Description

Background

Cystic fibrosis (CF) is the most common lethal inherited disease in North European populations, affecting approximately 1:2500 live births. It is a multisystem disorder with respiratory morbidity and mortality being the leading cause of death. Lung disease in CF is characterized by neutrophil-dominated inflammation and chronic bacterial infection of the airways, which results in deterioration of lung function and premature death [1]. Despite improved survival in successive birth cohorts, the current median survival age of patients with CF is about 40 years [2]. Understanding the initiating events of CF lung disease (e.g viral infections and microbiome) and their influence on disease progression throughout early childhood is essential to improve survival through targeted early interventions.

Objectives

The overarching aim of this study is to identify early life predictors of disease progression in children with CF. Therefore, this study implies three objectives, as follows: i) to investigate the effect of respiratory viral infections on microbiota dynamics in the first year of life in infants with CF, and to examine their influence on lung function at 1 year of age; ii) to examine whether deficits in lung function in the first year of life in infants with CF persist to pre- and school age and adolescence and are associated with impaired functional and structural abnormalities at 3, 6, 9, 12, 15 and 18 years of age; and iii) to determine the principal drivers of impaired lung function at 1 year and impaired lung function and structural outcomes at 3, 6, 9, 12, 15 and 18 years of age in individuals with CF.

Methods

Lung function, magnetic resonance imaging (MRI), respiratory symptoms and quality of life questionnaires, microbiology, medical history and clinical data will be collected during each phase of the study.

Recruitment and participation:

Infants with CF diagnosed by NBS will be recruited at the time of their first lung function test in Bern at the age of 4-8 weeks. As part of the protocol for the diagnosis and follow-up of CF infants diagnosed by NBS, which has been implemented by the Task Force for CF NBS on behalf of the Swiss Working Group for Cystic Fibrosis, optional infant lung function at the University Children's Hospital of Bern is proposed to all parents of newly diagnosed CF infants.

Information collected:

Lung function data:

• Tidal breathing parameters (minute ventilation, respiratory rate, tidal volume, tidal expiratory flow, tidal inspiratory flow, time to peak expiratory flow) averaged over 100 breaths
• Multiple breath washout (FRC, LCI, moment ratios) and single breath washout (molar mass)
• Spirometric forced expiratory volume loops (FVC, FEV1, PEF, MEF50)
• Body plethysmography (airway resistance, lung volumes: TLC, FRC, RV)
• Respiratory Rate over 60 seconds
• Fractional exhaled nitric oxide (marker of airway inflammation)
• Resistance interrupter measurement
• Electric nose
• Forced oscillation technique
• Electrical impedance tomography
• Impedance plethysmography

Microbiological data:

• Nasal swabs (respiratory virus and bacterial diagnostics, as well as host transcriptome analysis)
• Pharyngeal swabs (bacterial colonization and microbiota analysis)
• Sputum (to analyse the neutrophils)

Blood count (hemoglobin concentration, hematocrit, leukocyte number, lymphocyte number, lymphocyte count, eosinophil count, basophil count, monocyte count, promyelocyte count, myelocyte count, platelet count, immunoglobulin E level, interleukins, Granulocyte-Monocyte-Colony Forming Unit, Tumor Necrosis Factor alpha, Interferon gamma and Interferon lambda)

Urine (to estimate the tobacco exposure during pregnancy (amount of Cotinine) and the content of caffeine and steroid profile)

Lung MRI:

Functional and structural images of the lung

Skin-Prick Test (test for pollen, trees, house dust mite, cat and dog)

Questionnaires (to assess quality of life)

Medical history (information on respiratory symptoms, pulmonary exacerbations, hospitalisations and regular therapy)

Study database:

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

Funding

Schweizerischer Nationalfonds (SNF), Schweizerische Gesellschaft für Cystische Fibrose (CFCH), Departement Lehre und Forschung des Inselspitals Bern