David Miedinger

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.

Use of B-Type Natriuretic Peptide in the Risk Stratification of Acute Exacerbations of COPD

BACKGROUND In patients with COPD, prognosis might be determined at least in part by the extent of cardiac stress induced by hypoxia and pulmonary arterial hypertension. METHODS B-type natriuretic peptide (BNP), a quantitative marker of cardiac stress, was determined in 208 consecutive patients presenting to the emergency department with an acute exacerbation of COPD (AECOPD). The accuracy of BNP to predict death at a 2-year follow-up was evaluated as the primary end point. The need for intensive care and in-hospital mortality were determined as secondary end points. RESULTS BNP levels were significantly elevated during the acute exacerbation compared to recovery (65 pg/mL; interquartile range [IQR], 34 to 189 pg/mL; vs 45 pg/mL; IQR, 25 to 85 pg/mL; p < 0.001), particularly in those patients requiring ICU treatment (105 pg/mL; IQR, 66 to 553 pg/mL; vs 60 pg/mL; IQR, 31 to 169 pg/mL; p = 0.007). In multivariate Cox regression analysis, BNP accurately predicted the need for ICU care (hazard ratio, 1.13; 95% confidence interval [CI], 1.03 to 1.24 for an increase in BNP of 100 pg/mL; p = 0.008). In a receiver operating characteristic analysis to evaluate the potential of BNP levels to predict short-term and long-term mortality rates, areas under the curve were 0.55 (SD, 0.71; 95% CI, 0.41 to 0.68) and 0.56 (SD, 0.53; 95% CI, 0.45 to 0.66, respectively). CONCLUSIONS In patients with AECOPD, BNP levels independently predict the need for intensive care. However, BNP levels failed to adequately predict short-term and long-term mortality rates in AECOPD patients.

Plasma Pro-Adrenomedullin But Not Plasma Pro-Endothelin Predicts Survival in Exacerbations of COPD

BACKGROUND Plasma endothelin and adrenomedullin are increased in patients with pulmonary arterial hypertension, hypoxia, and pulmonary infections, conditions that predict survival in patients with COPD. We investigated whether plasma pro-endothelin-1 (proET-1) and/or pro-adrenomedullin (proADM) on admission to the hospital for acute exacerbation predict survival in patients with COPD. METHODS We examined 167 patients who had been admitted to the hospital for acute exacerbation, and we followed them up for 2 years. We measured plasma C-terminal (CT) proET-1 and mid-regional (MR) proADM on hospital admission, after 14 to 18 days, and after 6 months. In addition to plasma CT proET-1 and MR proADM, we assessed with Cox regression univariate and multivariate analyses the predictive value of clinical, functional, and laboratory parameters on 2-year survival. We analyzed the time to death by Kaplan-Meier curves. RESULTS Compared to recovery and stable state, CT-proET-1 and MR-proADM were significantly increased on hospital admission (p < 0.001 and p = 0.002, respectively). MR-proADM, but not CT-proET-1, was associated with increased in-hospital mortality (p = 0.049) and independently predicted 2-year survival (p = 0.017). ProADM plasma levels > 0.84 nmol/L on hospital admission increased the mortality risk within 2 years from 13 to 32% (p = 0.004). By contrast, age (p = 0.779), Charlson comorbidity score (p = 0.971), body mass index (p = 0.802), FEV(1) percent predicted (p = 0.741), PAo(2) (p = 0.744), PAco(2) (p = 0.284), leukocyte counts (p = 0.333), C-reactive protein (p = 0.772), procalcitonin (p = 0.069), pulmonary arterial hypertension (p = 0.971), and CT-proET-1 (p = 0.223) were not independently associated with 2-year survival. CONCLUSIONS This study shows that plasma proADM but not plasma proET-1 on admission to the hospital for acute exacerbation independently predicts survival, thus suggesting that this biomarker could be used to predict prognosis in patients with COPD.

Occupational Exposure to Dusts, Gases, and Fumes and Incidence of Chronic Obstructive Pulmonary Disease in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults

RATIONALE There is limited evidence from population-based studies demonstrating incidence of spirometric-defined chronic obstructive pulmonary disease (COPD) in association with occupational exposures. OBJECTIVES We evaluated the association between occupational exposures and incidence of COPD in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA). MEASUREMENTS AND MAIN RESULTS Prebronchodilator ratio of forced expiratory volume in 1 second over forced vital capacity (FEV(1)/FVC) was measured in 4,267 nonasthmatic SAPALDIA participants ages 18-62 at baseline in 1991 and at follow-up in 2001-2003. COPD was defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criterion (FEV(1)/FVC < 0.70) and Quanjer reference equation (FEV(1)/FVC < lower limit of normal [LLN]), and categorized by severity (≥ 80% and <80% predicted FEV(1) for stage I and stage II+, respectively). Using a job-exposure matrix, self-reported occupations at baseline were assigned exposures to biological dusts, mineral dusts, gases/fumes, and vapors, gases, dusts, or fumes (VGDF) (high, low, or unexposed as reference). Adjusted incident rate ratios (IRRs) of stage I and stage II+ COPD were estimated in mixed Poisson regression models. Statistically significant (P < 0.05) IRRs of stage II+ GOLD and LLN-COPD, indicating risks between two- and fivefold, were observed for all occupational exposures at high levels. Occupational exposure-associated risk of stage II+ COPD was observed mainly in males and ages ≥ 40 years, and remained elevated when restricted to nonsmokers. CONCLUSIONS In a Swiss working adult population, occupational exposures to biological dusts, mineral dusts, gases/fumes, and VGDF were associated with incidence of COPD of at least moderate severity.

Use of B‐type natriuretic peptide in the risk stratification of community‐acquired pneumonia

Background.  Community‐acquired pneumonia (CAP) is the leading infectious cause of death in developed countries. Risk stratification has previously been difficult.

General practitioner's adherence to the COPD GOLD guidelines: baseline data of the Swiss COPD Cohort Study

PRINCIPLES: Chronic obstructive pulmonary disease (COPD) is a major burden on patients and healthcare systems. Diagnosis and the management of COPD are often administered by general practitioners (GPs). This analysis investigated the adherence of GPs in Switzerland to the Global Initiative for Chronic Obstructive Lung Diseases (GOLD) guidelines. METHODS: As part of an ongoing investigation into the effect of GPs prescriptions on the clinical course of COPD, 139 GPs submitted a standardised questionnaire for each COPD patient recruited. Information requested included spirometric parameters, management and demographic data. Participating GPs were provided with and received instruction on a spirometer with automatic feedback on quality. Patients were grouped by the investigators into the GOLD COPD severity classifications, based on spirometric data provided. Data from the questionnaires were compared between the groups and management was compared with the recommendations of GOLD. RESULTS: Of the 615 patients recruited, 44% did not fulfil GOLD criteria for COPD. Pulmonary rehabilitation was prescribed to 5% of all patients and less than one-third of patients exercised regularly. Less than half the patients in all groups used short-acting bronchodilators. Prescribing long-acting bronchodilators or inhaled corticosteroids conformed to GOLD guidelines in two-thirds of patients with GOLD stage III or IV disease, and approximately half of the less severe patients. Systemic steroids were inappropriately prescribed during stable disease in 6% of patients. CONCLUSIONS: Adherence to GOLD (COPD) guidelines is low among GPs in Switzerland and COPD is often misdiagnosed or treated inappropriately. This is probably due to poor knowledge of disease definitions.

Quality of Spirometry in Primary Care for Case Finding of Airway Obstruction in Smokers

Background: Diagnosis of chronic obstructive pulmonary disease (COPD) and its severity determination is based on spirometry. The quality of spirometry is crucial. Objectives: Our aim was to assess the quality of spirometry performed using a spirometer with automated feedback and quality control in a general practice setting in Switzerland and to determine the prevalence of airflow limitation in smokers aged ≧40 years. Method: Current smokers ≧40 years of age were consecutively recruited for spirometry testing by general practitioners. General practitioners received spirometry training and were provided with an EasyOne™ spirometer. Spirometry tests were assigned a quality grade from A to D and F, based on the criteria of the National Lung Health Education Program. Only spirometry tests graded A–C (reproducible measurements) were included in the analysis of airflow limitation. Results: A total of 29,817 spirometries were analyzed. Quality grades A–D and F were assigned to 33.9, 7.1, 19.4, 27.8 and 11.8% of spirometries, respectively. 95% required ≤5 trials to achieve spirometries assigned grade A. The prevalence of mild, moderate, severe and very severe airway obstruction in individuals with spirometries graded A–C was 6, 15, 5 and 1%, respectively. Conclusion: Spirometries in general practice are of acceptable quality with reproducible spirometry in 60% of measurements. Airway obstruction was found in 27% of current smokers aged ≧40 years. Office spirometry provides a simple and quick means of detecting airflow limitation, allowing earlier diagnosis and intervention in many patients with early COPD.

Trends in incidence of occupational asthma, contact dermatitis, noise-induced hearing loss, carpal tunnel syndrome and upper limb musculoskeletal disorders in European countries from 2000 to 2012

Objectives The European Union (EU) strategy for health and safety at work underlines the need to reduce the incidence of occupational diseases (OD), but European statistics to evaluate this common goal are scarce. We aim to estimate and compare changes in incidence over time for occupational asthma, contact dermatitis, noise-induced hearing loss (NIHL), carpal tunnel syndrome (CTS) and upper limb musculoskeletal disorders across 10 European countries. Methods OD surveillance systems that potentially reflected nationally representative trends in incidence within Belgium, the Czech Republic, Finland, France, Italy, the Netherlands, Norway, Spain, Switzerland and the UK provided data. Case counts were analysed using a negative binomial regression model with year as the main covariate. Many systems collected data from networks of ‘centres’, requiring the use of a multilevel negative binomial model. Some models made allowance for changes in compensation or reporting rules. Results Reports of contact dermatitis and asthma, conditions with shorter time between exposure to causal substances and OD, were consistently declining with only a few exceptions. For OD with physical causal exposures there was more variation between countries. Reported NIHL was increasing in Belgium, Spain, Switzerland and the Netherlands and decreasing elsewhere. Trends in CTS and upper limb musculoskeletal disorders varied widely within and between countries. Conclusions This is the first direct comparison of trends in OD within Europe and is consistent with a positive impact of European initiatives addressing exposures relevant to asthma and contact dermatitis. Taking a more flexible approach allowed comparisons of surveillance data between and within countries without harmonisation of data collection methods.

The use of the Asthma Control Test in general practice and its correlation with asthma control according to the GINA guidelines.

Abstract Background: The GINA guidelines have redefined the primary goal of asthma treatment as achieving optimum control. Objectives: To document the level of asthma control in Switzerland, the correlations between the international guidelines by GINA and the ACT’s rating of asthma control, current treatment in adolescent and adult Swiss asthma patients and factors associated with asthma control. Methods: General practitioners and specialists (pulmonologists, allergologists and paediatricians) were invited to participate in the cross-sectional survey. Asthma control was assessed in 1093 asthma patients using both the ACT and the GINA classification for asthma control. Results: According to the GINA guidelines controlled asthma was found in 290 (27%) patients, when measured with the ACT 124 (11.5%) patients showed sufficient asthma control. Of the test results 65% were in accordance with each other, whereas in 85% of the non-matching results the ACT underestimated control according to GINA classification. An ACT cut-off score of ≤17 best identified uncontrolled asthma according to GINA guidelines. A total of 956 (87.7%) patients received controller medication and 849 (77.9%) patients received reliever medication. The following parameters were consistently identified to be significantly associated with insufficient asthma control in both GINA and ACT measurements: presence of exacerbation, use of reliever medication, switch of therapy and smoking. Study limitation: For this study only the ACT version for adults was used. Conclusion: Asthma control remains insufficient in the majority of patients, despite prescription of regular controller medication. This survey confirms the validated ACT to be useful and important in everyday practice as an objective measure for asthma control according to GINA guidelines in order to monitor control and adjust treatment.

Midregional proatrial natriuretic peptide predicts survival in exacerbations of COPD.

BACKGROUND Recently, the use of systemic biomarkers to monitor and assess the clinical evolution of respiratory disease has gained interest. We investigated whether midregional proatrial natriuretic peptide (MR-proANP) predicts survival in patients with COPD when they are admitted to the hospital for exacerbation. METHODS One hundred sixty-seven patients (mean age 70 years old, 75 men) admitted to the hospital for exacerbation were followed up for 2 years. MR-proANP was measured on admission, after 14 days, and at 6 months. The predictive value of clinical, functional, and laboratory parameters on admission were assessed by Cox regression analyses. The time to death was analyzed by Kaplan-Meier survival curves. RESULTS MR-proANP level was significantly higher on admission for exacerbation, compared with recovery and stable state (P = .004 for the comparison among all time points). MR-proANP correlated with the Charlson condition and age-related score (P < .0001), left ventricular ejection fraction (P < .0001), C-reactive protein (P = .037), and FEV(1)% predicted (P = .004). MR-proANP levels were similar in patients requiring ICU treatment and in those treated in the medical ward (P = .086). Thirty-seven patients (22%) died within 2 years. MR-proANP levels were higher in nonsurvivors compared with survivors (median [interquartile range] 185 pmol/L [110-286] vs 92 pmol/L [56-158], P < .001). Mortality was higher across MR-proANP quartiles (log rank P < .0001). Charlson condition and age-related score (P = .001), Paco(2) (P < .0001), and MR-proANP (P = .001) predicted mortality in the univariate Cox-regression model. Both MR-proANP and Paco(2) were independent predictors of mortality in the multivariate Cox regression model. CONCLUSIONS MR-proANP at exacerbation is associated with 2-year long-term survival in patients with exacerbation of COPD.