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Plasma metabolomics identifies differing endotypes of recurrent wheezing in preschool children differentiated by symptoms and social disadvantage.

ABSTRACT: Preschool children with recurrent wheezing are a heterogeneous population with many underlying biological pathways that contribute to clinical presentations. Although the morbidity of recurrent wheezing in preschool children is significant, biological studies in this population remain quite limited. To address this gap, this study performed untargeted plasma metabolomic analyses in 68 preschool children with recurrent wheezing to identify metabolomic endotypes of wheezing. K-means cluster analysis was performed on metabolomic dataset including a total of 1382 named and unnamed metabolites. We identified three metabolomic clusters which differed in symptom severity, exacerbation occurrence, and variables associated with social disadvantage. Metabolites that distinguished the clusters included those involved in fatty acid metabolism, fatty acids (long chain monounsaturated fatty acids, long chain polyunsaturated fatty acids, and long chain saturated fatty acids), lysophospholipids, phosphatidylcholines, and phosphatidylethanolamines. Pathway analyses identified pathways of interest in each cluster, including steroid metabolism, histidine metabolism, sphingomyelins, and sphingosines, among others. This study highlights the biologic complexity of recurrent wheezing in preschool children and offers novel metabolites and pathways that may be amenable to future study and intervention.

SUBMITTER: Fitzpatrick AM

PROVIDER: S-EPMC11233605 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Plasma metabolomics identifies differing endotypes of recurrent wheezing in preschool children differentiated by symptoms and social disadvantage.

Fitzpatrick Anne M AM Grunwell Jocelyn R JR Gaur Hina H Kobara Seibi S Kamaleswaran Rishikesan R

Scientific reports 20240709 1

Preschool children with recurrent wheezing are a heterogeneous population with many underlying biological pathways that contribute to clinical presentations. Although the morbidity of recurrent wheezing in preschool children is significant, biological studies in this population remain quite limited. To address this gap, this study performed untargeted plasma metabolomic analyses in 68 preschool children with recurrent wheezing to identify metabolomic endotypes of wheezing. K-means cluster analys ...[more]

PMID: 38982241

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Project description:BackgroundPreschool children with recurrent wheezing are heterogeneous, with differing responses to respiratory viral infections. Although neutrophils are crucial for host defense, their function has not been studied in this population.ObjectiveWe performed functional immunophenotyping on isolated blood neutrophils from 52 preschool children with recurrent wheezing (aeroallergen sensitization, n = 16; no sensitization, n = 36).MethodsBlood neutrophils were purified and cultured overnight with polyinosinic:polycytidylic acid [poly(I:C)] as a viral analog stimulus. Neutrophils underwent next-generation sequencing with Reactome pathway analysis and were analyzed for cytokine secretion, apoptosis, myeloperoxidase, and extracellular DNA release. CD14+ monocytes were also exposed to neutrophil culture supernatant and analyzed for markers of M1 and M2 activation.ResultsA total of 495 genes, related largely to the innate immune system and neutrophil degranulation, were differently expressed in children with versus without aeroallergen sensitization. Functional experiments identified more neutrophil degranulation and extracellular trap formation (ie, more myeloperoxidase and extracellular DNA) and less neutrophil proinflammatory cytokine secretion in children with aeroallergen sensitization. Neutrophils also shifted CD14+ monocytes to a more anti-inflammatory (ie, M2) phenotype in sensitized children and a more proinflammatory (ie, M1) phenotype in nonsensitized children. Although both groups experienced viral exacerbations, annualized exacerbation rates prompting unscheduled health care were also higher in children without aeroallergen sensitization after enrollment.ConclusionsSystemic neutrophil responses to viral infection differ by allergic phenotype and may be less effective in preschool children without allergic inflammation. Further studies of neutrophil function are needed in this population, which often has less favorable therapeutic responses to inhaled corticosteroids and other therapies directed at type 2-high inflammation.

Project description:Preschool children with recurrent wheezing are heterogeneous, with differing responses to respiratory viral infections. Although neutrophils are crucial for host defense, their function has not been studied in this population. We performed functional immunophenotyping on isolated blood neutrophils from 52 preschool children with recurrent wheezing (aeroallergen sensitization, n=16; no sensitization, n=36). Blood neutrophils were purified and cultured overnight with polyinosinic:polycytidylic acid (poly(I:C)) as a viral analog stimulus. Neutrophils underwent next-generation sequencing with Reactome pathway analysis and were analyzed for cytokine secretion, apoptosis, myeloperoxidase and extracellular DNA release. CD14+ monocytes were also exposed to neutrophil culture supernatant and analyzed for markers of M1 and M2 activation. 495 genes, related largely to the innate immune system and neutrophil degranulation, were differently expressed in children with versus without aeroallergen sensitization. Functional experiments identified more neutrophil degranulation and extracellular trap formation (i.e., more myeloperoxidase and extracellular DNA) and less neutrophil pro-inflammatory cytokine secretion in children with aeroallergen sensitization. Neutrophils also shifted CD14+ monocytes to a more anti-inflammatory (i.e., M2) phenotype in sensitized children and a more pro-inflammatory (i.e., M1) phenotype in non-sensitized children. Although both groups experienced viral exacerbations, annualized exacerbation rates prompting unscheduled healthcare were also higher in children without aeroallergen sensitization after enrollment. Systemic neutrophil responses to viral infection differ by allergic phenotype and may be less effective in preschool children without allergic inflammation. Further studies of neutrophil function are needed in this population, which often has less favorable therapeutic responses to inhaled corticosteroids and other therapies directed at T2-high inflammation.

Project description:BackgroundIn young healthy children, assessing airflow limitation may be difficult because of narrowing of the airways, which is a pathology of asthma, and responsiveness to bronchodilators.ObjectiveWe investigated whether lung sound analysis could predict the development of recurrent wheezing (RW), which is one of the signs of asthma.MethodsIn healthy children aged 3 to 24 months, we recorded and analyzed lung sounds before and after inhalation of bronchodilators and conducted a questionnaire survey. The children were followed up and assessed for the development of RW at age 3 years.ResultsOf the 62 patients analyzed, 19 (30.6%) developed RW. The parameters ratio of power and frequency at 50% of the highest frequency of the dB power spectrum (RPF50) and ratio of power and frequency at 75% of the highest frequency of the dB power spectrum (RPF75), calculated by lung sound analysis, were lower in the RW group, with odds ratios of 0.77 (95% CI = 0.61-0.98) and 0.81 (95% CI = 0.66-0.99), respectively. The rate of change of lung sound analysis parameters after bronchodilator inhalation did not differ among the participants as a group; however, in the subgroup of children with a history of atopic dermatitis, the fourth area under the curve (B4) divided by the total area under the curve of 100 Hz to the highest frequency of the dB power spectrum (AT) and difference between the values of the ratio of power and frequency at 50% of the highest frequency of the dB power spectrum (ΔRPF50) were elevated in the RW group (P = .015 and P = .041, respectively). In the subgroup of children with total a IgE level greater than 20 kUA/L, the sensitivities and specificities for predicting the development of RW were 85.7% (95% CI = 48.7-99.3) and 68.8% (95% CI = 44.4-85.8), respectively, when the cutoff value of ΔRPF50 was set at 10.5%.ConclusionThe method of lung sound analysis allows noninvasive assessment of the airway, including airway hypersensitivity, in young children and may predict the risk of development of RW.

Project description:BackgroundThe innate mechanisms associated with viral exacerbations in preschool children with recurrent wheezing are not understood.ObjectiveWe sought to assess differential gene expression in blood neutrophils from preschool children with recurrent wheezing, stratified by aeroallergen sensitization, at baseline and after exposure to polyinosinic:polycytidylic acid (poly(I:C)) and also to examine whether poly(I:C)-stimulated blood neutrophils influenced airway epithelial gene expression.MethodsBlood neutrophils were purified and cultured overnight with poly(I:C) and underwent next-generation sequencing with Reactome pathway analysis. Primary human small airway epithelial cells were treated with poly(I:C)-treated neutrophil culture supernatants and were analyzed for type 1 interferon gene expression with a targeted array. Symptoms and exacerbations were assessed in participants over 12 months.ResultsA total of 436 genes were differently expressed in neutrophils from children with versus without aeroallergen sensitization at baseline, with significant downregulation of type 1 interferons. These type 1 interferons were significantly upregulated in sensitized children after poly(I:C) stimulation. Confirmatory experiments demonstrated similar upregulation of type 1 interferons in IL-4-treated neutrophils stimulated with poly(I:C). Poly(I:C)-treated neutrophil supernatants from children with aeroallergen sensitization also induced a type 1 interferon response in epithelial cells. Children with aeroallergen sensitization also had higher symptom scores during exacerbations, and these symptom differences persisted for 3 days after prednisolone treatment.ConclusionsType 1 interferon responses are dysregulated in preschool children with aeroallergen sensitization, which is in turn associated with exacerbation severity. Given the importance of type 1 interferon signaling in viral resolution, additional studies of neutrophil type 1 interferon responses are needed in this population.

Dataset Information

Plasma metabolomics identifies differing endotypes of recurrent wheezing in preschool children differentiated by symptoms and social disadvantage.

Publications

Plasma metabolomics identifies differing endotypes of recurrent wheezing in preschool children differentiated by symptoms and social disadvantage.

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