Human herpesvirus-8 infection

INTRODUCTION — Human herpesvirus-8 (HHV-8), also known as Kaposi sarcoma-associated herpesvirus (KSHV), is a large deoxyribonucleic acid (DNA) virus belonging to the gamma herpesvirus family. It is endemic worldwide and can cause certain cancers in a minority of individuals with infection.

The virology, pathophysiology, epidemiology, clinical manifestations, diagnosis, and the role for direct anti-viral therapy of HHV-8 infection will be reviewed here. Specific clinical syndromes that are associated with HHV-8, including acquired immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma, Classic Kaposi sarcoma, organ transplant-associated Kaposi sarcoma, HHV-8-associated multicentric Castleman disease (MCD), and primary effusion lymphoma, are discussed elsewhere. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis" and "AIDS-related Kaposi sarcoma: Staging and treatment" and "Classic Kaposi sarcoma: Epidemiology, risk factors, pathology, and molecular pathogenesis" and "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment" and "Malignancy after solid organ transplantation", section on 'Kaposi sarcoma' and "HHV-8/KSHV-associated multicentric Castleman disease" and "Primary effusion lymphoma".)

VIROLOGY — Human herpesvirus-8 (HHV-8) is a large (165 kB) double-stranded DNA virus which, like its closest known relative Epstein-Barr virus (EBV), is a member of the gamma herpesvirus group [1].

HHV-8 is classified as a group 1 biological carcinogenic agent, defined as having sufficient evidence to definitively establish a link to carcinogenicity in humans, by the International Agency for Research on Cancer (IARC) [2,3].

HHV-8 is now established as the cause of several human tumors arising from distinct cells types, including Kaposi sarcoma (KS), primary effusion lymphoma, and, in the setting of human immunodeficiency virus (HIV), almost all cases of multicentric Castleman disease (MCD) [4,5]. Patients can manifest more than one of these tumors. It has also been implicated in an inflammatory syndrome distinct from HHV-8-associated MCD, the Kaposi sarcoma-associated herpesvirus (KSHV)/HHV-8 inflammatory cytokine syndrome (KICS) [6,7].

While HHV-8 associated tumors are most common in individuals with HIV, they have also been reported in other immunosuppressed and older individuals, and occasionally in patients with congenital immunodeficiencies [8,9]. Additionally, hemophagocytic syndrome has been reported after HHV-8 infection in infants with heterozygous mutations in perforin alleles [10].

PATHOGENESIS — Human herpesvirus-8 (HHV-8) can infect a variety of cells, including those of endothelial lineage, monocytes, and B cells. Thus, HHV-8-associated cancers derive from different cells of origin among the range of cells infected by HHV-8.

Like all herpesviruses, HHV-8 infection exhibits both latent and lytic phases, distinguished by their viral gene expression patterns [11]. During the latent phase of infection, only a few viral genes are expressed, while during the lytic phase, the full viral genetic program involving multiple genes is expressed and viral replication occurs along with destruction of the host cell.

●Latent phase – In its latent phase, HHV-8 is maintained as a circular episome in the nucleus, which is tethered to the host chromosome, thus maintaining its replication during host cell division. The host cell survives latent infection, which is characterized by extremely limited gene expression [12,13]. The genes expressed in latency are directed to enhance cell survival signals, promote angiogenesis, and redirect the host immune response away from the infected cell [11,13-15]. HHV-8 latent transcripts, including genes and miRNAs, function to subvert host signaling pathways and favor viral persistence. Although the primary function of latency-expressed genes in the normal HHV-8 lifecycle is to enable chronically infected cells to remain undetected in the body, these same genes can also promote tumorigenesis in certain circumstances. In the absence of an effective immune response, HHV-8 manipulates the host cell pathways to thwart cellular defenses and promote tumorigenesis.

●Lytic phase – Activation of the virally encoded "lytic switch" gene, RTA, causes HHV-8 to enter its lytic phase, in which the full complement of viral-encoded genes is expressed and the host cellular machinery is redirected to the manufacture and assembly of progeny virions [13]. The host cell is destroyed in this process. HHV-8 lytic genes have effects on the host cell, resulting in reprogramming of cellular metabolism, upregulation of survival pathways, stimulation of angiogenesis and inflammation, and escape from immune control.

Intermittent cycles of viral lytic activation are thought to serve two functions. First, it is during lytic phase that onward infection of additional hosts occurs (see 'Transmission' below). Second, by enabling infection of new cells within the host, these cycles are also thought to be important in maintaining viral persistence in the host. The triggers of lytic activation in vivo remain unclear, whereas in vitro there is evidence that activation of cellular response pathways (eg, hypoxia, oxidative stress, coinfection with HIV) trigger lytic activation [16-19].

There is evidence that some HHV-8 lytic genes also play key roles in tumorigenesis, particularly in HHV-8-associated multicentric Castleman disease (MCD).

HHV-8 encodes more than 85 genes, many of which have the potential to be antigenic. However, antibody responses to viral antigens are variable; certain antigens such as latency associated nuclear antigen (LANA) and capsid antigen K8.1 most reliably elicit strong immune responses. Intensity of immune response may also depend on immunocompetence, as well as the coexistence of an HHV-8-associated malignancy [20].

HHV-8-associated malignancies can be seen as an inadvertent byproduct of HHV-8's survival strategies, particularly those aimed at developing persistent infection and thwarting cellular defenses against viral infection. In the absence of an effective immune response to infection, the risk of HHV-8-associated tumors is substantially increased.

EPIDEMIOLOGY — HHV-8-associated tumors are estimated to account for just under 1 percent of all cancers occurring worldwide [21].

Although human herpesvirus-8 (HHV-8) infection is necessary to cause the associated tumors, the tumors require other cofactors (eg, untreated HIV infection, immunosuppression) in order to develop. The risk of developing HHV-8-associated diseases among individuals with HHV-8 without any contributing cofactors is low: only about 1 in 400 to 1 in 1500 individuals with HHV-8 develop Kaposi sarcoma (KS), with the incidence increasing with age (likely due to waning cellular immunity) [22-24]. In contrast, as many as one half of patients with HIV and HHV-8 coinfection will develop KS in the absence of effective antiretroviral treatment [25,26]. In the United States, up to 80 percent of cases of KS occur in people with HIV, whereas in sub-Saharan Africa, this proportion is thought to be lower [27].

Serologic surveys show that, unlike most other human herpesviruses, HHV-8 is not ubiquitous. Significant variations in prevalence occur geographically and across different behavioral groups.

●Geographic distribution – HHV-8 infection is very common in sub-Saharan Africa with seropositivity rates of over 50 percent; moderately prevalent in Mediterranean countries (20 to 30 percent); and much less common (well under 10 percent) in most of Europe, Asia, and the United States [22,28,29]. Even within a country, substantial regional variation can occur. For example, among blood donors in Italy, HHV-8 prevalence was estimated to be 7.3 percent in Northern and Central Italy and 24.6 percent in Southern Italy [30]. High HHV-8 antibody prevalence has also been reported in several smaller distinct populations: for example, 65 percent seroprevalence among Brazilian Native American adults [31]; 33 percent among Papua New Guinean adults [32]; 25 percent among Indigenous Australian adults in some regions of central Australia [32]. The reasons for this geographic variation remain unclear. Viral subtype variation across regions is limited but could be playing a role, while both environmental and host genetic factors have been explored without clear roles yet being established for either [33].

●Other populations with increased prevalence – HHV-8 prevalence also is elevated in certain behavioral groups regardless of geography [34]. Most strikingly, its prevalence is greatly elevated in men who have sex with men (MSM), independent of the increase in HIV prevalence also seen in that group [28]. Compared with a prevalence of approximately 5 percent in the general United States population, in American MSM, prevalence estimates range from 25 to 60 percent among MSM with HIV and 20 to 30 percent among MSM without HIV [35,36]. HHV-8 infection in MSM without HIV in other countries also appears common [37]. The mechanisms for this variation remain unclear but could relate to specific sexual practices.

TRANSMISSION — Human herpesvirus-8 (HHV-8) is primarily transmitted by saliva but can also be transmitted via organ donation or rarely, via blood transfusion.

●Salivary transmission – The mode of transmission of HHV-8 is known to be primarily via saliva. However, the mechanism by which salivary HHV-8 transmission occurs differs by epidemiologic context [38].

In endemic areas, including Africa, vertical (mother-to-child) salivary transmission is thought to be the major method [39-41]. In these areas, HHV-8 seropositivity is relatively uncommon in infants, and there is an age-dependent increase in HHV-8 seroprevalence during childhood, demonstrating that neither in utero nor vertical transmission by breast feeding are major contributors but showing that other routes of vertical and household transmission are likely to be important [41]. Children are more likely to be infected if they reside with an affected or seropositive mother or other family member [42]. Maternal pre-mastication of food is a likely contributor to this process, though other behaviors are also the subject of exploration [41]. Supporting the salivary theory of transmission, studies of salivary secretions show detectable HHV-8 DNA in a proportion of individuals with infection, often on an intermittent basis [38]. Increased oral HHV-8 DNA detection, with implications for onward transmission, is seen with untreated HIV infection, malaria parasitemia, and perhaps other infections including herpes simplex [43,44]

In contrast, vertical salivary transmission is uncommon outside endemic areas. In these settings, establishing the mechanisms by which elevated HHV-8 seroprevalence rates were established and maintained in key risk groups including men who have sex with men (MSM) has been challenging [35]. The age pattern of increases in prevalence is relatively late in nonendemic areas, occurring well after sexual debut (in contrast for example to salivary transmission of EBV around sexual debut in these settings) [35,45]. The elevated prevalence in MSM specifically and in people with more sexual partners generally is suggestive of routes of transmission related to sexual activity, potentially via saliva during intercourse [38,45,46]. Seminal fluid appears to be much less important in transmission, based on studies of HHV-8 detection in semen of individuals with infection [47,48].

●Organ donation – Transmission of HHV-8 of donor origin to recipients of solid organ transplants has been reported and may be more common than is generally recognized clinically [49]. Such transmission likely arises from HHV-8-infected mononuclear cells included in an organ transplanted to a seronegative recipient [50,51]. In one prospective study of 217 HHV-8 seronegative patients receiving transplants from seropositive organ donors, approximately 30 percent of recipients seroconverted to HHV-8 [52]. While most seroconversion in this setting is asymptomatic, clinical sequelae can occur, influenced in part by immunosuppression following transplantation. Severe inflammatory symptoms and fatal visceral Kaposi sarcoma (KS) with HHV-8-associated lymphoproliferation have been reported in seronegative recipients developing primary HHV-8 infection in this context [53,54] (see "Malignancy after solid organ transplantation", section on 'Kaposi sarcoma'). Consideration should be given to monitoring HHV-8 serostatus in solid organ donors and recipients and monitoring for clinical evidence of primary infection.

●Blood transfusion – HHV-8 transmission during transfusion of blood and blood products is possible, via HHV-8-infected mononuclear cells included in donated and transfused blood products. HHV-8 is generally not included in infectious diseases screening of donors and donated blood products. Despite this, however, in practice such transmission appears rare [55]. The lack of observed transmission likely reflects several factors. These include the impact of donor screening and laboratory testing for other infectious diseases, both of which likely also reduce the rates of HHV-8 infection in accepted blood donors, along with processing leucodepletion of products prior to transfusion. In addition, even in infected donors, rates of detectable viremia in peripheral blood (which would establish the conditions for onward transmission via donated blood) are extremely low [56]. In resource-limited settings where HHV-8 is endemic, donor screening more limited, and leucodepletion less common, HHV-8 transmission via transfusion may be more clinically important [55].

ASSOCIATED CLINICAL SYNDROMES — Aside from a generally asymptomatic primary infection, human herpesvirus-8 (HHV-8) is associated with multiple tumor syndromes and a clinical syndrome called Kaposi sarcoma inflammatory cytokine syndrome (KICS). Primary HHV-8 infection is described in detail below and the details of the other associated clinical syndromes are discussed in detail separately.

Primary infection — In most cases, primary infection with HHV-8 is either asymptomatic or minimally symptomatic. However, symptomatic primary infection syndrome has been described in immunocompetent children, immunocompetent adults, and immunocompromised individuals.

●Children – In some immunocompetent children, primary HHV-8 infection may be associated with fever and a maculopapular rash [57]. In a small series, five of six children with evidence of primary infection and seroconversion developed a centripetal maculopapular rash, appearing on the face and spreading gradually to the trunk and extremities. The median duration of the rash was six days (range three to eight days), and the median duration of fever was 10 days (range 2 to 14 days).

●Immunocompetent adults – In immunocompetent adults, studies in men who have sex with men (MSM) without HIV describe transient lymphadenopathy in association with HHV-8 seroconversion [36,58]. In a minority of cases, the lymphadenopathy was associated with a mild systemic illness including fatigue, diarrhea, and localized rash [36].

●Immunocompromised individuals – In immunocompromised adults, including solid organ transplant recipients and individuals with HIV, case reports describe significant systemic symptoms with primary infection. Features include fever, splenomegaly, lymphoid hyperplasia, pancytopenia, and in some cases rapid-onset KS [59]. These features resemble the inflammatory symptoms seen with HHV-8-associated multicentric Castleman disease (MCD) and with KICS, but the great majority of cases were transient and self-limited [6,7].

Kaposi sarcoma — Kaposi sarcoma (KS) is a multifocal angioproliferative tumor with four epidemiologic forms: Classic KS, endemic or African KS, AIDS-related KS, and organ transplant-associated KS (table 1). Regardless of these epidemiologic categories, the pathology of KS is similar, and with some exception, the clinical course is similar as well. KS usually manifests as red, purple, or brown papules or plaques on the skin or mucous membranes [60] (picture 1 and picture 2 and picture 3). Lesions may occur at any site, but there is a predilection for the extremities (picture 4 and picture 5), ears, nose (picture 6), and palate (picture 7) for reasons which remain unclear. KS involvement of visceral organs such as the lungs or gastrointestinal tract and effusions in serous body cavities are other manifestations of advanced disease and may be life threatening [61,62]. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis" and "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment" and "Malignancy after solid organ transplantation", section on 'Kaposi sarcoma'.)

Multicentric Castleman disease — HHV-8 is the etiologic agent of a plasmablastic form of MCD that is most common in the setting of HIV but can also arise in transplant recipients and in other patients without HIV [63]. HHV-8 associated MCD is a polyclonal B cell disorder characterized clinically by intermittent flares of inflammatory symptoms and signs, including fevers, night sweats, fatigue, and cachexia, and edema, together with lymphadenopathy and hepatosplenomegaly. Common laboratory abnormalities include anemia, thrombocytopenia, hypoalbuminemia, hyponatremia, and elevated inflammatory markers, most notably C-reactive protein (CRP) [5,64]. (See "HHV-8/KSHV-associated multicentric Castleman disease".)

HHV-8 (Kaposi sarcoma) inflammatory cytokine syndrome (KICS) — HHV-8/Kaposi sarcoma inflammatory cytokine syndrome (KICS) is a syndrome characterized by severe inflammatory symptoms and elevated HHV-8 viremia [6,7]. The clinical manifestations are similar to those of MCD, and include fevers, night sweats, fatigue, and cachexia, and edema. Hepatosplenomegaly is common whereas lymphadenopathy is not [7]. Laboratory abnormalities include anemia, thrombocytopenia, hypoalbuminemia, hyponatremia, and elevated inflammatory markers including C-reactive protein. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis", section on 'Inflammatory cytokine syndrome'.)

Primary effusion lymphoma (PEL) — PEL is a rare variant of B-cell non-Hodgkin lymphoma (NHL) notable for its unusual presentation and aggressive clinical course [65,66]. The great majority of reported cases occur in people with HIV, although it may also be seen following solid organ transplantation, in older adults, and in chronic hepatitis C virus infection [67]. PEL usually presents as a lymphomatous effusion in serous body cavities, with pleural involvement seen in 60 to 90 percent of patients, followed by involvement of other body cavity membranes, including peritoneal (30 to 60 percent), pericardial (up to 30 percent), joint spaces, and rarely meninges [65,66,68]. (See "Primary effusion lymphoma".)

DIAGNOSIS

When to suspect HHV-8 infection — Human herpesvirus-8 (HHV-8) infection should be suspected when an immunocompromised patient presents with symptoms or signs that are consistent with one of the HHV-8 associated clinical tumor syndromes (Kaposi sarcoma, multicentric Castleman disease, or primary effusion lymphoma).

Since primary HHV-8 infection is transient and self-limiting, even in immunocompromised individuals, diagnosis and treatment is not necessary.

There is no clinical role for screening asymptomatic individuals for HHV-8 infection.

Diagnostic tests — Available tests to detect HHV-8 include immunohistochemistry on body tissue/fluid, blood polymerase chain reaction (PCR), and serology. HHV-8 associated tumors are typically diagnosed by immunohistochemistry of body tissue samples or cells from body cavity effusions. In contrast, Kaposi sarcoma inflammatory cytokine syndrome (KICS) is typically diagnosed by detecting HHV-8 viremia by PCR in peripheral blood.

There is no US Food and Drug Administration (FDA)-approved diagnostic test for clinical purposes, such as documentation of acute infection. As a result, important clinical challenges exist related to the lack of a gold-standard confirmatory test for HHV-8 infection in subjects without a documented HHV-8-associated malignancy or detectable HHV-8 in the blood or saliva.

●Serology — Available serologic tests are not FDA approved and are not suitable for establishing the presence of HHV-8 at an individual level. Although assessment of HHV-8 prevalence in populations is based on serologic antibody testing, these assays are usually not sufficiently robust for clinical use to ascertain an individual's infection status (eg, to document acute or chronic infection), as discussed below [69]. Current HHV-8 serologic tests use either immunofluorescent assays (IFAs) or enzyme-linked immunoassays (ELISAs) against one or more HHV-8-encoded latent and/or lytic proteins: one lytic (K8.1) and latent (LANA) protein is commonly used to increase sensitivity while preserving specificity [29,70,71]. The sensitivity of these assays is variable, while the specificity is generally greater than 95 percent [69].

●Polymerase chain reaction (PCR) — There are several different PCR assays that employ primers unique for HHV-8. HHV-8 DNA can be identified using PCR in virtually all biopsy samples of Kaposi sarcoma (KS) and HHV-8-associated multicentric Castleman disease (MCD) and in the peripheral blood of individuals with KICS and MCD during active disease flares [5,7,72,73]. Clinical applications of PCR for HHV-8 disease are predominantly to support a diagnosis of HHV-8-associated MCD or KICS in those with characteristic clinical features.

HHV-8 quantification in plasma or peripheral blood mononuclear cells by PCR may be a useful means for diagnosing an active flare of HHV8-associated MCD or KICS, and in following response to treatment [7,72]. HHV-8 DNA can also be detected by PCR in tumor cells within the pleural fluid in individuals with PEL, but this is less clinically useful in diagnosis or monitoring therapeutic response [66].

HHV-8 viremia can also be detected in asymptomatic individuals. The prevalence of viremia in persons asymptomatically infected with HHV-8 ranges from 4 to 20 percent [56]; thus PCR testing should not generally be done in patients without symptoms concerning for KICS. A positive HHV-8 PCR in the blood of a patient who does not demonstrate symptoms of KICS or HHV-8 associated tumors is not indicative of active disease.

Most PCR-based methods do not distinguish between latent and lytically replicating virus. As HHV-8 is often present sporadically in tissue, detection of low-level viremia is frequent and usually of no clinical significance.

HHV-8 viremia may be prognostic in other settings but is not yet in common clinical use for this purpose. For example, in sub-Saharan Africa where the detection of HHV-8 in the peripheral blood is common among individuals with KS, the level of HHV-8 DNA in the plasma appears useful in both predicting survival and response to treatment after a diagnosis of KS [74].

TREATMENT — Several antiviral agents such as ganciclovir, foscarnet, and cidofovir inhibit human herpesvirus-8 (HHV-8) replication in vitro [75,76]. However, direct antiviral therapy of HHV-8 infection in patients has a very limited role. Primary HHV-8 infection is usually asymptomatic and if symptomatic, self-limited without treatment. Antiviral agents have not been shown to have activity in treating established Kaposi sarcoma (KS), although ganciclovir, when used to treat cytomegalovirus (CMV) retinitis, did lower the risk of KS in patients with AIDS in a study conducted in the pre-antiretroviral therapy (ART) era [77]. Case series and small studies have demonstrated that antiviral agents including ganciclovir alone or in combination with other agents can have activity in HHV-8 associated multicentric Castleman disease (MCD) [78,79], but its use has almost entirely been supplanted by immunomodulating therapies, most notably rituximab [63]. (See "AIDS-related Kaposi sarcoma: Staging and treatment" and "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment", section on 'Treatment' and "HHV-8/KSHV-associated multicentric Castleman disease", section on 'Treatment' and "Primary effusion lymphoma", section on 'Management'.)

HHV-8 infection cannot be eradicated although long-term remissions of the associated clinical syndromes are possible with reduction in immunosuppression in immunocompromised patients [80-83].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in adults and adolescents with HIV".)

SUMMARY AND RECOMMENDATIONS

●Virology and epidemiology – Human herpesvirus-8 (HHV-8) is a large (165 kB) double-stranded DNA gamma (γ2) herpesvirus which is endemic worldwide (especially in sub-Saharan Africa and parts of the Mediterranean) and more common in certain behavioral groups such as men who have sex with men (MSM). It is classified as a group 1 biological carcinogenic agent. (See 'Virology' above and 'Epidemiology' above.)

●Transmission – HHV-8 is primarily transmitted by saliva during childhood but can also be transmitted via organ donation or rarely, via blood transfusion. (See 'Transmission' above.)

●Associated clinical syndromes – Most individuals infected with HHV-8 will experience no clinical consequences. However, in some cases, especially in immunocompromised individuals, HHV-8 can cause Kaposi sarcoma (KS), one form of the inflammatory lymphoproliferative disorder multicentric Castleman disease (MCD; HHV-8-associated MCD), primary effusion lymphoma (PEL), and/or the inflammatory syndrome known as the HHV-8 inflammatory cytokine syndrome (KICS). (See 'Associated clinical syndromes' above.)

●Diagnosis

•HHV-8 infection should be suspected when an immunocompromised patient presents with symptoms that are consistent with one of the HHV-8 associated clinical syndromes (Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, or KICS). (See 'When to suspect HHV-8 infection' above.)

•Diagnosis of primary HHV-8 infection or screening of asymptomatic individuals for HHV-8 infection is not indicated. (See 'When to suspect HHV-8 infection' above.)

•HHV-8 associated tumors are typically diagnosed by immunohistochemistry of body tissue samples or cells from body cavity effusions. (See 'Diagnostic tests' above.)

●Treatment – There is no role for direct antiviral therapy of HHV-8 infection as most primary HHV-8 infections are asymptomatic and/or self-limited. Treatment of HHV-8 associated clinical syndromes are discussed separately. (See 'Treatment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Corey Casper, MD, MPH, who contributed to earlier versions of this topic review.