KIRS-study: expression of inhibitory receptors on polymorphonuclear neutrophils during sepsis in children

Sepsis is a potentially life threatening systemic inflammatory reaction of the
body to an infection. The immune system engages in an extreme inflammatory
cascade in an attempt to eradicate the infection. However, most of the
pathology associated with sepsis is not caused by the pathogen, but by the
extreme intensity of the immune response. Despite the development of
international treatment guidelines, sepsis is a leading cause of death
worldwide in both children and adults. Unfortunately, recent attempts at
finding a new therapeutic target for sepsis have thus far failed. To find a
proper treatment, the balance between clearing the infection without damaging
the body*s own cells must be restored.
Paediatric sepsis is not the same as adult sepsis, children have different
comorbidities and their bodies respond to sepsis in a completely different way.
There are significant differences in the immune response, especially
inflammation plays a larger role in sepsis pathophysiology in children than in
adults. This indicates that especially children suffering from sepsis could
profit from attenuating the immune system.
Inhibitory receptors function as downregulators of the immune response.
Identifying the specific inhibitory receptors that are expressed during sepsis
could be the first step towards a new therapeutic target. Signal Inhibitory
Receptor on Leukocytes-1 (SIRL-1) and Leukocyte-associated immunoglobulin-like
receptor 1 (LAIR-1) are tyrosine-based inhibitory motif (ITIM)-bearing immune
receptors expressed on human monocytes and neutrophils. Neutrophils play a
central role in sepsis pathology. Therefore, modulating the immune response of
neutrophils by means of inhibitory receptors could decrease sepsis related
morbidity and mortality.
We hypothesize that a decreased expression of inhibitory receptors plays a
central role in the pathophysiology of disproportional inflammation as seen in
sepsis. This is a relevant hypothesis, as immune inhibitory receptors could be
a potential new therapeutic target.

Primary Objective: To compare the expression of inhibitory receptors SIRL-1 and
LAIR-1 on blood neutrophils of patients under age 12 admitted with sepsis to
the paediatric intensive care with healthy controls and intensive care patients
without sepsis.

Secondary Objective: To determine the relationship between inhibitory receptor
expression and sepsis disease severity during the course of disease in children
under age 12.

This will be a single-centre observational study. Inclusion will be performed
from 01-08-2013 until 01-07-2017. Patients under age 12 admitted to the
intensive care department of the Wilhelmina Children*s Hospital (Wilhelmina
Kinderziekenhuis) in Utrecht, diagnosed with severe paediatric sepsis or
paediatric septic shock, may be included. Control groups will consist of
patients under age 12 admitted to the ICU for non-infectious pathology and
patients under age 12 that will undergo elective heart catheterisation (healthy
controls).
After informed consent has been obtained, a blood sample will be collected as
soon as possible. If possible, this will be combined with a regular diagnostic
blood draw or taken from a central venous or arterial line. Additional blood
samples will be obtained after approximately six hours, one day, two days, and
three days. However, these subsequent blood samples will only be taken when
blood is already being drawn for diagnostic or monitoring purposes, or if the
patient has a central venous or arterial line.
Disease severity will be monitored according to the PRISM-III score, PELOD-2
score and Inotropic score. Physiologic variables, age, and biochemical findings
of each patient that are necessary to calculate the disease severity scores are
part of normal care for sepsis patients and will be extracted from medical
records or requested from the attending physician.

A maximum of one blood sample will be taken separately from diagnostic
procedures (if possible this sample will also be combined with a diagnostic
blood draw). Any additional samples will only be taken as part of the normal
diagnostic process upon which an additional 0.5 mL of blood will be extracted.
Alternatively, these samples will be drawn from a central arterial or venous
catheter when the patient has one. Drawing venous blood by venepuncture is
moderately painful. The amount of blood was carefully determined according to
WHO guidelines and the patient will be monitored to keep risk to a minimum. Due
to the type of study, observational, with no additional invasive procedures on
top of routine diagnostics, no study related adverse events, serious adverse
events, or suspected unexpected serious adverse reactions are to be expected.