4. A 17-year-old patient received an adult kidney 3 months ago, EBV +ve/EBV -ve. Her EBV PCR reported 31000 copies. Currently, she is on Tacrolimus-based triple immunosuppression with excellent kidney function. No symptoms or signs suggested infection (viral and bacterial).
What are the risks involved in the given scenario?
How would you manage this patient?
104 Comments
Md Ashraful Alam
> high risk of developing PTLD as D+/ R- & has high viral load.
> reduce the immunosuppression & monitior EBV PCR, if still high viremia then go for PET-CT.
High risk of PTLD as it usually occur in early post transplant period especially in case of donor +ve/R-ve
so better to decrease immunosuppression dose and follow up in 1st week of transplant by EBV PCR then monthly for 3-6 months then every 3 month untill the end for 1st year
EBV has no definitive antiviral therapy
After immunosupp stopped and still viremia >you should proceed for Pet scan
What are the risks involved in the given scenario? · The transmission of EBV is universal from EBV+ donor to EBV- recipients and EBV-seronegative kidney transplant recipients have 10-50-fold increased risk for PTLD compared to EBV-seropositive recipients. It is well known that the majority of PTLD cases (> 85%) are observed in the first year post-transplant. · This index case is at high risk (D+/R-), he has a high viral load (31000 copies/ml 3 months post-transplant, after being exposed to the induction immunosuppression and kept of maintenance triple immunosuppression). · The KDIGO guideline recommended monitoring high-risk (D+/R-) KTRs for EBV by NAT (EBV PCR)once in the first week following transplantation, then monthly for 3– 6 months and then every 3 months until the end of the first year –transplant. Besides, it is required to be checked following treatment for acute rejection episodes. However, the draw back that there is no universal cut off threshold for EBV viral titre and there is wide laboratory variability, but some authors have chosen 4000 copies/ml to be the cut-off for increased risk for PTLD. How would you manage this patient? Take a detailed history including any weight loss, night sweats and night fever
Thorough clinical examination for lymphadenopathy and splenomegaly
Bloods: FBC( anaemia, thrombocytopenia or leukopenia), LDH, CA level and S. Urate
Tacrolimus trough levels
CMV PCR as CMV infection is a risk factor for PTLD
Radiological investigations: Do a CT scan of the chest and the abdomen to look for a mass(the gold standard of diagnosing PTLD is via histology)
No definitive treatment for EBV. Final decision depends on the CMV PCR values and the clinical finding and investigations
In this index asymptomatic case (D+/R-) and high EBV PCR in the early post-transplant period, we need to reduce immunosuppression and monitor his EBV PCR.
Reduce MMF by 50% or stop it. Reduce TAC and maintain a low trough level (focus on drug level rather than the dose).Some advocate switching from TAC to Sirolimus. Monitor graft function for rejection episodes .If EBV PCR remain high, proceed for PET CT.
References: 1. Erica F. Clinical Utility of Epstein-Barr Virus Viral Load Monitoring and Risk Factors for Posttransplant Lymphoproliferative Disorders After Kidney Transplantation: A Single-Center, 10-Year Observational Cohort Study. Transplantation Direct 3(7):p e182, July 2017. Allen UD, Preiksaitis JK; AST Infectious Diseases Community of Practice. Epstein-Barr virus and posttransplant lymphoproliferative disorder in solid organ transplantation. Am J Transplant. 2013; 13 (Suppl 4): 107–120.
· Q1: What are the risks involved in the given scenario? 17 years young recipient, pre-op EBV-serostatus (D+/R-) is at high-risk for EBV-related PTLD. Rising EBV-DNA 31,000 indicates florid and active viral proliferation. So, the risk of primary EBV as well as development of PTLD is very high in this patient. Children and younger recipients have higher risk of PTLD, mostly during first year post-transplant. In fact, PTLD is the most common malignancy in children – up to 50% after liver transplant, 5-15% following renal transplant. Intense immunosuppression, especially use of T-cell depleting agent is high risk factor. Tacrolimus based maintenance immunosuppression is associated with 3-5 times increased risk of PTLD.
Q2: How would you manage this patient Detail history (GI, CNS or visceral symptoms); physical examination (lymphadenopathy or organomegaly or CNS involvement). Imaging – whole body PET-CT, if available is diagnostic modality of choice. Else, CECT Chest, Abdomen and Pelvis – may yield RP lymphadenopathy, renal allograft SOL or visceral involvement. Immunosuppression Reduction /Optimization is necessary first step. MMF to be reduced 50%, with minimized dose of Tacrolimus keeping lowest target C0 (5ng/ml) à monitoring EBV-DNA monthly x 6months; then 3monthly x 2-3 years. If Viremia still high à stop MMF or switch to sirolimus or everolimus. There is no standardised cut-off for EBV viral load, but EBV-DNA more than 2000 copies need attention. No role of antiviral, except in PNS. Any enlarged Lymph node, visceral SOL or Graft dysfunction need biopsy, to detect PTLD early. Only renal allograft or limited organ involvement, shall be managed initially with Rituximab. Muti-organ involvement or persistent PTLD after Rituximab, need combined Chemotherapy (R-CHOP) +/- Radiation. 1. REFERENCE KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3: S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. PMID: 19845597.
2. Gaurav Agarwal and Roslyn B. Mannon. Post-Transplant Lymphoproliferative Disorder in a Kidney Transplant Recipient. Clin J Am Soc Nephrol. 2019 May 7; 14(5): 751-753. Published online 2019 Feb 25 3. Franceschini E, Plessi J, Zona S, et al. Clinical Utility of EBV Viral Load Monitoring and Risk Factors for PTLD after Kidney Transplantation: A Single-Centre 10-Year Observational Cohort Study. Transplant Direct. 2017 Jun 26;3(7): e182. doi: 10.1097/TXD.0000000000000703. PMID: 28706985; PMCID: PMC5498023.
Q1: The recipient is young (only 17 y/o) and EBV-seronegative before TX and received a kidney from EBV-seropositive donor (D+/R-). So, the risk of primary EBV is high and is associated with the development of PTLD.
Use of tacrolimus in maintenance immunosuppression is associated with 3-5 times increase in the rate of PTLD.
Q2: For the management:
Comprehensive history (about B symptoms) and physical examination (lymphadenopathy or organomegaly or CNS involvement) should be performed.
Imaging studies are needed properly. Reduction of immunosuppression is necessary. Stop MMF, switch to sirolimus or everlimus, reduce tacrolimus dose with its level monitoring.
Monitor for EBV PCR viral load and if persistently is high, use rituximab.
There is no standard for EBV viral load, but viral loads more than 2000 copies need attention.
· What are the risks involved in the given scenario?
This patient is high risk for PTLD, because of EBV +ve donor to EBV negative recipient and high viral load.
· How would you manage this patient?
High EBV viral load without confirmed PTLD, will need closer monitoring for PTLD, reduction of immunosuppression specially if he has no high risk for rejection. Cutting MMF by 50% and keeping FK level at lower end of target, around 5.
References: Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. PMID: 19845597.
Our recipient / donor EBV status is considered a risky one as evidenced by the development of EBV , apparent through the PCR .
Although currently asymptomatic , close follow up is needed through regular EBV quantitative PCR analysis , general examination and exclusion of any symptoms or signs for the fear of PTLD development .
Epstein-Barr virus (EBV) is a gamma herpesvirus associated with diseases ranging from asymptomatic viremia to post-transplant malignancies in kidney transplant recipients. EBV specifically is associated with post-transplantation lymphoproliferative disorder (PTLD), in kidney transplant recipients, with increased risk in EBV seronegative patients with EBV seropositive donors on intensified immunosuppression. The diagnosis of PTLD relies on clinical suspicion plus tissue biopsy with polymerase chain reaction (PCR) testing of blood currently used for risk determination in high-risk recipients. Therapeutic strategies for PTLD include reduction of immunosuppression, chemotherapy and rituximab, and consideration of sirolimus-based immunosuppression. Antivirals such as ganciclovir are used to prevent reactivation of cytomegalovirus and other herpes viruses but are not onco-therapeutic. Radiation therapy or surgery is indicated for bulky, disseminated or recalcitrant disease. Prognosis varies depending on the type of malignancy identified and stage of disease.
· What are the risks involved in the given scenario? Transplant recipient in the early post transplant period EBV – Recipient from EBV+ donor which could cause transmission of infection. Triple immunosuppressants (Tacrolimus based). Younger age and expected long duration of IS exposure that increases the incidence of cancers.
How would you manage this patient? transplant recipients have a threefold higher risk of cancer, particularly virally mediated cancers, compared with the general population . PTLD represents 21% of all cancers, kidney recipients have the lowest risk of PTLD , with a bimodal incidence in the early post-transplant period and a second peak later 10–14 years post-transplant. This patient is young age and it was shown that Early-onset PTLD is more common in children (2.4%–15% incidence), and it is characterized by EBV tissue positivity, extra-nodal disease, and a monomorphic subtype . EBV seronegative recipients receiving an EBV-positive organ have a 10- to 75-fold higher risk compared with seropositive recipients. She must be monitored frequently for increased viral load monthly until 6 months post-transplant, then every 3 months for up to 5 years. -renal biopsy if graft dysfunction occurred, or viral load increased. – swith to mTORi after 6 month was and reduction of MMF may reduce the incidence or delay occurrence of PTLD.
· What are the risks involved in the given scenario?Due to the serological characteristic of EBV for this transplant (D+/R-), this recipient is at high risk for the development of EBV and, consequently, PTLD in the first year after transplantation.Once the viral load is measured, with this high value at 3 months after transplantation, this risk becomes more evident.· How would you manage this patient?
The first step should be the decrease in immunosuppression (25% reduction in all immunosuppression) with the purpose of preventing the development of the disease and after that one would start a screening/staging through MRI of the whole body or PET-SCAN to assess whether there are already signs of active disease.
If there are signs of active disease, I would look for the best method to try to confirm it (biopsy for histopathology and immunohistochemistry) and, depending on the severity, I would try to wait for the result of the decrease in immunosuppression. If the result was not satisfactory, we should start with specific treatment with Rituximab and CHOP if necessary.
What are the risks involved in the given scenario?
Post-transplant malignancy with PTLD is the major risk in this given scenario.
How would you manage this patient?
The first line of management would be switching tacrolimus based immunosuppression to mTOR inhibitors till the onset of PTLD.
The risk factors in this patient are donor positive EBV + and negative EBV recipient….The patient is in the 3rd month of transplantation when the immunosuppression is high and this is also the period of first 12 months for high risk of PTLD onset…The patient also has high EBV DNA viral load (31000 copies)
How to manage the patient?
Patient should be under intense monitoring…Detailed blood examination by CBC, liver function test, LDH, Renal function test….baseline septic screening should be done…Patient should be asked for history of fever with night sweats and weight loss…PET CT scan of the whole body should be done to look for lymphadenopathy…IF there is lymphadenopathy we should plan biopsy with immunohistochemistry for diagnosis…EBV DNA is variable across different centers but value more than 4000 copies/ml is significant and it is associated with PTLD development…
KDIGO guidelines – Monitoring high risk transplant patients (donor EBV+ and recipient seronegative) for EBV is recommended…1st month – every week, monthly for first 3 to 6 months, then every 3 months until 1 year….there is also recommendations to reduce immunosuppression for EBV negative recipients with high EBV DNA viral load in those recipients with increasing EBV DNA load…
American society of transplantation – Monitoring EBV DNA in indicated in high risk population and routine screening in low risk population is not advised…
As the viral load of EBV is high, we need to reduce the immunosuppression. .I would reduce or stop anti-metabolite and continue tacrolimus with low dose steroids intially…
I will change to sirolimus from tacrolimus in a gradual way to reduce the risk of progression of PTLD… There are data to show that sirolimus conversion in PTLD reduces the the disease and prevent the progression1.
The use of rituximab is those with high EBV DNA viral load is recommended… data from HSCT recommend one dose of rituxmab if EBV DNA>1000 copies/ml itself…
I will give one dose of rituximab in this patient due to very high baseline EBV DNA load…
Pascual J. Post-transplant lymphoproliferative disorder—The potential of proliferation signal inhibitors. Nephrol. Dial. Transplant. 2007;22:i27–i35
Worth A, Conyers R, Cohen J, et al. Pre-emptive rituximab based on viraemia and T cell reconstitution: a highly effective strategy for the prevention of Epstein-Barr virus-associated lymphoproliferative disease following stem cell transplantation. Br J Haematol 2011; 155:377
What are the risks involved in the given scenario?
*Young age
*During the 1st year posttransplant
*heavy immunosuppressant medications
*Serostatus of EBV(D+/R-)
How would you manage this patient?
Close monitoring of EBV viral load, after the first week post transplantation, then monthly for the first 3 months, then every 3 months till the end of the first year.
Thorough history and physical examination
Investigations include: CBC, ESR, LFT , RFT, LDH, Ct chest, abdomen and pelvis.
Abdomenal US
Tissue biopsy
CMV PCR
Treatment include : high index of suspicion in case of PTLD
The mainstay for the treatment is RI by stopping MMF and maintain the CNIs on lower and safe level.
If no response,consider other options like
RTx
mTOR inhibitors
Surgical and radiological options may be need
Finally Adoptive immunotherapy has a promised results.
The following are the potential risks:
Seronegative recipient from seropositive donor
-Young age
Triple immunosuppressive therapy (calcineurin inhibitor-based)
Management of this patient
The patient was transplanted three months ago and has an EBV viral load of 31,000 copies and a serostatus of D+/R-, both of which put them at a high risk for PTLD.
The first step in management should involve compiling a comprehensive history and doing a careful physical examination.
Reducing immunosuppression in EBV seronegative recipients with a growing EBV virus load is advised by KDIGO recommendations.
The EBV viral load should be tested once the first week after transplant, once every month for the first three to six months, and once every three months until one year after transplant, according to KDIGO recommendations.
Put her under monitoring because this index case is currently a symptom.
It is recognized that a history of using T cell-depleting drugs as part of induction treatment increases the chance of developing PTLD.
Check the viral load after two weeks; if it is increasing, additional studies are required.
If the initial course of treatment is unsuccessful, the next step is to stop the antimetabolite, reduce the dosage of Tacrolimus, or switch to m-TOR.
Monitoring the EBV viral load is mandatory to evaluate the response to treatment.
Consider alternative treatment options, including Rituximab, radiotherapy, or surgery, if RIS is ineffective.
What are the risks involved in the given scenario?
EBV is the major risk for PTLD after SIT specially in the first year ,in this scenario with D+ to R- we need to follow the EBV PCR some centers started treatment if the PCR exceed 1000 copies other wise we can see mild increase in the EBV PCR post trasnaplnt .
In this case ,17 years old with KTX 3 month with 31000 copies of EBV PCR from positive donor .
so far this patient is doing well and asymptomatic but he will need close follow up and serial check for :
CBC,to have a look to nthe platlet count
check LDH which can be rise in the case of PTLD
THis patient need close follow up with multidiciplinary approach :
To do full hematological and serological work up including baseline investigations: CBC, ESR, PBF, UECs, LFTs, bone chemistry, LDH, uric acid, EBV PCR, HIV, CMV PCRSPEP/ UPEP, tacrolimus trough levels, graft ultrasound, BMA (for patients with cytopenias)
will need to have chest and abdomino and chest CT looking for hidden lymphadenopathy .PET scan and after that tissue biopsy and histopathology in the main corner for treatment .
the first step in managment of PTLD is to reduce the IS medication and most of nephrologist shift the patient to mTOR group.
then treat the condition according to what system is affected with rituximab being the main in all trials .
Some centers treat preemptively when EBV monitoring demonstrates >1000 EBV genome equivalents/mL, after confirmation of the value before initiating prophylactic treatment.
4. A 17-year-old patient received an adult kidney 3 months ago, EBV +ve/EBV -ve. Her EBV PCR reported 31000 copies. Currently, she is on Tacrolimus-based triple immunosuppression with excellent kidney function. No symptoms or signs suggested infection (viral and bacterial).
– excellent kidney function, no features of infection (viral or
bacterial)
What are the risks involved in the given scenario? (1-3)
– EBV serostatus: EBV D+/ R-
– overall degree of T cell immunosuppression: EBV-infected B cells are kept in check by cytotoxic T cells, prolonged exposure to high doses of tacrolimus
– time post-transplant: incidence of PTLD is highest in the 1st year posttransplant due to the intense immunosuppression
– other risk factors include: pretransplant malignancy, fewer HLA matches, induction therapy with ATG, CMV seromismatch
– if there is CNS involvement: Brain MRI and CSF analysis (cytology, flow cytometry, EBV PCR)
– imaging: Chest and Abdominopelvic CT scan to evaluate for masses, lymphadenopathy
– PET CT scan to measure disease activity (where available)
– tissue biopsy and histology
– prevention of PTLD entails:
· limiting exposure to aggressive immunosuppression,
· aggressive withdrawal and tapering of immunosuppressive agents – target tacrolimus trough level of 5-9ng/mL (7)
· antiviral prophylaxis – IV ganciclovir (8)
– preemptive treatment of EBV reactivation: (9)
· do EBV PCR monitoring for high-risk patients,
· administer preemptive treatment when the patient has >1000 EBV genome equivalents/mL
· initiate preemptive rituximab for EBV-associated PTLD and reduce immunosuppression
– the aim of treatment is to eradicate PTLD and preserve graft function
– treatment options include: (10, 11)
· Reduction in immunosuppression (RIS) – optimal method for RIS remains unknown e.g., discontinue the CNI and the antimetabolite, continue low-dose prednisone 5mg OD and initiate chemotherapy then after completion of chemotherapy start mTORi, if mTORi is not tolerated, begin azathioprine or mycophenolate
· Rituximab – anti-CD20 monoclonal antibody
· Chemotherapy: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
· Radiation therapy
· A combination of these therapies
· Adoptive immunotherapy – reserved for patients with persistent disease despite initial therapy
– Retransplantation: there is paucity of data on retransplantation in patients with PTLD (12)
References
1. Dharnidharka VR, Sullivan EK, Stablein DM, Tejani AH, Harmon WE. Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Transplantation. 2001 Apr 27;71(8):1065-8. PubMed PMID: 11374404. Epub 2001/05/26. eng.
2. Cockfield SM, Preiksaitis JK, Jewell LD, Parfrey NA. Post-transplant lymphoproliferative disorder in renal allograft recipients. Clinical experience and risk factor analysis in a single center. Transplantation. 1993 Jul;56(1):88-96. PubMed PMID: 8333073. Epub 1993/07/01. eng.
3. Opelz G, Döhler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2004 Feb;4(2):222-30. PubMed PMID: 14974943. Epub 2004/02/21. eng.
4. Tsai DE, Douglas L, Andreadis C, Vogl DT, Arnoldi S, Kotloff R, et al. EBV PCR in the diagnosis and monitoring of posttransplant lymphoproliferative disorder: results of a two-arm prospective trial. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2008 May;8(5):1016-24. PubMed PMID: 18312608. Epub 2008/03/04. eng.
5. Stevens SJ, Verschuuren EA, Pronk I, van Der Bij W, Harmsen MC, The TH, et al. Frequent monitoring of Epstein-Barr virus DNA load in unfractionated whole blood is essential for early detection of posttransplant lymphoproliferative disease in high-risk patients. Blood. 2001 Mar 1;97(5):1165-71. PubMed PMID: 11222357. Epub 2001/02/27. eng.
6. Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, et al. Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients – BCSH and BTS Guidelines. British journal of haematology. 2010 Jun;149(5):675-92. PubMed PMID: 20408847. Epub 2010/04/23. eng.
7. Shapiro R, Scantlebury VP, Jordan ML, Vivas C, Ellis D, Lombardozzi-Lane S, et al. Pediatric renal transplantation under tacrolimus-based immunosuppression. Transplantation. 1999 Jan 27;67(2):299-303. PubMed PMID: 10075598. Pubmed Central PMCID: PMC2975962. Epub 1999/02/12. eng.
8. Funch DP, Walker AM, Schneider G, Ziyadeh NJ, Pescovitz MD. Ganciclovir and acyclovir reduce the risk of post-transplant lymphoproliferative disorder in renal transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2005 Dec;5(12):2894-900. PubMed PMID: 16303002. Epub 2005/11/24. eng.
9. van Esser JW, Niesters HG, van der Holt B, Meijer E, Osterhaus AD, Gratama JW, et al. Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation. Blood. 2002 Jun 15;99(12):4364-9. PubMed PMID: 12036863. Epub 2002/05/31. eng.
10. European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.6.1. Cancer risk after renal transplantation. Post-transplant lymphoproliferative disease (PTLD): prevention and treatment. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association – European Renal Association. 2002;17 Suppl 4:31-3, 5-6. PubMed PMID: 12091638. Epub 2002/07/02. eng.
11. Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, et al. Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients – BCSH and BTS Guidelines. British journal of haematology. 2010 Jun;149(5):693-705. PubMed PMID: 20408848. Epub 2010/04/23. eng.
12. Johnson SR, Cherikh WS, Kauffman HM, Pavlakis M, Hanto DW. Retransplantation after post-transplant lymphoproliferative disorders: an OPTN/UNOS database analysis. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2006 Nov;6(11):2743-9. PubMed PMID: 17049062. Epub 2006/10/20. eng.
· EBV is associated with the majority of PTLD which is most common in EBV-negative recipients who develop primary EBV infection, usually from a graft from an EBV-positive donor
· The following abnormal laboratory studies may be seen in patients with PTLD:
1) Unexplained anemia, thrombocytopenia, or leukopenia
2) Elevated level of serum lactate dehydrogenase (LDH)
3) Hypercalcemia
4) Hyperuricemia
5) Monoclonal protein in the serum or urine
· Contrast-enhanced CT of the chest, abdomen, and pelvis should be performed in patients suspected of having PTLD.
· Some centers treat preemptively when EBV monitoring demonstrates >1000 EBV genome equivalents/mL, after confirmation of the value before initiating prophylactic treatment.
· Most centers administer preemptive rituximab therapy for patients at high risk of EBV-associated PTLD.
· Some centers favor reducing immunosuppression as prophylaxis.
What are the risks involved in the given scenario?
The risks involved in the above case are the EBV seropositivity of the donor to seronegative EBV recipient ,tacrolimus based immunosuppression and EBV viral load of 31000 copies /ml.Such patients have high chances of developing infectious mononucleosis and PTLD particularly in the first year post transplantation.
How would you manage this patient?
After detailed history and thorough examination including lymph nodes and or organimegaly -investigations like CBC,ESR,serum LDH,RFTs,LFTs ,Xray chest followed by CT scan Chest ,Abdomen and pelvis should be done and gold standard is the tissue biopsy.
Treatment :Till the diagnosis is confirmed ,in order to reduce the viral load..antimetabolite should be stopped and tacrolimus level should be kept between 5-7ng/ml or switched to mTor inhibitors..monitoring of viral load two weekly.If no response, and PTLD is confirmed then Rituximab with or without radiotherapy can be considered.
REFERENCES:
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155.
Post-transplant Lymphoproliferative Disorders (PTLD)-Lec By Ahmed Halawa Consultant Transplant Surgeon Associate Professor, University of Liverpool
A 17-year-old patient received an adult kidney 3 months ago, EBV +ve/EBV -ve. Her EBV PCR reported 31000 copies. Currently, she is on Tacrolimus-based triple immunosuppression with excellent kidney function. No symptoms or signs suggested infection (viral and bacterial). What are the risks involved in the given scenario?
EBV+VE/EBV -VE -high risk.
1st yr post transplant.
Young at 17 yrs.
Tacrolimus based IS
Mgt;
Monitor viremia as per KDIGO ;Week one then monthly for 3/12, then every 3/12 until 12/12,then every 2/12 in those with high risk like our case.
Any rise in EBV titers should prompt active inv for PTLD or active EBV i.e ;
FHG
LDH
UECS
URIC ACID
Thoraco abd CT.
Tac levels
LP for CSF EBV PCR in case CNS symptoms dev.
RIS is the initial key treatment strategies for EBV- keep TAC levels at 5-7 ng/dl, decrease or stop MMF and monitor EBV PCR and graft function.
Manage as PTLD if EBV turns out positive with the help of an oncologist and according to stage.
REF;
KDIGO; Clinical practice guidelines for care of KTR.Am J Transplant.2009 NOV;9.Suppl 3;51-155
EBV and Renal transplantation. Transplant Rev-Orlando.2017 jAN;31(1);55-60
· What are the risks involved in the given scenario?– High risk for PTLDs being EBV seronegative recipient while the donor is EBV seropositive especially with high EBV PCR titre.· How would you manage this patient?– High level of suspicion is the most important with full examination & investigation aiming for early diagnosis including basic labs, LDH , CTs , PET CT.
– PCR follow up monthly for the 1st 6 months & then every 3 months thereafter.
– Reduction of immunosuppression by reducing the dose of MMF & keeping lower trough level of tacrolimus with graft function monitoring
EBV D+/R-
HIGH RISK OF PTLD
Imaging is advised is symptomatic like fever weight loss , palpable LN ,
keeping IS at the lower level is the choice
RETUXIMAB is the drug of choice if PTLD is confirmed mainly on histopathology of biopsy sample from symptomatic lesion or graft
What are the risks involved in the given scenario?Patients with seronegative EBV who received graft from EBV seropositive donor of great risk of developing post-transplant PTLD that is why he need frequent monitoring and follow up. How would you manage this patient?
Reduction of immunosuppression is indicated in the form of half dose of MMF and keep tacrolimus on the lower level.
Monthly monitoring of EBV titer until clearance
High suspicious of PTLD and early screening either by PET CT or pan CT.
Some experts giving rituximab single dose as prophylactic dose. References
1. Wagner HJ, Wessel M, Jabs W, et al. Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction. Transplantation 2001; 72:1012.
2. Van Esser JW, Niesters HG, van der Holt B, et al. Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation. Blood 2002; 99:4364.
3. Worth A, Conyers R, Cohen J, et al. Pre-emptive rituximab based on viraemia and T cell reconstitution: a highly effective strategy for the prevention of Epstein-Barr virus-associated lymphoproliferative disease following stem cell transplantation. Br J Haematol 2011; 155:377.
4. Cesaro S, Murrone A, Mengoli C, et al. The real-time polymerase chain reaction-guided modulation of immunosuppression enables the pre-emptive management of Epstein-Barr virus reactivation after allogeneic haematopoietic stem cell transplantation. Br J Haematol 2005; 128:224.
The risk involved in this scenario
1.EBV serostatus (EBV+ve to EBV-ve) leading to higher risk of EBV infection
2.Young individual that is associated with higher risk of rejection, thus careful assessment is needed before cutting down his immunosuppression
3.EBV viral load of 31000 copies that potentially lead to PTLD
Management for EBV viraemia in EBV naive recipient
1.Reduction of immunosuppression as PCR >10 3 copies/ml
2.Careful monitoring of graft function
3.Monitoring EBV by Nucleic Acid Testing (every 2 weeks first 3-month, monthly first 3-6 month and every 3-monthly)
4.To consider CT head,neck,thorax, abdominal and pelvis +/-PET
5.If there is evidence of PTLD for haematologist referral
6.In the setting no PTLD to consider Rituximab
What are the risks involved in the given scenario?
EBV serostatus: D+/R-
Young age
On tripple immunosuppressive therapy
Viral load
Induction therapy How would you manage this patient?
Although there is no cut-off threshold for the EBV PCR, some authors have chosen 4000 copies/ml as the cut-off as a risk factor for PTLD.
KDIGO guidelines recommend; reducing the immunosuppression in EBV seronegative recipients with an increasing EBV viral load.
KDIGO guidelines recommend; the EBV viral load should be checked once in the first week following transplant, once every month for the first three to six months, and once every three months until one year after transplant.
History of induction therapy used as T cell depleting agents have been known to be a risk factor for developing PTLD.
Check viral load after 2 weeks if rising than will have to further investigations;
Complete blood count for anemia .
CMV PCR: CMV infection is a risk factor for PTLD
Lactate dehydrogenase: will be elevated in PTLD
Calcium: hypercalcemia will be found in PTLD
Uric acid: hyperuricemia will be found in PTLD
Tacrolimus levels (keep trough 4-6 ng/ml)
PAN CT scan of brain , chest , and abdominopelvic.
PET CT scan
If confirmed diagnosis (PTLD/EBV+).
The gold standard of diagnosis PTLD is through histology.
Treatment of EBV infection is mainly depending on immunosuppression reduction.
Discontinue antimetabolite and reduce Tacrolimus or change to m-TOR.
Monitoring EBV viral load .
If there is no response to RIS, considering other lines of treatment such as Rituximab, Radiotherapy or surgery.
The patient considered high risk of EBV infection (D+/R-).
Very high viral load can indicate development of PTLD (high viral load used to start investigate for disease in potential site & as preventive measure).
Screening of EBV seronegative recipients for EBV PCR, symptoms & lymphadenopathy for lifetime of their graft logistic & clinically sensible.
Guidelines recommend screening of EBV PCR in high risk group(D+/R-) for 1 year after transplantation.
Management:
CXR, chest & abdominal CT(for LAP).
Reduce dose or even discontinuation of MMF with maintain CNI dose within target.
Use of rituximab to depleting B cells numbers can reduce the incidence of early EBV related disease & PTLD.
References:
Ladford S., Lindahl J., Hansson S., Brandstrom P., Andersson R.,et al. Long-lasting chronic high load carriage of Epstein-Barr virus is more common in young pediatric renal transplant recipients. Pediatric Nephrology,2020;35:427-439.
Morton M., Coupes B., Robert A., Jahson S., Klapper P., et al. Estin-Barr Virus Infection in Adults Renal Transplant Recipients. American Journal of Transplantation, 2014;14:1619-1629.
Fellner M., Durand K., Solernou V., Bosaleh A., Balbarrey Z., et al. Epstein-Barr virus load in transplant recipients: Early detection of post transplant lymphoproliferative disorders. Rev.Argent.Microbiol, 2016;48(2): 110-118.
Risk involve
EBV D+/ R- Tx
Young age
Immunosuppressive drugs
Duration of the therapy
Viral load
Induction therapy Management
Despite the fact that the EBV PCR has no set cut-off threshold, some writers have picked 4000 copies/ml as the cut-off as a risk factor for PTLD.
Reducing immunosuppression in EBV seronegative recipients with a growing EBV virus load is advised by KDIGO recommendations.
The EBV viral load should be tested once the first week after transplant, once every month for the first three to six months, and once every three months until one year after transplant, according to KDIGO guidelines.
Immunosuppression reduction is the mainstay of EBV infection treatment.
Stop using the antimetabolite I.S., cut back on Tacrolimus, or switch to m-TOR.
monitoring the EBV viral load to assess how well RIS is working.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group.
What are the risks involved in the given scenario?Risks involved in this case:
EBV serostatus: D+/R-
Young age
On tripple immunosuppressive therapy
How would you manage this patient?The patient is 3 months post-transplant with high risk of PTLD due to the EBV serostatus D+/R- with EBV viral load of 31,000 copies.
Management should begin with a detailed history and thorough physical examination.
Blood works that include : CBC, UECS, LFT, LDH, Uric acid, tacrolimus trough levels
Imaging: CT abdomen, chest, pelvis and probable PET scan if available.
There is no cut off threshold to initiate therapy, it is generally expected the EBV viral load will increase in the first year post transplant. However some authors have used a cut-off of 4000 copies/ml.
This patient I would continue monitoring, KDIGO recommends monitoring from the first week, then monthly for the first 3 months, then every 3 months until 12 months.
I would reduce/withdraw antimetabolite, reduce the CNI trough levels.
There is a role of converting the CNI to sirolimus.
There is role of rituximab if the reduce immunosuppressive therapy fails.
References
Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline
Nimish Shah, Toby A. Eyre, David Tucker, Shireen Kassam, Jasvir Parmar, Carrie Featherstone, Peter Andrews, Elham Asgari, Sridhar Chaganti, Tobias F. Menne, Christopher P. Fox, Stephen Pettit, Abid Suddle, Kristian M. Bowles on behalf of the Haemato-Oncology Task Force of the British Society for Haematology and the British Transplantation Society Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x.
What are the risks involved in the given scenario?YOUNG AGE
DONOR POSTIVE EBV -RECEPIENT NEGATIVE EBV
IMMUNOSUPPRESANT STATUS
How would you manage this patient? Epstein-Barr virus (EBV) is associated with PTLD. PTLD occurs in approximately 1 percent of transplants and ranges in severity from benign” polyclonal lymphocytosis to highly malignant lymphomas.
The optimal strategy for the prevention of PTLD has not been established, although lesser degrees of immunosuppression appear to lower the risk
Excess rates of PTLD have been observedwith belatacept maintenance immunosuppression, notably in EBV seronegative recipients
Routine monitoring should be performed for higher risk patients (D+/R- for EBV)
many transplant centers have incorporated EBV monitoring into the routine evaluation of patients at high risk for PTLD, and preemptively treat PTLD at the time of viral reactivation with anti-B cell monoclonal antibody treatment.
Laboratory studies include a complete blood count with differential, chemistries with liver and renal function and electrolytes, lactate dehydrogenase (LDH), albumin, HIV, hepatitis B, Epstein-Barr virus (EBV) serology with quantitative polymerase chain reaction (PCR), and cytomegalovirus (CMV) PCR.
●Contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis should be performed in patients suspected of having PTLD. This study provides critical information on the measurement of disease prior to treatment, and aids in staging When available, we suggest obtaining a combined positron emission tomography (PET)/CT scan as a measure of disease activity
●Assessment of the function of the transplanted organ.
Antiviral prophylaxis
Data regarding the efficacy of antiviral prophylaxis in the prevention of PTLD in solid organ recipients is also limited.
Support for the use of antiviral prophylaxis in the prevention of PTLD comes from retrospective studies
•High-risk patients (eg, donor EBV-positive, recipient EBV-negative) were administered a minimum of 100 days of intravenous ganciclovir (6 to 10 mg/kg per day). •Low-risk patients (eg, donor EBV-negative, recipient EBV-positive or -negative; donor and recipient EBV-positive) received intravenous ganciclovir only during the period of hospitalization followed by oral acyclovir (40 mg/kg per day).
Target tacrolimus levels were lowered to 2 to 5 ng/mL in patients in whom a rising viral copy number was detected by PCR performed once per month. PTLD, which was defined as histologic evidence of B cell proliferation, was treated with the reinstitution of intravenous ganciclovir and the withdrawal of tacrolimus. At a mean follow-up of approximately 260 days, the following results were reported:
A retrospective multicenter case-control study of renal transplant recipients also found that prophylactic antiviral therapy reduced the risk of PTLD . In this report of 100 biopsy-confirmed cases and 375 matched controls, the risk of PTLD during the first year post-transplant decreased by 38 percent for every 30 days of treatment with ganciclovir (OR of 0.62, 95% CI 0.38-1.0).
The addition of immune globulin to ganciclovir does not appear to provide added benefit to ganciclovir alone among patients at increased risk for PTLD
1-What are the risks involved in the given scenario? This current case is high risk for PTLD due to; –Young Age, –1st year post transplant (3 months after KTX), –EBV +/ EBV- Tx; High risk for primary EBV infection or a reactivation in those who are already latently infected pre-transplantation can lead to uninhibited growth of EBV-infected B cells and subsequently to PTLD, –EBV PCR reported 31000 copies, –Triple immunosuppressants regimen. 2-How would you manage this patient? –Although there is no cut-off threshold for the EBV PCR, some authors have chosen 4000 copies/ml as the cut-off as a risk factor for PTLD. –KDIGO guidelines recommend; reducing the immunosuppression in EBV seronegative recipients with an increasing EBV viral load. –KDIGO guidelines recommend; the EBV viral load should be checked once in the first week following transplant, once every month for the first three to six months, and once every three months until one year after transplant. –As this index case is a symptomatic at time being , should put her under observation. –History of induction therapy used as T cell depleting agents have been known to be a risk factor for developing PTLD. –Check viral load after 2 weeks if rising than will have to further investigations; *Complete blood count; (check for unexplained anemia, thrombocytopenia or leucopenia) *CMV PCR: CMV infection is a risk factor for PTLD *Lactate dehydrogenase: will be elevated in PTLD *Calcium: hypercalcemia will be found in PTLD *Uric acid: hyperuricemia will be found in PTLD *Tacrolimus levels (keep trough 4-6 ng/ml) * PAN CT scan of brain , chest , and abdominopelvic. *PET CT scan
If confirmed diagnosis (PTLD/EBV+); –The gold standard of diagnosis PTLD is through histology. –Treatment of EBV infection is mainly depending on immunosuppression reduction. –Discontinue antimetabolite I.S. and reduce Tacrolimus or change to m-TOR. –Monitoring EBV viral load for evaluation the response to RIS. –If there is no response to RIS, considering other lines of treatment such as Rituximab, Radiotherapy or surgery.
*** Risk ivolved
High PTLD risk given high EBV viral load, young age, heavely immunosupressed first year post transplant
**** managment of asymptomatic
1- for EBV
monitor closely and check if the titre is rising then weigh cost benefit of reduction of immunosupression and graft loss from rejection and risk of PTLD keeping the immunological risk in the background. In the first instance, I would consider to decrease MMF and if did not help to hold. keep steroid at the back ground with tac. consider lower tac levels or even swich to mtor
2- Basic investigations of PTLD like LDH, uric acid + imaging
3- Screen for other viruses like CMV and BK virus
A 17-year-old patient received an adult kidney 3 months ago, EBV +ve/EBV -ve. Her EBV PCR reported 31000 copies. Currently, she is on Tacrolimus-based triple immunosuppression with excellent kidney function. No symptoms or signs suggested infection (viral and bacterial).
What are the risks involved in the given scenario? EBV +/ EBV- Tx, EBV viral load > 10 000. younger age, Induction IS (not mentioned in this case), Triple immunosuppressants regimen, 1st year post transplant How would you manage this Asymptomatic patient? 1- I will continue monitoring the EBV load in one week then monthly until 6 months post-transplant, then every 3 months for up to 2 to 5 years. 2- I will do graft biopsy when BKV-PCR load insistently exceeds > 10 000 copies/ml (4 log 10 genome (copies/ml)) with or without allograft dysfunction. Biopsy is the gold standard for diagnosing BKVN. 3- If BKVN is confirmed, I will start immunosuppressive reduction and continue monitoring graft function and viral load. 4- Approaches include withdrawal of antimetabolite drugs or change from MMF to azathioprine, sirolimus, or leflunomide, reducing the dose of CNI by 25–50% (target lower level of cyclosporine 50–100 ng/ml & tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI. Reference Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x.
Fakhriya Alalawia, Hind Alnoura, Mohsen El Kossib, John Jenkinsb, Anna Takud, Ajay K. Sharma, Ahmed Halawa, BK virus infection in renal transplant recipients: an overview, Journal of The Egyptian Society of Nephrology and Transplantation 20:127–150 DOI: 10.4103/jesnt.jesnt_ 48_19
What are the risks involved in the given scenario?This index case is high risk for PTLD due to
EBV +/ EBV- Tx
younger age
Induction IS(not mentioned in this case
Triple immunosuppressants regimen
1st year post transplant
How would you manage this patient
will have to keep the patient under observation as currently she is having no symptoms.
Current titer is high will have to repeat it after 2 week if rising than will have to
Investigate with CBC, RFT, LDH, S electrolytes Uric acid AND
Radiological tests(CT)
Optimization of Tac level 5ng/dl
Reduction/Stopping MMF with monitoring of EBV PCR
if progressing to PTLD(EBV+) then will have to manage on accordingly
Reduction of immunosuppression, lower trough level of tacrolimus (5-7)
Need to follow up PCR level and counsel the patients regarding the signs and symptoms of PTLD. (KDIGO guideline recommend Close monitoring of EBV- viral load in the first year after transplantation from the first week then every month till 3 months and every 3 months until 12 months then every 2 months after the first year. Need to keep a high index of clinical suspicion and investigate accordingly.
Reference Franceschini E, Plessi J, Zona S, Santoro A, Digaetano M, et al. Clinical Utility of Epstein-Barr Virus Viral Load Monitoring and Risk Factors for Posttransplant Lymphoproliferative Disorders After Kidney Transplantation: A Single-Center, 10-Year Observational Cohort Study. Transplant Direct. 2017 Jun 26;3(7):e182. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x.
If there is high index of suspicion, I would like to stop MMF and change it to m TOR-based (everolimus or sirolimus) immunosuppression along with minimizing the CNI dose in addition to EBV PCR viral load monitoring. Chemotherapy with rituximab to be consider only after confirmation of the diagnosis by tissue biopsy along with MDT with hemato-oncologist
The risks involved in this scenario:
D + /R- EBV, early transplant period with maximal immunosuppression meanwhile. The suppression of the cytotoxic T cells is the main potential risk factor.
Management:
Close monitoring for viral load and development of PTLD. In case of the development of PTLD, as shown by some studies, Rituximab can be considered. The viral load itself was not found to correlate well with the PTLD risk.
References: –Oertel S, Trappe RU, Zeidler K, Babel N, Reinke P, Hummel M, Jonas S, Papp-Vary M, Subklewe M, Dörken B, Riess H, Gärtner B. Epstein-Barr viral load in whole blood of adults with posttransplant lymphoproliferative disorder after solid organ transplantation does not correlate with clinical course. Ann Hematol. 2006 Jul;85(7):478-84. doi: 10.1007/s00277-006-0109-1. Epub 2006 Apr 4. PMID: 16586109.
-Nijland ML, Kersten MJ, Pals ST, Bemelman FJ, Ten Berge IJ. Epstein-Barr Virus-Positive Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation: Pathogenesis, Clinical Manifestations, Diagnosis, and Management. Transplant Direct. 2015;2(1):e48. Published 2015 Dec 15. doi:10.1097/TXD.0000000000000557.
What are the risks involved in the given scenario?The current scenario reflects increased risk of PTLD
Reasons
Young donor
Early transplant days
EBV+/ EBV- status
How would you manage this patient?1.EBV viral load monitoring
2.Switching Tac to Everolimus/Sirolimus
3.Holding MMF
3.Hematology/oncology consult
5.Rituximab
What are the risks involved in the given scenario?
This patient is at high risk of PTLD because of transplantation from EBV +ve donor /EBV -ve recipient in addition to highEBV viral load .
How would you manage this patient?
This patient in the given scenario has an asymptomatic high level of EBV PCR.
So we need to do a proper clinical examination looking for lymph nodes enlargements .
CBC,ESR,LDH level which will be high in PTLD , U&E, LFT , serum uric acid and radiological tests ,CXR
Tacrolimus level
Optimization of immunosuppression at therapeutic level .
As there is no cut off point to be found and there are no symptoms or signs suggestive of PTLD so just follow up PCR level and counsel the patients if he developed any alarming symptoms like fever weight loss .
Reference : 1. Epstein-Barr virus and renal transplantationTransplant Rev (Orlando. 2017 Jan;31(1):55-60. doi: 10.1016/j.trre.2016.12.001. Epub 2016 Dec 29
⭐The index case is high risk for EBV infection as being in pediatric age group, naieve for EBV infection (D+/R-), in addition to use of induction therapy in pediatric tx (especially if depleting antibodies as ATG (not mentioned in the scenario)), early period post transplant with intense IS (mostly tacrolimus based triple therapy.
⭐Here, although, no defined cut off level of EBV PCR to develop PTLD, but still this high titer is suspicious.
⭐Management:
_frequent monitoring OF EBV viral titer.
_oreemotive therapy (no specific antiviral therapy, but reduction of IS especially antiproliferative (MMF) and keep Tacrolimus at the lower therapeutic window.
_through clinical examination for any organomegally or lymphadenopathy.
_FU CBC (for cytopenias ), LDH, uric acid.
_Tiisue biopsy remains the gold standard for diagnosis of PTLD.
_Cases not responding to RIS in regression and reduction of viral titer are indicated for chemotherapy (CHOP) and or rituximab.
_adoptive immunotherapy is indicated in EBV postive cases.
What are the risks involved in the given scenario?
1. A young recipient 17 years old, EBV seronegative from EBV positive donor, is at high risk for EBV viral infection and PTLD.
2. Type of induction immunosuppression ( ATG vs basiliximab )also should be identified as induction with T cell depleting agent considered an additional risk.
3. Intense triple maintenance IS including CNI and MMF is an additional risk.
4. Three months post-transplantation (early time for both PTLD and rejection)
High EBV viral load 31000 (concerning PTLD)
To conclude this patient is at high risk of PTLD
How would you manage this patient?
This patient is already under surveillance with EBV viral load as she is high risk and her current EBV in 3 months after TX > 31000, if it raises the viral load then she should be investigated for possible PTLD including further history and examination for LAP, organomegaly, and B SYMPTOMS (Fever, night sweat, wt loss), FBC peripheral smear, LDH Tacrolimus trough level. Primary EBV Infectious mononucleosis (IM ) in adults frequently manifests as fever, lymphadenopathy, and pharyngitis in Over 50% of patients.
PTLD after kidney transplant as per reports shows low incidence (1-3%), and its bimodal, early peak in the first year is usually EBV-genome positive found. 90% and its B cell-PTLD, and late PTLD which can be EBV-negative PTLDIN 45% and more in older age (1).
Most of the international guidelines including the KDIGO guideline recommend Close monitoring of EBV-VL in the first year after transplantation from the first week then every month till 3 months and every 3 months until 12 months then every 2 months after the first year only in a high-risk candidate like our case, also there is no agreement about the EBV cutoff values among different labs for clinical interpretation so the key factor for the early diagnosis of PTLD is to keep a high index of clinical suspicion and investigate accordingly.
I would ask hematology opinion for peripheral blood smear, LDH and if further investigation is needed to confirm the diagnosis of PTLD as the definite diagnosis need tissue biopsy with IHC staining and flow cytometry in addition to further staging should be supported with PAN CT Images. In regards to the reduction of immunosuppression, it again depends on the local center policy and this should be considered as the first step like a modification to m TOR-based IS everolimus or sirolimus along with minimizing the CNI dose along with EBV -VL monitoring, chemotherapy including rituximab alone or in combination will be decided only after confirmation of the diagnosis of PTLD by tissue biopsy and should be decided and followed after a discussion through MDT approach along with hemato-oncology team and this is what we are doing in our center
In addition will screen for other co-viral infections like CMV, BKV
References
1.Franceschini E, Plessi J, Zona S, Santoro A, Digaetano M, Fontana F, Alfano G, Guaraldi G, Comoli P, Facchini F, Potenza L, Gennari W, Codeluppi M, Luppi M, Cappelli G, Gyssens IC, Mussini C. Clinical Utility of Epstein-Barr Virus Viral Load Monitoring and Risk Factors for Posttransplant Lymphoproliferative Disorders After Kidney Transplantation: A Single-Center, 10-Year Observational Cohort Study. Transplant Direct. 2017 Jun 26;3(7):e182. doi: 10.1097/TXD.0000000000000703. PMID: 28706985; PMCID: PMC5498023.
2. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond evolving concepts and practical applications. Blood. 2011 May 12;117(19):5019-32. doi 10.1182/blood-2011-01-293050. Epub 2011 Feb 7. PMID: 21300984; PMCID: PMC3109529.
3. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. PMID: 19845597.
Please use sub-headings under the heading ‘How would you manage this patient?’ to make easier to read your write-up. Please use bold or underline to highlight sub-headings.
What are the risks involved in the given scenario?
Early transplant period (3 months after KTX).
EBV+ Donor to EBV – Recipient ( can led to a primary EBV infection in EBV-seronegative patients receiving an EBV-seropositive donor organ or a reactivation in those who are already latently infected pre-transplantation can lead to uninhibited growth of EBV-infected B cells and subsequently to PTLD).
Tacrolimus based therapy. How would you manage this patient?
There is no clear cut-off point for a high or increasing EBV viral load can be given because of the high inter-laboratory variability in test results.
We should exclude EBV- associated PTLD.
Treatment of EBV infection is mainly depending on immunosuppression reduction and response to RIS can be measured by assessing changes in EBV viral load.
Any evidence of PTLD and there is no response to RIS we have another lines of treatment such as Rituximab, Radiotherapy or surgery. References:
1-Nijland ML, Kersten MJ, Pals ST, Bemelman FJ, Ten Berge IJ. Epstein-Barr Virus-Positive Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation: Pathogenesis, Clinical Manifestations, Diagnosis, and Management. Transplant Direct. 2015;2(1):e48. Published 2015 Dec 15. doi:10.1097/TXD.0000000000000557.
EBV PCR 31000 copies/ml, (although difficult to diagnose EBV infection based on the PCR value without clinical correlation, no standard time for monitoring, and no standard source of samples).
Triple immunosuppressants (Tacrolimus based).
The risk of development of PTLD with 4 types
Non-destructive, including infectious mononucleosis.
Polymorphic PTLD.
Monomorphic PTLD, (B-cell, T-cell, or NKC)
Classic non-Hodgkin lymphoma-like PTLD.
Management of the case
Serial follow-up EBV load.
Fine-tuning of immunosuppressants with monitoring allograft function.
IVIG to raise EBV-antibody titer.
Rituximab in established or high risk of PTLD.
References
Dharnidharka VR. A comprehensive review of post-organ transplant hematologic cancers. Am J Transplant 2018; 18: 537-549 [PMID: 29178667 DOI: 10.1111/ajt.14603] 2 Medscape. Post-transplant Lymphoproliferative Disease. Available from: URL: https://emedicine.medscape.com/article/431364-overview#showall 3 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66: 7-30 [PMID: 26742998 DOI: 10.3322/caac.21332] 4 Dierickx D, Habermann TM. Post-Transplantation Lymphoproliferative Disorders in Adults. N Engl J Med 2018; 378: 549-562 [PMID: 29414277 DOI: 10.1056/NEJMra1702693] 5 Penn I, Hammond W, Brettschneider L, Starzl TE. Malignant lymphomas in transplantation patients. Transplant Proc 1969; 1: 106-112 [PMID: 4944206] 6 Engels EA, Pfeiffer RM, Fraumeni JF, Kasiske BL, Israni AK, Snyder JJ, Wolfe RA, Goodrich NP, Bayakly AR, Clarke CA, Copeland G, Finch JL, Fleissner ML, Goodman MT, Kahn A, Koch L, Lynch CF, Madeleine MM, Pawlish K, Rao C, Williams MA, Castenson D, Curry M, Parsons R, Fant G, Lin M. Spectrum of cancer risk among US solid organ transplant recipients. JAMA 2011; 306: 1891-1901 [PMID:
What are the risks involved in the given scenario?
Pre-transplant seropositive donor (D+) to seronegative recipient (D-) for EBV.
The tacrolimus-based immunosuppressive regimen.
EBV viral load > 10 000.
======================= How would you manage this patient?
Firstly, I will continue monitoring the EBV load monthly until 6 months post-transplant, then every 3 months for up to 2 to 5 years (AST Infectious Diseases Guidelines & KDIGO guidelines).
Secondly, I will do graft biopsy when BKV-PCR load insistently exceeds > 10 000 copies/ml (4 log 10 genome (copies/ml)) with or without allograft dysfunction. Biopsy is the gold standard for diagnosing BKVN.
If BKVN is confirmed, I will start immunosuppressive reduction & continue monitoring graft function & viral load.
Approaches include withdrawal of antimetabolite drugs or change from MMF to azathioprine, sirolimus, or leflunomide, reducing the dose of CNI by 25–50% (target lower level of cyclosporine 50–100 ng/ml & tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI.
References
Fakhriya Alalawia, Hind Alnoura, Mohsen El Kossib, John Jenkinsb, Anna Takud, Ajay K. Sharma, Ahmed Halawa,
BK virus infection in renal transplant recipients: an overview, Journal of The Egyptian Society of Nephrology and Transplantation 20:127–150 DOI: 10.4103/jesnt.jesnt_ 48_19
Remember graft biopsy does not always give positive confirmation as you have to get a specimen near the medulla, and if positive the graft function by then will be affected!
So you have to take a decision in this index case with
Surveillance and follow up of the chemistry.
Modification of IS as you correctly mentioned.
What are the risks involved in the given scenario?
D+/ R- high risk
Tacrolimus-based triple immunosuppressive
How would you manage this patient?
patient now asymptomatic
should doing close and regular monitoring via PCR
there is no definitive special treatment for EBV
this early period …..highest risk of rejection ….so should close monitoring and balancing of immunosuppressive medications because the only approved treatment is adjustment /reduction of immunosuppressants
1-High risk for EBV (donor +/Recepient -ve)
2- incidence of PTLD is high in first year after transplantation (most intense immune suppression
Management
Weekly monitoring of EBV viral titers
Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of comprehensive clinical picture that includes EBV viral load assessment.
A fine-tuning the immunosuppressive burden to as low as clinically possible
1- the risk involved is development of PTLD
2- management:
clinical examination LN, hepatosplenomegaly
if GIT symptoms do upper and lower endoscopy and biopsy
biopsy to confirm diagnosis
if confirmed treat by RIS reduction of immunosuppression, chemotherapy also may be needed, rituximab
What are the risks involved in the given scenario?
1. KT in EBV serostatus D+/R-, carries high risk for EBV infection or reactivation in the post-transplant period.
2. High viral load is linked to infectious mononucleosis and Chronic Active EBV Infection (CAEBV)in pediatric population(1). 3. In most instances (approximately 90%), PTLD is associated with EBV(2). 4. The development of EBV infection and PTLD is normally associated with a high EBV viral load in peripheral blood(3). High viral load is associate with Extranodal NK/T-Cell Lymphoma, Nasal Type (ENKTL) and Chronic Active EBV Infection (CAEBV)(4).
How would you manage this patient?
1. While primary infection in childhood is usually asymptomatic, delayed infection is associated with infectious mononucleosis (IM), a febrile illness in which patients have high circulating viral loads and an exaggerated virus-induced immune response involving both CD8+ T cells and natural killer (NK) cells(5).
2. The patient should be thoroughly examined, looking for LNs involvement beside laboratory testing and imaging studies; CBC, KFT, LFT, LDH, other viral infection, CXR and CT scan(chest, abdomen and brain).
3. Despite of being asymptomatic, this KTR with high EBV-viral load should undergo modification and Reduction of immunosuppression to minimize complication and to prevent allograft dysfunction:
· immediate reduction in immunosuppression (RIS) by 25% in limited diseases and up to 50% in extensive disease. Response should be assessed within 2–4 weeks, If a complete remission (CR) is obtained, then no other therapy may be required.
· Patients that achieve a PR by RIS alone can either be monitored and reassessed within a further 2–4 weeks.
· Consider stopping AZA/MMF. Maintain prednisolone 7.5/10 mg/day.
References
1. Akihiko Maeda, Hiroshi Wakiguchi, Wakako Yokoyama, Hiroaki Hisakawa, Takashi Tomoda, Takanobu Kurashige, Persistently High Epstein-Barr Virus (EBV) Loads in Peripheral Blood Lymphocytes from Patients with Chronic Active EBV Infection, The Journal of Infectious Diseases, Volume 179, Issue 4, April 1999, Pages 1012–1015, https://doi.org/10.1086/314691
2. Al-Adra D, Al-Qaoud T, Fowler K, Wong G. De Novo Malignancies after Kidney Transplantation. Clin J Am Soc Nephrol. 2022 Mar;17(3):434-443. doi: 10.2215/CJN.14570920. Epub 2021 Mar 29. PMID: 33782034; PMCID: PMC8975024.
3. Yamada M, Nguyen C, Fadakar P, Ganoza A, Humar A, Shapiro R, Michaels MG, Green M. Epidemiology and outcome of chronic high Epstein-Barr viral load carriage in pediatric kidney transplant recipients. Pediatr Transplant. 2018 May;22(3):e13147. doi: 10.1111/petr.13147. Epub 2018 Feb 6. PMID: 29411474; PMCID: PMC7197440.
4. Hiroshi Kimura and Yok-Lam Kwong EBV Viral Loads in Diagnosis, Monitoring, and Response Assessment https://www.frontiersin.org/
5. Abbott RJ, Pachnio A, Pedroza-Pacheco I, Leese AM, Begum J, Long HM, Croom-Carter D, Stacey A, Moss PAH, Hislop AD, Borrow P, Rickinson AB, Bell AI. Asymptomatic Primary Infection with Epstein-Barr Virus: Observations on Young Adult Cases. J Virol. 2017 Oct 13;91(21):e00382-17. doi: 10.1128/JVI.00382-17. PMID: 28835490; PMCID: PMC5640854.
Considering this patient to be still in the( pediatric range) how can you differentiate between an infectious mononucleosis state and a primary infection D+R-.
So you decided to go to Pre-emptive management .!
1. Primary infection in childhood is commonly asymptomatic. Most people are infected with Epstein-Barr virus (EBV) during childhood or adolescence, resulting in a persistent, mostly latent EBV infection. 2. Globally EBV is causally linked to nearly 200000 incident cancers and 18000 deaths from multiple sclerosis annually with IM elevating the risk of Hodgkin lymphoma and multiple sclerosis for unknown reasons(1). 3. Functions of EBV antibody levels as predictors of disease risk is an active field of research. 4. Infectious mononucleosis (IM) is a febrile illness characterized by(2): a) anti-EBV IgM antibody positivity. b) high loads of circulating latently infected B cells. c) a marked lymphocytosis caused by hyperexpansion of EBV-specific CD8+ T cells plus a milder expansion of CD56dim NKG2A+ KIR– natural killer (NK) cells. 5. Disease severity and duration correlate much better with e.g. CD8+ cell counts than with the viral kinetics itself and the expansion of the CD8+ cell count is controlled in asymptomatic EBV infection despite virus loads similar to those experienced in symptomatic EBV infection.
References
1. Primary Epstein-Barr virus infection with and without infectious mononucleosis Klaus Rostgaard ,Henry H. Balfour Jr.,Ruth Jarrett,Christian Erikstrup,Ole Pedersen,Henrik Ullum,Lars Peter Nielsen,Marianne Voldstedlund, Henrik Hjalgrim Published: December 17, 2019https://doi.org/10.1371/journal.pone.0226436
2. Abbott RJ, Pachnio A, Pedroza-Pacheco I, Leese AM, Begum J, Long HM, Croom-Carter D, Stacey A, Moss PAH, Hislop AD, Borrow P, Rickinson AB, Bell AI. Asymptomatic Primary Infection with Epstein-Barr Virus: Observations on Young Adult Cases. J Virol. 2017 Oct 13;91(21):e00382-17. doi: 10.1128/JVI.00382-17. PMID: 28835490; PMCID: PMC5640854.
Thankyou for the effort but obviously to decide note that:
The viral load in the asymptomatic index case is very high although the cut off value is not yet defined so you have every reason to take it seriously.
IM in children is always symptomatic with fever throat rash and lymphocytosis ,and self limiting febrile illness.
As the goal of your training is decision taking ,the index case has to be considered very carefully as you wisely did.
4. A 17-year-old patient received an adult kidney 3 months ago, EBV +ve/EBV -ve. Her EBV PCR reported 31000 copies. Currently, she is on Tacrolimus-based triple immunosuppression with excellent kidney function. No symptoms or signs suggested infection (viral and bacterial).
What are the risks involved in the given scenario?
The majority of the cases of PTLD are associated with Epstein-Barr virus (EBV), and it occurs within the first posttransplant year.
High-dose immunosuppression is associated with a higher risk of PTLD.
90% of B-cell origin, 90% are EBV-related.
10% of T-cell origin, of which only 30% are EBV-related.
The cumulative risk increases with the length of time posttransplant (10% in the first 2 years, 30% in the next 3 years and 60% > 5 years post-transplant).
Recipient-origin PTLD presents LATE with multisystem involvement(mean 76 months after transplantation). Worse prognosis.
Commonest in children under 10 and adults above 60.
Tacrolimus is associated with a 3 to 5 folds increase in PTLD compared to Cyclosporine.
MMF, IL2R inhibitors and Alemtuzumab are not associated with a higher risk of PTLD, but there is an increased risk compared to the general population.
Differential Diagnosis
Given the highly diverse way in which PTLD presents, a differential diagnosis should generally be taken into account based on how the patient presents clinically.
The differential diagnosis should take into account frequent infectious etiologies, opportunistic infections, and rejection of allograft organ (in the case of graft involvement).
D/ EBV +ve R/EBV -ve + Age+ high dose immunosuppression = high risk of PTLD
====================================================================
How would you manage this patient?
Patients with PTLD medical history and physical examination, and the following investigations are also performed :-
Complete blood cell count (CBC) to evaluate unexplained anemia, thrombocytopenia or leukopenia.
Comprehensive chemistry panel.
Lactate dehydrogenase (LDH) to evaluate for tumor lysis syndrome.
Urine analysis for Monoclonal protein, hyperuricemia
EBV Status of recipient and donor.
Epstein-Barr virus (EBV) testes: EBV IgM, EBV IgG, EBV viral load (PCR). Also, serial EBV quantitative PCR measurement (that is rising) is more important and valuable than single positive EBV quantitative PCR.
Negative EBV PCR does not exclude the possibility of PTLD.
Radiological studies include computed tomography (CT), magnetic resonance imaging (MRI), and positive positron emission tomography (PET) scanning to evaluate spread.
Lumbar puncture with cerebral spinal fluid (CSF) analysis (EBV PCR in CSF fluid) in patients with PTLD with CNS involvement
Histopathologic examination of the tumor can only determine the definitive diagnosis.
Pre-transplant Management Vaccination
The recombinant vaccine has been tested. It reduces the incidence of symptomatic primary infection from 9% to 2% by reducing the viral load.
It does not reduce the incidence of asymptomatic EBV. More studies are required.
Screening
Serology rather than PCR of both the donors and recipients. Children < 1 year old are considered negative as maternal antibodies may give false positive results.
Post-transplant Surveillance
A modest increase in EBV viral load posttransplantation.
A marked increase in viral load in PTLD (3225 copies/100 μml vs 740 copies/100 μml).
An increase in the viral load is suggestive of PTLD (sensitivity 100%, specificity 81%, PPV 25% & NPV >90%), but the diagnosis is still based on histology.
Decrease in the viral load in responders.
No sufficient evidence to support routine surveillance of adult transplant recipients for EBV viraemia by PCR to identify patients at risk of PTLD or to initiate therapy.
No clinically useful cut-off value for the diagnosis of EBV viraemia and potential of PTLD due to differences between labs (whole blood, serum or peripheral lymphocytes).
Will miss EBV-negative PTLD and localized form.
Low PPV (<25%) in spite of high NPV (>90%).
In children at risk of primary EBV infection, routine surveillance is likely to aid in the pre-emptive identification of patients at high risk of PTLD.
Intense monitoring is required in the first year post-transplantation as this is the most vulnerable time to develop EBV primary infection and PTLD.
Treatment / Management
Many modalities tried
Antiviral Strategies
May play a role in prophylaxis.
Much of the EBV DNA does not come from the lytic phase (<1%) but from proliferating B cells with latent EBV.
Reduction of immunosuppression
Reduce vs hold Tacrolimus/CsA/Aza/MMF/steroids
The convention is to stop either CNI or anti-metabolite and reduce the other
Change to Sirolimus/mTORi?
Focus on drug levels, not the dose
Intensive surveillance for rejection
Rituximab may be tested; it has been used frequently as a preventative therapy since mTORi may have anti-viral activity.
Hanto DW. Classification of Epstein-Barr virus-associated posttransplant lymphoproliferative diseases: implications for understanding their pathogenesis and developing rational treatment strategies. Annu Rev Med 1995; 46:381.
Mizuno S, Hayasaki A, Ito T, Fujii T, Iizawa Y, Kato H, Murata Y, Tanemura A, Kuriyama N, Azumi Y, Kishiwada M, Usui M, Sakurai H, Isaji S. De Novo Malignancy Following Adult-to-Adult Living Donor Liver Transplantation Focusing on Posttransplantation Lymphoproliferative Disorder. Transplant Proc. 2018 Nov;50(9):2699-2704
Post-transplant Lymphoproliferative Disorders (PTLD) By Ahmed Halawa Consultant Transplant Surgeon Associate Professor, University of Liverpool – UK Programme Director of the Fellowship in Clinical Transplantation – WKA
Thank you for such detailed and confusing answer but I do not know is this a case of PTLD? In case your answer is ‘YES’ what is your support for this diagnosis?
You mentioned ‘EBV Status of recipient and donor.’ and this already given in the stem of the question D+/R-!!!!!!
Due to her high EBV viral load of 31000 copies/ml, the patient has a significant risk of acquiring EBV infection and Post Transplant Lymphoproliferative Disease.
According to KDIGO recommendations, the EBV viral load should be checked once in the first week following transplant, once every month for the first three to six months, and once every three months until one year after transplant.
– Early identification of primary infection and viral load monitoring allows therapeutic interventions to prevent progression to EBV disease.
– The EBV viral load becomes positive before the development of EBV disease.
– EBV-seronegative KTRs have 10-50-fold increased risk for EBV diseases (PTLD) in compared to EBV-seropositive KTRs.
– Studies showed that high levels of EBV DNA in peripheral blood of immunosuppressed patients indicate the onset of PTLD.
-PTLD is serious complication serious complication related to the intensity of post-transplant immunosuppression. The role of EBV in PTLD evolution is well established.
-The majority of PTLD cases (> 85%) are usually observed in the first post-transplant year. KDIGO guideline recommended monitoring high-risk (donor EBV seropositive/recipient seronegative) KTRs for EBV by NAT
• once in the first week after transplantation.
• then at least monthly for the first 3– 6 months after transplantation.
• then every 3 months until the end of the first post-transplant year.
• additionally after treatment for acute rejection.
EBV- PCR becomes a tool for early diagnosis as well as for monitoring, cut-off values are not, 4000 copies/ml is selected by some authors as a risk factor for PTLD.
The index case is at high risk (D+/R-), high viral load and only 3 months post-Tx ( exposed to aggressive immunosuppression). Therefore, reducing immunosuppressive medication is recommended to prevent progression to PTLD and it is effective in many patients. Management:
*Patient should be evaluated thoroughly:
– Clinically; any constitutional symptoms; fever, sweating, weight loss.
-Examination: vitals, weigh, lymphadenopathy, organomegaly.
-laboratory: CBC (anemia, thrombocytopenia), LFT, RFT, LDH, ESR, uric acid.
– Look for other concomitant viruses: CMV.
– CXR and abdomen US
Further work up guided by the history and results of the initial work up.
*Preemptive therapy:
-Reduce MMF by 50 % may need to completely stop it, if viral load rapidly rising despite reduction of the dose.
– Reduce Tacrolimus dose to the lowest possible dose to maintain graft function.
– Monitor response to therapy and graft function for rejection.
– May consider one dose of rituximab.
References:
Erica F. Clinical Utility of Epstein-Barr Virus Viral Load Monitoring and Risk Factors for Posttransplant Lymphoproliferative Disorders After Kidney Transplantation: A Single-Center, 10-Year Observational Cohort Study. Transplantation Direct 3(7):p e182, July 2017. Wagner HJ, Wessel M, Jabs W, Smets F, Fischer L, Offner G, Bucsky P. Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction. Transplantation. 2001 Sep 27;72(6):1012-9. doi: 10.1097/00007890-200109270-00006. PMID: 11579293.
Chadban, Steven J. BMed, PhD1,*; Ahn, Curie MD, PhD2; Axelrod, David A. MD, MBA3; Foster, Bethany J. MD, MSCE4; Kasiske, Bertram L. MD5; Kher, Vijah MD, DM6; Kumar, Deepali MD, MSc7; Oberbauer, Rainer MD, PhD8; Pascual, Julio MD, PhD9; Pilmore, Helen L. MD10; Rodrigue, James R. PhD11; Segev, Dorry L. MD, PhD12; Sheerin, Neil S. BSc, PhD13; Tinckam, Kathryn J. MD, MMSc7; Wong, Germaine MD, PhD14; Knoll, Gregory A. MD, MSc15,*. KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation. Transplantation 104(4S1):p S11-S103, April 2020. | DOI: 10.1097/TP.0000000000003136
Thank you, well done. For the sake of discussion, suppose the patient presented with fever, lymphadenopathy and splenomegaly, does this confirm or exclude PTLD? What you need to do to confirm or exclude your diagnosis?
These symptoms is highly suggestive of PTLD as its clinical presentation variable range from silent local disease to disseminated fulminating disease with multi-organ failure.
However, to confirm the diagnosis we need tissue diagnosis (biopsy).
What are the risks involved in the given scenario?
Generally speaking, Posttransplant lymphoproliferative disease is a potentially fatal complication after kidney transplantation and it is highly associated with Epstein-Barr virus infection. The EBV-specific cytotoxic T cell response that is essential in controlling the virus in healthy individuals is suppressed in transplant recipients using immunosuppressive drugs.
In the current scenario ,the recipient is at high risk to develop primary EBV infection in settings of EBV-seronegative status at the time of transplantation that can lead to uninhibited growth of EBV-infected B cells and subsequently to PTLD.
How would you manage this patient?
Notably, not every transplant recipient with increasing EBV viral load develops PTLD(One explanation is that most infected lymphoblasts transit into resting memory cells, and only cells that are not able to make this transition will start to proliferate freely). it is hard to decide how intensively these patients should be monitored and how and when a preemptive intervention should take place.
In the current index case ,there is no symptoms or signs suggestive of infection(triad of fever, lymphadenopathy, and pharyngitis). There is no available effective preventive strategies, such as vaccines or antiviral agents as well as there is no consensus on the optimal way to monitor for PTLD. Quantitative EBV PCR may be useful for surveillance, diagnostic and disease monitoring of PTLD because an increase in viral load correlates with the development of EBV-related PTLD. weekly to twice weekly monitoring during the first year or at least during the first months after transplantation has been recommended.
The preemptive intervention in the current case is reduction of immunosuppression, which has been shown to decrease the incidence of PTLD in addition to Rituximab which causes depletion of circulating B cells including those infected with EBV. stop all antiproliferative agents, and decrease CNIs by 50% and to continue with prednisolone.
References
Allen UD, Preiksaitis JK; AST Infectious Diseases Community of Practice. Epstein-Barr virus and posttransplant lymphoproliferative disorder in solid organ transplantation. Am J Transplant. 2013; 13 (Suppl 4): 107–120.
Parker A, Bowles K, Bradley JA, et al. Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients – BCSH and BTS Guidelines. Br J Haematol. 2010; 149: 693–705.
What are the risks involved in the given scenario? There is EBV positive to EBV negative kidney transplant. EBV viral load is high. There are no features of EBV . This indicates immune over suppression. EBV specifically is associated with post-transplantation lymphoproliferative disorder (PTLD), in kidney transplant recipients, with increased risk in EBV seronegative patients with EBV seropositive donors on intensified immunosuppression. The index case is at high risk of PTLD.
How would you manage this patient? Reduction of immune suppression MMF has to be reduced and Tacrolimus at lowest possible therapeutic levels. Use of Rituximab Close monitoring of Viral load.
What are the risks involved in the given scenario? –EBV negative recipient receiving graft from EBV positive donor
– EBV PCR reported 31000 copies.
– she is on Tacrolimus-based triple immunosuppression
monitoring EBV load routinely is mandatory in this case
Meanwhile EBV viral load is higher in seronegative patients that develop EBV/PTLD than in those with asymptomatic EBV conversion.
Viral load testing improved monitoring for EBV infection, but solely cannot be used to diagnose PTLD as it lack both sensitivity and specificity
Data from the Riddler study indicated that patients with PTLD had a viral load > 5000 EBV genome copies/106 blood mononuclear cells.
How would you manage this patient?
Complete evaluation will be needed starting by detailed history taking, full lab tests including basic lab and graft assessment investigations , CMV quantitative PCR , Tacrolimus level , as well as routine monitoring of EBV load
When viral load is high in primary infections close to the time of transplantation (within the first three months);
· The use of T-cell depleting agents should be avoided if possible . Anti-CD25 is preferred .
· Reduction of immunosuppression and switching from Tac to mTOR I can be introduced
· Prophylaxis using intravenous immunoglobulins and (Val)-Ganciclovir should be considered in EBV-seronegative recipients of EBV-seropositive donor .
· Chronic or persistent high EBV load carriers are more frequent in primary infections but are not clearly related to a higher risk of the development of EBV-positive PTLD.
· A rise in EBV load could be more informative regarding the risk of developing PTLD . Reference
-Green M and Michaels M G .Epstein–Barr Virus Infection and Posttransplant Lymphoproliferative Disorder .American Journal of Transplantation 2013; 13: 41–54
-Allen U, Alfieri C, Preiksaitis J, et al. Epstein-Barr virus infection in transplant recipients: Summary of a workshop on surveillance, prevention and treatment. Can J Infect Dis. 2002;13(2):89-99.
-San-Juan R. etal,Epstein-Barr virus-related post-transplant lymphoproliferative disorder in solid organ transplant recipients,Clinical Microbiology and Infection,2014 ,Volume 20, Supplement 7,Pages 109-118.
Thankyou so what is your starting management in this case:
will it be monitoring of viral load after the full clinical and lab workup.
Or with this viral load proceed to pre-emptive management?
The risks involved:
This is a recipient who was EBV negative and received a kidney from an EBV positive donor. She has a very high risk of developing EBV infection and Post Transplant Lymphoproliferative Disorder (PTLD)
Her EBV PCR is significantly high at 31000 copies/ml
KDIGO guidelines recommend only monitoring the EBV viral load in the high risk patients – EBV+ donors/EBV- recipients which is the case with the patient
the frequency of monitoring is:
Once in the first week post transplant
Monthly for the first 3-6 months then
Every three months until one year post-transplant
The KDIGO guidelines recommend reducing the immunosuppression in EBV seronegative recipients with an increasing EBV viral load
Although there is no cut-off threshold for the EBV PCR, some authors have chosen 4000 copies/ml as the cut-off as a risk factor for PTLD
Management:
Detailed history – night sweats, weight loss, fevers, fatigue
History of the induction agent used as T cell depleting agents have been known to be a risk factor for developing PTLD
Examination: Lymphadenopathy, hepatoplenomegally
Complete blood count – to assess for unexplained anemia, thrombocytopenia or leucopenia
CMV PCR – CMV infection is a risk factor for PTLD
Tacrolimus levels
Lactate dehydrogenase – will be elevated in PTLD
Calcium – hypercalcemia can be a feature of PTLD
Uric acid – hyperuricemia can be found in PTLD
Radiological investigations – A Ct scan of the chest and ultrasound of the abdomen
Her definitive treatment will depend on the finding of the history, examination and investigations
There is no agreed upon cut-off for EBV PCR and it is known that post kidney transplant in the first year, the EBV PCR will increase. However, some authors use 4000 copies/ml as the cut-off
An increased EBV PCR has to be taken in the context of the risk of the recipient. The risk for this particular recipient is high as she was EBV negative.
Therefore, I would first reduce the immunosuppression and monitor the EBV PCR if the radiological investigations did not reveal any mass – the gold standard of diagnosing PTLD is via histology
I would also change from tacrolimus to an mTOR inhibitor
If the EBV PCR does not reduce then the patient will need a PET CT
What are the risks involved in the given scenario?
In the index patient, the most feared complication is the development of PTLD in the recipient of the level of the EBV PCR that is 31000 copies.
The following are the identified risk in the patient
the donor age of 17 years – the younger patient’s risk of developing PTLD following transplantation is 1.2 – 10.1% compared to adults 1.0 -2.3%. Also, the increased incidence of PTLD in children and adolescence is seen within the first three months following transplantation
Donor origin is the source of the primary infection of EBV.
The use of Tacrolimus-based maintenance therapy has been associated with a 3-5 fold increase in PTLD
How would you manage this patient?
It is worth noting that, the guidelines for EBV diagnosis, or the initiation of treatments are not clear because there is a lack of standardization, and optimal specimens for measuring viral loads are unknown.
However, intense monitoring of the EBV viral loads is required in the first year, particularly among those that are vulnerable to developing EBV primary infection and PTLD.
The following will be done to manage the index patient
Further history will be obtained on the HLA matching and induction therapy used
CMV viral load
Tacrolimus trough level
Close monitoring of EBV viral load
CT scan of the chest, and abdominopelvic
Initial reduction of Tacrolimus drug to achieve a lower, but safe trough level to prevent graft rejection
If the above is not working, stop the tacrolimus
Change to mTORi as a replacement for tacrolimus
Intense surveillance for rejection via kidney function tests
If the EVB viral load is still rising during monitoring, Rituximab and CD20 could be used.
The following are the pitfalls that have emerged in preemptive strategy monitoring
First, cut-off values for EBV viral loads are not clear.
The sources of samples are not universal
There is absence of standard points of time to perform the monitoring.
References
Opelz G, Döhler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004; 4: 222-230
Dierickx D, Tousseyn T, Sagaert X, Fieuws S, Wlodarska I, Morscio J, et al . Single-center analysis of biopsy-confirmed posttransplant lymphoproliferative disorder: incidence, clinicopathological characteristics, and prognostic factors. Leuk Lymphoma 2013; 54: 2433-2440
Fedaey Abbas, Mohsen El Kossi, Ihab Sakr Shaheen, Ajay Sharma, Ahmed Halawa.Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020; 10(2): 29-46
This is an exellent, analytical answer.
So very close follow up for this index case is your decision or will you proceed with the pre-emptive measures.
The risks involved in this scenario include the risk of acute rejection, infection, and long-term kidney dysfunction. Additionally, due to the patient’s history of EBV infection, there is a risk of reactivation or recurrence of EBV.
mmunosuppressive medications can have serious side effects, such as increased risk of infection and malignancy (PTLD), so it is important to closely monitor the patient’s kidney function.
For this 17-year-old patient, I would begin by exploring her history of EBV infection and the current EBV PCR results. Depending on her history and the results of the EBV PCR, I may consider adjusting her immunosuppressive regimen or providing additional antiviral therapy such as acyclovir, ganciclovir, or valganciclovir. I would also recommend close monitoring of her kidney function, electrolytes, and urine output with regular testing of her EBV PCR to assess the efficacy of any treatments
EBV is a ubiquitous tumor virus belong to gamma herpes virus and it is associated with a variety of malignancies including PTLD.
This patient is at risk of PTLD and the risk factors here are: EBV+D to EBV-R, young patient, and presentation within the first year posttransplant with a very high load
This is likely to be primary EBV infection
The gold standard diagnosis of EBV-associated malignancy is biopsy but this may not be possible many times because of the patient condition or inaccessible tumor. Therefore, a non-invasive method such as EBV PCR may be welcomed in such situations.
Role of EBV PCR: I called it opportunities & challenges
A.Opportunities:
Diagnosis of EBV- associated diseases when you cannot get tissue biopsy
Management of EBV- associated disease e.g. pre-emptive reduction of immune-suppression
Monitoring patients at high risks of EBV- assocaited PTLD
Assessing response to therapy of EBV- associated malignancy
B.Challenges:
No consensus guideline on what threshold of EBV DNA that requires intervention
No consensus on what specimens to collect for EBV DNA, is it plasma, or whole blood ?
Different forms of EBV- DNA are present in the blood and different pathologies can be caused be EBV disease state
There is significant overlap between the EBV loads in patients with PTLD and in those without PTLD
Q2. Evaluation:–
-This patient needs further evaluation e.g.,CMV status before transplantation, as the also a risk factor for PTLD
-History looking for symptoms such as fever, night sweats, weight loss
-Physical examination e.g Temperature,BMI, anemia, jaundice, palpable disease such as lyphmadenopathy, spleenomegaly, & hepatomegaly. Neuro exam
-Simple blood work up: ESR, FBC, LFTs, UEcs
-Tacrolimus level
-Simple imaging: CXR, U/S abdominopelvic
-Further investigations: tissue biopsy or CTs will depend on the above findings 2.Intervention:
-Consulation with hemato-oncologist –Largely depend on many findings and not only increasing EBV DNA
-Having only increase EBV DNA is a grey area but it worth an attention
-Options :
The first step may be reduction of immune suppression in particular anti-metabolites
mTORi may have anti-viral activity, so one may convert CNIs to mTORi
Rituximab may be tried; this has been use frequently as a pre-emptive therapy
Monitoring of the viral load ?
Source:
-EBV viral load n diagnosis, monitoring, and response assessment by Kimura H, and Kwong YL
-Hand book of kidney transplantation, 6th edition
Excellent I agree with most of your comment but only few points to consider:
mTOR inhibitors role in these circumstances are unclear and I do not think there is no universal agreement about this option of treatment due to lack of good evidence.
Role of Rituximab again in a case like this post kidney or other solid organ transplant remained unclear and is not used which is completely different in bone marrow transplant where haematologists can use it in similar case scenario.
One of the suggestions by paediatricians in similar cases is to recommend tonsillectomy if the tonsils are inflamed and subject for histological evaluation.
A 17-year-old patient received an adult kidney 3 months ago, EBV +ve/EBV -ve. Her EBV PCR reported 31000 copies. Currently, she is on Tacrolimus-based triple immunosuppression with excellent kidney function. No symptoms or signs suggested infection (viral and bacterial). What are the risks involved in the given scenario? The risks given in the scenario: EBV D+/R-, EBV PCR of 31000 copies, and on triple Tacrolimus based IS maintenance– tacrolimus increase risk by 3-5 folds of EBV related PTLD, and a young age recipient.
The PTLD post -transplant 90% is EBV related usually occur in the first year, late PTLD more than 5 years’ post-transplant is usually non EBV related.
The patient has no signs and symptoms of any disease or infection with excellent kidney function, warrants only monitoring of viral load and kidney function and imaging’s when needed.
No cutoff viral load is set, but a cut of 4000 copies is considered by, Erica Franceschini et al (1).
However, this donor EBV+ derived PTLD, has better prognosis and usually confined to the organ transplanted.
How would you manage this patient? This patient is at high risk of primary EBV infection and early PTLD so:
History of any weight loss, fever or night sweats, or any constitutional symptoms.
Laboratory:
Complete blood count- lymphopenia, thrombocytopenia, or anemia. LDH: if high suggests PTLD. Liver function tests: AST, ALT, Alkaline phos, total serum protein and albumin, and bilirubin , PT, INR. Uric acid, calcium level: high suggest PTLD. ESR, CRP, and kidney function and electrolytes. PCR test for other viral infections: CMV ,HCV….etc Kappa, lambda light chains, beta 2 microglobin , and serum and urine protein electrophoresis. 3 . Radiology : but ultrasound abdomen and chest, abdomen and pelvic CT.
Preemptive therapeutic approach: 1. Reduction of immunosuppression is the main stay for management, keeping the tacrolimus to the lower therapeutic range accepted with frequent monitoring of the EBV viral load, and graft function, or shifting to m-TOR inhibitor. 2. The use of Rituximab. 3. Rarely, adoptive immunotherapy (IVIG) may be used. The use of EBV DNA load to monitor response to therapy is NOT recommended References: (1) Franceschini E, Plessi J, Zona S, Santoro A, Digaetano M, Fontana F, Alfano G, Guaraldi G, Comoli P, Facchini F, Potenza L, Gennari W, Codeluppi M, Luppi M, Cappelli G, Gyssens IC, Mussini C. Clinical Utility of Epstein-Barr Virus Viral Load Monitoring and Risk Factors for Posttransplant Lymphoproliferative Disorders After Kidney Transplantation: A Single-Center, 10-Year Observational Cohort Study. Transplant Direct. 2017 Jun 26;3(7):e182. doi: 10.1097/TXD.0000000000000703. PMID: 28706985; PMCID: PMC5498023. (2) Kimura H, Kwong YL. EBV Viral Loads in Diagnosis, Monitoring, and Response Assessment. Front Oncol. 2019 Feb 12;9:62. doi: 10.3389/fonc.2019.00062. PMID: 30809508; PMCID: PMC6379266. (3) Abbas, F., El Kossi, M., Shaheen, I. S., Sharma, A., & Halawa, A. (2020). Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World Journal of Transplantation, 10(2), 29.
What are the risks involved in the given scenario?This patient is high risk of PTLD. Risk factors include:
1. D EBV+/R EBV-
2. High EBV viral load (31000 copies)
3. Heavy immunosuppression therapy (3 months after transplantation)
How would you manage this patient?o Detailed history and comprehensive examination
o An aggressive approach to the evaluation of PTLD should be used as the diagnosis is suspected here
o PTLD should be suspected in the presence of any unexplained febrile illnesses in a SOT recipient, particularly those in the first year after transplantation or who use heavy immunosuppression for rejection
o PTLD should also be considered in any patient with an elevated EBV viral load and focal findings on examination or in a patient with primary EBV infection and increasing viral loads
o DNAemia levels considered significant can vary between centers (but a value of 4000 copies/mL may be a risk factor for PTLD onset)
o So, for this high risk patient of PTLD with high viral load (or patient developed EBV disease, including PTLD) I will reduce immunosuppression/conversion to mTORi with close monitoring of graft function
Kidney Disease: Improving Global Outcomes guidelines:
o Monitoring high-risk kidney transplants (defined as donor EBV seropositive and recipient EBV seronegative) for EBV by NAT after transplantation once in the first week, monthly for the first 3 to 6 months, then every 3 months until the end of the first posttransplant year, and additionally after treatment for acute rejection
o Reduce immunosuppressive medication in EBV-seronegative patients with an increasing EBV viral load (VL) and in patients with EBV disease, including PTLD
American Society of Transplantation guidelines:
o Do quantitative EBV-VL monitoring for PTLD prevention only in high-risk populations in the first year. Data to support monitoring in the population at low-risk for PTLD are lacking
A recent survey published by the European Study Group of Infections in Compromised Hosts:
o EBV-VL measurements are frequently used in Europe to guide both the diagnostic workup and the reduction of immunosuppression in SOT
o 38% of renal transplant centers perform EBV-VL surveillance in all recipients, independently from the EBV risk evaluation
o 77% perform preemptive treatments for patients with high-risk EBV DNAemia levels such as the reduction of immunosuppression, and the conversion to mTORi
o Up to 14.5% used rituximab for this indication and 7.3% reported the use of immune- adoptive T cell therapy
References
1. Erica F. Clinical Utility of Epstein-Barr Virus Viral Load Monitoring and Risk Factors for Posttransplant Lymphoproliferative Disorders After Kidney Transplantation: A Single-Center, 10-Year Observational Cohort Study. Transplantation Direct 3(7):p e182, July 2017.
2. Greena M, Michaels M. G. Epstein–Barr Virus Infection and Posttransplant
Lymphoproliferative Disorde. American Journal of Transplantation 2013; 13: 41–54.
3. Markouli M at el. Recent Advances in Adult Post-Transplant
Lymphoproliferative Disorder. Cancers 2022, 14, 5949.
EBV monitoring is indicated only in high risk transplant recipients for PTLD who are defined as the presence of one of the following:
Patents receiving aggressive immunosuppression, so PTLD are more common in heart transplantation and HLA incompatible transplantation and in patients with recurrent AR
Patients with seronegative EBV status especially if the donor is positive as these patients have 24 times higher risk for early PTLD than seropositive recipients
The current patient is considered high risk of PTLD because the seronegative status with a seropositive donor, so monitoring after transplantation is indicated.
Action that should be done upon detection of EBV
Reduction of immunosuppression is indicated upon detection of EBV in blood in the current case.
No clear titer can be used to suggest the risk of PTLD, but one study demonstrates that patients with PTLD have markedly elevated EBV load, with a median EBV viral load of 3225 copies/100 microL compared to < 740 copies/100 microL in patients without PTLD. (1)
Some experts recommend the use of preemptive one dose of Rituximab if PCR level is persistently > 1000 copies per ml in high risk patients. (2-4)
PTLD should be excluded in symptomatic patient by CT chest and abdomen or PET scan.
So in the current case
I will reduce the dose of MMF, and keep lower target trough for tacrolimus
I will start Rituximab one dose
I will follow the PCR every month till stabilization of the titer
References
1. Wagner HJ, Wessel M, Jabs W, et al. Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction. Transplantation 2001; 72:1012.
2. Van Esser JW, Niesters HG, van der Holt B, et al. Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation. Blood 2002; 99:4364.
3. Worth A, Conyers R, Cohen J, et al. Pre-emptive rituximab based on viraemia and T cell reconstitution: a highly effective strategy for the prevention of Epstein-Barr virus-associated lymphoproliferative disease following stem cell transplantation. Br J Haematol 2011; 155:377.
4. Cesaro S, Murrone A, Mengoli C, et al. The real-time polymerase chain reaction-guided modulation of immunosuppression enables the pre-emptive management of Epstein-Barr virus reactivation after allogeneic haematopoietic stem cell transplantation. Br J Haematol 2005; 128:224.
What are the risks involved in the given scenario?
Seronegative SOT patients had a 10- to 75-fold higher risk of PTLD than EBV seropositive TRs. This explains pediatric TRs’ high PTLD rate.
the incidence of PTLD has been reported to range from 0.8%- 2.5% in kidney transplant recipients (KTR).
The initial EBV infection causes PTLD in children the most. Considering enhancing patient and allograft survival.
Other factors: induction: T-depleting agent increases the risk of developing PTLD
Two peaks of PTLD incidence have been observed, the first peak: In the first post-transplant year (mostly EBV seropositive), and, the second peak: Usually present 5-15 years after transplant (mostly EBV seronegative). Furthermore, the evolution of the late PTLD (> 20 years post-transplant) has been on the rise
How would you manage this patient?
reduction of immunosuppressive medication with close monitoring of viral load and the manifestation of PTLD.
A consensus statement on PTLD classification and risk factors can reduce the risk of developing PTLD.
Before donor selection, donor and recipient EBV serostatus must be determined. EBV-negative TR benefits from EBV-negative donor grafts.
adjusting immunosuppression to the lowest clinically feasible level. Reactivation of other viruses like CMV or BK may cause over-immunosuppression, thus RI should be started.
Consider preemptive/prophylactic antiviral medication for high-risk populations. IVIG/CytoGam is recommended for high-titer anti-EBV antibody maintenance.
High-risk PTLD groups should seek preemptive treatment. In high-risk cases, monitoring EBV viral load, preemptive RI with growing titers, and allograft function monitoring are also advised.
Abbas, F., El Kossi, M., Shaheen, I. S., Sharma, A., & Halawa, A. (2020). Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World Journal of Transplantation, 10(2), 29.
History of weight loss, fever, night sweats, or constitutional problems.
Laboratory: Anemia, thrombocytopenia.
PTLD: high LDH.
Liver function tests: AST, ALT
High uric acid and calcium levels imply PTLD.
ESR, CRP, renal function, electrolytes.
CMV, HCV, etc. PCR tests.
Radiology, but ultrasound of the abdomen and chest, PET-CT, abdomen and pelvis CT.
There is a significant increase of EBV proliferation, reflecting over suppression post transplantation. However, no features of EBV disease were reported.There is an increasing risk of developing PTLD.Primary treatment is to reduce immune suppression, reconsider substitution with mTORi, and keep high index of suspicion.
> high risk of developing PTLD as D+/ R- & has high viral load.
> reduce the immunosuppression & monitior EBV PCR, if still high viremia then go for PET-CT.
High risk of PTLD as it usually occur in early post transplant period especially in case of donor +ve/R-ve
so better to decrease immunosuppression dose and follow up in 1st week of transplant by EBV PCR then monthly for 3-6 months then every 3 month untill the end for 1st year
EBV has no definitive antiviral therapy
After immunosupp stopped and still viremia >you should proceed for Pet scan
What are the risks involved in the given scenario?
· The transmission of EBV is universal from EBV+ donor to EBV- recipients and EBV-seronegative kidney transplant recipients have 10-50-fold increased risk for PTLD compared to EBV-seropositive recipients. It is well known that the majority of PTLD cases (> 85%) are observed in the first year post-transplant.
· This index case is at high risk (D+/R-), he has a high viral load (31000 copies/ml 3 months post-transplant, after being exposed to the induction immunosuppression and kept of maintenance triple immunosuppression).
· The KDIGO guideline recommended monitoring high-risk (D+/R-) KTRs for EBV by NAT (EBV PCR)once in the first week following transplantation, then monthly for 3– 6 months and then every 3 months until the end of the first year –transplant. Besides, it is required to be checked following treatment for acute rejection episodes. However, the draw back that there is no universal cut off threshold for EBV viral titre and there is wide laboratory variability, but some authors have chosen 4000 copies/ml to be the cut-off for increased risk for PTLD.
How would you manage this patient?
Take a detailed history including any weight loss, night sweats and night fever
References:
1. Erica F. Clinical Utility of Epstein-Barr Virus Viral Load Monitoring and Risk Factors for Posttransplant Lymphoproliferative Disorders After Kidney Transplantation: A Single-Center, 10-Year Observational Cohort Study. Transplantation Direct 3(7):p e182, July 2017.
Allen UD, Preiksaitis JK; AST Infectious Diseases Community of Practice. Epstein-Barr virus and posttransplant lymphoproliferative disorder in solid organ transplantation. Am J Transplant. 2013; 13 (Suppl 4): 107–120.
· Q1: What are the risks involved in the given scenario?
17 years young recipient, pre-op EBV-serostatus (D+/R-) is at high-risk for EBV-related PTLD.
Rising EBV-DNA 31,000 indicates florid and active viral proliferation.
So, the risk of primary EBV as well as development of PTLD is very high in this patient.
Children and younger recipients have higher risk of PTLD, mostly during first year post-transplant. In fact, PTLD is the most common malignancy in children – up to 50% after liver transplant, 5-15% following renal transplant.
Intense immunosuppression, especially use of T-cell depleting agent is high risk factor. Tacrolimus based maintenance immunosuppression is associated with 3-5 times increased risk of PTLD.
Q2: How would you manage this patient
Detail history (GI, CNS or visceral symptoms); physical examination (lymphadenopathy or organomegaly or CNS involvement).
Imaging – whole body PET-CT, if available is diagnostic modality of choice. Else, CECT Chest, Abdomen and Pelvis – may yield RP lymphadenopathy, renal allograft SOL or visceral involvement.
Immunosuppression Reduction /Optimization is necessary first step.
MMF to be reduced 50%, with minimized dose of Tacrolimus keeping lowest target C0 (5ng/ml)
à monitoring EBV-DNA monthly x 6months; then 3monthly x 2-3 years.
If Viremia still high à stop MMF or switch to sirolimus or everolimus.
There is no standardised cut-off for EBV viral load, but EBV-DNA more than 2000 copies need attention. No role of antiviral, except in PNS.
Any enlarged Lymph node, visceral SOL or Graft dysfunction need biopsy, to detect PTLD early.
Only renal allograft or limited organ involvement, shall be managed initially with Rituximab.
Muti-organ involvement or persistent PTLD after Rituximab, need combined Chemotherapy (R-CHOP) +/- Radiation.
1. REFERENCE
KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3: S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. PMID: 19845597.
2. Gaurav Agarwal and Roslyn B. Mannon. Post-Transplant Lymphoproliferative Disorder in a Kidney Transplant Recipient. Clin J Am Soc Nephrol. 2019 May 7; 14(5): 751-753. Published online 2019 Feb 25
3. Franceschini E, Plessi J, Zona S, et al. Clinical Utility of EBV Viral Load Monitoring and Risk Factors for PTLD after Kidney Transplantation: A Single-Centre 10-Year Observational Cohort Study. Transplant Direct. 2017 Jun 26;3(7): e182. doi: 10.1097/TXD.0000000000000703. PMID: 28706985; PMCID: PMC5498023.
Q1: The recipient is young (only 17 y/o) and EBV-seronegative before TX and received a kidney from EBV-seropositive donor (D+/R-). So, the risk of primary EBV is high and is associated with the development of PTLD.
Use of tacrolimus in maintenance immunosuppression is associated with 3-5 times increase in the rate of PTLD.
Q2: For the management:
Comprehensive history (about B symptoms) and physical examination (lymphadenopathy or organomegaly or CNS involvement) should be performed.
Imaging studies are needed properly. Reduction of immunosuppression is necessary. Stop MMF, switch to sirolimus or everlimus, reduce tacrolimus dose with its level monitoring.
Monitor for EBV PCR viral load and if persistently is high, use rituximab.
There is no standard for EBV viral load, but viral loads more than 2000 copies need attention.
· What are the risks involved in the given scenario?
This patient is high risk for PTLD, because of EBV +ve donor to EBV negative recipient and high viral load.
· How would you manage this patient?
High EBV viral load without confirmed PTLD, will need closer monitoring for PTLD, reduction of immunosuppression specially if he has no high risk for rejection. Cutting MMF by 50% and keeping FK level at lower end of target, around 5.
References:
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. PMID: 19845597.
Our recipient / donor EBV status is considered a risky one as evidenced by the development of EBV , apparent through the PCR .
Although currently asymptomatic , close follow up is needed through regular EBV quantitative PCR analysis , general examination and exclusion of any symptoms or signs for the fear of PTLD development .
Epstein-Barr virus (EBV) is a gamma herpesvirus associated with diseases ranging from asymptomatic viremia to post-transplant malignancies in kidney transplant recipients. EBV specifically is associated with post-transplantation lymphoproliferative disorder (PTLD), in kidney transplant recipients, with increased risk in EBV seronegative patients with EBV seropositive donors on intensified immunosuppression. The diagnosis of PTLD relies on clinical suspicion plus tissue biopsy with polymerase chain reaction (PCR) testing of blood currently used for risk determination in high-risk recipients. Therapeutic strategies for PTLD include reduction of immunosuppression, chemotherapy and rituximab, and consideration of sirolimus-based immunosuppression. Antivirals such as ganciclovir are used to prevent reactivation of cytomegalovirus and other herpes viruses but are not onco-therapeutic. Radiation therapy or surgery is indicated for bulky, disseminated or recalcitrant disease. Prognosis varies depending on the type of malignancy identified and stage of disease.
https://pubmed.ncbi.nlm.nih.gov/28089555/
· What are the risks involved in the given scenario?
Transplant recipient in the early post transplant period
EBV – Recipient from EBV+ donor which could cause transmission of infection.
Triple immunosuppressants (Tacrolimus based).
Younger age and expected long duration of IS exposure that increases the incidence of cancers.
How would you manage this patient?
transplant recipients have a threefold higher risk of cancer, particularly virally mediated cancers, compared with the general population .
PTLD represents 21% of all cancers, kidney recipients have the lowest risk of PTLD , with a bimodal incidence in the early post-transplant period and a second peak later 10–14 years post-transplant.
This patient is young age and it was shown that Early-onset PTLD is more common in children (2.4%–15% incidence), and it is characterized by EBV tissue positivity, extra-nodal disease, and a monomorphic subtype .
EBV seronegative recipients receiving an EBV-positive organ have a 10- to 75-fold higher risk compared with seropositive recipients.
She must be monitored frequently for increased viral load monthly until 6 months post-transplant, then every 3 months for up to 5 years.
-renal biopsy if graft dysfunction occurred, or viral load increased.
– swith to mTORi after 6 month was and reduction of MMF may reduce the incidence or delay occurrence of PTLD.
REFERENCE
Gaurav Agarwal and Roslyn B. Mannon.Post-Transplant Lymphoproliferative Disorder in a Kidney Transplant Recipient. Clin J Am Soc Nephrol. 2019 May 7; 14(5): 751–753.
Published online 2019 Feb 25
· What are the risks involved in the given scenario? Due to the serological characteristic of EBV for this transplant (D+/R-), this recipient is at high risk for the development of EBV and, consequently, PTLD in the first year after transplantation. Once the viral load is measured, with this high value at 3 months after transplantation, this risk becomes more evident. · How would you manage this patient?
The first step should be the decrease in immunosuppression (25% reduction in all immunosuppression) with the purpose of preventing the development of the disease and after that one would start a screening/staging through MRI of the whole body or PET-SCAN to assess whether there are already signs of active disease.
If there are signs of active disease, I would look for the best method to try to confirm it (biopsy for histopathology and immunohistochemistry) and, depending on the severity, I would try to wait for the result of the decrease in immunosuppression. If the result was not satisfactory, we should start with specific treatment with Rituximab and CHOP if necessary.
What are the risks involved in the given scenario?
Post-transplant malignancy with PTLD is the major risk in this given scenario.
How would you manage this patient?
The first line of management would be switching tacrolimus based immunosuppression to mTOR inhibitors till the onset of PTLD.
What are the risks involved in this patient?
The risk factors in this patient are donor positive EBV + and negative EBV recipient….The patient is in the 3rd month of transplantation when the immunosuppression is high and this is also the period of first 12 months for high risk of PTLD onset…The patient also has high EBV DNA viral load (31000 copies)
How to manage the patient?
Patient should be under intense monitoring…Detailed blood examination by CBC, liver function test, LDH, Renal function test….baseline septic screening should be done…Patient should be asked for history of fever with night sweats and weight loss…PET CT scan of the whole body should be done to look for lymphadenopathy…IF there is lymphadenopathy we should plan biopsy with immunohistochemistry for diagnosis…EBV DNA is variable across different centers but value more than 4000 copies/ml is significant and it is associated with PTLD development…
KDIGO guidelines – Monitoring high risk transplant patients (donor EBV+ and recipient seronegative) for EBV is recommended…1st month – every week, monthly for first 3 to 6 months, then every 3 months until 1 year….there is also recommendations to reduce immunosuppression for EBV negative recipients with high EBV DNA viral load in those recipients with increasing EBV DNA load…
American society of transplantation – Monitoring EBV DNA in indicated in high risk population and routine screening in low risk population is not advised…
As the viral load of EBV is high, we need to reduce the immunosuppression. .I would reduce or stop anti-metabolite and continue tacrolimus with low dose steroids intially…
I will change to sirolimus from tacrolimus in a gradual way to reduce the risk of progression of PTLD… There are data to show that sirolimus conversion in PTLD reduces the the disease and prevent the progression1.
The use of rituximab is those with high EBV DNA viral load is recommended… data from HSCT recommend one dose of rituxmab if EBV DNA>1000 copies/ml itself…
I will give one dose of rituximab in this patient due to very high baseline EBV DNA load…
*Young age
*During the 1st year posttransplant
*heavy immunosuppressant medications
*Serostatus of EBV(D+/R-)
Close monitoring of EBV viral load, after the first week post transplantation, then monthly for the first 3 months, then every 3 months till the end of the first year.
Thorough history and physical examination
Investigations include: CBC, ESR, LFT , RFT, LDH, Ct chest, abdomen and pelvis.
Abdomenal US
Tissue biopsy
CMV PCR
Treatment include : high index of suspicion in case of PTLD
The mainstay for the treatment is RI by stopping MMF and maintain the CNIs on lower and safe level.
If no response,consider other options like
RTx
mTOR inhibitors
Surgical and radiological options may be need
Finally Adoptive immunotherapy has a promised results.
The following are the potential risks:
Seronegative recipient from seropositive donor
-Young age
Triple immunosuppressive therapy (calcineurin inhibitor-based)
Management of this patient
The patient was transplanted three months ago and has an EBV viral load of 31,000 copies and a serostatus of D+/R-, both of which put them at a high risk for PTLD.
The first step in management should involve compiling a comprehensive history and doing a careful physical examination.
Reducing immunosuppression in EBV seronegative recipients with a growing EBV virus load is advised by KDIGO recommendations.
The EBV viral load should be tested once the first week after transplant, once every month for the first three to six months, and once every three months until one year after transplant, according to KDIGO recommendations.
Put her under monitoring because this index case is currently a symptom.
It is recognized that a history of using T cell-depleting drugs as part of induction treatment increases the chance of developing PTLD.
Check the viral load after two weeks; if it is increasing, additional studies are required.
If the initial course of treatment is unsuccessful, the next step is to stop the antimetabolite, reduce the dosage of Tacrolimus, or switch to m-TOR.
Monitoring the EBV viral load is mandatory to evaluate the response to treatment.
Consider alternative treatment options, including Rituximab, radiotherapy, or surgery, if RIS is ineffective.
What are the risks involved in the given scenario?
Mgt;
REF;
What are the risks involved in the given scenario?
In this case ,17 years old with KTX 3 month with 31000 copies of EBV PCR from positive donor .
so far this patient is doing well and asymptomatic but he will need close follow up and serial check for :
CBC,to have a look to nthe platlet count
check LDH which can be rise in the case of PTLD
THis patient need close follow up with multidiciplinary approach :
To do full hematological and serological work up including
baseline investigations: CBC, ESR, PBF, UECs, LFTs, bone chemistry, LDH, uric acid, EBV PCR, HIV, CMV PCRSPEP/ UPEP, tacrolimus trough levels, graft ultrasound, BMA (for patients with cytopenias)
will need to have chest and abdomino and chest CT looking for hidden lymphadenopathy .PET scan and after that tissue biopsy and histopathology in the main corner for treatment .
the first step in managment of PTLD is to reduce the IS medication and most of nephrologist shift the patient to mTOR group.
then treat the condition according to what system is affected with rituximab being the main in all trials .
Some centers treat preemptively when EBV monitoring demonstrates >1000 EBV genome equivalents/mL, after confirmation of the value before initiating prophylactic treatment.
references
uptodate
4. A 17-year-old patient received an adult kidney 3 months ago, EBV +ve/EBV -ve. Her EBV PCR reported 31000 copies. Currently, she is on Tacrolimus-based triple immunosuppression with excellent kidney function. No symptoms or signs suggested infection (viral and bacterial).
Issues/ concerns
– 17yo, KTx 3 months ago, EBV D+/ R-, EBV PCR 31,000 copies
– medications: tacrolimus-based triple regimen
– excellent kidney function, no features of infection (viral or
bacterial)
What are the risks involved in the given scenario? (1-3)
– EBV serostatus: EBV D+/ R-
– overall degree of T cell immunosuppression: EBV-infected B cells are kept in check by cytotoxic T cells, prolonged exposure to high doses of tacrolimus
– time post-transplant: incidence of PTLD is highest in the 1st year posttransplant due to the intense immunosuppression
– other risk factors include: pretransplant malignancy, fewer HLA matches, induction therapy with ATG, CMV seromismatch
How would you manage this patient? (4-6)
– further history and physical examination
– multidisciplinary approach: oncologist, pathologist
– baseline investigations: CBC, ESR, PBF, UECs, LFTs, bone chemistry, LDH, uric acid, EBV PCR, HIV, CMV PCRSPEP/ UPEP, tacrolimus trough levels, graft ultrasound, BMA (for patients with cytopenias)
– if there is CNS involvement: Brain MRI and CSF analysis (cytology, flow cytometry, EBV PCR)
– imaging: Chest and Abdominopelvic CT scan to evaluate for masses, lymphadenopathy
– PET CT scan to measure disease activity (where available)
– tissue biopsy and histology
– prevention of PTLD entails:
· limiting exposure to aggressive immunosuppression,
· aggressive withdrawal and tapering of immunosuppressive agents – target tacrolimus trough level of 5-9ng/mL (7)
· antiviral prophylaxis – IV ganciclovir (8)
– preemptive treatment of EBV reactivation: (9)
· do EBV PCR monitoring for high-risk patients,
· administer preemptive treatment when the patient has >1000 EBV genome equivalents/mL
· initiate preemptive rituximab for EBV-associated PTLD and reduce immunosuppression
– the aim of treatment is to eradicate PTLD and preserve graft function
– treatment options include: (10, 11)
· Reduction in immunosuppression (RIS) – optimal method for RIS remains unknown e.g., discontinue the CNI and the antimetabolite, continue low-dose prednisone 5mg OD and initiate chemotherapy then after completion of chemotherapy start mTORi, if mTORi is not tolerated, begin azathioprine or mycophenolate
· Rituximab – anti-CD20 monoclonal antibody
· Chemotherapy: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
· Radiation therapy
· A combination of these therapies
· Adoptive immunotherapy – reserved for patients with persistent disease despite initial therapy
– Retransplantation: there is paucity of data on retransplantation in patients with PTLD (12)
References
1. Dharnidharka VR, Sullivan EK, Stablein DM, Tejani AH, Harmon WE. Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Transplantation. 2001 Apr 27;71(8):1065-8. PubMed PMID: 11374404. Epub 2001/05/26. eng.
2. Cockfield SM, Preiksaitis JK, Jewell LD, Parfrey NA. Post-transplant lymphoproliferative disorder in renal allograft recipients. Clinical experience and risk factor analysis in a single center. Transplantation. 1993 Jul;56(1):88-96. PubMed PMID: 8333073. Epub 1993/07/01. eng.
3. Opelz G, Döhler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2004 Feb;4(2):222-30. PubMed PMID: 14974943. Epub 2004/02/21. eng.
4. Tsai DE, Douglas L, Andreadis C, Vogl DT, Arnoldi S, Kotloff R, et al. EBV PCR in the diagnosis and monitoring of posttransplant lymphoproliferative disorder: results of a two-arm prospective trial. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2008 May;8(5):1016-24. PubMed PMID: 18312608. Epub 2008/03/04. eng.
5. Stevens SJ, Verschuuren EA, Pronk I, van Der Bij W, Harmsen MC, The TH, et al. Frequent monitoring of Epstein-Barr virus DNA load in unfractionated whole blood is essential for early detection of posttransplant lymphoproliferative disease in high-risk patients. Blood. 2001 Mar 1;97(5):1165-71. PubMed PMID: 11222357. Epub 2001/02/27. eng.
6. Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, et al. Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients – BCSH and BTS Guidelines. British journal of haematology. 2010 Jun;149(5):675-92. PubMed PMID: 20408847. Epub 2010/04/23. eng.
7. Shapiro R, Scantlebury VP, Jordan ML, Vivas C, Ellis D, Lombardozzi-Lane S, et al. Pediatric renal transplantation under tacrolimus-based immunosuppression. Transplantation. 1999 Jan 27;67(2):299-303. PubMed PMID: 10075598. Pubmed Central PMCID: PMC2975962. Epub 1999/02/12. eng.
8. Funch DP, Walker AM, Schneider G, Ziyadeh NJ, Pescovitz MD. Ganciclovir and acyclovir reduce the risk of post-transplant lymphoproliferative disorder in renal transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2005 Dec;5(12):2894-900. PubMed PMID: 16303002. Epub 2005/11/24. eng.
9. van Esser JW, Niesters HG, van der Holt B, Meijer E, Osterhaus AD, Gratama JW, et al. Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation. Blood. 2002 Jun 15;99(12):4364-9. PubMed PMID: 12036863. Epub 2002/05/31. eng.
10. European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.6.1. Cancer risk after renal transplantation. Post-transplant lymphoproliferative disease (PTLD): prevention and treatment. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association – European Renal Association. 2002;17 Suppl 4:31-3, 5-6. PubMed PMID: 12091638. Epub 2002/07/02. eng.
11. Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, et al. Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients – BCSH and BTS Guidelines. British journal of haematology. 2010 Jun;149(5):693-705. PubMed PMID: 20408848. Epub 2010/04/23. eng.
12. Johnson SR, Cherikh WS, Kauffman HM, Pavlakis M, Hanto DW. Retransplantation after post-transplant lymphoproliferative disorders: an OPTN/UNOS database analysis. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2006 Nov;6(11):2743-9. PubMed PMID: 17049062. Epub 2006/10/20. eng.
· EBV is associated with the majority of PTLD which is most common in EBV-negative recipients who develop primary EBV infection, usually from a graft from an EBV-positive donor
· The following abnormal laboratory studies may be seen in patients with PTLD:
1) Unexplained anemia, thrombocytopenia, or leukopenia
2) Elevated level of serum lactate dehydrogenase (LDH)
3) Hypercalcemia
4) Hyperuricemia
5) Monoclonal protein in the serum or urine
· Contrast-enhanced CT of the chest, abdomen, and pelvis should be performed in patients suspected of having PTLD.
· Some centers treat preemptively when EBV monitoring demonstrates >1000 EBV genome equivalents/mL, after confirmation of the value before initiating prophylactic treatment.
· Most centers administer preemptive rituximab therapy for patients at high risk of EBV-associated PTLD.
· Some centers favor reducing immunosuppression as prophylaxis.
https://www.uptodate.com/contents/treatment-and-prevention-of-post-transplant-lymphoproliferative-disorders?search=EBV%20in%20transplant&topicRef=8283&source=see_link#:~:text=Treatment%20and%20prevention%20of%20post%2Dtransplant%20lymphoproliferative%20disorders
What are the risks involved in the given scenario?
The risks involved in the above case are the EBV seropositivity of the donor to seronegative EBV recipient ,tacrolimus based immunosuppression and EBV viral load of 31000 copies /ml.Such patients have high chances of developing infectious mononucleosis and PTLD particularly in the first year post transplantation.
How would you manage this patient?
After detailed history and thorough examination including lymph nodes and or organimegaly -investigations like CBC,ESR,serum LDH,RFTs,LFTs ,Xray chest followed by CT scan Chest ,Abdomen and pelvis should be done and gold standard is the tissue biopsy.
Treatment :Till the diagnosis is confirmed ,in order to reduce the viral load..antimetabolite should be stopped and tacrolimus level should be kept between 5-7ng/ml or switched to mTor inhibitors..monitoring of viral load two weekly.If no response, and PTLD is confirmed then Rituximab with or without radiotherapy can be considered.
REFERENCES:
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155.
Post-transplant Lymphoproliferative Disorders (PTLD)-Lec By Ahmed Halawa Consultant Transplant Surgeon Associate Professor, University of Liverpool
A 17-year-old patient received an adult kidney 3 months ago, EBV +ve/EBV -ve. Her EBV PCR reported 31000 copies. Currently, she is on Tacrolimus-based triple immunosuppression with excellent kidney function. No symptoms or signs suggested infection (viral and bacterial).
What are the risks involved in the given scenario?
Mgt;
REF;
· What are the risks involved in the given scenario?– High risk for PTLDs being EBV seronegative recipient while the donor is EBV seropositive especially with high EBV PCR titre.· How would you manage this patient?– High level of suspicion is the most important with full examination & investigation aiming for early diagnosis including basic labs, LDH , CTs , PET CT.
– PCR follow up monthly for the 1st 6 months & then every 3 months thereafter.
– Reduction of immunosuppression by reducing the dose of MMF & keeping lower trough level of tacrolimus with graft function monitoring
EBV D+/R-
HIGH RISK OF PTLD
Imaging is advised is symptomatic like fever weight loss , palpable LN ,
keeping IS at the lower level is the choice
RETUXIMAB is the drug of choice if PTLD is confirmed mainly on histopathology of biopsy sample from symptomatic lesion or graft
What are the risks involved in the given scenario?Patients with seronegative EBV who received graft from EBV seropositive donor of great risk of developing post-transplant PTLD that is why he need frequent monitoring and follow up.
How would you manage this patient?
Reduction of immunosuppression is indicated in the form of half dose of MMF and keep tacrolimus on the lower level.
Monthly monitoring of EBV titer until clearance
High suspicious of PTLD and early screening either by PET CT or pan CT.
Some experts giving rituximab single dose as prophylactic dose.
References
1. Wagner HJ, Wessel M, Jabs W, et al. Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction. Transplantation 2001; 72:1012.
2. Van Esser JW, Niesters HG, van der Holt B, et al. Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation. Blood 2002; 99:4364.
3. Worth A, Conyers R, Cohen J, et al. Pre-emptive rituximab based on viraemia and T cell reconstitution: a highly effective strategy for the prevention of Epstein-Barr virus-associated lymphoproliferative disease following stem cell transplantation. Br J Haematol 2011; 155:377.
4. Cesaro S, Murrone A, Mengoli C, et al. The real-time polymerase chain reaction-guided modulation of immunosuppression enables the pre-emptive management of Epstein-Barr virus reactivation after allogeneic haematopoietic stem cell transplantation. Br J Haematol 2005; 128:224.
The risk involved in this scenario
1.EBV serostatus (EBV+ve to EBV-ve) leading to higher risk of EBV infection
2.Young individual that is associated with higher risk of rejection, thus careful assessment is needed before cutting down his immunosuppression
3.EBV viral load of 31000 copies that potentially lead to PTLD
Management for EBV viraemia in EBV naive recipient
1.Reduction of immunosuppression as PCR >10 3 copies/ml
2.Careful monitoring of graft function
3.Monitoring EBV by Nucleic Acid Testing (every 2 weeks first 3-month, monthly first 3-6 month and every 3-monthly)
4.To consider CT head,neck,thorax, abdominal and pelvis +/-PET
5.If there is evidence of PTLD for haematologist referral
6.In the setting no PTLD to consider Rituximab
Reference
What are the risks involved in the given scenario?
EBV serostatus: D+/R-
Young age
On tripple immunosuppressive therapy
Viral load
Induction therapy
How would you manage this patient?
Although there is no cut-off threshold for the EBV PCR, some authors have chosen 4000 copies/ml as the cut-off as a risk factor for PTLD.
KDIGO guidelines recommend; reducing the immunosuppression in EBV seronegative recipients with an increasing EBV viral load.
KDIGO guidelines recommend; the EBV viral load should be checked once in the first week following transplant, once every month for the first three to six months, and once every three months until one year after transplant.
History of induction therapy used as T cell depleting agents have been known to be a risk factor for developing PTLD.
Check viral load after 2 weeks if rising than will have to further investigations;
Complete blood count for anemia .
CMV PCR: CMV infection is a risk factor for PTLD
Lactate dehydrogenase: will be elevated in PTLD
Calcium: hypercalcemia will be found in PTLD
Uric acid: hyperuricemia will be found in PTLD
Tacrolimus levels (keep trough 4-6 ng/ml)
PAN CT scan of brain , chest , and abdominopelvic.
PET CT scan
If confirmed diagnosis (PTLD/EBV+).
The gold standard of diagnosis PTLD is through histology.
Treatment of EBV infection is mainly depending on immunosuppression reduction.
Discontinue antimetabolite and reduce Tacrolimus or change to m-TOR.
Monitoring EBV viral load .
If there is no response to RIS, considering other lines of treatment such as Rituximab, Radiotherapy or surgery.
Risk involved in this scenario:
Management:
References:
Risk involve
EBV D+/ R- Tx
Young age
Immunosuppressive drugs
Duration of the therapy
Viral load
Induction therapy
Management
Despite the fact that the EBV PCR has no set cut-off threshold, some writers have picked 4000 copies/ml as the cut-off as a risk factor for PTLD.
Reducing immunosuppression in EBV seronegative recipients with a growing EBV virus load is advised by KDIGO recommendations.
The EBV viral load should be tested once the first week after transplant, once every month for the first three to six months, and once every three months until one year after transplant, according to KDIGO guidelines.
Immunosuppression reduction is the mainstay of EBV infection treatment.
Stop using the antimetabolite I.S., cut back on Tacrolimus, or switch to m-TOR.
monitoring the EBV viral load to assess how well RIS is working.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group.
What are the risks involved in the given scenario?Risks involved in this case:
EBV serostatus: D+/R-
Young age
On tripple immunosuppressive therapy
How would you manage this patient?The patient is 3 months post-transplant with high risk of PTLD due to the EBV serostatus D+/R- with EBV viral load of 31,000 copies.
Management should begin with a detailed history and thorough physical examination.
Blood works that include : CBC, UECS, LFT, LDH, Uric acid, tacrolimus trough levels
Imaging: CT abdomen, chest, pelvis and probable PET scan if available.
There is no cut off threshold to initiate therapy, it is generally expected the EBV viral load will increase in the first year post transplant. However some authors have used a cut-off of 4000 copies/ml.
This patient I would continue monitoring, KDIGO recommends monitoring from the first week, then monthly for the first 3 months, then every 3 months until 12 months.
I would reduce/withdraw antimetabolite, reduce the CNI trough levels.
There is a role of converting the CNI to sirolimus.
There is role of rituximab if the reduce immunosuppressive therapy fails.
References
Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline
Nimish Shah, Toby A. Eyre, David Tucker, Shireen Kassam, Jasvir Parmar, Carrie Featherstone, Peter Andrews, Elham Asgari, Sridhar Chaganti, Tobias F. Menne, Christopher P. Fox, Stephen Pettit, Abid Suddle, Kristian M. Bowles on behalf of the Haemato-Oncology Task Force of the British Society for Haematology and the British Transplantation Society
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x.
What are the risks involved in the given scenario?
This index case is high risk for PTLD due to
How would you manage this patient
What are the risks involved in the given scenario?YOUNG AGE
DONOR POSTIVE EBV -RECEPIENT NEGATIVE EBV
IMMUNOSUPPRESANT STATUS
How would you manage this patient?
Epstein-Barr virus (EBV) is associated with PTLD.
PTLD occurs in approximately 1 percent of transplants and ranges in severity from benign” polyclonal lymphocytosis to highly malignant lymphomas.
The optimal strategy for the prevention of PTLD has not been established, although lesser degrees of immunosuppression appear to lower the risk
Excess rates of PTLD have been observedwith belatacept maintenance immunosuppression, notably in EBV seronegative recipients
Routine monitoring should be performed for higher risk patients (D+/R- for EBV)
many transplant centers have incorporated EBV monitoring into the routine evaluation of patients at high risk for PTLD, and preemptively treat PTLD at the time of viral reactivation with anti-B cell monoclonal antibody treatment.
Laboratory studies include a complete blood count with differential, chemistries with liver and renal function and electrolytes, lactate dehydrogenase (LDH), albumin, HIV, hepatitis B, Epstein-Barr virus (EBV) serology with quantitative polymerase chain reaction (PCR), and cytomegalovirus (CMV) PCR.
●Contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis should be performed in patients suspected of having PTLD. This study provides critical information on the measurement of disease prior to treatment, and aids in staging When available, we suggest obtaining a combined positron emission tomography (PET)/CT scan as a measure of disease activity
●Assessment of the function of the transplanted organ.
Antiviral prophylaxis
Data regarding the efficacy of antiviral prophylaxis in the prevention of PTLD in solid organ recipients is also limited.
Support for the use of antiviral prophylaxis in the prevention of PTLD comes from retrospective studies
•High-risk patients (eg, donor EBV-positive, recipient EBV-negative) were administered a minimum of 100 days of intravenous ganciclovir (6 to 10 mg/kg per day).
•Low-risk patients (eg, donor EBV-negative, recipient EBV-positive or -negative; donor and recipient EBV-positive) received intravenous ganciclovir only during the period of hospitalization followed by oral acyclovir (40 mg/kg per day).
Target tacrolimus levels were lowered to 2 to 5 ng/mL in patients in whom a rising viral copy number was detected by PCR performed once per month. PTLD, which was defined as histologic evidence of B cell proliferation, was treated with the reinstitution of intravenous ganciclovir and the withdrawal of tacrolimus. At a mean follow-up of approximately 260 days, the following results were reported:
A retrospective multicenter case-control study of renal transplant recipients also found that prophylactic antiviral therapy reduced the risk of PTLD . In this report of 100 biopsy-confirmed cases and 375 matched controls, the risk of PTLD during the first year post-transplant decreased by 38 percent for every 30 days of treatment with ganciclovir (OR of 0.62, 95% CI 0.38-1.0).
The addition of immune globulin to ganciclovir does not appear to provide added benefit to ganciclovir alone among patients at increased risk for PTLD
1-What are the risks involved in the given scenario?
This current case is high risk for PTLD due to;
–Young Age,
–1st year post transplant (3 months after KTX),
–EBV +/ EBV- Tx;
High risk for primary EBV infection or a reactivation in those who are already latently infected pre-transplantation can lead to uninhibited growth of EBV-infected B cells and subsequently to PTLD,
–EBV PCR reported 31000 copies,
–Triple immunosuppressants regimen.
2-How would you manage this patient?
–Although there is no cut-off threshold for the EBV PCR, some authors have chosen 4000 copies/ml as the cut-off as a risk factor for PTLD.
–KDIGO guidelines recommend; reducing the immunosuppression in EBV seronegative recipients with an increasing EBV viral load.
–KDIGO guidelines recommend; the EBV viral load should be checked once in the first week following transplant, once every month for the first three to six months, and once every three months until one year after transplant.
–As this index case is a symptomatic at time being , should put her under observation.
–History of induction therapy used as T cell depleting agents have been known to be a risk factor for developing PTLD.
–Check viral load after 2 weeks if rising than will have to further investigations;
*Complete blood count; (check for unexplained anemia, thrombocytopenia or leucopenia)
*CMV PCR: CMV infection is a risk factor for PTLD
*Lactate dehydrogenase: will be elevated in PTLD
*Calcium: hypercalcemia will be found in PTLD
*Uric acid: hyperuricemia will be found in PTLD
*Tacrolimus levels (keep trough 4-6 ng/ml)
* PAN CT scan of brain , chest , and abdominopelvic.
*PET CT scan
If confirmed diagnosis (PTLD/EBV+);
–The gold standard of diagnosis PTLD is through histology.
–Treatment of EBV infection is mainly depending on immunosuppression reduction.
–Discontinue antimetabolite I.S. and reduce Tacrolimus or change to m-TOR.
–Monitoring EBV viral load for evaluation the response to RIS.
–If there is no response to RIS, considering other lines of treatment such as Rituximab, Radiotherapy or surgery.
*** Risk ivolved
High PTLD risk given high EBV viral load, young age, heavely immunosupressed first year post transplant
**** managment of asymptomatic
1- for EBV
2- Basic investigations of PTLD like LDH, uric acid + imaging
3- Screen for other viruses like CMV and BK virus
A 17-year-old patient received an adult kidney 3 months ago, EBV +ve/EBV -ve. Her EBV PCR reported 31000 copies. Currently, she is on Tacrolimus-based triple immunosuppression with excellent kidney function. No symptoms or signs suggested infection (viral and bacterial).
What are the risks involved in the given scenario?
EBV +/ EBV- Tx, EBV viral load > 10 000.
younger age, Induction IS (not mentioned in this case), Triple immunosuppressants regimen, 1st year post transplant
How would you manage this Asymptomatic patient?
1- I will continue monitoring the EBV load in one week then monthly until 6 months post-transplant, then every 3 months for up to 2 to 5 years.
2- I will do graft biopsy when BKV-PCR load insistently exceeds > 10 000 copies/ml (4 log 10 genome (copies/ml)) with or without allograft dysfunction. Biopsy is the gold standard for diagnosing BKVN.
3- If BKVN is confirmed, I will start immunosuppressive reduction and continue monitoring graft function and viral load.
4- Approaches include withdrawal of antimetabolite drugs or change from MMF to azathioprine, sirolimus, or leflunomide, reducing the dose of CNI by 25–50% (target lower level of cyclosporine 50–100 ng/ml & tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI.
Reference
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x.
Fakhriya Alalawia, Hind Alnoura, Mohsen El Kossib, John Jenkinsb, Anna Takud, Ajay K. Sharma, Ahmed Halawa,
BK virus infection in renal transplant recipients: an overview, Journal of The Egyptian Society of Nephrology and Transplantation 20:127–150 DOI: 10.4103/jesnt.jesnt_ 48_19
What are the risks involved in the given scenario?This index case is high risk for PTLD due to
How would you manage this patient
will have to keep the patient under observation as currently she is having no symptoms.
Current titer is high will have to repeat it after 2 week if rising than will have to
Thankyou
What are the risks involved in the given scenario?
EBV +ve donor /EBV -ve recipient along with high EBV viral load within 1 years have high risk of PTLD.
How would you manage this patient?
Through history and examination (use of induction agents, HLA match, symptoms of PTLD, any lymphadenopathy, organomegaly.
Lab investigation-CBC, ESR, LDH level, U&E, LFT, serum uric acid and radiological tests, CXR, Tacrolimus level
Reduction of immunosuppression, lower trough level of tacrolimus (5-7)
Need to follow up PCR level and counsel the patients regarding the signs and symptoms of PTLD. (KDIGO guideline recommend Close monitoring of EBV- viral load in the first year after transplantation from the first week then every month till 3 months and every 3 months until 12 months then every 2 months after the first year. Need to keep a high index of clinical suspicion and investigate accordingly.
Reference
Franceschini E, Plessi J, Zona S, Santoro A, Digaetano M, et al. Clinical Utility of Epstein-Barr Virus Viral Load Monitoring and Risk Factors for Posttransplant Lymphoproliferative Disorders After Kidney Transplantation: A Single-Center, 10-Year Observational Cohort Study. Transplant Direct. 2017 Jun 26;3(7):e182.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x.
Thankyou
How do you manage this index case?if the index of suspicion is high.
Thank you for the question Prof
If there is high index of suspicion, I would like to stop MMF and change it to m TOR-based (everolimus or sirolimus) immunosuppression along with minimizing the CNI dose in addition to EBV PCR viral load monitoring. Chemotherapy with rituximab to be consider only after confirmation of the diagnosis by tissue biopsy along with MDT with hemato-oncologist
The risks involved in this scenario:
D + /R- EBV, early transplant period with maximal immunosuppression meanwhile. The suppression of the cytotoxic T cells is the main potential risk factor.
Management:
Close monitoring for viral load and development of PTLD. In case of the development of PTLD, as shown by some studies, Rituximab can be considered. The viral load itself was not found to correlate well with the PTLD risk.
References:
–Oertel S, Trappe RU, Zeidler K, Babel N, Reinke P, Hummel M, Jonas S, Papp-Vary M, Subklewe M, Dörken B, Riess H, Gärtner B. Epstein-Barr viral load in whole blood of adults with posttransplant lymphoproliferative disorder after solid organ transplantation does not correlate with clinical course. Ann Hematol. 2006 Jul;85(7):478-84. doi: 10.1007/s00277-006-0109-1. Epub 2006 Apr 4. PMID: 16586109.
-Nijland ML, Kersten MJ, Pals ST, Bemelman FJ, Ten Berge IJ. Epstein-Barr Virus-Positive Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation: Pathogenesis, Clinical Manifestations, Diagnosis, and Management. Transplant Direct. 2015;2(1):e48. Published 2015 Dec 15. doi:10.1097/TXD.0000000000000557.
Short but the first paragraph is well explained.
What are the risks involved in the given scenario?The current scenario reflects increased risk of PTLD
Reasons
Young donor
Early transplant days
EBV+/ EBV- status
How would you manage this patient?1.EBV viral load monitoring
2.Switching Tac to Everolimus/Sirolimus
3.Holding MMF
3.Hematology/oncology consult
5.Rituximab
What are the investigations needed to rule out PTLD.
IN the index case what are the pros and cons of the surveillance that you will follow.?
She is young.
pearly issue.
Cutoff value is not universally defined.!
This patient is at high risk of PTLD because of transplantation from EBV +ve donor /EBV -ve recipient in addition to highEBV viral load .
How would you manage this patient?
Reference :
1. Epstein-Barr virus and renal transplantationTransplant Rev (Orlando. 2017 Jan;31(1):55-60. doi: 10.1016/j.trre.2016.12.001. Epub 2016 Dec 29
What do you really mean by ‘Optimization of immunosuppression at therapeutic level.’
I would like to see discontinuation or reduction in antimetabolites.
thank Prof Ajay yes totally agree reduction or discontinuation of antimetabolites keep the tacrolimus at lower therapeutic level (4-6)
⭐The index case is high risk for EBV infection as being in pediatric age group, naieve for EBV infection (D+/R-), in addition to use of induction therapy in pediatric tx (especially if depleting antibodies as ATG (not mentioned in the scenario)), early period post transplant with intense IS (mostly tacrolimus based triple therapy.
⭐Here, although, no defined cut off level of EBV PCR to develop PTLD, but still this high titer is suspicious.
⭐Management:
_frequent monitoring OF EBV viral titer.
_oreemotive therapy (no specific antiviral therapy, but reduction of IS especially antiproliferative (MMF) and keep Tacrolimus at the lower therapeutic window.
_through clinical examination for any organomegally or lymphadenopathy.
_FU CBC (for cytopenias ), LDH, uric acid.
_Tiisue biopsy remains the gold standard for diagnosis of PTLD.
_Cases not responding to RIS in regression and reduction of viral titer are indicated for chemotherapy (CHOP) and or rituximab.
_adoptive immunotherapy is indicated in EBV postive cases.
Is adoptive immunotherapy accepted clinically
What are the risks involved in the given scenario?
1. A young recipient 17 years old, EBV seronegative from EBV positive donor, is at high risk for EBV viral infection and PTLD.
2. Type of induction immunosuppression ( ATG vs basiliximab )also should be identified as induction with T cell depleting agent considered an additional risk.
3. Intense triple maintenance IS including CNI and MMF is an additional risk.
4. Three months post-transplantation (early time for both PTLD and rejection)
High EBV viral load 31000 (concerning PTLD)
To conclude this patient is at high risk of PTLD
How would you manage this patient?
This patient is already under surveillance with EBV viral load as she is high risk and her current EBV in 3 months after TX > 31000, if it raises the viral load then she should be investigated for possible PTLD including further history and examination for LAP, organomegaly, and B SYMPTOMS (Fever, night sweat, wt loss), FBC peripheral smear, LDH Tacrolimus trough level. Primary EBV Infectious mononucleosis (IM ) in adults frequently manifests as fever, lymphadenopathy, and pharyngitis in Over 50% of patients.
PTLD after kidney transplant as per reports shows low incidence (1-3%), and its bimodal, early peak in the first year is usually EBV-genome positive found. 90% and its B cell-PTLD, and late PTLD which can be EBV-negative PTLDIN 45% and more in older age (1).
Most of the international guidelines including the KDIGO guideline recommend Close monitoring of EBV-VL in the first year after transplantation from the first week then every month till 3 months and every 3 months until 12 months then every 2 months after the first year only in a high-risk candidate like our case, also there is no agreement about the EBV cutoff values among different labs for clinical interpretation so the key factor for the early diagnosis of PTLD is to keep a high index of clinical suspicion and investigate accordingly.
I would ask hematology opinion for peripheral blood smear, LDH and if further investigation is needed to confirm the diagnosis of PTLD as the definite diagnosis need tissue biopsy with IHC staining and flow cytometry in addition to further staging should be supported with PAN CT Images. In regards to the reduction of immunosuppression, it again depends on the local center policy and this should be considered as the first step like a modification to m TOR-based IS everolimus or sirolimus along with minimizing the CNI dose along with EBV -VL monitoring, chemotherapy including rituximab alone or in combination will be decided only after confirmation of the diagnosis of PTLD by tissue biopsy and should be decided and followed after a discussion through MDT approach along with hemato-oncology team and this is what we are doing in our center
In addition will screen for other co-viral infections like CMV, BKV
References
1.Franceschini E, Plessi J, Zona S, Santoro A, Digaetano M, Fontana F, Alfano G, Guaraldi G, Comoli P, Facchini F, Potenza L, Gennari W, Codeluppi M, Luppi M, Cappelli G, Gyssens IC, Mussini C. Clinical Utility of Epstein-Barr Virus Viral Load Monitoring and Risk Factors for Posttransplant Lymphoproliferative Disorders After Kidney Transplantation: A Single-Center, 10-Year Observational Cohort Study. Transplant Direct. 2017 Jun 26;3(7):e182. doi: 10.1097/TXD.0000000000000703. PMID: 28706985; PMCID: PMC5498023.
2. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond evolving concepts and practical applications. Blood. 2011 May 12;117(19):5019-32. doi 10.1182/blood-2011-01-293050. Epub 2011 Feb 7. PMID: 21300984; PMCID: PMC3109529.
3. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. PMID: 19845597.
I appreciate your well-referenced reply.
Please use sub-headings under the heading ‘How would you manage this patient?’ to make easier to read your write-up. Please use bold or underline to highlight sub-headings.
What are the risks involved in the given scenario?
Early transplant period (3 months after KTX).
EBV+ Donor to EBV – Recipient ( can led to a primary EBV infection in EBV-seronegative patients receiving an EBV-seropositive donor organ or a reactivation in those who are already latently infected pre-transplantation can lead to uninhibited growth of EBV-infected B cells and subsequently to PTLD).
Tacrolimus based therapy.
How would you manage this patient?
There is no clear cut-off point for a high or increasing EBV viral load can be given because of the high inter-laboratory variability in test results.
We should exclude EBV- associated PTLD.
Treatment of EBV infection is mainly depending on immunosuppression reduction and response to RIS can be measured by assessing changes in EBV viral load.
Any evidence of PTLD and there is no response to RIS we have another lines of treatment such as Rituximab, Radiotherapy or surgery.
References:
1-Nijland ML, Kersten MJ, Pals ST, Bemelman FJ, Ten Berge IJ. Epstein-Barr Virus-Positive Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation: Pathogenesis, Clinical Manifestations, Diagnosis, and Management. Transplant Direct. 2015;2(1):e48. Published 2015 Dec 15. doi:10.1097/TXD.0000000000000557.
I appreciate your well-referenced reply.
The risk associated with the above scenario
The risk of development of PTLD with 4 types
Management of the case
References
Dharnidharka VR. A comprehensive review of post-organ transplant hematologic cancers. Am J Transplant 2018; 18: 537-549 [PMID: 29178667 DOI: 10.1111/ajt.14603] 2 Medscape. Post-transplant Lymphoproliferative Disease. Available from: URL: https://emedicine.medscape.com/article/431364-overview#showall 3 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66: 7-30 [PMID: 26742998 DOI: 10.3322/caac.21332] 4 Dierickx D, Habermann TM. Post-Transplantation Lymphoproliferative Disorders in Adults. N Engl J Med 2018; 378: 549-562 [PMID: 29414277 DOI: 10.1056/NEJMra1702693] 5 Penn I, Hammond W, Brettschneider L, Starzl TE. Malignant lymphomas in transplantation patients. Transplant Proc 1969; 1: 106-112 [PMID: 4944206] 6 Engels EA, Pfeiffer RM, Fraumeni JF, Kasiske BL, Israni AK, Snyder JJ, Wolfe RA, Goodrich NP, Bayakly AR, Clarke CA, Copeland G, Finch JL, Fleissner ML, Goodman MT, Kahn A, Koch L, Lynch CF, Madeleine MM, Pawlish K, Rao C, Williams MA, Castenson D, Curry M, Parsons R, Fant G, Lin M. Spectrum of cancer risk among US solid organ transplant recipients. JAMA 2011; 306: 1891-1901 [PMID:
Well done.
What is the risk state of this index case?
Which step are you going to follow? all ore selected ones?
What are the risks involved in the given scenario?
=======================
How would you manage this patient?
References
Fakhriya Alalawia, Hind Alnoura, Mohsen El Kossib, John Jenkinsb, Anna Takud, Ajay K. Sharma, Ahmed Halawa,
BK virus infection in renal transplant recipients: an overview, Journal of The Egyptian Society of Nephrology and Transplantation 20:127–150 DOI: 10.4103/jesnt.jesnt_ 48_19
Remember graft biopsy does not always give positive confirmation as you have to get a specimen near the medulla, and if positive the graft function by then will be affected!
So you have to take a decision in this index case with
Surveillance and follow up of the chemistry.
Modification of IS as you correctly mentioned.
What are the risks involved in the given scenario?
How would you manage this patient?
Short and to the point.
1-High risk for EBV (donor +/Recepient -ve)
2- incidence of PTLD is high in first year after transplantation (most intense immune suppression
Management
1- the risk involved is development of PTLD
2- management:
clinical examination LN, hepatosplenomegaly
if GIT symptoms do upper and lower endoscopy and biopsy
biopsy to confirm diagnosis
if confirmed treat by RIS reduction of immunosuppression, chemotherapy also may be needed, rituximab
What are the risks involved in the given scenario?
1. KT in EBV serostatus D+/R-, carries high risk for EBV infection or reactivation in the post-transplant period.
2. High viral load is linked to infectious mononucleosis and Chronic Active EBV Infection (CAEBV)in pediatric population(1).
3. In most instances (approximately 90%), PTLD is associated with EBV(2).
4. The development of EBV infection and PTLD is normally associated with a high EBV viral load in peripheral blood(3). High viral load is associate with Extranodal NK/T-Cell Lymphoma, Nasal Type (ENKTL) and Chronic Active EBV Infection (CAEBV)(4).
How would you manage this patient?
1. While primary infection in childhood is usually asymptomatic, delayed infection is associated with infectious mononucleosis (IM), a febrile illness in which patients have high circulating viral loads and an exaggerated virus-induced immune response involving both CD8+ T cells and natural killer (NK) cells(5).
2. The patient should be thoroughly examined, looking for LNs involvement beside laboratory testing and imaging studies; CBC, KFT, LFT, LDH, other viral infection, CXR and CT scan(chest, abdomen and brain).
3. Despite of being asymptomatic, this KTR with high EBV-viral load should undergo modification and Reduction of immunosuppression to minimize complication and to prevent allograft dysfunction:
· immediate reduction in immunosuppression (RIS) by 25% in limited diseases and up to 50% in extensive disease. Response should be assessed within 2–4 weeks, If a complete remission (CR) is obtained, then no other therapy may be required.
· Patients that achieve a PR by RIS alone can either be monitored and reassessed within a further 2–4 weeks.
· Consider stopping AZA/MMF. Maintain prednisolone 7.5/10 mg/day.
References
1. Akihiko Maeda, Hiroshi Wakiguchi, Wakako Yokoyama, Hiroaki Hisakawa, Takashi Tomoda, Takanobu Kurashige, Persistently High Epstein-Barr Virus (EBV) Loads in Peripheral Blood Lymphocytes from Patients with Chronic Active EBV Infection, The Journal of Infectious Diseases, Volume 179, Issue 4, April 1999, Pages 1012–1015, https://doi.org/10.1086/314691
2. Al-Adra D, Al-Qaoud T, Fowler K, Wong G. De Novo Malignancies after Kidney Transplantation. Clin J Am Soc Nephrol. 2022 Mar;17(3):434-443. doi: 10.2215/CJN.14570920. Epub 2021 Mar 29. PMID: 33782034; PMCID: PMC8975024.
3. Yamada M, Nguyen C, Fadakar P, Ganoza A, Humar A, Shapiro R, Michaels MG, Green M. Epidemiology and outcome of chronic high Epstein-Barr viral load carriage in pediatric kidney transplant recipients. Pediatr Transplant. 2018 May;22(3):e13147. doi: 10.1111/petr.13147. Epub 2018 Feb 6. PMID: 29411474; PMCID: PMC7197440.
4. Hiroshi Kimura and Yok-Lam Kwong EBV Viral Loads in Diagnosis, Monitoring, and Response Assessment https://www.frontiersin.org/
5. Abbott RJ, Pachnio A, Pedroza-Pacheco I, Leese AM, Begum J, Long HM, Croom-Carter D, Stacey A, Moss PAH, Hislop AD, Borrow P, Rickinson AB, Bell AI. Asymptomatic Primary Infection with Epstein-Barr Virus: Observations on Young Adult Cases. J Virol. 2017 Oct 13;91(21):e00382-17. doi: 10.1128/JVI.00382-17. PMID: 28835490; PMCID: PMC5640854.
Considering this patient to be still in the( pediatric range) how can you differentiate between an infectious mononucleosis state and a primary infection D+R-.
So you decided to go to Pre-emptive management .!
1. Primary infection in childhood is commonly asymptomatic. Most people are infected with Epstein-Barr virus (EBV) during childhood or adolescence, resulting in a persistent, mostly latent EBV infection.
2. Globally EBV is causally linked to nearly 200000 incident cancers and 18000 deaths from multiple sclerosis annually with IM elevating the risk of Hodgkin lymphoma and multiple sclerosis for unknown reasons(1).
3. Functions of EBV antibody levels as predictors of disease risk is an active field of research.
4. Infectious mononucleosis (IM) is a febrile illness characterized by(2):
a) anti-EBV IgM antibody positivity.
b) high loads of circulating latently infected B cells.
c) a marked lymphocytosis caused by hyperexpansion of EBV-specific CD8+ T cells plus a milder expansion of CD56dim NKG2A+ KIR– natural killer (NK) cells.
5. Disease severity and duration correlate much better with e.g. CD8+ cell counts than with the viral kinetics itself and the expansion of the CD8+ cell count is controlled in asymptomatic EBV infection despite virus loads similar to those experienced in symptomatic EBV infection.
References
1. Primary Epstein-Barr virus infection with and without infectious mononucleosis Klaus Rostgaard ,Henry H. Balfour Jr.,Ruth Jarrett,Christian Erikstrup,Ole Pedersen,Henrik Ullum,Lars Peter Nielsen,Marianne Voldstedlund, Henrik Hjalgrim Published: December 17, 2019https://doi.org/10.1371/journal.pone.0226436
2. Abbott RJ, Pachnio A, Pedroza-Pacheco I, Leese AM, Begum J, Long HM, Croom-Carter D, Stacey A, Moss PAH, Hislop AD, Borrow P, Rickinson AB, Bell AI. Asymptomatic Primary Infection with Epstein-Barr Virus: Observations on Young Adult Cases. J Virol. 2017 Oct 13;91(21):e00382-17. doi: 10.1128/JVI.00382-17. PMID: 28835490; PMCID: PMC5640854.
Thankyou for the effort but obviously to decide note that:
The viral load in the asymptomatic index case is very high although the cut off value is not yet defined so you have every reason to take it seriously.
IM in children is always symptomatic with fever throat rash and lymphocytosis ,and self limiting febrile illness.
As the goal of your training is decision taking ,the index case has to be considered very carefully as you wisely did.
4. A 17-year-old patient received an adult kidney 3 months ago, EBV +ve/EBV -ve. Her EBV PCR reported 31000 copies. Currently, she is on Tacrolimus-based triple immunosuppression with excellent kidney function. No symptoms or signs suggested infection (viral and bacterial).
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What are the risks involved in the given scenario?
Differential Diagnosis
D/ EBV +ve R/EBV -ve + Age+ high dose immunosuppression = high risk of PTLD
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How would you manage this patient?
Pre-transplant Management
Vaccination
Screening
Post-transplant Surveillance
Treatment / Management
Many modalities tried
Antiviral Strategies
Reduction of immunosuppression
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Reference
Thank you for such detailed and confusing answer but I do not know is this a case of PTLD? In case your answer is ‘YES’ what is your support for this diagnosis?
Thanks alot for you Prof.Mohsen El Kossi
I appreciate your reply to Prof Kossi’s comments, dear Dr Wadi.
– Early identification of primary infection and viral load monitoring allows therapeutic interventions to prevent progression to EBV disease.
– The EBV viral load becomes positive before the development of EBV disease.
– EBV-seronegative KTRs have 10-50-fold increased risk for EBV diseases (PTLD) in compared to EBV-seropositive KTRs.
– Studies showed that high levels of EBV DNA in peripheral blood of immunosuppressed patients indicate the onset of PTLD.
-PTLD is serious complication serious complication related to the intensity of post-transplant immunosuppression. The role of EBV in PTLD evolution is well established.
-The majority of PTLD cases (> 85%) are usually observed in the first post-transplant year.
KDIGO guideline recommended monitoring high-risk (donor EBV seropositive/recipient seronegative) KTRs for EBV by NAT
• once in the first week after transplantation.
• then at least monthly for the first 3– 6 months after transplantation.
• then every 3 months until the end of the first post-transplant year.
• additionally after treatment for acute rejection.
EBV- PCR becomes a tool for early diagnosis as well as for monitoring, cut-off values are not, 4000 copies/ml is selected by some authors as a risk factor for PTLD.
The index case is at high risk (D+/R-), high viral load and only 3 months post-Tx ( exposed to aggressive immunosuppression). Therefore, reducing immunosuppressive medication is recommended to prevent progression to PTLD and it is effective in many patients.
Management:
*Patient should be evaluated thoroughly:
– Clinically; any constitutional symptoms; fever, sweating, weight loss.
-Examination: vitals, weigh, lymphadenopathy, organomegaly.
-laboratory: CBC (anemia, thrombocytopenia), LFT, RFT, LDH, ESR, uric acid.
– Look for other concomitant viruses: CMV.
– CXR and abdomen US
Further work up guided by the history and results of the initial work up.
*Preemptive therapy:
-Reduce MMF by 50 % may need to completely stop it, if viral load rapidly rising despite reduction of the dose.
– Reduce Tacrolimus dose to the lowest possible dose to maintain graft function.
– Monitor response to therapy and graft function for rejection.
– May consider one dose of rituximab.
References:
Erica F. Clinical Utility of Epstein-Barr Virus Viral Load Monitoring and Risk Factors for Posttransplant Lymphoproliferative Disorders After Kidney Transplantation: A Single-Center, 10-Year Observational Cohort Study. Transplantation Direct 3(7):p e182, July 2017.
Wagner HJ, Wessel M, Jabs W, Smets F, Fischer L, Offner G, Bucsky P. Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction. Transplantation. 2001 Sep 27;72(6):1012-9. doi: 10.1097/00007890-200109270-00006. PMID: 11579293.
Chadban, Steven J. BMed, PhD1,*; Ahn, Curie MD, PhD2; Axelrod, David A. MD, MBA3; Foster, Bethany J. MD, MSCE4; Kasiske, Bertram L. MD5; Kher, Vijah MD, DM6; Kumar, Deepali MD, MSc7; Oberbauer, Rainer MD, PhD8; Pascual, Julio MD, PhD9; Pilmore, Helen L. MD10; Rodrigue, James R. PhD11; Segev, Dorry L. MD, PhD12; Sheerin, Neil S. BSc, PhD13; Tinckam, Kathryn J. MD, MMSc7; Wong, Germaine MD, PhD14; Knoll, Gregory A. MD, MSc15,*. KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation. Transplantation 104(4S1):p S11-S103, April 2020. | DOI: 10.1097/TP.0000000000003136
Thank you, well done. For the sake of discussion, suppose the patient presented with fever, lymphadenopathy and splenomegaly, does this confirm or exclude PTLD? What you need to do to confirm or exclude your diagnosis?
this will suggest diagnosis of PTLD
CT chest and abdomen with biopsy from apparent lesion
Thank you Prof.
These symptoms is highly suggestive of PTLD as its clinical presentation variable range from silent local disease to disseminated fulminating disease with multi-organ failure.
However, to confirm the diagnosis we need tissue diagnosis (biopsy).
I appreciate your reply to Prof Kossi’s comments, dear Dr Badawi.
– presence of fever, lymphadenopathy and splenomegaly is highly suggestive of PTLD
– a lymph node biopsy is needed to confirm the diagnosis of PTLD (histological/ tissue diagnosis)
What are the risks involved in the given scenario?
Generally speaking, Posttransplant lymphoproliferative disease is a potentially fatal complication after kidney transplantation and it is highly associated with Epstein-Barr virus infection. The EBV-specific cytotoxic T cell response that is essential in controlling the virus in healthy individuals is suppressed in transplant recipients using immunosuppressive drugs.
In the current scenario ,the recipient is at high risk to develop primary EBV infection in settings of EBV-seronegative status at the time of transplantation that can lead to uninhibited growth of EBV-infected B cells and subsequently to PTLD.
How would you manage this patient?
Notably, not every transplant recipient with increasing EBV viral load develops PTLD(One explanation is that most infected lymphoblasts transit into resting memory cells, and only cells that are not able to make this transition will start to proliferate freely). it is hard to decide how intensively these patients should be monitored and how and when a preemptive intervention should take place.
In the current index case ,there is no symptoms or signs suggestive of infection(triad of fever, lymphadenopathy, and pharyngitis). There is no available effective preventive strategies, such as vaccines or antiviral agents as well as there is no consensus on the optimal way to monitor for PTLD. Quantitative EBV PCR may be useful for surveillance, diagnostic and disease monitoring of PTLD because an increase in viral load correlates with the development of EBV-related PTLD. weekly to twice weekly monitoring during the first year or at least during the first months after transplantation has been recommended.
The preemptive intervention in the current case is reduction of immunosuppression, which has been shown to decrease the incidence of PTLD in addition to Rituximab which causes depletion of circulating B cells including those infected with EBV. stop all antiproliferative agents, and decrease CNIs by 50% and to continue with prednisolone.
References
Allen UD, Preiksaitis JK; AST Infectious Diseases Community of Practice. Epstein-Barr virus and posttransplant lymphoproliferative disorder in solid organ transplantation. Am J Transplant. 2013; 13 (Suppl 4): 107–120.
Parker A, Bowles K, Bradley JA, et al. Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients – BCSH and BTS Guidelines. Br J Haematol. 2010; 149: 693–705.
Thankyou so it is SURVEILLANCE then decide.
What are the risks involved in the given scenario?
There is EBV positive to EBV negative kidney transplant. EBV viral load is high. There are no features of EBV . This indicates immune over suppression. EBV specifically is associated with post-transplantation lymphoproliferative disorder (PTLD), in kidney transplant recipients, with increased risk in EBV seronegative patients with EBV seropositive donors on intensified immunosuppression. The index case is at high risk of PTLD.
How would you manage this patient?
Reduction of immune suppression
MMF has to be reduced and Tacrolimus at lowest possible therapeutic levels.
Use of Rituximab
Close monitoring of Viral load.
Hand book of kidney transplant 6th edition
What are the risks involved in the given scenario?
–EBV negative recipient receiving graft from EBV positive donor
– EBV PCR reported 31000 copies.
– she is on Tacrolimus-based triple immunosuppression
monitoring EBV load routinely is mandatory in this case
Meanwhile EBV viral load is higher in seronegative patients that develop EBV/PTLD than in those with asymptomatic EBV conversion.
Viral load testing improved monitoring for EBV infection, but solely cannot be used to diagnose PTLD as it lack both sensitivity and specificity
Data from the Riddler study indicated that patients with PTLD had a viral load > 5000 EBV genome copies/106 blood mononuclear cells.
How would you manage this patient?
Complete evaluation will be needed starting by detailed history taking, full lab tests including basic lab and graft assessment investigations , CMV quantitative PCR , Tacrolimus level , as well as routine monitoring of EBV load
When viral load is high in primary infections close to the time of transplantation (within the first three months);
· The use of T-cell depleting agents should be avoided if possible . Anti-CD25 is preferred .
· Reduction of immunosuppression and switching from Tac to mTOR I can be introduced
· Prophylaxis using intravenous immunoglobulins and (Val)-Ganciclovir should be considered in EBV-seronegative recipients of EBV-seropositive donor .
· Chronic or persistent high EBV load carriers are more frequent in primary infections but are not clearly related to a higher risk of the development of EBV-positive PTLD.
· A rise in EBV load could be more informative regarding the risk of developing PTLD .
Reference
-Green M and Michaels M G .Epstein–Barr Virus Infection and Posttransplant Lymphoproliferative Disorder .American Journal of Transplantation 2013; 13: 41–54
-Allen U, Alfieri C, Preiksaitis J, et al. Epstein-Barr virus infection in transplant recipients: Summary of a workshop on surveillance, prevention and treatment. Can J Infect Dis. 2002;13(2):89-99.
-San-Juan R. etal,Epstein-Barr virus-related post-transplant lymphoproliferative disorder in solid organ transplant recipients,Clinical Microbiology and Infection,2014 ,Volume 20, Supplement 7,Pages 109-118.
Thankyou so what is your starting management in this case:
will it be monitoring of viral load after the full clinical and lab workup.
Or with this viral load proceed to pre-emptive management?
The risks involved:
This is a recipient who was EBV negative and received a kidney from an EBV positive donor. She has a very high risk of developing EBV infection and Post Transplant Lymphoproliferative Disorder (PTLD)
Her EBV PCR is significantly high at 31000 copies/ml
KDIGO guidelines recommend only monitoring the EBV viral load in the high risk patients – EBV+ donors/EBV- recipients which is the case with the patient
the frequency of monitoring is:
The KDIGO guidelines recommend reducing the immunosuppression in EBV seronegative recipients with an increasing EBV viral load
Although there is no cut-off threshold for the EBV PCR, some authors have chosen 4000 copies/ml as the cut-off as a risk factor for PTLD
Management:
Her definitive treatment will depend on the finding of the history, examination and investigations
There is no agreed upon cut-off for EBV PCR and it is known that post kidney transplant in the first year, the EBV PCR will increase. However, some authors use 4000 copies/ml as the cut-off
An increased EBV PCR has to be taken in the context of the risk of the recipient. The risk for this particular recipient is high as she was EBV negative.
Therefore, I would first reduce the immunosuppression and monitor the EBV PCR if the radiological investigations did not reveal any mass – the gold standard of diagnosing PTLD is via histology
I would also change from tacrolimus to an mTOR inhibitor
If the EBV PCR does not reduce then the patient will need a PET CT
Erica F et al Transplantation Direct.3(7);e182
Well done.
What are the risks involved in the given scenario?
In the index patient, the most feared complication is the development of PTLD in the recipient of the level of the EBV PCR that is 31000 copies.
The following are the identified risk in the patient
How would you manage this patient?
It is worth noting that, the guidelines for EBV diagnosis, or the initiation of treatments are not clear because there is a lack of standardization, and optimal specimens for measuring viral loads are unknown.
However, intense monitoring of the EBV viral loads is required in the first year, particularly among those that are vulnerable to developing EBV primary infection and PTLD.
The following will be done to manage the index patient
The following are the pitfalls that have emerged in preemptive strategy monitoring
References
This is an exellent, analytical answer.
So very close follow up for this index case is your decision or will you proceed with the pre-emptive measures.
The information is allready mentioned in the index case!
Q1.
A.Opportunities:
B.Challenges:
Q2.
Evaluation:–
-This patient needs further evaluation e.g.,CMV status before transplantation, as the also a risk factor for PTLD
-History looking for symptoms such as fever, night sweats, weight loss
-Physical examination e.g Temperature,BMI, anemia, jaundice, palpable disease such as lyphmadenopathy, spleenomegaly, & hepatomegaly. Neuro exam
-Simple blood work up: ESR, FBC, LFTs, UEcs
-Tacrolimus level
-Simple imaging: CXR, U/S abdominopelvic
-Further investigations: tissue biopsy or CTs will depend on the above findings
2.Intervention:
-Consulation with hemato-oncologist
–Largely depend on many findings and not only increasing EBV DNA
-Having only increase EBV DNA is a grey area but it worth an attention
-Options :
Source:
-EBV viral load n diagnosis, monitoring, and response assessment by Kimura H, and Kwong YL
-Hand book of kidney transplantation, 6th edition
Well done very comprehesive.
Thnxs, prof
Excellent I agree with most of your comment but only few points to consider:
mTOR inhibitors role in these circumstances are unclear and I do not think there is no universal agreement about this option of treatment due to lack of good evidence.
Role of Rituximab again in a case like this post kidney or other solid organ transplant remained unclear and is not used which is completely different in bone marrow transplant where haematologists can use it in similar case scenario.
One of the suggestions by paediatricians in similar cases is to recommend tonsillectomy if the tonsils are inflamed and subject for histological evaluation.
Thank you prof ,
A 17-year-old patient received an adult kidney 3 months ago, EBV +ve/EBV -ve. Her EBV PCR reported 31000 copies. Currently, she is on Tacrolimus-based triple immunosuppression with excellent kidney function. No symptoms or signs suggested infection (viral and bacterial).
What are the risks involved in the given scenario?
The risks given in the scenario: EBV D+/R-, EBV PCR of 31000 copies, and on triple Tacrolimus based IS maintenance– tacrolimus increase risk by 3-5 folds of EBV related PTLD, and a young age recipient.
The PTLD post -transplant 90% is EBV related usually occur in the first year, late PTLD more than 5 years’ post-transplant is usually non EBV related.
The patient has no signs and symptoms of any disease or infection with excellent kidney function, warrants only monitoring of viral load and kidney function and imaging’s when needed.
No cutoff viral load is set, but a cut of 4000 copies is considered by, Erica Franceschini et al (1).
However, this donor EBV+ derived PTLD, has better prognosis and usually confined to the organ transplanted.
How would you manage this patient?
This patient is at high risk of primary EBV infection and early PTLD so:
Complete blood count- lymphopenia, thrombocytopenia, or anemia.
LDH: if high suggests PTLD.
Liver function tests: AST, ALT, Alkaline phos, total serum protein and albumin, and bilirubin , PT, INR.
Uric acid, calcium level: high suggest PTLD.
ESR, CRP, and kidney function and electrolytes.
PCR test for other viral infections: CMV ,HCV….etc
Kappa, lambda light chains, beta 2 microglobin , and serum and urine protein electrophoresis.
3 . Radiology : but ultrasound abdomen and chest, abdomen and pelvic CT.
Preemptive therapeutic approach:
1. Reduction of immunosuppression is the main stay for management, keeping the tacrolimus to the lower therapeutic range accepted with frequent monitoring of the EBV viral load, and graft function, or shifting to m-TOR inhibitor.
2. The use of Rituximab.
3. Rarely, adoptive immunotherapy (IVIG) may be used.
The use of EBV DNA load to monitor response to therapy is NOT recommended
References:
(1) Franceschini E, Plessi J, Zona S, Santoro A, Digaetano M, Fontana F, Alfano G, Guaraldi G, Comoli P, Facchini F, Potenza L, Gennari W, Codeluppi M, Luppi M, Cappelli G, Gyssens IC, Mussini C. Clinical Utility of Epstein-Barr Virus Viral Load Monitoring and Risk Factors for Posttransplant Lymphoproliferative Disorders After Kidney Transplantation: A Single-Center, 10-Year Observational Cohort Study. Transplant Direct. 2017 Jun 26;3(7):e182. doi: 10.1097/TXD.0000000000000703. PMID: 28706985; PMCID: PMC5498023.
(2) Kimura H, Kwong YL. EBV Viral Loads in Diagnosis, Monitoring, and Response Assessment. Front Oncol. 2019 Feb 12;9:62. doi: 10.3389/fonc.2019.00062. PMID: 30809508; PMCID: PMC6379266.
(3) Abbas, F., El Kossi, M., Shaheen, I. S., Sharma, A., & Halawa, A. (2020). Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World Journal of Transplantation, 10(2), 29.
Thanks, Mohamed
What are the risks involved in the given scenario?This patient is high risk of PTLD. Risk factors include:
1. D EBV+/R EBV-
2. High EBV viral load (31000 copies)
3. Heavy immunosuppression therapy (3 months after transplantation)
How would you manage this patient?o Detailed history and comprehensive examination
o An aggressive approach to the evaluation of PTLD should be used as the diagnosis is suspected here
o PTLD should be suspected in the presence of any unexplained febrile illnesses in a SOT recipient, particularly those in the first year after transplantation or who use heavy immunosuppression for rejection
o PTLD should also be considered in any patient with an elevated EBV viral load and focal findings on examination or in a patient with primary EBV infection and increasing viral loads
o DNAemia levels considered significant can vary between centers (but a value of 4000 copies/mL may be a risk factor for PTLD onset)
o So, for this high risk patient of PTLD with high viral load (or patient developed EBV disease, including PTLD) I will reduce immunosuppression/conversion to mTORi with close monitoring of graft function
Kidney Disease: Improving Global Outcomes guidelines:
o Monitoring high-risk kidney transplants (defined as donor EBV seropositive and recipient EBV seronegative) for EBV by NAT after transplantation once in the first week, monthly for the first 3 to 6 months, then every 3 months until the end of the first posttransplant year, and additionally after treatment for acute rejection
o Reduce immunosuppressive medication in EBV-seronegative patients with an increasing EBV viral load (VL) and in patients with EBV disease, including PTLD
American Society of Transplantation guidelines:
o Do quantitative EBV-VL monitoring for PTLD prevention only in high-risk populations in the first year. Data to support monitoring in the population at low-risk for PTLD are lacking
A recent survey published by the European Study Group of Infections in Compromised Hosts:
o EBV-VL measurements are frequently used in Europe to guide both the diagnostic workup and the reduction of immunosuppression in SOT
o 38% of renal transplant centers perform EBV-VL surveillance in all recipients, independently from the EBV risk evaluation
o 77% perform preemptive treatments for patients with high-risk EBV DNAemia levels such as the reduction of immunosuppression, and the conversion to mTORi
o Up to 14.5% used rituximab for this indication and 7.3% reported the use of immune- adoptive T cell therapy
References
1. Erica F. Clinical Utility of Epstein-Barr Virus Viral Load Monitoring and Risk Factors for Posttransplant Lymphoproliferative Disorders After Kidney Transplantation: A Single-Center, 10-Year Observational Cohort Study. Transplantation Direct 3(7):p e182, July 2017.
2. Greena M, Michaels M. G. Epstein–Barr Virus Infection and Posttransplant
Lymphoproliferative Disorde. American Journal of Transplantation 2013; 13: 41–54.
3. Markouli M at el. Recent Advances in Adult Post-Transplant
Lymphoproliferative Disorder. Cancers 2022, 14, 5949.
Thanks, Mohamed
Very sensible answer
Thank you prof.
How would you manage this patient?
EBV monitoring is indicated only in high risk transplant recipients for PTLD who are defined as the presence of one of the following:
The current patient is considered high risk of PTLD because the seronegative status with a seropositive donor, so monitoring after transplantation is indicated.
Action that should be done upon detection of EBV
So in the current case
References
1. Wagner HJ, Wessel M, Jabs W, et al. Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction. Transplantation 2001; 72:1012.
2. Van Esser JW, Niesters HG, van der Holt B, et al. Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation. Blood 2002; 99:4364.
3. Worth A, Conyers R, Cohen J, et al. Pre-emptive rituximab based on viraemia and T cell reconstitution: a highly effective strategy for the prevention of Epstein-Barr virus-associated lymphoproliferative disease following stem cell transplantation. Br J Haematol 2011; 155:377.
4. Cesaro S, Murrone A, Mengoli C, et al. The real-time polymerase chain reaction-guided modulation of immunosuppression enables the pre-emptive management of Epstein-Barr virus reactivation after allogeneic haematopoietic stem cell transplantation. Br J Haematol 2005; 128:224.
Thanks, Sherif
Very sensible answer
What are the risks involved in the given scenario?
Seronegative SOT patients had a 10- to 75-fold higher risk of PTLD than EBV seropositive TRs. This explains pediatric TRs’ high PTLD rate.
the incidence of PTLD has been reported to range from 0.8%- 2.5% in kidney transplant recipients (KTR).
The initial EBV infection causes PTLD in children the most. Considering enhancing patient and allograft survival.
Other factors: induction: T-depleting agent increases the risk of developing PTLD
Two peaks of PTLD incidence have been observed, the first peak: In the first post-transplant year (mostly EBV seropositive), and, the second peak: Usually present 5-15 years after transplant (mostly EBV seronegative). Furthermore, the evolution of the late PTLD (> 20 years post-transplant) has been on the rise
How would you manage this patient?
reduction of immunosuppressive medication with close monitoring of viral load and the manifestation of PTLD.
A consensus statement on PTLD classification and risk factors can reduce the risk of developing PTLD.
Before donor selection, donor and recipient EBV serostatus must be determined. EBV-negative TR benefits from EBV-negative donor grafts.
adjusting immunosuppression to the lowest clinically feasible level. Reactivation of other viruses like CMV or BK may cause over-immunosuppression, thus RI should be started.
Consider preemptive/prophylactic antiviral medication for high-risk populations. IVIG/CytoGam is recommended for high-titer anti-EBV antibody maintenance.
High-risk PTLD groups should seek preemptive treatment. In high-risk cases, monitoring EBV viral load, preemptive RI with growing titers, and allograft function monitoring are also advised.
Abbas, F., El Kossi, M., Shaheen, I. S., Sharma, A., & Halawa, A. (2020). Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World Journal of Transplantation, 10(2), 29.
How would you rule out PTLD inn the index case?
History of weight loss, fever, night sweats, or constitutional problems.
Laboratory: Anemia, thrombocytopenia.
PTLD: high LDH.
Liver function tests: AST, ALT
High uric acid and calcium levels imply PTLD.
ESR, CRP, renal function, electrolytes.
CMV, HCV, etc. PCR tests.
Radiology, but ultrasound of the abdomen and chest, PET-CT, abdomen and pelvis CT.
There is a significant increase of EBV proliferation, reflecting over suppression post transplantation. However, no features of EBV disease were reported.There is an increasing risk of developing PTLD.Primary treatment is to reduce immune suppression, reconsider substitution with mTORi, and keep high index of suspicion.
Would you consider a reduction in or discontinuation of anti-metabolites?