Maarten Limper

Additional value of procalcitonin for diagnosis of infection in patients with fever at the emergency department

Objective: First, to determine whether procalcitonin (PCT) significantly adds diagnostic value in terms of sensitivity and specificity to a common set of markers of infection, including C-reactive protein (CRP), at the Emergency Department. Second, to create a simple scoring rule implementing PCT values. Third, to determine and compare associations of CRP and PCT with clinical outcomes. Design: The additional diagnostic value of PCT was determined using multiple logistic regression analysis. A score was developed to help distinguish patients with a culture-proven bacterial infection from patients not needing antibiotic treatment using 16 potential clinical and laboratory variables. The prognostic value of CRP and PCT was determined using Spearmans correlation and logistic regression. Setting: Emergency Department of a 310-bed teaching hospital. Patients: Patients between 18 and 85 years old presenting with fever to the Emergency Department. Interventions: None. Measurements and Main Results: A total of 211 patients were studied (infection confirmed, n = 73; infection likely, n = 58; infection not excluded, n = 46; no infection, n = 34). CRP and chills were the strongest predictors for the diagnosis of bacterial infection. After addition of PCT to these parameters, model fit significantly improved (p = .003). The resulting scoring rule (score = 0.01 * CRP + 2 * chills + 1 * PCT) was characterized by an AUC value of 0.83 (sensitivity 79%; specificity of 71%), which was more accurate than physician judgment or SIRS (systemic inflammatory response syndrome). PCT levels were significantly associated with admission to a special care unit, duration of intravenous antibiotic use, total duration of antibiotic treatment, and length of hospital stay, whereas CRP was related only to the latter two variables. Conclusions: These data suggest that PCT may be a valuable addition to currently used markers of infection for diagnosis of infection and prognosis in patients with fever at the Emergency Department.

PTX3 predicts severe disease in febrile patients at the emergency department

OBJECTIVES The long pentraxin PTX3 is a promising marker of disease severity in severely ill patients. In order to identify patients warranting critical care as quickly as possible, we investigated the value of PTX3 as a biomarker for disease severity in patients presenting with fever at the emergency department. METHODS Levels of PTX3 were measured in 211 febrile patients at the emergency and the levels were linked to markers of disease severity including admittance to a special care unit, bloodstream infection and congestive heart failure. RESULTS In comparison to median baseline levels of 2.30 ng/ml (interquartile range 1.66-3.67 ng/ml), levels of PTX3 were significantly elevated in patients admitted to the intensive-/medium care unit (median value 44.4 ng/ml, interquartile range 13.6-105.9 ng/ml) and in patients referred to the ward (median value 14.2 ng/ml, interquartile range 7.01-25.1 ng/ml). In addition, PTX3 was associated with duration of hospital stay and acute congestive heart failure. The levels were predictive for bloodstream infection (AUC=0.71; 95% CI 0.62-0.81). CONCLUSIONS PTX3 may be a useful marker for differentiation of patients with severe disease in patients presenting with fever to the emergency department.

Adult outpatient experience of the 2009 H1N1 pandemic: Clinical course, pathogens, and evaluation of case definitions

Summary Objectives The aim was to describe causative agents and clinical characteristics in adult outpatients with upper airway symptoms during the 2009 H1N1 pandemic and to evaluate case definitions that are used in clinical practice. Methods From August through December 2009, 964 symptomatic adult outpatients were included. RT-PCR was used to detect the following pathogens: influenza A (H1N1) and B, parainfluenza 1–4, adenovirus, respiratory syncytial virus, human rhinovirus, human metapneumovirus, human coronavirus (OC43, 229E, NL63), Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella species. The Dutch GHOR, American CDC and WHO, and British HPA case definitions were evaluated. Results A respiratory pathogen was detected in 41% of tested patient samples; influenza A (H1N1) and human rhinovirus were both detected in 16%. Clinical presentation of influenza cases was significantly more serious when compared to rhinovirus or negative-tested cases. Test characteristics were almost similar for all 4 case definitions, with an average sensitivity of 66%, specificity of 70%, positive predictive value of 34% and negative predictive value of 90%. Conclusions Influenza A (H1N1) and human rhinovirus were the major pathogens responsible for respiratory disease. The 2009 H1N1 pandemic in Amsterdam followed a mild course. Test characteristics of 4 different clinical case definitions seemed comparable but rather useless.

Copeptin as a predictor of disease severity and survival in leptospirosis.

Leptospirosis, a spirochaetal zoonotic disease, has been identified as an emerging infectious disease of global importance. Adequate discrimination between severe and non-severe cases of leptospirosis is of great importance. Commonly used biomarkers such as C-reactive protein (CRP) have been proven to be of little value in prompt distinction between severe and less-severe cases. Arginine vasopressin (AVP) or antidiuretic hormone (ADH) is secreted in response to hemodynamic and osmotic changes. It has been shown that circulating levels of the stoichiometrically releasedcopeptincorrelatewiththeseverityofbacterial sepsis,with the highest levels in patientswith septic shock. Recently, we described the predictive value of the long Pentraxin-3 (PTX3) for mortality in severe leptospirosis. The present sub-study evaluates the prognostic performance of copeptin in the same cohort of patients, compared to other commonly used biomarkers (such as CRP) and more experimental biomarkers (such as PCT). Study cohort and methods were described and published in the Journal by our group earlier. The study was carried out at the department of internal medicine in the Dr. Kariadi Hospital eDiponegoro University, Semarang, Indonesia from February 2005 until September 2006. Disease severity was stratified using sepsis criteria scored at

The Acute-phase Response Is Not Predictive for the Development of Arthritis in Seropositive Arthralgia - A Prospective Cohort Study

Objective. To evaluate whether markers of the acute-phase response in patients presenting with arthralgia and positive anticitrullinated protein antibodies (ACPA) and/or immunoglobulin M rheumatoid factor (IgM-RF) could be predictive for the development of arthritis. Methods. In total, 137 ACPA- and/or IgM-RF-positive patients were included. Patients were followed annually for the development of arthritis, defined as presence of 1 or more swollen joints at clinical examination. High-sensitivity C-reactive protein (hsCRP), procalcitonin (PCT), secretory phospholipase A2 (SPLA2), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), IL-12p70, IL-10, and interferon-γ (IFN-γ) were measured in baseline serum samples. Gene expression focusing on a predefined panel of genes coding for inflammatory molecules was measured by multiplex ligation-dependent probe amplification. Results. Thirty-five patients (26%) developed arthritis within a median time of 11 months (interquartile range 3.7–18 mo). Circulating levels of cytokines, SPLA2, hsCRP, and PCT were not different between patients with progression to clinical arthritis and those without progression. However, a trend for IL-12p70, TNF-α, IL-10, IL-6, and SPLA2 was observed. No correlation between messenger RNA (mRNA) expression levels of inflammatory genes and progression to arthritis was found. Subgroup analysis of patients with early progression to arthritis showed higher levels of mRNA expression of poly(A)-specific ribonuclease and polycomb complex protein BMI-1 compared to patients without progression to arthritis. Conclusion. Although low-grade inflammation is present before onset of clinical arthritis in large cohorts and can be detected using consecutive measurements, a single measurement of acute-phase reactants seems to have limited value for prediction of development of arthritis in individual patients.

Climate Factors as Important Determinants of Dengue Incidence in Curaçao

Macro‐ and microclimates may have variable impact on dengue incidence in different settings. We estimated the short‐term impact and delayed effects of climate variables on dengue morbidity in Curaçao. Monthly dengue incidence data from 1999 to 2009 were included to estimate the short‐term influences of climate variables by employing wavelet analysis, generalized additive models (GAM) and distributed lag nonlinear models (DLNM) on rainfall, temperature and relative humidity in relation to dengue incidence. Dengue incidence showed a significant irregular 4‐year multi‐annual cycle associated with climate variables. Based on GAM, temperature showed a U‐shape, while humidity and rainfall exhibited a dome‐shaped association, suggesting that deviation from mean temperature increases and deviation from mean humidity and rainfall decreases dengue incidence, respectively. Rainfall was associated with an immediate increase in dengue incidence of 4.1% (95% CI: 2.2–8.1%) after a 10‐mm increase, with a maximum increase of 6.5% (95% CI: 3.2–10.0%) after 1.5 month lag. A 1°C decrease of mean temperature was associated with a RR of 17.4% (95% CI: 11.2–27.0%); the effect was inversed for a 1°C increase of mean temperature (RR= 0.457, 95% CI: 0.278–0.752). Climate variables are important determinants of dengue incidence and provide insight into its short‐term effects. An increase in mean temperature was associated with lower dengue incidence, whereas lower temperatures were associated with higher dengue incidence.

Procalcitonin-guided therapy for the initiation of antibiotics in the ED: a systematic review

BACKGROUND Procalcitonin (PCT) is a new biomarker with a higher accuracy in the diagnosis of bacterial infections. Utilization of PCT may reduce the number of unnecessary antibiotics prescribed to patients and consequently may decrease the rise in antibiotic resistance. The aim of this systematic review is to determine if a PCT-guided algorithm can safely reduce the number of antibiotics prescribed to all patients with a suspected of infection in the emergency department (ED). METHODS MEDLINE, EMBASE, Web of Science, COCHRANE central, PubMed publisher, and Google scholar were searched. Two reviewers performed the screening independently. The QUADAS 2 tool was used to assess quality. RESULTS In total, 1621 articles were screened. Nine articles were included in the analysis. In the 6 studies on adult patients, only patients with respiratory tract infections were investigated. In these studies, a cutoff value of 0.25 μg/L was used, and PCT-guided therapy reduced the number of prescribed antibiotics significantly. Three studies were on pediatric patients, 2 on fever without source and 1 on respiratory complaints. Procalcitonin-guided therapy did not reduce antibiotic prescription in children. Procalcitonin-guided therapy did not result in an increase in adverse events in any of the studies. DISCUSSION Procalcitonin-guided therapy in the ED is only studied in subpopulations, where it was effective and safe in adult patients with respiratory tract infections and not effective but safe nonetheless in specific pediatric populations. Nonadherence is a significant problem in prospective PCT-guided therapy studies. There is not enough evidence to use PCT-guided therapy in a general ED population.

Procalcitonin guided antibiotic therapy in patients presenting with fever in the emergency department

In this journal, Tromp et al. reported on the biomarker procalcitonin (PCT), a precursor protein of calcitonin, in the diagnosis of bacterial infections. The study compared the accuracy of PCT, interleukin-6 (IL-6), lipopolysaccharidebinding protein (LBP), C-reactive protein (CRP) in diagnosing bacterial infections. PCT was tested the best single biomarker for the prediction of bacteraemia in septic patients in the emergency department (ED). We describe our findings of a study using PCT guided antibiotic therapy to reduce antibiotics prescription in the ED. We show a trend toward significance in reducing antibiotic prescription using a single PCT measurement, in undifferentiated febrile patients visiting the ED. The surviving sepsis campaign states that broadspectrum antibiotics have to be administered within one hour, when patients have a suspected infection with systemic inflammatory response syndrome (SIRS). This increases the rate of antibiotic prescriptions in the emergency department (ED), and may contribute to further resistance for antibiotics. Antimicrobial stewardship stands for targeted and effective antibacterial therapy, with special attention for the initiation and timely ending of antibiotics use. The goal of antimicrobial stewardship is to contain the increasing resistance of microorganisms. The aim of this study was to reduce the unnecessary antibiotics prescription by introducing a PCT guided therapy algorithm. Undifferentiated febrile ED patients were randomized to either PCT guided therapy or standard-ofcare. In both groups routine blood testing was performed, including CRP. Only in the PCT guided therapy group, a PCT value was reported to the physicians. The PCT results were appraised using cut-off points as found by other research groups, in which a PCT level of PCT > 0.5 mg/L was associated with bacterial infection. Samples for bacterial and viral cultures and polymerase chain reaction (PCR) were taken from the suspected focus of infection, to confirm a definitive diagnosis. Although PCT guided antibiotic prescription advice was given, the treating physician