Improvement In Airway Hyperresponsiveness Research Articles

Predictors of remitting, periodic, and persistent childhood asthma

The course of mild to moderate persistent asthma in children is not clearly established. To determine the rate and predictors for remitting, periodic, and persistent asthma in adolescence. The Childhood Asthma Management Program (CAMP) was a 4.3-year randomized, double-masked, multicenter trial in children with mild to moderate persistent asthma that compared continuous therapy with either budesonide or nedocromil, each to placebo, followed by a 4-year observational follow-up period. Asthma activity during the observation period included remitting (no asthma activity in the last year), persistent (asthma activity in every quarter), and periodic asthma (neither remitting nor persistent). Asthma was identified as remitting in 6%, periodic in 39%, and persistent in 55% of the 909 participants, with no effect noted from earlier anti-inflammatory treatment during the CAMP trial. Within all 3 asthma activity categories, improvements in airway hyperresponsiveness, eosinophilia, and asthma morbidity were observed over time. Features at entry into CAMP associated with remitting versus persistent asthma were lack of allergen sensitization and exposure to indoor allergens (odds ratio [OR], 3.23; P < .001), milder asthma (OR, 2.01; P = .03), older age (OR, 1.23; P = .01), less airway hyperresponsiveness (higher log methacholine FEV(1) PC(20) (OR, 1.39; P = .03), higher prebronchodilator FEV(1) percent predicted (OR, 1.05; P = .02), and lower forced vital capacity percent predicted (OR, 0.96; P = .04). Remission of asthma in adolescence is infrequent and not affected by 4 years of anti-inflammatory controller therapy. Factors such as sensitization and exposure, low lung function, and airway greater hyperresponsiveness decrease the likelihood of remitting asthma.

Repeated Bouts of Moderate-Intensity Aerobic Exercise Reduce Airway Reactivity in a Murine Asthma Model

We have reported that moderate-intensity aerobic exercise training attenuates airway inflammation in mice sensitized/challenged with ovalbumin (OVA). The current study determined the effects of repeated bouts of aerobic exercise at a moderate intensity on airway hyperresponsiveness (AHR) in these mice. Mice were sensitized/challenged with OVA or saline and exercised at a moderate intensity 3 times/week for 4 weeks. At protocol completion, mice were analyzed for changes in AHR via mechanical ventilation. Results show that exercise decreased total lung resistance 60% in OVA-treated mice as compared with controls; exercise also decreased airway smooth muscle (ASM) thickness. In contrast, exercise increased circulating epinephrine levels 3-fold in saline- and OVA-treated mice. Because epinephrine binds beta(2)-adrenergic receptors (AR), which facilitate bronchodilatation, the role of beta(2)-AR in exercise-mediated improvements in AHR was examined. Application of the beta(2)-AR antagonist butoxamine HCl blocked the effects of exercise on lung resistance in OVA-treated mice. In parallel, ASM cells were examined for changes in the protein expression of beta(2)-AR and G-protein receptor kinase-2 (GRK-2); GRK-2 promotes beta(2)-AR desensitization. Exercise had no effect on beta(2)-AR expression in ASM cells of OVA-treated mice; however, exercise decreased GRK-2 expression by 50% as compared with controls. Exercise also decreased prostaglandin E(2) (PGE(2)) production 5-fold, but had no effect on E prostanoid-1 (EP1) receptor expression within the lungs of OVA-treated mice; both PGE(2) and the EP1 receptor have been implicated in beta(2)-AR desensitization. Together, these data indicate that moderate-intensity aerobic exercise training attenuates AHR via a mechanism that involves beta(2)-AR.

Asthma control over 3 years in a real-life study

This was a 3-year "real-life" study, during which patients' medication was increased and decreased to achieve sustained asthma control. Patients (282) were randomised to receive treatment with SAL 50microg, FP 250microg, or SFC 50/250microg via a Diskustrade mark inhaler, bid. A 12-month double-blind period was followed by a 2-year open phase. The physician increased or decreased patients' medication to achieve and maintain asthma control at regular clinical assessments using criteria based on the asthma treatment guidelines. On completion 73% (168/229) of the subjects were receiving SFC to maintain control of their asthma, compared with 21% (49/229) receiving FP and 5% (12/229) receiving SAL. Odds ratio for requiring increased treatment were 2.66 (p=0.002) for patients initially randomised to FP and 9.38 (p<0.0001) SAL, compared with SFC. Time until 25% of patients first required an increase in study medication was 6months for patients initially treated with SAL compared to 12months for FP and 21months for SFC. Symptoms and use of rescue medication improved first, followed rapidly by PEF with the greatest improvements occurring over the first year. Airway hyperresponsiveness continued to improve throughout the study. The majority of patients achieved and maintained control of asthma over a 3-year period with physician-driven medication changes. Patients treated with SFC were more likely to achieve control than patients treated with FP or SAL alone. Continuing improvements in airway hyperresponsiveness indicate the importance of maintaining treatment after clinical control of symptoms and lung function are achieved.

Improvements in Airway Hyperresponsiveness and Inflammation in an Asthma Model via Upregulation of Anti-Oxidant Responses with 2-Cyano-3,12-Dioxooleana-1,9 (11)-Diene-28-Oic Acid Trifluoroethyl Amide (CDDO-TFEA)

Elevated levels of reactive oxygen species (ROS) induce cellular injury and promote airway inflammation and hyperresponsiveness (AHR) in animal models of asthma. CDDO-TFEA, a compound that upregulates transcriptional anti-oxidant response elements (ARE) through the Nrf2 pathway, may be useful in protecting against oxidative injury in asthma.

Changes in airway hyperresponsiveness following smoking cessation: Comparisons between Mch and AMP

Given the observed association between smoking, inflammation and airway hyperresponsiveness (AHR) one may predict that smoking cessation may improve AHR. However, only a few studies have investigated the effect of smoking on AHR and their results appear to be conflicting depending on the stimulus used in their bronchoprovocation protocol. The aim of the current study was to compare changes in AHR between direct (methacholine (Mch)) and indirect (adenosine 5'monophosphate (AMP)) stimuli before and at different time points after smoking cessation in smokers with allergic rhinitis (+/-asthma). We have prospectively studied changes in AHR to inhaled Mch and AMP in smokers with allergic rhinitis (+/-asthma), before and at 6 and 12 months after smoking cessation. It was found that 28% (16/57) of the participants had quit smoking by the end of the study. No significant change in AHR was observed in smoking cessation failures. A significant improvement in AHR to AMP but not Mch was observed 6 months after smoking cessation in quitters; a 1.2 doubling concentrations change in PC20 AMP was measured whereas only a 0.4 doubling concentrations change was observed for PC20 Mch. However, after 12 months smoking cessation the improvement in AHR became significant for both AMP and Mch, their dose-response curves being displaced to the right to a similar extent (1.4 and 1.1 doubling concentrations for AMP and Mch, respectively). Smoking cessation can improve AHR in smokers who quit with a 6 months improvement being reported for the airways response to AMP but not Mch. AMP challenge may detect earlier changes in AHR in smokers during smoking cessation.

Airway remodelling in asthma: models and supermodels?

Although currently anti-inflammatory treatments are effective for most of the 5 million patients treated in the UK they do not completely control symptoms, and a minority of asthmatics continue to experience severe debilitating disease [1]. Of note, although inhaled corticosteroids reduce the Th2type eosinophilic airway inflammation and airway hyperresponsiveness (AHR) that characterize asthma, they do not restore either variable to normal [2]. For this reason attention has been focused on structural changes in the asthmatic airway termed airway remodelling. These changes include epithelial damage and goblet cell hyperplasia [3], increased airway smooth muscle [4] and recruitment and activation of myofibroblasts [5]. Increased deposition of collagens and other extracellular matrix proteins such as tenascin and fibronectin occurs both in the reticular basement membrane (RBM) [6] and throughout the bronchial mucosa and this structural remodelling is accompanied by new blood vessel formation [7]. The clinical consequences of airway remodelling in asthma remain uncertain but contributions to AHR and fixed airflow obstruction have been suggested. Mathematical modelling predicts that airways with increased smooth muscle narrow to a much greater extent than airways with less smooth muscle volume for a given degree of circumferential smooth muscle shortening [8]. Asthmatic subjects show accelerated decline in lung function over time compared with non-asthmatic subjects, and this loss of lung function is more marked in asthmatic smokers [9, 10]. Although duration and severity of asthma are the most important risk factors for development of fixed obstruction the highest rate of loss of lung function is seen during the early course of the illness. Interestingly, remodelling changes are seen early in childhood and may even pre-date the onset of symptoms [11]. The impact of current anti-inflammatory treatment on remodelling is controversial. Although partial reversal of remodelling has been reported with inhaled corticosteroid treatment, responses are seen after prolonged therapy [12] and are not confirmed in all studies. The initial rapid improvement in AHR in asthma with inhaled corticosteroid treatment may be explained by reduction in airway inflammation [13], but additional improvements over many months may reflect changes in remodelling. Important questions about airway remodelling in asthma remain unanswered (see Fig. 1). These include:

High dose versus low dose inhaled corticosteroid as initial starting dose for asthma in adults and children.

Inhaled corticosteroids (ICS) form the basis of maintenance therapy in asthma and their efficacy is well established. However, the optimal starting dose of ICS is not clearly established. Recent reviews demonstrate a relatively flat efficacy curve for ICS and increasing side effects with increasing ICS doses. High doses are frequently prescribed and there are now reports of significant side effects occurring with high dose ICS use. These issues demonstrate the need to establish the optimal starting dose of ICS in asthma. To establish the optimal starting dose of ICS by evaluating the efficacy of initial high dose ICS with low dose ICS in subjects with asthma, not currently on ICS. We searched the Cochrane Airways Group trials register and reference lists of articles. Date of last search: January 2003 Randomised controlled trials of two different doses of the same ICS in adults and children with asthma with no concomitant ICS or OCS. Trial quality was assessed and data were extracted independently by two reviewers. Study authors were contacted for confirmation. Trials were analysed according to the following ICS dose comparisons: step down vs constant dose ICS (n=7); high vs moderate (n=11); high vs low (n=9); moderate vs low (n=11); fold change in dose (all studies). 31 papers reporting the results of 26 trials were included in the review. For studies that compared a step down approach to a constant moderate/low ICS dose, there were no significant differences in lung function, symptoms, rescue medications or asthma control between the two treatment approaches. Significant but clinically small improvements in percent predicted FEV(1) ( WMD 5.32, 95% CI 0.65 to 9.99) and non significant improvements in the change in morning PEF were found for high dose ICS compared to moderate dose ICS. There were no significant differences in efficacy between high and low dose ICS. For moderate dose ICS, compared to low dose ICS, there were significant improvements in the change in morning PEF l/min from baseline (WMD 11.14, 95% CI 1.34 to 20.93) and nocturnal symptoms (SMD -0.29, 95% CI -0.53 to -0.06 ). Commencing ICS at double or quadruple a base moderate or low dose had no greater effect than commencing with the base dose. Several studies reported greater improvement in airway hyperresponsiveness for high dose ICS. For patients with asthma who require ICS, commencing with a moderate dose ICS is equivalent to commencing with a high dose ICS and down-titrating. The small significant benefits of commencing with a high ICS dose are not of sufficient clinical benefit to warrant its use when compared to moderate or low dose ICS. Initial moderate ICS dose appears to be more effective than initial low ICS dose. High dose ICS may be more effective than moderate or low dose ICS for airway hyperresponsiveness. There is no benefit in doubling or quadrupling ICS in subjects with stable asthma.

What should we tell allergic families about pets?

What should we tell allergic families about pets?

Avoidance of allergens and air pollutants in respiratory allergy

Avoidance of allergens and air pollutants in respiratory allergy

Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response

Interleukin-12 (IL-12) is a macrophage-derived cytokine that modulates T lymphocyte responses and has the capacity to suppress allergic and eosinophilic inflammation. We carried out a double-blind, randomised, parallel group clinical study, in which patients with mild allergic asthma were given subcutaneous recombinant human IL-12 at increasing weekly injections of 0.1, 0.25, 0.5 microg/kg (n=19), or placebo (n=20). We compared responses to inhaled allergen challenge 24 h before the first injection and 24 h after the final injection. Airways hyper-responsiveness and concentrations of peripheral blood eosinophils and sputum eosinophils were also assessed. IL-12 caused a significant decrease from baseline in the main peripheral blood eosinophil count 24 h after the fourth injection compared with placebo (p=0.0001). Sputum eosinophils were also significantly decreased 24 h after allergen challenge when treated with IL-12 compared with placebo (p=0.024). IL-12 caused a non-significant trend towards improvement in airway hyper-responsiveness to histamine, but had no significant effect on the late asthmatic reaction after inhaled allergen challenge. After administration of IL-12, four of 19 patients withdrew prematurely; two with cardiac arrhythmias, one with abnormal liver function, and a single patient with severe flu-like symptoms. We have shown that IL-12 lowers numbers of blood and sputum eosinophils, but without any significant effects on airway hyper-responsiveness or the late asthmatic reaction. This questions the role of eosinophils in mediating these reactions, and has important implications for development of new anti-inflammatory treatments.

Airway hyperresponsiveness, inflammation, and subepithelial collagen deposition in recently diagnosed versus long-standing mild asthma. Influence of inhaled corticosteroids.

This study aimed at documenting airway inflammation and subepithelial collagen deposition in patients using only inhaled beta(2)-agonists with either recently diagnosed asthma (RDA: </= 2 yr, n = 16) or long-standing asthma (LSA: >/= 13 yr, n = 16) and at the influence of an intense inhaled corticosteroid (ICS) treatment on these parameters, in relation to changes in airway responsiveness. Patients had a methacholine inhalation test and a bronchoscopy with bronchial biopsies before and after an 8-wk treatment with inhaled fluticasone propionate (FP), 1,000 microgram/day. Baseline FEV(1) (mean +/- SEM) was normal and similar in both groups (RDA: 98.1 +/- 2.7, LSA: 94.5 +/- 4.6%). Geometric mean methacholine PC(20) was lower in LSA than in RDA (0.44 versus 3.37 mg/ml) at baseline and improved similarly by 1.85 and 1.86 double concentrations with FP treatment. PC(20) normalized (>/= 16 mg/ml) in five patients with RDA and two patients with LSA. Baseline mean bronchial cell counts (per mm(2) connective tissue surface) for CD3(+), CD4(+), CD8(+), CD25(+), EG1(+), CD45ro(+), and AA1(+) cells were similar in both groups. With FP, EG1(+) (p < 0.001), EG2(+) (p = 0.018), and AA1(+) counts (p = 0.009) decreased significantly in both groups while CD45ro(+) (p = 0.02) counts decreased only in LSA. Baseline type 1 and type 3 collagen deposition underneath the basement membrane was similar in RDA and LSA and did not change significantly after FP. This study shows that recent compared to long-standing mild asthma is associated with a similar degree of airway inflammation and subepithelial fibrosis, and a similar improvement in airway hyperresponsiveness after 8 wk on high-dose ICS. It also indicates that once asthma becomes symptomatic, airway responsiveness cannot normalize in most subjects over such a time period, even with a high dose of ICS.

Clinical effects of air cleaners in homes of asthmatic children sensitized to pet allergens

Background: Exposure to cat and dog allergens is very common in the Western World and is a serious cause of asthma in sensitized subjects. Objective: We sought to study the clinical effects of air cleaners in living rooms and bedrooms of asthmatic children sensitized to cat or dog allergens. Methods: Twenty asthmatic children sensitized to pet allergens (cat/dog) and with an animal at home participated in a double-blind, placebo-controlled, cross-over study in which the effects of air cleaners placed in the living room and bedroom for 3 months were compared with the effects of sham air cleaners. Before and after each study period, lung function, airway hyperresponsiveness (adenosine monophosphate), and peak flow variation were recorded. Cat and dog allergen levels were assessed in the filters of the air cleaners. Results: After a 3-month intervention with active air cleaners, airway hyperresponsiveness decreased significantly, showing a 1.2 doubling dose increase of PC 20 adenosine ( P = .003). Peak flow amplitude also decreased ( P = .045). Substantial amounts of airborne cat and dog allergen were captured by the air cleaners in living rooms and bedrooms as well. Allergen levels in floor dust were not changed. Conclusion: In young asthmatic patients sensitized and exposed to pets in the home, application of air cleaners in living rooms and bedrooms was accompanied by a significant improvement in airway hyperresponsiveness and a decrease in peak flow amplitude. (J Allergy Clin Immunol 1999;104:447-51.)

Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma

BACKGROUNDAirway hyperresponsiveness, induced sputum eosinophils, and exhaled nitric oxide (NO) levels have all been proposed as non-invasive markers for monitoring airway inflammation in patients with asthma. The aim of this...

Prognostic factors for toluene diisocyanate‐induced occupational asthma after removal from exposure

The outcome of isocyanate-induced occupational asthma remains to be further defined. There have been few studies on the role of specific antibodies in prognosis of toluene diisocyanate (TDI) induced occupational asthma. Moreover, to the best of our knowledge, there have been no studies on the improvement pattern of airway hyperresponsiveness (AH). We analysed the prognostic factors that affected the outcome of 35 toluene diisocyanate-induced occupational asthma. To define clinical and laboratory parameters predicting favourable prognosis for TDI-induced occupational asthma. After confirmation of bronchial sensitivity by TDI bronchoprovocation test (BPT), 35 patients were recommended to avoid exposure to TDI; they were also given anti-asthmatic medications including inhaled steroids and monitored for 2 years. Seventeen (49%) recovered completely with disappearance of airway hyperresponsiveness (AH) to methacholine during the follow-up period (mean duration: 12 months, range of 3-30 months). Eleven (31%) showed a significant improvement in AH for first year, which improvement stabilized in the next year with mild symptoms. Seven (20%) patients did not show any evidence of improvement in AH and had persistent symptoms. Favourable prognosis was associated with a short duration of asthmatic symptoms before diagnosis (P < 0.05), immediate cessation of exposure after diagnosis (P < 0.05), milder degree of AH at diagnosis (P < 0.05), and the presence of specific IgE antibodies to TDI-human serum albumin conjugate (0.05 < P < 0.1). No association was found with atopic and smoking status, age, exposure duration, or length of latent period (P > 0.05). These data suggest that early detection of TDI-induced asthma and immediate cessation of exposure are important factors for a favourable prognosis.

Effect of Long-term Treatment with an Inhaled Corticosteroid (Budesonide) on Airway Hyperresponsiveness and Clinical Asthma in Nonsteroid-dependent Asthmatics

Several short-term studies have shown that inhaled steroids can reduce airway hyper-responsiveness in asthma. To evaluate whether prolonged treatment can bring about full recovery, this double-blind, randomized, controlled trial examined the effect of budesonide, 400 micrograms daily for 1 yr, on airway hyperresponsiveness. The time course and characteristics of improvements and associated changes in clinical asthma severity were also evaluated. Thirty-two stable adult asthmatics, requiring bronchodilators alone, were selected. Before and monthly throughout the study, airway responsiveness to methacholine was measured and clinical asthma severity assessed by questionnaire, daily bronchodilator use, and number of asthma exacerbations. Patients receiving budesonide showed a fourfold mean improvement in airway responsiveness compared with those receiving placebo (p less than 0.0005), whose responsiveness remained very stable. Fifteen of the 16 budesonide subjects improved and 5 returned to the normal range. Largest improvements occurred during the first 3 months but, in some, were still progressing slowly at 1 yr. Improvements in responsiveness were accompanied by significant improvements in asthma symptoms, bronchodilator use, and number of asthma exacerbations. The results show that regular, prolonged use of inhaled steroid can produce marked improvements in airway hyperresponsiveness, sometimes with full resolution, and these improvements are accompanied by clinically significant improvements in clinical asthma.

Outpatient Management of Bronchial Asthma

The current approach to asthma treatment centers around the recognition that asthma is primarily an inflammatory condition; airway hyperresponsiveness and bronchospasm are secondary phenomena. Anti-inflammatory treatments that produce sustained improvement in airway hyperresponsiveness (environmental control, cromolyn, inhaled and ingested corticosteroids) are the mainstay of treatment to keep symptoms and bronchodilator use to a minimum. Adequate control of chronic asthma with clearly defined treatment goals, accompanied by early recognition and patient-initiated treatment of worsened asthma, generally with inhaled/ingested corticosteroid, can successfully reduce the high morbidity and the low, but significant, mortality from this common condition.