Wanzhen Yao

Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial

BACKGROUND Increased oxidative stress and inflammation has a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Drugs with antioxidant and anti-inflammatory properties, such as N-acetylcysteine, might provide a useful therapeutic approach for COPD. We aimed to assess whether N-acetylcysteine could reduce the rate of exacerbations in patients with COPD. METHODS In our prospective, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 40-80 years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity <0·7 and FEV1 of 30-70% of predicted) at 34 hospitals in China. We stratified patients according to use of inhaled corticosteroids (regular use or not) at baseline and randomly allocated them to receive N-acetylcysteine (one 600 mg tablet, twice daily) or matched placebo for 1 year. The primary endpoint was the annual exacerbation rate in patients who received at least one dose of study drug and had at least one assessment visit after randomisation. This study is registered with the Chinese Clinical Trials Registry, ChiCTR-TRC-09000460. FINDINGS Between June 25, 2009, and Dec 29, 2010, we screened 1297 patients, of whom 1006 were eligible for randomisation (504 to N-acetylcysteine and 502 to placebo). After 1 year, we noted 497 acute exacerbations in 482 patients in the N-acetylcysteine group who received at least one dose and had at least one assessment visit (1·16 exacerbations per patient-year) and 641 acute exacerbations in 482 patients in the placebo group (1·49 exacerbations per patient-year; risk ratio 0·78, 95% CI 0·67-0·90; p=0·0011). N-acetylcysteine was well tolerated: 146 (29%) of 495 patients who received at least one dose of N-acetylcysteine had adverse events (48 serious), as did 130 (26%) of 495 patients who received at least one dose of placebo (46 serious). The most common serious adverse event was acute exacerbation of COPD, occurring in 32 (6%) of 495 patients in the N-acetylcysteine group and 36 (7%) of 495 patients in the placebo group. INTERPRETATION Our findings show that in Chinese patients with moderate-to-severe COPD, long-term use of N-acetylcysteine 600 mg twice daily can prevent exacerbations, especially in disease of moderate severity. Future studies are needed to explore efficacy in patients with mild COPD (GOLD I). FUNDING Hainan Zambon Pharmaceutical.

Endogenous hydrogen sulfide reduces airway inflammation and remodeling in a rat model of asthma

Endogenous hydrogen sulfide (H(2)S) is hypothesized to have an important role in systemic inflammation. We investigated if endogenous H(2)S may be a crucial mediator in airway inflammation and airway remodeling in a rat model of asthma and if endogenous H(2)S may exert its anti-inflammatory effect by inhibiting inducible nitric oxide synthase (iNOS)/NO pathway. Cystathionine-gamma-lyase (CSE; a H(2)S-synthesizing enzyme) was mainly expressed in airway and vascular smooth muscle cells in rat lung tissue. Levels of endogenous H(2)S was decreased in pulmonary tissue in ovalbumin (OVA)-treated rats. Exogenous administration of NaHS alleviated airway inflammation and airway remodeling: peak expiratory flow (PEF) increased, goblet cell hyperplasia and collagen deposition score decreased, with decreased total cells recovered from bronchoalveolar fluid (BALF) and influx of eosinophils and neutrophils. The H(2)S levels of serum and lung tissue were positively correlated with PEF and negatively correlated with the level of eosinophils and neutrophils in BALF, score of lung pathology. NaHS treatment significantly attenuated pulmonary iNOS activation in OVA-treated rats. These results suggest that the CSE/H(2)S pathway plays an anti-inflammatory and anti-remodeling part in asthma pathogenesis and could be a novel target in prevention and treatment of asthma.

COPD in Chinese nonsmokers

Little is known about chronic obstructive pulmonary disease (COPD) in Chinese nonsmokers. The present study aimed to investigate the profiles of COPD among nonsmokers based on the Chinese Epidemiological Survey of COPD (CESCOPD). In the CESCOPD, 20,245 subjects aged 40 yrs or older were interviewed with questionnaires and spirometry tests. Subjects with a post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio of <0.70 were identified as having COPD. Data of 12,471 nonsmokers and 1,024 smoking COPD patients were analysed in the current study. The overall prevalence of COPD among nonsmokers was 5.2% (95% confidence interval 4.8–5.6). Being male, of advanced age, lower body mass index (BMI) and lower educational level, having exposure to environmental tobacco smoke, coal and/or biomass smoke, poor ventilation in the kitchen, a family history of respiratory disease and recurrent childhood cough were all independently associated with a higher risk of having COPD among nonsmokers. Nonsmokers with respiratory symptoms without airflow limitation showed a somewhat different pattern of risk factors. Nonsmokers with COPD were less likely to present with chronic productive coughs and lower BMI, while more likely to have received a physician diagnosis of asthma and respiratory diseases in childhood, than smokers with COPD. Chronic obstructive pulmonary disease is prevalent among Chinese nonsmokers, and nonsmoking chronic obstructive pulmonary disease may have different profiles from smoking chronic obstructive pulmonary disease.

Involvement of endogenous hydrogen sulfide in cigarette smoke-induced changes in airway responsiveness and inflammation of rat lung

Hydrogen sulfide (H₂S), recently considered the third endogenous gaseous transmitter, may have an important role in systemic inflammation. We investigated whether endogenous H₂S may be a crucial mediator in airway responsiveness and airway inflammation in a rat model of chronic exposure to cigarette smoke (CS). Rats randomly divided into control and CS-exposed groups were treated with or without sodium hydrosulfide (NaHS, donor of H₂S) or propargylglycine (PPG, inhibitor of cystathionine-γ-lyase [CSE], an H₂S-synthesizing enzyme) for 4-month exposure. Serum H₂S level and CSE protein expression in lung tissue were higher, by 2.04- and 2.33-fold, respectively, in CS-exposed rats than in controls (P<0.05). Exogenous administration of NaHS to CS-exposed rats alleviated airway reactivity induced by acetylcholine (Ach) or potassium chloride (KCl) by 17.4% and 13.8%, respectively, decreased lung pathology score by 32.7%, inhibited IL-8 and TNF- α concentrations in lung tissue by 34.2% and 31.4%, respectively, as compared with CS-exposed rats (all P<0.05). However, blocking endogenous CSE with PPG in CS-exposed rats increased airway reactivity induced by Ach or KCl, by 24.1% and 24.5%, respectively, and aggravated lung pathology score, by 44.8%, as compared with CS-exposed rats (all P<0.01). Incubation in vitro with NaHS, 1-3 mmol/L, relaxed rat tracheal smooth muscle precontracted by Ach or KCl. However, the NaHS-induced relaxation was not blocked by glibenclamide (10⁻⁴ mol/L), L-NAME (10⁻⁴ mol/L), or ODQ (1 μmol/L) or denudation of epithelium. Endogenous H₂S may have a protective role of anti-inflammation and bronchodilation in chronic CS-induced pulmonary injury.

Serum hydrogen sulfide as a novel marker predicting bacterial involvement in patients with community-acquired lower respiratory tract infections

Background and objective:  Endogenous hydrogen sulfide (H2S) may be involved in the pathogenesis of systemic inflammation. It was investigated whether serum H2S levels differed among patients with community‐acquired pneumonia, those with exacerbations of COPD or control subjects, and whether H2S may be used as a surrogate marker of the need for antibiotic treatment.

Chronic obstructive pulmonary disease in the absence of chronic bronchitis in China.

Background and objective:  COPD has a variable natural history and not all individuals follow the same course. The aim of this study was to assess the prevalence of COPD in the absence of chronic bronchitis (CB) based on a population survey in China, and to identify the determinants of CB in patients with COPD.

The relationship between particulate matter (PM10) and hospitalizations and mortality of chronic obstructive pulmonary disease: a meta-analysis.

Abstract Background: Numerous studies have reported variable associations between ambient particulate matter (PM) and chronic obstructive pulmonary disease (COPD) hospitalizations and mortality. Objective: To conduct a systematic study assessing the associations between hospitalizations and mortality from COPD and ambient PM10 (particulate matter with aerodynamic diameters ≤ 10 μm, PM10). Methods: Systematic searches were conducted in 6 common electronic databases. A meta-analysis was performed to estimate the odds ratio (OR) to evaluate the relationship between PM10 and COPD hospitalizations and mortality. Publication bias and heterogeneity of samples were tested by Begg funnel plot and Egger test, respectively. Study findings were analyzed using random-effect model and fixed-effect model. Results: The search yielded 31 studies suitable for the meta-analysis during the period from Jan 1, 2000 to Oct 31, 2011. A 10μg/m3 increase in PM10 was associated with a 2.7% (95%CI = 1.9%-3.6%) increase in COPD hospitalizations with an OR of 1.027 (95%CI: 1.019–1.036), and a 1.1% (95%CI: 0.8%–1.4%) increase in COPD mortality with an OR of 1.011 (95%CI: 1.008–1.014). Conclusions: Ambient PM10 is associated with increased COPD hospitalizations and mortality. Further research is needed to elucidate whether this association is causal and to clarify its mechanisms.

High-Dose N-Acetylcysteine in the Prevention of COPD Exacerbations: Rationale and Design of the PANTHEON Study

Abstract Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation; from a pathophysiological point of view it involves many components, including mucus hypersecretion, oxidative stress and inflammation. N-acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties. Long-term efficacy of NAC 600mg/d in COPD is controversial; a dose-effect relationship has been demonstrated, but at present it is not known whether a higher dose provides clinical benefits. The PANTHEON Study is a prospective, ICS stratified, randomized, double-blind, placebo-controlled, parallel-group, multi-center trial designed to assess the efficacy and safety of high-dose (1200 mg/daily) NAC treatment for one year in moderate-to-severe COPD patients. The primary endpoint is the annual exacerbation rate. Secondary endpoints include recurrent exacerbations hazard ratio, time to first exacerbation, as well as quality of life and pulmonary function. The hypothesis, design and methodology are described and baseline characteristics of recruited patients are presented. 1006 COPD patients (444 treated with maintenance ICS, 562 ICS naive, aged 66.27±8.76 yrs, average post-bronchodilator FEV1 48.95±11.80 of predicted) have been randomized at 34 hospitals in China. Final results of this study will provide objective data on the effects of high-dose (1200 mg/daily) long-term NAC treatment in the prevention of COPD exacerbations and other outcome variables.

Expert consensus on acute exacerbation of chronic obstructive pulmonary disease in the People's Republic of China

Chronic obstructive pulmonary disease (COPD) is a common disease that severely threatens human health. Acute exacerbation of COPD (AECOPD) is a major cause of disease progression and death, and causes huge medical expenditures. This consensus statement represents a description of clinical features of AECOPD in the People’s Republic of China and a set of recommendations. It is intended to provide clinical guidelines for community physicians, pulmonologists and other health care providers for the prevention, diagnosis, and treatment of AECOPD.

Exhaled Hydrogen Sulfide Predicts Airway Inflammation Phenotype in COPD

BACKGROUND: The role of exhaled H2S as a marker of airway inflammation and its relationship with COPD severity remain to be determined. METHODS: Airway inflammation was classified in 77 COPD subjects based on the presence of inflammatory cells in induced sputum. We investigated the association between disease phenotype and exhaled H2S, lung function, and plasma levels of several inflammatory factors, including tumor necrosis factor alpha, interleukin-8, and leukotriene B4. RESULTS: In total, 33.77% of enrolled COPD subjects were diagnosed with eosinophilia. These subjects had a longer disease course, smoked fewer cigarettes, and experienced more frequent exacerbation events before study enrollment. However, they also had worse lung function and larger residual volume, they demonstrated greater changes in FEV1 following bronchodilator inhalation. Although levels of plasma inflammatory factors did not significantly differ between subjects with and without eosinophilia, subjects without eosinophilia had significantly higher levels of exhaled H2S (9.19 ± 2.74 vs 7.24 ± 1.68 parts per billion, P = .01). Furthermore, exhaled H2S levels were negatively correlated with induced sputum eosinophils (r = −0.45, P = .05), and positively correlated with inspiratory capacity in COPD subjects (r = 0.51, P = .026), but did not correlate significantly with plasma inflammatory factors. A cut-off value of 7.10 parts per billion of exhaled H2S predicted a non-eosinophilic phenotype with 68.6% sensitivity and 77.9% specificity. CONCLUSIONS: Exhaled levels of H2S were lower in subjects with eosinophilia. Increased levels of exhaled H2S predicted a non-eosinophilic phenotype in our study population.