Nu.Q NETs shows promise in sepsis management
Sepsis is one of the most critical areas of unmet need in acute medicine and infectious
diseases. The condition is caused by the body’s exaggerated and extreme immune response
to an infection, which may lead to organ failure, tissue damage and even death.
Sepsis is the most expensive condition involving US hospital inpatient care, with
the aggregate cost of total sepsis hospital care in the US estimated at over $57.5bn in 2019, excluding subsequent outpatient skilled nursing facility care. Volition’s
Nu.Q NETs aims to be an accessible, accurate and rapid key diagnostic test to help
facilitate the management of this potentially devastating condition.
A brief review of sepsis incidence and pathophysiology
Bacterial infections (particularly from gram-positive sources) are the most common origin of sepsis, but the condition can also be caused
by viral and fungal infections. According to the Centers for Disease Control and Prevention,
80% of sepsis cases originate outside the hospital. The condition is more of a threat
to the elderly, people with weakened immune systems, hospitalized patients and those
with chronic medical conditions.
It was estimated that 1.7 million people in the United States developed sepsis in 2014, resulting in c 270,000 deaths. Sepsis
is believed to contribute to one in every three deaths among hospitalized patients. Globally, it is estimated that c 50 million people develop sepsis each year, resulting in c 11 million deaths. Those who survive
are often left with lasting physical (bodily organ) damage and/or neurological or
mental effects.
The underlying mechanisms by which sepsis develops and evolves are complex. As a brief
overview, the systemic immune response to a bacterial infection causes the activation
of various immune cells and production of inflammatory agents including cytokines
due to pathogen-associated molecular patterns, damage-associated molecular patterns
and lipopolysaccharides produced by the bacteria. In a normal infection, the immune
stimulation is fairly quickly resolved. However, in sepsis, the stimulus is far greater
and can lead to an excessive and dysregulated immune response.
While timely diagnosis is critical, limitations exist
The accurate diagnosis of sepsis (particularly at the early stage of disease presentation)
can be challenging due to the non-specific clinical signs and symptoms in the early
stages. Blood culture-based tests take upwards of 24–48 hours to return results and
physiological tests are only reliable 24–72 hours post admission, due to typical delays
in symptom presentation, and may lack accuracy if performed in the first 24 hours.
Given that the risk of mortality grows by c 8% for every hour that passes without (often antimicrobial) treatment for sepsis, patients
often progress to more serious stages before a definitive diagnosis can be made. A
quicker and effective quantifiable solution is therefore acutely necessary, in our
view.
To assess disease states and severity, the most widely used diagnostic approach that
has been validated for sepsis in intensive care unit (ICU) settings is the use of
Sequential Organ Failure Assessment (SOFA) scores. This test aims to assess performance on six physiological parameters, based
on the patient’s respiratory, cardiovascular, hepatic, coagulation, renal and neurological
systems, and assigns a score (0 to 4) based on the data obtained in each category.
A higher score indicates an increased probability of patient mortality (the highest
possible score is 24).
However, the scoring has been observed to be a better predictor of risk of mortality
only when conducted 72 hours after hospital admission. Alternatively, ICUs may also
employ Acute Physiology and Chronic Health Evaluation (APACHE II) scores, as well
as the Simplified Acute Physiology Score (SAPS II), to detect and monitor severe disease
and risk of death in critical care scenarios. However, these are all highly involved
and time-consuming processes, thus there is a significant need for a more rapid and
objective means to quantify disease progression, given the speed with which sepsis
can progress and worsen in critically ill patients.
Nu.Q NETs shows diagnostic promise for sepsis monitoring
Volition has been studying nucleosomes and neutrophil extracellular traps (NETs) and
ways to detect these structures using its proprietary diagnostic technologies and
antibodies. At the European Society of Intensive Care Medicine (ESICM) Annual Congress
on 5–9 October 2024, the company reported new data from three studies including more than 3,000 patients (comprising more than
14,000 patient samples), which showed how its nucleosome quantification technology
could be used to enhance sepsis management in clinical practice. Nucleosomes are strands
of DNA wrapped around proteins surrounding DNA called histones.
NETs: Key defensive pathway, but can be a double-edged sword
When infections occur, certain white blood cells (neutrophils) target the invading
pathogens (such as bacteria, viruses and fungi) and eject strings of nucleosomes (Exhibit
1) towards them. These nucleosomes combine to form NETs to trap the targeted entities
in a process called NETosis.
First reported in 2004, NETs are net-like structures, made up of nucleosomes, fragmented DNA and antimicrobial
proteins, which can catch and kill or inactivate bacteria and viruses, and sterilize
blood within minutes. NETs can catch bacteria and viruses and destroy them using cytotoxic
proteins (Exhibit 2).
NETosis involves the formation of NETs through a rapid decondensation of chromatin (within
the cell’s nucleus), followed by the release of web-like NETs containing long strands
of chromatin and associated antimicrobial enzymes.
While NETs can be a crucial defense mechanism, in extreme cases the body’s immune
system can over-respond to threats, resulting in the overproduction of NETs (such
as when NETs are produced faster than they can be removed) whereby they can migrate
beyond the initial site of infection or injury. Excessive NETs levels can damage healthy bodily tissues by blocking blood vessels and causing micro blood clots. This
process is called thromboinflammation and Volition argues that extracellular damage
and pathology is due to the indiscriminate binding of anionic (negatively charged)
components of the histones with elements of the circulation and vasculature.
Altogether, dysregulation and excessive NETs formation can contribute to or lead to
sepsis and other immunothrombotic disorders by creating a hyperinflammatory feedback
loop, leading to disseminated intravascular coagulation. These pathways can result
in tissue damage, multiple organ failure and eventually lead to death.
