American Thoracic Society 2011 International Conference, May 13-18, 2011 Denver, CO

The American Thoracic Society (ATS) International Conference continues to be one of the largest and most important gatherings of researchers and clinicians in pulmonary and critical care medicine. This year’s conference included over 5000 original scientific presentations and dozens of sessions and seminars on clinical practice. There were significant advances reported in many areas of pulmonary and critical care medicine, but perhaps the most notable were in the area of chronic obstructive pulmonary disease (COPD). All studies discussed in this report are either oral sessions or posters that were presented at the meeting. Additional information, including the abstracts of the studies, is available on the ATS website (www.thoracic.org).

Genetic Advances in COPD

Genetic research on cohorts of persons with COPD and kinship studies of related persons have begun to discover some of the genetic factors that increase susceptibility to COPD. Cho et al performed a genome-wide association study using participants from the ECLIPSE (Evaluation of COPD Longitudinally to Surrogate End-points), NAS (Normative Aging Study), NETT (National Emphysema Treatment Trial), GenKOLS (Genetic-Environmental Case-Control Study of COPD), and COPDGene (first phase of subjects) studies. Genotyping was performed on Illumina platforms (HumanHap550, Quad610, and Omni1); additional markers were imputed using MACH and the HapMap reference population. Researchers used logistic regression models to adjust for pack-years of cigarette smoking, age, and ancestry through principal components and a fixed-effects meta-analysis to summarize the results. A total of 3459 cases and 1911 smoking control subjects participated in the study. Investigators identified a locus for COPD susceptibility on chromosome 19q13 (odds ratio, 0.74; P = 4 x 10^-9). This region includes genes that have previously been identified to be associated with cigarette smoking behavior. A Japanese study found an association between smoking and COPD in the same genetic region, but that gene was also associated with COPD independent of tobacco use.

Merali et al reported another investigation of blood proteins from subjects in the National Institutes of Health genome-wide COPDGene study, which identified biomarkers of COPD. Researchers isolated a total of 712 unique proteins (29 proteins had increased expression in advanced COPD); four of these proteins were verified in 10 to 15 separate individuals with advanced COPD. Researchers concluded in the abstract, “Candidate biomarker proteins appear to be involved in multiple pathways which underlie the disease. Combinations of potential biomarkers are likely to lead to greater sensitivity and specificity in characterizing different COPD phenotypes and their pathogenic mechanisms.”

Smoking Effect on Body Composition in Elderly Persons  

In a study by van den Borst et al, a cohort of elderly persons with COPD were compared with an age-matched group of smokers and nonsmokers to determine the effects of smoking on body composition. The study included 260 elderly men and women with COPD (forced expiratory volume in 1 second [FEV₁] 63±18% predicted; median pack-years, 39), 157 age-matched smokers (FEV₁ 95±16% predicted; median pack-years, 32), and 891 age-matched never-smokers (FEV₁ 104±14% predicted) who were enrolled in the Health ABC (Health, Aging and Body Composition) study. There were no differences in the level of daily physical activity (P >.05) or in the prevalence of diabetes, depression, and cardiovascular disease (P >.05) between the study groups; however, researchers reported that, in both male and female participants, weight, lean mass, fat mass, bone mineral content, and quadriceps strength were comparably lower in smokers and in persons with COPD than in never-smokers (P <.05). Researchers concluded that not only is smoking an important risk factor in the etiology of COPD, but it also adversely affects body composition and muscle function independent of airflow obstruction, physical activity, and comorbidity.

New Drugs for COPD

Two new drugs are currently available for COPD: roflumilast and indacaterol. Roflumilast, a selective phosphodiesterase-4 inhibitor (PDE-4), was approved by the US Food and Drug Administration (FDA) in March 2011 for use in patients with COPD. Indacaterol, an ultra long–acting beta-2 agonist was just approved this month. Both drugs offer useful new options for the clinical management of COPD.

Roflumilast
Roflumilast is the first selective PDE-4 inhibitor agent to be approved in the United States to decrease the frequency of COPD exacerbations or worsening of symptoms, including breathlessness, chronic cough, and excessive phlegm. It is also the first new class of pharmacological agents to surface for the treatment of COPD in several decades. Preclinical animal studies of roflumilast have shown that it can mitigate key COPD-related disease mechanisms such as smoke-induced pulmonary inflammation, mucociliary dysfunction, lung parenchymal remodeling, and fibrosis. Roman studies have demonstrated positive effects on many cell types, including neutrophils and macrophages (the key inflammatory cells associated with COPD). These cellular effects are thought to be responsible for the improved lung function and reduced exacerbations in COPD seen with roflumilast.¹

During the ATS meeting, Hanania et al reported a retrospective analysis of pooled data from two 52-week studies examining the safety and efficacy of roflumilast in elderly versus younger persons. A total of 3091 patients with COPD were randomized to receive roflumilast (878 persons age ≤65 years and 659 persons age >65 years) or placebo (883 persons age ≤65 years and 671 persons age >65 years). Compared with placebo, roflumilast significantly reduced the rate of moderate or severe COPD exacerbations in both the ≤65 (15.3%; P = .0128) and >65 age groups (21.2%; P = .0035). In addition, subjects in both age groups who received treatment with roflumilast experienced similar and significant improvements in pre- and post-bronchodilator FEV₁ at all time points versus placebo (P <.0001). Patients >65 years experienced higher adverse event (AE) rates in all AE categories than patients ≤65 years in both the roflumilast and placebo groups; differences between the roflumilast and placebo arms remained consistent for both age groups. These findings indicate that roflumilast may be a useful addition to COPD therapy in preventing acute exacerbations when combined with other agents; it is not intended to be used alone as a bronchodilator.

Indacaterol
There have been multiple previous studies reporting excellent efficacy and safety of the 150-µg and 300-µg doses of indacaterol, but the FDA in its cautious approach to long-acting beta agonists has approved the 75-µg dose for use in the United States.

Two randomized, double-blind, placebo-controlled 12-week studies conducted by Kerwin et al (N = 641) using a 75-µg once-daily dose of indacaterol versus placebo demonstrated that indacaterol is very fast-acting, showing an improvement of FEV₁ at 5 minutes after the first dose of 90 to 100 mL and a sustained benefit at 12 weeks of trough FEV₁ (23.5 hours after the last dose) of 120 to 140 mL. Indacaterol-treated persons also reported improved quality of life as measured by the St. George’s Respiratory Questionnaire (P <.01), decreased use of a rescue inhaler (P <.001), and improvement in the Transition Dyspnea Index. Serious and nonserious AEs were similar between the treatment and placebo groups, and only two deaths occurred (in the placebo group). 

Mahler et al reported that the combination of indacaterol 150 µg and tiotropium 18 µg once daily was considerably more effective than tiotropium 18 µg alone. The researchers conducted two identical, randomized, double-blind, 12-week studies (N = 2276 subjects) that showed an improvement with the combination therapy over tiotropium alone in trough level of FEV₁ of 70 to 80 mL (P <.001), improved trough level inspiratory capacity of 100 to 130 mL (P <.01), and decreased use of a rescue inhaler.

Maintenance Therapy in COPD and Cost of Care

Two studies by Dalal et al on maintenance therapy (MT) in COPD were reported from Research Triangle Park, NC. The first study examined early versus late initiation of MT. This retrospective study employed a cohort design using administrative claims data on 3806 individuals over a 6.5-year period. Patients (age >40 years) with at least one COPD-related hospitalization/emergency department (ED) visit and continuous eligibility through the 1-year pre- and post-index periods were included in the study. The index date was the discharge date of the COPD-related hospitalization/ED visit. Outcomes of COPD-related exacerbations and costs were assessed in the 1-year period after the index date. Patients were classified as the early cohort if they initiated MT within the first 30 days and were classified as the delayed cohort if they initiated MT between 31 and 180 days. Researchers evaluated the differences between cohorts in the risk of COPD exacerbations and incremental effect of every 30-day delay up to 6 months after the index event on the risk of COPD exacerbations. Of the 3806 patients who met the inclusion criteria, 68.2% received early MT. During follow-up, a significantly lower proportion of subjects in the early cohort had a COPD-related hospitalization/ED visit as compared with the delayed cohort (18.0% vs 25.6%; P <.001), despite a higher proportion of the early MT group having been hospitalized at the index event (63% vs 43%). After controlling for baseline differences, the risk of a future COPD-related hospitalization/ED visit increased by 43% (P <.001) for the delayed cohort as compared with the early cohort. Researchers also found that every 30-day delay significantly increased the risk of a COPD-related hospitalization/ED visit by 9% (P = .002). Every 30-day delay in treatment also increased COPD-related total costs ($5012 vs $3585; P <.001), resulting in a 5.3% (P = .009) increase in total costs. Researchers concluded, “Early adoption of maintenance treatment results in effective secondary prevention as the risk of future COPD-related hospitalization/ED visits and COPD-related total costs are significantly reduced.”

The second study by Dalal et al compared combination MT with fluticasone propionate/salmeterol 250/50 mg (FSC) to short-acting anticholinergics (IPR) or long-acting anticholinergics (TIO) using healthcare claims data from a large administrative database over a 5.5-year period. There were 43,792 patients followed (FSC, n = 16,684; IPR, n = 14.449; TIO, n = 12,659). Results are as follows: risk for a COPD-related hospitalization/ED visit was significantly higher for IPR (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.50, 1.79) and TIO (HR, 1.29; 95% CI, 1.17, 1.41) than for FSC. COPD-related total healthcare costs were lower for FSC ($2068 ± $1190) than for the IPR ($2841 ± $1858) and TIO groups ($2407 ± $1511; both P <.001). In addition, the mean number of COPD-related hospitalizations, ED visits, outpatient visits, and outpatient visits in association with an oral corticosteroid or antibiotic were lower for FSC than for IPR and TIO (all P <.05). Elderly patients with COPD who were taking TIO had a significantly higher risk of COPD-related hospitalizations and ED visits as well as outpatient visits requiring either antibiotics and/or oral corticosteroids as compared with those taking FSC. Finally, COPD-related medical ($1304 vs $1754; P <.0001) and total costs ($2330 vs $2694; P <.0001) were significantly lower for FSC compared with TIO; however, subjects taking FSC had significantly higher pharmacy costs compared with subjects taking TIO.

New Therapies Under Investigation for COPD

Vitamin D
Impaired vitamin D metabolic function has been implicated in some studies of COPD risk factors. Poon et al studied single nucleotide polymorphisms for the vitamin D receptor and found three genotypes for this receptor. They obtained tissue samples for DNA testing from the Veterans Administration NAS that spanned over 40 years, and that database also provided clinical information on incidence and time to onset of COPD in this cohort. Analysis of the vitamin D receptor genotypes showed that decreased receptor expression was associated with significantly increased risk of developing COPD. In a companion study, Poon et al examined lung tissue samples for the presence of vitamin D receptors in patients with advanced COPD and in control patients without COPD, finding them to be decreased as compared with controls. Another study from Belgium by Hornikx et al postulated that vitamin D deficiency supplementation during the rehabilitation of patients with COPD could improve muscle function. Researchers randomized 50 subjects with COPD to rehabilitation plus a monthly dose of 100,000 IU of a vitamin D supplement for 3 months versus rehabilitation with a placebo supplement. Blood levels of vitamin D were low in both groups at baseline (22 ng/mL in the treatment group, 19 ng/mL in the placebo group). Over the 3 months of rehabilitation, the treatment group demonstrated a return to normal vitamin D levels (54 ng/mL), improved muscle strength, and improved work capacity as compared with the placebo group, although the baseline muscle function was lower in patients in the treatment group than in patients in the placebo group. This pilot study suggests that vitamin D may play an important role in muscle function and that vitamin D deficiency may play a significant role in the physical disabilities of COPD, although confirmation in a larger clinical trial is warranted.

Bitter Taste Receptors on Airway Smooth Muscle: Novel Mechanism for Bronchodilatation 
Researchers from the University of Maryland have discovered that airway smooth muscle has many of the same bitter taste receptors that are present on the tongue. Robinett et al initially postulated that these receptors may have developed by evolution to protect the lungs from toxins by causing bronchoconstriction. To their surprise, when they tested human airway smooth muscle cells Roman with bitter compounds (quinine and chloroquine), they observed complete relaxation of the muscle cells. Animal studies presented by the same researchers using asthmatic mouse models showed complete protection from bronchospasm when the mice were pretreated with a bitter aerosol before methacholine challenge with no apparent adverse effects. The researchers described the bronchorelaxation observed as far more complete and potent than that seen with the usual bronchodilators, such as the beta agonists and anticholinergics, used in clinical practice. There are thousands of natural and synthetic bitter substances that could potentially be active bronchodilators. The researchers are actively testing compounds in animal models and are preparing to start human trials in the near future.

Critical Care

Inhalation of Hydrogen Protects Lungs in Respiratory Failure
Patients who have severe lung or heart disease requiring prolonged ventilation and breathing with 100% oxygen frequently suffer from oxidative damage to the lungs, which can compound respiratory problems. Researchers from the University of Pittsburgh (Kawamura et al) found that adding a small amount of hydrogen (2%) to inhaled oxygen can significantly reduce oxidative damage. Hydrogen can induce the enzyme heme oxygenase-1, which is able to reduce reactive oxygen species and protect cells from oxidative damage. Hydrogen in a 2% mixture with oxygen is safe and physiologic, and, in a rat model, exposing the animals to 60 hours of 100% oxygen versus the mixture of 2% hydrogen and 98% oxygen demonstrated significantly better lung function in the hydrogen-protected group and less cytotoxic changes on histological sections of lung tissue. Human studies are under way.

Decision Aid Helps Communication in Intensive Care Patients on Ventilator
Approximately 300,000 persons require prolonged mechanical ventilation for the management of severe illness each year, with about 50% dying within a year, typically after spending most of their final days in a healthcare facility. In many cases, these patients have surrogate decision-makers to decide on their medical care and life-sustaining interventions.

Research collaborators from North Carolina, Pennsylvania, and Washington recognized that communication deficits between clinicians and surrogate decision-makers often exist and can lead to confusion about expectations, prognosis, and appropriate care. To overcome this problem, Cox et al developed a computer-based decision-aid tool in the form of a questionnaire to be completed by the surrogate. The questionnaire includes inquiries about the surrogate’s understanding of the patient’s disease, prognosis, treatment options, and likelihood of benefit. It also asks about the patient’s personal values and advance directives. The clinician, Intensive Care Unit staff member, and surrogate would meet after the questionnaire was completed and use the tool as the basis for a discussion about the patient’s condition, prognosis, and treatment options. Researchers piloted this tool with 30 surrogates and patients who were at risk for prolonged mechanical ventilation. Twenty surrogates used the tool and 10 served as usual-care controls. The results were quite positive, with surrogates who used the tool reporting better concordance with physicians and nurses regarding prognosis and survival, treatment goals, and less decisional conflict as compared with controls. In addition, patients whose surrogate received the decision aid had shorter hospital stays yet similar mortality rates as compared with controls. A larger trial of the decision-making tool is under way to see whether the pilot study results can be confirmed.

Thrombolytics Not Better Than Anticoagulants in Pulmonary Embolus
A large retrospective study (15,944 patients) from Spain by Jimenez et al reviewing interventions and outcomes in persons who had a pulmonary embolus revealed that aggressive therapy with thrombolytic agents generally did not improve outcomes over traditional anticoagulant therapy. Persons who had low blood pressure had a nonstatistically significant reduction in mortality with thrombolytics, but persons with normal blood pressure had a significant increase in mortality. Researchers concluded that persons with pulmonary embolus and normal blood pressure should not have thrombolytic therapy, and further study is needed to determine if clinical or other biomarkers might be helpful to determine which persons with low blood pressure might selectively benefit from thrombolytics.

Odds and Ends

New Treatment Option for Latent Tuberculosis
Approximately 4% of the US population, or 11 million persons, test positive for tuberculosis, and public health experts feel that if we are going to reduce the 11,000+ new cases of tuberculosis in this country we will have to treat latent tuberculosis more effectively. The Centers for Disease Control and Prevention (CDC) conducted a multicountry trial comparing the traditional 300-mg daily dose of isoniazid for 9 months (270 doses) with once-weekly supervised rifapentine 900 mg and isoniazid 900 mg for 3 months (12 doses) in 8053 persons who were then followed for 33 months after their date of enrollment. The new regimen was found to be safe and effective (7 new cases in the 12-week group vs 15 in the standard treatment group), and completion of treatment was higher in the 12-week group (82%) than in the standard group (69%). The researchers (Sterling et al) caution that this treatment regimen may only be applicable in countries with a low incidence and prevalence of tuberculosis, such as the United States and Canada, but based on this study, the CDC is already developing new guidelines for the treatment of latent tuberculosis.

Continuous Positive Airway Pressure Decreases Cardiovascular Mortality in Elderly Persons With Obstructive Sleep Apnea
Virtually all of the studies on interventions for obstructive sleep apnea (OSA) have been conducted in middle-aged persons. Researchers Martinez-Garcia et al from Spain conducted the first large clinical trial in elderly persons with OSA. The 939 subjects were randomized to four groups: a control group without OSA; a mild-to-moderate OSA group without continuous positive airway pressure (CPAP); a severe OSA group without CPAP; and a group with any degree of OSA with CPAP. The study showed that untreated severe OSA was associated with increased all-cause mortality, cardiovascular mortality, stroke, and heart failure mortality, and CPAP treatment reduced these risks. Untreated mild to moderate OSA was not associated with increased cardiovascular mortality.

The author reports no relevant financial relationships.

Reference

1. Hatzelmann A, Morcillo EJ, Lungarella G, et al. The preclinical pharmacology of roflumilast—a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2010;23(4):235-256.