PH associated with chronic lung disease: a constellation of phenotypes

The PVRI is leading an initiative to foster research in the study of Group 3 pulmonary hypertension, which has been highlighted as an area of great unmet medical need.

Pulmonary hypertension complicating chronic lung disease is one of the most frequent forms of pulmonary hypertension, although its exact prevalence is highly underestimated by the lack of systematic assessment of pulmonary hemodynamics. The diseases that most commonly present with pulmonary hypertension are chronic obstructive pulmonary disease (COPD) and interstitial lung disease. Pulmonary hypertension in chronic lung disease and hypoxia constitutes Group 3¹, also including diseases with mixed restrictive and obstructive pattern, hypoxia without lung disease (obesity hypoventilation syndrome, sleep apnoea syndrome, pulmonary hypertension at high altitude) and developmental lung disorders.

It has become increasingly clear in the last two decades, thanks to epidemiological studies and clinical trials, that Group 3 pulmonary hypertension is in fact a constellation of different and varied phenotypes.

In interstitial lung disease the INCREASE trial², which showed a clear benefit with inhaled Treprostinil, has raised hopes for the treatment of this very invalidating and deadly form. Idiopathic pulmonary fibrosis is the most common form associated with pulmonary hypertension and the lung vasculature is affected in nearly half of the patients undergoing transplant workup.

In COPD, pulmonary hypertension presents mostly later stages and is almost always mild-moderate; however, the small group presenting with severe hemodynamic compromise has strongly reduced survival compared to patients with mild-moderate pulmonary hypertension³. Therefore, right heart catheterization is only recommended when severe pulmonary hypertension is suspected: if confirmed, it warrants a referral to a specialised centre for lung transplant workup and/or the enrolment in a clinical trial. It is noteworthy that even in patients with COPD and severe pulmonary hypertension, who suffer a rare complication of a highly prevalent disease, therapeutic options are extremely reduced and mortality is particularly high.

On the other hand, suspicion of severe hemodynamic compromise in lung disease is often difficult to establish with echocardiography, due to its technical limitations in patients with altered lung structure; the clinical picture, i.e., “unjustified” or “disproportionate” dyspnoea and/or signs of right heart failure, is equally challenging because they constitute grey areas where the patient’s symptoms are often regarded as normal in the context of parenchymal and vascular lung disease.

Epidemiological studies^4,5 conducted in the last decade on data extracted from registries, have shown that pulmonary hypertension complicating COPD and interstitial lung disease have starkly different survival rates, with the former being much more benign than the latter. Whole-genome analyses⁶ conducted on pulmonary artery tissue from patients with COPD and idiopathic pulmonary fibrosis have further shown that the genetic profile of the two entities is significantly different, suggesting that clues to their divergent clinical phenotypes might be evidenced at the molecular level.

The collaboration of clinicians and researchers from different specialties and an interest in pulmonary vascular diseases, made possible by the PVRI, will hopefully advance the exploration of the constellation of phenotypes currently lumped in Group 3 pulmonary hypertension, thus providing insights into their characteristics and providing therapeutic options to this prevalent group of pulmonary hypertension patients.

By Lucilla Piccari, MD, on behalf of the Pulmonary Vascular Research Institute.

Pulmonary Hypertension Group III Workstream