Acute Bacterial Exacerbations of Chronic Bronchitis

Published 2006

Department of Pulmonary, Allergy, and Critical Care Medicine

References

National Guidelines

The COPD Guidelines Group of the Standards of Care Committee of the BTS.

Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease

Rene Theophile Hyacinthe Laennec first used the term "chronic bronchitis" in his classic bodytext, A Treatise on the Diseases of the Chest, in 1821. His chapter devoted to “pulmonary catarrh or bronchitis” separated the entity of chronic bronchitis from that of emphysema and stressed the difference between these disease states.¹ A century later, based on Laennec's work, a CIBA symposium proposed that (1) 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 etiology, and that (2) 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 are frequently caused by similar etiologies (ie, tobacco use) and often occur together. As a result, the umbrella term, "chronic obstructive pulmonary disease," is often used to synonymously 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 patients with COPD. In fact, bacterial exacerbations are the leading cause of death in COPD.⁶

This chapter presents a concise overview of ABECB. We address the definition, prevalence and epidemiology, pathology and pathophysiology, diagnosis, therapy, and outcomes. See also the Disease Management chapter on Chronic Obstructive Pulmonary Disease.

DEFINITION

The definition of bronchitis remains largely subjective and has few objective correlates. The America Thoracic Society defines chronic bronchitis as the presence of chronic productive cough for 3 months in each of 2 successive years when 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 et al attempted to stratify the severity of an ABECB based on these symptoms.⁸ According to the Anthonisen severity scale which are recognized and agreed upon as the mainstay of defining and diagnosing ABECB, type 1 (severe) episodes have all three clinical findings of dyspnea with increased sputum volume and increased purulence, and type 2 (moderate) episodes any two of those clinical findings. Type 3 exacerbations (mild) have one of the clinical findings plus one of the following: an upper respiratory tract infection in the previous 5 days, fever with no 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.

PREVALENCE AND EPIDEMIOLOGY

The worldwide prevalence of chronic bronchitis or ABECB is likely to be underestimated because the definition of COPD varies. Traditionally, it has been believed that chronic bronchitis is a major finding in 85% of COPD patients.¹⁰ In the United States alone, more than 16 million people have COPD, and it is estimated that more than 12 million of them have symptoms of chronic bronchitis.⁷ Acute exacerbations in more than 50% of cases of chronic bronchitis and COPD, particularly those meeting the Anthonisen criteria of increased sputum production, dyspnea, and purulent sputum production are likely caused by infectious pathogenic bacteria.^11,12 In general, acute COPD exacerbations caused by bacterial infection occur on an average of 2.4 to 3 times per year and last approximately 7 to 14 days per event.^13-15 Overall, these events occur more often in smokers than in nonsmokers. Ball et al discovered in a series of COPD patients that one factor predicting the likelihood of ABECB was the number of exacerbations experienced in the previous year.¹⁶ After an acute exacerbation, most patients may experience a decrease in quality of life, and more than 50% of patients will be readmitted with an ABECB more than once in the subsequent 6 months. Therefore, one of the main goals of therapy in managing COPD is to reduce the number and severity of exacerbations.

ABECB and COPD compromise a significant portion of the diagnosis as the cause for medical visits and hospitalizations, resulting in staggering economic costs.¹⁷ In one recent prospective series, the costs of treating COPD and ABECB were found to be almost twice those reported for asthma.¹⁷ The prevalence of COPD and thus the prevalence of ABECB continues to rise as the population "grays," and it is the only leading cause of death for which the mortality rate is currently increasing.^5,7

PATHOLOGY AND PATHOPHYSIOLOGY

The pathologic lesions of chronic bronchitis involve morphologic changes in both the large and small airways. In patients with chronic bronchitis, these airways show 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 the smooth muscle and in the connective tissue in the bronchial wall, as well as degeneration of the airway cartilage. The Reid index, defined as the ratio of gland to bronchial wall thickness, is the pathologic marker of the increase in cough and sputum production in chronic bronchitis.¹⁸ As the airway walls thicken, the lumens become smaller, causing mucous plugging. Autopsy specimens in patients with ABECB show evidence of bronchi obstructed by mucous plugging and laden with polymorphonuclear cells and bacteria.¹⁹ Mucous plugging represents the failure of the mucociliary system to clear the excessive mucus production as well as the weakening of the cough clearance mechanism.

Evidence is emerging that ABECB is associated with airway inflammation. There appears to be a clear association between the degree of inflammation and the severity and frequency of the exacerbations. Bronchoalveolar lavage specimens taken during ABECB show an increase in the absolute number and proportion of neutrophils.²⁰ Levels of interleukin-8 (a potent neutrophil chemotactic factor), leukotriene B4, and myeloperoxidase are all increased during ABECB.^21-23 In addition, cytokine levels in bronchoalveolar lavage fluid are higher during ABECB, and patients with higher baseline cytokine levels have more frequent exacerbations.²² Patients who have severe ABECB and require hospitalization also have evidence of more severe neutrophilic inflammation during exacerbations.²¹ Eosinophilic infiltration of the mucosa generally does not seem to be of major importance in stable chronic bronchitis but may be important during ABECB. Bronchial biopsies taken during ABECB have shown increased mucosal and submucosal eosinophils.^24,25

In a healthy person, the respiratory tree is sterile. In a patient with stable chronic bronchitis, the sputum produced is usually mucoid and scant. But even in this quiescent period, sputum culture can yield potentially pathogenic bacteria in 25% to 50% of cases. Nontypable Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae were the predominant organisms in early studies.²⁶ Later studies aimed at avoiding contamination by the bacterial flora of the upper respiratory tract, and used alternative sampling techniques, including transtracheal aspiration, bronchoscopic swabbing, and the protected brush specimen.²⁷ The results were similar to those seen in the earlier studies, showing again that the distal airways in 25% to 45% of patients with COPD were colonized during stable periods with H influenzae and S pneumoniae. Once these bacteria colonize the lower airway, they can directly cause airway inflammation and damage mucociliary clearance, perpetuating a vicious circle of impairing local defenses.²⁸ In patients who show evidence of severe obstruction, the colonizing organisms may differ, with gram-negative bacteria becoming predominant and with strains showing various antibiotic resistance patterns.²⁹

Bacteria have been isolated from the sputum in approximately 60% of ABECB cases. The most common organisms include H influenzae, Haemophilus parainfluenzae, S pneumoniae, and M catarrhalis (Table 1). The contribution of these four organisms may depend on the severity of underlying airway disease. Several studies have found more virulent organisms in the airways of patients with severe chronic bronchitis and acute exacerbations, including Staphylococcus aureus, Pseudomonas species, and members of the Enterobacteriaceae family. In general, many of the same bacteria that are found in the airways during clinically stable periods will be present during ABECB, but at higher colony counts. Acute events may also be associated with new acquisition of strains of nontypable H influenzae that differ from the colonization strains, possibly indicating an immunologic modification of existing strains or newly acquired strains that enable bacteria to elude host defenses.³⁰ The role of atypical pathogens such as Mycoplasma species and Chlamydia species seems to follow three separate mechanisms in ABECB. First, infection with Chlamydia pneumoniae infection at an early age may make airways more susceptible to effects of irritants such as cigarette smoke and may increase the risk of chronic bronchitis later in life.³¹ Second, both Mycoplasma and Chlamydia species may themselves cause ABECB. Last, atypical organisms and viruses may cause a primary infection that actually may lead to severe lower airway inflammation, enabling a secondary increase in bacterial proliferation that may lead to an exacerbation.³²

DIAGNOSIS

The clinical diagnosis of ABECB traditionally uses some combination of the original three Anthonisen criteria: increased sputum dyspnea, and increased sputum purulence from baseline. There are no characteristic laboratory or radiographic tests that will confirm the diagnosis of ABECB. Some authors have proposed major and minor criteria, with the major criteria consisting of the original Anthonisen criteria and the minor criteria consisting of wheezing, sore throat, cough, and symptoms of the common cold, including nasal congestion or discharge. They defined 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.¹⁴ There are no characteristic physical findings in ABECB either, although other authors have suggested that severe exacerbations may be associated with body temperatures greater than 38.5°C. This is highly controversial.^33,34

Chest radiographs are not helpful in diagnosing ABECB, although they may indicate the presence of pneumonia or other differential diagnoses such as congestive heart failure. The exception to this is a patient presenting to the emergency department or in the course of being hospitalized, where abnormalities in routing chest radiographs have led to changes in management in 16% to 21% of cases.^35-37

Sputum Gram stain and culture have a limited role in the etiology of ABECB because of frequent colonization of airways in chronic bronchitis patients. Sputum analysis should be reserved for patients with frequent exacerbations or patients with purulent sputum in whom there is a suspicion of more virulent or resistant bacteria.¹⁸

Spirometry during an acute exacerbation has little value. But forced expiratory volume in 1 second (FEV₁) in the nonexacerbation state is the best predictor of mortality and may help to predict the need for intensive care treatment.^38,39 Therefore, it is important to know the preexacerbation state of FEV₁ as a predictor of an adverse outcome of ABECB. Peak expiratory flow rates are not recommended in lieu of spirometry, and have not been shown to predict outcomes in COPD exacerbations.

THERAPY

The therapy of ABECB should be directed toward three major goals: (1) symptomatic relief, (2) the prevention of transient loss of pulmonary function that may lead to hospitalization, and (3) reassessment of the disease in an attempt to reduce the risk of further exacerbations. Patients should be removed from exposure to 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 management of these patients may be fraught with difficulties. A central issues is whether or not to give an antimicrobial and if yes, which one? Antimicrobial failure has been observed in the range of 17-32% depending on how failure is defined (continued sputum production or dyspnea or purlence production). Identification of patients at highest risk of failing may lead to a better antimicrobial prescribing pattern. In the landmark study by Anthonisen et al, demonstrated that high risk patients with either I or II severity scores by Anthonisen who were treated with an antibacterial agent experienced faster resolution of their symptoms compared to patients who received placebo only.⁸ In addition, in 2003 the Canadian Thoracic Society (CTS) along with an international group of experts on AECB postulated a four category classification of AECB and further identified patients that patients fitting CTS class II and III (FEV₁ < 50% predicted, > 4 exacerbations a year, concomitant cardiac disease, chronic use of supplemental oxygen or chronic oral steroid use and antibiotic use in the last three months ) require antimicrobial therapy.¹⁸ In this author's opinion the recent Canadian guidelines seem to provide further guidance regarding patients that will achieve better outcomes with initiation of antibiotic therapy.

The major oral antimicrobials used in the treatment of ABECB are listed in (Table 2). Antimicrobial therapy is appropriate for patients with an ABECB if they fall into the Anthonisen type 1 or type 2 categories, but is not warranted in patients with a type 3 exacerbation. High-risk patients, including those with significant pulmonary impairment (FEV₁ < 50% or lower than predicted), or four or more exacerbations per year or using supplemental oxygen or chronic oral corticosteroids, should be treated with antibiotic therapy during an ABECB. Because of emerging antimicrobial resistance, second-generation macrolides and some second- and third-generation cephalosporins may be used in the treatment of ABECB rather than traditional "first-line" agents (aminopenicillins, doxycycline, or trimethoprim-sulfamethoxazole[TMP/SMX]). A failure rate of 13% to 25% can be expected after treatment of an ABECB with a traditional first-line antibiotic (amoxicillin, TMP/SMX, tetracycline, or erythromycin).^16,^40,41,42 Patients with structural lung disease, chronic corticosteroid use, and frequent use of 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 previous 3 months for ABECB and present with a relapse or recurrence of ABECB should be treated with a different class of antibiotics.

Bronchodilator therapy, including inhaled beta-adrenergic agonists (albuterol, fenoterol, metaproterenol, and terbutaline) and anticholinergic agents (ipratropium bromide, tiotropium ) may improve airflow during acute exacerbations. Although long-acting beta agonists may provide longer symptomatic relief in theory, they have not been studied in ABECB and are not recommended at present. The choice of delivery system, metered-dose inhaler versus nebulized bronchodilators, should be determined based on cost and the patient’s ability to use a metered-dose inhaler with a spacer. For patients already taking an oral methylxanthine, this medication may be continued, keeping in mind that drug interactions with certain antibiotics (ie, ciprofloxacin or clarithromycin) may occur, and dosages may need to be adjusted accordingly.

For patients with moderate to severe exacerbations, there is currently good evidence to support the use of oral or parenteral corticosteroids for 5 to 14 days in general, but not beyond 2.¹⁴ Several randomized, placebo-controlled trials have demonstrated that systemic steroids lead to less treatment failure and lower hospitalization rates.^43,44 The mechanism by which steroids increase recovery in ABECB is not clear. Steroids are effective in decreasing airway edema and mucus hypersecretion, as well as increasing secretory leukoproteinase inhibitor in airway epithelial cells which may have antiviral and antibacterial activity.⁴⁵ There is no defined role for inhaled steroids at this time 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 whether supplemental home oxygen is needed for a period. Although expectorants or cough suppressants may provide subjective relief, there is no evidence that these agents improve lung function or hasten clinical recovery in ABECB. There is no beneficial effect of chest physiotherapy in recovery from ABECB.^46,47 Instead, patients should be kept adequately hydrated to decrease mucus viscosity. Currently, 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 stay in the hospital and intensive care unit.^48-50

OUTCOME

Hospitalization caused by ABECB carries a short-term mortality of approximately 4% in patients with mild to moderate disease.⁵¹ But the short-term mortality can be as high as 24% in patients admitted to an intensive care unit.³⁴ ^,52 The 1-year mortality for these patients with severe disease can be as high as 46%.^34,^52,53 Many of the patients hospitalized for ABECB will require subsequent readmission because of persistent symptoms and will often experience a temporary decrease in their functional abilities.⁵⁴ Overall, ABECB contributes significantly to the morbidity and diminished quality of life of people afflicted with COPD.¹⁵

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REFERENCES

Disclaimer

Marie M.
Budev, DO, MPH

Department of Pulmonary, Allergy, and Critical Care Medicine

Herbert P. Wiedemann, MD

Department of Pulmonary, Allergy, and Critical Care Medicine

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Introduction

Definition

Prevalence and Epidemiology

Pathology and Pathophysiology

Diagnosis

Therapy

Outcome

References