Received Date : 14-Nov-2016

Revised Date : 03-Jan-2017

Accepted Article
Accepted Date : 11-Jan-2017

Article type : Original Articles

A high neutrophil to lymphocyte ratio is associated with refractory

Kawasaki disease

Hong-Je Cho, So Young Bak, Su Yeong Kim, Rita Yoo, Hae-Sung Baek, Seung Yang, Il-Tae

Hwang, Ji-Eun Ban, MD*,

Department of Pediatrics, Hallym University Medical Center, Seoul, Republic of Korea

Category of manuscript: Original article

Short title: Neutrophil to Lymphocyte ratio in Kawasaki disease

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/ped.13240

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 * Corresponding Author: Ji-Eun Ban, MD, PhD

Department of Pediatrics, Hallym University Medical Center, Seoul, Republic of Korea

Accepted Article
150, Seongan-ro, Kangdong-gu, Seoul, Korea 05355

TEL: +82-2-2224-2251, FAX: +82-2-482-8334

E-mail: jeban@naver.com

Abstract

Background: The clinical significance of the neutrophil to lymphocyte ratio (NLR) has not

yet been fully elucidated in patients with Kawasaki disease (KD). The purpose of this study is

to investigate the relationship between NLR and the response to intravenous immunoglobulin

(IVIG) therapy affecting coronary abnormalities in KD

Methods: A total of 196 patients of KD who were treated with IVIG therapy were analyzed.

We evaluated the baseline NLR immediately before IVIG therapy and classified the study

patients into 2 groups according to the value of the NLR. The clinical data, other

inflammatory biomarkers, and coronary complications were also assessed.

Results: Patients with an NLR ≥ 5 had a greater incidence of IVIG refractoriness than the

NLR < 5 group (31.7 % vs. 4.3 %, P < 0.001). However, this was not related to the

development of coronary abnormalities in KD. The differences in NLR pre- and post- IVIG

were significantly decreased in coronary abnormality group (2.65 ± 1.88 vs. 3.81 ± 2.55, P =

0.042). In a multivariate analysis, high NLR and CRP were independent predictors for IVIG

refractoriness during the acute phase in patients with KD (P = 0.032 in NLR; P = 0.029 in

CRP, respectively).

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 Conclusions: The high NLR was closely associated with the resistant IVIG therapy, but it

was not related to the occurrence of coronary abnormalities in patients with KD. However,
Accepted Article
the lessened decrement of the NLR before and after IVIG therapy was significantly

demonstrated in coronary artery abnormalities.

Key Words: Kawasaki disease, Neutrophil to lymphocyte ratio

Introduction

Although intravenous immunoglobulin (IVIG) has been approved for the standard treatment

of Kawasaki disease (KD) in its acute phase, [1,2] a substantial number of patients

experience symptomatic refractoriness following initial IVIG treatment. [3,4] Refractory KD

has a potential risk of coronary artery complication. Therefore, the prediction of IVIG-

resistant KD is important for assessing the coronary involvement. Previously, several

inflammatory predictors related to the refractory KD were reported, such as neutrophil count,

erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), lactate dehydrogenase (LD),

and serum ferittin, which has been demonstrated as a parameter related to the systemic

inflammation. [3-6] Recently, the neutrophil to lymphocyte ratio (NLR) was reported as a

biomarker of systemic inflammation in adult patients with coronary artery disease. [7,8]

However, little data about the NLR exists regarding the predictors of clinical outcome in

patients with KD. [9,10] The recent data demonstrated that the NLR can be used for risk

stratification and as a predictor of coronary aneurysm development in KD. The aims of this

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 study are to investigate whether the high NLR before IVIG therapy affects the clinical course

and to identify the relationship between these variables and coronary abnormalities.
Accepted Article
Methods

Study population

A total of 196 patients who were treated with IVIG therapy for KD between January 2010

and June 2016 were analyzed retrospectively. We excluded the patients without IVIG

therapy, although the diagnosis was acceptable. The diagnosis of KD was established in

patients who fulfilled the diagnostic criteria of KD. Incompete KD was diagnosed if the

patients had symptoms were associated with KD and were compitable to the inflammatory

biomarker criteria. [1]

The included patient population was composed of 173 (88.3 %) in the IVIG responsive group

and 23 (11.7 %) in the IVIG resistant group. All of the patients were initially treated with

IVIG (2 g/kg) for 12 hours and additionally treated with IVIG in case of IVIG resistance.

IVIG resistance was defined as a persistent or recrudescent fever for > 48 hours after initial

IVIG completion. In the case of recurrent or persistent fever with twice IVIG therapy, we

managed with the fever with methylprednisolon pulse therapy or infliximap. After the acute

phase, all patients have were given low dose aspirin for 8 weeks. Low dose aspirin was

discontinued unless the coronary artery abnormalities persisted. Transthoracic

echocardiography was performed to define cardiac complications including coronary

abnormalities. In total, 119 (76.3 %) patients were given a respiratory viral study before IVIG

therapy. Laboratory details of each patient, clinical outcomes, and complication rates were

reviewed.

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 Inflammatory marker analysis

Prior to and after the IVIG treatment, all patients were evaluated for their total white blood
Accepted Article
cell, neutrophil and lymphocyte counts, ESR, CRP, LD, creatin kinase (CK), and B type

natriuretic peptide (BNP). We also assessed the NLR before and 2 days after IVIG therapy.

To evaluate the impact of the NLR associated with the effective IVIG therapy, we

categorized study patients as either IVIG resistant or IVIG responsive groups. In addition, we

also classified the subjects to the cut-off ratio of the NLR on the basis of the receive-

operating characteristics (ROC) curve. Then, we reclassified the study patient according to

the cutoff value of the NLR and reanalyzed the relationship between predicting variables and

coronary abnormality.

Coronary abnormalities analysis

All patients received transthoracic echocardiography to define the involvement of the

coronary arteries during the acute phase and were evaluated at an outpatient clinic at 2-3

weeks and 8 weeks. A 12-lead ECG was also performed to assess electrical abnormalities.

The coronary abnormalities analysis by echocardiography was performed off-line

retrospectively. Echocardiographic recordings at 3 different times were reviewed for each

patient. The measurement was collected at the left main coronary artery, left anterior

descending artery and right coronary artery. To identify the coronary abnormalities, we

assessed the Z value of coronary arteries according to the body surface area. We defined the

coronary abnormalities as coronary z score more than 2.5, the presence of wall irregularity,

no acute tapering of the coronary artery branch or a saccular or diffuse coronary aneurysm.

Coronary aneurysms were classified as small (< 5mm- internal diameter) medium (5- to 8-

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 mm internal diameter) or giant (>8-mm internal diameter). [1] In addition, we assessed the

valve regurgitation, the pericardial effusion, and ventricular dysfunction in each patient to
Accepted Article
assess the other cardiac complication of KD.

Statistical analysis

Continuous variables were expressed as the means ± standard deviation and categorical

variables as either a number or percentage. For continuous variables, the comparisons were

performed using Student’s t-test. Categorical variables were compared using the Fisher’s

exact test, or chi-square analysis, as appropriate. The area under the ROC curve was used to

evaluate the discrimination of prediction of IVIG non-responder and then to derive sensitivity

and specificity values for the NLR. The cutoff value of the NLR parametric variable was

determined by the ROC curve. The patients were divided into high and low NLR groups by

the cutoff value. Cox regression analysis was used to analyze the risk factor of IVIG resistant

and coronary abnormalities after IVIG therapy. A P-value ≤ 0.05 was considered statistically

significant.

Results

High NLR is associated with IVIG resistance but not coronary abnormalities

Among the total of 196 patients with KD, the mean age was 32 ± 21 months, and 59.2 %

were male. Twenty three patients (11.8 %) were included in the IVIG resistant group and

others were included in the IVIG responsive group. There were no significant differences in

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 age, sex, type of KD, and fever duration between the two groups. The IVIG resistant group

had a significantly increased total WBC count, neutrophil count and ratio compared with
Accepted Article
those in the IVIG responsive group (16.23 ± 5.29 *103/µL vs. 12.92 ± 4.34 *103/µL, P =

0.006 in total WBC count; 12.43 ± 5.47*103/µL vs. 8.46 ± 3.66 *103/µL, P = 0.002 in

neutrophil count; 74.79 ± 13.35 % vs. 64.18 ± 14.61 %, P = 0.002 in neutrophil ratio,

respectively). In addition, the NLR was much higher in patients in the IVIG resistant group

(9.05 ± 6.38 vs. 4.41 ± 4.25, P = 0.002) (Fig. 1a). CRP was also significantly increased in the

IVIG resistant group compared to the IVIG responsive group (105.26 ± 51.39 vs.79.23 ±

45.91, P = 0.001). There was no significant difference between the two groups with regard to

ESR, LD, CK, and BNP.

Figure 2 shows the ROC curve of the NLR, neutrophil count, and CRP for prediction of IVIG

resistance in KD. ROC analysis revealed the area under the curves was 0.797 (P < 0.001) for

NLR, 0.662 (P = 0.026) for CRP and 0.724 (P = 0.001) for neutrophil count. Using a cutoff

value of the NLR of 5, the sensitivity was 73.9 % (95 % confidence interval, 0.695 - 0.890)

and specificity was 77.5 % (95 % confidence interval, 0.701 - 0.832). We classified the study

patients according to a cutoff value of the NLR of 5. Table 1 summarizes the baseline

characteristics and inflammatory markers between the NLR ≥ 5 and NLR < 5 groups. Fifty

two patients were included in the high NLR group and the mean NLR was 10.36 ± 7.68. The

group with NLR ≥ 5 was likely to be older and to have a longer fever duration. Respiratory

viral isolation was not significantly different between the 2 groups. In the high NLR group,

the neutrophil count and ratio were significantly increased compared to the low NLR group.

Moreover, CRP was significantly related to the high NLR (105.83 ± 58.96 vs. 71.99 ± 46.43,

P = 0.001). The resistant IVIG therapy was significantly associated with the high NLR (32.7

% vs. 4.1 %, P < 0.001). However, there was not a significantly different occurrence of

coronary artery abnormalities between the 2 groups (P = 0.503).

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 Comparison of changes in NLR before and after IVIG therapy

In 196 patients, 2340 coronary lesions were assessed with 3 times serial echocardiography.
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The coronary abnormalities were demonstrated in 39 patients (19.8 %). Among them, 2

patients had significant coronary aneurysm (5- and 5.2- mm internal diameter, respectively)

with prolonged medication. A total of 59 lesions with coronary abnormalities were identified.

For each coronary abnormality analysis, 2 lesions in 18 patients, 3 lesions in 5 patients and 1

lesion in 26 patients were identified. As the other cardiac complication, mitral regurgitation

developed in 81 patients (41.3 %) and 2 patients have aortic regurgitation. Transient

pericardial effusion occurred in 5 patients. No patients developed myocardial dysfunction.

In subgroup analysis according to the coronary abnormalities, the mean age, sex, the type of

KD were not different between the 2 groups. However, fever duration was longer in the

abnormal coronary group with borderline statistical significance (5.75 ± 1.41 vs. 5.22 ± 1.12,

P = 0.064). In contrast to IVIG resistance, the NLR was not related to the coronary artery

abnormalities (4.78 ± 5.88 vs. 3.93 ± 2.43, P = 0.384) (Fig.1b). All biomarkers such as WBC

count, neutrophil count, CRP, and NLR demonstrated significant changes after IVIG therapy

regardless of normal coronary group or coronary abnormalities group (Fig. 3).

To compare the changes of biomarkers between the normal and abnormal coronary groups,

we analyzed the biomarkers pre- and post-IVIG therapy. Table 2 shows the comparison of

biochemical variables including NLR before and after IVIG therapy between the normal and

abnormal coronary groups. All biochemical variables before and after IVIG were not

different between the 2 groups. However, the differences in the NLR between pre- and post-

IVIG therapy were demonstrated with a significant decrement in the normal coronary artery

group compared to the abnormal coronary artery group (3.81 ± 2.55 vs. 2.65 ± 1.88, P =

0.042).

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 Predictors of responsiveness of IVIG therapy and occurrence of coronary abnormalities
Accepted Article
To predict the IVIG responsiveness and the occurrence of coronary abnormalities, we

analyzed the risk factor variables. Table 3 shows the cox-regression analysis of predictors for

IVIG resistance and coronary abnormalities in KD. The clinical predictive value of the

baseline high total WBC count, neutrophil count, NLR and CRP were more apparent in IVIG

resistance. In the multivariate analysis, the NLR and CRP were independent predictors of

IVIG resistance. However, there were no significantly different variables in predicting

coronary artery abnormalities in multivariate analysis, although a lower Δ NLR showed a

clinical correlation with coronary artery abnormalities in a univariate analysis.

Discussion

Main findings

Our findings demonstrate that the high NLR was closely associated with the resistant IVIG

therapy. However, it was not related to the occurrence of coronary abnormalities in patients

with KD. The cutoff value of the NLR was 5, with 73.9 % sensitivity and 77.5 % specificity.

The small decrement of the NLR before and after IVIG therapy was significantly related to

the development of coronary artery abnormalities. In addition, the NLR and CRP were

independent predictors of IVIG resistant therapy, although these variables did not reach to the

statistical correlation with the coronary abnormalities.

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 Relationship between NLR and IVIG resistance in Kawasaki Disease

Systemic inflammation has been demonstrated to play a role in the coronary complication in
Accepted Article
KD. It is well known that total neutrophil count is significantly associated with refractory

KD. We found that a high NLR was significantly associated with IVIG resistance but was not

related to coronary abnormalities. However, a small NLR decrement following initial IVIG

therapy, rather than an initial high NLR, was associated with the development of coronary

abnormalities with statistically significant strength. The precise mechanism of how a small

NLR decrement could be related to the coronary abnormalities following IVIG therapy is not

clear. It is assumed that the small change in the NLR reflects persistent systemic

inflammatory during acute phase of KD. It corresponds to prolonged fever that could be a

risk factor for coronary abnormalities.

However, we still cannot explain which factors could affect the development of coronary

abnormalities, beyond inflammatory biomarkers. We speculated that genetic predisposition,

which can modified the immune regulatory response, increased the coronary abnormalities,

caused by the persistent systemic inflammation represented in the NLR decrement following

IVIG cessation.

Clinical implications

Several investigators have demonstrated that the NLR is a predictor of cardiovascular

disease, especially coronary artery disease.[7,8] Recent pediatric data published the NLR

value in KD for predicting coronary abnormalities as well as the responsiveness to IVIG

therapy. [9,10] However, our study shows a slightly different result: the NLR can be a

predictor for IVIG therapy but not coronary abnormalities. This finding suggests that the

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 main cause of coronary artery abnormalities would be affected by additional other factors

such as genetic predisposition. Several gene studies for coronary aneurysm formation in KD
Accepted Article
have suggested the involvement of genetic factors including IL-10, ITPKC, HLA-E, HLA-B

associated transcript 2, 3, and 5, and ITPR3 genes. [11-16] These proposed genes are

associated with the immune-regulatory responses and are involved in cardiovascular-related

pathogenesis contributing to the susceptibility of coronary abnormalities in KD.

Our finding has clinical utility to detect the effectiveness of IVIG therapy because the

measurement of the NLR is very simple, reproducible, and widely available. Furthermore, the

strength of our study is that providing a cutoff value of 5 for the NLR allows the

identification of effective IVIG therapy for the treatment of KD. In addition, NLR decrement

is the somewhat important finding to predict the development of coronary abnormalities.

Thus, in this regard, higher NLR decrement may be crucial for assuming the favorable

clinical outcomes of KD in this study. We propose that a simple measurement of NLR may

serve as useful criteria to identify the refractoriness of IVIG treatment in patients with KD.

Study Limitations

Although we demonstrated that the correlation between a high baseline NLR and IVIG

resistance, a high NLR was not a predictable variable for coronary abnormalities. The

number of significant coronary aneurysm was relatively small in this study. This was a

retrospective study with a relatively small number of patients. Therefore, further prospective

studies with larger numbers of patients are warranted to draw more definitive conclusions.

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 Conclusions

The high NLR was closely associated with the resistant IVIG therapy, but it was not related
Accepted Article
to the occurrence of coronary abnormalities in patients with KD. However, the reduced

decrement of NLR was significantly demonstrated in coronary artery abnormalities. Further

study should determine if other co-factors affect the coronary complication.

Acknowledgements

None.

Conflicts of Interest

The authors declare no conflicts of interest.

Authors’ contributions

CH and PS contributed to the conception and design of this study and drafted the manuscript;

BH, YS and HI collected data; KS and YR performed the statistical analysis; BJ critically

reviewed the manuscript and supervised the whole study process. All authors read and

approved the final manuscript.

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 References
Accepted Article
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 9. Ha KS, Lee J, Jang GY, et al. Value of neutrophil-lymphocyte ratio in predicting outcomes

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 Figure legends
Accepted Article
Figure 1. Comparison of the neutropil to lymphocyte ratio in subjects

(a) The neutropil to lymphocyte ratio (NLR) was greatly increased in patients in the

intravenous immunoglobulin (IVIG) resistant group (9.05 ± 6.38 vs. 4.41 ± 4.25, P = 0.017).

(b) In contrast to IVIG resistance, NLR was not related to coronary artery abnormalities (4.78

± 5.88 vs. 3.93 ± 2.43, P = 0.384).

Figure 2. Receiver-operator characteristic curves for the neutrophil to lymphocyte ratio, C-

reactive protein and neutrophil count. The cutoff value of the neutropil to lymphocyte ratio

(NLR) for the prediction of IVIG resistance was determined to be 5 with 73.9 % sensitivity

and 77.5 % specificity.

AUC, area under the receiver-operator characteristic curve; CI, confidence interval

Figure 3. Comparison of biochemical variables before and after IVIG therapy between the

normal coronary group and abnormal coronary group. In both groups, total WBC count,

neutrophil count, NLR, and CRP were significantly decreased immediately after IVIG

therapy (P = 0.001 in WBC count; P < 0.001 in neutrophil count; P < 0.001 in NLR; P =

0.001 vs. P < 0001 in CRP, respectively).

CRP, C-reactive protein; IVIG, intravenous immunoglobulin; NLR, neutrophil to lymphocyte

ratio; WBC, white blood cell

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ccepted Articl
Table 1.Baseline characteristics and biochemical data on the basis of neutrophil to lymphocyte ratio of study patients

Total NLR ≥ 5 NLR < 5 P value

( n = 196) (n= 52) (n = 144 )

Age, months 32.67 ± 21.73 42.82 ± 21.11 29.01 ± 20.84 <0.001*

Men, n (%) 116 (59.2) 33 (63.5) 83 (57.6) 0.629

Atypical Kawasaki disease, n (%) 45 (22.9) 11 (21.1) 34 (23.6) 0.718

Fever duration before IVIG, days 5.29 ± 1.32 5.06 ± 1.51 5.37 ± 1.25 0.196

Total white blood cell count, *103/µL 13.31 ± 4.59 14.43 ± 5.12 12.93 ± 4.29 0.061

Neutrophil count, *103/µL 8.93± 4.11 11.92 ± 5.12 7.84 ± 3.27 <0.001*

Lymphocyte count, *103/µL 3.02 ± 1.74 1.41 ± 0.61 3.61 ± 1.65 0.002*

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ccepted Articl
Neutrophil ratio, % 65.72 ± 14.71 81.75 ± 6.84 59.92 ± 12.28 <0.001*

Lymphocyte ratio, % 23.67 ± 12.39 10.50 ± 4.51 28.46 ± 10.79 0.001*

Neutrophil/ Lymphocyte ratio 4.61 ± 5.38 10.36 ± 7.68 2.53 ± 1.32 <0.001*

Erythrocyte sedimentation rate, mm/hr 51.09 ± 22.78 49.84 ± 25.14 50.83 ± 21.89 0.621

C-reactive protein, mg/L 80.97 ± 52.11 105.83 ± 58.96 71.99 ± 46.43 0.001*

Lactate dehydrogenase, IU/L 332.59 ± 189.73 373.59 ± 268.77 317.78 ± 149.98 0.197

B-type natriuretic peptide, pg/mL 175.52 ± 204.09 236.11 ± 241.15 134.35 ± 154.38 0.084

Creatin kinase, IU/L 104.12 ± 153.26 115.83 ± 154.31 99.87 ± 153.34 0.571

Viral isolation, n (%) 34 (17.3) 10 (19.2) 24 (16.7) 0.675

IVIG resistant, n (%) 23 (11.7) 17 (32.7) 6 (4.1) <0.001*

Coronary artery abnormalities 40 (20.4) 12 (23.1) 27 (18.7) 0.503

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ccepted Articl
IVIG, intravenous immunoglobulin; NLR, neutrophil to lymphocyte ratio

*P<0.05

Table 2. Comparison of biochemical variables before and after intravenous immunoglobulin therapy

Pre-IVIG Post-IVIG

Normal CA Abnormal CA P value Normal CA Abnormal CA P value

(n=158) (N=38) (n=158) (n= 38)

Total WBC count, *103/µL 13.07 ± 4.59 14.35 ± 4.31 0.095 9.02 ± 6.25 9.32 ± 3.62 0.707

Neutrophil count, *103/µL 8.72 ± 4.25 9.74 ± 3.41 0.099 3.48 ± 2.58 4.02 ± 2.77 0.279

Lymphocyte count, *103/µL 3.01 ± 1.83 3.10 ± 1.47 0.821 3.53 ± 1.80 3.64 ± 1.64 0.745

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ccepted Articl
Neutrophil ratio, % 65.2 ± 15.5 67.8 ± 11.0 0.214 39.59 ± 17.89 41.68 ± 16.93 0.503

Lymphocyte ratio, % 24.1 ± 13.1 21.9 ± 8.82 0.189 43.53 ± 15.92 41.93 ± 14.33 0.548

NLR 4.78 ± 4.88 4.15 ± 3.01 0.384 1.35 ± 1.51 1.37 ± 1.02 0.174

ESR, mm/hr 50.73 ± 22.63 50.31±23.54 0.249 59.66 ± 25.63 48.53 ± 22.62 0.467

CRP, mg/L 77.59 ± 50.77 94.57 ± 55.80 0.148 34.42 ± 36.73 39.32 ± 22.62 0.738

LD, IU/L 333.59±183.48 334.9± 214.02 0.936 266.4 ± 59.0 259.78 ± 22.6 0.738

CK, IU/L 103.54±136.43 106.1 ± 201.11 0.945 72.1 ± 63.8 82.9 ± 76.7 0.545

BNP, pg/mL 186.85±258.42 227.06±232.11 0.344 108.4 ± 137.68 119.76 ± 127.83 0.693

Normal CA (n=158) Abnormal CA (N=38) P value

Δ Total WBC count, *103/µL 4.16 ± 3.93 5.07 ± 3.97 0.326

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ccepted Articl
Δ Neutrophil count, *103/µL 5.43 ± 3.83 6.07 ± 3.12 0.342

Δ Lymphocyte count, *103/µL -5.56 ± 1.52 -5.82 ± 1.69 0.931

Δ NLR 3.81 ± 2.55 2.65 ± 1.88 0.042*

Δ ESR, mm/hr -12.86 ± 26.45 -13.4 ± 30.18 0.927

Δ CRP, mg/L 45.33 ± 42.1 54.34 ± 45.79 0.071

Δ LD, IU/L 68.56 ± 79.2 74.12 ± 82.6 0.896

Δ CK, IU/L 34.5 ± 45.1 29.6 ± 31.5 0.567

Δ BNP, pg/mL 83.4 ± 92.6 97.2 ± 103.5 0.643

BNP, B type natriuretic peptide; CA, coronary artery; CK, Creatin kinase; CRP, C- reactive protein; ESR, Erythrocyte sedimentation rate; IVIG,

intravenous immunoglobulin; LD, lactate dehydrogenage; NLR, neutrophil to lymphocyte ratio; WBC, white blood cell; Δ, the differences

between pre- and post-IVIG therapy

*P < 0.05

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Accepted Article

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Accepted Article

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Accepted Article

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