Pharmacotberapy

Pharmacotherapy — treatment of intermittent asthma with ICSs

I ntermittent asthma is a common pattern in infants andchildren.^ Episodes are most often triggered by viral,upper respiratory tract infections (URTIs).^ Treatment

of URTI-associated wheeze in infants and young childrenis particularly problematic because this form of asthma isless likely to be associated with atopy, appears to have a dif-ferent natural history^ and its optimal therapy has not beenclearly determined. Because children with intermittentasthma are asymptomatic between episodes, treating exac-erbations with short courses of ICSs, thus minimizing ex-posure to inhaled and systemic exogenous steroids, wouldappear to be an attractive option.

Literature review

A MEDLINE search for relevant articles was carriedout using the terms "glucocordcoids, topical" and "asthma"and "intermittent." Synonyms for "intermittent" including"periodic," "occasional," "sporadic," "interrupted," "cyclic"and "infrequent" were obtained using the ARTEL Project,Roget's Thesaurus and Merriam-Webster Online, and thesearch was repeated. One additional article was found inelectronic abstracts firom the American Thoracic SocietyMeetings 1998-2002, using the same search strategy. TheCochrane Library was also searched using the above textwords, as well as "wheezing." The bibliography of eachidentified article was searched for relevant papers. Thechoice of articles to review was confirmed by consensusamong the co-authors.

Articles relating to this topic published through to De-cember 2004 were also reviewed, but contained insufficientdata to modify the recommendations.

Current evidence

Although few articles have examined the efficacy of in-termittent therapy with ICSs, this management strategy ap-pears to be prevalent in Canada. One survey indicated that55% of children with asthma use and 48% of adults withasthma use inhaled condcosteroids "when getting an attackor having difficulty breathing.""* Only 43% of children useinhaled cordcosteroids everyday on a regular basis to helpcontrol asthma.' In otir literature review, we found only 5articles and 1 abstract that address this issue. These studies2II used metered-dose inhalers and spacers, except whereotherwise noted.

Wilson and Silverman^ enrolled 3 5 children with asthma3ged 1-5 years (mean age 3.5 years) in a double-blindcrossover study in which they were given beclomethasone.

750 pLg 3 times daily for 5 days, or placebo for use duringasthma exacerbations. Twenty-four children completed thetrial. Beclomethasone had no significant effect on admis-sions to hospital or need for prednisone. Symptom scoreswere significantly lower with active treatment both at nightand during the day during the first week, but not duringthe second week. Symptoms were relatively mild in all chil-dren, but decreased significantly in the first week: scoreswere L36 in the placebo group and 0.92 in the active treat-ment group. The duration of symptoms was similar in bothgroups. Virtually all episodes appeared to be related to viralURTI. The authors questioned whether the older spacerdesign used in this study provided adequate drug delivery,potentially reducing the treatment effect. Overall, 19 of 35parents in the active treatment group thought that thetreatment helped versus 9 of 35 in the placebo group.

Connett and Lenney^ enrolled 32 children, aged 1-5years (mean age 3.5 years) with a history of wheezing asso-

. ciated with URTI, in a double-blind crossover study. Thechildren were given budesonide, 800 pg twice daily byspacer with mouthpiece (or 1600 pg twice daily by spacerwith mask) or placebo, imdl symptoms had resolved, or for7 days. Each drug was given for 1 episode. If prednisonewas needed, subjects could re-enroll for an additional pairof treatments. Twenty-five children completed the study.Children tended to require prednisone more often duringplacebo treatment (8 v. 2 courses of treatment among 28treatment pairs). During the first week of a URTI, daytimeand nighttime wheezing scores were significantly lowerduring treatment with budesonide. Cough symptom scoresand bronchodilator use was similar for both treatments.Parents' preference for the active treatment was significant.

Svedmyr and colleagues^ enrolled 31 children withasthma known to deteriorate with URTI in a double-bliridcrossover study. They were given budesonide, 200 ]jg 4times daily by Turbuhaler, tapered over 9 days or placebofor use during asthma exacerbations triggered by a URTI.Twenty-two children completed the study; their agesranged from 3 to 10 years (mean 5.3 years). About half theparticipants used sodium cromoglycate concurrently. Mostof the children were atopic. Moming and evening PEE val-ues were significantly higher during treatment with budes-onide than with placebo (104% v. 96% of predicted, re-spectively). Symptom scores were similar in the 2 groups.Emergency department visits tended to be fewer duringtreatment with budesonide (3 v. 8 visits) and oral steroiduse (with or without admission to hospital) was significantlylower during active treatment (0 v. 5 times), although thiswas not stated in the article.

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Beci<er et ai

In a subsequent st^dy,^ 55 children 1-3 years of age(mean age about 2 years) with asthma exacerbated byLTRTI were enrolled for a randomized, double-blind, paral-lel group study of budesonide, 400 pg 4 times daily, taperedover 10 days, or placebo. The study lasted up to 12 months.A quarter of the children were atopic. Total and daytimeasthma symptom scores were significantly lower in the ac-tive treatment group (0.38 v. 0.55), and nighttime symp-toms tended to be less severe. Cough, sleep disturbanceand noisy breathing scores were significantly lower withbudesonide, and wheezing and dyspnea scores tended to belower as well. Oral steroid use, visits to the emergency de-partment, admissions to hospital and bronchodilator usewere similar in the 2 groups.

In a study by Volovitz and coworkers,' 193 children,ranging in age from 1 to 16 years, received budesonide,200-400 pg 4 dmes daily tapered over 4—8 days, duringacute exacerbations, then budesonide, 100 jig twice daily,iindl they were symptom-free for 6-8 weeks. If, after thatdme, they remained asymptomadc for 3 weeks, they usedbudesonide only during exacerbadons. One hundred andfifty children completed the study. MDI and spacers wereused in younger children and Turbuhalers in children over7 years of age. Children were followed for an average of1 year. Oral cordcosteroids appeared to be needed less fre-quendy (7% v. 67% ofthe children) and there were feweradmissions to hospital (0% v. 33%) during the 1-year fol-low-up than in the 3 months before enrolment in the study.There was no control group in this study, rates of eventsand stadsdcs were not provided and the authors do not ac-count for any potendal spontaneous improvement in thenatural history of URTI-associated asthma.

In a study"^ of 413 adults with asthma (mean age 43years; 403 completed the study) received a tapering courseof prednisolone, starting with 40 mg, or fludcasone, 1000pg twice daily for 16 days, for an asthma exacerbationjudged severe enough to require oral steroids, but not se-vere enough to require admission to hospital. About 3 in 4pardcipants were using ICSs at study entry at a mediandose of 800 pg/day. Improvements in PEF and symptomswere similar in the 2 groups, although the oral pred-nisolone dose used was reladvely low. The propordon oftreatment "failures" was also similar (22.7% with pred-nisolone V. 27% with fludcasone).

In a study" in children (?z = 55, age range 5-12 years) re-ported only in abstract form, fludcasone, 500 pg twice dailyfor 10 days, oral prednisone for 5 days and placebo werecompared in terms of prevendon of asthma exacerbadonsassociated with URTI in children with mild asthma. Dur-ing the 2 weeks of treatment, morning PEFs were signifi-candy lower with placebo than with fludcasone or pred-nisone (221, 254 and 234 L/minute respectively), butrescue bronchodilator use was similar in all 3 groups (17,18 and 15 doses/week, respecdvely).

Nuhoglu and colleagues'" compared the effecdveness ofbudesonide, 400 jig 4 dmes daily, with oral methylpred-

nisolone in 60 children with asthma, aged 4—17 years, dur-ing an acute exacerbadon not requiring hospital admission,but unresponsive to bronchodilator use alone. Treatmentwas condnued for 3 days, and accompanied by mandaton-use of a bronchodilator 4 dmes a day. The padents' meanage was about 9 years, and just under 50% were taking pro-phylacdc inhaled steroids. The clinical score improved sig-nificandy more in the high-dose inhaled steroid group (2.6V. 1.9), and pulmonary funcdon improved significandy inboth groups (13.7% and 13.4% improvement).

Hedlin and colleagues'^ examined the systemic effects ofa short course of inhaled steroids compared with systemicsteroids in a companion paper to their 1999 study,* using apordon of the original study populadon. No significantchanges in serum cordsol, osteocalcin, bone markers, orurine cordsol-creatinine ratio occurred after treatmentwith budesonide, but significant changes in all of these lev-els, save serum cordsol, occurred with oral betamethasone.

Brieva and coworkers'** reported that in 31 adults (aver-age age 36 years), fludcasone, 250 pg twice daily for 2weeks, significandy reduced airway mucosal blood flow (by11.3%) resuldng in more normal values. Patients withasthma were noted to have a blunted vasodilator responseto salbutamol, which normalized after administradon offludcasone, suggesting reversal of a previous downregula-don of P-receptor funcdon. The authors suggest that in-termittent therapy may have some effect on airway physiol-ogy. Unfortunately, no similar data are available for apediatric populadon.

In a study of 52 adults, aged 20-50 years, Convery andcolleagues'^ reported that an improvement in methacholineresponsiveness conferred by fludcasone, 2000 jig daily for6 weeks, dissipated within 2 weeks of stopping therapy,suggesting that intermittent or "pulse" therapy was unlikelyto be effecdve in providing long-term asthma control.

Discussion

High-dose inhaled steroids given intermittently forasthma triggered by URTI appear to reduce asthma symp-tom scores, although duradon of symptoms does not ap-pear to be altered. The effect on symptom scores was gen-erally small and may not be clinically significant. Similarly,intermittent high-dose inhaled steroids appear to improvepulmonary funcdon, including PEF rates; however, moreclinically important outcomes, including visits to emer-gency departments, admissions to hospital and a require-ment for systemic steroids do not appear to be affected.Trials reported in the literature may have been too smaO todetect a small, but real, effect. It should be noted that regu-lar treatment with inhaled steroids has been shown to im-prove these asthma outcomes in many high-quality tdals inchildren, where most of the exacerbadons were almost cer-tainly triggered by viral URTIs.'-"^"" Although shortcourses of systemic steroid also appear to prevent severe ex-acerbadons,'^ repeated courses of oral steroids may have

S34 JAMC • 13 SEPT. 2005; 173 (6)

Pharmacotherapy

greater systemic effects than regular therapy with usualdoses of inhaled steroids.^" Systemic effects from intermit-tent high-dose inhaled steroids appear to be low, althoughthe evidence to confirm this is minimal. Nuhoglu and col-leagues ^ speculated that the rapid effects several studieshave noted with high-dose inhaled steroids may be due tothe rapid mucosal blanching resulting from reduction inmucosal edema and vasoconstriction produced by topicalapplication of high-potency glucocordcoids.

In a recent review of this subject, conclusions similar toours were reached by Hendeles and Sherman-' who notedthat inhaled steroids, "if started early and in high doses,provide modest benefit in the acute treatment of patientswith mild exacerbations of asthina. At home, early institu-tion prevented neither the need for intervention with oralcorticosteroid nor hospital admission in young childrenwith virus-induced asthma." However, somewhat confUct-ing findings were reported in a Cochrane review of inhaledsteroids for episodic viral wheezing.^^ This meta-analysiscontrasted reports from Connett and Lenney/' Wilson andSilverman' and Svedmyr and colleagues'^ with 2 studies"' "^that used regular treatment with conventional doses of in-haled steroids in children with recurrent wheezing associ-ated with viral URTIs. However, the participants in 1 ofthe 2-comparator trials had a history of parent-reportedwheezing, and it is unclear whether these patients hadasthma or recurrent , true wheezing. McKean and,Ducharme" concluded that "there is no evidence to suggestthat a low daily dose of inhaled corticosteroid is beneficialin the prophylaxis of mild episodic viral wheeze. Con-versely, high-dose episodic inhaled cordcosteroids appearpartially effective in preventing or attenuating viral-induced episode in children with predominantly mildepisodes." A recent placebo-controlled crossover trial ofregular treatment with fiudcasone in children with inter-mittent wheeze" reported a significant improvement in air-way resistance measured by the interrupter technique withactive treatment.

Treatment of children with intermittent courses of in-haled steroids has become a "community standard." Regu-lar use of low-dose inhaled steroids is currendy the recom-mended t rea tment for children, even those withintermittent asthma symptoms. The use of intermittenttreatment as a strategy for management of intermittentasthma in childhood requires furtiier validadon, pardcu-larly in very young children.^^

Implications for research

1- Large, randomized, placebo-controlled trials shouldevaluate the effect of intermittent treatment with high-dose inhaled steroids on important health outcomes, in-cluding the need for prednisone, visits to emergencydepartment and admission to hospital.

2. Studies should compare the efficacy and safety of inter-niittent treatment Avith high-dose inhaled steroids com-

pared with regular therapy with convendonal doses ofinhaled steroids, pardcularly for children with intermit-tent asthma triggered by viral URTI.

Implementation strategies

1. Community physicians will need to be aware that inter-mittent treatment with high-dose inhaled steroids ap-pears to have fairly minimal clinical effect, and in chil-dren placed on this form of therapy, careful monitoringis essendal to verify that the treatment is successful atachieving acceptable asthma control.

2. Further efforts are required to increase the awareness ofcommunity physicians that children who fail this formof therapy or who have more severe asthma must betreated with inhaled steroids administered on a long-term basis, at least during the season(s) when the childis at risk of asthma exacerbadons.

References

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2. Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F.Josephs L, etal. Community study of role of viral infections in exacerbations of asthma in9-11 year old children. BMJ 1995;310(6989): 122 5-9.

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6. Connett G, Lenney W. Prevention of viral induced asthina attacks using in-haled budesonide. Arch Dis Child 1993;68(l):85-7.

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10. Levy ML, Stevenson C, Maslen T. Comparison of short courses of oral pred-nisolone and fiudcasone propionate in the treatment of adults with acute ex-acerbadons of asthma in primary care. Thorax 1996;51(11): 1087-92.

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12. Nuhoglu Y, Bahceciler NN, Barlan IB, Mujdat Basaran M. The effecdvenessof high-dose inhaled budesonide therapy in the treatment of acute asthma ex-acerbadons in children. Ann Allergy Asthma /m7«Hno/2001;86(3):318-22.

13. Hedlin G, Svedmyr J, Ryden AC. Systemic effects of a short course of be-tamethasone compared with high-dose inhaled budesonide in early childhoodasthma. ^rtflPae^wrrI999i88(l):48-51.

14. Brieva JL, Danta I, Wanner A. Effect of an inhaled glucocordcosteroid onairway mucosal blood flow in mild asthma. Am J Respir Crit Care Med2000;161(l):293-6.

15. Convery RP, Leitch DN, Bromly C, Ward RJ, Bartlett G, Hendrick DJ. Ef-fect of inhaled fiudcasone propionate on airway responsiveness in treatment-naive individuals — a lesser benefit in females. Eur Respir J 2{iQQ\\S(\):\9-2'\.

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17. Long-term effects of budesonide or nedocromii in children with asthma. TheChildhood Asthma Management Program Research Group. N Engl J Med200a;343(15):1054-63.

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