A retrospective cohort study of major adverse cardiac events in children affected by Kawasaki disease with coronary artery aneurysms in Thailand.

Kawasaki disease (KD) is a common form of vasculitis in children that can be complicated by coronary artery aneurysms (CAAs). Data of long-term outcomes and major adverse cardiac events (MACE) in children with CAAs following KD in developing country are limited. Our aims were to determine the rates of MACE and identify risk factors associated with MACE in children with KD and CAAs in Thailand. We performed a retrospective analysis of data from 170 children diagnosed with KD and CAAs in two tertiary hospitals between 1994 and 2019. During a median (range) follow-up of 5.4 years (22 days to 23 years), 19 patients (11.2%) experienced MACE, that included 12 coronary artery bypass grafting, 2 percutaneous coronary intervention and 5 children with evidence of myocardial ischemia and coronary occlusion. Coronary interventions were performed at a median time of 4 years (0.01 to 9.5 years) after KD diagnosis. Forty-nine patients (28.8%) had giant CAAs. No MACE was reported in children with small CAAs. Independent risks of MACE were from the absence of intravenous immunoglobulin treatment (HR 7.22; 95% CI 2.21 to 23.59; p = 0.001), the presence of giant aneurysms (HR 13.59; 95% CI 2.43 to 76.09; p = 0.003), and CAAs that involved bilateral branches of coronary arteries (HR 6.19; 95% CI 1.24 to 30.92; p = 0.026). Among children with giant CAAs, the intervention-free rate was 93.8%, 78.7% and 52.2%, at 1, 5 and 10 years, respectively. Of note, 81% of the small CAAs regressed to a normal size, and for medium CAAs, 50% regressed to normal size. Overall, ~10% of children with CAAs following KD experienced MACE in this cohort. Timely IVIG treatment in children with KD following symptom onset will reduce the risk of MACE. Cautious surveillance to identify cardiac complications should be recommended for children once medium or giant CAAs develop. Trial registration: TCTR20190125004.

Introduction

Kawasaki disease (KD) is an acute febrile illness involving inflammation of medium-sized vessels, which primarily affects young children [1, 2]. Without treatment, patients can develop complications, including coronary artery aneurysms (CAAs) in 15% to 25% of cases [2, 3]. Intravenous immunoglobulin (IVIG) treatment within 10 days of symptom onset leads to a reduced incidence of CAAs by 4–10% [1-7]. Persistent CAAs subsequently lead to thrombosis and stenotic lesions that result in myocardial ischemia and infarction [3] and aggressive management such as revascularization intervention is sometimes necessary for patients with these complications [1, 6, 7].

The American Heart Association (AHA) first released guidelines for the diagnosis and therapy of KD in 2004 (2) and most recently updated in 2017 [1]. The latest AHA guideline stratifies patients into five risk levels according to their relative risk of myocardial ischemia and infarction, with indications for subsets of each risk level using the status of the coronary artery and Z-score. Serial myocardial stress tests are recommended in addition to regular echocardiography in the presence of CAAs [1, 5, 6]. Long-term outcomes and reports of major adverse cardiac events (MACE) related to KD have been published [5, 8, 9]. A large nationwide survey in Japan between 1999 and 2010 found that 209 patients with giant CAAs had a 10-year survival rate of 94.3% and a total cardiac event-free rate of 0.68 [8]. A retrospective study of 500 CAAs in 2,860 KD patients in the US reported MACE in 24 patients (4.8%) [9].

In Thailand, the incidence of KD from 1998 to 2002 was reported to be between 2.14 and 3.43 cases per 100,000 children aged 0–5 years, and 15.6% of children had IVIG-resistant KD [10]. The reported prevalence of incomplete KD in children was 29% in a single-center study in Northern Thailand [11]. The long-term outcome of CAAs after treatment, however, has not been reported in the Thai population. We conducted a surveillance study to revisit the natural history of patients with CAAs after KD and to identify risk factors associated with MACE in the pediatric population in Thailand.

Material and methods

Data were retrospectively collected from hospital databases from two large tertiary cardiac centers in Thailand: Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok and Faculty of Medicine Srinagarind Hospital, Khon Kaen University, Khon Kaen. The study was approved by the Siriraj Institutional Review Board, Faculty of Medicine, Siriraj Hospital, Mahidol University [Study number 294/2561 (EC1) and Srinagarind Hospital, Khon Kaen University (Reference No.HE611289). Both institutes waived informed consent from patients but required specific processes to ensure protection of subject confidentiality. All research methods were performed in accordance with Good Clinical Practice (GCP) guidelines and regulations.

Data from pediatric patients diagnosed with KD and CAAs between January 1, 1994 and June 30, 2019 were reviewed. Patients who had only a single echocardiography or angiography without any follow-up were considered as incomplete data and excluded. Demographic, clinical, initial laboratory, echocardiographic findings of CAAs and KD treatment were collected. Demographic data included gender, age at diagnosis of KD, clinical presentation, and criteria of diagnosis. Laboratory data recorded was erythrocyte sedimentation rate (ESR), white blood cell (WBC), and platelet count. The echocardiographic findings of CAAs were collected at the time of diagnosis, 6–8 weeks following diagnosis, and from the most recent follow-up visit. The dimensions of the right coronary artery (RCA), left main coronary artery (LMCA), left anterior descending artery (LAD), and left circumflex artery (LCx) were recorded with their Z-scores. The maximal dimension of CAAs was used to categorize the patients with small, medium, or giant aneurysms. Based on the 2017 AHA criteria [1], CAAs were classified as small aneurysms (Z-score 2.5 to <5), medium aneurysms (Z-score 5 to <10), or large or giant aneurysms (Z-score 10 or an absolute dimension >8 mm). Treatment of KD included receiving IVIG at onset of fever (within 10 days or after 10 days), retreatment with IVIG, and receiving adjunctive anti-inflammation medications. Coronary angiographic findings and data of stress myocardial perfusion imaging (MPI) consisted of stress radionuclide imaging, stress cardiac cardiovascular magnetic resonance (CMR), and exercise stress test. Long-term outcomes were examined, including MACE and mortality using either the current hospital’s databases or phone contact. MACE was defined as having cardiovascular-related illness including total coronary artery occlusion, heart failure, clinical or imaging evidence of myocardial ischemia (MI) by either stress CMR or stress radionuclide MPI, requirement of coronary artery bypass grafting (CABG), or percutaneous coronary intervention (PCI) following a diagnosis at their most recent follow-up visit in 2020.

Statistical methods

Statistical analyses were performed using SPSS 20.0 for Windows (SPSS Inc., Chicago, IL, USA). Demographic, clinical, laboratory, cardiac imaging data, and KD treatment data were presented as a frequency with percentages for the categorical variables and mean ± SD or median with range for continuous variables. Factors associated with MACE were analyzed using univariate and multivariate analyses with cox proportional hazard models. The Kaplan-Meier method was used to analyze intervention-free rates for CABG or PCI in patients after diagnosis with KD. A statistically significant difference was considered with a p-value <0.05.

Results

Patient characteristics

A total of 658 pediatric patients were diagnosed with KD in the two cardiac centers between 1994 and 2019, and 170 of these children (65% male) who had CAAs following KD were included in the analysis (Fig 1). MACE was reported in 19 of 170 patients (11.2%), comprised of 12 CABG, 2 PCI, and 5 with evidence of myocardial ischemia and coronary occlusion. Demographic, clinical, and laboratory data, and KD treatments of the patients are shown in Table 1. The maximal Z-score of coronary dimensions at KD diagnosis was 6.3 (range 2.6 to 85.5). There were 89 patients who had CAAs that involved bilateral branches of coronary arteries. Sixteen children (9.4%) did not receive IVIG. Ninety children (52.9%) received timely IVIG treatment within 10 days of onset of fever. Retreatment of IVIG was reported for 25 (14.7%) of children. All patients received 80–100 mg/kg/day of aspirin during the acute phase of KD per standard of care in Thailand followed by standard low-dose aspirin (3–5 mg/kg/day). An additional anticoagulant, primarily warfarin, was administered with aspirin in 36 patients (21.2%). Adjunctive anti-inflammatory medications were prescribed for 9 patients; 8 with steroids and 1 with abciximab (GP IIb/IIIa inhibitors).

Fig 1

Flow diagram of pediatric patients included in the analysis (n = 170).

Table 1

Baseline characteristics at initial diagnosis of Kawasaki disease.

Variable	Total (n = 170)	MACE (n = 19)	No MACE (n = 151)
Age at diagnosis (years)	1.68 (0.2–12.5)	2.72 (0.3–12.5)	1.65 (0.2–9.9)
Site
• Siriraj Hospital	135 (79.4%)	18 (94.7%)	117 (77.5%)
• Srinagarind Hospital	35 (20.6%)	1 (5.3%)	34 (22.5%)
Male sex	111 (65.3%)	17 (89.5%)	94 (62.3%)
Typical KD	66 (38.8%)	7 (36.8%)	59 (39.1%)
Atypical KD	88 (51.8%)	9 (47.4%)	79 (52.3%)
Uncertain typical or atypical KD	16 (9.4%)	3 (15.8%)	13 (8.6%)
Lack of IVIG treatment	16 (9.4%)	5 (26.3%)	11 (7.3%)
Timing of IVIG treatment
• ≤10 days of fever	90 (52.9%)	5 (26.3%)	85 (56.3%)
• >10 days of fever	51 (30%)	8 (42.1%)	43 (28.5%)
• Unknown timing	13 (7.7%)	1 (5.3%)	12 (7.9%)
Onset of fever received IVIG (day)	9 ± 4	12 ± 5	9 ± 4
Retreatment with 2nd IVIG	25 (14.7%)	4 (21.1%)	21 (13.9%)
Receiving adjunctive anti-inflammatory medication	9 (5.3%)	1 (5.3%)	8 (5.3%)
WBC (/mm3)	17,851 ± 7,550	19,651 ± 7,466	17,732 ± 7,571
Platelet (/mm3)	512,076 ± 189,334	652,250 ± 172,609	502,885 ± 187,376
ESR (mm/hr)	80 ± 29	93 ± 22	79 ± 29
Degree of coronary artery
• Small aneurysm	74 (43.5%)	-	74 (49%)
• Medium aneurysm	47 (27.6%)	2 (10.5%)	45 (29.8%)
• Giant aneurysm	49 (28.8%)	17 (89.5%)	32 (21.2%)
Initial Z-score of coronary dimension	5.4 (0.2–85.5)	23.2 (1.8–85.5)	4.6 (0.2–34.9)
Maximal Z-score of coronary dimension	6.3 (2.6–85.5)	24.2 (6.7–85.5)	5.4 (2.6–34.9)
Location of coronary artery aneurysms
RCA	32 (18.8%)	1 (5.3%)	31 (20.5%)
LAD+RCA	32 (18.8%)	7 (36.8%)	25 (16.6%)
LMCA+LAD+RCA	29 (17.1%)	4 (21.0%)	25 (16.6%)
LAD	24 (14.1%)	-	24 (15.9%)
LMCA	16 (9.4%)	-	16 (10.6%)
LAD+RCA+LCx	4 (2.4%)	3 (15.8%)	1 (0.6%)
LMCA+LAD	9 (5.3%)	1 (5.3%)	8 (5.3%)
LMCA+RCA	21 (12.4%)	2 (10.5%)	19 (12.6%)
LMCA+LAD+RCA+LCx	3 (1.7%)	1 (5.3%)	2 (1.3%)

Data presented as n (%), mean ± SD and median (range)

MACE = major adverse cardiac event; KD = Kawasaki disease; IVIG = intravenous immunoglobulin; LMCA = left main coronary artery; LAD = left anterior descending artery; RCA = right coronary artery; LCx = left circumflex artery; WBC = white blood cell; ESR = erythrocyte sedimentation rate

Patients with CAAs were classified into three groups: small CAAs [74 patients (43.5%)], medium CAAs [47 patients (27.6%)], and giant CAAs [49 patients (28.8%)] (Fig 1). Table 2 illustrates the investigations and treatment of patients depending on the size of CAAs, which included coronary angiography, MPI, and coronary interventions. Coronary artery bypass grafting (CABG) was a mainstay treatment for KD with coronary occlusion and myocardial infarction. Fourteen patients (1 medium-sized CAA and 13 giant CAAs) required coronary intervention (8.2%). Importantly, 4 patients with giant CAAs required a second operation for CABG due to the re-stenosis of the coronary artery.

Table 2

Management of CAAs at different risk levels.

	Small CAAs (n = 74)	Medium CAAs (n = 47)	Giant CAAs (n = 49)
Coronary angiography	9 (12.2%)	13 (27.7%)	35 (71.4%)
Myocardial perfusion imaging	5 (5.5%)	13 (27.7%)	(71.5%)
• Radionuclear stress MPI	1	4	16
• Stress CMR	4	7	16
• EST	-	2	3
Coronary interventions
• CABG	-	-	12 (24.5%)
• PCI	-	1 (2.1%)	1 (2%)
• None	74 (100%)	46 (97.9%)	36 (73.5%)

Data is shown as n (%). CAAs = coronary artery aneurysms; MPI = myocardial perfusion imaging; CMR = cardiovascular magnetic resonance; EST = exercise stress test; PCI = percutaneous coronary intervention; CABG = coronary artery bypass grafting

Clinical outcomes and survival

Nineteen patients (11.2%) experienced MACE after a median (range) follow-up of 5.4 years (22 days to 23 years)]. Of 19 patients, 11 patients had clinically ischemic heart disease. Fourteen patients required coronary intervention, including 12 CABG and 2 PCI, a median of 4 years (0.01 to 9.5 years) after their diagnosis of KD. One patient who underwent CABG at 7 years-of-age had a car accident and died in 2019 at the age of 21 years. Five patients had evidence of chronic total occlusion of coronary artery with well-developed collateral circulation, no coronary intervention has yet been performed. Details of the 19 patients who experienced MACE are provided as S1 Table. Notably, no MACE reports were found for patients with small CAAs. The intervention-free survival of patients with giant CAAs was significantly lower than that in patients with small CAAs (p-value < 0.001) and medium CAAs (p-value = 0.001) (Fig 2). The intervention-free rate in patients with giant CAAs were 93.8%, 78.7%, and 52.2% at 1, 5, and 10 years, respectively. Furthermore, the cardiac event-free rate in these patients were 87.6%, 72.1%, and 50.7% at 1, 5, and 10 years, respectively (Fig 3). The progression and regression of CAAs are shown in Fig 4. Ninety-six patients (56.4%) had regression of CAAs to normal coronary artery. Of the small CAAs, 81% regressed to a normal size, and for medium aneurysms, 50% regressed to a normal size (Fig 4).

Fig 2

Kaplan-Meier estimates of the intervention-free rate of patients with Kawasaki disease who had coronary artery aneurysms (CAAs) (n = 170); small CAAs (n = 74; blue line), medium CAAs (n = 47; green line), and giant CAAs (n = 49; black line) from the time of initial diagnosis.

Fig 3

Kaplan-Meier estimates of the cardiac event-free survival of patients with Kawasaki disease who had coronary artery aneurysms (CAAs) (n = 170); patients without giant CAAs (n = 121; blue line), and with giant CAAs (n = 49; green line) from time of initial KD diagnosis.

Fig 4

Progression and regression of coronary artery aneurysms (CAAs) until the most recent follow-up visit (n = 170).

Risk factors of MACE in children with CAAs following KD

Risk factors associated with MACE in patients with CAAs following KD are shown in Table 3. The absence of IVIG treatment, the presence of giant aneurysms and CAAs at bilateral branches of coronary involvement were identified as independent risks of MACE (adjusted HR 7.22; 95% CI 2.21–23.59; p-value = 0.001, adjusted HR 13.59; 95% CI 2.43–76.09; p-value = 0.003 and adjusted HR 6.19; 95% CI 1.24–30.92; p-value = 0.026, respectively) (Table 3).

Table 3

Risk analysis of major adverse cardiac events (MACE) in Kawasaki disease with coronary aneurysms (CAAs).

Variable	Crude HR (95%CI)	p-value	Adjusted HR (95% CI)	p-value
Age at diagnosis <1 year	0.71 (0.26–1.98)	0.518
Male sex	4.27 (0.99–18.49)	0.052	4.13 (0.9–18.87)	0.068
Atypical KD	1.05 (0.39–2.82)	0.924
Lack of IVIG treatment	4.72 (1.69–13.15)	0.003*	7.22 (2.21–23.59)	0.001*
Retreatment with 2nd IVIG	1.76 (0.58–5.33)	0.315
Received adjunctive anti-inflammatory medication	0.95 (0.13–7.10)	0.957
Referral from other hospitals	2.93 (0.68–12.67)	0.151	0.51 (0.09–2.86)	0.445
Elevated ESR (mm/hr)	1.01 (0.99–1.03)	0.281
Presence of giant CAAs	20.6 (4.76–89.26)	<0.001*	13.59 (2.43–76.09)	0.003*
Maximal Z-score of coronary involvement	1.14 (1.09–1.19)	<0.001*
Location of coronary artery aneurysm
-RCA	0.28 (0.04–2.12)	0.217
-LAD	0.39 (0–10.45)	0.255
-LAD+RCA	2.42 (0.95–6.15)	0.064
Presence of CAAs in bilateral branches of coronary arteries	8.09 (1.87–35.01)	0.005*	6.19 (1.24–30.92)	0.026*

Multivariate analysis by Cox regression

* Statistical significance at p-value < 0.05

MACE = major adverse cardiac event; KD = Kawasaki disease; IVIG = intravenous immunoglobulin; LMCA = left main coronary artery; LAD = left anterior descending artery; RCA = right coronary artery; WBC = white blood cell; ESR = erythrocyte sedimentation rate; CAAs = coronary artery aneurysms

Discussion

This is the first study reporting the prevalence of MACE in children with KD and CAAs in Thailand. Retrospective analysis of data from two large referral hospitals over the last 25 years revealed that a quarter of children with KD had CAAs complications (n = 170). MACE was reported in 19 patients (11.2%); 14 of which required coronary interventions and 5 had evidence of coronary occlusion. Notably, no MACE was reported in children with small CAAs. The absence of IVIG treatment, the presence of giant aneurysms and bilateral branches of coronary involvement were identified as independent risk factors for MACE in these children. This study supports the consensus that close clinical monitoring for MACE following KD is critical, especially for children who did not receive IVIG or with medium to giant aneurysms.

The proportion of CAAs in KD using the 2017 AHA criteria in our study was 25.8%, comparable to the proportions of 24.6% in Japan [3] and 27.1% in USA [12]. Nevertheless, these values are higher than other studies where the prevalence of CAAs was found to vary between 3.6 and 17.4% [7, 13–15]. Data from a national survey on KD in Korea showed differences in the prevalence of CAAs using AHA criteria (21–42%) versus Japanese guideline criteria (18%) for the same sample population [16]. The use of different guidelines and Z-score formulas can lead to different CAA prevalence and diagnostic classification of KD. At our two centers; however, the physicians routinely apply the AHA criteria and Z-scores, as used in this analysis. In addition, the lack of IVIG treatment (9.4%) and resistant IVIG KD (14.7%), which has been associated with the occurrence of coronary artery lesions in KD [13], were slightly higher, in this Korean cohort [16].

Regarding coronary dimensions over time, 56.4% of CAAs regressed to normal coronary artery dimensions in our study, with an overall regression in size of CAAs by 72%. This finding is consistent with a report by Friedman et al. that demonstrated a regression in CA aneurysms of 75% in KD patients [9]. Nevertheless, some patients still had a progressive increase in CAA sized over time, which indicates the need for caution and close follow-up [9, 13].

The incidence of MACE in our study in Thailand was 11.1%, which is higher than that the 4.8% reported in a US study in 2016 [9] but less than 21% reported in a study in Japan [17]. It has to be noted that MACE in our study included patients with clinical ischemic heart disease (6.4%) and asymptomatic patients with total coronary artery occlusion with imaging evidence of myocardial ischemia (MI) (4.7%). Our finding that most patients with MACE had giant aneurysms is consistent with previous publications [5, 9, 17]. Friedman and colleagues [9] reported no MACE in 313 patients with a coronary artery Z-score < 5, and 23% MACE in patients with a coronary Z-score > 10. Similarly, the recent 34-institution international registry of 1,651 KD patients with CAAs [5] showed no MACE in patients with small CAAs, while the patients with giant aneurysms had a cumulative incidence of significant luminal narrowing (20±3%), coronary artery thrombosis (18±2%), and composite MACE at 10 years (14±2%).

In the present study, 14 patients underwent coronary interventions after KD diagnosis 0.01 to 9.5 years. These include our anecdotal five-case series institutionally published in 2006 [18]. Overall, our 10-year cardiac event-free rate in patients with giant CAAs was 50.7%, which is less than the 65–75% reported in prior studies [8, 17, 19]. The independent risk factors of MACE in KD with CAAs in our study were the presence of giant aneurysms, bilateral branches of coronary involvement and a lack of IVIG treatment. Aneurysm size, a higher CAA Z-score, and a greater number of coronary artery branches being affected in KD patients have been shown to be important factors risks of MACE [5, 8, 9, 17, 19]. Aside from the larger size of CAAs, age less than 60 months, recurrent KD, parental history of KD, delayed admission, and IVIG-resistant KD have also been reported to lead to worse coronary outcomes at >30 days following diagnosis [13], while hypoalbuminemia was an additional risk of progressive coronary dilatation at one-year post KD diagnosis [20].

Study limitations

Our study has several limitations. Firstly, due to retrospective nature, there will be selection bias. To reduce the bias, we made every effort to only include patients with KD who had evidence of CAAs by echocardiographic studies and on follow-up at either of the centers. Echocardiographic data and clinical outcomes at their most recent follow-up in October 2020 were recorded, and patients who had a recent follow-up prior to 2020 were contacted via phone to assess their MACE and clinical status. Eighty-seven (51.2%) patients had their recent clinical status assessed in October 2020. Of the 83 patients with no record in 2020, their recent status based on the available medical database. Another limitation was the minimal variability for the clinical investigations, especially the type of cardiac stress test and adjunctive anti-inflammation treatment used at the two centers. Future research may further assess KD patients without CAAs regarding their coronary changes and MACE rate. In addition, change in diastolic properties and left atrial reservoir function may be interesting to research in longitudinal cohort of patients with KD [21].

Conclusion

The MACE rate was 11.2% for children KD with CAAs. A lack of IVIG treatment, the presence of giant aneurysms and bilateral branches of coronary involvement were independent risk factors for MACE in our population. Patients with giant CAAs following KD had an intervention-free survival rate that was significantly lower than that for patients with small and medium CAAs. The cardiac event and intervention-free rate at 10 years in patients with giant CAAs was ~50%. Once medium to giant aneurysms develop, cautious surveillance and early recognition of cardiac complications is recommended.

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Characteristics of 19 patients in the cohort who had major adverse cardiac events (MACE).

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9 Nov 2021

A Retrospective Cohort Study of Major Adverse Cardiac Events in Children Affected by Kawasaki Disease with Coronary Artery Aneurysms in Thailand

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#1. A Retrospective Cohort Study of Major Adverse Cardiac Events in Children Affected by Kawasaki Disease with Coronary Artery Aneurysms

-> Major Adverse Cardiac Events in Children Affected by Kawasaki Disease with Coronary Artery Aneurysms: a two-center, retrospective cohort study in Thailand

#2. Please discuss the paper below.

Kang SJ, Kwon YW, Hwang SJ, Kim HJ, Jin BK, Yon DK. Clinical Utility of Left Atrial Strain in Children in the Acute Phase of Kawasaki Disease. J Am Soc Echocardiogr. 2018 Mar;31(3):323-332. doi: 10.1016/j.echo.2017.11.012. Epub 2018 Jan 3. PMID: 29305035.

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Reviewer #1: Santimahakullert and colleagues present intruiguin data on a relatively large retrospective cohort of KD patients undergone treatment in Thailand. Specifics of clinical care are likely related to geographical area dn healthcare logistics, but these data provide confirming data on a number of clinical risk factors, with supporting long-term follow-up that is a plus of this study design.

I would like to raise some points to be considered before consideration for publication can be given.

- Time between symptom onset and diagnosis should be provided and treated as risk factor in the Cox regression model

- MACE: It is unclear if routine and universal myocardial perfusion study or stress test was implemented in the longitudinal follow-up of this cohort. Accordingly, it is of concern the inclusion of physician-driven ascertainment of some component of the outcome. Data should be reanalyzed taking out clinical or imaging evidence of myocardial ischemia (MI) by either stress CMR or stress radionuclide MPI component of the composite endpoint

-Comparison between KD patients with and without CAAs would be informative

-Low use of IV immunoglobulin should be further defined and explained

-Decision-making regarding need for additional myocardial ischemia testing and/or invasive angiography with comparative tables should be provided

- Missing data and eventual handling of missing data should be specified

Reviewer #2: The authors provide an instructional review of long term cardiac complication from KD in Thailand. Their results are a valuable contribution to the literature on this subject. They identify several risk factors that numerous other studies have shown, including the absence of IVIG treatment, presence of giant coronary aneurysms, location at branch points. Therefore, their results do not provide any surprising findings other than 2 pieces of data. First, the incidence of adverse events (called "MACE" in the manuscript) was much higher in Thailand than in the US, 11.1 vs 4.8%. This is quite a discrepancy and should be addressed with at least some speculation on this finding, or a closer look at the data to find an explanation. Second, the authors found that a surprisingly high proportion (28 of 49, 57%) of regression of giant aneurysms. Since giant aneurysms are the key risk factor for late complications, it would be helpful to make some comments on this particular finding.

**********

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18 Dec 2021

December 5, 2021

Dr. Dong Keon Yon, MD, FACAAI

Academic Editor

PLOS ONE

Manuscript Reference Number: PONE-D-21-17324

Title: A Retrospective Cohort Study of Major Adverse Cardiac Events in Children Affected by Kawasaki Disease with Coronary Artery Aneurysms in Thailand

Dear Editor,

Thank you for your careful consideration of our manuscript and we appreciate the extensive review. Please find below our responses (in blue font) to each of the points raised:

Additional Editor Comments (if provided):

Many thanks for your consideration to submit in Plos One. The reviewers and I read it with great interest, please address adequately comments of the reviewers.

#1. A Retrospective Cohort Study of Major Adverse Cardiac Events in Children Affected by Kawasaki Disease with Coronary Artery Aneurysms

-> Major Adverse Cardiac Events in Children Affected by Kawasaki Disease with Coronary Artery Aneurysms: a two-center, retrospective cohort study in Thailand

Answer: Sorry for the confusion. To clarify, we submitted the above referenced paper to the preprint research square platform in March 2021. Please note that this preprint version had not been published in any journal at that time. We subsequently reviewed and reanalyzed our data and new results were added before submitting the current version of the manuscript entitles “A Retrospective Cohort Study of Major Adverse Cardiac Events in Children Affected by Kawasaki Disease with Coronary Artery Aneurysms” to PLOS ONE in title on May 30, 2021.

#2. Please discuss the paper below.

Kang SJ, Kwon YW, Hwang SJ, Kim HJ, Jin BK, Yon DK. Clinical Utility of Left Atrial Strain in Children in the Acute Phase of Kawasaki Disease. J Am Soc Echocardiogr. 2018 Mar;31(3):323-332. doi: 10.1016/j.echo.2017.11.012. Epub 2018 Jan 3. PMID: 29305035.

Answer: Thank you pointing out this interesting and well-designed study. The peak left atrial longitudinal strain (PALS) and diastolic property were explored in acute phase and convalescent phase of KD patients compared to an age-matched control group. This article found that impaired left atrial reservoir function could be detected as decreased PALS, LV longitudinal peak systolic strain rate in patients with acute phase of KD. Unfortunately, given the retrospective nature of our study we were unable to explore these parameters; nevertheless, we have noted this information and cited this paper in the revised manuscript.

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Answer: There was no external grant or internal funding received for this study. This study involved reviewing hospital-databases following IRB approval. No specific funding was sought for this study.

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Answer: In-text citation for Table S1 has been included in the results: Clinical Outcomes and Survival.

Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Yes

Answer: Thank you for your consideration.

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Reviewer #1: Yes

Reviewer #2: Yes

Answer: Thank you for your consideration.

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The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Answer: Thank you for your consideration.

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Reviewer #1: Yes

Reviewer #2: Yes

Answer: Thank you for your consideration.

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Santimahakullert and colleagues present intriguing data on a relatively large retrospective cohort of KD patients undergone treatment in Thailand. Specifics of clinical care are likely related to geographical area and healthcare logistics, but these data provide confirming data on a number of clinical risk factors, with supporting long-term follow-up that is a plus of this study design.

I would like to raise some points to be considered before consideration for publication can be given.

- Time between symptom onset and diagnosis should be provided and treated as risk factor in the Cox regression model

Answer: Median time between symptom onset, such as fever, to diagnosis of Kawasaki disease was 7 days (range 0 to 36 days). Of note, there were 29 patients with late presentation with no clear history of fever leading to some uncertainty of the time between symptom onset and diagnosis. Consequently, delayed time between symptom onset and diagnosis was not related with MACE (p = 0.693). As patients with delayed diagnosis often received IVIG after 10 days of symptom onset or do not receive IVIG treatment, the authors used lack of IVIG treatment as one of the risk factors in the analysis.

- MACE: It is unclear if routine and universal myocardial perfusion study or stress test was implemented in the longitudinal follow-up of this cohort. Accordingly, it is of concern the inclusion of physician-driven ascertainment of some component of the outcome. Data should be reanalyzed taking out clinical or imaging evidence of myocardial ischemia (MI) by either stress CMR or stress radionuclide MPI component of the composite endpoint

Answer: Thank you for your question. As noted, a major adverse cardiac event (MACE) in our study was defined as having cardiovascular-related illness that included total coronary artery occlusion, heart failure, clinical or imaging evidence of myocardial ischemia (MI) by either stress cardiovascular magnetic resonance or stress radionuclide MPI, requirement of coronary artery bypass grafting (CABG), or percutaneous coronary intervention (PCI) following a diagnosis at their most recent follow-up visit in 2020, which may lead physician-driven ascertainment of some component of the outcome. Of 19 patients with MACE, 11 patients (6.4%) had clinical symptoms and 8 patients (4.7%) had evidence of perfusion deficit leading coronary intervention. The data was reanalyzed removing imaging evidence of myocardial ischemia (MI) by either stress CMR or stress radionuclide MPI following your suggestion. The HR using data of clinical MACE (n=11) are shown in the table below.

Table: Risk analysis of clinical major adverse cardiac event in Kawasaki disease with coronary aneurysms (CAAs)

Variable Crude HR (95%CI) p-value Adjusted HR

(95% CI) p-value

Age at diagnosis <1 year 0.44 (0.1-2.05) 0.296

Male sex 4.85 (0.62-37.94) 0.132# 4.14 (0.53-32.51) 0.177

Atypical KD 0.81 (0.23-2.89) 0.814

Lack of IVIG treatment 6.52 (1.9-22.29) 0.003# 9.37 (2.68-32.79) <0.001*

Retreatment with 2nd IVIG 1.45 (0.31-6.72) 0.636

Received adjunctive anti-inflammatory medication 0.05 (0-2483) 0.574

Referral from other hospitals 1.46 (0.31-6.74) 0.632

Elevated ESR (mm/hr) 22.79

(0-18160880) 0.652

Presence of giant CAAs 218.05

(0.63-75218.81) 0.071# N/A N/A

Presence of CAAs in bilateral branches of coronary arteries 9.043 (1.16-70.65) 0.036#

12.36 (1.54-98.9) 0.018*

# Statistical significance at p-value < 0.2

KD=Kawasaki disease; IVIG=intravenous immunoglobulin; ESR=erythrocyte sedimentation rate; CAAs=coronary artery aneurysms; N/A=not applicable

Using 11 patients with clinical MACE as the endpoint, lack of IVIG, presence of giant coronary aneurysms and bilateral coronary involvement were identified as dependent risk factors of MACE (p < 0.2) on univariate analysis. The absence of IVIG treatment and CAAs at bilateral branches of coronary involvement were identified as independent risks of MACE. All 11 patients with clinical MACE had giant aneurysms but this risk factor was unable to be assessed in the multivariate analysis even though it is likely an important risk factor of MACE. These results are consistent with the risk factors we identified in the original analysis. Nevertheless, we should be cautious of using only clinical MACE as some children cannot report their ischemic heart symptoms and this leads to late detection. Recent KD guidelines suggest to perform serial myocardial stress tests and manage the patients who are at risk. In our setting, when we detect perfusion deficit on myocardial stress tests, CAG would be performed and treatment would be considered. We therefore decided to include the eight patients who had coronary occlusion and perfusion deficit as patients with MACE.

We have added the number of patients with clinical MACE to the result and discussion section as suggested.

-Comparison between KD patients with and without CAAs would be informative

Answer: The inclusion criteria of this retrospective study only included consecutive patients with KD who had CAAs. Patients with no CAAs were not include in this analysis. Interestingly, no patients with small CAAs experienced MACE which may indicate that moderate and giant CAA could be risky more than small CAAs. Our team is currently performing research in KD patients without CAAs and assessing coronary changes and MACE and we expect the results will help answer this question.

-Low use of IV immunoglobulin should be further defined and explained

Answer: The use of IVIG in Thailand between 1990-2004 was limited due to lack of availability in the national health program and late diagnosis. IVIG usage in our retrospective study (between 1994 and 2019) was 91%.

-Decision-making regarding need for additional myocardial ischemia testing and/or invasive angiography with comparative tables should be provided

Answer: The decision making of additional myocardial ischemia testing and/or invasive angiography is based on the 2017 AHA KD guideline (McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. 2017;135(17):e927-e99), especially for patients with moderate to giant CAAs. The retrospective nature of our analysis will inevitably include some bias. The patients diagnosed with KD prior to 2017 would be performed additional testing as 2004 guideline suggestion. Traditional tests included coronary angiography and nuclear MPI while the current tests included stress cardiovascular magnetic resonance, exercise stress test up to patients’ classification.

- Missing data and eventual handling of missing data should be specified

Answer: We have highlighted this point as a study limitation. Clinical outcomes and echocardiographic data at the patients’ most recent follow-up in October 2020 were recorded. Patients who had a recent follow-up prior to 2020 were contacted via phone to assess clinical status and any MACE. Eighty-seven (51.2%) patients had their recent clinical status assessed in October 2020. Of the 83 patients with no record in 2020, their recent status based on the available medical database was used for data analysis.

Reviewer #2: The authors provide an instructional review of long term cardiac complication from KD in Thailand. Their results are a valuable contribution to the literature on this subject. They identify several risk factors that numerous other studies have shown, including the absence of IVIG treatment, presence of giant coronary aneurysms, location at branch points. Therefore, their results do not provide any surprising findings other than 2 pieces of data.

-First, the incidence of adverse events (called "MACE" in the manuscript) was much higher in Thailand than in the US, 11.1 vs 4.8%. This is quite a discrepancy and should be addressed with at least some speculation on this finding, or a closer look at the data to find an explanation.

Answer: The incidence of MACE in our study in Thailand was 11.1%, which is higher than the 4.8% reported in a US study in 2016, but less than the 21% reported in a study in Japan in 2017. One explanation may be the ethnicity of the populations. Notably, our study included 8 patients who were asymptomatic but had evidence of chronic total occlusion of coronary artery in the MACE group. If we exclude these patients, the proportion of symptomatic MACE patients was 11/170 (6.4%). However, we decided to include these patients with MACE as the study population was children and likely unable to report the ischemic symptoms. The myocardial stress tests may aid us to detect myocardial ischemia prior to symptom onset.

-Second, the authors found that a surprisingly high proportion (28 of 49, 57%) of regression of giant aneurysms. Since giant aneurysms are the key risk factor for late complications, it would be helpful to make some comments on this particular finding.

Answer: Of 49 patients with giant coronary aneurysms (CAAs), 21 patients (43%) had persistent giant CAAs, 4 patients (8%) regressed to medium sized CAAs, 11 patients (22.5%) regressed to small CAAs and 13 patients (26.5%) regressed to normal size. Initial evaluation of giant CAAs was performed by echocardiography. The progression or regression of CAAs were subsequently assessed by echocardiography and coronary angiography/ computerized tomography/ coronary magnetic resonance angiography. Associated factors of regression of giant CAAs were explored using univariate analysis and the results are shown in the table below. In this subgroup analysis, age of less than 1 year at the onset of Kawasaki syndrome, female sex, typical KD, received IVIG treatment, retreatment with 2nd IVIG, presence of CAAs in unilateral branch of coronary arteries were not associated with favorable resolution of CAAs. A larger study population is needed to provide robust predictors of giant CAAs regression. Please note that the morphology of CAAs such as fusiform CAAs or location of CAAs (distal or proximal portion of coronary artery) found to be favorable factors in a previous publication(1) were not assessed in our study due to lack of data. A study of 120 patients with CAAs in Eastern China(2) showed patients aged ≤ 1 year, received initial intravenous immunoglobulin (IVIG) treatment after the 10th day of illness, and IVIG non-responders were associated with the regression of persistent CAAs.

1) Takahashi M, Mason W, Lewis AB. Regression of coronary aneurysms in patients with Kawasaki syndrome. Circulation. 1987;75(2):387-94.

2) Tang Y, Yan W, Sun L, Xu Q, Ding Y, Lv H. Coronary artery aneurysm regression after Kawasaki disease and associated risk factors: a 3-year follow-up study in East China. Clin Rheumatol. 2018;37(7):1945-51.

Table: Univariate analysis of factors associated with regression of giant coronary aneurysms (n=49)

Variable Crude OR (95%CI) p-value

Age at diagnosis < 1 year 1.67 (0.76-3.66) 0.201

Female sex 1.05 (0.45-2.49) 0.905

Typical KD 0.50 (0.22-1.13) 0.094

Received IVIG treatment 1.11 (0.39-3.29) 0.842

Retreatment with 2nd IVIG 0.95 (0.36-2.54) 0.925

Not received adjunctive anti-inflammatory medication 21.71 (0.004-1117007) 0.483

Presence of CAAs in unilateral branch of coronary arteries 1.79 (0.75-4.26) 0.188

Received IVIG after 10 days 1.28 (0.54-3.02) 0.573

KD=Kawasaki disease; IVIG=intravenous immunoglobulin; CAAs=coronary artery aneurysms

Thank you for your time and consideration.

Best wishes,

Dr. Chodchanok Vijarnsorn

Division of Pediatric Cardiology

Department of Pediatrics, Faculty of Medicine

Siriraj Hospital, Mahidol University THAILAND

Submitted filename: Response to reviewers 17122021.docx

Click here for additional data file.

12 Jan 2022

A Retrospective Cohort Study of Major Adverse Cardiac Events in Children Affected by Kawasaki Disease with Coronary Artery Aneurysms in Thailand

PONE-D-21-17324R1

Dear Dr. Vijarnsorn,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Dong Keon Yon, MD, FACAAI

Academic Editor

PLOS ONE

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I congratulate you on this mesmerizing paper.

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Comments to the Author

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Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

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The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors have effectively answered the questions and suggestions of the reviewers and I would now favor acceptance.

**********

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Reviewer #2: No

17 Jan 2022

PONE-D-21-17324R1

A Retrospective Cohort Study of Major Adverse Cardiac Events in Children Affected by Kawasaki Disease with Coronary Artery Aneurysms in Thailand

Dear Dr. Vijarnsorn:

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