commentaries on ‘addition of long-acting beta-agonists to inhaled corticosteroids for chronic...

EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNALEvid.-Based Child Health 5: 959–966 (2010)Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ebch.498

Commentary

Commentaries on ‘Addition of long-acting beta-agoniststo inhaled corticosteroids for chronic asthma in children’Steve Turner,1 Mike Thomas,2* Stephen C. Lazarus,3** Moshe Zutler,3 Lori Connors,4 Paul K. Keith4***and Paul L. P. Brand5****1Child Health, University of Aberdeen, Aberdeen, Scotland2Centre of Academic Primary Care3University of California, San Francisco, CA, USA4Division of Allergy and Clinical Immunology, McMaster University, Ontario, Canada5Princess Amalia Children’s Clinic, The Netherlands

These are commentaries on a Cochrane review, published in this issue of EBCH, first published as: NiChroinin M, Lasserson TJ, Greenstone I, Ducharme FM. Addition of long-acting beta-agonists to inhaledcorticosteroids for chronic asthma in children. Cochrane Database of Systematic Reviews 2009, Issue 3. Art.No.: CD007949. DOI: 10.1002/14651858.CD007949.

Further information for this Cochrane review is available in this issue of EBCH in the accompanyingSummary article.

Commentary by Steve Turner and MikeThomas

Chronic childhood asthma is a global public healthproblem and is the commonest long-term illnessamongst children in industrialized societies (1,2). Theprevalence of childhood asthma has increased dramat-ically over the last 30 years, and although it mayhave leveled off in industrialized countries, a risecontinues in many developing countries (3). As nocure or effective primary prevention strategy exists,management is aimed at reducing the current impactof the disease and the risk of future complications,such as exacerbations and progressive impairment inlung function (4). Asthma is defined as ‘a chronicinflammatory disorder of the airways . . . inflamma-tion is associated with airways hyperresponsivenessthat leads to recurrent episodes of wheezing, breath-lessness, chest tightness and coughing . . . associ-ated with widespread, but variable, airflow obstructionwithin the lungs that is often reversible either sponta-neously or with treatment’ (1). As the main patho-logical features of asthma are airways inflammation

*Correspondence to: Dr Mike Thomas, Cotswold Cottage, Oakridge,Stroud, Gloucs GL6 7NZ, UK. E-mail: [email protected]∗∗Correspondence to: Stephen C. Lazarus, University of California,San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143-0111,USA. E-mail: [email protected]***Correspondence to: Paul K. Keith, Division of Allergy and ClinicalImmunology, McMaster University, 1280 Main Street West, Hamilton,Ontario, Canada, 905 525 9140. E-mail: [email protected]****Correspondence to: Paul L. P. Brand, Princess Amalia Children’sClinic, Isala Klinieken, PO Box 10400, 8000 GK Zwolle, TheNetherlands. E-mail: [email protected]

and bronchoconstriction, pharmacotherapy centres onanti-inflammatory and bronchodilator medication. Thesymptoms of asthma are, however, not exclusive andare also associated with lower respiratory tract infec-tion and viral induced wheeze, a recurrent wheezingcondition in preschool children; asthma symptoms inyoung children can cause diagnostic and therapeuticuncertainty.

For children diagnosed with asthma whose symp-toms are persistent and are present on more than twodays a week, initial pharmacological treatment is withlow dose inhaled corticosteroids (ICS); this step iseffective and known to improve symptom control andreduce the risk of exacerbations (5). Approximately90% of children in the UK aged 5–12 years who areprescribed ICS receive treatment at low doses (6).However, in one large US trial up to 50% of childrenreceiving low dose ICS treatment alone had episodesof poor control and over one-third had an exacer-bation requiring oral corticosteroids over a 48-weekstudy period (7). Clearly some children with asthmarequire treatment beyond low dose ICS. Current guide-lines recommend that the next treatment step afterlow dose ICS in children aged over 5 years is addi-tion of inhaled long acting B2 agonists (LABA) eitheras a second inhaler or in a fixed-dose combinationinhaler with an ICS (1,8). For individuals in whomthe addition of LABA does not result in good asthmacontrol, clinicians can either increase to an interme-diate ICS dose or consider other non-steroidal ‘addon’ treatments, i.e. leukotriene receptor antagonist ortheophylline. Although studies in adults support therecommendation to add on LABA to low dose ICS (9),

Copyright 2010 John Wiley & Sons, Ltd.

Addition of long-acting beta-agonists to inhaled corticosteroids for chronic asthma 960

there is a widespread perception that the evidence-baseunderpinning LABA treatment in children with asthmais inadequate (2); the recent Cochrane review with afocus on LABA is therefore timely (10). There area number of uncertainties as to LABA treatment inchildren with asthma. First, the efficacy of LABA inyounger age groups has been demonstrated in some butnot all studies (9). Second there is no consensus of thedose of ICS at which it is appropriate to add in LABAtreatment (8,11). Some children on low dose ICSmight benefit from an increased ICS dose whilst oth-ers will be close the plateau of the ICS dose-responsecurve and symptom control may be better with addi-tion of second agents such as LABA (12). Finally,there have been widely publicized recent safety con-cerns over LABAs in the treatment of asthma, withsuggestions that they may increase the risk of severeexacerbations (13) and even mortality (14).

The review by Ni Chroinin and colleagues summa-rizes the relevant literature (10). This review, pub-lished by the Cochrane Collaboration in 2009, extendsthe work of the same authors in 2005 (9) at whichtime only nine paediatric studies could be identified ofwhich only four were relevant to the primary outcome(asthma exacerbation requiring oral steroid prescrip-tion). The latest review identifies an additional 14randomized paediatric controlled trials published since2004. The fact that the majority of the evidence toguide patient management has been published in thelast 5 years is proof that researchers are actively look-ing to close the considerable knowledge gaps. In the2009 review, the selected trials were placed in oneof two groups: (i) comparing the addition of LABAto ICS at the same dose, and (ii) addition of LABAwith no increase in ICS dose to an increased ICSdose. As in the 2005 review, the primary outcomewas the number of asthma exacerbations requiring ashort course of systemic corticosteroids. Secondaryoutcomes included pulmonary function, daily symp-toms, adverse events and withdrawals.

There were 16 studies where LABA was added onto low-intermediate ICS doses (in children equivalent≤400 mgs budesonide diproprionate or equivalent).There were minor improvements in lung function (80mls FEV1) and less withdrawals (approximately 20%fewer) in those where LABA was introduced butno differences in primary outcome. Importantly, inseven studies the children were well controlled andit is questionable whether the addition of LABA toICS was indicated as symptoms could not be furtherimproved; inclusion of these seven studies is expectedto weaken any benefit from adding LABA to ICStreatment.

The outcomes in the seven studies where the addi-tion of LABA was compared to increasing ICS dosewere that firstly, there was no difference in primaryoutcome and secondly there were marginal improve-ment in lung function and growth in those receivingLABA treatment. When the results were pooled, theseseven studies included more than 1000 children, but

there may still be an issue of power since confidenceintervals were wide. The addition of LABA, com-pared to increasing ICS dose, was associated with a50% increased risk for primary outcome and 120%increased risk for hospitalisation but these failed toachieve significance; with more participants these dif-ferences may become significant.

The 2009 systematic review (10) makes an impor-tant contribution to the current understanding of animportant clinical question ‘What do I do with a childwith asthma whose symptoms are not controlled onlow dose ICS?’. The review highlights the enthusi-asm for this research question, and the uncertaintiesthat remain. The review also highlights challenges ininterpreting results of heterogeneous trials, includingthe use of: different doses of ICS; different steroidmolecules; different age-ranges; different symptomsscores on enrolment. In addition, these studies werenot primarily designed to address the safety concernsregarding LABAs that have recently influenced theFDA to alter the labeling of products containing thisclass of asthma medication (15) The clinician shouldnot deviate from current guidelines, but should care-fully assess the risks and benefits of treatment andclosely monitor the individual child to ensure that thetreatment is having the intended benefits, since differ-ent children may react in different ways to differenttherapies (12). Researchers should focus on guidelinerecommendations when designing studies, eg considerspecific ICS doses in specific age-ranges, and shoulddesign trials to encompass the heterogeneity of child-hood asthma (16). Rare but serious adverse eventsare of great importance in assessing the risk-benefitratios in a common condition such as asthma. Theauthors look forward to the 2015 Cochrane review onthis subject.

Declaration of Interest

None

References

1. Global Initiative for Asthma. http://www.ginasthma.com/.2. Holgate S, Bisgaard H, Bjermer L, Haahtela T, Haughney J,

Horne R, et al. The Brussels Declaration: the need for change inasthma management. Eur Respir J 2008; 32: 1433–1442.

3. Asher MI, Montefort S, Bjorksten B, Lai CK, Strachan DP,Weiland SK, et al. Worldwide time trends in the prevalence ofsymptoms of asthma, allergic rhinoconjunctivitis, and eczema inchildhood: ISAAC Phases One and Three repeat multicountrycross-sectional surveys. Lancet 2006; 368: 733–743.

4. Taylor DR, Bateman ED, Boulet L-P, Boushey HA, Busse WW,Casale TB, et al. A new perspective on concepts of asthma severityand control. Eur Respir J 2008; 32: 545–554.

5. Anonymous. Long-term effects of budesonide or nedocromilin children with asthma. The Childhood Asthma ManagementProgram Research Group. N Engl J Med 2000; 343: 1054–1063.

6. Turner S, Thomas M, von Ziegenweidt J, Price D. Prescribingtrends in asthma: a longitudinal observational study. Arch DisChild 2009; 94: 16–22.

Copyright 2010 John Wiley & Sons, Ltd. Evid.-Based Child Health 5: 959–966 (2010)DOI: 10.1002/ebch.498

961 S. Turner et al.

7. Sorkness CA, Lemanske RF, Jr., Mauger DT, Boehmer SJ,Chinchilli VM, Martinez FD, et al. Long-term comparison of3 controller regimens for mild-moderate persistent childhoodasthma: the Pediatric Asthma Controller Trial. J Allergy ClinImmunol 2007; 119: 64–72.

8. BTS/SIGN. British guideline on the management of asthma.http://www.sign.ac.uk/guidelines/fulltext/101/index.html 2008.

9. Ni Chroinin M, Greenstone IR, Danish A, Magdolinos H, MasseV, Zhang X, et al. Long-acting beta2-agonists versus placebo inaddition to inhaled corticosteroids in children and adults withchronic asthma. Cochrane Database of Systematic Reviews 2005;4.

10. Ni Chroinin M, Greenstone I, Lasserson TJ, Ducharme FM.Addition of inhaled long-acting beta2-agonists to inhaled steroidsas first line therapy for persistent asthma in steroid-naive adultsand children. Cochrane Database of Systematic Reviews 2009; 4.

11. Becker A, Berube D, Chad Z, Dolovich M, Ducharme F, D’UrzoT, et al. Canadian Pediatric Asthma Consensus guidelines, 2003.Can Medic Assoc J 2005; 173(6 Suppl): 13.

12. Lemanske RFJ, Mauger DT, Sorkness CA, et al. Stepup therapyfor children with uncontrolled asthma while receiving inhaled cor-ticosteroids. N Engl J Med 2010; DOI: 10.1056/NEJMoa1001278.

13. Palmer CN, Lipworth BJ, Lee S, Ismail T, Macgregor DF,Mukhopadhyay S. Arginine-16 beta2 adrenoceptor genotypepredisposes to exacerbations in young asthmatics taking regularsalmeterol. Thorax 2006; 61(11): 940–944.

14. Drazen JM, O’Byrne PM. Risks of long-acting beta-agonists inachieving asthma control. N Engl J Med 2009; 360: 1671–1672.

15. Kramer JM. Balancing the benefits and risks of inhaled long-actingbeta-agonists–the influence of values. N Engl J Med 2009; 360:1592–1595.

16. von Mutius E, Drazen JM. Choosing Asthma Step-up Care. N EnglJ Med 2010; DOI: 10.1056/NEJMe1002058.

Commentary by Moshe Zutler and StephenC. Lazarus

Although beta-agonists are the most widely prescribeddrugs for the treatment of asthma, controversy abouttheir safety has existed for decades. In the 1960s, amini-epidemic of asthma deaths in the UK was linkedto the use of isoproterenol forte, a potent and relativelynon-selective short-acting beta-agonist (SABA) (1).No increase in mortality was seen in the US or inEuropean countries where this drug was not marketed(2). In the 1970s and 1980s, increased asthma deathsin New Zealand were linked to a new, highly potentbeta-agonist fenoterol (3), and a 1992 Canadian case-control study utilizing a national pharmacy databaselinked excessive SABA use and death (4,5). In eachof these cases, careful analysis suggested either thatthese were effects of specific drug formulations andnot SABA class effects, or that increased SABA usewas a marker of poorly-controlled asthma.

Long-acting beta-agonists (LABAs) were first ap-proved in the US in the 1990s; however, almost20 years later, their exact role in asthma therapy hasyet to be defined. Just as for SABAs, concern aboutpossible side effects has led to confusion about theirposition in the therapeutic algorithm. The first indica-tor of possible concern came from a large UK surveil-lance study that compared the addition of salmeterolor albuterol to standard therapy in 25,180 adult asth-matics (6). There was a non-significant increase inthe number of respiratory and asthma-related deaths

in the salmeterol group (0.07% vs 0.02%, p = 0.105),although the salmeterol group had fewer withdrawalsbecause of worsening asthma (2.91% vs 3.79%, p =0.0002). Stimulated by these data and by the popu-lar use of salmeterol as monotherapy, the NHLBI’sAsthma Clinical Research Network compared inhaledsalmeterol or triamcinolone to placebo in adult patientswith moderately-severe asthma, finding that salmeterolmonotherapy was effective at improving airway func-tion and symptoms, but no better than placebo at pre-venting exacerbations or at reducing airway inflamma-tion. (7) Finally, in the SMART study, 26,355 patients12 years and older were given salmeterol or placeboin addition to usual care and followed for 28 weeks;there were more asthma-related deaths noted in the sal-meterol group (8). It has been difficult to draw conclu-sions from these studies in aggregate, because the datasuggesting a benefit from use of LABAs have beenmore convincing than those suggesting harm. Specif-ically, although many studies have shown a trendtoward increased adverse events, few have shown sta-tistically significant differences, and many have sug-gested that the risk may be limited to subgroups, suchas African Americans (8) or individuals harboring cer-tain beta-adrenergic receptor polymorphisms (9).

The relative paucity of conclusive data has ledto differing recommendations in national pediatricguidelines. Whereas a clear benefit from the additionof a LABA to an inhaled corticosteroid (ICS) regimenhas been shown in adults (10), this result has not borneout as conclusively in the pediatric population. Aprevious Cochrane Review of both children and adultswith uncontrolled asthma demonstrated a significantreduction in exacerbations and improvement in FEV1with the addition of a LABA to an ICS as compared toan ICS alone (11). Subsequent studies have questionedthe safety of LABA in the pediatric population whichprompted the authors to examine the efficacy andsafety of adding a LABA to the same or increaseddose of ICS solely in the pediatric population.

This review of 26 randomized controlled trialsencompassing over 5,000 children, found no signif-icant reduction in asthma exacerbation rates fromadding a LABA to either an existing or higher dose ofICS. However, there was a non-statistically significanttrend towards a two-fold increase in exacerbations andasthma-related hospitalizations in children receivingLABA therapy. Other secondary endpoints, includingFEV1 and peak flow, increased significantly in theLABA arm, although this did not translate into statis-tically improved symptoms, quality of life, symptom-free days or rescue medication use.

There was no difference in adverse events in theLABA vs. same or high-dose ICS comparison armsor a difference in withdrawals due to poor asthmacontrol except for a significantly higher growth rateover 1 year in the LABA group as compared tothe high-dose ICS group. However, this effect wasonly measured in two studies and thus is difficult toextrapolate to the group as a whole.



The methodology of this review was commendable.An extensive electronic search along with effortsto obtain unpublished data and missing informationfrom prior published studies was performed to updatethe previously published review (11). Randomizedcontrolled trials were evaluated and independentlyreviewed for inclusion in this analysis. The maindrawback to the quality of this meta-analysis is thequality of the studies available for review. Onlyseven out of 24 studies had information available tocompare the primary outcome of asthma exacerbationsin the LABA vs. same-dose ICS arm; two of sixstudies had primary outcome data in the LABAvs. high-dose ICS arm. As the authors admit, thisdecreased the power of the analysis to detect adiffering outcome between the two comparison groupsand validate the trends seen in the group receivingLABA therapy.

The discrepancy between the improvement in FEV1and peak flow in the LABA arm and the lackof improvement in the rate of asthma exacerba-tions or hospitalizations raises interesting questionsabout mechanisms. The spirometric improvement withLABAs likely reflects a direct bronchodilator effectwhereas asthma exacerbations represent a complexchain of inflammatory events involving multiple gene-environment interactions that likely require longerfollow-up studies to demonstrate a significant differ-ence in outcomes.

Unfortunately, this study cannot define the mostprudent escalation strategy for children with poorlycontrolled asthma. We are left to balance the improvedspirometric outcomes and improved growth rateagainst a possible, albeit not statistically significant,trend towards increased exacerbations and hospitaliza-tions.

Pediatricians are, appropriately, very conservativein their approach to pharmacotherapy, and are muchless tolerant of ‘potential’ side effects than are thosewho care for adults. Until recently the preponder-ance of clinical data suggested a beneficial effectfrom LABAs, and the data on risk were much lessconvincing. However, recent data on risk of LABAsin adults and children, while still mostly suggestive,has heightened concern (12). At its February 2010meeting the FDA reviewed the SMART Study (8),the Serevent Nationwide Surveillance Study (6), andtheir own meta-analyses. Although they concluded that‘. . . the benefits of LABAs continue to outweigh therisks’, they issued new guidelines emphasizing cau-tion in their use and mandated drug label changes(13). These new FDA regulations are an attempt tohighlight the potential concerns regarding LABAs andre-affirm recommendations that have been articulatedin prior guidelines and supported by current literature(14,15).

Clearly further research, including a randomizedcontrolled trial of significant duration and statisti-cal power along with further in-depth studies ofmechanism, is sorely needed to help parse out the

explanations for these persistent inconsistencies. Thispaper adds to the growing call of practitioners whocontinue to struggle with the available body of lit-erature in guiding their decision making regardingescalation of care in children with poorly controlledasthma.

Declaration of Interest

None

References

1. Inman WH, Adelstein AM. Rise and fall of asthma mortality inEngland and Wales in relation to use of pressurised aerosols.Lancet 1969; 2(7615): 279–285.

2. Stolley PD. Asthma mortality. Why the United States was sparedan epidemic of deaths due to asthma. Am Rev Respir Dis 1972;105(6): 883–890.

3. 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(8728):1391–1396.

4. Spitzer WO, Suissa S, Ernst P, Horwitz RI, Habbick B, Cock-croft D, Boivin JF, McNutt M, Buist AS, Rebuck AS. The use ofbeta-agonists and the risk of death and near death from asthma. NEngl J Med 1992; 326(8): 501–506.

5. Suissa S, Ernst P, Boivin JF, Horwitz RI, Habbick B, Cockroft D,Blais L, McNutt M, Buist AS, Spitzer WO. A cohort analysis ofexcess mortality in asthma and the use of inhaled beta-agonists.Am J Respir Crit Care Med 1994; 149(3 Pt 1): 604–610.

6. Castle W, Fuller R, Hall J, Palmer J. Serevent nationwidesurveillance study: comparison of salmeterol with salbutamol inasthmatic patients who require regular bronchodilator treatment.BMJ 1993; 306(6884): 1034–1037.

7. Lazarus SC, Boushey HA, Fahy JV, Chinchilli VM, LemanskeRF, Sorkness CA, et al. Long-Acting ß2-Agonist Monotherapy vsContinued Therapy With Inhaled Corticosteroids in Patients WithPersistent Asthma. A Randomized Controlled Trial. JAMA 2001;285: 2583–2593.

8. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM.The Salmeterol Multicenter Asthma Research Trial: a comparisonof usual pharmacotherapy for asthma or usual pharmacotherapyplus salmeterol. Chest 2006; 129(1): 15–26.

9. Wechsler ME, Lehman E, Lazarus SC, et al. Beta-Adrenergicreceptor polymorphisms and response to salmeterol. Am J RespirCrit Care Med 2006; 173(5): 519–526.

10. Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaledformoterol and budesonide on exacerbations of asthma. N EnglJ Med 1997; 337: 1405–1411.

11. Greenstone IR, Ni Chroinin MN, Masse V, Danish A, Magdali-nos H, Zhang X, Ducharme FM. Combination of inhaled long-acting beta2-agonists and inhaled steroids versus higher dose ofinhaled steroids in children and adults with persistent asthma.Cochrane Database Syst Rev 2005; (4): CD005533.

12. Drazen JM, O’Byrne PM. Risks of long-acting beta-agonists inachieving asthma control. N Engl J Med 2009; 360: 1671–1672.

13. Chowdhury BA, Dal Pan G. The FDA and Safe Use of Long-Acting Beta-Agonists in the Treatment of Asthma. N Engl J Med2010; Feb 24.

14. National Asthma Education and Prevention Program. Expert panelreport 3: guidelines for the diagnosis and management of asthma.Bethesda, MD: National Heart, Lung, and Blood Institute: 2007;1–440.

15. Global Strategy for Asthma Management and Prevention. GlobalInitiative for Asthma 2009; 1–92.



Commentary by Lori Connorsand Paul K. Keith

Asthma is an increasingly prevalent disease in thepediatric population. Current guidelines recommendthe use of inhaled corticosteroids (ICS) for asthmacontrol. For poorly controlled asthma the addition ofa long-acting beta2-agonist (LABA) or leukotriene-receptor anatagonist (LTRA) is suggested. For thepediatric population there has been some variabilityin guidelines for when to add a LABA. For instance,the Canadian guidelines recommend adding a LABAin children aged 6 to 11 years only after increasingthe ICS to moderate dose (201–400 mcg/day HFA-beclomethasone equivalent). They recommend addinga LABA in children over 12 years of age in com-bination with an ICS as add-on therapy only (1).The British Thoracic Society (BTS) guidelines rec-ommend adding a LABA to ICS when the ICS doseis in the moderate range (200–400 mcg/day HFA-beclomethasone equivalent) (2).

Ni Chroinin and colleagues sought to compare thesafety and benefit of adding LABA to ICS with thesame or an increased dose of ICS in children withpersistent asthma (3). In this systematic review andmeta-analysis they reviewed randomised controlledtrials comparing LABA plus ICS to the same orincreased dose of ICS. The review included 25 trialsand 5572 children.

Their primary outcome was asthma exacerbationrequiring systemic steroids. They separated their datainto Step 2 vs Step 3 therapy (LABA plus ICS vs samedose of ICS) and Step 3 vs Step 3 therapy (LABAplus ICS vs increased dose of ICS). These steps werebased on the GINA 2007 guidelines and the BTSguidelines (2,4). They found no significant differencein exacerbations in either subgroup, however, theyonly had data available from a total of 11 of the25 trials included in the review. The authors did tryto contact study investigators or study sponsors toobtain exacerbation data but were unsuccessful in themajority of cases.

The secondary outcomes included hospital admis-sions, pulmonary function tests, symptoms, quality oflife scores, use of rescue short-acting beta2-agonists(SABA), changes in measures of inflammation andrates of adverse effects. Again, the data was analyzedin two subgroups. They found no significant differ-ence in either subgroup for the secondary outcomes,with the exception of pulmonary function. There wasa small, but significant, improvement in FEV1 in thoseon combination therapy as compared to those on samedose ICS plus placebo or double dose ICS. There wasalso a significantly increased rate of growth in those oncombination therapy as compared to the other groups.

The main conclusion from this review is that weremain uncertain where and when LABAs should beused in pediatric asthma. Certainly, we know that aLABA should not be used alone, rather, it should beused in combination with an ICS. It remains unclear

if a LABA should be added prior to increasing ICSdose.

There is much left to learn about LABAs in pediatricasthma. We agree with the study authors that furtherdata is needed on rate of exacerbations as wellas hospital admissions in patients on combinationtherapy. It would be prudent to do further studies inthis area. Also, the lack of change in use of rescueinhalers as well as symptom scores is different fromthe data on combination therapy in adults with asthma.In adult studies it has been found that combinationtherapy leads to a decreased risk of exacerbationsrequiring oral steroids, increased number of symptom-free days, improved pulmonary function and decreaseduse of rescue medications (5).

There is a geographic variation in asthma guidelineson when to introduce a LABA in the management ofa child with asthma. From this review, it is difficultto recommend a change in current practice. However,if pulmonary function and growth are consideredimportant clinical outcomes in asthma this reviewstrengthens support for the use of LABAs in thepediatric population. A recent study on step-up therapyin pediatric patients with LABA plus ICS vs ICSstep-up or LTRA step-up found that LABA step-up was significantly more likely to provide the bestresponse using a composite endpoint which includedexacerbations that required prednisone. This crossoverstudy included 182 children with persistent asthma andtreated them for 16 weeks with each therapy (6).

The present analysis had difficulty obtaining the datafor the primary outcome. If all data had been availablethe authors may have been able to detect differences inthe primary or secondary outcomes. Follow-up timesin these studies may not have been long enough todetect an exacerbation requiring systemic steroids orhospitalization as studies as short as 28 days wereincluded. As per the study authors, we agree thatfurther studies require adequate follow-up time andmonitoring for all primary and secondary outcomes.Their suggested duration of 24 weeks would be helpfulto determine differences.

A recent FDA warning suggests that LABAs shouldbe used as combination therapy only (7). In additionit suggests that LABAs be used only in those whoseasthma is inadequately controlled on ICS. They alsosuggest LABAs should be used to gain control andthen therapy should be stepped down to ICS alonewhen control is achieved but little guidance is givenas to how long control needs to be achieved before thisis done. Certainly, further research in when and howto use LABA in combination with ICS in children iswarranted to clarify these issues.

Thus, in this review although adding a LABA toan ICS had a similar rate of moderate exacerba-tions or hospital admissions as doubling the dose ofinhaled corticosteroids, combination therapy improvedlung function and lead to greater growth in pedi-atric patients with persistent asthma. The review found



combination therapy of a LABA and ICS was welltolerated.

Declarations of Interest

None

References

1. Lougheed MD, Lemiere M, Dell SD, et al. Canadian ThoracicSociety Asthma Management Continuum – 2010 Consensussummary for children six years of age and over, and adults. CanRespir J 2010; 17(1): 15–24.

2. British Thoracic Society. British Guideline on the Management ofAsthma. BTS website www.brit-thoracic.org.uk 2007.

3. Ni Chroinin M, Lasserson TJ, Greenstone I, Ducharme FM.Addition of long-acting beta-agonists to inhaled corticosteroids forchronic asthma in children (Review). Evidence-Based Child Health:A Cochrane Review Journal 2010; in press.

4. Global Initiative for Asthma. Global Strategy for AsthmaManagement and Prevention. NIH Publication 2007:Available at:http://www.ginasthma.com.

5. Ni Chroinin M, Greenstone IR, Danish A, Magdolinos H,.6. Masse V, Zhang X, Ducharme FM. Long-acting beta2-agonists

versus placebo in addition to inhaled corticosteroids in childrenand adults with chronic asthma. Cochrane Database of SystematicReviews 2005; Issue (4):.

7. Lemanske RF Jr, Mauger DT, Sorkness CA, et al. Step-up therapyfor children with uncontrolled asthma receiving inhaled corticos-teroids. N Engl J Med 2010; DOI: 10.1056/NEJMoa1001278.

8. FDA Long-Acting Beta Agonist (LABA) Information. http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm199565.htm Updated February 18, 2010.

Commentary by Paul L. P. Brand

It has been the major dilemma in paediatric asthmamanagement for almost 20 years: what should bethe first choice of additional treatment when inhaledcorticosteroids alone are insufficient to control asthmain children? International evidence based guidelinesrecommend to add long-acting beta agonists (LABA),such as formoterol or salmeterol, as the first option inthis ‘step 3’ of asthma management (1,2). Well, thiswill have to be adapted now, because the Cochranereview published in this issue of Evidence Based Child

Health clearly shows that LABA do little, if anything,to improve asthma control in children.

Methodology and Main Findings of theCochrane Review of Laba Addition to Icsin Childhood Asthma

As expected with this group of seasoned Cochranereview authors, the methodology of the review issound. Although the authors admit that they haven’tbeen able to retrieve all the relevant data fromthe retrieved published and unpublished studies, thereview contains comprehensive data on a varietyof clinically relevant endpoints in childhood asthmamanagement from 25 studies on a total of 5572children. That is a big review, in particular in children,allowing for rather precise effect size estimates.

Results come from two groups of studies: onecomparing adding LABA to adding placebo to a stablelow ICS dose (400 µg/day), and the other comparinglow-dose ICS + LABA to an increased (usuallydoubled) dose of ICS. The main results are presentedin Table 1.

Exacerbation and hospitalization rates

The main reason to want to ‘step up’ in asthmamanagement is insufficient asthma control (3), andthe most problematic issue to patients in insufficientasthma control are asthma exacerbations. This is whya single exacerbation in any given year will shiftthe patient from the desired level of ‘completelycontrolled’ asthma to ‘partly controlled’ or ‘poorlycontrolled’ asthma (1,2). The one thing we would liketo see with add-on treatment, then, is a reduction ofasthma exacerbations. The clearest and most consistentfinding of the Cochrane review, however, is thatadding LABA to ICS treatment fails to reduce theasthma exacerbation rate. When compared to low-doseICS, the exacerbation risk is slightly lower in ICS +LABA, but the difference is not significant, and small(RR 0.92). Conversely, in comparison to high-doseICS, both the exacerbation and the hospitalization riskare higher in the ICS + LABA group, although againnot significantly. The trend is concerning, however.

Table I. Main results of the Cochrane review of adding LABA to ICS in childhood asthma insufficiently controlled on ICS alone

Effect parameterICS + LABA vs low-dose

ICS∗ICS + LABA vs high-dose

ICS∗∗

Exacerbation rate§, RR (95% CI) 0.92 (0.60 to 1.40) 1.5 (0.65 to 3.48)Hospital admission rate, RR (95% CI) Insufficient data 2.21 (0.74 to 6.64)Difference in FEV1, L (95% CI) 0.08 (0.06 to 0.11) Insufficient dataDifference in PEF, L/min (95% CI) Insufficient data Morning PEF: 7.55 (3.57 to 11.53)

Evening PEF: 5.5 (1.21 to 9.79)Symptoms, use of reliever medication, quality of life No significant differences Insufficient dataHeight growth (cm/year during the study) Only one study reported growth: 5.1 vs 4.5 cm/yr 1.2 (0.72 to 1.7)

∗ Low-dose ICS: 400 µg/day of beclomethasone or equivalent.∗∗ High-dose ICS: 800 µg/day of beclomethasone or equivalent.§ Exacerbation defined as an increase in asthma symptoms requiring treatment with oral corticosteroids.



At the very least it suggests that LABA use maymask deterioration of asthma control, causing a delayin seeking medical help (4). Alternative explanationsinclude tachyphylaxis (reduced response to beta 2agonists with daily use of the drugs) or direct toxiceffects of LABA. But the main reason for concernis not the possibility of deleterious effects of LABAin children; it’s the fact that they are not effective inreducing the risk of asthma exacerbations, their mainraison d’etre.

Lung function

The use of LABA is associated with a significantimprovement in lung function as compared to ICSmonotherapy, the review concludes. Although that istrue, the clinical relevance of the difference is, well,negligible. An improvement in FEV1 of 0.08 L or inPEF of 5.5 to 7.5 L/min does not exactly excite me,let alone the patients – it corresponds to about 2–3%of their normal lung function level. It’s a tiny effect,and it was to be expected. Because beta agonists, inparticular long acting ones, do improve lung functionjust a little bit in just about everyone, even in healthyindividuals.

And let’s face it – the trial designers (almost alwaysthe manufacturers of the LABA under study) did theirbest to include patients who would show a lung func-tion response – the majority of studies required chil-dren to have reduced lung function levels at baseline,along with a significant bronchodilator response. Bear-ing in mind that most children with asthma nowadayshave normal lung function (5–7) and little if any bron-chodilator response (7), it is unlikely that these patientswould have shown the significant improvement in lungfunction found in this Cochrane review.

Safety

Compared to high-dose ICS treatment, children receiv-ing low-dose ICS + LABA showed greater growthof about 1 cm/year. No surprises here. The dose-dependent effect of ICS on growth has been knownfor about 10 years (8,9). Even in children showingreduced growth during the first year of ICS therapy(and none of the studies in the Cochrane review lastedlonger than 1 year), ongoing low-dose ICS therapydoes not impair further growth or final adult height(10). So the message here is that low-dose ICS treat-ment is safe in terms of long-term growth, not thatLABA addition improves growth.

Implications for Research

The authors of the review suggest that we need addi-tional large trials in children with more severe asthma,and in younger children. We do. I would like to addthat it is imperative that these studies are designed, run,analyzed and reported independently, meaning without

support from the manufacturers of these drugs. Thenand only then will we be able to obtain reliable addi-tional data on the usefulness of LABA in children.The variable use of the combination of ICS and LABAin a single inhaler, which was succesful in reducingasthma exacerbations in an industry-sponsored study(11), should also be examined in independent stud-ies. Is it likely that such studies will be performedin the near future? I doubt it. If I worked with thepharmaceutical industry, I would not encourage suchstudies. Combination inhalers of ICS and LABA havegained a considerable chunk of the market of pae-diatric asthma management (12), despite the flimsyevidence base that the current Cochrane review has soelegantly demonstrated.

Implications for Practice

Back to the step 3 dilemma. What to do in chil-dren with asthma who fail to achieve satisfactoryasthma control on ICS maintenance therapy alone?The answer, clearly, is not grabbing your prescriptionpad for a combination inhaler of ICS and LABA. No,the answer is to get the basics right. Last year’s ERSconference buzzed with it – when a child with asthmais not doing well on ICS alone, scratch your headand get the basics right (Table 2) (13). Truly severeasthma is rare in children – most children with ‘severeasthma’ are either not severe (but they fail to taketheir maintenance medication reliably or are exposedto exacerbating factors) or they have a disease otherthan asthma which is responsible for their complaints.So the right thing to do is to analyze your patient’sproblem seriously and comprehensively. You will beunlikely to have to resort to add-on treatment in thelarge majority of cases. And if you do, the choice isentirely yours. There is no good evidence to help youin making a rational choice in step 3 asthma manage-ment in children. The challenge, therefore, is to remaina good clinician. Even when writing a comment to alargely negative systematic review, that’s an inspiringnote to finish with.

Declarations of Interest

None

Table II. Getting the basics right in asthma manage-ment – issues to consider in children who fail to achievesatisfactory asthma control on maintenance treatment withICS alone

• Poor adherence to therapy• Poor inhalation technique• Ongoing exposure to allergic or nonallergic stimuli (exposure toallergens, cigarette smoke, etc.)• Comorbidity (allergic rhinitis, obesity, food allergy, psychosocialproblems, etc.)• Other diagnosis than asthma (e.g. bronchomalacia, vascular ring)



References

1. Anonymus. Global initiative for asthma. Global strategy for asthmamanagement and prevention. Revised 2008.

2. National Heart LaBI, National Asthma Education and PreventionProgram. Expert Panel Report 3: Guidelines for the diagnosis andmanagement of asthma 2007; Bethesda, MD, USA, National Heart,Lung and Blood Institute.

3. Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW,Casale TB, et al. A new perspective on concepts of asthma severityand control. Eur Respir J 2008; 32: 545–554.

4. Nelson HS. Is there a problem with inhaled long-acting beta-adrenergic agonists? J Allergy Clin Immunol 2006; 117: 3–16.

5. Paull K, Covar R, Jain N, Gelfand EW, Spahn JD. Do NHLBIlung function criteria apply to children? A cross-sectionalevaluation of childhood asthma at National Jewish Medicaland Research Center, 1999–2002. Pediatr Pulmonol 2005; 39:311–317.

6. Spahn JD, Cherniack R, Paull K, Gelfand EW. Is forced expira-tory volume in one second the best measure of severity in child-hood asthma? Am J Respir Crit Care Med 2004; 169: 784–786.

7. Baatenburg de Jong A, Brouwer AFJ, Roorda RJ, Brand PLP.Normal lung function in children with mild to moderate persistentasthma well controlled by inhaled corticosteroids. J Allergy ClinImmunol 2006; 118: 280–282.

8. Brand PLP. Inhaled corticosteroids reduce growth. Or do they?Eur Respir J 2001; 17: 287–294.

9. Pedersen S. Do inhaled corticosteroids inhibit growth in children?Am J Respir Crit Care Med 2001; 164: 521–535.

10. Agertoft L, Pedersen S. Effect of long-term treatment with inhaledbudesonide on adult height in children with asthma. N Engl J Med2000; 343: 1064–1069.

11. Bisgaard H, Le Roux P, Bjamer D, Dymek A, Vermeulen JH,Hultquist C. Budesonide/formoterol maintenance plus relievertherapy: a new strategy in pediatric asthma. Chest 2006; 130:1733–1743.

12. Bisgaard H, Szefler S. Long-acting beta2 agonists and paediatricasthma. Lancet 2006; 367: 286–288.

13. Brand PL, Ratjen F, Aurora P, Dankert-Roelse JE, Ross-RussellRI, Kuehni CE, Midulla F, Hedlin G. Scientific assembly update.Paediatrics in Vienna. Eur Respir J 2010; 35: 1172–1178.


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