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I thank Bermejo-Martin et al for their interest in my commentary1Simpson S.Q. SIRS in the time of sepsis-3.Chest. 2018; 153: 34-38Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar and for their thoughtful letter.2Bermejo-Martin J.F. Almansa R. Yebenes J.C. New organ failure as an alternative endpoint to develop diagnostic criteria for sepsis.Chest. 2018; 153: 1278Abstract Full Text Full Text PDF Scopus (3) Google Scholar Fundamentally, we agree that predictive ability for mortality or even for prolonged ICU stay is not the ideal characteristic of diagnostic criteria for sepsis. Recent studies that demonstrated the utility of Sepsis-3 diagnostic criteria as a predictor of mortality in infected patients did not analyze the spectrum of treatments for sepsis in their cohort, whether early or late, adequate or inadequate.3Seymour C.W. Liu V.X. Iwashyna T.J. et al.Assessment of clinical criteria for sepsis.JAMA. 2016; 315: 762-774Crossref PubMed Scopus (2059) Google Scholar It is therefore impossible to determine whether the criteria identify patients who are undertreated, patients who are treated late, patients who will die regardless of adequate therapy, or an amorphous conglomerate. Preferably, a set of diagnostic criteria should screen for and be sensitive to the onset of organ dysfunction that may lead to increased risk of death, and do so early in a patient’s course so that physicians can intervene to mitigate both the organ dysfunction and the risk of death. Whether we call this “presepsis,” as Bermejo-Martin et al have done, or “possible sepsis,” as I have done, treatment at this phase has the greatest potential for improving patient survival. I have confidence that we will ultimately identify genomic, transcriptomic, or proteomic features (ie, biomarkers) that are the sine qua non of sepsis and become the basis of diagnosis, as troponin-I is the basis for diagnosing acute myocardial infarction. Bermejo-Martin et al share this notion and, in fact, have themselves pursued immunological markers as diagnostic tools.4Bermejo-Martin J.F. Andaluz-Ojeda D. Almansa R. et al.Defining immunological dysfunction in sepsis: a requisite tool for precision medicine.J Infect. 2016; 72: 525-536Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar One interesting possibility is monocyte cell volume, which is accessible from the WBC differential and can be used to separate sepsis and severe sepsis (by Sepsis-1 criteria) from noninfectious systemic inflammatory response syndrome (SIRS), augmenting the specificity of a SIRS finding.5Crouser E.D. Parrillo J.E. Seymour C. et al.Improved early detection of sepsis in the ED with a novel monocyte distribution width biomarker.Chest. 2017; 152: 518-526Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar Additionally, biomarker profiles are at least as good as Sepsis-3 diagnostic criteria in their predictive ability for mortality, calling into question why biomarkers should not replace clinical criteria as the benchmark for diagnosis, if mortality prediction were the true issue of interest.6Mikacenic C. Price B.L. Harju-Baker S. et al.A two biomarker model predicts mortality in the critically ill with sepsis.Am J Respir Crit Care Med. 2017; 196: 1004-1011Crossref PubMed Scopus (40) Google Scholar Even when excellent diagnostic tests become available, physicians need some combination of history and physical findings to prompt them to order such a test, and it is imperative that we continue to train doctors to recognize the clinical features of sepsis. SIRS criteria are simple to learn and to use at the bedside, which has been their strength over their decades of use. They should be emphasized in clinician training, not eliminated. New Organ Failure as an Alternative Endpoint to Develop Diagnostic Criteria for SepsisCHESTVol. 153Issue 5PreviewIn a recent editorial published in CHEST (January 2018), Dr Simpson1 expressed his concern about the potential lack of sensitivity of the new definition proposed by the Sepsis-3 consensus for the detection of sepsis in its early moments. This lack of sensitivity could be explained by the endpoint considered to develop the new definition: in-hospital mortality. Sepsis-3 proposes the use of the Sequential Organ Failure Assessment score to identify sepsis patients2 and discourages using the Systemic Inflammatory Response syndrome (SIRS) criteria because they showed a lower predictive validity for mortality than Sequential Organ Failure Assessment. Full-Text PDF SIRS in the Time of Sepsis-3CHESTVol. 153Issue 1PreviewSevere sepsis is a common, deadly, and diagnostically vexing condition. Recent recommendations for diagnosing sepsis, referred to as consensus guidelines, provide a definition of sepsis and remove the systemic inflammatory response syndrome (SIRS) as a component of the diagnostic process. A concise definition of sepsis is welcomed. However, the approach to developing these guidelines, although thorough, had weaknesses. Emphasis is placed on mortality prediction rather than on early diagnosis. Diagnostic criteria are recommended to replace current criteria without evidence of any effect that their use would have on mortality. Full-Text PDF