Introduction:
Pediatric pulmonary hypertension (PH) has emerged as a major clinical problem throughout the world. This problem has grown for two reasons: a) increased awareness of the strong impact of PH on short and long-term outcomes in more diverse diseases, which has lead to an increase in screening and diagnostic evaluations; and b) the availability of PH-specific drug therapies leading to improved survival.1,2 We have the honor of leading off this special issue of Pediatric Pulmonology with an overview of the many faces of PH in neonates, infants, children and adolescents, with particular emphasis on the importance and need for pediatric pulmonologists to develop a greater understanding of PH. While a large proportion of leaders in adult PH are pulmonologists, pediatric cardiologists have dominated the field in children with PH. With growing awareness of the importance of PH in dictating outcomes of many childhood lung diseases and the critical contribution of respiratory problems to outcomes of children with many forms of PH, it is clear that pediatric pulmonary specialists must become more knowledgeable and engaged in PH-related diseases. As reflected by the development of PH teams at many medical centers, it is evident that optimal care for these patients requires the collaboration of pediatric pulmonologists with pediatric cardiologists intensivists, neonatologists, pharmacists and others.2-4 As a result, the goal of this supplemental issue of Pediatric Pulmonology is to highlight and provide updates on key aspects of this important clinical field of pediatric PH.DEFINITIONS:
Pulmonary arterial hypertension (PAH) is defined as a patient with mean pulmonary artery pressure (PAP) > 20 mmHg, pulmonary capillary wedge pressure (PWCP) ≤ 15 mmHg and pulmonary vascular resistance index (PVRI) ≥ 3 WU m2 in individuals older than three months of age.1 Pulmonary hypertension (PH) with or without variable degrees of pulmonary vascular disease (PVD) can also occur in patients with conditions associated with post-capillary diseases of elevated mean PAP with elevated pulmonary capillary wedge or left atrial pressures, as in the setting of left heart disease (Nice Group 2; Table 1) or high pulmonary blood flow in the setting of congenital heart disease with marked left-to-right shunts as with atrial and ventricular septal defects or with a large patent ductus arteriosus. In addition, significant PVD may be present and complicate outcomes in the absence of overt PH in some children, as especially evident in the setting of hypoplastic heart syndrome and single ventricle physiology.
CLASSIFICATION:The World Symposium on Pulmonary Hypertension (WSPH), which includes the Pediatric Task Force,1 most recently updated the classification of PH-associated disorders in 2018 in Nice, France (Table 1).1 The role of the WSPH Classification is to improve understanding of underlying pathophysiology, natural history, therapeutic choices and clinical trial design. With regard to pediatric PH, most pediatric PH patients are categorized in Class I (pulmonary arterial disease) and3 (hypoxia or lung-associated diseases). As reviewed in this supplement, growing awareness of the roles of PH in neonatal lung diseases and their sequelae, especially in association with bronchopulmonary dysplasia (BPD), congenital diaphragmatic hernia (CDH), persistent pulmonary hypertension of the newborn (PPHN), Down syndrome, and lethal developmental lung diseases, has led to greater appreciation of the unique nature of pediatric PH.1,4-8 Pharmacotherapy trials have almost exclusively been performed in patients with Class I PAH and almost entirely in adults, and the need for multicenter randomized clinical trials in children with these diverse forms of PH is further highlighted in this supplement.9Based on the recognition of the differences in pediatric diseases and common co-morbidities that complicate PH outcomes, the pediatric committee of the international Pulmonary Vascular Research Institute (PVRI) proposed a more specific classification system for pediatric PVD during the meeting in Panama in 2011 (Table 2).10 This classification was derived independently from the WSPH Classification system to better reflect different etiologic categories of PH focused on infants, children and adolescents. However, the system is rather complex with overlapping categories, and Its adoption into clinical care and research has been mixed and not routinely applied.GENETICS PH is caused by both genetic and acquired factors, with key gene-environment interactions likely playing a major role in the pathobiology in many settings. Bone morphogenetic protein receptor II (BMPR2 ) is the most common genetic cause of PAH in adults, accounting for ~70% of familial cases and 10-20% of cases previously classified as idiopathic PAH.11Ongoing discoveries continue to expand the list of genes associated with PAH. However, the genetic causes of pediatric PAH may differ from adults, and the causes of other types of PH are less well studied. In this supplement, Dr. Chung et al provide a critical overview regarding the importance of understanding the genetic basis of pediatric PH, highlighting a different prevalence of specific genetic diseases in children in comparison with heritable etiologies in adult PH.11 Importantly, the etiology of PH in infancy and early childhood often stems from developmental disorders of lung growth and development, which are associated with mutations in key genes involved in lung development, including FOXF1 (alveolar capillary dysplasia), TBX4, ACRVL1 and surfactant-related genes, as highlighted by Mallory et al6 in this supplement.