Long-Term Azithromycin Reduces <i>Haemophilus influenzae</i> and Increases Antibiotic Resistance in Severe Asthma

Taylor, Steven; Leong, Lex E. X.; Mobegi, Fredrick M.; Choo, Jocelyn M.; Wesselingh, Steve; Yang, Ian A.; Upham, John W.; Reynolds, Paul N.; Hodge, Sandra; James, Alan; Jenkins, Christine; Peters, Matthew J.; Baraket, Melissa; Marks, Guy B.; Gibson, Péter G.; Rogers, Geraint B.; Simpson, Jodie L.

doi:10.1164/rccm.201809-1739oc

Cited by 132 publications

(130 citation statements)

References 46 publications

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“…However, previously reported response to the macrolide azithromycin in moderate-tosevere asthma was associated with positive bacterial culture, 13 and with reductions in Haemophilus influenzae in the overall population. 28 Our findings therefore suggest that the Haemophilus-high The development of well-validated, widely accessible, relevant biomarkers is integral to implementation of targeted therapies towards precision medicine in the clinic. We found that the γP:F ratio was the most sensitive and specific biomarker within our data set to identify the Haemophilus-high cluster.…”

Section: Discussionmentioning

confidence: 90%

Sputum microbiomic clustering in asthma and chronic obstructive pulmonary disease reveals a Haemophilus‐predominant subgroup

Diver

Richardson

Haldar

et al. 2019

Allergy

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Background: Airway ecology is altered in asthma and chronic obstructive pulmonary disease (COPD). Anti-microbial interventions might have benefit in subgroups of airway disease. Differences in sputum microbial profiles at acute exacerbation of airways disease are reflected by the γProteobacteria:Firmicutes (γP:F) ratio. We hypothesized that sputum microbiomic clusters exist in stable airways disease, which can be differentiated by the sputum γP:F ratio.Methods: Sputum samples were collected from 63 subjects with severe asthma and 78 subjects with moderate-to-severe COPD in a prospective single centre trial. Microbial profiles were obtained through 16S rRNA gene sequencing. Topological data analysis was used to visualize the data set and cluster analysis performed at genus level. Clinical characteristics and sputum inflammatory mediators were compared across the clusters. Results: Two ecological clusters were identified across the combined airways disease population. The smaller cluster was predominantly COPD and was characterized by dominance of Haemophilus at genus level (n = 20), high γP:F ratio, increased H influenzae, low diversity measures and increased pro-inflammatory mediators when compared to the larger Haemophilus-low cluster (n = 121), in which Streptococcus demonstrated the highest relative abundance at the genus level. Similar clusters were identified within disease groups individually and the γP:F ratio consistently differentiated between clusters.Conclusion: Cluster analysis by airway ecology of asthma and COPD in stable state identified two subgroups differentiated according to dominance of Haemophilus. The γP:F ratio was able to distinguish the Haemophilus-high versus Haemophilus-low subgroups, whether the Haemophilus-high group might benefit from treatment strategies to modulate the airway ecology warrants further investigation. K E Y W O R D S asthma, COPD, inflammation, microbiome, sputum | 809 DIVER Et al. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Diver S, Richardson M, Haldar K, et al. Sputum microbiomic clustering in asthma and chronic obstructive pulmonary disease reveals a Haemophiluspredominant subgroup. Allergy. 2020;75:808-817. https ://doi.

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Section: Discussionmentioning

confidence: 90%

Sputum microbiomic clustering in asthma and chronic obstructive pulmonary disease reveals a Haemophilus‐predominant subgroup

Diver

Richardson

Haldar

et al. 2019

Allergy

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“…Those treated with azithromycin for 48 weeks had reduced airway Haemophilus influenzae load, with no changes to total or pathogenic bacterial loads. Although sputum macrolide resistance genes increased in this group, there was a lower rate of antibiotic use and of adverse events due to clinically diagnosed infections [51,56].…”

Section: Harmsmentioning

confidence: 82%

Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline

et al. 2019

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This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including meta-analyses, were performed to summarise all available evidence relevant to the European Respiratory Society/American Thoracic Society Task Force's questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on six specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations: 1) suggest using anti-interleukin (IL)-5 and anti-IL-5 receptor α for severe uncontrolled adult eosinophilic asthma phenotypes; 2) suggest using a blood eosinophil cut-point ≥150 μL−1 to guide anti-IL-5 initiation in adult patients with severe asthma; 3) suggest considering specific eosinophil (≥260 μL−1) and exhaled nitric oxide fraction (≥19.5 ppb) cut-offs to identify adolescents or adults with the greatest likelihood of response to anti-IgE therapy; 4) suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite Global Initiative for Asthma (GINA) step 4–5 or National Asthma Education and Prevention Program (NAEPP) step 5 therapies; 5) suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype; and 6) suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels. These recommendations should be reconsidered as new evidence becomes available.

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“…Paired-end amplicon sequencing was performed on the V1-3 hypervariable region of the bacterial 16S rRNA gene by Illumina MiSeq [25] . Following quality filtering and merging of paired sequences, chimera removal, taxa assignment, and removal of contaminant reads, a minimum sub-sampling depth of 1062 reads was selected for all samples.…”

Section: Bacterial Quantification Measuresmentioning

confidence: 99%

Total bacterial load, inflammation, and structural lung disease in paediatric cystic fibrosis

Taylor

Leong

Ivey

et al. 2020

Journal of Cystic Fibrosis

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Long-Term Azithromycin Reduces Haemophilus influenzae and Increases Antibiotic Resistance in Severe Asthma

Cited by 132 publications

References 46 publications

Sputum microbiomic clustering in asthma and chronic obstructive pulmonary disease reveals a Haemophilus‐predominant subgroup

Sputum microbiomic clustering in asthma and chronic obstructive pulmonary disease reveals a Haemophilus‐predominant subgroup

Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline

Total bacterial load, inflammation, and structural lung disease in paediatric cystic fibrosis

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