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In Vivo and In Vitro – Why They Matter In The Early Detection Of Sepsis

Unmet Needs in Sepsis

Over the past decade, significant progress has been made in reducing sepsis mortality due to improvements in ICU technology, as well as numerous initiatives such as the Surviving Sepsis Campaign’s (SSC) recent move to a One-Hour Bundle, as well as the introduction in 2016 by the Sepsis-3 task force of an updated definition of sepsis. Not only does the Sepsis-3 definition, Sequential Organ Failure Assessment (SOFA), provide a scoring system that is far more sensitive in predicting sepsis mortality than earlier guidelines, the expanded Quick Sequential Organ Failure Assessment (qSOFA) facilitates identifying patients at risk of dying of sepsis outside the ICU.1 Given the mortality associated with a later diagnosis, these initiatives, aimed at advancing an earlier diagnosis and more rapid treatment of sepsis, remain the cornerstone of sepsis management. Yet, numerous unmet needs remain.

Toward a New Diagnostic Paradigm

Currently, no “gold standard” for the diagnosis of sepsis exists. The complexity of sepsis presents various diagnostic and treatment challenges, including its fast onset, nonspecific signs and symptoms, and the uncertainty of the pathogen.1 While the current approach to diagnosing sepsis looks at the pathogen, the current SSC One-Hour Sepsis Bundle, which focuses on treating the cause of infection, is limited by lab results that may take up to 24 to 48 hours, and can render the blood cultures negative in up 30 to 60 percent of the findings.2 Newer solutions that can promote earlier diagnosis and intervention in sepsis, such as biomarkers, are increasingly being studied as diagnostic tools for staging the disease, prognosis, and response to intervention.3

Expert Insights into Sepsis Decision-Making

Speaking with two sepsis experts, Victor Jeger, MD PhD, a physician and sepsis researcher and Bastiaan van Holthe, an expert in sepsis and critical care medicine, provides a window into understanding the multiple factors impacting the early detection and diagnosis of sepsis, particularly solutions that can advance earlier detection and more rapid treatment. What follows are the key highlights from an in-depth conversation with these two experts on how vital signs can be combined with laboratory findings to provide new solutions to the challenges of detection and diagnosis. This includes the increasing role of biomarkers, which can guide a more rapid sepsis diagnosis, as well as other sources of support for clinicians to maximize physician decision-making in detecting and managing sepsis.

Linking Lab Results, Including Biomarkers, With Vital Signs

In discussing sepsis detection, Dr. Jeger began by stating that clinicians tend to “focus mainly on what they can see.” He emphasized that in a busy emergency department (ED) or ICU, being able to link together all the available data–the clinical (vital) signs and blood work (laboratory) findings–can “facilitate a better interpretation of the data” in the detection and treatment of sepsis. In discussing the emerging role of biomarkers, he pointed out that, while all lab and clinical results can be considered biomarkers; the difference is that protein-based immunoassays or clinical chemistry assays, such as procalcitonin and lactate, which are already in the SSC guidelines, are useful in monitoring antibiotic therapy and indicators of disease progression.

Biomarkers are Underused in Detecting Sepsis

However, as van Holthe pointed out, there are also many other biomarkers, in addition to procalcitonin and lactate, that are available but underused. He noted that the challenge is to improve their use in the early detection and diagnosis of sepsis. Because sepsis affects so many organs and cell types, “there is no one stand-alone biomarker that could be used to detect sepsis.”   He also observed that combining machine learning with vital signs and biomarkers has the potential to help identify more quickly or predict sepsis deterioration.

Ideally, in a panel, biomarkers with different characteristics, such as release kinetics or cellular origin should be combined. An example of this might be interleukin-6 (IL-6), that is released shortly after inflammation and infection and has a relatively short half-life. In fact, multiple studies have shown that interleukin IL-6 is a sensitive early marker of infection and inflammation.4 Van Holthe also referenced the growing value of Point of Care Testing (POCT) in sepsis, in which lab tests can be performed in the ICU or ED.

Another challenging area of sepsis diagnosis, Dr. Jeger noted, is pediatrics. “Because the immune system of children is different, it’s important to integrate changes in their immune system in a diagnosis of sepsis.” Again, research shows that IL-6, in combination with clinical signs, is an increasingly important biomarker in diagnosing sepsis in newborns as well.4  

Machine Learning and Artificial Intelligence (AI) Can Complement Data

Both Dr. Jeger and Mr. van Holthe expressed how patient data is often scattered and the critical role of machine learning in “curating” the various data sources to detect sepsis and predict prognosis. One of the biggest hurdles clinicians face, especially in busy EDs and ICUs, is the complexity of all the data, making detection difficult. Bringing together curated data sources via machine learning can hopefully help the physician to “see” certain patterns in making a differential diagnosis.

For example, Dr. Jeger discussed how, based on his experience in treating numerous patients in the ED, having had disparate patient data imported onto one visible platform, would have processed changes in patient status much more quickly than the human brain and led to rapid detection. He suggested the use of some kind of portable device—such as an iPhone —could provide integrated digital decision support is such settings and situations.

Provide Support for Physician Decision-Making

In dealing with sepsis, Dr. Jeger noted that it’s important to support physicians—but “not to decide for them”; clinical judgement is more than just patient scores and assessments.  Both agreed that AI can help to avoid unnecessary paperwork, allowing physicians and nurses more time to focus on the patient. It was also noted that it’s important to have the flexibility of working with many solutions in sepsis— solutions that are intuitive and easy to use are more likely to become standard of practice in hospitals.

Solution-based Insights

The insights of these two experts can help pave the way for improvements in the current sepsis clinical practice by linking vital signs with laboratory findings in order to significantly improve the rapidity and accuracy of the diagnosis of sepsis, as well as support and enhance clinical decision-making. It was also clear from the discussion that the use of biomarkers in the future may help patient outcomes by potentially upgrading diagnostic accuracy, reducing the time to effective treatment, and limiting unnecessary lab tests and antibiotic treatments.2


1. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-JAMA,  February 2016. Accessed May 2, 2020

2. The Clinical Challenge of Sepsis Identification and Monitoring, PLOS Medicine, May 2016. Accessed May 3, 2020.

3. Biomarkers for Sepsis – Past, Present and Future, Qatar Critical Care Conference Abstract, Qatar Medical Journal. Accessed May 3, 2020.

4. Interleukin-6 in Surgery, Trauma, and Critical Care: Part I: Basic Science, Journal of Intensive Care Medicine, February 2011. Accessed May 3, 2020.