1. Epstein-Barr virus (EBV) commonly infects B cells and epithelial cells and is the leading cause of post-transplant lymphoproliferative disorder (PTLD). 2. PTLD risk is highest in the first year after transplant and among EBV-negative recipients of organs from EBV-positive donors. 3. Treatment of PTLD involves reducing immunosuppression when possible, along with antiviral agents, immune globulin, monoclonal antibodies, and chemotherapy.

1. ‫بسم‬‫هللا‬‫الرحمن‬‫الرحیم‬
EBV infection in Pediatrics
kidney transplant
Fahimeh Asgarain-MD
TUMS

2. Virology
o EBV is a double-stranded DNA virus.
o It is a member of the gamma herpesviruses.
o Gamma herpesviruses replicate in lymphoid cells.
o Target cells: B cells, T cells, Epithelial cells, myocytes

3. Virology
o Two distinct types of EBV, type 1 and type 2 have been
characterized.
o Dual infections with both types have been documented among
immunocompromised persons

4. Virology
o EBV-1 induces in vitro growth transformation of B lymphocytes
more efficiently than does EBV-2, but no type-specific disease
manifestations or clinical differences have been identified.
o EBV-2 has been shown to latently infect T cells and induce T cell
cytokines.

5. Virology
o Humans are the only known host of EBV.
o Transmission route :
o Exposure to saliva
o Transfusion of nonleukoreduced blood products
o In developing countries, 90% of children are infected before age 5
years, typically acquiring infection in an asymptomatic manner

6. What is the importance of EBV?

7. o Acute EBV infection leads to a polyclonal expansion of infected B
cells.
o In immunocompetent individuals, viral antigens expressed by these
B cells elicit a cytotoxic T cell response that eliminates the vast
majority of the infected B cells.

8. o A number of EBV-encoded proteins drive signaling events that
directly contribute to B cell growth and survival.
o LMP-1
o LMP-2A
o EBNA-2
o EBNA-lp

9. Manifestation of EBV
o PTLD
o Non PTLD malignancies
o Non PTLD manifestation

10. PTLD
o PTLD is one of the most devastating complications of organ
transplantation.
o PTLD is the most common malignancy complicating solid organ
transplantation( all age groups)

11. o Incidence of PTLD among EBV-negative recipients from 2006-2016
was 3.1% at 5 years posttransplant, compared with 0.8% among
EBV-positive recipients.
o The reported incidence of PTLD varies among transplant centers,
likely as a result of different patient populations, allograft types,
and immunosuppressive regimens.
OPTN/SRTR 2018 Annual Data Report: Kidney

13. o More than 80 % of PTLD occur in the first year after transplantation
o Although the highest rate of PTLD in the SOT setting is seen in the
first year after transplant, some analyses suggest that the incidence
of early PTLD (>90% EBV‐positive) is decreasing.( adult recipients)

14. Risk factors
Post‐transplant lymphoproliferative disorders, Epstein‐Barr
virus infection, and disease in solid organ transplantation:
Guidelines from the American Society of Transplantation
Infectious Diseases Community of Practice -2019

15. Risk factors
o An overwhelming risk factor in most analyses is EBV‐seronegativity
pre‐transplant and primary EBV infection, placing pediatric
populations at higher risk of developing PTLD than their adult
counterparts.
o R+ are not devoid of PTLD risk, and this risk appears higher in
pediatric than adult recipients

18. o Sampaio et al observed among pediatric recipients that donor
seropositivity (D+R−) and donor seronegativity (D−R−) resulted in
comparable risks for PTLD at three years post‐ transplant, perhaps
reflecting the high rate of community‐acquired infection in children

19. Risk factors
o Although PTLD rates increased after calcineurin inhibitors became
the backbone of most immunosuppressive regimens, it is likely that
the net state of immunosuppression, an entity difficult to
measure, is a major risk factor

20. o Effect of induction therapy on incidence of PTLD:
o Increased incidence:
o OKT3
o Alemtuzumab
o No increased risk
o Polyclonal anti–t cell agents
o IL2 receptor antagonists
Hall EC, Engels EA, Pfeiffer RM, Segev DL. Association of antibody induction immunosuppression with cancer after
kidney transplan‐ tation. Transplantation. 2015;99:1051‐1057.

21. o Maintenance immunosuppressive:
o Belatacept (costimulation blocker)
o Primary CNS lymphoma in EBV seronegative recipients
o It is contraindicated in EBV seronegative recipients.
o Tacrolimus?!
o CMV infection?

23. DIAGNOSTIC AND EVALUATIVE TESTS
o Non EBV related tests:
o CBC-diff (lymphopenia, anemia, thrombocytopenia)
o Renal and liver function tests
o Serum electrolytes
o LDH; Uric Acid
o Plasma CMV PCR

24. DIAGNOSTIC AND EVALUATIVE TESTS
o EBV related tests
o EBV serology
Anti‐VCA IgG and anti‐EBNA‐1 IgG are serologic tests most often used for EBV serostatus
assignment.
Anti–early antigen (EA) and anti‐VCA IgM, more commonly used for diagnosing primary infection in
immunocompetent hosts.

25. Viral load determination
o The optimal way to perform, interpret, and utilize quantitative EBV
viral load assays for surveillance, diagnostic, and disease monitoring
purposes remains uncertain

26. Viral load determination
o Whole blood or lymphocyte EBV viral load is higher and becomes
detectable earlier than plasma samples , making testing of this
sample type more sensitive for early detection of primary infection
and EBV reactivation events.
o Plasma testing may have better specificity for the detection and
monitoring of EBV‐related disease including PTLD.

27. Viral load determination
o Based upon historical studies in high‐risk asymptomatic SOT recipients
being serially monitored, the use of EBV viral load as a diagnostic test
(ie, levels above a specific quantitative threshold being diagnostic of
PTLD) has good sensitivity for detecting EBV‐positive early PTLD but
misses EBV‐negative as well as some cases of localized and donor‐derived
EBV + PTLD.
o However, it had poor specificity, resulting in good negative (greater than
90%) but poor positive predictive value (as low as 28% and not greater
than 65%) in these populations

28. Viral load determination
o When used in the diagnostic context, this would result in significant
unnecessary investigation of patients for PTLD.

29. Measurement of EBV viral load as routine evaluation
To Do
Or
Not To Do?

31. o We recommend EBV viral load surveillance and preemptive
interventions in patients who are EBV‐seronegative pre‐transplant
(weak/low).
o In patients who receive seropositive donor organs, monitoring
should occur weekly to biweekly, when possible over the first
post‐transplant year.

32. PREVENTION OF PTLD
o Identify high risk patients(EBV seronegative recipients)
o Monitor patients carefully for symptoms/signs of PTLD

33. Prevention of PTLD
⁉ Anti viral prophylaxis:
o Chemoprophylaxis:
❓ Acyclovir
❓ Ganciclovir
o Immunoprophylaxis:
o IVIG
o EBV vaccine

34. Imaging modalities
o CT scan
o Chest
o Abdomen
o Pelvic
o Brain CT scan/MRI

35. TREATMENT OF PTLD
o Reduction of immunosuppression
o The optimal strategy for immunosuppression reduction is uncertain.
o Common approaches used included:
o Reduction of CNIs by 30%‐50%
o Discontinuation of anti‐proliferative agents (azathioprine and MMF)
o Switching CNIs to mTOR inhibitors
o Most patients show evidence of a clinical response to reduced
immunosuppression within 2‐4 weeks.
Post‐transplant lymphoproliferative disorders, Epstein‐Barr virus infection, and disease in solid organ transplantation: Guidelines
from the American Society of Transplantation Infectious Diseases Community of Practice ; Clinical Transplantation. 2019;33:e13652.
https://doi.org/10.1111/ctr.13652

36. Treatment of PTLD
o Antiviral agents, immune globulin, and monoclonal antibodies
o When antiviral agents are employed, the agent of choice is ganciclovir
o Antiviral therapy and/or IVIG alone should not be used for PTLD in the
absence of other interventions (ie, RIS, rituximab, chemotherapy)
(strong/very low).
o There are insufficient data to recommend for or against their use as
adjunctive therapy.
Post‐transplant lymphoproliferative disorders, Epstein‐Barr virus infection, and disease in solid organ transplantation: Guidelines
from the American Society of Transplantation Infectious Diseases Community of Practice ; Clinical Transplantation. 2019;33:e13652.
https://doi.org/10.1111/ctr.13652

37. Treatment of PTLD
o We recommend rituximab monotherapy as the next level of
treatment for adult and pediatric CD20+ PTLD in patient with
progressive disease after RIS (adults: strong/high, pediatric strong/
moderate).
Post‐transplant lymphoproliferative disorders, Epstein‐Barr virus infection, and disease in solid organ transplantation: Guidelines
from the American Society of Transplantation Infectious Diseases Community of Practice ; Clinical Transplantation. 2019;33:e13652.
https://doi.org/10.1111/ctr.13652