Longitudinal Changes in Asthma Control with Omalizumab: 2-Year Interim Data from the EXCELS Study

Background. Asthma guidelines emphasize the importance of achieving and maintaining asthma control; however, many patients with moderate to severe asthma fail to achieve adequate control. Objective. This 2-year interim analysis evaluated the longitudinal effects of omalizumab on asthma control in patients treated in real-world clinical practice settings. Methods. EXCELS is an ongoing observational cohort study of approximately 5000 omalizumab-treated and 2500 non-omalizumab-treated patients aged ≥12 years with moderate to severe asthma. Asthma control was measured using the Asthma Control Test (ACT) every 6 months. Results. Subgroups of the omalizumab cohort included those who initiated omalizumab at baseline (new starts, n = 549) and those treated with omalizumab >7 days before baseline (established users, n = 4421). For reference, data are also presented for patients who were not receiving omalizumab prior to or at the time of enrolment (non-omalizumab, n = 2867). Over half of the new starts (54%) achieved improvement in ACT consistent with the minimally important difference (MID, defined as ≥3-point improvement) by Month 6 and this proportion increased throughout the follow-up period, reaching 62% at Month 24. Similar results were observed in patients stratified by moderate and severe asthma. Established users of omalizumab maintained asthma control throughout the observation period. Conclusion. Over a 2-year period, patients initiating omalizumab therapy experienced clinically relevant improvements in asthma control, which were maintained during 2 years of longitudinal follow-up. Established users of omalizumab maintained asthma control over the 2-year period with a small improvement similar to that seen in non-omalizumab users.     

Prediction of clinical response to omalizumab in moderate-to-severe asthma patients using the change in total serum IgE level

BackgroundOmalizumab (OMA) is an effective anti-immunoglobulin E (IgE) treatment for moderate-to-severe asthma. However, predicting an individual’s response is difficult. Monitoring change of total serum IgE may be useful for predicting the response to OMA. The purpose of this study was to determine if measuring the change in total IgE level could predict the response to OMA in patients with moderate-to-severe asthma.MethodsThis study included 25 patients (11 females and 14 males; mean age =46.1 years; mean pre-bronchodilator FEV1% =67.8%) with moderate-to-severe asthma. All patients were treated with OMA, and total IgE serum concentrations were measured at baseline before treatment (median baseline total serum IgE =210 IU/mL) and at 4 weeks after beginning treatment. Patients were divided into responders (i.e., excellent or good response) and non-responders (i.e., moderate or poor response) using the global treatment effectiveness (GETE) response method after 16 weeks of treatment. The characteristics of responders and non-responders were compared, and receiver operating characteristic (ROC) curve analysis was used to determine the ability of change in IgE level to predict treatment response.ResultsThere were 20 responders (80%) and 5 non-responders (20%), and responders demonstrated better improvements of asthma control test (ACT) and asthma control questionnaire (ACQ) scores, and reduction of oral corticosteroid use as compared with non-responders. Twenty-one patients had a total serum IgE 4-week-to-baseline ratio ≥2, and 20 of the patients responded to OMA. The area under the ROC curve (AUC) for baseline IgE level for predicting treatment response was 0.53 (95% CI: 0.18–0.88), and that of the week 4 IgE level was 0.69 (95% CI: 0.42–0.96). Using a cutoff value of 2, the 4-week: baseline IgE ratio achieved the highest AUC of 0.87 (95% CI: 0.64–1), with a sensitivity and specificity of 100% and 80%, respectively, for predicting treatment response.ConclusionsA total week 4 serum IgE level:baseline level ratio ≥2 can predict the response to OMA in patients with moderate-to-severe asthma after 16 weeks of treatment with high likelihood. Monitoring changes of total IgE level in asthma patients treated OMA may be useful for predicting clinical response.     

Response of Older Patients with IgE-Mediated Asthma to Omalizumab: A Pooled Analysis

Asthma in older adults is under-recognized and possibly associated with allergic triggers. We conducted a pooled analysis of omalizumab double-blind, placebo-controlled trials to evaluate efficacy in older adults. Data for the total study population and subjects aged ≥ 50 years with moderate-severe allergic asthma were examined. We used Poisson regression to analyze the number of asthma exacerbations and logistic regression to evaluate treatment effectiveness. Symptom scores and total rescue medication puffs were evaluated by analysis of covariance. Omalizumab reduced the risk of clinically significant asthma exacerbations, led to a significantly greater response in patient/investigator-reported global effectiveness, improved asthma symptom scores, and reduced rescue medication use in adults ≥50 years with moderate-severe allergic asthma.     

Increased Plasma Reactive Oxidant Levels and Their Relationship to Blood Cells,Total IgE,and Allergen-specific IgE Levels in Asthmatic Children

Asthma is a disorder characterized by inflammation of the airways. Oxidative stress may play a role in the pathophysiology of several diseases including asthma. Characterizing biomarkers of oxidative stress in the context of other systemic measures of immune function or inflammation could provide insight regarding underlying mechanisms inducing asthma. We evaluated whether oxidative stress in the form of plasma reactive oxidants differs between asthmatic and non-asthmatic children and elucidate relationships between plasma reactive oxidants and other asthma-related immunological markers. Plasma reactive oxidants, white blood cell counts, total serum immunoglobulin E (IgE), and a multi–allergen-specific IgE screen were measured in 74 asthmatic and 74 non-asthmatic children (9 to 13 years of age) from the Detroit, Michigan area. Plasma reactive oxidants were measured using a lucigenin-based chemiluminescence assay. Plasma reactive oxidants, eosinophils, and neutrophils (absolute counts and percent of total white blood cell counts), total IgE, and allergen-specific IgE levels were elevated in asthmatics after adjusting for age, gender, and ethnicity. IgE (total or allergen-specific), eosinophils and neutrophils were not significantly associated with plasma reactive oxidant levels. The association between plasma reactive oxidants and asthma status was similar when eosinophils, neutrophils, total IgE, or allergen-specific IgE were included as possible confounders in multivariate logistic regression models.

In conclusion, plasma reactive oxidants are elevated in asthmatics and appear to be an independent predictor of asthma status. Measurement of plasma reactive oxidants may be a useful adjunct diagnostic tool and potential mechanistic indicator relevant to the study of asthma and asthma exacerbation.     

Increased Plasma Reactive Oxidant Levels and Their Relationship to Blood Cells,Total IgE,and Allergen-specific IgE Levels in Asthmatic Children

Asthma is a disorder characterized by inflammation of the airways. Oxidative stress may play a role in the pathophysiology of several diseases including asthma. Characterizing biomarkers of oxidative stress in the context of other systemic measures of immune function or inflammation could provide insight regarding underlying mechanisms inducing asthma. We evaluated whether oxidative stress in the form of plasma reactive oxidants differs between asthmatic and non-asthmatic children and elucidate relationships between plasma reactive oxidants and other asthma-related immunological markers. Plasma reactive oxidants, white blood cell counts, total serum immunoglobulin E(IgE), and a multi–allergen-specific IgE screen were measured in 74 asthmatic and 74 non-asthmatic children(9 to 13 years of age) from the Detroit, Michigan area. Plasma reactive oxidants were measured using a lucigenin-based chemiluminescence assay. Plasma reactive oxidants, eosinophils, and neutrophils(absolute counts and percent of total white blood cell counts), total IgE, and allergen-specific IgE levels were elevated in asthmatics after adjusting for age, gender, and ethnicity. IgE(total or allergen-specific), eosinophils and neutrophils were not significantly associated with plasma reactive oxidant levels. The association between plasma reactive oxidants and asthma status was similar when eosinophils, neutrophils, total IgE, or allergen-specific IgE were included as possible confounders in multivariate logistic regression models. In conclusion, plasma reactive oxidants are elevated in asthmatics and appear to be an independent predictor of asthma status. Measurement of plasma reactive oxidants may be a useful adjunct diagnostic tool and potential mechanistic indicator relevant to the study of asthma and asthma exacerbation     

儿童支气管哮喘EOS、IL-17和IgE表达水平临床意义

目的探讨白细胞介素17(IL-17)、嗜酸性粒细胞(EOS)和免疫球蛋白E(Ig E)在支气管哮喘(BA)患儿中的表达水平及其相关性。方法选择93例轻中度支气管哮喘患儿缓解期和发作期IL-17、EOS和Ig E水平,同期选择80例健康体检儿童为对照组。结果患儿组血清EOS计数、血清IL-17和Ig E水平均显著上升,远高于对照组(P0.05),EOS计数随血清IL-17增高而增高,两者呈现正相关性(r=0.794,P=0.003),而Ig E和EOS计数、血清IL-17水平并无相关关系;哮喘发作期Ig E水平较缓解期高(P0.05),发作期患儿Ig E水平和IL-17呈现出正相关性(r=0.583,P=0.007)。结论儿童支气管哮喘血清EOS计数、血清IL-17和Ig E水平表达增高,可为判断病情提供理论依据。     

哮喘患者血PCT和IgE变化及其与病情的相关性

目的研究支气管哮喘患者血清降钙素原(PCT)、免疫球蛋白E(IgE)水平变化及其与患者病情相关性。方法对40例支气管哮喘患者(急性发作期组20例、缓解期组20例)、正常对照组20例健康受试者血清PCT、IgE水平进行检测,并分析PCT、IgE与第1秒用力呼气流量占预计值百分比(FEV1%)的相关性。结果急性发作期哮喘患者血清PCT和IgE均明显高于哮喘缓解期和健康对照组,差异具有统计学意义(P0.05);缓解期哮喘组血清PCT和IgE水平有所下降,但仍高于健康对照组,两组比较差异具有统计学意义(P0.05),支气管哮喘患者血清PCT和IgE均与FEV1%呈负相关(r=-0.314,P0.05和r=-0.587,P0.01)。结论支气管哮喘患者血清PCT和IgE处于高水平,而急性发作期升高程度更为显著,其变化与哮喘患者病情分期关系密切,能反映支气管哮喘患者的炎症反应和气道阻塞状态。     

Effect of Omalizumab as Add-On Therapy on Asthma-Related Quality of Life in Severe Allergic Asthma: A Brazilian Study (QUALITX)

Objective. To assess the impact of omalizumab as an add-on therapy to standard treatment with inhaled corticosteroids (ICS) and long-acting beta-2 agonists (LABA) on asthma-related quality of life (QoL) in patients with severe allergic asthma. Methods. This was a 20-week, randomized, open-label, study involving Brazilian patients (>12 years) with severe persistent allergic asthma inadequately controlled despite regular treatment with, at least, ICS (≥500 μg/day fluticasone or equivalent) + LABA. The primary objective was to assess the mean change from baseline in overall Asthma-related Quality of Life Questionnaire (AQLQ) score in omalizumab-treated patients compared with the control group. Secondary outcome measures included rescue medication use, incidence of asthma exacerbations, perception of treatment efficacy among patients, mean change from baseline in AQLQ score, and >1.5-point increase in overall AQLQ score. Results. In the omalizumab group, overall AQLQ score was 3.2 (0.9) (mean [SD]) at baseline and 4.4 (1.3) at week 20 versus 3.0 (1.0) at baseline and 3.0 (1.1) at week 20 in the control group. Mean change from baseline on overall AQLQ score at week 20 in the omalizumab group was 1.2 (0.2) versus 0 (0.1) in the control group, showing a significant increase in scores from baseline in the omalizumab group (p < .001). There was also a statistically significant difference (p < .001) in the number of patients who showed a >1.5-point increase from baseline in overall AQLQ score after 20 weeks, thus indicating a better QoL in the omalizumab group. There was no significant difference with respect to the use of rescue medication, incidence of asthma exacerbation, and adverse events between treatment groups. The global evaluation of treatment effectiveness was significantly better for omalizumab (p < .001). Conclusion. Omalizumab was well tolerated and significantly improved the overall AQLQ score. Hence, it is a potential add-on therapy for severe persistent allergic asthma not controlled by standard prescribed treatment in Brazilian patients.     

A 26-Week,Randomized, Double-Blind,Placebo-Controlled,Multicenter Study to Evaluate the Effect of Omalizumab on Asthma Control in Patients with Persistent Allergic Asthma

Objective. The 2007 National Heart, Lung, and Blood Institute (NHLBI) asthma guidelines shifted the focus of care from asthma severity to ongoing assessment of asthma control using the components of impairment and risk. We evaluated the effect of omalizumab on asthma control in patients with persistent allergic asthma inadequately controlled with NHLBI Step 4 or above asthma therapy. Methods. In this double-blind, placebo-controlled study, patients ≥12 years (n = 271) received omalizumab (n = 136) or placebo (n = 135) every 2 or 4 weeks for 24 weeks. The primary efficacy variable, change from baseline in Asthma Control Test (ACT) total score, and Investigator’s Global Evaluation of Treatment Effectiveness (IGETE, secondary efficacy variable) were evaluated at week 24. Results. ACT score improved more with omalizumab compared with placebo (least squares means [LSMs]: 5.01, 4.36); however, the difference was not significant (p = .1779). Similarly, IGETE was not significantly different (p = .1177), but more patients treated with omalizumab (26/127, 20%) compared with placebo (19/131, 15%) had IGETE rated as “Excellent.” Significant benefits were observed for omalizumab compared with placebo for change in ACT score (LSMs: 6.66, 5.27; p = .0334) and IGETE (p = .0321) at week 24 in a subgroup of patients with very poorly controlled asthma (ACT ≤ 15) at baseline. There were no significant differences for the subgroup of patients with forced expiratory volume in 1 second ≤ 80% predicted at baseline. Adverse events (AEs) were similar between groups with no drug-related serious AEs or deaths. Conclusions. For allergic asthma patients with NHLBI Step 4 or above asthma therapy, omalizumab consistently improved asthma control; however, compared with placebo, differences were not significant. Placebo-treated patients had substantial improvement in their ACT score, which may have limited the ability to detect differences between treatment groups. Subgroup analyses showed significant improvements with omalizumab versus placebo in patients with very poorly controlled asthma.     

沙美特罗氟替卡松对支气管哮喘患者血清IL-21和IgE水平的影响

目的探讨沙美特罗氟替卡松用于支气管哮喘治疗时对患者血清IL-21和Ig E水平的影响。方法采用沙美特罗氟替卡松吸入治疗78例支气管哮喘患者,同时选取45例健康体检人员作为对照组,分别检测支气管哮喘患者治疗前后及对照组人员血清IL-21及Ig E,并进行对比分析。结果 78例支气管哮喘患者总有效率为89.7%(70/78);支气管哮喘组血清IL-21及Ig E水平显著高于对照组(P0.01);治疗3个月后支气管哮喘组血清IL-21及Ig E显著降低(P0.01),但仍显著高于对照组(P0.01)。结论沙美特罗氟替卡松吸入治疗支气管哮喘能够有效降低血清IL-21及Ig E水平,减轻气道炎症反应,进而降低气道高反应性,疗效可靠。     

High Prevalence of Skin Test Positivity in Severe or Difficult-to-Treat Asthma

Background: Skin tests are considered the gold standard for detecting allergen-specific immunoglobulin E (IgE) in the clinical setting and are an important tool for diagnosing and managing allergic asthma. Objective: To assess the prevalence of skin testing in patients ≥ 12 years enrolled in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. Methods: Patients were asked whether they had ever been skin tested and, if so, they were asked to provide the test results. Clinical characteristics were used to compare positive (ST+), negative (ST?), and skin test not done (STND) patients. Results: Of 2,985 patients eligible, 85.8% recalled being skin tested. Of those tested, 93.5% were positive (allergist 95.7%, pulmonologist 87.3%). A high proportion of Whites (93.5%) and non-Whites (94.0%) were ST+; however, more non-Whites had never been skin tested (21.7% vs. 12.3%, respectively; p < 0.0001). Total serum IgE was 104.6 IU/mL for ST+ patients, 87.1 IU/mL for STND patients, and 32.4 IU/mL for ST? patients. Age at asthma onset, duration of asthma, and the prevalence of atopic disorders and asthma triggers differentiated the ST+ from the ST? group. Disease severity appeared similar between the two groups. In general, values for STND patients were closer to the ST+ group, suggesting that those not tested would have been ST+ if administered a test. Conclusions: The prevalence of ST+ patients was high in allergy and pulmonology practices, and in White and non-White patients. These data support the utility of a more complete allergic evaluation in severe asthmatics. Skin testing appears associated with disease pathophysiologies in asthma.     

Immunochromatographic Assay for Measurement of Total IgE in Tears,Nasal Mucus,and Saliva of Patients with Allergic Rhinoconjunctivitis

Objective Measurement of total immunoglobulin E (IgE) is clinically important for the diagnosis of allergic diseases. The total serum IgE level is normally measured because of its widespread use and convenience, but little attention has been paid to the measurement of local IgE concentrations. We evaluated whether the measurement of local production of IgE in tears, saliva, and nasal mucus was useful for the diagnosis of allergic rhinoconjunctivitis. Methods. A prospective, nonrandomized, cross-sectional study was conducted in 33 consecutive patients with seasonal allergic rhinoconjunctivitis (allergic group) and in 30 age- and sex-matched healthy control subjects (control group). The total IgE level was measured in tears, saliva, and nasal mucus from all subjects. Using a 4- or 5-point scale, symptoms (sneezing, rhinorrhea, nasal obstruction, ocular itching, and lacrimation) were assessed in each subject along with the activities of daily living (ADL) score and total symptom score for allergic conjunctivitis. Results. Total IgE could be assayed within 10 minutes of collection in all samples. The scores for all symptoms were higher in the allergic group than in the control group (p < .00001). The IgE scores for tear fluid samples (p < .00001) and undiluted saliva (p = .00003) were significantly higher in the allergic group than in the control group. The total IgE score of tear fluid samples was strongly correlated with the severity of symptoms of allergic conjunctivitis, including ocular itching (r = 0.769, p < .00001), tearing (r = 0.560, p = .00035), and ocular symptom score (r = 0.329, p = .03452). On the contrary, the total IgE scores for both saliva and nasal mucus were correlated with the severity of rhinitis-related symptoms, including sneezing (saliva r = 0.897, p < .00001; nasal mucus r = 0.871, p = .00024), nose blowing (saliva r = 0.764, p < .00001; nasal mucus r = 0.829, p = .00080), and nasal obstruction (saliva r = 0.519, p = .00099; nasal mucus r = 0.745, p = .00429). The ADL score was correlated with the total IgE level in each specimen (tear r = 0.705, p < .00001; saliva r = 0.468, p = .00301; nasal mucus r = 0.479, p = .06816). Conclusions. These results suggest that local production of IgE is closely correlated with local allergic symptoms. This rapid test for the measurement of local IgE is easy to perform on an outpatient basis and may be helpful in the diagnosis of allergic rhinitis and conjunctivitis.     

儿童过敏性鼻炎与支气管哮喘

很久以来一直认为儿童过敏性鼻炎与哮喘具有相关性。新近的流行病学研究证明,上、下呼吸道之间确实存在相互联系。而且,有多个学说解释过敏性鼻炎与哮喘的关系,两者具有相似的免疫学机制和病理生理学基础。越来越多的证据表明,过敏性鼻炎与哮喘具有共同的发病因素,且经常在同一个患者中并存,因此在制定治疗策略时应考虑完整气道的概念。     

Omalizumab in patients with severe asthma: the XCLUSIVE study

Background and Aims: Although the efficacy and safety of omalizumab (OMA) in uncontrolled severe allergic asthma has been demonstrated in several randomised controlled trials (RCTs), information on the treatment in a practice‐related setting is limited. Thus, the purpose of this prospective multi‐centre study (XCLUSIVE) was to investigate the efficacy, compliance and utilisation of OMA therapy in real‐life clinical practice in Germany. Methods: One hundred ninety‐five asthmatic patients initiated on anti‐Immunoglobulin E (IgE) IgE treatment were followed‐up for 6 months. Forced expiratory volume in 1 s (FEV₁), exacerbation rate, days of absence, asthma symptoms [Asthma Control Questionnaire (ACQ)], a Global Evaluation of Treatment Effectiveness (GETE) and medication use were assessed. Results: Measured outcome variables improved after a 16‐week treatment period with OMA (FEV₁+13.7% predicted P < 0.05, exacerbation rate ?74.9% P < 0.0001, days of absence ?92.1% P < 0.001, ACQ ?43.7% P < 0.0001). Investigators evaluated the effectiveness of OMA by GETE in 78.8% as excellent or good (responder), and in 12.6%/8.6% as moderate/poor or worse (non‐responder). Responders demonstrated better improvement of FEV₁, exacerbation rate, days of absence, ACQ and reduction of oral corticosteroids compared with non‐responders. Conclusion: Results of effectiveness strongly suggest that the efficacy demonstrated in RCTs can be transposed to a clinical practice‐related setting. Please cite this paper as: Schumann C, Kropf C, Wibmer T, Rüdiger S, Stoiber KM, Thielen A, Rottbauer W and Kroegel C. Omalizumab in patients with severe asthma: the XCLUSIVE study. Clin Respir J 2011; DOI:10.1111/j.1752‐699X.2011.00263.x.     

Smoking and Circulating IgE in Bronchial Carcinoma

ABSTRACT. The serum concentrations of total IgE were significantly raised in smokers compared to those who had never smoked (p<0.005) among male patients with bronchial carcinoma, while no differences were found between smoking and non-smoking female bronchial carcinoma patients. The total IgE levels in male and female patients with non-malignant pulmonary diseases were not correlated to smoking habits. No significant differences in the IgE levels were observed between smoking males sub-grouped according to the WHO histological types of bronchial carcinoma. Males with carcinoma who had stopped smoking more than 10 years ago had significantly reduced IgE levels compared to male cancer patients continously smoking (p<0.01). These data, indicating that smoking is associated with elevated IgE levels in males with bronchial carcinoma, might suggest that smoking in certain, preferably male, individuals induces an impaired cellular immunity which is reflected by an enhanced IgE synthesis and a depressed resistance to carcinogens of tobacco smoke.