WORK ACCOMPLISHED: Growing data suggest that patients with obstructive lung disease (OLD) such as asthma and chronic obstructive pulmonary disease (COPD) have an increased predisposition for obstructive sleep apnea, but the mechanism(s) remain unknown. One characteristic these patients share is use of inhaled corticosteroid (ICS). We recently found a dose-dependent relationship of ICS use with high OSA risk. Furthermore, in a 16-week observational inhaled fluticasone (FP) treatment study, we observed increased upper airway (UAW) collapsibility during sleep, as measured by the critical closing pressure (Pcrit), parallelin the improvement in lower airways obstruction, with the largest Pcrit deterioration in the subject with most sleep-disordered breathing (SDB) at baseline. These findings suggest an effect of ICS on the unified airway of steroid responsive patients and of those with more collapsible upper airways at baseline. We also found a dose-dependent relationship of ICS with obesity. Based on their known effects, ICSs could deleteriously affect UAW collapsibility through inducing dilators' myopathy and fat deposition around the UAW. FP is the most potent and commonly used ICS. HYPOTHESIS/AIMS: The central hypothesis is that FP will increase UAW collapsibility (less negative Pcrit) and worsen SDB in steroid responsive patients with OLD and those with UAWs more susceptible to collapse at baseline, through alterations in tongue muscle function and fat accumulation in the UAW surrounding structures. To address this hypothesis, we propose to test the effects of inhaled FP on: 1) UAW collapsibility during sleep and SDB severity, assessed by Pcrit and polysomnographic (PSG) measures. Exploratory aims will test the role of steroid responsiveness and baseline collapsibility as determinants of FP effects on Pcrit and SDB; 2) tongue strength and fatigability, and fat accumulation (fraction and volume, measured on MRI) in the surrounding UAW structures. Exploratory aims will test whether these effects underlie the increase in UAW collapsibility and the role of steroid responsiveness status as a mediator of these FP effects. DESIGN: We propose a proof-of-concept and mechanistic, randomized-controlled, parallel groups study of high (220 mcg, 4 puffs twice a day) vs. low (44 mcg twice a day) dose inhaled FP, followed by an 8- week wash-out period, in 58 steroid-naive subjects with OLD. Following baseline Pcrit, PSG, MRI and tongue function (using the Iowa Oral Performance Instrument) measurements, subjects will enter a 2-week low-dose FP run-in, with subsequent randomization to either high- vs. low-dose FP, for 16 weeks. At mid-period, Pcrit, tongue function and steroid responsiveness status (defined as e5% improvement from baseline in FEV1%) will be determined. At the end of treatment, Pcrit, PSG, MRI and tongue measurements will be taken. Then, subjects will enter an 8-week wash-out that ends with repeat Pcrit and tongue function assessments. SIGNIFICANCE: Millions of people, including many Veterans, are treated with ICS for OLD, and among those with COPD, these numbers are likely to escalate. However, do these medications alter UAW collapsibility and predispose to OSA in some individuals, as our preliminary observations suggest? This research is innovative because it will directly evaluate the effects of ICS on the UAW structure and function during sleep and wakefulness. At the study completion, it is our expectation that we will have elucidated the effects and governing mechanisms of ICS on UAW patency and SDB severity. Data generated will form the foundation for future research aimed at expanding our understanding of ICS's effects on UAW and means to mitigate/prevent them. The clinical implication of our findings will be experimental-based verification of deleterious effects of ICS on UAW and risk for OSA, which will ultimately be of enormous financial benefit to the VA and OLD management programs.
The Chairman of the Veterans' Disability Benefits Commission reported at a recent US Senate hearing that asthma, chronic obstructive pulmonary disease (COPD), and sleep apnea are among the top 13 most frequent diagnoses leading to disability under the Department of Defense and the VA system statutes. Recent research finds that sleep apnea is more common among asthma and COPD individuals, and this may be caused by inhaled corticosteroid use. Many Veterans are currently using inhaled corticosteroids, and many more will be prescribed such medications, given their recent inclusion in international treatment guidelines. As such, our study addresses a critical need by researching the role of a potent inhaled corticosteroid in promoting sleep apnea, the determinants of this response, and the ways through which it occurs. Results from this study will form the foundation for future research aimed at expanding our understanding of the effects of inhaled corticosteroids on the upper airway, as well as developing means to prevent or counteract them.
