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Enteroviruses
Definition
The enteroviruses belong to the genus Enterovirus in the family Picornaviridae. With the advent of molecular virology, the more than 110 recognized strains are classified on the basis of phylogenetic analysis of the nucleic acid sequence of VP1, which is the major enteroviral capsid protein ( Table 349-1 ).
TABLE 349-1
CLASSIFICATION OF ENTEROVIRUSES
| SPECIES | SEROTYPES |
|---|---|
| Enterovirus A 25 (sero)types |
CV- A2-A8, A10, A12, A14, A16 EV- A71, A76, A89-A92, A114, A119-125 |
| Enterovirus B 63 (sero)types |
CV- A9 CV- B1-B6 E- 1-7, 9, 11-21, 24-27, 29-33 EV- B69, B73-B75, B79-B88, B93, B97, B98, B100, B101, B106, B107, B110-114 |
| Enterovirus C 23 (sero)types |
PV- 1-3 CV- A1, A11, A13, A17, A19-A22, A24 EV- C95, C96, C99, C102, C104, C105, C109, C113, C116-C118 |
| Enterovirus D 5 (sero)types |
EV- D68, D70, D94, D111, D120 |
The Pathogens
Enteroviruses are small (30 nm in diameter), nonenveloped, icosahedral-shaped viruses. The viral capsid is composed of four viral proteins (VP1 to VP4). The enteroviruses possess an approximately 7.4-kilobase positive-sense single-stranded RNA genome. The 5′ end of the genome is covalently linked to a small protein, VPg. The genome is organized into a long (about 740 nucleotides) 5′ nontranslated region that precedes a single continuous open reading frame measuring about 6.63 kilobases. The open reading frame, which is followed by a short 3′ nontranslated region and a terminal polyadenylate tail, yields a single large polyprotein that is post-translationally modified to produce four capsid proteins, seven nonstructural proteins, and several functional protein intermediates. The 5′ and 3′ nontranslated regions participate in replication of the viral genome. The 5′ nontranslated region of the enterovirus is essential for translation and contains determinants of neurovirulence in the polioviruses.
Epidemiology
Worldwide, an estimated 1 billion or more enteroviral infections occur annually. In the United States about 30 to 50 million annual infections result in approximately 10 to 15 million symptomatic cases, with enterovirus D68, echovirus 30, coxsackievirus A6, echovirus 18, coxsackievirus B3, echovirus 9, and enterovirus 11 accounting for approximately 80% of enteroviral infections.
Humans are the only known reservoir for enteroviruses. Enteroviral infections are seasonal, and the majority of infections occur during the summer and early autumn in temperate regions. For example, more than 80% of infections occur in the United States from June through October. However, winter outbreaks highlight their panseasonal occurrence. In tropical and subtropical regions, infections continue year-round, with an increased incidence during the rainy season.
Globally, the dominant circulating enterovirus serotypes may vary annually by geographic region. In the United States 7 serotypes accounted for nearly 80% of all isolates reported ( Table 349-2 ).
TABLE 349-2
THE 13 MOST COMMON ENTEROVIRUS SEROTYPES REPORTED BY NATIONAL ENTEROVIRAL SURVEILLANCE SYSTEM LABORATORIES TO THE CDC, 2009–2013
From Centers for Disease Control and Prevention (CDC). Enterovirus and parechovirus surveillance—United States, 20014-2016. MMWR Morb Mortal Wkly Rep . 2018;67:515-518.
| ENTEROVIRUS SEROTYPE | PERCENTAGE |
|---|---|
| Enterovirus D68 | 55.9 |
| Echovirus 30 | 5.8 |
| Coxsackievirus A6 | 5.5 |
| Echovirus 18 | 4.2 |
| Coxsackievirus B3 | 4.0 |
| Echovirus 9 | 2.4 |
| Echovirus 11 | 2.3 |
| Parechovirus A3 | 2.3 |
| Coxsackievirus B4 | 2.0 |
| Coxsackievirus B5 | 1.9 |
| Coxsackievirus B2 | 1.8 |
| Coxsackievirus A9 | 1.5 |
| Echovirus 6 | 1.5 |
| Total | 90.9 |
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has impacted enteroviral surveillance. Globally, reports of acute flaccid paralysis cases have decreased by 33%. This decrease is most likely due to multiple factors including a reluctance to seek medical care as result of fear of contagion and decreased active surveillance during this period.
More than 80% of infections occur in individuals younger than age 20 years, with the highest incidence in infants and children ages 4 years and younger. Nearly 45% of all infections occur in infants younger than 1 year. Among household members of infected children, clinical or serologic evidence of secondary infection can be seen in more than 50% of susceptible individuals. A male preponderance is noted in persons younger than age 20 years (male-to-female ratio of 1.4 : 1) but not in older individuals.
Localized enteroviral outbreaks have been reported in neonatal units, nurseries, daycare centers, schools, camps, sports teams, and military facilities. Community-wide outbreaks are common. Extensive regional outbreaks of EV-A71 have occurred in the Asia-Pacific region. Occasional pandemics, such as acute hemorrhagic conjunctivitis caused by EV-D70 and CV-A24, also have occurred.
Effective antipolio immunization programs have eradicated 2 of the 3 wild-type poliovirus serotypes (serotypes 2 and 3) worldwide. Cases of serotype 1 are now restricted to only Afghanistan and Pakistan, where it remains endemic.
The use of live attenuated poliovirus vaccines led to the problem of vaccine-derived polioviruses as a result of the excretion of neurorevertant vaccine (Sabin) strains from individuals who have primary humoral immunodeficiencies, but not secondary humoral or other immunodeficiencies, or as a result of natural recombination between Sabin strains and members of the Enterovirus C species. Vaccine-derived polioviruses that can circulate in the environment with evidence of person-to-person transmission have been termed circulating vaccine-derived polioviruses . A third group, designated ambiguous vaccine-derived polioviruses, are clinical isolates from individuals without known immunodeficiency or sewage isolates whose ultimate source is unknown. Similar to wild-type poliovirus, circulating vaccine-derived polioviruses can cause acute flaccid paralysis in unimmunized or incompletely immunized individuals and have caused multiple outbreaks worldwide.
To reduce the risk for poliomyelitis owing to vaccine-derived polioviruses, all use of trivalent oral polio vaccine ceased globally in April 2016 and was replaced with a bivalent oral vaccine that contains only types 1 and 3 attenuated polioviruses. A monovalent type 2 oral polio vaccine is available for immunization in response to outbreaks. In an attempt to decrease the number of circulating vaccine-derived poliovirus outbreaks due to type 2 vaccine, a novel type 2 oral polio vaccine with a substantially lower risk of neurovirulence reversion has been approved for use by the World Health Organization.
Pathobiology
The polioviruses and the majority of the nonpolio enteroviruses are transmitted through a fecal-oral route. Notable exceptions include CV-A21 and EV-D68, which are spread by the respiratory route, and EV-D70, which may spread by contaminated fomites or ocular and respiratory secretions. Evidence also supports transplacental transmission of the enteroviruses.
Ingestion of the enteroviruses results in infection of cells of the pharynx and, because the virus is acid resistant, the lower gastrointestinal tract. Initial viral replication, which is thought to occur in the mucosal tissues of the nasopharynx and intestinal tract (i.e., tonsils and Peyer patches), leads to seeding of the deep cervical and mesenteric lymph nodes. Further replication at these sites results in a minor viremia with seeding of multiple organs, including the liver, lungs, heart, and central nervous system (CNS). Viral replication at these sites causes many of the clinical manifestations of infection and is followed by a major viremia that may infect the CNS if it was spared during the initial viremia. The virus is cleared by type-specific neutralizing antibodies directed at the capsid proteins by day 7 to 10 after infection. Immunoglobulin (Ig)A antibodies appear in the respiratory and gastrointestinal tracts 2 to 4 weeks after infection.
The host humoral immune response is pivotal in the prevention and eradication of enteroviral infections. Congenital or acquired B-cell immunodeficiencies may result in chronic or prolonged infection. Experimental evidence suggests that the interferons are important in limiting the spread of poliovirus once infection has occurred. Natural killer cells and gamma or delta T cells may play roles in regulating the host T-cell response.
Histopathologic findings in patients who died of poliomyelitis reveal neuronal necrosis in association with mononuclear and polymorphonuclear infiltrates that are initially perivascular in distribution but are later found diffusely within the gray matter of the anterior horns of the spinal cord, the reticular formation of the hindbrain, the vestibular nuclei, and the roof nuclei of the cerebellum. In nonpolio enterovirus CNS infections in immunocompetent hosts, findings include edema of the meninges and cerebral parenchyma, with microscopic perivascular lymphocytic infiltration, increased numbers of oligodendrocytes, and focal areas of necrosis and hemorrhage. In cases of enteroviral myocarditis ( Chapter 47 ), a mononuclear cell inflammation is associated with widespread myocardial necrosis followed by fibrosis, which may be focal but results in myocardial damage.
Clinical Manifestations
The incubation period for enterovirus infections is generally 3 to 6 days, with a range of 2 days to 2 weeks. Depending on serotype and the age of the patient, as many as 90% of infected individuals may have subclinical infections. The enteroviruses are responsible for a wide array of clinical syndromes that affect nearly every organ system, and no enteroviral serotype is uniquely associated with a single disease or clinical syndrome ( Table 349-3 ).
TABLE 349-3
CLINICAL MANIFESTATIONS OF NONPOLIO ENTEROVIRUS INFECTIONS ∗
From Modlin JR. Enterovirus. Cecil Textbook of Medicine . 23rd ed. Philadelphia: WB Saunders; 2008, with minor changes.
| CLINICAL SYNDROME | GROUP A COXSACKIEVIRUSES † | GROUP B COXSACKIEVIRUSES | ECHOVIRUSES | ENTEROVIRUSES |
|---|---|---|---|---|
| Asymptomatic infection | All serotypes | All serotypes | All serotypes | All serotypes |
| Undifferentiated febrile illness (“summer grippe”) with or without respiratory symptoms | All serotypes | All serotypes | All serotypes | D68, D70, A71 |
| Aseptic meningitis (often associated with an exanthem) | 1, 2 , 3, 4 , 5 , 6, 7 , 8, 9 , 10 , 11, 14, 16 , 17, 18, 22, 24 | 1 , 2 , 3 , 4 , 5 , 6 | 1, 2, 3, 4 , 5, 6 , 7, 8, 9 , 10, 11 , 12, 14, 16 , 17, 18, 19, 20, 21, 25, 30 , 31, 33 | D70 , A 71 |
| Encephalitis | 2, 4, 5, 6, 7, 9 , 10, 16 | 1, 2 , 3 , 4 , 5 | 2, 3, 4 , 6 , 7, 9 , 11 , 14, 17, 18, 19, 25, 30 , 33 | D70, A 71 |
| Acute flaccid paralysis (poliomyelitis-like) | 4 , 5, 6, 7 , 9 , 10, 11, 14, 16, 21, 24 | 1, 2 , 3 , 4 , 5 , 6 | 1, 2 , 4 , 6 , 7, 9 , 11 , 14, 16, 17, 18, 19, 30 | D68?, D 70 , A 71 |
| Myopericarditis | 1, 2, 4 , 5, 7, 8, 9 , 14, 16 | 1 , 2 , 3 , 4 , 5 , 6 | 1, 2, 3, 4, 6 , 7, 8, 9 , 11 , 14, 16, 17, 19, 25, 30 | |
| Pleurodynia | 1, 2, 4, 6, 9, 10, 16 | 1 , 2 , 3 , 4 , 5 , 6 | 1 , 2, 3, 6 , 7, 8, 9, 11, 12, 14, 16, 19, 25, 30 | |
| Herpangina | 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9, 10 , 16, 22 | 1 , 2, 3, 4, 5 | 6, 9, 11, 16 , 17, 22?, 25 | A71 |
| Hand-foot-and-mouth disease | 4, 5 , 6, 7, 9 , 10 , 16 | 2, 5 | 7 | A71 |
| Exanthems | 2, 4, 5, 6, 7, 9 , 10, 16 | 1, 2, 3, 4, 5 | 2, 4, 5, 6, 9 , 11 , 16 , 18, 25 | A71 |
| Common cold | 2, 10, 21 , 24 | 1, 2, 3, 4, 5 | 2, 4, 8, 9, 11, 20, 25 | |
| Lower respiratory tract infections (bronchiolitis, pneumonia) | 7, 9 , 16 | 1, 2, 3, 4, 5 | 4, 8, 9, 11, 12, 14, 19, 20, 21, 25, 30 | D68 , A71, C104 |
| Acute hemorrhagic conjunctivitis ‡ | 24 | D70 | ||
| Generalized disease of the newborn | 3, 9, 16 | 1, 2 , 3 , 4 , 5 | 3, 4, 6, 7, 9, 11 , 12, 14, 17, 18, 19, 20, 21, 30 |
∗ A great many enterovirus serotypes have been implicated in most of these syndromes, at least in sporadic cases. The serotypes listed are those that have been clearly or frequently implicated. Serotypes with a strong association are underlined.
† Because detection of many of the group A coxsackieviruses originally required suckling mouse inoculation, they are likely to be underreported as causes of illness.
‡ Conjunctivitis without hemorrhage is frequently seen in association with other manifestations in patients infected with many group A and group B coxsackieviruses and echoviruses, especially coxsackieviruses A9, A16, and B1 to B5 and echoviruses 2, 7, 9, 11, 16, and 30.
The most frequent enteroviral syndrome, seen in about 50 to 80% of cases, is nonspecific febrile illness, which occurs most commonly in infants, toddlers, and young children. The onset of illness is abrupt, with fever, poor appetite, lethargy, irritability, emesis, diarrhea, and upper respiratory tract symptoms. Physical findings are minimal and consist of mild pharyngeal and conjunctival injection and lymphadenopathy. Exanthems may be present in about 25% of cases.
Diagnosis
Nucleic acid amplification techniques (e.g., reverse transcription–polymerase chain reaction [RT-PCR] and nucleic acid–based sequence amplification) are the preferred methods for detection and identification of all enteroviruses. RT-PCR can detect enteroviruses in cerebrospinal fluid (CSF), blood, tissue, stool, and other body fluids within hours, and their rapid results can shorten hospitalizations, decrease the use of antibiotics, and reduce health care costs.
Serologic testing is of limited use, although a four-fold change in antibody titer to a specific serotype of enterovirus in paired acute and convalescent sera can help establish the diagnosis in patients who are no longer actively infected. Cell culture is not recommended.
Treatment and Prognosis
Nonspecific febrile enteroviral infections generally resolve in less than 5 days without sequelae. Because of concern for possible occult bacterial infection, however, significant numbers of young infants and children are hospitalized for evaluation and empirical therapy. After infection, virus may be shed into the nasopharynx for 2 to 6 weeks and in feces for several months.
Specific Clinical Syndromes
Central Nervous System Infections
Acute Flaccid Paralysis/myelitis
Clinical Manifestations and Diagnosis
During poliovirus epidemics, 90 to 95% of infections are subclinical. In another 4 to 8% of patients, infection results in fever, fatigue, headache, anorexia, myalgia, and sore throat, which resolve in 2 to 3 days. Paralytic polio develops in less than 1% of infected individuals.
Acute flaccid myelitis can be seen with other enteroviruses (especially CV-A7, EV-A71), and EV-D68, with sporadic cases or clusters reported worldwide. Cases of EV-A71 associated paresis have tended to occur in the Asia-Pacific region, although cases also have been reported from the United States and Europe. Rhombencephalitis may result in autonomic dysfunction, myoclonus, and ataxia. In United States, EV-D68 is believed to be the major cause of the biennial outbreaks of acute flaccid myelitis that have occurred since 2014, with the exception of 2020, the initial year of the SARS-CoV-2 pandemic. Acute flaccid myelitis predominantly affects children, the majority of whom have a prodrome of fever and respiratory symptoms. The onset of neurologic symptoms occurs within 10 days following the initiation of the prodromal phase. Early neurologic findings may include headache, nuchal rigidity, and meningismus. Weakness is preceded by pain in the involved muscles. The weakness and paralysis are flaccid in nature and asymmetric. Deep tendon reflexes in the involved extremities are decreased or absent. Upper extremities and proximal muscle groups are more frequently involved, but respiratory muscles, diaphragm, trunk, and neck can also be affected. The brainstem motor nuclei of the cranial nerves may be involved. Respiratory failure secondary to involvement of the muscles of respiration or brain stem may occur. Dysfunction of the bowel and bladder are common. Sensory pathways remain intact as does mental status.
CSF may reveal a normal cell count or a mild lymphocytic pleocytosis (<100 cells/µL) in association with mildly increased protein and normal glucose concentrations. Magnetic resonance imaging of the spinal cord demonstrates T2-weighted hyperintensity of the gray matter (anterior horn regions) that is longitudinally expansive. T2 hyperintensity can also be seen in the brainstem.
Treatment and Prognosis
No specific therapy exists. Efforts should focus on monitoring for the development of respiratory failure or airway compromise as well as control of pain associated with muscle spasms.
The mortality rate associated with spinal poliomyelitis is about 5%. The mortality rates for enteroviruses associated with nonpolio enteroviral acute flaccid paralysis are not known. Before modern methods of respiratory and cardiovascular support, mortality rates higher than 50% were common in patients with bulbar or medullary poliomyelitis. The ultimate outcome of the paralysis is highly variable and can range from complete resolution to lifelong persistence. The greatest gains in recovery of strength occur during the first 6 months of convalescence. Paralytic limbs become atrophic, thereby leading to skeletal deformities and sometimes to a post-polio syndrome that can mimic motor neuron diseases.
In a Colorado outbreak of EV-D68, about 75% of patients had limited or no improvement of their flaccid paralysis at 30 days, and the other 25% had only partial recovery by that time. By comparison, 93% of children with EV-A71 neurologic diseases in Colorado completely recovered within 2 months.
A syndrome of postpoliomyelitis muscle atrophy, which may be seen in 25 to 85% of individuals two to three decades after recovery from paralytic disease, is characterized by the gradual development of weakness, pain, and atrophy. Possible mechanisms include aging and neuronal dropout in compromised neuromuscular connections or, less likely, reactivation/ongoing poliovirus infection.
Meningitis
Worldwide, the enteroviruses, especially those within the Enterovirus B species, are the dominant cause of viral meningitis ( Chapter 381 ) in all ages. About 50% of all cases of meningitis and encephalitis in the United States are documented to be enteroviral infections.
Clinical Manifestations and Diagnosis
The clinical picture varies with age. In older infants and children, an abrupt onset of fever is the most frequent initial symptom. The fever may persist for 1 to 5 days and may exhibit a biphasic pattern. Irritability or lethargy is common. Other nonspecific symptoms include poor feeding, vomiting, diarrhea, and rash. Headache is present in nearly all children old enough to report it. Rash, malaise, sore throat, abdominal pain, and myalgia are common, and photophobia may be reported. Seizures occur in less than 5% of cases. Examination may reveal a full fontanelle. Signs of meningeal irritation (i.e., nuchal rigidity, Brudzinski and Kernig signs) occur in less than 10% of infants younger than 3 months and increase with age.
In adolescents and adults, headache is nearly always present and severe enough to require narcotic analgesics for control. Some patients report temporary relief of headache after lumbar puncture. Fever is not universal, but photophobia, signs of meningeal irritation, nausea, emesis, and neck stiffness occur in more than two thirds of patients. Myalgia is reported in 20 to 90% of patients. Less frequent findings include rash and abdominal pain.
CSF analysis generally reveals a mild to moderate lymphocytic pleocytosis (<500 cells/µL). Some patients, however, may have lymphocyte counts higher than 1000 or have neutrophilic pleocytosis early in the course of illness and then progress to a predominance of lymphocytes hours to days later. In a small percentage of patients, particularly infants, no pleocytosis is present even though enterovirus can be detected. The protein concentration may be increased. Although the glucose concentration is generally normal, hypoglycorrhachia may occur, particularly in association with group B coxsackievirus meningitis. Neuroimaging in cases of meningitis is generally unrevealing. Nucleic acid amplification testing can detect enteroviruses in CSF. The serotypes most frequently identified from CSF specimens are from the enterovirus B species.
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