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ARE WE STILL TALKING ABOUT CMV?

Luciano Potena, MD, PhD
University of Bologna, Italy

Stanley I Martin, MD
The Ohio State University, USA

Vincent G Valentine, MD
University of Texas Medical Branch, USA

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"Healing is a matter of time, but it is sometimes also a matter of opportunity." - Hippocrates

"'Tis healthy to be sick sometimes." - Henry David Thoreau

Cytomegalovirus (CMV) remains the most common opportunistic infection after thoracic transplantation, and remains an incessant topic of heated discussions, from a brew of scientific evidence and passionate faith. Despite the increasing knowledge about CMV over the years, we still struggle with a number of questions. We are better at treating CMV disease since the dawn of heart and lung transplantation. However, we still fret over the long-term sequelae of CMV reactivation and disease. CMV, after all, has been associated with everything from an increased risk of diabetes to bronchiolitis obliterans syndrome (BOS) and allograft vasculopathy (CAV) to misplacing car keys or texting while driving (OK, those last ones are exaggerations... maybe...).

Prophylactic strategies are undoubtedly beneficial in a number of studies related to organ transplantation, and meta-analyses suggest a survival benefit of prophylaxis unattainable by pre-emptive strategies. Palmer et al's important study in the Annals of Internal Medicine 2010 was the first multicenter, prospective, randomized, double-blind, comparative trial showing that lung transplant patients who received 12 months of valganciclovir prophylaxis had a greater freedom of CMV disease versus those who received a 3 month course. Similarly, in kidney transplantation, Humar reported that 6 months of prophylaxis was more efficacious than 3 months. Are these the final words on the subject? Some questions still linger and need addressing. Two members of the editorial board, "incidentally" involved in the CMV issue, have been interviewed to provide a unifying message.

S: Vincent and Luciano, the first point is: how long should patients receive prophylaxis? If 12 months of prophylaxis is superior to 3 months, then how about 6 months? How about 9 months? And how about longer?

L: The goal of anti-CMV strategies is not only to prevent CMV disease but also to minimize CMV subclinical replication to limit its "indirect" adverse consequences. However, CMV's DNA is among the widest viral genomes ever sequenced. One of its most intriguing characteristics is that about 65% of the coded genes are not essential for replication, but instead have a regulatory effect on the host cell's genome. Simply aiming for only one of the other 35% gene products (i.e. (val)ganciclovir inhibits just DNA polymerase), for either 3 or 12 months will not necessarily rid our patients of CMV. It would be more interesting to face the problem by acting on the interaction between CMV and the host with diagnostic and therapeutic tools. The real question to address is: what is the risk of CMV adverse events in my single patient? For example, a lung recipient is at higher risk of acute CMV disease than a heart recipient, a patient receiving thymoglobulin or any induction is at higher risk of one not receiving induction, and a patient not recovering his or her immunity may need a longer prophylaxis period than a patient recovering their immunity shortly after transplant. Thus, individualization of an anti-CMV approach may be more challenging, but seemingly more efficacious at determining duration of prophylaxis.

V. Before the availability of CMV prophylaxis, a number of lung recipients died of CMV induced ARDS within 2-12 weeks following lung transplantation. When ganciclovir became available via the HIV population and Merigan's study in heart transplant recipients, lung recipients were placed on ganciclovir prophylaxis intravenously for 6 weeks. All this did to lung recipients was delay the identification of infection, disease and ARDS by that many weeks with nearly identical incidences.

When Steve Duncan at Pittsburgh continued IV prophylaxis with ganciclovir up to 100 days, a similar delay of infection, disease and ARDS occurred. Associations with Gram negative respiratory infections and fungal infections were also observed. Also, consideration was given to restart ganciclovir intravenously, and later orally with the old poorly absorbed ganciclovir, and then eventually with the valine esterified formulation for better absorption. So instead of this on-off approach (a known means of promoting resistance), in 1995 the Ochsner lung transplantation program made a commitment to proceed with indefinite prophylaxis beginning with IV ganciclovir for 6 weeks, followed by thrice weekly until day 100, then the old oral agent indefinitely. There are many patients who remain on oral ganciclovir today, originally the old and now the new valine derivative by choice. They have witnessed the deaths of patients who seemingly have died as a consequence of discontinuing their ganciclovir primarily from cost. Three index cases occurred within several months of each other. All patients had stopped their ganciclovir, developed a CMV respiratory event quickly, followed by the development of BOS within months of CMV, then death within a year. A total of 11 similar cases were identified.

For all patients remaining on indefinite prophylaxis (n = 116), only 2 percent have developed a CMV event, from either excess replication, CMV culture of lavage fluid or CMV disease. Interestingly, the 5 patients who developed CMV pneumonitis in the past 15 years were seronegative recipients to CMV of seronegative donors to CMV.

S: What do you think is the role of CMV IVIg in preventing CMV disease?

L: CMV IVIg is a very intriguing drug. It is likely that its action is more on the interaction between CMV and the immune system than on CMV itself. Unfortunately it has not been studied in any proper randomized study and it is unknown if the potential protective effect is mediated by IVig in general or by CMV specificity. CMV IVIg may represent a useful resource in the effort to limit antiviral toxicity and provide some sort of immune modulation, especially in recipients with serological mismatch.

V: I agree, it seems to be most helpful in limiting the graft-related effect of the virus, more than the incidence of CMV disease itself (Valantine HA Transplantation 2001).

S: What, then, is the role of giving CMV prophylaxis indefinitely?

L: This approach is not justified. It may expose the patient to an excess of drug toxicity without a proven benefit. For example, the longer a patient receives antiviral drugs associated with a standard immunosuppression, which includes an antimetabolite, the greater the risk of leukopenia. At this point, what would you do? Reduce the antiviral drug, exposing the patient to the risk of viral resistance, or reduce the antimetabolite, exposing the patient to the risk of rejection?

V: I must admit, I disagree and I am biased. If herpes is forever, and immunosuppression is forever, then the risk of CMV (a herpes virus) reactivation, infection, disease and its long-term sequelae are always possible.

S: What are the real consequences of late onset CMV disease or reactivation in thoracic transplant patients?

L: Late onset CMV disease may be dangerous. The first reason is that it can be difficult to diagnose. The patient is often visited at long intervals and he or she may be seen in another hospital that may misdiagnose the syndrome. Then it may foster CMV indirect consequences on graft function, rendering useless the long period of time that he or she spent on prophylaxis. This may be a good reason for not prolonging universal prophylaxis beyond 3 months of post transplant follow-up and instead monitor for CMV viremia three to six months after the completion of prophylaxis. Monitoring for CMV specific immunity may help with treatment duration and identify patients at risk of developing late CMV disease.

V: The only way to avoid late infection is to continue prophylaxis indefinitely.

I leave you with these thoughts. If most of the adult population is immune to CMV (roughly 85%), think about how this group developed their immunity. Now consider who is at greater risk of CMV infection and damage to the allograft?

Lastly, the collateral benefits of this near-indefinite to indefinite prophylactic strategy are eliminating ARDS, reducing sudden death and preventing a slow suffocating death related to CMV-induced BOS. These benefits must be balanced with the risks of prolonged to indefinite (val)ganciclovir prophylaxis.

Well... is there a light in this fog? The message from our editorial board is not just what can be defined as a "unifying message", but what reflects the real world of differing opinions in the clinical environment where most of our readers practice, with personal experiences, biases, truths, and untruths heavily influencing tough decisions at least as much as the published evidence. The key message, however, is that in 2012 CMV is still a threat and, despite valganciclovir trials, an optimal strategy is yet to be determined. Thus, a watchful approach is recommended, regardless of the chosen strategy.

Until we have a better means of giving CMV immunity (vaccination) or treating or controlling CMV replication, we still will be wrestling the mad dog with what we should or shouldn't do.

Let's drink on it, have a beer!

Disclosure Statement: The authors have no conflicts of interest to disclose.