[Show abstract][Hide abstract] ABSTRACT: Whether the inflammatory biomarker procalcitonin provides prognostic information across clinical settings and different acute respiratory tract infections (ARI) is poorly understood. Herein, we investigated the prognostic value of admission procalcitonin levels to predict adverse clinical outcome in a large ARI population.
We analysed data from 14 trials and 4211 ARI patients to study associations of admission procalcitonin levels and setting specific treatment failure and mortality alone at 30 days. We used multivariable hierarchical logistic regression and conducted sensitivity analyses stratified by clinical settings and ARI diagnoses to assess the results' consistency.
Overall, 864 patients (20.5%) experienced treatment failure and 252 (6.0%) died. The ability of procalcitonin to differentiate patients with and without treatment failure was highest in the emergency department setting (treatment failure; area under the curve (AUC): 0.64 (95% confidence interval (CI): 0.61, 0.67), adjusted odds ratio (OR): 1.85 (95% CI: 1.61, 2.12), P <0.001 and mortality; AUC: 0.67 (95% CI: 0.63, 0.71), adjusted OR: 1.82 (95% CI: 1.45, 2.29), P <0.001). In lower respiratory tract infections, procalcitonin was a good predictor of identifying patients at risk for mortality (AUC: 0.71 (95% CI: 0.68, 0.74), adjusted OR: 2.13 (95% CI: 1.82, 2.49), P <0.001). In primary care and intensive care unit patients no significant associations of initial procalcitonin levels and outcome was found.
Admission procalcitonin levels are associated with setting specific treatment failure and provide most prognostic information in ARI in the emergency department setting.
Critical Care 12/2015; 19(1). DOI:10.1186/s13054-015-0792-1 · 4.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Copeptin is a stable surrogate marker of vasopressin (AVP) release; the peptides are stoichiometrically secreted from the neurohypophysis due to elevated plasma osmolality or non-osmotic stress. We hypothesized that following stress from pituitary surgery, patients with neurohypophyseal damage and eventual diabetes insipidus (DI) would not exhibit the expected pronounced copeptin elevation.
Evaluate copeptin's accuracy to predict DI following pituitary surgery.
Prospective multicenter observational cohort study.
Three Swiss or Canadian referral centers.
Consecutive pituitary surgery patients.
Copeptin was measured postoperatively daily until discharge. Logistic regression models and diagnostic performance measures were calculated to assess relationships of postoperative copeptin levels and DI.
Of 205 patients, 50 (24.4%) developing postoperative DI. Post-surgically, median [25th-75th percentile] copeptin levels were significantly lower in patients developing DI versus those not showing this complication: 2.9 [1.9-7.9] pmol/L vs 10.8 [5.2-30.4] pmol/L, P < 0.001. Logistic regression analysis revealed strong association between postoperative copeptin concentrations and DI, even after considering known predisposing factors for DI: adjusted odds ratio (95% confidence interval) 1.41 (1.16-1.73). DI was seen in 22/27 patients with copeptin >2.5 pmol/L (positive predictive value 81%, specificity 97%), but only 1/40 with copeptin >30 pmol/L (negative predictive value 95%, sensitivity 94%) on postoperative day 1.
Lack of standardized DI diagnostic criteria; postoperative blood samples for copeptin obtained during everyday care versus at fixed time points.
In patients undergoing pituitary procedures, low copeptin levels despite surgical stress reflect postoperative DI, while high levels virtually exclude it. Copeptin therefore may become a novel tool for early goal-directed management of postoperative DI. Primary Funding Sources: Study centers, Swiss National Foundation, Thermo Scientific Biomarkers.
The Journal of Clinical Endocrinology and Metabolism 04/2015; 100(6):jc20144527. DOI:10.1210/jc.2014-4527 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The polyuria-polydipsia syndrome comprises primary polydipsia (PP) and central and nephrogenic diabetes insipidus (DI). Correctly discriminating these entities is mandatory, since inadequate treatment causes serious complications. The diagnostic "gold standard" is the water deprivation test with assessment of arginine vasopressin (AVP) activity. However, test interpretation and AVP measurement are challenging.
Evaluate accuracy of copeptin, a stable peptide stoichiometrically co-secreted with AVP, in the differential diagnosis of polyuria-polydipsia syndrome.
Prospective multicenter observational cohort study.
Four Swiss or German tertiary referral centers.
Adults >18 years old with history of polyuria and polydipsia.
Standardized combined water deprivation/3% saline infusion test, terminated when serum sodium exceeded 147 mmol/L; circulating copeptin and AVP levels; final diagnosis based on water deprivation/saline infusion test results, clinical information, and treatment response.
Fifty-five patients were enrolled (11 complete central DI, 16 partial central DI, 18 PP, 10 nephrogenic DI). Without prior thirsting, a single baseline copeptin level >21.4 pmol/L differentiated nephrogenic DI from other etiologies with 100% sensitivity and specificity, rendering water deprivation testing unnecessary in such cases. Stimulated copeptin >4.9 pmol/L (at sodium levels >147 mmol/L) differentiated between patients with PP and patients with partial central DI with 94.0% specificity and 94.4% sensitivity; stimulated AVP >1.8 pg/ml differentiated between these same categories with 93.0% specificity and 83.0% sensitivity.
Incorporation bias from including AVP levels as a diagnostic criterion.
Copeptin is a promising new tool in the differential diagnosis of the polyuria-polydipsia syndrome, and a valid surrogate marker for AVP. Primary funding sources: Swiss National Science Foundation, University of Basel.
[Show abstract][Hide abstract] ABSTRACT: Whether or not antibiotic stewardship protocols based on procalcitonin levels results in cost savings remains unclear. Herein, our objective was to assess the economic impact of adopting procalcitonin testing among patients with suspected acute respiratory tract infection (ARI) from the perspective of a typical US integrated delivery network (IDN) with a 1,000,000 member catchment area or enrollment.
To conduct an economic evaluation of procalcitonin testing versus usual care we built a cost-impact model based on patient-level meta-analysis data of randomized trials. The meta-analytic data was adapted to the US setting by applying the meta-analytic results to US lengths of stay, costs, and practice patterns. We estimated the annual ARI visit rate for the one million member cohort, by setting (inpatient, ICU, outpatient) and ARI diagnosis.
In the inpatient setting, the costs of procalcitonin-guided compared to usual care for the one million member cohort was $2,083,545, compared to $2,780,322, resulting in net savings of nearly $700,000 to the IDN for 2014. In the ICU and outpatient settings, savings were $73,326 and $5,329,824, respectively, summing up to overall net savings of $6,099,927 for the cohort. Results were robust for all ARI diagnoses. For the whole US insured population, procalcitonin-guided care would result in $1.6 billion in savings annually.
Our results show substantial savings associated with procalcitonin protocols of ARI across common US treatment settings mainly by direct reduction in unnecessary antibiotic utilization. These results are robust to changes in key parameters, and the savings can be achieved without any negative impact on treatment outcomes.
Clinical Chemistry and Laboratory Medicine 01/2015; DOI:10.1515/cclm-2014-1015 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 to 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.
[Show abstract][Hide abstract] ABSTRACT: Background:
Intracerebral hemorrhage (ICH), a subtype of stroke associated with high mortality and disability, accounts for 13% of all strokes. Basic and clinical research has contributed to our understanding of the complex pathophysiology of neuronal injury in ICH. Outcome rates, however, remain stable, and questions regarding acute management of ICH remain unanswered. Newer research is aiming at matching measured levels of serum proteins, enzymes, or cells to different stages of brain damage, suggesting that blood biomarkers may assist in acute diagnosis, therapeutic decisions, and prognostication. This paper provides an overview on the most promising blood biomarkers and their potential role in the diagnosis and management of spontaneous ICH.
Information was collected from studies, reviews, and guidelines listed in PubMed up to November 2013 on blood biomarkers of nontraumatic ICH in humans. We describe the potential role and limitations of GFAP, S100B/RAGE, and ApoC-III as diagnostic biomarkers, β- Amyloid as a biomarker for etiological classification, and 27 biomarkers for prognosis of mortality and functional outcome. Within the group of prognostic markers we discuss markers involved in coagulation processes (e.g., D-Dimers), neuroendocrine markers (e.g., copeptin), systemic metabolic markers (e.g., blood glucose levels), markers of inflammation (e.g., IL-6), as well as growth factors (e.g., VEGF), and others (e.g., glutamate). Some of those blood biomarkers are agents of pathologic processes associated with hemorrhagic stroke but also other diseases, whereas others play more distinct pathophysiological roles and help in understanding the basic mechanisms of brain damage and/or recovery in ICH.
Numerous blood biomarkers are associated with different pathophysiological pathways in ICH, and some of them promise to be useful in the management of ICH, eventually contributing additional information to current tools for diagnosis, therapy monitoring, risk stratification, or intervention. Up to date, however, no blood biomarker of ICH has been studied sufficiently to find its way into clinical routine yet; well-designed, large-scale, clinical studies addressing relevant clinical questions are needed. We suggest that the effectiveness of biomarker research in ICH might be improved by international cooperation and shared resources for large validation studies, such as provided by the consortium on stroke biomarker research (http://stroke-biomarkers. com/page.php?title=Resources).
[Show abstract][Hide abstract] ABSTRACT: Background: Blood biomarkers are increasingly used to diagnose, guide therapy in, and risk-stratify community acquired pneumonia (CAP) patients in emergency departments (EDs). How pre-analytic factors affect these markers’
initial levels in this population is unknown.
Methods: In this secondary analysis of consecutive ED patients with CAP from a large multicentre antibiotic
stewardship trial, we used adjusted multivariate regression models to determine the magnitude and statistical
significance of differences in mean baseline concentrations of five biomarkers (procalcitonin [PCT], C-reactive protein [CRP], white blood cells count [WBC], proadrenomedullin [ProADM], copeptin) associated with six pre-analytic factors (antibiotic or corticosteroid pretreatment, age, gender, chronic renal failure or chronic liver insufficiency).
Results: Of 925 CAP patients (median age 73 years, 58.8% male), 25.5% had antibiotic pretreatment, 2.4%,
corticosteroid pretreatment, 22.3%, chronic renal failure, 2.4% chronic liver insufficiency. Differences associated
with pre-analytic factors averaged 6.1% ±4.6%; the three largest statistically significant changes (95% confidence interval) were: PCT, +14.2% (+2.1% to +26.4%, p = 0.02) with liver insufficiency; ProADM, +13.2% (+10.2% to +16.1%, p < 0.01) with age above median; CRP, -12.8% (-25.4% to -0.2%, p = 0.05) with steroid pretreatment. In post hoc sensitivity analyses, reclassification statistics showed that these factors did not result in significant changes of biomarker levels across clinically used cut-off ranges.
Conclusions: Despite statistically significant associations of some pre-analytic factors and biomarker levels, a
clinically relevant influence seems unlikely. Our observations reinforce the concept of using biomarkers in algorithms with widely-separated cut-offs and overruling criteria considering the entire clinical picture.
Trial registration: Identifier ISRCTN95122877.
[Show abstract][Hide abstract] ABSTRACT: 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: Prospective observational study. Methods: Twenty healthy adults (10 female) and 8 patients with central DI (4 female) underwent the Trier Social Stress Test (TSST) including, in order: 30-min waiting period, 10-min anticipation period, 10-min test period, 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, median [25th-75th percentile] copeptin concentration peaked immediately post-test period at 5.1 [3.2-7.0] pmol/L, versus 3.7 [2.6-5.4] pmol/L at baseline. Over the measurement course, copeptin concentration significantly rose (coefficient; 95% confidence interval) (0.14; 0.06-0.23, P = 0.002). The main copeptin increase predictors 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 as compared to healthy volunteers, p=0.006. Patients with DI showed no increase upon psychological stress (peak 2.15pmol/l [1.5-2.28], p=0.79). In 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 DI patients.
European Journal of Endocrinology 09/2014; 171(6). DOI:10.1530/EJE-14-0405 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Long-term outcome prediction in COPD is challenging. We conducted a prospective 5-7-year follow-up study in patients with COPD to determine the association of exacerbation type, discharge levels of inflammatory biomarkers including procalctionin (PCT), C-reactive protein (CRP), white blood cell count (WBC) and plasma proadrenomedullin (ProADM), alone or combined with demographic/clinical characteristics, with long-term all-cause mortality in the COPD setting. The analyzed cohort comprised 469 patients with index hospitalization for pneumonic (n = 252) or non-pneumonic (n = 217) COPD exacerbation. Five-to-seven-year vital status was ascertained via structured phone interviews with patients or their household members/primary care physicians. We investigated predictive accuracy using univariate and multivariate Cox regression models and area under the receiver operating characteristic curve (AUC). After a median [25th-75th percentile] 6.1 [5.6-6.5] years, mortality was 55% (95%CI 50%-59%). Discharge ProADM concentration was strongly associated with 5-7-year non-survival: adjusted hazard ratio (HR)/10-fold increase (95%CI) 10.4 (6.2-17.7). Weaker associations were found for PCT and no significant associations were found for CRP or WBC. Combining ProADM with demographic/clinical variables including age, smoking status, BMI, New York Heart Association dyspnea class, exacerbation type, and comorbidities significantly improved long-term predictive accuracy over that of the demographic/clinical model alone: AUC (95%CI) 0.745 (0.701-0.789) versus 0.727 (0.681-0.772), p = .043. In patients hospitalized for COPD exacerbation, discharge ProADM levels appeared to accurately predict 5-7-year all-cause mortality and to improve long-term prognostic accuracy of multidimensional demographic/clinical mortality risk assessment.
[Show abstract][Hide abstract] ABSTRACT: Context/objective:
To clarify ambiguous published data, we determined whether standardized nutrient intake influences serum copeptin concentrations.
Thirty healthy volunteers underwent oral glucose tolerance testing (OGTT) and mixed-meal tolerance testing (MMTT), respectively drinking 300 ml/237 ml of glucose-containing or fat/protein/carbohydrate-containing fluid. Copeptin was measured 30 min pre-("baseline")-180 min post-fluid intake.
Median [25th-75th percentile] copeptin fell from 4.9 [3.6-8.3]/4.9 [3.6-7.1] pmol/l at OGTT/MMTT baselines to 3.2 (2.8-5.9)/4.1 (2.7-6.1) pmol/l at post-OGTT/post-MMTT nadirs (150 min/120 min; p < 0.001, linear mixed-effect modeling).
Regardless of nutrient type ingested, copeptin did not increase, suggesting values can be interpreted independently of prandial status.