On What Day of Illness Does the Dilatation of Coronary Arteries in Patients With Kawasaki Disease Begin?

Abstract

Background: In the present study we used echocardiography to investigate coronary artery diameter at the time of diagnosis of Kawasaki disease (KD), before the start of treatment.

Methods and Results: Diameters of the right, left main, left anterior descending, and left circumflex coronary arteries were determined in 410 patients before KD treatment commenced. The maximum Z-score was considered to be the pretreatment, maximum coronary artery Z-score (preZmax). The cumulative probability of coronary arterial dilatation was analyzed using the Kaplan-Meier method. In the present study, 31 patients (7.6%) had a preZmax ≥3.0, 56 (13.7%) had a preZmax ≥2.5, and 96 (23.4%) had a preZmax ≥2.0. The cumulative probability of a preZmax ≥2.0 was >20% on Day 5 of illness, 40% on Day 7, and 70% on Day 10. The positive predictive value (PPV) of a preZmax of 2.0 was approximately 0.9 on Day 5 of illness.

Conclusions: The present study demonstrates that the coronary arteries may dilate before Day 5 of illness, and that the rate of dilatation increases gradually until Day 10. Because preZmax 2.0 has high PPV after Day 5 of illness, it is a useful marker of coronary artery dilatation in the early phase of KD.

Kawasaki disease (KD) is an acute, systemic vasculitis associated with fever, cervical lymphadenopathy, skin rash, conjunctival injection, strawberry tongue, and induration of the hands and feet; it is characterized by a high incidence of infiltration and dilatation of epicardial coronary arteries in children.¹ Histologically, the earliest changes in KD are seen in the media of vessel walls on Days 6–8 of illness. By Day 10 of illness, inflammation in the intima and adventitia merges and coronary artery dilatation occurs around Day 12 of illness.^2,3 Dilatation of the coronary arteries seems to reflect the histopathological changes in vessel walls. Echocardiography is the best tool for non-invasive evaluation of coronary artery dilatation in patients with KD.

In the present study we used echocardiography to investigate coronary artery diameters before the start of KD treatment and evaluated the diameters using Z-scores to determine the day of illness on which dilatation started. This information will be helpful for the cautious diagnosis of incomplete KD and prevent its coronary artery complications.

Methods

From January 2005 to March 2016, 410 children (226 male, 184 female) were diagnosed with KD at the NTT Sapporo Medical Center. Patient ages ranged from 0.2 to 13.8 years, with a median age of 2.2 years. Echocardiography was performed in all patients at the time of KD diagnosis, before treatment commenced, and coronary artery diameters were measured. Echocardiography was performed using a Prosound SSD-4000 (Hitachi Aloka Medical, Japan) and an Aplio XG (Toshiba Medical Systems, Japan). One pediatric cardiologist (S.F.) measured the diameters of the right, left main, left anterior descending, and left circumflex coronary arteries in all KD patients. Coronary artery diameters were measured according to standard methods for ultrasound imaging of coronary arteries in children.⁴ The Z-scores were retrospectively calculated for each coronary artery using the Z-score calculator in 2016, standardized for sex and body surface area.⁵ The maximum of 4 Z-scores was considered to be the pretreatment maximum coronary artery Z-score (preZmax) in patients with KD.⁶

Cumulative probability of coronary arterial dilatation was analyzed using the Kaplan-Meier method.

Due to the statistical nature of a normal distribution, a Z-score of 1.5 or greater is considered normal in 6.7%. A Z-score of 2.0 is normal in 2.3%, A Z-score of 2.5 is normal in 0.6%, A Z-score 3.0 is normal in 0.1%. The Z-score has a constant false-positive rate (FPR). As such, the positive predictive value (PPV) of the preZmax on the examination day was calculated as follows:

PPV=(cumulative probability−FPR)/cumulative probability

Statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for the R environment (R Foundation for Statistical Computing, Vienna, Austria).⁷

Results

Figure 1 shows preZmax plotted against examination day in patients with KD. The day of examination ranged from Day 2 to Day 12 (median, Day 5; interquartile range [IQR], Day 4–Day 6). The preZmax value ranged from −1.6 to 8.3 (median, 1.1; IQR 0.46–1.8). In Figure 1, patients diagnosed with abnormalities according to Japanese Circulation Society (JCS) guidelines⁸ are indicated by closed symbols. In all, 24 patients (5.9%) were diagnosed with coronary artery dilatation or aneurysm before commencing KD treatment. Patient distribution according to preZmax ranges is given in Table 1: 31 patients (7.6%) had a preZmax of ≥3.0, 56 (13.7%) had a preZmax of ≥2.5, and 96 (23.4%) had a preZmax of ≥2.0.

Figure 1.

Pretreatment maximum coronary artery Z-scores (PreZmax) plotted against day of examination for patients with Kawasaki disease. Closed symbols indicate the presence of coronary artery dilatation or aneurysm diagnosed according to Japanese Circulation Society (JCS) guidelines.⁸

Table 1. Pretreatment Maximum Coronary Artery Z-Score and Day of Examination for Patients With KD

Day	No. patients	preZmax
		>1.5	1.5–2.0	2.0–2.5	2.5–3.0	>3.0
2	13	9	2	1	1	0
3	49	29	5	8	3	4
4	110	70	14	12	3	11
5	121	83	14	11	9	4
6	72	47	10	5	5	5
7	27	16	3	3	2	3
8	7	5	0	0	1	1
9	3	2	0	0	0	1
10	3	0	0	0	1	2
11	1	1	0	0	0	0
12	1	0	1	0	0	0
13	1	1	0	0	0	0
15	1	1	0	0	0	0
20	1	1	0	0	0	0
Total	410	265	49	40	25	31

KD, Kawasaki disease; preZmax, pretreatment maximum coronary artery Z-score.

Assuming that the preZmax was reached on the day of examination, a cumulative probability curve could be constructed using the Kaplan-Meier method. The cumulative probability curve of coronary arterial dilatation was determined for preZmax values of 1.5, 2.0, 2.5, and 3.0. Using these curves, we were able to determine that coronary arteries dilated before Day 5 of illness and that their diameter increased gradually until Day 10.

The cumulative probability for preZmax ≥2.0 was >20% on Day 5 of illness, 40% on Day 7, and 70% on Day 10 (Figure 2; Table 2).

Figure 2.

Cumulative probability of pretreatment maximum coronary artery Z-scores (PreZmax) in patients with Kawasaki disease.

Table 2. Cumulative Probability of Pretreatment Maximum Coronary Artery Z-Scores in Patients With KD

Day	preZmax
	1.5–<2.0	2.0–<2.5	2.5–<3.0	≥3.0
2	0.010	0.005	0.002	ND
3	0.061	0.042	0.020	0.010
4	0.168	0.114	0.057	0.041
5	0.301*	0.203*	0.108	0.057
6	0.450*	0.305*	0.184	0.098
7	0.584*	0.429*	0.275*	0.158
8	0.631*	0.492*	0.356*	0.205*
9	0.664*	0.539*	0.414*	0.277*
10	0.790*	0.712*	0.634*	0.458*

*Indicate a probability of ≥0.200. ND, not determined. Abbreviations as in Table 1.

The PPVs for preZmax on different examination days are given in Table 3. The PPV of preZmax 2.0 was approximately 0.9 on Day 5 of illness. Using preZmax 2.5 resulted in a PPV of approximately 0.9 on Day 4 of illness.

Table 3. Cumulative Positive Predictive Value of Pretreatment Maximum Coronary Artery Z-Score in Patients With KD

Day	preZmax
	1.5–<2.0	2.0–<2.5	2.5–<3.0	≥3.0
2	–	–	–	–
3	–	0.452	0.700	0.900*
4	0.601	0.798	0.895*	0.976*
5	0.777	0.887*	0.944*	0.982*
6	0.851*	0.925*	0.967*	0.990*
7	0.885*	0.946*	0.978*	0.994*
8	0.894*	0.953*	0.983*	0.995*
9	0.899*	0.957*	0.986*	0.996*
10	0.915*	0.968*	0.991*	0.998*

*Indicate a positive predictive value of ≥0.800. Abbreviations as in Table 1.

Discussion

Coronary artery aneurysms develop in 20–25% of untreated patients with KD.⁹ Other studies have reported an aneurysm rate of approximately 4.0–5.0%, whereas the rate of aneurysms in patients receiving treatment for KD in Japan has been reported to be approximately 1.0%.^10,11 Coronary artery aneurysms do not occur suddenly. The increase in coronary artery diameter is gradual in KD patients. It has been suggested that the dilatation of coronary arteries begins before Day 5 or 7 of illness in KD, but there are no confirmatory reports other than pathological reports from autopsies.^2,3 It is difficult to determine the time when dilatation starts on the basis of pathological studies. The 22nd nationwide survey of KD in Japan revealed that, at the time of their first hospital visit, approximately 4% of patients had coronary aneurysms or coronary artery dilatation.¹⁰ This also suggests that coronary artery dilatation may exist from the early stages of the illness.

In the present study we used echocardiography to measure coronary artery diameter and calculate preZmax before treatment. We found that preZmax had already reached 2.0 in 23.4% of patients before treatment, and that these patients had a preZmax of ≥2.0 by Day 5 of illness.

However, clinician experience is that few patients have coronary artery abnormalities at their first visit (∼4%).¹⁰ It seems that preZmax ≥2.0 is able to detect subtle or initial dilatation, such that the proportion of patients with coronary artery dilatation at first visit is larger than that determined using JCS guidelines.⁸

According to the cumulative probability curve, preZmax ≥2.0 was present in approximately 20% of patients by Day 5 of illness, in 40% by Day 7, and in 70% by Day 10. This suggests that KD treatment should start before Day 10 of illness to achieve a good outcome.^12–14 Many patients with KD develop coronary artery pathological changes, with dilatation in approximately 70% of patients before treatment.

Although there are individual differences in the degree of coronary artery dilatation, it seems that dilatation progresses in a stepwise manner with each day of illness. However, it seems that the coronary artery does not expand uniformly and, after Day 10 of illness, pathological findings are evident.^2,3 Similar to interindividual differences in the severity of the symptoms of KD, it seems that there are also interindividual differences in KD patients in susceptibility to coronary artery dilatation.

Interestingly, after the Day 10 of illness, there were few new patients with a coronary artery diameter Z-score >2.0. Approximately 30% of patients did not develop a preZmax >2.0; these patients are considered to have mild KD and may not develop coronary artery aneurysms in the absence of treatment.

Because there was no way of knowing whether dilatation would be progressive, the boundary between “normal” and “abnormal” was ambiguous. The significance of dilatation is not the same during the early phase of illness as during convalescence. Histologically, edematous changes are seen in the media in the early phase of KD, which progress to neutrophil and macrophage infiltration in the intima and adventitia.² These changes in the coronary artery wall decrease wall tension, resulting in dilatation. After the convalescence phase, the internal and external elastic lamina and smooth muscle cells in the media are damaged by severe inflammation.¹⁵ These structural changes explain why coronary artery wall abnormalities persist for a long time. Dilatation of the coronary artery after the convalescence phase of KD may affect the prognosis.

There are 2 criteria for coronary artery abnormalities: (1) the American Heart Association (AHA)/American Academy of Pediatrics (APP) guidelines;¹⁴ and (2) the JCS guidelines.⁸ In the AHA/APP guidelines, coronary artery dilatation is defined as a Z-score >2.5,¹⁴ whereas in the JCS guidelines coronary artery dilatation is ambiguously defined as a localized dilatation <4.0 mm.⁸ As can be seen in Figure 1, the Z-scoring system of the AHA/APP guidelines¹² and the JCS guidelines⁸ differ fundamentally in their assessment of coronary artery anomalies.

In the US, the Z-score system has been accepted and widely used since 2004. In new (2017) AHA guidelines, coronary artery dilatation and aneurysm will be defined as Z-scores of ≥2.0 and ≥2.5, respectively.¹⁶ Although there are no reports of the early diagnosis of coronary artery dilatation before Day 5 of illness in KD, it is expected that coronary abnormalities will be detected earlier using these new diagnostic standards.

In both the AHA/APP and JCS guidelines, dilatation does not affect the prognosis during the early and convalescent phases of KD. However, we should consider the implications of the Z-score separately for diagnosis in the early phase and sequelae after the convalescence phase of KD.

In the early phase of KD, coronary artery dilatation can be measured for diagnosis, especially in cases of incomplete or atypical KD. Using coronary artery Z-scores with a high PPV (e.g., 0.9), a preZmax of 2.5 is suitable for use on Day 4 of illness. Because a high PPV is obtained after Day 5 of illness, even with a preZmax of 2.0, the diagnosis of coronary artery dilatation seems to be feasible. We propose that preZmax ≥2.5 on Day 4 of illness and preZmax ≥2.0 on Day 5 of illness are suggestive of coronary artery dilatation in KD. In such cases, intravenous immune globulin (IVIG) treatment should be considered, even in patients with incomplete KD.

Does fever affect the diameter of the coronary artery? Normative measurements from which coronary artery Z-scores are derived are based on the assessment of populations of healthy afebrile children. A small sized pilot study reported that coronary artery dimensions in patients with febrile illness other than KD were significantly larger than in the afebrile normative population, but smaller than in KD patients.¹⁷ The pathogenesis of coronary artery dilatation remains unknown in febrile disease states, but may be related to higher myocardial oxygen demand caused by fever and tachycardia. The subsequent increase in coronary blood flow results from compensatory dilation of the coronary arterys.¹⁸

Study Limitations

The aim of the present study was to examine patients before they started treatment for KD. These results differ from those obtained during the natural course of coronary artery dilatation in untreated KD patients. Because many coronary artery lesions developed when only aspirin treatment was available,¹⁹ it is believed that the rate and degree of coronary artery dilatation would be higher in the absence of KD treatment than the results of the present study after Day 10 of illness.

With regard to prognosis, it seems preZmax 2.5 is not the only risk factor. Age, gender, and treatment method also affect prognosis. Therefore, we cannot discuss the implications of preZmax on prognosis in the present study.

Conclusions

The present study showed changes in coronary preZmax dilatation using preZmax in the early phase of KD. Coronary arteries may dilate before Day 5 of illness, with the rate of dilatation increasing gradually until Day 10.

Up to Day 10 of illness, coronary artery dilatation was observed in approximately 70% of KD patients, based on a preZmax of 2.0 before KD treatment. Because preZmax 2.0 has a high PPV after Day 5 of illness, it is a useful marker of coronary artery dilatation in the early phase of KD.

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