Explore the vast range of titles available.

Viral respiratory tract infections are common and usually selflimited illnesses. For patients at risk of asthma, or with existing asthma, viral respiratory tract infections can have a profound effect on the expression of disease or loss of control. New evidence has shown that wheezing episodes early in life due to human rhinoviruses are a major risk factor for the later diagnosis of asthma at age 6 years. For those with existing asthma, exacerbations are a major cause of morbidity, can need acute care, and can, albeit rarely, result in death. Viral respiratory tract infections, predominantly those caused by human rhinoviruses, are associated with asthma exacerbations. There is also evidence that deficiencies in antiviral activity and the integrity of the airway epithelial barrier could make individuals with asthma more likely to have severe viral respiratory infections of the lower airway, and thus increase the risk of exacerbation. In view of the effect of respiratory viruses on many aspects of asthma, efforts to understand the mechanisms and risk factors by which these airway infections cause changes in airway pathophysiology are a first step towards improved treatment.

Benralizumab is a humanised, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils. We aimed to assess the efficacy and safety of benralizumab as add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts. In this randomised, double-blind, parallel-group, placebo-controlled, phase 3 study (CALIMA) undertaken at 303 sites in 11 countries, we enrolled patients aged 12–75 years with severe asthma uncontrolled by medium-dosage to high-dosage inhaled corticosteroids plus long-acting β₂-agonists (ICS plus LABA) and a history of two or more exacerbations in the previous year. Patients were randomly assigned (1:1:1) to receive 56 weeks of benralizumab 30 mg every 4 weeks (Q4W), benralizumab 30 mg every 8 weeks (Q8W; first three doses 4 weeks apart), or placebo (all subcutaneous injection). Patients were stratified (2:1) by baseline blood eosinophil counts 300 cells per μL or greater and less than 300 cells per μL, respectively. Patients and study centre staff were masked to treatment allocation. The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dosage ICS plus LABA with baseline blood eosinophils 300 cells per μL or greater (intention-to-treat analysis). Key secondary endpoints were pre-bronchodilator forced expiratory volume in 1 s (FEV1) and total asthma symptom score. This study is registered with ClinicalTrials.gov, number NCT01914757. Between Aug 21, 2013, and March 16, 2015, 2505 patients were enrolled, of whom 1306 patients were randomised; 425 patients were randomly assigned to and received benralizumab 30 mg Q4W, 441 to benralizumab 30 mg Q8W, and 440 to placebo. 728 patients were included in the primary analysis population. Benralizumab resulted in significantly lower annual exacerbation rates with the Q4W regimen (rate 0·60 [95% CI 0·48–0·74], rate ratio 0·64 [95% CI 0·49–0·85], p=0·0018, n=241) and Q8W regimen (rate 0·66 [95% CI 0·54–0·82], rate ratio 0·72 [95% CI 0·54–0·95], p=0·0188, n=239) compared with placebo (rate 0·93 [95% CI 0·77–1·12], n=248). Benralizumab also significantly improved pre-bronchodilator FEV1 (Q4W and Q8W) and total asthma symptom score (Q8W only) in these patients. The most common adverse events were nasopharyngitis (90 [21%] in the Q4W group, 79 [18%] in the Q8W group, and 92 [21%] in the placebo group) and worsening asthma (61 [14%] in the Q4W group, 47 [11%] in the Q8W group, and 68 [15%] in the group). Benralizumab significantly reduced annual exacerbation rates and was generally well tolerated for patients with severe, uncontrolled asthma with blood eosinophils 300 cells per μL or greater. Our data further refine the patient population likely to receive the greatest benefit from benralizumab treatment. AstraZeneca and Kyowa Hakko Kirin.

Abstract Rationale IL-17 signaling has been implicated in development and persistence of asthma. Cytokine-targeted strategies blocking IL-17 receptor signaling may be beneficial in asthma treatment. Objectives To determine efficacy and safety of brodalumab, a human anti–IL-17 receptor A monoclonal antibody, in subjects with inadequately controlled moderate to severe asthma taking regular inhaled corticosteroids. Methods Three hundred two subjects were randomized to brodalumab (140, 210, or 280 mg) or placebo. Primary endpoint was change in Asthma Control Questionnaire (ACQ) score from baseline to Week 12. Secondary endpoints included FEV1, symptom scores, and symptom-free days. Prespecified subgroup analyses were conducted to identify potential responsive subpopulations. Analyses included randomized subjects receiving one or more doses of investigational product using last-observation-carried-forward imputation. Measurements and Main Results Demographics and baseline characteristics were generally balanced among groups (n = 302; n = 226 brodalumab). For the overall study population, no treatment differences were observed. Nine prespecified subgroups were examined without corrections for multiple testing. In only the high-reversibility subgroup (post-bronchodilator FEV1 improvement ≥ 20%; n = 112) was an ACQ change with nominal significance noted; ACQ responses were nominally significant in the 210-mg group (estimated treatment difference, 0.53) but not significant in the higher 280-mg group (estimated treatment difference, 0.38). Adverse events, generally balanced among groups, were most commonly asthma, upper respiratory tract infection, and injection site reaction. Conclusions Inhibition of IL-17 receptor A did not produce a treatment effect in subjects with asthma. The results of the high-reversibility subgroup analysis are of uncertain significance, requiring further study of brodalumab in this asthma subpopulation. Clinical trial registered with www.clinicaltrials.gov (NCT01199289).

A recent study has found that rhinovirus-induced exacerbation of asthma is in part mediated by the release of neutrophil extracellular traps and double-stranded DNA by neutrophils in the airway.

Low-dose inhaled corticosteroids (ICS) are highly effective for reducing asthma exacerbations and mortality. Conventionally, ICS treatment is recommended for patients with symptoms on more than 2 days per week, but this criterion has scant evidence. We aimed to assess the validity of the previous symptom-based cutoff for starting ICS by establishing whether there was a differential response to budesonide versus placebo for severe asthma exacerbations, lung function, and asthma symptom control across subgroups identified by baseline asthma symptom frequency. We did a post-hoc analysis of the 3 year inhaled Steroid Treatment As Regular Therapy (START) study, done in 32 countries, with clinic visits every 3 months. Patients (aged 4–66 years) with mild asthma diagnosed within the previous 2 years and no previous regular corticosteroids were randomised to receive once daily, inhaled budesonide 400 μg (those aged <11 years 200 μg) or placebo. Coprimary outcomes for this analysis were time to first severe asthma-related event (SARE; hospital admission, emergency treatment, or death) and change from baseline in lung function after bronchodilator. Interaction with baseline symptom frequency was investigated, with patients grouped by more than two symptom days per week and two or fewer symptom days per week (divided into no days to 1 day, and more than 1 day to 2 days). Analysis was done by intention to treat. Of 7138 patients (n=3577 budesonide; n=3561 placebo), baseline symptom frequency was 0–1 days per week for 2184 (31%) participants, more than 1 and less than or equal to 2 symptom days per week for 1914 (27%) participants, and more than 2 symptom days per week for 3040 (43%) participants. For budesonide versus placebo, time to first SARE was longer across symptom frequency subgroups (hazard ratios 0·54 [95% CI 0·34–0·86] for 0–1 symptom days per week, 0·60 [0·39–0·93] for >1 to ≤2 symptom days per week, 0·57 [0·41–0·79] >2 symptom days per week, pinteraction=0·94), and the decline in postbronchodilator lung function was less at 3 years' follow-up (pinteraction=0·32). For budesonide versus placebo, severe exacerbations requiring oral or systemic corticosteroids were reduced (rate ratio 0·48 [0·38–0·61] 0–1 symptom days per week, 0·56 [0·44–0·71] >1 to ≤2 symptom days per week, and 0·66 [0·55–0·80] >2 symptom days per week, pinteraction=0·11), prebronchodilator lung function was higher, and symptom-free days were more frequent (p<0·0001 for all three subgroups), with no interaction by symptom frequency (prebronchodilator pinteraction=0·43; symptom-free days pinteraction=0·53). Similar results were noted when participants were classified by any guidelines criterion as so-called persistent versus so-called intermittent asthma. In mild recent-onset asthma, once daily, low-dose budesonide decreases SARE risk, reduces lung function decline, and improves symptom control similarly across all symptom subgroups. The results do not support restriction of inhaled corticosteroids to patients with symptoms on more than 2 days per week and suggest that treatment recommendations for mild asthma should consider both risk reduction and symptoms. AstraZeneca.

In four clinical trials, the use of a long-acting β 2 -agonist plus an inhaled glucocorticoid did not result in a higher frequency of serious asthma events than the use of an inhaled glucocorticoid alone but was associated with a lower frequency of exacerbations.

To evaluate the association between asthma exacerbations and the decline in lung function, as well as the potential effects of an inhaled corticosteroid, budesonide, on exacerbation-related decline in patients with asthma. To determine whether severe asthma exacerbations are associated with a persistent decline in lung function. The START (inhaled steroid treatment as regular therapy in early asthma) study was a 3-year, randomized, double-blind study of 7,165 patients (5-66 yr) with persistent asthma for less than 2 years, to determine whether early intervention with low-dose inhaled budesonide prevents severe asthma-related events (exacerbations requiring hospitalization or emergency treatment) and decline in lung function. There were 315 patients who experienced at least one severe asthma exacerbation, of which 305 were analyzable, 190 in the placebo group and 115 in the budesonide group. In the placebo group, the change in post-bronchodilator FEV(1) % predicted from baseline to the end of the study, in patients who did or did not experience a severe exacerbation was -6.44% and -2.43%, respectively (P < 0.001). A significant difference was seen in both children and in adults, but not in adolescents. In the budesonide group, the change in the post-bronchodilator FEV(1) % predicted in patients who did or did not experience a severe exacerbation was -2.48% and -1.72%, respectively (P = 0.57). The difference in magnitude of reduction afforded by budesonide, in patients who experienced at least one severe asthma-related event compared with those who did not, was statistically significant (P = 0.042). Severe asthma exacerbations are associated with a more rapid decline in lung function. Treatment with low doses of inhaled corticosteroid is associated with an attenuation of the decline.

Abstract Rationale Severe asthma (SA) remains poorly understood. Mast cells (MC) are implicated in asthma pathogenesis, but it remains unknown how their phenotype, location, and activation relate to asthma severity. Objectives To compare MC-related markers measured in bronchoscopically obtained samples with clinically relevant parameters between normal subjects and subjects with asthma to clarify their pathobiologic importance. Methods Endobronchial biopsies, epithelial brushings, and bronchoalveolar lavage were obtained from subjects with asthma and normal subjects from the Severe Asthma Research Program (N = 199). Tryptase, chymase, and carboxypeptidase A (CPA)3 were used to identify total MC (MCTot) and the MCTC subset (MCs positive for both tryptase and chymase) using immunostaining and quantitative real-time polymerase chain reaction. Lavage was analyzed for tryptase and prostaglandin D2 (PGD2) by ELISA. Measurements and Main Results Submucosal MCTot (tryptase-positive by immunostaining) numbers were highest in “mild asthma/no inhaled corticosteroid (ICS) therapy” subjects and decreased with greater asthma severity (P = 0.002). In contrast, MCTC (chymase-positive by immunostaining) were the predominant (MCTC/MCTot > 50%) MC phenotype in SA (overall P = 0.005). Epithelial MCTot were also highest in mild asthma/no ICS, but were not lower in SA. Instead, they persisted and were predominantly MCTC. Epithelial CPA3 and tryptase mRNA supported the immunostaining data (overall P = 0.008 and P = 0.02, respectively). Lavage PGD2 was higher in SA than in other steroid-treated groups (overall P = 0.02), whereas tryptase did not differentiate the groups. In statistical models, PGD2 and MCTC/MCTot predicted SA. Conclusions Severe asthma is associated with a predominance of MCTC in the airway submucosa and epithelium. Activation of those MCTC may contribute to the increases in PGD2 levels. The data suggest an altered and active MC population contributes to SA pathology.

Mindfulness-based stress reduction (MBSR) can improve symptoms of chronic inflammation; in asthma, improving asthma control and reducing airway inflammation. Understanding the neural mechanisms underlying these salubrious outcomes could help identify neuroimmune phenotypes and personalize interventions. Adults with asthma were randomized to 8 weeks of MBSR ( n  = 38) or a wait-list group ( n  = 34). Clinically relevant asthma-related and psychological outcomes were measured, and task-based fMRI data were acquired during exposure to emotional cues at baseline, post-intervention, and 6mo follow-up. Whole-brain group x time interactions and voxelwise regressions were used to evaluate changes in neural responses to emotion cues from baseline and their relationship to psychological and biological outcomes. Post-intervention, MBSR participants showed decreased lateral prefrontal/orbitofrontal cortex responses to aversive cues relative to controls, which was associated with increased mindfulness. Across participants, decreased salience network reactivity at post-intervention was associated with reduced psychological distress and airway inflammation. At 6 months, some relationships persisted while others did not. Results suggest that mindfulness training reduced effortful regulation of cognitive and affective responses to emotional cues, instead promoting more efficient processing strategies and reduced affective reactivity. Our findings clarify neural mechanisms underlying MBSR’s clinical benefits for asthma, underscoring mind-brain-immune relationships as a critical target for asthma treatment.

Severe asthma occurs more often in older adult patients. We hypothesized that the greater risk for severe asthma in older individuals is due to aging, and is independent of asthma duration. This is a cross-sectional study of prospectively collected data from adult participants (N=1130; 454 with severe asthma) enrolled from 2002 - 2011 in the Severe Asthma Research Program. The association between age and the probability of severe asthma, which was performed by applying a Locally Weighted Scatterplot Smoother, revealed an inflection point at age 45 for risk of severe asthma. The probability of severe asthma increased with each year of life until 45 years and thereafter increased at a much slower rate. Asthma duration also increased the probability of severe asthma but had less effect than aging. After adjustment for most comorbidities of aging and for asthma duration using logistic regression, asthmatics older than 45 maintained the greater probability of severe asthma [OR: 2.73 (95 CI: 1.96; 3.81)]. After 45, the age-related risk of severe asthma continued to increase in men, but not in women. Overall, the impact of age and asthma duration on risk for asthma severity in men and women is greatest over times of 18-45 years of age; age has a greater effect than asthma duration on risk of severe asthma.