Mirjam Christ-Crain

Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial

BACKGROUND Lower respiratory tract infections are often treated with antibiotics without evidence of clinically relevant bacterial disease. Serum calcitonin precursor concentrations, including procalcitonin, are raised in bacterial infections. We aimed to assess a procalcitonin-based therapeutic strategy to reduce antibiotic use in lower respiratory tract infections with a new rapid and sensitive assay. METHODS 243 patients admitted with suspected lower respiratory tract infections were randomly assigned standard care (standard group; n=119) or procalcitonin-guided treatment (procalcitonin group; n=124). On the basis of serum procalcitonin concentrations, use of antibiotics was more or less discouraged (<0.1 microg/L or <0.25 microg/L) or encouraged (> or =0.5 microg/L or > or =0.25 microg/L), respectively. Re-evaluation was possible after 6-24 h in both groups. Primary endpoint was use of antibiotics and analysis was by intention to treat. FINDINGS Final diagnoses were pneumonia (n=87; 36%), acute exacerbation of chronic obstructive pulmonary disease (60; 25%), acute bronchitis (59; 24%), asthma (13; 5%), and other respiratory affections (24; 10%). Serological evidence of viral infection was recorded in 141 of 175 tested patients (81%). Bacterial cultures were positive from sputum in 51 (21%) and from blood in 16 (7%). In the procalcitonin group, the adjusted relative risk of antibiotic exposure was 0.49 (95% CI 0.44-0.55; p<0.0001) compared with the standard group. Antibiotic use was significantly reduced in all diagnostic subgroups. Clinical and laboratory outcome was similar in both groups and favourable in 235 (97%). INTERPRETATION Procalcitonin guidance substantially reduced antibiotic use in lower respiratory tract infections. Withholding antimicrobial treatment did not compromise outcome. In view of the current overuse of antimicrobial therapy in often self-limiting acute respiratory tract infections, treatment based on procalcitonin measurement could have important clinical and financial implications.

Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial

CONTEXT In previous smaller trials, a procalcitonin (PCT) algorithm reduced antibiotic use in patients with lower respiratory tract infections (LRTIs). OBJECTIVE To examine whether a PCT algorithm can reduce antibiotic exposure without increasing the risk for serious adverse outcomes. DESIGN, SETTING, AND PATIENTS A multicenter, noninferiority, randomized controlled trial in emergency departments of 6 tertiary care hospitals in Switzerland with an open intervention of 1359 patients with mostly severe LRTIs randomized between October 2006 and March 2008. INTERVENTION Patients were randomized to administration of antibiotics based on a PCT algorithm with predefined cutoff ranges for initiating or stopping antibiotics (PCT group) or according to standard guidelines (control group). Serum PCT was measured locally in each hospital and instructions were Web-based. MAIN OUTCOME MEASURES Noninferiority of the composite adverse outcomes of death, intensive care unit admission, disease-specific complications, or recurrent infection requiring antibiotic treatment within 30 days, with a predefined noninferiority boundary of 7.5%; and antibiotic exposure and adverse effects from antibiotics. RESULTS The rate of overall adverse outcomes was similar in the PCT and control groups (15.4% [n = 103] vs 18.9% [n = 130]; difference, -3.5%; 95% CI, -7.6% to 0.4%). The mean duration of antibiotics exposure in the PCT vs control groups was lower in all patients (5.7 vs 8.7 days; relative change, -34.8%; 95% CI, -40.3% to -28.7%) and in the subgroups of patients with community-acquired pneumonia (n = 925, 7.2 vs 10.7 days; -32.4%; 95% CI, -37.6% to -26.9%), exacerbation of chronic obstructive pulmonary disease (n = 228, 2.5 vs 5.1 days; -50.4%; 95% CI, -64.0% to -34.0%), and acute bronchitis (n = 151, 1.0 vs 2.8 days; -65.0%; 95% CI, -84.7% to -37.5%). Antibiotic-associated adverse effects were less frequent in the PCT group (19.8% [n = 133] vs 28.1% [n = 193]; difference, -8.2%; 95% CI, -12.7% to -3.7%). CONCLUSION In patients with LRTIs, a strategy of PCT guidance compared with standard guidelines resulted in similar rates of adverse outcomes, as well as lower rates of antibiotic exposure and antibiotic-associated adverse effects. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN95122877.

Diagnostic and prognostic accuracy of clinical and laboratory parameters in community-acquired pneumonia

BackgroundCommunity-acquired pneumonia (CAP) is the most frequent infection-related cause of death. The reference standard to diagnose CAP is a new infiltrate on chest radiograph in the presence of recently acquired respiratory signs and symptoms. This study aims to evaluate the diagnostic and prognostic accuracy of clinical signs and symptoms and laboratory biomarkers for CAP.Methods545 patients with suspected lower respiratory tract infection, admitted to the emergency department of a university hospital were included in a pre-planned post-hoc analysis of two controlled intervention trials. Baseline assessment included history, clinical examination, radiography and measurements of procalcitonin (PCT), highly sensitive C-reactive protein (hsCRP) and leukocyte count.ResultsOf the 545 patients, 373 had CAP, 132 other respiratory tract infections, and 40 other final diagnoses. The AUC of a clinical model including standard clinical signs and symptoms (i.e. fever, cough, sputum production, abnormal chest auscultation and dyspnea) to diagnose CAP was 0.79 [95% CI, 0.75–0.83]. This AUC was significantly improved by including PCT and hsCRP (0.92 [0.89–0.94]; p < 0.001). PCT had a higher diagnostic accuracy (AUC, 0.88 [0.84–0.93]) in differentiating CAP from other diagnoses, as compared to hsCRP (AUC, 0.76 [0.69–0.83]; p < 0.001) and total leukocyte count (AUC, 0.69 [0.62–0.77]; p < 0.001). To predict bacteremia, PCT had a higher AUC (0.85 [0.80–0.91]) as compared to hsCRP (p = 0.01), leukocyte count (p = 0.002) and elevated body temperature (p < 0.001). PCT, in contrast to hsCRP and leukocyte count, increased with increasing severity of CAP, as assessed by the pneumonia severity index (p < 0.001).ConclusionPCT, and to a lesser degree hsCRP, improve the accuracy of currently recommended approaches for the diagnosis of CAP, thereby complementing clinical signs and symptoms. PCT is useful in the severity assessment of CAP.

Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract infections in primary care.

BACKGROUND Acute respiratory tract infections are the most common reason for antibiotic therapy in primary care despite their mainly viral etiology. A laboratory test measuring procalcitonin levels in blood specimens was suggested as a tool to reduce unnecessary prescribing of antibiotics. We consider whether antibiotic therapy guided by procalcitonin reduces the use of antibiotics without increasing the restrictions experienced by patients by more than 1 day. METHODS Fifty-three primary care physicians recruited 458 patients, each patient with an acute respiratory tract infection and, in the physicians opinion, in need of antibiotics. Patients were centrally randomized to either a procalcitonin-guided approach to antibiotic therapy or to a standard approach. For patients randomized to procalcitonin-guided therapy, the use of antibiotics was more or less strongly discouraged (procalcitonin level, < or =0.1 or < or =0.25 microg/L, respectively) or recommended (procalcitonin level, >0.25 microg/L). Follow-up data were collected at 7 days by treating physicians and at 14 and 28 days by blinded interviewers. RESULTS Adjusted for baseline characteristics, the mean increase at 14 days in days in which activities were restricted was 0.14 with procalcitonin-guided therapy (95% confidence interval [CI], -0.53 to 0.81 days), which met our criterion of an increase in days in which activities were restricted by no more than 1 day. With procalcitonin-guided therapy, the antibiotic prescription rate was 72% lower (95% CI, 66%-78%) than with standard therapy. Both approaches led to a similar proportion of patients reporting symptoms of ongoing or relapsing infection at 28 days (adjusted odds ratio, 1.0 [95% CI, 0.7-1.5]). CONCLUSIONS As an adjunct to guidelines, procalcitonin-guided therapy markedly reduces antibiotic use for acute respiratory tract infections in primary care without compromising patient outcome. In practice, this could be achieved with 1 to 2 procalcitonin measurements in patients for whom the physician intends to prescribe antibiotics.

The Orexigenic Effect of Ghrelin Is Mediated through Central Activation of the Endogenous Cannabinoid System

Introduction Ghrelin and cannabinoids stimulate appetite, this effect possibly being mediated by the activation of hypothalamic AMP-activated protein kinase (AMPK), a key enzyme in appetite and metabolism regulation. The cannabinoid receptor type 1 (CB1) antagonist rimonabant can block the orexigenic effect of ghrelin. In this study, we have elucidated the mechanism of the putative ghrelin-cannabinoid interaction. Methods The effects of ghrelin and CB1 antagonist rimonabant in wild-type mice, and the effect of ghrelin in CB1-knockout animals, were studied on food intake, hypothalamic AMPK activity and endogenous cannabinoid content. In patch-clamp electrophysiology experiments the effect of ghrelin was assessed on the synaptic inputs in parvocellular neurons of the hypothalamic paraventricular nucleus, with or without the pre-administration of a CB1 antagonist or of cannabinoid synthesis inhibitors. Results and Conclusions Ghrelin did not induce an orexigenic effect in CB1-knockout mice. Correspondingly, both the genetic lack of CB1 and the pharmacological blockade of CB1 inhibited the effect of ghrelin on AMPK activity. Ghrelin increased the endocannabinoid content of the hypothalamus in wild-type mice and this effect was abolished by rimonabant pre-treatment, while no effect was observed in CB1-KO animals. Electrophysiology studies showed that ghrelin can inhibit the excitatory inputs on the parvocellular neurons of the paraventricular nucleus, and that this effect is abolished by administration of a CB1 antagonist or an inhibitor of the DAG lipase, the enzyme responsible for 2-AG synthesis. The effect is also lost in the presence of BAPTA, an intracellular calcium chelator, which inhibits endocannabinoid synthesis in the recorded parvocellular neuron and therefore blocks the retrograde signaling exerted by endocannabinoids. In summary, an intact cannabinoid signaling pathway is necessary for the stimulatory effects of ghrelin on AMPK activity and food intake, and for the inhibitory effect of ghrelin on paraventricular neurons.

Pro-adrenomedullin to predict severity and outcome in community-acquired pneumonia [ISRCTN04176397]

IntroductionPro-adrenomedullin (proADM) is helpful for individual risk assessment and outcome prediction in sepsis. A major cause of sepsis is community-acquired pneumonia (CAP). The aim of this study was to investigate the value of proADM levels for severity assessment and outcome prediction in CAP.MethodsData from 302 patients admitted to the emergency department with CAP were included in a prospective observational study. Procalcitonin, C-reactive protein levels, leukocyte count, clinical variables and the pneumonia severity index (PSI) were measured. ProADM levels were measured with a new sandwich immunoassay for mid regional ProADM (MR-proADM, Brahms AG, Hennigsdorf/Berlin, Germany).ResultsProADM levels, in contrast to C-reactive protein and leukocyte count, increased with increasing severity of CAP, classified according to the PSI score (ANOVA, p < 0.001). In patients who died during follow-up, proADM levels on admission were significantly higher compared to levels in survivors (2.1 (1.5 to 3.0) versus 1.0 (0.6 to 1.6) nmol/l, p < 0.001). In a receiver operating characteristic (ROC) analysis for survival, the area under the ROC curve (AUC) for proADM was 0.76 (95% confidence interval (CI) 0.71–0.81), which was significantly higher compared to procalcitonin (p = 0.004), C-reactive protein (p < 0.001) and total leukocyte count (p = 0.001) and similar to the AUC of the PSI (0.73, p = 0.54). A clinical model including the PSI and proADM increased the prognostic accuracy to predict failure compared to a model relying on the PSI alone (AUC, 0.77 (0.70 to 0.84), p = 0.03).ConclusionProADM, as a novel biomarker, is a useful tool for the risk stratification of patients with CAP.

Elevated C-reactive protein and homocysteine values: cardiovascular risk factors in hypothyroidism? A cross-sectional and a double-blind, placebo-controlled trial.

Hypothyroidism is associated with premature atherosclerosis and cardiovascular disease. Recently, total homocysteine (tHcy) and C-reactive protein (CRP) emerged as additional cardiovascular risk factors. We first investigated CRP and tHcy in different severities of primary hypothyroidism and in a second study we evaluated the effect of L-thyroxine treatment in patients with subclinical hypothyroidism (SCH) in a double-blind, placebo-controlled trial. One hundred and twenty-four hypothyroid patients (63 with subclinical, 61 with overt hypothyroidism, OH) and 40 euthyroid controls were evaluated. CRP was measured using a latex-based high sensitivity immunoassay; tHcy was determined by a fluorescence polarization immunoassay. tHcy values were significantly elevated in OH (P=0.01). In SCH tHcy levels were not augmented as compared to controls. CRP values were significantly increased in OH (P=0.016) and SCH (P=0.022) as compared to controls. In a univariate analysis tHcy correlated significantly with fT4, vitamin B12, folic acid and creatinine levels. In multiple regression analysis only fT4 (beta=0.33) had a significant effect on tHcy. CRP did not correlate with thyroid hormones. In SCH, L-T4 replacement had no significant effect on either tHcy or CRP levels. This is the first paper to show that CRP values increase with progressive thyroid failure and may count as an additional risk factor for the development of coronary heart disease in hypothyroid patients. In contrast to overt disease, only CRP, but not tHcy values, are affected in SCH, yet without significant improvement after L-thyroxine therapy.

Copeptin: A Novel, Independent Prognostic Marker in Patients with Ischemic Stroke

Early prediction of outcome in patients with ischemic stroke is important. Vasopressin is a stress hormone. Its production rate is mirrored in circulating levels of copeptin, a fragment of provasopressin. We evaluated the prognostic value of copeptin in acute stroke patients.

Procalcitonin levels predict bacteremia in patients with community-acquired pneumonia : a prospective cohort trial

BACKGROUND Guidelines recommend blood culture sampling from hospitalized patients with suspected community-acquired pneumonia (CAP). However, the yield of true-positive results is low. We investigated the benefit of procalcitonin (PCT) on hospital admission to predict blood culture positivity in CAP. METHODS This was a prospective cohort study with a derivation and validation set including 925 patients with CAP who underwent blood culture sampling on hospital admission. RESULTS A total of 73 (7.9%) patients had true bacteremia (43 of 463 in the derivation cohort, 30 of 462 in the validation cohort). The area under the receiver operating characteristics curve of PCT in the derivation and validation cohorts was similar (derivation cohort, 0.83; 95% CI, 0.78-0.89; validation cohort, 0.79; 95% CI, 0.72-0.88). Overall, PCT was a significantly better predictor for blood culture positivity than WBC count, C-reactive protein, and other clinical parameters. In multivariate regression analysis, only antibiotic pretreatment (adjusted odds ratio, 0.25; P < .05) and PCT serum levels (adjusted odds ratio, 3.72; P < .001) were independent predictors. Overall, a PCT cutoff of 0.1 microg/L would enable reduction of the total number of blood cultures by 12.6% and still identify 99% of the positive blood cultures. Similarly, 0.25 microg/L and 0.5 microg/L cutoffs would enable reduction of blood cultures by 37% and 52%, respectively, and still identify 96% and 88%, respectively, of positive blood cultures. CONCLUSIONS Initial PCT level accurately predicted blood culture positivity in patients with CAP. PCT measurement has the potential to reduce the number of drawn blood cultures in the emergency department and to implement a more targeted allocation of limited health-care resources.

Copeptin, a stable peptide of the arginine vasopressin precursor, is elevated in hemorrhagic and septic shock.

Arginine vasopressin (AVP) levels are increased in hemorrhagic and septic shock. Measurement of AVP levels has limitations due to its short half-life and cumbersome detection method. Copeptin is a more stable peptide derived from the same precursor molecule. We evaluated the plasma copeptin concentration in two independent studies: first, in an experimental baboon model of hemorrhagic shock, and second, in a prospective observational study of 101 consecutive critically ill patients at a university hospital. Copeptin was measured with a newly developed sandwich immunoassay using two polyclonal antibodies to the C-terminal region (amino acid sequence 132-164) of pre-pro-AVP. Copeptin concentrations in hemorrhagic shock increased markedly from median (range) of 7.5 [2.7-13) to 269 pM (241-456 pM). After reperfusion, copeptin levels dropped within hours to a plateau of 27 pM (15-78 pM). In the critically ill patient cohort, copeptin values increased significantly with the severity of the disease and were in patients without sepsis [27.6 pM [2.3-297 pM]), in sepsis [50.0 pM [8.5-268 pM]), in severe sepsis [73.6 pM [15.3-317 pM]), and in septic shock [171.5 pM (35.1-504 pM] compared with 4.1 pM (1.0-13.8 pM) in healthy controls (P for all vs. controls <0.001). On admission, circulating copeptin levels were higher in nonsurvivors (171.5 pM, 46.5-504.0 pM) as compared with survivors (86.8 pM, 8.5-386.0 pM; P = 0.01). Copeptin levels correlated with basal cortisol levels (r = 0.42; P < 0.001) and osmolality (r = 0.42; P < 0.001). In a logistic regression model including other covariates besides copeptin (e.g., determinants of fluid status) on survival, serum copeptin levels were the only independent significant predictor of outcome (P = 0.03). Copeptin concentrations are elevated in hemorrhagic and septic shock. Copeptin was higher on admission in nonsurvivors as compared with survivors, suggesting copeptin as a prognostic marker in sepsis. The availability of a reliable assay for the measurement of AVP release can also prove useful for the assessment of fluid and osmosis status in various diseases.