Nicholas R. Anthonisen

Antibiotic Therapy in Exacerbations of Chronic Obstructive Pulmonary Disease

The effects of broad-spectrum antibiotic and placebo therapy in patients with chronic obstructive pulmonary disease in exacerbation were compared in a randomized, double-blinded, crossover trial. Exacerbations were defined in terms of increased dyspnea, sputum production, and sputum purulence. Exacerbations were followed at 3-day intervals by home visits, and those that resolved in 21 days were designated treatment successes. Treatment failures included exacerbations in which symptoms did not resolve but no intervention was necessary, and those in which the patients condition deteriorated so that intervention was necessary. Over 3.5 years in 173 patients, 362 exacerbations were treated, 180 with placebo and 182 with antibiotic. The success rate with placebo was 55% and with antibiotic 68%. The rate of failure with deterioration was 19% with placebo and 10% with antibiotic. There was a significant benefit associated with antibiotic. Peak flow recovered more rapidly with antibiotic treatment than with placebo. Side effects were uncommon and did not differ between antibiotic and placebo.

The Effects of a Smoking Cessation Intervention on 14.5-Year Mortality: A Randomized Clinical Trial

Context Although there are many health benefits for smokers who stop smoking, we still lack evidence from randomized, controlled trials that smoking cessation programs reduce mortality. Contribution In this randomized, controlled trial of a 10-week-long smoking cessation intervention in 5887 smokers with asymptomatic airway obstruction, 14-year mortality rates were higher in the usual care group than in the smoking cessation group (hazard ratio, 1.18 [95% CI, 1.02 to 1.37]). The mortality benefit was greatest among the 21.7% of the intervention group who actually managed to quit smoking. Implications Smoking cessation programs substantially reduce mortality even when only a minority of patients stop smoking. The Editors Smoking cessation almost certainly has beneficial effects on subsequent mortality (1). However, the strongest support for this assertion comes from cohort studies, where smokers and quitters were self-selected. Results from randomized trials, which avoid the selection issue, have largely been disappointing because mortality benefits have not been clear or have not been clearly attributable to smoking cessation (1). The Lung Health Study (LHS) was a randomized clinical trial of smoking cessation and inhaled bronchodilator (ipratropium) therapy in smokers 35 to 60 years of age who did not consider themselves ill but had evidence of mild to moderate airway obstruction (2). Individuals with serious disease, hypertension, obesity, or excessive alcohol intake were excluded. The primary research questions were whether a smoking cessation program and use of inhaled ipratropium would decrease the rate of decline of lung function and would affect mortality and morbidity over 5 years. These results have been reported elsewhere (3, 4). The smoking cessation program was associated with cumulative reduced decline in lung function (FEV1) that was largest in participants who stopped smoking early in the study; inhaled ipratropium produced a small noncumulative increase in FEV1 that disappeared when the drug was withdrawn (3). Intention-to-treat analysis after 5 years did not reveal differences in morbidity or mortality among treatment groups (4), although subgroup analysis showed that smoking cessation was associated with significant reductions in fatal or nonfatal cardiovascular disease and coronary heart disease. This paper reports the effects of the study intervention on mortality in LHS participants 14.5 years after randomization. Methods The design of the LHS has been described in detail elsewhere (2). The participants, all volunteers, were smokers who did not consider themselves ill but had evidence of airway obstruction and little evidence of other disease. Researchers recruited participants from the community using a wide variety of techniques (5). In 10 clinical centers, 5887 participants were randomly assigned to 3 groups. Two special intervention groups received an intensive 10-week smoking cessation program. Briefly, the cessation intervention consisted of a strong physician message and 12 two-hour group sessions, using behavior modification and nicotine gum. Quitters entered a maintenance program that stressed coping skills. One special intervention group also received ipratropium, while the other received a placebo inhaler. A third group received usual care. About 75% of the original participants were followed continuously for the subsequent 10 years by biannual telephone contacts and 1 clinic visit at approximately 11 to 12 years after randomization (6). Telephone contacts served to check smoking status, morbidity, and mortality and were not part of the intervention. All study participants provided written informed consent for the original LHS before beginning the study. The consent documents stated that smoking increases the risk for chronic obstructive pulmonary disease, respiratory tract cancer, and cardiovascular disease and that smoking cessation would decrease such risks. Additional written informed consent was obtained from persons who participated in the biannual telephone calls. Institutional review boards at each of the 10 clinical centers and the coordinating center approved the study design and consent documents. When biannual phone calls revealed a participant death, staff attempted to collect death certificates, autopsy reports, relevant medical records, and interviews with attending physicians or eyewitnesses. An independent mortality and morbidity review board examined these data and classified causes of death. In addition, a National Death Index review provided date and cause of death for all U.S. study participants through the end of 2001. Vital status at 31 December 2001 or 14.5 years, whichever was earlier, was successfully determined for 98.3% of all participants; missing individuals were Canadians who had been lost to follow-up and were not accessible through the National Death Index. Mortality end points were classified in 7 categories: coronary heart disease, cardiovascular disease including coronary heart disease, lung cancer, other cancer, respiratory disease excluding lung cancer, other, and unknown. The other category included but was not limited to liver disease, kidney disease, sepsis, accidents, suicide, and AIDS. Analyses were performed on an intention-to-treat basis, comparing the special intervention group with the usual care group. The special intervention group was a combination of the groups originally assigned to receive inhaled ipratropium or placebo therapy. Both of these groups, which were very similar at baseline, received the smoking cessation program and exhibited similar rates of smoking cessation (3). Participants were also divided into 3 groups according to smoking history during the initial 5 years of the trial. Sustained quitters were participants who stopped smoking in the first year after randomization and maintained biochemically validated abstinence (3) throughout follow-up. Continuing smokers were participants who reported smoking at all follow-up visits. Intermittent quitters were participants who reported smoking at some but not all of their follow-up visits or during the time between visits. Statistical Analysis Baseline differences between the special intervention and usual care groups were tested by using t-tests for continuous variables and chi-square statistics for categorical variables. Cause-specific death rates and times to events were analyzed by using the KaplanMeier product-limit method (7). Survival was compared among groups by using the log-rank test. Hazard ratios and adjusted analyses were obtained by using the Cox proportional hazards model. Interactions were assessed by comparing hierarchically related proportional hazards models. All P values result from 2-sided tests; no adjustments were made for multiple comparisons. Role of the Funding Source This study was funded by a contract and grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The funding source had a role in the design of the study and approved the manuscript before it was submitted for publication. Results Baseline characteristics of LHS participants are shown in Table 1. Most were middle-aged; smoked heavily; and had substantial smoking histories, airway obstruction (FEV1FVC ratio 70%), and borderline low FEV1 values. On average, participants were normotensive and had normal body mass indices. Most participants were of white ethnicity; 37% were women. The average participant had some postsecondary education and did not drink heavily. The special intervention and usual care groups did not significantly differ at baseline, except in percentage of participants who were married, which was higher in the special intervention group (P= 0.04). Smoking status after the first 5 years differed significantly between treatment groups (P 0.001). Among special intervention participants and usual care participants, respectively, 21.7% and 5.4% were sustained quitters, 29.3% and 23.3% were intermittent quitters, and 49.0% and 71.3% were continuing smokers. Table 1. Baseline Characteristics of Lung Health Study Participants There were 731 known deaths among LHS participants, as shown in Table 2. Lung cancer was the most common cause of death (n= 240 [33%]). Coronary heart disease accounted for 77 deaths (10.5%), and cardiovascular disease including coronary heart disease accounted for 163 deaths (22%). One hundred fifty-four participants (21%) died of cancer of organs other than the lung. Deaths due to respiratory disease other than cancer were relatively uncommon (n= 57 [7.8%]). The cause of death was unknown in only 17 participants (2.3%). Mortality did not significantly differ between the special intervention groups originally assigned to ipratropium or placebo (Table 2). Table 2. Causes of Death by Treatment Group Figure 1 shows all-cause survival rates in the 2 treatment groups. Death rates were significantly higher in the usual care group than in the special intervention group (10.38 per 1000 person-years vs. 8.83 per 1000 person-years; P= 0.03). The hazard ratio for mortality in the usual care group was 1.18 (95% CI, 1.02 to 1.37) compared with the special intervention group. Figure 2 shows categorical causes of death in the 2 treatment groups. In all categories except other, death rates were higher in the usual care group than in the special intervention group, but the difference was significant only for deaths from respiratory diseases not related to lung cancer (1.08 per 1000 person-years vs. 0.56 per 1000 person-years; P= 0.01). Figure 1. All-cause 14.5-year survival. P Figure 2. Mortality rates at 14.5 years by cause. When survival was analyzed according to smoking habit, it differed significantly between groups (P< 0.001), even after adjustment for baseline differences (data not shown). Mortality was 6.04 per 1000 person-years in sustained quitters, 7.77 per 1000 person-years in intermittent quitters, and 11.09 per 1000 p

Azithromycin for prevention of exacerbations of COPD.

BACKGROUND Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases. METHODS We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval. RESULTS A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. Georges Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04). CONCLUSIONS Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.).

Mortality in COPD: role of comorbidities

Chronic obstructive pulmonary disease (COPD) represents an increasing burden throughout the world. COPD-related mortality is probably underestimated because of the difficulties associated with identifying the precise cause of death. Respiratory failure is considered the major cause of death in advanced COPD. Comorbidities such as cardiovascular disease and lung cancer are also major causes and, in mild-to-moderate COPD, are the leading causes of mortality. The links between COPD and these conditions are not fully understood. However, a link through the inflammation pathway has been suggested, as persistent low-grade pulmonary and systemic inflammation, both known risk factors for cardiovascular disease and cancer, are present in COPD independent of cigarette smoking. Lung-specific measurements, such as forced expiratory volume in one second (FEV1), predict mortality in COPD and in the general population. However, composite tools, such as health-status measurements (e.g. St Georges Respiratory Questionnaire) and the BODE index, which incorporates Body mass index, lung function (airflow Obstruction), Dyspnoea and Exercise capacity, predict mortality better than FEV1 alone. These multidimensional tools may be more valuable because, unlike predictive approaches based on single parameters, they can reflect the range of comorbidities and the complexity of underlying mechanisms associated with COPD. The current paper reviews the role of comorbidities in chronic obstructive pulmonary disease mortality, the putative underlying pathogenic link between chronic obstructive pulmonary disease and comorbid conditions (i.e. inflammation), and the tools used to predict chronic obstructive pulmonary disease mortality.

An Official American Thoracic Society Public Policy Statement: Novel Risk Factors and the Global Burden of Chronic Obstructive Pulmonary Disease

RATIONALE Although cigarette smoking is the most important cause of chronic obstructive pulmonary disease (COPD), a substantial proportion of COPD cases cannot be explained by smoking alone. OBJECTIVES To evaluate the risk factors for COPD besides personal cigarette smoking. METHODS We constituted an ad hoc subcommittee of the American Thoracic Society Environmental and Occupational Health Assembly. An international group of members was invited, based on their scientific expertise in a specific risk factor for COPD. For each risk factor area, the committee reviewed the literature, summarized the evidence, and developed conclusions about the likelihood of it causing COPD. All conclusions were based on unanimous consensus. MEASUREMENTS AND MAIN RESULTS The population-attributable fraction for smoking as a cause of COPD ranged from 9.7 to 97.9%, but was less than 80% in most studies, indicating a substantial burden of disease attributable to nonsmoking risk factors. On the basis of our review, we concluded that specific genetic syndromes and occupational exposures were causally related to the development of COPD. Traffic and other outdoor pollution, secondhand smoke, biomass smoke, and dietary factors are associated with COPD, but sufficient criteria for causation were not met. Chronic asthma and tuberculosis are associated with irreversible loss of lung function, but there remains uncertainty about whether there are important phenotypic differences compared with COPD as it is typically encountered in clinical settings. CONCLUSIONS In public health terms, a substantive burden of COPD is attributable to risk factors other than smoking. To prevent COPD-related disability and mortality, efforts must focus on prevention and cessation of exposure to smoking and these other, less well-recognized risk factors.

C-reactive protein and mortality in mild to moderate chronic obstructive pulmonary disease

Background: Although C-reactive protein (CRP) levels are increased in chronic obstructive pulmonary disease (COPD), it is not certain whether they are associated with adverse clinical outcomes. Methods: Serum CRP levels were measured in 4803 participants in the Lung Health Study with mild to moderate COPD. The risk of all-cause and disease specific causes of mortality was determined as well as cardiovascular event rates, adjusting for important covariates such as age, sex, cigarette smoking, and lung function. Cardiovascular events were defined as death from coronary heart disease or stroke, or non-fatal myocardial infarction or stroke requiring admission to hospital. Results: CRP levels were associated with all-cause, cardiovascular, and cancer specific causes of mortality. Individuals in the highest quintile of CRP had a relative risk (RR) for all-cause mortality of 1.79 (95% confidence interval (CI) 1.25 to 2.56) compared with those in the lowest quintile of CRP. For cardiovascular events and cancer deaths the corresponding RRs were 1.51 (95% CI 1.20 to 1.90) and 1.85 (95% CI 1.10 to 3.13), respectively. CRP levels were also associated with an accelerated decline in forced expiratory volume in 1 second (p<0.001). The discriminative property of CRP was greatest during the first year of measurement and decayed over time. Comparing the highest and lowest CRP quintiles, the RR was 4.03 (95% CI 1.23 to 13.21) for 1 year mortality, 3.30 (95% CI 1.38 to 7.86) for 2 year mortality, and 1.82 (95% CI 1.22 to 2.68) for ⩾5 year mortality. Conclusions: CRP measurements provide incremental prognostic information beyond that achieved by traditional markers of prognosis in patients with mild to moderate COPD, and may enable more accurate detection of patients at a high risk of mortality.

Efficacy of Esomeprazole for Treatment of Poorly Controlled Asthma

BACKGROUND Gastroesophageal reflux is common among patients with asthma but often causes mild or no symptoms. It is not known whether treatment of gastroesophageal reflux with proton-pump inhibitors in patients who have poorly controlled asthma without symptoms of gastroesophageal reflux can substantially improve asthma control. METHODS In a parallel-group, double-blind trial, we randomly assigned 412 participants with inadequately controlled asthma, despite treatment with inhaled corticosteroids, and with minimal or no symptoms of gastroesophageal reflux to receive either 40 mg of esomeprazole twice a day or matching placebo. Participants were followed for 24 weeks with the use of daily asthma diaries, spirometry performed once every 4 weeks, and questionnaires that asked about asthma symptoms. We used ambulatory pH monitoring to ascertain the presence or absence of gastroesophageal reflux in the participants. The primary outcome was the rate of episodes of poor asthma control, as assessed on the basis of entries in asthma diaries. RESULTS Episodes of poor asthma control occurred with similar frequency in the placebo and esomeprazole groups (2.3 and 2.5 events per person-year, respectively; P=0.66). There was no treatment effect with respect to individual components of the episodes of poor asthma control or with respect to secondary outcomes, including pulmonary function, airway reactivity, asthma control, symptom scores, nocturnal awakening, or quality of life. The presence of gastroesophageal reflux, which was documented by pH monitoring in 40% of participants with minimal or no symptoms, did not identify a subgroup of patients that benefited from treatment with proton-pump inhibitors. There were fewer serious adverse events among patients receiving esomeprazole than among those receiving placebo (11 vs. 17). CONCLUSIONS Despite a high prevalence of asymptomatic gastroesophageal reflux among patients with poorly controlled asthma, treatment with proton-pump inhibitors does not improve asthma control. Asymptomatic gastroesophageal reflux is not a likely cause of poorly controlled asthma. (ClinicalTrials.gov number, NCT00069823.)

Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease

Background: Clinical studies suggest that inhaled corticosteroids reduce exacerbations and improve health status in chronic obstructive pulmonary disease (COPD). However, their effect on mortality is unknown. Methods: A pooled analysis, based on intention to treat, of individual patient data from seven randomised trials (involving 5085 patients) was performed in which the effects of inhaled corticosteroids and placebo were compared over at least 12 months in patients with stable COPD. The end point was all-cause mortality. Results: Overall, 4% of the participants died during a mean follow up period of 26 months. Inhaled corticosteroids reduced all-cause mortality by about 25% relative to placebo. Stratification by individual trials and adjustments for age, sex, baseline post-bronchodilator percentage predicted forced expiratory volume in 1 second, smoking status, and body mass index did not materially change the results (adjusted hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.55 to 0.96). Although there was considerable overlap between subgroups in terms of effect sizes, the beneficial effect was especially noticeable in women (adjusted HR 0.46; 95% CI 0.24 to 0.91) and former smokers (adjusted HR 0.60; 95% CI 0.39 to 0.93). Conclusions: Inhaled corticosteroids reduce all-cause mortality in COPD. Further studies are required to determine whether the survival benefits persist beyond 2–3 years.

A Comparison of the Bronchodilating Effects of a Beta-2 Adrenergic Agent (Albuterol) and an Anticholinergic Agent (Ipratropium Bromide), Given by Aerosol Alone or in Sequence

We evaluated the effect of anticholinergic and beta-adrenergic inhaled bronchodilators, alone or in sequence, in 11 patients with chronic obstructive pulmonary disease. We compared the agents albuterol and ipratropium bromide when each was used as a single aerosol in the maximal dose. After giving a maximal dose of one agent, we compared the effect of adding the other with that of adding a placebo. When used alone, both bronchodilators significantly increased airflow and relieved hyperinflation, and there was no significant difference between the two. After the improvement with the initial bronchodilator, the subsequent effect of a second inhaled bronchodilator was not greater than that of placebo. These results suggest that in the treatment of chronic obstructive pulmonary disease, these two aerosols are usually equipotent in maximal doses and the addition of a second agent is of no practical value. The data support the prescription of a single inhaled agent in most cases but do not rule out the value of combinations of agents under special circumstances.

Steroid Response in Stable Chronic Obstructive Pulmonary Disease

We compared a 2-week course of 32 mg/d methylprednisolone with placebo in a double-blind crossover trial in 46 well-characterized patients with stable chronic obstructive pulmonary disease. Placebo and steroid trials were separated by 2 weeks when no tablets were given. Response was assessed by measuring forced expiratory volume in 1 second (FEV1.0). Placebo responses were normally distributed (mean, 0.8% change in FEV1.0; range, -30% to 33%). Six patients showed a greater than 50% increase of FEV1.0 in response to steroid; a seventh showed a 36% increase and an eighth, a 29% increase. Because of these patients the group as a whole showed a significantly greater FEV1.0 after steroid than after placebo. The eight steroid responders did not differ from nonresponders in age, sex, smoking history, or duration and intensity of symptoms including wheeze. Baseline lung function and eosinophilia of blood or sputum did not differ between the two groups. Patients who responded to steroids also responded to inhaled beta agonists: Acute bronchodilator response averaged 25% in steroid responders and 13% in nonresponders, a difference that was statistically significant although there was overlap between the two groups.