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REAnimation Low Immune Status Markers (REALISM)

Primary Purpose

Septic Shock, Severe Trauma, Severe Burn

Status
Completed
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Blood sampling
Sponsored by
Hospices Civils de Lyon
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Septic Shock focused on measuring Septic shock, severe trauma, severe burn, major surgery, immunosuppression, Healthcare-Associated Infections

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion criteria for patients

  • Patient or next of kin having been informed of the conditions of the study and having signed the informed consent form

  • Patient hospitalized for :

    • Septic shock
    • Severe trauma (including severe burn)
    • Major surgery

Inclusion criteria for healthy volunteers

  • Normal clinical examination
  • Signed informed consent form
  • Person with social security insurance

Exclusion criteria for patients

  • Patient with severe neutropenia (neutrophil count <0.5 g/l)
  • Patients receiving immunosuppressive therapy
  • Patients receiving corticosteroids (IV or Per os)
  • Use of therapeutic antibodies
  • Hematological disease under treatment, or treated within 5 years before inclusion
  • End of chemotherapy within the 6 months prior to inclusion
  • Patient with innate or acquired immune deficiency (for example severe combined immunodeficiency, HIV or AIDS, any stage)
  • Patients for whom a care limitation was pronounced at time of enrolment
  • Anticipated length of stay before discharge from the ICU is estimated at less than 48 hours
  • Participation in an intervention study
  • Extra-corporeal circulation in the month preceding inclusion in case of cardiac surgery
  • Pregnant or breastfeeding women
  • Patient with no social security insurance, with restricted liberty or under legal protection

Exclusion criteria for healthy volunteers

  • Person with an infectious syndrome during the last 90 days
  • Extreme physical stress within the last week

  • Person having received within the last 90 days, a treatment based on

    • Antivirals
    • Antibiotics
    • Antiparasitics
    • Antifungics
  • Person having received within the last 15 days, a treatment based on non-steroidal anti-inflammatory drugs (NSAIDs)

  • Person having received within the last 24 months, a treatment based on

    • Immunosuppressive therapy
    • Corticosteroids (IV or Per os)
    • Therapeutic antibodies
    • Chemotherapy

  • History of :

    • innate or acquired immune deficiency
    • Hematological disease
    • Solid tumor
    • Severe chronic disease
    • Surgery or hospitalization within the last 2 years
    • Pregnancy within the last year
  • Participation to a phase I clinical assay during the last year
  • Pregnant or breastfeeding women
  • Person with restricted liberty or under legal protection

Sites / Locations

  • Service d'Anesthésie Réanimation - Hôpital Edouard Herriot

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Blood sampling

Arm Description

Blood sampling will be performed in all patients and healthy volunteers

Outcomes

Primary Outcome Measures

Percentage of patients meeting the definition of of injury-induced-immunosuppression
The immunosuppression status will be determined from two immunological reference tests: (1) lymphocyte proliferation in response to ex vivo T cell stimulation (adaptive immunity) (Poujol et al., 2014) and (2) the production of tumor necrosis factor (TNF) by monocytes in response to ex vivo stimulation by lipopolysaccharide (LPS) (innate immunity) (Duffy et al., 2014). The values measured will be defined as normal or abnormal, depending on whether they are within reference intervals (RI) derived from an independent set of healthy volunteers. For this purpose, the definition of immunosuppression will be: an abnormal result in at least one of the two "reference" tests (outside the reference intervals defining normal values), and on at least two consecutive samples. The same reference test must be abnormal in two successive samples examined for the patient to be considered immunosuppressed.

Secondary Outcome Measures

Proportion of patients with a deficiency of the innate or adaptive immunity
Intensity of the innate immune deficiency will be measured using the production of TNF by monocytes in response to ex vivo stimulation by LPS (Duffy et al., 2014). Intensity of the adaptive immune deficiency will be measured using the lymphocyte proliferation in response to ex vivo T cell stimulation (Poujol et al., 2014). The values measured will be defined as normal or abnormal, depending on whether they are within reference intervals derived from an independent set of healthy volunteers. We will describe for all groups of patients: The proportion of patients with a deficiency of the innate immunity, defined by an abnormal TNF secretion test result after LPS stimulation, for at least two consecutive samples. The proportion of patients with a deficiency of the adaptive immunity, defined by an abnormal lymphocyte proliferation, for at least two consecutive samples. The proportion of patients with at least one abnormal test on Days 1, 3-4, 5-7, 13/18, 26/36 and 52/68
Comparison of performance of the reference tests and new biomarkers for the diagnosis of immunosuppression
Reference tests being non-standardized and cumbersome to implement, and time to results being incompatible with clinical practice, the use of simpler and quicker tests, based on the use of new biomarkers, would allow the individualization of patient management based on the patient's immune status. One of the secondary objectives is to evaluate the performance of new biomarkers compared to the two reference tests to diagnose immunosuppression. Different types of markers and tests will be evaluated: Viral reactivation markers, host-response markers, immune functional assays, immunophenotyping.
Correlation between the immunosuppression status and the incidence of healthcare-associated infections
To evaluate the association between the immunosuppression status as defined in primary objective and the occurrence of secondary infections related to healthcare, the association of the immunosuppression status upon the occurrence of secondary infection will be examined first, and secondly any possible association between the levels of each of the reference tests and the occurrence of secondary infections will be characterized. In this analysis, a secondary infection related to healthcare will be defined as an infection occurring after inclusion in the study, between inclusion and day 28.
Correlation between immunosuppression and mortality
We will examine the association between immunosuppression (as defined in the primary objective) and in-hospital mortality. Association will be evaluated par measuring occurrence of mortality at days 14, 28, 60 and 90, in the different groups.
Comparison of immune status before and after surgery in the population of surgical patients
The possibility of taking a sample before surgical stress should allow measurements of the impact of the procedure on the host response, and especially on any subsequent onset of immunosuppression. Oncological pathologies and treatments implemented prior to surgery may also be associated with immunosuppression, and for this reason patients hospitalized for cancer surgery will be compared to those hospitalized for vascular surgery. Impact of surgery on immunosuppression will be measured by comparing immune status as defined by the reference tests, in the population of surgical patients before and after surgery.

Full Information

First Posted
December 18, 2015
Last Updated
September 14, 2018
Sponsor
Hospices Civils de Lyon
Collaborators
Bioaster, BioMérieux, Sanofi
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1. Study Identification

Unique Protocol Identification Number
NCT02638779
Brief Title
REAnimation Low Immune Status Markers
Acronym
REALISM
Official Title
REAnimation Low Immune Status Markers
Study Type
Interventional

2. Study Status

Record Verification Date
September 2018
Overall Recruitment Status
Completed
Study Start Date
December 11, 2015 (Actual)
Primary Completion Date
June 27, 2018 (Actual)
Study Completion Date
June 27, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hospices Civils de Lyon
Collaborators
Bioaster, BioMérieux, Sanofi

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The fact that sepsis disrupts immune system homeostasis by inducing an initial cytokine storm, that participates to occurrence of organ failures and early death, followed by a compensatory anti-inflammatory response leading to immunosuppression, is now well established. This immunomodulating response results in a higher risk of secondary infections and is associated to 2/3 of deaths related to septic shocks. Follow up of patients' immune status with time is crucial to guide therapy management. Objective of REALISM project is to demonstrate existence of this immunosuppression phase, by providing strong epidemiologic data for septic shock patients, but also by extension to other situations of inflammatory aggressions like severe severe trauma or burns, or major surgery. This project will provide tools to predict occurrence of secondary infections and guide patient management by comparing innovating immunomonitoring tools to reference tests non already adapted to a routine patient management. Targeted populations are adult patients hospitalized for septic shock, severe trauma (including severe burn) or major surgery and healthy volunteers, whom blood samples will serve to validate reference intervals of the two reference tests.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Septic Shock, Severe Trauma, Severe Burn, Major Surgery
Keywords
Septic shock, severe trauma, severe burn, major surgery, immunosuppression, Healthcare-Associated Infections

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
552 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Blood sampling
Arm Type
Experimental
Arm Description
Blood sampling will be performed in all patients and healthy volunteers
Intervention Type
Biological
Intervention Name(s)
Blood sampling
Intervention Description
Specific Blood sampling will be performed in patients and healthy volunteers
Primary Outcome Measure Information:
Title
Percentage of patients meeting the definition of of injury-induced-immunosuppression
Description
The immunosuppression status will be determined from two immunological reference tests: (1) lymphocyte proliferation in response to ex vivo T cell stimulation (adaptive immunity) (Poujol et al., 2014) and (2) the production of tumor necrosis factor (TNF) by monocytes in response to ex vivo stimulation by lipopolysaccharide (LPS) (innate immunity) (Duffy et al., 2014). The values measured will be defined as normal or abnormal, depending on whether they are within reference intervals (RI) derived from an independent set of healthy volunteers. For this purpose, the definition of immunosuppression will be: an abnormal result in at least one of the two "reference" tests (outside the reference intervals defining normal values), and on at least two consecutive samples. The same reference test must be abnormal in two successive samples examined for the patient to be considered immunosuppressed.
Time Frame
Up to 2 months after injury
Secondary Outcome Measure Information:
Title
Proportion of patients with a deficiency of the innate or adaptive immunity
Description
Intensity of the innate immune deficiency will be measured using the production of TNF by monocytes in response to ex vivo stimulation by LPS (Duffy et al., 2014). Intensity of the adaptive immune deficiency will be measured using the lymphocyte proliferation in response to ex vivo T cell stimulation (Poujol et al., 2014). The values measured will be defined as normal or abnormal, depending on whether they are within reference intervals derived from an independent set of healthy volunteers. We will describe for all groups of patients: The proportion of patients with a deficiency of the innate immunity, defined by an abnormal TNF secretion test result after LPS stimulation, for at least two consecutive samples. The proportion of patients with a deficiency of the adaptive immunity, defined by an abnormal lymphocyte proliferation, for at least two consecutive samples. The proportion of patients with at least one abnormal test on Days 1, 3-4, 5-7, 13/18, 26/36 and 52/68
Time Frame
Up to 2 months after injury
Title
Comparison of performance of the reference tests and new biomarkers for the diagnosis of immunosuppression
Description
Reference tests being non-standardized and cumbersome to implement, and time to results being incompatible with clinical practice, the use of simpler and quicker tests, based on the use of new biomarkers, would allow the individualization of patient management based on the patient's immune status. One of the secondary objectives is to evaluate the performance of new biomarkers compared to the two reference tests to diagnose immunosuppression. Different types of markers and tests will be evaluated: Viral reactivation markers, host-response markers, immune functional assays, immunophenotyping.
Time Frame
Up to one week after injury
Title
Correlation between the immunosuppression status and the incidence of healthcare-associated infections
Description
To evaluate the association between the immunosuppression status as defined in primary objective and the occurrence of secondary infections related to healthcare, the association of the immunosuppression status upon the occurrence of secondary infection will be examined first, and secondly any possible association between the levels of each of the reference tests and the occurrence of secondary infections will be characterized. In this analysis, a secondary infection related to healthcare will be defined as an infection occurring after inclusion in the study, between inclusion and day 28.
Time Frame
Up to 28 days after injury
Title
Correlation between immunosuppression and mortality
Description
We will examine the association between immunosuppression (as defined in the primary objective) and in-hospital mortality. Association will be evaluated par measuring occurrence of mortality at days 14, 28, 60 and 90, in the different groups.
Time Frame
Up to 90 days after injury
Title
Comparison of immune status before and after surgery in the population of surgical patients
Description
The possibility of taking a sample before surgical stress should allow measurements of the impact of the procedure on the host response, and especially on any subsequent onset of immunosuppression. Oncological pathologies and treatments implemented prior to surgery may also be associated with immunosuppression, and for this reason patients hospitalized for cancer surgery will be compared to those hospitalized for vascular surgery. Impact of surgery on immunosuppression will be measured by comparing immune status as defined by the reference tests, in the population of surgical patients before and after surgery.
Time Frame
Up to 2 months after surgery

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion criteria for patients Patient or next of kin having been informed of the conditions of the study and having signed the informed consent form Patient hospitalized for : Septic shock Severe trauma (including severe burn) Major surgery Inclusion criteria for healthy volunteers Normal clinical examination Signed informed consent form Person with social security insurance Exclusion criteria for patients Patient with severe neutropenia (neutrophil count <0.5 g/l) Patients receiving immunosuppressive therapy Patients receiving corticosteroids (IV or Per os) Use of therapeutic antibodies Hematological disease under treatment, or treated within 5 years before inclusion End of chemotherapy within the 6 months prior to inclusion Patient with innate or acquired immune deficiency (for example severe combined immunodeficiency, HIV or AIDS, any stage) Patients for whom a care limitation was pronounced at time of enrolment Anticipated length of stay before discharge from the ICU is estimated at less than 48 hours Participation in an intervention study Extra-corporeal circulation in the month preceding inclusion in case of cardiac surgery Pregnant or breastfeeding women Patient with no social security insurance, with restricted liberty or under legal protection Exclusion criteria for healthy volunteers Person with an infectious syndrome during the last 90 days Extreme physical stress within the last week Person having received within the last 90 days, a treatment based on Antivirals Antibiotics Antiparasitics Antifungics Person having received within the last 15 days, a treatment based on non-steroidal anti-inflammatory drugs (NSAIDs) Person having received within the last 24 months, a treatment based on Immunosuppressive therapy Corticosteroids (IV or Per os) Therapeutic antibodies Chemotherapy History of : innate or acquired immune deficiency Hematological disease Solid tumor Severe chronic disease Surgery or hospitalization within the last 2 years Pregnancy within the last year Participation to a phase I clinical assay during the last year Pregnant or breastfeeding women Person with restricted liberty or under legal protection
Facility Information:
Facility Name
Service d'Anesthésie Réanimation - Hôpital Edouard Herriot
City
LYON cedex 03
ZIP/Postal Code
69437
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34912347
Citation
Bodinier M, Peronnet E, Brengel-Pesce K, Conti F, Rimmele T, Textoris J, Vedrine C, Quemeneur L, Griffiths AD, Tan LK, Venet F, Maucort-Boulch D, Monneret G; REALISM study group. Monocyte Trajectories Endotypes Are Associated With Worsening in Septic Patients. Front Immunol. 2021 Nov 29;12:795052. doi: 10.3389/fimmu.2021.795052. eCollection 2021.
Results Reference
derived
PubMed Identifier
34795661
Citation
Mallet F, Diouf L, Meunier B, Perret M, Reynier F, Leissner P, Quemeneur L, Griffiths AD, Moucadel V, Pachot A, Venet F, Monneret G, Lepape A, Rimmele T, Tan LK, Brengel-Pesce K, Textoris J. Herpes DNAemia and TTV Viraemia in Intensive Care Unit Critically Ill Patients: A Single-Centre Prospective Longitudinal Study. Front Immunol. 2021 Nov 2;12:698808. doi: 10.3389/fimmu.2021.698808. eCollection 2021.
Results Reference
derived
PubMed Identifier
34534131
Citation
Venet F, Textoris J, Blein S, Rol ML, Bodinier M, Canard B, Cortez P, Meunier B, Tan LK, Tipple C, Quemeneur L, Reynier F, Leissner P, Vedrine C, Bouffard Y, Delwarde B, Martin O, Girardot T, Truc C, Griffiths AD, Moucadel V, Pachot A, Monneret G, Rimmele T; REALISM study group. Immune Profiling Demonstrates a Common Immune Signature of Delayed Acquired Immunodeficiency in Patients With Various Etiologies of Severe Injury. Crit Care Med. 2022 Apr 1;50(4):565-575. doi: 10.1097/CCM.0000000000005270.
Results Reference
derived
PubMed Identifier
28637738
Citation
Rol ML, Venet F, Rimmele T, Moucadel V, Cortez P, Quemeneur L, Gardiner D, Griffiths A, Pachot A, Textoris J, Monneret G; REALISM study group. The REAnimation Low Immune Status Markers (REALISM) project: a protocol for broad characterisation and follow-up of injury-induced immunosuppression in intensive care unit (ICU) critically ill patients. BMJ Open. 2017 Jun 21;7(6):e015734. doi: 10.1136/bmjopen-2016-015734.
Results Reference
derived

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REAnimation Low Immune Status Markers

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