Immune mechanisms during preterm sepsis

Every year, more than fifteen million newborns are born preterm worldwide.
Preterm newborns, defined as a gestational age below 37 weeks, have an immature
immune system and are highly susceptible to life-threatening infections and
sepsis. In the Netherlands, approximately 10% of mortality in newborns is due
to sepsis despite treatment with intravenous antibiotics. Newborn mainly depend
on the innate immune cells such as monocytes and granulocytes to fight
bacterial infections. However, it is largely unknown how the innate immune
system of preterm newborns responds to bacterial infections. In vitro research
with whole blood from preterm newborns can be used to investigate early life
preterm immune responses against bacteria. A better understanding of the immune
response to bacteria in preterm newborns will create more insights into the
susceptibility of preterm neonates to severe infections and may lead to novel
adjuvant therapy such as immunomodulatory therapy to balance the immune
response elicited during infections.

The quality and quantity of the innate immune response to bacteria should be
tightly regulated leading to resolution of infection while minimizing damage to
host tissue. We hypothesize that this regulation depends on gestational age at
delivery and postnatal age. The main objective of this study is to characterize
the functionality of the innate immune system of preterm newborns in the
context of bacterial infections at birth and in the first 10 weeks of life.

The study will be a prospective, observational study. Newborns born by vaginal
delivery and caesarean section will be included. Blood will be collected from
preterm and term newborns in the first 10 weeks of life. Per individual, blood
will be collected on multiple time points after birth to investigate the
development of the immune system per individual. The maximum frequency of
sampling per individual will be once a week for a maximum of 8-10 weeks. Our
study will not lead to additional venous or arterial punctures. Prematurity is
defined as deliveries ranging from 24 to 37 weeks of gestational age. Blood
from term newborns will be included as a control group. Term newborns are
defined as newborn born after 37 weeks of gestational age. To characterize
innate immune response to bacteria, we will measure inflammatory parameters in
plasma and we will perform multiple immune-assays after in vitro exposure of
blood to bacteria and synthetic bacterial stimuli. Because we are currently
already performing similar experiments with umbilical cord blood, we will be
able to compare the in vitro immune response after birth with the immune
response of the umbilical cord.

The use of blood from preterm and term newborns can have a substantial burden
and risk with participation. Key recommendations from the WHO that describe
acceptable blood draws from newborns will be followed (see Ethical Section
below). Blood will only be taken if a venous or arterial puncture is performed
for medical reasons (e.g. blood culture) or when an arterial catheter is in
situ. Our study will not lead to a direct benefit of the patient. However, a
better understanding of the immune response during bacterial infection in
preterm newborns may lead to earlier recognition of severe infections, more
effective treatment options and, thereby, a better outcome for the same patient
group in the future. This study cannot be performed in a different group of
patients, because the main objective is to study immune responses in this
specific group that is vulnerable for severe bacterial infections.