Although there are three predictive scores for IVIG resistance in patients with KD in Japan [18-20], there are currently no indicators to predict CAL before IVIG treatment. In this study, we identified five independent predictive factors for CAL development in patients with KD: P1-Zmax, a ΔZmax ≥1, male sex, <12 months of age, and resistance to the first IVIG administration. Although male sex, <12 months of age, and resistance to initial IVIG administration as risk factors for CAL development have been previously reported [2-6], P1 Z-score ≥1.43 and a ΔZmax ≥1.0 are novel predictors of CAL development in Japan. Evaluating serial changes in Z-score from pre-treatment to post-treatment provides important information that can aid in the choice of initial and additional treatments in high-risk patient groups.
CAL in patients with KD are associated with pathological changes in the coronary artery wall. Based on an analysis of autopsy cases, edematous changes in the media are seen in the early stages of KD [24], and coronary artery dilatation may also occur in the early stages of KD onset. As the evaluation of Z-score using echocardiography can consecutively recognize changes in coronary artery dimensions, it is possible that echocardiography may be more accurate than pathological observations for the prediction of CAL development in patients with KD.
The Z-score is an index of coronary artery dimensions that is standardized to sex and BSA. Therefore, the Z-score may be useful for direct and sensitive detection of early coronary artery dilatation compared with clinical findings, such as fever and serum CRP concentration. Fuse et al. reported that 23.4% of patients showed coronary artery dilatation (Z-score ≥2.0) after 5 days of illness during the pre-treatment phase [25], which is consistent with our findings (67/281, 23.8%).
Several studies [13-16] have shown that CAL development may be predicted using the P1 Z-score; however, this has not yet been shown in Japan. These studies reported that a P1-Zmax ≥2.0 is better than that of IVIG resistance for predicting CAL development. In addition, Dionne et al. reported that intensified initial therapy with steroids or infliximab in patients with a P1 Z-score ≥2.0 might prevent progression of coronary arterial dilatation [15]. Thus, if the P1 Z-score can predict CAL development and progression, it will be useful for pediatricians when selecting initial therapies, including intensified therapies. However, many patients in our study with a P1-Zmax ≥2.0 did not develop CAL (Figure 4). In other words, a P1-Zmax ≥2.0 had a low positive predictive value for predicting CAL (7/60, 11.7%). There are two possible reasons why our results are different compared with those of other studies. First, the number of days of illness at which 1st IVIG was administrated in other studies was greater than in our study. Although the median number of illness days at which 1st IVIG was administrated in a previous report was approximately 7 [13-16], the median in our cohort was 4 (IQR: 4–5). Therefore, there is an interval of approximately 3 days in terms of the number of days of illness at which P1 Z-score was measured in our cohort versus other studies. In the Nationwide Survey in Japan [4], the median number of illness days at which initial IVIG was administrated was also 5 (IQR 4-6). Patients with Kawasaki disease in Japan tend to start treatment earlier compared with patients in other studies. Fuse et al. reported that 42.9% of patients showed coronary artery dilatation (Z-score ≥2.0) after 7 days of illness during the pre-treatment phase, but only 11% of patients showed coronary artery dilatation (Z-score ≥2.0) after 4 days of illness according to the cumulative probability curve [25]. Thus, it may not be appropriate to predict CALs at a P1-Zmax ≥2.0 in cases where treatment is started earlier. Second, the treatment protocol is a very important factor for coronary outcomes and CAL development. Our treatment protocol included IVIG (first line), IVIG (second line), and CsA (third line), without using the predictive score of IVIG resistance. A total of 60 of 67 patients with a P1-Zmax ≥2 showed a ΔZmax <1 (Figure 4). It is very interesting that most patients with coronary artery dilatation, in spite of the number of early illness days, did not develop CAL. It is possible that our protocol may be effective for patients with severe KD and dilatation in the early acute phase. From the above, it is clear that a different predictor with a P1-Zmax ≥2 is needed. A total of 46 of 214 patients (21.5%) with a P1-Zmax <2 showed a ΔZmax ≥1 (Figure 4) and ΔZmax ≥1, even after treatment, which were strong predictors of CAL development (p=0.007, Table1). These data suggest another important point; Some patients with a P1-Zmax <2 may be treated with intensified initial therapy.
We attempted to examine the cutoff of P1-Zmax for CAL development using ROC curve analysis. A P1-Zmax ≥1.43 detected CAL development with an area under the ROC curve of 0.64 (sensitivity = 81.0%; specificity = 48.1%). Although the specificity of a P1-Zmax ≥1.43 was only 48.1% for predicting CAL development, the sensitivity was as high as 81.0%. A Z score <2.0 is usually in the normal range, but Fuse et al. reported that a P1-Zmax ≥1.5 was present in 30.1% of patients by 5 days of illness, 58.4% by 7 days of illness, and 79.0% by 10 days of illness [25]. According to the statistical normal distribution, a Z-score ≥1.5 is considered normal in 6.7%. Thus, Fuse et al. also calculated the positive predictive value of P1-Zmax ≥1.5 was 0.777 after 5 days of illness [25]. This may indicate that some patients with acute KD who have been treated by 5 days of illness and have a P1-Zmax ≥1.5 are at risk of CAL development.
Based on the results of the present study, we propose that patients with a P1-Zmax ≥1.43 should be treated with intensified initial therapy using CsA or steroids due to its high sensitivity to predict CAL development. In addition, patients with a ΔZmax ≥1 should also be treated with an intensified protocol when one is identified. It is possible that these two steps in the treatment strategy could reduce the incidence of CAL.
Study limitations
There are several limitations of the present study that should be highlighted. First, this study adopted a retrospective design and was carried out at a single institution. Moreover, the sample size was small because many patients were excluded to simplify the inclusion of different conditions. Thus, further multi-center studies should be performed to confirm the findings. Second, the treatment protocol used in this study was our protocol only, and other treatment protocols may demonstrate different rates of CAL development. Third, we could not detect all coronary artery segments in all phases. Fourth, the Z-score formula used in this report is different from the previous report. Thus, comparisons should be made with caution. Fifth, four coronary artery branches were measured in accordance with Japanese guidelines [17]. The AHA recommends not to rely on LMCA values, but to use RCA and LAD values instead. In the dominant left coronary artery situs or the dominant right coronary artery situs, patients can be considered as having a P1-Zmax >1.43.