Inhaled Fluticasone Effects on Upper Airway Patency in Obstructive Lung Disease

BACKGROUND: 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). The investigators recently found a
dose-dependent relationship of ICS use with high OSA risk. Furthermore, in a 16-week
observational inhaled fluticasone (FP) treatment study, the investigators observed increased
upper airway (UAW) collapsibility during sleep, as measured by the critical closing pressure
(Pcrit), paralleling 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. The investigators 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, the
investigators 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: The investigators 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 5% 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 the investigators'
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 the investigators expectation that they 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 the investigators'
understanding of ICS's effects on UAW and means to mitigate/prevent them. The clinical
implication of these 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.

Inclusion Criteria:

- American Veterans

- age 18 and above

- diagnosis of asthma and COPD per guidelines

- for asthma, persistent symptoms per guidelines

- for asthma, a pre-bronchodilator FEV1 55-90% and DLCO 80% predicted

- for asthma, physiologic confirmation by bronchodilator or methacholine challenge

- for COPD, a post-bronchodilator ratio of FEV1/FVC 70% and FEV1 50%

- overall smoking history of <10 pack-years for asthma and 10 pack-years for COPD.

Exclusion Criteria:

- any use of inhaled corticosteroid for >2 weeks at a time during the last 6 months, or
any use in the last 6 weeks;

- as needed use of nasal steroids in the prior 6 months

- select medications

- recent exacerbation requiring oral or systemic steroids in the past 6 months

- diagnosed vocal cords dysfunction

- other lung diseases (lung cancer, sarcoidosis, tuberculosis, lung fibrosis) or known
1-antitrypsin deficiency

- significant or actively unstable medical or psychiatric illnesses

- diagnosed osteopenia or osteoporosis

- established diagnosis of neuromuscular disease

- BMI 45 kg/m2 and higher

- treated OSA

- pregnancy (confirmed on urine test) or desire to get pregnant in the upcoming 6
months.

- smoking in the past 6 months

- metallic or electronic implants

- claustrophobia