1. What isolation should the patient be put in?

Patients should be put in enteric isolation. Enteroviruses are transmitted mostly by the fecal-oral route, but some serotypes may be spread by respiratory secretions or fomites.

2. What is known about the pathogenesis of the infection?

Differences in pathogenesis for the enteroviruses mainly result from differences in tissue tropism and cytolytic capacity of the virus.

The upper respiratory tract, the oropharynx, and the intestinal tract are the portals of entry for the enteroviruses. The virions are impervious to stomach acid, proteases, and bile. The virus initiates replication in the mucosa and lymphoid tissue of the tonsils and pharynx and later infects lymphoid cells of Peyer's patches underlying the intestinal mucosa. Primary viremia spreads the virus to receptor-bearing target tissues, where a second phase of viral replication may occur, resulting in symptoms and a secondary viremia. Virus shedding from the oropharynx can be detected for a short time before symptoms begin, whereas virus production and shedding from the intestine may last for 30 days or longer, even in the presence of a humoral immune response.

Coxsackieviruses and echoviruses recognize receptors expressed on many cell types and tissues and cause a broad repertoire of disease. These and other enteroviruses recognize receptors on cells of the central nervous system, heart, lung, pancreas, and other tissues.

Most enteroviruses are cytolytic, replicating rapidly and causing direct damage to the target cell.

Antibody is the major protective immune response to the enteroviruses. Secretory antibody can prevent the initial establishment of infection in the oropharynx and gastrointestinal tract, and serum antibody prevents viremic spread to the target tissue and therefore disease. Serum antibody is generally observed 7 to 10 days after infection.

Figure 1. Pathogenesis of enteroviruses. The target tissue infected by the enterovirus determines the predominant disease caused by the virus.

3. How is the viral infection detected?

The finding of >5 white blood cells/mm3 of CSF is abnormal and is indicative of meningitis. The patient was treated for bacterial meningitis because of the predominance of neutrophils in the CSF. Early in the course of viral meningitis (the first 24 to 48 h), neutrophils can be predominant. However, mononuclear cells are predominant later in the disease. The normal CSF glucose level also argues against bacterial meningitis. Finally, a positive CSF viral culture confirms the diagnosis of viral meningitis.

4. Why was there a neutrophil predominance on the LP?

Neutrophil is a common finding in early viral meningitis, but as indicated above, mononuclear cells predominate later in the disease.

5. What is the appropriate treatment for this viral infection?

The management of patients with enteroviral infections includes supportive care. Infection control measures are recommended for patients and their families to interrupt transmission of virus to others who may be susceptible. These include handwashing. This is of particular importance in day-care centers, where agents that are spread by the fecal-oral route are of particular concern.

A new drug that inhibits the uncoating of picornavirus particles is being evaluated in clinical trials. Pleconaril binds reversibly to a hydrophobic pocket in the outer coat protein (VPI) of picornaviruses. Binding in this site prevents uncoating of the virion RNA following attachment and penetration of the cell membrane. Inhibiting this step prevents replication of the RNA and production of progeny virions. The compound has undergone extensive in vitro sensitivity testing against over 215 clinical isolates of enterovirus strains known to cause serious human disease; over 90% of the 100 known rhinovirus serotypes at a concentration of 1 ug/ml. Pleconaril was protective in several mortality studies conducted in weanling, suckling and adult mice infected with several different strains of coxsackievirus.

Clinical Studies

Pleconaril has been studied in over 700 human adult and pediatric volunteers and patients in 17 completed clinical studies to date, as well as in six ongoing placebo controlled trials of the clinical trials conducted to date, pleconaril has been very well tolerated, with an aggregate side effect profile similar to placebo.

Phase I

Pleconaril exhibits dose-dependent linear pharmacokinetics resulting in plasma levels at pharmacodynamic steady state that are in excess of levels required to inhibit viral replication of rhinoviruses and enteroviruses. Pediatric pharmacokinetics are similar to that of adults, requiring no dosage adjustment for children. Neonatal pharmacokinetic studies are currently underway.

Viral Meningitis

In a placebo controlled adult enteroviral meningitis study, pleconaril treatment resulted in a statistically significant shortening of disease duration (54% reduction, 11 vs. 5 days; p = 0.0005) the primary endpoint of the study. Elements of the primary endpoint included clinically important symptoms of viral meningitis such as a reduction in severe incapacitating headache, which usually leads to hospitalization. Pleconaril was statistically superior to placebo in the secondary endpoints of the time to complete absence of headache (50% reduction, 14 vs. 7 days; p = 0.014), duration of analgesic use (50% reduction, 12 vs. 6 days; p = trends favoring pleconaril were also observed in other secondary endpoints, including a reduction in the time to return to work and a reduction in the time return to full levels of leisure activity.

Viral Respiratory Infections

Pleconaril demonstrated pronounced and clinically significant reductions in respiratory and systemic symptoms resulting from the intranasal administration of a safety-tested strain of coxsackievirus A-21 in health volunteers when compared to placebo. Clinical studies are currently underway in vial respiratory disease in odds media prone children, patients with asthma, and otherwise normal subjects.

Pharmaceutics

Pleconaril is supplied as a cherry-peppermint flavored oral liquid containing pleconaril at a concentration of 40 milligrams per milliliter in medium chain triglycerides (Miglyol 810) 2 % surfactants (Tween 80 and Arlacel) as well as 0.15% saccharin. This formulation is palatable when taken by children and adults. A tablet dosage form has been developed for the adult market.

6. Would this infection be likely to occur in February?

No. Enterovirus meningitis outbreaks generally occur in the late summer and early fall.