Harrisons Manual of Medicine, 18th Ed.

CHAPTER 112. Enteroviral Infections

MICROBIOLOGY

• Enteroviruses are so named because of their ability to multiply in the GI tract, but they do not typically cause gastroenteritis.

• Enteroviruses encompass 96 human serotypes: 3 serotypes of poliovirus, 21 serotypes of coxsackievirus A, 6 serotypes of coxsackievirus B, 28 serotypes of echovirus, enteroviruses 68–71, and 34 new enteroviruses (beginning with enterovirus 73) that have been identified by molecular techniques. In the United States, coxsackievirus B1 and echoviruses 18, 9, and 6 account for ~50% of all enteroviral infections.

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 up to 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) characterized by fever, malaise, sore throat, myalgias, and headache 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; presents ≥1 day after aseptic meningitis as severe back, neck, and muscle pain as well as a gradual development of 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 other frequently involved sites.

– Paralysis generally occurs only during the febrile phase.

– Physical examination reveals weakness, fasciculations, decreased muscle tone, and reduced or absent reflexes in affected areas; hyper-reflexia 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.

• 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 enteroviral 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 cases of viral encephalitis 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: Enteroviral 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.

– A Taiwan epidemic of enterovirus 71 infection in 1998 was associated with CNS disease, 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.

– However, stool and throat cultures may simply reflect colonization.

• In general, serotyping is not clinically useful.

• 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 Enteroviral Infections

• Most enteroviral illness resolves spontaneously, but immunoglobulin may be helpful in pts with γ globulin defects and chronic infection.

• Glucocorticoids are contraindicated.

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; of 1781 cases in 2009, ~80% were from Nigeria, India, Pakistan, and Afghanistan. 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 doses of OPV, 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 polio-virus 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.

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For a more detailed discussion, see Cohen JI: Enteroviruses and Reoviruses, Chap. 191, p. 1593, in HPIM-18.