Reduction of corticosteroid use in outpatient treatment of exacerbated COPD - Study protocol for a randomized, double-blind, non-inferiority study, (The RECUT-trial).

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major public health issue affecting approximately 4% to 7% of the Swiss population. According to current inpatient guidelines, systemic corticosteroids are important in the treatment of acute COPD exacerbations and should be given for 5 to 7 days. Several studies suggest that corticosteroids accelerate the recovery of FEV1 (forced expiratory volume in 1 second), enhance oxygenation, decrease the duration of hospitalization, and improve clinical outcomes. However, the additional therapeutic benefit regarding FEV1 recovery appears to be most apparent in the first 3 to 5 days. No data are available on the optimum duration of corticosteroid treatment in primary-care patients with acute COPD exacerbations. Given that many COPD patients are treated as outpatients, there is an urgent need to improve the evidence base on COPD management in this setting. The aim of this study is to investigate whether a 3-day treatment with orally administered corticosteroids is non-inferior to a 5-day treatment in acute exacerbations of COPD in a primary-care setting. METHODS/DESIGN: This study is a prospective double-blind randomized controlled trial conducted in a primary-care setting. It is anticipated that 470 patients with acutely exacerbated COPD will be recruited. Participants are randomized to receive systemic corticosteroid treatment of 40 mg prednisone daily for 5 days (conventional arm, n = 235) or for 3 days followed by 2 days of placebo (experimental arm, n = 235). Antibiotic treatment for 7 days is given to all patients with CRP ≥ 50 mg/l, those with a known diagnosis of bronchiectasis, or those presenting with Anthonisen type I exacerbation. Additional treatment after inclusion is left at the discretion of the treating general practitioner. Follow-up visits are performed on days 3 and 7, followed by telephone interviews on days 30, 90, and 180 after inclusion in the study. The primary endpoint is the time to next exacerbation during the 6-month follow-up period. DISCUSSION: The study is designed to assess whether a 3-day course of corticosteroid treatment is not inferior to the conventional 5-day treatment course in outpatients with exacerbated COPD regarding time to next exacerbation. Depending on the results, this trial may lead to a reduction in the cumulative corticosteroid dose in COPD patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02386735. Registered on 12 March 2015.

Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Clinical trials yielded conflicting data about the benefit of adding systemic corticosteroids for treatment of community-acquired pneumonia. We assessed whether short-term corticosteroid treatment reduces time to clinical stability in patients admitted to hospital for community-acquired pneumonia. METHODS: In this double-blind, multicentre, randomised, placebo-controlled trial, we recruited patients aged 18 years or older with community-acquired pneumonia from seven tertiary care hospitals in Switzerland within 24 h of presentation. Patients were randomly assigned (1:1 ratio) to receive either prednisone 50 mg daily for 7 days or placebo. The computer-generated randomisation was done with variable block sizes of four to six and stratified by study centre. The primary endpoint was time to clinical stability defined as time (days) until stable vital signs for at least 24 h, and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00973154. FINDINGS: From Dec 1, 2009, to May 21, 2014, of 2911 patients assessed for eligibility, 785 patients were randomly assigned to either the prednisone group (n=392) or the placebo group (n=393). Median time to clinical stability was shorter in the prednisone group (3·0 days, IQR 2·5-3·4) than in the placebo group (4·4 days, 4·0-5·0; hazard ratio [HR] 1·33, 95% CI 1·15-1·50, p<0·0001). Pneumonia-associated complications until day 30 did not differ between groups (11 [3%] in the prednisone group and 22 [6%] in the placebo group; odds ratio [OR] 0·49 [95% CI 0·23-1·02]; p=0·056). The prednisone group had a higher incidence of in-hospital hyperglycaemia needing insulin treatment (76 [19%] vs 43 [11%]; OR 1·96, 95% CI 1·31-2·93, p=0·0010). Other adverse events compatible with corticosteroid use were rare and similar in both groups. INTERPRETATION: Prednisone treatment for 7 days in patients with community-acquired pneumonia admitted to hospital shortens time to clinical stability without an increase in complications. This finding is relevant from a patient perspective and an important determinant of hospital costs and efficiency. FUNDING: Swiss National Science Foundation, Viollier AG, Nora van Meeuwen Haefliger Stiftung, Julia und Gottfried Bangerter-Rhyner Stiftung.

Granulomas are a source of interleukin-33 expression in pulmonary and extrapulmonary sarcoidosis.

Sarcoidosis is a chronic inflammatory disease characterized by noncaseating epithelioid granulomas. These granulomas consist of highly differentiated mononuclear phagocytes--epithelioid cells and multinucleated giant cells (MNGCs)--surrounded by a proinflammatory infiltrate. Interleukin-33 (IL-33) is an inflammatory cytokine that is constitutively expressed in barrier tissues such as skin and lung and up-regulated in inflammation. Because sarcoidosis occurs most frequently in lung and skin, we studied the expression of this cytokine by immunohistochemistry in these tissues from patients with sarcoidosis, with foreign body granulomas, with other granulomatous diseases, and in corresponding normal tissues. We identified nuclear IL-33 staining of epithelioid cells and MNGCs in biopsies of skin (18/25 patients, 72%) and lung (10/19 patients, 53%) sarcoidosis. In contrast, sarcoidal granulomas in lymph nodes did not show IL-33 expression. Other granulomatous diseases showed only occasional and weak IL-33 expression. In sarcoidosis, we found a strong correlation between IL-33 expression and systemic disease, presence of MNGCs, and an M2-like macrophage phenotype as assessed by CD163 staining. Therefore, we propose that IL-33 plays a critical role in pathogenesis and disease progression of sarcoidosis. Because IL-33 is less commonly and only weakly expressed in other granulomatous diseases, the detection of IL-33 might serve as an adjunctive diagnostic marker. IL-33 expression in sarcoidosis seems to be dependent on the specific tissue microenvironment of sarcoidal granulomas and represents a novel biomarker for systemic involvement.

Corticosteroid treatment for community-acquired pneumonia--the STEP trial: study protocol for a randomized controlled trial.

BACKGROUND: Community-acquired pneumonia (CAP) is the third-leading infectious cause of death worldwide. The standard treatment of CAP has not changed for the past fifty years and its mortality and morbidity remain high despite adequate antimicrobial treatment. Systemic corticosteroids have anti-inflammatory effects and are therefore discussed as adjunct treatment for CAP. Available studies show controversial results, and the question about benefits and harms of adjunct corticosteroid therapy has not been conclusively resolved, particularly in the non-critical care setting. METHODS/DESIGN: This randomized multicenter study compares a treatment with 7 days of prednisone 50 mg with placebo in adult patients hospitalized with CAP independent of severity. Patients are screened and enrolled within the first 36 hours of presentation after written informed consent is obtained. The primary endpoint will be time to clinical stability, which is assessed every 12 hours during hospitalization. Secondary endpoints will be, among others, all-cause mortality within 30 and 180 days, ICU stay, duration of antibiotic treatment, disease activity scores, side effects and complications, value of adrenal function testing and prognostic hormonal and inflammatory biomarkers to predict outcome and treatment response to corticosteroids. Eight hundred included patients will provide an 85% power for the intention-to-treat analysis of the primary endpoint. DISCUSSION: This largest to date double-blind placebo-controlled multicenter trial investigates the effect of adjunct glucocorticoids in 800 patients with CAP requiring hospitalization. It aims to give conclusive answers about benefits and risks of corticosteroid treatment in CAP. The inclusion of less severe CAP patients will be expected to lead to a relatively low mortality rate and survival benefit might not be shown. However, our study has adequate power for the clinically relevant endpoint of clinical stability. Due to discontinuing glucocorticoids without tapering after seven days, we limit duration of glucocorticoid exposition, which may reduce possible side effects. TRIAL REGISTRATION: 7 September 2009 on ClinicalTrials.gov: NCT00973154.

Clinical impact of screening for sleep related breathing disorders in atrial fibrillation.

OBJECTIVE: The aim of this study was to quantify daytime symptoms in atrial fibrillation (AF) patients with and without sleep related breathing disorders (SRBD). BACKGROUND: SRBD are common in patients with AF but little is known about daytime symptoms among those with SRBD. METHODS: Patients with AF admitted to clinics of two tertiary referral hospitals for a variety of different cardiovascular diseases were screened with a trans-nasal airflow measurement device allowing measurement of the apnea-hypopnea-index. Data on cardiac risk factors, left ventricular ejection fraction (LVEF) and cardiac medication were collected. Presence of SRBD was defined as an AHI ≥ 15/h. The Epworth sleepiness scale (ESS) was used to quantify daytime symptoms. RESULTS: Of 102 screened patients 8 were excluded due to device malfunction (n=1), dislocation of nasal cannula (n=6), or hyperthyroidism (n=1). Among the remaining 94 patients, 40 (43%) were diagnosed with SRBD. Patients with and without SRBD had similar age, body mass index, LVEF and cardiac medication. The prevalence of coronary artery disease was higher in patients with SRBD than in those without (50 vs. 17%; p=0.0007). ESS score was low and similar in both groups (no SRBD: median 4, interquartile range (IQR) 2-4 vs. SRBD: 5, IQR 3-8; p=0.14). Only 6/40 (5%) of the patients underwent overnight polysomnography and 2 (5%) started CPAP ventilation during follow-up. CONCLUSIONS: Even though SRBD are common in patients with AF, the prevalence of daytime symptoms is rare. Consequently, most patients will not initiate CPAP ventilation after positive SRBD screening.