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Keywords:

  • B-lymphocyte;
  • cytotoxic T lymphocyte surveillance;
  • Epstein-Barr virus;
  • posttransplant lymphoproliferation;
  • primary infection;
  • PTLD

Introduction

  1. Top of page
  2. Introduction
  3. Epidemiology
  4. Risk Factors
  5. Manifestations of Non-PTLD EBV Syndromes
  6. Manifestations and Diagnosis of PTLD
  7. Prevention of PTLD
  8. Treatment of PTLD
  9. Prognostic Indicators of PTLD
  10. Summary of Key Recommendations/Statements
  11. Acknowledgments
  12. Disclosures
  13. References

Posttransplant lymphoproliferative disorder (PTLD) is recognized as potentially one of the most devastating complications of organ transplantation. Epstein-Barr virus (EBV) is associated with the majority of PTLD cases. The entity referred to as EBV-associated PTLD encompasses a wide spectrum of clinical conditions characterized by lymphoproliferation after transplantation. These syndromes range from uncomplicated infectious mononucleosis to true malignancies (1–3). Disease may be nodal or extranodal, localized, often in the allograft, or widely disseminated. Patients may be symptomatic or asymptomatic. PTLD may resemble a self-limited infection or be indistinguishable from non-Hodgkin's lymphoma. Lesions may be localized and progress slowly or the patient may present with a fulminant multisystem sepsis-like syndrome.

The EBV genome is found in the majority (>90%) of B-cell PTLD occurring early (within the first year) after solid organ transplantation. This virus is known to play a major role in the development of PTLD. The pathogenesis of these disorders is complex, and related to EBV's ability to transform and immortalize B lymphocytes, sometimes combined with secondary genetic or epigenetic events that occur during uncontrolled proliferation. In this setting, immunomodulation caused directly by the virus and exogenous immunosuppressive drugs alter both EBV-specific cytotoxic T-lymphocyte (CTL) responses critical for controlling the proliferative response and survival of infected cells (4,5). Although B-cell transformation and PTLD are a result of latent EBV infection, lytic EBV infection appears to be extremely important during primary EBV infection prior to the development of the CTL response (6). For a patient experiencing EBV infection for the first time in the early posttransplant period, delay in development of the immune response theoretically would prolong the one-way self- amplifying circuit of naïve B-cell infection, latency in memory cells and reactivation with infectious virus production. The resulting high virion peak results in massive infection of the B-cell pool and perhaps other cells not normally infected (T cells, NK cells, memory B cells), thereby setting the stage for secondary events that lead to malignancy.

This document summarizes current recommendations and supporting data that guides the prevention, diagnosis and treatment of PTLD in the solid organ transplant recipient. Although the focus is largely on PTLD, relevant aspects of non-PTLD EBV syndromes are addressed, as appropriate.

Epidemiology

  1. Top of page
  2. Introduction
  3. Epidemiology
  4. Risk Factors
  5. Manifestations of Non-PTLD EBV Syndromes
  6. Manifestations and Diagnosis of PTLD
  7. Prevention of PTLD
  8. Treatment of PTLD
  9. Prognostic Indicators of PTLD
  10. Summary of Key Recommendations/Statements
  11. Acknowledgments
  12. Disclosures
  13. References

Humans are the only known hosts of EBV. In immunocompetent individuals, this virus is transmitted in the community by exposure to infected body fluids, such as saliva. Although infection may also be acquired in the community by the traditional routes of transmission seen in immunocompetent patients, for solid organ transplant recipients, EBV that is transmitted from the seropositive donor organ is an important source of infection. Transmission is also possible when nonleukoreduced blood products are used. In the least affluent nations, the vast majority of individuals are EBV-seropositive before the age of 5 years (7). However, in the more affluent developed nations, seropositivity can be delayed until the fourth decade of life.

The diagnosis of PTLD requires tissue examination. In many settings, tissue is not available or accessible. When laboratory evidence of EBV infection is present and other causes have been ruled out, investigators have used the term EBV ‘disease’ to describe a number of clinical syndromes where EBV is believed to play a causative role.

The highest rate of PTLD in the solid organ transplant setting is seen in the first year posttransplant. However, cases occurring in this time-frame represent only one fifth of the total cumulative 10-year PTLD burden (8). However, a significant proportion of late PTLD (21–38%) may be EBV-negative non-B cell and phenotypically monomorphic. The median time of onset of primary EBV infection after solid organ transplantation is 6 weeks and reactivation/infection events are initially most often observed in the 2- to 3-month period after transplantation. PTLD incidence is also dependent on the type of organ transplanted (6). In this regard, small intestinal transplant recipients are at the highest risk for development of PTLD (up to 32%), whereas recipients of pancreas, heart, lung and liver transplants are at moderate risk (3–12%). Renal transplants recipients are at relatively low risk (1–2%).

Risk Factors

  1. Top of page
  2. Introduction
  3. Epidemiology
  4. Risk Factors
  5. Manifestations of Non-PTLD EBV Syndromes
  6. Manifestations and Diagnosis of PTLD
  7. Prevention of PTLD
  8. Treatment of PTLD
  9. Prognostic Indicators of PTLD
  10. Summary of Key Recommendations/Statements
  11. Acknowledgments
  12. Disclosures
  13. References

The risk factors for the development of early (≤12 months after transplant) and late PTLD (>12 months after transplant) in solid organ transplant recipients are shown in Table 1 (8–11). Many of the risk factors are interrelated and multivariate analysis is required to identify independent risk factors. As previously indicated, the overwhelming risk factor is primary EBV infection. Individuals who are R+ are not devoid of PTLD risk. These individuals may account for up to 25% of PTLD cases in children (12). Intestinal transplant recipients who are EBV-seropositive remain at a high risk of PTLD. Given that children are more likely to be EBV-seronegative recipients receiving seropositive organs, they are several fold more likely to develop PTLD compared with their adult counterparts. Besides this variable, it is likely that the net state of immunosuppression is also a major risk factor. An important risk factor is the use of antilymphocyte globulins, particularly high dose or repetitive courses, which have the potential to negate the effect of cytotoxic T-lymphocyte surveillance activity.

Table 1.  Risk factors for PTLD in solid organ transplant recipients
  1. Contradictory/controversial evidence exists for the role of the following as risk factors for primary disease: tacrolimus in pediatric recipients, certain cytokine gene polymorphisms, preexisting chronic immune stimulation, Hepatitis C infection, viral strain virulence (EBV1 vs. EBV-2 and LMP1 deletion mutants).

Early PTLD
 Primary EBV infection
 Young recipient age
 Type of organ transplanted
 CMV mismatch or CMV disease
 OKT3 and polyclonal antilymphocyte antibodies
Late PTLD
 Duration of immunosuppression
 Type of organ transplanted
 Older recipient age

Manifestations of Non-PTLD EBV Syndromes

  1. Top of page
  2. Introduction
  3. Epidemiology
  4. Risk Factors
  5. Manifestations of Non-PTLD EBV Syndromes
  6. Manifestations and Diagnosis of PTLD
  7. Prevention of PTLD
  8. Treatment of PTLD
  9. Prognostic Indicators of PTLD
  10. Summary of Key Recommendations/Statements
  11. Acknowledgments
  12. Disclosures
  13. References

Although the most feared EBV-associated disease after transplantation is PTLD, patients may experience non-PTLD–related disease. The features of this might include the manifestations of infectious mononucleosis (fever, malaise, exudative pharyngitis, lymphadenopathy, hepatosplenomegaly and atypical lymphocytosis), specific organ diseases such as hepatitis, pneumonitis, gastrointestinal symptoms and hematological manifestations such as leucopenia, thrombocytopenia, hemolytic anemia and hemophagocytosis. Some of these manifestations may be identical to the features of PTLD (Table 2). EBV-associated leiomyosarcoma has also been described.

Table 2.  Presenting symptoms and signs in patients with lymphoproliferative disorder
Symptoms/complaintsSigns
Swollen lymph glandsLymphadenopathy
Weight lossHepatosplenomegaly
Fever or night sweatsSubcutaneous nodules
Sore throatTonsillar enlargement
Malaise and lethargyTonsillar inflammation
Chronic sinus congestion and discomfortSigns of bowel perforation
Focal neurologic signs
Anorexia, nausea and vomitingMass lesions
Abdominal pain
Gastrointestinal bleeding
Symptoms of bowel perforation
Cough and shortness of breath
Headache
Focal neurologic deficits

Manifestations and Diagnosis of PTLD

  1. Top of page
  2. Introduction
  3. Epidemiology
  4. Risk Factors
  5. Manifestations of Non-PTLD EBV Syndromes
  6. Manifestations and Diagnosis of PTLD
  7. Prevention of PTLD
  8. Treatment of PTLD
  9. Prognostic Indicators of PTLD
  10. Summary of Key Recommendations/Statements
  11. Acknowledgments
  12. Disclosures
  13. References

Clinical assessment

Relevant clinical information includes, but is not limited to the following:

  • • 
    EBV serostatus of transplant recipient and donor
  • • 
    CMV donor/recipient serostatus
  • • 
    Time from transplantation to PTLD diagnosis
  • • 
    Type of allograft

An adequate physical examination is required to detect the manifestations of PTLD, which may be quite nonspecific (Table 2). Given the predilection for the reticuloendothelial system to be involved, this clinical examination should include a meticulous assessment for lymphadenopathy and adenotonsillar hypertrophy. The general physical examination might elicit evidence of pallor or signs referable to the site(s) of organs affected by PTLD.

Laboratory tests

(i) Blood tests (non-EBV):  Initial tests include a complete blood count with white blood cell differential. In some patients with PTLD, there may be evidence of anemia that is usually normochromic, normocytic. In patients with gastrointestinal tract PTLD and occult bleeding over a prolonged period of time, there may be evidence of iron-deficiency anemia with hypochromia and microcytosis. The source of bleeding can be determined by performing additional testing, such as examination of the stools for occult blood. Thrombocytopenia has also been observed in non-PTLD EBV disease.

Depending on the location of PTLD lesions, there may be evidence of disturbance in serum electrolytes, liver and renal function tests. Elevations in serum uric acid and lactate dehydrogenase may occur. Serum immunoglobulin levels may be elevated as part of an acute phase reaction.

Cytomegalovirus may contribute to the net state of immunosuppression and is known to be a risk factor for PTLD. Diagnostic tests would include pp65 antigemiza assay, plasma or whole blood quantitative CMV viral load assessments on blood as well as the examination of biopsy tissue for viral inclusions, CMV DNA and CMV antigens by immunohistochemistry. HHV6 may also be an indirect cofactor for PTLD due to the potential for interaction with CMV (13).

Other adjunctive tests have been investigated. These include serum IgE, IL6 and IL10 (14–17). Based on current data, the relationship between these assays and PTLD are sufficiently inconsistent to limit their utility in the evaluation of PTLD. However, these and other tests remain the subject of research. For example, preliminary data suggest that polymorphisms in the IFN-γ (18) and Sic11a1 genes (19) of transplant recipients may be associated with increased PTLD risk and might be used in conjunction with viral load, although these data require further validation.

(ii) Blood tests (EBV-related):  The understanding is that the diagnostic utility of EBV-specific tests is compromised in the setting of EBV-negative PTLD.

EBV serology: In immunocompetent patients, primary EBV infection can be determined by measuring EBV anti-viral capsid antigen IgM and IgG antibodies, anti-early antigen (EA) and anti-Epstein Barr nuclear antigen. Persistence of anti-EA antibodies has been shown to be more likely in PTLD patients (20) and patients who are known to be seropositive before transplantation may have falling anti-EBNA-1 titers in the setting of elevated EBV loads and the presence of PTLD (21). Serology is unreliable as a diagnostic tool for either PTLD or primary EBV infection in immunocompromised patients, due to delayed or absent humoral responses. Another important drawback is that if these patients are receiving blood products, the passive transfer of antibodies may render EBV IgG antibody assays difficult to interpret. The most important role of EBV serology in the setting of transplantation is the determination of pretransplant donor and recipient EBV serostatus for PTLD risk assessment.

Detection of EBV nucleic acids or protein in tissue: Documenting the presence of EBV-specific nucleic acids in tissues is of value in the diagnosis of EBV-associated PTLD. RNA in situ hybridization targeting EBV-encoded small nuclear RNA (EBER) (22,23) is the preferred approach and is more sensitive for detecting EBV-infected cells than in situ hybridization directly targeting viral DNA, because EBERs are expressed at levels several orders of magnitude higher in infected cells. EBV latent antigens can also be detected in fixed tissues by immunohistochemistry using commercial antibodies directed against EBNA-1, EBNA-2 and LMP-1 (24) and used to document the presence of EBV, although these techniques are less sensitive than in situ hybridization. Direct EBV DNA amplification from tissue is less useful as it does not allow cellular localization or differentiation of EBV in lesions from that present in passenger lymphocytes.

Viral load determination: The optimal way to perform and utilize quantitative EBV viral load assays for surveillance, diagnostic and disease monitoring purposes remains uncertain (III). A major concern with viral load monitoring is that, in the absence of an international reference standard, the wide array of commercial and in house developed assays currently being used lack standardization. Data suggest that in most laboratories, intra-laboratory result reproducibility and result linearity over the dynamic range of the assay are reasonable. Therefore, trends in patients over time within individual institutions using a single assay are valid and more useful than single values (25,26). However, significant and extreme interlaboratory variability exists in both qualitative and quantitative viral load results, raising questions regarding the validity of interinstitutional result comparison in the absence of formal cross-referencing of assays between institutions (25,26). Optimal extraction methods, gene targets and instrument platforms for EBV viral load assessments have not been determined. Although EBV viral load in whole blood and lymphocytes appears comparable, controversy with respect to preferred sample type (whole blood vs. plasma) and reporting units remain (27,28).

Studies of the sensitivity and specificity of quantitative EBV viral load for the diagnosis of early PTLD and symptomatic EBV infection are limited (29–32). Pediatric populations have been the focus of many studies of EBV viral load after solid organ transplantation. In high-risk asymptomatic solid organ transplant recipients being serially monitored, the use of EBV viral load as a diagnostic test (i.e. levels above a specific quantitative threshold being diagnostic of PTLD) has good sensitivity for detecting EBV-positive PTLD but misses some cases of localized and donor-derived PTLD. However, it has poor specificity, resulting in good negative (greater than 90%) but poor positive predictive value (as low as 28% and not greater than 65%) in these populations. When used in the diagnostic context, this would result in significant unnecessary investigation of patients for PTLD.

Formal evaluation of EBV viral load assessments as a diagnostic tool using a single evaluation in patients presenting with symptoms and/or signs (usually mass lesions) with no history of recent or previous monitoring have not been carried out in populations at high risk for PTLD. However, an elevated load would be of concern in patients with an illness compatible with EBV disease/PTLD. In low-risk seropositive adults, transplant recipients presenting for investigation with signs and symptoms compatible with PTLD, high EBV viral load lacked sensitivity, understandably missing all cases of EBV-negative PTLD and some cases of localized EBV-positive PTLD, but was highly specific for EBV-positive PTLD (31). EBV viral load measured in plasma appears to improve the specificity of the test as a diagnostic tool for EBV-positive PTLD, while not significantly lowering its sensitivity relative to assessments in cellular blood compartments (31–33).

Among lung and heart–lung transplant patients in whom the lung is often the primary site of PTLD, the determination of EBV load on brochoalveolar lavage fluid has been suggested as a good predictor of PTLD and may be superior to peripheral viral load assays (34). Adjunctive laboratory testing may improve the specificity of high viral load as a predictor of PTLD. The best studied and most promising are assays measuring T-cell restoration or EBV-specific T-cell responses (35). Although data suggest that the specificity and positive predictive value of EBV viral load can be significantly improved by using concomitant EBV-specific T-cell elispot and tetramer assays, these assays are complex, costly and difficult to implement in a routine diagnostic laboratory. Viral gene expression profiling as an adjunct test has demonstrated no distinctive pattern in peripheral blood that is indicative of PTLD or PTLD risk, although data are limited (36).

(iii) Radiographic imaging:  Most centers employ a total body computerized tomography (CT) scan (head to pelvis) as part of the initial assessment of PTLD. Beyond this, the choice of tests depends largely on the location of suspected lesions and the historical sequence of prior radiographic testing. Many experts recommend that a head CT or MRI be included as part of the initial work-up, as the presence of central nervous system lesions will significantly influence treatment and outcome. CT scanning of the neck may help to define the extent of involvement or detect subtle early changes that necessitate biopsy to rule out PTLD.

Pulmonary lesions that are visible on chest radiographs may require high-resolution CT scanning for better delineation prior to biopsy. Furthermore, CT of the chest may reveal mediastinal adenopathy and small pulmonary nodules that are not visible on the plain chest radiograph. Suspected intraabdominal lesions may be evaluated with ultrasonography and CT scanning. This is in addition to other modalities of assessment, including GI endoscopy in the case of intestinal hemorrhage, persistent diarrhea and unexplained weight loss, where necessary.

Positron emission tomography–computerized tomography (PET–CT) is emerging to be a useful test in the evaluation of PTLD (37,38), although additional data are needed on its utility across the known heterogenous spectrum of PTLD lesions.

(iv) Histopathology:  Pathology remains the gold standard for PTLD diagnosis (2,39). Although excisional biopsy is preferred, needle biopsy is acceptable when larger biopsies are impractical, as in the case of allograft organ biopsy. The tissue specimen should be interpreted by a hematopathologist or pathologist familiar with histopathologic features of PTLD. Institutional protocols should be put in place to ensure that tissue is handled appropriately for ancillary diagnostic tests.

It is essential that reactive conditions such as plasma cell hyperplasia and infectious mononucleosis be clearly segregated in the classification process from potentially neoplastic lesions, which contain monoclonal elements. The Society for Hematopathology initially published a working categorization of PTLD, which has been updated under the auspices of the World Health Organization (39) and is recommended for use (III). Table 3 summarizes the key features of this classification system. Intrinsic weaknesses are present in the purely histologic classification of PTLD. Additional pathologic tools have provided a better understanding of the pathogenesis of PTLD with the goal of developing more effective and more targeted therapy. Use of ancillary diagnostic tests is strongly recommended, if available (AIII). These tests are as follows:

Table 3.  Categories of posttransplant lymphoproliferative disorder (PTLD)
  1. 1Some mass-like lesions in the posttransplant setting may have the morphologic appearance of florid follicular hyperplasia or other marked but non-IM-like lymphoid hyperplasias.

  2. 2Indolent small B-cell lymphomas arising in transplant recipients are not included among the PTLD.

  3. 3NOS denotes ‘not otherwise specified’.

Early lesions1
 Plasmacytic hyperplasia
 Infectious mononucleosis-like lesion
Polymorphic PTLD
Monomorphic PTLD (classify according to lymphoma they
 resemble)
B-cell neoplasms
 Diffuse large B-cell lymphoma
 Burkitt lymphoma
 Plasma cell myeloma
 Plasmacytoma-like lesion
 Other2
T-cell neoplasms
 Peripheral T-cell lymphoma, NOS3
 Hepatosplenic T-cell lymphoma
 Other2
Classical Hodgkin lymphoma-type PTLD
  • • 
    Cell phenotype and lineage
  • • 
    Clonality
  • • 
    Presence of EBV (EBER in situ hybridization)
  • • 
    Alterations in oncogenes, tumor suppressor genes or chromosomes
  • • 
    Donor versus recipient origin
  • • 
    Therapy dependent markers (expression of CD20, cytotoxic T-cell epitopes)

Clinical recurrence of PTLD has been estimated to occur in approximately 5% of cases. Recurrent PTLD may represent true recurrences (morphologically and clonally identical to the original tumor), PTLD in a more aggressive form or the emergence of a second primary tumor such as an EBV-associated leiomyosarcoma. For this reason, biopsy of such recurrences is encouraged (III) (2).

(v) Other tests:  Once the diagnosis of PTLD has been determined, or is highly suspected, additional diagnostic tests may be considered selectively to assist in defining the clinical stage of disease. These investigations may include a bone scan as part of a lymphoma work-up, a bone marrow biopsy and a lumbar puncture to assist in ruling out bone, bone marrow and CNS disease, respectively.

Clinical staging of PTLD:  No staging system currently exists for PTLD and no single system totally captures the full spectrum of what is classified as PTLD. Although the Ann Arbor staging has been used with the Cotswold's modifications, other staging approaches, such as the Murphy system, have been used in children (40). At the very minimum, staging should document the presence or absence of symptoms, the precise location of lesions, the involvement of the allograft and the presence of CNS involvement. In cases of EBV-positive PTLD documented by immunohistochemistry or in situ hybridization, an EBV viral load assay should be performed to better document the incidence and natural history of EBV viral load negative but EBV positive PTLD cases, currently being studied through the use of a registry.

Prevention of PTLD

  1. Top of page
  2. Introduction
  3. Epidemiology
  4. Risk Factors
  5. Manifestations of Non-PTLD EBV Syndromes
  6. Manifestations and Diagnosis of PTLD
  7. Prevention of PTLD
  8. Treatment of PTLD
  9. Prognostic Indicators of PTLD
  10. Summary of Key Recommendations/Statements
  11. Acknowledgments
  12. Disclosures
  13. References

Given the absence of reliably effective therapy for all stages or forms of PTLD, it would be ideal to have an effective preventive strategy. However, there is currently no universally acceptable preventive strategy. Although some centers have already introduced chemoprophylaxis and/or preemptive strategies using EBV viral load as a surveillance tool, for the prevention of this complication, published data in the form of prospective controlled trials in support of these protocols are currently limited and the role of antiviral agents is controversial. Potential strategies for prevention are listed as follows:

General

It is important to identify the patient at high-risk for PTLD development prior to transplantation. EBV serostatus should be determined on all transplant recipients (II-2). Identification of patients who are also at risk of primary CMV infection or severe CMV disease or receiving antithymocyte globulin for induction or rejection would select a particularly vulnerable subgroup of recipients because these factors have been identified as risk factors for PTLD. Such patients should be monitored carefully for clinical symptoms/signs (fever, diarrhea, lymphadenopathy, allograft dysfunction, etc.) and investigated aggressively for PTLD. Allograft biopsies from these patients should be reviewed carefully for evidence of early PTLD. Wherever appropriate, immunosuppression should be minimized and aggressive immunosuppression should only be employed in the presence of biopsy proven acute rejection (II-2). Because PTLD frequently presents with allograft dysfunction, it is important to make a pathologic diagnosis of rejection using standardized criteria and clearly distinguish early PTLD from rejection prior to the use of more potent anti-rejection therapy. The use of techniques to identify EBV-infected cells in tissues would be useful in this setting.

Antiviral prophylaxis

Chemoprophylaxis:  Although the antiviral agents, acyclovir and ganciclovir, have been employed as prophylactic antiviral agents for the prevention of PTLD, data to support this are limited and a definitive recommendation regarding their use cannot be made at this time (I). Because CMV disease is a cofactor in PTLD development, if employed, the use of ganciclovir is preferable to acyclovir use (41). However, PTLD has been documented in patients receiving antiviral prophylaxis. Some centers have adopted antiviral prophylaxis as standard of care for high-risk patients (EBV D+ R−) and preliminary data suggest antiviral therapy may reduce PTLD risk in renal transplant recipients (II-2) (41). EBV load has been shown to progressively rise in some patients whereas patients were on ganciclovir prophylaxis and no significant differences in EBV viral loads were seen when ganciclovir was compared with ganciclovir and immune globulin in a randomized trial involving EBV D+ R− solid organ transplant recipients (I) (42). However, these findings are not surprising because viral load measured in the cellular compartment of peripheral blood is composed of latently infected memory cells that are eliminated by normal B-cell homeostatic mechanisms; this does not imply an antiviral effect is absent (6). The impact of antiviral drugs on lytic virus could potentially decrease the recruitment of newly infected cells and the subsequent generation of latently infected memory cells, leading to a long-term decrease in viral load measured in cellular blood compartments; these responses will not be readily apparent in the short term. Antiviral therapy may have an indirect benefit on PTLD development by eliminating other viral infections that act as cofactors in the lymphoproliferative process (III).

Immunoprophylaxis:  The role of the passive administration of EBV-neutralizing antibodies (via IVIG) is unclear. A prospective randomized placebo-controlled trial of CMV-IVIG prophylaxis in EBV seronegative pediatric transplant recipients was inconclusive (I) (43). Similarly, a randomized trial involving immune globulin and ganciclovir was inconclusive (I) (42). However, an epidemiologic study by the Collaborative Transplant Group found that the use of anti-CMV-IVIG reduced the incidence of non-Hodgkin lymphoma in kidney transplant recipients but only in the first posttransplant year (44). Thus, although data are limited, prophylaxis with antiviral agents or immune globulin may have some effect in reducing the short-term risk of PTLD. However, at this time, all encompassing recommendation of the utility of this approach cannot be made (I).

Preemptive management

Because high viral load states often antedate the clinical presentation of PTLD, there are data to support quantitative EBV viral load monitoring for PTLD prevention in high-risk populations (29,32). Data to support this approach in populations at low risk of PTLD, such as adult transplant recipients seropositive for EBV before transplant, are lacking. Patients at high risk require frequent sampling (ideally weekly when possible over the high-risk period is recommended) because EBV viral load doubling times as short as 49–56 h have been documented (II-3). Data regarding the natural history of EBV viral load in transplant recipients in the absence of intervention are limited. This prevents clear definition of ‘trigger points’ that can be applied across all organ types that are predictive of PTLD development and at which preemptive intervention should take place.

Preemptive strategies in the solid organ transplant setting most commonly involve the use of reduction of immunosuppression and antiviral agents ± immune globulin (45) or the reduction of immunosuppression as the sole strategy (46). Some centers have reported a reduction in incidence of PTLD when routine viral load monitoring and these preemptive strategies were applied compared to historical cohorts (II-2). More aggressive interventions involving the use of low-dose rituximab (47) and adoptive immunotherapy (48,49) have been used primarily in hematopoietic stem cell transplant recipients; data regarding these interventions in the solid organ transplant setting are more limited (II-3). Although varying degrees of success have been observed with these strategies, there is insufficient evidence to dictate a specific course of action as this relates to preemptive management (III).

Treatment of PTLD

  1. Top of page
  2. Introduction
  3. Epidemiology
  4. Risk Factors
  5. Manifestations of Non-PTLD EBV Syndromes
  6. Manifestations and Diagnosis of PTLD
  7. Prevention of PTLD
  8. Treatment of PTLD
  9. Prognostic Indicators of PTLD
  10. Summary of Key Recommendations/Statements
  11. Acknowledgments
  12. Disclosures
  13. References

The treatment of PTLD remains a challenge. Currently, there is no unifying consensus that dictates the specific treatment approaches that should be undertaken for all categories of patients. Controlled interventional studies are lacking. The general approach to therapy involves a stepwise strategy that starts with reduced immunosuppression, with plans for further escalation of treatment based largely on the clinical response and the histopathologic characteristics of the PTLD.

Reduction of immunosuppression

Currently, it is well recognized that the primary approach to treatment of early EBV-positive PTLD starts with reduction or cessation of immunosuppression. This may result in the regression of PTLD lesions in up to 50% of cases (1,3) (II-3). The degree of reduction of immunosuppression varies, with some physicians being more comfortable reducing immunosuppression in a more aggressive manner in some organs (e.g. livers) but not others (e.g. hearts). Following the onset of a reduction in immunosuppression, it is not clear how long one should wait before proceeding to alternative therapeutic interventions. Consequently, no all-encompassing recommendations can be made in this regard. This notwithstanding, most patients would be expected to show evidence of a clinical response to reduced immunosuppression within 2–4 weeks (50).

Surgical resection/local irradiation

Complete or partial surgical resection, as well as local radiotherapy, have been used as adjunctive therapy along with reduced immunosuppression. When surgical excision or radiotherapy has been used for localized disease, long-term remission in the absence of additional therapy has been observed (51). Surgery is an essential component of the management of local complications such as gastrointestinal hemorrhage or perforation (III). Local radiotherapy may be indicated in the treatment of CNS lesions due to the fact that the CNS is an immunologically privileged site and special interventions are needed.

Antiviral agents (acyclovir, ganciclovir)/passive antibody (IVIG)

Acyclovir and ganciclovir have been used in the management of early PTLD, alone or in combination with immune globulin (1,3,12). Currently, when antiviral agents are employed, the agent of choice is ganciclovir, as in vitro it is 10 times more active against EBV compared with acyclovir. The efficacy of this approach is uncertain and there is no evidence to support the use of antiviral agents in the absence of other interventions such as decreasing immunosuppression or anti-CD20 therapy (III).

Monoclonal B-cell antibody therapy (anti-CD20)

The use of monoclonal antibodies have been explored in the setting of PTLD dating back to the late 1980s (anti-CD21 and anti-CD24). Presently, the anti-CD20 humanized chimeric monoclonal antibody (rituximab) is commercially available. There is a growing body of evidence in support of the use of this monoclonal antibody as the next step in the treatment of PTLD after reduction in immunosuppression (52–54). Although experience with the use of this agent is increasing, there is need for data from controlled clinical trials. The subsets of PTLD patients that would most likely benefit from rituximab therapy have not been clearly defined. In addition, the timing and duration of rituximab are unclear. The use of this agent requires the identification of CD20 markers in the PTLD tissue. Relapses have been observed after initial remission. Potential adverse events include a tumor lysis-like syndrome and prolonged depletion of B cells. Intestinal perforation at the PTLD site may occur in the recovery phase of the treatment of bowel PTLD. CMV reactivation and protracted hypogammaglobulinemia have been described earlier. This agent is best used in the setting of investigational treatment protocols.

Cytotoxic chemotherapy

It is well accepted that standard cytotoxic chemotherapy is not usually indicated as the first-line treatment of early EBV-positive B-cell PTLD (III). Prospective studies are limited in this regard. The role of chemotherapy in the management of PTLD was recently reviewed (54). Initial response rates of approximately 70–80% have been observed. Low-dose chemotherapy regimens in children have been associated with relapse rates of approximately 20%. Promising data are emerging on the use of this strategy with and without the use of rituximab (53). Patients who experience remission of PTLD following chemotherapy may succumb to complications related to chronic rejection and sepsis, although there is the suggestion of improvement in the latter in recent years (54). The use of chemotherapy is less controversial as first-line therapy in the setting of monomorphic PTLD occurring late in the posttransplant course, in EBV-negative, T-cell or CNS PTLD as well as in patients who are refractory to more conservative management approaches (III).

Other treatment modalities

Adoptive immunotherapy:  Adoptive immunotherapy using donor-derived cloned EBV-specific cytotoxic T cells has been used successfully for both the prevention and treatment of PTLD in allogeneic stem cell transplant recipients (48). But in the solid organ transplant setting, experience is limited. Obstacles include the fact that PTLD lesions are usually of recipient origin in contrast to donor origin in the stem cell transplant recipient. Cost and time required to clone cell lines may also limit the utility of this approach. Although dramatic responses of PTLD have been observed using HLA-matched unrelated donor EBV-CTL, these biologic products are currently not readily available (55). Thus, additional research is needed to define the role or adoptive immunotherapy, which in any event may not be feasible in many transplant centers experiencing small numbers of PTLD cases.

Immunomodulatory/anticytokine therapy:  α-Interferon has both antiviral and antiproliferative activity, and additionally affects the host immune response via its activity as a T-helper type 1-associated cytokine. Limited data in solid organ transplant recipients indicate that some patients may respond to α-interferon in conjunction with a reduction in immunosuppression (56) (III). However, there are concerns that interferon therapy could precipitate rejection. Thus, this agent is no longer commonly employed in the treatment of PTLD and its place in the stepwise management of PTLD has been largely replaced by anti-CD20 monoclonal antibody. Anti-IL6 therapy has been explored in the treatment of early PTLD (57). Data are limited and additional research is needed.

Use of viral load to monitor response to PTLD therapy and predict relapse:  In general, PTLD patients with high viral load as well as those receiving preemptive therapy, demonstrate a fall and clearance of viral load coincident with clinical and histologic regression (58). In contrast, some clinicians have observed that when rituximab is used, viral load measured in cellular blood components fell dramatically and remained low even in the face of progressive disease and disease relapse (59,60). However, recent data suggest that this may be a reflection of the sample type used for viral load monitoring as plasma monitoring appears to correlate better with treatment response than monitoring in the cellular compartment (31,61). Further studies to confirm this observation are required.

In pediatric patients, particularly those experiencing primary infection after transplant, asymptomatic intermittent or persistent viral load rebound occurs frequently with no short-term consequences. Adult PTLD patients have been observed to relapse in presence of persistently low viral load (60). These data, which involved viral load monitoring in cellular blood compartments, suggest that viral load monitoring after clearance cannot predict disease relapse and is not recommended. Although preliminary data are promising, it is uncertain whether monitoring in plasma might be more predictive (31,61).

Preliminary data suggest that pediatric cardiothoracic patients with sustained elevation of EBV viral load after asymptomatic infection or resolution of EBV disease or PTLD (chronic high load carriers) may be at significantly increased risk of late onset EBV-positive PTLD. This risk appears in part to be organ-specific and was not observed in pediatric liver transplant patients, although follow-up in this latter group was shorter (62,63). Another contributing factor to this differential risk may be differences in the net state of immunosuppression between these organ groups. Additional data from prospective studies are needed to confirm these observations.

Prognostic Indicators of PTLD

  1. Top of page
  2. Introduction
  3. Epidemiology
  4. Risk Factors
  5. Manifestations of Non-PTLD EBV Syndromes
  6. Manifestations and Diagnosis of PTLD
  7. Prevention of PTLD
  8. Treatment of PTLD
  9. Prognostic Indicators of PTLD
  10. Summary of Key Recommendations/Statements
  11. Acknowledgments
  12. Disclosures
  13. References

Several variables have been identified as indicators of prognosis in the management of PTLD. The extent to which findings can be generalized across centers is limited by the absence of a standardized approach to the pathologic diagnosis and treatment of PTLD. Table 4 summarizes some factors that have been associated with poorer outcomes.

Table 4.  Factors associated with poorer outcomes from PTLD
Poor performance status
Multisite disease
Central nervous system disease
T- or NK-cell PTLD
EBV-negative PTLD
Recipient origin disease relative to donor origin
Coinfection with hepatitis B or C
Monoclonal disease
Presence of mutation of proto-oncogenes or tumor suppressor genes

Summary of Key Recommendations/Statements

  1. Top of page
  2. Introduction
  3. Epidemiology
  4. Risk Factors
  5. Manifestations of Non-PTLD EBV Syndromes
  6. Manifestations and Diagnosis of PTLD
  7. Prevention of PTLD
  8. Treatment of PTLD
  9. Prognostic Indicators of PTLD
  10. Summary of Key Recommendations/Statements
  11. Acknowledgments
  12. Disclosures
  13. References
  • 1
    Primary EBV infection and high or repetitive doses of antilymphocyte globulin represents the best-documented risk factors for the development of early PTLD (II-2).
  • 2
    EBV serostatus should be determined on all transplant recipients to identify the patients at high-risk for PTLD development (II-2).
  • 3
    The most important role of EBV serology in the setting of transplantation is the categorization of serostatus of donors and recipients to determine the likely risk of PTLD (II-2).
  • 4
    Viral load assessments in peripheral blood for supporting preemptive PTLD prevention strategies, for PTLD diagnosis, monitoring response to treatment and predicting relapse have become standard of care at major transplant centers. Within individual institutions using a single assay, trending of results is valid and more useful than single values (II-2). Significant interlaboratory variability in reported results prohibits interinstitutional result comparison in the absence of formal cross-referencing of assays between institutions; an international reference standard is required (II-B). Results when using viral load assays for monitoring response to therapy, predicting relapse and for disease diagnosis should be interpreted with caution; interpretation may be sample type dependent (II-3).
  • 5
    Histopathology remains the gold standard for the diagnosis of PTLD (III).
  • 6
    Antivirals ± immune globulin are employed as EBV prophylaxis after transplantation among EBV D + R− patients. There is insufficient evidence to accept or refute this strategy (I). Where employed, a prophylaxis strategy similar to that for CMV may be considered (III).
  • 7
    The use of preemptive strategies in high-risk populations may lower PTLD incidence rates; reduction in immunosuppression is the best-documented intervention strategy (II-2). There are insufficient data to determine the efficacy of other intervention strategies such as antivirals, anti-CD20 antibody or adoptive immunotherapy (III). Prospective viral load monitoring and preemptive strategies are not useful in low-risk populations (II-3).
  • 8
    Additional data from prospective studies are needed to determine the significance of chronic, sustained elevations of EBV loads after transplantation (III).
  • 9
    The primary approach to the treatment of early PTLD starts with reduction or cessation of immunosuppression (II-2). Other modalities of therapy depend in part of on the histopathologic characteristics of PTLD and location of lesions.
  • 10
    Although chemotherapy is not usually first-line treatment in some forms of PTLD, this modality should be considered as first-line therapy in the setting of monomorphic PTLD occurring late in the posttransplant course, EBV-negative PTLD, T-cell PTLD, CNS PTLD as well as in patients who are refractory to more conservative management approaches (III).
  • 11
    Additional research is needed to address several unresolved issues and to enhance the levels of evidence for or against different aspects of the diagnosis, prevention and treatment of PTLD.

Acknowledgments

  1. Top of page
  2. Introduction
  3. Epidemiology
  4. Risk Factors
  5. Manifestations of Non-PTLD EBV Syndromes
  6. Manifestations and Diagnosis of PTLD
  7. Prevention of PTLD
  8. Treatment of PTLD
  9. Prognostic Indicators of PTLD
  10. Summary of Key Recommendations/Statements
  11. Acknowledgments
  12. Disclosures
  13. References

This document was modified from an initial guideline published by the American Society of Transplantation (Am J Transplant 2004; 4[Suppl 10]: 59–65. Avery R, Green M, eds.).

References

  1. Top of page
  2. Introduction
  3. Epidemiology
  4. Risk Factors
  5. Manifestations of Non-PTLD EBV Syndromes
  6. Manifestations and Diagnosis of PTLD
  7. Prevention of PTLD
  8. Treatment of PTLD
  9. Prognostic Indicators of PTLD
  10. Summary of Key Recommendations/Statements
  11. Acknowledgments
  12. Disclosures
  13. References
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