Efficacy of a Novel Palivizumab Prophylaxis Protocol for Respiratory Syncytial Virus Infection in Congenital Heart Disease: A Multicenter Study.

OBJECTIVE: To analyze the efficacy of a novel palivizumab protocol for hemodynamically significant congenital heart disease (hsCHD) in subtropical areas without clear respiratory syncytial virus seasonality. STUDY DESIGN: Since July 2013, the National Health Insurance program has provided reimbursement for palivizumab prophylaxis with a novel monthly protocol in selected patients with hsCHD under 1 year of age. We performed a multicenter study to assess the trend of respiratory syncytial virus hospitalizations in patients with hsCHD from 2010 to 2016 during the prepalivizumab, transition, and postpalivizumab periods, and compared treatment and propensity-matched control groups. RESULTS: A total of 747 patients were enrolled in the study group and 809 in the control group. The male:female was 836:720. Cyanotic CHD was observed in 42.9% of patients. The mean age at diagnosis of CHD was 32.9 days. After 516 685 patient-days of follow-up and a mean of 3.9 doses of palivizumab in the treatment group, respiratory syncytial virus hospitalization rates decreased by 53% and 49% before and after match compared with the control group (P = .009 and .029, respectively). Hospitalization days and intensive care unit admission rate also decreased similarly in the treatment group. The efficacy of this protocol was more prominent in patients with cyanotic hsCHD. The annual respiratory syncytial virus-associated hospitalization rates also decreased significantly from the prepalivizumab to the palivizumab period (from 4.8% to 2.0%; P = .038). CONCLUSION: Palivizumab prophylaxis through the novel monthly protocol for patients with hsCHD is effective in reducing respiratory syncytial virus-related hospitalizations.

Postnatal Risk of Acquiring Kawasaki Disease: A Nationwide Birth Cohort Database Study.

OBJECTIVE: To investigate the postnatal risk of Kawasaki disease and coronary complications from a nationwide birth cohort in Taiwan, a country with the third-highest incidence of Kawasaki disease worldwide. STUDY DESIGN: We enrolled children born between 2000 and 2009 with complete postnatal medical care records for 2000-2014 in the Taiwan national database. RESULTS: Out of a total of 2 150 590 live births, we identified 6690 (62.6% boys) patients with Kawasaki disease. The onset was mostly (93.9%) within the first 5 years of life (median, 16 months; 38% during infancy), but was rare within the first 3 months of life. The overall cumulative incidence of Kawasaki disease by age 5 years was 2.78‰ (3.33‰ for boys and 2.17‰ for girls; P < .001) and exhibited an increasing trend with birth year (from 2.28‰ for 2000 to 3.67‰ for 2009). The incidence ratio was 1.535 in boys and 1.055 in each increasing year. Kawasaki disease recurred more often in younger patients (cumulative incidence, 2.3% in infants vs 1.7% in children aged 1-4 years). Coronary complications occurred in 16.2% of the patients, including 4 cases of acute myocardial infarction (3 occuring during the acute stage and 1 occurring 5 years later). The probability of a major cardiac event (infarction, undergoing percutaneous coronary intervention or coronary artery bypass grafting, or death) by adolescence was 1.9%. CONCLUSIONS: The postnatal risk of Kawasaki disease was 3‰-4‰ and increased with every birth year. Patients with Kawasaki disease are at substantial risk for a major cardiac events during childhood.

Progressive Coronary Dilatation Predicts Worse Outcome in Kawasaki Disease.

OBJECTIVE: To explore the implication of serial coronary changes on the late coronary outcomes in patients with Kawasaki disease (KD) with coronary aneurysms ≧ 4 mm. STUDY DESIGN: We performed a retrospective review of 78 patients with KD with large coronary aneurysms (1980-2013, male: 76.9%; 792 patient-years). Progressive coronary dilatation was defined for those with progressive enlargement of coronary arteries in 3 consecutive echocardiograms. RESULTS: We studied 27 patients with KD with giant aneurysms (≧ 8 mm) and 51 patients with KD with medium aneurysms (4-8 mm). All the giant and 43.1% of medium aneurysms persisted during the study period. For the patients with giant aneurysms, their 10-year freedom from acute myocardial infarction/cardiovascular death and all ischemia was 66% and 52%, respectively. The median intervals for the aneurysm diameters reaching their peak were 3.3 months (giant) and 0.25 months (medium), respectively. In patients with giant aneurysms, the 10-year freedom from ischemia was much lower in those with progressive coronary dilatation (28% vs 59%, P = .021). In patients with medium aneurysms, the probability of 5-year persistence of aneurysm was much greater (67.2% vs 14.8%, P < 10(-3)) in those with progressive coronary dilatation. Male sex and intravenous immunoglobulin therapy were not associated with the late outcomes in the patients with KD who had aneurysms larger than 4 mm. CONCLUSIONS: In addition to coronary diameters 1 month after the onset of KD, progressive coronary dilatation at 2 or more months after diagnosis may be an indicator of duration, and the severity of vasculitis and adverse dilative remodeling were associated with worse late coronary outcomes.

Risk of Respiratory Syncytial Virus Infection in Cyanotic Congenital Heart Disease in a Subtropical Area.

OBJECTIVE: To compare the risk of respiratory syncytial virus (RSV)-associated hospitalization and analyze the epidemiology of RSV infection in patients with cyanotic and acyanotic congenital heart disease (CHD), we analyzed the nationwide health insurance database from 2005-2010. STUDY DESIGN: This study included 1050 patients with cyanotic CHD and 7077 patients with acyanotic CHD. Patients with acyanotic CHD were further classified into hemodynamically significant (hs)-acyanotic and non-hs-acyanotic groups according to whether they underwent surgery or took at least 2 anticongestive medications. RESULTS: RSV-associated hospitalization was higher in the cyanotic group than in hs-acyanotic and non-hs-acyanotic groups both before 1 year of age (4.8% vs 2.1% vs 1.5%, P < .001) and between 1 and 2 years of age (0.9% vs 0.56% vs 0.14%, P = .003). The hospitalization duration, intensive care, ventilator support prevalence, hospitalization cost, and mortality rate were significantly higher in the cyanotic group than in the other 2 groups. Logistic regression revealed that cyanotic CHD was the most significant risk factor for the ventilator support and RSV-associated mortality. In both patients with cyanotic and acyanotic CHD, RSV-associated hospitalization rate was higher in patients aged younger than 1 year and in spring and autumn in Taiwan, a subtropical country. CONCLUSIONS: The results show that patients with cyanotic CHD have a higher risk of severe RSV infection than do those with acyanotic CHD. RSV prophylaxis is more important and may reduce costs more for patients with cyanotic CHD.

Severe bacterial infection in patients with heterotaxy syndrome.

OBJECTIVE: To determine the incidence of sepsis in patients with heterotaxy syndrome. STUDY DESIGN: From our institutional database, we identified patients with heterotaxy syndrome and other complex congenital heart disease (CHD) born between 2001 and 2011. Severe bacterial infection was defined as sepsis with positive culture result or infection with abscess formation. RESULTS: We enrolled 95 patients with heterotaxy syndrome (88 with right atrial isomerism and 7 with left atrial isomerism) and 142 patients with complex CHD. With 1026 person-years follow-up, the 5-year survival was 52% and 65.7% in heterotaxy and complex CHD groups, respectively (P = .239). Community-acquired severe bacterial infection occurred only in heterotaxy syndrome (13 episodes in 10 patients, 3 of whom had spleen noted at imaging study) with 2- and 5 years cumulative severe bacterial infection rate of 9.6% and 14.5%, respectively. The overall mortality rate of those with community-acquired severe bacterial infection was 31%. Pneumococcus and Citrobacter freundii were the most common pathogens. Nosocomial severe bacterial infection occurred in 33.3% of all patients and 12.5% of all procedures. The rates (0.59 and 0.52/100 hospitalization days in heterotaxy and complex CHD group) and the pathogens of nosocomial severe bacterial infection were similar between heterotaxy and complex CHD groups. CONCLUSIONS: Patients with heterotaxy syndrome are at high risk for community-acquired severe bacterial infection and also have high mortality rate whether the spleen is present or not. The risk of nosocomial severe bacterial infection seems similar to that of patients with other complex CHD.

Long-term outcomes of pediatric sinus bradycardia.

OBJECTIVES: To delineate the long-term outcomes and mechanisms of pediatric sinus bradycardia. STUDY DESIGN: Participants with sinus bradycardia who were identified from a survey of 432,166 elementary and high school students, were enrolled 10 years after the survey. The clinical course, heart rate variability, and hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4) gene were assessed. RESULTS: A total of 104 (male:female was 60:44; prevalence, 0.025%) participants were observed to have sinus bradycardia at age 15.5 ± 0.2 years with a mean heart rate of 48.4 ± 0.4 beats per minute; 86 study participants (83%) responded to clinical assessment and 37 (36%) underwent laboratory assessment. Athletes composed 37.8% of the study participants. During the extended 10-year follow-up, 15 (17%) of the participants had self-limited syncopal episodes, but none had experienced life-threatening events. According to Holter recordings, none of the participants had heart rate <30 beats per minute or a pause longer than 3 seconds. Compared with 67 age- and sex-matched controls, the variables of heart rate based on the spectral and time domain analysis of the participants with sinus bradycardia were all significantly higher, indicating higher parasympathetic activity. The results of mutation analysis were negative in the HCN4 gene in all of our participants. CONCLUSIONS: The long-term outcomes of the children and adolescents with sinus bradycardia identified using school electrocardiographic survey are favorable. Parasympathetic hyperactivity, instead of HCN4 gene mutation, is responsible for the occurrence of sinus bradycardia.

Epidemiology of Kawasaki disease: prevalence from national database and future trends projection by system dynamics modeling.

OBJECTIVE: To update the epidemiologic trend in Kawasaki disease (KD) and develop models for projection. STUDY DESIGN: From our national databases 2000-2010 and previous studies, we obtained the epidemiologic data to develop and validate system dynamics models. Population model incorporated birth rate and mortality. KD model incorporated the population at risk, incidence, and risk of coronary complications. RESULTS: The average annual incidence in age group <5, 5-10, 10-15, and 15-20 years was 67.3, 5.75, 0.79, and 0.26 per 100,000. The KD population was 23,349 and the model estimated 20,254 patients with KD, and 25% of these patients received medical care or continued surveillance in 2010. Projection up to 2030 suggests an average of 725 new patients with KD annually and a KD population of 35,006 by 2030. In 2030, 1469 patients with KD will need medical care for coronary complications. Simulation on the model modified to US data is also effective and suggests an average of 6200 new patients annually and KD population of 161,776 by 2030, and 5664 patients will need coronary care in 2030. By 2030, there will be 1 per 700 people in Taiwan and 1 per 1600 in the US with a history of KD. CONCLUSION: Simulations on our system dynamics models tailored to any epidemiologic and outcome variables and any changes with medical advance can dynamically project the futures.

Prevalence of congenital heart disease at live birth in Taiwan.

OBJECTIVES: To investigate the prevalence at live birth of congenital heart disease (CHD) in Taiwan. STUDY DESIGN: Patients with CHD born from 2000 to 2006 were identified from National Health Insurance databases. RESULTS: CHD prevalence was 13.08 per 1000 live births: 12.05 (simple, 10.53; severe, 1.51) in male infants and 14.21 (simple, 12.90; severe, 1.32) in female infants. Ventricular septal defect (VSD; 4.0) was the most common defect, followed by secundum atrial septal defect (ASDII; 3.2), patent ductus arteriosus (PDA; 2.0), pulmonary stenosis (PS; 1.2), tetralogy of Fallot (TOF; 0.63), coarctation of aorta (CoA; 0.25), transposition of great arteries (TGA; 0.21), endocardial cushion defect (ECD; 0.20), double outlet of right ventricle (DORV; 0.15), total anomalous pulmonary venous return (TAPVR; 0.11), aortic stenosis (0.09), hypoplastic left heart syndrome (HLHS; 0.062), Ebstein anomaly (0.047), and tricuspid atresia (0.046). Female predominance was observed in VSD, ASDII, PDA, and ECD; and male predominance was observed in TGA and TOF. Ratios of western prevalence to our Asian prevalence were high for HLHS (3.68-4.5), CoA (1.13-1.96), TGA (1.09-1.83), and tricuspid atresia (1.09-2.57), but low for PS (0.15-0.99), TOF (0.41-0.92), and possibly ASDII. CONCLUSIONS: In this Asian population, the prevalence of CHD was at the high end of the reported range, with more PS and TOF, but fewer left-sided obstructions, TGA, and tricuspid atresia.

Population-based study of pediatric sudden death in Taiwan.

OBJECTIVES: We sought to estimate the incidence of pediatric sudden death (SD) in Taiwan. STUDY DESIGN: Cases of SD were identified from National Health Insurance databases, 2000 to 2006. RESULTS: In the Taiwan pediatric population (age, 0 to 18 years; 5.44 million), the neonatal, infant, postneonatal infant, and under-5 years mortality rates were 3, 6, 2.81, and 8.02 per 1000 live births, and the 1 to 18 years mortality rate was 33 per 100 000 person-years. There were 1528 SDs (59% boys). In the population 1 to 18 years, annual incidence of SD was 2.7 (95% confidence interval, 2.6 to 2.9), ranging from 0.7 (11 to 12 years) to 6.1 (1 to 2 years) per 100 000. Male predominance was noted (3.2 vs 2.2 per 100 000), particularly in groups ages 16, 17, and 18 years. The proportionate mortality ratio by SD ranged from 1.8% to 12.0% (8.9 +/- 2.2%), being lowest in the group ages 11 to 12 years. In infants, the incidence of SD was 0.36 per 1000 live births, and the proportionate mortality ratio by SD was 1.0% and 11.7% in the neonates and postneonatal infants. CONCLUSIONS: The incidence of pediatric SD in Taiwan, an Asian country with a child health care index comparable with that in the United States, was within the range from Western reports and indicated male predominance and a nadir around 11 to 12 years.

Reversal of cardiac dysfunction after enzyme replacement in patients with infantile-onset Pompe disease.

OBJECTIVE: To compare the effects of enzyme replacement therapy (ERT) on cardiac performance in symptomatic and symptom-free infants with Pompe disease. STUDY DESIGN: Patients diagnosed between 1983 and 2008 were identified. Before the initiation of ERT, systolic dysfunction appeared only in patients > or = 5 months; thus we used this cut-point in age to divide clinically symptomatic patients into early and late treatment groups (Clin-E and Clin-L). Newborn screening (NBS) identified symptom-free patients. RESULTS: Among a total of 40 patients, 14 received ERT: 5 in the Clin-L, 4 in the Clin-E, and 5 in the NBS groups. All patients showed cardiomegaly, hypertrophic myocardium, and elevated B-type natriuretic peptide (measured in the Clin-E and NBS groups). ERT improved the survival and outcomes. Regressed myocardial hypertrophy and lowered B-type natriuretic peptide level occurred after 1 to 6 months of ERT. Nonetheless, there were 2 deaths and 2 survivors requiring ventilator support in the Clin-L group. Despite the regressed QRS voltage and shortened QT dispersion, life-threatening arrhythmias were still observed in 3, but none in the NBS group. CONCLUSION: ERT may restore the cardiac function in both symptomatic and symptom-free patients, but the beneficial effect may be unpredictable if given after the age of 5 months.

Cardiac conduction disturbance detected in a pediatric population.

OBJECTIVE: To delineate the prevalence and clinical implications of cardiac conduction disturbance (CCD) in school-age children. STUDY DESIGN: Between 1999 and 2001, a citywide survey of 432,166 elementary and high school students had been performed in Taipei by questionnaire, electrocardiography, phonocardiography, and physical examination. Patients with any abnormalities on this survey were referred for final diagnosis. RESULTS: After excluding those with congenital heart disease (CHD), the prevalence of CCD was 0.75%, higher in males than in females (0.78% vs 0.71%). Incomplete right bundle branch block (IRBBB; 0.32%), complete right bundle branch block (CRBBB; 0.11%), ventricular premature contraction (0.11%), and Wolff-Parkinson-White syndrome (0.067 %) were the most common diagnoses. Second-degree atrioventricular block, IRBBB, CRBBB, and intraventricular conduction delay were more common in males; and atrial premature contraction was more common in females. The prevalence of CCD increased with age, from 0.48% in elementary school students to 0.97% in high school students. After detection of CCD, 39 patients with previously undiagnosed atrial septal defect (ASD) and 15 high-risk patients were found. The sensitivity of IRBBB in screening for ASD was 34.67%. CONCLUSIONS: The prevalence of CCD in children without CHD was 0.75%. Detection of CCD helped identify patients with unrecognized ASD and high-risk cardiac patients.

Noninvasive diagnosis of aortic coarctation in neonates with patent ductus arteriosus.

OBJECTIVES: To find a noninvasive method to detect coarctation of the aorta (CoA) in the presence of a patent ductus arteriosus (PDA) in neonates. STUDY DESIGN: From 1994 to 1998, 36 neonates with CoA and PDA confirmed by surgery or cardiac catheterization were studied; another 19 neonates with isolated PDA served as control patients. The prospective study was conducted from 2001 to 2002 on 162 neonates. RESULTS: Among the 36 neonates in the CoA group, 14 patients (39%) had blood pressure discrepancy, 26 patients (72%) had a visualized posterior shelf by echocardiogram, and the ratio of isthmus/descending aorta diameters (I/D ratio) was below 0.64 in 32 patients (89%). None of the control patients had these features. A diagnostic approach was subsequently proposed, according to which a neonate with PDA who fulfilled any of the above features was diagnosed as CoA plus PDA. In the prospective study, the sensitivity and positive predictive values of this method were both 91.7%, whereas the specificity and negative predictive values were both 99.3%. CONCLUSIONS: Echocardiographic measurements of I/D ratio along with the delineation of posterior shelf and a BP discrepancy can satisfactorily identify CoA in the presence of PDA in neonates.

Sudden death in patients with right isomerism (asplenism) after palliation.

OBJECTIVE: To define the risk of sudden death in patients with right isomerism (asplenia) after palliation. STUDY DESIGN: A total of 154 patients with right isomerism was identified from 1980 to 1999. Sudden death was defined as acute cardiovascular collapse from which death occurred within 24 hours. RESULTS: A total of 620 patient-years were evaluated. The 1-year and 5-year survival was 72% and 50%, respectively. There were 22 sudden unexpected deaths (14%, 35 events/1000 patient-years). Sudden death tended to occur in infancy or early childhood (12 +/- 9 months; median, 9 months). The mechanisms were classified as sudden tachyarrhythmic in 2 (9%), sudden cardiac but nontachyarrrhythmic (sudden onset severe cyanosis) in 15 (68%), and sudden noncardiac in 5 (23%)(fulminant sepsis with positive blood culture: streptococcus pneumonia (3), Escherichia coli (1), and yeast-like organism (1)). The incidence of sudden death steadily decreased with age until the age of 3 years. CONCLUSION: The incidence of sudden death in patients with right isomerism after initial palliation remained high. Sudden death was related to complex cardiac anomalies, a susceptibility to fulminant infection, and arrhythmia.