TABLE 4.

Existing gaps in evidence on treatments for pulmonary hypertension (PH) associated with chronic lung disease (CLD)

Gaps in the evidence	What is needed
Data on the incidence and prevalence of CLD-PH (and its subtypes) using the updated definition of PH	Multinational prospective registries with accurate and consistent use of diagnostic criteria and haemodynamic definitions
Phenotyping of PH in CLD	High-quality imaging and blood biobanking for omics and genetics studies
Accurate confirmation of the type and extent of parenchymal disease. Why are some CLDs associated with more severe PH than others?	Systematic collection and adjudication of both HRCT description and imaging data More sophisticated imaging modalities as well as use of AI and deep learning HRCT parenchymal imaging should be incorporated in the inclusion and exclusion criteria for group 1 PAH studies
Demographic, epidemiologic and clinical data on CLD-PH in patients with PVR 2–3 WU and mPAP 20–25 mmHg	This patient group needs to be studied prospectively to better understand disease progression and impact on outcomes, as well as the role of PH therapy on outcomes
Uniform definition or understanding of CPFE-PH, which is a distinct phenotype both in clinical behaviour and response to therapy	Pre-specified subgroup analyses of CPFE-PH patients in future clinical trials
Validated multimodal risk assessment scores to predict outcomes in the CLD-PH population	Prospective studies to identify such scoring systems
Validated predictive scoring systems to predict the presence of PH on CLD	Prospective studies to derive scores with subsequent validation cohorts
Delineation of pathogenetic and pathophysiologic pathways leading to PH in rare parenchymal lung diseases	Continued development of more precise animal models Procurement of human tissue or cells (e.g. explanted lung, other novel methods to acquire pulmonary vascular cells) Identification of circulating biomarkers that may be relevant to understanding the pathobiology of these diseases
Knowledge about the effect and safety of specific treatments for pulmonary vasculopathy, and impact of specific treatments for underlying respiratory diseases on the development and clinical behaviour of PH. Prognostic and assessment criteria and end-points to judge the efficacy of treatments for these diseases	Expansion of secondary and exploratory end-points in future clinical trials to understand which end-points are most relevant to CLD-PH patients Implementation of novel, adaptive trial designs in future CLD-PH trials
Lack of CLD-PH-specific patient-reported outcomes	Collection and validation of data to develop CLD-PH-specific patient-reported outcomes

PVR: pulmonary vascular resistance; WU: Wood units; mPAP: mean pulmonary arterial pressure; HRCT: high-resolution computed tomography; AI: artificial intelligence; PAH: pulmonary arterial hypertension; CPFE: combined pulmonary fibrosis and emphysema.