Introduction
Kawasaki disease, also known as mucocutaneous lymph node syndrome, is an acute, febrile vasculitis disorder, which is one of the leading causes of acquired coronary artery diseases among children 5 years of age or younger. Reference Sadeghi, Izadi and Mojtahedi1 The prevalence of Kawasaki disease varies greatly among different geographic locations. In western countries, the annual incidence of Kawasaki disease for children under 5 years old ranges from 4 to 25 per 100000. Reference Saundankar, Yim and Itotoh2–Reference Uehara and Belay4 Nevertheless, the incidence of Kawasaki disease tends to be higher in Northeast Asia. For example, in Japan, the incidence in children under 5 is approximately 243.1 per 100 000. Reference Makino, Nakamura and Yashiro5 In China, the annual incidence ranges from 5 to 69 per 100000. Reference Huang, Huang and Chang6–Reference DU, ZHANG and LIANG9 Besides geographic variations, racial and ethnic groups have demonstrated the incidence of Kawasaki disease. In Hawaii, among all ethnic groups, Japanese descendants below 5 years of age had the highest incidence of Kawasaki disease (210.5 per 100 000), while Caucasian children had the lowest (13.7 per 100 000). Reference Holman, Christensen and Belay10
Kawasaki disease is one of the most common causes of acquired heart disease in children worldwide. Reference Singh, Vignesh and Burgner11 Moreover, the long-term prognosis of Kawasaki disease is largely affected by the severity of coronary artery lesion. Reference Fujiwara and Hamashima12 For example, the average mortality rates among Kawasaki disease patients with cardiac sequelae, particularly coronary artery aneurysms, were higher than those without coronary artery aneurysms, which has been previously reported by Japanese studies. Reference Nakamura, Aso and Yashiro13,Reference Nakamura, Aso and Yashiro14 Moreover, in Kawasaki disease patients with both coronary artery aneurysms and stenoses, sudden cardiac death in the setting of myocardial infarction can occur from late childhood through adulthood. Reference Burns, Shike, Gordon, Malhotra, Schoenwetter and Kawasaki15 More importantly, coronary artery lesion is still observed in 5–20% of patients with acute Kawasaki disease even after intravenous immunoglobulin treatment. Reference Eleftheriou, Levin, Shingadia, Tulloh, Klein and Brogan16 Therefore, identifying effective biomarkers to predict coronary artery lesion formation could help develop a reliable method of predicting the prognosis for Kawasaki disease, thus eventually improving the quality of life in Kawasaki disease patients. However, the evidence on the relationship between clinical risk factors/biomarkers and the development of coronary artery lesion in Kawasaki disease children is nevertheless lacking.
Therefore, our study aimed to determine the potential severity risk factors of coronary artery lesion in paediatric Kawasaki disease patients based on a single-institution retrospective analysis from a Southern Chinese paediatric population. Our work could help clinicians in the early prediction of coronary artery lesion development once Kawasaki disease is diagnosed, which could help to improve the overall survival rates among Kawasaki disease patients.
Methods
Patients and diagnostic criteria
We retrospectively investigated a total of 260 paediatric patients with complete Kawasaki disease who were admitted to the Department of Cardiology at Guangzhou Women and Children’s Medical Center from June to December 2017. The protocol of the present study was reviewed and approved by the Guangzhou Women and Children’s Medical Center Ethics Committee (2021241A01). This study was conducted as the International Ethical Guidelines for Research Involving Human Subjects, as stated by the Declaration of Helsinki. Written, informed consent has been obtained from the legal guardians of patients.
According to American Heart Association guidelines in 2017, the presence of five principal clinical features: conjunctival injection, rash, strawberry tongue/red lips, neck lymphadenopathy, oedema, and erythema of the extremities led to the diagnosis of complete Kawasaki disease. Patients with ≥ 5 days of fever and > 4 of the aforementioned symptoms were diagnosed with complete Kawasaki disease. Alternatively, patients who met only two or three of the above criteria with the presence of ≥ 5 days of fever were considered to have incomplete Kawasaki disease and have been excluded from the study. Reference Newburger, Takahashi and Gerber17
Based on the 2017 American Heart Association criteria, coronary artery lesion has been classified into coronary dilation and coronary aneurysm primarily based on Z scores: no involvement (< 2); dilation only (≥ 2 – < 2.5); small aneurysm: (≥ 2.5 – <5); medium aneurysm (≥ 5 – < 10 and absolute dimension < 8 mm); and large or giant aneurysm: (≥ 10 or an absolute dimension ≥ 8 mm). Reference Newburger, Takahashi and Gerber17 The findings of coronary artery lesion were assessed by echocardiography and obtained by at least two experienced ultra-sonographers. The Philips EPIQ 7C color Doppler ultrasound imaging instrument was used for examination, and the Z-value was measured according to the left coronary artery trunk, left anterior descending artery, and right coronary artery of the paediatric patients. The collected analysis included: data on the incidence, severity, and location of each CAL.
Clinical examination
Clinical and laboratory data collected from the medical records of the patients enrolled in this study included the patient’s general information, history of present illness, results of laboratory examinations, echocardiography data, and history of medication usage. The laboratory examinations were measured upon admission. Intravenous immunoglobulin resistance was defined as recurrent or persistent fever (temperature, > 38.0°C) for at least 36 hours but no longer than 7 days after completion of the initial intravenous immunoglobulin infusion. Reference McCrindle, Rowley and Newburger18
Statistical analysis
Data were described as the mean and standard deviation for continuous variables and numbers and percentages for categorical variables. Continuous variables were compared using a t-test to estimate the significance of differences between patients with or without certain coronary artery lesion. Categorical variables were compared using χ 2 tests. Variables that presented statistical significance for at least one outcome were included in the multivariable logistic regression model. The logistic regression model was applied to explore the potential risk factors for each coronary artery lesion. A sensitivity analysis was carried out by adding the variable ‘whether they had intravenous immunoglobulin resistance’ into the final model, and to explore whether intravenous immunoglobulin resistance had a modification effect on the relationships that were found in the main analysis. Statistical analyses were performed using STATA software. A p-value of <0.05 was considered statistically significant.
Patient and public involvement
Patients and the public were not involved in the conduct of this study. The public was not consulted to participate in the study design or outcomes. In addition, we did not invite the public to participate in the interpretation of our findings. The public has not assisted in the writing or editing of this paper. There are no plans to directly involve the public or patients in disseminating research results.
Results
Patient’s characteristics
In total, 260 patients with Kawasaki disease were recruited for our study, with an average age of 24.05 months (standard deviation = 21.85 months) and the ratio of male to female 172:88. The mean duration of fever was 7.52 days (standard deviation = 3.27 days). The mean time of initial use of intravenous immunoglobulin after the onset of Kawasaki disease was 6.44 days (standard deviation = 2.12 days). Almost eighty-four percent of the participants used intravenous immunoglobulin 1 time (n = 218) and 3 (1.2 %) of the total sample never used intravenous immunoglobulin. Among those, thirty-nine children had intravenous immunoglobulin resistance, accounting for 15 % of the total participants. The detailed general information is listed in Table 1.
Description of general characteristics
IVIG = intravenous immunoglobulin; SD = standard deviation.
Description of coronary artery lesion
The prevalence of coronary artery lesions is displayed in Table 2. After the onset of Kawasaki disease, sixty-four (24.6 %) participants had coronary dilation, with a mean time of the first occurrence of 34.31 days (standard deviation = 70.34 days). In 34 (53.1 %) patients, coronary dilation was located only in the left coronary arteries. Coronary aneurysm affected thirty-nine (15 %) participants, with a mean time of the first occurrence of 11.73 days (standard deviation = 6.34 days) after the onset of Kawasaki disease. The coronary aneurysm was located in both left and right coronary arteries, in 22 (56.4 %) patients. The majority of patients had a coronary aneurysm of small size (84.6 %, n = 33), and 10.3% (n = 4), 2.6% (n = 1), and 2.6% (n = 1) patients had medium, large, and extra-large coronary aneurysms, respectively. The mean time of regression of coronary aneurysm was 50.13 days (standard deviation = 63.63 days) after the onset of Kawasaki disease for overall patients, and 39.06 days (standard deviation = 33.68), 207.50 days (standard deviation = 165.76), 30.00 days, and 300.00 days for patients with small, medium, large, and extra-large size of coronary aneurysm, respectively. Intimal thickening of coronary arteries was found in fifty-six patients (21.5 %). Most participants had intimal thickening only in the left coronary arteries, which is almost identical to coronary dilation. A thrombus was found in one patient. The mean time of total recovery was 81.27 days (standard deviation = 261 days). Disease progression is displayed in Figure 1. The median and interquartile range of days of coronary aneurysm onset from the initiation of disease is 10 (6) days, and the disappearance of coronary aneurysm is 45 (30) days. Coronary aneurysm appeared at a median of 8 (23) days. The median overall recovery time is 142.5 (150) days. Overlapping of coronary artery lesions is displayed in Figure 2. There are 15 patients had all three coronary artery lesions.
Disease progression for patients who had CA or CD (median, lower, and upper quartiles). CA = coronary aneurysm; CD = coronary dilation; IVIG = intravenous immunoglobulin.
Overlapping of coronary artery lesions. CA = coronary aneurysm; CAL = coronary artery lesion; CD = coronary dilation; IT = intimal thickening of coronary arteries.
Description of coronary artery lesion
SD = standard deviation.
Comparison of clinical biomarkers between participants with and without coronary artery lesion
For all the three coronary artery lesions, duration of fever and time of initial usage of intravenous immunoglobulin were significantly higher in patients who had the lesions than in those without, whereas the month of age and serum albumin level were lower. In addition, males are more likely than females to have coronary dilations (78.8 % vs. 61.9 %, p = 0.012). Erythrocyte sedimentation rate was higher in those with coronary aneurysms than in those without. White blood cell count was higher among patients with coronary aneurysms and intimal thickening than in their comparative groups. The time of the increase in platelets was lower in patients with coronary dilation, and the maximum value of platelets was lower in patients with coronary dilation and coronary aneurysm, in comparison to the groups without the lesions. Immunoglobulin G level was higher in patients with intimal thickening than in those without. Results of the comparison of clinical biomarkers between participants with and without coronary artery lesions are displayed in Table 3.
Comparison of clinical biomarkers between participants with and without CAL
ALT = alanine aminotransferase; CA = coronary aneurysm; CD = coronary dilation; CIT = coronary intimal thickening; CK-MB = creatine kinase isoenzyme; DBil = direct bilirubin; ESR = erythrocyte sedimentation rate; HB = haemoglobin; hsCRP = hypersensitive C-reactive protein; IBil = indirect bilirubin; IVIG = intravenous immunoglobulin; LDH = lactic dehydrogenase; PLT = platelet; SD = standard deviation; TBA = total bile acid; TBil = total bilirubin; WBC = white blood cell count.
*p < 0.05.
Multivariable analyses
In the main analysis (Table 4), age (odds ratio = 0.975, 95 % confidence interval: 0.955–0.994, p = 0.012), being female (odds ratio = 0.304, 95 % confidence interval: 0.142–0.648, p = 0.002) and serum albumin level (odds ratio = 0.926, 95 % confidence interval: 0.858–0.998, p = 0.045) were found to be negatively linked to the risk of coronary dilation, while time of initial use of intravenous immunoglobulin (odds ratio = 1.255, 95 % confidence interval: 1.047–1.503, p = 0.014) was positively linked. Age (odds ratio = 0.962, 95% CI: 0.933–0.991, p = 0.012) and serum albumin level (odds ratio = 0.890, 95 % confidence interval: 0.809–0.979, p = 0.017) were found to be negatively linked to the risk of coronary aneurysm, while white blood cell (odds ratio = 1.088, 95 % confidence interval: 1.012–1.169, p = 0.023) and time of initial use of intravenous immunoglobulin (odds ratio = 1.214, 95 % confidence interval: 1.003–1.469, p = 0.047) were positively linked. In terms of intimal thickening, age (odds ratio = 0.960, 95% confidence interval: 0.936–0.984, p = 0.001), and being female (odds ratio = 0.409, 95 % confidence interval: 0.188–0.889, p = 0.024) were negatively associated.
Result from multi-variable logistic regression
CA = coronary aneurysm; CD = coronary dilation; CIT = coronary intimal thickening; ESR = erythrocyte sedimentation rate; LDH = lactic dehydrogenase; PLT = platelet; SD = standard deviation; WBC = white blood cell.
*p < 0.05.
In the sensitivity analysis that added intravenous immunoglobulin resistance as covariance in each model (Table 5), the risk factors for coronary dilation and intimal thickening remained the same. The time of initial use of intravenous immunoglobulin and white blood cell for coronary aneurysms has become statistically in significant.
Result from sensitivity analysis
CA = coronary aneurysm; CD = coronary dilation; CIT = coronary intimal thickening; ESR = erythrocyte sedimentation rate; IVIG = intravenous immunoglobulin; LDH = lactic dehydrogenase; PLT = platelet; SD = standard deviation; WBC = white blood cell.
*p < 0.05.
Discussion
Few studies are exploring the association between biomarkers and coronary artery lesions in Kawasaki disease patients. For example, previous reports had suggested that lower albumin was a risk factor for coronary artery lesion in Kawasaki disease patients, which had been consistent with our findings. Reference Yang, Pei, Zhang, Weng, Jing and Yi19,Reference Kim, Choi and Kil20 Meanwhile, other risk factors that had been revealed in the current literature were: haemoglobin, fever duration, and C-reactive protein. For instance, Kim et al reported that compared to Kawasaki disease patients without coronary artery lesion, those with coronary artery lesion 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). Reference Shao, Zhou and Liu21 Li et al. revealed that red blood cell distribution width could be used as an independent predictor of coronary artery lesion in Kawasaki disease patients. Reference Ming, Cao, Li and Yu22 Shao et al. found Apo-A level, as a predictor of coronary artery lesion in Kawasaki disease patients, was significantly negatively linked to coronary artery lesion. Reference Okuma, Suda and Nakaoka23 In our study, factors such as duration of fever and platelet level were not found to be significantly associated with coronary artery lesion. The variance in ethnicity, geographic location, and seasonality could partially explain the divergence in our findings. In addition, a large body of evidence involved research on potential predictive biomarkers of coronary artery lesion in Kawasaki disease patients, which were novel but could not be easily measured and monitored in daily medical practice. The biomarkers included atropin, Reference Yang, Pei, Zhang, Weng, Jing and Yi19 plasminogen activator inhibitor-1, Reference Senzaki, Kobayashi and Nagasaka24 tenascin-C, Reference Ohnishi, Yasudo and Suzuki25 n-terminal pro-brain natriuretic peptide, Reference Huiling, Yaping and Xiufen26 circulating endothelial glycocalyx components, Reference Makino, Nakamura and Yashiro5 lymphocyte hydrogen sulphide production, and etc. Reference Bilal, Haseeb, Saeed and Sher Khan27 In contrast to these studies, we have included results from clinical blood examinations as potential risk factors, which could be easier and faster to be assessed in clinical practice. Furthermore, extracoronary echocardiographic findings and Z-values were also found to have had predictive values for coronary artery lesion. Reference Bilal, Haseeb, Saeed and Sher Khan27,Reference Lega, Bozio and Cimaz32,Reference Sun, Yuan and Yan33 In comparison to forenamed studies, the investigation of blood-based biomarkers avoided the influence of variance in equipment and technicians.
Moreover, in our study, a lower albumin level was found to be a risk factor for coronary artery lesion. Serum albumin has been commonly used as a parameter to negatively indicate the activity of inflammation as an acute phase reactant. Reference Al-Subaie, Reynolds and Myers34 Hypoalbuminaemia in Kawasaki disease 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 coronary artery lesion in Kawasaki disease patients. Reference Terai, Honda, Yasukawa, Higashi, Hamada and Kohno35–Reference Kariyazono, Ohno and Khajoee37
Although intravenous immunoglobulin combined with aspirin is commonly adopted as the mainstay of initial treatment that could effectively decrease the development of coronary artery lesion in Kawasaki disease patients, a high incidence of intravenous immunoglobulin resistance have been were reported in recent years. Reference Mori, Imagawa, Yasui, Kanaya and Yokota38–42 Approximately 10–20 % of paediatric patients with Kawasaki disease were reported to have persistent or recrudescent fever after the initial intravenous immunoglobulin therapy. Reference Egami, Muta and Ishii43,Reference Durongpisitkul, Soongswang, Laohaprasitiporn, Nana, Prachuabmoh and Kangkagate44 Patients that were not responsive to intravenous immunoglobulin therapy were considered at a higher risk of incidence for coronary artery lesion. Reference Ashouri, Takahashi, Dorey and Mason39,42 Several studies suggested potential underlying mechanisms that could partially explain the phenomenon. For example, through genome-wide association studies, several genetic markers associated with both intravenous immunoglobulin resistance and coronary artery lesion formation were found in Kawasaki disease patients, including inositol 1,4,5-trisphosphate 3-kinase C, caspase-3, FCGR2A, CD40, and interleukin1 beta. Reference Onouchi, Suzuki and Suzuki45,Reference Lee, Kuo and Chang46 Wang et al. found that the change in serum levels of interleukin-10 varied between patients with and without intravenous immunoglobulin resistance after the usage of the medication, and the genetic polymorphisms of interleukin-10 were correlated to coronary artery lesions. Reference Wang, Wang and Gong47 However, in our study, intravenous immunoglobulin resistance was not found to be associated with coronary artery lesion. The intravenous immunoglobulin resistance may suggest the severity of ongoing inflammation, nonetheless, the development of coronary artery lesion might have been affected by other factors such as haemodynamics, Reference Kobayashi, Inoue and Takeuchi48 of which the data were not collected in our study. Moreover, in the sensitivity analysis that involved intravenous immunoglobulin resistance, even though the responsiveness of intravenous immunoglobulin was not associated with coronary artery lesions directly, some of the other risk factors such as white blood cell and time of initial use of intravenous immunoglobulin became nonsignificant after the addition of intravenous immunoglobulin resistance. The mechanisms that lead to those variations should be investigated in future research.
It is crucial to identify the patients with an elevated risk of coronary artery lesion at an early stage of the disease, through surveillance of specific risk factors in Kawasaki disease patients. Our study suggested several risk factors including age, gender, and albumin, which might be useful in clinical practice because those factors are easy to measure and frequent testing would be possible. It could help the paediatrician to identify patients that may be at a high risk of coronary artery lesion at an early stage of the disease, mainly upon admission to the hospital. Meanwhile, our findings could offer the paediatrician guidance on monitoring and providing targeted preventive and therapeutic measures. It could be inferred that patients with Kawasaki disease could be benefited from timely medical treatment.
Strength and limitations
Our present study provided evidence on the associations between clinical biomarkers and the incidence of several coronary artery lesions. There were a plenty of strengths that made our study valuable and practical. First, although the study was retrospective, we used data from medical records, which had been obtained during the hospitalisation. The accuracy and reliability of the data largely reduced the potential recall bias. Second, by having included a group of clinical biomarkers as potential risk factors, combined with a comprehensive involvement of the three major outcomes, our study provided an overall insight into the topic. Third, Kawasaki disease has been more prevalent in the Asian area. Our study had been carried out in the Asian population (Chinese), which made our result proper to be generalised in the high-risk area of Asia. Forth, we investigated clinical characteristics and biomarkers that were easy to be examined, which made our conclusion much more empirical to be verified in future clinical research, and hence, to be implemented in clinics.
However, there are certain limitations of our study as well. Firstly, the duration of follow-up had been short. Kawasaki disease could have had a life-long influence on the patient’s health conditions. As reported by a Canadian study, 5% of myocardial infarction had been noted in patients less than 40 years of age who underwent coronary angiography and had lesions that were linked to sequelae of Kawasaki disease. Reference Daniels, Tjajadi and Walford49 Therefore, it was necessary to follow up with the participants for as long as possible, to investigate the longitudinal risk factors for coronary artery lesion. Secondly, the sample of our study was from a single centre, and the sample size was relevantly small. Due to the low incidence of Kawasaki disease in Guangdong province (approximately 5 per 100000), Reference Zhou, Wang and ZHao8 it could be time-consuming to recruit a large sample, even if it were a multi-centre research. Because of the inadequate sample size, we were not able to compare our findings between intravenous immunoglobulin responsive and nonresponsive patients, and were not able to carry out survival analysis. The single-centre small sample also limited the generalisability of the research findings and weakened the robustness of our conclusion. Thirdly, information on some of the potential confounders that could have influenced the result had not been collected in our study. Those factors included family history, diet, sleep, other life-style factors, genetic data, et al. That data could not be implemented due to the retrospective feature of the study. Forth, the patients were discharged during the considerable long follow-up duration (with the average time for regression of coronary aneurysm being 50.13 days). It would be possible that patients received treatment outside the hospital, which might have an impact on the final outcomes of the disease. This information was not collected in our retrospective data. Lastly, Nakamura et al. reported a higher risk of having developed coronary artery sequelae with the recurrent episode. Reference Tissandier, Lang, Lusson, Bœuf, Merlin and Dauphin50 However, we did not take that factor into consideration, which limited the generalisation of our conclusion.
Conclusion
Our study identified potential risk factors for coronary artery lesion development in paediatric patients with Kawasaki disease from single-centre data. After the onset of Kawasaki disease, 25.4 %, 15.0%, and 21.5% of participants had coronary dilation, coronary aneurysm, and intimal thickening of coronary arteries, respectively. We also concluded that youngsters, males, lower serum albumin levers, and later initial use of intravenous immunoglobulin were the risk factors for coronary artery lesions within the population that we had analysed. Our findings had high practicability and could be implemented in clinical practice. However, our conclusion should be verified by further multi-centre studies, long-term follow-ups, and other exposure factors for coronary artery lesion in Kawasaki disease patients.
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.
Acknowledgements
None.
Author contribution
X. Yang and J. Zou wrote the conception and design of the manuscript. H. Nie, G. Zhang, and Y. Liao collected the data. X. Yang, G. Zhang, and Y. Liao analysed the data. X. Yang, J. Zou, and H. Nie wrote the main manuscript text. J. Deng and Y. Wang were responsible for the supervision. All authors reviewed the manuscript.
Financial support
This work was funded by the National Natural Science Foundation of China (No. 82170519) and Municipality-University Joint Funding of Guangzhou Municipal Science and Technology Bureau (No. 202201020636).
Competing interests
None.
Ethics standard
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. All patients provided written informed consent to participate.
