Breathomics for Assessing the Effects of Treatment and Withdrawal With Inhaled Beclomethasone/Formoterol in Patients With COPD

Paolo Montuschi; Giuseppe Santini; Nadia Mores; Alessia Vignoli; Francesco Macagno; Rugia Shoreh; Leonardo Tenori; Gina Zini; Leonello Fuso; Chiara Mondino; Corrado Di Natale; Arnaldo D'Amico; Claudio Luchinat; Peter J Barnes; Tim Higenbottam

doi:10.3389/fphar.2018.00258

Breathomics for Assessing the Effects of Treatment and Withdrawal With Inhaled Beclomethasone/Formoterol in Patients With COPD

Front Pharmacol. 2018 Apr 17:9:258. doi: 10.3389/fphar.2018.00258. eCollection 2018.

Authors

Affiliations

¹ Department of Pharmacology, Faculty of Medicine, Catholic University of the Sacred Heart, University Hospital Agostino Gemelli Foundation, Rome, Italy.
² Magnetic Resonance Center (CERM), University of Florence, Florence, Italy.
³ Department of Internal Medicine and Geriatrics, Catholic University of the Sacred Heart, University Hospital Agostino Gemelli Foundation, Rome, Italy.
⁴ Department of Drug Sciences, Faculty of Pharmacy, University "G. d'Annunzio", Chieti, Italy.
⁵ Department of Hematology, Faculty of Medicine, Catholic University of the Sacred Heart, University Hospital Agostino Gemelli Foundation, Rome, Italy.
⁶ Department of Allergology, 'Bellinzona e Valli' Hospital, Bellinzona, Switzerland.
⁷ Department of Electronic Engineering, University of Tor Vergata, Rome, Italy.
⁸ Airway Disease Section, Faculty of Medicine, National Heart and Lung Institute, Imperial College, London, United Kingdom.
⁹ Faculty of Pharmaceutical Medicine, Royal College of Physicians, London, United Kingdom.

Abstract

Background: Prospective pharmacological studies on breathomics profiles in COPD patients have not been previously reported. We assessed the effects of treatment and withdrawal of an extrafine inhaled corticosteroid (ICS)-long-acting β₂-agonist (LABA) fixed dose combination (FDC) using a multidimensional classification model including breathomics. Methods: A pilot, proof-of-concept, pharmacological study was undertaken in 14 COPD patients on maintenance treatment with inhaled fluticasone propionate/salmeterol (500/50 μg b.i.d.) for at least 8 weeks (visit 1). Patients received 2-week treatment with inhaled beclomethasone dipropionate/formoterol (100/6 μg b.i.d.) (visit 2), 4-week treatment with formoterol alone (6 μg b.i.d.) (visit 3), and 4-week treatment with beclomethasone/formoterol (100/6 μg b.i.d.) (visit 4). Exhaled breath analysis with two e-noses, based on different technologies, and exhaled breath condensate (EBC) NMR-based metabolomics were performed. Sputum cell counts, sputum supernatant and EBC prostaglandin E₂ (PGE₂) and 15-F_2t-isoprostane, fraction of exhaled nitric oxide, and spirometry were measured. Results: Compared with formoterol alone, EBC acetate and sputum PGE₂, reflecting airway inflammation, were reduced after 4-week beclomethasone/formoterol. Three independent breathomics techniques showed that extrafine beclomethasone/formoterol short-term treatment was associated with different breathprints compared with regular fluticasone propionate/salmeterol. Either ICS/LABA FDC vs. formoterol alone was associated with increased pre-bronchodilator FEF_25-75% and FEV₁/FVC (P = 0.008-0.029). The multidimensional model distinguished fluticasone propionate/salmeterol vs. beclomethasone/formoterol, fluticasone propionate/salmeterol vs. formoterol, and formoterol vs. beclomethasone/formoterol (accuracy > 70%, P < 0.01). Conclusions: Breathomics could be used for assessing ICS treatment and withdrawal in COPD patients. Large, controlled, prospective pharmacological trials are required to clarify the biological implications of breathomics changes. EUDRACT number: 2012-001749-42.

Keywords: COPD; breathomics; inhaled corticosteroids; long-acting β2-agonists; pharmacotherapy.