Apheresis based treatment of sepsis

The presence of pathogens in the bloodstream can cause the onset of sepsis or
septic shock. It is thought that release of endotoxins from circulating
bacteria contributes to a hyperinflammatory response. One of the mechanisms to
protect the host from blood-borne infections is immune adherence clearance
(IAC), the process by which complement opsonized pathogens are bound by red
blood cells (RBCs) and transported to the liver and spleen where they are
engulfed by macrophages. Recently, we found that during sepsis a large number
of RBC-pathogen complexes, as a consequence of IAC, can be detected in the
patients* blood. The percentage of RBC-pathogen complexes was found to be as
high as 1-2% of the total number of circulating RBCs, which corresponds to a
pathogen load of 10-20.106/ml blood. Studying the mechanisms of pathogen
transfer from RBC to macrophages in vitro, we discovered that RBC that carry
pathogens adopt a particular phenotype. This phenotype facilitates the binding
of the RBC-pathogen complex to macrophages. Next, we were able to develop a
method that specifically captures RBC-pathogen complexes in peripheral blood
through an apheresis procedure, by capturing the RBC-pathogen complexes with a
specific filter in an apheresis setup. With this method the depletion of
RBC-pathogen complexes from the blood that is subjected to this procedure is
typically *95%, independent of the pathogen that the RBCs are carrying. We
expect to be able to use this method to deplete the number of circulating
RBC-pathogen complexes in vivo to >70% by processing the blood volume of the
patient 1,5 times by the apheresis machine. Thereby, we have potentially
identified a new generic treatment for sepsis. In this clinical trial, which
consists of two phases, we will investigate the efficacy of our apheresis setup
to deplete RBC-pathogen complexes. In the first phase, we will test the safety
of our setup on three healthy volunteers, to establish that there are no
effects on the quality of plasma and blood cell types including RBCs, platelets
and leukocytes and to ensure that our procedure is absolutely safe. If safe,
during the second phase we will treat ten septic patients with a one time
apheresis procedure, to determine whether the procedure is able to effectively
reduce the number of circulating RBC-pathogen complexes.

To determine the efficacy of a filter-based depletion of RBC-pathogen complexes
by a single apheresis tretatment in patients with sepsis.

The study consists of two phases, the first phase is a small safety study on
healthy volunteers, the second phase is a prospective, single center safety
trial on 10 sepsis patients.

At the start of apheresis, the patient may have a (transient) limited decrease
in blood pressure. Given that the extracorporeal blood volume is limited and
that patients in severe shock are excluded, we expect that the risk of a
transient lower blood pressure is negligible. Thereby, it is anticipated that
there are no burden or risks associated with participation except for the known
well described small risks associated with an apheresis procedure, especially
hypocalcaemic symptoms due to citrate infusion with the re-infusion of all
blood components. Patients with hepatic or renal insufficiency may be at
increased risk of citrate toxicity due to impaired metabolism of citrate.
Therefore, as part of standard care, ionized calcium levels of all patients
will be measured regularly and prophylactic calcium will be administered. Since
this is a new apheresis-based procedure the procedure will first be performed
on three healthy volunteers. The outcome of this first part of the trial will
first be communicated with the METC before starting the second part, involving
the septic patients. By following this schedule, we minimize any potential
risks associated with this procedure.