Olivier Le Rouzic

La broncho-pneumopathie chronique obstructive (BPCO) est une maladie inflammatoire chronique des voies aériennes dont le facteur de risque principal est l’exposition chronique à la fumée de cigarette. L’histoire de la maladie est fréquemment associée à une colonisation bactérienne des voies aériennes et ponctuée d’épisodes aigus d’exacerbation de la maladie associés à une morbi-mortalité importante. Ces exacerbations sont principalement d’origine infectieuses et plus particulièrement, associées à une bactérie dans 50 % des cas, majoritairement Haemophilus influenzae, Streptococcus pneumoniae et Moraxella catarrhalis. Le contrôle de ces infections bactériennes implique en particulier une réponse immunitaire de type Th17 efficace. Cette immunité Th17 médiée principalement par les cytokines IL-17A et IL-22 est impliquée dans la physiopathologie de la BPCO mais n’a été que peu étudiée dans le contexte des exacerbations. Notre hypothèse est que la réponse Th17 aux pathogènes est altérée dans la BPCO, mécanisme qui serait impliqué dans la susceptibilité aux infections respiratoires observée chez les patients.Différentes approches ont été utilisées pour tester cette hypothèse. Tout d’abord, une approche ex vivo, à partir de cellules mononucléées circulantes (PBMC) de patients atteints de BPCO comparées à celles issues de sujets sains non fumeurs et de sujets fumeurs sans obstruction bronchique, montrant un défaut de production par les PBMC des cytokines IL-17A et IL-22 mais également des cytokines IL-6 et IL-23 produites par les cellules présentatrices d’antigènes (CPA) et impliquées dans l’activation de cette immunité Th17, en réponse à une activation par S. pneumoniae. Ensuite, une approche in vitro, avec un modèle de cellules dendritiques dérivées de monocytes (MDDC) exposées à la fumée de cigarette. Ces MDDC présentaient un défaut de maturation, de production de cytokines pro-Th17 et de leur capacité à activer une réponse Th17 lymphocytaire en réponse à S. pneumoniae. Enfin, une approche in vivo, utilisant un modèle murin de souris exposées de façon chronique à la fumée de cigarette confirmant ces résultats avec un défaut de réponse IL-17A et IL-22 mais également de production des cytokines pro-Th17 IL-1β et IL-23 par les CPA en réponse à S. pneumoniae. Dans ce modèle, l’apport d’IL-22 permettait d’améliorer la clairance bactérienne et de réduire les lésions pulmonaires, suggérant des possibilités thérapeutiques pour améliorer la prise en charge de ces exacerbations infectieuses.Ces trois approches permettent d’apporter des arguments forts en faveur d’un défaut de réponse Th17 au cours des exacerbations bactériennes de la BPCO, hypothèse confortée par d’autres travaux de notre équipe montrant dans le modèle murin d’exposition chronique à la fumée de cigarette la présence d’un défaut de production d’IL-22 dans la réponse à Haemophilus influenzae. Ces travaux qui doivent maintenant être d’une part, confirmés par une étude clinique incluant des patients atteints de BPCO en exacerbation, et d’autre part, complétés pour préciser l’impact sur les cellules lymphoïdes innées productrices de ces cytokines et sur la réponse de l’épithélium bronchique à l’infection, ouvrent la voies à des perspectives thérapeutiques dans la prise en charge de ces exacerbations bactériennes.

Introduction Three previous publications have reported real-world comparative effectiveness of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) and budesonide/glycopyrrolate/formoterol fumarate (BUD/GLY/FORM) in patients with chronic obstructive pulmonary disease (COPD) in the USA. This subgroup analysis assessed treatment with FF/UMEC/VI and BUG/GLY/FORM in patients with COPD who stepped up from dual therapy, stratified by number of prior exacerbations and class of prior dual therapy. Methods Propensity score (PS)-weighted patients identified within healthcare claims from the Komodo Research database were used to compare annualized rates and time to first moderate-severe COPD exacerbation between FF/UMEC/VI and BUD/GLY/FORM initiators stepping up from dual therapy, stratified by the type of dual therapy (long-acting muscarinic antagonist plus long-acting β₂-agonist [LAMA/LABA] or inhaled corticosteroid [ICS] plus LABA) and by prior (none or ≥ 1) COPD exacerbation. Results are presented as events per patient year (PPY) and rate ratio (RR) with 95% confidence intervals (CIs). Results Approximately 14,000 patients contributed to this analysis, 10,093 FF/UMEC/VI and 3926 BUD/GLY/FORM initiators. Baseline characteristics were well balanced following PS weighting. Step-up to FF/UMEC/VI was associated with a statistically significant reduction in moderate-severe exacerbations compared with step-up to BUD/GLY/FORM irrespective of exacerbation history: no prior exacerbation, n = 7235, 0.48 vs 0.56 PPY, RR [95% CI] 0.86 [0.77, 0.95], P = 0.003; ≥ 1 prior exacerbation, n = 6784, 1.14 vs 1.41 PPY, RR [95% CI] 0.81 [0.74, 0.87], P < 0.001. Step-up to FF/UMEC/VI was also associated with a statistically significant reduction in moderate-severe exacerbations compared with step-up to BUD/GLY/FORM across both subgroups of prior dual therapy: LAMA/LABA, n = 5717, 0.71 vs 0.95 PPY; RR [95% CI] 0.75 [0.67, 0.83], P < 0.001; ICS/LABA, n = 8302, 0.85 vs 0.99 PPY; RR [95% CI] 0.86 [0.79, 0.93], P < 0.001. Conclusion Patients newly initiating FF/UMEC/VI following prior treatment with ICS/LABA or LAMA/LABA experienced a significantly lower rate of moderate-severe COPD exacerbations than those newly initiating BUD/GLY/FORM irrespective of number of prior exacerbations or prior dual therapy class.

Introduction Recent data suggest differences in effectiveness of single-inhaler triple therapies (SITTs) for patients with chronic obstructive pulmonary disease (COPD); however, data specifically from patients previously treated with dual bronchodilator therapy are lacking. This real-world comparative effectiveness study assessed patients with COPD treated with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) and budesonide/glycopyrrolate/formoterol fumarate (BUD/GLY/FORM) who stepped up from dual therapy. Methods This retrospective study used healthcare claims from the Komodo Research database to identify patients with COPD and Medicare Fee-for-Service insurance on dual therapy as their most recent treatment in the 90 days pre-index, stepping up to FF/UMEC/VI or BUD/GLY/FORM between January 1, 2016 and December 31, 2023. Primary outcome was annualized rate of moderate–severe exacerbations per patient-year (PPY) compared using rate ratios (RRs) and 95% confidence intervals (CIs) from Poisson regression models after adjustment with overlap weighting. Secondary outcomes were time to first moderate–severe exacerbation (analyzed as a composite and separately), reported using Kaplan–Meier (KM) analysis and compared using hazard ratios (HRs) with 95% CIs from weighted Cox regression models. All-cause mortality (KM analysis) was included as an exploratory outcome. Results Overall, 10,093 FF/UMEC/VI and 3926 BUD/GLY/FORM patients stepping up from dual therapy were included. Patients stepping up to FF/UMEC/VI experienced an 18% significantly lower rate of moderate–severe COPD exacerbations compared with BUD/GLY/FORM [0.80 vs. 0.98 PPY; RR (95% CI) 0.82 (0.77, 0.88); P < 0.001]. Stepping up to FF/UMEC/VI was also associated with a 14% lower risk of moderate–severe COPD exacerbations [HR (95% CI) 0.86 (0.81, 0.92); P < 0.001] and 18% lower risk of all-cause mortality [HR (95% CI) 0.82 (0.68, 0.99); P = 0.040] at 12 months compared with BUD/GLY/FORM. Conclusion In this real-world study, SITT with FF/UMEC/VI was associated with a significantly lower rate and risk of exacerbations compared with BUD/GLY/FORM in patients stepping up from dual therapy.

Purpose Sleep apnoea (SA) is associated with accelerated cognitive decline in patients with mild cognitive impairment (MCI). Treatment of SA by continuous positive airway pressure (CPAP) may slow this decline if patients comply with the treatment. The aim of this study was to assess the rate of CPAP compliance in this population. Methods In this single-centre retrospective study conducted in a tertiary care institution, patients with a diagnosis of MCI and SA initiating CPAP between January 2015 and August 2021 were included. Data from the initial sleep recording, the 3-month follow-up and compliance with at least 12 months of CPAP were analysed. Compliance was defined as an average CPAP use of at least 4 h per night. Results 55 patients were included (49% women, age 70.7 ± 8.9 years, body mass index 28.9 ± 6.5 kg/m²). Aetiology of MCI was vascular (45.5%), psychiatric (12.7%) and related to Alzheimer’s disease (7.3%), with 47.3% of amnesic disorders and 45.5% of dysexecutive disorders. The MiniMentalState score was 26.7 ± 3.1. SA was mostly obstructive (81.8%) with a mean apnoea-hypopnoea index of 41.1 ± 16.4/h. At 3 months, 38 patients were compliant (69%) with a CPAP median use of 5.9 h per night and 83% of nights. Self-reported tolerance was better in compliant patients (75.7% vs 38.5% p = 0.017). Thirty-four patients remained compliant at 12 months (62%). Conclusion Our results suggest a high rate of CPAP compliance in patients suffering from MCI. Compliance was related to the device tolerance, emphasizing the need to closely monitor and improve this factor.

Background: Cardiovascular and metabolic comorbidities in chronic obstructive pulmonary disease (COPD) are associated with higher symptoms burden. Few center-based studies have evaluated the impact of these comorbidities on short-term pulmonary rehabilitation outcomes with contrasting results. Research Question: This study aimed to determine whether cardiovascular diseases and metabolic comorbidities impacted long-term outcomes of a home-based PR program in COPD patients. Study Design and methods: Data of 419 consecutive COPD patients addressed to our pulmonary rehabilitation program between January 2010 and June 2016 were retrospectively analyzed. Our program consisted of once-weekly supervised home sessions, including therapeutic education and self-management support, with unsupervised retraining exercises and physical activities the other days for 8 weeks. Exercise capacity (6-min stepper test [6MST]), quality of life (visual simplified respiratory questionnaire), and anxiety and depression (hospital anxiety and depression scale) were assessed respectively, before (M0) and at the end (M2) of the pulmonary rehabilitation program, and at 6 (M8) and 12 months (M14) after its achievement. Results: Patients (mean age 64.1± 11.2 years, 67% males, mean forced expiratory volume in one second (FEV₁) 39.2± 17.0% predicted) were classified as having cardiovascular comorbidities (n=195), only metabolic disorders (n=122) or none of these comorbidities (n=102). After adjustment, all outcomes appeared similar between groups at baseline and improved after pulmonary rehabilitation with a greater effect at M14 for patients with only metabolic disorders on anxiety and depression score (− 5.0± 0.7 vs − 2.9± 0.8 and − 2.6± 0.6, p=0.021). Quality of life and exercise capacity improvements were not significantly different between the three groups at M2 and M14. Conclusion: Cardiovascular and metabolic comorbidities do not preclude COPD patients from obtaining clinically meaningful improvements in exercise capacity, quality of life and anxiety-depression up to 1 year after a home-based pulmonary rehabilitation.

Background: Chronic respiratory failure may occur as a consequence of chronic obstructive pulmonary disease (COPD) and is associated with significant morbidity and mortality. Hypoxemia is determined by underlying disease characteristics and comorbidities. Severe hypoxemia is typically only found in subjects with severe airflow obstruction (FEV₁< 50% predicted). However, how hypoxemia relates to disease characteristics is not fully understood. Methods: In the French Initiatives BPCO real-life cohort, arterial blood gases were routinely collected in most patients. Relationships between severe hypoxemia, defined by a Pa0₂< 60 mmHg (8 kPa) and clinical/lung function features, comorbidities and mortality were assessed. In subjects with severe hypoxemia, clinical characteristics and comorbidities were compared between those with non-severe versus severe airflow limitation. Classification and regression trees (CART) were used to define clinically relevant subgroups (phenotypes). Results: Arterial blood gases were available from 887 subjects, of which 146 (16%) exhibited severe hypoxemia. Compared to subjects with a PaO2≥ 60 mmHg, the severe hypoxemia group exhibited higher mMRC dyspnea score, lower FEV₁, higher RV and RV/TLC, more impaired quality of life, lower 6-minute walking distance, less frequent history of asthma, more frequent diabetes and higher 3-year mortality rate (14% versus 8%, p=0.026). Compared to subjects with Pa0₂< 60 mmHg and FEV₁< 50% (n=115, 13%), those with severe hypoxemia but FEV1≥ 50% predicted (n=31) were older, had higher BMI, less hyperinflation, better quality of life and a higher rate of diabetes (29% versus 13%, p=0.02). Severe hypoxemia was better related to CART-defined phenotypes than to GOLD ABCD classification. Conclusion: In this cohort of stable COPD subjects, severe hypoxemia was associated with worse prognosis and more severe symptoms, airflow limitation and hyperinflation. Compared to subjects with severe hypoxemia and severe airflow limitation, subjects with severe hypoxemia despite non-severe airflow limitation were older, had higher BMI and more diagnosed diabetes. Trial Registration: 04– 479.

Pulmonary rehabilitation, whether performed at home or in a specialised centre, is effective in the management of COPD. As gender-related differences in COPD were previously reported, we aimed to evaluate the impact of gender on pulmonary rehabilitation outcomes in the short, medium and long term.In this retrospective observational study of 170 women and 310 men with COPD, we compared the outcomes of an 8-week home-based pulmonary rehabilitation programme including an individualised plan of retraining exercises, physical activities, therapeutic education, and psychosocial and self-management support. Exercise tolerance, anxiety, depression, and quality of life (QOL) were assessed using the 6-min stepper test (6MST), Hospital Anxiety and Depression Scale (HADS) and Visual Simplified Respiratory Questionnaire (VSRQ), respectively. Assessments were carried out before, immediately after the pulmonary rehabilitation programme (T2) and at 8 (T8) and 14 months (T14).At baseline, women were younger (mean 62.1versus65.3 years), more often nonsmokers (24.7%versus7.7%) and had a higher body mass index (28versus26.4 kg·m⁻²). They more often lived alone (50.6%versus24.5%) and experienced social deprivation (66.7%versus56.4%). They had significantly lower exercise tolerance (−34 strokes, 6MST) and higher anxiety and depression (+3.2 HADS total score), but there were no between gender differences in QOL (VSRQ). Both groups showed similar improvements in all outcome measures at T2, T8 and T14 with a tendency for men to lose QOL profits over time.Despite some differences in baseline characteristics, women and men with COPD had similar short-, medium- and long-term benefits of a home-based pulmonary rehabilitation programme.

Background: Long-term effectiveness of pulmonary rehabilitation (PR) is still uncertain in older people with severe chronic obstructive pulmonary disease (COPD). The objective was to compare the effects of home-based PR in people with COPD above and below the age of 70 years. Methods: In this retrospective study, 480 people with COPD were recruited and divided into those ≤ 70 (n=341) and those > 70 years of age (n=139). All participants underwent an 8 weeks of home-based PR, consisting of a weekly supervised 90-minute home session. Six-minute stepper test (6MST), timed-up and go test (TUG), Hospital Anxiety and Depression Scale, and Visual Simplified Respiratory Questionnaire (VSRQ) were assessed at baseline (M0), at 2 (M2), 8 (M8), 14 (M14) months after baseline. Results: The older group was described by fewer current smokers (p < 0.001), more long-term oxygen therapy use (p = 0.024), higher prevalence of comorbidities (p< 0.001), lower 6MST score and higher TUG score (p< 0.001), compared to the younger group. Both groups improved every outcome at M2 compared to baseline. At M2, 88% of people ≤ 70 years of age and 79% of those above 70 were considered as responders in at least one evaluated parameter (p = 0.013). Both groups maintained the benefits at M14, except for the VSRQ score and the number of responders to this outcome in the older group. Conclusion: Regardless of the age, personalized home-based PR was effective for people with COPD in the short term. Above 70 years, an ageing effect appeared on the long-term effectiveness of quality of life benefit.