The Intensive Care Infection Score to predict microbial infection and its sequelae in critically ill lung and heart transplant patients.

Microbial infection in the ICU may lead to sepsis and other harmful sequelae.
Fear of under treatment contributes to ordering tests and prescribing
antibiotics, before results of cultures become available, while overtreatment
carries the risk of bacterial selection and overgrowth by induction of
resistance. Infectious complications remain on of the most important causes of
morbidity and mortality in lung and heart transplant patients. There are
numerous reasons why those patients have a heightened predisposition to
infection. One of those reasons is the usage of immunosuppressive medication to
prevent graft dysfunction. The immunosuppressive medication interferes with the
immune system giving a higher risk for developing infections. The systemic
inflammatory response syndrome (SIRS) criteria, including elevated white blood
cell counts (WBC) may not accurately predict microbial infection and the common
use of C-reactive protein (CRP) to predict infection, severity and outcome in
critically ill patients is controversial. Therefore reliable verification of a
systemic microbial infection is still the most challenging issue.

The host response to a microbial infection invariably starts with the
activation of the innate immune system. Consequently, it is reasonable to focus
on cell specific haematological information and methods aimed at detecting an
early response to systemic infection. Among activated innate immune cells in
the fist line of pathogen defense, polymorphonuclear neutrophils (PMN) form
50-60% of all circulating leukocytes. Once at the site of infection,
neutrophils release a variety of toxic products to kill and clear invading
pathogens by the process of phagocytosis, degranulation and generation of
reactive oxygen metabolites. Such immune reactions are easy to viualize
morphologically and are therefore measurable. When activated, neutrophils
produce and secrete macrophage inflammatory protein 1 (MIP-1) and other pro-
inflammatory cytokines resulting in recruitment, differentiation and activation
of antigen-presenting cells such as monocytes/ macrophages. Besides various
cytokines, soluble bacterial molecules and whole bacteria are well known
stimuli for receptors at the surface of macrophages. Once bacteria are
incorporated by phagocytosis, monocytes and macrophages unleash stored
bactericidal agents and lysosomal enzymes to eliminate pathogens. Monocytes and
macrophages are involved in inflammation induced anemia due to retention of
iron, resulting in an immediate decrease in haemoglobin synthesis and content
in reticulocytes. The difference in haemoglobin content between immature
erythrocytes (formed after the onset of infection) and the mature erythrocytes
(which were produced earlier) can therefore be used as an indirect early
indicator for monocyte/ macrophage activation.
Plasma cells or lymphoplasmocytoid cells are also involved in the first line
pathogen defense. Such antibody secreting lymphocytes (ASL) are not detectable
in the peripheral blood of healthy individuals. Thus the presence of
circulating ASL in a patient indicates an acute phase response to infection.
In addition to the activation of circulating immune cells, the bone marrow
responds to systemic infection by releasing immature granulocytes into the
peripheral blood. An increased immature/ total granulocyte ratio (i.e. a left
shift in granulopoiesis) has been found to be related to bacteremia.
Because of the complexity of the pathophysiology of systemic inflammation and
sepsis it a single parameter will have sufficient diagnostic accuracy for
sepsis. Therefore, a combination of parameters constitutes a diagnostic score,
the Intensive Care Infection Score (ICIS). This seems to be a more promising
method of predicting microbial infection in the ICU. The activation parameters
investigated consist of: a) fluorescence intensity of segmented neutrophils, b)
fluorescence intensity of antibody secreting cells and c) haemoglobin
concentration of newly formed red blood cells. In addition, two rapidly
detectable bone marrow response: d) total mature neutrophil count and e) total
immature granulocyte count. To generate the best sensitivity and specificity to
predict microbial infection we will develop the ICIS score, which consist of
above mentioned parameters, by using a score of 1 above the cut- off value for
the best AUC, a score of 2 above the cut- off value with specificity above 85%,
and a score of 4 above the cut off value with specificity above 95%. By adding
all weighting values for all five parameter components the maximum possible
ICIS score is.
Because immune suppression interferes with the natural host responses;
inhibiting T-cell activation, T-cell mediated B-cell activation, T-cell and
B-cell proliferation. It is not unreasonable to hypothesize interference with
the ICIS score in predicting infection in this specific patient population.
Assessing the influence of immunosuppressive therapy on the ICIS is essential
to take steps to implement this clinical score in the treatment of this
vulnerable patient population.

The aim of this study is to evaluate the predictive value of a blood cell
derived score, ICIS, for microbial infection, its likelihood, its invasiveness
(blood stream infection) and severity (septic shock or mortality) in patients
after lung or heart transplantation.

All patient who will undergo lung or heart transplantation can be included in
the ICIS study. When a transplant has become available and is HLA suitable for
the receiver, the patient will be admitted into the hospital for the last
routine checks prior to the transplantation. From this moment the patient can
be included into the ICIS study, this day will be defined as day 0. At day 0
extra blood will be drawn from the patient (1 K3EDTA aliquots of 4.5 ml) in
order to obtain the ICIS measurement.
The patient will be observed for a seven- day period after transplantation. The
second measurement will be performed directly postoperative; this will be
referred as day 1. In the next six days blood will be taken at 6 am in the
morning when other routine blood laboratory measurements will be taken from the
patient. Eight aliquots will be taken in total without the need for an extra
venepuncture. At day 0 the ICIS measurements will be taken when other routine
blood measurements are drawn from the patient. From day 1 until the end of the
follow up period, blood will be taken from an arterial catheter that is
routinely placed during the transplantation. An observational period of 28 days
will be used to establish each patient*s discharge from the ICU or death
(within ICU or hospital). In this period clinical and laboratory data obtained
in the routine management of these patients will be collected. The results of
the measured parameters will not be documented in the patient*s clinical
records.
Patients of both sex and older than 18 years old who will undergo lung or heart
transplantation are possibly eligible for this trial. Patients will be included
into this trial after they have given informed consent. Patients will be
excluded if they have neutropenia, defined as leukocyte count less then
0.5x109/L.

Blood will be drawn several times from an arterial cathether which is routinely
placed in this category of patients.