0
Original Research: COPD |

Benefits of High-Dose N-Acetylcysteine to Exacerbation-Prone Patients With COPDEffect of N-Acetylcysteine in High-Risk COPD FREE TO VIEW

Hoi Nam Tse, MBChB, FCCP; Luca Raiteri, MD; King Ying Wong, MBBS, FCCP; Lai Yun Ng, MBChB; Kwok Sang Yee, MBBS; Cee Zhung Steven Tseng, MBBCh BAO
Author and Funding Information

From the Kwong Wah Hospital (Drs Tse, Ng, and Tseng), Hong Kong, SAR; Medical Department (Dr Raiteri), Innovation & Medical Sciences, Zambon SpA, Vicenza, Italy; and Wong Tai Sin Hospital (Drs Wong and Yee), Hong Kong.

CORRESPONDENCE TO: Hoi Nam Tse, MBChB, FCCP, Medical and Geriatric Department, Kwong Wah Hospital, Waterloo Rd, Yau Ma Tei, Hong Kong, 852, Hong Kong; e-mail: drhoinam@gmail.com


FUNDING/SUPPORT: Zambon SpA donated the study drugs. This work was supported by the Tung Wah Group of Hospitals Research Fund.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(3):611-623. doi:10.1378/chest.13-2784
Text Size: A A A
Published online

BACKGROUND:  Although high-dose N-acetylcysteine (NAC) has been suggested to reduce COPD exacerbations, it is unclear which category of patients with COPD would benefit most from NAC treatment. The objective of this study was to compare the effect of high-dose NAC (600 mg bid) between high-risk and low-risk Chinese patients with COPD.

METHODS:  Patients with spirometry-confirmed stable COPD were randomized to treatment with either NAC 600 mg bid or placebo in addition to their usual treatments. Patients were followed up every 16 weeks for a total of 1 year. Further analysis was performed according to each patient’s exacerbation risk at baseline as defined by the current GOLD (Global Initiative for Chronic Obstructive Lung Disease) strategy to analyze the effect of high-dose NAC in high-risk and low-risk patients.

RESULTS:  Of the 120 patients with COPD randomized (men, 93.2%; mean age, 70.8 ± 0.74 years; prebronchodilator FEV1, 53.9 ± 2.0%; baseline characteristics comparable between treatment groups), 108 (NAC, 52; placebo, 56) completed the 1-year study. For high-risk patients (n = 89), high-dose NAC compared with placebo significantly reduced exacerbation frequency (0.85 vs 1.59 [P = .019] and 1.08 vs 2.22 [P = .04] at 8 and 12 months, respectively), prolonged time to first exacerbation (P = .02), and increased the probability of being exacerbation free at 1 year (51.3% vs 24.4%, P = .013). This beneficial effect of high-dose NAC vs placebo was not significant in low-risk patients.

CONCLUSIONS:  High-dose NAC (600 mg bid) for 1 year reduces exacerbations and prolongs time to first exacerbation in high-risk but not in low-risk Chinese patients with COPD.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT01136239; URL: www.clinicaltrials.gov

Figures in this Article

COPD is characterized by high oxidative stress. Frequent exacerbations not only deteriorate lung function and quality of life but also add a financial burden to the health-care system.1 Prevention of COPD exacerbation is of paramount importance in the management of COPD. The current GOLD (Global Initiative for Chronic Obstructive Lung Disease) strategy2 recommends using inhaled corticosteroids (ICSs) and phosphodiesterase (PDE-4) inhibitors in patients with COPD with a high exacerbation risk (categories C and D). However, concerns have been raised regarding the potential association between ICS and pneumonia. Therefore, further treatment modalities with alternative mechanisms may be deemed necessary to reduce COPD exacerbation risk.

Oral N-acetylcysteine (NAC), commonly known for its mucolytic effect, also possesses potent antioxidant and antiinflammatory properties.3 NAC acts directly as a reactive oxygen species scavenger as well as a precursor of reduced glutathione (GSH) for restoration of cellular redox status, which in turn modulates the inflammatory COPD pathway and could, therefore, reduce exacerbation as demonstrated in a previous Cochrane systematic review.4 However, the large, 3-year randomized Bronchitis Randomized on NAC Cost-Utility Study (BRONCHUS)5 failed to illustrate the beneficial effect of NAC on FEV1 decline and exacerbation frequency. The discordant clinical results might be attributable to an insufficient dose of NAC used in past trials (≤ 600 mg daily) because in vitro and in vivo studies3 suggested that a higher dose of NAC (≥ 1,200 mg daily) is needed to exert antioxidant and antiinflammatory properties. In fact, high-dose NAC (1,200 mg daily) has been shown to reduce gas trapping and improve exercise endurance in patients with emphysematous COPD.6 Moreover, the recent High-Dose N-Acetylcysteine in Stable COPD—a 1-Year, Double-Blind, Randomized, Placebo-Controlled Trial (HIACE) study,7 demonstrated that high-dose NAC (600 mg bid) could reduce COPD exacerbations and improve small airway function. However, the HIACE study involved a heterogeneous group of patients with COPD with various severities and exacerbation risks. Therefore, further analysis is needed to delineate the category of patients with COPD that would benefit most from high-dose NAC treatment. The objective of this post hoc analysis was to compare the effect of high-dose NAC (600 mg bid) between high-risk and low-risk Chinese patients with COPD.

Study Design

This study was a 1-year, double-blind, randomized placebo-controlled trial conducted in the Kwong Wah Hospital, Hong Kong. Full details of the methodology have been published previously.7

Patients with stable COPD were recruited from the COPD clinic or the COPD ambulatory rehabilitation clinic from March 1, 2010, to February 28, 2011, in Kwong Wah Hospital if they had spirometry-confirmed COPD showing a postbronchodilator FEV1/FVC < 0.70. Patients were excluded from the study if they refused to participate or failed to cooperate in the lung function tests. Patients who had coexisting pulmonary diseases or who were receiving long-term bilevel pressure ventilation or long-term oxygen therapy for chronic respiratory failure were also excluded.

Eligible patients with COPD who had experienced a recent exacerbation were treated accordingly and recruited at least 4 weeks after the exacerbation episode. After a 4-week run-in period, subjects were randomly allocated to a treatment group (NAC 600 mg bid) or a placebo group and continued taking their usual medications. Both the NAC and placebo medications were identical in appearance. The group allocation was concealed from both patients and responsible physicians, with details only known to a third party (two senior pharmacists of Kwong Wah Hospital).

Patients were followed and monitored every 16 weeks. During each follow-up, adverse drug effects, changes in current medications, and drug compliance were recorded by the attending physician. Physicians checked drug compliance by counting the number of returned pills; compliance was considered good if the patient consumed > 70% of medications. The study was approved by the Kowloon West Cluster Clinical Research Ethics Committee, Hospital Authority, Hong Kong (KWC-REC reference: KW/EX-09-140).

Subgroup Analysis

The post hoc subgroup analysis was performed according to patients’ exacerbation risk at baseline as stated in the 2013 GOLD strategy2 for the classification of exacerbation risk in patients with COPD. High exacerbation risk (categories C and D) was defined as a history of two or more exacerbations per year, FEV1 < 50%, or both. Low exacerbation risk (categories A and B) was defined as a history of fewer than two exacerbations per year and FEV1 ≥ 50% and no recent hospital admissions due to COPD exacerbations. In addition to subgroup analyses using this stratification by exacerbation risk, patients with COPD were stratified by FEV1 < 50% or ≥ 50% and by frequency of exacerbations (more than two or two or fewer in the past year).

Outcome Measures

COPD exacerbation was defined by the presence of any two of the following three symptoms including: (1) increased shortness of breath, (2) increased volume, and (3) increased purulence of sputum. The patients were requested to record their exacerbation date in a diary. A written action plan was provided about the use of systemic antibiotics and steroids for each exacerbation. The frequency of COPD exacerbations and admissions were recorded at every follow-up visit. Specifically, the date of every exacerbation and admission were obtained, with days to first exacerbation and admission being calculated. Patients were also assessed using the St. George’s Respiratory Questionnaire (SGRQ) and the 6-min walk distance.

Statistical Methods

The statistical analysis was done with SPSS, version 20.0 (IBM) software. Data are expressed as mean ± SEM unless otherwise stated, and all hypothesis tests were two-sided, with P < .05. Comparison of continuous variables between the NAC and placebo groups was analyzed by the Student t test or Mann-Whitney U test, as appropriate. The χ2 test was used for comparison of categorical variables between study groups. An intention-to-treat analysis was used in the study.

Differences in time to first exacerbation and admission between the treatment and placebo groups were analyzed with Kaplan-Meier plots, with the significance analysis performed by the log-rank test. The start date was the first day participants entered the study, whereas the end date was the date of first exacerbation or admission, if it occurred, or 1 year after the start date for patients without an exacerbation during the study period (censored cases).

Study Population and Baseline Characteristics

Of the 133 eligible patients with COPD screened, 120 were recruited after the 4-week run-in period. Among the high-risk group, 83.1% had two or more exacerbations in the past year, 52.8% had FEV1 < 50%, and 41.7% met both criteria. Of these high-risk patients, 44 and 45 received NAC and placebo, respectively, whereas in the low-risk group, 14 and 17 patients received NAC and placebo, respectively (Fig 1).

Figure Jump LinkFigure 1  Flowchart of the study design. FU = follow-up; NAC = N-acetylcysteine.Grahic Jump Location

In total, 12 patients dropped out of the study (seven from the high-risk group and five from the low-risk group). These patients had similar baseline demographic characteristics to those who completed the study (e-Tables 1, 2) and completed similar pharmacologic treatments (e-Table 3). By the end of the study, there were 80 patients in the high-risk group (NAC, 39; placebo, 41) and 28 in the low-risk group (NAC, 13; placebo, 15).

Subject demographics are summarized in Table 1. Compared with low-risk patients, high-risk patients had a lower BMI (P = .006), higher modified Medical Research Council dyspnea score (P = .02), and higher mean number of exacerbations and hospital admissions per patient in the prior year (P = .001). Regarding the lung function test, the high-risk patients had a lower FEV1 % (P = .001) as well as a higher degree of gas trapping (higher residual volume [P = .015] and residual volume/total lung capacity ratio [P = .001]) compared with the low-risk patients (Table 2).

Table Graphic Jump Location
TABLE 1  ] Baseline Demographic Characteristics of Patients With COPD

Data are presented as mean ± SEM, % (No.), and median (interquartile range). mMRC = modified Medical Research Council; NAC = N-acetylcysteine.

a 

P < .05.

Table Graphic Jump Location
TABLE 2  ] Patient Baseline Lung Function Parameters

Data are presented as mean ± SEM or %. FEF25%-75% = forced expiratory flow at 25% to 75% of vital capacity; IC = inspiratory capacity; ICS = inhaled corticosteroid; LABA = long-acting β-agonist; LAMA = long-acting muscarinic agonist; RV = residual volume, SABA = short-acting β2-agonist; SAMA = short-acting muscarinic agonist; TLC = total lung capacity. See Table 1 legend for expansion of other abbreviation.

a 

P < .05.

b 

In equivalent dose to beclomethasone/μg.

There was no significant difference in baseline demographic characteristics or lung function between patients who received NAC or placebo within the high-risk and low-risk subgroups (Tables 1, 2). In terms of drug treatment, a similar proportion of patients were receiving ICSs, long-acting muscarinic agonists (LAMAs), and combined ICS and long-acting β-agonists (LABAs) in both treatment groups, although a lower mean dose of ICS was used in the high-risk patients of the NAC group (Table 2).

COPD Exacerbations and Related Admissions

During the study, 50 COPD exacerbation episodes were recorded in the NAC group and 96 in the placebo group (13 and 133 episodes in low-risk and high-risk patients, respectively). In the overall analysis, the mean frequency of COPD exacerbations in the NAC group was significantly lower than that of placebo group by 0.75 times in the 1-year study period (NAC, 0.96/y; placebo, 1.71/y; P = .019). Moreover, patients receiving high-dose NAC had a longer time to first exacerbation (P = .2). They also had a higher chance of being exacerbation free at the end of the study compared with the placebo group (53.8% vs 37.5%), although such improvement did not reach statistical significance in the overall analysis (P = .088) (Figs 24).

Figure Jump LinkFigure 2  A-C, Kaplan-Meier curves showing the time to first exacerbation in the 1-y period (A) overall (NAC, 261.5 ± 18.4 d; placebo, 239.5 ± 17.9 d) and in the (B) low-risk (NAC, 272.1 ± 39.0; placebo, 337 ± 21.3 d), and (C) high-risk (NAC, 258.2 ± 20.8; placebo, 203.6 ± 20.4 d) groups. Cum = cumulative. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 3  A-C, Cumulative exacerbation frequencies over the 1-y study period (A) overall (total) and in the (B) low-risk and (C) high-risk groups. NS = not significant. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 4  Proportion of exacerbation-free patients in the 1-y study period. See Figure 1 and 3 legends for expansion of abbreviations.Grahic Jump Location

In the subgroup analysis, high-risk patients receiving NAC showed a significant prolongation in the time to first exacerbation (NAC, 258.2 ± 20.8; placebo, 203.6 ± 20.4 days; P = .02) and an increased likelihood of being exacerbation free at 1 year (NAC, 51.3%; placebo, 24.4%; P = .013). However, no significant difference was observed in these measures in low-risk patients between the NAC and placebo groups. Finally, the high-risk patients in the NAC group had a reduced exacerbation rate compared with the high-risk patients in the placebo group (0.51 vs 0.9 [P = .074], 0.85 vs 1.59 [P = .019], and 1.08 vs 2.22 [P = .04] at 4, 8, and 12 months, respectively), whereas no significant reductions in exacerbation rate were observed between NAC and placebo in low-risk patients (Figs 24).

In total, 71 admissions due to COPD exacerbation were recorded (three and 68 admissions in low-risk and high-risk patients, respectively). The NAC group had a lower mean frequency of COPD admissions (NAC, 0.5/y; placebo, 0.80/y; P = .196). A reduced number of admissions in the NAC vs placebo group was more prominent in the high-risk vs low-risk patients (0.31 ± 0.1 vs 0.29 ± 0.09 [P = .91], 0.49 ± 0.14 vs 0.56 ± 0.13 [P = .69], and 0.51 ± 0.14 vs 0.93 ± 0.18 [P = .079] at 4, 8, and 12 months, respectively). Meanwhile, the admission rate remained low and comparable between the NAC and placebo treatments in the low-risk patients (0.08 ± 0.08 vs 0.07 ± 0.07 [P = .9], 0.23 ± 0.12 vs 0.13 ± 0.13 [P = .6], and 0.31 ± 0.17 vs 0.13 ± 0.13 [P = .43] at 4, 8, and 12 months, respectively) (Fig 5).

Figure Jump LinkFigure 5  A-C, Cumulative frequencies of admissions due to exacerbation of COPD over the 1-y study period (A) overall and in the (B) low-risk and (C) high-risk groups. See Figure 1 legend for expansion of abbreviation.Grahic Jump Location
Subgroup Stratification

When the patients with COPD were stratified by FEV1 < 50%, there were no statistically significant differences between NAC and placebo regarding their effects. When frequent exacerbator was used as a stratification criterion, the subgroup with frequent exacerbations (more than two in the prior year) had a significant reduction in exacerbation frequency (1.21 ± 0.25 vs 2.3 ± 0.36; P = .016) as well as a tendency toward improvement in time to first exacerbation (P = .08) and exacerbation-free probability (P = .07) for those receiving NAC.

On the other hand, when patients were stratified by exacerbation risk as defined by FEV1 < 50%, exacerbation frequency of more than two in the prior year, or both, high-risk patients who received NAC showed significant improvement in all parameters, including time to first exacerbation (P = .022), exacerbation frequency (P = .04), and probability of remaining exacerbation free (P = .024) (Table 3).

Table Graphic Jump Location
TABLE 3  ] Subgroup Analysis Comparing Effects of NAC With Placebo in Subgroups Classified According to Various Stratification Criteria (A-C)

Data are presented as mean ± SEM or %. See Table 1 legend for expansion of abbreviation.

a 

More than two episodes in the prior year.

b 

FEV1 < 50%, frequency of exacerbation (more than two episodes in the prior year), or both.

c 

P < .05.

Adverse Effects and Other Outcome Parameters

No major adverse effects occurred in either the NAC or the placebo group. There were no increases in incidence of minor adverse effects with NAC vs placebo (e-Table 4). Regarding functional outcomes, there were no significant differences in modified Medical Research Council dyspnea score, SGRQ, and 6-min walk distance between NAC and placebo in either the high-risk or the low-risk patients.

This study showed that for patients with a high risk of exacerbation, high-dose NAC significantly reduced exacerbation frequency, prolonged time to first exacerbation, and increased the likelihood of being exacerbation free at 1 year compared with placebo, but these beneficial effects of high-dose NAC over placebo were not significant in low-risk patients. The frequency of exacerbations is considered an important outcome for the clinical history of COPD. Exacerbations become more frequent and severe as COPD severity increases. Moreover, a history of prior exacerbations can identify a distinct group of patients with COPD, termed the “frequent exacerbator phenotype,” who are at particularly high risk of further events and death. According to the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study,8 this COPD phenotype is present across all GOLD grades, including patients with grade 2 disease of whom 22% have frequent exacerbations. Greater levels of airway and systemic inflammation, mechanical factors (dynamic lung hyperinflation, small airway obstruction), change in bacterial strain with colonization, and a possible increased susceptibility to viral infection represent some complex and multifactorial factors underlying the pathophysiology of the frequent exacerbator phenotype.9 This group of patients has a worse quality of life, lower physical activity, a greater chance of recurrent exacerbations, a faster functional decline, more comorbid extrapulmonary diseases, and an increased rate of hospitalization and mortality.9 Thus, it is important to identify patients at risk for frequent exacerbations and target this group for therapy.

Severity of underlying COPD disease and history of prior exacerbations were major determinants in identifying patients with COPD of the “exacerbation-susceptible phenotype,”10 and the current GOLD strategy2 recommends a combined assessment approach for better guidance of pharmacologic treatments in patients with COPD. Reduction in exacerbation frequency has been found with ICS and LABA, alone and in combination,1115 and with LAMA.16 Recent evidence also has suggested that the PDE-4 inhibitor roflumilast reduces symptoms of chronic bronchitis, severe airflow limitation, exacerbation frequency, and the number of frequent exacerbators after 12 months of therapy compared with placebo in patients with COPD.8 Guidelines now indicate ICSs or PDE-4 inhibitors in addition to LAMA or LABA in patients with high exacerbation risk (categories C and D), as defined by a history of two or more exacerbations per year, FEV1 < 50%, or both.2

The current role of mucolytics/antioxidants in the treatment of patients with COPD remains ambiguous. Mucolytic-like carbocisteine was only recommended as an alternative treatment in patients with group D (more symptoms, higher risk) COPD.2 In fact, the effects of mucolytics/antioxidants may vary in various COPD phenotypes. For instance, the majority of patients in the BRONCUS trial,5 which failed to demonstrate the overall beneficial effect of NAC 600 mg daily on FEV1 decline and exacerbation, had moderate severity COPD (75% had GOLD stage II disease) and a low exacerbation rate (around 1.25-1.31 episodes). The BRONCUS investigators only suggested through their subgroup analysis that the exacerbation rate might be reduced with NAC in patients not treated with ICSs, and the secondary analysis suggested a beneficial effect on lung hyperinflation. In contrast, the majority of patients in the multicenter Effect of Carbocisteine on Acute Exacerbation of Chronic Obstructive Pulmonary Disease (PEACE) trial by Zheng et al,17 which suggested that the long-term use of high-dose carbocisteine (1,500 mg daily) could significantly reduce COPD exacerbations, were in the severe COPD groups (50% patients had GOLD stage III or above) at baseline. This difference in the composition of exacerbation-susceptible patients with COPD as well as the difference in drug dosage used in these trials may explain their observed discordant effects of mucolytics/antioxidants in patients with COPD.

The present study demonstrated that high-dose NAC plays a beneficial role in high-risk patients with COPD by prolonging their time to first exacerbation and reducing COPD exacerbation frequency regardless of symptoms, whereas such an effect was not significant in the low-risk patients. In contrast to the BRONCHUS study, the high-risk group in the present study had a lower FEV1 and higher exacerbation frequency. Moreover, the majority of high-risk patients in this study were already receiving ICSs (> 70%); around 40% of these patients were receiving LAMA or combined ICS-LABA treatment, implying that in this high-risk group of patients with COPD, high-dose NAC (600 mg bid) might be an effective add-on therapy to decrease exacerbation, even in those using ICS for the long term. We proposed that this might be a result of NAC and ICS acting on different parts of the inflammatory pathway in COPD, and further study on the combined use and the potential synergistic effect of high-dose NAC and ICSs/bronchodilators is warranted. Nevertheless, the study demonstrated that NAC may be beneficial predominately in high-risk patients with COPD (categories C and D), which represents a particular phenotype of patients with COPD.

Frequent COPD exacerbation signifies a higher oxidative burden, and NAC treatment may have a more significant effect by restoring oxidative imbalance. NAC exerts its direct and indirect antioxidative effects by acting as a free radial scavenger (a major cellular thiol antioxidant) as well as a precursor of reduced GSH (a major redox recycler); this in turn modulates the redox-sensitive cell signal transduction and expression of proinflammatory genes in patients with COPD,1820 contributing to the antiinflammatory effect. Previous in vivo and in vitro studies supported the theory of an antioxidant and antiinflammatory effect of NAC in COPD, showing that NAC could reduce hydrogen peroxide (H2O2)-induced damage in epithelial cells,21 attenuate airway wall epithelial thickening, and reduce secretory cell hyperplasia.22,23 Yet, in vivo studies have demonstrated the antiinflammatory effect of NAC by showing a rise in GSH level in BAL,24 a decrease exhaled H2O2 levels,25 and a reduction of inflammatory markers in smokers.26 In fact, COPD exacerbation is multifactorial, and the mucolytic effect of NAC is salient in exacerbation-susceptible patients with COPD because their consistently inflamed ciliated epithelial cells in the airway are the preferred site for bacterial attachment.27 Additionally, NAC could further inhibit the attachment of bacteria to the epithelium by disrupting the bacterial receptor sites on the epithelial surface and mucus.27,28 Moreover, the overexpressed adhesion molecules (eg, intercellular adhesion molecule-1) in patients with COPD cause excessive transmigration of neutrophils and were shown to be reduced by NAC treatment.29 Besides, NAC may improve small airway function in patients with COPD as illustrated by improvement in forced expiratory flow at 25% to 75% of vital capacity, and forced oscillation technique parameters7 as well as a reduction in gas trapping.6 A recent small pilot study also showed that a short course of 1,200 mg/d NAC can enhance the bronchodilator reversibility potential of antimuscarinic agents.30

Finally, NAC may also play a role in the host innate immune response. In a human lung model, cigarette smoke extract was shown to inhibit RIG-1 (viral-mediated retinoic acid-inducible gene), which is an important pattern recognition receptor for initiating antiviral response to influenza.31 In a dose-related manner, NAC could restore the antiviral response by preventing the suppression of the oxidant-sensitive RIG-1.31

The present results were different from the previous large-scale, 3-year BRONCUS,5 which failed to demonstrate the beneficial effect of NAC 600 mg daily on FEV1 decline and exacerbation. This discordant result is likely attributable to the dose-dependent property of NAC,5 as illustrated by in vitro studies3235 revealing that NAC exerts its mucolytic effect at a low dose (≤ 600 mg daily), whereas the antioxidant effect can only be exerted at higher dose (1,200-1,800 mg daily).3638

Likewise, the clinical outcome might also depend on the duration of NAC treatment. The present study demonstrates that high-dose NAC treatment could significantly reduce exacerbation frequency at 8 and 12 months but not before 4 months. In alignment with the PEACE study,17 which showed a reduction of exacerbation frequency in patients receiving high-dose carbocisteine from 6 months on, the present study highlights that a minimal treatment period (4 months) is needed for NAC 600 mg bid to exert its clinically significant antioxidant and antiinflammatory effects. In fact, if lower doses of NAC are used, an even longer period is needed for the effect to take place. Kasielski and Nowak38 suggested that low-dose NAC (600 mg daily) could reduce H2O2 levels in 9 to 12 months, but the H2O2 level did not change at 6 months, implying a longer treatment period was needed for low-dose NAC to take effect.

Notably, the high-risk patients had a very high rate of exacerbations resulting in hospital admissions compared with rates observed in previous studies. This increased rate may be attributable to a number of reasons specific to our locality: a particular lack of community health-care support for COPD exacerbation, an easily accessible and inexpensive public hospital service, and a lack of education on the management of COPD exacerbations. As a result, COPD admissions put a heavy burden on inpatient hospital resources.

Regarding the limitations, a small sample size, particularly of low-risk patients, limited the power of the study. Moreover, the stratification between high-risk and low-risk exacerbation-susceptible patients was not foreseen a priori because it was introduced by GOLD guidelines later in 2011.39

The HIACE study was conducted in only Chinese patients with COPD. Current international guidelines for COPD do not distinguish treatment options (including dosages) based on potential racial or cultural differences; hence, all currently available classes of respiratory medications are included in national guidelines. However, the Chinese ethnicity of the population sample may affect the generalizability of the results. Ethnicity has been a concern because different drug pharmacokinetics may be different between Chinese and white populations. For instance, it was shown that low-dose theophylline could significantly reduce the time to first exacerbation and improvement in SGRQ score in Chinese but not in white patients with COPD.40 The standard dosing of ICS also appears to be lower in China than in Europe. In addition, the present study only compared the effect of high-dose NAC to placebo, not NAC of varying dosages; therefore, the dose effect of NAC could not be directly inferred. Therefore, further study with a larger sample size, multicenter involvement, and preferably a three-arm design is warranted. Another potential limitation is that the study did not include patients with mild COPD. Additionally, our definition of acute exacerbation was slightly different from that used in the GOLD strategy.2 Finally, the majority of patients were receiving long-term ICSs, rendering it difficult to compare the effect of NAC in steroid-naive and steroid-treated patients. Therefore, potential combined or synergistic effects of NAC and other drugs such as ICSs, LAMAs, and LABAs could not be totally excluded.

The findings from this study suggest that 1-year treatment with high-dose NAC (600 mg bid) reduces exacerbation in high-risk but not in low-risk Chinese patients with COPD. Unlike previous studies proposing that the effect of mucolytics was only prominent in patients with COPD not using ICSs, the present study suggests that high-dose NAC could exert its effect even in patients with COPD using ICS or a combination of ICS with LABA or LAMA. To our knowledge, this study is the first to show that high-dose NAC (600 mg bid) could reduce exacerbations in high-risk exacerbation-susceptible Chinese patients with COPD but not in low-risk patients. We hope that the study results shed light on the use of high-dose NAC in exacerbation-susceptible patients with COPD.

Author contributions: L. R. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. H. N. T. served as principal author. H. N. T. and K. Y. W. contributed to the study concept and design; K. S. Y. contributed to the study supervision; H. N. T., K. Y. W., and L. Y. N. contributed to the data acquisition; H. N. T. and K. Y. W. contributed to the data interpretation; H. N. T. contributed to the data analysis; H. N. T. contributed to the drafting of the submitted manuscript; and L. R., K. Y. W., K. S. Y., L. Y. N., and C. Z. S. T. contributed to the revision of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Raiteri was an employee at Zambon SpA during the period of this study. Drs Tse, Wong, Ng, Yee, and Tseng have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: Zambon SpA did not place any restrictions on statements made in the final version of the manuscript. The Tung Wah Group of Hospitals Research Fund played no active role in the study.

Other contributions: The authors thank pharmacists Michael Ling, MS, BPharm; Joyce Ng, MSc Clinical Pharmacy; and Elaine Lo, MSc Clinical Pharmacy, for contributing to and participating in the randomization, group allocation, and drug dispensation. The authors also thank C. C. Cheng, BSc Nursing; H. M. Lau, BSc Nursing; K. H. Lo, BSc Nursing; W. K. Yeung, BSc Nursing; C. K. Hung, BSc Nursing; M. C. Siu, BSc Nursing; K. T. Cheung, BSc Nursing; S. Y. Wong, BSc Nursing; and F. Y. Chow, BSc Nursing for performing lung function tests.

Additional information: The e-Tables can be found in the Supplemental Materials section of the online article.

BRONCHUS

Bronchitis Randomized on N-Acetylcysteine Cost-Utility Study

GOLD

Global Initiative for Chronic Obstructive Lung Disease

GSH

glutathione

H2O2

hydrogen peroxide

ICS

inhaled corticosteroid

LABA

long-acting β-agonist

LAMA

long-acting muscarinic agonist

NAC

N-acetylcysteine

PDE-4

phosphodiesterase-4

SGRQ

St. George’s Respiratory Questionnaire

Seemungal TA, Hurst JR, Wedzicha JA. Exacerbation rate, health status and mortality in COPD—a review of potential interventions. Int J Chron Obstruct Pulmon Dis. 2009;2009(4):203-223. [CrossRef]
 
Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187(4):347-365. [CrossRef] [PubMed]
 
Sadowska AM, Manuel-Y-Keenoy B, De Backer WA. Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo dose-effects: a review. Pulm Pharmacol Ther. 2007;20(1):9-22. [CrossRef] [PubMed]
 
Poole P, Black PN. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2010;;(2):CD001287.
 
Decramer M, Rutten-van Mölken M, Dekhuijzen PN, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet. 2005;365(9470):1552-1560. [CrossRef] [PubMed]
 
Stav D, Raz M. Effect of N-acetylcysteine on air trapping in COPD: a randomized placebo-controlled study. Chest. 2009;136(2):381-386. [CrossRef] [PubMed]
 
Tse HN, Raiteri L, Wong KY, et al. High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study. Chest. 2013;144(1):106-118. [CrossRef] [PubMed]
 
Wedzicha JA, Rabe KF, Martinez FJ, et al. Efficacy of roflumilast in the COPD frequent exacerbator phenotype. Chest. 2013;143(5):1302-1311. [CrossRef] [PubMed]
 
Wedzicha JA, Brill SE, Allinson JP, Donaldson GC. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med. 2013;11:181. [CrossRef] [PubMed]
 
Hurst JR, Vestbo J, Anzueto A, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128-1138. [CrossRef] [PubMed]
 
Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review of randomized placebo-controlled trials. Am J Med. 2002;113(1):59-65. [CrossRef] [PubMed]
 
Mahler DA, Donohue JF, Barbee RA, et al. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest. 1999;115(4):957-965. [CrossRef] [PubMed]
 
Calverley PM, Anderson JA, Celli B, et al; TORCH Investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775-789. [CrossRef] [PubMed]
 
Vogelmeier C, Hederer B, Glaab T, et al; POET-COPD Investigators. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364(12):1093-1103. [CrossRef] [PubMed]
 
Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J. 2003;22(6):912-919. [CrossRef] [PubMed]
 
Tashkin DP, Celli B, Senn S, et al; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543-1554. [CrossRef] [PubMed]
 
Zheng JP, Kang J, Huang SG, et al. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet. 2008;371(9629):2013-2018. [CrossRef] [PubMed]
 
Aruoma OI, Halliwell B, Hoey BM, Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med. 1989;6(6):593-597. [CrossRef] [PubMed]
 
Cotgreave IA. N-acetylcysteine: pharmacological considerations and experimental and clinical applications. Adv Pharmacol. 1997;38:205-227. [PubMed]
 
Moldéus P, Cotgreave IA, Berggren M. Lung protection by a thiol-containing antioxidant: N-acetylcysteine. Respiration. 1986;50(suppl 1):31-42. [PubMed]
 
Cotgreave IA, Moldéus P. Lung protection by thiol-containing antioxidants. Bull Eur Physiopathol Respir. 1987;23(4):275-277. [PubMed]
 
Jeffery PK, Rogers DF, Ayers MM. Effect of oral acetylcysteine on tobacco smoke-induced secretory cell hyperplasia. Eur J Respir Dis Suppl. 1985;139:117-122. [PubMed]
 
Rubio ML, Sanchez-Cifuentes MV, Ortega M, et al. N-acetylcysteine prevents cigarette smoke induced small airways alterations in rats. Eur Respir J. 2000;15(3):505-511. [CrossRef] [PubMed]
 
Bridgeman MM, Marsden M, MacNee W, Flenley DC, Ryle AP. Cysteine and glutathione concentrations in plasma and bronchoalveolar lavage fluid after treatment with N-acetylcysteine. Thorax. 1991;46(1):39-42. [CrossRef] [PubMed]
 
Bergstrand H, Björnson A, Eklund A, et al. Stimuli-induced superoxide radical generation in vitro by human alveolar macrophages from smokers: modulation by N-acetylcysteine treatment in vivo. J Free Radic Biol Med. 1986;2(2):119-127. [CrossRef] [PubMed]
 
Eklund A, Eriksson O, Håkansson L, et al. Oral N-acetylcysteine reduces selected humoral markers of inflammatory cell activity in BAL fluid from healthy smokers: correlation to effects on cellular variables. Eur Respir J. 1988;1(9):832-838. [PubMed]
 
Niederman MS, Rafferty TD, Sasaki CT, Merrill WW, Matthay RA, Reynolds HY. Comparison of bacterial adherence to ciliated and squamous epithelial cells obtained from the human respiratory tract. Am Rev Respir Dis. 1983;127(1):85-90. [PubMed]
 
Suer E, Sayrac S, Sarinay E, et al. Variation in the attachment ofStreptococcus pneumoniaeto human pharyngeal epithelial cells after treatment with S-carboxymethylcysteine. J Infect Chemother. 2008;14(4):333-336. [CrossRef] [PubMed]
 
Riise GC, Qvarfordt I, Larsson S, Eliasson V, Andersson BA. Inhibitory effect of N-acetylcysteine on adherence ofStreptococcus pneumoniaeandHaemophilus influenzaeto human oropharyngeal epithelial cells in vitro. Respiration. 2000;67(5):552-558. [CrossRef] [PubMed]
 
Sinojia R, Shaikh M, Kodgule R, et al. Priming of beta-2 agonist and antimuscarinic induced physiological responses induced by 1200mg/day NAC in moderate to severe COPD patients: a pilot study. Respir Physiol Neurobiol. 2014;191:52-59. [CrossRef] [PubMed]
 
Wu W, Patel KB, Booth JL, Zhang W, Metcalf JP. Cigarette smoke extract suppresses the RIG-I-initiated innate immune response to influenza virus in the human lung. Am J Physiol Lung Cell Mol Physiol. 2011;300(6):L821-L830. [CrossRef] [PubMed]
 
Benrahmoune M, Thérond P, Abedinzadeh Z. The reaction of superoxide radical with N-acetylcysteine. Free Radic Biol Med. 2000;29(8):775-782. [CrossRef] [PubMed]
 
Gressier B, Cabanis A, Lebegue S, et al. Decrease of hypochlorous acid and hydroxyl radical generated by stimulated human neutrophils: comparison in vitro of some thiol-containing drugs. Methods Find Exp Clin Pharmacol. 1994;16(1):9-13. [PubMed]
 
Kharazmi A, Nielsen H, Schiøtz PO. N-acetylcysteine inhibits human neutrophil and monocyte chemotaxis and oxidative metabolism. Int J Immunopharmacol. 1988;10(1):39-46. [CrossRef] [PubMed]
 
Stolarek R, Białasiewicz P, Nowak D. N-acetylcysteine effect on the luminol-dependent chemiluminescence pattern of reactive oxygen species generation by human polymorphonuclear leukocytes. Pulm Pharmacol Ther. 2002;15(4):385-392. [CrossRef] [PubMed]
 
Bridgeman MM, Marsden M, Selby C, Morrison D, MacNee W. Effect of N-acetyl cysteine on the concentrations of thiols in plasma, bronchoalveolar lavage fluid, and lung tissue. Thorax. 1994;49(7):670-675. [CrossRef] [PubMed]
 
De Benedetto F, Aceto A, Dragani B, et al. Long-term oral n-acetylcysteine reduces exhaled hydrogen peroxide in stable COPD. Pulm Pharmacol Ther. 2005;18(1):41-47. [CrossRef] [PubMed]
 
Kasielski M, Nowak D. Long-term administration of N-acetylcysteine decreases hydrogen peroxide exhalation in subjects with chronic obstructive pulmonary disease. Respir Med. 2001;95(6):448-456. [CrossRef] [PubMed]
 
Abdool-Gaffar MS, Ambaram A, Ainslie GM, et al; COPD Working Group. Guideline for the management of chronic obstructive pulmonary disease–2011 update [published correction appears inS Afr Med J. 2011;101(5):288]. S Afr Med J. 2011;101(1 pt 2):63-73. [PubMed]
 
Zhou Y, Wang X, Zeng X, et al. Positive benefits of theophylline in a randomized, double-blind, parallel-group, placebo-controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year. Respirology. 2006;11(5):603-610. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1  Flowchart of the study design. FU = follow-up; NAC = N-acetylcysteine.Grahic Jump Location
Figure Jump LinkFigure 2  A-C, Kaplan-Meier curves showing the time to first exacerbation in the 1-y period (A) overall (NAC, 261.5 ± 18.4 d; placebo, 239.5 ± 17.9 d) and in the (B) low-risk (NAC, 272.1 ± 39.0; placebo, 337 ± 21.3 d), and (C) high-risk (NAC, 258.2 ± 20.8; placebo, 203.6 ± 20.4 d) groups. Cum = cumulative. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 3  A-C, Cumulative exacerbation frequencies over the 1-y study period (A) overall (total) and in the (B) low-risk and (C) high-risk groups. NS = not significant. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 4  Proportion of exacerbation-free patients in the 1-y study period. See Figure 1 and 3 legends for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 5  A-C, Cumulative frequencies of admissions due to exacerbation of COPD over the 1-y study period (A) overall and in the (B) low-risk and (C) high-risk groups. See Figure 1 legend for expansion of abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1  ] Baseline Demographic Characteristics of Patients With COPD

Data are presented as mean ± SEM, % (No.), and median (interquartile range). mMRC = modified Medical Research Council; NAC = N-acetylcysteine.

a 

P < .05.

Table Graphic Jump Location
TABLE 2  ] Patient Baseline Lung Function Parameters

Data are presented as mean ± SEM or %. FEF25%-75% = forced expiratory flow at 25% to 75% of vital capacity; IC = inspiratory capacity; ICS = inhaled corticosteroid; LABA = long-acting β-agonist; LAMA = long-acting muscarinic agonist; RV = residual volume, SABA = short-acting β2-agonist; SAMA = short-acting muscarinic agonist; TLC = total lung capacity. See Table 1 legend for expansion of other abbreviation.

a 

P < .05.

b 

In equivalent dose to beclomethasone/μg.

Table Graphic Jump Location
TABLE 3  ] Subgroup Analysis Comparing Effects of NAC With Placebo in Subgroups Classified According to Various Stratification Criteria (A-C)

Data are presented as mean ± SEM or %. See Table 1 legend for expansion of abbreviation.

a 

More than two episodes in the prior year.

b 

FEV1 < 50%, frequency of exacerbation (more than two episodes in the prior year), or both.

c 

P < .05.

References

Seemungal TA, Hurst JR, Wedzicha JA. Exacerbation rate, health status and mortality in COPD—a review of potential interventions. Int J Chron Obstruct Pulmon Dis. 2009;2009(4):203-223. [CrossRef]
 
Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187(4):347-365. [CrossRef] [PubMed]
 
Sadowska AM, Manuel-Y-Keenoy B, De Backer WA. Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo dose-effects: a review. Pulm Pharmacol Ther. 2007;20(1):9-22. [CrossRef] [PubMed]
 
Poole P, Black PN. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2010;;(2):CD001287.
 
Decramer M, Rutten-van Mölken M, Dekhuijzen PN, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet. 2005;365(9470):1552-1560. [CrossRef] [PubMed]
 
Stav D, Raz M. Effect of N-acetylcysteine on air trapping in COPD: a randomized placebo-controlled study. Chest. 2009;136(2):381-386. [CrossRef] [PubMed]
 
Tse HN, Raiteri L, Wong KY, et al. High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study. Chest. 2013;144(1):106-118. [CrossRef] [PubMed]
 
Wedzicha JA, Rabe KF, Martinez FJ, et al. Efficacy of roflumilast in the COPD frequent exacerbator phenotype. Chest. 2013;143(5):1302-1311. [CrossRef] [PubMed]
 
Wedzicha JA, Brill SE, Allinson JP, Donaldson GC. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med. 2013;11:181. [CrossRef] [PubMed]
 
Hurst JR, Vestbo J, Anzueto A, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128-1138. [CrossRef] [PubMed]
 
Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review of randomized placebo-controlled trials. Am J Med. 2002;113(1):59-65. [CrossRef] [PubMed]
 
Mahler DA, Donohue JF, Barbee RA, et al. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest. 1999;115(4):957-965. [CrossRef] [PubMed]
 
Calverley PM, Anderson JA, Celli B, et al; TORCH Investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775-789. [CrossRef] [PubMed]
 
Vogelmeier C, Hederer B, Glaab T, et al; POET-COPD Investigators. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364(12):1093-1103. [CrossRef] [PubMed]
 
Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J. 2003;22(6):912-919. [CrossRef] [PubMed]
 
Tashkin DP, Celli B, Senn S, et al; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543-1554. [CrossRef] [PubMed]
 
Zheng JP, Kang J, Huang SG, et al. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet. 2008;371(9629):2013-2018. [CrossRef] [PubMed]
 
Aruoma OI, Halliwell B, Hoey BM, Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med. 1989;6(6):593-597. [CrossRef] [PubMed]
 
Cotgreave IA. N-acetylcysteine: pharmacological considerations and experimental and clinical applications. Adv Pharmacol. 1997;38:205-227. [PubMed]
 
Moldéus P, Cotgreave IA, Berggren M. Lung protection by a thiol-containing antioxidant: N-acetylcysteine. Respiration. 1986;50(suppl 1):31-42. [PubMed]
 
Cotgreave IA, Moldéus P. Lung protection by thiol-containing antioxidants. Bull Eur Physiopathol Respir. 1987;23(4):275-277. [PubMed]
 
Jeffery PK, Rogers DF, Ayers MM. Effect of oral acetylcysteine on tobacco smoke-induced secretory cell hyperplasia. Eur J Respir Dis Suppl. 1985;139:117-122. [PubMed]
 
Rubio ML, Sanchez-Cifuentes MV, Ortega M, et al. N-acetylcysteine prevents cigarette smoke induced small airways alterations in rats. Eur Respir J. 2000;15(3):505-511. [CrossRef] [PubMed]
 
Bridgeman MM, Marsden M, MacNee W, Flenley DC, Ryle AP. Cysteine and glutathione concentrations in plasma and bronchoalveolar lavage fluid after treatment with N-acetylcysteine. Thorax. 1991;46(1):39-42. [CrossRef] [PubMed]
 
Bergstrand H, Björnson A, Eklund A, et al. Stimuli-induced superoxide radical generation in vitro by human alveolar macrophages from smokers: modulation by N-acetylcysteine treatment in vivo. J Free Radic Biol Med. 1986;2(2):119-127. [CrossRef] [PubMed]
 
Eklund A, Eriksson O, Håkansson L, et al. Oral N-acetylcysteine reduces selected humoral markers of inflammatory cell activity in BAL fluid from healthy smokers: correlation to effects on cellular variables. Eur Respir J. 1988;1(9):832-838. [PubMed]
 
Niederman MS, Rafferty TD, Sasaki CT, Merrill WW, Matthay RA, Reynolds HY. Comparison of bacterial adherence to ciliated and squamous epithelial cells obtained from the human respiratory tract. Am Rev Respir Dis. 1983;127(1):85-90. [PubMed]
 
Suer E, Sayrac S, Sarinay E, et al. Variation in the attachment ofStreptococcus pneumoniaeto human pharyngeal epithelial cells after treatment with S-carboxymethylcysteine. J Infect Chemother. 2008;14(4):333-336. [CrossRef] [PubMed]
 
Riise GC, Qvarfordt I, Larsson S, Eliasson V, Andersson BA. Inhibitory effect of N-acetylcysteine on adherence ofStreptococcus pneumoniaeandHaemophilus influenzaeto human oropharyngeal epithelial cells in vitro. Respiration. 2000;67(5):552-558. [CrossRef] [PubMed]
 
Sinojia R, Shaikh M, Kodgule R, et al. Priming of beta-2 agonist and antimuscarinic induced physiological responses induced by 1200mg/day NAC in moderate to severe COPD patients: a pilot study. Respir Physiol Neurobiol. 2014;191:52-59. [CrossRef] [PubMed]
 
Wu W, Patel KB, Booth JL, Zhang W, Metcalf JP. Cigarette smoke extract suppresses the RIG-I-initiated innate immune response to influenza virus in the human lung. Am J Physiol Lung Cell Mol Physiol. 2011;300(6):L821-L830. [CrossRef] [PubMed]
 
Benrahmoune M, Thérond P, Abedinzadeh Z. The reaction of superoxide radical with N-acetylcysteine. Free Radic Biol Med. 2000;29(8):775-782. [CrossRef] [PubMed]
 
Gressier B, Cabanis A, Lebegue S, et al. Decrease of hypochlorous acid and hydroxyl radical generated by stimulated human neutrophils: comparison in vitro of some thiol-containing drugs. Methods Find Exp Clin Pharmacol. 1994;16(1):9-13. [PubMed]
 
Kharazmi A, Nielsen H, Schiøtz PO. N-acetylcysteine inhibits human neutrophil and monocyte chemotaxis and oxidative metabolism. Int J Immunopharmacol. 1988;10(1):39-46. [CrossRef] [PubMed]
 
Stolarek R, Białasiewicz P, Nowak D. N-acetylcysteine effect on the luminol-dependent chemiluminescence pattern of reactive oxygen species generation by human polymorphonuclear leukocytes. Pulm Pharmacol Ther. 2002;15(4):385-392. [CrossRef] [PubMed]
 
Bridgeman MM, Marsden M, Selby C, Morrison D, MacNee W. Effect of N-acetyl cysteine on the concentrations of thiols in plasma, bronchoalveolar lavage fluid, and lung tissue. Thorax. 1994;49(7):670-675. [CrossRef] [PubMed]
 
De Benedetto F, Aceto A, Dragani B, et al. Long-term oral n-acetylcysteine reduces exhaled hydrogen peroxide in stable COPD. Pulm Pharmacol Ther. 2005;18(1):41-47. [CrossRef] [PubMed]
 
Kasielski M, Nowak D. Long-term administration of N-acetylcysteine decreases hydrogen peroxide exhalation in subjects with chronic obstructive pulmonary disease. Respir Med. 2001;95(6):448-456. [CrossRef] [PubMed]
 
Abdool-Gaffar MS, Ambaram A, Ainslie GM, et al; COPD Working Group. Guideline for the management of chronic obstructive pulmonary disease–2011 update [published correction appears inS Afr Med J. 2011;101(5):288]. S Afr Med J. 2011;101(1 pt 2):63-73. [PubMed]
 
Zhou Y, Wang X, Zeng X, et al. Positive benefits of theophylline in a randomized, double-blind, parallel-group, placebo-controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year. Respirology. 2006;11(5):603-610. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Supporting Data

Online Supplement

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543