Chronic Bronchitis and Chronic Obstructive Pulmonary Disease

Lung Function Decline

The presence of CB is associated with worsened airflow obstruction and a progressive decline in lung function. In a study that followed approximately 4,000 subjects for 12 years, those who had symptoms of CB (wheezing, cough, dyspnea, and phlegm) had a greater initial and longitudinal decline in FEV₁ (57). Two large epidemiologic studies have shown that chronic mucus hypersecretion was significantly and consistently associated with both an excessive decline in FEV₁ and an increased risk of COPD hospitalization (3, 5).

The presence of CB without airflow obstruction seems to predict the development of COPD. One study of an international cohort of more than 5,000 subjects 20 to 44 years old with normal lung function were followed for 11 years. Incident cases of COPD were those who had an FEV₁/FVC ratio less than 70% at the end of the follow-up. Chronic cough and phlegm were independent risk factors for COPD development (incidence rate ratio, 1.85; 95% CI, 1.17–2.93), and patients with CB symptoms had a nearly threefold increased risk of developing new COPD compared with asymptomatic subjects (16). In the Obstructive Lung Disease in Northern Sweden (OLIN) study, the 7-year cumulative incidence of COPD was higher in those with cough and recurrent wheeze (61). Finally, the presence of phlegm and other respiratory symptoms in the Framingham offspring cohort identified a group that was more susceptible to develop COPD (62).

Mortality

CB is a risk factor for respiratory-related deaths. Prescott and colleagues found that chronic mucus hypersecretion in hospitalized patients with COPD was associated with an increased risk of death by pulmonary infection (63). Respiratory symptoms of cough and phlegm in 8,427 white U.S. adults over a 9- to 12-year observational period were associated with increased COPD-related mortality (24). In addition, Pelkonen and colleagues found an increased risk of respiratory-related death when CB was present (22).

CB may increase all-cause mortality as well, independent of the level of obstructive airways disease. Table 2 summarizes selected studies that have addressed all-cause mortality. The reasons are unclear, but it has been proposed that the inflammatory state of the lung causes systemic inflammation and increases the risk of cardiac disease and other comorbidities. In the study by Pelkonen and colleagues, the multivariate hazard ratios (HRs) for all-cause mortality in those with persistent CB was 1.64 (95% CI, 1.23–2.19) after adjustment for lung function (22). In a post hoc analysis of the National Emphysema Treatment Trial, severe CB, defined as chronic cough, phlegm, and chest trouble, was associated with a higher mortality and hospitalization rate in those treated with medical therapy alone (64). The Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD) revealed that CB at study enrollment significantly increased the risk of all-cause mortality in those younger than 50 years old (HR, 2.2; 95% CI, 1.3–3.8) but not in those older than 50 years (HR, 1.0; 95% CI, 0.7–1.3) (5). CB was also associated with higher levels of serum IL-8 and C-reactive protein, which supports the hypothesis that systemic inflammation contributes to the increased risk for mortality.

However, there are other studies that reported no significant association of CB with all-cause mortality. For example, the National Health and Nutrition Epidemiologic Survey (NHANES) showed an increased mortality in those with CB and obstructive lung disease but not in those with CB symptoms without obstructive airways disease (65). Another study in 884 men reported only a trend for increased mortality with CB (OR, 1.65; 95% CI, 0.95–2.89) (66). Therefore, studies to date do not show a consistent effect of CB on all-cause mortality, and further epidemiologic studies are warranted to clarify this relationship.

COPD Exacerbation

CB has also been shown to increase the risk of COPD exacerbation. Table 3 provides an overview of some critical studies that reported the clinical characteristics of patients with CB compared with those without CB. Seemungal and colleagues found that CB significantly increased the odds of having frequent exacerbations in a group of 70 patients (67). A cross-sectional analysis of 433 patients also similarly found an increased risk of exacerbation in those with CB compared with those without CB (4). Another cross-sectional analysis of 1,061 subjects with GOLD stage 2 to 4 disease found that those with CB had a greater history of exacerbations in the year before study entry (1.21 ± 1.62/patient/yr vs. 0.63 ± 1.12/patient/yr, P = 0.027) (6). In longitudinal follow-up of 2,997 subjects in the COPDGene cohort, those with CB had a 47.6% higher total exacerbation frequency than those without CB (0.93 ± 2.11/patient/yr vs. 0.63 ± 1.69/patient/yr, P < 0.0001), and the adjusted HR of a frequent exacerbator phenotype (defined as more than two exacerbations per year) for CB was 1.38 (95% CI, 1.13–1.69) (68).

Health-related Quality of Life

Finally, CB is associated with a greater burden of respiratory symptoms and worse HRQoL. In a telemedicine study of 50 patients with severe COPD with more than 14,500 observation days, those who complained of more sputum symptoms on a daily basis also complained of more dyspnea, cough, wheeze, and nasal congestion and had lower peak flow measurements (69). Compared with subjects without CB, GOLD stage 2 to 4 subjects with CB symptoms in the COPDGene cohort also had more severe dyspnea, more allergic nasal and ocular symptoms, more frequent nocturnal awakenings by cough and dyspnea, and worse St. George’s Respiratory Questionnaire disease-specific quality of life scores (6). Similarly, worse HRQoL was noted in patients with COPD with CB in the COPD Clinical Research Network study of Azithromycin to Prevent COPD Exacerbations study and the PLATINO (Proyecto Latinoamericano de Investigacion en Obstruccion Pulmonar) study (21, 26). Even subjects with nonobstructed chronic bronchitis in the COPDGene cohort indicated worse HRQoL by St. George’s Respiratory Questionnaire (19).

Smoking Cessation

Smoking cessation can improve cough in many patients with CB by improving mucociliary function and by decreasing goblet cell hyperplasia (70). Smoking cessation has also been shown to decrease airway injury and lower levels of mucus in exfoliated sputum tracheobronchial cells compared with those who continued to smoke (71). A large longitudinal follow-up study found that the incidence rates of CB were much higher in current smokers compared with ex-smokers (42 vs. 26%) (22). Abstinence from cigarette smoke may also alter the natural history of COPD by altering the immune mechanisms leading to persistent inflammation and abnormal epithelial cell gene expression attributable to tobacco smoke (37). There is unfortunately a paucity of data regarding the effects of smoking cessation on CB symptomatology. Further studies are needed to elucidate how smoking cessation affects the severity and trajectory of CB in COPD.

Physical Measures

Mucus clearance is aided by maneuvers that promote coughing and increase minute ventilation, including exercise. This augments shear stresses on mucosal surfaces generated by increased airflow. It also increases humidification of the airway and regulates mucus hydration. Thus, methods such as application of positive expiratory pressure or use of flutter valves or high-frequency chest compression vests may be of value but have not been studied for use in COPD in large clinical trials. Although cystic fibrosis studies have demonstrated that chest percussion and postural drainage improve mucociliary clearance, these methods have not been well studied in the COPD patient population. Few studies have addressed chest physiotherapy or directed coughing techniques in COPD, which have shown some improvements in mucus clearance but no changes in lung function (72).

Expectorants and Mucolytics

Guaifenesin works by promoting vagally mediated increase in airway secretions (73). Although it has been shown to help with the common cold, long-term use of guaifenesin has not been shown to be of benefit in COPD or CB (74). Inhaled hypertonic saline works not only by rehydrating mucus by drawing water from epithelial cells but also by promoting cough (75, 76). Although this method has been proved to improve lung function in cystic fibrosis, it has only been shown in one study in COPD to improve dyspnea and exercise capacity (77). Inhaled dornase alfa hydrolyzes DNA, thereby improving lung function and decreasing exacerbation frequency in patients with cystic fibrosis, in whom airway mucus concentrations of DNA are high. However, the concentration of DNA in patients with COPD is much lower (78), and dornase alfa not only is not beneficial but it may also be harmful (79).

Methylxanthines and Short-Acting β-Adrenergic Receptor Agonists

Both methylxanthines and short-acting β-adrenergic receptor agonists (SABAs) promote mucus clearance by several mechanisms:

• Increase airway luminal diameter;

• Increase ciliary beat frequency via an increase in intracellular cyclic adenosine monophosphate levels; and

• Increase mucus hydration by stimulating airway Cl⁻ secretion via activation of the cystic fibrosis transmembrane regulator.

This decreases mucus viscosity, allowing for easier transport by airway cilia (80–82). In animal models, short-term administration of β-agonists is associated with up-regulation of mucociliary clearance (83, 84). Similarly, methylxanthines improve mucociliary clearance not only via their bronchodilatory properties but also by stimulating ciliary beat frequency, augmenting airway epithelial ion transport to increase mucus hydration and promoting mucus secretion in the lower airways (85). Clinical studies of theophylline in CB have shown improved lung function but no consistent change in cough and sputum production (86, 87).

Long-Acting β-Adrenergic Receptor Agonists

The effects of long-acting β-adrenergic receptor agonists (LABAs) on mucociliary function have been attributed to their beneficial effects on lung function (87–90). LABAs also reduce hyperinflation and increase peak expiratory flow, which are essential components of effective cough (91). In vitro evidence has shown that salmeterol can stimulate ciliary beat frequency (81). Similarly, formoterol significantly improves mucociliary clearance compared with placebo in patients with bronchitis (92).

Anticholinergics

Anticholinergics, by their action on the muscarinic receptor, are believed to help mucus clearance by increasing luminal diameter and by decreasing surface and submucosal gland mucin secretion (93–95). They are also believed to facilitate cough-induced mucus clearance. However, anticholinergics may desiccate airway secretions by depleting airway surface liquid, thereby making secretions more difficult to expectorate. In vivo, the literature does not support the use of anticholinergics for the treatment of CB. Ipratropium bromide has been shown to reduce the quantity and severity of coughs in chronic bronchitics (96) but is not effective in improving mucociliary clearance in COPD (97). In a study of 470 patients with FEV₁ 39% predicted, tiotropium improved lung function but did not affect cough symptoms (98). In another study of 39 patients with COPD, tiotropium reduced the number of coughs, but mucociliary clearance was not improved (99).

Glucocorticoids

There is in vitro evidence that glucocorticoids reduce inflammation and mucus production (100, 101). In a murine model of asthma, inhaled corticosteroids decrease goblet cell hyperplasia (102). Dexamethasone has also been shown to decrease epithelial mucin gene MUC5AC gene expression in human bronchial epithelial cells (103). They may also hasten mucociliary clearance (104). Inhaled corticosteroids reduce exacerbation frequency and improve quality-of-life scores in COPD (105–107). Whether inhaled corticosteroids are more beneficial in patients with COPD with CB or airway-predominant phenotypes remains to be determined.

Phosphodiesterase-4 Inhibitors

Phosphodiesterase-4 (PDE-4) inhibition decreases inflammation and promotes airway smooth-muscle relaxation by preventing the hydrolysis of cyclic adenosine monophosphate to its inactive metabolite. Cilomilast and roflumilast are highly specific second-generation oral PDE-4 inhibitors. A metaanalysis of 23 randomized trials of roflumilast or cilomilast compared with placebo found that treatment with a PDE-4 inhibitor only modestly increased FEV₁ (45.59 ml; 95% CI, 39.1–52.03) but reduced the likelihood of an exacerbation (OR, 0.78; 95% CI, 0.72–0.85) (108). Roflumilast significantly improved prebronchodilator FEV₁ and decreased the rate of moderate to severe exacerbations in a 52-week randomized trial of 3,091 patients with COPD. Compared with placebo, roflumilast decreased exacerbations by 17% (95% CI, 8–25%) (109). In two 24-week trials, 933 patients with moderate to severe COPD were randomly assigned to roflumilast plus salmeterol or salmeterol alone, and 743 patients were randomly assigned to roflumilast plus tiotropium or tiotropium alone (110). The overwhelming majority of patients (78–100%) in these trials had chronic cough and sputum production at enrollment. In both trials, roflumilast significantly improved the primary endpoint, prebronchodilator FEV₁, as well as the exacerbation rate. Thus, as CB increases risk for exacerbation, PDE-4 inhibitors may play a preferential role in preventing the development of exacerbation in patients with CB and COPD.

Antioxidants

As oxidative stress is crucial to the pathogenesis of COPD (111), antioxidant therapy may be of benefit in COPD treatment. Thiol compounds are powerful antioxidants and include N-acetylcysteine, N-acystelyn, carbocysteine, erdosteine, and fudosteine. The two most extensively studied antioxidant medications for COPD are N-acetylcysteine and carbocysteine. N-Acetylcysteine is a precursor of l-cysteine and reduced glutathione, which reduces cellular levels of oxidative stress and production of reactive oxygen species. N-Acetylcysteine also reduces disulfide bonds and sulfhydryl bonds that link together mucin polymers, thereby reducing sputum viscosity. Carbocysteine is a blocked thiol derivative of l-cysteine with in vitro free-radical scavenging and antiinflammatory properties and may work on the fucose and sialic acid content in mucus (112). Recent data have shed more light on the use of these agents in COPD.

The Bronchitis Randomized on NAC Cost-Utility Study (BRONCHUS) is the largest trial of N-acetylcysteine use in COPD to date (113). In this multicenter study, 523 patients with a mean FEV₁ of 57% predicted were randomized to N-acetylcysteine 600 mg daily or placebo and followed for 3 years. Mean exacerbation rates of the subjects were 2.4 to 2.5 exacerbations/yr. Primary outcomes were yearly reduction in FEV₁ and the number of exacerbations per year. There were no differences in FEV₁ decline over time or HRQoL between the two groups. There was also no overall difference in the number of exacerbations. However, in post hoc analysis, those without inhaled corticosteroids (about 30% of the entire group) had a significant reduction in exacerbations with N-acetylcysteine compared with the placebo. The Effect of Carbocysteine on Acute Exacerbation of Chronic Obstructive Pulmonary Disease (PEACE) study randomized 709 patients with at least two exacerbations within the 2 years before enrollment to carbocysteine 500 mg three times daily or placebo, with the primary endpoint of exacerbation rate over 1 year (114). Numbers of exacerbations per patient per year declined significantly in the carbocysteine group compared with the placebo group (1.01 [SE, 0.06]; vs. 1.35 [SE, 0.06]; risk ratio, 0.75 [95% CI, 0.62–0.92; P = 0·004]). There were no significant interactions between COPD severity, smoking, and use of inhaled corticosteroids and the primary endpoint.

These two studies provided conflicting results on the efficacy of antioxidants on exacerbation frequency. It has been argued that 600 mg daily of N-acetylcysteine was too low a dose to see a clinical effect, as 600 mg three times daily is used in those with idiopathic pulmonary fibrosis. In addition, in the PEACE trial, the mean FEV₁ was lower (44% predicted) and only 15 to 18% of patients were treated with inhaled corticosteroids. Therefore, perhaps antioxidant therapy is more efficacious in those with lower lung function. However, it is difficult to know the efficacy of these antioxidants in comparison with inhaled corticosteroids because of the differences in study populations.

Poole and Black performed a metaanalysis of mucolytic agents for CB or COPD (115). They included randomized, placebo-controlled studies of at least 2 months’ duration. They found 28 trials involving 7,042 participants to be methodologically acceptable for further analysis. The majority of the studies involved the use of N-acetylcysteine (n = 14) or carbocysteine (n = 4). Compared with placebo, there was a 21% reduction in number of exacerbations per patient with oral mucolytics (weighted mean difference, −0.04 per month; 95% CI, −0.05 to −0.03). There was no overall effect on lung function or increase in adverse effects from the medications.

Antibiotics

Chronic antibiotic therapy is generally not indicated for patients with emphysema or CB. Macrolide therapy, however, has been shown to have antiinflammatory properties and may have a role in the treatment of those with CB. They have been shown to inhibit proinflammatory cytokines, decrease neutrophil burst, inhibit migration and increase apoptosis, decrease eosinophilic inflammation, increase mucociliary transport, reduce goblet cell secretion, and decrease bronchoconstriction (116). The effect of chronic macrolide therapy on COPD exacerbations was assessed in 109 patients with COPD who were randomly assigned to receive erythromycin 250 mg or placebo twice daily for 1 year (117). The erythromycin group had significantly fewer exacerbations than the placebo group. A recent large, prospective, placebo-controlled, randomized trial on the use of azithromycin (250 mg daily for 1 year) to prevent acute exacerbations of COPD (118) showed that azithromycin was associated with a significant decrease in exacerbation frequency and an improvement in HRQoL. There was, however, no significant additional benefit of azithromycin in those with CB at baseline.

Future Directions

It is evident that CB has significant clinical impact in COPD. Why some smokers develop CB and others do not remains a mystery. Current therapeutic options beyond bronchodilators and inhaled corticosteroids are limited. In addition, it is not clear how smoking cessation affects the natural history of CB. Further studies are desperately needed to elucidate the underlying pathophysiology to understand the nature of this disorder. This will ultimately lead to better therapies that directly target CB to improve symptoms, alter the risk of exacerbations, and reduce mortality.