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com [CLOSE WINDOW] Authors and Disclosures Parameswaran Nair Firestone Institute for Respiratory Health, St. Joseph's Healthcare and Departme nt of Medicine, McMaster University, Hamilton, Ontario, Canada Correspondence to Dr Parameswaran Nair, MD, PhD, FRCP, FRCPC, Firestone Institute for Respiratory Health, St Joseph's Healthcare, 50 Charlton Avenue East, Hamilton, ON L8N 4A6, C anada Tel: +1 905 522 1155 x35044; fax: +1 905 521 6183; e-mail: parames@mcmaste r.ca From Current Opinion in Pulmonary Medicine Early Interventions with Inhaled Corticosteroids in Asthma: Benefits and Risks Parameswaran Nair Posted: 02/21/2011; Curr Opin Pulm Med. 2011;17(1):12-15. © 2011 Lippincott Willia ms & Wilkins Abstract and Introduction Abstract Purpose of review The present review examines the effects of early intervention with inhaled corticosteroids (ICSs) on clinical efficacy and natural history of asthma based on two recent clinical trials: the Inhaled Steroid Treatment as Reg ular Therapy in Early Asthma (START) and Prevention of Early Asthma in Kids (PEA K) trials, and a comparison of the effect of regular vs. intermittent therapy ba sed on the Improving Asthma Control Trial (IMPACT). Recent findings In most patients, both adults and children, who have a new diagn osis of asthma and whose symptoms are mild but persistent, treatment with ICS sh ould be recommended as soon as the diagnosis is made. This is a cost-effective a nd well tolerated treatment. However, symptoms may recur and lung function may d ecline again if treatment is discontinued. Summary ICS is the most cost-effective initial treatment for both adults and chi ldren with a new diagnosis of asthma. If patients are reluctant to use ICS daily for long periods, it would be reasonable to delay the onset of treatment with I CS. Initial therapy with leukotriene receptor antagonist is not likely to be as effective as initial therapy with ICS. Biomarkers of airway inflammation such as sputum cell counts and exhaled nitric oxide are probably not necessary to treat patients with mild intermittent asthma. Introduction Inhaled corticosteroids (ICSs) are the most effective anti-inflammatory drugs in the management of asthma. They control airway inflammation, particularly eos inophilic inflammation, improve airway calibre and airway hyperresponsiveness , protect the airway against bronchoconstrictor stimuli such as exercise a nd allergen and prevent asthma exacerbations. These effects result in impr oved symptoms and quality of life and decreased morbidity and asthma-related mor tality. Despite more than 25 years of experience with these drugs, there are lingering doubts whether they are necessary for patients with mild asthma as soo n as they are diagnosed, whether they need to be taken continuously and whether they alter the natural history of asthma, particularly in children. This review examines the effects of early intervention with ICS on clinical efficacy and nat ural history of asthma. Early Intervention Studies Most guidelines recommend a step-wise approach to asthma therapy, starting with
Children receivin g budesonide also needed significantly less intervention with other ICSs (12. Haahtela et al. Patien ts on budesonide had fewer courses of systemic corticosteroids and more symptomfree days than did those on placebo. The relative risk of a severe asthma-related event was reduced by 40% (P = 0. Seven thousa nd forty-one patients aged 5 66 years with mild persistent asthma of less than 2 y ears of duration were enrolled. the primary outcome was asthma exacerbations. Further. It was an effectiveness rather than an efficacy study and i ncluded a significantly larger number of children. However.012). At the end of this period. However.0001) after 1 year and by 0. Overall. but. the delayed therapy group had a higher neutrophil count and higher concentrations of eosinophilic cationi c protein and myeloperoxidase in induced sputum. 22. It was larger and included significan tly milder patients. 7221 patients were included in the safety analysis. The above-mentioned benefit of early intervention was confirmed in the recently published Inhaled Steroid Treatment as Regular Therapy in Early Asthma (START) s tudy. This group had also used more a sthma medication and had more hospital days. patients who were switched from placebo to budesonide showed a significant imp rovement in lung function. the increase in PEF in patients in whom the in troduction of budesonide was delayed for 2 years was consistently about half tha t seen in patients receiving budesonide from the start of the study. The numbers of deaths .3 v s. The effect of treatment was independent of the baseline lung function or baseline medication. At the end of the 3 years of double-blind treatment. with trends toward decreased usage of systemic corticosteroids and inhaled short-acting beta-2-agonists.48 % (P < 0.0005) after 3 years (expressed a s percentage of the predicted value).9] of 103 patients w ith asthma diagnosed less than 12 months previously. P < 0. P < 0. After the follow-up period. Most importantly. However . and a total of 21 520 adverse events were reported (10 850 in the budesonide group and 10 670 in the placebo group). multicenter study[8. their lung function was still significantly lower than that in patients who had received budesonide from the start of the study. 198 of 3568 patients on pla cebo and 117 of 3597 patients on budesonide had at least one severe asthma exace rbation.5% over 3 years. it seems reasonable to start treatment with ICSs as soon as asthma is diagnosed.45 0. hazard ratio 0.short-acting beta-agonists for symptomatic relief and using ICSs when the asthma is mildly uncontrolled.0001).01). because even the mildest form of asthma is ass ociated with airway inflammatory changes.88% (P = 0. The dose of ICS used was lowe r.d. Patients treated with budes onide 600 mg twice daily (b. This is one of the largest asthma studies ever conducted. early interv ention in younger children is not consistently associated with improvement in lu ng function in longitudinal studies. However. The most comprehensive study of early intervention with ICSs is a two-stage.[10 ] recently published their observations on this cohort of patients. no statistically signi ficant differences in clinical or functional variables were found between patien ts given early or delayed budesonide therapy.i. Treatment with low-dose ICS for 3 years was not associated with any more adverse effects than observed with placebo. Similar overall benefit was also seen in the 1000 children who received budesoni de compared with the 974 children who received placebo.71. which was maintained throughout the 2-year study period compared with the terbutaline-treated patients. Patients were randomized to low-dose budesonide (400 µg once daily for adults and 200 µg once daily for children) or placebo in addi tion to their usual therapy for 3 years. after 1 0 further years of follow-up.56 (95% confidence interval 0.) showed a rapid and significant increase in pea k expiratory flow (PEF). Their PEF was well maintained f or a further year when they were switched to a lower dose of budesonide. all patients received budesonide (open-label) for 2 more years. budesonide increased postbronchodilator forced expiratory volume in 1 s (FEV1) from baseline by 1. at the end of the year. Compared with placebo. This study differed from the previous studies in a number of respects.
at the end of the 5-year study period. 225 adults were randomized to either intermittent short-course cor ticosteroid treatment guided by a symptom-based action plan alone or in addition to daily treatment with either inhaled budesonide or oral zafirlukast. Although during the treatment period. the degree of asthma contro l. irrespective of assigned treatment during the double-bli nd phase. or lun g function during the observation period. Asthma symptoms could be effectively controlled to the same degree as patients treated early with ICSs through additional treatment with long-acting bronchodilators. the Improving Asthma Control Tr ial (IMPACT). It would therefore appear that the prescription of ICSs can be del ayed in some patients who may be reluctant to take them without significant dele terious effects as later introduction allows a catch-up of lung function. the choice of initial therapy may depend on in dividual preferences and values. Lung. By the end of th e trial. this study would suggest t hat there was no significant advantage of starting treatment with budesonide. Regular vs. Ho wever. in pre school children at high risk for asthma. 2 years of ICS therapy did not change t he development of asthma symptoms or lung function during a third. The prim ary outcome was morning PEF. the mean increase in height was 1. treatment-fre e year. This was exami ned in a clinical trial conducted by the Childhood Asthma Research and Education Network. In a double-blind trial. Other outcomes included FEV1 before and after bronc hodilator treatment.3%. Natural History of Asthma The recommendation to use inhaled steroids regularly would be strengthened if th is altered the natural history of asthma. the number of symptom-free days and the quality of life. there was greater use of concomitant additional medications in the contro l group. as c ompared with placebo use. a lower rate of exacerbations and of supplementary use o f controller medication.7 cm less in the ICS group. 0. However.i. some patients may prefer to use ICSs inte rmittently.) or masked placebo for 2 years. approximately 32 l per minut .15%). long-acting bronchodilators and cromones. Hence. For adult patients. use of the ICS was associated with a greater proportio n of episode-free days. This may not be an option for young children in whom these drugs are not recomme nded for use. the mean height increase was 0. especially in children. There was no signi ficant difference in lung function in either group compared with the start of th e study. The treatment was not associated with significant adverse effects. the frequency of exacerbations. The primary outcome was the proportion of episode-f ree days during the observation year. postbronchodilator FEV1 percenta ge predicted decreased. Intermittent Therapy The efficacy of intermittent treatment with ICSs was investigated in patients wi th mild persistent asthma over a 1-year period in a clinical trial conducted by the Asthma Clinical Research Network supported by the US National Heart.and serious adverse events were similar for children and adults in both groups.22% (standard error. a nd Blood Institute. This is because the patients who had not earlier received budesonide ca ught up quickly with the treatment group when they received budesonide. The three treatments produced similar increases in morning PEF (7. The numb er of exacerbations in this group was also no more frequent than in the patients who received budesonide throughout the study. Long-term treatment with budesonide appe ared to be cost-effective. Some minor adverse reversible effects such as skin thinning may be associated w ith moderate doses of ICS (budesonide in daily doses of 400 800 µg) in prepubertal c hildren with newly detected asthma. These included ICSs other than budesonide.d.1 cm less at 24 months than in the placebo group. by an average of 2.1 8. Thus. Thus. Two hundred eighty-five participants aged about 2 or 3 years with a positive asthma predictive index were randomized to treatment with fluticasone propionate (at a dose of 88 µg b. followed by a 1-year observation period without study medication [the Prevention of Early A sthma in Kids (PEAK) study]. no significant differences were seen between the two gr oups in the proportion of episode-free days. In the ICS group. the number of exacerbations. especially in the younger patients.
it is reasonable to draw the following conclusion s: in most patients. but not in postbronchodilator FEV1 or in the quality of life.[24. both adults and children who have a new diagnosis of asthma . . If patients are reluc tant to use ICSs daily for long periods. et al. Effect of an inhaled corticosteroi d on airway inflammation and symptoms in asthma. small experimental studies involving allergen inhalation by patients wit h mild asthma have demonstrated that although regular treatment with low doses o f ICSs improves baseline airway hyperresponsiveness and decreases baseline infla mmation measured in sputum. The Role of Biomarkers There is very good evidence that biomarkers such as eosinophil count in sputum a nd fraction of nitric oxide in exhaled air may guide the use of anti-inflammator y therapy in asthma. treatment with ICSs should be considered. Zwinderman AH. 3. it appears th at it may be possible to treat mild persistent asthma with short. it is unlikely to change the natural history of asthma. [ CLOSE WINDOW ] References 1. et al. Patients should be cautioned that wi th short-term treatment their symptoms may recur and their lung function may dec line again if treatment is discontinued. N Engl J Med 1995. Thus. bronchial reactivi ty. even though the intermittent-treatm ent group took budesonide. 332:868 873. Inhaled glucocorticoids for asthma. Indeed.Barnes PJ. Timmers MC. Wilson JW.Djukanovic R. The effect of inhaled corticosteroid s on the maximal degree of airway narrowing to methacholine in asthmatic subject s. at least in atopic patients with purely seasonal asthma. the percentage of eosinophils in sputum and the fraction of nitric oxide in exhaled breath (in a subset of patients in whom this was measured). intermittent c ourses of inhaled or oral corticosteroids taken when symptoms worsen. intermittent ICSs are likely to be efficacious in attenuating a llergen-induced responses. Britten KM. it would be reasonable to offer them in termittent therapy with ICSs if they have mild persistent symptoms. Conclusion On the basis of this evidence. for only 0. Thus. Am Rev Respir Dis 1992.[20. Although treatment adjustments based on eosinophil counts i n sputum can reliably predict short-term responses to corticosteroids and decrea se exacerbations in patients with moderate and severe asthma. these benefits are lost when treatment is discontinu ed for as short as 36 48 h.5 week of the year.21] The benefits are no better than single doses of corticosteroids given immediately before an allergen challenge. scores for a sthma control and the number of symptom-free days. Am Rev Respir Dis 1991. It should be noted that it is debatable whether the primary outcome variable of PEF was th e most clinically relevant outcome variable in such a study. Long-term studies have not been conducted to test whe ther this strategy is effective to maintain lung function and symptom control. Their roles to guide intermittent therapy or to initiate early intervention with anti-inflammatory treatment have not been inves tigated. When compa red with intermittent therapy or daily zafirlukast therapy.Bel EH. Initial ther apy with other anti-inflammatory therapies such as leukotriene receptor antagoni sts is not likely to be as effective as ICSs. ICSs are al so effective in attenuating allergen-induced responses when given during the ear ly or the late responses. on average. Daily zafirlukast therapy did not differ signif icantly from intermittent treatment in any outcome measured.25] it may not offer any additional advantage over current guideline-based treatment strategies for patients with mild asthma. 143:109 113. Biomarkers of airway inflammation such as sputum cell counts and exhaled nitric oxide are probably not necessary t o treat patients with mild intermittent asthma.e) and similar rates of asthma exacerbation. 2. 145:669 6 74. daily budesonide the rapy produced greater improvements in prebronchodilator FEV1. Even if treatment is continued regularl y.
Can Respir J 2000 . J Allergy Clin I mmunol 2009. et al. 5. Kava T. N Engl J Med 2005. Beclomethasone given after the early asthmatic response inhibits the late response and the increased methachol ine responsiveness and cromolyn does not. Protective effects of fluticasone on alle rgen-induced airway responses and sputum inflammatory markers. 6. Mowinckel P.Suissa S. Lofdahl CG. Pediatr Allergy Immunol 2006. 19. Buxton M. 12. 14. J Allergy Clin Immunol 1993. 331:700 705. O'Byrne PM. and Blood Inst itute's Asthma Clinical Research Network. King TS. Dorman SC.Haahtela T. N Engl J Med 2006. 112:1229 1236. Silverman M. Postma DS. et al. et al. et al. 352:1519 1528. Thirteen-year follow-up of early inter vention with an inhaled corticosteroid in patients with asthma. 17. Woolcock AJ. N Engl J Med 1997. with an inhaled corticosteroid. National Heart. J Allergy Clin Immunol 2008. J A llergy Clin Immunol 2005. Morgan WJ.4. In a follow-up to their landmark studies in the New England Journal of Medicine i n 1991 and 1994. Rerecich T. 91:1163 116 . 7.Pauwels RA.Chen YZ. et al. et al. Devulapalli CS. Early intervention of recent onset mild persistent asthma in children aged under 11 yrs: the Steroid Treatment As Regul ar Therapy in early asthma (START) trial. Kava T.Parameswaran K. et al. Sorkness CA. Pedersen S. delayed the rapy with inhaled corticosteroids in newly diagnosed asthmatics does not seem to have too many negative outcomes. Pauwels RA. Zeiger RS. Effects of inhaled budesonide on alle rgen-induced airway responses and airway inflammation. Tamminen K. budesonide.Sullivan SD. 13. Comparison of a beta-2 agonist. 18.Guilbert TW. 337:1405 1411. 11. 94:48 54. Am J Respir Crit Care Med 2001. 21:814 822. The Hel sinki early intervention childhood asthma study.Haahtela T. START Investigators Group. Am J Respir Crit Care Med 1996. Pediatr Res 2010. Ernst P.Nair P. Lung. 354:1985 1997. Lung function at 10 yrs is not improved by early corticosteroid treatment in asthmatic children. 10.Cockcroft DW. Rowe BH.Sheffer AL. Kava T. Pediatr Allergy Immunol 2010. Pedersen S. et al. Watson RM. 20. et al. 124:1180 1185. START Investigators Group. Protection by budesonide and flutic asone on allergen-induced airway responses after discontinuation of therapy. Early int ervention with budesonide in mild persistent asthma: a randomised. 361:1071 1076. Cost-effectiveness analysis of ea rly intervention with budesonide in mild persistent asthma. Andersson LF. N En gl J Med 1991. et al. Benayoun S. Lancet 2003. et al. Long-term safety of once-daily b udesonide in patients with early-onset mild persistent asthma: results of the In haled Steroid Treatment as Regular Therapy in Early Asthma (START) study. O'Byrne PM. Pedersen S. Skin thickness in children treated with daily or periodical inhaled budesonide for mild persistent asthma. 9. Busse WW. et al. terbuta line. 21. et al. 115:745 750. Raitio H. Haahtela and colleagues report that 13 years later. Ann Al lergy Asthma Immunol 2005. double-blind trial.Subbarao P. 16. in newly detected asthma. Protective effect of inhaled co rticosteroids in exercise-induced bronchospasm: a systematic review [abstract].Haahtela T. et al. 325:388 392. Doctor J.Turpeinen M. 7:313 319. Effects of reducing or discontinuing in haled budesonide in patients with mild asthma. 17(Suppl ):7 13. 343:332 336. 121:1167 1174. Jarvinen M. et al. Busse WW. 8. et al. McParland CP.Lødrup Carlsen KC. Effect of inhaled formoterol and bud esonide on asthma exacerbations. Low-dose inhaled corticosteroids and the prevention of death from asthma. J Allergy Clin Immun ol 2003. N Engl J Med 1994. Daily versus as-needed corticosteroids for mild persistent asthma. The Inhal ed Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year fol low-up: effectiveness of early intervention with budesonide in mild persistent a sthma. 154:1267 1271. Watson RM. Inman MD. N Engl J Med 2000. et al. 67:221 225. Pelkonen AS. 22.Gauvreau GM.Pauwels RA. Inman MD.Busse WW.Boushey HA. Jarvinen M. 15. 163:A587. Long-term inhaled corticosteroids i n preschool children at high risk for asthma. et al.
Lancet 2002. et al. Morelli MC.Green RH. 27:483 494 . Dente FL. McKenna S. hav e been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current Wor ld Literature section in this issue (p. Eur Respir J 2006. Cook RJ. Determining asthma treatment by mon itoring sputum cell counts: effect on exacerbations.17(1):12-15. 23. Am J Respir Crit Care Med 1994. et al. Asthma exacerbations and sputum eo sinophil counts: a randomised controlled trial. © 2011 Lippincott Williams & Wilkins . published within the annual period of review.N. Brightling CE. is supported by a Canada Research Chair in Airway Inflammometry. 2011. 51). 149:14 47 1451. Postallergen inhaled budesonide red uces late asthmatic response and inhibits the associated increase of airway resp onsiveness to methacholine in asthmatics.Paggiaro PL. 24. Papers of particular interest. Acknowledgement P. Pizzichini MM. 25.Jayaram L. Curr Opin Pulm Med. 360:1715 1721.8. et al.
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