The role of serum lipid in predicting coronary artery lesions and intravenous immunoglobulin resistance in Kawasaki disease: a cohort study

Abstract

Objective

To assess the predictive value of the serum lipid profile for initial intravenous immunoglobulin (IVIG) resistance and coronary artery lesions (CALs) in patients with Kawasaki disease (KD).

Methods

This retrospective cohort study enrolled patients with KD and divided them into IVIG-responsive and IVIG-resistant groups. They were also stratified based on the presence of CALs (CALs and non-CALs groups). Clinical, echocardiographic and biochemical values were evaluated. A subgroup analysis was performed on complete and incomplete KD. Predictors of initial IVIG resistance and CALs were determined by multivariate logistic regression analysis.

Results

A total of 649 KD patients were enrolled: 151 had CALs and 76 had initial IVIG resistance. Low-density lipoprotein cholesterol (LDL-C) was significantly lower in the IVIG-resistant group than in the IVIG-responsive group. LDL-C and apolipoprotein (Apo) B were significantly lower in the CALs group compared with the non-CALs group. Multivariate logistic regression failed to identify the serum lipid profile (LDL-C, Apo A or Apo B) as an independent risk factor for initial IVIG resistance or CALs in KD patients.

Conclusion

KD patients might have dyslipidaemia in the acute phase, but the serum lipid profile might not be suitable as a single predictor for initial IVIG resistance or CALs.

Keywords

Kawasaki disease intravenous immunoglobulin resistance coronary artery lesions serum lipid

Introduction

Kawasaki disease (KD), previously known as mucocutaneous lymph node syndrome, is a self-limited febrile illness of unknown cause that mainly affects children <5 years of age.¹ KD has been reported in more than 60 countries since it was first described in Japan and is now recognized as one of the most common causes of acquired heart disease in children in developed countries.² KD can lead to coronary artery disease, ischaemic heart disease and sudden death in severe cases. Timely intravenous immunoglobulin (IVIG) therapy can reduce the risk of coronary artery lesions (CALs) and mortality in KD.³ However, approximately 10–20% of patients with KD are resistant to IVIG treatment and have an increased risk of developing CALs.⁴ Consequently, KD patients with an initial IVIG resistance are usually treated with additional IVIG or other interventions such as steroids, infliximab or plasma exchange. Thus, early identification of IVIG resistance is important to reduce the risk of CALs and lower the treatment costs.

Disorders of serum lipid metabolism are closely related to cardiovascular diseases and systemic inflammation.⁵ The serum lipid profile change during the acute phase of KD has been well documented.^6,7 However, the predictive value of serum lipid for CALs and IVIG resistance was extremely limited. Therefore, this retrospective cohort study was undertaken to evaluate the role of serum lipid profiles in predicting CALs and IVIG resistance in KD patients.

Patients and methods

Study design and population

This retrospective cohort study consecutively enrolled all patients with KD treated at the Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China between January 2016 and December 2019. The clinical diagnosis of KD (including complete and incomplete KD) was made according to the criteria of the American Heart Association guideline from 2017.¹ One experienced KD specialist (at least 5 years of clinical expertise in KD) confirmed the diagnosis. Complete KD was diagnosed in children with a fever who also had four or more of the following clinical features: (i) mucosal changes (erythema and cracking of lips, strawberry tongue, erythema and prominent fungiform papillae, and/or erythema of the oral and pharyngeal mucosa); (ii) conjunctivitis; (iii) polymorphous rash; (iv) extremity changes; (v) acute, non-suppurative, cervical lymphadenopathy. Incomplete KD was defined as a child with a fever with less than four major symptoms and compatible laboratory or echocardiographic findings.¹

The inclusion criteria were as follows: (i) patients were ≤18 years old; (ii) patients first diagnosed with KD; (iii) patients received standard treatment with IVIG 2 g/kg as a single infusion in the acute phase within 10 days. The exclusion criteria were as follows: (i) recurrent KD; (ii) patients who had received IVIG in the 3 months prior to admission; (iii) patients who did not receive IVIG or the initial dose was <2 g/kg; (iv) lack of the clinical or laboratory information; (v) patients with a family history of hyperlipidaemia, or those using medications influencing on lipid values, as steroids, thiazides and propranolol; (vi) liver, kidney impairment or an abnormal body mass index (BMI). BMI categories were based on Centers for Disease Control and Prevention guidelines for age and sex-specific BMI percentiles. Abnormal BMI includes underweight, overweight and obese. Patients within the BMI percentile ≤5th were underweight; those with BMI > 85th and ≤95th percentile were overweight; and those with BMI > 95th percentile were obese; (vii) uncertain diagnoses that cannot be distinguished from other diseases, such as septicaemia and juvenile idiopathic arthritis.

The Chengdu Women’s and Children’s Central Hospital Ethics Committee approved the study protocol (Approval No. B202215) and waived the requirement for informed consent. All methods were carried out in accordance with the Declaration of Helsinki. This study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.⁸ Data that could be used to identify patients or care providers were removed to protect the confidentiality of patients.

Group assignment

Patients who met the inclusion criteria were divided into two groups based on their response to initial IVIG treatment: IVIG-responsive and IVIG-resistant groups. Initial IVIG resistance was defined as those with persistent fever for at least 36 h after the first IVIG infusion.¹ For CALs, the patients were classified into two groups: the CALs group and the non-CALs group. An echocardiographer performed echocardiography to detect CALs during hospitalization. CALs were defined as Z scores on the normalization of dimensions for body surface area. The coronary artery abnormalities were defined as follows:¹ (i) no involvement: Z score <2.0; (ii) only dilation: Z score 2 to <2.5; (iii) small coronary aneurysm: Z score ≥2.5 to <5; (iv) medium coronary aneurysm: Z score ≥5 to <10, and absolute dimension <8 mm; (v) large or giant coronary aneurysm: Z score ≥10, or absolute dimension ≥8 mm. Patients with a Z score ≥2.0 were considered to be CALs. The Z-score was measured using a previously published formula.⁹ If more than one echocardiography was performed, the maximum Z-scores of the left main coronary artery, left anterior descending coronary artery, left circumflex artery and right coronary artery were chosen.

Treatment protocol

All KD patients received the same standard treatment with a single 2 g/kg dosage of IVIG and aspirin (30–50 mg/kg per day during the acute phase of illness) during the acute phase. The aspirin was lowered to 3–5 mg/kg per day after the patients were afebrile. No additional treatment, including infliximab or plasma exchange, was considered in the standard treatment protocol. Combined antiplatelet and anticoagulation therapy was recommended for patients with giant aneurysms.

Data collection

All data were extracted from the electronic medical system, including demographic, laboratory data and clinical outcomes. Laboratory data of venous blood samples were collected from the patients during the acute stage of the disease before initial IVIG treatment.

Statistical analyses

All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 25.0 (IBM Corp., Armonk, NY, USA). The Kolmogorov–Smirnov test was used to determine the normality of the variable distribution. Continuous variables are presented as mean ± SD or median and interquartile range (IQR) if not normally distributed. Categorical variables are presented as frequency and proportion in each category. χ²-test or Fisher’s exact test was applied to compare categorical data. Student’s t-test or Mann–Whitney U-test was used for continuous data. Multivariate logistic regression analyses were performed to determine the risk factors of CALs and IVIG resistance in patients with KD. The receiver operating characteristic curve (ROC) was analysed to assess the predictive accuracy of the serum lipid profile and its validity in predicting both CALs and IVIG resistance. A subgroup analysis was performed on complete KD and incomplete Kawasaki disease. A P-value <0.05 was considered statistically significant.

Results

A total of 989 patients were diagnosed with KD during the study period (Figure 1). A total of 340 were excluded: 32 had recurrent KD, seven received initial IVIG dose <2 g/kg, five received steroids during the initial treatment and 296 had incomplete clinical or laboratory data. After exclusion, 649 KD patients (390 boys and 259 girls) who met the inclusion criteria were enrolled in this study, with 151 having CALs and 76 children having initial IVIG resistance.

Figure 1.

Flow diagram showing the progress through enrolment, inclusion and analysis of patients with Kawasaki disease (KD) who were enrolled in a retrospective cohort study undertaken to evaluate the role of serum lipid profiles in predicting coronary artery lesions (CALs) and intravenous immunoglobulin (IVIG) resistance.

The baseline demographic and clinical characteristics of the patients with KD stratified into the IVIG-responsive and IVIG-resistant groups are presented in Table 1. Of the 649 patients, 573 (88.29%) responded to IVIG treatment, whereas 76 (11.71%) were resistant to the initial IVIG. The prevalence of CALs in the IVIG-resistant group (28 of 76; 36.84%) was significantly higher than in the IVIG responsive-group (123 of 573; 21.47%) (P = 0.003). No significant differences were found in the sex, diagnosis, white blood cell (WBC) count, haemoglobin, erythrocyte sedimentation rate (ESR), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), apolipoprotein (Apo) A and Apo B between the IVIG-responsive and IVIG-resistant groups. The IVIG-resistant group had significantly older age and longer length of hospitalization than the IVIG-responsive group (P < 0.001 for both comparisons). Furthermore, the neutrophil %, C-reactive protein (CRP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the IVIG-resistant group were significantly higher than in IVIG-responsive group (P < 0.05 for all comparisons). The IVIG-resistant group had significantly lower platelet (PLT) count, lymphocyte % and low-density lipoprotein cholesterol (LDL-C) levels than the IVIG-responsive group (P < 0.05 for all comparisons). Similar results were found in the complete KD subgroup (see supplementary materials, Appendix S1). Moreover, a significant difference (P = 0.033) was observed in Apo A between the two groups in the complete KD subgroup. No significant differences were found in the laboratory data (except PLT count; P = 0.047) between the two groups in the incomplete KD subgroup analysis (see supplementary materials, Appendix S2).

Table 1.

Demographic and clinical characteristics of patients with Kawasaki disease (KD) (n = 649) stratified according to intravenous immunoglobulin (IVIG) resistance.

Characteristic	IVIG responsive-groupn = 573	IVIG-resistant groupn = 76	U or χ²	Statistical analyses^a
Age, months	23 (12–37)	33 (17–49)	−3.987	P < 0.001
Sex
Male	338 (58.99)	52 (68.42)	2.490	NS
Female	235 (41.01)	24 (31.58)
Diagnosis
Complete Kawasaki	533 (93.02)	71 (93.42)	0.017	NS
Incomplete Kawasaki	40 (6.98)	5 (6.58)
Length of hospitalization, days	7 (6–9)	12 (9–13)	−8.578	P < 0.001
Coronary artery lesions	123 (21.47)	28 (36.84)	8.886	P = 0.003
WBC count, ×10⁹/l	14.05 (11.38–17.72)	11.75 (8.86–16.30)	−1.244	NS
HB, g/l	108 (100–116)	107 (100–110)	−0.969	NS
PLT count, ×10⁹/l	338 (261–431)	319 (233–391)	−2.942	P = 0.003
NEUT %	66.0 (56.8–76.2)	76.7 (59.8–87.6)	−5.265	P < 0.001
LYMPH %	23.5 (15.7–32.7)	16.8 (9.7–28.5)	−4.976	P < 0.001
CRP, mg/l	78 (44–118)	101 (58–137)	−3.641	P < 0.001
ESR, mm/h	72 (49–92)	74 (48–95)	−1.44	NS
ALT, IU/l	29.8 (16.1–75.6)	38.2 (20.6–97.3)	−3.433	P = 0.001
AST, IU/l	33.8 (24.8–55.0)	41.0 (31.1–53.7)	−3.093	P = 0.002
TG, mmol/l	2.18 (1.39–3.51)	2.27 (1.42–3.85)	−0.195	NS
TC, mmol/l	2.33 (1.44–3.41)	2.13 (1.29–2.99)	−1.912	NS
HDL-C, mmol/l	0.88 (0.75–1.08)	0.82 (0.73–0.98)	−0.158	NS
LDL-C, mmol/l	1.78 (1.43–2.24)	1.70 (1.11–2.40)	−3.754	P < 0.001
Apo A, g/l	0.81 ± 0.22	0.76 ± 0.21	1.222	NS
Apo B, g/l	0.82 ± 0.19	0.81 ± 0.24	0.165	NS

Data presented as mean ± SD, median (IQR) or n (%).

χ²-test or Fisher’s exact test was applied to compare categorical data; Student’s t-test or Mann–Whitney U-test was used for continuous data; NS, not significant (P ≥ 0.0).

WBC, white blood cell; HB, haemoglobin; PLT, platelet; NEUT, neutrophil; LYMPH, lymphocyte; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TG, triglycerides; TC, total cholesterol; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; Apo A, apolipoprotein A; Apo B, apolipoprotein B.

A total of 151 KD patients had CALs and 498 did not have CALs. The baseline demographic and clinical characteristics of the patients with KD stratified into the CALs and non-CALs groups are presented in Table 2. There were no significant differences between the two groups in the diagnosis, WBC count, haemoglobin, PLT count, neutrophil %, lymphocyte %, ESR, ALT, AST, TG, TC, HDL-C and Apo A. The CALs group had significantly younger age, longer hospitalization and more males than the non-CALs group (P < 0.05 for all comparisons). IVIG resistance and CRP levels were significantly higher in the CALs group compared with the non-CALs group (P < 0.05 for both comparisons). The patients in the CALs group had significantly lower LDL-C levels (P < 0.001) and significantly lower Apo B levels (P = 0.043) compared with the non-CALs group. In the subgroup analysis of complete KD, the CALs group had significantly lower LDL-C and Apo B compared with the non-CALs group (see supplementary materials, Appendix S3) (P < 0.05 for both comparisons. No significant differences were found in the laboratory data between the two groups in the incomplete subgroup analysis (see supplementary materials, Appendix S4).

Table 2.

Demographic and clinical characteristics of patients with Kawasaki disease (KD) (n = 649) stratified according to the presence of coronary artery lesions (CALs).

Characteristic	CALs groupn = 151	Non-CALs groupn = 498	U or χ²	Statistical analyses^a
Age, months	20 (8–42)	22 (12–36)	−2.398	P = 0.016
Sex
Male	107 (70.86)	283 (56.83)	9.515	P = 0.002
Female	44 (29.14)	215 (43.17)
Diagnosis
Complete Kawasaki	132 (87.42)	470 (94.38)	1.105	NS
Incomplete Kawasaki	19 (12.58)	28 (5.62)
Length of hospitalization, days	8.00 (6.00–10.00)	6.00 (6.00–9.00)	−4.206	P < 0.001
Coronary artery lesions	28 (18.54)	48 (9.64)	8.886	P = 0.003
WBC count, ×10⁹/l	14.41 (10.97–16.08)	13.56 (10.30–15.70)	−0.415	NS
HB, g/l	106.62 ± 13.59	108.08 ± 11.31	−1.323	NS
PLT count, ×10⁹/l	340 (264–394)	326 (272–475)	−0.474	NS
NEUT %	63.9 (56.8–77.2)	65.6 (58.3–78.6)	−0.19	NS
LYMPH %	25.5 (16.9–32.0)	25.6 (15.5–32.5)	−0.048	NS
CRP, mg/l	113 (54–152)	42 (26–131)	−4.057	P < 0.001
ESR, mm/h	72.4 ± 31.14	69.51 ± 31.54	0.989	NS
ALT, IU/l	26.7 (19.7–79.9)	28.2 (17.5–63.1)	−1.581	NS
AST, IU/l	39.6 (24.9–67.3)	34.2 (24.8–64.7)	−0.503	NS
TG, mmol/l	1.97 (1.34–3.72)	3.34 (2.18–4.12)	−1.895	NS
TC, mmol/l	2.80 (1.43–3.58)	1.43 (1.13–2.73)	−0.211	NS
HDL-C, mmol/l	0.84 (0.76–1.08)	0.94 (0.73–0.98)	−1.153	NS
LDL-C, mmol/l	1.82 (1.21–2.16)	1.99 (1.71–2.26)	−3.205	P < 0.001
Apo A, g/l	0.78 (0.66–0.93)	0.78 (0.71–0.94)	−0.72	NS
Apo B, g/l	0.78 ± 0.18	0.83 ± 0.2	−2.029	P = 0.043

Data presented as mean ± SD, median (IQR) or n (%).

χ²-test or Fisher’s exact test was applied to compare categorical data; Student’s t-test or Mann–Whitney U-test was used for continuous data; NS, not significant (P ≥ 0.05).

Multivariate logistic regression analyses included statistically significant variables from the univariate analyses. The multivariate logistic regression analyses failed to demonstrate that serum LDL-C level (P = 0.554) was an independent initial IVIG-resistant risk factor (Table 3). Similarly, neither LDL-C (P = 0.248) nor Apo B (P = 0.108) was identified as an independent risk factor for CALs.

Table 3.

Multivariate logistic regression analysis of intravenous immunoglobulin (IVIG) resistance and coronary artery lesions in patients with Kawasaki disease (n = 649).

Variates	β	S.E.	Wald	P-value	OR	95% CI of OR
Variates	β	S.E.	Wald	P-value	OR	Lower	Upper
Initial IVIG resistance
Age	0.021	0.008	7.576	P = 0.006	1.022	1.006	1.037
Length of hospitalization	0.334	0.052	40.958	P < 0.001	1.396	1.260	1.546
PLT count	0.001	0.001	0.230	P = 0.631	1.001	0.998	1.003
NEUT%	0.019	0.015	1.600	P = 0.206	1.019	0.990	1.050
LYMPH%	0.011	0.015	0.531	P = 0.466	1.011	0.981	1.042
CRP	−0.001	0.003	0.048	P = 0.827	0.999	0.994	1.005
ALT	0.002	0.002	1.971	P = 0.160	1.002	0.999	1.005
AST	0.000	0.001	0.037	P = 0.848	1.000	0.998	1.003
LDL-C	0.163	0.276	0.351	P = 0.554	1.177	0.686	2.022
Coronary artery lesions
Age	−0.021	0.008	6.082	P = 0.014	0.980	0.964	0.996
Sex	0.729	0.319	5.226	P = 0.022	2.073	1.110	3.872
Length of hospitalization	0.074	0.053	1.962	P = 0.161	1.077	0.971	1.195
CRP	0.004	0.003	1.915	P = 0.166	1.004	0.998	1.010
LDL-C	0.569	0.493	1.335	P = 0.248	1.767	0.673	4.643
Apo B	−2.372	1.477	2.580	P = 0.108	0.093	0.005	1.686

OR, odds ratio; CI, confidence interval; PLT, platelet; NEUT, neutrophil; LYMPH, lymphocyte; CRP, C-reactive protein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDL, low-density lipoprotein cholesterol; Apo B, apolipoprotein B.

A ROC curve analysis was performed to identify the validity of the serum lipid profile in predicting initial IVIG resistance and CALs in patients with KD. The cut-off of LDL-C ≤1.71 mmol/l produced a sensitivity of 67.11% and a specificity of 57.42% for predicting IVIG resistance in KD patients. The area under the ROC curve (AUC) value of LDL-C was 0.632 (P < 0.001) (Figure 2a). In the subgroup of complete KD, the best cut-off values of LDL-C and Apo A for predicting IVIG resistance were ≤1.71 mmol/l and ≤0.79 g/l with AUCs of 0.621 (P = 0.001) and 0.622 (P = 0.034); yielding sensitivities of 66.20% and 76.00%, and specificities of 56.66% and 53.09%, respectively (Figure 2b).

Figure 2.

Receiver operating characteristic curve analyses of the predictive ability of serum lipids for intravenous immunoglobulin (IVIG) resistance and coronary artery lesions (CALs) in patients with Kawasaki disease (KD): (a) low-density lipoprotein cholesterol (LDL-C) for predicting IVIG resistance in KD patients; (b) LDL-C and apolipoprotein A (Apo A) for predicting IVIG resistance in the subgroup of complete KD; (c) LDL-C and Apo A for predicting CALs in KD patients and (d) LDL-C and Apo A for predicting CALs in the subgroup of complete KD. The colour version of this figure is available at: http://imr.sagepub.com.

The cut-off values of LDL-C and Apo B for predicting CALs were ≤1.42 mmol/l and ≤0.70 g/l, with AUC values of 0.586 (P = 0.001) and 0.572 (P = 0.060), respectively. The sensitivities were 35.76% and 40.79%, and the specificities were 78.11% and 73.97%, respectively (Figure 2c). Subgroup analysis revealed similar results in complete KD. The optimal cut-off values of LDL-C (AUC = 0.589, P = 0.001) and Apo B (AUC = 0.582, P = 0.044) in complete KD for predicting CALs were ≤1.42 mmol/l and ≤0.70 g/l; yielding sensitivities of 36.09% and 43.55%, and specificities of 77.49% and 73.30, respectively (Figure 2d).

Discussion

This current retrospective study aimed to evaluate the role of the serum lipid profile in predicting initial IVIG resistance and CALs in patients with KD. The study found that the KD patients with initial IVIG resistance have a significantly lower LDL-C level than those without IVIG resistance, which was also confirmed by the subgroup analysis. In addition, subgroup analysis showed that the IVIG-resistant group had a lower Apo A level than the IVIG-responsive group. Furthermore, KD patients with CALs had lower LDL-C and Apo B levels than the non-CALs KD patients. Subgroup analysis showed similar results in complete KD. However, multivariate logistic regression analysis failed to identify the serum lipid profile (LDL-C, Apo A or Apo B) as an independent risk factor for initial IVIG resistance or CALs in KD patients. These current results suggest that KD patients have dyslipidaemia in the acute phase and the serum lipid profile might not be suitable as a single predictor for initial IVIG resistance or CALs.

The most devastating complication of KD is CALs, which are speculated to be caused by acute systemic inflammation.¹⁰ CALs may lead to severe outcomes, including ischaemia, cardiogenic shock and sudden cardiac death.¹¹ IVIG is the first line of treatment in KD and has been known to be effective in abolishing vascular inflammation leading to CALs.⁴ Timely IVIG therapy plus aspirin can effectively lower the incidence of CALs.¹ However, approximately 10–20% of KD patients do not respond to the initial IVIG treatment and are at a higher risk of developing CALs.¹ Thus, the early prediction of IVIG resistance and CALs is the focus of considerable research in KD.¹² Several scoring systems for predicting IVIG resistance^13,14 and risk factors of CALs^15,16 have been extensively studied. Nevertheless, the low sensitivity and specificity in different populations limits the wide generality of those scoring systems.^17,18

In the present study, the prevalence of IVIG resistance and CALs were 11.71% and 23.27%, respectively, which was similar to previous reports.^19–21 This current study found that the IVIG-resistant group were significantly older; and they had significantly longer hospitalization and a significantly higher incidence of CALs compared with the IVIG-responsive group, which was in line with the previous studies.^22,23 The longer hospitalization might be due to the higher incidence of CALs and the requirement for additional therapies in IVIG non-responders. Moreover, the IVIG-responsive group had a significantly higher levels of neutrophil %, CRP, ALT and AST compared with the IVIG-responsive group, which indicates a more severe inflammatory response in KD patients with IVIG resistance during the acute phase.²⁴ Based on the findings of previous studies,^25,26 hepatic dysfunction is a common complication during the acute phase of KD and is characterized by elevated serum liver enzymes. Meanwhile, lymphocyte % and LDL-C were significantly lower in KD patients with IVIG resistance compared with the IVIG-responsive group. For CALs, LDL-C and Apo B levels were significantly lower than in those patients without CALs. Similar results were found in the subgroup analyses for the IVIG resistance and CALs in KD patients.

Accumulating evidence suggests a change in serum lipid profile during the acute phase or even during long-term follow-up among different KD populations,^6,27–29 which is also confirmed in the present study. A study published in 1982 first reported the abnormalities of serum lipids in KD.³⁰ The study found total serum cholesterol, LDL-C and HDL-C decreased in the acute phase.³⁰ Further studies showed similar results that showed that HDL-C, LDL-C and Apo A were significantly reduced during the early stage of KD.^31–33 The current findings about LDL-C and Apo A levels in IVIG-resistant KD patients were similar to a recent study,³⁴ which demonstrated that LDL-C and Apo A concentrations were significantly reduced in initial IVIG-resistant and repeated IVIG-resistant patients. As for KD patients with CALs in the current study, lower LDL-C and Apo B levels were observed, which was compatible with a previous study that reported that coronary artery disease occurs at much lower levels of LDL-C in Asian Indians.³⁵ The reason for the decrease in LDL-C level in KD remains unknown. One possible explanation is the involvement of LDL-C oxidization in the pathogenesis of vasculitis, leading to LDL-C consumption in acute inflammation.³⁶ Alterations in lipid profile are believed to cause endothelial dysfunction that may occur many years after KD.³⁷ LDL can be oxidized and modified into oxidized low-density lipoprotein (oxLDL) under oxidative stress, which can bind to lectin-like Ox-LDL receptor 1 (LOX-1), causing vascular endothelial damage.³⁸ The interaction between oxLDL and LOX-1 mediates the endocytosis and degradation of oxLDL by endothelial cells and activates a series of intracellular signalling pathways, such as p38MAPK/NF-κB and reactive oxygen species.³⁹ Furthermore, the Z-scores of the coronary artery were positively correlated with plasma oxLDL concentration and LOX-1 mRNA expression, suggesting that endothelial dysfunction is more pronounced in KD with CALs.⁴⁰ The coronary artery involvement in KD is more likely to lead to LDL-C oxidization and oxLDL formation. Thus, the lower LDL-C levels in KD patients with IVIG resistance or CALs seem to be reasonable considering IVIG-resistant KD patients tend to have a higher risk of CALs. Additionally, Apo A and Apo B are the major protein constituents of HDL-C and LDL-C, respectively. Therefore, the simultaneous reduction of these four indicators is a consistent finding.

However, multivariate logistic regression analysis failed to identify the serum lipid profile (LDL-C, Apo A or Apo B) as an independent risk factor for initial IVIG resistance or CALs. The discrepancy between the univariate and multivariate regression analysis results might be related to the normative values of LDL-C and Apo B. The mean values of LDL-C and Apo B were still within the normal range in this current study, although KD patients with IVIG resistance had a significantly lower level of LDL-C and Apo B than the IVIG-responsive patients. The current results indicate that the predictive abilities of the above parameters as a single marker were insufficient. Therefore, a prediction model combined with various parameters might be more reliable, considering other factors may easily influence a single inflammatory parameter. Some serum lipid profiles, such as LDL-C, could be complementary laboratory markers for predicting initial IVIG resistance and CALs.

This current study had several limitations. First, selection or information bias may exist, considering this retrospective cohort study was performed in one institution. Secondly, all participants were Chinese, which limits the generalizability of the results. Therefore, multicentre prospective studies including different ethnic groups are needed to verify the present results. Thirdly, the study only evaluated the coronary artery involvement in the acute phase. More information is needed during the follow-up, including the sub-acute and convalescent phases. Further studies should have a longer observational period from KD onset.

In conclusion, KD patients had dysregulated lipid profiles in the acute phase. LDL-C level was significantly lower in KD patients with IVIG resistance or CALs. None of the serum lipid profiles was identified as independent risk factors for either initial IVIG resistance or CALs. The serum lipid profile might not be suitable as a single predictor for initial IVIG resistance or CALs. Some serum lipid profiles, such as LDL-C, could be complementary laboratory markers for predicting initial IVIG resistance or CALs. Early detection of the serum lipid profile might provide valuable information for predicting severe outcomes and to guide further therapeutic strategies.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605241252115 - Supplemental material for The role of serum lipid in predicting coronary artery lesions and intravenous immunoglobulin resistance in Kawasaki disease: a cohort study

Supplemental material, sj-pdf-1-imr-10.1177_03000605241252115 for The role of serum lipid in predicting coronary artery lesions and intravenous immunoglobulin resistance in Kawasaki disease: a cohort study by Hongxi Zhang, Jianghui Cai, Rui Zhang, Shuping Shuai, Mi Tang, Rong Ju, Ying Hu, Tianrui Zuo and Yanfeng Yang in Journal of International Medical Research

Footnotes

Author contributions

Y.Y. had full access to all of the data in the study and was responsible for the study conception. H.Z., R.Z., S.S. and J.C. drafted the manuscript. M.T., R.J. and Y.H. had a role in collecting the data. T.Z. did the statistical analyses. All authors read and approved the final manuscript.

Declaration of conflicting interest

The authors declare that there are no conflicts of interest.

Funding

This manuscript was supported by grants from Chengdu Medical Research Project (no. 2023101), Sichuan Hospital Association Medical Management Branch (no. SCYW037) and Chengdu Medical Research Project (no. 2022065).

ORCID iD

Yanfeng Yang

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