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Yale University School of Medicine, New Haven, Connecticut
ASTHMA
Stephen T. Holgate
Division of Respiratory Cell and Molecular Biology Southampton General Hospital Southampton, England
This session highlighted articles pertaining to the following four topics: (1) the value of anti-IgE monoclonal antibody therapy in asthma, (2) the role of antileukotriene therapy in childhood asthma, (3) the potential for adenosine to be a new diagnostic and therapeutic target in asthma, and (4) the issue of whether there are indices in early life that can predict the development of asthma later in childhood.
The first highlighted article addressed the question whether omalizumab, the IgG monoclonal antibody directed against the receptor binding site of IgE, benefits patients with allergic asthma refractory to corticosteroid therapy (1). In this randomized, double-blind, placebo-controlled trial, 246 patients with severe allergic asthma were randomized to receive omalizumab or placebo in addition to baseline therapy with fluticasone (> 1,000 µg/d) and long-acting ß-agonist every 4 wk for a total of 16 wk. In a subsequent add-on phase of the study, subjects had gradual withdrawal of inhaled steroids over a further 16 wk. The primary endpoint was corticosteroid withdrawal, and secondary endpoints included pulmonary function, symptoms, and asthma-related quality of life (QOL). Patients who received omalizumab achieved greater reductions in fluticasone dose as compared with those who received placebo (60% versus 50%, p = 0.003). Seventy-four percent of patients receiving omalizumab and 51% of patients receiving placebo achieved a 
50% reduction in fluticasone dose (difference between groups, p = 0.001). Anti-IgE therapy led to significantly improved symptoms, lung function, and QOL and reduced controller medication use throughout both phases of the study. This study is important because many patients with severe allergic asthma continue to have poor control of asthma symptoms and have impaired QOL despite the regular use of long-acting bronchodilators and inhaled corticosteroids at doses at which the risk of adverse effects of inhaled steroid are increased. This trial demonstrates that such patients can benefit from anti-IgE therapy.
The second article highlighted in this session (2) was a 12-mo, multicenter, double-blind, parallel-group study of 549 children with asthma between the ages of 2 and 5 yr to address the question whether antileukotriene therapy could reduce viral-induced asthma exacerbations in this patient population. The study was highlighted because intermittent virus-associated asthma exacerbations in children may respond poorly to inhaled corticosteroid treatment and because respiratory viruses have been shown recently to induce cysteinyl leukotriene production (3), yet the role of oral antileukotriene therapy in young children with asthma is not fully clear. The patients included in the study were known to have a history of asthma exacerbations induced by viral upper respiratory infections but minimal symptoms between exacerbations. Patients were randomized to receive montelukast (4 mg or 5 mg, depending on age) or placebo daily for 12 mo. As compared with placebo, montelukast reduced the virus-induced exacerbation rate by 32%, delayed the median time to first exacerbation by approximately 2 mo, and reduced the use of inhaled corticosteroid courses over the course of the 12-mo study. Thus, montelukast seems to be a promising therapy in the management of childhood virus-associated asthma exacerbations.
The third article that was discussed in detail evaluated the role of adenosine, a known bronchoconstrictor substance, as a modulator of inflammation in asthma. Twenty-one nonsmoking patients with asthma underwent inhaled bronchial challenge with adenosine 5'-monophosphate (AMP) and methacholine on separate occasions (4). Sputum was induced and analyzed for eosinophils before and 1 h after each of the inhalation challenges. Provocation with AMP (but not methacholine) led to a > 2-fold increase in sputum eosinophils without concomitant change in number of other inflammatory cells. The conclusions from this study were that AMP not only can cause bronchoconstriction but also stimulates a Th-2–like inflammatory response in the airways. Given that other studies have recently shown that the adenosine A2B receptor is expressed on a variety of airway structural cells and that adenosine pathways are involved in Th-2– mediated airway inflammation (5), adenosine and its receptors may prove to be a new diagnostic marker and/or therapeutic target for asthma.
The fourth article that was highlighted (6) sought to determine whether there are early life factors that can predict the development of asthma later in childhood. Baseline lung function and airways hyper-responsiveness to inhaled histamine were evaluated among 243 Australian children. The children were followed prospectively over the subsequent 11 yr, and measures of lung function, atopy, and airways responsiveness were made at 4 and 11 yr of age. The presence of wheezing at 11 yr of age was associated with lower lung function during infancy (1 mo of age). The prevalence of wheezing at 4–6 yr of age that persisted by 11 yr of age was greatest among persons with reduced lung function during infancy and with ongoing atopy and hyper-responsiveness at 11 yr of age. The investigators concluded that reduced airway function in early infancy was associated with persistent asthma symptoms at 11 yr of age independent of increased airways responsiveness and atopy. Furthermore, a role was suggested for both intrinsic disturbance in lung function (possibly related to lung development, maternal factors, and/or environmental factors close to time of birth) and later development of atopy and hyper-responsiveness in the pathogenesis of asthma later in childhood. Additional work is needed to clarify these issues.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Michael D. L. Morgan
Department of Respiratory Medicine and Thoracic Surgery University Hospitals of Leicester Leicester, England
Seven clinical trials were discussed in this session. The first trial (7) highlighted the marked impact of chronic obstructive pulmonary disease (COPD) on patients' ability to perform activities of daily living. A physical activity monitor capable of distinguishing walking from standing, sitting, and lying down was used to evaluate the patterns of daily movement among 50 patients with COPD as compared with 25 healthy age-matched control subjects. Compared with healthy persons, the patients with COPD had reduced walking and standing time and reduced movement intensity during walking. They also spent greater portions of the day sitting and lying. Daily activities that involved walking and standing correlated best with the 6-min walk test among patients with COPD, whereas baseline peak VO2 correlated best with daily walking time among healthy persons. This study reiterates the impact of COPD on activity limitation in daily life and confirms the utility of activity monitors in demonstrating the degree to which individuals experience activity limitation.
Three articles highlighted in this session addressed lung hyperinflation in COPD. The first of these evaluated the ability of the degree of hyperinflation to predict mortality among patients with COPD (8). A group of 689 patients with COPD underwent baseline pulmonary function testing, 6-min walk test, and measurement of body mass index and dyspnea severity assessment and was followed prospectively over 5 yr. Logistic regression analysis was done to evaluate the predictive value of the variables tested on mortality. Of the variables tested, the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index (9) was the overall best predictor of mortality. However, the inspiratory capacity/total lung capacity (IC/TLC) ratio was also a good predictor of mortality independent of the BODE score. The majority of the mortality (71%) occurred among patients with an IC/TLC ratio < 25% (a marker of severe hyperinflation). The IC/TLC ratio was a better predictor of mortality than was FEV1 or the 6-min walk test. The authors concluded that the IC/TLC ratio should be considered in the routine clinical assessment of patients with COPD.
The second article addressing lung hyperinflation (10) evaluated the effects of the long acting anticholinergic bronchodilator tiotropium bromide on hyperinflation, dyspnea, and exercise tolerance in 187 patients with COPD. The study was a randomized, multicenter study comparing the effects of tiotropium versus placebo on lung function, dyspnea severity, and exercise performance (defined as constant work rate cycling at 75% of VO2). Treatment with tiotropium led to significant (21%) gains in exercise endurance time, associated with isotime reductions in dyspnea and improved inspiratory capacity with reduction in lung hyperinflation. This study furthers our knowledge of the ways in which bronchodilator therapy may improve symptoms for patients with COPD. Bronchoscopic lung volume reduction surgery was illustrated by the third article (11) as another method of reducing hyperinflation. Surgical lung volume reduction surgery has been demonstrated to improve hyperinflation and exercise tolerance of some patients with COPD. In this article, 19 patients with a heterogeneous distribution of emphysema (generally considered to be poor candidates for surgical lung reduction) underwent unilateral bronchoscopic endobronchial occlusion with a one-way valve. Lung function, exercise performance, and health status were assessed at baseline and 4 wk after the intervention. Bronchoscopic lung reduction led to a 39% improvement in exercise time at 80% of maximal workload. Some improvements were seen in inspiratory capacity and end-expiratory lung volume (i.e., there was reduced hyperinflation) and in the diffusing capacity for carbon monoxide, and 47% of patients were considered to have "improved." There were no early complications, but two patients subsequently developed pneumothoraces. In summary, bronchoscopic lung reduction afforded some short-term benefit to some but not all of the patients, and the long-term effects of this intervention are unknown. Further work is needed to identify the mechanisms by which this technique may benefit patients with emphysema and to clarify which persons may be optimal candidates for this procedure.
Significant interest has arisen recently in the potential role of oxygen as a means of improving exercise tolerance for persons with COPD even in the absence of arterial hypoxemia. In the fifth article that was highlighted, data were presented evaluating whether oxygen treatment enhances recovery from maximal exercise in patients with COPD (12). This study was a randomized, single-blind, placebo-controlled trial in which 18 patients with COPD received oxygen or air (at identical flow rate) on recovery from exercise. Oxygen therapy led to a shorter time to resolution of dynamic hyperinflation (DH) after maximal exercise but did not reduce the severity or hasten the resolution of dyspnea. The mechanism by which DH was improved by oxygen therapy in this study was not clear, and the clinical significance of such a reduction in DH resulting from the use of oxygen therapy during recovery from exercise is not certain. Therefore, the use of oxygen principally to reduce symptoms of dyspnea after exercise cannot be recommended at this time.
The final two articles in this session addressed the relationship between inflammation and COPD. In the first of these, the relationship between the presence of airway inflammation and lung function in COPD was assessed (13). The rationale for this study is the finding that COPD is a heterogeneous disorder with varying clinical phenotypes, including differing degrees of bronchodilator reversibility, airways hyper-responsiveness, hyperinflation, and impairment in diffusing capacity. Lung function, results of methacholine challenge testing, induced sputum analysis, exhaled nitric oxide, and total IgE levels were analyzed in a cross-sectional analysis of 114 patients with COPD (who had been recruited as part of another study). In this study, measures of airflow limitation (FEV1 and FEV1/FVC), asthma-like factors (bronchodilator reversibility, IgE levels, and hyper-responsiveness), and airway inflammation (sputum eosinophils and neutrophils) were separate and independent dimensions of COPD characterization but accounted for only 63% of the total variance. Hence, additional factors likely are important in the characterization of the disease. This study lays the foundation for further investigations of the heterogeneity of clinical phenotypes of patients with COPD.
The final study addressed the question of whether nonrespiratory mortality, such as cardiovascular disease relating to ongoing systemic inflammation (as manifest by high C-reactive protein [CRP] levels), can be affected by inhaled corticosteroid therapy in patients with COPD. This was a randomized, placebo-controlled, double-blind study of 41 patients with mild to moderate COPD. All study participants who were taking inhaled corticosteroids had these withdrawn over a 4-wk period, and subjects were randomized to receive inhaled fluticasone, oral prednisone, or placebo for 2 wk. After 2 wk, all patients received fluticasone 500 µg bid, and after 8 wk they received fluticasone 1,000 µg bid for a further 8 wk. Measurements of CRP levels and the cytokines IL-6 and MCP-1 (as markers of systemic inflammation) were made at baseline, 2 wk, 8 wk, and 16 wk. CRP levels were noted to increase by 70% among persons who initially had their inhaled corticosteroid withdrawn, and the CRP levels declined again after reinitiating inhaled fluticasone or oral prednisone therapy. Smaller reductions were seen in the circulating levels of IL-6 and MCP-1. This study suggests that airways inflammation and systemic inflammation can be affected by treating patients with COPD with corticosteroids. Nonrespiratory mortality (e.g., related to cardiovascular disease, which is associated with COPD) may be affected by the use of inhaled steroid therapy, and there may be unappreciated risks of withdrawal of steroid therapy among such patients with COPD. Such effects on nonrespiratory mortality remain to be proven.
EXERCISE AND REHABILITATION
Richard Casaburi
Rehabilitation Clinical Trials Center Harbor-UCLA Medical Center Torrance, California
Four key articles published within the past year regarding exercise and rehabilitation were highlighted in this session. The first study, a randomized trial, compared the effects of traditional endurance training to the combination of endurance plus strength training for 24 patients with severe COPD (15). Outcome measures included muscle strength, quality of life (QOL), exercise performance, and quadriceps fatigability, after as compared with before the rehabilitation intervention. Endurance training alone did not lead to gains in muscle strength, whereas combined training led to significant improvements in quadriceps (23.6%), hamstring (26.7%), pectoralis major (17.5%), and latissimus dorsi (20%) strength. Both training groups had improvements in exercise endurance, 6-min walk test distance, QOL, and quadriceps fatigability, but there were no significant differences between groups in these parameters. This study confirms the findings of prior studies that strength training can improve the muscle strength of patients with COPD but that the addition of this training to endurance training does not lead to improvement in overall exercise capacity or health-related QOL. Strength training is, however, routinely included as a component of most pulmonary rehabilitation programs because it is easy to implement, carries low risk, and may favorably affect other outcomes, such as performance of activities of daily living.
One ongoing issue in the field of pulmonary rehabilitation is the question of which patients benefit the most from the rehabilitation intervention. Plankeel and colleagues (16) hypothesized that the factors limiting exercise at baseline would affect the exercise outcomes of pulmonary rehabilitation. In this retrospective analysis, 290 nonhypoxemic patients with COPD who had undergone pulmonary rehabilitation were classified as having ventilatory limitation (VL), cardiovascular limitation (CVL), mixed ventilatory and cardiovascular limitation (VLCVL), or noncardiopulmonary limitation (NL) based on prerehabilitation exercise testing, and the change in exercise capacity following rehabilitation was assessed. Pulmonary rehabilitation led to a significant (30%, p < 0.0001) increase in timed walk distance and maximal oxygen consumption (85 mL/min, p < 0.0001) in the whole study population. Timed walk distance improved to a comparable degree (26–36%) in all patient subgroups. Based on stepwise multiple regression analysis, age, ventilatory reserve at peak exercise, and exercise PaO2 were individual predictors of improvement in VO2 max after rehabilitation. Improvements in VO2 max were noted in all patient subgroups, with the greatest improvements seen in the NL subgroup (111 ml/min), CVL subgroup (109 ml/min), and VLCVL subgroup (61 ml/min) as compared with the VL subgroup (30 ml/min). The investigators concluded that patients with COPD who have a nonventilatory basis of exercise limitation experience the greatest improvement in VO2 max after pulmonary rehabilitation. However, consistent with the findings of other studies, improvements in exercise tolerance (endurance and VO2max) can be made in rehabilitation even by persons with severe baseline ventilatory limitation. Thus, severe ventilatory limitation to exercise does not constitute grounds to exclude patients from pulmonary rehabilitation programs. There are no clear characteristics that can be used to determine which patients will not benefit from pulmonary rehabilitation, and as such persons who remain symptomatic with dyspnea and activity limitation despite optimal medical therapy remain candidates for pulmonary rehabilitation programs irrespective of severity of disease.
The third study investigated outcomes of pulmonary rehabilitation (PR) conducted at a consortium of 10 PR programs in the general medical community in California (17). Patient demographic data, three health status questionnaires, use of supplemental oxygen, pulmonary function tests (where available), 6-min walk test data, and use of healthcare resources in the preceding 3-mo period were collected at baseline, after rehabilitation, and at 3-, 6-, 12-, and 18-mo follow-up. Out of 647 patients enrolled initially at nine centers, evaluations from at least two of the four follow-up time points were completed by 415 patients at eight centers. The patient population had a mean age of 68 yr, 42% were male, and the mean FEV1 was 44% predicted. Baseline QOL was impaired as assessed by the health status questionnaires, and there was a high degree of use of healthcare resources (hospitalizations, urgent care visits, doctor visits, and telephone calls) within the 3-mo period before PR. After rehabilitation, significant improvements were noted in symptoms, QOL, and use of healthcare resources. Consistent results were noted across a variety of PR programs of differing structure in varying clinical practice settings. This study highlights the feasibility of implementing successful PR in the general medical community (apart from specialized tertiary care referral centers) and suggests that community-based PR programs can lead to a reduction in use of healthcare resources and improved patient QOL. Because patients tend to be referred to PR when they are experiencing a decline in health status and an increase in symptoms, the comparison time point of 3 mo before rehabilitation used in this study may not be optimal for use as a time-point for comparison to postrehabilitation and may have biased the results of the study.
Patients with COPD are typically referred to PR programs while in stable medical condition. However, COPD exacerbations are a common cause of functional decline for patients with COPD. The final study addressed the timing of initiation of PR after an exacerbation of COPD. This was a single-center, randomized, controlled trial in which 42 patients admitted to the hospital with an acute exacerbation of COPD were randomized to receive an 8-wk outpatient PR program started within 10 d of hospital discharge or usual medical care (18). Primary outcome measures were the distance walked in the incremental shuttle walk test, disease-specific health status (St. George's Respiratory Questionnaire and Chronic Respiratory Disease Questionnaire [CRQ]), and generic health status (SF-36 Questionnaire) at 3 mo after hospital discharge. Pulmonary rehabilitation implemented early after a COPD exacerbation led to significant improvements in exercise tolerance (60 m increase in shuttle walk distance, p = 0.0002), mean SGRQ score (–12.7, p = 0.002), each of the four domains of the CRQ, and the mental component score of the SF-36 (20.1, p = 0.02). This study demonstrated that PR administered early after a COPD exacerbation is effective, leads to improved exercise capacity and health status 3 mo after discharge, and can be done safely in carefully selected patients. The optimal timing for implementing PR after COPD exacerbations is not clear but likely depends on the severity of the disease and the exacerbation and on other medical comorbidities and the nature of the PR program to be undertaken. Another important finding from this study was that patients who had undergone PR early after their exacerbations had 39% fewer hospital readmissions, 30% fewer hospital days, and 70% fewer emergency room visits in the 3 mo after discharge from the hospital than did the patients who received usual medical care. Although these gains did not all reach statistical significance in this small study, confirmation of the findings in a larger longer-term study would likely provide the grounds for initiating PR early after COPD exacerbations on a routine basis.
CRITICAL CARE MEDICINE
Michael A. Matthay
Division of Pulmonary and Critical Care Medicine University of California San Francisco, San Francisco, California
Four articles were highlighted that addressed optimal management strategies for patients with acute lung injury (ALI) and adult respiratory distress syndrome (ARDS). In a study by Brower and colleagues (19), 549 patients with ALI and ARDS were randomized to receive mechanical ventilation with a lower positive end expiratory pressure (PEEP) (mean 8.3 ± 3.2 cm H2O) or higher PEEP (mean 13.2 ± 3.5 cm H2O) using a ventilation strategy designed to reach a tidal volume goal of 6 ml/kg body weight and an end-inspiratory plateau pressure limit of 30 cm H2O. PEEP levels were chosen based on predetermined combinations of PEEP and inspired concentration of oxygen. There proved to be no significant difference between groups regarding rates of death before hospital discharge or in the total number of days spent breathing unassisted from Days 1 to 28. Therefore, clinical outcomes were similar whether lower or higher levels of PEEP were used during mechanical ventilation.
The second study was a prospective, unblinded, multicenter, randomized, controlled trial to evaluate whether prone positioning could improve mortality among 791 patients with hypoxemic acute respiratory failure (20). Patients were randomized to receive prone positioning as early as possible for at least 8 h/d or traditional supine positioning. The primary outcome measure was 28-d mortality, and secondary outcomes were 90-d mortality, duration of mechanical ventilation, incidence of nosocomial pneumonia, and oxygenation. There was no significant difference noted between the patient groups in any of the outcomes measures, except for a slight reduction in the incidence of ventilator-associated pneumonia per 100 patient-days of intubation (1.66 versus 2.14 episodes in the prone and supine groups, respectively, p = 0.046) and that the PaO2/FIO2 ratio was higher in the prone group during the 28-d follow–up period. Concern was raised regarding the use of prone positioning because of an increased incidence of pressure sores, endotracheal tube obstruction, and selective intubation in the prone ventilation group.
Two studies dealt with the question of whether surfactant therapy is useful for the treatment of ALI and ARDS. The first group of investigators conducted two multicenter, randomized, double-blind trials comparing standard therapy versus standard therapy plus up to four doses of recombinant surfactant protein C–based surfactant given intratracheally within a period of 24 h among 448 adult patients with ARDS (21). Overall 28-d survival was 66%, and the median number of ventilator-free days was 0. Although patients who received the surfactant had significantly greater improvements in oxygenation during the initial 24 h of treatment, there was no difference between groups in mortality or the need for mechanical ventilation. The second randomized controlled trial evaluated whether surfactant therapy (intratracheal delivery of two doses of 80 ml/m2 surfactant or placebo, given 12 h apart and within 48 h of endotracheal intubation for hypoxemic respiratory failure) could shorten the course of respiratory failure among 21 children (age 1 wk to 21 yr) (22). Primary outcome measures were ventilator-free days and mortality; secondary outcome measures were hospital course, adverse events, and failure of conventional mechanical ventilation. In this study, the surfactant therapy led to improved oxygenation after 12 h as compared with placebo, and the mortality was greater in the placebo group as compared with the surfactant group (27/75 versus 15/77; odds ratio, 2.32). A greater number of patients in the placebo group did not respond to conventional mechanical ventilation. There was no difference between the groups in the number of ventilator-free days, duration of intensive care unit (ICU) stay, or hospital stay. Thus, surfactant therapy improved early outcomes of acute hypoxemic respiratory failure among pediatric patients but did not seem to change the longer-term outcomes of the patients.
Two final articles addressed fluid resuscitation and antibiotic therapy, respectively. A study by Finfer and colleagues (23) was a randomized trial comparing the 28-d mortality among patients admitted to the ICU who received 4% albumin (n = 3,497) versus normal saline (n = 3,500) for fluid resuscitation over a 28-d period. There was no significant difference in 28-d mortality (726 deaths in the albumin group and 729 in the saline group), proportion of patients with new single- or multiple-organ failures, mean number of days spent in the ICU, days spent in the hospital, days of renal replacement therapy, or days of mechanical ventilation. Thus, the use of albumin (4%) did not prove to be superior to normal saline as a method of fluid resuscitation over a 28-d period. Mickek and colleagues (24) conducted a randomized, controlled, prospective trial investigating the utility of an antibiotic discontinuation policy on clinical outcomes of 290 patients receiving therapy for ventilator-associated pneumonia (VAP). Patients were randomized to have the duration of antibiotic therapy for VAP determined by the discontinuation policy or by their treating physician team (conventional group). Baseline severity of disease was similar between the two patient groups. The use of the antibiotic discontinuation policy was associated with a shorter duration of antibiotic therapy as compared with the conventional group (p = 0.001 for difference between groups), but there was no difference between the groups in the incidence of a secondary episode of VAP (17.3% versus 19.3%, p = 0.667), in-hospital mortality (32% versus 37.1%, p = 0.357), or length of ICU stay. These results suggest that a specified antibiotic discontinuation policy may lead to overall shorter duration of therapy for VAP (with potential for decreasing risk of developing resistant organisms and lowering cost of therapy) without leading to worse clinical outcomes in the ICU.
FOOTNOTES
* Co-Chair, Clinical Year in Review 
This is the last of four executive summaries from the Clinical Year in Review Symposium presented at the 2005 International Meeting of the American Thoracic Society. The salient points of each talk have been abstracted by the session chair based on the annotated bibliography submitted by the presenters.
Conflict of Interest Statement: C.L.R. serves on the COPD Advisory Board for Novartis and received $3,000 in 2005 for this work. She also is a member of the Speakers Bureau for GlaxoSmithKline and Boehringer Ingelheim and receives research grant funding for participating in a multicenter clinical trial sponsored by Boehringer Ingelheim.
REFERENCES
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