Correspondence Eosinophil count and efficacy of omalizumab treatment To the Editor: I read with interest the article by Busse et al1 assessing the effect of omalizumab in a group of asthmatic patients in relation to their eosinophil counts. In their well-performed study they found that the primary end point (a decrease in asthma exacerbations) was not met. In the subgroup analysis, according to the eosinophil count (low, 300 cells/ mL), they were able to demonstrate efficacy in patients within the high-count group. It is intriguing that the primary end point was not achieved despite omalizumab being a proved therapy for allergic asthma.2,3 To understand this paradox, it is necessary to take a closer look at this study. First, they chose patients who, despite being symptomatic, had normal lung function (FEV1 >80%). Second, prior use of systemic corticosteroids (oral or intravenous), a classic sign of severity, was an exclusion and not an inclusion criteria. Finally, after carefully reading the article and the additional information in the article’s Online Repository, I did not find any reference about the allergens to which these patients were allergic. Defining asthma as atopic based only on the serum total IgE level (30-1300 IU/mL), as apparently was done, is certainly not enough. The authors should clarify this last point and, if they have this information, plot it against the eosinophil level. It would probably show that (as expected) patients with positive results to allergen did much better than patients with negative results to allergen and had the highest eosinophil counts. Once again, this study also shows that those who derive the most benefit from omalizumab have atopic asthma that is symptomatic despite optimal treatment, are in need of frequent steroid bouts, and have abnormal lung function test results.

corticosteroids with or without other controller medications. To clarify, this study was done as a postmarketing commitment from the US Food and Drug Administration in which we were to evaluate patients with atopic asthma and normal lung function. Atopic asthma was not determined solely based on serum IgE levels; patients also had to have positive skin test responses or in vitro (RAST or ImmunoCAP) test responses to 1 relevant perennial aeroallergen, such as cat or house dust mite. The exclusion of prior use of systemic corticosteroids (oral or intravenous) was only if it had been in close proximity to the screening visit because this would indicate that the patient had a recent asthma exacerbation that could affect his or her lung function. The time restriction would also allow systemic steroids to have cleared from the patients’ bodies so there would be no effect on baseline scores. Dr Panasoff was correct in noting that despite its proved efficacy in patients with allergic asthma, the study did not show a significant difference for omalizumab versus placebo in rate of exacerbations and that this might have been in part due to the patient population enrolled in the study. Reasons for poorly controlled asthma in the studied population might include poor compliance with therapy, improper use of inhaled medication, or chronic exposure to a potent antigen or the patients might be smokers. Omalizumab, by virtue of being administered every 2 or 4 weeks in the physician’s office, might improve compliance. However, we believe that given the highly limiting patient eligibility for enrollment, the study was underpowered to demonstrate a statistically significant treatment effect in the primary end point. Because all patients in the study had positive results to allergen, we have not addressed Dr Panasoff’s request to plot eosinophil levels against allergen-positive/allergen-negative status. We do appreciate his thorough review and the opportunity to provide a more in-depth explanation of the eligibility criteria and their effect on study outcome. Karin Ros en, MD, PhDa William Busse, MDb

Josef Panasoff, MD From the Allergy Department, Lin Medical Center, Clalit Health Services, Haifa, Israel. E-mail: [email protected]. Disclosure of potential conflict of interest: J. Panasoff declares that he has no relevant conflicts of interest. REFERENCES 1. Busse W, Spector S, Rosen K, Wang Y, Alpan O. High eosinophil count: a potential biomarker for assessing successful omalizumab treatment effects. J Allergy Clin Immunol 2013;132:485-6. 2. McKeage K. Omalizumab: a review of its use in patients with severe persistent allergic asthma. Drugs 2013;73:1197-212. 3. From the Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2012. Available at: http://www.ginasthma.org. Accessed December 18, 2013. http://dx.doi.org/10.1016/j.jaci.2014.01.011

From aGenentech, South San Francisco, Calif, and bthe Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis. E-mail: [email protected]. Disclosure of potential conflict of interest: K. Rosen is employed by Roche and receives stock/stock options as part of her compensation. W. Busse receives compensation as a board member for Merck; has consultant arrangements with Novartis, GlaxoSmithKline, Genentech, Boston Scientific, and ICON; has received research support from the National Institutes of Health/National Institute of Allergy and Infectious Disease and the National Institutes of Health/National Heart, Lung, and Blood Institute; and receives royalties from Elsevier. REFERENCES 1. Panasoff J. Eosinophil count and efficacy of omalizumab treatment. J Allergy Clin Immunol 2014;133:1231. 2. Busse W, Spector S, Rosen K, Wang Y, Alpan O. High eosinophil count: a potential biomarker for assessing successful omalizumab treatment effects. J Allergy Clin Immunol 2013;132:485-6. http://dx.doi.org/10.1016/j.jaci.2014.01.013

Reply To the Editor: We would like to thank Dr Panasoff1 for his comment on our report2 of the EXACT trial (NCT00096954) of omalizumab, which studied patients with atopic asthma with preserved pulmonary function who remained symptomatic on inhaled

Exhaled breath condensate eicosanoid levels in asthma: Still questioned To the Editor: We read with great interest the article by Kazani et al1 who compared the levels of eicosanoid in exhaled breath condensate 1231

1232 CORRESPONDENCE

(EBC) in healthy controls and patients with asthma. The fact that cysteinyl-leukotrienes (Cys-LTs) in the EBC were undetectable appeared inconsistent with that in children with asthma exacerbations (mean, 12.7 pg/mL) and children with or without exerciseinduced asthma (mean, 42.2 and 11.7 pg/mL).2,3 We questioned the source of the observed variance, for it remained unknown whether a prolonged storage (2 years in patients with asthma vs 6 months in healthy controls) of specimens might reduce the bioavailability of Cys-LTs,4 the markers readily decomposed by oxidants and transition ions. Curiously, leukotriene B4 was measured in the EBC as a surrogate, which was established merely on the assumption that leukotriene A4 hydroxylase and glutathione-S-transferrase were equivalently potent. If so, the Cys-LTs might have been rapidly metabolized by some unknown mechanisms; however, there should be a high level of leukotriene E4, indicating accumulation of end products of Cys-LTs pathway. Alternatively, the specifically significant attenuation of Cys-LTs pathway could not be interpreted by the data set presented in the current study. However, the authors did not discuss the aforementioned findings. We therefore postulated whether 5-hydroxyeicosatetraeionic acid, an upstream surrogate marker of the leukotriene pathways, might be more reliable and preferable for the measurement in EBC, since the ELISA kits have also been commercially available and there have been studies reporting the levels in healthy subjects5 and patients who had granulomatosis with polyangiitis.6 It would be particularly revealing if the authors could demonstrate the profiles of 5-hydroxyeicosatetraeionic acid in healthy individuals and different severity of asthma, and compare with the level of leukotriene B4 and leukotriene A4. This might help determine the causes of diminished levels of Cys-LTs detected in the EBCs in this cohort.

J ALLERGY CLIN IMMUNOL APRIL 2014

Wei-Jie Guan, PhDa Xue-Yan Zheng, PhDb Jin-Ping Zheng, MDa From athe State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China; and bthe Department of Epidemiology, School of Public Health and Tropical Medicine, Southern Medical University, Guangdong, China. E-mail: [email protected]. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. Editor’s note: There is no accompanying reply to this correspondence.

REFERENCES 1. Kazani S, Planaguma A, Ono E, Bonini M, Zahid M, Marigowda G, et al. Exhaled breath condensate eicosanoid levels associate with asthma and its severity. J Allergy Clin Immunol 2013;132:547-53. 2. Baraldi E, Carraro S, Alinovi R, Pesci A, Ghiro L, Bodini A, et al. Cysteinyl leukotrienes and 8-isoprostane in exhaled breath condensate of children with asthma exacerbation. Thorax 2003;58:505-9. 3. Carraro S, Corradi M, Zanconato S, Alinovi R, Pasquate MF, Zacchello F, et al. Exhaled breath condensate cysteinyl leukotrienes are increased in children with exercise-induced bronchoconstriction. J Allergy Clin Immunol 2005;115: 764-70. 4. Tsuburai T, Mita H, Tsurikisawa N, Oshikata C, Ono E, Fukutomi Y, et al. Relationship between cysteinyl leukotriene in exhaled breath condensate and the severity of asthma in adult asthmatics in Japan. Arerugi 2008;57: 121-9. 5. Sanak M, Gielicz A, Nagraba K, Kaszuba M, Kumik J, Szczeklik W. Targeted eicosanoids lipidomics of exhaled breath condensate in healthy subjects. J Chromatogr B Analyt Technol Biomed Life Sci 2010;878:1796-800. 6. Szczeklik W, Sanak M, Sokolowska B, Jakiela B, Sznajd J, Gielicz A, et al. Distinct eicosanoid profile in exhaled breath condensates from granulomatosis with polyangiitis (Wegener’s) patients. Clin Rheumatol 2013;32:1549-52. Available online February 12, 2014. http://dx.doi.org/10.1016/j.jaci.2014.01.006

Corrections With regard to the December 2013 article entitled ‘‘Diminished allergic disease in patients with STAT3 mutations reveals a role for STAT3 signaling in mast cell degranulation’’ (J Allergy Clin Immunol 2013;132:1388-96.e3), the Editorial Office regrets that the name of Celeste Nelson, one of the authors, was inadvertently omitted. The list of author names should read as follows: Andrea M. Siegel, PhD, Kelly D. Stone, MD, PhD, Glenn Cruse, PhD, Monica G. Lawrence, MD, Ana Olivera, PhD, Mi-yeon Jung, PhD, John S. Barber, BA, Alexandra F. Freeman, MD, Steven M. Holland, MD, Michelle O’Brien, RN, Nina Jones, RN, Celeste G. Nelson, MS, CRNP, Laura B. Wisch, RN, Heidi H. Kong, MD, MHSc, Avanti Desai, MA, Orly Farber, Alasdair M. Gilfillan, PhD, Juan Rivera, PhD, and Joshua D. Milner, MD. Celeste G. Nelson declares that she has no relevant conflicts of interest. With regard to the January 2014 article entitled ‘‘High-content cytometry and transcriptomic biomarker profiling of human B-cell activation’’ (J Allergy Clin Immunol 2014;133:172-80.e10), author Christian Hennig declares that he is currently founding a company commercializing Chipcytometry. With regard to the January 2014 article entitled ‘‘Unsuspected mild emphysema in nonsmoking patients with chronic asthma with persistent airway obstruction’’ (J Allergy and Clin Immunol 2014;133:263-5.e3), the appropriate lung photomicrograph for Fig 1 appears in Fig E1, C, and the appropriate photomicrograph for Fig E1, C, appears in Fig 1. The authors regret the error. With regard to the November 2013 article entitled ‘‘Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia’’ (J Allergy Clin Immunol 2013;132:1086-96.e5), the authors report that Fig 2, C contains an error. The placebo and benralizumab screening images were incorrectly inserted into the figure. They are both post dose images from a placebotreated subject, not screening images. The day 84 images for placebo and benralizumab are correct. The error does not affect the integrity of the data or the study conclusions. The authors regret the error. With regard to the February 2014 article entitled ‘‘Targeted next-generation sequencing: A novel diagnostic tool for primary immunodeficiencies’’ (J Allergy Clinical Immunol 2014;133:529-34.e1), the authors report that a mistake appears in the Results section. The c.1009A>G p.(Lys337Ter) mutation in the CXCR4 gene should be c.997A>T p.(Lys333Ter). The authors regret the error.

Exhaled breath condensate eicosanoid levels in asthma: still questioned.

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