Infectious Disease and Microbiology – Human Herpesvirus Type 8

Overview

Human herpesvirus type 8 (HHV-8) is an enveloped, double-stranded DNA herpesvirus best known for its strong association with Kaposi sarcoma. It is therefore also called Kaposi sarcoma-associated herpesvirus (KSHV).

Like other herpesviruses, HHV-8 establishes lifelong latent infection after acquisition and can reactivate. Clinically important disease is particularly associated with immunosuppression, including advanced HIV infection and transplantation.

Classification

Virus: Human herpesvirus type 8 (HHV-8)

Alternative name: Kaposi sarcoma-associated herpesvirus (KSHV)

Family: Herpesviridae

Subfamily: Gammaherpesvirinae

HHV-8 is an oncogenic herpesvirus because infection is associated with the development of several neoplastic and lymphoproliferative disorders.

Microbiologic Characteristics

HHV-8 is:

• A double-stranded DNA virus

• Enveloped

• Equipped with an icosahedral capsid

• Capable of establishing latent infection

• An important oncogenic virus

The source specifically identifies its double-stranded DNA genome.

Incubation Period

The incubation period is:

Unknown

The interval between initial HHV-8 infection and development of associated tumors can be prolonged and depends strongly on host immune status.

Epidemiology

HHV-8 prevalence varies considerably around the world.

Infection is particularly important in populations with increased risk of Kaposi sarcoma and in patients with significant immunosuppression.

Transmission can occur through:

• Saliva

• Sexual exposure

• Blood exposure

• Organ transplantation

Kaposi Sarcoma

Major Clinical Association

The most important association is:

HHV-8 → Kaposi sarcoma

HHV-8 infection is considered essential to the pathogenesis of Kaposi sarcoma, although infection alone does not mean that an individual will develop the malignancy.

Impaired immune surveillance is an important factor in disease development.

Clinical Appearance

Kaposi sarcoma commonly produces:

Red, violaceous, purple, or brown lesions

that may involve:

• Skin

• Oral mucosa

• Lymph nodes

• Gastrointestinal tract

• Lungs

Visceral disease can occur even when external lesions are limited.

Major Forms of Kaposi Sarcoma

Kaposi sarcoma is traditionally divided into several epidemiologic forms:

• Classic Kaposi sarcoma

• Endemic African Kaposi sarcoma

• HIV/AIDS-associated Kaposi sarcoma

• Iatrogenic or transplant-associated Kaposi sarcoma

All are associated with HHV-8.

HIV-Associated Kaposi Sarcoma

HHV-8 is particularly important in patients with HIV-associated immunosuppression.

Kaposi sarcoma may involve multiple cutaneous and visceral sites.

Effective control of HIV and restoration of immune function can substantially improve HIV-associated Kaposi sarcoma.

Other HHV-8-Associated Diseases

HHV-8 is associated with more than Kaposi sarcoma.

Important additional associations include:

Primary effusion lymphoma (PEL)

and

HHV-8-associated multicentric Castleman disease (MCD)

These associations are especially important in immunocompromised patients.

Primary Effusion Lymphoma

Primary effusion lymphoma is an HHV-8-associated B-cell lymphoma.

It classically presents as a malignant effusion within a body cavity, such as the:

• Pleural cavity

• Pericardial cavity

• Peritoneal cavity

A solid tumor mass may be absent in the classic presentation.

Multicentric Castleman Disease

HHV-8 can also contribute to multicentric Castleman disease, particularly in patients with HIV.

Possible manifestations include:

• Fever

• Generalized lymphadenopathy

• Constitutional symptoms

• Hepatosplenomegaly

• Cytopenias

• Systemic inflammatory findings

High-Yield HHV-8 Associations

Remember the major disease triad:

HHV-8

→ Kaposi sarcoma

→ Primary effusion lymphoma

→ Multicentric Castleman disease

Kaposi sarcoma is by far the most classic examination association.

Diagnosis

The source lists:

• Cell culture

• Serology

However, these are not generally the primary methods used to diagnose HHV-8-associated Kaposi sarcoma.

Diagnosis of Kaposi Sarcoma

A suspicious lesion is generally evaluated with:

Tissue biopsy and histopathologic examination

HHV-8-associated latent nuclear antigen (LANA) can be demonstrated by immunohistochemistry, supporting the diagnosis.

Molecular methods can also detect HHV-8 DNA in appropriate clinical settings.

Treatment

The source lists:

Foscarnet

and

Symptomatic treatment

However, antiviral suppression of HHV-8 itself is not the standard primary treatment for established Kaposi sarcoma.

Treatment instead depends on the specific HHV-8-associated disease, its extent, and the patient’s immune status.

HIV-Associated Kaposi Sarcoma

For HIV-associated Kaposi sarcoma, a fundamental component of management is effective:

Antiretroviral therapy (ART)

Restoration of immune function may lead to substantial regression of Kaposi sarcoma.

More extensive or visceral disease may require systemic anticancer therapy in addition to ART.

Localized Kaposi Sarcoma

Selected localized lesions may be treated with approaches such as:

• Local excision

• Radiation therapy

• Other lesion-directed therapies

Treatment is individualized according to the location, number, symptoms, and extent of lesions.

Transplant-Associated Disease

In transplant recipients, management may include carefully modifying the degree or type of immunosuppression, balanced against the risk of graft rejection.

Specialist management is generally required.

High-Yield Clinical Pattern – Kaposi Sarcoma

Patient with significant immunosuppression

• ●

Multiple violaceous skin or oral lesions

• ●

Spindle-cell vascular tumor on biopsy

→ Think HHV-8-associated Kaposi sarcoma

High-Yield Clinical Pattern – Primary Effusion Lymphoma

Immunocompromised patient

• ●

Pleural, pericardial, or peritoneal effusion

• ●

Malignant lymphoid cells

• ●

Little or no solid tumor mass

→ Consider HHV-8-associated primary effusion lymphoma

HHV-6 vs. HHV-8

HHV-6

→ Roseola infantum

→ High fever followed by rash after defervescence

→ Febrile seizures

→ Encephalitis after stem-cell transplantation

HHV-8

→ Kaposi sarcoma

→ Primary effusion lymphoma

→ Multicentric Castleman disease

→ Particularly important with immunosuppression

Exam Essentials

Virus: Human herpesvirus 8

Alternative name: Kaposi sarcoma-associated herpesvirus (KSHV)

Genome: Double-stranded DNA

Envelope: Present

Incubation: Unknown

Biologic behavior: Latency with possible reactivation

Major association: Kaposi sarcoma

Classic lesion: Violaceous/purple skin or mucosal lesion

Other major diseases: Primary effusion lymphoma and multicentric Castleman disease

Important host factor: Immunosuppression

HIV-associated Kaposi management: Effective ART is fundamental

Kaposi diagnosis: Tissue biopsy with histopathology; HHV-8 LANA immunohistochemistry can support diagnosis

Source treatment: Foscarnet/symptomatic treatment

Important treatment clarification: Antiviral therapy directed solely at HHV-8 is not standard primary treatment for established Kaposi sarcoma

Key clinical pearl: HHV-8, or Kaposi sarcoma-associated herpesvirus, is an oncogenic double-stranded DNA herpesvirus. The highest-yield association is HHV-8 + immunosuppression + violaceous skin or oral lesions → Kaposi sarcoma; also remember its associations with primary effusion lymphoma and multicentric Castleman disease.