Role of Epithelial Barrier Integrity in Biologic Treatment Response of Severe Asthmatics With/Out Chronic Rhinosinusitis With Nasal Polyps (CRSwNP).

Role of Epithelial Barrier Integrity in Biologic Treatment Response of Severe Asthmatics With/Out Chronic Rhinosinusitis With Nasal Polyps (CRSwNP). Can Shedding of Epithelial Barrier Proteins be Used as Biomarker in Severe Asthma With/Out CRSwNP Management?

Advances in understanding the pathophysiology of asthma development and severity have pointed towards a prominent role of the bronchial epithelium, especially in more chronic and severe disease. Studies suggest that airway eosinophilic inflammation in asthma is linked to epithelial injury and structural changes of the airways, co called airway wall remodeling. Together the chronic airway inflammation and remodeling are associated with bronchial hyperresponsiveness, fixed airflow obstruction or progressive loss of lung function and clinical severity of asthma. Chronic rhinosinusitis with nasal polyps (CRSwNP), is another respiratory inflammatory disease often co-existing with severe asthma, sharing similar pathophysiology. The investigators hypothesize that epithelial barrier integrity may play a role in the pathophysiology of severe eosinophilic asthma and nasal polyposis and in response to anti-IL5 therapy of severe asthmatics, and that shedding of epithelial barrier proteins may be used as biomarker in the management of severe asthma. In order to study that, the investigators will conduct a prospective cohort study of adult severe asthmatics with/out CRSwNP, who live on the island of Crete, Greece and who meet the criteria for entering anti-IL5 treatment, as assessed by pulmonologist. The participants will be recruited with a convenience sampling in a period of 2 years, under real life conditions, and will be followed up for 1 year after treatment initiation. A control group of subjects diagnosed with nasal polyposis without severe asthma will be used. Eligible subjects will undergo clinical assessment with radiological (CT) and endoscopic investigations. Samples of serum, sputum, nasal secretions, as well as nasal and bronchial biopsies will be obtain for assessing clinicopathological differences among the 3 groups but also response to anti-IL5 therapy in SEA w/o CRSwNP.

Study Overview

• Status: Recruiting
• Conditions: Severe Eosinophilic Asthma w/wo CRSwNP
• Intervention / Treatment: Drug: Mepolizumab 100 MG

• Study Type: Observational
• Enrollment (Estimated): 85

Contacts and Locations

• Study Contact: Name: Nikolaos Tzanakis, Professor; Phone Number: 6984643636; Email: tzanakis@med.uoc.gr
• Study Contact Backup: Name: Katerina Antoniou, Professor; Phone Number: 6972300105; Email: kantoniou@uoc.gr

Study Locations

• Greece
  • Crete
    • Heraklion, Crete, Greece, 71500
      • Active, not recruiting
      • "PAGNI" University Hospital, Crete
    • Heraklion, Crete, Greece, 71500
      • Recruiting
      • Aikaterini Antoniou
      • Contact: Aikaterini Antoniou, Professor; Phone Number: +306972300105; Email: kantoniou@uoc.gr
      • Sub-Investigator: Aikaterini Antoniou, Professor

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

Adults with severe eosinophilic asthma, naive to anti-IL5/anti-IL5R treatment with or without CRSwNP who meet requirements for biologic therapy with anti-IL5 (Mepolizumab)

Description

Inclusion Criteria:

• Able to provide informed written consent (study participation informed consent form): Able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form. Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials.
• Anti-IL5/IL5R naïve
• Confirmed asthma diagnosis and severity and treatment requirements (for severe asthma group see boxes 1-3). For the 2nd control group, patients with CRSwNP must have a diagnosis of mild asthma (GINA steps 1-2) or no asthma by pulmonologist.
• Polyposis must be bilateral, to be considered as CRSwNP
• Triggers and relevant co-morbidity have been assessed and are well controlled Triggers such as active or passive smoking, beta-blockers, aspirin/NSAIDs, allergen exposure;Comorbidities such as rhinitis, obesity, GERD, OSA, VCD, depression/anxiety.
• Age: Adults ≥18 years of age
• Any smoking status
• Any ethnicity
• Be affiliated to or a beneficiary of a social security category and/health insurance.
• Gender: Male and Eligible Female. To be eligible for entry into the study, females of childbearing potential must commit to consistent and correct use of an acceptable method of birth control for the duration of the follow up (and for 4 months after the last injection administration). A serum pregnancy test is required of all females. This test will be performed at the initial screening visit. In addition, a urine pregnancy test can be offered (optional) for all females during each scheduled treatment visit prior to the infusion of biologic product until the 1-year follow-up visit.

Laboratory abnormality: No evidence of clinically significant abnormality (other than those seen in SEA) in the haematological, biochemical or urinalysis screen at Visit 1, as judged by the investigator.

• Asthma Exacerbation: Subjects with an ongoing asthma exacerbation should have their screening and treatment initiation visit delayed until the investigator considers the subject has returned to their baseline asthma status. If the 4-week screening period (visits 1 and 1a) has elapsed, then the subject should be considered a screening failure. An exacerbation is defined as worsening of asthma requiring the use of systemic CS and/or emergency department visit, or hospitalisation. For subjects on maintenance oral corticosteroids, an exacerbation requiring oral CS is defined as the use of oral/systemic corticosteroids at least double the existing dose for at least 3 days.
• Maintenance Asthma Therapy: No changes in the dose or regimen of baseline ICS and/or additional controller medication during the screening period (except for treatment of an exacerbation).
• Maintenance CRSwNP: No changes in the dose or regimen of baseline intranasal CS and/or additional controller medication during the screening period (except for treatment of an exacerbation).
• Subjects with a previous surgery for the removal of nasal polyps are allowed to participate and will be considered as subjects with CRSwNP (with severe asthma or not). However, any subject who had at least one surgery for removal of nasal polyps, even if at study screening he/she is free of nasal polyps, cannot be considered as a subject without CRSwNP.
• Severe asthma patients must meet requirements for biologic therapy with anti-IL5 treatment (Mepolizumab)

Exclusion Criteria:

• Pregnancy
• Current exacerbation at visit 1 (repeat screening when stable). If exacerbation is lasting up until Visit 1a then exclude subject.
• Cognitive impairment preventing completion of data collection forms
• People highly dependent on medical care
• People with significant life limiting co-morbidity
• Other eosinophilic conditions (eosinophilic granulomatosis polyangiitis (Churg-Strauss syndrome), eosinophilic oesophagitis etc)
• Unilateral polyposis
• Primary diagnosis of lung disease other than asthma (chronic obstructive lung disease (COPD), asthma-COPD overlap (ACO), interstitial lung disease, sarcoidosis, bronchiectasis, cystic fibrosis, primary ciliary dyskinesia, active tuberculosis, allergic bronchopulmonary aspergillosis (ABPA))
• Current lung cancer or other blood, lymphatic or solid organ malignancy
• Autoimmune diseases of the skin, muscle-skeletal or gastrointestinal system needing systemic corticosteroids, immunosuppressants or biologic treatment as well as individuals with granulomatosis with polyangiitis (Wegener's granulomatosis)
• Inability to attend study and treatment visits
• Inability to understand and speak Greek or English language

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Severe asthma without CRSwNP; control group; n~20 of anti-IL5 naïve severe asthmatics	Drug: Mepolizumab 100 MG; Patients with SEA eligible to receive anti-IL5 treatment, which is a biologic treatment for SEA
Severe asthma with CRSwNP; n~40 of anti-IL5 naïve severe asthmatics	Drug: Mepolizumab 100 MG; Patients with SEA eligible to receive anti-IL5 treatment, which is a biologic treatment for SEA
subjects CRSwNP with mild or no asthma; ~25;2nd control group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in sputum columnar epithelial cells (CEPs) among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in sputum CEPs in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	We will employ flow cytometry on freshly isolated sputum cell suspensions from participants to measure CEPs proportion and count. Previously proposed cut-off value for normal range sputum CEP proportion (CEP % high = ≥11%) or number (CEP count high = ≥18.1 × 10^4/mL) may be considered.	Baseline and 1 year
Differences in E-cadherin protein level in sputum and nasal secretions among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in E-cadherin protein level in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	Soluble E-cadherin in sputum and nasal secretions measured with ELISA. Data will be expressed as nanograms per milliliter in original sputum/secretion. Cell surface expression of E-cadherin on columnar epithelial cells may be analyzed by flow cytometry.	Baseline and 1 year
Differences in nasal and bronchial epithelial thickness among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in epithelial thickness in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	Epithelial thickness will be determined in biopsies by dividing the epithelial surface area by the basement membrane (BM) length	Baseline and 1 year
Differences in nasal and bronchial epithelial integrity among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in epithelial integrity in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	Epithelial integrity will be assessed in biopsy sections and expressed as percentage (%) of BM covered with normal epithelium (a layer of basal and ciliated columnar epithelial cells without detachment from the BM)	Baseline and 1 year
Differences in nasal and bronchial epithelial E-cadherin expression among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in protein expression in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	Epithelial E-cadherin expression in biopsies will be measure with immonohistochemistry and expressed as the percentage of BM covered with E-cadherin-positive intact epithelium and/or as strong, moderate and weak epithelial E-cadherin staining	Baseline and 1 year
Differences in nasal and bronchial basement membrane thickness (BM) among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in Basement membrane thickness in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	BM thickness in biopsies will be expressed as BM surface area divided by BM length	Baseline and 1 year
Differences in CT-assessed airway wall thickness (WT) among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in WT in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	We will use high resolution computer tomography of the chest to measureairway wall thickness (WT). Airway dimensions will be measured at on contiguous slices of the right apical segmental bronchus and right posterior basal segmental bronchus, from which tangential views of the bronchi can be obtained. The averaged values of the 2 bronchi will be used for analysis	Baseline and 1 year
Differences in CRSwNP stage among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in CRSwNP stage in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	The Lund-Mackay score is widely used in radiological staging of chronic rhinosinusitis. Although there are many scoring systems in place for sinonasal computed tomography (CT) analysis, the Lund-Mackay system has the best inter- and intraob-server agreement. In LMK scoring, the sinuses (maxillary, anterior/posterior ethmoid, sphenoid, and frontal) are each scored on a scale of 0-2 opacification (0, normal; 1, partial opacification; 2, total opacification). The ostiomeatal complex is scored on a two-point scale of 0 and 2 (0, not occluded; 2, occluded). The scores on each side ranged from 0 (complete translucency of all sinuses) to 12 (complete opacity of all sinuses), leading to a total LMK score of 24 for both sides.Of note, an aplastic (absent) frontal sinus receives a score of 0.	Baseline and 1 year
Differences in exacerbation rate among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in exacerbation rate in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	Number of exacerbation in the past 12 months. An exacerbation is defined as worsening of asthma requiring the use of systemic CS and/or emergency department visit, or hospitalisation. For subjects on maintenance oral corticosteroids, an exacerbation requiring oral CS is defined as the use of oral/systemic corticosteroids at least double the existing dose for at least 3 days	Baseline and 1 year
Differences in lung function among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in lung function in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	FEV1 (liters and %predicted), FVC (liters and %predicted, FEV1/FVC (%) including pre and post bronchodilator test	Baseline and 1 year
Differences in need for sinus surgery among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in need for sinus surgery in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	Number (%) of participants with a reduced need for sinus surgery at 1 year. Surgery will be deemed required with an ENP score of >=3, or an ENP score of 2 and a TNSS score of >7. Polyp (ENP) score: 0=No polyps,1=Small polyps in the middle meatus not reaching below the inferior border of the middle turbinate, 2=Polyps reaching below the lower border of the middle turbinate, 3=Large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate, 4=Large polyps causing complete obstruction of the inferior nasal cavity. The higher of the two nostril scores will be derived and used for the analysis. With a VAS (0 to 10 cm) the severity of 4 nasal polyposis symptoms (one VAS for each symptom): rhinorrhea; mucus in the throat; nasal blockage; loss of smell, and for total nasal symptom score (TNSS). The left-hand side of the scale (0) represents "not troublesome," and the right-hand side of the scale (10) represents "worst possible troublesome.	Baseline and 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in total IgE among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in total IgE in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	Total serum IgE (UI/ml)	Baseline and 1 year
Differences in blood eosinophil count among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in blood eosninophil count in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	Blood eosinophil differential counts (number and percentage)	Baseline and 1 year
Differences in sputum eosinophil count among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in sputum eosinophil count in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	Eosinophils count (number x10^4/mL and %) in a differential cell count obtained from induced sputum	Baseline and 1 year
Differences in FeNO among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in FeNO in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	Fractional Exhaled Nitric Oxide (FeNO in parts per billion)	Baseline and 1 year
Differences in Asthma Control Test (ACT) among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in asthma control in1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	ACT includes 5 items, with 4-week recall (on symptoms and daily functioning). More specifically, ACT assesses the frequency of shortness of breath and general asthma symptoms, use of rescue medications, the effect of asthma on daily functioning, and overall self-assessment of asthma control. There is 5-point scale (for symptoms and activities: 1=all the time to 5= not at all; for asthma control rating: 1=not controlled at all to 5=completely controlled).The scores range from 5 (poor control of asthma) to 25 (complete control of asthma), with higher scores reflecting greater asthma control. An ACT score >19 indicates well-controlled asthma.	Baseline and 1 year
Differences in quality of life among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in quality of life in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	With the Asthma Quality of Life Questionnaire (AQLQ) we will assess quality of life and psychological morbidity. The Asthma Quality of Life Questionnaire (AQLQ) is a 32-item questionnaire used to assess the physical, occupational, emotional, and social qualities of adults aged 17 to 70 years with asthma (Juniper et al, 2005). The AQLQ has 4 domains: symptoms (12 items), activity limitation (6 generic and 5 patient-specific items), emotional function (5 items), and environmental stimuli (4 items). The AQLQ was developed for patients exhibiting mild to moderate asthma (Aburuz et al, 2007). The AQLQ items are each scored on a 7-point Likert scale, with 1 representing maximal impairment and 7 representing no impairment. The original AQLQ includes 5 patient-specific questions in the activity limitation domain. As part of the initial interview, the patient indicates 5 activity limitations due to asthma. These 5 activity limitations are used for the remaining follow-up visits.	Baseline and 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in Asthma Control Questionnaire (ACQ) among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in asthma control in1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	ACQ has a multidimensional construct assessing symptoms (5 items--self-administred) and rescue inbronchodilator use (1 item-self-administered) with 1 week recall (for items on symptoms and rescue inhaler use), and FEV1% (1 item) completed by clinic staff. There is 7-point scale (0=no impairment, 6= maximum impairment for symptoms and rescue use; and 7 categories for FEV1%) and scores range between 0 (totally controlled) and 6 (severely uncontrolled). ACQ >1.5 will be considered inadequately controlled asthma	Baseline and 1 year
Differences in CT-assessed airway wall thickness percentage (WT%) among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in WT% in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	We will use high resolution computer tomography of the chest to measure the WT% calculated using the formula [WT/outer dimaeter] × 100), on contiguous slices of the right apical segmental bronchus and right posterior basal segmental bronchus, from which tangential views of the bronchi can be obtained. The averaged values of the 2 bronchi will be used for analysis	Baseline and 1 year
Differences in CT-assessed percentage of wall area (WA%) among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in WA% in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP	We will use high resolution computer tomography of the chest to measure the percentage of wall area (WA%) calculated using the formula [airway wall area/outer area of the bronchus] × 100), on contiguous slices of the right apical segmental bronchus and right posterior basal segmental bronchus, from which tangential views of the bronchi can be obtained. The averaged values of the 2 bronchi will be used for analysis	Baseline and 1 year

Collaborators and Investigators

• Sponsor: University of Crete

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2022
• Primary Completion (Estimated): May 15, 2025
• Study Completion (Estimated): November 16, 2025

Study Registration Dates

• First Submitted: January 18, 2022
• First Submitted That Met QC Criteria: May 3, 2022
• First Posted (Actual): May 9, 2022

Study Record Updates

• Last Update Posted (Actual): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 17, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Hematologic Diseases; Bronchial Diseases; Otorhinolaryngologic Diseases; Pathological Conditions, Anatomical; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Nose Diseases; Leukocyte Disorders; Polyps; Eosinophilia; Hypereosinophilic Syndrome; Asthma; Nasal Polyps; Pulmonary Eosinophilia
• Other Study ID Numbers: 10961[213755]

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No