Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT04117568 |
| Other study ID # |
AKB-Block |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
September 4, 2019 |
| Est. completion date |
April 1, 2020 |
Study information
| Verified date |
August 2021 |
| Source |
Göteborg University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Surgical trauma elicits an immune response aiming to initiate healing and remove debris and
damaged tissue locally at the wound site (1). This local reaction includes a considerable
production of cytokines and chemokines that enters the circulation and initiate a systemic
inflammatory response mediated by circulating cytokines and chemokines. This response is
called systemic inflammatory immune response (SIRS) and is an aseptic systemic inflammation.
Postoperative inflammation produces proinflammatory cytokines, mainly IL-6, IL1 beta, and
tumor necrosis factor alfa (2). Neutrophils and emergency granulopoesis Polymorphonuclear
neutrophils constitute the most abundant population of white blood cells. Their main task is
to provide innate immune protection of the host from microbial attack, migrating to the site
of infection, engulfing the microbes by phagocytosis, and killing the prey through attack by
reactive oxygen species (ROS) and antimicrobial granule pro¬teins (22). Upon systemic
infection or inflammation, e.g., sepsis or trauma, the bone marrow enters a state of
emergency granulopoiesis, drenched in cytokines that augment production and survival of
neutrophils for rapid delivery to the blood (23-25). Recently, advanced techniques have
evolved that al¬low the isolation of different developmental stages of steady-state and
emergency neutrophils, and characterization of these has just begun (26). Glycans Glycans
(polysaccharides) attached to proteins and lipids on the surfaces on immune cells serve as
ligands for glycan-binding proteins, lectins. Several neutrophil processes are directed by
gly¬can - lectin interactions; selectin-directed rolling on the endothelium, siglec-mediated
in¬hibitory signals, and activation of effector function by galectins. Many of the proteins
that end up in neutrophil intra-cellular granules are highly glycosylated, but not much is
known about if and how the neutrophil glycome evolves during the 'targeting-by-timing'
process of differentiation and how this is affected by emergency granulopoiesis during
systemic infection and inflammation. Here is a clear knowledge gap.
Description:
Postoperative complications of any sort occurs in many of the patients undergoing high risk
cancer surgery such as surgery for pancreatic, esophageal or ovarian malignancy (3, 4) These
patients have a risk of wound infection mainly due to malnutrition and challenging surgical
conditions (5, 6) A prolonged inflammatory response (overshoot) in some patients may lead to
multiple organ failure (MOF) (7, 8).
Postoperative immunosuppression However, to handle the postoperative proinflammatory actions,
patients also produce anti-inflammatory cytokines, mainly IL-4, IL-10 and IL-1 Ra. This is
called compensatory inflammatory response syndrome (CARS). In cases of complications or
malnutrition there may instead be an overshoot of the CARS mechanisms that lead to a
suppression of the immune response (9, 10).
The surgical stress resulting in an imbalance in the inflammatory systems consume the
circulating neutrophils and stresses the bone marrow to release immature, less efficient
neutrophils, into the bloodstream, an event called emergency granulopoesis(11, 12).
Sepsis and ARDS Sepsis is one of the leading causes of death in Sweden and globally, and is
characterized by an uncontrolled inflammatory reaction (13). The disease can affect everyone,
including previously healthy people, and occurs when a normal bacterial infection invades the
bloodstream and the body then responds with an inflammatory reaction. Acute organ dysfunction
in sepsis primarily affects respiratory and circulatory systems (14). Pneumonia is the most
common underlying cause of sepsis and respiratory insufficiency is the most common organ
dysfunction in septic shock (15). Pneumonia with septic shock can develop into respiratory
distress syndrome (ARDS) associated with a very high mortality rate, around 40% (16-18)
Recently, ARDS was shown to be associated with migration of neutrophils, into the lung
alveoli, and that such infiltration drives an inflammatory reaction, for which the
pathophysiological mechanisms are incompletely mapped. Increased knowledge of the neutrophil
role in ARDS could thus benefit the understanding of this complex syndrome(19, 20). In
sepsis, the demand for enough circulating neutrophils to fight the infection is so high that
reserve pools are exhausted and granulopoiesis switches to emergency mode. This results in
release of immature neutrophils into circulation, the so-called left shift, used as an
indicator of sepsis. As a result, circulating neutrophils in sepsis can be very
heterogeneous, an effect also seen in autoimmune diseases and cancer (21). There are
currently no tools to properly investigate these emergency neutrophil populations to utilize
for diagnosis and disease follow-up.
Neutrophils and emergency granulopoesis Polymorphonuclear neutrophils constitute the most
abundant population of white blood cells. Their main task is to provide innate immune
protection of the host from microbial attack, migrating to the site of infection, engulfing
the microbes by phagocytosis, and killing the prey through attack by reactive oxygen species
(ROS) and antimicrobial granule pro¬teins (22). Upon systemic infection or inflammation,
e.g., sepsis or trauma, the bone marrow enters a state of emergency granulopoiesis, drenched
in cytokines that augment production and survival of neutrophils for rapid delivery to the
blood (23-25). Recently, advanced techniques have evolved that al¬low the isolation of
different developmental stages of steady-state and emergency neutrophils, and
characterization of these has just begun (26). Glycans Glycans (polysaccharides) attached to
proteins and lipids on the surfaces on immune cells serve as ligands for glycan-binding
proteins, lectins. Several neutrophil processes are directed by gly¬can - lectin
interactions; selectin-directed rolling on the endothelium, siglec-mediated in¬hibitory
signals, and activation of effector function by galectins. Many of the proteins that end up
in neutrophil intra-cellular granules are highly glycosylated, but not much is known about if
and how the neutrophil glycome evolves during the 'targeting-by-timing' process of
differentiation and how this is affected by emergency granulopoiesis during systemic
infection and inflammation. Here is a clear knowledge gap.
Settings, research designs, patients and methods This project is a collaboration between the
Sahlgrenska University Hospital, and Gothenburg University, Gothenburg, Sweden.
Adult patients (>18 years of age) are found from the surgical waiting list at the Sahlgrenska
University hospital as they are assessed and scheduled for surgery for different kinds of
malignancies, pancreatic malignancy, esophageal malignancy and ovarian malignancy.
Furthermore, in a second study we will include patients undergoing cardiac surgery, with a
heart lung machine in operation during the surgery. These patients will also be included from
the surgical waiting list.
Patients in septic shock will be included from daily rounds at the central intensive care
unit at the Sahlgrenska university Hospital. Septic shock is defined by criteria from
Surviving sepsis campaign or sepsis III. As only around 30% of patients that are diagnosed
with septic shock has a positive blood culture we will include both patients with or without
a positive blood culture. After obtaining informed consent, patients will leave venous blood
samples 3-5 times during their admission. The rationale for this was that we are not entirely
sure of when patients may or may not enter the stage of emergency granulopoesis, but based on
results from previous studies, and to achieve reasonable feasibility of the study protocol
with as little missing data as possible these three sampling occasions seemed a reasonable
compromise.
Clinical significance The basic characterization of glycome and glycoproteome in neutrophil
granules will give in¬sights into, and be correlated with, the glycoconjugate status in the
cell precursor populations that may be prematurely released from the bone marrow upon
emergency granulopoiesis in¬duced by disease, such as sepsis, severe aseptic inflammation
(trauma), autoimmune disease and cancer. Hence, our studies of neutrophils from blood and
bone marrow, as well as emergency neutrophils from patients with sepsis and corresponding
model systems will enable us not only to build mechanistic models and glycan databases, but
also to develop novel diagnostic tools to identify and monitor disease. Here, our primary
focus is sepsis and the subsequent development of ARDS. In ARDS neutrophils migrate into the
alveoli of the lungs and degranulate in order to kill off bacteria. However, in the process
lung tissue is injured and the inflammatory process causing severe hypoxemia and life
threatening respiratory failure is fueled-on. As the glycome and glycoproteome seems to play
a role in discriminating between harmful bacteria and endogenous structures it is of
importance to clarify if there is any possible interactions that could be made to control
this part of the destructive inflammation.
