Published: August 2010
Based on Laennec’s work,1 the CIBA symposium proposed that chronic bronchitis was to be defined as “chronic or recurrent excessive mucus secretion in the bronchial tree” manifested clinically by cough and expectoration of no other origin, and that bronchitis found in chronic obstructive pulmonary disease (COPD) should be distinguished from that of nuisance bronchitis or Laennec’s catarrh by the presence of airflow limitation.2,3 Chronic bronchitis and emphysema often have similar causes (tobacco use) and often occur together. As a result, the umbrella term of chronic obstructive pulmonary disease is often used synonymously to describe both clinical entities.4,5 The disabling and debilitating nature of COPD is often punctuated by intermittent acute bacterial exacerbations of chronic bronchitis (ABECB) that contribute greatly to the morbidity and the overall diminished quality of life in these patients. In fact, bacterial exacerbations are the leading cause of death in COPD.6
The definition of bronchitis is one that remains largely subjective and has few rare objective correlates. The American Thoracic Society defines chronic bronchitis as the presence of chronic productive cough for 3 months in each of the 2 successive years in a patient in whom other disease states that can cause similar symptoms have been excluded.7 The most commonly used definition of an ABECB is a subjective increase in dyspnea, increased sputum volume, or increased sputum purulence. Anthonisen and colleagues attempted to stratify the severity of an ABECB based on these very symptoms.8 According to the Anthonisen severity scale, type I (severe) episodes of ABECB have all three clinical findings, and type II (moderate) exhibit two clinical findings. Type III exacerbations (mild) have one of the clinical findings plus one of the following: an upper respiratory tract infection in the past 5 days, fever without any other apparent cause, increased cough or wheezing, or a 20% increase in the respiratory rate or heart rate above baseline.9 In many guidelines, this scale is used to assess the severity of an exacerbation and direct management.
The worldwide prevalence of chronic bronchitis and ABECB is likely to be underestimated due to the variability in the definition of COPD. Traditionally, it has been believed that chronic bronchitis is a major component in 85% of patients with COPD.10 In the United States alone, more than 16 million people are affected with COPD, and it is estimated that more than 12 million of those suffer from chronic bronchitis symptoms.7 Acute exacerbations in more than 50% of cases of chronic bronchitis and COPD, particularly those meeting the Anthonisen criteria, are likely the result of infectious pathogenic bacteria. Overall, these exacerbations occur more often in smokers than in nonsmokers. After an acute exacerbation, many patients experience a decrease in quality of life, and subsequently more than 50% of patients are readmitted with an ABECB more than once in the following 6 months. Therefore, one of the main goals of therapy in managing COPD is to reduce the number and severity of exacerbations.
Acute exacerbations of chronic bronchitis and COPD are the main causes of medical visits and hospitalizations, resulting in economic costs in excess of $5 billion yearly. In one prospective series, the costs of treating COPD and ABECB were found to be almost twice those reported for asthma. The prevalence of COPD, and thus the prevalence of ABECB, continues to rise as the population ages, and it is the only leading cause of death for which the mortality rate is currently increasing.5,7
The pathologic lesions of chronic bronchitis involve morphologic changes in both the large and small airways. In patients with chronic bronchitis, these airways contain a marked presence of inflammatory cells with a predominance of monocytes, lymphocytes, and CD8+ cells as well as neutrophils in the airway lumen. In the large airways, inflammation leads to metaplasia of both the columnar and goblet cells that line the epithelium. In addition, there is an increase in the size of the mucus-secreting glands in smooth muscle, connective tissue in the bronchial wall, and degeneration of the airway cartilage.
Evidence is emerging that ABECBs are associated with increased airway inflammation. There appears to be a clear association between the degree of inflammation and the severity and frequency of the exacerbations. Bronchoalveolar lavage (BAL) specimens taken during ABECB show increases in the absolute number and percentage of neutrophils. Levels of interleukin8 (IL-8), a potent neutrophil chemotactic factor, leukotriene B4, and myeloperoxidase (MPO) all have been found to be increased during ABECB. In addition, cytokine levels in BAL fluid have been noted to be higher during ABECB.
In a normal patient, the respiratory tree is sterile. In a stable chronic bronchitis patient, the sputum produced is usually mucoid and scant. Even in this quiescent period, however, cultures of sputum can yield potentially pathogenic bacteria in 25% to 50% of cases. Organisms including nontypeable Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae have been found to be the predominant organisms in early studies. Once these bacteria colonize the lower airway, they can directly cause airway inflammation and impaired mucociliary clearance, perpetuating a vicious circle of impairing local defenses.
Bacteria have been isolated from the sputum in approximately 60% of ABECB cases. The most common organisms isolated include H. influenzae, Haemophilus parainfluenzae, S. pneumoniae, and M. catarrhalis (Box 1). The contributions of these four organisms can depend on the severity of underlying airway disease. A number of studies have found more virulent organisms in the airways of severe chronic bronchitis patients with acute exacerbations, including Staphylococcus aureus, Pseudomonas species, and members of the Enterobacteriaceae family. In general, during ABECB, many of the same bacteria that are found in the airways during clinically stable periods are present but at higher colony counts. The role of atypical pathogens such as Mycoplasma and Chlamydia species seem to follow three separate mechanisms in ABECB. First, infection with Chlamydia pneumoniae infection at an early age can make airways more susceptible to effects of irritants such as cigarette smoke and can increase the risk of chronic bronchitis later in life. Second, both these species can cause ABECB themselves. Last, atypical organisms and viruses can cause a primary infection that can lead to severe lower airway inflammation, enabling a secondary increase in bacterial proliferation that can lead to an exacerbation.
|Box 1 Responsible Bacteria in Acute Exacerbations of Chronic Bronchitis|
|Common Bacterial Pathogens (30%-50%)|
|Less-Common Bacterial Pathogens (10%-15%)|
|Other gram-negative bacilli|
|Other gram-positive cocci|
|Atypical Pathogens (5%-15%)|
The clinical diagnosis of ABECB traditionally uses some combination of the original three Anthonisen criteria: increased cough, dyspnea, or increased sputum purulence from baseline. There are no characteristic laboratory or radiographic tests that can confirm the diagnosis of ABECB.
Some clinicians have proposed major and minor criteria; the major criteria consist of the original Anthonisen criteria and the minor criteria consist of wheezing, sore throat, cough, and symptoms of the common cold, including nasal congestion or discharge. They define an ABECB as the presence of at least two major symptoms or one major symptom and one minor symptom for at least 2 consecutive days.
There are no characteristic physical findings in ABECB. Some have suggested that severe exacerbations may be associated with body temperatures greater than 38.5° C, although this is highly controversial. Chest radiographs are not helpful in making the diagnosis of ABECB, but they can indicate pneumonia or other diagnoses, such as congestive heart failure. The exception to this is a patient presenting to the emergency department or being hospitalized where routing chest x-rays have revealed abnormalities that led to changes in management (16% to 21% of cases). Sputum Gram stain and culture have a limited role in diagnosing ABECB due to frequent colonization of airways in chronic bronchitis patients. Sputum analysis should be reserved for patients with frequent exacerbations or in patients with purulent sputum in whom there is a suspicion of more virulent or resistant bacteria. Spirometry during an acute exacerbation has little value, but it is important to know the pre-exacerbation state forced expiratory volume in 1 second (FEV1) as a predictor of an adverse outcome of ABECB.
Therapy should be directed toward three major goals: relief of symptoms, prevention of transient loss of pulmonary function (can lead to hospitalization), and reassessment of the disease in an attempt to reduce the risk of any further exacerbations. Patients should be removed from any further airway irritants including dust, pollutants, and cigarette smoke. Pharmacologic therapy should be aimed at decreasing the work of breathing, decreasing airway inflammation, lowering the bacterial burden of the lower airways, and treating resulting hypoxia.
The role of antimicrobial therapy in the treatment of ABECB remains controversial despite numerous therapeutic trials of antibiotics for more than 50 years. Most comparative trials have found equivalence in the use of antimicrobials. Differences in study end points, differences in patient groups studied, and variations in antibiotics used have made the comparison of these studies difficult. Not all antibiotics used to treat ABECB have the same spectrum of activity or pharmacokinetic properties. Therefore, numerous factors should be considered when selecting an antimicrobial agent.
Antibiotics should have both in vitro and in vivo activities against the most commonly associated pathogens implicated in ABECB, including H. influenzae, S. pneumoniae, and M. catarrhalis. In certain subgroups of patients with severe obstructive disease, coverage might need to be extended to include other pathogens such as S. aureus, Pseudomonas aeruginosa, species in the family Enterobacteriaceae, and atypical pathogens. Special attention should be paid to local and regional resistance profiles for the major bacterial pathogens. For example, at the Cleveland Clinic Foundation, the resistance rate of S. pneumoniae to penicillin is 42%; in Detroit, it is as low as 5.2%.9
The major oral antimicrobials used to treat ABECB are listed in Table 1. Antimicrobial therapy is appropriate for patients with an ABECB if they fall into the Anthonisen type I or type II categories but is not warranted in patients with a type III exacerbation. High-risk patients, including patients who have significant pulmonary impairment (FEV1 < 50% or lower than predicted), who have four or more exacerbations per year, or who use supplemental oxygen or chronic oral corticosteroids, should be treated with antibiotics during ABECB. Due to emerging antimicrobial resistance, second-generation macrolides and some second- and third-generation cephalosporins may be used to treat ABECB rather than traditional first-line agents (aminopenicillins, doxycycline, trimethoprim-sulfamethoxazole [TMP-SMX]). A failure rate of 13% to 25% can be expected after treatment of ABECB with a traditional first-line antibiotic (amoxicillin, TMP-SMX, tetracycline, erythromycin). Patients who have structural lung disease, who chronically use corticosteroids, and who frequently use antimicrobials are at higher risk for P. aeruginosa infection and should be treated with antipseudomonal agents such as the fluoroquinolones. Patients who have been treated in the past 3 months for ABECB and who present with a relapse or reoccurrence of ABECB should be treated with a different class of antibiotics.
|Antibiotic||Spectrum of Activity and Resistance Pattern||Comments|
|Amoxicillin||No activity against atypical and beta-lactamase-producing bacteria||Resistance limits use|
|Penicillin resistance concerning with Streptococcus pneumoniae|
|Limited activity against Enterobacteriaceae|
|Amoxicillin-clavulanate||Activity against major pathogens||More costly|
|No activity against atypical bacteria||Gastrointestinal side effects|
|Penicillin resistance concerning with S. pneumoniae|
|Moderate activity against Enterobacteriaceae|
|General||Activity against major pathogens||Alternative to beta-lactam agents and generally as effective|
|No activity against atypical bacteria|
|Resistance concerning with S. pneumoniae|
|Moderate activity against Enterobacteriaceae|
|Cefaclor||Can be destroyed by Haemophilus influenzae and Moraxella catarrhalis enzymes||Associated with failure in patients with severe disease|
|Cefprozil||Moderate H. influenzae activity|
|Loracarbef||Moderate H. influenzae activity|
|Cefibuten||No activity against Staphylococcus aureus||Poor gram-positive activity limits use|
|Marginal activity against S. pneumoniae|
|Cefixime||Poor activity against S. aureus|
|General||Macrolide resistance concerning with S. pneumoniae|
|Active against atypical organisms|
|Not active against Enterobacteriaceae|
|Azithromycin||Greatest activity against H. influenzae||Short course of 3-5 days may be used|
|Clarithromycin||Greatest activity against S. pneumoniae||Alteration of taste may be an issue with bid dosing|
|Erythromycin||Poor activity against H. influenzae||Limited spectrum of activity|
|Doxycycline||Covers major pathogens and atypical organisms S. pneumoniae resistance is common||Maybe an alternative to quinolones and macrolides when atypical coverage is needed|
|Minocycline||Similar to doxycycline||Limited spectrum of activity|
|Tetracycline||Limited activity against major pathogens|
|Active against atypical bacteria|
|General||Active against all major pathogens, atypical pathogens, Enterobacteriaceae, and Pseudomonas aeruginosa|
|Ciprofloxacin||Least active against S. pneumoniae||Use if P. aeruginosa coverage is required|
|Greatest activity against P. aeruginosa|
|Gatifloxacin||Enhanced gram-positive activity|
|Moxifloxacin||Greatest activity against S. pneumoniae|
|Trimethoprim-sulfamethoxazole||Covers major pathogens||Resistance limits use|
|No atypical coverage|
|S. pneumoniae resistance is common|
Adapted from Dever LL, Shashikumar K, Johanson WG: Antibiotics in the treatment of acute exacerbations of chronic bronchitis. Expert Opin Investig Drugs 2002;11:911-925.
Bronchodilator therapy, including inhaled β-adrenergic agonists (albuterol, fenoterol, metaproterenol, terbutaline) and anticholinergic agents (ipratropium bromide), might improve airflow during acute exacerbation. Although long-acting β agonists in theory provide longer symptomatic relief, these agents have not been studied in ABECB and are not recommend at present. The choice of delivery system-metered dose inhaler (MDI) versus nebulized bronchodilators-should be determined based on cost and the patient’s ability to use an MDI with a spacer. For patients already taking an oral methylxanthine, it is acceptable to continue this medication, keeping in mind that drug interactions with certain antibiotics (ciprofloxacin, clarithromycin) can occur and dosages need to be adjusted accordingly. In patients with moderate to severe exacerbations , good evidence supports treatment with oral or parenteral steroids for 5 to 14 days in general but not beyond 2 weeks. A number of randomized, placebo-controlled trials have demonstrated that systemic steroids lead to decreased treatment failure and shorten hospitalization rates. The mechanism by which steroids increase recovery in ABECB is not clear. Steroids are effective in decreasing airway edema and mucus hypersecretion and in increasing secretory leukoproteinase inhibitor (SLPI) in airway epithelial cells, which can have antiviral and antibacterial activities. There is no defined role for inhaled steroids in ABECB.
Supplemental oxygen should be provided carefully during an acute exacerbation to avoid hypoxemia, with the goal of maintaining a partial pressure of oxygen in arterial gas at or just above 60 mm Hg. The decision regarding long-term need for oxygen should not be made during an acute exacerbation, but patients should have an ambulatory desaturation study performed before discharge from the hospital to determine if supplemental home oxygen is needed. Expectorants or cough suppressants can provide subjective relief, but no evidence shows that these agents improve lung function or hasten clinical recovery in ABECB. There is no beneficial effect of chest physiotherapy in recovery from an ABECB. Instead, patients should be kept adequately hydrated to decrease viscosity of mucus. There is no evidence supporting the use of leukotriene receptor antagonists in ABECB. In appropriate patients, noninvasive ventilation in acute exacerbations of COPD has been shown to reduce mortality, decrease the need for intubation and mechanical ventilation, and decrease the length of hospital and intensive care unit stay.
Hospitalization due to ABECB carries a short-term mortality rate of approximately 4% in patients with mild to moderate disease. The 1-year mortality rate for patients with severe disease can be as high as 46%. Many of the patients hospitalized for ABECB require subsequent readmissions because of persistent symptoms and often experience a temporary decrease in their functional abilities. Overall, ABECB contributes significantly to the morbidity and the diminished quality of life experienced by people with COPD.