Discovery and Validation of a Volatile Signature of Eosinophilic Airway Inflammation in Asthma
Rosa Peltrini, Rebecca L. Cordell, Michael Wilde, Shahd Abuhelal, Eleanor Quek, Nazanin Zounemat Kermani, Wadah Ibrahim, Matthew Richardson, Paul Brinkman, Florence Schleich, Pierre‐Hugues Stefanuto, Hnin Aung, Neil Greening, Sven Erik Dahlén, Ratko Djukanović, Ian M. Adcock, Christopher E. Brightling, P. S. Monks, Salman Siddiqui
Abstract
Abstract Rationale Volatile organic compounds (VOCs) in asthmatic breath may be associated with sputum eosinophilia. We developed a volatile biomarker signature to predict sputum eosinophilia in asthma. Methods VOCs emitted into the space above sputum samples (headspace) from patients with severe asthma (n = 36) were collected onto sorbent tubes and analyzed using thermal desorption gas chromatography–mass spectrometry (GC-MS). Elastic net regression identified stable VOCs associated with sputum eosinophilia ⩾ 3% and generated a volatile biomarker signature. This VOC signature was validated in breath samples from: 1) patients with acute asthma according to blood eosinophilia ⩾0.3 × 109cells/L or sputum eosinophilia of ⩾3% in the UK EMBER (East Midlands Breathomics Pathology Node) consortium (n = 65) and 2) U-BIOPRED-IMI (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes Innovative Medicines Initiative) consortium (n = 42). Breath samples were collected onto sorbent tubes (EMBER) or Tedlar bags (U-BIOPRED) and analyzed by GC-MS (GC × GC-MS for EMBER or GC-MS for U-BIOPRED). Measurements and Main Results The in vitro headspace identified 19 VOCs associated with sputum eosinophilia, and the derived VOC signature yielded good diagnostic accuracy for sputum eosinophilia ⩾3% in headspace (area under the receiver operating characteristic curve [AUROC] 0.90; 95% confidence interval [CI], 0.80–0.99; P < 0.0001), correlated inversely with sputum eosinophil percentage (r s = −0.71; P < 0.0001), and outperformed fractional exhaled nitric oxide (AUROC 0.61; 95% CI, 0.35–0.86). Analysis of exhaled breath in replication cohorts yielded a VOC signature AUROC (95% CI) for acute asthma exacerbations of 0.89 (0.76–1.0) (EMBER cohort) with sputum eosinophilia and 0.90 (0.75–1.0) in U-BIOPRED, again outperforming fractional exhaled nitric oxide in U-BIOPRED (0.62 [0.33–0.90]). Conclusions We have discovered and provided early-stage clinical validation of a volatile biomarker signature associated with eosinophilic airway inflammation. Further work is needed to translate our discovery using point-of-care clinical sensors.