Ex-vivo mucolytic and anti-inflammatory activity of BromAc in tracheal aspirates from COVID-19.

COVID-19 is a lethal disease caused by the pandemic SARS-CoV-2, which continues to be a public health threat. COVID-19 is principally a respiratory disease and is often associated with sputum retention and cytokine storm, for which there are limited therapeutic options. In this regard, we evaluated the use of BromAc®, a combination of Bromelain and Acetylcysteine (NAC). Both drugs present mucolytic effect and have been studied to treat COVID-19. Therefore, we sought to examine the mucolytic and anti-inflammatory effect of BromAc® in tracheal aspirate samples from critically ill COVID-19 patients requiring mechanical ventilation. METHOD: Tracheal aspirate samples from COVID-19 patients were collected following next of kin consent and mucolysis, rheometry and cytokine analysis using Luminex kit was performed. RESULTS: BromAc® displayed a robust mucolytic effect in a dose dependent manner on COVID-19 sputum ex vivo. BromAc® showed anti-inflammatory activity, reducing the action of cytokine storm, chemokines including MIP-1alpha, CXCL8, MIP-1b, MCP-1 and IP-10, and regulatory cytokines IL-5, IL-10, IL-13 IL-1Ra and total reduction for IL-9 compared to NAC alone and control. BromAc® acted on IL-6, demonstrating a reduction in G-CSF and VEGF-D at concentrations of 125 and 250 µg. CONCLUSION: These results indicate robust mucolytic and anti-inflammatory effect of BromAc® ex vivo in tracheal aspirates from critically ill COVID-19 patients, indicating its potential to be further assessed as pharmacological treatment for COVID-19.

Effects of Anti-T2 Biologic Treatment on Lung Ventilation Evaluated by MRI in Adults With Prednisone-Dependent Asthma.

BACKGROUND: The functional consequence of airway obstruction in asthma can be regionally measured using inhaled gas MRI. Ventilation defects visualized by MRI persist post-bronchodilator in patients with severe asthma with uncontrolled sputum eosinophilia and may be due to eosinophil-driven airway pathology that is responsive to "anti-T2" therapy. RESEARCH QUESTION: Do anti-T2 therapies that clear eosinophils from the airway lumen decrease ventilation defects, measured by inhaled gas MRI, in adults with prednisone-dependent asthma? STUDY DESIGN AND METHODS: Inhaled hyperpolarized gas MRI was performed before and after bronchodilation in 10 prednisone-dependent patients with asthma with uncontrolled eosinophilic bronchitis (sputum eosinophils ≥3%) at baseline and 558 (100-995) days later when their eosinophilic bronchitis had been controlled (sputum eosinophils <3%) by additional anti-T2 therapy. The effect of anti-T2 therapy on ventilation defects, quantified as the MRI ventilation-defect-percent (VDP), was evaluated before and after bronchodilation for all patients and compared between patients dichotomized based on the median percentage of sputum eosinophils at baseline (15.8%). RESULTS: MRI VDP was improved pre- (ΔVDP+anti-T2: -3% ± 4%, P = .02) and post-bronchodilator (ΔVDP+anti-T2: -3% ± 4%; P = .04) after additional anti-T2 therapy that controlled eosinophilic bronchitis (n = 2 mepolizumab, n = 2 reslizumab, n = 3 benralizumab, n = 1 dupilumab, n = 2 increased daily prednisone). A greater post-bronchodilator ΔVDP+anti-T2 was observed in those patients with median or higher percentage of sputum eosinophils at baseline (≥15.8%; P = .01). In 7 of 10 patients with asthma, residual ventilation defects persisted despite bronchodilator and anti-T2 therapy. INTERPRETATION: Controlling sputum eosinophilia with anti-T2 therapies improves ventilation defects, measured by inhaled gas MRI, in adults with prednisone-dependent asthma.

Xiaoqinglong decoction (a traditional Chinese medicine) combined conventional treatment for acute exacerbation of chronic obstructive pulmonary disease: A systematic review and meta-analysis.

BACKGROUND: A traditional Chinese medicine classic herbal formula named Xiaoqinglong decoction (XQLD) is widely used in China for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The efficacy and safety of XQLD for AECOPD was evaluated in this systematic review. METHODS: Five databases, including the Cochrane Library, PubMed, China National Knowledge Infrastructure, Wanfang database, and Chinese Science and Technology Periodical Database were searched up to October 5, 2018 for randomized control trials in treating AECOPD with XQLD. RESULT: Thirty-eight trials were identified. Compared with conventional therapy (CT), XQLD plus CT significantly improve the total clinical efficacy rate (Risk Ratio [RR] = 1.22, 95% confidence interval [CI] = 1.18-1.26, P < .00001). Forced expiratory volume in the first second (FEV1) (mean difference [MD] = 0.37, 95% CI = 0.27-0.46; P < .00001), FEV1%pre (MD = 4.52, 95% CI = 2.42-6.62; P < .00001), FEV1/forced vital capacity (MD = 5.11, 95% CI = 4.21-6.00; P < .00001), PaO2 (MD = 7.17, 95% CI = 4.80-9.54; P < .00001); lowered cough symptom score (MD = -0.65; 95% CI = -0.70 to -0.59; P < .00001), sputum symptom score (MD = -0.41; 95% CI = -0.45 to -0.37; P < .00001), wheezing symptom score (MD = -0.49; 95% CI = -0.60 to -0.38; P < .00001); reduce cough relief time (MD = -1.28; 95% CI = -1.53 to -1.02; P < .00001), sputum relief time (MD = -1.19; 95% CI = -1.42 to -0.96; P < .00001), wheezing relief time (MD = -1.65; 95% CI = -2.63 to -0.68; P = .0009), lassitude relief time (MD = -2.16; 95% CI = -3.44 to -0.89; P = .0009), and PaCO2 (MD = -7.63, 95% CI = -9.62 to -5.63; P < .00001). Benefit for interleukin (IL)-4 (MD = -9.20, 95% CI = -13.59 to -4.81; P < .00001), IL-6 (MD = -5.07, 95% CI = -8.14 to -2.01; P = .001), IL-8 (MD = -5.59, 95% CI = -6.09 to -5.08; P < .00001), tumor necrosis factor (TNF)-α (MD = -5.93, 95% CI = -6.97 to -4.89; P < .00001), Interferon (INF)-γ (MD = 18.03, 95% CI = 13.22-22.84; P < .00001), and C-reactive protein (MD = -3.93, 95% CI = -5.97 to -1.89; P = .0002). For adverse events, there were no difference between XILD plus CT and CT. CONCLUSION: XQLD plus CT was more effective than CT alone for treating chronic obstructive pulmonary disease. Further higher quality trials are needed. The safety of XQLD remained uncertain.

Diagnostic value of fractional exhaled nitric oxide for asthma-chronic obstructive pulmonary disease overlap syndrome.

To examine the difference in the fractional exhaled nitric oxide (FeNO) between chronic obstructive pulmonary disease (COPD) patients with asthma-COPD overlap syndrome (ACOS) and patients with Non-ACOS COPD (Non-ACOS) and to investigate the correlation between FeNO levels and the differential cell counts of eosinophils in induced sputum, in order to explore the diagnostic value of FeNO in ACOS.A prospective, case-control study was performed on 53 cases of ACOS group and 53 cases of Non-ACOS group in the Respiratory Medicine Outpatient of Zhangzhou Municipal TCM Hospital, Affiliated to Fujian University of Traditional Chinese Medicine. The FeNO levels and induced sputum cell counts were determined and the correlation between FeNO levels and eosinophile percentage was analyzed by Pearson linear correlation analysis.The FeNO levels in patients with ACOS (37[24.5-53.0]) ppb were significantly higher than those of patients with Non-ACOS (20 [15.5-24.5] ppb) (P < .01). Also, the percentage of eosinophils in induced sputum in the ACOS group (5.70 [1.50-17.62]%) were significantly higher than those of the Non-ACOS group (0.50 [0.00-1.00]%) (P < .01). FeNO in both groups correlated positively with the percentage of eosinophils in induced sputum (P < .01), with a correlation coefficient r of 0.521. The area under the receiver operating curve of FeNO for the diagnosis of ACOS phenotype was 0.815 (P < .01), the sensitivity and specificity reach highest when the cut off value was 25.50 ppb.The FeNO in patients from the ACOS group were significantly higher than those in Non-ACOS group and were moderately correlated with the percentage of eosinophils in induced sputum. The results indicated that FeNO may be used as a diagnostic index for ACOS, in addition to the induced sputum.

Vitamin D3 supplementation in adults with bronchiectasis: A pilot study.

Vitamin D supplementation prevents acute respiratory infections and, through modulating innate and adaptive immunity, could have a potential role in bronchiectasis management. The primary aims of this pilot study were to assess serum 25-hydroxyvitamin D (25(OH)D) levels in New Zealand adults with bronchiectasis, and their 25(OH)D levels after vitamin D3 supplementation. Adults with bronchiectasis received an initial 2.5 mg vitamin D3 oral loading dose and 0.625 mg vitamin D3 weekly for 24 weeks. The primary outcome was serum 25(OH)D levels before and after vitamin D3 supplementation. Secondary outcomes (time to first infective exacerbation, exacerbation frequency, spirometry, health-related quality of life measures, sputum bacteriology and cell counts and chronic rhinosinusitis) were also assessed. This study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12612001222831). The initial, average 25(OH)D level was 71 nmol/L (95% confidence interval (CI): [58, 84]), rising to 218 nmol/L (95% CI: [199, 237]) at 12 weeks and 205 nmol/L (95% CI: [186, 224]) at 24 weeks. The initial serum cathelicidin level was 25 nmol/L (95% CI: [17, 33]), rising to 102 nmol/L (95% CI: [48, 156]) at 12 weeks and 151 nmol/L (95% CI: [97, 205]) at 24 weeks. Over the 24-week study period, we observed statistically significant changes of 1.11 (95% CI: [0.08, 2.14]) in the Leicester Cough Questionnaire and -1.97 (95% CI: [-3.71, -0.23]) in the Dartmouth COOP charts score. No significant adverse effects were recorded. Many New Zealand adults with bronchiectasis have adequate 25(OH)D levels. Weekly vitamin D3 supplementation significantly improved 25(OH)D levels.

Biomarkers and asthma management: analysis and potential applications.

PURPOSE OF REVIEW: Asthma features a high degree of heterogeneity in both pathophysiology and therapeutic response, resulting in many asthma patients being treated inadequately. Biomarkers indicative of underlying pathological processes could be used to identify disease subtypes, determine prognosis and to predict or monitor treatment response. However, the newly identified as well as more established biomarkers have different applications and limitations. RECENT FINDINGS: Conventional markers for type 2-high asthma, such as blood eosinophils, fraction of exhaled nitric oxide, serum IgE and periostin, feature limited sensitivity and specificity despite their significant correlations. More distinctive models have been developed by combining biomarkers and/or using omics techniques. Recently, a model with a positive predictive value of 100% for identification of type 2-high asthma based on a combination of minimally invasive biomarkers was developed. SUMMARY: Individualisation of asthma treatment regimens on the basis of biomarkers is necessary to improve asthma control. However, the suboptimal properties of currently available conventional biomarkers limit its clinical utility. Newly identified biomarkers and models based on combinations and/or omics analysis must be validated and standardised before they can be routinely applied in clinical practice. The development of robust biomarkers will allow development of more efficacious precision medicine-based treatment approaches for asthma.

A randomized, controlled, crossover study in patients with mild and moderate asthma undergoing treatment with traditional Chinese acupuncture.

OBJECTIVES: This study sought to verify the effects of acupuncture as an adjuvant treatment for the control of asthma. METHODS: This was a randomized, controlled, crossover trial conducted at the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. A total of 74 patients with mild/moderate, persistent asthma were randomized into two therapeutic groups: Group A - 31 patients underwent 10 real weekly acupuncture sessions, followed by a 3-week washout period and 10 sham weekly acupuncture sessions; and Group B - 43 patients underwent 10 sham weekly acupuncture sessions, followed by a 3-week washout period and 10 real weekly acupuncture sessions. Patients used short- and long-acting ß-2 agonists and inhaled corticosteroids when necessary. Prior to treatment and after each period of 10 treatment sessions, the patients were evaluated for spirometry, induced sputum cell count, exhaled nitric oxide (NO) and with the Short Form 36 (SF-36) and Questionnaire on Quality of Life-Asthma (QQLA) questionnaires. Daily peak flow and symptom diaries were registered. The level of significance adopted was 5% (α=0.05). RESULTS: In Group B, after real acupuncture, there was a decrease in eosinophils (p=0.035) and neutrophils (p=0.047), an increase in macrophages (p=0.001) and an improvement in peak flow (p=0.01). After sham acupuncture treatment, patients experienced less coughing (p=0.037), wheezing (p=0.013) and dyspnea (p=0.014); similarly, after real acupuncture, patients reported less coughing (p=0.040), wheezing (p=0.012), dyspnea (p<0.001) and nocturnal awakening episodes (p=0.009). In Group A, there was less use of rescue medication (p=0.043). After the sham procedure, patients in Group A experienced less coughing (p=0.007), wheezing (p=0.037), dyspnea (p<0.001) and use of rescue medication (p<0.001) and after real acupuncture, these patients showed improvements in functional capacity (p=0.004), physical aspects (p=0.002), general health status (p<0.001) and vitality (p=0.019). Sham acupuncture also led to significant differences in symptoms, but these were not different from those seen with real acupuncture. Spirometry and exhaled NO levels did not show a difference between sham and real acupuncture treatment. In addition, no significant difference was demonstrated between treatments regarding the quality of life evaluation. CONCLUSION: Real and sham acupuncture have different effects and outcomes on asthma control. The crossover approach was not effective in this study because both interventions led to improvement of asthma symptoms, quality of life and inflammatory cell counts. Thus, sham acupuncture cannot serve as a placebo in trials with acupuncture as the main intervention for asthma.

A randomized, controlled, crossover study in patients with mild and moderate asthma undergoing treatment with traditional Chinese acupuncture

OBJECTIVES:This study sought to verify the effects of acupuncture as an adjuvant treatment for the control of asthma.METHODS:This was a randomized, controlled, crossover trial conducted at the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. A total of 74 patients with mild/moderate, persistent asthma were randomized into two therapeutic groups: Group A - 31 patients underwent 10 real weekly acupuncture sessions, followed by a 3-week washout period and 10 sham weekly acupuncture sessions; and Group B - 43 patients underwent 10 sham weekly acupuncture sessions, followed by a 3-week washout period and 10 real weekly acupuncture sessions. Patients used short- and long-acting β-2 agonists and inhaled corticosteroids when necessary. Prior to treatment and after each period of 10 treatment sessions, the patients were evaluated for spirometry, induced sputum cell count, exhaled nitric oxide (NO) and with the Short Form 36 (SF-36) and Questionnaire on Quality of Life-Asthma (QQLA) questionnaires. Daily peak flow and symptom diaries were registered. The level of significance adopted was 5% (α=0.05).RESULTS:In Group B, after real acupuncture, there was a decrease in eosinophils (p=0.035) and neutrophils (p=0.047), an increase in macrophages (p=0.001) and an improvement in peak flow (p=0.01). After sham acupuncture treatment, patients experienced less coughing (p=0.037), wheezing (p=0.013) and dyspnea (p=0.014); similarly, after real acupuncture, patients reported less coughing (p=0.040), wheezing (p=0.012), dyspnea (p<0.001) and nocturnal awakening episodes (p=0.009). In Group A, there was less use of rescue medication (p=0.043). After the sham procedure, patients in Group A experienced less coughing (p=0.007), wheezing (p=0.037), dyspnea (p<0.001) and use of rescue medication (p<0.001) and after real acupuncture, these patients showed improvements in functional capacity (p=0.004), physical aspects (p=0.002), general health status (p<0.001) and vitality (p=0.019). Sham acupuncture also led to significant differences in symptoms, but these were not different from those seen with real acupuncture. Spirometry and exhaled NO levels did not show a difference between sham and real acupuncture treatment. In addition, no significant difference was demonstrated between treatments regarding the quality of life evaluation.CONCLUSION:Real and sham acupuncture have different effects and outcomes on asthma control. The crossover approach was not effective in this study because both interventions led to improvement of asthma symptoms, quality of life and inflammatory cell counts. Thus, sham acupuncture cannot serve as a placebo in trials with acupuncture as the main intervention for asthma.

Vitamin D reduces eosinophilic airway inflammation in nonatopic asthma.

BACKGROUND: Low levels of vitamin D are associated with asthma severity, airway remodeling, and exacerbation rate increase, especially in nonatopic asthma. Reduced steroid responsiveness or impaired antimicrobial defense might be underlying mechanisms. OBJECTIVE: We sought to evaluate the effect of vitamin D supplementation on eosinophilic and neutrophilic airway inflammation in patients with nonatopic asthma. METHODS: In a double-blind, randomized, placebo-controlled trial, we investigated the effect of long-acting vitamin D3 (400,000 IU) on sputum neutrophils and eosinophils in 44 patients with nonatopic asthma with neutrophilic (≥53%) and/or eosinophilic (≥3%) airway inflammation. Sputum induction was performed at baseline and after 9 weeks. Other measurements included questionnaires, blood samples, and pulmonary function. RESULTS: Treatment with vitamin D did not significantly affect sputum neutrophils or eosinophils compared with treatment with placebo in the total group. Regarding sputum eosinophils, the effect of vitamin D appeared to be dependent on baseline sputum eosinophil levels (interaction P = .015). In patients with eosinophil levels of 26.2% or more (median in patients with sputum eosinophilia, >3%), eosinophils decreased from a median of 41.0% to 11.8% after vitamin D treatment as compared with an increase from 51.8% to 63.3% in patients receiving placebo (P = .034). Vitamin D treatment also resulted in slightly better Asthma Control Questionnaire scores (P = .08). CONCLUSIONS: Vitamin D supplementation reduced eosinophilic airway inflammation in patients with nonatopic asthma with severe eosinophilic airway inflammation, but did not affect sputum neutrophils. Also, a small effect on asthma control was observed. These findings suggest that vitamin D might have potential as an add-on treatment option in eosinophilic asthma.

The effect of omega-3 fatty acids on bronchial hyperresponsiveness, sputum eosinophilia, and mast cell mediators in asthma.

BACKGROUND: Omega-3 fatty acid supplements have been reported to inhibit exercise-induced bronchoconstriction (EIB). It has not been determined whether omega-3 supplements inhibit airway sensitivity to inhaled mannitol, a test for bronchial hyperresponsiveness (BHR) and model for EIB in people with mild to moderate asthma. METHODS: In a double-blind, crossover trial, subjects with asthma who had BHR to inhaled mannitol (n = 23; 14 men; mean age, 28 years; one-half taking regular inhaled corticosteroids) were randomized to omega-3 supplements (4.0 g/d eicosapentaenoic acid and 2.0 g/d docosahexaenoic acid) or matching placebo for 3 weeks separated by a 3-week washout. The primary outcome was the provoking dose of mannitol (mg) to cause a 15% fall in FEV1 (PD15). Secondary outcomes were sputum eosinophil count, spirometry, Asthma Control Questionnaire (ACQ) score, serum triacylglyceride level, and lipid mediator profile in urine and serum. RESULTS: PD15 (geometric mean, 95% CI) to mannitol following supplementation with omega-3s (78 mg, 51-119 mg) was not different from placebo (88 mg, 56-139 mg, P = .5). There were no changes in sputum eosinophils (mean ± SD) in a subgroup of 11 subjects (omega-3, 8.4% ± 8.2%; placebo, 7.8% ± 11.8%; P = .9). At the end of each treatment period, there were no differences in FEV1 % predicted (omega-3, 85% ± 13%; placebo, 84% ± 11%; P = .9) or ACQ score (omega-3, 1.1% ± 0.5%; placebo, 1.1% ± 0.5%; P = .9) (n = 23). Omega-3s caused significant lowering of blood triglyceride levels and expected shifts in serum fatty acids and eicosanoid metabolites, confirming adherence to the supplements; however, no changes were observed in urinary mast cell mediators. CONCLUSIONS: Three weeks of omega-3 supplements does not improve BHR to mannitol, decrease sputum eosinophil counts, or inhibit urinary excretion of mast cell mediators in people with mild to moderate asthma, indicating that dietary omega-3 supplementation is not useful in the short-term treatment of asthma. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00526357; URL: www.clinicaltrials.gov.

Novel biomarkers for asthma stratification and personalized therapy.

A stepwise pharmacological treatment is currently recommended for all asthma patients and is personalized mainly on disease severity, aiming for the lowest disease-controlling step. Nevertheless, asthma comprises several related pathologies with similar clinical manifestations resulting from distinct underlying mechanisms. Therefore novel biomarkers could lead to asthma stratification and thus improve upon the current stepwise approach. The aim of this review is to update the reader with regard to different assays proposed in the recent asthma literature for measuring potential biomarkers for patient stratification and treatment personalization. Promising biomarkers are sputum eosinophils, serum periostin and exhaled nitric oxide. Periostin could differentiate between Th2-high and Th2-low asthma (Th2-high patients are more responsive to glucocorticoids) and the less-defined asthma types which often present a therapeutic challenge. Several other biomarkers, mainly cytokines, leukotrienes and exhaled air components, can be quantified in body fluids and exhaled breath and could also be useful for asthma stratification.

Effects of ex vivo γ-tocopherol on airway macrophage function in healthy and mild allergic asthmatics.

Elevated inflammation and altered immune responses are features found in atopic asthmatic airways. Recent studies indicate γ-tocopherol (GT) supplementation can suppress airway inflammation in allergic asthma. We studied the effects of in vitro GT supplementation on receptor-mediated phagocytosis and expression of cell surface molecules associated with innate and adaptive immunity on sputum-derived macrophages. Cells from nonsmoking healthy (n = 6) and mild house dust mite-sensitive allergic asthmatics (n = 6) were treated ex vivo with GT (300 µM) or saline (control). Phagocytosis of opsonized zymosan A bioparticles (Saccharomyces cerevisiae) and expression of surface molecules associated with innate and adaptive immunity were assessed using flow cytometry. GT caused significantly decreased (p < 0.05) internalization of attached zymosan bioparticles and decreased (p < 0.05) macrophage expression of CD206, CD36 and CD86 in allergic asthmatics but not in controls. Overall, GT caused downregulation of both innate and adaptive immune response elements, and atopic status appears to be an important factor.

Vitamin E, γ-tocopherol, reduces airway neutrophil recruitment after inhaled endotoxin challenge in rats and in healthy volunteers.

Epidemiologic studies suggest that dietary vitamin E is an important candidate intervention for asthma. Our group has shown that daily consumption of vitamin E (γ-tocopherol, γT) has anti-inflammatory actions in both rodent and human phase I studies. The objective of this study was to test whether γT supplementation could mitigate a model of neutrophilic airway inflammation in rats and in healthy human volunteers. F344/N rats were randomized to oral gavage with γT versus placebo, followed by intranasal LPS (20µg) challenge. Bronchoalveolar lavage fluid and lung histology were used to assess airway neutrophil recruitment. In a phase IIa clinical study, 13 nonasthmatic subjects completed a double-blinded, placebo-controlled crossover study in which they consumed either a γT-enriched capsule or a sunflower oil placebo capsule. After 7 days of daily supplementation, they underwent an inhaled LPS challenge. Induced sputum was assessed for neutrophils 6 h after inhaled LPS. The effect of γT compared to placebo on airway neutrophils post-LPS was compared using a repeated-measures analysis of variance. In rats, oral γT supplementation significantly reduced tissue infiltration (p<0.05) and accumulation of airway neutrophils (p<0.05) that are elicited by intranasal LPS challenge compared to control rats. In human volunteers, γT treatment significantly decreased induced sputum neutrophils (p=0.03) compared to placebo. Oral supplementation with γT reduced airway neutrophil recruitment in both rat and human models of inhaled LPS challenge. These results suggest that γT is a potential therapeutic candidate for prevention or treatment of neutrophilic airway inflammation in diseased populations.

Breathing exercises for asthma: a randomised controlled trial.

BACKGROUND: The effect of breathing modification techniques on asthma symptoms and objective disease control is uncertain. METHODS: A prospective, parallel group, single-blind, randomised controlled trial comparing breathing training with asthma education (to control for non-specific effects of clinician attention) was performed. Subjects with asthma with impaired health status managed in primary care were randomised to receive three sessions of either physiotherapist-supervised breathing training (n = 94) or asthma nurse-delivered asthma education (n = 89). The main outcome was Asthma Quality of Life Questionnaire (AQLQ) score, with secondary outcomes including spirometry, bronchial hyper-responsiveness, exhaled nitric oxide, induced sputum eosinophil count and Asthma Control Questionnaire (ACQ), Hospital Anxiety and Depression (HAD) and hyperventilation (Nijmegen) questionnaire scores. RESULTS: One month after the intervention there were similar improvements in AQLQ scores from baseline in both groups but at 6 months there was a significant between-group difference favouring breathing training (0.38 units, 95% CI 0.08 to 0.68). At the 6-month assessment there were significant between-group differences favouring breathing training in HAD anxiety (1.1, 95% CI 0.2 to 1.9), HAD depression (0.8, 95% CI 0.1 to 1.4) and Nijmegen (3.2, 95% CI 1.0 to 5.4) scores, with trends to improved ACQ (0.2, 95% CI 0.0 to 0.4). No significant between-group differences were seen at 1 month. Breathing training was not associated with significant changes in airways physiology, inflammation or hyper-responsiveness. CONCLUSION: Breathing training resulted in improvements in asthma-specific health status and other patient-centred measures but not in asthma pathophysiology. Such exercises may help patients whose quality of life is impaired by asthma, but they are unlikely to reduce the need for anti-inflammatory medication.

Combination treatment with high-dose vitamin C and alpha-tocopherol does not enhance respiratory-tract lining fluid vitamin C levels in asthmatics.

Oxidative stress plays a significant role in allergic airway inflammation. Supplementation with alpha-tocopherol (alone or combined with ascorbate/vitamin C) has been assessed as an intervention for allergic airway diseases with conflicting results. Enhancing levels of airway antioxidants with oral supplements has been suggested as an intervention to protect individuals from the effect of inhaled oxidants, although it is unclear whether supplementation changes tocopherol or vitamin C levels in both serum and airway fluids. Our objective was to obtain pilot safety and dosing data from 14 allergic asthmatic volunteers examining the effect of daily combination oral therapy with 500 mg alpha-tocopherol (alpha T) and 2 g vitamin C for 12 wk. We examined serum and airway fluid and cellular levels of alpha- and gamma-tocopherol (gamma T) and vitamin C to plan for future studies of these agents in asthma and allergic rhinitis. Six volunteers completed 12 wk of active treatment with alpha T and vitamin C and 8 completed placebo. Blood and sputum samples were obtained at baseline and at 6 wk and 12 wk of therapy and were analyzed for alpha T, gamma T, and vitamin C levels in the serum, sputum supernatant, and sputum cells. Combination treatment increased serum vitamin C and significantly decreased sputum alpha T and serum gamma T levels. No changes were found in sputum supernatant or sputum cell vitamin C or serum alpha T levels in the active treatment group. In conclusion, supplementation with alpha T and high-dose vitamin C does not augment vitamin C levels in the respiratory-tract lining fluid.

Effect of n-3 polyunsaturated fatty acids in asthma after low-dose allergen challenge.

BACKGROUND: We investigated the anti-inflammatory potential of n-3 polyunsaturated fatty acids (PUFA) on specific bronchial inflammation. Allergic asthmatics were challenged using a low-dose allergen provocation model. METHODS: Our parallel double-blinded study randomly assigned 23 house dust mite-allergic asthmatics (aged 22-29 years; 13 females, 10 males) to dietary supplementation with either an n-3 PUFA-enriched fat blend (0.69 g/day) or placebo for 5 weeks. After 3 weeks, the patients were challenged daily with low doses of mite allergen for 2 weeks. Primary outcome parameters were effects on lung function (forced expiratory volume in 1 s, FEV(1)) and exhaled nitric oxide (eNO) as a marker of bronchial inflammation. RESULTS: Even before the bronchial challenge, eNO was significantly lower in the n-3 PUFA group (p=0.014). Levels of eNO increased during allergen exposure in both groups, but differences in means were significantly lower in the n-3 PUFA group (p=0.022). During the low-dose allergen challenge, there were no differences between the groups with regard to symptoms, FEV(1) or the allergen dose required to induce deterioration of lung function (PD(20)). Numbers of sputum eosinophils did not differ significantly, while serum eosinophils (10.1+/-0.1.84 vs. 5.79+/-0.69%) as well as changes in eosinophilic cationic protein (20.5+/-9.93 vs. -1.68+/-4.36 ng/ml) and in vitro cysteinyl leukotriene release (2,889+/-872 vs. 1,120+/-173 ng/ml) were significantly lower in the n-3 PUFA group (p<0.05 each). CONCLUSION: Our results provide evidence that dietary supplementation with n-3 PUFA is able to reduce bronchial inflammation even after low-dose allergen challenge.

Fluticasone propionate protects against ozone-induced airway inflammation and modified immune cell activation markers in healthy volunteers.

BACKGROUND: Ozone exposure induces airway neutrophilia and modifies innate immune monocytic cell-surface phenotypes in healthy individuals. High-dose inhaled corticosteroids can reduce O(3)-induced airway inflammation, but their effect on innate immune activation is unknown. OBJECTIVES: We used a human O(3) inhalation challenge model to examine the effectiveness of clinically relevant doses of inhaled corticosteroids on airway inflammation and markers of innate immune activation in healthy volunteers. METHODS: Seventeen O(3)-responsive subjects [>10% increase in the percentage of polymorphonuclear leukocytes (PMNs) in sputum, PMNs per milligram vs. baseline sputum] received placebo, or either a single therapeutic dose (0.5 mg) or a high dose (2 mg) of inhaled fluticasone proprionate (FP) 1 hr before a 3-hr O(3) challenge (0.25 ppm) on three separate occasions at least 2 weeks apart. Lung function, exhaled nitric oxide, sputum, and systemic biomarkers were assessed 1-5 hr after the O(3) challenge. To determine the effect of FP on cellular function, we assessed sputum cells from seven subjects by flow cytometry for cell-surface marker activation. RESULTS: FP had no effect on O(3)-induced lung function decline. Compared with placebo, 0.5 mg and 2 mg FP reduced O(3)-induced sputum neutrophilia by 18% and 35%, respectively. A similar effect was observed on the airway-specific serum biomarker Clara cell protein 16 (CCP16). Furthermore, FP pretreatment significantly reduced O(3)-induced modification of CD11b, mCD14, CD64, CD16, HLA-DR, and CD86 on sputum monocytes in a dose-dependent manner. CONCLUSIONS: This study confirmed and extended data demonstrating the protective effect of FP against O(3)-induced airway inflammation and immune cell activation.

Lycopene-rich treatments modify noneosinophilic airway inflammation in asthma: proof of concept.

Antioxidant-rich diets are associated with reduced asthma prevalence. However, direct evidence that altering intake of antioxidant-rich foods affects asthma is lacking. The objective was to investigate changes in asthma and airway inflammation resulting from a low antioxidant diet and subsequent use of lycopene-rich treatments. Asthmatic adults (n=32) consumed a low antioxidant diet for 10 days, then commenced a randomized, cross-over trial involving 3 x 7 day treatment arms (placebo, tomato extract (45 mg lycopene/day) and tomato juice (45 mg lycopene/day)). With consumption of a low antioxidant diet, plasma carotenoid concentrations decreased, Asthma Control Score worsened, %FEV(1) and %FVC decreased and %sputum neutrophils increased. Treatment with both tomato juice and extract reduced airway neutrophil influx. Treatment with tomato extract also reduced sputum neutrophil elastase activity. In conclusion, dietary antioxidant consumption modifies clinical asthma outcomes. Changing dietary antioxidant intake may be contributing to rising asthma prevalence. Lycopene-rich supplements should be further investigated as a therapeutic intervention.