Association Between Clinical Risk Factors and Coronary Artery Lesions in Children with Kawasaki Disease

Abstract

Background: Kawasaki disease (KD) is one of the leading causes of acquired coronary artery diseases in childhood. In KD patients, the evidence on the association between easy-to-assess clinical risk factors and development of coronary artery lesion (CAL). Our study aimed to determine the clinical biomarkers that were associated with latent occurrence of CAL in pediatric patients with KD. 

Methods: 260 pediatric KD patients were recruited. The outcome of our study is CAL, including coronary dilation, coronary aneurysm, and intimal thickening of coronary arteries. Data of general information, medical history, results of laboratory examinations and echocardiography data were collected. Logistic regression method was carried out to explore the associations between biomarkers and each CAL.

Results: Sixty-six (25.4 %), thirty-nine (15 %) and fifty-six patients (21.5 %) of the participants had coronary dilation, coronary aneurysm, and intimal thickening of coronary arteries, respectively. Single-variable analysis found age, gender, duration of fever, time of initial use of IVIG, ESR, WBC, time of platelet increase, maximum value of platelet, albumin and IgG level were associated with CAL. In multivariable logistic analysis, younger in age and male were associated with all three outcomes of CAL. Lower serum albumin level and later initial use of IVIG were linked to higher risk of coronary dilation and coronary aneurysm.

Conclusion: In a Chinese pediatric population of KD, younger in age, male, lower serum albumin lever, and later initial use of IVIG were risk factors of CAL. Our findings had high practicability to be implemented in clinical practice, however, is to be verified by future studies.

Background

Kawasaki disease (KD), also called mucocutaneous lymph node syndrome, is an acute, febrile vasculitis disorder which is one of the leading causes of acquired coronary artery diseases in childhood, especially in pediatric patients younger than five years.

The epidemiology of KD varies greatly by geographic location. In western countries, the annual incidence of KD for children under five years old ranged from 4 to 25 per 100000 [1–3]. Nevertheless, the incidence of KD was higher among north and east Asians. For example, in Japan, the accordingly incidence in children under 5 was 243.1 per 100 000 in 2011, and 264.8 per 100000 in 2012 [4]. In China, the annual incidence ranged from 5 to 69 per 100000 [5–8]. Meanwhile, the incidence in Asian area was on increase [8–10]. Besides regional difference, the higher incidence in Japanese children was also linked to the ethnic variation. It was reported that among all ethnic groups in children under 5 years old in Hawaii, children of Japanese descent had the highest incidence (210.5 per 100 000), while Caucasian children had the lowest (13.7 per 100 000) [11]. The above-mentioned evidence highlighted the importance of relevant studies in Asian countries.

KD is one of the most common causes of acquired heart disease in children worldwide [9], furthermore, it is a condition with potential life-long health affect [12]. The long-term prognosis is determined by the level of coronary artery lesion (CAL) [13]. For instance, Japanese studies reported that the standardized mortality ratios in KD patients with cardiac sequelae, for example coronary artery aneurysms, were higher than those without [14, 15]. Moreover, in KD patients with coronary artery aneurysms and stenoses, sudden death of myocardial infarction (MI) can occur many years later in childhood and even in adulthood [16]. Therefore, for the purpose of giving effective and targeted treatment which could possibly have life-long benefits, it is important to recognize patients who are at elevated risk with CAL in the early stage of KD. Determine easy-to-assess clinical characteristics and biomarkers, which were associated with the progression of CAL, could help pediatrician provide timely preventive and therapeutic measures to reduce the prevalence of CAL. Clinical characteristics and biomarkers such as laboratory findings are useful in supporting a diagnosis of KD [17], however, the evidence on the association between them and development of CAL in pediatric KD patients are lacking.

Given the scarce findings and the clinical importance on clinical risk factors CAL in KD patients, we conducted the current study, aiming to determine the clinical biomarkers that were associated with latent occurrence of CAL in pediatric patients with KD. Multiple outcomes (coronary dilation, coronary aneurysm, and intimal thickening of coronary arteries) were involved in our study, to provide more comprehensive evidence on the topic.

Methods

Results

Discussion

In total, 260 patients with infantile KD were recruited in our study, with a mean age of 24 month. Sixty-six (25.4%), thirty-nine (15%) and fifty-six patients (21.5%) of the participants had coronary dilation, coronary aneurysm, and intimal thickening of coronary arteries, respectively. Single-variable analysis found age, gender, duration of fever, time of initial use of IVIG, ESR, WBC, time of platelet increase, maximum value of platelet, albumin and IgG level were associated with CAL. In multi-variable logistic analysis, younger in age, male, lower serum albumin level, and later initial use of IVIG were found to be potential risk factors of CAL in the studied population. In the sensitivity analysis that added IVIG resistance as a covariance in the models, the risk factors for coronary dilation and intimal thickening remained the same.

There are few studies that explored the association between biomarkers and CAL in KD patients. A number of them found similar results to our study, suggested that lower albumin was a risk factor of CAL in KD patients [20, 21]. Meanwhile, other risk factors have also been revealed in the current literature, such as hemoglobin, fever duration, C-reactive protein, and so on. For instance, H.J. Kim et al reported that compared to KD patients without CAL, those with CAL had significantly higher serum interleukin-6 levels (228.26 ng/mL vs. 39.18 ng/mL), and lower body mass index (15.09 vs. 16.60) [22]. Li et al. revealed that red blood cell distribution width could be used as an independent predictor of CAL in KD patients [23]. Shao et al. found Apo-A level, as a predictor of CAL in KD patients, was significantly negatively linked to CAL [24]. In our study, factors such as duration of fever and platelet level were not found to be significantly associated with CAL. The variance in ethnicity, geographic location and seasonality could partially explain the divergences in our findings. In addition, a large body of evidence involved research on potential predictive biomarkers of CAL in KD patients, which were novelty but could not be easily measured and monitored in the general medical practice. The biomarkers included adropin [20], plasminogen activator inhibitor-1 [25], tenascin-C [26], n-terminal pro-brain natriuretic peptide [27–33], circulating endothelial glycocalyx components [26], lymphocyte hydrogen sulfide production [28], to mention a few. Different from these studies, we included results from clinical blood examinations as potential risk factors, which could be easier and faster to be assessed in the clinical practice. Furthermore, extracoronary echocardiographic findings and Z-values were also found to have predictive value for CAL [28, 33, 34]. Compared to those studies, investigation on blood-based biomarkers avoided the influence of variance in equipment and technicians.

In our study, lower albumin level was found to be a risk factor of CAL. Serum albumin is commonly used as a parameter to negatively indicate the activity of inflammatory as an acute phase reactant [35]. Hypoalbuminemia in KD patients was reported to be caused by vascular leakage, which was due to the elevation of vascular endothelial growth factor. Studies have found that vascular endothelial growth factor and its receptors (Fms-related tyrosine kinase-1 and kinase insert domain receptor) were involved in the development and progression of CAL in KD patients [36–38].

Although IVIG combined with aspirin were commonly adopted as the mainstay of initial treatment which could effectively decrease the development of CAL in KD patients, the high incidence of IVIG-resistant were reported in recent years [39–43]. Approximately 10–20% of pediatric patients with KD were reported to have persistent or recrudescent fever after the initial IVIG therapy [44, 45]. Patients that were not responsive to IVIG therapy were considered as at higher risk of incidence for CAL [40, 43]. Several studies suggested potential underlying mechanism that could partially explain the phenomenon. For example, through genome-wide association studies (GWAS), a number of genetic markers associated with both IVIG resistance and CAL formation were found in KD patients, including inositol 1,4,5-trisphosphate 3-kinase C (ITPKC), caspase-3 (CASP3), FCGR2A, CD40, and interleukin1 beta (IL-1B) [46, 47]. Wang et al. found that the change of serum levels of IL-10 varied between patients with and without IVIG resistance after the usage of the medication, and the genetic polymorphisms of IL-10 were corelated to CAL [48]. However, in our study, IVIG resistance was not found to be associated with CAL. The potential reasons could be as followed. The IVIG resistance may suggest the severity of ongoing inflammation, nevertheless development of CAL might also be affected by other factors such as hemodynamics [49], of which the data were not collected in our study. Moreover, in the sensitivity analysis that involved IVIG resistance, even though the responsiveness of IVIG was not found to be associated with CAL directly, some of the other risk factors such as WBC and time of initial use of IVIG became nonsignificant after the addition of IVIG resistance. The mechanisms that lead to the variation should be investigated in future research.

It is crucial to identify the patients with elevated risk of CAL at early stage of the disease, through surveillance on specific risk factors in KD patients. Our study suggested several risk factors including age, gender and albumin, with might be useful in clinical practice because these factors are easy to be measured and are possible to be tested frequently. It could help the pediatrician identify patients that might at high risk of CAL at early stage of the disease, for example upon admission to the hospital. Meanwhile, our findings could offer the pediatrician guidance on monitoring and providing targeted preventive and therapeutic measures. It could be inferred that patients with KD could be benefited from the timely medical treatment.

Conclusion

Our study analyzed data from a Chinese pediatric population with KD, and found that younger in age, male, lower serum albumin lever, and later initial use of IVIG were risk factors of CAL in this population. Our findings had high practicability to be implemented in clinical practice, however, future prospective multi-center studies, with longer follow-up duration, and involving more comprehensive exposure factors are essential to further verify our conclusion.

Declarations

Ethics approval and consent to participate 

The protocol of the present study was reviewed and approved by the Guangzhou Women and Children Medical Center Ethics Committee (2021241A01) and was conducted according to the International Ethical Guidelines for Research Involving Human Subjects stated in the Declaration of Helsinki. The children’s families provide written informed consent.

Consent for publication

Our manuscript does not contain information or images that could lead to identification of a study participant.

Availability of data and materials

The datasets generated and analysed during the current study are not publicly available due to the requirements of the hospital, but are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Funding

This work was supported by Research project of Traditional Chinese Medicine Bureau of Guangdong Province (Grant no. :20201269, Grant recipient: Xiaogang Chen; Grant no. :20212175, Grant recipient: Xiangna Yang)

Authors’ contribution

Conception and design: XY, XC; Data collection: XY, JD, YW; Analysis and interpretation of data: XY, ZL; Writing the manuscript and preparing tables: XY, XC; Critical revision of the manuscript: XY, XC, JD; Administrative, technical, or material support: XY, XC, YW; Obtaining funding: XY, XC; Supervision: XC; Review of the manuscript: all authors.

Acknowledgements

The authors acknowledge and thank all of the participating patients and their families. 

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