Microbiology
- Enteroviruses are so named because of their ability to multiply in the GI tract, but they do not typically cause gastroenteritis.
- Enteroviruses are members of the family Picornaviridae and encompass >115 human serotypes: 3 serotypes of poliovirus, 21 serotypes of coxsackievirus A, 6 serotypes of coxsackievirus B, 28 serotypes of echovirus, enteroviruses 68-71, and multiple enteroviruses (beginning with enterovirus 73) recently identified by molecular techniques. In the United States, 58% of all enterovirus infections are caused by coxsackieviruses A6, A9, and B4; echoviruses 6, 11, 18, and 30; and human parechovirus 3.
Pathogenesis
- Studies of poliovirus infection form the basis of our understanding of enteroviral pathogenesis.
- After ingestion, poliovirus infects GI-tract mucosal epithelial cells, spreads to regional lymph nodes, causes viremia, and replicates in the reticuloendothelial system; in some cases, a second round of viremia occurs.
- Virus gains access to the CNS either via the bloodstream or via direct spread from neural pathways.
- Virus is present in blood for 3-5 days. It is shed from the oropharynx for up to 3 weeks and from the GI tract for up to 12 weeks after infection. Hypogammaglobulinemic pts can shed virus for >20 years.
- Infection is controlled by humoral and secretory immunity in the GI tract.
Epidemiology
- Enteroviruses cause disease worldwide, especially in areas with crowded conditions and poor hygiene.
- Infants and young children are most often infected and are the most frequent shedders.
- Transmission takes place mainly by the fecal-oral route, but airborne transmission and placental transmission have been described.
- The incubation period ranges from 2 to 14 days but usually is <1 week in duration. Pts are most infectious shortly before and after the onset of symptoms.
Clinical Manifestations
Poliovirus
After an incubation period of 3-6 days, ∼5% of pts present with a minor illness (abortive poliomyelitis) that is characterized by fever, malaise, sore throat, myalgias, and headache and that usually resolves within 3 days.
- Asymptomatic infection: >90% of all infections
- Aseptic meningitis (nonparalytic poliomyelitis): occurs in ∼1% of pts. Examination of CSF reveals normal glucose and protein concentrations and lymphocytic pleocytosis (with PMNs sometimes predominating early).
- Paralytic disease: the least common form, presenting ≥1 day after aseptic meningitis as severe back, neck, and muscle pain as well as gradually developing motor weakness
- The weakness is usually asymmetric and proximal and is most common in the legs. The arms and the abdominal, thoracic, and bulbar muscles are also frequently involved.
- Paralysis generally occurs only during the febrile phase.
- Physical examination reveals weakness, fasciculations, decreased muscle tone, and reduced or absent reflexes in affected areas; hyperreflexia may precede the loss of reflexes. Bulbar paralysis is associated with dysphagia, difficulty handling secretions, or dysphonia.
- Respiratory insufficiency due to aspiration or neurologic involvement may develop. Severe medullary infection may lead to circulatory collapse.
- Most pts recover some function, but around two-thirds have residual neurologic sequelae.
- Vaccine-associated poliomyelitis: The risk of acquiring poliomyelitis after vaccination with the live oral vaccine is estimated to be 1 case per 2.5 million doses and is ∼2000 times higher among immunodeficient persons, especially pts with hypo- or agammaglobulinemia.
- Postpolio syndrome: new weakness 20-40 years after poliomyelitis. Onset is insidious, progression is slow, and plateau periods can last 1-10 years.
Other Enteroviruses
In the United States, 5-10 million cases of symptomatic enteroviral disease other than poliomyelitis occur each year. More than 50% of nonpoliovirus enterovirus infections are subclinical.
- Nonspecific febrile illness (summer grippe): Pts present with acute-onset fever, malaise, and headache, with occasional upper respiratory symptoms.
- Disease resolves within a week.
- Disease frequently occurs during the summer and early fall.
- Generalized disease of the newborn: Neonates, typically within the first week of life, present with an illness resembling bacterial sepsis, with fever, irritability, and lethargy.
- Myocarditis, hypotension, hepatitis, DIC, meningitis, and pneumonia are complications.
- A history of a recent flu-like illness in the mother should prompt consideration of this disease.
- Aseptic meningitis and encephalitis: Enteroviruses cause 90% of cases of aseptic meningitis among children and young adults in which an etiologic agent can be identified; 10-35% of viral encephalitis cases are due to enteroviruses.
- Pts have an acute onset of fever, chills, headache, photophobia, nausea, and vomiting, with meningismus on examination. Diarrhea, rashes, myalgias, pleurodynia, myocarditis, and herpangina may occur. Encephalitis is much less common and is usually mild, with an excellent prognosis in healthy hosts.
- CSF examination reveals pleocytosis, with PMNs sometimes predominating early but a shift to lymphocyte predominance within 24 h. Total cell counts usually do not exceed 1000/µL. CSF glucose and protein levels are typically normal.
- Symptoms resolve within 1 week, but CSF abnormalities persist longer.
- Pleurodynia (Bornholm disease): Pts have an acute onset of fever associated with spasms of pleuritic chest pain (more common among adults) or upper abdominal pain (more common among children) that typically last 15-30 min. Fever subsides when pain resolves.
- Coxsackievirus B is the most common cause.
- Disease lasts for a few days and can be treated with NSAIDs and heat application to the affected muscles.
- Myocarditis and pericarditis: Enteroviruses (e.g., coxsackievirus B) cause up to one-third of cases of acute myocarditis. Pts have upper respiratory symptoms followed by fever, chest pain, dyspnea, arrhythmias, and occasionally heart failure.
- Disease occurs most often in newborns (who are most severely ill), adolescents, and young adults.
- A pericardial friction rub, ST-segment and T-wave abnormalities on electrocardiography, and elevated serum levels of myocardial enzymes can be present.
- Up to 10% of pts develop chronic dilated cardiomyopathy.
- Exanthems: Enterovirus infection is the leading cause of exanthems among children in the summer and fall. Echoviruses 9 and 16 are common causes.
- Hand-foot-and-mouth disease: generally due to coxsackievirus A16 and enterovirus 71. Pts present with fever, anorexia, and malaise, which are followed by sore throat and vesicles on the buccal mucosa, tongue, and dorsum or palms of the hands and occasionally on the palate, uvula, tonsillar pillars, or feet.
- The disease is highly infectious, with attack rates of almost 100% among young children. Symptoms resolve within a week.
- Epidemics of enterovirus 71 infection occurred in Taiwan in 1998 and have occurred annually in China since 2008, with hundreds of thousands of cases and hundreds of deaths each year. These epidemics were associated with CNS disease (e.g., brain-stem encephalitis, seizures), myocarditis, and pulmonary hemorrhage. Deaths occurred primarily among children ≤5 years old.
- Herpangina: usually caused by coxsackievirus A infection. Pts develop fever, sore throat, odynophagia, and grayish-white papulovesicular lesions on an erythematous base that ulcerate and are concentrated in the posterior portion of the mouth.
- Lesions can persist for weeks.
- In contrast to herpes simplex stomatitis, enteroviral herpangina is not associated with gingivitis.
- Acute hemorrhagic conjunctivitis: associated with enterovirus 70 and coxsackievirus A24. Pts experience an acute onset of severe eye pain, blurred vision, photophobia, and watery eye discharge; edema, chemosis, and subconjunctival hemorrhage are evident. Symptoms resolve within 10 days.
Diagnosis
- Enterovirus can be isolated from throat or rectal swabs, stool, and/or normally sterile body fluids.
- Positive results for normally sterile body fluids, such as CSF and serum, reflect disease.
- In contrast, positive stool and throat cultures may simply reflect colonization.
- In general, serotyping is not clinically useful outside of epidemiologic studies.
- PCR detects all serotypes that infect humans, with high sensitivity (70-100%) and specificity (>80%).
- PCR of CSF is less likely to be positive if pts present ≥3 days after meningitis onset or with enterovirus 71 infection.
- PCR of serum is also useful in disseminated disease.
TREATMENT |
Enterovirus Infections
- Most enteroviral illness resolves spontaneously, but immunoglobulin may be helpful in pts with γ; globulin defects and chronic infection.
- Glucocorticoids are contraindicated.
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Prevention and Eradication
- Hand hygiene, use of gowns and gloves, and enteric precautions (for 7 days after disease onset) prevent nosocomial transmission of enteroviruses during epidemics.
- The availability of poliovirus vaccines and the implementation of polio eradication programs have largely eliminated disease due to wild-type poliovirus; in 2016, there were 37 cases of wild-type polio, all of which occurred in Nigeria, Pakistan, and Afghanistan-the only countries where polio remains endemic. Wild-type poliovirus types 2 and 3 are no longer circulating anywhere in the world. Outbreaks and sporadic disease due to vaccine-derived poliovirus occur.
- Both oral poliovirus vaccine (OPV) and inactivated poliovirus vaccine (IPV) induce IgG and IgA antibodies that persist for at least 5 years.
- Most developing countries, particularly those with persistent wild-type poliomyelitis, use OPV because of its lower cost and ease of administration. The suboptimal seroconversion rate among children in low-income countries, even after multiple OPV doses, contributes to difficulties in eradication.
- Most industrialized countries have adopted all-IPV childhood vaccination programs.
- Unvaccinated adults in the United States do not need routine poliovirus vaccination but should receive three doses of IPV (the second dose 1-2 months after the first and the final dose 6-12 months later) if they are traveling to polio-endemic areas or might be exposed to wild-type poliovirus in their communities or workplaces.
- Adults at increased risk of exposure who have received their primary vaccination series should receive a single dose of IPV.