Evaluation of late cardiac effects after multisystem inflammatory syndrome in children.

Introduction: Multisystem inflammatory syndrome in children (MIS-C) is associated with important cardiovascular morbidity during the acute phase. Follow-up shows a swift recovery of cardiac abnormalities in most patients. However, a small portion of patients has persistent cardiac sequelae at mid-term. The goal of our study was to assess late cardiac outcomes of MIS-C. Methods: A prospective observational multicenter study was performed in children admitted with MIS-C and cardiac involvement between April 2020 and March 2022. A follow-up by NT-proBNP measurement, echocardiography, 24-h Holter monitoring, and cardiac MRI (CMR) was performed at least 6 months after MIS-C diagnosis. Results: We included 36 children with a median age of 10 (8.0-11.0) years, and among them, 21 (58%) were girls. At diagnosis, all patients had an elevated NT-proBNP, and 39% had a decreased left ventricular ejection fraction (LVEF) (<55%). ECG abnormalities were present in 13 (36%) patients, but none presented with arrhythmia. Almost two-thirds of patients (58%) had echocardiographic abnormalities such as coronary artery dilation (20%), pericardial effusion (17%), and mitral valve insufficiency (14%). A decreased echocardiographic systolic left ventricular (LV) function was detected in 14 (39%) patients. A follow-up visit was done at a mean time of 12.1 (±5.8) months (range 6-28 months). The ECG normalized in all except one, and no arrhythmias were detected on 24-h Holter monitoring. None had persistent coronary artery dilation or pericardial effusion. The NT-proBNP level and echocardiographic systolic LV function normalized in all patients, except for one, who had a severely reduced EF. The LV global longitudinal strain (GLS), as a marker of subclinical myocardial dysfunction, decreased (z < -2) in 35%. CMR identified one patient with severely reduced EF and extensive myocardial fibrosis requiring heart transplantation. None of the other patients had signs of myocardial scarring on CMR. Conclusion: Late cardiac outcomes after MIS-C, if treated according to the current guidelines, are excellent. CMR does not show any myocardial scarring in children with normal systolic LV function. However, a subgroup had a decreased GLS at follow-up, possibly as a reflection of persistent subclinical myocardial dysfunction.

Blood transcriptomics to facilitate diagnosis and stratification in pediatric rheumatic diseases - a proof of concept study.

BACKGROUND: Transcriptome profiling of blood cells is an efficient tool to study the gene expression signatures of rheumatic diseases. This study aims to improve the early diagnosis of pediatric rheumatic diseases by investigating patients' blood gene expression and applying machine learning on the transcriptome data to develop predictive models. METHODS: RNA sequencing was performed on whole blood collected from children with rheumatic diseases. Random Forest classification models were developed based on the transcriptome data of 48 rheumatic patients, 46 children with viral infection, and 35 controls to classify different disease groups. The performance of these classifiers was evaluated by leave-one-out cross-validation. Analyses of differentially expressed genes (DEG), gene ontology (GO), and interferon-stimulated gene (ISG) score were also conducted. RESULTS: Our first classifier could differentiate pediatric rheumatic patients from controls and infection cases with high area-under-the-curve (AUC) values (AUC = 0.8 ± 0.1 and 0.7 ± 0.1, respectively). Three other classifiers could distinguish chronic recurrent multifocal osteomyelitis (CRMO), juvenile idiopathic arthritis (JIA), and interferonopathies (IFN) from control and infection cases with AUC ≥ 0.8. DEG and GO analyses reveal that the pathophysiology of CRMO, IFN, and JIA involves innate immune responses including myeloid leukocyte and granulocyte activation, neutrophil activation and degranulation. IFN is specifically mediated by antibacterial and antifungal defense responses, CRMO by cellular response to cytokine, and JIA by cellular response to chemical stimulus. IFN patients particularly had the highest mean ISG score among all disease groups. CONCLUSION: Our data show that blood transcriptomics combined with machine learning is a promising diagnostic tool for pediatric rheumatic diseases and may assist physicians in making data-driven and patient-specific decisions in clinical practice.

Thrombocytopenia in severe iron deficiency anemia in children.

AIM: Iron deficiency anemia (IDA) is common in the pediatric population and often accompanied by mild thrombocytosis, but rarely profound thrombocytopenia is seen. We describe the data of children with IDA and thrombocytopenia in two centers and discuss the published data in the literature. METHODS: In this retrospective case series, the medical records of patients under the age of 19 years old diagnosed with IDA in two tertiary medical centers over the last 10 years, were reviewed. The data were collected and compared to the data published in the medical literature. RESULTS: All the patients presented with severe IDA and thrombocytopenia improved with iron treatment. Although none of the patients had signs of major bleeding, the thrombocytopenia could mostly be classified as severe (platelet count <50×10E9/L). Due to the severity of the anemia, in about half of the cases, a red blood cell transfusion was given. The peak of the platelet count was seen in the first month after the start of iron treatment. In eight cases of children with IDA, the thrombocytopenia appeared after the supplementation of iron was started. CONCLUSION: Clinically stable children with severe IDA and thrombocytopenia, where other causes are very unlikely, warrant an empiric monotherapy with iron to prevent unnecessary investigations and treatments.

Determinants of Physical Fitness in Children with Repaired Congenital Heart Disease.

The aim of this study was to determine factors associated with physical fitness (PF) in children who underwent surgery for congenital heart disease (CHD). Sixty-six children (7-14 years) who underwent surgery for ventricular septal defect (n = 19), transposition of great arteries (n = 22), coarctation of aorta (n = 10), and tetralogy of Fallot (n = 15) were included. All children performed PF tests: cardiorespiratory fitness, upper- and lower-limb muscle strength, speed, balance, and flexibility. Cardiac evaluation was done via echocardiography and cardiopulmonary exercise test. Factors related to child's characteristics, child's lifestyle, physical activity motivators/barriers, and parental factors were assessed. Linear regression analyses were conducted. The results showed no significant differences in physical activity (PA) level by CHD type. Boys had better cardiorespiratory fitness (difference = 1.86 ml/kg/min [0.51;3.22]) and were more physically active (difference = 19.40 min/day [8.14;30.66]), while girls had better flexibility (difference = - 3.60 cm [- 7.07;- 0.14]). Physical activity motivators showed an association with four out of six PF components: cardiorespiratory fitness, coefficient = 0.063 [0.01;0.11]; upper-limb muscle strength, coefficient = 0.076 [0.01;0.14]; lower-limb muscle strength, coefficient = 0.598 [0.07;1.13]; and speed, coefficient = 0.03 [0.01;0.05]. Age, sex, and motivators together reached a maximum adjusted R2 = 0.707 for upper-limb strength. Adding other possible determinants did not significantly increase the explained variance. Apart from age and sex as non-modifiable determinants, the main target which might improve fitness would be the introduction of an intervention which increases the motivation to be active.

Muscle strength field-based tests to identify European adolescents at risk of metabolic syndrome: The HELENA study.

OBJECTIVES: To determine whether handgrip strength (HG) and/or standing long jump (SLJ) are capable of detecting risk of metabolic syndrome (MetS) in European adolescents, and to identify age- and sex-specific cut points for these tests. DESIGN: Cross-sectional study. METHODS: Participants included 969 (aged 12.5-17.5 years old) adolescents from 9 European countries (n = 520 girls). Absolute and relative HG and SLJ tests were used to assess upper and lower muscle strength, respectively. MetS status was determined using the age- and sex-specific cut points proposed by Jolliffe and Janssen´s, Additionally, we computed a continuous cardiometabolic risk index with the average z-score of four cardiometabolic risk factors: Wait circumference, mean arterial pressure, triglycerides/high-density lipoprotein cholesterol, and fasting insulin. RESULTS: The prevalence of MetS was 3.1% in European adolescents. Relative HG and absolute SLJ were the best tests for detecting the presence of MetS (Area under the receiver operating characteristic (AUC) = 0.799, 95%CI:0.773-0.824; and AUC = 0.695 95%CI:0.665-0.724), respectively) and elevated cardiometabolic risk index (AUC = 0.873, 95%CI:0.838-0.902; and AUC = 0.728 95%CI:0.698-0.756), respectively) and, regardless of cardiorespiratory fitness. We provide age- and sex-specific cut points of upper and lower muscle strength for European adolescents to identify the presence of MetS and elevated cardiometabolic risk index. CONCLUSIONS: The proposed health-related cut points could be used as a starting point to define health-related levels of upper and lower muscle strength in adolescents. Likewise, the diagnostic statistics provided herein can be used to offer feedback to adolescents, parents, and education and health professionals about what it means to meet or fail test standards.

Body mass index in adults with congenital heart disease.

OBJECTIVE: To investigate the status of body mass index (BMI) in adult people with congenital heart disease (ACHD). METHODS: Five hundred thirty-nine adults with CHD (53.8% men) were seen in the outpatient clinic from 2013 to 2015 and compared to a reference population (n = 1737). The severity of CHD was categorized as mild, moderate, and severe according to standard guidelines. Patients were categorized based on BMI as underweight (<18.5), overweight (25-30), or obese (>30). Echocardiography and magnetic resonance imaging were used to measure ventricular function while exercise capacity was estimated via cardiopulmonary exercise test. RESULTS: Adults with CHD had slightly lower BMI than the reference group (24.1 ± 4.3 vs 24.6 ± 4.3; P = .012). Men in the mild and severe group (23.9 ± 3.6; 23.3 ± 4.4 vs 25.1 ± 3.7; P = .007; P = .023) and women in the severe group (21.6 ± 3.3 vs 24.2 ± 4.7; P < .001) had lower BMI compared to the reference group. In the subgroups, men with ventricular septal defect, coarctation of aorta/ventricular septal defect and Fontan circulation and women with Fontan circulation had lower BMI than the reference group. Underweight was more prevalent in women with severe lesions compared to the reference group (22.2% vs 3.8%; P < .001). BMI was associated with age and exercise capacity in patients with mild and moderate lesions, while higher BMI was related to better ventricular function in women with Fontan circulation. CONCLUSION: Underweight was more prevalent in ACHD patients with severe lesions. Special attention should be paid to the possible existence of underweight-related comorbidities.

Use of Nutritional Supplements in Youth with Medicated and Unmedicated Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: To find out whether use of nutritional supplements (NUS) differs between children and adolescents with attention-deficit/hyperactivity disorder (ADHD; medicated or unmedicated), compared with those without the disorder. METHODS: We used cross-sectional data from the population-based I.Family study conducted between 2013 and 2014 in eight European countries. Parents completed questionnaires and participated in interviews, for example, on health and medical history of their child. Data from 5067 children and adolescents aged 5-17 years were included. Exposures were medicated (with ADHD-approved medication) and unmedicated ADHD. The outcome was the use of NUS, measured by use of any or multiple different NUS. Multivariable logistic regression adjusted for sociodemographics and health determinants was used to find ADHD-depending differences. RESULTS: The study sample comprised 4490 children and adolescents without ADHD and 51 medicated and 76 unmedicated subjects with ADHD. Regarding the use of any NUS, no statistically significant differences were found between children and adolescents without ADHD (18%) and those with medicated (18%) or unmedicated ADHD (22%). However, discrepancies appear when considering multiple use of NUS, not reported for any medicated ADHD subject but remarkably often for unmedicated ADHD subjects (13%), resulting in an adjusted odds ratio of 2.6 (95% confidence interval, 1.2-5.6) when compared with those without ADHD (5%). CONCLUSION: Children and adolescents who were not using medication for treating ADHD potentially took NUS as oral remedies. Given the potential for a delay of indicated treatments and for use of those NUS which have no proven effectiveness, pediatricians should actively explore whether NUS have been used to treat ADHD core symptoms, and families should be informed that the average effect size has to be considered small.

Longitudinal association between psychosocial stress and retinal microvasculature in children and adolescents.

BACKGROUND: Retinal microvessels provides a window to assess the microcirculation of heart and brain, and might reflect cardio- or cerebrovascular disease risk. Limited information exist on the relation between psychosocial stress and the microcirculation, even though psychosocial stress might trigger vascular diseases. This study investigates whether childhood psychosocial stress is a predictor of retinal microvasculature. METHODS: We followed-up 182 Belgian children, aged 5.7-11.3 years at baseline (53.3% boys). Information about psychosocial stress was obtained using emotional, behavioral and negative life events questionnaires and hair cortisol, an objective stress marker. Retinal photographs were used to calculate vessel diameters, bifurcation angles and optimality deviation with semiautomated software. Cross-sectional and longitudinal associations were explored using multivariable regression analysis with retinal parameters in 2015 as outcome, while adjusting for age, sex, socioeconomic status, cardiovascular parameters and lifestyle factors. RESULTS: Feelings of happiness, sadness and negative life events were associated with retinal vascular diameter, but behavior and hair cortisol were not. High stress levels over a 4-year time period (less happy, sadder and higher total negative emotions) were associated with larger venules (ß = 0.21-0.43) and children who experienced more negative life events had smaller arterioles (ß = -0.15). No consistent patterns were seen with bifurcation angles and optimality deviation. CONCLUSION: Based on the results, we conclude that high levels of childhood psychosocial stress unfavorably affect the retinal vascular diameters, potentially reflecting the microvasculature of the heart and brain. It seems this might even be independent of lifestyle and BMI, but further research on mechanisms is necessary.

Associations between exclusive breastfeeding and physical fitness during childhood.

PURPOSE: Exposure to breastfeeding improves the survival, health, and development of children; therefore, breast milk is recommended as the exclusive nutrient source for feeding term infants during the first 6 months. This cross-sectional study aimed to determine the possible association between exposure to exclusive breastfeeding and physical fitness performance in children and, if so, whether this association is influenced by the breastfeeding duration. METHODS: A total of 2853 (52.3 % girls) European children from the IDEFICS study aged 6-11 years with complete data on physical fitness (cardiorespiratory fitness, muscular strength, flexibility, balance, speed) and exclusive breastfeeding duration (never, 1-3, 4-6, 7-12 months) were included in the present study. Multivariate and mixed linear regression models were estimated and adjusted for sex, age, birth weight, diet, physical activity, body mass index, and parental factors (age, body mass index, educational attainment). RESULTS: We found a positive association between exclusive breastfeeding and lower-body explosive strength (ß = 0.034) as well as flexibility (ß = 0.028). We also found a positive association between breastfeeding and balance in boys (ß = 0.039), while this association was negative in girls (ß = -0.029). To improve lower-body explosive strength, 1-3 months of exclusive breastfeeding were enough; a longer duration did not lead to increasing benefit. In contrast, 4-6 months of breastfeeding were necessary to have any benefit on flexibility or balance, although this became nonsignificant after adjustment for body mass index and physical activity. CONCLUSIONS: Exclusive breastfeeding seems a natural way of slightly improving some physical fitness components (mainly lower-body muscle strength) and thus future health.

Physical Fitness and Metabolic Syndrome in Children with Repaired Congenital Heart Disease Compared with Healthy Children.

OBJECTIVE: To determine whether children who underwent surgery for congenital heart disease (CHD) are as fit as their peers. STUDY DESIGN: We studied 66 children (6-14 years) who underwent surgery for ventricular septal defect (n = 19), coarctation of aorta (n = 10), tetralogy of Fallot (n = 15), and transposition of great arteries (n = 22); and 520 healthy children (6-12 years). All children performed physical fitness tests: cardiorespiratory fitness, muscular strength, balance, flexibility, and speed. Metabolic score was assessed through z-score standardization using 4 components: waist circumference, blood pressure, blood lipids, and insulin resistance. Assessment also included self-reported and accelerometer-measured physical activity. Linear regression analyses with group (CHD vs control) as a predictor were adjusted for age, body mass index, physical activity, and parental education. RESULTS: Measured physical activity level, body mass index, cardiorespiratory fitness, flexibility, and total metabolic score did not differ between children with CHD and controls, whereas reported physical activity was greater in the CHD group than control group. Boys with CHD were less strong in upper muscular strength, speed, and balance, whereas girls with CHD were better in lower muscular strength and worse in balance. High-density lipoprotein was greater in boys and girls with CHD, whereas boys with CHD showed unhealthier glucose homeostasis. CONCLUSION: Appropriate physical fitness was achieved in children after surgery for CHD, especially in girls. Consequently, children with CHD were not at increased total metabolic risk. Lifestyle counseling should be part of every patient interaction.

Determinant factors of physical fitness in European children.

OBJECTIVES: This study was designed to explore the determinants of physical fitness in European children aged 6-11 years, cross-sectionally and longitudinally. METHODS: There were sufficient data on 4903 children (50.6 % girls) on measured physical fitness (cardio-respiratory, muscular strength, flexibility, balance, and speed) and possible determinants related to child characteristics, child lifestyle and parental factors. Multivariate and mixed linear regression models were conducted. RESULTS: Age, sex, children's BMI and physical activity were independent and strong determinants of children's fitness. Significant but small effects were found for low maternal BMI, high psychosocial well-being and fruit and vegetable intake as protective determinants. Sleep duration, breakfast intake, parental age and education and paternal BMI did not have a consistently significant effect on physical fitness. The role of determinants depended on children's sex and the specific PF component. Longitudinal analyses especially highlighted the importance of child's BMI as physical fitness determinant, independent of physical activity. CONCLUSIONS: BMI together with physical activity, diet and psychosocial factors are modifiable targets to enhance physical fitness. This calls for policy approaches that combine these factors in a systematic way.

The Impact of Oral Intake of Dydrogesterone on Fetal Heart Development During Early Pregnancy.

Congenital heart disease is the most frequent form of congenital anomaly in newborn infants and accounts for more than a quarter of all serious congenital afflictions worldwide. A genetic etiology is identified in <20 % of cases of congenital heart defects, and in most cases the etiology remains a mystery. In the context of the health burden caused by congenital heart disease, the contribution of non-inherited risk factors is important especially if it turns out to be caused by a drug which can be avoided during pregnancy. We sought to determine whether maternal dydrogesterone treatment in early pregnancy is associated with congenital heart disease in the infant. We conducted a retrospective case-control study of birth defects and associated risk factors. Data were obtained and compared between 202 children born with congenital heart disease and a control group consisting of 200 children. All children were born in the period of 2010-2013. Dydrogesterone exposure was defined as any reported use during the first trimester of pregnancy. Exclusion criteria included stillbirths, children with chromosomal abnormalities and infants of mothers with chronic medical illnesses, e.g., diabetes. Binary logistic regression analyses were used to analyze the data and attempt to identify a causal relationship between drug exposure and congenital heart disease. Mothers of children born with congenital heart disease received more dydrogesterone during first trimester of pregnancy than mothers of children in the control group [adjusted odds ratio 2.71; (95 % CI 1.54-4.24); P = 0.001]. We identified a positive association between dydrogesterone usage during early pregnancy and congenital heart disease in the offspring. Nevertheless, further studies are needed to confirm these results.

Crossed pulmonary arteries with double aortic arch: a rare association.

Crossed pulmonary arteries is a rare, benign congenital anomaly. Both pulmonary arteries cross each other on their course to each respective lung, thus forming a crisscross pattern. We report an infant with crossed pulmonary arteries and a complete vascular ring formed by double aortic arch.

Prevalence of congenital heart disease among Palestinian children born in the Gaza Strip.

OBJECTIVE: This study was designed to estimate the birth prevalence of children with congenital heart disease born in the Gaza Strip during 2010 and to compare these with estimates from elsewhere. METHODS: We reviewed the medical records of all children born in 2010 who were diagnosed, treated, and/or followed up in the four paediatric cardiology clinics in the Gaza Strip. Data were also obtained from El Makassed Hospital in East Jerusalem and from the Schneider Hospital, Wolfson Medical Center, and Tel HaShomer Hospital in Israel, where we had referred some of our patients for percutaneous or surgical treatment. RESULTS: A total of 598 children with congenital heart disease were detected among the 59,757 children born alive in the Gaza Strip during 2010, yielding a birth incidence of 10 per 1000 live births. The most frequently occurring conditions were ventricular septal defects (28%), ostium secundum atrial septal defects (17%), patent ductus arteriosus (8.5%), and pulmonary valve abnormalities (8%). In this study, 7% of the children died. The actuarial survival at 6 months and 1 year of age was 94% and 93%, respectively, and remained stable over 18 months of follow-up. CONCLUSION: The birth incidence of congenital heart disease in the Gaza Strip in 2010 (10 per 1000) is higher than most estimates in Western Europe (8.2 per 1000 live births) and North America (6.9 per 1000 live births) but is similar to estimates from other parts of Asia (9.3 per 1000 live births).

Pulmonary function in children after surgical and percutaneous closure of atrial septal defect.

This study aimed to study differences in lung function after surgical and percutaneous atrial septal defect (ASD) closure. Several studies have demonstrated abnormalities of pulmonary function in adults and children with ASD. These abnormalities persist even a few years after correction. This study compared pulmonary function between patients who underwent ASD closure by surgery and those who had closure by device. This is the ideal pediatric population for studying changes in lung function caused by cardiopulmonary bypass or sternotomy. The 46 patients in this study were treated by percutaneous closure (group 1) or surgical closure (group 2) of ASD and then scheduled for pulmonary function testing an average of 5.8 years after ASD closure. The mean values of functional residual capacity, total lung capacity, and residual volume did not differ between the two groups. The surgical group showed a significant decrease in expiratory reserve volume (p < 0.04) and forced vital capacity (p < 0.03). Expiratory flow at 25, 50, and 75% of forced vital capacity did not differ between the two groups but was on the lower limit of normal in both groups. Percutaneous closure of ASD can minimize the side effects of surgical closure on lung function. Longitudinal lung function follow-up assessment after cardiac surgery is warranted to detect and measure restrictive abnormalities in this type of congenital heart disease and others.

The fate of the aortic root after early repair of tetralogy of Fallot.

OBJECTIVE: Late aortic root dilatation is a growing concern in patients operated on for tetralogy of Fallot (ToF). This longitudinal follow-up study sought to evaluate the changes in the aortic root dimensions in relation to body growth, assuming that early repair of tetralogy of Fallot might prevent late aortic dilatation. METHODS: A retrospective analysis of the aortic root dimensions was performed in 88 patients repaired early for tetralogy of Fallot by echocardiographic measurement of aortic annulus, sinus of Valsalva and sinotubular junction, adjusted for body surface area and expressed as z-scores. Mean age at repair was 9.7 + or - 7.4 months. Median age was 7.3 months (range 45 days-29 months). RESULTS: At the time of repair, all root dimensions were enlarged: z-score of the annulus 3.32 + or - 1.66; sinus 3.54 + or - 1.49; sinotubular junction 2.74 + or - 1.19. Within a mean follow-up of 6.9 + or - 4.4 years, the mean z-scores of both annulus and sinotubular junction significantly decreased to normal size at 7 years postoperatively: z-score of annulus 0.95 + or - 0.7 (p=0.006), z-score of sinotubular junction 0.99 + or - 1.47 (p=0.006). The z-score of the aortic sinuses appeared to regress slower to 2.78 + or - 1.26 (p=0.262). The indexed sinus diameter however regressed significantly from a mean of 51.4 + or - 13.4 mmm(-2) at correction to 28.9 + or - 7.2 mmm(-2) (p=0.0001) at latest follow-up. Evolution of aortic root size after repair was independent of aortic arch side, sex, age at repair or previous shunt palliation. CONCLUSIONS: The initially dilated aortic root in tetralogy of Fallot normalises in size at the level of the annulus and sinotubular junction within 7 years after early repair. This process seems delayed at the level of the aortic sinuses, although the indexed root diameter shows significant regression over time. These results suggest that early repair of ToF abrogates the enlargement of the aortic root, validating one aspect of the need for tetralogy correction at a young age.

Transthoracic echocardiography guidance of transcatheter atrial septal defect closure in children.

Transesophageal echocardiography (TEE) guidance is part of interventional closure of secundum atrial septal defect (ASD) in children and adults. However, sometimes TEE is impossible for technical or anatomical reasons. If available, intracardiac echocardiography can be used, but especially in children, transthoracic echocardiography (TTE) can be an easy, safe, and cheap alternative. We report two cases in which TEE was replaced by TTE during percutaneous ASD closure. In the first case VACTERL association with a surgically repaired tracheoesophageal fistula was a relative contraindication to TEE. In the second case, technical failure of the transesophageal probe occurred during the procedure. In both cases the ASD was successfully closed with an atrial septal occluder device under TTE guidance. Using TTE can be sufficient and safe in children with good imaging windows, especially from subcostal views.