New test detects BOS in lung transplant patients

Individuals developing a debilitating, life-threatening condition that causes scar tissue to build up in the lungs and chokes the ability to breathe may undergo a lung transplant. After a year of lung transplantation more than half recipients apparently suffer from bronchiolitis obliterans syndrome (BOS). Experts from the University of Michigan have now developed a diagnostic tool for anticipating BOS, so physicians can intervene earlier and eventually provide life-saving treatments.

During the study it was registered that patients with a high number of stem cells in their lungs six months after transplantation face elevated chances of being diagnosed with BOS as compared to those with lower counts. It was mentioned that cells may be a hallmark in both human repair as well as disease. Scientists were supposedly unable to gauge the precise link between the mesenchymal stromal cells and BOS. It is known that spikes within the cell counts can be witnessed shortly after transplantation as the body responds to the injury.

Even though the levels seemingly taper off, a second rise of cell counts after about six months raises the likelihood of BOS. Vibha Lama, M.D., M.S., an assistant professor of pulmonary and critical care medicine at the University of Michigan Medical School, and colleagues believe that the findings can be extremely helpful for those suffering from various types of lung disease, including idiopathic pulmonary fibrosis (IPF).

The study appears online and will be published in the American Journal of Respiratory and Critical Care Medicine.

From: HealthJockey.com

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ISHLT 2009: Azithromycin for Bronchiolitis Obliterans Prophylaxis in Lung Graft Patients Gets Mixed Reviews

From Medscape Medical News

Neil Osterwell

April 24, 2009 (Paris, France) — In the never-ending search for therapies to prevent chronic lung allograft rejection, macrolide antibiotics, such as azithromycin, show promise, but only in about half of patients, report the authors of 2 European studies here at the International Society for Heart and Lung Transplantation 29th Annual Meeting and Scientific Sessions.

The first interim analysis from a randomized, double-blind trial comparing azithromycin and placebo showed that about half of patients with established bronchiolitis obliterans syndrome (BOS) had a response to azithromycin, reported Robin Vos, MD, a fellow in pathophysiology at Katholieke Universiteit and University Hospital Gasthuisberg, in Leuven, Belgium.

In addition, the efficacy of the drug appears to be related to grade of BOS, with close to half of patients with BOS grade 0p responding compared with only about 7% of patients with BOS grades 1 to 3, reported Federica Meloni, PhD, MD, from the Department of Hematological, Pneumological, and Cardiovascular Sciences, Respiratory Disease Section, at the University of Pavia, in Italy.

The results from the Belgian study support evidence of both an inflammatory and a fibroproliferative component to BOS, with the former likely to respond to azithromycin (Zithromax, Pfizer) and the latter unlikely to respond, the Belgian researchers suggested.

"We found an inflammatory phenotype with mainly neutrophils in the airways, and we found a phenotype with a more rapid decline in lung function later on, after transplantation, without cellular inflammation. We could clearly demonstrate that only those patients who have a high neutrophilia, without being infected, will respond to azithromycin, whereas the patients who don't have BAL [bronchoalveolar lavage] evidence of neutrophilia do not respond. So neutrophilia is really the driving force for an effect of azithromycin," said senior author Geert Verleden, MD, professor of immunology at Katholieke Universiteit, in an interview with Medscape Transplantation.

In the study, lung-transplant patients treated from September 2005 through December 2007 were randomized at discharge to receive either placebo or azithromycin 250 mg per day 3 times a week in addition to conventional therapies.

The primary study end points were BOS-free survival and overall survival at 2 and 3 years after lung transplantation. Under the protocol, patients who develop grade 1 or higher BOS are withdrawn from the study, started on open-label azithromycin, and are followed with forced expiratory volume at 1 second (FEV1) and airway inflammation studies.

At the most recent follow-up (2.3 years), 23 of the 83 enrolled patients discontinued because of the development of grade 1 or higher BOS, 5 had died (not from obliterative bronchiolitis), and 7 had dropped out because of adverse gastrointestinal events, suture problems, malignancy, or sepsis; 3 of these patients have since died.

Of the 23 who withdrew from the study as a result of BOS, 1 died and 22 were started on open-label azithromycin. Of this group, 12 were responders to azithromycin and 10 were nonresponders.

The researchers found that patients with airway neutrophilia in BAL at 3 months showed a trend toward the development of BOS (P = .05; correlation coefficient [r], 0.20). Azithromycin responders tended to have an earlier diagnosis of BOS than nonresponders (236.6 vs 322 days, respectively; P = .03), but the responders had a positive correlation with improvement in FEV1 after starting on azithromycin (P = .04; r = 0.6).

In the second study, Dr. Meloni and colleagues looked at the effects of 12 to 30 months of azithromycin therapy on 62 lung-transplant recipients, 43.5% with grade 0p BOS, 34% with grade 1 BOS, 8.1% with grade 2 BOS, and 14.5% with grade 3 BOS. As in the Belgian study, the patients received azithromycin 250 mg 3 times each week.

Patients with at least 12 months of follow-up (53 of the 62 patients) were stratified by change in FEV1 as being either responders (increase of greater than 10% in FEV1), having stable disease (change up or down within 10% of baseline), or nonresponders (decline of greater than 10% in FEV1).

There were a total of 12 responders, 10 of whom had grade 0p BOS, and 2 of whom had grade 1 to 3 BOS. Among patients with stable disease, 10 had grade 0p BOS and 21 had grade 1 to 3 BOS. Of the nonresponders, 2 had grade 0p BOS, and 8 had grade 1 to 3 BOS. The differences among the groups in the distribution of grades, on the basis of the chi-squared test, were statistically significant (P = .0045).

Among 23 patients with nearly 3 years of follow-up, the 7 nonresponders continued to show a decline in graft function, as measured by FEV1. Of patients with stable BOS, only 1 had a decline in function at 30 months, with a significant decline in FEV1 over baseline. Of the 8 responders, 7 showed improvement in FEV1 after starting on azithromycin, but 2 had a decrease in graft function at the last follow-up.

When they looked at peripheral blood cell parameters as possible indicators of efficacy, they found no significant differences, except for a significant decrease in the percentage of neutrophils at 12 months in the responders compared with the non responders, Dr. Meloni said. They also found that azithromycin significantly reduced proinflammatory chemokines, irrespective of treatment response.

The researchers concluded that chronic azithromycin therapy could result in long-term stabilization or improvement in graft function, but that this effect is highly dependent on disease grade, with 43% of patients with grade 0p disease having a response, compared with only 6.6% of those with grade 1 to 3 BOS.

A lung-transplant specialist who was not involved in the studies but who attended the session where they were presented said that the reason azithromycin is effective in some patients but not others needs to be elucidated.

"Are you dealing with 2 different diseases, 2 stages of a single disease, or . . . 2 different diseases coexisting in the same patient, like rheumatoid arthritis and osteoarthritis?" Marshall I Hertz, MD, professor of medicine at the University of Minnesota, in Minneapolis, wondered in an interview with Medscape Transplantation.

"A lot of us are working on biomarker development to get reproducible markers of one or the other phenotype so that you can measure biochemically something that we're not measuring very clinically. What we're doing right now is like treating hypertension by measuring strokes, when patients reach something very far down the road, when you'd really like something like a blood-pressure cuff."

Dr. Vos, Dr. Meloni, and Dr. Hertz have disclosed no relevant financial relationships.

International Society for Heart and Lung Transplantation (ISHLT) 29th Annual Meeting and Scientific Sessions: Abstracts 153 and 155. Presented April 23, 2009.

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Popcorn Workers Lung Victim, Wife Awarded $7.5 Million

Popcorn Lung is the name given for Bronchiolitis Obliterans that occurs in workers in factories that use diacetyl in the production of "buttery" popcorn. I understand that diacetyl is no longer being used but I think I'll stick with plain popcorn and real butter.

NewsInferno.com

A jury has ruled in favor of a plaintiff in a Popcorn Workers Lung lawsuit. According to The Associated Press, the federal jury in Iowa yesterday ordered a flavorings manufacturer to pay the victim - who died just a day before of complications from Popcorn Workers Lung - and his wife $7.5 million for causing his injuries.

Popcorn Workers Lung is a potentially life threatening ailment, for which the only cure is a lung transplant. The disease - also known as bronchiolitis obliterans - has been linked to diacetyl, a chemical used to give microwave popcorn and other snack foods a buttery flavor.

In 2003 and 2004, the National Institute on Occupational Safety and Health found an association between diacetyl and the development of Popcorn Workers Lung among hundreds of workers at six Midwestern popcorn factories. In April 2007, the Centers for Disease Control reported that workers at food flavoring factories, as well as popcorn plants, were at risk for the disease.

Since the link between diacetyl and Popcorn Workers Lung was established, hundreds of stricken workers have filed lawsuits against flavorings manufacturers. According to The Associated Press, more than 300 other cases are pending around the country, and verdicts as high as $20 million have been awarded in previous cases.

According to The Associated Press, 69-year-old Ronald Kuiper and his wife had filed suit in 2006 against four companies that made popcorn flavoring used at the American Pop Corn Co. Kuiper had worked at American Pop Corn Co. in Sioux City as a butter flavor mixer since the 1990s, the Associated Press said. All of the companies, with the exception of Givaudan Flavors Corp. of Cincinnati, had resolved the Kuipers’ claims.

The Iowa jury agreed with the Kuipers that diacetyl from Givaudan Flavors’ butter flavoring had caused Ronald Kuiper’s illness. According to the Associated Press, Ronald Kuiper was awarded $2 million for future pain and suffering and $750,000 for past pain and suffering; $2 million for future loss of function of the mind and body and $750,000 for past loss of function of the mind and body; $500,000 for future medical expenses and $50,000 for past medical expenses. The jury also awarded $1 million for future loss of spousal consortium and $500,000 for loss of past spousal consortium to Ronald Kuiper’s wife.

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Antibiotic Reverses Airflow Obstruction in Lung Transplant Recipients

News from Medscape Pulmonary Medicine

NEW YORK (Reuters Health) Sept 15 - The long-term survival of lung transplant recipients is limited by the development of bronchiolitis obliterans syndrome (BOS), a condition thought to be irreversible, but UK researchers suggest that the drop in lung function can, in fact, be reversed through treatment with azithromycin (Zithromax).

Encouraging findings from a pilot study, led Dr. Paul A. Corris, from The Freeman Hospital in Newcastle upon Tyne, and colleagues to retrospectively evaluate the effects of azithromycin on lung function in 20 lung allograft recipients with established BOS.

Azithromycin was introduced at a mean of 82 months after transplantation, according to the report in the September issue of the American Journal of Respiratory and Critical Care Medicine. All of the subjects were treated with immunosuppressive regimens that included a cell-cycle inhibitor, oral corticosteroids, and a calcineurin inhibitor.

After 3 months of treatment, azithromycin therapy was tied to a 110 mL median increase in FEV1 (p = 0.002), the authors point out. Moreover, the majority of patients who experienced an early benefit showed sustained improvements at up to 11 months.

"This case series," the authors observe, "confirms the benefit of azithromycin in not only halting, but reversing the declining lung function seen in patients with BOS."

"Low-dose macrolides," they conclude, "offer a new and exciting therapeutic strategy for the treatment of progressive BOS, and further clinical and translational mechanistic studies are required."

Am J Respir Crit Care Med 2005;172:772-775.