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.