The purpose of the study is to compare airway physiologic reactions to physical exercise in a cold air environment (-5°C, 60% relative humidity) between normal volunteers and subjects with mild/moderate asthma. For this purpose, the investigators intend to evaluate the effect of a cold air exercise test on the Forced Expiratory Volume in 1 second (FEV1), respiratory symptoms, functional airway integrity, local and systemic inflammation and on the airway microbiome.

This study also features as an exploratory study for a subsequent interventional study in order to establish the feasibility of the cold air exercise protocol and to determine the extent of the effects in subjects with mild/moderate asthma.

It is already demonstrated that exercising during cold air exposure and at a high altitude may induce asthmatic symptoms, a variable degree of airway obstruction and increased neutrophilic airway inflammation in asthmatic patients. Therefore, in this project, the investigators want to evaluate the feasibility, of a shorter standardized "cold air exercise test" (a submaximal exercise challenge in a controlled cold air (-5°C, relative humidity 60%) environment) and to compare the respiratory physiologic reactions to physical exercise during cold exposure between healthy volunteers and asthmatic patients. For this purpose, they intend to evaluate the effect of a cold air exercise test on FEV1, respiratory symptoms, functional airway integrity, local and systemic inflammation and on the airway microbiome.

This study features as an exploratory study for a subsequent interventional study, that will assess the protective effect of azithromycin versus placebo on the cold air exercise induced changes in patients with mild/moderate asthma (ALASCAIR2 study). The present preparatory study is needed to standardize the cold air exercise test in a controlled environment so that it would be possible to use it as challenge test in an interventional study and to identify the most appropriate design for such a study.

The primary objective of this study is to compare the proportional change in FEV1, pre to post a 90 minutes submaximal exercise in a cold air environment between healthy volunteers versus mild/moderate asthmatics, calculated as a time-weighted average over the 30 minutes post-exposure.

The primary endpoint is the change in FEV1, calculated as a time-weighted average over the 30 minutes after the cold exercise test. At each time point (pre-exposure, 5' post-exposure, and at 15, 25 and 35 minutes post-exposure), FEV1 (L) will be measured in triplicate.

They want to evaluate whether the exercise test in a cold air environment produces respiratory symptoms (such as nasal discharge or obstruction, dyspnea, cough and/or mucus production, etc.), has an impact on airway integrity (nasal patency, airflow obstruction, lung ventilation inhomogeneity & small airway dysfunction, bronchial hyperreactivity, cough reflex hypersensitivity), induces local or systemic inflammatory changes (biomarkers in nasal fluid, sputum and blood) or changes to the airway microbiome (in nasal fluid and sputum) in healthy volunteers and in mild/moderate asthmatics. The study group also want to compare the observed changes induced by the cold air exercise test between the healthy volunteers and the mild/moderate asthmatics.

The secondary endpoints of this study include the observed changes in (respiratory) symptom score, Peak Nasal Inspiratory Flow (PNIF), Forced Vital Capacity (FVC), Forced Expiratory Flow (FEF25-75), Fraction of Exhaled Nitric Oxide (FeNO), histamine provocative concentration causing 20% drop in FEV1 (PC20), cough threshold C2 & C5, sputum differential cell count, biomarkers in nasal fluid, sputum and blood, nasal and sputum microbial communities between the healthy volunteers and the mild/moderate asthmatics.

INCLUSION CRITERIA - healthy volunteers

• age between 18 and 60 years at time of signing informed consent
• BMI between 18-28 kg/m2
• able to comply with study protocol, in the investigator's judgement
• non-smoking or ex-smokers for at least 12 months with less than 10 pack years
• no immunoglobulin E (IgE) mediated hypersensitivity
• normal spirometry & normal ECG at screening
• negative histamine provocation (defined as His- if PC20 >/= 8 mg/ml and His+ healthy controls if PC20 > 4 mg/ml and < 8 mg/ml)

INCLUSION CRITERIA - asthmatic patients

• age between 18 and 60 years at time of signing informed consent
• BMI between 18-28 kg/m2
• able to comply with study protocol, in the investigator's judgement
• non-smoking or ex-smokers for at least 12 months with less than 10 pack years
• physician-diagnosed asthma for more than 6 months
• post bronchodilator FEV1 of ≥ 80% at screening
• documented airway reversibility either by means of post bronchodilator reversibility of > 12% and > 200 ml or in the previous 6 months or by means of documented airway hyperresponsiveness (histamine PC20 <8 mg/ml) at screening
• Asthma Control Questionnaire (ACQ) < 1,5
• regular treatment with inhaled corticosteroids (ICS) with or without long-acting beta-agonists (LABA) (unchanged dose for at least 1 month)
• normal ECG at screening

EXCLUSION CRITERIA - healthy volunteers

• physician-diagnosed asthma or history of (post)infectious bronchial hyperreactivity
• major pulmonary or cardiovascular disease
• treatment with β-blockers
• pregnancy

EXCLUSION CRITERIA - asthmatics patients

• unable to produce sputum with sputum induction
• previous history of intubation or admission to the intensive care unit due to asthma
• severe asthma exacerbation within one year prior to screening visit
• treatment with oral or systemic steroids within one year prior to screening visit
• previous treatment with biologics for asthma
• treatment with β-blockers
• other major concurrent pulmonary (such as chronic obstructive pulmonary disease, cystic fibrosis, sarcoidosis, interstitial lung disease, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis, bronchiectasis) or cardiovascular disease
• pregnancy