Study of the Immunological Pathophysiological Mechanisms Associated With Acute Respiratory Distress Syndrome

Study of the Immunological Pathophysiological Mechanisms Associated With Acute Respiratory Distress Syndrome

About 10% of patients admitted to the ICU suffer from ARDS, with a mortality rate of around 35-45%. The lack of therapeutic innovation in ARDS can be partly explained by the heterogeneity of patients included under this definition.

A better understanding of the pathophysiological mechanisms underlying the different patient phenotypes is essential to develop new therapeutic strategies.

Objectives:

To characterize the inflammatory profile of patients with ARDS using circulating biomarkers and single-cell RNA sequencing of pulmonary immune cells.

The investigators hypothesize that there is a correlation between the profile of serum biomarkers (inflammatory sub-phenotypes), the transcriptome of pulmonary immune cells.

Briefly the experimental scheme is as follow:

• Population: patients with ARDS under invasive mechanical ventilation in the ICU.

• Intervention:

  1. Determination of the inflammatory subphenotype on circulatory inflammatory biomarkers.
  2. Characterization of inflammation by single cell RNA sequencing on lung immune cells collected on broncho-alveolar fluid.

Acute Respiratory Distress Syndrome (ARDS) is the most severe form of pulmonary failure. It is defined by bilateral radiologic opacities associated with severe hypoxemia, confirmed by a PaO₂/FiO₂ ratio <300 in the absence of a cardiac cause. About 10% of patients admitted to the Intensive Care Units (ICU) develop ARDS, and this diagnosis is associated with an in-hospital mortality of 35-45%. Like sepsis, ARDS leads to long-term complications. It is associated with physical deconditioning and reduced quality of life that can persist up to five years after the episode. Survivors are readmitted to the ICU within a year in 30% of cases. Moreover, excess mortality among ARDS survivors is attributable, in nearly one-third of cases, to a new acute respiratory infection.

The lack of therapeutic advances in ARDS has led researchers to better characterize patients with this condition. Different subphenotypes have been identified based on plasma inflammatory biomarker profiles, which are associated with distinct responses to treatments (such as corticosteroids, ventilatory management, and fluid management) and variable prognoses. The mechanisms underlying these different biological subphenotypes remain unknown. To further explore this concept, it is necessary to precisely identify subpopulations of patients who present with similar clinical features but distinct biological phenotypes driven by unique pathophysiological mechanisms. Establishing these different ARDS endotypes is essential for the development of innovative and targeted therapeutic strategies.

Our hypothesis is that the different biological subphenotypes of ARDS reflect distinct profiles of pulmonary immune cell populations, representing a first step toward understanding ARDS endotypes.

Identifying these endotypes is a crucial step for developing targeted and innovative therapeutic strategies aimed at reducing ARDS-related morbidity and mortality. This is the objective of the proposed project.

Inclusion Criteria:

• ARDS risk factors: bacterial or viral pneumonia, extrapulmonary infection, major trauma, transfusion, inhalation injury, or shock.
• Pulmonary edema not explained by a cardiogenic cause or volume overload.
• Onset of respiratory symptoms within <7 days.
• Bilateral pulmonary involvement on chest X-ray, CT scan, or ultrasound.
• PaO₂/FiO₂ ≤ 300 assessed with PEEP ≥ 5 cmH₂O.

Exclusion Criteria:

• ARDS with intubation for more than 48 hours.
• Contraindications to bronchoscopy: effective anticoagulation, dual antiplatelet therapy, thrombocytopenia <50 G/L.
• Pre-existing immunodeficiency: active solid tumor or remission <5 years, active hematologic malignancy or remission <5 years, systemic disease (even without specific treatment), solid organ or bone marrow transplant, HIV infection with CD4 <200/mm³.
• Cardiac arrest with a poor prognosis (NSE >60, malignant EEG, diffuse ischemia on imaging, loss of trunk reflexes).
• Patients <18 year-old
• Patients under legal guardianship, curatorship, or deprived of liberty.
• Ongoing pregnancy.
• Patients without social security coverage.