Khuder Alagha

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.

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 (M1–M5); its association rate for the M3 receptor is similar to that of ipratropium and 2.6 times faster than that of tiotropium. Aclidinium dissociates slightly faster from M2 and M3 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).

We Should Prohibit Warfarin in Idiopathic Pulmonary Fibrosis

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Epithelial ciliated beating cells essential for ex vivo ALI culture growth

BackgroundBronchial 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.MethodsA 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.Results463 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).ConclusionThis 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.

Iatrogenic eosinophilic pleural effusion

To the Editor: Chronic pleural effusions are sometimes difficult to manage. Some cases remain unresolved despite invasive investigations. Iatrogenic pleural effusions are not rare but the diagnosis is mostly putative and difficult to ascertain. Herein, we report two cases of eosinophilic pleural effusions that are potentially iatrogenic and review the current literature accordingly. A 38-yr-old male, nonsmoker has been followed for 13 yrs in the Dept of Neurology (AP-HM, Marseille, France) for treatment of multiple sclerosis. Until 2 yrs ago he had been treated with bolus of cyclophosphamide, and is currently being treated with 10 mg prednisolone per day, with significant neurological sequelae. His treatment includes prednisolone 10 mg q.d. , dantrolene 100 mg t.i.d. (doubled 3 months ago), osomeprazole 20 mg q.d. , fluoxetine 20 mg q.d. and paracetamol in case of pain. 1 month ago the patient noted chest pain and dyspnoea at rest with no other respiratory, extra-thoracic or general symptoms. Chest pain increased leading to hospitalisation in the Dept of Neurology. Clinical examination found no serious organ failure, fever or signs of respiratory distress; however, the pulmonary examination showed a pleural syndrome of the left hemi-thorax. The rest of the physical examination was unremarkable, taking into account the patients pre-existing neurological sequelae. Laboratory tests showed leukocytosis with 85% of neutrophils without eosinophilia, C-reactive protein (CRP) of 15 mg·L−1, brain natriuretic peptide of 20 pg·mL−1 and normal hepatic, renal, thyroid and adrenal tests. The chest radiograph showed a left pleural effusion, right mediastinal deviation and a blunting of right costophrenic angle, without any associated parenchymal lesion. The computed tomography (CT) scan showed a large left pleural effusion, a small right pleural effusion and a moderate pericardial effusion. The CT scan did not show any parenchymal lesion, except a left lower lobe atelectasis in contact …