This study aims to determine whether the ILC populations differ in the lungs of different phenotypes of asthmatic patients and healthy subjects and how these cells are regulated by bronchial epithelial cells. Furthermore we want to study how this is…
ID
Source
Brief title
Condition
- Allergic conditions
- Viral infectious disorders
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part 1
1. Determination of the different ILC populations in the lungs and peripheral
blood of allergic and non-allergic asthma patients, both with high blood
eosinophils and compare these to healthy non-allergic controls
2. Determination of the differences in innate cytokine production between
bronchial epithelial cells from these groups, at baseline and after in vitro
RV16 infection.
3. Study the interactions between ILCs and bronchial epithelial cells, DCs, B
cells and eosinophils.
Part 2
1. Investigate the effects of a RV16-induced exacerbation in asthmatics and
healthy subjects on the proportion of the different pulmonary and peripheral
blood ILC populations, as well as their activation and cytokine production.
2. Determination of the differences in innate cytokine production between
bronchial epithelial cells from these groups, at baseline and after
experimental RV16 infection.
3. Study the interaction between bronchial epithelial cells obtained before and
after experimental RV16 infection and ILCs.
Secondary outcome
Part 1
1. Other immunological parameters, such as BAL cellular influx (neutrophils,
eosinophils, basophils, T cells, B cells, macrophages, NK cells) and
inflammatory mediator production.
2. Asses if the ILC populations in the lungs correlate with BAL cellular
influx, inflammatory mediator production, lung function parameters.
3. Assess oxidative stress and cyto-protective responses in sputum supernatant
and sputum macrophages.
Part 2
1. Difference in maximum drop in FEV1, change in baseline morning or evening
FEV1 on days 1-14 after RV16 challenge after RV16 infection between healthy and
asthmatic subjects.
2. Effects on Asthma Control Diary (ACD) and Wisconsin Upper Respiratory
Symptom Survey - 21 question version (WURSS-21).
3. Other immunological parameters, such as BAL cellular influx (neutrophils,
eosinophils, basophils, T cells, B cells, macrophages, NK cells) and
inflammatory mediator production.
4. Assess if the different ILC populations in the lungs after RV16 challenge
correlate with clinical parameters, such as the maximum drop in FEV1, change in
baseline morning or evening FEV1 on days 1-14 after RV16 challenge, ACD and
WURSS-21.
5. Detection of RV16 specific B cells.
6. Assess oxidative stress and cyto-protective responses in sputum supernatant
and sputum macrophages.
Background summary
Asthma is a very heterogeneous disease and recent studies have come up with
different phenotypes of asthma. Many patients with asthma frequently suffer
from exacerbations, which are characterized by episodes of acute aggravation of
their symptoms. The majority of asthma exacerbations have a viral etiology,
rhinovirus being the most prominent pathogen. The mechanisms underlying these
exacerbations are still not completely understood. We recently discovered of
type 2 human innate lymphoid cells (ILC2s) capable of promptly producing high
amounts of IL-5, IL-9 and IL-13 upon activation. Murine studies point to an
essential role of these cells in asthma and asthma exacerbations, ILC2 may be
the main initiating cells in type 2 responses in asthma and asthma
exacerbations in humans. The activation of these cells is driven by IL-33,
IL-25 and TSLP, which are mainly produced by bronchial epithelial cells.
Study objective
This study aims to determine whether the ILC populations differ in the lungs of
different phenotypes of asthmatic patients and healthy subjects and how these
cells are regulated by bronchial epithelial cells. Furthermore we want to study
how this is affected by rhinovirus infection.
Study design
Part 1:
After screening the patients will have one visit were blood will be drawn and a
bronchoscopy will be performed. During the bronchoscopy a lavage will be done,
an epithelial brush and 6 biopsies will be taken.
Part 2:
After screening the participants will undergo 2 bronchoscopies. During the
bronchoscopy a lavage will be done, an epithelial brush and 6 biopsies will be
taken. This will be done 5 days before and 2 days after infection with RV16.
Moreover blood will be drawn on day -5, 2, 14 and 6-8 weeks after RV16 and lung
function tests will be done. OPtionally on day -1 and 6 a sputum induction will
be performed.
Intervention
In part 2 all participants will undergo a RV16 infection.
Study burden and risks
Part 1:
2 visits, 2x blood sampling, 2x lung function tests and 1x bronchoscopy
Part 2:
6 visits, 5x blood sampling, 5x lung function tests and 2x bronchoscopy, 1x
RV16 infection and during 3 weeks daily recording of common cold and asthma
scores and their FEV1 in a diary.
2 optional visits for sputum collection.
The bronchoscopy, with a lavage, brushes and biopsies, is an invasive procedure
that- even though lidocaine anesthesia is applied- can be unpleasant and can
induce dry cough and a sore throat. The brushing of the airways and the
biopsies can give rise to a superficial bleeding which usually stops rapidly.
The experimental infection with RV16 will induce common cold complaints,
probably to a lesser extend in the healthy volunteers. RV16 infection can
exacerbate the asthma complaints.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
Asthmatic patients part 1:
Adult-onset eosinophilic asthma patients with a physician*s diagnosis of asthma that started after the age of 18.
Stable on asthma medication, no exacerbation or changes in asthma medication in the past 4 weeks.
Non-smoking, or ex-smoking (<10py) if the patient has at least 12% improvement in FEV1 after inhalation of 400 µg salbutamol.
Sputum eosinophilia >3%.
Atopic and non-atopic patients will be distinguished based on total serum IgE. Atopy will be defined as a serum IgE levels >= 100.;Asthmatic patients part 2:
Mild-moderate asthmatic patients will be selected using the following inclusion
Age between 18 - 50 years at the screening visit
History of episodic chest tightness and wheezing
Controlled asthma according to the criteria by the Global Initiative for Asthma
Non-smoking or stopped smoking more than 12 months ago and <= 5 pack years (PY)
Clinically stable, no exacerbations within the last 6 weeks prior to the study
Use of ICS at a stable dose-equivalent of <= 500mcg/day fluticasone propionate
Baseline FEV1 > 80% of predicted
Airway hyperresponsiveness, indicated by a positive acetyl-ß-methylcholine bromide (MeBr) challenge with PC20 < 9.8 mg/ml
Positive skin prick test (SPT) to one or more of the 12 common aeroallergen extracts, defined as a wheal with an average diameter of >3 mm;Control subjects:
Age between 18 - 65 years at the screening visit
Non-smoking or stopped smoking more than 12 months and <= 5 PY
Baseline FEV1 > 80% of predicted
MeBr challenge with PC20 > 9.8 mg/ml
Steroid-naïve or those participants who are currently not on corticosteroids and have not taken any corticosteroids by any dosing-routes within 8 weeks prior to the study
Negative history of pulmonary or any other relevant diseases
Exclusion criteria
For part 1 and 2:
Women who are pregnant, lactating or have a positive urine pregnancy test at visit 1
Participation in any clinical investigational drug treatment protocol within the preceding 30 days
Concomitant disease or condition which could interfere with the conduct of the study, or for which the treatment might interfere with the conduct of the study, or which would, in the opinion of the investigator, pose an unacceptable risk to the patient;Furthermore the following additional exclusion criteria will be used in part 2 of the study:
RV16 titre > 1:6 in serum, measured at visit 1
History of clinical significant hypotensive episodes or symptoms of fainting, dizziness, or light-headedness
Usage of high dose ICS (>500 µg/day to fluticasone or equivalent). Use of low or medium dose ICS (<=500 µg/day fluticasone or equivalent) with or without permitted controller medications e.g LABA, LTRA is allowed
Experience of an asthma exacerbation in the 12 weeks prior to visit 1 requiring management with systemic steroids
Has had any acute illness, including a common cold, within 4 weeks prior to visit 1
Ongoing use of tobacco products of any kind or previous usage with >= 6 total PY
Close contact with young children (< 2 years)
Has donated blood or has had a blood loss of more than 450 mL within 60 days prior to screening visit 1 or plans to donate blood during the study
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 |
|---|---|
| CCMO | NL48912.018.14 |
| Other | NTR zal worden aangevraagd |