A sputum 6-gene signature predicts future exacerbations of poorly controlled asthma

Michael Fricker, Peter G. Gibson, Heather Powell, Jodie L. Simpson, Ian A. Yang, John W. Upham, Paul N. Reynolds, Sandra Hodge, Alan L. James, Christine Jenkins, Matthew J. Peters, Guy B. Marks, Melissa Baraket, Katherine J. Baines

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: Improved diagnostic tools for predicting future exacerbation frequency in asthmatic patients are required. A sputum gene expression signature of 6 biomarkers (6-gene signature [6GS], including Charcot-Leyden crystal galectin [CLC]; carboxypeptidase 3 [CPA3]; deoxyribonuclease 1-like 3 [DNASE1L3]; alkaline phosphatase, liver/bone/kidney [ALPL]; CXCR2; and IL1B) predicts inflammatory and treatment response phenotypes in patients with stable asthma. Recently, we demonstrated that azithromycin (AZM) add-on treatment in patients with uncontrolled moderate-to-severe asthma significantly reduced asthma exacerbations (AMAZES clinical trial). Objectives: We sought to test whether the 6GS predicts future exacerbation and inflammatory phenotypes in a subpopulation of AMAZES and to test the effect of AZM therapy on 6GS expression and prognostic capacity. Methods: One hundred forty-two patients (73 placebo-treated and 69 AZM-treated patients) had sputum stored for quantitative PCR of 6GS markers at baseline and after 48 weeks of treatment. Logistic regression and receiver operating characteristic and area under the curve (AUC) determination were performed on baseline measures, and in an exploratory analysis the predictive value of the 6GS was compared with conventional biomarkers for exacerbation and inflammatory phenotypes. Results: The 6GS significantly predicted all future exacerbation phenotypes tested. Calculated AUCs for the 6GS were significantly greater than AUCs for peripheral blood eosinophil counts, sputum neutrophil counts, and combined sputum eosinophil and neutrophil counts. 6GS AUCs were also numerically but not significantly greater than those for fractional exhaled nitric oxide values and sputum eosinophil counts. AZM treatment altered neither 6GS expression nor the predictive capacity of the 6GS for future exacerbation phenotypes. The 6GS was a significant predictor of airway inflammatory phenotype in this population. Conclusion: We demonstrate that a sputum gene signature can predict future exacerbation phenotypes of asthma, with the greatest biomarker performance in identifying those who would experience frequent severe exacerbations. AZM therapy did not modify 6GS expression or biomarker performance, suggesting the therapeutic action of AZM is independent of 6GS-related inflammatory pathways.

LanguageEnglish
Pages51-60.e11
Number of pages21
JournalJournal of Allergy and Clinical Immunology
Volume144
Issue number1
Early online date22 Jan 2019
DOIs
Publication statusPublished - 1 Jul 2019

Fingerprint

Sputum
Asthma
Azithromycin
Genes
Phenotype
Transcriptome
Area Under Curve
Biomarkers
Eosinophils
Therapeutics
Neutrophils
Galectins
Carboxypeptidases
Deoxyribonucleases
ROC Curve
Alkaline Phosphatase
Nitric Oxide
Logistic Models
Placebos
Clinical Trials

Keywords

  • Asthma
  • azithromycin
  • biomarker
  • clinical trial
  • eosinophil
  • exacerbation
  • gene signature
  • inflammation
  • macrolide
  • sputum

Cite this

Fricker, M., Gibson, P. G., Powell, H., Simpson, J. L., Yang, I. A., Upham, J. W., ... Baines, K. J. (2019). A sputum 6-gene signature predicts future exacerbations of poorly controlled asthma. Journal of Allergy and Clinical Immunology, 144(1), 51-60.e11. https://doi.org/10.1016/j.jaci.2018.12.1020
Fricker, Michael ; Gibson, Peter G. ; Powell, Heather ; Simpson, Jodie L. ; Yang, Ian A. ; Upham, John W. ; Reynolds, Paul N. ; Hodge, Sandra ; James, Alan L. ; Jenkins, Christine ; Peters, Matthew J. ; Marks, Guy B. ; Baraket, Melissa ; Baines, Katherine J. / A sputum 6-gene signature predicts future exacerbations of poorly controlled asthma. In: Journal of Allergy and Clinical Immunology. 2019 ; Vol. 144, No. 1. pp. 51-60.e11.
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abstract = "Background: Improved diagnostic tools for predicting future exacerbation frequency in asthmatic patients are required. A sputum gene expression signature of 6 biomarkers (6-gene signature [6GS], including Charcot-Leyden crystal galectin [CLC]; carboxypeptidase 3 [CPA3]; deoxyribonuclease 1-like 3 [DNASE1L3]; alkaline phosphatase, liver/bone/kidney [ALPL]; CXCR2; and IL1B) predicts inflammatory and treatment response phenotypes in patients with stable asthma. Recently, we demonstrated that azithromycin (AZM) add-on treatment in patients with uncontrolled moderate-to-severe asthma significantly reduced asthma exacerbations (AMAZES clinical trial). Objectives: We sought to test whether the 6GS predicts future exacerbation and inflammatory phenotypes in a subpopulation of AMAZES and to test the effect of AZM therapy on 6GS expression and prognostic capacity. Methods: One hundred forty-two patients (73 placebo-treated and 69 AZM-treated patients) had sputum stored for quantitative PCR of 6GS markers at baseline and after 48 weeks of treatment. Logistic regression and receiver operating characteristic and area under the curve (AUC) determination were performed on baseline measures, and in an exploratory analysis the predictive value of the 6GS was compared with conventional biomarkers for exacerbation and inflammatory phenotypes. Results: The 6GS significantly predicted all future exacerbation phenotypes tested. Calculated AUCs for the 6GS were significantly greater than AUCs for peripheral blood eosinophil counts, sputum neutrophil counts, and combined sputum eosinophil and neutrophil counts. 6GS AUCs were also numerically but not significantly greater than those for fractional exhaled nitric oxide values and sputum eosinophil counts. AZM treatment altered neither 6GS expression nor the predictive capacity of the 6GS for future exacerbation phenotypes. The 6GS was a significant predictor of airway inflammatory phenotype in this population. Conclusion: We demonstrate that a sputum gene signature can predict future exacerbation phenotypes of asthma, with the greatest biomarker performance in identifying those who would experience frequent severe exacerbations. AZM therapy did not modify 6GS expression or biomarker performance, suggesting the therapeutic action of AZM is independent of 6GS-related inflammatory pathways.",
keywords = "Asthma, azithromycin, biomarker, clinical trial, eosinophil, exacerbation, gene signature, inflammation, macrolide, sputum",
author = "Michael Fricker and Gibson, {Peter G.} and Heather Powell and Simpson, {Jodie L.} and Yang, {Ian A.} and Upham, {John W.} and Reynolds, {Paul N.} and Sandra Hodge and James, {Alan L.} and Christine Jenkins and Peters, {Matthew J.} and Marks, {Guy B.} and Melissa Baraket and Baines, {Katherine J.}",
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Fricker, M, Gibson, PG, Powell, H, Simpson, JL, Yang, IA, Upham, JW, Reynolds, PN, Hodge, S, James, AL, Jenkins, C, Peters, MJ, Marks, GB, Baraket, M & Baines, KJ 2019, 'A sputum 6-gene signature predicts future exacerbations of poorly controlled asthma', Journal of Allergy and Clinical Immunology, vol. 144, no. 1, pp. 51-60.e11. https://doi.org/10.1016/j.jaci.2018.12.1020

A sputum 6-gene signature predicts future exacerbations of poorly controlled asthma. / Fricker, Michael; Gibson, Peter G.; Powell, Heather; Simpson, Jodie L.; Yang, Ian A.; Upham, John W.; Reynolds, Paul N.; Hodge, Sandra; James, Alan L.; Jenkins, Christine; Peters, Matthew J.; Marks, Guy B.; Baraket, Melissa; Baines, Katherine J.

In: Journal of Allergy and Clinical Immunology, Vol. 144, No. 1, 01.07.2019, p. 51-60.e11.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A sputum 6-gene signature predicts future exacerbations of poorly controlled asthma

AU - Fricker, Michael

AU - Gibson, Peter G.

AU - Powell, Heather

AU - Simpson, Jodie L.

AU - Yang, Ian A.

AU - Upham, John W.

AU - Reynolds, Paul N.

AU - Hodge, Sandra

AU - James, Alan L.

AU - Jenkins, Christine

AU - Peters, Matthew J.

AU - Marks, Guy B.

AU - Baraket, Melissa

AU - Baines, Katherine J.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Background: Improved diagnostic tools for predicting future exacerbation frequency in asthmatic patients are required. A sputum gene expression signature of 6 biomarkers (6-gene signature [6GS], including Charcot-Leyden crystal galectin [CLC]; carboxypeptidase 3 [CPA3]; deoxyribonuclease 1-like 3 [DNASE1L3]; alkaline phosphatase, liver/bone/kidney [ALPL]; CXCR2; and IL1B) predicts inflammatory and treatment response phenotypes in patients with stable asthma. Recently, we demonstrated that azithromycin (AZM) add-on treatment in patients with uncontrolled moderate-to-severe asthma significantly reduced asthma exacerbations (AMAZES clinical trial). Objectives: We sought to test whether the 6GS predicts future exacerbation and inflammatory phenotypes in a subpopulation of AMAZES and to test the effect of AZM therapy on 6GS expression and prognostic capacity. Methods: One hundred forty-two patients (73 placebo-treated and 69 AZM-treated patients) had sputum stored for quantitative PCR of 6GS markers at baseline and after 48 weeks of treatment. Logistic regression and receiver operating characteristic and area under the curve (AUC) determination were performed on baseline measures, and in an exploratory analysis the predictive value of the 6GS was compared with conventional biomarkers for exacerbation and inflammatory phenotypes. Results: The 6GS significantly predicted all future exacerbation phenotypes tested. Calculated AUCs for the 6GS were significantly greater than AUCs for peripheral blood eosinophil counts, sputum neutrophil counts, and combined sputum eosinophil and neutrophil counts. 6GS AUCs were also numerically but not significantly greater than those for fractional exhaled nitric oxide values and sputum eosinophil counts. AZM treatment altered neither 6GS expression nor the predictive capacity of the 6GS for future exacerbation phenotypes. The 6GS was a significant predictor of airway inflammatory phenotype in this population. Conclusion: We demonstrate that a sputum gene signature can predict future exacerbation phenotypes of asthma, with the greatest biomarker performance in identifying those who would experience frequent severe exacerbations. AZM therapy did not modify 6GS expression or biomarker performance, suggesting the therapeutic action of AZM is independent of 6GS-related inflammatory pathways.

AB - Background: Improved diagnostic tools for predicting future exacerbation frequency in asthmatic patients are required. A sputum gene expression signature of 6 biomarkers (6-gene signature [6GS], including Charcot-Leyden crystal galectin [CLC]; carboxypeptidase 3 [CPA3]; deoxyribonuclease 1-like 3 [DNASE1L3]; alkaline phosphatase, liver/bone/kidney [ALPL]; CXCR2; and IL1B) predicts inflammatory and treatment response phenotypes in patients with stable asthma. Recently, we demonstrated that azithromycin (AZM) add-on treatment in patients with uncontrolled moderate-to-severe asthma significantly reduced asthma exacerbations (AMAZES clinical trial). Objectives: We sought to test whether the 6GS predicts future exacerbation and inflammatory phenotypes in a subpopulation of AMAZES and to test the effect of AZM therapy on 6GS expression and prognostic capacity. Methods: One hundred forty-two patients (73 placebo-treated and 69 AZM-treated patients) had sputum stored for quantitative PCR of 6GS markers at baseline and after 48 weeks of treatment. Logistic regression and receiver operating characteristic and area under the curve (AUC) determination were performed on baseline measures, and in an exploratory analysis the predictive value of the 6GS was compared with conventional biomarkers for exacerbation and inflammatory phenotypes. Results: The 6GS significantly predicted all future exacerbation phenotypes tested. Calculated AUCs for the 6GS were significantly greater than AUCs for peripheral blood eosinophil counts, sputum neutrophil counts, and combined sputum eosinophil and neutrophil counts. 6GS AUCs were also numerically but not significantly greater than those for fractional exhaled nitric oxide values and sputum eosinophil counts. AZM treatment altered neither 6GS expression nor the predictive capacity of the 6GS for future exacerbation phenotypes. The 6GS was a significant predictor of airway inflammatory phenotype in this population. Conclusion: We demonstrate that a sputum gene signature can predict future exacerbation phenotypes of asthma, with the greatest biomarker performance in identifying those who would experience frequent severe exacerbations. AZM therapy did not modify 6GS expression or biomarker performance, suggesting the therapeutic action of AZM is independent of 6GS-related inflammatory pathways.

KW - Asthma

KW - azithromycin

KW - biomarker

KW - clinical trial

KW - eosinophil

KW - exacerbation

KW - gene signature

KW - inflammation

KW - macrolide

KW - sputum

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U2 - 10.1016/j.jaci.2018.12.1020

DO - 10.1016/j.jaci.2018.12.1020

M3 - Article

VL - 144

SP - 51-60.e11

JO - The Journal of Allergy and Clinical Immunology

T2 - The Journal of Allergy and Clinical Immunology

JF - The Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 1

ER -