[Small airway diseases and immune deficiency]. / Atteinte des voies aériennes distales et immunodépression.

INTRODUCTION: Innate or acquired immune deficiency may show respiratory manifestations, often characterized by small airway involvement. The purpose of this article is to provide an overview of small airway disease across the major causes of immune deficiency. BACKGROUND: In patients with common variable immune deficiency, recurrent lower airway infections may lead to bronchiolitis and bronchiectasis. Follicular and/or granulomatous bronchiolitis of unknown origin may also occur. Bronchiolitis obliterans is the leading cause of death after the first year in patients with lung transplantation. Bronchiolitis obliterans also occurs in patients with allogeneic haematopoietic stem cell transplantation, especially in the context of systemic graft-versus-host disease. VIEWPOINT AND CONCLUSION: Small airway diseases have different clinical expression and pathophysiology across various causes of immune deficiency. A better understanding of small airways disease pathogenesis in these settings may lead to the development of novel targeted therapies.

Prevalence and reversibility of lung hyperinflation in adult asthmatics with poorly controlled disease or significant dyspnea.

BACKGROUND: In asthma, inflammation affects both the proximal and distal airways and may induce significant hyperinflation (HI). This study sought to evaluate the prevalence of HI in asthmatic patients with poorly controlled disease and/or dyspnea. METHODS: Poor asthma control was defined by an Asthma Control Test (ACT) score <20 (n = 287), and dyspnea was defined as a modified Medical Research Council score ≥1 (n = 18). HI was defined as either a residual volume/total lung capacity (RV/TLC) above the upper limit of normal (RV-HI) or a functional residual capacity (FRC) >120% predicted (FRC-HI). HI reversibility after administration of salbutamol (400 µg) was defined as a decrease in RV >20% or a reduction in FRC >10%. Changes in dyspnea and chest tightness were evaluated on a visual analogue scale. RESULTS: Both RV-HI and FRC-HI were observed in 48% of the 305 patients (mean ± SD age: 49 ± 17; FEV1 : 75 ± 18% predicted) included in the study. The prevalence of HI was higher in patients with a FEV1 <60% predicted (93% for RV-HI and 71% for FRC-HI, vs 21% and 41% in patients with a FEV1 > 80%). In patients with HI, the ACT score was lower and chest tightness higher. HI reversibility was obtained in 38% of the asthmatics with FRC-HI and 29% of the asthmatics with RV-HI, whereas FEV1 reversibility was obtained in half of these patients. CONCLUSIONS: HI is highly prevalent in poorly controlled asthmatics suggesting small airway dysfunction and may represent an additional criteria for evaluating responsiveness to bronchodilators.

[Prevention of COPD exacerbation: a fundamental challenge]. / Prévention des exacerbations de BPCO : un enjeu fondamental.

INTRODUCTION: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a cause of suffering for patients and a burden for healthcare systems and society. Their prevention represents individual and collective challenge. The present article is based on the work of a group of experts who met on 5th and 6th May 2011 and seeks to highlight the importance of AECOPD. STATE OF THE ART: In the absence of easily quantifiable criteria, the definition of AECOPD varies in the literature, making identification difficult and affecting interpretation of study results. Exacerbations increase mortality and risk of cardiovascular disease. They also increase the risk of developing further exacerbations, accelerate the decline in lung function and contribute to reduction in muscle mass. By limiting physical activity and affecting mental state (anxiety, depression), AECOPD are disabling and impair quality of life. They increase work absenteeism and are responsible for about 60% of the global cost of COPD. PERSPECTIVES: Earlier identification with simple criteria, possibly associated to patient phenotyping, could be helpful in preventing hospitalization. CONCLUSIONS: Given their immediate and delayed impact, AECOPD should not be trivialized or neglected. Their prevention is a fundamental issue.

[Lung volume reduction surgery for emphysema and bullous pulmonary emphysema]. / Chirurgie de réduction volumique et des bulles géantes dans l'emphysème pulmonaire.

The improvement of respiratory symptoms for emphysematous patients by surgery is a concept that has evolved over time. Initially used for giant bullae, this surgery was then applied to patients with diffuse microbullous emphysema. The physiological and pathological concepts underlying these surgical procedures are the same in both cases: improve respiratory performance by reducing the high intrapleural pressure. The functional benefit of lung volume reduction surgery (LVRS) in the severe diffuse emphysema has been validated by the National Emphysema Treatment Trial (NETT) and the later studies which allowed to identify prognostic factors. The quality of the clinical, morphological and functional data made it possible to develop recommendations now widely used in current practice. Surgery for giant bullae occurring on little or moderately emphysematous lung is often a simpler approach but also requires specialised support to optimize its results.

[Eosinophilic pleural effusion related to taking valproic acid]. / Une pleurésie à éosinophiles liée à la prise d'acide valproïque.

Eosinophilic pleural effusions have multiple aetiologies. We report on the case of a 40-year-old man who experienced an eosinophilic pleural effusion with blood hypereosinophilia that occurred nine weeks after a treatment with valproic acid was introduced. Usual aetiologies of eosinophilic pleural effusion were excluded. Once valproic acid was discontinued, both pleural effusion and blood eosinophilia decreased rapidly. The persistence of a residual pleural effusion required the introduction of oral corticosteroids, which resulted in the effusion disappearing completely and rapidly. Valproic acid is a rare cause of eosinophilic pleural effusion. The effusion usually regresses when treatment is discontinued but short-term oral corticotherapy may be necessary in order to heal the patient.

[Symptoms and natural history of COPD: role of the distal airways]. / Symptômes et histoire naturelle de la BPCO : rôle des voies aérienne distales.

Symptoms and natural history of COPD: role of the distal airways. The natural history of chronic obstructive pulmonary disease (COPD) is characterized by a progressive worsening of airway obstruction and health-related quality of life, and an increased risk of death. Symptoms of COPD are dominated by cough, sputum production and dyspnoea whose intensity varies between individuals and during the progression of the disease. The symptoms and natural history of COPD result from damage to the airways, including remodelling and inflammation, which commence and are predominant in the distal airways (DA). This article examines the relationship between symptoms and the natural history of COPD in the light of large cohorts published in the literature. The role of the DA in the development and intensity of symptoms and in the natural history of COPD is difficult to define. We have attempted to examine this role using either published studies which have evaluated the relationship between lung structure and the clinical phenotypes of COPD or studies involving the earlier stages of the disease when damage to the DA are known to be predominant. These data suggest a potential role for early therapies targeting remodelling and inflammation in the distal airways of patients suffering from COPD.

[Management of acute and severe complications in adults with cystic fibrosis]. / Prise en charge des complications aiguës sévères chez l'adulte mucoviscidosique.

The natural history of cystic fibrosis (CF) may be associated both with acute respiratory complications (respiratory exacerbations, haemoptysis, pneumothorax) and with non-respiratory complications (distal intestinal obstruction syndrome, dehydration) that may result in hospitalizations. The aim of this article is to describe the main therapeutic approaches that are adopted in the management of acute complications occurring in CF adults, and to discuss indications for admission of these patients to intensive care units. Adult CF patients admitted to intensive care unit often benefit from antibiotic courses adapted to their chronic bronchial infection, especially when the hospitalization is related to respiratory disease (including haemoptysis and pneumothorax). Nutritional support, including hypercaloric diet, control of hyperglycemia and pancreatic enzyme supplementation is warranted. The recommended therapy for major haemoptysis is bronchial artery embolization. Patient with significant pneumothorax should have a chest tube inserted, while the treatment of distal intestinal obstruction syndrome will most often be medical. In case of respiratory failure, non-invasive ventilation is the preferred mode of ventilatory support because invasive ventilation is associated with poor outcomes. Therapeutic options should always have been discussed between the patient, family members and the CF medical team to allow for informed decision making.

Update on the roles of distal airways in COPD.

This review is the summary of a workshop on the role of distal airways in chronic obstructive pulmonary disease (COPD), which took place in 2009 in Vence, France. The evidence showing inflammation and remodelling in distal airways and the possible involvement of these in the pathobiology, physiology, clinical manifestations and natural history of COPD were examined. The usefulness and limitations of physiological tests and imaging techniques for assessing distal airways abnormalities were evaluated. Ex vivo studies in isolated lungs and invasive measurements of airway resistance in living individuals have revealed that distal airways represent the main site of airflow limitation in COPD. Structural changes in small conducting airways, including increased wall thickness and obstruction by muco-inflammatory exudates, and emphysema (resulting in premature airway closure), were important determinants of airflow limitation. Infiltration of small conducting airways by phagocytes (macrophages and neutrophils), dendritic cells and T and B lymphocytes increased with airflow limitation. Distal airways abnormalities were associated with patient-related outcomes (e.g. dyspnoea and reduced health-related quality of life) and with the natural history of the disease, as reflected by lung function decline and mortality. These data provide a clear rationale for targeting distal airways in COPD.

Pseudomonas aeruginosa induces vascular endothelial growth factor synthesis in airway epithelium in vitro and in vivo.

Pseudomonas aeruginosa (PA) airway infection and bronchial blood vessel proliferation are features of bronchiectasis. Because vascular endothelial growth factor (VEGF)-A regulates angiogenesis, we hypothesised that PA infection induces VEGF synthesis in epithelium and peribronchial angiogenesis. Because epidermal growth factor receptor (EGFR) activation regulates VEGF synthesis in cancer, we also evaluated the roles of EGFR. Airway epithelial cells were incubated for 24 h with PA supernatants and VEGF concentrations were measured in culture medium by ELISA. C57BL/6N mice were instilled intratracheally with sterile agarose beads or with agarose beads coated with the PA strain PAO1 (mean ± sem 6 × 10(5) ± 3 × 10(5) cfu · animal(-1)), with or without the EGFR inhibitor AG1478 (12.5 mg · kg(-1) · day(-1) intraperitoneally). Epithelial immunostaining for VEGF and phosphorylated EGFR, and peribronchial vascularity, were quantified using morphometric analysis. VEGF expression was further assessed by western blot in mouse lung homogenates. PA supernatants induced dose-dependent VEGF synthesis in cultured airway epithelial cells, effects which were prevented by EGFR antagonists. In mice, persistent PAO1 infection increased immunostaining for VEGF and phosphorylated EGFR in airway epithelium, and resulted in increased peribronchial vascularity within 7 days. These effects were reduced by EGFR inhibition. Persistent PA infection induced VEGF synthesis in airway epithelium and peribronchial angiogenesis, at least in part via EGFR-dependent mechanisms.

Report of the 2nd "French Clinical Vaccinology Meeting Jean-Gerard Guillet": immunization and respiratory diseases.

The 2nd French Clinical Vaccinology conference held on 20th April 2009 in Paris (France) was a unique opportunity to discuss basic and translational research in vaccinology and its implications for patients for respiratory diseases. This conference is organized by the Clinical Research Center Cochin-Pasteur, that has been involved for several years clinical research in vaccines. We report on here the key findings of the conference, especially the immunization of the chronic respiratory diseases, the clinical effectiveness of vaccines and the development of new vaccines in pulmonology.

Non-classic cystic fibrosis associated with D1152H CFTR mutation.

BACKGROUND: Limited knowledge exists on phenotypes associated with the D1152H cystic fibrosis transmembrane conductance regulator (CFTR) mutation. METHODS: Subjects with a D1152H allele in trans with another CFTR mutation were identified using the French Cystic Fibrosis Registry. Phenotypic characteristics were compared with those of pancreatic insufficient (PI) and pancreatic sufficient (PS) cystic fibrosis (CF) subjects in the Registry (CF cohort). RESULTS: Forty-two subjects with D1152H alleles were identified. Features leading to diagnosis included chronic sinopulmonary disease (n = 25), congenital absence of the vas deferens (n = 11), systematic neonatal screening (n = 4), and genetic counseling (n = 2). Median age at diagnosis was 33 [interquartile range (IQR, 24-41)] years in D1152H subjects. Median sweat chloride concentrations were 43.5 (39-63) mmol/l in D1152H subjects and were markedly lower than in PI and PS CF subjects (p < 0.05). Bronchiectasis was present in 67% of D1152H subjects, but Pseudomonas aeruginosa colonization and pancreatic insufficiency were present in <30% of subjects. Estimated rates of decline in forced expiratory volume in 1 s (FEV(1)) were lower in D1152H subjects vs PI CF subjects (p < 0.05). None of the D1152H subjects identified since 1999 had died or required lung transplantation. CONCLUSIONS: When present in trans with a CF-causing mutation, D1152H causes significant pulmonary disease, but all subjects had prolonged survival.

Prognostic factors for lung function in systemic sclerosis: prospective study of 105 cases.

The aims of the present study were to identify prognostic factors for systemic sclerosis (SSc)-related interstitial lung disease and to clarify the possible causative role of manometric oesophageal involvement. Consecutive SSc patients underwent pulmonary function tests and oesophageal manometry. They were included in the study if pulmonary function tests were repeated >12 months after baseline. The primary end-point was a decrease of >or=10% of the predicted value in forced vital capacity (FVC). The secondary end-points were a decrease of >or=15% pred in lung carbon monoxide diffusing capacity (D(L,CO)) and a decrease of >or=20% pred in FVC. Of the 105 patients (45 diffuse SSc; median disease duration 2.0 yrs), 23 (23%) had a FVC of <80% pred, 60 (59%) had a D(L,CO) of <80% pred and 57 (54%) showed severe oesophageal hypomotility at baseline. Over 72+/-46 months, 29 (28%) patients displayed a decrease of >or=10% pred in FVC, 39 (40%) of 98 patients displayed D(L,CO) decline and 19 (18%) patients displayed a decrease of >or=20% pred in FVC. On multivariate analysis, diffuse SSc was a significant predictor for a decrease of >or=10% pred in FVC (p = 0.01). No other predictor of a decrease in pulmonary function was identified. Only diffuse SSc was predictive of a decrease in pulmonary function in this early-SSc cohort. This does not support preliminary data suggestive of a causative role of oesophageal involvement.

[Treatments targeting distal airways in asthma: update on clinical studies]. / Les traitements ciblant les voies aériennes distales dans l'asthme: analyse des études cliniques.

Two strategies are possible for targeting distal airways in asthma. The first one is systemic, with the delivery of medications either orally or intravenously. Montelukast is the only oral drug that has demonstrated its efficacy on distal airways by reducing lung hyperinflation. The second possible strategy is to deliver inhaled medications using ultrafine particles. Studies performed with formoterol-HFA solution (Formoair Modulite), the only available long-acting beta2 agonist with ultrafine particles have shown a non-inferior bronchodilator effect and a good tolerance as compared to inhaled long acting beta2 agonists with non-ultrafine particles. Studies performed with BDP-HFA alone (QVAR) or combined BDP-HFA/formoterol (Fostair) with ultrafine particles have mostly demonstrated their clinical non- inferiority on bronchodilation, quality of life, and symptoms in asthmatic subjects as compared to non-ultrafine inhaled medications. With the exception of a few studies, most publications have been performed in a limited number of patients and for only short durations. The available studies have not yet demonstrated a long-term benefit in terms of additional clinical efficacy of these ultrafine inhaled medications on symptoms, control and exacerbations of asthma.