Preschool asthma : infant lung function, inflammation and skin barrier function in early life

Background: Asthma is among the most common obstructive respiratory disorders in children, characterized by airway inflammation with features such as wheeze, cough and shortness of breath. Though the etiology behind the disease partly remains unknown, the roots likely origin from early life. Lower lung function, skin barrier impairment, as well as eosinophil inflammation are factors related to asthma development, but are largely unexplored in early life. The overall aim of this doctoral thesis was to explore early risk factors for the development of preschool asthma, related to infant lung function, eosinophil inflammation and skin barrier function in early life.

Methods: All four sub studies (I-IV) were based on data prospectively collected from children actively participating in the Preventing Atopic Dermatitis and ALLergies in children (PreventADALL) mother-child cohort (n=2394) recruited from the general population in Sweden and Norway. First, with infant lung function measured in both the awake and sleeping state at three months, we aimed to determine whether lung function by tidal flow-volume (TFV) loops differed according to arousal state (sub study I). Thereafter, we investigated the potential association between infant lung function while awake and preschool asthma at three years (sub study IV). Second, we aimed to explore if infant skin barrier function by transepidermal water loss (TEWL), eczema at three months and mutations in the skin barrier filaggrin (FLG) gene were associated with infant lung function at three months (sub study II) and/or preschool asthma at three years (sub study IV). Third, we aimed to identify if higher levels of inflammation by serum eosinophil-derived neurotoxin (EDN) at one and three years were associated with preschool asthma at three years (sub study III). Lastly, we aimed to assess if the potential associations between infant lung- and skin barrier function as well as early-life eosinophil inflammation and preschool asthma differed by sex (sub study III-IV).

Results: Among 91 infants with paired lung function measurements, TFV loop parameters overall differed, with a higher ratio of time to peak tidal expiratory flow to expiratory time, tPTEF/tE, shorter tE but similar tPTEF while awake compared to the sleeping state. Studying 563 children with information on infant lung function while awake and preschool asthma, a five respectively three-fold higher odds ratio (OR) of asthma was observed among infants with lower tPTEF/tE (<0.25) and shorter tPTEF (<0.17 s). While the presence of eczema or FLG mutations were not associated with a shorter tPTEF in 899 infants, a high TEWL was. Similarly, a two-fold higher OR of preschool asthma was observed in infants with high TEWL, but not eczema or FLG mutations among 1337 children. Among 1233 children with available serum eosinophil-derived neurotoxin (EDN) levels, EDN levels >26.7 μg/L in late infancy and >20.5 μg/L at preschool age were associated with preschool asthma, increasing the OR by two- and almost five-fold at respective age. Overall, boys had higher rates of preschool asthma compared to girls; >15% versus <9%. Similarly, infant lung function was lower in boys compared to girls; 0.38 versus 0.40 for tPTEF/tE and 0.20 versus 0.21 s for tPTEF, whereas TEWL, eczema and FLG mutations were distributed equally across the sexes. Boys had higher EDN levels in late infancy and at preschool age (32.0 and 20.9 μg/L) compared to girls (24.5 and 19.0 μg/L). The associations to preschool asthma differed by sex, with an eight- and three-fold higher OR in boys with a lower tPTEF/tE respectively shorter tPTEF, and a four-fold higher OR observed in girls with FLG mutations, only, whereas neither eczema nor high TEWL remained significant risk factors. Higher EDN levels in late infancy increased the OR of preschool asthma by four-fold in boys only, whereas at preschool age, higher levels increased the OR in both sexes.

Conclusion: Based on our findings, we conclude that lower lung function in the awake state, skin barrier impairment as well as eosinophil inflammation in early life overall may be linked to preschool asthma. However, as the associations to preschool asthma differed by sex, with a higher OR observed in boys with lower lung function, while FLG gene mutations increased the OR in girls, and in late infancy, higher EDN levels remained a significant risk factor in boys, only, our observations point to the importance of potential sex differences.

List of scientific papers

I. Bains KES*, Färdig M*, Gudmundsdóttir HK, Almqvist C, Hedlin G, Nordhagen LS, Rehbinder EM, Skjerven HO, Söderhäll C, Vettukattil R, Nordlund B, Lødrup Carlsen KC. Infant tidal flow-volume parameters and arousal state. ERJ Open Res. 2022 Oct 17;8(4):00163-2022. *Shared first authorship.
https://doi.org/10.1183/23120541.00163-2022

II. Färdig M, Gudmundsdóttir HK, Hoyer A, Bains KES, Almqvist C, Monceyron Jonassen C, Rehbinder EM, Skjerven HO, Staff AC, Vettukattil R, Söderhäll C, Carlsen KCL, Nordlund B. Skin Barrier Function and Infant Tidal Flow-Volume Loops-A Population-Based Observational Study. Children. 2022 Dec 31;10(1):88.
https://doi.org/10.3390/children10010088

III. Färdig M, Lie A, Borres MP, Ekenkrantz T, Granum B, Haugen G, Jonassen CM, Movérare R, Rehbinder EM, Skjerven HO, Staff AC, Vettukattil R, Lødrup Carlsen KC, Söderhäll C, Nordlund B. Eosinophil derived-neurotoxin levels by sex and in relation to preschool asthma – a prospective observational study. [Submitted]

IV. Färdig M, Hoyer A, Almqvist C, Bains KES, Lødrup Carlsen KC, Gudmundsdóttir HK, Granum B, Haugen G, Hedlin G, Jonassen CM, Konradsen JR, Lie A, Rehbinder EM, Skjerven HO, Staff AC, Vettukattil R, Söderhäll C, Nordlund B. Infant lung function and early skin barrier impairment in the development of preschool asthma. [Submitted]