A Note On Primary Herpes Simplex Virus Infections.......Extracted from Burket’s Oral Medicine

There are approximately 600,000 new cases of primary HSV infections per year in the United States. Primary HSV infection occurs in patients who do not have immunity resulting from previous contact with the virus. HSV is contracted after intimate contact with an individual who has active HSV primary or recurrent lesions. Primary HSV may also be spread by asymptomatic shedders with HSV present in salivary secretions. The majority of oral HSV infections is caused by HSV1, but primary oral HSV2 infections may also occur chiefly as a result of oral-genital contact. Infection of the fingers (herpetic whitlows) of health professionals may occur during treatment of infected patients. Dentists may experience primary lesions of the fingers from contact with lesions of the mouth or saliva of patients who are asymptomatic carriers of HSV, although the incidence of this disorder should be minimal if gloves are worn. Use of gloves should also prevent the spread of HSV from the fingers of health care workers infected with herpetic whitlows to patients.

Primary herpetic whitlow on the finger of a dentist

Primary HSV infection of the newborn was previously believed to be caused by direct contact with vaginal HSV lesions during birth, but it has now been established that a majority of mothers giving birth to children with primary HSV are asymptomatic carriers without lesions. These infections of the newborn result in viremia and disseminated infection of the brain, liver, adrenals, and lungs.

Newborns of mothers with antibody titers are protected by placentally transferred antibodies during the first 6 months of life. After 6 months of age, the incidence of primary HSV1 infection increases. The incidence of primary HSV1 infection reaches a peak between 2 and 3 years of age. Incidence of primary HSV2 infection does not increase until the age when sexual activity begins. Studies of neutralizing and complement-fixing antibodies to HSV have shown a continual rise in the percentage of patients who have had contact with the virus until 60 years of age, demonstrating that although the primary infection with HSV1 is chiefly a disease of infants and children, new cases continue to appear during adult life. This is consistent with the many reports of adults with primary herpetic gingivostomatitis.

The incidence of primary herpes infection has been shown to vary according to socioeconomic group. In lower socioeconomic groups, 70 to 80% of the population have detectable antibodies to HSV by the second decade of life, indicating prior HSV infection, whereas, in a group of middle class individuals, only 20 to 40% of the patients in the same age group have evidence of contact with HSV.

A significant percentage of cases of primary herpes are subclinical, although the apparently low incidence of a history of classic primary herpetic gingivostomatitis is also influenced by the young age of patients who develop the infection, by the improper diagnosis of some cases, and by the cases of primary herpetic pharyngitis that cannot be clinically distinguished from other causes of viral pharyngitis.

CLINICAL MANIFESTATIONS OF PRIMARY ORAL HERPES

The patient usually presents to the clinician with full-blown oral and systemic disease, but a history of the mode of onset is helpful in differentiating lesions of primary HSV infection from other acute multiple lesions of the oral mucosa. The incubation period is most commonly 5 to 7 days but may range from 2 to 12 days. Patients with primary oral herpes have a history of generalized prodromal symptoms that precede the local lesions by 1 or 2 days. This information is helpful in differentiating this viral infection from allergic stomatitis or erythema multiforme, in which local lesions and systemic symptoms appear together. These generalized symptoms include fever, headache, malaise, nausea, and vomiting. A negative past history of recurrent herpes labialis and a positive history of direct intimate contact with a patient with primary or recurrent herpes are also helpful in making the diagnosis.

Approximately 1 or 2 days after the prodromal symptoms occur, small vesicles appear on the oral mucosa; these are thin-walled vesicles surrounded by an inflammatory base. The vesicles quickly rupture, leaving shallow round discrete ulcers. The lesions occur on all portions of the mucosa. As the disease progresses, several lesions may coalesce, forming larger irregular lesions.

A 12-year-old female with primary herpetic gingivostomatis causing discrete vesicles and ulcers surrounded by inflammation

An  important diagnostic criterion in this disease is the appearance of generalized acute marginal gingivitis. The entire gingiva is edematous and inflamed. Several small gingival ulcers are often present. Examination of the posterior pharynx reveals inflammation, and the submandibular and cervical lymph nodes are characteristically enlarged and tender. On occasion, primary HSV may cause lesions of the labial and facial skin without intra-oral lesions.

      Acute marginal gingivitis characteristic of primary HSV infection. A, mandibular anterior gingiva; B,  vesicles and inflammation around mandibular molars

Primary HSV in otherwise healthy children is a self-limiting disease. The fever ordinarily disappears within 3 or 4 days, and the lesions begin healing in a week to 10 days, although HSV may continue to be present in the saliva for up to a month after the onset of disease.

LABORATORY DIAGNOSIS

The diagnosis of primary herpetic gingivostomatitis is straight-forward when patients present with a typical clinical picture of generalized symptoms followed by an eruption of oral vesicles, round shallow symmetric oral ulcers, and acute marginal gingivitis. Laboratory tests are rarely required in these cases. Other patients, especially adults, may have a less typical clinical picture, making the diagnosis more difficult. This is especially important when distinguishing primary herpes from erythema multiforme since proper therapy differs significantly.

The following laboratory tests are helpful in the diagnosis of a primary herpes infection.

Cytology

 For cytology, a fresh vesicle can be opened and a scraping made from the base of the lesion and placed on a microscope slide. The slide may be stained with Giemsa, Wright’s, or Papanicolaou’s stain and searched for multinucleated giant cells, syncytium, and ballooning  degeneration of the nucleus. Fluorescent staining of cytology smears has been shown to be more sensitive (83%) compared with routine cytology (54%); it is the cytologic test of choice, when available.

                  Cytology smear stained with Giemsa, demonstrating multinucleated giant cells

HSV Isolation

Isolation and neutralization of a virus in tissue culture is the most positive method of identification and has a specificity and sensitivity of 100%. A clinician must remember that isolation of HSV from oral lesions does not necessarily mean that HSV caused the lesions. Patients who have lesions from other causes may also be asymptomatic shedders of HSV.

Antibody Titers

Conclusive evidence of a primary HSV infection includes testing for complement-fixing or neutralizing antibody in acute and convalescent sera. However, it is rarely necessary in routine clinical situations and is often not helpful since the results are not available until the infection is gone. In special circumstances, such as immunocompromised patients, an acute serum specimen should be obtained within 3 or 4 days of the onset of symptoms. The absence of detectable antibodies plus the isolation of HSV from lesions is compatible with the presence of a primary HSV infection. Antibody to HSV will begin to appear in a week and reach a peak in 3 weeks. A convalescent serum can confirm the diagnosis of primary HSV infection by demonstrating at least a fourfold rise in anti-HSV antibody. If anti-HSV antibody titers are similar in both the acute and convalescent sera, then the lesions from which HSV was isolated were recurrent lesions.

TREATMENT

A significant advance in the management of herpes simplex infections was the discovery of acyclovir, which has no effect on normal cells but inhibits DNA replication in HSV-infected cells.  Acyclovir has been shown to be effective in the treatment of primary oral HSV in children when therapy was started in the first 72 hours. Acyclovir significantly decreased days of fever, pain, lesions, and viral shedding. Newer anti-herpes drugs are now available, including valacyclovir and famciclovir. The advantage of the newer drugs is increased bioavailability, allowing for effective treatment with fewer doses. Milder cases can be managed with supportive care only.

Routine supportive measures include aspirin or acetaminophen for fever and fluids to maintain proper hydration and electrolyte balance. If the patient has difficulty eating and drinking, a topical anesthetic may be administered prior to meals. Dyclonine hydrochloride 0.5% has been shown to be an excellent topical anesthetic for the oral mucosa. If this medication is not available, a solution of diphenhydramine hydrochloride 5 mg/mL mixed with an equal amount of milk of magnesia also has satisfactory topical anesthetic properties. Infants who are not drinking because of severe oral pain should be referred to a pediatrician for maintenance of proper fluid and electrolyte balance.

Antibiotics are of no help in the treatment of primary herpes infection, and use of corticosteroids is contraindicated. Future therapy may include prevention of the infection with use of a genetically disabled HSV vaccine.