Immune Alveolar Alterations During Pneumonia-Associated Acute Respiratory Distress Syndrome

Study Overview
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Brief Summary
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Sepsis is a dysregulated host response to severe life-threatening infections, leading to organ failure and death in up to 40% of patients with septic shock. Pulmonary infections are the main cause of community-acquired sepsis and frequently lead to the development of acute respiratory distress syndrome(ARDS). Features of immunosuppression, including diminished cell surface monocyte human leukocyte antigen DR (mHLA-DR) expression, are strongly associated with hospital mortality. Such decrease in HLA-DR expression on antigen-presenting cells has been associated with impairment of microbial antigens to Tcells. Septic patients also show elevated expression of inhibitory receptors associated with cell exhaustion.. Yet, biochemical, flow cytometric and immunohistochemical findings consistent with immunosuppression have been observed in lungs and spleen of patients died of sepsis and multiple organ failure, demonstrating the relevance of studying these defects directly in organ tissues. A novel approach aimed to characterize the role and prognostic value of alveolar biomarkers measured directly in the injured lungs is warranted and supported by: -disappointing results of previous clinical trials attempting to restore the level of biomarkers measured on circulating cells; -evidences of regional immunosuppression in lungs of ARDS patients; -lung is the main site of hospital-acquired infections with a prevalence of ventilator-associated pneumonia in 30% over the course of Intensive Care Unit(ICU) stay in ARDS patients. Investigators speculate that biomarkers measured on alveolar leukocytes (AL) surface, are important predictors of outcome and potential therapeutic targets in ICU patients with pneumonia-associated ARDS. Investigators aim to explore whether biomarkers measured directly on AL from patients with pneumonia-associated ARDS are associated to regional pulmonary immunosuppression using leukocyte functional tests; and predictors of outcomes. Bronchoalveolar lavage fluid(BALF) and blood samples will be collected in ARDS patients. Leukocyte populations and cell membrane biomarkers will be quantified using flow cytometry. Leukocyte functional tests will be performed ex vivo on leukocytes collected from BALF and blood samples. Pharmacological interventions will be performed ex vivo. This project aims to identify biomarkers associated with outcomes and potential therapeutic targets.

Official Title
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Immune Alveolar Alterations During Pneumonia-Associated Acute Respiratory Distress Syndrome

Conditions
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Acute Respiratory Distress Syndrome

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Affiliated to a social security system Patient informed and have given his non opposition verbally (trustworthy or a family member non opposition is required if the patient is unable to give his non opposition) Groupe 1 : - Patient with ARDS secondary to pneumonia defined by following criteria: Intubation and mechanical ventilation for less than 48 hours Lung infection evolving since less than 7 days Bilateral pulmonary radiological opacities compatible with edema pulmonary lesion PaO2 / FiO2 ratio ≤ 300 mmHg with a positive expiratory pressure level ≥ 5 cmH2O - Absence of immunosuppression (No HIV infection, bone marrow or solid organ transplantation, post-chemotherapy aplasia, immunosuppressive therapy or corticosteroid therapy (>200 mg / day of hydrocortisone or equivalent in the 4 weeks prior to inclusion)) Group 2 - Patient with ARDS secondary to pneumonia defined by following criteria: Intubation and mechanical ventilation for less than 48 hours Lung infection evolving since less than 7 days Bilateral pulmonary radiological opacities compatible with edema pulmonary lesion PaO2 / FiO2 ratio ≤ 300 mmHg with a positive expiratory pressure level ≥ 5 cmH2O - Previously known immunosuppression (patient with HIV, solid tumor, solid organ transplantation or under corticosteroids therapy since at least 4 weeks before inclusion) Group 3 LBA indicated in usual care Absence of ARDS Absence of evolutionary infection Absence of infiltrative lung disease Absence of immunosuppression (No HIV infection, bone marrow or solid organ transplantation, post-chemotherapy aplasia, immunosuppressive therapy, corticosteroid therapy (> 200 mg / day of hydrocortisone or equivalent in the 4 weeks prior to inclusion)) Exclusion Criteria: Chronic respiratory insufficiency treated by long-term oxygen therapy and / or long-term respiratory assistance Child-Pugh C cirrhosis Pulmonary fibrosis Active lymphoid and myeloid malignant hemopathies Neutropenia (neutrophils <1500 / mm3) Patient moribund the day of inclusion or having an IGS II score greater than 90 Irreversible neurological pathology: cerebral involvement, encephalic death Decision to limit active therapies Deep hypoxemia (PaO2 / FiO2 <75 mmHg) Patient protected by law Pregnant or lactating woman

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Immunocompetent ARDS patients<br>(n=50) Patients with moderate-to-severe pneumonia-associated Acute Respiratory Distress Syndorme (ARDS) and no immunosuppression (excluding patients with HIV infection, solid tumor or hematological malignancies, organ transplant or taking steroids since more than 4 weeks). | |
| Immunosuppressed ARDS patients<br>(n=50) Patients with moderate-to-severe pneumonia-associated Acute Respiratory Distress Syndorme (ARDS) (Berlin definition (2)) and previously known immunosuppression (as listed above). These patients will allow comparing the cell defects observed in the study population to those observed in immunosuppressed patients. | |
| Controls<br>(n=10) Patients undergoing a bronchoscopy with Bronchoalveolar Liquid (BAL) as part of routine care but having neither ARDS nor active lung infection, infiltrating lung disease or immunosuppression. These patients will allow quantifying normal levels of the studied biomarkers in the alveolar and blood compartments. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HLA-DR expression level of alveolar monocytes at the early phase of infectious Acute Respiratory Distress Syndrome (ARDS) | Measurement by flow cytometry phagocytosis and TNF-α synthesis of alveolar monocytes in immunocompetent patients, compared to immunocompromised patients | at day 1 to day 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of the level of expression of PD-1 by alveolar CD8 + lymphocytes on their function during septic ARDS in immunocompetent and immunocompromised patients. | Level of expression of PD-1 by alveolar CD8+ lymphocytes | at day 1 to day 3 | 
| Comparaison of the level of HLA-DR expression of alveolar monocytes between immunocompetent and immunosuppressed patients being managed for septic ARDS. | Level of HLA-DR expression of alveolar monocytes | at day 1 to day 3 | 
| Link between the alveolar monocyte HLA-DR expression level and the prognosis of immunocompetent and immunosuppressed patients being managed for septic ARDS. | Number of days without complication | day 28 | 
| Determine wether alveolar biomarkers (HLA-DR and PD-1) are potential candidates for immunomodulation | To determine if the level of expression of HLA-DR and PD-1 can be modulated by pharmacological intervention | at day 1 to day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute respiratory distress syndrome (ARDS), Pneumonia, Septic Shock, bronchoalveolar lavage