Variability of fractional exhaled nitric oxide is associated with the risk and aetiology of COPD exacerbations.

BACKGROUND AND OBJECTIVE: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are heterogeneous in aetiology and accelerate disease progression. Here, we aimed to investigate the association of fractional exhaled nitric oxide (FeNO) and its variability with AECOPD of different aetiology. METHODS: FeNO was determined in 2157 visits (1697 stable, 133 AECOPD and 327 follow-up) of 421 COPD patients from the PREVENT study, an investigator-initiated, longitudinal and interventional study, who were on daily treatment with inhaled corticosteroids/long-acting ß2-agonists. RESULTS: Longitudinal measurements of FeNO revealed an intra-subject variability of FeNO that was significantly higher in exacerbators compared to non-exacerbators (p < 0.001) and positively associated with the number of AECOPD. As FeNO variability increased, the probability of patients to remain AECOPD-free decreased. In patients included in the highest FeNO variability quartile (≥15.0 ppb) the probability to remain free of AECOPD was only 35% as compared to 80% for patients included in the lowest FeNO variability quartile (0.50-4.39 ppb). The change of FeNO from the last stable visit to AECOPD was positively associated with the probability of viral infections and this association was stronger in current smokers than ex-smokers. In contrast, the change in FeNO from the last stable visit to an AECOPD visit was inversely associated with the probability of bacterial infections in ex-smokers but not in current smokers. CONCLUSION: FeNO variability was associated with the risk and aetiology of AECOPD differentially in current and ex-smokers.

Secreted heat shock proteins control airway remodeling: Evidence from bronchial thermoplasty.

BACKGROUND: Increased airway smooth muscle mass is a key pathology in asthma. Bronchial thermoplasty is a treatment for severe asthma based on selective heating of the airways that aims to reduce the mass of airway smooth muscle cells (ASMCs), and thereby bronchoconstriction. However, short heat exposure is insufficient to explain the long-lasting effect, and heat shock proteins (HSPs) have been suggested to play a role. OBJECTIVE: We sought to determine the role of HSP70 and HSP90 in the control of airway wall remodeling by bronchial thermoplasty. METHODS: Bronchoalveolar lavage fluid and endobronchial biopsies of 20 patients with severe asthma were obtained before and after thermoplasty. Isolated epithelial cells and ASMCs were exposed to 65oC for 10 seconds, mimicking thermoplasty. Proteins were determined by immunohistochemistry, Western blotting, immunofluorescence, and ELISA; proliferation by cell counts and antigen Ki67 (MKI67) expression. RESULTS: Thermoplasty significantly increased the expression of HSP70 and HSP90 in the epithelium and bronchoalveolar lavage fluid. In ASMCs, thermoplasty reduced both HSPs. These cell-type-specific effects were detectable even 1 month after thermoplasty in tissue sections. In epithelial cells, ex vivo exposure to heat (65oC, 10 seconds) increased the expression and secretion of HSP70 and HSP90. In addition, epithelial cell proliferation was upregulated by heat or treatment with human recombinant HSP70 or HSP90. In ASMCs, heat exposure or exogenous HSPs reduced proliferation and differentiation. In both cell types, HSP70 and HSP90 activated the signaling cascade of serine/threonine-protein kinase →mammalian target of rapamycin→ribosomal protein S6 kinase 1 and CCAAT/enhancer binding protein-ß→protein arginine methyltransferase 1→ mitochondria activity. CONCLUSIONS: Epithelial cell-derived HSP70 and HSP90 improve the function of epithelial cells, but block ASMC remodeling.

Laryngopharyngeal reflux in chronic obstructive pulmonary disease - a multi-centre study.

Reflux of gastric content has been associated with recurrent exacerbations of chronic obstructive pulmonary disease (COPD). We aimed to assess the prevalence of laryngopharyngeal reflux (LPR) in COPD and if LPR is a contributing factor to clinically relevant outcomes in COPD. We evaluated a total of 193 COPD patients (GOLD I-IV) with a 24-h laryngo-pharyngeal pΗ-monitor. LPR was observed in 65.8% of COPD patients and it was not significantly associated with clinically relevant outcomes of COPD. Treatment with PPI significantly decreased the upright RYAN score (p = 0.047) without improving lung function. Furthermore, the presence or severity of LPR cannot be diagnosed based solely on symptoms and questionnaires.

Oxygen desaturation during flexible bronchoscopy with propofol sedation is associated with sleep apnea: the PROSA-Study.

BACKGROUND: Obstructive sleep apnea (OSA) is characterized by repetitive episodes of complete or partial obstruction of the upper airways during sleep. Conscious sedation for flexible bronchoscopy (FB) places patients in a sleep-like condition. We hypothesize that oxygen desaturation during flexible bronchoscopy may help to detect undiagnosed sleep apnea. METHODS: Single-centre, investigator-initiated and driven study including consecutive patients undergoing FB for clinical indication. Patients completed the Epworth Sleepiness Scale (ESS), Lausanne NoSAS score, STOP-BANG questionnaire and the Berlin questionnaire and underwent polygraphy within 7 days of FB. FB was performed under conscious sedation with propofol. Oxygen desaturation during bronchoscopy was measured with continuous monitoring of peripheral oxygen saturation with ixTrend (ixellence GmbH, Germany). RESULTS: 145 patients were included in the study, 62% were male, and the average age was 65.8 ± 1.1 years. The vast majority of patients (n = 131, 90%) proved to fulfill OSA criteria based on polygraphy results: 52/131 patients (40%) had mild sleep apnea, 49/131 patients (37%) moderate sleep apnea and 30/131 patients (23%) severe sleep apnea. Patients with no oxygen desaturation had a significantly lower apnea-hypopnea index than patients with oxygen desaturation during bronchoscopy (AHI 11.94/h vs 21.02/h, p = 0.011). This association remained significant when adjusting for the duration of bronchoscopy and propofol dose (p = 0.023; 95% CI 1.382; 18.243) but did not hold when also adjusting for age and BMI. CONCLUSION: The severity of sleep apnea was associated to oxygen desaturation during flexible bronchoscopy under conscious sedation. Patients with oxygen desaturation during bronchoscopy might be considered for sleep apnea screening. TRIAL REGISTRATION: The Study was approved by the Ethics Committee northwest/central Switzerland, EKNZ (EK 16/13) and was carried out according to the Declaration of Helsinki and Good Clinical Practice guidelines. Due to its observational character, the study did not require registration at a clinical trial registry.

Endothelial dysfunction is not a predictor of outcome in chronic obstructive pulmonary disease.

BACKGROUND: Local airway inflammation may cause systemic changes which result in endothelial dysfunction. Only a few studies have used reactive hyperemia peripheral arterial tonometry (RH-PAT) in patients with chronic obstructive pulmonary disease (COPD) in order to measure their endothelial dysfunction. OBJECTIVE: To determine the efficacy of endothelial dysfunction, measured by RH-PAT, in assessing disease severity and systemic burden in a cohort of COPD patients. METHODS: In this prospective, monocentric study, 157 patients with moderate to very severe COPD (GOLD class II-IV) were examined for endothelial dysfunction using RH-PAT (Itamar medical Ltd., Caesarea, Israel). In a nested-cohort, examination was repeated at exacerbation. The association between reactive hyperemia index (RHI), augmentation index (AI) and disease severity and outcome parameters was analysed. RESULTS: 57% of the COPD patients had a dysfunctional endothelium and the median (IQR) RHI was 1.42 (1.27-1.53). Exacerbation of COPD was not associated with a significant change in RHI (p = 0.625) or ΑΙ (p = 0.530). None of the diagnostic or clinical outcomes of COPD was associated with RHI or arterial stiffness. CONCLUSION: Endothelial dysfunction is common in COPD. However, it does not seem to be a predictor neither of disease severity, nor of outcome and does not change during exacerbations of the disease.

Multiplex bacterial polymerase chain reaction in a cohort of patients with pleural effusion.

BACKGROUND: The identification of the pathogens in pleural effusion has mainly relied on conventional bacterial culture or single species polymerase chain reaction (PCR), both with relatively low sensitivity. We investigated the efficacy of a commercially available multiplex bacterial PCR assay developed for pneumonia to identify the pathogens involved in pleural infection, particularly empyema. METHODS: A prospective, monocentric, observational study including 194 patients with pleural effusion. Patients were evaluated based on imaging, laboratory values, pleura ultrasound and results of thoracentesis including conventional microbiology studies during hospitalisation. Multiplex bacterial PCR (Curetis Unyvero p55) was performed in batch and had no influence on therapeutic decisions. RESULTS: Overall, there were 51/197 cases with transudate and 146/197 with exudate. In 42% (n = 90/214) there was a clinical suspicion of parapneumonic effusion and the final clinical diagnosis of empyema was made in 29% (n = 61/214) of all cases. The most common microorganisms identified in the cases diagnosed with empyema were anaerobes [31] followed by gram-positive cocci [10] and gram-negative rods [4]. The multiplex PCR assay identified more of the pathogens on the panel than the conventional methods (23.3% (7/30) vs. 6.7% (2/30), p = 0.008). CONCLUSION: The multiplex PCR-based assay had a higher sensitivity and specificity than conventional microbiology when only the pathogens on the pneumonia panel were taken into account. A dedicated pleural empyema multiplex PCR panel including anaerobes would be needed to cover most common pathogens involved in pleural infection.

Serum levels of hyaluronic acid are associated with COPD severity and predict survival.

Hyaluronic acid (HA) and its degradation products play an important role in lung pathophysiology and airway remodelling in chronic obstructive pulmonary disease (COPD).We investigated if HA and its degrading enzyme hyaluronidase (HYAL)-1 are associated with COPD severity and outcome.Serum HA was assessed in a discovery cohort of 80 COPD patients at stable state and exacerbations. HA, HYAL-1 and HYAL-1 enzymatic activity were evaluated at stable state, exacerbations and 4 weeks after exacerbations in 638 COPD patients from the PROMISE validation cohort.In the discovery cohort, serum HA was higher at exacerbations compared with the stable state (p=0.015). In the validation cohort, HA was higher at moderate and severe exacerbations than at baseline (p<0.001), and remained higher after 4 weeks (p<0.001). HA was strongly predictive for overall survival since it was associated with time to death (p<0.001) independently of adjusted Charlson score, annual exacerbation rate and BODE (body mass, airflow obstruction, dyspnoea, exercise capacity) index. Serum HYAL-1 was increased at moderate (p=0.004) and severe (p=0.003) exacerbations, but decreased after 4 weeks (p<0.001). HYAL-1 enzymatic activity at stable state was inversely correlated with FEV1 % pred (p=0.034) and survival time (p=0.017).Serum HA is associated with COPD severity and predicts overall survival. Degradation of HA is associated with airflow limitation and impairment of lung function.

IFNΛ3/4 locus polymorphisms and IFNΛ3 circulating levels are associated with COPD severity and outcomes.

BACKGROUND: Interferon lambdas (IFNLs) have important anti-viral/bacterial and immunomodulatory functions in the respiratory tract. How do IFNLs impact COPD and its exacerbations? METHODS: Five hundred twenty eight patients were recruited in a prospective observational multicentre cohort (PROMISE) study. The genetic polymorphisms (rs8099917 and rs12979860) within the IFNL3/4 gene region and circulating levels of IFNL3 in COPD patients were determined and associated with disease activity and outcome during a median follow-up of 24 months. RESULTS: The GG genotype significantly influenced severe exacerbation rate (42 vs. 23%; p = 0.032) and time to severe exacerbation (HR = 2.260; p = 0.012). Compared to the TT or TG genotypes, the GG genotype was associated with severe dyspnoea (modified medical research council score ≥ median 3; 22 vs 42%, p = 0.030). The CC genotype of the rs12979860 SNP was associated with a poorer prognosis (body mass index, airflow obstruction, dyspnea and exercise capacity index ≥ median 4; 46 vs. 36% TC vs. 20.5% TT; p = 0.031). Patients with stable COPD and at exacerbation had significantly lower circulating IFNL3 compared to healthy controls (p < 0.001 and p < 0.001, respectively). Circulating IFNL3 correlated to post-bronchodilator FEV1%predicted and the tissue maturation biomarker Pro-collagen 3. CONCLUSION: IFNL3/4 polymorphisms and circulating IFNL3 may be associated with disease activity and outcomes in COPD. TRIAL REGISTRATION: Clinical Trial registration http://www.isrctn.com/ identifier ISRCTN99586989 on 16 April 2008.

Treatment of COPD Exacerbation in Switzerland: Results and Recommendations of the European COPD Audit.

BACKGROUND: The European COPD Audit initiated by the European Respiratory Society (ERS) evaluated the management of hospital admissions due to exacerbation of chronic obstructive pulmonary disease (COPD) in several European countries. Data on the treatment of severe acute exacerbations of COPD (AECOPDs) in Switzerland are scarce. OBJECTIVES: In light of the GOLD 2010 guidelines, this work aims to examine the quality of care for AECOPD and to provide specific recommendations for the management of severe AECOPD in Switzerland. METHODS: A total of 295 patients requiring hospital admission to 19 Swiss hospitals due to exacerbation of COPD during a predefined 60 days in 2011 were included in the study. We compared the Swiss data to the official GOLD 2010 recommendations and to the results of the other European countries. RESULTS: Approximately 43% of the Swiss patients with severe AECOPD were current smokers at hospital admission, compared to 33% of the patients in other European countries (p < 0.001). In Switzerland and in Europe, spirometry data were not available for most patients at hospital admission (65 and 60%, respectively; p = 0.08). In comparison to other European countries, antibiotics were prescribed 14% less often in Switzerland (p < 0.001). Only 79% of the patients in the Swiss cohort received treatment with a short-acting bronchodilator at admission. CONCLUSIONS: Considering the overall high standard of health care in Switzerland, in light of the GOLD 2010 guidelines we are able to make 7 recommendations to improve and standardize the management of severe AECOPD for patients treated in Switzerland.

Impact of bronchoalveolar lavage on the management of immunocompromised hosts.

BACKGROUND: Respiratory infections are an important cause of morbidity and mortality in immunocompromised individuals. Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is an important tool to detect infectious agents in immunocompromised patients with low respiratory tract infections (LRTI). RESEARCH QUESTION: BAL changes the management of immunocompromised patients with suspected LRTI. STUDY DESIGN AND METHODS: Immunocompromised patients with a suspicion of LRTI underwent diagnostic BAL. The primary composite outcome consisted of pre-defined modifications in the management of the immunocompromised patients following BAL. We quantified the impact of bronchoscopy up to 30 days after the procedure. RESULTS: A total of 2666 visits from 1301 patients were included in the study and immunosuppression was classified as haematological (n = 1040; 544 patients), solid organ transplantation (n = 666; 107 patients) and other causes (n = 960; 650 patients). BAL led to a change in management in 52.36% (n = 1396) of all cases. This percentage, as well as the 30-day mortality differed significantly amongst the three groups. Age, C-reactive protein and aetiology of infection determined significantly the risk of 30-day mortality in all patients. In 1.89% (n = 50) of all cases, a combination of 2 respiratory viral agents was identified and 24.23% (n = 646) were diagnosed with a single respiratory viral agent. INTERPRETATION: BAL leads to changes in management in the majority of immunosuppressed patients. There is a high prevalence of multimicrobial infections and respiratory viral infections in immunocompromised patients with respiratory symptoms. Individual virus infection is associated with diverse risk of a negative outcome.

Single and multiple breath nitrogen washout compared with the methacholine test in patients with suspected asthma and normal spirometry.

BACKGROUND: Methods used to assess ventilation heterogeneity through inert gas washout have been standardised and showed high sensitivity in diagnosing many respiratory diseases. We hypothesised that nitrogen single or multiple breath washout tests, respectively nitrogen single breath washout (N2SBW) and nitrogen multiple breath washout (N2MBW), may be pathological in patients with clinical suspicion of asthma but normal spirometry. Our aim was to assess whether N2SBW and N2MBW are associated with methacholine challenge test (MCT) results in this population. We also postulated that an alteration in SIII at N2SBW could be detected before the 20% fall of forced expiratory volume in the first second (FEV1) in MCT. STUDY DESIGN AND METHODS: This prospective, observational, single-centre study included patients with suspicion of asthma with normal spirometry. Patients completed questionnaires on symptoms and health-related quality-of-life and underwent the following lung function tests: N2SBW (SIII), N2MBW (Lung clearance index (LCI), Scond, Sacin), MCT (FEV1 and sGeff) as well as N2SBW between each methacholine dose. RESULTS: 182 patients were screened and 106 were included in the study, with mean age of 41.8±14 years. The majority were never-smokers (58%) and women (61%). MCT was abnormal in 48% of participants, N2SBW was pathological in 10.6% at baseline and N2MBW abnormality ranged widely (LCI 81%, Scond 18%, Sacin 43%). The dose response rate of the MCT showed weak to moderate correlation with the subsequent N2SBW measurements during the provocation phases (ρ 0.34-0.50) but no correlation with N2MBW. CONCLUSIONS: Both MCT and N2 washout tests are frequently pathological in patients with suspicion of asthma with normal spirometry. The weak association and lack of concordance across the tests highlight that they reflect different but not interchangeable pathological pathways of the disease.

Peripheral arterial tonometry versus polysomnography in suspected obstructive sleep apnoea.

BACKGROUND: Polysomnography (PSG) is the gold standard for the diagnosis of obstructive sleep apnoea (OSA). Home sleep apnoea testing with peripheral arterial tonometry (PAT) is a recommended diagnostic alternative for patients with an increased risk for OSA. In a large clinical cohort, we investigated concordance and predictors for discordance in diagnosing OSA using PAT and PSG, and three-year cardiovascular risk in patients with discordant OSA diagnosis. METHODS: Retrospective monocentric cohort study. Patients with a PAT AHI ≥ 5/h followed by an in-hospital PSG within three months were included. All patients with a PAT AHI ≥ 5/h but a PSG AHI < 5/h were classified as discordant. Patients with PAT and PSG AHI ≥ 5/h were classified as concordant. To ascertain cardiovascular risk, major adverse cardiovascular events (MACE) were analyzed in discordant patients and sex, age, body mass index (BMI) and cardiovascular disease-matched concordant patients over a follow-up time of 3.1 ± 0.06 years. RESULTS: A total of 940 patients, 66% male with an average age of 55 ± 0.4 years and BMI of 31 ± 0.2 kg/m2 were included. Agreement in OSA diagnosis was observed in 80% of patients (55% in mild and 86% in moderate and severe OSA). Factors significantly associated with a discordant diagnosis were female sex, younger age and lower BMI, but not comorbidities. There was no significant difference in MACE (p = 0.920) between discordant patients (n = 155) and matched concordant patients (n = 274) with or without therapy. CONCLUSIONS: Concordance between PAT and PSG diagnosis of sleep apnoea is good, particularly in moderate and severe OSA. Predictors for discordant results between PAT and PSG were age, sex and BMI. MACE risk is similar in those with OSA diagnosed by PAT or PSG.

Multiplex bacterial PCR in the bronchoalveolar lavage fluid of non-intubated patients with suspected pulmonary infection: a quasi-experimental study.

Background: Early pathogen identification in pulmonary infection is crucial to guide antibacterial therapy and decrease length of hospital stay. We hypothesise that compared to conventional diagnostic methods, a multiplex bacterial polymerase chain reaction assay has a higher diagnostic yield in bronchoalveolar lavage (BAL) fluid and improved clinical outcomes in patients with suspicion of pulmonary infection. Methods: A prospective, monocentric, quasi-experimental, observational study was carried out. Unselected patients with suspected pulmonary infection who underwent bronchoscopy with BAL were included in the study over a period of 1 year. In addition to conventional diagnostic methods, a multiplex PCR bacterial assay was performed in BAL on a 2 week on: 1 week off pre-determined schedule. No therapeutic recommendations were provided to the treating physician. Results: 605 cases were included, 54% of whom were immunosuppressed. Conventional diagnostic methods detected 56% of the bacteria evidenced by PCR. PCR failed to detect bacteria in 4% of the cases with a positive conventional diagnostic result. After bronchoscopy, 42% of the patients received antibacterial therapy for pulmonary infection for a median of 12 antibiotic days. There was no statistically significant difference in length of hospital stay (median 8 versus 8; p=0.839), antibiotic exposure (median 11 versus 14; p=0.362) or number of antibiotics prescribed (median 2 versus 2; p=0.595) between the two groups. Conclusions: A multiplex bacterial PCR detected more bacteria in BAL fluid than conventional diagnostic methods. However, without a specific antibiotic stewardship approach and a clear understanding of the clinical implications of a positive or negative PCR result, the PCR results did not influence clinical outcomes.

Fast multiplex bacterial PCR of bronchoalveolar lavage for antibiotic stewardship in hospitalised patients with pneumonia at risk of Gram-negative bacterial infection (Flagship II): a multicentre, randomised controlled trial.

BACKGROUND: PCR-based testing has transformed the management of suspected respiratory viral infections. We aimed to determine whether multiplex bacterial PCR of bronchoalveolar lavage fluid aids antibiotic stewardship in patients with pneumonia. METHODS: This investigator-initiated, multicentre, randomised controlled trial was conducted at two tertiary care centres in Switzerland (University Hospital of Basel and Kantonsspital St Gallen). Patients aged 18 years or older who were admitted to hospital with suspected pneumonia, had a clinical indication for bronchoscopy with bronchoalveolar lavage, and were at risk of Gram-negative bacterial infection were included. Patients were randomly assigned (1:1) to either the multiplex bacterial PCR group or the conventional microbiology control group using a random allocation sequence. Treating physicians were not masked, but the committee panel was masked to patient randomisation. All patients underwent bronchoscopy with bronchoalveolar lavage and samples were assessed by conventional microbiological culture (and additionally, in the PCR group, by multiplex bacterial PCR for Gram-negative rods using the Unyvero Hospitalized Pneumonia [HPN] Cartridge; Curetis, Holzgerlingen, Germany). Patients received empirical antibiotic therapy as clinically indicated by the treating physician. In the PCR group, a recommendation regarding antibiotic therapy was made approximately 5 h after taking the sample. The primary outcome was the time in hours on inappropriate antibiotic therapy from bronchoscopy to discharge or to 30 days after bronchoscopy. This trial was registered with the International Clinical Trials Registry Platform, ISRCTN95828556. FINDINGS: Between May 31, 2017, and Sept 25, 2019, 740 patients with pneumonia were screened for eligibility and 208 were included and randomly assigned to the PCR group (n=100) or conventional microbiology control group (n=108). The mean age of patients was 65·9 years (SD 14·0) and 135 (65%) were male. After daily follow-up until hospital discharge or for a maximum of 30 days, the duration of inappropriate antibiotic treatment was significantly shorter by 38·6 h (95% CI 19·5-57·7) in the PCR group than in the control group (adjusted mean 47·1 h [34·7-59·5] vs 85·7 h [78·8-95·6]; p<0·0001), which translates as a decrease in the duration of inappropriate antibiotic therapy of 45·0% (37·9-52·1). Adverse events due to antimicrobial therapy occurred in nine patients (five [5%] in the PCR group vs four [4%] in the control group) and due to bronchoscopy occurred in four patients (two [1%] vs two [1%]). There were eight (8%) deaths in the PCR group and 11 (10%) in the control group. All in-hospital deaths were attributed to a respiratory cause. INTERPRETATION: Multiplex bacterial PCR examination of bronchoalveolar lavage decreases the duration of inappropriate antibiotic therapy of patients admitted to hospital with pneumonia and at risk of Gram-negative rod infection. This approach warrants further consideration in future antibiotic stewardship strategies. FUNDING: Curetis and the Clinic of Respiratory Medicine and Pulmonary Cell Research, University Hospital Basel, Switzerland.

Interleukin-targeted therapy for metabolic syndrome and type 2 diabetes.

Interleukin-1ß Interleukin-1ß (IL-1ß) is a key regulator of the body's inflammatory response and is produced after infection, injury, and an antigenic challenge. Cloned in 1984, the single polypeptide IL-1ß has been shown to exert numerous biological effects. It plays a role in various diseases, including autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, and Type 1 diabetes, as well as in diseases associated with metabolic syndrome such as atherosclerosis, chronic heart failure, and Type 2 diabetes. The macrophage is the primary source of IL-1ß, but epidermal, epithelial, lymphoid, and vascular tissues also synthesize IL-1. Recently, IL-1ß production and secretion have also been reported from pancreatic islets. Insulin-producing ß-cells ß-cells within the pancreatic islets are specifically prone to IL-ß-induced destruction and loss of function. Macrophage-derived IL-1ß production in insulin-sensitive organs leads to the progression of inflammation inflammation and induction of insulin resistance in obesity. This chapter explains the mechanisms involved in the inflammatory response during diabetes progression with specific attention to the IL-1ß signal effects influencing insulin action and insulin secretion insulin secretion . We highlight recent clinical studies, rodent and in vitro experiments with isolated islets using IL-1ß as a potential target for the therapy of Type 2 diabetes.

Stability of the Blood Eosinophilic Phenotype in Stable and Exacerbated COPD.

BACKGROUND: There is controversy regarding the use of blood eosinophil levels as a biomarker of exacerbation risk and responsiveness of patients to inhaled corticosteroids (ICS). METHODS: Patients in stable COPD with Gold Initiative for Chronic Obstructive Lung Disease airflow obstruction grades II to IV were enrolled in an observational multicenter trial. Concordance was defined as blood eosinophil values persistently lower than or persistently higher than the absolute cutoff points of 150 cells/µL and 300 cells/µL, or the percentage cutoff points of 2%, 3%, and 4%. Discordance was obtained when the blood eosinophil values varied between any two visits. ICS treatment data were recorded at one time point at the inclusion of the study. RESULTS: A total of 210 patients with 2,059 visits were included in the study. Seventy percent of the patients were male, and 36% were current smokers; their average age was 67.7 ± 9.4 years, and 81% were receiving ICS at the start of the study. Assessing eosinophil levels over time (median, 7 days [4; 12]), irrespective of exacerbation or hospitalization, there was a discordance of 77%, 60%, and 42% when using the 2%, 3% and 4% cutoffs, respectively. This outcome changed to 34.5%, 24%, and 17.2% discordance when only using two visits for the analysis. The discordance was similar when using absolute eosinophil values. Patients in a stable state had higher discordant values than patients with mild/moderate exacerbations. The same was seen in patients hospitalized for other illnesses compared with patients hospitalized for severe exacerbation of COPD. Discordancy was high regardless of whether patients were taking ICS at the beginning of the study period. CONCLUSIONS: These study data suggest that blood eosinophil levels present significant variability throughout the course of COPD, and a single measurement may therefore not be a reliable predictor of ICS response.

Does trumpet playing affect lung function?-A case-control study.

OBJECTIVES: The effect a wind instrument has on lung function is a much-discussed topic with inconclusive data, not least because existing studies combine all wind instruments as one entity. The aim of this study was to investigate the effect of playing a trumpet/cornet/flugelhorn on lung function. METHODS: A prospective, multicentre, cross-sectional, case-control study. Participants were recruited from wind orchestra or brass bands throughout Switzerland. Inclusion criteria: aged 16 or older, reporting at least one year of playing a trumpet/cornet/flugelhorn. Controls were members of an orchestra, who had never played a wind instrument. The primary end-point of the study was the difference in FEV1%predicted between trumpet/cornet/flugelhorn players and controls. RESULTS: 147 subjects were included in the study. Controls (n = 48) were significantly younger, more commonly male, current smokers and had a lower body mass index compared to trumpet/cornet/flugelhorn players (n = 99). There was no significant difference in FEV1%predicted (91.9% vs 94.2%; p = 0.316) or FVC %predicted (89.4% vs 92.6%; p = 0.125) between controls and trumpet/cornet/flugelhorn players, respectively, in crude and adjusted analyses. However, there was a significant negative association between the number of years playing a trumpet/cornet/flugelhorn and FVC %predicted after adjusting for smoking status, gender, and height. Trumpet/cornet/flugelhorn players had a similar amount of respiratory symptoms to controls (questionnaire score 3.2±3.2 vs 2.8±2.4, p = 0.717). CONCLUSION: Lung function in trumpet/cornet/flugelhorn players was similar to controls. However, the number of years playing a trumpet/cornet/flugelhorn seems to have an adverse effect on forced vital capacity.

Collagen Degradation and Formation Are Elevated in Exacerbated COPD Compared With Stable Disease.

BACKGROUND: The role of the extracellular matrix (ECM) structure and remodeling thereof in lung diseases is gaining importance. Pathology-related changes in ECM turnover may result in deleterious changes in lung architecture, leading to disease in the small airways. Here, degradation fragments of type I (C1M), type IV (α1 chain, C4M2), and type IV (α3 chain, C4Ma3) collagen, all degraded by metalloproteinases and the pro-form of collagen type V (PRO-C5) were investigated and associated with COPD severity and outcome. METHODS: In a prospective, observational, multicenter study including 498 patients with COPD Gold Initiative for Chronic Obstructive Lung Disease stage 2 to 4, ECM markers were assessed in serum at stable state, exacerbation, and at follow-up 4 weeks after exacerbation. RESULTS: At stable state, there was a significant inverse association between FEV1 % predicted and C1M, C4Ma3, and Pro-C5. C1M, C4M2, C4Ma3, and Pro-C5 were associated with BMI, airflow obstruction, dyspnea, and exercise capacity (BODE) index and the modified Medical Research Council (MMRC) score. C1M, C4M2, C4Ma3, and Pro-C5 were significantly increased from stable state to exacerbation and decreased at follow-up. Furthermore, the biomarkers were significantly higher during severe exacerbation compared with moderate exacerbation. Multivariate analysis adjusted for BMI, MMRC score, unadjusted Charlson score, and FEV1 %predicted showed a significant influence of C1M, C4Ma3, and C4M2 on time to exacerbation. None of the biomarkers were predictors for mortality. CONCLUSIONS: Serologically assessed collagen remodeling appears to play a significant role in COPD severity (airflow limitation, dyspnea) and disease outcome (time to exacerbation and prognosis as assessed by the BODE index).