Dataset Information

IL1RL1 gene variants and nasopharyngeal IL1RL-a levels are associated with severe RSV bronchiolitis: a multicenter cohort study.

ABSTRACT: Targets for intervention are required for respiratory syncytial virus (RSV) bronchiolitis, a common disease during infancy for which no effective treatment exists. Clinical and genetic studies indicate that IL1RL1 plays an important role in the development and exacerbations of asthma. Human IL1RL1 encodes three isoforms, including soluble IL1RL1-a, that can influence IL33 signalling by modifying inflammatory responses to epithelial damage. We hypothesized that IL1RL1 gene variants and soluble IL1RL1-a are associated with severe RSV bronchiolitis.We studied the association between RSV and 3 selected IL1RL1 single-nucleotide polymorphisms rs1921622, rs11685480 or rs1420101 in 81 ventilated and 384 non-ventilated children under 1 year of age hospitalized with primary RSV bronchiolitis in comparison to 930 healthy controls. Severe RSV infection was defined by need for mechanical ventilation. Furthermore, we examined soluble IL1RL1-a concentration in nasopharyngeal aspirates from children hospitalized with primary RSV bronchiolitis. An association between SNP rs1921622 and disease severity was found at the allele and genotype level (p?=?0.011 and p?=?0.040, respectively). In hospitalized non-ventilated patients, RSV bronchiolitis was not associated with IL1RL1 genotypes. Median concentrations of soluble IL1RL1-a in nasopharyngeal aspirates were >20-fold higher in ventilated infants when compared to non-ventilated infants with RSV (median [and quartiles] 9,357 [936-15,528] pg/ml vs. 405 [112-1,193] pg/ml respectively; p<0.001).We found a genetic link between rs1921622 IL1RL1 polymorphism and disease severity in RSV bronchiolitis. The potential biological role of IL1RL1 in the pathogenesis of severe RSV bronchiolitis was further supported by high local concentrations of IL1RL1 in children with most severe disease. We speculate that IL1RL1a modifies epithelial damage mediated inflammatory responses during RSV bronchiolitis and thus may serve as a novel target for intervention to control disease severity.

SUBMITTER: Faber TE

PROVIDER: S-EPMC3344820 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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IL1RL1 gene variants and nasopharyngeal IL1RL-a levels are associated with severe RSV bronchiolitis: a multicenter cohort study.

Faber Tina E TE Schuurhof Annemieke A Vonk Annelies A Koppelman Gerard H GH Hennus Marije P MP Kimpen Jan L L JL Janssen Riny R Bont Louis J LJ

PloS one 20120504 5

<h4>Background</h4>Targets for intervention are required for respiratory syncytial virus (RSV) bronchiolitis, a common disease during infancy for which no effective treatment exists. Clinical and genetic studies indicate that IL1RL1 plays an important role in the development and exacerbations of asthma. Human IL1RL1 encodes three isoforms, including soluble IL1RL1-a, that can influence IL33 signalling by modifying inflammatory responses to epithelial damage. We hypothesized that IL1RL1 gene vari ...[more]

PMID: 22574108

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Project description:BackgroundSevere bronchiolitis (ie, bronchiolitis requiring hospitalization) during infancy is a major risk factor for childhood asthma. However, the exact mechanism linking these common conditions remains unclear.ObjectivesThis study sought to examine the integrated role of airway microbiome (both taxonomy and function) and host response in asthma development in this high-risk population.MethodsThis multicenter prospective cohort study of 244 infants with severe bronchiolitis (median age, 3 months) examined the infants' nasopharyngeal metatranscriptomes (microbiomes) and transcriptomes (hosts), as well as metabolomes at hospitalization. The longitudinal relationships investigated include (1) major bacterial species (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis), (2) microbial function, and (3) host response with risks of developing asthma by age 6 years.ResultsFirst, the abundance of S pneumoniae was associated with greater risks of asthma (P = .01), particularly in infants with nonrhinovirus infection (Pinteraction = .04). Second, of 328 microbial functional pathways that are differentially enriched by asthma development, the top pathways (eg, fatty acid and glycolysis pathways; false discovery rate [FDR] < 1 × 10-12) were driven by these 3 major species (eg, positive association of S pneumoniae with glycolysis; FDR < 0.001). These microbial functional pathways were validated with the parallel metabolome data. Third, 104 transcriptome pathways were differentially enriched (FDR < .05)-for example, downregulated interferon-α and -γ and upregulated T-cell activation pathways. S pneumoniae was associated with most differentially expressed transcripts (eg, DAGLB; FDR < 0.05).ConclusionsBy applying metatranscriptomic, transcriptomic, and metabolomic approaches to a multicenter cohort of infants with bronchiolitis, this study found an interplay between major bacterial species, their function, and host response in the airway, and their longitudinal relationship with asthma development.

Project description:BackgroundWhile infant bronchiolitis contributes to substantial acute (eg, severity) and chronic (eg, asthma development) morbidities, its pathobiology remains uncertain. We examined the integrated relationships of local (nasopharyngeal) and systemic (serum) responses with bronchiolitis morbidities.MethodsIn a multicenter prospective cohort study of infants hospitalized for bronchiolitis, we applied a network analysis approach to identify distinct networks (modules)-clusters of densely interconnected metabolites-of the nasopharyngeal and serum metabolome. We examined their individual and integrated relationships with acute severity (defined by positive pressure ventilation [PPV] use) and asthma development by age 5 years.ResultsIn 140 infants, we identified 285 nasopharyngeal and 639 serum metabolites. Network analysis revealed 7 nasopharyngeal and 8 serum modules. At the individual module level, nasopharyngeal-amino acid, tricarboxylic acid (TCA) cycle, and carnitine modules were associated with higher risk of PPV use (r > .20; P < .001), while serum-carnitine, amino acid, and glycerophosphorylcholine (GPC)/glycerophosphorylethanolamine (GPE) modules were associated with lower risk (all r < -.20; P < .05). The integrated analysis for PPV use revealed consistent findings-for example, nasopharyngeal-TCA (adjOR: 2.87, 95% CI: 1.68-12.2) and serum-GPC/GPE (adjOR: 0.54, 95% CI: 0.38-0.80) modules-and an additional module-serum-glucose-alanine cycle module (adjOR: 0.69, 95% CI: 0.56-0.86). With asthma risk, there were no individual associations, but there were integrated associations (eg, nasopharyngeal-carnitine module; adjOR: 1.48, 95% CI: 1.11-1.99).ConclusionIn infants with bronchiolitis, we found integrated relationships of local and systemic metabolome networks with acute and chronic morbidity. Our findings advance research into the complex interplay among respiratory viruses, local and systemic response, and disease pathobiology in infants with bronchiolitis.

Project description:BackgroundWe sought to identify predictors of asthma development following severe early childhood RSV bronchiolitis. Different definitions of asthma were also compared.MethodsThis longitudinal, observational study (N = 343) followed patients (<2 years old) from a placebo-controlled trial (N = 979) of montelukast after RSV bronchiolitis to identify clinical, demographic, or biochemical predictors of asthma, atopic disorders, and chronic asthma therapy use at 6 years of age (Clinical Trials Registry Number: NCT01140048). Asthma (primary definition) was based on parental identification of wheeze at 6 AND 12 months before 6 years of age; definitions based on physician diagnosis as well as parental identification of wheeze at 6 OR 12 months (to consider seasonal effect) were also assessed. Post-hoc analyses evaluated agreement among asthma diagnosis criteria.ResultsPrevalence of asthma (primary definition by parental identification), asthma (physician diagnosis), atopic disorders, and chronic asthma therapy use (parental identification) was 6.1%, 22.4%, 36.2%, and 14.5%, respectively. Predictors for asthma (primary definition) included male gender, a relative with asthma, and RAST positive for dog dander; for physician diagnosis of asthma, high severity score for RSV bronchiolitis, high respiratory rate, and asthma diagnosis before enrollment. Predictors of atopic disorders included allergic rhinitis before enrollment, a relative with asthma, and the plasma biomarkers IL-5, IL-16, and IL-18. Predictors of chronic asthma therapy use included asthma diagnosis before enrollment and geographic region (Europe and Africa). Only 42% of patients with asthma (primary definition) also met the asthma definition by physician diagnosis and chronic asthma therapy use.ConclusionAmong children with early RSV bronchiolitis, hereditary factors (i.e., having a relative with asthma) and RSV bronchiolitis severity were predictors of asthma and atopic disorders at 6 years of age. Of interest, there was poor agreement among the asthma definitions evaluated. Pediatr Pulmonol. 2016;51:1382-1392. © 2016 Wiley Periodicals, Inc.

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IL1RL1 gene variants and nasopharyngeal IL1RL-a levels are associated with severe RSV bronchiolitis: a multicenter cohort study.

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IL1RL1 gene variants and nasopharyngeal IL1RL-a levels are associated with severe RSV bronchiolitis: a multicenter cohort study.

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