Gisli G. Einarsson1,2, Andrew J. Lee1, 2, Aya Alkhatib1, 3, Katherine O’Neill1, 2, Vanessa Brown1, Deirdre F. Gilpin1, 3, Gerhild Angyalosi4, Vincent Malaterre4, Michael R. Loebinger5,6, James D. Chalmers7, Francesco Blasi8,9, Charles S. Haworth10,11, J. Stuart Elborn1,2, Michael M. Tunney1,3
1 Queen’s University Belfast, Belfast, UK
2 Halo Research Group, Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK
3 Halo Research Group, School of Pharmacy, Queen's University Belfast, Belfast, UK
4 Novartis Pharma AG
5 Host Defence Unit, Royal Brompton Hospital and Harefield NHS Foundation Trust, London, UK
6 Imperial College London, London, UK
7 Scottish Centre for Respiratory Research, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, UK
8 Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
9 Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
10 Cambridge Centre for Lung Infection, Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK
11 Department of Medicine, University of Cambridge, Cambridge, UK
Introduction: Chronic infection with Pseudomonas aeruginosa (PA) is associated with elevated disease progression, pulmonary exacerbation (PEx) frequency and declining lung function in people with BE. Tobramycin inhalation powder (TIP) is currently approved for treatment of PA infection in cystic fibrosis and is a potential treatment option in BE.
Aim: To determine changes in the airway microbiota and inflammatory biomarkers in patients with BE receiving three different dose-regimens of TIP or placebo in the iBEST study.
Methods: As part of the exploratory objectives, we processed sputum samples (n=610) from patients (n=107) with documented PA infection and ≥2 PEx requiring oral antibiotics or ≥1 requiring IV antibiotics in the 12 months prior to screening. Patients received TIP, in either a continuous daily (Cohort A = 3 capsules OD [84mg]; Cohort B = 5 capsules OD [140mg]; Cohort C = 4 capsules BID [224mg]) or cyclical regimens (Cohorts A-C TIP + Placebo month on/month off) or placebo for 16 weeks (day 1, 8, 29, 57, 85 and 113) of treatment and at follow-up (Days 141 and 169). Microbial community profiles were determined by sequencing the 16S rRNA gene using the Illumina MiSeq and total bacterial load of PA was assessed by quantitative PCR (qPCR) targeting the oprL gene. Continuous variables were compared using ANOVA or Kruskal-Wallis test. For comparison of β-diversity (group differences) centred log-ratio transformation was used on count data and statistical significance assessed by PERMANOVA.
Results: Reduction in the mean relative abundance (RA) for Pseudomonas spp. and total PA load was observed in all treatment cohorts compared to placebo, consistent with the study primary objective (Day 1 to Day 29), measuring the reduction of PA sputum density for treatment vs placebo by bacterial culture. At Day 29 all treatment cohorts showed significant reduction in RA for Pseudomonas spp. compared to placebo (p=0.0002). However, when we considered the total sampling period (Day 1 to Day 113), adjusted for multiple testing, only continuous treatment with TIP in Cohort C was statistically significant (p=0.0001). There was a significant negative correlation between high RA of Pseudomonas spp. and ecological parameters and lung function. In contrast, communities with higher RA of Streptococcus spp., Haemophilus spp., Prevotella spp. or Veillonella spp. showed a positive correlation with richness, diversity and lung function. There was a significant negative correlation between richness, diversity and evenness and inflammatory cytokine levels (Elastase, IL8, IL1b and Calprotectin), while dominance displayed positive correlation with increased levels of inflammation. Analysis of community composition between cohorts demonstrated a significant effect of TIP treatment, with all cohorts being similar at Day 1 (p=0.341) and then dispersing away from the placebo cohort on Day 8 and Day 29 (p<0.001). Switching to placebo in the cyclic treatment cohorts (TIP + Placebo) on Day 29, the communities moved back towards the placebo group, indicating a transient effect of TIP (Day 29 to Day 57). During the second cycle of TIP treatment (Day 57 to Day 85), communities dispersed away from the placebo cohort, followed by overlapping of all the cohorts with the placebo cohort by the end of the treatment (Day 113).
Conclusion TIP significantly affects community composition and inflammation in the airways of individuals with BE. The results indicate that the most significant effect on PA relative abundance is at the start of active treatment and in individuals receiving the highest continuous dose of TIP and the effect is transient in the cyclical arms.
Acknowledgements: Supported by EU/EFPIA IMI iABC grant n° 115721
| Period | 16 Dec 2020 → 19 Dec 2020 |
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| Event title | 4th World Bronchiectasis & NTM Conference |
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| Event type | Conference |
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| Conference number | 4 |
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| Degree of Recognition | International |
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