Oncogenic γ Herpesviruses EBV and HHV8 in Kidney Transplantation

Oncogenic γ Herpesviruses EBV and HHV8 in Kidney Transplantation Jade Le, MD Summary: Epstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8) are γ herpesviruses associated with post-transplant malignancies in kidney transplant recipients. EBV is associated with post-transplantation lymphoproliferative disorder (PTLD), with increased risk in EBV-seronegative patients on intensified immunosuppression. Human herpesvirus-8 is associated with Kaposi’s sarcoma (KS), with an increased risk in certain patient populations. Diagnosis of PTLD and KS relies on tissue biopsy. The mainstay of therapy for both PTLD and Kaposi’s sarcoma is a reduction of immunosuppression, and in the case of PTLD, consideration of rituximab. Chemotherapy, radiation therapy, or surgery is provided for disseminated or recalcitrant disease. The prognoses vary depending on the type of malignancy identified and stage of disease. Semin Nephrol 36:362-371 C 2016 Elsevier Inc. All rights reserved. Keywords: Epstein-Barr virus, post-transplant lymphoproliferative disorder, HHV-8, Kaposi’s sarcoma

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pstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8) are γ herpesviruses associated with post-transplant malignancies in kidney transplant recipients.

EPSTEIN-BARR VIRUS Virology of the Virus EBV, also known as human herpesvirus 4, is a member of the γ herpesvirus family, and is associated with posttransplantation lymphoproliferative disorder (PTLD) in kidney transplant (KT) recipients.1 Its viral structure consists of a 172–kilobase pair, double-stranded DNA surrounded by an icosahedral nucleocapsid, which is surrounded by an amorphous protein tegument and an outer envelope containing glycoprotein spikes gp 350/220.2 There are two strains of EBV in the human population, EBV-1 (formerly known as EBVA) and EBV-2 (formerly known as EBV-B), that maintain extensive homology except for differences in the latent infection cycle Epstein-Barr nuclear antigen genes. In addition, EBV-1 predominates in the United States and Europe, whereas EBV-1 and EBV-2 are equally prevalent in Africa and New Guinea, with possible clinical implications in terms of types of cancer associations.3 EBV undergoes viral replication in oropharyngeal epithelial cells, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX. Financial support: Supported in part by the Dedman Family Scholar in Clinical Care Grant. Conflict of interest statement: none. Address reprint requests to Jade Le, MD, Department of Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX75390. E-mail: [email protected] 0270-9295/ - see front matter & 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semnephrol.2016.05.013

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subsequently infecting circulating B cells through interaction of gp 350/220 with the B-cell surface receptor CD21. The virus becomes internalized through lysosomal fusion, its genome enters the Bcell nucleus where its linear DNA circularizes, and it exists either as an episome or becomes integrated into chromosomal DNA. EBV then establishes viral latency through the Epstein-Barr early RNA, latent membrane protein, and Epstein-Barr nuclear antigen genes, using cellular DNA polymerases for replication and immortalization. These EBV-infected latent B cells are triggered through various mechanisms to undergo lytic cycle replication, mediated by the Bam HI Z Leftward reading Frame 1 gene product Zta encoded by Bam HI Z Leftward reading Frame 1 and immediate early and early proteins,4 leading to cellular cytopathic changes, active viral replication, and release. A robust T-cell response involving cytotoxic T lymphocytes directed toward the immediate early antigens can terminate the lytic cycle, killing the infected B cells and releasing viral and cellular antigens, resulting in symptoms of infectious mononucleosis. Thus, EBV establishes both latent and lytic replicative cycles in the human host. Epidemiology of the Virus EBV transmission occurs person-to-person mainly through saliva, with possible transmission through sexual intercourse.5 After infection, virus may be shed in the saliva for up to 6 months after the onset of symptoms,6 however intermittent shedding in saliva may occur for decades. Most infections are subclinical, with worldwide distribution according to the strain. Seroprevalence rates vary according to socioeconomic status, with 100% seroprevalence by age 4 in developing countries, compared to 81% seroprevalence by age 14 in lower socioeconomic groups versus 50% seroprevalence in higher socioeconomic groups in the United States.7 Most infections in industrialized Seminars in Nephrology, Vol 36, No 5, September 2016, pp 362–371

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nations in the higher socioeconomic groups occur in adolescence and early adulthood, with up to 89% of the population infected by age 19.8 Most immunocompetent persons do not manifest EBVassociated diseases after initial infection, however, in KT recipients, EBV-associated PTLD is problematic. The cumulative incidence ranges from 1% to 5% in KT recipients, as compared to 2% to 10% in heart and lung transplant recipients, and 5% to 20% in intestinal and multivisceral transplant recipients.9 The Collaborative Transplant Study showed KT recipients had nonHodgkin lymphoma 11.8-fold more commonly than in an age-matched nontransplant population.10 PTLD represents 11% of all cancers in KT recipients in the Cincinnati Transplant Tumor Registry (CTTR).11 Mortality resulting from PTLD ranges from 40% to 60% in all solid-organ transplants, with poor prognosis as a result of the following: (1) multiple site involvement, (2) tumor monoclonality, (3) central nervous system involvement, (4) lateonset PTLD, (5) poor Eastern Cooperative Oncology Group performance status (42), and, finally, (6) CD20negative PTLD.12,13 EBV serostatus at transplantation and the intensity of immunosuppression (namely T-cell suppression) influences the risk of PTLD, in addition to time posttransplantation, age, and ethnicity.1,14 EBVseronegative KT recipients who receive organs from EBV-seropositive donors (approximately 85% of donors) are at the highest risk for primary EBV infection, leading to a 10- to 76-fold greater incidence of early PTLD.15 PTLD has a bimodal peak, with the highest incidence within the first 2 years, followed by a second peak between 5 and 10 years after KT, as noted in the New Zealand Dialysis and Transplant Registry.10,16 Although donor transmission of EBV to the EBV-seronegative KT recipient increases the risk of PTLD, more than 90% of PTLD is host-derived, meaning naive recipient B cells infected with EBV from the donor organ proliferate in a graft environment that prohibits apoptosis, leading to PTLD within the allograft as well as outside (multisystem disease), with poorer prognosis.17 Immunosuppression plays a significant role in the development of PTLD in KT recipients, with registries in Canada, Australia, New Zealand, and the United States noting an increased incidence of PTLD increasing with era (perhaps owing to cumulative effects of multidrug protocols, use of induction therapy, or increasing use of calcineurin inhibitors).18–20 An increased risk of PTLD has been noted with the use of antilymphocyte antibodies (antithymocyte globulin and/or muromomab-CD3),20–22 fusion proteins that block co-stimulation (belatacept and efalizumab)23,24 but not the anti-CD52 monoclonal antibody alemtuzumab,25 or the interleukin (IL)-2–receptor antagonists basiliximab or daclizumab,10,21,22 or

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mycophenolate mofetil.26 In addition, use of the mammalian target of rapamycin (mTOR) inhibitors such as sirolimus or everolimus may be beneficial in patients who develop PTLD, but the results are conflicting.27 KT recipients younger than age 10 years (presumably more likely to be EBV seronegative) and patients older than age 60 years in the Collaborative Transplant Study registry were at higher risk of PTLD.10,14,16,20 Caucasians are 1.5- to 2-fold more likely to develop PTLD than African Americans.19,20,28 Finally, cytomegalovirus seromismatch may further increase the risk for PTLD,15,20 but other studies have not supported this.1 Clinical Manifestations Associated With the Virus EBV-associated PTLD clinical manifestations vary depending on the organ transplanted, the time of manifestation post-transplantation, and the nature of the lymphoproliferation. The spectrum of EBV-PTLD clinical presentations range from signs and symptoms consistent with infectious mononucleosis such as fever, sore throat, malaise, and fatigue, to more constitutional symptoms consistent with lymphoma such as fever, nightsweats, and weight loss. More than half (465%-80%) of PTLD cases present as extranodal masses with a spectrum of histologic presentations from polymorphic clonal/nonclonal lesions to monomorphic clonal lesions.10,29 The World Health Organization classifies four main categories of PTLD: (1) plasmacytic hyperplasia and infectious mononucleosis-like PTLD, (2) polymorphic PTLD, (3) monomorphic PTLD, and (4) classic Hodgkin lymphoma-like PTLD (Table 1).30 The extranodular sites (70% of cases of PTLD)11 most involved include the gastrointestinal tract (stomach/intestine, 15%-30%), lungs, skin (5%-10%), liver, Table 1. Classification of Post-Transplant Lymphoproliferative Disorders30 Early lesions (benign polyclonal lymphoproliferation) Plasmacytic hyperplasia Infectious mononucleosis-like PTLD Polymorphic PTLD Monomorphic PTLD B-cell neoplasms Diffuse large B-cell lymphoma Burkitt lymphoma Plasma cell myeloma Plasmacytoma-like lesion T-cell neoplasms Peripheral T-cell lymphoma, not otherwise specified Hepatosplenic T-cell lymphoma Classic Hodgkin lymphoma-type PTLD Follicular lymphoma, small lymphocytic lymphoma, and marginal zone lymphoma are not considered PTLD.

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central nervous system (CNS), and the allograft (20%25%) which may lead to allograft loss.31 KT recipients may present with masses in their renal allograft or a decease in renal function. KT recipients tend to have the highest rate of CNS PTLD, which may comprise 20% to 25% of all PTLD disease compared with other solid-organ transplant recipients, often presenting late post-transplant with altered mental status or focal neurologic findings, with a poor prognosis.1,10,32 Gastrointestinal involvement may be focal or aggressive, presenting as weight loss, gastrointestinal bleeding, bowel obstruction/perforation, or protein-losing enteropathy leading to low albumin. Early PTLD, usually occurring within the first year of transplantation, tends to be associated with EBV infection, involve the allograft (57%), is polymorphic, and responds to a reduction of immunosuppression, whereas late PTLD is more likely to be present in older patients, disseminated with extranodal involvement (less allograft involvement, only 15%), EBV negative, monoclonal, and resistant to immunosuppression reduction.33 Non-PTLD EBV-associated presentations may include subclinical viremia with graft loss,34 an infectious mononucleosis presentation (younger patients) with fever and tonsillar/cervical lymph node enlargement that is sometimes associated with dissemination, and a sepsis-like presentation that is often fatal in more than 75% cases. EBV-associated gastric carcinoma35 or smooth muscle tumors,36 autoimmune hemolytic anemia,37 and hemophagocytic syndrome38 have been described. Diagnosis Given the varied presentation of EBV-associated PTLD after KT, a high index of suspicion for PTLD is of utmost importance when evaluating KT patients with risk factors. Patients post-KT, with constitutional symptoms such as fever, nightsweats, or weight loss, unexplained hematologic abnormalities, lymphadenopathy, or signs/symptoms related to extranodal manifestation of PTLD should undergo evaluation for PTLD. Coupled with clinical signs and symptoms, a high EBV viral load may be suggestive of PTLD, as are cytopenias, increased lactate dehydrogenase, hyperuricemia/hypercalcemia, or monoclonal gammopathy in the blood or urine.39 EBV viral load monitoring in the past has been hampered by the absence of an international reference standard, with much variability among institutions with differing viral load cut-off values and differing methods (whole blood versus plasma), making interpretation of results difficult. However, despite establishment of the World Health Organization International Standard for EBV for Nucleic Acid Techniques, interlaboratory variation is still prominent.40 Quantitative EBV polymerase chain reaction (PCR) monitoring for patients at high risk of EBV PTLD (EBV donor seropositive/recipient

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seronegative [Dþ/R-]) is instituted at many transplant centers during the first year post-transplant (with testing schedules varied), given data suggesting that high EBVDNA viral loads correlate with an increased risk of PTLD in high-risk transplant recipients.41,42 However a high EBV-DNA viral load does not always correlate with PTLD onset.43 In addition to blood and urine tests, radiographic imaging is useful in localizing and staging disease. This includes computed tomography of the chest/ abdomen/pelvis and positron emission tomography scans. Magnetic resonance imaging of the brain should be ordered if CNS PTLD is suspected. Ultimately, a tissue biopsy, preferably an excisional biopsy, will ensure an accurate diagnosis of PTLD upon evaluation of the morphology, immunophenotype, molecular genetic studies, presence/absence of EBV, antigenreceptor gene rearrangement studies, and therapydependent markers (CD20 expression, cytotoxic Tcell epitopes).44 A summary of the initial work-up of a KT recipient for PTLD is suggested (Table 2).

Treatment Given the morbidity and mortality accompanying a diagnosis of PTLD, prevention strategies are used to try to reduce the incidence. Measures include serial Table 2. Evaluation of the Patient With Suspected PTLD History and physical examination Laboratory work-up Complete blood count Complete metabolic panel including calcium Uric acid, lactate dehydrogenase Serum and urine electrophoresis EBV PCR EBV serologies (if patient was EBV seronegative and mismatch) Radiographic imaging Ultrasound of the kidney if patient has increased creatinine levels CT of the chest, abdomen, and pelvis Consider CT or magnetic resonance imaging of the brain if the patient has neurologic symptoms or headache Positron emission tomography (for staging) and identification of extranodal sites Biopsy Any suspicious skin lesions Excisional biopsy of abnormal lymph nodes Suspect GI PTLD: esophagogastroduodenoscopy or colonoscopy for biopsy of suspicious lesions Suspect pulmonary, hepatic, or renal PTLD: CT-guided biopsy of suspicious hepatic, renal, or pulmonary lesions Other work-up Suspect CNS PTLD: lumbar puncture for cerebrospinal fluid analysis, EBV PCR, cytology, flow cytometry

γHerpesviruses EBV and HHV8

monitoring of EBV PCRs in high-risk EBV Dþ/R-KT recipients during the first year post-transplantation. Once EBV monitoring shows increasing EBV viral loads or persistently elevated viral loads in patients with or without mononucleosis-like symptoms, the primary strategy to reduce PTLD risk is the reduction of immunosuppression, tempered by the increased risk of graft rejection if immunosuppression is decreased too agressively.45 There is no consensus about switching from calcineurin-based immunosuppression to mTOR-inhibitor–based therapy owing to conflicting reports of efficacy.46,47 Antivirals, such as ganciclovir or valganciclovir, sometimes are administered to EBV-seronegative transplant recipients to prevent EBV viremia or reduce the risk of PTLD, but remain controversial because these antivirals have no activity against the latent form of virus and require viral thymidine kinase expressed during the lytic cycle for activation.48 However, in a multicenter case-control study, prophylactic antiviral use with ganciclovir as compared with acyclovir post-transplantation was associated with an up to 83% reduction of PTLD risk, especially in the first year post-transplant.49 A phase 1/2 trial of arginine butyrate, which induces the lytic phase of EBV replication leading to expression of thymidine kinase, plus ganciclovir in patients with EBV-associated lymphoid malignancies, led to 4 complete remissions and 6 partial remissions in 15 patients, with one treatment cycle.50 The addition of immune globulin to ganciclovir, in a randomized controlled trial involving solid-organ transplant recipients, did not prevent PTLD.51 However, a retrospective analysis of KT recipients showed that those who received anticytomegalovirus immunoglobulin did not develop posttransplant non-Hodgkin lymphoma as compared with those who did not.52 More recently, use of rituximab, a murine/chimeric monoclonal antibody targeting CD20 antigen, is being used increasingly for the prevention of PTLD in high-risk solid-organ transplant recipients with increased EBV viral loads, however, caution is advised given the possibility of increased risk of infections.53–55 Finally, adoptive T-cell therapy with EBV-specific cytotoxic T cells has been used with some success in the prevention of PTLD in solid-organ transplant recipients, however, the facilities and expertise required to perform this are prohibitive at this time for application to a larger population.56 There are currently no effective vaccines for the prevention of EBV infection, but vaccines are under development. Once PTLD has been diagnosed, management strategies vary across institutions and among guidelines.53,57 However, most strategies incorporate reduction of immunosuppression, immunotherapy with rituximab (for CD20þ PTLD), chemotherapy, radiation therapy, or a combination of these treatment modalities depending on the following: (1) functional status of the patient; (2) type, extent, and severity of

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PTLD; (3) transplant type and risk of rejection; and (4) immunosuppressive drugs administered.58,59 Reduction of immunosuppression, if feasible, is usually the first step. Some centers reduce prednisone alone for low-level PTLD, because the role of switching to mTOR inhibitors is not clearly defined. Poor responses to reduction of immunosuppression include the following: (1) bulky disease, (2) lactate dehydrogenase level greater than 2.5 times the upper limit of normal, (3) organ dysfunction, and (4) multiple visceral sites of disease.60 Unfortunately, reduction of immunosuppression may lead to graft rejection in up to 39% of solid-organ transplant recipients, regardless of response to therapy.60 Fortunately, KT recipients can undergo more aggressive reduction of immunosuppression than recipients of other organ transplants, as a result of the following: (1) they can be monitored closely for rejection (via urinalysis and monitoring creatinine level), (2) they usually have lower rates of rejection, and (3) they can resume hemodialysis if their graft is rejected.61 If the PTLD can be treated successfully, re-transplantation within 1 to 2 years is safe and may not result in PTLD relapse.62 The administration of single-dose rituximab may lead to response rates of 44% to 59% in solid-organ transplant recipients with PTLD.55 Early lesions may be managed with reduction of immunosuppression with consideration of rituximab.63 Note, however, that poor response to rituximab includes late-onset PTLD (onset 4 1 year post-transplant), CNS involvement, and involvement of multiple viscera.64 Polymorphic PTLD treatment also includes reduction of immunosuppression, with addition of rituximab for CD20þ PTLD. Monomorphic PTLD, on the other hand, involves reduction of immunosuppression, rituximab for CD20þ PTLD, and chemotherapy, immunotherapy, and in some cases surgical resection, yet largely remains institutionspecific.65 Chemotherapy regimens vary by institution but may include 1) cyclophosphamide, doxorubicin, vincristine, and prednisone þ/ rituximab, 2) prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, and methotrexate, or other regimens, depending on the PTLD type, the patient’s functional status, and institutional expertise. Radiation therapy may be considered for localized or CNS disease.66 Adoptive immunotherapy with EBV-specific cytotoxic T lymphocytes is not widely used in solid-organ transplant recipients with PTLD given the difficulty with logistics and risk of graft-versus-host disease with allogeneic T cells. Summary and Conclusions In summary, EBV infection, via establishment of latent and lytic infectious cycles, can lead to the development of PTLD in 1% to 5% of KT recipients, especially

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those who are EBV Dþ/R, with high mortality rates depending on risk factors. PTLD presents with a variety of manifestations ranging from early polyclonal lesions to classic Hodgkin lymphoma–like PTLD. Thus, heightened awareness of the risk of PTLD, and routine EBV viral load screening within the first few years post-KT is recommended for EBV Dþ/R patients. Increasing or persistent EBV-DNA levels may signal the development of PTLD, with strategies such as reduction of immunosuppression or administration of rituximab to prevent PTLD. Diagnosis relies on tissue biopsy and radiographic imaging for localization and staging. Treatment modalities differ based on the type and extent of PTLD, ranging from only reduction of immunosuppression to the addition of rituximab, chemotherapy, radiation therapy, and surgery if warranted. Advances with regards to EBV PTLD diagnosis and treatment have been made, but we have more to learn about improved diagnostic testing strategies, what threshold of EBV viremia necessitates therapy, prevention of PTLD without risking graft rejection, and safe but effective therapies.

HHV-8 Virology of the Virus HHV-8, also known as Kaposi’s sarcoma-associated herpesvirus, is a γ herpesvirus associated with Kaposi’s sarcoma (KS) after KT. It infects a wide variety of cells such as B cells, endothelial cells, macrophages, and epithelial cells, through binding of its envelope glycoprotein B to the ubiquitous host cell-surface heparan-sulfate–like molecules. The HHV-8 replication cycle includes both a latent and a lytic phase, residing as a circular episomal DNA in latency, with multiple possible triggers for the activation of the lytic phase, such as viral co-infection, cytokines such as interferon-γ, and the presence of tissue hypoxia.67 T-cell responses are believed to play a strong role in controlling KS, with regression of the tumor upon reduction of immunosuppression in transplant recipients.68 In addition, HHV-8 contains a large number of host cellular genomes, acquired during its evolution through molecular piracy, with some encoding for angiogenesis mediated via vascular endothelial growth factor, regulation of antiviral immunity, and alteration of cellular growth through viral oncogenes and antiapoptotic proteins.69 It produces a viral analogue of human IL-6, which binds to human IL-6 cellular receptors, leading to inflammation and angiogenesis. Lytic replication is characterized by the presence of HHV-8 DNA in plasma and is associated significantly with KS.70 Epidemiology of the Virus Transmission of HHV-8 may be sexual, or nonsexual with family clustering, through blood transfusions or

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through organ transplantation.71 HHV-8 can be detected in saliva, semen, prostatic tissue, female cervicovaginal secretions, the gastrointestinal tract of men who have sex with men, and breast milk.72 The risk of development of KS in KT recipients mirrors the geographic prevalence of HHV-8 in the region, with variation worldwide. In the general population, HHV-8 prevalence is highest in sub-Saharan Africa, indigenous tribes of Amazonia and Papua New Guinea, followed by intermediate prevalence in southern Italy and other Mediterranean areas as well as South America, West Africa, Southeast Asia, and, finally, low prevalence in Northern Europe and the United States.73 In the United States, KS incidence is approximately 0.4% in KT recipients according to the CTTR,74 but represents 4% to 5.7% of malignancies after transplantation (excluding skin cancer).74 In contrast, in Saudi Arabia, KS incidence is 5.3%, but represents 87.5% of tumors in KT recipients.75Incidence post-transplantation is 54-fold (in the United States) and 400- to 500-fold (in Canada) compared with the general population.76,77 KS is more frequent in Arab, Greek, black, Italian, Turkish, and Jewish transplant recipients.11 HHV-8 seropositivity pre-KT increases the risk of KS post-transplantation, with up to 15% to 58% of HHV-8–seropositive patients developing KS as compared with less than 1% in HHV-8–seronegative patients.78,79 However HHV-8 transmission from KT donors to recipients has been reported with up to 2% to 24% seroconversion,80 occurring at a mean of 5 months posttransplantation, preceding the development of KS by 11.5 months.81 In addition, donor progenitor cells were identified within recipient KS tissue in five of eight transplant recipients from HHV-8–positive donors.82 HHV-8 is found more frequently in males than females in the general population, as well as in transplant recipients, with a female to male ratio ranging from 2 to 40.83 Seroprevalence studies have shown an increase in HHV-8 seropositivity with age,84 with risk of KS similarly increasing with recipient age at transplantation.76 KS risk peaks in the first 2 years post-transplantation,76 with a mean delay between transplant and diagnosis of KS of approximately 13 months, ranging from a few weeks to 18 years.85 After 2 years, the incidence of KS decreases, most likely coincident with reduction of immunosuppression. Calcineurin inhibitor use reduces the time to alteration of development of KS,83 although KS regression has been noted after switching from calcineurin inhibitor–based regimens to mycophenolate-based regimens. In addition, mTOR inhibitors such as sirolimus have antitumor and anti-angiogenic effects, with one study showing high levels of vascular endothelial growth factor in KS lesions and resolution of all cutaneous KS lesions in 15 KT recipients after switching from cyclosporine to sirolimus.86 In addition, in a cohort of 7217 KT recipients in Italy, KS among the most common de novo cancers post-transplant, use of mTOR inhibitors reduced the risk of all cancers by

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46%.87 Interestingly, severe bacterial and/or Pneumocystis carinii infections were found to be associated with increased KS risk among HHV-8–seropositive transplant recipients.79 Clinical Manifestations Associated With the Virus Most KS lesions post-transplantation are mucocutaneous lesions (90%), starting as macules and progressing to plaques or violaceous nodules that may ulcerate or bleed. Skin lesions may be localized or disseminated. Most appear on the lower extremities, often preceded by edema by a few months, but truncal and upper extremity lesions also occur. Mucocutaneous lesions may appear as purplish discoloration or gingival hyperplasia and can be associated with gastrointestinal KS.88 Up to 40% of transplant recipients may develop visceral KS, with involvement of the gastrointestinal tract, the lymph nodes, lungs, bladder, or eye.89 Gastrointestinal (GI) KS, which is predominantly localized to the stomach and upper GI tract, may be characterized by nausea, gastrointestinal bleeding with anemia, obstruction, or perforation. Pulmonary involvement may lead to dyspnea, hypoxemia with pulmonary nodules, and/or pleural effusions noted on radiographic imaging. In addition, primary effusion lymphoma is associated with HHV-8 and has been reported in patients with KS with recurrent effusions.90 One case describes HHV-8 and EBV-positive monotypic large B-cell PTLD co-existing with mixed-variant Castleman’s disease in a KT recipient.91 In addition, bone marrow failure with fever and splenomegaly was reported in a KT recipient with HHV-8 seroconversion and viremia.71 To date, there are no reports of KS herpesvirus-associated inflammatory cytokine syndrome in KT recipients.

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KS will have positive serologies for HHV-8 because the risk of developing KS increases with HHV-8 seropositivity. Immunofluorescence assays may be able to detect both latent and lytic phase antibodies, with lower sensitivity with the latent assays, and higher sensitivity but lower specificity with lytic assays in low-prevalence populations.95 Multiple enzyme-linked immunosorbent assays have been developed with 67% to 100% sensitivity in patients with KS, but lower sensitivity in low-risk populations. Combined immunofluorescence assay/enzyme-linked immunosorbent assay strategies have been proposed and may optimize sensitivity and specificity. Multiple Western blot assays have been developed using latent or lytic antigens, however, these assays are primarily researchbased and further studies are warranted to determine their specificity and clinical use. Once cutaneous KS is established, patients should be queried for symptoms to determine if evaluation for other sites of involvement is warranted. Depending on symptoms, patients may require a CT of the chest to evaluate for pulmonary disease with bronchoscopy if abnormalities are noted on CT,and esophagogastroduodenoscopy if GI symptoms are present. Staging determines the extent of disease, with no uniform guidelines, with two models proposed based on investigator experiences. The Al-Khader et al96 stage is based on 11 transplant patients in Saudi Arabia developing KS, and the Brambilla et al97 stage is based on 300 patients with classic Kaposi’s sarcoma in Italy (Table 3).

Table 3. Different Staging Systems for Kaposi’s Sarcoma Stage Al-Khader et al Staging99 Brambilla et al Staging100 1

Diagnosis Diagnosis of KS requiresa tissue biopsy for histopathologic confirmation, evaluating for typical features (spindle-shaped cells) that stain for CD34þ and factor VIII–related antigen.92 Immunostains directed against HHV-8 latent antigens may be helpful. PCR assays can detect HHV-8 DNA in biopsy specimens with high sensitivity and specificity, but cannot differentiate latent from lytic viral infection. PCR can detect HHV-8 viral genome in the blood, with viremia noted in patients with disease progression.93 However, some patients with KS may not have detectable viremia, whereas patients with multicentric Castleman’s disease tend to have high levels of viremia.94 Serologic assays to measure antibodies to HHV-8 can determine prior exposure to HHV-8, but are of limited use during active infection. Most patients with

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3

4

Localized skin lesion Macronodular: small involving one limb only macules and nodules primarily confined to the lower extremities Widespread skin lesions Infiltrative: plaques mainly involving lower involving more than extremities, sometimes one limb associated with a few nodules Florid:multiple Generalized involving angiomatous plaques viscera and/or lymph and nodules involving nodes and/or skin the lower extremities that often are ulcerated Disseminated:multiple Any of the earlier-listed angiomatous nodules categories in the and plaques extending presence of either beyond the lower associated lifeextremities threatening infection or other neoplastic tumor

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Treatment Treatment options for HHV-8–associated KS rely on reduction of immunosuppression, or consideration of switch from calcineurin-based therapy to mTOR inhibitor–based therapy. Reduction of immunosuppression may lead to 16% (visceral KS) to 17% (mucocutaneous) resolution with remission, according to the CTTR.74 If reduction of immunosuppression is not effective or not feasible given the risk of graft rejection, consider more traditional therapies such as the following: (1) cryotherapy, (2) cryosurgery, (3) laser or surgical removal, (4) topical therapy such as imiquimod or cis-retinoic acid, (5) intralesional chemotherapy (vinblastine or bleomycin), (6) systemic chemotherapy (liposomal doxorubicin), or (7) radiotherapy. Antiviral agents such as foscarnet, cidofovir, and ganciclovir inhibit HHV-8 DNA synthesis,98 but are not active against latently expressed virus, and therefore use in transplant-associated KS is not widespread. Interferon alfa is approved for the treatment of acquired immune deficiency virus–associated KS in the United States, but is not recommended for the KT recipients because of the risk of rejection. Mortality from KS in KT recipients is lower than in the general population (11% of patients with cutaneous versus 57% of patients with visceral involvement, per the Cincinnati registry).74Reduction of immunosuppression for the treatment of KS in KT recipients may lead to loss of graft in 50% of patients; however, re-transplantation is an option with mixed results in terms of recurrence of KS, with the possibility of using calcineurin inhibitors and antimetabolites after retransplantation.99,100 Summary and Conclusions In summary, HHV-8, found more frequently in patients of African or Mediterranean descent, is associated with KS, causing a wide variety of manifestations ranging from cutaneous to visceral involvement. Risk factors are HHV-8 seropositivity and intensified immune suppression. Diagnosis requires biopsy and HHV-8 DNA can be detected in the tissue. Treatment includes reduction of immunosuppression and consideration of sirolimus-based regimens, surgery, chemotherapy, or radiation therapy. More studies are needed to determine optimal screening strategies, treatment modalities that do not lead to rejection, and prevention strategies.

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