Herpesviruses in Man

The human herpesviruses, including Herpes simplex virus (HSV), Varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), and human herpesvirus 8 (HHV-8) may produce a variety of clinically significant manifestations either as self-limited infections or non-resolving opportunistic infections.

Many herpesviruses commonly infect man, but clinically apparent or life-threatening illness are most often seen in persons who are immunocompromised, including persons with primary or secondary immunodeficiencies (including AIDS), persons undergoing cancer chemotherapy, transplant recipients, persons with lymphoreticular malignancies involving the hematologic and/or mononuclear phagocyte system, persons receiving chronic corticosteroid therapy or having increased endogenous corticosteroid production (Cushing's syndrome), and persons who are severely debilitated and/or malnourished.

Electron micrographic appearance of herpesviruses

HERPESVIRUSES, TYPES 1 AND 2

VARICELLA ZOSTER VIRUS

Both HSV types 1 (HSV-1) and 2 (HSV-2) primarily infect skin and mucus membranes (mucocutaneous infections) to produce inflammation, often vesicular, progressing to sharply demarcated ulcerations. Herpes simplex type 1 mainly involves the oral cavity, often as the so-called "cold sores" that many people have experienced. HSV-2 more often involves the genital region as a sexually transmitted disease. However, either body region may be infected by either subtype to produce clinically and histologically indistinguishable disease, which is not surprising, given the 50% homology between the genomes of HSV-1 and -2. The lesions, though small, can be quite painful.

Two distinct clinical manifestations are seen with the Varicella zoster virus (VZV):

Chicken pox as a primary infection (varicella) in children
"Shingles" as reactivation of latent infection (Herpes zoster virus, or HZV) in adults.

Images:: Herpes simplex, skin, vesicle, low power microscopic.; Herpes simplex, skin, multinucleated cells with inclusions at arrows, medium power microscopic.; Herpes simplex esophagitis, gross.; Herpes simplex esophagitis, low power microscopic.; Herpes simplex esophagitis, high power microscopic.; Herpes simplex esophagitis, high power microscopic.; Herpes simplex keratitis, gross, fluorescein stain.; Herpes simplex keratitis, high power microscopic.; Herpes simplex encephalitis, acute, with hemorrhage, gross.; Herpes simplex encephalitis, remote, gross.

CLINICAL FEATURES OF HSV AND VZV

All herpesviruses exhibit latency following initial infection. Either HSV or VZV infection initially occurs through mucosal surfaces or through abraded skin via contact with a person who is excreting virus through active, usually ulcerative, lesions. Excretion of HSV-1 can be detected in 2 to 9% of asymptomatic adults, while HSV-2 can be isolated from the genital tract in up to 5% of males and up to 8% of females in sexually transmitted disease clinics.

Viral replication begins within epithelium and underlying dermis or within submucosa. From these initial sites, HSV or VZV spreads to nerve endings and is transported intra-axonally to neurons in ganglia, from which spread is then via peripheral sensory nerves back to other, usually adjacent, skin and mucosal sites.

Thus, vesicular HSV or VZV lesions may later appear or recur away from the initial site of involvement.

After an initial host response in which both cell-mediated and humoral mechanisms take part, the infection usually becomes latent, with HSV or VZV present but not actively replicating within ganglia. It is unclear just how reactivation of HSV, or VZV as HZV, occurs but lack of cell-mediated immunity in immunocompromised patients may be implicated.

Clinical Diagnosis:

Diagnosis of HSV or HZV infections is suggested by the appearance of crops of clear vesicles in groups on mucocutaneous surfaces. Vesicles may resolve completely, but in some cases infection becomes persistent and ulcerations occur, most commonly with HSV infections about the oral cavity or perianal region. The typical patient with HSV or HZV has a grouped vesicular skin eruption that ruptures, crusts, and heals in seven to ten days. Infection may be associated with a history of severe pain, often persisting for months after the skin lesions resolve. Scarring also occurs, and secondary bacterial infection may complicate herpetic lesions.

Ulceration may obscure the features and make diagnosis difficult unless a Tzanck preparation, biopsy, or viral culture is done to establish the diagnosis. Multiple herpetic lesions tend to ulcerate due to persistence for prolonged periods (with or without therapy), excoriation, or secondary infection.

Chronic HZV infections may be characterized by pseudocarcinomatous hyperplasia, verrucous epidermal hyperplasia, and massive hyperkeratosis.
Reactivation of VSV as HZV with shingles may often occur as an early manifestation of immune compromise.
Internal organ involvement with HSV and HZV is infrequent, and disseminated infections are uncommon, but the clinical course can be one of recurrences.
Herpetic mucocutaneous lesions of immunocompromised patients, including those with AIDS, have been reported to be more extensive, more severe, and longer-lasting, with more ulceration, necrosis, and pain than in immunocompetent patients.

Microbiologic Diagnosis:

Viral culture remains the most sensitive clinical method for HSV or HZV diagnosis; methods for antigen detection are less sensitive. Culture sensitivity is higher when the herpetic vesicular lesions first appear and before they ulcerate. Later ulcerative lesions may have no detectable virus. Serologic testing is mainly of value for detection of past infection, but not acute infection, for immunocompromised patients are unlikely to mount a significant (fourfold or greater) rise in anti-HSV titer between acute and convalescent samples.

Tissue Diagnosis:

Microscopically, lesions of HSV and HZV both in tissue biopsies or from cytologic preparations (Tzanck or Pap smears) demonstrate characteristic acantholytic epithelial or discohesive parenchymal cells, often multinucleated or in clusters, with mauve to pink to steel-gray ground glass intranuclear (Cowdry type A) inclusions. The cytoplasm of infected cells is not prominent and, unlike CMV, does not contain inclusion bodies of any kind. With ulceration, such cells may be infrequent or autolyzed. Surrounding sqaumous epithelium may show ballooning degeneration.

For HZV, typical cytologic features most often occur in cells between papillae and dermal adnexae. On average, cells infected with HSV or HZV do not reach the size of those with CMV, and the intranuclear inclusions of CMV tend to be darker and larger, and intracytoplasmic inclusions may accompany CMV. Immunoperoxidase staining with primary antibody against HSV-1, HSV-2, and HZV will help to exclude other viral etiologies such as CMV, EBV, and human papillomavirus (HPV).

Organ Involvement:

Encephalitis from HSV is the most common viral infection of the CNS in the U.S., with an estimated incidence of 2.3 cases per million per year. The clinical course and radiologic findings of HSV encephalitis may closely mimic those of progressive multifocal leukoencephalopathy (PML), though computed tomograpahic or magnetic resonance imaging scans showing evidence of hemorrhage, a mass effect, or gray matter involvement more strongly suggest herpes.

Grossly, HSV produces areas of necrosis most commonly in temporal lobe, inferior frontal lobe, insula, or cingulate gyrus. Microscopically, herpetic lesions can have petechiae with fibrinoid necrosis, perivascular mononuclear inflammatory cell infiltrates, and Cowdry type A inclusions in either neurons or glial cells.

Ocular herpes is the most frequent etiology for corneal blindness in the U.S. However, with AIDS deeper infection is more frequent, with the complication of chorioretinitis reported.

Additional visceral organ involvement with HSV or HZV is quite uncommon, even in immunocompromised hosts. Reported involvement includes findings of hepatitis, glomerulonephritis, adrenalitis, and arthritis. Pancreas and bone marrow may also be involved.

Treatment:: Acyclovir has been found to be effective therapy for treating most mucocutaneous herpetic infections and may be useful prophylactically in persons with frequent recurrences. Anorectal herpetic lesions often respond to acyclovir therapy and may disappear following treatment. Acyclovir appears effective for visceral herpetic infections as well. However, both HSV and HZV infections have been reported that are resistant to acyclovir. Foscarnet has shown to be of use in some of these cases.

CYTOMEGALOVIRUS (CMV)

Antibodies to cytomegalovirus (CMV) can be demonstrated in about 70% of all persons. Thus, CMV is a very common subclinical infection. CMV can become a clinically relevant infection in persons who are immunocompromised. CMV may also be manifested as a congenital infection.

Microscopic diagnosis of CMV is based upon finding the characteristic intranuclear inclusions within enlarged cells, in most cases presents no problems. The clear halo that often surrounds intranuclear inclusions also helps in distinguishing CMV. Herpes simplex virus and adenovirus may produce intranuclear inclusions, but the cells are never as large as CMV, and do not have the cytoplasmic basophilic inclusions of CMV. In some cases the plane of sectioning may miss the intranuclear inclusion body of the CMV cell, and the cytoplasmic basophilic granular bodies may resemble bradyzoites of Toxoplasma gondii pseudocysts. However, bradyzoites are more uniform in size, and the pseudocyst usually has a more prominent border. In questionable cases, immunohistochemical staining or electron microscopy can provide adequate differentiation.

Images:: Cytomegalovirus pneumonitis, high power microscopic.; Cytomegalovirus pneumonitis, high power microscopic.; Cytomegalovirus adrenalitis, medium power microscopic.; Congenital cytomegalovirus in fetal kidney, high power microscopic.

Treatment for CMV infection has received increasing attention since the observation that the drug 9-(1,3-dihydroxy-2-propoxymethyl) guanine, commonly known as ganciclovir, inhibited in vitro replication of human herpesviruses, including CMV. Several reports have detailed the clinical use and response of AIDS patients treated with ganciclovir Previous attempts to treat CMV with adenine arabinoside, alpha-interferon, and acyclovir met with poor results.

EPSTEIN-BARR VIRUS (EBV)

Epstein-Barr virus (EBV) infection is common. An acute illness due to EBV is infectious mononucleosis. However, many EBV infections are subclinical. EBV is being increasingly recognized as a factor in development of neoplasia. EBV-infected cells can more easily undergo malignant transformation. EBV is thought to play a role in development of:

Infectious mononucleosis
Nasopharyngeal carcinoma
African Burkitt's lymphoma
Non-Hodgkin's lymphomas in AIDS
Oral hairy leukoplakia (in AIDS)

There are no specific clinical features of acute EBV infection, aside from infectious mononucleosis.

Images:: Atypical lymphocytes, infectious mononucleosis, peripheral blood smear.; Diffuse large cell lymphoma, medium power microscopic.; Immunoblastic sarcoma, medium power microscopic,

HUMAN HERPESVIRUS 6 (HHV-6)

HHV-6 demonstrates T-lymphocyte tropism, and it has been found to replicate in a variety of cell types, including CD4+ lymphocytes. Serologic evidence for previous HHV-6 infection is frequent, and the majority of children have been infected by the age of 3.

HHV-6 has been implicated as a cause for the following diseases:

Roseola (exanthem subitum) in children.
An acute febrile illness without a rash in children
Pneumonitis, encephalitis, or bone marrow failure in immunocompromised hosts.

HUMAN HERPESVIRUS 7 (HHV-7)

HHV-7 is quite common, with serologic evidence for previous infection in about 85% of adults in the U.S. It appears to infect persons later in life than HHV-6. At present, no specific disease has been linked to HHV-7 infection.

HUMAN HERPESVIRUS 8 (HHV-8)

A human herpesvirus-like agent (HHV-8) has been identified in skin lesions of Kaposi's sarcoma (KS) in both classical and AIDS-associated forms as well as in the KS of HIV negative homosexual males. This agent appears to be sexually transmissible independently of HIV and accounts for the increased incidence of KS in certain risk groups.

Kaposi's sarcoma, also called "multiple idiopathic hemorrhagic sarcoma," was rarely seen prior to the AIDS epidemic but now has become one of the commonest diagnostic diseases with AIDS. Kaposi's sarcoma occurs in the following clinical patterns: classic (sporadic), endemic African (benign nodular, aggressive, florid, and lymphadenopathic), iatrogenic (seen in immunocompromised patients such as recipients of organ transplants, those patients on immunosuppressive drug therapy, or patients with connective tissue diseases), and epidemic (AIDS-associated).

All forms of KS have a male predominance, but this is even more pronounced with AIDS where it is seen most frequently in homosexual and bisexual males who have a 10-fold risk compared with intravenous drug users, though the incidence of KS with AIDS appears to be decreasing slightly over time. Heterosexuals have a 2 to 3-fold risk compared with intravenous drug users. Kaposi's sarcoma is infrequently seen in persons whose risk for AIDS is parenteral exposure to HIV, blacks, and children. Kaposi's sarcoma is less common in women than men, with a male:female ratio of 6:1 in the United States, though in Africa the ratio is 2:1.

A presumptive clinical diagnosis of KS indicative of AIDS can be made by finding a characteristic gross appearance of an erythematous or violaceous plaque-like lesion on skin or mucous membrane.

Images:: Kaposi's sarcoma, skin, gross.; Kaposi's sarcoma, skin, microscopic.; Kaposi's sarcoma, skin, microscopic.; Kaposi's sarcoma, skin, hyaline globules, high magnification microscopic.; Kaposi's sarcoma, stomach, gross.

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