Study of the Involvement of IL-17 / IL-22 Pathway in Bacterial Exacerbations of COPD

Study Overview
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Brief Summary
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Chronic obstructive pulmonary disease (COPD) is a worldwide chronic inflammatory disease of the airways linked to environmental exposure. The chronic course of COPD is often interrupted by acute exacerbations which have a major impact on the morbidity and mortality of COPD patients. A bacterial etiology for these exacerbations is common (almost 50%). Moreover, airway bacterial colonization linked to an increased susceptibility is observed in COPD patients. Effective Th17 immune response is needed to develop a good response against bacteria. Thus, this study aims to demonstrate that there is a defective IL-17/ IL-22 response to bacteria in COPD leading to airway bacterial colonization and infection.

Official Title
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Study of the Involvement of IL-17 / IL-22 Pathway in Bacterial Exacerbations of COPD

Conditions
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Pulmonary Disease, Chronic Obstructive, Bacterial Infections

Intervention / Treatment
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* Other: Sample collecting
* Other: Lung function measure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed COPD according GOLD guidelines Current or ex-smoker (at least 10 pack-years) Hospitalized for COPD exacerbation Exclusion Criteria: Asthma or Cystic fibrosis No other chronic lung disease Solid Tumor unhealed or not considered in remission Inhaled drug consumption Women of childbearing potential without effective contraception Pregnant or breastfeeding women Incapable of consent Lack of social security coverage

Ages Eligible for Study
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Minimum Age: 40 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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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Bacterial exacerbations<br>Patients with at least 10^7 UFC/ml bacteria in their sputum during their first COPD exacerbation. | Other: Sample collecting<br>* Collect sputum, blood and nasopharyngeal swab during the exacerbation and at steady state 8 to 16 weeks later.<br>Other: Lung function measure<br>* Measure lung function and follow it during 4 years<br>|
| Other: Non-bacterial exacerbations<br>Patients without detected bacteria or below 10^7 UFC/ml in sputum during their first COPD exacerbation. | Other: Sample collecting<br>* Collect sputum, blood and nasopharyngeal swab during the exacerbation and at steady state 8 to 16 weeks later.<br>Other: Lung function measure<br>* Measure lung function and follow it during 4 years<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure cytokines by ELISA | Compare the delta of IL-17 and IL-22 cytokines between exacerbation and steady-state in the sputum,between the two groups of patients. | At inclusion (exacerbation) and between 8 to 16 weeks (steady-state) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare the delta of IL-17 and IL-22 cytokines between exacerbation and steady-state in the blood. | Measure cytokines by ELISA in the blood at exacerbation and at steady-state. Compare the delta of these cytokines between the two groups of patients. | At inclusion (exacerbation) and between 8 to 16 weeks (steady-state) | 
| Identify IL-17 and IL-22 producing cells in the blood | Identify by flow cytometry, IL-17 and/or IL-22 positive immune cell types in the blood. | At inclusion (exacerbation) and between 8 to 16 weeks (steady-state) | 
| Identify IL-17 and IL-22 producing cells in the sputum | Identify by flow cytometry, IL-17 and/or IL-22 positive immune cell types in the sputum. | At inclusion (exacerbation) and between 8 to 16 weeks (steady-state) | 
| Quantification of immune cell types in the blood | Quantify by flow cytometry different immune cells in the blood: monocytes, macrophages, B and T cells, innate lymphocytes. | At inclusion (exacerbation) and between 8 to 16 weeks (steady-state) | 
| Quantification of immune cell types in the sputum | Quantify by flow cytometry different immune cells in the sputum: monocytes, macrophages, B and T cells, innate lymphocytes. | At inclusion (exacerbation) and between 8 to 16 weeks (steady-state) | 
| Quantification of pro-inflammatory cytokines in blood | Quantify by ELISA Th1 (IL-12, IFN gamma), Th2 (IL-4, IL-5), Th17 (IL-1 beta, IL-6, IL-23, TGF beta), regulatory (IL-10) and pro-inflammatory cytokines (IL-8) in the blood. | At inclusion (exacerbation) and between 8 to 16 weeks (steady-state) | 
| Quantification of pro-inflammatory cytokines in sputum | Quantify by ELISA Th1 (IL-12, IFN gamma), Th2 (IL-4, IL-5), Th17 (IL-1 beta, IL-6, IL-23, TGF beta), regulatory (IL-10) and pro-inflammatory cytokines (IL-8) in the sputum. | At inclusion (exacerbation) and between 8 to 16 weeks (steady-state) | 
| Identify pathogens linked to the exacerbation | Research of classical bacteria and fungi by usual microbial cultures from sputum and of respiratory virus and non conventional bacteria (Mycoplasma, Legionella, Bordetella pertussis and parapertussis and Chlamydophila pneumoniae) by PCR on nasopharyngeal swab. | At inclusion (exacerbation) | 
| Identify persistent pathogens at steady-state | Research of classical bacteria and fungi by usual microbial cultures from sputum and of respiratory virus and non conventional bacteria (Mycoplasma, Legionella, Bordetella pertussis and parapertussis and Chlamydophila pneumoniae) by PCR on nasopharyngeal swab. | Between 8 to 16 weeks (steady-state) | 
| Compare sputum microbiota between exacerbation and steady-state | Metagenomic analysis on sputum | At inclusion (exacerbation) and between 8 to 16 weeks (steady-state) | 
| Compare oxidative stress in the blood between exacerbation and steady-state | Quantification by ELISA in the blood of oxidative stress markers (isoprostane, superoxyde dismutase, 3-nitrotyrosine, peroxyde, catalase). | At inclusion (exacerbation) and between 8 to 16 weeks (steady-state) | 
| Quantification of oxidative stress in exhaled condensates | Quantification by ELISA of nitrite species in exhaled condensates. | At inclusion (exacerbation) and between 8 to 16 weeks (steady-state) | 
| Describe exacerbation phenotype | Collect respiratory symptoms, received treatments and hospitalization duration. | At inclusion (exacerbation) | 
| Describe environmental exposure | Collect informations on the patient's occupation, occupational exposures and smoking. | At inclusion (exacerbation), between 8 to 16 weeks (steady-state) and annually for 4 years | 
| Describe COPD clinical phenotype | Collect morphological informations, history of exacerbations | At inclusion (exacerbation), between 8 to 16 weeks (steady-state) and annually for 4 years | 
| Describe COPD radiological phenotype | Realization of a chest CT scan if not performed during the 2 previous years. | Between 8 to 16 weeks (steady-state) | 
| Quantify Quality of Life | Realization of the COPD Assessment Test (CAT), a quality of life questionnaire. | At inclusion (exacerbation), between 8 to 16 weeks (steady-state) and annually for 4 years | 
| Describe COPD treatments | Collect informations on treatments related to COPD including inhaled treatments, influenza and pneumococcal vaccinations, oxygen therapy and respiratory rehabilitation. | At inclusion (exacerbation), between 8 to 16 weeks (steady-state) and annually for 4 years | 
| Measure static lung function | Test the lung function with spirometry and plethysmography repeated annually to measure the decline of respiratory function. | Between 8 to 16 weeks (steady-state) and annually for 4 years | 
| Measure airway resistances | Measure resistances with the forced oscillation technique. | Between 8 to 16 weeks (steady-state) and at 2 and 4 years | 
| Measure exercise tolerance | Perform a 6-minute walk-test. | At inclusion (end of the hospitalization for exacerbation), between 8 to 16 weeks (steady-state) and annually for 4 years | 
| Analysis exercise tolerance | Perform a cardiopulmonary exercise test on a bicycle. | Between 8 to 16 weeks (steady-state) and at 2 and 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Interleukin-17, Interleukin-22, Microbiota, Exacerbations, Immunity, Mucosal