EBV in the Transplant Patient

Epstein-Barr virus (EBV) causes the most important malignant complication of transplantation, post-transplant lymphoproliferative disorder (PTLD). PTLD is best understood not as a single disease but as a spectrum. When transplant immunosuppression weakens the T cells that normally control EBV, EBV-infected B cells proliferate, and that proliferation ranges from a reactive overgrowth resembling infectious mononucleosis at one end to a fully malignant, monoclonal lymphoma at the other. The classification, the timing of onset, and the intensity of treatment required all follow from where on this spectrum a given case sits and from how far EBV is still driving it. At the reactive end, reducing immunosuppression allows the T-cell response to recover and the proliferation to regress; at the malignant end, the disease behaves as a lymphoma and is treated as one.

What a lymphoproliferative disorder is

A lymphoproliferative disorder is a proliferation (an overgrowth) of lymphocytes, here almost always B cells. It is not a single state but a continuum, conventionally marked by three points:

• Hyperplasia: a reactive, polyclonal overgrowth, with many different B cells dividing in response to a stimulus, as in infectious mononucleosis, the lymph-node architecture preserved and no genetic hallmarks of malignancy.
• Neoplasia: the overgrowth has become clonal and has begun to efface normal tissue but does not yet meet the criteria for a defined lymphoma. Malignant transformation has begun but is incomplete.
• Malignancy: a monoclonal lymphoma carrying the genetic lesions of cancer and behaving as a lymphoma does.

PTLD denotes this spectrum when it arises after transplantation. Progression along it reflects the balance between EBV-driven B-cell proliferation and the T-cell control of EBV: immunosuppression impairs T-cell surveillance and shifts the balance towards proliferation.

Classification: how it was, and how it has changed

The 2022 revision is best understood as an evolution of the earlier scheme rather than a replacement: the established categories persist, renamed and regrouped, and supplemented by a more functional reading.

The earlier classification

Until recently the World Health Organization (WHO) treated PTLD as a standalone disease with four histological categories, spanning the spectrum from reactive to malignant:

Category	What it is	Clonality	Typical timing
Non-destructive (early) lesions	Reactive overgrowth: plasmacytic hyperplasia, mononucleosis-like, florid follicular hyperplasia. Architecture preserved	Polyclonal	Early
Polymorphic PTLD	A mixed infiltrate that has begun to transform but does not meet criteria for a named lymphoma	Often clonal	Early
Monomorphic PTLD	A frank lymphoma, usually diffuse large B-cell lymphoma (occasionally Burkitt, plasma-cell, or T/NK-cell types)	Monoclonal	Early or late
Classic Hodgkin lymphoma PTLD	Hodgkin-type histology; the least common form	Monoclonal	Usually late

An EBV-encoded RNA (EBER) in-situ hybridisation stain is performed on every case to establish EBV status, because EBV status shapes both behaviour and treatment.

The 2022 revision

Two independent classifications published in 2022, the WHO 5th edition and the International Consensus Classification (ICC), took the same step: they stopped treating PTLD as its own entity and incorporated it into one larger family, lymphoid proliferations and lymphomas arising in the setting of immune deficiency and dysregulation (IDD). The rationale is that the same lesions, with the same EBV biology, appear wherever immune control is lost: not only after transplant but also in inborn errors of immunity (inherited immune defects), human immunodeficiency virus (HIV) infection, autoimmune disease, drug and therapy-related immunosuppression, and the immune senescence of old age. Rather than describe the same disease separately in each setting, the two systems now classify it once, by shared biology, with EBV the unifying driver across most of the family.

No histological detail is lost in the change. The categories persist (the ICC retains the term “non-destructive” for the reactive end, while the WHO prefers “hyperplasia”, though the two are equivalent). Each lesion is now designated in three parts: the histological diagnosis, the driving virus, and the immune setting in which it arose.

1. Histological diagnosis	2. Viral association	3. Immune setting
Hyperplasia (specify type), polymorphic lymphoproliferative disorder, mucocutaneous ulcer, or a named lymphoma (classified as for an immunocompetent patient)	EBV positive or negative; KSHV/HHV-8 positive or negative	Inborn error of immunity, HIV, post-transplant (solid organ or bone marrow), autoimmune disease, drug or therapy-related, or immune senescence

A transplant case is therefore designated, for example, “polymorphic lymphoproliferative disorder, EBV-positive, post-transplant (solid organ)”. PTLD has not disappeared but has been situated within a larger family: it is the post-transplant member, and the immune setting now forms part of the name because the same lesion may behave differently in different settings. The framework also accommodates newer entities on the spectrum, such as the EBV-positive mucocutaneous ulcer, a localised and often self-limiting EBV lesion of skin or mucosa.

A functional reading of the spectrum

Alongside the formal histology, a functional framework maps the spectrum onto treatment intensity, sorting it into three groups according to how far EBV drives the disease and how far it behaves as a true lymphoma:

Group	Histology	EBV association	Behaves like, and treated as
Post-transplant EBV	Viraemia only, no lesion	EBV-positive	Asymptomatic infection: observe and reduce immunosuppression
Quintessential PTLD	Non-destructive (hyperplasia), polymorphic, and monomorphic EBV-positive large B-cell lymphoma	Almost always positive for hyperplasia and polymorphic (over 95 per cent); usually positive for the large-cell form	EBV-driven hyperplasia and neoplasia: often controllable with low-intensity treatment (reduced immunosuppression, surgery, or rituximab, with low-dose chemotherapy if needed)
Post-transplant lymphoma	Monomorphic lymphomas: EBV-negative large B-cell, Burkitt, high-grade B-cell, T/NK-cell, plasma-cell, and classic Hodgkin lymphoma	Often EBV-negative for the large-cell, high-grade, T/NK and plasma-cell types (under half); Burkitt and Hodgkin usually positive	A true lymphoma in an immunosuppressed host: treated as the matching lymphoma would be in an immunocompetent patient

The principal distinction is whether a case is quintessential, EBV-driven PTLD (reactive hyperplasia through to EBV-positive large-cell neoplasia, much of it controllable with low-intensity treatment) or a post-transplant lymphoma (a lymphoma that behaves as it would in an immunocompetent patient and requires lymphoma-directed treatment). EBV status is the principal discriminator: EBV-positive disease is more often the controllable, quintessential form, whereas EBV-negative disease should raise concern for a true lymphoma. The distinction is a practical one, since the two cannot always be separated on appearance alone, and a minority of quintessential cases (of the order of a third) prove refractory to low-intensity treatment and require lymphoma-type chemotherapy.

Pathogenesis

EBV infects B cells for life. In its latent state it can switch on a set of genes (the latency III growth programme, including the EBNA and LMP proteins) that drive the B cell to keep dividing. In a healthy person this is controlled by EBV-specific cytotoxic T cells (CTLs), which recognise and kill the infected B cells. Transplant immunosuppression is directed at T cells, so it removes that surveillance and allows the EBV-driven B cells to grow unchecked. This is why the degree of T-cell suppression is the central risk factor and why restoring T-cell function, by reducing immunosuppression, is the first treatment.

Two patterns at opposite ends of the spectrum behave very differently:

• EBV-positive PTLD arises early, often from a primary EBV infection in a previously uninfected patient, expresses the full latency growth programme, and carries few of the additional genetic lesions of ordinary lymphoma. It is the more responsive, quintessential end of the disease.
• EBV-negative PTLD arises late, typically years after transplant, is usually a monomorphic lymphoma carrying the same genetic changes as the diffuse large B-cell lymphoma of immunocompetent people, and is more aggressive. It is an important and growing subset: up to half of monomorphic PTLD after solid-organ transplant is EBV-negative. Why it occurs is uncertain (a “hit-and-run” EBV effect that leaves no trace, other viruses, or chronic immune stimulation by the graft).

A second distinction is the origin of the proliferating cells. Where the lymphoma arises from the recipient’s own B cells it tends to present as late, multisystem disease; where it arises from donor lymphocytes carried in the graft it tends to be early, confined to the transplanted organ, and to regress once immunosuppression is reduced.

Risk factors

The dominant risk factor is the EBV serostatus of donor and recipient, and, exactly as with cytomegalovirus, the high-risk combination inverts between the two transplant types.

• In solid-organ transplant (SOT), the seronegative recipient of a seropositive organ (donor positive, recipient negative) is at highest risk. Such a recipient meets EBV for the first time (a primary infection) while immunosuppressed, with no EBV-specific T cells to contain it. This is why PTLD is disproportionately a disease of children, who are most often EBV-naive at transplant.
• In stem-cell transplant (allogeneic haematopoietic cell transplant, HCT), the relationship reverses: the graft is the new immune system, so the seropositive recipient of a seronegative or T-cell-depleted donor is at highest risk, because the incoming donor immunity carries no EBV-specific T cells. Most PTLD after HCT is donor-derived, almost always EBV-associated, and appears within the first year.

The other major driver is the degree and type of immunosuppression. T-cell-depleting induction (antithymocyte globulin, the historical OKT3) drives early PTLD, while cumulative maintenance immunosuppression drives late disease. The intensity of immunosuppression an organ requires gives an organ-type hierarchy of incidence:

Transplant	Approximate PTLD incidence
Kidney	Around 1 to 2 per cent
Pancreas, liver	A few per cent
Heart	Several per cent
Lung	Up to around 10 per cent
Intestinal or multivisceral	Up to around 20 per cent
Stem-cell (allogeneic)	A few per cent overall, far higher with T-cell depletion, cord-blood or haploidentical grafts

(These figures vary with the era and the immunosuppressive regimen and should be read as orders of magnitude.) The timing is bimodal: an early peak in the first year, mostly EBV-positive, and a late peak at five to fifteen years, often EBV-negative. The history of tacrolimus illustrates the immunosuppression link: when it was introduced for paediatric kidney transplantation, PTLD incidence rose, and fell again once centres tapered it more aggressively to lower target levels. Belatacept is specifically associated with central-nervous-system PTLD in EBV-seronegative recipients.

Clinical presentation

PTLD is clinically heterogeneous, from an incidental finding to fulminant, disseminated disease that can resemble sepsis. Nonspecific constitutional features (fever, weight loss, fatigue, night sweats) are common, and the picture can resemble infectious mononucleosis. The feature that distinguishes PTLD from ordinary lymphoma is the high rate of extranodal disease: more than half present with extranodal masses, a substantial minority involve the central nervous system (CNS) (rare in ordinary lymphoma), and a similar proportion infiltrate the transplanted allograft itself, which can drive graft dysfunction (renal failure, heart failure, respiratory compromise) and mimic rejection. Children more often present with isolated cervical lymphadenopathy, intussusception or bowel-wall thickening, while adults more often have extranodal gastrointestinal, allograft or CNS disease. Early, donor-origin disease tends to be confined to the graft; late, EBV-negative disease tends to be extranodal, monomorphic and aggressive.

Several laboratory findings support the suspicion: unexplained anaemia, thrombocytopenia or leukopenia, a raised lactate dehydrogenase (LDH), hypercalcaemia, hyperuricaemia, and a monoclonal protein in serum or urine. The monoclonal protein is a useful, inexpensive, noninvasive marker: its appearance can indicate developing PTLD and its disappearance tracks remission. The two differentials to keep in mind throughout are allograft rejection (especially when the graft is involved) and infection.

Diagnosis

Diagnosis combines two complementary tools: a blood test that adjusts the level of suspicion, and a biopsy that establishes the diagnosis.

EBV-DNA viral-load monitoring. Many transplant recipients show a modest rise in blood EBV-DNA after transplant, but the great majority of patients with EBV-positive PTLD show a markedly higher load, so a high or rapidly rising load indicates increased risk and prompts pre-emptive action in high-risk patients. The limits, however, are real and contrast with the better-standardised cytomegalovirus picture:

• There is no universal threshold, and because laboratories use different assays and report in different ways, loads cannot be compared between institutions.
• The test is better at excluding PTLD than confirming it: a low or absent load makes PTLD less likely, but a high load is only suggestive, since many patients with high loads never develop disease.
• The sample matters: cell-free plasma EBV-DNA is more specific for established disease, while whole blood is more sensitive for surveillance.
• Monitoring is most intensive early, in the first months after transplant when EBV-positive disease is most likely, and in the highest-risk patients, then spaced out as risk falls. Exact schedules and trigger thresholds vary by centre, assay and transplant type, and are not standardised.
• Serial loads also track response: in responders the load falls quickly once effective treatment starts, while a rising load predicts failure.

The blood EBV load cannot diagnose established PTLD and never substitutes for tissue: a high load is suggestive, but a normal load does not fully exclude the disease.

The definitive diagnosis is histological. It requires a tissue biopsy, preferably a generous excisional biopsy reviewed by a haematopathologist, characterised by morphology, immunophenotype (including CD20 status, which determines whether rituximab can be used), EBER in-situ hybridisation for EBV, and clonality and genetic studies. Staging then follows lymphoma practice: cross-sectional imaging of chest, abdomen and pelvis, increasingly positron emission tomography (PET) with computed tomography (CT) for disease activity, assessment of graft function, bone-marrow examination where there are cytopenias, and dedicated brain imaging with cerebrospinal-fluid analysis where CNS disease is suspected.

Management

Two goals govern treatment and frequently conflict: eradicate the PTLD and preserve the graft. Reducing immunosuppression serves the first but threatens the second, and which goal takes precedence depends on whether the organ can be supported by other means (a failing kidney can return to dialysis; a failing heart cannot). The functional framework sets the intensity: quintessential, EBV-driven PTLD is treated with the lowest-intensity approach that is effective, escalating only as needed, while a post-transplant lymphoma is treated as the corresponding lymphoma would be in an immunocompetent patient. Within that, treatment follows a graded ladder.

Reduce immunosuppression first. This is the foundation for every subtype. The calcineurin inhibitor is reduced and the antimetabolite usually stopped, to the lowest level the graft can tolerate, balanced against the risk of rejection (which is greatest, and most dangerous, in heart, lung and liver recipients). Early, EBV-driven, low-burden disease responds well; response is poorest in late, EBV-negative, bulky or CNS disease.

Add rituximab. Rituximab is a monoclonal antibody against CD20, a protein on the surface of B cells, so it is effective only in CD20-positive disease. Added to reduced immunosuppression, it controls a large proportion of quintessential PTLD, and remission on rituximab alone can spare a patient chemotherapy. Hepatitis B status is checked first, because rituximab can reactivate hepatitis B.

Escalate to chemotherapy when needed. Disease that does not respond to reduced immunosuppression and rituximab, and post-transplant lymphomas from the outset, are treated with lymphoma chemotherapy (a regimen such as rituximab combined with CHOP, which is cyclophosphamide, doxorubicin, vincristine and prednisone), commonly in a response-guided sequence in which rituximab is given first and chemotherapy added for incomplete responders. CD20-negative disease is treated with chemotherapy without rituximab, and Burkitt or other specific lymphomas with their own dedicated regimens.

Restore EBV-specific immunity. Adoptive cellular therapy restores the immunity that immunosuppression had removed: T cells that recognise and kill EBV-infected B cells. It applies only to EBV-positive disease and is most effective after stem-cell transplant. Off-the-shelf, third-party EBV-specific T cells are now reaching practice for relapsed or refractory EBV-positive PTLD, and unlike donor lymphocyte infusion they carry little risk of graft-versus-host disease.

Emerging directions. Several newer approaches are under study and may broaden the options over time: antibody-drug conjugates directed at CD30 (an activation marker expressed across PTLD types), antibodies against the B-cell growth signal interleukin-6, and the continued expansion of EBV-specific cellular therapies. These remain specialised and are noted in principle rather than as established regimens, and their availability differs widely between settings.

CNS disease and surgery. PTLD in the central nervous system is treated on the lines of a primary CNS lymphoma, because most standard chemotherapy does not penetrate the brain. Surgery is reserved for localised complications such as bowel perforation or obstruction, and occasionally for genuinely localised disease.

Why antivirals have no role in treatment. The proliferating B cells carry EBV in its latent state, in which the virus is not replicating and does not express the thymidine kinase that activates aciclovir or ganciclovir. These drugs therefore have nothing to act on once PTLD is established.

Prevention

Prevention addresses the same balance. The first measure is to avoid excessive immunosuppression: limiting cumulative exposure and tapering to the lowest effective level measurably lowers PTLD. The second is avoiding a seropositive donor for a seronegative stem-cell recipient where donor choice allows. The third, and the most actively practised, is EBV surveillance with pre-emptive treatment: high-risk patients are monitored, and a confirmed, rising load prompts either reduced immunosuppression or a pre-emptive dose of rituximab before disease declares itself, although the exact trigger and the benefit of this approach remain unsettled. Antiviral prophylaxis shows a weak epidemiological signal of reduced PTLD risk, but the evidence is inconsistent and it is no substitute for surveillance, for the same reason antivirals do not treat established disease.

Prognosis

Outcomes have improved markedly since rituximab entered practice. Older series reported survival of only a quarter to a third, with the poorest outcomes in monomorphic and T-cell disease; current response-guided treatment achieves durable remission in the majority of quintessential, EBV-positive cases. Adverse prognostic factors include older age, impaired graft function, raised LDH, CNS or serosal involvement, monomorphic or T-cell histology, poor performance status, multiple disease sites, bone-marrow involvement and low albumin, and these cluster: the more adverse factors present, the worse the outlook. Even so, a substantial minority of quintessential disease, and most true post-transplant lymphomas, still require intensive treatment, and a proportion relapse. Re-transplantation is feasible for selected patients who have cleared their PTLD, generally some years later.

South African context

EBV seroprevalence in South Africa is very high and infection occurs in early childhood, so the seronegative adult recipient at risk of a primary infection is uncommon; the donor-positive, recipient-negative risk is therefore most relevant in paediatric transplantation. EBV-DNA PCR is available through the National Health Laboratory Service for surveillance, and rituximab is available for treatment; the newer cellular therapies are not generally available, so refractory EBV-positive disease is managed by reducing immunosuppression and with chemotherapy at tertiary level. (This section is a general orientation and would be strengthened by a local transplant-unit protocol.)

References and recommended reading

• Dierickx D, Habermann TM. Post-Transplantation Lymphoproliferative Disorders in Adults. New England Journal of Medicine 2018;378(6):549-562. DOI 10.1056/NEJMra1702693. The concise review underpinning the classification, risk factors and treatment paradigm.
• El-Mallawany NK, Rouce RH. EBV and post-transplant lymphoproliferative disorder: a complex relationship. Hematology (American Society of Hematology Education Program) 2024. Source for the functional framework of post-transplant EBV, quintessential PTLD and post-transplant lymphoma, and the EBV-by-histology pattern.
• Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia 2022;36(7):1720-1748. DOI 10.1038/s41375-022-01620-2. The WHO immune deficiency and dysregulation (IDD) framework and the three-part nomenclature.
• Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms. Blood 2022;140(11):1229-1253. DOI 10.1182/blood.2022015851. The parallel 2022 classification adopting the same IDD framework.
• Chen EY, Dilwali N, Mysore KR, et al. Navigating Epstein-Barr Virus and Post-Transplant Lymphoproliferative Disorder in Pediatric Liver Transplantation. Viruses 2025;17(2):254. DOI 10.3390/v17020254. Current detection methods, the WHO and ICC comparison, and emerging therapeutic directions.
• Friedberg JW, Aster JC. Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders; and Negrin RS, Brennan DC, Treatment and prevention of post-transplant lymphoproliferative disorders. UpToDate (Wolters Kluwer); accessed June 2026. Clinical manifestations, EBV-DNA monitoring, the diagnostic approach and the treatment ladder (paraphrased).
• Richman DD, Whitley RJ, Hayden FG (eds.). Clinical Virology, 4th edition (EBV chapter, PTLD section). Washington: ASM Press; 2016. Foundational pathogenesis and the donor-positive, recipient-negative primary-infection risk.