for early detection of abnormalities	Needs further studies for KD patients; complex model may hinder practical application

D represents the measured coronary artery diameter. μ is the mean diameter of the reference population. σ is the standard deviation of the reference population. KD: Kawasaki disease.

This study aimed to address these gaps by systematically evaluating the performance of six distinct Z-score formulas in diagnosing coronary patients with KD, providing insights into their clinical applicability across diverse populations[4-9].

POPULATION Z-SCORE FORMULA

Kobayashi formula

Kobayashi’s formula was developed based on data obtained from Japanese children. The study cohort included approximately 1045 patients with KD from multiple medical centers across Japan, ranging in age from infancy to school. The study evaluates coronary artery diameters to identify coronary artery dilation and aneurysms.

The strength of the Kobayashi Formula lies in its specific development for Japanese children. Since the data were entirely derived from this population, it is particularly suitable for evaluating coronary artery status in Asian children. Given that Japanese children tend to have smaller body sizes, the Kobayashi formula demonstrated high accuracy in reflecting the coronary artery dimensions in this demographic group. In addition, it is tailored for KD-related coronary artery dilation assessment, aiding clinicians in the early detection and management of CALs. As the incidence of KD is high in Japan, the Kobayashi formula is a vital tool in clinical practice in Japan and other Asian countries.

However, Kobayashi’s formula has some limitations. Its applicability to non-Asian populations or children with larger body sizes is limited, and it may not accurately reflect the coronary artery dimensions in these groups. Although the formula performs well in Japan and other Asian countries, its global applicability has not been fully validated. Clinicians should exercise caution when applying the Kobayashi formula to non-Asian populations and may need to use additional assessment tools to ensure accuracy.

In summary, the Kobayashi formula is highly significant for coronary artery assessment in Japanese and other Asian children with KD. However, further research is needed to confirm its applicability in other populations globally.

Kurotobi formula

The Kurotobi formula was developed in a study involving 539 Japanese KD patients. Unlike the Kobayashi formula, Kurotobi's method emphasizes greater precision in assessing different segments of the coronary arteries, particularly in detecting early mild dilation. It was designed specifically for the body characteristics of Japanese children and provides precise measurements of different coronary artery segments.

The main advantage of the Kurotobi formula is its ability to assess the individual coronary artery segments in detail. In contrast to the Kobayashi formula, the Kurotobi formula considers BSA and is specifically designed to evaluate various parts of the coronary arteries, enabling the earlier detection of mild dilation in patients with KD. However, the limitations of this formula are evident. It is less applicable to non-Japanese populations, particularly large children, as it may not accurately reflect the normal coronary artery range in these groups[10]. Therefore, caution is needed when using the Kurotobi formula for non-Japanese or non-Asian populations, and other tools may be necessary to ensure an accurate diagnosis.

Overall, the Kurotobi formula plays a significant role in coronary artery assessment in Japanese patients with KD. However, its global applicability requires further validation and adjustment.

De Zorzi formula

The De Zorzi formula was developed based on a study conducted at the Boston Children’s Hospital involving 125 patients with KD. Initially, the coronary arteries of these patients were assessed using the Japanese Ministry of Health criteria for normality (a coronary artery internal diameter > 3.0 mm in children under five years old or > 4.0 mm in children over five years old was considered abnormal). However, after adjusting for BSA, 27% of patients with KD showed coronary artery dilation, indicating that even in cases previously classified as normal, coronary artery abnormalities could be present. This finding led to the development of the de Zorzi formula, which aims to address the limitations of the Japanese standards, particularly for larger children or those from different racial backgrounds.

The primary advantage of the de Zorzi formula is its precision in adjusting coronary artery size based on BSA, allowing for earlier detection of CALs. This is crucial for the long-term management of patients with KD and enables clinicians to identify and monitor minor abnormalities more effectively. Despite its strong performance in the United States, its applicability to children from other regions or racial backgrounds is limited, and the complexity of the formula makes it less practical for routine clinical use.

In summary, the de Zorzi formula provides a more accurate method for coronary artery size evaluation but requires further validation for broader clinical applications.

McCrindle formula

The McCrindle formula was developed based on a large multicenter study involving 190 patients with KD in the United States and Canada. Patients’ coronary artery dimensions were evaluated using standardized Z-scores to detect coronary artery abnormalities more accurately. The study included several major children’s hospitals, such as Toronto’s Hospital for Sick Children and various United States institutions, to ensure a diverse and widely applicable dataset.

The McCrindle formula uses a nonlinear regression model to adjust the coronary artery size for BSA and generates standardized Z-scores considering age and body size differences. This method demonstrated high applicability across various populations and racial backgrounds. It is particularly effective for the early identification and follow-up of coronary artery dilation in patients with KD.

The main advantages of the McCrindle formula are its broad applicability and high accuracy. Its development from a diverse North American cohort makes it suitable for use with different body sizes, age groups, and racial backgrounds. However, the complexity of this formula requires additional calculations, which makes it less convenient for clinical use in some settings. Although broadly applicable, clinicians must consider the individual patient characteristics when using this formula.

In conclusion, the McCrindle formula offers a precise and widely applicable method for KD coronary artery evaluation, particularly in diverse populations; however, it requires clinical discretion owing to its complexity.

Olivieri formula

The Olivieri formula is based on data from a study of 432 healthy children aged 0-20 years without any clinical evidence of heart disease. Children underwent echocardiographic measurements of the right coronary artery (RCA), left main coronary artery (LMCA), and left anterior descending artery (LAD), and the data were analyzed using linear regression models adjusted for BSA.

A notable feature of the Olivieri formula is its precise adjustment of Z-scores for BSA, making it applicable to children with different backgrounds and body sizes. The study sample included children from urban, suburban, and rural areas of North America, making the formula broadly applicable. It is an accurate and easy-to-use tool for interpreting echocardiographic results, particularly in KD follow-ups.

Although the Olivieri formula performs well in diverse populations, its complexity may limit its use in clinical settings. Calculating the Z-score requires a logarithmic transformation of the BSA and relies on precise formulas and models, making the formula relatively complex in clinical practice and possibly requiring the use of calculation tools to assist in the process. Additionally, although the Olivieri formula has shown excellent results in diverse populations in North America, its applicability in other regions and among specific ethnic groups requires further validation.

In summary, the Olivieri formula provides an accurate and widely applicable method for calculating coronary artery Z-scores and is particularly suited for coronary artery assessments and long-term follow-up in KD among diverse populations. However, in clinical practice, their use should be tailored and adjusted according to specific situations.

Dallaire formula

The Dallaire formula was developed as an improved method based on an in-depth analysis and critical evaluation of the existing formulas for calculating coronary artery Z-scores. The formula is based on a large study involving 1033 healthy children from the Quebec and Montreal regions in Canada who underwent echocardiography with no clinical evidence of heart disease. The research team applied rigorous statistical methods, particularly weighted least-squares regression, to optimize the accuracy of the Z-score calculations, ensuring a stable and accurate assessment across children of different ages and body sizes.

The advantages of the Dallaire formula include high accuracy and applicability. The formula was developed using a large dataset of healthy children and generates normally distributed Z-scores by predicting the coronary artery dimensions based on a square-root model of BSA. Because of the robustness of this statistical approach, the Dallaire formula performs well in children of varying body sizes and reduces potential errors in cross-racial applications. This makes the Dallaire formula an ideal tool for evaluating coronary artery size in healthy children, especially for determining normal ranges and the early detection of abnormalities, which has significant clinical implications.

However, the limitations of the Dallaire formula should be noted. Although its performance in healthy populations is remarkable, further clinical studies are required to support its use in patients with KD. Because the coronary artery structure in patients with KD may differ from that in healthy children, the applicability of the formula in this specific group has not yet been fully established. Additionally, although the accuracy of the formula is a major advantage, its relatively complex statistical model may require more calculations and analyses in clinical practice, which could increase the difficulty of its use in some situations.

Overall, the Dallaire formula provides a precise and robust method for assessing coronary artery size, making it particularly suitable for early detection of abnormalities and follow-up. However, its application in diseased populations should be approached with caution and is supported by further evidence.

RETROSPECTIVE STUDY

A retrospective study conducted at the Affiliated Children's Hospital of Soochow University analyzed 1509 confirmed KD cases between January 2018 and December 2020 to compare the clinical performance of six commonly used coronary artery Z-score formulas[10]. The primary goal was to evaluate the diagnostic sensitivity and specificity of these formulas across different coronary artery segments, particularly for diagnosing moderate to large coronary artery aneurysms (CAA).

The study included a comprehensive collection of clinical data including patient demographics, fever duration, and echocardiographic measurements. We specifically assessed the diameters of the LMCA, LAD, and RCA. This study demonstrated significant differences in the performance of the formulas depending on the coronary artery segment.

Notably, the Kobayashi and Dallaire formulas exhibited higher sensitivity for detecting coronary artery dilation, especially in younger patients with prolonged fever, in whom CALs were more easily detected. Specifically, the Kobayashi formula was highly effective in Asian children, whereas the Dallaire formula, known for its broad applicability and precision, was effective across diverse populations.

In addition, we stratified the patient data based on age groups (≤ 12 months, 13-30 months, and > 30 months) and fever duration (≤ 5 days, 6-7 days, 8-9 days, and ≥ 10 days) to further analyze the diagnostic differences among these populations. The findings of this study, combined with data from the Suzhou region, support the recommendations of the revised 2020 Chinese Clinical Guidelines for Managing CALs in KD[11].

This study confirmed that the Kobayashi and Dallaire formulas are reasonable and effective for Chinese children, offering more accurate diagnostic data. Furthermore, the findings from the Suzhou region reinforce the importance of these formulas in clinical practice, providing pediatricians with a reference for choosing appropriate Z-score formulas for different clinical scenarios. Through this study, domestic pediatricians can better understand and apply these formulas to ensure accurate KD diagnosis and timely intervention, thereby improving long-term patient outcomes.

CONCLUSION

In this study, we analyzed the diagnostic performance of six Z-score formulas for assessing CALs in patients with KD in Suzhou, China. Our findings revealed significant differences among the formulas, especially in terms of sensitivity and specificity for diagnosing coronary artery dilation and aneurysms.

The Kobayashi and Dallaire formulas emerged as the most effective tools for diagnosing CAD in our cohort, especially in Asian populations. For instance, in a clinical scenario in which a pediatric patient presents with prolonged fever and elevated inflammatory markers, the use of the Kobayashi formula might guide clinicians in identifying CAD earlier, leading to timely intervention. Conversely, in multiethnic settings, the Dallaire formula can facilitate an accurate diagnosis across diverse populations, ensuring that non-Asian children are also assessed effectively.

Our analysis highlights the importance of employing a combination of formulas for a more comprehensive assessment, because different formulas may excel in various diagnostic aspects. For example, although the Kobayashi formula is tailored for Asian populations, the broader applicability of the Dallaire formula makes it valuable in diverse settings. This distinction is essential for clinicians when deciding which formula to apply based on patient characteristics, including age and fever duration.

Furthermore, our findings indicated that longer fever duration and younger age were correlated with higher diagnostic rates of CAD and CAA. This underscores the need for heightened vigilance in these high-risk groups because early detection can significantly influence long-term outcomes. Therefore, clinicians should be particularly attentive to these factors when evaluating patients with KD.

In light of these findings, we recommend that the Kobayashi formula be used specifically for Asian pediatric populations, whereas the Dallaire formula is more suitable for multiethnic settings. Clinicians are encouraged to use a combination of formulas to enhance diagnostic accuracy and improve treatment decisions, especially in complex cases.