Eosinophils Endotypes in Chronic Airway Inflammatory Diseases (PLEIAD)

Peripheral Eosinophils Phenotypes in Airway Inflammatory Diseases: Towards Proper Clustering and Therapeutic Targeting

Asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) are frequently described as unified airway inflammatory diseases. Both heavily impacts quality of life with substantial productivity loss. They share the same pathophysiologic pattern based upon proTh2 immune response with blood eosinophils recruitment. Eosinophils are the major actor of persistent mucosal inflammation by promoting their own survival, by attracting other inflammatory cells and by producing cytotoxic proteins involved in mucosal remodeling.

Promising anti-Th2 therapeutic approaches (i.e.anti-IgE, anti-interleukin 5 (IL-5), anti-IL-4, anti-IL-13) are considered as effective alternative options to long-term corticosteroid treatment. Their advantage in recalcitrant CRSwNP is under consideration. Moreover, we still need to delineate the good responders to improve theirs indications.

The objective is to assess blood eosinophil immunophenotypes in asthma or CRSwNP. Flow cytometric expression of activation markers on eosinophil membrane will be compared with a group of healthy subjects. Innovative data on eosinophil involvement in airway diseases will be obtained. The major outcome will be to depict patients' endotypes for a better selection of immunotherapies.

Study Overview

• Status: Recruiting
• Conditions: Chronic Sinusitis; Eosinophilic Asthma; Eosinophilic Rhinitis

• Study Type: Observational
• Enrollment (Estimated): 80

Contacts and Locations

• Study Contact: Name: Cécile Chenivesse, MD,PhD; Phone Number: +33 03 20 44 59 48; Email: cecile.chenivesse@chru-lille.fr

Study Locations

• France
  • Lille, France, 59000
    • Recruiting
    • CHU Lille
    • Contact: Cécile Chenivesse, MD, Ph; Phone Number: +33 03 20 44 59 48; Email: cecile.chenivesse@chru-lille.fr
    • Contact: Corine Glineur, Ph; Phone Number: +33 03 20 87 71 83; Email: corine.glineur@pasteur-lille.fr
    • Principal Investigator: Cécile Chenivesse, MD,Ph

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

All patients for the study will be targeted either during hospitalization in Pneumology for uncontrolled asthma patients, during ENT visit for scheduling of sinus surgery (recalcitrant CRSwNP).

The healthy subjects are going to be screened in the Clinical Investigation Center of the University Hospital of Lille. Subjects will be contacted by phone after selection in the database.

Description

Inclusion Criteria:

For all groups:

• Social insured patient
• Patient willing to comply with all procedures of the study and its duration
• Provision of signed and dated informed consent form prior to any study specific procedure

For Group 1:

- Patients with moderate to severe uncontrolled asthma, confirmed by relevant clinical symptoms and proven variable airway obstruction, and assessed by an expert pulmonologist according to spirometry criteria (absolute and weighed Forced Expiratory Volume (FEV) and Forced Vital Capacity (FVC) before and after 2 test),(see CRF for details). Uncontrolled asthma will be defined by an ACQ score ≥ 1.5. or acute exacerbation

For Groups 2 and 3:

• Patients with medically refractory bilateral sino-nasal polyposis requiring sinus surgery, according to an expert rhinologist. CRSwNP diagnosis is based on the presence of bilateral nasal polyps from both side of middle turbinates on nasoendoscopy and bilateral sinus opacification on CT scan. Briefly, CRSwNP is considered as refractory when symptoms are still not controlled after 3 courses of oral corticosteroid and double dose of nasal corticosteroid during the last 12 months
• Patients with both uncontrolled asthma and recalcitrant CRSwNP with or without concomitant aspirin-exacerbated respiratory disease (AERD) (group 3)

For Group 4:

- Healthy subjects without any airway disease or any atopic status, as assessed by a questionnaire and a medical examination

Exclusion Criteria:

For all groups:

• Patients with any other form of secondary CRSwNP (eg, cystic fibrosis, primary ciliary dyskinesia).
• Patients with any form of secondary severe asthma (eg (non)eosinophilic granulomatosis with polyangiitis, allergic bronchopulmonary aspergillosis)
• Patients taking or having taken systemic corticosteroid, leukotriene receptor antagonist, theophylline or long-term macrolide therapy within 1 month prior to sample collections, anti-immunoglobulin E therapy (omalizumab) anti-IL-5/5R or anti IL-4R/anti-IL13 therapies within 6 months before inclusion
• Patients followed up for another inflammatory or auto-immune disease
• Previous allogeneic bone marrow transplant
• Patients with ongoing sub-cutaneous or sub-lingual anti-allergenic immunotherapies
• Patients with active smoking or history of smoking > 10 packages-year for asthma patients
• Pregnant, breastfeeding, or lactating women
• Non-coverage by the social security insurance
• Patient unable to receive informed information
• Refusal to sign the consent form
• Unwillingness or inability to follow the study procedures, in the opinion of the investigator
• Person deprived of the liberty
• Person benefiting from a system of legal protection (guardianship…)

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Patients with moderate to severe uncontrolled asthma; Patients with moderate to severe uncontrolled asthma defined on clinical assessment and spirometric criteria. Non controlled asthma is considered when ACQ score ≥ 1.5 or in case of acute exacerbation
Patients with recalcitrant CRSwNP requiring sinus surgery; The medical failure in CRSwNP is defined as persistent disease in spite of 3 courses of oral corticosteroid and double dose of local corticoid over 12 months
Patients with concomitant CRSwNP and uncontrolled asthma; Patients with concomitant CRSwNP and moderate to severe uncontrolled asthma
Healthy subjects; Patients without any airway inflammatory disease or atopy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of blood eosinophils with expression of CD69 marker in patients with uncontrolled asthma alone, recalcitrant chronic rhinosinusitis with nasal polyps (CRSwNP) alone, uncontrolled asthma and recalcitrant CRSwNP and in healthy subjects.	CD69 expression is measured with flow cytometry on blood eosinophils cell surface. The percentage of blood eosinophils positive for CD69 is compared between the four groups of patients (uncontrolled asthma alone, recalcitrant CRSwNP alone, uncontrolled asthma and recalcitrant CRSwNP and in healthy subjects)	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of blood eosinophils with expression of HLADR marker in patients with uncontrolled asthma alone, recalcitrant CRSwNP alone, uncontrolled asthma and recalcitrant CRSwNP and in healthy subjects.	HLADR expression is measured with flow cytometry on blood eosinophils cell surface. The percentage of blood eosinophils positive for HLADR is compared between the four groups of patients (uncontrolled asthma alone, recalcitrant CRSwNP alone, uncontrolled asthma and recalcitrant CRSwNP and in healthy subjects)	baseline
Percentage of activated blood eosinophils in patients with uncontrolled asthma alone, recalcitrant CRSwNP alone, uncontrolled asthma and recalcitrant CRSwNP and in healthy subjects.	Activated status of blood eosinophils is based on concomittant expression of biomarkers ( CD69, HLADR, CCR3) with flow cytometry. The percentage of activated blood eosinophils is compared between the four groups of patients (uncontrolled asthma alone, recalcitrant CRSwNP alone, uncontrolled asthma and recalcitrant CRSwNP and in healthy subjects).	baseline
Comparison of the percentage of activated eosinophils in blood with the percentage of activated eosinophils in induced sputum in uncontrolled asthma (with or without CRSwNP).	Activated status of eosinophils in blood and in induced sputum is based on concomittant expression of biomarkers ( CD69, HLADR, CCR3) with flow cytometry.	baseline
Comparison of the percentage of activated eosinophils in blood with the percentage of activated eosinophils in nasal polyps in CRSwNP patients (with or without uncontrolled asthma).	Activated status of eosinophils in blood and in nasal polyps is based on concomittant expression of biomarkers ( CD69, HLADR, CCR3) with flow cytometry.	baseline
Comparison of qualitative transcriptomic profiles of blood eosinophils in patients with uncontrolled asthma alone, recalcitrant chronic rhinosinusitis with nasal polyps (CRSwNP) alone, uncontrolled asthma and recalcitrant CRSwNP.	Transcriptomic profiles will be compared between CRSwNP with or without uncontrolled asthma and between uncontrolled asthma with or without CRSwNP. A two-fold differential expression will be used for comparison.	baseline

Collaborators and Investigators

• Sponsor: University Hospital, Lille
• Investigators: Principal Investigator: Cécile Chenivess, MD,PhD, University Hospital, Lille

Study record dates

Study Major Dates

• Study Start (Actual): March 3, 2020
• Primary Completion (Estimated): March 1, 2024
• Study Completion (Estimated): March 1, 2024

Study Registration Dates

• First Submitted: December 3, 2019
• First Submitted That Met QC Criteria: December 3, 2019
• First Posted (Actual): December 5, 2019

Study Record Updates

• Last Update Posted (Estimated): December 8, 2023
• Last Update Submitted That Met QC Criteria: December 7, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: asthma; Eosinophil; biotherapy; chronic rhinosinusitis with nasal polyps; endotype
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Hematologic Diseases; Otorhinolaryngologic Diseases; Paranasal Sinus Diseases; Nose Diseases; Leukocyte Disorders; Eosinophilia; Hypereosinophilic Syndrome; Sinusitis; Rhinitis; Pulmonary Eosinophilia
• Other Study ID Numbers: 2018_81; 2019-A01457-50 (Other Identifier: ID-RCB number,ANSM)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No