33: Troll of Transplantation Part 1

He is an Internal Medicine resident at Beth Israel Deaconess Medical Center in Boston. And if you haven't heard it already, I would definitely recommend checking out Kevin's previous episode on Cryptococcus, which is episode 17, also known as Yeastie Boys. Next I will introduce our guest today, Joseph Sassine is an Assistant Professor of Medicine and a Transplant ID physician at the University of Oklahoma Health Sciences Center.

He previously completed his Internal Medicine residency at the Icahn School of Medicine at Mount Sinai and St. Luke's Roosevelt Hospital Center in New York City. This was followed by his ID fellowship at the University of Texas Health Sciences Center and MD Anderson Cancer Center in Houston. Today is part one of the Troll of Transplantation, where we're going to talk a little bit about CMV and solid organ transplant recipients.

Stay tuned for part two was Dr. Camille Kotton that'll be coming out two weeks from this episode, thinking more about resistant and refractory CMV disease. All right, let's get started. Welcome to the show guys.

His PMH is also notable for a large B cell lymphoma, s/p splenectomy and gastric wedge resection seven years ago, for which he received six cycles of chemotherapy. It has been in remission since, as well as coronary artery disease.

Regarding his transplant history, he underwent a deceased donor renal transplant in October 2020 with serologies pre-transplant being hepatitis B negative/ non-immune, Hepatitis A negative, Hepatitis C negative, CMV serology negative, donor CMV antibody positive, EBV negative, donor EBV indeterminate, and Toxoplasma negative, donor Toxo negative. He was induced with basiliximab and was maintained on a regimen of tacrolimus, mycophenolate and prednisone.

His postoperative course was complicated by delayed graft function, which eventually improved. His prednisone had been tapered off prior to discharge from his transplant admission, and his DSA has remained below the median range. He was initially given prophylaxis against PCP with Bactrim [trimethoprim-sulfamethaxazole] and CMV with valganciclovir with the anticipated duration of the latter being six months, given his high risk CMV status.

Now, before we get back to the case, Dr. Sassine, we wanted to pause here to discuss this last point. There are two major strategies for CMV disease prevention after solid organ transplant -- antiviral prophylaxis and preemptive therapy. Would you be able to give us a brief overview of the difference between these approaches and how we utilize the serostatus of the donor and the recipient to help stratify the risk of infection?

As well as through its indirect effects, CMV is an immunomodulatory virus and CMV reactivations have been associated with graft rejection, graft versus host disease, and worsening immunosuppression by virtue of the virus or some of its therapies. Thus leading to a higher incidence of bacterial and fungal infections. For these reasons, it's very important to be proactive when it comes to CMV issues in this patient population.

As you mentioned, there are two strategies that can be used and that actually are not mutually exclusive. The first one is prophylaxis, which is the administration of an antiviral drug to all patients who are at risk for a determined period of time after the transplant, and that duration is usually based on their risk level. Prophylaxis is an effective strategy in preventing direct and indirect CMV effects. It was proven effective in large randomized controlled trials.

It is easy to coordinate and apply since you are following an algorithm and it has a positive impact on the indirect outcomes, such as graft loss and mortality. Nevertheless, with prophylaxis, you will be exposing all of your patients to the antiviral, whereas some of these patients might never develop the CMV infection or disease. Uh, so there's always the risk of over-treatment. And with that comes the risk of unnecessary toxicities and higher drug cost.

Prophylaxis might also delay CMV specific immune reconstitution, and lastly, one should be aware of the risk of post-prophylaxis delayed-onset CMV disease, particularly in the highest risk patients. And the drugs currently use for prophylaxis in solid organ transplant recipients are oral valganciclovir, like your patient here, or IV ganciclovir.

Letermovir was approved for prophylactic use and hematopoietic cell transplant recipients, but it's not yet approved for using solid organ transplantations. One of the trials looking into prophylaxis with letermovir in kidney transplant recipients is estimated to be completed in April 2022, so stay tuned for news on that front.

On the other hand, preemptive therapy is based on the concept of surveillance of viremia after transplant and the administration of antiviral therapy to patients who reach a certain threshold of viremia or what we call CMV infection. To halt the progression of viremia and end-organ disease.

This strategy essentially tampers down many of the disadvantages of prophylaxis by targeting therapy to the patients who are at highest risk of disease, minimizing over treatment, minimizing toxicities, and minimizing the drug costs. However, a strategy that's purely based on preemptive therapy would miss some cases of CMV end organ disease that are not preceded by viremia.

And most notably here, you're talking about GI disease, so colitis and gastritis, which can be seen with undetectable viremia in the peripheral blood. This strategy, the preemptive strategy, also relies on the availability of sensitive CMV testing. Uh, currently we rely on quantitative nucleic acid amplification testing, as opposed to pp65 antigenemia detection in, in older days. And that used to rely on the number of lymphocytes present in the peripheral blood.

You also want your CMV test to have a quick turn around time to allow for a quick and rapid response. So you would want 24, 48 hours at most in terms of, uh, turnaround time. In real life, we actually use a mix of both, uh, prophylaxis and preemptive therapy. This is why I said earlier they're not necessarily mutually exclusive. What proportions of each strategy, uh, are used, depends on the individual patient risks.

As a general principle, the major risk factor for CMV disease after solid organ transplant is a qualitative or quantitative deficiency in global immunity and / or in CMV specific immunity. To estimate the patient's risk, we usually measure pre-transplant serologies for both the donor and the recipient. There are certain assays that measure CMV specific cell-mediated immunity. The use of those assays in the pre-transplant stage is still investigational, we will come back to those a little later.

The highest risk group when you measure serologies, is going to be the recipients who are seronegative but to receive an organ from a seropositive donor. And this is what we refer to as D+R-. The moderate risk group would be seropositive recipients, so R+. Within that group, those who receive an organ from a seropositive donor, so D+R+ are at higher risk compared to those who have a seronegative donor, so D-R+.

The lowest risk group are the recipients who are seronegative and who receive an organ from a seronegative donors. So this is D-R-. Just a side note, in hematopoietic stem cell transplant, it's different. It's usually a recipient seropositive that's the major determinant. Beyond seropositivity for both the donor and the recipient, there are additional risk factors for CMV reactivation.

These include lymphodepleting agents, such as antithymocyte globulin, alemtuzumab, quite high doses of maintenance immunosuppression, allograft rejection, especially that this is after accompanied by another round of lymphodepleting therapy, and the type of organ being transplanted. So lungs and small intestines are higher risk than other organs. The use of mTOR inhibitors, such as sirolimus and everolimus, is actually associated with a lower risk of a CMV.

There's an interesting concept called the net state of immunosuppression, uh, which is kind of important to estimate each individual patient's risk of impact. There's a nice paper that addresses it in CID in 2020 by Dr. Jay Fishman, so I can refer to that. With this in mind, the AST ID COP Guidelines of 2019 recommend antiviral prophylaxis with valganciclovir, uh, usually administered at 900 mg once a day or ganciclovir as five mg/kg, ideally once a day.

And these are doses for normal renal function, and this regimen, or one of these two agents, are recommended for high-risk D+R- patients, as well as for moderate-risk R+ patients. The duration of prophylaxis that is recommended varies between 3 and 12 months, depending on the level of risk of the patient, whether they high-risk versus moderate risk. And depending on the organ being transplanted.

So lung and heart-lung transplants have the longest durations, and these are the ones that will reach the 12 month. The guidelines also provide recommendations regarding the preemptive therapy as an option. If logistic support is available, they also provide instructions on monitoring intervals. They do not provide a specific viral load threshold to initiate therapy, but they rather recommend this threshold be assay specific, center specific, and risk specific.

Some patients might require longer prophylaxis and/or monitoring than the recommended duration. So we have to keep an open mind with those numbers, but particularly if they receive further lymphodepleting therapy for the treatment of rejection.

Now this constellation of symptoms prompted him to present to the ER. In the ED, he was noted to have creatinine elevated to 1.5 from baseline of 0.9 to 1.1. Leukocytosis to 13.8 with a total neutrophil count of around 13,000, and a total lymphocyte count of 740. Bicarb was 11, anion gap of 19, as well as LFTs notable for a mild transaminitis, ALT of 73 and AST of 101 and alk phos 123, and a T-bili 0.6.

His LDH was 345 and he was a little hypoalbuminemic to 3.4 and his lactate was elevated at 2.6. His tacrolimus trough was drawn and it turned out to be 4.4. His UA was not pyuric and they did get some blood and urine cultures that are pending. A little bit of additional history for this patient. He was born and raised in Massachusetts and now lives in Boston. He never traveled outside North America, but has roamed around the United States, west coast, Midwest as well as Canada.

He hasn't traveled at all since this transplant last year and is currently retired, but used to work at an office desk job. Previously did have a pet cat, but the cat's now staying at his children's since his transplant and he's been being diligent and avoiding raw foods. He's never used tobacco. Doesn't drink alcohol and uses no recreational drugs. And when you go and talk to him, he's not in distress, but a little uncomfortable when his abdomen is palpated.

He's a little bit tender non-specifically without any signs of guarding or rebound. He's not fluid overloaded. In fact, he appears a little bit dry and a RUQ ultrasound obtained in the ED illustrates some cholelithiasis, but no hepatobiliary ductal dilatation and no signs of cholecystitis.

Now with all of these details together, we just wanted to see what you're thinking about so far and while we certainly suspect that CMV is probably the issue here, we do want to keep an open mind about what should be on the infectious diseases differential for diarrhea in a solid organ transplant recipient.

There are various efforts that can be done to prevent this, including close clinical follow up, and early treatment when symptoms occur like here, uh, or routine viral surveys after completion of prophylaxis, further prolongation of antiviral prophylaxis, but that usually comes at the expense of, uh, significant myelotoxicity, and/or immunologic monitoring at the end of prophylaxis and thereafter, usually with things like lymphocyte count, CD4 count, or CMV specific cell-mediated immunity.

To get back to your original question, the differential diagnosis of diarrhea and solid organ transplant recipients, as you can imagine, it's very broad. To follow the classical scheme of infectious versus non-infectious, infections include bacteria. C diff is a big one. Campylobacter, Salmonella, Aeromonas, E.coli, bacterial overgrowth. Viruses, obviously such as CMV, but also the GI viruses, Norovirus, Adenovirus, and the others. And parasites.

The classic Giardia and Entamoeba, but also the traditional GI opportunistic parasites. So Cryptosporidium, Microsporidium, Cystisospora, and Cyclospora. Keep in mind that these patients can have noninfectious causes of diarrhea. Uh, mostly medication-related. Immunosuppressives such as mycophenolate, tacrolimus, sirolimus, cyclosporine, and just plain other non immunosuppressive medications.

Diarrhea can also be a manifestation of graft versus host disease or post-transplant lymphoproliferative disease. For the sake of time, I will not go into the timeline of infections after organ transplantation, but there's a nice comprehensive figure in again, Dr. Fishman's review of infections and organ transplant recipients in NEJM back in 2007, and I think that still holds up to this day.

In this paper, CMV infection is defined as virus isolation, or detection of viral proteins or nucleic acids in any body fluid or tissue specimen. When this specimen is the blood, then the assays can measure virus in the plasma, serum, or whole blood-- we talk about viraemia, which is culturing virus from the blood. Antigenemia, which is detecting the pp65 antigen that's specific for CMV. Or DNAemia, which is detection of CMV DNA, which is the most common technique nowadays.

CMV disease includes end organ disease caused by CMV, such as pneumonia, GI disease, hepatitis, retinitis, et cetera, as well as CMV syndrome, which is an entity that is only described in solid organ transplant. And that includes detection of CMV in the blood with at least two of the following-- a fever, new or increased malaise or fatigue, leukopenia and neutropenia, atypical lymphocytes (more than 5%), thrombocytopenia, elevated AST or ALT to twice the upper limit of normal.

The AST ID Guidelines summarize those definitions, including the ones for proven and probable end organ disease in their first table in the guidelines. To use those definitions would make it easier to determine what diagnostic workup is needed. With our case here, we do suspect CMV GI disease. The approach would be endoscopic examination would be necessary.

We rely on the presence of symptoms, the presence of macroscopic mucosal lesions, documentation of CMV in the tissue either by histopathology, immunohistochemistry, culture, or DNA hybridization techniques to determine a proven or definite GI CMV disease. If you just have symptoms with documented CMV in the tissue, but without microscopic mucosal lesions, that would make it a probable GI CMV disease.

Now that distinction might be more important for clinical trials rather than the clinical practice, but the definitions help you know what tests to order and that to diagnose GI CMV disease, you do need an endoscopic evaluation, both microscopic and tissue. Documenting CMV in the blood alone is not sufficient to diagnose the CMV GI disease.

Would you be able to teach us a little bit about these CMV treatment regimens, especially the differences between induction and maintenance therapy. When do you make the transition and when do you stop maintenance after that?

For mild to moderate disease, oral valganciclovir and IV ganciclovir are considered equally effective. There was a randomized trial establishing this non-inferiority back in 2007. For the patients who can not tolerate ganciclovir or valganciclovir, and that's usually because of cytopenias, or for those patients who fail to respond to these agents, and here we would be going into their refractory resistant CMV chapter, second line agents include foscarnet or cidofovir.

These agents are reserved for the second line due to their significant nephrotoxicity. And just to get an idea of the nephrotoxicity with foscarnet, there's a study out of Johns Hopkins in 2016, showed that 50% of the patients who received foscarnet for refractory resistant CMV developed renal dysfunction by the end of treatment and 28% after 6 months.

Now for these folks who failed to respond to ganciclovir or valganciclovir, a new agent maribavir was recently approved by the FDA in November 2021 with a much better safety profile. So that's an exciting development. There have been case reports using letermovir as a second line agent off-label. I personally would not use it in the setting of active, viral replication due to the high risk of resistance development. As you mentioned, there are two stages of therapy.

They call them induction and maintenance. You can think of induction as the full dose therapy stage. Here, you administer antivirals at the full therapeutic dose, which I just mentioned. Maintenance is essentially a secondary prophylaxis phase to prevent early recurrence of CMV. There is no preset duration or blanket duration for induction therapy.

In the valganciclovir trial I mentioned earlier, they limited therapy for three weeks and a significant proportion of patients still had viremia by three weeks, suggesting that these patients probably needed longer durations of antiviral therapy. This is why the AST ID Guidelines list three criteria that you need to meet before ending induction therapy. The first one is resolution of clinical symptoms.

The second is virologic clearance below a threshold negative value, and this value is a test specific, based on weekly lab monitoring either with a quantitative nucleic acid amplification assay, or if you still use pp65 antigenemia. And they defined that as needing two consecutive results or a single negative, if you're using a highly sensitive assay. The third condition you have to meet is a minimum of two weeks of antiviral treatment.

So once you meet those three conditions and you come, you complete full dose antiviral treatment, the guidelines state that secondary prophylaxis may be considered in certain high-risk patients. And here you would be using the prophylaxis doses as compared to the treatment doses, so once a day instead of twice a day for a normal renal function. The duration of antivirals and the stages are defined by the guidelines. Different centers use different approaches.

Most of them will use something between one and three months. It also depends on the individual patient's situation, particularly in regards to lymphopenia. Some centers are starting to CMV specific cell-mediated immunity assays to guide that decision. There was a retrospective study published in CID in 2017, looking at secondary prophylaxis with valganciclovir. It showed the reduction and relapse with a hazard ratio of 0.19. So it was a significant reduction.

Uh, but this was only in the first six weeks following treatment completion. The benefit did not extend beyond six weeks of secondary prophylaxis. I think this is still an area that deserves more investigations to determine the optimal approach and how to incorporate the use of CMV specific cell-mediated immunity and allow for CMV specific T-cell immune reconstitution. Before concluding the treatment chapter, there are a few more interventions to mention.

A cautious reduction in immunosuppression should be considered, especially in moderate to severe disease. And usually that comes in collaboration with our transplant colleagues, because you want to weigh this against the risk of rejection. You can switch from IV ganciclovir to oral valganciclovir once there is clinical and virologic improvement, even if you have not competed, uh, full dose therapy yet. And as long as you don't have concerns for GI malabsorption.

You should dose adjust ganciclovir and valganciclovir based on renal function, but you should not adjust them down if your patient develops neutropenia or leukopenia or cytopenias. Under dosing is actually a risk factor for resistance. So if you still would like to use those agents, you can support with growth factors or a switch to a second line agent.

Intravenous immunoglobulins, uh, or CMV specific immunoglobulins may be considered for patients with life-threatening disease, for patients with CMV pneumonitis, or those who have hypogammaglobulinemia.

And after his CMV viral loads were undetectable two times in a row, uh, after the seven total weeks of induction, he was eventually transitioned to maintenance valganciclovir. He continued the maintenance valganciclovir for about another 10 weeks. As you said, he eventually discontinued it. And since then bi-weekly monitoring for CMV did not show any recurrent viremia. His monitoring was then discontinued after two months. So overall a good outcome.

To end the episode, there is always some exciting news in the transplant ID world, and you alluded to a little bit of this earlier. Would you be able to tell us about the latest in CMV care or new therapies available for our patients?

Some areas where we might hear news in the near future or where we need to better develop our understanding-- the use of letermovir in organ transplant recipients. I mentioned the ongoing primary prophylaxis trial. We also need to better understand the place of letermovir in secondary prophylaxis in, both in organ transplant and hematopoietic cell transplant. Uh, we also need to find the best way to incorporate the use of CMV cell-mediated immunity assays in our daily clinical practice.

The use of adoptive immunotherapy for treatment, particularly using CMV specific cytotoxic T lymphocytes. This is mostly a field of investigation in hematopoietic cell transplant recipients. Finally, I recently came across a very interesting paper published earlier this year. It's more a hematopoietic cell transplant paper.

They actually looked at circulating cell-free DNA profiling in those patients and how this can be used to inform all the major complications of a hematopoietic cell transplant, including GVHD, disease relapse, but also infections by plasma virome screening. So I just found this to be very cool.

At the end, I want to have a special mention and recognition to my mentor, Dr. Roy Chemaly, who has taught me everything I know about CMV and, uh, and has accompanied me in developing that the interest of mine.

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