['COPD is characterized by chronic inflammation. In\xa0vitro and ex\xa0vivo observations suggest that this inflammatory response is partially resistant to the effect of corticosteroids and that low-dose theophylline can restore this response via enhancement of histone deacetylase (HDAC) activity. Whether this occurs in\xa0vivo and what its potential clinical consequences are is unclear.', 'The objective of this trial was to determine whether low-dose theophylline on top of inhaled long-acting β2-agonists and inhaled corticosteroids (ICS) in patients with COPD (1) enhances HDAC activity and the antiinflammatory effects of ICS in\xa0vivo, (2) reduces the concentration of inflammatory markers, and (3) reduces exacerbation frequency.', 'In this prospective, double-blind, placebo-controlled clinical trial, we randomized patients with COPD (FEV1\xa0< 50%\xa0predicted plus at least one hospitalization due to exacerbation in the previous year) to ICS plus theophylline 100\xa0mg bid or matched placebo. We determined the following at baseline and at the end of 52\xa0weeks of follow-up: (1) HDAC activity in blood monocytes and sputum macrophages, (2) the concentration of several inflammatory markers (IL-8, IL-6, IL-1β, and tumor necrosis factor -α) in serum and sputum supernatant, and (3) the rates of exacerbations and adverse effects.', 'Seventy patients were randomized-36 to theophylline and 34 to placebo. HDAC activity and inflammatory marker levels were not different in the two arms either at baseline or after 52\xa0weeks. Likewise, the rate of exacerbations during follow-up was similar in both groups.'] Does oral Low-dose Theophylline on Top of Inhaled Fluticasone-Salmeterol Reduce Exacerbations in Patients With Severe COPD : A Pilot Clinical Trial?