Phenotypes of idiopathic pulmonary arterial hypertension.

In recent work, 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 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). Of note, patients classified as having sporadic pulmonary veno-occlusive disease (PVOD) in the Registro Español de Hipertensión Arterial Pulmonar (REHAP) between 2011 and 2022 showed a similar survival free of lung transplantation when compared with IPAH-LP in the paper by Hoeper and colleagues. In our cohort, 1-year survival free of lung transplantation was 85·4%, 3-year survival was 56·4%, and 5-year survival was 24·2% in sporadic PVOD (figure). These numbers resemble findings for patients classified as having IPAH-LP in the work concerning COMPERA and ASPIRE data. After comprehensive and detailed phenotyping, including genetics, we found that patients classified as having sporadic PVOD had a median age of 55·0 years, were predominantly male and previous smokers, and were mostly in functional class III or IV (90·2%). In this group, the median distance walked was 360·0 m, median NT-proBNP was measured as 1359·0 pg/mL, mean pulmonary artery pressure was 42·5 mm Hg, and median pulmonary vascular resistance was 6·7 Wood units. Importantly, DLCO in this population was 33·0% (IQR 27·0–36·0), also comparable with the DLCO in the group with IPAH-LP. Histological confirmation of PVOD was possible in ten of the 22 patients in this cohort who were classified as having sporadic PVOD. In a French study describing sporadic and heritable PVOD, patients with sporadic PVOD were also predominantly male, previous smokers, and had considerably low DLCO values.2Eyries M Montani D Girerd B et al.EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension.Nat Genet. 2014; 46: 65-69Crossref PubMed Scopus (274) Google Scholar Misdiagnosis of pulmonary hypertension with a predominantly venous involvement is a frequent problem, both in clinical practice and in registries.3Hernandez-Gonzalez I Navas P Escribano-Subias P Letter by Hernandez-Gonzalez et al regarding article, “Phenotypic characterization of EIF2AK4 mutation carriers in a large cohort of patients diagnosed clinically with pulmonary arterial hypertension”.Circulation. 2018; 137: 2411-2412Crossref PubMed Scopus (3) Google Scholar We have previously described that patients with sporadic PVOD commonly exhibit at least two radiological findings suggestive of this severe condition.4Pérez Núñez M Alonso Charterina S Pérez-Olivares C et al.Radiological findings in Multidetector Computed Tomography (MDCT) of hereditary and sporadic pulmonary veno-occlusive disease: certainties and uncertainties.Diagnostics (Basel). 2021; 11: 141Crossref PubMed Scopus (5) Google Scholar Despite an extensive description of the findings on chest CT, the work 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 missing a description of septal lines, mediastinal lymphadenopathies, and ground-glass opacities. Those CT findings would have been of special interest to discriminate PVOD from IPAH-LP. Likewise, it would have been crucial to clearly exclude heritable PVOD by genetic testing, since prognosis is also considerably poor (figure). AC-U has received research funding from Instituto de Salud Carlos III (ISCIII), Ministry of Science and Innovation, Spain; and fees for lectures or consultations from Merck Sharp & Dohme, Ferrer, Gossamer Bio, and Janssen. CP-O received fees for lectures or consultations from Merck Sharp & Dohme and Janssen. AM-M received fees for lectures or consultations from Janssen, Merck Sharp & Dohme, AOP Orphan, Chiesi, Rovi, and Leo Pharma. ML-M received fees for lectures or consultations from Janssen, Merck Sharp & Dohme, and Ferrer. PE-S has received research funding from ISCIII, Ministry of Science and Innovation, Spain; and received fees for lectures or consultations from Acceleron, Janssen, Merck Sharp & Dohme, Ferrer, Bayer, Bago, and Gossamer Bio. Phenotypes 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 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 read with great interest the registry analysis by Marius M Hoeper and colleagues1 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.1 But what is the exact meaning of classical IPAH now? 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