SCCMPod-564 CCE: Endotoxin Activity and Precision Medicine in Septic Shock

Mar 4, 2026

John A. Kellum, a critical care nephrology leader at the University of Pittsburgh, explains using endotoxin activity as a potential endotype in septic shock. He discusses the endotoxin activity assay, how combining it with organ failure flags a high‑risk subgroup, challenges to clinical use, and how precision medicine and targeted trials could reveal treatable sepsis subgroups.

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INSIGHT

Endotoxin Defines A Treatable Septic Shock Endotype

Sepsis is heterogeneous and can be divided into mechanistic endotypes to guide targeted therapies.
Endotoxin is a targetable mechanism; identifying patients with high endotoxin could define an actionable endotype for septic shock.

INSIGHT

Delta Phenotype Mirrors Endotoxin Injury Pattern

Four clinical sepsis phenotypes (alpha, beta, gamma, delta) differ in mortality and organ dysfunction patterns discovered via machine learning.
The delta phenotype shows high rates of AKI, hepatic and endothelial dysfunction, resembling endotoxin-driven injury in animals and rare human cases.

INSIGHT

EAA Identifies Endotoxic Shock More Than Sepsis Risk

The endotoxin activity assay (EAA) isn't widely available clinically and is limited as a sepsis predictor.
EAA excels at identifying patients with true bloodstream endotoxin who might benefit from anti-endotoxin therapies.

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There is enormous heterogeneity in clinical outcomes and severity of septic shock, with some patients needing only supportive care in the ICU and others progressing to multiorgan system failure and death. How can clinicians identify patients at higher risk of death?

In this episode of the Society of Critical Care Medicine (SCCM) Podcast, host Marilyn Bulloch, PharmD, BCPS, FCCM, is joined by John A. Kellum, MD, FCCM, to discuss high endotoxin activity as a possible endotype for septic shock. Dr. Kellum’s article, “Organ Failure, Endotoxin Activity, and Mortality in Septic Shock,” was published in the September 2025 compendium of Critical Care Explorations. Dr. Kellum is a professor and director of the Center for Critical Care Nephrology, as well as vice chair for the Department of Critical Care Medicine, at the University of Pittsburgh in Pittsburgh, Pennsylvania, USA.

The study used a novel biomarker called the endotoxin activity assay (EAA) to detect endotoxin in the blood. While the EAA is not good at identifying patients who are at risk for sepsis, Dr. Kellum said that, when combined with organ failure, it identifies patients at high risk for endotoxic septic shock. In the study, these patients had a mortality rate of 60%.

Neither the EAA nor the anti-endotoxin therapy is readily available. And, although endotoxic septic shock is rare, occurring in only a quarter of patients with septic shock, Dr. Kellum hopes that, through precision medicine, segmenting this population into treatable subgroups may allow better diagnostics and opportunities to develop or repurpose therapies in the future. This episode is sponsored by Prenosis.

Resources referenced in this episode:

Organ Failure, Endotoxin Activity, and Mortality in Septic Shock (Molinari L, et al. Crit Care Explor. 2025;7:e1308)

Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis (Seymour CW, et al. JAMA. 2019;321:2003-2017)

Safety and Efficacy of Polymyxin B Hemoperfusion (PMX) for Endotoxemic Septic Shock in a Randomized, Open-Label Study (TIGRIS) (ClinicalTrials.gov. ID NCT03901807. Last update posted January 9, 2026)