Evaluation of left ventricular function in immunoglobulin‐resistant children with Kawasaki disease: a two‐dimensional speckle tracking echocardiography study

Abstract Background Kawasaki disease (KD) patients who are unresponsive to intravenous immune globulin (IVIG) have a high occurrence of coronary artery lesions (CALs). The characteristics of left ventricular (LV) function alternation in IVIG‐resistant patients are not well‐described. Hypothesis Two‐dimensional speckle tracking echocardiography (STE) is a useful technique that can accurately detect myocardium subclinical dysfunction in resistant patients and may assist in differentiating patients with KD at a higher risk of IVIG resistance. Methods A consecutive sample of 50 IVIG‐resistant patients (25 males, 2.2 ± 0.9 years), 50 IVIG‐responsive patients (27 males, 2.2 ± 0.7 years) and 50 normal subjects (27 males, 2.1 ± 0.9 years) were analyzed using STE, and receiver operating characteristic curve (ROC) analysis was utilized to determine the threshold values of STE parameters associated with IVIG resistance. Results Compared with normal children, IVIG‐resistant patients had lower global longitudinal strain (GLS) (15.82 ± 3.32 vs 20.01 ± 2.98, P = 0.000) and lower global circumferential strain (GCS) (16.65 ± 3.12 vs 20.11 ± 2.86, P = 0.042). Both GLS and GCS in IVIG‐resistant patients were significantly lower than in IVIG‐responsive patients (15.82 ± 3.32 vs 19.95 ± 3.01, 16.65 ± 3.12 vs 19.01 ± 3.00, P = .000, .030, respectively). ROC analysis demonstrated that the absolute values of GLS < 16.8% and GCS < 15.9% were optimal predictors of IVIG unresponsiveness (area under the curve = 0.78, 0.75; sensitivity = 0.83, 0.79; specificity = 0.69, 0.65, respectively). Conclusion IVIG‐resistant patients presented with more severe LV systolic dysfunction compared with IVIG‐responsive patients, which may be the result of myocarditis rather than CALs. STE may be a helpful diagnostic tool that provides supportive criteria to detect KD patients at a higher risk of IVIG resistance.


| INTRODUCTION
Kawasaki disease (KD) is an acute systemic vasculitis with an unknown cause that mainly affects children <5 years of age. KD is currently the leading cause of acquired heart disease in children in developed countries. 1 The occurrence of coronary artery aneurysm can reach 25% in untreated KD patients. 2 The most effective treatment for KD is timely intravenous immune globulin (IVIG), which can decrease the occurrence of coronary artery aneurysm from 25% to 5% 3 ; however, approximately 10% to 15% of patients remain resistant to IVIG. 4 Previous studies showed that IVIG-resistant patients are at high risk of developing coronary artery lesions (CALs) and need an additional dose of IVIG [4][5][6] ; therefore, early detection of such patients is extremely helpful for clinicians to adopt optimal treatment and good prognosis.
Currently, the most commonly utilized scoring systems for identifying IVIG-resistant patients are mainly from Japan, [7][8][9] but the sensitivity and specificity in these risk prediction models are low, especially in non-Japanese populations. 10,11 In addition, echocardiographic parameters are not included in these scoring systems. Twodimensional speckle tracking echocardiography (STE) is a useful technique that can accurately quantify myocardial function and detect left ventricular (LV) subclinical dysfunction with high reproducibility. [12][13][14] To the best of our knowledge, this is the first study using STE to assess and predict IVIG-resistant patients. In this study, we aimed to explore the characteristics of LV systolic function of IVIG-resistant patients and also aimed to determine whether STE can assist in identifying KD patients who are unresponsive to IVIG.

| Study population
In the acute phase (prior to IVIG), we recruited 50 consecutive IVIGresistant KD patients and 50 consecutive IVIG-responsive KD patients who were age-and gender-matched in the First Affiliated Hospital, Xi'an Jiaotong University from January 2016 through April 2018. We also enrolled 50 age-and gender-matched normal children who were referred to our hospital to undergo an echocardiography examination for a murmur without evidence of cardiac abnormalities. All KD patients met the diagnostic criteria of American Heart Association. 1 All patients in the acute phase were treated with IVIG (2 g/kg over 12 hours) and high-dose aspirin (80 mg/kg/day divided every 6 hours). The IVIG unresponsive patients were determined to have a persistent or recrudescent fever ≥38.3 C, which occurred for more than 36 hours after the end of IVIG infusion up to 7 days after completion of the infusion. IVIG-responsive patients were defined as patients who had a good clinical response to IVIG and did not have persistent or recrudescent fever. The IVIG-resistant patients were further divided into the CALs subgroup or no CALs subgroup. CALs was reflected by dilation of the right coronary artery, left coronary artery and left anterior descending coronary artery, which was defined as a Z score of ≥2.5 (SD units from the coronary artery internal diameter normalized for body surface area [BSA]). 1 Patients with structural heart disease, chronic renal disease, severe arrhythmia and insufficient image quality were all excluded. This study was approved by the research committee of the First Affiliated Hospital of Xi'an Jiaotong University, and written informed consents were obtained from the guardians of all participants.

| Conventional echocardiogram and laboratory data
All the KD patients in the acute phase and normal children underwent transthoracic echocardiography using a commercially available ultrasonic machine (Philips EPIQ 7C, Andover, Massachusetts) equipped with a S8-3 transducer. Both the KD patients and normal children were placed in a calm environment for the echocardiographic examination, and subjects who were uncooperative during the echocardiographic examination were sedated with oral hydrate (25-50 mg/kg).
The LV ejection fraction (LVEF) was acquired by biplane Simpson's method of disks, and LV shortening fraction was obtained according to the guideline. 15 The LV mass (LVM) was acquired from standard Mmode echocardiography, 16,17 and the LV mass index (LVMI) was obtained by LVM indexed to BSA. The laboratory data of all patients in the acute phase were also acquired.

| STE analysis
The digital images of three consecutive cardiac cycles were obtained and stored for subsequent STE analysis with a commercially available software package (Qlab version 10.6, Speckle Tracking; Philips). At least 95% of myocardial wall thickness was set to cover. When the trace of the myocardial wall was unsatisfactory, a manual adjustment was used to obtain an adequate speckle tracking image. The width region of interest was set at 5 mm, and the frame rate was set between 60 and 80 frames per second. The zero-baseline reference point was set at the onset of the QRS complex of the electrocardiogram and was referred to as the LV end-diastole. 18 LV longitudinal parameters were measured from apical-3 view, apical-2 view and apical-4 view, after which global longitudinal strain (GLS) and global longitudinal strain rate (GLSR) were generated. 18 The LV long axis was set to be perpendicular to the plane of the mitral annulus in the LV apical views. Circumferential parameters were measured using parasternal short-axis views, including LV basal level, middle level, and apical level. Then, global circumferential strain (GCS) and global circumferential strain rate (GCSR) were generated. All of the measurements were performed by two observers who were blinded to the results.

| Reproducibility
To determine intra-observer variability, STE parameters from 20 randomly assigned patients, including GLS, GLSR, GCS, and GCSR, were reanalyzed by the same observer 2 months after the initial analysis.
For inter-observer variability, the same patients and the same cardiac cycles were analyzed by a second observer.

| Statistical analysis
Statistical analyses were performed using SPSS 22.0 (Statistical Product and Service Solutions Company, Chicago). Mean and SD were reported for the quantitative echocardiographic data and laboratory data. The categorical data were expressed as the count and percent.
The continuous variables were first assessed for normality. For between group differences, the independent-samples t tests were used for normally distributed continuous variables, and Wilcoxon rank-sum tests were used for non-normally distributed continuous variables. The differences in the parameters among IVIG-resistant group, IVIG-responsive group and normal group were analyzed using a one-way analysis of variance with the Student-Newman-Keuls test to evaluate the differences between the two groups. A χ 2 analysis was used to assess the categorical data differences. The cutoff values of STE measurements associated with IVIG unresponsiveness were determined by receiver operating characteristic curve (ROC) curve analysis. Test reliability was assessed by calculating intra-observer variability, inter-observer variability, and intraclass correlation coefficients (ICCs) with a 95% confidence interval. 19 The statistical significance was defined as a P-value <.05.

| RESULTS
3.1 | The characteristics of IVIG-responsive group, IVIG-resistant group, and normal group The age ranges of IVIG-resistant patients, IVIG-responsive patients and normal children were 2.2 ± 0.9, 2.2 ± 0.7, and 2.1 ± 0.9 years, respectively. There were 25 males, 27 males, and 27 males in responsive group, resistant group, and normal group, respectively. No significant differences were found in terms of age or gender. In the IVIGresistant group, 10 patients with a mild or moderate CALs and two patients with aneurysm were found, whereas in the IVIG-responsive group, only three patients with mild CALs were found.
3.2 | Comparison of conventional echocardiographic data and STE data among the IVIG-responsive group, IVIG-resistant group, and normal group The conventional echocardiographic data and STE data are shown in  were no significant differences in GLSR and GCSR.

| ROC analysis
The

| Reproducibility
The ICCs for inter-observer concordance was 0. and lateral LV peak early diastolic tissue Doppler velocity of the mitral annulus compared to the IVIG-responsive group; however, they did not find any significant difference in systolic velocity. The reason for the lack of a difference in LV systolic function may be that TDI is angle-dependent and has a disadvantage in that only regional function represents global LV function. The systolic strain rate was regarded to be a more robust parameter reflecting myocardial function than strain 26 ; however, we did not find any differences in both GLSR and