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Overview of Enterovirus Infections

By

Brenda L. Tesini

, MD, University of Rochester School of Medicine and Dentistry

Last full review/revision Sep 2019| Content last modified Sep 2019
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Enteroviruses, along with rhinoviruses (see Common Cold) and human parechoviruses, are picornaviruses (pico, or small, RNA viruses). Human parechoviruses types 1 and 2 were previously named echovirus 22 and 23 but have now been reclassified. All enteroviruses are antigenically heterogeneous and have wide geographic distribution.

Enteroviruses include

  • Coxsackieviruses A1 to A21, A24, and B1 to 6

  • Echoviruses (enteric cytopathic human orphan viruses) 1 to 7, 9, 11 to 21, 24 to 27, and 29 to 33

  • Enteroviruses 68 to 71, 73 to 91, and 100 to 101

  • Polioviruses types 1 to 3

Enteroviruses are shed in respiratory secretions and stool and sometimes are present in the blood and cerebrospinal fluid of infected patients. Infection is usually transmitted by direct contact with respiratory secretions or stool but can be transmitted by contaminated environmental sources (eg, water).

Enteroviral diseases or epidemics in the US are more common in summer and fall.

Infection transmitted by a mother during delivery can cause severe disseminated neonatal infection, which may include hepatitis or hepatic necrosis, meningoencephalitis, myocarditis, or a combination of these, and can lead to sepsis or death.

Intact humoral immunity and B-cell function are required for control of enteroviral disease. Severe enteroviral infections (often manifesting as a slowly progressive meningoencephalitis, dermatomyositis, and/or hepatitis) occur in patients with defects in B lymphocyte function such as X-linked agammaglobulinemia , but usually not in those with other immune deficiencies.

Diseases Caused by Enteroviruses

Enteroviruses cause various syndromes (see table Syndromes Caused by Enteroviruses). The following are caused almost exclusively by enteroviruses:

Table
icon

Syndromes Caused by Enteroviruses

Syndrome

Serotypes Most Often Implicated

Coxsackieviruses A2, 4, 7, 9, and others and B2–5

Poliovirus types 1–3

Echoviruses 4, 6, 7, 9, 11, 30, and others

Human parechoviruses 1–4

Aseptic meningitis with rash

Coxsackieviruses A9 and B4

Echoviruses 4 and 16

Enterovirus 71

Enterovirus 70

Coxsackievirus A24

Epidemic pleurodynia (Bornholm disease)

Coxsackieviruses B1–6

Coxsackieviruses A6, 9, 16, and others

Coxsackieviruses B2–5

Enterovirus 71

Coxsackieviruses A2, 4–6, 8, and 10

Probably coxsackieviruses B3 and others

Coxsackieviruses A4 and 16 and B1–5

Echoviruses 9 and human parechovirus 1

Paralysis

Polioviruses 1–3

Coxsackieviruses A7 and others

Echoviruses 4, 6, 9, and others

Enteroviruses 71, D68, D70

Coxsackieviruses A9 and B1, 3, 4, and 5 (also implicated: A4–6 and 16)

Echoviruses 9 and 16 (also implicated: 2, 4, 11, 14, 19, and 25)

Echoviruses 4, 8, 9, 11, 20, and others

Coxsackieviruses A21 and 24 and B1 and 3–5

Enterovirus D68

Other disorders (eg, aseptic meningitis, myopericarditis) may be caused by enteroviruses or other organisms.

Aseptic meningitis

Aseptic meningitis is most common among infants and children. In infants and young children, the cause is frequently one of the following:

  • A group A or B coxsackievirus

  • An echovirus

  • A human parechovirus

In older children and adults, other enteroviruses as well as other viruses may cause aseptic meningitis.

The course is usually benign. A rash may accompany enteroviral aseptic meningitis. Rarely, encephalitis, which may be severe, also occurs.

Enterovirus D68

Enterovirus D68 (EV-D68) causes a respiratory illness, primarily in children; symptoms usually resemble those of a cold (eg, rhinorrhea, cough, malaise, fever in a few children). Some children, particularly those with asthma, have more serious symptoms involving the lower respiratory tract (eg, wheezing, respiratory distress).

Healthy adults can be infected, but they tend to have few or no symptoms. Immunocompromised adults may have severe respiratory disease.

Every year, respiratory infections caused by EV-D68 are identified in a few children, and small outbreaks tend to occur every other year. However, in the late summer and fall of 2014, over 1000 cases were confirmed in a large outbreak across the US. Severe respiratory distress developed in a significant number of children, and a few children died. At the same time, case clusters of children with focal limb weakness or paralysis with spinal cord lesions (seen on MRI) consistent with acute flaccid myelitis (AFM) after a respiratory illness also were reported; EV-D68 was identified in respiratory specimens in two thirds of cases in two distinct outbreak clusters and in the blood of one child during the progression of the paralysis. Sequenced viruses were nearly identical and shared homology with poliovirus and enterovirus D70, which are known to be associated with AFM and supports a potential causal role of EV-D68 in AFM paralysis (1). Ongoing surveillance by the Centers for Disease Control and Prevention (CDC) detected 120 cases of AFM in the fall of 2014, coinciding with the EV-D68 outbreak. Continued surveillance in 2015 detected 16 cases of AFM for the entire year, with no cases of EV-D68 reported that year (2).

Another large outbreak of EV-D68-associated respiratory illness peaked in the US in September 2018. Active CDC surveillance detected the virus in 13.9% of pediatric patients with acute respiratory illness at several large US medical centers, compared to only 0.08% of similar patients in 2017. Two-thirds of the patients with EV-D68 required hospitalization, highlighting the severity of illness. There was also a contemporaneous increase in reported AFM with over 200 CDC-confirmed cases in 2018 compared to only 35 in 2017, which further supports an association between EV-D68 infection and AFM (3).

EV-D68 should be considered as an etiology for otherwise unexplained severe respiratory infection, particularly if associated with a cluster of cases in late summer to fall. Specific testing in potential outbreaks is recommended and can be arranged through public health officials.

Hemorrhagic conjunctivitis

Rarely, hemorrhagic conjunctivitis occurs in epidemics in the US. Importation of the virus from Africa, Asia, Mexico, and the Caribbean may make outbreaks more common.

The eyelids rapidly swell. Hemorrhagic conjunctivitis, unlike uncomplicated conjunctivitis, often leads to subconjunctival hemorrhages or keratitis, causing pain, tearing, and photophobia. Systemic illness is uncommon. However, when hemorrhagic conjunctivitis is due to enterovirus 70, transient lumbosacral radiculomyelopathy or poliomyelitis-like illness (with paralysis) can occur but is rare. Recovery is usually complete within 1 to 2 weeks of onset.

Coxsackievirus A24 also causes hemorrhagic conjunctivitis, but subconjunctival hemorrhage is less frequent, and neurologic complications have not been described. Most patients recover in 1 to 2 weeks.

Myopericarditis

Cardiac infection may occur at any age, but most patients are 20 to 39 years old. Patients may present with chest pain, arrhythmias, heart failure, or sudden death. Recovery is usually complete, but some patients develop dilated cardiomyopathy. Diagnosis of myopericarditis may require reverse transcriptase (RT)–PCR of myocardial tissue.

Myocarditis neonatorum (cardiac infection at birth) is caused by group B coxsackieviruses, some echoviruses, and human parechoviruses. It causes fever and heart failure and has a high mortality rate.

Neonatal infection

Usually, several days after birth, the neonate suddenly develops a syndrome resembling sepsis with fever, lethargy, disseminated intravascular coagulation, bleeding, and multiple organ (including heart) failure. Central nervous system, hepatic, myocardial, pancreatic, or adrenal lesions may occur simultaneously.

Recovery may occur within a few weeks, but death may result from circulatory collapse or, if the liver is involved, liver failure.

Rashes

Certain coxsackieviruses, echoviruses, and human parechoviruses may cause rashes, often during epidemics. Rashes are usually nonpruritic, do not desquamate, and occur on the face, neck, chest, and extremities. They are sometimes maculopapular or morbilliform but occasionally hemorrhagic, petechial, or vesicular. Fever is common. Aseptic meningitis may develop simultaneously.

The course is usually benign.

Respiratory infections

These infections may result from enteroviruses. Symptoms include fever, coryza, pharyngitis, and, in some infants and children, vomiting and diarrhea. Bronchitis and interstitial pneumonia occasionally occur in adults and children.

The course is usually mild but can be severe as evidenced by the 2014 enterovirus D68 outbreak.

General references

  • 1. Greninger AL, Naccache SN, Messacar K, et al: A novel outbreak enterovirus D68 strain associated with acute flaccid myelitis cases in the USA (2012-14): A retrospective cohort study. Lancet Infect Dis 15(6):671–682, 2015. doi: 10.1016/S1473-3099(15)70093-9.

  • 2. Sejvar JJ, Lopez AS, Cortese MM, et al: Acute flaccid myelitis in the United States, August-December 2014: Results of nationwide surveillance. Clin Infect Dis 63(6):737-745, 2016. doi: 10.1093/cid/ciw372. 

  • 3. Kujawski SA, Midgley CM, Rha B, et al: Enterovirus D68-associated acute respiratory illness - New Vaccine Surveillance Network, United States, July-October, 2017 and 2018. MMWR Morb Mortal Wkly Rep 68(12):277-280, 2019. doi: 10.15585/mmwr.mm6812a1. 

Diagnosis

  • Clinical evaluation

  • Sometimes culture or reverse transcriptase–polymerase chain reaction (RT-PCR)

Diagnosis of enteroviral diseases is usually clinical.

Laboratory diagnosis is usually unnecessary but can often be made by

  • Culturing the virus

  • Detecting viral RNA using RT-PCR

  • Less commonly, demonstrating seroconversion

Enteroviruses that cause aseptic meningitis can be detected in a sample from the throat, stool, blood, or cerebrospinal fluid with RT-PCR tests done on blood and cerebrospinal fluid. However, human parechoviruses are not identified by most standard enterovirus RT-PCR tests; specific parechovirus RT-PCR testing is required. Commercially available multiplex PCR panels for respiratory pathogens often cannot distinguish between rhinoviruses and enteroviruses.

Treatment

  • Supportive

Treatment of enteroviral disease is supportive.

Patients with agammaglobulinemia are treated with IV immune globulins with variable success.

The oral antiviral drug pleconaril, which has shown activity against a number of picornaviruses, is being investigated for treatment of severe neonatal enteroviral disease (1).

Treatment reference

  • 1. Abzug MJ, Michaels MG, Wald E, et al: A randomized, double-blind, placebo-controlled trial of pleconaril for the treatment of neonates with enterovirus sepsis. J Pediatric Infect Dis Soc 5 (1):53–62, 2016. doi: 10.1093/jpids/piv015.

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