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The author replies.

e1144 www.ccmjournal.org November 2016 • Volume 44 • Number 11 The author replies: Drs. Zimmerman and Davis (1) raise several interesting points and their comments reflect their intelligence, experience, and commitment to the care of septic patients. I truly appreciate the opportunity to respond. Although technology has unquestionably improved, the ability to diagnose infection is not at the heart of the sepsis “problem.” Rather, the key difficulty lies in separating those patients who are septic from those who are simply infected. Thus, the focus of Sepsis-3 (2–4) was not on infection; rather, it was on identifying at the earliest point possible who, from among a group of patients with suspected, presumed, or documented infection, had sepsis or was likely to develop sepsis. In this regard, the writers’ point regarding false negative and positive results is particularly germane. The systemic inflammatory response syndrome criteria (changes in temperature, respiratory rate, heart rate, and WBC count), when applied to patients suspected of having infection, are extremely sensitive—they identify almost all the patients identified as having sepsis by the measures recommended by the Sepsis-3 task force (3). However, they also identify a large number of patients who have infection but who are not really ill, for example, anyone with a bad cold (3). Thus, one aim of the task force was to provide clinical criteria that reduced the number of false positive results— something accomplished by use of either a Sequential Organ Failure Assessment (SOFA) score greater than or equal to 2 or meeting two of three quick SOFA criteria (3). The studies referenced in the letter are directed at discriminating between critically ill infected patients and equally ill but uninfected patients (5–9). In contrast, all those included in Sepsis-3 met criteria for suspected, presumed, or documented infection (3). Of greater consequence is the concern that “focusing on organ dysfunction ... may divert attention away from earlier events” and detract from identification of “earlier events (that), if detected, could lead to earlier interventions to prevent organ dysfunction.” The term “organ dysfunction” is indeed included in the “definition” of sepsis. However, no real attempt is made to indicate just what constitutes organ dysfunction. Indeed, the same “earlier events” about which Drs. Zimmerman and Davis (1) are justifiably concerned may indeed be the very earliest manifestations of organ dysfunction. For example, the multigene or multiprotein signatures referred to may be a consequence of some as yet unrecognized pathologic process, or, conversely, an adaptive response to such a process. We fully recognized that the definition includes terms (organ DOI: 10.1097/CCM.0000000000001981 appears earlier than more obvious but later organ dysfunction, which is the focus of critical care intervention. Molecular biomarker-based signatures of sepsis appear to be much more sensitive and specific with corresponding higher negative and positive predictive value for detecting sepsis, as compared to current clinical criteria (6–11). Meanwhile, real time, point-of-care testing is rapidly becoming a reality, and before long one or more of these molecular assays may become a bedside reality. Combining molecular pathogen detection and sepsis host response biomarkers may bring clinicians and interventions closer to the “essence of sepsis” (within 1–2 hr of suspicion of sepsis). It is our view that ultimately, newer diagnostic approaches based on combinations of molecular biomarkers, as implemented in point-of-care assays, have potential to supplant, or at the least complement, the standard clinical indicators for recognizing sepsis. Accordingly, another 15 years will likely not be required to significantly improve on the current definition/clinical criteria for sepsis. Dr. Zimmerman received funding from the Children’s University Medical Group University of Washington (salary support) and from Elsevier Publishing (editorial royalties for the textbook, Pediatric Critical Care). He disclosed other support from the Society of Critical Care Medicine (reimbursement to attend board meetings) and disclosed off-label product use (protein and gene expression biomarkers discussed only in a general sense; no specific products identified). His institution received funding from the Seattle Children’s Research Institute (research funding), Immunexpress (Seattle, WA-research funding), and the NIH/NICHD (research funding). Dr. Davis received funding from Immunexpress.