Background
Asthma is a chronic inflammatory airways disease, leading to reversible broncho-constriction, airway hyperresponsiveness and variable airflow limitation. In children, asthma is a heterogeneous disease, while classical asthma symptoms (cough, wheeze and chest-tightness) may be ascribed also to non-asthmatic causes. Diagnosing asthma is mainly clinical, based on a history of typical symptoms, supported by findings of bronchial obstruction that is responsive to broncho-dilators, and/or bronchial hyperresponsiveness. The younger the child, the more likely that the symptoms may have causes other than asthma, thus, diagnosing asthma in young children is challenging. Consequently, a variety of asthma outcomes include number of wheeze episodes, doctor’s diagnosis of asthma and wheeze with or without associations with allergic sensitization. Despite a vast number of studies reporting asthma outcomes, there is no uniform, unequivocal and standardized definition of asthma in early childhood. In clinical trials determining incident asthma is challenging, particularly in asthma (primary) prevention trials, where robust and standardized asthma definitions are pivotal. From school age, lung function tests are important for supporting the asthma diagnosis, and significant improvement after inhaled bronchodilator (reversibility test) is a commonly used to document bronchodilator response (BDR) in clinical settings. The forced expiratory volume in the first second (FEV1) and FEV1/forced vital capacity (FVC) are frequently used, while small airway parameters are probably more sensitive to early airway function changes, but needs further exploration. However, children with asthma may have normal lung function when asymptomatic, and lung function values based upon reference values may not identify impaired lung function for individual patients. Although a positive BDR (classically defined as ≥ 12 % improvement in FEV1) supports the diagnosis of asthma in childhood, physiological improvement in lung function after inhaling a bronchodilator may occur also among non-asthmatic subjects. The prevalence of a BDR among a general child population as well as among children with previous or recent asthma symptoms is not clear. Also, it is not clear if airway reversibility measured by small airway function parameters may improve diagnostic precision for childhood asthma in an epidemiological setting.
The atopic march suggests that atopic dermatitis and/or sensitization to food allergens may lead to development of other allergic diseases in childhood, probably in part through allergic sensitisation (the presence of specific IgE antibodies towards allergens). Also, reduced barrier function has been hypothesized as common mechanisms in atopic dermatitis and in asthma. The PreventADALL study was designed as a randomised clinical trial (RCT) as well as an exploratory prospective birth cohort study, providing an important basis for improved knowledge of asthma development, and the potential to prevent asthma through a theoretical improvement of the skin barrier and/or inducing tolerance to common allergens by early food introduction.
Objective and aims
Main objective
This project will improve the validity of asthma diagnosis in early school age, and subsequently explore the potential for reducing asthma by early introduction to food allergens.
Specific aims
- To determine the prevalence of a BDR in children with and without asthma symptoms
- To determine the prevalence of asthma in early school age based upon different, commonly used definitions, including BDR, baseline lung function values and allergic sensitisation
- Explore if early introduction to allergenic foods reduces the risk of asthma in early childhood
Material and methods
This project will combine existing data from the general population-based randomised clinical trial PreventADALL, with data from follow-up investigations at 6-7 years (in 2022-23) of 2394 mother-child pairs who were recruited antenatally in 2014-16. Approximately 1200 will be attending Oslo University Hospital, the rest at Østfold Hospital Trust and Karolinska University Hospital. To avoid analytic challenges due to missing data, we will link to the relevant national patient- and medicinal registries in Norway and Sweden for diagnosis and treatment of asthma.
The follow-up study will focus on securing relevant interview-based information in relation to obstructive airways symptoms, clinical assessments to document baseline lung function (spirometry) as well as BDR; ie repeat spirometry 15 minutes after inhaling beta-2 agonist (bronchodilator) in the absence of bronchodilators in the last 24 hours prior to investigation, allergic sensitisation to allergens by skin prick tests to common inhalant and food allergens, as well as collecting relevant biological samples corresponding to those collected from 0-3 years of age.
The main data will concern:
- asthma-like symptoms, signs and medication use recorded in electronic questionnaires at 12, 18, 24 months + 3, 4, 5, 6, 7 years of age as well as interviews at 2 & 3 years + during follow-up visit, all relevant data from birth-including 3 years follow-up are already categorised by symptoms and medication use
- baseline lung function (FEV1 and FEV1/FVC ratio) during follow-up visit
- BDR primarily by changes in FEV1, exploring changes in FEV1/FVC ratio during follow-up visit
- allergic sensitisation by skin prick test (positive or negative to any allergen, to inhalant or food allergens) performed standardised at 6 + 12 months, at 3 years and during the follow-up visit
Briefly, the PreventADALL study (Clinicaltrial.gov: NCT02449850) was designed to investigate if allergic diseases can be prevented by early life interventions, as well as to identify early life factors implicated in non-communicable disease development. Mother-child pairs were recruited from the 18-week routine fetal ultrasound screening in Oslo, Østfold and Stockholm from December 2014. Children were randomly assigned at birth to one of four groups, based on a factorially designed 2x2 trial with interventions consisting of early skin barrier enhancement and early complementary feeding from 3 months of age. Lung function was measured in the awake state at 3 and 12 months of age by tidal breathing flow-volume loops.
Student tasks
- as part of a study team (nurses and PhD students) participate in the follow-up investigations at 6-7 years, 2-3 days per week for 12 months from August 2022 at the Paediatric Clinical Research Unit, Ullevål. Tasks include skin assessment using validated scoring tools, lung function testing before and after bronchodilator inhalation, blood sampling, allergy testing by skin prick test, blood pressure measurements, brief structured interview
- sign up for relevant science courses during the first 1-2 years
- be first author of paper related to aim 1, with the possibility to lead developing a paper related to aim 2 and co-author a paper for aim 3, providing sufficient original articles for a PhD thesis, if wanted
- learn how to work within an established large database (PreventADALL) at Tjeneste for Sensitive data (TSD) at the UiO, analyse data sets including pre-existing and new data from the follow-up study prepared by the study data manager, prepare the manuscript in collaboration with supervisors and co-authors
- become member of a well-established research group with multi-disciplinary competence
- present scientific work in the research group, at PreventADALL symposia and at an international congress
Research environment
The project is run within the ORAACLE (Oslo Research group of Asthma and Allergies in Children; the Lung and Environment) in close collaboration with researchers in Oslo, Østfold and Stockholm, Sweden. You will be part of a research team, and learn generic and project specific research tasks. Through bi-weekly ORAACLE meetings, and in PreventADALL PhD fora you will practice discussion, preparing and presenting your research, together with other PhD and senior researchers. The supervisors are highly experienced in supervising PhD projects, network between researchers within and outside the ORAACLE is facilitated and you will experience the progress from medical studies to publish relevant results that will be implemented in clinical and scientific community worldwide. You will be heartily welcome as a member of a well-established and highly productive research group. All supervisors are senior paediatricians at the Dpt of Paediatrics, Oslo University Hospital.
Main supervisor: professor Karin C. Lødrup Carlsen
Senior researcher Håvard O. Skjerven and MD PhD student Anine Lie (from 2023)