Pneumonia Clinical Trial
Official title:
The Effect of Leukocyte Dna mEthylation and micRoBIOME Diversity on Host Defense Mechanisms During Community-acquired Pneumonia
Community-acquired pneumonia (CAP) represents a major health care problem and mortality and
morbidity associated with severe pneumonia remain considerable, despite state of the art
care.
While the role of altered DNA methylation in cancer has been widely studied, knowledge of its
impact on antibacterial defense is highly limited. In addition, recent preclinical studies
showed that the gut and respiratory microbiota contributes to host defense against bacterial
pneumonia.
This study aims to explore a completely novel research area linking the extent of DNA
methylation in blood leukocyte (monocytes and neutrophils) and function of gut and
respiratory microbiota on the influence of innate immune responses to and host defense
against CAP
Rationale:
Community-acquired pneumonia (CAP) represents a major health care problem and mortality and
morbidity associated with severe pneumonia remain considerable, despite state of the art
care.
While the role of altered DNA methylation in cancer has been widely studied, knowledge of its
impact on antibacterial defense is highly limited. In addition, recent preclinical studies
showed that the gut and respiratory microbiota contributes to host defense against bacterial
pneumonia.
This study aims to explore a completely novel research area linking the extent of DNA
methylation in blood leukocyte (monocytes and neutrophils) and function of gut and
respiratory microbiota on the influence of innate immune responses to and host defense
against CAP.
Primary Objectives:
1. To obtain insight in the role of altered DNA methylation in blood leukocytes (monocytes
and neutrophils) in innate immune responses and host defense in patients with CAP.
2. To determine the composition and function of the gut and respiratory microbiota in
patients with CAP.
Secondary Objective:
1. To assess the influence of the gut microbiota on leukocyte DNA methylation in patients
with CAP
Study design:
Observational study among patients with CAP at the Emergency Department and Internal Medicine
Ward of the Academic Medical Center Amsterdam
Study population:
231 CAP patients and 115 healthy subjects above 18 years of age.
Methods:
From above mentioned patients and healthy volunteers, a maximum of 90 ml of blood will be
drawn to analyze DNA methylation patterns of purified monocytes and neutrophils, which will
be analyzed in connection with DNA methyltransferase and ten eleven translocation (TET)
activity, RNA gene expression and a selection of standard innate immune function tests.
Moreover, isolated monocytes and neutrophils from admission samples will be stimulated in
vitro with Streptococcus pneumoniae and Klebsiella pneumoniae. In addition, rectal and
nasopharyngeal swabs will be obtained to investigate the role of the gut and respiratory
microbiota composition and function. Patient material will be obtained upon inclusion and on
day 28, when patients will be seen in the outpatient clinic for follow up.
Nature and extent of the burden and risks associated with participation, benefit and group
relatedness:
Participating in this observational study will not benefit the participants and healthy
volunteers. The study will provide information about the influence of leukocyte DNA
methylation as well as the gut and respiratory microbiota on host defense mechanisms during
CAP. The knowledge obtained can potentially benefit CAP patients in the future by providing
alternative immune modulating treatment options that modify the host response. The burden and
risks for patients participating in the ELDER-BIOME study is minimal. The investigators will
take 90ml of blood, 4 rectal swabs and 2 nasopharyngeal swabs divided over two time-points
(day of presentation and day 28 post presentation). Healthy volunteers will be subjected to
one blood draw (70 ml) and 2 rectal - and 2 nasopharyngeal swabs at one time-point.
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