Actigraphy methodology in the Kids Mod PAH trial: Physical activity as a functional endpoint in pediatric clinical trials.

Pulmonary vasodilator treatment can improve hemodynamics, right ventricular function, symptoms, and survival in pediatric pulmonary hypertension (PH). However, clinical trial data are lacking due to many constraints. One major limitation is the lack of relevant trial endpoints reflective of hemodynamics or functional status in patients in whom standard exercise testing is impractical, unreliable, or not reproducible. The Kids Mod PAH trial (Mono- vs. Duo Therapy for Pediatric Pulmonary Arterial Hypertension) is an ongoing multicenter, Phase III, randomized, open-label, pragmatic trial to compare the safety and efficacy of first-line combination therapy (sildenafil and bosentan) to first-line monotherapy (sildenafil alone) in 100 pediatric patients with PH across North America. Investigators will measure participants' physical activity with a research-grade, wrist-worn actigraphy device at multiple time points as an exploratory secondary outcome. Vector magnitude counts per minute and activity intensity will be compared between the treatment arms. By directly and noninvasively measuring physical activity in the ambulatory setting, we aim to identify a novel, simple, inexpensive, and highly reproducible approach for quantitative assessment of exercise tolerance in pediatric PH. These data will increase the field's understanding of the effect of pulmonary vasodilator treatment on daily activity - a quantitative measure of functional status and wellbeing in pediatric PH and a potential primary outcome for future clinical trials in children with cardiopulmonary disorders.

Kids Mod PAH trial: A multicenter trial comparing mono- versus duo-therapy for initial treatment of pediatric pulmonary hypertension.

Pulmonary hypertension (PH) is a significant health problem that contributes to high morbidity and mortality in diverse cardiac, pulmonary, and systemic diseases in children. Evidence-based advances in PH care have been challenged by a paucity of quality endpoints for assessing clinical course and the lack of robust clinical trial data to guide pharmacologic therapies in children. While the landmark adult AMBITION trial demonstrated the benefit of up-front combination PH therapy with ambrisentan and tadalafil, it remains unknown whether upfront combination therapy leads to more rapid and sustained clinical benefits in children with various categories of PH. In this article, we describe the inception of the Kids Mod PAH Trial, a multicenter Phase III trial, to address whether upfront combination therapy (sildenafil and bosentan vs. sildenafil alone) improves PH outcomes in children, recognizing that marked differences between the etiology and therapeutic response between adults and children exist. The primary endpoint of this study is WHO functional class (FC) 12 months after initiation of study drug therapy. In addition to the primary outcome, secondary endpoints are being assessed, including a composite measure of time to clinical worsening, WHO FC at 24 months, echocardiographic assessment of PH and quantitative assessment of right ventricular function, 6-min walk distance, and NT-proBNP levels. Exploratory endpoints include selected biomarkers, actigraphy, and assessments of quality of life. This study is designed to pave the way for additional clinical trials by establishing a robust infrastructure through the development of a PPHNet Clinical Trials Network.

Bronchopulmonary dysplasia - associated pulmonary hypertension: An updated review.

Bronchopulmonary dysplasia (BPD) is the leading cause of chronic lung disease in infants and the commonest complication of prematurity. Advances in respiratory and overall neonatal care have increased the survival of extremely low gestational age newborns, leading to the continued high incidence of BPD. Pulmonary hypertension (PH) represents the severe form of the pulmonary vascular disease associated with BPD, and affects almost one-third of infants with moderate to severe BPD. PH responds suboptimally to pulmonary vasodilators and increases morbidity and mortality in BPD infants. An up-to-date knowledge of the pathogenesis, pathophysiology, diagnosis, treatment, and outcomes of BPD-PH can be helpful to develop meaningful and novel strategies to improve the outcomes of infants with this disorder. Therefore, our multidisciplinary team has attempted to thoroughly review and summarize the latest advances in BPD-PH in preventing and managing this morbid lung disorder of preterm infants.

Atrial septal defect closure is associated with improved clinical status in patients ≤ 10 kg with bronchopulmonary dysplasia.

Patients with bronchopulmonary dysplasia (BPD) have shown clinical improvement after secundum atrial septal defect (ASD) closure. We sought to determine if this post-ASD closure improvement is secondary to the expected course in BPD patients or related to the closure itself. A novel BPD-ASD score was created to assess patients' clinical status (higher score = worse disease) and applied to 10 BPD-ASD inpatients weighing ≤ 10 kg who underwent ASD closure. The score and its subcomponents were retrospectively calculated serially ranging from 8 weeks pre- to 8 weeks post-intervention, and pre- and post-intervention score slopes were created. These slopes were compared using mixed regression modeling with an interaction term. There was a significant difference in pre- versus post-intervention slope with the most score drop the first week post-intervention (-2.1 + /- 0.8, p = 0.014). The mean score also dropped through weeks 2 (slope -0.8 + /- 0.8, p = 0.013) and 4 (slope -1.0 + /- 0.5, p = 0.001) post-intervention. There was a significant difference in pre- and post-intervention slopes for diuretics (p = 0.018) and the combined score of respiratory support, FiO2 need, and respiratory symptoms (p = 0.018). This study demonstrated significant improvement in BPD-ASD score, diuretic need, and respiratory status after ASD closure in BPD-ASD patients ≤ 10 kg that was outside of the natural course of BPD. Our study was limited by its small, single-center, retrospective nature. Future studies should be performed in a larger multicenter population to both validate the scoring system and compare to non-intervention infants.

Corrigendum: Case report: Selexipag in pediatric pulmonary hypertension: initiation, transition, and titration.

[This corrects the article DOI: 10.3389/fped.2023.1050508.].

The cascade screening in heritable forms of pulmonary arterial hypertension.

Heritable pulmonary artery hypertension (HPAH) is an increasingly recognized type of pulmonary arterial hypertension, in both pediatric and adult population. Intrinsic to hereditary disease, screening for genetic mutations within families is an important component of diagnosis and understanding burden of disease. Recently, consensus guidelines are published for genetic screening in PAH. These guidelines include recommendations for screening at diagnosis, noting individuals with presumed PAH due to familial, or idiopathic etiologies. Cascade genetic testing is specifically recommended as a testing paradigm to screen relatives for detection of mutation carriers, who may be asymptomatic. Without targeted genetic testing, familial mutation carriers may only come to attention when pulmonary vascular disease burden is high enough to cause symptoms, suggesting more advanced disease. Here, we present our collective experience with HPAH in five distinct families, specifically to report on the clinical courses of patients who were diagnosed with genetic mutation at diagnosis versus those who were offered genetic screening. In three families, asymptomatic mutation carriers were identified and monitored for clinical worsening. In two families, screening was not done and affected family members presented with advanced disease.

Measurement of Physical Activity by Actigraphy in Infants and Young Children with Pulmonary Arterial Hypertension.

OBJECTIVE: To evaluate the feasibility, tolerability, and adherence with wearable actigraphy devices among infants and children with pulmonary arterial hypertension (PAH). STUDY DESIGN: This multicenter, prospective, observational study included children ages 0-6 years with and without PAH. Participants wore the ActiGraph wGT3X-BT on the hip and FitBit Inspire on the wrist during waking hours for 14 days. Steps, vector magnitude counts per minute, activity intensity, heart rate, and heart rate variability were compared between groups. RESULTS: Forty-seven participants (18 PAH, 29 control) were enrolled from 10 North American sites. PAH patients were mostly functional class II (n = 16, 89%) and treated with oral medications at the time of enrollment. The number of wear days was not significantly different between the groups (ActiGraph: 10 [95% CI: 5.5, 12.2] in PAH vs 8 [4, 12] in control, P = .20; FitBit 13 [10, 13.8] in PAH vs 12 [8, 14] in control, P = .87). Complete data were obtained in 81% of eligible ActiGraph participants and 72% of FitBit participants. PAH participants demonstrated fewer steps, lower vector magnitude counts per minute, more sedentary activity, and less intense physical activity at all levels compared with control participants. No statistically significant differences in heart rate variability were demonstrated between the 2 groups. CONCLUSIONS: Measurement of physical activity and other end points using wearable actigraphy devices was feasible in young children with PAH. Larger studies should determine associations between physical activity and disease severity in young patients with PAH to identify relevant end points for pediatric clinical trials.

Hereditary pulmonary arterial hypertension burden in pediatrics: A single referral center experience.

Introduction: Hereditary pulmonary arterial hypertension (HPAH) is a rare yet serious type of pulmonary arterial hypertension (PAH). The burden in the pediatric population remains high yet underreported. The objective of this study is to describe the distribution of mutations found on targeted PAH panel testing at a large pediatric referral center. Methods: Children with PAH panel administered by the John Welsh Cardiovascular Diagnostic Laboratory at Texas Children's Hospital and Baylor College of Medicine in Houston, Texas between October 2012 to August 2021 were included into this study. Medical records were retrospectively reviewed for clinical correlation. Results: Sixty-six children with PAH underwent PAH genetic testing. Among those, 9 (14%) children were found to have pathogenic mutations, 16 (24%) children with variant of unknown significance and 41 (62%) children with polymorphism (classified as likely benign and benign). BMPR2 mutation was the most common pathogenic mutation, seen in 6 of the 9 children with detected mutations. Hemodynamic studies showed higher pulmonary vascular resistance among those with pathogenic mutations than those without (17.4 vs. 4.6 Wood units). All children with pathogenic mutations had severe PAH requiring triple therapy. There were tendencies for higher lung transplantation rate but lower mortality among those with pathogenic mutations. Conclusions: Abnormalities on genetic testing are not uncommon among children with PAH, although majority are of unclear significance. However, children with pathogenic mutations tended to present with more severe PAH requiring aggressive medical and surgical therapies. Genetic testing should be routinely considered due to consequences for treatment and prognostic implications. Larger scale population studies and registries are warranted to characterize the burden of HPAH in the pediatric population specifically.

Prevalence of malnutrition in pediatric pulmonary hypertension cohort and role for registered dietitian involvement.

Introduction: Pediatric pulmonary hypertension (PH) is a serious condition with increased risk for malnutrition due to increased caloric needs and reduced energy intake. This combination of disease and dynamic elements make it particularly challenging to meet expected growth patterns. Pediatric PH patients require close monitoring and individualized nutrition interventions to best meet nutrient needs. The prevalence of malnutrition and effective nutrition interventions in pediatric PH has not been studied. Methods: Using our electronic medical record (EMR) patient care dashboard, malnutrition prevalence was assessed by reviewing the active problem list of all active PH patients at our center. A chart review compared patients with diagnosed malnutrition in the EMR to those with malnutrition identified by a registered dietitian (RD) using a standardized tool. Chart reviews also assessed outcomes of RD interventions. Results: 195 patients were identified as active PH patients followed by our PH center during the study period (November 2021 to January 2023). Of these, 5% (10/195) had an ICD-10 code for malnutrition listed in their chart. However, upon further chart review of the remaining 185 patients, 22% (41/185) had malnutrition identified by a RD using Texas Children's Malnutrition Tool, totaling 51/195 (26%) malnourished patients. The PH RD saw 25/51 (49%) patients during PH clinic visits in the study period. At follow up visits (3-4 months after initial assessment), 56% (14/25) patients seen by the PH RD either improved or resolved their malnutrition status by z-score assessment. Conclusion: Malnutrition is present in pediatric PH, although underappreciated and underdiagnosed. Managing malnutrition in pediatric PH requires close monitoring, multidisciplinary involvement, and individualized nutrition recommendations. This is best achieved by a dedicated PH RD who is familiar with the unique needs of this population and available to provide consistent nutritional assessments and interventions to reduce malnutrition in this population.

Case Report: Selexipag in pediatric pulmonary hypertension: Initiation, transition, and titration.

Selexipag, a selective prostacyclin receptor agonist, is approved for treating pulmonary arterial hypertension in WHO Group 1 adult patients. Compared to parenteral prostacyclin formulations, selexipag offers a significant improvement in patient's and caregiver's quality of life because of its oral formulation, frequency of administration, and mechanism of action. Although experience in the pediatric population is limited to case reports in older adolescent patients and selexipag is not approved for use in the pediatric pulmonary hypertension population, many pediatric centers are expanding the use of this therapy to this population. We report our institution's experience in the use of selexipag to treat pulmonary hypertension in children under 10 years of age, between 10 and 30 kg. Seven patients were initiated on selexipag therapy including de novo initiation and transition from intravenous treprostinil to oral selexipag. All patients were on stable background therapy with phosphodiesterase-5 inhibitor and endothelin receptor antagonist therapies at baseline. All patients reached their planned goal selexipag dose during admission without the need for changes to the titration schedule and without hemodynamic deterioration. In our experience, oral selexipag is safe and well-tolerated in young pediatric patients with pulmonary hypertension. Based on our favorable experience, we developed an institution-specific selexipag process algorithm for continued successful use in the pediatric population.

Building a dedicated pediatric pulmonary hypertension program: A consensus statement from the pediatric pulmonary hypertension network.

Pediatric pulmonary hypertension (PH) is a severe, life-threatening disease associated with diverse cardiac, pulmonary, and systemic disorders, which generally requires expertise from multiple disciplines for management. Unfortunately, expert centers are limited, often due to inadequate resources or unfamiliarity with needed components for success. The Pediatric Pulmonary Hypertension Network (PPHNet) includes expert centers in North America specifically dedicated to advancing the field of pediatric PH through research and excellent clinical care. PPHNet member sites were queried for valuable program components and these findings were discussed for consensus. Here we provide a collective overview of key elements of an optimal pediatric PH program: team composition, access to services, and commitment to education. It is our intention that this document will assist newer and/or smaller programs identify avenues and resources for growth and provide avenues for collaboration.

Prematurity and Pulmonary Vein Stenosis: The Role of Parenchymal Lung Disease and Pulmonary Vascular Disease.

Pulmonary vein stenosis (PVS) has emerged as a critical problem in premature infants with persistent respiratory diseases, particularly bronchopulmonary dysplasia (BPD). As a parenchymal lung disease, BPD also influences vascular development with associated pulmonary hypertension recognized as an important comorbidity of both BPD and PVS. PVS is commonly detected later in infancy, suggesting additional postnatal factors that contribute to disease development, progression, and severity. The same processes that result in BPD, some of which are inflammatory-mediated, may also contribute to the postnatal development of PVS. Although both PVS and BPD are recognized as diseases of inflammation, the link between them is less well-described. In this review, we explore the relationship between parenchymal lung diseases, BPD, and PVS, with a specific focus on the epidemiology, clinical presentation, risk factors, and plausible biological mechanisms in premature infants. We offer an algorithm for early detection and prevention and provide suggestions for research priorities.

Cardiac Catheterization and Hemodynamics in a Multicenter Cohort of Children with Pulmonary Hypertension.

Rationale: Hemodynamic assessments direct care among children with pulmonary hypertension, yet the use of cardiac catheterization is highly variable, which could impact patient care and research. Objectives: We analyzed hemodynamic findings from right heart catheterization (RHC) and left heart catheterization and acute vasodilator testing (AVT) and the safety of catheterization in children with World Symposium on Pulmonary Hypertension (WSPH) group 1 and 3 subtypes in a large multicenter North American cohort. Methods: Of 1,475 children enrolled in the Pediatric Pulmonary Hypertension Network Registry (2014-2020), there were 1,383 group 1 and 3 patients, of whom 671 (48.5%) underwent RHC at diagnosis and were included for analysis. Results: Compared with those without diagnostic RHC, these children were older, less likely to be an infant or preterm, more often female, treated with targeted pulmonary hypertension medications at diagnosis, and had advanced World Health Organization functional class. Catheterization was performed without a difference in complication rates between WSPH groups. Pulmonary capillary wedge pressure was well correlated with left ventricular end-diastolic pressure and left atrial pressures. Results of AVT using three different methods were comparable; positive AVT results were observed in 8.0-11.8% of subjects, did not differ between WSPH groups 1 and 3, and were not associated with freedom from the composite endpoint of lung transplantation or death during follow-up. Conclusions: In a large pediatric pulmonary hypertension cohort, diagnostic RHC with or without left heart catheterization in WSPH group 1 and 3 patients was performed safely at experienced pediatric pulmonary hypertension centers. Hemodynamic differences were noted between group 1 and 3 subjects. Higher mean pulmonary arterial pressure and mean pulmonary arterial pressure/mean systemic arterial pressure ratio were associated with a higher risk of death/transplantation. Findings suggest overall safety and potential value of RHC as a standard diagnostic approach to guide pulmonary hypertension management in children.

Endothelial Adenosine Monophosphate-Activated Protein Kinase-Alpha1 Deficiency Potentiates Hyperoxia-Induced Experimental Bronchopulmonary Dysplasia and Pulmonary Hypertension.

Bronchopulmonary dysplasia and pulmonary hypertension, or BPD-PH, are serious chronic lung disorders of prematurity, without curative therapies. Hyperoxia, a known causative factor of BPD-PH, activates adenosine monophosphate-activated protein kinase (AMPK) α1 in neonatal murine lungs; however, whether this phenomenon potentiates or mitigates lung injury is unclear. Thus, we hypothesized that (1) endothelial AMPKα1 is necessary to protect neonatal mice against hyperoxia-induced BPD-PH, and (2) AMPKα1 knockdown decreases angiogenesis in hyperoxia-exposed neonatal human pulmonary microvascular endothelial cells (HPMECs). We performed lung morphometric and echocardiographic studies on postnatal day (P) 28 on endothelial AMPKα1-sufficient and -deficient mice exposed to 21% O2 (normoxia) or 70% O2 (hyperoxia) from P1-P14. We also performed tubule formation assays on control- or AMPKα1-siRNA transfected HPMECs, exposed to 21% O2 or 70% O2 for 48 h. Hyperoxia-mediated alveolar and pulmonary vascular simplification, pulmonary vascular remodeling, and PH were significantly amplified in endothelial AMPKα1-deficient mice. AMPKα1 siRNA knocked down AMPKα1 expression in HPMECs, and decreased their ability to form tubules in normoxia and hyperoxia. Furthermore, AMPKα1 knockdown decreased proliferating cell nuclear antigen expression in hyperoxic conditions. Our results indicate that AMPKα1 is required to reduce hyperoxia-induced BPD-PH burden in neonatal mice, and promotes angiogenesis in HPMECs to limit lung injury.

Outcomes of COVID-19 infection in pediatric pulmonary hypertension: A single-center experience.

BACKGROUND: The global COVID-19 pandemic was particularly concerning for the pediatric pulmonary hypertension (PH) population due to immature immune systems and developmental comorbidities. This study aims to describe a single-center experience of pediatric PH patients diagnosed with COVID-19 disease. METHODS: A retrospective cohort study of all pediatric patients followed by the PH Center at Texas Children's Hospital diagnosed with COVID-19 infection from April 2020 to February 2021. RESULTS: We identified 23 patients with a median age of 58 months (interquartile range [IQR]: 25-75th, 21-132 months), 48% being Hispanics. Eight patients (35%) required hospitalization; median length of stay was 6 days (IQR: 25-75th, 5-8 days). Only three of these eight patients required increased respiratory support. Targeted PH therapy was escalated in four patients (two in dual and two in triple therapy). There was one mortality in a patient with failing Fontan physiology. Ninety-one percent of patients have had post-COVID outpatient follow-up, median of 101 days (IQR: 25-75th, 50-159 days) from diagnosis. Of the five patients with 6 min walk test (6MWT) data, three (60%) children walked less distance, median of -12 m (IQR: 25-75th, -12 to +49 m) compared to pre-COVID testing. Postinfection pulmonary function testing (PFT) was notable for decrease in predicted forced vital capacity (FVC; median -6%, range -11% to +6%) and forced expiratory volume in one second (FEV1; median -14%, range -12% to -18%) in 75% of the patients with PFT data. CONCLUSION: In our institution, COVID-19 was found more frequently in Hispanics and associated with low mortality.

Pulmonary hypertension is an important co-morbidity in developmental lung diseases of infancy: Bronchopulmonary dysplasia and congenital diaphragmatic hernia.

Bronchopulmonary dysplasia (BPD) following preterm birth and congenital diaphragmatic hernia (CDH) are both forms of developmental lung disease that may result in persistent pulmonary and pulmonary vascular morbidity in childhood. The pulmonary vascular disease (PVD) which accompanies BPD and CDH is due to developmental abnormalities and ongoing perinatal insults. This may be accompanied by evidence of elevated right heart pressures and pulmonary vascular resistance, leading to diagnosis of pulmonary hypertension (PH). The development of PH in these conditions is associated with increased morbidity and mortality in the vulnerable BPD and CDH populations. We present a review of PVD pathogenesis and evaluation in BPD and CDH and discuss management of related sequelae of PH co-morbidity for affected infants.

Assessing the atria in pediatric sickle cell disease: Beyond the dilation.

BACKGROUND: Diastolic dysfunction (DD) and pulmonary hypertension (PH) are common causes of mortality for sickle cell disease (SCD) patients in developed countries. We hypothesized that left and right atrial strain (LAS-Ɛ, RAS-rƐ) are decreased in SCD adolescents, and that worsening values correlate with laboratory markers of disease severity. METHODS: Prospective cohort study of patients with HbSS genotype of SCD was compared with healthy controls. LAS and RAS were measured from 4- and 2-chamber views by a blinded reader. Peak strain and strain rate values were obtained for atrial contraction (ac), reservoir (res), and conduit (con) phases. Mitral/tricuspid Doppler velocities, left atrial volume, right atrial area were obtained. Laboratory variables were obtained from the electronic record with the three prior values being averaged. Differences in variables were assessed with Wilcoxon rank sum test, and correlations assessed with Spearman's coefficient. RESULTS: There were 33 SCD patients compared to 35 healthy controls of similar age, gender, and size. SCD patients had increased left atrial volume and right atrial area. For LAS, Ɛres was significantly lower in SCD patients. For RAS, RƐcon was significantly lower. Neither measurement correlated with clinical markers. The majority of SCD patients had relatively normal atrial strain values. Those with markedly lower values had similar atrial size. CONCLUSIONS: A sub-set of SCD patients have markedly low Ɛres and rƐcon. No correlation with clinical markers was identified. Larger, longitudinal studies may determine utility of atrial strain as a screening tool in this at-risk population.

Multiple mitochondrial dysfunctions syndrome 1: An unusual cause of developmental pulmonary hypertension.

Pulmonary hypertension (pHTN) is a severe, life-threatening disease, which can be idiopathic or associated with an underlying syndrome or genetic diagnosis. Here we discuss a patient who presented with severe pHTN and was later found to be compound heterozygous for pathogenic variants in the NFU1 gene causing multiple mitochondrial dysfunctions syndrome 1 (MMDS1). Review of autopsy slides from an older sibling revealed the same diagnosis along with pulmonary findings consistent with a developmental lung disorder. In particular, these postmortem, autopsy findings have not been described previously in humans with this mitochondrial syndrome and suggest a possible developmental basis for the severe pHTN seen in this disease. Given the rarity of patients reported with MMDS1, we review the current state of knowledge of this disease and our novel management strategies for pHTN and MMDS1-associated complications in this population.