Addition of anti-leukotriene agents to inhaled corticosteroids for adults and adolescents with persistent asthma

Juan Carlos Ivancevich Tuesday, 21 March 2017 11:12

Bhupendrasinh F Chauhan, Maya M Jeyaraman, Amrinder Singh Mann, Justin Lys, Ahmed M Abou-Setta, Ryan Zarychanski, Francine M Ducharme

 

Abstract

Background

Asthma management guidelines recommend low-dose inhaled corticosteroids (ICS) as first-line therapy for adults and adolescents with persistent asthma. The addition of anti-leukotriene agents to ICS offers a therapeutic option in cases of suboptimal control with daily ICS.

Objectives

To assess the efficacy and safety of anti-leukotriene agents added to ICS compared with the same dose, an increased dose or a tapering dose of ICS (in both arms) for adults and adolescents 12 years of age and older with persistent asthma. Also, to determine whether any characteristics of participants or treatments might affect the magnitude of response.

Search methods

We identified relevant studies from the Cochrane Airways Group Specialised Register of Trials, which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, the Allied and Complementary Medicine Database (AMED), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the trial registries clinicaltrials.gov and ICTRP from inception to August 2016.

Selection criteria

We searched for randomised controlled trials (RCTs) of adults and adolescents 12 years of age and older on a maintenance dose of ICS for whom investigators added anti-leukotrienes to the ICS and compared treatment with the same dose, an increased dose or a tapering dose of ICS for at least four weeks.

Data collection and analysis

We used standard methods expected by Cochrane. The primary outcome was the number of participants with exacerbations requiring oral corticosteroids (except when both groups tapered the dose of ICS, in which case the primary outcome was the % reduction in ICS dose from baseline with maintained asthma control). Secondary outcomes included markers of exacerbation, lung function, asthma control, quality of life, withdrawals and adverse events.

Main results

We included in the review 37 studies representing 6128 adult and adolescent participants (most with mild to moderate asthma). Investigators in these studies used three leukotriene receptor antagonists (LTRAs): montelukast (n = 24), zafirlukast (n = 11) and pranlukast (n = 2); studies lasted from four weeks to five years.

Anti-leukotrienes and ICS versus same dose of ICS

Of 16 eligible studies, 10 studies, representing 2364 adults and adolescents, contributed data. Anti-leukotriene agents given as adjunct therapy to ICS reduced by half the number of participants with exacerbations requiring oral corticosteroids (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.29 to 0.86; 815 participants; four studies; moderate quality); this is equivalent to a number needed to treat for additional beneficial outcome (NNTB) over six to 16 weeks of 22 (95% CI 16 to 75). Only one trial including 368 participants reported mortality and serious adverse events, but events were too infrequent for researchers to draw a conclusion. Four trials reported all adverse events, and the pooled result suggested little difference between groups (RR 1.06, 95% CI 0.92 to 1.22; 1024 participants; three studies; moderate quality). Investigators noted between-group differences favouring the addition of anti-leukotrienes for morning peak expiratory flow rate (PEFR), forced expiratory volume in one second (FEV1), asthma symptoms and night-time awakenings, but not for reduction in β2-agonist use or evening PEFR.

Anti-leukotrienes and ICS versus higher dose of ICS

Of 15 eligible studies, eight studies, representing 2008 adults and adolescents, contributed data. Results showed no statistically significant difference in the number of participants with exacerbations requiring oral corticosteroids (RR 0.90, 95% CI 0.58 to 1.39; 1779 participants; four studies; moderate quality) nor in all adverse events between groups (RR 0.96, 95% CI 0.89 to 1.03; 1899 participants; six studies; low quality). Three trials reported no deaths among 834 participants. Results showed no statistically significant differences in lung function tests including morning PEFR and FEV1 nor in asthma control measures including use of rescue β2-agonists or asthma symptom scores.

Anti-leukotrienes and ICS versus tapering dose of ICS

Seven studies, representing 1150 adults and adolescents, evaluated the combination of anti-leukotrienes and tapering-dose of ICS compared with tapering-dose of ICS alone and contributed data. Investigators observed no statistically significant difference in % change from baseline ICS dose (mean difference (MD) -3.05, 95% CI -8.13 to 2.03; 930 participants; four studies; moderate quality), number of participants with exacerbations requiring oral corticosteroids (RR 0.46, 95% CI 0.20 to 1.04; 542 participants; five studies; low quality) or all adverse events (RR 0.95, 95% CI 0.83 to 1.08; 1100 participants; six studies; moderate quality). Serious adverse events occurred more frequently among those taking anti-leukotrienes plus tapering ICS than in those taking tapering doses of ICS alone (RR 2.44, 95% CI 1.52 to 3.92; 621 participants; two studies; moderate quality), but deaths were too infrequent for researchers to draw any conclusions about mortality. Data showed no improvement in lung function nor in asthma control measures.

Authors' conclusions

For adolescents and adults with persistent asthma, with suboptimal asthma control with daily use of ICS, the addition of anti-leukotrienes is beneficial for reducing moderate and severe asthma exacerbations and for improving lung function and asthma control compared with the same dose of ICS. We cannot be certain that the addition of anti-leukotrienes is superior, inferior or equivalent to a higher dose of ICS. Scarce available evidence does not support anti-leukotrienes as an ICS sparing agent, and use of LTRAs was not associated with increased risk of withdrawals or adverse effects, with the exception of an increase in serious adverse events when the ICS dose was tapered. Information was insufficient for assessment of mortality.

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Reslizumab and Eosinophilic Asthma: One Step Closer to Precision Medicine?

Juan Carlos Ivancevich Wednesday, 15 March 2017 13:08
imageGilda Varricchi1,2imageGianenrico Senna3imageStefania Loffredo1,2imageDiego Bagnasco4imageMatteo Ferrando4 and imageGiorgio Walter Canonica5*
1Division of Clinical Immunology and Allergy, Department of Translational Medical Sciences, School of Medicine, University of Naples Federico II, Naples, Italy
2Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
3Asthma Center and Allergy Unit, Verona University, General Hospital, Verona, Italy
4Allergy and Respiratory Diseases, DIMI Department of Internal Medicine, IRCCS AOU San Martino-IST, University of Genova, Genova, Italy
5Personalized Medicine Clinic Asthma and Allergy Humanitas Clinical and Research Center, Department of Biomedical Science, Humanitas University, Rozzano, Milano, Italy

Human eosinophils represent approximately 1% of peripheral blood leukocytes. However, these cells have the propensity to leave the blood stream and migrate into inflamed tissues. Eosinophilic inflammation is present in a significant proportion of patients with severe asthma. Asthma is a chronic inflammatory disorder that affects more than 315 million people worldwide, with 10% having severe uncontrolled disease. Although the majority of patients can be efficiently treated, severe asthmatics continue to be uncontrolled and are at risk of exacerbations and even death. Interleukin-5 (IL-5) plays a fundamental role in eosinophil differentiation, maturation, activation and inhibition of apoptosis. Therefore, targeting IL-5 is an appealing approach to the treatment of patients with severe eosinophilic asthma. Reslizumab, a humanized anti-IL-5 monoclonal antibody, binds with high affinity to amino acids 89–92 of IL-5 that are critical for binding to IL-5 receptor α. Two phase III studies have demonstrated that reslizumab administration in adult patients with severe asthma and eosinophilia (≥400 cells/μL) improved lung function, asthma control, and symptoms. Thus, the use of blood eosinophils as a baseline biomarker could help to select patients with severe uncontrolled asthma who are likely to achieve benefits in asthma control with reslizumab. In conclusion, targeted therapy with reslizumab represents one step closer to precision medicine in patients with severe eosinophilic asthma.


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Inhaled Corticosteroid Claims and Outpatient Visits After Hospitalization for Asthma Among Commercially Insured Children

Juan Carlos Ivancevich Thursday, 09 March 2017 12:09
 

Abstract

OBJECTIVE:

To determine rates of inhaled corticosteroid (ICS) claims and outpatient follow-up after asthma hospitalization among commercially insured children.

METHODS:

We conducted a retrospective cohort analysis of children hospitalized for asthma using 2013 national Truven MarketScan data. Covariates included age, sex, region, length of stay, and having an ICS claim within 35 days before hospitalization. Outcome variables were a claim for any ICS-containing medication and outpatient visit within 30 days after discharge. Multivariable analysis used logistic regression.

RESULTS:

A total of 5471 children aged 2 to 17 were included; 61% were boys, and mean age was 6.8 years. Forty-one percent had a claim for an ICS and 76% had an outpatient visit within 30 days after hospital discharge. In multivariable analysis, children who had an ICS claim within 35 days before the hospitalization were more likely to have an ICS claim within 30 days after discharge (relative risk [RR] 1.3, 95% confidence interval [CI] 1.2-1.5). The strongest predictor of an ICS claim within 30 days after discharge was attendance at an outpatient appointment (RR 1.4, 95% CI 1.3-1.6). Children aged 2 to 6 were more likely to attend an outpatient appointment (RR 1.1, 95% CI 1.1-1.2). Children with an ICS claim before admission were also more likely to attend an outpatient appointment (RR 1.1, 95% CI 1.004-1.1).

CONCLUSIONS:

In this national sample of commercially insured children with asthma, rates of ICS claims after hospitalization are low despite high rates of outpatient visits. Both inpatient and outpatient physicians must play a role in increasing ICS adherence in this high-risk population of children with asthma.

Natural killer cell–mediated inflammation resolution is disabled in severe asthma

Juan Carlos Ivancevich Saturday, 11 March 2017 12:04
RESEARCH ARTICLE
ASTHMA

NK cells in severe asthma—Failed resolution

Anti-inflammatory corticosteroids are a first line of defense against many types of asthma, but patients with severe asthma do not frequently respond to this therapy. Duvall et al. now report that this lack of response may be due in part to defects in natural killer (NK) cells, which are important mediators of inflammation resolution. They found that NK cells from patients with severe asthma had impaired killing and that corticosteroid exposure further inhibited the function of these cells, whereas the proresolving mediator LXA4 preserved NK cell effector mechanisms. Therefore, corticosteroids may be a counterproductive therapy in patients with severe asthma, and specifically activating NK cells may provide an alternate therapeutic target.

Abstract

Severe asthma is typically characterized by chronic airway inflammation that is refractory to corticosteroids and associated with excess morbidity. Patients were recruited into the National Heart, Lung, and Blood Institute–sponsored Severe Asthma Research Program and comprehensively phenotyped by bronchoscopy. Bronchoalveolar lavage (BAL) cells were analyzed by flow cytometry. Compared with healthy individuals (n = 21), patients with asthma (n = 53) had fewer BAL natural killer (NK) cells. Patients with severe asthma (n = 29) had a marked increase in the ratios of CD4+ T cells to NK cells and neutrophils to NK cells. BAL NK cells in severe asthma were skewed toward the cytotoxic CD56dim subset, with significantly increased BAL fluid levels of the cytotoxic mediator granzyme A. The numbers of BAL CD56dim NK cells and CCR6CCR4 T helper 1–enriched CD4+ T cells correlated inversely with lung function [forced expiratory volume in 1 s (FEV1) % predicted] in asthma. Relative to cells from healthy controls, peripheral blood NK cells from asthmatic patients had impaired killing of K562 myeloid target cells despite releasing more cytotoxic mediators. Ex vivo exposure to dexamethasone markedly decreased blood NK cell lysis of target cells and cytotoxic mediator release. NK cells expressed airway lipoxin A4/formyl peptide receptor 2 receptors, and in contrast to dexamethasone, lipoxin A4–exposed NK cells had preserved functional responses. Together, our findings indicate that the immunology of the severe asthma airway is characterized by decreased NK cell cytotoxicity with increased numbers of target leukocytes, which is exacerbated by corticosteroids that further disable NK cell function. These failed resolution mechanisms likely contribute to persistent airway inflammation in severe asthma.

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Japanese guidelines for adult asthma 2017☆

Juan Carlos Ivancevich Tuesday, 21 February 2017 04:03

Abstract

Adult bronchial asthma is characterized by chronic airway inflammation, and presents clinically with variable airway narrowing (wheezes and dyspnea) and cough. Long-standing asthma induces airway remodeling, leading to intractable asthma. The number of patients with asthma has increased; however, the number of patients who die of asthma has decreased (1.2 per 100,000 patients in 2015). The goal of asthma treatment is to enable patients with asthma to attain normal pulmonary function and lead a normal life, without any symptoms. A good relationship between physicians and patients is indispensable for appropriate treatment. Long-term management by therapeutic agents and elimination of the causes and risk factors of asthma are fundamental to its treatment. Four steps in pharmacotherapy differentiate between mild and intensive treatments; each step includes an appropriate daily dose of an inhaled corticosteroid, varying from low to high levels. Long-acting β2-agonists, leukotriene receptor antagonists, sustained-release theophylline, and long-acting muscarinic antagonist are recommended as add-on drugs, while anti-immunoglobulin E antibody and oral steroids are considered for the most severe and persistent asthma related to allergic reactions. Bronchial thermoplasty has recently been developed for severe, persistent asthma, but its long-term efficacy is not known. Inhaled β2-agonists, aminophylline, corticosteroids, adrenaline, oxygen therapy, and other approaches are used as needed during acute exacerbations, by choosing treatment steps for asthma in accordance with the severity of exacerbations. Allergic rhinitis, eosinophilic chronic rhinosinusitis, eosinophilic otitis, chronic obstructive pulmonary disease, aspirin-induced asthma, and pregnancy are also important issues that need to be considered in asthma therapy.

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Editor: Juan C. Ivancevich, MD

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