The emergence of a lung phenotype of patients with idiopathic pulmonary arterial hypertension (IPAH) who have low diffusion capacity for carbon monoxide (DLCO) and a smoking history challenges the current diagnostic classification rubric for pulmonary hypertension (PH). This was among study findings published in The Lancet Respiratory Medicine.
Researchers sought to better understand and define this emerging IPAH phenotype, which often presents in older individuals with comorbidities who lack overt signs of parenchymal lung disease. The investigators therefore compared the characteristics, therapy response, and survival rates of patients with this lung phenotype (defined by a smoking history and DLCO of less than 45% predicted) with 2 others groups of patients: who those with classical IPAH (characterized by an absence of cardiopulmonary comorbidities and DLCO of 45% or less), and those with PH due to lung disease, who are classified as having group 3 PH.
The researchers compared patient data from 2 European PH registries, COMPERA (ClinicalTrials.gov identifier: NCT01347216), a registry launched in 2007, and ASPIRE, which includes data from 2001 onwards. The 3 study cohorts were as follows: (1) 128 COMPERA patients and 185 ASPIRE patients with classical IPAH; (2) 268 COMPERA patients and 139 ASPIRE patients with IPAH and a lung phenotype; and (3) 910 COMPERA patients and 375 ASPIRE patients with group 3 PH.
Results of the analysis showed that most patients with IPAH and a lung phenotype had normal or near normal spirometry results and a severe reduction in DLCO, with the majority exhibiting little or no parenchymal lung involvement on chest computed tomography.
The median age of participants with IPAH and a lung phenotype was 72 years in COMPERA and 71 years in ASPIRE, whereas those with group 3 PH in COMPERA had a median age of 71 years and those in ASPIRE had a median age of 69 years. These 2 groups were older than those with classical IPAH, in whom the median age was 45 years in COMPERA and 52 years in ASPIRE (P <.001 for IPAH with a lung phenotype vs classical IPAH in both registries).
Although 77% of patients in COMPERA and 72% in ASPIRE with classical IPAH were female, a lower proportion of females was reported in the IPAH lung phenotype cohort (35% in COMPERA and 54% in ASPIRE), as well as in those with group 3 PH (37% in COMPERA and 39% in ASPIRE).
In COMPERA, response to PAH therapies at first follow-up demonstrated improvements in World Health Organization functional class in 54% of those with classical IPAH, 26% of patients with IPAH and a lung phenotype, and 22% of individuals with group 3 PH
(P <.001 for classical IPAH vs IPAH with a lung phenotype; P =.194 for IPAH with a lung phenotype vs group 3 PH).
Median improvements in 6-minute walking distance were 32 meters, 25 meters, and
23 meters for the 3 cohorts, respectively (P =.0015 for classical IPAH vs IPAH with a lung phenotype; P =.64 for IPAH with a lung phenotype vs group 3 PH). Median reductions in N-terminal-pro-brain-natriuretic peptide were 58%, 27%, and 16%, respectively (P =.0043 for classical IPAH vs IPAH with a lung phenotype; P =.14 for IPAH with a lung phenotype vs group 3 PH).
In both registries, the survival of patients with IPAH and a lung phenotype (1 year: 89% in COMPERA and 79% in ASPIRE; 5 years: 31% in COMPERA and 21% in ASPIRE) and those with group 3 PH (1 year: 78% in COMPERA and 64% in ASPIRE; 5 years: 26% in COMPERA and 18% in ASPIRE) was worse than the survival among patients with classical IPAH (1 year: 95% in COMPERA and 98% in ASPIRE; 5 years: 84% in COMPERA and 80% in ASPIRE; P < .0001 for IPAH with a lung phenotype vs classical IPAH in both registries).
Among the limitations of the current study are its post hoc nature, the fact that there were values missing, and the absence of imaging data available in the COMPERA registry. Further, heterogeneities between the 2 registries should be taken into account.
“A 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,” study authors concluded. “These observations have pathogenetic, diagnostic, and therapeutic implications, which require further exploration.”
Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Hoeper MM, Dwivedi K, Pausch C, et al. Phenotyping of idiopathic pulmonary arterial hypertension: a registry analysis. Lancet Respir Med. 2022;10(10):937-948. doi:10.1016/S2213-2600(22)00097-2