www.medscape.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.[1] They control airway inflammation, particularly eos inophilic inflammation,[2] improve airway calibre and airway hyperresponsiveness ,[3] protect the airway against bronchoconstrictor stimuli such as exercise[4] a nd allergen[5] and prevent asthma exacerbations.[6] These effects result in impr oved symptoms and quality of life and decreased morbidity and asthma-related mor tality.[7] 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

short-acting beta-agonists for symptomatic relief and using ICSs when the asthma is mildly uncontrolled. However, because even the mildest form of asthma is ass ociated with airway inflammatory changes, it seems reasonable to start treatment with ICSs as soon as asthma is diagnosed. The most comprehensive study of early intervention with ICSs is a two-stage, multicenter study[8,9] of 103 patients w ith asthma diagnosed less than 12 months previously. Patients treated with budes onide 600 mg twice daily (b.i.d.) showed a rapid and significant increase in pea k expiratory flow (PEF), which was maintained throughout the 2-year study period compared with the terbutaline-treated patients. Their PEF was well maintained f or a further year when they were switched to a lower dose of budesonide. However , patients who were switched from placebo to budesonide showed a significant imp rovement in lung function, but, at the end of the year, their lung function was still significantly lower than that in patients who had received budesonide from the start of the study. Further, 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. Haahtela et al.[10 ] recently published their observations on this cohort of patients, after 1 0 further years of follow-up. After the follow-up period, no statistically signi ficant differences in clinical or functional variables were found between patien ts given early or delayed budesonide therapy. However, the delayed therapy group had a higher neutrophil count and higher concentrations of eosinophilic cationi c protein and myeloperoxidase in induced sputum. This group had also used more a sthma medication and had more hospital days. 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.[11] This is one of the largest asthma studies ever conducted. Seven thousa nd forty-one patients aged 5 66 years with mild persistent asthma of less than 2 y ears of duration were enrolled. Patients were randomized to low-dose budesonide (400 g once daily for adults and 200 g once daily for children) or placebo in addi tion to their usual therapy for 3 years. At the end of this period, all patients received budesonide (open-label) for 2 more years. This study differed from the previous studies in a number of respects. It was larger and included significan tly milder patients. It was an effectiveness rather than an efficacy study and i ncluded a significantly larger number of children. The dose of ICS used was lowe r. Most importantly, the primary outcome was asthma exacerbations. At the end of the 3 years of double-blind treatment, 198 of 3568 patients on pla cebo and 117 of 3597 patients on budesonide had at least one severe asthma exace rbation; hazard ratio 0.56 (95% confidence interval 0.45 0.71, P < 0.0001). Patien ts on budesonide had fewer courses of systemic corticosteroids and more symptomfree days than did those on placebo. Compared with placebo, budesonide increased postbronchodilator forced expiratory volume in 1 s (FEV1) from baseline by 1.48 % (P < 0.0001) after 1 year and by 0.88% (P = 0.0005) after 3 years (expressed a s percentage of the predicted value). The effect of treatment was independent of the baseline lung function or baseline medication. Similar overall benefit was also seen in the 1000 children who received budesoni de compared with the 974 children who received placebo.[12] The relative risk of a severe asthma-related event was reduced by 40% (P = 0.012). Children receivin g budesonide also needed significantly less intervention with other ICSs (12.3 v s. 22.5% over 3 years; P < 0.01), with trends toward decreased usage of systemic corticosteroids and inhaled short-acting beta-2-agonists. However, early interv ention in younger children is not consistently associated with improvement in lu ng function in longitudinal studies.[13] Treatment with low-dose ICS for 3 years was not associated with any more adverse effects than observed with placebo.[14] Overall, 7221 patients were included in the safety analysis, and a total of 21 520 adverse events were reported (10 850 in the budesonide group and 10 670 in the placebo group). The numbers of deaths

and serious adverse events were similar for children and adults in both groups. 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 g) in prepubertal c hildren with newly detected asthma.[15] Long-term treatment with budesonide appe ared to be cost-effective, especially in the younger patients.[16] However, at the end of the 5-year study period, postbronchodilator FEV1 percenta ge predicted decreased, irrespective of assigned treatment during the double-bli nd phase, by an average of 2.22% (standard error, 0.15%).[17] There was no signi ficant difference in lung function in either group compared with the start of th e study. This is because the patients who had not earlier received budesonide ca ught up quickly with the treatment group when they received budesonide. The numb er of exacerbations in this group was also no more frequent than in the patients who received budesonide throughout the study. Hence, this study would suggest t hat there was no significant advantage of starting treatment with budesonide. Ho wever, there was greater use of concomitant additional medications in the contro l group. These included ICSs other than budesonide, long-acting bronchodilators and cromones. 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. Asthma symptoms could be effectively controlled to the same degree as patients treated early with ICSs through additional treatment with long-acting bronchodilators. This may not be an option for young children in whom these drugs are not recomme nded for use. For adult patients, the choice of initial therapy may depend on in dividual preferences and values. Thus, some patients may prefer to use ICSs inte rmittently. Natural History of Asthma The recommendation to use inhaled steroids regularly would be strengthened if th is altered the natural history of asthma, especially in children. This was exami ned in a clinical trial conducted by the Childhood Asthma Research and Education Network.[18] 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 g b.i.d.) or masked placebo for 2 years, followed by a 1-year observation period without study medication [the Prevention of Early A sthma in Kids (PEAK) study]. The primary outcome was the proportion of episode-f ree days during the observation year. Although during the treatment period, as c ompared with placebo use, use of the ICS was associated with a greater proportio n of episode-free days, a lower rate of exacerbations and of supplementary use o f controller medication, no significant differences were seen between the two gr oups in the proportion of episode-free days, the number of exacerbations, or lun g function during the observation period. In the ICS group, the mean increase in height was 1.1 cm less at 24 months than in the placebo group. By the end of th e trial, the mean height increase was 0.7 cm less in the ICS group. Thus, 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, treatment-fre e year. The treatment was not associated with significant adverse effects. Regular vs. 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, Lung, a nd Blood Institute.[19] In a double-blind trial, the Improving Asthma Control Tr ial (IMPACT), 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. The prim ary outcome was morning PEF. Other outcomes included FEV1 before and after bronc hodilator treatment, the frequency of exacerbations, the degree of asthma contro l, the number of symptom-free days and the quality of life. The three treatments produced similar increases in morning PEF (7.1 8.3%; approximately 32 l per minut

e) and similar rates of asthma exacerbation, even though the intermittent-treatm ent group took budesonide, on average, for only 0.5 week of the year. When compa red with intermittent therapy or daily zafirlukast therapy, daily budesonide the rapy produced greater improvements in prebronchodilator FEV1, bronchial reactivi ty, 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), scores for a sthma control and the number of symptom-free days, but not in postbronchodilator FEV1 or in the quality of life. Daily zafirlukast therapy did not differ signif icantly from intermittent treatment in any outcome measured. Thus, it appears th at it may be possible to treat mild persistent asthma with short, intermittent c ourses of inhaled or oral corticosteroids taken when symptoms worsen. 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. Indeed, 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, these benefits are lost when treatment is discontinu ed for as short as 36 48 h.[20,21] The benefits are no better than single doses of corticosteroids given immediately before an allergen challenge.[20] ICSs are al so effective in attenuating allergen-induced responses when given during the ear ly[22] or the late responses.[23] Thus, at least in atopic patients with purely seasonal asthma, intermittent ICSs are likely to be efficacious in attenuating a llergen-induced responses. Long-term studies have not been conducted to test whe ther this strategy is effective to maintain lung function and symptom control. 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. 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,[24,25] it may not offer any additional advantage over current guideline-based treatment strategies for patients with mild asthma. Their roles to guide intermittent therapy or to initiate early intervention with anti-inflammatory treatment have not been inves tigated. Conclusion On the basis of this evidence, it is reasonable to draw the following conclusion s: in most patients, both adults and children who have a new diagnosis of asthma , treatment with ICSs should be considered. 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. Even if treatment is continued regularl y, it is unlikely to change the natural history of asthma. If patients are reluc tant to use ICSs daily for long periods, it would be reasonable to offer them in termittent therapy with ICSs if they have mild persistent symptoms. Initial ther apy with other anti-inflammatory therapies such as leukotriene receptor antagoni sts is not likely to be as effective as ICSs. 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. [ CLOSE WINDOW ] References 1.Barnes PJ. Inhaled glucocorticoids for asthma. N Engl J Med 1995; 332:868 873. 2.Djukanovic R, Wilson JW, Britten KM, et al. Effect of an inhaled corticosteroi d on airway inflammation and symptoms in asthma. Am Rev Respir Dis 1992; 145:669 6 74. 3.Bel EH, Timmers MC, Zwinderman AH, et al. The effect of inhaled corticosteroid s on the maximal degree of airway narrowing to methacholine in asthmatic subject s. Am Rev Respir Dis 1991; 143:109 113.

4.Parameswaran K, Inman MD, O'Byrne PM, Rowe BH. Protective effect of inhaled co rticosteroids in exercise-induced bronchospasm: a systematic review [abstract]. Am J Respir Crit Care Med 2001; 163:A587. 5.Gauvreau GM, Doctor J, Watson RM, et al. Effects of inhaled budesonide on alle rgen-induced airway responses and airway inflammation. Am J Respir Crit Care Med 1996; 154:1267 1271. 6.Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and bud esonide on asthma exacerbations. N Engl J Med 1997; 337:1405 1411. 7.Suissa S, Ernst P, Benayoun S, et al. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000; 343:332 336. 8.Haahtela T, Jarvinen M, Kava T, et al. Comparison of a beta-2 agonist, terbuta line, with an inhaled corticosteroid, budesonide, in newly detected asthma. N En gl J Med 1991; 325:388 392. 9.Haahtela T, Jarvinen M, Kava T, et al. Effects of reducing or discontinuing in haled budesonide in patients with mild asthma. N Engl J Med 1994; 331:700 705. 10.Haahtela T, Tamminen K, Kava T, et al. Thirteen-year follow-up of early inter vention with an inhaled corticosteroid in patients with asthma. J Allergy Clin I mmunol 2009; 124:1180 1185. In a follow-up to their landmark studies in the New England Journal of Medicine i n 1991 and 1994, Haahtela and colleagues report that 13 years later, delayed the rapy with inhaled corticosteroids in newly diagnosed asthmatics does not seem to have too many negative outcomes. 11.Pauwels RA, Pedersen S, Busse WW, et al, START Investigators Group. Early int ervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003; 361:1071 1076. 12.Chen YZ, Busse WW, Pedersen S, et al. 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. Pediatr Allergy Immunol 2006; 17(Suppl ):7 13. 13.Ldrup Carlsen KC, Devulapalli CS, Mowinckel P, et al. Lung function at 10 yrs is not improved by early corticosteroid treatment in asthmatic children. Pediatr Allergy Immunol 2010; 21:814 822. 14.Sheffer AL, Silverman M, Woolcock AJ, 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. Ann Al lergy Asthma Immunol 2005; 94:48 54. 15.Turpeinen M, Raitio H, Pelkonen AS, et al. Skin thickness in children treated with daily or periodical inhaled budesonide for mild persistent asthma. The Hel sinki early intervention childhood asthma study. Pediatr Res 2010; 67:221 225. 16.Sullivan SD, Buxton M, Andersson LF, et al. Cost-effectiveness analysis of ea rly intervention with budesonide in mild persistent asthma. J Allergy Clin Immun ol 2003; 112:1229 1236. 17.Busse WW, Pedersen S, Pauwels RA, et al, START Investigators Group. 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. J Allergy Clin Immunol 2008; 121:1167 1174. 18.Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids i n preschool children at high risk for asthma. N Engl J Med 2006; 354:1985 1997. 19.Boushey HA, Sorkness CA, King TS, et al, National Heart, Lung, and Blood Inst itute's Asthma Clinical Research Network. Daily versus as-needed corticosteroids for mild persistent asthma. N Engl J Med 2005; 352:1519 1528. 20.Nair P, Inman MD, Watson RM, et al. Protective effects of fluticasone on alle rgen-induced airway responses and sputum inflammatory markers. Can Respir J 2000 ; 7:313 319. 21.Subbarao P, Dorman SC, Rerecich T, et al. Protection by budesonide and flutic asone on allergen-induced airway responses after discontinuation of therapy. J A llergy Clin Immunol 2005; 115:745 750. 22.Cockcroft DW, McParland CP, O'Byrne PM, et al. Beclomethasone given after the early asthmatic response inhibits the late response and the increased methachol ine responsiveness and cromolyn does not. J Allergy Clin Immunol 1993; 91:1163 116

8. 23.Paggiaro PL, Dente FL, Morelli MC, et al. Postallergen inhaled budesonide red uces late asthmatic response and inhibits the associated increase of airway resp onsiveness to methacholine in asthmatics. Am J Respir Crit Care Med 1994; 149:14 47 1451. 24.Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eo sinophil counts: a randomised controlled trial. Lancet 2002; 360:1715 1721. 25.Jayaram L, Pizzichini MM, Cook RJ, et al. Determining asthma treatment by mon itoring sputum cell counts: effect on exacerbations. Eur Respir J 2006; 27:483 494 . Papers of particular interest, published within the annual period of review, 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. 51). Acknowledgement P.N. is supported by a Canada Research Chair in Airway Inflammometry. Curr Opin Pulm Med. 2011;17(1):12-15. 2011 Lippincott Williams & Wilkins