Background
Preschool wheeze is a risk factor for asthma development. However, the molecular mechanism behind a wheezing episode is not well understood.
Objective
Our aims were to assess the ...association of plasma proteins with acute preschool wheeze and to study the proteins with differential expression at the acute phase at revisit after 3 months. Additionally, to investigate the relationship between protein expression and clinical parameters.
Method
We measured 92 inflammatory proteins in plasma and clinical parameters from 145 children during an episode of preschool wheeze (PW) and at the revisit after 3 months (PW‐R, n = 113/145) and 101 healthy controls (HC) aged 6–48 months in the GEWAC cohort using the antibody‐mediated proximity extension‐based assay (Olink Proteomics, Uppsala).
Results
Of the 74 analysed proteins, 52 were differentially expressed between PW and HC. The expression profiles of the top 10 proteins, Oncostatin M (OSM), IL‐10, IL‐6, Fibroblast growth factor 21 (FGF21), AXIN1, CXCL10, SIRT2, TNFSF11, Tumour necrosis factor β (TNF‐β) and CASP8, could almost entirely separate PW from HC. Five out of 10 proteins were associated with intake of oral corticosteroids (OCS) 24 h preceding blood sampling (OSM, CASP8, IL‐10, TNF‐β and CXCL10). No differences in protein expression were seen between PWs with or without OCS in comparison to HC. At the revisit after 3 months, differential protein expressions were still seen between PW‐R and HC for three (IL‐10, SIRT2 and FGF21) of the 10 proteins.
Conclusion
Our results contribute to unravelling potential immunopathological pathways shared between preschool wheeze and asthma.
One third of all toddlers are in need of medical care because of acute wheeze and many of these children have persistent asthma at school age. Our aims were to assess risk factors for and the ...prevalence of asthma at age 7 in a cohort of children suffering from an acute wheezing episode as toddlers. A total of 113 children, included during an acute wheezing episode (cases), and 54 healthy controls were followed prospectively from early pre-school age to 7 years. The protocol included questionnaires, ACT, FeNO, nasopharyngeal virus samples, blood sampling for cell count, vitamin D levels, and IgE to food and airborne allergens. The prevalence of asthma at age 7 was 70.8% among cases and 1.9% among controls (p < 0.001). Acute wheeze caused by rhinovirus (RV) infection at inclusion was more common among cases with asthma at age 7 compared to cases without asthma (p = 0.011) and this association remained significant following adjustment for infection with other viruses (OR 3.8, 95% CI 1.4–10.5). Cases with asthma at age 7 had been admitted to hospital more often (p = 0.024) and spent more days admitted (p = 0.01) during the year following inclusion compared to cases without asthma. RV infection stands out as the main associated factor for wheeze evolving to persistent asthma. Cases who developed asthma also had an increased need of hospital time and care for wheeze during the year after inclusion.
Preschool wheeze affects one third of all toddlers up to the age of three years and half of the children before six years of age. Approximately one third of these children will develop asthma in ...school age, and several risk factors have been proposed. However, as of today, it is not possible to reliably predict which children, with preschool wheeze, will develop asthma.All four studies in this thesis are based on the Gene Expression in Wheezing and Asthmatic Children (GEWAC) study, a longitudinal case-control study in which 156 cases and 102 healthy controls, ages 6-48 months, were included. The cases were recruited from the pediatric emergency department at Astrid Lindgren’s Children’s Hospital in Stockholm, when seeking care for an episode of acute wheeze. They came to a revisit after approximately 3 months and were followed annually up to the age of 7 years and a follow-up at age 11. The age-matched healthy controls were recruited from the same hospital at the surgical day-care ward and came to a follow-up at ages 7 and 11 years.The study protocol included nasopharyngeal swabs for viral detection at inclusion, blood sampling, questionnaires, physical examination, measurements of lung function and fractional exhaled nitric oxide (FeNO).Study I consisted of 113 children with an episode of preschool wheeze (cases) and 52 healthy controls who came to the 7-year follow-up. The prevalence of asthma at age 7 was 70.8 % among cases and 1.9 % in healthy controls. Rhinovirus-induced preschool wheeze was more common among cases with asthma in comparison to cases without asthma at age 7 years (48.1 % vs. 21.9 %, p = 0.011; OR 3.3, 95 % CI 1.3-8.5) and this association remained after adjustment for infection with other viruses (OR 3.8, 95 % CI 1.4-10.5). Cases with asthma at age 7 years were admitted to hospital more often because of respiratory difficulties (p = 0.024) and spent more time hospitalized (p = 0.01) during the year after inclusion in the study.In study II we evaluated 107 cases and 46 healthy controls at the 11-year follow-up. We found that 62.6 % of cases and 13.0 % of healthy controls had asthma at age 11 years. Early-life factors associated with asthma at age 11 years, among cases, were rhinovirus-induced wheeze (OR 2.4, 95 % CI 1.02-5.6) and allergic sensitization at 2 years of age (OR 2.9, 95 % CI 1.05-8.1). However, in multivariate logistic regression only allergic sensitization at age 2 years (adjusted OR 3.0, 95 % CI 1.02-8.7) and parental heredity for asthma and/or allergy (adjusted OR 3.4, 95 % CI 1.1-9.9) were associated with asthma at age 11 years. Cases with both rhinovirus-induced wheeze at inclusion and allergic sensitization at age 7 years had a higher prevalence of asthma at age 11 years, in comparison to cases with rhinovirus-induced wheeze at inclusion but without allergic sensitization at age 7 years (92.9 % vs. 57.1 %, p = 0.03).In study III we measured 92 inflammatory-related plasma proteins during an episode of acute preschool wheeze in 145 cases and compared them to 101 healthy controls. With unsupervised clustering we found that the ten most differentially expressed inflammatory-related proteins could almost entirely separate cases from healthy controls. Seven proteins exhibited a higher expression in cases (OSM, IL-10, IL-6, CXCL10, FGF21, AXIN1 and SIRT2) and three proteins had a lower expression (TNFSF11, TNF-b and CASP8), in comparison to healthy controls. These proteins are implicated to be involved in airway epithelial dysfunction, airway remodelling, viral defence, and type 2 inflammation. Among the ten proteins, three (FGF21, SIRT2 and IL-10) were still differentially expressed between cases and controls at the revisit 3 month later.Finally, in study IV we investigated sensitization to multiple allergen molecules longitudinally and its relation to asthma development at 7 years using the multiplex ImmunoCAP ISAC measuring 112 allergen molecules. In this study 72 cases were included and 43 healthy controls. Sensitization to each additional allergen molecule from preschool age to 7 years was associated with asthma at 7 years (OR 1.2; 95 % CI 1.01-1.5). The median number of sensitizing molecules increased from 3 (1-14) at inclusion to 10.5 (1-21) at 7 years of age among sensitized cases with asthma at 7 years of age (p = 0.038). No significant increase was seen in cases without asthma (p = 0.26). Lastly, the number of sensitizing allergen molecules at 7 years was associated with asthma at the same age (OR 1.2; 95 % CI 1.02-1.42).In summary, we found rhinovirus-induced wheeze to be associated with asthma at both 7 and 11 years of age, although probably acting as an unveiling factor in children already predisposed to asthma development. We highlighted the importance of allergic sensitization in asthma development with molecular spreading and polysensitization being involved in disease development. Finally, we found ten inflammatory-related plasma proteins that could contribute to the understanding of why preschool wheeze is a risk factor for asthma development.
Introduction: Allergic sensitization in early life has been identified as a strong risk factor for subsequent asthma in childhood. It is still unclear why only a part of sensitized children develop ...asthma, and the role of specific allergen molecules in asthma pathogenesis is ambiguous Pharmacol Ther. 2009 Feb;121(2):174–84. We assessed the sensitization to multiple allergen molecules longitudinally and explored its relation to persistent asthma at 7 years. Methods: Seventy-two children included during an acute wheezing episode (cases) were followed prospectively from early preschool age (EPA) to age 7, and compared to 43 healthy controls at EPA. Allergen molecules were analyzed at EPA and age 7 using ImmunoCAP Solid-phase Allergen Chip (ISAC). Asthma diagnosis at 7 years was based on symptoms, medication, and spirometry. Results: At EPA, cases compared to controls showed a tendency toward having a higher prevalence of allergic sensitization (23.6% vs. 9.3%, p = 0.055). The prevalence of sensitization increased in cases from EPA to 7 years (23.6% vs. 38.9%; p = 0.048) as well as the median number (range) of immunoglobulin E (IgE)-reactive molecules 3 (3–14) versus 6.5 (1–21); p = 0.024. Sensitization to each additional molecule from EPA to the age of 7 was significantly related to asthma at 7 (OR = 1.25, 95% confidence interval 1.01, 1.54). Conclusion: Polysensitization, assessed by allergen molecules, had a significant impact on persistent asthma at school age. The extent of sensitization, illustrated by molecular spreading from preschool to school age, was related to asthma diagnosis at 7 years in children with a history of wheezing at early life.
Aim
This study explored whether early‐life factors, such as rhinovirus‐induced wheeze and allergic sensitisation, were related to asthma at 11 years of age.
Methods
We focused on 107 children aged ...6–48 months, who attended the paediatric emergency department at Astrid Lindgren's Children's Hospital in Stockholm, Sweden, with acute wheeze in 2008–2012. They also attended follow‐up visits at 11 years of age and were compared with 46 age‐matched healthy controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated with logistic regression.
Results
We found that 62.6% of the acute wheeze cases had asthma at 11 years of age. Rhinoviruses at inclusion were the only common airway viruses associated with an increased asthma risk (OR 2.4, 95% CI 1.02–5.6). Other increased risks were parental heredity for asthma and/or allergies (adjusted OR 3.4, 95% CI 1.1–9.9) and allergic sensitisation at 2 years of age (adjusted OR 3.0, 95% CI 1.02–8.7). The highest prevalence of asthma was when children had both rhinovirus‐induced wheeze at inclusion and allergic sensitisation at 7 years of age.
Conclusion
Our findings highlight the importance of hereditary factors and allergic sensitisation on the development of asthma and suggest that rhinoviruses are associated with asthma development in predisposed children.
PDF
