Defining the "Frequent Exacerbator" Phenotype in COPD: A Hypothesis-Free Approach.

BACKGROUND: The COPD "frequent exacerbator" phenotype is usually defined by at least two treated exacerbations per year and is associated with a huge impact on patient health. However, existence of this phenotype and corresponding thresholds still need to be formally confirmed by statistical methods analyzing exacerbation profiles with no specific a priori hypothesis. The aim of this study was to confirm the existence of the frequent exacerbator phenotype with an innovative unbiased statistical analysis of prospectively recorded exacerbations. METHODS: Data from patients with COPD from the French cohort in Exacerbations of COPD Patients (EXACO) were analyzed using the KmL method designed to cluster longitudinal data and receiver operating characteristic (ROC) curve analysis to determine the best threshold to allocate patients to identified clusters. Univariate and multivariate analyses were performed to study characteristics associated with different clusters. RESULTS: Two clusters of patients were identified based on exacerbation frequency over time, with 2.89 exacerbations per year on average in the first cluster (n = 348) and 0.71 on average in the second cluster (n = 116). The best threshold to distinguish these clusters was two moderate to severe exacerbations per year. Frequent exacerbators had more airflow limitation, symptoms, and health-related quality of life impairment. A simple clinical score was derived to help identify patients at risk of exacerbations. CONCLUSIONS: These analyses confirmed the existence and clinical relevance of a frequent exacerbator subgroup of patients with COPD and the currently used threshold to define this phenotype.

Mast cells are associated with exacerbations and eosinophilia in children with severe asthma.

The role of mast cells in the pathogenesis of childhood asthma is poorly understood. We aimed to estimate the implication of airway mucosal mast cells in severe asthma and their relationship with clinical, functional, inflammatory and remodelling parameters.Bronchial biopsies were performed in 36 children (5-18 years) with severe asthma: 24 had frequent severe exacerbations and/or daily symptoms in the previous year (symptomatic group), and 12 had few symptoms and a persistent obstructive pattern (paucisymptomatic group). Nine children without asthma were included as control subjects. We assessed mast cells in the submucosa and airway smooth muscle using c-kit antibodies and in the entire biopsy area using Giemsa.The number of submucosal mast cells was higher in the symptomatic group than in the paucisymptomatic group (p=0.02). The number of submucosal mast cells correlated with the number of severe exacerbations (p=0.02, r=0.37). There were positive correlations between the number of submucosal mast cells (p<0.01, r=0.44), airway smooth muscle mast cells (p=0.02, r= 0.40), mast cells stained by Giemsa (p<0.01, r=0.44) and submucosal eosinophils.Mast cells are associated with severe exacerbations and submucosal eosinophilic inflammation in children with severe asthma.

Clinical characteristics and quality of life in women with COPD: an observational study.

BACKGROUND: The impact of COPD on patient's quality of life is well established, but gender differences have received little attention. METHODS: To describe factors associated with the health-related quality of life by gender: A cross-sectional observational study (NCT01007734) was conducted in COPD patients followed by pulmonologists. The first patient included had to be a woman. Data concerning the patient, COPD and their management were collected by the physician. The patient had to fill in several questionnaires: Saint-George Hospital respiratory Questionnaire (SGRQ-C), and motivation to quit smoking. RESULTS: Four hundred and thirty patients were included: mean age 63.9 ± 11.3 years; 57.4% were women. Women were significantly younger than men (61.9 vs. 66.6) and their tobacco use was lower (37.1 vs. 40.4 PY). Cardiovascular comorbidities were more frequent in men while osteoporosis, anxiety and depression were frequent in women. The frequency of cough, sputum and the severity of dyspnea did not differ significantly between genders. Lung function impairment was less severe in women than in men (mean FEV1 52% predicted normal vs. 47. 8%). Anxiety score was higher (score 9.8 vs. 7.1) and quality of life (SGRQ-C) more impaired in women (scores 50.6 vs. 45.4; p < 0.02) than in men. Moreover, in multivariate analysis, chronic sputum was associated with higher SGRQ-C scores in women but not in men. CONCLUSIONS: This study underlines that despite less airflow limitation, quality of life is more impacted by chronic sputum in women than in men.

Crohn's disease and nontropical endomyocardial fibrosis.

The pathogenesis of endomyocardial fibrosis (EMF) is poorly understood. EMF may result from autoimmune scarring of the endocardium. Clinically, EMF presents as a restrictive cardiomyopathy. EMF is commonly reported in tropical countries. In Western countries, EMF is associated with hypereosinophilia and reported as Loeffler endocarditis. We report a Caucasian patient with Crohn's disease and EMF, and discuss a possible linkage between the two conditions.

Small airways diseases, excluding asthma and COPD: an overview.

This review is the summary of a workshop on small airways disease, which took place in Porquerolles, France in November 2011. The purpose of this workshop was to review the evidence on small airways (bronchiolar) involvement under various pathophysiological circumstances, excluding asthma and chronic obstructive pulmonary disease. Histopathological patterns associated with small airways disease were reviewed, including cellular and obliterative bronchiolitis. Many pathophysiological conditions have been associated with small airways disease including airway infections, connective tissue diseases and inflammatory bowel diseases, bone marrow and lung transplantation, common variable immunodeficiency disorders, diffuse panbronchiolitis, and diseases related to environmental exposures to pollutants, allergens and drugs. Pathogenesis, clinical presentation, a computed tomography scan and pulmonary function test findings are reviewed, and therapeutic options are described with the objective of providing an integrative approach to these disorders.

The lung is involved in juvenile dermatomyositis.

BACKGROUND: Juvenile dermatomyositis (JDM) is the main cause of chronic idiopathic inflammatory myopathy of autoimmune origin in children. The aim of this multicenter prospective study was to describe respiratory status and treatment of children followed for JDM. METHODS AND PATIENTS: Clinical manifestations, pulmonary function tests (PFT), chest high-resolution computed tomography (HRCT) scan results, and treatments and their adverse effects were analyzed in children followed for JDM. RESULTS: Twenty-one patients (median age: 9.9 years; range: 20 months-18 years) were included. The median of disease duration at the time of the analysis was 3 years (range: 6 months-9 years 4 months). Overall 16 (76%) of 21 children presented with a respiratory involvement related to JDM including interstitial lung disease (n = 3) and/or respiratory muscle involvement (n = 7). Seven patients presented with other nonspecific manifestations. Three children had aspiration pneumonia. A chest HRCT was performed in 15 children, and abnormalities were observed in 12. PFT were performed in 20 of 21 patients. Seven showed functional abnormalities: restrictive ventilatory defect (n = 3) or obstructive ventilatory defect (n = 4). Six patients had abnormal respiratory muscle tests, including three with a restrictive ventilatory defect and one with an obstructive ventilatory defect. One other child with an acute aspiration pneumonia had a clearly muscle respiratory involvement but was too young to perform respiratory muscle tests and confirm this diagnosis. Treatment comprised systemic corticosteroid for all patients and adjuvant immunosuppressive therapy for 11. Adverse effects linked to treatment were reported in eight patients. CONCLUSION: The frequency of lung involvement in children with JDM justifies systematic respiratory assessment with PFT including measures of respiratory muscle strength. We suggest that a chest HRCT scan is indicated in cases of respiratory symptoms and/or PFT abnormalities. Longitudinal studies are needed to assess pediatric characteristics, long-term outcomes, and responses to treatment taking into account the risk-benefit ratio.

Difficult childhood asthma: management and future.

Diagnosis and management of severe asthma implies the definition of different entities, that is, difficult asthma and refractory severe asthma, but also the different phenotypes included in the term refractory severe asthma. A complete evaluation by a physician expert in asthma is necessary, adapted for each child. Identification of mechanisms involved in different phenotypes in refractory severe asthma may improve the therapeutic approach. The quality of care and monitoring of children with severe asthma is as important as the prescription drug, and is also crucial for differentiating between severe asthma and difficult asthma, whereby expertise is required.

Do we need exercise tests to detect gas exchange impairment in fibrotic idiopathic interstitial pneumonias?

In patients with fibrotic idiopathic interstitial pneumonia (f-IIP), the diffusing capacity for carbon monoxide (DLCO) has been used to predict abnormal gas exchange in the lung. However, abnormal values for arterial blood gases during exercise are likely to be the most sensitive manifestations of lung disease. The aim of this study was to compare DLCO, resting PaO(2), P(A-a)O(2) at cardiopulmonary exercise testing peak, and oxygen desaturation during a 6-min walk test (6MWT). Results were obtained in 121 patients with idiopathic pulmonary fibrosis (IPF, n = 88) and fibrotic nonspecific interstitial pneumonias (NSIP, n = 33). All but 3 patients (97.5%) had low DLCO values (35 mmHg) and 100 (83%) demonstrated significant oxygen desaturation during 6MWT (>4%). Interestingly 27 patients had low DLCO and normal P(A-a)O(2), peak and/or no desaturation during the 6MWT. The 3 patients with normal DLCO also had normal PaO(2), normal P(A-a)O(2), peak, and normal oxygen saturation during 6MWT. Our results demonstrate that in fibrotic IIP, DLCO better defines impairment of pulmonary gas exchange than resting PaO(2), exercise P(A-a)O(2), peak, or 6MWT SpO(2).

Frequent and widespread vascular abnormalities in human signal transducer and activator of transcription 3 deficiency.

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) deficiency is responsible for autosomal dominant hyperimmunoglobulin E syndrome, characterized by recurrent bacterial and fungal infections, connective tissue abnormalities, hyperimmunoglobulin E, and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics, and etiology of these features have yet to be described. METHODS AND RESULTS: We prospectively screened 21 adult STAT3-deficient patients [corrected] (median age, 26 years; range, 17-44 years) [corrected] for vascular abnormalities. We explored the entire arterial vasculature with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography, and echo-tracking-based imaging specifically for the [corrected] carotid arteries. We also assayed for serum biomarkers of inflammation and endothelial dysfunction. Finally, we studied murine models of aortic aneurysm in the presence and absence of inhibitors of STAT3-dependent signaling. Ninety-five percent of patients showed brain abnormalities (white matter hyperintensities, lacunar lesions suggestive of ischemic infarcts, and atrophy). We reported peripheral and brain artery abnormalities in 84% of the patients and detected coronary artery abnormalities in 50% of the patients. The most frequent vascular abnormalities were ectasia and aneurysm. The carotid intima-media thickness was markedly decreased, with a substantial increase in circumferential wall stress, indicating the occurrence of hypotrophic arterial remodeling in this STAT3-deficient population. Systemic inflammatory biomarker levels correlated poorly with the vascular phenotype. In vivo inhibition of STAT3 signaling or blockade of IL-17A resulted in a marked increase in aneurysm severity and fatal rupture in mouse models. CONCLUSIONS: Vascular abnormalities are highly prevalent in patients with STAT3 deficiency. This feature is consistent with the greater susceptibility to vascular aneurysm observed after inhibition of STAT3-dependent signaling in mouse models.

[When to consider COPD and how to assess it?]. / Quand penser a la BPCO et comment I'evaluer?

Detected in 30% of COPD patients and underdiagnosed, COPD must be systematically investigated in all about 40 years-old smokers, without waiting for clinical symptoms, late and inconstant. The diagnosis is made with spirometry. Search for a status of "frequent exacerbations", co-morbidities (including cardio-vascular disease), evaluation of dyspnea intensity with a scale (MRC), assessment of disease impact on daily life, allow to identify risk groups and to target the therapeutic management overall. Pulmonary rehabilitation, in addition to medication, improves dyspnea, and decreases the impact of COPD on daily life.

Pulmonary manifestations of Sjögren's syndrome.

Sjögren's syndrome is a chronic inflammatory disorder characterized by lymphocytic infiltration of exocrine glands, mainly the lacrimal and salivary glands. However, extraglandular organ systems may frequently be involved, including the lungs. Although subclinical pulmonary inflammation exists in more than 50% of patients, clinically significant pulmonary involvement affects approximately 10% of patients and may be the first manifestation of the disease. The entire respiratory tract may be involved, with a wide spectrum of manifestations including xerotrachea and bronchial sicca, obstructive small airway disease, various patterns of interstitial lung disease, lymphoinfiltrative or lymphoproliferative lung disease, such as lymphoma (usually of MALT type), pulmonary hypertension, pleural involvement, lung cysts, and pulmonary amyloidosis.

Immuno-reactive proteins from Mycobacterium immunogenum useful for serodiagnosis of metalworking fluid hypersensitivity pneumonitis.

Metalworking fluid-associated hypersensitivity pneumonitis (MWF-HP) is a pulmonary disease caused by inhaling microorganisms present in the metalworking fluids used in the industrial sector. Mycobacterium immunogenum is the main etiological agent. Among the clinical, radiological and biological tools used for diagnosis, serological tests are important. The aim of this study was to identify immunogenic proteins in M. immunogenum and to use recombinant antigens for serological diagnosis of MWF-HP. Immunogenic proteins were detected by two-dimensional Western blot and candidate proteins were identified by mass spectrometry. Recombinant antigens were expressed in Escherichia coli and tested by enzyme-linked immunosorbent assay (ELISA) with the sera of 14 subjects with MWF-HP and 12 asymptomatic controls exposed to M. immunogenum. From the 350 spots visualized by two-dimensional gel electrophoresis with M. immunogenum extract, 6 immunogenic proteins were selected to be expressed as recombinant antigens. Acyl-CoA dehydrogenase antigen allowed for the best discrimination of MWF-HP cases against controls with an area under the receiver operating characteristics (ROC) curve of 0.930 (95% CI=0.820-1), a sensitivity of 100% and a specificity of 83% for the optimum threshold. Other recombinant antigens correspond to acyl-CoA dehydrogenase FadE, cytosol aminopeptidase, dihydrolipoyl dehydrogenase, serine hydroxymethyltransferase and superoxide dismutase. This is the first time that recombinant antigens have been used for the serodiagnosis of hypersensitivity pneumonitis. The availability of recombinant antigens makes it possible to develop standardized serological tests which in turn could simplify diagnosis, thus making it less invasive.

Predictive factors for evaluation of response to fluticasone propionate/salmeterol combination in severe COPD.

BACKGROUND: The predictive factors for treatment response in patients with severe chronic obstructive pulmonary disease (COPD) are unknown. We investigated predictive factors for response to fluticasone propionate/salmeterol (FSC) in severe COPD patients. METHODS: This prospective, open-label, non-comparative study included 921 adult patients with severe COPD (baseline forced expiratory volume in 1 s (FEV(1)) <50% of predicted), a history of repeated exacerbations, and symptoms despite bronchodilator treatment. FSC (500 µg/50 µg) was delivered via an inhaler, twice a day, for 12 weeks. The primary efficacy endpoint was the response rate for inspiratory capacity (IC), FEV(1), or quality of life (QoL), assessed with the Saint George's respiratory questionnaire, at week 6 and week 12. RESULTS: The overall response rate to FSC at 6 and 12 weeks was 79%. The corresponding rates for FEV(1), IC, and QoL were 38%, 55%, and 62%, respectively. More than 40% of patients showed a response for IC and/or QoL without being responders for FEV(1.) Overall lung function and QoL were improved. FSC was well tolerated with a safety profile consistent with that observed previously. CONCLUSION: Nearly 80% of patients responded to FSC treatment in this real-life study. Improvements in IC and QoL at 12 weeks revealed a clinically relevant response in patients with no improvement in FEV(1). IC reversibility to salbutamol before treatment might represent, better than FEV1, a prognostic factor of response to FSC in severe COPD. Moreover these tests are easy to perform routinely and in large numbers of patients.

Cryptogenic hemoptysis in chronic obstructive pulmonary disease: characteristics and outcome.

BACKGROUND: Hemoptysis is a common presenting symptom and cause of hospitalization in the department of respiratory diseases. In a number of patients with chronic obstructive pulmonary disease (COPD) presenting with this symptom, investigations fail to reveal a precise etiology. Little data are available regarding characteristics and outcome of COPD patients presenting with cryptogenic hemoptysis (CH). OBJECTIVES: Our study goal was to assess the functional characteristics of these subjects, the risk factors for CH and the severity of hemoptysis, as well as long-term outcome. METHODS: For more than 1 year, we enrolled and followed a group of 39 consecutive COPD patients admitted to our center with CH. RESULTS: Between 1988 and 2003, 39 patients with COPD were admitted for CH in which investigation failed to reveal an etiology. The mean age was 51.3 years. All subjects were active smokers. Twenty-one patients (54%) had at least 1 risk factor for prolonged bleeding. Patients with more severe airflow obstruction tended to have more severe bleeding. Bronchoscopy appeared as useful as a computed tomography in locating the bleeding site. Arterial embolization succeeded in controlling bleeding in all patients who underwent angiography. One patient experienced a relapse in bleeding at 2 months. One developed lung cancer after 1 year. Thirty-four patients were followed for an average of 5 years. Only 2 subjects experienced recurrent hemoptysis. None died. CONCLUSIONS: CH in patients with COPD is associated with a favorable short- and long-term outcome when managed with timely angiographic embolization. Long-term incidence of lung cancer was uncommon after an episode of CH, and recurrences of hemoptysis were rare.

[Improving the control of asthma]. / Comment améliorer le contrôle de l'asthme ?

Asthma control is the cornerstone of monitoring for patients with this disease. Monitoring limited to questions of the type "how is your asthma?" underestimates the real effects of the disease. Measuring control requires assessing several criteria, which differ by the kinetics of their course during treatment. Basing monitoring on only a single criterion risks overestimating control, stepping down treatment too early, and losing control of the disease. In the case of inadequate control, uncontrolled comorbid conditions and aggravating factors or poor treatment adhesion must be sought before determining that the treatment itself is insufficient. After stepping up treatment, the chances of obtaining adequate control increase progressively with time, for at least a year. When the physician and patient jointly determine that the current treatment is the maximum acceptable, waiting may be a solution. Similarly, in seeking the minimal efficacious treatment, treatment must not be stepped down too rapidly. Once control is obtained, continuation of the treatment maintains long-term control for most patients.