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Although it is a rare disease, the number of available therapeutic options for treating pulmonary arterial hypertension has increased since the late 1990s, with multiple drugs developed that are shown to be effective in phase 3 randomised controlled trials. Despite considerable advancements in pulmonary arterial hypertension treatment, prognosis remains poor. Existing therapies target pulmonary endothelial dysfunction with vasodilation and anti-proliferative effects. Novel therapies that target proliferative vascular remodelling and affect important outcomes are urgently needed. There is need for additional innovations in clinical trial design so that all emerging candidate therapies can be rigorously studied. Pulmonary arterial hypertension trial design has shifted from short-term submaximal exercise capacity as a primary endpoint, to larger clinical event-driven trial outcomes. Event-driven pulmonary arterial hypertension trials could face feasibility and efficiency issues in the future because increasing sample sizes and longer follow-up durations are needed, which would be problematic in such a rare disease. Enrichment strategies, innovative and alternative trial designs, and novel trial endpoints are potential solutions that could improve the efficiency of future pulmonary arterial hypertension trials while maintaining robustness and clinically meaningful evidence.

BACKGROUND: Activins are novel therapeutic targets in pulmonary arterial hypertension (PAH). We therefore studied whether key members of the activin pathway could be used as PAH biomarkers. METHODS: Serum levels of activin A, activin B, α-subunit of inhibin A and B proteins, and the antagonists follistatin and follistatin-like 3 (FSTL3) were measured in controls and in patients with newly diagnosed idiopathic, heritable, or anorexigen-associated PAH (n=80) at baseline and 3 to 4 months after treatment initiation. The primary outcome was death or lung transplantation. Expression patterns of the inhibin subunits, follistatin, FSTL3, Bambi, Cripto, and the activin receptors type I (ALK), type II (ACTRII), and betaglycan were analyzed in PAH and control lung tissues. RESULTS: Death or lung transplantation occurred in 26 of 80 patients (32.5%) over a median follow-up of 69 (interquartile range, 50–81) months. Both baseline (hazard ratio, 1.001 [95% CI, 1.000–1.001]; P =0.037 and 1.263 [95% CI, 1.049–1.520]; P =0.014, respectively) and follow-up (hazard ratio, 1.003 [95% CI, 1.001–1.005]; P =0.001 and 1.365 [95% CI, 1.185–1.573]; P P =0.009) and 0.17 (95% CI, 0.06–0.45; P P =0.019) and 0.27 (95% CI, 0.09–0.78, P =0.015), respectively. Prognostic values of activin A and FSTL3 were confirmed in an independent external validation cohort. Histological analyses showed a nuclear accumulation of the phosphorylated form of Smad2/3, higher immunoreactivities for ACTRIIB, ALK2, ALK4, ALK5, ALK7, Cripto, and FSTL3 in vascular endothelial and smooth muscle layers, and lower immunostaining for inhibin-α and follistatin. CONCLUSIONS: These findings offer new insights into the activin signaling system in PAH and show that activin A and FSTL3 are prognostic biomarkers for PAH.

BACKGROUND Risk assessment is essential in pulmonary arterial hypertension (PAH) management. We investigated the effect of riociguat on REVEAL Lite 2 score, an abridged version of the REVEAL risk score, and its association with long-term outcomes in PATENT. METHODS PATENT-1 was a randomized, double-blind study of riociguat vs placebo in patients with PAH. In the PATENT-2 open-label extension, all patients received riociguat up to 2.5 mg three times daily (n = 396). REVEAL Lite 2 scores were calculated at baseline, PATENT-1 Week 12, and PATENT-2 Week 12, with patients stratified as low- (1-5), intermediate- (6-7), or high-risk (≥8). Kaplan-Meier and Cox proportional hazards analyses assessed association of riociguat with survival and clinical worsening-free survival (CWFS). RESULTS REVEAL Lite 2 score improved with riociguat 2.5 mg at PATENT-1 Week 12 (least-squares mean difference vs placebo: -0.8; p = 0.0004). More patients receiving riociguat 2.5 mg stabilized or improved risk stratum at PATENT-1 Week 12 vs placebo (p = 0.0005) and achieved low-risk status. REVEAL Lite 2 score at baseline and PATENT-1 Week 12 were associated with survival and CWFS (all p < 0.0001), as was change in score from baseline to Week 12 (p = 0.0002 and p < 0.0001, respectively). Survival and CWFS differed between risk strata at baseline (p < 0.0001) and PATENT-1 Week 12 (p < 0.0001). CONCLUSIONS This analysis confirms the risk-reduction benefits of riociguat in patients with PAH and further contributes to the validation of REVEAL Lite 2 in facilitating PAH risk assessment.

International audience; Rationale: The relationship between the initial treatment strategy and survival in pulmonary arterial hypertension (PAH) remains uncertain. Objectives: To evaluate the long-term survival of patients with PAH categorized according to the initial treatment strategy. Methods: A retrospective analysis of incident patients with idiopathic, heritable, or anorexigen-induced PAH enrolled in the French Pulmonary Hypertension Registry (January 2006 to December 2018) was conducted. Survival was assessed according to the initial strategy: monotherapy, dual therapy, or triple-combination therapy (two oral medications and a parenteral prostacyclin). Measurements and Main Results: Among 1,611 enrolled patients, 984 were initiated on monotherapy, 551 were initiated on dual therapy, and 76 were initiated on triple therapy. The triple-combination group was younger and had fewer comorbidities but had a higher mortality risk. The survival rate was higher with the use of triple therapy (91% at 5 yr) as compared with dual therapy or monotherapy (both 61% at 5 yr) (P < 0.001). Propensity score matching of age, sex, and pulmonary vascular resistance also showed significant differences between triple therapy and dual therapy (10-yr survival, 85% vs. 65%). In high-risk patients (n = 243), the survival rate was higher with triple therapy than with monotherapy or dual therapy, whereas there was no difference between monotherapy and double therapy. In intermediate-risk patients (n = 1,134), survival improved with an increasing number of therapies. In multivariable Cox regression, triple therapy was independently associated with a lower risk of death (hazard ratio, 0.29; 95% confidence interval, 0.11-0.80; P = 0.017). Among the 148 patients initiated on a parenteral prostacyclin, those on triple therapy had a higher survival rate than those on monotherapy or dual therapy. Conclusions: Initial triple-combination therapy that includes parenteral prostacyclin seems to be associated with a higher survival rate in PAH, particularly in the youngest high-risk patients.

Common variable immunodeficiency (CVID) is known to cause infectious, inflammatory, and autoimmune manifestations. Pulmonary hypertension (PH) is an unusual complication of CVID with largely unknown characteristics and mechanisms. We report the clinical, functional, hemodynamics, radiologic and histologic characteristics, and outcomes of CVID-associated PH patients from the French PH Network. Ten patients were identified. The median (range) age at CVID diagnosis was 36.5 (4–49) years and the median delay between CVID and PH diagnosis was 12 (0–30) years. CVID-associated PH affected predominantly women (female-to-male ratio 9:1). Most patients were New York Heart Association functional class III with a severe hemodynamic profile and frequent portal hypertension (n = 6). Pulmonary function tests were almost normal in 70% of patients and showed a mild restrictive syndrome in 30% of patients while the diffusing capacity for carbon monoxide was decreased in all but one patient. High-resolution computed tomography found enlarged mediastinal nodes, mild interstitial infiltration with reticulations and nodules. Two patients had a CIVD-interstitial lung disease, and one presented with bronchiectasis. Pathologic assessment of lymph nodes performed in 5 patients revealed the presence of granulomas (n = 5) and follicular lymphoid hyperplasia (n = 3). At last follow-up (median 24.5 months), 9 patients were alive, and one patient died of Hodgkin disease. PH is a possible complication of CVID whose pathophysiological mechanisms, while still unclear, would be due to the inflammatory nature of CVID. CVID-associated PH presents as precapillary PH with multiple possible causes, acting in concert in some patients: a portal hypertension, a pulmonary vascular remodeling, sometimes a pulmonary parenchymal involvement and occasionally an extrinsic compression by mediastinal lymphadenopathies, which would be consistent with its classification in group 5 of the current PH classification.

Right ventricular failure (RVF) is a common cause of admission to the intensive care unit and its presence is a major prognostic factor in acute pulmonary embolism (PE) and chronic pulmonary hypertension (PH). RVF results from an incapacity of the RV to adapt to an increase in afterload so it can become critical in acute PE and chronic PH. The presence of RVF in cases of acute PE with haemodynamic instability is an indication for thrombolytic therapy. RVF represents the most common cause of death in chronic PH. Factors triggering RV failure in PH, such as infection, PE, arrhythmias, or unplanned withdrawal of pulmonary arterial hypertension (PAH)-targeted therapy, have to be considered and treated if identified. However, RVF may also represent progression to end-stage disease. The management of RVF in patients with PH requires expertise and consists of optimization of fluid balance (with diuretics), cardiac output (with inotropic support such as dobutamine), perfusion pressure (with norepinephrine), and reduction of RV afterload with PAH-targeted therapies. Extracorporeal life support, lung transplantation or heart-lung transplantation should be considered in cases of refractory RVF in eligible patients.

Although ventriculoarterial coupling is associated with better survival in pulmonary arterial hypertension (PAH), existing PAH risk assessment method has not considered echocardiographic criteria of right ventricular to pulmonary artery coupling. We aimed to test the prognostic value of the echocardiographic tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (TAPSE/sPAP) ratio for noninvasive PAH risk assessment.We retrospectively studied a cohort of 659 incident PAH patients from 4 independent French PH centers (training cohort: n = 306, validation cohort n = 353) who underwent follow-up TAPSE/sPAP measurement in addition to previously validated noninvasive risk stratification variables. The primary composite outcome was 3-year all-cause mortality or lung transplantation from re-evaluation.Mean age was 55 ± 17 years-old with a majority of female (66%). The three main PAH causes were connective tissue disease (26%), idiopathic (24%) and porto-pulmonary (19%). The primary composite outcome occurred in 71 (23%) patients. Multivariable Cox regression analysis retained 3 noninvasive low-risk criteria as associated with the primary composite outcome: NYHA I-II (p = 0.001), NTproBNP300 ng/L or BNP50 ng/L (p = 0.004), and TAPSE/sPAP0.33 mm/mmHg (p = 0.004). The more the low-risk criteria achieved at follow-up, the better the event-free survival both in the training and validation cohort (log-rank p0.001). In the training cohort, the c-index for these 3 criteria, for COMPERA 2.0 and for the noninvasive French Pulmonary Hypertension Network method were 0.75, 95%CI(0.70-0.82), 0.72 95%CI(0.66-0.75), 0.71 95%CI(0.62-0.73), respectively.The 3 following dichotomized low-risk criteria: TAPSE/sPAP0.33 mm/mmHg, NYHA I-II and NTproBNP300 ng/L or BNP50 ng/L allow to identify low-risk PAH patients at follow-up.

BackgroundRisk stratification and assessment of disease progression in patients with pulmonary arterial hypertension (PAH) are challenged by the lack of accurate disease-specific and prognostic biomarkers. To date, brain natriuretic peptide (BNP) and/or its N-terminal fragment (NT-proBNP) are the only markers for right ventricular dysfunction used in clinical practice, in association with echocardiographic and invasive haemodynamic variables to predict outcome in patients with PAH.MethodsThis study was designed to identify an easily measurable biomarker panel in the serum of 80 well-phenotyped PAH patients with idiopathic, heritable or drug-induced PAH at baseline and at first follow-up. The prognostic value of identified cytokines of interest was secondly analysed in an external validation cohort of 125 PAH patients.ResultsAmong the 20 biomarkers studied with the multiplex Ella platform, we identified a three-biomarker panel composed of β-NGF, CXCL9 and TRAIL that were independently associated with prognosis both at the time of PAH diagnosis and at the first follow-up after initiation of PAH therapy. β-NGF and CXCL9 were predictors of death or transplantation, whereas high levels of TRAIL were associated with a better prognosis. Furthermore, the prognostic value of the three cytokines was more powerful for predicting survival than usual non-invasive variables (New York Heart Association Functional Class, 6-min walk distance and BNP/NT-proBNP). The results were validated in a fully independent external validation cohort.ConclusionThe monitoring of β-NGF, CXCL9 and TRAIL levels in serum should be considered in the management and treatment of patients with PAH to objectively guide therapeutic options.

Background Although preserved right ventricular (RV) function is consistently associated with better survival in pulmonary arterial hypertension (PAH), the French risk assessment method has not yet considered echocardiographic criteria of RV function. Purpose In the present study, we tested the value of tricuspid annular plane systolic excursion (TAPSE) measured by echocardiography for non-invasive PAH risk assessment. Methods We retrospectively studied a cohort of 306 incident PAH patients treated in two French expert centers who underwent follow-up TAPSE measurement from echocardiographic apical 4-chamber view in addition to previously validated invasive and non-invasive risk stratification variables. The primary composite outcome was 3-year lung transplantation free survival after follow-up assessment. Results At re-evaluation, 66% of patients were in NYHA functional class I-II and mean pulmonary arterial pressure, cardiac index, N-Terminal pro brain natriuretic peptide (NTproBNP), and 6-minute walk distance (6MWD) were 40±16 mmHg, 3.5±1.1 L/min/m2, 270 [interquartile range (IQR) 896] ng/L and 401 (IQR 213) meters, respectively. The primary outcome occurred in 58 (19%) patients. In multivariable Cox regression analysis, NYHA functional class I-II (p=0.02), NTproBNP 440m (p=0.049) and TAPSE≥17 mm (p=0.02) were associated with lung transplantation free survival. TAPSE provided similar information over 6MWD when both were used alternatively to stratify PAH patients at low risk (log-rank Conclusion Three dichotomized low-risk criteria (TAPSE, 6MWD and NTproBNP or BNP plasma levels) allow non-invasive risk assessment in PAH. Funding Acknowledgement Type of funding sources: None. 3-years transplant-free survival

Introduction: Whipple’s disease (WD) is a rare multivisceral disorder with few descriptions of pulmonary hypertension (PH) Aims and objectives: To describe the association between PH and WD (PH-WD). Methods: We report the characteristics and outcomes of two patients with PH-WD hospitalized in the French PH reference center. Results: PH-WD was diagnosed in two men (54 and 59-yo) hospitalized for right heart failure. Both reported a deterioration in general state over the previous year, associated with diarrhea and mood change (patient 1) and a seronegative polyarthritis and purpura (patient 2). Initial right heart catheterization (RHC) confirmed severe precapillary PH in patient 1: mean pulmonary artery pressure 40 mmHg, cardiac index 2 L/min/m2, pulmonary artery wedge pressure13 mmHg, pulmonary vascular resistance 8 WU. The second patient presented with advanced right heart failure, high echocardiographic probability of PH and no evidence of left heart disease. Both patients were treated with intravenous dobutamine and large spectrum antibiotics. The diagnosis of WD was established by duodenal biopsies and positive T. whipplei PCR in the saliva (patient 1) and in the blood and stools (patient 2). The first patient rapidly improved and experienced complete recovery after one year of treatment associating bosentan, tadalafil, doxycycline and hydroxychloroquine. The second patient rapidly deteriorated and died 24h after his admission because of end-stage right heart failure. Conclusions: WD is a rare cause of severe but potentially reversible PH. Due to poor awareness, delayed diagnosis may lead to death due to end-stage right heart failure.

RationaleThe characteristics of patients with respiratory complaints and/or lung radiologic abnormalities after hospitalisation for coronavirus disease 2019 (COVID-19) are unknown. The objectives were to determine their characteristics and the relationships between dyspnoea, radiologic abnormalities and functional impairment.MethodsIn the COMEBAC (Consultation Multi-Expertise de Bicêtre Après COVID-19) cohort study, 478 hospital survivors were evaluated by telephone 4 months after hospital discharge, and 177 who had been hospitalised in an intensive care unit (ICU) or presented relevant symptoms underwent an ambulatory evaluation. New-onset dyspnoea and cough were evaluated, and the results of pulmonary function tests and high-resolution computed tomography of the chest were collected.ResultsAmong the 478 patients, 78 (16.3%) reported new-onset dyspnoea, and 23 (4.8%) new-onset cough. The patients with new-onset dyspnoea were younger (56.1±12.3 versus 61.9±16.6 years), had more severe COVID-19 (ICU admission 56.4% versus 24.5%) and more frequent pulmonary embolism (18.0% versus 6.8%) (all p≤0.001) than patients without dyspnoea. Among the patients reassessed at the ambulatory care visit, the prevalence of fibrotic lung lesions was 19.3%, with extent versus 56±14 years, p=0.03), more frequently managed in an ICU (87.9 versus 47.4%, pversus 84.9±14.8% pred, pDLCO) (73.3±17.9 versus 89.7±22.8% pred, pDLCO ConclusionsNew-onset dyspnoea and mild fibrotic lesions were frequent at 4 months, but the association of new-onset dyspnoea, fibrotic lesions and low DLCO was rare.

Previous studies have suggested an association between uric acid (UA) and the severity of pulmonary arterial hypertension (PAH), but it is unknown whether UA contributes to disease pathogenesis.The aim of this study was to determine the prognostic value of circulating UA in the era of current management of PAH and to investigate the role of UA in pulmonary vascular remodelling.Serum UA levels were determined in idiopathic, heritable or anorexigen PAH at baseline and first re-evaluation in the French Pulmonary Hypertension Network. We studied protein levels of xanthine oxidase (XO) and the voltage-driven urate transporter 1 (URATv1) in lungs of control and PAH patients and of monocrotaline (MCT) and Sugen/hypoxia (SuHx) rats. Functional studies were performed using human pulmonary artery smooth muscle cells (PA-SMCs) and two animal models of pulmonary hypertension (PH).High serum UA levels at first follow-up, but not at baseline, were associated with a poor prognosis. Both the generating enzyme XO and URATv1 were upregulated in the wall of remodelled pulmonary arteries in idiopathic PAH patients and MCT and SuHx rats. High UA concentrations promoted a mild increase in cell growth in idiopathic PAH PA-SMCs, but not in control PA-SMCs. Consistent with these observations, oxonic acid-induced hyperuricaemia did not aggravate MCT-induced PH in rats. Finally, chronic treatment of MCT and SuHx rats with benzbromarone mildly attenuated pulmonary vascular remodelling.UA levels in idiopathic PAH patients were associated with an impaired clinical and haemodynamic profile and might be used as a non-invasive indicator of clinical prognosis during follow-up. Our findings also indicate that UA metabolism is disturbed in remodelled pulmonary vascular walls in both experimental and human PAH.

Common variable immunodeficiency (CVID) is known to cause infectious, inflammatory, and autoimmune manifestations. Pulmonary hypertension (PH) is an unusual complication of CVID with largely unknown characteristics and mechanisms.We report the clinical, functional, hemodynamics, radiologic and histologic characteristics, and outcomes of CVID-associated PH patients from the French PH Network.Ten patients were identified. The median (range) age at CVID diagnosis was 36.5 (4-49) years and the median delay between CVID and PH diagnosis was 12 (0-30) years. CVID-associated PH affected predominantly women (female-to-male ratio 9:1). Most patients were New York Heart Association functional class III with a severe hemodynamic profile and frequent portal hypertension (n = 6). Pulmonary function tests were almost normal in 70% of patients and showed a mild restrictive syndrome in 30% of patients while the diffusing capacity for carbon monoxide was decreased in all but one patient. High-resolution computed tomography found enlarged mediastinal nodes, mild interstitial infiltration with reticulations and nodules. Two patients had a CIVD-interstitial lung disease, and one presented with bronchiectasis. Pathologic assessment of lymph nodes performed in 5 patients revealed the presence of granulomas (n = 5) and follicular lymphoid hyperplasia (n = 3). At last follow-up (median 24.5 months), 9 patients were alive, and one patient died of Hodgkin disease.PH is a possible complication of CVID whose pathophysiological mechanisms, while still unclear, would be due to the inflammatory nature of CVID. CVID-associated PH presents as precapillary PH with multiple possible causes, acting in concert in some patients: a portal hypertension, a pulmonary vascular remodeling, sometimes a pulmonary parenchymal involvement and occasionally an extrinsic compression by mediastinal lymphadenopathies, which would be consistent with its classification in group 5 of the current PH classification.

The function of the right ventricle is of great clinical importance in end-stage pulmonary hypertension since it determines the prognosis of patients. The occurrence of acute right-heart failure remains the most frequent cause of death with a dismal prognosis over the short term, highlighting the need for earlier recognition and better management options. Intensive care of acute decompensated PH is based on the treatment of triggering factors, careful fluid management, and strategies to improve cardiac function and reduce right ventricular afterload. However, the medical strategy is not always sufficient to restore a long-lasting balance between the afterload imposed on the right ventricle and its capacity for compensation. In the case of refractory right-heart failure despite maximal medical treatment, the use of mechanical support can now be considered in selected candidates for lung transplantation, or less commonly as a bridge to recovery in patients with a treatable cause of right-sided heart failure. Management of such patients requires expert centers with multidisciplinary teams able to offer all modern treatment options combining implementation of novel medical, instrumental, and surgical management of right-heart failure.

Background and Objective Ventilatory inefficiency (high V′E/V′CO2) and resting hypocapnia are common in pulmonary vascular disease and are associated with poor prognosis. Low resting PaCO2 suggests increased chemosensitivity or an altered PaCO2 set-point. We aimed to determine the relationships between exercise gas exchange variables reflecting the PaCO2 set-point, exercise capacity, hemodynamics and V′E/V′CO2. Methods Pulmonary arterial hypertension (n = 34), chronic thromboembolic pulmonary hypertension (CTEPH, n = 19) and pulmonary veno-occlusive disease (PVOD, n = 6) patients underwent rest and peak exercise arterial blood gas measurements during cardiopulmonary exercise testing. Patients were grouped according to resting PaCO2: hypocapnic (PaCO2 ≤34 mmHg) or normocapnic (PaCO2 35–45 mmHg). The PaCO2 set-point was estimated by the maximal value of end-tidal PCO2 (maximal PETCO2) between the anaerobic threshold and respiratory compensation point. Results The hypocapnic group (n = 39) had lower resting cardiac index (3.1 ±0.8 vs. 3.7 ±0.7 L/min/m2, p Conclusions Resting hypocapnia is associated with worse cardiac function, more ventilatory inefficiency and reduced exercise capacity. This could be explained by elevated chemosensitivity and lower PaCO2 set-point. Maximal PETCO2 may be a useful non-invasive marker of PaCO2 setpoint and disease severity even with submaximal effort.

Background Viral respiratory infections are the main causes of asthma exacerbation. The susceptibility of asthmatics to develop an exacerbation when they present with severe pneumonia due to SARS-CoV-2 infection is unknown. The objective of this study was to investigate the characteristics and outcomes of asthmatic patients with COVID-19 pneumonia who required hospitalisation during the spring 2020 outbreak in Paris, France. Methods A prospective cohort follow-up was carried out from March 15 to April 15, 2020 in Bicêtre Hospital, University Paris-Saclay, France. All hospitalised patients with a SARS-CoV-2 infection who reported a history of asthma were included. Results Among 768 hospitalised patients, 37 (4.8%) reported a history of asthma, which had been previously confirmed by a pulmonologist in 85% of cases. Patients were mainly female (70%), non-smokers (85%), with a median age of 54 years (interquartile range, IQR 42–67). None of them presented with an asthma exacerbation. Twenty-two (59%) had major comorbidities and 31 (84%) had a body mass index ≥25 kg·m−2. The most common comorbidities were obesity (36%), hypertension (27%) and diabetes (19%). All patients had a confirmed diagnosis of COVID-19 pneumonia on computed tomography of the chest. Eosinopenia was a typical biologic feature with a median count of 0/mm3 (IQR 0–0). Eleven patients (30%) were admitted in intensive care unit with three death (8.1%) occurring in the context of comorbidities. Conclusion Asthmatics were not overrepresented among patients with severe pneumonia due to SARS-CoV-2 infection who required hospitalisation. Worst outcomes were observed mainly in patients with major comorbidities., Asthmatics were not overrepresented among patients with severe pneumonia due to SARS-CoV-2 infection who require hospitalisation. None of them presented with an asthma exacerbation. Worst outcomes were observed mainly in patients with major comorbidities.

Pre-capillary pulmonary hypertension is a rare and heterogenous complication in sarcoidosis. 6-min walking distance is a robust and consistent prognostic factor, but the role of pulmonary arterial hypertension-targeted treatments remains controversial.http://bit.ly/2J27Yps

Periodic risk stratification is recommended for patients with pulmonary arterial hypertension (PAH). The purpose of this article is to review the available risk stratification tools in PAH.Validated tools, such as the REVEAL (Registry to Evaluate Early And Long-term PAH Disease Management) score or European Society of Cardiology/European Respiratory Society (ESC/ERS) risk assessment table incorporate clinical, exercise, imaging, and hemodynamic variables to obtain a multidimensional estimate of prognosis. Recent studies from REVEAL and European registries have further validated these tools and improved our understanding of prognostic factors in PAH. Serial risk assessment over time, especially after treatment initiation or modification, provides more useful information than at a single time point, with changes in risk profiles being particularly informative. A brief, simplified approach includes counting the number of ESC/ERS low-risk criteria achieved, with 3 or 4 low-risk criteria associated with an excellent prognosis. When a more precise estimation of risk is desired, the REVEAL score can delineate five risk groups with 1-year survival rates between 97.3% (low risk) and 50.2% (very high risk).The REVEAL and ESC/ERS risk table are useful, validated, multidimensional risk stratification tools that should be periodically applied to patients with PAH in practice.

Background:Hemodynamic variables such as cardiac index and right atrial pressure have consistently been associated with survival in pulmonary arterial hypertension (PAH) at the time of diagnosis. Recent studies have suggested that pulmonary arterial compliance may also predict prognosis in PAH. The prognostic importance of hemodynamic values achieved after treatment initiation is less well established.Methods:Our objective was to evaluate the prognostic importance of clinical and hemodynamic variables during follow-up, including pulmonary arterial compliance, after initial management in PAH. We evaluated incident patients with idiopathic, drug- and toxin-induced, or heritable PAH enrolled in the French pulmonary hypertension registry between 2006 and 2016 who had a follow-up right-sided heart catheterization (RHC). The primary outcome was death or lung transplantation. We used stepwise Cox regression and the Kaplan-Meier method to assess variables obtained at baseline and at first follow-up RHC.Results:Of 981 patients, a primary outcome occurred in 331 patients (33.7%) over a median follow-up duration of 2.8 years (interquartile range, 1.1–4.6 years). In a multivariable model considering only baseline variables, no hemodynamic variables independently predicted prognosis. Median time to first follow-up RHC was 4.6 months (interquartile range, 3.7–7.8 months). At first follow-up RHC (n=763), New York Heart Association functional class, 6-minute walk distance, stroke volume index (SVI), and right atrial pressure were independently associated with death or lung transplantation, adjusted for age, sex, and type of PAH. Pulmonary arterial compliance did not independently predict outcomes at baseline or during follow-up. The adjusted hazard ratio for SVI was 1.28 (95% confidence interval, 1.11–1.49;P2decrease and for right atrial pressure was 1.05 (95% confidence interval, 1.02–1.09;P−1·m−2, 6-minute walk distance >440 m, and New York Heart Association class I or II functional class, lower SVI was still associated with higher rates of death or lung transplantation (PConclusions:SVI and right atrial pressure were the hemodynamic variables that were independently associated with death or lung transplantation at first follow-up RHC after initial PAH treatment. These findings suggest that the SVI could be a more appropriate treatment target than cardiac index in PAH.

IntroductionContemporary risk assessment tools categorise patients with pulmonary arterial hypertension (PAH) as low, intermediate or high risk. A minority of patients achieve low risk status with most remaining intermediate risk. Our aim was to validate a four-stratum risk assessment approach categorising patients as low, intermediate-low, intermediate-high or high risk, as proposed by the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) investigators.MethodsWe evaluated incident patients from the French PAH Registry and applied a four-stratum risk method at baseline and at first reassessment. We applied refined cut-points for three variables: World Health Organization functional class, 6-min walk distance and N-terminal pro-brain natriuretic peptide. We used Kaplan–Meier survival analyses and Cox proportional hazards regression to assess survival according to three-stratum and four-stratum risk approaches.ResultsAt baseline (n=2879), the four-stratum approach identified four distinct risk groups and performed slightly better than a three-stratum method for predicting mortality. Four-stratum model discrimination was significantly higher than the three-stratum method when applied during follow-up and refined risk categories among subgroups with idiopathic PAH, connective tissue disease-associated PAH, congenital heart disease and portopulmonary hypertension. Using the four-stratum approach, 53% of patients changed risk category from baseline compared to 39% of patients when applying the three-stratum approach. Those who achieved or maintained a low risk status had the best survival, whereas there were more nuanced differences in survival for patients who were intermediate-low and intermediate-high risk.ConclusionsThe four-stratum risk assessment method refined risk prediction, especially within the intermediate risk category of patients, performed better at predicting survival and was more sensitive to change than the three-stratum approach.

Introduction Malgre les progres realises dans l’evaluation pronostique de l’hypertension arterielle pulmonaire (HTAP), plus de 50 % des patients inscrits sur liste de transplantation pulmonaire ou cardio-pulmonaire ont recours a un acces prioritaire a la greffe en France. Lors du dernier congres mondial de l’hypertension pulmonaire (HTP), l’utilisation des differentes methodes d’evaluation du risque a ete proposee pour poser l’indication d’une inscription sur liste de transplantation. Methodes L’objectif de notre etude etait d’evaluer les methodes d’evaluation du risque sur une population de 208 patients suivis pour une HTAP et inscrits sur liste de transplantation entre 2006 et 2018. Au moment de l’inscription sur liste, le risque a ete calcule pour chaque patient selon les criteres ERS-ESC et le score REVEAL 2.0. Le critere de jugement principal etait la survie globale apres inscription sur liste. Les criteres de jugement secondaire etaient la mortalite sur liste, la survie post-transplantation et l’incidence cumulee de dysfonction chronique du greffon. Resultats La survie globale apres inscription sur liste de transplantation pulmonaire ou cardiopulmonaire etait significativement plus faible chez les patients a « risque eleve » selon les criteres ERS-ESC, avec la methode proposee par le reseau francais de l’HTP (p = 0,005) et celle du registre COMPERA (p = 0,001), ou bien selon le score REVEAL 2.0 (p = 0,02). Le taux de mortalite sur liste de transplantation etait plus eleve chez les patients a « risque eleve » (de 13 % a 19%) et le recours a un acces prioritaire a la greffe plus frequent (de 70% a 90 %) quelle que soit la methode utilisee. La survie post-transplantation etait sensiblement plus faible chez les patients a « risque eleve » sans difference significative, avec une tendance a une incidence cumulee plus elevee de dysfonction chronique du greffon. Conclusion Les patients avec HTAP identifies comme a « risque eleve » selon les differentes methodes d’evaluation du risque au moment de l’inscription sur liste de transplantation ont un moins bon pronostic malgre un recours plus frequent a la super urgence. Anticiper l’inscription sur liste de transplantation et prioriser les patients a « risque eleve » dans le systeme d’attribution des greffons pourrait aider a diminuer le temps d’attente sur liste, diminuer le recours a la super urgence et ameliorer la morbi-mortalite de ces patients.

Introduction Les guidelines ESC/ERS 2015 recommandent un traitement combine d’emblee incluant une prostacyline parenterale dans l’hypertension arterielle pulmonaire (HTAP) a risque eleve de mortalite. L’interet d’une tritherapie initiale incluant une prostacyline parenterale repose deux etudes retrospectives de faibles effectifs (Sitbon O, et al. Eur Respir J 2014; D’Alto M, et al. Chest 2020). Les donnees de survie a long-terme avec cette strategie demeurent encore mal connues. Methodes Analyse retrospective a partir du registre francais de l’hypertension pulmonaire de tous les cas incidents d’HTAP initiees en tritherapie associant une prostacycline parenterale (epoprostenol par voie IV ou treprostinil par voie sous-cutanee), un antagoniste des recepteurs de l’endotheline et un inhibiteur de la PDE-5 entre 2007 et 2018. Recueil des donnees cliniques, fonctionnelles (classe fonctionnelle [CF] NYHA, distance parcourue au test de marche de six minutes [DM6]), biologiques (NT-proBNP) et hemodynamique (catheterisme cardiaque droit) au diagnostic, a la premiere et a la derniere reevaluation. Analyses de la survie globale et sans transplantation. Resultats Quatre-vingt-cinq patients (80 % de femmes, âge moyen 43 ± 15 ans) atteints d’HTAP (44 idiopathiques, 25 heritables, 10 associees a une connectivite, 3 hypertensions porto-pulmonaires, 3 autres). Le Tableau 1 montre les caracteristiques cliniques et hemodynamiques au diagnostic et leurs modifications au cours du suivi. Le suivi moyen etait de 4.6 ± 2.9 ans. Six patients sont decedes apres 2 mois (2), 8 mois (1), 13 mois (1) et 2 ans (2), et 16 ont beneficie d’une transplantation pulmonaire (11 HTAP idiopathiques et 5 heritables) apres 2.4 ± 1.8 ans. La survie globale etait de 96 %, 92 %, 92 % et 92 % a 1, 3, 5 et 10 ans; la survie sans transplantation de 94 %, 82 %, 78 % et 72 %. Dix-huit patients ont arrete le traitement par prostacycline parenterale en raison d’une amelioration hemodynamique majeure. Conclusion Nous confirmons qu’une tritherapie initiale incluant une prostacycline parenterale ameliore de facon majeure les symptomes, les capacites a l’exercice et l’hemodynamique dans une large cohorte de patients avec HTAP severe. Cette strategie est associee a un excellent pronostic a long terme avec une survie de 92 % a 10 ans.

Acute decompensated pulmonary arterial hypertension (PAH) is characterized by rapid worsening of clinical signs of right heart failure (RHF) with subsequent congestion and systemic circulatory insufficiency that can lead to multisystem organ failure [1–3]. Short-term outcomes of acute decompensated RHF is very poor and remains the first cause of mortality in PAH [4, 5]. Intensive care of acute decompensated PAH is based on treatment of triggering factors, careful fluid management, and strategies to improve cardiac function and reduce right ventricular afterload [1]. However, this medical strategy is not always sufficient to restore a long-lasting balance between the afterload imposed on the right ventricle and its capacity for compensation. In case of refractory RHF despite maximal medical treatment, the use of mechanical support should now be considered in selected candidates for lung transplantation, or less commonly as a bridge to recovery in patients with a treatable cause of right-sided heart failure [1]. Veno-arterial extracorporeal membrane oxygenation (ECMO) is currently the most widely used strategy to support the right ventricle in PAH patients. This strategy, combined with changes in organ allocation rules to prioritize patients with a short-term life-threatening condition should contribute to improve survival of eligible patients with end-stage PAH [6]. However, long-term survival of patients admitted in ICU for severe acute RHF management has not been studied extensively in the modern management era of mechanical support and high-priority lung transplantation. 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. Savale reports personal fees from Actelion, personal fees from Bayer, grants and personal fees from GSK, outside the submitted work; . Conflict of interest: Dr. Vuillard has nothing to disclose. Conflict of interest: Dr. Pichon has nothing to disclose. Conflict of interest: Dr. Boucly has nothing to disclose. Conflict of interest: Dr. Roche has nothing to disclose. Conflict of interest: Dr. Jevnikar has nothing to disclose. Conflict of interest: Dr. Ebstein has nothing to disclose. Conflict of interest: Dr. Jais has nothing to disclose. Conflict of interest: Dr. Le Pavec has nothing to disclose. Conflict of interest: Pr. MONTANI reports grants and personal fees from Actelion, grants and personal fees from Bayer, personal fees from GSK, personal fees from Pfizer, grants, personal fees and non-financial support from MSD, personal fees from Chiesi, personal fees from Boerhinger, non-financial support from Acceleron, personal fees from Incyte Biosciences France, outside the submitted work. Conflict of interest: Dr. Mercier has nothing to disclose. Conflict of interest: Dr. SITBON reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, grants and personal fees from Bayer HealthCare, grants and non-financial support from Merck, grants, personal fees and non-financial support from GlaxoSmithKline, personal fees from Arena Pharmaceuticals, outside the submitted work; . Conflict of interest: Dr. Fadel has nothing to disclose. Conflict of interest: Dr. Humbert reports personal fees from Acceleron, grants and personal fees from Actelion, grants and personal fees from Bayer, personal fees from GSK, personal fees from Merck, personal fees from Novartis, personal fees from Astrazeneca, personal fees from Sanofi, outside the submitted work.

Introduction L’hypertension pulmonaire (HTP) postcapillaire constitue la cause la plus frequente des HTP. On distingue les HTP post-capillaires pures (HTPpcp si resistances vasculaires pulmonaires (RVP) Objectif Determiner les facteurs predictifs d’une composante precapillaire au sein d’une cohorte d’HTP post-capillaire. Methodes Etude retrospective monocentrique, incluant les patients avec une HTP post-capillaire (PAP moyenne > 20 mmHg et PAPO > 15 mmHg au catheterisme cardiaque droit) entre novembre 2016 et juillet 2018. Realisation d’analyses uni- et multivariees des caracteristiques demographiques, cliniques, echocardiographiques, ECG et EFR pour predire l’existence d’une composante precapillaire (HTPm). Realisation de courbes ROC pour determiner les meilleurs seuils des facteurs predictifs d’HTPm trouves en analyse multivariee. Resultats Cent un patients ont ete inclus (65 ± 13 ans ; 62 % de femmes, n = 50 HTPpcp ; n = 51 HTPm). En analyses univariees : l’âge, le debit de filtration glomerulaire, le diabete, l’antecedent de chirurgie cardiaque ou de stent, la classe fonctionnelle NYHA 3 ou 4, la distance parcourue au test de marche de 6 minutes, le NTproBNP, la dilatation et la dysfonction ventriculaire droite, le VEMS, et la DLCO sont des facteurs predictifs d’HTPm. Le sexe, l’indice de masse corporelle, le tabac, la fibrillation atriale, l’HTA, la dyslipidemie, les donnees ECG, l’hypertrophie ventriculaire gauche, la dilatation de l’oreillette gauche, la fraction d’ejection ventriculaire gauche, la presence d’une valvulopathie, les pressions de remplissage ventriculaire gauche elevees, la dilatation de l’oreillette droite, la PO2 et la PCO2 ne permettent pas de distinguer les HTPpcp des HTPm. En analyse multivariee seule la DLCO abaissee est predictive d’HTPm (p = 0,001). D’apres la courbe ROC de la DLCO, le meilleur seuil pour distinguer les HTPm des HTPpcp est 63 % : OR = 18,8 ; IC95 % : 3,9–90,3 ; p = 0,001 ; avec une sensibilite de 94 % et une valeur predictive negative de 91 %. Conclusion Au sein d’une cohorte d’HTP post-capillaire, la DLCO abaissee (sous le seuil de 63 %) est un excellent facteur predictif de la presence d’une composante precapillaire associee.

Background: Some previous reports suggested that “persistent PH” leads to poor surgical outcome after endarterectomy in patients with CTEPH. Dilatated BAs in patients with CTEPH would be decreased after endarterectomy, however some cases would not be changed. It might reflect the development of small-vessel remodeling and lead to “persistent PH”. Aim: To clarify that the BA total cross-sectional area(CSA) predicts the extent of persistent PH after endarterectomy. Method and Result: We retrospectively reviewed 81 CTEPH patients from the French PH Registry that underwent PEA from 2014 to 2018 (age: 59.2±13.6[SEM] years, male39/ female42). Pre- and post-operative total CSA of BAs was measured by computed tomography, and its correlation with surgical outcome was assessed. After endarterectomy, the total CSA of BAs was significantly reduced (pre-operative 12.22±4.3 [SEM] mm2 vs post-operative 7.4±3.0 [SEM] mm2, p Conclusion: After PEA, the total CSA of the BAs significantly decreased in patients with CTEPH. There is a significant correlation between pre-operative total CSA of the BAs and pre-operative hemodynamic data. Furthermore, accumulations of numbers are needed to better understand that total CSA of the BAs and its changes with predict of surgical outcomes in CTEPH.

Treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) have recently evolved with the availability of balloon pulmonary angioplasty (BPA) and pulmonary vasodilators. Our aim was to analyze the prognostic variables associated with long-term outcome in a cohort of patients with not-operated CTEPH.From January 2006 to December 2016, 343 newly diagnosed consecutive patients with not-operated CTEPH were diagnosed and followed up in the French Reference Center for Pulmonary Hypertension. Overall long-term survival and prognostic factors according to the diagnosis period (early period, 2006-2012, vs recent period, since 2013, i.e., one year before availability of BPA) were analyzed.In the overall population, baseline New York Heart Association functional class, right atrial pressure, 6-minute walk distance (6MWD), and diagnosis period were independent predictors of survival. The 1- and 3-year survival rates of patients diagnosed in the recent period (n = 170) were 91.6% and 85.0%, compared with 89.0% and 74.3% in patients diagnosed in the early period (n = 173), respectively (p = 0.030). Multivariate analysis from patients diagnosed in the recent period found that baseline 6MWD (per 20 m increase in distance) (hazard ratio [HR], 0.879; 95% confidence interval [CI], 0.832-0.928, p0.001) and BPA (HR, 0.307; 95% CI, 0.099-0.957; p = 0.042) were independently associated with survival.Survival of not-operated patients with CTEPH has significantly improved in the recent management era. New treatment options, including BPA, might have the potential to improve the prognosis of patients with inoperable CTEPH.

Metallo-β-lactamase (MBL)-producing Gram-negative bacteria are often extremely resistant, leading to a real therapeutic dead end. Here, we evaluated the in vitro and in vivo efficacy of aztreonam in combination with ceftazidime-avibactam, ceftolozane-tazobactam, or amoxicillin-clavulanate for the treatment of infections caused by MBL-producing Enterobacteriaceae, MBL-producing Pseudomonas aeruginosa, and extremely drug-resistant Stenotrophomonas maltophilia. First, we report two clinical cases, namely, a urinary tract infection caused by an NDM-5-producing Escherichia coli isolate and a pulmonary infection caused by a S. maltophilia isolate efficiently treated with the association of aztreonam-ceftazidime-avibactam and aztreonam-amoxicillin-clavulanate, respectively. Then, a total of 50 MBL-producing Enterobacteriaceae isolates, 3 MBL-producing P. aeruginosa isolates, and 5 extremely drug-resistant S. maltophilia isolates were used to test aztreonam susceptibility in combination with ceftolozane-tazobactam, ceftazidime-avibactam, or amoxicillin-clavulanate. The Etest strip superposition method was used to determine the MICs of the aztreonam/inhibitor combinations. According to CLSI breakpoints, aztreonam susceptibility was fully restored for 86%, 20%, and 50% of the MBL-producing Enterobacteriaceae isolates when combined with ceftazidime-avibactam, ceftolozane-tazobactam, and amoxicillin-clavulanate, respectively. In P. aeruginosa, the aztreonam-ceftazidime-avibactam combination was the most potent, even though the reduction in MICs was at most 2-fold. With the 5 S. maltophilia isolates, aztreonam-ceftazidime-avibactam and aztreonam-amoxicillin-clavulanate were found to be equal (100% susceptibility). Overall, aztreonam-ceftazidime-avibactam was the most potent combination to treat infections caused by MBL producers compared with aztreonam-amoxicillin-clavulanate and aztreonam-ceftolozane-tazobactam. However, in many cases aztreonam-amoxicillin-clavulanate was found to be as efficient as aztreonam-ceftazidime-avibactam, offering the main advantage to be markedly cheaper. We also confirmed the validity of Etest superpositions as a very simple method to determine MICs of aztreonam combinations.

Background To date, nothing is known about the evolution of survival in systemic sclerosis-associated pulmonary arterial hypertension (PAH) over the last decade. Methods This study used a multivariate Cox regression model adjusted for clinically relevant baseline confounders to assess the association between the occurrence of death and date of PAH diagnosis comparing two periods of the same duration (2006-2011 vs 2012-2017). Interactions between the two diagnosis periods and baseline variables were tested. Results A total of 306 incident patients were included, 167 (54.6%) with a PAH diagnosis occurring in 2006 to 2011 and 139 (45.4%) in 2012 to 2017. No significant difference in survival was observed between patients diagnosed with PAH in 2012 to 2017 compared with those diagnosed in 2006 to 2011 (hazard ratio [HR], 0.76 [0.46-1.26]; P = .29). A significant interaction was observed between PAH diagnosis periods and age (P = .05). When stratifying according to age (based on the median age of 70 years), a significant increase was observed in survival in patients aged ≤ 70 years between the 2006 to 2011 period and the 2012 to 2017 period (HR, 0.40 [0.17-0.99]; P = .046) but not in older patients (HR, 1.29 [0.67-2.51]; P = .44). A significantly higher proportion of initial (ie, within the first 4 months) endothelin receptor antagonist/phosphodiesterase type 5 inhibitor combination therapy was observed in younger patients diagnosed from 2012 to 2017 vs those diagnosed from 2006 to 2011 (42.9% vs 19.5%; P = .002) but not in older patients. Conclusions Over the period 2006 to 2017, survival in systemic sclerosis-associated PAH improved over time in patients aged ≤ 70 years but not in older patients. Further investigations are needed to confirm this relation, as general improvement in medical care and management may also be a possible explanation.