Kaposi Sarcoma Herpes Virus Infection in Solid Organ Transplant Recipients

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Virology

In 1994 Chang and colleagues, by using representational difference analysis (RAD), identified in Kaposi’s’ sarcoma tissue from patients with acquired immunodeficiency syndrome (AIDS), DNA sequences of a previously unrecognized herpesvirus, which has been called Kaposi’s sarcoma–associated herpesvirus (Kaposi sarcoma herpes virus, also known as human herpesvirus 8) (28). Kaposi sarcoma herpes virus is a γ-herpesvirus that is homologous but different from the Gammaherpersvirinae Epstein-Barr virus and Herpesvirus saimiri. Open reading frame (ORF)-K1 is used to subtype Kaposi sarcoma herpes virus: subtypes A, B, C and D have been identified, and display between 15 and 30% amino-acid differences between their ORF-K1-coding regions (68, 76). Within these four subtypes, over 15 clades have now been described.

The subtypes have close associations with the geographical and ethnic background of individuals. Subtype B is found almost exclusively in patients from Africa, subtype C in individuals from the Middle East and Mediterranean Europe, subtype A in Western Europe and North America and subtype D has only so far been described in individuals from the Pacific Islands. A new subtype (E) has been described from South American indigenous people. So far, no subtype appears to correlate with a specific disease entity or with a more aggressive course for Kaposi’s sarcoma. Kaposi sarcoma herpes virus infects a wide variety of cells type, including B cells, endothelial cells macrophages and epithelial cells (2, 6). A number of putative cellular receptors for Kaposi sarcoma herpes virus have been defined. As is the case with all herpesviruses, the Kaposi sarcoma herpes virus life cycle includes both latent and lytic phase (82). The exact mode of transmission for Kaposi sarcoma herpes virus remains unknown. Several seroepidemiologic studies suggest that Kaposi sarcoma herpes virus may be sexually transmitted. Epidemiologic and virologic data suggest that the virus may be transmitted through saliva, and salivary spread could explain both the sexual and horizontal transmission of Kaposi sarcoma herpes virus. In endemic areas, Kaposi sarcoma herpes virus transmission through blood transfusion has been documented, however, studies from the US and Western Europe have not found evidence to support Kaposi sarcoma herpes virus transmission through blood transfusion suggesting that Kaposi sarcoma herpes virus transmission via blood transfusion is rare (21). Transmission of Kaposi sarcoma herpes virus from organ donor to recipients has been documented through assessment of serostatus before and after transplantation and by molecular epidemiologic studies (10, 61, 88).

Epidemiology

Unlike most herpes viruses, human infection with Kaposi sarcoma herpes virus is not ubiquitous. Seroprevalence rates vary widely, depending on the geographic region. Besides having different prevalence rates in different geographic regions, the specific risk groups for seropositivity appear to be quite different, depending upon the location.

Seroprevalence is estimated to be between 0 and 5% in North America, northern Europe and Asia, between 5 and 20% in the Mediterranean and Middle East and >50% in parts of Africa (72). However, it should be noted that the comparison of prevalence are limited by whether antibodies to latent or lytic Kaposi sarcoma herpes virus antigens were detected and the test formats used. Expectedly, the incidence of active Kaposi sarcoma herpes virus infection after solid organ transplantation, which may occur either as secondary reactivation of an endogenously latent virus, or as primary infection in Kaposi sarcoma herpes virus seronegative recipients of allograft from Kaposi sarcoma herpes virus seropositive donors (4, 10, 61, 65, 79, 88), reflects these geographic differences in seroprevalence and epidemiology. Hence, the incidence of Kaposi sarcoma after transplantation ranges from as low as 0.5% among transplant recipients from North America, Asia and northern Europe to as high as 28% among Kaposi sarcoma herpes virus seropositive transplant recipients from the Middle East (38, 85).

Clinical Manifestations

The first disease associated with Kaposi sarcoma herpes virus infection was Kaposi’s sarcoma. However, several other conditions, especially body cavity based lymphoma, also known as primary effusion lymphoma or PEL, and multicentric Castelman’s disease, were also linked to this virus. Host factors and other related issues influence disease expression.

Primary Kaposi sarcoma herpes virus infection in immunocompetent individuals is associated with mild nonspecific symptoms of diarrhea, fatigue, rash and lymphadenopathy. Infection in immunocompetent individuals results in the generation of pathogen-specific CD8+ T-cell responses that control Kaposi sarcoma herpes virus replication and prevent its progression to neoplastic disease (5, 98).

In immunocompromised persons, fever, splenomegaly, lymphoid hyperplasia, pancytopenia and occasionally rapid onset Kaposi sarcoma have been described in association with apparent primary Kaposi sarcoma herpes virus infection (62, 78). A very severe clinical picture associated with primary Kaposi sarcoma herpes virus infection has recently been observed also by the author in a series of 5 liver transplant recipients in southern Italy. All patients presented with fever, pleural effusion and skin rash at a median of 128 (range 42-178) days after transplantation. All patients died of multiorgan failure at a median of 73 (range 16-95) days after the onset of the disease (manuscript in preparation).

In addition, clonal gammopathy has been reported after transplantation (87). However, in immunocompromised transplant recipients Kaposi sarcoma herpes virus is more often associated with neoplastic diseases.

Kaposi’s Sarcoma

Although Kaposi’s sarcoma was first described by Moritz Kaposi in the 1870s, the disease was a medical curiosity in Europe and the United States until the acquired immunodeficiency syndrome was recognized in 1981. Kaposi sarcoma is a multicentric neoplasm of lymphatic endothelium-derived cells infected with Kaposi sarcoma herpes virus. Four epidemiological forms of Kaposi sarcoma with different clinical parameters, such as anatomic involvement and aggressiveness of the clinical course, have been described.

Classic Kaposi Sarcoma

The classical form of Kaposi sarcoma is an indolent tumor affecting the elderly men, in Mediterranean countries such as Italy, Israel and Turkey. The lesions tend to be found in the lower extremities and the disease, due to its non aggressive course, usually does not kill those affected.

Epidemic or AIDS-Related Kaposi Sarcoma

In the context of AIDS, Kaposi sarcoma is an AIDS defining illness in the Centers for Disease Control and Prevention (CDC) guidelines, and is the most common malignancy in this population (30). AIDS associated Kaposi sarcoma is a more aggressive tumor than classic Kaposi sarcoma and can disseminate into the viscera with a greater likelihood of death. Unlike classic Kaposi sarcoma, it presents more often multifocally and more frequently on the upper body and head regions.

Endemic Kaposi Sarcoma

Kaposi sarcoma herpes virus was prevalent in Africa prior to the HIV epidemic and therefore was responsible for the large prevalence of Kaposi sarcoma seen on the continent before the AIDS epidemic. The endemic form is found in all parts of equatorial Africa, affecting men with an average age of 35 and very young children. In Africa endemic Kaposi sarcoma is found more often in women and children than in other areas of the world. The endemic Kaposi sarcoma is not typically associated with immunodeficiency, is frequently more aggressive than classic Kaposi sarcoma and may be accompanied by dissemination to lymph nodes.

Iatrogenic or Organ Transplant-Associated Kaposi Sarcoma

Kaposi sarcoma is increasingly recognized as a complication that may occur after solid organ transplantation. Kaposi sarcoma prevalence after organ transplantation parallels the overall prevalence of Kaposi sarcoma herpes virus infection in different countries. In the United States, the incidence of Kaposi sarcoma after transplantation is estimated to be 0.4% and Kaposi sarcoma represents 5.7% of malignancies after transplantation (83).

Post-transplant Kaposi sarcoma has been associated with most immunosuppressive regimen including corticosteroids, purine synthesis inhibitors and calcineurin inhibitors (45). Antithymocyte globulin has been pointed out as a high risk factor for Kaposi sarcoma (37). Recently mTOR inhibitors were shown to inhibit the progression of dermal Kaposi’s sarcoma in kidney-transplant recipients while providing effective immunosuppression (19, 96). However, HIV-1 negative kidney transplant recipients, who developed primary effusion lymphoma (PEL) or Kaposi sarcoma while receiving rapamycin as immunosuppressive treatment have been recently reported, suggesting that rapamycin may not protect Kaposi sarcoma herpes virus infected renal transplant recipients from occurrence of PEL or Kaposi sarcoma (8, 14).

Clinical Features

Transplant-associated Kaposi Sarcoma is similar to epidemic Kaposi Sarcoma in its clinical manifestations. Kaposi Sarcoma manifests clinically as multifocal progressive mucocutaneous lesions with potential dissemination to the visceral organs, including the transplanted allograft (58). Mucocutaneous lesions have been reported in more than 90% of all cases. Like in other Kaposi sarcoma subsets, cutaneous lesions have a dark blue or purplish color. They start as macules that progress and may coalesce to form large plaques or nodular and fungiform tumors. They are mainly localized on lower limbs but they are also frequently seen on the trunk and the upper limbs. Edema of the lower limbs often precedes skin lesions. Some lesions may be located on scars, especially the transplantation scar (70). Face involvement is less frequent than in epidemic Kaposi Sarcoma. Oral lesions involve predominantly the palate with purple stains. Gingival hyperplasia may occur and may be confused with hyperplasia induced by cyclosporine.

Visceral Kaposi Sarcoma predominantly affects the lymph nodes, gastrointestinal tract and the lungs (9). Although Kaposi sarcoma can be present throughout the entire gastrointestinal tract, it is most frequently localized to the stomach and duodenum. The lesions rarely cause clinical and biological symptoms and in most cases they are detected at endoscopic examination. Pulmonary involvement is less frequent and appears at a more advanced stage of the disease. Many other localization have been reported, especially in the hepatosplenic or cardiac areas (90).

The median time to the onset of Kaposi sarcoma is 30 months after transplantation, although it may occur as early as 3 months to as late as 124 months after transplantation (6). One study reported an earlier onset of Kaposi sarcoma after liver (approximately 10 months) compared to kidney (34 months) transplantation (42). In Italy a 5 fold higher Kaposi sarcoma risk was found in the first year after transplantation, significantly higher than in the subsequent period (84).

Primary Effusion Lymphoma

Mostly observed in HIV-1-infected patients, primary effusion lymphoma (PEL) is a less common neoplastic disease associated with Kaposi sarcoma herpes virus in solid organ transplant recipients (14, 35, 51). The tumor has a distinctive presentation, with malignant peritoneal, pericardial, or pleural effusions in the absence of an identifiable tumor mass or nodal involvement. PEL tumor cells display pleiomorphic morphology and frequently lack B-cell lineage antigen expression, despite their B-cell monoclonal origin. These cells are latently infected with Kaposi sarcoma herpes virus, and co-infected with EBV in most cases (15).

Castelman’s Disease

Castelman’s disease (CD, angiofollicular lymph node hyperplasia) is a lymphoproliferative disorder that has attracted attention because of its association with the human immunodeficiency virus (HIV) and Kaposi sarcoma herpes virus. Castelman’s disease comprises at least two distinct diseases with very different prognoses. It is associated with a number of malignancies, including Kaposi's sarcoma, non-Hodgkin lymphoma, Hodgkin lymphoma, and POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes; also called osteosclerotic myeloma). Castelman’s disease was first described in 1956 by Benjamin Castleman, who identified a series of patients with solitary hyperplastic mediastinal lymph nodes containing small, hyalinized follicles, and a marked interfollicular vascular proliferation (hyaline vascular variant of Castelman’s disease) (27). The same investigators later identified lymph nodes with a similar vascular proliferation associated with large hyperplastic germinal centers and sheets of interfollicular plasma cells. Hyalinized follicles were present in some but not all such cases, which were dubbed the plasma cell variant of Castelman’s disease. All of the patients described in these early papers had localized disease, which is now termed unicentric Castelman’s disease. Unicentric Castelman’s disease is associated with systemic symptoms in a subset of cases.

A multicentric form of Castelman’s disease was recognized in 1978 (40). The multicentric form of Castelman’s disease is a systemic disease with generalized peripheral lymphadenopathy, hepatosplenomegaly, frequent fevers, and night sweats that is usually associated with the plasma cell variant. Unlike unicentric Castelman’s disease, multicentric Castelman’s disease is strongly associated with immunosuppression and Kaposi sarcoma herpes virus infection (94). Plasmablastic lymphomas arising out of Kaposi sarcoma herpes virus + multicentric Castelman’s disease are monoclonal. It is hypothesized that the hyperproliferative state induced by Kaposi sarcoma herpes virus permits the accumulation of new mutations in the infected B immunoblasts. Positive selection for clones bearing mutations that enhance growth and survival then allows an initially reactive process to evolve over time into an overt lymphoma. This model is similar to that proposed for the continuum of lymphoproliferative disorders that are associated with Epstein-Barr virus in immunosuppressed patients. Castelman’s disease is a rare condition, with the real incidence unknown (91). Only very few cases have been reported in solid organ transplant recipients (3, 41). It occurs equally in women and men, and no race predominance has been observed.

Laboratory Diagnosis

Polymerase Chain Reaction

For the detection of active Kaposi sarcoma herpes virus infection, there are now data to support the use of nucleic acid amplification assays to quantitate Kaposi sarcoma herpes virus load in clinical samples.

Several different PCR assays employing primers unique for Kaposi sarcoma herpes virus have been described. Kaposi sarcoma herpes virus DNA can be identified using PCR in virtually all biopsies of Kaposi sarcoma, including AIDS-associated Kaposi sarcoma, classic Kaposi sarcoma, and endemic Kaposi sarcoma. Clinical applications of PCR for Kaposi sarcoma herpes virus disease are limited. The detection of Kaposi sarcoma herpes virus DNA in the peripheral blood can support a diagnosis of Kaposi sarcoma. The prevalence of viremia in persons asymptomatically infected with Kaposi sarcoma herpes virus ranges from 4 to 20 percent (36, 97). Among persons with HIV disease, the detection and quantification of Kaposi sarcoma herpes virus in the peripheral blood is associated with an increased risk for development of Kaposi sarcoma, hence monitoring of Kaposi sarcoma herpes virus load in peripheral blood mononuclear cells could be a useful tool for monitoring transplant patients with Kaposi sarcoma (36). Even among persons with Kaposi sarcoma, however, viremia is not universal, limiting the utility of PCR for the diagnosis of Kaposi sarcoma (18, 36). In contrast to Kaposi sarcoma, asymptomatic individuals with Kaposi sarcoma herpes virus associated multicentric Castleman’s disease are universally viremic with active disease flares (77). Kaposi sarcoma herpes virus quantification in plasma or peripheral blood mononuclear cells by PCR may be a useful means for diagnosing an active flare of multicentric Castelman’s disease or following response to treatment (26). The routine use of Kaposi sarcoma herpes virus viral load measurements to follow patients with Kaposi sarcoma and to assess response to therapy has also been suggested (82).

Serology

Various tests have been developed based on immunofluorescence, Western blot, and enzyme-linked immunosorbent assays (ELISAs) to detect antibodies against latent and lytic genes. So far, good tools are available for seroepidemiologic studies, although their usefulness in clinical daily practice is debated. Adding to the uncertainty of using serological assays for diagnosis are the non-standardized methodologies since various assays are directed against different antigens. Moreover, the sensitivity of serological assays is variable and ranges from approximately 80% to greater than 90% (57, 95). Most patients with Kaposi sarcoma have antibodies to both latent and lytic phage antigens. In comparative studies between laboratories, relatively good consistency has been achieved with Immunofluorescent assay (IFA) measuring antibodies against latent antigens (86).

However, the results of assays directed at lytic antigens are more variable and have given rise to controversy about the true prevalence of Kaposi sarcoma herpes virus infection in different populations. The optimal serologic assay technique cannot be determined at present. A study comparing seven different immunofluorescence and ELISA assays found that, while the sensitivity for detecting Kaposi sarcoma herpes virus antibodies was fairly good in patients with Kaposi sarcoma (67 to 100 percent), there was significant discordance among the various methods in low risk populations (e.g., blood donors) (86). This variability between different testing modalities makes it difficult to know which test is most accurate for seroprevalence studies in the general population. It has been suggested that a combination of whole virion ELISA and lytic IFA may be the most sensitive method for diagnosing Kaposi sarcoma herpes virus.

Prior to transplantation, donor and recipient serological screening may help stratify the risk of infection and clinical disease after solid organ transplantation, especially in high-risk populations in areas of high endemicity. However, a recent Italian survey showed that only 24.5% of the Italian transplant centers routinely screen the candidates and only 9.4% of the donors are screened for anti-Kaposi sarcoma herpes virus antibodies (92). Furthermore, serology is generally unavailable prior to deceased donor organ transplantation and a donor screening policy may be adopted almost exclusively for living donors. Many studies have suggested the potential utility of screening of Kaposi sarcoma herpes virus antibodies among organ donors and recipients. However, to date the results of these studies have argued in favor of Kaposi sarcoma herpes virus screening, even in low-Kaposi sarcoma herpes virus infection prevalence countries, not to exclude the graft but to have the Kaposi sarcoma herpes virus status information in order to have the opportunity to monitor, clinically and biologically, patients at risk for Kaposi sarcoma herpes virus-related disease development. The detection of Kaposi sarcoma herpes virus antibodies could be done in the days after the transplantation and the results transmitted to the physicians retrospectively. In conclusion, the question of screening donors and recipients for Kaposi sarcoma herpes virus, even in low-Kaposi sarcoma herpes virus infection prevalence countries, is still debated, and prospective studies are needed to evaluate the benefit of pre- and post-transplantation strategies.

Western Blot

A number of Western blot assays have been developed using recombinant proteins produced from the Kaposi sarcoma herpes virus genome. Latent antigens that have been used include a protein produced from a part of the genome identified as open reading frame 73, which is named latency associated nuclear antigen (LANA). Recombinant lytic antigens have also been produced and used in Western blot assays. These proteins have included open reading frame 65 (a capsid related protein), K 8.1, and open reading frame 26 (minor capsid protein). Although it might be assumed that the Western blot assays have better specificity than IFAs, the testing characteristics for these assays have not been systematically established.

Immunohistochemistry

Immunohistochemistry using monoclonal antibodies against Kaposi sarcoma herpes virus antigens is useful for the pathological diagnosis of Kaposi sarcoma and other angiogenic proliferative diseases (58).

Initial Staging of Kaposi Sarcoma

The exhaustive clinical examination includes otorhinolaryngeal, ophthalmologic, and genital examinations. A dated scheme with photographs of all mucocutaneous lesions makes it possible to accurately follow the evolution of dermatologic lesions. Chest involvement is detected by radiography and computed tomography. If a thoracic disease is suspected, a bronchoscopy with bronchoalveolar lavage will be performed to confirm the diagnosis of Kaposi sarcoma and exclude other diseases, especially opportunistic infections, which may be associated with lung Kaposi sarcoma. Gastrointestinal involvement is detected by esogastroduodenoscopy and less frequently by colonoscopy. Deep lymph node involvement is detected by chest and abdomen computed tomography.

Pathogenesis

Lytic Replication

As is the case with all herpesviruses, the Kaposi sarcoma herpes virus life cycle includes both latent and lytic phases (81). In studies of transformed cell lines, latent virus can be "induced" to upregulate viral replication and expression. In the lytic phase, the virus produces a wide range of structural and replicative gene products that lead to the production of intact virions. Much research has focused on understanding viral gene expression and the events leading to activation of lytic infection. Several viral gene products of Kaposi sarcoma herpes virus are able to affect both cell cycle regulation and the control of apoptosis. Kaposi sarcoma herpes virus contains viral oncogenes that are important in the pathogenesis of tumor formation. Clinical observations suggest that T-cells play an important role in the control of Kaposi sarcoma, as evidenced by the increased incidence of Kaposi sarcoma among transplant and AIDS patients, the regression of Kaposi sarcoma with the reduction of immunosuppressive treatment following transplant, and clinical improvement of Kaposi sarcoma in subjects with immune reconstitution following HAART. Several studies also support a role for replicating Kaposi sarcoma herpes virus in the pathogenesis of Kaposi sarcoma. The presence of replicating Kaposi sarcoma herpes virus in the peripheral blood has been shown to be one of the strongest predictors for the development of Kaposi sarcoma (1, 56, 93, 99), and in vitro work has revealed that a small amount of lytic Kaposi sarcoma herpes virus infection is required for the initiation and maintenance of Kaposi sarcoma tumors (44). In prospective clinical trials of intravenous (71) and high-dose oral (66) ganciclovir for the treatment of AIDS-associated cytomegalovirus disease, the rate of new Kaposi sarcoma development was reduced by 40 and 75 percent, respectively, among antiviral drug recipients. As ganciclovir is only active against replicating Kaposi sarcoma herpes virus, theses studies provide indirect evidence for the role of replicating Kaposi sarcoma herpes virus in the development of Kaposi sarcoma and suggest that Kaposi sarcoma can be prevented in high-risk patients. Finally, Kaposi sarcoma herpes virus has been shown to produce a viral analogue of human interleukin-6 (vIL-6), which has been implicated in the development of Kaposi sarcoma and Castleman’s disease. Viral IL-6, which binds to human IL-6 cellular receptors, has a number of inflammatory and angiogenic properties (7).

Latent Kaposi sarcoma herpes virus Infection

While in latency, the virus exists as circular episomal DNA (89) and expresses limited gene products, including LANA-1, v-cyclin, and v-FLIP. Latency is common in a variety of cell types including B lymphocytes and glandular epithelial cells.

ANTIVIRAL THERAPY

Despite significant progress over the past decade in understanding the pathophysiology of Kaposi sarcoma herpes virus-associated diseases, treatment of these diseases today remains both toxic and incompletely efficacious. In each of the Kaposi sarcoma herpes virus-associated diseases, ongoing viral replication plays a key role in the development or persistence of the disease. However, the effect of antiviral agents on Kaposi sarcoma herpes virus replication has not been extensively studied. There are several reports of in vitro testing of herpesvirus DNA polymerase inhibitors against Kaposi sarcoma herpes virus. These agents would presumably be effective against the lytic phase of the virus but would probably have less activity in the latent phase in host or tumor tissues. However, recent basic science data found that it may be feasible to induce cells latently infected with Kaposi sarcoma herpes virus to lytic replication with valproic or glycyrrhizic acid or bortezomib, thereby ‘sensitizing’ the tumor to antiviral therapy (17, 32, 53).

In Vitro Activity

The effectiveness of different agents can be compared by testing the ability to block stimulation of lytic replication in Kaposi sarcoma herpes virus-infected cell lines (e.g., BCBL-1). Ganciclovir, cidofovir, foscarnet, adefovir, and lobucavir all have some in vitro activity in this type of testing system; by contrast, acyclovir did not appear to have high levels of activity. Cidofovir was found to have the greatest in vitro activity against Kaposi sarcoma herpes virus. However, it is important to note, that Kaposi sarcoma herpes virus is much more sensitive than CMV to cidofovir. Therefore, it is possible that much lower doses would be sufficient to suppress reactivation of Kaposi sarcoma herpes virus (20, 23, 33, 39, 52, 69, 75).

In vivo activity

In vivo data are limited. A double-blind, placebo-controlled, crossover trial assessed the efficacy of oral valganciclovir (900 mg once daily) versus placebo in 26 men infected with Kaposi sarcoma herpes virus (25). Valganciclovir use was associated with significantly less oropharyngeal shedding of Kaposi sarcoma herpes virus as detected by daily quantitative polymerase chain reaction assays (23 versus 44 percent with placebo). In contrast, a report of seven HIV-infected individuals receiving intravenous ganciclovir or foscarnet for CMV retinitis found no difference in pre- and post-treatment Kaposi sarcoma herpes virus DNA levels in peripheral blood mononuclear cells (12). Only one trial has evaluated the use of antiviral medication for the treatment of Kaposi sarcoma, finding that cidofovir was ineffective by itself for the treatment of both epidemic and classic Kaposi sarcoma (60). Although Kaposi sarcoma is more common, it might be expected that the Kaposi sarcoma herpes virus-associated diseases, which are characterized by more extensive viral replication, would be the best candidates for treatment with antiviral therapy. Successful treatment of PEL, alone or with adjunctive chemotherapy, immunotherapy or HAART, has been described to date with both ganciclovir and cidofovir (31, 48, 63, 80). Similar results have been observed in MCD patients treated with ganciclovir, but failures have been reported with cidofovir (11, 22).

ADJUNCTIVE THERAPY

Until now, the cornerstone in treatment of post-transplant Kaposi sarcoma is to reduce the immunosuppressive regimens to the lowest possible level, while attempting to keep the allograft functional, which is of vital importance in case of liver, heart or lung transplantation.

mTOR Inhibitors

mTOR inhibitors, while providing effective immunosuppression, may have a useful role in the treatment of transplant recipients who develop Kaposi's sarcoma associated with herpesvirus-8, especially if the disease is confined to the skin (19, 96). However, kidney transplant recipients, who developed primary effusion lymphoma or Kaposi sarcoma while receiving rapamycin as immunosuppressive treatment have recently been reported, suggesting that mTOR inhibitors may not protect Kaposi sarcoma herpes virus infected renal transplant recipients from occurrence of primary effusion lymphoma or Kaposi sarcoma (8, 14). Furthermore, the possibility of Kaposi sarcoma recurrence after increasing sirolimus dose suggests that regression of Kaposi sarcoma may be for some patients only the result of diminished immunosuppression and not the direct antineoplastic effect of rapamycin (13). Further studies are needed to evaluate the role of mTOR inhibitors in treatment of Kaposi's sarcoma and to determine the optimal treatment schedule for patients with more advanced disease. Despite these controversial results, the switch from calcineurin inhibitors to rapamycin is now considered as first line treatment of Kaposi sarcoma in transplant recipients.

Steroids

It has been shown that hydrocortisone acts directly on BCBL-1 cells to activate the lytic cycle of Kaposi sarcoma herpes virus, providing further support for the hypothesis that Kaposi sarcoma herpes virus is activated in corticosteroid-treated immunocompromised patients (49). Furthermore, corticosteroid withdrawal has led, in some cases, to Kaposi sarcoma tumor regression.

Local Therapies

A small number of cutaneous or mucous lesions advocate for cryotherapy, cryosurgery, laser, or surgical removal, whose result is aesthetically good. Intralesional chemotherapy is also recommended, but it is painful.

Radiation

Kaposi’s sarcoma is a radiosensitive tumor. Radiation therapy was the primary form of local therapy for Kaposi sarcoma before the AIDS epidemic. Response rates of greater than 80% were achieved. Radiation therapy is indicated for large tumor masses, especially those that interfere with normal function. The rate of regression of individual lesions following radiotherapy is 80% to 90%. A total dose of 20 to 30 Gy delivered in individual doses of 4 to 5 Gy is required. Lymph nodes are treated with a total target goal of 40 Gy (5 × 2 Gy/week).

Systemic Chemotherapy

Systemic chemotherapy for Kaposi sarcoma is indicated for patients with rapidly progressive mucocutaneous disease, causing lymphedema, ulceration and pain, and for those with symptomatic visceral involvement and debilitating Kaposi sarcoma-related symptoms. Liposomal anthracyclines (doxorubicin, daunorubicin) are the first choice for treatment of advanced or rapidly progressing Kaposi sarcoma. Taxanes (paclitaxel, docetaxel) are generally used after failure of first line therapy. α-Interferon, which is widely used in endemic Kaposi sarcoma, is not recommended after kidney transplantation because of the rejection risk. It however seems to be better tolerated after hepatic transplantation; it has in fact been prescribed to treat viral hepatitis recurrence on the allograft and in some isolated cases of Kaposi sarcoma (47).

The heterogeneity and the rarity of multicentric Castelman's disease have precluded properly designed studies to determine the optimal therapy for the condition. Therefore, treatment recommendations are based on small series of patients, results obtained in other similar conditions, or expert opinion (91). Both multicentric Castelman's disease and primary effusion lymphoma are primarily diseases of B lymphocytes. Consequently, monoclonal antibody therapy (rituximab) directed at CD20, expressed on all mature B-cells, has been used successfully in the treatment of both multicentric Castelman's disease and primary effusion lymphoma (16, 29, 43, 50, 54, 59, 64, 67, 74). However, at this time, insufficient data exist to recommend any specific agent in clinical practice.

Novel Chemotherapy

In the effort to make chemotherapy more effective and less toxic, great progress has been made in the past decade to target specific molecules involved in oncogenesis. Many HHV-8-associated conditions exhibit features making them ideal targets for molecularly directed therapy (24, 34). Recent translational studies have identified several new targets for potential future therapies, including inhibitors of viral replication, cell signaling, inflammation and angiogenesis, but the efficacy of these strategies can only be established through careful controlled clinical trials. Impairment of Kaposi sarcoma herpes virus-specific immune response in HIV and non HIV-associated Kaposi sarcoma cases as compared with tumor free Kaposi sarcoma herpes virus-infected patients has been reported (46, 55). These findings support the development of adoptive strategies to boost Kaposi sarcoma herpes virus-specific cytotoxic T-lymphocyte response in patients with Kaposi sarcoma. These hopeful therapeutic ways, associated with a more accurate modulation of immunosuppression, will probably allow improvement of the prognosis of Kaposi sarcoma.

ENDPOINTS FOR MONITORING THERAPY

Each patient with documented Kaposi sarcoma herpes virus infection or Kaposi sarcoma herpes virus-associated disease should be monitored according to the clinical severity and the toxicity of the drugs used for its treatment. Measurement and serial photographs of all mucocutaneous lesions makes it possible to accurately follow the evolution of dermatologic lesions. X-ray or computed tomography of the chest and/or the abdomen together with bronchoscopy, esogastroduodenoscopy or colonoscopy, according to the clinical presentation, should be performed at each visit or in case of appearance of new signs and symptoms. Quantitative Kaposi sarcoma herpes virus-DNA detection by PCR should be performed at least on a monthly basis during the first six months after transplantation. During systemic treatment with antivirals or chemotherapy, quantitative monitoring of Kaposi sarcoma herpes virus-DNA in blood is strongly advised.

VACCINES THAT ARE COMMERCIALLY AVAILABLE

No vaccine is currently available for Kaposi sarcoma herpes virus infection prevention.

ANTIVIRAL PROPHYLAXIS

Since the currently available antiviral drugs have limited activity, optimal strategies for prevention of Kaposi sarcoma herpes virus transmission or reactivation have not been defined, thus definitive recommendations for post-transplant prophylaxis cannot be made at the present time. Valganciclovir prophylaxis may be considered, based on a single study showing that valganciclovir use was associated with significantly less oropharyngeal shedding of Kaposi sarcoma herpes virus as detected by daily quantitative polymerase chain reaction assays. To allow a timely initiation of antiviral therapy, Kaposi sarcoma herpes virus-DNA monitoring in blood is recommended, at least monthly, until 6 months after transplantation, in Kaposi sarcoma herpes virus seropositive recipients and if donor seropositive, recipient seronegative.

INFECTION CONTROL MEASURES

No specific infection control measures are required for Kaposi sarcoma herpes virus infection in solid organ transplant recipients. Horizontal transmission by saliva appears the most common route not only in families in endemic regions, but also among high-risk groups in Western countries. Standard precautions and the use of a surgical mask is the only recommendation for close contact with the affected patients.

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