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Inhaled anti-inflammatory therapy in childhood asthma
REVUE FRAN~AISE D'ALLERGOLOGIE
ET D'IMMUNOLOGIECLINIQUE
Inhaled anti-inflammatory therapy in childhood asthma L. LE CLAINCHE, M. LE BOURGEOIS, J. DE BLIC, P. SCHEINMANN
KEY-WORDS: Asthma - Children - Infants - Inhaled corticosteroids - Inflammation.
MOTS-CLt~S: Asthme - Enfants - Nourrissons Corticoides inhalts - Inflammation.
It is widely a c c e p t e d t h a t a s t h m a is an inflammatory disease [ 1]. Inhaled corticosteroids have become established as the mainstay of chronic asthma treatment [2]. The mode of action of corticosteroids and particularly the molecular mechanisms of steroid action are much better understood. The control of asthma is mainly exerted via inhibition of NF-kB [3, 4]. The efficacy and the overall safety of inhaled corticosteroids have recently been emphasized [3, 5,6]. Inhaled corticosteroids are advocated in children with persistent symptoms [7, 8] . Inhaled corticosteroids are also advocated in children with frequent episodic symptoms (equivalent to step 2 of the N I H consensus), w h e n s o d i u m cromoglycate fails to control symptoms, and beta 2 agonists continue to be required more than 3 times a week [7]. The efficacy of inhaled steroids is observed when assessing several o u t c o m e measures : symptom control, normalization of lung function, r e d u c t i o n of airway h y p e r r e s p o n s i v e n e s s ,
m i n i m i z a t i o n o f m o r t a l i t y [9-10] a n d also, possibly, prevention of irreversible airway damage (airway remodelling) [ 11 ]. However several issues remain controversial. C o n c e r n s have been raised a b o u t potential adverse effects of i n h a l e d steroids on bone metabolism and linear growth. In a recent study conducted in 56 prepubertal children with asthma it has been shown that collagen turnover and growth velocyty were reduced by inhaled steroids [12]. This study seems in agreement with a previous study by Doull, et al. which had concluded that even conventional doses of inhaled corticosteroids can decrease statural growth, at least in children with mild asthma [13]. Similar conclusion were given by A. Verberne [14] and FER Simons in their one year studies comparing the efficacy of monotherapy with salmeterol versus beclomethasone dipropionate (200 pg twice daily) [15]. This disturbing studies are at variance with comprehensive meta-analysis [16] and review
Service de Pneumologie et d'Allergologie Ptdiatriques, H6pital des Enfants Malades, PARIS, (France). Correspondence : E Scheinmann. Service de Pneumologie et d'Allergologie Ptdiatriques, Htpital des Enfants Malades, 149 Rue de S~vres, 75743 PARIS Cedex 15 (France). Interasma Marrakech' 98.
LE CLAINCHE L., LE BOURGEOIS L., DE BLIC J., SCHEINMANN R Inhaled anti-inflammatory therapy in childhood asthma. Rev.fr. Allergol., 1998, 38 (7S), $266-$268.
© Expansion Scientifique Publications, 1998
/ INHALED ANTI-INFLAMMATORY THERAPY IN CHILDHOOD ASTHMA •
showing no substantial effect o f i n h a l e d c o r t i c o s t e r o i d s on l o n g - t e r m growth or on biochemical markers of b o n e formation and resorption [17], at least w h e n i n h a l e d c o r t i c o s t e r o i d s are p r e s c r i b e d within their r e c o m m a n d e d dose ranges (i.e., up to 400 p g / day with b u d e s o n i d e or b e c l o m e t h a s o n e dipropionate) [17]. Recent studies have confirmed that growth is normal in children with persistent asthma treated with fluticasone propionate ( 50 and 100 lag twice daily[18] or budrsonide 200 lag twice daily [19]. It was even shown that side effects do not accumulate with length of t r e a t m e n t a n d that i n h a l e d corticosteroids, once started in asthmatic children not controlled on prophylactic sodium cromoglycate, should be continued [19]. Moreover Silverstein et al. have demonstrated that the attained height of asthmatic children treated with (inhaled) corticosteroids was not different from the adult height of children not treated with corticosteroids [20]. The absence of clinically relevant side-effects of conventional doses of ICS reinforces S. Pedersen's therapeutic concepts [9,21]. In children with persistent disease, i.e. in children who require c o n t i n u o u s anti a s t h m a t r e a t m e n t , i n h a l e d corticosteroids should be used as early first line therapy. Provided that the dose is tailored to the severity of the disease, side effects are minimal if any. Children started early have better lung function and lung growth at a lower accumulated dose than children in which treatment with inhaled corticosteroids has been delayed [21, 22]. Pedersen has emphasized that a mean of 4.5 years of treatment with inhaled b u d e s o n i d e at an average daily dose of 504 lag has no detectable adverse effect on total bone mineral density, total bone mineral capacity, total bone calcium, or b o d y c o m p o s i t i o n in children with chronic asthma when the dose is tailored to the severity of the disease [23]. More caution should probably be employed in infants [22]. The dilemna we face with wheezy infants is the risk of overtreating infants who will
$267
show spontaneous recession [22]. On the other hand, epidemiological prospective studies have clearly shown the risk of deterioration in lung fonction in children with early and persistent symptoms [24]. Empirical approach should be to prescribe inhaled corticosteroids to infants with severe persistent symptoms. The efficacy of this approach has been demonstrated with nebulized budesonide in severe infantile asthma [25]. A starting dose of 1 mg twice daily seems to be the correct schedule for the initiation of treatment [26]. Whatever the cause, it is likely that wheezing and dyspnoea reflect chronic airway inflammation, the presence of which is attested by elevated levels of mediators of inflammation and TNF alpha in bronchoalveolar lavage [2%29]. Safety assessed by clinical parameters appears excellent [25]. Bone metabolism was also shown to be normal in infants inhaling a mean of 597 lag of beclomethasone daily during 6 months [30]. In practice, the benefits of early treatment with inhaled corticosteroids are much greater than the putative side effects on growth a n d b o n e metabolism, at least in children with persistent symptoms. Continuous efforts should be made to reduce inhaled corticosteroids to the lowest dose that maintains good control of symptoms and of disease [15,31,32]. With regard to this important paediatric aim, a combination of therapies is probably more desirable than one treatment at a (too) high dose. Convincing data, in adults with asthma have favoured the concurrent use of inhaled corticosteroids and long acting beta 2 agonists [33-37]. It is highly likely that similar results will be obtained in children with persistent severe asthma. In children there is a real need for combination studies of inhaled corticosteroids with antileucotrienes or cromones [36-38]. Finally the main obstacle to an a d e q u a t e m a n a g e m e n t of childhood asthma might well be the non adherence to asthma treatment. In this regard steroid phobia may be one of the biggest p r o b l e m s in the c u r r e n t therapy of asthma [39-41].
REFERENCES
1. Holgate S.T. - The cellular and mediator basis of asthma in relation to natural history. Lancet, 1997, 350 (suppl II), 5-9. 2. Barnes P.J. -Assessment and management of asthma in the future. Eur. Respir. Rev., 19.97, 369-373.
Rev. fr. Allergol., 1998, 38, 7S
3. Barnes P.J., Pedersen S., Busse W.W. Efficacy and safety of inhaled corticosteroids. New developments. Am. J. Respir. Crit. Care Med., 1998, 157, 1-$53. 4. Barnes P.J., Karin M. - Nuclear factor-kB : a pivotal transcription factor in chronic inflammatioii: N. Engl.J. Med., 1997, 336, 1066-71.
• L. LE CLAINCHE E T AL. /
$268 5. Calpin C., Macarthur C., Stephens D., Feldman W., Parkin EC. Effectiveness of prophylactic i n h a l e d steroids in c h i l d h o o d asthma : A systematic review of the literature. J. Allergy Clin. Immunol., 1997, 100, 452457. 6. Perera B.J.C. - Efficacy and cost effectiveness of inhaled steroids in asthma in a developing country. Arch. Dis. Child., 1995, 72, 312316. 7. W a r n e r J.O., Naspitz C.K., Cropp G.J.A. - Third international Pediatric Consensus Statement on the M a n a g e m e n t of c h i l d h o o d Asthma. Pediatr PulmonoL, 1998, 25, 1-17. 8. NIH E x p e r t panel r e p o r t 2 - Guidelines for the diagnosis and the m a n a g e m e n t of asthma. National Institutes of Health Publication n ° 97. 4051, Bethesda, Kpril 1997. 9. Pedersen S. - A s t h m a : what needs to be assessed? Eur. Respir. Rev., 1997, 7: 50, 352-355. 10. Cockcroft D.W., Swystun V.A. - Asthma control versus asthma severity.J. Allergy Ckin. ImmunoL, 1996, 98, 1016-1018. 11. H a a h t e l a T. - Airway r e m o d e l l i n g takes place in asthma - What are the clinical implications? Clin. Exp. Allergy, 1997, 27, 351-353. 12. Crowley S., Trivedi E, Risteli L., et al. - Collagen metabolism and growth in p r e p u b e r t a l children with asthma treated with inhaled steroids.J. Pediatr., 1998, 132, 409-413. 13. Doull I.J.M., Freezer N.J., Holgate S.T. - Growth of prepubertal children with mild asthma treated with inhaled b e c l o m e t h a s o n e dipropionate. Am.J. Respir. Crit. Care Med., 1995, 151, 1715-1729. 14. Verberne AAPH, Frost C., Roorda R.J., van der Laag H., Kerrebijn K.E O n e year t r e a t m e n t with salmeterol c o m p a r e d with b e c l o m e t h a s o n e in children with asthma. Am. J. Respir. Crit. Care Med., 1997, 156, 688-695. -
25. de Blic J., Delacourt C., Le Bourgeois M., et al. - Efficacy of nebulized b u d e s o n i d e in t r e a t m e n t of severe infantile asthma : A double-blind study. J. Allergy Clin. ImmunoL, 1996, 98, 4-20. 26. Volovitz B., Soferman R., Blau H., Nussinovitch M., Varsano I. Rapid induction of clinical response with a short-term high-dose starting schedule of b u d e s o n i d e nebulizing suspension in young c h i l d r e n with r e c u r r e n t w h e e z i n g episodes. J. Allergy Clin. Immunol., 1998, 101, 464-469. 27. Galoppin L., de Blic J., Azevedo I., Vargaftig B.B., Bachelet M. Nonspecific refractoriness to adenyl cyclase s t i m u l a t i o n in alveolar macrophages from infants with r e c u r r e n t bronchiolitis. Allergy Clin. Immunol., 1994, 93, 885-890. 28. Azevedo I., de BlicJ., Scheinmann E, Vargaftig B.B., Bachelet M. Enhanced arachidonic acid metabolism in alveolar macrophages from wheezy infants. Modulation by dexarnethasone. Am. J. Respir. Crit. CareMed., 1995, 152, 1208-1214. 29. Azevedo I., de Blic J., D u m a r e y C.H., et al. - I n c r e a s e d spontaneous release of t u m o r necrosis factor a l p h a by alveolar macrophages from wheezy infants. Eur. Respir. J., 1997, 10, 17671773. 30. Le Bourgeois M., Cormier C., Kindermans C., et al. - Inhaled b e c l o m e t h a s o n e and b o n e metabolisme in young asthmatic children: A six-month study. J. Allergy Clin. Immunol., 1995, 96, 4, 565-567. 31. WagenerJ.S., Wojtczak H.A. - I n h a l e d steroids in children : risks versus rewards.J. Pediatr., 1998, 132, 381-383. 32. Lemanske R.E, Allen D.B. - Choosing a long-term controller m e d i c a t i o n in c h i l d h o o d asthma. The proverbial two-edged sword. Am.J. Respir. Crit. Care Med., 1997, 156, 685-687.
15. Simons FER. - A comparison o f b e c l o m e t h a s o n e , salmeterol and placebo in children with asthma. N. Engl.J. Med., 1997, 337, 16591665.
33. Moore R.H., Khan A., Dickey B.E - Long-acting inhaled beta 2 agonists in asthma therapy. Chest, 1998, 113, 1095-1108.
16. Allen D.B., Mullen M.L., Mullen B. - A meta-analysis of the effect of oral and inhaled corticosteroids on growth. J. Allergy Clin. ImmunoL, 1994, 93, 967-976.
34. G r e e n i n g A.E, Northfield M. - A d d e d salmeterol versus higherdose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet, 1994, 344, 219-224.
17. Efthimion J., Barnes P.J. - Effect of inhaled corticosteroids on bones and growth. Eur. Respir.J., 1998, 11, 1167-1177.
35. Pauwels R.A., L6fdahl C.G., Postma D.S., et al. - Effect of inhaled formoterol and b u d e s o n i d e on exacerbations of asthma. N. Engl. J. Med., 1997, 337, 1405-1411.
18. Allen D.B., Bronsky E.A., La Force C.E, et al. - Growth in asthmatic children treated with fluticasone propionate. J. Pediatr., 1998, 132, 472-477. 19. Nikolaizik W.H., Preece M.A., W a r n e r J.O. - O n e year follow-up study of e n d o c r i n e and l u n g function of asthmatic children on inhaled budesonide. Eur. Respir.J., 1997, 10, 2596-2601. 20. Silverstein M.D., Yunginger J.W., Reed C.E., et al. - Attained adult h e i g h t after c h i l d h o o d asthma : effect of glucocorticoid therapy. J. Allergy Clin. ImmunoL, 1997, 99, 466-474. 21. Agertoft L., Pedersen S. - Effects of long-term treatment with an inhaled corticosteroids on growth a n d p u l m o n a r y function in asthmatic children. Respir. Med., 1994, 88, 373-381. 22. Pedersen S., WarnerJ.O., PriceJ.E - Early use of inhaled steroids in children with asthma. Clin. Exp. Allergy, 1997, 27, 995-1006. 23. Agertoft L., Pedersen S. - Bone m i n e r a l density in children with asthma receiving long-term treatment with inhaled budesonide. Am,~ Respiq: Crit. Care Med., 1998, 157, 178-183. 24. Martinez ED., Wright A.L., Taussig L.M., et al. - Asthma and wheezing in the first six years of life. N. Engl. J. Med., 1995, 332, 133-138.
36. Horwitz R.J. McGill K.A., Busse W.W. - The role of lenkotriene modifiers in the t r e a t m e n t of asthma. Am.J. Respi~: Crit. CareMed., 1996, 157, 1363-1371. 37. Petersen W., Karup, Pedersen E, Friis B., et al. - Sodium cromoglycate as a r e p l a c e m e n t for inhaled corticostero~ds in mild-to-moderate c h i l d h o o d asthma. Allergy, 1996, 51, 870-875. 38. K t n i g P., Shaffer J. - The effect of d r u g therapy on long-term o u t c o m e of c h i l d h o o d asthma : A possible preview of the international guidelines, f Allergy Clin. Immununol., 1996, 98, 1103-1111. 39. Gibson N.A., F e r g u s o n A.E., A i t c h i s o n T.C., P a t o n J.Y. C o m p l i a n c e with i n h a l e d a s t h m a m e d i c a t i o n in p r e s c h o o l children. Thorax, 1995, 50, 1274-1279. 40. Milgrom H., B e n d e r B., Ackerson L., et al. - N o n c o m p l i a n c e and t r e a t m e n t failure in c h i l d r e n with asthma. J. Allergy Clin. Immununol., 1996, 98, 1051-1057. 41. Milgrom H., Bender B. - N o n a d h e r e n c e to asthma t r e a t m e n t a n d failure of therapy. Curt. Opinion Pediatr., 1997, 9, 590-595.
Re~.fr. AllergoL, 1998, 38, 7S
ET D'IMMUNOLOGIECLINIQUE
Inhaled anti-inflammatory therapy in childhood asthma L. LE CLAINCHE, M. LE BOURGEOIS, J. DE BLIC, P. SCHEINMANN
KEY-WORDS: Asthma - Children - Infants - Inhaled corticosteroids - Inflammation.
MOTS-CLt~S: Asthme - Enfants - Nourrissons Corticoides inhalts - Inflammation.
It is widely a c c e p t e d t h a t a s t h m a is an inflammatory disease [ 1]. Inhaled corticosteroids have become established as the mainstay of chronic asthma treatment [2]. The mode of action of corticosteroids and particularly the molecular mechanisms of steroid action are much better understood. The control of asthma is mainly exerted via inhibition of NF-kB [3, 4]. The efficacy and the overall safety of inhaled corticosteroids have recently been emphasized [3, 5,6]. Inhaled corticosteroids are advocated in children with persistent symptoms [7, 8] . Inhaled corticosteroids are also advocated in children with frequent episodic symptoms (equivalent to step 2 of the N I H consensus), w h e n s o d i u m cromoglycate fails to control symptoms, and beta 2 agonists continue to be required more than 3 times a week [7]. The efficacy of inhaled steroids is observed when assessing several o u t c o m e measures : symptom control, normalization of lung function, r e d u c t i o n of airway h y p e r r e s p o n s i v e n e s s ,
m i n i m i z a t i o n o f m o r t a l i t y [9-10] a n d also, possibly, prevention of irreversible airway damage (airway remodelling) [ 11 ]. However several issues remain controversial. C o n c e r n s have been raised a b o u t potential adverse effects of i n h a l e d steroids on bone metabolism and linear growth. In a recent study conducted in 56 prepubertal children with asthma it has been shown that collagen turnover and growth velocyty were reduced by inhaled steroids [12]. This study seems in agreement with a previous study by Doull, et al. which had concluded that even conventional doses of inhaled corticosteroids can decrease statural growth, at least in children with mild asthma [13]. Similar conclusion were given by A. Verberne [14] and FER Simons in their one year studies comparing the efficacy of monotherapy with salmeterol versus beclomethasone dipropionate (200 pg twice daily) [15]. This disturbing studies are at variance with comprehensive meta-analysis [16] and review
Service de Pneumologie et d'Allergologie Ptdiatriques, H6pital des Enfants Malades, PARIS, (France). Correspondence : E Scheinmann. Service de Pneumologie et d'Allergologie Ptdiatriques, Htpital des Enfants Malades, 149 Rue de S~vres, 75743 PARIS Cedex 15 (France). Interasma Marrakech' 98.
LE CLAINCHE L., LE BOURGEOIS L., DE BLIC J., SCHEINMANN R Inhaled anti-inflammatory therapy in childhood asthma. Rev.fr. Allergol., 1998, 38 (7S), $266-$268.
© Expansion Scientifique Publications, 1998
/ INHALED ANTI-INFLAMMATORY THERAPY IN CHILDHOOD ASTHMA •
showing no substantial effect o f i n h a l e d c o r t i c o s t e r o i d s on l o n g - t e r m growth or on biochemical markers of b o n e formation and resorption [17], at least w h e n i n h a l e d c o r t i c o s t e r o i d s are p r e s c r i b e d within their r e c o m m a n d e d dose ranges (i.e., up to 400 p g / day with b u d e s o n i d e or b e c l o m e t h a s o n e dipropionate) [17]. Recent studies have confirmed that growth is normal in children with persistent asthma treated with fluticasone propionate ( 50 and 100 lag twice daily[18] or budrsonide 200 lag twice daily [19]. It was even shown that side effects do not accumulate with length of t r e a t m e n t a n d that i n h a l e d corticosteroids, once started in asthmatic children not controlled on prophylactic sodium cromoglycate, should be continued [19]. Moreover Silverstein et al. have demonstrated that the attained height of asthmatic children treated with (inhaled) corticosteroids was not different from the adult height of children not treated with corticosteroids [20]. The absence of clinically relevant side-effects of conventional doses of ICS reinforces S. Pedersen's therapeutic concepts [9,21]. In children with persistent disease, i.e. in children who require c o n t i n u o u s anti a s t h m a t r e a t m e n t , i n h a l e d corticosteroids should be used as early first line therapy. Provided that the dose is tailored to the severity of the disease, side effects are minimal if any. Children started early have better lung function and lung growth at a lower accumulated dose than children in which treatment with inhaled corticosteroids has been delayed [21, 22]. Pedersen has emphasized that a mean of 4.5 years of treatment with inhaled b u d e s o n i d e at an average daily dose of 504 lag has no detectable adverse effect on total bone mineral density, total bone mineral capacity, total bone calcium, or b o d y c o m p o s i t i o n in children with chronic asthma when the dose is tailored to the severity of the disease [23]. More caution should probably be employed in infants [22]. The dilemna we face with wheezy infants is the risk of overtreating infants who will
$267
show spontaneous recession [22]. On the other hand, epidemiological prospective studies have clearly shown the risk of deterioration in lung fonction in children with early and persistent symptoms [24]. Empirical approach should be to prescribe inhaled corticosteroids to infants with severe persistent symptoms. The efficacy of this approach has been demonstrated with nebulized budesonide in severe infantile asthma [25]. A starting dose of 1 mg twice daily seems to be the correct schedule for the initiation of treatment [26]. Whatever the cause, it is likely that wheezing and dyspnoea reflect chronic airway inflammation, the presence of which is attested by elevated levels of mediators of inflammation and TNF alpha in bronchoalveolar lavage [2%29]. Safety assessed by clinical parameters appears excellent [25]. Bone metabolism was also shown to be normal in infants inhaling a mean of 597 lag of beclomethasone daily during 6 months [30]. In practice, the benefits of early treatment with inhaled corticosteroids are much greater than the putative side effects on growth a n d b o n e metabolism, at least in children with persistent symptoms. Continuous efforts should be made to reduce inhaled corticosteroids to the lowest dose that maintains good control of symptoms and of disease [15,31,32]. With regard to this important paediatric aim, a combination of therapies is probably more desirable than one treatment at a (too) high dose. Convincing data, in adults with asthma have favoured the concurrent use of inhaled corticosteroids and long acting beta 2 agonists [33-37]. It is highly likely that similar results will be obtained in children with persistent severe asthma. In children there is a real need for combination studies of inhaled corticosteroids with antileucotrienes or cromones [36-38]. Finally the main obstacle to an a d e q u a t e m a n a g e m e n t of childhood asthma might well be the non adherence to asthma treatment. In this regard steroid phobia may be one of the biggest p r o b l e m s in the c u r r e n t therapy of asthma [39-41].
REFERENCES
1. Holgate S.T. - The cellular and mediator basis of asthma in relation to natural history. Lancet, 1997, 350 (suppl II), 5-9. 2. Barnes P.J. -Assessment and management of asthma in the future. Eur. Respir. Rev., 19.97, 369-373.
Rev. fr. Allergol., 1998, 38, 7S
3. Barnes P.J., Pedersen S., Busse W.W. Efficacy and safety of inhaled corticosteroids. New developments. Am. J. Respir. Crit. Care Med., 1998, 157, 1-$53. 4. Barnes P.J., Karin M. - Nuclear factor-kB : a pivotal transcription factor in chronic inflammatioii: N. Engl.J. Med., 1997, 336, 1066-71.
• L. LE CLAINCHE E T AL. /
$268 5. Calpin C., Macarthur C., Stephens D., Feldman W., Parkin EC. Effectiveness of prophylactic i n h a l e d steroids in c h i l d h o o d asthma : A systematic review of the literature. J. Allergy Clin. Immunol., 1997, 100, 452457. 6. Perera B.J.C. - Efficacy and cost effectiveness of inhaled steroids in asthma in a developing country. Arch. Dis. Child., 1995, 72, 312316. 7. W a r n e r J.O., Naspitz C.K., Cropp G.J.A. - Third international Pediatric Consensus Statement on the M a n a g e m e n t of c h i l d h o o d Asthma. Pediatr PulmonoL, 1998, 25, 1-17. 8. NIH E x p e r t panel r e p o r t 2 - Guidelines for the diagnosis and the m a n a g e m e n t of asthma. National Institutes of Health Publication n ° 97. 4051, Bethesda, Kpril 1997. 9. Pedersen S. - A s t h m a : what needs to be assessed? Eur. Respir. Rev., 1997, 7: 50, 352-355. 10. Cockcroft D.W., Swystun V.A. - Asthma control versus asthma severity.J. Allergy Ckin. ImmunoL, 1996, 98, 1016-1018. 11. H a a h t e l a T. - Airway r e m o d e l l i n g takes place in asthma - What are the clinical implications? Clin. Exp. Allergy, 1997, 27, 351-353. 12. Crowley S., Trivedi E, Risteli L., et al. - Collagen metabolism and growth in p r e p u b e r t a l children with asthma treated with inhaled steroids.J. Pediatr., 1998, 132, 409-413. 13. Doull I.J.M., Freezer N.J., Holgate S.T. - Growth of prepubertal children with mild asthma treated with inhaled b e c l o m e t h a s o n e dipropionate. Am.J. Respir. Crit. Care Med., 1995, 151, 1715-1729. 14. Verberne AAPH, Frost C., Roorda R.J., van der Laag H., Kerrebijn K.E O n e year t r e a t m e n t with salmeterol c o m p a r e d with b e c l o m e t h a s o n e in children with asthma. Am. J. Respir. Crit. Care Med., 1997, 156, 688-695. -
25. de Blic J., Delacourt C., Le Bourgeois M., et al. - Efficacy of nebulized b u d e s o n i d e in t r e a t m e n t of severe infantile asthma : A double-blind study. J. Allergy Clin. ImmunoL, 1996, 98, 4-20. 26. Volovitz B., Soferman R., Blau H., Nussinovitch M., Varsano I. Rapid induction of clinical response with a short-term high-dose starting schedule of b u d e s o n i d e nebulizing suspension in young c h i l d r e n with r e c u r r e n t w h e e z i n g episodes. J. Allergy Clin. Immunol., 1998, 101, 464-469. 27. Galoppin L., de Blic J., Azevedo I., Vargaftig B.B., Bachelet M. Nonspecific refractoriness to adenyl cyclase s t i m u l a t i o n in alveolar macrophages from infants with r e c u r r e n t bronchiolitis. Allergy Clin. Immunol., 1994, 93, 885-890. 28. Azevedo I., de BlicJ., Scheinmann E, Vargaftig B.B., Bachelet M. Enhanced arachidonic acid metabolism in alveolar macrophages from wheezy infants. Modulation by dexarnethasone. Am. J. Respir. Crit. CareMed., 1995, 152, 1208-1214. 29. Azevedo I., de Blic J., D u m a r e y C.H., et al. - I n c r e a s e d spontaneous release of t u m o r necrosis factor a l p h a by alveolar macrophages from wheezy infants. Eur. Respir. J., 1997, 10, 17671773. 30. Le Bourgeois M., Cormier C., Kindermans C., et al. - Inhaled b e c l o m e t h a s o n e and b o n e metabolisme in young asthmatic children: A six-month study. J. Allergy Clin. Immunol., 1995, 96, 4, 565-567. 31. WagenerJ.S., Wojtczak H.A. - I n h a l e d steroids in children : risks versus rewards.J. Pediatr., 1998, 132, 381-383. 32. Lemanske R.E, Allen D.B. - Choosing a long-term controller m e d i c a t i o n in c h i l d h o o d asthma. The proverbial two-edged sword. Am.J. Respir. Crit. Care Med., 1997, 156, 685-687.
15. Simons FER. - A comparison o f b e c l o m e t h a s o n e , salmeterol and placebo in children with asthma. N. Engl.J. Med., 1997, 337, 16591665.
33. Moore R.H., Khan A., Dickey B.E - Long-acting inhaled beta 2 agonists in asthma therapy. Chest, 1998, 113, 1095-1108.
16. Allen D.B., Mullen M.L., Mullen B. - A meta-analysis of the effect of oral and inhaled corticosteroids on growth. J. Allergy Clin. ImmunoL, 1994, 93, 967-976.
34. G r e e n i n g A.E, Northfield M. - A d d e d salmeterol versus higherdose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet, 1994, 344, 219-224.
17. Efthimion J., Barnes P.J. - Effect of inhaled corticosteroids on bones and growth. Eur. Respir.J., 1998, 11, 1167-1177.
35. Pauwels R.A., L6fdahl C.G., Postma D.S., et al. - Effect of inhaled formoterol and b u d e s o n i d e on exacerbations of asthma. N. Engl. J. Med., 1997, 337, 1405-1411.
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