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Global Panel of Sepsis Experts Examines Clinical Potential of a NET-Associated Circulating Nucleosome Assay

By VolitionRx

Epigenetics diagnostics firm VolitionRx convened a panel of 10 experts in sepsis care from five countries in September to discuss how Nu.Q NETs — a rapid blood test that can evaluate disease severity by detecting components of neutrophil extracellular traps — could best be used in clinical practice. The panel concluded that the test has the potential to aid in the early diagnosis of sepsis and to guide and monitor response to therapy.

Sepsis is the number one cause of death in hospitals worldwide. It kills an estimated 11 million people a year, which is more than cancer or coronary disease. Almost half of cases are in children. In 2017, there were an estimated 20 million cases and 2.9 million deaths in under-fives. Half of the survivors are left with psychological and/or physical sequelae. They may struggle to remember everyday things, no longer be able to walk, or be unable to dress or bathe themselves without help.

An image with photos introducing the panel. Djillali Annane, panel chair, Professor in medicine at University Paris-Saclay and University Versailles SQY and Chief Counsellor of the French Minister of Health. Evangelos J. Giamarellos-Bourboulis, event host, Professor of internal medicine and infectious diseases at the National and Kapodistrian University of Athens and chair of the European Sepsis Alliance. Michael Bauer, Professor and Chair of the Department of Anaesthesiology and Intensive Care Medicine at Jena University Hospital. Guillaume Monneret, a professor of immunology at Hospices Civils de Lyon. Mervyn Singer, a professor of intensive care medicine at University College London. Co-chaired Sepsis-3 Definitions International Task Force; past-Chair, International Sepsis Forum; Sepsis Topic Adviser to NICE; Emeritus NIHR Senior Investigator. Adrienne Randolph, a paediatric critical care physician at Boston Children's Hospital, Professor of Anaesthesia and Paediatrics at Harvard Medical School and chair of the International Sepsis Forum. Lea Payen, a professor in molecular biology and toxicology at the University of Lyon I and Hospices Civils de Lyon. Dr. Tanya Novak, a PhD scientist at Boston Children's Hospital and an instructor at Harvard Medical School. Dr. Andrew Aswani, a consultant in intensive care medicine and anaesthesia at Guy's and St Thomas' Hospital in London and co-founder and Chief Medical Officer of Santersus AG. Dr. Andrew Retter, an intensive care consultant at Guys and St Thomas' Hospital in London and a medical consultant to Volition.


A growing understanding of the biology of neutrophils and, in particular, neutrophil extracellular traps (NETs) could improve the diagnosis, monitoring, and treatment of sepsis. Released by neutrophils when they detect bacterial, viral, or other threats, these webs of decondensed chromatin can be angels or devils. They play an important role in the body’s response to infection; they trap and kill invading pathogens, stopping the threat from spreading around the body. However, excessive NETs production is associated with a dysregulated immune response and poor patient outcomes in a range of life-threatening conditions, including sepsis, in which the excessive host immune response to an infection can cause widespread organ damage.

Nu.Q NETs is the first approved clinical assay to assess disease severity by quantifying circulating nucleosomes, a critical component of NETs.

An educational illustration showing that chromosomes and NETs (neutrophil extracellular traps) are made of nucleosomes. On the left, a cell is expelling NETs composed of a purple chromosome structure unraveling into strands with green nucleosomes attached. These nucleosomes consist of DNA wrapped around histones, depicted as green spheres labeled 'H3'. A DNA strand extends from the chromosome to the right, progressively unwinding to reveal individual nucleosomes. Antibodies, shown as red Y-shaped symbols, are binding to the nucleosomes and NETs. At the bottom, a magnetic bead attached to a brown stick represents a tool for capturing these components. The text 'Volition test accurately measures NETs' indicates the function of the illustrated process.


Measuring NETs for Early Diagnosis

One of the key themes of the discussions and presentations included whether measuring NETs would assist in the early diagnosis of sepsis. According to panelist Andrew Retter, an intensive care consultant at Guys and St Thomas’ Hospital in London and a medical consultant to Volition, time delays and misdiagnoses can be fatal. “Detecting sepsis early is critical to saving lives,” he said. “Mortality increases as much as 8 percent for every hour that treatment is delayed.”

Currently, physicians use a combination of clinical signs and blood, microbiological, and other tests to make their diagnosis. However, the process is time-consuming and far from foolproof; the symptoms of sepsis overlap with those of many other conditions and, even in the sickest patients, only about a third of blood cultures are positive. Nu.Q NETs is a simple, low-cost, and routine blood test that can be deployed throughout the hospital, including the emergency department, and may facilitate diagnosis. “Measurement of NETs could potentially identify severe illness that may not be apparent yet clinically,” said panelist Adrienne Randolph, pediatric critical care physician at Boston Children’s Hospital, professor at Harvard Medical School, and chair of the International Sepsis Forum.

Nu.Q NETs measures levels of the histone H3.1, a building block of NETs. In an August 2022 study published in Biomolecules, levels of this histone in septic shock patients were found to correlate with the SOFA score, a measure of organ dysfunction. Additionally, H3.1 levels different between sepsis patients and COVID-19 patients, indicating potential to help differentiate between conditions.

For a biomarker test to be widely adopted, it has to be practical in routine settings. A recent validation study by panelist Lea Payen, professor of molecular biology and toxicology at the University of Lyon, found the Nu.Q NETs assay to be compatible with existing biochemistry robots. It also showed that blood can be collected in citrate and EDTA tubes and samples can be kept for up to 24 hours, allowing reflex testing.

Treatment Monitoring and Patient Stratification

Sepsis patients can deteriorate rapidly. If patients who aren’t responding to treatment could be identified earlier, they could be changed to a new line of treatment earlier, improving outcomes.

Research led by panelist Guillaume Monneret, professor of immunology at Hospices Civils de Lyon, presented at ESICM 2023 and published in Annals of Intensive Care, found a correlation between high H3.1 levels and 28-day mortality in septic shock patients. This suggests that Nu.Q NETs could be used to identify the sickest patients for treatment revaluation.

Preliminary results of the RECORDS trial presented by Annane indicate an association between high levels of H3.1 and the need for mechanical ventilation and vasopressors. Early data also points to elevated H3.1 being predictive of mortality.

The panelists discussed how Nu.Q NETs could be used to stratify patients for treatment, for example, by helping physicians decide whether to move a patient into the ICU. There was also interest in whether the assay could be used to triage and prioritize discharge, to help planning with both admissions and discharge from critical care.

Treatment Selection

Another important theme was whether the results of Nu.Q NETs could guide the use of treatments beyond the current standard therapies. “Patient-centered benefit based on a biomarker guiding personalized intervention would be the holy grail,” said Michael Bauer, professor and chair of the Department of Anesthesiology and Intensive Care Medicine at Jena University Hospital.

Fundamental to this is the role of NETs in sepsis — whether they are a main actor or a bystander. They may be part of the dysregulated host immune response to infection that drives sepsis, or a useful bystander — a sign of, rather than a contributor to, the dysregulated response.

If it is the former and NETs are part of the dysregulated host immune response, they could be a valuable treatment target. For example, therapies that clear NETs from the blood could be helpful. In animal studies, Santersus co-founder and chief medical officer, panelist Andrew Aswani, has shown that the company’s NucleoCapture technology can remove NETs from the blood of pigs with sepsis. The “blood-cleansing” device has also been successfully used in the regeneration of damaged lungs — a finding that further demonstrates the association between NETs and organ damage.

Another option could be giving treatments that prevent the activation of neutrophils and the release of NETs into the bloodstream. The panel discussed ongoing research that has identified TNF-α to be crucial for the activation of neutrophils, suggesting TNF blockers could be useful.

If NETs are, however, not directly toxic but sign a particular subtype of sepsis, this could allow the personalization of treatment. For example, if high levels of NETs signify a hyperinflammatory endotype, patients might benefit from corticosteroids or complement inhibitors.

The growing knowledge of the biology of NETs also raises the possibility of revisiting some old treatments. There have been more than 100 Phase III trials in the last 20 to 25 years, but none have led to therapies that are still used today. One reason for this is thought to be that many trials failed to consider that sepsis is a complicated condition made up of many different subtypes. There is a possibility that some treatments that either failed in trials or were withdrawn from use could improve outcomes when directed at patients with high levels of NETs. For example, NETs are known to down-regulate natural anti-coagulant mechanisms, which suggests that the treatment of patients with excessive levels of NETs with activated protein C is worthy of exploration.

Conclusions and Future Research

There was agreement among the panel that, while more work needs to be done, NETs represent an interesting avenue for early diagnosis for therapy selection and monitoring. Valuable sources of further data will include EPICTETUS, a one-year prospective study evaluating Nu.Q NETs in 500 patients with sepsis or septic shock. Launched in October 2023, the observational study will assess how the Nu.Q NETs assay performs in diagnosis, clinical course prediction, and prognosis of sepsis.

About Volition

Volition is a multi-national epigenetics company powered by Nu.Q, its proprietary nucleosome quantification platform. Volition is developing simple, easy-to-use, cost-effective blood tests to help diagnose and monitor a range of life-altering diseases including some cancers and diseases associated with NETosis such as sepsis.

Nu.Q® and Nucleosomics™ are trademarks of VolitionRx Limited and its subsidiaries.

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This sponsored content is provided by an advertiser and published in collaboration with the GW Custom Solutions Group, a division of GenomeWeb. The content was not produced by the editors or reporters of GenomeWeb, 360Dx, or Precision Oncology News, and does not represent the views of these publications or GenomeWeb's parent company, Crain Communications Inc.