Press Release

July 2004

Vital Amino Acid Levels Lower in Asthmatics

Researchers have revealed that patients with asthma, when compared to normal controls without the disease, had much lower levels of plasma arginine, an amino acid that produces nitric oxide (NO) through enzymatic activity in the body. Recently, investigators have started to believe that NO deficiency plays a significant role in the pathogenesis of asthma.

Writing in the second issue for July 2004 of the American Thoracic Society’s peer-reviewed American Journal of Respiratory and Critical Care Medicine, Claudia R. Morris, M.D, of the Department of Emergency Medicine, Children’s Hospital and Research Center at Oakland, Oakland, California, along with five associates, measured amino acid levels and nitric oxide metabolites in the blood of 26 patients with asthma who were in varying stages of disease exacerbation.

“NO is an important vasodilator of the bronchial circulation, with both bronchodilatory and anti-inflammatory properties,” said Dr. Morris. “Recent studies suggest that asthma may be a condition of decreased NO bioavailability, rather than overproduction as a result of inflammation.”

According to the authors, much attention has been paid recently to the measurement of exhaled NO in asthmatics. As a result, it is widely regard as a marker of airway inflammation found in both children and adults with asthma.

However, to date, no other studies in individuals with asthma have measured circulating levels of arginine, which is fundamental to NO production. NO is naturally produced from the amino acid arginine by enzymes called NO synthases.

“In the study, reductions occurred in plasma levels of many amino acids in patients experiencing acute exacerbation of respiratory symptoms,” said Dr. Morris. “Strikingly, the greatest decrease was in plasma levels of arginine, which were approximately half those of normal control subjects.”

Among the 26 patients in the study who had exacerbations, 10 were managed on an outpatient basis and 16 were admitted to the hospital. The median age of the asthmatics in the study was 10 years, but the range was from 2 to 52. Fourteen of the 26 were male. Fifteen individuals without asthma were enrolled as normal controls. Their median age was 12 years, with the age range from 2 to 34. Nine of the control patients were male.

“With recent studies supporting the role of NO deficiency in airway hyperreactivity, our findings have significant clinical relevance and represent a new focus for asthma research,” said Dr. Morris. “Decreased arginine levels may reflect substrate depletion owing to increased demand for NO in asthmatics to maintain basal bronchodilator tone while compensating for increased NO consumption during oxidative stress. . .”

According to the authors, asthma is estimated to affect 15 million people in the United States, and is the frequent reason for preventable childhood hospitalizations costing billions of dollars annually.

Respiratory Viral Infections Offer Distinct Risk for Lung Transplant Patients

Lung transplant patients who develop community-acquired respiratory viral infections such as respiratory syncytial virus, parainfluenza, influenza, and adenovirus during the months after their surgery had twice the risk of developing a potential killer syndrome called bronchiolitis obliterans. If the viral infection involved the lower respiratory tract, the risk was tripled. According to the researchers, the hazards from infection were distinct from those attributable to acute organ rejection.

Writing in the second issue for July 2004 of the American Thoracic Society’s peer-reviewed American Journal of Respiratory and Critical Care Medicine, Michael J. Walter, M.D., of the Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, Missouri, along with eight associates, described the results from studying the records of 228 patients who underwent lung transplantation at the institution between January 1, 1996, and December 31, 2000. Data were accrued through July 1, 2002. Of this group, 21 patients suffered from community-acquired respiratory viral infections, including 8 cases of respiratory syncytial virus, 7 of parainfluenza, 4 of influenza, and 2 of adenovirus. Within this group, six patients died as a result of bronchiolitis obliterans syndrome (BOS).

BOS is the fibrotic destruction of the small airways that constitutes the major long-term cause of mortality in lung transplant patients. According to the authors, BOS is the cause of death in approximately one-third of patients after 1 year, and affects one-half of lung transplant recipients alive at 5 years.

“Identification of community-acquired respiratory viral infections as a unique BOS risk factor has important clinical implications and suggests that antiviral strategies aimed to prevent or treat viral infection may provide a strategy to modify the onset or progression connected with the syndrome,” said Dr. Walter.

He continued: “In the context of previous work describing BOS risk factors, our study is the first to demonstrate that community-acquired viral infections were associated with an increased risk of developing BOS stage 1, BOS stage 2, death, and death from BOS and the first to separate the contribution of these infections from the risk attributable to acute rejection and cytomegalovirus pneumonitis.”

During the first year after transplantation, all lung patients underwent five surveillance bronchoscopies that were scheduled monthly during the first 3 months, and again at 6 and 12 months. Clinically indicated bronchoscopies were conducted as a result of new respiratory symptoms or signs.

“Three of eight recipients with respiratory syncytial virus underwent treatment with inhaled ribavirin, and none of these three patients developed BOS, whereas four of five untreated recipients developed BOS,” said Dr. Walter.

The authors recommended that lung transplant patients avoid contact with sick persons, where possible, and that they receive appropriate community-acquired respiratory viral infection vaccinations, as well as chemoprophylaxis when indicated. They advocated that viral testing should be performed with all surveillance bronchoscopies, using more sensitive and comprehensive methods than previously employed. In the event of infection, antiviral treatment should be considered on an individual case basis and continued monitoring should be examined in case of possible respiratory decline.

The investigators also recommended that physicians treating lung transplant patients develop a heightened awareness of the potential detrimental consequences of community-acquired respiratory viral infections.

Unique Lung Cancer Signatures Offer Biomarkers For High- and Low-Risk Patient Outcomes

Researchers used lung tumor biopsies from 23 patients with proven lung cancer to identify unique tumor signatures that proved to be biomarkers for clinical outcome at an 87 percent accuracy rate

Charles A. Powell, M.D., Department of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, New York, along with seven associates, utilized residual material from lung biopsies to identify a classifier set of 42 genes that were associated with risk of lung cancer death within 12 months. The group also identified genes with low-risk outcomes. The study appears in the second issue for July 2004 of the American Thoracic Society’s peer-reviewed American Journal of Respiratory and Critical Care Medicine.

According to the authors, lung cancer is the leading cause of death from cancer in the United States, with 187,000 cases and 165,000 deaths expected in 2004. Despite improvements in diagnostic testing, surgical resection, and treatment techniques, five-year survival rates have remained at about 15 percent over the past three decades. This rate is markedly lower than those for other common cancers, including malignancies of the breast, colon, and prostate. They note that this discrepancy could be due to either biological differences or to absence of proven screening programs that effectively detect cancers at an early, curable stage.

“The potential role of lung biopsy gene expression profiling in the management of early-stage non-small cell carcinoma would be to identify patients with high-risk tumors who would be most likely to benefit from neoadjuvant systemic therapy,” said Dr. Powell. “The potential utility of this approach has been demonstrated in breast carcinoma. For example, gene profiles obtained from breast tumors have been show to predict short-term clinical response to neoadjuvant docetaxel.”

In addition, the authors point out that in vitro studies have demonstrated that the response of lung cancer cells and other cancer cells to single chemotherapeutic agents can be predicted by distinct gene expression profiles.

“Also, because our data set was composed entirely of lung carcinoma biopsies, we could not examine the utility of biopsy gene profiles to distinguish malignant tumors from benign modules,” said Dr. Powell. “Experience with screening using chest computerized tomography indicates a high prevalence of nodules, from 25 to 66 percent, of which only a small fraction, 1 to 3 percent, are malignant. Although nodule size and internal change in size are useful tools to distinguish malignant from benign lesions, it is possible that gene expression profiles of CT-detected nodules may enhance diagnostic algorithms and the clinical utility of the procedure.”

Since the procedures for this technique are safe and feasible, the researchers suggest that the gene expression signatures generated by lung biopsies are at the point where the technique is now appropriate for prospective clinical trials.