BACKGROUND:Pulmonary hypertension (PH) frequently complicates interstitial lung diseases (ILDs), adversely affecting outcome. Identifying prognostic factors of patients with PH associated with ILD (ILD-PH) could facilitate early identification of patients who may benefit from PH therapy. METHODS:We included patients with ILD-PH from the prospective HYPID cohort and the French National Pulmonary Hypertension Registry (2007-2022). Univariable and multivariable analyses were performed to identify predictors of 1-year mortality. RESULTS:A total of 581 patients (mean age 69.4±9.3 years; 450 males) were analysed. ILD diagnoses were combined pulmonary fibrosis and emphysema (CPFE) syndrome (30.8%), idiopathic pulmonary fibrosis (29.6%), unclassifiable ILD (13.1%) and fibrotic hypersensitivity pneumonitis (10.3%). Mean pulmonary arterial pressure was 40.7±9.1 mmHg and mean pulmonary vascular resistance (PVR) was 7.6±3.5 Wood units (WU). Off-label PH therapy was initiated after initial evaluation in 215 patients (37%). The median transplant-free survival time was 17 (95% CI 15.2-not reached) months. Multivariable analysis identified male sex (p<0.001), World Health Organization functional class (WHO FC) III (p=0.003) or IV (p=0.003), 6-min walk distance (6MWD) ≤228 m (p<0.001), PVR >5 WU (p=0.008) and absence of PH therapy (p<0.001) as independent predictors of death or lung transplantation at 1 year. CONCLUSION:Non-invasive (6MWD and WHO FC) and invasive (PVR) variables are associated with prognosis in patients with ILD-PH, including in patients with CPFE. PH medication might improve outcomes in this patient population.

BACKGROUND:Portopulmonary hypertension (PoPH) may coexist with hepatopulmonary syndrome (HPS), a condition characterized by intrapulmonary vascular dilatations (IPVDs) and hypoxemia. Although pulmonary arterial hypertension (PAH) therapies are commonly used to treat PoPH, their effects on gas exchange remain insufficiently characterized. RESEARCH QUESTION:What are the effects of PAH-specific therapies on gas exchange and the development of IPVDs in patients with PoPH? STUDY DESIGN AND METHODS:A retrospective cohort of patients with PoPH was used to assess changes in the alveolar-arterial oxygen gradient (A-aDO2) following initiation of PAH therapy. A prospective cohort underwent systematic screening for IPVDs to assess their prevalence at baseline and incidence during treatment. RESULTS:The retrospective cohort included 107 patients (70% male; mean age, 55 ± 8 years) with a baseline mean A-aDO2 of 37.1 ± 13.0 mm Hg. Eighty-three patients received initial oral monotherapy and 24 received dual oral therapy. After a median follow-up of 4.5 months, A-aDO2 remained stable overall (mean change, -0.92 mm Hg; 95% CI, -3.2 to 1.3; P = .42), with substantial interindividual variability. Changes in A-aDO2 were not associated with variation in 6-minute walk distance or World Health Organization/New York Heart Association functional class. Baseline A-aDO2 and cardiac output were independently associated with subsequent improvement in A-aDO2. Treatment-induced reductions in mean pulmonary artery pressure and increases in cardiac output correlated with greater A-aDO2 improvement. In the prospective cohort (n = 28), HPS was present in 39% of patients newly diagnosed with PoPH. Baseline IPVDs did not influence A-aDO2 evolution; however, 4 patients developed new IPVDs within the first year following PAH therapy initiation. INTERPRETATION:Our results show that PAH therapy was not associated with overall deterioration in gas exchange in PoPH, despite substantial individual variability. Changes in oxygenation were linked to baseline and treatment-induced hemodynamic parameters. The development of new IPVDs in some patients warrants careful longitudinal monitoring.

BACKGROUND:Noonan syndrome is a RASopathy inherited in an autosomal dominant manner, mainly caused by gain-of-function variants activating the RAS/mitogen-activated protein kinase signalling pathway. Pulmonary hypertension (PH) may occur in Noonan syndrome, but its mechanisms, clinical characteristics and outcomes remain poorly defined. METHODS:We analysed data from the French PH Network to characterise the phenotype of Noonan syndrome patients who develop PH, and conducted a systematic analysis of the literature. RESULTS:Seven patients were identified from the French PH Network (male/female ratio 1.3:1), with a median (range) age at PH diagnosis of 9 (5-21) years. Genetic analysis revealed five pathogenic variants in PTPN11 and one in SHOC2. Associated features included facial dysmorphism, growth retardation, atrial septal defect and pulmonary valve stenosis. Haemodynamics showed severe pre-capillary PH without acute vasodilator response: mean pulmonary arterial pressure 55 (40-78) mmHg, cardiac output 3.95 (3.12-4.95) L·min-1 and pulmonary vascular resistance 13 (10-15.3) WU. Computed tomography of the chest identified perivascular ground-glass opacities, mediastinal infiltration, dilated bronchial arteries, distal pulmonary vascular tortuosity and possible arteriovenous shunts. Five patients were treated with drugs approved for pulmonary arterial hypertension. Three patients died and one underwent lung transplantation. Explanted lungs revealed plexiform lesions associated with diffuse lymphangiectasia. 12 additional cases from the literature included seven with pre-capillary PH, four with post-capillary PH due to cardiomyopathy and one without right heart catheterisation. CONCLUSION:Pre-capillary and post-capillary PH may complicate the course of Noonan syndrome, potentially in association with congenital heart defects and multisystem manifestations. Further studies are needed to better delineate the phenotype of PH in patients with Noonan syndrome.

BACKGROUND:EPHB4 loss of function is associated with type 2 capillary malformation-arteriovenous malformation syndrome, an autosomal dominant vascular disorder. The phenotype partially overlaps with hereditary haemorrhagic telangiectasia (HHT) due to epistaxis, telangiectases and cerebral arteriovenous malformations, but a similar liver involvement has never been described. METHODS:Members of the French HHT network reported their cases of EPHB4 mutation identified after an initial suspicion of HHT. Clinical, radiological and genetic characteristics were analysed. RESULTS:Among 21 patients with EPHB4, 15 had a liver imaging, including 7 with HHT-like abnormalities (2 female patients and 5 male patients, ages 43-69 years). Atypical epistaxis and telangiectases were noted in two cases each. They were significantly older than the eight patients with normal imaging (median: 51 vs 20 years, p<0.0006).The main hepatic artery was dilated in all the cases (diameter: 8-11 mm). Six patients had hepatic telangiectases. All kind of shunts were described (arteriosystemic: five patients, arterioportal: two patients, portosystemic: three patients). The overall liver appearance was considered as typical of HHT in six cases.Six EPHB4 variants were classified as pathogenic and one as likely pathogenic, with no specific hot spot. CONCLUSION:EPHB4 loss-of-function variants can be associated with HHT-like hepatic abnormalities and should be tested for atypical HHT presentations.

Background Riociguat and balloon pulmonary angioplasty (BPA) are treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, randomised controlled trials comparing these treatments are lacking. We aimed to evaluate the efficacy and safety of BPA versus riociguat in patients with inoperable CTEPH. Methods In this phase 3, multicentre, open-label, parallel-group, randomised controlled trial done in 23 French centres of expertise for pulmonary hypertension, we enrolled treatment-naive patients aged 18-80 years with newly diagnosed, inoperable CTEPH and pulmonary vascular resistance of more than 320 dyn.s/cm5. Patients were randomly assigned (1:1) to BPA or riociguat via a web-based randomisation system, with block randomisation (block sizes of two or four patients) without stratification. The primary endpoint was change in pulmonary vascular resistance at week 26, expressed as percentage of baseline pulmonary vascular resistance in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of riociguat or had at least one BPA session. Patients who completed the RACE trial continued into an ancillary 26-week follow-up during which symptomatic patients with pulmonary vascular resistance of more than 320 dyn.s/cm5 benefited from add-on riociguat after BPA or add-on BPA after riociguat. This trial is registered at ClinicalTrials.gov, NCT02634203, and is completed. Findings Between Jan 19, 2016, and Jan 18, 2019, 105 patients were randomly assigned to riociguat (n=53) or BPA (n=52). At week 26, the geometric mean pulmonary vascular resistance decreased to 39.9% (95% CI 36.2-44.0) of baseline pulmonary vascular resistance in the BPA group and 66.7% (60.5-73.5) of baseline pulmonary vascular resistance in the riociguat group (ratio of geometric means 0.60, 95% CI 0.52-0.69; p<0.0001). Treatment-related serious adverse events occurred in 22 (42%) of 52 patients in the BPA group and five (9%) of 53 patients in the riociguat group. The most frequent treatment-related serious adverse events were lung injury (18 [35%] of 52 patients) in the BPA group and severe hypotension with syncope (two [4%] of 53 patients) in the riociguat group. There were no treatment-related deaths. At week 52, a similar reduction in pulmonary vascular resistance was observed in patients treated with first-line riociguat or first-line BPA (ratio of geometric means 0.91, 95% CI 0.79-1.04). The incidence of BPA-related serious adverse events was lower in patients who were pretreated with riociguat (five [14%] of 36 patients vs 22 [42%] of 52 patients). Interpretation At week 26, pulmonary vascular resistance reduction was more pronounced with BPA than with riociguat, but treatment-related serious adverse events were more common with BPA. The finding of fewer BPArelated serious adverse events among patients who were pretreated with riociguat in the follow-up study compared with those who received BPA as first-line treatment points to the potential benefits of a multimodality approach to treatment in patients with inoperable CTEPH. Further studies are needed to explore the effects of sequential treatment combining one or two medications and BPA in patients with inoperable CTEPH.

Rationale: The relationship between initial treatment strategy and survival in pulmonary arterial hypertension (PAH) remains uncertain. Objectives: To evaluate long-term survival in PAH according to initial treatment strategy. Methods: Retrospective analysis of incident patients with idiopathic, heritable or anorexigen-induced PAH enrolled in the French Registry (01/2006 to 12/2018). Survival was assessed according to initial strategy: monotherapy, dual or triple combination (two oral medications and a parenteral prostacyclin). Results: Among 1611 enrolled patients, 984 were initiated with monotherapy, 551 with dual and 76 with triple therapy. The triple combination group was younger with fewer comorbidities but higher mortality risk. Survival was better with triple therapy (91% at 5 years) as compared to dual or monotherapy (both 61% at 5 years), p<0.001. A propensity score matching on age, sex and pulmonary vascular resistance also showed significant differences between triple and dual therapy (10-year survival 85% vs 65%). In high-risk patients (n=243), survival was better with triple therapy vs monotherapy or dual therapy, while there was no difference between monotherapy and double therapy. In intermediate-risk patients (n=1134), survival improved with 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 with a parenteral prostacyclin, those on triple therapy had better survival than those on monotherapy or dual therapy. Conclusions: Initial triple combination therapy including parenteral prostacyclin seems to be associated with better survival in PAH, particularly in the youngest high-risk patients.

Rationale: Pulmonary hypertension (PH) associated with neurofibromatosis type 1 (NF1) is a rare and largely unknown complication of NF1.Objectives: To describe characteristics and outcomes of PH-NF1.Methods: We reported the clinical, functional, radiologic, histologic, and hemodynamic characteristics, response to pulmonary arterial hypertension (PAH)-approved drugs, and transplant-free survival of patients with PH-NF1 from the French PH registry.Measurements and Main Results: We identified 49 PH-NF1 cases, characterized by a female/male ratio of 3.9 and a median (minimum-maximum) age at diagnosis of 62 (18-82) years. At diagnosis, 92% were in New York Heart Association functional class III or IV. The 6-minute-walk distance was 211 (0-460) m. Pulmonary function tests showed low DlCO (30% [12-79%]) and severe hypoxemia (PaO2 56 [38-99] mm Hg). Right heart catheterization showed severe precapillary PH with a mean pulmonary artery pressure of 45 (10) mm Hg and a pulmonary vascular resistance of 10.7 (4.2) Wood units. High-resolution computed tomography images revealed cysts (76%), ground-glass opacities (73%), emphysema (49%), and reticulations (39%). Forty patients received PAH-approved drugs with a significant improvement in functional class and hemodynamic parameters. Transplant-free survival at 1, 3, and 5 years was 87%, 54%, and 42%, respectively, and four patients were transplanted. Pathologic assessment showed nonspecific interstitial pneumonia and major pulmonary vascular remodeling.Conclusions: PH-NF1 is characterized by a female predominance, a low DlCO, and severe functional and hemodynamic impairment. Despite a potential benefit of PAH treatment, prognosis remains poor, and double-lung transplantation is an option for eligible patients.

Background & Aims: Long-term outcomes in portopulmonary hypertension (PoPH) are poorly studied in the current era of pulmonary hypertension management. We analysed the effect of pulmonary arterial hypertension (PAH)-targeted therapies, survival and predictors of death in a large contemporary cohort of patients with PoPH. Methods: Data from patients with PoPH consecutively enrolled in the French Pulmonary Hypertension Registry between 2007 and 2017 were collected. The effect of initial treatment strategies on functional class, exercise capacity and cardiopulmonary haemodynamics were analysed. Survival and its association with PAH- and hepatic-related characteristics were also examined. Results: Six hundred and thirty-seven patients (mean age 55 +/- 10 years; 58% male) were included. Fifty-seven percent had mild cirrhosis, i.e. Child-Pugh stage A. The median model for end-stage liver disease (MELD) score was 11 (IQR 9-15). Most patients (n = 474; 74%) were initiated on monotherapy, either with a phosphodiesterase-5 inhibitor (n = 336) or with an endothelin-receptor antagonist (n = 128); 95 (15%) were initiated on double oral combination therapy and 5 (1%) on triple therapy. After a median treatment time of 4.5 months, there were significant improvements in functional class (p<0.001), 6-minute walk distance (6MWD) (p<0.0001) and pulmonary vascular resistance (p<0.0001). Overall survival rates were 84%, 69% and 51% at 1, 3 and 5 years, respectively. Baseline 6MWD, sex, age and MELD score or Child-Pugh stage were identified as independent prognostic factors. Survival from PoPH diagnosis was significantly better in the subgroup of patients who underwent liver transplantation (92%, 83% and 81% at 1, 3 and 5 years, respectively). Conclusion: Survival of patients with PoPH is strongly associated with the severity of liver disease. Patients who underwent liver transplantation had the best long-term outcomes. Lay summary: Portopulmonary hypertension is defined by the presence of pulmonary arterial hypertension in the context of chronic liver disease and is characterized by progressive shortness of breath and exercise limitation. The presence of severe pulmonary arterial hypertension in liver transplant candidates represents a contraindication for such a surgery; however, treatments targeting pulmonary arterial hypertension are efficacious, allowing for safe transplantation and conferring good survival outcomes in those who undergo liver transplantation. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Introduction: Pulmonary hypertension associated with neurofibromatosis type 1 (PH-NF1) is a rare but severe complication of NF1. The largest study about PH-NF1 described 8 patients and there are few data about outcomes on PH treatment. Methods: We report clinical, functional, radiologic, and hemodynamic characteristics and outcomes of patients with pre-capillary PH-NF1 identified within the French PH Registry. Computed tomography (CT) at PH diagnosis were analysed by a pneumologist and a radiologist. Results: We identified 39 NF1-PH cases, characterized by a female predominance (77%) and a median age at PH diagnosis of 63 [min-max 35-82] y-o. At diagnosis, 90% were in NYHA functional class III or IV. Median 6-min walk distance was 209 [50-460] m. Pulmonary function tests showed normal or mild abnormalities except low DLCO (29 [20-58] %). PH was severe with a mean pulmonary artery pressure of 45 [29-71] mmHg, a cardiac index of 2.3 [1.2-3.6] L/min/m2 and pulmonary vascular resistance of 9.8 [4.6-20.1] WU. CT showed pulmonary cysts (72%), ground glass opacities (67%) and emphysema (49%). 38 patients received PAH-specific therapy. Transplant-free survival rates at 1, 3 and 5 years were 92%, 64% and 44%, respectively. Four patients underwent lung transplantation. Conclusions: PH-NF1 was characterized by female predominance, advanced age, severe hemodynamic impairment and poor prognosis.

Background: Medical therapy with riociguat and balloon pulmonary angioplasty (BPA) are two therapeutic options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Controlled studies comparing these two treatments are lacking. Methods: The multicenter, randomised, controlled RACE trial evaluated the efficacy and safety of riociguat versus BPA in newly diagnosed and treatment-naïve patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class (FC) I-IV with a pulmonary vascular resistance (PVR) >320 dyn.s/cm5 were randomly assigned, in a 1:1 ratio, to receive a treatment with riociguat or BPA. The primary endpoint was resting PVR at week 26, expressed as percentage of PVR at baseline. Secondary endpoints included changes from baseline in 6-min walk distance (6MWD), WHO FC, NT-proBNP, time to clinical worsening, and safety. Results: Between January 2016 and January 2019, 105 patients were randomised in 14 centers belonging to the French Pulmonary Hypertension Network: 53 to riociguat, 52 to BPA. Baseline characteristics are depicted in the table. The full study results will be available in June 2019. Conclusion: RACE study will provide important informations on the effect of riociguat compared to that of BPA as first-line therapy in treatment-naïve patients with inoperable CTEPH.

This study aimed to describe the long-term outcomes of pulmonary arterial hypertension (PAH) induced by dasatinib.21 incident, right heart catheterisation-confirmed cases of dasatinib-induced PAH were identified from the French Pulmonary Hypertension Registry. Clinical and haemodynamic variables were compared from baseline to last follow-up (median (range) 24 (1-81) months).Median age was 52 years and 15 patients were female (71%). 19 patients received dasatinib for chronic myelogenous leukaemia for a median (range) duration of 42 (8-74) months before PAH diagnosis. No bone morphogenic protein receptor-2 (BMPR2) mutations were found in the 10 patients tested. Dasatinib was uniformly discontinued and 11 patients received PAH medications. Four patients died during follow-up. New York Heart Association functional class improved from 76% in class III/IV to 90% in class I/II (p<0.01). Median (range) 6-min walk distance improved from 306 (0-660) to 430 (165-635) m (p<0.01). Median (range) mean pulmonary arterial pressure improved from 45 (30-70) to 26 (17-50) mmHg (p<0.01) and pulmonary vascular resistance from 6.1 (3.2-27.3) to 2.6 (1.2-5.9) Wood units (p<0.01). Patients treated with PAH medications had worse baseline haemodynamics but similar long-term outcomes to untreated patients. PAH persisted in 37% of patients.Dasatinib-induced PAH frequently improves after discontinuation but persisted in over one-third of patients, therefore systematic follow-up is essential.

BACKGROUND:Portopulmonary hypertension is defined by the presence of pulmonary arterial hypertension associated with portal hypertension. Its presence is a major stake for cirrhotic patients requiring liver transplantation (LT), with increased postoperative mortality and unpredictable evolution after transplantation. The aim was to study outcomes after liver transplantation in patients with portopulmonary hypertension and to identify factors associated with normalization of pulmonary hypertension.METHODS:Patients with portopulmonary hypertension who underwent LT between 2008 and 2016 in 8 French centers were retrospectively included. Pulmonary artery pressure was established by right heart catheterization before and after LT. Primary endpoint was the normalization of pulmonary artery pressure after LT.RESULTS:Twenty-three patients who received liver transplant between 2008 and 2016 were included. Two (8.7%) patients died in the immediate posttransplant period from right heart failure. With appropriate vasoactive medical treatment and LT, pulmonary arterial pressure was normalized in 14 patients (60.8%), demonstrating recovery from portopulmonary hypertension. In univariate analysis, the use of vasoactive combination therapy was the only prognostic factor for pulmonary arterial hypertension normalization after LT.CONCLUSIONS:Treatment of portopulmonary hypertension with a combination of vasoactive drugs allows LT with acceptable postoperative cardiovascular-related mortality and normalization of pulmonary hypertension in the majority of the patients.

OBJECTIVES:Despite the wide use of the 6 min walk distance (6MWD), no study has ever assessed its validity as a surrogate marker for haemodynamics and predictor of outcome in isolated pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH). We designed this work to address this issue. METHODS:Treatment-naïve patients with SSc-PAH were prospectively included from two sources: the French PAH Network (a prospective epidemiological cohort) (n=83) and randomised clinical trials submitted for drug approval (Food and Drug Administration) (n=332). Correlations between absolute values of the 6MWD and haemodynamics at baseline, as well as between variations of 6MWD and haemodynamics during follow-up, were studied in both populations. RESULTS:In the French cohort, baseline cardiac output (CO) (R(2)=0.19, p=0.001) and New York Heart Association class (R(2)=0.10, p<0.001) were significantly and independently correlated with baseline 6MWD in multivariate analysis. A significant, independent, but weaker, correlation with CO was also found in the Food and Drug Administration sample (R(2)=0.04, p<0.001). During follow-up, there was no association between the changes in 6MWD and haemodynamic parameters in patients under PAH-specific treatments. CONCLUSIONS:In SSc-PAH, CO independently correlates with 6MWD at baseline, but accounts for a small amount of the variance of 6MWD in both study samples. This suggests that other non-haemodynamic factors could have an impact on the walk distance. Moreover, variations of 6MWD do not reflect changes in haemodynamics among treated patients. Our results suggest that 6MWD is not an accurate surrogate marker for haemodynamic severity, nor an appropriate outcome measure to assess changes in haemodynamics during follow-up in treated SSc-PAH.

Tyrosine kinase inhibitors (TKIs) targeting BCR/ABL such as imatinib, nilotinib, dasatinib, bosutinib and ponatinib have revolutionised the management of patients with chronic myeloid leukaemia (CML) [1]. Pleural effusions and pulmonary arterial hypertension (PAH) have been reported in patients treated with these agents [2–4]. These side-effects are more frequently observed with dasatinib use, with partial or complete reversibility after drug withdrawal [3]. Bosutinib is a second-generation TKI prescribed in case of intolerance or resistance to imatinib, nilotinib or dasatinib. In the present report, we describe two cases of worsening of dasatinib-induced PAH and two cases of severe pleural effusions, suggesting overlapping pulmonary toxicity of bosutinib and dasatinib. Pulmonary complications of bosutinib therapy and potential cross-intolerance with dasatinib We acknowledge the French pulmonary hypertension pharmacovigilance network, VIGIAPATH, supported by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM).

Marchand-Adam, Sylvain Diot, Bruno Magro, Pascal De Muret, Anne Guignabert, Christophe Kannengiesser, Caroline Londono-Vallejo, Arturo Draskovic, Irena Toutain, Annick Diot, Patrice United States Am J Respir Crit Care Med. 2013 Aug 1;188(3):402-4. doi: 10.1164/rccm.201301-0010LE.