Correspondence

Anti–Interleukin-5 Therapy and Severe Asthma

N Engl J Med 2009; 360:2576-2578June 11, 2009

Article

To the Editor:

Haldar and coworkers (March 5 issue)1 report a significant reduction of severe exacerbations of asthma after eosinophil suppression with mepolizumab in a population of patients with severe, refractory asthma in Leicestershire, United Kingdom. However, patients receiving mepolizumab still had a mean of 2.0 severe exacerbations per year.1 Could this excess be due to air pollution, since exposure to small particles is strongly linked to exacerbations of asthma?2 The Web site of the Leicester City Council provides 24-hour monitoring of particle concentrations that are less than 10 μm in aerodynamic diameter (PM₁₀) in the urban Leicester area.3 According to our calculations, during the study period (from April 1, 2006, through August 31, 2008, a total of 884 days), the mean 24-hour PM₁₀ concentrations exceeded the maximum air-quality guidelines of the World Health Organization4 (50 μg per cubic meter) a total of 230 times in three of eight measurement sites located along the Leicester motorway system. Given the effective suppression of eosinophilic inflammation reported in the study by Haldar et al., their data combined with those from the Leicester Web site provide a unique opportunity for assessment of the magnitude of air-pollution–induced exacerbations of asthma,5 which still remains unknown.

Sotirios Zarogiannis, Ph.D.
Konstantinos I. Gourgoulianis, M.D., Ph.D.
Konstantinos Kostikas, M.D., Ph.D.
University of Thessaly Medical School, 41110 Larissa, Greece
szarog@med.uth.gr

5 References

1. 1

   Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009;360:973-984
   Full Text | Web of Science | Medline

2. 2

   Leicester Air Quality Monitoring Network. Leicester, UK: Leicester City Council. (Accessed May 21, 2009, at http://rcweb.leicester.gov.uk/pollution/asp/home.asp.)
   

3. 3

   Kunzli N, Perez L, Lurmann F, Hricko A, Penfold B, McDonnell R. An attributable risk model for exposures assumed to cause both chronic disease and its exacerbations. Epidemiology 2008;19:179-185
   CrossRef | Web of Science | Medline

4. 4

   Air quality guidelines: global update. Geneva: World Health Organization, 2005:217-80.
   

5. 5

   McCreanor J, Cullinan P, Nieuwenhuijsen MJ, et al. Respiratory effects of exposure to diesel traffic in persons with asthma. N Engl J Med 2007;357:2348-2358
   Full Text | Web of Science | Medline

To the Editor:

The articles by Haldar et al. and Nair et al.1 indicate that mepolizumab has positive therapeutic effects in selected patients with refractory eosinophilic asthma and frequent exacerbations despite treatment with corticosteroids. Since previous clinical trials involving patients with less severe asthma have not shown efficacy, the heterogeneity in the biologic response to the drug might depend on the phenotype of asthma. The patients in the studies by Haldar et al. and Nair et al. had a difficult-to-treat, eosinophilic asthma with an onset in the patients' mid-20s; 30 to 40% of them had nasal polyps. This phenotype is reminiscent of aspirin-sensitive asthma.2,3 I wonder, therefore, whether the patients underwent aspirin-provocation testing and, if not, whether they had a history of intolerance to nonsteroidal antiinflammatory drugs.

Andrew Szczeklik, M.D., Ph.D.
Jagiellonian University Medical College, 31-066 Krakow, Poland
mmszczek@cyf-kr.edu.pl

3 References

1. 1

   Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009;360:985-993
   Full Text | Web of Science | Medline

2. 2

   Szczeklik A, Nizankowska-Mogilnicka E, Sanak M. Hypersensitivity to aspirin and nonsteroidal anti-inflammatory drugs. In: Adkinson NF Jr, Busse WW, Bochner BS, Holgate ST, Simons FER, Lemanske RF Jr, eds. Middleton's allergy: principles and practice. 7th ed. Philadelphia: Mosby Elsevier, 2009:1227-43.
   

3. 3

   Wenzel SE. Asthma: defining of the persistent adult phenotypes. Lancet 2006;368:804-813
   CrossRef | Web of Science | Medline

To the Editor:

The articles by Haldar et al. and Nair et al. show the beneficial effect of an anti–interleukin-5 monoclonal antibody on exacerbations of asthma and provide support for a pathophysiological role for eosinophils. However, in her accompanying editorial, Wenzel1 questions the prevalence of eosinophil-associated asthma and the importance of the pathogenic contributions of eosinophils to asthma. Haldar et al. report that 52.3% of patients attending their refractory-asthma clinic had a history of sputum eosinophilia of more than 3% in the previous 2 years. This finding suggests that a majority of their patients may have benefited from infusions of anti–interleukin-5 monoclonal antibodies. Although these monoclonal antibodies are clinically efficacious, they only partially reduce the eosinophil-mediated effects in asthma.2 For example, eosinophils are reduced in number, but they are not eliminated, and the deposition of granule major basic protein is not altered.3 Thus, the demonstration of a benefit from an eosinophil-specific drug in patients with asthma could be regarded as a proof of principle and lead to even more potent medications.

Gerald J. Gleich, M.D.
University of Utah Health Sciences Center, Salt Lake City, UT 84132
gerald.gleich@hsc.utah.edu

Dr. Gleich reports receiving grant support and lecture fees from GlaxoSmithKline and grant support from Novartis, and holding equity interest in Ception Therapeutics. No other potential conflict of interest relevant to this letter was reported.

3 References

1. 1

   Wenzel SE. Eosinophils in asthma -- closing the loop or opening the door? N Engl J Med 2009;360:1026-1028
   Full Text | Web of Science | Medline

2. 2

   Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med 2003;167:199-204
   CrossRef | Web of Science | Medline

3. 3

   Gleich GJ. Mechanisms of eosinophil-associated inflammation. J Allergy Clin Immunol 2000;105:651-663
   CrossRef | Web of Science | Medline

Author/Editor Response

With respect to the comments of Zarogiannis et al. and Szczeklik about our article: they are correct that a significant number of exacerbations of asthma occurred despite mepolizumab treatment. This occurrence implies that processes independent of eosinophilic airway inflammation make an important contribution to the pathogenesis of some asthmatic events. The airway response to outdoor air pollution is one potentially modifiable factor, and the excellent information on PM₁₀ concentrations provided by the Leicester City Council does provide an opportunity to investigate temporal and geographic links to exacerbations of asthma. However, we doubt that our study was large enough to investigate these associations definitively.

Unfortunately, we did not perform aspirin-provocation testing, so we are not in a position to determine whether subjects with aspirin-induced asthma are more or less likely to have a response to mepolizumab. This is an important research question that should be addressed in larger studies, since previous research has shown that patients with aspirin-induced asthma often have marked eosinophilic airway inflammation.1

Ian D. Pavord, D.M., F.R.C.P.
Andrew J. Wardlaw, Ph.D., F.R.C.P.
Pranabashis Haldar, M.R.C.P.
Glenfield Hospital, Leicester LE3 9QP, United Kingdom
ian.pavord@uhl-tr.nhs.uk

1 References

1. 1

   Nasser SM, Pfister R, Christie PE, et al. Inflammatory cell populations in bronchial biopsies from aspirin-sensitive asthmatic subjects. Am J Respir Crit Care Med 1996;153:90-96
   Web of Science | Medline

Author/Editor Response

With respect to the comments of Szczeklik: three patients in our study had self-reported intolerance to aspirin. None of the patients underwent a challenge with oral or inhaled aspirin. Since expression of interleukin-5 and granulocyte–macrophage colony-stimulating factor has been reported to be increased in the airways of patients with aspirin-intolerant asthma, as compared with patients with aspirin-tolerant asthma,1 it is reasonable to speculate that the airway eosinophilia in patients with aspirin-intolerant asthma2 will be responsive to treatment with anti–interleukin-5 monoclonal antibodies.

Parameswaran Nair, M.D., Ph.D.
Frederick E. Hargreave, M.D.
Paul O'Byrne, M.B.
McMaster University, Hamilton, ON L8N 4A6, Canada
parames@mcmaster.ca

2 References

1. 1

   Sousa AR, Lams BE, Pfister R, Christie PE, Schmitz M, Lee TH. Expression of interleukin-5 and granulocyte-macrophage colony-stimulating factor in aspirin-sensitive and non-aspirin-sensitive asthmatic airways. Am J Respir Crit Care Med 1997;156:1384-1389
   Web of Science | Medline

2. 2

   Szczeklik A, Sladek K, Dworski R, et al. Bronchial aspirin challenge causes specific eicosanoid response in aspirin-sensitive asthmatics. Am J Respir Crit Care Med 1996;154:1608-1614
   Web of Science | Medline

Author/Editor Response

Gleich is correct that a body of evidence supports a pathogenic role of eosinophils in asthma. However, I respectfully disagree with his suggestions concerning the breadth and scope of their effect. Eosinophils (in tissue, sputum, and blood) were largely absent in the subjects who received anti–interleukin-5 monoclonal antibodies. Yet there was no effect on chronic symptoms, the forced expiratory volume in 1 second, or the patient's perception that he or she was receiving active treatment. This lack of effect does not mirror the more global effects of corticosteroids and suggests that broader approaches to reducing eosinophils will have little further effect on these rather important outcomes. Finally, although eosinophilic inflammation may be present in 50% of patients who have well-characterized, severe asthma, many of whom require oral corticosteroids for symptom control, in large populations of patients with difficult-to-treat asthma, the percentage is likely to be much lower. Thus, from a drug-development standpoint, the cost-effective use of treatment with anti–interleukin-5 monoclonal antibodies (or perhaps any targeted eosinophilic approach) will probably be limited to a small fraction of the population of patients with asthma.

Sally E. Wenzel, M.D.
University of Pittsburgh, Pittsburgh, PA 15213

Citing Articles (3)

Citing Articles

1. 1

   Mohammad Tabrizi, Cherryl Funelas, Hamza Suria. (2010) Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies. The AAPS Journal 12:4, 592-601
   CrossRef

2. 2

   C Edward Rose, Joanne A Lannigan, Paul Kim, James J Lee, Shu Man Fu, Sun-sang J Sung. (2010) Murine lung eosinophil activation and chemokine production in allergic airway inflammation. Cellular and Molecular Immunology 7:5, 361-374
   CrossRef

3. 3

   Angel F Lopez, Timothy R Hercus, Paul Ekert, Dene R Littler, Mark Guthridge, Daniel Thomas, Hayley S Ramshaw, Frank Stomski, Michelle Perugini, Richard D'Andrea, Michele Grimbaldeston, Michael W Parker. (2010) Molecular basis of cytokine receptor activation. IUBMB Life 62:7, 509-518
   CrossRef