Bridging the Sepsis Diagnosis Gap: How Host Response Diagnostics Are Changing the Front Line

Sepsis remains one of the deadliest and most expensive challenges in US hospitals, accounting for nearly one-third of inpatient deaths and costing more than $62 billion annually. Early, accurate diagnosis is crucial, yet it remains elusive due to sepsis’s varied presentation and the absence of a definitive diagnostic test. Providers rely on clinical judgment and a patchwork of indicators, such as complete blood count, lactate, blood cultures, and electronic medical record alerts. While these can flag infection or signs of inflammation, they do not diagnose sepsis or predict who is at high risk of poor outcomes. This gap leads to variability in care, delayed treatment, and wasted resources. 

A new class of tools—host response diagnostics—could close that gap by enabling rapid, accurate detection based on the body’s immune response, not just the presence of pathogens.

Host response diagnostics offer a new front line

When applied to sepsis, host response diagnostics allow for earlier identification of disease progression. For example, IntelliSep uses a simple blood draw to provide a direct readout of sepsis-related immune activation and is scalable for population-level testing. A recent peer-reviewed study highlights significant benefits to using this test when integrated into clinical workflows: improved patient outcomes and optimized laboratory and healthcare resources. 

For laboratory teams, this means the opportunity to engage in a more structured, protocol-driven diagnostic pathway. Clinicians can begin with a host response test to assess for sepsis, then pursue targeted pathogen identification as needed. This approach eliminates unnecessary tests, provides greater diagnostic clarity, and supports better clinical decision-making.

Why pathogen-first testing falls short

Equating sepsis with bacteremia is a common misconception. While bacteria in the blood can be an indicator of sepsis, its presence does not define it. Up to 49 percent of sepsis cases are culture negative, with no bacteria detected, yet the patient is experiencing a dangerous immune overreaction. Further, there have been numerous reports about SARS-CoV-2 and other viral agents causing sepsis.

Despite the fact that sepsis is now understood as a dysregulated immune response to infection, many sepsis diagnostic tools remain focused on pathogens. Blood cultures and other pathogen ID tests, like multiplex PCR or next-generation sequencing, provide useful data for optimizing antibiotic therapy, but they’re less effective as a frontline screening tool in the emergency department (ED). They’re expensive, can take hours to yield results and don’t actually diagnose sepsis.

As Chadd K. Kraus, DO, DrPH, FACEP, an emergency physician and researcher, explains: “In the ED, our first priority is to rapidly identify sepsis so that interventions can be quickly initiated to stabilize the patient. While pathogen identification is important for tailoring therapy, the timely diagnosis of sepsis is critical in reducing morbidity and mortality.” 

To close the gap, clinicians need rapid diagnostics that measure host immune response, not just pathogen presence. The most effective strategy may be to lead with a host response diagnostic to test for sepsis and to help laboratories be more selective in using pathogen identification for only those patients at highest risk. This provides a full clinical picture to help clinicians identify and treat sepsis before it's too late.

Aligning lab and clinical teams around early sepsis detection

Adopting a host response-based model requires collaboration between laboratory and clinical teams. Breaking down traditional silos is essential to achieving a more synchronized, patient-centered approach to sepsis diagnosis. At Froedtert Hospital, part of the Froedtert & the Medical College of Wisconsin health network, we’ve seen dramatic patient care improvements from a cross-disciplinary implementation of a host response diagnostic. Initial analyses indicated length of stay was reduced by more than a full day for patients tested with the new sepsis diagnostic, with further research underway to quantify the full impact.

For laboratories, implementing host response diagnostics doesn’t just support better patient outcomes, it reduces unnecessary pathogen identification testing and allows for earlier interventions. It also positions the lab as a proactive partner in clinical decision-making, rather than a downstream service.

As our understanding of sepsis has evolved, so too must our diagnostic approach. 

Clinical labs are uniquely positioned to lead this shift by:

• Integrating host response diagnostics into early testing protocols
• Collaborating closely with clinical teams on workflow redesign
• Championing evidence-based, immune-driven diagnostic pathways

By taking these steps, labs can help drive earlier interventions, reduce sepsis-related deaths, and redefine the lab’s role as a frontline clinical partner.