An interdisciplinary consensus approach to pulmonary hypertension in developmental lung disease

Abstract

It is increasingly recognised that diverse genetic respiratory disorders present as severe pulmonary hypertension (PH) in the neonate and young infant, but many controversies and uncertainties persist regarding optimal strategies for diagnosis and management to maximise long-term outcomes. To better define the nature of PH in the setting of developmental lung disease (DEVLD), in addition to the common diagnoses of bronchopulmonary dysplasia and congenital diaphragmatic hernia, we established a multidisciplinary group of expert clinicians from stakeholder paediatric specialties to highlight current challenges and recommendations for clinical approaches, as well as counselling and support of families. In this review, we characterise clinical features of infants with DEVLD/DEVLD-PH and identify decision-making challenges including genetic evaluations, the role of lung biopsies, the use of imaging modalities and treatment approaches. The importance of working with team members from multiple disciplines, enhancing communication and providing sufficient counselling services for families is emphasised to create an interdisciplinary consensus.

FIGURE 1

Age at onset of clinical disease associated with developmental lung diseases. BPD: bronchopulmonary dysplasia; CDH: congenital diaphragmatic hernia; ACD: alveolar capillary dysplasia; PIG: pulmonary interstitial glycogenosis.

FIGURE 2

Imaging panel to exemplify developmental lung diseases (DEVLDs). a) Acinar dysplasia: 1-day-old, 38-week gestational age neonate with hypoplastic left heart syndrome and small lung volumes (45% of expected) related to acinar dysplasia. Chest radiography demonstrates small lung volumes and right chest tubes placed for a pneumothorax. Small lung volumes and air leaks are common in diffuse DEVLDs such as acinar dysplasia. b) Alveolar capillary dysplasia: 3-week-old, full-term neonate with hypoxaemia and pulmonary hypertension (PH) attributable to ACD. Chest radiography shows diffuse pulmonary opacities. Such opacities could also be compatible with a genetic surfactant disorder, underscoring the non-specific nature of the imaging findings associated with some DEVLDs. c) Surfactant protein B (SP-B) deficiency: 4-week-old, near-term neonate with respiratory failure due to genetic SP-B deficiency. Chest computed tomography (CT) shows diffuse ground-glass pulmonary opacities consistent with known surfactant disorder. d) Bronchopulmonary dysplasia (BPD): 4-month-old, former 26-week gestational age premature infant with respiratory failure and PH from severe BPD. Chest CT reveals multiple cystic-appearing hyperlucent pulmonary lobules (arrows) characteristic of the alveolar growth disorder in BPD. e) Filamin A: 7-month-old with progressive respiratory insufficiency related to Filamin A-associated lung disease. Chest CT shows marked upper lobe hyperexpansion and hyperlucency (star) resembling emphysema, and dependent lower lobe atelectasis (arrow), findings characteristic of this disorder. f) Normal chest CT in a 3-month-old full-term infant for comparison.

FIGURE 3

Histopathology of select developmental lung diseases (DEVLDs) associated with pulmonary hypertension. a) Normal lung development with bronchovascular bundle (asterisk marks airway) surrounded by numerous alveoli showing thin and delicate alveolar septa and appropriate secondary septation (arrows). b) Alveolar capillary dysplasia. Widened alveolar septa with paucity of centrally placed capillaries (arrows) are present in this classic case of ACD. c) ACD with misalignment of pulmonary veins (MPV). Thin-walled venous channels (stars) are noted closely associated with bronchovascular bundles consistent with MPV. Marked medial hypertrophy of the pulmonary artery branch is present (arrow), consistent with pulmonary hypertensive changes. d) TBX4-related DEVLD. Explanted lungs from a patient with TBX2/4 mutation show impaired alveolar development characterised by enlarged and simplified airspaces lacking secondary septations. Alveolar septa are widened with a double capillary layer throughout with mild interstitial fibrosis. e) TBX4-related DEVLD. Congenital acinar dysplasia is depicted, characterised by virtually absent alveolar development. Note the airway profiles (asterisks) surrounded by abundant mesenchyme and few primitive airspaces (arrows). The patchy and at times subtle nature of the disease highlights the importance of appropriate sampling.

FIGURE 4

A deep wedge biopsy should be performed to evaluate for developmental lung disease. a) A scale bar is placed over an infant wedge biopsy to demonstrate that it should be at least 1 cm deep excluding the staple line. b) After removal of the staple line (which cannot be processed for histology), tissue is taken for special studies from the edges, and the central portion is inflated with formalin and sectioned perpendicular to the staple line (yellow dotted lines indicates cutting lines). c) Histology cross-sections of an adequate biopsy (left) that is >1 cm deep and a suboptimal biopsy (right) that is <1 cm deep are shown for size comparison (dotted black line represents the staple line). A US dime is shown for size comparison (∼1.8 cm diameter). d) The adequate biopsy and e) the suboptimal biopsy with superimposed interlobular septa (yellow), veins (red) and arteries (blue) show the difference in the number of vessels available for evaluation in the two different sized biopsies. The smaller biopsy has few bronchovascular bundles for evaluation and those that are present are clustered at the staple edge, which may have crush artefacts. As children grow, they increase the number of alveoli between each bronchovascular bundle, so older children need larger biopsies to achieve adequate architectural evaluation.

FIGURE 5

Flowchart of consensus summary for diagnostic evaluation and approach to management in developmental lung diseases associated with pulmonary hypertension (DEVLD-PH). Approach to the DEVLD-PH infant requires a comprehensive, stepwise approach. CMA: chromosomal microarray; PGE: prostaglandin E; ECMO: extracorporeal membrane oxygenation; P_aCO2: partial pressure of arterial carbon dioxide; SPC: specialised palliative care; PDA: patent ductus arteriosus.