Update on Oral Herpes Virus Infections

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Key points

  • Oral herpes virus infections (OHVIs) are commonly encountered in clinical practice.

  • OHVIs can resemble other types of oral mucosal diseases.

  • Diagnosis of OHVIs is usually based on patient history and clinical examination findings, but adjunctive laboratory tests may be necessary to establish the diagnosis.

  • Treatment of OHVIs usually consists of palliative care, but may include use of topical or systemic antiviral medications.

  • Immunosuppressed patients with OHVIs are potentially at risk of

HSV

HSV-1 and HSV-2 are the two major types of herpes viruses known to cause most common oral and perioral infections.11, 12 They can be distinguished by the distinct antibodies that are formed against each type of virus or by analysis of the nuclear DNA by restriction endonuclease analysis.1, 2 Classically, HSV-1 causes most cases of oral and pharyngeal infection, meningoencephalitis, and dermatitis above the waist; HSV-2 is implicated in most genital and anal infections.1, 2 Depending on sexual

Primary herpes simplex infections

The incidence of primary infections with HSV-1 increases after 6 months of age as a result of loss of anti-HSV antibodies acquired from the mother during gestation. The incidence of primary HSV-1 infection reaches a peak between 2 and 3 years of age.1, 2 Primary HSV-1 infections may still occur in adolescents and adults, with occasional cases being reported in patients older than 60 years.14 Incidence of primary HSV-2 infection does not increase until sexual activity begins. In a prevalence

Recurrent herpes simplex infection

After resolution of a primary HSV infection, the virus migrates to the trigeminal nerve ganglion, where it is capable of remaining in a latent state. Reactivation of virus may follow exposure to cold, exposure to sunlight, stress, trauma, or immunosuppression and cause recurrent infection.1, 2 Recurrent herpes labialis (RHL) is the most common form of recurrent HSV infection, typically appearing on the mucocutaneous junction of the lip, and is often referred to as a cold sore or fever blister (

Differential Diagnosis

Most HSV infections are diagnosed clinically; however, a differential diagnosis should be formulated that includes other vesiculoulcerative diseases. Recurrent aphthous stomatitis (RAS) is commonly misdiagnosed as an HSV infection; however, there are key clinical features that are unique to each disease.2 HSV infections typically have a prodrome of systemic symptoms before vesicle/ulcer eruption; RAS generally does not have the same prodromal symptoms before ulcer formation. HSV infections

Virologic tests

The classic standard for virus identification and diagnosis is isolation in tissue culture. The goal of virus isolation is to observe cytopathic effects (CPE) of the cells inoculated with virus. CPE are the degenerative changes that cells undergo when infected with virus. The rate at which CPE develops is dependent on the type of host cell, the type of virus, and the concentration of virus.1, 2 When viewed at high power via light microscopy, virally infected cells show multinucleated giant

Cytology smears

A smear taken of epithelial cells at the base of a suspected lesion may be analyzed to determine if these cells show changes consistent with HSV infection. The most common stain used is Giemsa, and virally infected cells have the same characteristics that are shown by virologic testing. When a Papanicolaou stain is performed, eosinophilic intranuclear viral inclusion bodies (Lipschutz or Cowdry type A) can be seen.

Immunomorphologic tests

The diagnosis of herpes virus infections can be made more quickly and accurately by using immunomorphologic techniques.32 In the direct fluorescent assay (DFA), the specimen is incubated with fluorescein isothiocyanate–labeled HSV type-specific monoclonal antibody.33 The positively infected cells are fluorescent green when examined under a fluorescent microscope, and this technique is often used for the rapid diagnosis of a clinical specimen.34 Studies have concluded that the overall

Polymerase chain reaction test

Polymerase chain reaction (PCR) is the most sensitive method for HSV diagnosis.37 PCR does not require viable virus or infected cells for detection, unlike tissue culture and direct assays. Also, real-time detection allows for PCR to be carried out promptly, and it may be used to discriminate HSV types.38 Detection of viral DNA by PCR is considered the test of choice for HSV diagnosis.

Serologic tests

Serologic tests are conducted to detect antibody formation in a patient’s blood sample. If serology is used in the diagnosis of suspected HSV infection, an acute specimen should be obtained within the initial 3 days of the infection and a convalescent specimen approximately 4 weeks later. Because of the delayed humoral response, antibodies are not present in the acute specimen but appear during convalescence; a 4-fold or greater antibody increase in convalescent serum is required for the

VZV

VZV is responsible for two major clinical infections: the primary type is chickenpox (varicella) and the recurrent type is shingles (herpes zoster [HZ]).

HZ

After primary infection, VZV becomes latent in dorsal root or cranial nerve ganglia. In 0.3% to 0.5% of the population, the virus becomes reactivated, causing HZ.1, 2 The nerves most commonly affected with HZ are C-3, T-5, L-1, and L-2. When HZ involves the trigeminal nerve, the first division (ophthalmic branch or V1) is most commonly involved, and ocular involvement is a potentially serious complication.1, 2 Consultation with an ophthalmologist is necessary in these cases. The live virus HZ

EBV

EBV is a herpesvirus that preferentially infects B lymphocytes. Infection of humans with EBV usually occurs by contact with oral secretions, and more than 95% of the world’s adult population is seropositive and chronically infected.3 The virus replicates in epithelial cells of the oropharynx, and nearly all seropositive persons actively shed virus in the saliva.3, 48 Whereas most EBV infections of infants and children are asymptomatic or have non-specific symptoms, infections of adolescents and

CMV

CMV, also referred to as human CMV, is a frequent cause of asymptomatic infection in humans and may cause significant clinical disease in immunosuppressed patients.55 The virus is mainly transmitted via contaminated blood and bodily secretions, including breast milk, saliva, and genital fluids.1, 2

Neonates may develop cytomegalic inclusion disease, an often fatal disease resulting from congenitally acquired CMV infection.56 In its most severe form, this disease is associated with microcephaly,

HHV-6

HHV-6 was discovered in 1986, when it was isolated from peripheral blood lymphocytes of six individuals with lymphoproliferative disorders.70 Studies showed that CD4 T cells were the major type of cell infected by HHV-6.71, 72 Two variants of HHV-6 have been differentiated: HHV-6A and HHV-6B. Eighty percent to 90% of the population intermittently shed HHV-6 (and HHV-7) in saliva.73

Primary infection with HHV-6 can be asymptomatic or cause an unspecified febrile illness or a specific clinical

HHV-7

HHV-7 was discovered in 1990, when the virus was isolated from activated CD4 T cells obtained from a healthy individual. The genomes of HHV-7 and both variants of HHV-6 are closely related, with 20% to 75% nucleic acid homology depending on the genes being compared.74

Primary infection with HHV-7 is most often asymptomatic; however, it may cause pityriasis rosea, presenting as a single rose-colored, scaling, and herald patch. Oral lesions involving HHV-7 are rare and may present as punctate

HHV-8

HHV-8 was isolated in tumor tissue from a patient with AIDS-associated KS in 1994 and named KS herpesvirus (KSHV).7 Moritz Kaposi, a Hungarian-born dermatologist, first described idiopathic multiple, pigmented sarcoma of the skin in 1872 and suggested a possible infectious cause for KS.74

KSHV is capable of inducing malignant tumors in humans. Of the KSHV-associated malignant diseases, the most prominent is KS.8 KSHV is believed to stimulate angiogenic and inflammatory cytokines and gene

Summary

Oral herpes virus infections are often encountered in clinical practice. An appropriate diagnosis and treatment plan requires advanced knowledge of these diseases. Clinicians should be aware of the potentially critical nature of herpes virus infections, especially in immunocompromised patients, and manage these cases accordingly.

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    A version of this article appeared as Stoopler, ET. Oral herpetic infections (HSV 1–8). Dent Clin N Am 2005;49:15–29.

    Disclosures for authors: no disclosures.

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