Development of better animal models of PH in both COPD and ILD encouraged

• – Differential molecular mechanisms (parenchymal versus vascular)

• – Identification of novel molecular targets

Novel techniques employing ex vivo cultured human lung tissue to identify the key cellular and molecular drivers of pathological lung and vascular remodelling and for individualised drug testing

• – (Co-)cultured human pulmonary vascular cells, viable human lung slices, ex vivo grown or iPSC-derived human lung organoids

Research into biomarkers for group 3 PH encouraged

• – Classical circulating peptides, circulating RNA subsets, monocyte/leukocyteomics, volatile exhaled compounds, exhaled “genomic fingerprint”

• – Shared access to existing biobanks/biosamples from disparate registries, trials including industry-sponsored studies, regulatory agency involvement

  – Patients enrolled into future clinical trials should be consented to enable sharing of their biospecimens

Clinical variables for enrolment in group 3 clinical trials require more sophisticated “deep phenotyping”

• – Image phenotyping of parenchymal and vascular changes, novel imaging techniques including CT “vascular morphometry”, SPECT/CT, PET “metabolomics”, four-dimensional MRI, artificial intelligence machine learning (“radiomics”)

  – Nature, extent and spatial distribution of the parenchymal and vascular abnormalities

Optimal patient phenotype for trials of therapy

• – Best haemodynamic variable(s) and threshold to define the patient phenotype; evaluation of right ventricular dysfunction for enrolment; extent of permissible parenchymal lung disease?

  – Combination of pulmonary function testing, haemodynamic profile and imaging required

Clinical trial end-points in PH with underlying lung disease

• – Phase 2 studies: physiological variables (e.g. right ventricular function, haemodynamics, 6MWT) and biomarkers (e.g. BNP) acceptable

• – Phase 3 studies: comprehensive patient centric clinical outcomes preferable: composite end-point, time to clinically meaningful change (clinical worsening and/or improvement)

• – Clinical worsening events may include: mortality, hospitalisation (cardiopulmonary), categorical changes in a functional test (e.g. 6MWT), QoL measures, NYHA Functional Class change, need for supplemental oxygen, disease exacerbation, lung transplantation

6MWT: improve its group 3 informative value (“integrate” distance, deoxygenation, Borg dyspnoea score, heart rate recovery?)

Encourage cardiopulmonary exercise testing for more elaborate distinction between respiratory versus circulatory limitation (problem: supplemental oxygen dependency)

Haemodynamic assessment while exercising is encouraged and is to be standardised

Inclusion spectrum in group 3 in view of different aetiology, molecular pathology and clinical course: “narrow versus broad”?

IIP can be studied together with chronic hypersensitivity pneumonitis and occupational lung disease

Sarcoidosis-PH sufficiently different and should be studied independently

COPD-PH should be studied independently

CPFE-PH included in ILD-PH studies; permissible provided the extent of their emphysema is not too great; or risk for confounding signal?

Studies employing inhaled PH therapies are an attractive option as this may enable better ventilation/perfusion matching and limit systemic side-effects

Future studies should focus on the prevention/inhibition/reversal of vascular remodelling in addition to vasodilation CLD-PH

Future studies should also target role of the vascular compartment in driving parenchymal abnormalities (“vascular therapy beyond PH”)

Further studies of the role of pulmonary rehabilitation (exercise training) in lung disease complicated by PH are encouraged