Metabo-Endotypes of Asthma Reveal Differences in Lung Function: Discovery and Validation in Two TOPMed Cohorts

Kelly, Rachel S.; Mendez, Kevin; Huang, Mengna; Hobbs, Brian D.; Clish, Clary B.; Gerszten, Robert E.; Cho, Michael H.; Wheelock, Craig E.; McGeachie, Michael J.; Chu, Su H.; Celedón, Juan C.; Weiss, Scott T.; Lasky‐Su, Jessica

doi:10.1164/rccm.202105-1268oc

Cited by 18 publications

(4 citation statements)

References 52 publications

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“…For example, a recent analysis of three cohort studies of bronchiolitis in the USA and Finland has revealed that the phenotype characterised by a history of breathing problems, allergic predisposition and rhinovirus infection had a significantly increased risk for asthma12—which is in line with the present analysis. Additionally, previous reports using global metabolomics (ie, not lipidomics) have suggested pathobiological roles of complex lipids in the pathobiology of both acute respiratory infections17 38–42 and asthma 19 43 44. For example, concordant with the endotype B (clinical severe lipid sphingolipids-high ) observed in the current study, a metabolomic analysis of 144 infants with bronchiolitis has reported a positive association of sphingolipids in the upper airway with higher bronchiolitis severity 15.…”

Section: Discussionsupporting

confidence: 82%

Nasopharyngeal lipidomic endotypes of infants with bronchiolitis and risk of childhood asthma: a multicentre prospective study

Fujiogi

Zhu

Raita

et al. 2022

Thorax

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BackgroundBronchiolitis is the leading cause of hospitalisation of US infants and an important risk factor for childhood asthma. Recent evidence suggests that bronchiolitis is clinically heterogeneous. We sought to derive bronchiolitis endotypes by integrating clinical, virus and lipidomics data and to examine their relationship with subsequent asthma risk.MethodsThis is a multicentre prospective cohort study of infants (age <12 months) hospitalised for bronchiolitis. We identified endotypes by applying clustering approaches to clinical, virus and nasopharyngeal airway lipidomic data measured at hospitalisation. We then determined their longitudinal association with the risk for developing asthma by age 6 years by fitting a mixed-effects logistic regression model. To account for multiple comparisons of the lipidomics data, we computed the false discovery rate (FDR). To understand the underlying biological mechanism of the endotypes, we also applied pathway analyses to the lipidomics data.ResultsOf 917 infants with bronchiolitis (median age, 3 months), we identified clinically and biologically meaningful lipidomic endotypes: (A) cinicalclassiclipidmixed (n=263), (B) clinicalseverelipidsphingolipids-high (n=281), (C) clinicalmoderatelipidphospholipids-high (n=212) and (D) clinicalatopiclipidsphingolipids-low (n=161). Endotype A infants were characterised by ‘classic’ clinical presentation of bronchiolitis. Profile D infants were characterised by a higher proportion of parental asthma, IgE sensitisation and rhinovirus infection and low sphingolipids (eg, sphingomyelins, ceramides). Compared with endotype A, profile D infants had a significantly higher risk of asthma (22% vs 50%; unadjusted OR, 3.60; 95% CI 2.31 to 5.62; p<0.001). Additionally, endotype D had a significantly lower abundance of polyunsaturated fatty acids (eg, docosahexaenoic acid; FDR=0.01). The pathway analysis revealed that sphingolipid metabolism pathway was differentially expressed in endotype D (FDR=0.048).ConclusionsIn this multicentre prospective cohort study of infants with bronchiolitis, integrated clustering of clinical, virus and lipidomic data identified clinically and biologically distinct endotypes that have a significantly differential risk for developing asthma.Delete

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Section: Discussionsupporting

confidence: 82%

Nasopharyngeal lipidomic endotypes of infants with bronchiolitis and risk of childhood asthma: a multicentre prospective study

Fujiogi

Zhu

Raita

et al. 2022

Thorax

View full text Add to dashboard Cite

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“…The second approach involves mass spectrometry for quantifying biomolecules (lipids, proteins, or metabolites) in cells or tissues [21]. In a study utilizing metabolome-wide data and clustering, five clusters were discerned in asthmatic children, showcasing variations in lung function parameters [22]. Metabolomics data from Exhaled Breath Condensate (EBC) underwent analysis using clustering algorithms, revealing three clusters distinguished by blood eosinophil percentage and other factors [23].…”

Section: Pediatric Asthma Endotypesmentioning

confidence: 99%

What's new in pediatric asthma and rhinitis phenotypes and endotypes?

Roberto,

Barberi,

Marseglia

et al. 2024

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of review This review explores the evolving landscape of pediatric asthma and rhinitis, focusing on identifying and characterizing different subtypes. Recent findings Childhood asthma and rhinitis are prevalent respiratory conditions frequently occurring together. To address the need for a precise definition of these diseases, an unbiased and comprehensive phenotyping approach has been undertaken with hypothesis-free analysis of extensive datasets to uncover new relationships among clinical, environmental, and biological characteristics. On the other hand, the concept of endotype is elaborate and multifaceted, representing distinct pathophysiological mechanisms underlying the clinical presentation and requires the identification of reliable biomarkers. The recognition of multiple inflammatory endotypes underscores the need for in-depth characterization, which could revolutionize the treatment landscape. Summary Comprehending phenotypes and endotypes is crucial for customizing effective and personalized management approaches for children with asthma and rhinitis. More precise and efficient care can be administered through recognition and detailed characterization, ultimately enhancing patients’ quality of life.

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“…(10, 11) Metabolomic and proteomic analyses of airway samples have also been used to delineate patient subtypes. (12, 13) However, the technical demands and cost of these ‘omic approaches preclude their widespread clinical use.…”

Section: Introductionmentioning

confidence: 99%

Sputum alarmin levels delineate distinct T2 cytokine pathways and patient subgroups in asthma

Gautam

Chu

Cohen

et al. 2022

Preprint

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RationaleAsthma is a chronic airway disease driven by multiple immunologic pathways that determine the clinical response to therapy. Current diagnostic methods are incapable of discriminating subtypes of asthma and guiding targeted treatment. We hypothesized that sputum cytokine profiles could help to identify immunologically-defined disease subtypes and individualize therapy in patients with severe asthma.ObjectivesDefine asthma subtypes associated with sputum alarmin and cytokine levels.MethodsCross-sectional analysis of clinical features and sputum from 200 asthmatic patients was performed. 10 cytokines belonging to alarmin, T2, and non-T2 pathways were measured. Pearson correlation was used to identify cytokine modules. Latent class analysis was used to cluster patients by cytokine expression.Measurements and Main ResultsThree modules of highly correlated cytokines were identified including a non-T2 module, the IL-1βmod (IL-1β, IL-6, GCSF), and two distinct T2 modules: TSLPmod (TSLP, IL-4, IL-5, IL-9) and IL-33mod (IL-33, IL-13, IL-21). The TSLPmod was associated with asthma severity, airway obstruction, eosinophilia, and elevated FeNO. Patient clustering revealed three subgroups; two different subgroups showed expression of T2 modules.ConclusionsAnalysis of sputum cytokines revealed three discrete signaling modules in patients with asthma. Unexpectedly, the inclusion of alarmins led to separation of canonical T2 cytokines into two unique modules; IL-5 grouped with TSLP, while IL-13 grouped with IL-33. In addition, patient clustering revealed two distinct endotypes associated with T2 immune signaling. These findings indicate a new layer of immunologic heterogeneity within the T2 paradigm, and suggest that sputum cytokine profiling may hold diagnostic utility for patients with asthma.

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Metabo-Endotypes of Asthma Reveal Differences in Lung Function: Discovery and Validation in Two TOPMed Cohorts

Cited by 18 publications

References 52 publications

Nasopharyngeal lipidomic endotypes of infants with bronchiolitis and risk of childhood asthma: a multicentre prospective study

Nasopharyngeal lipidomic endotypes of infants with bronchiolitis and risk of childhood asthma: a multicentre prospective study

What's new in pediatric asthma and rhinitis phenotypes and endotypes?

Sputum alarmin levels delineate distinct T2 cytokine pathways and patient subgroups in asthma

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