Kinetics of INF-γ Production in Intensive Care Patients

Official title

Kinetics of INF-γ Production in Intensive Care Patients-Monitoring of INF-γ in Intensive Care

Overview

Most patients admitted to intensive care after severe trauma, high-risk surgery, or acute respiratory distress are frequently characterized by significant initial inflammation accompanied by a compensatory anti-inflammatory response, which can lead to profound post-aggressive immunosuppression. This immunosuppression is associated with an increased risk of nosocomial infections, viral reactivations, prolonged ICU stays, and ultimately, increased mortality. Consequently, immunostimulation with agents such as interferon gamma (IFN-γ) has been proposed as a means to restore immune defense in the most severe patients. However, in a recent study conducted on mechanically ventilated patients with acute organ failure, treatment with interferon gamma-1b compared to placebo did not significantly reduce the incidence of nosocomial pneumonia or 28-day mortality and was even associated with an increase in severe side effects, leading to the premature termination of the trial. These results, along with previous studies, suggest that for IFN-γ to be effective, it must be targeted at patients who have reached the immunosuppressive phase. In the absence of evident clinical signs, the use of biomarkers could guide clinicians in identifying the appropriate patients and the optimal timing for this therapy. In a recent monocentric study, they evaluated a new automated IFN-γ assay on a cohort of 22 septic patients to monitor T lymphocyte functionality independently of antigen. As expected, the results showed a marked decrease in IFN-γ release, which correlated with altered classical cellular parameters (CD8+ T cells, mHLA-DR). Since the test is performed using whole blood, requires no technician intervention, and provides results within four hours, this project propose to characterize the evolution of the immune status of a large cohort of ICU patients, including those with severe trauma, high-risk surgery, or acute respiratory distress syndrome.

Detailed description

Most patients admitted to intensive care after severe trauma, high-risk surgery, or acute respiratory distress are frequently characterized by significant initial inflammation accompanied by a compensatory anti-inflammatory response, which can lead to profound post-aggressive immunosuppression. This immunosuppression is associated with an increased risk of nosocomial infections, viral reactivations, prolonged ICU stays, and ultimately, increased mortality. Consequently, immunostimulation with agents such as interferon gamma (IFN-γ) has been proposed as a means to restore immune defense in the most severe patients. However, in a recent study conducted on mechanically ventilated patients with acute organ failure, treatment with interferon gamma-1b compared to placebo did not significantly reduce the incidence of nosocomial pneumonia or 28-day mortality and was even associated with an increase in severe side effects, leading to the premature termination of the trial. These results, along with previous studies, suggest that for IFN-γ to be effective, it must be targeted at patients who have reached the immunosuppressive phase. In the absence of evident clinical signs, the use of biomarkers could guide clinicians in identifying the appropriate patients and the optimal timing for this therapy.

Among the described immune alterations and associated biomarkers in critically ill patients, the decrease in Human Leukocyte Antigen (HLA-DR) expression on monocytes (mHLA-DR) has been studied more extensively and is now considered a reliable biomarker for guiding myeloid-targeted immunotherapies. While functional tests are the best means to explore acquired immunosuppression in the ICU, as they directly measure the capacity of a given cell population to respond to an in vitro stimulus, they present analytical obstacles to their deployment. Most protocols are "homemade" and lack standardization, which is a major obstacle to large-scale trials and their use in clinical practice.

In a recent monocentric study, they evaluated a new automated IFN-γ assay on a cohort of 22 septic patients to monitor T lymphocyte functionality independently of antigen. As expected, the results showed a marked decrease in IFN-γ release, which correlated with altered classical cellular parameters (CD8+ T cells, mHLA-DR). Since the test is performed using whole blood, requires no technician intervention, and provides results within four hours, this project propose to characterize the evolution of the immune status of a large cohort of ICU patients, including those with severe trauma, high-risk surgery, or acute respiratory distress syndrome.

Interventions

• Other blood sampling
  After informing eligible patients (or their trusted support person, relative/guardian/curator where applicable) and in the absence of any opposition, they are included in the research. Blood samples from an arterial catheter already in place will be taken every day from D1 to D7, then every 72 hours until discharge from intensive care, or until D28. For each of these samples, a maximum volume of 4 ml will be collected in a heparinized tube. Samples will not be taken if the hemoglobin level is b

Primary outcome measures

• INF-γ production in patients admitted to intensive care after severe trauma, high-risk surgery, or acute respiratory distress [Time frame: Daily value from day 1 to day 7, then every 72 hours until discharge from intensive care (assessed up to day 28).]

Secondary outcome measures (8)

• ICU discharge Vital status [Time frame: at ICU discharge, and at the latest Day 28]
• Incidence of nosocomial infections [Time frame: From ICU-admission to ICU-discharge, and at the latest Day 28]
• Incidence of viral reactivations for CMV and HSV [Time frame: From ICU-admission to ICU-discharge, and at the latest Day 28]
• Length of mechanical ventilation [Time frame: From ICU-admission to ICU-discharge, and at the latest Day 28]
• Presence of septic shock [Time frame: From ICU-admission to ICU-discharge, and at the latest Day 28]
• Renal impairment [Time frame: From ICU-admission to ICU-discharge, and at the latest Day 28]
• mHLA-DR expression [Time frame: Daily value from day 1 to day 7, then every 72 hours until discharge from intensive care (assessed up to day 28).]
• Length of ICU stay [Time frame: at ICU discharge, and at the latest day 28]

Eligibility criteria

Inclusion criteria

• Aged 18 years or older
• Patients admitted to intensive care after severe trauma, or presenting with acute respiratory distress, or undergoing cardiac, vascular, or digestive surgery with planned postoperative intensive care. Exclusion Criteria

Exclusion criteria

• Expressed opposition from the patient, a relative (if applicable), or their legal representative (guardian, curator)
• Pregnant woman
• Hemoglobin less than 7g/dl at inclusion

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

France · 7 centers

• Reanimation department, Annecy Genevois hospital — Annecy
• Reanimation department, Clermont-Ferrand Hospital — Clermont-Ferrand
• Reanimation department, Lyon hospital — Lyon
• Réanimation cardio-chirurgicale - Pitié-Salpêtrière hospital — Paris
• Réanimation chirurgicale Gaston Cordier - Pitié-Salpêtrière hospital — Paris
• Réanimation chirurgicale Husson Mourrier - Pitié-Salpêtrière hospital — Paris
• Réanimation neuro-chirurgicale - Pitié-Salpêtrière hospital — Paris

Identifiers

NCT: NCT06549374 · APHP240860

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗