Infectious Diseases

Kaposi’s Sarcoma (Microbiology)

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpes virus 8 (HHV-8), is a member of the family Herpesviridae. KSHV, like Epstein-Barr virus (EBV), is a lymphocryptovirus that belongs to the subfamily of gammaherpesviruses. KSHV is further subclassified as a gamma-2 herpesvirus, or rhadinovirus.

What is the best treatment?

  • Ganciclovir, foscarnet, and cidofovir are clinically available agents that have activity against KSHV. However, these agents that inhibit lytic replication of KSHV have limited clinical utility in the diseases associated with KSHV, which are pathologically due to latently infected cell proliferation rather than viral replication and lytic destruction of host cells. Newer regimens are being explored based on the fact that some lytic viral proteins are expressed in certain disease states, potentially making infected cells vulnerable to drugs activated by viral replicative proteins.

  • KSHV is associated with three major clinically significant syndromes or diseases: Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and Multicentric Castleman’s disease (MCD). Although KS may occur in immunocompetent hosts and has been known since the 19th century, HIV infection and other immunosuppressive conditions are commonly associated with KS in the United States. The treatment of KS, PEL, and MCD is, therefore, primarily directed at either reducing underlying immunosuppression or directly treating the proliferating cells with chemotherapeutic regimens similar to those used for other malignancies.

    • KS treatment: The mainstay of treatment is to treat HIV infection with highly active antiretroviral therapy (HAART) or to reduce other iatrogenic immunosuppression. KS lesions often regress with successful reversal of immunosuppression or control of HIV. If disease is limited to cutaneous lesions, radiotherapy or intralesional injection of vinblastine is effective, although lesions may recur. Topical alitretinoin 0.1% may also be effective.

      • For visceral involvement or disseminated disease, single agent treatment with a variety of drugs has been employed, although toxicity is often limiting in severely immunosuppressed patients. Doxorubicin, bleomycin, vincristine, vinblastine, etoposide, and taxol have all been used singly and in combination.

      • Pegylated anthracyclines (doxorubicin or daunorubicin) appear to provide the greatest efficacy with the least toxicity compared to multi-agent regimens when administered in combination with HAART.

      • Although ganciclovir and foscarnet are not clinically useful against KS lesions, preventing lytic replication may prevent development of KS in asymptomatically infected individuals. Patients with HIV and low CD4 counts receiving ganciclovir as prophylaxis or treatment for cytomegalovirus (CMV) disease had a significantly reduced incidence of KS development.

    • PEL treatment: PEL are a rare subset of AIDS-related lymphomas (ARL). PEL presents as an effusion in serous cavities, such as the abdomen or pleural space without masses or adenopathy.

      • The majority of PEL are co-infected with EBV and KSHV, although a small number (about 10%) are only KSHV-positive.

      • Because of the rarity of PEL, there are no definitive data on optimal therapy.

      • Most series have reported limited success with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or similar regimens, with complete remission rates of less than 50% and median survival times of approximately 6 months.

      • Rituximab, which is often used as a component of treatment regimens for other ARL, is not particularly useful in PEL as the proliferating cells generally do not express CD20, the target antigen for rituximab.

    • MCD treatment: KSHV-associated MCD in the setting of HIV infection has been treated successfully with both rituximab and conventional chemotherapy. For aggressive MCD, combination of rituximab with etoposide has been shown to be effective.

      • Treatment of the underlying HIV infection with HAART is an important component of any treatment strategy for MCD.

      • Exacerbation of underlying KS or development of KS de novo during treatment of MCD with rituximab has been observed.

      • Concurrent treatment with ganciclovir and treatment of underlying KS with chemotherapy has therefore been advocated if monotherapy with rituximab is planned.

  • Combination of ganciclovir and zidovudine, both of which are phosphorylated by KSHV gene products, leading to toxic metabolites, has been shown to be clinically active in MCD.

    • A pilot clinical trial to compare efficacy of various combinations of antiviral therapy, monoclonal antibody, immunomodulation, and chemotherapy in MCD is currently accruing patients at the National Cancer Institutes and is open until 2018.

    • A multicenter phase I study sponsored by the AIDS Malignancy Clinical Trials Consortium and the National Cancer Institute to evaluate bortezomib, a proteasome inhibitor, in KS is accruing patients with a projected closing date of 2016.

How do patients contract this infection, and how do I prevent spread to other patients?

  • Epidemiology

    • KSHV transmission is incompletely characterized. The highest transmission of KSHV infection occurs among men who have sex with men (MSM). Intrafamilial transmission is common in endemic areas and most likely occurs via saliva, which contains high titers of virus compared to samples from other body sites. Transmission occurs less frequently by blood transfusion. Transmission by organ transplantation has been well documented, particularly in areas of high seroprevalence.

    • KSHV prevalence varies dramatically among geographic regions. In adults, infections rates measured by serology are less than 5% overall in the United States, Northern Europe, and Asia. Prevalence in the Mediterranean countries, Middle East, and the Caribbean may be as high as 20%, whereas prevalence in Africa is greater than 50%. Prevalence of KSHV infection appears to have varied markedly between different areas within Africa prior to the onset of the HIV epidemic. Those areas with high seroprevalence have experienced a remarkable increase in the incidence of KS, and, in some countries in Africa, KS is the most common cancer in men.

  • Infection control issues

    • Gloves and other personal protective equipment (PPE) are appropriate when exposure to blood or other bodily fluids is expected.

    • There is no currently available vaccine for KSHV.

What host factors protect against this infection?

  • The major determinant of protection against KSHV-induced disease is cell mediated immunity as shown by the dramatically increased incidence of KS as a consequence of immunodeficiency in HIV infection and iatrogenic immunosuppression. In addition, it is likely that other arms of the immune response are important in combatting KSHV as the virus expresses a variety of proteins that inhibit multiple immune response pathways.

  • MSM are at highest risk for contracting KSHV infection. HIV infection, especially in endemic areas, increases risk of KSHV-associated disease. For unknown reasons, KS is more common in males infected with KSHV. KS is also more common in some areas in Africa than in others with similar rates of KSHV infection, indicating that other unknown cofactors increase risk of tumor development.

What are the clinical manifestations of infection with this organism?

  • Primary infection with KSHV most often goes unrecognized or is asymptomatic. Several cases of KSHV seroconversion associated with fever and a facial rash in children have been reported. Similar findings have been reported in adults. In transplant patients, primary infection may lead to disseminated KS or marrow failure.

    • KS: KS has been described in four clinical settings with different manifestations.

      • Classical KS, as described by Moritz Kaposi, occurs primarily in elderly men in Mediterranean and East European countries and presents as an indolent, slowly progressive cutaneous tumor of the lower extremities. The violaceous, vascular, pigment-laden lesions progress from a patch to plaque to nodular morphology. Intralesional hemorrhage is common. The morphologic progression is accompanied by a change in the histology as the lesions become increasingly composed of KSHV-infected spindle cells.

      • Endemic KS, occurring in Africa prior to the HIV epidemic, may resemble classical KS but also involve other areas of the body and be accompanied by lymphadenopathy. It also pursues a more aggressive clinical course, particularly in children.

      • Epidemic KS, exemplified by the presentation in HIV-positive individuals, presents as lesions that may occur at virtually any cutaneous location, including the face. Oral and visceral involvement are common.

      • Transplant-associated KS is often disseminated and rapidly progressive.

    • PEL: PEL is rare, comprising approximately 3% of ARL and an even lower percentage of non AIDS-related lymphomas. Presentation is usually as an effusion, with the pleural cavity being the most common site of involvement. Rare cases of nodal involvement followed by effusion have been reported. PEL usually occurs in the most immunocompromised patients and has a poor prognosis, with a median survival less than 6 months. The longest survival and remissions have been reported in patients treated with HAART.

    • MCD: MCD is frequently characterized by fever, hepatosplenomegaly, and generalized lymphadenopathy. Other manifestations include splenomegaly, pleural effusion, autoimmune hemolytic anemia, rash, jaundice, and neurological symptoms.

      • MCD may present as POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes).

      • KSHV infection is present in virtually all cases of HIV-associated MCD, and in approximately one-half of cases without HIV infection.

      • Importantly, the CD4 count or HAART do not appear to be related to the incidence of MCD.

      • Both human interleukin-6 (hIL-6) and a KSHV-encoded homolog of IL-6 (vIL-6) are detectable at high levels in the blood of patients with KSHV-associated MCD and are thought to drive the proliferation of infected and uninfected B-cells.

      • Elevated levels of KSHV DNA are detected in the blood and serve as a marker of disease activity.

      • Disease activity also correlates with CRP levels.

How should I identify the organism?

  • Biopsy of KS lesions, lymph nodes affected by MCD, and fluid from PEL effusions provide suitable material for routine histologic examination and immunohistochemistry with KSHV-specific antibodies.

  • Staining for KSHV nuclear antigen is useful for confirming KSHV infection in clinical samples from all KSHV-associated syndromes. Each disease has distinctive cytologic or histologic characteristics.

    • KS: The pathognomonic cell in KS is the spindle cell, an elongated cell with endothelial characteristics. The exact cell type that gives origin to the spindle cell is a matter of debate. It is possible that progenitor cells earlier in development are infected by KSHV and subsequently express endothelial or lymphatic cell markers. KS lesions often contain many KSHV-uninfected mononuclear cells that lead to an inflammatory phenotype. The lesions also display neovascularization and angiogenesis. These areas are prone to hemorrhage. Much of the inflammation and angiogenesis mediated by uninfected cells may be induced by the paracrine action of cytokines and other molecules secreted by KSHV-infected spindle cells.

    • PEL: PEL cells are characteristically devoid of T- or B-cell markers but do stain for CD45, establishing their hematopoietic lineage. PEL cells are typically large, with basophilic cytoplasm and may appear immunoblastic, plasmablastic, or anaplastic. Immunoglobulin gene rearrangement is frequently present. Cells stain positive for KSHV latency-associated nuclear antigen (LANA) and are usually also positive for EBV infection, which may be readily detected by in situ hybridization for EBV EBER RNAs.

    • MCD: In MCD, affected lymph nodes display enlarged germinal centers with plasma cell hyperplasia. The lymphocytes are characteristically large, with prominent nucleoli, arranged in a peripheral distribution, giving rise to a "clock-face" nucleus. These "plasmablasts" are positive for KSHV LANA by immunohistochemistry and are IgM and lambda light chain positive. Biopsy of lymph nodes may be negative because of patchy involvement, and repeat biopsy may be necessary to make the diagnosis.

  • KSHV cannot be cultured in vitro from clinical samples. Cell lines may be established from PEL samples for research purposes. Cell lines established from KS lesions, however, typically do not contain KSHV.

  • Quantitative PCR for KSHV in peripheral blood can be used to follow disease activity of MCD. However, PCR is not highly sensitive for documentation of infection.

  • Several serological assays are commercially available. They may vary in sensitivity and specificity but are generally concordant.

How does this organism cause disease?

  • KSHV-associated tumors are often highly responsive to reversal of immunosuppression. In addition, the tumors are often polyclonal or oligoclonal, suggesting a unique mode of oncogenesis. KSHV encodes a multitude of proteins with immunomodulatory function.

  • Although the mechanism of action of these proteins are beyond the scope of this text, it is important to note that KSHV expresses proteins that affect CTL function, the interferon and complement pathways, apoptosis, antigen presentation and signal transduction, angiogenesis, and inflammation. Indeed, up to one-quarter of the viral genes play such roles in modulating the host response. Thus, in addition to encoding proteins, such as LANA, that are important in cellular transformation and expressed during viral latency, many KSHV proteins play a pathogenic role by affecting the behavior and growth of cells even in the absence of malignant transformation.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Areste, C, Blackbourn, DJ. "Modulation of the immune system by Kaposi’s sarcoma-associated herpesvirus". Trends Microbiol. vol. 17. 2009. pp. 119-29.

(A comprehensive review of immune system modulation by KSHV.)

Bower, M. "How I treat HIV-associated multicentric Castleman disease". Blood. vol. 116. 2010. pp. 4415-21.

(A practical review of options for MCD therapy.)

Ganem, D, Knipe, DM, Howley, PM. "Kaposi’s sarcoma-associated herpesvirus". Fields virology. vol. Vol 2. Wolters Kluwer/Lippincott Williams & Wilkins. 2007. pp. 2847-88.

(A comprehensive review of the virology, epidemiology, and pathology of KSHV infection and its role in disease causation.)
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