5. A 24-years old CKD 5 received a kidney from his brother 8 months ago. 111 mismatch, no DSA and negative FCXM. He is on CNI-based double immunosuppression with excellent kidney function. His EBV viral load increased from 200 copies/ml prior to the operation rose to 740 copies/ml 6 months after transplantation.
What is the role of EBV monitoring in this scenario?
How do you manage this case?
226 Comments
Tahani Ashmaig
To monitor the risk of increasing EBV titers.
Management
If there is a rise in EBV titers we must evaluate the primary intervention by rreducing immunosuppression to decrease the risks of PTLD . The secondline of management is the screnning for PTLD for early diagnosis and management.
What is the role of EBV monitoring in this scenario?
The role of EBV monitoring in this scenario is crucial in the detection and management of post-transplant lymphoproliferative disorders (PTLDs), which are severe complications that can arise in both hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT) due to immunodeficiency. PTLD is characterized by the presence of altered B-cell lymphocytes, often infected with Epstein-Barr virus (EBV). The incidence of PTLD varies depending on the type of organ transplanted, with rates ranging from 5% to 20% for intestinal and multiorgan transplants, and 2% to 10% for lung and heart transplants. Among renal transplant recipients, the incidence of PTLD is relatively lower, affecting approximately 1% to 5% of patients at risk.
Monitoring EBV DNA levels using quantitative PCR-based detection methods plays a crucial role in the early diagnosis of PTLD and can serve as an indirect means of identifying patients at risk and monitoring their response to therapy. However, there are certain challenges associated with interpreting preemptive EBV PCR monitoring results. These challenges include the lack of a defined cutoff value for result interpretation, uncertainty about the optimal timing for conducting the monitoring, and variations in the sources of samples used for testing.
Recent reports suggest that measuring cell-free plasma EBV DNA levels may provide a more accurate indication of EBV activity and help in monitoring the progression of PTLD. Additionally, higher plasma EBV loads at the time of diagnosis have been associated with poorer outcomes and increased mortality rates, indicating that cell-free EBV DNA levels can also have prognostic value in assessing the severity and prognosis of PTLD cases.
How do you manage this case?
According to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, high-risk kidney transplant recipients (KTRs) with a donor who is EBV seropositive and a recipient who is seronegative should be monitored for EBV using nucleic acid testing (NAT). The recommended monitoring schedule includes testing once in the first week after transplantation, then at least monthly for the initial 3 to 6 months post-transplant, followed by testing every 3 months until the end of the first year, and additionally after treatment for acute rejection.
In cases where EBV-seronegative patients show an increasing EBV load, a reduction in immunosuppressive medication should be considered. If EBV disease, including PTLD, is diagnosed, a reduction or cessation of immunosuppressive medication may be warranted. Further investigations, including the use of tissue biopsies, a multidisciplinary team (MDT) approach, modifications to mTOR inhibitors, and the utilization of specific drugs such as rituximab, is necessary to advance the treatment strategies for PTLD.
● EBV load, as measured by quantitative molecular analysis of the viral genome, serves as a biomarker for predicting and monitoring the course of PTLD .
● And it becomes a routine test for monitoring transplant recipients at high risk of PTLD or under therapy for PTLD.
● PTLD patients nearly always have high levels of EBV DNA in whole blood and in plasma
● Receiver operator characteristic (ROC) curve analysis showed sensitivity and specificity values of 100% and 86% for PTLD using a cutoff of 2,000 copies/μg, 100% and 90% for 3,000 copies/μg, and 67% and 94% for 5,000 copies/μg.
● For redicting PTLD with greater accuracy, some investigators suggest calculating a mean viral load over time instead of using a single cutoff value.
● Rituximab was given when the EBV load exceeded 10,000 copies per ml of serum or when symptoms suggested EBV disease
● Preemptive therapy may include reducing immunosuppression and infusing anti-CD20 antibody or donor T cells
● Routine monitoring of EBV load in high-risk patients can help identify PTLD before signs and symptoms appear .
◇ In this case monitoring of the EBV titre is the best choice . No need for C.T or starting preemptive therapy or reduction of immunosuppression therapy.
References:
.
Margaret L. Gulley and Weihua Tang .Using Epstein-Barr Viral Load Assays To Diagnose, Monitor, and Prevent Posttransplant Lymphoproliferative Disorder . Clin Microbiol Rev. 2010 Apr; 23(2): 350–366.
Improving Global Outcomes guidelines suggest monitoring high-risk kidney transplants (donor EBV seropositive and recipient EBV seronegative) for EBV by nucleic acid PCR after on regular frequent basis especially close to transplantation (the first week, monthly for the first 3 to 6 months, then every 3 months until the end of the first posttransplant year) and particularly after treatment for acute rejection.
Management
Viral load of EBV is only significant for values of 4000 copies/mL, other studies suggested 1000 copies/mL.
Provided there are no symptoms in the form of fever, cytopenia, night sweats, and lymphadenopathy with low detected levels.
The principle management is reduction of immunosuppression if EBV confirmed, better to stop antimetabolites as MMF and to switch from CNI to mTORi.
Multidisciplinary team including infectious diseases specialist expert along with transplant specialist.
EBV monitoring according to KDIGO guidelines is recommended for the first week, then monthly for 3 months, and then every 3 months for the remainder of the first year. However, this case is not a high-risk recipient for EBV because both donor and recipient (D+/R+) are positive and have no DSA, half match kidney with negative FCXM, and no rejection. In this case, as the EBV copy number is low, there is no need for more evaluation or treatment. Following KDIGO guideline is OK.
What is the role of EBV monitoring in this scenario? Transplant recipient, with 111 mismatch, good graft function on dual immunosuppression. EBV viral load was monitored and in increased from 200 copies/ml to 740 copies/ml at 6 months post-transplant. No clinical symptoms or signs of active infection No data about induction thereby No data about serostatus of the donor nor the recipient before transplantation. Improving Global Outcomes guidelines suggest monitoring high-risk kidney transplants (defined as donor EBV seropositive and recipient EBV seronegative) for EBV by nucleic acid testing 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. In contrast with the guidelines, a recent survey published by the European Study Group of Infections in Compromised Hosts showed that EBV-VL measurements are frequently used in Europe to guide both the diagnostic workup and the reduction of immunosuppression in solid organ transplants. EBV monitoring is routinely used in 86% of the transplant programs; in particular, 38% of renal transplant centers perform EBV-VL surveillance in all recipients, independently from the EBV risk evaluation. 77% perform preemptive treatments for patients with high-risk EBV DNAemia levels such as the reduction of immunosuppression (50.9%), and the conversion to mammalian target of rapamaycin inhibitors (mTORi) (30.9%). In the index case due incomplete data about serostatus of donor and recipient we might assume that the donor was positive and the recipient was negative
How do you manage this case? EBV DNAemia levels considered to be significant for PTDL vary between centers. Some studies mentioned , the value of 4000 copies/mL other studies mentioned 1000 copies/mL . In this case scenario level increased from 200 to 750 which is below cut off , (which is expected within the first year),with no symptoms so just wait and keep monitoring of viremia. Management would be required in case of signs and symptoms suggesting EBV-related disease or primary infection (fever, cytopenia, night sweats, and lymphadenopathy), or in patients considered at major risk of viral reactivation by the clinicians (eg, increased immunosuppression, human immunodeficiency virus) or viremia reached the cut-off of the center by reduction. Management mainly by in immunosuppression , or better to shift to mTORi as he is on dual immunosuppression. EBV-VL assays may be avoided in low-risk patients/period in the absence of a strong clinical PTLD suspicion without increasing patients’ risk of developing the disease. This represents a safe and cost-saving clinical strategy . References: Erica Franceschini, MD,1Jessica Plessi, MD,1Stefano Zona,.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 Jul; 3(7): e182.
What is the role of EBV monitoring in this scenario?EBV monitoring is not routinely done unless the donor is EBV positive to a seronegative recipient. It is performed in the first week then montly in first 3 month then every 3 months. Till the end of the first year and also at time of rejection episodes. There is no universal cut off point for the viral load to point toward patients at increased risk for PTLD. However, cut off> 1000 copies/ml appear to be significant
How do you manage this case?In this index case, it appears from the monitoring that the donor was EBV (+) and the recipient is (-). However, this patient is asymptomatic (need to confirm absence of night sweats, fever, and weight loss) and his viral load did not reach the cut-off point. So, we need only to continue monitoring of the viral load to early identify patients in whom intervention can prevent development of PTLD.
If the patient became symptomatic or reached the cut-off value then management is by reduction in immunosuppression especially CNI and MMF (no clear guidelines for that). In this patient, he is only on dual immunosuppression and has 3 mismatches. So, such reduction need to be done cautiously to avoid rejection episodes.
References:
Allen UD, Preiksaitis JK; AST Infectious Diseases Community of Practice. Post-transplant lymphoproliferative disorders, Epstein-Barr virus infection, and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep; 33(9):e13652.San-Juan R, Manuel O, Hirsch HH, Fernández-Ruiz M, López-Medrano F, Comoli P, Caillard S, Grossi P, Aguado JM; ESGICH PTLD Survey Study Group,; European Study Group of Infections in Compromised Hosts (ESGICH) from the European Society of Microbiology and Infectious Diseases (ESCMID). Current preventive strategies and management of Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplantation in Europe. Results of the ESGICH Questionnaire-based Cross-sectional Survey. Clin Microbiol Infect. 2015 Jun; 21(6):604.e1-9.Kimura H, Ito Y, Suzuki R, Nishiyama Y. Measuring Epstein-Barr virus (EBV) load: the significance and application for each EBV-associated disease. Rev Med Virol. 2008 Sep-Oct; 18(5):305-19.
What is the role of EBV monitoring in this scenario?
PTLD displays highly variable patterns of incidence in kidney transplant recipients, with peaks in the first year and subsequently in the latter post-transplantation period. More than 90% of B cell PTLD that develop within the first year of transplantation includes the EBV genome. Hence, EBV monitoring is used to prevent PTLDs. There is considerable disagreement surrounding routine EBV viral load in adult SOT recipients to prevent the onset of PTLD. In practice, the majority of European doctors frequently use EBV viral load to direct both diagnostic workup and preventive medication, despite international guidelines advocating EBV-VL surveillance only in high-risk patients.
KDIGO guidelines recommend monitoring for EBV after transplantation in high risk recipients, once in the first week, monthly for the first 3 to 6 months, then every 3 months until the end of the first post-transplant year, as well as following treatment for acute rejection.
Immunosuppressive medicine, particularly antimetabolite medications, should be lowered in patients with increasing viral loads over the screening period, especially in EBV-seronegative patients, with subsequent monitoring of viral load.
Not all patients with high EBV virus loads develop PTLD. However, rising viral load in the presence of clinical picture Because of the aforementioned factors, PTLD assessment should be aggressive when clinical PTLD signs are present. Any unexplained febrile infections in a SOT recipient should raise the possibility of PTLD, especially if they occur within the first year after transplantation, in particular in patients who received potent induction and maintenance immunosuppression.
· How do you manage this case?
In the patient with low risk for rejection, having negative DSA, FCXM and 111 mismatch, the initial step in this approach is to reduce immunosuppression and followup in viral load.
Patient should be asked about specific symptoms related to PTLD. Screening for PTLD in high risk patients (SEROPOSITIVE TO SERONEAGTIVE) is indicated when clinically indicated.
What is the role of EBV monitoring in this scenario?
While many transplant recipients demonstrate a modestly increased EBV viral load in the peripheral blood post-transplant,the vast majority of patients with EBV-positive PTLD will demonstrate a more marked elevation in the EBV viral load. As an example, in one study, plasma from patients with PTLD had a median EBV viral load of 3225 copies/100 microL, while immunosuppressed controls without evidence of PTLD had fewer than 740 copies/100 microL.While an increased EBV viral load is suggestive of PTLD, the diagnosis of PTLD is based on the histologic evaluation of a tissue biopsy.
Managment-
With no sign and symotoms of PTLD in this case,i will repeat EBV PCR after 2 to 3 weeks to check for increasing /decreasing trend.If it is increasing trend ,i will decrease immunosuppression.Increasing value is more commonly associated with PTLD rather than any absolute value.
What is the role of EBV monitoring in this scenario?
The role of monitoring is to monitor the risk of increasing EBV titers.
How do you manage this case?
If there is an increase in EBV titers, evaluate the primary intervention, which is the reduction of immunosuppression in order to reduce the risks of PTLD.
If this is not enough, I would start screnning for PTLD in an attempt at an early diagnosis.
What is the role of EBV monitoring in this scenario?
The serology status of both the donor and recipient must be known before transplantation.
There’s no consensus about the cut off value of viral load to be considered significant.
As the incidence of PTLD is higher during the first year post transplantation, so EBV monitoring done after the first week , then monthly for the first 3 months, and every 3 months for the rest of the year.
How do you manage this case?
If the viral load is increasing rapidly with the presence of symptoms, so reducing IS is the main for treatment, if the viral load still increasing we can switch CNIs to mTORi.
Also adoptive immunotherapy has a role in the treatment.
Reference
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Fedaey Abbas, Mohsen El Kossi, Ihab Sakr Shaheen, Ajay Sharma, Ahmed Halawa
What is the role of EBV monitoring in this scenario? EBV DNA viral load (quantitative PCR) is used to diagnose PTLD, and also to monitor therapeutic response. It has been observed that transplant recipients with very high EBV viral load are more prone to the develop PTLD. The index case, has rising EBV viral load from 200copies to 740 copies within 6 months post-transplant, is a point of concern to decide about pre-emptive treatment. Higher viral load invites more risk for PTLD evolution. In a study, median plasma EBV DNA level from patients with PTLD was 3225 copies/ml, while immunosuppressed controls without PTLD had fewer than 740 copies/ml. EBV viral load for PTLD in SOT has shown a positive predictive value of (28%-100% and negative predictive value of 75%-100%, with “cell-free plasma EBV DNA” been reported as better marker of EBV activity. However, pre-emptive EBV PCR monitoring has following limitations – 1. No clear cut off value for interpretation. 2. sources of samples are not universal 3. absence of usual points of time to do the monitoring How do you manage this case?
Assess the risk from pre-transplant sero-status of the recipient and donor
Continue monitoring EBV DNA by NAT
Maintain tacrolimus trough level between 5-8ng/ml
Reduction of immunosuppression if the EBV viral load is increasing
Close monitoring of kidney allograft function
Look for symptoms and organs involved – may be biopsy of lymphadenopathy (if any) or renal allograft for early detection of PTLD
References
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.
Jonathan W Friedberg, Jon C Aster. Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders. UpToDate. 2023.
Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Hematology Guideline.
Tsai DE, Nearey M, Hardy CL, et al. Use of EBV PCR for the diagnosis and monitoring of PTLD in adult solid organ transplant patients. Am J Transplant 2002 Nov; 2(10): 946-54. doi: 10.1034/j.1600-6143.2002.21011 PMID: 12482147.
What is the role of EBV monitoring in this scenario?
Keep EBV monitoring ,low level of EBV load .
Kdiqo suggest monitoring high-risk kidney transplants (defined as donor EBV
seropositive and recipient EBV seronegative) for EBV by nucleic acid testing 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.
How do you manage this case?
This normal level no need for alteration of immunosuppression or drugs therapy.
References:
1. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIQO
clinical practice guideline for the care of kidney transplant recipients. Am J Transplant.
2009;9(Suppl 3):S1–S155.
What is the role of EBV monitoring in this scenario?
Firstly, seropositive status of the donor and the recipient should be known. Literature review revealed no cut off limit of EBV viral load for high risk patients i.e., EBV negative recipients with EBV positive donors and values vary from center to center. Monitoring of EBV viral load should be done in the first week, then monthly for 3 months, and then 3 monthly up to first year post-transplant to detect and diagnose PTLD early as high load suggest PTLD. In low risk cases, no need for monitoring.
How do you manage this case?
After taking detailed history and examination and checking the seropositive status of the donor and recipient, investigations like CBC, LDH,LFTs ,RFTs, Serum calcium uric acid and serum protein electrophoresis and urinalysis should be done to rule out PTLD. If excluded the just close monitoring of viral load and timely detection of acute rejection and PTLD for early intervention is must.In the above case ,only monitoring is needed and if viral load continued to rise ,then reduction of immunosuppression should be done and if become symptomatic,then treatment of PTLD and switching of CIs to mTORi is must
REFERENCES:
1-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
2- Marieke L Epstein-Barr Virus–Positive Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation: Pathogenesis, Clinical Manifestations, Diagnosis, and Management, Transplantation Direct 2016;2: e48
EBV monitoring is not routinely done unless the donor is EBV positive to a seronegative recipient. It is performed in the first week then montly in first 3 month then every 3 months.
No clear cut off point of the exact viral load to be a high risk for PTLD but 100 copies per ml may be a cut off value
If the patient is asymptotic or didn’t reach cut off value so just monitoring of viral load is recommended.
If symptomatic or reached cut off value then management with decrease immunosuppression especially CNI and MMF with minimal dose steroids or even start antiviral medications.
– The role of EBV monitoring in this case: This patient is not a high risk because he was EBV positive before renal transplantation, therefore routine monitoring is not recommended as long as suspicion of active clinical infection is not present. 2- Management:
Monitoring of viral load after one month
Close monitoring of symptoms of active EBV infection
If no rise in EBV titer and no symptoms of infection, then monthly follow up for one year
If symptoms appears or the titter increases:
-full evaluation to exclude PTLD -reduce IS (stop MMF and reduce CNI 30-50%) and monitor response after 2-4 weeks, monitor for rejection.
What is the role of EBV monitoring in this scenario?
In this case, the answer is A as we need to observe the viral load; as we all know that in the early post-transplant period, there is a mild elevation in the number of copies of EBV, especially in the first 3-month post. No action needs further at this stage.
If we suspect PTLD with positive EBV, the viral load is expected to be sky-high, .but in this case, with mild elevations of EBV copies could be related to IS effect.
Just observe.
How do you manage this case?
Just follow the viral load in an asymptomatic patient, as he has CPVL.
In case the viral load exceed 1000 copies /ml , then it will need for further workup
EBV negative recipients are high risk of getting PTLD
our patient is EBV positive
ANSWER is A
EBV COPIES NEED TO BE MONITERED
CT scan is advised if symptomatic
Reduction of IS is the first response for PTLD and not for rise of EBV
Chemotherapy is overkill
the keystone of PTLD diagnosis is the clinical suspicion. Our study suggests that, in line with guidelines, EBV-VL assays may be avoided in low-risk patients in the absence of a strong clinical PTLD suspicion without increasing patients’ risk of developing PTLD. This represents a safe and cost-saving clinical strategy .
The more recent American Society of Transplantation guidelines state that there are data to support 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.
In contrast with the guidelines, a recent survey published by the European Study Group of Infections in Compromised Hosts showed that EBV-VL measurements are frequently used in Europe to guide both the diagnostic workup and the reduction of immunosuppression in solid organ transplants.
EBV DNAemia levels considered significant can vary between centers. In our study, the value of 4000 copies/mL has been chosen based on literature data evaluating such a threshold as a risk factor for PTLD onset.
Reference
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
Erica Franceschini, MD, Jessica Plessi, MD, […], and Cristina Mussini, MD
As the patient is asymptomatic, only EBV viral load monitoring is needed till establishment of the state of chronic viral load phenotype(set point);considering the viral load is not more than 1000 copies/ml
Monitoring after the first year is indicated if there is rejection episode, the IS is changing, or if the viral set point has not achieved.
Serial EBV viral load monitoring late following transplant with reaching the set point and pre-emptive interventions like reduction in IS is not routinely indicated.
A: true…B,C,D,D:False.
Reference:
Allen UD, Preiksaitis JK; AST Infectious Diseases Community of Practice. Post-transplant lymphoproliferative disorders, Epstein-Barr virus infection, and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13652. doi: 10.1111/ctr.13652. Epub 2019 Jul 23.
The given scenario is a 24 year old CKD % patient who received a kidney from his brother 8 months ago… There is haplomatch, no DSA and Negative FCXM….IL2 receptor antibody would have been the induction agent of choice in him and ATG would not have been used in view of low risk transplant….
He is currently on double immunosuppression with excellent kidney function…. He had EBV DNA before transplant and it had increased to 740 copies/ml 6 months after transplantation….
EBV monitoring is usually not justified unless there are few indications… This patient is EBV Positive Recipient who received a kidney, so theoretically the risk is low…The patient also is a low risk patient with no rejection and no additional immunosuppressants like ATG were received….
The only risk factor for development of PTLD in this patient is the relative young age…
Patient needs annual or 6th monthly monitoring of EBV viral load after renal transplant….
There is no role for reducing immunosuppression as there is no symptomatic EBV infection now, no need for chemotherapy, no need for further imaging also
KDIGO guidelines do recommend monitoring for EBV DNA Plasma within the first week after transplant followed by monthly monitoring for the next 3 to 6 months and then once in 3 months.. They also recommend to monitor after the treatment of acute rejection… .
PTLD cannot be diagnosed by EBV monitoring alone..It needs tissue diagnosis along with symptoms and positive EBV IgM or EBV DNA
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.
What is the role of EBV monitoring in this scenario?
EBV monitoring can guide us in planning investigations and diagnostic workup in solid organ transplant recipients. In this case EBV was positive pre transplant but showed a surge in viral load post transplant. The load was 740 copies /ml which is quite below crucial level of 4000 copies/ml. EBV has significant role in development of PTLD. EBV viral load monitoring by EBV PCR is required in first year in high risk patients.
How do you manage this case?
No specific treatment is required except monitoring of EBV PCR. This case is a high risk for EBV infection. He will need monitoring by EBV PCR. It should be done weekly in first month, then monthly for next three months. Following that it should continue 3 monthly till first year is complete.
If symptoms develop or There is rising trend of EBV PCR levels, then further testing like imaging or biopsy will be needed.
If PTLD develops then reduction of immune suppression will be required. We can switch from CNI To mTORi. Severe or resistant cases may require chemotherapy.
Gulley ML, Tang W. Using Epstein-Barr viral load assays to diagnose, monitor, and prevent posttransplant lymphoproliferative disorder. Clin Microbiol Rev. 2010 Apr;23(2):350-66.
24yr old CKD received kidney from brother 8/12 ago.
111 mismatch. no DSA, negative FCXM.
CNI based double immunosuppressive, good graft function.
EBV VL increased from 200 – 740 copies/ml 6/12 post transplant.
ROLE OF EBV MONITORING.
The pt is still in 1st year of transplant with max immunosuppression and at risk of PTLD and also graft dysfunction with RIS, The VL is rising but is yet to get to a threshold of 4000 which would demand action, besides, he is not high risk(D+VE/R-VE) and thus as per KIDIGO guidelines we will monitor VL in 1st 1 yr. In resource limited areas ,to save on costs, VL monitoring is not done in low risk patients unless we suspect PTLD clinically.
A slight increase in VL is expected with immunosuppression and we just monitor. KIDIGO advises RIS in seronegative recipients with persistently rising VL.
MGT OF THIS CASE.
Whatever has been documented (VL 200 to 740 in 6/12) is expected, considering this pt is asymptomatic, we monitor and do nothing.
If VL continues going up and gets to a threshold of 4000,we consider RIS, reduce CNI by 50%,if no improvement withdraw antimetabolites and consider stopping all immunosuppression in severe life threatening infection. We closely monitor graft function while tinkering with immunosuppression.
In the event PTLD is diagnosed, RIS, switch to MTORi and in consultation with an oncologist consider RTX +/- Chemo/DXT
REF;
Allen U et al;EBV related PTLD in SOT 1988-97,a Canadian multicenter experience .paeds transplantation 2001 jun5(3).198;20
Shan N et al; Haemato-oncology task force of British Society for Hematology and BTS; Frontline mgt of PTLD in adult SOT recipients ;A British society for hematology guidelines ,Br J Haematol may 193(4);727-740
What is the role of EBV monitoring in this scenario
Use monitoring of viral loads to help follow the clinical course of patients with established PTLD
1)An EBV load below 1.08log gEq per 105 PBMC implies low risk. Thus, the patient’s routine monitoring should be continued.
(2)An EBV load between 1.08log and 2.48log gEq per 105 PBMC involves an increased risk. A more frequent monitoring of the EBV load in PBMC is required to detect a kinetic variation, plus the monitoring of viral levels in plasma. The detection of a kinetic variation in PBMC and/or an EBV load in plasma greater than 2log gEq/ml involves high PTLD risk.
(3)An EBV load above 2.48log gEq per 105 PBMC plus the detection of viral levels greater than 2.52log gEq/ml in plasma imply a high risk of neoplastic PTLD. The greater the EBV load and/or the simultaneous detection of a kinetic variation, the greater the risk of neoplastic PTLD stages.
How do you manage this case?
A small increase in viral levels may be associated with PTLD Follow up with viral monitoring
References :
M.A. Bingler, B. Feingold, S.A. Miller, M.G. Michaels, M. Green, R.M. Wadowsky, D.T. Rowe, S.A. Webber.
Chronic high Epstein–Barr viral load state and risk for late-onset posttransplant lymphoproliferative disease/lymphoma in children.
5. A 24-years old CKD 5 received a kidney from his brother 8 months ago. 111 mismatch, no DSA and negative FCXM. He is on CNI-based double immunosuppression with excellent kidney function. His EBV viral load increased from 200 copies/ml prior to the operation rose to 740 copies/ml 6 months after transplantation.
Issues/ concerns
– 24yo, CKD5, kidney transplant 8months ago
– donor brother, 111 mismatch, no DSA, negative FCXM
– CNI-based dual immunosuppression, excellent kidney function
– EBV viral load increased from 200copies/ml (pretransplant) to 740copies/ml (6months post-transplant)
What is the role of EBV monitoring in this scenario?
– EBV infection is associated with an increased risk of PTLD post-kidney transplant
– the EBV serostatus pre-transplant is essential in risk-stratification of transplant pairs
– EBV D+/ R- transplant pairs have the highest risk
– EBV viral load monitoring is done to evaluate patients for PTLD and allow for preemptive treatment if there is evidence of viral reactivation
– PTLD is a serious and fatal complication of chronic immunosuppression in SOT resulting in outgrowth of EBV positive cell proliferation
– therefore, EBV viral load monitoring is essential for early detection of PTLD in high-risk patients, this helps avert the poor outcomes
– risk factors for development of PTLD: degree of overall immunosuppression, recipient’s EBV serostatus, time post-transplant
– prevention of PTLD: limit aggressive immunosuppressive therapy, taper and withdraw immunosuppression appropriately, offer antiviral prophylaxis
– assess for any radiological masses – CT Chest, CT Abdomen and pelvis, PET scan, Brain MRI and CSF analysis (if there is CNS involvement)
– BMA (in patients with cytopenias), tissue biopsy
– PTLD management: –
depends on the type of PTLD, patient’s performance status, comorbidities, type of transplant, status of the graft, immunosuppressive regimen
immunosuppression reduction is the cornerstone – 50% CNI reduction, withdrawal of antimetabolites, maintain corticosteroids, if critically ill withdraw all immunosuppressants and maintain on high-dose steroids
other therapies include rituximab, chemotherapy, radiotherapy, combination therapy
adoptive immunotherapy using EBV-specific cytotoxic T cells is reserved for patients with persistent disease in spite of the above therapies
goal of treatment is to preserve graft function and eradicate PTLD – these two goals are conflicting since addressing one goal will lead to an untoward effect hence it requires a tight balance
– this patient can be considered as a high-risk patient given the 111 mismatch, rising viral load hence it would be prudent to monitor his EBV PCR viral load
– if there is a sustained rise in the viral load then we can consider a reducing his immunosuppression as we closely monitor his graft function
References
1. Allen U, Hébert D, Moore D, Dror Y, Wasfy S. Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplant recipients, 1988-97: a Canadian multi-centre experience. Pediatric transplantation. 2001 Jun;5(3):198-203. PubMed PMID: 11422823. Epub 2001/06/26. eng.
2. Straathof KC, Savoldo B, Heslop HE, Rooney CM. Immunotherapy for post-transplant lymphoproliferative disease. British journal of haematology. 2002 Sep;118(3):728-40. PubMed PMID: 12181039. Epub 2002/08/16. eng.
3. 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.
4. 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.
A risk factor for the development of PTLD is primary EBV infection. Since PTLD shows poor prognosis, early diagnosis is crucial. A suitable parameter for monitoring is needed for this.
The recipients at greatest risk of PTLD are those who were EBV-negative and received EBV-positive donor organs. Such patients have to be monitored closely for the development of EBV disease after transplantation since EBV viremia > 4000 EBV genome copies is associated with PTLD.
Management of this case
Most often healthy transplant recipients may demonstrate a modest increase in EBV viral load after transplantation. For this case, we must continue to further monitor the level of viraemia.
EBV prophylaxis ought to be initiated with acyclovir or preferably ganciclovir.
If the threshold of 1000 copies is exceeded, immunosuppression may be reduced keeping CNI levels at the lowest acceptable levels.
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;9(Suppl 3):S1–S155.
Regarding this case, CHOOSE one or more of the following options: A. Monitor the EBV titre. B. CT chest, abdomen, and pelvis. C. Reduce immunosuppression. D. Start chemotherapy. E. All the above
Answer is A.
It would be beneficial to monitor EBV loads monthly for this patient and reduce immunosuppression if the load exceeds the critical limit of 1000 copies.
· What is the role of EBV monitoring in this scenario? · EBV is responsible for 90% of early onset PTLD that develop during first year post transplantation and KDIGO guidelines recommend regular monitoring of EBV in high risk recipient ( EBV positive donor to negative recipient ) once during first week posttransplantation , monthly for 3 months then every 3 month till end of first year aiming at early detection of EBV reactivation and DNAemia and in this case preemptive intervention with decreasing doses of IS or switch to m TOR can decrease the risk of PTLD development. Many transplantation centers recommend regular monitoring of EBV for both high and standard risk (as this patient) recipients. In this index case, he was EBV positive before transplantation with increasing the level of EBV DNA and as there is no cut off value for EBV DNA to initiate treatment ,so decision to use chemotherapy and retuximab will depend on presence of PTLD. · How do you manage this case? 1- Risk assessment including a- Presence of associated HIV . b- If he was symptomatic or not , presence of fever,lymphadenopathy or cytopenia. c- Screening for PTLD. 2- Frequent monitoring of EBV DNA level . 3- Reduce IS doses with close monitoring of graft function. Ref: 1- Al-Mansour Z, Nelson BP, Evens AM. Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep. 2013 Sep;8(3):173-83. doi: 10.1007/s11899-013-0162-5. PMID: 23737188; PMCID: PMC4831913. 2- 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)
What is the role of EBV monitoring? How do manage this case?
EBV is ubiquitous in the general population and may cause an asymptomatic presentation in the immunocompetent host.
In kidney transplant recipients it has a bimodal peak, in the first year post-transplant then later.
EBV genome is found in 90% of PTLD occurring in the first year post-transplant while those that occur later 45% are EBV negative.
Kidney transplant recipients are at risk of viral reactivation due to use of IS.
KDIGO recommends monitoring high risk recipients (D+/R-) once in the first week, monthly for the first 3-6 months, then 3 monthly until one year and after treatment for acute rejection.
KDIGO also recommends reduction of IS in EBV seronegative individuals with a rising viral load.
Thus EBV VL load are used to guide diagnostic workup and reduce IS.
This scenario the recipient was EBV seropositive prior to transplant and the VL has been slowly rising post-transplant. The use of EBV monitoring in this scenario is controversial since this patient is not a high risk individual as per the KDIGO guidelines.
A study conducted in one transplant centre showed that the use of EBV VL monitoring in low risk patient had reduced utility and could be avoid in the absence of clinical presentation suspicious for PTLD.
Thus in this case doesn’t warrant any treatment as per now, though the VL is rising it is still below the threshold of 4000copies/ml. Thus only warrants monitoring of VL.
References
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
KDIGO clinical practice guideline for the care of kidney transplant recipients.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group
case summery is
recent living related kidney transplant just 8 months post-transplant
immunological risk is low as haplotype matching and No DSA and FCXM is negative
maintained on dual immunosuppression with no clear history regarding induction
now during follow up there is increase in the viral load of EBV data missed in this scenario is
1-induction therapy (depleting induction?)
2-pretransplant viral immunological status of both donor and recipient (D+ve to R -ve?)
3-kind of test used to detect EBV viral load (cell free EBV plasma DNA)
4-Primary kidney disease of the recipient (GN and he received multiple immunosuppression before transplant?)
to take it briefly there is NO universal agreement regarding monitoring of EBV viral load in all patients post-transplant as no there is no cutoff of treatment, agreement regarding best test for detection and timing for monitoring and this practice usually limited to high risk group who are heavily immunosuppressed or at high risk of developing PTLD post-transplant. suppose that this patient is high risk so monitoring will be of value for
· she will need to be maintained on low dose of immunosuppression which may expose her to risk of rejection
· early detection of PTLD and treatment
· regarding use of antiviral treatment for prophylactic (no virus detected) or treatment (viral load detected) of week evidence.
· regarding use of rituximab as prophylactic for PTLD of week evidence
How to manage
considering this case high risk patient frequent monitoring till stable level is achieved (chronic viral load phenotype CVLP) with regular clinical examination of patients LN on regular intervals. If CVLP not achieved and PCR is progressively increasing then modification of immunosuppression maybe needed after counselling patient about risk of rejection 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.
Allen UD, Preiksaitis JK; AST Infectious Diseases Community of Practice. Post-transplant lymphoproliferative disorders, Epstein-Barr virus infection, and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13652. doi: 10.1111/ctr.13652. Epub 2019 Jul 23. PMID: 31230381.
San-Juan R, Manuel O, Hirsch HH, Fernández-Ruiz M, López-Medrano F, Comoli P, Caillard S, Grossi P, Aguado JM; ESGICH PTLD Survey Study Group,; European Study Group of Infections in Compromised Hosts (ESGICH) from the European Society of Microbiology and Infectious Diseases (ESCMID). Current preventive strategies and management of Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplantation in Europe. Results of the ESGICH Questionnaire-based Cross-sectional Survey. Clin Microbiol Infect. 2015 Jun;21(6):604.e1-9. doi: 10.1016/j.cmi.2015.02.002. Epub 2015 Feb 14. PMID: 25686696.
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.Le J, Durand CM, Agha I, Brennan DC. Epstein-Barr virus and renal transplantation. Transplant Rev (Orlando). 2017 Jan;31(1):55-60. doi: 10.1016/j.trre.2016.12.001. Epub 2016 Dec 29. PMID: 28089555.
Kimura H, Ito Y, Suzuki R, Nishiyama Y. Measuring Epstein-Barr virus (EBV) load: the significance and application for each EBV-associated disease. Rev Med Virol. 2008 Sep-Oct;18(5):305-19. doi: 10.1002/rmv.582. PMID: 18494041.
Kanakry JA, Hegde AM, Durand CM, Massie AB, Greer AE, Ambinder RF, Valsamakis A. The clinical significance of EBV DNA in the plasma and peripheral blood mononuclear cells of patients with or without EBV diseases. Blood. 2016 Apr 21;127(16):2007-17. doi: 10.1182/blood-2015-09-672030. Epub 2016 Jan 7. PMID: 26744460; PMCID: PMC4841041.
⭐The index case is high risk for EBV infection (D+/R-), so frequent monitoring of EBV PCR is essential (done weekly in 1st month, then monthly for 3 months then every 3 months for the remaining months in 1 st year).
.⭐ As regard the managemnt of the case:
_Till now, no further mangemnet is needed rather than follow up Of EBV PCR titer.
_Further FU of the trend of rising titre of viral PCR or appearance of symptoms as fever malaise, fatigue , cytopenias or lymphadenopathy will indicate further imaging and tissue biopsy.
_once diagnosis of EBV Related PTLD is confirmed …reduction of IS or shift from CNI to mTORi.is indicated
_Resistent cases may require additional chemotherapy.
👉 The index case is high risk for EBV infection (D+/R-), so frequent monitoring of EBV PCR is essential (done weekly in 1st month, then monthly for 3 months then every 3 months for the remaining months in 1 st year).
👉 as regard the managemnt of the case:
_Till now, no further mangemnet is needed rather than follow up Of EBV PCR titer.
_Further FU of the trend of rising titre of viral PCR or appearance of symptoms as fever malaise, fatigue , cytopenias or lymphadenopathy will indicate further imaging and tissue biopsy.
_once diagnosis of EBV Related PTLD is confirmed …reduction of IS or shift from CNI to mTORi.is indicated
_Resistent cases may require additional chemotherapy.
What is the role of EBV monitoring in this scenario?
EBV monitoring is achieved to guide both the diagnostic workup and the reduction of immunosuppression in solid organ transplants. In this scenario of KT at 8 months, the EBV was positive in the pre-transplant period and the EBV-VL showed exacerbation in the post-transplant period. Although the VL not reaching the significant threshold(> 4000 copies/ml), EBV monitoring is still crucial as the patient in the first-year post-transplant.
Epstein Barr virus (EBV) plays a major role in PTLD development, which is an important cause of morbidity and mortality in solid organ transplants. Guidelines recommend EBV viral load (VL) monitoring in high-risk populations in the first year. In line with guidelines, EBV-VL assays may be avoided in low-risk patients in the absence of a strong clinical PTLD suspicion without increasing patients’ risk of developing PTLD. This represents a safe and cost-saving clinical strategy(1).
1. Kidney Disease: Improving Global Outcomes guidelines suggest monitoring high-risk kidney transplants (defined as donor EBV seropositive and recipient EBV seronegative) for EBV by nucleic acid testing 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.
2. Kidney Disease: Improving Global Outcomes guidelines recommend reducing immunosuppressive medication in EBV-seronegative patients with an increasing EBV viral load (VL) and in patients with EBV disease, including PTLD.
3. American Society of Transplantation guidelines state that there are data to support 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.
4. In contrast with guidelines, the European Study Group of Infections in Compromised Hosts showed that EBV-VL measurements are frequently used in Europe to guide both the diagnostic workup and the reduction of immunosuppression in solid organ transplants.
· EBV monitoring is routinely used in 86% of the transplant programs.
· 38% of renal transplant centers perform EBV-VL surveillance in all recipients, independently from the EBV risk evaluation.
· 77% perform preemptive treatments for patients with high-risk EBV DNAemia levels such as the reduction of immunosuppression (50.9%), and the conversion to mammalian target of rapamaycin inhibitors (mTORi) (30.9%). Up to 14.5% had used rituximab for this indication and 7.3% reported the use of immune- adoptive T cell therapy.
5. EBV DNAemia levels considered significant can vary between centers. The value of 4000 copies/mL has been chosen based on literature data evaluating such a threshold as a risk factor for PTLD onset.
6. The suspicion driven by disease symptoms and clinician experience appears to be the keystone for PTLD diagnosis and treatment.
How do you manage this case? The index case is a KTR, having EBV infection with exacerbating EBV-VL from 200 copies/ml to 740 copies/ml. 1. The patient didn’t complete the first-year post-transplant and there’s an exacerbating VL, so monitoring of EBV-VL for this patient is indicated. 2. Being asymptomatic and with VL below 4000 copies/ml, nothing else is needed other than monitoring. 3. If the patient is symptomatic or with high suspicion of PTLD, adjustment of immunosuppression should be achieved. 4. If the diagnosis of PTLD is established, the followings are deserved to be accomplished: reduction of immunosuppression, shifting to mTORi, RTX +/- chemotherapy and adaptive immunotherapy.
References
1. Franceschini, Erica MD1; Plessi, Jessica MD1; Zona, Stefano MD1; Santoro, Antonella MD1; Digaetano, Margherita MD1; Fontana, Francesco MD2; Alfano, Gaetano MD2; Guaraldi, Giovanni MD3; Comoli, Patrizia MD4; Facchini, Francesca MD2; Potenza, Leonardo MD, PhD5; Gennari, William MD6; Codeluppi, Mauro MD1; Luppi, Mario MD, PhD5; Cappelli, Gianni MD2; Gyssens, Inge C. MD, PhD7,8; Mussini, Cristina MD3. 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. | DOI: 10.1097/TXD.0000000000000703
2. 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.
25 year, his EBV load increased from 200 pre ml to 740, 6 months after Tx.
What is the role of EBV in monitoring this scenario?
Some transplant units’ monitor the EBV viral load post transplantation. However, there is little evidence to guide this strategy and there is no agreement whether to use a blood sample or a plasma one. Or what clinical action to take if EBVDNA viremai is detected, an ongoing trial EVITA is trying to answer these questions. How would you manage this case?
· KDIGO guidelines suggest monitoring high-risk kidney transplants (defined as donor EBV seropositive and recipient EBV seronegative) for EBV by nucleic acid testing 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 post-transplant year, and after treatment for acute rejection. · American Society of Transplantation guidelines state that there are datato support quantitative EBV-VL monitoring for PTLD prevention only in high-risk populations in the first year. · In Europe EBV-VL measurements are frequently used to guide both the diagnostic workup and the reduction of immunosuppression in solid organ trans- plants. · In Europe some perform preemptive treatments for patients with high-risk EBV DNAemia levels such as the reduction of immunosuppression, and the conversion to mammalian target of rapamaycin inhibitors. Some had used rituximab for this indication and others reported the use of immune- adoptive T cell therapy. · The value of 4000 copies/mL EBV DNAemia threshold is used as a risk factor for PTLD onset. · We should first determine the risk of recipient as he is considered negative for EBV (positive if more Than 400 copies per ml), by checking the pre-transplant donor viral status. · If the donor was positive, then he is at high risk of developing post- transplant viral replication. · We would monitor his viral load according to the current guidelines. · Important is to follow him for the development of clinical EBV infection, infectious mononucleois and involvement of organ specific involvement. · For EBV-related localized extranodally PTLD (most common) and lymphadenopathy and B-symptoms. References:
1. Erica Franceschini, 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 2017;3:e182
2. Marieke L Epstein-Barr Virus–Positive Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation: Pathogenesis, Clinical Manifestations, Diagnosis, and Management, Transplantation Direct 2016;2: e48.
· What is the role of EBV monitoring in this scenario? Monitoring of EBV viral load is recommended for high risk patient ( seropositive donor to seronegative recipient) to detect EBV viremia early and intervene early before development of PTLD. · How do you manage this case? Detailed history of recipient presenting complaints, EBV sero status for recipient and donor, induction medications, current maintenance medications, any rejection history and its treatment. Also any similar history. · KDIGO suggest monitoring high-risk (donor EBV seropositive/recipient seronegative) KTRs using NAT. Also they suggest reduction or cessation of IS medication in patients who are EBV-seronegative with an increasing EBV load. They also Suggest reduction or cessation of IS medication in patients who have EBV disease, including PTLD. · Close of monitoring of symptoms and signs of PTLD and frequent monitoring of viral load. · Reduction of immunosuppression starting by 50% of antimetabolite if he is on and keeping CNI at lower end of target level. References: 1-Managing KIDNEY TRANSPLANT RECIPIENTS KDIGO guidelines 2017
What is the role of EBV monitoring in this scenario?
NO SPECIFIC ROLE ,JUST WARNING SIGN DEPEND ON Observational studies
Measurement of EBV viral load
patients with EBV-positive PTLD will demonstrate a more marked elevation in the EBV viral load.
the diagnosis of PTLD is based on the histologic evaluation of a tissue biopsy. Similarly, while the absence of EBV in the peripheral blood makes PTLD less likely, it does not completely exclude the diagnosis
Due to the use of different methods, EBV viral load measurements cannot be compared between institutions. The optimal primer set, the relative importance of intracellular versus free plasma EBV, and the baseline profile in an organ transplant population remain to be established
Since the vast majority of EBV-positive PTLD occurs in the first year after transplantation, it is reasonable to monitor high-risk patients more frequently during the initial post-transplant period and to increase the time span between samples as the time from transplantation increases.
Many transplant centers have incorporated EBV monitoring into the routine evaluation of patients at high risk for PTLD.
Risk factors For the development of PTLD are the degree of T cell immunosuppression and the Epstein-Barr virus (EBV) serologic status of the recipient.- time post-transplant, recipient age, and ethnicity
How do you manage this case?
history and physical examination
Laboratory studies
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, obtaining a combined positron emission tomography (PET)/CT scan as a measure of disease activity
●Assessment of the function of the transplanted organ. ●Unilateral bone marrow aspiration and biopsy is suggested for patients with cytopenias. ●Men and women with child-bearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures.
prevention largely relies upon limiting patient exposure to aggressive immunosuppressive regimens, rapid withdrawal and/or tapering of agents required for graft acceptance, and anti-viral prophylaxis. Attention to such measures may lessen the incidence of PTLD. In addition, 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
Tapering immunosuppressive therapy
a relatively high incidence of PTLD was found with the introduction of tacrolimus (FK506) for renal allograft recipients. Therefore, the aggressive tapering of this agent may limit the development of this disorder.
maintenance target trough concentration of 5 to 9 ng/mL
What is the role of EBV monitoring in this scenario?
The quantification of circulating Epstein Barr virus (EBV) DNA loads has played an important role in the diagnosis and management of EBV-associated lymphoid malignancies.
Viral load measurement is particularly useful for monitoring EBV-DNA in hematopoietic stem cell transplant patients.
Rise to 740 copies/ 100microL in this case would suggest reduction in immunosuppressant’s and EBV DNA monitoring closely which could be suggestive of early PTLD.
Cell-free EBV-DNA in plasma can be used as a biomarker for estimating the severity or prognosis of lymphomas.
How do you manage this case?
This patient have low risk for rejection, with negative DSA, FCXM and 111 mismatch.
We treat him firstly to reduce immunosuppression .
followup the viral load.
Taking history about PTLD.
Screening for PTLD in high risk patients (SEROPOSITIVE TO SERONEAGTIVE) is important. References
1. Kimura H, Ito Y, Suzuki R, Nishiyama Y. Measuring Epstein-Barr virus (EBV) load: the significance and application for each EBV-associated disease. Rev Med Virol. (2008) 18:305–19. 10.1002/rmv.582 [PubMed] [CrossRef] [Google Scholar]
2. Kanakry J, Ambinder R. The biology and clinical utility of EBV monitoring in blood. Curr Top Microbiol Immunol. (2015) 391:475–99. 10.1007/978-3-319-22834-1_17 [PubMed] [CrossRef] [Google Scholar]
3. Cohen JI, Kimura H, Nakamura S, Ko YH, Jaffe ES. Epstein-Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: a status report and summary of an international meeting, 8-9 September 2008. Ann Oncol. (2009) 20:1472–82. 10.1093/annonc/mdp064 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
1- The role of EBV monitoring in this case:
according to KDIGO guidelines for the care of renal transplant recipient, 2009:
this patient is not a high risk as he has positive EBV serology before renal transplantation
so, monitoring is not recommended as long as no clinical suspicious of infection is present
2- Management:
being young age, with rising of the EBV viral load in the first year of transplantation
monitor the viral load after 1 month
close monitoring for any symptoms
exclude any history of recent transfusion or contact with infected persons
IF no rising in the titer or symptoms occur: maintain follow -up monthly till the end of the first -year
If symptoms appears or the titer increases:
-full evaluation to exclude PTLD by Ct scan or PET scan
-reduce IS (stop MMF and reduce CNI 30-50%) and monitor response after 2-4 weeks.
What is the role of EBV monitoring in this scenario?
In the current scenario donor EBV seronegative or sero positive and Recipient EBV seropositive. Patient falls in low-risk category of early PTLD. But if there is a high index of suspicion, I need to screen the patient for PTLD.
As EBV DNAemia levels considered significant can vary between centers. In one study, the value of 4000 copies/mL has been chosen based on literature data evaluating such a threshold as a risk factor for PTLD onset.
Reference Franceschini, Erica MD1; Plessi, Jessica MD1; Zona, Stefano MD1; Santoro, Antonella MD1; Digaetano, Margherita MD1; Fontana, Francesco MD2; Alfano, Gaetano MD2; Guaraldi, Giovanni MD3; Comoli, Patrizia MD4; Facchini, Francesca MD2; Potenza, Leonardo MD, PhD5; Gennari, William MD6; Codeluppi, Mauro MD1; Luppi, Mario MD, PhD5; Cappelli, Gianni MD2; Gyssens, Inge C. MD, PhD7,8; Mussini, Cristina MD3. 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. | DOI: 10.1097/TXD.0000000000000703
How do you manage this case?
Through history and detail physical examination.
Investigation: CBC, LFT, LDH, RFT,Ultrasonography of abdomen, chest x ray, Drug level Tac,Other viruses screening.
The diagnosis of PTLD require high index of suspension and tissue diagnosis as clinically indicated.
Once PTLD is excluded, follow-up of the viral load with optimization or reduction of immunosuppression is the main stay in managing these patients .
EBV is postulated to be the cause of PTLD, although almost 30% of the cases of PTLD are EBV negative. The risk is highest in door+/recipient- cases and with the use of tacrolimus.
The role of EBV monitoring is debatable although many centers practice it. There is no clinically defined cut-off value above which the patient can be diagnosed to have PTLD and it will miss EBV negative PTLD (which accounts for 30% of the PTLD cases). It also has. low positive predictive value of 25%.
However, a rise in the EBV titers in high risk patients can suggest PTLD. However, a histological diagnosis is required before initiating treatment with chemotherapy.
In our patients case, he will need further work-up:
History – of weight loss, gland enlargement
Examination: lymphadenopathy, hepatosplenomegally
Laboratory Ix:
CBC: anemia, thrombocytopenia, leucopenia
LDH: will be elevated in PTLD
Uric acid levels: Will be high due to high cell turnover
Urine protein electrophoresis
Radiological Ix:
CT scan of the chest, abdomen and pelvis
If there are any suspicious lymph nodes or lesions on the CT scan, the patient will require a biopsy
If the biopsy makes a diagnosis of PTLD, then he should be treated as such:
ISS reduction
Switch the tacrolimus to sirolimus
Rituximab with or without CHOP regimen
If there was no lesion detected, then the viral load should be monitored
What is the role of EBV monitoring in this scenario?
Quantitative polymerase chain reaction (PCR) of unfractionated whole blood, plasma, or peripheral blood mononuclear cells of individuals at high risk of acquiring this condition allows for the early detection of PTLD.
The type of graft, the extent of ongoing immunosuppression, and the pattern of EBV virus loads to date must all be taken into account when deciding whether to check less regularly.
An uncomplicated kidney transplant recipient may start receiving monitoring as soon as one week after the transplant. Thereafter, they may have monitoring once a month for the next three to six months, then once every three months for the remainder of the first year.
How to manage
If you experience any signs of EBV viremia, repeat the EBV NAT every month while keeping a tight eye on yourself.
If things goes worse that is increasing load, or sign and symptoms of PTLD next step is reduction of immunosupression .
Dear All Thank you very much for your replies. I’m not impressed with most of the answers. Regarding this case, CHOOSE one or more of the following options: A. Monitor the EBV titre. B. CT chest, abdomen, and pelvis. C. Reduce immunosuppression. D. Start chemotherapy. E. All the above
The index patient, if asymptomatic, would require nothing more than follow-up with monitoring of EBV viral load.
Monitoring should be done till a viral “set point” is reached, developing a state called chronic viral load phenotype, CVLP (1).
Ongoing monitoring beyond the first year is done if the patient has a rejection episode, the immunosuppression is fluctuating, or if the viral “set point” has not reached (that is the viral load is progressively increasing).
Ongoing serial EBV viral load monitoring late after transplant in CVLP with pre-emptive interventions like reduction in immunosuppression is not routinely recommended (1).
Reference:
Allen UD, Preiksaitis JK; AST Infectious Diseases Community of Practice. Post-transplant lymphoproliferative disorders, Epstein-Barr virus infection, and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13652. doi: 10.1111/ctr.13652. Epub 2019 Jul 23. PMID: 31230381.
False: B, C D, E
In asymptomatic elevation of EBV viral load, monitoring alone is sufficient unless the viral load is more than significant cut-off value (>1000 copies/ml in most of the studies). No justification for reducing immunosuppression, starting chemotherapy or getting CT chest, abdomen and pelvis in this scenario at this stage.
C. This is because increasing EBV viral load is highly suggestive of PTLD. I did not choose A because they are no specific cut off values to diagnose PTLD and also no consensus on time to perform monitoring. I did not think D is the answer because this is probably an early disease as there are no reported symptoms. The reduction of immunosuppression can reverse PTLD in 20-80% of cases.
Reference Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020 Feb 28;10(2):29-46. doi: 10.5500/wjt.v10.i2.29. PMID: 32226769; PMCID: PMC7093305.
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
I will do regular follow-up with detailed history and examination with continuous monitoring of viral load. EBV DNAemia levels considered significant can vary between centers (a value of 4000 copies/mL may be a risk factor for PTLD onset)
EBV disease, including PTLD at any level of viral load is an indication of immunosuppressive reduction and conversion to mTORi
PTLD and EBV viral load:
o Viral load alone cannot be used to diagnose PTLD as the test can lack both sensitivity and specificity
o The viral load will be low if the site of PTLD is protected such (graft itself or in some gastrointestinal lesions)
o Patients with elevated EBV VL do not always have or develop EBV/PTLD
o For the above reasons, an aggressive approach to the evaluation of PTLD should be used when this diagnosis is suspected
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 loaed and focal findings on examination or in a patient with primary EBV infection and increasing viral loads
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.
To me all is correct
as this patient need monitoring and if further work up of PTLD as it can be a symptomtic and need extensive investigation including CT chest and pelvic and might need tissue biopsy if any.
treatment of PTLD is reduction of immunosupression and chemotherapy
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
A&C (Correct) According KDIGO guidelines; -Suggest monitoring high-risk (donor EBV seropositive/recipient seronegative) KTRs for EBV by NAT. (2C) -Once in the first week after transplantation (2D) , -Then at least monthly for the first 3–6 months after transplantation (2D), -Then every 3 months until the end of the first post-transplant year (2D) ,and additionally after treatment for acute rejection. (2D) -Suggest that EBV-seronegative patients with an increasing EBV load have immunosuppressive medication reduced. (2D)
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
Prof. Halawa. Thanks
I would like to answer your question along with main question of scenario in conjunction. Before, I move ahead, I would like to make few statements regarding EBV post transplantation.
Clinical suspicion is the key to diagnosis of EBV infection and PTLD.
High risk patient is defined as donor seropositive and recipient seronegative.
There is no consensus on value of significant EBV DNAemia but as per various center policies 4000 copies/ml may be considered significant.
Kidney transplant recipients are at relatively low risk of developing PTLD in comparison of other solid organ transplants.
Serial EBV viral load monitoring does not help in diagnosing PTLD.
In view of above statements,
recipient was seropositive pre-transplant and hence is low risk candidate,
increase in number of copies is not significant,
patient is asymptomatic.
There is currently no standard guideline of rate and role of monitoring of EBV viral load to predict and diagnose PTLD. EVITA study is under process to answer these questions.
Hence, I will keep high index of suspicion for development of clinical symptoms but not advice serial viral load monitoring to the patient though some centers will do that. I will also not reduce immune suppression as of now.
Therefore, the best possible answer to Prof. Halawa’s MCQ is A ( as per European study group) but as per KDIGO and American society, the answer is non of the above.
REF:
Franceschini, Erica MD1; Plessi, Jessica MD1; Zona, Stefano MD1; Santoro, Antonella MD1; Digaetano, Margherita MD1; Fontana, Francesco MD2; Alfano, Gaetano MD2; Guaraldi, Giovanni MD3; Comoli, Patrizia MD4; Facchini, Francesca MD2; Potenza, Leonardo MD, PhD5; Gennari, William MD6; Codeluppi, Mauro MD1; Luppi, Mario MD, PhD5; Cappelli, Gianni MD2; Gyssens, Inge C. MD, PhD7,8; Mussini, Cristina MD3. 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.
Fulchiero Rosanna, Amaral Sandra. Post-transplant lymphoproliferative disease after pediatric kidney transplant. Frontiers in Pediatrics. (10) 2022
Excellent Yashu The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
Answer is A
We only need to monitor the viral load after 3 months unless there is high index of suspicion for PTLD
EBV DNAemia levels considered significant can vary between centers. In one study, the value of 4000 copies/mL has been chosen based on literature data evaluating such a threshold as a risk factor for PTLD onset.
Franceschini, Erica MD1; Plessi, Jessica MD1; Zona, Stefano MD1; Santoro, Antonella MD1; Digaetano, Margherita MD1; Fontana, Francesco MD2; Alfano, Gaetano MD2; Guaraldi, Giovanni MD3; Comoli, Patrizia MD4; Facchini, Francesca MD2; Potenza, Leonardo MD, PhD5; Gennari, William MD6; Codeluppi, Mauro MD1; Luppi, Mario MD, PhD5; Cappelli, Gianni MD2; Gyssens, Inge C. MD, PhD7,8; Mussini, Cristina MD3. 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. | DOI: 10.1097/TXD.0000000000000703
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
I would choose A and B
There is a significant rise in the EBV titers. If the CT scan of the chest, abdomen and pelvis are negative, the patient should have the viral load monitored to ensure that there is reduction of the viral load
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
Lower risk patients (D-/R+, D+/R+):
Monthly EBV PCR monitoring for first 3 months post transplant.
Three monthly from 3 month until 1 year post transplant.
Reference
Guideline Title: Epstein Barr Virus (EBV)- Post Transplant Management UHL Renal transplant Guideline Page 2 of 4 Approved by Reanl Transplant MDT Approval Date 23/05/2022, Trust Ref: C22/2022
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
A. True: this may be better answer but still this issue of EBV monitoring has many pitfalls e.g., cut off not clear, source of sample is another problem e.g., whole blood or plasma.
B. False: there are no symptoms reported to suggest PLTD in the history. We are only told about raising viral load. This may not be enough to justify imaging even though the PTLD might be asymptomatic
C.False: It is difficult to make this decision on two viral load only and absence of any symptoms to points toward PTLD. It may make more if we have serial & progressive raising in the viral load. More over she on the daul immune suppression and to reduce that easily it can be challenging. We don’t know the status of the donor & the recipient regarding EBV & CMV. Does this patient received fusion inhibitors such as belatacept , again not mentioned in the history. All these information are necessary to make decisions. We expect EBV PCR to go up with immune suppression specially in the first 6 months but does this requires manipulation for immune suppression ? the answer is it depends !
D. False: Simply chemotherapy for what ?. We don’t have serial and progressive viral load. IF we are considering PTLD, it has to be a tissue diagnosis at first place and you have to stage the disease by PET-CTor CT, discuss with haemato-oncology. We don’t have all these data to consider chemo
E. False: Although debatable monitoring viral load might sound better than any other answer here
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
Regarding this case, CHOOSE one or more of the following options: A. Monitor the EBV titre.- True – it is recommended to monitor EBV in such patients recieveing graft from EBV +D /-R, in the first week and monthly for 3 months then Q 3 months for the first year – peroid most commonly encounterd EBV related PTLD. B. CT chest, abdomen, and pelvis- False – the pt in index case has no symptoms, and nothing mentioned about physical exam, if there is symptoms or any lymphnodes or organomegaly, or if the viral load continue to increase then the CT is indicated. C. Reduce immunosuppression- False, with no evidence of any disease/PTLD – no reduction of immunosuppression recommended. D. Start chemotherapy.- False E. All the above- False.
References: 1) 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. (2) Le J, Durand CM, Agha I, Brennan DC. Epstein-Barr virus and renal transplantation. Transplant Rev (Orlando). 2017 Jan;31(1):55-60. doi: 10.1016/j.trre.2016.12.001. Epub 2016 Dec 29. PMID: 28089555. (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.
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
First of all monitoring is indicated only in high risk transplant recipients for PTLD
High risk patients are defined as the presence of one of the following: (1) Patents receiving aggressive immunosuppression, so PTLD are more common in heart transplantation, HLA incompatible transplantation and in patients with recurrent AR, (2) 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 use of ATG, OKT3, Belatacept and tacrolimus was found to be associated with higher risk of PTD, On the other hand MMF, sirolimus, and alemtuzumab are not associated with this risk.
The current patient is considered low risk of PTLD because of the low immunological risk transplantation, and the patient was seropositive before transplantation. So monitoring of EBV status is not indicated in the current patient.
Once we measure EBV viral load in low risk patient and we found increase in the titer, I will adjust only immunosuppression, not reduce the dose below recommended, but if this happen in high risk patient I will consider reduction of immunosuppression.
In the current patient I will monitor the titer every 3 months till the end of the first year.
If the titer is rising I will consider reduction of immunosuppression and follow up.
No clear titer can be used to suggest the PTLD risk, 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)
If symptoms of PTLD happen I will investigate.
Lastly, detection of EBV does not mean PTLD, so no need for CT and no indication for the use of chemotherapy. On the contrary absence of EBV make the diagnosis of PTLD unlikely but it does not exclude (5,6)
So the true answer is A 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.
5. Baldanti F, Rognoni V, Cascina A, et al. Post-transplant lymphoproliferative disorders and Epstein-Barr virus DNAemia in a cohort of lung transplant recipients. Virol J 2011; 8:421.
6. Shimizu H, Saitoh T, Koya H, et al. Discrepancy in EBV-DNA load between peripheral blood and cerebrospinal fluid in a patient with isolated CNS post-transplant lymphoproliferative disorder. Int J Hematol 2011; 94:495.
First of all monitoring is indicated only in high risk transplant recipients for PTLD
High risk patients are defined as the presence of one of the following: (1) Patents receiving aggressive immunosuppression, so PTLD are more common in heart transplantation, HLA incompatible transplantation and in patients with recurrent AR, (2) 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 use of ATG, OKT3, Belatacept and tacrolimus was found to be associated with higher risk of PTD, On the other hand MMF, sirolimus, and alemtuzumab are not associated with this risk.
The current patient is considered low risk of PTLD because of the low immunological risk transplantation, and the patient was seropositive before transplantation. So monitoring of EBV status is not indicated in the current patient.
Once we measure EBV viral load in low risk patient and we found increase in the titer, I will adjust only immunosuppression, not reduce the dose below recommended, but if this happen in high risk patient I will consider reduction of immunosuppression.
In the current patient I will monitor the titer every 3 months till the end of the first year.
If the titer is rising I will consider reduction of immunosuppression and follow up.
No clear titer can be used to suggest the PTLD risk, 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)
If symptoms of PTLD happen I will investigate.
Lastly, detection of EBV does not mean PTLD, so no need for CT and no indication for the use of chemotherapy. On the contrary absence of EBV make the diagnosis of PTLD unlikely but it does not exclude (5,6)
So the true answer is A
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.
5. Baldanti F, Rognoni V, Cascina A, et al. Post-transplant lymphoproliferative disorders and Epstein-Barr virus DNAemia in a cohort of lung transplant recipients. Virol J 2011; 8:421.
6. Shimizu H, Saitoh T, Koya H, et al. Discrepancy in EBV-DNA load between peripheral blood and cerebrospinal fluid in a patient with isolated CNS post-transplant lymphoproliferative disorder. Int J Hematol 2011; 94:495.
I appreciate your very wise clinical approach.I agree with your arguments that are well-supported with evidence. However, 3 monthly estimation of EBV is not goo enough. I would do it at least every month if not every fortnight until it starts resolving
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
Answer: A
EBV monitoring is recommended in high risk individuals by most transplant centers. While some recommend EBV monitoring for all transplant recipients.
Elevated viral load can be seen in asymptomatic individuals, and does not mean PTLD as PTLD require tissue diagnosis and can be seen in low viral load. Therefore, this test is not specific.
In rapidly progressively rising titer immunosuppression reduction is the first step in high risk individuals to control viral replication.
Screening with imaging is required if there is high index of suspicion for PTLD, and chemotherapy is indicated PTLD in those who did not improve on immunosuppression reduction.
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. PMID: 19845597.
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
Epstein Barr virus (EBV) plays a major role in PTLD development.
Guidelines recommend EBV viral load (VL) monitoring in high-risk populations in the first year.
Monitoring viral load without specific treatment is important in this pateint.
KDIGO guideline for kidney transplant recipients 2009
Rickinson AB, Long HM, Palendira U, M€unz C, Hislop AD. Cellular immune controls over Epstein-Barr virus infection: new lessons from the clinic and the laboratory. Trends Immunol. 2014;35:159–169.
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
A. monitor the EBV titer
Asymptomatic elevations in EBV load are a regular occurrence. Patients who sustain many infections from different pathogens at the same time that their EBV load steadily increases yet show no symptoms may be incorrectly classified as having EBV disease. In circumstances like these, an EBV disease can only be confirmed by the examination of tissue.
To begin, I will inquire about the symptoms, which include a high temperature and diarrhea. Examination of the lymph nodes
careful monitoring of the EBV as well as the symptoms that came before it.
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
Monitoring of EBV viral load is recommended for high risk patient ( seropositive donor to seronegative recipient) to detect EBV viremia early and intervene early before development of PTLD.
KDIGO suggest monitoring high-risk (donor EBV seropositive/recipient seronegative) KTRs using NAT. Also they suggest reduction or cessation of IS medication in patients who are EBV-seronegative with an increasing EBV load. They also Suggest reduction or cessation of IS medication in patients who have EBV disease, including PTLD. · · Reduction of immunosuppression starting by 50% of antimetabolite if he is on and keeping CNI at lower end of target level. References: 1-Managing KIDNEY TRANSPLANT RECIPIENTS KDIGO guidelines 2017
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
A, B and C
A : KDIGO recommend monitoring EBV DNA with NAT for high risk patients , while many transplantation centers routinely monitor both high and standard risk recipents and adopt preemptive sratigy with reducing IS or switch to m TOR to decrease the risk of PTLD.
b : for lymphadenopathy or tissue invasion .
C: is the corner stone in prevention and treatment of PTLD.
while (D) : chemotherapy and or rituximab are preserved to confirmed cases of PTLD
Ref :
Al-Mansour Z, Nelson BP, Evens AM. Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep. 2013 Sep;8(3):173-83. doi: 10.1007/s11899-013-0162-5. PMID: 23737188; PMCID: PMC4831913.
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
I think, in the absence of symptoms and being sero positive recipient , Watchful approach is indicated in this context. There is no consensus EBV DNA-emia plasma level upon which anti EBV measures are implemented. The ongoing EVITA study is supposed to answer this question.
Reference:
1]Jan Styczynski et al, Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines.Vol. 101 No. 7 (2016): July, 2016.
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
C is controversial because patient has low risk factors (brother *related donor with low mismatch , no DSA, CNI based double not triple immunosuppression). However, viral loading still increase during 6 months. For me, I think it is appropriate to reduce immunosuppression . Therefore C is true
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
A: true
monitoring of the EBV VL is needed in the first-year post-transplant as recommended by most of the guidelines.
B: false
these screening tests are used when there’s suspicion of PTLD
C:true
although the VL not reaching the cut-value by most centers(> 4000copies/ml),this patient showed exacerbation of the EBV-VL from 200 to 740copies/ml which may further progress to severe form of EBV disease. Reduction of immunosuppression can be justified in the view of possible disease progression and complication.
The correct answer is A This is the expected level when any EBV-positive patient commences on immunosuppression. No need for CT, reduction of immunosuppression or chemotherapy.
I will go with answer A and C based on the indexed case we need to close monitor the viral load along with the reduction of immunosuppression(RI) as it considers the key step in the management of PTLD. In fact a reduction of IS can reverse the PTLD by 20-80% as per one report
A: correct
B:False no need to screening and expose patient to radiation
c:false patient already on dual immunosuppresion
d:false patient doesn’t have PTLD to be treated by chemothrapy
⭐ The correct answer is A.
_such. Case is high risk for EBV infection as donor +/Recipient – serology prior to transplantation.
_Frequent monitoring of the viral titer is essential to take a decision if rising titre or symptoms appear , here the decision to modify or reduce immunosupression.
_No need for CT or any imaging.
_No need for reduction of IS or starting chemotherapy at this stage.
The correct answer is A : it is reasonable to follow EBV level in this patient as it start to increase
answer B,C,D,E : False the patient has no symptoms suggestive of PTLD to justify radiation exposure ,reduction of immunosuppression
A.
monitoring maybe every 2-3 months for viral load. With this low viral load, no specific treatment is needed. Chest CT may be needed later when PTLD is suspected (periodic physical examination, LDH etc showed be monitored)
A, B and C A : KDIGO recommend monitoring EBV DNA with NAT for high risk patients , while many transplantation centers routinely monitor both high and standard risk recipents and adopt preemptive sratigy with reducing IS or switch to m TOR to decrease the risk of PTLD. b : for lymphadenopathy or tissue invasion . C: is the corner stone in prevention and treatment of PTLD. while (D) : chemotherapy and or rituximab are preserved to confirmed cases of PTLD Ref : Al-Mansour Z, Nelson BP, Evens AM. Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep. 2013 Sep;8(3):173-83. doi: 10.1007/s11899-013-0162-5. PMID: 23737188; PMCID: PMC4831913.
– KDIGO suggests monitoring EBV viral load post-kidney transplant in high-risk patients (i.e., EBV D+/ R-) by NAT (nucleic acid testing) once in the 1st week, monthly for the first 3-6months, then every 3 months until the end of the 1st post-transplant year as well as following treatment for acute rejection (1-3)
– KDIGO also recommends immunosuppression reduction in EBV seronegative patients with a rising EBV viral load and in patients with EBV disease including PTLD (1-3)
– so in this case, the initial step is to monitor EBV viral load, if noted to be increasing then immunosuppression reduction can be considered
References
1. KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Nov;9 Suppl 3:S1-155. PubMed PMID: 19845597. Epub 2009/10/23. eng.
2. Allen UD, Preiksaitis JK. Epstein-Barr virus and posttransplant lymphoproliferative disorder in solid organ transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2013 Mar;13 Suppl 4:107-20. PubMed PMID: 23465004. Epub 2013/03/08. eng.
3. 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.
· Use monitoring of viral loads to help follow the clinical course of patients with established PTLD
1)An EBV load below 1.08log gEq per 105 PBMC implies low risk. Thus, the patient’s routine monitoring should be continued.
(2)An EBV load between 1.08log and 2.48log gEq per 105 PBMC involves an increased risk. A more frequent monitoring of the EBV load in PBMC is required to detect a kinetic variation, plus the monitoring of viral levels in plasma. The detection of a kinetic variation in PBMC and/or an EBV load in plasma greater than 2log gEq/ml involves high PTLD risk.
(3)An EBV load above 2.48log gEq per 105 PBMC plus the detection of viral levels greater than 2.52log gEq/ml in plasma imply a high risk of neoplastic PTLD. The greater the EBV load and/or the simultaneous detection of a kinetic variation, the greater the risk of neoplastic PTLD stages.
References :
M.A. Bingler, B. Feingold, S.A. Miller, M.G. Michaels, M. Green, R.M. Wadowsky, D.T. Rowe, S.A. Webber.Chronic high Epstein–Barr viral load state and risk for late-onset posttransplant lymphoproliferative disease/lymphoma in children.
A – We monitor as the increase in VL can happen with impaired immunity at onset of immunosuppressive meds, no need for treatment yet unless the viral load is constantly increasing.
REF ;
Allen UD et al. PTLD,EBV infection and DX in SOT; Guidelines from AST infectious dx community practice. Clin transplant.2019 sep;33(9) e13652
A is the best choice.
B it is not necessary
C we only need to reduce immunosuppression if clinical changes or laboratory increase of viral load or hepatotoxicity
D is not indicated. And we will have a lot of complications (hemolytic anemia is one)
What is the role of EBV monitoring in this scenario?
PTLD can be detected early by monitoring the viral load of patients at high risk of developing this complication. Although diagnosis of PTLD is based on histology of a tissue biopsy, increased EBV viral load is highly suggestive of PTLD. However, while the absence of EBV in the blood cannot completely exclude PTLD, it makes it less likely.
Serial measurement of EBV-DNA levels in the blood can also be used to monitor response to treatment.
How do you manage this case?
Thorough history and examination – History of wight loss, fever, drenching night sweats. organ specific symptoms like headache, mood changes (in CNS PTLD for example). Examination findings may include pallor, lymphadenopathy, splenomegaly etc.
What is the role of EBV monitoring in this scenario?
EBV serology is important in the pre-TX risk stratification for PTLD (ie, the identification of D+R– subjects) (level AII evidence).
The risk of PTLD may be reduced if it were possible to give EBV-seronegative recipients EBV-seronegative organs. However, this form of donor-recipient matching is often impractical due to the scarcity of donor organs.
Serology has limited or no value after transplantation unless it is part of an evaluative study (level DIII evidence).
Because of the very poor prognosis of PTLD, early diagnosis is essential to maximize the chances of a successful outcome. This requires an appropriate surveillance & monitoring system.
Primary EBV infection is a risk factor for the development of PTLD. Therefore, it is important to identify patients at risk by performing EBV serology before TX.
The patients at highest risk of PTLD are EBV-negative recipients who received EBV-positive organs. After transplantation, such patients should be monitored for the acquisition of EBV infection.
An abnormally elevated EBV viremia correlated with PTLD development (Riddler et al and Savoie et al).
Studies have advocated the establishment of a threshold value for EBV viremia to distinguish high risk PTLD patients from those at low risk.
Riddler reported that patients with PTLD had a viral load > 5000 EBV genome copies/106 PBMC.
The test is more useful in ruling out PTLD than in indicating its presence. It has a poor positive predictive value & high negative predictive value.
============================== How do you manage this case?
Treatment or prevention of PTLD depends on an accurate diagnosis & the ability to distinguish it from graft rejection, particularly if transplanted organ is involved.
Detection of EBV nucleic acids or protein in biopsy specimens is considered a valuable method to assist in the diagnosis of PTLD; however, it has limited prognostic value & may lack sensitivity in diffuse PTLD cases.
EBV prophylaxis
The role of this approach in preventing EBV infection among transplant recipients is less well established.
A number of studies have assessed the role & the current evidence for antiviral agents & immunoglobulin in preventing EBV infection, as well as EBV-related PTLD.
A well-designed, multicenter trials are required, according to the available evidence.
It is important to determine whether ganciclovir should be used alone or in conjunction with immunoglobulin.
Treatment of EBV-related PTLD:
Several reasons made the treatment of PTLD suboptimal:
Inherent difficulties in the treatment of malignancies
Paucity of multicentre clinical trials of different treatment options.
Absence of a clear consensus definition of PTLD.
A lack of a standardized approach to the pathology of PTLD.
Role of reduction or withdrawal of immunosuppression:
There is no consensus on the best approach; however, this modality is regarded as an essential component of the treatment of PTLD.
The level of reduction is generally in the region of 50% (level III evidence).
What is the duration of reduction or withdrawal of IS before alternative therapy is considered?
Variable approaches depending on organ transplant types & individual patient differences.
Duration was generally felt to be 2 to 3 weeks (level III evidence).
The role of antivirals & immunoglobulin in the treatment of PTLD:
The use of ganciclovir & immunoglobulin is recommended in the initial management of PTLD (level BIII evidence).
Ganciclovir is preferred over acyclovir because of its greater in vitro activity against the EBV.
References
Allen et al., Epstein-Barr virus infection in transplant recipients: Summary of a workshop on surveillance, prevention and treatment, Can J Infect Dis Vol 13 No 2 March/April 2002
Does it really work as I quote you, “The use of ganciclovir & immunoglobulin is recommended in the initial management of PTLD (level BIII evidence). Ganciclovir is preferred over acyclovir because of its greater in vitro activity against the EBV” ??
What is the role of EBV monitoring in this scenario?
– KTRs are vulnerable to a higher risk of infections that may lead to significant morbidity and mortality.
-EBV infection is associated with an increased incidence of PTLD in KTRs, especially among the first year post transplantation.
-The risk is increased among seronegative recipient, receiving organ from seropositive donor.
-EBV monitoring is recommended in high risk individuals by most transplant centers. While some recommend EBV monitoring for all transplant recipients. Pitfalls in monitoring strategy:
-Cut-off values are not clear
-Sources of samples are not universal; whole blood, plasma, or peripheral blood mononuclear cells
– Absence of standard points of time to perform the monitoring.
– The precise definition of at high risk patients has not been established yet
KDIGO recommended EBV PCR: within the first week after transplant followed by monthly monitoring for the next three to six months and then every three months for the rest of the first year and additionally after treatment of acute rejection.
– Serial measurement of EBV loads in previously seronegative patients allows the identification of onset of infection
– Identification of patients with newly detectable or rapidly rising EBV load offers the opportunity to preemptively intervene and potentially prevent progression to EBV disease including PTLD.
-The EBV viral load measurement is sensitive, but not specific, for EBV disease and PTLD, as it can also be elevated in asymptomatic patients, and PTLD diagnosis is based on the histologic evaluation of a tissue biopsy, and PTLD ca not be excluded if viral load was undetectable. How do you manage this case?
-Careful evaluation of history and physical examination.
– Review donor and recipient EBV status to determine the risk.
– CBC, LFT, LDH, RFT.
– Drug level Tac.
– Other viruses screening.
– The diagnosis of PTLD require high index of suspension and tissue diagnosis as clinically indicated.
– Frequent monitoring to EBV viral load and graft function.
*Viremia management if rapidly rising:
– Reduction of immunosuppression RIS is the mainstay to control viral replication by restoring EBV-specific cellular immunity.
– RI plan includes 50% reduction of CNI, in addition to withdrawal of the antimetabolites , with the exception of glucocorticoids.
– withdrawal of all immunosuppressive medications in critically ill cases should be considered.
* In the index case KTR with EBV viremia and rising viral load:
– We need to clarify further the IS regimen as he is on double IS.
– Keeping in mind the risk of rejection as patient is high immunological risk 111 mismatch.
– Keep monitoring viral load.
– If viral load continue rising: consider reducing Tacrolimus level and monitor the response in 2-4 weeks.
– close monitoring of graft function.
References:
Shah N, Eyre TA, Tucker D, Kassam S, Parmar J, Featherstone C, Andrews P, Asgari E, Chaganti S, Menne TF, Fox CP, Pettit S, Suddle A, Bowles KM; Haemato-Oncology Task Force of the British Society for Haematology and the British Transplantation Society. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients – A British Society for Haematology Guideline. Br J Haematol. 2021 May;193(4):727-740. doi: 10.1111/bjh.17421. Epub 2021 Apr 20. PMID: 33877688.
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.
Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020 Feb 28;10(2):29-46. doi: 10.5500/wjt.v10.i2.29. PMID: 32226769; PMCID: PMC7093305.
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.
A 24-years old CKD 5 received a kidney from his brother 8 months ago. 111 mismatch, no DSA and negative FCXM. He is on CNI-based double immunosuppression with excellent kidney function. His EBV viral load increased from 200 copies/ml prior to the operation rose to 740 copies/ml 6 months after transplantation. What is the role of EBV monitoring in this scenario? Epstein Barr virus (EBV) is a ubiquitous tumor virus that belongs to the gammaherpesvirus subfamily. EBV is associated with a variety of lymphomas/leukemias, and epithelial malignancies, including nasopharyngeal carcinoma (NPC), lymphoepithelioma-like carcinoma, and gastric cancer. EBV viral load quantification has recently played a more important role in the diagnosis and management of EBV-associated diseases, particularly useful for monitoring EBV-DNA in transplant patients with risks of EBV-associated post-transplant lymphoproliferative disease (PTLD), and assessing the response to therapy. In the index case no data about the EBV serostatus in donor and recipient, if the the recipient is seronegative for EBV and donor positive EBV IgG, then frequent monitoring of viral load at the first week and monthly for 3 months then every 3 months for the first year, and after treatment of an acute rejection is mandatory. If the level continue to increase modification of immunosuppression is wise ( decreasing tacrolimus to lower therapeutic trough level, and MMF , and/or introduction of m-TOR inhibitors). EBV encoded small RNA (EBER) in situ hybridization or viral antigen detection is performed, to prove EBV related PTLD, but not the EBV DNA (viral load), that can be used to diagnose EBV-PTLD when biopsy could not be taken, monitoring PTLD in HSCTand response to treatment. Guidelines also moderately recommend that significant amounts of EBV-DNA without clinical symptoms of EBV disease are an indication for preemptive therapy (RITUXIMAB). routine surveillance for EBV-DNA by quantitative PCR is not recommended, Solid organ allograft recipients carry chronic high EBV loads without symptoms consistent with PTLD, but the significance of a high EBV load in terms of long-term health is unknown. In Hodgkin’s lymphoma: EBV-DNA in plasma is highly correlated with EBV tumor status in HL and is significant for determining the prognosis before therapy and at follow-up after 6 months. In Extranodal NK/T-Cell Lymphoma, Nasal Type (ENKTL): EBV-DNA levels in peripheral blood are a surrogate biomarker of tumor load, used in making a diagnosis, prognostic assessment and response to treatment. Chronic Active EBV Infection (CAEBV): characterized by fever, lymphadenopathy, hepatosplenomegaly, pancytopenia, interstitial pneumonitis, and skin involvement (hypersensitivity to mosquito bites or hydroa vacciniforme), The diagnosis of CAEBV is based on: (1) infectious mononucleosis-like symptoms lasting >3 months. (2) increased EBV-DNA in peripheral blood or the demonstration of EBER in affected tissues. (3) the exclusion of known immunodeficiencies, malignancies, or autoimmune disorders. Monitoring for EBV-DNA is also useful for assessing the treatment response.
How do you manage this case? From the medical chart of both donor and recipient I’ll check for the serostatus of EBV, high risk being D+/R-, those receiving induction therapy. I would check the laboratory result for any hint on possibility of PTLD, anemia, thrombocytopenia, lymphopenia, high LDH, calcium, liver function test or paraproteinemia, urinalysis and kidney function as well. Detailed history (fever, night sweats, wt. loss.. etc), and thorough clinical examination (lymphnodes, organomegaly, throat lesions.. etc), are needed to identify if EBV related PTLD present. If nothing with PTLD, will continue monitoring till the end of first year (the EBV-PTLD more frequently seen). If any rejection episode occur even after the first year will monitor the EBV viral load. If the patient is asymptomatic, the viral load continues to rise then I’ll consider reduction of immunosuppressive medication especially CNI to the lower therapeutic trough level, with frequent monitoring of kidney function to prevent and treat rejection episode immediately. If symptomatic, identification of the PTLD and treating accordingly, reduce or discontinue the immunosuppression, may use m-TOR inhibitors.
References: (1) 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. (2) Le J, Durand CM, Agha I, Brennan DC. Epstein-Barr virus and renal transplantation. Transplant Rev (Orlando). 2017 Jan;31(1):55-60. doi: 10.1016/j.trre.2016.12.001. Epub 2016 Dec 29. PMID: 28089555. (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.
A 24-years old CKD 5 received a kidney from his brother 8 months ago. 111 mismatch, no DSA and negative FCXM. He is on CNI-based double immunosuppression with excellent kidney function. His EBV viral load increased from 200 copies/ml prior to the operation rose to 740 copies/ml 6 months after transplantation. What is the role of EBV monitoring in this scenario?
We are looking for EBV serostatus of the donor and the recipient, as recipient with EBV seronegative renal transplant recipients /EBV seropositive donor should be monitored in first week, then monthly for 3 months, and then 3 monthly till the end of first year post-transplant, in addition to at the time of acute rejection treatment.
But in low risk patient, no need to follow BV viral load assays, specially without clinical possibility of PTLD without increasing the risk of disease occurrence , representing a safe and cost-effective policy . How do you manage this case?
There is no consensus regarding the EBV viral load cut-off thought to be significant (for PTLD), if our patient clinically free and PTLD is excluded, follow-up of the viral load, but if rising titer with manifestations we should optimize the immunosuppression . References: 1- 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. 2- American Journal of Transplantation 2013; 13: 41–54 doi: 10.1111/ajt.12004 .
What is the role of EBV monitoring in this scenario?
The index patient is a 24-year-old living donor renal recipient with 111 mismatch having excellent graft function on dual immunosuppression. His EBV viral load is being monitored and being found to have risen from 200 copies/ml at transplant to 740 copies/ml at 6 months post-transplant.
The data missing in this scenario is with respect to the EBV serostatus of the donor and the recipient. Also, the immunosuppression used is not mentioned.
According to guidelines, EBV seronegative renal transplant recipients receiving a kidney from EBV seropositive donor should be monitored for EBV by nucleic acid testing (NAT) in first week, then monthly for 3 months, and then 3 monthly till the end of first year post-transplant, in addition to at the time of acute rejection treatment (1,2).
As there is monitoring of EBV viral load in this patient, it seems that the donor was seropositive in this scenario. But according to a study, almost 86% of transplant centres perform EBV viral load testing routinely and 77% reported pre-emptive treatment in case of significant EBV viremia (3). A study conducted concluded that in low-risk patients, EBV viral load assay monitoring in absence of clinical symptoms is not cost-effective and may be avoided in renal transplant recipients (4).
How do you manage this case?
The index patient has an increasing level of EBV DNA load on testing at 6 month post-transplant. There is no consensus regarding the EBV viral load cut-off thought to be significant (for PTLD) and different studies use different cutoffs, but most use a cut-off more than 1000 copies/ml as significant (4-6).
The patient would require detailed history for symptoms (night sweats, fever, weight loss) and detailed physical examination.
The index patient, if asymptomatic, would require nothing more than follow-up with monitoring of EBV viral load. Monitoring should be done till a viral “set point” is reached, developing a state called chronic viral load phenotype, CVLP (2). Ongoing monitoring beyond the first year is done if the patient has a rejection episode, the immunosuppression is fluctuating, or if the viral “set point” has not reached (that is the viral load is progressively increasing).
Ongoing serial EBV viral load monitoring late after transplant in CVLP with pre-emptive interventions like reduction in immunosuppression is not routinely recommended (2).
A rising EBV viral load can identify patients in whom intervention can prevent development of PTLD (1).
If the patient is symptomatic, or if the levels increase to significant level, then pre-emptive treatment in form of immunosuppression reduction may be required (1). But there is no consensus on this strategy.
We should know the immunosuppression being taken by the patient. If patient is on calcineurin inhibitor and steroids, the dose of calcineurin inhibitor can be reduced. Reduction of immunosuppression in this patient with 111 mismatch and dual immunosuppression is fraught with risk of rejection.
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.
Allen UD, Preiksaitis JK; AST Infectious Diseases Community of Practice. Post-transplant lymphoproliferative disorders, Epstein-Barr virus infection, and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13652. doi: 10.1111/ctr.13652. Epub 2019 Jul 23. PMID: 31230381.
San-Juan R, Manuel O, Hirsch HH, Fernández-Ruiz M, López-Medrano F, Comoli P, Caillard S, Grossi P, Aguado JM; ESGICH PTLD Survey Study Group,; European Study Group of Infections in Compromised Hosts (ESGICH) from the European Society of Microbiology and Infectious Diseases (ESCMID). Current preventive strategies and management of Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplantation in Europe. Results of the ESGICH Questionnaire-based Cross-sectional Survey. Clin Microbiol Infect. 2015 Jun;21(6):604.e1-9. doi: 10.1016/j.cmi.2015.02.002. Epub 2015 Feb 14. PMID: 25686696.
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.Le J, Durand CM, Agha I, Brennan DC. Epstein-Barr virus and renal transplantation. Transplant Rev (Orlando). 2017 Jan;31(1):55-60. doi: 10.1016/j.trre.2016.12.001. Epub 2016 Dec 29. PMID: 28089555.
Kimura H, Ito Y, Suzuki R, Nishiyama Y. Measuring Epstein-Barr virus (EBV) load: the significance and application for each EBV-associated disease. Rev Med Virol. 2008 Sep-Oct;18(5):305-19. doi: 10.1002/rmv.582. PMID: 18494041.
Kanakry JA, Hegde AM, Durand CM, Massie AB, Greer AE, Ambinder RF, Valsamakis A. The clinical significance of EBV DNA in the plasma and peripheral blood mononuclear cells of patients with or without EBV diseases. Blood. 2016 Apr 21;127(16):2007-17. doi: 10.1182/blood-2015-09-672030. Epub 2016 Jan 7. PMID: 26744460; PMCID: PMC4841041.
5. A 24-years old CKD 5 received a kidney from his brother 8 months ago. 111 mismatch, no DSA and negative FCXM. He is on CNI-based double immunosuppression with excellent kidney function. His EBV viral load increased from 200 copies/ml prior to the operation rose to 740 copies/ml 6 months after transplantation.
==================================================================== HISTORY
A 24-year-old CKD 5 recipient received a kidney 8 months after transplantation, with 111 mismatch, no DSA, and negative FCXM.
What is the role of EBV monitoring in this scenario?
EBV-PTLDs are severe complications of HSCT and SOT, with immunodeficiency leading to de novo infection or reactivation of EBV, which drives immortalization of infected lymphocytes.
PTLD is defined by the presence of altered B-cell lymphocytes that are frequently Epstein-Barr virus infected (EBV).
The incidence of PTLD varies by the organ(s) transplanted: intestinal and multiorgan transplants (5%-20%), lung and heart transplants (2%-10%).
Renal transplant recipients have the lowest incidence of PTLD, which is between 1 to 5% of patients at risk.
Quantitative PCR-based EBV DNA detection may be used for early diagnosis as well as an indirect approach of identifying patients at risk for PTLD and tracking their therapeutic response.
However, there are many restrictions on how the preemptive EBV PCR monitoring should be interpreted, including the lack of a clear cutoff value for interpretation, the lack of typical times to conduct the monitoring, and the use of non-universal sample sources.
According to reports, cell-free plasma EBV DNA is a more accurate indicator of EBV activity.
On the other hand, plasma EBV loads were higher at diagnosis in patients who were deceased compared to patients that survived, suggesting that cell-free EBV-DNA has prognostic value.
==================================================================== How do you manage this case?
The key risk factors for PTLD include pretransplant EBV serology status, primary renal illness, type of induction IS, and ongoing immunosuppressive treatment.
CBC, LDH, serum calcium uric acid, and Total protein .
Monitoring for allograft failure should focus on falling GFR and donor-derived cell free DNA, and baseline tests should be performed.
According the KDIGO 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 monthsafter transplantation , then every 3 months until the end of the first posttransplant year and additionally after treatment for acute rejection.
If EBV-seronegative patients withan increasing EBV load have immunosuppressive medication reduced.
If — EBV disease,including PTLD, a reduction or cessationof immunosuppressive medication.
Further research, tissue biopsies, the MDT strategy, modifications to mTOR inhibitors, and monotherapy drugs like rituximab are all necessary for treating PTLD.
Shahid S, Prockop SE. Epstein-Barr virus-associated post-transplant lymphoproliferative disorders: beyond chemotherapy treatment. Cancer Drug Resist 2021;4:646-64. http://dx.doi.org/10.20517/cdr.2021.34
KDIGO guideline for kidney transplant recipients 2009
Rickinson AB, Long HM, Palendira U, M€unz C, Hislop AD. Cellular immune controls over Epstein-Barr virus infection: new lessons from the clinic and the laboratory. Trends Immunol. 2014;35:159–169.
Viral infection is a common post transplant complication & associated with significant patient & graft loss.
90% of population are EBV seropositive in high & middle income countries.
Post transplant primary or reactivated EBV infection can cause PTLD.
KDIGO guidelines suggest monitoring of high risk kidney transplant recipient(EBV D+/R-) of EBV by NAT at Everest week, every month for 3-6 months then every 3 months during first post transplant year.
KDIGO guidelines recommend reduce immunosuppression in EBV seronegative patients with high viral load & patients with EBV disease including PTLD.
EBV DANemia level considered significant can differ between centers.
EBV DNAemia <1000 copies/ml in asymptomatic patients associated with low risk of PTLD.
This recipient had low-level of EBV DNAemia & no EBV disease(asymptomatic) so not need ant intervention.
No role for frequent EBV viral load measurment.
References:
Baldanti F., Grossi P., Furione M., Simoncini L., Sarasini A., et al. High Level of Epstein-Barr Virus DNA in Blood of Solid Organ Transplant Recipients and Their Value in Predicting Posttransplant Lymphoproliferative Disorder. Journal of Clinical Microbilogy, 2000;613-619.
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-Cnter, 10 year Observational Cohort Study. Transplantation Direct, 2017.
Whilst I agree with your approach but you may wish to know the sero status of both donor and recipient to stratify the risk and you may also want to know the immunosuppression in this case and viral load monitoring will depend largely on these factors as well as absence of symptoms as you suggested.
-What is the role of EBV monitoring in this scenario?
Guidelines recommended EBV viral load monitoring in high-risk groups in the first year; 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.
EBV viral load assays have no need to be done in low-risk patients those without clinical possibility of PTLD without increasing the risk of disease occurrence , representing a safe and cost-effective policy .
-How do you manage this case?
The current case has EBV positive with increasing level.
Immunosuppressive therapy can be reduced with close monitoring of the graft function.
Monitoring EBV PCR every month for first 3 months after transplant.
from 3 rd month till 1 year post transplant it can be monitored every 3 months .
If titres are greater than 1000 copies/ml , immunosuppression need to be reduced.
Then titres can be assessed after 2 weeks .
· If titres decreased PCR can be monitored every two weeks till negative
· If titres are increasing even if the patient is asymptomatic, further immunosuppression reduction and PanCT or even PET can be done to screen for PTLD
Reference –Franceschini E, Plessi J, Zona S, 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;3(7):e182. Published 2017 Jun 26.
-Guideline Title: Epstein Barr Virus (EBV)- Post Transplant Management University Hospital of Leicester Renal transplant Guideline Approved by Renal Transplant MDT Approval Date 23/05/2022, Trust Ref: C22/2022
This patient is sero-positive to start with , however , it has risen significantly thereafter, nevertheless, it would not be as risky and potentially pathogenic as when its developed in a sero-negative recipient, Therefore he is not a high risk recipient.As per KDIGO guideline follow up of EBV DNAemia is recommended for high risk patient for developing PTLD mainly those EBV donor positive / recipient negative cases.However , highly increasing DNAemia might portend a significant risk factor that warrant close follow up. It s advocated that symptoms are the cornerstone in predicting PTLD rather than EBV DNA .
References:
1] Franceschini, Erica MD 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.Transplantation Direct 3(7):p e182, July 2017.
Thank you Dr. Mohsen ,
The history of patient details that anti-EBV titer was 200 before transplantation that has risen to 730 afterwards. being sero-positive to start with is less risky regarding development of PTLD than developing de novo EBV infection.
· What is the role of EBV monitoring in this scenario?
PTLD displays highly variable patterns of incidence in kidney transplant recipients, with peaks in the first year and subsequently in the latter post-transplantation period. More than 90% of B cell PTLD that develop within the first year of transplantation includes the EBV genome. Hence, EBV monitoring is used to prevent PTLDs. There is considerable disagreement surrounding routine EBV viral load in adult SOT recipients to prevent the onset of PTLD. In practice, the majority of European doctors frequently use EBV viral load to direct both diagnostic workup and preventive medication, despite international guidelines advocating EBV-VL surveillance only in high-risk patients.
KDIGO guidelines recommend monitoring for EBV after transplantation in high risk recipients, once in the first week, monthly for the first 3 to 6 months, then every 3 months until the end of the first post-transplant year, as well as following treatment for acute rejection.
Immunosuppressive medicine, particularly antimetabolite medications, should be lowered in patients with increasing viral loads over the screening period, especially in EBV-seronegative patients, with subsequent monitoring of viral load.
Not all patients with high EBV virus loads develop PTLD. However, rising viral load in the presence of clinical picture Because of the aforementioned factors, PTLD assessment should be aggressive when clinical PTLD signs are present. Any unexplained febrile infections in a SOT recipient should raise the possibility of PTLD, especially if they occur within the first year after transplantation, in particular in patients who received potent induction and maintenance immunosuppression.
· How do you manage this case?
In the patient with low risk for rejection, having negative DSA, FCXM and 111 mismatch, the initial step in this approach is to reduce immunosuppression and followup in viral load.
Patient should be asked about specific symptoms related to PTLD. Screening for PTLD in high risk patients (SEROPOSITIVE TO SERONEAGTIVE) is indicated when clinically indicated.
Thank you Dr Mohamad Habli
I agree with your approach. I’ve a reservation for reducing immunosuppression when his match is 111 and only maintained on dual immunosuppressions which you need to verify what are these immunosuppressions before any reductions?
What is the role of EBV monitoring in this scenario?
EBV monitoring is important as a preemptive strategy of decreased incidence and prevention of EBV disease and PTLD in high risk patients by early reductions of immune suppression .
Assessment of severity of infection as well as monitoring the response to treatment .
How do you manage this case?
The above-mentioned patient developed rising EBV viral load 6 months after kidney transplantation testing .
EBV viral load alone has low sensitivity and specificity in diagnosis of PTLD because it may remain low in case of the protected site of PTLD such as in some gastrointestinal lesions or when occurring in the transplanted kidney .
Elevated EBV viral load does not mean the presence of EBV/PTLD .
*For these reasons our approach in this patient to confirm presence or absence of PTLD starting from full history and proper clinical examination and investigations,full blood count ,liver function test and liver enzymes LDH.
-Radiographic evaluation using CT of neck, chest and abdomen. *If PTLD is excluded, follow-up of the viral load with optimization or reduction of immunosuppression is the main stay in managing these patients .
Reference :
American Journal of Transplantation 2013; 13: 41–54 doi: 10.1111/ajt.12004 .
Thank you Dr Nada AlHassan
Excellent and sensible answer but are you proposing CT scan for this case based on this level of viraemia?
Your strategy is sensible but high index of suspicion of PTLD is probably more appropriate before considering unnecessary exposure to high dose of radiation especially many of these cases happen in youngsters.
Thank you Prof. Mohsin in this case if there no history or clinical findings suggestive of PTLD there no need to expose the patient to the risk of radiation .
EBV virus is associated with many disesseds post kidney transplat from assymtomatic viremia to post-transplant malignancies in kidney transplant recipients.
EBV specifically is associated with post-transplantation lymphoproliferative disorder (PTLD).
Asymptomatic low level EBV viremia may be picked up on screening with no symptoms.
EBV-associated PTLD, is the most serious and problematic presentation in KT recipients
The incidence of PTLD is lower in KT recipients of 1-5%.
EBV-associated PTLD signs and symptoms vary, depending on the type of PTLD.
The spectrum of EBV-PTLD clinical presentations range from infectious mononucleosis-like syndrome with fever, sore throat, malaise, and fatigue, to more constitutional “B” symptoms consistent with lymphoma such as fever, night sweats, weight loss. The majority (> 65- 80%) of PTLD presents as extranodal masses with a spectrum of histologic presentations from polymorphic clonal and non-clonal lesions to monomorphic clonal lesions.
EBV viral load monitoring has an absence of an international reference standard, with much variability amongst institutions with differing viral load cutoffs and differing methods (whole blood versus plasma), making interpretation of results diffucult.
Negative EBV PCR results with a cut-off value of < 1000 EBV copies/mL in plasma, have excellent negative predictive value for PTLD approaching 100%.
Patients with PTLD have high titer (> 10,000 copies/mL) EBV DNA detectable in plasma.
preventive stratgey include serial monitoring of EBV PCRs in-risk KT recipients during the first year post-transplantation.
the first approach is to reduce immunosuppression while being aware that rejection may occur if immunosuppression is lowered too aggressively.
There is no consensus about switching from calcineurin-based immunosuppression to mTORinhibitor-based therapy due to conflicting reports of efficacy.
For most patients on standard immunosuppressive regimens, some centers choose to stop the adjuvant agent, decrease the calcineurin inhibitor exposure, and keep the prednisone dose at 5-10mg/day. Most centers may try a multimodal treatment strategy based on reduction of immunosuppression, immunotherapy with rituximab (for CD20 positive PTLD), chemotherapy, radiation therapy, or a combination of these treatment modalitie.
Polymorphic PTLD treatment also includes reduction of immunosuppression, with addition of rituximab for CD20 positive PTLD.
Monomorphic PTLD, on the other hand,involves reduction of immunosuppression, rituximab for CD20 positive PTLD, and chemotherapy, immunotherapy, and in some cases surgical resection.
Thank you Dr Mohamed Gaffar
Well done with such detailed discussion and explanation. I’ve few points:
1- There is a mix in your answer between PTLD management and EBV viraemia
2-We are seeking your opinion and management plan in this particular case with the above specifications
3- Why we only monitor the viral load without any specific treatment?
What is the role of EBV monitoring in this scenario?
o In kidney transplant recipients, PTLD has shown bimodal patterns of incidence, with peaks in the first year and then in the later posttransplantation period
o The EBV genome is found in more than 90% of B cell PTLD occurring during the first year after transplantation
o The role of EBV monitoring is PTLD avoidance
o Routine EBV-VL in adult SOT recipients to avoid PTLD development is still debated. Despite international guidelines suggesting EBV-VL monitoring only in high-risk recipients, in real life, the majority of European clinicians routinely use EBV-VL to guide both diagnostic workup and preemptive therapy
How do you manage this case?
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
I will do regular follow-up with detailed history and examination with continuous monitoring of viral load. EBV DNAemia levels considered significant can vary between centers (a value of 4000 copies/mL may be a risk factor for PTLD onset)
EBV disease, including PTLD at any level of viral load is an indication of immunosuppressive reduction and conversion to mTORi
PTLD and EBV viral load:
o Viral load alone cannot be used to diagnose PTLD as the test can lack both sensitivity and specificity
o The viral load will be low if the site of PTLD is protected such (graft itself or in some gastrointestinal lesions)
o Patients with elevated EBV VL do not always have or develop EBV/PTLD
o For the above reasons, an aggressive approach to the evaluation of PTLD should be used when this diagnosis is suspected
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 loaed and focal findings on examination or in a patient with primary EBV infection and increasing viral loads
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.
· What is the role of EBV monitoring in this scenario?
In solid organ transplant recipients, patients will demonstrate mild increase in EBV after transplantation, but majority of EBV positive PTLD will show more marked elevation in viral load. [1] Based on this observation early detection of PTLD was suggested for EBV positive PTLD. [1, 2] Centers with regards to definitions of high risk patients and cuff offs differ and hence no limit is determined. Rise to 740 copies/ 100microL in this case would suggest reduction in immunosuppressant’s and EBV DNA monitoring closely which could be suggestive of early PTLD. [1] Due to using different methods EBV viral load measurements cannot be compared between institutions. Since majority of PTLD occurs in first year after transplantation so it is reasonable to monitor high risk patient more frequently. Some guidelines societies would recommend EBV monitoring foe all transplants recipients. [3] · How do you manage this case? As this patient is asymptomatic with no illness defining symptoms so reduction of immunosuppressant with close surveillance for allograft rejection would be recommended. Allograft dysfunction monitoring should be on declining in GFR and where applicable donor derived cell free DNA. EBV DNA should be monitor for response. Base line investigation like CBC, LDH, Serum calcium uric acid and serum protein body scan should be done accordingly and monitor later for response. If progressive disease than will need to manage on the line of PTLD.
References
1. 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. 2. Tsai DE, Douglas L, Andreadis C, Vogl DT, Arnoldi S, Kotloff R, Svoboda J, Bloom RD, Olthoff KM, Brozena SC, Schuster SJ, Stadtmauer EA, Robertson ES, Wasik MA, Ahya VN. EBV PCR in the diagnosis and monitoring of posttransplant lymphoproliferative disorder: results of a two-arm prospective trial. Am J Transplant. 2008 May;8(5):1016-24. doi: 10.1111/j.1600-6143.2008.02183.x. Epub 2008 Feb 29. PMID: 18312608. 3. EBPG Expert Group on Renal Transplantation. 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. Nephrol Dial Transplant. 2002;17 Suppl 4:31-3, 35-6. doi: 10.1093/ndt/17.suppl_4.31. PMID: 12091638.
What is the role of EBV monitoring in this scenario?
PTLD is characterized by the presence of transformed lymphocytes of B-cell origin which are frequently infected by the Epstein-Barr virus (EBV)especially early time after transplantation like the indexed case
Around 1-15% of patients at risk of developing PTLD, renal transplant recipients having the lowest incidence of PTLD (0.8–2!.5%). early PTLD course more in pediatric and associated with EBV positive donor /Recipient negative with mortality rate in some reports was in the range of 40-70%. While PTLD EBV negative usually in adults and old age usually after first year of transplantation and another peak after 10 years (2).
EBV DNA detection by using quantitative PCR may have the role for the early diagnosis and also can provide an indirect method of identifying patients at risk for PTLD and to monitor their response to therapy, so this indexed case has gradually increasing EBV viral load which is concerning and put him at risk of PTLD. The assessment of the viral load via PCR amplification of peripheral blood EBV DNA is mandated to monitor preemptive PTLD therapy. It has been observed that transplant candidate with PTLD usually expresses an increased EBV viral load as compared to PTLD free recipient. This higher viral load invites more risk for PTLD evolution. However, there is a lot of limitation for the interpretation of the preemptive EBV PCR monitoring includes:
1. No clear cut off value for interpretation.
2. absence of usual points of time to do the monitoring
3. sources of samples are not universal
the positive and negative predictive of EBV viral load values for both SOT (28%-100% and 75%-100%, respectively, “cell-free plasma EBV DNA” has been reported as a better marker of EBV activity(3). How do you manage this case?
Further history a bout pre-transplant EBV serology status for both donor and recipient, address the primary renal disease and previous viral exposure with intense IS for treatment of primary renal disease like SLE , the type of induction IS ( T cell depleting agent like ATG , or alemtuzumab and the current immunosuppression protocol, CNI trough level, as the main two risk factors for PTLD is the cumulative dose of IS and the oncogenic viral effect of EBV.
Symptoms like fever, wt. loss, LAP, respiratory or GI symptoms, CNS manifestation.
Further investigation like FBC, LDH, LFT, Virology: HIV type 1 & 2, Hepatitis B and C,and EBV serology, CMV/EBV DNA titers( molecular and serological testing )
immunohistochemistry by immunoglobulin staining and flow cytometry Tissue biopsy needed like LN biopsy to confirm the diagnosis of PTLD.
for now need frequent monitoring and reduction of IS as first step if the mentioned above work up confirm the diagnosis of PTLD including tissue biopsy with staging then we need MDT approach including transplant physician, oncology- hematologist, pathologist and reduction of immunosuppression is main treatment including modification to m TOR inhibitors, may consider monotherapy agents like rituximab with or without chemotherapy .
References
1.Tsai DE, Nearey M, Hardy CL, Tomaszewski JE, Kotloff RM, Grossman RA, Olthoff KM, Stadtmauer EA, Porter DL, Schuster SJ, Luger SM, Hodinka RL. Use of EBV PCR for the diagnosis and monitoring of post-transplant lymphoproliferative disorder in adult solid organ transplant patients. Am J Transplant. 2002 Nov;2(10):946-54. doi: 10.1034/j.1600-6143.2002.21011.x. PMID: 12482147.
2. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Hematology Guideline.
3.Kenagy DN, Schlesinger Y, Weck K, Ritter JH, Gaudreault-Keener MM,
Storch GA. Epstein-Barr virus DNA in peripheral blood leukocytes of
patients with posttransplant lymphoproliferative disease. Transplantation 1995; 60: 547–554.
Important in diagnosis and monitoring of EBV-associated lymphoid malignancy.
To monitor treatment response.
Assessing the severity and prognosis.
Management of the case
The viral load is a little bit high, but not that indicate EBV-associated lymphoma.
Whole blood EBV load of > 20,000 copies and plasma of > 1000 copies are significant for EBV-associated LPD.
Monitor EBV load monthly and then accordingly.
If EBV load increases we considered ISR by monitoring drug level and graft function.
References KDIGO kidney transplantation 2009
Longnecker R, Kieff E, Cohen JI. Epstein-Barr virus. In: Knipe DM, Howley PM, editors. Fields Virology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; (2013). p. 1898–959.
Kimura H, Ito Y, Suzuki R, Nishiyama Y. Measuring Epstein-Barr virus (EBV) load: the significance and application for each EBV-associated disease. Rev Med Virol. (2008) 18:305–19. 10.1002/rmv.582 – DOI – PubMed
Kanakry J, Ambinder R. The biology and clinical utility of EBV monitoring in blood. Curr Top Microbiol Immunol. (2015) 391:475–99. 10.1007/978-3-319-22834-1_17
What is the role of EBV monitoring in this scenario?
The following points are to be noted in the index case
living related donor with good HLA matching
Absence of DSA
Use of double immunosuppression
Good graft function
Rise of EBV viral load from 200copies to 740 copies within 6 months
It has been observed that transplant recipients with very high EBV levels are more prone to the development of PTLD compared to those with less level of EVB viral load.
In one study, plasma from patients with PTLD had a median EBV viral load of 3225 copies/ml, while immunosuppressed controls without evidence of PTLD had fewer than 740 copies/m.
In view of the above, many centers have included routine checking of EBV viral load among their high-risk patients for early detection of EBV along sides clinical symptoms and histological findings on the affected organ.
Furthermore, if the patient starts receiving treatment for PTLD, the EBV viral load will be a good tool to measure response to the treatment
Pitfalls in the preemptive monitoring of the EBV viral loads.
Lack of clear cut-off values of EBV viral load for diagnosis of PTLD
The sources of samples are not universal
The absence of standard points of time to perform the monitoring.
How do you manage this case?
Assess the risk status of the recipient before the surgery along with the donor
Continue monthly check of EBV NAT
Maintain tacrolimus trough level between 5-8ng/ml
Reduction of immunosuppression if the EBV viral load is increasing
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.
Jonathan W Friedberg, Jon C Aster. Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders. UpToDate. 2023.
A 24-years old CKD 5 received a kidney from his brother 8 months ago. 111 mismatches, no DSA and negative FCXM. He is on CNI-based double immunosuppression with excellent kidney function. His EBV viral load increased from 200 copies/ml prior to the operation rose to 740 copies/ml 6 months after transplantation.
What is the role of EBV monitoring in this scenario?
How do you manage this case? EBV monitoring in all patients with high risk of PTLD:
Monitoring of high-risk kidney transplant recipients by nucleic acid testing post transplantation once in the first week, monthly for the first 3-6 months, then every 3 months until the end of the first post-transplant year, and additionally after treatment for acute rejection.
KDIGO also recommends reducing immunosuppressive medication in EBV seronegative patients with an increasing EBV viral load and in patients with EBV disease including PTLD.
How do you manage this case?
Details History and Examination (Constitutional, GIT Symptoms & LNs).
D/C or Decrease MMF, Decrease CNIs.
Close Monitor viral load & previous symptoms, monthly is recommended for the first 3-6 months, If persist viral load raising will consider more workup and Biopsy diagnosis then a 2nd Line Chemotherapy as indicated. References:
*EBPG Expert Group on Renal Transplantation. 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. Nephrol Dial Transplant 2002; 17 Suppl 4:31.
*Recipient serostatus on the incidence of post-transplant lymphoproliferative disorder in kidney transplant recipients. Nephrol Dial Transplant. 2012; 27:2971–2979.
I like your detailed well-structured summary well supported by references.I appreciate your sensible clinical approach in managing this patient.Typing whole sentence in bold amounts to shouting
What is the role of EBV monitoring in this scenario?
many healthy transplant recipients will demonstrate a modest increase in EBV viral load post-transplant
The vast majority of patients with EBV-positive PLTD will demonstrate a more marked elevation in EBV viral load.
PTLD may be detected early by monitoring of EBV viral load by PCR of blood , plasma of patients with a high risk of developing this complication.
While an increase in EBV viral load is suggestive of PTLS however , the diagnosis of PTLS is still made by histologic evaluation of tissue biopsy.
the absence of EBV viral load makes PTLS less likely, but doesn’t exclude the diagnosis .
Many transplant centers have incorporate EBV monitoring into the routine evaluation of patient with high risk .
I think our patient is a low-risk factor and this is a normally rise in EBV viral load, however, I recommend monitoring.
antiviral prophylaxis with gancyclovir,
Reduce tacrolimus target level to 2 to 5.
Many of you are replying without looking at the details provided. Are we really dealing with cancer or PTLD here.
Just because there increasing EBV viremia does not mean that you suggest chemotherapy without histopathological confirmation of PTLD! You need to use clinico-pathological corelation keeping in mind the clinical detail rather than any possiblity that are not even mentioned in the case recirds.
Is lymphocyte transfer from donor a clinically applicable well-accepted innovation?
PTLD is a serious and fatal complication of renal transplantation that occur mainly due to chronic T cell immunosuppression and proliferation of EBV B cells. Although EBV negative cases can occur
In order to prevent EBV related PTLD the following should be done:
Avoid intensification of immunosuppression especially tacrolimus
If possible avoiding seropositive donors
Antiviral prophylaxis according to EBV status (gancyclovir, valgancyclovir, acyclovir) may decrease the incidicen of PTLD (1-4), the use of these drugs may decrease the incidence of EBV replication and PTLD but no clear recommendation for the use of this approach in EBV prophylaxis since data regarding its efficacy in prevention of PTLD in SOT is limited and is taken from retrospective studies and single-arm prospective studies (1,2,5,6)
Monitoring of EBV in all patients with high risk of PTLD and if positive reduction of immunosuppression should be done to avoid transformation top PTLD. EBV load should be monitored in high risk patients within the first week after transplantation, monthly for 3-6 months then / 3 months till the end of the first year (7).
Some experts recommend the use of use preemptive one dose of Rituximab if PCR level > 1000 copies per ml (preemptive therapy) (8-10)
So in the current patient
There is no rule for monitoring since the patient is low risk
But in the current case I will adjust CNI dose to lower target
Decrease MMF dose
Monitor viral load, if rise > 1000 I will consider 1 dose of Rituximab
Monitoring monthly is recommended for the first 3-6 months
References
1- Funch DP, Walker AM, Schneider G, et al. Ganciclovir and acyclovir reduce the risk of post-transplant lymphoproliferative disorder in renal transplant recipients. Am J Transplant 2005; 5:2894.
2- McDiarmid SV, Jordan S, Kim GS, et al. Prevention and preemptive therapy of postransplant lymphoproliferative disease in pediatric liver recipients. Transplantation 1998; 66:1604.
3- Ellis D, Jaffe R, Green M, et al. Epstein-Barr virus-related disorders in children undergoing renal transplantation with tacrolimus-based immunosuppression. Transplantation 1999; 68:997.
4- Holmes RD, Sokol RJ. Epstein-Barr virus and post-transplant lymphoproliferative disease. Pediatr Transplant 2002; 6:456.
5- Humar A, Hébert D, Davies HD, et al. A randomized trial of ganciclovir versus ganciclovir plus immune globulin for prophylaxis against Epstein-Barr virus related posttransplant lymphoproliferative disorder. Transplantation 2006; 81:856.
6- Opelz G, Daniel V, Naujokat C, et al. Effect of cytomegalovirus prophylaxis with immunoglobulin or with antiviral drugs on post-transplant non-Hodgkin lymphoma: a multicentre retrospective analysis. Lancet Oncol 2007; 8:212.
7- EBPG Expert Group on Renal Transplantation. 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. Nephrol Dial Transplant 2002; 17 Suppl 4:31.
8- 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.
9- 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.
10- 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.
I like your detailed well-structured summary well supported by a very good list of appropriate references.I appreciate your sensible clinical approach in managing this patient.
Close monitoring of EBV viral load within 3 months after transplant can predict a high risk of PTLD.
EBV transmission to naive recipients increases the risk of PTLD. The risk of PTLD is much higher in these patients.
KDIGO suggests monitoring of high risk kidney transplant recipients by nucleic acid testing post transplantation once in the first week, monthly for the first 3-6 months, then every 3 months until the end of the first post transplant year, and additionally after treatment for acute rejection.
KDIGO also recommends reducing immunosuppressive medication in EBV seronegative patients with an increasing EBV viral load and in patients with EBV disease including PTLD.
Management
EBV DNA monitoring and early intervention is to be done. This includes reduction in immunosuppression and possibly Rituximab if there is significant increase in viral load.
PET imaging can be done to rule out PTLD in the patient.
If titers are greater than 1000 copies/ml (620 IU/ml) then
Discuss with virologist about EBV DNA PCR on whole blood and plasma. This is because elevated whole viremia in whole blood in comparison with plasma would reveal that the virus is mainly intracellular, and possibly less clinically significant.
Check titers two weeks later and,
If titers are decreasing, monitor with PCR every two week till negative
If titers are raising and even if the patient is asymptomatic, reduce the immunosuppression dose further, and do head and neck, chest, abdomen and pelvis CT to rule out PTLD. PET scan can also be considered.
If PTLD is found on CT/PET scan, then refer to hematologist, and patient will be managed with a multidisciplinary team including transplant nephrologist.
If no PTLD is detected, then Rituximab treatment can be considered.
References
Sampaio MS, Cho YW, Shah T, et al. Impact of Epstein-Barr virus donor and recipient serostatus on the incidence of post-transplant lymphoproliferative disorder in kidney transplant recipients. Nephrol Dial Transplant. 2012;27:2971–2979.
Guidance on the microbiological safety of human organs, tissues and cells used in transplantation. London, United Kingdom: Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO), Department of Health; 2011
What is the role of EBV monitoring in this scenario?
We need to assess the risk to the recipient by reviewing the donor’s status
We suggest monitoring high-risk (donor EBV seropositive/recipient seronegative) KTRs for EBV by NAT
Monitoring NAT is recommended for high-risk KTRs (donor EBV seropositive/recipient seronegative):
• once in the first week after transplantation
• once in the first week after transplantation
EBV-seronegative patients with a rising EBV load should receive less immunosuppressive treatment.
EBV patients, including PTLD, should reduce or stop the immunosuppressive medication.
How do you manage this case?
First, I will ask about the symptoms: fever and diarrhea. Lymph node examination.
I will keep the CNI at the lower level (3-5).
close observation of the EBV and the previous symptoms.
Asymptomatic EBV load increases are common. If individuals acquire intercurrent pathogen infections while having an asymptomatic EBV load rise, such patients may be misdiagnosed with EBV illness. In such cases, only a tissue diagnosis can confirm an EBV illness.
A primary EBV infection following kidney donation significantly increases the probability of EBV illness and PTLD. A PTLD diagnosis revealed high EBV loads.
EBV load rises 4–16 weeks before PTLD, indicating patients who may benefit from intervention.
Preemptive antiviral medication for growing virus loads is controversial. Reduced immunosuppressive drug (tacrolimus) use without antiviral treatment lowered EBV PTLD risk.
Preemptive antiviral medication (e.g., acyclovir, ganciclovir) for increased or growing EBV load without immunosuppression is unproven.
References: Eckardt, K. U., Kasiske, B. L., & Zeier, M. G. (2009). KDIGO clinical practice guideline for the care of kidney transplant recipients. American Journal of Transplantation, 9, S1-S155.
1.What is the role of EBV monitoring in this scenario?
-EBV is a ubiquitus tumour virus belong to gamma herpes virus and it is associated with a variety of malignancies incluing PTLD. The gold standard diagnosis of EBV-associated malignancy is biopsy but this may not be possible many times because of the patient condition or unaccessible 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
2.How do you manage this case?
1.Evaluation:
–This patient needs further evaluation e.g.,EBV status before transplantation, the donor EBV status, CMV status for the R and D
-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: Largely depend on many findings and not only increasing EBV DNA
-Having only increase EBV DNA is a grey area
-If the initial investigations were negative and he remained symptomatic with no abnormal findings :
Do nothing
Wait & see
He is already on dual immune-suppression and reduction without clear evidence of risk might not be justified and the risk of rejection may increase
Monitor EBV DNA?
-If we got something from the investigations, then the first step would be reduction of the immune suppression and evaluate the response
Thnxs prof, my views are here but they are not necessarily correct
He is already on dual immune suppression according to the history, he does not have clear evidence of PTLD so far and raising EBV viral load is not necessarily PTLD. He needs to evaluated further
The cut off value of EBV PCR to guide us for reduction of immune suppression is not known!
Overall,this is a grey area, I may continue the current treatment without reduction of immune suppression because I donot have evidence of PTLD here.
EBV Viral load determination in the peripheral blood:
Rocchi et al (1977) was the first to suggest a relationship between PTLD and the number of EBV-infected cells in peripheral blood. Where they reported that healthy EBV-seropositive individuals had a peripheral blood count of 0.1 to 1 EBV-immortalizing unit/106 peripheral blood mononuclear cells (PBMCs). In 1994, Riddler et al reported that an abnormally elevated EBV viremia correlated with PTLD development. showed that patients with PTLD had 1000 or more EBV-immortalizing units/106 PBMC . Data from the Riddler study indicated that using semiquantitative polymerase chain reaction (PCR), patients with PTLD had a viral load greater than 5000 EBV genome copies/106 PBMC Data from two Canadian centres indicate that the negative predictive values of different levels of EBV viremia are in the region of 90% to 100%, while the positive predictive values are only 50% to 60% at best. So viral load can be used better to exclude the presence of PTLD (1) There is also conflicting data on whether a long-lasting period of high EBV load is a predictor for the later development of EBV-related PTLD. (2)
The utility of routinely performing EBV-VL in adult solid organ transplant recipients to avoid PTLD development is still debated (3)
The suspicion driven by disease symptoms and clinician experience appears to be the keystone for PTLD diagnosis and treatment (3) So the number of copies mentioned in the case needs risk assessment including CMV PCR, IS load , Clinical evaluations, laboratory tests, ultrasounds, or CT-scans of suspected organs were performed and additional investigations such as biopsy of lymph nodes and specific organs should be considered Accordingly
1- Although different guidelines define different viral load level to assess the PTLD risk, the level mentioned in the case is low so follow up for viral load monthly is advised
2- Prophylaxis against CMV
3- Patient education for the risk and importance of follow up
4- If the patient is chronic high load carrier : reduction of IS targeting TAC to trough level of <5 ng/ml and reducing MMF and evaluation viral load monthly if continued high MMF can be stopped
5- Screening for PTLD as mentioned above
6- Use of anti-viral is controversial Ref 1- Allen U, Alfieri C, Preiksaitis J, Humar A, Moore D, Tapiero B, Tellier R, Green M, Davies D, Hébert D, Weitzman S, Petric M, Jacobson K; Canadian PTLD Workshop Group – 1999. Epstein-Barr virus infection in transplant recipients: Summary of a workshop on surveillance, prevention and treatment. Can J Infect Dis. 2002 Mar;13(2):89-99
2- Ladfors, S.W., Lindahl, J.K., Hansson, S. et al. Long-lasting chronic high load carriage of Epstein-Barr virus is more common in young pediatric renal transplant recipients. Pediatr Nephrol35, 427–439 (2020). 3- Franceschini, Erica MD1; Plessi, Jessica MD1; 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. Transplantation Direct 3(7):p e182, July 2017.
1-What is the role of EBV monitoring in this scenario? –The role of EBV in the pathogenesis of PTLD among solid organ transplant recipients. EBV-positive disease; -In most affected patients, PTLD is an Epstein-Barr virus (EBV)-positive B cell proliferation occurring in the setting of immunosuppression and decreased T cell immune surveillance. EBV-negative disease; -EBV-negative PTLD has been documented in up to 30 percent of PTLD in some series. -As an example, post-transplantation primary effusion lymphoma may be associated with human herpes virus 8 (HHV-8) infection. 2-How do you manage this case? Diagnosis; -An accurate diagnosis of PTLD requires a high index of suspicion. -Radiologic evidence of a mass, or elevated serum markers (such as increased lactate dehydrogenase [LDH] levels) are suggestive of PTLD. -Positive positron emission tomography (PET) scanning also favors the diagnosis. -A tissue biopsy, preferably an excisional biopsy, with review by an expert hematopathologist, is required to ensure an accurate diagnosis. -Diagnosis of central nervous system or cardiac lymphoma is particularly difficult. Treatment of PTLD; -Management of PTLD has varied significantly according to the PTLD subtype and the type of transplant, as well as from institution to institution. -The two main goals of therapy are eradication of the PTLD and preservation of graft. -Reduction in immunosuppression (RIS); by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function. -Switch to mTOR Inhibitors; some studies have shown successful PTLD regression with sirolimus, others have shown higher incidence of PTLD with its use. -Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond adequately to RIS as initial therapy. -Rituximab is an anti-CD-20 monoclonal antibody with efficacy against CD-20 positive PTLD. -Chemotherapy;Indications of Immunochemotherapy include:
Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI. -Adoptive immunotherapy; with EBV-specific cytotoxic T cells, are generally reserved for persistent disease despite initial therapy. -Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity. -Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD. –G-CSF; is recommended for patients receiving chemotherapy. -PJP prophylaxis; should be offered to all patients with diagnosis of PTLD. –Re-transplantation; is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed. References; –European best practice guidelines for renal transplantation. Nephrol Dial Transplant 2002. -Post-Transplant Lymphoproliferative Disorder: A Clinical Perspective Nalaka Gunawansa1,2 , Roshni Rathore2,3, Ajay Sharma2,4 and Ahmed Halawa2,5*may 2019. –Randhawa PS, Jaffe R, Demetris AJ, et al. Expression of Epstein-Barr virus-encoded small RNA (by the EBER-1 gene) in liver specimens from transplant recipients with post-transplantation lymphoproliferative disease. N Engl J Med 1992; 327:1710. –Leblond V, Davi F, Charlotte F, et al. Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity? J Clin Oncol 1998; 16:2052. –Craig FE, Johnson LR, Harvey SA, et al. Gene expression profiling of Epstein-Barr virus-positive and -negative monomorphic B-cell posttransplant lymphoproliferative disorders. Diagn Mol Pathol 2007; 16:158.
What is the role of EBV monitoring in this scenario? How do you manage this case?
To answer these both questions, we need to know whether the recipient is a high risk or low risk.
For that we need to know the EBV status of donor and recipient.
The KDIGO guidelines state that
We suggest monitoring high-risk (donor EBV seropositive/recipient seronegative) KTRs for EBV by NAT (2C):
once in the first week after transplantation (2D);
then at least monthly for the first 3– 6 months after transplantation (2D);
then every 3 months until the end of the first post-transplant year (2D);
additionally after treatment for acute rejection. (2D)
We suggest that EBV-seronegative patients with an increasing EBV load have immunosuppressive medication reduced. (2D)
So, if this recipient if EBV seronegative, then we should judiciously decrease the immunosuppression an look for the viral load.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9(Suppl 3):S1–S155.
EBV load can be used for diagnosis, monitor and prevent PTLD
EBV load may be higher or increased even without appearance of symptoms and signs
should be used as a measure for the tumor burden and for early detection and prevention of progression and also can monitor the response to treatment which can be done by RIS.
high load suggest high susceptibility for development of PTLD or impending PTLD
so it allows early intervention to prevent the disease
qualitative PCR for EBV is mostly positive in immunosuppressed patients, so the quantitative PCR is more valuable
management:
1- RIS which carries the risk of graft rejection and loss, but can be done to the least trough level with normal graft function with close monitor of graft function and EBV PCR
2- infusing donor lymphocytes 3-infusing EBV-specific cytotoxic T cells that are grown ex vivo by exposing HLA-matched T cells to EBV antigens 4-infusing anti-CD20 monoclonal antibody ( rituximab)
5-traditional cancer treatment with radiation and multidrug chemotherapy
chronic high EB viral load (CHL) was defined as the presence of EBV DNA ≥ 4.2 log10 Geq/ml in whole blood, in > 50 % of the samples for ≥ 6 months as previously.
Non-CHL consisted of patients with undetectable EB viral load (UVL) and patients with low EB viral load (LVL). UVL was defined as having no more than one sample of detectable EBV DNA levels following transplantation, and low EB viral load (LVL) included patient not meeting criteria for UVL nor CHL.
Margaret L. Gulley,Weihua Tang. Using Epstein-Barr Viral Load Assays To Diagnose, Monitor, and Prevent Posttransplant Lymphoproliferative Disorder. Clin Microbiol Rev. 2010 Apr; 23(2): 350–366.
What is the role of EBV monitoring in this scenario?
How do you manage this case?
This patient is R+, donor status is not known
Algorithm D-/R+, D+/R+
Do Monthly EBV PCR for 3 months
Then Three monthly until 1 year
If
Titres > 1000 copies/ml Or > 620 IU/ml Reduce IS (MMF/Aza/Tac/CyA)
Check titres 2 weeks later
Titres increasing– Arrange CT scan Head/Neck/Chest/Abdomen/Pelvis to rule out PTLD even if patient is asymptomatic. PET should be considered
PTLD on CT- Refer to Haematology. Patient managed at multidisciplinary level with transplant nephrologists.
If titres are decreasing, monitor PCR fortnightly
In the index case He is on CNI-based double immunosuppression with excellent kidney function. His EBV viral load increased from 200 copies/ml prior to the operation rose to 740 copies/ml 6 months after transplantation.so will keep monitoring his EBV PCR monthly to look for increasing or decreasing trend.If EBV PCR goes above 1000 will reduce his MMF first and recheck and if still increasing then will decreae his CNI to achieve lower level of therapeutic target for the month post transplant.
To monitor the risk of increasing EBV titers.
Management
If there is a rise in EBV titers we must evaluate the primary intervention by rreducing immunosuppression to decrease the risks of PTLD . The secondline of management is the screnning for PTLD for early diagnosis and management.
I will keep monitoring the EBV titre and try to minimise the immunosuppressive medication to make him secure from the risk of PTLD
What is the role of EBV monitoring in this scenario?
The role of EBV monitoring in this scenario is crucial in the detection and management of post-transplant lymphoproliferative disorders (PTLDs), which are severe complications that can arise in both hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT) due to immunodeficiency. PTLD is characterized by the presence of altered B-cell lymphocytes, often infected with Epstein-Barr virus (EBV). The incidence of PTLD varies depending on the type of organ transplanted, with rates ranging from 5% to 20% for intestinal and multiorgan transplants, and 2% to 10% for lung and heart transplants. Among renal transplant recipients, the incidence of PTLD is relatively lower, affecting approximately 1% to 5% of patients at risk.
Monitoring EBV DNA levels using quantitative PCR-based detection methods plays a crucial role in the early diagnosis of PTLD and can serve as an indirect means of identifying patients at risk and monitoring their response to therapy. However, there are certain challenges associated with interpreting preemptive EBV PCR monitoring results. These challenges include the lack of a defined cutoff value for result interpretation, uncertainty about the optimal timing for conducting the monitoring, and variations in the sources of samples used for testing.
Recent reports suggest that measuring cell-free plasma EBV DNA levels may provide a more accurate indication of EBV activity and help in monitoring the progression of PTLD. Additionally, higher plasma EBV loads at the time of diagnosis have been associated with poorer outcomes and increased mortality rates, indicating that cell-free EBV DNA levels can also have prognostic value in assessing the severity and prognosis of PTLD cases.
How do you manage this case?
According to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, high-risk kidney transplant recipients (KTRs) with a donor who is EBV seropositive and a recipient who is seronegative should be monitored for EBV using nucleic acid testing (NAT). The recommended monitoring schedule includes testing once in the first week after transplantation, then at least monthly for the initial 3 to 6 months post-transplant, followed by testing every 3 months until the end of the first year, and additionally after treatment for acute rejection.
In cases where EBV-seronegative patients show an increasing EBV load, a reduction in immunosuppressive medication should be considered. If EBV disease, including PTLD, is diagnosed, a reduction or cessation of immunosuppressive medication may be warranted. Further investigations, including the use of tissue biopsies, a multidisciplinary team (MDT) approach, modifications to mTOR inhibitors, and the utilization of specific drugs such as rituximab, is necessary to advance the treatment strategies for PTLD.
● EBV load, as measured by quantitative molecular analysis of the viral genome, serves as a biomarker for predicting and monitoring the course of PTLD .
● And it becomes a routine test for monitoring transplant recipients at high risk of PTLD or under therapy for PTLD.
● PTLD patients nearly always have high levels of EBV DNA in whole blood and in plasma
● Receiver operator characteristic (ROC) curve analysis showed sensitivity and specificity values of 100% and 86% for PTLD using a cutoff of 2,000 copies/μg, 100% and 90% for 3,000 copies/μg, and 67% and 94% for 5,000 copies/μg.
● For redicting PTLD with greater accuracy, some investigators suggest calculating a mean viral load over time instead of using a single cutoff value.
● Rituximab was given when the EBV load exceeded 10,000 copies per ml of serum or when symptoms suggested EBV disease
● Preemptive therapy may include reducing immunosuppression and infusing anti-CD20 antibody or donor T cells
● Routine monitoring of EBV load in high-risk patients can help identify PTLD before signs and symptoms appear .
◇ In this case monitoring of the EBV titre is the best choice . No need for C.T or starting preemptive therapy or reduction of immunosuppression therapy.
References:
.
Margaret L. Gulley and Weihua Tang .Using Epstein-Barr Viral Load Assays To Diagnose, Monitor, and Prevent Posttransplant Lymphoproliferative Disorder . Clin Microbiol Rev. 2010 Apr; 23(2): 350–366.
Improving Global Outcomes guidelines suggest monitoring high-risk kidney transplants (donor EBV seropositive and recipient EBV seronegative) for EBV by nucleic acid PCR after on regular frequent basis especially close to transplantation (the first week, monthly for the first 3 to 6 months, then every 3 months until the end of the first posttransplant year) and particularly after treatment for acute rejection.
Management
Viral load of EBV is only significant for values of 4000 copies/mL, other studies suggested 1000 copies/mL.
Provided there are no symptoms in the form of fever, cytopenia, night sweats, and lymphadenopathy with low detected levels.
The principle management is reduction of immunosuppression if EBV confirmed, better to stop antimetabolites as MMF and to switch from CNI to mTORi.
Multidisciplinary team including infectious diseases specialist expert along with transplant specialist.
the answer is monitoring the EBV TITER
EBV monitoring according to KDIGO guidelines is recommended for the first week, then monthly for 3 months, and then every 3 months for the remainder of the first year.
However, this case is not a high-risk recipient for EBV because both donor and recipient (D+/R+) are positive and have no DSA, half match kidney with negative FCXM, and no rejection. In this case, as the EBV copy number is low, there is no need for more evaluation or treatment. Following KDIGO guideline is OK.
What is the role of EBV monitoring in this scenario?
Transplant recipient, with 111 mismatch, good graft function on dual immunosuppression.
EBV viral load was monitored and in increased from 200 copies/ml to 740 copies/ml at 6 months post-transplant.
No clinical symptoms or signs of active infection
No data about induction thereby
No data about serostatus of the donor nor the recipient before transplantation.
Improving Global Outcomes guidelines suggest monitoring high-risk kidney transplants (defined as donor EBV seropositive and recipient EBV seronegative) for EBV by nucleic acid testing 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.
In contrast with the guidelines, a recent survey published by the European Study Group of Infections in Compromised Hosts showed that EBV-VL measurements are frequently used in Europe to guide both the diagnostic workup and the reduction of immunosuppression in solid organ transplants.
EBV monitoring is routinely used in 86% of the transplant programs; in particular, 38% of renal transplant centers perform EBV-VL surveillance in all recipients, independently from the EBV risk evaluation.
77% perform preemptive treatments for patients with high-risk EBV DNAemia levels such as the reduction of immunosuppression (50.9%), and the conversion to mammalian target of rapamaycin inhibitors (mTORi) (30.9%).
In the index case due incomplete data about serostatus of donor and recipient we might assume that the donor was positive and the recipient was negative
How do you manage this case?
EBV DNAemia levels considered to be significant for PTDL vary between centers.
Some studies mentioned , the value of 4000 copies/mL other studies mentioned 1000 copies/mL .
In this case scenario level increased from 200 to 750 which is below cut off , (which is expected within the first year),with no symptoms so just wait and keep monitoring of viremia.
Management would be required in case of signs and symptoms suggesting EBV-related disease or primary infection (fever, cytopenia, night sweats, and lymphadenopathy), or in patients considered at major risk of viral reactivation by the clinicians (eg, increased immunosuppression, human immunodeficiency virus) or viremia reached the cut-off of the center by reduction.
Management mainly by in immunosuppression , or better to shift to mTORi as he is on dual immunosuppression.
EBV-VL assays may be avoided in low-risk patients/period in the absence of a strong clinical PTLD suspicion without increasing patients’ risk of developing the disease. This represents a safe and cost-saving clinical strategy .
References:
Erica Franceschini, MD,1 Jessica Plessi, MD,1 Stefano Zona,.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 Jul; 3(7): e182.
What is the role of EBV monitoring in this scenario?EBV monitoring is not routinely done unless the donor is EBV positive to a seronegative recipient. It is performed in the first week then montly in first 3 month then every 3 months. Till the end of the first year and also at time of rejection episodes. There is no universal cut off point for the viral load to point toward patients at increased risk for PTLD. However, cut off> 1000 copies/ml appear to be significant
How do you manage this case?In this index case, it appears from the monitoring that the donor was EBV (+) and the recipient is (-). However, this patient is asymptomatic (need to confirm absence of night sweats, fever, and weight loss) and his viral load did not reach the cut-off point. So, we need only to continue monitoring of the viral load to early identify patients in whom intervention can prevent development of PTLD.
If the patient became symptomatic or reached the cut-off value then management is by reduction in immunosuppression especially CNI and MMF (no clear guidelines for that). In this patient, he is only on dual immunosuppression and has 3 mismatches. So, such reduction need to be done cautiously to avoid rejection episodes.
References:
Allen UD, Preiksaitis JK; AST Infectious Diseases Community of Practice. Post-transplant lymphoproliferative disorders, Epstein-Barr virus infection, and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep; 33(9):e13652.San-Juan R, Manuel O, Hirsch HH, Fernández-Ruiz M, López-Medrano F, Comoli P, Caillard S, Grossi P, Aguado JM; ESGICH PTLD Survey Study Group,; European Study Group of Infections in Compromised Hosts (ESGICH) from the European Society of Microbiology and Infectious Diseases (ESCMID). Current preventive strategies and management of Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplantation in Europe. Results of the ESGICH Questionnaire-based Cross-sectional Survey. Clin Microbiol Infect. 2015 Jun; 21(6):604.e1-9.Kimura H, Ito Y, Suzuki R, Nishiyama Y. Measuring Epstein-Barr virus (EBV) load: the significance and application for each EBV-associated disease. Rev Med Virol. 2008 Sep-Oct; 18(5):305-19.
PTLD displays highly variable patterns of incidence in kidney transplant recipients, with peaks in the first year and subsequently in the latter post-transplantation period. More than 90% of B cell PTLD that develop within the first year of transplantation includes the EBV genome. Hence, EBV monitoring is used to prevent PTLDs. There is considerable disagreement surrounding routine EBV viral load in adult SOT recipients to prevent the onset of PTLD. In practice, the majority of European doctors frequently use EBV viral load to direct both diagnostic workup and preventive medication, despite international guidelines advocating EBV-VL surveillance only in high-risk patients.
KDIGO guidelines recommend monitoring for EBV after transplantation in high risk recipients, once in the first week, monthly for the first 3 to 6 months, then every 3 months until the end of the first post-transplant year, as well as following treatment for acute rejection.
Immunosuppressive medicine, particularly antimetabolite medications, should be lowered in patients with increasing viral loads over the screening period, especially in EBV-seronegative patients, with subsequent monitoring of viral load.
Not all patients with high EBV virus loads develop PTLD. However, rising viral load in the presence of clinical picture Because of the aforementioned factors, PTLD assessment should be aggressive when clinical PTLD signs are present. Any unexplained febrile infections in a SOT recipient should raise the possibility of PTLD, especially if they occur within the first year after transplantation, in particular in patients who received potent induction and maintenance immunosuppression.
· How do you manage this case?
In the patient with low risk for rejection, having negative DSA, FCXM and 111 mismatch, the initial step in this approach is to reduce immunosuppression and followup in viral load.
Patient should be asked about specific symptoms related to PTLD. Screening for PTLD in high risk patients (SEROPOSITIVE TO SERONEAGTIVE) is indicated when clinically indicated.
The answer for Question,
A. true,
B. false,
C. false,
D. false.
E. false.
What is the role of EBV monitoring in this scenario?
While many transplant recipients demonstrate a modestly increased EBV viral load in the peripheral blood post-transplant, the vast majority of patients with EBV-positive PTLD will demonstrate a more marked elevation in the EBV viral load. As an example, in one study, plasma from patients with PTLD had a median EBV viral load of 3225 copies/100 microL, while immunosuppressed controls without evidence of PTLD had fewer than 740 copies/100 microL.While an increased EBV viral load is suggestive of PTLD, the diagnosis of PTLD is based on the histologic evaluation of a tissue biopsy.
Managment-
With no sign and symotoms of PTLD in this case,i will repeat EBV PCR after 2 to 3 weeks to check for increasing /decreasing trend.If it is increasing trend ,i will decrease immunosuppression.Increasing value is more commonly associated with PTLD rather than any absolute value.
The role of monitoring is to monitor the risk of increasing EBV titers.
If there is an increase in EBV titers, evaluate the primary intervention, which is the reduction of immunosuppression in order to reduce the risks of PTLD.
If this is not enough, I would start screnning for PTLD in an attempt at an early diagnosis.
What is the role of EBV monitoring in this scenario?
The serology status of both the donor and recipient must be known before transplantation.
There’s no consensus about the cut off value of viral load to be considered significant.
As the incidence of PTLD is higher during the first year post transplantation, so EBV monitoring done after the first week , then monthly for the first 3 months, and every 3 months for the rest of the year.
How do you manage this case?
If the viral load is increasing rapidly with the presence of symptoms, so reducing IS is the main for treatment, if the viral load still increasing we can switch CNIs to mTORi.
Also adoptive immunotherapy has a role in the treatment.
Reference
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Fedaey Abbas, Mohsen El Kossi, Ihab Sakr Shaheen, Ajay Sharma, Ahmed Halawa
World J Transplant 2020 February 28; 10(2): 29-46
What is the role of EBV monitoring in this scenario?
EBV DNA viral load (quantitative PCR) is used to diagnose PTLD, and also to monitor therapeutic response.
It has been observed that transplant recipients with very high EBV viral load are more prone to the develop PTLD.
The index case, has rising EBV viral load from 200copies to 740 copies within 6 months post-transplant, is a point of concern to decide about pre-emptive treatment.
Higher viral load invites more risk for PTLD evolution.
In a study, median plasma EBV DNA level from patients with PTLD was 3225 copies/ml, while immunosuppressed controls without PTLD had fewer than 740 copies/ml.
EBV viral load for PTLD in SOT has shown a positive predictive value of (28%-100% and negative predictive value of 75%-100%, with “cell-free plasma EBV DNA” been reported as better marker of EBV activity.
However, pre-emptive EBV PCR monitoring has following limitations –
1. No clear cut off value for interpretation.
2. sources of samples are not universal
3. absence of usual points of time to do the monitoring
How do you manage this case?
References
Kdiqo suggest monitoring high-risk kidney transplants (defined as donor EBV
seropositive and recipient EBV seronegative) for EBV by nucleic acid testing 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.
This normal level no need for alteration of immunosuppression or drugs therapy.
References:
1. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIQO
clinical practice guideline for the care of kidney transplant recipients. Am J Transplant.
2009;9(Suppl 3):S1–S155.
Firstly, seropositive status of the donor and the recipient should be known. Literature review revealed no cut off limit of EBV viral load for high risk patients i.e., EBV negative recipients with EBV positive donors and values vary from center to center. Monitoring of EBV viral load should be done in the first week, then monthly for 3 months, and then 3 monthly up to first year post-transplant to detect and diagnose PTLD early as high load suggest PTLD. In low risk cases, no need for monitoring.
After taking detailed history and examination and checking the seropositive status of the donor and recipient, investigations like CBC, LDH,LFTs ,RFTs, Serum calcium uric acid and serum protein electrophoresis and urinalysis should be done to rule out PTLD. If excluded the just close monitoring of viral load and timely detection of acute rejection and PTLD for early intervention is must.In the above case ,only monitoring is needed and if viral load continued to rise ,then reduction of immunosuppression should be done and if become symptomatic,then treatment of PTLD and switching of CIs to mTORi is must
REFERENCES:
1-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
2- Marieke L Epstein-Barr Virus–Positive Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation: Pathogenesis, Clinical Manifestations, Diagnosis, and Management, Transplantation Direct 2016;2: e48
EBV monitoring is not routinely done unless the donor is EBV positive to a seronegative recipient. It is performed in the first week then montly in first 3 month then every 3 months.
No clear cut off point of the exact viral load to be a high risk for PTLD but 100 copies per ml may be a cut off value
If the patient is asymptotic or didn’t reach cut off value so just monitoring of viral load is recommended.
If symptomatic or reached cut off value then management with decrease immunosuppression especially CNI and MMF with minimal dose steroids or even start antiviral medications.
– The role of EBV monitoring in this case:
This patient is not a high risk because he was EBV positive before renal transplantation, therefore routine monitoring is not recommended as long as suspicion of active clinical infection is not present.
2- Management:
-full evaluation to exclude PTLD
-reduce IS (stop MMF and reduce CNI 30-50%) and
monitor response after 2-4 weeks, monitor for rejection.
Kdiqo suggest monitoring high-risk kidney transplants (defined as donor EBV
seropositive and recipient EBV seronegative) for EBV by nucleic acid testing 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.
This normal level no need for alteration of immunosuppression or drugs therapy.
References:
1. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIQO
clinical practice guideline for the care of kidney transplant recipients. Am J Transplant.
2009;9(Suppl 3):S1–S155.
In this case, the answer is A as we need to observe the viral load; as we all know that in the early post-transplant period, there is a mild elevation in the number of copies of EBV, especially in the first 3-month post. No action needs further at this stage.
If we suspect PTLD with positive EBV, the viral load is expected to be sky-high, .but in this case, with mild elevations of EBV copies could be related to IS effect.
Just observe.
Just follow the viral load in an asymptomatic patient, as he has CPVL.
In case the viral load exceed 1000 copies /ml , then it will need for further workup
references
Porf Halalwa lectuers
EBV negative recipients are high risk of getting PTLD
our patient is EBV positive
ANSWER is A
EBV COPIES NEED TO BE MONITERED
CT scan is advised if symptomatic
Reduction of IS is the first response for PTLD and not for rise of EBV
Chemotherapy is overkill
the keystone of PTLD diagnosis is the clinical suspicion. Our study suggests that, in line with guidelines, EBV-VL assays may be avoided in low-risk patients in the absence of a strong clinical PTLD suspicion without increasing patients’ risk of developing PTLD. This represents a safe and cost-saving clinical strategy .
The more recent American Society of Transplantation guidelines state that there are data to support 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.
In contrast with the guidelines, a recent survey published by the European Study Group of Infections in Compromised Hosts showed that EBV-VL measurements are frequently used in Europe to guide both the diagnostic workup and the reduction of immunosuppression in solid organ transplants.
EBV DNAemia levels considered significant can vary between centers. In our study, the value of 4000 copies/mL has been chosen based on literature data evaluating such a threshold as a risk factor for PTLD onset.
Reference
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
Erica Franceschini, MD, Jessica Plessi, MD, […], and Cristina Mussini, MD
As the patient is asymptomatic, only EBV viral load monitoring is needed till establishment of the state of chronic viral load phenotype(set point);considering the viral load is not more than 1000 copies/ml
Monitoring after the first year is indicated if there is rejection episode, the IS is changing, or if the viral set point has not achieved.
Serial EBV viral load monitoring late following transplant with reaching the set point and pre-emptive interventions like reduction in IS is not routinely indicated.
A: true…B,C,D,D:False.
Reference:
The given scenario is a 24 year old CKD % patient who received a kidney from his brother 8 months ago… There is haplomatch, no DSA and Negative FCXM….IL2 receptor antibody would have been the induction agent of choice in him and ATG would not have been used in view of low risk transplant….
He is currently on double immunosuppression with excellent kidney function…. He had EBV DNA before transplant and it had increased to 740 copies/ml 6 months after transplantation….
EBV monitoring is usually not justified unless there are few indications… This patient is EBV Positive Recipient who received a kidney, so theoretically the risk is low…The patient also is a low risk patient with no rejection and no additional immunosuppressants like ATG were received….
The only risk factor for development of PTLD in this patient is the relative young age…
Patient needs annual or 6th monthly monitoring of EBV viral load after renal transplant….
There is no role for reducing immunosuppression as there is no symptomatic EBV infection now, no need for chemotherapy, no need for further imaging also
KDIGO guidelines do recommend monitoring for EBV DNA Plasma within the first week after transplant followed by monthly monitoring for the next 3 to 6 months and then once in 3 months.. They also recommend to monitor after the treatment of acute rejection… .
PTLD cannot be diagnosed by EBV monitoring alone..It needs tissue diagnosis along with symptoms and positive EBV IgM or EBV DNA
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.
What is the role of EBV monitoring in this scenario?
EBV monitoring can guide us in planning investigations and diagnostic workup in solid organ transplant recipients. In this case EBV was positive pre transplant but showed a surge in viral load post transplant. The load was 740 copies /ml which is quite below crucial level of 4000 copies/ml. EBV has significant role in development of PTLD. EBV viral load monitoring by EBV PCR is required in first year in high risk patients.
How do you manage this case?
No specific treatment is required except monitoring of EBV PCR. This case is a high risk for EBV infection. He will need monitoring by EBV PCR. It should be done weekly in first month, then monthly for next three months. Following that it should continue 3 monthly till first year is complete.
If symptoms develop or There is rising trend of EBV PCR levels, then further testing like imaging or biopsy will be needed.
If PTLD develops then reduction of immune suppression will be required. We can switch from CNI To mTORi. Severe or resistant cases may require chemotherapy.
Gulley ML, Tang W. Using Epstein-Barr viral load assays to diagnose, monitor, and prevent posttransplant lymphoproliferative disorder. Clin Microbiol Rev. 2010 Apr;23(2):350-66.
OUR CASE;
ROLE OF EBV MONITORING.
MGT OF THIS CASE.
REF;
What is the role of EBV monitoring in this scenario
Use monitoring of viral loads to help follow the clinical course of patients with established PTLD
How do you manage this case?
A small increase in viral levels may be associated with PTLD Follow up with viral monitoring
References :
M.A. Bingler, B. Feingold, S.A. Miller, M.G. Michaels, M. Green, R.M. Wadowsky, D.T. Rowe, S.A. Webber.
Chronic high Epstein–Barr viral load state and risk for late-onset posttransplant lymphoproliferative disease/lymphoma in children.
Am J Transplant, 8 (2008), pp. 442-445
http://dx.doi.org/10.1111/j.1600-6143.2007.02080.x | Medline
5. A 24-years old CKD 5 received a kidney from his brother 8 months ago. 111 mismatch, no DSA and negative FCXM. He is on CNI-based double immunosuppression with excellent kidney function. His EBV viral load increased from 200 copies/ml prior to the operation rose to 740 copies/ml 6 months after transplantation.
Issues/ concerns
– 24yo, CKD5, kidney transplant 8months ago
– donor brother, 111 mismatch, no DSA, negative FCXM
– CNI-based dual immunosuppression, excellent kidney function
– EBV viral load increased from 200copies/ml (pretransplant) to 740copies/ml (6months post-transplant)
What is the role of EBV monitoring in this scenario?
– EBV infection is associated with an increased risk of PTLD post-kidney transplant
– the EBV serostatus pre-transplant is essential in risk-stratification of transplant pairs
– EBV D+/ R- transplant pairs have the highest risk
– EBV viral load monitoring is done to evaluate patients for PTLD and allow for preemptive treatment if there is evidence of viral reactivation
– PTLD is a serious and fatal complication of chronic immunosuppression in SOT resulting in outgrowth of EBV positive cell proliferation
– therefore, EBV viral load monitoring is essential for early detection of PTLD in high-risk patients, this helps avert the poor outcomes
– risk factors for development of PTLD: degree of overall immunosuppression, recipient’s EBV serostatus, time post-transplant
– prevention of PTLD: limit aggressive immunosuppressive therapy, taper and withdraw immunosuppression appropriately, offer antiviral prophylaxis
How do you manage this case? (1-4)
– multidisciplinary approach: oncologist
– diagnosis requires a high index of suspicion
– baseline investigations: CBC, UECs, LFTs, Tacrolimus trough levels, LDH, HIV Ab, HBsAg, HCV Ab, EBV PCR, CMV PCR, graft ultrasound, ECHO (for patients with cardiac disease)
– monitor the EBV PCR viral load
– assess for any radiological masses – CT Chest, CT Abdomen and pelvis, PET scan, Brain MRI and CSF analysis (if there is CNS involvement)
– BMA (in patients with cytopenias), tissue biopsy
– PTLD management: –
– this patient can be considered as a high-risk patient given the 111 mismatch, rising viral load hence it would be prudent to monitor his EBV PCR viral load
– if there is a sustained rise in the viral load then we can consider a reducing his immunosuppression as we closely monitor his graft function
References
1. Allen U, Hébert D, Moore D, Dror Y, Wasfy S. Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplant recipients, 1988-97: a Canadian multi-centre experience. Pediatric transplantation. 2001 Jun;5(3):198-203. PubMed PMID: 11422823. Epub 2001/06/26. eng.
2. Straathof KC, Savoldo B, Heslop HE, Rooney CM. Immunotherapy for post-transplant lymphoproliferative disease. British journal of haematology. 2002 Sep;118(3):728-40. PubMed PMID: 12181039. Epub 2002/08/16. eng.
3. 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.
4. 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.
Role of EBV monitoring
A risk factor for the development of PTLD is primary EBV infection. Since PTLD shows poor prognosis, early diagnosis is crucial. A suitable parameter for monitoring is needed for this.
The recipients at greatest risk of PTLD are those who were EBV-negative and received EBV-positive donor organs. Such patients have to be monitored closely for the development of EBV disease after transplantation since EBV viremia > 4000 EBV genome copies is associated with PTLD.
Management of this case
Most often healthy transplant recipients may demonstrate a modest increase in EBV viral load after transplantation. For this case, we must continue to further monitor the level of viraemia.
EBV prophylaxis ought to be initiated with acyclovir or preferably ganciclovir.
If the threshold of 1000 copies is exceeded, immunosuppression may be reduced keeping CNI levels at the lowest acceptable levels.
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;9(Suppl 3):S1–S155.
Regarding this case, CHOOSE one or more of the following options:
A. Monitor the EBV titre.
B. CT chest, abdomen, and pelvis.
C. Reduce immunosuppression.
D. Start chemotherapy.
E. All the above
Answer is A.
It would be beneficial to monitor EBV loads monthly for this patient and reduce immunosuppression if the load exceeds the critical limit of 1000 copies.
· What is the role of EBV monitoring in this scenario?
· EBV is responsible for 90% of early onset PTLD that develop during first year post transplantation and KDIGO guidelines recommend regular monitoring of EBV in high risk recipient ( EBV positive donor to negative recipient ) once during first week posttransplantation , monthly for 3 months then every 3 month till end of first year aiming at early detection of EBV reactivation and DNAemia and in this case preemptive intervention with decreasing doses of IS or switch to m TOR can decrease the risk of PTLD development. Many transplantation centers recommend regular monitoring of EBV for both high and standard risk (as this patient) recipients. In this index case, he was EBV positive before transplantation with increasing the level of EBV DNA and as there is no cut off value for EBV DNA to initiate treatment ,so decision to use chemotherapy and retuximab will depend on presence of PTLD.
· How do you manage this case?
1- Risk assessment including
a- Presence of associated HIV .
b- If he was symptomatic or not , presence of fever,lymphadenopathy or cytopenia.
c- Screening for PTLD.
2- Frequent monitoring of EBV DNA level .
3- Reduce IS doses with close monitoring of graft function.
Ref:
1- Al-Mansour Z, Nelson BP, Evens AM. Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep. 2013 Sep;8(3):173-83. doi: 10.1007/s11899-013-0162-5. PMID: 23737188; PMCID: PMC4831913.
2- 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)
What is the role of EBV monitoring?
How do manage this case?
EBV is ubiquitous in the general population and may cause an asymptomatic presentation in the immunocompetent host.
In kidney transplant recipients it has a bimodal peak, in the first year post-transplant then later.
EBV genome is found in 90% of PTLD occurring in the first year post-transplant while those that occur later 45% are EBV negative.
Kidney transplant recipients are at risk of viral reactivation due to use of IS.
KDIGO recommends monitoring high risk recipients (D+/R-) once in the first week, monthly for the first 3-6 months, then 3 monthly until one year and after treatment for acute rejection.
KDIGO also recommends reduction of IS in EBV seronegative individuals with a rising viral load.
Thus EBV VL load are used to guide diagnostic workup and reduce IS.
This scenario the recipient was EBV seropositive prior to transplant and the VL has been slowly rising post-transplant. The use of EBV monitoring in this scenario is controversial since this patient is not a high risk individual as per the KDIGO guidelines.
A study conducted in one transplant centre showed that the use of EBV VL monitoring in low risk patient had reduced utility and could be avoid in the absence of clinical presentation suspicious for PTLD.
Thus in this case doesn’t warrant any treatment as per now, though the VL is rising it is still below the threshold of 4000copies/ml. Thus only warrants monitoring of VL.
References
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
KDIGO clinical practice guideline for the care of kidney transplant recipients.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group
case summery is
recent living related kidney transplant just 8 months post-transplant
immunological risk is low as haplotype matching and No DSA and FCXM is negative
maintained on dual immunosuppression with no clear history regarding induction
now during follow up there is increase in the viral load of EBV
data missed in this scenario is
1-induction therapy (depleting induction?)
2-pretransplant viral immunological status of both donor and recipient (D+ve to R -ve?)
3-kind of test used to detect EBV viral load (cell free EBV plasma DNA)
4-Primary kidney disease of the recipient (GN and he received multiple immunosuppression before transplant?)
to take it briefly there is NO universal agreement regarding monitoring of EBV viral load in all patients post-transplant as no there is no cutoff of treatment, agreement regarding best test for detection and timing for monitoring and this practice usually limited to high risk group who are heavily immunosuppressed or at high risk of developing PTLD post-transplant.
suppose that this patient is high risk so monitoring will be of value for
· she will need to be maintained on low dose of immunosuppression which may expose her to risk of rejection
· early detection of PTLD and treatment
· regarding use of antiviral treatment for prophylactic (no virus detected) or treatment (viral load detected) of week evidence.
· regarding use of rituximab as prophylactic for PTLD of week evidence
How to manage
considering this case high risk patient frequent monitoring till stable level is achieved (chronic viral load phenotype CVLP) with regular clinical examination of patients LN on regular intervals. If CVLP not achieved and PCR is progressively increasing then modification of immunosuppression maybe needed after counselling patient about risk of rejection
References:
⭐The index case is high risk for EBV infection (D+/R-), so frequent monitoring of EBV PCR is essential (done weekly in 1st month, then monthly for 3 months then every 3 months for the remaining months in 1 st year).
.⭐ As regard the managemnt of the case:
_Till now, no further mangemnet is needed rather than follow up Of EBV PCR titer.
_Further FU of the trend of rising titre of viral PCR or appearance of symptoms as fever malaise, fatigue , cytopenias or lymphadenopathy will indicate further imaging and tissue biopsy.
_once diagnosis of EBV Related PTLD is confirmed …reduction of IS or shift from CNI to mTORi.is indicated
_Resistent cases may require additional chemotherapy.
👉 The index case is high risk for EBV infection (D+/R-), so frequent monitoring of EBV PCR is essential (done weekly in 1st month, then monthly for 3 months then every 3 months for the remaining months in 1 st year).
👉 as regard the managemnt of the case:
_Till now, no further mangemnet is needed rather than follow up Of EBV PCR titer.
_Further FU of the trend of rising titre of viral PCR or appearance of symptoms as fever malaise, fatigue , cytopenias or lymphadenopathy will indicate further imaging and tissue biopsy.
_once diagnosis of EBV Related PTLD is confirmed …reduction of IS or shift from CNI to mTORi.is indicated
_Resistent cases may require additional chemotherapy.
What is the role of EBV monitoring in this scenario?
EBV monitoring is achieved to guide both the diagnostic workup and the reduction of immunosuppression in solid organ transplants. In this scenario of KT at 8 months, the EBV was positive in the pre-transplant period and the EBV-VL showed exacerbation in the post-transplant period. Although the VL not reaching the significant threshold(> 4000 copies/ml), EBV monitoring is still crucial as the patient in the first-year post-transplant.
Epstein Barr virus (EBV) plays a major role in PTLD development, which is an important cause of morbidity and mortality in solid organ transplants. Guidelines recommend EBV viral load (VL) monitoring in high-risk populations in the first year. In line with guidelines, EBV-VL assays may be avoided in low-risk patients in the absence of a strong clinical PTLD suspicion without increasing patients’ risk of developing PTLD. This represents a safe and cost-saving clinical strategy(1).
1. Kidney Disease: Improving Global Outcomes guidelines suggest monitoring high-risk kidney transplants (defined as donor EBV seropositive and recipient EBV seronegative) for EBV by nucleic acid testing 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.
2. Kidney Disease: Improving Global Outcomes guidelines recommend reducing immunosuppressive medication in EBV-seronegative patients with an increasing EBV viral load (VL) and in patients with EBV disease, including PTLD.
3. American Society of Transplantation guidelines state that there are data to support 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.
4. In contrast with guidelines, the European Study Group of Infections in Compromised Hosts showed that EBV-VL measurements are frequently used in Europe to guide both the diagnostic workup and the reduction of immunosuppression in solid organ transplants.
· EBV monitoring is routinely used in 86% of the transplant programs.
· 38% of renal transplant centers perform EBV-VL surveillance in all recipients, independently from the EBV risk evaluation.
· 77% perform preemptive treatments for patients with high-risk EBV DNAemia levels such as the reduction of immunosuppression (50.9%), and the conversion to mammalian target of rapamaycin inhibitors (mTORi) (30.9%). Up to 14.5% had used rituximab for this indication and 7.3% reported the use of immune- adoptive T cell therapy.
5. EBV DNAemia levels considered significant can vary between centers. The value of 4000 copies/mL has been chosen based on literature data evaluating such a threshold as a risk factor for PTLD onset.
6. The suspicion driven by disease symptoms and clinician experience appears to be the keystone for PTLD diagnosis and treatment.
How do you manage this case?
The index case is a KTR, having EBV infection with exacerbating EBV-VL from 200 copies/ml to 740 copies/ml.
1. The patient didn’t complete the first-year post-transplant and there’s an exacerbating VL, so monitoring of EBV-VL for this patient is indicated.
2. Being asymptomatic and with VL below 4000 copies/ml, nothing else is needed other than monitoring.
3. If the patient is symptomatic or with high suspicion of PTLD, adjustment of immunosuppression should be achieved.
4. If the diagnosis of PTLD is established, the followings are deserved to be accomplished: reduction of immunosuppression, shifting to mTORi, RTX +/- chemotherapy and adaptive immunotherapy.
References
1. Franceschini, Erica MD1; Plessi, Jessica MD1; Zona, Stefano MD1; Santoro, Antonella MD1; Digaetano, Margherita MD1; Fontana, Francesco MD2; Alfano, Gaetano MD2; Guaraldi, Giovanni MD3; Comoli, Patrizia MD4; Facchini, Francesca MD2; Potenza, Leonardo MD, PhD5; Gennari, William MD6; Codeluppi, Mauro MD1; Luppi, Mario MD, PhD5; Cappelli, Gianni MD2; Gyssens, Inge C. MD, PhD7,8; Mussini, Cristina MD3. 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. | DOI: 10.1097/TXD.0000000000000703
2. 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.
View Full Text | PubMed | CrossRef
Thanks
25 year, his EBV load increased from 200 pre ml to 740, 6 months after Tx.
What is the role of EBV in monitoring this scenario?
Some transplant units’ monitor the EBV viral load post transplantation. However, there is little evidence to guide this strategy and there is no agreement whether to use a blood sample or a plasma one. Or what clinical action to take if EBVDNA viremai is detected, an ongoing trial EVITA is trying to answer these questions.
How would you manage this case?
· KDIGO guidelines suggest monitoring high-risk kidney transplants (defined as donor EBV seropositive and recipient EBV seronegative) for EBV by nucleic acid testing 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 post-transplant year, and after treatment for acute rejection.
· American Society of Transplantation guidelines state that there are data to support quantitative EBV-VL monitoring for PTLD prevention only in high-risk populations in the first year.
· In Europe EBV-VL measurements are frequently used to guide both the diagnostic workup and the reduction of immunosuppression in solid organ trans- plants.
· In Europe some perform preemptive treatments for patients with high-risk EBV DNAemia levels such as the reduction of immunosuppression, and the conversion to mammalian target of rapamaycin inhibitors. Some had used rituximab for this indication and others reported the use of immune- adoptive T cell therapy.
· The value of 4000 copies/mL EBV DNAemia threshold is used as a risk factor for PTLD onset.
· We should first determine the risk of recipient as he is considered negative for EBV (positive if more Than 400 copies per ml), by checking the pre-transplant donor viral status.
· If the donor was positive, then he is at high risk of developing post- transplant viral replication.
· We would monitor his viral load according to the current guidelines.
· Important is to follow him for the development of clinical EBV infection, infectious mononucleois and involvement of organ specific involvement.
· For EBV-related localized extranodally PTLD (most common) and lymphadenopathy and B-symptoms.
References:
1. Erica Franceschini, 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 2017;3:e182
2. Marieke L Epstein-Barr Virus–Positive Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation: Pathogenesis, Clinical Manifestations, Diagnosis, and Management, Transplantation Direct 2016;2: e48.
Thanks
· What is the role of EBV monitoring in this scenario?
Monitoring of EBV viral load is recommended for high risk patient ( seropositive donor to seronegative recipient) to detect EBV viremia early and intervene early before development of PTLD.
· How do you manage this case?
Detailed history of recipient presenting complaints, EBV sero status for recipient and donor, induction medications, current maintenance medications, any rejection history and its treatment. Also any similar history.
· KDIGO suggest monitoring high-risk (donor EBV seropositive/recipient seronegative) KTRs using NAT. Also they suggest reduction or cessation of IS medication in patients who are EBV-seronegative with an increasing EBV load. They also Suggest reduction or cessation of IS medication in patients who have EBV disease, including PTLD.
· Close of monitoring of symptoms and signs of PTLD and frequent monitoring of viral load.
· Reduction of immunosuppression starting by 50% of antimetabolite if he is on and keeping CNI at lower end of target level.
References:
1-Managing KIDNEY TRANSPLANT RECIPIENTS KDIGO guidelines 2017
Would you reduce immunosuppression just by seeing this report, a single one?
What is the role of EBV monitoring in this scenario?
NO SPECIFIC ROLE ,JUST WARNING SIGN DEPEND ON Observational studies
Measurement of EBV viral load
patients with EBV-positive PTLD will demonstrate a more marked elevation in the EBV viral load.
the diagnosis of PTLD is based on the histologic evaluation of a tissue biopsy. Similarly, while the absence of EBV in the peripheral blood makes PTLD less likely, it does not completely exclude the diagnosis
Due to the use of different methods, EBV viral load measurements cannot be compared between institutions. The optimal primer set, the relative importance of intracellular versus free plasma EBV, and the baseline profile in an organ transplant population remain to be established
Since the vast majority of EBV-positive PTLD occurs in the first year after transplantation, it is reasonable to monitor high-risk patients more frequently during the initial post-transplant period and to increase the time span between samples as the time from transplantation increases.
Many transplant centers have incorporated EBV monitoring into the routine evaluation of patients at high risk for PTLD.
Risk factors For the development of PTLD are
the degree of T cell immunosuppression and the Epstein-Barr virus (EBV) serologic status of the recipient.- time post-transplant, recipient age, and ethnicity
How do you manage this case?
history and physical examination
Laboratory studies
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, obtaining a combined positron emission tomography (PET)/CT scan as a measure of disease activity
●Assessment of the function of the transplanted organ.
●Unilateral bone marrow aspiration and biopsy is suggested for patients with cytopenias.
●Men and women with child-bearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures.
prevention largely relies upon limiting patient exposure to aggressive immunosuppressive regimens, rapid withdrawal and/or tapering of agents required for graft acceptance, and anti-viral prophylaxis. Attention to such measures may lessen the incidence of PTLD. In addition, 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
Tapering immunosuppressive therapy
a relatively high incidence of PTLD was found with the introduction of tacrolimus (FK506) for renal allograft recipients. Therefore, the aggressive tapering of this agent may limit the development of this disorder.
maintenance target trough concentration of 5 to 9 ng/mL
References UpTo DATE
Would you reduce immunosuppression just by seeing this report, a single one?
What is the role of EBV monitoring in this scenario?
The quantification of circulating Epstein Barr virus (EBV) DNA loads has played an important role in the diagnosis and management of EBV-associated lymphoid malignancies.
Viral load measurement is particularly useful for monitoring EBV-DNA in hematopoietic stem cell transplant patients.
Rise to 740 copies/ 100microL in this case would suggest reduction in immunosuppressant’s and EBV DNA monitoring closely which could be suggestive of early PTLD.
Cell-free EBV-DNA in plasma can be used as a biomarker for estimating the severity or prognosis of lymphomas.
How do you manage this case?
This patient have low risk for rejection, with negative DSA, FCXM and 111 mismatch.
We treat him firstly to reduce immunosuppression .
followup the viral load.
Taking history about PTLD.
Screening for PTLD in high risk patients (SEROPOSITIVE TO SERONEAGTIVE) is important.
References
1. Kimura H, Ito Y, Suzuki R, Nishiyama Y. Measuring Epstein-Barr virus (EBV) load: the significance and application for each EBV-associated disease. Rev Med Virol. (2008) 18:305–19. 10.1002/rmv.582 [PubMed] [CrossRef] [Google Scholar]
2. Kanakry J, Ambinder R. The biology and clinical utility of EBV monitoring in blood. Curr Top Microbiol Immunol. (2015) 391:475–99. 10.1007/978-3-319-22834-1_17 [PubMed] [CrossRef] [Google Scholar]
3. Cohen JI, Kimura H, Nakamura S, Ko YH, Jaffe ES. Epstein-Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: a status report and summary of an international meeting, 8-9 September 2008. Ann Oncol. (2009) 20:1472–82. 10.1093/annonc/mdp064 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
I appreciate your clinical approach.
1- The role of EBV monitoring in this case:
according to KDIGO guidelines for the care of renal transplant recipient, 2009:
this patient is not a high risk as he has positive EBV serology before renal transplantation
so, monitoring is not recommended as long as no clinical suspicious of infection is present
2- Management:
being young age, with rising of the EBV viral load in the first year of transplantation
-full evaluation to exclude PTLD by Ct scan or PET scan
-reduce IS (stop MMF and reduce CNI 30-50%) and monitor response after 2-4 weeks.
I appreciate your very wise clinical approach.I agree with your arguments that are well-supported with evidence.
What is the role of EBV monitoring in this scenario?
In the current scenario donor EBV seronegative or sero positive and Recipient EBV seropositive. Patient falls in low-risk category of early PTLD. But if there is a high index of suspicion, I need to screen the patient for PTLD.
As EBV DNAemia levels considered significant can vary between centers. In one study, the value of 4000 copies/mL has been chosen based on literature data evaluating such a threshold as a risk factor for PTLD onset.
Reference
Franceschini, Erica MD1; Plessi, Jessica MD1; Zona, Stefano MD1; Santoro, Antonella MD1; Digaetano, Margherita MD1; Fontana, Francesco MD2; Alfano, Gaetano MD2; Guaraldi, Giovanni MD3; Comoli, Patrizia MD4; Facchini, Francesca MD2; Potenza, Leonardo MD, PhD5; Gennari, William MD6; Codeluppi, Mauro MD1; Luppi, Mario MD, PhD5; Cappelli, Gianni MD2; Gyssens, Inge C. MD, PhD7,8; Mussini, Cristina MD3. 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. | DOI: 10.1097/TXD.0000000000000703
How do you manage this case?
Through history and detail physical examination.
Investigation: CBC, LFT, LDH, RFT,Ultrasonography of abdomen, chest x ray, Drug level Tac,Other viruses screening.
The diagnosis of PTLD require high index of suspension and tissue diagnosis as clinically indicated.
Once PTLD is excluded, follow-up of the viral load with optimization or reduction of immunosuppression is the main stay in managing these patients .
I appreciate your clinical approach.
EBV is postulated to be the cause of PTLD, although almost 30% of the cases of PTLD are EBV negative. The risk is highest in door+/recipient- cases and with the use of tacrolimus.
The role of EBV monitoring is debatable although many centers practice it. There is no clinically defined cut-off value above which the patient can be diagnosed to have PTLD and it will miss EBV negative PTLD (which accounts for 30% of the PTLD cases). It also has. low positive predictive value of 25%.
However, a rise in the EBV titers in high risk patients can suggest PTLD. However, a histological diagnosis is required before initiating treatment with chemotherapy.
In our patients case, he will need further work-up:
If there are any suspicious lymph nodes or lesions on the CT scan, the patient will require a biopsy
If the biopsy makes a diagnosis of PTLD, then he should be treated as such:
If there was no lesion detected, then the viral load should be monitored
Would you reduce immunosuppression just by seeing this report, a single one?
With just the titers only I wouldn’t reduce the immunosuppression
What is the role of EBV monitoring in this scenario?
Quantitative polymerase chain reaction (PCR) of unfractionated whole blood, plasma, or peripheral blood mononuclear cells of individuals at high risk of acquiring this condition allows for the early detection of PTLD.
The type of graft, the extent of ongoing immunosuppression, and the pattern of EBV virus loads to date must all be taken into account when deciding whether to check less regularly.
An uncomplicated kidney transplant recipient may start receiving monitoring as soon as one week after the transplant. Thereafter, they may have monitoring once a month for the next three to six months, then once every three months for the remainder of the first year.
How to manage
If you experience any signs of EBV viremia, repeat the EBV NAT every month while keeping a tight eye on yourself.
If things goes worse that is increasing load, or sign and symptoms of PTLD next step is reduction of immunosupression .
Epstein-Barr virus infection in transplant recipients: Summary of a workshop on surveillance, prevention and treatment
Upton Allen, Caroline Alfieri, Jutta Preiksaitis, Atul Humar, Dorothy Moore, Bruce Tapiero,Raymond Tellier, Michael Green, Dele Davies, Diane Hébert, Sheila Weitzman, Martin Petric, Kevan Jacobson,
KDIGO CLINICAL PRACTICE GUIDELINE ON THE EVALUATION AND MANAGEMENT OF CANDIDATES FOR KIDNEY TRANSPLANTATION
European best practice guidelines for renal transplantation
I appreciate your sound clinical approach.
It’s important to detect PTLD and help in diagnostic work up and reduction of immunosuppressive drug
History important for looking of fever and lymphadenopathy and pharyngitis
Also shift to m TOR inhibitors with reducing immunosuppressive therapy
I appreciate your sound clinical approach.
Dear All
Thank you very much for your replies. I’m not impressed with most of the answers.
Regarding this case, CHOOSE one or more of the following options:
A. Monitor the EBV titre.
B. CT chest, abdomen, and pelvis.
C. Reduce immunosuppression.
D. Start chemotherapy.
E. All the above
A. Monitor the EBV titre: True
The index patient, if asymptomatic, would require nothing more than follow-up with monitoring of EBV viral load.
Monitoring should be done till a viral “set point” is reached, developing a state called chronic viral load phenotype, CVLP (1).
Ongoing monitoring beyond the first year is done if the patient has a rejection episode, the immunosuppression is fluctuating, or if the viral “set point” has not reached (that is the viral load is progressively increasing).
Ongoing serial EBV viral load monitoring late after transplant in CVLP with pre-emptive interventions like reduction in immunosuppression is not routinely recommended (1).
Reference:
False: B, C D, E
In asymptomatic elevation of EBV viral load, monitoring alone is sufficient unless the viral load is more than significant cut-off value (>1000 copies/ml in most of the studies). No justification for reducing immunosuppression, starting chemotherapy or getting CT chest, abdomen and pelvis in this scenario at this stage.
I appreciate your very wise clinical approach.
I agree that chemotherapy is very illogical in this case.
C. This is because increasing EBV viral load is highly suggestive of PTLD. I did not choose A because they are no specific cut off values to diagnose PTLD and also no consensus on time to perform monitoring. I did not think D is the answer because this is probably an early disease as there are no reported symptoms. The reduction of immunosuppression can reverse PTLD in 20-80% of cases.
Reference
Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020 Feb 28;10(2):29-46. doi: 10.5500/wjt.v10.i2.29. PMID: 32226769; PMCID: PMC7093305.
Hmmm.
Please see my reply above in response to Dr Amit Sharma’s short write-up.
and Dr Mhammed Alabd below.
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
The answer is A
I will do regular follow-up with detailed history and examination with continuous monitoring of viral load. EBV DNAemia levels considered significant can vary between centers (a value of 4000 copies/mL may be a risk factor for PTLD onset)
EBV disease, including PTLD at any level of viral load is an indication of immunosuppressive reduction and conversion to mTORi
PTLD and EBV viral load:
o Viral load alone cannot be used to diagnose PTLD as the test can lack both sensitivity and specificity
o The viral load will be low if the site of PTLD is protected such (graft itself or in some gastrointestinal lesions)
o Patients with elevated EBV VL do not always have or develop EBV/PTLD
o For the above reasons, an aggressive approach to the evaluation of PTLD should be used when this diagnosis is suspected
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 loaed and focal findings on examination or in a patient with primary EBV infection and increasing viral loads
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.
I appreciate your very wise clinical approach.
A is correct should be monitoring of EBV viral load in first year post transplant
because it’s associated with PTLD and burkittis lymphoma
I appreciate your very wise clinical approach.
Thank you
To me all is correct
as this patient need monitoring and if further work up of PTLD as it can be a symptomtic and need extensive investigation including CT chest and pelvic and might need tissue biopsy if any.
treatment of PTLD is reduction of immunosupression and chemotherapy
Hmmm.
Please see my reply above in response to Dr Amit Sharma’s short write-up.
and Dr Mhammed Alabd as above
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
A&C (Correct)
According KDIGO guidelines;
-Suggest monitoring high-risk (donor EBV seropositive/recipient seronegative) KTRs for EBV by NAT. (2C)
-Once in the first week after transplantation (2D) ,
-Then at least monthly for the first 3–6 months after transplantation (2D),
-Then every 3 months until the end of the first post-transplant year (2D) ,and additionally after treatment for acute rejection. (2D)
-Suggest that EBV-seronegative patients with an increasing EBV load have immunosuppressive medication reduced. (2D)
A is perfect.
But C really ?
Please see my reply above in response to Dr Amit Sharma’s short write-up.
and Dr Mhammed Alabd below.
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
Prof. Halawa. Thanks
I would like to answer your question along with main question of scenario in conjunction. Before, I move ahead, I would like to make few statements regarding EBV post transplantation.
In view of above statements,
There is currently no standard guideline of rate and role of monitoring of EBV viral load to predict and diagnose PTLD. EVITA study is under process to answer these questions.
Hence, I will keep high index of suspicion for development of clinical symptoms but not advice serial viral load monitoring to the patient though some centers will do that. I will also not reduce immune suppression as of now.
Therefore, the best possible answer to Prof. Halawa’s MCQ is A ( as per European study group) but as per KDIGO and American society, the answer is non of the above.
REF:
I appreciate your very wise clinical approach.
I agree with your arguments that are well-supported with evidence
Thank you sir
Excellent Yashu
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
Answer is A
We only need to monitor the viral load after 3 months unless there is high index of suspicion for PTLD
EBV DNAemia levels considered significant can vary between centers. In one study, the value of 4000 copies/mL has been chosen based on literature data evaluating such a threshold as a risk factor for PTLD onset.
Franceschini, Erica MD1; Plessi, Jessica MD1; Zona, Stefano MD1; Santoro, Antonella MD1; Digaetano, Margherita MD1; Fontana, Francesco MD2; Alfano, Gaetano MD2; Guaraldi, Giovanni MD3; Comoli, Patrizia MD4; Facchini, Francesca MD2; Potenza, Leonardo MD, PhD5; Gennari, William MD6; Codeluppi, Mauro MD1; Luppi, Mario MD, PhD5; Cappelli, Gianni MD2; Gyssens, Inge C. MD, PhD7,8; Mussini, Cristina MD3. 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. | DOI: 10.1097/TXD.0000000000000703
I appreciate your very wise clinical approach.
I agree with your arguments that are well-supported with evidence
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
I would choose A and B
There is a significant rise in the EBV titers. If the CT scan of the chest, abdomen and pelvis are negative, the patient should have the viral load monitored to ensure that there is reduction of the viral load
A is perfect.
But B really ?
Please see my reply above in response to Dr Amit Sharma’s short write-up.
and Dr Mhammed Alabd below.
Thank you Professor Sharma for the clarification
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
Thank you Professor Halawa
There are some centers that use a cut off of 1000 copies per ml for identifying probable disease
A true
B,C,D,E false
I appreciate your very wise clinical approach.
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
The answer: A
I appreciate your very wise clinical approach.
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
A- monitor the EBV titer
Lower risk patients (D-/R+, D+/R+):
Monthly EBV PCR monitoring for first 3 months post transplant.
Three monthly from 3 month until 1 year post transplant.
Reference
Guideline Title: Epstein Barr Virus (EBV)- Post Transplant Management UHL Renal transplant Guideline Page 2 of 4 Approved by Reanl Transplant MDT Approval Date 23/05/2022, Trust Ref: C22/2022
I appreciate your very wise clinical approach.
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
A. True: this may be better answer but still this issue of EBV monitoring has many pitfalls e.g., cut off not clear, source of sample is another problem e.g., whole blood or plasma.
B. False: there are no symptoms reported to suggest PLTD in the history. We are only told about raising viral load. This may not be enough to justify imaging even though the PTLD might be asymptomatic
C.False: It is difficult to make this decision on two viral load only and absence of any symptoms to points toward PTLD. It may make more if we have serial & progressive raising in the viral load. More over she on the daul immune suppression and to reduce that easily it can be challenging. We don’t know the status of the donor & the recipient regarding EBV & CMV. Does this patient received fusion inhibitors such as belatacept , again not mentioned in the history. All these information are necessary to make decisions. We expect EBV PCR to go up with immune suppression specially in the first 6 months but does this requires manipulation for immune suppression ? the answer is it depends !
D. False: Simply chemotherapy for what ?. We don’t have serial and progressive viral load. IF we are considering PTLD, it has to be a tissue diagnosis at first place and you have to stage the disease by PET-CTor CT, discuss with haemato-oncology. We don’t have all these data to consider chemo
E. False: Although debatable monitoring viral load might sound better than any other answer here
I appreciate your very wise clinical approach.
Weclome prof
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
Yes,prof
Regarding this case, CHOOSE one or more of the following options:
A. Monitor the EBV titre.- True – it is recommended to monitor EBV in such patients recieveing graft from EBV +D /-R, in the first week and monthly for 3 months then Q 3 months for the first year – peroid most commonly encounterd EBV related PTLD.
B. CT chest, abdomen, and pelvis- False – the pt in index case has no symptoms, and nothing mentioned about physical exam, if there is symptoms or any lymphnodes or organomegaly, or if the viral load continue to increase then the CT is indicated.
C. Reduce immunosuppression- False, with no evidence of any disease/PTLD – no reduction of immunosuppression recommended.
D. Start chemotherapy.- False
E. All the above- False.
References:
1) 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.
(2) Le J, Durand CM, Agha I, Brennan DC. Epstein-Barr virus and renal transplantation. Transplant Rev (Orlando). 2017 Jan;31(1):55-60. doi: 10.1016/j.trre.2016.12.001. Epub 2016 Dec 29. PMID: 28089555.
(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 very wise clinical approach.I agree with your arguments that are well-supported with evidence.
Typing whole sentence in bold amounts to shouting.
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
A & C (Correct).
B, D & E (False).
A is perfect.
But C really ?
Please see my reply above in response to Dr Amit Sharma’s short write-up.
and Dr Mhammed Alabd below.
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
First of all monitoring is indicated only in high risk transplant recipients for PTLD
High risk patients are defined as the presence of one of the following: (1) Patents receiving aggressive immunosuppression, so PTLD are more common in heart transplantation, HLA incompatible transplantation and in patients with recurrent AR, (2) 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 use of ATG, OKT3, Belatacept and tacrolimus was found to be associated with higher risk of PTD, On the other hand MMF, sirolimus, and alemtuzumab are not associated with this risk.
The current patient is considered low risk of PTLD because of the low immunological risk transplantation, and the patient was seropositive before transplantation. So monitoring of EBV status is not indicated in the current patient.
Once we measure EBV viral load in low risk patient and we found increase in the titer, I will adjust only immunosuppression, not reduce the dose below recommended, but if this happen in high risk patient I will consider reduction of immunosuppression.
In the current patient I will monitor the titer every 3 months till the end of the first year.
If the titer is rising I will consider reduction of immunosuppression and follow up.
No clear titer can be used to suggest the PTLD risk, 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)
If symptoms of PTLD happen I will investigate.
Lastly, detection of EBV does not mean PTLD, so no need for CT and no indication for the use of chemotherapy. On the contrary absence of EBV make the diagnosis of PTLD unlikely but it does not exclude (5,6)
So the true answer is A
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.
5. Baldanti F, Rognoni V, Cascina A, et al. Post-transplant lymphoproliferative disorders and Epstein-Barr virus DNAemia in a cohort of lung transplant recipients. Virol J 2011; 8:421.
6. Shimizu H, Saitoh T, Koya H, et al. Discrepancy in EBV-DNA load between peripheral blood and cerebrospinal fluid in a patient with isolated CNS post-transplant lymphoproliferative disorder. Int J Hematol 2011; 94:495.
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.
5. Baldanti F, Rognoni V, Cascina A, et al. Post-transplant lymphoproliferative disorders and Epstein-Barr virus DNAemia in a cohort of lung transplant recipients. Virol J 2011; 8:421.
6. Shimizu H, Saitoh T, Koya H, et al. Discrepancy in EBV-DNA load between peripheral blood and cerebrospinal fluid in a patient with isolated CNS post-transplant lymphoproliferative disorder. Int J Hematol 2011; 94:495.
I appreciate your very wise clinical approach.I agree with your arguments that are well-supported with evidence.
However, 3 monthly estimation of EBV is not goo enough. I would do it at least every month if not every fortnight until it starts resolving
That is a REPETITION of your own response given below.
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
Answer: A
EBV monitoring is recommended in high risk individuals by most transplant centers. While some recommend EBV monitoring for all transplant recipients.
Elevated viral load can be seen in asymptomatic individuals, and does not mean PTLD as PTLD require tissue diagnosis and can be seen in low viral load. Therefore, this test is not specific.
In rapidly progressively rising titer immunosuppression reduction is the first step in high risk individuals to control viral replication.
Screening with imaging is required if there is high index of suspicion for PTLD, and chemotherapy is indicated PTLD in those who did not improve on immunosuppression reduction.
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. PMID: 19845597.
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
A, ,
Correct
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
B. CT chest, abdomen, and pelvis.
C. Reduce immunosuppression.
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
Thanks Prof. Ahmed Halawa
Noted
Many thanks Prof.Halaw
A Monitor the EBV titre
A is perfect.
Please see my reply above in response to Dr Amit Sharma’s short write-up.
and Dr Mhammed Alabd below.
Many thanks Prof.Sharma
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
Many thanks Prof.Halawa
A. monitor the EBV titer
Asymptomatic elevations in EBV load are a regular occurrence. Patients who sustain many infections from different pathogens at the same time that their EBV load steadily increases yet show no symptoms may be incorrectly classified as having EBV disease. In circumstances like these, an EBV disease can only be confirmed by the examination of tissue.
To begin, I will inquire about the symptoms, which include a high temperature and diarrhea. Examination of the lymph nodes
careful monitoring of the EBV as well as the symptoms that came before it.
A is perfect.
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
A and C..
Monitoring of EBV viral load is recommended for high risk patient ( seropositive donor to seronegative recipient) to detect EBV viremia early and intervene early before development of PTLD.
KDIGO suggest monitoring high-risk (donor EBV seropositive/recipient seronegative) KTRs using NAT. Also they suggest reduction or cessation of IS medication in patients who are EBV-seronegative with an increasing EBV load. They also Suggest reduction or cessation of IS medication in patients who have EBV disease, including PTLD.
·
· Reduction of immunosuppression starting by 50% of antimetabolite if he is on and keeping CNI at lower end of target level.
References:
1-Managing KIDNEY TRANSPLANT RECIPIENTS KDIGO guidelines 2017
A is perfect.
But C really ?
Please see my reply above in response to Dr Amit Sharma’s short write-up.
and Dr Mhammed Alabd below.
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
A, B and C
A : KDIGO recommend monitoring EBV DNA with NAT for high risk patients , while many transplantation centers routinely monitor both high and standard risk recipents and adopt preemptive sratigy with reducing IS or switch to m TOR to decrease the risk of PTLD.
b : for lymphadenopathy or tissue invasion .
C: is the corner stone in prevention and treatment of PTLD.
while (D) : chemotherapy and or rituximab are preserved to confirmed cases of PTLD
Ref :
Al-Mansour Z, Nelson BP, Evens AM. Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep. 2013 Sep;8(3):173-83. doi: 10.1007/s11899-013-0162-5. PMID: 23737188; PMCID: PMC4831913.
A is perfect.
But B and C really ?
Please see my reply above in response to Dr Amit Sharma’s short write-up.
and Dr Mhammed Alabd below.
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
My answer is A.
I think, in the absence of symptoms and being sero positive recipient , Watchful approach is indicated in this context. There is no consensus EBV DNA-emia plasma level upon which anti EBV measures are implemented. The ongoing EVITA study is supposed to answer this question.
Reference:
1]Jan Styczynski et al, Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines.Vol. 101 No. 7 (2016): July, 2016.
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
A is absolutely true
B D E is false
C is controversial because patient has low risk factors (brother *related donor with low mismatch , no DSA, CNI based double not triple immunosuppression). However, viral loading still increase during 6 months. For me, I think it is appropriate to reduce immunosuppression . Therefore C is true
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
Correct answer at this time A , if more progresses, may require all of the above
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
A: true
monitoring of the EBV VL is needed in the first-year post-transplant as recommended by most of the guidelines.
B: false
these screening tests are used when there’s suspicion of PTLD
C:true
although the VL not reaching the cut-value by most centers(> 4000copies/ml),this patient showed exacerbation of the EBV-VL from 200 to 740copies/ml which may further progress to severe form of EBV disease. Reduction of immunosuppression can be justified in the view of possible disease progression and complication.
D: false
no indiction to start chemotherapy.
E: false
The correct answer is A
This is the expected level when any EBV-positive patient commences on immunosuppression.
No need for CT, reduction of immunosuppression or chemotherapy.
I will go with answer A and C based on the indexed case we need to close monitor the viral load along with the reduction of immunosuppression(RI) as it considers the key step in the management of PTLD. In fact a reduction of IS can reverse the PTLD by 20-80% as per one report
A: correct
B:False no need to screening and expose patient to radiation
c:false patient already on dual immunosuppresion
d:false patient doesn’t have PTLD to be treated by chemothrapy
⭐ The correct answer is A.
_such. Case is high risk for EBV infection as donor +/Recipient – serology prior to transplantation.
_Frequent monitoring of the viral titer is essential to take a decision if rising titre or symptoms appear , here the decision to modify or reduce immunosupression.
_No need for CT or any imaging.
_No need for reduction of IS or starting chemotherapy at this stage.
Thank you prof Halawa :
The correct answer is A : it is reasonable to follow EBV level in this patient as it start to increase
answer B,C,D,E : False the patient has no symptoms suggestive of PTLD to justify radiation exposure ,reduction of immunosuppression
A.
monitoring maybe every 2-3 months for viral load. With this low viral load, no specific treatment is needed. Chest CT may be needed later when PTLD is suspected (periodic physical examination, LDH etc showed be monitored)
(A) The correct answer==> (Monitor the EBV titre) ===> Elevation of EBV viral load excepted when immunosuppressed EBV-positive patient.
A, B and C
A : KDIGO recommend monitoring EBV DNA with NAT for high risk patients , while many transplantation centers routinely monitor both high and standard risk recipents and adopt preemptive sratigy with reducing IS or switch to m TOR to decrease the risk of PTLD.
b : for lymphadenopathy or tissue invasion .
C: is the corner stone in prevention and treatment of PTLD.
while (D) : chemotherapy and or rituximab are preserved to confirmed cases of PTLD
Ref :
Al-Mansour Z, Nelson BP, Evens AM. Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep. 2013 Sep;8(3):173-83. doi: 10.1007/s11899-013-0162-5. PMID: 23737188; PMCID: PMC4831913.
Answer: A
– KDIGO suggests monitoring EBV viral load post-kidney transplant in high-risk patients (i.e., EBV D+/ R-) by NAT (nucleic acid testing) once in the 1st week, monthly for the first 3-6months, then every 3 months until the end of the 1st post-transplant year as well as following treatment for acute rejection (1-3)
– KDIGO also recommends immunosuppression reduction in EBV seronegative patients with a rising EBV viral load and in patients with EBV disease including PTLD (1-3)
– so in this case, the initial step is to monitor EBV viral load, if noted to be increasing then immunosuppression reduction can be considered
References
1. KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Nov;9 Suppl 3:S1-155. PubMed PMID: 19845597. Epub 2009/10/23. eng.
2. Allen UD, Preiksaitis JK. Epstein-Barr virus and posttransplant lymphoproliferative disorder in solid organ transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2013 Mar;13 Suppl 4:107-20. PubMed PMID: 23465004. Epub 2013/03/08. eng.
3. 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.
correct answer A
· Use monitoring of viral loads to help follow the clinical course of patients with established PTLD
References :
M.A. Bingler, B. Feingold, S.A. Miller, M.G. Michaels, M. Green, R.M. Wadowsky, D.T. Rowe, S.A. Webber.Chronic high Epstein–Barr viral load state and risk for late-onset posttransplant lymphoproliferative disease/lymphoma in children.
Am J Transplant, 8 (2008), pp. 442-445
http://dx.doi.org/10.1111/j.1600-6143.2007.02080.x | Medline
the correct answer is A
this excepted increase in EBV Titre after transplantation as a result of immunosuppression medication
A – We monitor as the increase in VL can happen with impaired immunity at onset of immunosuppressive meds, no need for treatment yet unless the viral load is constantly increasing.
REF ;
Allen UD et al. PTLD,EBV infection and DX in SOT; Guidelines from AST infectious dx community practice. Clin transplant.2019 sep;33(9) e13652
EBV titre monitoring only
A- correct
B C D E- False
A is the best choice.
B it is not necessary
C we only need to reduce immunosuppression if clinical changes or laboratory increase of viral load or hepatotoxicity
D is not indicated. And we will have a lot of complications (hemolytic anemia is one)
(A) The correct answer==> (Monitor the EBV titre) ===> Elevation of EBV viral load excepted when immunosuppressed EBV-positive patient.
The correct answer is A
A. Monitor the EBV titre
The correct answer is A. If the recipient remains asymptomatic, only EBV viral load is necessary.
What is the role of EBV monitoring in this scenario?
PTLD can be detected early by monitoring the viral load of patients at high risk of developing this complication. Although diagnosis of PTLD is based on histology of a tissue biopsy, increased EBV viral load is highly suggestive of PTLD. However, while the absence of EBV in the blood cannot completely exclude PTLD, it makes it less likely.
Serial measurement of EBV-DNA levels in the blood can also be used to monitor response to treatment.
How do you manage this case?
3. Treatment
Reference
Reference
Robert SN et al. Treatment and prevention of post-transplant lymphoproliferative disease. UpToDate
Is adoptive immunotherapy a standard clinical practice now?
Not yet.
What is the role of EBV monitoring in this scenario?
==============================
How do you manage this case?
EBV prophylaxis
Treatment of EBV-related PTLD:
Role of reduction or withdrawal of immunosuppression:
What is the duration of reduction or withdrawal of IS before alternative therapy is considered?
The role of antivirals & immunoglobulin in the treatment of PTLD:
References
Does it really work as I quote you, “The use of ganciclovir & immunoglobulin is recommended in the initial management of PTLD (level BIII evidence). Ganciclovir is preferred over acyclovir because of its greater in vitro activity against the EBV” ??
What is the role of EBV monitoring in this scenario?
– KTRs are vulnerable to a higher risk of infections that may lead to significant morbidity and mortality.
-EBV infection is associated with an increased incidence of PTLD in KTRs, especially among the first year post transplantation.
-The risk is increased among seronegative recipient, receiving organ from seropositive donor.
-EBV monitoring is recommended in high risk individuals by most transplant centers. While some recommend EBV monitoring for all transplant recipients.
Pitfalls in monitoring strategy:
-Cut-off values are not clear
-Sources of samples are not universal; whole blood, plasma, or peripheral blood mononuclear cells
– Absence of standard points of time to perform the monitoring.
– The precise definition of at high risk patients has not been established yet
KDIGO recommended EBV PCR: within the first week after transplant followed by monthly monitoring for the next three to six months and then every three months for the rest of the first year and additionally after treatment of acute rejection.
– Serial measurement of EBV loads in previously seronegative patients allows the identification of onset of infection
– Identification of patients with newly detectable or rapidly rising EBV load offers the opportunity to preemptively intervene and potentially prevent progression to EBV disease including PTLD.
-The EBV viral load measurement is sensitive, but not specific, for EBV disease and PTLD, as it can also be elevated in asymptomatic patients, and PTLD diagnosis is based on the histologic evaluation of a tissue biopsy, and PTLD ca not be excluded if viral load was undetectable.
How do you manage this case?
-Careful evaluation of history and physical examination.
– Review donor and recipient EBV status to determine the risk.
– CBC, LFT, LDH, RFT.
– Drug level Tac.
– Other viruses screening.
– The diagnosis of PTLD require high index of suspension and tissue diagnosis as clinically indicated.
– Frequent monitoring to EBV viral load and graft function.
*Viremia management if rapidly rising:
– Reduction of immunosuppression RIS is the mainstay to control viral replication by restoring EBV-specific cellular immunity.
– RI plan includes 50% reduction of CNI, in addition to withdrawal of the antimetabolites , with the exception of glucocorticoids.
– withdrawal of all immunosuppressive medications in critically ill cases should be considered.
* In the index case KTR with EBV viremia and rising viral load:
– We need to clarify further the IS regimen as he is on double IS.
– Keeping in mind the risk of rejection as patient is high immunological risk 111 mismatch.
– Keep monitoring viral load.
– If viral load continue rising: consider reducing Tacrolimus level and monitor the response in 2-4 weeks.
– close monitoring of graft function.
References:
Shah N, Eyre TA, Tucker D, Kassam S, Parmar J, Featherstone C, Andrews P, Asgari E, Chaganti S, Menne TF, Fox CP, Pettit S, Suddle A, Bowles KM; Haemato-Oncology Task Force of the British Society for Haematology and the British Transplantation Society. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients – A British Society for Haematology Guideline. Br J Haematol. 2021 May;193(4):727-740. doi: 10.1111/bjh.17421. Epub 2021 Apr 20. PMID: 33877688.
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.
Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020 Feb 28;10(2):29-46. doi: 10.5500/wjt.v10.i2.29. PMID: 32226769; PMCID: PMC7093305.
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 very wise clinical approach.I agree with your arguments that are well-supported with evidence.
A 24-years old CKD 5 received a kidney from his brother 8 months ago. 111 mismatch, no DSA and negative FCXM. He is on CNI-based double immunosuppression with excellent kidney function. His EBV viral load increased from 200 copies/ml prior to the operation rose to 740 copies/ml 6 months after transplantation.
What is the role of EBV monitoring in this scenario?
Epstein Barr virus (EBV) is a ubiquitous tumor virus that belongs to the gammaherpesvirus subfamily. EBV is associated with a variety of lymphomas/leukemias, and epithelial malignancies, including nasopharyngeal carcinoma (NPC), lymphoepithelioma-like carcinoma, and gastric cancer.
EBV viral load quantification has recently played a more important role in the diagnosis and management of EBV-associated diseases, particularly useful for monitoring EBV-DNA in transplant patients with risks of EBV-associated post-transplant lymphoproliferative disease (PTLD), and assessing the response to therapy.
In the index case no data about the EBV serostatus in donor and recipient, if the the recipient is seronegative for EBV and donor positive EBV IgG, then frequent monitoring of viral load at the first week and monthly for 3 months then every 3 months for the first year, and after treatment of an acute rejection is mandatory.
If the level continue to increase modification of immunosuppression is wise ( decreasing tacrolimus to lower therapeutic trough level, and MMF , and/or introduction of m-TOR inhibitors).
EBV encoded small RNA (EBER) in situ hybridization or viral antigen detection is performed, to prove EBV related PTLD, but not the EBV DNA (viral load), that can be used to diagnose EBV-PTLD when biopsy could not be taken, monitoring PTLD in HSCTand response to treatment.
Guidelines also moderately recommend that significant amounts of EBV-DNA without clinical symptoms of EBV disease are an indication for preemptive therapy (RITUXIMAB).
routine surveillance for EBV-DNA by quantitative PCR is not recommended, Solid organ allograft recipients carry chronic high EBV loads without symptoms consistent with PTLD, but the significance of a high EBV load in terms of long-term health is unknown.
In Hodgkin’s lymphoma: EBV-DNA in plasma is highly correlated with EBV tumor status in HL and is significant for determining the prognosis before therapy and at follow-up after 6 months.
In Extranodal NK/T-Cell Lymphoma, Nasal Type (ENKTL): EBV-DNA levels in peripheral blood are a surrogate biomarker of tumor load, used in making a diagnosis, prognostic assessment and response to treatment.
Chronic Active EBV Infection (CAEBV): characterized by fever, lymphadenopathy, hepatosplenomegaly, pancytopenia, interstitial pneumonitis, and skin involvement (hypersensitivity to mosquito bites or hydroa vacciniforme), The diagnosis of CAEBV is based on:
(1) infectious mononucleosis-like symptoms lasting >3 months.
(2) increased EBV-DNA in peripheral blood or the demonstration of EBER in affected tissues.
(3) the exclusion of known immunodeficiencies, malignancies, or autoimmune disorders.
Monitoring for EBV-DNA is also useful for assessing the treatment response.
How do you manage this case?
From the medical chart of both donor and recipient I’ll check for the serostatus of EBV, high risk being D+/R-, those receiving induction therapy.
I would check the laboratory result for any hint on possibility of PTLD, anemia, thrombocytopenia, lymphopenia, high LDH, calcium, liver function test or paraproteinemia, urinalysis and kidney function as well.
Detailed history (fever, night sweats, wt. loss.. etc), and thorough clinical examination (lymphnodes, organomegaly, throat lesions.. etc), are needed to identify if EBV related PTLD present.
If nothing with PTLD, will continue monitoring till the end of first year (the EBV-PTLD more frequently seen).
If any rejection episode occur even after the first year will monitor the EBV viral load.
If the patient is asymptomatic, the viral load continues to rise then I’ll consider reduction of immunosuppressive medication especially CNI to the lower therapeutic trough level, with frequent monitoring of kidney function to prevent and treat rejection episode immediately.
If symptomatic, identification of the PTLD and treating accordingly, reduce or discontinue the immunosuppression, may use m-TOR inhibitors.
References:
(1) 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.
(2) Le J, Durand CM, Agha I, Brennan DC. Epstein-Barr virus and renal transplantation. Transplant Rev (Orlando). 2017 Jan;31(1):55-60. doi: 10.1016/j.trre.2016.12.001. Epub 2016 Dec 29. PMID: 28089555.
(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 very wise clinical approach.I agree with your arguments that are well-supported with evidence.
A 24-years old CKD 5 received a kidney from his brother 8 months ago. 111 mismatch, no DSA and negative FCXM. He is on CNI-based double immunosuppression with excellent kidney function. His EBV viral load increased from 200 copies/ml prior to the operation rose to 740 copies/ml 6 months after transplantation.
What is the role of EBV monitoring in this scenario?
We are looking for EBV serostatus of the donor and the recipient, as recipient with EBV seronegative renal transplant recipients /EBV seropositive donor should be monitored in first week, then monthly for 3 months, and then 3 monthly till the end of first year post-transplant, in addition to at the time of acute rejection treatment.
But in low risk patient, no need to follow BV viral load assays, specially without clinical possibility of PTLD without increasing the risk of disease occurrence , representing a safe and cost-effective policy .
How do you manage this case?
There is no consensus regarding the EBV viral load cut-off thought to be significant (for PTLD), if our patient clinically free and PTLD is excluded, follow-up of the viral load, but if rising titer with manifestations we should optimize the immunosuppression .
References:
1- 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.
2- American Journal of Transplantation 2013; 13: 41–54 doi: 10.1111/ajt.12004 .
I appreciate your very wise clinical approach.I agree with your arguments that are well-supported with evidence.
The index patient is a 24-year-old living donor renal recipient with 111 mismatch having excellent graft function on dual immunosuppression. His EBV viral load is being monitored and being found to have risen from 200 copies/ml at transplant to 740 copies/ml at 6 months post-transplant.
The data missing in this scenario is with respect to the EBV serostatus of the donor and the recipient. Also, the immunosuppression used is not mentioned.
According to guidelines, EBV seronegative renal transplant recipients receiving a kidney from EBV seropositive donor should be monitored for EBV by nucleic acid testing (NAT) in first week, then monthly for 3 months, and then 3 monthly till the end of first year post-transplant, in addition to at the time of acute rejection treatment (1,2).
As there is monitoring of EBV viral load in this patient, it seems that the donor was seropositive in this scenario. But according to a study, almost 86% of transplant centres perform EBV viral load testing routinely and 77% reported pre-emptive treatment in case of significant EBV viremia (3). A study conducted concluded that in low-risk patients, EBV viral load assay monitoring in absence of clinical symptoms is not cost-effective and may be avoided in renal transplant recipients (4).
The index patient has an increasing level of EBV DNA load on testing at 6 month post-transplant. There is no consensus regarding the EBV viral load cut-off thought to be significant (for PTLD) and different studies use different cutoffs, but most use a cut-off more than 1000 copies/ml as significant (4-6).
The patient would require detailed history for symptoms (night sweats, fever, weight loss) and detailed physical examination.
The index patient, if asymptomatic, would require nothing more than follow-up with monitoring of EBV viral load. Monitoring should be done till a viral “set point” is reached, developing a state called chronic viral load phenotype, CVLP (2). Ongoing monitoring beyond the first year is done if the patient has a rejection episode, the immunosuppression is fluctuating, or if the viral “set point” has not reached (that is the viral load is progressively increasing).
Ongoing serial EBV viral load monitoring late after transplant in CVLP with pre-emptive interventions like reduction in immunosuppression is not routinely recommended (2).
A rising EBV viral load can identify patients in whom intervention can prevent development of PTLD (1).
If the patient is symptomatic, or if the levels increase to significant level, then pre-emptive treatment in form of immunosuppression reduction may be required (1). But there is no consensus on this strategy.
We should know the immunosuppression being taken by the patient. If patient is on calcineurin inhibitor and steroids, the dose of calcineurin inhibitor can be reduced. Reduction of immunosuppression in this patient with 111 mismatch and dual immunosuppression is fraught with risk of rejection.
References:
I appreciate your very wise clinical approach.I agree with your arguments that are well-supported with evidence.
Your write-up is of highest quality
5. A 24-years old CKD 5 received a kidney from his brother 8 months ago. 111 mismatch, no DSA and negative FCXM. He is on CNI-based double immunosuppression with excellent kidney function. His EBV viral load increased from 200 copies/ml prior to the operation rose to 740 copies/ml 6 months after transplantation.
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HISTORY
What is the role of EBV monitoring in this scenario?
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How do you manage this case?
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Reference
I appreciate your very wise clinical approach.I agree with your arguments that are well-supported with evidence.
Your write-up is of highest quality
References:
Whilst I agree with your approach but you may wish to know the sero status of both donor and recipient to stratify the risk and you may also want to know the immunosuppression in this case and viral load monitoring will depend largely on these factors as well as absence of symptoms as you suggested.
-What is the role of EBV monitoring in this scenario?
Guidelines recommended EBV viral load monitoring in high-risk groups in the first year; 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.
EBV viral load assays have no need to be done in low-risk patients those without clinical possibility of PTLD without increasing the risk of disease occurrence , representing a safe and cost-effective policy .
-How do you manage this case?
The current case has EBV positive with increasing level.
Immunosuppressive therapy can be reduced with close monitoring of the graft function.
Monitoring EBV PCR every month for first 3 months after transplant.
from 3 rd month till 1 year post transplant it can be monitored every 3 months .
If titres are greater than 1000 copies/ml , immunosuppression need to be reduced.
Then titres can be assessed after 2 weeks .
· If titres decreased PCR can be monitored every two weeks till negative
· If titres are increasing even if the patient is asymptomatic, further immunosuppression reduction and PanCT or even PET can be done to screen for PTLD
Reference
–Franceschini E, Plessi J, Zona S, 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;3(7):e182. Published 2017 Jun 26.
-Guideline Title: Epstein Barr Virus (EBV)- Post Transplant Management University Hospital of Leicester Renal transplant Guideline Approved by Renal Transplant MDT Approval Date 23/05/2022, Trust Ref: C22/2022
I’m not sure what evidence you based your answer about the level of 1000 copies to reduce immunosuppression?
Reference ;EPSTEIN BARR VIRUS (EBV)- POST TRANSPLANT MANAGEMENT UHL RENAL TRANSPLANT GUIDELINE ,University Hospital of Leicester (NHS trust)(C22/2022)
This patient is sero-positive to start with , however , it has risen significantly thereafter, nevertheless, it would not be as risky and potentially pathogenic as when its developed in a sero-negative recipient, Therefore he is not a high risk recipient.As per KDIGO guideline follow up of EBV DNAemia is recommended for high risk patient for developing PTLD mainly those EBV donor positive / recipient negative cases.However , highly increasing DNAemia might portend a significant risk factor that warrant close follow up. It s advocated that symptoms are the cornerstone in predicting PTLD rather than EBV DNA .
References:
1] Franceschini, Erica MD 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.Transplantation Direct 3(7):p e182, July 2017.
Thank you Dr Wael Jebur
I’m not sure how you know that this patient is sero positive and this would be more risky compared to seronegative?
Thank you Dr. Mohsen ,
The history of patient details that anti-EBV titer was 200 before transplantation that has risen to 730 afterwards. being sero-positive to start with is less risky regarding development of PTLD than developing de novo EBV infection.
Would you reduce immunosuppression just by seeing this report, a single one?
· What is the role of EBV monitoring in this scenario?
PTLD displays highly variable patterns of incidence in kidney transplant recipients, with peaks in the first year and subsequently in the latter post-transplantation period. More than 90% of B cell PTLD that develop within the first year of transplantation includes the EBV genome. Hence, EBV monitoring is used to prevent PTLDs. There is considerable disagreement surrounding routine EBV viral load in adult SOT recipients to prevent the onset of PTLD. In practice, the majority of European doctors frequently use EBV viral load to direct both diagnostic workup and preventive medication, despite international guidelines advocating EBV-VL surveillance only in high-risk patients.
KDIGO guidelines recommend monitoring for EBV after transplantation in high risk recipients, once in the first week, monthly for the first 3 to 6 months, then every 3 months until the end of the first post-transplant year, as well as following treatment for acute rejection.
Immunosuppressive medicine, particularly antimetabolite medications, should be lowered in patients with increasing viral loads over the screening period, especially in EBV-seronegative patients, with subsequent monitoring of viral load.
Not all patients with high EBV virus loads develop PTLD. However, rising viral load in the presence of clinical picture Because of the aforementioned factors, PTLD assessment should be aggressive when clinical PTLD signs are present. Any unexplained febrile infections in a SOT recipient should raise the possibility of PTLD, especially if they occur within the first year after transplantation, in particular in patients who received potent induction and maintenance immunosuppression.
· How do you manage this case?
In the patient with low risk for rejection, having negative DSA, FCXM and 111 mismatch, the initial step in this approach is to reduce immunosuppression and followup in viral load.
Patient should be asked about specific symptoms related to PTLD. Screening for PTLD in high risk patients (SEROPOSITIVE TO SERONEAGTIVE) is indicated when clinically indicated.
Thank you Dr Mohamad Habli
I agree with your approach. I’ve a reservation for reducing immunosuppression when his match is 111 and only maintained on dual immunosuppressions which you need to verify what are these immunosuppressions before any reductions?
The above-mentioned patient developed rising EBV viral load 6 months after kidney transplantation testing .
*For these reasons our approach in this patient to confirm presence or absence of PTLD starting from full history and proper clinical examination and investigations,full blood count ,liver function test and liver enzymes LDH.
-Radiographic evaluation using CT of neck, chest and abdomen.
*If PTLD is excluded, follow-up of the viral load with optimization or reduction of immunosuppression is the main stay in managing these patients .
Reference :
Thank you Dr Nada AlHassan
Excellent and sensible answer but are you proposing CT scan for this case based on this level of viraemia?
Your strategy is sensible but high index of suspicion of PTLD is probably more appropriate before considering unnecessary exposure to high dose of radiation especially many of these cases happen in youngsters.
Thank you Prof. Mohsin in this case if there no history or clinical findings suggestive of PTLD there no need to expose the patient to the risk of radiation .
Thank you Dr Mohamed Gaffar
Well done with such detailed discussion and explanation. I’ve few points:
1- There is a mix in your answer between PTLD management and EBV viraemia
2-We are seeking your opinion and management plan in this particular case with the above specifications
3- Why we only monitor the viral load without any specific treatment?
What is the role of EBV monitoring in this scenario?
o In kidney transplant recipients, PTLD has shown bimodal patterns of incidence, with peaks in the first year and then in the later posttransplantation period
o The EBV genome is found in more than 90% of B cell PTLD occurring during the first year after transplantation
o The role of EBV monitoring is PTLD avoidance
o Routine EBV-VL in adult SOT recipients to avoid PTLD development is still debated. Despite international guidelines suggesting EBV-VL monitoring only in high-risk recipients, in real life, the majority of European clinicians routinely use EBV-VL to guide both diagnostic workup and preemptive therapy
How do you manage this case?
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
I will do regular follow-up with detailed history and examination with continuous monitoring of viral load. EBV DNAemia levels considered significant can vary between centers (a value of 4000 copies/mL may be a risk factor for PTLD onset)
EBV disease, including PTLD at any level of viral load is an indication of immunosuppressive reduction and conversion to mTORi
PTLD and EBV viral load:
o Viral load alone cannot be used to diagnose PTLD as the test can lack both sensitivity and specificity
o The viral load will be low if the site of PTLD is protected such (graft itself or in some gastrointestinal lesions)
o Patients with elevated EBV VL do not always have or develop EBV/PTLD
o For the above reasons, an aggressive approach to the evaluation of PTLD should be used when this diagnosis is suspected
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 loaed and focal findings on examination or in a patient with primary EBV infection and increasing viral loads
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.
I appreciate your sensible clinical approach in managing this patient that includes modification of immunosuppression.
· What is the role of EBV monitoring in this scenario?
In solid organ transplant recipients, patients will demonstrate mild increase in EBV after transplantation, but majority of EBV positive PTLD will show more marked elevation in viral load. [1] Based on this observation early detection of PTLD was suggested for EBV positive PTLD. [1, 2] Centers with regards to definitions of high risk patients and cuff offs differ and hence no limit is determined. Rise to 740 copies/ 100microL in this case would suggest reduction in immunosuppressant’s and EBV DNA monitoring closely which could be suggestive of early PTLD. [1] Due to using different methods EBV viral load measurements cannot be compared between institutions. Since majority of PTLD occurs in first year after transplantation so it is reasonable to monitor high risk patient more frequently. Some guidelines societies would recommend EBV monitoring foe all transplants recipients. [3]
· How do you manage this case?
As this patient is asymptomatic with no illness defining symptoms so reduction of immunosuppressant with close surveillance for allograft rejection would be recommended. Allograft dysfunction monitoring should be on declining in GFR and where applicable donor derived cell free DNA. EBV DNA should be monitor for response. Base line investigation like CBC, LDH, Serum calcium uric acid and serum protein body scan should be done accordingly and monitor later for response. If progressive disease than will need to manage on the line of PTLD.
References
1. 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.
2. Tsai DE, Douglas L, Andreadis C, Vogl DT, Arnoldi S, Kotloff R, Svoboda J, Bloom RD, Olthoff KM, Brozena SC, Schuster SJ, Stadtmauer EA, Robertson ES, Wasik MA, Ahya VN. EBV PCR in the diagnosis and monitoring of posttransplant lymphoproliferative disorder: results of a two-arm prospective trial. Am J Transplant. 2008 May;8(5):1016-24. doi: 10.1111/j.1600-6143.2008.02183.x. Epub 2008 Feb 29. PMID: 18312608.
3. EBPG Expert Group on Renal Transplantation. 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. Nephrol Dial Transplant. 2002;17 Suppl 4:31-3, 35-6. doi: 10.1093/ndt/17.suppl_4.31. PMID: 12091638.
I appreciate your sensible clinical approach in managing this patient.
What is the role of EBV monitoring in this scenario?
PTLD is characterized by the presence of transformed lymphocytes of B-cell origin which are frequently infected by the Epstein-Barr virus (EBV)especially early time after transplantation like the indexed case
Around 1-15% of patients at risk of developing PTLD, renal transplant recipients having the lowest incidence of PTLD (0.8–2!.5%). early PTLD course more in pediatric and associated with EBV positive donor /Recipient negative with mortality rate in some reports was in the range of 40-70%. While PTLD EBV negative usually in adults and old age usually after first year of transplantation and another peak after 10 years (2).
EBV DNA detection by using quantitative PCR may have the role for the early diagnosis and also can provide an indirect method of identifying patients at risk for PTLD and to monitor their response to therapy, so this indexed case has gradually increasing EBV viral load which is concerning and put him at risk of PTLD. The assessment of the viral load via PCR amplification of peripheral blood EBV DNA is mandated to monitor preemptive PTLD therapy. It has been observed that transplant candidate with PTLD usually expresses an increased EBV viral load as compared to PTLD free recipient. This higher viral load invites more risk for PTLD evolution. However, there is a lot of limitation for the interpretation of the preemptive EBV PCR monitoring includes:
1. No clear cut off value for interpretation.
2. absence of usual points of time to do the monitoring
3. sources of samples are not universal
the positive and negative predictive of EBV viral load values for both SOT (28%-100% and 75%-100%, respectively, “cell-free plasma EBV DNA” has been reported as a better marker of EBV activity(3).
How do you manage this case?
Further history a bout pre-transplant EBV serology status for both donor and recipient, address the primary renal disease and previous viral exposure with intense IS for treatment of primary renal disease like SLE , the type of induction IS ( T cell depleting agent like ATG , or alemtuzumab and the current immunosuppression protocol, CNI trough level, as the main two risk factors for PTLD is the cumulative dose of IS and the oncogenic viral effect of EBV.
Symptoms like fever, wt. loss, LAP, respiratory or GI symptoms, CNS manifestation.
Further investigation like FBC, LDH, LFT, Virology: HIV type 1 & 2, Hepatitis B and C,and EBV serology, CMV/EBV DNA titers( molecular and serological testing )
immunohistochemistry by immunoglobulin staining and flow cytometry Tissue biopsy needed like LN biopsy to confirm the diagnosis of PTLD.
for now need frequent monitoring and reduction of IS as first step if the mentioned above work up confirm the diagnosis of PTLD including tissue biopsy with staging then we need MDT approach including transplant physician, oncology- hematologist, pathologist and reduction of immunosuppression is main treatment including modification to m TOR inhibitors, may consider monotherapy agents like rituximab with or without chemotherapy .
References
1.Tsai DE, Nearey M, Hardy CL, Tomaszewski JE, Kotloff RM, Grossman RA, Olthoff KM, Stadtmauer EA, Porter DL, Schuster SJ, Luger SM, Hodinka RL. Use of EBV PCR for the diagnosis and monitoring of post-transplant lymphoproliferative disorder in adult solid organ transplant patients. Am J Transplant. 2002 Nov;2(10):946-54. doi: 10.1034/j.1600-6143.2002.21011.x. PMID: 12482147.
2. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Hematology Guideline.
3.Kenagy DN, Schlesinger Y, Weck K, Ritter JH, Gaudreault-Keener MM,
Storch GA. Epstein-Barr virus DNA in peripheral blood leukocytes of
patients with posttransplant lymphoproliferative disease. Transplantation 1995; 60: 547–554.
I like your detailed well-structured summary well supported by references.I appreciate your sensible clinical approach in managing this patient.
EBV level monitoring
Management of the case
References
KDIGO kidney transplantation 2009
What is the role of EBV monitoring in this scenario?
The following points are to be noted in the index case
It has been observed that transplant recipients with very high EBV levels are more prone to the development of PTLD compared to those with less level of EVB viral load.
In one study, plasma from patients with PTLD had a median EBV viral load of 3225 copies/ml, while immunosuppressed controls without evidence of PTLD had fewer than 740 copies/m.
In view of the above, many centers have included routine checking of EBV viral load among their high-risk patients for early detection of EBV along sides clinical symptoms and histological findings on the affected organ.
Furthermore, if the patient starts receiving treatment for PTLD, the EBV viral load will be a good tool to measure response to the treatment
Pitfalls in the preemptive monitoring of the EBV viral loads.
How do you manage this case?
References
I like your detailed well-structured summary well supported by references.I appreciate your sensible clinical approach in managing this patient.
I like a list of 3 pitfalls.
Thank you prof Ajay
A 24-years old CKD 5 received a kidney from his brother 8 months ago. 111 mismatches, no DSA and negative FCXM. He is on CNI-based double immunosuppression with excellent kidney function. His EBV viral load increased from 200 copies/ml prior to the operation rose to 740 copies/ml 6 months after transplantation.
What is the role of EBV monitoring in this scenario?
How do you manage this case?
EBV monitoring in all patients with high risk of PTLD:
Intense immunosuppressive Protocols, EBV sero-status MM, pre-transplant malignancy, higher mismatch recipient.
KDIGO Guidlines Suggests:
Monitoring of high-risk kidney transplant recipients by nucleic acid testing post transplantation once in the first week, monthly for the first 3-6 months, then every 3 months until the end of the first post-transplant year, and additionally after treatment for acute rejection.
KDIGO also recommends reducing immunosuppressive medication in EBV seronegative patients with an increasing EBV viral load and in patients with EBV disease including PTLD.
How do you manage this case?
Details History and Examination (Constitutional, GIT Symptoms & LNs).
D/C or Decrease MMF, Decrease CNIs.
Close Monitor viral load & previous symptoms, monthly is recommended for the first 3-6 months, If persist viral load raising will consider more workup and Biopsy diagnosis then a 2nd Line Chemotherapy as indicated.
References:
*EBPG Expert Group on Renal Transplantation. 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. Nephrol Dial Transplant 2002; 17 Suppl 4:31.
*Recipient serostatus on the incidence of post-transplant lymphoproliferative disorder in kidney transplant recipients. Nephrol Dial Transplant. 2012; 27:2971–2979.
I like your detailed well-structured summary well supported by references.I appreciate your sensible clinical approach in managing this patient.Typing whole sentence in bold amounts to shouting
many healthy transplant recipients will demonstrate a modest increase in EBV viral load post-transplant
The vast majority of patients with EBV-positive PLTD will demonstrate a more marked elevation in EBV viral load.
PTLD may be detected early by monitoring of EBV viral load by PCR of blood , plasma of patients with a high risk of developing this complication.
While an increase in EBV viral load is suggestive of PTLS however , the diagnosis of PTLS is still made by histologic evaluation of tissue biopsy.
the absence of EBV viral load makes PTLS less likely, but doesn’t exclude the diagnosis .
Many transplant centers have incorporate EBV monitoring into the routine evaluation of patient with high risk .
high-risk patients are :
1-higher immunosuppressive approach.
2-EBV serostatus.
3-pretransplant malignancy.
4-higher mismatch recipient.
I think our patient is a low-risk factor and this is a normally rise in EBV viral load, however, I recommend monitoring.
antiviral prophylaxis with gancyclovir,
Reduce tacrolimus target level to 2 to 5.
Dear colleagues,
Many of you are replying without looking at the details provided. Are we really dealing with cancer or PTLD here.
Just because there increasing EBV viremia does not mean that you suggest chemotherapy without histopathological confirmation of PTLD! You need to use clinico-pathological corelation keeping in mind the clinical detail rather than any possiblity that are not even mentioned in the case recirds.
Is lymphocyte transfer from donor a clinically applicable well-accepted innovation?
PTLD is a serious and fatal complication of renal transplantation that occur mainly due to chronic T cell immunosuppression and proliferation of EBV B cells. Although EBV negative cases can occur
In order to prevent EBV related PTLD the following should be done:
So in the current patient
References
1- Funch DP, Walker AM, Schneider G, et al. Ganciclovir and acyclovir reduce the risk of post-transplant lymphoproliferative disorder in renal transplant recipients. Am J Transplant 2005; 5:2894.
2- McDiarmid SV, Jordan S, Kim GS, et al. Prevention and preemptive therapy of postransplant lymphoproliferative disease in pediatric liver recipients. Transplantation 1998; 66:1604.
3- Ellis D, Jaffe R, Green M, et al. Epstein-Barr virus-related disorders in children undergoing renal transplantation with tacrolimus-based immunosuppression. Transplantation 1999; 68:997.
4- Holmes RD, Sokol RJ. Epstein-Barr virus and post-transplant lymphoproliferative disease. Pediatr Transplant 2002; 6:456.
5- Humar A, Hébert D, Davies HD, et al. A randomized trial of ganciclovir versus ganciclovir plus immune globulin for prophylaxis against Epstein-Barr virus related posttransplant lymphoproliferative disorder. Transplantation 2006; 81:856.
6- Opelz G, Daniel V, Naujokat C, et al. Effect of cytomegalovirus prophylaxis with immunoglobulin or with antiviral drugs on post-transplant non-Hodgkin lymphoma: a multicentre retrospective analysis. Lancet Oncol 2007; 8:212.
7- EBPG Expert Group on Renal Transplantation. 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. Nephrol Dial Transplant 2002; 17 Suppl 4:31.
8- 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.
9- 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.
10- 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.
I like your detailed well-structured summary well supported by a very good list of appropriate references.I appreciate your sensible clinical approach in managing this patient.
Role of EBV monitoring
Close monitoring of EBV viral load within 3 months after transplant can predict a high risk of PTLD.
EBV transmission to naive recipients increases the risk of PTLD. The risk of PTLD is much higher in these patients.
KDIGO suggests monitoring of high risk kidney transplant recipients by nucleic acid testing post transplantation once in the first week, monthly for the first 3-6 months, then every 3 months until the end of the first post transplant year, and additionally after treatment for acute rejection.
KDIGO also recommends reducing immunosuppressive medication in EBV seronegative patients with an increasing EBV viral load and in patients with EBV disease including PTLD.
Management
EBV DNA monitoring and early intervention is to be done. This includes reduction in immunosuppression and possibly Rituximab if there is significant increase in viral load.
PET imaging can be done to rule out PTLD in the patient.
If titers are greater than 1000 copies/ml (620 IU/ml) then
Check titers two weeks later and,
If PTLD is found on CT/PET scan, then refer to hematologist, and patient will be managed with a multidisciplinary team including transplant nephrologist.
If no PTLD is detected, then Rituximab treatment can be considered.
References
I like your detailed well-structured summary well supported by references.I appreciate your clinical approach in managing this patient.
We need to assess the risk to the recipient by reviewing the donor’s status
Monitoring NAT is recommended for high-risk KTRs (donor EBV seropositive/recipient seronegative):
• once in the first week after transplantation
• once in the first week after transplantation
EBV-seronegative patients with a rising EBV load should receive less immunosuppressive treatment.
First, I will ask about the symptoms: fever and diarrhea. Lymph node examination.
I will keep the CNI at the lower level (3-5).
close observation of the EBV and the previous symptoms.
Asymptomatic EBV load increases are common. If individuals acquire intercurrent pathogen infections while having an asymptomatic EBV load rise, such patients may be misdiagnosed with EBV illness. In such cases, only a tissue diagnosis can confirm an EBV illness.
A primary EBV infection following kidney donation significantly increases the probability of EBV illness and PTLD. A PTLD diagnosis revealed high EBV loads.
EBV load rises 4–16 weeks before PTLD, indicating patients who may benefit from intervention.
Preemptive antiviral medication for growing virus loads is controversial. Reduced immunosuppressive drug (tacrolimus) use without antiviral treatment lowered EBV PTLD risk.
Preemptive antiviral medication (e.g., acyclovir, ganciclovir) for increased or growing EBV load without immunosuppression is unproven.
References:
Eckardt, K. U., Kasiske, B. L., & Zeier, M. G. (2009). KDIGO clinical practice guideline for the care of kidney transplant recipients. American Journal of Transplantation, 9, S1-S155.
I appreciate your step-wise clinical approach in managing this patient that is well supported by evidence.
You suggest a reduction in CNI, but there is no mention of you action regarding antimetabolites.
1.What is the role of EBV monitoring in this scenario?
-EBV is a ubiquitus tumour virus belong to gamma herpes virus and it is associated with a variety of malignancies incluing PTLD. The gold standard diagnosis of EBV-associated malignancy is biopsy but this may not be possible many times because of the patient condition or unaccessible 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:
B.Challenges:
2.How do you manage this case?
1.Evaluation:
–This patient needs further evaluation e.g.,EBV status before transplantation, the donor EBV status, CMV status for the R and D
-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: Largely depend on many findings and not only increasing EBV DNA
-Having only increase EBV DNA is a grey area
-If the initial investigations were negative and he remained symptomatic with no abnormal findings :
-If we got something from the investigations, then the first step would be reduction of the immune suppression and evaluate the response
Source: EBV viral load n diagnosis, monitoring, and response assessment by Kimura H, and Kwong YL
Your replies regarding immunosuppression are equivocal.
Thnxs prof, my views are here but they are not necessarily correct
EBV Viral load determination in the peripheral blood:
Rocchi et al (1977) was the first to suggest a relationship between PTLD and the number of EBV-infected cells in peripheral blood. Where they reported that healthy EBV-seropositive individuals had a peripheral blood count of 0.1 to 1 EBV-immortalizing unit/106 peripheral blood mononuclear cells (PBMCs).
In 1994, Riddler et al reported that an abnormally elevated EBV viremia correlated with PTLD development. showed that patients with PTLD had 1000 or more EBV-immortalizing units/106 PBMC .
Data from the Riddler study indicated that using semiquantitative polymerase chain reaction (PCR), patients with PTLD had a viral load greater than 5000 EBV genome copies/106 PBMC
Data from two Canadian centres indicate that the negative predictive values of different levels of EBV viremia are in the region of 90% to 100%, while the positive predictive values are only 50% to 60% at best. So viral load can be used better to exclude the presence of PTLD (1)
There is also conflicting data on whether a long-lasting period of high EBV load is a predictor for the later development of EBV-related PTLD. (2)
The utility of routinely performing EBV-VL in adult solid organ transplant recipients to avoid PTLD development is still debated (3)
The suspicion driven by disease symptoms and clinician experience appears to be the keystone for PTLD diagnosis and treatment (3)
So the number of copies mentioned in the case needs risk assessment including CMV PCR, IS load , Clinical evaluations, laboratory tests, ultrasounds, or CT-scans of suspected organs were performed and additional investigations such as biopsy of lymph nodes and specific organs should be considered
Accordingly
1- Although different guidelines define different viral load level to assess the PTLD risk, the level mentioned in the case is low so follow up for viral load monthly is advised
2- Prophylaxis against CMV
3- Patient education for the risk and importance of follow up
4- If the patient is chronic high load carrier : reduction of IS targeting TAC to trough level of <5 ng/ml and reducing MMF and evaluation viral load monthly if continued high MMF can be stopped
5- Screening for PTLD as mentioned above
6- Use of anti-viral is controversial
Ref
1- Allen U, Alfieri C, Preiksaitis J, Humar A, Moore D, Tapiero B, Tellier R, Green M, Davies D, Hébert D, Weitzman S, Petric M, Jacobson K; Canadian PTLD Workshop Group – 1999. Epstein-Barr virus infection in transplant recipients: Summary of a workshop on surveillance, prevention and treatment. Can J Infect Dis. 2002 Mar;13(2):89-99
2- Ladfors, S.W., Lindahl, J.K., Hansson, S. et al. Long-lasting chronic high load carriage of Epstein-Barr virus is more common in young pediatric renal transplant recipients. Pediatr Nephrol 35, 427–439 (2020).
3- Franceschini, Erica MD1; Plessi, Jessica MD1; 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. Transplantation Direct 3(7):p e182, July 2017.
Does any anti-viral really work in this situation?
thanks Sir for kind reply
trials for the use of antiviral failed to show any benefit
1-What is the role of EBV monitoring in this scenario?
–The role of EBV in the pathogenesis of PTLD among solid organ transplant recipients.
EBV-positive disease;
-In most affected patients, PTLD is an Epstein-Barr virus (EBV)-positive B cell proliferation occurring in the setting of immunosuppression and decreased T cell immune surveillance.
EBV-negative disease;
-EBV-negative PTLD has been documented in up to 30 percent of PTLD in some series.
-As an example, post-transplantation primary effusion lymphoma may be associated with human herpes virus 8 (HHV-8) infection.
2-How do you manage this case?
Diagnosis;
-An accurate diagnosis of PTLD requires a high index of suspicion.
-Radiologic evidence of a mass, or elevated serum markers (such as increased lactate dehydrogenase [LDH] levels) are suggestive of PTLD.
-Positive positron emission tomography (PET) scanning also favors the diagnosis.
-A tissue biopsy, preferably an excisional biopsy, with review by an expert hematopathologist, is required to ensure an accurate diagnosis.
-Diagnosis of central nervous system or cardiac lymphoma is particularly difficult.
Treatment of PTLD;
-Management of PTLD has varied significantly according to the PTLD subtype and the type of transplant, as well as from institution to institution.
-The two main goals of therapy are eradication of the PTLD and preservation of graft.
-Reduction in immunosuppression (RIS); by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function.
-Switch to mTOR Inhibitors; some studies have shown successful PTLD regression with sirolimus, others have shown higher incidence of PTLD with its use.
-Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond adequately to RIS as initial therapy.
-Rituximab is an anti-CD-20 monoclonal antibody with efficacy against CD-20 positive PTLD.
-Chemotherapy; Indications of Immunochemotherapy include:
Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI.
-Adoptive immunotherapy; with EBV-specific cytotoxic T cells, are generally reserved for persistent disease despite initial therapy.
-Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity.
-Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD.
–G-CSF; is recommended for patients receiving chemotherapy.
-PJP prophylaxis; should be offered to all patients with diagnosis of PTLD.
–Re-transplantation; is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed.
References;
–European best practice guidelines for renal transplantation. Nephrol Dial Transplant 2002.
-Post-Transplant Lymphoproliferative Disorder: A Clinical Perspective Nalaka Gunawansa1,2 , Roshni Rathore2,3, Ajay Sharma2,4 and Ahmed Halawa2,5*may 2019.
–Randhawa PS, Jaffe R, Demetris AJ, et al. Expression of Epstein-Barr virus-encoded small RNA (by the EBER-1 gene) in liver specimens from transplant recipients with post-transplantation lymphoproliferative disease. N Engl J Med 1992; 327:1710.
–Leblond V, Davi F, Charlotte F, et al. Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity? J Clin Oncol 1998; 16:2052.
–Craig FE, Johnson LR, Harvey SA, et al. Gene expression profiling of Epstein-Barr virus-positive and -negative monomorphic B-cell posttransplant lymphoproliferative disorders. Diagn Mol Pathol 2007; 16:158.
I disagree with your answer. Please review your answer and try again
Thanks; our Prof. ; sorry: because I answered the management of PTLD in general, and i dont reflex my answer on current case.
Introduction;
-In current case with low viral load of EBV and rising from 200 copies/ml prior to the operation to 740 copies/ml 6 months after transplantation (which still unsignificant)
-Full medical history for patient and his brother should be taken before and after transplantation.
-Complete physical examination & Further investigations including (D-EBV / R-EBV) status pre Tx , D/R CMV, HIV , Tac trough)
Role of What is the role of EBV monitoring in this scenario;
-PTLD may be detected early by monitoring the EBV viral load by quantitative polymerase chain reaction (PCR) of unfractionated whole blood, plasma, or peripheral blood mononuclear cells of patients at high risk of developing this complication.
–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.
-The decision to monitor less frequently must be individualized and take into consideration many factors including the type of graft, the degree of ongoing immunosuppression, and the pattern of EBV viral loads to date.
-Monitoring for an uncomplicated hematopoietic cell transplantation (HCT) recipient may begin with screening on the day of transplantation, weekly monitoring for the first three months, followed by monthly monitoring for at least one year.
–Styczynski J, Reusser P, Einsele H, et al. Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia. Bone Marrow Transplant 2009; 43:757.
–Monitoring for an uncomplicated kidney transplant recipient may begin with screening within the first week after transplant followed by monthly monitoring for the next three to six months and then every three months for the rest of the first year.
–EBPG Expert Group on Renal Transplantation. 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. Nephrol Dial Transplant 2002; 17 Suppl 4:31.
Management of this case;
1-Repeat EBV NAT monthly with close observation if developed any symptoms of EBV viremia.
2-Review I.S. medications (Tac level 6-8 ng/ml).
3-If EBV Viral load increasing , i will go to RIS.
According KDIGO guidelines;
-Suggest monitoring high-risk (donor EBV seropositive/recipient seronegative) KTRs for EBV by NAT. (2C)
-Once in the first week after transplantation (2D) ,
-Then at least monthly for the first 3–6 months after transplantation (2D),
-Then every 3 months until the end of the first post-transplant year (2D) ,and additionally after treatment for acute rejection. (2D)
-Suggest that EBV-seronegative patients with an increasing EBV load have immunosuppressive medication reduced. (2D)
-Recommend that patients with EBV disease, including PTLD, have a reduction or cessation of immunosuppressive medication. (1C)
I appreciate your clinical approach in managing this patient that is well supported by level of recommendation
What is the role of EBV monitoring in this scenario?
How do you manage this case?
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9(Suppl 3):S1–S155.
How would you manage this case Abhijit?
EBV load can be used for diagnosis, monitor and prevent PTLD
EBV load may be higher or increased even without appearance of symptoms and signs
should be used as a measure for the tumor burden and for early detection and prevention of progression and also can monitor the response to treatment which can be done by RIS.
high load suggest high susceptibility for development of PTLD or impending PTLD
so it allows early intervention to prevent the disease
qualitative PCR for EBV is mostly positive in immunosuppressed patients, so the quantitative PCR is more valuable
management:
1- RIS which carries the risk of graft rejection and loss, but can be done to the least trough level with normal graft function with close monitor of graft function and EBV PCR
2- infusing donor lymphocytes
3-infusing EBV-specific cytotoxic T cells that are grown ex vivo by exposing HLA-matched T cells to EBV antigens
4-infusing anti-CD20 monoclonal antibody ( rituximab)
5-traditional cancer treatment with radiation and multidrug chemotherapy
chronic high EB viral load (CHL) was defined as the presence of EBV DNA ≥ 4.2 log10 Geq/ml in whole blood, in > 50 % of the samples for ≥ 6 months as previously.
Non-CHL consisted of patients with undetectable EB viral load (UVL) and patients with low EB viral load (LVL). UVL was defined as having no more than one sample of detectable EBV DNA levels following transplantation, and low EB viral load (LVL) included patient not meeting criteria for UVL nor CHL.
Susanne Westphal Ladfors, Jenny K. Lindahl, Sverker Hansson, Per Brandström, Rune Andersson, Marianne Jertborn, Magnus Lindh, Susanne Woxenius, Vanda Friman.Long-lasting chronic high load carriage of Epstein-Barr virus is more common in young pediatric renal transplant recipients. Pediatric Nephrology volume 35, pages 427–439 (2020)
Margaret L. Gulley, Weihua Tang. Using Epstein-Barr Viral Load Assays To Diagnose, Monitor, and Prevent Posttransplant Lymphoproliferative Disorder. Clin Microbiol Rev. 2010 Apr; 23(2): 350–366.
I disagree with your answer. Please review your answer and try again
This patient is R+, donor status is not known
Algorithm
D-/R+, D+/R+
Do Monthly EBV PCR for 3 months
Then Three monthly until 1 year
If
Titres > 1000 copies/ml Or > 620 IU/ml Reduce IS (MMF/Aza/Tac/CyA)
Check titres 2 weeks later
Titres increasing– Arrange CT scan Head/Neck/Chest/Abdomen/Pelvis to rule out PTLD even if patient is asymptomatic. PET should be considered
PTLD on CT- Refer to Haematology. Patient managed at multidisciplinary level with transplant nephrologists.
If titres are decreasing, monitor PCR fortnightly
In the index case He is on CNI-based double immunosuppression with excellent kidney function. His EBV viral load increased from 200 copies/ml prior to the operation rose to 740 copies/ml 6 months after transplantation.so will keep monitoring his EBV PCR monthly to look for increasing or decreasing trend.If EBV PCR goes above 1000 will reduce his MMF first and recheck and if still increasing then will decreae his CNI to achieve lower level of therapeutic target for the month post transplant.
EPSTEIN BARR VIRUS (EBV)- POST TRANSPLANT MANAGEMENT UHL RENAL TRANSPLANT GUIDELINE