Asthma Deterioration Research Articles

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Methods A 2–3-week run-in period with twice daily (BID) MF100μg, MF-200μg, or MF-400μg was performed before subject (≥12y) randomization to BID: MF/F-100/10μg, MF100μg, F-10μg, or placebo for 26weeks (n=746); MF/F-200/ 10mg, MF-200μg, F-10μg, or placebo for 26weeks (n=781); MF/F-200/10μg, MF/F-400/10μg, or MF-400μg for 12weeks (n=728 ). Assessment of asthma deterioration (ie, 20% decrease in forced expiratory volume in 1s [FEV1]; 30% decrease in peak expiratory flow [PEF] on ≥2 consecutive days; or clinically judged deterioration [ie, emergency treatment, hospitalization, or treatment with excluded medications]) was a co-primary endpoint for studies, and a secondary endpoint for study. Post hoc pair-wise comparisons of pooled MF/F vs MF, F, and placebo treatment groups were performed.

Mometasone furoate/formoterol reduces asthma deteriorations and improves lung function

This study evaluated the effect of mometasone furoate (MF)/formoterol (F) versus its monocomponents, each administered via metered-dose inhaler, on asthma deteriorations and lung function. This 26-week, multicentre, double-blind, placebo-controlled study included subjects aged ≥12 yrs with not well-controlled asthma on low-dose inhaled corticosteroids. After a 2-3-week open-label run-in (MF 100 μg b.i.d.), 746 subjects were randomised to receive placebo, F 10 μg, MF 100 μg or MF/F 100/10 μg b.i.d. Co-primary end-points were time to first asthma deterioration (MF/F versus F to assess effect of MF) and change in forced expiratory volume in 1 s (FEV(1)) area under the curve of serial spirometry measurements over the 12-h period following the morning dose (AUC(0-12h)) (baseline to week 12; MF/F versus MF to assess effect of F). The therapeutic effect of MF in the combination was demonstrated by a reduction in asthma deterioration incidence with MF/F versus F and a delayed time to first asthma deterioration (p<0.001). Asthma deterioration incidence was also reduced with MF/F versus MF (p=0.006). The therapeutic effect of F in the combination was demonstrated by MF/F versus MF in FEV(1) AUC(0-12h) change (4.00 versus 2.53 L·h, respectively; p=0.001). MF/F treatment also resulted in a marked improvement in health-related quality of life. MF/F 100/10 μg b.i.d. treatment showed greater clinical efficacy than its individual components or placebo; both components contributed to the efficacy of MF/F.

Reduction in Asthma Deteriorations in Subjects With Persistent Asthma Uncontrolled on Low-, Medium-, or High-Dose Inhaled Corticosteroids: A Pooled Analysis From Three Clinical Trials Using Combined Mometasone Furoate/Formoterol

Methods A 2–3-week run-in period with twice daily (BID) MF100μg, MF-200μg, or MF-400μg was performed before subject (≥12y) randomization to BID: MF/F-100/10μg, MF100μg, F-10μg, or placebo for 26weeks (n=746); MF/F-200/ 10mg, MF-200μg, F-10μg, or placebo for 26weeks (n=781); MF/F-200/10μg, MF/F-400/10μg, or MF-400μg for 12weeks (n=728 ). Assessment of asthma deterioration (ie, 20% decrease in forced expiratory volume in 1s [FEV1]; 30% decrease in peak expiratory flow [PEF] on ≥2 consecutive days; or clinically judged deterioration [ie, emergency treatment, hospitalization, or treatment with excluded medications]) was a co-primary endpoint for studies, and a secondary endpoint for study. Post hoc pair-wise comparisons of pooled MF/F vs MF, F, and placebo treatment groups were performed.

Persistence of rhinovirus RNA and IP‐10 gene expression after acute asthma

ABSTRACT Background and objective: Viral nucleic acid may be detected for up to 6 months after an acute asthma deterioration, but the pattern and consequences of viral persistence after acute asthma are incompletely understood. This study investigates the frequency of viral persistence after acute asthma, assesses viral infectivity and determines the host inflammatory responses to viral persistence. Methods: Adults and children presenting to hospital with acute asthma and a confirmed respiratory virus infection were studied acutely and at recovery 4–6 weeks later by clinical evaluation and induced sputum for viral and inflammatory mediator detection. Results: Viral RNA was detected during both acute asthma and recovery visits in 17 subjects (viral persistence), whereas in 22 subjects viral RNA had cleared by recovery (viral clearance). The following viruses were detected at recovery: human rhinovirus: 16; respiratory syncytial virus: 2; influenza: 2. In subjects with viral persistence, eight isolates were different to the virus detected at Visit 1. Forty‐four per cent of the human rhinovirus isolates were infective at recovery. Asthma and infection severity were similar in the viral clearance and viral persistence groups. Viral persistence was associated with elevated IL‐10 mRNA and inducible protein‐10 gene expression. Conclusions: Respiratory viral detection after acute asthma is common, and most often persistence is with non‐infective human rhinovirus. There is a host inflammatory response with an altered cytokine environment, and the viral RNA can be source of persistent infection. These effects may have longer‐term consequences in asthma.

Efficacy and safety of medium and high doses of mometasone furoate/formoterol (MF/F) combination treatment in subjects with severe persistent asthma

Background Multiple strengths of mometasone furoate/formoterol (MF/F) MDI combination therapy are under investigation as new treatments for asthma. We report efficacy/ safety findings from a 3-month MF/F study in subjects with severe asthma. Materials and methods This was a 3-month, randomized, double-blind, parallelgroup, multicenter study with a 2-3-week open-label, run-in period of mometasone furoate (MF) 400 μg twice-daily (BID). Subjects (≥12 years) were randomized to MF/F (200/10 μg or 400/10 μg BID) or MF (400 μg BID). The primary endpoint was the area under the curve (AUC) of the change in serial FEV1 (0-12 hours) for MF/F 400/10 μg vs MF 400 μg from baseline to Week 12. Adverse events (AEs) and other clinical safety measures were recorded. Results A total of 728 subjects (mean: age = 47.9 y, asthma duration = 14.0 y, FEV1 % predicted = 66.3, reversibility = 22.9%, Asthma Control Questionnaire [ACQ] score = 1.93) were randomized. Improvements in mean changes from baseline in FEV1 AUC0-12 h (L ×h ) at Week 12 were MF/F 200/10 μg = 3.59, MF/F 400/10 μg = 4.19, and MF 400 μg = 2.04, with both MF/F doses significantly better than MF (p < 0.001). These FEV1s correspond to average hourly increases of 0.30, 0.35, and 0.17 L, respectively. MF/F was associated with rapid (<5 min) and sustained improvement in lung function. The percentage of subjects experiencing asthma deterioration (ie, severe asthma exacerbation) was 12.4% (MF/F 200/10 μg), 12.2% (MF/F 400/10 μg), and 18.3% (MF 400 μg). There were no notable differences in AEs between the groups. Conclusions Both medium- and high-dose MF/F combination therapy led to significantly greater improvements in lung function compared with high-dose MF monotherapy in severe asthmatics.

S157 Prevalence of asthma related to employment in the UK

<h3></h3> It is widely held that 10–15% of adult asthma is causally related to occupation. It is likely that this fraction varies importantly depending on historical and international variations in employment. Further uncertainties arise from misclassification in the diagnosis of asthma and in exposure assessment, particularly if based on self-report. We carried out a postal survey of adults listed as asthmatic through general practices across the UK. Cases, who were defined as those who had experienced onset of asthma or worsening of pre-existing childhood asthma within 2 years of starting a new job, were compared to controls who declared an equivalent onset or deterioration more than 2 years from the start of a job. Of 8535 individuals targeted, 3115 (37%) returned a completed questionnaire. Almost 40% of these (n=1198) experienced a deterioration of pre-existing childhood asthma or onset of adult asthma whilst working; 441 were cases and 757 controls. A priori analysis of risk was performed using an asthma-specific JEM, the ECRHS asthma ‘high risk occupations’ and data from the UK SWORD surveillance scheme. Odds ratios (adjusted for sex, smoking and era of onset and stratified by onset type)—displayed in Abstract S157 Table 1—did not suggest an increased risk of asthma within 2 years of starting a high-risk job. A posteriori analysis of all occupations demonstrated an increased risk of asthma within 2 years of starting a new job in sales and elementary occupations. The calculated population attributable risk (PAR) for these occupations was 15.9% and was higher in women than men. The results from this study suggest that a priori assessment of risk does not identify occupation as a significant cause of asthma in this contemporary adult workforce in the UK. Jobs which do appear to increase risk of new asthma are not those typically associated with an excess risk of the disease. These findings highlight the disparity between epidemiological and clinical assessments of asthma related to occupation, and the need to consider novel occupations as a cause of asthma.

Efficacy and safety of combined medium-dose mometasone furoate/formoterol (MF/F) in persistent asthmatics

Background The availability of controller therapies at multiple strengths is important to treat different severities of asthma (NHLBI and GINA guidelines). The clinical effect of medium-dose mometasone furoate/formoterol (MF/F) combination administered via single inhaler had never been characterized in asthmatic subjects versus placebo. We investigated the effect of medium-dose MF/F administered via an MDI on asthma deteriorations (ie, severe asthma exacerbations) and pulmonary function in moderately-severe asthmatics inadequatelycontrolled on medium-dose inhaled corticosteroids (ICS) ± long-acting b2-agonists (LABA). Materials and methods After 2-3-weeks open-label run-in with MF 200μ gB ID, subjects (≥12 years) were randomized to 26-weeks treatment BID with MF/F 200/10μg, MF 200μg, F 10μg, or placebo. Coprimary endpoints were time-to-first asthma deterioration over the treatment period (MF/F vs F), and the area under the curve (AUC) of the change in serial FEV1 [0-12 hr] to Week 12 (MF/F vs MF). Results 781 subjects (mean: age=42.4 y, asthma duration=16.07 y, FEV1 % predicted=72.62%, reversibility=18.80%, ACQ score=1.51) were randomized. MF/F increased the timeto-first asthma deterioration and decreased the proportion of subjects who experienced asthma deteriorations (MF/F=30.4%; MF=33.9% [p=0.565]; F=54.0% [p<0.001]; placebo=55.6% [p<0.001]) .M F/F treatment improved lung function more than MF within 5 minutes following administration (p<0.001); mean Week-12 FEV1AUC0-12h (L x h over baseline): MF/F=3.11, MF=1.30, F=1.93, and placebo=0.57 (effect was maintained throughout the treatment period). Adverse events were rare and similar across treatment groups. Conclusions MF/F 200/10μg was more effective in reducing asthma deteriorations and improving lung function in asthmatics uncontrolled on medium-dose ICS±LABA than placebo, MF or F.

Twenty-six-week efficacy and safety study of mometasone furoate/formoterol 200/10 μg combination treatment in patients with persistent asthma previously receiving medium-dose inhaled corticosteroids

Asthma is a heterogeneous condition characterized by reduced lung function, chronic inflammation, and periodic asthma deteriorations. This study was performed to evaluate the effect of mometasone furoate (MF)/formoterol (F) combination, 200/10 microg, administered twice daily (b.i.d.) on asthma deteriorations and pulmonary function in patients with asthma uncontrolled on medium-dose inhaled corticosteroid (ICS). After 2- to 3-week open-label run-in with MF 200 microg b.i.d., patients (>or=12 years) were randomized to 26 weeks of treatment with MF/F 200/10 microg, MF 200 microg, F 10 microg, or placebo b.i.d. Coprimary end points were time to first asthma deterioration (MF/F versus F) and bronchodilation, assessed by the area under the curve of the change in forced expiratory volume in 1 second 0-12 hours (FEV(1) AUC(0-12h); MF/F versus MF). A total of 781 patients were randomized. Treatment with MF/F 200/10 microg reduced asthma deteriorations and clinically judged deteriorations (i.e., deterioration resulting in emergency treatment, hospitalization, or treatment with additional excluded asthma medication [i.e., systemic corticosteroids]). The proportion of patients experiencing asthma deteriorations was MF/F, 30.4%; MF, 33.9%; F, 54.0%; placebo, 55.6% (p < 0.001, MF/F versus F and placebo). There was a sixfold reduction in clinically judged deteriorations with MF/F versus F and placebo (p < 0.001). Lung function improved more rapidly with MF/F than MF and placebo. Mean change from baseline FEV(1) AUC(0-12h) at week 12 was MF/F, 11.7% versus MF, 5.7%; F, 8.5%; and placebo, 3.9% (p < 0.001). Treatment-related AEs were rare and similar across groups. Treatment with MF/F 200/10 microg was effective in reducing the risk of asthma deteriorations. MF/F was safe and provided rapid and sustained bronchodilation in patients with asthma.

Salbutamol Modulates the Balance of Th1 and Th2 Cytokines by Mononuclear Cells from Allergic Asthmatics

Background: There is evidence that excessive use of inhalational β₂-agonists induces the deterioration of asthma. Although the exact mechanism of this remains to be elucidated, overuse of β₂-agonists may impair the Th1/Th2 balance in asthmatic airways. The aim of the present study was to evaluate whether salbutamol, a representative inhalational β₂-agonist, modifies the production of Th1- and Th2-type cytokines by mononuclear cells separated from patients with asthma and healthy volunteers. Methods: Peripheral blood mononuclear cells (PBMCs) obtained from 8 healthy volunteers and 10 patients with mild persistent asthma allergic to house dust mites were treated with either salbutamol or medium alone. PBMCs were then stimulated with either medium alone, house dust mite (Dermatophagoides farina, Df) allergen or a combination of ionomycin plus phorbol 12-myristate 13-acetate ester (PMA). Concentrations of IFN-γ, IL-13, TNF-α and RANTES in the cell supernatants were measured using ELISA. Results: In PBMCs from healthy volunteers, salbutamol did not modify IFN-γ production, but increased the spontaneous production of IL-13. In contrast, salbutamol significantly inhibited the spontaneous and ionomycin- plus PMA-stimulated production of IFN-γ by PBMCs from asthmatics. Salbutamol significantly enhanced both spontaneous and Df-induced production of IL-13 by PBMCs from asthmatics. Salbutamol did not modify the production of TNF-α. Finally, salbutamol enhanced the production of RANTES induced by Df allergen in asthmatics. Conclusions: Salbutamol inhibits IFN-γ and enhances IL-13 production by PBMCs from asthmatics. These effects would promote a Th1/Th2 imbalance in the airways and may therefore contribute to the deterioration of asthma.

Efficacy and Safety of Combined Medium-Dose Mometasone Furoate/Formoterol (MF/F) in Persistent Asthmatics

Background The availability of controller therapies at multiple strengths is important to treat different severities of asthma (NHLBI and GINA guidelines). The clinical effect of medium-dose mometasone furoate/formoterol (MF/F) combination administered via single inhaler had never been characterized in asthmatic subjects versus placebo. We investigated the effect of medium-dose MF/F administered via an MDI on asthma deteriorations (ie, severe asthma exacerbations) and pulmonary function in moderately-severe asthmatics inadequatelycontrolled on medium-dose inhaled corticosteroids (ICS) ± long-acting b2-agonists (LABA). Materials and methods After 2-3-weeks open-label run-in with MF 200μ gB ID, subjects (≥12 years) were randomized to 26-weeks treatment BID with MF/F 200/10μg, MF 200μg, F 10μg, or placebo. Coprimary endpoints were time-to-first asthma deterioration over the treatment period (MF/F vs F), and the area under the curve (AUC) of the change in serial FEV1 [0-12 hr] to Week 12 (MF/F vs MF). Results 781 subjects (mean: age=42.4 y, asthma duration=16.07 y, FEV1 % predicted=72.62%, reversibility=18.80%, ACQ score=1.51) were randomized. MF/F increased the timeto-first asthma deterioration and decreased the proportion of subjects who experienced asthma deteriorations (MF/F=30.4%; MF=33.9% [p=0.565]; F=54.0% [p<0.001]; placebo=55.6% [p<0.001]) .M F/F treatment improved lung function more than MF within 5 minutes following administration (p<0.001); mean Week-12 FEV1AUC0-12h (L x h over baseline): MF/F=3.11, MF=1.30, F=1.93, and placebo=0.57 (effect was maintained throughout the treatment period). Adverse events were rare and similar across treatment groups. Conclusions MF/F 200/10μg was more effective in reducing asthma deteriorations and improving lung function in asthmatics uncontrolled on medium-dose ICS±LABA than placebo, MF or F.

Airway Epithelial Changes in Smokers but Not in Ex-Smokers with Asthma

Smoking has detrimental effects on asthma outcome, such as increased cough, wheezing, sputum production, and frequency of asthma attacks. This results in accelerated lung function decline. The underlying pathological process of smoke-induced deterioration of asthma is unknown. To compare bronchial inflammation and remodeling in never-smokers, ex-smokers, and current smokers with asthma. A total of 147 patients with asthma (66 never-smokers, 46 ex-smokers, and 35 current smokers) were investigated. Lung function, exhaled nitric oxide levels, and symptom questionnaires were assessed, and induced sputum and bronchial biopsies were obtained for determination of airway inflammation and remodeling. Smokers with asthma had lower FEV(1) and alveolar and bronchial nitric oxide levels than never-smokers. Smokers also had more goblet cells and mucus-positive epithelium, increased epithelial thickness, and a higher proliferation rate of intact and basal epithelium than ex-smokers and never-smokers. Smokers had higher numbers of mast cells and lower numbers of eosinophils than never-smokers. Ex-smokers had similar goblet cell numbers and mucus-positive epithelium, epithelial thickness, epithelial proliferation rate, and mast cell numbers as never-smokers. Smokers with asthma have epithelial changes that are associated with increased asthma symptoms, such as shortness of breath and phlegm production. The fact that epithelial characteristics in ex-smokers are similar to those in never-smokers suggests that the smoke-induced changes can be reversed by smoking cessation.

Increased vascular permeability precedes cellular inflammation as asthma control deteriorates

Airway microcirculation is abnormal in asthma but the role of vascular changes in asthma deteriorations remains poorly defined. We prospectively assessed the vascular changes accompanying worsening of asthma control by using an inhaled corticosteroid (ICS) dose-reduction model. To evaluate airway vascularity, vascular permeability and expression of vascular endothelial growth factor (VEGF) in early asthma deterioration induced by ICS back-titration. Twenty mild-to-moderate persistent symptomatic asthmatics on low-to-moderate ICS were recruited and treated with 4 weeks of high-dose fluticasone propionate (1000 microg/day) to achieve symptom control. This was followed by dose reduction to half of the pre-study doses for 4-8 weeks until the symptoms began to return. Endobronchial biopsy and bronchoalveolar lavage (BAL) samples were obtained after both treatment periods. Vascularity as measured by the number and size of blood vessels, as well as VEGF expression did not change following ICS reduction. Even on high-dose ICS, perivascular albumin staining and BAL microalbumin levels in asthmatic subjects, as markers of permeability, were elevated when compared with normal subjects and both further increased significantly after ICS reduction. There was a significant association between changes in vascular leakiness and clinical deterioration. Increases in airway albumin correlated with previously reported increases in airway wall infiltration with T lymphocytes. Our results suggest that airway vascular leakage is a major pathophysiologic feature of early asthma deterioration, occurring before recrudescence of cellular inflammation.

Chronic intranasal administration of Aspergillus fumigatus spores leads to aggravation of airway inflammation and remodelling in asthmatic rats

Epidemiological evidence indicates a close link between exposure to fungi and deterioration of asthma. However, the role of fungi as an exogenous precipitant for initiation and progression of asthma has been incompletely explored. In this study, the effects of Aspergillus fumigatus exposure on airway inflammation and remodelling in a rat model of chronic asthma were investigated. The rat model of chronic asthma was established by systemic sensitization and repeated challenge with ovalbumin (OVA). The asthmatic rats were exposed to chronic intranasal inhalation of A. fumigatus spores. Changes in airway inflammation, remodelling and BHR were measured after exposure to the fungus. Chronic inhalation of A. fumigatus spores elevated the production of T helper 2 (Th2) cytokines, increased the concentration of total serum IgE, and resulted in the recruitment of eosinophils and lymphocyte infiltration into the airways of asthmatic rats. Goblet cell hyperplasia, mucus hyperproduction and subepithelial collagen deposition were also induced by inhalation of the fungus. The remodelling changes induced by inhalation of the fungus paralleled the changes in BHR in this rat model of asthma. Chronic exposure to A. fumigatus aggravated Th2 airway inflammation, promoted airway remodelling and increased BHR in OVA-sensitized and -challenged rats.

Effect of formoterol with or without budesonide in repeated low-dose allergen challenge

The use of combination therapy in mild asthma is debated. The current authors evaluated the effects of formoterol alone and a formoterol/budesonide combination inhaler on asthma deterioration induced by repeated low-dose allergen exposure. In total, 15 subjects with intermittent allergic asthma inhaled low doses of allergen on seven consecutive weekdays in a three-period, crossover, double-blind, double-dummy comparison between formoterol 4.5 microg Turbuhaler, budesonide 160 microg/formoterol 4.5 microg Turbuhaler and placebo, each taken as two puffs 30 min after allergen dosing. The outcome variables were: provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second (PD(20)), exhaled nitric oxide fraction (F(eNO)), sputum eosinophils and prostaglandin D(2), and diary card recordings of symptoms (on a scale of 0-10), short-acting beta(2)-agonist use and evening forced expiratory volume in one second (FEV(1)). With placebo treatment, allergen exposure caused significant increases in airway hyperresponsiveness (geometric mean (coefficient of variation) PD(20): 397 (98) microg before versus 168 (82) microg after), F(eNO) (mean+/-sd 46+/-31 ppb before versus 73+/-46 ppb after) and asthma symptom score (mean+/-sd 0.39+/-0.55 before versus 0.68+/-0.67 after). Budesonide/formoterol abolished these changes and significantly improved baseline FEV(1). Formoterol alone, while providing symptom relief, was no better than placebo in protecting against the allergen-induced increase in airway inflammation. Signs of deteriorating asthma, provoked by low-dose allergen, are prevented by short-term use of budesonide/formoterol but not by temporary use of formoterol alone.

Budesonide/formoterol for maintenance and reliever therapy: new quality in asthma management

Asthma is a chronic inflammatory disease of the airways with variable symptoms and airway obstruction. The strategy of asthma management aims to prevent and relieve acute attacks and achieve long-term control of symptoms. Symbicort® is a fixed combination of the corticosteroid budesonide and the long-acting β2-agonist formoterol – the first component treats inflammation, the second provides rapid and long-term smooth muscle relaxation. These two components make budesonide/formoterol suitable for both maintenance and reliever asthma therapy (Symbicort SMART®). There is increasing evidence from clinical trials that such a regimen is an effective and safe treatment option. The patient taking budesonide/formoterol for symptom relief simultaneously increases the dose of inhaled corticosteroids. Therefore, the pharmacological intervention provides an earlier step up in controller therapy, just prior to asthma deterioration, and thus prevents exacerbations. Such a regimen better reflects the nature of asthma and...

Exhaled nitric oxide and asthma control: a longitudinal study in unselected patients

Controlled studies have shown that monitoring of the exhaled nitric oxide fraction (F(eNO)) improves asthma management. However, the studies seldom consider the full range of patients seen in clinical practise. In the present study, the ability of F(eNO) to reflect asthma control over time is investigated in a regular clinical setting, and meaningful F(eNO) cut-off points and changes are identified. Answers to the Asthma Control Questionnaire and F(eNO) were recorded at least once in 341 unselected asthma patients. The whole population and subgroups were considered, i.e. both inhaled corticosteroid (ICS)-naïve and low or high-to-medium (</= or >500 mug beclomethasone dipropionate equivalents.day(-1)) ICS-dose groups. An F(eNO) decrease <40% or increase <30% precludes asthma control optimisation or deterioration, respectively (negative predictive value 79 and 82%, respectively). In the present study's low-dose group, a decrease >40% indicated asthma control optimisation (positive predictive value (PPV) 83%). In ICS-naïve patients, F(eNO) >35 ppb predicted asthma control improvement in response to ICS (PPV 68%). In most cases, forced expiratory volume in one second assessments were not useful. In conclusion, in a given patient, exhaled nitric oxide fraction was found to be significantly related to asthma control over time. The overall ability of exhaled nitric oxide fraction to reflect asthma control was reduced in patients using high doses of inhaled corticosteroids. Forced expiratory volume in one second had little additional value in assessing asthma control.

Airway cell and cytokine changes in early asthma deterioration after inhaled corticosteroid reduction

Back-titration of inhaled corticosteroid (ICS) dose in well-controlled asthma patients is emphasized in clinical guidelines, but there are few published data on the airway cell and cytokine changes in relation to ICS reduction. In our study, 20 mild-to-moderate persistent (inspite of low-moderate dose ICS treatment) asthmatic subjects prospectively rendered largely asymptomatic by high-dose ICS were assessed again by clinical, physiological, and airway inflammatory indices after 4-8 weeks of reduced ICS treatment. We aimed at assessing the underlying pathological changes in relation to clinical deterioration. Patients recorded daily symptom scores and peak expiratory flows (PEF). Spirometry and airways hyperreactivity (AHR) were measured and bronchoscopy was performed with assessment of airway biopsies (mast cells, eosinophils, neutrophils, and T lymphocytes), bronchoalveolar lavage (BAL) IL-5 and eotaxin levels and cellular profiles at the end of high-dose ICS therapy and again after ICS dose reduction. Baseline data were compared with symptomatic steroid-free asthmatics (n=42) and non-asthmatic controls (n=28). After ICS reduction, subjects experienced a variable but overall significant increase in symptoms and reductions in PEF and forced expiratory volume in 1 s. There were no corresponding changes in AHR or airways eosinophilia. The most relevant pathogenic changes were increased CD4(+)/CD8(+) T cell ratio, and decreased sICAM-1 and CD18 macrophage staining (potentially indicating ligand binding). However, there was no relationship between the spectrum of clinical deterioration and the changes in cellular profiles or BAL cytokines. These data suggest that clinical markers remain the most sensitive measures of early deterioration in asthma during back-titration of ICS, occurring at a time when AHR and conventional indices of asthmatic airway inflammation appear unchanged. These findings have major relevance to management and to how back-titration of ICS therapy is monitored.

Effects of Medical Treatments on an Improvement of Asthma in the Early Stages of Life

Effective pediatric asthma care is believed to help prevent the development and exacerbation of asthma. The aim of this study was to evaluate the method of intervention by identifying asthma management in a large population. We designed a special questionnaire to evaluate the method of asthma management, which contributes to asthma deterioration in the early stage of life. Questions regarding asthma management were based on care techniques and the medications used. We retrospectively enrolled 547 of 1,495 children (3-years old) who had for a periodic medical checkup organized by Gunma Prefecture from December 2004 to November 2005 who had been diagnosed to have asthma by physicians and/or the American Thoracic Society-Division of Lung Diseases, National Heart Lung, and Blood Institute (ATS-DLD) questionnaire. The children with sufficiently improved asthma totalled 376 (68.7%), while 171 (31.3%) did not have sufficiently improved asthma. Children with asthma who were treated in hospitals improved more freq...

Association of Obesity With Pulmonary and Nonpulmonary Complications of Pregnancy in Asthmatic Women

To evaluate whether maternal obesity is associated with pulmonary and nonpulmonary pregnancy complications in asthmatic women. This is a secondary analysis of the prospective cohort Asthma During Pregnancy Study. Asthma patients were classified as having either mild or moderate to severe disease at the beginning of the study. Rates of pulmonary complications of asthma in asthmatic women and rates of nonpulmonary complications of pregnancy among asthma patients and controls, were compared between obese (body mass index > or = 30 kg/m2) and nonobese women. Maternal body mass index and pregnancy outcome data were available for 1,699 of 1,812 asthmatic women and for 867 of 881 controls. Of the asthma subjects, 30.7% (521) were obese compared with 25.5% of the controls, P = .006. Obese women, regardless of whether they had asthma, were more likely to undergo cesarean delivery (OR 1.6, 95% confidence interval [CI]1.3-2.0) to develop preeclampsia or gestational hypertension (OR 1.7 95% CI 1.3-2.3) and gestational diabetes (OR 4.2, 95% CI 2.8-6.3). There were no differences in the rates of overall asthma improvement (20.6% compared with 23.6%, P = .36) or deterioration (33.3% compared with 28.8%, P = .20) between obese and nonobese asthma patients. After adjustment for confounding variables, obesity, not asthma, was associated with nonpulmonary complications of pregnancy, and obesity was associated with an increase in asthma exacerbations as well (OR 1.3, 95% CI 1.1-1.7). Obesity is associated with an increased risk of asthma exacerbations during pregnancy. The increased rate of nonpulmonary complications of pregnancy in asthma patients is associated with obesity in this population and not with asthma status. II-1.

Concluding Remarks: Can We Explain the Association of β -Agonists With Asthma Mortality?: A Hypothesis

Beta-agonists have clearly demonstrated benefits for the treatment of both acute and chronic asthma. Therefore, it is perhaps surprising that many of the articles in this issue have focused on concerns about their safety. Much of this concern can be traced back to the "beta-agonist controversy"--the association of high-dose isoprenaline and fenoterol inhalers with asthma mortality in the 1960s and 1970s. Although a causal link was never proven, lingering doubts about the safety of beta-agonists remain. It is unclear whether a similar adverse effect is responsible for recently reported association of long-acting beta-agonists with asthma deaths. No mechanism for the beta-agonist controversy was established, but the evidence presented in this collection of articles points to a number of contributing factors. I suggest that a combination of these effects provides a plausible mechanism for the association of frequent beta-agonist use with asthma mortality. Rebound bronchoconstriction and bronchial hyperresponsiveness occur on withdrawal of regular beta-agonist treatment. Regular use of fenoterol is associated with a reduction in morning peak flow suggesting that the overnight interval between doses is sufficient to allow rebound bronchoconstriction. This has not been observed with terbutaline or salbutamol, although rebound phenomena do occur when these drugs are withdrawn for slightly longer periods. Regular use of beta-agonists also leads to tolerance to their bronchoprotective and bronchodilator effects. Tolerance becomes more apparent with worsening bronchoconstriction. In severe asthma, this could result in a poor response to emergency treatment. The combination of rebound deterioration of asthma and a poor response to beta-agonist treatment resulting from tolerance could explain the increased mortality associated with fenoterol and isoprenaline. Both effects are probably caused by downregulation of beta-receptors which occurs with all beta-agonists. Long-acing beta-agonists cause a similar degree of tolerance to short-acting beta-agonists, but avoid the problem of overnight withdrawal. Long-acting beta-agonists have also been shown to improve asthma control when taken in combination with inhaled corticosteroids. The clinical significance of tolerance in this context remains to be determined.