Eosinophils Predicts Coronary Artery Dilatation and Long-term Prognosis in Children with Kawasaki Disease after Intravenous Immunoglobulin Therapy

doi:10.21203/rs.3.rs-2994670/v1

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Eosinophils Predicts Coronary Artery Dilatation and Long-term Prognosis in Children with Kawasaki Disease after Intravenous Immunoglobulin Therapy

https://doi.org/10.21203/rs.3.rs-2994670/v1

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Background: Coronary artery dilation is the main cause of poor prognosis in children with Kawasaki disease. Whether eosinophils can predict coronary artery dilation and long-term prognosis in children after intravenous immunoglobulin (IVIG) treatment for Kawasaki disease (KD).

Methods: From January 2018 to December 2020, a total of 664 children with Kawasaki disease were continuously enrolled.

Results: With a sensitivity of 77.78% and a specificity of 74.38%, the optimal cut-off value for predicting coronary artery dilatation is eosinophils ≥ 0.24. According to the cut-off value, the children were separated into two groups: eosinophils<0.24 group (n = 461) and eosinophils ≥ 0.24 group (n = 203). Eosinophils ≥ 0.24 as the ideal cut-off value for predicting cardiovascular death with an area under the curve (AUC) of 0.772 [95% confidence interval (CI): 0.720 ~ 0.823, P < 0.001], a sensitivity of 72.88%, and a specificity of 78.57%. The incidence of cardiovascular death, heart failure and multiple organ dysfunction was greater in the eosinophils ≥ 0.24 group, although there was no significant difference in the incidence of pericarditis procedures following IVIG between the two groups. Eosinophils ≥ 0.24 was also an independent predictor of cardiovascular death (hazard ratio = 4.95, 95% confidence interval (CI):2.98 ~ 8.23, P < 0.001). However, eosinophils have a lower sensitivity (23.08%) for predicting the recurrence of Kawasaki disease.

Conclusion: eosinophils ≥ 0.24 was independently associated with coronary artery dilatation and poor clinical outcomes for children in Kawasaki disease after IVIG treatment.

eosinophils

coronary artery dilatation

prognosis

IVIG

1. Eosinophils had a relatively predictive value for coronary artery dilation.

2. Patients with eosinophils ≥ 0.24 had a remarkable increase in cardiovascular death, significantly increasing heart failure.

3. Eosinophils ≥ 0.24 was an independent predictor of long-term prognosis and coronary artery dilation in KD children after IVIG treatment.

Kawasaki disease (KD) is the most common cause of acquired heart disease in children in developed countries. Currently, intravenous immunoglobulin (IVIG) therapy remains the preferred treatment of choice for children with Kawasaki disease¹. Coronary artery dilation, a serious complication, still occurs in approximately 4% of children after IVIG therapy, and there are few effective treatment options². Consequently, early risk stratification in children with Kawasaki disease to identify high-risk individuals was crucial. We expected discovering an indicator capable that predicts the incidence and stratifies the long-term prognosis of coronary artery dilation in children with Kawasaki disease.

Eosinophils are developed in the bone marrow and play a homeostatic role in body³. Studies have shown an association between eosinophils and the development of coronary artery disease and prognosis in children with Kawasaki disease⁴. Eosinophils are associated with coronary artery disease and play a protective role in cardiovascular^5,6. We intend to determine if eosinophils may more accurately predict coronary artery dilatation and long-term prognosis in children with Kawasaki disease after IVIG treatment.

This is a retrospective, single-center cohort study. From January 2018 to December 2020, 664 KD children who underwent at Shengjing Hospital of China Medical University were selected consecutively. Inclusion criteria: the children were diagnosed with KD according to the 2019 guidelines for the diagnosis and treatment of KD as proposed by the American Heart Association (AHA)¹. Exclusion criteria: cardiogenic shock, severe hepatic and renal insufficiency, systemic immune disease, malignancy, hematological disorders. Our ethics committee at Shengjing Hospital of China Medical University approved this study (2018PS507K).

All hospitalized children underwent standard blood tests, ECG and cardiac ultrasound, and laboratory tests were reexamined after 3 days of IVIG treatment. We counted the results after 3 days of continuous IVIG treatment. A diagnostic color Doppler ultrasound with a child-size transducer was selected for the cardiac ultrasound examination, and measurements were diagnosed as coronary artery dilation with an intracoronary diameter > 3 mm in children under 5 years of age, coronary artery diameter > 5mm in children over 5 years old, and more than 1.5 times the proximal intracoronary diameter at one site⁷. Three cardiologists were blinded to this study and assessed for coronary artery dilatation. Our hospital information system had the baseline characteristics of the children. All the included children were recommended for post-discharge outpatient review to complete blood tests, ECG and cardiac ultrasound. The review schedule was: once a week for 1 month after onset, followed by reviews at the 2nd, 6th and 12th months.

All registered children received telephone follow-up. Cardiovascular death, coronary artery dilatation or coronary aneurysm, KD recurrence were the primary endpoints. Secondary endpoint included all cause death, heart failure, myocardial infarction, myocarditis, pericarditis, multiple organ function damage.

SPSS 23.0 software was used for statistical analysis. The normality test was used to determine whether the sample met the normal distribution. Normal distribution data was expressed by mean ± standard deviation, comparison between the two groups independent the t-test. Non normal distribution data was expressed by median (interquartile range), and the comparison between groups used Mann-Whitney U-test. Enumeration data were expressed as numbers (percentages), which were compared between groups using chi-square test. Receiver operating characteristic (ROC) curve analysis was applied to predict power and optimal cut-off value of eosinophils for cardiovascular death and coronary artery dilation. The Kaplan-Meier survival curve method was applied for survival analysis between the two groups and log-rank tests were applied for survival comparisons. Logistic regression was used to analyze independent risk factors for coronary artery dilation after IVIG treatment and Cox proportional hazards model was used to evaluate the effect of eosinophils on prognosis of patients. All tests were two-sided, P < 0.05 was regarded as statistically significant.

4.1 Inclusion criteria

Between 1 January 2018 and 31 January 2020, a total of 1035 children with KD were treated with IVIG in our center. Excluding 171 children with incomplete KD, 130 children with atypical KD, 9 children with cardiogenic shock, 7 children with severe liver and kidney insufficiency, 4 children with systemic immune diseases, 4 children with malignant tumors, 5 children with blood system diseases and 41 children with no routine test available, the final study cohort consisted of 664 children.

4.2 ROC curves obtain the cut-off value

In Fig. 1A, the ROC curve shows the significance of eosinophils in predicting long-term prognosis of KD children after IVIG treatment. The area under the curve (AUC) of eosinophils predict cardiovascular death was 0.772 (95% CI: 0.720 ~ 0.823, P < 0.001), with a sensitivity of 72.88% and a specificity of 78.57%. According to the cut-off value, we classified the 664 children into two groups: eosinophils ≥ 0.24 group and eosinophils < 0.24 group.

Figure 1A shows the predictive usefulness of eosinophils for cardiovascular mortality. The best cut-off value was eosinophils ≥ 0.24 with a sensitivity 72.88% and specificity 78.57%. There was no statistical difference between eosinophils and NT-proBNP in predicting cardiovascular death (Z = 0.02, 95% CI: -0.068 ~ 0.069, P = 0.988). Previous studies have showed that serum NT-proBNP predicts early coronary artery dilation in the hyperacute phase of KD⁸, which is consistent with our findings. According to the Delong test NT-proBNP was superior to eosinophils in its ability to predict coronary artery dilation, with statistically significant differences (Z = 2.17, 95% CI: 0.008 ~ 0.156, P = 0.030). We also found that there is no statistically difference between eosinophils and NT-proBNP in predicting KD recurrence (Z = 0.21, 95% CI: -0.141 ~ 0.175, P = 0.833)

4.3 Baseline characteristics of KD children

Table 1 summarized the baseline characteristics of the patients. The children with eosinophils ≥ 0.24 group were predominantly male. Heart rate, hemoglobin, platelets, C-reactive protein, erythrocyte sedimentation rate, transaminase, creatine kinase-MB, and blood creatinine values did not differ across groups. Compared to the eosinophils < 0.24 group, the eosinophils ≥ 0.24 group tended to be younger, as well as higher leukocytes, neutrophils, and NT-proBNP levels. The eosinophils ≥ 0.24 group exhibited more clinical symptoms, and a large incidence of coronary artery dilatation in color Doppler ultrasound.

Table 1

Baseline clinical characteristics.
Variables	Total (n = 664)	Eosinophils < 0.24 (n = 461)	Eosinophils ≥ 0.24 (n = 203)	p-value
Age (years)	4.11 ± 2.20	4.37 ± 2.12	3.52 ± 2.26	＜0.001
Male	323 (48.6)	212 (46.0)	111 (54.7)	0.039
Heart rate (beat/min)	118.58 ± 27.04	118.36 ± 28.12	119.06 ± 24.41	0.760
WBC (10⁹/L)	13.20 ± 5.70	12.31 ± 5.32	15.24 ± 6.02	＜0.001
Neutrophils(10⁹/L)	9.43 ± 4.03	9.11 ± 3.86	10.16 ± 4.31	0.002
Eosinophils(10⁹/L)	0.21 ± 0.11	0..15 ± 0.05	0.34 ± 0.07	＜0.001
Hemoglobin (g/L)	130.25 ± 8.91	130.21 ± 8.86	130.33 ± 9.04	0.871
Platelet(10⁹/L)	281.61 ± 41.92	280.24 ± 37.18	284.74 ± 50.94	0.203
CRP (mg/L)	55.95 ± 51.19	55.29 ± 50.79	57.45 ± 52.08	0.618
ESR (mm/h)	52.38 ± 25.50	53.25 ± 25.49	50.41 ± 25.42	0.187
ALT (U/L)	27.08 ± 8.85	26.87 ± 9.01	27.54 ± 8.45	0.370
AST (U/L)	24.31 ± 6.58	24.21 ± 6.30	24.54 ± 7.18	0.552
Cre (umol/L)	28.56 ± 5.63	28.75 ± 5.54	28.13 ± 5.81	0.195
Urea (mmol/L)	4.30 ± 1.00	4.30 ± 0.96	4.32 ± 1.08	0.828
CK-MB (U/L)	12.40 ± 6.00	12.52 ± 5.96	12.11 ± 6.08	0.411
NT-proBNP (pg/ml)	244.74 ± 165.23	158.57 ± 96.88	375.00 ± 188.32	＜0.001
Left coronary dilatation	47 (7.1)	12(2.6)	35(17.2)	＜0.001
Right coronary dilatation	36 (5.4)	7(1.5)	29(14.3)	＜0.001
Cervical lymphadenopathy	225 (33.9)	75(16.3)	150(73.9)	＜0.001
Polymorphous exanthema	531 (80.0)	228(49.5)	203(100)	＜0.001
Fissure lips	544 (81.9)	353(76.6)	191(94.1)	＜0.001
Strawberry tongue	546 (82.2)	345(74.8)	201(99.0)	＜0.001
Indurations of extremities	530 (79.8)	329(71.4)	201(99.0)	＜0.001

Data are presented as n (%), median (IQR), or mean ± SD. WBC, white blood cell; CRP, C reacted protein; ESR, erythrocyte sedimentation rate; ALT, glutamic pyruvic transaminase; AST, aspartate transaminase; Cre, creatinine; CK-MB, creatine phosphokinase-MB; NT-proBNP, N-terminal pro brain natriuretic peptide. Bold values means P < 0.05.

4.4 Logistic regression analysis to predict coronary artery dilation

Analysis using univariate logistic revealed that age, leukocytes, eosinophils ≥ 0.24, NT-proBNP can predict coronary artery dilatation. In Table 2, age(OR = 0.81, 95% CI: 0.69 ~ 0.97, P = 0.024), eosinophils ≥ 0.24 (OR = 1.96, 95% CI: 1.65 ~ 3.75, P = 0.017) and NT-proBNP (OR = 1.01, 95% CI: 1.01 ~ 1.01, P < 0.001) remained independent predictors based on the results of multivariate logistic regression (Table 2).

Table 2

Logistic regression analyses for coronary dilatation
Variable	Un-adjusted OR(95% CI)	p-value	Adjusted OR(95% CI)	p-value
Age	0.76(0.65 ~ 0.88	< 0.001	0.81(0.69 ~ 0.97)	0.024
Male	1.36(0.81 ~ 2.29)	0.250	-	-
Heart rate	1.01(1.00 ~ 1.01)	0.328	-	-
WBC	1.04(1.00 ~ 1.09)	0.049	0.94(0.85 ~ 1.04)	0.252
Neutrophils	1.05(0.99 ~ 1.12)	0.129	-	-
Eosinophils ≥ 0.24	10.16(5.46 ~ 18.91)	< 0.001	1.96(1.65 ~ 3.75)	0.017
Hemoglobin	0.98(0.95 ~ 1.01)	0.190	-	-
Platelet	1.00(0.99 ~ 1.00)	0.466	-	-
CRP	1.00(1.00 ~ 1.01)	0.108	-	-
ESR	1.00(0.99 ~ 1.01)	0.499	-	-
ALT	1.00(0.98 ~ 1.03)	0.786	-	-
Cre	1.04(1.00 ~ 1.09)	0.061	-	-
CK-MB	0.98(0.94 ~ 1.02)	0.310	-	-
NT-proBNP	1.01(1.01 ~ 1.01)	< 0.001	1.01(1.01 ~ 1.01)	< 0.001

WBC, white blood cell ; CRP, C reacted protein;ESR, erythrocyte sedimentation rate; ALT, glutamic pyruvic transaminase; Cre, creatinine; CK-MB, creatine phosphokinase-MB; NT-proBNP, N-terminal pro brain natriuretic peptide

Bold values mean P < 0.05.

4.5 Eosinophils predict clinical outcome

Table 3 shows the adverse clinical results that occurred after a median follow-up time of 11 (Q1-Q3: 9–15) months. Patients in the eosinophils < 0.24 group experienced a total of 32 episodes of cardiovascular death, including 22 cases of pericarditis, 17 cases of worsening heart failure, and 8 cases of multiple organ dysfunction, 35 KD recurrences. In eosinophils ≥ 0.24 group, there were 86 cases of cardiovascular death occurred, including 12 cases of pericarditis, 47 cases of worsening heart failure, 10 cases of multiple organ dysfunction, and 17 cases of KD recurrence.

Table 3

Long-term follow-up outcomes.
Variables	Eosinophils < 0.24 (n = 461)	Eosinophils ≥ 0.24 (n = 203)	p-value
Cardiovascular death	32(6.9)	86(42.4)	＜0.001
Pericarditis	22(4.8)	12(5.9)	0.851
Heart failure	17(3.9)	47(23.2)	＜0.001
Multiple organ function damage	8(1.7)	10(4.9)	0.044
KD recurrence	35(7.6)	17(8.4)	0.995

Bold values mean P < 0.05.

4.6 Eosinophils predict prognosis

In terms of cardiovascular death, heart failure and multiple organ dysfunction, there were statistically significant differences between the two groups. Nevertheless, there was no difference in KD recurrence after IVIG treatment. The Kaplan-Meier method revealed that the risk of cardiovascular death, heart failure and multiple organ function was significantly higher in eosinophils ≥ 0.24 group than in the eosinophils < 0.24 group (P < 0.05, Figs. 2A,B,D), while the risk of KD recurrence after IVIG treatment was not statistically different between the two groups (P = 0.133, Fig. 2C).

4.7 Cox regression analysis to predict long-term prognosis

Analysis using univariate cox revealed that age, male, leukocytes, neutrophils, eosinophils ≥ 0.24, NT-proBNP and coronary artery dilation are risk factors for cardiovascular death. In Table 4, eosinophils ≥ 0.24 (OR = 4,95, 95% CI: 2.98 ~ 8.23, P < 0.001) and coronary artery dilatation (OR = 8.87, 95% CI: 5.79 ~ 13.61, P < 0.001) are independent risk factors for cardiovascular death based on the results of multivariate cox regression (Table 4).

Table 4

Cox regression of long-term prognosis.
Variables	Un-adjusted OR(95% CI)	p-value	Adjusted OR(95% CI)	p-value
Age	0.84(0.76 ~ 0.93)	0.001	0.98(0.89 ~ 1.07)	0.607
Male	1.48(1.02 ~ 2.13)	0.037	1.33(0.91 ~ 1.93)	0.140
Heart rate	1.00(0.99 ~ 1.01)	0.602	-	-
WBC	1.05(1.02 ~ 1.08)	0.002	1.02(0.97 ~ 1.09)	0.439
Neutrophils	1.05(1.00 ~ 1.10)	0.033	1.00(0.92 ~ 1.08)	0.953
Eosinophils ≥ 0.24	7.69(5.07 ~ 11.67)	< 0.001	4.95(2.98 ~ 8.23)	< 0.001
Hemoglobin	0.98(0.96 ~ 1.00)	0.055	-	-
Platelet	1.00(0.99 ~ 1.00)	0.169	-	-
CRP	1.00(1.00 ~ 1.01)	0.479	-	-
ESR	1.00(1.00 ~ 1.01)	0.309	-	-
ALT	1.00(0.98 ~ 1.02)	0.645	-	-
Cre	1.00(0.97 ~ 1.03)	0.996	-	-
CK-MB	1.02(0.99 ~ 1.05)	0.197	-	-
NT-proBNP	1.00(1.00 ~ 1.00)	< 0.001	1.00(1.00 ~ 1.00)	0.270
Coronary artery dilatation	14.30(9.81 ~ 20.86)	< 0.001	8.87(5.79 ~ 13.61)	< 0.001

WBC, white blood cell;CRP, C reacted protein; ESR, erythrocyte sedimentation rate; ALT, glutamic pyruvic transaminase; Cre, creatinine; CK-MB, creatine phosphokinase-MB; NT-proBNP, N-terminal pro brain natriuretic peptide

Bold values means P < 0.05.

The study’s key findings were as follows: (1) Eosinophils had a relatively predictive value for coronary artery dilation, moreover, patients with eosinophils ≥ 0.24 had a remarkable increase in cardiovascular death, significantly increasing heart failure, and (2) Eosinophils ≥ 0.24 was an independent predictor of long-term prognosis and coronary artery dilation in KD children after IVIG treatment.

Previous study has found that baseline echocardiography and body surface area adjusted for clinical variables (Z score) predict the presence of advanced coronary artery aneurysms⁹. Carotid intima-media thickness and ankle-brachial index have been correlated with coronary artery dilation¹⁰. The number of coronary interventions can also be used as a reference for early prediction of coronary artery dilatation, and the combination of testing with age, IgM and IgA can improve the accuracy and sensitivity of prediction¹¹. However, these methods are more cumbersome and expensive than laboratory markers. Therefore, we have focused our predictive tools on laboratory markers. Previous study on laboratory markers has focused on acute phase reactant levels¹², neglecting the clinical role of eosinophils in blood cells.

Eosinophils may affect wound healing and epithelial remodeling¹³. A series studies have proven eosinophils maintain a tendency to be elevated in patients with cardiac X syndrome¹⁴ and may be used to predict left atrial thrombosis in patients with atrial fibrillation¹⁵. The immune system makes an important contribution to normal cardiac function and response to injury¹⁶. Pentraxin 3, a major component of the innate immune system, may be used as a predictor of IVIG resistance and subsequent coronary artery dilation formation in patients with KD¹⁷, and eosinophils accumulation may reflect the immune response to Kawasaki disease-related antigens in affected children¹⁸. Previous study found an important role for eosinophils in the diagnosis of Kawasaki disease, so we speculated whether eosinophils could also be used as a prognostic indicator for Kawasaki disease.

Coronary artery dilation is one of the most important problems following IVIG treatment. It is a risk factor for myocardial infarction in early adulthood¹⁹ and may lead to long-term cardiac sequelae in children with Kawasaki disease in adulthood²⁰. The pathophysiological mechanisms underlying coronary artery dilation are not fully understood, but may be related to immune cell infiltration and activation of the coronary artery wall²¹. In our study, eosinophil is a predictor of coronary artery dilation, with a sensitivity of 77.78% and a specificity of 74.38%.

We were not surprised that NT-proBNP levels could predicted the occurrence of long-term adverse clinical outcomes in children with Kawasaki disease, as previous studies had shown that NT-proBNP values correlate with cardiac systolic and diastolic function, and electrocardiographic changes²². Our investigation demonstrated that eosinophil was the best cut-off value for predicting cardiovascular death, with a sensitivity of 72.88% and specificity of 78.57%. Kaplan-Meier survival analysis showed that patients with KD with eosinophils ≥ 0.24 were more likely to have cardiovascular death, heart failure and multiple organ impairment, even if the incidence of KD recurrence was not statistically between the two groups (P = 0.313). This may be due to the relationship between KD recurrence and infection, resistance and genetic polymorphisms²³.

Eosinophils produce granular proteins and chemical mediators that may cause tissue damage, play a homeostatic role in the body's immune response and are targets for therapeutic intervention. In addition to glucocorticoids, immunosuppressants are emerging as a new approach to directly or indirectly target eosinophil therapy³. The commonly used immunosuppressant cyclophosphamide, which acts on the cell cycle and affects DNA synthesis, may be able to prevent further coronary artery dilation²⁴. Another immunosuppressant, cyclosporine, also reduces the occurrence of coronary artery dilation²⁵. Infliximab, which is directly cytotoxic to immune cells, similarly decreases the risk of coronary aneurysms²⁶. Therefore, children at high risk of Kawasaki disease can improve their prognosis by controlling their immune levels. Owing to the side effects of this kind of drugs, the specific application needs to be further investigated.

Our study also suffers from the following shortcomings: Firstly, it is a single-center retrospective analysis with an inherent bias in the study design and a limited number of patients. Second, there is a lack of basic experimental studies on the mechanisms of eosinophilia in KD.

Due to its excellent specificity, eosinophils can be used as an indicator of risk stratification for poor prognosis, as identified in our study. I believe that this value has many uses, especially in predicting coronary artery dilation. Early intervention for coronary artery dilation and poor prognosis can help improve the prognosis of children with KD and be used to guide the clinical treatment.

Author Contributions: Conceptualization, J.S. and C.S.; methodology, J.S. and C.S.; validation, J.S. and J.W.; formal analysis, X.C., J.Q. and L.H.; investigation, X.C., J.Q. and L.H.; data curation, Q.Z., C.G. and J.J.; writing—original draft preparation, J.S. and C.S.; writing—review and editing, J.S. and J.W.; supervision, J.S. and J.W. All authors have read and agreed to the published version of the manuscript.

Ethical Approval and Trial Registration Statements: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Shengjing Hospital (2018PS507K).

Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patients to publish this paper.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data Availability Statement: The data underlying this article will be shared on reasonable request to the corresponding author

Conflict of Interest Statement: The authors declare no conflict of interests.

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No competing interests reported.

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Eosinophils Predicts Coronary Artery Dilatation and Long-term Prognosis in Children with Kawasaki Disease after Intravenous Immunoglobulin Therapy

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Abstract

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Highlights

1. Introduction

2. Materials and methods

3. Statistical analysis

4. Results

4.1 Inclusion criteria

4.2 ROC curves obtain the cut-off value

4.3 Baseline characteristics of KD children

4.4 Logistic regression analysis to predict coronary artery dilation

4.5 Eosinophils predict clinical outcome

4.6 Eosinophils predict prognosis

4.7 Cox regression analysis to predict long-term prognosis

5. Discussion

6. Conclusion

Declarations

References

Additional Declarations

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