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Dr. Orens is Associate Professor of Medicine, Johns Hopkins Hospital, Division of Pulmonary and Critical Care.
Correspondence to: Jonathan B. Orens, MD, FCCP, Associate Professor of Medicine, Johns Hopkins Hospital, Division of Pulmonary and Critical Care, 600 North Wolfe St/Blalock 910, Baltimore, MD 21287
Lung transplantation may prolong survival and improve symptoms for patients with end-stage lung disease. However, many shortcomings plague this procedure, including a lack of donor organs, the need for lifelong immunosuppression, allograft rejection, limited long-term patient survival, the high financial costs of the surgery and subsequent care, and the constant threat of infection. Of the infectious complications, cytomegalovirus (CMV) stands out as an important agent causing significant morbidity and mortality.
The clinical spectrum of CMV includes three manifestations: infection, syndrome, and disease. CMV "infection" is defined by culturing the organism from any body tissue or fluid, while CMV "syndrome" is infection with symptoms. CMV "disease" is characterized by infection associated with symptoms and histologic evidence of tissue invasion. The risk of developing CMV disease depends on the serologic status of both donor and recipient. The greatest risk occurs in recipients who are CMV antibody negative and receive an organ from a CMV antibody-positive donor.1 Clinical manifestations depend on the site of tissue invasion (ie, lung, GI tract, eye, etc.).
In lung transplant recipients, CMV infection is associated with the development of obliterative bronchiolitis (OB), the pathologic manifestation of chronic allograft rejection.2 Because OB is the leading cause of long-term morbidity and mortality following lung transplantation,3 many strategies have been proposed to reduce risk factors for this problem. Several prophylactic regimens have been studied to prevent CMV infection. These include IV and oral ganciclovir, IV CMV hyperimmune globulin, and matching CMV-naïve recipients with CMV-negative donors.4 5 However, the "best" prophylactic strategy in lung transplant recipients remains controversial. Although several studies document the effectiveness of IV ganciclovir in preventing CMV infection following lung transplantation, the appropriate duration of therapy with ganciclovir either as a single agent or in combination with CMV hyperimmune globulin remains unclear. Furthermore, the cost-benefit ratio of prolonged prophylaxis with ganciclovir has not been well described. Most importantly, the impact of CMV prevention on the long-term outcome of lung transplant recipients remains unknown.
In this issue of CHEST (see page 1265), Gerbase and colleagues add to our options by describing the costs and outcomes of long-course ganciclovir in lung transplant recipients. IV ganciclovir was administered for 20 weeks to 22 patients at risk for CMV infection. The course of 20 weeks was chosen to cover the period of maximal immunosuppression. Outcomes assessed included evidence of CMV infection, therapy-related complications, and the overall cost of this treatment. These results were compared to results of previously reported 12-week prophylaxis protocols. As anticipated, the authors found a decreased incidence of CMV infections during the longer course of prophylaxis. This was not associated with significant side effects or complications, and there was no evidence of increased resistance to ganciclovir when the drug was required for subsequent infections. Although this study revealed a decreased incidence of CMV infection with 20 weeks of ganciclovir, the authors were unable to show a cost advantage for this strategy. They noted that the cost of long-duration prophylaxis was higher than the cost of treating the few extra cases of CMV infection prevented by this protocol. The additional costs of treating specific complications associated with this regimen were not presented in the analysis. Although the results of this study are interesting, they must be interpreted with caution since the comparisons were made to other published trials without the benefit of a contemporaneous control group. Thus, we have a therapy that may be clinically efficacious for preventing CMV infection but of unclear financial benefit.
Since CMV infection is associated with the development of OB, it makes intuitive sense that prevention of this infection in lung transplant recipients is important. However, studies to date only show an association of CMV with OB, but not causality. Whether prevention of CMV will ultimately reduce the incidence of OB remains unclear. Furthermore, the cost of this extra therapy in relation to long-term outcome (morbidity and mortality of CMV infection and subsequent development of OB) may not be justified.
So should lung transplant patients at risk for CMV infection receive prophylaxis with IV ganciclovir for 12 or 20 weeks? This question is difficult to answer with a small study from a single center. This and other questions, such as the utility of oral ganciclovir, or the combination of ganciclovir with CMV hyperimmune globulin, will only be answered by prospective clinical trials that enroll sufficient numbers of patients. Given the small number of patients at individual lung transplant programs, large trials are only feasible through multicenter networks. The success of this approach has been demonstrated by other cooperative groups, such as the National Institutes of Health-sponsored ARDS network. Until such collaborations are established in the transplant community and studies are completed, we can only speculate about the best therapies for our patients.
References
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