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Background The incidence of subsegmental pulmonary embolism (SSPE) has increased with improvements in imaging technology. There is clinical equipoise for SSPE treatment, with conflicting evidence of improved mortality or reduced venous thromboembolism recurrence with anticoagulation. SSPE studies have significant heterogeneity and often lack adequately matched disease comparator groups. Objectives To determine the prevalence, management, and outcomes of SSPE and compare them to patients with main, lobar, segmental, and no pulmonary embolism (PE). Patients/Methods All adult patients undergoing CT pulmonary angiography (CTPA) between 2013 and 2019, at 3 UK hospitals were included in the study. CTPA reports were text mined for language relating to PE, and then further manually screened for the presence and anatomical location of PE. Patient groups were propensity matched by age, sex, and year of CTPA prior to analysis. 3-month outcomes of major bleeding, VTE recurrence, and death were recorded. Results 79 (3.8%) SSPEs were identified from 2,055 diagnoses of PE, and 14,300 CTPA reports. 44 (56%) of SSPEs were single artery emboli, 25 (32%) were multiple unilateral emboli, and 10 (13%) were multiple bilateral emboli. Mortality, VTE recurrence and major bleeding were similar at 3 months across all groups. 87.3% of SSPE imaging reports had an additional radiological diagnosis, with pleural effusion (30%), consolidation (19%), and cardiomegaly (19%) being the most common. Conclusion The prevalence of SSPE was 3.8% of all PEs and there were a substantial number of additional radiological findings in the SSPE group that may have accounted for their symptoms.

Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular disease (CVD) and concomitant disease leads to reduced quality of life, increased hospitalisations and worse survival. Acute pulmonary exacerbations are an important contributor to COPD burden and are associated with increased cardiovascular (CV) events. Both COPD and CVD represent a significant global disease impact and understanding the relationship between the two could potentially reduce this burden. The association between CVD and COPD could be a consequence of (1) shared risk factors (environmental and/or genetic) (2) shared pathophysiological pathways (3) coassociation from a high prevalence of both diseases (4) adverse effects (including pulmonary exacerbations) of COPD contributing to CVD and (5) CVD medications potentially worsening COPD and vice versa. CV risk in COPD has traditionally been associated with increasing disease severity, but there are other relevant COPD subtype associations including radiological subtypes, those with frequent pulmonary exacerbations and novel disease clusters. While the prevalence of CVD is high in COPD populations, it may be underdiagnosed, and improved risk prediction, diagnosis and treatment optimisation could lead to improved outcomes. This state-of-the-art review will explore the incidence/prevalence, COPD subtype associations, shared pathophysiology and genetics, risk prediction, and treatment of CVD in COPD.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed disease of uncertain etiology. Altered endothelial homeostasis, defective angiogenesis and inflammation are implicated. Angiopoietin 2 (Ang2) impairs acute thrombus resolution and is associated with vasculopathy in idiopathic pulmonary arterial hypertension. METHODS: We assessed circulating proteins associated with these processes in serum from patients with CTEPH (n = 71) before and after pulmonary endarterectomy (PEA), chronic thromboembolic pulmonary disease without pulmonary hypertension (CTEPD, n = 9) and healthy controls (n = 20) using Luminex multiplex arrays. Comparisons between groups were made using multivariable rank regression models. Ang2 and high-sensitivity C-reactive protein (hsCRP) were measured in a larger validation dataset (CTEPH = 277, CTEPD = 26). Cox proportional hazards models were used to identify markers predictive of survival. RESULTS: In CTEPH patients, Ang2, interleukin (IL) 8, tumor necrosis factor α, and hsCRP were elevated compared to controls, while vascular endothelial growth factor (VEGF) c was lower (p < 0.05). Ang2 fell post-PEA (p < 0.05) and was associated with both pre- and post-PEA pulmonary hemodynamic variables and functional assessments (p < 0.05). In the validation dataset, Ang2 was significantly higher in CTEPH compared to CTEPD. Pre-operative hsCRP was an independent predictor of mortality. CONCLUSIONS: We hypothesize that CTEPH patients have significant distal micro-vasculopathy and consequently high circulating Ang2. Patients with CTEPD without pulmonary hypertension have no discernible distal micro-vasculopathy and therefore have low circulating Ang2. This suggests Ang2 may be critical to CTEPH disease pathogenesis (impaired thrombus organization and disease severity).

BACKGROUND Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of acute pulmonary emboli necessitating lifelong anticoagulation. Despite this, few data exist on the safety and efficacy of vitamin K antagonists (VKAs) in CTEPH and none for direct oral anticoagulants (DOACs). OBJECTIVES To evaluate outcomes and complication rates in CTEPH following pulmonary endarterectomy (PEA) for individuals receiving VKAs or DOACs. METHODS Consecutive CTEPH patients undergoing PEA between 2007 and 2018 were included in a retrospective analysis. Postoperative outcomes, recurrent venous thromboembolism (VTE), and bleeding events were obtained from patient medical records. RESULTS Seven hundred ninety-four individuals were treated with VKAs and 206 with DOACs following PEA. Mean observation period was 612 (standard deviation: 702) days. Significant improvements in hemodynamics and functional status were observed in both groups following PEA (P

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial [CHEST-2]). Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified. © 2020 The Authors Eli Lilly and Company; Pfizer; Bayer; GlaxoSmithKline; Merck; Actelion Pharmaceuticals; Meso Scale Diagnostics; United Therapeutics Corporation; Novartis Pharma; Merck Sharp and Dohme; GlaxoSmithKline Australia; Deutsche Forschungsgemeinschaft; Grupo Ferrer Internacional, S.A The EXPERT registry was funded by Bayer AG (Berlin, Germany) and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA. The authors acknowledge the database administration by Torsten Tille, Dresden, and the project administration of Mrs Romy Hoppenz and Mrs Linda Kottke at GWT-TUD GmbH, Dresden. Medical writing services provided by Richard Murphy PhD of Adelphi Communications Ltd, Macclesfield, UK were funded by Bayer AG in accordance with Good Publication Practice (GPP3) guidelines. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof Marius M. Hoeper reports personal fees from Bayer AG, during the conduct of the study; personal fees from Actelion, personal fees from Acceleron, personal fees from MSD, personal fees from Jansen, personal fees from Pfizer, outside the submitted work. Dr Hans Klose reports speaker and consultancy fees from Actelion, Bayer AG, GSK, Novartis, Pfizer, and United Therapeutics and research support from Actelion, Bayer AG, GSK, Pfizer, and MSD. Dr Michael Halank reports personal fees and non-financial support from Actelion, AstraZeneca, Bayer AG, Berlin-Chemie, GSK, OMT, MSD, and Novartis. Dr George Giannakoulas reports speaker and consultancy fees from Actelion, Bayer, ELPEN Pharmaceuticals, GSK, Pfizer, Lilly, and United Therapeutics, and research support from GSK, ELPEN Pharmaceuticals, and Galenica. Dr Henning Gall has received honoraria and/or other support from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. Dr Pavel Jansa reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Prof Ekkehard Grünig reports research grants and speaker honoraria/consultancy fees from Actelion and Bayer/MSD, research grants from GSK, United Therapeutics, Bellerophon, OMT GmbH, Pfizer, Reata, and Novartis, and speaker honoraria from Bial, Medscape, and OrPha Swiss GmbH. Prof David Pittrow reports personal fees from Actelion, Bayer AG, Aspen, Boehringer Ingelheim, Sanofi, Biogen, Shire, and MSD outside the submitted work. Silvia Ulrich reports research grants and personal fees from Actelion, Bayer, MSD, and Orpha Swiss. Tobias J. Lange has received personal fees from Actelion, MSD, Pfizer, and OMT orphan. Dr Iraklis Tsangaris reports speaker and consultancy fees from Actelion, Bayer AG, ELPEN, GSK, MSD, Pfizer, and United Therapeutics. Stephan Rosenkranz reports remunerations for lectures and/or consultancy from Abbott, Actelion, Arena, Bayer, Ferrer, GSK, MSD, Novartis, Pfizer, and United Therapeutics; and research support to his institution from Actelion, Bayer, Novartis, Pfizer, and United Therapeutics. Repke J. Snijder reports grants from Pfizer and Actelion Pharmaceuticals. Prof Iveta Šimková reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Dr Marc Humbert reports grants and personal fees from Bayer and GSK, and personal fees from Actelion, Merck, and United Therapeutics. Marion Delcroix has received investigator, speaker, consultant, and steering committee member fees from Actelion, Bayer AG, Bellerophon, Eli Lilly, GlaxoSmithKline, MSD, Pfizer, and Reata, and research grants from Actelion. Joan A. Barberà reports receipt of honoraria for consultation or speaker fees from Actelion and Merck; and research support through his institution from Actelion, Merck, GlaxoSmithKline, and Ferrer. Joanna Pepke-Zaba reports research grants and speaker honoraria/consultancy fees from Actelion, Bayer/MSD, and GSK. Jean-Luc Vachiéry reports ongoing consultancies to Actelion, Sonnivie, Arena Pharma, Bial Portela, and Respira Therapeutics, past consultancies to AstraZeneca, BayerShering, CardioMEMS, GlaxoSmithKline, Pfizer, Merck, and United Therapeutics, and current membership of an advisory board or similar group for Actelion and GlaxoSmithKline. Jean-Luc Vachiéry's institution receives funding from Actelion Pharmaceuticals for performing clinical studies. Regina Steringer-Mascherbauer, Jens Klotsche, and Miguel-Angel Gomez Sanchez have no conflicts of interest relevant to the EXPERT study. Hossein-Ardeschir Ghofrani reports personal fees for advisory board work, and payment for lectures including service on speaker bureaus, from Actelion, Bayer, GSK, Novartis, and Pfizer; consultancy fees from Actelion, Bayer, Bellerophon Pulse Technologies, GSK, MSD, Novartis, and Pfizer; and grants from Deutsche Forschungsgemeinschaft (DFG). Pilar Escribano Subias reports personal fees from Actelion, Bayer AG, GlaxoSmithKline, and Merck Sharp & Dohme, and grants from Actelion, Bayer AG, GlaxoSmithKline, and Ferrer, outside the submitted work. Gérald Simonneau reports personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees and non-financial support from MSD, outside the submitted work. Douglas S. Helmersen reports industry-sponsored research with Bayer AG, United Therapeutics, and Gilead Sciences, Inc., and advisory board/speaker fees from Bayer AG and Actelion. David Langleben reports honoraria, consultation fees, research support, and/or travel expenses from Actelion, Arena, Bayer AG, Northern Therapeutics, PhaseBio, Acceleron, Janssen, and United Therapeutics. Anco Boonstra reports consultancy fees from Pfizer BV and hospitality from Teva Nederland. Lisa M. Mielniczuk reports speaker fees and honoraria from Bayer AG, and speaker fees, consultancy fees, and travel fees from Actelion. Evgenia Williams and Christian Meier are employees of Bayer AG.

Supplemental Digital Content is available in the text., Background: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

Thrombotic events that frequently occur in COVID-19 are predominantly venous thromboemboli (VTE) and are associated with increasing disease severity and worse clinical outcomes. Distinctive microvascular abnormalities in COVID-19 include endothelial inflammation, disruption of intercellular junctions and microthrombi formation. A distinct COVID-19-associated coagulopathy along with increased cytokines and activation of platelets, endothelium and complement occur in COVID-19, which is more frequent with worsening disease severity. This proinflammatory milieu may result in immunothrombosis, a host defence mechanism that can become dysregulated, leading to excess formation of immunologically mediated thrombi which predominantly affect the microvasculature. The haemostatic and immune systems are intricately linked, and multifactorial processes are likely to contribute to VTE and immunothrombosis in COVID-19. This state-of-the-art review will explore the pathobiological mechanisms of immunothrombosis and VTE in COVID-19 focusing on: COVID-19-associated coagulopathy, pathology, endothelial dysfunction and haemostasis, the immune system and thrombosis, genetic associations and additional thrombotic mechanisms. An understanding of the complex interplay between these processes is necessary for developing and assessing how new treatments affect VTE and immunothrombosis in COVID-19.

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (K co ; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K co and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.

Background Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon disorder characterised by persistent obstruction of the pulmonary arteries by thromboembolic material, usually following an acute pulmonary embolus.1 Pulmonary endarterectomy (PEA) is the gold standard treatment for eligible patients and is potentially curative.1Whilst pre-operative parameters have been associated with post-operative mortality no sytematic method for predicting individualised PEA risk presently exists. Objectives To identify pre-operative risk factors of 90 day mortality (90DM), five year mortality (5YM) and improvement in self-reported functional status (DQ) following PEA for inclusion in a clinically-implementable risk prediction tool. Methods Consecutive patients undergoing PEA for CTEPH at Royal Papworth Hospital, UK between 2007 and 2017 were included. Potential pre-operative predictors including patient demographics, medical history and results of functional, physiological and patient self-reported measures were included in a hypothesis-free approach. Three stastical predictive models were considered (linear regression, lasso regression and random forest), each of which were calibrated, fitted and assessed using cross-validation ensuring internal consistency. Results 1336 individuals were included in risk modelling. 96 patients (6.4%) died within 90 days of hospital discharge and 154 (11.5%) within five years of PEA. Random forest based predictions were more accurate than linear or lasso based. All post-operative outcomes were predicted well from pre-operative variables (90DM: AUROC 0.82 (95% CI 0.78, 0.87); 5YM: C-Index 0.81 (0.76, 0.85); DQ (Spearman’s correlation 0.47 (0.43, 0.51)) using random forest modelling. The strongest individual pre-operative predictor of 90DM and 5YM was left atrial dilatation and of DQ, pulmonary vasodilator therapy. Post-hoc analysis confirmed not only excess mortaltiy following PEA in those with left atrial dilatation secondary to diastolic dysfunction but adverse functional, haemodynamic and patient-reported outcomes in this group. Conclusions Outcomes from PEA can be predicted from pre-operative observations to a clinically useful degree enabling individualised risk prediction. Post-hoc analysis highlights the under-recognised adverse outcomes in those with left atrial dilatation. We present an online application to facilitate use of these tools. Further work validating our model in other centres will be necessary and aided by the open availability of our methodology. Reference Galie N, Humbert M, Vachiery J-L, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J2016;37(1):67–119.

While traffic and air pollution exposure is associated with increased mortality in numerous diseases, its association with disease severity and outcomes in pulmonary arterial hypertension (PAH) remains unknown.Exposure to particulate matter with a 50% cut-off aerodynamic diameter ≤2.5 μm (PM2.5), nitrogen dioxide (NO2) and indirect measures of traffic-related air pollution (distance to main road and length of roads within buffer zones surrounding residential addresses) were estimated for 301 patients with idiopathic/heritable PAH recruited in the UK National Cohort Study of Idiopathic and Heritable PAH. Associations with transplant-free survival and pulmonary haemodynamic severity at baseline were assessed, adjusting for confounding variables defined a priori.Higher estimated exposure to PM2.5 was associated with higher risk of death or lung transplant (unadjusted hazard ratio (HR) 2.68 (95% CI 1.11–6.47) per 3 μg·m−3; p=0.028). This association remained similar when adjusted for potential confounding variables (HR 4.38 (95% CI 1.44–13.36) per 3 μg·m−3; p=0.009). No associations were found between NO2 exposure or other traffic pollution indicators and transplant-free survival. Conversely, indirect measures of exposure to traffic-related air pollution within the 500–1000 m buffer zones correlated with the European Society of Cardiology/European Respiratory Society risk categories as well as pulmonary haemodynamics at baseline. This association was strongest for pulmonary vascular resistance.In idiopathic/heritable PAH, indirect measures of exposure to traffic-related air pollution were associated with disease severity at baseline, whereas higher PM2.5 exposure may independently predict shorter transplant-free survival.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of acute pulmonary emboli necessitating lifelong anticoagulation. Despite this, little data exists on the safety and efficacy of Vitamin K Antagonists (VKAs) in CTEPH and none for Direct Oral Anticoagulants (DOACs). Objectives: To evaluate outcomes and complication rates in CTEPH following Pulmonary Endarterectomy (PEA) for individuals receiving VKAs or DOACs. Methods: Consecutive CTEPH patients undergoing PEA between 2007 and 2018 were included in a retrospective analysis. Post-operative outcomes, recurrent venous thromboembolism (VTE) and bleeding events were obtained from patient medical records. Results: 794 individuals were treated with VKAs and 206 with DOACs following PEA. Mean observation period was 612 (SD 702) days. Significant improvements in haemodynamics and functional status were observed in both groups following PEA (p < 0.001). Major bleeding events were equivalent (p = 1) in those treated with VKAs (0.67%/person-year) and DOACs (0.68%/person-year). VTE recurrence was proportionately higher (p = 0.008) with DOACs (4.62%/person-year) than VKAs (0.76%/person-year), although survival did not differ. Conclusions: Post-PEA functional and haemodynamic outcomes appear unaffected by anticoagulant choice. Bleeding events were similar, but recurrent VTE rates significantly higher in those receiving DOACs. Our study provides a strong rationale for prospective registry data and/or studies to evaluate the safety of DOACs in CTEPH., NIHR Biomedical Research Council

Chronic thromboembolic pulmonary hypertension (CTEPH) is an important consequence of pulmonary embolism that is associated with abnormalities in haemostasis. We investigated the ADAMTS13–von Willebrand factor (VWF) axis in CTEPH, including its relationship with disease severity, inflammation, ABO groups and ADAMTS13 genetic variants. ADAMTS13 and VWF plasma antigen levels were measured in patients with CTEPH (n=208), chronic thromboembolic disease without pulmonary hypertension (CTED) (n=35), resolved pulmonary embolism (n=28), idiopathic pulmonary arterial hypertension (n=30) and healthy controls (n=68). CTEPH genetic ABO associations and protein quantitative trait loci were investigated. ADAMTS13–VWF axis abnormalities were assessed in CTEPH and healthy control subsets by measuring ADAMTS13 activity, D-dimers and VWF multimeric size. Patients with CTEPH had decreased ADAMTS13 (adjusted β −23.4%, 95% CI −30.9– −15.1%, p, The ADAMTS-13–VWF axis is dysregulated in chronic thromboembolism with and without pulmonary hypertension and is implicated in the pathogenesis http://ow.ly/J9SC30nh5T0

IntroductionThe purpose of the quality standards document is to provide healthcare professionals, commissioners, service providers and patients with a guide to standards of care that should be met for outpatient management of pulmonary embolism in the UK, together with measurable markers of good practice. Quality statements are based on the British Thoracic Society (BTS) Guideline for the Initial Outpatient Management of Pulmonary Embolism.MethodsDevelopment of BTS Quality Standards follows the BTS process of quality standard production based on the National Institute for Health and Care Excellence process manual for the development of quality standards.ResultsSix quality statements have been developed, each describing a standard of care for the outpatient management of pulmonary embolism in the UK, together with measurable markers of good practice.DiscussionBTS Quality Standards for Outpatient Management of Pulmonary Embolism form a key part of the range of supporting materials that the society produces to assist in the dissemination and implementation of a guideline’s recommendations.

BackgroundPulmonary endarterectomy (PEA) is the recommended treatment for eligible patients with chronic thromboembolic pulmonary hypertension (CTEPH). The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) score is an internationally validated patient-reported outcome (PRO) measure for CTEPH. It assesses three domains: activity, quality of life (QoL) and symptoms. We assessed PROs in patients with CTEPH undergoing PEA.MethodsThis retrospective observational study of consecutive CTEPH patients undergoing PEA at the UK national PEA centre between 2006 and 2017 assessed change in CAMPHOR score from baseline (pre-PEA) until up to 5 years post-PEA. CAMPHOR scores were compared between 1) those with and without clinically significant residual pulmonary hypertension and 2) those undergoing PEA and propensity-matched CTEPH patients who were not operated on. The minimally clinically important difference (MCID) was calculated using an anchor-based method.ResultsOut of 1324 CTEPH patients who underwent PEA, 1053 (80%) had a CAMPHOR score recorded pre-PEA, 934 (71%) had a score recorded within a year of PEA and 784 (60%) had both. There were significant improvements between pre- and post-PEA in all three CAMPHOR domains (median±interquartile range activity −5±7, QoL −4±8, symptoms −7±8; all pConclusionsPROs are markedly improved by PEA in patients with CTEPH, more so in those without clinically significant residual pulmonary hypertension.

Introduction Pulmonary endarterectomy (PEA) is the treatment of choice for Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and can be offered to selected patients with Chronic Thromboembolic Disease without pulmonary hypertension (CTED). Our aim was to map the pathway of UK patients referred to the National PEA MDT and their onwards management. Methods All consecutive individuals referred to the National PEA MDT at Papworth Hospital between June 2015 and May 2016 were included. Patients were divided into CTEPH/CTED groups and their pathways followed until July 2017. Results Of the 316 referrals to the PEA MDT there were 246 cases of CTEPH, 46 of CTED and 24 with alternate diagnoses. Age range of referrals was 22–88 years (mean 59 years). 51% were male. The majority of CTEPH cases had technically operable disease (n=200, 81%) with 130 proceeding to PEA (65%). 53% of all CTEPH cases were operated on (figure 1). Median time from first MDT discussion to PEA was 230 days with a median surgical waiting list time of 115 days. 11 patients required ongoing targeted therapy post-operatively. Of the 70 individuals with an operable disease distribution who did not proceed to PEA, 34 patients chose to decline surgery and 36 were rejected by the surgical team due to co-morbid conditions (n=28) or limited symptoms (n=8). Two patients with distal CTEPH underwent Balloon Pulmonary Angioplasty (BPA). Remaining patients were medically managed with targeted therapy. Of CTED cases, 28 (61%) had an operable disease distribution with 8 (29%) proceeding to PEA. 17% of total CTED referrals were operated on. Conclusion This patient pathway mapping is the first undertaken for any national CTEPH/CTED cohort. The majority of UK CTEPH cases suitable for PEA are operated on (65%). The duration of time between MDT referral and PEA is reflective of disease complexity and decision-making process. We observe a group of highly selected individuals with Chronic Thromboembolic Disease (CTED) without pulmonary hypertension who undergo PEA after careful consideration of their symptoms and operative risk.

Introduction The CAMPHOR (Cambridge Pulmonary Hypertension Outcome Review) score is an internationally validated patient reported outcome (PRO) measure for pulmonary hypertension, including chronic thromboembolic pulmonary hypertension (CTEPH). It assesses 3 areas: activity (score 0–30), symptoms (0–25) and quality of life (QoL) (0–25); with a higher score indicating a worse PRO. CTEPH frequently causes debilitating symptoms and functional impairment, which can be improved in selected patients with pulmonary endarterectomy (PEA). However, a subset will have residual pulmonary hypertension. We aim to assess PROs in patients with CTEPH undergoing PEA. Methods Consecutive CTEPH patients undergoing PEA from June 2006 to August 2016 at the UK National PEA centre, were included in this retrospective analysis. Patients are reviewed after PEA every 6–12 months for at least 5 years. CAMPHOR scores were recorded prospectively when patients attended hospital assessment and at each follow-up, ensuring high capture. Results 1151 patients underwent PEA during the study period. Of those, 937 (81%) had a CAMPHOR score recorded at baseline (pre-PEA) and 816 (77% of 1059 alive) at follow-up within a year of PEA (post-PEA). We confirmed significant improvements in 6 min walk distance and haemodynamics post-PEA (pre/post-PEA median ±IQR: 6 mwd 300±199 Metres/360±165; mPAP 45±15/25±13 mmHg; PVR 669±478/246±214 dynes.s.cm-5; CI 2.2±0.8/2.3±0.7 L/min/m2). The difference in median CAMPHOR scores pre- and post-PEA improved by 6,7 and 9 points for activity, QoL and symptoms respectively. The median difference for individuals having consecutive paired pre- and post-PEA scores also improved (median ±IQR: activity 4±7; QoL 4±8; symptoms 7±8). Patients were dichotomised into those with significant residual pulmonary hypertension (previously reported risk threshold of ≥30 mmHg , n=302) and those without (n=569). The improvement in CAMPHOR score was greater and more sustained in those without residual pulmonary hypertension (fsigure 1). Conclusion PROs relating to activity, QoL and symptoms improve after PEA in CTEPH when evaluated by CAMPHOR score. The improvement is sustained up to 5 years in those without residual pulmonary hypertension. Ongoing work will examine the utility of PROs in addition to traditional clinical outcome measures. Acknowledgements National Pulmonary Hypertension Centres UK and Ireland for referring patients considered for PEA.

Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) Results from failure of thrombus resolution following acute pulmonary embolism. Abnormalities in haemostasis are implicated in the pathobiology, including elevated levels of von Willebrand factor (VWF), which is normally regulated by ADAMTS13. Interim analysis of a genome-wide association study (GWAS) identified a significant association in CTEPH with the ADAMTS13 and ABO gene loci. We aimed to determine if ADAMTS13 protein levels are altered in CTEPH. Methods ADAMTS13 and VWF plasma antigen levels were measured by ELISA in 208 individuals with CTEPH and compared to 68 healthy controls. Levels were also measured in subjects with chronic thromboembolic disease but without pulmonary hypertension (CTED), and other disease comparator groups summarised in figure 1. In 22 CTEPH individuals ADAMTS13 and VWF levels were measured pre-operatively and at least 3 months post-pulmonary endarterectomy (PEA). Results ADAMTS13 levels were decreased in CTEPH (median ±IQR: 0.88±0.40 µg/ml; p=5.7x10-09) and CTED (0.83±0.22 µg/ml; p=2.1x10-06) patients compared to healthy controls (1.15±0.30 µg/ml) (figure 1). ADAMTS13 levels remained low in CTEPH patients following PEA (pre: 0.78±0.27 µg/ml vs. post: 0.83±0.29 µg/ml; p=0.92) even in those with normalised mean pulmonary arterial pressures ( Conclusions Plasma ADAMTS13 antigen levels are markedly decreased in CTEPH. This is not secondary to pulmonary hypertension, as demonstrated by the similarly low levels in CTED, and individuals with normal pulmonary artery pressures post-PEA. Thus, the VWF/ADAMTS13 axis is implicated in the underlying disease pathophysiology. Ongoing work will clarify if there is a causal link by defining whether genetic variation at the ADAMTS13 locus contributes to reduced ADAMTS13 protein levels and CTEPH.

Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is an infrequent but important complication of acute pulmonary embolism (PE). Thrombophilias and non-O blood groups are genetic risk factors for venous thromboembolism (VTE), however they are not independently associated with CTEPH. Identifying genetic risk factors for CTEPH would provide important insights into pathobiology and might allow risk-stratification following PE. We undertook a genome-wide association study (GWAS) in CTEPH to identify novel disease loci. Methods To date, 1457 Caucasian CTEPH patients were enrolled from 10 European and US Centres and compared to 1536 healthy Caucasian controls from the Wellcome Trust Case Control Consortium. Genotyping was performed using the HumanOmniExpressExome-8 array. Quality control criteria and statistical analysis are summarised in figure 1. Results 1250 CTEPH cases, 1492 controls and 7 million single-nucleotide polymorphisms (SNPs) were included after quality control exclusions. Two loci, in chromosomes 4 and 9 were significantly associated with CTEPH (figure 1). The lead SNP in chr9 (rs532436, OR=2.38, p=4.6x10-32) is highly correlated with the tagging SNP for the A1 blood group (rs507666, R2=0.99). Reconstructing genetic ABO groups confirmed an over-representation of the A1A1 group in CTEPH compared to controls (7% vs. 2.9%, OR 4.5). Additionally, there were 11 significant SNPs in the chr9 ADAMTS13 gene locus that is moderately correlated with ABO (R2=0.33). The lead SNP in chr4 (rs13130318, OR=1.4, p=5.6x10-8) is highly correlated with a missense variant in FGG (rs6050, R2=0.89) associated with decreased fibrinogen protein and increased resistance to fibrinolysis in CTEPH. There were no associations at the F5 locus, which is highly significant in VTE. Conclusions We report the first GWAS in CTEPH, identifying at least 2 genetic loci associated with the disease. The ABO association is driven by the A1 blood group and represents the largest population attributable genetic risk factor for CTEPH, which is higher than previously reported for VTE. The potential ADAMTS13 association is a plausible biological candidate, and further work will establish whether it is independent from ABO. The lack of associations with other loci found in VTE suggests that ABO might have a pathobiological role in CTEPH in addition to its contribution to VTE.

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlie most heritable forms of PAH. Since the missing heritability likely involves genetic variation confined to small numbers of cases, we performed whole genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses revealed significant overrepresentation of rare variants in novel genes, namely ATP13A3, AQP1 and SOX17, and provided independent validation of a critical role for GDF2 in PAH. We provide evidence for familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, led to reduced secretion from transfected cells. In addition, we identified pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings provide new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

While traffic and air pollution exposure is associated with increased mortality in numerous diseases, its association with disease severity and outcomes in pulmonary arterial hypertension (PAH) remains unknown.Exposure to particulate matter ≤2.5 μm3 (PM2.5), nitrogen dioxide (NO2) and indirect measures of traffic-related air pollution (distance to main road and length of roads within buffer zones surrounding residential addresses) were estimated for 301 patients with idiopathic/heritable PAH recruited in the UK PAH national Cohort study. Associations with transplant-free survival and pulmonary hemodynamic severity at baseline were assessed, adjusting for confounding variables defined a priori.Higher estimated exposure to PM2.5 was associated with higher risk of death or lung transplant (Unadjusted hazard ratio (HR) 2.68; 95% CI 1.11-6.47 per 3 μg·m-3, p=0.028). This association remained similar when adjusted for potential confounding variables (HR 4.38; 95% CI 1.44-13.36 per 3 μg·m-3, p=0.009). No associations were found between NO2 exposure or other traffic pollution indicators and transplant-free survival Conversely, indirect measures of exposure to traffic-related air pollution within the 500-1000 m buffer zones correlated with the ERS/ESC risk categories as well as pulmonary hemodynamics at baseline. This association was strongest for pulmonary vascular resistance.In idiopathic/heritable PAH, indirect measures of exposure to traffic-related air pollution were associated with disease severity at baseline, whereas higher PM2.5 exposure may independently predict shorter transplant-free survival.

Introduction Recent studies have demonstrated that metabolomic profiling can identify metabolites and pathways which may have importance in the pathobiology of pulmonary arterial hypertension. However, the plasma metabolome in chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic vascular occlusions without pulmonary hypertension (CTED) has not been well characterised. Objective To profile circulating metabolites in CTEPH and CTED and assess metabolite gradients across the pulmonary circulation. Methods In the patient group, multisite blood sampling was performed at the time of right heart catheterisation. Blood samples were collected from the superior vena cava, pulmonary artery and radial artery. Venous blood samples from patients were compared to healthy controls to identify the metabolites present and to assess the difference between health and disease. Additionally, in the disease group, transpulmonary gradients were assessed by analysis of fold change in metabolite concentration between paired samples from the pulmonary artery and radial artery. Untargeted, semi-quantitative metabolic profiling of plasma was performed using the Metabolon DiscoveryHD4™ platform (Metabolon, NC, USA), utilising 2 ultra-high performance liquid chromatography methods, coupled with tandem mass spectrometry. Kruskal-Wallis analysis was used to compare metabolites between disease and control, with false discovery rate correction for multiple testing. Results The disease group included patients with a spectrum of chronic pulmonary vascular occlusions (Table 1). A total of 1375 metabolites were detected in 70 venous plasma samples analysed from 43 patients and 27 healthy controls. Amongst endogenous metabolites, 266 showed a significant difference between disease and control. In the disease group there were increases in acylcarnitine metabolites, long chain fatty acids, polyamines, glycogen metabolites and primary bile acid metabolites compared to healthy controls. There was a reduction in lysolipids, plasmalogens, aminosugars, branched chain amino acid metabolites, glutathione metabolites and a number of steroids (Table 1). Analysis of transpulmonary gradients revealed primarily a reduction in metabolite concentration across the pulmonary circulation. This included depletion of energy substrates, lysolipids, lysoplasmalogens and acylcholines. Conclusions This pilot study of circulating metabolites in patients with CTEPH, CTED and healthy controls reveals differences between health and disease in several biological pathways. Measurement of the transpulmonary gradient of metabolites indicated predominant clearance of circulating metabolites associated with energy metabolism and cell turnover. These findings require confirmation in a larger population.

The mantra that pre-test probability (PTP) scoring should be the first stage in diagnosing pulmonary embolism is supported by a wealth of evidence.1 2 3 Unfortunately, the performance of diagnostic algorithms and PTP scores in clinical settings is often overlooked; when applied incorrectly the predictive potential is negated. Our retrospective study of …

Introduction Pre-test probability (PTP) scores are widely used to risk stratify pulmonary emboli (PE). A multitude of scores exist; however diagnosing PE remains challenging. We aim to identify whether patients were correctly PTP scored and what effect rescoring with the correct information has on predicting PE. We will identify the effect different PTP scores have on the likelihood of PE. Methods We conducted a retrospective study of inpatient computer tomography pulmonary angiograms (CTPA) within a large teaching hospital over a 1-year period. We recorded the originally submitted PTP score (modified Wells score), D-Dimer result and the CTPA outcome (PE-positive or negative cohorts). The accuracy of the PTP score was assessed from the original clinical information; rescoring when appropriate. We also rescored using alternative PTP systems (Geneva and simplified BTS). We analysed whether any factor or PTP scores could predict the presence of PE. Results 202 CTPAs were performed (70, 35% PE positive; 131, 65% PE negative). Baseline characteristics did not differ (age, gender, requesting team, inflammatory markers, mortality). PE was more likely with a higher D-dimer (682 vs. 853; p Table 1 ). Geneva score did not accurately predict PE (2.3 vs. 2.5; p=0.25); whereas the simplified BTS score did (0.9 vs. 1.3; p Conclusions Patients without a PE were significantly more likely to have an incorrect PTP score. Clinicians may have poor concordance with scoring to meet CTPA requesting criteria. The originally calculated PTP score was not predictive of PE. However, when scores were adjusted with the correct information, a higher PTP score was predictive of PE. Simple PTP scoring systems performed well compared with more complex versions. PTP scores are only effective at predicting PE when used accurately; this may not occur in practise.

We echo Spence’s sentiments that the clinical examination could be improved.1 In our experience, doctors teach and assess in a traditional rather than evidence based manner. Reliability is the agreement between doctors that a clinical sign can be independently elicited in the same patient when it is present. When learning …

Introduction Vitamin D binding protein (DBP) plays a role in macrophage activation and neutrophil chemotaxis, both functions being relevant to COPD and airway infection. We have shown previously that DBP is present in the COPD lung and relates directly to macrophage activation.1 Transcription of DBP is stimulated by inflammatory cytokines,2 which tend to be raised in exacerbations. DBP is also cleaved from its binding site on neutrophils by the action of neutrophil elastase.3 We reasoned that DBP would be elevated in the lung and systemic circulation during exacerbations of COPD compared to the stable state. Methods 20 patients with a known diagnosis of COPD were studied in the stable state and at the start of an exacerbation. Circulating CRP, elastase, AAT and DBP were measured at each time point, together with sol phase DBP, AAT and CRP, where sufficient sample was available (n=9). All clinical parameters were studied in the stable state only. Relationships between exacerbation and stable state were sought using pair-wise tests for each individual, whilst group relationships between DBP, CRP and elastase were sought using Spearman9s rank correlation. Results No significant differences between stable state and exacerbation were seen for circulating or sol phase DBP (both p>0.4). Circulating CRP and AAT were significantly higher in exacerbation (mean difference 3.95, p Conclusions The level of local and systemic inflammation, with consequent elastase release, during a COPD exacerbation is insufficient to alter DBP levels. As such it is unlikely that DBP-derived macrophage activation is important in their pathogenesis or resolution.