Impact of a telerehabilitation programme combined with continuous positive airway pressure on symptoms and cardiometabolic risk factors in obstructive sleep apnea patients.

Background: Obstructive sleep apnea syndrome is a common sleep-breathing disorder associated with adverse health outcomes including excessive daytime sleepiness, impaired quality of life and is well-established as a cardiovascular risk factor. Continuous positive airway pressure is the reference treatment, but its cardiovascular and metabolic benefits are still debated. Combined interventions aiming at improving patient's lifestyle behaviours are recommended in guidelines management of obstructive sleep apnea syndrome but adherence decreases over time and access to rehabilitation programmes is limited. Telerehabilitation is a promising approach to address these issues, but data are scarce on obstructive sleep apnea syndrome. Methods: The aim of this study is to assess the potential benefits of a telerehabilitation programme implemented at continuous positive airway pressure initiation, compared to continuous positive airway pressure alone and usual care, on symptoms and cardiometabolic risk factors of obstructive sleep apnea syndrome. This study is a 6-months multicentre randomized, parallel controlled trial during which 180 obese patients with severe obstructive sleep apnea syndrome will be included. We will use a sequential hierarchical criterion for major endpoints including sleepiness, quality of life, nocturnal systolic blood pressure and inflammation biological parameters. Discussion: m-Rehab obstructive sleep apnea syndrome is the first multicentre randomized controlled trial to examine the effectiveness of a telerehabilitation lifestyle programme in obstructive sleep apnea syndrome. We hypothesize that a telerehabilitation lifestyle intervention associated with continuous positive airway pressure for 6 months will be more efficient than continuous positive airway pressure alone on symptoms, quality of life and cardiometabolic risk profile. Main secondary outcomes include continuous positive airway pressure adherence, usability and satisfaction with the telerehabilitation platform and medico-economic evaluation. Trial registration: Clinicaltrials.gov Identifier: NCT05049928. Registration data: 20 September 2021.

Anti-interleukin 5 therapies failure criteria in severe asthma: a Delphi-consensus study.

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.

Goblet cell hyperplasia as a feature of neutrophilic asthma.

BACKGROUND: Goblet cell hyperplasia (GCH) is a pathological finding classically reported across asthma severity levels and usually associated with smoking. Multiple biological mechanisms may contribute to excessive mucus production. OBJECTIVE: We aimed to decipher the clinical meanings and biological pathways related to GCH in non-smokers with asthma. METHODS: Cough and sputum assessment questionnaire (CASA-Q) responses at entry and 1 year later were compared to clinical and functional outcomes in 59 asthmatic patients. GCH was assessed through periodic-acid shift (PAS) staining on endobronchial biopsies obtained at entry in a subset of 32 patients. RESULTS: Periodic-acid shift-staining analysis revealed a double wave distribution discriminating patients with (>10% of the epithelial area) or without GCH. CASA-Q scores were mostly driven by overall asthma severity (P < 0.0001). CASA-Q scores remained stable at 1 year and were independently associated with BAL eosinophil content irrespective of the presence of GCH. GCH was unrelated to the presence of bronchiectasis at CT, GERD or chronic rhinosinusitis, but correlated well with neutrophilic inflammatory patterns observed upon BAL cellular analysis (P = 0.002 at multivariate analysis). BALF bacterial loads were unrelated to GCH or to CASA-Q. CONCLUSIONS AND CLINICAL RELEVANCE: Goblet cell hyperplasia is disconnected from chronic cough and sputum when assessed by a specific questionnaire. GCH is related to neutrophilic asthma whereas symptoms are related to airway eosinophilia. The clinical counterpart of GCH is unlikely assessed by the CASA-Q.

Epithelial ciliated beating cells essential for ex vivo ALI culture growth.

BACKGROUND: Bronchial epithelium plays a key role in orchestrating innate and adaptive immunity. The fate of ex vivo airway epithelial cultures growing at the air liquid interface (ALI) derived from human endobronchial biopsies or brushings is not easy to predict. Calibrating and differentiating these cells is a long and expensive process requiring rigorous expertise. Pinpointing factors associated with ALI culture success would help researchers gain further insight into epithelial progenitor behavior. METHODS: A successful ALI culture was defined as one in which a pseudostratified epithelium has formed after 28 days in the presence of all differentiated epithelial cell types. A 4-year prospective bi-center study was conducted with adult subjects enrolled in different approved research protocols. RESULTS: 463 consecutive endobronchial biopsies were obtained from normal healthy volunteers, healthy smokers, asthmatic patients and smokers with COPD. All demographic variables, the different fiber optic centers and culture operators, numbers of endo-bronchial biopsies and the presence of ciliated cells were carefully recorded. Univariate and multivariate models were developed. A stepwise procedure was used to select the final logistic regression model. ALI culture success was independently associated with the presence of living ciliated cells within the initial biopsy (OR = 2.18 [1.50-3.16], p < 0.001). CONCLUSION: This finding highlights the properties of the cells derived from the epithelium dedifferentiation process. The preferential selection of samples with ciliated beating cells would probably save time and money. It is still unknown whether successful ALI culture is related to indicators of general cell viability or a purported stem cell state specifically associated with ciliated beating cells.

Persistent severe hypereosinophilic asthma is not associated with airway remodeling.

Hypereosinophilic asthma (HEA) is considered as a specific severe asthma phenotype. Whether eosinophils have a link with airway remodeling characterized by pathological (thickening of the basement membrane), functional (persistent airflow impairment and decline in lung function) and imaging features (increase airway wall thickness at CT scan) is still debated. In a one year prospective cohort of 142 severe asthma patients (according to IMI), 14 persistent HEA patients (defined by a persistent blood eosinophilia >500/mm(3) at two consecutive visits) were identified and compared with ten patients without any blood eosinophilia during the follow-up period (NEA, blood eosinophilia always <500/mm(3)). Airflow and lung volumes were recorded. Bronchial biopsies obtained at enrollment were stained for eosinophils (EG2) and basement membrane thickness (BM) was quantified. Imaging by CT scan acquisition was standardized and bronchial abnormalities quantified. ACQ score and exacerbations were prospectively recorded. HEA was not associated with preeminent features of airway remodeling assessed by airflow impairment (Best ever FEV1 values 97% ± 20 in HEA vs. 80 ± 24% in NEA, p = 0.020), decline of FEV1 (FEV1 Decline 40 ± 235 ml/y in HEA vs. 19 ± 40 ml/y in NEA, P = 0.319), submucosal abnormalities (BM thickness 7.80 ± 2.66 µm in HEA vs. 6.84 ± 2.59 in NEA, p = 0.37) and airway wall thickening at CT-scan (0.250 ± 0.036 mm vs. 0.261 ± 0.043, p = 0.92). Eosinophils blood count was inversely correlated with semiquantitative imaging score (rho -0.373, p = 0.039). Smoking history and positive skin prick tests were independent risk factors for increased BM thickening. Outcomes were similar in both populations (Control and exacerbations). Persistent HEA is not associated with evidences of airway remodeling.

Tobacco smoke in infants with bronchopulmonary dysplasia.

UNLABELLED: Exposure to tobacco smoke has been not evaluated in children with bronchopulmonary dysplasia (BPD). We evaluate the association of in utero smoking (IUS) and environmental tobacco smoke (ETS) with the respiratory events of BPD and non-BPD children. Two hundred sixty-two children born before 35 weeks of gestational age (GA) and regularly followed up in our regional network for preterms were enrolled. They were paired according to their BPD status, their gestational age and birth weight (131 children with BPD and 131 without BPD, 28 mean weeks GA; mean weight 1000 g). Respiratory data were obtained prospectively during their first 2 years of life. A complementary questionnaire was completed by the parents about their child's respiratory health at the age of 2, their home environment, and tobacco status. IUS concerned 12.6 %; ETS, 48.8 % (67 % in BPD children treated with oxygen at home). No further influence on respiratory outcome could be found by exposure to intrauterine smoke or extrauterine tobacco smoke in this patient sample. CONCLUSION: IUS and ETS exposures are as high in preterm children as in a general pediatric population. The highest exposure occurs among BPD infants treated with oxygen at home. WHAT IS KNOWN: • Environmental tobacco smoke (ETS) and in utero smoking (IUS) are responsible for many morphological, functional, and clinical changes in children. • Children with bronchopulmonary dysplasia (BPD) have more respiratory events in their first years of life than preterm children without BPB, maybe triggered by ETS and IUS. What is New: • The exposition to ETS and IUS is high in preterm children with and without BDP, as high as in a general. • Pedaitric population, particularly in children with BPD and treated with oxygen at home. • No further influence on respiratory outcome could be found by exposure to ETS or IUS in our studied population.

Bronchial thermoplasty: a new therapeutic option for the treatment of severe, uncontrolled asthma in adults.

Bronchial thermoplasty is a young yet promising treatment for severe asthma whose benefit for long-term asthma control outweighs the short-term risk of deterioration and hospitalisation in the days following the treatment. It is an innovative treatment whose clinical efficacy and safety are beginning to be better understood. Since this is a device-based therapy, the overall evaluation of risk-benefit is unlike that of pharmaceutical products; safety aspects, regulatory requirements, study design and effect size assessment may be unfamiliar. The mechanisms of action and optimal patient selection need to be addressed in further rigorous clinical and scientific studies. Bronchial thermoplasty fits in perfectly with the movement to expand personalised medicine in the field of chronic airway disorders. This is a device-based complimentary asthma treatment that must be supported and developed in order to meet the unmet needs of modern severe asthma management. The mechanisms of action and the type of patients that benefit from bronchial thermoplasty are the most important challenges for bronchial thermoplasty in the future.

Long-acting muscarinic receptor antagonists for the treatment of chronic airway diseases.

Acetylcholine (neuronal and non-neuronal origin) regulates bronchoconstriction, and mucus secretion. It has an inflammatory effect by inducing attraction, survival and cytokine release from inflammatory cells. Muscarinic receptors throughout the bronchial tree are mainly restricted to muscarinic M1, M2 and M3 receptors. Three long-acting muscarinic receptor antagonists (LAMAs) were approved for the treatment of chronic obstructive pulmonary disease (COPD) in Europe: once-daily tiotropium bromide; once-daily glycopyrronium bromide; and twice-daily aclidinium bromide. All have higher selectivity for M3 receptors than for M2 receptors, and dissociate more slowly from the M3 receptors than they do from the M2 receptors. Some LAMAs showed anti-inflammatory effects [inhibition of neutrophil chemotactic activity and migration of alveolar neutrophils, decrease of several cytokines in the bronchoalveolar lavage (BAL) including interleukin (IL)-6, tumor necrosis factor (TNF)-α and leukotriene (LT)B4] and antiremodeling effects (inhibition of mucus gland hypertrophy and decrease in MUC5AC-positive goblet cell number, decrease in MUC5AC overexpression). In the clinic, LAMAs showed a significant improvement of forced expiratory volume in 1 second (FEV1), quality of life, dyspnea and reduced the number of exacerbations in COPD and more recently in asthma. This review will focus on the three LAMAs approved in Europe in the treatment of chronic airway diseases.

[Definitions of asthma, assessment of disease severity and control]. / Définitions de l'asthme, evaluation de la sévérité et du contrôle.

The definitions of asthma are numerous, often descriptive and non evidences based. They have been used in the clinic to suspect, diagnose a condition which remains in 2011, more a syndrome than a disease. Acute severity, control and severity are current concepts to be used to evaluate a given patient at a given time. They should be better defined and understood to be used more appropriately. At present, these notions are often interchangeable in the literature, used without precisions and no real benefit for the patients and physicians. In the present review, we try to clarify the wording of definitions to be used in the daily practice including difficult asthma. Control of asthma is related to recent daily symptoms and exacerbations; it represents the ultimate goal of treatments according to current guidelines. Acute severe asthma represents the highest point of a severe exacerbation requiring a standardized management in emergency. Chronic severity refers to a longer period of time including the importance of the treatment to maintain a good or optimal control, as well as future risks. It is more linked to the natural history representing a marker of a persistent chronic disease.

An update on the efficacy and safety of aclidinium bromide in patients with COPD.

Aclidinium is a potent and selective muscarinic antagonist, which interacts rapidly with muscarinic receptors and shows subnanomolar affinity for the five human muscarinic receptors (M(1)-M(5)); its association rate for the M(3) receptor is similar to that of ipratropium and 2.6 times faster than that of tiotropium. Aclidinium dissociates slightly faster from M(2) and M(3) receptors than tiotropium but much more slowly than ipratropium. A potent bronchodilatory activity has been observed after inhaled administration of aclidinium. Aclidinium undergoes rapid hydrolysis in the plasma into two major compounds, the alcohol (LAS34823) and the carboxylic acid (LAS34850) metabolites, resulting in low and transient systemic exposure to the active drug. The two major metabolites show no significant affinity for human muscarinic receptors. A potent bronchodilatory activity has been observed after inhaled administration of aclidinium. Clinical trials have provided evidence of sustained bronchodilation similar to that observed with tiotropium. Trial results have confirmed the positive safety profile of aclidinium, particularly in terms of a very low propensity to cause anticholinergic adverse events. Aclidinium is now moving to phase III clinical development for chronic obstructive pulmonary disease (COPD).

[Asthma phenotypes]. / Phénotypes de l'asthme.

The phenotype is the result of the observable characteristics of a subject resulting from the interactions between a genotype and its environment. Phenotyping asthmatic patients is a current search to better capture the heterogeneity of this disease with potential overlaps with other chronic bronchial disease such as COPD. This aspect is crucial in severe asthma where important unmet needs are found. The criteria used to phenotype asthma are issued from current clinical, functional and pathophysiological findings. The defined phenotypes will take benefit from more focused therapeutical avenues.