Enteroviruses, along with rhinoviruses (see Common Cold) and human parechoviruses, are in the genus of picornaviruses (pico, or small, RNA viruses). There are over 100 enterovirus serotypes (including polioviruses, group A coxsackieviruses, group B coxsackieviruses, echoviruses, and numbered enteroviruses) that cause a large spectrum of disease and have a wide geographic distribution (1).
Enteroviruses are shed in stool, in respiratory secretions, and from skin/mucosal lesions, and are primarily transmitted by the fecal-oral or respiratory route. Less commonly, enteroviruses are transmitted by direct contact with skin/mucosal lesions. Enteroviruses can be detected in blood and cerebrospinal fluid in some cases of invasive or neurologic disease.
Circulation of enteroviruses and epidemics of associated diseases are more common in summer and fall in temperate climates (2).
Infection late in pregnancy can result in perinatal transmission and cause severe disseminated neonatal infection and sepsis with multiorgan system dysfunction, including hepatitis, meningoencephalitis, myocarditis, and pneumonia, and is associated with a high mortality rate.
Intact humoral immunity is important for control of enteroviral infections. Severe, chronic enteroviral infections (including meningoencephalitis, dermatomyositis, and/or hepatitis) can occur in patients with humoral immunodeficiency, such as patients with agammaglobulinemia3).
Parechoviruses
Human parechoviruses are picornaviruses that were previously classified as enteroviruses (eg, echovirus 22 and 23) but have been reclassified into a separate genus (4). Parechovirus A can infect humans and has at least 19 types; most cause mild gastrointestinal and respiratory illness, but some types, particularly parechovirus A3, can cause viral sepsis and/or meningoencephalitis in infants (5). Human parechoviruses are not detected by standard enterovirus reverse transcriptase–polymerase chain reaction (RT-PCR) tests; specific parechovirus RT-PCR testing is required (6, 7).
Diseases Caused by Enteroviruses
Enteroviruses cause various syndromes (see table Syndromes Caused by Enteroviruses).
The following are caused almost exclusively by enteroviruses:
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 | |
Aseptic meningitis with rash | Coxsackieviruses A9 and B4 Echoviruses 4 and 16 Enterovirus A71 |
Enterovirus D70 Coxsackievirus A24 | |
Epidemic pleurodynia (Bornholm disease) | Coxsackieviruses B1–6 |
Coxsackieviruses A6, 9, 16, and others Coxsackieviruses B2–5 Enterovirus A71 | |
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 | |
Polioviruses 1–3 Coxsackieviruses A7 and others Echoviruses 4, 6, 9, and others Enteroviruses A71, 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 |
Aseptic meningitis
Aseptic meningitis is most common among infants and children, but can occur at any age.
The course is usually self-limited and benign, but may be biphasic with symptoms recurring after initial improvement. 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 some children). Some children, particularly those with asthma, have more serious asthma-like symptoms involving the lower respiratory tract (eg, wheezing, respiratory distress) (8). Healthy adults can be infected, but they tend to have milder symptoms. Immunocompromised adults may have more severe disease.
Starting in 2014 in the United States, increased circulation of EV-D68 with widespread outbreaks of respiratory disease occurred in a seasonal (late summer to early fall), biennial pattern (2014, 2016, 2018) (9). In August to October 2014, during an outbreak of EV-D68 respiratory disease, case clusters of children with focal limb weakness and spinal cord lesions on MRI, now termed AFM, were also reported (10). A causal role of EV-D68 in AFM paralysis has subsequently been established through epidemiologic, virologic, immunologic, and laboratory animal model data (11).
Ongoing surveillance in the United States by the Centers for Disease Control and Prevention (CDC) detected AFM upsurges 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). There was no significant EV-D68 circulation or upsurge in AFM cases reported between 2019 and 2021, presumably due to nonpharmacologic interventions for the COVID-19 pandemic, which also limited transmission of other respiratory viruses. In 2022, a large outbreak of EV-D68 respiratory disease occurred without a significant increase in AFM cases. The reasons behind this decoupling from COVID-19 remain unclear and are under investigation.
EV-D68 should be considered as an etiology when patients have otherwise unexplained, severe, asthma-like respiratory infection, particularly if associated with a cluster of cases in late summer to fall (12; see also CDC: Clinical Guidance for the Acute Medical Treatment of AFM ). Specific EV-D68 RT-PCR testing in potential outbreaks of respiratory disease is recommended and can be arranged through public health officials.
Diagnosis of AFM requires physical examination findings of acute flaccid limb weakness, which can be accompanied by cranial nerve dysfunction in approximately 30% of cases (13). Lumbar puncture should be performed and often demonstrates a lymphocytic cerebrospinal fluid pleocytosis. Confirmation of the diagnosis is through MRI of the spinal cord demonstrating a longitudinal lesion in the gray matter, which may be accompanied by brainstem lesions (14). Prompt collection of biologic specimens (nasopharyngeal and oropharyngeal swabs, stool, blood, and cerebrospinal fluid) for testing arranged through public health officials is critical for detection of a causative pathogen and to rule out poliovirus.
Management of AFM should involve neurology and infectious disease specialists. Supportive care remains the mainstay of treatment. While a number of treatments, including intravenous immune globulin, have been considered for AFM, currently there is insufficient evidence from human trials to support any specific treatment for management of AFM (see CDC: Clinical Guidance for the Acute Medical Treatment of AFM).
Hemorrhagic conjunctivitis
Hemorrhagic conjunctivitis due to enterovirus occurs rarely in epidemics in the United States, and is more common in tropical areas.
Hemorrhagic conjunctivitis, unlike uncomplicated conjunctivitis, often leads to subconjunctival hemorrhages or keratitis, causing pain, tearing, and photophobia. The eyelids rapidly swell. Recovery is usually complete within 1 to 2 weeks of onset. Systemic illness is uncommon. However, when hemorrhagic conjunctivitis is due to enterovirus D70, paralysis similar to poliomyelitis and AFM, can occur but is rare (15).
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 an enterovirus may occur at any age. Patients may present with chest pain, arrhythmias, heart failure, or sudden death. Recovery is usually complete, but some patients develop dilated cardiomyopathy. Diagnosis of an enteroviral cause of myopericarditis can be made through detection of enterovirus in blood or shedding at nonsterile sites (stool, respiratory), but may require RT–PCR of myocardial tissue.
Respiratory infections
Respiratory infections may result from some enteroviruses. Symptoms include fever, coryza, pharyngitis, and, in some infants and children, more severe asthma-like symptoms of wheezing and increased work of breathing. 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.
Rash
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.
Neonatal infection
In infants born to mothers infected with enterovirus late in pregnancy or infants infected with enterovirus in the first several days after birth, the infant can develop a syndrome resembling sepsis with temperature instability, lethargy, disseminated intravascular coagulation, bleeding, and multiple organ (including heart) failure. Central nervous system, hepatic, myocardial, pulmonary, pancreatic, or adrenal involvement 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.
Myocarditis neonatorum (perinatal cardiac infection) is primarily caused by group B coxsackieviruses, some echoviruses, and human parechoviruses (16). It causes fever and heart failure and has a high mortality rate.
References
1. Simmonds P, Gorbalenya AE, Harvala H, et al: Recommendations for the nomenclature of enteroviruses and rhinoviruses [published correction appears in Arch Virol. 2020 Jun;165(6):1515. doi: 10.1007/s00705-020-04558-x]. Arch Virol. 2020;165(3):793-797. doi:10.1007/s00705-019-04520-6
2. Pons-Salort M, Oberste MS, Pallansch MA, et al: The seasonality of nonpolio enteroviruses in the United States: Patterns and drivers. Proc Natl Acad Sci U S A. 2018;115(12):3078-3083. doi:10.1073/pnas.1721159115
3. McKinney RE Jr, Katz SL, Wilfert CM: Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Rev Infect Dis. 1987;9(2):334-356. doi:10.1093/clinids/9.2.334
4. 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
5. Harvala H, Wolthers KC, Simmonds P: Parechoviruses in children: understanding a new infection. Curr Opin Infect Dis. 2010;23(3):224-230. doi:10.1097/qco.0b013e32833890ca
6. 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
7. Nix WA, Maher K, Johansson ES, et al: Detection of all known parechoviruses by real-time PCR. J Clin Microbiol. 2008;46(8):2519-2524. doi:10.1128/JCM.00277-08
8. Rao S, Messacar K, Torok MR, et al: Enterovirus D68 in Critically Ill Children: A Comparison With Pandemic H1N1 Influenza. Pediatr Crit Care Med. 2016;17(11):1023-1031. doi:10.1097/PCC.0000000000000922
9. Park SW, Pons-Salort M, Messacar K, et al: Epidemiological dynamics of enterovirus D68 in the United States and implications for acute flaccid myelitis. Sci Transl Med. 2021;13(584):eabd2400. doi:10.1126/scitranslmed.abd2400
10. Messacar K, Schreiner TL, Maloney JA, et al: A cluster of acute flaccid paralysis and cranial nerve dysfunction temporally associated with an outbreak of enterovirus D68 in children in Colorado, USA. Lancet. 2015;385(9978):1662-1671. doi:10.1016/S0140-6736(14)62457-0
11. 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
12. 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
13. Murphy OC, Messacar K, Benson L, et al: Acute flaccid myelitis: cause, diagnosis, and management. Lancet. 2021;397(10271):334-346. doi:10.1016/S0140-6736(20)32723-9
14. Maloney JA, Mirsky DM, Messacar K, Dominguez SR, Schreiner T, Stence NV: MRI findings in children with acute flaccid paralysis and cranial nerve dysfunction occurring during the 2014 enterovirus D68 outbreak. AJNR Am J Neuroradiol. 2015;36(2):245-250. doi:10.3174/ajnr.A4188
15. Neurovirulence of enterovirus 70: Lancet. 1982;1(8268):373-374.
16. Ng KF, Gibb J, Struik S, et al: Remember the heart: neonatal myocarditis. Arch Dis Child. 2023;108(5):417-419. doi:10.1136/archdischild-2023-325316
Diagnosis of Enterovirus Infections
History and physical examination
Reverse transcriptase–polymerase chain reaction (RT-PCR)
Diagnosis of syndromes due to enteroviruses is usually clinical.
Laboratory diagnosis of enteroviruses as the cause of disease can often be made by
Detecting viral RNA using RT-PCR
Less commonly, culturing the virus or demonstrating seroconversion
Enteroviruses can be detected using RT-PCR testing on a sample from sterile sites (blood, cerebrospinal fluid) or shedding from nonsterile sites (stool, respiratory, skin/mucosal lesions). Identifying the causative organism is important mainly in cases of neurologic disease (aseptic meningitis, AFM, poliomyelitis) or severe disease (neonatal sepsis, chronic infection in humoral immunodeficiency).
Commercially available multiplex PCR panels for respiratory pathogens often cannot distinguish between rhinoviruses and enteroviruses and may not detect all enteroviruses. Additional typing by molecular sequencing or enterovirus-specific RT-PCT is needed to discriminate rhinovirus and enterovirus species- and type-specificity.
Treatment of Enterovirus Infections
Supportive care
Treatment of enteroviral disease is supportive.
Patients with humoral immunodeficiencies, such as agammaglobulinemia, can receive intravenous immunoglobulin (IVIG), which decreases the risk of chronic enterovirus infection and may be used as treatment in newly diagnosed disease (1, 2).
Treatment references
1. Stiehm ER, Orange JS, Ballow M, Lehman H: Therapeutic use of immunoglobulins. Adv Pediatr. 2010;57(1):185-218. doi:10.1016/j.yapd.2010.08.005
2. Planitzer CB, Farcet MR, Schiff RI, Ochs HD, Kreil TR: Neutralization of different echovirus serotypes by individual lots of intravenous immunoglobulin. J Med Virol. 2011;83(2):305-310. doi:10.1002/jmv.21980
