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Controlling the Troll: Management of Cytomegalovirus Infection after Transplantation

Stephen Dummer, MD
[+] Article, Author, and Disclosure Information

From Vanderbilt University Medical Center, Nashville, TN 37232.

Potential Financial Conflicts of Interest: Consultancies: Roche Labs; Honoraria: Roche Labs.

Requests for Single Reprints: Stephen Dummer, MD, Vanderbilt University Medical Center, 911 Oxford House, Nashville, TN 37232; e-mail, Stephen.dummer@vanderbilt.edu.

Ann Intern Med. 2005;143(12):913-914. doi:10.7326/0003-4819-143-12-200512200-00010
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Twenty-five years ago, Henry Balfour coined the phrase “troll of transplantation” to denote the insidious influence that cytomegalovirus (CMV) infection exerted on the outcome of transplantation (1). At that time, CMV was the most common serious pathogen in transplant recipients. Like the troll in the fairy tale, the virus was a hidden threat, latent in the recipient's or donor's tissues but ready to emerge under the pressure of immunosuppression. Although some patients only experienced subclinical CMV infection, other patients progressed to having overt CMV disease. These patients were readmitted to the hospital 1 to 2 months after transplantation and suffered weeks of fevers and debilitation. All too frequently, CMV infection led to viral pneumonia graft dysfunction or even to the patient's death. Twenty-five years ago, reduction of immunosuppression was the only treatment and rapid diagnostic tests for CMV were not available.

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Understanding the Troll: How to Best Prevent Cytomegalovirus after Transplantation?
Posted on January 23, 2006
Andre C. Kalil
University of Nebraska
Conflict of Interest: None Declared

We read with interest the editorial from Dr Dummer (1) about our study (2). However, we would like to make some clarifications.

We agree with Dr Dummer's recommendation that due to potential confounding factors related to outcome that differs between the preemptive and prophylactic trials, ""¦it would be unwise to directly compare the results achieved with the 2 strategies". Our study made no formal, direct comparisons between the 2 strategies. In the discussion section, we clearly state that comparison of these two approaches needs to be based on a "prospective trial directly comparing universal prophylaxis with a preemptive approach".

Dr Dummer states that "The rates of CMV disease in the control groups were higher in the prophylaxis groups (16% vs 9.5%; P<0.025 [chi-square test]), as were the rates of acute rejection (40% vs 22.7%; P<0.001 [chi-square test])." These two chi-square analyses that Dr Dummer refers to are not from our study. These chi-square tests do not account for variability across the trials within a treatment approach which may cause misleading results, and furthermore, contradict the warning against direct comparisons made in the same editorial. Moreover, the rates of CMV organ disease and allograft rejection were statistically significantly decreased by both universal prophylaxis and preemptive approaches. Hence, the different event rates in the control groups did not preclude the detection of significant results in the two analyses cited in the editorial.

Dr. Dummer's statement ""¦the 2 types of trials differed qualitatively, because all of the large (>100 patients) placebo- controlled trials were studies of prophylaxis" is not correct since the Hibberd et al. trial (3) included 113 patients. We agree that for rare outcomes where the odds ratio estimates were closer to 1, the preemptive trials may have been underpowered. Even though we understand that no single study will likely be adequately powered for all primary and secondary outcomes, the meta-analysis statistical methodology that we used adjusted treatment effect and standard error estimates for the variability in the individual trial sample sizes.

Last, an important result such as the statistically significant reduction in CMV organ disease with the use of acyclovir alone for universal prophylaxis was not discussed in the editorial. The potential differences in CMV organ disease, CMV-indirect effects, CMV resistance, late-onset CMV disease, and cost-effectiveness between acyclovir and ganciclovir/valganciclovir may have fundamental clinical implications for our transplant patients, and this can only be resolved by a head-to-head trial.

Andre C Kalil, M.D.; Elizabeth Lyden, M.S.; Julie Stoner, Ph.D.

University of Nebraska, Nebraska Medical Center Omaha, NE 68198-5400

1. Dummer S. Controlling the troll: management of cytomegalovirus infection after transplantation. Ann Intern Med. 2005;143(12):913-4.

2. Kalil AC, Levitsky J, Lyden E, Stoner J, Freifeld AG. Meta- analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients. Ann Intern Med. 2005;143(12):870-80.

3. Hibberd PL, Tolkoff-Rubin NE, Conti D, Stuart F, Thistlethwaite JR, Neylan JF, Snydman DR, Freeman R, Lorber MI, Rubin RH. Preemptive ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus antibody-positive renal transplant recipients. A randomized controlled trial. Ann Intern Med. 1995;123(1):18-26.

Conflict of Interest: None declared

Conflict of Interest:

None declared

Management of cytomegalovirus infection
Posted on February 9, 2006
Stephen Dummer
Vanderbilt University School of Medicine
Conflict of Interest: None Declared

To the Editor:

In response to Kalil and colleagues' letter concerning my editorial, I would also like to make a few clarifications. Their recently published meta-analysis of CMV management trials is an important contribution to the literature that should be widely cited (1). The goal of my editorial (2) was not to rephrase or critique their article, which can stand on its own merits. Rather, I hoped to communicate some historical perspective on the topic and discuss the current controversy between prophylactic and preemptive approaches to the management cytomegalovirus (CMV) infection.

One concern I had was that some readers might see CMV prophylaxis as the better overall strategy, because the meta-analysis found more benefits for this management strategy than for preemptive therapy. I wanted to issue a caveat against drawing this sort of conclusion. In order to strengthen that caveat, I extracted and analyzed data from their article that, in fact, showed that the preemptive and prophylactic populations in their study were quantitatively and qualitatively different. I believe that this was a valid and legitimate exercise and that it supported my claim was that no reliable conclusion could be drawn from the data favoring either approach to CMV management.

I stand by my statement the all of the large (>100 patient) placebo-controlled trials cited in the study were studies of prophylaxis. The trial by Hibberd and colleagues (3) was randomized and contained more than 100 patients, but it was not placebo-controlled or blinded. It is important to recognize that more resources have been invested in the study of CMV prophylaxis than preemptive therapy of CMV and this may have produced a playing field that is not completely flat.

Finally, this letter gives me an opportunity to redress my neglect of acyclovir, whose prophylactic use was shown by the meta-analysis to reduce CMV disease. Acyclovir is clearly less potent that ganciclovir (4) and is never used for preemptive therapy or therapy of established CMV disease, but as Kalil and colleagues have shown it has proved benefits in the prophylactic setting. Further studies of acyclovir analogues seem warranted. A particularly intriguing regimen to study in high-risk patients would be the combination of valacyclovir prophylaxis and valganciclovir preemptive therapy.

Stephen Dummer MD Vanderbilt University School of Medicine Nashville, TN 37232

1. Kalil AC, Levitsky J, Lyden E, Stoner J, Freifeld.AG. Meta- analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients: Ann Int Med 2005;143:870-80

2. Dummer S. Controlling the Troll: Management of cytomegalovirus infection after transplantation. Ann Intern Med. 2005; 143:913-14

3. Hibberd PL, Tolkoff-Rubin NE, Conti D, Stuart F, Thistlewaite JR, Neylan JF, Snydman DR, Freeman R, Lorber MI, Rubin RH. Preemptive ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus antibody-positive renal transplant recipients. A randomized controlled trial. Ann Int Med 1995; 123:18-26

4. Cole NL, Balfour HH Jr. In vitro susceptibility of cytomegalovirus isolates from immunocompromised patients to acyclovir and ganciclovir. Diag Micro Inf Dis 1987;6:255-61

Conflict of Interest:

Roche Labs: honoraria and consultancies

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