Subproject 5 - Severity and co-morbidities of allergic diseases

Severity and co-morbidities of allergic diseases: Mechanisms, biomarker and targets for novel therapeutic options

A substantial subgroup of patients with allergies develop chronic or even progressive symptoms, with a significant proportion suffering from unstable disease, frequent exacerbations, and/ or side-effects of a maximum treatment regimen. Especially patients with high specific-IgE levels or sensitization against multiple allergens and several allergic (e.g. allergic asthma (AA), food allergy (FA)) and non-allergic co-morbidities (e.g. obesity) are at risk for severe symptoms or even life-threatening anaphylaxis. This sub-project will focus on the mechanisms leading to progression of allergic diseases to more severe allergic (SA) subtypes. Understanding which factors and co-morbidities are important or responsible for the worsening of the most prevalent chronic disease in childhood is key for novel preventive strategies or treatment options.

The primary goal of the project is to identify key factors involved in the progression to severe allergic diseases, with a focus on children with polvalent and strong allergic sensitization and allergic and non-allergic co-morbidities.

We hypothesize that a combination of genetic, epigenetic and environmental factors is required to induce and maintain disease progression and severity which ultimately will be utilized to predict children at risk. Respiratory infections and strong polyvalent sensitization, lack of specific anti-allergic therapy, and co-morbidities such as obesity, attention deficit hyperactivity disorder (ADHD), and allergic rhinitis/ polyposis (AR) are key factors.

The novel aspect is that we will compare data from SA (German Asthma Net) with mild phenotypes (SP 3, 6), and study the impact of co-morbid obesity and/or ADHD (Register for novel widespread diseases in children, NIKI).

As main result we expect to identify key factors responsible for development of severe and chronic allergic diseases enabling us to define children at risk and novel strategies for prevention.

We will use two already established cohorts to study the mechanisms of disease severity and the influence of co-morbidities:

1. WP1 will investigate clinical and biological data in patients with severe disease in order to delineate the underlying mechanisms (“endotype”) of disease progression to severe phenotypes.
   Severe Asthma Register in the German Asthma Net (GAN): Over 750 patients (10% children, 6-17 years of age) from >40 centers in 3 countries with severe (90% allergic) disease, defined by levels of symptom control, lung function and maintenance medication. Detailed information (E-data bank) on family history, socio-economic status, disease onset, current status and severity, allergen sensitization, medication and co-morbidities is available. Patients are followed by regular visits. Methods: DNA for genetics and epigenetics (coop. SP6), whole blood for RNA sequencing (SP6), faeces and nasopharyngeal swabs for microbiota (SP1) will be obtained from all patients. Quality of life (QoL) questionnaires are available from all patients (SP2). Data will be compared to less severe forms of allergic diseases (SP3, SP5, data integration SP1). Patients with SA and co-morbid FA or AD will be compared to children with only FA or AD (SP4).
2. WP2 will identify the impact of co-morbidities with a focus on FA (in coop with SP 4), obesity and ADHD on disease progression and severity.
   The NIKI cohort: Children 6-12 years of age (ongoing until 10-2016, appr. 200 of 400 included) with allergic diseases (AA, AR, FA, AD) with or without co-morbid obesity and/or ADHD with detailed clinical information (E-data bank) on socio-economic status, sensitization, food pattern, feeding and sleeping habits, psychological signs and symptoms. Methods: DNA for genetics and epigenetics (SP6) will be obtained from all patients. Serum samples for RNA sequencing (SP6), and QoL questionnaires are available from all patients (SP2). Data will be compared to allergic diseases with no co-morbid obesity and/ or ADHD (SP3, SP5, data integration SP1).

Professor Hamelmann has many years of experience in clinical and experimental research in allergology, immunology / genetics. Based on these experimental studies on immune mechanisms of allergen-induced sensitization and airway inflammation, now Prof. Hamelmann's study group focuses on clinical questions on allergy treatment and prevention. 

Team members at Children’s Center Bethel in Bielefeld are Dr. Ines Gellhaus (MD, pediatrician, allergologist, nutrition scientist) and Gabriele Siekmann (Secretary).