Longitudinal Observational Study on the Course of Cystic Fibrosis Lung Disease in Patients Following Newborn Screening

Longitudinal Observational Study on the Course of Cystic Fibrosis Lung Disease in Patients Following Newborn Screening

The purpose of this study is to further characterize early CF lung disease in newborns, infants and toddlers with cystic fibrosis (CF).

Cystic fibrosis (CF) is the most common lethal genetic multisystem disease in Germany. Although life expectancy increased over the last decades, most of the CF patients die in young adulthood due to chronic CF lung disease with respiratory failure. CF lung disease is caused by a disturbed transport of salt and water by airway epithelia and dehydration of airway surfaces as a result of the underlying genetic defect in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gen. Up to now, no causal therapies for the majority of patients with CF are available. Little is known about onset and natural course as well as influencing factors of CF lung disease. Therefore, the first aim of this prospective, multicenter, uncontrolled, non-randomized, explorative longitudinal study is characterization of the onset and early course of CF lung disease. For this reason we will primarily include patients diagnosed by CF newborn screening (CF-NBS) or for any other reason in the first four months of life (early diagnosed, ED). In a second step we will compare data from these patients to those diagnosed clinically later in life (late diagnosed, LD). This will allow us to investigate the effect of early diagnosis and start of therapy. Starting at diagnosis, we will use data from annual routine check-ups (imaging like chest MRI, pulmonary function tests, microbiology from swabs and sputum, laboratory values, anthropometry) as well as data from a facultative, study-related bronchoscopy with lavage (microbiology, inflammation and immunology) for correlation with the course of CF lung disease (generation of hypotheses). Further study-related investigations are monthly telephone interviews on bronchopulmonary symptoms by a study nurse on the basis of a questionnaire and quarterly assessment of health-related quality of life on the basis of a validated questionnaire.

We expect to gain a deeper insight into onset and early course of CF lung disease from the results of this study. So far, there is no trial that investigated the different aspects of CF lung disease (function, morphology, infectiology, inflammation) complementary in a longitudinal setting. We assume that knowledge on the natural history of CF lung disease in the vulnerable phase of early childhood has a great impact on the future development of new therapies (from symptomatic to causal). This shall lead to a further improvement in life expectancy and quality of life of patients with CF.

Inclusion Criteria:

1. Newly diagnosed patients with Cystic Fibrosis (CF). Diagnosis of CF: at least one of the following three international accepted criteria is fulfilled: i) sweat chloride ≥ 60mEq/L and/or ii) 2 CF-causing mutations in the CFTR gene and/or iii) changes typical for CF in the transepithelial potential difference in nasal or rectal epithelium.

2. Age and mode of diagnosis:

   • Early diagnosed (ED): Initial diagnosis following CF-NBS or for other reasons in the first 4 months of life (in preterms corrected age of 4 months) after January 1st, 2006. Other reasons could be prenatal diagnostics, meconium ileus or positive family history.
   • Late diagnosed (LD): Diagnosed after the fourth month of life due to clinical symptoms; initial diagnosis after January 1st, 2006.

Exclusion Criteria:

All patients are excluded who themselves or whose parents do not want to participate or that withdraw from the study; or those in whom the diagnosis of CF is unsure.

Further exclusion criteria are:

1. Preterms <30th week of gestation
2. Longer period of mechanical ventilation in first 3 months of life
3. A significant medical disease or condition other than CF likely to interfere with the child's ability to complete the entire protocol
4. Previous major surgery except for meconium ileus or atresia of the intestine
5. Other major organ dysfunction, excluding pancreatic or hepatic dysfunction or another condition due to CF
6. Physical findings that would compromise the safety of the subject or the quality of the study data as determined by investigator
7. Chronic lung disease other than CF (e.g. bronchopulmonary dysplasia)
8. History of adverse reaction to medication for sedation or known claustrophobia

Criteria, which lead to a displacement of the procedures in sedation until the child has recovered: - Clinically significant upper airway obstruction as determined by investigator (e.g.

severe laryngomalacia, markedly enlarged tonsils, significant snoring, diagnosed obstructive sleep apnoea)

- Severe gastroesophageal reflux, defined as persistent frequent emesis despite anti-reflux therapy