How Do We Achieve Cost-effective Options in Lower Respiratory Tract Infection Therapy?

How Do We Achieve Cost-effective Options in Lower Respiratory Tract Infection Therapy?* Ronald F. Grossman, MD, FCCP

Acute bronchitis and acute exacerbations of chronic bronchitis, common illnesses encountered by general and family physicians, account for approximately 14 million physician visits per year. The pattern of antibiotic prescribing for these infections varies from country to country, but there is no clear rationale for these antimicrobial choices. A recent meta-analysis of all randomized, placebo-controlled trials of patients treated with antibiotics for acute exacerbations of chronic bronchitis concluded that a small but statistically significant improvement could be expected in antibiotic-treated patients. Haemophilus injluenzae is the most commonly isolated organism from sputum in patients with acute exacerbations of chronic obstructive lung disease but other Haemophilus species, Streptococcus pneumoniae, and Moraxella catarrhalis may also be found. High-risk patients can be defmed as being elderly, with significant impairment of lung function, having poor performance status with other comorbid conditions, having frequent exacerbations, and often requiring oral corticosteroid medication. Well-defined clinical trials measure efficacy of a drug but not the effectiveness in a real world situation. Future studies of new antimicrobials should examine their efficacy in patients with an increased risk of true bacterial infection. (CHEST 1998; 113:205S-210S)

is the fourth leading cause of death in the C OPD United States and continues to afflict 20% of the population despite public education regarding smoking.1·2 Acute bronchitis and acute exacerbations of chronic bronchitis, which are common illnesses encountered by general and family physicians, account for approximately 14 million physician visits per year in the United States. 3 •4 One quarter of all primary care visits in the United Kingdom are related to respiratory disease and more than half of these are due to upper and lower respiratory tract infections.5 Bronchitis is associated with 28 million lost working days and 5% of deaths per year in the United Kingdom. 6 In 1992, approximately 12 million prescriptions were given for lower respiratory tract infections, accounting for £47.2 million in expenditures.7 In Europe, >80% of all lower respiratory tract infections are treated with antibiotics. 8 Most physicians do not differentiate acute bronchitis, acute exacerbations of chronic bronchitis, community-acquired pneumonia, and viral respiratory tract infections. The pattern of antibiotic prescribing for these infections varies from country to country, but there is no clear rationale for these antimicrobial choices.9 COPD is a progressive disease characterized by *From the University of Toronto and the Division of Respiratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.

abnormal expiratory flow that is relatively stable over several months of observation. 1 Chronic bronchitis is defined clinically as excessive cough, productive of sputum on most days, for at least 3 months during at least 2 consecutive years. 11 Many patients experience acute exacerbations of this chronic disease and it would be useful to be able to differentiate who would benefit from antibiotics and which antibiotic would be the most cost-effective.

°

RISK FACTORS FOR CHRONIC BRONCHITIS

The risk of developing chronic bronchitis is intimately linked to cumulative smoking history, but occupational exposure to dust pollution, particularly sulfur dioxide, and childhood respiratory infection may also be implicated. 12- 14 Adenovirus infection may increase susceptibility to some of the other risk factors implicated in the development of chronic bronchitis. 15 The risk of chronic cough and sputum production increases with age. 12 The link with passive smoke exposure is less clear, but this may be a risk factor for subsequent development of chronic bronchitis.l6 ACUTE EXACERBATIONS OF CHRONIC BRONCHITIS

The diagnosis is based on a history of increased cough and sputum production, increasing sputum CHEST I 113 I 3 I MARCH, 1998 SUPPLEMENT

205S

purulence, and increased dyspneaY Most acute exacerbations are due to infection, but exposure to allergens, pollutants, or inhaled irritants may all precipitate worsening symptoms of chronic bronchitis.18 While lung function declines acutely with each exacerbation, most studies do not show a correlation between the number of infectious flares and an accelerated decline in lung function.l 9 Nevertheless, hospital admission may be required if transient worsening of pulmonary function occurs in patients with poor pulmonary reserve. These hospital admissions are associated with significant morbidity and some mortality, particularly if associated with hypercapnia.20·21 Role of Bacterial Infection Most patients with acute exacerbations of chronic bronchitis are treated with antibiotics, but the role of bacteria and the effectiveness of this treatment have been disputed. 22 A causal relationship is suggested by the presence of increased numbers of bacteria and neutrophils in sputum during exacerbations. 23·24 An acute antibody response in serum to such bacteria and an increase in inflammatory mediators in purulent sputum strengthen this argument. 25 ·26 Bacterial exacerbations are usually limited to the bronchial mucosa and many cases resolve spontaneously.27 Anthonisen and coworkers 17 demonstrated that, in patients with at least two of increased dyspnea, sputum volume, and sputum purulence, broad-spectrum antibiotics (amoxicillin, trimethoprim -sulfamethoxazole, or doxycycline) lead to improved clinical outcomes, fewer therapeutic failures , and a more rapid recovery of lung function compared with placebo. A recent meta-analysis of all randomized, placebo-controlled trials of patients treated with antibiotics for acute exacerbations of chronic bronchitis concluded that a small but statistically significant improvement could be expected in antibiotictreated patients. 28 Bacterial Pathogens Up to two thirds of all exacerbations are bacterial in origin. 18 Haemophilus influenzae is the most commonly isolated organism from sputum in patients with acute exacerbations of chronic obstructive lung disease, but other Haemophilus species, Streptococcus pneumoniae, and Moraxella catarrhalis may also be found. 29 Studies utilizing the protected specimen brush technique indicated that similar organisms were associated with acute exacerbations albeit in higher number.30·31 In a longitudinal study, exacerbations were caused by endogenous or exogenous reinfection by H influenzae. Persistently infected patients kept the same H influenzae strain for longer 2068

periods and antibiotic therapy was not effective in eradicating H influenzae. 32 13-Lactamase-mediated amoxicillin resistance can be expected in 20 to 40% of H influenzae strains in North America and Europe and in almost 100% of M catarrhalis strains.33-35 Definition of Risk Factors It would be preferable to define a target population at risk based on severity of disease as has been done for patients with pneumonia. 36 Patients with significant compromise of lung function may develop acute respiratory failure as a consequence of an acute exacerbation. Mechanical ventilation may be required in 20 to 60% of hospitalized patients, average hospital and ICU length of stays are long and expensive, and hospital mortality rates for patients in acute respiratory failure range from 10 to 30%.37 Factors associated with in-hospital mortality include age :::::::65 years, severity of respiratory and nonrespiratory organ system dysfunction, and hospital length of stay before ICU admission.38 The major determinants of survival are age and degree of airway obstruction in patients with COPD followed up for 3 years. 39 Performance status and oral steroid medication usage have also been linked to survival. 4 Coexistent cardiopulmonary disease and the number of previous exacerbations have been identified as risk factors for hospitalization or returning to the physician following institution of antibiotic therapy.41 High-risk patients can be defined as being elderly, with significant impairment of lung function, having poor performance status with other comorbid conditions, having frequent exacerbations, and often requiring oral corticosteroid medication. An aggressive approach to the treatment of exacerbations of COPD in this targeted population might lead to improved outcomes, an approach that needs to be confirmed in randomized, controlled trials.

°

Stratification of Patients According to Risk Factors Therapeutic failure might be expected to lead to more hospitalizations, increased costs due to extra physician visits, prolonged absences from work, further diagnostic tests, and repeated courses of antibiotics in high-risk individuals. Routine chemotherapy fails in :::::::13% of exacerbations. 42 ·43 Simple stratification of patients into risk categories should allow the physician to select high-risk individuals and select targeted antimicrobial therapy to prevent some of these consequences. While several stratification schemes have been proposed, none have been validated in a prospective randomized trial.44 ·4s All of the classification schemes are similar and define separate groups with increasing risk of significant Disease Management of Pulmonary Infections

impairment of health and possible adverse consequences of an acute exacerbation. A new classification based on a better understanding of risk factors and treatment outcome with antibiotics has been proposed (Table 1). Group 1 patients have acute bronchitis that is usually viral in etiology. Since there is no underlying lung disease in this group, the illness is usually self-limited and benign. Comparative studies of antibiotics in this group of patients must demonstrate equivalence and cost -effectiveness cannot be demonstrated. In the face of persistent symptoms, treatment with a macrolide or doxycycline is rational to eradicate potential infection with Mycoplasnw pneurrwniae or Chlamydia pneurrwniae. Group 2 patients are young (:::::;60 years), have only mild-to-moderate impairment of lung function (FEV 1 :::::::50% predicted), and have less than four exacerbations per year. Common organisms found are H injluenzae, S pneurrwniae, and M catarrhalis, although viral infections often precede bacterial superinfection. Treatment with a 13-lactam is usually successful and the prognosis is excellent. Since most of these patients respond to therapy, treatment differences will be very difficult to find and a cost minimization analysis would be appropriate. Group 3 patients are older, with poor underlying lung function (FEV 1 :::;50% predicted), or only moderate impairment of lung function (FEV 1 between 50% and 65% predicted) but with concurrent significant medical illnesses (diabetes mellitus, congestive heart failure , chronic renal disease, chronic liver disease) and/or experience four or more exacerbations per year. H injluenzae, S pneurrwniae, and M catarrhalis continue to be the predominant organisms. In this group of patients, initial treatment failure has major implications for the patient and health-care system, including increased time lost from work and/or hospitalization. Treatment with medications directed toward resistant organisms, such as a quinolone, amoxicillin-clavulanic acid, second- or third-generation cephalosporin, or a secondgeneration macrolide, would be expected to demonstrate cost -effectiveness since the cost of therapeutic failure in this group of patients is high.

Group 4 patients suffer from chronic bronchial infection with frequent exacerbations characterized by increased sputum production, increased sputum purulence, cough, and worsening dyspnea. These individuals tend to have a chronic progressive course and an aggressive therapeutic approach should be offered. Beside the usual respiratory organisms, other Gram-negative organisms, including Enterobacteriaceae and Pseudomonas species, should be considered as potential pathogens. The use of sputum cultures in this group of patients to identify potential multiresistant organisms and target specific therapy would be useful. Frequently, a quinolone is used for this group.

PRINCIPLES OF PHARMACOECONOMIC ANALYSIS OF ANTIBIOTIC THERAPY

Economic analyses examine alternative choices making explicit the assumptions and criteria by which decisions of resource allocation are made. 4 6 There are four basic types of economic evaluation: cost-benefit analysis, cost-effectiveness analysis, cost-minimization analysis (CMA), and cost-utility analysis. All forms of analysis must clarify the perspective from which the analysis is made. In general, a broad societal perspective should be adopted to minimize the risk so that benefits or costs borne by other people or sectors are ignored.47

CosT -MINIMIZATION ANALYSIS

If the outcome of two treatments is identical in studies where adequate statistical power can detect clinically important differences, CMA is the most appropriate analytic technique. In this analysis, the treatment with the lowest acquisition cost should be chosen since this is the most efficient use of resources. Once any treatment differences can be demonstrated, this analytic technique cannot be utilized. An example of an appropriate use of this type of analysis would be generic substitutions of established antibiotics.

Table !-Proposed Classification of Patients Baseline Clinical Status

Criteria/Risk Factors

Pathogens

Usually viral No underlying structural disease l. Acute tracheobronchitis H influenzae, M ac tarrhalis, S pneurrwniae (possible 2. Simple chronic bronchitis FEV1 > 50%, increased sputum volume .and ~-lactam resistance) purulence 3. Complicated chronic bronchitis As for class 2 + any one of: FEV1 <50%, advanced H influenzae, M catarrhalis, S pneurrwniae (resistance to ~-lactams common) age, ~4 exacerbations/yr. significant comorbidity Above + Enterobacteriaceae, Pseudorrwnas 4. Chronic bronchial infection Class 3 + continuous sputum throughout year aeruginosa

CHEST I 113 I 3 I MARCH, 1998 SUPPLEMENT

2078

COST-EFFECTIVENESS ANALYSIS

This technique can be used if the competing therapies have different clinical effectiveness and the most relevant outcome for the therapeutic choices is the same. If one therapeutic option is cheaper and has an improved outcome, then this is a win-win scenario and the choice is obvious. When a treatment is more effective but also more costly, the best option demonstrates the least cost per outcome measure gained. An example of this would be using a more expensive antibiotic in a patient with an infection caused by an organism resistant to the alternative agent. The more expensive agent would eradicate the organism and cure the infection, whereas the less expensive would not. The rationale choice would be for the more expensive antibiotic. This analysis cannot be used when comparing different diseases or programs.

CosT-UTILITY ANALYSis

This analysis captures the impact of a therapy on the quality of life. Quality of life has been described as domains of physical, social, and emotional health that are important to the patient. In most clinical trials, quality of life measures evaluate effects of therapy usually expressed as a change of that score over time. While there are many instruments capable of measuring quality of life, utility measures determine the quality of life (quality-adjusted life years [QALY]) as a single number along a continuum from death (0.0) to full health (1.0). Cost utility analysis measures the cost of an intervention compared with the number of QALY gained by the application of the intervention. The preferred strategy is the selection of the therapeutic option with the lowest cost per QALY.

COST-BENEFIT ANALYSIS

This analysis measures benefit in monetary terms instead of physical terms and computes a net dollar gain or loss. Cost-benefit analysis is not often used to compare medical therapies because of the ethical concern of placing a monetary value on health and life and how the values are assigned.

PREVENTIVE MEASURES

Theoretically, preventive measures should be costeffective since, for the most part, there is little associated cost. The main factor associated with rapid longitudinal decline in FEV1 and poor out2088

come is persistent smoking. Therefore, the most important intervention in treating patients with chronic bronchitis is aggressive smoking cessation. The recent Lung Health Study confirmed that smoking intervention greatly reduces the rate of decline of FEV1 .48 Previous retrospective studies have suggested similar results 49 and the benefit of smoking cessation is seen even in patients >60 years.50 Smoking cessation may result in a small initial improvement in FEVv although this is usually not dramatic.48 However, smoking cessation often produces dramatic symptomatic benefits in patients with chronic cough and sputum production. Most patients have clearing of their cough and chronic sputum production often within 4 weeks of stopping smoking.si Most remaining patients will notice a significant decrease in the amount of cough and sputum production. Smoking cessation is difficult and no single effective technique for quitting has been described. Counseling by a physician has been shown to be the most effective measure in aiding patients to stop smoking. 52 However, nicotine replacement therapy (gum, patch, and nasal spray) is effective for long-term smoking cessation in motivated smokers. 53·54 Unfortunately, most patients will fail initial attempts at smoking cessation with 1-year failure rates of approximately 80%. Influenza virus can lead to a transient loss in pulmonary function and worsens the epithelial damage seen in patients with chronic bronchitis. It may therefore predispose to subsequent bacterial infection. All patients with chronic bronchitis should receive influenza vaccine annually.55 Morbidity and mortality from influenza are reduced by approximately 50% in vaccinated elderly patients. 56 For elderly citizens living in the community, influenza vaccination has been demonstrated to be cost -effective, leading to reductions in hospitalization and deaths from influenza and its complications as well as direct dollar savings. The beneficial effects of pneumococcal vaccine in patients with chronic bronchitis have not been firmly established. However, current recommendations are that patients with obstructive lung disease receive pneumococcal vaccine polyvalent at least once in their lives and consideration be given to repeating the vaccine every 5 to 10 years.57 Finding vaccines to protect against the more common infectious pathogens seen in chronic bronchitis is a theoretically attractive goal. Asingle randomized, double-blind, placebo-controlled trial of the administration of an oral immunostimulating agent containing lyophilized fractions of the eight most common pathogens isolated in respiratory tract infections was found to reduce the incidence of acute exacerbations of chronic bronchitis by 40% in institutionalized elderly patients.ss Disease Management of Pulmonary Infections

ANTIBIOTIC TREATMENT OF ACUTE EXACERBATIONS OF CHRONIC BRONCHITIS

With few exceptions, most comparative trials of antibiotics in this therapeutic arena have shown clinical equivalence. 59-6 1 Before immediately claiming that a CMA is appropriate, other factors should be reviewed. Most clinical trials are performed for registration purposes. As such, these trials contain clear inclusion and exclusion criteria and are usually conducted in the research environment. In most studies, patients with potential pathogens resistant to one of the test agents are excluded from further study. The dose and duration of therapy are clearly defined and compliance is monitored. In general practice, the situation is very different in that the individual practitioner decides the type, dose, and duration of therapy. Baseline pathogens are almost never identified and compliance is rarely, if ever, measured. Well-defined clinical trials measure efficacy of a drug but not the effectiveness in a real world situation. 62 Future studies of new antimicrobials should examine their efficacy in patients with an increased risk of true bacterial infection. The proposed classification system would help select patients more likely to benefit from an antibiotic and those falling into the last two categories would be most appropriate. 63 It is only in these patients that the potential benefits of broad-spectrum, 13-lactamase-stable, potent antibiotics can be demonstrated. The inclusion of patients from the first two categories can only dilute the results and minimize the advantages of more potent antibiotics. Future studies should include a well-defined prospective economic analysis from a societal perspective that includes a quality of life assessment to ascertain the cost-utility of the antibiotic in question.

REFERENCES 1 US Bureau of the Census. Statistical abstract of the United States: 1994. ll4th ed. Washington, DC: US Bureau of the Census, 1994; 95 2 Woolcock AJ. Epidemiology of chronic airways disease. Chest 1989; 96(suppl 3):302S-06S 3 Garibaldi RA. Epidemiology of community acquired respiratory tract infections in adults: incidence, etiology, and impact. Am J Med 1985; 78(suppl 6B):32-37 4 Verheij TJM, Kaptein AA, Mulder JD. Acute bronchitis: etiology, symptoms and treatment. J Fam Pract 1989; 6:66-69 5 Morrell DC. Expressions of morbidity in general practice. BMJ 1971; 2:454-58 6 Turner-Warwick M, Hodson ME, Corrin B, et al. Clinical atlas of respiratory diseases. London: Gower Medical Publishing, 1990 7 Intercontinental Medical Statistics (IMS). Ruislip, Middlesex: BPI/MDI, 1993 8 Huchon GJ, Gialdroni-Grassi G, Leophonte P, et al. Initial antibiotic therapy for lower respiratory tract infection in the

community: a European survey. Eur Respir J 1996; 9:1590-95 9 Dorea J, Torres A. Lower respiratory tract infections in the community: towards a more rational approach. Eur Respir J 1996; 9:1588-89 10 American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987; 136:225-44 ll Medical Research Council. Definition and classification of chronic bronchitis for clinical and epidemiological purposes. Lancet 1965; 1:775-79 12 Burrows B, Lebowitz MD. Quantitative relationships between cigarette smoking and chronic productive cough. Int J Epidemiol 1977; 6:107-13 13 Xu X, Christiani DC, Dockery DW, et al. Exposure-response relationships between occupational exposures and chronic illness: a community-based study. Am Rev Respir Dis 1992; 146:413-18 14 Burge PS. Occupation and chronic obstructive pulmonary disease (COPD). Eur Respir J 1994; 7:1032-34 15 Matsuse T, Hayashi S, Kuwano K, et al. Latent adenoviral infection in the pathogenesis of chronic airways obstruction. Am Rev Respir Dis 1992; 146:177-84 16 Fielding JE, Phenow KJ. Health effects of involuntary smoking. N Eng! J Med 1988; 319:1452-60 17 Anthonisen NR, Manfreda J, Warren CPW, et al. Antibiotic therapy in exacerbations of chronic obstructive lung disease. Ann Intern Med 1987; 106:196-204 18 Gump DW, Phillips CA, Forsyth BR, et al. Role of infection in chronic bronchitis. Am Rev Respir Dis 1976; 113:465-73 19 Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ 1977; 1:1645-48 20 Schmidt GA, Hall JB. Acute or chronic respiratory failure: assessment and management of patients with COPD in the emergent setting. JAMA 1989; 261:3444-53 21 Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbations of severe chronic obstructive lung disease. Am J Respir Crit Care Med 1996; 154:959-67 22 Tager I, Speizer FE. Role of infection in chronic bronchitis. N Eng! J Med 1975; 292:563-71 23 Fisher M, Akhtar AJ, Calder MA, et al. Pilot study of factors associated \vith exacerbations of chronic bronchitis. BMJ 1969; 4:187-92 24 Medici TC, Chodosh S. The reticuloendothelial system in chronic bronchitis. Am Rev Respir Dis 1972; 105:792-804 25 Musher DM, Kubutschek KR, Crennon J, et al. Pneumonia and acute febrile tracheobronchitis due to Haemophilus influenzae. Ann Intern Med 1983; 99:444-50 26 Stockley RA, Burnett D. Serum derived protease inhibitors and leucocyte elastase in sputum and the effect of infections. Bull Eur Physiopathol Respir 1980; 16:261-71 27 Murphy TF, Seithi S. State of the art: bacterial infection in chronic obstructive lung disease. Am Rev Respir Dis 1992; 146:1067-83 28 Saint S, Bent S, Vittinghoff E, et al. Antibiotics in chronic obstructive pulmonary disease exacerbations: a meta-analysis. JAMA 1995; 273:957-60 29 Chodosh S. Acute bacterial exacerbations in bronchitis and asthma. Am J Med 1987; 82(suppl 4A):154-63 30 Fagon J-Y, Chastre J, Trouillet J-L, et al. Characterization of the distal bronchial microflora during acute exacerbation of chronic bronchitis. Am Rev Respir Dis 1990; 142:1004-08 31 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; 152:1316-20 32 Groeneveld K, van Alphen L, Eijk PP, et al. Endogenous and exogenous reinfections with Haerrwphilus injluenzae in paCHEST I 113 I 3 I MARCH, 1998 SUPPLEMENT

2095

33

34 35 36

37 38

39 40 41 42 43 44 45 46 47 48

tients with chronic obstructive pulmonary disease: the effect of antibiotic treatment on persistence. J Infect Dis 1990; 161:512-17 Kayser FH, Morenzoni G, Santanam P. The second European collaborative study on the frequency of antimicrobial resistance in Haemophilus injluenzae. Eur J Clin Microbial Infect Dis 1990; 9:810-17 Jorgensen JH. Update on mechanisms and prevalence of antimicrobial resistance in Haerrwphilus injluenzae. Clin Infect Dis 1992; 14:1119-23 Doem GV. Trends in antimicrobial susceptibility of bacterial pathogens of the respiratory tract. Am J Med 1995; 99(suppl 6B):3S-7S American Thoracic Society. Guidelines for initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity and initial antimicrobial therapy. Am Rev Respir Dis 1993; 148:1418-26 Derenne JP, Fleury B, Pariente R. Acute respiratory failure of chronic obstructive lung disease. Am Rev Respir Dis 1988; 138:1006-33 Seneff MG, Wagner DP, Wagner RP, et a!. Hospital and 1-year survival of patients admitted to intensive care units with acute exacerbation of chronic obstructive lung disease. JAMA 1995; 274:1852-57 Anthonisen NR, Wright EC, Hodgkin JE, et a!. Prognosis in chronic obstructive pulmonary disease. Am Rev Respir Dis 1986; 133:14-20 Strom K. Survival of patients with chronic obstructive pulmonary disease receiving long-term domiciliary oxygen therapy. Am Rev Respir Dis 1993; 147:585-91 Ball P, Harris JM , Lawson D, et a!. Acute infective exacerbations of chronic bronchitis. Q J Med 1995; 88:61-68 MacFarlane JT, Colville A, Guion A, eta!. Prospective study of aetiology and outcome of adult lower-respiratory tract infections in the community. Lancet 1993; 341:511-14 Balter MS, Hyland RH, Low DE, eta!. Recommendations on the management of chronic bronchitis. Can Med Assoc J 1994; 15l(suppl):7-23 Wilson R. Outcome predictors in bronchitis. Chest 1995; 108:53S-57S Lode H. Respiratory tract infections: when is antibiotic therapy indicated? Clin Ther 1991; 13:149-56 Freund DA, Dittus RS. Principles of pharmacoeconomic analysis of drug therapy. Pharmacoeconomics 1992; 1:20-32 Eisenberg JM. Clinical economics: a guide to the economic analysis of clinical practices. JAMA 1989; 262:2879-86 Anthonisen NR, Connett JE, Kiley JP, et a!. Effects of smoking intervention and the use of an inhaled anticholin-

210S

49 50 51

52 53 54 55 56

57 58

59 60 61 62 63

ergic bronchodilator on the rate of decline of FEV1 : the Lung Health Study. JAMA 1994; 272:1497-1505 Dockery DW, Speizer FE, Ferris BG Jr, et a!. Cumulative and reversible effects of lifetime smoking on simple tests of lung function in adults. Am Rev Respir Dis 1988; 137:286-92 Higgins MW, Enright PL, Kronmal RA, et a!. Smoking and lung function in elderly men and women: the cardiovascular health study. JAMA 1993; 269:2741-48 Wynder EL, Kaufman PL, Lesser RL. A short-term follow-up study on ex-cigarette smokers: with special emphasis on persistent cough and weight gain. Am Rev Respir Dis 1967; 96:645-55 Jayanthi V, Probert CSJ, Sher KS, et a!. Smoking and prevention. Respir Med 1991; 85:179-83 The Smoking Cessation Clinical Practice Guideline Panel and Staff. The agency for health care policy and research smoking cessation clinical practice guideline. JAMA 1996; 275:1270-80 Fiscella K, Franks P. Cost-effectiveness of the transdermal nicotine patch as an adjunct to physicians' smoking cessation counseling. JAMA 1996; 275:1247-51 Douglas RG Jr. Prophylaxis and treatment of influenza. N Eng! J Med 1990; 322:443-50 Nichol KL, Margolis KL, Wuorenma J, eta!. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N Eng! J Med 1994; 331:778-84 Butler JC, Breinan RF, Campbell JF, et a!. Pneumococcal polysaccharide vaccine efficacy: an evaluation of current recommendations. JAMA 1993; 270:1826-31 Orcel B, Delclaux B, Baud M, et a!. Oral immunization with bacterial extracts for protection against acute bronchitis in elderly institutionalized patients with chronic bronchitis. Eur Respir J 1994; 7:446-52 Dark D. Azithromycin versus cefaclor in the treatment of acute exacerbations of chronic bronchitis. Curr Ther Res 1993; 53:203-11 Neu H, Chick TW. Efficacy and safety of clarithromycin compared to cefixime as outpatient treatment of lower respiratory tract infections. Chest 1993; 104:1393-99 Phillips H, Van Hook CJ, Butler T, et a!. A comparison of cefpodoxime proxetil and cefaclor in the treatment of acute exacerbation of COPD in adults. Chest 1993; 104:1387-92 Tugwell P, Bennett K, Sackett D. The measurement iterative loop: a framework for the critical appraisal of need, benefits and costs of health interventions. J Chronic Dis 1985; 38:339-51 Wilson R, Tillotson G, Ball P. Clinical studies in chronic bronchitis: a need for better definition and classification of severity. J Antimicrob Chemother 1996; 37:205-07

Disease Management of Pulmonary Infections