Two pathways to septic shock

Loss of endothelial function is induced through two different pathophysiological processes

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Two pathways to septic shock

HENNIGSDORF, Germany & BERLIN—Diagnostics company SphingoTec GmbH reported today that two distinct processes are involved in the development of septic shock. SphingoTec also notes that these biomarkers for endothelial function and cardiovascular depression allow early identification of these underlying mechanisms, which require different interventions. 

Researchers have summarized the available evidence in a review of two distinct pathophysiological processes leading to endothelial dysfunction, and the subsequent development of shock and organ failure in sepsis. The two molecules acting on the vasculature and influencing patient outcomes are bioactive adrenomedullin (bio-ADM) and dipeptidyl peptidase 3 (DPP3). These biomarkers can support an early and precise diagnosis and monitoring of sepsis patients.

One distinct pathway originates in the loss of endothelial barrier integrity, which causes edema and loss of intravascular volume. To compensate for this leakage, production of the repair hormone bio-ADM is increased. But bio-ADM also has a secondary function of vascular relaxation, and the increased production leads to vasodilation, generating a loss of tissue resistance and ultimately ending in shock. 

Data from the observational study AdrenOSS-1 show that elevations of bio-ADM levels reflect the loss of endothelial function, and translate into poor outcome in sepsis. And the results of the biomarker-guided interventional study AdrenOSS-2 have confirmed that this pathway is a valid therapeutic target. 

The second underlying mechanism for loss of endothelial function is the depletion of angiotensin II, which affects the renin-angiotensin-aldosterone system (RAAS) — ultimately leading to cardiovascular depression and reduced vascular tone. The main process generating the depletion of the cardiovascular stimulating hormone angiotensin II is the release of DPP3 into the bloodstream, through sepsis-induced cell damage.

Data from AdrenOSS-2 also show that clinical trials can benefit from the use of biomarkers as an enrichment strategy. In the study, patients with sepsis-associated endothelial dysfunction were identified by increased bio-ADM, and received therapy with either placebo or adrecizumab, an antibody targeting the loss of vascular integrity by maintaining protective bio-ADM concentrations in the blood. When excluding patients with additionally high DPP3 blood concentrations, outcomes could further be improved. Therapies blocking DPP3-activity have also been shown to improve outcomes in various preclinical models.

“Following a deep understanding of the disease biology, we have developed diagnostic solutions that can now unravel the etiology of the mortality drivers in sepsis. The evidence confirms the utility of our biomarkers in supporting clinicians, [who can] make more informed decisions and ultimately improve patient management,” said Dr. Andreas Bergmann, CEO of SphingoTec.

SphingoTec has created new diagnostics for the quantification of bio-ADM and DPP3. These diagnostics are available as microtiter plate assays, as well as point-of-care tests, on the Nexus IB10 immunoassay platform. The platform can provide test results on whole blood samples in 20 minutes.

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