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

Brightling, Chris; Haldar, Koirobi; Busby, John; Mistry, Vijay; Micieli, Claudia; Brown, Vanessa; Cox, Ciara; Yang, Freda; Borg, Catherine; Shrimanker, Rahul; Ramsheh, Mohammadali Yavari; Hardman, Timothy C.; Arron, Joseph R.; Bradding, Peter; Cowan, Douglas C.; Mansur, Adel; Fowler, Stephen J.; Lordan, Jim; Menzies‐Gow, Andrew; Robinson, Douglas S.; Matthews, John G.; Pavord, Ian D.; Chaudhuri, Rekha; McDowell, P Jane; Barer, Michael R.

doi:10.1111/all.15425

Cited by 10 publications

(8 citation statements)

References 57 publications

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“…In a group of 140 patients with severe asthma microbial composition before and after at least 3 months of mepolizumab was assessed. In this study, no significant change to the bacterial load or predominant organism of the airway microbiome in the post treatment subgroup was demonstrated ( 68 ).…”

Section: The Effect Of Asthma Treatment On the Respiratory Microbiomementioning

confidence: 56%

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The role of the respiratory microbiome in asthma

Campbell

Gleeson

2023

Front. Allergy

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Asthma is a common airways disease and the human microbiome plays an increasingly recognised role in asthma pathogenesis. Furthermore, the respiratory microbiome varies with asthma phenotype, endotype and disease severity. Consequently, asthma therapies have a direct effect on the respiratory microbiome. Newer biological therapies have led to a significant paradigm shift in how we treat refractory Type 2 high asthma. While airway inflammation is the generally accepted mechanism of action of all asthma therapies, including both inhaled and systemic therapies, there is evidence to suggest that they may also alter the microbiome to create a more functionally balanced airway microenvironment while also influencing airway inflammation directly. This downregulated inflammatory cascade seen biochemically, and reflected in improved clinical outcomes, supports the hypothesis that biological therapies may in fact affect the microbiome-host immune system dynamic and thus represent a therapeutic target for exacerbations and disease control.

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Section: The Effect Of Asthma Treatment On the Respiratory Microbiomementioning

confidence: 56%

“…Similarly, FeNO or fraction exhaled Nitric Oxide is often used as a surrogate marker for eosinophilic inflammation in asthma. A high FeNO has been shown to be associated with a lower prevalence of pathogenic organisms in sputum, including Haemophilus ( 68 ).…”

Section: Microbiome and Asthma Endotypesmentioning

confidence: 99%

The role of the respiratory microbiome in asthma

Campbell

Gleeson

2023

Front. Allergy

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“…Thus the effects of type 2 immunity may be context specific and affected by the cellular source and concomitant inflammatory milieu, and at steady state may promote airway epithelial barrier function. Inhibition of homeostatic tonic T2 signalling might therefore have deleterious effects which may have an impact clinically, and might explain an enhanced propensity to proteobacterial colonisation or infection, as was observed in the MEX(39) and RASP-UK(40) studies amongst participants with very low T2 biomarkers.…”

Section: Discussionmentioning

confidence: 99%

The effects of inhaled corticosteroids on healthy airways

Marchi,

Hinks,

Richardson

et al. 2023

Preprint

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RationaleThe effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined.ObjectivesTo delineate the effects of ICS on gene expression in healthy airways, without confounding caused by changes in disease-related genes and disease-related alterations in ICS-responsiveness.MethodsRandomised open-label bronchoscopy study of high dose ICS therapy in 30 healthy adult volunteers randomised 2:1 to i) fluticasone propionate 500 mcg bd or ii) no treatment, for 4 weeks. Laboratory staff were blinded to allocation. Biopsies and brushings were analysed by immunohistochemistry, bulk RNA sequencing, DNA methylation array and metagenomics.Measurements and main resultsICS induced small between-group differences in blood and lamina propria eosinophil numbers, but not in other immunopathological features, blood neutrophils, FeNO, FEV1, microbiome or DNA methylation. ICS treatment upregulated 72 genes in brushings and 53 genes in biopsies, and downregulated 82 genes in brushings and 416 genes in biopsies. The most downregulated genes in both tissues were canonical markers of type-2 inflammation (FCER1A, CPA3, IL33, CLEC10A, SERPINB10 and CCR5), T cell-mediated adaptive immunity (TARP, TRBC1, TRBC2, PTPN22, TRAC, CD2, CD8A, HLA-DQB2, CD96, PTPN7), B cell immunity (CD20, immunoglobulin heavy and light chains), and innate immunity, including CD48, Hobit, RANTES, Langerin and GFI1. An IL-17-dependent gene signature was not upregulated by ICS.ConclusionsIn healthy airways, 4-week ICS exposure reduces gene expression related to both innate and adaptive immunity, and reduces markers of type-2 inflammation. This implies that homeostasis in health involves tonic type-2 signalling in the airway mucosa, which is exquisitely sensitive to ICS.

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“…In acute asthma, several studies have documented the heterogeneity of attacks,32–39 with the presence of sputum inflammation characterised by elevated eosinophils32 33 36–38 or neutrophils 34–38. Importantly, these inflammatory phenotypes are indistinguishable from the point of view of initial symptoms or lung function 38.…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, these inflammatory phenotypes are indistinguishable from the point of view of initial symptoms or lung function 38. Other features are high BEC and elevated FeNO,37 increased levels of IL-8 in sputum35 36 or serum C reactive protein (CRP)37 or a different microbial flora related to FeNO values 39. However, treatment responses to acute systemic corticosteroid and antibiotic courses have not been related to the type 2 inflammatory phenotype and the presence of airway infection, respectively.…”

Section: Introductionmentioning

confidence: 99%

Phenotyping the Responses to Systemic Corticosteroids in the Management of Asthma Attacks (PRISMA): protocol for an observational and translational pilot study

Celis-Preciado,

Leclerc,

Duval

et al. 2023

BMJ Open Resp Res

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IntroductionAsthma and its associated exacerbation are heterogeneous. Although severe asthma attacks are systematically prescribed corticosteroids and often antibiotics, little is known about the variability of response to these therapies. Blood eosinophils and fractional exhaled nitric oxide (FeNO) are type 2 inflammation biomarkers that have established mechanistic, prognostic and theragnostic values in chronic asthma, but their utility in acute asthma is unclear. We speculate that the clinical and biological response to those treatments varies according to inflammometry and microbiological test results.Methods and analysisAn observational longitudinal pilot study with multimodal clinical and translational assessments will be performed on 50 physician-diagnosed ≥12-year-old asthmatics presenting with an asthma attack and 12 healthy controls, including blood eosinophil count (venous and point-of-care (POC) capillary blood), FeNO and testing for airway infection (sputum cultures and POC nasopharyngeal swabs). People with asthma will be assessed on day 0 and after a 7-day corticosteroid course, with home monitoring performed in between. The primary analysis will be the change in the forced expiratory volume in 1 s according to type 2 inflammatory status (blood eosinophils ≥0.15×109/L and/or FeNO ≥25 ppb) after treatment. Key secondary analyses will compare changes in symptom scores and the proportion of patients achieving a minimal clinically important difference. Exploratory analyses will assess the relationship between clinical, lung function, inflammatory and microbiome parameters; satisfaction plus reliability indices of POC tests; and sex–gender variability in treatment response. Ultimately, this pilot study will serve to plan a larger trial comparing the clinical and biological response to systemic corticosteroids according to inflammatory biomarkers, offering valuable guidance for more personalised therapeutic strategies in asthma attacks.Ethics and disseminationThe protocol has been approved by the Research Ethics Committee of the CIUSSS de l'Estrie–CHUS, Sherbrooke, Quebec, Canada (#2023-4687). Results will be communicated in an international meeting and submitted to a peer-reviewed journal.Trial registration numberClinicalTrials.gov Registry (NCT05870215).

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

Cited by 10 publications

References 57 publications

The role of the respiratory microbiome in asthma

The role of the respiratory microbiome in asthma

The effects of inhaled corticosteroids on healthy airways

Phenotyping the Responses to Systemic Corticosteroids in the Management of Asthma Attacks (PRISMA): protocol for an observational and translational pilot study

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