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出境医 / 临床实验 / Immune Alveolar Alterations During Pneumonia-Associated Acute Respiratory Distress Syndrome (PICARD2)

Immune Alveolar Alterations During Pneumonia-Associated Acute Respiratory Distress Syndrome (PICARD2)

Study Description
Brief Summary:

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.


Condition or disease
Acute Respiratory Distress Syndrome

Study Design
Layout table for study information
Study Type : Observational
Estimated Enrollment : 110 participants
Observational Model: Other
Time Perspective: Prospective
Official Title: Immune Alveolar Alterations During Pneumonia-Associated Acute Respiratory Distress Syndrome
Estimated Study Start Date : June 1, 2019
Estimated Primary Completion Date : June 4, 2022
Estimated Study Completion Date : June 28, 2022
Arms and Interventions
Group/Cohort
Immunocompetent ARDS patients
(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
(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
(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.
Outcome Measures
Primary Outcome Measures :
  1. HLA-DR expression level of alveolar monocytes at the early phase of infectious Acute Respiratory Distress Syndrome (ARDS) [ Time Frame: at day 1 to day 3 ]
    Measurement by flow cytometry phagocytosis and TNF-α synthesis of alveolar monocytes in immunocompetent patients, compared to immunocompromised patients


Secondary Outcome Measures :
  1. Impact of the level of expression of PD-1 by alveolar CD8 + lymphocytes on their function during septic ARDS in immunocompetent and immunocompromised patients. [ Time Frame: at day 1 to day 3 ]
    Level of expression of PD-1 by alveolar CD8+ lymphocytes

  2. Comparaison of the level of HLA-DR expression of alveolar monocytes between immunocompetent and immunosuppressed patients being managed for septic ARDS. [ Time Frame: at day 1 to day 3 ]
    Level of HLA-DR expression of alveolar monocytes

  3. Link between the alveolar monocyte HLA-DR expression level and the prognosis of immunocompetent and immunosuppressed patients being managed for septic ARDS. [ Time Frame: day 28 ]
    Number of days without complication

  4. Determine wether alveolar biomarkers (HLA-DR and PD-1) are potential candidates for immunomodulation [ Time Frame: at day 1 to day 3 ]
    To determine if the level of expression of HLA-DR and PD-1 can be modulated by pharmacological intervention


Biospecimen Retention:   Samples Without DNA
Bronchoalveolar lavage fluid and blood samples (2 heparinized tubes (8 ml) for performing functional tests in the blood compartment and 1 dry 4 ml tube for subsequent cytokine assay (Luminex® analysis) on serum) will be collected in ARDS patients within 48 hours of intubation and in controls.

Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Group 1 : Immunocompetent Acute Respiratory Distress Syndorme (ARDS) patients Group 2 : Immunosuppressed ARDS patients Group 3 : Controls (no ARDS)
Criteria

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
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Nicolas DE PROST, Doctor 01 49 81 23 94 ext 0033 nicolas.de-prost@aphp.fr

Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Layout table for investigator information
Principal Investigator: Nicolas DE PROST Assistance Publique Hôpitaux de Paris - CHU Henri Mondor - Créteil
Tracking Information
First Submitted Date May 29, 2019
First Posted Date June 3, 2019
Last Update Posted Date June 3, 2019
Estimated Study Start Date June 1, 2019
Estimated Primary Completion Date June 4, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: May 29, 2019)
HLA-DR expression level of alveolar monocytes at the early phase of infectious Acute Respiratory Distress Syndrome (ARDS) [ Time Frame: at day 1 to day 3 ]
Measurement by flow cytometry phagocytosis and TNF-α synthesis of alveolar monocytes in immunocompetent patients, compared to immunocompromised patients
Original Primary Outcome Measures Same as current
Change History No Changes Posted
Current Secondary Outcome Measures
 (submitted: May 29, 2019)
  • Impact of the level of expression of PD-1 by alveolar CD8 + lymphocytes on their function during septic ARDS in immunocompetent and immunocompromised patients. [ Time Frame: at day 1 to day 3 ]
    Level of expression of PD-1 by alveolar CD8+ lymphocytes
  • Comparaison of the level of HLA-DR expression of alveolar monocytes between immunocompetent and immunosuppressed patients being managed for septic ARDS. [ Time Frame: at day 1 to day 3 ]
    Level of HLA-DR expression of alveolar monocytes
  • Link between the alveolar monocyte HLA-DR expression level and the prognosis of immunocompetent and immunosuppressed patients being managed for septic ARDS. [ Time Frame: day 28 ]
    Number of days without complication
  • Determine wether alveolar biomarkers (HLA-DR and PD-1) are potential candidates for immunomodulation [ Time Frame: at day 1 to day 3 ]
    To determine if the level of expression of HLA-DR and PD-1 can be modulated by pharmacological intervention
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Immune Alveolar Alterations During Pneumonia-Associated Acute Respiratory Distress Syndrome
Official Title Immune Alveolar Alterations During Pneumonia-Associated Acute Respiratory Distress Syndrome
Brief Summary

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.

Detailed Description Not Provided
Study Type Observational
Study Design Observational Model: Other
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples Without DNA
Description:
Bronchoalveolar lavage fluid and blood samples (2 heparinized tubes (8 ml) for performing functional tests in the blood compartment and 1 dry 4 ml tube for subsequent cytokine assay (Luminex® analysis) on serum) will be collected in ARDS patients within 48 hours of intubation and in controls.
Sampling Method Non-Probability Sample
Study Population Group 1 : Immunocompetent Acute Respiratory Distress Syndorme (ARDS) patients Group 2 : Immunosuppressed ARDS patients Group 3 : Controls (no ARDS)
Condition Acute Respiratory Distress Syndrome
Intervention Not Provided
Study Groups/Cohorts
  • Immunocompetent ARDS patients
    (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
    (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
    (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.
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Not yet recruiting
Estimated Enrollment
 (submitted: May 29, 2019)
110
Original Estimated Enrollment Same as current
Estimated Study Completion Date June 28, 2022
Estimated Primary Completion Date June 4, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria

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
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts
Contact: Nicolas DE PROST, Doctor 01 49 81 23 94 ext 0033 nicolas.de-prost@aphp.fr
Listed Location Countries Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number NCT03971006
Other Study ID Numbers APHP 190092
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: No
Plan Description: DATAS ARE OWN BY ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS, PLEASE CONTACT SPONSOR FOR FURTHER INFORMATION
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor Assistance Publique - Hôpitaux de Paris
Collaborators Not Provided
Investigators
Principal Investigator: Nicolas DE PROST Assistance Publique Hôpitaux de Paris - CHU Henri Mondor - Créteil
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date May 2019