Primarily, we aim to identify SNPs and transcripts that are associated with the degree of endotoxin tolerance. To increase the chances of success, the genomic and transcriptomic data obtained in vivo will be integrated with data obtained by a…
ID
Source
Brief title
Condition
- Immune disorders NEC
- Ancillary infectious topics
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Single-nucleotide polymorphisms (SNPs), genome-wide differential mRNA
expression of monocytes obtained before and 4 hours after the first endotoxin
challenge, and plasma cytokine concentration profiles upon the first and second
endotoxin challenge (including but not limited to TNF*, IL-6, IL-8, and IL-10)
to determine extent of endotoxin tolerance (which is expressed as the decrease
in plasma cytokine levels between the first and second endotoxin challenge).
These data will be integrated to determine the SNPs/transcripts that are
predictive of the extent of endotoxin tolerance developed by the subjects.
Secondary outcome
.
Background summary
Sepsis remains the number one cause of death in the ICU and incident rates are
rising. The focus of sepsis research has shifted away from the
hyperinflammatory phase towards the detrimental role of immunosuppression, a
phenomenon known as * sepsis-induced immunoparalysis* . Because to a high level
of heterogeneity and a lack of appropriate biomarkers, a much-warranted
precision medicine approach is not possible. The identification of novel
biomarkers for sepsis-induced immunoparalysis is also hampered by the extreme
heterogeneity of the patient population. Experimental human endotoxemia is a
highly standardized, controlled and reproducible model, which results in the
development of endotoxin tolerance, an immunologic state capturing many
hallmarks of sepsis-induced immunoparalysis. This study aims to identify
genomic and transcriptomics biomarkers of endotoxin tolerance. Ultimately, this
will lead to the identification of novel biomarkers for the early
identification of patients who are prone to develop sepsis-induced
immunoparalysis, and facilitate precision medicine for this highly vulnerable
group.
Study objective
Primarily, we aim to identify SNPs and transcripts that are associated with the
degree of endotoxin tolerance. To increase the chances of success, the genomic
and transcriptomic data obtained in vivo will be integrated with data obtained
by a previously performed in vitro study. Secondary objectives include SNPs and
transcripts associated with the inflammatory response, and epigenomic changes,
metabolites, and proteins associated with the inflammatory response and the
degree of endotoxin tolerance. Furthermore, we will explore the role of gender
and sex hormones in the inflammatory response and endotoxin tolerance, as well
as the relationship between ex vivo and in vivo inflammatory responses.
Study design
An explorative, prospective study in 100 healthy volunteers who will be
challenged with endotoxin twice. The study takes place at the research unit of
the department of Intensive Care Medicine of the Radboud University Medical
Center, Nijmegen.
Intervention
This study aims to identify the genomic and transcriptomic factors linked to
the development of endotoxin tolerance in vivo. To this end, subjects will be
intravenously challenged with endotoxin (1 ng/kg LPS) to evoke a transient
systemic inflammatory response and subsequent development of endotoxin
tolerance, which will be quantified by the response upon the second endotoxin
challenge one week later. During both endotoxin challenges, the subjects will
be hospitalized for 8 hours during which vital parameters are monitored
carefully.
Study burden and risks
This study will yield a comprehensive insight into genomic/transcriptomic
profiles underlying the in vivo inflammatory response in humans, and will
improve our understanding of systemic inflammation, endotoxin tolerance, and
sepsis, and possibly reveal new therapeutic targets to improve sepsis outcome.
Furthermore, a unique cohort will be created, enabling extensive (future)
applications and collaboration opportunities.
The burden consists of filling out several questionnaires (maximum of 45
minutes), 5 visits to the hospital (2x 10 min, 1x 30 min, 2x 8 hours) and the
dis-comfort associated with endotoxemia (transient flu-like symptoms for 3-4
hours). The risks to the subjects in this study is classified as a *negligible
risk* (low risk on minor harms). A subject fee is provided. Our department is
highly experienced, having conducted >30 endotoxemia studies with approximately
670 volunteers over the last 15 years.
Geert Grooteplein 10
Nijmegen 6500HB
NL
Geert Grooteplein 10
Nijmegen 6500HB
NL
Listed location countries
Age
Inclusion criteria
* Written informed consent
* Age *18 and *35 yrs
* Healthy (as confirmed by medical history, physical examination,
electrocardiography, laboratory tests)
Exclusion criteria
* Pregnancy (confirmed by negative result of pregnancy tests prior to both
endotoxin challenges)
* Use of any medication
* Smoking
* History or signs of atopic syndrome (asthma, rhinitis with medication and/or
eczema)
* Known anaphylaxis or hypersensitivity to the non-investigational products or
their excipi-ents.
* History or signs of hematological disease:
* Thrombocytopenia (<150*10^9/ml) or anemia (for males: hemoglobin < 8.0 mmol/L
and for females: hemoglobin < 7.4 mmol/L)
* Abnormalities in leukocyte differential counts
* History, signs or symptoms of cardiovascular disease, in particular:
* Previous spontaneous vagal collapse
* History of atrial or ventricular arrhythmia
* Cardiac conduction abnormalities on the ECG consisting of a 2nd degree
atrioventricular block or a complete left bundle branch block
* Hypertension (defined as RR systolic > 160 or RR diastolic > 90)
* Hypotension (defined as RR systolic < 100 or RR diastolic < 50)
* Renal impairment (defined as plasma creatinine >120 *mol/l)
* Liver enzyme abnormalities (above 2x the upper limit of normal)
* Medical history of any disease associated with immune deficiency
* Signs of infection (CRP > 20 mg/L, WBC > 12x109/L or < 4 x109/L)
* Clinically significant acute illness, including infections, within 1 month of
the first endotoxin challenge
* Previous (participation in a study with) endotoxin (LPS) administration
* Any vaccination within 3 months within of the first endotoxin challenge
* Participation in a drug trial or donation of blood within 3 months prior to
first endotoxin challenge
* Recent hospital admission or surgery with general anesthesia within 3 months
prior to first endotoxin challenge
* Use of recreational drugs within 1 month of the first endotoxin challenge
* Inability to personally provide written informed consent (e.g. for linguistic
or mental rea-sons) and/or take part in the study.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL68166.091.18 |