Identification of a Novel Elastin-Degrading Enzyme from the Fish Pathogen Flavobacterium psychrophilum.

Hydrolytic extracellular enzymes degrading host tissues potentially play a role in bacterial pathogenesis. Flavobacterium psychrophilum is an important bacterial pathogen of salmonid fish reared in freshwater throughout the world. Diversity among isolates has been described at the phenotypic, serological, and genomic levels, but the links between these various traits remain poorly understood. Using a genome-wide association study, we identified a gene encoding a novel elastinolytic enzyme in F. psychrophilum To formally demonstrate enzymatic activity, this gene (FP0506 from strain JIP 02/86) was expressed in the elastinolysis-deficient strain OSU THCO2-90, resulting in proficient elastin-degrading cells. The encoded protein is predicted to be a cell-surface-exposed lipoprotein with no homology to previously reported elastases. FP0506 might belong to the zincin tribe and gluzincin clan of metalloproteases, and this new elastase-encoding gene seems to be present only in some members of the family FlavobacteriaceaeIMPORTANCE Elastin is an important proteinaceous component of vertebrate connective tissues (e.g., blood vessels, lung, and skin), to which it confers elasticity. Elastases have been identified in a number of pathogenic bacteria. They are thought to be required for tissue penetration and dissemination, acting as "spreading factors." Flavobacterium psychrophilum is a devastating bacterial pathogen of salmonid fish (salmon and trout) that is responsible for severe economic losses worldwide. This pathogen displays strong proteolytic activities. Using a variety of techniques, including genome comparisons, we identified a gene encoding a novel elastase in F. psychrophilum The encoded protein is predicted to be a cell-surface-exposed lipoprotein with no homology to previously reported elastases. In addition, this elastase likely belongs to a new family of proteases that seems to be present only in some members of this important group of bacteria.

[Interstitial lung disease in connective tissue diseases]. / Pneumopathies interstitielles liées aux connectivites.

Interstitial lung disease represents a major clinical aspect of the four major connective tissue diseases: rheumatoid arthritis, scleroderma, polymyositis/dermatomyositis and systemic lupus erythematosus (SLE). Early recognition in the course of the disease is essential, as interstitial lung disease will often determine the vital prognosis of these patients. Treatment is most frequently based on experts' opinion, because there are only few randomized controlled trials in this field.

[New therapeutic approaches in 2014 in pulmonary medicine: COPD, asthma and lung fibrosis]. / Pneumotogie. BPCO, asthme et fibrose pulmonaire.

In 2014, among new therapeutic approaches in pulmonary medicine, the role of inhaled corticosteroids has to be revaluated after the publication of the WISDOM and other studies. Their prescription should no longer be systematic even for "at risk" groups of patients, as defined by the GOLD consensus, but rather be considered on an individual basis. In the field of asthma, two major studies confirm the efficacy of mepoluzimab for the treatment of severe, eosinophilic asthma. Finally, for idiopathic pulmonary fibrosis, 2014 has taught us that treatment with N-acetylcystein is of no proven benefit, while pirfenidone and nintedanib are two new drugs that may attenuate the downhill course of the disease.

[Non-infectious lung diseases after hematopoietic stem cell transplantation]. / Pathologies pulmonaires non infectieuses après transplantation de cellules-souches hématopoïétiques.

Non-infectious pulmonary complications following hematopoietic stem cell transplantation are entities occuring early or late, depending on whether they occur before or after 100 days post-transplantation. They have firstly to be differentiated from infectious complications, which is not always easy, as their clinical and radiological aspects can mimic a viral or bacterial pneumonia. Corticosteroids are the most given treatment but a significant subset of patients have a fatal outcome. This article will review the clinical, radiological, functionnal features and the therapeutic options of six entities (engraftment syndrome, diffuse alveolar hemorrage, idiopathic pneumonia syndrome, organizing pneumonia, bronchiolitis obliterans, post-transplantation lympho-proliferative disease).

Incidence and outcomes of respiratory viral infections in lung transplant recipients: a prospective study.

BACKGROUND: The incidence and outcomes of respiratory viral infections in lung transplant recipients (LTR) are not well defined. The objective of this prospective study conducted from June 2008 to March 2011 was to characterise the incidence and outcomes of viral respiratory infections in LTR. METHODS: Patients were seen in three contexts: study-specific screenings covering all seasons; routine post-transplantation follow-up; and emergency visits. Nasopharyngeal specimens were collected systematically and bronchoalveolar lavage (BAL) was performed when clinically indicated. All specimens underwent testing with a wide panel of molecular assays targeting respiratory viruses. RESULTS: One hundred and twelve LTR had 903 encounters: 570 (63%) were screening visits, 124 (14%) were routine post-transplantation follow-up and 209 (23%) were emergency visits. Respiratory viruses were identified in 174 encounters, 34 of these via BAL. The incidence of infection was 0.83 per patient-year (95% CI 0.45 to 1.52). The viral infection rates upon screening, routine and emergency visits were 14%, 15% and 34%, respectively (p<0.001). Picornavirus was identified most frequently in nasopharyngeal (85/140; 60.7%) and BAL specimens (20/34; 59%). Asymptomatic viral carriage, mainly of picornaviruses, was found at 10% of screening visits. Infections were associated with transient lung function loss and high calcineurin inhibitor blood levels. The hospitalisation rate was 50% (95% CI 30% to 70.9%) for influenza and parainfluenza and 16.9% (95% CI 11.2% to 23.9%) for other viruses. Acute rejection was not associated with viral infection (OR 0.4, 95% CI 0.1 to 1.3). CONCLUSIONS: There is a high incidence of viral infection in LTR; asymptomatic carriage is rare. Viral infections contribute significantly to this population's respiratory symptomatology. No temporal association was observed between infection and acute rejection.

Interactions between SERPINA1 PiMZ genotype, occupational exposure and lung function decline.

OBJECTIVES: We evaluated interactions between SERPINA1 PiMZ genotype, associated with intermediate α1-antitrysin deficiency, with outdoor particulate matter ≤10 µm (PM10), and occupational exposure to vapours, dusts, gases and fumes (VGDF), and their effects on annual change in lung function. METHODS: Pre-bronchodilator spirometry was performed in 3739 adults of the Swiss Cohort Study on Air Pollution and Lung Disease in Adults (SAPALDIA) for whom SERPINA1 genotypes were available. At baseline in 1991, participants were aged 18-62 years; follow-up measurements were conducted from 2001 to 2003. In linear mixed regression models of annual change in lung function, multiplicative interactions were evaluated between PiMZ genotype (PiMM as reference) and change in PM10 (µg/m(3)), and VGDF exposure (high-level, low-level or no exposure as reference) during follow-up. RESULTS: Annual declines in forced expiratory flow at 25-75% of forced vital capacity (FEF25-75%) (-82 mL/s, 95% CI -125 to -39) and forced expiratory volume in 1 s over forced vital capacity (FEV1/FVC) (-0.3%, 95% CI -0.6% to 0.0%) in association with VGDF exposure were observed only in PiMZ carriers (Pinteraction<0.0001 and Pinteraction=0.03, respectively). A three-way interaction between PiMZ genotype, smoking and VGDF exposure was identified such that VGDF-associated FEF25-75% decline was observed only in ever smoking PiMZ carriers (Pinteraction=0.01). No interactions were identified between PiMZ genotype and outdoor PM10. CONCLUSIONS: SERPINA1 PiMZ genotype, in combination with smoking, modified the association between occupational VGDF exposure and longitudinal change in lung function, suggesting that interactions between these factors are relevant for lung function decline. These novel findings warrant replication in larger studies.

[Assessment and management of chronic cough in adults]. / Toux chronique de l'adulte: evaluation et prise en charge.

Chronic cough is one of the most common symptoms for which outpatient care is sought. The most frequent causes are upper airway cough syndrome, asthma, and gastroesophageal reflux. It is often difficult to determine the origin of chronic cough based on the medical history and physical examination. Empirical treatment directed at the three aforementioned etiologies is thus of considerable value in the initial workup. Treatment failure is most commonly due to insufficient treatment (dosage or duration) or to the coexistence of several causes needing simultaneous use of different drugs.

[Invasive pulmonary aspergillosis and chronic pulmonary aspergillosis]. / Aspergillose pulmonaire invasive et aspergilttose pulmonaire chronique.

Aspergillus pulmonary infection causes a spectrum of diverse diseases according to host immunity. The two major entities are invasive pulmonary aspergillosis and chronic pulmonary aspergillosis. The later can be divided into aspergilloma, then into chronic cavitary, more or less fibrosing aspergillosis, and finally into chronic necrotizing aspergillosis, or semiinvasive aspergillosis. The present article reviews this complex classification, which is necessary to reflect the diverse clinical aspect of the disease. Allergic broncho-pulmonary aspergillosis (ABPA), which is more a hypersensitivity reaction than an infectious process, will not be discussed here.

Genome-wide association study of body mass index in 23 000 individuals with and without asthma.

BACKGROUND: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. OBJECTIVE: To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. METHODS: In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. RESULTS: We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms(SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1BSNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. CONCLUSIONS AND CLINICAL RELEVANCE: DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.

Agreement between spirometers: a challenge in the follow-up of patients and populations?

BACKGROUND: Long-term cohort studies and lung function laboratories are confronted with the need for replacement of spirometers. Lack of agreement between spirometers might affect the longitudinal comparison of data, notably when replacing conventional by portable spirometers. OBJECTIVES: To compare the handheld EasyOne (EO) with the conventional SensorMedics (SM) spirometer, and to analyze the interdevice reproducibility of EO spirometers. METHODS: In total, 82 volunteers completed spirometry sessions with 1 SM and 2 of 3 EO spirometers following a Latin square design. Analyses of differences in forced vital capacity (FVC), forced expiratory flow in 1 s (FEV1), FEV1/FVC and mean forced expiratory flow calculated between 25 and 75% of the FVC between spirometers used a mixed effect model with a random intercept for each subject and the effect of the device as fixed effect adjusted for sex, age, height and order of spirometer tested. Bland-Altman plots show the 95% limits of agreement. RESULTS: Comparisons between EO and SM showed relatively small mean differences of <3%, but systematically lower values for FVC and FEV1 in all EO devices. The 95% agreement exceeded the limits for FEV1 by 50 ml in 2 EO spirometers. The EO interdevice comparisons showed mean differences and limits of agreement within established thresholds, thus indicating fair accuracy when comparing devices. Repeats with the same spirometer did not result in statistically significant differences. CONCLUSIONS: This study suggests fair agreement between the handheld and the conventional spirometer. Differences slightly exceeding limits for FEV1 in 2 EO devices might be considered mostly irrelevant for clinical practice. However, the systematically lower FVC and FEV1 observed with EO may be significant for epidemiological studies, thus justifying inspection before replacing devices.

Diagnosis and management of chronic obstructive pulmonary disease: the Swiss guidelines. Official guidelines of the Swiss Respiratory Society.

The new Swiss Chronic Obstructive Pulmonary Disease (COPD) Guidelines are based on a previous version, which was published 10 years ago. The Swiss Respiratory Society felt the need to update the previous document due to new knowledge and novel therapeutic developments about this prevalent and important disease. The recommendations and statements are based on the available literature, on other national guidelines and, in particular, on the GOLD (Global Initiative for Chronic Obstructive Lung Disease) report. Our aim is to advise pulmonary physicians, general practitioners and other health care workers on the early detection and diagnosis, prevention, best symptomatic control, and avoidance of COPD as well as its complications and deterioration.

[Bronchiectasis: diagnostic workup]. / Bronchiectasies chez l'adulte: recherche d'une étiologie.

Bronchiectasis is a condition defined by permanent dilation of the bronchi, either idiopathic or associated with other disease states. Diagnostic workup for bronchiectasis is essential in determining management and treatment. For diffuse bronchiectasis, we propose a workup plan that includes testing for humoral immunodeficiency by measuring serum IgG and anti-pneumococcal antibodies, looking for primary ciliary dyskinesia by exhaled nasal NO and cytologic brush biopsy of the nasal mucosa, looking for cystic fibrosis by chloride sweat testing and genotyping, evaluation for allergic bronchopulmonary aspergillosis, and testing for alpha-1-antitrypsin deficiency. Workup studies should be guided by the patient's history and clinical context.

[Pulmonary medicine 2012: news for the general practitioner]. / Pneumologie.

This review reports on papers published in 2012 that will most likely impact on daily medical practice in four different areas of pulmonary medicine. How should treatment of asthma with inhaled corticosteroids be adjusted on the long run? Should idiopathic pulmonary fibrosis receive treatment with immunosuppressive drugs? Is a long-term treatment with azithromycine for bronchiectasis supported by evidence, apart from patients with cystic fibrosis? And finally, can treatment of obstructive sleep apnea with continuous positive pressure (CPAP) prevent the occurrence of new, systemic hypertension?

[Cryptogenic organizing pneumonia]. / La pneumonie organisée cryptogénique.

Cryptogenic organizing pneumonia (COP) is a distinct clinico-pathologic entity described for the first time by Davison in 1983 and 2 years later by Epler under the name of idiopathic Bronchiolitis Obliterans Organizing Pneumonia (BOOP). It most often presents with the clinical and radiological features of an infectious pneumonia which fails to respond to antibiotic therapy. In this article, we will review the clinical and radiographic features, diagnostic assessment, and the treatment of COP.

[The role of surgery in early stage small cell lung cancer: should it be re-evaluated?]. / Chirurgie du cancer pulmonaire à petites cellules de stade précoce: doit-on réévaluer son rôle?

Two historical randomized controlled trials have demonstrated that chemo-radiotherapy offers the best survival advantage over surgery in small cell lung carcinoma (SCLC) and led to abandon surgery for the treatment of SCLC. Yet, widespread use of CT scanning increases the detection of early and very early stage SCLC. Therefore, the traditional 2 stages classification scheme--namely limited and extensive stage disease--is no longer sufficient for such early stage disease and must be completed by the TNM classification. Although randomized controlled trials are lacking, retrospective case series and large population databases suggest a beneficial role of surgery for the earliest SCLC stages. It is thus currently recommended to consider surgery in the multimodal treatment of stage I SCLC.

[Pulmonary medicine. Four major papers in 2010-2011]. / Pneumologie. Quatre importantes publications.

We have selected four papers which brought major, new contributions to pulmonary medicine over the last year. These publications address following issues: The effect of low-dose CT-screening on lung cancer mortality; treatment of lung emphysema by bronchoscopy with endobronchial valves drainage of pleural infections with combined fibrinolytic agent and desoxyribonuclease; and long-term treatment of COPD with azithromycin. Each of these studies has brought novel and relevant information. It is too early to say that current practice has to be changed following these studies. However, they certainly open from now new diagnostic and therapeutic considerations on a case by case basis.

[Systemic and oropharyngeal side effects of inhaled corticosteroids]. / Effets secondaires systémiques et oropharyngés des corticostéroïdes inhalés.

The use of inhaled corticosteroids (ICS) is an important component of asthma management. Although their main impact is on airway inflammation, ICS are not devoid of systemic side effects (adrenal insufficiency, osteoporosis, brittle skin, ocular effects, growth retardation). Oropharyngeal side effects are also reported. These effects appear dose and duration dependent. They also vary according to the type of ICS used, its method of administration and drug interactions. It is recommended to titrate ICS to the lowest effective dose, to regularly reconsider their indication and to be aware of drug interactions. In addition, a change in ICS may have a favorable impact on side effects.

[What is the role of outdoor air pollution in asthma?]. / Quel est le rôle de la pollution atmosphérique dans l'asthme?

Strong scientific evidence has shown that ordinary peaks of outdoor air pollution worsen the symptoms and control of asthma. As for chronic exposure, elevated mean level of local, near-road air pollution may cause increased incidence of asthma among children, and probably also among adults. By contrast, while there is no doubt that air pollution worsens allergic inflammatory processes, it is not clearly established that it may increase allergic sensitization among the general population. In this regard, more research is needed, particularly on the effects of outdoor air pollution in the early periods of life.

Determinants of change in airway reactivity over 11 years in the SAPALDIA population study.

We investigated determinants of change in bronchial reactivity in the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA), a population-based cohort with wide age range (29-72 yrs at follow-up). The role of sex, age, atopic status, smoking and body mass index (BMI) on percentage change in bronchial reactivity slope from the baseline value was analysed in 3,005 participants with methacholine tests in 1991 and 2002, and complete covariate data. Slope was defined as percentage decline in forced expiratory volume in 1 s from its maximal value per micromole of methacholine. Bronchial hyperreactivity prevalence fell from 14.3 to 12.5% during follow-up. Baseline age was nonlinearly associated with change in reactivity slope: participants aged <50 yrs experienced a decline and those above an increase during follow-up. Atopy was not associated with change, but accentuated the age pattern (p-value for interaction = 0.038). Smoking significantly increased slope by 21.2%, as did weight gain (2.7% increase per BMI unit). Compared with persistent smokers, those who ceased smoking before baseline or during follow-up experienced a significant decrease in slope (-27.7 and -23.9%, respectively). Differing, but not statistically different, age relationships and effect sizes for smoking and BMI between sexes were found. Mean bronchial reactivity increases after 50 yrs of age, possibly due to airway remodelling or ventilation-perfusion disturbances related to cumulative lifetime exposures.

Effect modification of immunoglobulin E-mediated atopy and rhinitis by glutathione S-transferase genotypes in passive smokers.

BACKGROUND: Experimental studies suggest that glutathione S-transferase (GST) genotypes modify nasal allergen responses induced by secondhand smoke (SHS) exposure. OBJECTIVE: We aimed to investigate whether GSTs affected systemic IgE and allergic rhinitis (AR) in SHS-exposed individuals from a population-based cohort. METHODS: Analyses comprised 2309 never-smokers from the Swiss study on air pollution and health in adults cohort, reporting SHS status at baseline and 11 years later. Outcomes were defined by total serum IgE≥100 kU/L, specific serum IgE determined by Phadiatop® ≥0.35 kU/L and self-reported AR. GSTP1 Ile105Val, GSTM1 and GSTT1 gene deletion genotypes were identified at the follow-up survey. RESULTS: After adjustment for relevant covariates, the homozygous GSTP1 105-Val genotype was negatively associated with high total IgE and high-specific IgE by Phadiatop®, notably in subjects persistently exposed to SHS (OR: 0.20, 95% CI 0.05-0.75; P=0.02, for high total IgE and OR: 0.29, 95% CI 0.10-0.89; P=0.03, for high specific IgE by Phadiatop®). Carrying at least one copy of the GSTM1 gene (non-null) showed a similar association for high specific IgE by Phadiatop® (OR: 0.41, 95% CI 0.22-0.76; P=0.004). No significant associations were found between GSTs and rhinitis. CONCLUSION AND CLINICAL RELEVANCE: In this large cohort, homozygosity for GSTP1 105-Val or carrying the GSTM1 non-null genotype decreased the risk of high total IgE or high specific IgE using Phadiatop® by nearly half in subjects exposed to SHS, as compared with subjects carrying opposite alleles. These findings underline the value of genetic susceptibility when evaluating the effects of environmental exposure on allergic illness. The potential long-term effects of persistent SHS exposure in genetically vulnerable individuals may be of public health relevance.