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Aim: Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction and development of emphysema. Among the comorbidities associated with COPD, skeletal muscle dysfunction is known to affect exercise capacity and the survival rate of patients. Pulmonary rehabilitation (PR), via exercise training, is essential for COPD patients. However, the response to PR is most often moderate. An animal model that recapitulates critical features of chronic human disease and provides access to muscle function should therefore be useful to improve PR benefits. Methods: We used a rat model of induced emphysema based on pulmonary instillations of elastase (ELA) and lipopolysaccharides (LPS). We assessed the long‐term effects of ELA/LPS and the potential effectiveness of endurance training on the skeletal muscle function. In vivo strength of the animals, and ex vivo contractility, endurance, type 1 fiber proportion, fiber cross‐sectional area, and capillarization of both soleus and extensor digitorum longus (EDL) were assessed. Results: An impaired overall muscle strength with decreased force, reduced capillarization, and atrophy of type 1 fiber of EDL was observed in ELA/LPS rats. Soleus was not affected. Endurance training was able to reduce fatigability, and increase type 1 fiber proportion and capillarization of soleus, and improve force, endurance, and capillarization of EDL in control and ELA/LPS rats. Conclusion: Our rat model of induced emphysema, which shares some features with the phenotype present in patients with COPD, could represent a suitable model to study skeletal muscle dysfunction and the effects of exercise training on muscle function in patients. [ABSTRACT FROM AUTHOR]

Background: The objective was to compare sevoflurane, a volatile sedation agent with potential bronchodilatory properties, with propofol on respiratory mechanics in critically ill patients with COPD exacerbation. Methods: Prospective study in an ICU enrolling critically ill intubated patients with severe COPD exacerbation and comparing propofol and sevoflurane after 1:1 randomisation. Respiratory system mechanics (airway resistance, PEEPi, trapped volume, ventilatory ratio and respiratory system compliance), gas exchange, vitals, safety and outcome were measured at inclusion and then until H48. Total airway resistance change from baseline to H48 in both sevoflurane and propofol groups was the main endpoint. Results: Sixteen patients were enrolled and were sedated for 126 h(61–228) in the propofol group and 207 h(171–216) in the sevoflurane group. At baseline, airway resistance was 21.6cmH2O/l/s(19.8–21.6) in the propofol group and 20.4cmH2O/l/s(18.6–26.4) in the sevoflurane group, (p = 0.73); trapped volume was 260 ml(176–290) in the propofol group and 73 ml(35–126) in the sevoflurane group, p = 0.02. Intrinsic PEEP was 1.5cmH2O(1–3) in both groups after external PEEP optimization. There was neither early (H4) or late (H48) significant difference in airway resistance and respiratory mechanics parameters between the two groups. Conclusions: In critically ill patients intubated with COPD exacerbation, there was no significant difference in respiratory mechanics between sevoflurane and propofol from inclusion to H4 and H48. [ABSTRACT FROM AUTHOR]

Purpose: Oral corticosteroid (OCS) use for asthma is associated with considerable healthcare resource utilization (HCRU) and costs. However, no study has investigated this in relation to patterns of intermittent OCS prescription. Methods: This historical UK cohort study used primary care medical records, linked to Hospital Episode Statistics, from 2008 to 2019, of patients (≥ 4 years old) with asthma prescribed intermittent OCS. Patients were categorized by OCS prescribing pattern (one-off [single], less frequent [≥ 90-day gap] and frequent [< 90-day gap]) and matched 1:1 (by sex, age and index date) with people never prescribed OCS with/without asthma. HCRU (reported as episodes, except for length of hospital stay [days] and any prescription [records]) and associated costs were compared between intermittent OCS and non-OCS cohorts, and among intermittent OCS prescribing patterns. Results: Of 149,191 eligible patients, 50.3% had one-off, 27.4% less frequent, and 22.3% frequent intermittent OCS prescribing patterns. Annualized non-respiratory HCRU rates were greater in the intermittent OCS versus non-OCS cohorts for GP visits (5.93 vs 4.70 episodes, p < 0.0001), hospital admissions (0.24 vs 0.16 episodes, p < 0.0001), and length of stay (1.87 vs 1.58 days, p < 0.0001). In the intermittent OCS cohort, rates were highest in the frequent prescribing group for GP visits (7.49 episodes; p < 0.0001 vs one-off), length of stay (2.15 days; p < 0.0001) and any prescription including OCS (25.22 prescriptions; p < 0.0001). Mean per-patient non-respiratory related and all-cause HCRU-related costs were higher with intermittent OCS than no OCS (£ 3902 vs £ 2722 and £ 8623 vs £ 4929, respectively), as were mean annualized costs (£ 565 vs £ 313 and £ 1526 vs £ 634, respectively). A dose–response relationship existed; HCRU-related costs were highest in the frequent prescribing cohort (p < 0.0001). Conclusion: Intermittent OCS use and more frequent intermittent OCS prescription patterns were associated with increased HCRU and associated costs. Improved asthma management is needed to reduce reliance on intermittent OCS in primary care. [ABSTRACT FROM AUTHOR]

Objectives This study aimed to estimate the prevalence of ANCA-associated vasculitis (AAV). That is, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), in Southern France in 2018, and evaluate differences among Europeans and non-Europeans. Methods This population-based, cross-sectional study used four sources (hospitals, community-based physicians, laboratories, National Health Insurance) to identify adults ≥15 years diagnosed with GPA, MPA or EGPA, living in Hérault and Gard in 2018. Cases were defined using the ACR/EULAR classification criteria, and if necessary, the European Medicines Agency algorithm. Prevalence estimates were standardised to the world population and capture-recapture analysis was used to assess the comprehensiveness of the estimation. The influence of geographical origin was evaluated. Results A total of 202 patients were selected, with 86 cases of GPA (42.6%), 85 cases of MPA (42.1%) and 31 cases of EGPA (15.3%). The standardised prevalence estimates per million inhabitants for 2018 were: 103 (95%CI 84–125) for AAV, 48 (95%CI 35–64) for GPA, 39 (95%CI 28–53) for MPA and 16 (95%CI 9–26) for EGPA, 36 (95%CI 25–50) for anti-PR3 positive AAV, 46 (95%CI 34–61) for anti-MPO positive AAV, and 16 (95%CI 9–26) for ANCA-negative AAV. The global estimation of comprehensiveness by capture-recapture analysis was 80.5%. The number of AAV cases was higher for non-European residents (P  = 0.001), particularly for MPA (P   <  0.0001). Conclusion We provide a new estimate of AAV prevalence in France and show a higher prevalence of MPA in non-European patients. [ABSTRACT FROM AUTHOR]

One of the major challenges in managing allergic bronchopulmonary aspergillosis remains consistent and reproducible assessment of response to treatment. What are the most relevant changes in CT scan parameters over time for assessing response to treatment? In this ancillary study of a randomized clinical trial (NebuLamB), patients with asthma with available CT scan and without exacerbation during a 4-month allergic bronchopulmonary aspergillosis exacerbation treatment period (corticosteroids and itraconazole) were included. Changed CT scan parameters were assessed by systematic analyses of CT scan findings at initiation and end of treatment. CT scans were assessed by two radiologists anonymized to the clinical data. Radiologic parameters were determined by selecting those showing significant changes over time. Improvement of at least one, without worsening of the others, defined the radiologic response. Agreement between radiologic changes and clinical and immunologic responses was likewise investigated. Among the 139 originally randomized patients, 132 were included. We identified five CT scan parameters showing significant changes at end of treatment: mucoid impaction extent, mucoid impaction density, centrilobular micronodules, consolidation/ground-glass opacities, and bronchial wall thickening (P <.05). These changes were only weakly associated with one another, except for mucoid impaction extent and density. No agreement was observed between clinical, immunologic, and radiologic responses, assessed as an overall response, or considering each of the parameters (Cohen κ, −0.01 to 0.24). Changes in extent and density of mucoid impaction, centrilobular micronodules, consolidation/ground-glass opacities, and thickening of the bronchial walls were found to be the most relevant CT scan parameters to assess radiologic response to treatment. A clinical, immunologic, and radiologic multidimensional approach should be adopted to assess outcomes, probably with a composite definition of response to treatment. ClinicalTrials.gov; No.: NCT02273661; URL: www.clinicaltrials.gov) [ABSTRACT FROM AUTHOR]

Background and Objective: Variants in surfactant genes SFTPC or ABCA3 are responsible for interstitial lung disease (ILD) in children and adults, with few studies in adults. Methods: We conducted a multicentre retrospective study of all consecutive adult patients diagnosed with ILD associated with variants in SFTPC or ABCA3 in the French rare pulmonary diseases network, OrphaLung. Variants and chest computed tomography (CT) features were centrally reviewed. Results: We included 36 patients (median age: 34 years, 20 males), 22 in the SFTPC group and 14 in the ABCA3 group. Clinical characteristics were similar between groups. Baseline median FVC was 59% ([52–72]) and DLco was 44% ([35–50]). An unclassifiable pattern of fibrosing ILD was the most frequent on chest CT, found in 85% of patients, however with a distinct phenotype with ground‐glass opacities and/or cysts. Nonspecific interstitial pneumonia and usual interstitial pneumonia were the most common histological patterns in the ABCA3 group and in the SFTPC group, respectively. Annually, FVC and DLCO declined by 1.87% and 2.43% in the SFTPC group, respectively, and by 0.72% and 0.95% in the ABCA3 group, respectively (FVC, p = 0.014 and DLCO, p = 0.004 for comparison between groups). Median time to death or lung transplantation was 10 years in the SFTPC group and was not reached at the end of follow‐up in the ABCA3 group. Conclusion: SFTPC and ABCA3‐associated ILD present with a distinct phenotype and prognosis. A radiologic pattern of fibrosing ILD with ground‐glass opacities and/or cysts is frequently found in these rare conditions. [ABSTRACT FROM AUTHOR]

Purpose: Associations between systemic glucocorticoid (SGC) exposure and risk for adverse outcomes have spurred a move toward steroid-sparing treatment strategies. Real-world changes in SGC exposure over time, after the introduction of steroid-sparing treatment strategies, reveal areas of successful risk mitigation as well as unmet needs. Patients and Methods: A population-based ecological study was performed from the Optimum Patient Care Research Database to describe SGC prescribing trends of steroid-sparing treatment strategies in primary care practices before and after licensure of biologics in the United Kingdom from 1990 to 2019. Each analysis year included patients aged ≥ 5 years who were registered for ≥ 1 year with a participating primary care practice. The primary analysis was SGC exposure, defined as total cumulative SGC dose per patient per year, for asthma, severe asthma, chronic obstructive pulmonary disease (COPD), nasal polyps, Crohn's disease, rheumatoid arthritis, ulcerative colitis, and systemic lupus erythematosus. Secondary outcomes were percentages of patients prescribed SGCs and number of SGC prescriptions per patient per year. Results: The number of patients who met study inclusion criteria ranged from 219,862 (1990) to 1,261,550 (2019). At the population level, patients with asthma or COPD accounted for 67.7% to 73.2% of patients per year with an SGC prescription. Over three decades, decreases in SGC total yearly dose ≥ 1000 mg have been achieved in multiple conditions. Patients with COPD prescribed SGCs increased from 5.8% (1990) to 34.8% (2017). SGC prescribing trends for severe asthma, Crohn's disease, and ulcerative colitis show decreased prescribing trends after the introduction of biologics. Conclusion: Decreases in total yearly SGC doses have been shown in multiple conditions; however, for conditions such as severe asthma and COPD, an unmet need remains for increased awareness of SGC burden and the adoption or development of SGC-sparing alternatives to reduce overuse. [ABSTRACT FROM AUTHOR]

Objectives: COVID-19 pandemic seems to be under control. However, despite the vaccines, 5 to 10% of the patients with mild disease develop moderate to critical forms with potential lethal evolution. In addition to assess lung infection spread, chest CT helps to detect complications. Developing a prediction model to identify at-risk patients of worsening from mild COVID-19 combining simple clinical and biological parameters with qualitative or quantitative data using CT would be relevant to organizing optimal patient management. Methods: Four French hospitals were used for model training and internal validation. External validation was conducted in two independent hospitals. We used easy-to-obtain clinical (age, gender, smoking, symptoms' onset, cardiovascular comorbidities, diabetes, chronic respiratory diseases, immunosuppression) and biological parameters (lymphocytes, CRP) with qualitative or quantitative data (including radiomics) from the initial CT in mild COVID-19 patients. Results: Qualitative CT scan with clinical and biological parameters can predict which patients with an initial mild presentation would develop a moderate to critical form of COVID-19, with a c-index of 0.70 (95% CI 0.63; 0.77). CT scan quantification improved the performance of the prediction up to 0.73 (95% CI 0.67; 0.79) and radiomics up to 0.77 (95% CI 0.71; 0.83). Results were similar in both validation cohorts, considering CT scans with or without injection. Conclusion: Adding CT scan quantification or radiomics to simple clinical and biological parameters can better predict which patients with an initial mild COVID-19 would worsen than qualitative analyses alone. This tool could help to the fair use of healthcare resources and to screen patients for potential new drugs to prevent a pejorative evolution of COVID-19. Clinical Trial Registration: NCT04481620. Clinical relevance statement: CT scan quantification or radiomics analysis is superior to qualitative analysis, when used with simple clinical and biological parameters, to determine which patients with an initial mild presentation of COVID-19 would worsen to a moderate to critical form. Key Points: • Qualitative CT scan analyses with simple clinical and biological parameters can predict which patients with an initial mild COVID-19 and respiratory symptoms would worsen with a c-index of 0.70. • Adding CT scan quantification improves the performance of the clinical prediction model to an AUC of 0.73. • Radiomics analyses slightly improve the performance of the model to a c-index of 0.77. [ABSTRACT FROM AUTHOR]

Background: Dupilumab, a human monoclonal antibody, blocks the shared receptor component for interleukins‐4/13, key and central drivers of type 2 inflammation. The TRAVERSE (NCT02134028) open‐label extension study demonstrated the long‐term safety and efficacy of dupilumab in patients ≥12 years who completed a previous dupilumab asthma study. The safety profile was consistent with that observed in the parent studies. Here, we assess whether dupilumab sustains long‐term efficacy in patients regardless of inhaled corticosteroid (ICS) dose at parent study baseline (PSBL). Methods: Patients from phase 2b (NCT01854047) or phase 3 (QUEST; NCT02414854) studies receiving high‐ or medium‐dose ICS at PSBL and enrolled in TRAVERSE were included. We analyzed unadjusted annualized severe exacerbation rates, change from PSBL in pre‐bronchodilator (BD) forced expiratory volume in 1 second (FEV1), 5‐item asthma control questionnaire, and type 2 biomarkers in patients with type 2 asthma at baseline (blood eosinophils ≥150 cells/μL or fractional exhaled nitric oxide [FeNO] ≥25 ppb), and subgroups defined by baseline blood eosinophils or FeNO. Results: Of patients with type 2 asthma (n = 1666), 891 (53.5%) were receiving high‐dose ICS at PSBL. In this subgroup, unadjusted exacerbation rates for dupilumab versus placebo were 0.517 versus 1.883 (phase 2b) and 0.571 versus 1.300 (QUEST) over the parent study (52 weeks) and remained low throughout TRAVERSE (0.313–0.494). Improvements in pre‐BD FEV1 were sustained throughout TRAVERSE. Similar clinical efficacy was observed among patients receiving medium‐dose ICS at PSBL and biomarker subgroups. Conclusions: Dupilumab showed sustained efficacy for up to 3 years in patients with uncontrolled, moderate‐to‐severe type 2 asthma on high‐ or medium‐dose ICS. [ABSTRACT FROM AUTHOR]

To identify patients treated with Bx/TSD from a dynamic dispensing database using an algorithm-based methodology.Methods: We used the LRx database (Lifelink Treatment dynamics, IQVIA) which covers nearly 45% of the French retail pharmacies. Patients who had at least one Bx/TSD dispensing from April 2021 to March 2022 were included. An algorithm was designed to determine the indication of the Bx/TSD prescription analyzing all previous drug dispensation since March 2012 following a 3-steps procedure.Results: A total of 21,677 patients received at least one Bx/TSD between March 2021 and April 2022. The algorithm identified 91.7% (n = 19,884) patients with a T2 disease (AD = 18.4%, CRSwNP = 1.5%, SA = 59.5%, and CSU = 12.4%), the rest having either an association of diseases (1%) or an undetermined one (7.3%). SA was the main reason for Bx/TSD initiation (52%), followed by AD (29%), CSU (14%) and CRSwNP (5%). For SA patients already under biologic at entry, omalizumab was the most frequently prescribed (48%) followed by benralizumab, mepolizumab (22% each) and dupilumab (8%). Dupilumab was mostly prescribed for AD patients (89% for patient-initiated vs 96% for patient-renewed) followed by baricitinib.Conclusion: The algorithm was able to identify patients with T2 diseases under Bx/TSD treatments. This tool may help to follow the evolution of prescription patterns in the future.Plain Language Summary: Nowadays, physicians have a choice of multiple biologics. Although some prospective cohorts of patients receiving those therapeutics exist, there are very few large up-to-date databases. Our algorithm based on a nationwide dynamic dispensing database was able to identify the T2 diseases of patients under biologics or targeted synthetic drugs and to characterize this population. This is a step toward a better understanding and monitoring of prescription patterns in a nationwide setting. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is the second most frequent tumor worldwide. In cases of pulmonary artery invasion, arterial sleeve lobectomy has progressively gained acceptance as an advantageous alternative to pneumonectomy, but few studies have considered lung perfusion and respiratory function. This single-center retrospective cohort study aimed to assess the impact of arterial reconstruction techniques on lung perfusion and respiratory function. Between January 2001 and December 2020, a comparative analysis of 48 patients' preoperative and postoperative functional outcomes (FEV1) and 28 patients' preoperative and postoperative lung perfusion results was conducted. Regardless of the type of vascular reconstruction, the study revealed no significant difference between the perfusion ratio of the remaining parenchyma before and after surgery. Moreover, arterial reconstruction did not negatively affect the expected postoperative respiratory function. Arterial sleeve lobectomy is a valid parenchymal-sparing technique in terms of perfusion and respiratory function. Background: The aim of this single-center retrospective cohort study was to assess the impact of arterial reconstruction technique on lung perfusion. The second objective was to ascertain the functional validity of arterial sleeve lobectomy. Method: Between January 2001 and December 2020, a total of 81 patients underwent lobectomy with pulmonary artery (PA) reconstruction for lung cancer at the University Hospital of Montpellier. After excluding patients with an incomplete postoperative pulmonary function test, we conducted a comparative analysis of the preoperative and postoperative functional outcomes (FEV1) of 48 patients, as well as the preoperative and postoperative Technetium99m scintigraphic pulmonary perfusion results of 28 patients. Then, we analyzed postoperative perfusion results according to the pulmonary artery reconstruction techniques use. Results: PA reconstruction types were as follows: 9 direct angioplasties (19%), 14 patch angioplasties (29%), 7 end-to-end anastomoses (15%), 6 prosthetic bypasses (12%), 11 arterial allograft bypasses (23%), and 1 custom-made xenopericardial conduit bypass. Regardless of the type of vascular reconstruction performed, the comparative analysis of lung perfusion revealed no significant difference between the preoperative and postoperative perfusion ratio of the remaining parenchyma (median = 29.5% versus 32.5%, respectively; p = 0.47). Regarding the pulmonary functional test, postoperative predicted FEV1 significantly underestimated the actual postoperative measured FEV1 by about 260 mL (11.4%) of the preoperative value. The patency rate was 96% and the 5-year overall survival was 49% for a mean follow up period of 34 months. Conclusion: Lobectomy with PA reconstruction is a valid parenchymal-sparing technique in terms of perfusion and respiratory function. [ABSTRACT FROM AUTHOR]

Objective Pulmonary arterial hypertension (PAH) is a leading cause of death in MCTD. We aimed to describe PAH in well-characterized MCTD patients. Methods MCTD patients enrolled in the French Pulmonary Hypertension Registry with a PAH diagnosis confirmed by right heart catheterization were included in the study and compared with matched controls: MCTD patients without PAH, SLE patients with PAH and SSc patients with PAH. Survival rates were estimated by the Kaplan–Meier method and risk factors for PAH in MCTD patients and risk factors for mortality in MCTD-PAH were sought using multivariate analyses. Results Thirty-six patients with MCTD-PAH were included in the study. Comparison with MCTD patients without PAH and multivariate analysis revealed that pericarditis, polyarthritis, thrombocytopenia, interstitial lung disease (ILD) and anti-Sm antibodies were independent predictive factors of PAH/PH in MCTD. Estimated survival rates at 1, 5 and 10 years following PAH diagnosis were 83%, 67% and 56%, respectively. MCTD-PAH presentation and survival did not differ from SLE-PAH and SSc-PAH. Multivariate analysis revealed that tobacco exposure was an independent factor predictive of mortality in MCTD-PAH. Conclusion PAH is a rare and severe complication of MCTD associated with a 56% 10-year survival. We identified ILD, pericarditis, thrombocytopenia and anti-Sm antibodies as risk factors for PAH in MCTD and tobacco exposure as a predictor of mortality in MCTD-PAH. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease involving airway closure and parenchyma destruction (emphysema). Cardiovascular diseases are the main causes of morbi-mortality in COPD and, in particular, hypertension and heart failure with preserved ejection fraction (HFpEF). However, no mechanistic link has currently been established between the onset of COPD, elevated blood pressure (BP) and systemic vascular impairment (endothelial dysfunction). Thus, we aimed to characterize BP and vascular function and remodeling in a rat model of exacerbated emphysema focusing on the role of sympathetic hyperactivity. Emphysema was induced in male Wistar rats by four weekly pulmonary instillations of elastase (4UI) and exacerbation by a single dose of lipopolysaccharides (LPS). Five weeks following the last instillation, in vivo and ex vivo cardiac and vascular functions were investigated. Exacerbated emphysema induced cardiac dysfunction (HFpEF) and a BP increase in this COPD model. We observed vasomotor changes and hypotrophic remodeling of the aorta without endothelial dysfunction. Indeed, changes in contractile and vasorelaxant properties, though endothelium-dependent, were pro-relaxant and NO-independent. A β1-receptor antagonist (bisoprolol) prevented HFpEF and vascular adaptations, while the effect on BP increase was partial. Endothelial dysfunction would not trigger hypertension and HFpEF in COPD. Vascular changes appeared as an adaptation to the increased BP. The preventing effect of bisoprolol revealed a pivotal role of sympathetic hyperactivation in BP elevation. The mechanistic link between HFpEF, cardiac sympathetic activation and BP deserves further studies in this exacerbated-emphysema model, as well as in COPD patients. [ABSTRACT FROM AUTHOR]

Nasal polyps, T2 inflammation, Chronic Rhinosinusitis, Tezepelumab, biologics, asthma, eosinophils Targeting T2 inflammation in CRSwNP, and especially TSLP, may reverse structural changes such as nasal polyps through the "reprogramming" of structural cells and their interaction with the environment. Keywords: Chronic Rhinosinusitis; nasal polyps; T2 inflammation; Tezepelumab; biologics; asthma; eosinophils EN Chronic Rhinosinusitis nasal polyps T2 inflammation Tezepelumab biologics asthma eosinophils 821 825 5 07/31/23 20230801 NES 230801 1. Recent cases in the literature report the combination of biologics in severe asthma, either to reach a better control of asthma in poor controlled severe asthma patients or insufficiently controlled associated comorbidities such as CRSwNP. [Extracted from the article]

Airway–liquid interface cultures of primary epithelial cells and of induced pluripotent stem-cell-derived airway epithelial cells (ALI and iALI, respectively) are physiologically relevant models for respiratory virus infection studies because they can mimic the in vivo human bronchial epithelium. Here, we investigated gene expression profiles in human airway cultures (ALI and iALI models), infected or not with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), using our own and publicly available bulk and single-cell transcriptome datasets. SARS-CoV-2 infection significantly increased the expression of interferon-stimulated genes (IFI44, IFIT1, IFIT3, IFI35, IRF9, MX1, OAS1, OAS3 and ISG15) and inflammatory genes (NFKBIA, CSF1, FOSL1, IL32 and CXCL10) by day 4 post-infection, indicating activation of the interferon and immune responses to the virus. Extracellular matrix genes (ITGB6, ITGB1 and GJA1) were also altered in infected cells. Single-cell RNA sequencing data revealed that SARS-CoV-2 infection damaged the respiratory epithelium, particularly mature ciliated cells. The expression of genes encoding intercellular communication and adhesion proteins was also deregulated, suggesting a mechanism to promote shedding of infected epithelial cells. These data demonstrate that ALI/iALI models help to explain the airway epithelium response to SARS-CoV-2 infection and are a key tool for developing COVID-19 treatments. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a clinical entity of increasing significance. COPD involves abnormalities of the airways and, in emphysema, parenchymal pulmonary destruction. Cardiovascular disease has emerged as a significant comorbidity to COPD. Heart failure with preserved ejection fraction (HFpEF) appears to be particularly associated with COPD-emphysema. Traditional treatments have shown limited efficacy in improving COPD-associated HFpEF. This lack of therapeutic efficacy highlights the need to identify potential mechanisms that link COPD-emphysema to HFpEF. Therefore, we aimed to study the delayed cardiac physiological impacts in a rat model with acute exacerbated emphysema. Emphysema was induced by four weekly 4 units elastase (ELA) intratracheal pulmonary instillations and exacerbation by one final additional lipolysaccharide (LPS) instillation in male Wistar rats. At 5 weeks after the ELA and LPS exposure, in vivo and ex vivo pulmonary and cardiac measurements were performed. Experimental exacerbated emphysema resulted in decreased pulmonary function and exercise intolerance. Histological analysis revealed parenchymal pulmonary destruction without signs of inflammation or cardiac fibrosis. In vivo cardiac functional analysis revealed diastolic dysfunction and tachycardia. Ex vivo analysis revealed a cellular cardiomyopathy with decreased myofilament Ca2+ sensitivity, cross-bridge cycling kinetics, and increased adrenergic PKA (protein kinase A)-dependent phosphorylation of troponin-I. Experimental exacerbated emphysema was associated with exercise intolerance that appeared to be secondary to increased β-adrenergic tone and subsequent cardiac myofilament dysfunction. A β1-receptor antagonist treatment (bisoprolol) started 24 hours after ELA-LPS instillation prevented in vivo and ex vivo diastolic dysfunction. These results suggest that novel treatment strategies targeted to the cardiac myofilament may be beneficial to combat exacerbated emphysema–associated HFpEF. [ABSTRACT FROM AUTHOR]

Epithelial cytokines are involved in the orchestration of T1/T2 inflammatory patterns. We question the persistence of this trait in air–liquid interface (ALI) epithelial cultures and whether this local orientation can be related to systemic patterns (e.g., blood eosinophil counts [BECs]). We investigated alarmin release related to high versus low T2 phenotypes associated with chronic airway diseases. ALIs were reconstituted from 32 control, 40 chronic obstructive pulmonary disease, and 20 asthmatic patients. Interleukin‐8 (IL‐8; a T1‐cytokine), IL‐25, IL‐33, and thymic stromal lymphopoietin (T2‐alarmins) concentrations were assessed in subnatants at steady state and used to explain blood neutrophil and eosinophil counts. IL‐25 and IL‐8 levels were highest in asthma ALI‐subnatants, whereas IL‐33 was sparsely detected. Thymic stromal lymphopoietin levels were similar among groups. All asthma cell cultures were T1‐high/T2‐high, while chronic obstructive pulmonary disease and controls tended to be mixed. BECs were independently explained by both disease and in‐culture T2‐alarmin levels, irrespective of the T2‐alarmin considered. The epithelial ALI‐T2 signature was more frequently high in patients with a BEC > 300/mm3. Despite removal from an in vivo environment for ≥2 months, ALIs release disease‐specific cytokine "cocktails" into their subnatants, suggesting continued persistence of alarmin orientation in differentiated cell line environments. [ABSTRACT FROM AUTHOR]

An algorithm to describe patterns of intermittent oral corticosteroid use in the UK (n = 476,167) found that one-third of patients receiving intermittent oral corticosteroids for asthma only had short gaps (<90 days) between oral corticosteroid prescriptions sometime during follow-up. The increasing frequency pattern was more likely in patients with greater asthma severity and with more short-acting β2-agonist use at baseline. Our approach may provide a clinically relevant representation of intermittent oral corticosteroid use in asthma. [ABSTRACT FROM AUTHOR]

(1) Background: We have previously shown that sputum rheology can discriminate between patients with COPD and other muco-obstructive lung diseases, and that it is correlated with mucin content and sputum eosinophilia. We now hypothesize that it could be a more-accurate guide than clinical evaluation for the prescription of azithromycin to prevent exacerbations of COPD and to reduce exposure to antibiotics; (2) Methods: "COPD CaRhe" is a multicentric, randomized, controlled trial comparing outcomes in two parallel arms (36 vs. 36 patients). Patients will be recruited in the university hospitals of Montpellier, Bordeaux, and Toulouse, in France, and they should have a diagnosis of COPD with frequent exacerbations (≥3/year). Enrollment will occur during a routine visit to a respiratory department, and follow-up visits will occur every 3 months for a period of 1 year. At each visit, a 3-month prescription of azithromycin will be provided to those patients who obtain a score of <70 on the Cough and Sputum Assessment Questionnaire (CASA-Q) or a critical stress score of σc > 39 on a rheological assessment of sputum, depending upon their randomization group. The primary outcome will be the number of exacerbations of COPD; (3) Discussion: By using sputum rheology, the COPD CaRhe study may provide clinicians with an objective biomarker to guide the prescription of azithromycin while reducing the cumulative exposure to macrolides. [ABSTRACT FROM AUTHOR]

Background: Obesity is known to diminish lung volumes and worsen asthma. However, mechanistic understanding is lacking, especially as concerns small‐airway responsiveness. The objective of this study was therefore to compare small‐airway responsiveness, as represented by the change in expiratory:inspiratory mean lung density ratios (MLDe/i, as determined by computed tomography [CT]) throughout methacholine testing in obese versus non‐obese women with asthma. Methods: Thoracic CT was performed during methacholine bronchoconstriction challenges to produce standardized response curves (SRC: response parameter versus ln[1 + % PD20], where PD20 is the cumulative methacholine dose) for 31 asthma patients (n = 18 non‐obese and n = 13 obese patients). Mixed models evaluated obesity effects and interactions on SRCs while adjusting for age and bronchial morphology. Small airway responsiveness as represented by SRC slope was calculated for each third of the MLDe/i response and compared between groups. Results: Obesity‐associated effects observed during experimental bronchoconstriction included: (i) a significant baseline effect for forced expiratory volume in 1 second with lower values for the obese (73.11 ± 13.44) versus non‐obese (82.19 ± 8.78; p = 0.002) groups prior to methacholine testing and (ii) significantly higher responsiveness in small airways as estimated via differences in MLDe/i slopes (group×ln(1 + % PD20 interaction; p = 0.023). The latter were pinpointed to higher slopes in the obese group at the beginning 2/3 of SRCs (p = 0.004 and p = 0.021). Significant obesity effects (p = 0.035 and p = 0.008) indicating lower forced vital capacity and greater % change in MLDe/I (respectively) throughout methacholine testing, were also observed. Conclusion: In addition to baseline differences, small‐airway responsiveness (as represented by the change in MLDe/i) during methacholine challenge is greater in obese women with asthma as compared to the non‐obese. [ABSTRACT FROM AUTHOR]

Background: Biological therapies have revolutionized the treatment of severe asthma with type 2 inflammation. Although such treatments are very effective in reducing exacerbation and the dose of oral steroids, little is known about the persistence of symptoms in severe asthma patients treated with biologics. Purpose: We aim to describe asthma control and healthcare consumption of severe asthma patients treated with biologics. Design: The Second Souffle study is a real-life prospective observational study endorsed by the Clinical Research Initiative in Severe Asthma: a Lever for Innovation & Science Network. Methods: Adults with a confirmed diagnosis of severe asthma for at least 12 months' duration were enrolled in the study. A self-administered questionnaire including the Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire (AQLQ) and a compliance evaluation test was given to the patients. Healthcare consumption within 12 months prior to enrolment was documented. In patients receiving biologics, doctors indicated whether the patients were biologic responders or non-responders. Results: The characteristics of 431 patients with severe asthma were analysed. Among them, 409 patients (94.9%) presented asthma with type 2 inflammation (T2 high) profile, and 297 (72.6%) patients with a T2 high phenotype were treated with a biologic. Physicians estimated that 88.2% of patients receiving biologics were responders. However, asthma control was only achieved in 25.3% of those patients (ACQ > 0.75). A high proportion of patients (77.8%) identified as responders to biologics were not controlled according to the ACQ score. About 50% of patients continue to use oral corticosteroids either daily (25.2%) or more than three times a year for at least three consecutive days (25.6%). Gastro-oesophageal Reflux Disease (GERD) and Obstructive Sleep Apnoea syndrome (OSA) were identified as independent factors associated with uncontrolled asthma. Conclusion: Although a high proportion of severe asthma patients respond to biologics, only 25.3% have controlled asthma. GERD and OSA are independent factors of uncontrolled asthma. [ABSTRACT FROM AUTHOR]

The GINA Science Committee consists of highly skilled and experienced asthma experts, who continually review and synthesize scientific evidence to provide guidance on asthma prevention, diagnosis and management. Global initiative for asthma: 30 years of promoting evidence-based asthma care The GINA Board of Directors has a global geographic representation and draws its membership from leaders with an outstanding demonstrated commitment to asthma research, asthma clinical management, public health and patient advocacy. Asthma is a serious global health problem affecting all age groups. [Extracted from the article]

Objective: Novel biomarkers related to main clinical hallmarks of Chronic obstructive pulmonary disease (COPD), a heterogeneous disorder with pulmonary and extra-pulmonary manifestations, were investigated by profiling the serum levels of 1305 proteins using Slow Off-rate Modified Aptamers (SOMA)scan technology. Methods: Serum samples were collected from 241 COPD subjects in the multicenter French Cohort of Bronchial obstruction and Asthma to measure the expression of 1305 proteins using SOMAscan proteomic platform. Clustering of the proteomics was applied to identify disease subtypes and their functional annotation and association with key clinical parameters were examined. Cluster findings were revalidated during a follow-up visit, and compared to those obtained in a group of 47 COPD patients included in the Melbourne Longitudinal COPD Cohort. Results: Unsupervised clustering identified two clusters within COPD subjects at inclusion. Cluster 1 showed elevated levels of factors contributing to tissue injury, whereas Cluster 2 had higher expression of proteins associated with enhanced immunity and host defense, cell fate, remodeling and repair and altered metabolism/mitochondrial functions. Patients in Cluster 2 had a lower incidence of exacerbations, unscheduled medical visits and prevalence of emphysema and diabetes. These protein expression patterns were conserved during a follow-up second visit, and substanciated, by a large part, in a limited series of COPD patients. Further analyses identified a signature of 15 proteins that accurately differentiated the two COPD clusters at the 2 visits. Conclusions: This study provides insights into COPD heterogeneity and suggests that overexpression of factors involved in lung immunity/host defense, cell fate/repair/ remodelling and mitochondrial/metabolic activities contribute to better clinical outcomes. Hence, high throughput proteomic assay offers a powerful tool for identifying COPD endotypes and facilitating targeted therapies. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) restore immune response against cancer cells that can lead to immune-related adverse effects. While cardiovascular immune-related adverse effects are known to be associated with checkpoint inhibitors, recent case reports have raised concerns about the potential association with pulmonary hypertension (PH). By using the global pharmacovigilance database VigiBase, we investigated the onset of PH associated with ICI and propose a comprehensive description of the 42 cases of PH reported with ICI recorded in this database. Through this study and review of the cases published in the literature, we discuss the possible link between PH and ICI in the context of cancer in order to better understand this rare but potentially fatal event. [ABSTRACT FROM AUTHOR]

Background: Many severe asthma patients with high oral corticosteroid exposure (HOCS) often do not initiate biologics despite being eligible. This study aimed to compare the characteristics of severe asthma patients with HOCS who did and did not initiate biologics. Methods: Baseline characteristics of patients with HOCS (long-term maintenance OCS therapy for at least 1 year, or ≥ 4 courses of steroid bursts in a year) from the International Severe Asthma Registry (ISAR; https://isaregistries.org/), who initiated or did not initiate biologics (anti-lgE, anti-IL5/5R or anti-IL4R), were described at the time of biologic initiation or registry enrolment. Statistical relationships were tested using Pearson's chi-squared tests for categorical variables, and t-tests for continuous variables, adjusting for potential errors in multiple comparisons. Results: Between January 2015 and February 2021, we identified 1412 adult patients with severe asthma from 19 countries that met our inclusion criteria of HOCS, of whom 996 (70.5%) initiated a biologic and 416 (29.5%) did not. The frequency of biologic initiation varied across geographical regions. Those who initiated a biologic were more likely to have higher blood eosinophil count (483 vs 399 cells/μL, p=0.003), serious infections (49.0% vs 13.3%, p< 0.001), nasal polyps (35.2% vs 23.6%, p< 0.001), airflow limitation (56.8% vs 51.8%, p=0.013), and uncontrolled asthma (80.8% vs 73.2%, p=0.004) despite greater conventional treatment adherence than those who did not start a biologic. Both groups had similar annual asthma exacerbation rates in the previous 12 months (5.7 vs 5.3, p=0.147). Conclusion: Around one third of severe HOCS asthma patients did not receive biologics despite a similar high burden of asthma exacerbations as those who initiated a biologic therapy. Other disease characteristics such as eosinophilic phenotype, serious infectious events, nasal polyps, airflow limitation and lack of asthma control appear to dictate biologic use. [ABSTRACT FROM AUTHOR]

Introduction: Discriminating asthma from chronic obstructive pulmonary disease (COPD) using medico-administrative databases is challenging but necessary for medico-economic analyses focusing on respiratory diseases. Artificial intelligence (AI) may improve dedicated algorithms.Objectives: To assess performance of different AI-based approaches to distinguish asthmatics from COPD patients in medico-administrative databases where the clinical diagnosis is absent. An "Asthma COPD Overlap" category was defined to further test whether AI can detect complexity.Methods: This study included 178,962 patients treated by two "R03" treatment prescriptions at least from January 2016 to December 2018 and managed by either a general practitioner and/or a pulmonologist participating in a permanent longitudinal observatory of prescription in ambulatory medicine (LPD). Clinical diagnoses are available in this database and were used as gold standards to develop diagnostic rules. Three types of AI approaches were explored using data restricted to demographics and treatment dispensations: multinomial regression, gradient boosting and recurrent neural networks (RNN). The best performing model (based on metric properties) was then applied to estimate the size of asthma and COPD populations based on a database (LRx) of treatment dispensations between July, 2018 and June, 2019.Results: The best models were obtained with the boosting approach and RNN, with an overall accuracy of 68%. Performance metrics were better for asthma than COPD. Based on LRx data, the extrapolated numbers of patients treated for asthma and COPD in France were 3.7 and 1.2 million, respectively. Asthma patients were younger than COPD patients (mean, 49.9 vs. 72.1 years); COPD occurred mostly in men (68%) compared to asthma (33%).Conclusion: AI can provide models with acceptable accuracy to distinguish between asthma, ACO and COPD in medico-administrative databases where the clinical diagnosis is absent. Deep learning and machine learning (RNN) had similar performances in this regard. [ABSTRACT FROM AUTHOR]

Despite increasing insight into the genetics of infertility, the developmental disease processes remain unclear due to the lack of adequate experimental models. The advent of induced pluripotent stem cell (iPSC) technology has provided a unique tool for in vitro disease modeling enabling major advances in our understanding of developmental disease processes. We report the full characterization of complex genetic abnormalities in two infertile patients with either azoospermia or XX male syndrome and we identify genes of potential interest implicated in their infertility. Using the erythroblasts of both patients, we generated primed iPSCs and converted them into a naive-like pluripotent state. Naive-iPSCs were then differentiated into primordial germ-like cells (PGC-LCs). The expression of early PGC marker genes SOX17, CD-38, NANOS3, c-KIT, TFAP2C, and D2-40, confirmed progression towards the early germline stage. Our results demonstrate that iPSCs from two infertile patients with significant genetic abnormalities are capable of efficient production of PGCs. Such in vitro model of infertility will certainly help identifying causative factors leading to early germ cells development failure and provide a valuable tool to explore novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Oral corticosteroids (OCS) have long been a mainstay of treatment for asthma exacerbations and chronic severe asthma. However, it is increasingly recognized that both long-term and short-term OCS use are directly associated with a wide range of serious adverse effects, and as such OCS-sparing treatment alternatives are now widely recommended for patients with severe asthma. While several international guidelines recommend these treatments, guidance on OCS tapering, and which patients are most likely to tolerate OCS reduction and/or discontinuation, is still lacking. Several biologics have demonstrated efficacy in patients with OCS-dependent asthma. One OCS-sparing treatment is the anti-interleukin-5 monoclonal antibody mepolizumab, which is approved for the treatment of severe eosinophilic asthma. In addition to improved exacerbation rates, asthma control, quality of life, and lung function among patients with severe eosinophilic asthma, mepolizumab also has an OCS-sparing effect, which has been demonstrated in randomized controlled trials and real-world studies. Both physicians and patients express concerns about the adverse effects of OCS, and additional data from the randomized, controlled SIRIUS trial (NCT01691508) highlight the high level of concern among patients regarding OCS-related burden. In this article, we discuss current guidance on OCS-sparing strategies for patients with severe asthma, provide a summary of the available evidence of the OCS-sparing effect of mepolizumab, and highlight patient and physician perspectives on the use of OCS and OCS-sparing treatments in severe asthma. [ABSTRACT FROM AUTHOR]

Background: Chronic Obstructive Pulmonary Disease (COPD), a major cause of mortality and disability, is a complex disease with heterogeneous and ill-understood biological mechanisms. Human induced pluripotent stem cells (hiPSCs) are a promising tool to model human disease, including the impact of genetic susceptibility. Methods: We developed a simple and reliable method for reprogramming peripheral blood mononuclear cells into hiPSCs and to differentiate them into air–liquid interface bronchial epithelium within 45 days. Importantly, this method does not involve any cell sorting step. We reprogrammed blood cells from one healthy control and three patients with very severe COPD. Results: The mean cell purity at the definitive endoderm and ventral anterior foregut endoderm (vAFE) stages was >80%, assessed by quantifying C-X-C Motif Chemokine Receptor 4/SRY-Box Transcription Factor 17 (CXCR4/SOX17) and NK2 Homeobox 1 (NKX2.1) expression, respectively. vAFE cells from all four hiPSC lines differentiated into bronchial epithelium in air–liquid interface conditions, with large zones covered by beating ciliated, basal, goblets, club cells and neuroendocrine cells, as found in vivo. The hiPSC-derived airway epithelium (iALI) from patients with very severe COPD and from the healthy control were undistinguishable. Conclusions: iALI bronchial epithelium is ready for better understanding lung disease pathogenesis and accelerating drug discovery. [ABSTRACT FROM AUTHOR]

Background: The forced vital capacity (FVC) of healthy individuals depends on their age, sex, ethnicity and height. Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterised by loss of FVC. We compared FVC values in the subjects with SSc-ILD in the SENSCIS trial of nintedanib versus placebo with values from hypothetical matched healthy references.Methods: The SENSCIS trial enrolled subjects with SSc with first non-Raynaud symptom in the prior ≤ 7 years, extent of fibrotic ILD on HRCT ≥ 10%, and FVC ≥ 40% predicted. FVC at baseline and decline in FVC over 52 weeks were compared with FVC values in hypothetical healthy reference subjects matched 1:1 to the subjects in the trial for age, sex, ethnicity and height, determined using equations published by the European Respiratory Society Global Lung Function Initiative.Results: At baseline, mean (SD) FVC was 2460 (737) mL in the nintedanib group (n = 287) compared with 3403 (787) mL in the hypothetical matched healthy references. Mean (SD) FVC was 2544 (817) mL in the placebo group (n = 286) compared with 3516 (887) mL in the hypothetical matched healthy references. Mean (SE) changes in FVC at week 52, i.e., age-related loss of lung function, in the hypothetical healthy references matched to the nintedanib and placebo groups, respectively, were - 26.3 (0.5) mL and - 25.8 (0.5) mL. The difference in the change in FVC at week 52 between the nintedanib group and the hypothetical healthy references was 26.6 mL (95% CI: 1.2, 52.0; p = 0.04). The difference in the change in FVC at week 52 between the placebo group and the hypothetical healthy references was 77.5 mL (95% CI: 51.4, 103.7; p < 0.0001).Conclusions: Subjects with SSc-ILD in the SENSCIS trial had impaired lung function at baseline and experienced further deterioration over 52 weeks. The decline in FVC in the placebo group was four-fold greater than in a hypothetical group of matched healthy references, whereas the decline in FVC in patients who received nintedanib was two-fold greater than in hypothetical healthy references. These data highlight the clinical relevance of the slowing of FVC decline provided by nintedanib. Trial registration Registered 5 November 2015, https://clinicaltrials.gov/ct2/show/NCT02597933 . [ABSTRACT FROM AUTHOR]

Objectives: We analyzed the results of the QuantiFERON Glod Plus assay (QFT) and cytokine patterns associated with active tuberculosis (ATB) among patients with positive QFT. Methods: A total of 195 patients are QFT-positive, among which 24 had an ATB and 171 had a latent tuberculosis infection (LTBI). Interferon-gamma (IFN-γ) secretion was analyzed relative to interleukin-2 (IL-2), IFN-γ inducible protein or CXCL-10 (IP-10), and monokine induced by IFN-γ or CXCL-9 (MIG) secretion, and then compared between two sets of peptide antigens [tube 1 - cluster of differentiation 4 (CD4+) T cell stimulation; tube 2 - CD4+/CD8+ T cell response]. Results: Higher IFN-γ responses were measured in the ATB group (p = 0.0089). The results showed that there was a lower ratio of tube 1/tube 2 IFN-γ concentrations in the ATB group (p = 0.0009), and a median [interquartile ranges (IQR)] difference between the two sets at −0.82 IU/ml (−1.67 to 0.18) vs. −0.07 IU/ml (−0.035 to 0.11, p < 0.0001) in the ATB group compared to the LTBI group, respectively. In addition, patients with low ratios of IL-2/IFN-γ, IP-10/IFN-γ, and MIG/IFN-γ were much more likely to have ATB. Conclusion: High levels of IFN-γ secretion, preferential IFN-γ response in tube 2, and lower secretion of IL-2, IP-10, and MIG release relative to IFN-γ secretion were more likely observed in subjects with ATB. These features of T cell response may be helpful in low prevalence settings to suspect ATB in patients tested positive for IFN-γ release assays (IGRA). [ABSTRACT FROM AUTHOR]

Background: Whether the COVID-19 pandemic impacts Positive Airway Pressure (PAP) adherence over the long-term is unknown and only preliminary short-term data have been reported. Methods: With the aim of describing the impact of the first and second waves of COVID-19 on PAP adherence during 2020 in France, we designed a cross-sectional study of Sleep-Apnea (SA)-patients under PAP telemonitoring. To examine PAP adherence in adult SA patients, we assessed de-identified data from a non-profit healthcare provider database during the period January 1, 2019 to December 31, 2020. Included patients met the following criteria: (i) PAP-treated for at least 4 months before January 1, 2019 and with continuous PAP during both 2019 and 2020; (ii) ≥ 360 daily PAP telemonitored data per year. For PAP adherence, data were collected using the PAP-software. Results: 8477/10482 patients were finally included in the analysis [72.4% male, median age 70 years (IQ25–75: 61–77], 25.6% < 62 years old, initial Apnea–Hypopnea Index (AHI) of 41 (31–59)/h. Median PAP adherence was 7.21 (6.12–8.10) h/day in 2020 versus 7.12 (6.05–8.02) h/day in 2019, p < 0.001. The median difference in PAP adherence between the first 2020 lockdown and the corresponding 2019 weeks was 9.75 (CI95% 8.75–10.75) min/day, p < 0.001. The median difference in PAP adherence between the second 2020 lockdown and the corresponding 2019 weeks was 5.00 (CI95% 4.00–6.00) min/day, p < 0.001. If we consider the minimal clinically important difference of 30 min for PAP adherence, 30.4% and 26% of the patients increased their PAP adherence by at least 30 min during the first and second lockdowns respectively; 17.6% and 19.3% of the patients lowered their PAP adherence by at least 30 min in the first and second lockdowns, respectively. Conclusion: During the first and second lockdowns, the COVID-19 pandemic had a clinically irrelevant effect on PAP adherence for the study population. Future studies are needed to describe COVID-19 pandemic impact on PAP adherence not only for long-term PAP-treated SA patients but also for incident cases. Trial registration The COVADENE study was registered on March 1st, 2021 on ClinicalTrials.gov (Identifier: NCT04775966) [ABSTRACT FROM AUTHOR]

Objective: This exploratory cross-sectional study aimed to evaluate the associations between the chemokine ligand 18 (CCL18) blood level and phenotypic characteristics of asthma. Methods: We evaluated in a sample of 173 asthmatic adult patients from the Cohort of Bronchial obstruction and Asthma (63.4% women; median age 50 ± interquartile range 27.5 years; median level of CCL18 was 44.1 ± interquartile range 27.5 ng/mL) the association between CCL18 blood level and allergic features of asthma using a multivariate analysis. Results: We found an association between the log-transformed value of blood CCL18 and age (+0.7% [0.1; 1.3] per 1-year increase, p = 0.033), gender (−25.1% [−42; −3.2] in women, p = 0.029), and nasal polyposis (+38.1% [11.6; 70.9], p = 0.004). No association was observed between CCL18 level and the other main phenotypic characteristics of asthma. Conclusions: Our exploratory study suggests that CCL18 is not an effective biomarker of allergic asthma endotype but may rather be a biomarker of tissue eosinophilia as supported by its association with nasal polyposis. [ABSTRACT FROM AUTHOR]

Effective treatment of inflammatory diseases is often challenging owing to their heterogeneous pathophysiology. Understanding of the underlying disease mechanisms is improving and it is now clear that eosinophils play a complex pathophysiological role in a broad range of type 2 inflammatory diseases. Standard of care for these conditions often still includes oral corticosteroids (OCS) and/or cytotoxic immune therapies, which are associated with debilitating side effects. Selective, biological eosinophil‐reducing agents provide treatment options that improve clinical symptoms associated with eosinophilic inflammation and reduce OCS use. Mepolizumab is a humanized monoclonal antibody that binds to and neutralizes interleukin‐5, the major cytokine involved in eosinophil proliferation, activation, and survival. Mepolizumab is approved for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Additionally, the efficacy of add‐on mepolizumab has been observed in patients with severe chronic rhinosinusitis with nasal polyposis and chronic obstructive pulmonary disease with an eosinophilic phenotype. Here, we review the development, approval, and real‐world effectiveness of mepolizumab for the treatment of patients with severe eosinophilic asthma, from the DREAM to REALITI‐A studies, and describe how knowledge from this journey extended to the use of mepolizumab and other biologics across a broad spectrum of eosinophilic diseases. [ABSTRACT FROM AUTHOR]

Background: The application of CRISPR/Cas9 technology in human induced pluripotent stem cells (hiPSC) holds tremendous potential for basic research and cell-based gene therapy. However, the fulfillment of these promises relies on the capacity to efficiently deliver exogenous nucleic acids and harness the repair mechanisms induced by the nuclease activity in order to knock-out or repair targeted genes. Moreover, transient delivery should be preferred to avoid persistent nuclease activity and to decrease the risk of off-target events. We recently developed bacteriophage-chimeric retrovirus-like particles that exploit the properties of bacteriophage coat proteins to package exogenous RNA, and the benefits of lentiviral transduction to achieve highly efficient, non-integrative RNA delivery in human cells. Here, we investigated the potential of bacteriophage-chimeric retrovirus-like particles for the non-integrative delivery of RNA molecules in hiPSC for CRISPR/Cas9 applications. Results: We found that these particles efficiently convey RNA molecules for transient expression in hiPSC, with minimal toxicity and without affecting the cell pluripotency and subsequent differentiation. We then used this system to transiently deliver in a single step the CRISPR-Cas9 components (Cas9 mRNA and sgRNA) to generate gene knockout with high indel rate (up to 85%) at multiple loci. Strikingly, when using an allele-specific sgRNA at a locus harboring compound heterozygous mutations, the targeted allele was not altered by NHEJ/MMEJ, but was repaired at high frequency using the homologous wild type allele, i.e., by interallelic gene conversion. Conclusions: Our results highlight the potential of bacteriophage-chimeric retrovirus-like particles to efficiently and safely deliver RNA molecules in hiPSC, and describe for the first time genome engineering by gene conversion in hiPSC. Harnessing this DNA repair mechanism could facilitate the therapeutic correction of human genetic disorders in hiPSC. [ABSTRACT FROM AUTHOR]

Introduction: Pirfenidone, an antifibrotic medication for idiopathic pulmonary fibrosis (IPF), is now available in France in two formulations: tablets since April 2018, and the initial capsules form. We conducted a cohort study to describe tolerance and acceptability of capsules and/or tablets of pirfenidone in patients with IPF. Methods: This study was nested within the French, non-randomized, multicenter RaDiCo-ILD (Rare Disease Cohort–Interstitial Lung Diseases). Included patients with IPF received at least one dose of pirfenidone tablets or capsules from July 2017 to June 2019 in three populations: the inclusion population (patients treated at least once with pirfenidone during the study period, n = 288); the potential switch population (patients treated with pirfenidone during the switch period starting April 2018, n = 256); the newly treated population (patients who initiated pirfenidone during the study period, n = 162). Each of those last two populations included three subgroups (tablets, capsules, and substitution). Results: In 288 patients treated, 162 newly initiated pirfenidone during the study period: there were no meaningful differences in the baseline characteristics with the 256 patients treated during the potential switch period. In the newly treated population, 30.3% started pirfenidone treatment with tablet formulation. In the potential switch population, 44.9% of patients shifted from capsule to tablet. Half of the patients shifted to tablet formulation within the first 10 months. The mean treatment duration was 21.5 months with a mean dose of 2106.7 mg/day; 46.5% of patients discontinued treatment, mainly because of adverse events. There were fewer discontinuations in the tablets and substitution subgroups than in the capsules-only subgroup. The most reported adverse event was skin rash (11.5%). No new adverse event was identified. Conclusions: This real-life cohort assessing the characteristics of the prescription of pirfenidone tablets and capsules suggests a good acceptability of the tablet formulation by patients with IPF. Trial Registration: Clinical trial registered with www.clinicaltrials.gov (NCT04238871). [ABSTRACT FROM AUTHOR]

Background: Current practices for assessing response to anti-interleukin 5/R treatment in severe asthma patients are heterogeneous. The objective of this study was to achieve an expert consensus defining failure criteria for anti-interleukin 5/R treatment in severe asthma patients. Methods: Experts were invited to a 5-round Delphi exercise if they were pulmonologists managing ⩾30 patients at a nationally recognized severe asthma expert centre. Following two rounds of statement-generating brainstorming, the expert panel ranked each statement according to a 5-point Likert-type scale during three additional rounds. Positive consensus was considered achieved when ⩾80% of experts agreed with a statement with >50% strong agreement and <15% disagreement. Results: Twenty experts participated in the study. All experts agreed that predefined treatment goals defining effectiveness should be personalized during shared decision making via a patient contract. Treatment failure was defined as (1) absence of a reduction in exacerbation rates by ⩾25% or (2) absence of a reduction in oral corticosteroid therapy by ⩾25% of the initial dosage or (3) occurrence of emergency room visits or hospitalizations after 6 months of treatment. Treatment failure should result in discontinuation. For partial responders, treatment discontinuation was not recommended unless an alternative from another therapeutic class exists and should be discussed in a multidisciplinary consultation. Conclusion: The present study provides objective criteria for anti IL5 or IL5R failure in severe asthma and suggests consensus based guidelines for prescription, evaluation and discontinuation decision-making. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Asthma exacerbations are inflammatory events that rarely result in full hospitalization following an ER visit. Unfortunately, certain patients require prolonged support, including occasional external lung support through ECMO or ECCOR (with subsequent further exposure to other life‐threatening issues), and some die. In parallel, biologics are revolutionizing severe asthma management, mostly in T2 high patients. Methods: We extensively reviewed the current unmet needs surrounding ICU‐admitted asthma exacerbations, with a focus on currently available drugs and the underlying biological processes involved. We explored whether currently available T2‐targeting drugs can reasonably be seen as potential players not only for relapse prevention but also as candidate drugs for a faster resolution of such episodes. The patient's perspective was also sought. Results: About 30% of asthma exacerbations admitted to the ICU do not resolve within five days. Persistent severe airway obstruction despite massive doses of corticosteroids and maximal pharmacologically induced bronchodilation is the main cause of treatment failure. Previous ICU admission is the main risk factor for such episodes and may eventually be considered as a T2 surrogate marker. Fatal asthma cases are hallmarked by poorly steroid‐sensitive T2‐inflammation associated with severe mucus plugging. New, fast‐acting T2‐targeting biologics (already used for preventing asthma exacerbations) have the potential to circumvent steroid sensitivity pathways and decrease mucus plugging. This unmet need was confirmed by patients who reported highly negative, traumatizing experiences. Conclusions: There is room for improvement in the management of ICU‐admitted severe asthma episodes. Clinical trials assessing how biologics might improve ICU outcomes are direly needed. [ABSTRACT FROM AUTHOR]