Gary N Gross , MDChief, Allergy Division, Presbyterian Hospital of Dallas

Originally printed in:
» US Respiratory Care 2005 - February 2005

Reference Section a report by Gary N Gross, MD Chief, Allergy Division, Presbyterian Hospital of Dallas Asthma continues to be a significant health problem in the US.The cost of asthma care and the burden on the individual and society continue to grow. Of the 20 million people who have asthma,there were 1.8 million emergency room (ER) visits and almost half a million hospitalizations in 2000, as well as 4,500 deaths from asthma.1 Those patients who have asthma also have a progressive deterioration of lung function,2 which seems to be more pronounced in younger asthmatics whose disease is not controlled.3 The persistence of high rates of morbidity and mortality in asthmatics has led to renewed interest in a better understanding of the pathophysiology of the disease. Despite the fact that significant advances have been made in defining the inflammatory process in asthma, there has not been a parallel reduction in the untoward effects of the disease. One area of recent interest in regard to new forms of therapy has been the importance of the small airways. The involvement of these airways of less than 2mm diameter has been recognized as part of the disease for many years.

Autopsy studies comparing asthmatics who died during an asthma attack with non-asthmatic, non-smoking patients who died of non-respiratory causes showed significant differences in the small airways.4 The area occupied by muscle in the wall of the small airways was increased as might be expected. Furthermore, eosinophils were significantly increased in these peripheral airways, demonstrating that the disease process extends throughout the entirety of the lungs.

Histological evidence of small airway inflammation was provided by Hamid in his study comparing surgically resected specimens from patients with asthma with normals matched for age, sex, smoking history, and lung function.5 These investigators showed evidence of increased numbers of total and activated eosinophils as well as CD3+ T-cells in the small (<2mm) airways of asthmatic subjects.Autopsy studies of fatal and non-fatal asthma have also demonstrated small airway involvement. Carrol et al. showed that total wall area was significantly greater in the small membranous bronchioles of both fatal and non-fatal asthmatics compared with control subjects similarly studied.

Although these changes were observed in both small and large airways of fatal asthma, they were mainly confined to the small airways in non-fatal asthma.6 Using immunostaining with monoclonal antibodies, Synek et al. identified mast cells, eosinophils, monocyte/macrophages, neutophils and T-cells in airways from asthmatics who died of the disease and others who died of unrelated causes.7 The numbers of CD3+ T-cells in the epithelium of larger airways was lower in fatal asthma than non-fatal, while the number of eosinophils infiltrating the walls of these larger airways was greater in fatal asthma.The authors suggest that with deteriorating disease the inflammatory response may be more marked proximally.

Despite the histological studies showing involvement of small airways in asthma, a means of studying the small airways have never been readily available to the Evaluating and Treating Small Airway Disease in Asthma 1 B USINESS BRIEFING: US RESPIRATORY CARE 2005 1. Mannino D M, Homa D M,Akinbami L J, Moorman J E, Gwynn C, Redd S C,ýSurveillance for Asthma ý United States, 1980ý1999ý, Morb. Mortal.Wkly. Rep. MMWR (2002), 51 (SS01): pp. 1ý13.

2. Peat J K,Woolcock A J, Cullen K,ýRate of decline of lung function in subjects with asthmaý, Eur. J. Resp. Dis. (1987), 70: pp.

171ý179.

3. Cibella F, Cuttitta G, Bellia V, Bucchieri S, DýAnna S, Guerrera D, Bonsignore G, ýLung Function Decline in Bronchial Asthmaý, Chest (2002), 122: pp. 1,944ý1,948.

4. Saetta M, Di Stefano A, Rosina C,Thiene G, Fabbri L M,ýQuantitative Structural Analysis of Peripheral Airways and Arteries in Sudden Fatal Asthma 1-4ý, Am. Rev. Resp. Dis. (1991), 143: pp. 138ý143.

5. Hamid Q, Song Y Kotsimbos,T C, Minshall E, Bai T R, Hegele R G, Hogg J C, ýRespiratory pathophysiologic responses.

Inflammation of small airways in asthmaý, Allergy Clin. Immunology (1997), 100: pp. 44ý51.

6. Carroll N, Elliot J, Morton A, James A,ýThe Structure of Large and Small Airways in Nonfatal and Fatal Asthmaý, Am. Rev.

Resp. Disease (1993), 147: pp. 405ý410.

7. Synek M, Beasley R, Frew A J, Goulding D, Holloway L, Lampe F C, Roche W R, Holgate S T,ýCellular Infiltration of the Airways in Asthma of Varying Severityý, Am. J. Resp. Crit. Care Med. (1996), 154: pp. 224ý230.

clinician.Wagner et al. used a double lumen catheter inserted into a bronchoscope that had been wedged into a sub-segmental bronchus.8 In this study comparing mild asthmatics and normals, there was no difference in the pulmonary functions of either group as measured by spirometry or body plethysmography.

However, peripheral lung resistance was increased more than seven-fold in the asthmatics. Even treatment with a bronchodilator did not bring the peripheral resistance to normal. Similar increases in peripheral lung resistance were found in a study by Yanai et al.9 These investigators studied 20 patients with bronchial asthma and compared results with five normal, non- smoking subjects.These people were all studied while awake with a lateral-sensing micromanometer wedged into a 3mm internal diameter bronchus in the right lower lobe. The asthmatic patients were subdivided into two groups. The first group were asymptomatic and the duration of their asthma was less than two years. Their forced expiratory volume in one second (FEV1) was >80% of predicted.The second group of asthmatics had asthma for a longer time (>20 years) and their FEV1 was <70% of predicted. They found that the asthmatic patients having longer-standing disease and more severe airflow obstruction as measured by FEV1 also had increased peripheral resistance when compared with both normals and milder, more recent onset asthma.This finding suggests that therapy for small airways might be even more effective when started earlier in the course of the disease. Unfortunately, these findings implicating the smaller airways as a site of significant airway obstruction, and possibly the site of permanent obstruction in long-standing asthma, cannot be easily translated to terms the clinician commonly considers.

This disparity in what is clearly happening in the small airways and the clinicianýs concern about these airways stems, in part, from a lack of availability of an easy tool to measure small airway function. It also relates to years of reliance on the FEV1 and peak expiratory flows as the primary measurements to determine severity of asthma.

Although these measurements are clearly helpful in following the asthmatic, they may not be the most sensitive to early changes or even to significant obstructive disease in many patients. In a study from The Netherlands, two groups of asthmatics were matched for their age, post-bronchodilator FEV1,provocative concentration (PC20) methacholine, and for at least atopic status or sex.10 One of the groups consisted of difficult-to-control asthma,characterized by two or more exacerbations requiring a course of oral corticosteroids for at least seven days despite regular high-dose inhaled corticosteroid therapy.This group was compared with a group using a similar high-dose inhaled corticosteroid but who did not experience exacerbations in the previous 12 months. The authors found that the asthmatics who experienced exacerbation of their disease in the previous 12 months could be distinguished from the other group by an increased closing capacity and closing volume. These findings are compatible with persistence of small airway pathology during clinically well-controlled periods as a possible marker of future exacerbations.Other measures of lung volume (total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV)) were not significantly different in the two groups.

As part of a series of studies evaluating and characterizing the physiologic changes in nocturnal asthma, Martin, Kraft, and others studied patients at 0400 hours and 1600 hours with endobronchial and transbronchial biopsies.11 They were able to demonstrate that the inflammatory response related to nocturnal asthma involves distal airway units, specifically alveolar tissue. Inflammation in these distal units was accentuated in nocturnal asthma and correlated temporally with worsening lung function. Since a majority of deaths from asthma occur during sleep-related hours, these findings offer further evidence that small airways could play a significant role in the on-going morbidity and mortality in asthma. Recent studies using high- resolution computed tomography (CT) have also demonstrated small airway involvement in patients with near-fatal asthma.12 These data suggest that the clinician will not be able to totally differentiate the asthmatic at risk for an exacerbation based on currently available clinical tools.

This lack of ability to distinguish between patients who may have an exacerbation could be the reason for studies showing that ýmildý asthmatics are equally likely Evaluating and Treating Small Airway Disease in Asthma B USINESS BRIEFING: US RESPIRATORY CARE 2005 2 8. Wagner E M, Liu M C,Weinmann G G, Permutt S, Bleecker E R, ýPeripheral Lung Resistance in Normal and Asthmatic Subjectsý, Am. Rev. Resp. Dis. (1990), 141: pp. 584ý588.

9. Yanai M, Sekizawa K, Ohrui T Sasaki, H,Takishima T,ýSite of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressureý, J. Appl. Physiol. (1992), 72: pp. 1,016ý1,023.

10. in ýt Veen J C C M, Beekman A J, Bel E H, Sterk P J,ýRecurrent Exacerbations in Severe Asthma Are Associated with Enhanced Airway Closure During Stable Episodesý, Am. J. Respir. Crit. Care Med. (2000), 161: pp. 1,902ý1,906.

11. Kraft M, Djukanovic R,Wilson S, Holgate S T Martin, R J,ýAlveolar Tissue Inflammation in Asthmaý, Am. J. Respir. Crit.

Care Med. (1996), 154: pp. 1,505ý1,510.

12. Lee Y, Park J, Hwang J, Uh S T, Kim Y H, Park C S, "High-resolution CT findings in patients with near-fatal asthma", Chest (2004), 126:pp1840ý1848 to have a fatal exacerbation as ýsevereý asthmatics.13 These studies show inflammatory changes in the small airways and the role small airways may play in both nocturnal exacerbations of asthma and increasing the likelihood of a worsening asthma.The relationship of these findings and therapeutic options has recently taken on more practical importance. The presence of glucocorticoid receptors in alveolar walls was demonstrated by Adcock et al.14 These investigators found the localization of glucocorticoid receptors in both normal and asthmatic lung tissue was similar.The presence of these receptors in smaller airways may be of importance now that newer drug delivery methods can distribute inhaled corticosteroids more evenly throughout more areas of the lung.

The initial drug on the market with the characteristics necessary to reach the smaller airways was hydrofluoroalkane (HFA)-beclomethasone (QVAR).

HFA-flunisolide and HFA-ciclesonide may soon be available in the US. These drugs differ from other products available in that they are solutions of drug compared with the suspensions in most metered dose inhalers (MDIs). The fact that they are delivered as solutions allows the mass median aerodynamic diameter (MMAD) to be significantly smaller (1.1ým) than other products (2.5ý4.0ým) and the deposition is therefore different. A comprehensive review by Vanden Burgt of the initial studies of HFA-beclomethasone, as well as the deposition characteristics of the drug, has been published.15 In addition to the advantage of the smaller particle size, the HFA solution product is minimally deposited on the oropharynx (only 33% compared with 91%) without the use of a spacer. There are other characteristics of the new formulation that provide for easier delivery of the drug and greater convenience in using it. In vivo studies show that approximately 50% of this preparation is delivered to the lung compared with only about 4% of the chlorofluorocarbon (CFC) suspension preparation. Furthermore, radiolabelled studies have demonstrated a much wider area of distribution in the lung when the newer preparation is used. Perhaps because of this characteristic, the HFA solution formulation has been shown to be as effective as the same molecule delivered at twice the dose from a CFC suspension MDI.16 Studies comparing both low dose (800ýg/day) or high dose (1,600ýg/day) budesonide with HFA-beclomethasone at half the dose (400ýg/day or 800ýg/day) showed similar control of asthma and safety evaluations.17,18 Comparative studies with fluticasone (FP) show equivalent asthma control when HFA-beclomethasone (BDP) was given at comparable doses (BDP 400ýg/day versus FP 400ýg/day and BDP 800ýg/day versus FP 1,000ýg/day) with similar safety profiles.19,20 There have been two ways in which the effectiveness of these inhaled steroid solutions have been evaluated with regard to potential effects of reducing inflammation and airway hyper-reactivity. In one study, 10 healthy volunteers inhaled either CFC-BDP or HFA-BDP at a dose of 800ýg/day for 14 days.21 As a marker of anti-inflammatory effects of inhaled corticosteroids, tumor necrosis factor (TNF)-? production from alveolar macrophages was measured following stimulation with lipopolysaccharide and other stimulants. The macrophages from subjects treated with HFA-BDP showed suppression of the TNF-? production compared with those patients on CFC-BDP, suggesting that the small particle preparation was capable of modifying the inflam- 3 B USINESS BRIEFING: US RESPIRATORY CARE 2005 Reference Section 13. Robertson C F, Rubinfeld A R, Bowes G,ýPediatric asthma deaths in Victoria: the mild are at riský, Pediatr.Pulmonol. (1992), 13: pp. 95ý100.

14. Adcock J M, Gilbey T Gelder, C M, Chung K F, Barnes P J,ýGlucocorticoid Receptor Localization in Normal and Asthmatic Lungý, Am. J. Resp. Crit. Care Med. (1996), 154: pp. 771ý782.

15. Vanden Burgt J A, Busse W W, Martin R J, Szefler S J, Donnell D,ýEfficacy and safety overview of a new inhaled corticosteroid, QVAR (hydrofluoroalkane-beclomethasone extrafine inhalation aerosol), in asthmaý, J. Allergy Clin. Immunol. (2000), 106: pp. 1,209ý1,226.

16. Busse W, Brazinsky S, Jacobson K, Stricker W, Schmitt K,Vanden Burgt J, Donnell D, Hannon S, Colice G L,ýEfficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellantý, J. Allergy Clin. Immunol. (1999), 104: pp. 1,215ý1,222.

17.Worth H,ýA comparison of HFA-BDP Autohaler(tm) with budesonide Turbuhaler(r) in asthma control of adult patients with mild to moderately severe diseaseý, Respir. Med. (2000), 94: pp. S27ýS30.

18.Worth H, Muir J F, Pieters W R, ýComparison of Hydrofluoroalkane-Beclomethasone Dipropionate Autohaler(tm) with Budesonide Turbuhaler(tm) in Asthma Controlý, Respiration (2001), 68: pp. 517ý526.

19.Fairfax A, Hall I, Spelman R, ýA randomized, double-blind comparison of beclomethasone dipropionate extrafine aerosol and fluticasone propionateý, Ann.Allergy Asthma Immunol. (2001), 86: pp. 575ý582.

20.Aubier M,Wettenger R, Gans S J M,ýEfficacy of HFA-beclomethasone dipropionate extra-fine aerosol (800 ýg day-1) versus HFA-fluticasone propionate (1,000ýg day-1) in patients with asthmaý, Respir. Med. (2001), 95: pp. 212ý220.

21.Marshall B G,Wangoo A, Harrison L I,Young D B, Shaw R J, ýTumour necrosis factor-a production in human alveolar macrophages: modulation by inhaled corticosteroidý, Eur. Resp. J. (2000), 15: pp. 764ý770.

matory potential of alveolar macrophages.

Functional studies comparing the two preparations have also been undertaken. Using functional helical thin-section CT, Goldin et al. were able to show inhibition of the bronchoconstricting effects of methacholine in subjects treated with small particle size HFA-BDP compared with CFC-BDP.22 These investigators concluded that the HFA-BDP might have greater efficacy in the peripheral airways leading to less air trapping in these airways following methacholine challenge.The use of helical thin-section CT might be a better non-invasive way of evaluating the effect of therapy on small airways and perhaps even help in the initial evaluation of those airways.

An open-label pilot study has added further to the possible role of small particle size inhaled corticosteroids in asthma therapy. In this study, patients already receiving high dose inhaled steroids were treated with additional steroids consisting of either FP 330ýg/day or HFA-BDP 320ýg/day for three months.23 In the group receiving the small particle size inhaled steroid in addition to conventional steroid there was a significant improvement in forced expiratory flow (FEF)25-75% as well as other measures of small airway function (closing volume/vital capacity ratio). This study suggests that rather than increasing the dose of inhaled steroid, switching to a small particle size product may provide improvement in control of inflammation in the smaller airways.

The availability of safe and effective medications to treat small airway disease opens a new era of asthma therapy.

Clinicians should broaden their view of ways to measure effective therapy. Factors such as quality of life, symptoms such as breathlessness or cough, and objective findings such as FEF25-75%, which may be a surrogate marker of small airways obstruction if performed properly, should be evaluated along with FEV1. Using safe inhaled medication that can reach more of the lung surface area might allow effective early treatment of the disease and prevent some of the irreversible changes that occur. Treatment of patients previously thought to be suboptimally controlled with inhaled corticosteroids may improve with new formulations of medications.

The more ýpatient-friendlyý inhalation from an HFA solution inhaler may lead to better satisfaction and compliance with the inhaled corticosteroids. a73 Evaluating and Treating Small Airway Disease in Asthma B USINESS BRIEFING: US RESPIRATORY CARE 2005 4 22. Goldin J G,Tashkin D P , Kleerup E C, Greaser L E, Haywood U M, Sayre J W, Simmons M D, Suttorp M, Colice G L, Vanden Burgt J A, Aberle D R, ýComparative effects of hydrofluoroalkane and chlorofluorocarbon beclomethasone dipropionate inhalation on small airways: Assessment with functional helical thin-section computed tomographyý, J. Allergy Clin. Immun.

(1999); 104: pp. S258ý67.

23.Thongngarm T, Silkoff P, Kossack W S, Nelson H S, ý272 Hydrofluoroalkane-134a Beclomethasone or Chlorofluorocarbon Fluticasone: Effect on Small Airways in Poorly Controlled Asthmaý, (abstract) JACI (Feb. 2003); part 2,Vol. 111, No, 2.