Personalised anti-inflammatory therapy for bronchiectasis and cystic fibrosis

selecting patients for controlled trials of neutrophil elastase inhibition

Holly R. Keir, Christopher J. Fong, Megan L. Crichton, Philip Barth, Eric Chevalier, Gill Brady, Gwen Kennedy, Johann Zimmermann, Piet L. B. Bruijnzeel, Alison J. Dicker, James D. Chalmers (Lead / Corresponding author)

Research output: Contribution to journalArticle

1 Citation (Scopus)
47 Downloads (Pure)

Abstract

Background: Neutrophil elastase (NE) has been linked to lung neutrophil dysfunction in bronchiectasis and cystic fibrosis (CF), making NE inhibition a potential therapeutic target. NE inhibitor trials have given mixed result perhaps because not all patients have elevated airway NE activity.

Methods: We tested whether a single baseline sputum NE measurement or a combination of clinical parameters could enrich patient populations with elevated NE activity for "personalised medicine". Intra- and interindividual variations of total and active NE levels in induced sputum from patients with CF or bronchiectasis were monitored over 14 days. Patients with established CF and bronchiectasis (n=5 per group) were recruited. NE was measured using three different methods: one total and two active NE assays. Subsequently, we analysed the association between clinical parameters and NE from a large bronchiectasis cohort study (n=381).

Results: All three assays showed a high degree of day-to-day variability (0-233% over 14 days). There were strong correlations found between all assays (p<0.0001). Despite high day-to-day variability, patients could be stratified into "high" or "low" groups based on moderate cut-off levels. In the bronchiectasis cohort study, factors most associated with high sputum NE levels were: Pseudomonas aeruginosa infection (β-estimate 11.5, 95% CI -6.0-29.0), sputum colour (β-estimate 10.4, 95% CI 4.3-16.6), Medical Research Council dyspnoea score (β-estimate 6.4, 95% CI 1.4-11.4) and exacerbation history (β-estimate 3.4, 95% CI 1.4-5.3). Collectively, P. aeruginosa infection, sputum colour and exacerbation frequency provided the greatest specificity for "high" NE (98.7%, 95% CI 7.0-99.6%).

Conclusion: These results show that patients with bronchiectasis and CF can be effectively divided into "high" or "low" groups, based on sputum NE assays or clinical inclusion criteria.

Original languageEnglish
Article number00252-2018
Pages (from-to)1-9
Number of pages9
JournalERJ Open Research
Volume5
Issue number1
DOIs
Publication statusPublished - 1 Feb 2019

Fingerprint

Leukocyte Elastase
Bronchiectasis
Cystic Fibrosis
Anti-Inflammatory Agents
Sputum
Therapeutics
Pseudomonas Infections
Pseudomonas aeruginosa
Cohort Studies
Color
Secretory Proteinase Inhibitory Proteins
Precision Medicine
Dyspnea
Biomedical Research
Neutrophils
History

Cite this

@article{8f70c12e88d74f9ebc499a660206a65c,
title = "Personalised anti-inflammatory therapy for bronchiectasis and cystic fibrosis: selecting patients for controlled trials of neutrophil elastase inhibition",
abstract = "Background: Neutrophil elastase (NE) has been linked to lung neutrophil dysfunction in bronchiectasis and cystic fibrosis (CF), making NE inhibition a potential therapeutic target. NE inhibitor trials have given mixed result perhaps because not all patients have elevated airway NE activity.Methods: We tested whether a single baseline sputum NE measurement or a combination of clinical parameters could enrich patient populations with elevated NE activity for {"}personalised medicine{"}. Intra- and interindividual variations of total and active NE levels in induced sputum from patients with CF or bronchiectasis were monitored over 14 days. Patients with established CF and bronchiectasis (n=5 per group) were recruited. NE was measured using three different methods: one total and two active NE assays. Subsequently, we analysed the association between clinical parameters and NE from a large bronchiectasis cohort study (n=381).Results: All three assays showed a high degree of day-to-day variability (0-233{\%} over 14 days). There were strong correlations found between all assays (p<0.0001). Despite high day-to-day variability, patients could be stratified into {"}high{"} or {"}low{"} groups based on moderate cut-off levels. In the bronchiectasis cohort study, factors most associated with high sputum NE levels were: Pseudomonas aeruginosa infection (β-estimate 11.5, 95{\%} CI -6.0-29.0), sputum colour (β-estimate 10.4, 95{\%} CI 4.3-16.6), Medical Research Council dyspnoea score (β-estimate 6.4, 95{\%} CI 1.4-11.4) and exacerbation history (β-estimate 3.4, 95{\%} CI 1.4-5.3). Collectively, P. aeruginosa infection, sputum colour and exacerbation frequency provided the greatest specificity for {"}high{"} NE (98.7{\%}, 95{\%} CI 7.0-99.6{\%}).Conclusion: These results show that patients with bronchiectasis and CF can be effectively divided into {"}high{"} or {"}low{"} groups, based on sputum NE assays or clinical inclusion criteria.",
author = "Keir, {Holly R.} and Fong, {Christopher J.} and Crichton, {Megan L.} and Philip Barth and Eric Chevalier and Gill Brady and Gwen Kennedy and Johann Zimmermann and Bruijnzeel, {Piet L. B.} and Dicker, {Alison J.} and Chalmers, {James D.}",
note = "Support statement: J.D. Chalmers is supported by the GSK/British Lung Foundation Chair of Respiratory Research. The repeatability study was funded by a grant from Polyphor AG (Basel, Switzerland). The TAYBRIDGE study was funded by Tenovus Scotland and the European Respiratory Society through the clinical research collaboration EMBARC. Funding information for this article has been deposited with the Crossref Funder Registry.",
year = "2019",
month = "2",
day = "1",
doi = "10.1183/23120541.00252-2018",
language = "English",
volume = "5",
pages = "1--9",
journal = "ERJ Open Research",
issn = "2312-0541",
publisher = "European Respiratory Society",
number = "1",

}

Personalised anti-inflammatory therapy for bronchiectasis and cystic fibrosis : selecting patients for controlled trials of neutrophil elastase inhibition. / Keir, Holly R.; Fong, Christopher J.; Crichton, Megan L.; Barth, Philip; Chevalier, Eric; Brady, Gill; Kennedy, Gwen; Zimmermann, Johann; Bruijnzeel, Piet L. B.; Dicker, Alison J.; Chalmers, James D. (Lead / Corresponding author).

In: ERJ Open Research, Vol. 5, No. 1, 00252-2018, 01.02.2019, p. 1-9.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Personalised anti-inflammatory therapy for bronchiectasis and cystic fibrosis

T2 - selecting patients for controlled trials of neutrophil elastase inhibition

AU - Keir, Holly R.

AU - Fong, Christopher J.

AU - Crichton, Megan L.

AU - Barth, Philip

AU - Chevalier, Eric

AU - Brady, Gill

AU - Kennedy, Gwen

AU - Zimmermann, Johann

AU - Bruijnzeel, Piet L. B.

AU - Dicker, Alison J.

AU - Chalmers, James D.

N1 - Support statement: J.D. Chalmers is supported by the GSK/British Lung Foundation Chair of Respiratory Research. The repeatability study was funded by a grant from Polyphor AG (Basel, Switzerland). The TAYBRIDGE study was funded by Tenovus Scotland and the European Respiratory Society through the clinical research collaboration EMBARC. Funding information for this article has been deposited with the Crossref Funder Registry.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Background: Neutrophil elastase (NE) has been linked to lung neutrophil dysfunction in bronchiectasis and cystic fibrosis (CF), making NE inhibition a potential therapeutic target. NE inhibitor trials have given mixed result perhaps because not all patients have elevated airway NE activity.Methods: We tested whether a single baseline sputum NE measurement or a combination of clinical parameters could enrich patient populations with elevated NE activity for "personalised medicine". Intra- and interindividual variations of total and active NE levels in induced sputum from patients with CF or bronchiectasis were monitored over 14 days. Patients with established CF and bronchiectasis (n=5 per group) were recruited. NE was measured using three different methods: one total and two active NE assays. Subsequently, we analysed the association between clinical parameters and NE from a large bronchiectasis cohort study (n=381).Results: All three assays showed a high degree of day-to-day variability (0-233% over 14 days). There were strong correlations found between all assays (p<0.0001). Despite high day-to-day variability, patients could be stratified into "high" or "low" groups based on moderate cut-off levels. In the bronchiectasis cohort study, factors most associated with high sputum NE levels were: Pseudomonas aeruginosa infection (β-estimate 11.5, 95% CI -6.0-29.0), sputum colour (β-estimate 10.4, 95% CI 4.3-16.6), Medical Research Council dyspnoea score (β-estimate 6.4, 95% CI 1.4-11.4) and exacerbation history (β-estimate 3.4, 95% CI 1.4-5.3). Collectively, P. aeruginosa infection, sputum colour and exacerbation frequency provided the greatest specificity for "high" NE (98.7%, 95% CI 7.0-99.6%).Conclusion: These results show that patients with bronchiectasis and CF can be effectively divided into "high" or "low" groups, based on sputum NE assays or clinical inclusion criteria.

AB - Background: Neutrophil elastase (NE) has been linked to lung neutrophil dysfunction in bronchiectasis and cystic fibrosis (CF), making NE inhibition a potential therapeutic target. NE inhibitor trials have given mixed result perhaps because not all patients have elevated airway NE activity.Methods: We tested whether a single baseline sputum NE measurement or a combination of clinical parameters could enrich patient populations with elevated NE activity for "personalised medicine". Intra- and interindividual variations of total and active NE levels in induced sputum from patients with CF or bronchiectasis were monitored over 14 days. Patients with established CF and bronchiectasis (n=5 per group) were recruited. NE was measured using three different methods: one total and two active NE assays. Subsequently, we analysed the association between clinical parameters and NE from a large bronchiectasis cohort study (n=381).Results: All three assays showed a high degree of day-to-day variability (0-233% over 14 days). There were strong correlations found between all assays (p<0.0001). Despite high day-to-day variability, patients could be stratified into "high" or "low" groups based on moderate cut-off levels. In the bronchiectasis cohort study, factors most associated with high sputum NE levels were: Pseudomonas aeruginosa infection (β-estimate 11.5, 95% CI -6.0-29.0), sputum colour (β-estimate 10.4, 95% CI 4.3-16.6), Medical Research Council dyspnoea score (β-estimate 6.4, 95% CI 1.4-11.4) and exacerbation history (β-estimate 3.4, 95% CI 1.4-5.3). Collectively, P. aeruginosa infection, sputum colour and exacerbation frequency provided the greatest specificity for "high" NE (98.7%, 95% CI 7.0-99.6%).Conclusion: These results show that patients with bronchiectasis and CF can be effectively divided into "high" or "low" groups, based on sputum NE assays or clinical inclusion criteria.

UR - http://www.scopus.com/inward/record.url?scp=85065960120&partnerID=8YFLogxK

U2 - 10.1183/23120541.00252-2018

DO - 10.1183/23120541.00252-2018

M3 - Article

VL - 5

SP - 1

EP - 9

JO - ERJ Open Research

JF - ERJ Open Research

SN - 2312-0541

IS - 1

M1 - 00252-2018

ER -