Mark R. Schleiss
The history of the identification of human herpesvirus 8 (HHV-8; also known as Kaposi sarcoma herpesvirus [KSHV] or Kaposi sarcoma [KS] virus) was unique among the Herpesviridae insofar as the virus was initially “discovered” purely on a molecular biologic basis using a powerful detection technique.1 Hence, the novel gamma herpesvirus, HHV-8, appeared to be a new herpesvirus associated with human malignancy, Kaposi sarcoma. Eventually HHV-8 was cultivated in tissue culture, proving that these DNA sequences corresponded to a morphologically identifiable viral particle.2
The epidemiology of primary human herpes-virus 8 (HHV-8) infection appears to vary considerably worldwide. The routes of acquisition of infection and mechanisms responsible for person-to-person transmission remain uncertain. After the virus was initially discovered, the unique role it seemed to play in inducing malignant disease in HIV-infected patients suggested that the primary route of transmission of HHV-8 was through sexual contact, particularly among gay men. However, more recent evidence suggests that other routes of infection exist, including transmission by saliva.4 A cross-sectional study of the seroprevalence of HHV-8 in children and adolescents in the United States indicated a prevalence of approximately 1%.5 There appears to be considerable regional variation in prevalence in the United States. In a population of children in south Texas, the seroprevalence was 26%, strongly suggesting that nonsexual modes of transmission predominate.6 In sub-Saharan Africa, prevalence in children is even higher, approaching 60% in some studies (reviewed in 7). There are reports of maternal-to-child transmission that suggest the possible of vertical infection (reviewed in 8), but the mechanisms of transmission and clinical manifestations in newborns are unclear. HHV-8 can also be transmitted by blood transfusion.9
Structurally, human herpesvirus 8 (HHV-8) consists of a prototypical enveloped particle, morphologically similar to other herpesviruses. The virus presumably establishes latent infection following primary infection, although the site(s) of latency are unknown. Evolutionarily, HHV-8 appears to have undergone considerable recombination with host genes, and the viral genome contains a variety of transduced cellular oncogenes and chemokine homologs that are probably important in the pathogenesis of KS.3 It is estimated that 10% of the genes encoded by HHV-8 promote KS development due to mitogenic, antiapoptotic, chemoattractive, angiogenic, or transforming activities.
Most primary infections with human herpes-virus 8 (HHV-8) are probably asymptomatic, although the clinical course of primary symptomatic HHV-8 infection in immunocompe-tent children with fever and rash was more recently described.10 The rash first appeared on the face and gradually spread to the trunk, arms, and legs. It initially consisted of discrete red macules that blanched with pressure and eventually became papular. The median duration of the rash was 6 days; fever persisted for a median of 10 days, and some children had high fever (temperature, 39°C). An upper respiratory tract infection occurred in most, and a lower respiratory tract infection appeared in one third, although major respiratory complications did not occur during the course of primary HHV-8 infection.
Prior HHV-8 infection appears to be necessary, but not sufficient, for the development of Kaposi sarcoma (KS), which is a multifocal vascular neoplasm involving skin, visceral organs, and lymph nodes. Lesions histopatho-logically contain distinctive proliferating cells, so-called “spindle” cells, as well as activated endothelial cells, fibroblasts, smooth muscle cells, and infiltrating inflammatory cells. Three variants of KS are described11: “classical” KS, which is chiefly an indolent, slowly progressive form of KS seen in elderly, HIV-negative Mediterranean men; “endemic” KS, a variant seen in Africa (including a “lymphadenopathic” form seen predominantly in young children); and “epidemic” KS, seen in HIV-infected patients.
Other malignant diseases have been associated with HHV-8, including multicentric Castleman disease (MCD), a lymphoproliferative syndrome associated with HIV infection, and another AIDS-associated malignancy, primary effusion lymphomas (PEL) (eTable 313.1 ). Links between HHV-8 and pemphigus, sarcoidosis, and Kikuchi disease have been postulated,11 and more recently there have been associations reported between HHV-8 and hemophagocytic syndromes.12
DIAGNOSIS AND THERAPY
In the absence of standardized serologic assays, serodiagnosis of human herpesvirus 8 (HHV-8) infection is problematic. Tissue from any case of Kaposi sarcoma (KS), primary effusion lymphomas (PEL), or multicentric Castleman disease (MCD) that is encountered in a child should probably be investigated for the presence of HHV-8 DNA sequences, in collaboration with a reference laboratory. HIV serology should also be performed in such patients. AIDS-associated KS has been reported to regress following administration of highly active antiretroviral therapy (HAART), suggesting that reversal of immuno-suppression may promote resolution of the tumor. No controlled trials of specific antiviral therapy have been conducted for KS, although treatment with either oral or intravenous ganciclovir (GCV) was associated with a strongly reduced risk of KS in AIDS patients prior to the advent of HAART, suggesting an antiviral effect of GCV against HHV-8. Although these are intriguing data, chemotherapy and radiation therapy remain the mainstays of therapy for most cases of KS, as well as other HHV-8-associated tumors.