Risk stratification refinements with inclusion of haemodynamic variables at follow-up in patients with pulmonary arterial hypertension.

BACKGROUND AND AIMS: Haemodynamic variables are prognostic factors in pulmonary arterial hypertension (PAH). However, right heart catheterization (RHC) is not systematically recommended to assess the risk-status during follow-up. This study aimed to assess the added value of haemodynamic variables in prevalent patients to predict the risk of death or lung transplantation according to their risk status assessed by the non-invasive 4 strata model as recommended by the European guidelines. METHODS: We evaluated incident patients with PAH enrolled in the French PAH Registry between 2009 and 2020 who had a first follow-up RHC. Cox regression identified, in each follow-up risk status, haemodynamic variables significantly associated with transplant-free survival (TFS). Optimal thresholds were determined by time-dependent Receiver-Operating Characteristics. Several multivariable Cox regression models were performed to identify the haemodynamic variables improving the non-invasive risk stratification model. RESULTS: We analysed 1240 incident patients reassessed within a year by RHC. None of haemodynamic variable were significantly associated with TFS among low-risk (n=386) or high-risk (n=71) patients. Among patients at intermediate (-low, n=483, -high, n=300) risk at first follow-up, multivariable models including either stroke volume index (SVi) or mixed venous oxygen saturation (SvO2) were the best. The prognostic performance of refined 6 strata risk stratification model including the non-invasive 4 strata model and SVi>37 mL·m-2 and/or SvO2>65% for patients at intermediate-risk (Area Under the Curve 0.81, c-index 0.74), was better than that of 4 strata model (0.79, p=0.009; c-index 0.72). CONCLUSIONS: Cardiopulmonary haemodynamics may improve risk stratification at follow-up in patients at intermediate-risk.

COVID-19 in Patients with Pulmonary Hypertension: A National Prospective Cohort Study.

Rationale: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with pulmonary endothelial dysfunction. There are limited data available on the outcomes of coronavirus disease (COVID-19) in patients with pulmonary hypertension (PH), a disease characterized by pulmonary endothelial dysfunction. Objectives: To describe characteristics and outcomes of patients with precapillary PH and COVID-19. Methods: We prospectively collected characteristics, management, and outcomes of adult patients with precapillary PH in the French PH network who had COVID-19 between February 1, 2020, and April 30, 2021. Clinical, functional, and hemodynamic characteristics of PH before COVID-19 were collected from the French PH registry. Measurements and Main Results: A total of 211 patients with PH (including 123 with pulmonary arterial hypertension, 47 with chronic thromboembolic PH, and 41 with other types of PH) experienced COVID-19, and 40.3% of them were outpatients, 32.2% were hospitalized in a conventional ward, and 27.5% were in an ICU. Among hospitalized patients (n = 126), 54.0% received corticosteroids, 37.3% high-flow oxygen, and 11.1% invasive ventilation. Right ventricular and acute renal failure occurred in 30.2% and 19.8% of patients, respectively. Fifty-two patients (all hospitalized) died from COVID-19. Overall mortality was 24.6% (95% CI [confidence interval], 18.8-30.5) and in-hospital mortality 41.3% (95% CI, 32.7-49.9). Nonsurvivors were significantly older, more frequently male and suffering comorbidities (diabetes, chronic respiratory diseases, systemic hypertension, chronic cardiac diseases, and/or chronic renal failure), and had more severe PH at their most recent evaluation preceding COVID-19 diagnosis (in terms of functional class and 6-minute-walk distance; all P < 0.05). Use of pulmonary arterial hypertension therapy was similar between survivors and nonsurvivors. Conclusions: COVID-19 in patients with precapillary PH was associated with a high in-hospital mortality. The typical risk factors for severe COVID-19 and severity of PH were associated with mortality in this population.

Real-life evaluation of the clinical, functional, and hematological effects of mepolizumab in patients with severe eosinophilic asthma: Results of a single-centre observational study.

Mepolizumab is a humanized monoclonal antibody which targets interleukin-5 (IL-5) and is nowadays available in many countries for add-on biological therapy of severe eosinophilic asthma. Although the approval of mepolizumab use in clinical practice has been made possible by several successful pre-marketing controlled trials, so far only a very few studies have been performed in a real-life setting. Within such a context, our present observational investigation refers to 14 patients with refractory eosinophilic asthma, currently treated with mepolizumab at the Respiratory Unit of "Magna Græcia" University Hospital located in Catanzaro, Italy, whose anti-IL-5 treatment began between June 2017 and January 2018. These patients experienced a significant increase in asthma control test (ACT) score, that was evaluated at baseline (13.64 ±â€¯3.00), as well as after 4 weeks (18.86 ±â€¯3.15; p < 0.0001) and 24 weeks (20.07 ±â€¯1.94; p < 0.0001) of add-on therapy with mepolizumab. This relevant improvement in symptom control was paralleled by a dramatic fall of blood eosinophil numbers, counted at baseline (647.1 ±â€¯274.7 cells/µl), and at the 4th (147.8 ±â€¯66.5 cells/µl; p < 0.0001) and 24th week (98.6 ±â€¯40.3 cells/µl; p < 0.0001) after starting add-on treatment with mepolizumab. These changes were associated with significant and stable increases in FEV1, which was recorded at baseline (1389 ±â€¯454.3 mL), as well as after 4 weeks (1711 ±â€¯482.3 mL; p < 0.001) and 24 weeks (1701 ±â€¯456.0 mL; p < 0.01). Moreover, in comparison to the 6 months preceding the beginning of treatment with mepolizumab, after 24 weeks of anti-IL-5 therapy significant decreases were detected with regard to exacerbation numbers (from 3.64 ±â€¯1.86 to 1.0 ±â€¯0.78; p < 0.001) and oral intake of prednisone (from 24.11 ±â€¯10.36 mg/day to 1.78 ±â€¯3.82 mg/day). Therefore, these preliminary data referring to our single-centre observational study corroborate, in a real-life environment, the efficacy of mepolizumab for treatment of patients with exacerbation-prone, corticosteroid-refractory, severe eosinophilic asthma.

Pulmonary veno-occlusive disease: illustrative cases and literature review.

Pulmonary veno-occlusive disease (PVOD), also known as "pulmonary arterial hypertension (PAH) with overt features of venous/capillary involvement", is a rare cause of PAH characterised by substantial small pulmonary vein and capillary involvement, leading to increased pulmonary vascular resistance and right ventricular failure. Environmental risk factors have been associated with the development of PVOD, such as occupational exposure to organic solvents and chemotherapy, notably mitomycin. PVOD may also be associated with a mutation in the EIF2AK4 gene in heritable forms of disease. Distinguishing PVOD from PAH is critical for guiding appropriate management. Chest computed tomography typically displays interlobular septal thickening, ground-glass opacities and mediastinal lymphadenopathy. Life-threatening pulmonary oedema is a complication of pulmonary vasodilator therapy that can occur with any class of PAH drugs in PVOD. Early referral to a lung transplant centre is essential due to the poor response to therapy when compared with other forms of PAH. Histopathological analysis of lung explants reveals microvascular remodelling with typical fibrous veno-occlusive lesions. This review covers the main features distinguishing PVOD from PAH and two clinical cases that illustrate the challenges of PVOD management.

Outcomes and risk assessment in pulmonary veno-occlusive disease.

Introduction: Pulmonary veno-occlusive disease (PVOD) is a rare and severe subtype of pulmonary arterial hypertension (PAH). Although European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines advise assessing PAH severity at baseline and during follow-up, no existing risk assessment methods have been validated for PVOD. This study aimed to identify prognostic factors, examine the impact of treatment strategies and evaluate risk assessment methods for PVOD patients. Methods: The study analysed all incident PVOD patients included in the French Pulmonary Hypertension Registry between 2006 and 2021. Survival was assessed based on initial treatment strategy and risk status and compared to a matched (age, sex, pulmonary vascular resistance) PAH group. Six risk assessment methods (number of four low-risk and three noninvasive low-risk variables, ESC/ERS guidelines three-strata and four-strata models, REVEAL 2.0 and Lite 2) were applied at baseline and early follow-up, and their accuracy was compared using Harrell's c-statistic. Results: Among the 327 included PVOD patients, survival rates at 1, 3 and 5 years were 86%, 50% and 27%, respectively. Multivariate analysis showed that only 6-min walk distance was associated with survival, with no significant difference based on initial treatment strategy. All six risk assessment methods could discriminate mortality risk, and the ESC/ERS four-strata model was the most accurate at both baseline and follow-up (C-index 0.64 and 0.74). PVOD survival rates were consistently lower than PAH when comparing baseline risk status using the ESC/ERS four-strata model. Conclusion: PVOD is associated with poor outcomes, and initial treatment strategies do not significantly affect survival. Risk assessment methods can be useful in predicting survival for PVOD patients.

Diagnosis and management of pulmonary veno-occlusive disease.

INTRODUCTION: Pulmonary veno-occlusive disease (PVOD) is an orphan disease and uncommon etiology of pulmonary arterial hypertension (PAH) characterized by substantial small pulmonary vein and capillary involvement. AREAS COVERED: PVOD, also known as 'PAH with features of venous/capillary involvement' in the current ESC/ERS classification. EXPERT OPINION: In recent years, particular risk factors for PVOD have been recognized, including genetic susceptibilities and environmental factors (such as exposure to occupational organic solvents, chemotherapy, and potentially tobacco). The discovery of biallelic mutations in the EIF2AK4 gene as the cause of heritable PVOD has been a breakthrough in understanding the molecular basis of PVOD. Venous and capillary involvement (PVOD-like) has also been reported to be relatively common in connective tissue disease-associated PAH (especially systemic sclerosis), and in rare pulmonary diseases like sarcoidosis and pulmonary Langerhans cell granulomatosis. Although PVOD and pulmonary arterial hypertension (PAH) exhibit similarities, including severe precapillary PH, it is essential to differentiate between them since PVOD has a worse prognosis and requires specific management. Indeed, PVOD patients are characterized by poor response to PAH-approved drugs, which can lead to pulmonary edema and clinical deterioration. Due to the lack of effective treatments, early referral to a lung transplantation center is crucial.

Pharmacological management of connective tissue disease-associated pulmonary arterial hypertension.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a severe, progressive pulmonary vasculopathy (Group 1 Pulmonary Hypertension (PH)) that complicates the course of many connective tissue diseases (CTD). Detailed testing is required to differentiate PAH from other types of PH caused by CTD such as left heart disease (Group 2 PH), pulmonary parenchymal disease (Group 3 PH), and chronic thromboembolic pulmonary hypertension (Group 4 PH). PAH is most frequently seen in systemic sclerosis but can also be seen with systemic lupus erythematosus, mixed CTD, and primary Sjogren's syndrome. AREAS COVERED: This review discusses the epidemiology of CTD-associated PAH, outlines the complex diagnosis approach, and finishes with an in-depth discussion on the current treatment paradigm. Focus is placed on challenges faced in the treatment of CTD-associated PAH, (decreased efficacy and poorer tolerance of pharmacological therapies) and includes a discussion on the future investigational treatments. EXPERT OPINION: Despite significant advances over the past decades with more aggressive treatment algorithms, CTD-associated PAH patients continue to have poorer survival compared to those with idiopathic PAH. This review highlights factors leading to disparate outcomes compared to other forms of PAH, and discusses on further improvements that may increase quality of life and survival for CTD-associated PAH patients.