Cystic fibrosis (CF) is the most common lethal inherited disease in Caucasian populations. To improve survival, it is essential to understand the development, progression and treatment of CF lung disease throughout early childhood.

Therefore the overall objective is to prospectively assess the clinical utility of novel and non-invasive measuring methods, namely Multiple Breath Washout and functional lung MRI in the longitudinal clinical surveillance of patients with CF and compare the results to those of healthy controls.

Background and project rationale:

Cystic fibrosis (CF), the most common lethal inherited disease in Caucasian populations, affects approximately 1:2500 live births. It is a multisystem disorder with respiratory morbidity and mortality being the leading cause of death. Despite improved survival in successive birth cohorts, the current median survival age of patients with CF is about 40 years. To improve survival, it is essential to understand the development, progression and treatment of CF lung disease throughout early childhood. Therefore tracking of lung function throughout childhood may provide important insights into the development and progression of CF lung disease. Spirometry, the standard lung function test for decades, is sensitive only for airflow limitation arising in large airways and insensitive for assessment of small or peripheral airway involvement, whereby the CF lung disease emerges in the small airways. Two promising techniques to assess small airway function in young children include the multiple breath washout (MBW) lung function test and functional Matrix-Pencil magnetic resonance imaging (MP-MRI).

Project Objectives and Design:

The overall objective of this project is to prospectively assess the clinical utility of MBW and MP-MRI in the longitudinal clinical surveillance of patients with CF. Therefore this study: i) Examines differences in MBW and MP-MRI outcomes between patients with CF and healthy controls. ii) Assesses the short term (over 1h) repeatability of MBW and MP-MRI outcomes in patients with CF and healthy controls. iii) Assesses whether MBW and MP-MRI outcomes are associated with clinical lung disease in patients with CF. iv) Determines whether changes in MBW and MP-MRI outcomes are associated with progression of lung disease in patients with CF. v) Compares the breath-by-breath regional and temporal changes in functional MRI signal with breath-by-breath changes in MBW phase outcomes in patients with CF and healthy controls.

Methods:

Data of MBW, MP-MRI, morphological MRI, Spirometry and body plethysmography, clinical respiratory symptoms and microbiology will be collected during this study.

Recruitment and participation:

Children and adults with CF will be recruited from the outpatient and inpatient clinics at the Inselspital in Bern. Healthy controls will be recruited from the local community in Bern and surrounding areas.

Information collected:

Lung function:

• Multiple Breath Washout (FRC, LCI, Scond, Sacin)
• Spirometry (FEV1, FVC, FEFx)
• Body plethysmography (sReff, FRCpletz, TLC)

Respiratory symptoms and clinical data:

CF:

• respiratory symptoms (cough, sputum characteristics, shortness of breath, weight loss, appetite fatigue)
• clinical data (increased work of breathing, hypoxemia, wheeze, crackles, differential air entry)

Healthy controls:

Presence of respiratory symptoms in the last four weeks preceding visit.

Functional and structural MRI:

• Functional MRI (percentage of the lung volume with impaired fractional ventilation (RFV) and relative perfusion (RQ)
• Structural MRI( Eichinger MRI scoring system to assess the presence and extent of bronchiectasis, mucous plugging, and air trapping)

Medical history:

CF: demographics, genetic mutation, pulmonary exacerbations, hospitalisations, regular therapy and medication, complications, microbiological data and laboratory reports

Microbiology:

CF: bacterial analysis of oropharyngeal swabs

Quality of life:

CF: CF-specific quality of life and symptoms

Sputum:

CF:

• spontaneously expectorated sputum
• Induced sputum

Study database:

All study data is recorded in an Access-database with SQL Servers. The database is accordant to the HFG and was adapted together with the CTU.

Funding:

The Swiss National Foundation (32003B_182719) and Vertex-Pharmaceuticals Cystic Fibrosis Research Innovation Award provide financial and material support for this observational study

Inclusion Criteria:

Individuals with CF:

• Diagnosis of CF
• Signed written informed consent
• ≥3 - 18 years of age, depending on the cooperation and if lung function measurements are possible

Healthy volunteers:

• Signed written informed consent
• Informed consent of participant and if under 18 years, legal representative respectively
• Children and adults with no history of chronic lung disease or acute respiratory infection in the four weeks prior to the study visit
• ≥3 - 18 years of age, depending on the cooperation and if lung function measurements are possible

Exclusion Criteria:

The presence of any one of the following exclusion criteria will lead to exclusion of the participant, for example:

• Women who are pregnant or breast feeding.
• Intention to become pregnant during the course of the study
• Lack of safe contraception, defined as: Female participants of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases.
• Please note that female participants who are surgically sterilised/hysterectomised or post-menopausal for longer than 2 years are not considered as being of child bearing potential.
• Other clinically significant concomitant disease states (e.g. renal failure, hepatic dysfunction, cardiovascular disease, etc.)
• Known or suspected non-compliance, drug or alcohol abuse
• Continuous glucose monitor
• Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, etc. of the participant
• Metal in body, e.g. pacemaker
• Participation in another study with investigational drug within the 30 days preceding and during the present study
• Subjects which are respiratory insufficient to attend on the lung function measurements (oxygen demand)
• Subjects who are unable to perform the MRI without sedation
• Participants which were born preterm (<36. week of pregnancy)
• Current smokers

In addition for individuals with CF:

• Known diseases other than related to CF

In addition for healthy individuals:

• Current upper respiratory infection (cough, cold, fever) will lead to postponement of the visit to 4 weeks after the end of symptoms

Children and adults with CF and healthy volunteers from the local community in Bern and surrounding areas.