CARBOCISTEINE REDUCES FREQUENCY OF COMMON COLDS AND EXACERBATIONS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE
To the Editor: Various kind of viruses, including rhinovirus and influenza virus, have been reported to cause chronic obstructive pulmonary disease (COPD) exacerbations.1 Mucolytic drugs prevent acute exacerbations of chronic obstructive bronchitis.2 Mucolytic drugs, including carbocisteine, have various effects, such as the reduction of elastic modules of mucus and improvement of mucociliary transport.3 Therefore, it is conceivable that mucolytic drugs may modulate the function of airway epithelial cells, including the expression of intercellular adhesion molecule-1, a receptor for major rhinoviruses that are the most commonly implicated pathogens of common colds,4 although the effects of carbocisteine have not been studied on the prevention of the common cold in patients with COPD.
In the present study, a prospective, randomized, double-blind, controlled trial was performed to examine the effects of carbocisteine on the frequency of common colds and exacerbations in patients with COPD. Patients diagnosed with COPD5 were enrolled and treated with sustained-release theophylline, inhaled oxitropium bromide, inhaled β2-agonist, or a combination of these but did not receive inhaled or oral corticosteroids. One hundred fifty-six patients were randomly assigned to receive carbocisteine therapy (1,500 mg/d, 78 patients, carbocisteine group) or placebo therapy with tablets of lactose (1,500 mg/d, 78 patients, control group) until the end of the study, between October 2001 and June 2005 at the Tohoku University Hospital, Sendai, Japan. Ten symptoms of upper respiratory tract infections were recorded in each patient, and common cold was defined as a total symptom score of greater than 5, as described previously.6 A COPD exacerbation was defined as an acute and sustained worsening of COPD symptoms requiring changes to regular treatment, as previously described.7 The primary endpoints of this study were to compare the rate and number of common colds and exacerbations of the carbocisteine group and the control group. The rate and number of common colds and acute exacerbations of COPD were observed for 12 months. It was estimated that 50 patients per group needed to be enrolled on the basis of experimental-treatment group to confer a power of 80% for a two-sided 0.05 level by sample size analysis.8 Actual accrual was 78 eligible patients in each group. The sample sizes for the two groups were thought to be sufficient to demonstrate the primary endpoints in the present study. Significance was accepted at P<.05. The Tohoku University Ethics Committee approved the study, and written informed consent was obtained from all patients.
None of the patients in either group died or had any apparent adverse effects from carbocisteine therapy during the study period. None of the 156 patients with COPD were lost to follow-up, and all were analyzable. Age, sex, smoking history, stage of COPD, and lung function test were matched between the two groups (Table 1). The mean number±standard deviation of common colds for 12 months was significantly lower in the carbocysteine group (1.69±0.18 per person) than in the control group (3.14±0.35 per person; P<.001, Student t test) (Table 1). The use of carbocisteine was closely associated with a lower frequency of development of common colds more than twice per year in patients with COPD (relative risk=0.4, 95% confidence interval (CI)=0.2–0.8, P=.009). The number of exacerbations for 12 months was also significantly lower in the carbocisteine group than in the control group (P<.001, Student t test) (Table 1). One hundred eight COPD exacerbations related to 245 common colds (44%) occurred in the control group and 42 exacerbations related to 132 common colds (32%) in the carbocisteine group. The relative risk of experiencing an exacerbation in the carbocisteine group compared with that in the control group was 0.3 (95% CI=0.2–0.7, P=.002).
| Characteristic | Control Group (n=78) | Carbocisteine Group (n=78) | Odds Ratio (95% Confidence Interval) | P-value |
|---|---|---|---|---|
| Age, mean±SE | 72.8±1.0 | 72.5±1.0 | .82 | |
| Sex, n | ||||
| Male | 67 | 66 | .82 | |
| Female | 11 | 12 | ||
| Smoking history (pack-year), mean±SE | 46.6±3.1 | 42.1±3.0 | .29 | |
| COPD stage, n | ||||
| I | 23 | 28 | .39 | |
| II | 43 | 42 | .87 | |
| III | 12 | 8 | .34 | |
| Pulmonary function, mean±SE | ||||
| FVC, L | 2.19±0.03 | 2.19±0.03 | .99 | |
| FEV1, L/s | 1.41±0.05 | 1.41±0.05 | .99 | |
| FEV1/FVC, % | 64.4±2.2 | 64.4±2.2 | .99 | |
| FEV1, % predicted | 61.5±2.2 | 61.4±2.1 | .98 | |
| Total common colds/year, n | 245 | 132 | ||
| Mean common colds/year, mean±SE | 3.14±0.35 | 1.69±0.18 | <.001 | |
| Total patients with≥2 common colds/year, n (%) | 53 (68) | 35 (45) | 0.4 (0.2–0.8) | .009 |
| Total exacerbations/year, n | 108 | 42 | ||
| Mean exacerbations/year, mean±SE | 1.38±0.20 | 0.54±0.11 | <.001 | |
| Total patients with≥1 exacerbations/year, n (%) | 47 (60) | 28 (36) | 0.3 (0.2–0.7) | .002 |
- SE=standard error; FVC=forced vital capacity; FEV1=forced expiratory volume in 1 second.
In this study, the number of common colds and exacerbations was significantly lower in the carbocisteine group than in the control group. The lower rate of COPD exacerbations observed in this study is consistent with a previous report using carbocisteine.2 The mucolytic drug ambroxol inhibits influenza virus proliferation,9 although the inhibitory effects of carbocisteine on the influenza virus and rhinovirus, major pathogens of COPD exacerbations, were not studied in the present study.1 Alternatively, another mucolytic drug, S-carboxymethylcysteine, inhibits neutrophil activation, which plays a key role in COPD exacerbations.10 These antiviral and antiinflammatory effects of carbocisteine might be associated with the prevention of common colds and exacerbations in patients with COPD in the present study. Carbocisteine may have beneficial effects on the prevention of common colds and exacerbations in patients with COPD.
ACKNOWLEDGMENTS
We thank Mr. Grant Crittenden for English corrections.
Financial Disclosures: Dr. Yasuda was partly supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture (17790524) of the Japanese government. Dr. Yamaya was partly supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture (16590732), and the Ministry of Welfare and Labor of the Japanese government. Drs. T. Sasaki, Inoue, Nakayama, Tomita, Yoshida, and H. Sasaki do not have a financial relationship with a commercial entity that has an interest in the subject of this letter.
Author Contributions: Dr. Yasuda, Dr. Yamaya, Dr. Nakayama: study concept and design, acquisition of data, analysis and interpretation of data, and preparation of letter. Dr. T. Sasaki, Dr. Tomita, and Dr. Yoshida: acquisition of data. Dr. H. Sasaki: study concept and design, analysis and interpretation of data.
Sponsor's Role: None.
