Treatment upon diagnosis is key when attempting to prevent airway remodeling in patients with bronchial asthma.
Asthma prevalence has increased over the past 20 years. In most countries where it has been studied, asthma affects approximately 10% of the population. It is of key importance to understand the mechanisms of inflammation in asthma, as well as the treatment modalities used to prevent and counter the inflammatory process if the development of fixed airway obstruction and attendant respiratory insufficiency is to be avoided.
The patient was a 40-year-old Hispanic female who presented several years ago for evaluation and treatment of bronchial asthma. She had developed asthma during childhood. The patient had never smoked; she gave a history of seasonal allergies, especially during tree and grass pollination. There were no pets in the home environment, nor was there any history of occupational exposure to possible asthma-sensitizing agents. For the most part, she had been treated with b-agonists via metered-dose inhaler and theophylline. Upon evaluation, she had diminished breath sounds and scattered wheezing. Her forced expiratory volume in 1 second (FEV1) was 45% of the predicted value; after administration of a bronchodilator, this increased to 55% of the predicted value. Upon administration of oral corticosteroids (as a pulsed dose with subsequent tapering), her FEV1 was maximized at 65% of the predicted value.
Her maintenance schedule has included a long-acting b-agonist, a high-dose corticosteroid inhaler, theophylline, and singular/rescue treatment using a short-acting ß-agonist. Her FEV1, however, has not increased beyond 67% to 70% of the predicted value. There is no evidence of bronchiectasis, an a1-antitrypsin deficiency, or any systemic disorder. We have categorized her as having bronchial asthma with a component of fixed airway obstruction.
This case illustrates a common clinical presentation and disease course for many asthma patients. Their disease presents similarities to that of patients with chronic obstructive pulmonary disease in the form of fixed airway obstruction.
Airway Inflammation in Asthma
Asthma is now thought of as a chronic inflammatory disease of the airway. It was believed to be a large-airway disease, based on bronchoscopic biopsy studies. These have shown increases in eosinophils, lymphocytes (especially CD4 lymphocytes), and mast cells in all patients with asthma. Increases in neutrophils have been seen during exacerbations of asthma. Information regarding the small airways has come from data reported by Carroll et al.1,2 Asthma is best categorized as increases in lymphocytes throughout the bronchial tree, with variability regarding eosinophil counts and their distribution.
Allergens or respiratory viruses can trigger the activation of the mast cell and the macrophage. This will result in events that involve eosinophils, T lymphocytes, epithelial cells, platelets, neutrophils, myofibro-blasts, and basophils. These cells release, manufacture, and recruit mediators involved in the inflammatory diathesis.
Activated mast cells release mediators such as histamine, leukotriene D4 and prostaglandin D2. These mediators are involved in the initiation of the acute bronchoconstriction typical of the early asthmatic response.3 Macrophages, on the other hand, are involved in both acute and chronic asthma. Increased numbers are found in the airways of asthma patients. They release prostaglandin, as well as cytokines such as interleukin (IL) 1, which is involved in chronic inflammation. Macrophages are inhibited by corticosteroids.
Eosinophil infiltration is the feature that distinguishes asthmatic inflammation from other types of inflammation. Eosinophil infiltration is found even in asymptomatic asthma patients. Eosinophils release a number of mediators involved in airway inflammation.4
Cytokines are important in the amplification and persistence of inflammation. They can activate inflammatory genes, which lead, in turn, to the expression of inflammatory proteins key to the perpetuation of the inflammatory response. Inflammatory cells and their products also activate certain structural cells, such as airway epithelial cells, causing them to begin secreting mediators. These mediator-producing structural cells then propagate the inflammation independently.5,6 The structural cells become the major source of mediators.
It has become evident that, for a number of asthma patients, airway obstruction is not completely reversible. This irreversible airway obstruction is presumed to be the result of inflammation-induced structural changes, or remodeling of the airway.7 Evidence for irreversible airway obstruction has been shown in multiple studies8-12 in which FEV1 is persistently reduced, despite clinical remission of the patients asthma symptoms. The degree of this irreversible airway obstruction correlates with the duration and/or severity of asthma.13
The described changes of airway remodeling include subepithelial fibrosis, goblet-cell hyperplasia/hypertrophy, submucosal-gland hypertrophy, smooth-muscle hyperplasia/hypertrophy, bronchovascular permeability/edema, inflammatory-cell infiltration, and epithelial damage/desquamation.14 A direct relationship has been found between the amount of subepithelial collagen and the severity of asthma. Myofibroblasts have been identified as a source of the collagen. The number of myofibroblasts has also been correlated with the duration of asthma.15
Measuring Inflammation and Remodeling
The association between airway inflammation and FEV1 and peak expiratory flow (PEF) is tenuous.16 Recording the forced vital capacity at the provocative concentration of an agonist that causes a 20% decrease in FEV1 (PC20) has been proposed.17 Airway hyperresponsiveness, in terms of the PC20, is the most commonly used measure of the response to bronchoconstrictor challenge tests; it is currently the best-validated physiological marker of the acute and chronic features of airway inflammation in asthma.18 Unfortunately, this is not a tool that can be used with PEF or FEV1 monitoring.
Invasive methods for measuring inflammation include bronchial biopsy, bronchoalveolar lavage, and bronchial washings. Noninvasive methods include examination of sputum, blood, and urine, as well as measurement of exhaled nitric oxide.19
There are studies20,21 showing that inhaled corticosteroids reduce the amount of collagen deposition beneath the basement membrane. There is also a study22 suggesting that inhaled corticosteroids reduce goblet-cell numbers in the airway. Where airway hyperreactivity is concerned, reduction in reactivity to methacholine lasts for a week after treatment is stopped.23,24 If airway remodeling had been reversed through the use of inhaled corticosteroids, a longer period of decreased reactivity would be expected.
Nonetheless, inhaled corticosteroids do have significant effects in preventing airway remodeling. In a study25 of 200 children treated using inhaled corticosteroids for 3 years, those who began therapy later than 5 years after the onset of asthma had significantly lower FEV1 values than children who began therapy within the first 2 years of its onset. A study26 of adults showed that when treatment using inhaled corticosteroids was delayed for 2 years after diagnosis, physiologic and clinical responses were poorer than when treatment was started at the time of diagnosis.
Airway remodeling (structural changes) occurs early in the disease; the greatest loss of lung function occurs at the beginning stages of the course of the disease.27 For this reason, early corticosteroid treatment is recommended for asthma patients. Corticosteroids inhibit the manufacture of cytokines and the recruitment of eosinophils. They act on almost every cell involved in inflammation.
ß-Agonists relax smooth muscle. There are some in vitro data indicating that these agents have antiinflammatory effects (inhibiting mast-cell mediator release, decreasing vascular permeability, and increasing mucociliary clearance). In vivo, however, there has been no demonstrated significant anti-inflammatory effect.
Theophylline also has minimal anti-inflammatory activity. Its purported mechanism is an effect on eosinophil infiltration of the bronchial mucosa, accompanied by a decrease in T lymphocytes in the bronchial mucosa.
For leukotriene inhibitors, the full effect of antiinflammatory activity has not been determined, but they appear to act on the arachidonic acid pathway. They decrease airway reactivity and permit reduction in inhaled corticosteroid dosages.28 They also have been shown to decrease the indirect markers of airway inflammation.
Nedocromil sodium and cromolyn sodium both have some antiinflammatory effects. Where inflammation and airway remodeling are concerned, however, inhaled corticosteroids alone have been shown to prevent or reverse structural changes. The key element is early treatment with inhaled corticosteroids, even in patients with mild, persistent disease. The rationale for early treatment is that the earlier the patient with asthma receives corticosteroid therapy, the more likely it is to prevent remodeling. Treatment using inhaled corticosteroids also reverses some of the airway structural changes that have already developed.
Louis Sasso, MD, Thomas Kilkenny, DO, Michael Castellano, MD, Theodore Maniatis, MD, Ralph Ciccone, MD, and James Bruno, MD, are all pulmonologists and critical care specialists in the Department of Pulmonary Medicine, Staten Island University Hospital, Staten Island, NY.
1. Carroll N, Cooke C, James A. The distribution of esinophils and lymphocytes in the large and small airways of asthmatics. Eur Respir J. 1997;10:292-300.
2. Carroll N, Elliot J, Morton A, James AL. The structure and function of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis. 1993;147:405-410.
3. Barnes PJ, Chung KF, Page CP. Inflammatory mediators of asthma2. Pharmacol Review 1998.
4. Weller PF. The immunobiology of eosinophils. N Engl J Med. 1991;324:1110-1118.
5. Levine SJ. Bronchial epithelial cell-cytosine interactions in airway epithelium. J Investig Med. 1995;43:241-249.
6. Johnson SR, Knox AJ. Synthetic functions of airway smooth muscle in asthma. Pharmacol Science. 1997;18:288-292.
7. Redington AE, Howarth PH. Airway wall remodeling in asthma. Thorax. 1997;52:310-312.
8. Beale HD, Fowler WS, Comme JH. Pulmonary function studies in 20 asthmatic patients in the symptom free interval. J Allergy. 1952;23:1-10.
9. Cade JF, Pain MCF. Pulmonary function during clinical remission of asthma: how reversible is asthma? Aust N Z J Med. 1973;3:545-551.
10. Palmer KNV, Kalman GR. Pulmonary function in asthmatic patients in remission. BMJ. 1975;I:485-486.
11. McCarthy DS, Sigurdson M. Lung elastic recoil and reduced airflow in clinically stable asthma. Thorax. 1980;35:298-302.
12. Brown PJ, Greville M, Finucane KE. Asthma and irreversible airflow obstruction. Thorax. 1984;39:131-136.
13. Uirick CS, Backer V, Dirksen A. A 10 year follow-up of 180 adults with bronchial asthma: factors important for the decline in lung function. Thorax. 1992;47:14-18.
14. Djukanovic R, Roche WR, Wilson JW, et al. State of the art: mucosal inflammation in asthma. Am Rev Respir Dis. 1990;142:434-457.
15. Minshall EM, Leung DYM, Martin RJ, et al. Eospinophil-associated TGF-b1 mRNA expression and airways fibrosis in bronchial asthma. Am J Respir Cell Mol Biol. 1997;17:326-333.
16. Sont JK, van Krieken JHJM, Evertse CE, et al. Relationship between the inflammatory infiltrate in bronchial biopsy specimens and clinical severity of asthma in patients treated with inhaled steroids. Thorax. 1996;51:496-502.
17. Gibbons WJ, Sharma A, Lougheed D, Macklem PT. Detection of excessive bronchoconstriction in asthma. Am J Respir Crit Care Med. 1996;163:582-689.
18. Sont JK, Willems LNA, Evertse CE, et al. Repeatability of measures of inflammatory cell number in bronchial biopsies in atopic asthma. Eur Respir J. 1997;10:2602-2609.
19. Kharitonov SA, Alving K, Samos PJ. Exhaled nasal nitric oxide measurements: recommendations. Eur Respir J. 1997;10:1683-1693.
20. Trigg CJ, Manolitsas ND, Wang J, et al. Placebo-controlled immunopathologic study of 4 months of inhaled corticosteroids in asthma. Am J Respir Crit Care Med. 1994;150:17-22.
21. Oliveri D, Chetta A, Del Donna A, et al. Effect of short-term treatment with low dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: a placebo controlled study. Am J Respir Crit Care Med. 1997;156:1864-1871.
22. Laitinen L, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a b2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial. J Allergy Clin Immunol. 1992;90:32-42.
23. Vathenen AS, Knox AJ, Wisniewski A, Tattersfield AE. Time course of change in bronchial reactivity with an inhaled corticosteroid in asthma. Am Rev Respir Dis. 1991;143:1317-1321.
24. Gershman NH, Wong HH, Liu J, Liu H, Fahy JV. Comparison of high versus low dose fluticasone propionate (FP) on clinical outcomes and markers of inflammation in asthmatic subjects. Am J Respir Crit Care Med. 1997;155:A288.
25. Agertoft L, Pedersen S. Effects of long term treatment with an inhaled corticosteroid on growth, and pulmonary function in asthmatic children. Respir Med. 1994;88:373-381.
26. Haahtela T, Jarvinen M, Kava T, et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med. 1994;331:700-705.
27. Ulrick CS, Lange P. Decline in lung function in adults with bronchial asthma. Am J Respir Crit Care Med. 1994;150:629-634.
28. Tamaoki J, Kondo M, Sakai N, et al. Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid. Am J Respir Crit Care Med. 1997;155:1235-1240.