Chronic Bronchitis (Exacerbations of Chronic Obstructive Pulmonary Disease)
Authors: Antonio Anzueto, M.D.
Several scientific organizations and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) have proposed to define exacerbations of chronic obstructive pulmonary disease (COPD) as an event in the natural course of the disease characterized by a change in the patient’s baseline dyspnea, cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management (10, 29, 36). These organizations have also proposed an operational classification of severity as: Level I: treated at home; Level II: requires hospitalization; and Level III: leads to respiratory failure. Various factors likely contribute to the acute exacerbations of COPD, including industrial pollutants, allergens, sedatives, congestive heart failure, and infections (viral and bacterial). The cause of an exacerbation may be multi-factorial, so that viral infection or levels of air pollution may exacerbate the existing inflammation in the airways, which in turn, may predispose to secondary bacterial infections (Table 1). It is estimated that bacterial infections play a part in between one-half and two-thirds of exacerbations (3, 10, 36).
Epidemiology
Acute exacerbations of chronic bronchitis (AECB) are a common cause of morbidity and mortality in this patient population (10, 36, 47). AECB is associated with frequent visits to physicians, up to 14 million doctor’s office visits and 600,000 hospitalizations (35, 43). COPD is the second leading cause of work disability (back pain is the leading cause) and is the third most frequent diagnosis for home-care services (20). The cost to treat COPD is around 24 billion dollars each year, including hospitalization costs and days off work. Significant numbers of hospitalized patients with acute exacerbations have modifiable risk factors including influenza vaccination, oxygen supplementations, smoking and occupational exposures (21, 22, 40). Several studies identified the risk factors associated with mortality in patients with AECB (11) (Table 2). AECB is associated with significant morbidity and mortality; 180-day mortality rate 33% and the two-year mortality rate 49% (11, 40).
These exacerbations also have major impact on the patients' quality of life. COPD patients are twice as likely as the general population to rate their health as being only fair or poor, nearly twice as likely to report recent limitations in their usual activities, and a large portion of them report frequent visits to their physician (39, 16). Studies have shown that exacerbation frequency is an important determinant of decline in lung function in COPD.
Relapse
Despite treatment with antibiotics, bronchodilators, and corticosteroids, up to 28% of patients discharged form the Emergency Department with acute exacerbations have recurrent symptoms within 14 days and 17% relapse and require hospitalization (2). The availability to identify patients who are at risk for relapse should improve decisions about hospital admissions and follow-up appointments. The risk factor for an exacerbation relapses are summarized in Table 3.
Role of Infection
The role of bacteria in AECB is complex and takes into consideration several factors including the acquisition of new bacteria strains, changes in airway inflammation, and the ability of the host to overcome the infection (47). The most common bacteria associated with AECB are: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, and Streptococcus pneumoniae (3, 6, 38); Atypical pathogens such as Mycoplasma pneumoniae and Chlamydia pneumoniaecan also be responsible for AECB (7) (Figure 1).
Patients with the most severe obstructive lung disease have a significantly higher prevalence of Gram-negative organisms such as Enterobacteriaceae and Pseudomonas species (17, 26). Patients were studied based on FEV1 (<50% versus <50% predicted). There were significantly larger numbers of H. influenzae and P. aeruginosa in the patients with FEV1 <50% of predicted (p<0.05). In contrast, there were significantly larger numbers of non-potentially pathogenic microorganisms in the group with FEV1 < 50% (p<0.05). H. influenzae was cultured significantly more commonly in patients who were actively smoking and whose FEV1 was <50% predicted. P. aeruginosa was also cultured significantly more frequently in those with poor lung function, FEV1<50% (26).
These bacterial pathogens can be isolated from sputum in an acute COPD exacerbation and during stable disease (28). During an exacerbation, 33% of the visits resulted in isolation of a new strain of a bacterial pathogen. Isolation of a new strain of H. influenzae, M. catarrhalis, or S. pneumoniae was associated with a significantly increased risk of an exacerbation (41). Thus the association between an exacerbation and the isolation of a new strain of a bacterial pathogen supports the causative role of bacteria in AECOPD.
DIAGNOSTIC PROCEDURES
Chest radiography and arterial blood gas sampling are useful in order to evaluate disease severity and to rule out pneumonia. Spirometric assessment at presentation or during treatment of acute exacerbation is not useful in judging the severity or guiding the management of the patient (3, 10, 36). Patient with recurrent exacerbations should have sputum sample collected for gram stain and culture in order to prescribe appropriate antimicrobial therapy.
TREATMENT
The objectives of treatment of AECB are: improve the patient’s symptoms; treat underlying infection if present; avoid additional invasive therapeutic maneuvers; increase the length of time between exacerbations (exacerbation-free interval); provide treatment as an outpatient; and decrease the need for hospitalization (3, 10, 36).
Antibiotic Resistance
Until the early 1980's, most bacteria species associated with acute exacerbation of chronic bronchitis could be assumed to be sensitive to ampicillin, erythromycin, tetracycline, and trimethoprim-sulfamethoxazole. These antibiotics were used for the management of these exacerbations, but in the 1990's the emergence of bacterial resistance has significantly compromised their use. Currently, 35% to 40% of Haemophilus influenzae and 95 - 100 % of the Moraxella catarrhalisisolates produced a beta-lactamase enzyme (15, 46). These microbes are resistant not only to ampicillin, but often resistant to erythromycin, trimethoprim-sulfamethoxazole and tetracycline (15, 46). There are also reports of the emergence ofpenicillin-resistant Streptococccus pneumoniae(PRSP). Data from surveillance studies have showed that in 2006 up to 35% PRSP; 24% were intermediately susceptible isolates and 10 – 15 % were highly resistant isolates (15, 46). The PRSP resistance is classified as high if the minimal inhibitory concentration (MIC) is more than 2 mc grams per ml. PRSP isolates are known to be also associated with decreased susceptibility to other antibiotics including cephalosporins, macrolides (clarithromycin (Biaxin®), erythromycin and azithromycin (Zithromax®), trimethoprim-sulfamethoxazole and tetracyclines. In the United States PRSP is not associated with decreased susceptibility to quinolones (15, 46). Risk factors that are present in patients that have infections with PRSP are summarized in (Table 5) (23).
Antibiotics
The specific etiology of acute exacerbation of COPD is difficult to determine. Sputum studies have significant limitations including the delay in obtaining the results, cost, and lack of sensitivity and specificity (3, 44). Scientific societies recommend antibiotic choices be based on local antibiotic susceptibilty patterns of the most common pathogens associated with acute exacerbation of COPD (10, 29, 36).
Many studies have demonstrated a benefit of antibiotics during an acute exacerbation, but not in preventing exacerbations (4, 5, 14, 34). Patients who are more likely to benefit from antibiotics are the ones that have all three clinical symptoms of an exacerbation (increased shortness of breath, increased sputum production, and a change in sputum purulence) at initial presentation. Overall, antibiotic-treated patients showed a more rapid improvement in peak flow and a greater percentage of clinical successes compared to those who received placebo.
There are additional potential benefits of antibiotic therapy for patients AECB. Antibiotics can reduce the burden of bacteria in the airway (19). 25% of stable COPD patients are colonized (usually <103 organisms) with potentially pathogenic bacteria (18, 27). However, a much larger percentage (50-75%) of patients with acute exacerbations have potentially pathogenic microorganisms in addition to significantly higher concentrations (frequently > 104 organisms) of bacteria in the large airways. The eradication of bacteria by antibiotics is thought to break the vicious cycle of infection, i.e., lung destruction leading to progression of the lung disease (19).
If the use of antibiotics to treat acute exacerbation of COPD has all the potential benefits discussed, does it matter which agent is chosen? The recommendations for what agent to use is based on the concept of risk-stratification of patients by clinical parameters and a targeted approach for the treatment of AECB (10, 36, 25). The classification of severity is based on patient’s presenting symptoms (Table 5). Selection of antibiotics based on these categories are summarize in Table 6.
Bronchodilators
Inhaled β-agonists and anticholinergic agents have been documented to decrease obstruction during an AECB (3, 9, 10, 12, 36, 24).
Corticosteroids
Systemic corticosteroids are indicated in the management of AECB (1, 3,10, 13, 32, 33, 36, 37, 45, 49). Clinical studies demonstrated that corticosteroids are associated with a faster improvement in FEV1, lower number of treatment failures, prolonged time to relapse, improved dyspnea, and shorter length of hospital stay. Prednisone treated patients experienced more side effects including increased appetite, weight gain, insomnia and were also more likely to experience hyperglycemia.
PREVENTION
The two most important prevention measures are smoking cessation and active immunizations, including influenza and pneumococcal vaccinations (10, 36). The frequency of lower respiratory infections, their morbidity and mortality are marked reduced with influenza vaccination (19, 30, 31). The polyvalent vaccine based on pneumococcal capsular serotypes have being shown to be effective in preventing pneumococcal bacteremia and pneumonia (8, 42). The pneumococcal and influenza vaccines can be given simultaneously immediately after an episode of pneumonia or acute exacerbation of COPD.
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Tables
Table 1: The Most Common Causes of Acute Exacerbation of COPD (AECB)
| Common | |||
|---|---|---|---|
| Environmental conditions | |||
 High air pollution exposure |
|||
 Allergic conditions |
|||
| Infectious process: |
- Viral : | Rhinovirus sp, influenza | |
| - Bacteria : | H. influenzae, .S pneumonia, M catharrhalis, Enterobacteraceas sp., Pseudomonas sp. | ||
| Other | |||
| Inappropriate use of bronchodilator therapy |
|||
| No influenza vaccinations | |||
| Use of supplemental oxygen therapy |
|||
| Non-compliance with long-term oxygen therapy | |||
| Active or passive smoking |
|||
| Occupational exposures |
|||
| Non pulmonary rehabilitation | |||
(References 3, 10, 36)
Table 2: Predictors of Mortality in Patients with AECB
|
(From references 11,40)
Table 3: Risk Factor for AECB Relapse
|
(From references 2,3,10)
Table 4: Clinical Risk Factors Associated with Penicillin Resistant and Multidrug Resistant Streptococccus pneumoniae.*
|
* These factors have being identified in patients with community acquired pneumonia (23).
Table 5: Patient Profiles from the Canadian Chronic Bronchitis Guidelines
Acute bronchitis (Group 1) Healthy people without previous respiratory problems |
“Simple” chronic bronchitis (Group 2) Age £ 65 years old and < 4 exacerbations per year and Minimal or no impairment in pulmonary function and No co-morbid conditions |
“Complicated” chronic bronchitis (Group 3) Age > 65 years old or FEV1 < 50% predicted or ³ 4 exacerbations per year |
“Complicated” chronic bronchitis with co-morbid illness (Group 4) Above criteria for Group 3, plus: Congestive heart failure or Diabetes or Chronic renal failure or Chronic liver disease or Other chronic disease |
Adapted from Balter MS, et al (25)
Table 6 : Association Between Classification of Severity, Probably Pathogens and Recommended Antibiotic Therapy
Category |
Probable Pathogen |
Therapy |
|---|---|---|
Acute Bronchitis (Group 1) |
Viral |
Symptomatic |
"Simple" AECOPD (Group 2) |
Haemophilus spp.(H. influenzae),M. catarrhalis, S. pneumoniae, Atypical organisms (possibly) |
Doxycycline or macrolide (azithromycin/clarithromycin) orcephalosporins. Respiratory Fluoroquinolones * |
"Complicated" AECOPD (Groups 3 & 4) |
As above, with the possible addition of Pseudomonas spp, Enterobacteriaceae, & other Gram negative organisms |
Respiratory Fluoroquinolones * * |
* Consider in patients with risk factors for resistant pathogens.
** If at risk for Pseudomonas infection, use Ciprofloxacin or high dose levofloxacin..
lang="da" xml:lang="da">Adapted from Balter MS, et al (25).
Figure 1: Bacterial etiologies of acute exacerbations of chronic bronchitis
What's New
Babu Suresh K, et al. Role of long term antibiotics in chronic respiratory diseases. Respir Med 2013 Epub ahead of pub.
Wenzel RP, et al. Antibiotic prevention of acute exacerbations of COPD. N Engl J Med 2012;367:340-347.
Nouira S, et al. Standard Versus Newer Antibacterial Agents in the Treatment of Severe Aacute Exacerbation of Chronic Obstructive Pulmonary Disease: a Randomized Trial of Trimethoprim-Sulfamethoxazole Versus Ciprofloxacin. Clin Infect Dis. 2010 Jul 15;51:143-9.