The goal of this exploratory method-development study is to to establish and evaluate novel non-invasive methods to monitor airway inflammation induced by allergen challenge (both by instillation during bronchoscopy and by inhalation) in patients with mild allergic asthma.
The investigator wants to further profile and develop the allergen challenge model by investigating the utility of various non-invasive monitoring methods. The hypothesis of the project is that local inflammatory changes in the lung induced by allergen can be captured by gas-enhanced magnetic resonance imaging (MRI) and analysis of exhaled breath.
The validation of cellular outcome measures and non-invasive inflammometry can be used in future clinical trials for proof of concept of novel anti-inflammatory medications.
Participants will undergo
* methacholine challenge * 2 inhaled allergen challenges * 2 MRI with hyperpolarized xenon and gadolinium based contrast agent * 2 bronchoscopies with bronchoalveolar lavage (BAL) * segmental allergen challenge during the first bronchoscopy * spirometry * skin prick test and skin prick dilution tests * measurement of particles in exhaled air * nasal filter * nasal lavage * sputum induction * peak flow meter tests * exhaled NO (nictric oxide) * blood sampling (in total approx. 190 ml)
Able and willing to give written informed consent.
Not pregnant, as confirmed by pregnancy test (see assessment schedule), and not nursing.
Of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarcheal or post-menopausal, with documented proof of hysterectomy or tubal ligation, or meets clinical criteria for menopause and has been amenorrhoeic for more than 1 year prior to the Screening Visit).
Of childbearing potential and using a highly effective method of contraception during the entire study (vasectomised partner, sexual abstinence, implants, injectables, combined oral contraceptives, hormonal Intrauterine Devices (IUDs) or double-barrier methods, i.e. any double combination of IUD, condom with spermicidal gel, diaphragm, sponge, and cervical cap).
Any clinically relevant abnormal findings in physical examination, clinical chemistry, hematology, urinalysis, vital signs, lung function or ECG at Screening Visit, which, in the opinion of the investigator, may either put the subject at risk because of participation in the study or may influence the results of the study, or the subject's ability to participate in the study.
Past or present disease, which as judged by the investigator, may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease, hematological disease, neurological disease, metabolic disease (asymptomatic Gilbert's syndrome is allowed), endocrine disease (stable and asymptomatic hypothyroidism with or without hormone replacement therapy (HRT) is allowed), or pulmonary disease (including but not confined to chronic bronchitis, emphysema, tuberculosis, bronchiectasis or cystic fibrosis).
Regular intake of any prescribed or over the counter medication. Exceptions include paracetamol for pain relief, contraceptive medication, hormonal replacement therapy, dietary and vitamin supplements.
Specific Immunotherapy (SIT) within three years prior to the study.
Single group
allergen challenge
Other interventionPatients will undergo inhaled allergen challenge followed by different measures like MRI and induced sputum. At least 4 weeks later patients will undergo segmental allergen challenge followed by different measures like bronchoalveolar lavage.
Exploratory (1. priority) Changes in soluble mediators [i.e. IL-4, IL-5, IL-8, IL-13, IL-33, TSLP, IL-1, IL-6, INF-alpha, MMP-9, CXCL1, SP-D, albumin] in Bronchoalveolar lavage (BAL) after segmental allergen challenge
Quantification of allergic inflammatory response induced by segmental allergen challenge in BAL by analyzing soluble mediators using Meso Scale Discovery (MSD) multiplex assays -\> At least, but not limited to Interleukin(IL)-4, IL-5, IL-8, IL-13, IL-33, Thymus-Stroma-Lymphopoietin (TSLP), IL-1, IL-6, Interferon-alpha (INF-alpha), Matrix-Metallopeptidase 9 (MMP-9), Chemokine (C-X-C motif) ligand 1 (CXCL1), Surfactant protein D (SP-D), albumin \[pg/ml\]
Exploratory (1. priority) Changes in soluble mediators [i.e. IL-4, IL-5, IL-8, IL-13, IL-33, TSLP, IL-1, IL-6, NF-alpha, MMP-9, CXCL1, SP-D, albumin] in Sputum after inhalative allergen challenge
Quantification of allergic inflammatory response induced by inhalation in sputum by analyzing soluble mediators using MSD multiplex assays -\> At least, but not limited to IL-4, IL-5, IL-8, IL-13, IL-33, TSLP, IL-1, IL-6, NF-alpha, MMP-9, CXCL1, SP-D, albumin \[pg/ml\]
Exploratory (1. priority) Changes in non-invasive exhaled particles [i.e.IL-4, IL-5, IL-8, IL-13, IL-33, TSLP, IL-1, IL-6, NF-alpha, MMP-9, CXCL1, SP-D, albumin]after inhalative allergen challenge
Quantification of allergic inflammatory response induced by inhalation in non-invasive exhaled particles at multiple time-points by analyzing soluble mediators using MSD multiplex assays -\> At least, but not limited to IL-4, IL-5, IL-8, IL-13, IL-33, TSLP, IL-1, IL-6, INF-alpha, MMP-9, CXCL1, SP-D, albumin \[pg/ml\]
Exploratory (1. priority) Changes in non-invasive exhaled particles [i.e.IL-4, IL-5, IL-8, IL-13, IL-33, TSLP, IL-1, IL-6, NF-alpha, MMP-9, CXCL1, SP-D, albumin]after segmental allergen challenge
Quantification of allergic inflammatory response induced by segmental allergen challenge in non-invasive exhaled particles at multiple time-points by analyzing soluble mediators using MSD multiplex assays -\> At least, but not limited to IL-4, IL-5, IL-8, IL-13, IL-33, TSLP, IL-1, IL-6, INF-alpha, MMP-9, CXCL1, SP-D, albumin \[pg/ml\]
Exploratory (2. priority) Detection of Ribonucleic acid (RNA) in exhaled particles
Detection of RNA in exhaled particles -\>Verification and quantification of RNA
Exploratory (2. priority) Changes in Fractional exhaled nitric oxide (FeNO) after inhalative allergen challenge
Quantification of inflammation in the central airways by FeNO in the kinetic of the allergic response after inhalation challenge -\> Measurement of FeNO \[ppB\] and comparison with induced sputum
Exploratory (2. priority) Changes in FeNO after segmental allergen challenge
Quantification of inflammation in the central airways by FeNO in the kinetic of the allergic response after segmental challenge -\> Measurement of FeNO \[ppB\] and comparison with induced sputum
Exploratory (2. priority) Quantification of regional ventilation, perfusion, and diffusion by magnetic resonance imaging (MRI)
Quantification of regional ventilation, perfusion, and diffusion assessed by MRI -\> change from baseline of MRI assessed parameters in relation to inflammatory reaction (eosinophil numbers \[×10\^6 cells/ml\] in sputum and BAL) and pulmonary function (FEV1 and maximal forced expiratory flow (MFEF) of 25 to 75% of Vital Capacity of the lungs (MFEF25-75))
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