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.

Shareable abstract

Interdisciplinary consensus is presented for approaches to improve clinical recognition, more efficient diagnosis and tailored treatment for infants with pulmonary hypertension due to developmental lung disease https://bit.ly/4c0hPH8

Introduction

Developmental lung diseases (DEVLDs) are a heterogeneous group of diseases characterised by impaired growth and differentiation of the lungs [1, 2] including diverse interstitial lung diseases (ILDs) such as surfactant dysfunction due to genetic mutations, interstitial pneumonias, pulmonary lymphangiectasias, Filamin A-related disorders, bronchopulmonary dysplasia (BPD), pulmonary hypoplasia from congenital diaphragmatic hernia (CDH), oligohydramnios, congenital pulmonary adenomatoid malformations, omphalocele, fetal lung compression or a narrow thoracic cage and dysplasias of lung structures (alveolar capillary dysplasia (ACD), congenital alveolar dysplasia and congenital pulmonary venous malformations). BPD, CDH and Trisomy 21-related lung disease are the most common causes of DEVLD [1]; however, the landscape is changing rapidly with greater recognition of rare DEVLDs [2] and discovery at autopsy. These diseases vary in pathogenesis, clinical progression and prognosis, but share molecular signalling pathways that affect lung parenchyma and vascular development [3].

Although distal airspace and vascular development are distinct, they are interrelated and coordinated [4], so an arrest in growth may lead to abnormally formed and fewer alveoli, smaller and fewer pulmonary vessels or both through disruption of fibroblast growth factor and vascular endothelial growth factor (VEGF) pathways [3, 5]. All DEVLDs have some aspect of pulmonary vascular disease (PVD), often reflecting impaired angiogenesis with dysmorphic growth, which can contribute to elevated pulmonary vascular resistance (PVR) and pulmonary hypertension (PH). The simplified and hypoplastic pulmonary circulation in DEVLDs is unable to fully accommodate right heart cardiac output and often undergoes progressive vascular remodelling, leading to progressive cardiorespiratory morbidities, poor clinical outcomes and high mortality.

The importance of recognising DEVLDs as a cause of PH and identifying ongoing knowledge gaps was highlighted by the Pulmonary Vascular Research Institute Paediatric Task Force in 2011 [6] and the Paediatric Task Force of the 2018 World Symposium on Pulmonary Hypertension (WSPH) at which PVD in DEVLD was noted as an increasingly prevalent cause of PH in children [7]. However, the development of PVD and PH in this group of diseases is varied and understanding these nuances is important as they affect clinical practice. In the current PH classification systems, all DEVLDs are grouped together, potentially obscuring the heterogeneity of developmental abnormalities and unique features that distinguish clinical presentations, natural history and outcomes among these diseases. This may carry the unintentional consequence of limiting sufficient diagnostic evaluations and therapeutic interventions to optimise clinical decision making for the clinical team and family. Although much has been studied regarding guidelines for the care of children with more common DEVLDs such as BPD and CDH [8–11], the diagnosis and management of more rare diseases remains unclear. Organisations such as the Children's Interstitial Lung Disease Foundation (chILD), the European Research Collaboration for Children's Interstitial Lung Disease (ChILD EU) and TBX4Life provide recommendations for comprehensive care of children with specific ILDs [1, 12, 13], yet recommendations for PH evaluations and specific management remain lacking.

To address this gap between classification and practice, we brought together a diverse group of stakeholder clinicians from the Pediatric Pulmonary Hypertension Network (PPHNet) member sites, representing cornerstone paediatric specialties (neonatology, pulmonology, cardiology, critical care, extracorporeal life support, palliative care, genetics, pathology, radiology and nursing) to characterise DEVLD with PH (DEVLD-PH), highlight current challenges and make recommendations for care, diagnosis and management through shared experience and knowledge to present consensus recommendations despite the lack of evidence-based guidelines at this time.

It is our intention that this expert consensus will offer more support for the medical teams caring for this population, encourage the development of evidence-based guidelines and highlight the need for PH classification systems which reflect the complexities and contributions of DEVLDs to the pathogenesis of PH in susceptible infants.

Methodology

A consensus development conference approach was established from members of the PPHNet, which planned and organised the overall strategy. Working group leaders (N.P.V., S.H.A., E.D.A., M.P.M. and C.G.) and multidisciplinary groups of content experts were identified at the 15th International Conference Neonatal & Childhood Pulmonary Vascular Disease (San Francisco, CA, USA) in February 2022. Working groups were categorised to focus on key areas: clinical presentation of DEVLD and DEVLD-associated PH, diagnostic evaluation with genetic and pathological subgroups, treatment options and supportive care with a palliative care subgroup. These working groups met virtually on a regular basis (March–December 2022) for review of published literature, identification of challenges, discussion and agreement on recommendations. These were further refined during extensive discussions of the multidisciplinary groups to reach consensus (June–December 2023) and then reviewed for approval by all members (January–April 2024).

Clinical presentation of DEVLD and DEVLD-associated PH

Identified challenges

• Delayed recognition

• Broad differential diagnosis

The differential diagnosis for DEVLD-PH may be broad, depending on the age at presentation (figure 1), comorbid conditions and type of PH (arterial, venous or mixed). Clinical suspicion must remain high and diagnostic workup initiated promptly and thoughtfully, including consideration for basic laboratory work. In some cases, bronchoscopy may be indicated for airway evaluation and infectious workup. Many DEVLD conditions present at birth with severe hypoxaemic respiratory failure and PH, causing extrapulmonary right-to-left shunt across a patent ductus arteriosus (PDA) and may be clinically indistinguishable from persistent PH of the newborn (PPHN) [13, 14]. Other DEVLDs are diagnosed later in life, often with chronic, refractory respiratory symptoms, but can also present with PH in the absence of clinically apparent parenchymal lung abnormalities. Therefore, DEVLD should be included in differential diagnoses for unexplained lung disease or PH at all ages, particularly if associated with relevant family history or past medical history of even “transient” PPHN. The neonate with DEVLD may need a level of support disproportionate to the degree of perceived lung disease: “too much” relative to PPHN expectations. It is unusual for a neonate with PPHN to require extracorporeal membrane oxygenation (ECMO) support or to have significant PH or right ventricular (RV) dysfunction which lasts longer than 7–10 days [13–15]. Since there may be more than one diagnosis affecting the clinical picture, increased awareness of multiple possible contributors to clinical deterioration is necessary.

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.

There are certain clinical constellations seen in DEVLDs which may heighten suspicion. For example, TBX4 variants may present with pneumothoraces, right-to-left cardiac shunts (PDA and atrial septal defect (ASD)) and/or RV dysfunction [13]. Infants with TBX4 variants may improve after initial stabilisation only to present with signs and symptoms of PH again later in life.

The typical presentation of ACD is severe hypoxaemic respiratory failure at birth, a presentation similar to severe PPHN [16]. Neonates with ACD may be unable to wean off inhaled nitric oxide, prostanoids and ECMO, and display minimal clinical improvement. Conversely, some ACD cases may demonstrate mild PPHN or delayed transition in the perinatal period but continue to have clinical signs of PVD beyond infancy. Abnormalities in other organ systems may suggest disease as well: imperforate anus, absent gallbladder and malrotation, brain abnormalities, hypoplastic left heart syndrome, other left heart obstructive lesions and total anomalous pulmonary venous return [17–20]. However, atypical presentations with therapeutic responses and varying disease course, related to genotypic variations and/or mosaicism, are increasingly recognised [21, 22]. Therefore, ACD should not be disregarded from differential diagnoses in older infants and children.

Pulmonary vein stenosis (PVS) may be a complicating comorbidity or a masquerader of DEVLD. Infants with PVS (congenital or acquired) may present with hypoxaemia, acute/chronic respiratory failure, recurrent pulmonary oedema and clinical instability. PVS may be isolated or occur in conjunction with DEVLDs, such as BPD, owing to shared aberrations in parenchymal and vascular (arterial and venous) development [23]. This is particularly true in prematurely born infants with BPD who make up almost 40% of PVS paediatric cases, due to causes related to prematurity and postnatal care [24–26]. In some instances, PVS may bring an infant to clinical attention because of increasing oxygen requirement, haziness on chest radiography or worsening PH on echocardiography, and further workup may reveal an underlying DEVLD [27]. Conversely, an infant with DEVLD-PH may have progressively worsening clinical status and PVS is discovered in the workup.

Consensus points: clinical presentation

• Transient PPHN or modest PH at birth is not unusual. However, DEVLD should be considered in term or near-term infants who present with unexpected severe respiratory distress with hypoxaemia, especially with refractory PPHN that is unexplained, poorly responsive to aggressive therapy or persists beyond the first several days of life.

• The differential diagnosis for neonatal respiratory distress is broad and may include PPHN and DEVLDs such as TBX4 and PVS, among other cardiorespiratory disorders.

• Due to genotype–phenotype variations, DEVLDs may have atypical presentations with respect to age of onset and severity of clinical symptoms.

• A constellation of clinical findings, such as early pneumothorax, may suggest high risks for DEVLDs.

Diagnostic evaluation of DEVLD

Identified challenges

• No formal guidelines on workup

• Uncertainty regarding “the best test”

• Lack of clarity on timing of testing (genetics and biopsy)

• Variable availability of testing and expertise among centres

Lung imaging

What is the best way to image the lung parenchyma to diagnose neonatal or infant DEVLD? How should it be ordered and when? Does a normal study rule out disease?

In certain conditions, prenatal ultrasound may detect lung abnormalities that can be better defined anatomically (and in the case of hypoplasia, quantified) through advanced imaging (i.e. fetal magnetic resonance imaging (MRI)) [28]. However, the initial study for a newborn or child with respiratory failure is plain radiography of the chest, regardless of prenatal information. Radiographs provide a rough estimate of the lung volumes and heart size, and may demonstrate diffuse or focal pulmonary opacities, or complications such as pneumothorax.

Typically, computed tomography (CT) of the chest is done when the infant's clinical course seems disproportionate to the perceived or expected disease severity. CT of the chest is largely the current standard in paediatric thoracic imaging and is preferred for depiction of lung parenchymal detail, best performed with reconstruction of thin-section, high-resolution images to appreciate fine detail which may differentiate conditions (figure 2). Although administration of intravenous contrast is generally not necessary for evaluation of lung parenchyma, contrast should be administered if there is concern for cardiac or pulmonary vascular anatomical abnormalities, vascular compression of airway structures or PVS [29–31]. Imaging extrathoracic organs should also be considered during evaluation of the child with presumed DEVLD, to assess for associated abnormalities in the gastrointestinal system (ACD), skeletal system (TBX4) or neurological system (ACD, Filamin A and TTF-1/NKX2-1) [1, 13, 17, 32].

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.

Due to limitations in detailing lung parenchyma and frequent need for sedation, MRI is not routinely used in this disease population. However, MRI as an imaging modality for paediatric DEVLD is an increasingly popular area of research, particularly in pre-term lung disease [33, 34]. The use of hyperpolarised xenon MRI has demonstrated ventilation abnormalities and heterogeneity, speaking to different functional phenotypes within the BPD population. When combined with gas-exchange MRI techniques, MRI may be able to provide functional detail regarding PVD, a current limitation of CT [35, 36]. Although very promising, this modality is still in the research phase and is not widely available.

Nuclear medicine ventilation/perfusion (V/Q) scans have traditionally been used to assess for certain PVDs such as pulmonary emboli, shunts and differential lung perfusion, but their use in paediatric populations, specifically infants, is variable. Considerations may be given for doing either the ventilation (V) or perfusion (Q) part of the study as an adjunct to another imaging modality, such as echocardiography or CT.

Challenges with imaging include questions on study type and timing, especially if anaesthesia is needed for test completion. Advanced discussion with one's local imaging specialist is strongly recommended to clarify: 1) specific choice of study (studies); 2) particulars around the precise order to be placed and study technique (e.g. contrast or gating of the study); 3) management of the child's breathing patterns during the study and timing of images; 4) whether sedation is required to achieve testing and balancing risks and diagnostic yield; 5) best time of day to pursue the study at the institution to ensure adequate support and staff for optimised testing; and 6) child's condition for transport and visualisation of thoracic structures. Has the child been intubated for a prolonged period and therefore has widespread atelectasis? Or is there pulmonary oedema that would benefit from diuresis? Both conditions may obscure parts of the lung parenchyma and therefore compromise complete radiographic assessment, so minimising these conditions will help to optimise visualisation and radiographic evaluation [37].

Genetic testing

The approach to DEVLDs in infants has evolved with advances in applied genetics. In the modern era, the testing menu for genetics is considerable: chromosomal microarray (CMA) panel, predetermined specific gene evaluation panels and whole exome sequence (WES)/whole genome sequence (WGS) analyses are available to varying degrees from institutional and commercial laboratories in most clinical centres. Common concerns are: Which is the right genetic test to order? What is covered by insurance? What is the turnaround time of the test I choose? Will the results be available fast enough for me to act on them? Is genetic testing more informative than a lung biopsy?

The diagnostic yield of genetic testing is high for paediatric DEVLDs presenting in infancy and childhood, and consideration for genetic testing is strongly recommended for all paediatric DEVLD patients [3]. In some cases, genetic testing may occur prior to, or in the absence of, histopathological data from lung biopsy, lung transplant or autopsy to guide test choice. The genetic assessment should generally start with a candidate gene panel sequencing, such as a neonatal lung disease and/or PH panel (table 1), in the affected individual (i.e. the patient), with revision as additional genes are identified. The testing should include sequencing and methods such as multiplex ligation-dependent probe amplification (MLPA), quantitative PCR or sequence-based methods to quantify read count to assess intragenic or whole gene deletions or duplications for such genes as TBX4, since these occur frequently. As a practical consideration, the current approach to include both DEVLD-focused genes and PH-focused genes currently requires most clinicians using industry-led (e.g. private laboratories which provide testing according to American College of Medical Genetics and Genomics (ACMG) Technical Standards for Clinical Genetics Laboratories) genetic testing programmes as there may not be one panel sufficient for all current genes of interest. Consideration should be given for a CMA if syndromic phenotypic features exist.

TABLE 1.

Genetic mutations to be considered in workup of neonatal respiratory distress

ACVRL1	AQP1	ATP13A3	BMPR2	ABCA3	SFTPB
CAV1	EIF2AK4	ENG	GDF2	FOXF1	SFTPC
KCNK3	SMAD9	SOX17	TBX4	NKX2-1

It is important to realise that most gene “panels” from ACMG standard laboratories actually employ next-generation sequencing (NGS) (e.g. exome or genome sequencing) to conduct “panel” testing [38]. For subjects without a gene discovery by panel testing, an initial next step may be a direct conversation with the ACMG laboratory employed for that testing about any available NGS data. Further, at the point of engaging NGS (whether using the prior sample or sending a new sample of DNA for testing), it may be useful to incorporate the testing of parental DNA to better interpret potential de novo variants in the affected patient. In this case, the genetic testing strategy remains a balance between cost of testing, insurance coverage and turnaround time for results. Once a pathogenic variant is identified in the family, targeted testing can be performed for the familial pathogenic variant in both symptomatic and asymptomatic family members.

A key opportunity and challenge of genetic testing in this era is the rapid expansion of scientists’ understanding of the contribution of genetic variations across the genome and the technology to survey the genome. Since most commercial “targeted gene panels” are conducted as part of WES/WGS assays, individuals who undergo this genetic testing have broader genome data acquired but not all is analysed; testing is only reported out for the genes on the panel. It is prudent to remember this and consider revisiting existing data with the genetic laboratory every 2–3 years as new genes and/or variants of interest may exist that were not previously explored bioinformatically. Most commercial laboratories offer this updated analysis, either for free or for a service fee [39].

Of note, with its rapid expansion, the diagnostic efficacy of NGS in concert with CMA has risen in popularity. Recently, the ACMG adjusted its recommendation to state that WES/WGS may be considered as the first- or second-tier approach of genetic testing for infants with multiple congenital anomalies or children with intellectual disability or developmental delay [40]. This may be particularly relevant for neonatal and young infant conditions, but it is unclear how this recommendation fits into the care of a child with DEVLD [41]. At this time, we recommend that in most cases a candidate gene panel sequencing is the first step in genetic analysis, preferably conducted in concert with subspecialty genetics support.

Genetic counselling

The medical team should include geneticists and genetic counsellors who are familiar with cardiopulmonary disease and who are aware of the local hospital/centre policies and regulations about ordering genetic testing. Collaboration with these specialists is crucial to ensure family counselling on the risks and benefits of testing for DEVLD, as testing can reveal mutations or variants that were not clinically suspected, introducing new anxieties and complexities to care. Disseminating information about genetic test results to family members can be challenging due to a variety of reasons, including the complex nature of the information, guilt associated with transmission from parent to child and other family dynamics. Genetic professionals serve as a critical liaison for families to educate and counsel family members once a pathogenic variant has been identified.

Lung biopsy

Lung wedge biopsy is an important diagnostic tool in the evaluation of DEVLD, particularly paediatric ILD, although frequency of lung biopsy varies extensively across institutions [12]. Recent advances in genetic evaluation and imaging methods have created new decision points surrounding lung biopsy, typically in the following clinical scenarios: infant dependent upon ventilator/ECMO support, unexplained imaging findings, respiratory symptoms that are disproportionate to the clinical or imaging findings, lack of improvement with standard therapy, unexplained severity of PH after medical/surgical intervention and PH that is unresponsive to standard vasodilatation therapy and/or complicated by pulmonary oedema. The oft-asked question is: In these scenarios, do the benefits of tissue examination outweigh the risks of surgical biopsy? Benefits of lung biopsy may include a tissue-based assessment to guide medical therapy and guide decision making regarding lung transplantation and withdrawal of life-sustaining therapies. In addition, biopsy can often exclude disease aetiologies in the clinical differential diagnosis critical for DEVLD patient management (figure 3).

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.

Two components are vital to successful pathology interpretation: 1) a lung biopsy specimen with all key anatomical structures represented, and 2) critical clinical and radiographic findings, including key test results. Recommended tissue-processing approaches have been published [42], but ensuring that the lung biopsy is optimised to differentiate among the entities in the differential diagnosis requires communication between the clinical service, the surgeon and the pathologist. It is not infrequent that timing of biopsy can affect interpretation as many patients may be suffering from oxygen toxicity, baro- or volutrauma. The identification of iatrogenic damage patterns is a crucial aspect of lung biopsy interpretation and in some cases may limit robust reading. Consultation with pathologists with pulmonary expertise is therefore recommended to take these considerations into account and increase the diagnostic yield of lung biopsy as many paediatric lung disease entities are rare and thus not commonly encountered in routine practice. As knowledge of paediatric lung disease advances, new diseases are being described, the genetic basis of diseases are being identified and diagnostic techniques are evolving, making the interpretation of lung biopsy specimens challenging for the general pathologist lacking subspecialty expertise and experience in paediatric pulmonary pathology. Additionally, lung disease diagnosis often requires integration of the pathological findings with clinical, radiological, serological and genetic findings, necessitating an interdisciplinary collaborative approach. Thus, pathologists with expertise and special interest in paediatric pulmonary disease can often provide additional diagnostic insights based upon their experience reviewing multiple lung biopsies across institutions.

To assess airways, pulmonary arteries and pulmonary veins, an adequate diagnostic wedge biopsy which includes bronchovascular bundles and interlobular septa is the preferred tissue sample. While transbronchial biopsies provide airway/carinal samples, they do not provide sufficient material to fully evaluate for structural abnormalities for diagnosis. Discussion of the key differential diagnoses prior to obtaining the biopsy will also ensure that the tissue is optimally prioritised for pathological assessment and ancillary studies (tissue culture, flow cytometry, electron microscopy and freezing tissue for molecular and genetic analysis) (figure 4). This prioritisation of tissue allocation is particularly important in small infants, critically ill patients and when the biopsy tissue that is feasible to obtain is scant. Although the goal of every biopsy is to yield a definitive diagnosis with a clear aetiology, biopsies are also critical to exclude entities in the differential diagnosis as well, which may result in identification of a working diagnosis. An experienced pathologist aware of the clinical scenario can optimise the diagnostic yield of the lung biopsy by ensuring the acquired tissue is processed in a manner that best addresses the clinical context.

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.

Consideration should also be given to performing the biopsy in a medical facility that can handle clinical deterioration following surgical biopsy, as advanced mechanical support (i.e. ECMO) may be necessary for stabilisation. If there is a high pre-test probability that the lung biopsy will show a disease that may be amenable to lung transplant, or require ECMO support, communication with a lung transplant team and potentially transfer should be initiated before biopsy is undertaken. This conversation may be helpful to avoid biopsy-related complications that may affect transplant candidacy.

Integrating genetic testing with the pathological findings enhances diagnostic yield, as these two evaluations are complementary and give important insights into disease aetiology. Pathological findings are important for guiding genetic testing in cases with negative targeted gene panel results and for confirming phenotypic alterations when variants of unknown significance are identified. Disease-modifying conditions such as infection, chronic lung disease of prematurity and pulmonary interstitial glycogenosis (PIG) are also identified by pathological evaluation. For genetic variants with as-yet undefined phenotypic outcomes, tissue examination plays a key role in interpretating the clinical significance of the genetic findings as well as identifying new disease entities, clarifying genotype–phenotype relationships and defining heterogeneity in genetic disease severity. For example, in TBX4-related disease, there is a clear phenotypic spectrum including neonatal death, disease progression requiring transplantation and survival into adulthood that is not ascertained by TBX4 alteration alone. Genotype–phenotype correlations can be made by jointly evaluating histology and regional molecular alterations, which is particularly valuable in cases of patchy disease presentation and mosaicism, and therefore supportive for genetic counselling and further testing.

Postmortem examination is an additional mechanism to extend care for a patient's family. Most centres offer autopsy for deceased patients free of charge to the family. A systematic full-body examination can achieve diagnoses, evaluate multiorgan disease manifestations not characterised during life and better define existing diagnoses. Important information can be obtained to inform and counsel family members on the extent and nature of disease, confirm the diagnosis, and potentially benefit siblings, family members or others afflicted with the disease.

Consensus points: diagnostic evaluation

• CT scan of the chest should be used to assess lung parenchymal involvement and contrast should be administered if assessment of pulmonary vascular anatomy is desired.

• If available, candidate gene panel sequencing should be the first step in the diagnosis of DEVLD. If negative, expanded testing (WES/WGS) or lung biopsy may be considered. Decisions will be affected by laboratory constraints (i.e. testing availability and turnaround time), family preferences after counselling, patient stability and personnel resources (surgery, pathology). When considering genetic studies, it is recommended that the clinical team collaborate with a genetic counselling team in advance of testing and upon return of results.

• Considerations for lung biopsy include clinical data, patient stability (which includes consideration for ECMO support services) and implications for long-term management. Adequacy of the tissue specimen and handling is imperative for appropriate review by experienced pathologists.

Approach to DEVLD-PH

Identified challenges

• Uncertainty regarding timing for initial echocardiography and follow-up testing intervals

• Concerns for effect on clinical stability may dissuade echocardiography

• Role of cardiac shunts in DEVLD

• Assessment of pulmonary oedema in the setting of lung disease

The incidence of DEVLD-PH is uncertain due to the diversity of underlying diseases, variability in clinical course, and underappreciation of PH and DEVLD. Furthermore, PH-focused registries are primarily enriched with WSPH Group 1 pulmonary arterial hypertension (PAH) cases or simply classify all lung disease into WSPH Group 3 PH, resulting in registries under-capturing the true prevalence of DEVLD-PH. The PPHNet Registry is an 11-centre, North American cohort of 1475 patients, of which 718 were classified as Group 3 PH (prevalent and incident), mostly BPD, CDH and ILD (ACD, PIG and surfactant protein deficiencies) [11]. The reported experience from the UK is similar, with a high distribution of BPD and CDH representing Group 3 patients [43]. Although PH incidence has been studied and screening recommendations have been made in BPD, they are lacking for other DEVLDs, so the true burden of disease is uncertain, with estimates ranging widely [27, 44].

Echocardiography

The infant who presents with hypoxaemic respiratory failure should undergo urgent echocardiography to rule out structural heart disease, particularly ductal-dependent cyanotic heart disease or obstructed pulmonary veins, quantify RV systolic pressure, evaluate ventricular size and function, and determine size and direction of intra- or extracardiac shunts. Assessment of RV pressure may be performed through assessment of the tricuspid regurgitant jet plus the right atrial v-wave using the modified Bernoulli equation, by assessing the gradient across a PDA or ventricular septal defect (VSD) or by determination of ventricular septal position. Assuming reasonable stability for testing, dedicated echocardiography should not be delayed because results may significantly impact clinical decision making.

In patients with evidence of PH by echocardiography, imaging should specifically focus on ventricular function. Quantitative measures of RV systolic function including tricuspid annular plane systolic excursion (TAPSE) and RV fractional area change are associated with survival, and such measures should be followed serially throughout the clinical course [45–47]. Quantitative measures of RV systolic function are superior to qualitative assessment of ventricular function as they can be tracked longitudinally and may improve risk stratification, discussion of prognosis and assessment of treatment efficacy. Additionally, these measures have been associated with catheter-derived haemodynamics in small, single-centre studies of patients with CDH and BPD [48]. Therefore, echocardiography may provide a reliable method of evaluation and monitoring of congenital defects or shunts prior to proceeding to cardiac catheterisation.

The frequency with which to monitor DEVLD infants for development of PH by echocardiography is less clear. Extrapolating from BPD data demonstrating an early relationship between vascular disease and lung development [49–51], it is reasonable that any infant with concern for DEVLD and persistent ventilator requirement on day 7 of life undergo repeat echocardiograms for evaluation of PH, ventricular dysfunction and development of PVS [8]. Echocardiography should also be considered in patients requiring prolonged respiratory support, especially with recurrent episodes of hypoxaemia, to re-screen for development of RV dysfunction, right-to-left shunting or PVS. Per the 2017 PPHNet consensus statement, the recommendation is that echocardiograms should be routinely performed in pre-term infants meeting clinical criteria for BPD at 36 weeks post-menstrual age [8].

Cardiac catheterisation

Indications for cardiac catheterisation in DEVLD include recurrent or persistent pulmonary oedema, diuretic dependence that is disproportionate to the level of respiratory disease, lack of perceived clinical improvement despite optimised respiratory support and guidance for PH therapy [52]. Benefits are assessment of pre-capillary PAH; exclusion of left-sided heart disease; assessment of response to pulmonary vasodilator therapy, further evaluation of intracardiac or extracardiac shunts, distal peripheral pulmonary artery stenosis or PVS; measurement of pulmonary venous desaturation to support concern for parenchymal lung disease; and evaluation of haemodynamics in the setting of lymphatic system evaluation.

The role and availability of specialists for cardiac catheterisation, cardiovascular anaesthesiology, ECMO and infant critical care may affect availability and consideration for timing of catheterisation. In addition, risk for hypothermia, dislodgement of respiratory support and clinical instability associated with transport and general anaesthesia must be evaluated against benefit of catheterisation [53].

Lack of large clinical trials demonstrating benefit and concern for potential complications contribute to variability in timing of the procedure and decisions regarding closure of intracardiac or extracardiac shunts [53]. However, in the DEVLD infant, thoughtful consideration must be given to cardiac shunts, specifically ASD and PDA. Are they contributors to disease, indicators of disease or both? Will closure of an intracardiac shunt early in the course negate a possible rescue from disease later in the course? Mechanistically, balancing pulmonary blood flow to a compromised pulmonary vascular bed is intuitive and has been reported to be well tolerated and associated with improved outcomes [10, 54–56]. In the setting of multiple shunt lesions, high pressure shunts such as PDA or VSD are typically closed first and then if there is a continued need for closure of an atrial level shunt, it can be done subsequently. Caution is emphasised in the setting of severe RV dysfunction and particularly in patients who are unable to wean from ECMO. In this specific population, salvage PDA stenting (to physiologically simulate a reverse Potts shunt) may be considered to allow for RV decompression and improved function [57, 58]. However, this should be undertaken with caution as patients with lung disease and critical illness who underwent creation of a decompressive pulmonary artery-to-aorta shunt had worse outcomes in the international Pott Shunt registry [59].

The contribution of left ventricular (LV) diastolic dysfunction to cardiorespiratory status is increasingly recognised in some forms of DEVLDs, including CDH and BPD. In single-centre studies, LV diastolic dysfunction, indicated by elevated pulmonary capillary wedge pressure on cardiac catheterisation, has been demonstrated in 40–50% of patients with CDH [60]. Echocardiography often fails to identify LV diastolic dysfunction due to relative tachycardia in neonates and infants, ventricular non-compliance even in healthy infants, and lack of echocardiographic surrogates for left heart filling pressure [61–63].

Therefore, cardiac catheterisation to assess haemodynamics should be considered in patients with recurrent or persistent pulmonary oedema, diuretic dependence that is disproportionate to the level of respiratory disease, lack of perceived clinical improvement despite optimised respiratory support or if additional PH treatment, beyond one therapy, is needed [52].

Consensus points: approach

• All near-term and term infants with fulminant acute respiratory failure should have echocardiography done at presentation to rule out structural heart disease and assess for PH physiology.

• Continued presence of PH or persistent need for aggressive therapies, including ECMO, beyond the first week of life should prompt further consideration and evaluation for DEVLD.

• Cardiac shunt lesions should be evaluated by cardiac catheterisation if there is persistent pulmonary oedema, disproportionate diuretic dependence, failure to improve and/or plateau of progress.

• Consideration should be given for closure of cardiac shunt lesions in the setting of large left-to-right flows without high PVR, as based on cardiac catheterisation.

Approaches to treatment for DEVLD-PH

Identified challenges

• Treatment hinges on correct diagnosis

• No specific versus non-specific treatment

• Concurrent PH treatment

• Treating comorbidities

Therapeutic decisions in DEVLD-PH are dependent on the underlying disease process and severity of disease. Multidisciplinary discussions involving the bedside clinician, PH specialist, pulmonologist and cardiologist are recommended, and should focus on the patient's and family's goals of care. Multiple variables can both contribute to disease and therefore be targets for disease management.

Initial treatments should focus on stabilisation of the infant. Treatments include antibiotics, mechanical ventilation, sedation, paralytics, vasopressors and, in some instances, ECMO. Unfortunately, there is no disease-proven therapy for DEVLDs in general nor for DEVLD-PH. First-line therapy is optimising respiratory status to minimise effects on PVR.

Invasive mechanical ventilation approaches, including positive end-expiratory pressure (PEEP) ranges, will vary based on the underlying aetiology of the DEVLD, lung and airway mechanics, which may be further informed by imaging (chest radiography and CT) [64]. For instance, in the setting of restrictive lung disease or lung (and vascular) hypoplasia, strategies employed in CDH may be utilised, focusing on higher ventilation rates and short inspiratory times, with lower tidal volumes (∼5–8 cm·kg⁻¹) for lung protection [65, 66]. This differs from more obstructive physiology conditions such as BPD in which lower rates, higher inspiratory times, high tidal volumes and higher PEEP are recommended [67]. Mechanical ventilation should be utilised to minimise alveolar collapse, optimise exhalation and minimise volutrauma while achieving a normal pH, typically with partial pressure of carbon dioxide in the 50–60 mmHg range. The DEVLD infant who is optimised will appear comfortable, demonstrate good growth and tolerate rehabilitation therapies.

Adverse consequences of invasive support, including impediments to ongoing lung growth and alveolarisation (occurring in concert with pulmonary vascular growth), should also be considered and transition from invasive ventilation to non-invasive support considered once optimised lung volume and clinical status has been achieved [68, 69]. Non-invasive modes of respiratory support may limit the risks of invasive mechanical ventilation (e.g. barotrauma and need for sedating medications). Oxygen should be used to meet oxygenation targets, typically >92%, and lower PVR for the DEVLD-PH infant; however, care should be taken to minimise hyperoxia.

Steroid therapy may be considered, extrapolating from the treatment of various inflammatory respiratory conditions such as asthma and ILD. Postnatal lung disease may be associated with inflammation due to mechanical ventilation, oxygen supplementation, fluid overload, infection and air leak syndromes. Glucocorticoids may therefore be helpful in these situations by stimulation of surfactant production, stimulation of cell maturation and differentiation, inhibition of DNA synthesis, changes in interstitial tissue components, stimulation of antioxidant enzymes, and regulation of pulmonary fluid metabolism [70]. Although steroids have been used in DEVLDs, indication varies based on clinical findings and comorbidities. It should be noted that glucocorticoid use is different from acute mineralocorticoid use (i.e. hydrocortisone), which is used for inadequate stress response or vasoplegia.

Antifibrotic agents are a more specific group of medications used in ILDs; however, their role in DEVLDs is less studied. Nintedanib is an intracellular tyrosine kinase inhibitor (TKI) that inhibits progression of pulmonary fibrosis [71] and is of particular interest in PH due to VEGF inhibition and prevention of inappropriate angiogenesis. However, no data are available to support recommended use of TKIs in DEVLD [72].

Treatment considerations for DEVLD-PH

If the clinical condition declines despite optimal ventilation, treatment with vasodilators may be considered, extrapolating strategies from other respiratory diseases (BPD and CDH) and heritable conditions. In the perinatal and acute setting, inhaled PH therapies are favoured due to short half-life and improved V/Q mismatch. Inhaled nitric oxide is typically the first-line agent in most US institutions due to wide availability in intensive care units. Iloprost or inhaled epoprostenol are second-line therapies, although access may be limited. If there is RV dysfunction, suspected suprasystemic PH and/or delayed fetal transition, prostaglandin E1 (PGE) may be considered to maintain ductal patency [15]. A native or PGE-supported unrestrictive PDA provides a natural pulmonary-to-systemic shunt, decreases pressure in the pulmonary arteries and decreases RV afterload. Once the pre/post-ductal saturation differential has resolved and the echocardiogram shows all left-to-right PDA shunt, PGE should be weaned off to minimise relative overcirculation to the underdeveloped pulmonary vascular bed.

In the setting of acute critical illness with suprasystemic PH, low-dose epinephrine (<0.05 µg·kg⁻¹·min⁻¹) may be considered to augment contractility and utilise ventricular interdependence. Vasopressin may be helpful by increasing systemic vascular resistance, neutralising the ventricular septal position, and improving stroke volume and cardiac output [10]. Low doses are recommended given the propensity of these agents to promote pulmonary vasoconstriction at medium and higher doses, although the precise dose burdens at which this occurs are unclear, and likely vary according to the patient and other factors. While appropriate in some settings, we emphasise caution if utilising milrinone in the case of suprasystemic RV pressure, due to the potential for systemic afterload reduction which could lead to worsening position of the interventricular septum, reduced effectiveness of LV systolic function and potentially decreased cardiac output.

For the DEVLD-PH infant with fulminant cardiorespiratory disease, ECMO may be considered, typically veno-arterial cannulation. ECMO is not offered universally, and expertise may vary from centre to centre. However, if available, ECMO support may offer stability to seek additional diagnostic testing such as imaging (if stable for transport), lung biopsy or even transport to an experienced DEVLD-PH centre.

Systemic treatments targeting the nitric oxide, endothelin receptor and prostacyclin pathways have been used in DEVLD-PH, with most reports in BPD and CDH populations [73–80]. Inhaled treprostinil has shown improved exercise capacity from baseline on serial 6-min walk tests in adults with ILD-associated PH [81]. Extrapolation of these results to DEVLD-PH has not been universal due to age-related developmental challenges with administration nor have results been formally evaluated in these infants or children [82]. If systemic therapies are started, recommendation is for monitoring for administration-related transient hypoxaemia or increased oxygen requirements, as this may indicate an exacerbation of DEVLD-related V/Q mismatch.

Acute-on-chronic PH exacerbations should be supported with acute agents such as inhaled nitric oxide, iloprost and/or inhaled epoprostenol. Evaluation for infection, aspiration or exacerbation of chronic respiratory failure should be conducted to identify and treat variables affecting clinical stability.

Lung transplantation should be considered for DEVLD with anticipated reduced survival and/or persistence or progression of disease despite maximal interventions. Transplant candidacy requires adequate nutrition, and absence of life- and graft-threatening comorbidities and congenital malformations, so a thorough evaluation should be done to ensure appropriate referral. Unfortunately, paediatric lung transplantation is only offered in specialised centres, and few have expertise with infant transplantation. Therefore, evaluation for transplantation may require transfer, which may not be feasible in all circumstances. When contemplating lung transplantation referral, consultation with a paediatric lung transplant specialist is recommended to navigate potential candidacy and evaluation barriers.

Consensus points: approaches to treatment

• Respiratory status (ventilation and lung recruitment) should be optimised and secondary conditions or symptoms that may threaten respiratory stability should be investigated. Hypoxaemia and significant hypercarbia should be avoided.

• Pressors should be considered for stabilisation.

• For severe PH, short-acting inhaled therapies, such as inhaled nitric oxide or inhaled prostanoids, should be offered as first line for acute management.

• In the neonate, PGE may be considered if there is RV dysfunction to provide pressure relief to the failing ventricle.

• Chronic PH may be amenable to treatment with PH-directed vasodilator therapy.

Supportive care for infants with DEVLD and DEVLD-PH

Identified challenges

• Education for professionals and caregivers

• Lack of recognised network to provide expert consultations and ongoing support

Supporting patients

Growth and nutrition

Many patients with DEVLDs with or without PH complication may demonstrate improvement over time with good growth and lung protection. Because of this, adequate nutrition and growth is of utmost importance. Respiratory support weans should be considered when a patient is demonstrating adequate linear and somatic growth and haemodynamics are favourable [83].

Unsafe feeding practices and associated aspiration can subject the child to recurrent respiratory infections, bronchial inflammation, bronchiectasis, hypoxaemia and poor growth. When respiratory status is optimised and safe for testing conditions, evaluation of swallow and ascending and descending aspiration by bedside or videofluoroscopic swallow study is recommended for any child with DEVLD. In some instances, safe feeding alternatives to oral feeding such as tube feeds may need to be considered for ongoing lung protection. Owing to inherent risks of aspiration with dislodged nasal tube feeds, surgical interventions for more secure long-term tube feeds (gastrostomy/gastrojejunostomy) should be considered to provide a safer feeding practice.

Failure to thrive is not uncommon in this population, given high caloric expenditure, and this may be heightened in the DEVLD-PH setting due to fluid restrictions. Consultation with a dietitian and serial follow-up encounters are recommended to assess nutritional interventions and monitor response. Interventions include appetite stimulants, formula fortification and supplements.

Developmental therapies

Children with DEVLD may be at increased risk for developmental delays, requiring prompt identification and implementation of early intervention to address these and any associated behavioural concerns to support growth and development, and improve overall patient outcomes [84]. Children in the outpatient setting must regularly see their primary care team for ongoing developmental assessments, and subspecialists should augment screening and referral. Children with tracheostomy and ventilator dependence require special provisions and additional specialised therapists and support technologies, and screenings should be modified to meet their needs. When ready, speaking valves may be used to support communication and feeding progression [85, 86].

Provision of adequate respiratory support should allow DEVLD patients the comfort to tolerate consistent engagement during developmental therapies. Tools such as the Behavioral Signs of Respiratory Instability Score (BSRI) [87] are helpful to compare engagement and tolerance of therapies over time and to assess tolerance of respiratory support weans. If a patient is consistently unable to engage in developmental therapies secondary to respiratory distress, agitation (from air hunger) or fatigue, an increase in respiratory support or reassessment for PH may be warranted.

Developmental outcomes are often affected by psychosocial and biological factors including tobacco exposure, early daycare entry, income level and initial birthweight [88]. Clinicians caring for patients with DEVLD and DEVLD-PH must assess for these factors as well.

Transition to adult care

With improvements in recognition and support of infantile DEVLDs, more children may survive beyond adolescence, requiring transition to adult care. However, access to transition may be impaired due to lack of DEVLD-experienced internal medicine physicians, geographic distance to appropriate centre, insurance/coverage issues and other social determinants [89]. Borrowing from transition models in other diseases such as cystic fibrosis and congenital heart disease, the inclusion of the DEVLD patient/caregiver in all conversations, expanding training access and awareness, and combined discussions between paediatric and adult medical teams will result in minimising these risks [90, 91].

Prognosis

Prognosis is variable and dynamic in DEVLD as this is a grouping term encompassing multiple, heterogeneous diseases. Prognosis is also affected by numerous factors including severity of disease at diagnosis, comorbidities (such as PH) and genetic factors. Communication among team members is paramount, especially in the setting of confounding clinical variables as they may require the expertise of multiple subspecialists working together for the patient's benefit. When possible, consultation and counselling should be sought at an expert DEVLD and/or PH centre as there may be more experience and resources for the medical team and caregiver(s), to anticipate and support disease progression.

Supporting caregivers and medical teams

Palliative care involvement

Having a child with DEVLD causes significant distress for caregivers, which may be amplified by medical decision making, uncertain prognosis, and time and resources spent on healthcare. There is a natural grief over unmet expectations for a child's health, growth and development which may affect the medical team's ability to provide care as families wrestle with doubts: Am I making the right decision for my child? How do we know if this treatment will work? What if it doesn't? Are we at end of life?

However, medical teams and providers may also struggle with the same doubts, affecting confidence in decision making. Lack of available data and guidelines for DEVLD, and even further for DEVLD-PH, should prompt medical teams to seek guidance from other physicians and healthcare providers. With ever rapidly expanding global networks, medical teams may be able to connect with expert colleagues around the world. Likewise, caregivers may communicate with other caregivers in the same hospital system or through social media platforms, to connect on similar issues.

Palliative care support should be an integrated treatment into medical management for children with DEVLD and DEVLD-PH [92–94]. Paediatric palliative care is an interdisciplinary, patient- and family-centred approach to care that focuses on quality of life and minimising suffering and distress [95]. Regardless of specialty, all clinicians should be comfortable with “first-line” palliative care skills, including elucidating goals of care, communication about prognosis and treatment options, family support, shared decision making, symptom management, and advance care planning [96]. However, in more complex scenarios, i.e. unique family or team needs, refractory symptoms and/or discordant goals of care, specialised palliative care (SPC) services provided by an interdisciplinary team to address physical, social, psychological and spiritual needs may be of significant value [95, 97]. SPC teams may be consulted at any point in the disease trajectory from diagnosis to end of life, although early and regular consultation is recommended, especially in conditions of uncertain diagnosis or prognosis such as in DEVLD [94, 96].

Advance care planning

Advance care planning is the process of using a patient and family's goals of care to guide the medical care plan in the case of progressive or advancing disease or decline. These conversations are appropriate at any stage of disease, and may include discussions about the utility of treatment strategies, life-sustaining interventions such as cardiopulmonary resuscitation (“code status”) and hospice care (defined as SPC offered to patients with an expected prognosis of <6 months of life). Through provisions of the US Affordable Care Act (2010), some families may elect to enrol their child in a hospice while continuing to seek subspecialty care from their DEVLD-PH team [95]. Advance care planning conversations are most effective when initiated and led by a known and trusted healthcare team member, although SPC team collaboration with the primary medical team may be helpful to address barriers in discussion [8, 96, 98].

Transition to end of life

Unfortunately for some DEVLD/DEVLD-PH patients, survival is unlikely and focus may shift to providing end-of-life care. Death in children with DEVLD may occur at home (e.g. from tracheostomy-related complication or acute aspiration event) or in a hospital (e.g. critical illness in the face of acute infection or progression of disease), while death in children with DEVLD-PH may be more likely to occur in the hospital after discontinuation of respiratory support, ECMO, prostacyclins or other vasoactive medications.

Support from the healthcare team to the family during this time can include validation of the family's decisions and love for their child, increased psychosocial support for heightened spiritual, psychological and social needs, and exploration of the patient/family's wishes and goals during end of life and in the bereavement period. Notably, the healthcare team may also need additional support during this time as personal grief, conflicting goals and moral distress may create conflict within or between care team members, particularly around DEVLD and PH, both of which may be associated with fulminant uncertainties [94, 95]. Symptom management and grief support are of high importance during the end-of-life process and clinicians should provide anticipatory guidance about the dying process as desired by the family. SPC teams may be crucial for both family and staff support during the transition to end-of-life care and bereavement periods [96, 99, 100].

Consensus points: supportive care

• Support of DEVLD patients should include regular assessments of growth/nutrition, feeding practices and development.

• For DEVLD/DEVLD-PH survivors, collaboration with an adult care medical team is important to ensure appropriate transition.

• Consultation with a DEVLD and/or PH centre is recommended for centres without regular SPC support.

• Palliative care principles and SPC teams may be helpful for optimising quality of life, minimising distress, facilitating communication and assisting with decision making for the patient, family and healthcare team.

• Palliative care may consist of routine caregiver support or transition to hospice care, in the setting of fulminant, declining disease.

Conclusions

DEVLDs make up a heterogeneous group of respiratory diseases with considerable risk for PH, due to a shared abnormality in respiratory and vascular development and continued threats to stability from respiratory failure. Although it is known that DEVLDs are associated with PH, there is an underappreciation for how broad “DEVLD” exactly is and how often PH occurs in this group. Increased genetic and histopathological discoveries and descriptions of these conditions require that global organisations recognise the intricacies of pulmonary development and the implications of maldevelopment on the aetiology of this particular subgroup of DEVLD (table 2). It is not infrequent that infants with DEVLD are first recognised because of their PH and the inclusion of DEVLD in the differential diagnosis for these infants is advised, with caution that vigilance is needed to recognise DEVLD when it does present as expected.

TABLE 2.

Proposed classification of developmental lung diseases (DEVLDs) with increased risk of pulmonary hypertension

Developmental disorders due to immaturity	Bronchopulmonary dysplasia
Chromosomal syndromes associated with DEVLD	Trisomy 13
	Trisomy 18
	Trisomy 21
Genetic mutations associated with abnormal lung development	FOXF1 (alveolar capillary dysplasia)
	TBX4 (small patella syndrome)
	SPB, SPC, ABCA3, TTF/NKX2-1 (surfactant protein abnormalities)
	FGF10 (lacrimo-auriculo-dental disorder, acinar dysplasia, congenital alveolar dysplasia)
	FLNA (Filamin A)
Lung hypoplasia syndromes	Inadequate development (oligohydramnios)
	Fetal lung compression (omphalocele, congenital diaphragmatic hernia, congenital pulmonary airway malformation, other fetal tumours)
	Narrow thoracic cage (skeletal dysplasia)

Therefore, the expert consensus (figure 5) of this multidisciplinary group of expert clinicians is presented to specifically address clinical challenges, offer a framework for counselling and support, and impart the need for more robust classification. The landscape of DEVLD is changing rapidly and with advances in understanding, knowledge gaps will be continuously identified. Disease prevalence, genetic burden, testing strategies, and treatment modalities and longitudinal care are all areas of growing attention and dedication. It is the hope of the authors that this interdisciplinary consensus statement will provide the momentum needed to formalise guidelines, to further build and educate the community of patient care professionals, and to serve DEVLD and DEVLD-PH patients globally through a more transdisciplinary approach.

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.

Shareable PDF

This one-page PDF can be shared freely online.

Shareable PDF ERJ-00639-2024.Shareable ^{(531.6KB, pdf)}