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.

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.

[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.

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.

Role of A disintegrin and metalloprotease-12 in neutrophil recruitment induced by airway epithelium.

Among proteases, metalloproteases are implicated in tissue remodeling, as shown in numerous diseases including allergy. ADAMs (A Disintegrin And Metalloprotease) metalloproteases are implicated in physiologic processes such as cytokine and growth factor shedding, cell migration, adhesion, or repulsion. Our aim was to measure ADAM-12 expression in airway epithelium and to define its role during the allergic response. To raise this question, we analyzed the ADAM-12 expression ex vivo after allergen exposure in patients with allergic rhinitis and in vitro in cultured primary human airway epithelial cells (AEC). Clones of BEAS-2B cells transfected with the full-length form of ADAM-12 were generated to study the consequences of ADAM-12 up-regulation on AEC function. After allergen challenge, a strong increase of ADAM-12 expression was observed in airway epithelium from patients with allergic rhinitis but not from control subjects. In contrast with the other HB-epidermal growth factor sheddases, ADAM-10 and -17, TNF-alpha in vitro increased the expression of ADAM-12 by AEC, an effect amplified by IL-4 and IL-13. Up-regulation of ADAM-12 in AEC increased the expression of alpha3 and alpha4 integrins and to the modulation of cell migration on fibronectin but not on collagen. Moreover, overexpression of ADAM-12 in BEAS-2B enhanced the secretion of CXCL1 and CXCL8 and their capacity to recruit neutrophils. CD47 was strongly decreased by ADAM-12 overexpression, a process associated with a reduced adhesion of neutrophils. These effects were mainly dependent on epidermal growth factor receptor activation. In summary, ADAM-12 is produced during allergic reaction by AEC and might increase neutrophil recruitment within airway mucosa.

[Refractory asthma: diagnosing allergic bronchopulmonary aspergillosis]. / Asthme réfractaire: évoquer une aspergillose bronchopulmonaire allergique.

Allergic bronchopulmonary aspergillosis (ABPA) results from a twofold mechanism: Th2-like hypersensitivity reaction and bronchial colonization by Aspergillus fumigatus. This relatively rare disease occurs in immunocompetent patients in two very different situations: refractory asthma and cystic fibrosis. Diagnosis in asthma patients is relatively easy; it is based on the association of several criteria: clinical (recurrent exacerbations despite adequate therapy and a positive A. fumigatus skin prick-test), laboratory (inconsistent blood eosinophilia, high serum levels of total IgE, presence of A. fumigatus-specific IgE and IgG) and radiological (mainly central bronchiectasis, sometimes transitory pulmonary infiltrates). Diagnosis is more difficult in patients with cystic fibrosis because of the similarity of their various criteria. Long-term prognosis is good in the early stages of the illness, although the natural history and course of the disease are not fully understood. Early diagnosis and active screening for exacerbations are recommended to prevent bronchiectasis and progression to end-stage lung disease. Two drugs have shown their efficacy in treating ABPA: corticosteroids and itraconazole. They are recommended in acute exacerbations and should not be used as long-term therapy, except in corticosteroid-dependent asthma and in some cases of cystic fibrosis.

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.

Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors.

BACKGROUND: Diagnosis of pulmonary embolism (PE) is difficult in patients with chronic obstructive pulmonary disease (COPD) and exacerbation. OBJECTIVE: To evaluate PE in patients with COPD and exacerbation of unknown origin and explore factors associated with PE. DESIGN: Prospective cohort study. SETTING: University-affiliated hospital in France. PATIENTS: 211 consecutive patients, all current or former smokers with COPD, who were admitted to the hospital for severe exacerbation of unknown origin and did not require invasive mechanical ventilation. MEASUREMENTS: Spiral computed tomography angiography (CTA) and ultrasonography within 48 hours of admission and assessment of the Geneva score. Patients were classified as PE positive (positive results on CTA or negative results on CTA and positive results on ultrasonography) or PE negative (negative results on CTA and negative results on ultrasonography or negative results on CTA and no recurrence of PE at follow-up 3 months later). RESULTS: 49 of 197 patients (25% [95% CI, 19% to 32%]) met the diagnostic criteria for PE. Clinical factors associated with PE were previous thromboembolic disease (risk ratio, 2.43 [CI, 1.49 to 3.94]), malignant disease (risk ratio, 1.82 [CI, 1.13 to 2.92]), and decrease in PaCO2 of at least 5 mm Hg (risk ratio, 2.10 [CI, 1.23 to 3.58]). A total of 9.2% (CI, 4.7% to 15.9%) of patients with a low-probability Geneva score received a diagnosis of PE. An exploratory analysis suggested that substituting malignant disease for recent surgery in the Geneva score might improve its performance in excluding PE in this sample who were more likely to have malignant disease than to have had recent surgery. However, this improvement seems insufficient to exclude PE with enough certainty to withhold therapy for low-risk patients on the basis of the modified score. LIMITATIONS: This study was done in only 1 center. Patients with COPD requiring invasive mechanical ventilation in the intensive care unit were not included. The upper bound of the 95% CI for the low probability of PE according to the Geneva score is too high to rule out PE. The classification of COPD exacerbation of unknown origin was based on the clinician's assessment, not on a standard evaluation for all patients. CONCLUSION: This study showed a 25% prevalence of PE in patients with COPD hospitalized for severe exacerbation of unknown origin. Three clinical factors are associated with the increased risk for PE. The Geneva score and the modified Geneva score should be prospectively evaluated in patients with COPD.

Pulmonary manifestations of Pyoderma gangrenosum.

INTRODUCTION: Pyoderma gangrenosum is an uncommon ulcerative cutaneous disorder. Extracutaneous localizations are rare. Respiratory system involvement has been described in a few cases, but the pulmonary features reported were highly variable. CASE: We report two cases of patients with Pyoderma gangrenosum combining cutaneous and pulmonary manifestations. One case presented multiple nodular lesions, some with cavitation. The underlying disease was varicella-zoster virus infection. The second presented pneumonitis with bronchiolar micronodules. DISCUSSION: Few cases have reported Pyoderma gangrenosum with pulmonary involvement, which appears to be manifested mainly as nodules or interstitial lung disease. The principal differential diagnosis is Wegener's granulomatosis.

[IqE dependent hypersensitivity and allergic inflammation]. / Hypersensibilité IgE-dépendante et inflammation allergique.

The development of the IgE-dependent inflammatory reaction is made of 3 successives phases. The initiation period is related to dendritic cells, present everywhere in peripheral tissues, able after maturation to migrate to the draining lymph-node and to present immunogenic peptides to the naïve T lymphocyte. After this first step of sensitization, in case of a new contact with allergens, the inflammatory phase is rapidly developing: mast cell activation, then massive influx of eosinophils, neutrophils and mononuclear phagocytes, all phenomenas under the control of different T-lymphocyte subpopulations: T-CD4+ cells with a pro-allergic Th2 profile but also newly identified T regulatory cells (Tr-1, T CD4+ CD25+). The third phase concerns the repair process or more often in case of repeated allergenic aggressions, a remodelling process such as observed in patients with severe allergic asthma. All these data have lead to reconsider our understanding of the allergic reaction. In fact allergy seems to result from an aberrant immune response to the environmental allergens, while the non-atopic subject, exposed to the same allergens will develop a natural tolerance.

Costs of hospitalization for severe acute asthma of patients not treated according to guidelines and recommendations. French prospective study of 169 cases.

This prospective study of 169 adult patients hospitalized for severe acute asthma in four pneumology wards compared the incidence and costs of patients who were managed (group A) or not managed (group P) before hospitalization, according to the guidelines and international recommendations (11 criteria judged by experts). Ambulatory costs were calculated by questioning patients. Valuation of hospital costs was based DRGs weighted by length of stay. The incidence in group P patients was estimated at 70%; A patients were 14 years younger than those in group P and had less severe asthma. Their annual ambulatory care prior to hospitalization was less costly irrespective of age category or degree of severity (euro 685 vs. euro 1,145 in group A); their length of hospital stay was shorter (6.03 vs. 10.78 days), resulting in a lower cost of hospitalization (euro 2,820 vs. euro 4,843). In group P a specific education program based on increased understanding, compliance, self-management, and smoking cessation, particularly in young patients should lead to reductions in hospitalizations.

[Diagnosis of asthma in adult]. / Diagnostic de l'asthme chez l'adulte.

Asthma is underdiagnosed in France. Asthma can often be diagnosed on the basis of symptoms, help by specific questions useful to consider the diagnosis. Measurement of lung function is important, for diagnosis, evaluation of the reversibility, the variability and the severity of bronchial obstruction. Indeed, patient with asthma may have a poor recognition of their symptoms and a poor perception of bronchial obstruction. Peak expiratory flow meter is an important aid in the diagnosis of asthma but measurements do not always correlate with other measurements of lung function. Allergic status and risk factors must be identified to control environmental exposure.

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.

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.