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Diagnosis & Monitoring

Identifying patients with EBV+ PTLD

The development of EBV+ PTLD can be an unexpected and distressing 
complication for transplant recipients.

Early identification of at-risk patients and prompt recognition of early signs 
are key to achieving timely diagnosis and reducing disease burden.

Monitoring higher-risk patients and following a structured diagnostic approach 
support timely intervention and improved outcomes.

Key aspects in identifying patients with EBV+ PTLD

Risk Factors

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Signs & Symptoms

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Monitoring & Diagnosis

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Risk factors for EBV+ PTLD

The risk of developing EBV+ PTLD varies among transplant recipients and is
influenced by both patient and transplant characteristics.

Careful assessment of individual risk factors following SOT or HCT can support
early identification and monitoring of high-risk patients.Chronic sinus congestion

Risk factors post-SOT1-3

Early PTLD risk factors 
(<12 months after transplant)

  • Primary EBV infcetion derived from the donor
    • EBV serological status is a significant risk factor for PTLD–EBV-naïve patients (commonly paediatric/younger age) show the highest risk due to a lack of pre-formed anti-EBV cytotoxic immunity4,5
  • Younger age (children)
  • Treatment with anti-lymphocyte antibodies
  • Type of organ transplanted
    Incidence of EBV+ PTLD in recipients based on organ type:3
0.8-2.5% - Kidney
0.5-5% - Pancreatic
1.5-5% - Liver
2-8% - Heart
3-10% - Lung
<20% - Multiorgan and intestinal

Adapted from Dierickx D, et al. The New England Journal of Medicine. 2018

Late PTLD risk factors 
(>12 months after transplant)

  • Duration of immunosuppresive treatment
  • Type of organ transplanted
  • Older age (adults)

Risk factors post-HCT2,3,6

Pre-transplant risk factors

  • Degree of T-cell reduction (considered the primary risk factor for EBV+ PTLD6) and impairment
  • EBV sero-mismatch
  • Stem cell source (i.e., cord blood transplantation)
  • HLA mismatch

Post-transplant risk factors

  • Severe acute/chronic GvHD
  • High/rising EBV viral load (DNAemia)
  • Treatment with mesenchymal stem cells

Signs & symptoms of EBV+ PTLD

The clinical presentation of EBV+ PTLD is highly variable, ranging from asymptomatic EBV infection to fulminant disease with multi-organ involvement.1,2,7

Because progression can be rapid and aggressive, vigilance for early signs is essential – timely recognition supports earlier diagnosis, optimised treatment, and reduced disease burden.

Signs & Symptoms can include:1,2,6,7

Lethargy Icon

Malaise and Lethargy

Fever or night sweats

Sore throat

Enlargement or swelling of the lymph nodes

Weight loss

Chronic sinus congestion

Abdominal pain

Nausea and vomiting

Anorexia

GI symptoms, e.g. bleeding, bowel perforation

End-organ disease, e.g. hepatitis

As EBV+ PTLD progresses, it can involve any organ, such as the gastrointestinal tract, bone marrow, liver, spleen, lung, kidney, and CNS3,7 
In patients with EBV+ PTLD, fever and lymphadenopathy are associated with rapidly progressive multi-organ failure and death6 

Monitoring & diagnosis

Monitoring

In addition to vigilant monitoring for clinical symptoms, 
EBV viral-load testing (DNAemia) can be included in 
post-transplant surveillance to help inform pre-emptive 
management decisions:2,4,6

  • Pre-emptive therapy includes any intervention provided 
    to a patient with EBV DNAemia to prevent EBV disease6,8
  • Prophylaxis includes any intervention provided to an 
    asymptomatic EBV-seropositive patient to prevent EBV 
    DNAemia6,8

EBV viral load monitoring can be considered for SOT and 
HCT patients at increased risk of developing PTLD1,2

High-risk groups include:

  • Allogeneic HCT recipients
  • EBV-seronegative SOT recipients receiving organs from 
    EBV-seropositive donors
  • EBV-seronegative paediatric SOT recipients
  • EBV-seropositive SOT-recipient children <1 year of age
  • Intestinal transplant recipients

Recommendations for monitoring EBV viral load

  SOT1 HCT6
Testing method

qPCR
Sample type Whole blood, plasma, lymphocytes Whole blood, plasma, serum
Timing Suggested weekly to biweekly over the high-risk period (first-year) Begin within the first month. Continue for at least 4 months post-HCT, 1x/week

Diagnosis

For patients in whom progression to EBV+ PTLD is suspected:

TISSUE DIAGNOSIS 
The gold standard for confirming PTLD diagnosis is histological examination and immunophenotyping of tumor tissue, preferably through excisional biopsy or resection of suspected sites of disease; if not possible, core needle biopsy is an alternative4,6,9

NON-INVASIVE ASSESSMENT
Additional diagnostic confirmation can involve non-invasive methods, including quantification of EBV viral load (DNAemia) and PET-CT/CT imaging4,6,9,10 and can be considered for patients unable to undergo tissue biopsy6

Diagnostic workup includes:6,9,10

  • Physical exam and evaluation of performance status
  • History of immunosuppressive regimen
  • PET-CT/CT imaging
  • Tissue biopsy with ISH/IHC staining for viral antigens and/or flow cytometry
  • EBV viral load (DNAemia) and serology assessment
  • Laboratory assessments: complete blood count with differential and metabolic panel (e.g. liver enzymes, renal function)
  • Bone marrow evaluation in select cases
  • Endoscopy in cases of GI symptoms
  • Echocardiography where appropriate
  • Fertility-preserving treatment for eligible patients

Staging

Staging of EBV+ PTLD

Staging helps determine disease extent and guide treatment planning. Although no system is specific to EBV+ PTLD,
established lymphoma classifications can support staging.

Ann Arbor classification

  • Established for staging 
    Lymphoma
  • Used to describe sites of 
    involvement and the 
    presence of symptoms

Lugano classification

  • Recommended following 
    PET-CT in FDG-avid nodal 
    lymphomas in adults and 
    children

STAGING SYSTEM4,6,9

WHO-HAEM5

Classification of PTLD

The 2022 revision of the WHO Classification of Haematolymphoid Tumours (WHO-HAEM5) introduced major updates to the categorisation of immunodeficiency-associated lymphoproliferative disorders, establishing a unified overarching framework.11

Evolution of PTLD classification:
from WHO-HAEM4 to WHO-HAEM511

WHO-HAEM4 WHO-HAEM5
Non-destructive PTLD

Post-transplant hyperplasia:

  • Follicular hyperplasia
  • Mononucleosis-like hyperplasia
  • Plasma cell hyperplasia
  • KSH/HHV8 MCD

EBV+ in most cases12
Polymorphic PTLD

Post-transplant polymorphic LPDs

  • The majority is EBV+; onset can be early or late after transplant12
Monomorphic PTLD

Post-transplant lymphoma

  • Majority of early-onset disease is EBV+ while late-onset monomorphic DLBCL-like subtype is often EBV−12
CHL-PTLD

(Classic Hodgkin) lymphoma

  • CHL-PTLD is an uncommon subtype13 and the majority is EBV+12,13

Nomenclature

Nomenclature in the immune deficiency/dysregulation setting according to WHO-HAEM5 
WHO-HAEM5 has additionally introduced a standardised nomenclature to encompass the various settings of immune dysfunction.11

Three-part nomenclature for lymphoid proliferations and lymphomas11

Histological diagnosis Viral association Immune deficiency/
dysregulation setting
  • Hyperplasia (specify type)
  • Polymorphic lymphoproliferative disorder
  • Mucocutaneous ulcer
  • Lymphoma (classify as for immunocompetent patients)
  • EBV+/–
  • KSHV/HHV8 +/–
  • Inborn error of immunity (type)
  • HIV infection
  • Post-transplant (organ/stem cells)
  • Autoimmune disease  
  • Iatrogenic/ therapy-related (specify)
  • Immune senescence

Adapted from Alaggio R, et al., Leukemia. 2022. https://creativecommons.org/licenses/by/4.0/.Table title abridged.

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References
  1. Allen UD, Preiksaitis JK. Clin Transplant. 2019;33(9):e13652.
  2. Yamada M, et al. J Pediatric Infect Dis Soc. 2024;13(Suppl 1):S31–S38.
  3. Dierickx D, Habermann TM. N Engl J Med. 2018;378(6):549–62.
  4. Nijland ML, et al. Transplant Direct. 2015;2(1):e48.
  5. Clerico M, et al. J Clin Med. 2022;11(24):7542.
  6. Styczynski J, et al. Haematologica. 2016;101(7):803–11.
  7. Fujimoto A, Suzuki R. Cancers (Basel). 2020;12(2):328.
  8. Sureda A, et al. The EBMT Handbook: Haematopoietic Stem Cell Transplantation and Cellular Therapies. 8th edition. Cham (CH): Springer; 2024. 
  9. Shah N, et al. Br J Haematol. 2021;193(4):727–40.
  10. Samant H, et al. Posttransplant Lymphoproliferative Disorders. StatPearls Publishing; 2023. 
  11. Alaggio R, et al. Leukemia. 2022;36(7):1720–48.
  12. Atallah-Yunes SA, et al. Br J Haematol. 2023;201(3):383–95.
  13. Rosenberg AS, et al. Am J Hematol. 2016; 91(6): 560–5.
Abbreviations
  • CHL, Classic Hodgkin Lymphoma
  • CNS, central nervous system
  • CT, computed tomography
  • DLBCL, diffuse large B-cell lymphoma
  • EBV(+), Epstein–Barr virus (positive)
  • FDG, 18F-fluorodeoxyglucose
  • GI, Gastrointestinal
  • GvHD, graft-versus-host disease
  • HCT, haematopoietic cell transplantation
  • HHV8, human herpesvirus-8
  • HLA, human leukocyte antigen
  • IHC, immunohistochemistry
  • ISH, in-situ hybridisation
  • KSH(V), Kaposi sarcoma-associated herpesvirus
  • LPD, lymphoproliferative disorder
  • MCD, multicentric Castleman disease
  • PET, positron emission tomography
  • PTLD, post-transplant lymphoproliferative disorder
  • qPCR, quantitative real-time polymerase chain reaction
  • SOT, solid organ transplant
  • WHO, World Health Organization
  • WHO-HAEM, World Health Organization Classification of Haematolymphoid Tumours