Prevalence and disparities in influenza vaccination among patients with COPD: A French nationwide population study.

INTRODUCTION: Despite concordant international recommendations, many surveys found disappointing rates of influenza vaccination in at-risk populations, ranging from 23% in overall COPD population to more than 70% in more severe COPD subjects. Therefore, we assessed the proportion of French COPD patients non-vaccinated for influenza and their clinical and socio-demographic factors. MATERIEL AND METHODS: This was a national retrospective study based on the French health insurance database. We identified "diagnosed COPD", defined as subjects hospitalized at least once in 2017 with a principal or associated diagnosis of COPD, and "suspected COPD" as those who were prescribed at least thrice long-acting bronchodilators (LAB), after exclusion of patients with a principal diagnosis or secondary associated diagnosis of asthma or cystic fibrosis, patients deceased before the influenza season and patients hospitalized in long-term or in palliative care unit. Multivariate logistic regression was used to assess the association between patients' characteristics and the lack of influenza vaccination. RESULTS: From the national database, 1 474 396 subjects were identified as "suspected COPD" of whom 528 114 were excluded because of previous diagnosis of asthma or cystic fibrosis, and 350 566 as "diagnosed COPD". Among the 1 296 848 patients included, 646 687 patients (53.3%) were vaccinated against influenza. Non-vaccinated subjects were significantly younger (62.1 vs 71.6 years old), more often women (47.9% vs 43.1%) and had fewer comorbidities assessed by Charlson's index (3.0 ± 2.2 vs 4.3 ± 2.1). Lack of vaccination was also associated with a lower LAB usage. Also, non-vaccinated subjects neither had severe exacerbation during the study period. Besides there was a significant heterogeneity in vaccination rate by geographic region, from 47% to 57%. In multivariate analysis, variables independently associated with the lack of influenza vaccination were female gender, younger age, fewer comorbidities and lower socio-economic level. CONCLUSIONS: This study using the French exhaustive health insurance database shows that influenza vaccination among COPD patients remains dramatically low and must become a high-priority public-health strategy.

[Medication management of COPD]. / Prise en charge médicamenteuse de la BPCO.

MEDICATION MANAGEMENT OF COPD. The management of chronic obstructive pulmonary disease (COPD) is based on drug and non-drug measures. Inhaled therapies are the major issues including the use of short-acting bronchodilators for respiratory symptoms. If symptoms are daily, such as disabling dyspnea or frequent exacerbations, daily treatment with a long-acting bronchodilator is proposed: anti-muscarinic (LAMA) or ß2-agonist (LABA). If there is no improvement, escalation to dual and then triple therapy is proposed. Another major issue in the management of COPD is de-escalation in the event of ineffectiveness or side effects of inhaled corticosteroids (ICS). Finally, the role of blood eosinophils and other biomarkers is even more important that biotherapies could expand the therapeutic options for some subtypes of COPD patients.

PRISE EN CHARGE MÉDICAMENTEUSE DE LA BPCO. La prise en charge de la bronchopneumopathie chronique obstructive (BPCO) repose sur des mesures médicamenteuses et non médicamenteuses. Le principe des traitements médicamenteux dans la BPCO comprend des traitements inhalés, et notamment l'utilisation de bronchodilatateurs de courte durée d'action en cas de symptômes respiratoires. Si les symptômes sont quotidiens à type de dyspnée invalidante ou en cas d'exacerbations fréquentes, un traitement de fond quotidien par un bronchodilatateur de longue durée d'action est indiqué : antimuscarinique (LAMA) ou ß2-agoniste (LABA). En l'absence d'amélioration, une escalade est proposée par bithérapie puis trithérapie. Un autre enjeu majeur de la prise en charge de la BPCO est la désescalade thérapeutique en cas d'inefficacité ou d'effets indésirables des corticostéroïdes inhalés (CSI). Enfin, la place du dosage des éosinophiles et autres biomarqueurs sanguins est d'autant plus importante que les biothérapies pourraient venir élargir l'arsenal thérapeutique pour certains soustypes de patients atteints de BPCO.

Immune checkpoint inhibitor rechallenge in patients who previously experienced immune-related inflammatory arthritis: a multicentre observational study.

OBJECTIVE: Another course of immune checkpoint inhibitors (ICIs) is often considered in patients with cancer progression and previous immune-related adverse events, including inflammatory arthritis (ICI-IA), but there are limited data regarding safety of ICI rechallenge in this setting. We aimed to assess the rate and clinical features associated with ICI-IA flare/recurrence on ICI rechallenge. METHODS: We conducted a multicentre observational study including cancer patients with ICI-IA who started a second course of ICI more than 3 months after ICI discontinuation in four French university hospitals. Primary outcome was the frequency of ICI flare/recurrence after ICI rechallenge. RESULTS: Twenty-three patients were included. At the time of ICI rechallenge, 18 patients reported no symptoms of ICI-IA (78%) and 5 had grade 1 (22%), 11 patients (48%) were not receiving any ICI-IA treatment, 11 (48%) were still on prednisone, 2 (9%) were on conventional synthetic disease-modifying antirheumatic drugs and 1 (4%) on anti-IL-6. ICI-IA flare/recurrence occurred in 12 patients (52%) with a median time of 1 month after ICI rechallenge. ICI-IA phenotype, disease activity and ICI-IA treatment at the time of ICI rechallenge did not differ according to ICI-IA flare/recurrence status. CONCLUSION: In this first observational study of ICI-IA patients rechallenged with ICI, about half of the patients experienced ICI-IA flare/recurrence with a similar phenotype but occurring earlier than the initial ICI-IA, warranting close monitoring during the first month of retreatment. Risk of flare did not differ according to baseline immunosuppressive treatment at the time of rechallenge.

The Non-Paced 3-Minute Sit-to-Stand Test: Feasibility and Clinical Relevance for Pulmonary Rehabilitation Assessment.

Pulmonary rehabilitation (PR) improves health-related quality-of-life (HRQoL) in individuals with chronic obstructive pulmonary disease (COPD), notably by increasing exercise tolerance. Easy-to-implement sit-to-stand tests can facilitate the assessment of exercise tolerance in routine practice. This retrospective study conducted in a real-life setting was designed to describe the non-paced 3-min sit-to-stand test (3-STST) and to evaluate its relationship with HRQoL (VQ11 questionnaire) to identify the determinants of 3-STST performance and to analyze the evolution of 3-STST performance and HRQoL over the course of a community-based PR program. Seventy-one COPD patients (age 69 ± 10 years old; 51% with GOLD spirometric stages III-IV) were included. Mean ± SD 3-STST performance at the initial PR assessment was 43 ± 15 repetitions. This performance was significantly associated with HRQoL and other indicators of clinical severity (lung function, dyspnea, and functional capacities). During the multivariate analysis, younger age, exertional dyspnea with mMRC ≤ 1, and better HRQoL were significantly associated with better 3-STST performance. From the initial to second PR assessment, changes in 3-STST performance were significantly associated with changes in HRQoL. This study provides evidence that the non-paced 3-STST is feasible and might be clinically relevant in the assessment of patients with COPD referred for community-based PR. This test deserves to be prospectively validated.

Impact of pharmacological and non-pharmacological interventions on mortality in chronic obstructive pulmonary disease (COPD) patients.

PURPOSE: This review aimed to summarise evidence about the impact of pharmacological and non-pharmacological interventions on survival in COPD patients. METHODS: We performed a narrative literature review on the effect of pharmacological and non-pharmacological interventions on survival in COPD patients. RESULTS: Inhaled therapies are central to reduce symptoms in COPD. In particular, inhaled steroids seem to have the greatest effect on mortality. Despite the anti-inflammatory effects attributed to statins, their benefit in COPD has been shown only in cases of combined cardiovascular diseases. The use of beta-blockers in COPD has not been associated with increased COPD-related mortality and a beneficial effect on all-cause mortality has even been shown in COPD patients with cardiovascular diseases. Influenza and pneumococcal vaccination reduced the occurrence of exacerbations and mortality due to COPD. In addition, long-term oxygen therapy (LTOT) (≥15h/day) in COPD patients with severe hypoxemia had a positive effect on survival. Regarding non-pharmacological interventions, it has been demonstrated that smoking cessation, treatment compliance and nutritional supplementation for underweight patients also have a positive effect on survival. Non-invasive ventilation results were dependent on patient PaCO2 levels. In patients with advanced COPD, further prospective studies are needed to know the effect of bronchoscopic lung volume reduction and lung transplant on COPD survival. Regarding lung transplant, a survival benefit in patients with a pre-transplant BODE score of ≥7 has been shown in retrospective studies. CONCLUSION: Most of the studies did not evaluate survival as the main criteria and further long-term studies on the global management of COPD are required.

Development and external validation of a prediction model for the transition from mild to moderate or severe form of COVID-19.

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.

Short-range interactions between fibrocytes and CD8+ T cells in COPD bronchial inflammatory response.

Bronchi of chronic obstructive pulmonary disease (COPD) are the site of extensive cell infiltration, allowing persistent contact between resident cells and immune cells. Tissue fibrocytes interaction with CD8+ T cells and its consequences were investigated using a combination of in situ, in vitro experiments and mathematical modeling. We show that fibrocytes and CD8+ T cells are found in the vicinity of distal airways and that potential interactions are more frequent in tissues from COPD patients compared to those of control subjects. Increased proximity and clusterization between CD8+ T cells and fibrocytes are associated with altered lung function. Tissular CD8+ T cells from COPD patients promote fibrocyte chemotaxis via the CXCL8-CXCR1/2 axis. Live imaging shows that CD8+ T cells establish short-term interactions with fibrocytes, that trigger CD8+ T cell proliferation in a CD54- and CD86-dependent manner, pro-inflammatory cytokines production, CD8+ T cell cytotoxic activity against bronchial epithelial cells and fibrocyte immunomodulatory properties. We defined a computational model describing these intercellular interactions and calibrated the parameters based on our experimental measurements. We show the model's ability to reproduce histological ex vivo characteristics, and observe an important contribution of fibrocyte-mediated CD8+ T cell proliferation in COPD development. Using the model to test therapeutic scenarios, we predict a recovery time of several years, and the failure of targeting chemotaxis or interacting processes. Altogether, our study reveals that local interactions between fibrocytes and CD8+ T cells could jeopardize the balance between protective immunity and chronic inflammation in the bronchi of COPD patients.

Impact of triple therapy on mortality in COPD.

Only a few therapies have been shown to prolong survival in specific patients with COPD. In recent years, the IMPACT and the ETHOS trials suggested that triple therapy (a combination of inhaled corticosteroid (ICS), long-acting muscarinic antagonist (LAMA) and long-acting ß2-agonist (LABA) given in a single inhaler) may reduce mortality compared with dual bronchodilation. These results need however to be interpreted with caution. These trials were not powered by design to evaluate the impact of triple therapy on mortality as mortality was a secondary outcome. In addition, mortality reduction has to be put in perspective with the low mortality rate in both studies (<2%). Furthermore, a key methodological issue is that up to 70-80% of patients had ICS withdrawal at the enrolment in the LABA/LAMA arms, but none in the ICS-containing treatment arms. It is possible that ICS withdrawal may have contributed to some early death events. Finally, the inclusion and exclusion criteria of both trials were designed to select patients likely to respond to ICS. There are no conclusive data yet that triple therapy reduces mortality in COPD. Future, well-designed and -powered trials are needed to validate the findings on mortality.

International use of objective structured clinical examinations in respiratory training: a European Respiratory Society early career member survey.

This international overview of the use of objective structured clinical examinations (OSCEs) in respiratory training highlights the heterogeneity in use between countries as well as the positive experience of OSCEs amongst users https://bit.ly/3Zee6zP.

Brief Report: Severe Sotorasib-Related Hepatotoxicity and Non-Liver Adverse Events Associated With Sequential Anti-Programmed Cell Death (Ligand)1 and Sotorasib Therapy in KRASG12C-Mutant Lung Cancer.

INTRODUCTION: Sequential anti-programmed cell death protein 1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) followed by small targeted therapy use is associated with increased prevalence of adverse events (AEs) in NSCLC. KRASG12C inhibitor sotorasib may trigger severe immune-mediated hepatotoxicity when used in sequence or in combination with anti-PD-(L)1. This study was designed to address whether sequential anti-PD-(L)1 and sotorasib therapy increases the risk of hepatotoxicity and other AEs. METHODS: This is a multicenter, retrospective study of consecutive advanced KRASG12C-mutant NSCLC treated with sotorasib outside clinical trials in 16 French medical centers. Patient records were reviewed to identify sotorasib-related AEs (National Cancer Institute Common Classification Criteria for Adverse Events-Version 5.0). Grade 3 and higher AE was considered as severe. Sequence group was defined as patients who received an anti-PD-(L)1 as last line of treatment before sotorasib initiation and control group as patients who did not receive an anti-PD-(L)1 as last line of treatment before sotorasib initiation. RESULTS: We identified 102 patients who received sotorasib, including 48 (47%) in the sequence group and 54 (53%) in the control group. Patients in the control group received an anti-PD-(L)1 followed by at least one treatment regimen before sotorasib in 87% of the cases or did not receive an anti-PD-(L)1 at any time before sotorasib in 13% of the cases. Severe sotorasib-related AEs were significantly more frequent in the sequence group compared with those in the control group (50% versus 13%, p < 0.001). Severe sotorasib-related AEs occurred in 24 patients (24 of 48, 50%) in the sequence group, and among them 16 (67%) experienced a severe sotorasib-related hepatotoxicity. Severe sotorasib-related hepatotoxicity was threefold more frequent in the sequence group compared with that in the control group (33% versus 11%, p = 0.006). No fatal sotorasib-related hepatotoxicity was reported. Non-liver severe sotorasib-related AEs were significantly more frequent in the sequence group (27% versus 4%, p < 0.001). Severe sotorasib-related AEs typically occurred in patients who received last anti-PD-(L)1 infusion within 30 days before sotorasib initiation. CONCLUSIONS: Sequential anti-PD-(L)1 and sotorasib therapy are associated with a significantly increased risk of severe sotorasib-related hepatotoxicity and severe non-liver AEs. We suggest avoiding starting sotorasib within 30 days from the last anti-PD-(L)1 infusion.

Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting.

Chronic obstructive pulmonary disease (COPD) is a worldwide prevalent respiratory disease mainly caused by tobacco smoke exposure. COPD is now considered as a systemic disease with several comorbidities. Among them, skeletal muscle dysfunction affects around 20% of COPD patients and is associated with higher morbidity and mortality. Although the histological alterations are well characterized, including myofiber atrophy, a decreased proportion of slow-twitch myofibers, and a decreased capillarization and oxidative phosphorylation capacity, the molecular basis for muscle atrophy is complex and remains partly unknown. Major difficulties lie in patient heterogeneity, accessing patients' samples, and complex multifactorial process including extrinsic mechanisms, such as tobacco smoke or disuse, and intrinsic mechanisms, such as oxidative stress, hypoxia, or systemic inflammation. Muscle wasting is also a highly dynamic process whose investigation is hampered by the differential protein regulation according to the stage of atrophy. In this review, we report and discuss recent data regarding the molecular alterations in COPD leading to impaired muscle mass, including inflammation, hypoxia and hypercapnia, mitochondrial dysfunction, diverse metabolic changes such as oxidative and nitrosative stress and genetic and epigenetic modifications, all leading to an impaired anabolic/catabolic balance in the myocyte. We recapitulate data concerning skeletal muscle dysfunction obtained in the different rodent models of COPD. Finally, we propose several pathways that should be investigated in COPD skeletal muscle dysfunction in the future.

Pulmonary rehabilitation after severe exacerbation of COPD: a nationwide population study.

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (COPD) lead to a significant reduction in quality of life and an increased mortality risk. Current guidelines strongly recommend pulmonary rehabilitation (PR) after a severe exacerbation. Studies reporting referral for PR are scarce, with no report to date in Europe. Therefore, we assessed the proportion of French patients receiving PR after hospitalization for COPD exacerbation and factors associated with referral. METHODS: This was a national retrospective study based on the French health insurance database. Patients hospitalized in 2017 with COPD exacerbation were identified from the exhaustive French medico-administrative database of hospitalizations. In France, referral to PR has required as a stay in a specialized PR center or unit accredited to provide multidisciplinary care (exercise training, education, etc.) and admission within 90 days after discharge was assessed. Multivariate logistic regression was used to assess the association between patients' characteristics, comorbidities according to the Charlson index, treatment, and PR uptake. RESULTS: Among 48,638 patients aged ≥ 40 years admitted for a COPD exacerbation, 4,182 (8.6%) received PR within 90 days after discharge. General practitioner's (GP) density (number of GPs for the population at regional level) and PR center facilities (number of beds for the population at regional level) were significantly correlated with PR uptake (respectively r = 0.64 and r = 0.71). In multivariate analysis, variables independently associated with PR uptake were female gender (aOR 1.36 [1.28-1.45], p < 0.0001), age (p < 0.0001), comorbidities (p = 0.0013), use of non-invasive ventilation and/or oxygen therapy (aOR 1.52 [1.41-1.64], p < 0.0001) and administration of long-acting bronchodilators (p = 0.0038). CONCLUSION: This study using the French nationally exhaustive health insurance database shows that PR uptake after a severe COPD exacerbation is dramatically low and must become a high-priority management strategy.

Sputum-Rheology-Based Strategy for Guiding Azithromycin Prescription in COPD Patients with Frequent Exacerbations: A Randomized, Controlled Study ("COPD CARhE").

(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.

Cellular interplay in skeletal muscle regeneration and wasting: insights from animal models.

Skeletal muscle wasting, whether related to physiological ageing, muscle disuse or to an underlying chronic disease, is a key determinant to quality of life and mortality. However, cellular basis responsible for increased catabolism in myocytes often remains unclear. Although myocytes represent the vast majority of skeletal muscle cellular population, they are surrounded by numerous cells with various functions. Animal models, mostly rodents, can help to decipher the mechanisms behind this highly dynamic process, by allowing access to every muscle as well as time-course studies. Satellite cells (SCs) play a crucial role in muscle regeneration, within a niche also composed of fibroblasts and vascular and immune cells. Their proliferation and differentiation is altered in several models of muscle wasting such as cancer, chronic kidney disease or chronic obstructive pulmonary disease (COPD). Fibro-adipogenic progenitor cells are also responsible for functional muscle growth and repair and are associated in disease to muscle fibrosis such as in chronic kidney disease. Other cells have recently proven to have direct myogenic potential, such as pericytes. Outside their role in angiogenesis, endothelial cells and pericytes also participate to healthy muscle homoeostasis by promoting SC pool maintenance (so-called myogenesis-angiogenesis coupling). Their role in chronic diseases muscle wasting has been less studied. Immune cells are pivotal for muscle repair after injury: Macrophages undergo a transition from the M1 to the M2 state along with the transition between the inflammatory and resolutive phase of muscle repair. T regulatory lymphocytes promote and regulate this transition and are also able to activate SC proliferation and differentiation. Neural cells such as terminal Schwann cells, motor neurons and kranocytes are notably implicated in age-related sarcopenia. Last, newly identified cells in skeletal muscle, such as telocytes or interstitial tenocytes could play a role in tissular homoeostasis. We also put a special focus on cellular alterations occurring in COPD, a chronic and highly prevalent respiratory disease mainly linked to tobacco smoke exposure, where muscle wasting is strongly associated with increased mortality, and discuss the pros and cons of animal models versus human studies in this context. Finally, we discuss resident cells metabolism and present future promising leads for research, including the use of muscle organoids.

The telomerase activator TA-65 protects from cigarette smoke-induced small airway remodeling in mice through extra-telomeric effects.

Small airway remodeling (SAR) is a key phenomenon of airflow obstruction in smokers, leading to chronic obstructive pulmonary disease (COPD). SAR results in an increased thickness of small airway walls, with a combination of peribronchiolar fibrosis with increased fibrous tissue and accumulation of mesenchymal and epithelial cells. SAR pathogenesis is still unclear but recent data suggest that alterations in telomerase activity could represent a possible underlying mechanism of SAR. Our study was dedicated to identify a potential protective role of TA-65, a pharmacological telomerase activator, in a cigarette smoke (CS) model of SAR in mice, and to further precise if extra-telomeric effects of telomerase, involving oxidative stress modulation, could explain it. C57BL/6J mice were daily exposed to air or CS during 4 weeks with or without a concomitant administration of TA-65 starting 7 days before CS exposure. Morphological analyses were performed, and mucus production, myofibroblast differentiation, collagen deposition, as well as transforming growth factor-ß1 (TGF-ß1) expression in the small airway walls were examined. In addition, the effects of TA-65 treatment on TGF-ß expression, fibroblast-to-myofibroblast differentiation, reactive oxygen species (ROS) production and catalase expression and activity were evaluated in primary cultures of pulmonary fibroblasts and/or mouse embryonic fibroblasts in vitro. Exposure to CS during 4 weeks induced SAR in mice, characterized by small airway walls thickening and peribronchiolar fibrosis (increased deposition of collagen, expression of α-SMA in small airway walls), without mucus overproduction. Treatment of mice with TA-65 protected them from CS-induced SAR. This effect was associated with the prevention of CS-induced TGF-ß expression in vivo, the blockade of TGF-ß-induced myofibroblast differentiation, and the reduction of TGF-ß-induced ROS production that correlates with an increase of catalase expression and activity. Our findings demonstrate that telomerase is a critical player of SAR, probably through extra-telomeric anti-oxidant effects, and therefore provide new insights in the understanding and treatment of COPD pathogenesis.

Respiratory recovery trajectories after severe-to-critical COVID-19: a 1-year prospective multicentre study.

BACKGROUND: Survivors of severe-to-critical coronavirus disease 2019 (COVID-19) may have functional impairment, radiological sequelae and persistent symptoms requiring prolonged follow-up. This pragmatic study aimed to describe their clinical follow-up and determine their respiratory recovery trajectories, and the factors that could influence them and their health-related quality of life. METHODS: Adults hospitalised for severe-to-critical COVID-19 were evaluated at 3 months and up to 12 months post-hospital discharge in this prospective, multicentre, cohort study. RESULTS: Among 485 enrolled participants, 293 (60%) were reassessed at 6 months and 163 (35%) at 12 months; 89 (51%) and 47 (27%) of the 173 participants initially managed with standard oxygen were reassessed at 6 and 12 months, respectively. At 3 months, 34%, 70% and 56% of the participants had a restrictive lung defect, impaired diffusing capacity of the lung for carbon monoxide (D LCO) and significant radiological sequelae, respectively. During extended follow-up, both D LCO and forced vital capacity percentage predicted increased by means of +4 points at 6 months and +6 points at 12 months. Sex, body mass index, chronic respiratory disease, immunosuppression, pneumonia extent or corticosteroid use during acute COVID-19 and prolonged invasive mechanical ventilation (IMV) were associated with D LCO at 3 months, but not its trajectory thereafter. Among 475 (98%) patients with at least one chest computed tomography scan during follow-up, 196 (41%) had significant sequelae on their last images. CONCLUSIONS: Although pulmonary function and radiological abnormalities improved up to 1 year post-acute COVID-19, high percentages of severe-to-critical disease survivors, including a notable proportion of those managed with standard oxygen, had significant lung sequelae and residual symptoms justifying prolonged follow-up.

Incidence, management, and outcome of lung cancer in patients with long-term oxygen therapy.

BACKGROUND: Here, we aimed to assess the specific features of lung cancer in patients with long-term oxygen therapy (LTOT), and compare their outcomes with patients suffering from lung cancer without LTOT. METHODS: This retrospective, case-controlled study included patients with LTOT and an incident diagnosis of lung cancer treated at Rouen University Hospital. RESULTS: Out of 2201 patients with LTOT, 31 were diagnosed with lung cancer. Among 24 patients with proven lung cancer, the most frequent histological type was squamous cell carcinoma (n = 12/24, 50%). Active treatment of any type was given in 19/31 (61%) and 41/62 (66%) of patients in the LTOT and control groups, respectively (p = 0.83). In the LTOT group, median survival was 38 days with best supportive care and 462 days with active treatment (p = 0.003). However, when adjusting on performance status and disease stage, LTOT was not significantly associated with a worse outcome. Hazard ratio (HR): 1.56 (95% confidence interval [CI]: 0.87 to 2.81) (p = 0.137). Administration of any treatment was associated with a better prognostic: HR: 0.35 (95% CI: 0.19 to 0.66). Both groups had a similar treatment safety profile. CONCLUSION: Incidence of lung cancer in patients with LTOT was comparable to the general population. The proportion of LTOT patients who received active treatment was similar to controls, and overall survival did not differ from controls in a multivariate analysis. Although reaching a histological diagnosis may be challenging in LTOT patients, the efficacy and safety of the management strategies of lung cancer seem preserved.

Muscarinic receptor M3 activation promotes fibrocytes contraction.

Fibrocytes are monocyte-derived cells able to differentiate into myofibroblasts-like cells. We have previously shown that they are increased in the bronchi of Chronic Obstructive Pulmonary Disease (COPD) patients and associated to worse lung function. COPD is characterized by irreversible airflow obstruction, partly due to an increased cholinergic environment. Our goal was to investigate muscarinic signalling in COPD fibrocytes. Fibrocytes were isolated from 16 patients with COPD's blood and presence of muscarinic M3 receptor was assessed at the transcriptional and protein levels. Calcium signalling and collagen gels contraction experiments were performed in presence of carbachol (cholinergic agonist) ± tiotropium bromide (antimuscarinic). Expression of M3 receptor was confirmed by Western blot and flow cytometry in differentiated fibrocytes. Immunocytochemistry showed the presence of cytoplasmic and membrane-associated pools of M3. Stimulation with carbachol elicited an intracellular calcium response in 35.7% of fibrocytes. This response was significantly blunted by the presence of tiotropium bromide: 14.6% of responding cells (p < 0.0001). Carbachol induced a significant contraction of fibrocytes embedded in collagen gels (13.6 ± 0.3% versus 2.5 ± 4.1%; p < 0.0001), which was prevented by prior tiotropium bromide addition (4.1 ± 2.7% of gel contraction; p < 0.0001). Finally, M3-expressing fibrocytes were also identified in situ in the peri-bronchial area of COPD patients' lungs, and there was a tendency to an increased density compared to healthy patient's lungs. In conclusion, around 1/3 of COPD patients' fibrocytes express a functional muscarinic M3 receptor. Cholinergic-induced fibrocyte contraction might participate in airway diameter reduction and subsequent increase of airflow resistance in patients with COPD. The inhibition of these processes could participate to the beneficial effects of muscarinic antagonists for COPD treatment.

A Prospective Study to Detect Immune Checkpoint Inhibitors Associated With Myocarditis Among Patients Treated for Lung Cancer.

Background: Immune checkpoint inhibitors (ICIs) are widely used in lung cancer management. However, myocarditis, which is a rare, yet potentially severe adverse-related event associated with ICIs, could be under-reported. Objectives: This study is aimed to prospectively evaluate the cumulative incidence rate of myocarditis, through systematic screening, among patients receiving ICIs for lung cancer. Methods: All patients who received the first administration of ICIs for non-small cell (NSCLC) and small cell lung cancer (SCLC), between May and November 2020, in the pulmonary department of Bordeaux University Hospital, were included. Echocardiography (ECG), troponin-I, and natriuretic peptide dosages before ICIs' first administration and before each infusion were recorded. ECG and magnetic resonance imaging (MRI) were done additionally, in case of at least three times increase in troponin levels, ECG modifications, and the onset of cardiovascular symptoms. Second, if possible, coronarography than endomyocardial biopsy was assessed. The primary outcome was defined as ICIs related to myocarditis onset, while secondary outcomes included other cardiovascular events, disease-free, and overall survival. Results: During the period of interest, 99 patients received their first infusion of ICIs for lung cancer (mean age 64 ± 9 years; 52 men, 67% with adenocarcinoma). Three cases of myocarditis without major adverse cardiac events (MACEs) occurred (two definite and one possible), and the mean duration between the first ICIs' administration and myocarditis onset was 144 ± 3 days. Median disease-free survival and overall survival were 169 [102; 233] days and 209 [147; 249] days, respectively. Conclusion: In our study, systematic screening of myocarditis associated with ICIs leads to a more frequent incidence and a later onset than previously reported. None of them were severe. Additional prospective evidence is needed before we could adopt routine cardiac screening in unselected patients starting ICIs; however, these data shed new light on the risk of myocarditis associated with ICIs administration.

Second-line lurbinectedin as a new treatment option for small-cell lung cancer: Preliminary results in real-clinical practice.

INTRODUCTION: Few strategies exist for treatment of patients with small-cell lung cancer (SCLC) extended-stage after failure of first-line platinum-based chemotherapy. Lurbinectedin is a novel RNA-polymerase-II inhibitor investigated as a second-line therapy for SCLC. However, its efficacy and safety profile in real clinical practice remain to be determined. OBJECTIVE: To determine the efficacy and safety of lurbinectedin in real-life among patients with SCLC previously treated with first-line platinum-based chemotherapy. METHODS: We retrospectively evaluated patients who received at least one dose of lurbinectedin (3.2 mg/m2 ) between March 2020 and November 2021, in the pulmonary department of Bordeaux University Hospital. Endpoints were time to treatment discontinuation, progression-free survival, overall survival, and safety profile. RESULTS: Thirteen patients were included. The median age was 60 years (range: 42-77), seven (54%) were females, nine (69%) having a performance status of 0-1. Lurbinectedin was given as second-line treatment before platinum rechallenge in four (31%) patients. After a mean follow-up of 4.1 months, the objective response rate (ORR) was 17%. The median time to treatment discontinuation (TTD) was 2.3 months (interquartile range [IQR], 1.2-3.6). The median progression-free survival (PFS) and overall survival (OS) were, respectively, 1.9 (IQR, 0.1.8) and 4.1 (IQR, 2.0-3.5) months. No significant difference regarding TTD, PFS or OS was found in the two groups according to treatment history or according to chemotherapy-free intervall (CMI) 〈1 or 〉1 month. The most common adverse events (AEs) were asthenia, nausea, and anemia in nine (70%) patients. Grade 3 AEs were reported, fatigue, vomiting, nausea, anorexia, and neutropenia. CONCLUSIONS: Lurbinectedin in real clinical practice could have had a lower efficacy than in phase II trial, but a better hematological and bioclinical tolerance than previously reported. Early relapse after platinum-based chemotherapy seems to have a lower response to lurbinectedin.