Title: Can Procalcitonin Differentiate Sepsis From Systemic Inflammatory Response Syndrome Without Infection?
Abstract: Take-Home MessageProcalcitonin must be used cautiously, in conjunction with the clinical picture, when differentiating sepsis from noninfectious systemic inflammatory response syndrome.Data SourcesMEDLINE, EMBASE, ISI Web of Knowledge, the Cochrane Library, Scopus, BioMed Central, and Science Direct were searched between inception and February 21, 2012. The reference lists of included articles and previous systematic reviews were searched as well.Study SelectionArticles in English, German, or French assessing the ability of procalcitonin to distinguish sepsis from systemic inflammatory response syndrome without infection were chosen.Data Extraction and SynthesisThe true-positive, false-negative, false-positive, and true-negative rates were extracted from each study. A bivariate mixed-effects regression model was used to perform a meta-analysis of the data to provide summary estimates of sensitivity and specificity. The authors calculated I2 statistics to assess heterogeneity. The methodological quality of the included studies was assessed with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist, and κ statistics were calculated to assess agreement between the investigators. Procalcitonin must be used cautiously, in conjunction with the clinical picture, when differentiating sepsis from noninfectious systemic inflammatory response syndrome. MEDLINE, EMBASE, ISI Web of Knowledge, the Cochrane Library, Scopus, BioMed Central, and Science Direct were searched between inception and February 21, 2012. The reference lists of included articles and previous systematic reviews were searched as well. Articles in English, German, or French assessing the ability of procalcitonin to distinguish sepsis from systemic inflammatory response syndrome without infection were chosen. The true-positive, false-negative, false-positive, and true-negative rates were extracted from each study. A bivariate mixed-effects regression model was used to perform a meta-analysis of the data to provide summary estimates of sensitivity and specificity. The authors calculated I2 statistics to assess heterogeneity. The methodological quality of the included studies was assessed with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist, and κ statistics were calculated to assess agreement between the investigators. Thirty studies comprising 31 data sets were included in the analysis. Each study fulfilled between 4 and 12 of the 14 QUADAS checklist criteria, with an interrater reliability (κ) of 0.59. A total of 3,244 patients were analyzed, of whom 1,863 (57%) had sepsis and 1,381 (43%) had systemic inflammatory response syndrome of noninfectious cause. The pooled estimate of sensitivity was 0.77 (95% confidence interval [CI] 0.72 to 0.81), specificity was 0.79 (95% CI 0.74 to 0.84), and the area under the receiver operating characteristic (ROC) curve was 0.85 (95% CI 0.81 to 0.88). There was significant heterogeneity between the studies, with an I2 statistic of 96% for the bivariate model. A wide range of cutoffs was used for procalcitonin in the studies (median 1.1 ng/mL; interquartile range 0.5 to 2.0). Early identification of sepsis is important, in part because early delivery of antibiotics has been shown to decrease mortality.1Gaieski D.F. Mikkelsen M.E. Band R.A. et al.Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department.Crit Care Med. 2010; 38: 1045-1053Crossref PubMed Scopus (736) Google Scholar Differentiating patients with systemic inflammatory response syndrome of noninfectious cause from those with sepsis can be difficult, and reliance on source testing and culture results can lead to both delays in diagnosis and false-negative results.2Bates D.W. Sands K. Miller E. et al.Predicting bacteremia in patients with sepsis syndrome. Academic Medical Center Consortium Sepsis Project Working Group.J Infect Dis. 1997; 176: 1538-1551Crossref PubMed Scopus (165) Google Scholar Serum biomarkers (including procalcitonin, c-reactive protein, and interleukin-6) may aid in the diagnosis of sepsis and lead to earlier and more appropriate antibiotic use.3Ventetuolo C.E. Levy M.M. Biomarkers: diagnosis and risk assessment in sepsis.Clin Chest Med. 2008; 29 (vii): 591-603Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar This systematic review was limited by several factors. There was substantial heterogeneity among the included studies, which differed widely with respect to location, disease severity, and procalcitonin cutoff value (range 0.1 to 15.75 ng/mL). Although inclusion required infection to be microbiologically confirmed or clinically suspected, there was little information about how it was proved in most of the studies. Given the high rate of culture-negative sepsis previously reported,4Phua J. Ngerng W.J. See K.C. et al.Characteristics and outcomes of culture-negative versus culture-positive severe sepsis.Crit Care. 2013; 17: R202Crossref PubMed Scopus (219) Google Scholar inclusion of studies using culture alone as the criterion standard could lead to an increased false-positive rate for procalcitonin, decreasing the perceived specificity. In addition, the majority of studies recruited patients from ICUs, whereas only 4 studies included patients recruited from the emergency department. Finally, significant publication bias was detected: studies with less desirable results appeared less likely to be published, potentially inflating the diagnostic accuracy of the test in the meta-analysis. The authors suggested that although procalcitonin alone cannot differentiate noninfectious systemic inflammatory response syndrome from sepsis, it can be used in conjunction with additional clinical information to aid in diagnosis and management. The reported pooled sensitivity and specificity from the meta-analysis correspond to positive and negative likelihood ratios of 3.7 and 0.29, which will result in only small changes in disease probability. Therefore, caution will need to be exercised when test results are interpreted. Interval likelihood ratios may provide more clinically useful information but were not provided. If procalcitonin is to become a relevant aspect of sepsis care, additional research will need to identify a particular clinical role with an improvement in patient-oriented outcomes.