IL1RL1 gene variations are associated with asthma exacerbations in children and adolescents using inhaled corticosteroids.
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ABSTRACT:
SUBMITTER: Dijk FN
PROVIDER: S-EPMC7176513 | biostudies-literature | 2020 Apr
REPOSITORIES: biostudies-literature
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IL1RL1 gene variations are associated with asthma exacerbations in children and adolescents using inhaled corticosteroids.
Dijk F Nicole FN Vijverberg Susanne J SJ Hernandez-Pacheco Natalia N Repnik Katja K Karimi Leila L Mitratza Marianna M Farzan Niloufar N Nawijn Martijn C MC Burchard Esteban G EG Engelkes Marjolein M Verhamme Katia M KM Potočnik Uroš U Pino-Yanes Maria M Postma Dirkje S DS Maitland-van der Zee Anke-Hilse AH Koppelman Gerard H GH
Allergy 20191217 4
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Project description:BackgroundInhalation corticosteroids (ICS) are prescribed for treatment of asthma in approximately 3% of all children in Denmark. Despite limited evidence, case reports suggest that ICS-related behavioural adverse drug events (ADEs) may be frequent. In general, underreporting of ADEs to official databases is common, and little is known about doctor's clinical experiences with behavioural ADEs when prescribing ICS for children with asthma. The objective was to investigate the extent of behavioural ADEs in children with asthma treated with ICS by comparing database findings to experiences of specialist doctors.MethodsFirst, databases of the European Medicines Agency (EMA) and the Danish Medicines Agency (DKMA) were searched for reports made by healthcare professionals about behavioural ADEs in children from 2009 to 2018. Second, questionnaire data on behavioural ADEs were collected from eight of the 11 specialist doctors responsible for treating children with asthma at the six paediatric departments in Central Denmark Region and North Denmark Region.ResultsEMA and DKMA had registered 104 and 3 reports, respectively, on behavioural ADEs during the 10-year study period. In contrast, five of the eight specialist doctors (45.5%) had experienced patients who had developed behavioural changes during ICS treatment. However, none of the five specialist doctors had filed reports on these events to DKMA.ConclusionBehaviour-related ADEs to ICS in children with asthma are likely to be highly underreported in official databases and doctors treating children with ICS should be aware of potential ADEs and consider submitting ADE reports whenever appropriate.
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Project description:BackgroundNonadherence to inhaled corticosteroids (ICS) is a significant risk factor for poor asthma outcomes in minority adolescents with persistent asthma.ObjectiveTo identify factors associated with nonadherence to daily ICS in this target population.MethodsAdolescents 11 to 16 years old, self-identified as African American or Hispanic, diagnosed with persistent asthma and with an active prescription for daily ICS were invited to participate. Participant adherence to ICS was electronically measured during 14 days. Concurrently, participants completed the following assessments: demographic information, asthma history, asthma control, asthma exacerbations, media use, depression, asthma knowledge, ICS knowledge, and ICS self-efficacy. Of the 93 subjects, 68 had low (<48%) adherence and 25 had high (>48%) adherence.ResultsOlder age and low ICS knowledge each were associated with low (≤48%) adherence (P < .01 for the 2 variables).ConclusionOlder age and low ICS knowledge each may be associated with poor adherence to ICS in minority adolescents with persistent asthma. Although older age often is associated with the assignment of increased responsibility for medication-taking behavior, it may not be associated with increased adherence. Continued and expanded efforts at promoting asthma education and specifically knowledge of ICS may increase adherence to ICS.
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Project description:Asthma is a polygenic disease that may onset during childhood. Inhaled corticosteroids (ICS) are the main therapy in asthma, although their efficacy varies among individuals. Nuclear factor κB (NF-κB) is an important target of ICS treatment of asthma. Recent research has reported that GRB2 associated binding protein 1 (GAB1) gene may participate in the pathogenesis of asthma by regulating the NF-κB pathway. Therefore, we used the technique of an improved multiplex ligation detection reaction to sequence GAB1 gene and investigated the involvement of Single-nucleotide variants (SNVs) in GAB1 gene in asthma and ICS efficacy in asthmatic children. We found no differences between asthma cases and controls in allele or genotype frequencies of GAB1. Haplotype analysis showed an increased tendency for AGGAGC frequency in asthma patients compared with controls (OR = 2.69, p = 0.018). The percentage of EOS and genotype distribution of rs1397527 were associated (p = 0.007). The EOS percentage was higher in GT genotype when compared to the GG genotype (5.50 vs 3.00, Bonferroni adjusted p = 0.005). After 12-weeks ICS treatment, GAB1 rs1397527 TT and GT genotype carriers had a smaller change in forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) than GG carriers (p = 0.009), and rs3805236 GG and AG genotype carriers also had a smaller change in FEV1/FVC than AA carriers (p = 0.025). For ICS response, the frequency of GG genotype of rs1397527 was significantly higher in good responders (p = 0.038). The generalized multifactor dimensionality reduction (GMDR) analysis showed a best significant four-order model (rs1397527, allergen exposure, environmental tobacco smoke exposure, and pet exposure) involving gene-environment interactions (p = 0.001). In summary, we found that GAB1 SNVs were not associated with asthma susceptibility. Haplotype AGGAGC was a risk factor for asthma. GAB1 variants were associated with eosinophils and ICS response in asthmatics. Furthermore, gene-environment interaction was observed.
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Project description:BackgroundFor children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids (ICS), evidence to guide step-up therapy is lacking.MethodsWe randomly assigned 182 children (6 to 17 years of age), who had uncontrolled asthma while receiving 100 microg of fluticasone twice daily, to receive each of three blinded step-up therapies in random order for 16 weeks: 250 microg of fluticasone twice daily (ICS step-up), 100 microg of fluticasone plus 50 microg of a long-acting beta-agonist twice daily (LABA step-up), or 100 microg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily (LTRA step-up). We used a triple-crossover design and a composite of three outcomes (exacerbations, asthma-control days, and the forced expiratory volume in 1 second) to determine whether the frequency of a differential response to the step-up regimens was more than 25%.ResultsA differential response occurred in 161 of 165 patients who were evaluated (P<0.001). The response to LABA step-up therapy was most likely to be the best response, as compared with responses to LTRA step-up (relative probability, 1.6; 95% confidence interval [CI], 1.1 to 2.3; P=0.004) and ICS step-up (relative probability, 1.7; 95% CI, 1.2 to 2.4; P=0.002). Higher scores on the Asthma Control Test before randomization (indicating better control at baseline) predicted a better response to LABA step-up (P=0.009). White race predicted a better response to LABA step-up, whereas black patients were least likely to have a best response to LTRA step-up (P=0.005).ConclusionsNearly all the children had a differential response to each step-up therapy. LABA step-up was significantly more likely to provide the best response than either ICS or LTRA step-up. However, many children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child's asthma therapy. (ClinicalTrials.gov number, NCT00395304.)
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