The new england journal of medicine7. Seung KB, Park D-W, Kim Y-H, et al. Stents versus coronaryarterybypass grafting for left main coronary artery disease. N EnglJ Med 2008;358:1781-92.8. Buszman PE, Kiesz SR, Bochenek A, et al. Acute and lateoutcomes of unprotected left main stenting in comparison withsurgical revascularization. J Am Coll Cardiol 2008;51:538-45.9. Sianos G, Morel M-A, Kappetein AP, et al. The SYNTAXscore: an angiographic tool grading the complexity of coronaryartery disease. EuroIntervention 2005;1:219-27.10. Valgimigli M, Serruys PW, Tsuchida K, et al. Cyphering thecomplexity of coronary artery disease using the Syntax score topredict clinical outcome in patients with three-vessel lumen obstructionundergoing percutaneous coronary intervention. Am JCardiol 2007;99:1072-81.Copyright © 2009 Massachusetts Medical Society.Eosinophils in Asthma — Closing the Loopor Opening the Door?Sally E. Wenzel, M.D.Although the origin of the concept that eosinophilsare critical to asthma pathobiology remainscontroversial, there is consensus that Paul Ehrlichfirst identified a bilobed nucleated cell as an“eosin”-ophil in 1879 on the basis of the cell’sgranular uptake of his newly discovered dye. Thesecells were soon found in airway tissues and “catarrh”(sputum) of patients with asthma. Over theyears, eosinophils were identified as a prominentcell type in asthma, yet their role as either an “effector”or “innocent bystander” was not confirmeduntil the publication of articles by Nair et al. 1 andHaldar et al. 2 in this issue of the Journal.In each of these studies, treatment with mepolizumab,a monoclonal antibody against interleukin-5(a proeosinophilic cytokine), significantlyreduced the number of lung and blood eosinophilsin a small group of patients with severe corticosteroid-resistantasthma. Since both studiesshowed a significant reduction in asthma exacerbationsin patients receiving mepolizumab, itwould seem that the eosinophil does, in fact, playa central role in asthma and its outcomes. Ordoes it?To address this question, it may be helpful toreview the role of eosinophils in asthma. Soon afterEhrlich’s studies, asthma was considered to bean eosinophilic disease, with a general consensusthat eosinophils were the sentinel inflammatorycell. This view prevailed until two clinical studies3,4 of a mononclonal antibody against interleukin-5were completed about a decade ago. One ofthese studies used a laboratory model of humanasthma on the basis of an inhaled-allergen challenge,and the other study analyzed traditionalsafety and efficacy measures in patients with mildto-moderateasthma. The results of both thesestudies were completely negative with respect tothe role of eosinophils in the asthma outcomesthat were measured. The combination of thesestudies hit the “eosinophil as center of the asthmauniverse” community by storm; soon manyresearchers were questioning the wisdom of focusingon eosinophils as the key effector cell inasthma.With these findings in mind, an emerging appreciationof the heterogeneity of asthma led tothe description of two asthma phenotypes on thebasis of the presence or absence of tissue eosinophils.5 Patients with asthma who had eosinophiliahad greater airway remodeling and moreexacerbations, whereas those without eosinophiliahad more airway obstruction. Subsequently, numerousstudies supported the concept that althoughmany patients with asthma do not haveany eosinophilic inflammation, the presence ofsuch inflammation identifies a more exacerbationpronephenotype. 6-9The identification of this “eosinophilic” phenotypeled to two clinical trials 8,10 in which investigatorsmodified the amount of corticosteroid(which has antieosinophilic effects) that the patientswere receiving on the basis of the numberof eosinophils in the sputum. The investigators,who were from the same groups as the authors ofthe two studies in this issue of the Journal, reportedthat the use of eosinophil numbers in sputumto determine the corticosteroid dose lowered therate of asthma exacerbations. Furthermore, inthe absence of eosinophils, a safe reduction in thecorticosteroid dose was possible without triggeringexacerbations. However, since corticosteroidshave many effects on inflammatory processes beyondthat on eosinophils, the causative role of eo-1026n engl j med 360;10 nejm.org march 5, 2009Downloaded from www.nejm.org by LEONARDO FABBRI MD on March 30, 2010 .Copyright © 2009 Massachusetts Medical Society. All rights reserved.
editorialssinophils in reducing exacerbations could not beconfirmed. Corticosteroids were simply not a biologicallyinformative intervention.Thus, the studies by Nair et al. and Haldar etal. were built on three concepts: that the inhibitionof interleukin-5 reduces eosinophilic inflammation,that not all asthma is eosinophilic, andthat a reduction in eosinophils was associatedwith a decreased rate of exacerbations. Bothgroups of investigators used mepolizumab as anintervention and enrolled only patients with severeasthma who had persistent eosinophilic inflammationdespite corticosteroid treatment. Althoughmany treatment outcomes were measured,the only outcome that consistently improved wasthe exacerbation rate.How do these new studies help move our understandingforward? Unlike previous studies ofanti–interleukin-5 agents, the patients in thesestudies had a highly eosinophilic form of asthma.The persistent eosinophilic inflammation despitecorticosteroid treatment appears to be more commonin patients with adult-onset asthma than inthose with childhood-onset asthma. 6,7 In bothstudies, the average age at asthma onset was themid-to-late 20s, and the percentage of patientswith atopic disease was lower than expected. 1Asthma that starts in adulthood is less likely tobe typical “allergic asthma.” Rather, late-onseteosinophilic asthma is associated with sensitivityto nonsteroidal antiinflammatory medications (aspirin)and with tissue eosinophilia. 7 Although upto 40% of cases of severe asthma start later in life,the eosinophilic form of asthma probably representsless than 5% of the total number of casesof adult-onset asthma. Thus, the phenotype inthese studies represents a small percentage of allpatients with asthma and is perhaps more representativeof a type of “hypereosinophilic” syndrome,which has previously been shown to respondto anti–interleukin-5 therapy, than actualasthma. 11,12 The Canadian center where Nair etal. conducted their study screened hundreds ofsubjects to get the 20 that they studied. Eventhen, several subjects did not meet the reversibilityor airway-hyperresponsiveness definition of“asthma.”In these two trials, the selective removal of eosinophilshad no effect on other asthma outcomes,including the forced expiratory volume in 1 second,symptoms, and asthma control. Althoughthere was a differential effect of mepolizumabtherapy on the patients’ quality of life, the improvementwas not clinically meaningful. Thislack of effect becomes more obvious when comparingthe patients’ responses to systemic corticosteroidtreatment. In contrast to the narrowrange of effects related to eosinophils in patientsreceiving mepolizumab, the broader antiinflammatoryeffects of systemic corticosteroid significantlyimproved the outcomes independent ofmepolizumab therapy. The results imply that eosinophilsare not the only (or perhaps even themajor) cell involved in disease pathogenesis, evenin patients with severe asthma.Finally, these two studies must be examinedin light of the negative outcomes of anti–interleukin-5therapy in patients with milder, more typicalasthma. 4 In patients with mild asthma (eitherbefore or after anti–interleukin-5 therapy), levelsof eosinophilic inflammation did not have an effecton clinical outcomes in any way. This findingraises the question as to whether some eosinophilphenotypes respond differently to corticosteroidtreatment and variably contribute to asthmaoutcomes.These studies clearly confirm that in a subgroupof patients with eosinophilic asthma, eosinophilsplay a role in exacerbations. These particulareosinophils contribute to the pathobiology ofasthma, and in this small subgroup, mepolizumabtherapy had some clinical benefit. However, manypatients with asthma do not have eosinophilia,and even in patients with eosinophilic asthma,mepolizumab had no effect on other physiologicaland clinical factors. These findings open thedoor, perhaps even further, to investigations of alternativecells and mediators in the broader worldof asthma.Dr. Wenzel reports receiving consulting fees from Glaxo-SmithKline, Novartis, Genentech, Wyeth, Amgen, MedImmune,Johnson & Johnson, Amira, Epigenesis, and Altair, lecture feesfrom Merck, and grant support from Ception, MedImmune, andGlaxoSmithKline. No other potential conflict of interest relevantto this article was reported.From the University of Pittsburgh, Pittsburgh.1. Nair P, Pizzichini MMM, Kjarsgaard M, et al. Mepolizumabfor prednisone-dependent asthma with sputum eosinophilia. NEngl J Med 2009;360:985-93.2. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumaband exacerbations of refractory eosinophilic asthma. N Engl JMed 2009;360:973-84.3. Leckie MJ, ten Brinke A, Khan J, et al. Effects of an interleukin-5blocking monoclonal antibody on eosinophils, airway hy-n engl j med 360;10 nejm.org march 5, 2009 1027Downloaded from www.nejm.org by LEONARDO FABBRI MD on March 30, 2010 .Copyright © 2009 Massachusetts Medical Society. All rights reserved.
The new england journal of medicineper-responsiveness, and the late asthmatic response. Lancet 2000356:2144-8.4. Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluatesafety and efficacy of mepolizumab in patients with moderatepersistent asthma. Am J Respir Crit Care Med 2007;176:1062-71.5. Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence thatsevere asthma can be divided pathologically into two inflammatorysubtypes with distinct physiologic and clinical characteristics.Am J Respir Crit Care Med 1999;160:1001-8.6. Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis andclinical asthma phenotypes. Am J Respir Crit Care Med 2008;178:218-24.7. Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE. Distinguishingsevere asthma phenotypes: role of age at onset and eosinophilicinflammation. J Allergy Clin Immunol 2004;113:101-8.8. Green RH, Brightling CE, McKenna S, et al. Asthma exacerbationsand sputum eosinophil counts: a randomised controlledtrial. Lancet 2002;360:1715-21.9. Simpson JL, Scott RJ, Boyle MJ, Gibson PG. Differential proteolyticenzyme activity in eosinophilic and neutrophilic asthma.Am J Respir Crit Care Med 2005;172:559-65.10. Jayaram L, Pizzichini MM, Cook RJ, et al. Determining asthmatreatment by monitoring sputum cell counts: effect on exacerbations.Eur Respir J 2006;27:483-94.11. Plötz S-G, Simon H-U, Darsow U, et al. Use of an anti–inter-leukin-5 antibody in the hypereosinophilic syndrome with eosinophilicdermatitis. N Engl J Med 2003;349:2334-9.12. Garrett JK, Jameson SC, Thomson B, et al. Anti-interleukin-5(mepolizumab) therapy for hypereosinophilic syndromes. J AllergyClin Immunol 2004;113:115-9.Copyright © 2009 Massachusetts Medical Society.p o w e r p o i n t s l i d e s o f j o u r n a l f i g u r e s a n d t a b l e sAt the Journal’s Web site, subscribers can automatically create PowerPoint slides.In a figure or table in the full-text version of any article at NEJM.org, clickon Get PowerPoint Slide. A PowerPoint slide containing the image, with its titleand reference citation, can then be downloaded and saved.1028n engl j med 360;10 nejm.org march 5, 2009Downloaded from www.nejm.org by LEONARDO FABBRI MD on March 30, 2010 .Copyright © 2009 Massachusetts Medical Society. All rights reserved.