Risk Factors, Signs, and Symptoms of EBV+ PTLD

Jennifer Amengual, MD: Hi and welcome. Today, we'll be discussing EBV-positive post-transplant Lymphoproliferative disorder or EBV-positive PTLD, a serious complication that can arise following organ or hematopoietic stem cell transplantation. My name is Jennifer Amengual. I'm an associate professor at Columbia University Irving Medical Center, and I'm joined by two colleagues and experts in the field. I'm excited to have a chat with them. Welcome. Would you guys both please introduce yourselves?

Samuel Yamshon, MD: Hi, I'm Sam Yamshon. I'm an assistant professor of medicine at Weill Cornell Medicine, also in New York City.

Joe Schroers-Martin, MD, PhD: Great. I'm Joe Schroers-Martin. I'm an assistant professor of oncology at Stanford University in California.
In terms of risk factors, certainly, the depth of immunosuppression required for different types of grafted organs, as you described, is a risk factor in the pediatric transplant population. Serodiscordance between hosts who have never had an EBV infection and donors who have had it has been described as a major risk factor with donor-derived EBV and early fluoride infections. In the adult population, where most people have already had EBV exposure early in adulthood and have detectable anti-EBV antibodies, the risks for reactivation in the detection of reactivation are a little bit more complicated.

Dr Amengual: Dr Yamshon, maybe you could dive in a little more about key risk factors for EBV-positive PTLD that health care providers should be aware of and just be on the lookout for.

Dr Yamshon: Sure. We talked about this a bit, but I think that the main risk factors that we see, especially in the adult population, as Dr Schroers-Martin alluded to, is the depth and duration of immunosuppression. That's very critical. Also, kind of the question of, is there a mismatch in the EBV status of the donor versus the recipient. So for people who, because I think, as we know, the main reason why PTLD occurs is because the immune system isn't able to keep this in check. So, as a college student or whatnot, you get mono, and you have it for years, and it's kind of lying there waiting, and now, all of a sudden, we've wiped out your immune system for an extended period of time. But if, say, the donor cells, in the case of a hematopoietic stem cell transplant, never was infected with PTLD, then the t cells that are coming back in aren't going to know to fight those.

That kind of mismatch between the donor and the recipient, and kind of the other direction and solid organ transplants, is really, I think, the key critical risk factor. We know that, basically, how long patients require strong immunosuppression, how deep that immunosuppression is, and then the mismatch between donor and recipient in terms of EBV status, I think are really the critical ones. The other piece that I do think comes up sometimes is other things that can be immunosuppressive, like autoimmune disease or, say, HIV, which can also be an additional risk factor. We know for EBV lymphomas in general, but especially for PTLD as well,

Dr Amengual: Thank you so much for that. I think when we're evaluating patients who have had organ or hematopoietic stem cell transplants, some of the signs and symptoms that we see in the early stages of developing PTLD can be very broad range. It could start with just sort of symptoms related to EBV Viremia, such as low-grade fevers and malaise. Sometimes, you can see a slight elevation in liver function tests, which can go all the way across the spectrum to what we might see in aggressive lymphomas such as drenching, night sweats, and weight loss, in addition to fevers and malaise. Also, we see, occasionally, allograft dysfunction as oftentimes PTLD and solid organ transplants can happen within the engrafted organ as well. Then, there are localizing symptoms, just like with any other lymphoma, based on lymph node enlargement. If the disease is present in the GI tract, which we do see fairly commonly, then there may be abdominal pain, small bowel obstruction-like symptoms, blood in the stool, or hematochezia. We might also see symptoms relating to bone marrow involvement, and rarely, I would say, also see CNS involvement as well.

It's really sometimes tricky to sort of differentiate between EBV-positive PTLD and infection. So, it's really critical to sort of rule out other potential infectious causes as these patients are immunosuppressed, making sure there's not CMV viremia or other types of infections that might be causing similar symptoms. Also to make sure there's no organ rejection ongoing at the time of diagnosis.

Okay. Well, I really thank both of you for a great discussion on EBV-positive PTLD. I look forward to collaborating with you both in the future.  I think we still have so much to learn, and I think some of these new treatments that have emerged are going to pave the way for exciting times in this space.