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.

Pembrolizumab in a Patient With a Metastatic CASTLE Tumor of the Parotid.

Carcinoma showing thymus-like elements (CASTLE) is a rare tumor, most commonly found in the thyroid gland. Here we report a case of CASTLE tumor localized to the parotid gland, recognized in retrospect after a late manifestation of symptomatic pleural carcinomatosis. The original tumor in the parotid gland was treated by surgery followed by radiotherapy. Ten years later, a metastatic disease with recurrent pleural effusions occurred. Pleural carcinomatosis was strongly positive for CD5, CD117, and p63 as was the original tumor of the parotid, which allowed the diagnosis of a CASTLE tumor. Additionally, the pleural tumor expressed high levels of programmed death ligand 1 (PD-L1), and the patient underwent treatment with the monoclonal PD-L1 inhibitor pembrolizumab achieving a partial remission. To the best of our knowledge, this is the first patient with a metastatic CASTLE tumor treated with a PD-L1 inhibitor.

Airway reactivity to mannitol is similarly increased in chronic cigarette and water pipe smokers.

Background: In contrast to cigarette smoking, the association between water pipe smoking and airway hyperresponsiveness remains widely unexplored. Methods: A bronchoprovocation challenge with mannitol was performed in young adults recruited at the University of Basel, Switzerland. Subjects were categorized as acute water pipe smokers (single episode of water pipe smoking, no or <0.5 pack-years cigarette smoking); chronic water pipe smokers (weekly for ≥4 weeks, no or <0.5 pack-years cigarette smoking); cigarette smokers (no water pipe smokers); and never-smokers (no cigarette or water pipe smokers). Primary outcomes were airway reactivity as measured by the response-to-dose ratio (RDR) and airway responsiveness measured by the provocation dose to cause a 15% fall in forced expiratory volume in 1s (FEV1; PD15). Results: Seventy-four subjects with a mean age of 22.5±2.5 years and FEV1 % predicted 90.1%±8.6% were included. Subgroups were matched in terms of age, gender, and spirometry results. RDR in chronic water pipe smokers and cigarette smokers was similar (0.013%/mg [0.010-0.015] vs 0.023%/mg [0.011-0.051], respectively; p=0.12) but significantly higher than in never-smokers (0.007%/mg [0.005-0.010], p<0.01). Neither a history of asthma (p=0.88) nor a positive skin prick test (p=0.69) was associated with increased airway reactivity to the mannitol challenge test. PD15 differed significantly between cigarette smokers and never-smokers (155 mg [115-395] vs 315 mg [155-475], respectively; p=0.04). Conclusion: Weekly water pipe smoking may increase airway reactivity to a similar extent as cigarette smoking.

Treatment with long acting muscarinic antagonists stimulates serum levels of irisin in patients with COPD.

Long acting muscarinic antagonists (LAMA) are currently considered the therapeutic mainstay for patients with COPD and have been shown to improve clinical outcomes including symptoms, exercise capacity and airflow limitation. Irisin, is a newly discovered hormone-like myokine generated by skeletal muscle cells in response to exercise and it is suggested to regulate energy expenditure and exercise capacity. The aim of the present study was to investigate if treatment with LAMA alters serum irisin levels in patients with COPD. Irisin was assessed by ELISA in the serum of 506 patients with COPD, GOLD II-IV, with a smoking history >10 PY, who were included in the PROMISE-COPD cohort. The effect of inhaled LAMA on serum irisin levels was evaluated in a proof-of-concept cohort of 40 COPD patients. Univariate linear regression analysis revealed that there was a significant negative association of irisin with age-adjusted Charlson score (p = 0.003) and a positive association of irisin with 6-min walking distance (6MWD) (p = 0.018) and treatment with LAMA (p = 0.004) but not with LABA or ICS. Multivariate analysis revealed that the association of irisin with LAMA treatment remains significant after adjustment for age-adjusted score and 6MWD. In the proof-of-concept cohort a single inhalation of LAMA stimulated serum irisin levels after 4 h. These findings imply that treatment of COPD patients with LAMA increase circulating irisin, thus explaining some of the beneficial extra-pulmonary effects of these drugs when used in the treatment of COPD.

Prognostic assessment in COPD without lung function: the B-AE-D indices.

Several composite markers have been proposed for risk assessment in chronic obstructive pulmonary disease (COPD). However, choice of parameters and score complexity restrict clinical applicability. Our aim was to provide and validate a simplified COPD risk index independent of lung function.The PROMISE study (n=530) was used to develop a novel prognostic index. Index performance was assessed regarding 2-year COPD-related mortality and all-cause mortality. External validity was tested in stable and exacerbated COPD patients in the ProCOLD, COCOMICS and COMIC cohorts (total n=2988).Using a mixed clinical and statistical approach, body mass index (B), severe acute exacerbations of COPD frequency (AE), modified Medical Research Council dyspnoea severity (D) and copeptin (C) were identified as the most suitable simplified marker combination. 0, 1 or 2 points were assigned to each parameter and totalled to B-AE-D or B-AE-D-C. It was observed that B-AE-D and B-AE-D-C were at least as good as BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity), ADO (age, dyspnoea, airflow obstruction) and DOSE (dyspnoea, obstruction, smoking, exacerbation) indices for predicting 2-year all-cause mortality (c-statistic: 0.74, 0.77, 0.69, 0.72 and 0.63, respectively; Hosmer-Lemeshow test all p>0.05). Both indices were COPD specific (c-statistic for predicting COPD-related 2-year mortality: 0.87 and 0.89, respectively). External validation of B-AE-D was performed in COCOMICS and COMIC (c-statistic for 1-year all-cause mortality: 0.68 and 0.74; c-statistic for 2-year all-cause mortality: 0.65 and 0.67; Hosmer-Lemeshow test all p>0.05).The B-AE-D index, plus copeptin if available, allows a simple and accurate assessment of COPD-related risk.

Therapy with proton-pump inhibitors for gastroesophageal reflux disease does not reduce the risk for severe exacerbations in COPD.

BACKGROUND AND OBJECTIVE: Gastroesophageal reflux disease (GERD) symptoms are associated with a higher risk of chronic obstructive pulmonary disease (COPD) exacerbation. We hypothesize that treatment with proton pump inhibitors reduces the risk of exacerbation in patients with stable COPD. METHODS: A total of 638 patients with stable COPD for ≥6 weeks, ≥10 pack-years of smoking and Global Initiative for Chronic Obstructive Lung Disease II-IV seeking care in tertiary hospitals in eight European countries in the Predicting Outcome using Systemic Markers in Severe Exacerbations-COPD cohort was prospectively evaluated by us. Comorbidities including associated medical treatment were assessed at baseline, at exacerbation and at biannual visits. Median observation time was 24 months. The primary study outcomes were exacerbation and/or death. RESULTS: A total of 85 (13.3%) of COPD patients were on anti-GERD therapy. These patients had higher annual and higher severe exacerbation rates (P = 0.009 and P = 0.002), decreased quality of life (SF-36: activity score P = 0.004, St. George's Respiratory Questionnaire: physical functioning P = 0.013 and social functioning P = 0.007), higher body mass airflow obstruction, dyspnea and exercise capacity index (P = 0.033) and Modified Medical Research Council scores (P = 0.002), shorter 6-min walking distance (P = 0.0004) and a higher adjusted Charlson score (P < 0.0001). Anti-GERD therapy was associated with a shorter time to severe exacerbation (HR 2.05 95% CI 1.37-3.08). Using three multivariable Cox-regression models, this association was independent of the following: (i) adjusted Charlson score and FEV1% predicted (HR 1.91 95% CI 1.26-2.90); (ii) adjusted Charlson score, body mass, airflow obstruction, dyspnea and exercise capacity index and Modified Medical Research Council (HR 1.62 95% CI 1.04-2.54); and (iii) adjusted Charlson score, FEV1% predicted and nine classes of medication for comorbidities (HR 1.63 95% CI 1.04-2.53). CONCLUSION: These findings suggest that patients with stable COPD receiving acid-suppressive therapy with proton pump inhibitors remain at high risk of frequent and severe exacerbations.

Vasoactive Intestinal Peptide for Diagnosing Exacerbation in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Vasoactive intestinal peptide (VIP) is the most abundant neuropeptide in the lung. VIP has been linked to pulmonary arterial hypertension and hypoxia. OBJECTIVES: We aimed to assess circulating VIP levels at exacerbation and at stable chronic obstructive pulmonary disease (COPD) and to evaluate the diagnostic performance in a well-characterized cohort of COPD patients. METHODS: The nested cohort study included patients with Global Initiative for Chronic Obstructive Lung Disease stage II-IV. Patients were examined at stable state and at acute exacerbation of COPD (AE-COPD), and dedicated serum was collected at both conditions. Serum VIP levels were determined by enzyme-linked immunosorbent assay. Diagnostic accuracy was analyzed by receiver operating characteristic curve and area under the curve (AUC). RESULTS: Patients with acute exacerbation (n = 120) and stable COPD (n = 163) had similar characteristics at baseline. Serum VIP levels did not correlate with oxygen saturation at rest (p = 0.722) or at exercise (p = 0.168). Serum VIP levels were significantly higher at AE-COPD (130.25 pg/ml, 95% CI 112.19-151.83) as compared to stable COPD (40.07 pg/ml, 95% CI 37.13-43.96, p < 0.001). The association of increased serum VIP with AE-COPD remained significant after propensity score matching (p < 0.001). Analysis of the Youden index indicated the optimal serum VIP cutoff value as 56.6 pg/ml. The probability of AE-COPD was very low if serum VIP was ≤35 pg/ml (sensitivity >90%) and very high if serum VIP was ≥88 pg/ml (specificity >90%). Serum VIP levels presented a robust performance to diagnose AE-COPD (AUC 0.849, 95% CI 0.779-0.899). CONCLUSIONS: Increased serum VIP levels are associated with AE-COPD.

Predictors of marked weight gain in a population of health care and industrial workers following smoking cessation.

BACKGROUND: Concerns about postcessational weight gain might hamper rather than encourage smokers to quit smoking. METHODS: We conducted a comprehensive multi-institutional smoking cessation program for health care and industrial workers (n = 654) employed at University Hospital Basel (Switzerland) and two local health industry companies (Novartis International AG, F. Hoffmann-La Roche AG). The program contained counselling with an option of pharmacological support. Changes in body weight were observed during 24 months of follow-up. Factors associated with longitudinal weight gain (> 5 % of baseline weight) were identified by cox-regression analysis. RESULTS: In 51 % of permanent quitters no significant changes of mean body weight were observed after 12 (0.52 kg, SD ± 2.87 kg) and 24 months (0.40 kg, SD ± 2.99 kg). Marked weight gain following smoking cessation was characterized by a wide margin of changes. In more than a half of former smokers (58 %) weight increases were moderate (< 5 kg), whereas excessive increases (> 10 kg) were seen in only 10 % of quitters. Lower baseline BMI (HR 0.60, 95 % CI 0.40- 0.80, p = 0.03), daily consumption of less than ten cigarettes (HR 0.53, 95 % CI 0.27- 0.63, p = 0.04) and ischemic cardiopathy (HR 0.21, 95 % CI 0.07-0.62; p < 0.01) were associated with a lower risk for weight gain. Employees with lower educational levels (HR 2.60, 95 % CI 1.60-5.50, p < 0.01), diabetes mellitus (HR 3.05, 95 % CI 2.20-8.06, p = 0.02) and those smoking to reduce boredom in life (HR 1.68, 95 % CI 1.21-2.33, p < 0.01) were at highest risk. CONCLUSION: Marked postcessational weight gain occurs less often than expected, but remains difficult to be predicted. Our findings might be helpful to alleviate weight concerns in the average smoker willing to quit.

Prospective analysis of adrenal function in patients with acute exacerbations of COPD: the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial.

OBJECTIVE: To analyze prospectively the hypothalamic-pituitary-adrenal (HPA) axis and clinical outcome in patients treated with prednisone for exacerbated chronic obstructive pulmonary disease (COPD). DESIGN: Prospective observational study. SUBJECTS AND METHODS: Patients presenting to the emergency department were randomized to receive 40 mg prednisone daily for 5 or 14 days in a placebo-controlled manner. The HPA axis was longitudinally assessed with the 1 µg corticotropin test and a clinical hypocortisolism score at baseline, on day 6 before blinded treatment, at hospital discharge, and for up to 180 days of follow-up. Prednisone was stopped abruptly, irrespective of the test results. Patients discharged with pathological test results received instructions about emergency hydrocortisone treatment. RESULTS: A total of 311 patients were included in the analysis. Mean basal and stimulated serum total cortisol levels were highest on admission (496±398 and 816±413 nmol/l respectively) and lowest on day 6 (235±174 and 453±178 nmol/l respectively). Pathological stimulation tests were found in 63, 38, 9, 3, and 2% of patients on day 6, at discharge, and on days 30, 90, and 180 respectively, without significant difference between treatment groups. Clinical indicators of hypocortisolism did not correlate with stimulation test results, but cortisol levels were inversely associated with re-exacerbation risk. There were no hospitalizations or deaths as a result of adrenal crisis. CONCLUSION: Dynamic changes in the HPA axis occur during and after the treatment of acute exacerbations of COPD. In hypocortisolemic patients who were provided with instructions about stress prophylaxis, the abrupt termination of prednisone appeared safe.

The ADO index as a predictor of two-year mortality in general practice-based chronic obstructive pulmonary disease cohorts.

BACKGROUND: Existing prediction models for mortality in chronic obstructive pulmonary disease (COPD) patients have not yet been validated in primary care, which is where the majority of patients receive care. OBJECTIVES: Our aim was to validate the ADO (age, dyspnoea, airflow obstruction) index as a predictor of 2-year mortality in 2 general practice-based COPD cohorts. METHODS: Six hundred and forty-six patients with COPD with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages I-IV were enrolled by their general practitioners and followed for 2 years. The ADO regression equation was used to predict a 2-year risk of all-cause mortality in each patient and this risk was compared with the observed 2-year mortality. Discrimination and calibration were assessed as well as the strength of association between the 15-point ADO score and the observed 2-year all-cause mortality. RESULTS: Fifty-two (8.1%) patients died during the 2-year follow-up period. Discrimination with the ADO index was excellent with an area under the curve of 0.78 [95% confidence interval (CI) 0.71-0.84]. Overall, the predicted and observed risks matched well and visual inspection revealed no important differences between them across 10 risk classes (p = 0.68). The odds ratio for death per point increase according to the ADO index was 1.50 (95% CI 1.31-1.71). CONCLUSIONS: The ADO index showed excellent prediction properties in an out-of-population validation carried out in COPD patients from primary care settings.

Mortality risk prediction in COPD by a prognostic biomarker panel.

Chronic obstructive pulmonary disease (COPD) is a complex disease with various phenotypes. The simultaneous determination of multiple biomarkers reflecting different pathobiological pathways could be useful in identifying individuals with an increased risk of death. We derived and validated a combination of three biomarkers (adrenomedullin, arginine vasopressin and atrial natriuretic peptide), assessed in plasma samples of 385 patients, to estimate mortality risk in stable COPD. Biomarkers were analysed in combination and defined as high or low. In the derivation cohort (n = 142), there were 73 deaths during the 5-year follow-up. Crude hazard ratios for mortality were 3.0 (95% CI 1.8-5.1) for one high biomarker, 4.8 (95% CI 2.4-9.5) for two biomarkers and 9.6 (95% CI 3.3-28.3) for three high biomarkers compared with no elevated biomarkers. In the validation cohort (n = 243), 87 individuals died. Corresponding hazard ratios were 1.9 (95% CI 1.1-3.3), 3.1 (95% CI 1.8-5.4) and 5.4 (95% CI 2.5-11.4). Multivariable adjustment for clinical variables as well as the BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index and stratification by the Global Initiative for Chronic Obstructive Lung Disease stages provided consistent results. The addition of the panel of three biomarkers to the BODE index generated a net reclassification improvement of 57.9% (95% CI 21.7-92.4%) and 45.9% (95% CI 13.9-75.7%) at 3 and 5 years, respectively. Simultaneously elevated levels of adrenomedullin, arginine vasopressin and atrial natriuretic peptide are associated with increased risk of death in patients with stable COPD.

Exertional hypoxemia in stable COPD is common and predicted by circulating proadrenomedullin.

BACKGROUND: The prevalence of exertional hypoxemia in unselected patients with COPD is unknown. Intermittent hypoxia leads to adrenomedullin (ADM) upregulation through the hypoxia-inducible factor-1 pathway. We aimed to assess the prevalence and the annual probability to develop exertional hypoxemia in stable COPD. We also hypothesized that increased ADM might be associated with exertional hypoxemia and envisioned that adding ADM to clinical variables might improve its prediction in COPD. METHODS: A total of 1,233 6-min walk tests and circulating proadrenomedullin (proADM) levels from 574 patients with clinically stable, moderate to very severe COPD enrolled in a multinational cohort study and followed up for 2 years were concomitantly analyzed. RESULTS: The prevalence of exertional hypoxemia was 29.1%. In a matrix derived from a fitted-multistate model, the annual probability to develop exertional hypoxemia was 21.6%. Exertional hypoxemia was associated with greater deterioration of specific domains of health-related quality of life, higher severe exacerbation, and death annual rates. In the logistic linear and conditional Cox regression multivariable analyses, both FEV1% predicted and proADM proved independent predictors of exertional hypoxemia (P < .001 for both). Adjustment for comorbidities, including cardiovascular disorders, and exacerbation rate did not influence results. Relative to using FEV1% predicted alone, adding proADM resulted in a significant improvement of the predictive properties (P = .018). Based on the suggested nonlinear nomogram, patients with moderate COPD (FEV1% predicted = 50%) but high proADM levels (> 2 nmol/L) presented increased risk (> 30%) for exertional desaturation. CONCLUSIONS: Exertional desaturation is common and associated with poorer clinical outcomes in COPD. ADM improves prediction of exertional desaturation as compared with the use of FEV1% predicted alone. TRIAL REGISTRY: ISRCTN Register; No.: ISRCTN99586989; URL: www.controlled-trials.com.

Adrenomedullin refines mortality prediction by the BODE index in COPD: the "BODE-A" index.

The BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index is well-validated for mortality prediction in chronic obstructive pulmonary disease (COPD). Concentrations of plasma pro-adrenomedullin, a surrogate for mature adrenomedullin, independently predicted 2-year mortality among inpatients with COPD exacerbation. We compared accuracy of initial pro-adrenomedullin level, BODE and BODE components, alone or combined, in predicting 1-year or 2-year all-cause mortality in a multicentre, multinational observational cohort with stable, moderate to very severe COPD. Pro-adrenomedullin was significantly associated (p<0.001) with 1-year mortality (4.7%) and 2-year mortality (7.8%) and comparably predictive to BODE regarding both (C statistics 0.691 versus 0.745 and 0.635 versus 0.679, respectively). Relative to using BODE alone, adding pro-adrenomedullin significantly improved 1-year and 2-year mortality prognostication (C statistics 0.750 and 0.818, respectively; both p<0.001). Pro-adrenomedullin plus BOD was more predictive than the original BODE including 6-min walk distance. In multivariable analysis, pro-adrenomedullin (likelihood ratio Chi-squared 13.0, p<0.001), body mass index (8.5, p=0.004) and 6-min walk distance (7.5, p=0.006) independently foretold 2-year survival, but modified Medical Research Council dyspnoea score (2.2, p=0.14) and forced expiratory volume in 1 s % predicted (0.3, p=0.60) did not. Pro-adrenomedullin plus BODE better predicts mortality in COPD patients than does BODE alone; pro-adrenomedullin may substitute for 6-min walk distance in BODE when 6-min walk testing is unavailable.

Predictors of success for smoking cessation at the workplace: a longitudinal study.

BACKGROUND: The effectiveness of worksite interventions to reduce smoking is debatable. OBJECTIVES: A comprehensive smoking cessation intervention was implemented in a community of more than 17,000 employees at three different health care companies. The primary endpoint was abstinence at 24 months (self-reported and confirmed by exhaled carbon monoxide ≤ 6 parts per million). Predictors of long-term abstinence were analysed by multivariable regression analysis. METHODS: The study was designed as an investigator-initiated and investigator-driven, open, multicentre, cohort study; 887 smokers were enrolled in the programme. The intervention included intensive individual counselling as well as nicotine replacement and/or bupropion according to individual preferences. Re-interventions for relapse were offered during the 24-month follow-up. RESULTS: The abstinence rate was 37% at 24 months and did not differ among the various medication groups (p > 0.05 for all). Predictors of successful cessation were higher age (odds ratio, OR 1.47, 95% confidence interval, CI 1.08-2.00, p < 0.01), breathlessness on exertion (OR 2.26, 95% CI 1.1-4.9, p = 0.03), and a higher educational level (OR 1.81, 95% CI 1.06-3.09, p = 0.03). Higher Fagerström (OR 0.76, 95% CI 0.59-0.97, p < 0.01) and craving scores (OR 0.75, 95% CI 0.63-0.89, p < 0.01), chronic sputum production (OR 0.52, 95% CI 0.31-0.87, p = 0.01) and use of antidepressants (OR 0.54, 95% CI 0.32-0.91, p = 0.02) were associated with ongoing smoking. CONCLUSION: A comprehensive smoking cessation intervention at the workplace achieves high, stable, long-term abstinence rates. Elderly, well-educated employees with breathlessness on exertion have higher odds of quitting smoking. In contrast, those with high physical dependency and more intense craving, and those reporting use of antidepressant medication or sputum production have poorer chances to quit.

Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial.

IMPORTANCE: International guidelines advocate a 7- to 14-day course of systemic glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the optimal dose and duration are unknown. OBJECTIVE: To investigate whether a short-term (5 days) systemic glucocorticoid treatment in patients with COPD exacerbation is noninferior to conventional (14 days) treatment in clinical outcome and whether it decreases the exposure to steroids. DESIGN, SETTING, AND PATIENTS REDUCE: (Reduction in the Use of Corticosteroids in Exacerbated COPD), a randomized, noninferiority multicenter trial in 5 Swiss teaching hospitals, enrolling 314 patients presenting to the emergency department with acute COPD exacerbation, past or present smokers (≥20 pack-years) without a history of asthma, from March 2006 through February 2011. INTERVENTIONS: Treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled, double-blind fashion. The predefined noninferiority criterion was an absolute increase in exacerbations of at most 15%, translating to a critical hazard ratio of 1.515 for a reference event rate of 50%. MAIN OUTCOME AND MEASURE: Time to next exacerbation within 180 days. RESULTS: Of 314 randomized patients, 289 (92%) of whom were admitted to the hospital, 311 were included in the intention-to-treat analysis and 296 in the per-protocol analysis. Hazard ratios for the short-term vs conventional treatment group were 0.95 (90% CI, 0.70 to 1.29; P = .006 for noninferiority) in the intention-to-treat analysis and 0.93 (90% CI, 0.68 to 1.26; P = .005 for noninferiority) in the per-protocol analysis, meeting our noninferiority criterion. In the short-term group, 56 patients (35.9%) reached the primary end point; 57 (36.8%) in the conventional group. Estimates of reexacerbation rates within 180 days were 37.2% (95% CI, 29.5% to 44.9%) in the short-term; 38.4% (95% CI, 30.6% to 46.3%) in the conventional, with a difference of -1.2% (95% CI, -12.2% to 9.8%) between the short-term and the conventional. Among patients with a reexacerbation, the median time to event was 43.5 days (interquartile range [IQR], 13 to 118) in the short-term and 29 days (IQR, 16 to 85) in the conventional. There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean cumulative prednisone dose was significantly higher (793 mg [95% CI, 710 to 876 mg] vs 379 mg [95% CI, 311 to 446 mg], P < .001), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently. CONCLUSIONS AND RELEVANCE: In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN19646069.

Pancreatic stone protein predicts positive sputum bacteriology in exacerbations of COPD.

BACKGROUND: Pancreatic stone protein/regenerating protein (PSP/reg) serum levels are supposed to be increased in bacterial inflammation. PSP/reg levels also might be useful, therefore, as a predictor of bacterial infection in COPD. METHODS: Two hundred consecutive patients presenting to the ED due to acute exacerbation of COPD were prospectively assessed. Patients were evaluated based on clinical, laboratory, and lung functional parameters at admission (exacerbation) and after short-term follow-up (14-21 days). PSP/reg serum values were measured by a newly developed enzyme-linked immunosorbent assay. RESULTS: PSP/reg levels were elevated in subjects with COPD exacerbation (23.8 ng/mL; 95% CI, 17.1-32.7) when compared with those with stable disease (19.1 ng/mL; 95% CI, 14.1-30.4; P 5 .03) and healthy control subjects (14.0 ng/mL; 95% CI , 12.0-19.0; P , .01). Higher PSP/reg values were observed in exacerbations with positive sputum bacteriology compared with those with negative sputum bacteriology (26.1 ng/mL [95% CI, 19.2-38.1] vs 20.8 ng/mL [95% CI , 15.6-27.2]; P , .01). Multivariate regression analysis revealed PSP/reg level as an independent predictor of positive sputum bacteriology. A combination of a PSP/reg cutoff value of . 33.9 ng/mL and presence of discolored sputum had a specificity of 97% to identify patients with pathogenic bacteria on sputum culture. In contrast, PSP/reg levels , 18.4 ng/mL and nonpurulent sputum ruled out positive bacterial sputum culture (sensitivity, 92%). In survival analysis, high PSP/reg levels at hospital admission were associated with increased 2-year mortality. CONCLUSIONS: Serum PSP/reg level might represent a promising new biomarker to identify bacterial etiology of COPD exacerbation.

Impact of adherence to the GOLD guidelines on symptom prevalence, lung function decline and exacerbation rate in the Swiss COPD cohort.

PRINCIPLES: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines aim to optimise chronic obstructive pulmonary disease (COPD) diagnosis and treatment. However, little is known about the extent to which general practitioners' (GP) adherence to GOLD guidelines improves patient outcomes. METHODS: In this questionnaire-based study, COPD patients were screened and enrolled; exacerbation history was recorded, and demographic, spirometric and management data were collected for 12 months. Spirometry was performed at least every 6 months according to American Thoracic Society guidelines. Based on these data, patients were grouped into GOLD COPD severity classifications. Data were expressed as the difference between baseline and month 12. RESULTS: Among 139 GPs, 454 patients were analysed regarding baseline and 12 month data. There was no significant change in distribution of GOLD COPD severity grades, lung function or guideline adherence. Chronic cough and sputum production were significantly reduced (p <0.001; p <0.020), as was exacerbation rate (p = 0.041). Factors associated with exacerbations were male sex, asthma and cerebrovascular insult as a co-morbidity. Exacerbation rate was significantly reduced in patients treated with combination therapy (long-acting ß2-agonist (LABA)+ inhaled corticosteroids (ICS); p = 0.0178) and long-acting anticholinergics (LAAC; p = 0.0011). Patients treated per guidelines had no advantage in lung function, estimation of symptom prevalence or, most importantly, exacerbation rate. CONCLUSIONS: While there was no improvement in adherence to GOLD guidelines, disease severity was not affected detrimentally, suggesting that guideline adherence does not seem to impact symptom prevalence, exacerbation rate or lung function decline after one year of follow up.

Response to add-on inhaled corticosteroids in COPD based on airway hyperresponsiveness to mannitol.

BACKGROUND: The use of inhaled corticosteroids in mild to moderate COPD is controversial. The aim of this study was to determine whether airway hyperresponsiveness to mannitol might identify patients who are likely to respond to add-on inhaled corticosteroids. METHODS: Ninety subjects with mild to moderate COPD were recruited and 68 subsequently randomized in a double-blind manner to receive inhaled budesonide (1,600 µg/d, n = 31) or placebo (n = 37) for 3 months. Thirty-eight subjects had airway hyperresponsiveness to mannitol (17 received budesonide, 21 placebo). All subjects received tiotropium throughout the study, including 4 weeks before randomization. Spirometry, quality of life (St. George Respiratory Questionnaire), degree of dyspnea, airway responsiveness to mannitol, and exhaled nitric oxide were assessed at week 0 (recruitment), week 4 (baseline prior to randomization), and week 16 (posttreatment). RESULTS: Compared with placebo, budesonide was associated with improved quality of life in subjects showing airway hyperresponsiveness to mannitol (difference of changes in quality of life score between randomization and study completion, −9.1; 95% CI, −15.8 to −2.3; P < .01). Treatment with inhaled budesonide also led to a reduction in airway responsiveness to mannitol compared with placebo (difference in log10 response-dose ratio, −0.3; 95% CI, −0.6 to −0.04; P < .01). However, postrandomization changes in FEV1 % predicted, quality of life, and exhaled nitric oxide showed no difference between budesonide and placebo. CONCLUSIONS: In subjects with mild to moderate COPD and airway hyperresponsiveness to mannitol, quality of life and airway responsiveness improved after treatment with inhaled corticosteroids added to long-acting bronchodilator therapy.