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Expression of activation markers on basophilsin a controlled model of anaphylaxis: General,methodologic, and clinical issues
To the Editor:We appreciated the article by Gober et al1 considering
flow-assisted analysis to monitor the effects of intentionalsting challenges. However, we would like to addressseveral issues.
First, the authors state that CD63 is rapidly mobilizedon the basophil surface by IL-3. In fact, priming with IL-3does not elicit upregulation of CD63 expression byitself.2,3 Remarkably, both of these articles are referred
J ALLERGY CLIN IMMUNOL
SEPTEMBER 2007
726 Correspondence
Reply
To the Editor:Lipworth1 raises some very important points regarding
asthma outcomes and the use of meta-analysis to informmanagement decisions. Although it is unfortunate thathis conclusion retreats to the position of trusting expertsover evidence for guideline development, the body ofthe letter warrants careful consideration.
The first point relates to the assessment of asthmacontrol using composite measures. Asthma control hasemerged as a very useful concept that makes sense to bothpatients and their doctors. The clinical criteria for assess-ing asthma control are well described in recent guidelinesand include symptoms, b2-agonist use, activity limitation,and measures of airway caliber, such as peak expiratoryflow. It is fallacious to see these as solely a reflection ofsmooth muscle responsiveness. Inflammation and smoothmuscle responsiveness are not separate features of asthma,but rather, inflammation in asthma modulates airwaysmooth muscle responsiveness, leading to changes inasthma control. This is why b2-agonist use increaseswhen an exacerbation occurs because of a proinflamma-tory trigger such as allergen exposure, and why theindividual components of control are improved when in-haled corticosteroids (ICSs), a solely anti-inflammatorytherapy with no direct smooth muscle relaxant action,are used. This was nicely demonstrated in the Cochranereviews that compare leukotriene receptor antagonist(LTRA) as add-on to ICS. The studies used b2-agonist re-versibility as an entry criterion, and ICSs, with no smoothmuscle relaxant activity, were shown to be superior toLTRA in symptom reduction, use of rescue b2-agonists,and lung function—that is, measures of asthma control.Therefore, the composite asthma control measures areuseful and sensitive to the effects of anti-inflammatorytherapy.
Could the ICS-LABA studies be biased in favor of long-acting b-agonist (LABA)? This seems unlikely, becausethe studies were of sufficient duration to allow the anti-inflammatory effects of ICS to occur, and as stated, thecontrol measures are responsive to the effects of ICS.2
What is more significant, however, is whether the resultsof these studies can be generalized to all people who arediagnosed with asthma. The answer is no, at least not giventhe current state of knowledge. It is increasingly clear thatmany people with symptoms consistent with asthma donot have increased b2 responsiveness, yet may respondto ICS. The efficacy of LABA in this group will requirefurther study, because there are few, if any, studies ofLABA efficacy in patients with asthma without b2 respon-siveness. Indeed, the individual Cochrane LABA reviewsdo alert readers to this potential problem. There is someexperience from chronic obstructive pulmonary diseasein which the efficacy of long-acting bronchodilators hasbeen compared on the basis of degree of b2 responsive-ness. In those studies, the long-acting bronchodilatorwas still effective in the less b2–responsive patients, butthe effect size was smaller. Until this issue is resolved,
we consider the results of our review that recommendsICS as first-line therapy to be useful and consistent withcurrent guidelines.
Meta-analyses represent a useful addition to data syn-thesis, and when performed using Cochrane methodology,they have less bias than industry-sponsored meta-analy-ses. This has specifically examined and confirmed forasthma reviews performed by the Cochrane AirwaysGroup.3 Performing a review without appropriate meta-analysis can be misleading, as was recently seen whenthe efficacy of LABA and LTRA were compared.4,5
In conclusion, composite asthma control measures areuseful outcomes that are sensitive to the effects of anti-inflammatory therapy in asthma. We have extended theiruse to describe a method for using composite asthmacontrol scores in the setting of meta-analysis.
Peter G. Gibson, MBBS, FRACPa
Francine M. Ducharme, MD, MSc, FRCPb
Christopher Joseph Cates, BM, BChc
From athe John Hunter Hospital, Newcastle, Australia; bthe Montreal Chil-
dren’s Hospital of the McGill University Health Center, Montreal, Quebec,
Canada; and cSt George’s, University of London, United Kingdom. E-mail:
Disclosure of potential conflict of interest: P. G. Gibson has received grant
support from GlaxoSmithKline, Novartis, and Pharmaxis and is on the
speakers’ bureau for AstraZeneca, GlaxoSmithKline, and Novartis. C. J.
Cates is employed as Co-coordinating Editor of the Cochrane Airways
Review Group. F. M. Ducharme has consulting arrangements with and
has received grant support from GlaxoSmithKline.
REFERENCES
1. Lipworth BJ. Benefits of long-acting b2-agonists. J Allergy Clin Immunol
2007;120:725.
2. Gibson PG, Powell H, Ducharme FM. Differential effects of maintenance
long-acting beta-agonist and inhaled corticosteroid on asthma control and
asthma exacerbations. J Allergy Clin Immunol 2007;119:344-50.
3. Jadad AR, Moher M, Browman GP, Booker L, Sigouin C, Fuentes M,
et al. Systematic reviews and meta-analyses on treatment of asthma:
critical evaluation. BMJ 2000;320:537-40.
4. Currie GP, Lee DK, Srivastava P. Long-acting bronchodilator or leukotri-
ene modifier as add-on therapy to inhaled corticosteroids in persistent
asthma? Chest 2005;128:2954-62.
5. Ducharme FM, Lasserson TJ, Cates CJ. Long-acting beta2-agonists versus
anti-leukotrienes as add-on therapy to inhaled corticosteroids for chronic
asthma. Cochrane Database Syst Rev 2006;4:CD003137.
Available online June 22, 2007.doi:10.1016/j.jaci.2007.04.043