Thanks to a recent pilot study at Johns Hopkins, Jonathan Orens, M.D., medical director of Lung Transplantation and associate professor of medicine at Hopkins, has reason to feel more optimistic about a major lung transplant complication. Following lung transplantation, chronic allograft rejection remains the leading cause of long-term morbidity and mortality. This problem is usually recognized by progressive loss of lung function and histologically appears as bronchiolitis obliterans, progressive scarring around small air passageways. The term brochiolitis obliterans syndrome (BOS) is applied when the diagnosis is established based on falling lung function without tissue confirmation.   Using the macrolide antibiotic azithromycin in six lung transplant recipients (250 milligrams orally three times per week for a mean of 13.7 weeks) to treat BOS, Orens and fellow researchers discovered significant  improvement in pulmonary function in five of these patients. The data suggest a potential role for maintenance macrolide therapy in the treatment of BOS in lung transplant recipients. "We believe these results may have immediate clinical impact, since to date, no other pharmacologic agent has improved lung function in BOS," says Orens.   Lung rejection following transplantation is hardly uncommon. And although short-term survival is improved with transplantation, long-term survival is limited because of the common development of BOS, which affects 12 percent 18 percent of lung transplant recipients at one year and up to 75 percent of individuals by five years.   Nationally, the five-year survival rate following lung transplantation has remained at 45 percent, although Hopkins reports a 58 percent five-year survival rate post transplant. "If not for this single important problem, the long-term survival after lung transplantation would be dramatically better," says Orens.    The maintenance azithromycin study is part of a much larger project in the "HOPGENE" Program in Genomics Genomics Application (PGA), a comprehensive effort to demystify the causes of chronic rejection and other lung diseases. Hopkins received a generous grant to study eight specific lung diseases, allowing researchers to study the genes associated with chronic rejection. (...)  "This study allows us in rapid fashion to detect which genes may be up- or downregulated in association with the disease process. Through such gene characterization, we may ultimately understand the basic mechanism(s) behind BOS and some of the other diseases that are currently under study here at Hopkins," says Orens.    Jonathan Orens, M.D. To see if there is rejection, Orens and his associates use a test called bronchoscopy to obtain tissue and fluid from the transplanted lung. By utilizing some of this fluid and tissue for research purposes, Orens and his colleagues can compare the genes present in samples from the pre- and post-rejection state. "Once we identify the genes responsible for chronic rejection, it will be much easier to find ways to regulate the disease," he notes.   With support from the "HOPGENE" PGA, more investigative trials using genomic tools will soon emerge. Precise intervention targeting will become the norm as we enter a new era in biomedical research. Clearly, Orens is determined to find solutions for chronic rejection in lung transplantation. In his words, "Chronic rejection is the Achilles' heel of lung transplantation. We've got to figure this out or we will never improve the survival outcomes of lung  transplantation." For more information about the azithromycin study, see Gerhardt, SG, McDyer, JF, Girgis, RE, Conte, JV, Yang, SC and Orens, JB. "Maintenance Azithromycin Therapy for Bronchiolitis Obliterans Syndrome: Results of a Pilot Study," AJRCCM, Winter 2002. For information on HOPGENE