E-Only Content

Conference News Update

European Respiratory Society 2009 Annual Congress—Vienna

• LABA and SABA Risks Greatest in New and Long-Term Users
• Novel Anti-Inflammatory Agent Reduces COPD Exacerbations
• Childhood Asthma Risk Quadrupled by Low Birth Weight and Maternal Smoking
• Menstrual Cycle Affects Lung Function in Women With Asthma
• New Screening Possibilities for Mesothelioma
• Mechanism That Perpetuates Cell Suicide Is Unveiled

LABA and SABA Risks Greatest in New and Long-Term Users

The risks of death and hospitalization due to status asthmaticus are similar in asthma patients receiving long-acting β₂-agonist (LABA) therapy and those receiving short-acting β-agonists (SABA) or inhaled corticosteroid (IC) therapy, reported Frank de Vries, PhD, PharmD, General Practice Research Database, Medicines and HealthCare Products Regulatory Agency, London.

Using a novel approach to describe hazard-rate patterns of asthma outcomes with changes in drug exposure, researchers analyzed 507,966 patients, ages 18 and older, who received a prescription for inhaled SABA or LABA between1993 and 2007. Investigators focused on convergence and divergence of hazard rates rather than estimation of relative rates.

Higher relative rates of all outcomes were found in asthma patients who had recently started treatment or in long-term users with very frequent prescriptions (13 or more) in the year before. Heavy long-term users had increased risks of asthma death with all medications and the death-risk patterns were similar for LABA with or without ICS therapy. Similarly, no major difference was found in risk patterns for acute myocardial infarction between patients treated with LABA, SABA, and IC therapies.

Overall, Dr. de Vries concluded that while the risk patterns for death and hospitalization varied considerably with exposure, these were broadly similar in patients using the three different therapies. The risk patterns for myocardial infarction were also similar, suggesting that there were no major differences between these drugs.

Novel Anti-Inflammatory Agent Reduces COPD Exacerbations

Roflumilast, an oral, once-daily anti-inflammatory agent that inhibits the enzyme phosphodiesterase-4 (PDE4), improves lung function and reduces exacerbations in patients with moderate to severe COPD, researchers report. Four studies presented and published simultaneously in a special COPD edition of The Lancet show a significant improvement in lung function and a significant reduction in exacerbation rates with the treatment.

Two six-month trials and two 12-month trials of roflumilast involved more than 4,000 patients in 10 countries. By inhibiting PDE4, an enzyme central to the inflammatory process in COPD, this therapeutic approach aims at targeting the pathogenetic mechanism of the disease rather than merely treating the symptoms and was found also to be beneficial in combination with traditional COPD medications, such as salmeterol and tiotropium.

Researchers found concomitant regimens improved FEV₁ significantly, reduced the rate of exacerbations, and improved respiratory symptoms compared with a placebo. The safety profile of was consistent with that previously reported for roflumilast. Diarrhea, nausea, and weight loss were the most common treatment-related side effects.

“When the PDE4-inhibitor roflumilast is co-administered with long-acting bronchodilators, the combination may add beneficial effects,” reported Leonardo Fabbri, MD, University of Modena, Italy, and Peter Calverley, MD, University of Liverpool, UK. “This treatment, however, is not suitable for all patients, because of class-related adverse effects that usually arise soon after initiation of treatment.”

Childhood Asthma Risk Quadrupled by Low Birth Weight and Maternal Smoking

A combination of fetal exposure to smoking and low birth weight (LBW) carries a four to six times greater risk of developing childhood asthma, Swedish researchers reported. These two parameters contribute synergistically to asthma in childhood, said Anders Bjerg, MD, PhD, of Sunderby Central Hospital of Norrbotten, Sweden.

Children in three cities in Northern Sweden participated in a questionnaire about respiratory symptoms, physician diagnoses, medication use, and possible determinants of disease at ages 7 to 8 and again at ages 11 to 12. Children in two cities were also tested for skin allergen sensitivity, a known risk factor for asthma.

Researchers gathered complete data, including birth weight and maternal smoking, from 3,010 participants and found the prevalence of LBW (< 2,500 g) among study participants was 4.1%, and 24.3% of participants were exposed to smoking in pregnancy. The mean birth weight was 211 g lower in children born to mothers who smoked than in children of nonsmoking mothers. In LBW children, the prevalence of physician-diagnosed asthma was 11.5%, compared to 7.7% in non-LBW children. If smoking in pregnancy was added, the corresponding figures were 23.5% and 9.5%, respectively.

Since Sweden has a comparatively low prevalence of both LBW and smoking, relatively few children in this study were born at LBW and to smoking mothers. Of these children, however, almost one-fourth had a physician’s diagnosis of asthma at age 11 to 12, which emphasizes the importance of the respiratory morbidity in this group.

Menstrual Cycle Affects Lung Function in Women With Asthma

A heavy methyl–sensitive detection assay of the SHOX2 gene may be used in the work-up of patients with suspected lung cancer, researchers reported.

“Confirming malignancy often remains a challenge, because the tumor may not be accessible for biopsy by bronchoscopy and cytology is inconclusive,” the investigators explained. “This potentially triggers additional diagnostic procedures bearing risks for the patient and eventually causing a delay in diagnosis.”

In a retrospective study analysis, John K. Field, PhD, of the University of Liverpool Cancer Research Center in Liverpool, United Kingdom, and colleagues evaluated the use of the recently developed assay to diagnose suspected bronchial carcinoma. Of 423 patients with suspected lung cancer, 237 patients had lung cancer and 186 patients had benign lung disease (controls). Flexible bronchoscopy with bronchial lavage of the specimens taken from suspicious regions was performed.

Sixty-three of 84 patients (75%) with squamous cell lung cancer were positive for SHOX2 methylation, with 99% sensitivity. Stage-specific analysis of the patients showed a sensitivity of 70%, 89%, and 76% for International Union Against Cancer stages I, II, and II, respectively.

There was a 59% sensitivity and a 99% specificity for all lung carcinomas (ie, 84 squamous carcinomas, 98 adenocarcinomas, 12 small–cell lung cancers, and 43 other types), the study authors found.

New Screening Possibilities for Mesothelioma

In a study of patients with advanced non–small cell lung cancer, combination therapy with bevacizumab and erlotinib improved progression-free survival compared with erlotinib treatment alone, researchers reported. There was no improvement in overall survival, they noted.

In the BeTa lung study, investigators randomized patients to receive erlotinib (150 mg/daily) with bevacizumab (15 mg/kg), or erlotinib with placebo (15 mg/kg), intravenously for every three weeks. Of 477 patients who provided tissue samples, investigators reported progression-free survival and overall survival of 0.63 and 1.03 for patients EGFR immunohistochemistry. In addition, patients with EGFR fluorescence in situ hybridization results had 0.62 and 1.24 for progression-free survival and overall survival, respectively, compared with patients with EGFR mutation (0.62 and 1.09). In patients with K-ras mutations, progression-free survival was 0.63 and overall survival was 1.10.

“These patients were representative of the overall enrolled patient population,” Roy S. Herbert, Chief of the Section of Thoracic Oncology at the University of Texas, and colleagues concluded. “The progression-free survival and overall survival results for biomarker defined subgroups were consistent with the overall results of the trial.”found.

Mechanism That Perpetuates Cell Suicide Is Unveiled

Angiotensin II not only is a key player in the cardiovascular system but also seems to be an important mediator of alveolar apoptosis, a pivotal event in the pathogenesis of lung diseases such as idiopathic pulmonary fibrosis (IPF) or acute lung injury (ALI), researchers suggested.

The investigators elucidated the mechanism by which a less-studied angiotensin-converting enzyme—ACE-2—promotes lung cell death, namely by converting angiotensin II into an antiapoptotic peptide. In addition to causing cell death in these conditions, angiotensin II perpetuates the process by producing more angiotensin II in dying alveolar epithelial cells, which in turn promotes the death of more cells.

Although previous studies have shown that agents such as ACE-1 inhibitors or angiotensin II-receptor blockers may have an effect in preventing pulmonary fibrosis, this is the first time that researchers have looked at the effect of another enzyme in the fibrogenic process in the lungs.

In exploratory research of cell lines from mice and rats, ACE-2 inhibition increased apoptosis of alveolar epithelial cells, suggesting that potential therapeutic targets for the prevention of IPF or ALI may be discovered in this pathway. The treatment of cell lines with Angiotensin 1-7 (ANG1-7) before an injury such as induced by bleomycin prevented apoptosis, the researchers discovered, but they also discovered that blocking the specific ANG1-7 receptor prevented ANG1-7 from exerting its antiapoptotic actions.

The favorable effect of the antiapoptotic ACE-2 product ANG1-7 versus that of ACE-1 suggests a counterbalancing interaction of these two enzyme homologues in the physiological regulation of lung cell apoptosis, said Bruce Uhal, PhD, from the Department of Physiology at Michigan State University.

“Focusing on regulating the ACE-2 enzyme and its products may be important, much in the same way as ACE-1 inhibition became a breakthrough two decades ago.”