Abstract
Long-term risk for malignancy is higher among solid organ transplant (SOT) recipients compared to the general population. Four non-hepatitis viruses have been recognized as oncogenic in SOT recipients—EBV, cause of EBV-associated lymphoproliferative diseases; human herpes virus 8 (HHV8), cause of Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease; human papilloma virus, cause of squamous cell skin cancers, and Merkel cell polyomavirus, cause of Merkel cell carcinoma. Two of these viruses (EBV and HHV8) belong to the human herpes virus family. In this review, we will discuss key aspects regarding the clinical presentation, diagnosis, treatment, and prevention of diseases in SOT recipients associated with the two herpesviruses.
Human Herpes Virus 8 in Solid Organ Transplantation
Introduction
HHV8 is a DNA virus that belongs to the gamma-herpes virus subfamily. It was first discovered in 1994 as the etiologic agent of Kaposi’s sarcoma (KS) [1]. Four types of KS are distinguished: classic-, endemic-, immunosuppression‐associated-, and AIDS-associated KS [2]. Other HHV8 associated neoplastic disorders include primary effusion lymphoma and multicentric Castleman disease [3, 4].
In SOT recipients, KS is ∼200 fold more frequent than the general population, with cumulative incidence of ∼3%–5% in endemic areas, and <1% in non-endemic areas [5, 6]. Post-transplant KS is a consequence of reactivation of latent infection in seropositive recipients, or a primary donor derived infection in seronegative recipients [7].
Non-neoplastic disorders associated with HHV8 are peripheral cytopenias, hemophagocytic syndromes, acute hepatitis, and KS‐associated herpesvirus inflammatory cytokine syndrome (KICS) [8, 9].
Epidemiology
The seroprevalence of HHV8 depends on the geographic region. African countries have the highest seroprevalence rates (>50%), whereas seroprevalence in Europe, North America, South and East Asia is lower [10–14]. In low seroprevalence regions, men who have sex with men (MSM) are at increased risk [15].
Both sexual and non-sexual transmission (including blood transfusion and organ transplantation) of HHV8 occurs. SOT recipients may be infected either before transplantation and reactivate the virus post-transplantation, or acquire the virus as a donor-derived infection. Primary HHV8 infection post-transplant increase the risk for HHV8-associated disease [16].
Non-Malignant HHV8 Disorders
HHV8 infection in immunocompetent individuals is generally asymptomatic, although occasionally associated with a febrile rash in children [17]. In immunocompromised individuals, HHV8 infection has been associated with fever, splenomegaly, maculopapular rash, lymphadenopathy and cytopenia [18] and rarely causes systemic disease with multi-organ failure post-transplantation [6]. Bone marrow suppression, with or without hemophagocytosis was linked to donor derived HHV8 infection in the early post-transplant period [19–21], and rare cases of sexually transmitted primary HHV8 infections post-transplantation were associated with hemophagocytosis [22].
Malignant HHV8 Disorders
Post-Transplant Kaposi Sarcoma (PT-KS)
PT-KS is the most commonly encountered HHV8‐related neoplastic disease [23]. PT-KS mostly develops within the first year post-transplantation [6], and may cause skin lesions involving the extremities, the trunk and the oral cavity [6]. Lesions are characterized by red-blue or purple discoloration, representing the vascular nature of the disease [18]. Visceral involvement occurs in ∼10% of PT‐KS cases, with higher rates (up to 50%) in liver transplant recipients and associated with high a mortality [24, 25]. Disseminated disease without skin lesions exists, and lesions may appear at atypical localizations including the tonsils, urinary bladder and liver [26–28]. The disease can be rapidly-progressive, especially in donor derived cases [29]. In addition to primary infection, risk factors for KS in SOT have been described, with the most prominent factor being residence/origin in endemic countries. Other risk factors include (from higher to lower risk) older age, male gender, thoracic transplantation, and use of cyclosporine and antilymphocyte antibody [18, 30, 31].
Multicentric Castleman Diseases (MCD)
MCD is characterized by B‐cell transformation to plasmablasts, which subsequently infiltrate multiple lymph nodes and distort their architecture. It typically presents with fever, lymphadenopathy, hepatosplenomegaly, and cytopenia [6]. MCD and PT-KS may occur concomitantly in SOT patients [32–34].
Primary Effusion Lymphoma (PEL)
PEL is a non‐Hodgkin lymphoma that rarely develops after SOT and affects serous body cavities (pleura, pericardium, and peritoneum) [6]. The median time of presentation is 8 years after transplant, with a wide range from 5 months to 28 years [35]. It presents as a body cavity effusion in the absence of tumor masses. The prognosis is dismal [35].
Kaposi Sarcoma Herpes Virus (KSHV) Inflammatory Cytokine Syndrome (KICS)
KICS is a systemic inflammation that resembles MCD without pathologic findings in lymph nodes. Generally, patients with KICS also have KS and to a lesser extent may have PEL. Patients with KICS have more severe symptoms, and an increased risk of death [36]. Two cases of KICS have been reported in SOT recipients (Table 1) [8, 37].
TABLE 1
| Recipient | Donor | Organ | Presentation | Findings | KS |
|---|---|---|---|---|---|
| 38 years old female, PSC and CKD, HHV8 IgG Negative | 42 years old, HHV8 IgG positive | Liver and Kidney | Persistent fever 12 months after transplantation | Severe anemia and worsening of renal function, severe splenomegaly and small-sized generalized lymphadenopathy, HHV8 viral load ∼189,000 copies/mL | No |
| 54 years old male, TOF, HHV8 IgG Negative | 39 years old, Eastern Europe, high risk sexual behavior, HIV negative, positive HHV8 IgG | Heart | Persistent fever 11 months after transplantation | Pancytopenia, ↑creatinine, bilateral pleural effusion, generalized lymphadenopathy, HHV8 viral load ∼183,000 copies/mL | yes |
Case reports of KSHV Inflammatory Cytokine Syndrome (KICS) in solid organ transplant recipients.
CKD, chronic kidney disease; HHV8, human herpesvirus 8; HIV, human immunodeficiency virus; KS, Kaposi sarcoma; KSHV, Kaposi sarcoma Herpes virus; PSC, primary sclerosing cholangitis; TOF, tetralogy of Fallot.
Screening and Diagnosis of HHV8 Infection
Recent American society of transplant (AST) guidelines on HHV8 provide a weak recommendation for pre-transplant serological screening of donors and recipients in endemic areas in order to stratify the risk for HHV8 associated disease [6]. In non-endemic areas it is suggested to consider screening for at-risk donors and recipients only (i.e., MSM, people living with HIV or who inject drugs), or for immigrants from endemic countries [8].
The rationale behind recommending serologic screening in endemic settings is the increased risk for KS among seropositive kidney transplant recipients as compared to seronegative recipients (23%–28% vs. 0.7%) [38]. In addition, donor derived post-transplant HHV8 transmission from seropositive donors to seronegative recipients has been described. Nevertheless, HHV8 seropositive individuals are not excluded from organ donation [6]. Preventive reduction of immunosuppression has been suggested in D+R− cases [23].
Lack of standardization of serological assays, variable sensitivity and specificity of these tests, and the absence of an algorithm for management according to serologic findings, result in low rates of pre-transplant screening in practice. In a survey including 51 transplant centers, only one-third performed pre-transplant HHV8 serology. High HHV8 seroprevalence (>6% seropositivity), Italian centers, available protocols for post-transplant viral load monitoring, and having had a recent case of HHV8 disease were associated with screening.
In a study that assessed six different serologic HHV8 assays the Biotrin–DiaSorin IFA and ABI IFA showed the highest agreement with a reference standard of ≥2 concordant positive assays [39].
No AST recommendations are available to direct a schedule of blood viral DNA monitoring in D+R− or R+ SOT recipients, beyond a general recommendation for monitoring in these patients [6]. In a recent survey, 41% of centers reported performing HHV8 PCR monitoring post-transplant, with variable indications including symptomatic patients only, risk-based approaches or universal screening [40]. In case of detectable HHV8 DNAemia, most centers reduced the immunosuppression or changed from calcineurin inhibitors (CNI) to m-TOR inhibitors, with or without addition of antivirals [40]. For viremic patients, guidelines suggest immunosuppression reduction or change to mTOR inhibitors. The rationale for the latter is the antiviral and antiangiogenic effects of sirolimus, though no clinical benefit has been demonstrated in studies [6]. Screening for viral DNA in bronchoalveolar fluid has been suggested for lung transplant recipients and is now under investigation (NCT05081141).
Immune monitoring by HHV8 ELISPOT test is used by some centers as adjunct to HHV8 PCR monitoring in high-risk patients [40]. Absent anti-HHV8 cytotoxic T-cell response has been demonstrated in SOT recipients with KS. It has been suggested that ELISPOT may assist in identifying patients at higher risk for developing KS, and if negative, reducing the immunosuppression may be considered [9].
Table 2 provides a proposed approach for screening or HHV8 pre and post-transplant.
TABLE 2
| Serologya | PCRb | ELISPOT | Physical exam | Management | |
|---|---|---|---|---|---|
| Pre transplant | Yes | No | No | No | No |
| Post transplant | Among D+R− repeated serology may indicate seroconversion—no schedule suggested [40] | Among D+R−, PCR once every 2 weeks for 3 months followed by once monthly to complete 2 years- Among R+, PCR once monthly for 2 years [40] | Among D+R− or R+ may assist as adjunctive test to PCR | For D+R−, skin and mucosal surfaces routine examinations [6] | If PCR positive negative → reduction in immunosuppression or change to mTOR inhibitor [6] If ELISPOT negative → consider immunosuppression reduction [9] |
Proposed approach for HHV8 screening pre- and post-transplant.
If a screening approach is not implemented, the following signs and symptoms should merit an investigation for HHV8 if no other cause is found: fever, splenomegaly, maculopapular rash, lymphadenopathy and cytopenia.
bThere is no gold standard serology assay.
cQuantitative cut-offs for PCR tests are missing; optimal testing frequency and duration of surveillance have not been determined. Whole blood may be more sensitive than plasma, because if inclusion of the cellular component. Screening is not routinely used by the authors of this review.
Diagnosis of HHV8 Associated Disease
The gold standard for diagnosing KS, MCD and PEL is histopathological examination of tissue. Immunohistochemical staining of HHV8 latency-associated nuclear antigen confirms the diagnosis. Tissue PCR for HHV8 may assist in confirming the diagnosis. There is no established role for peripheral blood PCR in diagnosing KS. Positive PCR supports the diagnosis of KS, however, it may be negative in ∼20% of KS cases [41]. Highest DNAemia levels were reported in MCD, followed by PEL. Hence, PCR may be more sensitive in these cases, and it has been suggested that negative HHV8 PCR may be used to exclude MCD [42]. High HHV8 DNAemia (>10,000 copies/mL) supports the diagnosis of MCD over KS [43]. In patients with PEL, high viral loads have been demonstrated in effusion fluids [42]. Due to limitations of serology discussed above, it is not currently indicated for diagnosis of HHV8 associated disease [44].
Patients with KICS are almost universally DNAemic. The diagnosis of KICS is based on high levels HHV8 DNAemia, exclusion of other possible causes, and possibly detection of HHV8 in involved organs (bone marrow, liver, and others) [9, 36]. A cutoff value of viral load in plasma ≥1,000 copies/mL or ≥100 copies/106 cells in peripheral blood mononuclear cells has been suggested for diagnosis of KICS [36].
Prevention
(Val)ganciclovir, cidofovir and foscarnet inhibit the replication of human herpes viruses, including HHV8. Among HIV patients, (val)ganciclovir proved to decrease the incidence of KS [45]. However, effectiveness of these drugs as pre-emptive therapy in cases of positive HHV8 PCR has not been demonstrated.
The need for a vaccine to prevent HHV8 associated malignancies in susceptible populations has been recently raised by the National Cancer Institute. Since the HHV8 genome is highly conserved, it is possible that a single vaccine would provide protection worldwide [46].
Treatment of HHV8 Related Diseases
Treatment of HHV8 associated malignancies and non-malignant conditions in SOT recipients should first include reduction in immunosuppression (RIS) and/or change from CNI to mTOR inhibitors [47, 48]. Older studies demonstrated between 70% and 100% complete response (CR) of KS following a change from cyclosporin to sirolimus, and 20%–50% CR of KS with RIS [5, 38, 49].
In a more recent study, including 145 SOT recipients with KS, immunosuppression reduction with/without switch to mTOR inhibitors, resulted in a response in >80% of patients [5].
Systemic chemotherapy with an anthracycline or paclitaxel is usually required for KS patients with visceral involvement, extensive lymph node or mucocutaneous involvement, and for patients not responding to reduction/change in immunosuppression [6, 9]. Immunomodulatory therapy with interferon-α is avoided in the SOT setting because of the risk for rejection [50]. Specific chemotherapy regimens are routinely used for the management of MCD and PEL, in addition to immunosuppression reduction [9, 45].
Immunological (ELISPOT) and virological (HHV8 PCR) tests are suggested as part of follow up in the management of KS and other HHV8 related diseases [9].
Several antivirals have in-vitro activity against HHV8, including ganciclovir, foscarnet, and cidofovir, while acyclovir is not highly active [51]. Recent NIH guidelines for HIV management do not recommend antivirals as part of KS therapy, based on studies showing limited efficacy [45]. For the treatment of PEL, antiviral drugs may be used as a possible adjunctive therapy, with a CIII level of recommendation [45]. For MCD, two retrospective studies demonstrated remissions using ganciclovir as part of the treatment regimen in HIV patients [45]. This is supported by the rationale of lytic HHV8 infection being present in MCD [52]. There is limited data to support the use of anti-IL6 inhibitors for MCD with no recommendation for general use of these drugs for this indication [45]. Adoptive immunotherapy with cytotoxic T-lymphocytes specific for HHV8 could have a therapeutic role, though there is currently no commercial product available [9].
Epstein-Barr Virus in Solid Organ Transplantation
Introduction
Epstein–Barr virus (EBV) is a double-stranded DNA virus of the γ-herpesviridae subfamily [53]. The virus was discovered in 1964 from cultured lymphoblasts of Burkitt’s lymphoma biopsies before being identified as the causative agent of mononucleosis in 1968 [54, 55]. EBV was the first known human oncogenic virus and it efficiently transforms human B-lymphocytes [56–58]. Upon infection, EBV establishes life-long latency in memory B-cells [59, 60]. The pathogenesis of EBV-associated oncogenesis is complex and it is related to the ability of the virus to transform and immortalize B-cells and to impede apoptosis of infected cells [53, 61]. EBV is associated with a large spectrum of diseases, including benign diseases (infective mononucleosis, oral hairy leukoplakia), a number of lymphoproliferative disorders (Burkitt’s lymphoma, some Hodgkin lymphomas, EBV-positive diffuse large B-cell lymphomas, natural killer/T-cell lymphoma, nasal type angiocentric lymphomas, chronic active EBV), epithelial cancers (nasopharyngeal carcinoma, some forms of gastric cancer), smooth muscle cell tumors, and diseases related to immune dysfunction (multiple sclerosis, EBV-associated hemophagocytic lymphohistiocytosis) [61, 62].
In SOT patients, EBV is known to play a major role in the development of EBV-positive post-transplant lymphoproliferative disorders (PTLD), one of the most devastating complications of organ transplantation [53, 63, 64].
Epidemiology
Seroepidemiologic surveys indicate that >90% of adults are infected with EBV [65, 66]. In developed countries, primary EBV infection tends to occur later nowadays as compared to the past [67–69]. In the transplant setting, donor transmitted EBV infection is common in EBV mismatched (donor EBV+/recipient EBV−) patients. Children are more likely to be EBV-negative, and may acquire the virus from the donor organ or by natural infection, putting them at increased risk for post-transplant primary infection.
EBV Associated Diseases in SOT Recipients
Post-Transplant Lymphoproliferative Disorders (PTLD)
Since the first description of five lymphoma cases in kidney transplant recipients (KTR) in 1969, PTLD has been recognized as a serious complication of SOT [70]. PTLD encloses a heterogeneous spectrum of conditions characterized by lymphoproliferation after transplantation. These disorders range from uncomplicated infectious mononucleosis-like pathology to true malignancies [71]. PTLD is categorized according to the World Health Organization (WHO) 2017 classification, based on its histopathological appearance (Table 3) [77]. Additionally, PTLD is classified according to its temporal occurrence: early-onset PTLD arises within the first year post-transplant, whereas late-onset PTLD occurs thereafter [78]. In contrast to late-onset PTLD, most cases of early-onset PTLDs are associated with EBV [72, 79, 80]. While the incidence rate for EBV-positive PTLD is highest early after transplant, the incidence rate of EBV-negative PTLD is low immediately after transplantation and increases after 4–5 years, resulting in a biphasic pattern of overall PTLD occurrence [81, 82].
TABLE 3
| WHO 2017 category | EBV-association | Clonality | Frequency | Clinical features |
|---|---|---|---|---|
| Non-destructive PTLD | ∼100% [72, 73] | No | ∼5% | Early-onset, Benign |
| - Plasmatic hyperplasia | ||||
| - Infectious mononucleosis-like PTLD | ||||
| - Florid follicular hyperplasia | ||||
| Polymorphic PTLD | ∼90% [72, 73] | Variable | ∼10% | Early and late-onset |
| Monomorphic PTLD | ∼50% [72] | Yes | ∼80% | Early > late |
| B-cell neoplasm | ||||
| - Diffuse large B-cell lymphoma | ||||
| - Burkitt (like) lymphoma | ||||
| - Plasmablastic lymphoma | ||||
| - Plasmacytoma like lymphoma | ||||
| - Others | ||||
| T-cell neoplasms | ∼20% | Yes | <5% | Late-onset |
| - Peripheral T-cell lymphoma | ||||
| - Others | ||||
| Hodgkin/Hodgkin-like lymphoma | ∼90% [74] | Yes | <5% | Early and late-onset |
Overview of post-transplant lymphoproliferative disorders.
Early-onset, within 1 year post-transplant. Late-onset, >1 year post-transplant. EBV, Epstein-Barr virus; PTLD, post-transplant lymphoproliferative disorder; WHO, world health organization.
A major risk factor for development of EBV-positive PTLD is EBV‐seronegativity pre‐transplant (hazard rate 5–18 as compared to EBV-seropositive individuals) [80, 83–87]. However, in liver transplant recipients the association of EBV-seronegativity and PTLD risk is less pronounced [87]. As children are more likely to be EBV-seronegative before transplantation, PTLD is more common in pediatric SOT recipients. Further, the risk is affected by the type of transplanted organ with intestinal transplant recipients (∼18%) being at highest risk for developing PTLD [88, 89], followed by lung (3%–10%), heart (2%–8%), liver (1%–6%), and kidneys (1%–2%) [90]. In the current era, there was no conclusive association between the type of induction therapy and PTLD risk [91, 92]. The contribution of each immunosuppressive agent to PTLD development is unclear, since patients receive multiple agents in different doses at different times [91]. However, concerns regarding the use of belatacept in EBV-seronegative transplant recipient have been raised [93]. It is for this reason that belatacept is contraindicated in patients who are EBV-seronegative or whose EBV serostatus is unknown prior to transplant [94].
The clinical presentation of PTLD is heterogeneous and depends on the type (non-destructive-, polymorphic-, monomorphic-PTLD) and the localization of disease. Non-specific constitutional symptoms such as fever, unintended weight loss, night-sweats, and fatigue are common. Lymphadenopathy, tonsillar hypertrophy, dysfunction of involved organs, or compression of surrounding structures may occur. More than half of cases presents with extranodal involvement [72, 83, 95]. PTLD frequently involves the gastrointestinal tract (20%–30%), the allografts (10%–15%), and the central nervous system (CNS, 5%–20%) [72, 83, 95]. Therefore, not only lymphadenopathy but also gastrointestinal bleeding or ulcers, allograft dysfunction in combination with masses, and focal neurological signs should rise suspicion for PTLD.
EBV-Associated Smooth Muscle Cell Tumor (EBV-SMT)
EBV-SMT is an uncommon neoplasm of immunocompromised individuals [96]. The role of EBV in the tumorigenesis is poorly understood. EBV-SMT is thought to be derived from myogenous vascular smooth muscle cells [97]. The clinical presentation of EBV-SMT is unspecific and depends on the localization of the tumor [98]. Biopsies of smooth muscle tumors in SOT recipients should be evaluated with EBV‐encoded small nuclear RNA (EBER) stains, to establish the diagnosis of EBV-SMT [98] and the differential diagnosis should include KS and mycobacterial spindle cell pseudotumor [96].
Non-Malignant EBV-Associated Disease After SOT
The features of these EBV manifestations may include infective mononucleosis, oral hairy leukoplakia [99], and end-organ infections such as encephalitis/myelitis [100] or hepatitis [101]. Some of these manifestations may share clinical features of PTLD (e.g., encephalitis vs. CNS PTLD). Therefore, careful evaluation of these cases is warrant.
Due to the overwhelming clinical importance of PTLD, we will focus on aspects related to PTLD in this review.
Diagnosis of Post-Transplant Lymphoproliferative Disorders (PTLD)
The diagnosis of PTLD is based on the histopathological examination of appropriate tissue biopsies. Assessing the presence of latent EBV infection of affected cells by (preferably) RNA-in-situ-hybridization targeting EBV-encoded small RNAs (EBER) or by immunohistochemistry targeting latent membrane protein 1 (LMP1) is essential for the diagnosis of EBV‐associated PTLD [102]. Preceding to tissue sampling, radiographic imaging is a crucial initial step to come to a tentative diagnosis. The radiographic evaluation is similar to that used in the evaluation of suspected lymphoma in the non-transplant population [103]. A computed tomography scan (neck to pelvis) is the first step in most centers. MRI may be the preferred modality for suspected cerebral PTLD [104]. Positron emission tomography‐computerized tomography has emerged as a useful imaging modality for detecting suspicious lymph nodes and extranodal lesions and may be helpful to identify optimal sites for biopsy [105]. Establishing a PTLD diagnosis can be difficult and occasionally multiple attempts for getting conclusive tissue biopsies are necessary (especially for gastrointestinal PTLD). In SOT recipients with persistent gastrointestinal symptoms, PTLD should be part of the differential diagnosis and endoscopy with biopsy of ulcers/lesions should be performed [106].
Studies evaluating the diagnostic test characteristics of EBV DNAemia measurements for diagnosing EBV-positive PTLD are limited. In summary, EBV DNAemia above a specific threshold has good sensitivity (∼90%) for detecting EBV-positive PTLD but lacks specificity [107–109] and EBV PCR is not useful for detection of EBV-negative PTLD.
Prevention of EBV Associated Disease in SOT Recipients
Monitoring EBV DNAemia With Reduction of Immunosuppression for Prevention of EBV-Positive PTLD
A monitoring strategy of repeated EBV DNAemia measurement with RIS if a certain threshold is reached or if DNAemia is increasing, is applied by many transplant centers [110], especially for high-risk patients (EBV D+/R−) [108, 111–115]. However, the optimal way to apply this strategy remains unclear. This is also related to the inter-laboratory variability of EBV DNAemia measurements, despite previous efforts for harmonizing results by introducing an international standard [116, 117]. In clinical practice, EDTA plasma or whole blood is used for monitoring EBV DNAemia (Table 4). EBV DNAemia levels are higher when determined in whole blood as compared to EDTA plasma [118, 119]. Therefore, the sensitivity for detection of EBV DNAemia is higher when using whole blood. However, the specificity for detection of EBV‐related disease is better when using EDTA plasma samples [120]. The controversy with respect to the preferred sample type for monitoring EBV DNAemia is ongoing. In our opinion, it is more relevant to ensure that the same type of sample is used and that DNAemia is determined in the same laboratory when longitudinally assessing EBV DNAemia, instead of focusing on the discussion about the preferred sample type. Even though there is no evidence from randomized-controlled trials supporting the usefulness of EBV DNAemia monitoring and RIS, there is some evidence from cohort studies supporting this approach [75, 76, 111]. However, the results of these studies have to be interpreted with caution because of using historic controls [75, 76] (problematic because of decreasing PTLD incidence over time, most likely related to less intense immunosuppression in contemporary versus historic cohorts [72, 111, 121] and the lack of statistical power to show differences due to the rarity of the disease [111]). Although it seems to be appealing from a pathophysiological point of view, there is no strong evidence supporting EBV DNAemia monitoring with RIS for prevention of EBV-positive PTLD. Furthermore, no specific cut-off value for EBV DNAemia to guide preemptive therapy is available, with some studies using any positive titer [122] while others using increasing loads (>10-fold or >1 log10 cp/mL) [122].
TABLE 4
| Serology | PCR | ELISPOT | Physical exam | Management | |
|---|---|---|---|---|---|
| Pre transplant | Yes | No | No | No | No |
| Post transplant | Among D+R− repeated serology may indicate seroconversion—in clinical practice, measurement of EBV DNA in peripheral blood has largely replaced serology for the diagnosis of primary EBV infection | Among D+R−, PCR once every 2–4 weeks for 12 months [75, 76] (author’s personal opinion, week evidence) | For research purpose only | Check for lymphadenopathy during routine clinical controls (author’s personal opinion, no evidence) | Reduction in immunosuppression if high EBV DNAemiaa (author’s personal opinion, week evidence) Actively search for PTLD if EBV DNAemia is persistently highb |
Proposed approach for EBV screening pre- and post-transplant.
There is no uniformly accepted EBV DNAemia uniform cut-off for reduction in immunosuppression. This is related to the different types of samples (whole blood vs. EDTA plasma) used for EDTA monitoring and the considerable inter-laboratory variations in EBV DNAemia measurements (even when using the WHO standard).
bThere is no established EBV DNAemia cut-off (neither DNAemia level nor duration of persistent DNAemia) for triggering radiologic examinations.
Antiviral Prophylaxis for Prevention of EBV-Positive PTLD
Several antiviral drugs such as (val)acyclovir, (val)ganciclovir, cidofovir, foscarnet and maribavir inhibit lytic EBV replication [123, 124]. However, these drugs have no effect on latent EBV infection. Since primary EBV infection after transplantation is a major PTLD risk factor, reducing donor‐derived EBV transmission may have an impact on PTLD occurrence. A reduction of primary EBV infection was observed in a cohort of EBV seronegative pediatric KTRs on (val)ganciclovir prophylaxis versus no antiviral prophylaxis [125]. In another cohort of EBV mismatched adult KTRs, antiviral prophylaxis for 3–6 months delayed the rate of EBV primary infection at 100 days post-transplant, but the seroconversion rate 12 months post-transplant was identical with and without prophylaxis (72% vs. 74%) [126]. Recent cohort studies did not find a protective effect of antiviral prophylaxis on PTLD occurrence [72, 127]. These findings are consistent with results of a systematic review published in 2017, concluding that antiviral prophylaxis in high-risk EBV-naive patients has no effect on the incidence of PTLD [128].
Rituximab for Prevention of EBV-Positive PTLD
The preemptive use of rituximab for prevention of PTLD has become a common strategy in EBV viremic hematologic stem-cell transplant (HSCT) [129, 130]. B-cell depletion before or directly after HSCT, has shown to reduce EBV replication [131, 132] and the incidence of EBV-positive PTLD [133–135] in high-risk patients. The potential effect of rituximab on subsequent PTLD development may be attributable to the depletion of CD20+ B-cells, which represent the major reservoir for latent EBV infection. The reduced abundance of these cells at risk for malignant transformation might be linked to a lower PTLD risk [72]. Rituximab use is less well established for prevention of EBV-positive PTLD in SOT recipients. A recent multi-center cohort study reported that rituximab given as part of the induction regimen (mostly in ABO-incompatible kidney transplantation) is associated with a decreased risk for PTLD [72]. A single‐center cohort study reported diminished PTLD rates with rituximab use in heart transplant recipients whose EBV DNAemia did not respond to RIS using a historic control group [75]. Similarly, EBV‐mismatched KTRs with persistent EBV DNAemia or symptomatic EBV infection given rituximab simultaneously with RIS were less likely to develop PTLD compared to contemporaneous controls [114].
Treatment and Prognosis of PTLD
The first therapeutic measure in treatment of PTLD is RIS under close monitoring of the graft function. There are no evidence-based guidelines on how to reduce immunosuppression, but in clinical practice, stopping anti-proliferative agents and dose reduction of the CNI is the common approach [90]. Significant RIS may not be feasible in all cases and is especially difficult to achieve in thoracic organ transplant recipients due to the risk of life-threatening graft rejection [136]. RIS eradicates the majority of non-destructive PTLD cases. However, for polymorphic and monomorphic PTLD the response to RIS alone is often insufficient [137, 138]. A radiologic reassessment is performed two to 4 weeks after RIS, and if a CR is achieved no further treatment is needed.
In the following section, we summarize the treatment options for polymorphic PTLD and monomorphic diffuse large B-cell lymphoma (DLBCL) PTLD. Treatment of non-DLBCL monomorphic PTLD depends on the histologic classification of the respect lymphoma and follows the same chemotherapy regimens as for immunocompetent patients, and will not be reviewed here. Immunochemotherapy for treatment of DLBCL PTLD is associated with significant toxicity and many SOT recipients are not fit for highly intensive regimens [139]. Therefore, sequential and risk-stratified treatments are applied for treatment of CD20+ monomorphic DLBCL PTLD. The PTLD-1 [140], the PTLD-1 third amended [141] and PTLD-2 [142] phase 2 trials are landmark studies that established sequential, risk-stratified PTLD treatment modalities. The PTLD-1 study proved the efficacy and safety of a sequential treatment of four cycles rituximab monotherapy followed by four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for patients who did not achieve complete remission with RIS [140]. The most favorable outcomes were seen in patients who achieved a response to rituximab alone prior to chemotherapy, indicating that these patients may belong to a “good-risk group”. In consequence, the PTLD-1 third amended trial assessed a risk-stratified protocol: patients who achieved a CR after four doses of rituximab, received consolidation with rituximab alone while those who did not achieve CR were treated with four cycles of R-CHOP [141]. This trial proved that withholding chemotherapy and performing a rituximab consolidation in patients with CR to rituximab alone is safe and associated with less toxicity [141]. The PTLD-1 third amended trial identified two subgroups with poor prognosis: thoracic transplant recipients and patients with an International Prognostic Index (IPI) score >2 [141]. The PTLD-2 trial, inter alia, assessed treatment escalation (alternating R-CHOP and R-DHOAx- rituximab, dexamethasone, cytarabine, oxaliplatin) in these patients with poor prognosis [142]. However, the number of patients in this subgroup was low (n = 9), the outcome was poor and the treatment related toxicity was substantial [142].
For further information about novel, less established PTLD treatment options such as infusion of third-party EBV-specific cytotoxic T-lymphocytes, CAR-T cell therapy, proteasome inhibitors, burton-tyrosine kinase inhibitors, and histone deacetylase inhibitors in combination with antiviral nucleoside analogues we refer to the recent review of Atallah-Yunes et al. [143].
The introduction of rituximab, the administration of sequential risk stratified treatment regimens, and optimized supportive care have improved the outcome for patients with PTLD. In the PTLD-1 trial, the median overall survival was 6.6 years [140]. Patients with a CR to rituximab alone have better prognosis as compared to rituximab non-responders [141] and thoracic transplant recipients show less favorable outcome as compared to non-thoracic transplant recipients [141, 142].
Statements
Author Contributions
AA and DY reviewed the HH8 literature, drafted the HHV8 part and critically reviewed the EBV part of the manuscript. CH reviewed the EBV literature, drafted the EBV part and critically reviewed the HHV8 part of the manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
Chang Y Cesarman E Pessin MS Lee F Culpepper J Knowles DM et al Identification of Herpesvirus-Like DNA Sequences in AIDS-Associated Kaposi's Sarcoma. Science (1994) 266(5192):1865–9. 10.1126/science.7997879
2
Nagy S Gyulai R Kemeny L Szenohradszky P Dobozy A . Iatrogenic Kaposi's Sarcoma: HHV8 Positivity Persists But the Tumors Regress Almost Completely Without Immunosuppressive Therapy. Transplantation (2000) 69(10):2230–1. 10.1097/00007890-200005270-00053
3
Nador RG Cesarman E Chadburn A Dawson DB Ansari MQ Sald J et al Primary Effusion Lymphoma: A Distinct Clinicopathologic Entity Associated With the Kaposi's Sarcoma-Associated Herpes Virus. Blood (1996) 88(2):645–56. 10.1182/blood.v88.2.645.bloodjournal882645
4
Soulier J Grollet L Oksenhendler E Cacoub P Cazals-Hatem D Babinet P et al Kaposi's Sarcoma-Associated Herpesvirus-Like DNA Sequences in Multicentric Castleman's Disease. Blood (1995) 86(4):1276–80.
5
Delyon J Rabate C Euvrard S Harwood CA Proby C Gulec AT et al Management of Kaposi Sarcoma After Solid Organ Transplantation: A European Retrospective Study. J Am Acad Dermatol (2019) 81(2):448–55. 10.1016/j.jaad.2019.03.028
6
Pellett Madan R Hand J Practice Astidco . Human Herpesvirus 6, 7, and 8 in Solid Organ Transplantation: Guidelines From the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transpl (2019) 33(9):e13518. 10.1111/ctr.13518
7
Lebbe C Legendre C Frances C . Kaposi Sarcoma in Transplantation. Transpl Rev (Orlando) (2008) 22(4):252–61. 10.1016/j.trre.2008.05.004
8
Mularoni A Gallo A Riva G Barozzi P Miele M Cardinale G et al Successful Treatment of Kaposi Sarcoma-Associated Herpesvirus Inflammatory Cytokine Syndrome After Kidney-Liver Transplant: Correlations With the Human Herpesvirus 8 miRNome and Specific T Cell Response. Am J Transpl (2017) 17(11):2963–9. 10.1111/ajt.14346
9
Riva G Luppi M Barozzi P Forghieri F Potenza L . How I Treat HHV8/KSHV-Related Diseases in Posttransplant Patients. Blood (2012) 120(20):4150–9. 10.1182/blood-2012-04-421412
10
Zhang T Wang L . Epidemiology of Kaposi's Sarcoma-Associated Herpesvirus in Asia: Challenges and Opportunities. J Med Virol (2017) 89(4):563–70. 10.1002/jmv.24662
11
Chatlynne LG Ablashi DV . Seroepidemiology of Kaposi's Sarcoma-Associated Herpesvirus (KSHV). Semin Cancer Biol (1999) 9(3):175–85. 10.1006/scbi.1998.0089
12
Gao SJ Kingsley L Hoover DR Spira TJ Rinaldo CR Saah A et al Seroconversion to Antibodies Against Kaposi's Sarcoma-Associated Herpesvirus-Related Latent Nuclear Antigens Before the Development of Kaposi's Sarcoma. N Engl J Med (1996) 335(4):233–41. 10.1056/NEJM199607253350403
13
Mayama S Cuevas LE Sheldon J Omar OH Smith DH Okong P et al Prevalence and Transmission of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) in Ugandan Children and Adolescents. Int J Cancer (1998) 77(6):817–20. 10.1002/(sici)1097-0215(19980911)77:6<817::aid-ijc2>3.0.co;2-x
14
Belec L Cancre N Hallouin MC Morvan J Si Mohamed A Gresenguet G . High Prevalence in Central Africa of Blood Donors Who Are Potentially Infectious for Human Herpesvirus 8. Transfusion (1998) 38(8):771–5. 10.1046/j.1537-2995.1998.38898375517.x
15
Liu Z Fang Q Zuo J Chen Y Minhas V Wood C et al Global Epidemiology of Human Herpesvirus 8 in Men Who Have Sex With Men: A Systematic Review and Meta-Analysis. J Med Virol (2018) 90(3):582–91. 10.1002/jmv.24960
16
Luppi M Barozzi P Santagostino G Trovato R Schulz TF Marasca R et al Molecular Evidence of Organ-Related Transmission of Kaposi Sarcoma-Associated Herpesvirus or Human Herpesvirus-8 in Transplant Patients. Blood (2000) 96(9):3279–81. 10.1182/blood.v96.9.3279.h8003279_3279_3281
17
Andreoni M Sarmati L Nicastri E El Sawaf G El Zalabani M Uccella I et al Primary Human Herpesvirus 8 Infection in Immunocompetent Children. JAMA (2002) 287(10):1295–300. 10.1001/jama.287.10.1295
18
Ariza-Heredia EJ Razonable RR . Human Herpes Virus 8 in Solid Organ Transplantation. Transplantation (2011) 92(8):837–44. 10.1097/TP.0b013e31823104ec
19
Karras A Thervet E Legendre C, Groupe Coopératif de Transplantation d'Ile de France. Hemophagocytic Syndrome in Renal Transplant Recipients: Report of 17 Cases and Review of Literature. Transplantation (2004) 77(2):238–43. 10.1097/01.TP.0000107285.86939.37
20
Luppi M Barozzi P Rasini V Riva G Re A Rossi G et al Severe Pancytopenia and Hemophagocytosis After HHV-8 Primary Infection in a Renal Transplant Patient Successfully Treated With Foscarnet. Transplantation (2002) 74(1):131–2. 10.1097/00007890-200207150-00023
21
Luppi M Barozzi P Schulz TF Setti G Staskus K Trovato R et al Bone Marrow Failure Associated With Human Herpesvirus 8 Infection After Transplantation. N Engl J Med (2000) 343(19):1378–85. 10.1056/NEJM200011093431905
22
Cohen GM Langer AL Sima H Chang C Troy K Taimur S . Hemophagocytic Lymphohistiocytosis Due to Primary HHV-8 Infection in a Liver Transplant Recipient. Transpl Direct (2018) 4(12):e411. 10.1097/TXD.0000000000000850
23
Mikulska M Balletto E Mularoni A . Human Herpesvirus 8 and Kaposi Sarcoma: How Should We Screen and Manage the Transplant Recipient?Curr Opin Infect Dis (2021) 34(6):646–53. 10.1097/QCO.0000000000000792
24
Fu W Merola J Malinis M Lacy J Barbieri A Liapakis AH et al Successful Treatment of Primary Donor-Derived Human Herpesvirus-8 Infection and Hepatic Kaposi Sarcoma in an Adult Liver Transplant Recipient. Transpl Infect Dis (2018) 20(5):e12966. 10.1111/tid.12966
25
Benhammane H Mentha G Tschanz E El Mesbahi O Dietrich PY . Visceral Kaposi's Sarcoma Related to Human Herpesvirus-8 in Liver Transplant Recipient: Case Report and Literature Review. Case Rep Oncol Med (2012) 2012:137291. 10.1155/2012/137291
26
Nair V Sheikh F Hirschwerk D Fahmy A Bhaskaran M Grodstein E et al An Unusual Case of Kaposi Sarcoma Masquerading as Cystitis in a Kidney Transplant Recipient. Transpl Infect Dis (2019) 21(5):e13132. 10.1111/tid.13132
27
Howard JH 3rd Darrow M Chen LX Alnimri M Jen KY . Tonsillar Kaposi Sarcoma in a Renal Transplant Patient. Transpl Infect Dis (2020) 22(5):e13347. 10.1111/tid.13347
28
Ocwieja KE Vargas SO Elisofon SA Shulman DS Lee CK Fawaz R et al Pediatric Post-Transplant Hepatic Kaposi Sarcoma Due to Donor-Derived Human Herpesvirus 8. Pediatr Transpl (2019) 23(3):e13384. 10.1111/petr.13384
29
Copeland MMM Trainor J Cash WJ Braniff C . Fatal Donor-Derived Kaposi Sarcoma Following Liver Transplantation. BMJ Case Rep (2021) 14(6):e236061. 10.1136/bcr-2020-236061
30
Garcia-Astudillo LA Leyva-Cobian F . Human Herpesvirus-8 Infection and Kaposi's Sarcoma After Liver and Kidney Transplantation in Different Geographical Areas of Spain. Transpl Immunol (2006) 17(1):65–9. 10.1016/j.trim.2006.09.008
31
Mbulaiteye SM Engels EA . Kaposi's Sarcoma Risk Among Transplant Recipients in the United States (1993-2003). Int J Cancer (2006) 119(11):2685–91. 10.1002/ijc.22233
32
Patel A Bishburg E Zucker M Tsang P Nagarakanti S Sabnani I . Concomitant Kaposi Sarcoma and Multicentric Castleman's Disease in a Heart Transplant Recipient. Heart Lung (2014) 43(6):506–9. 10.1016/j.hrtlng.2014.07.005
33
Gaitonde S Vidanovic V Ni H . Concomitant and Fatal HHV-8+ Multicentric Castleman's Disease and Kaposi's Sarcoma in the Same Lymph Node of an HIV- Liver Transplant Patient. Histopathology (2007) 50(7):954–8. 10.1111/j.1365-2559.2007.02702.x
34
Mandel C Silberstein M Hennessy O . Case Report: Fatal Pulmonary Kaposi's Sarcoma and Castleman's Disease in a Renal Transplant Recipient. Br J Radiol (1993) 66(783):264–5. 10.1259/0007-1285-66-783-264
35
Zanelli M Sanguedolce F Zizzo M Palicelli A Bassi MC Santandrea G et al Primary Effusion Lymphoma Occurring in the Setting of Transplanted Patients: A Systematic Review of a Rare, Life-Threatening Post-Transplantation Occurrence. BMC Cancer (2021) 21(1):468. 10.1186/s12885-021-08215-7
36
Polizzotto MN Uldrick TS Wyvill KM Aleman K Marshall V Wang V et al Clinical Features and Outcomes of Patients With Symptomatic Kaposi Sarcoma Herpesvirus (KSHV)-Associated Inflammation: Prospective Characterization of KSHV Inflammatory Cytokine Syndrome (KICS). Clin Infect Dis (2016) 62(6):730–8. 10.1093/cid/civ996
37
Antonio R Laura G Nicolina C Elena S Luca V Tiziana L et al Donor-Derived Human Herpesvirus 8 Infection With Kaposi Sarcoma and Kaposi Sarcoma Inflammatory Cytokine Syndrome in a Heart Transplant Recipient: A Case Report. Transpl Infect Dis (2021) 23(4):e13609. 10.1111/tid.13609
38
Euvrard S Kanitakis J Claudy A . Skin Cancers After Organ Transplantation. N Engl J Med (2003) 348(17):1681–91. 10.1056/NEJMra022137
39
Chiereghin A Barozzi P Petrisli E Piccirilli G Gabrielli L Riva G et al Multicenter Prospective Study for Laboratory Diagnosis of HHV8 Infection in Solid Organ Donors and Transplant Recipients and Evaluation of the Clinical Impact After Transplantation. Transplantation (2017) 101(8):1935–44. 10.1097/TP.0000000000001740
40
Mularoni A Mikulska M Giannella M Adamoli L Slavin M Van Delden C et al International Survey of Human Herpes Virus 8 Screening and Management in Solid Organ Transplantation. Transpl Infect Dis (2021) 23(5):e13698. 10.1111/tid.13698
41
Engels EA Biggar RJ Marshall VA Walters MA Gamache CJ Whitby D et al Detection and Quantification of Kaposi's Sarcoma-Associated Herpesvirus to Predict AIDS-Associated Kaposi's Sarcoma. AIDS (2003) 17(12):1847–51. 10.1097/00002030-200308150-00015
42
Jary A Leducq V Palich R Gothland A Descamps D Joly V et al Usefulness of Kaposi's Sarcoma-Associated Herpesvirus (KSHV) DNA Viral Load in Whole Blood for Diagnosis and Monitoring of KSHV-Associated Diseases. J Clin Microbiol (2018) 56(6):e00569-18. 10.1128/JCM.00569-18
43
Sayer R Paul J Tuke PW Hargreaves S Noursadeghi M Tedder RS et al Can Plasma HHV8 Viral Load Be Used to Differentiate Multicentric Castleman Disease From Kaposi Sarcoma? Int J STD AIDS (2011) 22(10):585–9. 10.1258/ijsa.2011.010464
44
Hosseini-Moghaddam SM Soleimanirahbar A Mazzulli T Rotstein C Husain S . Post Renal Transplantation Kaposi's Sarcoma: A Review of Its Epidemiology, Pathogenesis, Diagnosis, Clinical Aspects, and Therapy. Transpl Infect Dis (2012) 14(4):338–45. 10.1111/j.1399-3062.2011.00714.x
45
Clinical INFO. Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV. National Institutes of Health, Centers for Disease Control and Prevention, HIV Medicine Association, and Infectious Diseases Society of America (2023). Available From: https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection (Accessed September 25, 2023).
46
Casper C Corey L Cohen JI Damania B Gershon AA Kaslow DC et al KSHV (HHV8) Vaccine: Promises and Potential Pitfalls for a New Anti-Cancer Vaccine. NPJ Vaccin (2022) 7(1):108. 10.1038/s41541-022-00535-4
47
Dollard SC Annambhotla P Wong P Meneses K Amin MM La Hoz RM et al Donor-Derived Human Herpesvirus 8 and Development of Kaposi Sarcoma Among 6 Recipients of Organs From Donors With High-Risk Sexual and Substance Use Behavior. Am J Transpl (2021) 21(2):681–8. 10.1111/ajt.16181
48
Gonzalez-Cruz C Ferrandiz-Pulido C Ferrer Fabregas B Garcia-Patos Briones V . Posttransplant Kaposi Sarcoma: Analysis of a Series of 13 Patients. Med Clin (Barc) (2021) 157(7):339–43. 10.1016/j.medcli.2021.04.030
49
Campistol JM Gutierrez-Dalmau A Torregrosa JV . Conversion to Sirolimus: A Successful Treatment for Posttransplantation Kaposi's Sarcoma. Transplantation (2004) 77(5):760–2. 10.1097/01.tp.0000115344.18025.0b
50
Esser S Schofer H Hoffmann C Classen J Kreuter A Leiter U et al S1 Guidelines for the Kaposi Sarcoma. J Dtsch Dermatol Ges (2022) 20(6):892–904. 10.1111/ddg.14788
51
Casper C Wald A . The Use of Antiviral Drugs in the Prevention and Treatment of Kaposi Sarcoma, Multicentric Castleman Disease and Primary Effusion Lymphoma. Curr Top Microbiol Immunol (2007) 312:289–307. 10.1007/978-3-540-34344-8_11
52
Parravicini C Chandran B Corbellino M Berti E Paulli M Moore PS et al Differential Viral Protein Expression in Kaposi's Sarcoma-Associated Herpesvirus-Infected Diseases: Kaposi's Sarcoma, Primary Effusion Lymphoma, and Multicentric Castleman's Disease. Am J Pathol (2000) 156(3):743–9. 10.1016/S0002-9440(10)64940-1
53
Munz C . Latency and Lytic Replication in Epstein-Barr Virus-Associated Oncogenesis. Nat Rev Microbiol (2019) 17(11):691–700. 10.1038/s41579-019-0249-7
54
Epstein MA Achong BG Barr YM . Virus Particles in Cultured Lymphoblasts From Burkitt's Lymphoma. Lancet (1964) 1(7335):702–3. 10.1016/s0140-6736(64)91524-7
55
Henle G Henle W Diehl V . Relation of Burkitt's Tumor-Associated Herpes-Ytpe Virus to Infectious Mononucleosis. Proc Natl Acad Sci U S A (1968) 59(1):94–101. 10.1073/pnas.59.1.94
56
Henle W Diehl V Kohn G Zur Hausen H Henle G . Herpes-Type Virus and Chromosome Marker in Normal Leukocytes After Growth With Irradiated Burkitt Cells. Science (1967) 157(3792):1064–5. 10.1126/science.157.3792.1064
57
Pope JH . Establishment of Cell Lines From Peripheral Leucocytes in Infectious Mononucleosis. Nature (1967) 216(5117):810–1. 10.1038/216810a0
58
Pope JH Horne MK Scott W . Transformation of Foetal Human Keukocytes In Vitro by Filtrates of a Human Leukaemic Cell Line Containing Herpes-Like Virus. Int J Cancer (1968) 3(6):857–66. 10.1002/ijc.2910030619
59
Babcock GJ Decker LL Volk M Thorley-Lawson DA . EBV Persistence in Memory B Cells In Vivo. Immunity (1998) 9(3):395–404. 10.1016/s1074-7613(00)80622-6
60
Chaganti S Heath EM Bergler W Kuo M Buettner M Niedobitek G et al Epstein-Barr Virus Colonization of Tonsillar and Peripheral Blood B-Cell Subsets in Primary Infection and Persistence. Blood (2009) 113(25):6372–81. 10.1182/blood-2008-08-175828
61
Young LS Yap LF Murray PG . Epstein-Barr Virus: More Than 50 Years Old and Still Providing Surprises. Nat Rev Cancer (2016) 16(12):789–802. 10.1038/nrc.2016.92
62
Yu H Robertson ES . Epstein-Barr Virus History and Pathogenesis. Viruses (2023) 15(3):714. 10.3390/v15030714
63
Nijland ML Kersten MJ Pals ST Bemelman FJ Ten Berge IJ . Epstein-Barr Virus-Positive Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation: Pathogenesis, Clinical Manifestations, Diagnosis, and Management. Transpl Direct (2016) 2(1):e48. 10.1097/TXD.0000000000000557
64
Cesarman E . Gammaherpesvirus and Lymphoproliferative Disorders in Immunocompromised Patients. Cancer Lett (2011) 305(2):163–74. 10.1016/j.canlet.2011.03.003
65
Kuri A Jacobs BM Vickaryous N Pakpoor J Middeldorp J Giovannoni G et al Epidemiology of Epstein-Barr Virus Infection and Infectious Mononucleosis in the United Kingdom. BMC Public Health (2020) 20(1):912. 10.1186/s12889-020-09049-x
66
Rahman S Wathington D Waterboer T Pawlita M Villa LL Lazcano-Ponce E et al Seroprevalence of Chlamydia trachomatis, Herpes Simplex 2, Epstein-Barr Virus, Hepatitis C and Associated Factors Among a Cohort of Men Ages 18-70 Years From Three Countries. PLoS One (2021) 16(6):e0253005. 10.1371/journal.pone.0253005
67
Fourcade G Germi R Guerber F Lupo J Baccard M Seigneurin A et al Evolution of EBV Seroprevalence and Primary Infection Age in a French Hospital and a City Laboratory Network, 2000-2016. PLoS One (2017) 12(4):e0175574. 10.1371/journal.pone.0175574
68
Balfour HH Jr. Sifakis F Sliman JA Knight JA Schmeling DO Thomas W . Age-Specific Prevalence of Epstein-Barr Virus Infection Among Individuals Aged 6-19 Years in the United States and Factors Affecting Its Acquisition. J Infect Dis (2013) 208(8):1286–93. 10.1093/infdis/jit321
69
Takeuchi K Tanaka-Taya K Kazuyama Y Ito YM Hashimoto S Fukayama M et al Prevalence of Epstein-Barr Virus in Japan: Trends and Future Prediction. Pathol Int (2006) 56(3):112–6. 10.1111/j.1440-1827.2006.01936.x
70
Penn I Hammond W Brettschneider L Starzl TE . Malignant Lymphomas in Transplantation Patients. Transpl Proc (1969) 1(1):106–12.
71
Alaggio R Amador C Anagnostopoulos I Attygalle AD Araujo IBO Berti E et al The 5th Edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia (2022) 36(7):1720–48. 10.1038/s41375-022-01620-2
72
Walti LN Mugglin C Sidler D Mombelli M Manuel O Hirsch HH et al Association of Antiviral Prophylaxis and Rituximab Use With Posttransplant Lymphoproliferative Disorders (PTLDs): A Nationwide Cohort Study. Am J Transpl (2021) 21(7):2532–42. 10.1111/ajt.16423
73
Liu Y Wang BC Zuppan CW Chau P Fitts J Chinnock R et al Relationship of Post-Transplant Lymphoproliferative Disorders (PTLD) Subtypes and Clinical Outcome in Pediatric Heart Transplant Recipients: A Retrospective Single Institutional Analysis/Experience of 558 Patients. Cancers (Basel) (2023) 15(3):976. 10.3390/cancers15030976
74
Pitman SD Huang Q Zuppan CW Rowsell EH Cao JD Berdeja JG et al Hodgkin Lymphoma-Like Posttransplant Lymphoproliferative Disorder (HL-Like PTLD) Simulates Monomorphic B-Cell PTLD Both Clinically and Pathologically. Am J Surg Pathol (2006) 30(4):470–6. 10.1097/00000478-200604000-00007
75
Choquet S Varnous S Deback C Golmard JL Leblond V . Adapted Treatment of Epstein-Barr Virus Infection to Prevent Posttransplant Lymphoproliferative Disorder After Heart Transplantation. Am J Transpl (2014) 14(4):857–66. 10.1111/ajt.12640
76
Lee TC Savoldo B Rooney CM Heslop HE Gee AP Caldwell Y et al Quantitative EBV Viral Loads and Immunosuppression Alterations Can Decrease PTLD Incidence in Pediatric Liver Transplant Recipients. Am J Transpl (2005) 5(9):2222–8. 10.1111/j.1600-6143.2005.01002.x
77
Swerdlow SHHN Jaffe ES Pileri SA Stein H Thiele J . World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC (2017).
78
Allen UD Preiksaitis JK Practice Astidco . 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 Transpl (2019) 33(9):e13652. 10.1111/ctr.13652
79
Vergote VKJ Deroose CM Fieuws S Laleman W Sprangers B Uyttebroeck A et al Characteristics and Outcome of Post-Transplant Lymphoproliferative Disorders After Solid Organ Transplantation: A Single Center Experience of 196 Patients Over 30 Years. Transpl Int (2022) 35:10707. 10.3389/ti.2022.10707
80
Peters AC Akinwumi MS Cervera C Mabilangan C Ghosh S Lai R et al The Changing Epidemiology of Posttransplant Lymphoproliferative Disorder in Adult Solid Organ Transplant Recipients Over 30 Years: A Single-Center Experience. Transplantation (2018) 102(9):1553–62. 10.1097/TP.0000000000002146
81
Quinlan SC Pfeiffer RM Morton LM Engels EA . Risk Factors for Early-Onset and Late-Onset Post-Transplant Lymphoproliferative Disorder in Kidney Recipients in the United States. Am J Hematol (2011) 86(2):206–9. 10.1002/ajh.21911
82
Dharnidharka VR . Comprehensive Review of Post-Organ Transplant Hematologic Cancers. Am J Transpl (2018) 18(3):537–49. 10.1111/ajt.14603
83
Caillard S Lamy FX Quelen C Dantal J Lebranchu Y Lang P et al Epidemiology of Posttransplant Lymphoproliferative Disorders in Adult Kidney and Kidney Pancreas Recipients: Report of the French Registry and Analysis of Subgroups of Lymphomas. Am J Transpl (2012) 12(3):682–93. 10.1111/j.1600-6143.2011.03896.x
84
Opelz G Daniel V Naujokat C Dohler B . Epidemiology of Pretransplant EBV and CMV Serostatus in Relation to Posttransplant Non-Hodgkin Lymphoma. Transplantation (2009) 88(8):962–7. 10.1097/TP.0b013e3181b9692d
85
Liu M Husain S Famure O Li Y Kim SJ . Incidence, Risk Factors, Clinical Management, and Outcomes of Posttransplant Lymphoproliferative Disorder in Kidney Transplant Recipients. Prog Transpl (2019) 29(2):185–93. 10.1177/1526924819835834
86
Sampaio MS Cho YW Shah T Bunnapradist S Hutchinson IV . Impact of Epstein-Barr Virus Donor and Recipient Serostatus on the Incidence of Post-Transplant Lymphoproliferative Disorder in Kidney Transplant Recipients. Nephrol Dial Transpl (2012) 27(7):2971–9. 10.1093/ndt/gfr769
87
Dharnidharka VR Lamb KE Gregg JA Meier-Kriesche HU . Associations Between EBV Serostatus and Organ Transplant Type in PTLD Risk: An Analysis of the SRTR National Registry Data in the United States. Am J Transpl (2012) 12(4):976–83. 10.1111/j.1600-6143.2011.03893.x
88
Wozniak LJ Mauer TL Venick RS Said JW Kao RL Kempert P et al Clinical Characteristics and Outcomes of PTLD Following Intestinal Transplantation. Clin Transpl (2018) 32(8):e13313. 10.1111/ctr.13313
89
Devine K Ranganathan S Mazariegos G Bond G Soltys K Ganoza A et al Induction Regimens and Post-Transplantation Lymphoproliferative Disorder After Pediatric Intestinal Transplantation: Single-Center Experience. Pediatr Transpl (2020) 24(5):e13723. 10.1111/petr.13723
90
Dierickx D Habermann TM . Post-Transplantation Lymphoproliferative Disorders in Adults. N Engl J Med (2018) 378(6):549–62. 10.1056/NEJMra1702693
91
Sprangers B Nair V Launay-Vacher V Riella LV Jhaveri KD . Risk Factors Associated With Post-Kidney Transplant Malignancies: An Article From the Cancer-Kidney International Network. Clin Kidney J (2018) 11(3):315–29. 10.1093/ckj/sfx122
92
Hill P Cross NB Barnett AN Palmer SC Webster AC . Polyclonal and Monoclonal Antibodies for Induction Therapy in Kidney Transplant Recipients. Cochrane Database Syst Rev (2017) 1(1):CD004759. 10.1002/14651858.CD004759.pub2
93
Durrbach A Pestana JM Florman S Del Carmen Rial M Rostaing L Kuypers D et al Long-Term Outcomes in Belatacept- Versus Cyclosporine-Treated Recipients of Extended Criteria Donor Kidneys: Final Results From BENEFIT-EXT, a Phase III Randomized Study. Am J Transpl (2016) 16(11):3192–201. 10.1111/ajt.13830
94
Archdeacon P Dixon C Belen O Albrecht R Meyer J . Summary of the US FDA Approval of Belatacept. Am J Transpl (2012) 12(3):554–62. 10.1111/j.1600-6143.2011.03976.x
95
L'Huillier AG Dipchand AI Ng VL Hebert D Avitzur Y Solomon M et al Posttransplant Lymphoproliferative Disorder in Pediatric Patients: Survival Rates According to Primary Sites of Occurrence and a Proposed Clinical Categorization. Am J Transpl (2019) 19(10):2764–74. 10.1111/ajt.15358
96
Dekate J Chetty R . Epstein-Barr Virus-Associated Smooth Muscle Tumor. Arch Pathol Lab Med (2016) 140(7):718–22. 10.5858/arpa.2015-0120-RS
97
Chaves NJ Kotsimbos TC Warren MA McLean CA Spelman DW Williams TJ et al Cranial Leiomyosarcoma in an Epstein-Barr Virus (EBV)-Mismatched Lung Transplant Recipient. J Heart Lung Transpl (2007) 26(7):753–5. 10.1016/j.healun.2007.05.007
98
Jonigk D Laenger F Maegel L Izykowski N Rische J Tiede C et al Molecular and Clinicopathological Analysis of Epstein-Barr Virus-Associated Posttransplant Smooth Muscle Tumors. Am J Transpl (2012) 12(7):1908–17. 10.1111/j.1600-6143.2012.04011.x
99
Petti S Polimeni A Berloco PB Scully C . Orofacial Diseases in Solid Organ and Hematopoietic Stem Cell Transplant Recipients. Oral Dis (2013) 19(1):18–36. 10.1111/j.1601-0825.2012.01925.x
100
Ridha M Jones DG Lerner DP Vytopil M Voetsch B Burns JD et al The Spectrum of Epstein-Barr Virus Infections of the Central Nervous System After Organ Transplantation. Virol J (2021) 18(1):162. 10.1186/s12985-021-01629-6
101
Rehman F Makkeyah Y Buraq AA Aldous G Ahmad S . Life-Threatening Epstein-Barr Virus (EBV)-Related Hepatitis in a Renal Transplant Patient. Clin Med (Lond) (2020) 20(Suppl. 2):s38. 10.7861/clinmed.20-2-s38
102
Gulley ML Glaser SL Craig FE Borowitz M Mann RB Shema SJ et al Guidelines for Interpreting EBER In Situ Hybridization and LMP1 Immunohistochemical Tests for Detecting Epstein-Barr Virus in Hodgkin Lymphoma. Am J Clin Pathol (2002) 117(2):259–67. 10.1309/MMAU-0QYH-7BHA-W8C2
103
Cheson BD Fisher RI Barrington SF Cavalli F Schwartz LH Zucca E et al Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol (2014) 32(27):3059–68. 10.1200/JCO.2013.54.8800
104
Pons-Escoda A Naval-Baudin P Velasco R Vidal N Majos C . Imaging of Lymphomas Involving the CNS: An Update-Review of the Full Spectrum of Disease With an Emphasis on the World Health Organization Classifications of CNS Tumors 2021 and Hematolymphoid Tumors 2022. AJNR Am J Neuroradiol (2023) 44(4):358–66. 10.3174/ajnr.A7795
105
Song H Guja KE Iagaru A . 18)F-FDG PET/CT for Evaluation of Post-Transplant Lymphoproliferative Disorder (PTLD). Semin Nucl Med (2021) 51(4):392–403. 10.1053/j.semnuclmed.2020.12.009
106
Ylinen E Merras-Salmio L Jahnukainen T . Gastrointestinal Symptoms and Endoscopy Findings After Pediatric Solid Organ Transplantation: A Case Series. Pediatr Transpl (2022) 26(7):e14374. 10.1111/petr.14374
107
Seo E Kim J Oh SH Kim KM Kim DY Lee J . Epstein-Barr Viral Load Monitoring for Diagnosing Post-Transplant Lymphoproliferative Disorder in Pediatric Liver Transplant Recipients. Pediatr Transpl (2020) 24(4):e13666. 10.1111/petr.13666
108
Dharnidharka VR . Peripheral Blood Epstein-Barr Viral Nucleic Acid Surveillance as a Marker for Posttransplant Cancer Risk. Am J Transpl (2017) 17(3):611–6. 10.1111/ajt.13982
109
Gulley ML Tang W . Using Epstein-Barr Viral Load Assays to Diagnose, Monitor, and Prevent Posttransplant Lymphoproliferative Disorder. Clin Microbiol Rev (2010) 23(2):350–66. 10.1128/CMR.00006-09
110
San-Juan R Manuel O Hirsch HH Fernandez-Ruiz M Lopez-Medrano F Comoli P et al 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) 21(6):604 e1–9. 10.1016/j.cmi.2015.02.002
111
Ruijter BN Wolterbeek R Hew M van Reeven M van der Helm D Dubbeld J et al Epstein-Barr Viral Load Monitoring Strategy and the Risk for Posttransplant Lymphoproliferative Disease in Adult Liver Transplantation: A Cohort Study. Ann Intern Med (2023) 176(2):174–81. 10.7326/M22-0364
112
Ishihara M Tanaka E Sato T Chikamoto H Hisano M Akioka Y et al Epstein-Barr Virus Load for Early Detection of Lymphoproliferative Disorder in Pediatric Renal Transplant Recipients. Clin Nephrol (2011) 76(1):40–8. 10.5414/cn106572
113
Gregorek H Jankowska I Dzierzanowska-Fangrat K Teisseyre J Sawicka A Kasztelewicz B et al Long-Term Monitoring of Epstein-Barr Virus DNA Load and Humoral Parameter Abnormalities in Pediatric Liver Transplant Recipients Before Development of Malignancy. Pediatr Transpl (2010) 14(5):629–35. 10.1111/j.1399-3046.2010.01293.x
114
Martin SI Dodson B Wheeler C Davis J Pesavento T Bumgardner GL . Monitoring Infection With Epstein-Barr Virus Among Seromismatch Adult Renal Transplant Recipients. Am J Transpl (2011) 11(5):1058–63. 10.1111/j.1600-6143.2011.03478.x
115
Bakker NA Verschuuren EA Erasmus ME Hepkema BG Veeger NJ Kallenberg CG et al Epstein-Barr Virus-DNA Load Monitoring Late After Lung Transplantation: A Surrogate Marker of the Degree of Immunosuppression and a Safe Guide to Reduce Immunosuppression. Transplantation (2007) 83(4):433–8. 10.1097/01.tp.0000252784.60159.96
116
Rychert J Danziger-Isakov L Yen-Lieberman B Storch G Buller R Sweet SC et al Multicenter Comparison of Laboratory Performance in Cytomegalovirus and Epstein-Barr Virus Viral Load Testing Using International Standards. Clin Transpl (2014) 28(12):1416–23. 10.1111/ctr.12473
117
Semenova T Lupo J Alain S Perrin-Confort G Grossi L Dimier J et al Multicenter Evaluation of Whole-Blood Epstein-Barr Viral Load Standardization Using the WHO International Standard. J Clin Microbiol (2016) 54(7):1746–50. 10.1128/JCM.03336-15
118
Ruf S Behnke-Hall K Gruhn B Bauer J Horn M Beck J et al Comparison of Six Different Specimen Types for Epstein-Barr Viral Load Quantification in Peripheral Blood of Pediatric Patients After Heart Transplantation or After Allogeneic Hematopoietic Stem Cell Transplantation. J Clin Virol (2012) 53(3):186–94. 10.1016/j.jcv.2011.11.010
119
Rzepka M Depka D Gospodarek-Komkowska E Bogiel T . Diagnostic Value of Whole-Blood and Plasma Samples in Epstein-Barr Virus Infections. Diagnostics (Basel) (2023) 13(3):476. 10.3390/diagnostics13030476
120
Kanakry JA Hegde AM Durand CM Massie AB Greer AE Ambinder RF et al The Clinical Significance of EBV DNA in the Plasma and Peripheral Blood Mononuclear Cells of Patients With or Without EBV Diseases. Blood (2016) 127(16):2007–17. 10.1182/blood-2015-09-672030
121
Sprangers B Riella LV Dierickx D . Posttransplant Lymphoproliferative Disorder Following Kidney Transplantation: A Review. Am J Kidney Dis (2021) 78(2):272–81. 10.1053/j.ajkd.2021.01.015
122
San-Juan R Comoli P Caillard S Moulin B Hirsch HH Meylan P et al Epstein-Barr Virus-Related Post-Transplant Lymphoproliferative Disorder in Solid Organ Transplant Recipients. Clin Microbiol Infect (2014) 20(Suppl. 7):109–18. 10.1111/1469-0691.12534
123
Pagano JS Whitehurst CB Andrei G . Antiviral Drugs for EBV. Cancers (Basel) (2018) 10(6):197. 10.3390/cancers10060197
124
Andrei G Trompet E Snoeck R . Novel Therapeutics for Epstein(-)Barr Virus. Molecules (2019) 24(5):997. 10.3390/molecules24050997
125
Hocker B Bohm S Fickenscher H Kusters U Schnitzler P Pohl M et al (Val-)Ganciclovir Prophylaxis Reduces Epstein-Barr Virus Primary Infection in Pediatric Renal Transplantation. Transpl Int (2012) 25(7):723–31. 10.1111/j.1432-2277.2012.01485.x
126
Ville S Imbert-Marcille BM Coste-Burel M Garandeau C Meurette A Cantarovitch D et al Impact of Antiviral Prophylaxis in Adults Epstein-Barr Virus-Seronegative Kidney Recipients on Early and Late Post-Transplantation Lymphoproliferative Disorder Onset: A Retrospective Cohort Study. Transpl Int (2018) 31(5):484–94. 10.1111/tri.13085
127
Cheyssac E Savadogo H Lagoutte N Baudouin V Charbit M Novo R et al Valganciclovir Is Not Associated With Decreased EBV Infection Rate in Pediatric Kidney Transplantation. Front Pediatr (2022) 10:1085101. 10.3389/fped.2022.1085101
128
AlDabbagh MA Gitman MR Kumar D Humar A Rotstein C Husain S . The Role of Antiviral Prophylaxis for the Prevention of Epstein-Barr Virus-Associated Posttransplant Lymphoproliferative Disease in Solid Organ Transplant Recipients: A Systematic Review. Am J Transpl (2017) 17(3):770–81. 10.1111/ajt.14020
129
Styczynski J van der Velden W Fox CP Engelhard D de la Camara R Cordonnier C 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. Haematologica (2016) 101(7):803–11. 10.3324/haematol.2016.144428
130
Worth A Conyers R Cohen J Jagani M Chiesa R Rao K 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(3):377–85. 10.1111/j.1365-2141.2011.08855.x
131
Dominietto A Tedone E Soracco M Bruno B Raiola AM Van Lint MT et al In Vivo B-Cell Depletion With Rituximab for Alternative Donor Hemopoietic SCT. Bone Marrow Transpl (2012) 47(1):101–6. 10.1038/bmt.2011.28
132
Burns DM Rana S Martin E Nagra S Ward J Osman H et al Greatly Reduced Risk of EBV Reactivation in Rituximab-Experienced Recipients of Alemtuzumab-Conditioned Allogeneic HSCT. Bone Marrow Transpl (2016) 51(6):825–32. 10.1038/bmt.2016.19
133
Van Besien K Bachier-Rodriguez L Satlin M Brown MA Gergis U Guarneri D et al Prophylactic Rituximab Prevents EBV PTLD in Haplo-Cord Transplant Recipients at High Risk. Leuk Lymphoma (2019) 60(7):1693–6. 10.1080/10428194.2018.1543877
134
Patel C Pasciolla M Abramova R Salerno D Gomez-Arteaga A Shore TB et al Pre-Hematopoietic Stem Cell Transplantation Rituximab for Epstein-Barr Virus and Post-Lymphoproliferative Disorder Prophylaxis in Alemtuzumab Recipients. Transpl Cel Ther (2023) 29(2):132 e1–132132.e5. 10.1016/j.jtct.2022.10.023
135
Fujimoto A Hiramoto N Yamasaki S Inamoto Y Ogata M Sugio Y et al Low Incidence of Posttransplant Lymphoproliferative Disorder After Allogeneic Stem Cell Transplantation in Patients With Lymphoma Treated with Rituximab. Hematol Oncol (2020) 38(2):146–52. 10.1002/hon.2714
136
Swinnen LJ LeBlanc M Grogan TM Gordon LI Stiff PJ Miller AM et al Prospective Study of Sequential Reduction in Immunosuppression, Interferon Alpha-2B, and Chemotherapy for Posttransplantation Lymphoproliferative Disorder. Transplantation (2008) 86(2):215–22. 10.1097/TP.0b013e3181761659
137
Reshef R Vardhanabhuti S Luskin MR Heitjan DF Hadjiliadis D Goral S et al Reduction of Immunosuppression as Initial Therapy for Posttransplantation Lymphoproliferative Disorder(★). Am J Transpl (2011) 11(2):336–47. 10.1111/j.1600-6143.2010.03387.x
138
Tsai DE Hardy CL Tomaszewski JE Kotloff RM Oltoff KM Somer BG et al Reduction in Immunosuppression as Initial Therapy for Posttransplant Lymphoproliferative Disorder: Analysis of Prognostic Variables and Long-Term Follow-Up of 42 Adult Patients. Transplantation (2001) 71(8):1076–88. 10.1097/00007890-200104270-00012
139
Choquet S Trappe R Leblond V Jager U Davi F Oertel S . CHOP-21 for the Treatment of Post-Transplant Lymphoproliferative Disorders (PTLD) Following Solid Organ Transplantation. Haematologica (2007) 92(2):273–4. 10.3324/haematol.10595
140
Trappe R Oertel S Leblond V Mollee P Sender M Reinke P et al Sequential Treatment With Rituximab Followed by CHOP Chemotherapy in Adult B-Cell Post-Transplant Lymphoproliferative Disorder (PTLD): The Prospective International Multicentre Phase 2 PTLD-1 Trial. Lancet Oncol (2012) 13(2):196–206. 10.1016/S1470-2045(11)70300-X
141
Trappe RU Dierickx D Zimmermann H Morschhauser F Mollee P Zaucha JM et al Response to Rituximab Induction Is a Predictive Marker in B-Cell Post-Transplant Lymphoproliferative Disorder and Allows Successful Stratification Into Rituximab or R-CHOP Consolidation in an International, Prospective, Multicenter Phase II Trial. J Clin Oncol (2017) 35(5):536–43. 10.1200/JCO.2016.69.3564
142
Zimmermann H Koenecke C Dreyling MH Pott C Duhrsen U Hahn D et al Modified Risk-Stratified Sequential Treatment (Subcutaneous Rituximab With or Without Chemotherapy) in B-Cell Post-Transplant Lymphoproliferative Disorder (PTLD) After Solid Organ Transplantation (SOT): The Prospective Multicentre Phase II PTLD-2 Trial. Leukemia (2022) 36(10):2468–78. 10.1038/s41375-022-01667-1
143
Atallah-Yunes SA Salman O Robertson MJ . Post-Transplant Lymphoproliferative Disorder: Update on Treatment and Novel Therapies. Br J Haematol (2023) 201(3):383–95. 10.1111/bjh.18763
Summary
Keywords
human herpes virus 8, Epstein-Barr virus, Kaposi sarcoma, multicentic Castleman disease, primary effusion lymphoma, posttransplant lymphoproliferative disorders
Citation
Atamna A, Yahav D and Hirzel C (2023) Prevention of Oncogenic Gammaherpesvirinae (EBV and HHV8) Associated Disease in Solid Organ Transplant Recipients. Transpl Int 36:11856. doi: 10.3389/ti.2023.11856
Received
27 July 2023
Accepted
07 November 2023
Published
17 November 2023
Volume
36 - 2023
Updates
Copyright
© 2023 Atamna, Yahav and Hirzel.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Alaa Atamna, a.atamna86@gmail.com
†These authors share last authorship
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.