Sandrine Andrea Urwyler

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.

Prognostic Value of Copeptin One-Year Outcome in Patients With Acute Stroke

Background and Purpose— An accurate long-term outcome prediction may improve management of stroke patients. We investigated the ability of copeptin to predict 1-year outcome in stroke patients. Methods— In this preplanned post hoc analysis, the National Institutes of Health Stroke Scale score and copeptin levels were measured on admission in a cohort of patients with ischemic stroke. The primary end point was functional outcome (modified Rankin Scale score <3 or 3–6) after 1 year. The secondary end point was all-cause mortality. Results— Of 362 patients, 341 (94.2%) completed the 1-year follow-up, 146 (43%) patients had an unfavorable functional outcome, and 66 (20%) died. Multivariate logistic-regression analysis adjusted for age and National Institutes of Health Stroke Scale score showed that copeptin was an independent predictor of functional outcome (odds ratio=4.00; 95% CI, 1.94–8.19) and death (odds ratio=2.68; 95% CI, 1.24–5.82). The area under the receiver operating characteristic curve of copeptin was 0.72 (95% CI, 0.67–0.77) for functional outcome and 0.74 (95% CI, 0.69–0.78) for mortality. Copeptin improved the area under the receiver operating characteristic curve of the National Institutes of Health Stroke Scale score for functional outcome from 0.70 (95% CI, 0.64–0.74) to 0.76 (95% CI, 0.71–0.82; P=0.002) and for mortality from 0.74 (95% CI, 0.69–0.78) to 0.78 (95% CI, 0.71–0.85; P=0.04). Conclusions— Copeptin levels are a useful, complementary tool to predict functional outcome and mortality 1 year after stroke. Clinical Trial Registration— ISCTRN 00390962; clinicaltrials.gov No. NCT00390962.

Copeptin as a stress marker prior and after a written examination – the CoEXAM study

Abstract The stress hormone copeptin, which is co-secreted with arginine vasopressin, increases in seriously ill patients and can predict outcome in several organic diseases. Information about the influence of psychological stress on copeptin levels is lacking, but is important for interpretation of copeptin levels in the clinical setting. The aim of this study was to evaluate the influence of psychological stress on copeptin levels. We measured copeptin levels in 25 healthy medical students before and after a written examination. The primary endpoint was change in copeptin levels from immediately prior to examination compared with after the examination. Median copeptin levels prior to the examination were significantly higher than those after its conclusion. Similar results were found for serum cortisol and salivary cortisol. Serum cortisol prior to examination was significantly higher in students with a superior examination result, compared to those with a lower score. In conclusion, psychological stress leads to a subtle increase in copeptin level and might therefore be taken into account as a confounding factor in disorders with small diagnostic copeptin range. Higher cortisol levels, but not copeptin, correlated with a better academic performance in this cohort of students.

Copeptin concentrations during psychological stress: the PsyCo study

OBJECTIVE The prognostic/diagnostic biomarker copeptin, an arginine vasopressin surrogate, reflects physical stress. Whether copeptin concentration increases upon psychological stress is unknown. We investigated psychological stress effects on copeptin secretion in healthy volunteers and patients with central diabetes insipidus (DI). DESIGN A prospective observational study was conducted to study the relation between copeptin concentration and psychological stress. METHODS A total of 20 healthy adults (ten female) and eight patients with central DI (four female) underwent the Trier Social Stress Test including, in order, 30-min waiting period, 10-min anticipation period, 10-min test period and 40-min recovery. Serum copeptin and cortisol concentrations and self-rated stress component feelings were determined in the pre-/post-anticipation period, post-test period and twice post-recovery. RESULTS In healthy volunteers, the median (25th-75th percentile) copeptin concentration peaked immediately during the post-test period at 5.1 (3.2-7.0) pmol/l, vs 3.7 (2.6-5.4) pmol/l at baseline. Over the measurement course, copeptin concentration significantly elevated (coefficient; 95% CI) (0.14; 0.06-0.23, P=0.002). The important predictors of increase in copeptin concentration were feelings of tension (0.06; 0.04-0.08, P<0.001) and avoidance (0.07; 0.04-0.10; P<0.001). Copeptin and cortisol levels were associated (0.43; 0.13-0.72, P<0.005). Patients with DI had lower baseline concentrations (1.55 (1.2-3.1) pmol/l) when compared with healthy volunteers, P=0.006. Patients with DI showed no increase upon psychological stress (peak 2.15 pmol/l (1.5-2.28), P=0.79). By contrast, cortisol values were similar in patients and volunteers. CONCLUSIONS In healthy volunteers, copeptin levels significantly increased after psychological stress testing; this response was blunted in patients with DI.

Interleukin-1 Antagonism Decreases Cortisol Levels in Obese Individuals

Context Increased cortisol levels in obesity may contribute to the associated metabolic syndrome. In obesity, the activated innate immune system leads to increased interleukin (IL)-1β, which is known to stimulate the release of adrenocorticotropin hormone (ACTH). Objectives We hypothesized that in obesity IL-1 antagonism would result in downregulation of the hypothalamo-pituitary-adrenal axis, leading to decreased cortisol levels. Design and Participants In this prospective intervention study, we included 73 patients with obesity (body mass index [BMI] ≥30 kg/m2) and at least one additional feature of the metabolic syndrome. Outcome Measures The primary end point was change in morning cortisol from baseline to after the administration of the IL-1 receptor antagonist (anakinra/Kineret®, total dose 3 × 100 mg). Secondary end points were effects on salivary cortisol and ACTH. Results Median age was 56 years, 50.7% of patients were female, and median BMI was 36.3 kg/m2. Median morning serum cortisol levels (nmol/L) decreased significantly after IL-1 antagonism [from baseline, 452 to 423; absolute difference, -38.7; 95% confidence interval (CI), -64 to -13.4; P = 0.0019]. Similar effects were found for salivary cortisol levels (-2.8; 95% CI, -4.4 to -1.3; P = 0.0007), ACTH levels (-2.2; 95% CI; -4.2 to -0.1; P = 0.038), systolic blood pressure (-5.2, 95% CI, -8.5 to -1.8; P = 0.0006), and heart rate (-2.9; 95% CI, -4.7 to -1.0; P = 0.0029). Conclusion IL-1 antagonism in obese individuals with features of the metabolic syndrome leads to a decrease in serum cortisol, salivary cortisol, and ACTH levels along with a reduction in systolic blood pressure and heart rate.

IL-1 Antagonism in Men With Metabolic Syndrome and Low Testosterone: A Randomized Clinical Trial

Context Hypogonadism is highly prevalent among obese men with metabolic syndrome. Chronic low-grade inflammation is suspected to be a major cause for low testosterone levels in obese individuals. Objectives To test the inflammatory hypothesis of testosterone deficiency in metabolic syndrome. Design, Setting, Participants, and Intervention In this randomized, placebo-controlled, double-blind trial involving men with metabolic syndrome, we randomly assigned 33 patients to receive 100 mg of anakinra (recombinant human IL-1 receptor antagonist) subcutaneously twice daily for 4 weeks and 34 patients to receive placebo. Main Outcome Measures The primary endpoint was the change from baseline in total testosterone levels after 4 weeks. Results The mean age was 54 years and baseline total testosterone levels were 9.3 nmol/L (95% CI, 8.7 to 10.0). At 4 weeks, total testosterone levels increased by 1.2 nmol/L (95% CI, 0.3 to 2.0; P = 0.01) in the anakinra group as compared with no change in the placebo group (0.01 nmol/L; 95% CI, -0.5 to 0.5; P = 0.99), resulting in a between-group difference of 0.96 nmol/L (95% CI, 0.3 to 1.9; P = 0.04). The effects were most pronounced with baseline C-reactive protein >2 mg/L (between-group difference 2.14 nmol/L; 95% CI, 0.11 to 4.17; P = 0.04) and body mass index >40 kg/m2 (between-group difference 2.64 nmol/L; 95% CI, 0.19 to 5.09; P = 0.04). Anakinra treatment did not exert benefits on fatigue and sexual dysfunction, but it improved grip strength of nondominant hand by 3.5 kg (95% CI 0.23 to 6.81; P = 0.04) and reduced mean arterial blood pressure by 2.9 mm Hg (95% CI, -5.99 to 0.19; P = 0.07). Conclusions Anti-inflammatory treatment with an antagonist of IL-1 led to an increase in testosterone levels in obese men with testosterone deficiency.

Copeptin levels and commonly used laboratory parameters in hospitalised patients with severe hypernatraemia - the “Co-MED study”

BackgroundHypernatraemia is common in inpatients and is associated with substantial morbidity. Its differential diagnosis is challenging, and delayed treatment may have devastating consequences. The most important hormone for the regulation of water homeostasis is arginine vasopressin, and copeptin, the C-terminal portion of the precursor peptide of arginine vasopressin, might be a reliable new parameter with which to assess the underlying cause of hypernatraemia.MethodsIn this prospective, multicentre, observational study conducted in two tertiary referral centres in Switzerland, 92 patients with severe hyperosmolar hypernatraemia (Na+ > 155 mmol/L) were included. After a standardised diagnostic evaluation, the underlying cause of hypernatraemia was identified and copeptin levels were measured.ResultsThe most common aetiology of hypernatraemia was dehydration (DH) (n = 65 [71%]), followed by salt overload (SO) (n = 20 [22%]), central diabetes insipidus (CDI) (n = 5 [5%]) and nephrogenic diabetes insipidus (NDI) (n = 2 [2%]). Low urine osmolality was indicative for patients with CDI and NDI (P < 0.01). Patients with CDI had lower copeptin levels than patients with DH or SO (both P < 0.01) or those with NDI. Copeptin identified CDI with an AUC of 0.99 (95% CI 0.97–1.00), and a cut-off value ≤ 4.4pmol/L showed a sensitivity of 100% and a specificity of 99% to predict CDI. Similarly, urea values were lower in CDI than in DH or SO (P < 0.05 and P < 0.01, respectively) or NDI. The AUC for diagnosing CDI was 0.98 (95% CI 0.96–1.00), and a cut-off value < 5.05 mmol/L showed high specificity and sensitivity for the diagnosis of CDI (98% and 100%, respectively). Copeptin and urea could not differentiate hypernatraemia induced by DH from that induced by SO (P = 0.66 and P = 0.30, respectively).ConclusionsCopeptin and urea reliably identify patients with CDI and are therefore helpful tools for therapeutic management in patients with severe hypernatraemia.Trials registrationClinicalTrials.gov, NCT01456533. Registered on 20 October 2011.

Comparison of 1 mg versus 2 mg Dexamethasone Suppression Test in Patients with Obesity

In this study, we compared the 2 mg dexamethasone suppression test (DST) with the gold-standard 1 mg DST in obese patients in order to reduce the false-positive rate for Cushings syndrome (CS). The primary endpoint was the comparison of serum cortisol levels after 1 mg versus 2 mg DST in patients with a BMI >30 kg/m2 and at least one additional feature of the metabolic syndrome. Secondary endpoints were comparison of salivary cortisol and ACTH levels, respectively. Fifty-four obese patients were included. Median serum cortisol levels after 1 mg DST and 2 mg DST were similar [28 nmol/l (20; 36) vs. 28 nmol/l (20; 38), p=0.53]. Salivary cortisol was 8.2 nmol/l (4.7; 11.7) after the 1 mg DST vs. 6.7 nmol/l (4.2; 9.5) after the 2 mg test, p=0.09. ACTH levels were higher after the 1 mg DST compared to the 2 mg DST [10.0 pg/ml (7.6; 10.7) vs. 5.0 pg/ml (5.0; 5.1), p<0.0001]. The false positive rate after the 1 mg DST was 14.8% (n=8) and was reduced to 11.1% (n=6) after the 2 mg DST. All non-suppressors (n=8) had type 2 diabetes and most of them took a medication interacting with cytochrome P450 3A4 (CYP3A4). In individuals with obesity, the 2 mg DST was not superior to the 1 mg DST in regard to serum cortisol levels. However, in some patients, particularly with poorly controlled diabetes or medication interacting with CYP3A4 and without adequate suppression after the 1 mg DST, the 2 mg DST might prove helpful to reduce the false-positive rate for CS. ClinicalTrials.gov Number: NCT02227420.