Last updated on April 2018

Pediatric Arm of DZL All Age Asthma Cohort


Brief description of study

Despite its common occurrence, still little is known about pathomechanisms determining different wheeze and asthma trajectories and phenotypes in children, and those beginning in adulthood. Therefore, deciphering underlying determinants for different childhood and adult asthma phenotypes is urgently needed to develop personalized treatment approaches targeting distinct underlying mechanisms. Thereby, secondary prevention early in the disease process can also be achieved. The decoding of such mechanisms and their translation to the individual patient is the aim of the Disease Area Asthma Allergy of the 'German Centre for Lung Research' (DZL).

Detailed Study Description

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) nave wheeze/asthma patients and wheeze/asthma patients under controller therapy are being recruited in addition to healthy controls. Following recruitment, yearly 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:

  1. 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.
  2. 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:

  1. Identification of molecular phenotypes, predictors and biomarkers for distinct wheeze/asthma phenotypes and trajectories.
     The investigators aim to recruit in total 360 cases and 150 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 from
     outpatient clinics. 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 the following 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 yearly 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 herein: 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 heir 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.

2. Identification of risk factors for and mechanisms underlying exacerbations.

     Exacerbations are being assessed in cases by numbers, triggers, severity and clinical
     features via questionnaires at all visits. In addition, study participants will present
     with acute exacerbations defined as acute worsening of symptoms and once post
     exacerbation for clinical evaluation and sampling of the following biomaterials and
     analyses: (i) blood; ii) nasal secretions; iii) pharyngeal swabs. Furthermore, primary
     epithelial cells will be collected by nasal brushings. To facilitate recruitment, new
     asthma cases may also be enrolled during exacerbation. This will allow time course
     analyses of biomarkers differing between triggers and wheeze /asthma phenotypes.

Clinical Study Identifier: NCT02496468

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