Phenotypes of idiopathic pulmonary arterial hypertension

We read with great interest the registry analysis by Marius M Hoeper and colleagues1Hoeper MM Dwivedi K Pausch C et al.Phenotyping of idiopathic pulmonary arterial hypertension: a registry analysis.Lancet Respir Med. 2022; 10: 937-948Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar suggesting that patients with idiopathic pulmonary arterial hypertension (IPAH) and a lung phenotype defined by a lung diffusion capacity for carbon monoxide (DLCO) of less than 45% of the predicted value and a smoking history have a worse prognosis than do patients with more classical IPAH.1Hoeper MM Dwivedi K Pausch C et al.Phenotyping of idiopathic pulmonary arterial hypertension: a registry analysis.Lancet Respir Med. 2022; 10: 937-948Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar But what is the exact meaning of classical IPAH now? The historical National Institute of Health (NIH) registry of “primary pulmonary hypertension” established a classical IPAH phenotype of predominantly female, young to middle-aged adults with no cardiac or respiratory diseases. In that registry, close to half of the patients were smokers and approximately one-third of the patients had a very low DLCO.2Rich S Dantzker DR Ayres SM et al.Primary pulmonary hypertension. A national prospective study.Ann Intern Med. 1987; 107: 216-223Crossref PubMed Scopus (1732) Google Scholar As a crude estimate, some 15–30% of the patients would have presented with a lung phenotype. In the case-control study that identified appetite suppressants as a cause of IPAH, a smoking history was found to be unrelated to the disease.3Abenhaim L Moride Y Brenot F et al.Appetite-suppressant drugs and the risk of primary pulmonary hypertension.N Engl J Med. 1996; 335: 609-616Crossref PubMed Scopus (1075) Google Scholar As mentioned by Hoeper and colleagues, the smoking rodent is an experimental model of emphysema, not PAH.1Hoeper MM Dwivedi K Pausch C et al.Phenotyping of idiopathic pulmonary arterial hypertension: a registry analysis.Lancet Respir Med. 2022; 10: 937-948Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar The lung phenotype of IPAH might be three times more common in some registries than in others.1Hoeper MM Dwivedi K Pausch C et al.Phenotyping of idiopathic pulmonary arterial hypertension: a registry analysis.Lancet Respir Med. 2022; 10: 937-948Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar Thus, further studies might be needed to better define the lung phenotype of IPAH and its pathophysiology. In the meantime, we might prefer to understand classical IPAH as defined in the NIH registry. Another intriguing aspect of the report by Hoeper and colleagues1Hoeper MM Dwivedi K Pausch C et al.Phenotyping of idiopathic pulmonary arterial hypertension: a registry analysis.Lancet Respir Med. 2022; 10: 937-948Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar is that more than half of their patients with classical IPAH achieved a low-risk status at follow-up, whereas most (67%) of them were on only one targeted therapy. In the Italian Pulmonary Hypertension network, this good result was achieved in only 31% of the patients with IPAH, with 70% of them on monotherapies. Other registries show even less favourable results.4Weatherald J Boucly A Chemla D et al.Prognostic value of follow-up hemodynamic variables after initial management in pulmonary arterial hypertension.Circulation. 2018; 137: 693-704Crossref PubMed Scopus (109) Google Scholar Whether these differences can be explained only by exclusion or inclusion of patients with very low DLCO deserves scrutiny. However, over-optimistic results of monotherapies in classical IPAH or very poor prognosis in the lung phenotype IPAH should not distract clinicians from treating these patients with initial combinations of drugs following updated risk assessment-guided treatment algorithms.5Badagliacca R D'Alto M Ghio S et al.Risk reduction and hemodynamics with initial combination therapy in pulmonary arterial hypertension.Am J Respir Crit Care Med. 2021; 203: 484-492Crossref PubMed Scopus (27) Google Scholar The current tendency is to optimise titration of therapies based not only on risk scores, but also with determination of pulmonary vascular resistance and imaging of the right heart. Hoeper and colleagues are to be commended for their painstaking efforts to identify PAH subphenotypes in large registries. Their notion of a lung phenotype of IPAH deserves attention but requires validation in prospective explorations. As always with excellent studies, this one begs for more. RB reports personal fees from UT, Dompè, Ferrer, Bayer, MSD, AOP, and Orphan Pharmaceuticals, outside of the submitted work. RLB reports grants from Actelion, Bayer, Bellerophon, Eiger, and Abbott. GM declares no competing interests. KT has received speaking fees from Actelion and Bayer, outside of the submitted work. RN reports relationships including consultancies, speaker's fees, and membership of advisory boards with AOP, Orphan Pharmaceuticals, Johnson & Johnson, Lung Biotechnology Corporation, and United Therapeutics. All authors contributed to writing of this Correspondence and approved the manuscript for submission. Phenotyping of idiopathic pulmonary arterial hypertension: a registry analysisA cohort of patients meeting diagnostic criteria for IPAH with a distinct, presumably smoking-related form of pulmonary hypertension accompanied by a low DLCO, resemble patients with pulmonary hypertension due to lung disease rather than classical IPAH. These observations have pathogenetic, diagnostic, and therapeutic implications, which require further exploration. Full-Text PDF Open AccessPhenotypes of idiopathic pulmonary arterial hypertensionWe applaud the recent article in The Lancet Respiratory Medicine by Marius M Hoeper and colleagues,1 which highlights a unique group of patients with pulmonary hypertension who meet the diagnostic criteria for group 1 pulmonary arterial hypertension (PAH) but have a lung phenotype characterised by older age, substantial smoking history, male predominance, substantial reduction of diffusion capacity for carbon monoxide, and a clinical course that is similar to group 3 pulmonary hypertension rather than group 1. Full-Text PDF Phenotypes of idiopathic pulmonary arterial hypertensionIn recent work, Marius M Hoeper and colleagues1 showed a remarkably high mortality among patients classified as having idiopathic pulmonary arterial hypertension with a lung phenotype (IPAH-LP). In their elegant paper combining data from the COMPERA and ASPIRE registries, this phenotype was composed of predominantly male patients with a smoking habit, and a median diffusing capacity for carbon monoxide (DLCO) of 30% (COMPERA) and 27% (ASPIRE). Full-Text PDF Phenotypes of idiopathic pulmonary arterial hypertension – Authors' replyAlejandro Cruz-Utrilla and colleagues suggest that the cohort we described as having idiopathic pulmonary arterial hypertension (IPAH) with a lung phenotype1 might have pulmonary veno-occlusive disease (PVOD). However, IPAH with a lung phenotype is distinct from PVOD: chest CT studies from ASPIRE were reviewed by radiologists with expertise in pulmonary disease, and radiological features of PVOD were not identified in our study; patients with PVOD might develop pulmonary oedema following pulmonary arterial hypertension therapy (however, this has not been observed in our cohort); histological data from 24 patients with IPAH with a lung phenotype show vascular pruning with capillary rarefication, whereas only 13% had features mimicking PVOD;2 PVOD remains uncommon, whereas our carefully phenotyped cohort might be more prevalent than classical IPAH;3 and pulmonary venous involvement can be found in a third of IPAH lung specimens,4 so histological demonstration of pulmonary venous involvement is insufficient to diagnose PVOD, a condition characterised by widespread venous obliteration, dilated capillaries, and angioproliferative lesions. Full-Text PDF