In busy emergency departments, sepsis is often discussed as something we “cannot miss” rather than a diagnosis we can confidently make. Patients may arrive with signs of an infection and physiologic abnormalities, yet fall into the gray zone where sepsis is possible, but far from certain. Over the last decade our definition of sepsis has evolved to recognize that sepsis is more than an infection and our clinical approach has become more aggressive, driven by the Surviving Sepsis Campaign and protocols like SEP-1. Yet while our protocols for sepsis treatment have evolved, our diagnostic tools are decades old and many were never intended to assess potential for sepsis in the first place.
As ED clinicians, we know that we must act quickly when sepsis is suspected. But that urgency often leads to over-indexing on sepsis in an effort to capture every septic patient, knowing you are likely treating a lot of non-septic patients as well. The consequences are real: resource overuse, missed alternative diagnoses and potential harm to patients who are not actually septic. To meaningfully improve outcomes, we must bridge the gap between our aggressive protocols and the technologies that support them. For sepsis, this means moving beyond tools that detect infection or inflammation alone and toward diagnostics that assess the underlying biology of a dysregulated immune response. Yet, traditional diagnostic tests in the ED cannot definitively answer the question clinicians most need to answer: “Is this sepsis?”
When every minute matters, guesswork is not good enough
When a patient arrives at the ED with signs and symptoms of possible infection, tachycardia, hypoxia or fever, the race begins to detect sepsis. Because every hour of delayed treatment is associated with increased mortality, clinicians often initiate IV fluids and antibiotics before diagnostic certainty is achieved. Abnormal vitals and clinical suspicion trigger the sepsis pathway: antibiotics, IV fluids, and a battery of tests. But our “go-to tests,” lactic acid and blood cultures, are insufficient to diagnose sepsis. While they can tell us about infection and potential for organ dysfunction, they cannot tell us whether a patient is experiencing the immune dysregulation that defines the condition.
Lactic acid reflects cellular metabolism and perfusion and is elevated in many non-septic conditions, including cardiac ischemia, dehydration and diabetic emergencies. Blood cultures can identify bloodstream infection, but they are often negative in sepsis patients and take 48 to 72 hours to return results, which is far too slow for ED decision-making. Unlike stroke and STEMI, which can be rapidly confirmed with computerized tomography (CT) imaging or electrocardiography (EKG), sepsis lacks a rapid, confirmatory diagnostic test. As a result, clinicians often assume many patients with an infection might be septic. This leads to over-testing, over-treating and over-utilizing resources in an effort to avoid missing the sickest patients. Following the implementation of sepsis-focused performance measures, ED blood cultures for discharged patients jumped by nearly 76 percent over the last decade. Further, 50 percent of cultures are drawn on patients who are ultimately discharged home, representing a massive drain on resources. This approach is not efficient. And it may compromise patient outcomes.
The risk of the wrong pathway
The danger of our aggressive, but imprecise strategy becomes clear when sepsis mimics other conditions. Consider a patient with shortness of breath and low blood pressure. Is this sepsis-related pneumonia, or an exacerbation of congestive heart failure? If it is sepsis, immediate IV fluids and antibiotics are life-saving. If it is congestive heart failure, those fluids could be catastrophic, triggering pulmonary edema and respiratory failure. Without a reliable way to distinguish between these scenarios in real time, we risk putting patients on the wrong clinical pathway.
Host response diagnostics: a potential shift in sepsis assessment
One emerging area of interest in sepsis evaluation is the use of host response diagnostics. Rather than attempting to identify a causative pathogen or relying on downstream physiologic markers, these approaches focus on measuring the patient’s immune response. By assessing cellular behavior associated with immune dysregulation, host response diagnostics aim to reflect the underlying biology that defines sepsis. Early studies suggest that host response-based tests may better discriminate between sepsis and noninfectious causes of physiologic instability compared with traditional biomarkers such as lactate or white blood cell count. Importantly, these tools are being developed to deliver results on a clinically relevant timescale, potentially within minutes, making them more compatible with ED workflows.
If validated in broader, real-world populations, host response diagnostics could serve as an adjunct to clinical judgment and existing protocols. They may help identify patients at higher risk who warrant aggressive sepsis management, while also helping clinicians recognize patients whose abnormal vital signs are driven by alternative processes such as viral illness, cardiac disease, or metabolic derangements. Such tools are not intended to replace clinical assessment or established sepsis pathways. Rather, they represent a potential step toward improving early risk stratification in a setting where decisions must be made rapidly and often with incomplete information.
Diagnostic clarity and system efficiency
The implications of diagnostic uncertainty extend beyond individual patient care and increasingly shape ED operations. When clinicians cannot confidently distinguish sepsis from other causes of physiologic instability, patients are often committed to prolonged observation, serial laboratory testing and precautionary admission. While this approach is understandable given the stakes, it contributes to ED overcrowding, inpatient bed shortages and delayed care for other critically ill patients. Greater diagnostic clarity earlier in the ED course could help clinicians better align resources with risk. More precise tools may allow providers to limit unnecessary blood cultures, avoid admissions driven primarily by diagnostic uncertainty and reduce the downstream burden on laboratory services and critical care beds.
Future of sepsis care: Rapid action meets real accuracy
Over the past decade, emergency medicine has rightly emphasized rapid recognition and early intervention for suspected sepsis. These efforts have saved lives. But they have also exposed the limitations of a strategy that prioritizes speed in the absence of diagnostic specificity. Aggressive treatment alone cannot compensate for persistent uncertainty about who is truly septic. The next phase of progress in sepsis care will depend less on escalating treatment intensity and more on improving our ability to identify the underlying biology driving a patient’s presentation. Emerging approaches that assess host immune responses represent one potential step toward aligning diagnostic tools with our current understanding of sepsis as a syndrome of immune dysregulation rather than infection alone.
Host response tests vary in their clinical utility. As these tools enter clinical practice, clinicians and health systems must evaluate them with the same rigor applied to any diagnostic advance, examining the FDA indication for use, understanding whether the test is intended as an aid in sepsis detection, and assessing how it performs in real-world emergency populations. Thoughtful adoption will determine whether these innovations meaningfully improve care. Sepsis demands urgency, but patients also deserve accuracy. The future of sepsis care lies not in choosing between speed and precision, but in finally bringing the two together.
Jasjot S. Johar is a physician executive.
