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BackgroundIt is currently unknown if disease severity modifies response to therapy in pulmonary arterial hypertension (PAH). We aimed to explore if disease severity, as defined by established risk-prediction algorithms modified response to therapy in randomized clinical trials in PAH.MethodsWe performed a meta-analysis using individual participant data from 18 randomized clinical trials of therapy for PAH submitted to the United States Food and Drug Administration to determine if predicted risk of one-year mortality at randomization modified the treatment effect on three outcomes: change in six-minute walk distance (6MWD), clinical worsening at 12 weeks, and time-to-clinical worsening.ResultsOf 6561 patients with a baseline U.S. Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL 2.0) score, we found that individuals with higher baseline risk had higher probabilities of clinical worsening but no difference in change in 6MWD. We detected a significant interaction of REVEAL 2.0 risk and treatment assignment on change in 6MWD. For every three-point increase in REVEAL 2.0 score, there was a 12.49 meter (95%CI 5.86–19.12, p=0.001) greater treatment effect in change in 6MWD. We did not detect a significant risk by treatment interaction on clinical worsening with most of the risk prediction algorithms.ConclusionsWe found that predicted risk of one-year mortality in PAH modified treatment effect as measured by 6MWD, but not clinical worsening. Our findings highlight the importance of identifying sources of treatment heterogeneity by predicted risk to tailor studies to patients most likely to have the greatest treatment response.

Evidence suggests that lung injury, inflammation and extracellular matrix remodelling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodelling in community-dwelling adults sampled without regard to respiratory symptoms or smoking.We measured high attenuation areas (HAA; percentage of lung voxels between −600 and −250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis.HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3–11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8–13.0), lower forced vital capacity (FVC) (mean adjusted difference −82 mL, 95% CI −119–−44), lower 6-min walk distance (mean adjusted difference −40 m, 95% CI −1–−80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43–2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39–1.79).High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodelling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults.

IntroductionWhile the performance of the emPHasis-10 (e10) score has been evaluated against limited patient characteristics within the United Kingdom, there is an unmet need for exploring the performance of the e10 score among pulmonary arterial hypertension (PAH) patients in the United States.MethodsUsing the Pulmonary Hypertension Association Registry, we evaluated relationships between the e10 score and demographic, functional, haemodynamic and additional clinical characteristics at baseline and over time. Furthermore, we derived a minimally important difference (MID) estimate for the e10 score.ResultsWe analysed data from 565 PAH (75% female) adults aged mean±sd 55.6±16.0 years. At baseline, the e10 score had notable correlation with factors expected to impact quality of life in the general population, including age, education level, income, smoking status and body mass index. Clinically important parameters including 6-min walk distance and B-type natriuretic peptide (BNP)/N-terminal proBNP were also significantly associated with e10 score at baseline and over time. We generated a MID estimate for the e10 score of −6.0 points (range −5.0–−7.6 points).ConclusionsThe e10 score was associated with demographic and clinical patient characteristics, suggesting that health-related quality of life in PAH is influenced by both social factors and indicators of disease severity. Future studies are needed to demonstrate the impact of the e10 score on clinical decision-making and its potential utility for assessing clinically important interventions.

The presence of a systemic autoimmune rheumatic disease (ARD) is a well-known risk factor for interstitial lung disease (ILD). For example, 33% of adults with rheumatoid arthritis (RA) have subclinical ILD [1]. Higher serum levels of IgM rheumatoid factor (RF), IgA RF, and anti-cyclic citrullinated peptide antibody 2 are associated with subclinical ILD in community-dwelling adults [2]. It is unknown whether this relationship between autoimmunity and subclinical ILD is limited to RA-related autoantibodies, or extends more broadly to other epitopes. High attenuation areas (HAA) and interstitial lung abnormalities (ILA) are validated quantitative and qualitative subclinical ILD phenotypes, respectively. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Bernstein reports grants from NIH/NIAMS, grants and personal fees from Boehringer Ingelheim, grants from Pfizer, outside the submitted work. Conflict of interest: Dr. Austin has nothing to disclose. Conflict of interest: Dr. Kawut has served in an advisory capacity (for grant review and other purposes) for United Therapeutics, Akros Pharmaceuticals, Glaxo SmithKline, and Complexa, Inc. without financial support or in-kind benefits. Conflict of interest: Dr. Raghu reports grants and personal fees from Boehringer Ingleheim, outside the submitted work. Conflict of interest: Eric A. Hoffman, PhD is a founder and share holder of VIDA Diagnostics, a company commercializing lung image analysis software developed, in part, at the University of Iowa. Conflict of interest: Dr. Newell reports grants from NIH, during the conduct of the study; personal fees from VIDA, grants from NIH, grants from Siemens Healthineers, outside the submitted work; In addition, Dr. Newell has a patent with VIDA issued, and a patent with University of Iowa issued. Conflict of interest: Dr. Watts reports personal fees from Genentech, personal fees from Boehringer Ingelheim, personal fees from France Foundation, outside the submitted work. Conflict of interest: Dr. Nath has nothing to disclose. Conflict of interest: Dr. Sonavane reports grants from NIH, during the conduct of the study. Conflict of interest: Dr. Barr reports grants from NIH, during the conduct of the study; grants from NIH, grants from COPD Foundation, outside the submitted work. Conflict of interest: Dr. Lederer is a full time employee of Regeneron Pharmaceuticals. The work in this article was performed solely while Dr. Lederer was an employee of Columbia University and does not represent work by Regeneron Pharmaceuticals, Inc. Dr. Lederer reports personal fees from Roche, Sanofi Genzyme, Philips Respironics, Fibrogen, Global Blood Therapeutics, Boehringer-Ingelheim, Veracyte, and Galapagos unrelated to the current work; institutional grant support from Fibrogen, Global Blood Therapeutics, and Boehringer-Ingelhim. He has performed unpaid consulting work for Galecto, Pliant therapeutics, and Bristol Myers Squibb. Columbia University has received fees from the Pulmonary Fibrosis Foundation for Dr. Lederer's consulting services.

The clinical course of pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) is not known except in advanced disease.488 subjects in a placebo-controlled study of ambrisentan in IPF with mild–moderate restriction in lung volume, underwent right heart catheterisation (RHC) at baseline and 117 subjects (24%) had repeated haemodynamic measurements at 48 weeks.The subjects were categorised into a) World Health Organization (WHO) Group 3 PH (PH associated with pulmonary disease), n=68 (14%); b) WHO Group 2 PH (PH associated with left-sided cardiac disease), n=25 (5%); c) no PH but elevated pulmonary artery wedge pressure (PAWP), n=21 (4%); and d) no PH but without elevation of PAWP, n=374 (77%). The WHO Group 3 PH subjects had a lower diffusion capacity, 6MWD and oxygen saturation compared to the subjects with no PH. There was no significant change in mean pulmonary arterial pressure with ambrisenten or placebo after 12 months.Subjects with IPF associated with WHO Group 3 PH had impaired gas exchange and exercise capacity compared to patients without PH. An additional 9% of the subjects had haemodynamic evidence of subclinical left-ventricular dysfunction. Pulmonary artery pressures remained stable over 1 year in the majority of the cohort.

Prediction modelling is critical for improving ALS respiratory care. Assessing external validity of a model should account for discrimination, calibration, and cohort characteristics. Further work on outcomes is necessary before practice implementation.http://bit.ly/2XbfeUq

Female sex is a risk factor for pulmonary arterial hypertension (PAH), yet females have better survival than males. We sought to determine if sex was associated with baseline haemodynamics in subjects with PAH, and whether age modified these relationships. We conducted a pooled analysis from 11 randomised trials submitted to the US Food and Drug Administration. The study sample included 1211 subjects with idiopathic PAH, 25% of whom were males, and 489 subjects with connective tissue disease-associated PAH, 13% of whom were males. After multivariable adjustment, right atrial pressure was 1.36 mmHg higher (95% CI 0.44-2.27, p=0.004), cardiac index was -0.14 L · min(-1) · m(-2) lower (95% CI -0.23-0.04, p=0.01) and pulmonary vascular resistance was 1.23 Wood units higher (95% CI 0.18-2.27, p=0.02) in males compared with females. Younger males had 5.43 mmHg (95% CI 2.20-8.66, p=0.001) higher mean pulmonary arterial pressures than younger females, but these relationships were attenuated after age 45 years. In the subgroup of connective tissue disease-associated PAH, males may have had higher right atrial pressure. These findings implicate age as a modifier and provide further evidence of sexual dimorphism in PAH.

Airflow obstruction is an independent risk factor for cardiovascular events in the general population. The affected vascular bed and contribution of emphysema to cardiovascular risk are unclear. We examined whether an obstructive pattern of spirometry and quantitatively defined emphysema were associated with subclinical atherosclerosis in the carotid, peripheral and coronary circulations. The Multi-Ethnic Study of Atherosclerosis recruited participants aged 45-84 yrs without clinical cardiovascular disease. Spirometry, carotid intima-media thickness (IMT), ankle-brachial index (ABI) and coronary artery calcium (CAC) were measured using standard protocols. Percentage of emphysema-like lung was measured in the lung windows of cardiac computed tomography scans among 3,642 participants. Multiple linear regression was used to adjust for cardiac risk factors, including C-reactive protein. Decrements in forced expiratory volume in 1 s (FEV(1)) and FEV(1)/forced vital capacity ratio were associated with greater internal carotid IMT, particularly among smokers (p=0.03 and p

The supplemental oxygen flow rate is a common bedside measure of gas exchange impairment. We aimed to determine whether a titrated oxygen requirement (TOR) predicted mortality in idiopathic pulmonary fibrosis (IPF). We examined 104 adults with IPF enrolled in a prospective cohort study and a validation cohort of 151 adults with a variety of interstitial lung diseases (ILDs). The TOR was defined as the lowest oxygen flow rate required to maintain an oxyhaemoglobin saturation of 96% while standing. Cox proportional hazards models and time-dependent receiver operating characteristic curves were used to examine survival time. A higher TOR was associated with a greater mortality rate independent of forced vital capacity and 6-min walk test results in IPF (adjusted hazard ratio (per 1 L·min(-1)) 1.16, 95% CI 1.06-1.27). The TOR was at least as accurate as pulmonary function and 6-min walk testing at predicting 1-yr mortality. Findings were similar in other ILDs. The TOR is a simple, inexpensive bedside measurement that aids prognostication in IPF.

Patients with connective tissue disease (CTD)-associated pulmonary arterial hypertension (APAH) experience poorer outcomes than those with idiopathic PAH (IPAH) [1–6]. In the USA, patients with systemic sclerosis (SSc) are most commonly affected by CTD-APAH and have the worst survival [1]. Similarly, 74% of a large cohort with CTD-APAH in the UK had SSc, and these patients had poorer survival than those with systemic lupus erythematosus (SLE) or polymyositis/dermatomyositis [7]. Few published studies have described the clinical features and outcomes of patients with CTD-APAH in Asia. Chung et al. [8] found that Korean patients with SLE-pulmonary hypertension had much worse survival than those with IPAH, with 1- and 5-year survival rates of 51% and 17% for SLE-pulmonary hypertension compared with 77% and 68% for IPAH. A more recent study of 70 Japanese patients with CTD-APAH found that mixed connective tissue disease (MCTD) was the most common underlying CTD (43%), followed by SLE (29%), SSc (19%) and primary Sjogren’s syndrome (10%) [9]. This study found no significant difference in survival among the different CTD-APAH subgroups, but did find improved survival rates in those diagnosed more recently. In this issue of the European Respiratory Journal , Hao et al. [10] describe the clinical features and outcomes of 129 Chinese patients with CTD-APAH confirmed by right heart catheterisation between July 2006 and May 2011. It is known that the prevalence of SLE in the Chinese population is much higher than in Caucasians [11, 12], while SSc is more common in Caucasians than in the Chinese population [13]. Consistent with this epidemiology, SLE was the …

Chronic obstructive pulmonary disease (COPD) is defined by the presence of airflow limitation which is not fully reversible, but COPD encompasses numerous phenotypes [1]. Phenotypes are the products of genetic and environmental interactions, with “environment” being broadly defined. The systematic measurement and analysis of clinical and other qualitative and quantitative traits may refine COPD phenotypes, features of which may be shared between different disease states [2, 3]. Han et al. [4] have defined clinical phenotypes in COPD as “a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression, or death).” Identification of such phenotypes would not only facilitate outcome prediction and “personalised” treatment, but also improve the understanding of critical biological and mechanistic disease pathways. The systemic impact of COPD has led to consideration of extrapulmonary disease manifestations in recent efforts to construct these phenotypes. This issue of the European Respiratory Journal contains one of two recent studies that focus on cardiovascular phenotyping in COPD [5, 6]. Hurdman et al. [5] have carefully evaluated the phenotype of severe pulmonary hypertension (PH) (mean pulmonary artery pressure ≥40 mmHg) in COPD (PH-COPD) in comparison to the mild–moderate PH phenotype in a prospective cohort of patients referred to a specialty centre over almost a decade [7]. Echocardiography, spirometry and lung computed tomography (CT) imaging were performed with standardised interpretation. 59 patients with severe PH-COPD were compared to 42 patients with mild–moderate PH-COPD, with complete follow-up in all. Patients with severe PH-COPD had worse oxygenation and a lower diffusing capacity for carbon monoxide ( D LCO), but higher forced expiratory volume in 1 s (FEV1), forced vital capacity …

Well-established disease correlates may be inadequate surrogate end-points for outcomes in paediatric and adult PAH http://ow.ly/EUYOQ