The inflammatory profile of exacerbations in patients with severe refractory eosinophilic asthma receiving mepolizumab (the MEX study): a prospective observational study

McDowell, P Jane; Diver, Sarah; Yang, Freda; Borg, Catherine; Busby, John; Brown, Vanessa; Shrimanker, Rahul; Cox, Ciara; Chaudhuri, Rekha; Pavord, Ian; Heaney, Liam G.; Wise, Christopher M.; McAnally, Christine; Drain, Stephen; Mistry, Vijay; Arnold, H.; Micieli, Claudia; Monterio, W; Jones, M.T.; Ellis, Hattie; Thulborn, Samantha; Cheyne, Linda; Ramsey, Esther; Howes, Sarah; Bourne, Michelle; Thorton, Tracy; Edwards, Sarah; Evans, Helen; Smith, Steven G.; Grandison, Tracyanne

doi:10.1016/s2213-2600(21)00004-7

Cited by 53 publications

(36 citation statements)

References 33 publications

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“…[35][36][37][38] FeNO is an attractive biomarker of T2 inflammation in view of its wide accessibility and relative ease of measurement and has recently demonstrated potential utility in determining inflammatory phenotype at acute exacerbation in severe asthma. 5 FeNO has previously been shown to correlate with the alpha-diversity of the mycobiome, but was unrelated to the microbiome, in asthma. 38 In our study, a FeNO ≥50 ppb indicated a subgroup with low intersubject variability in microbial profiles, with a low relative abundance of pathogenic organisms, including Haemophilus; increased abundance of which has been shown to predict response to macrolide therapy.…”

Section: Discussionmentioning

confidence: 93%

Relationship between inflammatory status and microbial composition in severe asthma and during exacerbation

Brightling

Haldar

Busby³

et al. 2022

Allergy

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Background: In T2-mediated severe asthma, biologic therapies, such as mepolizumab, are increasingly used to control disease. Current biomarkers can indicate adequate suppression of T2 inflammation, but it is unclear whether they provideThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Discussionmentioning

confidence: 93%

Relationship between inflammatory status and microbial composition in severe asthma and during exacerbation

Brightling

Haldar

Busby³

et al. 2022

Allergy

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“…Actually, induced sputum is currently the best available noninvasive assessment of bronchial inflammation in asthma, and it is regarded as the gold standard for asthma inflammatory phenotyping [ 45 ]. This method has been widely adopted in many of studies [ 46 – 48 ]. GINA guideline also recommends to use the method to confirm asthma inflammatory phenotype [ 49 ] .…”

Section: Discussionmentioning

confidence: 99%

Weighted gene co-expression network analysis to identify key modules and hub genes associated with paucigranulocytic asthma

Zhu

Wang

et al. 2021

BMC Pulm Med

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Background Asthma is a heterogeneous disease that can be divided into four inflammatory phenotypes: eosinophilic asthma (EA), neutrophilic asthma (NA), mixed granulocytic asthma (MGA), and paucigranulocytic asthma (PGA). While research has mainly focused on EA and NA, the understanding of PGA is limited. In this study, we aimed to identify underlying mechanisms and hub genes of PGA. Methods Based on the dataset from Gene Expression Omnibus(GEO), weighted gene coexpression network analysis (WGCNA), differentially expressed genes (DEGs) analysis and protein–protein interaction (PPI) network analysis were conducted to construct a gene network and to identify key gene modules and hub genes. Functional enrichment analyses were performed to investigate the biological process, pathways and immune status of PGA. The hub genes were validated in a separate dataset. Results Compared to non-PGA, PGA had a different gene expression pattern, in which 449 genes were differentially expressed. One gene module significantly associated with PGA was identified. Intersection between the differentially expressed genes (DEGs) and the genes from the module that were most relevant to PGA were mainly enriched in inflammation and immune response regulation. The single sample Gene Set Enrichment Analysis (ssGSEA) suggested a decreased immune infiltration and function in PGA. Finally six hub genes of PGA were identified, including ADCY2, CXCL1, FPRL1, GPR109B, GPR109A and ADCY3, which were validated in a separate dataset of GSE137268. Conclusions Our study characterized distinct gene expression patterns, biological processes and immune status of PGA and identified hub genes, which may improve the understanding of underlying mechanism and provide potential therapeutic targets for PGA.

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“…An intriguing observation of early randomized clinical trials with mepolizumab is that similar reductions in exacerbations are obtained with a range of mepolizumab doses, even though a significant population of residual sputum eosinophils persists in patients receiving lower doses of therapy [22]. In addition, eosinophilic exacerbations (sputum eosinophils >2%) still make up to 50% of residual asthma exacerbations in patients receiving mepolizumab, in spite of marked reductions in blood eosinophil counts [81]. It was also noted that mepolizumab does not alter the expression of activation markers on residual lung tissue eosinophils [82], nor does it elicit any detectable transcriptional alterations in blood eosinophils [83].…”

Section: Refining the Role Of Eosinophils In Asthma Through Eosinophil-targeting Biological Therapiesmentioning

confidence: 99%

“…It was also noted that mepolizumab does not alter the expression of activation markers on residual lung tissue eosinophils [82], nor does it elicit any detectable transcriptional alterations in blood eosinophils [83]. In addition, the risk for SEA exacerbations is better predicted with a combination of elevated blood eosinophil counts and elevated fractional exhaled nitrogen oxide (FeNO) than either parameter alone [73,84], and elevated FeNO levels are good predictors of eosinophilic exacerbations in mepolizumab-treated patients [81]. FeNO is mostly produced in response to IL-13-stimulated production of inducible nitric oxide synthase in lung epithelial cells and is often considered a good surrogate of ongoing type-2 inflammation in asthma [85].…”

Section: Refining the Role Of Eosinophils In Asthma Through Eosinophil-targeting Biological Therapiesmentioning

confidence: 99%

Eosinophils as Drivers of Severe Eosinophilic Asthma: Endotypes or Plasticity?

Hulst

Bureau

2021

IJMS

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Asthma is now recognized as a heterogeneous disease, encompassing different phenotypes driven by distinct pathophysiological mechanisms called endotypes. Common phenotypes of asthma, referred to as eosinophilic asthma, are characterized by the presence of eosinophilia. Eosinophils are usually considered invariant, terminally differentiated effector cells and have become a primary therapeutic target in severe eosinophilic asthma (SEA) and other eosinophil-associated diseases (EADs). Biological treatments that target eosinophils reveal an unexpectedly complex role of eosinophils in asthma, including in SEA, suggesting that “not all eosinophils are equal”. In this review, we address our current understanding of the role of eosinophils in asthma with regard to asthma phenotypes and endotypes. We further address the possibility that different SEA phenotypes may involve differences in eosinophil biology. We discuss how these differences could arise through eosinophil “endotyping”, viz. adaptations of eosinophil function imprinted during their development, or through tissue-induced plasticity, viz. local adaptations of eosinophil function through interaction with their lung tissue niches. In doing so, we also discuss opportunities, technical challenges, and open questions that, if addressed, might provide considerable benefits in guiding the choice of the most efficient precision therapies of SEA and, by extension, other EADs.

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The inflammatory profile of exacerbations in patients with severe refractory eosinophilic asthma receiving mepolizumab (the MEX study): a prospective observational study

Cited by 53 publications

References 33 publications

Relationship between inflammatory status and microbial composition in severe asthma and during exacerbation

Relationship between inflammatory status and microbial composition in severe asthma and during exacerbation

Weighted gene co-expression network analysis to identify key modules and hub genes associated with paucigranulocytic asthma

Eosinophils as Drivers of Severe Eosinophilic Asthma: Endotypes or Plasticity?

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