Viral Infections of the Mouth (cont 3)

Coxsackievirus

Background

The coxsackieviruses belong to the Picornaviridae family and, more specifically, to the Enterovirus genus. Enteroviruses are further divided into 4 subgroups: polioviruses, group A coxsackieviruses, group B coxsackieviruses, and echoviruses. Group A coxsackieviruses comprise 23 serotypes, and group B coxsackieviruses comprise 6 serotypes.

Coxsackieviruses cause 3 conditions that can manifest in the oral cavity: hand-foot-and-mouth disease, herpangina, and acute lymphonodular pharyngitis. Hand-foot-and-mouth disease is usually caused by coxsackievirus A16 and, less commonly, by types A5, A7, A10, B2, and B5 and Enterovirus 71 (EV-71). EV-71 outbreaks are often associated with more serious manifestations, including meningitis. Herpangina outbreaks and individual cases are mainly associated with coxsackieviruses A1-6, A8, A10, and A22. Acute lymphonodular pharyngitis is associated with the A10 subgroup.

Pathophysiology

Enteroviruses infect humans mainly via the fecal-oral route. Spread of the disease can also occur via direct contact with nasal and throat secretions from individuals who are infected.

The virus attaches and replicates in susceptible areas of the pharynx or in the distal part of the GI tract. After multiplying in the submucosal lymphoid tissues, enteroviruses move to the regional lymph nodes (cervical and mesenteric) and produce a minor viremia that is transient and undetectable. Most infections are subclinical, and viral replication stops or is halted by host defense mechanisms. Oral and cutaneous lesions result from secondary infection of the small blood vessels during the viremia stage. The incubation period is 2 days to 2 weeks but is generally 3-5 days. A patient who is infected sheds the virus several days before symptoms appear and can continue to excrete the virus several weeks after the illness.

Frequency

Hand-foot-and-mouth disease

In the United States, most cases (individual and outbreaks) occur in the summer and early fall.

Internationally, major outbreaks of hand-foot-and-mouth disease related to EV-71 occurred in Malaysia in 1997³⁷ and in Taiwan in 1998.

Herpangina and acute lymphonodular pharyngitis

In the United States, illness usually occurs as summer outbreaks, peaking between August and October. Infections occur with higher frequency in younger age groups, in people who live in crowded areas, and in people who are economically disadvantaged. Under these conditions, the rate of infection with 1 or more enteroviruses can be more than 50%.

Mortality/morbidity

Oral symptoms, such as mild pharyngitis and erythema of the oral mucosa, occur with hand-foot-and-mouth disease, herpangina, and acute lymphonodular pharyngitis. In hand-foot-and-mouth disease, an accompanying rash also occurs. Other than the oral discomfort and general malaise that accompany herpangina, acute lymphonodular disease, and most forms of hand-foot-and-mouth disease, mortality and morbidity rates are low.

Hand-foot-and-mouth disease caused by EV-71 is often accompanied by more life-threatening manifestations, such as respiratory distress and aseptic meningitis.

A major outbreak of hand-foot-and-mouth disease was reported in Taiwan in 1998; this outbreak resulted in a number of deaths. The etiologic agent implicated was EV-71, which is 1 of 2 possible agents implicated in hand-foot-and-mouth disease. Most patients who were hospitalized developed rapid cardiopulmonary failure and died soon afterward. This event is the third known EV-71 outbreak leading to rapid deterioration and death in children. Previous outbreaks in young children occurred in Bulgaria in 1975 and in Malaysia from April through June in 1997.³⁷

Race

No racial predilection is reported.

Sex

No sexual predilection is apparent.

Age

Hand-foot-and-mouth disease most often occurs in children younger than 5 years. Herpangina most frequently occurs in children aged 3-10 years. Acute lymphonodular pharyngitis also most frequently occurs in children.

Clinical history

Hand-foot-and-mouth disease

After an incubation period of 3-6 days, a mild fever usually occurs, accompanied by malaise, anorexia, and a sore mouth. Oral vesicular lesions usually follow after 1-2 days. Skin lesions follow oral lesions in approximately 75% of children who are infected, whereas only 10% of adults who are infected present with a cutaneous rash. The infection usually lasts 5-8 days. Oral lesions generally occur in groups of 5-10 vesicles that soon rupture and often coalesce, resulting in shallow ulcerations surrounded by erythematous halos. Involved sites include the anterior buccal mucosa, the tongue, and the soft palate.

Accompanying skin lesions occur on the dorsal or lateral aspects of the hands and feet and on the fingers and toes. Skin lesions are approximately 3-7 mm in diameter and consist of a mixture of papules and clear vesicles with a surrounding zone of erythema.

Herpangina

In herpangina, the sudden onset of infection is characterized by fever, sore throat, and painful swallowing. These symptoms manifest several hours to a day prior to the appearance of vesicular lesions on the posterior aspect of the pharynx. Other symptoms include headache, anorexia, vomiting, and abdominal pain. The fever usually subsides in 2-4 days, but ulcers may be present for as long as 1 week. Most cases of herpangina are mild and resolve spontaneously.

The oral lesions begin as punctate macules that evolve over a 24-hour period into 2- to 4-mm erythematous papules. Vesicular change and central ulceration follow, with the development of peripheral zones of erythema. The lesions usually occur in groups of 2-6 and are moderately painful. They occur on the soft palate, usually between the tonsils and the uvula. The lesions are less frequently observed on the tonsils, on the posterior aspect of the pharyngeal wall, or on the buccal mucosa.

Acute lymphonodular pharyngitis

Acute lymphonodular pharyngitis is considered a variant of herpangina. The pattern of distribution of oral lesions is similar to that observed in herpangina. The main difference is that in acute lymphonodular pharyngitis, the pharyngeal lesions remain papular without progression to vesicles and ulcers.

Differentials

Hand-foot-and-mouth disease

Aphthous Stomatitis

Herpetiform ulcers

Primary and secondary herpetic stomatitis

Herpangina

Herpangina

Primary herpetic gingivostomatitis

Acute herpetic pharyngotonsillitis

Aphthous Stomatitis

Herpetiform stomatitis

Gonococcal pharyngitis

Erythema Multiforme

Bacterial tonsillitis

Viral pharyngitis

Acute lymphonodular pharyngitis

Viral pharyngitis

Erythema Multiforme

Workup

Laboratory studies

The diagnosis for each of the 3 entities can usually be established based on the clinical symptoms. However, if laboratory confirmation is necessary, viral isolation via cell culturing, polymerase chain reaction, or serologic testing can be used. Cell culturing is the most widely used method for confirming the diagnosis.

Genomic sequencing of the virus is likely to be used for confirmation in the future.

Procedures

Swabs can be taken from the oral lesions or from the stool samples submitted for viral testing.

Histologic findings

Initially, intracellular and intercellular edema occurs with formation of an intraepithelial vesicle. This progresses to reticular degeneration, followed by ulceration. A mixed lymphocytic and neutrophilic inflammatory cell infiltrate is often present.

Medical care

Medical care is not usually necessary. 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.

Medication

See Medication.