Pediatric Arm of DZL All Age Asthma Cohort

About 25-30% of children have at least one episode of wheeze before their 3rd birthday, but considerable clinical heterogeneity exists. Many of these children become symptom-free between 3 and 8 years of age, but some go on to persistent asthma in later childhood and adulthood. Despite its high prevalence, still little is known about pathomechanisms determining the different wheeze trajectories and phenotypes in children, and those beginning in adulthood. Frequency and severity of exacerbations may play an important role in the chronification process but underlying mechanisms are equally not well understood. Therefore, deciphering the role of airway mechanics, genetic, environmental and molecular determinants for different childhood and adult asthma phenotypes for exacerbations and chronification processes is urgently needed to develop personalized treatment approaches targeting distinct underlying mechanisms. Thereby, secondary prevention early in the disease process can also be achieved.

In order to do so, a clinical cohort for childhood asthma has been set up with identical, standardized instruments (quality assurance plan: standard operating procedures (SOPs) for clinical and lab modules, shipment, biobanking and analysis as well as quality control measures via audits and site visits have been developed) across the participating 'German Center for Lung Research' (DZL) sites. Here, new-onset steroid/leukotriene receptor antagonist (LTRA) naïve wheeze/asthma patients and wheeze/asthma patients under controller therapy are being recruited in addition to healthy controls. Following recruitment, regularly follow-ups and exacerbation visits of included patients are being performed with identical study instruments and meticulous quality control checks as at baseline.

PROJECT HYPOTHESES:

• Specific molecular phenotypes are associated with distinct wheeze/asthma phenotypes and trajectories. Thereby, underlying mechanisms as well as predictors and biomarkers for persistent asthma will be identified.
• Individuals at risk for exacerbations can be identified by clinical and molecular biomarkers, which will become novel targets for therapy and secondary prevention.

WORK PROGRAM:

Identification of molecular phenotypes, predictors and biomarkers for distinct wheeze/asthma phenotypes and trajectories.

The investigators aim to recruit over 1000 cases and controls to ensure sufficient statistical power for multivariate statistical analyses. Recruitment of study participants will be continued and cases will undergo 'deep phenotyping' as described below. In addition, healthy age and sex matched controls will be recruited. Cases and controls undergo a comprehensive clinical assessment including questionnaires (browser-based online data entry into extensive database with audit trail, plausibility and quality control checks implemented, data dictionary accessible), physical examination and lung function tests (spirometry and bodyplethysmography including bronchodilator response, multiple breath washout, exhaled nitric oxide). Biomaterials will be collected for analyses: i) blood samples; ii) nasal secretions; iii) pharyngeal swabs; iv) induced sputum; v) stool samples. Furthermore, epithelial cells will be collected by nasal brushings. Breath samples will be collected for analyses of volatile organic compounds. The cases will be followed up regularly using the same clinical tools and collecting the same biomaterials as at the initial visit to assess trajectories over time. Two closely interacting working groups have been established for all aims described: one lab and one data management/analysis group, each headed by expert members of the participating sites. The lab group will initiate and supervise all measurements of biomaterials; the data management/analysis group will expand the combined and shared data base and coordinate statistical analyses across sites. A common publication policy has already been developed. Using advanced bioinformatics, systems biology and machine learning approaches, the investigators will develop predictive (diagnostic) algorithms including clinical and molecular biomarkers for transient and persistent wheeze/asthma phenotypes and their trajectories. These analyses will also identify underlying mechanisms and thereby potential targets for future personalized therapy comparing childhood and adult findings. During data collection. The investigators attempt to minimize missing data. In all cases where missing data will reduce power for subsequent analyses, imputation will be used in order to omit power loss.

Inclusion criteria

• informed consent by parents (and by children if age > 8 years)
• age 6 months to 18 years
• term delivery (≥ 37 weeks)
• active/passive understanding of German
• age 6 months - < 6 years: preschool wheeze (more than two episodes of wheeze during 12 months prior to inclusion)
• age at least 6 years: doctor diagnosed asthma (according to current guidelines)

Exclusion criteria

• known inborn or perinatal pulmonary disease
• airway malformation
• oxygen therapy after birth with a duration of more than 24 hours
• ventilator support or mechanical ventilation after birth
• diagnoses of cystic fibrosis; primary ciliary dyskinesia
• heart failure diagnosed after birth affecting pulmonary circulation
• major respiratory diseases such as e.g. interstitial lung disease
• any current non-atopic comorbidity
• fever of at least 38.5°C during the last two weeks prior to the planned first visit