Clinical Asthma Exacerbations Research Articles

Effects of Pregnancy-Onset Asthma on Perinatal Outcomes: A Retrospective Cohort Study

BackgroundIt is unknown whether women with pregnancy-onset asthma are predisposed to worse pregnancy outcomes compared to women with pre-pregnancy asthma. ObjectiveTo explore whether pregnancy-onset asthma leads to worse perinatal outcomes compared with pre-pregnancy asthma. MethodsWomen who were discharged with a diagnosis of asthma and gave birth to a live singleton were included in this retrospective cohort analysis. Women were separated into groups based on whether the asthma was diagnosed during or before pregnancy. Clinical characteristics, perinatal outcomes, and asthma exacerbations (AE) between the two groups were compared. Results335 women were included in this study, of whom 39 (11.6%) had pregnancy-onset asthma and 296 had pre-pregnancy asthma. All the pregnant women in the pregnancy-onset group experienced asthma exacerbations (AE) during pregnancy. The proportion of chronic hypertension, chronic hypertension with superimposed preeclampsia, and spontaneous preterm births in the pregnancy-onset group was significantly higher than that in the pre-pregnancy asthma group. After adjusting for age, BMI, onset of asthma during pregnancy, and severity of AE through multivariate analysis, pregnancy-onset asthma was an independent risk factor for spontaneous preterm birth (aOR 7.71, 95% CI 1.30–46.12), severe AE was an independent risk factor for gestational hypertension and preeclampsia (aOR 3.58, 95% CI 1.30–9.87). ConclusionsDuring pregnancy, pregnancy-onset asthma in women is associated with an exacerbation of the condition. Obstetricians should be vigilant for signs of asthma onset during pregnancy. Other health-care providers should watch out for symptoms of gestational hypertension and preeclampsia in pregnant women with pre-existing or new-onset asthma.

The effect of Ma-Xin-Gan-Shi decoction on asthma exacerbated by respiratory syncytial virus through regulating TRPV1 channel

Ethnopharmacological relevanceThe incidence and mortality of bronchial asthma are increasing, and respiratory syncytial virus (RSV) is widely regarded as the common cause of clinical exacerbation of asthma. Ma-Xing-Gan-Shi decoction (MXGSD), a classic traditional Chinese medicine prescription, is well-known for treating respiratory diseases, while the mechanism of effecting on RSV-exacerbated asthma remains to be explored. Aim of the studyIn this study, we investigated the mechanism by which MXGSD exerts a protective effect on asthma exacerbated by RSV in vivo and in vitro. Materials and methodsMXGSD is composed of four Chinese medicine, including Ephedra intermedia Schrenk & C.A.Mey. (herbaceous stem, 27g), Prunus armeniaca L. (dry seed, 27g), Glycyrrhiza uralensis Fisch. (radix and rhizome, 18g), and Gypsum fibrosum (main component: CaSO4·2H2O, 54g). In the present study, the exacerbated asthmatic mice model with the treatment of OVA plus RSV was replicated, and accompanied by the TMT proteomic analysis and further experimental investigations. Then, the protective effect of MXGSD (13.2, 6.6, 3.3 g/kg/d, 7d) on the mice treated by OVA plus RSV, and the mechanism of regulating TRPV1 was explored. In addition, the intracellular Ca2+ concentration of 16HBE cells pretreated with MXGSD medicated serum was also tested after stimulation with the TRPV1 agonist capsaicin. ResultsThe results suggested that MXGSD could reduce the levels of inflammation cells, airway hyperresponsiveness, and pathological damage of lung tissue. TMT quantitative proteomics analysis and further experimental exploration revealed that MXGSD could reduce the levels of IL-4, IL-13, PGE2, and SP in BAL and down-regulate the expression of TRPV1 mRNA and protein in lung tissue. Furthermore, 16HBE cells stimulated by capsaicin showed an increased intracellular Ca2+ concentration, while the pretreatment of MXGSD medicated serum could reduce it. ConclusionMSGSD showed a protective effect on RSV-exacerbated asthma, which may be related to its regulation of TRPV1 expression and reduction of Th2 cytokines and neurogenic inflammatory mediators. It may provide an objective basis and reference for the clinical application of MXGSD.

Clinical Outcomes and Health-Care Resource Use Associated With Reslizumab Treatment in Adults With Severe Eosinophilic Asthma in Real-World Practice

Reslizumab, an anti-IL-5 monoclonal antibody, is indicated as add-on maintenance treatment for adults with severe eosinophilic asthma. What are the real-world outcomes associated with reslizumab use in patients with severe eosinophilic asthma in a US clinical practice? In this retrospective study, patient-level data from adults treated with reslizumab were obtained from center- and panel-based medical chart reviews. Eligible patients had available medical records and treatment history for≥ 6months before initiation of reslizumab treatment (index date) to≥ 7months after reslizumab initiation. The primary outcome was response to reslizumab treatment, based on clinical expert predefined definitions of response. Other outcomes included clinical asthma exacerbations (CAEs), use of maintenance oral corticosteroids (OCS), FEV1 percent predicted, Asthma Control Test (ACT) score, and health-care resource use (HRU). Medical charts were obtained for 215 patients. Most patients (58.6%) showed an excellent response, 16.3%showed a clinically meaningful response, 21.9%showed a partial response, and 3.3%were nonresponders or treatment failures. A significant reduction was observed in the proportion of patients experiencing a CAE in a 6-month period (from 86.0%to 40.5%; P< .001) and in the mean number of CAEs per patient (2.84 [SD, 2.41] vs0.94 [SD,1.86]) after reslizumab initiation. Improvements were observed in FEV1 percent predicted (65.1%[SD, 20.5%] vs73.1%[SD, 23.1%]; P< .001) and in ACT scores (13.8 [SD, 4.2] vs18.6 [SD, 4.0]; P< .001) before to after reslizumab initiation. Among patients using maintenance OCS at baseline, more than half discontinued use of these by approximately 10months after reslizumab initiation. Significant reductions in asthma-related HRU were observed after reslizumab initiation. In clinical practice, reslizumab may have been initiated in response to heavy symptom burden and CAEs. Reslizumab was associated with improved clinical and patient-reported outcomes and significant reductions in asthma-related HRU.

Efficacy of Reslizumab Treatment in Exacerbation-Prone Patients with Severe Eosinophilic Asthma

Patients with severe eosinophilic asthma have increased risk of clinical asthma exacerbations (CAEs), impaired lung function, and lower quality of life (QoL) compared with patients with noneosinophilic asthma. The efficacy and safety of intravenous reslizumab have been demonstrated in 2 duplicate, randomized, double-blind, placebo-controlled, phase 3 studies. We present findings from post hoc analyses of the subgroup of patients from the phase 3 studies with severe (Global Initiative for Asthma [GINA] Step 4 or 5) eosinophilic asthma who had ≥2 or ≥3 CAEs in the 12 months before screening. Patients aged ≥12 years with severe eosinophilic asthma were randomized (1:1) to reslizumab 3.0 mg/kg or placebo every 4 weeks for 1 year. Outcomes assessed included CAEs, forced expiratory volume in 1 second (FEV1), and Asthma Control Questionnaire 6 (ACQ-6) and Asthma QoL Questionnaire (AQLQ) scores. Of 953 patients randomized, 318 (reslizumab: n= 156; placebo: n= 162) and 164 (reslizumab: n= 72; placebo: n= 92) were GINA 4/5 with ≥2 CAEs in the prior year and ≥3 CAEs in the prior year, respectively. Reslizumab significantly improved CAE rate, time to first CAE, and the proportion of patients who experienced ≥1 CAE versus placebo in both CAE subgroups. Improvements in FEV1, ACQ-6 and AQLQ scores, and systemic corticosteroid burden were also observed with reslizumab versus placebo after 52 weeks of treatment in both CAE subgroups. Reslizumab reduced CAE frequency and improved lung function, asthma control, and QoL versus placebo in patients with severe eosinophilic asthma with a high CAE rate before treatment.

Reslizumab as add-on therapy in patients with refractory asthma

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D202 RESCUE MEDICATION USE AND INHALATION PATTERNS DURING ASTHMA EXACERBATIONS RECORDED BY DIGIHALER

Inhalation parameters, such as peak inspiratory flow (PIF) and inhalation volume, are correlated to inhaler technique for dry powder inhalers (DPIs) and could be markers of worsening disease. Digihaler, a multi-dose DPI with an integrated electronic module, delivers 90mcg albuterol/dose, records date/time stamps and inhalation profile parameters when used. This paper summarizes albuterol use patterns and inhalation parameters during ±14-day window around clinical asthma exacerbations (CAEs).

P224 REAL-WORLD EVIDENCE OF IMPROVED PATIENT OUTCOMES WITH RESLIZUMAB IN ADULTS WITH SEVERE EOSINOPHILIC ASTHMA (SEA)

Reslizumab, an anti-interleukin-5 antibody, is approved in the U.S. as add-on therapy for patients with SEA, who typically have elevated eosinophil levels, impaired lung function, and increased risk of clinical asthma exacerbations (CAEs). This study assessed real-world outcomes associated with reslizumab in U.S. clinical practice.

Efficacy of Intravenous Reslizumab in Oral Corticosteroid–Dependent Asthma

Reslizumab displays efficacy in patients with inadequately controlled eosinophilic asthma; previous reports in oral corticosteroid-dependent asthma are limited. To assess efficacy of reslizumab in oral corticosteroid-dependent patients and benefits on oral corticosteroid burden. We report post hoc analyses of pooled data from duplicate, placebo-controlled phase 3 trials. Patients aged 12 to 75 years with inadequately controlled, moderate-to-severe asthma were randomized 1:1 to receive intravenous reslizumab 3.0 mg/kg or placebo every 4 weeks for 52 weeks, stratified by oral corticosteroid use at enrollment and by region. Assessments included efficacy and predictors of clinical asthma exacerbation response in oral corticosteroid-dependent patients, and systemic corticosteroids burden in the overall population. Patients were randomized to reslizumab (n= 477) or placebo (n= 476); 73 (15%) patients in each group were taking oral corticosteroids at baseline. Reslizumab was favored over placebo for all efficacy end points in oral corticosteroid-dependent patients, with numerically greater improvements in oral corticosteroid-dependent patients than the overall population. Having 2 or more versus 1 clinical asthma exacerbation in the previous 12 months was the strongest positive predictor of reduced exacerbation risk with reslizumab (risk reduction, 77.5% vs 15.2%; P ≤ .02). Significantly fewer new systemic corticosteroid prescriptions were issued per patient receiving reslizumab versus placebo (mean ± SD, 0.5 ± 1.07 vs 1.0 ± 1.52; P < .0001). Total and per-patient systemic corticosteroid burdens were lower: 121,135 versus 290,977 mg and 254 versus 611 mg/patient, respectively (both P < .0001). Oral corticosteroid-dependent patients benefited from reslizumab across asthma efficacy outcome measures. Reslizumab-treated patients required fewer new systemic corticosteroid prescriptions and had a lower systemic corticosteroid burden compared with placebo.

A Predictive Model for Clinical Asthma Exacerbations Using Albuterol eMDPI (ProAir Digihaler): A Twelve-Week, Open-Label Study

Background The ability to identify an impending clinical asthma exacerbation (CAE) would improve asthma action plans and provide opportunities for pre-emptive treatment. Increased use of inhaled rescue medications, such as albuterol, has been observed in the days prior to a CAE, but other potential predictive factors are poorly understood. Approved by the US Food and Drug Administration (FDA) in late 2018, ProAir Digihaler with built-in sensors registers when patients use the inhaler and has been shown previously to accurately measure both peak inspiratory flow and inhalation volume, confirming the device’s ability to reliably record objective information on inhaler usage and technique. Objective Data collected from the ProAir Digihaler provides, for the first time, a more complete picture of patients’ use of inhaled medication, and thereby offers an opportunity to develop a predictive model of an impending CAE, and the potential to better implement asthma action plans and facilitate early treatment. Methods Patients (≥18 years old) with exacerbation-prone asthma were recruited to a 12-week, open-label study. Patients used the ProAir Digihaler (albuterol 90 µg 1–2 inhalations q4 hours) as needed. The electronic component of Digihaler recorded each use and inhalation variables (peak inspiratory flow, volume inhaled, time to peak flow, and inhalation duration). Data were downloaded from the inhalers and, together with clinical data, subjected to a machine-learning algorithm to develop models predictive of an impending CAE as defined by the need for oral corticosteroids. The generated model was evaluated by receiver operating characteristic (ROC) curve analysis. Results Three hundred and sixty patients made ≥1 valid inhalation from the Digihaler and were included in the analysis. Of these, 64 patients experienced a total of 78 CAEs. The strongest predictive factor during the 5 days before a CAE was the average number of albuterol inhalations per day. The predictive model was strengthened by supplementing these data with other inhalation features collected by Digihaler, including peak inhalation flow, inhalation volume, night-time usage, and trends of these parameters over time. This model predicted an impending exacerbation over the 5 days with a ROC AUC value of 0.75. Conclusions This study represents, to our knowledge, the first successful attempt to develop a model to predict CAE derived from the use of a rescue medication inhaler device equipped with an integrated sensor and capable of measuring inhalation parameters. The predictive power of the model would benefit from further development with larger populations of asthma patients.

Factors Associated with Positive Adenosine Challenge Test in Young Children with Suspected Asthma.

Background: To investigate the predictive factors associated with positive adenosine monophosphate challenge using the auscultation method (AMP-PCW) test results. Methods: This is a prospective study of young children with suspected asthma who underwent AMP-PCW test. Patients with a positive AMP-PCW test were compared with those with a negative AMP-PCW. A multivariate logistic regression model was performed to identify the independent determinants of positive AMP-PCW. Results: A total of 159 patients completed the AMP-PCW test. The median age was 53 months. In total, 54.0% of patients had a positive AMP-PCW. The prevalence of atopic dermatitis and family history of asthma and allergy were significantly higher among the positive AMP-PCW group (P = 0.04, P = 0.02, and P = 0.007, respectively), as were the prevalences of elevated immunoglobulin E (IgE), peripheral blood eosinophils percentage (P = 0.003, P < 0.001, respectively), and number of emergency department (ED) visits/hospitalizations before AMP-PCW test (P = 0.006). A significant inverse correlation exists between peripheral blood eosinophils percentage and serum IgE levels with the AMP end-point concentrations (r = -0.302, P = 0.001, and r = -0.312, P = 0.001, respectively). In multivariate logistic regression model, peripheral blood eosinophils percentage, IgE levels, and the number of ED visits/hospitalizations before the AMP-PCW test were found as independent predictors for positive AMP-PCW test result. Conclusions: Our results suggest that bronchial responsiveness to AMP-PCW is related to proxy markers of airway inflammation (elevated eosinophils and IgE levels) and clinical exacerbation of asthma before the test. This may support the role of AMP-PCW in detecting inflammatory changes and monitoring their trend among young children with suspected asthma.

Predicting Responders to Reslizumab after 16 Weeks of Treatment Using an Algorithm Derived from Clinical Studies of Patients with Severe Eosinophilic Asthma.

Reslizumab is a humanized anti-IL-5 monoclonal antibody used as add-on maintenance treatment for patients with uncontrolled eosinophilic asthma. To predict response and nonresponse to intravenous reslizumab at 52 weeks with an algorithm we developed based on clinical indicators from pivotal clinical trials. Patients aged 18 years and older who met Global Initiative for Asthma 4 or 5 criteria and received intravenous reslizumab (n = 321) in two trials ( www.clinicaltrials.gov identifiers, NCT01287039 and NCT01285323) were selected as the data source. A mathematical model was constructed that was based on change from baseline to 16 weeks in Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores and FEV1, and number of clinical asthma exacerbations during the year before enrollment and in the first 16 weeks of treatment, and these measures were evaluated for their ability to predict the outcome at 52 weeks: responder, nonresponder, or indeterminate. The algorithm predicted that 276 patients would be classified as responders; in 248 (89.9%), the prediction was correct. In comparison, 26 patients were predicted to be nonresponders; 50.0% of these predictions were correct. Nineteen patients were classified as indeterminate. The algorithm had 95.4-95.5% sensitivity and 40.6-54.1% specificity. Jackknife and cross-study validation confirmed the robustness of the algorithm. Our algorithm enabled prediction at 16 weeks of treatment of the response to intravenous reslizumab treatment at 52 weeks, but it was not suitable for predicting nonresponse. A positive score at 16 weeks should encourage continued treatment, and a negative score should prompt close monitoring to determine whether discontinuation is warranted.

Reslizumab Compared with Benralizumab in Patients with Eosinophilic Asthma: A Systematic Literature Review and Network Meta-Analysis

The interaction of IL-5 with its receptor on eosinophils increases the activation and maintenance of eosinophils; blocking this interaction reduces asthma symptoms in patients with the eosinophilic phenotype. Reslizumab, which binds to IL-5, and benralizumab, which targets the IL-5 receptor α subunit, have not been compared in head-to-head trials. To indirectly compare reslizumab with benralizumab in similar patient populations using a network meta-analysis. A systematic literature review was conducted and a network meta-analysis was performed on eligible studies using the Markov Chain Monte-Carlo simulation method and a Bayesian statistical framework. Eleven studies were identified, 4 of which evaluated clinically relevant doses and had outcomes at similar time points. To control for population differences, subgroups were selected for the base-case efficacy analysis: a benralizumab subgroup with blood eosinophil levels of greater than or equal to 300 cells/μL (n= 1537) and a reslizumab subgroup in Global Initiative for Asthma step 4/5 with 2 or more previous exacerbations and greater than or equal to 400 eosinophils/μL (n= 318). Safety was analyzed in the full population (N= 3462). Reslizumab significantly improved Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) scores compared with benralizumab once every 4 weeks and there were reasonably high posterior probabilities that reslizumab is superior to benralizumab once every 4 weeks and once every 8 weeks for ACQ score, AQLQ score, FEV1, and clinical asthma exacerbations. This indirect comparison suggests that reslizumab may be more efficacious than benralizumab in patients with eosinophilic asthma in Global Initiative for Asthma step 4/5 with elevated blood eosinophil levels (benralizumab, ≥300/μL; reslizumab, ≥400/μL) and 2 or more exacerbations in the previous year.

Effects of Reslizumab on Asthma Outcomes in a Subgroup of Eosinophilic Asthma Patients with Self-Reported Chronic Rhinosinusitis with Nasal Polyps

An estimated 7% of patients with asthma have chronic rhinosinusitis with nasal polyps (CRSwNP), and more than 80% have at least some radiographic evidence of sinonasal inflammation. Aspirin sensitivity is strongly associated with elevated blood eosinophil levels and increased asthma severity. Intravenous (IV) reslizumab has been shown to improve asthma control in patients with nasal polyps. These post hoc analyses of pooled data from 2 BREATH phase 3 clinical trials, studies 1 and 2 (NCT01287039 and NCT01285323), examined asthma-related outcomes in patients with comorbid, self-reported CRSwNP with and without aspirin sensitivity. Patients aged 12-75 years with elevated blood eosinophils (≥400 cells/μL) and inadequately controlled asthma were randomized to receive placebo or reslizumab (3 mg/kg IV) every 4 weeks for 52 weeks. Patients continued their background asthma maintenance therapy during the study. Information regarding the presence of CRSwNP was obtained through patient-reported medical history. Add-on reslizumab treatment reduced the frequency of clinical asthma exacerbations by 83% versus placebo among patients with CRSwNP. Among patients with and without aspirin sensitivity, reductions of 79% and 84%, respectively, were observed. Patients with CRSwNP (with and without aspirin sensitivity) treated with reslizumab add-on therapy also had significant improvements in lung function, as measured by forced expiratory volume in 1 second, compared with placebo. Among patients with CRSwNP, reslizumab was also associated with improvements in patient-reported asthma control and asthma quality of life. Patients with eosinophilic asthma and self-reported CRSwNP, with and without aspirin sensitivity, are highly responsive to treatment with reslizumab for asthma-related outcomes. These findings suggest that prospective investigation of reslizumab in this patient population is warranted.

Tumor necrosis factor-alpha protein concentrations in bronchoalveolar lavage fluid from healthy horses and horses with severe equine asthma

The objective of this study was to determine if TNF-α protein concentration differs in bronchoalveolar lavage fluid (BALF) obtained from healthy horses, horses with naturally occurring exacerbations of severe equine asthma and horses in remission from severe equine asthma. Tumor necrosis factor-alpha (TNF- α) protein concentrations were determined in BALF by commercial equine ELISA. Horses with naturally occurring exacerbation of severe equine asthma were found to have significantly lower BALF TNF-α protein concentrations than healthy horses (p = 0.0026). There was no significant difference in BALF TNF-α concentration between horses in exacerbation and remission from disease, but there was a decrease in median TNF-α concentration between healthy horses and horses with clinical exacerbation of severe equine asthma. These findings suggest, that similar to human asthma, the role of TNF-α in chronic lower airway inflammation of horses may differ between disease phenotypes and disease state. Furthermore, the method with which TNF-α is measured (mRNA expression vs. protein concentration) may affect results when studying the role of TNF-α in horses with severe equine asthma.

Using Predictive Analytics to Identify Risk of Clinical Asthma Exacerbations

Using Predictive Analytics to Identify Risk of Clinical Asthma Exacerbations

Reslizumab in Eosinophilic Asthma: A Review.

Reslizumab (Cinqaero®; Cinqair®) is a humanized monoclonal antibody against interleukin-5 (IL-5), a cytokine mediator of eosinophilic airway inflammation. Reslizumab is indicated as an add-on treatment for severe eosinophilic asthma in adults, on the basis of data from the BREATH phase III clinical trial programme. In three double-blind BREATH studies of up to 52weeks' duration, adding intravenous reslizumab (3mg/kg, once every 4weeks) to the current asthma therapy of patients (aged 12-75years) with eosinophilic asthma inadequately controlled with inhaled corticosteroids resulted in significant reductions in clinical asthma exacerbation frequency and significant improvements in lung function, asthma control and health-related quality of life relative to adding placebo. Pooled data from the two trials of 52weeks' duration indicated similar benefits with reslizumab across various patient subgroups, including patients with severe eosinophilic asthma. Reslizumab was generally well tolerated, with very few recipients experiencing severe or serious treatment-related adverse events. Moreover, in an open-label extension study, continued use of reslizumab for up to 2years was associated with durable lung function benefit, without any new tolerability concerns. Thus, intravenous reslizumab extends the valuable add-on treatment options for adults with severe eosinophilic asthma inadequately controlled with standard therapies.

Reslizumab in patients with inadequately controlled late-onset asthma and elevated blood eosinophils

IntroductionAsthma with adult onset and elevated blood eosinophils is a difficult-to-treat subgroup. This post hoc analysis evaluated reslizumab, an anti-interleukin-5 monoclonal antibody, in patients with late-onset eosinophilic asthma. MethodsData from two 52-week placebo-controlled trials of reslizumab IV 3 mg/kg every 4 weeks in patients aged 12–75 years with inadequately controlled asthma, ≥1 asthma exacerbation within 12 months, and screening blood eosinophils ≥400/μL (NCT01287039/NCT01285323) were stratified by age of asthma onset (<40 or ≥40 years). Annual clinical asthma exacerbation rates, change in lung function, and patient-reported outcomes were analyzed. Results273 patients with late-onset asthma (placebo, n = 130; reslizumab, n = 143) and 658 with early-onset asthma (placebo, n = 336; reslizumab, n = 322) were included. Baseline demographics were similar between groups. The interaction between age at onset of asthma and effect of reslizumab on asthma exacerbations was statistically significant (p = 0.0083). Compared with placebo, reslizumab produced a 75% relative reduction in asthma exacerbations in patients with late-onset asthma (rate ratio [RR] 0.25; 95% confidence interval [CI], 0.16, 0.40), substantially larger than the reduction in earlier onset patients (RR 0.58; 95% CI, 0.44, 0.76). Similar findings were observed for other measures of asthma, including forced expiratory volume in 1 s (FEV1). The adverse event profile of reslizumab was similar in patients with early- or late-onset asthma. ConclusionsCompared with placebo, reslizumab produced larger reductions in asthma exacerbations and larger improvements in lung function in patients with late versus early-onset asthma.

Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials

Elevated numbers of blood eosinophils are a risk factor for asthma exacerbations. Reslizumab is a humanised anti-interleukin 5 monoclonal antibody that disrupts eosinophil maturation and promotes programmed cell death. We aimed to assess the efficacy and safety of reslizumab in patients with inadequately controlled, moderate-to-severe asthma. We did two duplicate, multicentre, double-blind, parallel-group, randomised, placebo-controlled phase 3 trials. Both trials enrolled patients with asthma aged 12-75 years (from 128 clinical research centres in study 1 and 104 centres in study 2) from Asia, Australia, North America, South America, South Africa, and Europe, whose asthma was inadequately controlled by medium-to-high doses of inhaled corticosteroid based therapy and who had blood eosinophils of 400 cells per μL or higher and one or more exacerbations in the previous year. Patients were randomly assigned (1:1) to receive either intravenous reslizumab (3·0 mg/kg) or placebo every 4 weeks for 1 year by computerised central randomisation. Patients and investigators were masked to treatment assignment during the study. Each patient received a specific volume of study drug (reslizumab or matching placebo) on the basis of the patient's body weight and randomly assigned treatment group. Additionally, the sponsor's clinical personnel involved in the study were masked to the study drug identity until the database was locked for analysis and the treatment assignment revealed. The primary outcome was the annual frequency of clinical asthma exacerbations and was analysed by intention to treat. We assessed safety outcomes in the patients who had received one or more dose of the drug. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT01287039 (study 1) and NCT01285323 (study 2). Study 1 was done between April 12, 2011, and March 3, 2014 and study 2 between March 22, 2011, and April 9, 2014. Of 2597 patients screened, 953 were randomly assigned to receive either reslizumab (n=477 [245 in study 1 and 232 in study 2]) or placebo (n=476 [244 and 232]). In both studies, patients receiving reslizumab had a significant reduction in the frequency of asthma exacerbations (study 1: rate ratio [RR] 0·50 [95% CI 0·37-0·67]; study 2: 0·41 [0·28-0·59]; both p<0·0001) compared with those receiving placebo. Common adverse events on reslizumab were similar to placebo. The most common adverse events were worsening asthma symptoms (127 [52%] for placebo and 97 [40%] for reslizumab in study 1; 119 [51%] for placebo and 67 [29%] for reslizumab for study 2), upper respiratory tract infections (32 [13%] and 39 [16%]; 16 [7%] and eight [3%]), and nasopharyngitis (33 [14%] and 28 [11%]; 56 [24%] and 45 [19%]). Two patients in the reslizumab group had anaphylactic reactions; both responded to standard treatment at the study centre and resolved, and the patients were withdrawn from the study. These results support the use of reslizumab in patients with asthma and elevated blood eosinophil counts who are inadequately controlled on inhaled corticosteroid-based therapy. Teva Branded Pharmaceutical Products R&D.

The NR3C1 Glucocorticoid Receptor Gene Polymorphisms May Modulate the TGF-beta mRNA Expression in Asthma Patients.

Glucocorticosteroids (GCs) are basic drugs in therapy of a number of diseases, including chronic diseases of the respiratory system. They are the most important anti-inflammatory drugs in the treatment of asthma. GCs after binding to the glucocorticoid receptor (GR) form the complex (transcription factor), which acts on promoter and regulatory parts of genes enhancing the expression of anti-inflammatory proteins and decreasing the proinflammatory protein synthesis, including numerous cytokines mediating inflammation in the course of asthma. Non-sensitivity or resistance to GCs favours an increase in the TGF-β expression. This cytokine plays a central role in asthma inducing fibroblast differentiation and extracellular matrix synthesis. TGF-β isoforms, 1, 2 and 3, are located on chromosome 19q13, 1q41 and 14q24, respectively. GCs reduce TGF-β 1 and TGF-β 2 production and significantly decrease the expression of upregulated TGF-β 1 and TGF-β 2 mRNA induced by exogenous TGF-β. In asthma, TGF-β may play a role in the development of the peribronchiolar and subepithelial fibrosis, which contributes to a significant clinical exacerbation of asthma. Therefore, it is possible that NR3C1 glucocorticoid receptor gene polymorphisms could exert varied effects on the TGF-β mRNA expression and fibrotic process in lungs of asthmatic patients. The aim of the study was to evaluate the impact of polymorphic forms (Tth111I, BclI, ER22/23EK, N363S) of the NR3C1 gene on the level of the TGF-β 1 mRNA expression. A total of 173 patients with asthma and 163 healthy volunteers participated in the study. Genotyping of Tth111I, BclI, ER22/23EK, and N363S polymorphisms of the NR3C1 gene was performed by using PCR-HRM and PCR-RFLP techniques. TGF-β mRNA was assessed by real time RT-PCR. Tth111I SNP significantly (p = 0.0115) correlated with the TGF-β 1 mRNA expression level. The significance of AA and GG genotypes of Tth111I SNP in increasing and decreasing the level of the TGF-β 1 mRNA expression was demonstrated. Both BclI SNP and ER22/23EK SNP did not affect the expression level of the cytokine analysed. The N363S SNP AA genotype of NR3C1 gene statistically significantly influenced the increase in the level of the TGF-β 1 mRNA expression. Thus, SNPs of NR3C1 gene play an important regulatory function in the bronchi of patients suffering from asthma. In the case of the occurrence of Tth111I and N363S polymorphic forms of the gene studied, a reduced ability of GCs to inhibit the TGF-β 1 expression can be observed.

Differences in respiratory syncytial virus and influenza infection in a house-dust-mite-induced asthma mouse model: consequences for steroid sensitivity

A significant number of clinical asthma exacerbations are triggered by viral infection. We aimed to characterize the effect of virus infection in an HDM (house dust mite) mouse model of asthma and assess the effect of oral corticosteroids. HDM alone significantly increased eosinophils, lymphocytes, neutrophils, macrophages and a number of cytokines in BAL (bronchoalveolar lavage), all of which were sensitive to treatment with prednisolone (with the exception of neutrophils). Virus infection also induced cell infiltration and cytokines. RSV (respiratory syncytial virus) infection in HDM-treated animals further increased all cell types in BAL (except eosinophils, which declined), but induced no further increase in HDM-elicited cytokines. However, while HDM-elicited TNF-α (tumour necrosis factor-α), IFN-γ (interferon-γ), IL (interleukin)-2, IL-5 and IL-10 were sensitive to prednisolone treatment, concomitant infection with RSV blocked the sensitivity towards steroid. In contrast, influenza infection in HDM- challenged animals resulted in increased BAL lymphocytes, neutrophils, IFN-γ, IL-1β, IL-4, IL-5, IL-10 and IL-12, but all were attenuated by prednisolone treatment. HDM also increased eNO (exhaled NO), which was further increased by concomitant virus infection. This increase was only partially attenuated by prednisolone. RSV infection alone increased BAL mucin. However, BAL mucin was increased in HDM animals with virus infection. Chronic HDM challenge in mice elicits a broad inflammatory response that shares many characteristics with clinical asthma. Concomitant influenza or RSV infection elicits differing inflammatory profiles that differ in their sensitivity towards steroids. This model may be suitable for the assessment of novel pharmacological interventions for asthmatic exacerbation.