CMV - 2

Cytomegalovirus and Lung Transplantation

AbstractCytomegalovirus (CMV) infection remains a serious problem in lung transplant recipients. Development of potent oral antiviral agents, molecular techniques for the detection of infection and its response to therapy and the emergence of isolates with antiviral resistance have had significant impacts on the approach to CMV in these patients. CMV has been associated with, though not causally linked to, the development of acute and chronic rejection. Potential immunomodulatory effects of CMV may predispose patients to infection with opportunistic organisms or the development of post-transplant lymphoproliferative disease. Cytomegalovirus increases the costs associated with solid organ transplants by 40-50%

Risk of CMV Infection and Disease in Lung Transplant Recipients -The incidence of CMV infection and disease following lung transplantation in the postganciclovir era ranges from 30 to 86% with an associated mortality rate of 2-12%. Innate host immunity, the type of organ transplanted with its viral burden, viral coinfection and the net state of immunosuppression affect the risk of developing CMV infection. The Papworth group showed that seronegative heart-lung recipients of CMV-positive organs are at the highest risk of developing severe, sometimes fatal, disease. Lung transplantation involves the transfer of large amounts of lymphatic tissue harboring greater amounts of latent CMV than other organs, theoretically increasing the risk and severity of CMV infection.Therefore, some authors recommend that all lung transplant recipients should be considered high-risk. Coinfection with other betaherpesviruses (HHV-6 and HHV-7) with inherent immunomodulating properties enhances CMV replication. Use of antilymphocytic antibodies for induction therapy or treatment of steroid-resistant rejection increases the rate of CMV reactivation.

CMV and Acute Chronic Allograft Injury -The relationship between CMV and allograft injury is bidirectional. Cytokines, chemokines and growth factors are induced in response to both CMV infection and rejection, resulting in activation of the vascular endothelium and inflammatory cells. It is not surprising that CMV reactivation occurs in response to acute rejection. Intensified immunosuppression to treat rejection can amplify viral replication

Strategies to Prevent CMV Infection -Three potential mechanisms of CMV infection have been recognized: transmission by the donor organ, blood products or reactivation of latent virus in the recipient. Based on these potential mechanisms of infection, four strategies to prevent CMV infection have been utilized: matching the donor-recipient pair by CMV serologic status, use of CMV-negative blood products, antiviral agents to suppress viral replication and immunoglobulin preparations to provide passive immunization. Therefore, it seems prudent to strictly adhere to use of CMV-negative blood products in seronegative lung transplant recipients. Seromatching recipients and donors may be ideal but is impractical given the current shortage of donor organs. Furthermore, seromatching, while perhaps desirable, is most likely no longer necessary to prevent the direct effects on morbidity and mortality given the efficacy of antivirals and immunoglobulins in decreasing the incidence and severity of primary CMV infections.  Many retrospective or case-controlled series have demonstrated the benefit of antivirals or immunoglobulin preparations alone or in combination in decreasing or delaying the onset of CMV infection following lung transplantation.

Monitoring Techniques - Rapid and accurate diagnostic tests are critical for the appropriate management of CMV following lung transplantation. Qualitative or quantitative polymerase chain reaction (PCR)  Weinberg et al. evaluated serial CMV blood cultures, antigenemia, and qualitative and quantitative plasma PCR tests for their value in predicting CMV disease and for guiding preemptive therapy after lung transplantation. They found that PCR and antigenemia tests were the most effective predictors of symptomatic CMV infections and the response to therapy.

Prophylaxis of CMV Infection - Before the development of effective antiviral agents, CMV caused illness in the majority of lung transplant recipients, and primary infection in D+/R- recipients was severe and often life-threatening. Following the development of ganciclovir it soon became clear that the acute morbidity and mortality of CMV infections could be controlled with therapeutic courses of intravenous ganciclovir..While it is difficult to summarize and compare the published reports on CMV prophylaxis in lung transplant recipients, as they utilized different lengths of prophylaxis in patients receiving different immunosuppressive strategies based on the year of transplant, the published studies can be categorized as those employing ganciclovir or immunoglobulin monotherapy or combination strategies.Ganciclovir MonotherapyEarly studies found that short courses of prophylactic ganciclovir (2-3 weeks) delayed the onset of CMV infection but had limited efficacy in preventing CMV infection or disease.Studies employing extended prophylactic therapy with ganciclovir for 6-12 weeks suggested that prolonged ganciclovir infusion decreased the incidence of CMV infection and disease, however, the benefit was lost when patients were followed more than a year post-transplant. These reports point out the importance of long-term follow up when comparing published reports and confirm that ganciclovir monotherapy delays rather than prevents the onset of CMV infection following lung transplantation..An alternative strategy to prolonged infusion of ganciclovir is the use of oral ganciclovir. Bhorade et al. found that 12 weeks of oral ganciclovir (3 g per day) decreased the incidence of CMV to levels similar to those seen with intravenous ganciclovir. Cytomegalovirus disease developed in 10/34(29%) lung transplant recipients with an average onset of 4 months. However, 24% of the patients developed asymptomatic, breakthrough viremia. While none of these patients developed CMV disease, this breakthrough viremia may predispose to or be a marker of the emergence of ganciclovir resistance.The availability of valganciclovir, which provides antiviral exposure similar to intravenous ganciclovir (comparable AUCs), obviates the need for prolonged intravenous access and allows prolonged high-level antiviral exposure. Valganciclovir was at least as effective as oral ganciclovir in preventing CMV infections and produced more complete viral suppression without the development of antiviral resistance in solid organ recipients.When the published results of intravenous ganciclovir monotherapy are pooled, the incidence of CMV infection and disease remains 59% and 42%, respectively  While differing lengths of prophylaxis and types of immunosuppression were employed in these studies, taken in sum, these data suggest that while ganciclovir decreases the incidence of CMV infections compared with placebo or oral acyclovir, there is still a significant incidence of CMV infection following lung transplantation with ganciclovir monotherapy strategies.

Combination Prophylaxis.  CMV-IVIG in combination with ganciclovir decreased the incidence of CMV infection to 21% and disease to 31%, their severity and delayed its onset.More recently, Valantine et al. reported improved outcomes with fewer infections, decreased acute rejection and BOS at 12 and 24 months in the combined therapy group compared with the ganciclovir-only group.

Preemptive Therapy -Some centers advocate preemptive therapy based on detection of CMV antigenemia or DNAemia in routinely collected blood samples. The advantage of this strategy is that only high-risk patients are exposed to therapy, which would be expected to decrease cost and toxicity. Several small studies have suggested that this approach is indeed effective in lung transplant recipients. Egan et al. showed that preemptive treatment of CMV infection as determined by antigenemia prevented progression to CMV disease in heart and lung transplant recipients. Kelly et al. found that preemptive therapy directed by the antigenemia assay was as effective as universal prophylaxis with 6 weeks of intravenous ganciclovir and concluded that it was also more cost-effective. There are several potential disadvantages of preemptive therapy: (1) in large geographic regions, it may be difficult to routinely obtain blood samples from the patients, (2) the cost of surveillance may be high, and (3) some patients escape detection and present with severe CMV disease.  Whether the use of combination therapy followed by oral ganciclovir decreases the recurrence risk further is presently unknown.

Antiviral Resistance -Antiviral-resistant CMV is increasing in all solid organ transplants and is particularly problematic following lung transplantation with an incidence of 3-16%. These estimates are imprecise, as much of the data has been collected retrospectively and there is significant variability among centers, some of which is owing to the fact that genotypic testing of isolates provides greater sensitivity in detecting resistance than the culture-based methods in use at most centers. It is concerning that antiviral resistance has been associated not only with treatment failure, but poor long-term allograft function and decreased patient survival. Kruger et al. found an incidence of ganciclovir resistance in their lung transplant cohort of 5.2%, which resulted in increased positive viral blood cultures, CMV pneumonia, decreased overall survival and the earlier onset of BOS.The most important risk factors for antiviral resistance are D+/R- status and the intensity of immunosuppression. Suboptimal antiviral prophylaxis, which may occur with oral ganciclovir owing to its poor bioavailability, is another risk factor for resistance. Finally, the intensity of the immunosuppressive regimen, particularly the use of antithymocyte globulin or OKT3 for induction therapy or treatment of rejection episodes, is associated with the development of antiviral resistance. Resistance should be suspected in patients who fail to respond to intravenous ganciclovir therapy of tissue-invasive CMV infections, who have persistent viremia or recurrent viremia during or after ganciclovir prophylaxis.  While prolonged exposure to intravenous ganciclovir was associated with the development of resistance and it has been asserted that less antiviral for shorter time periods is beneficial, it is still being debated whether prolonged exposure to potent antivirals or intermittent exposure with preemptive therapy will induce similar levels of resistance. Contrary to what is claimed by advocates of the preemptive approach, such a strategy does not always prevent the emergence of ganciclovir resistance. Finally, given the association of CMV pneumonia with BOS, this risk must be weighed against that of developing ganciclovir resistance with prolonged therapy.

Future Directions in CMV Management -Lung transplant programs still need to refine the types of CMV prophylactic strategies that best match individual recipients of seropositive and seronegative allografts and the type of immunosuppression utilized. It seems clear that universal prophylaxis is warranted for high-risk D+/R- recipients. However, it remains unclear as to whether R+ recipients are also at higher risk than other solid-organ recipients and whether they should receive universal prophylaxis or preemptive therapy. The use of antilymphocyte globulin would also appear to warrant the use of targeted, preemptive therapy with intravenous ganciclovir followed by 2-3 months of an oral agent. The development of high oral bioavailable drugs such as valganciclovir may provide a more convenient method of prophylaxis or treatment of CMV infections. Combination therapy may also provide the opportunity to prevent and treat chronic and progressive allograft injury, particularly in the thoracic organs. Finally, molecular techniques should be employed for the detection of CMV infection, for determining the response to and duration of therapy and for the determination of the emergence of ganciclovir-resistant isolates. Ongoing studies should help to answer these issues as well as generating new hypotheses in the role of CMV infection in chronic allograft failure following lung transplantation. (Source: American Journal of Transplantation 2004)