Press Release

June 2007

Treatment Outcomes of Patients with HIV and Tuberculosis

In a retrospective study of 700 patients with culture-positive tuberculosis (TB), relapse rates were found to be significantly higher in HIV-infected patients compared to HIV-uninfected patients following a rifamycin-based regimen. Furthermore, TB relapse rates were higher in HIV-infected patients who received intermittent or standard 6-month therapy when compared to those receiving daily or longer treatment..

The results appear in the first issue for June 2007 of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

Payam Nahid, M.D., M.P.H., of the University of California, San Francisco General Hospital, and eight associates reviewed TB cases reported to the San Francisco Tuberculosis Control Program from January 1, 1990, through December 31, 2001. 

As a rationale for their study, the researchers state that the optimal duration of TB therapy in HIV-infected subjects is unknown and may differ from HIV-uninfected individuals.

According to the authors, the current preferred regimen for treating drug-susceptible TB in HIV-uninfected patients is a 6-month, rifamycine-based regimen that includes pyrazinamide during the first two months. Current guidelines for the treatment of TB do not distinguish between those infected with the virus that causes AIDS and those who are uninfected in terms of the optimum length of treatment when using rifamycine.

“Standard 6-month therapy may be insufficient to prevent relapse in patients with HIV,” said Dr. Nahid.

The TB relapse rate for HIV-infected patients was found to be  6.6 percent versus  0.8 percent in uninfected/unknown patients. This finding was in contrast to other studies that did not find any significant difference between HIV-infected and HIV-uninfected/unknown patients. However, this finding was corroborated by a similar study that also used molecular genotyping as a relapse indicator. 

HIV-infected patients who received 6 months of rifamycin-based TB treatment or who were treated intermittently (one to three times per week), were four times more likely to have a reoccurrence than those r who took their medicine daily or who were treated for longer periods.

The study also found that the use of highly active antiretroviral therapy (HAART) during TB treatment was associated with a faster Mycobacterium tuberculosis negative culture conversion, and an improved survival rate. Prior studies by others have shown HAART treatment beneficial in preventing TB in HIV-infected individuals, but reported no beneficial TB treatment outcomes. 

HIV-infected patients were significantly more likely to develop drug resistance (4.2 percent in HIV-infected versus 0.5 percent in HIV-uninfected) to rifampin , and to experience adverse reactions to TB regimens. 

The investigators noted that there is a need for large randomized clinical trials to establish the optimal duration for TB therapy in HIV-infected patients, and the timing of HAART treatment in patients with HIV-related TB. 

According to an editorial commenting on the research in the same issue of the journal, future HIV-related TB treatment regimens and relapse studies should broaden their focus to include rates of acquired drug resistance. The editorial cites a report published in the Lancet of an extensively drug resistant TB strain found in a HIV co-infected South African patient as particularly worrisome. 

Citing the journal article, the editorialists also cast the HAART findings (quicker reduction of mycobacterial burden) as relevant in deterring TB drug resistance. They suggest that short-course, intermittent regimens may be necessary in areas where resources are limited, and that additional research on regimens (including the use of secondline drugs) suitable for field use must continue.

Study Explains Why Patients with Obstructive Sleep Apnea Are At Higher Risk for Cardiovascular Disease

Researchers have found that patients with obstructive sleep apnea (OSA) have higher levels of a type of dead cells (apoptotic cells) from the lining (endothelium) of their blood vessels circulating in their bloodstream than people who do not have OSA. The finding may help explain why those with OSA are at higher risk for cardiovascular disease (CVD).

According to the researchers, “levels of apoptotic endothelial cells are correlated with abnormal endothelial vasorelaxation, a precursor of atherosclerosis-related events,” and that treatment with nasal continuous positive airway pressure (nasal CPAP) can reduce levels of circulating apoptotic endothelial cells in OSA patients.

These findings appear in the June 1 issue of the American Journal of Respiratory and Critical Care Medicine, a publication of the American Thoracic Society.

Lead researcher Ali El Sohl, M.D., M.P.H., said the study was done “to explain why patients with OSA had a higher risk of cardiovascular morbidity and mortality.” He added that “the increased levels of circulating apoptotic endothelial cells would mean less production of nitric oxide that is crucial to artery vasodilatation. The less nitric oxide, the higher potentially is the risk of hypertension and acute heart attack. CPAP treatment would likely restore the physiologic function of the lining of the blood vessels.”

For the study, 14 men with OSA were recruited from the Sleep Clinic at the Erie County Medical Center, a hospital affiliated with the University of Buffalo, in New York. The patients were nonsmokers without any coexisting diseases, and they did not use medications. Ten healthy nonsmokers were recruited from a wellness clinic at the same hospital to serve as controls.

The OSA patients were given polysomnographic testing to verify the diagnosis. This involved evaluating brain waves, electrical activity of muscles, eye movements, breathing rates, blood pressure, blood oxygen saturation and heart rhythm, as well as direct observation of patients during sleep.

The men were comparable in age, blood pressure and metabolic profiles, but the OSA patients had a higher body–mass index, though the difference was not statistically significant. The OSA patients also had more apoptotic cells circulating in their bloodstreams and had vasomotor dysfunction.

The OSA patients were given nasal CPAP treatment for eight weeks. Use of CPAP ranged from four to seven hours per night. At the end of the study, the patients’ vascular reactivity and circulating endothelial apoptotic cells were reevaluated and compared to the controls.

There were no significant differences in body measurements and metabolism in the men from baseline, but most of the patients who received CPAP had reduced circulating endothelial apoptotic cells and had marked improvements in brachial artery vascular reactivity.

The study had some limitations. Women were excluded to keep the study population homogeneous. Said Dr. El Sohl, “a follow-up study would be required to look at this phenomenon in women and in particular the hormonal effect on apoptosis in OSA.” The researchers “did not perform a thorough assessment for excluding coronary disease.”

More research is needed before these results can be applied clinically, according to Dr. El Sohl. While CPAP is currently used to treat OSA, looking for circulating apoptotic endothelial cells as a marker to fine-tune the therapy is one potential application. This may potentially reduce OSA patients’ risk of CVD. Dr. El Sohl mentioned that statins, angiotensin converting enzyme inhibitors, and vitamin C reduce enthothelial apoptosis, but it is not known if these agents could help patients with OSA.

According to Dr. El Sohl, further research will investigate if the improvements in vascular function correlate with actual improvements in the sleep patterns of patients with OSA.

Premature Vascular and Bone Changes Occur in COPD Patients

Researchers in the United Kingdom have found that patients with COPD, or chronic obstructive pulmonary disease, have greater arterial stiffness. The researchers also found that those COPD patients with osteoporosis, a common complication of the respiratory disease, had even greater arterial stiffness. These premature signs of aging may explain why COPD patients are at greater risk for cardiovascular disease.

Their research results appear in the second issue for June 2007 of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

Dennis J. Shale, M.D., of the Department of Respiratory Medicine at Cardiff University in the United Kingdom, and eight associates studied 75 clinically stable COPD patients who had various levels of airway obstruction, and 42 smoker or ex-smoker control subjects who did not have cardiovascular disease or COPD.

All participants in the study underwent spirometry to determine lung function, had their aortic pulse wave velocity measured along with another indirect measurement of arterial stiffness, took bone mineral density tests of their spine and hips, and had their blood sampled for inflammatory mediators.

COPD, the fourth leading cause of death in the United States and the world, involves persistent obstruction of the airways caused by emphysema or chronic bronchitis. In most instances, both conditions result from years of smoking cigarettes.

Though the exact link between COPD and arterial stiffness was not identified by the researchers, they did find elevated levels of inflammation markers in those with COPD. Other researchers have demonstrated that inflammatory processes are involved in arteriosclerosis, the cardiovascular disease commonly known as “hardening of the arteries.”  

There is also evidence that inflammation plays a role in osteoporosis. In this study, patients with osteoporosis had the greatest arterial stiffness.

“Increased arterial stiffness was present in patients with COPD over a wide range of severity of airway obstruction and was greatest in those with osteoporosis,” said Dr. Shale. “Our findings indicate vascular changes predictive of cardiovascular disease occur and remain undetected in mild or early lung disease and may underlie the excess cardiovascular risk in COPD.”

The researchers noted that age was an important factor influencing arterial stiffness, a problem that reflects the increasing rigidity of the aortic artery. The average age of the study cohort was 63.

“The increased arterial stiffness in patients within each decade is similar to changes seen in type I diabetes mellitus and suggest that age-related vascular changes occur prematurely in COPD, as compared with disease-free individuals,” said Dr. Shale. “However, unlike diabetes mellitus, the risk of premature excess cardiovascular disease in COPD is not appreciated.”

At the beginning of the study, none of the participants had a history of heart disease or possessed cardiovascular symptoms. Of the 75 COPD patients studied, 18 had osteoporosis, while among the controls, only two individuals suffered from abnormal loss of bony tissue. Also, those who had osteoporosis of the hip had a greater aortic pulse wave velocity than those without the hip problem.

In an editorial on the study in the same issue of the journal, Claus Vogelmeier, M.D., and Robert Bals, M.D., of Philipps-University, Marburg in Germany, said that the study provides “important new information” on the relationship of cardiovascular disease and COPD.

They noted that aortic pulse wave velocity—considered the most clinically relevant measure of arterial stiffness—has been shown to predict cardiovascular outcome in various populations. The authors also highlighted the study’s correlation of pulse wave velocity and COPD severity as important.

“The more severe the flow limitation, the higher the pulse wave velocity values,” wrote Drs. Vogelmeier and Bals. “Thus, COPD may induce arterial stiffness, which in turn may promote vascular remodeling, thickening of arterial walls and plaque formation. The process may start in the early stages of COPD and worsen with the decline of lung function.”

The editorialists also commented on osteoporosis, which was the second focus of the study: “The authors found that bone mineral density was lower in patients with COPD than in control subjects. Among the patients with COPD, 32 percent had osteoporosis and this was not restricted to those with severe COPD.”

Although the editorialists termed the relationship between COPD and osteoporosis in the study was not “novel,” they noted that those patients with osteoporosis also had the greatest arterial stiffness values—a new finding.

They concluded that future research is necessary to uncover further relationships between this study’s findings and accelerated aging processes in COPD, which might then be avoided.

Elevated Pepsin Levels May Lead to Rejection of Lung Transplants

Researchers in the United Kingdom have demonstrated that high levels of pepsin, a digestive enzyme that is a marker for gastric aspiration, are associated with acute rejection of a lung transplant. This research provides further evidence that lung rejection may be caused by factors other than alloimmunity, the attack the body mounts to protect itself against “foreign” cells.

“We think gastric aspiration [the taking of stomach fluids into the lung] may contribute to an overall injury to the transplanted lung,” said Chris Ward, Ph.D., lead author of the study. “This pattern of injury may be similar to rejection or increase the risk for further rejection.”

Dr. Ward, of Newcastle University, and the other researchers reported their findings in the June 15, 2007, issue of American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

The study included 36 lung transplant recipients, 17 subjects with normal lung function but unexplained cough who served as “disease controls” for the study, and 4 normal, nonsmoking control subjects. The researchers determined pepsin levels in all the subjects using bronchoalveolar lavage (BAL)

“Our primary finding was that, compared with control subjects,” wrote the researchers, “BAL pepsin levels were elevated in stable lung transplant recipients, subjects with acute rejection, and subjects with bronciolitis obliterans [a common manifestation of lung transplant rejecton]. Our secondary finding was that the highest levels of pepsin appeared in the transplant recipients with clinically significant acute rejection (grade A2 or greater).”

These findings support the growing recognition that gastroesophageal reflux (GER) is a potential cause for post-transplant lung injury and other airway and lung diseases.  Although none of the transplant patients were formally evaluated for GER, nearly all were treated with acid suppression medications, which is standard therapy after lung transplantation.

Despite those medications, known as proton pump inhibitors, the researchers found evidence of gastric aspiration. “It is important to recognize that proton pump inhibitors do not prevent reflux per se, but rather act to cut down on acidic reflux,” the researchers noted.  They also noted, that in addition to the damage that might be done to the new lung by acid reflux, pepsin is not targeted by these drugs and may be a separate cause of lung injury.

The researchers reported that the “disease control” group—those with normal lung function, but unexplained cough—did not have pepsin in their lungs, even when 10 of 17 were diagnosed during the study as having gastroesophageal reflux disease (GERD). “A diagnosis of GERD does not mean that patients are refluxing out of the esophagus and hence aspirating,” they explained. “Even if the refluxate reaches the upper airway, it is almost certainly cleared by a hyperactive cough reflex.”

In their article, the researchers note ongoing studies being done at Duke University that appear to show lung transplant patients who undergo fundoplication, a surgical procedure that strengthens the valve between the stomach and the esophagus, before the transplant have longer survival rates and delayed onset of bronchiolitis obliterans syndrome than those who do not. 

If fundoplication is confirmed as a useful prophylaxis in preventing lung rejection, they write, “markers of aspiration may contribute to identifying patients who might derive clinical benefit.”

This study was supported by fellowships from Newcastle-upon-Tyne Hospitals Special Trustees a European Society Fellowship, and the Medical Research Council of the United Kingdom, as well as a grant-in-aid from GlaxoSmithKline.

New Statement on Pulmonary Function Testing in Children

The ATS and European Respiratory Society (ERS) published a new statement on pulmonary function testing in preschool children. The document, which appears in the June 15 issue of the American Journal of Respiratory and Critical Care Medicine, addresses the clinical, technical and epidemiological implications of pulmonary function testing in children aged 2 to 6.

“Preschoolers present a number of special challenges,” said Stephanie Davis, M.D., co-chair of the 33-member ATS/ERS working group that produced the guidelines. “The children are generally too old to sedate, as is done with infants, and less cooperative than an older child. However, investigators have demonstrated that preschool lung function testing is now feasible.”

The working group hopes its recommendations—which focus on spirometry, tidal breathing measurements, the interrupter technique, forced oscillation, gas washout techniques and bronchial responsiveness tests—will serve as a resource for healthcare professionals and facilitate good laboratory practices by providing guidelines on how to perform the various techniques and how to interpret the measurements. 

“Evaluating lung function in this age group is important, not only for clinical reasons, but also due to the considerable growth and development of the respiratory system that occurs with associated changes in lung mechanics,” said Dr. Davis. “The working group envisions that these guidelines will help facilitate multi-center collaboration using these pulmonary function testing techniques,” said Dr. Davis.

To read the statement in full, please visit www.thoracic.org/sections/publications/statements/index.html.