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Gene Expression Profile and Inflammation Profile of Classic Asthma, Cough Variant Asthma and Eosinophilic Bronchitis

This study is currently recruiting participants.
See Contacts and Locations
Verified September 2015 by Rui Zhang, State Key Laboratory of Respiratory Disease
Sponsor:
Information provided by (Responsible Party):
Rui Zhang, State Key Laboratory of Respiratory Disease
ClinicalTrials.gov Identifier:
NCT02555345
First received: September 7, 2015
Last updated: September 17, 2015
Last verified: September 2015
  Purpose
This study aims to identify and validate the gene expression differentials of peripheral blood mononuclear cells and differential inflammation profiles and other aspects in classic asthma, cough-variant asthma and eosinophilic bronchitis.

Condition
Asthmatic Bronchitis

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Cross-Sectional
Official Title: Difference in Gene Expression Profile in Peripheral Blood Mononuclear Cells and Inflammation Profile in Patients With Classic Asthma, Cough Variant Asthma, and Eosinophilic Bronchitis Compared With Healthy Controls

Resource links provided by NLM:


Further study details as provided by Rui Zhang, State Key Laboratory of Respiratory Disease:

Primary Outcome Measures:
  • Difference in Gene Expression Profile of Peripheral Blood Mononuclear Cells in Classic Asthma,Cough Variant Asthma and Eosinophilic Bronchitis Compared with Healthy Controls [ Time Frame: 15 months ]
    Five milliliters of venous blood was collected. The peripheral blood mononuclear cells(PBMC) were isolated by the Ficoll-Paque plus(GE Healthcare Bio-Sciences Corp, NJ ) according to the manufacture's recommendations. RNA from PBMC was extracted. RNA-seq, a high throughput RNA sequencing technology, would characterize the transcriptome by sequencing complementary cDNAs followed by mapping of the sequence reads to the genome.


Secondary Outcome Measures:
  • Induced sputum cytology [ Time Frame: 15 months ]
    Before sputum induction, subjects were instructed to rinse their mouth to remove any cellular debris. Nebulization was conducted using 3% saline via an ultrasonic nebulizer. Following expectoration into the clear sterile plastic pot, the sputum plugs were weighed and treated with 4 aliquots of dithiothreitol to completely dissolve the mucus. The mixture was subsequently vortexed, shaked and centrifuged. The supernatant was stored at -80℃ for inflammation profile analysis. The cell pallets were mounted on a glass slide for fixation with polyaldehyde and Haematoxylin-eosin staining. Samples with 5% or fewer epithelial cells of the total cell count were deemed eligible. This entailed counting of 400 non-squamous cells for cytology assessment. Inflammation phenotype was assigned based on a sputum eosinophil cutoff of greater than 3% and a sputum neutrophil cutoff of greater than 61%.

  • Airway inflammation indices [ Time Frame: 15 months ]
    Sputum Interleukin-1β(IL-1β), IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, IL-17, G-CSF, GM-CSF, IFN-γ, IP-10 (CXCL10), MCP-1 (CCL2), MIP-1β(CCL4) and C-reactive protein (CRP) were measured using Luminex xMAP multiplex technology. Comparison in airway inflammation in patients with classic asthma, cough variant asthma and eosinophilic bronchitis was performed.

  • Fractional exhaled nitric oxide Measurements [ Time Frame: 15 months ]
    Fractional exhaled nitric oxide Measurements will be performed by using a NIOX MINO device(Aerocrine, Sweden),based on the recommendations of international guidelines. The relationship between FENO levels and eosinophilic airway inflammation was assessed in patients with classic asthma, cough variant asthma and eosinophilic bronchitis.

  • Peripheral blood eosinophil counts, serum IgE assessment [ Time Frame: 15 months ]
    Blood was drawn for differential and total cell counts.Serum total Immunoglobulin E(IgE) and specific IgE was measured using the Unicap system(Pharmacia Diagnostics, Uppasala, Sweden ).Relationship between peripheral blood eosinophilia and IgE was assessed.Relationship between peripheral blood eosinophilia and sputum eosinophilia was assessed.Relationship between FENO and peripheral blood eosinophilia was assessed.Relationship between FENO and sputum eosinophilia was assessed.

  • Cumulative provocative dose causing 20% fall in FEV1 measured through the Methacholine bronchial challenge test [ Time Frame: 15 months ]
    Spirometric values at the baseline are referred to as FEV1, FVC, FEV1/FVC and MMEF. Spirometry tests are carried out using a spirometer (Jaeger, Germany). All operation procedures meet the joint recommendation by ATS and ERS.The predicted values are selected based on the reference regression model established by Jinping Zheng and nanshan Zhong.Methacholine bronchial challenge test was performed only in subjects with a baseline FEV1 greater than 60% predicted using hand-squeeze nebulizers.The bronchial challenge was ceased in case of FEV1 fall being 20% or greater, or the maximal cumulative dose of methacholine (2.50mg) had been given. Airway hyperresponsiveness (AHR) was defined as 20% or greater fall in FEV1.The cumulative provocative dose causing 20% fall in FEV1 (PD20FEV1-MCh) was reported in subjects with AHR. Relationship between FENO,serum IgE,airway and systematic inflammation and AHR was assessed.

  • Using LCQ to evaluate the impact of cough on recruited patients with classic asthma, CVA and EB. [ Time Frame: 15 months ]
    The questionnaire of Leicester Cough Questionnaire(LCQ) comprises 19 questions. Scores range from 3 to 21, with higher scores representing a better quality of life. Comparison in LCQ total scores in patients with classic asthma, cough variant asthma and eosinophilic bronchitis was performed.

  • Circulating markers of inflammation [ Time Frame: 15 months ]
    Serum was collected for analysis of systematic inflammation.systematic inflammation indices including IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, IL-17, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1βand CRP.Comparison in systematic inflammation in patients with classic asthma, cough variant asthma and eosinophilic bronchitis was performed.


Biospecimen Retention:   Samples With DNA
Blood sample collection for future analysis (including genetic tests on DNA) on the pathobiology of diseases.

Estimated Enrollment: 250
Study Start Date: October 2014
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Groups/Cohorts
classic asthma/No intervention
Patients with classic asthma were stable.Chest X-ray or CT scan was normal.Fenofibrate(FeNO) was performed.Spirometry was needed. The leicester cough questionnaire (LCQ) was offered to physicians.Sputum,blood and urine samples were collected to study genetic, inflammation and other aspects of these diseases.
CVA/No intervention
Chest X-ray or CT scan was normal.FeNO was performed. Spirometry was needed. The LCQ was offered to physicians. Sputum,blood and urine samples were collected to study genetic, inflammation and other aspects of these diseases.
EB/No intervention
Chest X-ray or CT scan was normal.FeNO was performed. Spirometry was needed. The LCQ was offered.Sputum,blood and urine samples were collected to study genetic, inflammation and other aspects of these diseases.
Healthy/No intervention
Chest X-ray or CT scan was normal.FeNO was performed.Spirometry was needed. Sputum,blood and urine samples were collected to study genetic, inflammation and other aspects of these diseases.

Detailed Description:

Asthma is a common and heterogeneous respiratory disorder affecting millions of people, posing a considerable burden on health care systems globally. The disease is characterized by inflammation of the airways with eosinophils, neutrophils, mast cells, lymphocytes, airway epithelial cells, smooth muscle cells and other cells, by airflow obstruction and by bronchial hyperresponsiveness. The disease is triggered by multiple gene-environment interactions. Asthma heterogeneity is recognized in terms of clinical phenotypes of asthma whereby classic asthma (CA) and cough variant asthma (CVA) are identified. classic asthma is a common phenotype of asthma that presents episodic dyspnoea and wheezing with or without cough. Cough variant asthma is a phenotype of asthma that presents solely cause of chronic cough.

Eosinophilic bronchitis (EB) is a common cause of chronic cough, which like eosinophils asthma is characterized by airway eosinophilic inflammation, but unlike asthma there is no airway hyperresponsiveness or variable airflow obstruction.

Improvement of disease diagnosis and management require a better understanding of disease heterogeneity. A useful biomarker for phenotype recognition will represent underlying pathologic mechanisms of disease, marking heterogeneity and guiding personalized treatment approaches. Our hypothesis was that the different clinical manifestos in patients with eosinophilic bronchitis, classic asthma, and cough-variant asthma could be caused by differential gene expression profiles of peripheral blood mononuclear cells (PBMC) and differential inflammation profiles and other aspects.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
All of subjects with classic asthma, CVA, eosinophilic bronchitis, and healthy volunteers are recruited from respiratory outpatient clinics and from staff at the First Affiliated Hospital of Guangzhou Medical College between October 25, 2014 and January 20,2016.
Criteria

Inclusion Criteria:

The patients with classic asthma inclusion criteria Asthmatic patient inclusion criteria

  1. Male or female patients aged ≥ 18 and ≤ 65, who have signed an Informed Consent form prior to initiation of any study-related procedure.
  2. The patients with classic asthma had a history of episode dyspnea and wheezing with or without cough.
  3. Clinical diagnosis of asthma confirmed by a chest physician according to international guidelines (GINA 2014); methacholine airway hyperresponsiveness (provocative concentration of methacholine causing a 20% fall in FEV1(forced expiratory volume at one second )【PD20】),>12% improvement in FEV1 10 min after inhaling 200ug of salbutamol.
  4. None of the patients with classic asthma had used inhaled or oral corticosteroids, long-acting β2-agonists, leukotriene antagonists, sodium cromoglycate,or nedocromil sodium, anticholinergic agents, during four weeks prior to entry into the study.

The patients with CVA inclusion criteria

  1. Male or female patients aged ≥ 18 and ≤ 65, who have signed an Informed Consent form prior to initiation of any study-related procedure.
  2. The diagnosis of CVA is based on isolated cough lasting for ≥ 8 weeks without wheezing or dyspnea, airway hyperresponsiveness (AHR), and relief of cough with bronchodilators according to recommendations in the Chinese national guidelines on the diagnosis and management of cough.
  3. None of the patients with CVA had used inhaled or oral corticosteroids, long-acting β2-agonists, leukotriene antagonists, sodium cromoglycate,or nedocromil sodium, anticholinergic agents, during four weeks prior to entry into the study.

The patients with EB inclusion criteria

  1. Male or female patients aged ≥ 18 and ≤ 65, who have signed an Informed Consent form prior to initiation of any study-related procedure.
  2. The diagnosis of EB is based on cough lasting for ≥ 8 weeks according to recommendations in the Chinese national guidelines on the diagnosis and management of cough.
  3. None of the patients with EB had used inhaled or oral corticosteroids, long-acting β2-agonists, leukotriene antagonists, sodium cromoglycate,or nedocromil sodium, anticholinergic agents, during four weeks prior to entry into the study.

Healthy subjects inclusion criteria

  1. Male or female patients aged ≥ 18 and ≤ 65, who have signed an Informed Consent form prior to initiation of any study-related procedure.
  2. Normal spirometry: baseline FEV1 ≥ 80% of the predicted normal value, FEV1/FVC(forced vital capacity) > LLN (lower limit of normal).
  3. Normal airways responsiveness.
  4. Healthy subjects have no any disease or negative allergen skin prick test results.

Exclusion Criteria:

Patients with classic asthma, CVA and EB exclusion criteria

The presence of any of the following will exclude a subject from study enrolment:

Current smokers, ex-smokers. Individuals with respiratory infection during the previous one month. Clinical history of chronic obstructive pulmonary disease(COPD), bronchiectasis, pulmonary embolism.

Clinical history of haematological, immunologic, renal, neurologic, hepatic, endocrinal or other disease, or any condition that might compromise the results or interpretation of the study.

Asthma exacerbation and unstable asthma . Pregnant or lactating women.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02555345

Contacts
Contact: Kefang Lai, PHD 8620-83062887 klai@163.com
Contact: Nanshan Zhong, MD 8620-83062718 nanshan@vip.163.com

Locations
China, Guangdong
The First Affiliated Hospital of Guangzhou Medical University Recruiting
Guangzhou, Guangdong, China, 510120
Contact: Kefang Lai, PHD    8620-83062887    Klai@163.com   
Contact: Nanshan Zhong, MD    8620-83062718    nanshan@vip.163.com   
Sub-Investigator: Rui Zhang, PHD         
Sub-Investigator: Hongkai Wu, PHD         
Sponsors and Collaborators
State Key Laboratory of Respiratory Disease
Investigators
Principal Investigator: Kefang Lai, PHD The First Affiliated Hospital of Guangzhou Medical University
  More Information

Responsible Party: Rui Zhang, RUI ZHANG, State Key Laboratory of Respiratory Disease
ClinicalTrials.gov Identifier: NCT02555345     History of Changes
Other Study ID Numbers: RZ-689
Study First Received: September 7, 2015
Last Updated: September 17, 2015

Keywords provided by Rui Zhang, State Key Laboratory of Respiratory Disease:
classic asthma, cough variant asthma,eosinophilic bronchitis

Additional relevant MeSH terms:
Asthma
Inflammation
Bronchitis
Acute Disease
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Pathologic Processes
Respiratory Tract Infections
Disease Attributes

ClinicalTrials.gov processed this record on August 18, 2017