Original Article

Mepolizumab and Exacerbations of Refractory Eosinophilic Asthma

Pranabashis Haldar, M.R.C.P., Christopher E. Brightling, Ph.D., F.R.C.P., Beverley Hargadon, R.G.N., Sumit Gupta, M.R.C.P., William Monteiro, M.Sc., Ana Sousa, Ph.D., Richard P. Marshall, Ph.D., M.R.C.P., Peter Bradding, D.M., F.R.C.P., Ruth H. Green, M.D., F.R.C.P., Andrew J. Wardlaw, Ph.D., F.R.C.P., and Ian D. Pavord, D.M., F.R.C.P.

N Engl J Med 2009; 360:973-984March 5, 2009DOI: 10.1056/NEJMoa0808991

Abstract

Background

Exacerbations of asthma are associated with substantial morbidity and mortality and with considerable use of health care resources. Preventing exacerbations remains an important goal of therapy. There is evidence that eosinophilic inflammation of the airway is associated with the risk of exacerbations.

Full Text of Background...

Methods

We conducted a randomized, double-blind, placebo-controlled, parallel-group study of 61 subjects who had refractory eosinophilic asthma and a history of recurrent severe exacerbations. Subjects received infusions of either mepolizumab, an anti–interleukin-5 monoclonal antibody (29 subjects), or placebo (32) at monthly intervals for 1 year. The primary outcome measure was the number of severe exacerbations per subject during the 50-week treatment phase. Secondary outcomes included a change in asthma symptoms, scores on the Asthma Quality of Life Questionnaire (AQLQ, in which scores range from 1 to 7, with lower values indicating more severe impairment and a change of 0.5 unit considered to be clinically important), forced expiratory volume in 1 second (FEV₁) after use of a bronchodilator, airway hyperresponsiveness, and eosinophil counts in the blood and sputum.

Full Text of Methods...

Results

Mepolizumab was associated with significantly fewer severe exacerbations than placebo over the course of 50 weeks (2.0 vs. 3.4 mean exacerbations per subject; relative risk, 0.57; 95% confidence interval [CI], 0.32 to 0.92; P=0.02) and with a significant improvement in the score on the AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; 95% CI, 0.08 to 0.62; P=0.02). Mepolizumab significantly lowered eosinophil counts in the blood (P<0.001) and sputum (P=0.002). There were no significant differences between the groups with respect to symptoms, FEV₁ after bronchodilator use, or airway hyperresponsiveness. The only serious adverse events reported were hospitalizations for acute severe asthma.

Full Text of Results...

Conclusions

Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with refractory eosinophilic asthma. The results of our study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population. (Current Controlled Trials number, ISRCTN75169762.)

Full Text of Discussion...

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Media in This Article

Figure 1Numbers of Patients Who Were Screened, Enrolled, and Assigned to a Study Group and Who Completed the Study.

Figure 2Severe Exacerbations during the Course of the Study.

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Article

Asthma is a complex chronic inflammatory disorder of the bronchial tree. Persons with asthma present with variable symptoms of cough, breathlessness, and wheezing; these episodes may be punctuated by periods of more severe and sustained deterioration in control of symptoms — termed exacerbations — that necessitate emergency treatment. Exacerbations are associated with substantial morbidity and mortality and with considerable health care costs.1

Exacerbations differ from day-to-day symptoms in that they respond poorly to usual inhaled therapy and are more closely linked to increased airway inflammation.2 The link to eosinophilic airway inflammation may be particularly important, since infiltration of the airway mucosa with activated eosinophils is seen in postmortem examinations of patients who have died of acute severe asthma,3 and markers of eosinophilic airway inflammation increase well before the onset of exacerbations that are induced by the withdrawal of corticosteroid treatment.4,5 Moreover, management strategies that control eosinophilic airway inflammation as well as the clinical manifestations of asthma are associated with a reduction in the frequency of exacerbations.6,7

A study of asthma therapy involving mepolizumab, a humanized monoclonal antibody against interleukin-5, offers the prospect of clarifying the role of eosinophils in exacerbations, since mepolizumab is a selective and effective inhibitor of eosinophilic inflammation.8-11 Results of clinical trials of this agent among persons with asthma have been disappointing,9,11 although these studies have focused on outcome measures that are not closely associated with eosinophilic airway inflammation and have included populations that were selected on the basis of clinical and physiological characteristics rather than the presence of eosinophilic airway inflammation.12

We tested the hypothesis that eosinophils are important in the pathogenesis of asthma exacerbations by studying the effect of treatment with mepolizumab for 12 months on the frequency of exacerbations among subjects who had refractory asthma and evidence of eosinophilic airway inflammation despite treatment with high doses of corticosteroids. Secondary aims included assessments of the effects of treatment on airway inflammation, asthma symptoms, asthma-related quality of life, forced expiratory volume in 1 second (FEV₁), and, since chronic eosinophilic airway inflammation may be associated with airway remodeling,8 airway structure as assessed with the use of computed tomography (CT).

Methods

Subjects

All subjects were older than 18 years of age and had a clinical diagnosis of asthma that was supported by one or more of the following criteria: variability in the maximum diurnal peak expiratory flow of more than 20% over the course of 14 days, an increase in FEV₁ of more than 15% after inhalation of 200 μg of albuterol, and a 20% reduction in FEV₁ in response to a provocative concentration of inhaled methacholine (PC₂₀) of less than 8 mg per milliliter. Subjects were recruited among patients attending a refractory-asthma clinic that provided secondary asthma care for a mixed urban and rural population of 1 million people and tertiary care for 4 million people. Patients who attend this clinic undergo a standardized assessment, which includes a noninvasive assessment of airway inflammation every 2 to 4 months by means of an analysis of induced-sputum specimens. Inclusion criteria were a diagnosis of refractory asthma according to American Thoracic Society criteria,13 a sputum eosinophil percentage of more than 3% on at least one occasion in the previous 2 years despite high-dose corticosteroid treatment, and at least two exacerbations requiring rescue prednisolone treatment in the previous 12 months. Additional criteria for inclusion were stable treatment requirements and an absence of exacerbations for more than 6 weeks before enrollment in the study. Exclusion criteria were current smoking, serologic evidence of a parasitic infection, a serious coexisting illness, the possibility of conception, and poor adherence to treatment.

All subjects provided written informed consent. The study protocol was approved by the local research ethics committee and the United Kingdom Medicines and Healthcare Products Regulatory Agency.

Design of the Study

The study was a single-center, randomized, double-blind, placebo-controlled, parallel-group clinical trial conducted from April 2006 through August 2008. The funding organization (GlaxoSmithKline) supplied the study drug and placebo but had no role in the accrual or analysis of the data. Representatives of the funding organization contributed to the study design and to the preparation of the manuscript. The academic authors made the decision to submit the manuscript for publication and vouch for the accuracy and integrity of the contents.

The study measurements are described in the Supplementary Appendix (available with the full text of this article at NEJM.org), and the protocol is summarized in Figure 1 in the Supplementary Appendix. At a baseline visit, information on demographic characteristics was collected from all subjects, and spirometry was performed before and after use of a bronchodilator. Regular treatment was kept constant from this time until completion of the study. After a 2-week run-in period, baseline PC₂₀ was measured; a day later, the fraction of exhaled nitric oxide (FE_NO) was measured, symptoms were assessed, and the Asthma Quality of Life Questionnaire (AQLQ) was administered. Symptoms were assessed with the use of three 100-mm visual-analogue scales — one assessing cough, one assessing breathlessness, and one assessing wheezing — each of which had “no symptoms” at one end and “the worst symptoms ever” at the other end, and with the use of the modified Juniper Asthma Control Questionnaire (JACQ), which assesses daytime and nighttime symptoms and activity limitation on the basis of five questions that are scored on a scale of 0 to 6, with lower numbers representing better control of symptoms.14 Quality of life was assessed with the use of the AQLQ, a questionnaire comprising 32 items, each of which is scored on a scale of 1 to 7, with higher scores indicating better asthma-related quality of life.15 The items are grouped into four domains, and the reported score is the mean of responses across the four domains. The minimal clinically important change in the JACQ and AQLQ scores is 0.5.14

To assess both the responsiveness of symptoms, FE_NO, and FEV₁ to treatment with oral corticosteroids and the way in which the responsiveness was influenced by mepolizumab therapy, subjects were treated with oral prednisolone for 2 weeks at a dose of 0.5 mg per kilogram of body weight per day, with a maximum dose of 40 mg per day, at the beginning and end of the study. For the subgroup of participants who consented to have a bronchoscopic examination, the procedure was performed before treatment with prednisolone. At visit 3, after completing the 2-week course of prednisolone and before receiving the first study treatment, subjects underwent a further assessment of symptom scores, measurement of FE_NO, and spirometry before and after bronchodilator use, as well as CT scanning in the subgroup of patients who provided consent for this assessment.

Subjects were randomly assigned with the use of the minimization method (Table 1Table 1Baseline Characteristics of Subjects in the Intention-to-Treat Population.) to receive 12 infusions of either 750 mg of mepolizumab delivered intravenously or matched placebo (150 ml of 0.9% saline) at monthly intervals between visits 3 and 14. The criteria used for minimization were the frequency of exacerbations in the previous 12 months, the baseline eosinophil count in the sputum, and the number of subjects taking oral corticosteroids. FE_NO, spirometry before and after use of a bronchodilator, and symptom scores were recorded at each visit; the AQLQ was administered at visits 5, 8, 11, and 14; and PC₂₀ was measured the day before visits 8 and 14. The treatment phase ended 2 weeks after visit 14 — that is, 50 weeks after treatment was started. At this time, bronchoscopy was performed in subjects who consented to the procedure, and all subjects were given an additional 2-week course of oral prednisolone. After the course of oral prednisolone was completed, FE_NO and symptom scores were assessed, and spirometry and, in the subgroup of patients who provided consent, CT scanning were performed.

Exacerbations during the treatment phase of the study were managed in accordance with standard clinical guidelines.16 Subjects who initiated treatment at home did so with guidance from their personalized management plan. In all cases, subjects were instructed to seek medical advice as soon as possible after starting therapy. Oral prednisolone therapy was prescribed at a dose of 0.5 mg per kilogram per day, with a maximum dose of 40 mg per day. Decisions about whether to use adjunctive therapy such as antibiotics and about the need for hospitalization were made by the study physician or the subject's general practitioner. For subjects who were assessed by the study team within 72 hours after an exacerbation, assessments included symptom scores, FE_NO, peak expiratory flow, and spirometry performed before and after use of a bronchodilator. In addition, sputum samples were obtained for cell counts and microbial analysis.

Because of the expected anti-eosinophil effects of mepolizumab, results of FE_NO measurements, sputum analyses, and leukocyte differential counts that were obtained during scheduled and unscheduled visits were not disclosed to investigators. Exacerbations requiring hospitalization were managed by the admitting clinical team, whose members were unaware of the treatment assignments and of the results of the measurements of inflammatory factors.

Safety Assessment

Safety was assessed on the basis of laboratory tests, physical examinations, measurement of vital signs both before and after infusion, and adverse-event reports. Serious adverse events were also reported to GlaxoSmithKline as part of their ongoing collection of data.

Statistical Analysis

The primary outcome measure of the study was the number of severe exacerbations of asthma per subject; exacerbations were defined as periods of deterioration in asthma control in subjects who had been treated with high-dose oral prednisolone for at least 5 days.14 Exacerbations that occurred in the 50 weeks between the completion of the first treatment visit and 2 weeks after the final treatment visit were included in the analysis. A recurrence of asthma symptoms shortly after completion of a course of prednisolone was recorded as a separate exacerbation if baseline control of symptoms had been restored for a period of at least 5 days. Secondary outcome measures were changes in eosinophil values in blood and sputum samples, FE_NO, FEV₁ (percent of the predicted value) after bronchodilator use, PC₂₀, AQLQ score, symptom scores, CT assessment of airway-wall geometry, and bronchoscopic assessment of eosinophilic airway inflammation.

All subjects who completed at least one treatment visit were included in an intention-to-treat analysis of the primary outcome. In the case of subjects who withdrew from the study, the adjusted number of exacerbations was calculated with the use of the following equation: recorded number of exacerbations + [(visits remaining ÷ total visits) × mean exacerbation frequency in the study group]. Exacerbation frequency was calculated and compared between the study groups with the use of a negative binomial model and verified with the Mann–Whitney U test, as previously described.17 In a study of a similar cohort,6 the mean (±SD) number of exacerbations was 3.2±2.1 per subject per year. Assuming a mean of two exacerbations per subject per year, we needed to include 60 subjects in order to have 80% power to detect a 50% reduction in exacerbation frequency. Secondary-outcome values were log-transformed where appropriate. Between-group and within-group comparisons were made for the mean change between baseline values and the mean or geometric mean of the posttreatment values with the use of unpaired and paired t-tests, respectively, for parametric distributions and the Mann–Whitney U test for nonparametric distributions. Proportions were compared with the use of Fisher's exact test. Statistical software packages used for various analyses included SPSS, version 13 (SPSS), Stata, version 7 (Stata), and GraphPad Prism, version 4 (GraphPad Software).

Results

Enrollment and Baseline Characteristics

Figure 1Figure 1Numbers of Patients Who Were Screened, Enrolled, and Assigned to a Study Group and Who Completed the Study. shows the numbers of subjects who were screened, enrolled, and randomly assigned to a study group and who completed the study. A total of 61 of the 63 subjects who were screened started treatment and constituted the modified intention-to-treat population. Thirty-two subjects were randomly assigned to receive placebo. Overall, 94.9% of treatment visits were completed. Subjects who withdrew completed a mean of 4.6 treatment visits (38.3%). Subjects in the two groups were well matched with respect to baseline characteristics (Table 1).

Efficacy

Frequency of Severe Exacerbations

The median treatment period was 348 days in the mepolizumab group and 340 days in the placebo group (P=0.30). During this period, a total of 57 exacerbations occurred in the group of subjects who were assigned to receive mepolizumab and 109 in the group assigned to receive placebo (Figure 2AFigure 2Severe Exacerbations during the Course of the Study.). The mean number of severe exacerbations per subject was 2.0 in the mepolizumab group, as compared with 3.4 in the placebo group (relative risk, 0.57; 95% confidence interval [CI], 0.32 to 0.92; P=0.02) (Figure 2A and 2B). The difference in the number of exacerbations remained significant with nonparameteric analysis (P=0.04). Thirty-one percent of the subjects in the mepolizumab group had no exacerbations during the study period, as compared with 16% in the placebo group (P=0.23) (Figure 2B). The mean duration of prednisolone therapy per exacerbation was similar in the two groups (10.9 days in the mepolizumab group and 11.7 days in the placebo group, P=0.31). There were three hospital admissions for exacerbations of asthma in the mepolizumab group, as compared with 11 admissions in the placebo group (P=0.07). The total number of days in the hospital was significantly less for the subjects receiving mepolizumab treatment than for those receiving placebo (12 days vs. 48 days, P<0.001).

Treatment for an exacerbation was initiated by the subject in 20% of the cases, by the primary care physician or a physician at a hospital other than the study site in 25%, and by the study team in 55%. In the 77% of cases in which exacerbations were assessed within 72 hours after the initiation of prednisolone therapy, there were no significant differences between the groups in peak expiratory flow, FEV₁ before and after bronchodilator use, symptom scores, or rescue bronchodilator use. Sputum samples were obtained from patients during 61% of the exacerbations. The geometric mean eosinophil percentage in the sputum during an exacerbation was significantly lower in the mepolizumab group than in the placebo group (1.5% vs. 4.4%), with the values differing by a factor of 2.9 (95% CI, 1.4 to 6.1; P=0.005), but the mean total neutrophil count in the sputum did not differ significantly between the two groups (3846 cells per milligram of sputum in the mepolizumab group and 4122 cells per milligram in the placebo group, P=0.80). The eosinophil percentage in the sputum was higher than 3% in 59% of the episodes in the placebo group and in 36% of the episodes in the mepolizumab group (P=0.04).

Inflammatory Markers

Mepolizumab therapy was associated with significant between-group and within-group reductions in eosinophil counts in both blood and sputum (Figure 3AFigure 3Comparison of Secondary Outcomes between Study Groups.). The geometric mean of eosinophil counts in the blood during the treatment phase, as compared with the baseline value, was reduced by a factor of 6.6 in the mepolizumab group and by a factor of 1.1 in the placebo group, with the changes from baseline differing between the groups by a factor of 6.1 (95% CI, 4.1 to 8.9; P<0.001). Sputum induction at 90% of visits resulted in cytospin preparations that could be assessed for eosinophil counts. The geometric mean eosinophil count in the sputum was reduced by a factor of 7.1 in the mepolizumab group and by a factor of 1.9 in the placebo group, with the changes from baseline differing between the groups by a factor of 3.7 (95% CI, 1.6 to 8.4; P=0.002). There were no significant between-group differences in the change in FE_NO (P=0.29) or the total neutrophil count in the sputum (P=0.22) (Figure 3B, and Table 1 in the Supplementary Appendix).

Paired bronchial-biopsy specimens (specimens obtained before and after the study treatment) were available for 14 subjects (of whom 9 were in the mepolizumab group), paired bronchoalveolar-lavage specimens for 11 subjects (8 in the mepolizumab group), and paired bronchial-wash specimens for 10 subjects (7 in the mepolizumab group). Changes in eosinophil counts after infusions of mepolizumab, as compared with changes after placebo infusions, were reduced by a factor of 2.1 (95% CI, 0.6 to 68.1; P=0.68) in bronchial-biopsy specimens, by a factor of 8.2 (95% CI, 0.9 to 75.4; P=0.06) in bronchoalveolar-lavage specimens, and by a factor of 16.0 (95% CI, 1.8 to 140; P=0.02) in bronchial-wash specimens (see Table 1 and Fig. 2 in the Supplementary Appendix).

Other Outcomes

There were no significant differences between the groups in the change from baseline symptom scores, whether they were assessed with the use of visual-analogue scales or JACQ (Figure 3B, and Table 1 in the Supplementary Appendix). The mean improvement in the AQLQ score was 0.55 in the mepolizumab group, as compared with 0.19 in the placebo group (mean difference between the groups, 0.35; 95% CI, 0.08 to 0.63; P=0.02) (Figure 3A). There were no significant between-group differences in changes from baseline values for FEV₁ after bronchodilator use or PC₂₀ (Figure 3B, and Table 1 in the Supplementary Appendix).

There were no significant between-group differences in the changes in FEV₁ or symptom scores after prednisolone treatment given at the end of the study period, as compared with prednisolone given at the beginning of the study period (Figure 3B, and Table 2 in the Supplementary Appendix). Nine subjects who were assigned to the mepolizumab group had more than a 0.5-point decrease in JACQ scores after the 2-week course of prednisolone that was given before the initiation of mepolizumab therapy. These subjects had a similar within-group decrease in JACQ scores after the prednisolone treatment that was given at the end of the study (mean reduction, 1.2 points before mepolizumab therapy and 0.9 points afterward; mean difference, −0.3; 95% CI, −1.0 to 0.4; P=0.32).

CT scans were obtained before and after the treatment phase of the study in 26 patients in each group. The results of all CT assessments are shown in Fig. 3 and Table 1 in the Supplementary Appendix. There was a significant between-group difference in the change from baseline for airway wall area (mean between-group difference, 1.1 mm² per square meter of body-surface area; 95% CI, 0.2 to 2.1; P=0.02) and in the change in total area (mean between-group difference, 1.5 mm² per square meter; 95% CI, 0.2 to 2.8; P=0.03).

At the completion of the study, subjects were asked to guess their treatment assignment. Forty-five percent of the subjects were unsure of their treatment assignment, 36% guessed correctly, and 19% guessed incorrectly. There was no significant difference between the study groups in the proportions of patients choosing each response (P=0.42).

Safety

Intravenous mepolizumab had an acceptable adverse-event and side-effect profile throughout the 12 months of treatment. The only serious adverse events reported were hospitalizations for acute severe asthma (Table 2Table 2Reported Adverse Events during the 50-Week Treatment Phase of the Study.). No local effects of infusion were observed. One subject was withdrawn from the study because of a transient maculopapular rash that developed 24 hours after the first infusion of mepolizumab.

Discussion

We found that mepolizumab treatment significantly reduced the number of asthma exacerbations that resulted in the prescription of corticosteroid therapy and increased asthma-related quality of life in subjects who had refractory eosinophilic asthma and a history of recurrent exacerbations. There was no significant improvement in symptoms or in FEV₁, measures that are commonly used for quantifying asthma control. Treatment effectively lowered eosinophil counts in the blood and sputum and was well tolerated over the course of the 12-month study period.

Previous studies of mepolizumab treatment in patients with less severe asthma have been too short to evaluate the effect of treatment on the frequency of exacerbations, although the largest study to date, like ours, showed a reduction in severe exacerbations, which approached significance.9 The lack of effect of mepolizumab on symptoms, FEV₁, and airway responsiveness in our study is also consistent with the results of previous studies.8-11 Treatment had a larger effect on eosinophil numbers in blood and sputum samples than on those in biopsy specimens, findings that are consistent with earlier work,10 although sputum eosinophilia was present in 36% of the exacerbations, despite mepolizumab therapy. Further studies are required to investigate the mechanisms underlying heterogeneity in the biologic response to mepolizumab and the relative resistance of eosinophils in tissue to anti–interleukin-5.

We have previously shown that the main effect of a management strategy that suppresses eosinophilic airway inflammation is a reduction in the frequency of exacerbations and have suggested a causal link between eosinophilic airway inflammation and exacerbations.6 This view is strongly supported by the results of the current study, since mepolizumab is a selective inhibitor of eosinophilic airway inflammation.

Mepolizumab treatment had no effect on asthma symptoms, FE_NO, or lung function, although these measures did improve in some subjects after prednisolone treatment, even when the prednisolone was administered after mepolizumab treatment, when eosinophilic airway inflammation was suppressed. This finding suggests that symptoms, FE_NO, and lung function can be disassociated from eosinophilic inflammation and are improved with corticosteroid treatment through another mechanism. Modulation of the interaction between airway smooth muscle and infiltrating mast cells18 is a possible explanation for the effect of prednisolone on lung function and symptoms. The absence of an association between the risk of exacerbations and eosinophilic airway inflammation, on the one hand, and lung function and day-to-day clinical manifestations of asthma, on the other, has important implications for the way asthma is managed and assessed in patients with refractory asthma. Our study showed a small but significant improvement in asthma-related quality of life with mepolizumab therapy, perhaps reflecting the value to patients of the prevention of exacerbations.

We found that airway-wall thickness and total wall area, as measured by CT, were reduced in subjects who were treated with mepolizumab as compared with those who were given placebo. The CT scans were obtained after a 2-week course of prednisolone and after administration of bronchodilators, so the findings are unlikely to be confounded by bronchomotor tone and acute airway inflammation. Whether the changes in airway-wall dimensions translate into important long-term clinical effects requires further investigation.

The therapeutic effect that was seen with mepolizumab treatment shows how we can learn more about the pathogenesis of different airway responses by studying selective inhibitors of inflammation. The patients who were included in this study had refractory eosinophilic asthma despite maximum tolerated therapy, which in many cases included regular use of oral corticosteroids. Their asthma resembled the exacerbation-prone phenotype of severe asthma, as described by Moore et al.,19 and the phenotype of asthma with predominant eosinophilic inflammation, which we have described.20 Our results should not be extrapolated beyond the highly selected group of patients we recruited for this study. However, further clinical trials should be performed to establish more clearly the risks and benefits of mepolizumab treatment in a wider population of patients. Many patients with fluctuating respiratory symptoms and eosinophilic airway inflammation do not meet current criteria for a diagnosis of asthma,18,21-23 and we have previously argued that new ways of classifying airway disease are needed to allow proper evaluation of new therapies.24 Investigators planning future trials should be mindful of disease characteristics that suggest a response to therapy and should include patients with airway disease and eosinophilic airway inflammation rather than only those who meet arbitrary physiological criteria.

Supported by an unrestricted educational grant from GlaxoSmithKline.

Dr. Brightling reports receiving lecture fees, consulting fees, and grant support from AstraZeneca, GlaxoSmithKline, and MedImmune; Dr. Wardlaw, receiving consulting fees from MedImmune and GlaxoSmithKline, lecture fees from Merck, and grant support from GlaxoSmithKline and AstraZeneca; Dr. Pavord, receiving lecture fees from AstraZeneca, GlaxoSmithKline, and Aerocrine, consulting fees from Merck, GlaxoSmithKline, Wyeth, and AstraZeneca, and grant support from GlaxoSmithKline; Dr. Bradding, receiving consulting fees from GlaxoSmithKline; and Drs. Sousa and Marshall, being employees of GlaxoSmithKline and holding equity in that company. No other potential conflict of interest relevant to this article was reported.

This article (10.1056/NEJMoa0808991) was updated on February 9, 2011, at NEJM.org.

We thank Debbie Parker, Natalie Neale, and Katie Roach for their help in the laboratory; Maria Shelley, Sue McKenna, Hilary Pateman, Michelle Bourne, and Amisha Singapuri for their help with assessments of the patients; Anita Raj, Shiron Saha, Mona Bafadhel, Jon Bennett, James Entwisle, and Dean Mawby for their help with preparation of study drugs, bronchoscopy, and CT; and the study participants for their unfailing commitment and enthusiasm.

Source Information

From the Institute for Lung Health, Glenfield Hospital, University Hospitals of Leicester National Health Service Trust, Leicester (P.H., C.E.B., B.H., S.G., W.M., P.B., R.H.G., A.J.W., I.D.P.); and Exploratory Medical Science, Discovery Medicine, Respiratory and Inflammation Center of Excellence for Drug Discovery, GlaxoSmithKline, Stevenage (A.S., R.P.M.) — all in the United Kingdom.

Address reprint requests to Dr. Pavord at the Institute for Lung Health, Glenfield Hospital, University Hospitals of Leicester National Health Service Trust, Groby Rd., Leicester LE3 9QP, United Kingdom, or at ian.pavord@uhl-tr.nhs.uk.

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Citing Articles (331)

Citing Articles

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   Paul D. Robinson, Peter Asperen. (2013) Newer Treatments in the Management of Pediatric Asthma. Pediatric Drugs
   

2. 2

   D. T. S. Z. Miranda, A. L. Zanatta, B. C. L. Dias, R. T. H. Fogaça, J. B. B. Maurer, L. Donatti, P. C. Calder, A. Nishiyama. (2013) The Effectiveness of Fish Oil Supplementation in Asthmatic Rats is Limited by an Inefficient Action on ASM Function. Lipids
   

3. 3

   Monica L. Gavala, Hiba Bashir, James E. Gern. (2013) Virus/Allergen Interactions in Asthma. Current Allergy and Asthma Reports 13:3, 298-307
   

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   Steven Greenberg. (2013) Asthma exacerbations. Current Opinion in Allergy and Clinical Immunology 13:3, 225-236
   

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   Alexandra Adams, Sejal Saglani. (2013) Difficult-to-Treat Asthma in Childhood. Pediatric Drugs 15:3, 171-179
   

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   Garry M. Walsh. (2013) Therapeutic Potential of Targeting Interleukin 5 in Asthma. BioDrugs
   

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   G. J. Gleich, A. D. Klion, J. J. Lee, P. F. Weller. (2013) The consequences of not having eosinophils. Allergyn/a-n/a
   

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   L. Wang, T. J. Jenkins, M. Dai, W. Yin, J. C. Pulido, E. LaMantia-Martin, M. R. Hodge, T. Ocain, R. Kolbeck. (2013) Antagonism of chemokine receptor CCR8 is ineffective in a primate model of asthma. Thorax 68:6, 506-512
   

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   Martijn J Schuijs, Monique A Willart, Hamida Hammad, Bart N Lambrecht. (2013) Cytokine targets in airway inflammation. Current Opinion in Pharmacology 13:3, 351-361
   

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    J.C. Virchow. (2013) Asthma bronchiale. Der Pneumologe 10:S1, 16-22
    

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    Yoshihiro Kanemitsu, Hisako Matsumoto, Kenji Izuhara, Yuji Tohda, Hideo Kita, Takahiko Horiguchi, Kazunobu Kuwabara, Keisuke Tomii, Kojiro Otsuka, Masaki Fujimura, Noriyuki Ohkura, Katsuyuki Tomita, Akihito Yokoyama, Hiroshi Ohnishi, Yasutaka Nakano, Tetsuya Oguma, Soichiro Hozawa, Tadao Nagasaki, Isao Ito, Tsuyoshi Oguma, Hideki Inoue, Tomoko Tajiri, Toshiyuki Iwata, Yumi Izuhara, Junya Ono, Shoichiro Ohta, Mayumi Tamari, Tomomitsu Hirota, Tetsuji Yokoyama, Akio Niimi, Michiaki Mishima. (2013) Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids. Journal of Allergy and Clinical Immunology
    

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    M. Lommatzsch. (2013) Die DREAM-Studie – Abschluss einer Selbstfindung und Beginn einer Zeitenwende. Der Pneumologe
    

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    Wenzel , Sally , Ford , Linda , Pearlman , David , Spector , Sheldon , Sher , Lawrence , Skobieranda , Franck , Wang , Lin , Kirkesseli , Stephane , Rocklin , Ross , Bock , Brian , Hamilton , Jennifer , Ming , Jeffrey E. , Radin , Allen , Stahl , Neil , Yancopoulos , George D. , Graham , Neil , Pirozzi , Gianluca , . Dupilumab in Persistent Asthma with Elevated Eosinophil Levels. New England Journal of Medicine 0:0,
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    Wechsler , Michael E. , . Inhibiting Interleukin-4 and Interleukin-13 in Difficult-to-Control Asthma. New England Journal of Medicine 0:0,
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    Kiyoshi Hirahara, Amanda Poholek, Golnaz Vahedi, Arian Laurence, Yuka Kanno, Joshua D. Milner, John J. O’Shea. (2013) Mechanisms underlying helper T-cell plasticity: Implications for immune-mediated disease. Journal of Allergy and Clinical Immunology 131:5, 1276-1287
    

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    S. J. Arbes, A. Calatroni, H. E. Mitchell, P. J. Gergen. (2013) Age-dependent interaction between atopy and eosinophils in asthma cases: results from NHANES 2005-2006. Clinical & Experimental Allergy 43:5, 544-551
    

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    Anastasia Papaporfyriou, Eleni Tseliou, Stelios Loukides, Konstantinos Kostikas, Petros Bakakos. (2013) Noninvasive evaluation of airway inflammation in patients with severe asthma. Annals of Allergy, Asthma & Immunology 110:5, 316-321
    

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    J. Charriot, A.-S. Gamez, M. Humbert, P. Chanez, A. Bourdin. (2013) Thérapies ciblées dans l’asthme sévère : À la découverte de nouvelles molécules. Revue des Maladies Respiratoires
    

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    Parameswaran Nair. (2013) What is an “eosinophilic phenotype” of asthma?. Journal of Allergy and Clinical Immunology
    

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    Kwang Je Baek, Jae Youn Cho, Peter Rosenthal, Laura E. Crotty Alexander, Victor Nizet, David H. Broide. (2013) Hypoxia potentiates allergen induction of HIF-1α, chemokines, airway inflammation, TGF-β1, and airway remodeling in a mouse model. Clinical Immunology 147:1, 27-37
    

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    James F. Donohue, Neal Jain. (2013) Exhaled nitric oxide to predict corticosteroid responsiveness and reduce asthma exacerbation rates. Respiratory Medicine
    

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    S. Létuvé, C. Taillé. (2013) Physiopathologie de la réponse inflammatoire dans l’asthme de l’adulte. EMC - Pneumologie 10:2, 1-8
    

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    Alexandra Sittka, Julio Vera, Xin Lai, Bernd T. Schmeck. (2013) Asthma phenotyping, therapy, and prevention: what can we learn from systems biology?. Pediatric Research 73:4-2, 543-552
    

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    Timothy R. Hercus, Urmi Dhagat, Winnie L.T. Kan, Sophie E. Broughton, Tracy L. Nero, Michelle Perugini, Jarrod J. Sandow, Richard J. D’Andrea, Paul G. Ekert, Timothy Hughes, Michael W. Parker, Angel F. Lopez. (2013) Signalling by the ßc family of cytokines. Cytokine & Growth Factor Reviews
    

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    Ian D Pavord. (2013) Complex airway disease: an approach to assessment and management. The Lancet Respiratory Medicine 1:1, 84-90
    

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    Bethan L. Barker, Christopher E. Brightling. (2013) Phenotyping the heterogeneity of chronic obstructive pulmonary disease. Clinical Science 124:6, 371-387
    

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    Massimo Caruso, Emanuele Crisafulli, Shirin Demma, Stephen Holgate, Riccardo Polosa. (2013) Disabling inflammatory pathways with biologics and resulting clinical outcomes in severe asthma. Expert Opinion on Biological Therapy 13:3, 393-402
    

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    Matthew C. Bell, William W. Busse. (2013) Severe Asthma: An Expanding and Mounting Clinical Challenge. The Journal of Allergy and Clinical Immunology: In Practice 1:2, 110-121
    

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    Kai-Michael Beeh, Frank Kanniess, Frank Wagner, Cordula Schilder, Ingomar Naudts, Anya Hammann-Haenni, Joerg Willers, Hans Stocker, Philipp Mueller, Martin F. Bachmann, Wolfgang A. Renner. (2013) The novel TLR-9 agonist QbG10 shows clinical efficacy in persistent allergic asthma. Journal of Allergy and Clinical Immunology 131:3, 866-874
    

30. 30

    Samuel Louie, Amir A Zeki, Michael Schivo, Andrew L Chan, Ken Y Yoneda, Mark Avdalovic, Brian M Morrissey, Timothy E Albertson. (2013) The asthma–chronic obstructive pulmonary disease overlap syndrome: pharmacotherapeutic considerations. Expert Review of Clinical Pharmacology 6:2, 197-219
    

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    (2013) The Editor takes a closer look at some of this month's articles. Clinical & Experimental Allergy 43:3, 263-263
    

32. 32

    Trevor T Hansel, Sebastian L Johnston, Peter J Openshaw. (2013) Microbes and mucosal immune responses in asthma. The Lancet 381:9869, 861-873
    

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    Douglas S Robinson. (2013) Mepolizumab for severe eosinophilic asthma. Expert Review of Respiratory Medicine 7:1, 13-17
    

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    Sabina Antonela Antoniu. (2013) Monoclonal antibodies for asthma and chronic obstructive pulmonary disease. Expert Opinion on Biological Therapy 13:2, 257-268
    

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    Douglas S Robinson. (2013) Mepolizumab treatment for asthma. Expert Opinion on Biological Therapy 13:2, 295-302
    

36. 36

    Osama Eltboli, Christopher E Brightling. (2013) Eosinophils as diagnostic tools in chronic lung disease. Expert Review of Respiratory Medicine 7:1, 33-42
    

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    Florence E. Roufosse, Jean-Emmanuel Kahn, Gerald J. Gleich, Lawrence B. Schwartz, Anish D. Singh, Lanny J. Rosenwasser, Judah A. Denburg, Johannes Ring, Marc E. Rothenberg, Javed Sheikh, Ann E. Haig, Stephen A. Mallett, Deborah N. Templeton, Hector G. Ortega, Amy D. Klion. (2013) Long-term safety of mepolizumab for the treatment of hypereosinophilic syndromes. Journal of Allergy and Clinical Immunology 131:2, 461-467.e5
    

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    Pierre-Olivier Girodet, Annaig Ozier, Gabrielle Carvalho, Olga Ilina, Olga Ousova, Alain-Pierre Gadeau, Hugues Begueret, Heike Wulff, Roger Marthan, Peter Bradding, Patrick Berger. (2013) Ca ²⁺ -Activated K ⁺ Channel–3.1 Blocker TRAM-34 Attenuates Airway Remodeling and Eosinophilia in a Murine Asthma Model. American Journal of Respiratory Cell and Molecular Biology 48:2, 212-219
    

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    Patricia C. Fulkerson, Marc E. Rothenberg. (2013) Targeting eosinophils in allergy, inflammation and beyond. Nature Reviews Drug Discovery 12:2, 117-129
    

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    Animal Models of Human Pathology. In: Eosinophils in Health and Disease. Elsevier, 2013:537-575.
    

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    Eric S. Papierniak, David T. Lowenthal, Eloise Harman. (2013) Novel Therapies in Asthma. American Journal of Therapeutics 20:1, 79-103
    

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    David R. Ball, Barry E. McGuire. Airway Pharmacology. In: Benumof and Hagberg's Airway Management. Elsevier, 2013:159-183.e9.
    

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    Eosinophils in Human Disease. In: Eosinophils in Health and Disease. Elsevier, 2013:431-536.
    

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    Florence N Schleich, Maité Manise, Jocelyne Sele, Monique Henket, Laurence Seidel, Renaud Louis. (2013) Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. BMC Pulmonary Medicine 13:1, 11
    

45. 45

    Philip M Hansbro, Grace V Scott, Ama-Tawiah Essilfie, Richard Y Kim, Malcolm R Starkey, Duc H Nguyen, Paul D Allen, Gerard E Kaiko, Ming Yang, Jay C Horvat, Paul S Foster. (2013) Th2 cytokine antagonists: potential treatments for severe asthma. Expert Opinion on Investigational Drugs 22:1, 49-69
    

46. 46

    Antieosinophil Therapeutics. In: Eosinophils in Health and Disease. Elsevier, 2013:577-605.
    

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    Eosinophil-Mediated Tissue Remodeling and Fibrosis. In: Eosinophils in Health and Disease. Elsevier, 2013:391-429.
    

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    Dhananjay Desai, Sumit Gupta, Salman Siddiqui, Amisha Singapuri, William Monteiro, James Entwisle, Sudha Visvanathan, Harsukh Parmar, Radhika Kajekar, Christopher E Brightling. (2013) Sputum mediator profiling and relationship to airway wall geometry imaging in severe asthma. Respiratory Research 14:1, 17
    

49. 49

    Eosinophil Cell–Cell Communication. In: Eosinophils in Health and Disease. Elsevier, 2013:329-390.
    

50. 50

    Gerald J. Gleich. Historical Overview and Perspective on the Role of the Eosinophil in Health and Disease. In: Eosinophils in Health and Disease. Elsevier, 2013:1-11.
    

51. 51

    Ting-Yu Lin, Audrey H. Poon, Qutayba Hamid. (2013) Asthma phenotypes and endotypes. Current Opinion in Pulmonary Medicine 19:1, 18-23
    

52. 52

    Stephanie Korn, Marisa Hübner, Matthias Jung, Maria Blettner, Roland Buhl. (2013) Severe and uncontrolled adult asthma is associated with vitamin D insufficiency and deficiency. Respiratory Research 14:1, 25
    

53. 53

    Rachid Berair, Fay Hollins, Christopher Brightling. (2013) Airway Smooth Muscle Hypercontractility in Asthma. Journal of Allergy 2013, 1-7
    

54. 54

    Luca Gallelli, Maria Teresa Busceti, Alessandro Vatrella, Rosario Maselli, Girolamo Pelaia. (2013) Update on Anticytokine Treatment for Asthma. BioMed Research International 2013, 1-10
    

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    F. Braido, S. Holgate, G.W. Canonica. (2012) From “blockbusters” to “biosimilars”: An opportunity for patients, medical specialists and health care providers. Pulmonary Pharmacology & Therapeutics 25:6, 483-486
    

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    S. Gonem, V. Raj, A. J. Wardlaw, I. D. Pavord, R. Green, S. Siddiqui. (2012) Phenotyping airways disease: an A to E approach. Clinical & Experimental Allergy 42:12, 1664-1683
    

57. 57

    Richard B. Moss. (2012) The use of biological agents for the treatment of fungal asthma and allergic bronchopulmonary aspergillosis. Annals of the New York Academy of Sciences 1272:1, 49-57
    

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    Girolamo Pelaia, Alessandro Vatrella, Rosario Maselli. (2012) The potential of biologics for the treatment of asthma. Nature Reviews Drug Discovery 11:12, 958-972
    

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    Helene F. Rosenberg, Kimberly D. Dyer, Paul S. Foster. (2012) Eosinophils: changing perspectives in health and disease. Nature Reviews Immunology 13:1, 9-22
    

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    E. A. Jacobsen, R. A. Helmers, J. J. Lee, N. A. Lee. (2012) The expanding role(s) of eosinophils in health and disease. Blood 120:19, 3882-3890
    

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    Vincent Cottin, Jean-François Cordier. (2012) Eosinophilic Lung Diseases. Immunology and Allergy Clinics of North America 32:4, 557-586
    

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    Ynuk Bossé. (2012) Asthmatic airway hyperresponsiveness: the ants in the tree. Trends in Molecular Medicine 18:11, 627-633
    

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    E. Campos Alberto, E. MacLean, C. Davidson, N. S. Palikhe, J. Storie, C. Tse, D. Brenner, I. Mayers, H. Vliagoftis, A. El-Sohemy, L. Cameron. (2012) The single nucleotide polymorphism CRTh2 rs533116 is associated with allergic asthma and increased expression of CRTh2. Allergy 67:11, 1357-1364
    

64. 64

    Sophie E. Broughton, Urmi Dhagat, Timothy R. Hercus, Tracy L. Nero, Michele A. Grimbaldeston, Claudine S. Bonder, Angel F. Lopez, Michael W. Parker. (2012) The GM-CSF/IL-3/IL-5 cytokine receptor family: from ligand recognition to initiation of signaling. Immunological Reviews 250:1, 277-302
    

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    Zhaleh J. Amini-Vaughan, Margarita Martinez-Moczygemba, David P. Huston. (2012) Therapeutic Strategies for Harnessing Human Eosinophils in Allergic Inflammation, Hypereosinophilic Disorders, and Cancer. Current Allergy and Asthma Reports 12:5, 402-412
    

66. 66

    Leticia Lintomen, Marina C. Calixto, André Schenka, Edson Antunes. (2012) Allergen-Induced Bone Marrow Eosinophilopoiesis and Airways Eosinophilic Inflammation in Leptin-Deficient ob/ob Mice. Obesity 20:10, 1959-1965
    

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    Sheldon Laurence Spector, Ricardo Antonio Tan. (2012) Is a Single Blood Eosinophil Count a Reliable Marker for “Eosinophilic Asthma?”. Journal of Asthma 49:8, 807-810
    

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    Miyoung Kim, Jeehye Maeng, Kyunglim Lee. (2012) Dimerization of TCTP and its clinical implications for allergy. Biochimie
    

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    Jennifer L. Ingram, Monica Kraft. (2012) IL-13 in asthma and allergic disease: Asthma phenotypes and targeted therapies. Journal of Allergy and Clinical Immunology 130:4, 829-842
    

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    Sally E. Wenzel, Catherine A. Vitari, Manisha Shende, Diane C. Strollo, Allyson Larkin, Samuel A. Yousem. (2012) Asthmatic Granulomatosis. American Journal of Respiratory and Critical Care Medicine 186:6, 501-507
    

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    Ho Jeong Na, Robert G. Hamilton, Amy D. Klion, Bruce S. Bochner. (2012) Biomarkers of eosinophil involvement in allergic and eosinophilic diseases: Review of phenotypic and serum markers including a novel assay to quantify levels of soluble Siglec-8. Journal of Immunological Methods 383:1-2, 39-46
    

72. 72

    Arnaud Bourdin, Marc Humbert, Pascal Chanez. (2012) Immunologic Therapeutic Interventions in Asthma. Clinics in Chest Medicine 33:3, 585-597
    

73. 73

    Russell S. Traister, Sally E. Wenzel. (2012) Inflammatory phenotypes in asthma pathogenesis. Drug Discovery Today: Disease Mechanisms
    

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    Robert P. Yim, Anastassios C. Koumbourlis. (2012) Steroid-resistant asthma. Paediatric Respiratory Reviews 13:3, 172-177
    

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    Parameswaran Nair, Angira Dasgupta, Christopher E. Brightling, Kian Fan Chung. (2012) How to Diagnose and Phenotype Asthma. Clinics in Chest Medicine 33:3, 445-457
    

76. 76

    Guiquan Jia, Richard W. Erickson, David F. Choy, Sofia Mosesova, Lawren C. Wu, Owen D. Solberg, Aarti Shikotra, Richard Carter, Séverine Audusseau, Qutayba Hamid, Peter Bradding, John V. Fahy, Prescott G. Woodruff, Jeffrey M. Harris, Joseph R. Arron. (2012) Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. Journal of Allergy and Clinical Immunology 130:3, 647-654.e10
    

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    Mina Gaga, Eleftherios Zervas, Konstantinos Samitas, Elisabeth H. Bel. (2012) Severe Asthma in Adults. Clinics in Chest Medicine 33:3, 571-583
    

78. 78

    Audrey H Poon, Qutayba Hamid. (2012) Asthma endotypes: the right direction towards personalized medicine for asthma. Expert Review of Clinical Immunology 8:7, 595-596
    

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    Renaud Louis, Florence Schleich, Peter J. Barnes. (2012) Corticosteroids. Clinics in Chest Medicine 33:3, 531-541
    

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    Tania Maes, Guy F. Joos, Guy G. Brusselle. (2012) Targeting Interleukin-4 in Asthma: Lost in Translation?. American Journal of Respiratory Cell and Molecular Biology 47:3, 261-270
    

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    Simone Hashimoto, Elisabeth H Bel. (2012) Targeting IL-5 in severe asthma: a DREAM come true?. The Lancet 380:9842, 626-627
    

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    Felix Wantke. (2012) Asthma bronchiale bei Erwachsenen – Diagnostik & Therapie. Wiener klinische Wochenschrift Education 7:1, 1-20
    

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    M. Kupczyk, S. Wenzel. (2012) US and European severe asthma cohorts: what can they teach us about severe asthma?. Journal of Internal Medicine 272:2, 121-132
    

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    Sally E. Wenzel. (2012) Tissue-Based and Bronchoalveolar Lavage–Based Biomarkers in Asthma. Immunology and Allergy Clinics of North America 32:3, 401-411
    

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    ALISON M. GOWERS, PAUL CULLINAN, JON G. AYRES, H. ROSS ANDERSON, DAVID P. STRACHAN, STEPHEN T. HOLGATE, INGA C. MILLS, ROBERT L. MAYNARD. (2012) Does outdoor air pollution induce new cases of asthma? Biological plausibility and evidence; a review. Respirology 17:6, 887-898
    

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    Mark Ballow, Cezmi A. Akdis, Thomas B. Casale, Andrew J. Wardlaw, Sally E. Wenzel, Zuhair Ballas, Jan Lötvall. (2012) Immune response modifiers in the treatment of asthma: A PRACTALL document of the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology. Journal of Allergy and Clinical Immunology 130:2, 311-324
    

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    David Gibeon, Andrew N Menzies-Gow. (2012) Targeting interleukins to treat severe asthma. Expert Review of Respiratory Medicine 6:4, 423-439
    

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    A.R. Koczulla, B. Beutel, T. Greulich, A. Jerrentrup, C. Vogelmeier. (2012) Allergische Reaktionen der Lunge. Der Internist 53:8, 924-933
    

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    Rafeul Alam. (2012) Biomarkers in Asthma and Allergy. Immunology and Allergy Clinics of North America 32:3, xi-xii
    

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    Ian D Pavord, Stephanie Korn, Peter Howarth, Eugene R Bleecker, Roland Buhl, Oliver N Keene, Hector Ortega, Pascal Chanez. (2012) Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. The Lancet 380:9842, 651-659
    

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    Amir A. Zeki, Nicholas J. Kenyon, Ken Yoneda, Samuel Louie. (2012) The Adult Asthmatic. Clinical Reviews in Allergy & Immunology 43:1-2, 138-155
    

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    Lora Stewart, Rohit K. Katial. (2012) Exhaled Nitric Oxide. Immunology and Allergy Clinics of North America 32:3, 347-362
    

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    J. V. Thaikoottathil, R. J. Martin, P. Y. Di, M. Minor, S. Case, B. Zhang, G. Zhang, H. Huang, H. W. Chu. (2012) SPLUNC1 Deficiency Enhances Airway Eosinophilic Inflammation in Mice. American Journal of Respiratory Cell and Molecular Biology 47:2, 253-260
    

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    Zeynep Mat, Barbara Grensemann, Yakup Yakin, Jürgen Knobloch, Andrea Koch. (2012) Effect of lipoteichoic acid on IL-2 and IL-5 release from T lymphocytes in asthma and COPD. International Immunopharmacology 13:3, 284-291
    

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    F. Schleich, R. Louis. (2012) Intérêt de la mesure de l’inflammation en clinique dans l’asthme. EMC - Pneumologie 9:3, 1-10
    

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    Nestor A Molfino. (2012) Targeting of eosinophils in asthma. Expert Opinion on Biological Therapy 12:7, 807-809
    

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    Erick Forno, Jessica Lasky-Su, Blanca Himes, Judie Howrylak, Clare Ramsey, John Brehm, Barbara Klanderman, John Ziniti, Erik Melén, Goran Pershagen, Magnus Wickman, Fernando Martinez, Dave Mauger, Christine Sorkness, Kelan Tantisira, Benjamin A. Raby, Scott T. Weiss, Juan C. Celedón. (2012) Genome-wide association study of the age of onset of childhood asthma. Journal of Allergy and Clinical Immunology 130:1, 83-90.e4
    

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    Mats W. Johansson, Kristin A. Gunderson, Elizabeth A. B. Kelly, Loren C. Denlinger, Nizar N. Jarjour, Deane F. Mosher. (2012) Anti-IL-5 attenuates activation and surface density of β2-integrins on circulating eosinophils after segmental antigen challenge. Clinical & Experimental Allergyn/a-n/a
    

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    I. Agache, C. Akdis, M. Jutel, J. C. Virchow. (2012) Untangling asthma phenotypes and endotypes. Allergy 67:7, 835-846
    

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     Shamsah Kazani, Elliot Israel. (2012) Update in Asthma 2011. American Journal of Respiratory and Critical Care Medicine 186:1, 35-40
     

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     Maurizio Luisetti, Ian M. Balfour-Lynn, Simon R. Johnson, Marc Miravitlles, Charlie Strange, Bruce C. Trapnell, Hans van Bronswijk, Claus Vogelmeier. (2012) Perspectives for improving the evaluation and access of therapies for rare lung diseases in Europe. Respiratory Medicine 106:6, 759-768
     

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     Seisuke Kusano, Mutsuko Kukimoto-Niino, Nobumasa Hino, Noboru Ohsawa, Masashi Ikutani, Satoshi Takaki, Kensaku Sakamoto, Miki Hara-Yokoyama, Mikako Shirouzu, Kiyoshi Takatsu, Shigeyuki Yokoyama. (2012) Structural basis of interleukin-5 dimer recognition by its α receptor. Protein Science 21:6, 850-864
     

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     Santiago Quirce, Irina Bobolea, Pilar Barranco. (2012) Emerging drugs for asthma. Expert Opinion on Emerging Drugs 17:2, 219-237
     

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     G L Piacentini, E Cattazzo, G Tezza, D G Peroni. (2012) Exhaled nitric oxide in pediatrics: what is new for practice purposes and clinical research in children?. Journal of Breath Research 6:2, 027103
     

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     Riccardo Polosa, Thomas Casale. (2012) Monoclonal antibodies for chronic refractory asthma and pipeline developments. Drug Discovery Today 17:11-12, 591-599
     

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     Glenn J. Whelan. Monoclonal Antibodies in the Treatment of Asthma. In: Antibody-Mediated Drug Delivery Systems. John Wiley & Sons, Inc., 2012:457-472.
     

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     Weiyuan Chang. Pulmonary Targeting of Nanoparticles and Monoclonal Antibodies. In: Antibody-Mediated Drug Delivery Systems. John Wiley & Sons, Inc., 2012:391-405.
     

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     Sally E Wenzel. (2012) Asthma phenotypes: the evolution from clinical to molecular approaches. Nature Medicine 18:5, 716-725
     

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     Cezmi A Akdis. (2012) Therapies for allergic inflammation: refining strategies to induce tolerance. Nature Medicine 18:5, 736-749
     

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     Stephen T Holgate. (2012) Innate and adaptive immune responses in asthma. Nature Medicine 18:5, 673-683
     

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     D. Gibeon, K. F. Chung. (2012) The investigation of severe asthma to define phenotypes. Clinical & Experimental Allergy 42:5, 678-692
     

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     A. H. Poon, D. H. Eidelman, J. G. Martin, C. Laprise, Q. Hamid. (2012) Pathogenesis of severe asthma. Clinical & Experimental Allergy 42:5, 625-637
     

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     V. M. McDonald, P. G. Gibson. (2012) Exacerbations of severe asthma. Clinical & Experimental Allergy 42:5, 670-677
     

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     C. E. Brightling, S. Gupta, S. Gonem, S. Siddiqui. (2012) Lung damage and airway remodelling in severe asthma. Clinical & Experimental Allergy 42:5, 638-649
     

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     A. Magnan, A. Colchen, A. Cavaillès, A. Pipet. (2012) Asthme difficile à contrôler. EMC - Pneumologie 9:2, 1-10
     

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     Stephen T. Holgate. (2012) Trials and tribulations in identifying new biologic treatments for asthma. Trends in Immunology 33:5, 238-246
     

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     P. M. O'Byrne, N. Naji, G. M. Gauvreau. (2012) Severe asthma: future treatments. Clinical & Experimental Allergy 42:5, 706-711
     

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     S. Wenzel. (2012) Severe asthma: from characteristics to phenotypes to endotypes. Clinical & Experimental Allergy 42:5, 650-658
     

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     S. Hashimoto, E. H. Bel. (2012) Current treatment of severe asthma. Clinical & Experimental Allergy 42:5, 693-705
     

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     N. A. Molfino, D. Gossage, R. Kolbeck, J. M. Parker, G. P. Geba. (2012) Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor. Clinical & Experimental Allergy 42:5, 712-737
     

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