A qPCR-based metric of Th2 airway inflammation in asthma

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Abstract

Background

Using microarray profiling of airway epithelial cells, we previously identified a Th2-high molecular phenotype of asthma based on expression of periostin, CLCA1 and serpinB2 and characterized by specific inflammatory, remodeling, and treatment response features. The goal of the current study was to develop a qPCR-based assay of Th2 inflammation to overcome the limitations of microarray-based methods.

Methods

Airway epithelial brushings were obtained by bronchoscopy from two clinical studies comprising 44 healthy controls and 62 subjects with asthma, 39 of whom were studied before and after a standardized 8 week course of inhaled corticosteroids (ICS). The qPCR-based expression of periostin, CLCA1 and serpinB2 were combined into a single metric.

Results

In asthma, the three-gene-mean of periostin, CLCA1 and serpinB2 correlated with FeNO (r = 0.75, p = 0.0002), blood eosinophils (r = 0.58, p = 0.003) and PC ₂₀ methacholine (r = -0.65, p = 0.0006), but not total serum IgE (r = 0.33, p = 0.1). Higher baseline three-gene-mean correlated with greater improvement in FEV ₁ with ICS at 2, 4 and 8 weeks (all p < 0.05). By ROC analysis, the area under the curve (AUC) of the three-gene-mean for FEV ₁ improvement with ICS at 4 and 8 weeks was 0.94 and 0.87, respectively, which are higher than the AUCs of FeNO, blood eosinophils, IgE or PC ₂₀. Th2 airway inflammation as measured by this three-gene-mean also had predictive capacity for an improvement in symptoms.

Conclusions

The three-gene-mean of periostin, CLCA1 and serpinB2 in airway epithelial brushings identifies Th2-high and low populations, is correlated with other Th2 biomarkers, and performs well for prediction of FEV ₁ improvement with ICS. The three-gene-mean provides a measurement of Th2 airway inflammation that is clinically relevant and that can serve as a valuable tool to evaluate non-invasive biomarkers to predict treatment responses to existing and emerging asthma therapies.

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Most cited references 17

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Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.

Ian D Pavord, Stephanie Korn, Peter Howarth … (2012)

Some patients with severe asthma have recurrent asthma exacerbations associated with eosinophilic airway inflammation. Early studies suggest that inhibition of eosinophilic airway inflammation with mepolizumab-a monoclonal antibody against interleukin 5-is associated with a reduced risk of exacerbations. We aimed to establish efficacy, safety, and patient characteristics associated with the response to mepolizumab. We undertook a multicentre, double-blind, placebo-controlled trial at 81 centres in 13 countries between Nov 9, 2009, and Dec 5, 2011. Eligible patients were aged 12-74 years, had a history of recurrent severe asthma exacerbations, and had signs of eosinophilic inflammation. They were randomly assigned (in a 1:1:1:1 ratio) to receive one of three doses of intravenous mepolizumab (75 mg, 250 mg, or 750 mg) or matched placebo (100 mL 0·9% NaCl) with a central telephone-based system and computer-generated randomly permuted block schedule stratified by whether treatment with oral corticosteroids was required. Patients received 13 infusions at 4-week intervals. The primary outcome was the rate of clinically significant asthma exacerbations, which were defined as validated episodes of acute asthma requiring treatment with oral corticosteroids, admission, or a visit to an emergency department. Patients, clinicians, and data analysts were masked to treatment assignment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01000506. 621 patients were randomised: 159 were assigned to placebo, 154 to 75 mg mepolizumab, 152 to 250 mg mepolizumab, and 156 to 750 mg mepolizumab. 776 exacerbations were deemed to be clinically significant. The rate of clinically significant exacerbations was 2·40 per patient per year in the placebo group, 1·24 in the 75 mg mepolizumab group (48% reduction, 95% CI 31-61%; p<0·0001), 1·46 in the 250 mg mepolizumab group (39% reduction, 19-54%; p=0·0005), and 1·15 in the 750 mg mepolizumab group (52% reduction, 36-64%; p<0·0001). Three patients died during the study, but the deaths were not deemed to be related to treatment. Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma. GlaxoSmithKline. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Lebrikizumab treatment in adults with asthma.

Jonathan Corren, Robert F Lemanske, Nicola A Hanania … (2011)

Many patients with asthma have uncontrolled disease despite treatment with inhaled glucocorticoids. One potential cause of the variability in response to treatment is heterogeneity in the role of interleukin-13 expression in the clinical asthma phenotype. We hypothesized that anti-interleukin-13 therapy would benefit patients with asthma who had a pretreatment profile consistent with interleukin-13 activity. We conducted a randomized, double-blind, placebo-controlled study of lebrikizumab, a monoclonal antibody to interleukin-13, in 219 adults who had asthma that was inadequately controlled despite inhaled glucocorticoid therapy. The primary efficacy outcome was the relative change in prebronchodilator forced expiratory volume in 1 second (FEV(1)) from baseline to week 12. Among the secondary outcomes was the rate of asthma exacerbations through 24 weeks. Patient subgroups were prespecified according to baseline type 2 helper T-cell (Th2) status (assessed on the basis of total IgE level and blood eosinophil count) and serum periostin level. At baseline, patients had a mean FEV(1) that was 65% of the predicted value and were taking a mean dose of inhaled glucocorticoids of 580 μg per day; 80% were also taking a long-acting beta-agonist. At week 12, the mean increase in FEV(1) was 5.5 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.02). Among patients in the high-periostin subgroup, the increase from baseline FEV(1) was 8.2 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.03). Among patients in the low-periostin subgroup, the increase from baseline FEV(1) was 1.6 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.61). Musculoskeletal side effects were more common with lebrikizumab than with placebo (13.2% vs. 5.4%, P = 0.045). Lebrikizumab treatment was associated with improved lung function. Patients with high pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab than did patients with low periostin levels. (Funded by Genentech; ClinicalTrials.gov number, NCT00930163 .).

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Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study.

Jean Bousquet, Søren Pedersen, Romain Pauwels … (2004)

For most patients, asthma is not controlled as defined by guidelines; whether this is achievable has not been prospectively studied. A 1-year, randomized, stratified, double-blind, parallel-group study of 3,421 patients with uncontrolled asthma compared fluticasone propionate and salmeterol/fluticasone in achieving two rigorous, composite, guideline-based measures of control: totally and well-controlled asthma. Treatment was stepped-up until total control was achieved (or maximum 500 microg corticosteroid twice a day). Significantly more patients in each stratum (previously corticosteroid-free, low- and moderate-dose corticosteroid users) achieved control with salmeterol/fluticasone than fluticasone. Total control was achieved across all strata: 520 (31%) versus 326 (19%) patients after dose escalation (p < 0.001) and 690 (41%) versus 468 (28%) at 1 year for salmeterol/fluticasone and fluticasone, respectively. Asthma became well controlled in 1,071 (63%) versus 846 (50%) after dose escalation (p < 0.001) and 1,204 (71%) versus 988 (59%) at 1 year. Control was achieved more rapidly and at a lower corticosteroid dose with salmeterol/fluticasone versus fluticasone. Across all strata, 68% and 76% of the patients receiving salmeterol/fluticasone and fluticasone, respectively, were on the highest dose at the end of treatment. Exacerbation rates (0.07-0.27 per patient per year) and improvement in health status were significantly better with salmeterol/fluticasone. This study confirms that the goal of guideline-derived asthma control was achieved in a majority of the patients.

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Author and article information

Journal

Journal ID (nlm-ta): Clin Transl Allergy

Journal ID (iso-abbrev): Clin Transl Allergy

Title: Clinical and Translational Allergy

Publisher: BioMed Central

ISSN (Electronic): 2045-7022

Publication date Collection: 2013

Publication date (Electronic): 17 July 2013

Volume: 3

Page: 24

Affiliations

[1 ]Cardiovascular Research Institute, University of California, San Francisco, USA

[2 ]Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy, University of California, Room HSE-1355A, 513 Parnassus Avenue, Box 0130, San Francisco, CA 94143, USA

[3 ]Genentech, Inc, South San Francisco, CA, USA

Article

Publisher ID: 2045-7022-3-24

DOI: 10.1186/2045-7022-3-24

PMC ID: 3724712

PubMed ID: 23866775

SO-VID: a9b0b2ee-e600-48a4-ac0e-2a0a5b97b4b3

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 7 June 2013

Date accepted : 16 June 2013

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A qPCR-based metric of Th2 airway inflammation in asthma

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Abstract

Background

Methods

Results

Conclusions

Related collections

Biomarkers for Inflammatory Lung Disease

Most cited references 17

Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.

Lebrikizumab treatment in adults with asthma.

Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study.

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Cited by 21

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