Deterioration In Asthma Control Research Articles

Validity study of the Japanese version of the Nijmegen Questionnaire for verifying dysfunctional breathing in Japanese asthma patients

Dysfunctional breathing (DB) is a clinical condition characterized by irregular breathing patterns presenting a sensation of dyspnea and a feeling of chest tightness. DB is a known comorbidity of asthma that is difficult to control, leading to poor quality of life, so early diagnosis and therapeutic intervention are essential to improve the clinical condition of asthma. The Nijmegen Questionnaire (NQ), developed to screen for DB and translated into various languages, is used worldwide. However, a Japanese NQ (JNQ) is unavailable, so DB has not been clinically verified in people with asthma in Japan. This study aimed to prepare a JNQ, verify its reliability and validity, and demonstrate its clinical benefits in asthma treatment. The JNQ was prepared by back-translating the NQ with the author's consent. The answers to self-administered questionnaires, including the JNQ, Asthma Control Test (ACT), Asthma Control Questionnaire (ACQ), Mini Asthma Quality of Life Questionnaire (Mini-AQLQ), and Patient Health Questionnaire 9 (PHQ-9), were obtained with the consent of 68 people with asthma (average age ± SD, 52.04± 12.43 years) who visited Nihon University Itabashi Hospital. The reliability of the JNQ was analyzed by the Cronbach alpha coefficient. Acomparative test was conducted for each questionnaire (ACT, ACQ, Mini-AQLQ, PHQ-9), considering a JNQ score of 23 as the cutoff value. Patients with a score of 23 or more were assigned to the DB group, whereas patients with a score of less than 23 were assigned to the non-DB group. We analyzed the correlation between the JNQ and each questionnaire. The JNQ showed sufficient reliability (Cronbach alpha= 0.875). Correlation analysis between the JNQ score and each questionnaire revealed negative correlations with the ACT score (r= 0.262) and Mini-AQLQ score (r= -0.453) and positive correlations with the ACQ score (r= 0.337) and PHQ-9 score (r= 0.539). All of these correlations were statistically significant. As a result of the comparative test, the DB and non-DB groups showed a significant difference in Mini-AQLQ (P= .023) and PHQ-9 (P= .003) scores. No significant difference was observed between ACT (P= .294) and ACQ (P= .177) scores. The JNQ validates DB in Japanese people with asthma and reflects the deterioration of asthma control, decreased quality of life, and depression. Using the JNQ, early diagnosis and therapeutic intervention (eg, breathing exercises and a psychosomatic approach) for DB in people with asthma may help suppress the severity of asthma in Japan.

Regular (up to 10 puffs 4-hourly) inhaled salbutamol should be prescribed at discharge after an asthma attack: myth or maxim?

Over the past 20 years, the concept of asthma weaning plans on discharge after an attack has crept into common practice, although the precise origin of these plans is unclear. High use of short-acting β2-agonists (SABAs) may result in tolerance to their bronchodilator effects, thus diminishing their efficacy, particularly when they are most needed at the time of an acute attack. Furthermore, key warning signs of a deterioration in asthma control may be masked and the weaning plan may encourage the over-use and over-reliance on SABAs. Side-effects from over-use may also occur, including lactic acidosis, downregulation of the β2-adrenoreceptor, increased allergen response and pro-inflammatory effects. The need for asthma education at discharge, a personal asthma action plan and vigilance about prescribing and ensuring adherence to maintenance therapy are definitely important. However, the current authors conclude that the benefit of prescribing regular salbutamol (up to 10 puffs every 4 h) at discharge after an acute asthma attack is a myth, and a very dangerous one.

SABAs as Reliever Medications in Asthma Management: Evidence-Based Science.

The role of as-needed inhaled short-acting β2-agonists (SABAs) in the management of asthma has become a subject of debate due to differing opinions in the professional community relating to the use of SABAs. In this article, we summarize the current position of SABAs when used as reliever medications and examine the challenges to appropriate use including a critique of the data that have led to the condemnation of SABA used as a reliever. We consider the evidence for the appropriate use of SABA as a reliever together with practical solutions to ensure such use, including identifying patients at risk of misusing their SABA relievers and managing issues of inhaler technique and treatment adherence. We conclude that inhaled corticosteroid (ICS)-based maintenance treatment with SABA used as-needed as a reliever is an effective and safe treatment for patients with asthma, with no scientific evidence of a causal link between SABA use as a reliever and mortality or serious adverse events (including exacerbations). Increased SABA use warns of a deterioration in asthma control, and patients at risk of misusing their ICS and SABA medication should be rapidly identified to ensure they are receiving adequate ICS-based controller therapy. Appropriate use of ICS-based controller therapy and as-needed SABA should be encouraged and promoted with educational activities.

Home administration of biological treatment in severe asthma in real-life experience: impact on asthma control and quality of life.

Introduction. Several biological agents for the treatment of severe asthma have been approved for self-administration on an outpatient basis in the last years. However, data on the impact of home administration in outcomes such as asthma control and quality of life in real-life settings are sparse. Being this knowledge crucial for clinical practice, this study aimed to assess asthma control and quality of life in patients who transitioned from day hospital administration of biological therapy to home administration. Methods. A single-center prospective analysis of 33 patients treated with biologics for severe asthma, who switched from hospital to home treatment was performed. Asthma Control Test (ACT), Control of Allergic Rhinitis and Asthma Test (CARAT), Asthma Life Quality (ALQ) and the number of exacerbations were assessed 3 months before and 3 and 6 months after of home-use. Results. ACT and CARAT did not show statistical differences comparing to the baseline values (21.8 ± 2.7 and 23.8 ± 5.5) within 3 months (22.1 ± 2.4, p = 0.609; 23.2 ± 5.3, p = 0.572) or 6 months (23.4 ± 0.9, p = 0.553; 23.7 ± 6.2, p = 0.149) of home administration. Also, ALQ score did not show meaningful variations between baseline (9.5 ± 3.2) and after 3 months (11.2 ± 4.4, p = 0.275) and 6 months (10.3 ± 3.8, p = 0.209) of home-use. Regarding asthma exacerbations, we did not record a significant difference comparing to the baseline values of 3 months/patient exacerbations (0.2 ± 0.4) and after 3 months (0.2 ± 0.5, p = 0.786) or 6 months (0.2 ± 0.4, p = 1.000) of change in modality treatment. There was no cases of anaphylaxis or other serious adverse effects in those patients treated at home. Conclusions. Transition of day hospital administration of biologic treatment for severe asthma to home administration did not lead to any deterioration of asthma control or quality of life. Our results emphasized the efficacy and safety of home administration of biologic treatment and provide support on changing the paradigm of the administration of biological treatment in severe asthma.

MyAirCoach: the use of home-monitoring and mHealth systems to predict deterioration in asthma control and the occurrence of asthma exacerbations; study protocol of an observational study

IntroductionAsthma is a variable lung condition whereby patients experience periods of controlled and uncontrolled asthma symptoms. Patients who experience prolonged periods of uncontrolled asthma have a higher incidence of exacerbations...

Azithromycin for Acute Exacerbations of Asthma

Guidelines recommend against antibiotic use to treat asthma attacks. A study with telithromycin reported benefit, but adverse reactions limit its use. To determine whether azithromycin added to standard care for asthma attacks in adults results in clinical benefit. The Azithromycin Against Placebo in Exacerbations of Asthma (AZALEA) randomized, double-blind, placebo-controlled clinical trial, a United Kingdom-based multicenter study in adults requesting emergency care for acute asthma exacerbations, ran from September 2011 to April 2014. Adults with a history of asthma for more than 6 months were recruited within 48 hours of presentation to medical care with an acute deterioration in asthma control requiring a course of oral and/or systemic corticosteroids. Azithromycin 500 mg daily or matched placebo for 3 days. The primary outcome was diary card symptom score 10 days after randomization, with a hypothesized treatment effect size of -0.3. Secondary outcomes were diary card symptom score, quality-of-life questionnaires, and lung function changes, all between exacerbation and day 10, and time to a 50% reduction in symptom score. Of 4582 patients screened at 31 centers, 199 of a planned 380 were randomized within 48 hours of presentation. The major reason for nonrecruitment was receipt of antibiotics (2044 [44.6%] screened patients). Median time from presentation to drug administration was 22 hours (interquartile range, 14-28 hours). Exacerbation characteristics were well balanced across treatment arms and centers. The primary outcome asthma symptom scores were mean (SD), 4.14 (1.38) at exacerbation and 2.09 (1.71) at 10 days for the azithromycin group and 4.18 (1.48) and 2.20 (1.51) for the placebo group, respectively. Using multilevel modeling, there was no significant difference in symptom scores between azithromycin and placebo at day 10 (difference, -0.166; 95% CI, -0.670 to 0.337), nor on any day between exacerbation and day 10. No significant between-group differences were observed in quality-of-life questionnaires or lung function between exacerbation and day 10, or in time to 50% reduction in symptom score. In this randomized population, azithromycin treatment resulted in no statistically or clinically significant benefit. For each patient randomized, more than 10 were excluded because they had already received antibiotics. clinicaltrials.gov Identifier: NCT01444469.

The Editor takes a closer look at some of this month's articles

Clinical & Experimental AllergyVolume 44, Issue 10 p. 1205-1205 Editor's ChoiceFree Access The Editor takes a closer look at some of this month's articles First published: 22 September 2014 https://doi.org/10.1111/cea.12396AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Adherence: the key to success in treatment of chronic airway disease The main cause for treatment failure in asthma and rhinitis is suboptimal adherence to inhaled corticosteroids 1. The need to take these medications regularly to obtain maximum effect even when asymptomatic is a particular problem for seasonal allergic rhinitis (hay fever) where symptoms are often episodic. The reasons for suboptimal adherence are complex, but the key to successful management is good education both in the rationale for treatment and inhaler technique. Telemedicine has found its way into most corners of health care, but there is relatively little published on its potential role in allergic disease. Therefore, Pizzulli and colleagues (pp. 1246–1254) have undertaken an original study looking at the value of telemonitoring on adherence to topical corticosteroids in children with severe hay fever. They demonstrated an improvement in both adherence and disease knowledge, and the informatics platform was positively received by the study participants. No improvement was seen in disease control, but pollen counts were low during the study period, and the study may also have been relatively underpowered for treatment efficacy endpoints. Antonio Pizzulli Estimated frequency (normal approximation) of daily consumption of mometasone in 63 children with hay fever, by allocation to AllergyMonitor or to usual care. [see figure 3 in A. Pizzulli et al. (pp. 1246–1254)]. Asthma and viral exacerbations: basophils get in on the act It is well established that upper respiratory tract viral infections particularly with rhinovirus are associated with the majority of exacerbations of asthma. The mechanisms involved have been studied in detail although the precise pathways involved remain elusive. Basophils have been relatively ignored as a player in the rhinovirus–asthma axis. However, the role of basophils may need to be reconsidered following the paper by Agrawal et al. (pp. 1266–1273), in which they have made the original observation that basophils become activated after rhinovirus infection with the maximal effect seen as late as 3 weeks after infection. A deterioration in asthma control is often prolonged after rhinovirus infection including an increase in airways hyperresponsiveness that can last for several weeks. It is intriguing to think that basophils, often the bridesmaid to mast cells, may be responsible. Rachana Agrawal Basophile Granulocyte. [Photo credit: User CS99 at German Wikipedia; Wikimedia Commons]. Patterns of inflammation in asthma: does it depend on your age? Asthma can start at any age, and there is an increasing interest in whether asthma that develops in older people is in any way different to asthma that develops in childhood or early adulthood. Evidence that this might be the case comes from a paper by Brandenberger and colleagues (pp. 1282–1292), who investigated the nature of the inflammatory response to house dust mite challenge in young and old mice. Interestingly, they found that whereas there was more airway hyperresponsiveness in young mice, there was a greater inflammatory response in the older mice which included a Th17-neutrophilic component. One might speculate that this may be due to the development of a different microbiota in the airways of the older mice. As steroid responsiveness is closely linked to Th2 responses in asthma, this raises the possibility that older asthmatics may be more resistant to inhaled corticosteroids. This observation now needs to be translated into clinical asthma. Christina Brandenberger Representative light photomicrographs of lung tissue sections stained with haematoxylin and eosin, showing a peribronchiolar and perivascular mixed inflammatory cell infiltration in HDM mice (arrows). b: bronchiolar airspace, a: alveoli, v: blood vessel, scale bar: 50 lm. [see figure 1b in Brandenberger et al. (pp. 1282–1292)]. Reference 1Bourdin A, Halimi L, Vachier I et al. Adherence in severe asthma. Clin Exp Allergy 2012; 42: 1566– 74. Caption to cover illustration: Patient taking a mannitol bronchial challenge test for diagnosing asthma (Image courtesy of Dr Brian Lipworth, Scottish Centre for Respiratory Research, Univ of Dundee Ninewells Hospital and Medical School). This logo highlights the Editor's Choice articles on the cover and the first page of each of the articles. Volume44, Issue10October 2014Pages 1205-1205 ReferencesRelatedInformation

Mepolizumab for Severe Eosinophilic Asthma (DREAM): A Multicentre, Double-Blind, Placebo-Controlled Trial

To elucidate the efficacy, safety, and patient characteristics of responsiveness to mepolizumab (a humanized monoclonal antibody against interleukin 5). Previous small, proof-of-concept studies in subjects with severe, eosinophilic asthma revealed that mepolizumab decreased exacerbation rates.From 81 multinational centers, 621 pa-tients were enrolled. Major inclusion criteria included: age 12 to 74 years, asthma diagnosis with objective measures, ≥2 asthma exacerbations requiring oral corticosteroids in the last year, refractory asthma as defined by the American Thoracic Society criteria, and signs of eosinophilic inflammation (sputum eosinophil count ≥3%, an exhaled nitric oxide concentration ≥50 ppb, peripheral blood eosinophil count ≥0.3 × 109/L, or prompt deterioration of asthma control with inhaled or oral steroid weaning). Smokers, present or former (≥10 pack-years), were excluded.Subjects were randomized to receive placebo or 1 of 3 doses of mepolizumab (75, 250, or 750 mg). Every 4 weeks for 13 cycles, patients received infusions. Asthma symptom scores, objective lung testing results, and blood eosinophil counts were collected at baseline and follow-up visits. The primary outcome of verified, clinically significant exacerbations during treatment and 4 weeks thereafter was defined a priori.All mepolizumab-treated groups demonstrated a significant decrease in clinically significant exacerbations (75 mg: –48% [P < .0001]; 250 mg: –39% [P = .005]; 750 mg: –52% [P < .0001]). Visits to emergency departments and admissions also decreased; however, no significant changes in spirometry or asthma control scores were noted. No treatment-associated deaths occurred, and other potential adverse events were equivocal in the placebo and treatment groups.Mepolizumab is generally safe and reduces exacerbation rates in select patients with asthma who have the severe, refractory, eosinophilic subtype.Using more clinically available inclusion criteria and a larger cohort, mepolizumab provides another tool in select patients with severe, eosinophilic asthma. The study supports the clinical importance of asthma phenotyping in effectively treating asthma subjects but provides no insight for efficacy in other asthma phenotypes. The equivalent responses from the 75- and 750-mg dose might improve the cost to benefit ratio of mepolizumab depending on the manufacturer’s pricing strategy. Despite seemly optimized design and execution, all results must be viewed through a scrutinizing lens because the manufacturer participated in all aspects ranging from design to writing.

Clinical characteristics of women with menstrual-linked asthma

Menstrual-linked asthma (MLA) is described in pre-menopausal women who experience a deterioration of asthma control peri-menstrually. The clinical characteristics of MLA remain incompletely defined. Our objective was to define the characteristics of MLA in a large female asthma cohort. Cross-sectional population survey. A comprehensive health questionnaire that included questions about MLA was administered to 1260 consecutive female asthma patients aged 12-55 years. Univariate and multivariate analyses were completed. The survey response rate was 43% (540/1260). The prevalence of self-reported MLA was 11% (60/540). Univariate: women with MLA compared to women without MLA had more urgent/emergent asthma-related healthcare visits/year, 6.18 (SD = ± 6.67) vs. 4.71 (SD = ± 5.91) (p=0.033), more emergency room visits, 1.50 (SD = ± 3.57) vs. 0.88 (SD = ± 2.27) (p=0.035), higher asthma-related absenteeism, 33/60 (57%) vs. 170/471 (37%) (p=0.003), and used almost twice the number of B(2)-agonist rescue doses/day, 1.13 (SD = ± 1.70) vs. 0.68 (SD = ± 1.32) (p=0.015). Multivariate: statistical significance was retained for absenteeism (p=0.016) and B(2)-agonist use (p=0.007) but lost for urgent healthcare visits (p=0.150) and emergency room visits (p=0.068). Self-reported MLA is common. Women with MLA in our population had a greater frequency of urgent healthcare visits, a higher rate of absenteeism, and used significantly more B(2)-agonist rescue than women without MLA. The association of increased health services use was not confirmed on multivariate analysis indicating that baseline characteristics associated with MLA in our population affected this outcome. MLA should be considered by healthcare providers when developing an asthma management plan.

小児気管支喘息長期管理におけるステップダウン時の呼気一酸化窒素による増悪の予測に関する検討

【目的】気道炎症の指標となる呼気一酸化窒素（FeNO）が，小児喘息の長期管理におけるステップダウン（SD）後の増悪予想に有用であるかを検討した． 【方法】定期通院中の喘息児のうち，臨床症状の安定後にSDした児43名（5～11歳）のSD前，SD時，SD後における小児喘息コントロールテスト（C-ACT），ピークフロー（PEF），FeNOを測定し，症状の変化との関係を解析した． 【結果】43名中12名でSD後に症状の増悪を認めた．C-ACT値と％PEFは，増悪群ならびに非増悪群においてSD前後での有意な変動を認めなかったが，FeNOは増悪群においてSD前の値に比してSD時に有意に上昇していた（変化率：増悪群81.4±107％ vs. 非増悪群-4.9±33％，p=0.015）． 【結語】臨床症状が安定している時であっても，FeNOが上昇傾向にある時にステップダウンすると，その後にコントロール状態が悪化する可能性が高いことが示唆された．

Management of severe acute asthma in the emergency department

Asthma is one of the most common chronic diseases in most developed countries and control may be elusive. Deterioration in asthma control is common when patients are exposed to airway irritants, viruses, and/or when adherence to chronic anti-inflammatory medications is suboptimal. Acute asthma exacerbations are common, important reasons for presentations to emergency departments, and severe cases may result in hospitalization. Important knowledge gaps exist in what is known and what care is delivered at the bedside. The literature in asthma is rapidly expanding and recent advances in the care are important to summarize. Systematic reviews, especially high-quality syntheses performed using Cochrane methods, provide the best evidence for busy clinicians to remain current. Management of asthma is based on early recognition of severe disease with aggressive therapy using multimodal interventions that focus on both bronchoconstriction and inflammatory mechanisms. Treatment of severe acute asthma can effectively and safely reduce hospitalizations, airway interventions, and even death. Using the approach outlined herein will enable clinicians to assist patients to rapidly regain asthma control, return to normal activities, and improve their quality of life in the follow-up period.

Rola zakażeń Chlamydia pneumoniae i Mycoplasma pneumoniae w przebiegu astmy

Respiratory infections are one of the major causes of asthma exacerbations. Among numerous pathogens that may lead to exacerbations, particular attention should be paid to atypical bacteria: Chlamydia pneumoniae and Mycoplasma pneumoniae. Despite significant frequency, infections caused by these species are underestimated due to untypical clinical course and lack of easily accessible diagnostic tests. Although acute infection can be easily linked with deterioration of asthma control, the role of respiratory colonisation by Chlamydia pneumoniae or Mycoplasma pneumoniae has not been precisely defined. It is known that serologic signs of both past infection and chronic current infection (IgA) with Chlamydia pneumoniae or Mycoplasma pneumoniae are found more often in asthmatics compared to healthy controls. Besides respiratory colonisation by Chlamydia pneumoniae or Mycoplasma pneumoniae confirmed by culture or molecular tests is also more common in asthmatics. This is particularly relevant in cases of uncontrolled asthma that followed symptoms of respiratory infection. This may lead to the conclusion that atypical infections can play a role in asthma induction in previously healthy individuals as well as deteriorations in the course of the disease. Studies mentioned above have led to the new therapeutic possibility—eradication of Chlamydia pneumoniae. In some of the studies on eradication with macrolides promising results have been gained in terms of asthma control, but in most of the cases improvement was only temporary.

What happens to patients who have their asthma device switched without their consent?

To identify asthma patients who have experienced a non-consented switch (NCS) of their inhaler device and to explore the circumstances and impact of these switches. Nineteen asthma patients who had experienced an NCS of their inhaler device were recruited to participate in qualitative, semistructured one-to-one interviews. All 19 participants reported a switch in their asthma inhaler without consultation or approval. There was deterioration in asthma control reported by some participants, many remained unchanged, and two reported better outcomes. Regardless of any change in asthma control, all patients expressed discontent with the NCS. Many felt it had damaged their relationship with their doctor, their confidence in their asthma medication, and their perception of control over their disease. These qualitative interviews highlight the need to maintain clear and open communication with patients. Switching of patients' inhalers without their consent may diminish the self-control associated with good asthma management, leave the doctor-patient relationship damaged, increase resource utilisation, and waste medication.

Exhaled nitric oxide as a marker of asthma control in smoking patients

Exhaled nitric oxide fraction (F(eNO)), which is a reliable marker of eosinophilic airway inflammation, is partially suppressed by tobacco smoking. Consequently, its potential as a biomarker in asthma management has never been evaluated in smoking patients. In the present study, the authors tested the validity of F(eNO) to predict asthma control in this population. F(eNO) and the Asthma Control Questionnaire (ACQ) were recorded at least once in 411 nonsmoking (345 with at least two visits) and 59 smoking (51 with at least two visits) asthma patients. Despite similar mean ACQ scores (1.5 versus 1.7), F(eNO) was reduced in smoking asthmatics (18.1 ppb versus 33.7 ppb). A decrease in F(eNO) of <20% precludes asthma control improvement in nonsmoking (negative predictive value (NPV) 78%) and in smoking patients (NPV 72%). An increase in F(eNO) <30% is unlikely to be associated with deterioration in asthma control in both groups of patients (NPV = 86% and 84% in nonsmoking and smoking patients, respectively). It is concluded that, even in smokers, sequential changes in F(eNO) have a relationship with asthma control. The present study is the first to indicate that cigarette smoking does not obviate the clinical value of measuring F(eNO) in asthma among smokers.

Asthma symptom re-emergence after omalizumab withdrawal correlates well with increasing IgE and decreasing pharmacokinetic concentrations

Physicians have questioned whether omalizumab can be discontinued or the dose reduced after clinical improvement is seen in patients with severe asthma. To examine the relationships among omalizumab, free IgE, and clinical outcomes in a randomized, placebo-controlled trial in patients with severe persistent allergic asthma following a posology based on pretreatment total IgE and body weight. A pharmacokinetic-pharmacodynamic binding model was used to calculate free IgE, omalizumab, and total IgE concentrations during the 28-week treatment and 16-week follow-up of the INvestigation of Omalizumab in seVere Asthma TrEatment (INNOVATE) study. These were plotted against the mean changes in the total asthma symptom score, morning peak expiratory flow, and rescue medication use for physician-defined treatment responders and nonresponders. The model accurately fitted omalizumab and free and total IgE, allowing reconstruction of the entire time course for each patient. Free IgE was rapidly suppressed below the 50 ng/mL (20.8 IU/mL) target, although there was a notable period before clinical measures stabilized. After treatment cessation, free IgE and omalizumab returned toward baseline and, after a delay, asthma symptoms re-emerged. Model-derived omalizumab and free IgE concentrations correlated well with changes in clinical outcomes, particularly in omalizumab-treated responders. Asthma symptoms exhibited different correlations during response onset compared with response offset (hysteresis), indicative of physiological time delays between changes in IgE levels and pulmonary function. Omalizumab and free IgE correlated well with clinical symptoms. Reducing omalizumab doses below those in the dosing table cannot be recommended; the resulting increase in free IgE would cause a deterioration in asthma control.

Predicting worsening asthma control following the common cold

The asthmatic response to the common cold is highly variable, and early characteristics that predict worsening of asthma control following a cold have not been identified. In this prospective multicentric cohort study of 413 adult subjects with asthma, the mini-Asthma Control Questionnaire (mini-ACQ) was used to quantify changes in asthma control and the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) to measure cold severity. Univariate and multivariable models were used to examine demographic, physiological, serological and cold-related characteristics for their relationship to changes in asthma control following a cold. Clinically significant worsening of asthma control was observed following a cold (mean+/-SD increase in mini-ACQ score of 0.69+/-0.93). Univariate analysis demonstrated that season, centre location, cold duration and cold severity measurements were all associated with a change in asthma control. Multivariable analysis of the covariates available within the first 2 days of cold onset revealed that the day 2 and cumulative sum of day 1 and 2 WURSS-21 scores were significant predictors of the subsequent changes in asthma control. In asthmatic subjects, cold severity within the first 2 days can be used to predict subsequent changes in asthma control. This information may help clinicians prevent deterioration in asthma control following a cold.

β‐Arrestins specifically constrain β2‐adrenergic receptor signaling and function in airway smooth muscle

Chronic use of inhaled beta-agonists by asthmatics is associated with a loss of bronchoprotective effect and deterioration of asthma control. Beta-agonist-promoted desensitization of airway smooth muscle beta-2-adrenergic receptors, mediated by G protein-coupled receptor kinases and arrestins, is presumed to underlie these effects, but such a mechanism has never been demonstrated. Using in vitro, ex vivo, and in vivo murine models, we demonstrate that beta-arrestin-2 gene ablation augments beta-agonist-mediated airway smooth muscle relaxation, while augmenting beta-agonist-stimulated cyclic adenosine monophosphate production. In cultures of human airway smooth muscle, small interfering RNA-mediated knockdown of arrestins also augments beta-agonist-stimulated cyclic adenosine monophosphate production. Interestingly, signaling and function mediated by m2/m3 muscarinic acetylcholine receptors or prostaglandin E(2) receptors were not affected by either beta-arrestin-2 knockout or arrestin knockdown. Thus, arrestins are selective regulators of beta-2-adrenergic receptor signaling and function in airway smooth muscle. These results and our previous findings, which demonstrate a role for arrestins in the development of allergic inflammation in the lung, identify arrestins as potentially important therapeutic targets for obstructive airway diseases.

Deterioration in Asthma Control When Subjects Receiving Fluticasone Propionate/Salmeterol 100/50 mcg Diskus are “Stepped-Down”

In this study, 647 subjects stable on fluticasone propionate/salmeterol Diskus 100/50 mcg BID (FSC) were randomized to continue FSC 100/50 mcg BID or “step down” to either fluticasone propionate (FP) 100mcg BID, salmeterol (SAL) 50 mcg BID, or montelukast (MON) 10 mg once daily for 16 weeks. Overall asthma control significantly improved in the FSC group; whereas, “stepping down” to FP, SAL, or MON resulted in deterioration in asthma control, as determined by decreased measures of lung function and clinical features. This study provides support that treatment of both inflammation and smooth muscle dysfunction may be necessary to achieve and maintain asthma control in patients uncontrolled on ICS.

Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids

Although inhaled corticosteroids (ICSs) are effective in preventing deterioration in asthma control, at least half of subjects with mild-to-moderate asthma will remain stable when these agents are discontinued. We sought to determine whether noninvasive markers of inflammation predict which individuals maintain asthma control after discontinuation of ICSs. We analyzed data obtained from 164 subjects with mild-to-moderate asthma who participated in a 16-week trial comparing the effects of continued ICS use with the effects of a switch to salmeterol or placebo. In comparison with continued ICS use, a switch to salmeterol or placebo was associated with increased rates of asthma deterioration over 16 weeks (9.3% vs 24.1% and 37.5%, respectively; P = .04 and P < .001, respectively). We found that neither exhaled nitric oxide nor methacholine PC 20 , when measured at randomization or 2 weeks after randomization, were significant predictors of subsequent asthma control in subjects who discontinued ICSs. However, both induced sputum eosinophil counts measured 2 weeks after a switch from ICS to placebo and changes in sputum eosinophil counts from before cessation of ICSs to after a switch to placebo predicted subsequent asthma deterioration (area under the receiver-operating characteristic curve, 0.771 [ P < .001] and 0.825 [ P < .001], respectively). On the basis of a model treatment strategy, we estimate that allocating subjects to ICS therapy on the basis of changes in sputum eosinophil counts after a trial discontinuation could allow 48% of subjects with mild-to-moderate asthma to discontinue ICS therapy without an increased risk of asthma deterioration over a period of at least 14 weeks.

A randomized, double-blind, double-dummy, parallel-group, multicenter, dose-reduction trial of the minimal effective doses of budesonide and fluticasone dry-powder inhalers in adults with mild to moderate asthma

Background: Inhaled corticosteroids are established first-line anti-inflammatory treatment for asthma. Clinical trials comparing inhaled corticosteroids must take into consideration that because of their excellent effect at low doses, they typically induce a near-maximal response in asthma patients. Objective: The aim of the present dose-response study was to estimate the minimal effective doses (MEDs) of budesonide and of fluticasone propionate via dry-powder inhaler in adults with mild to moderate asthma. Methods: This was a randomized, double-blind, double-dummy, parallel-group, multicenter, dose-reduction trial performed in adults to compare these 2 inhaled corticosteroids. After a 4- to 6-week run-in period with beclomethasone dipropionate 2000 pg/d, patients fulfilling defined criteria for asthma control were randomly allocated to treatment with budesonide or fluticasone, both administered BID at a total of 800 pg/d. At 5-week intervals, the dose was reduced to 400 and then 200 pg/d (200 and 100 pg BID) if asthma control was maintained according to further defined criteria. The MED was defined as the last dose level before deterioration of asthma control. Results: Subjects were 197 asthmatic patients with a mean age of 40.6 years in the budesonide group and 41.5 years in the fluticasone group. In both groups, baseline mean forced expiratory volume in 1 second (FEV 1) was 79.4% of the predicted normal volume and baseline mean FEV 1 reversibility was 22.3%. The median MED for both groups was 400 μg/d, with no detectable difference in dis-tributions. The budesonide-to-fluticasone ratio for the geometric mean MED was 123% (95% CI, 99–153 [not significant]). No statistically significant differences regarding lung function, symptom scores, or rescue medication usage were found between the treatment groups during the first treatment period. Adverse-event profiles were similar in both groups, and no unexpected adverse events were considered to be caused by the study drugs. Conclusion: This effect-controlled study did not detect a statistically significant difference between the MEDs for budesonide and fluticasone via dry-powder inhaler in adults with mild to moderate asthma.