Background:

Asthma is a heterogeneous respiratory disease and the most common chronic disease in children. A small subset of children has continuous poor asthma control despite appropriate adherence to asthma medication. There is a clinical need to identify these children as early as possible to optimize treatment and/or to find therapeutic alternatives. Therefore, the "Systems Pharmacology approach to uncontrolled Pediatric Asthma" (SysPharmPediA) study was set up.

Objective:

To establish a cohort of pediatric moderate-to-severe uncontrolled and controlled patients with asthma in order to investigate pathophysiological mechanisms underlying uncontrolled moderate-to-severe asthma in children on maintenance treatment, using a multi-omics systems medicine approach.

Methods:

In this multicenter observational case-control study, moderate-to-severe asthmatic children (n=145, age 6-17 years), were included in specialized hospitals in four European countries (Netherlands, Germany, Spain and Slovenia). Recruited subjects were selected based on good asthma control (controlled asthmatics, n=54) or poor asthma control / recurrent exacerbations (uncontrolled asthmatics, n=91). Comprehensive details concerning demographics, current and past patient/family history and clinical characteristics were collected. In addition, systems-wide omics layers, including epi(genomics), transcriptomics, microbiome, proteomics and metabolomics will be evaluated from multiple collected, relatively non-invasive, samples of from the recruited individuals, such as: blood, feces, saliva, nasal swabs and exhaled breath. Follow-up visits were performed 6 and 12 months after inclusion.

Inclusion Criteria:

General:

• Between 6-17 years of age
• Doctor diagnosis of asthma

In addition to the general criteria, a case with uncontrolled asthma (case group A) should meet:

• Asthma treatment Global INitiative of Asthma (GINA) step 3 or higher

  ≥ 1of the following criteria (based on the guideline 'Childhood Asthma' of the section paediatric pulmonology of the Dutch Society of Paediatricians, 2007):

• Frequent exacerbations requiring OCS use (≥1 in the past year) and/or

• Severe exacerbations requiring hospitalization or ER visits in the past year and/or

• ACQ/ACT scores indicating uncontrolled asthma

In addition to the general criteria, a case with an acute exacerbation (case group B) should meet:

• Asthma treatment Global INitiative of Asthma (GINA) step 2 or higher
• Current severe asthma exacerbation requiring hospitalization

In addition to the general inclusion criteria, a control (controlled asthma) should meet the following criteria:

• Asthma treatment Global INitiative of Asthma (GINA) step 3 or higher
• Lack of severe exacerbations requiring OCS use or hospitalizations or ER visits in the past year
• ACQ/ACT scores indicating well controlled asthma or few reported asthma symptoms during asthma checks in the past year.

Exclusion Criteria:

• Recent use of a course of antibiotics (< 1 month). This will affect the microbiome analyses.

A patient can be re-screened 1 month after the use of the antibiotic treatment has finished.

Four tertiary care centers from four European countries (the Netherlands, Germany, Spain, and Slovenia) recruited 145 asthmatic children and adolescents (6-17 years old). All centers obtained approval from their local medical ethics committee (ethics committee of University Regensburg, Germany (18-1034-101); Clinical Research Ethics Committee of the Basque Country, Spain (PI2015075 (SO)); Medical Ethics Committee of the University Medical Center Utrecht (UMC Utrecht), Utrecht, the Netherlands (NL55788.041.15); National Medical Ethics Committee, Slovenia (0120-569/2017/4)) and written informed consents were collected from the parents/caregivers and/or the recruited children when appropriate.

In case other researchers are interested to work with data that is collected within SysPharmPediA; we kindly request to contact the PI of the study (Prof. dr. A.H. Maitland-van der Zee - a.h.maitland@amsterdamumc.nl)

1. The PIs will refer to an up-to-list of planned publications, which includes ongoing and planned analysis work from SysPharmPediA partners and from those granted access to specific data, to determine potential duplication of work.
2. To understand and draw sound scientific results those groups planning to work on SysPharmPediA data should engage with the SysPharmPediA members who have generated the data in question.
3. A summary of the Data Analysis Plan (DAP) must be attached to the data access request form.
4. If the analysis deviates substantially from the summary DAP or provides results which the SysPharmPediA group feel mis-represent the data, the SysPharmPediA group may raise an objection with the publication concerned.