In this phase 2 proof-of-concept study we examined the safety and efficacy of selexipag, an orally available, selective prostacyclin receptor (IP receptor) agonist, as a treatment for pulmonary ...arterial hypertension (PAH). 43 adult patients with symptomatic PAH (receiving stable endothelin receptor antagonist and/or a phosphodiesterase type-5 inhibitor therapy) were randomised three to one to receive either selexipag or placebo. Dosage was up-titrated in 200-μg increments from 200 μg twice daily on day 1 to the maximum tolerated dose by day 35 (maximum allowed dose of 800 μg twice daily). Change in pulmonary vascular resistance at week 17 expressed as a percentage of the baseline value was the primary efficacy end-point, and was analysed in the per protocol set first and then in the all-treated set to assess robustness of results. A statistically significant 30.3% reduction in geometric mean pulmonary vascular resistance was observed after 17 weeks' treatment with selexipag compared with placebo (95% confidence limits -44.7- -12.2; p=0.0045, Wilcoxon rank sum test). This was supported by a similar result from the all-treated set. Selexipag was well tolerated with a safety profile in line with the expected pharmacological effect. Our results encourage the further investigation of selexipag for the treatment of PAH.
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.
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.
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).
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.
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.
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•Portopulmonary hypertension is a severe complication of portal hypertension.•Therapies targeting pulmonary arterial hypertension improve cardiopulmonary haemodynamics.•Combining these therapies and liver transplantation is associated with excellent long-term outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
3.
Sputum handling for rheology Esteban Enjuto, Lydia; Robert de Saint Vincent, Matthieu; Maurin, Max ...
Scientific reports,
05/2023, Volume:
13, Issue:
1
Journal Article
Peer reviewed
Open access
The rheology of sputum is viewed as a powerful emerging biophysical marker for monitoring muco-obstructive pulmonary diseases such as cystic fibrosis (CF) and non-CF bronchiectasis (NCFB). However, ...there is no unified practice to process sputa from collection to analysis, which can lead to highly variable, and sometimes inconsistent results. The main objective of this study is to bring light into the handling of sputum samples to establish a standardised and robust protocol before rheological measurements. Sputum collected from 22 CF and 10 NCFB adults, was divided into control (vortexed and fresh: non-heated and non-frozen) and three treated conditions (either non-vortexed, heated or frozen). In addition, 6 CF expectorations were used to study the dynamics of ageing over 24 h. Sputum's mechanical properties were measured with a rotational rheometer to obtain their properties at rest, elastic (Formula: see text) and viscous moduli (Formula: see text), and at the onset of flow, critical deformation (Formula: see text) and critical stress (Formula: see text). We demonstrate that heating sputum is completely destructive while freezing sputa at Formula: see text has no discernible effect on their rheology. We also show that the variability of rheological measurements largely resulted from the sample's macroscopic heterogeneity, and can be greatly reduced by non-destructive vortex homogenisation. Finally, we observed contrasted ageing effects as a fonction of purulence: while the viscoelasticity of purulent samples reduced by half within 6 h after collection, semi-purulent samples did not evolve. These results guide towards a robust unified protocol for simple sputum handling in rheometry. We therefore suggest to vortex and snap freeze sputum samples immediately after collection when direct testing is not possible.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung reducing clinical consequences of cholinergic hyperactivity. The ...AIRFLOW-1 study assessed safety and TLD dose in patients with moderate-to-severe, symptomatic COPD. This analysis evaluated the long-term impact of TLD on COPD exacerbations, pulmonary function, and quality of life over 3 years of follow up.
TLD was performed in a prospective, energy-level randomized (29 W vs 32 W power), multicenter study (NCT02058459). Additional patients were enrolled in an open label confirmation phase to confirm improved gastrointestinal safety after procedural modifications. Durability of TLD was evaluated at 1, 2, and 3 years post-treatment and assessed through analysis of COPD exacerbations, pulmonary lung function, and quality of life.
Three-year follow-up data were available for 73.9% of patients (n = 34). The annualized rate of moderate to severe COPD exacerbations remained stable over the duration of the study. Lung function (FEV
, FVC, RV, and TLC) and quality of life (SGRQ-C and CAT) remained stable over 3 years of follow-up. No new gastrointestinal adverse events and no unexpected serious adverse events were observed.
TLD in COPD patients demonstrated a positive safety profile out to 3 years, with no late-onset serious adverse events related to denervation therapy. Clinical stability in lung function, quality of life, and exacerbations were observed in TLD treated patients over 3 years of follow up.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pulmonary arterial hypertension (PAH) is a rare disease leading to right heart failure and death. Prognosis remains poor, particularly for patients with severe disease, i.e. World Health Organization ...functional class IV. There have been significant improvements in treatment options. Several agents are available that target the three main established PAH disease pathways, and can be combined sequentially or upfront. Strong scientific evidence supports the use of intravenous epoprostenol in severe PAH; however, despite recommendations, many patients do not receive parenteral prostanoids and there is a lack of evidence from randomised clinical trials supporting the value of other PAH medications alone in severe PAH. Lung transplantation is an important option in patients with severe PAH who have not responded sufficiently to therapy, or who have worsened despite maximal treatment. Bridging techniques are available for patients who worsen while awaiting transplantation. The type of bridging technique used depends on various factors including patient illness severity, physician experience and the anticipated waiting time for transplantation. With the aim to facilitate the treatment decision-making process, herein we review the medical treatment options available for patients with severe PAH, and the bridging techniques that may be used to sustain patients awaiting transplantation.
Even for patients who are very stable while receiving i.v. epoprostenol over a long period of time, anytransition to selexipag warrants careful long-term clinical and haemodynamic follow-up ...becauseworsening is likely to occur.
The progression of chronic obstructive pulmonary disease (COPD) is characterized by episodes of acute exacerbation (AECOPD) of symptoms, decline in respiratory function, and reduction in ...quality-of-life increasing morbi-mortality and often requiring hospitalization. Exacerbations can be triggered by environmental exposures, changes in lifestyle, and/or physiological and psychological factors to greater or lesser extents depending on the individual's COPD phenotype. The prediction and early detection of an exacerbation might allow patients and physicians to better manage the acute phase. We summarize the recent scientific data on remote telemonitoring (TM) for the prediction and management of acute exacerbations in COPD patients. We discuss the components of remote monitoring platforms, including the integration of environmental monitoring data; patient reported outcomes collected via interactive Smartphone apps, with data from wearable devices that monitor physical activity, heart rate, etc.; and data from medical devices such as connected non-invasive ventilators. We consider how telemonitoring and the deluge of data it potentially generates could be combined with electronic health records to provide personalized care and multi-disease management for COPD patients.
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Endothelial function and microvesicle concentration changes after acute bouts of continuous eccentric exercise have not been assessed previously nor compared with concentric exercise at similar ...aerobic power outputs. This method of training may be useful among some clinical populations, but acute responses are not well described. As such, 12 healthy males completed 2 experimental sessions of either 45 min of eccentric or concentric cycling at a matched aerobic power output below the ventilatory threshold. Brachial artery vascular function was assessed throughout 5 min of forearm ischemia and 3 min thereafter, before and at 5 and 40 min of recovery following each exercise session flow-mediated dilation (FMD). Venous blood samples were acquired before each vascular function assessment. FMD significantly decreased after eccentric cycling by 40 min of recovery (
< 0.05), but was unaltered after concentric exercise. No differences in peak hyperemic blood flow velocity occurred neither between modalities nor at any time point (
> 0.05). Platelet-derived microvesicles increased by ~20% after both exercise modalities (
< 0.05) while endothelial-derived microvesicles were unchanged (
> 0.05). Moderate relationships with cardiac output, a surrogate for shear stress, and norepinephrine were apparent (
< 0.05), but there were no relationships with inflammatory or acute phase proteins. In summary, eccentric endurance exercise induced macrovascular endothelial dysfunction; however, endothelial activation determined by endothelial microvesicles did not occur suggesting that this modality may induce oxidative stress but no significant endothelial damage. In addition, the increase in platelet microvesicle concentrations may induce beneficial microvascular adaptations as suggested by previous research.
Continuous eccentric cycling exercise induces substantial skeletal muscle, tendon, and bone strain providing a potentially beneficial stimulus among clinical populations. This modality also induces temporary endothelial dysfunction but no apparent damage or activation of the endothelium indicated by microvesicle production, whereas proangiogenic platelet microvesicles are released similarly following both concentric and eccentric cycling and may relate to the shear stress and catecholamine response to exercise.
Farmer's lung (FL) is a common type of hypersensitivity pneumonitis. It is often considered that fibrosis is the most frequent finding in chronic FL. Nevertheless, three cohort studies have suggested ...that some patients with chronic FL may develop emphysema. We aimed to evaluate the current prevalence of emphysema in active FL, to describe the radiological and functional features of emphysema in active FL, and to identify risk factors associated with emphysema in this population.
Patients aged over 18 years with active FL were prospectively recruited through the SOPHIA study (CPP Est; P-2009-521), between 2007 and 2015. Each patient had complete medical history screening, clinical examination, high resolution computed tomodensitometry, bronchoalveolar lavage, pulmonary function tests and serum precipitins.
Among 33 patients with active FL, the prevalence of emphysema in this series of incident active FL cases was higher (48.5%) than that of fibrosis (12%) and was not dependent on smoking habits. Most patients with emphysema did not have lung hyperinflation. The possible risk factors for emphysema in active FL were a longer duration of exposure to organic dusts, and at a higher level.
Emphysema is found in half of patients with active FL and may be influenced by exposure patterns.
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