Small-Particle Steroids Target Resistant Asthma
KEYSTONE, COLO. — Small-particle–size inhaled corticosteroids may provide increased clinical efficacy in tough-to-control asthma with marked distal airways inflammation.
“A lot of our asthma patients are really easy to treat—it doesn't matter what medication you use, so long as there's an inhaled steroid in there,” Dr. Richard J. Martin said at a meeting on allergy and respiratory disease. “But we should really ask in some of our more difficult-to-control patients if we are missing the inflammatory response in the distal lung.”
Only a few inhaled corticosteroid (ICS) products have the requisite median particle diameter (less than 2 mcm) needed to reach the alveolar tissue in the distal tracheobronchial tree, including beclomethasone dipropionate HFA (QVAR), flunisolide HFA (Aerospan), and ciclesonide (Sepracor). All three contain ultrafine particles in a solution aerosol; other ICSs consist of larger particles in a suspension aerosol, explained Dr. Martin, chairman of the department of medicine at National Jewish Health and professor of medicine at the University of Colorado, both in Denver.
The final word isn't in yet as to whether ICS particle size alters treatment outcomes in asthma. Long-term double-blind comparative trials with multiple end points are needed. But the short-term results are positive, Dr. Martin noted, and anecdotal clinical experience has been favorable.
Most encouraging of all are the findings of a recently presented but not yet published large, real-world study using the United Kingdom General Practice Research Database, Dr. Martin continued at a meeting sponsored by National Jewish Health.
That was a 1-year retrospective study involving more than 4,000 asthma patients. They were on one of three ICSs: large-particle fluticasone, large-particle beclomethasone with a now-banned chlorofluorocarbon propellant, or ultrafine-particle beclomethasone in a solution aerosol—that is, QVAR.
At the end of 1 year, there were significantly more asthma exacerbations requiring an unscheduled office visit and a course of oral steroids in the fluticasone and beclomethasone CFC groups than with beclomethasone HFA, despite the fact that the small-particle ICS was used at half the dose of beclomethasone CFC.
Moreover, the odds of asthma control were significantly worse with large-particle beclomethasone than with QVAR.
High-resolution CT studies have documented that narrowing and hyper-responsiveness of the small airways are common in asthma patients. Because the combined surface area and total volume of the distal airways are far greater than for the central airways, inflammatory changes in the distal airways can make treatment much more difficult.
Inflammation in the large airway often is uncoupled from that in the distal airway. That may explain the normal measurements of forced expiratory volume in 1 second (FEV1) often present in asthma patients.
Radio-labeled drug deposition studies show that 80%–85% of large-particle ICS in suspension aerosol never reaches the lungs, being deposited instead in the oropharynx.
In contrast, 56% of beclomethasone HFA and 68% of flunisolide HFA particles are deposited in the lung. When those products are used with a spacer to filter out the larger particles, drug deposition in the oropharynx declines, the physician said.
One obstacle is the lack of a simple, noninvasive means of measuring distal airway inflammation that could be used to guide the decision to prescribe a small-particle ICS.
For now, the practical approach is to consider turning to a small-particle ICS when asthma patients aren't well controlled on a large-particle product. It's made a real difference in his own practice, Dr. Martin said.
Disclosures: Dr. Martin has served on the advisory board and speakers bureau for Teva Pharmaceutical Industries, which markets QVAR. He is also a consultant and/or adviser to Genentech, Novartis, Schering-Plough, AstraZeneca, GlaxoSmithKline, and Kalobios Pharmaceuticals.
'We should really ask … if we are missing the inflammatory response in the distal lung.'
Source DR. MARTIN
