The European Respiratory Society Congress • Munich, Germany • September 2-6, 2006

The European Respiratory Society Congress is the largest medical meeting on respiratory health in the world, with attendance this year surpassing the American Thoracic Society annual meeting. This year, more than 17,000 healthcare professionals participated in the 4 1/2-day Congress in Munich, Germany. The sessions covered all aspects of respiratory health, but this year’s meeting was dominated by papers and presentations on chronic obstructive pulmonary disease (COPD), with more than 1100 presentations of original research related to this topic.

COPD Symposium

Recognizing the growing importance of COPD, the program committee of the European Respiratory Society has planned a series of three annual core content review symposia on COPD. This year’s symposium focused on epidemiology, risk factors, molecular and cellular features of pathology, and primary care management. The following are some highlights from the symposium.

In the 1990s, COPD was ranked 12th among the major chronic diseases in overall burden of disability and mortality; by the year 2020 it is projected to rank 3rd. It is the only one of the major chronic diseases that is showing an increasing rate of mortality. A worldwide effort to better understand the epidemiology of COPD is currently underway with the Burden Of Lung Disease (BOLD) study, which will be discussed further below.

Study of the etiology of COPD shows that it is a complex disease that appears to be an interaction between a genetic predisposition and environmental exposures. This interaction produces an abnormal and destructive inflammatory process in the lungs. Not only does this process destroy lung parenchyma, but these same inflammatory factors have systemic effects as well that contribute to the common comorbidities of COPD such as osteoporosis and coronary disease. Kindred studies have shown that an individual who smokes and is a sibling of a person with COPD has a 4.7 times greater risk of developing COPD than an age-matched smoker. A large genetic study of 720 sibling pairs with COPD is underway using genome-linked scanning to try to identify common genetic patterns. Early findings suggest different genetic patterns for small airway obstruction phenotype of COPD (chronic bronchitis), as opposed to the emphysema phenotype.

The genetic research in COPD has led to the discovery of the defect in alpha-1 antitrypsin deficiency. People with this disease (about 1% of all persons with COPD) produce a mutant form of alpha-1 antitrypsin that chains with itself forming a polymer. That polymer gets deposited in the lung epithelial cells and not only has no antitrypsin functionality, but it also incites inflammation in the cell by attracting and activating circulating polymorphonuclear cells and macrophages. Researchers have been able to design a molecule that can prevent this chaining reaction in vitro, giving hope to the possibility of a cure for this devastating form of COPD.

Understanding the genetic defect in the alpha-1 antitrypsin form of COPD, which is a form of proteinase/inhibitor imbalance, has led to the discovery of other similar pathways involving other proteinase systems (eg, metalloproteinases, neutrophil elastase) that can lead to destruction of lung parenchyma. It appears that in genetically susceptible individuals, the exposure to smoke and other pollutants, as well as the reactive oxygen species associated with smoke, impair the regulatory function of the proteinase inhibitors. This allows the inflammatory reaction in the lung to go unchecked and causes excessive parenchymal damage.

Another characteristic of this abnormal inflammatory process associated with COPD is the increased apoptosis or cell death of lung epithelial cells. The airway’s normal reparative processes are also inhibited, resulting in accumulation of dead cells in the airway that further stimulate the inflammatory reaction. These destructive processes of unchecked proteinase activity, oxidative damage, and increased apoptosis seem to amplify one another, and the inflammation can become self-sustaining, even in the face of quitting smoking.

The BOLD Study

This year the first interim report of the BOLD study was presented. This is an ongoing study that is focused on getting accurate prevalence and epidemiological data on COPD using consistent definitions and measurement criteria worldwide. All of the major countries of the world are participating, and 11 countries, including the United States, have already completed their part of the study. The initial findings are very interesting, and suggest that COPD is more prevalent in essentially all countries than previously appreciated (14-25% of persons over age 40 years), and approximately 50% of persons with COPD are undiagnosed. Most COPD in western countries is caused by smoking or air pollution, but aging is also a significant risk factor. Researchers in Germany reported that more than 50% of persons over the age of 70 years had COPD when measured with spirometry, (FEV1/FVC ratio < 70% predicted, or FEV1 < 80% predicted), and this statistic appears to hold true for most western countries.

There is some question about the clinical significance of mild-to-moderate COPD in old age, since some of this loss of lung function may be “normal” aging of the lung. However, one presenter showed that older persons with decreased FEV1 (< 80% predicted) or decreased FEV1/ FVC ratio (< 70% predicted), regardless of their prior smoking status, had increased frequency of hospitalizations and mortality when compared with persons of similar age with normal lung function.

The TORCH Trial

The long awaited TOwards a Revolution in COPD Health (TORCH) trial was presented at this meeting. The TORCH trial is one of the largest and longest (3 years) clinical trials in COPD to date. More than 6000 patients with moderate-to-severe COPD (mean age = 65 years, mean post-bronchodilator FEV1 = 44% of predicted) were randomized to one of four parallel treatment arms: (1) fluticasone (F) 500 mcg bid; (2) salmeterol (S) 50 mcg bid; (3) combination fluticasone 500 mcg/salmeterol 50 mcg (F/S) bid; vs (4) placebo (P). The primary study endpoint was all-cause mortality and the combination F/S proved to be the superior intervention, reducing mortality by 17.5% when compared to P (P value depending on the type of analysis = .031-.052). This is the first COPD intervention other than smoking cessation and oxygen therapy to demonstrate a clinically significant reduction in mortality. To put this in perspective, a meta-analysis of 17 statin trials showed a 16% relative risk reduction in all-cause mortality in persons with coronary heart disease. The combination F/S also showed significant benefits in other outcomes; improved lung function (FEV1 92 ml > than P; P < .001), improved health status (St. George’s Respiratory Questionnaire, 3.1 points lower than P; P = .001), reduced exacerbations by 25% vs P; P < .001); reduced hospitalizations by 30% vs P; P < .001). These findings are even more impressive in light of the fact that there were higher placebo dropout rates early in the study, and many of those subjects likely went on to various combinations of therapy, including F/S, during the subsequent years of follow-up, and thus reduced the perceived differences with the treatment group. This is truly a landmark study and likely will influence future guideline recommendations.

Procalcitonin: A New Biomarker for Bacterial Pneumonia

Procalcitonin (PCT) is a new biomarker that is quite sensitive to such bacterial infections as pneumonia. Overuse of antibiotics—especially for respiratory diseases—has been a major health problem, and has been the primary cause of antibiotic-resistant strains of bacteria. The use of PCT levels in a Swiss study assessing and treating lower respiratory infections in the community setting reported a 70% reduction in antibiotic use. In most clinical practices, patients presenting with lower respiratory symptoms suspicious for bacterial pneumonia are started on antibiotics empirically. Various diagnostic tests including sputum smears, cultures white blood counts, and C-reactive protein levels are frequently employed to support the diagnosis or monitor the disease, but they all have poor predictive value. One of the common dilemmas facing the clinician is when to discontinue antibiotics that were started empirically. PCT has been shown to be useful both in ruling out a bacterial etiology for respiratory symptoms and in monitoring the course of a bacterial pneumonia. If a patient’s initial PCT level is normal (less than 0.1 mcg/L), then bacterial etiology is unlikely. If, even in the face of a normal PCT level, the clinician decides to start antibiotics, a repeat PCT on day 2-3 that remains normal assures the clinician that antibiotics can be safely discontinued. On the other hand, if the PCT level is elevated (> 0.15 mcg/L), then bacterial etiology is very likely, and the clinician has a useful marker for following the course of the infection. When PCT levels again return to normal, antibiotics can be discontinued, and studies suggest that this may be sooner than a typical full course of antibiotics. A persisting elevated PCT level is a bad prognostic sign.

Inhaled Insulin

Several studies reported on the use of the new form of inhaled insulin (IH). This is a short-acting insulin that is used similarly to regular insulin, typically for mealtime or periodic supplements to longer-acting insulin in persons with type 1 diabetes. Investigators reported that it was well-tolerated, provided good glycemic control, and most subjects preferred it to injectable insulin. Some subjects experienced a slight cough shortly after taking the IH. There are a number of clinical circumstances that physicians should be aware of when prescribing IH. It can cause a slight decrease in lung function (FEV1 decreases 1-3%), and therefore is relatively contraindicated in persons with significant asthma or COPD. All persons considering using IH must have pulmonary function testing before starting, and periodic monitoring of lung function. The change in lung function occurs early in the course of therapy, remains stable thereafter, and it reverts to baseline when IH is discontinued. Smokers cannot use IH because they absorb the insulin rapidly from the lung and can have hypoglycemia. Persons who quit smoking continue to have an increased absorption rate, approximately 50% that of active smokers, but they do not seem to have hypoglycemic problems. Interestingly, passive smoke exposure appears to slow IH absorption, so it is not a risk for hypoglycemia.

Sleep Apnea

Research on obstructive sleep apnea (OSA) continues to reveal new associations with other health problems, and OSA is especially common in older persons. OSA has long been associated with an increased risk of hypertension, but it is also carries an increased risk for metabolic syndrome, impaired glucose control in persons with diabetes, myocardial infarction, stroke, gastroesophageal reflux disease, depression, anxiety, and chronic fatigue. Studies of the epidemiology of OSA indicate that it is underdiagnosed, especially in the elderly. The diagnosis of OSA is missed more often in women, in part, because they often present with symptoms/complaints (eg, insomnia, restless legs, nightmares, nocturia) that are not the classic snoring and witnessed apnea associated with OSA. More than 50% of persons with untreated OSA have daytime episodes of falling asleep without intending to or being aware of it. This, of course, is a serious health hazard for persons who smoke or drive a motor vehicle. Risk factors for OSA include advanced age, obesity and metabolic syndrome, use of alcohol, sedative, or hypnotics, and male gender; however, the gender difference lessens with age. The best treatment for OSA is the use of continuous positive airway pressure (CPAP) ventilation, which, when used successfully, reduces or eliminates all of the health risks associated with OSA. The goal of CPAP therapy is to achieve 4-5 hours of ventilator-assisted breathing per night. Unfortunately, patient compliance can be a problem since many patients on CPAP are bothered by dry nose and mouth, vasomotor rhinitis, or frequent awakenings due to mask irritation. Advances in CPAP ventilator design, including automated pressure titration (C-FlexTM by Respironics), heated humidification, and better design of face masks, have done much to improve comfort and compliance.

Abstracts from the ERS Congress are available online at www.ersnet.org and can be searched using a key word index.