Viral Infections of the Mouth (cont 1)

Differentials

Primary herpetic gingivostomatitis

Recurrent herpetic gingivostomatitis

Herpes Zoster

Herpetiform aphthae

Aphthous minor, multiple

Erythema Multiforme

Acute necrotizing gingivostomatitis

Infectious mononucleosis

Herpangina

Hand-Foot-and-Mouth Disease

Traumatic Ulcers

Burns, Chemical

Factitial injuries

Vesiculobullous disease

Primary chickenpox

Behçet Disease

Reactive Arthritis

CMV ulceration

Recurrent herpetic gingivostomatitis

Primary herpetic gingivostomatitis

Herpes Zoster

Herpetiform aphthae

Aphthous minor

Acute necrotizing gingivostomatitis

Traumatic Ulcers

Burns, Chemical

Squamous Cell Carcinoma

Factitial injury

Herpangina

Hand-Foot-and-Mouth Disease

Erythema Multiforme

Vesiculobullous disease

CMV ulceration

Syphilis

Tuberculosis

Deep fungal infection

Foreign body reaction

Hairy leukoplakia¹¹

Traumatic keratosis (tongue chewing)

Epithelial dysplasia

Squamous Cell Carcinoma

Lichen Planus^11,12

Burns, Chemical

Oral KS

Amalgam tattoo

Other tattoo

Hemangioma

Varix

Nevocellular nevus

Blue Nevi

Ecchymosis

Oral Melanoacanthoma

Melanoma

Workup

Imaging studies

Radiography of suspected early KS may be useful to differentiate it from an amalgam tattoo. In many amalgam tattoos, the amalgam is visible as discrete radiopaque particles.

Procedures

Diagnosis is often made based on the clinical findings alone, especially for HHV-1, HHV-2, and HHV-3. A smear of an intact viral vesicle may be helpful to confirm the clinical diagnosis. Smear results may reveal virally altered epithelial cells. Direct immunofluorescence antibody tests and culturing help identify the causative virus. Biopsy is usually required to confirm a diagnosis of KS, and it may be required to confirm the diagnosis of other conditions.

Histologic findings

Herpes simplex infection is characterized by an acantholytic intraepidermal vesicle with epithelial giant cells. The cells exhibit nuclear molding and peripheral accentuation of the nucleoplasm. Underlying leukocytoclastic vasculitis is typically present. Zoster has similar findings, but the leukocytoclastic vasculitis is more pronounced.

CMV infection manifests as enlarged endothelial cells. The cells have ample cytoplasm and an owl’s eye nucleus.

KS is typically a neoplastic spindle cell proliferation with erythrocytes in slitlike spaces and extravasation between the neoplastic cells.

Medical care

Establishing the diagnosis is important because the differential diagnoses include diseases that are conventionally treated with immunosuppressive agents. Immunosuppressive therapy may not be prudent for an active herpetic infection because it could promote dissemination.

Herpesvirus infections may trigger erythema multiforme. If recurrences are common and debilitating, long-term suppressive antiviral therapy may reduce the recurrence of herpes and thus erythema multiforme.

Patients should be counseled about the routes of infectivity.

Primary HHV-1/HHV-2

The goals of treatment are to make the patient comfortable and to prevent secondary infections or worsening systemic illness. The patient should maintain fluid intake and a balanced diet with the use of liquid food replacement if necessary. Analgesics, such as acetaminophen, may make the patient more comfortable. Aspirin should be avoided in pediatric patients because of the possibility of Reye syndrome. Topical anesthetics and coating agents may make the patient more comfortable and may aid in the consumption of food; however, they do not speed healing.

Patients should be advised about the potential for autoinoculation if they touch the herpetic lesion and then touch a mucous membrane or an eye. Controlling autoinoculation can be a challenge if the patient is a young child.

Recurrent orofacial HHV-1/HHV-2¹³

Some patients find that sunburn triggers the recurrence of labial lesions. Sun avoidance with the use of hats or shading or the application of a sunscreen or sunblock may reduce the frequency of recurrences.

If the decision is made to use systemic antiviral treatment, it should be initiated as early as possible in the prodromal stage to reduce the size, severity, and duration of the lesions. Topical antiviral medications are minimally useful in treating recurrent HHV-1 infection in healthy patients. Emollient preparations may make the patient more comfortable. Systemic prophylactic antiviral medication may be indicated for patients who experience 6 or more recurrences a year or for patients who experience repeated bouts of erythema multiforme induced by herpes.

HHV-3 (varicella-zoster virus)

Antiviral therapy is most effective in limiting the area of involvement and the duration of the symptoms if instituted within the first 48-72 hours. Acyclovir may control the size of the lesions, but it is less effective than valacyclovir or famciclovir in reducing pain and in lessening the risk of postherpetic neuralgia. Postherpetic neuralgia is especially common in older patients, and it may be appropriately managed with short-term, high-dose corticosteroid prophylaxis in conjunction with or following antiviral therapy. The pain of postherpetic neuralgia can also be managed with anticonvulsants, antidepressants, painkillers, or topical anesthetics.

Prevention of chicken pox/varicella infection can be accomplished via vaccination. Two vaccines are available in the United States for the prevention of varicella infection. The first is a single-antigen varicella vaccine (Varivax; Merck & Co), which was licensed in 1995 in the United States. It is indicated for use in healthy children older than 12 months, adolescents, and adults. The second vaccine is a combination of the measles, mumps, rubella, and varicella components (ProQuad; Merck & Co), which was licensed in 2005 in the United States for use in children aged 12 months to 12 years.¹⁴

The following are the Advisory Committee on Immunization Practices most recent recommendations for varicella vaccine^{15,16,17,18,19} :

• Routine 2-dose varicella vaccination regimen for children, with the first dose given at age 12-15 months and the second dose given at age 4-6 years
• Second catch-up dose of varicella vaccine for children, adolescents, and adults who previously received 1 dose
• Routine vaccination of all healthy individuals aged 13 years or older who do not have evidence of immunity
• Prenatal assessment and postpartum vaccination
• Varicella vaccination of HIV-infected children with age-specific CD4⁺ T lymphocyte percentages of 15-24% and adolescents and adults with CD4⁺ T lymphocyte counts equal to or greater than 200 cells/μ L
• Establishing middle school, high school, and college entry vaccination requirements

The Advisory Committee on Immunization Practices also recommends the use of a live-attenuated vaccine for the prevention of herpes zoster (shingles) and its sequelae. The US Food and Drug Administration (FDA) licensed this vaccine in 2006.

The zoster vaccine is a lyophilized, live-attenuated virus strain of varicella-zoster virus and is the same strain used in the varicella vaccines. Its minimum potency is at least 14 times that of the single-strain varicella vaccine. It is partially efficacious in reducing the severity and duration of pain and in preventing postherpetic neuralgia. It is recommended in individuals older than 60 years who have no contraindications, including those who have had a previous episode of zoster and those with chronic medical conditions.

Persons with either varicella or zoster may benefit from oral antiviral drugs.

HHV-4 (EBV)

Topical tretinoin gel may be used to manage oral hairy leukoplakia, but it often is not necessary. Topical podophyllin applications (a keratotic agent) may help to control EBV-associated hairy leukoplakia. Repeated treatment may be necessary to obtain satisfactory results. Management of the underlying immunosuppressed status may be a more useful strategy. Occasionally, the use of systemic antiviral medication may be warranted. Potential toxicity, adverse effects, and complications of systemic therapy combined with a high risk of lesion reappearance and the benign nature of hairy leukoplakia support a conservative approach in the management of hairy leukoplakia.

HHV-5 (CMV)

Similar to HHV-1/HHV-2, CMV-related ulceration of the oral cavity requires immediate referral to an ophthalmologist if ocular involvement is of concern. Systemic antiviral treatment (ie, with ganciclovir or valganciclovir) is the treatment of choice for oral lesions.

HHV-8²⁰

Patients diagnosed with HHV-8–associated KS should be referred to a health care provider experienced in the treatment of this disease. The best results in the treatment of KS are achieved by improving systemic immune functions. When limited to the oral cavity, low-dose radiation therapy, intralesional injections of vinblastine and/or sodium tetradecyl sulfate (Sotradecol), and/or interferon alfa (IFN-A) have been reported to result in the resolution of the lesions.

Consultations

Patients with ocular lesions should be immediately referred to an ophthalmologist.

Patients with KS are commonly referred to an appropriate subspecialist for treatment.

Patients with confirmed hairy leukoplakia or KS should undergo a thorough investigation of their immune status.

Medication

See Medication.

Medical/legal pitfalls

• Failure to inform the patient of the potential for disease transmission
• Failure to search for underlying immunosuppression, if appropriate
• Failure to make necessary medical referrals
• Failure to indicate treatment availability