Immune paralysis in trauma patients: an explorative study

Despite numerous efforts to improve trauma care and traffic safety, trauma
still remains one of the major causes of death in people under the age of 50 in
the Western world. Patients die either shortly after trauma due to sustained
injuries, or after several days/weeks, often due to post-injury immunological
complications caused by a dysfunctional immune system, called immune paralysis,
such as sepsis and multi organ failure (MOF).Immune paralysis is a condition
frequently observed after trauma. This condition is characterized by
unresponsiveness of the immune system to pathogens. It has been suggested that
immune paralysis is caused by a pronounced compensatory reaction to activation
of the immune system shortly after trauma. Another hypothesis involves the
exhaustion of the immune system by the initial hit.
A number of clinical trials with immunomodulatory interventions have been
performed in an attempt to prevent immune paralysis in trauma patients.
However, no definite conclusions can be drawn from these studies. In order to
identify targets for preventive and/or therapeutic treatments, additional
knowledge on the factors involved in pathogenesis of immune paralysis is
necessary. Moreover, it is crucial to map the time-course of the immune
response to the initial trauma and state of the innate immune system after
trauma, to identify immunoparalyzed patients eligible for tailor-made
immunomodulatory treatment.
The immune system is activated by binding of pathogen associated molecular
patterns (PAMPs) to pattern recognition receptors (PRRs). As such, pathogens
can be recognized via this route, but PRRs also bind so-called danger
associated molecular patterns (DAMPs). DAMPs are factors that are released by
damaged or stressed cells. In case of trauma, extensive tissue damage leads to
the release of large amounts of DAMPs. Therefore, it appears plausible that
DAMPs have a major impact on the immune response following trauma.
Recently it was discovered that mitochondrial DNA (mtDNA) represents a DAMP in
trauma patients. Increased concentrations of mtDNA have been reported in trauma
patients. The similarities between mtDNA and bacterial DNA result in the
binding of mtDNA to PRRs recognizing bacterial DNA. Zhang et al recently
described inflammatory responses following injury caused by circulating
mitochondrial DAMPs. These inflammatory responses could ultimately lead to the
development of immuno paralysis.
In this study, we will investigate the levels and effects of DAMPs, with an
initial focus on mtDNA, in trauma patients. A relation between the presence of
mtDNA and the development of immune paralysis could indicate a role for mtDNA
in the pathogenesis of immune paralysis and therefore be a potential
therapeutic target.
Next to the investigation of DAMPs/mtDNA, this study also focuses on
mechanistic factors involved in immune paralysis. It has been suggested that
decreased Human Leukocyte Antigen - DR (HLA-DR) expression on monocytes plays a
role in, or is indicative for the development of immune paralysis. Suppression
of Tumorigenicity 2 (ST-2) is a negative regulator of macrophage function and
is also described to be important in immune paralysis. IL-1R-associated
kinase-M (IRAK-M) is an inhibitor of the innate immune response has been linked
to immune paralysis in septic patients. Analysis of mRNA expression of these
factors and its time-course could provide more insight on the relation between
immune paralysis and the expression of HLA-DR, IRAK-M, ST-2 and other potential
markers.
In conclusion, the aim of this observational study is to determine the relation
between factors released after trauma, e.g. mtDNA, and the development of
immune paralysis, the time-course of the inflammatory response to injury and
state of the immune system following trauma, and the underlying cellular
mechanisms of immuno paralysis. This could result in the identification of
predictive markers, potential therapeutic targets and a timeframe for
therapeutic intervention.

Identifying the factors and underlying mechanisms involved in the pathogenesis
of immune paralysis in trauma patients. Mapping the time-course of immune
paralysis in trauma patients.

Patients that are 18 years or older and suffered trauma can be included in the
study. Blood will be sampled at time-points:
- MMT (Sampled by MMT helicopter team, if applicable)
- SEH (Sampled at time of admission at the emergency department)
- Day 1 after trauma
- Day 3 after trauma
- Day 5 after trauma
- Day 7 after trauma
- Day 10 after trauma
- Day 14 after trauma
When possible, an existent arterial line or intravenous line will be used to
sample blood. A venapuncture will only be performed when necessary. Informed
consent will be asked if a venapuncture is necessary to obtain blood.

The only intervention in this study is the sampling of blood. No risks are
associated.
The patients in this study have suffered serious injury. In most cases, the
patient will be sedated during the first days after admission to the hospital.
The burden of the study will be neglectable in these patients, because blood
can be drawn from the arterial or venous line so no vena puncture will be
necessary. This research may be considered group-related, since scientific
knowledge on the immunological reactions in trauma patients can only be
obtained by studying this specific group of patients.