Historically, idiopathic pulmonary arterial hypertension (IPAH) is associated with extremely poor survival in adults, but even a worse prognosis in children, with an estimated median survival in children of only 10 months [2
]. Beyond IPAH, pulmonary vascular disease continues to have significant morbidity and mortality in many settings, including pulmonary, cardiac, and hematologic disorders. In the past, pulmonary hypertension was generally categorized as either ‘primary’ (now idiopathic) or ‘secondary’ (associated with other diseases). The World Health Organization (WHO) Classification helped discern different types of pulmonary hypertension [4
]. More recently, experts with extensive experience in experimental and clinical aspects of pulmonary hypertension gathered at the 4th World Symposium on Pulmonary Hypertension, Dana Point, California, USA (see below list), to review progress in our understanding of the pathobiology, diagnosis, and treatment of pulmonary hypertension and to update the classification system [5
- Bone morphogenetic receptor type 2 (BMPR2).
- Activin receptor-like kinase type 1 (ALK1), endoglin (with or without hereditary hemorrhagic telangiectasia).
- Drugs and toxins induced.
- Associated with [associated pulmonary arterial hypertension (APAH)]:
- Connective tissue diseases.
- HIV infection.
- Portal hypertension.
- Congenital heart disease (CHD).
- Chronic hemolytic anemia.
- Persistent pulmonary hypertension of the newborn.
(1) Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis.
(2) Pulmonary hypertension due to left heart disease:
- Systolic dysfunction.
- Diastolic dysfunction.
- Valvular disease.
(3) Pulmonary hypertension due to lung diseases and/or hypoxemia:
- Chronic obstructive pulmonary disease.
- Interstitial lung disease.
- Other pulmonary diseases with mixed restrictive and obstructive pattern.
- Sleep-disordered breathing.
- Alveolar hypoventilation disorders.
- Chronic exposure to high altitude.
- Developmental abnormalities.
(4) Chronic thromboembolic pulmonary hypertension.
(5) Pulmonary hypertension with unclear and/or multi-factorial mechanisms:
- Hematological disorders: myeloproliferative disorders, splenectomy.
- Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis.
- Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders.
- Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis.
As with past classifications, the newest version outlined five major categories of disease, based on physiologic and histologic patterns or clinical settings. Recent changes reflect growing recognition of heritable forms of PAH that may lack familial patterns, as related to the BMPR2, ALK1, and unknown genes [6
]. The category of ‘systemic to pulmonary shunt’ has been replaced by ‘CHD’, recognizing the many different factors involved. In addition, schistosomiasis, perhaps the most common cause of pulmonary hypertension worldwide, and chronic hemolytic anemias now appear as subgroups within the type 1 category. Although often with different clinical signs and therapeutic approaches, pulmonary veno-occlusive disease and/or capillary hemangiomatosis were maintained within type 1 disease but as a distinct subgroup, as these patients respond poorly to vasodilator therapy.
Although many aspects of disease are similar between adult and pediatric pulmonary hypertension [7••
], distinct differences exist, including etiologic mechanisms, disease course, frequent associations with genetic syndromes, and treatment responses [8
]. Whether the Dana Point Classification is sufficient for use in children with pulmonary hypertension is uncertain for several reasons. First, pediatric pulmonary hypertension is intrinsically linked to issues of lung growth and development, including many prenatal and early postnatal influences [11
]. The development of pulmonary hypertension in the neonate and young infant is often related to impaired functional and structural adaptation of the pulmonary circulation during transition from fetal to postnatal life. In particular, the timing of pulmonary vascular injury is a critical determinant of the subsequent response of the developing lung to such adverse stimuli as hyperoxia, hypoxia, hemodynamic stress, inflammation, and others. In fact, adult pulmonary hypertension may have its origins in disruptions or alterations that take place during development, perhaps related to genetic, epigenetic, or environmental (e.g., hemodynamic, inflammatory, or others) triggers [17••
Abnormalities of the lung circulation are significant beyond the adverse hemodynamic effects of pulmonary hypertension alone. The developing lung circulation plays critical roles in lung organogenesis and development of the distal airspace, maintenance of lung structure, metabolism, gas exchange, the ability to tolerate increased workloads imposed by exercise, and others. Experimentally, disruption of lung vascular growth can impair distal airspace structure during development and contributes to the pathobiology of diverse lung diseases, especially as related to premature infants [11
]. Finally, there are apparent differences in primary diseases and vascular function, structure, genetics, and perhaps responsiveness to therapies between adults and children with pulmonary hypertension [19
]. Therapeutic strategies for adult pulmonary hypertension have not been sufficiently studied in children, especially regarding potential toxicities or optimal dosing, and age-appropriate endpoints for clinical and research use are lacking.
Although the recent Dana Point Classification has excluded PVR from the definition [6
], most physicians taking care of children continue to embrace the inclusion of PVR index at least 3 Woods units × m2
as an important criterion. As infants and young children can often have mean systemic blood pressure 50–70 mmHg or less, it may be more appropriate to define pulmonary hypertension according to the value of the ratio of the pulmonary arterial systolic pressure to the systemic arterial systolic pressure.
Data on pediatric epidemiology remain scarce and the exact incidence and prevalence of pulmonary hypertension in children is not known. Although several registries of adult patients exist, such registries for children with pulmonary hypertension are less well established and underpowered for sufficient analysis [9••
]. PAH may be idiopathic or heritable or associated with specified diseases (‘associated PAH’). On the basis of the available data in children, the predominant diagnoses are pulmonary hypertension associated with CHD and IPAH. However, this likely reflects local patterns of clinical practice, as many pulmonary hypertension centers, especially those with multidisciplinary teams, are managing care for a growing population of patients with bronchopulmonary dysplasia (BPD), congenital diaphragmatic hernia (CDH), sickle cell anemia, and other diseases other than IPAH or CHD [22
]. Pulmonary vascular disease is often a silent contributor to morbidity and mortality of many disorders in pediatrics, including BPD, cystic fibrosis, sickle cell disease (SCD), and various interstitial lung diseases. Pulmonary hypertension appears to predict early death in adults with SCD and is already present by echocardiogram in about 20% of the children with SCD [25
]. Clinical strategies that anticipate the development of PAH in these diverse clinical settings may allow earlier recognition and more aggressive therapy, thereby slowing the development of PAH in many chronic lung parenchymal and cardiovascular diseases.