By Tamo Sultan
Principal supervisor: Professor Klaus Bønnelykke, MD, PhD
Co-supervisors: Professor Bo Chawes, MD, PhD, DMSc
Co-supervisors: Professor Jakob Stokholm, MD, PhD, Associate professor Ann-Marie Malby Schoos, MD, PhD, DMSc, Associate professor Nicklas Brustad, MD, PhD
Chairperson: Klaus Gottlob Müller, MD, PhD, DMSc, Professor (Chair), Department of Clinical Medicine, University of Copenhagen, Denmark
Opponent: Sejal Saglani, MD, PhD, Professor, Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College London, United Kingdom
Opponent: Mika Mäkelä, MD, PhD, Professor, Department of Dermatology, Allergology and Venereology, University of Helsinki, Finland
Summary
Childhood asthma is a chronic, heterogeneous disease that affects many children worldwide. It presents through observable traits and biological mechanisms, i.e. phenotypes and endotypes. Subgrouping by these features informs disease severity and treatment and is clinically valuable. Type 2 inflammation is central in atopic asthma, characterized by elevated blood eosinophils, fractional exhaled nitric oxide (FeNO) and plasma immunoglobulin E (IgE). These biomarkers reflect the underlying immune response via release of key cytokines. Beyond biomarkers, symptoms of cough and wheeze are common in early childhood and represent distinct clinical patterns related to asthma. However, the roles of IgE and cytokines in childhood type 2 inflammation remain insufficiently defined, especially in clinically applicable studies. Likewise, the implications of early-life cough and wheeze for later asthma, lung development, and type 2 inflammation are not well understood. In this thesis, we examine type 2 inflammation and symptom-based phenotypes to clarify their mechanistic and clinical roles in childhood asthma.
The roles of total and specific IgE as biomarkers of type 2 inflammation are less well defined than other used markers. In Paper I, longitudinal measurements by seven timepoints from the COPSAC2000 and COPSAC2010 birth cohorts were used to assess the predictive and endotyping value of total and specific IgE for type 2 (T2)-high and T2-low asthma, compared with blood eosinophils and FeNO. Total and specific IgE showed similar predictive and endotyping performance for discriminating T2-high asthma and T2-low asthma in early and later childhood and overlapped substantially with other type 2 biomarkers. These findings support total and specific IgE as useful biomarkers for type 2-high asthma.
It remains unknown whether airway cytokines can function as biomarkers of type 2 inflammation to the same extent as blood eosinophils, FeNO and IgE, or whether they provide airway-specific or superior performance relative to these other markers. In Paper II, 24 cytokines were measured non-invasively in nasal samples of epithelial lining fluid from six-year-old children in the COPSAC2010 cohort. Using diseases linked to type 2 inflammation, which includes T2-high asthmatics, both allergic rhinitis and conjunctivitis, and atopic dermatitis, together with the established type 2 biomarkers from Paper I, we assessed their associations with airway cytokines. A consistent pattern emerged, with cytokines interleukin-5 (IL-5) and also C-C motif chemokine ligand 17 (CCL17) significantly elevated among type 2 inflammatory diseases and in children with elevation of type 2 relevant biomarkers. To compare predictive and endotyping performance, a supervised type 2 airway17cytokine score was compared with blood eosinophils, showing no difference. Effects were strongest for airway-specific type 2 diseases of T2-high asthma and allergic rhinitis. These findings indicate that nasal cytokine testing is a useful, non-invasive approach for airway-specific assessment of type 2 inflammation in children, with IL-5 and CCL17 particularly informative.
It remains uncertain whether early-life asthma-like symptom patterns hold predictive clinical value akin to biomarker profiling. In Paper III, over 5 million symptom daily diary entries quantified early- life cough and wheeze burden together with infection during the first three years of life in the COPSAC2010 cohort. These symptoms were then used to define cough- and wheeze-dominant phenotypes in children with recurrent asthma-like symptoms. In mutually adjusted models in the full cohort, only greater cough burden independently predicted later asthma, whereas only greater wheeze burden independently predicted lower lung function. Phenotype-specific analyses of cough-only and cough+wheeze phenotypes showed higher asthma risk for both compared to healthy, but persistent lung function deficits only in the cough+wheeze phenotype, which also showed greater infection burden. Type 2 biomarker profiles did not differ between the phenotypes. Asthmatic signatures from early-life gut and airway microbiome, airway cytokines and genetics suggested overlapping type 2 and non-type 2 pathways in both phenotypes with a clear distinction from healthy children. These findings support symptom-based phenotyping as a complementary approach that may provide prognostic information beyond biomarker-based profiling.
In conclusion, total and specific IgE, alongside nasal cytokine profiles dominated by IL-5 and CCL17, were useful for identifying T2-high asthma in childhood. Early-life cough and wheeze burden captured distinct trajectories, with cough linked to later asthma and wheeze to persistent lung function deficits. Together, these results support integrating biomarker-based endotyping and symptom-based phenotyping to improve understanding and clinical management of childhood asthma.
