Enteroviruses, along with rhinoviruses (see Common Cold) and human parechoviruses, are a genus of picornaviruses (pico, or small, RNA viruses). 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 United States are more common in summer and fall.
Infection during pregnancy can result in perinatal transmission and 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.
Parechoviruses
Human parechoviruses types 1 and 2 are picornaviruses that were previously named echovirus 22 and 23. However, the parechoviruses have been reclassified into a separate genus (1). Parechovirus A can infect humans and has at least 19 types; most cause mild gastrointestinal and respiratory illness similar to the enteroviruses, but some types are a common cause of viral sepsis and/or meningitis in infants. Human parechoviruses are not identified by most standard enterovirus RT-PCR tests; specific parechovirus RT-PCR testing is required (2).
Diseases Caused by Enteroviruses
Enteroviruses cause various syndromes (see table Syndromes Caused by Enteroviruses).
The following are caused almost exclusively by enteroviruses:
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.
Acute flaccid myelitis (AFM)
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, larger outbreaks with severe morbidity and some fatalities have occurred. In the late summer and fall of 2014, over 1000 cases were confirmed in a large outbreak across the United States and additional outbreaks were reported worldwide. 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 AFM after a respiratory illness were also 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 acute flaccid myelitis and supports a potential causal role of EV-D68 in AFM paralysis (3). Ongoing surveillance by the Centers for Disease Control and Prevention (CDC) detected 120 cases of acute flaccid myelitis in the fall of 2014, coinciding with the EV-D68 outbreak. AFM upsurges occurred in 2014, 2016, and 2018 with 120, 153, and 238 cases reported to CDC each year, respectively, and only 22 and 38 cases reported in the intervening years. These biennial peaks correspond to periods of increased EV-D68 activity (see CDC: AFM Cases and Outbreaks).
Overall, these epidemiologic links along with animal model data strongly suggest a causal relationship between EV-D68 infection and AFM (4).
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 (5; see also CDC: Clinical Guidance for the Acute Medical Treatment of AFM ). Specific testing in potential outbreaks is recommended and can be arranged through public health officials.
Management of AFM should involve neurology and infectious disease specialists. There are a number of treatments that are considered for AFM; however, currently no targeted treatment has enough evidence to endorse or discourage use for the treatment or management of AFM (see CDC: Clinical Guidance for the Acute Medical Treatment of AFM).
Hemorrhagic conjunctivitis
Rarely, hemorrhagic conjunctivitis due to enterovirus occurs in epidemics in the United States. 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 due to enterovirus 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 temperature instability, 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, certain 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
Respiratory 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.
References
1. Sridhar A, Karelehto E, Brouwer L, et al: Parechovirus A Pathogenesis and the Enigma of Genotype A-3. Viruses 11(11):1062, 2019. Published 2019 Nov 14. doi:10.3390/v11111062
2. de Crom SC, Rossen JW, van Furth AM, et al: Enterovirus and parechovirus infection in children: a brief overview. Eur J Pediatr 175(8):1023-9, 2016. Epub 2016 May 7. PMID: 27156106; PMCID: PMC4930465. doi: 10.1007/s00431-016-2725-7
3. 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
4. Messacar K, Asturias EJ, Hixon AM, et al: Enterovirus D68 and acute flaccid myelitis-evaluating the evidence for causality. Lancet Infect Dis 18(8):e239-e247, 2018. doi: 10.1016/S1473-3099(18)30094-X
5. Dinov D, Donowitz JR: Acute flaccid myelitis a review of the literature. Front Neurol 13:1034607, 2022. Published 2022 Dec 20. doi:10.3389/fneur.2022.1034607
Diagnosis of Enterovirus Infections
History and physical examination
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 can be detected using RT-PCR testing on a sample from the involved site (eg, throat or nasopharynx, blood, cerebrospinal fluid) or from stool, in which the organism is often present even when the clinically involved site is elsewhere; identifying the causative organism is important mainly in cases of aseptic meningitis. Commercially available multiplex PCR panels for respiratory pathogens often cannot distinguish between rhinoviruses and enteroviruses and may not identify all enteroviruses. Additional typing by molecular sequencing is needed to discriminate rhinovirus and enterovirus species- and type-specificity.
Treatment of Enterovirus Infections
Supportive
Treatment of enteroviral disease is supportive.
Patients with agammaglobulinemia are treated with intravenous immunoglobulin (IVIG) with variable success.
