Asthma Origins and Remission Study
Asthma Origins and Remission Study
Asthma is characterized by chronic airway inflammation of the large and small airways. Asthma
 patients often have episodes with symptoms of dyspnea, wheezing and nocturnal awakening.
 Currently available inhaled anti-inflammatory treatments reduce the airway inflammation and
 treatment but do not cure the disease. Therefore asthma patients often need life-long
 treatment to control their asthma.

 In a small subset of patients, their asthma resolves spontaneously. This phenomenon is called
 asthma remission. Subjects with asthma remission do not experience symptoms or signs of
 airway inflammation anymore and do not require inhaled treatments. Some subjects with asthma
 remission also have a completely normal lung function without signs of bronchial
 hyperresponsivess: they have complete asthma remission. Unfortunately, asthma remission
 occurs only in a small subset of 15-25% of asthma patients.Objective: to determine the
 underlying mechanisms and molecular events leading to remission of asthma.
Rationale: Asthma inception occurs only in susceptible individuals, and is often triggered by
 specific environmental factors, such as respiratory viruses and aeroallergens. Although
 asthma is generally viewed as a chronic persistent disease, remission of asthma is possible
 in a subset of patients. This is highly relevant, since understanding mechanisms that
 contribute to asthma inception and remission may teach us how asthma can be stopped and thus
 may provide novel avenues for the treatment of asthma. In adulthood, average remission rates
 of asthma are approximate 2% per year 1. We observed that remission in adulthood is more
 likely with earlier onset of asthma, less airway obstruction, more severe bronchial
 hyperresponsiveness, and smoking cessation. A proper definition of remission is very
 important; we therefore introduced the terms 'clinical remission' and 'complete remission' 2.
 Clinical remission was defined as the absence of asthma symptoms and no use of asthma
 medication, complete remission as the absence of asthma symptoms, no use of asthma
 medication, normal lung function and no bronchial hyperresponsiveness. In a longitudinal
 study of 119 allergic asthmatic children followed-up for 30 years, our group found that
 clinical remission occurred in 30% and complete remission in 22% of all cases.

 Objective: to determine the underlying mechanisms and molecular events involved in the
 inception and remission of asthma.

 Methods: We will include a 40 subjects divided over the following 4 groups: i) clinical
 asthma remission (10 subjects), ii) complete asthma remission (10 subjects), iii) ongoing
 asthma (10 patients), iv) non-asthmatic healthy controls (10 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 remission. Finally,
 bronchoscopy with bronchial biopsies and brushes will be performed under conscious sedation.
 Bronchial biopsies from all four patient groups will be used for index FACS sorting of the
 three most important cell types orchestrating the asthmatic inflammatory process: i.e. B
 lymphocytes, CD4+ T cells and CD8+ T cells. We will perform single cell whole-genome
 transcriptome sequencing on at least 100 cells of each type and the primary outcome of the
 study is to identify how the transcriptomic profile of bronchial epithelial cells is changed
 between asthma patients and healthy controls as a consequence of asthma inception and what
 transcriptomic profile changes occur in CD4+ CD8+ and B lymphocytes in the airways from
 subjects with asthma remission compared to patients with ongoing asthma and healthy controls.
Inclusion criteria for all subjects:

 -  Age between 40 and 65 years old.

 -  Smoking history ≤ 10 packyears.

 Inclusion criteria for all asthmatics and asthma remission subjects:

 • Development of asthma symptoms before 21 years.

 Specific inclusion criteria for the 4 different groups:

 -  Group 1. Subjects with clinical asthma remission:

 -  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.

 -  No use of asthma medications such as inhaled or oral corticosteroids, β2-agonists
 or anticholinergic in the last 3 years.

 -  No symptoms of wheeze or asthma attacks during the last 3 years.

 -  Group 2. Subjects with complete asthma remission

 -  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.

 -  No use of asthma medications such as inhaled or oral corticosteroids, β2-agonists
 or anticholinergics in the last 3 years.

 -  No symptoms of wheeze or asthma attacks during the last 3 years.

 -  FEV1 > 90% predicted.

 -  Absence of bronchial hyperresponsiveness, i.e. both PC20 methacholine > 8 mg/ml
 and PC20 AMP > 320 mg/ml.

 -  Group 3. Patients with ongoing asthma

 -  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.

 -  Use of inhaled corticosteroids 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.

 -  PC20 methacholine < 8 mg/ml.

 -  Group 4. Non-asthmatic controls

 -  No history of asthma.

 -  No use of inhaled corticosteroids or β2-agonists for a period longer than 1
 month.

 -  No symptoms of wheeze, nocturnal dyspnea, or bronchial hyperresponsiveness.

 -  PC20 methacholine > 8 mg/ml, FEV1/FVC > 70% and FEV1 > 80% predicted.