To determine underlying mechanisms and molecular events in asthma.
ID
Source
Brief title
Condition
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Identify key in vivo pathogenic features of airway wall cells in asthma, as
reflected by single-cell transcriptomics of primary bronchial epithelial cells
(BEC), as well as mesenchymal, endothelial and immune cells.
Secondary outcome
Questionnaires: ELON, ACQ, SADT and post-bronchoscopy questionnaire.
Spirometry: FEV1, FVC, FEF25, FEF50, FEF75, FEF 25-75.
Body box: TLC, RV< FRC, VC, IVC, airway conductance, airway resistance.
Impulse oscillometry: R5, R20, X5, R5-R20.
Skinpricktest for allergies
Blood: Hemoglobin, leukocytes and differentiation, trombocytes. DNA, RNA, total
IgE, phadiatop and CRP. PBMCs.
Provocation with methacholine.
HRCT scan
NO measurement in different airflow.
Multiple breath Nitrogen Washout test.
Cell countin sputum.
mRNA, microRNA, long non-coding RNA and DNA methylation in airway biopties and
brushes.
Background summary
Asthma is characterized by chronic airway inflammation, which is multifactorial
in origin. It is a heterogeneous disease, characterized by chronic airway
inflammation, mucus hypersecretion, airway hyperresponsiveness,
bronchoconstriction and airway wall remodeling. The underlying mechanisms of
this complex disease are not yet understood but previous studies find a genetic
predisposition. Several lines of evidence indicate that in asthma patients the
airway epithelium is primarily affected, including increased basal cell
proliferation, a loss of differentiated epithelial cells and reduced numbers of
ciliated cells. In order to further identify and study the mechanisms, clinical
information and single cell RNA analyses on epithelial cells from the bronchi
and nose will combined in this study.
Study objective
To determine underlying mechanisms and molecular events in asthma.
Study design
We will include 78 subjects divided over three groups: asthma patients (52
subjects) of which half stop their medication and half does not, and
non-asthmatic healthy controls (26 subjects) in a cross-sectional study. All
subjects will be extensively clinically characterized including respiratory
symptoms/questionnaires, in- and expiratory CT-scans, and parameters of large
and small airway function and inflammation. In addition, blood and nasal
epithelial brushes will be obtained to study the genetic and epigenetic
mechanisms of asthma. Finally, bronchoscopy with bronchial biopsies and brushes
will be performed under conscious sedation. Bronchial biopsies from both
patient groups will be used for single cell transcriptional analysis.
Study burden and risks
Risks for participants in this study are:
1. Developing or worsening of asthma symptoms.
2. Dyspnea during sputum induction and provocation test with methacholine.
3. Bronchospasm during bronchoscopy and / or desaturation during the
bronchoscopy.
Measures for treatment or prevention:
Ad 1: Subjects who cease medication in order to partake will perform a baseline
spirometry and if there is a fall of 15% in FEV1, subjects will be excluded.
Ad 2: Before the sputum induction and after the methacholine every subject will
be given inhaled salbutamol to prevent or treat dyspnea.
Ad 3: If bronchospasms occur during the bronchoscopy the procedure will be
stopped immediately and if necessary subject will be given extra bronchodilator
medication by inhalation. This will treat bronchospasm properly. Monitoring of
oxygen saturation will be performed during the whole procedure. If
necessary the bronchoscopy will be stopped.
Hanzeplein 1
Groningen 9713GZ
NL
Hanzeplein 1
Groningen 9713GZ
NL
Listed location countries
Age
Inclusion criteria
All groups:
• Age between 18 and 65.
o Group 1. Patients with asthma, GINA step 1-3 (who stop using ICS/LABA in
order to partake in the study)
• Documented history of asthma diagnosed according to latest GINA guidelines,
i.e. respiratory symptoms and either bronchodilator reversibility (improvement
in FEV1 of more than 12% of baseline (and at least 200 mL) after inhalation of
800 µg salbutamol) or PC20 methacholine < 8 mg/ml.
• Use of low or medium dose inhaled corticosteroids, possibly combined with
LABA (as GINA step 2-3) at baseline or either persistent symptoms of wheeze,
cough, or dyspnea or regular use of β2 agonists at least once a week during the
last 2 months (step 1).
o Group 2: Patients with asthma GINA class 2-5 (who continue using their
medication)
• Documented history of asthma diagnosed according to latest GINA guidelines,
i.e. respiratory symptoms and either bronchodilator reversibility (improvement
in FEV1 of more than 12% of baseline (and at least 200 mL) after inhalation of
800 µg salbutamol) or PC20 methacholine < 8 mg/ml.
• Use of inhaled or oral corticosteroids.
o Group 3: Non-asthmatic controls
• No history of asthma.
• No use of inhaled corticosteroids or β2-agonists for a period longer than 1
month in their lifetime and not during the 6 weeks before inclusion.
• No symptoms of wheeze, nocturnal dyspnea, or bronchial hyperresponsiveness.
• PC20 methacholine > 8 mg/ml, FEV1/FVC > 70% and FEV1 > 80% predicted.
Exclusion criteria
• FEV1 <1.2 L,
• Subjects must be able to adhere to the study visit schedule and other
protocol requirements.
• A subject is not eligible to enter and participate if he has not signed and
dated a written informed consent form prior to participation in the study.
• A subject is not eligible to enter and participate if he does not agree that
we inform his general practitioner and will inform them of incidental findings.
• Upper respiratory tract infection (e.g. colds), within 6 weeks.
• Serious acute infections (such as hepatitis, pneumonia or pyelonephritis) in
the previous 3 months.
• Signs or symptoms of severe, progressive or uncontrolled renal, hepatic,
hematologic, endocrine, pulmonary, cardiac, neurologic or cerebral disease.
• Malignancy within the past 5 years (except for squamous or basal cell
carcinoma of the skin that has been treated with no evidence of recurrence).
• Known recent substance abuse (drug or alcohol).
• Females of childbearing potential without an efficient contraception unless
they meet the following definition of post-menopausal: 12 months of natural
(spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH
>40 mIU/mL or the use of one or more of the following acceptable methods of
contraception:
a) Surgical sterilization (e.g. bilateral tubal ligation,
hysterectomy).
b) Hormonal contraception (implantable, patch, oral, injectable).
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | NL201900308 |
| CCMO | NL69765.042.19 |