There are several ways of optimising outcomes for PTLD, and I'm sure for many of my colleagues this is a very important complication of transplant. We think about it as a man-made disease that does not exist when we don't transplant patients, so we created it, so we should fix it. It has a significant impact on patients' quality of life, and a significant psychological impact. These are mostly patients who have had a significant medical event, either a haematopoietic stem cell transplant, or a liver transplant, or lung transplants to cure one disease. Sometimes within even a few months they're diagnosed with PTLD, which can be a life-threatening lymphoma. So there is first of all importance in being aware, so increasing the awareness to this complication is very important, because that would lead you to monitor patients more frequently and more aggressively. Of course, also when patients present already with symptoms, PTLD should be on the top of our mind when thinking about the potential diagnosis that could occur in a patient who had an organ transplant or a haematopoietic stem cell transplant.

Allogenic stem cell transplantation is the only curative therapy currently available for many haematologic malignant and non-malignant disease. Unfortunately, these patients are highly immunosuppressed in general, and they can also develop complications like a graft versus host disease where they would need, even, a long-term immunosuppressive therapy and high-dose steroids. When it comes to immunosuppression, unfortunately, this is where we see in these patients viral reactivations. One significant and major complication we see is the EBV reactivation and the development of EBV-related lymphoma and this is usually about the proliferation of these B cells, usually from the donor, which integrated the virus EBV.

One needs to be reminded that there are some specific risk factors that may aggravate or increase the incidence of viral reactivations like CMV or EBV or even the development of EBV⁺PTLD. For example, a T-cell depletion whether in vitro or in vivo, the use of numerous immunosuppressive therapies, the use of high-dose steroids for a long-term period, the use of mismatched donors—all of these situations can lead to an increased risk of EBV reactivations and, at some point, development of EBV⁺PTLD.

When it comes to serious and severe complications after allogenic stem cell transplantation, improving outcomes goes together with very close monitoring of the patient. One needs to pay attention to the clinical symptoms of course but, actually, in those patients who, for example, are at higher risk of viral complications, viral reactivation you need to establish a very close and very precise monitoring of the viral load and whenever there is a suspicion about a tumoral mass, then you need to use the imaging techniques—CT scan, PET scan—because we know very well that a rapid and very quick intervention is crucial towards improving the outcome of these patients.

EBV is a naturally oncogenic virus and although 95 per cent of the adult population in the world is infected with EBV, importantly it needs very good T-cell responses both in terms of T-cell numbers and function to maintain control of the virus over our lifetime. So perhaps it's no surprise then, if we reduce the numbers of effective T cells or the function of T cells, that there's a risk that EBV can drive a lymphoproliferative process through expression of a range of latent proteins.

PTLD that occurs following a stem cell transplant is directly related to the depth and duration of T-cell immunosuppression and these lymphoproliferative disorders that we term PTLD and can be very aggressive clinically.

In the UK practice, at least in terms of monitoring EBV viral load following stem cell transplant, most centres now will adopt a weekly monitoring schedule usually coinciding with the patient's visit to the clinic. That we would continue monitoring weekly typically for at least four-to-six months.

We described a relatively large cohort of cases that we published in BMT a few years ago of patients with proven or probable PTLD. One important finding in that setting was the wide variability between patients of the level of EBV DNAaemia at the time of PTLD diagnosis. That varied over a number of log₁₀ scale so it's quite a significant variability. I think the important message from that finding is that one shouldn't discount the possibility of PTLD with a patient with a relatively low or modest viral load.

For patients at risk of or developing PTLD after stem cell transplant, key points for clinicians to remember would include a low index of suspicion. Any patient who has symptoms that aren't easily explained, such as a fever that's not explained by other aetiologies, or B symptoms, or unexpected lymphadenopathy, then we really need to have PTLD at the top of the differential diagnosis. It can present quite heterogeneously, so in those patients we need to be doing an urgent EBV viral load and often, and proceeding to cross-sectional imaging with either CT or PET-CT.