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EBV and kidney transplant

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A review on EBV diagnosis and manifestation in kidney trnansplant

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EBV and kidney transplant

  1. 1. ‫بسم‬‫هللا‬‫الرحمن‬‫الرحیم‬ EBV infection in Pediatrics kidney transplant Fahimeh Asgarain-MD TUMS
  2. 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. 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. 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. 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. 6. What is the importance of EBV?
  7. 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. 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. 9. Manifestation of EBV o PTLD o Non PTLD malignancies o Non PTLD manifestation
  10. 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. 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
  12. 12. 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)
  13. 13. 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
  14. 14. 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
  15. 15. 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
  16. 16. 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
  17. 17. 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.
  18. 18. 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?
  19. 19. 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
  20. 20. 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.
  21. 21. 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
  22. 22. 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.
  23. 23. 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
  24. 24. Viral load determination o When used in the diagnostic context, this would result in significant unnecessary investigation of patients for PTLD.
  25. 25. Measurement of EBV viral load as routine evaluation To Do Or Not To Do?
  26. 26. 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.
  27. 27. PREVENTION OF PTLD o Identify high risk patients(EBV seronegative recipients) o Monitor patients carefully for symptoms/signs of PTLD
  28. 28. Prevention of PTLD ⁉ Anti viral prophylaxis: o Chemoprophylaxis: ❓ Acyclovir ❓ Ganciclovir o Immunoprophylaxis: o IVIG o EBV vaccine
  29. 29. Imaging modalities o CT scan o Chest o Abdomen o Pelvic o Brain CT scan/MRI
  30. 30. 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
  31. 31. 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
  32. 32. 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

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