The Role of Infection in Acute Exacerbations of Chronic Obstructive Pulmonary Disease

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1 ...SYMPOSIUM PROCEEDINGS... The Role of Infection in Acute Exacerbations of Chronic Obstructive Pulmonary Disease Robert E. Hillberg, MD Presentation Summary Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and the second leading cause of work disability. Extensive data indicate that bacterial infection has an important role in acute exacerbations of COPD. Antibiotic therapy has been shown to benefit patients with exacerbations of COPD by improving clinical outcomes and hastening clinical and physiologic recovery. Antibiotics also provide long-term benefits such as preventing the progression of disease, minimizing secondary colonization with resistant organisms, and prolonging the time between exacerbations. Classifying an episode of COPD as uncomplicated, complicated, or at risk for Pseudomonas is useful in determining antibiotic therapy for patients with an acute exacerbation. Although patients with less severe uncomplicated disease can be treated with older antimicrobial agents, those with serious comorbid conditions or advanced structural lung disease require treatment with new more potent agents. Knowing the patterns of antimicrobial resistance in the respiratory pathogens, antibiotic pharmocokinetics, and factors influencing patient compliance is necessary to prevent treatment failures. The role of infection in acute exacerbation of chronic obstructive pulmonary disease (COPD) is sometimes disputed because many patients improve without antibiotic treatment. However, potentially pathogenic microorganisms are found in approximately half of all patients with COPD. Extensive data indicate that microbial infection has an important role in this disorder and that antimicrobial therapy can improve clinical outcome. Epidemiologic Factors of COPD Smoking is the most common cause of COPD, which is the second leading cause of work disability. 1 Recent estimates indicate that as much as 20% of the US population may have COPD. This may be attributed to the fact that most Americans started smoking in the 1940s and 1950s, and the effects of this continued habit have taken several decades to become apparent. VOL. 6, NO. 8, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S427

2 ... SYMPOSIUM PROCEEDINGS... When the forced expiratory volume in one second (FEV-1) is less than 50% of the predicted value, the 5-year survival rate of patients is about 50%. Thus the mortality rate in those with severe COPD is about equal to that in patients with congestive heart failure or a malignancy. The national cost of medical care for those with COPD is more than $14 billion per year. The Scope of COPD The term COPD includes chronic bronchitis, emphysema, and asthma. Chronic bronchitis is a productive cough of no definable cause that lasts for at least 3 months in each of 2 successive years. In patients with chronic bronchitis, the tracheobronchial mucosa is inflamed and swollen, excess mucus develops, and the carinae are often blunted or soft instead of sharp. The inflammatory process in the mucosa is associated with submucosal inflammation and airway smooth muscle contraction (bronchospasm), but the understanding of that process is in its infancy. In contrast, emphysema is a permanent destruction and dilation of respiratory bronchioles and alveoli. In patients with emphysema, alveoli are injured by the action of leukocyte-derived elastase, a proteolytic enzyme released by inflammatory neutrophils. Elastase dissolves the structural proteins of the lung (reticulin, fibrin, and elastin), and over decades causes the destruction of alveolar walls, loss of airway support, and pulmonary hyperinflation. Chronic bronchitis and emphysema are different diseases that can often be differentiated quite easily. However, most patients with COPD have a combination of chronic bronchitis, emphysema, and intermittent wheezing. In a healthy person 25 years of age, the lungs are at their peak of maturity and development. Thereafter, FEV-1 naturally declines at a rate of approximately 14 ml per year. However, this age-related decline in pulmonary function does not cause disability. In contrast, approximately 20% of all smokers lose FEV-1 at double the normal rate. They tend to develop symptoms of pulmonary disease at the approximate age of 55, to be disabled by the age of 65, and often to die a few years afterward from COPD. Smokers who quit in their 30s and 40s experience a slower agerelated decline in lung function but do not recover from the damage completely. They often become disabled at an older age (their mid-80s or 90s) and tend to be disabled for a longer time. Sudden brief declines in pulmonary function are referred to as exacerbations, and the terms acute exacerbations of COPD and acute exacerbations of chronic bronchitis are often used interchangeably. Exacerbations can be caused by allergens, particularly in patients younger than 40 years of age; environmental pollutants; viruses, which often precipitate episodes and enable bacterial colonization and invasion; and bacterial infections. Common Outcomes for Acute Exacerbations of COPD Acute exacerbations of COPD are associated with poor outcomes. In 1996, Connors et al 2 reported the outcome results of a study involving 1016 patients with a COPD flare. Eleven percent of the patients studied died during their acute hospitalization, and 446 patients were readmitted 754 times during the next 6 months. At 6 months, only 26% of the patients reported having a good quality of life. After 2 years, the mortality rate was 49% in the study participants. Most patients who are hospitalized for treatment of an acute exacerbation survive that episode but do not thrive over time. In the study by Connors et al, 2 hospital costs per patient averaged $7100 (range, $4100 to $16,000) for S428 THE AMERICAN JOURNAL OF MANAGED CARE MAY 2000

3 ... THE ROLE OF INFECTION IN ACUTE EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE... the index admission, and the average length of stay was 9 days (range, 5 to 15 days). These data are similar to those reported in patients with community-acquired pneumonia. Patients who experience flares are prone to recurrent exacerbations. In a recent study by Ball et al, 3 factors predictive of treatment failure in patients with acute exacerbations of chronic bronchitis were examined. In that study, 58% of 471 patients demonstrated moderate or severe airflow obstruction. Approximately equal numbers of patients suffered from fewer than 3 episodes per year, 3 or 4 episodes per year, or more than 4 episodes per year. However, patients with prior cardiopulmonary disease or those who experienced more than 4 acute exacerbations per year were most prone to recurrent exacerbations within the 2 months after discharge than were those who had experienced fewer flares. Current Therapy Acute exacerbations of COPD are treated with a variety of pharmacologic and nonpharmacologic strategies. Pharmacologic agents include aerosolized bronchodilators, betaagonists, and anticholinergics. The beta-agonists are available in longand short-acting formulations and are delivered via hand-held nebulizers, metered-dose inhalers, or dry-powder preparations. Ipratropium is the only anticholinergic drug currently in use, but long-acting anticholinergics will soon be released. Other agents used to treat COPD include short- and long-acting oral theophylline preparations; intravenous theophylline; and various potencies of corticosteroids in intravenous, oral, or inhaled forms. Antibiotics, mucolytics, anxiolytics, and other therapies are used to treat comorbid conditions. Nonpharmacologic therapies include oxygen and noninvasive ventilation. The techniques of pulmonary rehabilitation are invaluable in improving the patient s quality of life and in minimizing healthcare costs. Potentially Pathogenic Microorganisms in COPD Quantifying the role of bacterial infection in the exacerbation of COPD has been the focus of several studies. 4,5 Fagon et al 4 evaluated 54 patients with acute exacerbation of COPD who required intubation and mechanical ventilation. Before they received antibiotic therapy, the patients studied underwent bronchoscopy with a protective specimen brush, which is the best method of obtaining uncontaminated specimens from the lower respiratory tract. In In 50% of the study participants, potentially pathogenic microorganisms (most often Streptococcus pneumoniae or Haemophilus influenzae) were isolated. 50% of the study participants, potentially pathogenic microorganisms (most often Streptococcus pneumoniae or Haemophilus influenzae) were isolated. A high level of bacterial infection occurs in some cases of stable COPD. Monso et al 5 found potentially pathogenic microorganisms in 25% of patients with stable COPD who underwent bronchoscopy with the protective specimen brush. In a group of patients experiencing an acute exacerbation of COPD, pathogenic microorganisms were isolated in 52%. The numbers of bacteria recovered during exacerbations were similar to those in patients with acute community-acquired pneumonia. The Benefits of Antibiotic Therapy Antibiotics benefit patients with VOL. 6, NO. 8, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S429

4 ... SYMPOSIUM PROCEEDINGS... exacerbations of COPD by improving clinical outcome and hastening clinical and physiologic recovery. Saint et al 6 performed a meta-analysis of randomized placebo-controlled studies of antibiotic use in patients experiencing a COPD flare. Six COPD trials conducted between 1957 and 1992 were examined. The data revealed a small but statistically significant improvement that was due to antibiotic therapy in all but one study. The effect of antibiotic treatment was greater in inpatients than in outpatients. In addition, there was a more rapid return to baseline peak flow rate in patients who received antibiotics when compared with those who received placebo. The first large, prospective, placebo-controlled study of antibiotic use in patients with COPD flare was conducted by Anthonisen et al 7 in During a 3.5-year period, 173 patients who experienced a total of 362 exacerbations were treated with either placebo or antibiotic. The patients were divided into 3 groups defined by clinical criteria such as increased sputum volume, increased dyspnea, and increased sputum purulence. Patients classified as type I had all of those symptoms, type II patients had 2 of the 3 symptoms, and type III patients had only 1 of the 3. The study showed that patient types I and II improved clinically on antibiotics when compared with those who had received placebo. These types of criteria are still used to determine whether antibiotics should be prescribed to treat COPD exacerbations. Other data support the use of antimicrobials in COPD patients with acute exacerbation. Grossman et al 8 conducted a 1-year community-based study of antibiotic treatment in patients with acute exacerbation. The study results showed that antibiotic use was associated with clinical and economic benefits in patients with the following characteristics: more than 4 type I or type II exacerbations within the past year; a comorbid condition, such as diabetes, asthma, or a history of coronary artery disease; or marked airway obstruction. Antibiotic therapy provided the greatest benefit to patients with the most risk factors. Microbiologic Factors in Severe Exacerbations Soler et al 9 studied bronchial microbial patterns in 50 patients with severe exacerbations of COPD who required mechanical ventilation. A high rate of infection was seen; 72% of those patients had positive cultures or serology for potentially pathogenic microorganisms. In addition, Pseudomonas aeruginosa or other gram-negative enteric bacteria were isolated in 28% of the patients. The authors reported that they were not able to predict the presence of specific microorganisms using clinical criteria. In contrast, a relationship between bacteriologic etiology and lung function was demonstrated in an important study reported by Eller et al 10 in That study involved 112 patients with COPD flare. Patients were stratified according to the following classifications of disease severity: patients with FEV-1 greater than 50% of predicted (stage I), FEV-1 between 35% and 50% (stage II), and FEV-1 less than 35% (stage III). Microbiologic evaluation of those patients showed that as the COPD worsened from stage I to II to III, the pathogens changed (Figure 1). In the patients with mild illness, S pneumoniae and gram-positive cocci were the most frequently isolated pathogens noted. In the moderately ill patients, H influenzae and Moraxella catarrhalis were the most prevalent. In patients who were severely ill, enteric gram-negative bacilli and Pseudomonas were prevalent. These data are currently being used by most pulmonologists to guide the choice of antibiotics (see Antibiotic Therapy Guidelines). S430 THE AMERICAN JOURNAL OF MANAGED CARE MAY 2000

5 ... THE ROLE OF INFECTION IN ACUTE EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE... Long-Term Benefits of Antimicrobial Therapy Antibiotic therapy provides immediate treatment of bronchial infection and may offer long-term benefits such as preventing the progression of airway disease. It is well known, for example, that intermittent use of aerosolized tobramycin in patients with cystic fibrosis or bronchiectasis prevents or minimizes disease progression and improves FEV-1. Many clinicians believe that in patients with COPD who produce excessive purulent sputum and exhibit chronic colonization, periodically removing the bacteria or minimizing their density prevents disease progression. Antibiotic use may interrupt the vicious cycle of disease progression by eliminating bacteria and the toxins they produce. Removal of toxins has a beneficial anti-inflammatory effect that is also imparted by some antibacterial medications. The emerging thought is that colonization may in fact represent subclinical infection, and clinicians are becoming much more aggressive in treating it. Treatment with antimicrobials may also help to prevent secondary colonization by resistant organisms. Smoldering infections potentiate conditions in which virulent pathogens become established. A study by Chodosh et al 11 has demonstrated that a course of ciprofloxacin prolongs the time between exacerbations of COPD when compared to clarithromycin. Antibiotic Resistance in Major Pathogens Antibiotic resistance in major respiratory pathogens is becoming increasingly important. As many as 44% of S pneumoniae isolates are resistant to penicillin and as many as half of those exhibit high-grade antibiotic resistance. Such microorganisms have developed changes in their cell-wall proteins (the penicillin binding proteins), so beta-lactam antibiotics cannot attach to and destroy the bacteria. Other mechanisms have evolved to affect macrolide resistance. An efflux pump mechanism can pump out the antibiotic before it can become effective, or methylation of ribosomes can prevent the macrolide antibiotic from inhibiting protein synthesis. Penicillin resistance is associated with resistance to all the macrolides, the cephalosporins, and trimethoprim/sulfamethoxazole. 12 Pathogen resistance to fluoroquinolones and vancomycin remains very low. However, it has been reported in Canada that as prescriptions for ciprofloxacin have increased, a concomitant increase in isolates of S pneumoniae with reduced susceptibility to fluoroquinolones has occurred. 13 Several clinical risk factors for the development of drug-resistant S pneumoniae have been elucidated, such as extremes of age (younger than 5 or older than 65 years of age), recent antimicrobial treatment, immunodeficiency, comorbid disease or alcohol abuse, human immunodeficiency virus infection, attendance Figure 1. Relation of Lung Function and Bacterial Infection in Patients With COPD Flare Stage I Stage II Stage III S pneumoniae and gram-positive cocci H influenzae/ M catarrhalis Enterobacteriaceae Pseudomonas spp. Stage I = Forced expiratory volume in 1 second (FEV-1), greater than 50% predicted; Stage II = FEV-I, between 35% and 50% predicted; Stage III = FEV-I, less than 35% predicted; COPD: chronic obstructive pulmonary diseases. Source: Adapted from reference 10. VOL. 6, NO. 8, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S431

6 ... SYMPOSIUM PROCEEDINGS... at a daycare center or being a family member of a child attending daycare, and recent hospitalization or institutionalization. According to these criteria, almost everyone is at risk of infection by drug-resistant S pneumoniae. Approximately one third of H influenzae isolates produce beta-lactamases and are resistant to betalactam antibiotics, and that rate of resistance has been relatively stable. Resistance to fluoroquinolones is rare, and azithromycin, clarithromycin, and tetracycline remain effective against H influenzae. However, low levels of a new type of resistance characterized by the modification of penicillin-binding proteins and resistance to all betalactams have been reported. 14 Approximately 90% to 100% of M catarrhalis isolates produce beta-lactamases and are resistant to ampicillin and other beta-lactam antibiotics. Fortunately, this organism remains sensitive to most other agents. Many of the tried and true antibiotics are now less effective because of antibiotic resistance issues and evolving pathogen patterns. For example, amoxicillin, ampicillin, and first-generation cephalosporins are not effective against the atypicals or beta-lactamase-producing microorganisms. Erythromycin has poor activity against H influenzae, and the newer macrolides, azithromycin and clarithromycin, may not be effective against drug-resistant S pneumoniae. Trimethoprim-sulfamethoxazole is ineffective against atypicals and drug-resistant S pneumoniae, and tetracycline is not always reliable against S pneumoniae. The Ideal Antibiotic Important considerations in the selection of the ideal antibiotic to treat acute exacerbation of COPD include the likelihood of recurrent infections and the patient s ability to tolerate such recurrences; risk factors for resistant bacteria; cost effectiveness of therapy, which includes potential lost workdays and treatment failures that may require the patient s hospitalization; and the general need for potent antibiotic use in the more severely ill patients. Patient compliance must also be considered. According to 1995 US data collected by The Gallup Organization, 54% of patients do not complete antibiotic therapy as prescribed; they either terminate the course of therapy or skip doses. Fiftyfour percent of those patients stop taking their antibiotics when they feel better, even if they have not completed the full course of therapy. With regard to regimen, 82% of patients prefer an antibiotic that can be taken once or twice a day, and only 5% prefer a full 14-day course of therapy. Many factors reduce adherence to antibiotic therapy. Compliance is less if the patient is already taking multiple drugs, experiencing side effects, or taking more than 2 doses per day. A patient is also less likely to comply if using the drug conflicts with lifestyle or behavior or if the consequences of noncompliance appear minimal. Although the ideal antibiotic varies according to the patient, it should be beta-lactamase resistant, effective against the most common pathogens, and able to penetrate the site of infection thoroughly. The patient should be able to take the drug once- or twice-per-day, and it should be cost effective. Antibiotics that have good penetration into sputum, bronchial mucosa, epithelial lining fluid, and macrophages include the quinolones and the newer macrolides azithromycin and clarithromycin. Beardon and Rodvold 15 have demonstrated that azithromycin concentrates in the epithelial lining fluid 10-fold greater than in plasma or serum and 100-fold or more in the alveolar macrophages. The tetracyclines, clindamycin, and trimethoprim-sulfamethoxazole also penetrate S432 THE AMERICAN JOURNAL OF MANAGED CARE MAY 2000

7 ... THE ROLE OF INFECTION IN ACUTE EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE... well into the lungs. In contrast, aminoglycosides do not penetrate well, particularly in acidic environments, and the beta-lactams can vary in their penetration. Emerging Therapies for Respiratory Infections The spectrum of activity of the newer fluoroquinolones allows monotherapy much of the time. Bioavailability following oral doses is equivalent to intravenous dosing with many of the agents and their long half-life allows once-a-day dosing. They offer excellent penetration into the respiratory tract and the options of intravenous and oral formulations enable sequential dosing patterns. The newer quinolones have improved activity against gram-positive organisms, including S pneumoniae and methicillin-susceptible Staphylococcus aureus, and they have excellent activity against many gram-negative bacteria and the atypicals. 16,17 In a prospective, randomized, multicenter trial 18 of treatments for the acute exacerbation of chronic bronchitis, a 10-day course of levofloxacin produced a slightly better clinical response and microbiological eradication profile than did a 10-day course of cefuroxime axetil. The clinical response produced by the recently approved agent gatifloxacin in a multinational, randomized, multicenter, double-blind study 19 was better than that produced by cefuroxime axetil, and bacterial eradication rates were considerably better when gatifloxacin was used (Figure 2). Similar pathogens were present in both of these studies, and S pneumoniae, H influenzae, and M catarrhalis were the most common isolates. These results appear to reflect the increased potency of these antibiotics against respiratory pathogens. Antibiotic Therapy Guidelines Because of the issue of increasing resistance, clinicians must be prudent in their antimicrobial prescribing habits and must use the most effective therapy. According to Williams and Heymann, 20 it is unlikely that resistance will decrease rapidly because clinicians are more prudent in their use of antimicrobial agents. However, if clinicians are not prudent, the problem of antibiotic resistance will certainly worsen. Based on the work of Lode and Balter 21,22, guidelines can be established. Therapy guidelines can help optimize the use of antibiotics. One strategy is to classify patients into 3 categories: those with uncomplicated COPD, complicated COPD, or the most severe COPD (those in whom P aeruginosa may develop (Table 1). In general, patients classified as having uncomplicated COPD can be of any age. They usually experience fewer than 4 exacerbations per year, have no comorbid illness, and have an FEV-1 greater than 50%. In that group of patients, the core respiratory pathogens, H influenzae, M catarrhalis, S pneumoniae, and Haemophilus parainfluenzae, tend to be seen. Because beta-lactamase resistance is possible, antibiotic thera- Figure 2. Clinical Response to and Bacterial Eradication Rates Produced by Gatifloxacin* and Cefuroxime Axetil in AECB Clinical Response Bacteriologic Eradication AECB = Acute exacerbations of chronic bronchitis. For 7 days po: *400 mg per day, 250 mg bid. Source: Adapted from reference 19. gatifloxacin cefuroxime axetil VOL. 6, NO. 8, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S433

8 ... SYMPOSIUM PROCEEDINGS... Table 1. Classification of Patients With COPD py for type I and type II exacerbations in uncomplicated COPD includes azithromycin, clarithromycin, one of the new cephalosporins, or doxycycline. COPD = Chronic obstructive pulmonary disease; FEV-1 = forced expiratory volume in 1 second. Table 2. Comparison of Treatments With Corticosteroids Versus Placebo in Patients With COPD Exacerbation Outcome Corticosteroids Placebo P value Treatment Failure at 30 Days 23% 33% 0.04 Treatment Failure at 90 Days 37% 48% 0.04 Length of Hospital Stay 8.5 days 9.7 days 0.03 Hyperglycemia 15% 4% COPD = Chronic obstructive pulmonary disease. Source: Adapted from reference 19. COPD CLASSIFICATION Patient At Risk for Characteristics Uncomplicated Complicated Pseudomonas Age Any Older* Older* No. Exacerbations/Year <4 >4 >4 Comorbid Illness None Common Common FEV-1 >50% <50% <35% Other Chronic bronchial infections Frequent antibiotic therapy Corticosteroid therapy Pathogens H influenzae H influenzae H influenzae M catarrhalis M catarrhalis M catarrhalis S pneumoniae S pneumoniae S pneumoniae H parainfluenzae H parainfluenzae H parainfluenzae Resistant Resistant grampathogens negative Enteric gram- bacteria, negative bacteria, including occasional Pseudomonas Pseudomonas Patients with complicated COPD tend to be older than 60 years of age, and they have often experienced more than 4 exacerbations per year. Comorbid illness is common in that group, and the FEV-1 is usually less than 50% of predicted. In addition to the core organisms, resistant pathogens and enteric gram-negative bacteria are also found frequently. Thus, the consequences of treatment failure are greater in these patients and many result in hospital admission, intensive care, or possibly mechanical ventilation. Treatment choices for this group must be precise. Therapies for patients with a type I or type II exacerbation include fluoroquinolones or amoxicillin with clavulanic acid. Patients with exacerbations who are at high risk for Pseudomonas have an FEV-1 that is less than 35% of predicted. Often those patients have undergone frequent courses of antibiotic therapy for the treatment of chronic bronchial infections and are taking corticosteroids. They are at risk for infection by core bacteria, resistant gram-negative bacilli, and Pseudomonas, so ciprofloxacin is usually recommended because it is the quinolone with the best potency against Pseudomonas. However, ciprofloxacin is not very effective against S pneumoniae, and cases of streptococcal pneumonia have developed in patients treated with that agent. Clinicians should be aware of this potential problem and should perform surveillance cultures as a precaution. Although there is controversy about the need to obtain sputum cultures in all patients before antimicrobial therapy is initiated, there is a general agreement that cultures should be obtained in a patient whose illness does not promptly improve as a result of empiric antibiotic treatment. The Role of Corticosteroid Therapy Although corticosteroids are widely used in the treatment of COPD S434 THE AMERICAN JOURNAL OF MANAGED CARE MAY 2000

9 ... THE ROLE OF INFECTION IN ACUTE EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE... exacerbation, the extent of their benefit is unknown. A recently published study by Niewoehner et al 23 demonstrated that there is a slight-tomoderate benefit when systemic corticosteroids are used. That prospective, randomized, placebo-controlled study involved 271 smokers older than 50 years of age who were hospitalized with severe COPD. Patients with asthma were excluded. The study participants were treated with 2 or 8 weeks of systemic corticosteroids or with placebo. Treatment with methylprednisolone was initiated at 125 mg intravenously every 6 hours for 3 days; this was followed by oral prednisone in an initial dose of 60 mg per day and that was tapered to 20 mg in the group treated for 2 weeks and 5 mg in the group treated for 8 weeks. Equivalent responses were seen in patients who received 2 or 8 weeks of corticosteroid therapy. At 30 and 90 days of therapy, significantly fewer treatment failures were observed in the patients who received corticosteroids when compared with treatment failures in those who received placebo (Table 2). The length of the initial hospital stay was significantly shorter for those who received corticosteroids, and the improvement in the FEV-1 in the first day of treatment was 100 ml greater than in those who received placebo. The mortality rate (9%) in all groups was similar, but a higher rate of hyperglycemia was reported in the group who received the corticosteroids. The Prevention of Acute Exacerbations The importance of preventing acute exacerbations of chronic bronchitis must be emphasized. Patients should stop smoking and avoid industrial, domestic, and environmental pollutants and irritants. Patients should avoid crowds during periods of viral epidemics. Vaccination against influenza and the pneumococcal infection is important and together will help prevent exacerbations. Although the vaccine against Haemophilus infection is available, its efficacy in preventing acute exacerbations has not been proven. Early antibiotic treatment of type I or II exacerbations may prevent serious consequences of infection. In the future, immunostimulants may prevent COPD exacerbations. A recent study of the immunostimulant OM85BV, which consists of components of 8 common respiratory pathogens, showed that this substance reduced morbidity and the number of hospitalizations during the study period REFERENCES Niroumand M, Grossman RF. Airway infection. Infect Dis Clin North Am 1998;12: Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. Am J Respir Crit Care Med 1996;154(4 Pt 1): Ball P, Harris JM, Lowson D, Tillotson G, Wilson R. Acute infective exacerbations of chronic bronchitis. QJM 1995;88: Fagon JY, Chastre J, Trouillet JL, et al. Characterization of distal bronchial microflora during acute exacerbation of chronic bronchitis. Use of the protected specimen brush technique in 54 mechanically ventilated patients. Am Rev Respir Dis 1990;142: Monso E, Ruiz J, Rosell A, et al. Bacterial infection in chronic obstructive pulmonary disease. A study of stable and exacerbated outpatients using the protected specimen brush. Am J Respir Crit Care Med 1995;152(4 Pt 1): Saint S, Bent S, Vittinghoff E, Grady D. Antibiotics in chronic obstructive pulmonary disease exacerbations. A meta-analysis. JAMA 1995;273: Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987;106: Grossman R, Mukherjee J, Vaughan D, et VOL. 6, NO. 8, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S435

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