Press Release

December 2004

New Treatment Offers Marked Improvement in Deadly Pulmonary Arterial Hypertension

Researchers showed that 16 weeks of treatment with the oral drug bosentan led to marked improvement in all clinical and hemodynamic parameters of the deadly disease severe pulmonary arterial hypertension (PAH) associated with human immunodeficiency virus (HIV) infection.

Writing in the first issue for December 2004 of the American Thoracic Society’s peer-reviewed American Journal of Respiratory and Critical Care Medicine, Olivier Sitbon, M.D., of Hôpital Antoine Bécière, Clarmart, France, along with 9 associates, studied 16 patients with PAH using bosentan, an oral, dual endothelin receptor antagonist. In HIV patients, endothelin is believed to be produced excessively, causing vasoconstriction, cell proliferation, fibrosis and inflammation.

“High serum concentrations of endothelin are present in patients with PAH of unknown cause and correlate with disease severity,” said Dr. Sitbon. “PAH is also observed in all groups of patients with HIV. It results from chronic obstruction of small pulmonary arteries due in part to endothelial and vascular smooth muscle dysfunction and proliferation.”

In most cases, earlier death occurs as a direct result of PAH.

For the 16 patients, all of whom completed the study, the efficacy end points of their treatment consisted of exercise capacity, cardiopulmonary hemodynamics, their New York Heart Association functional class and quality of life.

“Overall, in the present study, significant improvements were reported for those parameters that are considered prognostic indicators of survival in idiopathic PAH, such as the 6-minute walk distance, the cardiac index, pulmonary vascular resistance, and the right atrial area and eccentricity index on echocardiography,” said Dr. Sitbon.

All patients in the study suffered at least one adverse side effect of bosentan treatment, including peripheral edema, headache, abnormal liver function, muscle cramps, fluid retention and vomiting.

“A major objective of the study was to assess the safety profile of bosentan in this high risk population,” said Dr. Sitbon. “The main concern with bosentan is an increase in liver enzymes. . .Despite the enrollment of four patients co-infected with chronic hepatitis B and C, and co-treatment with potentially hepatotoxic antiretroviral therapies in 15 of the 16 patients, the number of cases of abnormal hepatic function observed in this study was 2 out of 16 patients, which is within the range of previous experience.”

The authors believe that a larger study is needed to confirm their results. However, they said that bosentan treatment appears to be a suitable option in the management of patients with symptomatic PAH associated with HIV infection.

Reducing Costs in Treating Obstructive Sleep Apnea Patients

Spanish investigators published results from a large study showing that simpler, cheaper methods can be used to determine the optimal pressure for continuous positive airway pressure (CPAP) devices which are used to successfully treat a serious disorder, obstructive sleep apnea.

Writing in the first issue for December 2004 of the American Thoracic Society’s peer-reviewed American Journal of Respiratory and Critical Care Medicine, Juan F. Masa, M.D., of San Pedro de Alcántara Hospital, Cáceres, Spain, reported results on 315 patients in a multi-center trial designed to determine whether optimizing pressure levels at home with an autoadjusted CPAP device or using a predicted formula was as effective as determining levels involving the more expensive, time-consuming full night sleep test.

Obstructive sleep apnea is a serious disorder that occurs when a sleeping person stops breathing for 10 seconds or more, decreasing the amount of oxygen in the blood and brain and increasing carbon dioxide. The problem is caused by a temporary blockage in the throat or upper airway. Prolonged sleep apnea often causes excessive daytime sleepiness, headaches, mental fuzziness and pulmonary insufficiency, which can lead to potential heart failure.

“Sleep apnea syndrome is a disorder that affects 2 to 4 percent of the adult population,” said Dr. Masa. “Nasal continuous airway pressure is the most effective treatment in patients with these symptoms.”

The CPAP device is worn like an oxygen mask while sleeping, delivering a mixture of air and oxygen to the patient through the nose. The instrument is intended to keep the airway open which aids in regular breathing.

The study patients were divided into 3 groups. One group underwent a second sleep test (polysomnography) for manual CPAP pressure determination (titration). The second group received information on the autoCPAP, and then slept at home to determine effective pressure. The third group had optimal pressure estimated from a published equation.

“We obtained effective autoCPAP titration at home using only one night in 82 percent of the patients,” said Dr. Masa. “Two additional nights were performed with the patients that failed during the first night. As a consequence, optimum CPAP pressure was obtained in 96 percent of all subjects in the autoadjusted group.”

According to the authors, out of the 466 patients initially included in the study, 45 dropped out and 106 were excluded, leaving a total of 315. The main reason for the exclusion was the presence of a disorder that prevented these persons from being evaluated for quality of life.

“In our study, the improvement in symptoms such as sleepiness, arousal index, oxygen saturation, and the apnea/hypopnea index was very similar in all the groups although the predicted formula group had a higher number of residual apneas and hypopneas,” said Dr. Masa.

The authors said that their study had important economic and practical implications, since fewer expensive sleep tests would be needed to adjust these devices. This result could lead to considerable cost savings and to a significant reduction in waiting lists for sleep center tests to calculate CPAP pressure settings.

In an editorial on the study in the same issue of the journal, John R. Stradling,M. D., of the Oxford Center for Respiratory Medicine, Churchill Hospital, Oxford, England, indicated that the process of using expensive polysomnography to determine the right pressure for CPAP might have been a more attractive to doctors because it offered a significant reimbursement opportunity. He suggested a more pragmatic approach.

“It has been realized by many that the purpose of the sleep study is really to detect sleep fragmentation due to upper airway obstruction or, even more pragmatically, ‘CPAP-responsive disease,’” said Dr. Stradling. “If such CPAP responsiveness is taken as the outcome of primary interest, then simplified diagnostic tests, even just simple oximetry, have been shown to be at least as good as polysomnography. There is now a real acceptance by most that simplified tests are clearly the way of the future in routine clinical practice, particularly in the face of increasing disease burden.”

He notes that the current study points out that “obessional CPAP titration is not supported when subjected to the power of controlled trials.”

“Such randomized and controlled trial work gives us the evidence to justify reducing the complexity, and thus the costs, of treatment,” said Dr. Stradling. “This has to be good for patients since it provides cheaper and simpler CPAP therapy, available to greater numbers. The authors are to be congratulated for addressing this issue.”

Improving Diagnosis by Molecular Methods in Difficult Viral Infections

In a study of 148 bronchoalveolar lavage specimens collected for analysis from patients with suspected hard-to-detect acute respiratory infections, only about 1 in 3 cases that were identified as virus positive by molecular methods were also revealed through cell culture analysis.

Writing in the first issue for December 2004 of the American Thoracic Society’s peer-reviewed American Journal of Respiratory and Critical Care Medicine, Laurent Kaiser, M.D., of the Department of Medicine, Division of Infectious Diseases, University Hospitals of Geneva, Geneva, Switzerland, analyzed the specimens for the presence of 11 different viruses, as well as several types of pneumonia plus Legionnaire’s Disease.

“Respiratory viruses were identified in 34 of 117 BAL specimens (29 percent) obtained in patients with suspected respiratory infection and in only 2 of 31 control patients,” said Dr. Kaiser.

The researchers used reverse transcription chain-reaction assay for their molecular analysis.

According to the authors, viruses in the lower respiratory tract are a leading cause of disease, hospitalization, and antibiotic use in patients with immunosuppressive and/or chronic lung diseases. However, in 70 to 80 percent of the cases, the identity of the virus remains undetermined.

“This lack of diagnosis exists because appropriate lower respiratory tract samples are often not available and routine diagnostic procedures are limited both in their sensitivity and in the number of agents routinely targeted,” said Dr. Kaiser.

To collect the BAL specimens, doctors wedge a bronchoscope into a small airway in the lung, and then instill saline solution through the instrument. The fluid is then suctioned back through the scope, bringing with it cellular material for analysis.

During the 1-year study period, 148 BAL specimens from 111 patients were analyzed. The mean age of the patients was 54 and 56 percent were male.

“The sensitive molecular tool better estimated the frequency of respiratory viral infection in hospitalized patients and permitted the identification of the cause of a respiratory event in patients who did not respond to conventional empirical antibiotic treatment,” said Dr. Kaiser.

The researchers suggest that the timely use of reverse transcription-polymerase chain reaction assay to detect viruses, followed by appropriate treatment, could have a major impact on clinical care and outcome, particularly in patients at high risk for complications.

High-Risk Asthma Patients Reduce Medication Use After Hospitalization

In a study of high-risk patients with severe asthma who were hospitalized for serious exacerbations, researchers showed that within 7 days after discharge their use of prescribed inhaled corticosteroids and oral corticosteroids had fallen rapidly to approximately 50 percent of their prescribed dose.

Writing in the second issue for December 2004 of the American Thoracic Society’s peer-reviewed American Journal of Respiratory and Critical Care Medicine, Jerry A. Krishnan, M.D., of Johns Hopkins Asthma and Allergy Center at Johns Hopkins University in Baltimore, Maryland, along with seven associates, measured post-hospital adherence in 52 inner-city asthmatics by means of electronic medication monitors, self-report, canister weight (for inhaled corticosteriods), and pill counts (for oral corticosteroids). They found that electronically measured adherence to both types of corticosteroids had dropped to approximately 50 percent within 7 days of discharge.

“This investigation is the first to evaluate prospectively and objectively the use of medications after a severe asthma exacerbation,” said Dr. Krishnan. “We focused on corticosteorids because they are recommended for treatment of severe asthma exacerbations. Our results provide strong evidence that even under optimal conditions with free medications and intensive inpatient education, discontinuation of both inhaled corticosteorids and oral corticosteroids is common within 7 days of discharge home.”

The participants were almost exclusively African-American with 65 percent (34) being female and almost half having a history of near-fatal asthma. For the most part, they were unemployed and unmarried.

According to the authors, asthma affects from 15 to 20 million people in the U.S. The disease is characterized by chronic airway inflammation and regular episodes of respiratory symptoms. Although effective medical therapies are available, the illness results in severe asthma exacerbations, causing 465,000 hospitalizations and 5,000 deaths per year. Hospitalizations represent the single largest portion of the $12.7 billion per year in asthma-related expenditures.

“Poor outcomes are particularly common among African-American and inner-city patients,” said Dr. Krishnan. “Both hospitalizations and deaths related to asthma exacerbations are two to three times more likely in these groups than in other patient populations.”

The researchers said that self-report, canister weight and pill count had low levels of reliability in detecting poor adherence to medication use.

The investigators concluded that although adherence to inhaled corticosteorids and oral corticosteroids deteriorates within days of hospital discharge, it may not be recognized in a substantial portion of patients.

They advocate rigorous monitoring of adherence to therapy in clinical practice. Since patients with the worst asthma control were also the ones least likely to have used corticosteorids after discharge, they suggest that home visits from nurses be tried to improve outcomes, especially in high-risk asthma populations.

Loss of Bone Density with Inhaled Corticosteroids

Study participants with mild to moderate chronic obstructive pulmonary disease (COPD) who used 1,200 micrograms per day over 3 years of an inhaled corticosteroid, triamcinalon, in an attempt to slow lung function decline showed reduced bone density in both the lumbar spine and neck of the femur (thigh).

Writing in the second issue for December 2004 of the American Thoracic Society’s peer-reviewed American Journal of Respiratory and Critical Care Medicine, John E. Connett, Ph.D., of the Lung Health Study Coordinating Center at the University of Minnesota in Minneapolis, along with 11 associates, investigated bone metabolism in COPD in 412 subgroup participants involved in Lung Health Study II. All subjects, who were either current smokers or recent quitters, underwent bone mineral density scans of the hip and lumbar spine with dual-energy X-ray absorptiometry at the start of the study, after 1 year and at the end of year 3.

(In COPD, patients have persistent obstruction of the airways associated with either emphysema or chronic bronchitis. Following years of cigarette smoking, emphysema can enlarge the tiny air sacs in the patient’s lungs and destroy the walls. Persistent cough that produces sputum is the hallmark of chronic bronchitis in COPD.)

“Participants with COPD assigned to use 1,200 micrograms per day of inhaled triamcinolone for 3 years demonstrated reduced bone mass of both the lumbar spine and the femoral neck compared with participants assigned to placebo,” said Dr. Connett. “They showed a mean deficit of 1.78 percent in femoral neck bone mass density and 1.33 percent in lumbar spine bone mass density. These declines in bone mass density occurred in both men and women.”

Involved in the study were 107 males on inhaled corticosteroids; 109 men on placebo; 94 women on inhaled corticosteroids and 102 females on placebo. Their ages ranged from 55 to 57 years. Current smoking among the group ran from over 83 percent to over 90 percent.

The group’s adherence to inhaled corticosteroids was monitored by metered-dose inhaler canister weight during 3-month visits. Good adherence (more than 9 puffs per day over 3 years) was seen in 46.6 percent of the participants; 21 percent had satisfactory adherence (6 to almost 9 puffs per day), over 13 percent had less than satisfactory adherence (3 to less than 6 puffs per day) and the balance rated poor adherence.

“An important and unexpected finding of the study was the delay in the decline of bone mineral density, which was not apparent during the first year of the study,” said Dr. Connett. “There was little or no change in bone mineral density during the first year of the study, although bone calcium levels indicated that the metabolic effect of the inhaled corticosteroid began early. The losses in bone mineral density occurred during the second and third years of the trial.”

Consequently, the authors pointed out that a short-term study of the effect of inhaled corticosteorids on bone density could not be used to predict longer-term effects.

“The effect of continued smoking on the rate of decline in spine bone mineral density was significant in this study,” said Dr. Connect. “Other studies support this observation. Smoking prevalence is high in persons with COPD. Therefore, if inhaled corticosteroids are prescribed, smoking cessation should be encouraged for this reason among others.”

The investigators did not observe an increase in clinical indicators of osteoporosis during the study.

Searching for the Cause of Sarcoidosis

In a large study involving 10 clinical research centers throughout the United States, researchers found strong positive associations between the disease sarcoidosis and occupational exposure to insecticides in both agricultural and industrial settings, as well as with occupational exposure to “moldy” and “musty” environments.

Writing in the second issue for December 2004 of the American Thoracic Society’s peer-reviewed American Journal of Respiratory and Critical Care Medicine, Lee S. Newman, M.D., M.A., F.C.C.P., of the Division of Environmental and Occupational Health Sciences at the National Jewish Medical and Research Center in Denver, Colorado, along with 22 associates, studied 706 newly diagnosed sarcoidosis patients, together with an equal number of age-, race-, and sex-matched control subjects. They were trying to understand what environmental and occupational exposures were associated with the disease.

Although it has no known etiology, sarcoidosis is an illness in which abnormal clusters of inflammatory cells (granulomas) form in many organs of the body, especially in the lungs. In the lungs, the disease produces inflammation that can lead to scarring and cyst formation. These problems can cause coughing and shortness of breath, among other symptoms. In 70 percent of the cases, the liver is also affected.

“Although we did not identify a single, predominant cause of sarcoidosis, we identified several exposures associated with sarcoidosis risk, including insecticides, agricultural employment and microbial bioaerosols,” said Dr. Newman.

The authors noted that one of the strongest positive associations in the study was for occupational exposure to insecticides at any time before participation in the study, particularly in the 3 years preceding diagnosis. Although cases reported insecticide exposure in both agricultural and industrial setting, home use was not significantly connected to the disease.

“Agricultural workers potentially encounter a variety of high level exposures to chemicals, aerosolized particulates, including grains, bedding materials, silicates, animal proteins, insect proteins, fungi, bacteria, mycotoxins, and endotoxins,” said Dr. Newman.

The researchers pointed out that exposure to tobacco smoke at any time in the past seemed to have a strong negative association with sarcoidosis.

In an editorial on the study in the same issue, Anthony Newman Taylor, M.D., and Paul Cullinan, M.D., discussed new evidence for genetic influences on the development of sarcoidosis.

“To be informative, future epdemiologic studies investigating putative external causes of sarcoidosis will probably need to take indicators of genetic susceptibility into account,” wrote the authors of the editorial.