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Aseptic Meningitis and Other Enterovirus Infections 

Enteroviruses (polioviruses, coxsackieviruses, echoviruses) are among the most common and significant causes of infectious illness in infants and children. They are associated with a broad spectrum of clinical syndromes, including aseptic meningitis, herpangina, hand-foot-mouth disease, conjunctivitis, pleurodynia, myopericarditis, poliomyelitis, various exanthems, and nonspecific febrile illness. In the neonate, enteroviral infection can cause a sepsis-like picture or meningoencephalitis, either of which can be severe. Newer technologies such as polymerase chain reaction (PCR) may provide rapid and sensitive testing methods for diagnosis of enteroviral infections, which may expand the list of diseases attributable to this group of pathogens. Although treatment of enteroviral infections remains unsatisfactory, immunization against poliovirus has been remarkably successful, and new immunization regimens using live and killed virus vaccines have been developed. A role has been postulated for enteroviruses in the pathogenesis of asepic, mengitis

Characteristics of Enteroviruses

The enteroviruses are a subgroup of single-stranded RNA, non-enveloped viruses belonging to the Picornaviradae family (pico=small, RNA=ribonucleic acid). They include the polioviruses, coxsackie-viruses, echoviruses (echo=enteric cytopathogenic human orphan), and unclassified

Epidemiology

Enteroviruses are commonly referred to as "summer viruses" because resulting infections occur primarily during the warmer, summer months (May through October) in temperate northern

TABLE 1 -- Human Enteroviruses
GROUP SEROTYPES
Poliovirus 1-3
Coxsackievirus group A 1-22, 24
Coxsackievirus group B 1-6
Echovirus 1-9, 11-27, 29-33
Enterovirus 68-72 *
*Hepatitis A virus was enterovirus type 72, but recently has been reclassified as a Heparnavirus.


The fecal-oral route is the most common mode of transmission, but oral-oral and respiratory spread also are possible. Risk factors for infection include poor sanitation, crowded living conditions, and low

Pathogenesis

The incubation period for most enteroviral infections ranges from 3 to 10 days. The virus enters the host via the oral cavity and/or respiratory tract, then invades and replicates in the upper respiratory tract and small intestine, with a predilection for lymphoid tissues in these regions (Peyer patches,

Clinical Presentations of Infection With Nonpolio Enteroviruses

Nonpolio enteroviruses are estimated to cause 10 to 15 million symptomatic infections in the United States annually. They cause a wide spectrum of disease that can involve almost any organ system (Table 3) . Disease severity can range from life-threatening with significant morbidity to mild or

NONSPECIFIC FEBRILE ILLNESS

The most common clinical presentation of nonpolio enterovirus infection is a nonspecific febrile illness. Typically, fever develops suddenly, without a prodrome, and temperatures range from 38.5 to 40C (101 to 104F) and last for an average of 3 days. Occasionally, a biphasic pattern of symptoms can

ASEPTIC MENINGITIS

Nonpolio enteroviruses are the leading causes of aseptic meningitis, accounting for 80% to 90% of all cases from which an etiologic agent is identified. The most common enterovirus types associated with

TABLE 3 -- Clinical Syndromes and Associated Enteroviruses
SYNDROME PREDOMINANT VIRUS CLINICAL FEATURES
Nonspecific febrile illness All types Febrile illness (occasionally biphasic), with non-specific upper respiratory and gastrointestinal tract symptoms
Aseptic meningitis Echovirus and group B coxsackieviruses Fever, meningeal signs with mild cerebrospinal (CSF) pleocytosis, usually normal CSF glucose and protein, and absence of bacteria
Herpangina Group A coxsackieviruses Fever, painful oral vesicles on tonsils and posterior pharynx
Hand-foot-mouth disease Coxsackievirus A16 Fever, vesicles on buccal mucosa and tongue and on interdigital surfaces of hands and feet
Nonspecific exanthem Echoviruses Variable rash (usually rubelliform but may be petechial or vesicular), +/- fever
Pleurodynia Coxsackievirus B3, B5 Uncommon, epidemic, fever, and severe muscle pain of chest and abdomen
Carditis Group B coxsackievirus Uncommon, myocarditis/pericarditis, which can present with heart failure or dysrhythmia
Acute hemorrhagic conjunctivitis Enterovirus 70 Epidemic cause of conjunctivitis with lid swelling, subconjunctival hemorrhage, and eye pain without systemic symptoms
Neonatal disease Group B coxsackieviruses and echoviruses Sepsis-like picture, meningoencephalitis, hepatitis, myocarditis

photophobia, with 50% of children older than 1 to 2 years of age also developing nuchal rigidity. Approximately one third of these older children will have a positive Kernig and/or Brudzinski sign.

HERPANGINA

Herpangina is an enanthemous (mucous membrane) disease characterized by a painful vesicular eruption of the oral mucosa associated with fever, sore throat, and pain on swallowing. It is seen most commonly in children ages 3 to 10 years. Group A coxsackieviruses are the most common etiologic agents, but group B coxsackie-viruses and echoviruses also have been isolated from patients.

Lymphonodular pharyngitis, a variant of herpangina, presents similarly but differs in the appearance of the oral lesions, which are tiny, firm, white nodules (packed with lymphocytes) in the same distribution.

The differential diagnosis for herpangina is discussed in the next section.

HAND-FOOT-MOUTH (HFM) DISEASE

HFM disease is characterized clinically by a vesicular eruption on the hands and feet and in the oral cavity. Toddlers and school-age children are affected most commonly. Coxsackie-virus A16 is the primary etiologic agent, but other enteroviruses have been implicated as well.

The differential diagnosis for hand-foot-mouth disease includes infection by herpes simplex or varicella-zoster virus, herpangina, and aphthous stomatitis. In contrast to HFM, varicella lesions are located more centrally, are more extensive, and usually spare the palms and soles. Additionally, resolution of varicella lesions involves crusting, whereas HFM vesicles resolve by resorption of fluid. In herpetic gingivostomatitis, patients usually appear more ill, may have gingival erythema or bleeding, present with higher temperatures, and exhibit significant cervical lymphadenopathy and lesions confined to the oral cavity without extremity involvement. These findings may help distinguish herpetic stomatitis from HFM. Herpangina also may resemble HFM, but the herpangina oral lesions usually are located in the posterior aspects of the pharynx; the extremities are spared. Aphthous stomatitis is

NONSPECIFIC EXANTHEM

Nonpolio enteroviruses are the leading cause of exanthems in children during the summer and fall months. The most common serotype causing exanthem is echovirus 9. The classic enteroviral exanthem consists of a pink, macular, blanching, rubelliform rash. Unlike rubella, this rash usually is

ADDITIONAL CLINICAL MANIFESTATIONS

Nonpolio enterovirus can cause a wide range of symptoms that are clinically indistinguishable from those of other viral syndromes. These include upper or lower respiratory tract infections, arthritis,

Other Relevant Syndromes

Several illnesses, although relatively uncommon, are classically associated with enteroviral infection.

PLEURODYNIA (BORNHOLM DISEASE)

Pleurodynia or epidemic myalgia is characterized by an acute onset of severe muscular pain in the chest and abdomen accompanied by fever. Coxsackieviruses B3 and B5 are the major causes of

MYOCARDITIS/PERICARDITIS

Enteroviral myocarditis and/or pericarditis is associated with group B coxsackievirus (B5 most commonly) in up to 50% of cases. Patients present with fatigue, dyspnea on exertion, or more

ACUTE HEMORRHAGIC CONJUNCTIVITIS (AHC)

This explosive epidemic conjunctivitis, first described in 1969 in Africa and Asia, is now found worldwide. It is more common in tropical and densely populated regions. The majority of outbreaks have been caused by enterovirus serotype 70, but recently coxsackievirus A24 has been isolated

Neonatal Disease

Neonates infected with nonpolio enteroviruses are at high risk for developing significant illness, including a sepsis-like condition, meningoencephalitis, myocarditis, and/or hepatitis. Echoviruses and group B coxsackieviruses account for the majority of neonatal entero-virus infections. Infection is

Infants younger than 10 days of age are at higher risk for severe enterovirus infections because of their relative inability to mount a significant immune response.

Infection occurs in 20% to 50% of infants in whom there is a maternal history of illness in the week preceding delivery. The severity of the neonatal illness is related to the severity of maternal illness at the time of delivery as well as to the age of the infant at onset of infection. Infants younger than 10

Clinical Manifestations of Infection With Poliovirus

Most infections caused by poliovirus are asymptomatic or subclinical; only about 1% become clinically apparent. Of the three serotypes of poliovirus, type 1 causes the majority of epidemics.

Emerging Roles Of Enteroviruses

The role of enteroviruses, specifically group B coxsackieviruses, in the pathogenesis of type 1 diabetes mellitus has been studied extensively. A growing amount of epidemiologic and experimental research suggests a strong association. For example, new-onset type 1 diabetes mellitus occurs in clusters, with a seasonal pattern that peaks 1 to 2 months after the enteroviral season.

Diagnosis

Enteroviral infection usually is diagnosed clinically without isolation and identification of the specific virus. Factors that aid in diagnosis include seasonality, knowledge of exposure, and characteristic

Treatment

No effective antiviral therapy currently is available for enteroviral infections; treatment is symptomatic and supportive. Corticosteroids have been of some benefit in the treatment of myocarditis, but their use is generally not recommended because administration in experimental animal models has had

Prophylaxis

The only enterovirus for which a vaccine is available is poliovirus. Use of poliovirus vaccines has eradicated polio from the Western Hemisphere and dramatically decreased the incidence worldwide. The first poliovirus vaccine, developed by Salk in 1955, was an inactivated poliovirus vaccine (IPV).

After its introduction, OPV was adopted rapidly worldwide as the vaccine of choice. Its advantages over IPV include ease of administration, secondary immunization of vaccinee contacts, and stimulation of local immunity in the gastrointestinal tract. Because the pathogenesis of polio infection depends on intestinal entry, high levels of neutralizing antibodies locally (ie, in intestinal mucosa) are optimal for

OPV in developing countries is less immunogenic, as measured by seroconversion rates. Several factors are probably responsible for this phenomenon, including inadequate refrigeration of the vaccine, poor nutrition among recipients, and coinfection of the gastrointestinal tract with other enteroviruses, all of which may cause diminished immunogenicity.

The primary risk associated with OPV administration is development of vaccine-associated paralytic poliomyelitis (VAPP). The last case of wild-type poliomyelitis in the United States was seen in 1979. Since then, there have been 8 to 10 cases per year of paralytic poliomyelitis, all attributed to the live