Coxsackievirus B3 Infection Early in Pregnancy Induces Congenital Heart Defects Through Suppression of Fetal Cardiomyocyte Proliferation.

Background Coxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through coxsackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation. Methods and Results We infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose-response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of ventricular septal defect (33.6%), abnormal myocardial architecture resembling noncompaction (23.5%), and double-outlet right ventricle (4.4%) among 209 viable fetuses examined. We observed a direct relationship between viral titers and severity of congenital heart defects, with apparent predominance among female fetuses. Infected dams remained healthy; we did not observe any maternal heart or placental injury suggestive of direct viral effects on developing heart as likely cause of congenital heart defects. We examined signaling pathways in CVB3-exposed hearts using RNA sequencing, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and immunohistochemistry. Signaling proteins of the Hippo, tight junction, transforming growth factor-ß1, and extracellular matrix proteins were the most highly enriched in CVB3-infected fetuses with ventricular septal defects. Moreover, cardiomyocyte proliferation was 50% lower in fetuses with ventricular septal defects compared with uninfected controls. Conclusions We conclude prenatal CVB3 infection induces congenital heart defects. Alterations in myocardial proliferate capacity and consequent changes in cardiac architecture and trabeculation appear to account for most of observed phenotypes.

Lessons learnt from COVID-19 in adult congenital heart patient in Tehran: a survey-based study of prevention, exposure, susceptibility, and outcomes.

BACKGROUND: COVD-19 pandemic has overwhelmed many healthcare systems worldwide. Underlying cardiovascular disease predisposes to greater disease susceptibility and more complications including mortality. Such data is unverified in adults with congenital heart disease (ACHD). The aim of the study is to report the Tehran experience with respect to preventative self-care measures, disease exposure, susceptibility, and outcomes after COVD-19 infection in ACHD patients. METHODS: A telephone-based survey was conducted in ACHD patients, focusing on new-onset symptoms that might indicate COVID-19 infection, prevention measures, confirmed infection rates, and outcomes. RESULTS: Three-hundred and nine ACHD patients, with a mean age of 29.13 years (range from 14 to 72 years, SD = 10.64), and 170 (55%) women were assessed. The majority (86.7%) had moderate or complex ACHD. Two-thirds (67.3%) of the patients practiced high-level preventative self-care measures. After community exposure, 33.3% developed COVID-19, and after household exposure, 43.7% developed COVID-19. There was only one mortality in a post-operative patient. Thirty-seven patients (12%) reported new symptoms including cough (10%), fatigue (8%), fever (7%), and new dyspnoea (6.5%). Amongst 18 (6%) with confirmed COVID-19, there was only 1 mortality in a post-operative patient. Age (adjusted OR = 1.19, 95% CI: 1.07-1.31, p = 0.001), contact with confirmed COVID-19 cases (adjusted OR = 59.34, 95% CI: 3.68-955.10, p = 0.004) were independently associated with COVID-19 infection. CONCLUSIONS: Mortality risk associated with COVID-19 infection in ACHD patients with moderate or severe disease appears to be relatively low, similar to the general population. Such risk appears to act through conventional risk factors, and in this cohort, we demonstrated age as a significant risk factor in addition to exposure to the development of COVID-19 infection. Preventative self-care measures are a potentially significant and impactful intervention target for intervention and for improving outcomes.

Epidemiology of respiratory syncytial virus infection and its effect on children with heart disease in Hong Kong: a multicentre review.

OBJECTIVES: There is no guideline in Hong Kong regarding respiratory syncytial virus (RSV) immunoprophylaxis for children with heart disease because of a lack of local data on RSV infection. Therefore, this study evaluated the epidemiology and impact of RSV infection on children with heart disease in Hong Kong, with the goal of providing recommendations regarding RSV immunoprophylaxis. METHODS: This multicentre retrospective case-control study on paediatric RSV infection was conducted in four local regional hospitals from 2013 to 2015. The patients' demographic and clinical data were retrieved and analysed. RESULTS: There were 3538 RSV hospitalisations during the study period, and the mortality rate was 0.14%. Some RSV seasonality was present in Hong Kong, primarily in spring and summer. Respiratory syncytial virus infection was positively correlated with relative humidity and negatively correlated with wind speed and atmospheric pressure. Patients with heart disease had a more severe outcome than those without, including longer median hospital stay (4 vs 2 days, P<0.001), higher complication rate (28.6% vs 9.8%, P<0.001), and higher rates of intensive care (11.6% vs 1.4%, P<0.001) and mechanical ventilation (3.6% vs 0.4%, P=0.003). Complications in non-cardiac patients included myocarditis and Kawasaki disease. Predictors of severe RSV infection in patients with heart disease were heart failure, pulmonary hypertension, and severe airway abnormalities associated with congenital heart disease. CONCLUSIONS: Respiratory syncytial virus infection occurs mainly in spring and summer in Hong Kong, and is related to meteorological conditions. Respiratory syncytial virus infection poses a heavy disease burden on children with heart disease. A local guideline on RSV immunoprophylaxis for these children is therefore needed.

Challenges in a unique presentation of congenital dengue with congenital heart disease.

Vertical transmission of dengue has been documented and is associated with diverse presentations in newborns. Care of such babies requires meticulous support to maintain homeostasis until the baby recovers. We present a neonate diagnosed with congenital dengue, born to a mother diagnosed with dengue on the second day after delivery. Baby was diagnosed by serological tests, underwent appropriate management in neonatal intensive care but was noted to have had coexistent persistent ductus arteriosus and pulmonary hypertension complicating pneumonia and seizures. Management of the baby was complicated by persistent haematological derangements caused by dengue and haemodynamic alterations caused by the heart disease.

Maternal Viral Infection and Risk of Fetal Congenital Heart Diseases: A Meta-Analysis of Observational Studies.

Background At present, the association between maternal viral infection and risk of congenital heart diseases ( CHD ) in offspring is uncertain; additionally, a complete overview is missing. A meta-analysis of observational studies was performed to address the question of whether women who had a history of viral infection in early pregnancy were at an increased risk of CHD in offspring, compared with mothers without viral infection. Methods and Results Unrestricted searches were conducted, with an end date parameter of July 15, 2018, of PubMed, Embase, Google Scholar, Cochrane Libraries, and Chinese databases, to identify studies that met prestated inclusion criteria. Seventeen case-control studies involving 67 233 women were included for analysis. Both fixed-effects models (odds ratio [OR], 1.83; 95% CI , 1.58-2.12; P<0.0001) and random-effects models ( OR , 2.28; 95% CI , 1.54-3.36; P<0.0001) suggested that mothers who had a history of viral infection in early pregnancy experienced a significantly increased risk of developing CHD in offspring. For specific viral infections, the risk of developing CHD in offspring was significantly increased among mothers with rubella virus (OR, 3.49, 95% CI, 2.39-5.11 in fixed-effects models; and OR, 3.54; 95% CI, 1.75-7.15 in random-effects models) and cytomegalovirus (OR, 3.95; 95% CI, 1.87-8.36 in fixed-effects models) in early pregnancy; however, other maternal viral infections in early pregnancy were not significantly associated with risk of CHD in offspring. Sensitivity analysis yielded consistent results. No evidence of publication bias was observed. Conclusions Although the role of potential bias and evidence of heterogeneity should be carefully evaluated, the present study suggests that maternal viral infection is significantly associated with risk of CHD in offspring.

Respiratory virus prophylaxis in congenital heart disease.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections and causes up to 200,000 infant deaths a year worldwide. The average rate of hospitalization for severe RSV infection is 5 per 1000 children, and the rate is three-times higher in those with congenital heart disease (CHD). Palivizumab, a monoclonal antibody, reduces hospitalization rates and intensive care admissions. It is used prophylactically and is administered as monthly doses during the RSV season. Hemodynamically unstable CHD is the most susceptible CHD to a severe episode of RSV infection. This review explores current evidence surrounding therapies, patterns of infection and identifies groups which may still be vulnerable to severe RSV infection.

Ultrasound Findings Associated With Antepartum Viral Infection.

This article reviews the sonographic manifestations of fetal infection and the role of ultrasound in the evaluation of the fetus at risk for congenital infection. Several ultrasound findings have been associated with in utero fetal infections. For the patient with a known or suspected fetal infection, sonographic identification of characteristic abnormalities can provide useful information for counseling and perinatal management. Demonstration of such findings in the low-risk patient may serve to identify the fetus with a previously unsuspected infection. The clinician should understand the limitations of ultrasound in the prenatal diagnosis of congenital infection and discuss them with the patient.

Respiratory syncytial virus hospitalization risk in the second year of life by specific congenital heart disease diagnoses.

Children with hemodynamically significant congenital heart disease (CHD) are at elevated risk of morbidity and mortality due to respiratory syncytial virus (RSV) disease compared to their healthy peers. Previous studies have demonstrated lower RSV hospitalization risk among all children with CHD at 12-23 months of age versus 0-11 months of age. However, RSV hospitalization risk at 12-23 months of age by specific CHD diagnosis has not been characterized. Both case-control and cohort studies were conducted using data from the US National Inpatient Sample from 1997 to 2013 to characterize relative risk of RSV hospitalization among children 12-23 months of age with CHD. Related CHD diagnoses were combined for analysis. Hospitalizations for RSV and unspecified bronchiolitis were described by length of stay, mechanical ventilation use, mortality, and total charges. Over the 17-year period, 1,168,886 live birth hospitalizations with CHD were identified. Multiple specific CHD conditions had an elevated odds ratio or relative risk of RSV hospitalization. Mean total RSV hospitalization charges were significantly higher among children with CHD relative to those without CHD ($19,650 vs $7,939 in 2015 dollars) for this period. Compared to children without CHD, children with Ebstein's anomaly, transposition of the great arteries, aortic stenosis, heterotaxia, and aortic arch anomalies had 367-, 344-, 203-, 117- and 47-fold increased risk of inpatient RSV mortality, respectively. Unspecified bronchiolitis hospitalization odds and relative risk across CHD diagnoses were similar to those observed with RSV hospitalization; however, unspecified bronchiolitis hospitalizations were associated with shorter mean days of stay and less frequently associated with mechanical ventilation or mortality. Among children with more severe CHD diagnoses, RSV disease remains an important health risk through the second year of life. These data can help inform decisions regarding interventions to protect children with CHD from severe RSV disease during their second year of life.

Secondary congenital aphakia.

UNLABELLED: Abstract PURPOSE: We present the clinical, paraclinical and therapeutic features in a patient with secondary congenital aphakia. METHODS: A 2-year-old patient, diagnosed with congenital rubella syndrome including sensorineural deafness, congenital heart disease, intellectual disability, microcephaly, microphthalmia, and congenital cataract, presented to our clinic for the surgical treatment of cataract. RESULTS: During the surgery, the absence of the lens' cortex was observed, hence, the final diagnose was of secondary congenital aphakia. Surgery was then continued with a posterior capsulorhexis and an anterior vitrectomy, deciding to postpone the implantation of the posterior chamber intraocular lens.

Respiratory syncytial virus-associated intensive care unit admission in children in Southern China.

BACKGROUND: There are incomplete data on the global burden of viral lower respiratory tract infection, in particular the role of Respiratory Syncytial Virus, in children requiring health services. FINDINGS: In this study set in a large urban area of southern China from 1 January 2007 to 31 December 2010, children 1 month to 14 years of age with RSV-associated "severe" or "very severe pneumonia" according to World Health Organization definitions, and meeting local criteria for admission to the pediatric intensive care unit, were followed for the course of their admission. The median age was 3 months and 79% (135/171) of children with RSV were under six months of age. All children needed supplemental oxygen, and 22% required mechanical ventilatory support. The mortality rate was 3.5%. In multivariate analysis, congenital heart disease and Trisomy 21 were associated with death. CONCLUSIONS: Children admitted to an intensive care unit with RSV-associated severe/very pneumonia in a large urban setting in southern China were most commonly ≤ six months old and almost one quarter of these had respiratory failure. The overall mortality rate was 3.5%. RSV vaccine strategies that would protect children from early infancy are urgently needed.

The use of humanized monoclonal antibodies for the prevention of respiratory syncytial virus infection.

Monoclonal antibodies are widely used both in infants and in adults for several indications. Humanized monoclonal antibodies (palivizumab) have been used for many years for the prevention of respiratory syncytial virus infection in pediatric populations (preterm infants, infants with chronic lung disease or congenital heart disease) at high risk of severe and potentially lethal course of the infection. This drug was reported to be safe, well tolerated and effective to decrease the hospitalization rate and mortality in these groups of infants by several clinical trials. In the present paper we report the development and the current use of monoclonal antibodies for prophylaxis against respiratory syncytial virus.

Impact of palivizumab on RSV hospitalizations for children with hemodynamically significant congenital heart disease.

The objective of this study was to evaluate the impact of palivizumab prophylaxis on respiratory syncytial virus (RSV) hospitalizations among children with hemodynamically significant congenital heart disease (CHD). In 2003, the American Academy of Pediatrics (AAP) revised the bronchiolitis policy statement and recommended the use of palivizumab in children <24 months old with hemodynamically significant CHD (HS-CHD). California statewide hospital discharge data from years 2000-2002 (pre-AAP policy revision) were compared to those from years 2004-2006 (post-AAP policy revision). Hospitalizations due to RSV bronchiolitis for children <2 years of age were identified by IDC-9 CM codes 4661.1, 480.1, and 079.6 as the Principal Diagnosis. Children with CHD and children with HS-CHD were identified by the codiagnoses. The overall RSV hospitalization rate was 71 per 10,000 children <2 years of age. Of all RSV hospitalizations, 3.0% were among children with CHD, and 0.50% among children with HS-CHD. HS-CHD patients accounted for 0.56% of RSV hospitalizations in 2000-2002, compared to 0.46% RSV hospitalizations in 2004-2006. That represents a 19% reduction in RSV hospitalizations among HS-CHD patients after 2003. The 19% decrease in RSV hospitalizations equates to seven fewer hospitalizations (76 hospital days) per year among HS-CHD patients. We conclude that, since the recommendation of palivizumab for children with HS-CHD in 2003, the impact on RSV hospitalizations in California among HS-CHD patients has been limited. Considering the high cost of palivizumab administration, the cost-benefit of RSV prophylaxis with palivizumab warrants further investigation.

Cost effectiveness of palivizumab in children with congenital heart disease in Germany.

OBJECTIVES: To assess the cost effectiveness of palivizumab, a humanised monoclonal antibody, used as prevention against severe respiratory syncytial virus (RSV) infection requiring hospitalisation, in infants with haemodynamically significant congenital heart disease (CHD) in the German healthcare setting. STUDY DESIGN: A decision-tree model was used to estimate the cost effectiveness of palivizumab for a hypothetical cohort of patients. The analysis was based on a lifetime follow-up period in order to capture the impact of palivizumab on long-term morbidity and mortality resulting from an RSV infection. Data sources included published literature, the palivizumab pivotal trials, official price/tariff lists and national population statistics. The study was conducted from the perspective of society (primary analysis) and the healthcare purchaser (secondary analysis). RESULTS: From the societal perspective, use of palivizumab results in an incremental cost-effectiveness ratio (ICER) of €2,615 per quality-adjusted life-year (QALY) without discounting, which increases to €9,529/QALY after discounting. From the perspective of the German healthcare purchaser, use of palivizumab results in an ICER of €4,576/QALY without discounting, which increases to €16,673/QALY after discounting. Probabilistic sensitivity analyses confirmed the robustness of the model. The study is limited by a number of conservative assumptions. It was assumed that palivizumab only affects the occurrence of RSV hospitalisation and does not influence the severity of the RSV infection. Another assumption was that international clinical trial data and data on utilities could be applied to the German healthcare setting. CONCLUSION: This analysis showed that palivizumab represents a cost-effective means of prophylaxis against severe RSV infection requiring hospitalisation in infants with haemodynamically significant CHD.

Cost effectiveness of palivizumab for RSV prevention in high-risk children in the Netherlands.

BACKGROUND: Respiratory syncytial virus (RSV) is a common pathogen that is the leading cause of lower respiratory tract infections in young children. High-risk children are at risk of severe infection, which may require hospitalisation. RSV is also associated with a high risk for respiratory morbidity and mortality, which may have long-term clinical and economic consequences. OBJECTIVE: To assess the cost effectiveness of palivizumab, a humanised monoclonal antibody, used as prevention against severe respiratory syncytial virus (RSV) infection requiring hospitalisation, in the indication of preterm infants and infants with preterm/bronchopulmonary dysplasia and in the second indication of children with congenital heart disease in the Dutch healthcare setting. METHODS: A decision-tree model was used to estimate the cost effectiveness of palivizumab, used as a preventative treatment against severe respiratory syncytial virus (RSV) infection, in high-risk groups of children in the Netherlands. The analysis was based on a lifetime follow-up period in order to capture the impact of palivizumab on long-term morbidity and mortality resulting from an RSV infection. Data sources included published literature, the palivizumab pivotal trials, official price/tariff lists and national population statistics. The study was conducted from the perspective of society in the Netherlands. RESULTS: The use of palivizumab results in undiscounted incremental cost-effectiveness ratios of €12,728/QALY and €4,256/QALY in preterm/bronchopulmonary dysplasia and congenital heart disease indications, respectively. Inclusion of indirect costs leads to even more favourable cost-effectiveness outcomes. The study is limited by a number of conservative assumptions. It was assumed that palivizumab only affects the occurrence of RSV hospitalisation and does not influence the severity of the RSV infection. Another assumption was that international clinical trial data and data on utilities could be applied to the Dutch healthcare setting. CONCLUSION: Palivizumab provides cost-effective prophylaxis against RSV in high-risk infants. The use of palivizumab in these children results in positive short- and long-term health-economic benefits.

Human herpes virus 6 in archival cardiac tissues from children with idiopathic dilated cardiomyopathy or congenital heart disease.

OBJECTIVE: To explore the possible role of human herpes virus 6 (HHV-6) in cardiac disorders in childhood in a retrospective study on archival specimens of explanted hearts. METHODS: 16 children (median age at transplantation 11.0 years) with idiopathic dilated cardiomyopathy (DCM) and 19 children (median age at transplantation 1.0 year) with congenital heart disease (CHD), previously found to be negative for other cardiotropic viruses such as enteroviruses, adenovirus, parvovirus B19, cytomegalovirus and Epstein-Barr virus, were tested for HHV-6 by quantitative real-time PCR and by genotyping. In addition, HHV-7/8 infection was investigated by qualitative PCR. RESULTS: HHV-6 B variant was detected in 11 of 35 samples (31.4%) with a mean viral load of 3.1 x 102 copies/microg of DNA. When assessed by heart disorder, the prevalence was different in the two groups (43.7% in DCM and 21% in CHD) while the mean viral loads were similar. In a logistic multivariate analysis HHV-6 was independently associated with DCM, taking CHD as reference and adjusting for age (best estimate: OR = 6.94; 95% CI 1.00 to 49.85; p = 0.05). CONCLUSIONS: Although the clinical significance of the results is unknown, HHV-6 B genome is frequently detected in explanted hearts from children with DCM and to a lesser extent with CHD, thus adding evidence for HHV-6 cardiac involvement.

Nationwide survey of palivizumab for respiratory syncytial virus prevention in Japanese children with congenital heart disease.

A questionnaire study was performed to determine the current status of palivizumab prophylaxis against respiratory syncytial virus infection in Japanese children with congenital heart disease <2 years of age. Palivizumab prophylaxis decreased the respiratory syncytial virus hospitalization rate by 42.8%.

Palivizumab in congenital heart disease: should international guidelines be revised?

Palivizumab has reduced the incidence of respiratory syncytial virus hospitalization in infants and children with congenital heart disease by 45%. Although the mortality rate of children with congenital heart disease hospitalized with respiratory syncytial virus infection has declined from 37% to approximately 3% over the past 3 decades, palivizumab has not been shown to improve mortality. There has been considerable controversy over the cost-effectiveness of administering palivizumab according to international guidelines, including children with congenital heart disease. In particular, the number of children that need to be treated with palivizumab to prevent one respiratory syncytial virus hospitalization increases dramatically in children > 12 months of age. As a result, the authors recommend that countries re-examine their recommendations for providing palivizumab up to age 24 months in children with congenital heart disease.