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Progress Toward "Ruling Out" Sepsis.

Every day in hospitals across the world when a patient presents with a possible infection, clinicians ask themselves “could this be sepsis?” Despite the simplicity of the question, it often is not easy to answer. Sepsis is a complex syndrome that frequently presents with nonspecific symptoms (1). Sepsis screening tools based on systemic inflammatory response syndrome (SIRS) criteria in combination with suspected infection have come under criticism as lacking both sensitivity and specificity. In one study of ICU patients in Australia, 8% of patients with sepsis lacked SIRS criteria (2), indicating potential problems with the sensitivity of SIRS criteria for recognizing sepsis, and in other studies, SIRS criteria have been demonstrated to lack specificity for sepsis (3–6). Despite the challenges in diagnosis of sepsis, the imperative to do so early and accurately is clear. Timely recognition and management have been associated with improved patient outcomes in numerous studies (7–12). However, timely recognition remains a challenge, and there are potential downsides to potentially overly sensitive screening tests for sepsis, including overuse of antibiotics, and distraction from the true diagnosis in patients without sepsis. Consequently, there has been a high level of interest in the use of biomarkers to help diagnose sepsis, but studies of single biomarkers have been of limited impact to date (13). In this issue of Critical Care Medicine, Mearelli et al (14) report the development and validation of a predictive algorithm to rule out sepsis using a combination of a clinical nomogram combined with a panel of biomarkers including procalcitonin, soluble interleukin-2 (IL-2) receptor α, soluble phospholipase A 2 group IIA, presepsin, and soluble triggering receptor expressed on myeloid cell-1. The model was developed in a broad cohort of patients presenting to three emergency departments in Italy with two or more SIRS criteria and subsequently validated in two other emergency departments. There were few exclusion criteria (age < 18, pregnancy, witnessed aspiration, or refused consent). Using the conclusion of the treating physician at discharge and corroborated by an independent physician, patients in the