Affiliations: Baltimore, MD
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.2Because OB
is the leading cause of long-term morbidity and mortality following
lung transplantation,3many 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
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.
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