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Preventative therapy in adults with asthma
Respirator), Medicine (1991) 85, 355-357
Preventative therapy in adults with asthma P. J. BARNES
National Heart and Lung Institute, London SW3, U.K.
Asthma as an Inflammatory Disease
Asthma is a chronic inflammatory condition of the airways, which is characterized by infiltration of inflammatory cells (predominantly eosinophils and Tlymphocytes), plasma exudation and oedema, hypertrophy of smooth muscle and shedding of epithelium. Features of inflammation are present even in mild asthmatics when the patient may have few symptoms (1-3). The precise role of the different inflammatory cells and the mediators they release is not yet certain, and it is likely that they may differ from patient to patient, and in the same patient at different times (4). The mechanisms by which the airway develops inflammation in asthma are uncertain, but appear to be linked to allergen exposure in many patients. The consequences of inflammation are the development o fairway hyperresponsiveness, in which airways narrow too readily to a wide range of provoking stimuli (triggers), resulting in asthma symptoms. Inflammation of the airways may also directly lead to symptoms (e.g. cough and chest tightness) through activation of sensory nerves. Chronic inflammation may also lead to irreversible airflow obstruction, which is well recognised in poorly controlled asthmatics (5,6). This may be the result of airway smooth muscle hyperplasia or of subepithelial fibrosis (7).
but they suppress inflammation at every step (9,10). Steroids inhibit eosinophil infiltration into tissues, inhibit release ofcytokines in lymphocytes and macrophages, inhibit release of mediators from macrophages and eosinophils, reduce tissue mast cell content and inhibit microvascular leakage in airways.
Inhaled Steroids
When given by inhalation steroids are effective, well tolerated and have minimal side-effects in adults and children. Local side-effects include oral thrush and dysphonia, which are related to oropharyngeal deposition of the steroid. Large volume spacers (Nebuhaler, Volumatic, Aerochamber) markedly cut down oropharyngeal deposition and decrease systemic effects of inhaled steroids (I 1), and such a device should be considered when the use of inhaled steroids exceeds 800 pg day- ~. Systemic side-effects and adrenal suppression are unusual below doses of 1500 pg day- i. Inhaled steroids should be given twice daily when asthma is under control (although four times daily dosing may be preferable until control is achieved). Inhaled steroids should be introduced when asthma symptoms occur daily, or when there are nocturnal symptoms. Perhaps the need for a bronchodilator inhaler more than once daily is sufficient indication.
Anti-inflammatory Treatment Cromoglycate and Nedocromil Sodium
Since asthma is primarily an inflammatory condition it follows that a logical approach to treatment is to suppress this inflammatory response. This will lead to control of other symptoms and, in the long-term, this may reduce the decline in lung function with time and the risk of death. Anti-inflammatory treatments should therefore be introduced much earlier in the disease (8). Corticosteroids are by far the most effective antiinflammatory therapy available, since they work in most patients with asthma. Indeed, objective improvement in lung function and of symptoms after steroids is the hallmark of asthma. The precise mechanisms by which steroids work in asthma is not yet certain, 0954-6111/91/090355 + 03 $03.00/0
Cromoglycate is less useful than inhaled steroids, since it is only effective in a proportion of adult patients with mild asthma, and the response cannot be predicted on clinical grounds. It is often introduced in children because it has a proven safety record, but has the relative disadvantage that it must be taken four times daily. It provides equivalent symptom control to low dose inhaled steroids (less than 500pg daily), which are safe to use even in children. Cromoglycate is sometimes useful in preventing exercise-induced asthma in the few patients who fail to have it prevented by inhaled fl-agonists. © 1991 Baillirre Tindall
356
P. J. B a r n e s
Nedocromil sodium is somewhat more potent than cromoglycate in experimental asthma challenge studies, and in a dose of 4 mg qds may have a similar prophylactic effect to low dose inhaled steroids (12,13). As it has no obvious advantages, its place in clinical management is not yet clear (14), although it may be useful in patients who are unwilling to use inhaled steroids or in whom the local side-effects of inhaled steroids are a problem (despite the use of a spacer). Ketotifen
Ketotifen is claimed to have prophylactic effects in asthma but there are no convincing controlled trials which have demonstrated clinically useful effects and, therefore, it has no current place to play in the prophylaxis of asthma. Oral Steroids
Oral steroids must be kept to the minimal dose necessary in order to avoid side-effects. Short courses of oral steroids (prenisolone 30--40 mg d a y - ~ for 1-3 weeks) are used to treat acute exacerbations, sometimes to establish control of asthma before starting inhaled steroids, and to detect asthma in patients with chronic 'irreversible' airflow obstruction. Courses of oral steroids may be self-administered by patients according to a written action plan, and there is evidence that this improves control of asthma and reduces the need for hospital admission (15). Chronic (maintenance) oral steroids should be kept to the lowest dose possible and should only be used when patients have been treated with high dose inhaled steroids (up to 2 mg daily) and have had a trial of theophylline and anticholinergic therapy. Relatively few patients now require oral steroids to control their asthma. Alternate day dosing may reduce side-effects but it is not always as effective. Methotrexate
Immunosuppressants such as methotrexate may have a steroid-sparing effect and may be equivalent to 5-10 mg prednisolone (16,17). Methotrexate (15 mg orally per week) should be considered only when oral steroids are producing problems (e.g. osteoporosis in post-menopausal women, and patients with diabetes). Haematology and liver function should be monitored closely. Bronehodilators as Preventive Treatment
While bronchodilators, such as fl2-agonists, theophylline and anticholinergic drugs, may relieve symptoms of asthma (largely by reducing airway smooth
muscle contraction), there is little to suggest that they modify the chronic inflammation and bronchial hyperreactivity. Thus, conventional fl-agonists have no effect on the late response to allergen, or the increased reactivity which follows allergen (18), nor do they reduce bronchial hyperresponsiveness in asthmatic patients (19,20). Similarly, theophylline fails to prevent allergen-induced hyperreactivity or to reduce asthmatic hyperresponsiveness (21,22). This suggests that bronchodilators used alone may be potentially harmful, since they may "mask' the underlying inflammatory response, particularly when taken frequently and in high doses (e.g. by nebulizer). Salmeterol has recently become available and another long-acting fl2-agonist (formoterol) is already available in some countries. Whether they have any anti-inflammatory effect not shown by the other bronchodilators is not yet certain, but perhaps they should at first be treated with caution and should always be co-prescribed with an anti-inflammatory drug (23).
References
1. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial respiratory tract in patients with asthma. Am Rev Respir Dis 1985; 131: 599-606. 2. Beasley R, Roche WR, Roberts JA, Holgate ST. Cellular events in the bronchi in mild asthma after bronchial provocation. Am Rev Respir Dis 1989; 139:806-817. 3. Jeffery PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial biopsies in asthma: an ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 1989; 140: 1745-1753. 4. Barnes PJ. New concepts in the pathogenesis of bronchial hyperresponsiveness and asthma. J Allergy Clin Immunol 1989; 83: 1013-1026. 5. Brown JP, Greville WH, Finucane KE. Asthma and irreversible airflow obstruction. Thorax 1984; 39: 131136. 6. Peat JK, Woolcock AJ, Cullen K. Rate ofdecline of lung function in subjects with asthma. Eur J Respir Dis 1987; 70: 171-179. 7. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1989; i: 520-524. 8. Barnes PJ. A new approach to asthma therapy. N Engl J Med 1989; 321: 1517-1527. 9. Reed CE. Aerosol glucocorticoid treatment of asthma: adults. Am Rev Respir Dis 1990; 140: $82-$88. 10. Barnes PJ. Effect of corticosteroids on airway hyperresponsiveness. Am Rev Respir Dis 1990; 140: $70-$76. 1I. Toogood JH, Baskerville J, Jennings B. Use of spacers to facilitate inhaled corticosteroid treatment of asthma. Am Rev Respir Dis 1984; 129: 723-729. 12. Bone MF, Kubik MM, Keaney NP et al. Nedocromil sodium in adults with asthma dependent on inhaled corticosteroids in a double-blind, placebo-controlled study. Thorax 1989; 44: 654-659.
Preventative therapy in asthma 13. Bergmann KC, Bauer CP, Overlack A. A placebo controlled blind comparison of nedocromil sodium and beclomethasone dipropriate in bronchial asthma. Curr Med Res Opin 1989; I I: 533-542. 14. Thomson NC. Nedocromil sodium: an overview. Respir Med 1989; 83: 269-276. 15. Beasley R, Cushley M, Holgate ST. A self management plan in the treatment of adult asthma. Thorax 1989; 44: 200-204. 16. Mullarkey MF, Blumenstein BA, Mandrade WP, Bailey GA, Olason I, Wetzel CE. Methotrexate in the treatment ofcorticosteroid-dependent asthma. N Engl J Med 1988; 318: 683-687. 17. Shiner R J, Nunn A J, Chung KF, Geddes DM. Randomized, double-blind, placebo-controlled trial of methotrexate in steroid-dependent asthma. Lancet 1990; 336: 137-140. 18. Cockroft DW, Murdoch KY. Comparative effects of inhaled sabutamol, sodium cromoglycate and BDP on allergen-induced early asthmatic responses, late asthmatic responses and increased bronchial responsiveness to histamine. J Allergy Clin lmmuno11987; 79: 734-740.
357
19. Kraan J, Koeter GH, Van der Mark TW, Sluiter H J, De Vries K. Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesohide and terbutaline. J Allergy Clin tmmunol 1985; 76: 628-636. 20. Kerrebijn KF, Von Essen-Zandvliet EEM, Neijens HJ. Effect of long-term treatment with inhaled corticosteroids and beta-agonists on bronchial responsiveness in asthmatic children. JAllergy Clin Immuno11987; 79: 653-659. 21. Cockroft DW, Murdock KY, Gore BP, O'Byrne PM, Manning P. Theophylline does not inhibit allergeninduced increase in airway responsiveness to methacholine. J Allergy Clin Immuno11991; 83: 913-920. 22. Dutoit JI, Salome CM, Woolcock AJ. Inhaled corticosteroids reduce the severity of bronchial hyperresponsiveness in'asthma, but oral theophylline does not. Am Rev Respir Dis 1987; 136:1174-1178. 23. Rabe KF, Chung KF. The challenge of long-acting fl-adrenoceptor agonists. Respir Med 1991; 85: 5-10.
Preventative therapy in adults with asthma P. J. BARNES
National Heart and Lung Institute, London SW3, U.K.
Asthma as an Inflammatory Disease
Asthma is a chronic inflammatory condition of the airways, which is characterized by infiltration of inflammatory cells (predominantly eosinophils and Tlymphocytes), plasma exudation and oedema, hypertrophy of smooth muscle and shedding of epithelium. Features of inflammation are present even in mild asthmatics when the patient may have few symptoms (1-3). The precise role of the different inflammatory cells and the mediators they release is not yet certain, and it is likely that they may differ from patient to patient, and in the same patient at different times (4). The mechanisms by which the airway develops inflammation in asthma are uncertain, but appear to be linked to allergen exposure in many patients. The consequences of inflammation are the development o fairway hyperresponsiveness, in which airways narrow too readily to a wide range of provoking stimuli (triggers), resulting in asthma symptoms. Inflammation of the airways may also directly lead to symptoms (e.g. cough and chest tightness) through activation of sensory nerves. Chronic inflammation may also lead to irreversible airflow obstruction, which is well recognised in poorly controlled asthmatics (5,6). This may be the result of airway smooth muscle hyperplasia or of subepithelial fibrosis (7).
but they suppress inflammation at every step (9,10). Steroids inhibit eosinophil infiltration into tissues, inhibit release ofcytokines in lymphocytes and macrophages, inhibit release of mediators from macrophages and eosinophils, reduce tissue mast cell content and inhibit microvascular leakage in airways.
Inhaled Steroids
When given by inhalation steroids are effective, well tolerated and have minimal side-effects in adults and children. Local side-effects include oral thrush and dysphonia, which are related to oropharyngeal deposition of the steroid. Large volume spacers (Nebuhaler, Volumatic, Aerochamber) markedly cut down oropharyngeal deposition and decrease systemic effects of inhaled steroids (I 1), and such a device should be considered when the use of inhaled steroids exceeds 800 pg day- ~. Systemic side-effects and adrenal suppression are unusual below doses of 1500 pg day- i. Inhaled steroids should be given twice daily when asthma is under control (although four times daily dosing may be preferable until control is achieved). Inhaled steroids should be introduced when asthma symptoms occur daily, or when there are nocturnal symptoms. Perhaps the need for a bronchodilator inhaler more than once daily is sufficient indication.
Anti-inflammatory Treatment Cromoglycate and Nedocromil Sodium
Since asthma is primarily an inflammatory condition it follows that a logical approach to treatment is to suppress this inflammatory response. This will lead to control of other symptoms and, in the long-term, this may reduce the decline in lung function with time and the risk of death. Anti-inflammatory treatments should therefore be introduced much earlier in the disease (8). Corticosteroids are by far the most effective antiinflammatory therapy available, since they work in most patients with asthma. Indeed, objective improvement in lung function and of symptoms after steroids is the hallmark of asthma. The precise mechanisms by which steroids work in asthma is not yet certain, 0954-6111/91/090355 + 03 $03.00/0
Cromoglycate is less useful than inhaled steroids, since it is only effective in a proportion of adult patients with mild asthma, and the response cannot be predicted on clinical grounds. It is often introduced in children because it has a proven safety record, but has the relative disadvantage that it must be taken four times daily. It provides equivalent symptom control to low dose inhaled steroids (less than 500pg daily), which are safe to use even in children. Cromoglycate is sometimes useful in preventing exercise-induced asthma in the few patients who fail to have it prevented by inhaled fl-agonists. © 1991 Baillirre Tindall
356
P. J. B a r n e s
Nedocromil sodium is somewhat more potent than cromoglycate in experimental asthma challenge studies, and in a dose of 4 mg qds may have a similar prophylactic effect to low dose inhaled steroids (12,13). As it has no obvious advantages, its place in clinical management is not yet clear (14), although it may be useful in patients who are unwilling to use inhaled steroids or in whom the local side-effects of inhaled steroids are a problem (despite the use of a spacer). Ketotifen
Ketotifen is claimed to have prophylactic effects in asthma but there are no convincing controlled trials which have demonstrated clinically useful effects and, therefore, it has no current place to play in the prophylaxis of asthma. Oral Steroids
Oral steroids must be kept to the minimal dose necessary in order to avoid side-effects. Short courses of oral steroids (prenisolone 30--40 mg d a y - ~ for 1-3 weeks) are used to treat acute exacerbations, sometimes to establish control of asthma before starting inhaled steroids, and to detect asthma in patients with chronic 'irreversible' airflow obstruction. Courses of oral steroids may be self-administered by patients according to a written action plan, and there is evidence that this improves control of asthma and reduces the need for hospital admission (15). Chronic (maintenance) oral steroids should be kept to the lowest dose possible and should only be used when patients have been treated with high dose inhaled steroids (up to 2 mg daily) and have had a trial of theophylline and anticholinergic therapy. Relatively few patients now require oral steroids to control their asthma. Alternate day dosing may reduce side-effects but it is not always as effective. Methotrexate
Immunosuppressants such as methotrexate may have a steroid-sparing effect and may be equivalent to 5-10 mg prednisolone (16,17). Methotrexate (15 mg orally per week) should be considered only when oral steroids are producing problems (e.g. osteoporosis in post-menopausal women, and patients with diabetes). Haematology and liver function should be monitored closely. Bronehodilators as Preventive Treatment
While bronchodilators, such as fl2-agonists, theophylline and anticholinergic drugs, may relieve symptoms of asthma (largely by reducing airway smooth
muscle contraction), there is little to suggest that they modify the chronic inflammation and bronchial hyperreactivity. Thus, conventional fl-agonists have no effect on the late response to allergen, or the increased reactivity which follows allergen (18), nor do they reduce bronchial hyperresponsiveness in asthmatic patients (19,20). Similarly, theophylline fails to prevent allergen-induced hyperreactivity or to reduce asthmatic hyperresponsiveness (21,22). This suggests that bronchodilators used alone may be potentially harmful, since they may "mask' the underlying inflammatory response, particularly when taken frequently and in high doses (e.g. by nebulizer). Salmeterol has recently become available and another long-acting fl2-agonist (formoterol) is already available in some countries. Whether they have any anti-inflammatory effect not shown by the other bronchodilators is not yet certain, but perhaps they should at first be treated with caution and should always be co-prescribed with an anti-inflammatory drug (23).
References
1. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial respiratory tract in patients with asthma. Am Rev Respir Dis 1985; 131: 599-606. 2. Beasley R, Roche WR, Roberts JA, Holgate ST. Cellular events in the bronchi in mild asthma after bronchial provocation. Am Rev Respir Dis 1989; 139:806-817. 3. Jeffery PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial biopsies in asthma: an ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 1989; 140: 1745-1753. 4. Barnes PJ. New concepts in the pathogenesis of bronchial hyperresponsiveness and asthma. J Allergy Clin Immunol 1989; 83: 1013-1026. 5. Brown JP, Greville WH, Finucane KE. Asthma and irreversible airflow obstruction. Thorax 1984; 39: 131136. 6. Peat JK, Woolcock AJ, Cullen K. Rate ofdecline of lung function in subjects with asthma. Eur J Respir Dis 1987; 70: 171-179. 7. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1989; i: 520-524. 8. Barnes PJ. A new approach to asthma therapy. N Engl J Med 1989; 321: 1517-1527. 9. Reed CE. Aerosol glucocorticoid treatment of asthma: adults. Am Rev Respir Dis 1990; 140: $82-$88. 10. Barnes PJ. Effect of corticosteroids on airway hyperresponsiveness. Am Rev Respir Dis 1990; 140: $70-$76. 1I. Toogood JH, Baskerville J, Jennings B. Use of spacers to facilitate inhaled corticosteroid treatment of asthma. Am Rev Respir Dis 1984; 129: 723-729. 12. Bone MF, Kubik MM, Keaney NP et al. Nedocromil sodium in adults with asthma dependent on inhaled corticosteroids in a double-blind, placebo-controlled study. Thorax 1989; 44: 654-659.
Preventative therapy in asthma 13. Bergmann KC, Bauer CP, Overlack A. A placebo controlled blind comparison of nedocromil sodium and beclomethasone dipropriate in bronchial asthma. Curr Med Res Opin 1989; I I: 533-542. 14. Thomson NC. Nedocromil sodium: an overview. Respir Med 1989; 83: 269-276. 15. Beasley R, Cushley M, Holgate ST. A self management plan in the treatment of adult asthma. Thorax 1989; 44: 200-204. 16. Mullarkey MF, Blumenstein BA, Mandrade WP, Bailey GA, Olason I, Wetzel CE. Methotrexate in the treatment ofcorticosteroid-dependent asthma. N Engl J Med 1988; 318: 683-687. 17. Shiner R J, Nunn A J, Chung KF, Geddes DM. Randomized, double-blind, placebo-controlled trial of methotrexate in steroid-dependent asthma. Lancet 1990; 336: 137-140. 18. Cockroft DW, Murdoch KY. Comparative effects of inhaled sabutamol, sodium cromoglycate and BDP on allergen-induced early asthmatic responses, late asthmatic responses and increased bronchial responsiveness to histamine. J Allergy Clin lmmuno11987; 79: 734-740.
357
19. Kraan J, Koeter GH, Van der Mark TW, Sluiter H J, De Vries K. Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesohide and terbutaline. J Allergy Clin tmmunol 1985; 76: 628-636. 20. Kerrebijn KF, Von Essen-Zandvliet EEM, Neijens HJ. Effect of long-term treatment with inhaled corticosteroids and beta-agonists on bronchial responsiveness in asthmatic children. JAllergy Clin Immuno11987; 79: 653-659. 21. Cockroft DW, Murdock KY, Gore BP, O'Byrne PM, Manning P. Theophylline does not inhibit allergeninduced increase in airway responsiveness to methacholine. J Allergy Clin Immuno11991; 83: 913-920. 22. Dutoit JI, Salome CM, Woolcock AJ. Inhaled corticosteroids reduce the severity of bronchial hyperresponsiveness in'asthma, but oral theophylline does not. Am Rev Respir Dis 1987; 136:1174-1178. 23. Rabe KF, Chung KF. The challenge of long-acting fl-adrenoceptor agonists. Respir Med 1991; 85: 5-10.