Use of Inhaled Corticosteroids in Pediatric Asthma

Pediatric Pulmonology, Supplement 15:27 33 (1997) Use of Inhaled Corticosteroids in Pediatric Asthma Hans Bisgaard, MD* Summary. Inhaled corticosteroids reduce asthma symptoms and exacerbations, improve lung function, and reduce airway inflammation and bronchial hyperreactivity more effectively than other treatments. However, inhaled corticosteroids may be unable to return lung function and bronchial hyperreactivity to normal when introduced for moderately severe asthma. This finding highlights the need to improve treatment strategy in pediatric asthma. The natural progression of persistent asthma may lead to loss of lung function and chronic bronchial hyperreactivity for children and adults. There is evidence to suggest that asthma acts via a chronic inflammatory process that causes remodeling of the airways with mucosal thickening and smooth muscle hypertrophy. An optimal treatment strategy would be one aimed at reducing the ongoing airway inflammation. Inhaled steroids ameliorate the inflammation, whereas this has not been documented for any other treatment. Delayed introduction of inhaled steroids appears to result in reduced improvement in lung function compared with the early use of inhaled steroids. This improved response from the earlier use of inhaled steroids appears to be valid at any stage of the disease. Therefore, a change in treatment strategy toward earlier introduction of corticosteroids may impede airway remodeling, bronchial hyperreactivity, and airway damage. No other treatment has been found to affect the course of the disease. Systemic side-effects, particularly inhibition of growth in asthmatic children using inhaled corticosteroids, do not seem to be cause for concern. Growth retardation has not been reported when inhaled corticosteroid doses of 400 µg daily are individually tailored to each child s needs. The ongoing change in treatment strategy toward the earlier use of inhaled steroids in childhood asthma, as reflected in current revisions of various treatment strategies, therefore seems well founded. Pediatr. Pulmonol. 1997; Supplement 15:27 33. 1997 Wiley-Liss, Inc. Key words: pediatric asthma; inhaled corticosteroids; beneficial effects; treatment guidelines. INTRODUCTION Revisions of the various international treatment strategies have gradually changed the attitude toward early use of inhaled steroids to emphasize their early introduction in childhood asthma. This development seems to be well founded in controlled trials and possibly may be developed even further. SYMPTOM CONTROL 1997 Wiley-Liss, Inc. Comparative studies of inhaled corticosteroids and other treatments indicate that inhaled corticosteroids are more effective at reducing asthma symptoms and exacerbations, improving lung function, and reducing bronchial reactivity in children with asthma (irrespective of severity). Inhaled corticosteroids have been shown to be more effective than sodium cromoglycate, 1,2 theophylline, 3 short- 4 and long-acting 2 -agonists 5, as well as combinations of nonsteroidal treatments. 6 Such superior effects were obtained with low-to-moderate doses of inhaled steroid. No controlled clinical studies have found any other drug to be more effective than inhaled steroids in controlling asthma morbidity. If control of disease is considered to be the control of asthma symptoms, improved lung function with minimized morbidity, and reduced number of exacerbations, this control is reliably obtained by inhaled steroids at any stage of the disease. DISEASE CONTROL Control of the disease may also be considered in terms of control of the underlying disease process. Can inhaled steroids also control the underlying disease process at any stage of disease? This question has been indirectly addressed in a Dutch study designed to compare the efficacy of inhaled steroids versus regular inhalation of a 2 -agonist. The effect of 22 months BUD treatment (200 g, three times daily) on lung function was compared with that of placebo in 116 children aged 7 16 years old with moderate asthma. 4 The children receiving BUD had significantly fewer asthma symptoms, better Department of Pediatrics, National University Hospital, Copenhagen, Denmark. *Correspondence to: Dr. Hans Bisgaard, Department of Paediatrics, National University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: bisgaard@rh.dk

28 Bisgaard lung function, and less bronchial reactivity compared with placebo. However, this study also ascertained that after 22 months of inhaled corticosteroid therapy lung function had returned to normal in only 40% of children. Similarly, bronchial reactivity only returned to the normal range in 26% of children receiving inhaled corticosteroid therapy. In a separate study the effect of 12 week s treatment with inhaled fluticasone propionate 100 g twice daily was compared with placebo in 307 adult asthma patients with moderate asthma. Fluticasone propionate improved asthma symptoms and lung function, and reduced use of rescue medication. However, the percentage of patients who achieved normal lung function (>85% of predicted) was 10% in the placebo group compared with 28% in the fluticasone propionate group. 7 Based on such evidence, inhaled steroids would seem to be unable to revert lung function and bronchial reactivity to normal if introduced late during the course of the disease. These studies document the efficacy of inhaled corticosteroids in controlling morbidity of childhood asthma, but raise the questions of why does bronchial hyperreactivity persist in children with moderately severe asthma even after long-term treatment with efficient steroid therapy, and why does lung function not return to normal? Irrespective of how efficient inhaled steroids are at controlling asthma morbidity, they may not always be able to affect the underlying pathophysiology. It is possible that the lack of effect of inhaled steroids may be the result of abnormalities of airway function that precede the onset of wheezing. 8,9 Narrower airways during childhood may increase the risk of developing asthma. This theory would imply that reduced lung function was a cause rather than a consequence of the asthma; hence, the condition may persist independent of asthma symptoms. An alternative explanation could be that despite control of symptoms, underlying inflammation could cause persistent airway narrowing. Evidence of persistent inflammation despite inhaled corticosteroid therapy has been reported. 10 A third possible explanation could be that the disease process itself has caused irreversible airway damage with permanent ventilatory deficit and bronchial hyperreactivity. It is possible that the suboptimal response to inhaled steroids (in terms of persistently reduced lung function and bronchial hyperreactivity) is caused by a delay in antiinflammatory treat-ment, which allows uncontrolled airway inflammation to cause airway damage Abbreviations BDP Beclomethasone dipropionate BUD Budesonide FEF 25 75 Forced expiratory flow in the middle section of the forced vital capacity FEV 1 Forced expiratory volume in 1 second during the early stages of the disease. This finding would call for reappraisal of the positioning of inhaled steroids as second-line treatment in the present treatment strategy, and would suggest earlier introduction of treatment. IRREVERSIBLE AIRWAY OBSTRUCTION FROM PERSISTENT ASTHMA The natural course of persistent asthma may lead to irreversible airflow obstruction both in children and in adults. Retrospective studies have reported reduced lung function in symptom-free adults and adolescents with a history of asthma in childhood but no symptoms during recent years (compared with age-matched controls), 11 14 although sequelae seem to disappear in adults remaining free of symptoms and medication since childhood. 15 17 Asthmatic children with persistent asthma into adulthood have baseline lung function that is worse than healthy age-matched controls. In a short-term, prospective study, Backer and Ulrik 18 reported significantly reduced lung growth in asthmatic children. A Dutch longitudinal study of adolescents monitored lung function in 269 teenagers every 6 months between 1978 and 1985, and reported a persistent reduction in FEV 1 of 0.2 L in males who reported prepuberty respiratory symptoms (this probably includes asthma, bronchitis, and pneumonia). 19 Spirometry measurements have been found to worsen over time among children with persistent wheezing, 17,18 bronchial hyperreactivity, 20 or asthma. 21 In the latter study, 21 it could be predicted that a female who developed asthma at the age of 7 years would experience a 7% deficit in lung function by 15 years of age. The Melbourne cohort 18,19 followed 247, randomly selected, 7-year-old children over 3 decades. Reduced lung function was found in children with persistent wheezing, and this correlated with the degree of wheezing. In addition, the resting airway obstruction in these asthmatic children increased with age. A prospective cohort of 10,792 children, aged 6 to 18 years, was examined annually between 1974 and 1989 in six United States cities. FEV 1 values were 6% lower, and FEF 25 75 values were 17% lower, in white asthmatics with current symptoms. 22 Martinez and coworkers 8 studied 120 randomly selected infants during the first 6 years of life, and found a significantly reduced increase in lung function in those with persistent wheezing, and this approximated to 14% of the cohort. These findings would suggest that airway damage can result from persistent wheezing symptoms during childhood. Considering the prevailing treatment strategy in these studies, it is likely that the outcome reflects that of steroid-naive asthma patients. These childhood studies are in agreement with the findings of an increased rate of decline of FEV 1 found in adult asthmatics compared with

Inhaled Corticosteroids in Pediatric Asthma 29 healthy controls. 23 Furthermore, this decline is most pronounced in those patients with the greatest degree of airflow obstruction, 24 and with the greatest loss of lung function during the early years after diagnosis. 25 A recent study in Holland compared the outcome of treatment with inhaled BDP (200 g twice daily) with that of salmeterol (50 g twice daily) for 1 year in children with mild-to-moderate asthma. 5 The improvement in lung function, decrease in bronchial reactivity, and decrease in number of exacerbations were all significantly greater for the inhaled BDP group compared with the salmeterol group. It is interesting to note that over the 1-year observation period, the control group exhibited a reduction in FEV 1 as well as increased bronchial reactivity. It has been suggested that regular 2 -agonist therapy may cause deterioration of asthma, 26,27 but this is disputed, and the development may rather reflect deterioration of the uncontrolled airway inflammation. 28 What is clear from these studies is that if asthma is not controlled it may lead to airway damage. AIRWAY INFLAMMATION There is evidence to suggest that the disease acts through a chronic inflammatory process, with thickening of the basal membrane and smooth muscle hyperplasia and hypertrophy causing airway remodeling. Bronchial hyperreactivity may be the result of such airway remodeling and may serve as a surrogate marker for the disease process. Several independent research groups have documented the features of chronic inflammation in the airways of newly diagnosed, steroid-naive, mild asthmatic adults. 29 32 There is severe damage of the airway epithelium with areas of denudation and areas of regeneration, and the ratio of normal ciliated cells:goblet cells is decreased. Generalized significant edema and severe submucosal inflammation predominates, with an intense inflammatory reaction comprised of activated eosinophils, lymphocytes, plasma cells, and degranulated mast cells. Consistent features include thickening of the reticular membrane, hyperplasia, and hypertrophy of the bronchial smooth muscle and the mucous glands. In addition, collagen accumulates in the submucosa in asthma patients compared with normal controls. 33 Such irreversible structural changes seem to develop early in the course of the disease. 32 Basement membrane thickening has been described in asthmatic children, 34 and shortly after onset of asthma. 35 Inhaled corticosteroids restore airway epithelium to normal and reduce the number of cells involved in inflammation; hence, these drugs have a disease modifying effect. In contrast, bronchodilator treatment reduces the symptoms but has no effect on the underlying inflammation. 29 31 Cromones have also never been documented to modify airway inflammation. The thickened basement membrane reticular collagen cannot be reversed by inhaled corticosteroid treatment. 30 31 This remodeling of the airways may reflect the irreversible airway damage previously discussed, which would point to the necessity of earlier preventative treatment. EARLY INTERVENTION Haahtela et al. 36 examined the effect of delayed intervention with inhaled corticosteroids in 74 adults with mild asthma. Subjects were randomized to receive either an inhaled corticosteroid or a 2 -agonist for 2 years. After this period, those patients receiving the 2 -agonist received the same inhaled corticosteroid treatment as the other group. Comparison of the two treatment groups revealed that those who were first treated with a 2 - agonist for 2 years, and only subsequently treated with BUD, did not reach the same level of lung function and improved bronchial hyperreactivity within the third year as those who were treated with BUD from the beginning of the study had obtained during the initial study year. Overbeck et al. 37 reported similar findings in adult patients who had asthma for a long period of time and found that the potential for inhaled steroid treatment to improve bronchial responsiveness was impaired in patients in whom treatment was delayed by 2 years. In a 25-year follow-up study of young adult asthma patients, 21% had outgrown their bronchial hyperresponsiveness. 38 Absence of bronchial hyperresponsiveness after 25 years was significantly associated with a shorter period between onset of asthma symptoms and specialized treatment of the disease. Patients with mild symptoms treated only with bronchodilators as needed exhibited a significant worsening in spirometry measurements compared with patients with severe asthma treated with an inhaled steroid, as reported in a recent retrospective uncontrolled analysis of data from chart reviews. 39 This finding may substantiate the deteriorating course of uncontrolled asthma and suggest that anti-inflammatory treatment should be started earlier. Delay in starting sodium cromoglycate, but not inhaled corticosteroids, had a negative effect on both clinical outcome and pulmonary function. This finding suggests treatment with sodium cromoglycate should be started early, but the findings need to be interpreted with caution based on the retrospective nature of the report. In a controlled prospective study, the lung function of 216 asthmatic children, whose asthma history was well documented, was determined at 6-month intervals for 1 2 years before the study and 3 6 years after commencing treatment with an inhaled 2 -agonist and an inhaled corticosteroid. 6 After 3 years of treatment with an inhaled corticosteroid, children who started this therapy more than 5 years after the onset of symptoms had a

30 Bisgaard significantly reduced improvement in FEV 1 compared with those children who received the inhaled corticosteroid within the first 2 years after the onset of asthma. The group who received the inhaled corticosteroid therapy early after the onset of asthma were younger than the group who received therapy after a prolonged disease period. However, the negative correlation between the response to treatment and the years since onset of asthma was still present within a more narrow grouping of the children, according to delay of steroid treatment. These findings suggest that earlier intervention with inhaled corticosteroids may prevent airway damage that might otherwise occur during the course of childhood asthma. A similar study in adults with asthma reported the same negative correlation between time between onset of symptoms and start of steroid treatment and improvement in FEV 1. 40 Thus, it would appear that structural changes are more difficult to reverse once they have occurred than they are to prevent with prophylactic therapy. The additional ability of inhaled corticosteroids to modify the course of the disease and prevent airway damage would, therefore suggest, they should be used as first-line therapy in chronic asthma. HOW EARLY IS EARLY? The concept of early intervention should not be misinterpreted as a strategy to introduce inhaled corticosteroids at the first sign of wheeze in small children with very mild episodic disease. 41 To date, there is insufficient data on the development of asthma and the disease modifying effect of inhaled steroids to recommend such a radical approach, and it is not known whether the natural course of mild asthma is to develop into severe asthma, which could call for such an aggressive approach. All studies on early intervention have been conducted in secondary or tertiary referral centers, and in most studies asthma had been established for some years. However, the same conclusion seems to emerge irrespective of the stage of the disease studied: in persistent asthma early intervention achieves better results compared with delayed intervention. In the clinic it is not possible to separate patients with a self-limiting course of asthma symptoms from those who will continue to have persistent asthma symptoms. Finally, even children with a good prognosis should have the optimal treatment in the meantime. Therefore, it seems logical to start all asthmatic children on inhaled steroids as soon persistent asthma symptoms appear, provided there is a continuous attempt to taper down the dose (Fig. 1). Such continuous downtitration of the minimal effective dose required to maintain the patient free of symptoms should mean that treatment is stopped in those who outgrow asthma, whereas those with persistent asthma will continue on inhaled Fig. 1. Titrating inhaled corticosteroids to the minimum effective dose, based on peak expiratory flow (PEF) or symptoms. steroids at the minimal effective dose allowing the treatment to modify the course of the disease. The revisions of the international treatment strategy guidelines have clearly moved toward the increasingly earlier use of inhaled steroids, and it is possible that this progression has not come to an end. SAFETY OF INHALED CORTICOSTEROIDS In children, clinical side-effects of inhaled corticosteroids primarily focus on the risk of growth retardation. Children with mild, infrequent, episodic asthma should not receive regular treatment with inhaled steroids, as effectiveness has not been documented and reduced growth rate may occur. In a recent study, such a group of children was treated with a moderately high dose of inhaled steroid. Inhaled steroids had no effect on their normal lung function but did stunt growth, 42 confirming that children not requiring regular inhaled steroids may experience side-effects of such overtreatment. It is not justified to extrapolate the findings of studies of side-effects in subjects without established asthma to the risk of treating children with established asthma. In studies examining the systemic activity of inhaled steroids, healthy subjects had more pronounced adrenal suppression than asthma patients. 43 46 This finding may be the result of a reduced lung dose, a reduced absorption, or an increased susceptibility of asthma patients compared with healthy controls. It is important to note that many chronic diseases, including asthma, may themselves reduce the growth rate of children, and a significant relationship between inhibition of growth and asthma severity has been reported. 6,47 It is, therefore, important to emphasize the need for individualized tailored dosing in the use of inhaled steroids. The majority of asthmatic children achieve a final height in the normal range. 48 In a metaanalysis of 21 studies composed of 810 asthmatic children using inhaled corticosteroids to control asthma

Inhaled Corticosteroids in Pediatric Asthma 31 for the children being studied. Growth retardation has not been reported from tailored corticosteroid doses of 400 g daily. 6 CONCLUSION Fig. 2. Dose response curves for the therapeutic effect and systemic activity of increasing doses of inhaled corticosteroid. symptoms and exacerbations, it was concluded that inhaled corticosteroids did not adversely affect their final height. 49 This does not, however, exclude the possibility of increased susceptibility of certain individuals. Therefore, it is important to monitor growth as well as using the minimum effective dose. The optimal clinical effects of inhaled corticosteroids are obtained in the majority of children with mild to moderate asthma with doses ranging from 100 200 g daily, depending on the steroid and the inhalation device used. 1,50,51 Increases in dose are not accompanied by proportional increases in effect, but increasing doses do result in increased systemic bioavailability (Fig. 2). 52,53 Our treatment approach is, therefore, to start with a high dose for a short period to establish clinical control (induction therapy), 54 and then titrate the dose down, often stopping treatment to establish whether the child requires regular inhaled corticosteroid treatment. Loss of control is followed by increasing the titrated dose to one that controls the asthma (maintenance therapy). Such a lowdose strategy is probably at the expense of patients experiencing more exacerbations than when on a continuous high-dose strategy, but allows for the inclusion of short bursts of high doses for exacerbations (relapse therapy) and means the overall use of steroids is minimized. In conclusion, there is no universal dose for a child; the dose for each child has to be individually and continuously titrated. Clinical studies examining the risk of growth retardation in children receiving inhaled corticosteroids should determine the potential risk of this side-effect only after the minimally effective steroid dose has been individually tailored. Controlled trials reporting growth retardation have frequently used doses that appear inappropriate It would appear that asthma acts via a chronic inflammatory process resulting in mucosal thickening and airway remodeling. Hence, an optimal treatment strategy is one aimed at reducing ongoing airway inflammation. Low-dose inhaled corticosteroids reduce asthma symptoms and exacerbations, improve lung function, and reduce airway inflammation and bronchial hyperreactivity more effectively than any other treatment. Uncontrolled asthma may lead to irreversible loss of lung function and increased bronchial hyperreactivity, of which both can be ameliorated by earlier corticosteroid treatment. In moderately severe asthma, airway damage that is not reversible has often occurred. However, further progression is usually stopped by inhaled corticosteroids. There are no controlled data published to suggest that control of inflammation can be obtained by any other treatment, including cromones. Therefore, a change in treatment strategy toward the earlier introduction of corticosteroids may prevent airway remodeling, bronchial hyperreactivity, and airway damage. Inhaled corticosteroids do have some systemic activity, and concern over systemic sideeffects in children focuses on possible growth retardation. However, growth retardation has not been reported when individually tailored inhaled corticosteroid doses of 400 g daily are used. Furthermore, evidence is accumulating in support of the on-going change in treatment strategy for persistent childhood asthma to one of earlier use of inhaled steroids. REFERENCES 1. Price JF, Weller PH. Comparison of fluticasone propionate and sodium cromoglycate for the treatment of childhood asthma (an open parallel group study). Respir Med. 1995; 89:363 368. 2. Edmunds AT, Goldberg RS, Duper B, Devichand P, Follows RM. A comparison of budesonide 800 g and 400 g via Turbohaler with disodium cromoglycate via Spinhaler for asthma prophylaxis in children. Br J Clin Res. 1994; 5:11 23. 3. Meltzer EO, Orgel HA, Ellis EF, Eigen HN, Hemstreet MP. Longterm comparison of three combinations of albuterol, theophylline, and beclomethasone in children with chronic asthma. J Allergy Clin Immunol. 1992; 90:2 11. 4. van Essen-Zandvliet E, Hughes MD, Waalkens HJ, Duiverman EJ, Pocock SJ, Kerrebijn KF. Effects of 22 months of treatment with inhaled corticosteroids and/or beta-2-agonists on lung function, airway responsiveness, and symptoms in children with asthma. The Dutch Chronic Non-specific Lung Disease Study Group. Am Rev Respir Dis. 1992; 146:547 554. 5. Verberne AAPH, Frost C, Bogaard JM, Kerrebijn KF. One year treatment with salmeterol compared to inhaled corticosteroid in children with mild to moderate asthma (abstract). Am J Respir Crit Care Med. 1996; 153:A408.

32 Bisgaard 6. 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. 7. Scheffer AL, LaForce C, Chervinsky P, Pearlman D, Schaberg A. Fluticasone propionate aerosol: efficacy in patients with mild to moderate asthma. J Fam Pract. 1996; 42:369 375. 8. Martinez FD, Wright AL, Taussig LM, Holberg C, Halonen M, Morgan WJ, and the Group Health Medical Associates. Asthma and wheezing in the first six years of life. N Engl J Med. 1995; 332:133 138. 9. Tager IB, Hanrahan JP, Tosteson TD, Castille RG, Brown RW, Weiss ST, Speizer FE. Lung function, pre- and post-natal smoke exposure, and wheezing in the first year of life. Am Rev Respir Dis. 1993; 147:811 817. 10. Sont JK, Han J, van Krieken JM, Evertse CE, Hooijer R, Willems LN, Sterk PJ. 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. 11. Burrows B, Knudson RJ, Lebowitz MD. The relationship of childhood respiratory illness to adult obstructive airway disease. Am Rev Respir Dis. 1977; 115:751 760. 12. Kerribijn KF, Fioole AC, van Bemtveld RDW. Lung function in asthmatic children after a year or more with out symptoms or treatment. Br Med J. 1978; i:886 888. 13. Cade JF, Pain MC. Pulmonary function during clinical remission of asthma. How reversible is asthma? Aust N Z J Med. 1983; 3:545 551. 14. Mosfeldt-Laursen E, Kaae-Hansen K, Backer V, Bach-Mortensen N, Prahl P, Koch C. Pulmonary function in adolescents with childhood asthma. Allergy. 1993; 48:267 272. 15. Godden DJ, Ross S, Abdalla M, McMurray D, Douglas A, Oldman D, Friend JAR, Legge JS, Douglas JG. Outcome of wheeze in childhood. Am J Respir Crit Care Med. 1994; 149:106 112. 16. Martin AJ, Landau LI, Phelan PD. Lung function in young adults who had asthma in childhood. Am Rev Respir Dis. 1980; 122: 609 616. 17. Kelly WJ, Hudson I, Raven J, Phelan PD, Pain MC, Olinsky A. Childhood asthma and adult lung function. Am Rev Respir Dis. 1988; 138:26 30. 18. Backer V, Ulrik CS. Development of lung function in relation to increased degree of bronchial responsiveness. J Asthma. 1992; 29:331 341. 19. Borsboom GJJM, van Pelt W, Quanjer PH. Pubertal growth curves of ventilatory function: relationship with childhood respiratory symptoms. Am Rev Respir Dis. 1993; 147:372 378. 20. Sherrill D, Sears MR, Lebowitz MD, Holdaway MD, Hewitt CJ, Flannery EM, Herbison GP, Silva PA. The effects of airway hyperresponsiveness, wheezing and atopy on longitudinal pulmonary function in children: a 6-year follow-up study. Pediatr Pulmonol. 1992; 13:78 85. 21. Weiss ST, Tosteson TD, Segal MR, Tager IB, Redline S, Speizer FE. Effects of asthma on pulmonary function in children. Am Rev Respir Dis. 1992; 145:58 64. 22. Gold DR, Wypij D, Wang X, Speizer FE, Pugh M, Ware JH, Ferris BG, Dockery DW. Gender- and race-specific effects of asthma and wheeze on level and growth of lung function in children in six US cities. Am J Respir Crit Care Med. 1994; 149: 1198 1208. 23. Peat JK, Woolcock, Cullen K. Rate of decline of lung function in subjects with asthma. Eur J Respir Dis. 1987; 70:171 179. 24. Ulrik 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. 25. Ulrik CS, Lange P. Decline of lung function in adults with bronchial asthma. Am J Respir Crit Care Med. 1994; 150:629 634. 26. Sears MR, Taylor DR, Print CG, Lake DC, Li QQ, Flannery EM, Yates DM, Lucas MK, Herbison GP. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet. 1990; 336:1391 1396. 27. van Schayck CP, Graafsma SJ, Visch MB, Dompeling E, van- Weel C, van Herwaarden CL. Increased bronchial hyperresponsiveness after inhaling salbutamol during 1 year is not caused by subsensitization to salbutamol. J Allergy Clin Immunol. 1990; 86:793 800. 28. McFadden ER Jr. The beta 2-agonist controversy revisited. Ann Allergy Asthma Immunol. 1995; 75:173 176. 29. Laitinen LA, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroids, budesonide, and a beta 2- agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial. J Allergy Clin Immunol. 1992; 97:32 42. 30. Jeffery PK, Godfrey RW, Adelroth E, Nelson F, Rogers A, Johansson SA. Effects of treatment on airway inflammation and thickening of basement membrane reticular collagen in asthma. A quantitative light and electron microscopic study. Am Rev Respir Dis. 1992; 145:890 899. 31. Djukanovic R, Wilson JW, Britten KM, Wilson SJ, Walls AF, Roche WR, Howarth PH, Holgate ST. Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis. 1992; 145:669 674. 32. Laitinen LA, Laitinen A, Haahtela T. Airway mucosal inflammation even in patients with newly diagnosed asthma. Am Rev Respir Dis. 1993; 147:697 704. 33. Wilson JW, Li X. The measurement of reticular basement membrane and submucosal collagen in the asthmatic airway. Clin Exp Allergy. 1997; 27:363 371. 34. Cutz E, Levison H, Cooper DM. Ultrastructure of airways in children with asthma. Histopathology. 1978; 2:407 421. 35. Saetta M, DiStefano A, Maestrelli P, DeMarzo N, Milani GF, Pivirotto F, Mapp CE, Fabbri LM. Airway mucosal inflammation in occupational asthma induced by toluene diisocyanate. Am Rev Respir Dis. 1992; 145:160 168. 36. Haahtela T, Jarvinen M, Kava T, Kiviranta K, Koskinen S, Lehtonen K, Nikander K, Persson T, Selroos O, Sovijarvi A, et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med. 1994; 331:700 705. 37. Overbeck SE, Kerstjens HAM, Bogaard JM, Mulder PGH, Postma DS, and the Dutch Chronic Non-specific Lung Disease Study Group. Is delayed introduction of inhaled corticosteroids harmful in patients with obstructive airways disease (asthma and COPD)? Chest. 1996; 110:35 41. 38. Panhuysen CIM, Vonk JM, Koëter GH, Schouten JP, van Altena R, Bleecker ER, Postma DS. Adult patients may outgrow their asthma. Am J Respir Crit Care Med. 1997; 155:1267 1272. 39. König P, Schaffer J. The effect of drug therapy on long-term outcome of childhood asthma: a possible preview of the international guidelines. J Allergy Clin Immunol. 1996; 98:1103 1111. 40. Selroos O, Pietinalho A, Lofroos AB, Riska H. Effect of early vs late intervention with inhaled corticosteroids in asthma. Chest. 1995; 108:1228 1234. 41. Warner JO. Asthma treatment in children and adolescents. Eur Respir Rev. 1997; 7:15 18. 42. Doull IJM, Freezer NJ, Holgate ST. Growth of pre-pubertal children with mild asthma treated with inhaled beclomethasone dipropionate. Am J Respir Crit Care Med. 1995; 151:1715 1719. 43. Derom E, Van Schoor J, Vincken W, Kuybrechts M, Remgård P, Persson M, Pauwels R. A comparison of the systemic activity of two doses of inhaled fluticasone propionate and budesonide in asthmatics patients. Eur Respir J. 1996; 9(Suppl 23):162s. 44. Lönnebo A, Grahnen A, Jansson B, Brundin RM, Ling-Andersson A, Eckernäs SÅ. An assessment of the systemic effects of single

Inhaled Corticosteroids in Pediatric Asthma 33 and repeated doses of inhaled fluticasone dipropionate and inhaled budesonide in healthy volunteers. Eur J Clin Pharmacol. 1996; 49:459 463. 45. Clark DJ, Grove A, Cargill RI, Lipworth BJ. Comparative adrenal suppression with inhaled budesonide and fluticasone propionate in adult asthmatic patients. Thorax. 1996; 51:262 266. 46. Boorsma M, Andersson N, Larsson P, Ullman A. Assessment of the relative systemic potency of inhaled fluticasone and budesonide. Eur Respir J. 1996; 9:1427 1432. 47. Ninan TK, Russell G. Asthma, inhaled corticosteroid treatment, and growth. Arch Dis Child. 1992; 67:703 705. 48. Martin AJ, McLennan LA, Landau LI, Phelan PD. The natural history of childhood asthma to adult life. Br Med J. 1980; 280: 1397 1400. 49. Allen DB, Mullen M, Mullen B. A meta-analysis of the effect of oral and inhaled corticosteroids on growth. J Allergy Clin Immunol. 1994; 93:967 976. 50. MacKenzie CA, Weinberg EG, Tabachnik E, Taylor M, Havnen J, Crescenzi K. A placebo controlled trial of fluticasone propionate in asthmatic children. Eur J Pediatr. 1993; 152:856 860. 51. Pedersen S, Hansen OR. Budesonide treatment of moderate and severe asthma in children: a dose-response study. J Allergy Clin Immunol. 1995; 95:29 33. 52. Geddes DM. Inhaled corticosteroids: benefits and risks (editorial). Thorax. 1992; 47:404 407. 53. Lipworth B. Clinical pharmacology of corticosteroids in bronchial asthma. Pharmacol Ther. 1993; 58:173 209. 54. Haahtela T. Airway remodelling takes place in asthma what are the clinical implications? (editorial). Clin Exp Allergy. 1997; 27: 351 353.