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

• Published in: Allergy (Copenhagen) Vol. 77; no. 11; pp. 3362 - 3376
• Main Authors: Diver, Sarah, Haldar, Koirobi, McDowell, Pamela Jane, Busby, John, Mistry, Vijay, Micieli, Claudia, Brown, Vanessa, Cox, Ciara, Yang, Freda, Borg, Catherine, Shrimanker, Rahul, Ramsheh, Mohammadali Yavari, Hardman, Tim, Arron, Joseph, Bradding, Peter, Cowan, Douglas, Mansur, Adel Hasan, Fowler, Stephen J., Lordan, Jim, Menzies‐Gow, Andrew, Robinson, Douglas, Matthews, John, Pavord, Ian D., Chaudhuri, Rekha, Heaney, Liam G., Barer, Michael R., Brightling, Christopher
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.11.2022
• Subjects: Asthma; Asthma - diagnosis; Asthma - drug therapy; Asthma - microbiology; biologics; Biomarkers; Clinical trials; Eosinophils; Firmicutes; Humans; infection; Inflammation; Leukocytes (eosinophilic); Leukocytes (neutrophilic); microbial load; Microbiomes; microorganisms; Monoclonal antibodies; Proteobacteria; Respiratory System - microbiology; Respiratory tract; species diversity; Sputum; Sputum - microbiology; infection; asthma; biologics; biomarkers
• ISSN: 0105-4538; 1398-9995; 1398-9995
• DOI: 10.1111/all.15425

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 provide information about airway microbial composition. We investigated the relationships between current T2 biomarkers and microbial profiles, characteristics associated with a ProteobacteriaHIGH microbial profile and the effects of mepolizumab on airway ecology. Methods Microbiota sequencing was performed on sputum samples obtained at stable and exacerbation state from 140 subjects with severe asthma participating in two clinical trials. Inflammatory subgroups were compared on the basis of biomarkers, including FeNO and sputum and blood eosinophils. ProteobacteriaHIGH subjects were identified by Proteobacteria to Firmicutes ratio ≥0.485. Where paired sputum from stable visits was available, we compared microbial composition at baseline and following ≥12 weeks of mepolizumab. Results Microbial composition was not related to inflammatory subgroup based on sputum or blood eosinophils. FeNO ≥50 ppb when stable and at exacerbation indicated a group with less dispersed microbial profiles characterised by high alpha‐diversity and low Proteobacteria. ProteobacteriaHIGH subjects were neutrophilic and had a longer time from asthma diagnosis than ProteobacteriaLOW subjects. In those studied, mepolizumab did not alter airway bacterial load or lead to increased Proteobacteria. Conclusion High FeNO could indicate a subgroup of severe asthma less likely to benefit from antimicrobial strategies at exacerbation or in the context of poor control. Where FeNO is <50 ppb, biomarkers of microbial composition are required to identify those likely to respond to microbiome‐directed strategies. We found no evidence that mepolizumab alters airway microbial composition. FeNO ≥50 ppb, when stable and at exacerbation, indicates a subgroup with an even microbial composition, with high alpha‐diversity measures and low relative abundance of Proteobacteria. ProteobacteriaHIGH severe asthmatics are neutrophilic and have a longer duration of disease than those who are ProteobacteriaLOW. In a small subset with paired data at baseline and ≥12 weeks, mepolizumab suppressed blood eosinophils but did not increase total airway bacterial load or lead to increased proportions of Proteobacteria.Abbreviations: FeNO, fractional exhaled nitric oxide; GINA, Global Initiative for Asthma; MEX, Exploring Asthma Exacerbations in Mepolizumab Treated Patients; ppb, parts per billion; RASP‐UK, A Pragmatic Trial of Corticosteroid Optimisation in Severe Asthma; rDNA, ribosomal DNA; seq, sequencing