Paving the Way for Personalized Medicine in Sepsis
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Providing the right treatment at the right time is critical in the management of sepsis – early detection of septic shock helps clinicians to make informed treatment decisions and leads to improved outcomes for patients.
Findings from a study recently published in the Journal of Internal Medicine reveal that two distinct pathways leading to the development of septic shock can be identified via specific biomarkers. Diagnostic testing to detect these biomarkers could pave the way for personalized medicine in sepsis.
To learn more about septic shock and the role of the two pathways identified in the study, we spoke to Dr Andreas Bergmann, chief executive officer of SphingoTec, a diagnostic company developing in vitro diagnostic tests for novel biomarkers. In this interview, Dr Bergmann also discusses how the quantification of the two pathway-specific biomarkers can support the diagnosis, monitoring and treatment of sepsis patients.
Anna MacDonald (AM): Can you give an overview of what septic shock is?
Dr Andreas Bergmann (AB): Worldwide, more people die of sepsis than of cancer.1,2 The global burden of sepsis counts for 49 million cases a year, with a high mortality rate of 11 million deaths.1 Sepsis is a life-threatening condition that arises when the body’s response to an infection injures its own tissues. Even for the less aggravated form of the illness, the in-hospital mortality is greater than 10%. In its severe form, also called septic shock, the blood pressure drops to critically low levels, or hypotension, which can lead to multiple organ failure and death. In shock, the pathophysiological abnormalities are profound enough to increase mortality to more than 40%.3
AM: What role does endothelial dysfunction plays in sepsis?
AB: The endothelium is the interior wall of the blood vessels, keeping them tight. This is a forgotten organ in medicine, and it has not received the needed acknowledgment so far. Its malfunction plays a central role in the pathophysiology of shock. In sepsis, the barrier function of the endothelium is compromised and the blood vessels become leaky,4 inducing the loss of tissue resistance and cardiovascular dysfunction which culminates in shock.
The distribution of the blood in the body is jeopardized and the low oxygenation escalates to organ dysfunction. Given the bad prognosis of shock patients, clinicians need to detect endothelial dysfunction early so that they can adapt the treatment in the initial stage of sepsis to improve organ function and ultimately survival.
AM: How is septic shock currently detected? What are the limitations of these methods?
AB: Nowadays diagnosing septic shock is based on a checklist of signs and symptoms. While sepsis is characterized by organ dysfunction, septic shock is the dangerous drop in blood pressure.3 The assessment of these symptoms is showing the consequences of the onset of sepsis, respectively septic shock, but the underlying mechanisms responsible for the evolution of the disease remain hidden.
Part of our mission at SphingoTec is to help clinicians identify these pathophysiological processes in real-time. We pioneer the development of assays that give access to previously blind spots in the disease evolution and open new avenues for early intervention for improved outcomes.
AM: In a recent study, two distinct pathways leading to the development of septic shock were revealed. Can you tell us more about the study and these pathways?
AB: Researchers have summarized the available evidence on two independent pathways leading to endothelial dysfunction, which is responsible for the development of shock and organ failure in sepsis.5
One pathophysiological process originates in the loss of endothelial barrier integrity, causing loss of intravascular volume resulting in edema. To compensate for this leakage, the body increases the production of the repair hormone bioactive Adrenomedullin (bio-ADM). bio-ADM regulates both vascular integrity and vasodilation. Due to this double function, increased production of bio-ADM not only has the role of re-sealing the compromised barrier, but it also leads to vascular relaxation, and therefore to a dangerous side effect of vasodilation. This generates a loss of tissue resistance which ultimately culminates in shock.
The second underlying mechanism accountable for the loss of cardiovascular function is the depletion of angiotensin II and subsequent effects on the renin-angiotensin-aldosterone system (RAAS), which plays a vital role in the regulation of the cardiovascular system. This ultimately leads to cardiac depression and reduced vascular tone, a deadly combination in need of selective treatment strategies. The process leading to the depletion of the cardiovascular stimulating hormone angiotensin II is the release of the protease Dipeptidyl Peptidase 3 (DPP3) into the bloodstream caused by sepsis-induced cell damage.6
AM: How can quantification of bio-ADM and DPP3 support the diagnosis, monitoring, and treatment of sepsis patients?
AB: Both bio-ADM and DPP3 are biologically active molecules and measuring their concentration in blood gives the physicians vital information regarding the risk of shock development and the causes of shock. The newly identified biomarkers are paving the way for a tailored medicine in the field of sepsis: the two distinct pathways respond to different treatments. In the context of endothelial dysfunction generated by the loss of tissue resistance, the stabilization of blood pressure by vasoactive agents should start as soon as possible to improve survival chances. Once the heart function is compromised, as indicated by elevated DPP3 levels, alternative treatment should be considered. In septic shock, timing is highly critical in taking therapeutic decisions, and responding on a patient-specific basis can significantly improve patient management.
Both pathways are independent of each other, and both biomarkers can be used in conjunction to improve critical care diagnostics.
AM: Could you elaborate more on the role of bio-ADM in septic shock?
AB: Clinical data from more than 35,000 patients demonstrate that high bio-ADM levels independently from inflammation and co-morbidities indicate distortions in the barrier function of the inner cell sheet of blood vessels, the endothelium. Loss of this barrier function is considered a key driver in the development of hypotension and eventually septic shock with loss of organ perfusion in sepsis patients.7,8 By measuring bio-ADM blood levels, clinicians can now identify those septic patients at high risk of shock even before the hypotension symptoms become visible.9 Data from the observational study AdrenOSS-1 show7 that elevations of bio-ADM levels reflect the loss of endothelial function and translate into poor outcomes in sepsis. Furthermore, the results of the biomarker-guided AdrenOSS-2 trial10 confirm that this pathway is a valid therapeutic target, supporting endothelial function by the innovative drug Adrecizumab.
AM: Up until early 2021, the role of DPP3 in sepsis was unknown. Could you give us an overview of the latest insights?
AB: DPP3 is at the core of a newly identified disease mechanism, which was initially discovered in cardiogenic shock11 and recently revealed in sepsis.6 It has been shown in preclinical models that DPP3 in the bloodstream induces loss of heart function12 and its inhibition with the antibody Procizumab is instantly restoring heart function.13 A growing body of evidence shows that DPP3 is strongly associated with short-term organ dysfunction and unfavorable outcomes in cardiogenic shock,11 burn patients,14 surgery,15 and most recently in sepsis.6
In an international multicentric study,6 it has been shown that DPP3 levels can predict multiple short-term organ failure and the need for organ support therapies in sepsis patients. High or persistent high DPP3 values indicate the patient is at the highest health risk and rapid interventions are necessary.
According to the newly discovered pathophysiological processes, DPP3 can identify a group with vasopressor resistant shock which has a particularly high mortality risk early. By adding on top of standard parameters, but also by correlating with sepsis severity, measuring DPP3 blood levels can open new doors for early intervention.
AM: SphingoTec has developed new diagnostics for the quantification of bio-ADM and DPP3. Can you tell us more about these?
AB: Following a deep understanding of the disease biology, we have developed diagnostic solutions that now unravel the etiology of the mortality drivers in sepsis. The biomarkers bio-ADM and DPP3 identify these pathophysiological processes responsible for some of the most commonly seen abnormalities responsible for septic shock, facilitating an early and precise diagnosis and monitoring of sepsis patients.
To support the critical care community, we have made available the diagnostics for quantification of bio-ADM and DPP3 as microtiter plate assays as well as rapid point-of-care tests on our established NexusIB10 whole blood immunoassay platform. After initiating collaborations with leading University Hospitals for clinical validation of our biomarkers, we see now a rapid increase in the routine usage of our biomarkers.
AM: How do you think these innovations will influence sepsis management in the future?
AB: Sepsis has always been the Achille’s heel of health care, taking lives and driving up costs. Today, clinicians face a disease where the underlying mechanisms leading to organ dysfunction and mortality are unknown. The information reaching them comes usually too late and is unspecific.
With the cutting-edge diagnostics developed at Sphingotec we help uncover the mortality drivers in sepsis. Our biomarker innovations are indicating in real-time the different disease mechanisms requiring different treatment strategies. Together with the critical care community, we work to increase the awareness of these latest scientific advancements and translate them into routinely used diagnostic solutions that offer actionable information. Our goal is to support better management of sepsis patients and ultimately improve survival.
Dr Andreas Bergmann was speaking to Anna MacDonald, Science Writer for Technology Networks.
References:
1. Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: Analysis for the Global Burden of Disease Study. The Lancet. 2020;395(10219):200-211. doi:10.1016/S0140-6736(19)32989-7
2. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Abate D, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: A systematic analysis for the global burden of disease study. JAMA Oncol. 2019;5(12):1749. doi:10.1001/jamaoncol.2019.2996
3. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801. doi:10.1001/jama.2016.0287
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5. Lier D van, Kox M, Pickkers P. Promotion of vascular integrity in sepsis through modulation of bioactive adrenomedullin and dipeptidyl peptidase 3. J Intern Med. 2020. doi.org/10.1111/joim.13220
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7. AdrenOSS-1 study investigators, Mebazaa A, Geven C, et al. Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study. Crit Care. 2018;22(1):354. doi:10.1186/s13054-018-2243-2
8. Caironi P, Latini R, Struck J, et al. Circulating biologically active adrenomedullin (bio-ADM) predicts hemodynamic support requirement and mortality during sepsis. Chest. 2017;152(2):312-320. doi:10.1016/j.chest.2017.03.035
9. Lemasle L, Blet A, Geven C, et al. Bioactive adrenomedullin, organ support therapies, and survival in the critically ill: Results from the French and European Outcome Registry in ICU study. Crit Care Med. 2020;48(1):49-55. doi:10.1097/CCM.0000000000004044
10. Geven C, Blet A, Kox M, et al. A double-blind, placebo-controlled, randomised, multicentre, proof-of-concept and dose-finding phase II clinical trial to investigate the safety, tolerability and efficacy of adrecizumab in patients with septic shock and elevated adrenomedullin concentration (AdrenOSS-2). BMJ Open. 2019;9(2):e024475. doi:10.1136/bmjopen-2018-024475
11. Takagi K, Blet A, Levy B, et al. Circulating dipeptidyl peptidase 3 and alteration in haemodynamics in cardiogenic shock: Results from the OptimaCC trial. Eur J Heart Fail. 2020;22(2):279-286. doi:10.1002/ejhf.1600
12. Deniau B, Blet A, Santos K, et al. Inhibition of circulating dipeptidyl-peptidase 3 restores cardiac function in a sepsis-induced model in rats: A proof of concept study. Lionetti V, ed. PLoS ONE. 2020;15(8):e0238039. doi:10.1371/journal.pone.0238039
13. Deniau B, Rehfeld L, Santos K, et al. Circulating dipeptidyl peptidase 3 is a myocardial depressant factor: Dipeptidyl peptidase 3 inhibition rapidly and sustainably improves haemodynamics. Eur J Heart Fail. 2020;22(2):290-299. doi:10.1002/ejhf.1601
14. Dépret F, Amzallag J, Pollina A, et al. Circulating dipeptidyl peptidase-3 at admission is associated with circulatory failure, acute kidney injury and death in severely ill burn patients. Crit Care. 2020;24(1):168. doi:10.1186/s13054-020-02888-5
15. Gombert A, Barbati M, Kotelis D, et al. In-hospital mortality and organ failure after open and endovascular thoraco-abdominal aortic surgery can be predicted by increased levels of circulating dipeptidyl peptidase 3. Eur J Cardiothorac Surg. 2020. doi:10.1093/ejcts/ezaa413
