Association of Yersinia Infection With Kawasaki Disease: A Prospective Multicenter Cohort Study.

BACKGROUND: Yersinia infection is known to present with Kawasaki disease (KD)-like symptoms although differentiating the 2 has been a challenge. The present study aimed to describe the clinical characteristics and prevalence of Yersinia infection presenting with KD-like symptoms. METHODS: The present, prospective, multicenter study enrolled patients who received a diagnosis of KD between January 2021 and January 2022 at 2 hospitals in Tokyo. Stool samples were collected within 3 days of the start of KD treatment, and cultures were performed for Yersinia . Clinical history and symptoms suggestive of Yersinia infection were also evaluated. RESULTS: During the study period, 141 KD patients were screened and 117 patients with evaluable stool samples were registered. Only 1 patient was positive for Yersinia pseudotuberculosis , which was detected from both stool and blood cultures. The patient was refractory to KD treatment but improved after initiation of appropriate antibiotic therapy. CONCLUSIONS: Routine screening for Yersinia is not appropriate for patients with KD and should be limited to certain patients in high-risk areas and those who are refractory to the standard KD treatment.

Clinical implications of gallbladder enlargement in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) presents with gallbladder enlargement (GBE) or hydrops in the acute phase. Although GBE is highly specific to KD, epidemiological data on GBE have not been updated. In this study we evaluated the occurrence rate of GBE in KD and characterized the clinical features of patients who developed GBE. METHODS: The present study was a prospective, observational study. The maximum longitudinal area of the gallbladder and the common bile duct diameter in KD patients were measured by ultrasonography at the start of initial intravenous immunoglobulin (IVIG) therapy (day 0) and on days 7, 30, and 60 of therapy. The primary outcome was the complication rate of GBE (z- score ≥2.0) on day 0. The secondary outcome was the association of GBE with cholestasis, unresponsiveness to IVIG, and coronary artery lesions (CAL). RESULTS: Gallbladder enlargement occurred in 35% (35/101) of patients on day 0. Cholestasis and severe patients (Kobayashi score [KS] ≥5) were more common in the GBE group (20.6% vs. 1.6%, p = 0.002, and 54.3% vs. 15.2%, p < 0.001, respectively). In patients with a KS of ≤4, the non-responder rate was higher in the GBE group (44% vs. 20%, p = 0.0495) but did not differ in those with a KS of ≥5 (21% vs. 20%, p = 0.95). The rate of CAL occurrence did not differ significantly between the groups (8.6% vs. 6.1%, p = 0.64). CONCLUSIONS: Gallbladder enlargement occurred in 35% of KD patients and was associated with cholestasis. Gallbladder enlargement may not only be a diagnostic finding, but also a severity marker in KD patients.

Identifying Kawasaki Disease With a Low Coronary Artery Aneurysm Risk.

INTRODUCTION: Kawasaki disease (KD) patients with a high risk of coronary artery aneurysm (CAA) development are well characterized and targeted for intensified primary intravenous immunoglobulin (IVIG) treatment. However, the characteristics of KD patients with a low CAA risk are less well-known. METHODS: The present study was a secondary analysis of Prospective Observational study on STRAtified treatment with Immunoglobulin plus Steroid Efficacy for Kawasaki disease (Post RAISE), a multicenter, prospective cohort study of KD patients in Japan. The target of the analysis was patients with a Kobayashi score <5 who were predicted to respond to IVIG. The incidence of CAA during the acute phase, the primary outcome, was assessed based on all echocardiographic evaluations performed between week 1 (days 5-9) and month 1 (days 20-50) after the start of primary treatment. Multivariable logistic regression was used to identify the independent risk factors of CAA during the acute phase, based on which a decision tree was created to identify a subpopulation of patients with KD with a low CAA risk. RESULTS: Multivariate analysis found that a baseline maximum Z score >2.5, age <12 months at fever onset, nonresponsiveness to IVIG, low neutrophils, high platelets and high C-reactive protein were independent predictors of CAA during the acute phase. The decision tree created by using these risk factors identified 679 KD patients who had a low incidence of CAA during the acute phase (4.1%) and no medium or large CAA. CONCLUSIONS: The present study identified a KD subpopulation with a low CAA risk comprising around a quarter of the entire Post RAISE cohort.

Analysis of Coronary Arterial Aneurysm Regression in Patients With Kawasaki Disease by Aneurysm Severity: Factors Associated With Regression.

Background Coronary arterial aneurysms (CAAs) associated with Kawasaki disease (KD) significantly affect prognosis. However, the clinical course of CAAs and factors associated with CAA regression have not been well analyzed. Methods and Results The cohort of the Z-Score 2nd Project Stage study, a multicenter, retrospective, cohort study involving 44 institutions in Japan including 1006 patients with KD, was examined. CAAs were classified by the z score of their internal diameter in the acute phase: small (z<5), medium (5≤z<10), and large (z≥10). The lower limit of small CAA was based on the Japanese Ministry of Health, Labour and Welfare criteria. In the right coronary artery, the CAA regression rates 10 years after diagnosis were 95.5% for small, 83.2% for medium, and 36.3% for large. In the proximal left anterior descending artery, the regression rates 10 years after diagnosis were 95.3% for small, 80.1% for medium, and 28.8% for large. Cox regression analysis showed that diagnosis under the age of 1 year and onset of KD in 2010 to 2012 for the right coronary artery and the left anterior descending artery, and female for the right coronary artery were significantly associated with a high regression rate, whereas large CAAs for the right coronary artery and the left anterior descending artery were significantly associated with a low regression rate. Conclusions The current study, the largest Japanese study of its kind, found that small aneurysm, recent onset, and diagnosis under the age of 1 year predict regression, and that even giant aneurysms could regress. These data may contribute to long-term management of coronary aneurysms. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000010606.

A registry study of Kawasaki disease patients with coronary artery aneurysms (KIDCAR): a report on a multicenter prospective registry study three years after commencement.

The long-term prognosis of patients with Kawasaki disease (KD) complicated by coronary artery aneurysms (CAA) is still unclear. The present, multicenter registry study aimed to study the factors associated with coronary events (CE) and determine an appropriate management method for patients with KD complicated with CAA. Patients with KD with onset after 2015 and with a medium-sized or large CAA having an actual diameter ≥ 4 mm or a Z-score ≥ 5.0 at 30 days and later after KD onset were included in the annual survey. The primary endpoint was the time-dependent incidence of CE. Associated factors were also examined. In total, 179 patients from 53 centers were enrolled and followed up for a median of 501 days. The median age at KD onset was 2.2 years, 137 patients were male (77%), 47 had incomplete KD (26%), and 36 had large CAA (20%). CE occurred in 13 patients (7%; 95% confidence interval: 4-12%); eight (62%) experienced CE within 1 year, and all the patients experienced a CE within 2 years. All but one patient received antiplatelet drugs and warfarin. Patients with a large CAA had significantly more CAA (2.8 vs. 1.7, p < 0.001), more cases of warfarin use (86% vs. 43%, p < 0.001), and were more likely to have CE (28% vs. 2%, p < 0.001) than those with a medium-sized CAA. On univariate Cox regression analysis, the factors significantly associated with CE were large CAA (hazard ratio (HR): 17.0), three or more CAA (HR: 23.3), and beaded CAA (HR: 15.9). Multivariable Cox regression analysis revealed that the only associated factor was a large CAA. CONCLUSION: Patients with a large CAA were more likely to have a CE within 2 years. Antithrombotic therapy with warfarin did not eliminate the CE risk, and better therapies are desirable. WHAT IS KNOWN: • Coronary artery aneurysms are a serious complication of Kawasaki disease, and coronary events are sometimes fatal. • In previous, retrospective studies in Japan, large aneurysms, male sex, and refractoriness to initial immunoglobulin therapy were considered risk factors for coronary events. WHAT IS NEW: • Of 179 patients with a medium sized or large aneurysm, 13 (7%) experienced coronary events, all of which occurred within 2 years of onset. Factors significantly associated with coronary events were large aneurysms, three or more aneurysms, and beaded aneurysms.

Efficacy of SubcutAneous implantable cardioVErter-defibrillators in ≤18 year-old CHILDREN: SAVE-CHILDREN registry.

BACKGROUND: In adult patients, subcutaneous implantable cardioverter defibrillators (S-ICDs) have been reported to be non-inferior to transvenous ICDs with respect to the incidence of device-related complications and inappropriate shocks. Only a few reports have investigated the efficacy of S-ICDs in the pediatric field. This study aimed to investigate the utility and safety of S-ICDs in patients ≤18 years old. METHODS: This study was a multicenter, observational, retrospective study on S-ICD implantations. Patients <18 years old who underwent S-ICD implantations were enrolled. The detailed data on the device implantations and eligibility tests, incidence of appropriate- and inappropriate shocks, and follow-up data were assessed. RESULTS: A total of 62 patients were enrolled from 30 centers. The patients ranged in age from 3 to 18 (median 14 years old [IQR 11.0-16.0 years]). During a median follow up of 27 months (13.3-35.8), a total of 16 patients (26.2%) received appropriate shocks and 13 (21.3%) received inappropriate shocks. The common causes of the inappropriate shocks were sinus tachycardia (n = 4, 30.8%) and T-wave oversensing (n = 4, 30.8%). In spite of the physical growth, the number of suitable sensing vectors did not change during the follow up. No one had any lead fractures or device infections in the chronic phase. CONCLUSIONS: Our study suggested that S-ICDs can prevent sudden cardiac death in the pediatric population with a low incidence of lead complications or device infections. The number of suitable sensing vectors did not change during the patients' growth.

Exercise Stress Electrocardiography Using the Two-Minute Jump Test in Children.

Although the treadmill and cycle ergometer are commonly used for exercise stress electrocardiography (ECG) testing, they are often difficult to perform with children. We herein evaluated the utility and safety of the 2-minute jump test (2MJT) as a simple, alternative exercise test. One hundred patients, including 60 male patients, with an average age at study commencement of 10.7±3.5 years (mean±standard deviation) and with no exercise restriction who underwent a cardiac check-up between November 2020 and March 2022 at the study center were included. After recording their resting ECG, they jumped for 2 minutes during ECG recording, and the change in heart rate (HR), ECG findings, and occurrence of adverse events were investigated. As a result, patients jumped 185±60 times in two minutes, and their HR increased from 76±13 beats/min at rest to 172±18 beats/min at peak during the test. Ninety (90%) patients attained the ideal target HR of > 150 beats/minute. During the recovery period after loading, five patients had abnormal ECG findings (ventricular extrasystoles, second-degree atrioventricular block, and atrial extrasystoles in two, two, and one patient, respectively) but completely resolved spontaneously within three minutes. Our findings suggested that the 2MJT is a useful and safe exercise test capable of inducing sufficient increase in HR in a short time in children.

A prospective cohort study of sensorineural hearing loss associated with Kawasaki disease.

AIM: About 60 cases of sensorineural hearing loss (HL) have been reported in patients with Kawasaki disease (KD), but the current estimate of its prevalence is uncertain. The present study aimed to determine the prevalence and risk factors of sensorineural HL associated with KD. METHODS: The present, prospective cohort study, conducted from May 2019 to May 2020, evaluated patients with a diagnosis of KD who received the initial therapy and underwent two auditory brainstem response (ABR) tests. HL was defined as a threshold of 40 dB or more, and borderline hearing was defined as a threshold of 30 dB. RESULTS: In total, 107 patients were enrolled, and 75 underwent two ABR tests. Thirty-one patients (30.0%) received prednisolone with their initial intravenous immune globulin and acetylsalicylic acid therapy. HL was present in only one patient who had congenital conductive HL. Five patients had borderline hearing but had normal hearing behavior. There was no significant difference between the patients with normal hearing and those with borderline hearing in terms of the clinical variables. CONCLUSIONS: In Japan, the prevalence of sensorineural HL after KD is not high. It may therefore be unnecessary to perform routine hearing tests for all patients with KD. NAME OF TRIAL REGISTER: Association between Kawasaki Disease and Sensorineural Hearing Loss. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000037019 (the date of registration: June 11, 2019).

Control of Heart Rate in Infant and Child Tachyarrhythmia With Reduced Cardiac Function Using Landiolol (HEARTFUL)　- Results of a Prospective, Multicenter, Uncontrolled Clinical Study.

BACKGROUND: The prospective Control of HEART rate in inFant and child tachyarrhythmia with reduced cardiac function Using Landiolol (HEARTFUL) study investigated the effectiveness and safety of landiolol, a short-acting ß1 selective blocker, in children.Methods and Results: Twenty-five inpatients aged ≥3 months to <15 years who developed supraventricular tachyarrhythmias (atrial fibrillation, atrial flutter, supraventricular tachycardia, and inappropriate sinus tachycardia) were treated with landiolol. The primary endpoint, the percent of patients with a reduction in heart rate ≥20% from the initial rate of tachycardia, or termination of tachycardia at 2 h after starting landiolol, was achieved in 12/25 patients (48.0%; 95% CI 28.4-67.6), which exceeded the predetermined threshold (38.0%). At 2 h after starting landiolol administration, heart rate had decreased by ≥20% in 45.8% (11/24) and recovery to sinus rhythm was achieved in 40.0% (6/15) of the patients. Adverse reactions (ARs) occurred in 24.0% (6/25) of patients, and the study was discontinued in 4.0% (1/25) of the patients; however, none of these ARs were considered serious. The most common AR was hypotension (20.0% [5/25] of patients). CONCLUSIONS: The HEARTFUL study has demonstrated the efficacy of landiolol, by reducing heart rate or terminating tachycardia, in pediatric patients with supraventricular tachyarrhythmias. Although serious ARs and concerns were not identified in this study, physicians should be always cautious of circulatory collapse due to hypotension.

Kawasaki Disease (KD) With Linear Facial Erythema Coinciding With Blaschko's Lines.

Kawasaki disease (KD) is a self-limited, systemic vasculitis developing in early childhood. Skin findings of KD are polymorphous, varying from diffuse maculopapular eruptions to psoriasiform lesions. We described herein an 18-month-old male patient with KD who presented with linear, facial erythema coinciding with Blaschko's lines. Parental consent for this case report was obtained in written and verbal form.

Retrospective Echocardiographic Analysis of West Syndrome During Adrenocorticotropic Hormone Therapy.

Background: Ventricular hypertrophy is a well-known side effect of adrenocorticotropic hormone (ACTH) therapy in patients with West syndrome (WS), but there are only a few reports of echocardiographic evaluation of these patients' diastolic function. Methods: The present, retrospective study analyzed echocardiographic findings in 24 patients with WS treated with ACTH therapy between April 2010 and December 2014. The therapy protocol involved administering tetracosactide acetate 0.01-0.0125 mg/kg via intramuscular injection once a day for weeks 1-2, then gradually tapering off. Echocardiographic evaluation was done before treatment initiation and at weeks 1, 2, and 4 after the initiation of treatment. Results: The systolic and diastolic blood pressure values were elevated at week 1 after commencement of the therapy and remained elevated throughout its duration. Both the interventricular septal end-diastolic thickness and left ventricular posterior wall end-diastolic diameter increased in thickness at week 1 and remained thickened. None of the patients experienced heart failure or systolic dysfunction. Early diastolic mitral flow velocity (E)/early diastolic mitral annular velocity (E') increased at week 1 and remained high at weeks 2 and 4. The E wave deceleration time (DcT) was prolonged at week 2 and returned to the baseline at week 4. Conclusion: Increased ventricular wall thickness, decreased diastolic capacity, and elevated BP were noted in children with WS during ACTH therapy. Cardiac function, including ventricular wall thickness and diastolic function, should be monitored during ACTH therapy. E/E' and DcT are useful in evaluating diastolic function.

Risk Factors of Coronary Artery Aneurysms in Kawasaki Disease with a Low Risk of Intravenous Immunoglobulin Resistance: An Analysis of Post RAISE.

OBJECTIVE: To detect risk factors of coronary artery aneurysm (CAA) development in patients with Kawasaki disease determined to have a low risk for resistance to primary intravenous immunoglobulin (IVIG) treatment based on the Kobayashi score. STUDY DESIGN: This study included 1757 predicted IVIG responders from Prospective Observational study on STRAtified treatment with Immunoglobulin plus Steroid Efficacy for Kawasaki disease (Post RAISE), a large-scale, multicenter, prospective cohort study of Kawasaki disease in Japan. Predicted IVIG responders were defined as patients with Kawasaki disease with a Kobayashi score of <5, a predictive scoring system for IVIG resistance created in Japan. The primary outcome was CAA development at 1 month after disease onset. CAA was defined as a Z score of ≥2.5. Multivariable logistic regression was used to identify the independent risk factors of CAA. The variables for inclusion were identified based on univariate analysis results and previously reported risk factors of CAA. RESULTS: Among 1632 patients who had complete coronary outcome data, CAA developed in 90 patients (5.5%) at 1 month after disease onset. Multivariable analysis found that a baseline maximum Z score of >2.5, age of <12 months at fever onset, and nonresponsiveness to IVIG were significant, independent risk factors of CAA development at 1 month after disease onset. Among the risk factors, a baseline maximum Z score of >2.5 was most strongly associated with CAA development (OR, 7.1; 95% CI, 4.1-12.2; P ≤ .001). CONCLUSIONS: Predicted IVIG responders with CAA risk factors identified in this study may be candidates for future clinical trials of intensified primary IVIG treatment with prednisolone, cyclosporine or infliximab.

Follow-Up Duration of Echocardiography in Patients with Kawasaki Disease with No Initial Coronary Aneurysms.

OBJECTIVE: To evaluate the optimal duration of echocardiographic follow-up in patients with Kawasaki disease without an initial coronary aneurysm. STUDY DESIGN: In this single-center, retrospective, observational study, we reviewed the results of follow-up echocardiography in children with Kawasaki disease enrolled in the Prospective Observational Study on Stratified Treatment with Immunoglobulin Plus Steroid Efficacy for Kawasaki Disease from a children's hospital. The main enrollment criterion was the absence of coronary aneurysms, defined as a maximum z-score (Zmax) ≥2.5, in the proximal right coronary artery and the proximal left anterior descending artery within 9 days from treatment initiation. The primary outcome was Zmax on follow-up echocardiography at up to 5 years. RESULTS: Among 386 patients, 106 (27.5%) received prednisolone with intravenous immunoglobulin for first-line therapy, and 57 (14.8%) showed a poor response. Echocardiography at 1 month detected 9 patients with a Zmax ≥2, including 3 (0.8%) with coronary aneurysms requiring additional antithrombotic treatment and observation. Of 7 patients (1.8%) with normal echocardiographic findings at 1 month but a Zmax ≥2 later, 2 were lost to follow-up and 5 experienced spontaneous resolution, but none of the 7 patients required any change in management. CONCLUSIONS: The optimal duration of echocardiographic follow-up may be 1 month in patients with no initial coronary aneurysms and a Zmax <2 at 1 month. Coronary artery abnormalities observed after 1 month are rare and mostly benign in this category of patients.

Multisystem Imaging Manifestations of Kawasaki Disease.

Kawasaki disease (KD) is a common pediatric vasculitis syndrome involving medium- and small-sized arteries that is especially prevalent in early childhood (ie, age 6 months to 5 years). The diagnosis of KD is made on the basis of clinical features, such as fever, characteristic mucocutaneous changes, and nonsuppurative cervical lymphadenopathy. However, early diagnosis is often challenging because many children with KD present with atypical symptoms. The most serious complication of KD is coronary artery aneurysm caused by coronary arteritis. Prompt intravenous immunoglobulin therapy reduces the risk of cardiac morbidity. In addition, the systemic extension of KD-related vasculitis during the acute phase causes a variety of multisystem manifestations, including encephalopathy, stroke, retropharyngeal edema, pericarditis, myocarditis, KD shock syndrome, pulmonary lesions, intestinal pseudo-obstruction, gallbladder hydrops, arthritis, and myositis. These complications tend to be more common in affected children with atypical presentation. Radiologists can play an important role in the timely identification of diverse KD-associated morbidities and thus may contribute to the early diagnosis of atypical KD. Online supplemental material is available for this article. ©RSNA, 2021.

Outcomes of hypertrophic cardiomyopathy in Japanese children: a retrospective cohort study.

There has been no multicenter study on the prognosis of pediatric hypertrophic cardiomyopathy (HCM) in Japan. Therefore, we conducted a retrospective multicenter observational study on the long-term survival rate in patients diagnosed with HCM under the age of 18 between 1990 and 2014. Twenty institutions participated. A total of 180 patients were identified. The median age at diagnosis was 5.8 years old and median duration of observation was 8.3 years. Although six patients (3%) deteriorated into the dilated phase of HCM, no patient received heart transplantation. Freedom from death at 1, 5, 10, and 20 years were 97%, 92%, 84%, and 80%, respectively. There were 26 deaths. Among them, 11 patients died suddenly, presumably due to arrhythmia, and 15 patients died of heart failure. The presence of heart failure symptoms and a greater cardiothoracic ratio were significant risk factors for heart failure-related death. There were no significant risk factors identified for arrhythmia-related death. In conclusion, the prognosis of pediatric HCM in Japan is good and similar to those reported in population-based studies in the United States and Australia. Significant risk factors for heart failure-related death were identified in pediatric patients with HCM in Japan.

Echocardiographic Left Ventricular Z-Score Utility in Predicting Pulmonary-Systemic Flow Ratio in Children With Ventricular Septal Defect or Patent Ductus Arteriosus.

BACKGROUND: The correlation between the Z-score of the left ventricular (LV) diameter and the LV volume-overload due to pulmonary over-circulation in children with ventricular septal defect (VSD) or patent ductus arteriosus (PDA) remains unclear.Methods and Results:The present, retrospective study enrolled 70 children (aged 0.3-16.8 years; 33 males, 37 females) with a diagnosis of isolated VSD and/or PDA who underwent cardiac catheterization (CC) between 2015 and 2019. Patients with chromosomal/genetic anomalies, growth disorder, right-ventricular enlargement or other conditions causing LV enlargement were excluded. Echocardiographic parameters were retrospectively evaluated from the medical records, converted to a Z-score, then compared with CC data. The pulmonary-systemic flow ratio on CC (cQp/Qs) correlated significantly with the Z-score of both the LV end-diastolic diameter (Zd) (r=0.698, P<0.0001) and LV end-systolic diameter (r=0.593, P<0.0001). Regression analysis and curve-fitting were used to predict the cQp/Qs based on the Zd, and a significant regression equation was found on cubic regression (R2of 0.524, P<0.0001) showing a strong correlation with the cQp/Qs (r=0.724, P<0.0001). CONCLUSIONS: The Z-score of the LV diameter can be a useful, non-invasive marker for evaluating LV volume overload and determining the surgical indications in children with VSD or PDA because of its strong correlation with the cQp/Qs.

A Classification System Specific for Recurrent Inguinal Hernia Following Open Hernia Surgery.

BACKGROUND/AIM: Currently, there is no classification system specializing in recurrent inguinal hernia (RIH) after open-surgery. For this reason, in this study we proposed one so as to understand the causes of RIH. PATIENTS AND METHODS: Recurrence of IH after suture-repair was classified either as the tissue-loosening (TL) or the tissue-disruption (TD) type. Recurrence after open-mesh-repair was classified according to the locational relation between the hernia-defect and the mesh, as follows: i) mesh-distant (MD), ii) para-mesh (PM), iii) mesh-migration (MM), and iv) unclassifiable (UC). Fifty-two RIHs in 48 patients were classified, using this system, and analyzed. RESULTS: This system-based classification led to the identification of: i) MM in 11 lesions, ii) PM in 11, iii) MD in 10, iv) TL in 7, v) TD in 5, and vi) UC in 8 lesions. The median time to recurrence (MTR) was significantly shorter in patients who had previously undergone a mesh-repair (n=34) compared to those who had undergone a suture-repair (n=13) [Mesh-repair vs. suture-repair MTR: 1.6 years (0.1-20) vs. 30 years (15-72), p<0.001]. MTR was significantly shorter in the following order: i) MM [0.5(0.1-2.0)]), ii) PM [2.6(0.2-15)]), iii) MD [11(0.5-20)], iv) TD [20(15-30)], and v) TL [40(30-72)] (p<0.001). CONCLUSION: This classification system helps understand the causes of RIH, leading to improved outcomes following open-surgery in the future.