Early interventions in asthma with inhaled corticosteroids Lauri A. Laitinen, MD, PhD,a Alan Altraja, MD,a Eeva-Maija Karjalainen, MD,a and Annika Laitinen, MD, PhDb Helsinki, Finland
We have earlier shown epithelial damage in the airway mucosa in patients with asthma. Later other structural changes have been recognized in asthma, such as deposition of collagen and tenascin in the subepithelial basement membrane and changes in the laminin subchain composition. These processes are modified by an inflammatory process in the airways. Both the United States National Institutes of Health and the British Thoracic Society guidelines on the management of asthma emphasize the need for early use of anti-inflammatory drugs. Many clinical studies that used airway biopsy specimens have shown a decrease in airway inflammatory cell numbers after inhaled corticosteroid therapy. However, there is very little information on the effects of asthma medication on the structural components of the airways. Both the synthesis and degradation of many extracellular matrix components may be affected by the disease process and the drugs resulting in altered remodeling and gene expression in the airways. Because there are only a few studies that try to identify early changes in asthma, it is not known whether the anti-inflammatory treatment of asthma proposed by the guidelines is started early enough. (J Allergy Clin Immunol 2000;105:S582-5.) Key words: Asthma, airways inflammation, inhaled corticosteroid, basement membrane, tenascin, laminin remodelling
Several new asthma guidelines stress early antiinflammatory drug use in asthma. Already in 1994 National Asthma Programme in Finland1 proposed that the treatment should be started with anti-inflammatory medication immediately after the diagnosis of asthma is established. In corticosteroid therapy, treatment should be started with a dose that controls symptoms, after which the lowest dose that keeps the patient in good condition should be sought. Inhaled steroids can also be used alternately with chromoglycate or nedocromil. Concomitant use is seldom necessary but can be considered in children who receive high doses of steroids or if steroids have caused side-effects and only temporarily when therapy is being changed from steroids to chromoglycate or nedocromil. The length of regular therapy depends on the patient’s condition and the results of pulmonary function tests. If bronchial reactivity has increased and there are marked variations in peak expiratory flow (PEF) values,
From athe Department of Medicine, Helsinki University Central Hospital, and bthe Institute of Biomedicine, Department of Anatomy, University of Helsinki. Supported by a grant from the Sigrid Juselius Foundation. Reprint requests: Prof Lauri A. Laitinen, Department of Medicine, Helsinki University Central Hospital, PO Box 341, FIN-00029 HYKS, Finland. Copyright © 2000 by Mosby, Inc. 0091-6749/2000 $12.00 + 0 1/0/100195
Abbreviation used PEF: Peak expiratory flow
regular drug therapy should be continued until pulmonary function is normal. This may take 1 to 2 years in adults. In children, the situation may normalize sooner. Both the United States National Institutes of Health and the British Thoracic Society have recently updated their guidelines on the management of asthma in 1997.2,3 They both emphasize the need for early use of antiinflammatory drugs in accordance with the Finnish National Asthma Programme. The US version, however, uses a 4-step classification for asthma severity (mild-intermittent, mild-persistent, moderate-persistent, and severe-persistent) and recommends starting inhaled corticosteroids, chromoglycate, or nedocromil at the mild-persistent stage.
STUDIES SUPPORTING EARLY USE OF ANTIINFLAMMATORY DRUGS IN ASTHMA The Expert Panel of the US National Asthma Education and Prevention Program4 reviewed more than 6000 scientific articles to produce the new guidelines. We will present some of our own studies leading to the recognition of asthma as an inflammatory disease that should be treated early on with anti-inflammatory medication. In 1985, we evaluated bronchial biopsy specimens taken from patients with asthma and compared them with those specimens taken from a healthy volunteer.5 We found airway epithelial damage, particularly the destruction of ciliated cells, and the presence of mast cells. We suggested that this increased exposure of intraepithelial nerves to various stimuli could be the cause of bronchial hyperresponsiveness in patients with asthma. A few years later we published a quantitative assessment of the inflammatory cells in patients with mild asthma.6 We compared biopsy specimens taken from patients with newly diagnosed asthma (duration, ≤12 months) with specimens taken from control subjects. In patients with newly diagnosed asthma, the epithelium contained significantly increased numbers of mast cells, eosinophils, lymphocytes, and macrophages. In addition, there were significant increases in the number of eosinophils, lymphocytes, macrophages, and plasma cells in the lamina propria. We have also conducted a 2-phase clinical study in 103 patients with newly diagnosed asthma (symptoms present for <12 months). The first phase of the study ran
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for 2 years.7 All patients received either the glucocorticosteroid, budesonide 600 µg twice daily, or the β2-agonist, terbutaline 375 µg twice daily, delivered by Nebuhaler (Astra Draco, Lund, Sweden). After 6 weeks of treatment, budesonide markedly decreased the sensitivity of the airways to histamine compared with the pretreatment baseline. This improvement in bronchial hyperresponsiveness was sustained throughout the treatment period and was significantly more than that seen in patients who received terbutaline. PEF also improved significantly more in patients receiving budesonide than in those receiving terbutaline, both in the morning and in the evening. Budesonide significantly relieved symptoms and decreased the need for additional β2-agonist medication, compared with the prestudy treatment and terbutaline therapy. The second phase of the study ran for an additional year.8 Patients who previously received budesonide entered a new double-blind stage. They randomly received either a lower dose of inhaled budesonide (200 µg, twice daily) or placebo, delivered by Turbuhaler. The previously terbutaline-treated group received open-label budesonide 600 µg, twice daily, by Nebuhaler. The results of the double-blind stage showed that reducing the dose of inhaled budesonide maintains the previous improvement in airway responsiveness and lung function in most patients. However, in most patients who received placebo, lung function declined and bronchial responsiveness worsened. The differences in respiratory parameters between the 2 groups were significant (FEV1, P = .007; bronchial responsiveness to histamine, P = .025; morning PEF, P = .040). Along with the previous clinical study, we assessed bronchial biopsy specimens taken from 14 patients, before and after 3 months of treatment.9 Patients randomly received either 375 µg terbutaline, twice daily, or 600 µg budesonide, twice daily. The pretreatment biopsy specimens from both groups showed that the airway epithelium was severely damaged and contained increased numbers of goblet and inflammatory cells (mast cells, eosinophils, and lymphocytes). After 3 months of treatment, budesonide improved the structure of the bronchial epithelium and decreased airway inflammation. The ciliated-cell:goblet-cell ratio in the epithelium increased, and the total inflammatory cell count fell significantly. Individual cell counts showed that, compared with baseline, budesonide significantly reduced the number of eosinophils and lymphocytes in the epithelium. The decrease in eosinophils was significantly greater in the budesonide-treated group than in the terbutalinetreated group. Budesonide improved the histologic appearance of the bronchial epithelium.
IS THE ANTI-INFLAMMATORY TREATMENT OF ASTHMA PROPOSED BY THE GUIDELINES STARTED EARLY ENOUGH? There are few studies that try to identify the crucial early changes in asthma. Laitinen et al6 in 1993 studied
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bronchial biopsy specimens from 14 patients with newly diagnosed asthma, who have had asthma symptoms less than 1 year (mean, 7.4 months). We concluded that, in asthma, an airway inflammatory process is present even at a clinically early stage of the disease. In the asthmatic airways, there are signs of a general inflammatory response caused by more than one cell type. A major difficulty to the study of the early changes in asthma or patients with asthma-like symptoms is to find the right patient groups. We have recently investigated patients with seasonal birch pollen–sensitive asthma, elite long-distance skiers with asthma-like symptoms, patients with chronic cough, and patients with asthmalike symptoms but with normal lung function and without bronchial hyperresponsiveness.
Patients with seasonal birch pollen–sensitive asthma We have studied bronchial biopsy specimens from 17 patients with seasonal birch pollen asthma.10 We measured immunoreactivity of tenascin and fibronectin, which are extracellular matrix glycoproteins expressed during morphogenesis and tissue repair, and a number of inflammatory cells. The results showed an increase in tenascin immunoreactivity in the bronchial subepithelial reticular basement membrane layer in patients with seasonal asthma compared with control subjects. The tenascin immunoreactivity, appearing as an intense wide subepithelial band in asthma, was seen only occasionally in the basement membrane of control specimens. Instead, a diffuse immunoreaction against both total fibronectin and locally produced extradomain A fibronectin was similarly visible in the airway mucosa of both patients and control subjects. Despite the significant increase in the airway mucosa of eosinophils in patients with seasonal asthma, there was no correlation between the number of these cells and level of tenascin expression. In patients with birch pollen–sensitive asthma during the birch pollen season, inhaled corticosteroid treatment (budesonide 400 µg twice daily) decreased tenascin immunoreactivity, in comparison with effects of placebo. Our results suggest that the higher amount of tenascin reflects disease activity in asthma and may be an indicator of a remodeling process rather than of injury itself.
Elite skiers with asthma-like symptoms A high prevalence of bronchial hyperresponsiveness, asthma-like symptoms, and asthma has been reported among elite cross-country skiers. Forty competitive cross-country skiers (mean age, 17.5 ± 0.22 years) were included in the study.11 Methacholine challenge test was performed, and 30 study subjects were determined hyperresponsive with mean PD20(FEV1) levels being 1.2 ± 0.08 mg methacholine. Twelve healthy medical students (mean age, 25 ± 0.70 years) served as a control group. Spirometry was normal in both groups. The control subjects were symptomless, but 30% of skiers had asthma-like symptoms. Bronchial mucosal biopsy speci-
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TABLE I. Inclusion criteria 1. Cough and/or sputum production and/or wheezing on most days for at least 2 months before the study but not longer than 2 years 2. Elevated sputum ECP concentration (>500 µg/L) in the sample collected within 4 weeks before the study 3. Normal FEV1 and forced vital capacity levels in volume-flow spirometry 4. Diurnal variation in peak flow values less than 20% and increase in PEF values after inhaling β2 agonist less than 15% 5. PD15 (FEV1) for histamine over 1.0 mg
mens were taken with a fiberoptic bronchoscope. The cryostate sections were immunostained by the APAAPmethod and monoclonal antibodies to detect eosinophils (EG2), T lymphocytes (CD3), macrophages (BerMac), and mast cells (AA1). There was a significant difference between skiers and control subjects in the inflammatory cell counts: eosinophils, 39.9 ± 7.3 versus 10.2 ± 2.4/mm2 (P < .05); T lymphocytes, 679.9 ± 84.5 versus 145 ± 124.8/mm2 (P < .01); and macrophages, 131.1 ± 15.9 versus 45.7 ± 38.9/mm2 (P < .05). Mast-cell counts did not differ between groups. We conclude that there are inflammatory changes in the airways of young elite cross-country skiers probably because of strenuous exercise in cold air. In a further study, we divided the skiers into 2 groups: 12 skiers received 22.3 weeks of treatment (range, 10-32 weeks) with budesonide 400 µg, twice daily (Pulmicort Turbuhaler), and 13 skiers received placebo. Biopsy specimens were taken before and after treatment. We were not able to show any significant differences between the treatment groups regarding extracellular matrix proteins or the inflammatory cell numbers in the biopsy specimens.12
Patients with chronic cough We have studied bronchial biopsy specimens from 8 patients with chronic cough of unknown cause that has lasted from 9 to 324 months. None of the patients met the criteria for diagnosis of bronchial asthma or chronic obstructive pulmonary disease, as judged by their medical history, symptoms, physical findings, or spirometry data, obtained with a spirometer (Vitalograph). The patients did not show a clinically significant increase in FEV1 levels after 1 mg inhaled terbutaline (Bricanyl Turbuhaler). The median change in FEV1 level after the bronchodilator represented a decrease by 1.6% (range, –8.7% to 4.8%). Bronchial hyperreactivity was evaluated by methacholine challenge test described by Löwhagen,13 according to which a provocative concentration causing a PC20 (FEV1) less than 4 mg/mL is considered as indicative of bronchial hyperreactivity. Four patients were proved to have bronchial hyperreactivity with PC20FEV1 from 0.25 to 2.0 mg/mL methacholine (median, 1.13 mg/mL). The patients with chronic cough were compared with
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TABLE II. Effects of beclomethasone (B) and nedocromil (N) on laminin α2 and β2 chains in bronchial biopsy specimens in patients with asthma-like symptoms Laminin Before Patient
1 2 3 4 5 6 7 8 9
N B B N N B B N N
– – – – – – – – –
+ + + + + + + + +
– + – + + + + + +
+ + + + + + + + +
+, Positive immunofluorescence staining reaction in the airway subepithelial basement membrane area with a monoclonal antibody against laminin α2 or β2 subchains; –, no staining.
a control group consisting of 12 healthy persons from Tartu, Estonia. The control subjects had no history of any respiratory or systemic illness, nor had they had any acute respiratory tract infection within 4 weeks before the study. None of the control subjects had current medical symptoms. They were all nonsmokers and nonatopic, as assessed by history and skin prick tests with 12 commonly used allergens (ALK; Allergologisk Laboratorium A/S, Horsholm, Denmark). All control persons had normal lung function with no significant diurnal variability in PEF rate and with no significant response in FEV1 to 3 × 200 µg inhaled rimiterol (Pulmadil; 3M Health Care Ltd, Loughborough, UK). We found that the thickness of expression of tenascin and laminin β2 chain was significantly greater in patients with chronic cough than in control subjects. Also, numbers of mucosal eosinophils, T lymphocytes, and macrophages were significantly higher in patients with chronic cough. We concluded that the bronchial inflammation that occurs in chronic cough resembles the bronchial inflammation in asthma.
Patients with asthma-like symptoms In this study we have tried to find patients whose symptoms would later lead to asthma (Table I). In our earlier study,14 we showed that in clinically severe asthma there is expression of laminin α2 (Ln α2) chain along the epithelial margin of the basement membrane. In the patients of the present study, Ln α2 chain staining was negative in the specimens taken before the treatment. In 8 of 10 patients, Ln α2 chain staining turned out to be positive in the second biopsy specimen taken 12 weeks afterwards (Table II). This happened despite the fact that the patients had meanwhile received anti-inflammatory treatment with beclomethasone (0.5 mg, twice daily; Easyhaler, Orion Company Ltd, Espoo, Finland) or nedocromil (4 mg, 4 times daily; Fisonair, RPR, Paris,
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France). Appearing of Ln α2 chain in the airways of these patients may speak in favor of patients experiencing the development of asthma.
SUMMARY It is widely accepted that anti-inflammatory medication is a proper treatment even for early asthma. Decision about the timing of inhaled corticosteroid treatment is under debate. We propose that anti-inflammatory treatment should be considered when there is any sign of airway inflammation. REFERENCES 1. Asthma Programme in Finland 1994-2004. Clin Exp Allergy 1996;26(suppl):1-24. 2. The British Guidelines on Asthma Management 1995 Review and Position Statement. Thorax 1997;52(Suppl. 1):S1-S21. 3. Expert Panel Report 2. Guidelines for the diagnosis and management of asthma. NIH Publication No. 97-4051, July 1997. 4. Woodhead P and Associates Ltd. Early intervention in asthma: The START study. Lund (Sweden): Astra Draco AB; 1996. 5. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Rev Respir Dis 1985;131:599-606. 6. Laitinen LA, Laitinen A, Haahlela T. Airway mucosal inflammation even in patients with newly diagnosed asthma. Am Rev Respir Dis 1993;147:696-704.
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7. Haahtela T, Jarvinen M, Kava T, Kiviranta K, Koskinen S, Lelitonen K, et al. Comparison of a β2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991;325:38892. 8. Haahtela T, Jarvinen M, Kava T, Kiviranta K, Koskinen S, Lehtonen K, et al. Effects of reducing or discontinuating inhaled budesonide in patients with mild asthma. N Engl J Med 1994;331:700-5. 9. Laitinen LA, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a β2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, doubleblind, parallel-group controlled trial. J Allergy Clin Immunol 1992;90:32-42. 10. Laitinen A, Altraja A, Kämpe M, Linden M, Virtanen I, Laitinen LA. Tenascin is increased in airway basement membrane of asthmatics and decreased by an inhaled steroid. Am J Respir Crit Care Med 1997;156:18. 11. Karjalainen E-M, Laitinen A, Sue-Chu M, Altraja A, Larsson L, Bjermer L, Laitinen LA. Airway inflammation and bronchial hyperresponsiveness in young elite cross-country skiers [abstract]. Am J Respir Crit Care Med 1997;155(suppl):A962. 12. Karjalainen E-M, Laitinen A, Sue-Chu M, Larsson L, Bjermer L, Laitinen LA. Effect of inhaled budesonide on airway inflammation in young cross country skiers [abstract]. Am J Respir Crit Care Med 1998;157 (suppl):A98. 13. Löwhagen 0. Methodological aspects of assessment of non-specific bronchial hyperreactivity. Eur J Respir Dis 1994;6(suppl):33-40. 14. Altraja A, Laitinen A, Virtanen I, et al. Expression of laminins in the airways of various types of asthmatic patients: a morphometric study. Am J Respir Cell Mol Biol 1996;15:482-8.