Human Herpesvirus 8 (Kaposi Sarcoma–Associated Herpesvirus)

Description of the Pathogen

HHV-8 is the only human γ2-herpesvirus. Epstein-Barr virus (EBV), a γ1-herpesvirus, is the most closely related human virus. HHV-8 is a large, double-stranded, enveloped DNA virus. Its genome has a central unique region of about 140 kb encoding the known open reading frames and flanked by terminal repeat sequences that contain signals for packaging and cleavage. ^, Multiple viral subtypes have been recognized, with infecting subtypes influenced by the regional viral strain distribution. While links between HHV-8 subtype and disease progression have been reported, the importance of this is uncertain. The HHV-8 genome contains micro RNAs and several cellular homologs related to human oncogenes, cytokines, and chemokines. These molecules inhibit tumor suppressor pathways by affecting control of cellular growth and inhibition of apoptosis as well as promoting inflammation and angiogenesis. ^,

HHV-8 infects multiple cell types, with evidence suggesting that glycoprotein B (gB) is the virus attachment protein. This is able to bind to DC-SIGN (dendritic cell−specific intercellular adhesion molecule-3−grabbing nonintegrin, also known as CD209) and its isomer DC-SIGNR as cell receptor molecules on dendritic cells, activated macrophages, B lymphocytes, and on endothelial cells, respectively, triggering viral fusion. ^, After initial infection, the HHV-8 genome persists as covalently closed episomal circles, establishing lifelong latent infection. Monocytes and B lymphocytes are the major reservoirs. ^, HHV-8 can be propagated in cell cultures, but most patients are latently infected and lytic infection must be induced.

Epidemiology

In contrast to other herpesviruses, HHV-8 does not cause ubiquitous worldwide infection. Its prevalence mirrors the incidence of KS, with substantial geographic variation identified. The highest rates of infection are reported in sub-Saharan Africa, ranging from 14% to >60%. In Cameroon, Ghana, Uganda, Zambia, Tanzania, and among indigenous groups in the Amazon of Brazil, 30%–60% of children <10 years of age are seropositive. ^{, ,} In a meta-analysis of studies reporting on seroprevalence in African children, rates ranging from 2% to 69% were reported, with seropositivity generally increasing with age. Seroprevalence is 6%–20% in most Mediterranean countries and is lowest, 0%–5%, in northern Europe, the US, Latin America, and Asia. Seropositivity and disease can vary widely among countries within the same region. High-risk groups exist even in countries with low HHV-8 seroprevalence. For example, in the US, 15%–40% of men who have sex with men (MSM) are seropositive, with the highest rates occurring among HIV-infected MSM. ^, Seroprevalence is not as high among other HIV-infected populations, especially children.

The putative modes of acquisition of HHV-8 include nonsexual and sexual horizontal transmission, vertical transmission, blood transfusions, and organ transplantation. ^{, , , ,} In areas with low HHV-8 prevalence, transmission is mainly sexual and predominantly among MSM. In areas with high HHV-8 seroprevalence, transmission appears to be nonsexual, occurring among families and close contacts, with high seropositivity present among children before adolescence and continuing to increase thereafter. ^,

Viral DNA is detected most frequently and in highest levels in saliva, but also is in semen and peripheral blood mononuclear cells. ^{, ,} Blood transfusions have been correlated with HHV-8 seropositivity among children from endemic countries, but appear to have no appreciable role in transmission in the US. ^{, ,} No evidence exists for transmission through breast milk. Vertical transmission has been suggested by detection of HHV-8 DNA in the blood of a few neonates.

Clinical Manifestations

HHV-8 has a clear causal role in KS, primary effusion lymphoma, multicentric Castleman disease, and a KSHV cytokine inflammatory syndrome associated with HIV infection. ^, Many diseases have been associated with HHV-8 infection but not confirmed causally, including multiple myeloma, sarcoidosis, and basal and squamous cell carcinomas in transplant recipients.

Clinical manifestations of HHV-8 infection primarily are associated with KS, a multifocal neoplasm of vascular endothelium. ^, KS lesions are vascular, purplish nodules that range from isolated cutaneous lesions to widespread disease involving the lung, biliary tract, and other viscera ( Fig. 209.1 ).

HHV-8 infection is a necessary, but not sufficient, factor contributing to the development of KS. ^, Four KS variants have been described: classical, endemic/sub-Saharan African, epidemic (AIDS-associated), and immunosuppression-associated forms. The classical type, primarily affecting older men from Mediterranean and eastern European countries, is indolent, involves mainly the skin, and is associated with long survival. The endemic form occurs predominantly in parts of sub-Saharan Africa and affects both adults and children. In some areas of Central Africa, KS is among the most common tumors, causing up to 25% of all childhood malignancies. ^, Endemic HIV-negative KS in African children is distinct from the adult form and characteristically is a more aggressive, often fatal, lymphadenopathic disease, usually with no cutaneous manifestations. Endemic KS has been reported in children born to consanguineous parents, suggesting inherited immunodeficiency as a possible mechanism of KS disease development in areas of high HHV-8 prevalence.

Epidemic KS associated with HIV usually is aggressive, with widespread cutaneous and visceral involvement, and is associated with a poor prognosis without treatment. Since the advent of combination antiretroviral treatment (cART) for HIV infection, the incidence of KS has declined and the outcome improved substantially. ^{, , ,} Epidemic KS in children more closely resembles the endemic form, with lymphadenopathy as a prominent feature. Other common sites of involvement include the oral mucosa and the gastrointestinal and respiratory tracts. Immune reconstitution inflammatory syndrome KS may cause worsening signs and symptoms of KS in children newly started on cART and necessitate more aggressive treatment. ^, KS associated with immunosuppression not related to HIV most frequently occurs in endemic areas in solid-organ transplant recipients with previous HHV-8 infection. ^,

Descriptions of primary infection are limited but indicate that most are likely asymptomatic. Clinical expression varies geographically and according to comorbidities. ^, Among young immunocompetent children residing in endemic areas, primary infection was identified in 7% of those presenting with acute febrile illnesses. Clinical manifestations included fever, upper respiratory tract signs, and a nonspecific maculopapular rash. A mononucleosis-like illness also has been described. Acquisition of primary HHV-8 infection in children following transfusion is associated with increased mortality for 2–10 weeks after the event.

Among immunocompromised patients, primary infection often is asymptomatic but sometimes manifests as a febrile illness of varying severity, with lymphadenopathy, splenomegaly, arthralgia, pancytopenia, and occasionally acute onset of KS. ^{, ,}