Oral Low-dose Theophylline on Top of Inhaled Fluticasone-Salmeterol Does Not Reduce Exacerbations in Patients With Severe COPD: A Pilot Clinical Trial.

BACKGROUND: COPD is characterized by chronic inflammation. In vitro and ex vivo 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 vivo and what its potential clinical consequences are is unclear. OBJECTIVES: The objective of this trial was to determine whether low-dose theophylline on top of inhaled long-acting ß2-agonists and inhaled corticosteroids (ICS) in patients with COPD (1) enhances HDAC activity and the antiinflammatory effects of ICS in vivo, (2) reduces the concentration of inflammatory markers, and (3) reduces exacerbation frequency. METHODS: In this prospective, double-blind, placebo-controlled clinical trial, we randomized patients with COPD (FEV1 < 50% predicted plus at least one hospitalization due to exacerbation in the previous year) to ICS plus theophylline 100 mg bid or matched placebo. We determined the following at baseline and at the end of 52 weeks of follow-up: (1) HDAC activity in blood monocytes and sputum macrophages, (2) the concentration of several inflammatory markers (IL-8, IL-6, IL-1ß, and tumor necrosis factor -α) in serum and sputum supernatant, and (3) the rates of exacerbations and adverse effects. RESULTS: 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 weeks. Likewise, the rate of exacerbations during follow-up was similar in both groups. CONCLUSIONS: The combination of low-dose oral theophylline and ICS did not enhance the antiinflammatory properties of ICS in vivo or influence exacerbation rate. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01599871; URL: www.clinicaltrials.gov.

Differential effects of smoking and COPD upon circulating myeloid derived suppressor cells.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by an enhanced and persistent innate and acquired immune response to tobacco smoking. Myeloid-derived suppressor cells (MDSCs) modulate T-cell responses by down-modulating the T cell receptor ζ chain (TCR ζ) through the catabolism of l-arginine. The effects of smoking on MDSCs and their potential participation in COPD immunopathogenesis have not been explored so far. METHODS: To investigate it, we compared the level of circulating Lineage-/HLA-DR-/CD33+/CD11b+ MDSCs, the serum concentration of arginase I (ARG I) and the expression of peripheral T-cell receptor ζ chain (TCR ζ) in never smokers, smokers with normal spirometry and COPD patients. Flow cytometry was used to quantify circulating MDSCs and TCR ζ expression. Serum ARG I levels were determined by ELISA. RESULTS: The main findings of this study were that: (1) current smoking upregulates and activates circulating MDSCs both in smoker controls and COPD patients; and, (2) at variance with the smokers with normal spirometry, in patients with COPD this effect persists after quitting smoking and is accompanied by a significant and specific down-regulation of the TCR ζ chain expression in circulating T lymphocytes. CONCLUSION: Smoking modulates circulating MDSCs. Their regulation appears altered in patients with COPD.