## Protocol Section
### Identification Module
**NCT ID:** NCT02638779

**Acronym:** REALISM

**Brief Title:** REAnimation Low Immune Status Markers

**Official Title:** REAnimation Low Immune Status Markers

#### Organization Study ID Info
**ID:** 69HCL15_0379
#### Organization
**Class:** OTHER
**Full Name:** Hospices Civils de Lyon
#### Secondary ID Infos
**Domain:** ID-RCB
**ID:** 2015-A01293-46
**Type:** OTHER
### Status Module
#### Completion Date
**Date:** 2018-06-27

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2018-09-17

**Type:** ACTUAL

**Last Update Submit Date:** 2018-09-14

**Overall Status:** COMPLETED

#### Primary Completion Date
**Date:** 2018-06-27

**Type:** ACTUAL

#### Start Date
**Date:** 2015-12-11

**Type:** ACTUAL

**Status Verified Date:** 2018-09

#### Study First Post Date
**Date:** 2015-12-23
**Type:** ESTIMATED
**Study First Submit Date:** 2015-12-18
**Study First Submit QC Date:** 2015-12-18
### Sponsor Collaborators Module

#### Collaborators

**Class:** OTHER

**Name:** Bioaster

**Class:** INDUSTRY

**Name:** BioMérieux

**Class:** INDUSTRY

**Name:** Sanofi

#### Lead Sponsor

**Class:** OTHER

**Name:** Hospices Civils de Lyon

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Oversight Has DMC:** False

### Description Module

**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.

### Conditions Module

**Conditions:**

- Septic Shock

- Severe Trauma

- Severe Burn

- Major Surgery

**Keywords:**

- Septic shock

- severe trauma

- severe burn

- major surgery

- immunosuppression

- Healthcare-Associated Infections

### Design Module

#### Design Info

**Allocation:** NA

**Intervention Model:** SINGLE_GROUP

##### Masking Info

**Masking:** NONE

**Primary Purpose:** DIAGNOSTIC

#### Enrollment Info

**Count:** 552

**Type:** ACTUAL

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Blood sampling will be performed in all patients and healthy volunteers

**Intervention Names:**

- Biological: Blood sampling

**Label:** Blood sampling

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Blood sampling

**Description:** Specific Blood sampling will be performed in patients and healthy volunteers

**Name:** Blood sampling

**Type:** BIOLOGICAL

### Outcomes Module

#### Primary Outcomes

**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.

**Measure:** Percentage of patients meeting the definition of of injury-induced-immunosuppression

**Time Frame:** Up to 2 months after injury

#### Secondary Outcomes

**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

**Measure:** Proportion of patients with a deficiency of the innate or adaptive immunity

**Time Frame:** Up to 2 months after injury

**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.

**Measure:** Comparison of performance of the reference tests and new biomarkers for the diagnosis of immunosuppression

**Time Frame:** Up to one week after injury

**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.

**Measure:** Correlation between the immunosuppression status and the incidence of healthcare-associated infections

**Time Frame:** Up to 28 days after injury

**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.

**Measure:** Correlation between immunosuppression and mortality

**Time Frame:** Up to 90 days after injury

**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.

**Measure:** Comparison of immune status before and after surgery in the population of surgical patients

**Time Frame:** Up to 2 months after surgery

### Eligibility Module

**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

**Healthy Volunteers:** True

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** LYON cedex 03

**Country:** France

**Facility:** Service d'Anesthésie Réanimation - Hôpital Edouard Herriot

**Zip:** 69437

### IPD Sharing Statement Module

**IPD Sharing:** NO

### References Module

#### References

**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.

**PMID:** 34912347

**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.

**PMID:** 34795661

**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. Erratum In: Crit Care Med. 2022 Jun 1;50(6):e618.

**PMID:** 34534131

**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.

**PMID:** 28637738

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000012769

- Term: Shock

- ID: D000010335

- Term: Pathologic Processes

- ID: D000018805

- Term: Sepsis

- ID: D000007239

- Term: Infections

- ID: D000018746

- Term: Systemic Inflammatory Response Syndrome

- ID: D000007249

- Term: Inflammation

### Condition Browse Module - Browse Branches

- Abbrev: BC01

- Name: Infections

- Abbrev: All

- Name: All Conditions

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: BC26

- Name: Wounds and Injuries

### Condition Browse Module - Browse Leaves

- ID: M10283

- Name: Infections

- Relevance: LOW

- As Found: Unknown

- ID: M6368

- Name: Communicable Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M17685

- Name: Wounds and Injuries

- Relevance: LOW

- As Found: Unknown

- ID: M15580

- Name: Shock, Septic

- Relevance: HIGH

- As Found: Septic Shock

- ID: M15577

- Name: Shock

- Relevance: LOW

- As Found: Unknown

- ID: M5326

- Name: Burns

- Relevance: LOW

- As Found: Unknown

- ID: M6642

- Name: Cross Infection

- Relevance: LOW

- As Found: Unknown

- ID: M20864

- Name: Sepsis

- Relevance: LOW

- As Found: Unknown

- ID: M16869

- Name: Toxemia

- Relevance: LOW

- As Found: Unknown

- ID: M16355

- Name: Syndrome

- Relevance: LOW

- As Found: Unknown

- ID: M20818

- Name: Systemic Inflammatory Response Syndrome

- Relevance: LOW

- As Found: Unknown

- ID: M10293

- Name: Inflammation

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000012772

- Term: Shock, Septic

### Misc Info Module

- Version Holder: 2024-05-24
