The 17th Annual Congress of the European Respiratory Society

Stockholm, Sweden
September 15-19, 2007

The European Respiratory Society’s Annual Congress is the largest international gathering of health professionals and researchers involved in respiratory medicine in the world. This year, over 15,000 persons attended the meeting held in Stockholm, Sweden. This forum has increasingly become the preferred venue for the presentation of important new research findings and landmark clinical trials in the field of respiratory medicine. Some highlights from the scientific sessions are listed below, with abstracts from the entire proceedings available online by going to www.ersnet.org, click on “Congresses,” click on “Stockholm 2007 Highlights,” and then on “Abstracts.”

Chronic Obstructive Pulmonary Disease

VENT
Several important clinical trials on interventions in chronic obstructive pulmonary disease (COPD) were presented at this year’s Congress. The endobronchial Valve for Emphysema palliatioN Trial (VENT) was an eagerly awaited international study of the use of an endobronchial valve for palliation in emphysema. The VENT concept is to reduce the need for lung volume reduction surgery in patients with severe COPD by bronchoscopically placing a one-way valve in the bronchus of an emphysematous lobe of the lung. The one-way valve prevents inspired air from entering the severely diseased lobe, yet allows trapped air to escape on expiration. This results in collapse of the emphysematous lobe. It is intended to accomplish the same improvement in pulmonary mechanics and ventilation perfusion that is seen with lung volume reduction surgery without the high perioperative morbidity and mortality associated with that surgery. Candidates for the study were carefully screened with chest computerized tomography and selected on the basis of a high heterogeneity score. In other words, there had to be both severely involved lobes, but also areas of lung less involved that could benefit from the volume reduction.

Safety and efficacy endpoints were studied at 6 months, and the results were quite promising. There was a significant improvement in the primary efficacy measures (FEV₁, 6-minute walk test) in the treatment versus control arms (P < 0.025). There was also a significant improvement in secondary measures (maximum workload, quality-of-life questionnaire, and dyspnea scale) in the treatment group (P < 0.025). Use of supplemental oxygen did not change between groups. The study also met the primary safety endpoint with no increased mortality in the treatment arm; however, there were increased adverse events associated with the valve placement. Complications included obstruction of the valve with secretions, infection in the lobe with the valve, misplacement of the valve, poor tolerance of the procedure, and granuloma formation at the site of the valve. The researchers did demonstrate that the valve can be safely removed in the event of a complication, and concluded that the endobronchial valve is a beneficial procedure in selected patients.

INSPIRE
Another major clinical trial in COPD presented was the Investigating New Standards for Prophylaxis In Reduction of Exacerbations (INSPIRE) study. This study reported the results of the first major head-to-head comparison of the two primary drugs commonly used for the clinical management of COPD (tiotropium bromide 18 mcg/day vs salmeterol 50 mcg/day plus fluticasone 500 mcg/day). The study involved over 600 subjects in each treatment arm with moderately severe COPD (mean FEV₁, 39% predicted) who were followed on treatment for a two-year period. Baseline characteristics including age, gender, smoking history, and previous history of exacerbations were very similar in both groups. The primary study endpoint for a measurement of efficacy was the rate of exacerbations that required healthcare utilization. That outcome measure was essentially the same for both treatments (1.28 exacerbations annually for fluticasone/salmeterol, and 1.32 exacerbations for tiotropium bromide; P = 0.656). However, treatment of exacerbations differed somewhat with the fluticasone/salmeterol group more often receiving antibiotics and the tiotropium bromide group more often receiving systemic corticosteroids. Other study results included decreased mortality in the fluticasone/salmeterol group versus tiotropium bromide (3% [18] vs 5% [34]; P < 0.012), fewer dropouts from the fluticasone/salmeterol treatment arm, and better scores reported on quality-of-life questionnaires than the tiotropium bromide group. However, there were more pneumonias reported in the fluticasone/salmeterol group (5% vs 3%) and more oral candidiasis (6% vs 3%) than in the tiotropium bromide group. Although the primary efficacy endpoint did not differ between treatment groups, the study tended to support the benefit of fluticasone/salmeterol in reduction of mortality (also reported previously in the TORCH study) and improvement in quality of life in patients with COPD.

Obstructive Sleep Apnea

It is estimated that up to 25% of older persons suffer from obstructive sleep apnea (OSA), and OSA has been shown to be associated with an increased risk for cardiovascular disease (CVD). A challenge in the clinical management of persons with OSA has been to identify which of those persons might be at increased risk for CVD. A recent study followed newly diagnosed older patients (n = 851, all over the age of 67) with OSA to see if there were characteristics of the disease that could predict CVD risk. Subjects at the time of study were free of any known CVD. Elevated levels of C-reactive protein (CRP) were found in persons with more severe OSA (nocturnal oxygen desaturation index > 13/h) and with increased body mass index (BMI). Intervention with continuous positive airway pressure ventilation was associated with improvement in CRP. Researchers concluded that repeated nocturnal hypoxic events underlie inflammatory processes in OSA that may lead to CVD. They suggested that screening for OSA, often unrecognized in elderly, should be proposed as standard care in the elderly. Screening is necessary to identify those persons who have OSA, but more importantly, to identify those persons whose disease characteristics might warrant more aggressive treatment to reduce risk of serious cardiovascular events.

Another group of researchers from Grenoble, France, studied persons with OSA to try to identify a simple surrogate biological marker that might correlate with risk for CVD. They studied 98 newly diagnosed persons with OSA and no previous history of CVD or use of vasoactive medications. They used clinical blood pressure readings and 24-hour blood pressure monitoring to assess for the presence of hypertension and carotid wall intimal media thickness to assess for the presence of atherosclerosis. They found that urinary albumin excretion (UAE), an easily available urinary marker of CVD risk, correlated well with these more expensive and time/labor-intensive measures. A high normal UAE (> 9 mg/g) was associated with an increased risk ratio of 3.4 for hypertension and 3.5 for carotid plaques. Sixteen of the 98 subjects had elevated UAE, yet the severity of their OSA and their BMI did not differ significantly from the other subjects. However, subjects with high UAE were more likely to have higher systolic blood pressure and fasting blood glucose. The researchers concluded that use of this simple and relatively inexpensive measurement could help identify those persons with OSA at increased risk for CVD.

Estrogens and Respiratory Health

Since the early 1980s, the prevalence of COPD in women in the United States has been greater than in men, and since 2000, the death rate from COPD among women in the United States has surpassed that of men. This change in epidemiology has largely been ascribed to greater smoking rates seen in women over the same period. However, there has also been a clinical observation that is less well explained: that COPD in women often appears to be a more aggressive and destructive disease than in men. Chronic obstructive pulmonary disease is a disease that typically has its onset in persons in their 40s or 50s, or approximately the same time period that women are experiencing menopause. A sample of 1304 menopausal women was recruited from a large cohort study of women in Europe, and was studied with spirometry, blood hormone levels, and symptom questionnaires. Researchers reported a significant drop in lung function, reduction of both FEV₁ and FVC, and increased problems with both asthma and COPD in women who had been amenorrheic (low estrogen level) for 6 months or more. This led to the observation that estrogens may have a protective anti-inflammatory effect on the lungs, which can be lost at menopause.

Several animal studies reported at this meeting also supported that observation. Female mice that were oophorectomized were randomized to placebo or estrogen replacement. The placebo group was significantly more susceptible to the induction of bronchoconstriction from a methacholine challenge than the mice that were treated with estrogen. Another study reported that both female rats and guinea pigs that had lung damage induced from hypoxia or toxin exposure had significantly less tissue damage if they had been pretreated with estrogen. The use of hormone replacement therapy in women must be decided on an individual basis, but there appears to be a significant benefit for lung health.

Asthma

Several interesting studies linking asthma control to dietary fat and fatty acids were presented at the meeting. A Swedish researcher, Bengt Samuelsson, whose previous research in the area of asthma won him a Nobel prize for discovering the role of leukotrienes in asthma, has identified eicosanoids or fatty acids that can be associated with pro- and anti-inflammatory activity in the lungs. Eoxins are eicosanoids produced in respiratory tissues that can cause inflammation and edema, leading to airway obstruction. Lipoxins are another group of eicosanoids that have been shown to have an anti-inflammatory effect on lung tissues. Samuelsson has postulated that persons who have asthma control problems may have an imbalance of one or both of the fatty acids. If these observations bear out in future research, it could lead to novel interventions and dietary recommendations for asthma control.

Previous research has shown that the ratio of omega-6 fatty acids (α-linoleic acid) to omega-3 fatty acids (α-linolenic acid and fish oils) in the diet is important in the balance of metabolic pathways in the body. Too great a preponderance of omega-6 fatty acids (greater than 10:1 ratio) will drive the arachidonic acid pathway, resulting in the overproduction of inflammatory prostaglandins. Thus, dietary fatty acid intake may have relevance in the management of any inflammatory disorder. A study reported from Mexico tended to support this theory of a relationship between dietary fats and the inflammation of asthma and allergy. The researchers hypothesized that a diet that had a healthy balance of fatty acids (Mediterranean diet) would result in fewer problems with asthma and allergy control. They used a random sample of 1476 children (ages 6-7) from the Mexicali area of Baja, Mexico, and collected a 70-item food frequency questionnaire regarding the children’s diet over the previous 12 months. Asthma and allergy symptoms for the same period were assessed using the International Study of Asthma and Allergies in Childhood questionnaire. They found that children with a higher adherence to the Mediterranean diet had a 30-60% reduction in the risk of asthma, wheezing, and allergic rhinitis. This retrospective observational study has obvious limitations, and these findings may not be generalizable to other age groups. Nevertheless, it supports further investigation into an area that could have significant implications for a number of diseases that are driven by abnormal inflammation.

Several other asthma-related studies reported findings that can have practical implications for clinical management. A large study of 20,183 U.S. farmers reported a significant increase in the prevalence of both allergic and non-allergic asthma in farmers exposed to pesticides. Twelve different pesticides were associated with increased risk, but fortunately five of them have already been removed from the market. Of those still available, S-Ethyl dipropylthiocarbamate (EPTC), paraquat, lindane, parathion (less widely used) and coumaphos, diazinon, and captan (very widely used) are associated with increased risk, and farmers or gardeners, especially those who already have asthma, need to be warned about this hazard.

Many physicians suggest swimming or pool exercises to patients who have weight-bearing or mobility problems. If those patients have a flare-up of asthma symptoms, it may be related to the chlorine in the pool or hot tub. Several research reports from Europe (Italy and Belgium) showed increase incidence in asthma in school children who swam in chlorinated pools. One study compared the incidence of new asthma cases in children attending a school with a chlorinated pool versus a school in the same city that used a copper-based sanitizing agent, and showed significantly fewer cases of asthma (300% less) in the nonchlorinated setting. In chlorinated pools, the 8-10 cm of air immediately above the water have fairly high concentrations of chlorine gas that is evaporating from the pool, and that is directly irritating to the lungs. Chlorine also complexes with proteins in the water from human secretions and forms chloramines that are also volatile and quite allergenic. Although the studies were done in children, the potential for causing or aggravating asthma in persons of any age seems quite possible, and perhaps should be considered in someone who uses a chlorinated pool and has developed respiratory symptoms.

On the Horizon

Stem cells have been used in the hopes of repairing damaged organs in a number of diseases with some success (Parkinson’s disease, diabetes, heart failure), but to date, no one has successfully performed stem cell transplants for pulmonary diseases. Successful stem cell therapies could have enormous clinical benefit with the over 20 million persons in the United States alone suffering from COPD. The lung has been a challenging target organ for tissue engineers since it is quite complex with a large variety of cells, some of which have a very slow renewal rate. This year, however, a British research team reported early success in cultivating murine stem cells that had shown the capacity to differentiate into lung tissue. They then had to demonstrate that they could get the stem cells to work in a living animal. They induced lung injury in experimental mice and injected tagged stems cells into the tail vein. Two days later, they sacrificed the animals and examined the lungs for evidence of stem cell presence. They were surprised and delighted that the stem cells had not only selectively gone to the lung, but they colonized at the site of lung injury. The researchers state that human clinical applications are a long way off, but expressed optimism that this research could lead to significant breakthroughs.