Dennis E. Niewoehner

Effect of Systemic Glucocorticoids on Exacerbations of Chronic Obstructive Pulmonary Disease

BACKGROUND AND METHODSnAlthough their clinical efficacy is unclear and they may cause serious adverse effects, systemic glucocorticoids are a standard treatment for patients hospitalized with exacerbations of chronic obstructive pulmonary disease (COPD). We conducted a double-blind, randomized trial of systemic glucocorticoids (given for two or eight weeks) or placebo in addition to other therapies, for exacerbations of COPD. Most other care was standardized over the six-month period of follow-up. The primary end point was treatment failure, defined as death from any cause or the need for intubation and mechanical ventilation, readmission to the hospital for COPD, or intensification of drug therapy.nnnRESULTSnOf 1840 potential study participants at 25 Veterans Affairs medical centers, 271 were eligible for participation and were enrolled; 80 received an eight-week course of glucocorticoid therapy, 80 received a two-week course, and 111 received placebo. About half the potential participants were ineligible because they had received systemic glucocorticoids in the previous 30 days. Rates of treatment failure were significantly higher in the placebo group than in the two glucocorticoid groups combined at 30 days (33 percent vs. 23 percent, P=0.04) and at 90 days (48 percent vs. 37 percent, P=0.04). Systemic glucocorticoids (in both groups combined) were associated with a shorter initial hospital stay (8.5 days, vs. 9.7 days for placebo, P=0.03) and with a forced expiratory volume in one second that was about 0.10 liter higher than that in the placebo group by the first day after enrollment. Significant treatment benefits were no longer evident at six months. The eight-week regimen of therapy was not superior to the two-week regimen. The patients who received glucocorticoid therapy were more likely to have hyperglycemia requiring therapy than those who received placebo (15 percent vs. 4 percent, P=0.002).nnnCONCLUSIONSnTreatment with systemic glucocorticoids results in moderate improvement in clinical outcomes among patients hospitalized for exacerbations of COPD. The maximal benefit is obtained during the first two weeks of therapy. Hyperglycemia of sufficient severity to warrant treatment is the most frequent complication.

Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator: A Randomized Trial

Context Tiotropium, a new once-daily inhaled anticholinergic bronchodilator, has been shown to improve lung function in patients with chronic obstructive pulmonary disease (COPD). Previous studies have suggested that it may also decrease the frequency of exacerbations and hospitalizations in these patients. Contribution This randomized, parallel-group, double-blind, placebo-controlled study in patients with moderate to severe COPD showed a small but statistically significant decrease in the exacerbation rate during the 6-month study period. Cautions The study period was relatively short, and the beneficial effects were modest. The Editors Exacerbations of chronic obstructive pulmonary disease (COPD) can lead to costly and clinically significant consequences. Proven treatments for exacerbations are only modestly effective (1, 2). Recovery from even mild exacerbations may be protracted (3). Frequent exacerbations are associated with impaired quality of life and a more rapid decline in lung function over time (4, 5). Patients with severe exacerbations commonly seek care in emergency departments, and many of these patients are hospitalized. In 2000, COPD was responsible for 1.5 million emergency department visits and 726000 hospitalizations in the United States (6). Economic analyses suggest that hospitalization alone consumes up to 70% of all medical expenses for patients with COPD (7, 8). Interventions that reduce the frequency or severity of exacerbations are a highly desirable but poorly met medical need. An expert panel convened by the National Heart, Lung, and Blood Institute assigned a high priority to clinical research that might improve the management of COPD exacerbations (9). Tiotropium is a newly developed, once-daily inhaled anticholinergic bronchodilator. Because of its very slow dissociation from muscarinic M3 receptors, 1 inhaled dose produces sustained bronchodilation for at least 24 hours (10). In controlled clinical trials, compared with placebo or the short-acting anticholinergic bronchodilator ipratropium, tiotropium improved lung function, dyspnea, and health-related quality of life in patients with COPD (11, 12). An analysis of adverse event reports submitted during those studies suggested that tiotropium might also reduce exacerbation and COPD-related hospitalization rates. Therefore, we designed a clinical trial to prospectively test the hypothesis that tiotropium reduces exacerbations and hospitalizations due to COPD. Methods Study Design Our study was a parallel-group, randomized, double-blind, placebo-controlled trial in patients with moderate to severe COPD conducted at 26 Veterans Affairs medical centers in the United States. The sole intervention was tiotropium given by inhalation once daily. The principal outcomes were the percentage of patients experiencing at least 1 exacerbation and the percentage of patients with at least 1 hospitalization due to a COPD exacerbation during a 6-month treatment period. The protocol is consistent with the principles of Helsinki. The institutional review boards of participating medical centers approved the study. All trial participants provided written informed consent. Patients All men and women receiving medical care at participating Veterans Affairs medical centers were potential study participants. We enrolled enough participants to ensure a minimum of 1800 randomly assigned patients. Eligibility criteria included an age of 40 years or older, a cigarette smoking history of 10 pack-years or more, a clinical diagnosis of COPD, and an FEV1 of 60% predicted or less and 70% or less of the FVC. Exclusion criteria were a clinical diagnosis of asthma, a myocardial infarction within the previous 6 months, a serious cardiac arrhythmia or hospitalization for heart failure within the previous year, known moderate to severe renal impairment, moderate to severe symptomatic prostatic hypertrophy or bladder-neck obstruction, narrow-angle glaucoma, current radiation or chemotherapy for a malignant condition, or inability to give informed consent. We also excluded patients who took systemic corticosteroids at unstable doses, or in regular daily doses of 20 mg or more of prednisone (or equivalent), or who had not fully recovered from an exacerbation for at least 30 days before the first study visit. We gathered baseline data on respiratory disease and other relevant medical history by questionnaire. Procedures We allocated eligible patients in equal numbers to receive tiotropium or placebo according to a centrally generated blocked randomization list. We generated a single randomization and assigned blocks to centers. We provided randomly assigned patients with training and detailed instructions on the use of the dry powder inhalation device (HandiHaler, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany) (13). Blinding of supplies was performed at Boehringer Ingelheim before distribution to investigational sites. The double-blind remained in place until all patients were clinically complete or until a serious adverse event required unblinding. Each morning during the trial, patients inhaled 1 capsule of tiotropium (18 g) or 1 identical placebo capsule. Participants otherwise received usual medical care, except that they could not take any open-label anticholinergic bronchodilator. They continued taking all other respiratory medications (including inhaled corticosteroids and long-acting -agonists), and primary providers were allowed to prescribe additional medications according to medical need. Primary providers also prescribed antibiotics and systemic steroid prescriptions for exacerbations without restrictions. For purposes of recall, patients kept a daily diary throughout the treatment period, recording information about specific respiratory symptoms, medications taken for exacerbations, clinic visits, and hospitalizations. We collected information about exacerbations and health care utilization by interviews when patients made site visits at 3 and 6 months and by telephone calls at 1-month intervals between visits. We assessed study drug adherence by query and by counting returned capsules. Participants performed spirometry before and 90 minutes after inhalation of study drug at baseline and again at the 3-month and 6-month visits. We encouraged patients to complete study visits and to provide all requested medical information even if they prematurely discontinued the study drug therapy. However, patients who discontinued the study drug therapy did not have 90-minute postinhalation spirometry testing at subsequent study visits. All open-label bronchodilators and the study drug were withheld overnight before spirometry. Study sites performed spirometry by using a common predictive nomogram with equipment and methods that conformed to American Thoracic Society recommendations (14, 15). Objectives We aimed to determine whether tiotropium decreased COPD exacerbations and hospitalizations due to exacerbations. Outcome Measures The coprimary outcomes were the percentage of patients with a COPD exacerbation and the percentage of patients with a hospitalization due to COPD exacerbation. We defined an exacerbation as a complex of respiratory symptoms (increase or new-onset) of more than 1 of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids, hospitalization, or both. The study team at each site requested discharge summaries for all hospitalizations, wherever they occurred. We identified hospitalizations due to COPD exacerbations from events on case report forms that met the protocol definition of an exacerbation and where review of discharge summaries and other available medical records indicated that the event resulted in a hospitalization. We also considered an event to be a hospitalization if a patient was held and treated for an acute respiratory condition in an urgent care department or in an observation unit for longer than 24 hours. Admissions to nursing homes or other extended care facilities were not considered hospitalizations. Secondary outcomes included time to first COPD exacerbation and time to first hospitalization due to COPD exacerbation, the frequencies of exacerbations and of exacerbation-related health care utilization (hospitalizations, hospitalization days, unscheduled clinic visits, antibiotic treatment days, and systemic corticosteroid treatment days), the frequencies of all-cause hospitalizations and hospitalization days, and results of spirometry. Statistical Analysis We analyzed the data by using a modified intention-to-treat principle. Therefore, we included all available data for the patients with any follow-up contact who took at least 1 capsule of study drug in the analysis up to their first event (for the time-to-event end points) or their withdrawal from the trial. For the time-to-event end points, we censored patients without an event at the end of their participation in the trial. Although we intended to follow all patients for the full 6 months, some patients were lost to follow-up. We handled missing data by using longitudinal data analysis methods (spirometry), analysis of observed data only (number of events), or analysis methods for censored data (time-to-event data). For the percentage of patients with an event, we considered that patients who discontinued the study drug therapy before having an event did not have an event. We analyzed the coprimary end points by using a CochranMantelHaenszel test with center as a stratum. We used a stepwise procedure to test the percentage of patients with an exacerbation and, if rejected, to test percentage of patients with a hospitalization due to COPD exacerbation, each at a 2-sided level of 0.05. Because of the prespecified closed testing procedure, no adjustment for multiplicity was required. We calculated that a sample size of 1800 patients would have 80% power to dete

Management of Stable Chronic Obstructive Pulmonary Disease: A Systematic Review for a Clinical Practice Guideline

In the United States, more than 5% of adults have symptomatic chronic obstructive pulmonary disease (COPD), which is a leading cause of morbidity and mortality (1, 2). Treatment options include inhaled pharmacologic therapy with short- or long-acting bronchodilators or corticosteroids, pulmonary rehabilitation, disease management, and supplemental oxygen (3). Long-acting inhaled bronchodilators and pulmonary rehabilitation have been recommended for patients with spirometrically detected obstruction, even without symptoms (3). Addition of inhaled corticosteroids to long-acting bronchodilators (combination therapy) has been recommended for individuals with repeated exacerbations and an FEV1 less than 50% predicted. Information about therapeutic effectiveness and adverse effects of common treatment options and how clinical and spirometric characteristics affect outcomes is not well known but is important for clinicians caring for patients with stable COPD. This review updates a report prepared for the Agency for Healthcare Research and Quality (AHRQ) and serves as the background paper for an American College of Physicians Clinical Practice Guideline (4). It addresses the following questions: Which inhaled therapies are effective for treatment and maintenance of stable COPD? When should clinicians consider pulmonary rehabilitation and disease management? When should clinicians prescribe oxygen therapy? Should clinicians base treatment decisions on spirometric results, symptoms, or both? Detailed information on the use of spirometry for diagnosis and case finding is available in the original AHRQ report at www.ahrq.gov/clinic/tp/spirotp.htm. Spirometry for case finding and management would be useful if it identified individuals who were not clinically detected as candidates for COPD treatments, excluded individuals with false-positive clinical presentations for COPD, or independently identified thresholds to guide initiation or modification of therapies. Our previous report identified insufficient evidence to support these conditions. Methods Data Sources and Selection For our previous report, we searched PubMed and the Cochrane Library for articles published in English from 1966 through May 2005. The current review extends the search related to COPD therapies through March 2007 by using search terms used in a 2003 review by Sin and colleagues (5) to identify randomized, controlled trials (RCTs), controlled clinical trials, meta-analyses, and reviews published since the completion of their search in 2002. To supplement our search, we examined the Cochrane Database of Systematic Reviews of Effectiveness, examined bibliographies of published articles, and contacted experts. We categorized interventions as 1) inhaled medications (2-agonists, anticholinergics, combination 2-agonists and anticholinergics, inhaled corticosteroids, and combination inhaled corticosteroids and long-acting 2-agonists or anticholinergics), 2) pulmonary rehabilitation, 3) disease management programs, and 4) oxygen therapy. Two reviewers used standardized data abstraction sheets to examine titles and abstracts of newly identified references. If both reviewers agreed on eligibility, we included the article. Disagreement among reviewers, although rare, was resolved by discussion, with final decision by the lead author. Trials were eligible if they were randomized; involved persons with COPD that was defined clinically or by spirometry; and measured clinical outcomes, including exacerbations, standardized respiratory health status measures, hospitalizations, and deaths. Studies reporting only spirometry outcomes were ineligible. Inhaled therapy trials had to include 50 or more participants per treatment group and at least 3 months of follow-up. Trials of pulmonary rehabilitation programs had to include at least 6 weeks of follow-up and a usual care comparison group. We excluded studies that compared different types of pulmonary rehabilitation, and we included systematic reviews and meta-analyses of COPD therapies. Data Extraction Two individuals extracted data onto standardized forms. The lead author resolved any disagreements. Main outcomes for all interventions were the percentage of participants experiencing at least 1 exacerbation, mean change in respiratory health status, hospitalization, and death. Respiratory health status was assessed by the validated St. George Respiratory Questionnaire (SGRQ) or the Chronic Respiratory Disease Questionnaire (CRDQ). A 4-unit reduction (out of 100) on the SGRQ and a 0.5-unit increase per question on the 7-question CRDQ are defined as clinically noticeable improvements (6). For pulmonary rehabilitation, we collected information on the 6-minute walk test and defined a minimally clinically significant effect size as 53 meters or more. We collected data on adverse effects of long-acting inhaled therapies (including specifically described adverse effects, serious adverse effects, treatment adherence, study withdrawals, and withdrawals due to adverse effects) from trials that lasted at least 1 year and from systematic reviews that specifically addressed adverse effects. We assessed whether these studies used placebo or active control run-in periods, as well as the number and reasons for exclusion of potentially eligible patients from randomization during the run-in period. Study Quality Assessment We used the methods of Schulz and colleagues (7) to assess the quality of randomized trials on the basis of allocation concealment. We assessed blinding, intention-to-treat analysis, length of follow-up, withdrawals or loss to follow-up, and funding source. We rated the quality of systematic reviews or meta-analysis according to the Strength of Recommendation Taxonomy (8). An RCT was considered high quality if it had allocation concealment, blinding (if possible), intention-to-treat analysis, adequate size, and adequate follow-up (>80%). Systematic reviews or meta-analysis with high-quality studies and consistent findings are indicated as good-quality, patient-oriented evidence. Data Synthesis and Analysis Intervention effectiveness was described according to baseline respiratory symptom status, spirometrically defined level of airflow obstruction, acute change in spirometry, or spirometric change over time (inhaled medications and use of spirometry to guide therapy). The magnitude of effect across interventions (inhaled therapies and oxygen) was based on relative risks and absolute risk differences, as well as comparison with previously determined, minimally important clinical differences in respiratory health status and exercise capacity. Study results were combined, if appropriate, to produce pooled estimates. We calculated relative risks and 95% CIs for categorical variables and weighted mean differences and 95% CIs for continuous variables. We conducted analyses by using a DerSimonianLaird random-effects model in Review Manager software, version 4.2 (The Cochrane Collaboration, Oxford, United Kingdom) (9). We assessed heterogeneity by using a chi-square test and the I2 test. An I2 statistic of 50 or greater indicates substantial heterogeneity (10). If heterogeneity existed, we conducted sensitivity analyses to explore potential causes of heterogeneity. Role of the Funding Source This project was funded by the AHRQ, U.S. Department of Health and Human Services. The updated synthesis was conducted in collaboration with the American College of Physicians Clinical Efficacy Assessment Subcommittee. Panel members assisted in the formulation of questions and reviewing drafts of this report. The funding source had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Results Yield of the Literature Search Figure 1 shows that 42 RCTs involving short- or long-acting inhaled monotherapy or combination therapy (ipratropium [1117], tiotropium [14, 15, 1825]), long-acting 2-agonists (11, 13, 14, 17, 18, 21, 2641), corticosteroids (28, 29, 32, 33, 3847), dual D2 dopamine receptor2-agonist (sibenadet) (30, 48, 49), short-acting 2-agonists, and ipratropium (5052) versus placebo or active control and 8 meta-analyses of RCTs (5, 5359) were included for assessment of COPD inhaled therapies. We have identified 10 RCTs and 5 systematic reviews since our AHRQ report. Our updated search yielded an additional 16 RCTs and 2 systematic reviews of nonpharmacologic treatments. Three systematic reviews of 39 unique RCTs and 6 additional RCTs evaluated pulmonary rehabilitation (6 RCTs and 1 systematic review were added for our review) (5, 6090). Two systematic reviews of 13 unique RCTs and 2 additional trials evaluating disease management, education, and follow-up were eligible (2 RCTs and 1 systematic review were added for our review) (5, 91106). Supplemental oxygen therapy was not addressed in our original report. We included 8 RCTs and 1 systematic review evaluating 7 of these 8 trials (5, 107114). Figure 1. Data search and selection. RCT= randomized, controlled trial. Quality Assessment Appendix Table 1 and other systematic reviews (5, 60, 61, 91) describe the included randomized trials. We identified no study quality differences according to type of inhaled medication. Appendix Table 1. Treatments, Baseline Characteristics, and Study Quality of Individual Trials of Treatments for Chronic Obstructive Pulmonary Disease Concealment of treatment allocation for inhaled therapies was adequate in 17 studies (12, 22, 25, 26, 2931, 3640, 42, 44, 46, 47, 49). All trials were double-blind, and nearly all used intention-to-treat analyses. Several included only participants who were taking at least 1 dose or who had 1 valid postbaseline measurement (17, 23, 30, 32, 38, 42, 44, 48, 49) or excluded participants because of noneligibility after randomization or good practice or ethics violations by individual study sites (26, 39). All but 7 studies were funded by pharmaceutical companies.

Spirometry as a Motivational Tool to Improve Smoking Cessation Rates: A Systematic Review of the Literature

Obtaining spirometric testing and providing those results to individuals who smoke has been advocated as a motivational tool to improve smoking cessation. However, its effectiveness is not known. We conducted a systematic review to determine if this approach improves rates of smoking cessation. Data sources included MEDLINE (1966 to October 2005), the Cochrane Library, and experts in the field. Eligible randomized controlled trials (RCTs) enrolled at least 25 smokers per arm, evaluated spirometry with associated counseling or in combination with other treatments, followed subjects at least 6 months, and provided smoking abstinence rates. Results from nonrandomized studies also were summarized. The primary outcome was patient-reported long-term (at least 6 months) sustained abstinence with biological validation. Additional outcomes included self-reported abstinence and point-prevalence abstinence. Seven RCTs (N = 6,052 subjects) met eligibility criteria. Follow-up duration ranged from 9 to 36 months. In six trials, the intervention group received concomitant treatments previously demonstrated to increase cessation independently. The range of abstinence was 3%-14% for control subjects and 7%-39% among intervention groups, statistically significantly in favor of intervention in four studies. The only RCT that assessed the independent contribution of spirometry in combination with counseling demonstrated a nonsignificant 1% improvement in patient-reported point-prevalence abstinence at 12 months in the group that received spirometry plus counseling versus counseling alone (6.5% versus 5.5%). Findings from observational studies were mixed, and the lack of controls makes interpretation problematic. Available evidence is insufficient to determine whether obtaining spirometric values and providing that information to patients improves smoking cessation compared with other smoking cessation methods. Spirometric values are of limited benefit as a predictor of smoking cessation or as a tool to customize smoking cessation strategies.

Serum carcinoembryonic antigen as an adjunct to preoperative staging of lung cancer

OBJECTIVEnTo determine whether measurement of preoperative serum carcinoembryonic antigen concentrations adds useful prognostic data to current preoperative staging of lung cancer by computed tomography, bronchoscopy, and mediastinoscopy.nnnMETHODSnA prospective cohort study of 130 consecutive patients was evaluated for suspected lung cancer from July 1991 through December 1992 at a university-affiliated Veterans Affairs Medical Center. Serum concentrations of carcinoembryonic antigen were measured before diagnosis, staging, or resection of cancer.nnnRESULTSnMalignant disease was diagnosed by bronchoscopy, needle biopsy, mediastinoscopy, or resection in 111 of 130 patients. In the 50 patients undergoing resection with curative intent, multivariate analysis indicated that carcinoembryonic antigen was a significant predictor of survival independent of patient age, pathologic stage, histologic type, and tumor size (P=.0357).nnnCONCLUSIONSnElevated preoperative serum concentrations of carcinoembryonic antigen predict a poor prognosis for lung cancer independent of other conventional staging parameters and have an adjunctive role in the staging of lung cancer.

Viral pathogens in acute exacerbations of chronic obstructive pulmonary disease

The objective of this study is to determine the prevalence of respiratory syncytial virus (RSV) and other viral respiratory pathogens in emergency department (ED) patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). COPD patients presenting to the ED with <10xa0days of AECOPD symptoms were eligible. We used PCR to test nasal swabs for common viral respiratory pathogens. We completed viral studies on 76 patients from two EDs. Patients had a mean age of 72xa0years, and were 68% male, 99% white, and 29% current smokers. Influenza vaccination was reported by 87%. Viruses were detected in 19 of 76 patients (25%). These included RSV A (2) and B (4); parainfluenza 1 (1), 2 (0), and 3 (2); influenza A (3) and B (0); rhinovirus (4); and human metapneumovirus (3). A putative viral etiology was identified in 25% of AECOPD presenting for emergency care, of which approximately one-third were RSV-related.

The Role of Systemic Corticosteroids in Acute Exacerbation of Chronic Obstructive Pulmonary Disease

The administration of systemic corticosteroids for patients with exacerbations of chronic obstructive pulmonary disease (COPD) has become common practice over the past 25 years. This practice remained somewhat controversial because corticosteroids can have serious adverse effects and initial clinical trials provided inconclusive evidence concerning their efficacy.Results from recent clinical trials indicate that systemic corticosteroids are modestly effective in shortening the duration of severe exacerbations of COPD. Systemic corticosteroids administered intravenously or orally to hospitalized patients with exacerbations of COPD reduced the absolute treatment failure rate by about 10%, increased the forced expiratory volume in 1 second (FEV1) by about 100ml, and shortened the hospital stay by 1 to 2 days. Oral corticosteroids probably confer similar benefits when used for treating moderately severe COPD exacerbations in an out-patient setting.The optimal starting dose of corticosteroids is not known, but the duration of treatment should not extend longer than 2 weeks. Hyperglycemia is the most common adverse event, but secondary infections, mental disturbances, and myopathies may also occur.

Premature discontinuation of patients: A potential bias in COPD clinical trials

Premature discontinuation from clinical trials may bias results against effective therapies. In the present study mortality rates were retrospectively reviewed in a 6-month, randomised, placebo-controlled trial in which tiotropium 18u2005μg daily was shown to decrease chronic obstructive pulmonary disease exacerbations. Patients participated for 6u2005months even if trial medication was prematurely discontinued. Exposure-adjusted incidence rates (IRs) were calculated for randomisation–end trial, randomisation–end trial drug (0–ED) and end trial drug–end trial (ED–ET). Of 1,829 patients (forced expiratory volume in one second 1.04u2005L (36% predicted), mean age 68u2005yrs, 99% male), 16% tiotropium and 27% placebo patients prematurely stopped trial medication. The number of fatal events for the entire cohort was: 62 all cause, including 16 cardiac and 16 lower respiratory. IRs for fatal events per 100u2005patient-yrs were higher in the discontinued period: 1.9 (0–ED) versus 23.0 (ED–ET) in the tiotropium group and 1.8 versus 19.0 in the placebo group. Respective IRs for fatal cardiac events were 0.7 versus 2.8 (tiotropium) and 0.5 versus 6.2 (placebo); for fatal lower respiratory events were 0.7 versus 2.8 (tiotropium) and 0.8 versus 5.4 (placebo). Rate ratios (tiotropium/placebo) for fatal events were lower in the discontinued period: 1.4 versus 0.5 for cardiac and 0.9 versus 0.5 for lower respiratory. Higher incidence rates of fatal events occurred following premature discontinuation of study medication. Incomplete information from rate ratios occurs as a result of failure to consider outcomes of patients who discontinue early from clinical trials.

Lung cancer surgery: A critical review of the evidence

Surgery is generally considered to be the treatment of choice for anatomically localized non-small-cell lung cancer, but its effectiveness remains unproven. Observational studies have been of limited value because the criteria by which patients are selected for surgery create substantial differences between patients who undergo surgery and those who do not. One small randomized trial of surgery vs radiotherapy was inconclusive, but several large trials of lung cancer screening have provided indirect evidence against a benefit from surgery. Two ongoing randomized trials, one on extensive vs limited resection and the other on the effect of surgery in more extensive disease, may provide further insight into the effectiveness of surgery in the treatment of localized non-small-cell lung cancer. Development of a large randomized trial to directly assess the effectiveness of surgery in the treatment of localized non-small-cell lung cancer has been precluded by ethical concerns, but may need to be reconsidered if indicated by the findings of the two ongoing studies.

Clinical Efficacy of OM-85 BV in COPD and Chronic Bronchitis: A Systematic Review

OM-85 BV is an immunomodulatory agent used for prevention of exacerbations in persons with chronic lung disease. We conducted a systematic review of OM-85 BV to evaluate its efficacy and safety. A systematic search for relevant articles was performed. Studies were included if they involved persons with chronic obstructive pulmonary disease or chronic bronchitis and were randomized to OM-85 BV or placebo. Investigators extracted data on study design, participant characteristics, and clinical outcomes. Thirteen trials involving 2066 individuals met inclusion criteria. Three trials enrolled an older, more homogenous population with chronic obstructive pulmonary disease. Utilizing quantitative pooled analysis in these studies, with one or more acute exacerbations as the endpoint, we found a non-statistically significant trend in favor of OM-85 BV [relative risk 0.83, 95% confidence interval 0.65–1.05]. Ten trials enrolled a heterogeneous population with chronic bronchitis. In these trials, exacerbation rates were less with OM-85 BV in 4 of 9 trials reporting this outcome. Varied results in the outcomes of hospitalization, symptom scores, and antibiotic or steroid use were found across studies. Withdrawals and adverse events were similar between OM-85 BV and placebo. While OM-85 BV is used to prevent exacerbations in persons with chronic lung disease, consistent evidence across multiple important outcomes does not exist to clearly demonstrate clinical benefit. Further randomized controlled trials enrolling large numbers of persons with well-defined COPD are necessary to confirm the effectiveness of this agent.