Pediatric Enteroviral Infections
Enteroviruses, a group of single-stranded sense RNA viruses, are commonly encountered infections, especially in infants and children. They are responsible for a myriad of clinical syndromes, including hand-foot-and-mouth (HFM) disease, herpangina, myocarditis, aseptic meningitis, and pleurodynia.
Patients with enterovirus infections may present with symptoms as benign as an uncomplicated summer cold or as threatening as encephalitis, myocarditis, or neonatal sepsis. Enteroviral infections annually result in a large number of physician and emergency department visits. In 1998, Pichichero et al performed a prospective study and found that nonpolio enteroviral infections resulted in direct medical costs ranging from $69-771 per case.  In addition, patients with nonpolio enteroviral infections missed a minimum of 1 day of school or camp; some missed as many as 3 days of school or camp. The significant economic and medical impacts of enteroviral infections occur mostly during the peak months of summer and fall. In temperate climates, enteroviral outbreaks occur year-round.
Enteroviruses belong to the Picornaviridae (small RNA viruses) family. The enteroviral group includes coxsackievirus, echovirus, and poliovirus. Enteroviruses are believed to have 2 distinct classes: polioviruses (types 1, 2, and 3) and nonpolioviruses (coxsackievirus, enterovirus, echoviruses, and unclassified enteroviruses). Enteroviral infections consist of 23 coxsackievirus A, 6 coxsackievirus B, 28 echovirus, and 5 unclassified enteroviruses.
More recently, a related genus of viruses, Parechovirus, has been described; two enterovirus species (echovirus types 22 and 23) were reassigned as parechovirus.  To date, more than a dozen parechovirus strains have been described; however, not all sequences have been published. The clinical appearance of Parechovirus infection can be similar to enteroviral infections, but tests for Parechovirus are mostly confined to research laboratories.
The US Centers for Disease Control and Prevention (CDC) reported a 2014 outbreak of enterovirus 68 (also called enterovirus D68) that began in at least six US states from mid-August to mid-September, including Colorado, Illinois, Iowa, Kansas, Kentucky, and Missouri.  This outbreak has since spread coast to coast, with 175 cases in 27 states. The additional reported states include Alabama, California, Connecticut, Georgia, Indiana, Louisiana, Michigan, Minnesota, Montana, Nebraska, New Jersey, New York, Oklahoma, Pennsylvania, Virginia, and Washington.  The total number of confirmed cases is higher because this figure does not include cases confirmed by individual state laboratories. enterovirus 68 was first identified in 1962 in California but had not been commonly reported in the United States before the 2014 outbreak. The CDC identified that among the enterovirus 68 cases in Missouri and Illinois, children with asthma seemed to have a higher risk for severe respiratory illness. 
Enterovirus 71 has gained notoriety in recent years for causing a rapidly fatal rhombencephalitis, in association with epidemics of HFM disease in East Asian countries. This appears to be a particularly aggressive neutrophic serotype of enterovirus.
Coxsackievirus A6 was recently described as a somewhat distinct clinical entity of “atypical hand foot mouth disease”, as the skin lesions described are vesiculobullous rather than the typical flat ulcers seen in HFM disease and may be more extensive, often involving areas of preexisting eczema.
Each virus obtains its antigenicity from the capsid proteins that surround the RNA core. According to the CDC, 65 human serotypes of enteroviruses have been identified; however, a small number cause most outbreaks. Since the implementation of polio vaccines, the incidence of wild-type polio has been eradicated in the western hemisphere.
The most common form of human transmission is the fecal-to-oral route. Although respiratory and oral-to-oral routes are possible, they are more likely to occur in crowded living conditions. Enteroviruses are quite resilient. They remain viable at room temperature for several days and can survive the acidic pH of the human GI tract. The incubation period is usually 3-10 days.
The enterovirus enters the human host through the GI or respiratory tract. The cell surfaces of the GI tract serve as viral receptors, and initial replication begins in the local lymphatic GI tissue. The virus seeds into the bloodstream, causing a minor viremia on the third day of infection. The virus then invades organ systems, causing a second viremic episode on days 3-7. This second viremic episode is consistent with the biphasic prodromal illness. The infection can progress to CNS involvement during the major viremic phase or at a later time. Antibody production in response to enteroviral infections occurs within the first 7-10 days.
Coxsackievirus notoriously replicates in the pharynx (herpangina), the skin (HFM disease), the myocardium (myocarditis), and the meninges (aseptic meningitis). It can also involve the adrenal glands, pancreas, liver, pleura, and lung.
Echovirus can replicate in the liver (hepatic necrosis), the myocardium, the skin (viral exanthems), the meninges (aseptic meningitis), the lungs, and the adrenal glands.
After exposure, poliovirus replicates in the oropharynx and GI tissue. Following this replication, polio advances, invading the motor neurons of the anterior horn cells of the spinal cord. It can progress to other CNS regions, including the motor cortex, cerebellum, thalamus, hypothalamus, midbrain, and medulla, causing death of neurons and paralysis. Neuropathy occurs due to direct cellular destruction. Antibody production occurs in the lymphatic system of the GI tract, prior to invasion of the CNS tissue. Infants retain transplacental immunity for the first 4-6 months of life.
The enteroviruses are capable of directing almost all cellular protein translation to viral genes through the modification of host cell translation factors (messenger RNA [mRNA] cap-binding proteins) and using internal ribosome entry sites (IRES) to bypass the crippled host machinery. As such, they are highly damaging to the cells they infect.
Nonpolio enteroviral infections cause an estimated 10-15 million symptomatic infections per year in the United States. Many are treated as potential episodes of sepsis, and antibiotics and acyclovir are administered to treat possible bacterial or herpetic infection.
In 1952, an epidemic of polio occurred in the United States, causing 3,000 deaths and 57,879 cases. The vaccine has virtually eliminated wild-type polio in the United States. In 1994, the World Health Organization (WHO) declared the eradication of wild polio in the Western hemisphere. Approximately 6 cases of vaccine-associated paralytic polio (VAPP) occur yearly, leading to the recommendation of inactivated vaccine because the risk of natural disease is so rare in the United States. VAPP is linked to the concomitant administration of live (oral) polio vaccine with intramuscular injections (perhaps allowing the virus better access to myocytes and neuronal axons) and occurs in 1 per 2-4 million vaccinations (paralytic polio occurs in 1 in 200 wild-type infections).
In 1979, an outbreak occurred in numerous Amish communities throughout the United States. A smaller outbreak occurred in 2005 in an Amish community in Minnesota. Genetic sequencing of the virus surprisingly revealed that it was only 2.3% different from the Sabin vaccine strain and was likely acquired from subclinical circulating infections from overseas.
Poliomyelitis still occurs in many developing countries as a result of poor health care and an inability to access vaccines.  The CDC reported 6227 cases in 1998.  This significant drop from the previous decade, in which 35,251 cases were reported, is due to aggressive vaccination programs. Worldwide eradication is hoped to occur in the near future.
Recently, setbacks have been noted in Nigeria, where suspicion about the motivations of the vaccination program led to a refusal to vaccinate children. One outbreak in 2003 crossed 15 other African countries and even spread as far as Indonesia, resulting in the paralysis of over 200 children. A more recent outbreak in 2006 affected mostly adults who were missed by vaccination campaigns. As of June 2006, 7 people had died and 27 people had been paralyzed. Nigeria had about half of the reported polio infections in the first 3 months of 2009.
With war and civil unrest, new cases have been seen in Somalia and Syria, as reported below. Somalia in particular has been hard hit, as militant activity and specific attacks against Medecins Sans Frontieres staff who have been coordinating large parts of the vaccination efforts resulted in the organization pulling out of the country entirely in late 2013.
Worldwide polio cases from 2013 are reported as follows: 
Nigeria (endemic) – 53 (801 cases in 2008)
India (now eradicated) – 0 (559 cases in 2008)
Pakistan (endemic) – 93 (118 cases in 2008)
Afghanistan (endemic) – 14 (31 cases in 2008)
Ethiopia (outbreak) – 9 (3 cases in 2008)
Kenya (outbreak) – 14 (0 cases in 2008)
Somalia (outbreak) – 190 (0 in 2008)
Syria (outbreak) – 23 (0 in 2008)
3 more cases confirmed in June 2017 
Cameroon (outbreak) – 4 (unknown in 2008 but last previous case was in 2009)
Democratic Republic of Congo- 4 cases confirmed in June 2017 
Much of the success of the WHO polio eradication campaign has been through aggressive vaccination and grass-roots support from religious, tribal, and social leaders. A monovalent oral polio vaccine (mOPV) is increasingly used in areas with a single circulating strain because it appears to be more effective at inducing protective immunity. However, vaccine-associated paralysis is more likely with the live-attenuated oral polio vaccine (OPV). To fully eradicate paralytic polio, the WHO is working towards a global transition to the inactivated polio vaccine where possible.
Some genetic evidence suggests that if the poliovirus is eradicated, genetic recombination between other enteroviruses may result in a phenotypically similar virus. However, this appears to be of academic interest only at this time.
The overall mortality rate for nonpolio viruses is extremely low. The patients at greatest risk are those with neonatal sepsis.
Occasionally, enteroviruses cause global encephalitis, which has a good prognosis; however, a few fatalities have been reported. Enterovirus 71 has been linked with a rhombencephalitis (inflammation of the brain stem) in outbreaks of hand-foot-and-mouth disease in the eastern hemisphere (Taiwan, Japan, Malaysia, and Australia). Fatality rates from these outbreaks have been as high as 14%. Myoclonus is a poor prognostic indicator, as are lethargy, persistent fever, and peak temperature higher than 38.5 º C. 
Most cases of myocarditis and pericarditis are self-limited, but a potentially significant mortality rate is associated with myocarditis. Older patients can develop a dilated cardiomyopathy following myocarditis.
The overall mortality rate for paralytic polio is 2-10%. For those who survive, a 6-month period is allowed to predict how much muscle function will return.
Enteroviruses have a worldwide distribution and are not race-specific infections.
Males and females are equally affected. Males are more likely to be symptomatic.
People of all ages, including adults, elderly people, and young people, are at risk of manifesting symptoms of enteroviruses. Children have a higher rate of infection because of exposure, hygiene, and immunity status. The infection course tends to be benign in older children and more serious in neonates. Unlike most cases of nonpolio enteroviral infections, acute hemorrhagic conjunctivitis occurs most frequently in adults aged 20-50 years.
Picornaviridae Study Group. New and Re-classified TypesGenus Parechovirus, species Human parechovirus. Available at http://www.picornastudygroup.com/types/parechovirus/hpev.htm. Accessed: 3/14/09.
Centers for Disease Control and Prevention. Enterovirus D68. Available at http://www.cdc.gov/non-polio-enterovirus/about/EV-D68.html. Accessed: September 23, 2014.
Lowes R. Enterovirus-D68 Is Now Coast to Coast. Medscape Medical News. Available at http://www.medscape.com/viewarticle/832019. Accessed: September 23, 2014.
Tra My PV, Rabaa MA, Vinh H, Holmes EC, Hoang NV, Vinh NT, et al. The emergence of rotavirus G12 and the prevalence of enteric viruses in hospitalized pediatric diarrheal patients in southern Vietnam. Am J Trop Med Hyg. 2011 Oct. 85(4):768-75. [Medline]. [Full Text].
Ikeda T, Mizuta K, Abiko C, Aoki Y, Itagaki T, Katsushima F, et al. Acute respiratory infections due to enterovirus 68 in Yamagata, Japan between 2005 and 2010. Microbiol Immunol. 2012 Feb. 56(2):139-43. [Medline].
Puenpa J, Theamboonlers A, Korkong S, Linsuwanon P, Thongmee C, Chatproedprai S, et al. Molecular characterization and complete genome analysis of human enterovirus 71 and coxsackievirus A16 from children with hand, foot and mouth disease in Thailand during 2008-2011. Arch Virol. 2011 Nov. 156(11):2007-13. [Medline].
Poliovirus. Pediatrics. 2011 Oct. 128(4):805-8. [Medline].
CDC. Enterovirus surveillance–United States, 1997-1999. MMWR Morb Mortal Wkly Rep. 2000 Oct 13. 49(40):913-6. [Medline].
Global Polio Eradication Initiative. Wild Poliovirus Weekly Update. Global Polio Eradication. Available at http://www.polioeradication.org/casecount.asp. Accessed: 2-16-2014.
Polio Outbreak in Syria Poses Vaccination Dilemma for WHO -. Medscape. Available at http://www.medscape.com/viewarticle/881378. Jun 09, 2017; Accessed: June 16, 2017.
WHO Confirms Congo Polio Outbreaks in New Eradication Setback. Medscape. Available at http://www.medscape.com/viewarticle/881568. Jun 13, 2017.; Accessed: June 16, 2017.
Ooi MH, Wong SC, Mohan A, Podin Y, Perera D, Clear D, et al. Identification and validation of clinical predictors for the risk of neurological involvement in children with hand, foot, and mouth disease in Sarawak. BMC Infect Dis. 2009 Jan 19. 9:3. [Medline]. [Full Text].
Feder HM Jr, Bennett N, Modlin JF. Atypical hand, foot, and mouth disease: a vesiculobullous eruption caused by Coxsackie virus A6. Lancet Infect Dis. 2014 Jan. 14(1):83-6. [Medline].
Nahmias AJ, Froeschle JE, Feorino PM, McCord G. Generalized eruption in a child with eczema due to coxsackievirus A16. Arch Dermatol. 1968 Feb. 97(2):147-8. [Medline].
Chonmaitree T, Menegus MA, Powell KR. The clinical relevance of ‘CSF viral culture’. A two-year experience with aseptic meningitis in Rochester, NY. JAMA. 1982 Apr 2. 247(13):1843-7. [Medline].
Singer JI, Maur PR, Riley JP, Smith PB. Management of central nervous system infections during an epidemic of enteroviral aseptic meningitis. J Pediatr. 1980 Mar. 96(3 Pt 2):559-63. [Medline].
Ahmed A, Brito F, Goto C, et al. Clinical utility of the polymerase chain reaction for diagnosis of enteroviral meningitis in infancy. J Pediatr. 1997 Sep. 131(3):393-7. [Medline].
Tan CW, Lai JK, Sam IC, Chan YF. Recent developments in antiviral agents against enterovirus 71 infection. J Biomed Sci. 2014 Feb 12. 21(1):14. [Medline].
Wood DL. Increasing immunization coverage. American Academy of Pediatrics Committee on Community Health Services. American Academy of Pediatrics Committee on Practice and Ambulatory Medicine. Pediatrics. 2003 Oct. 112(4):993-6. [Medline]. [Full Text].
Hyoty H, Hiltunen M, Knip M, et al. A prospective study of the role of coxsackie B and other enterovirus infections in the pathogenesis of IDDM. Childhood Diabetes in Finland (DiMe) Study Group. Diabetes. 1995 Jun. 44(6):652-7. [Medline].
Abzug MJ, Keyserling HL, Lee ML, et al. Neonatal enterovirus infection: virology, serology, and effects of intravenous immune globulin. Clin Infect Dis. 1995 May. 20(5):1201-6. [Medline].
Abzug MJ, Levin MJ, Rotbart HA. Profile of enterovirus disease in the first two weeks of life. Pediatr Infect Dis J. 1993 Oct. 12(10):820-4. [Medline].
Andrus JK, Strebel PM, de Quadros CA, Olive JM. Risk of vaccine-associated paralytic poliomyelitis in Latin America, 1989-91. Bull World Health Organ. 1995. 73(1):33-40. [Medline].
Ballow M. Mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory diseases. J Allergy Clin Immunol. 1997 Aug. 100(2):151-7. [Medline].
Gaspar BG, Kinnon C. Humoral Immunodeficiency: X-linked agammaglobulinemia. Immunol Allergy Clin North Am. 2001. 21(1):
Huang CC, Liu CC, Chang YC, et al. Neurologic complications in children with enterovirus 71 infection. N Engl J Med. 1999 Sep 23. 341(13):936-42. [Medline].
Jiang P, Faase JA, Toyoda H, et al. Evidence for emergence of diverse polioviruses from C-cluster coxsackie A viruses and implications for global poliovirus eradication. Proc Natl Acad Sci U S A. 2007 May 29. 104(22):9457-62. [Medline]. [Full Text].
Kohler KA, Banerjee K, Gary Hlady W, Andrus JK, Sutter RW. Vaccine-associated paralytic poliomyelitis in India during 1999: decreased risk despite massive use of oral polio vaccine. Bull World Health Organ. 2002. 80(3):210-6. [Medline].
Morag A, Ogra P. Enteroviruses. Nelson Textbook of Pediatrics. 16th ed. Philadelphia, Pa: WB Saunders Co; 2000.
Norris CM, Danis PG, Gardner TD. Aseptic meningitis in the newborn and young infant. Am Fam Physician. 1999 May 15. 59(10):2761-70. [Medline].
Prager P, Nolan M, Andrews IP, Williams GD. Neurogenic pulmonary edema in enterovirus 71 encephalitis is not uniformly fatal but causes severe morbidity in survivors. Pediatr Crit Care Med. 2003 Jul. 4(3):377-81. [Medline].
Prevots DR, Burr RK, Sutter RW, Murphy TV,. Poliomyelitis prevention in the United States. Updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2000 May 9. 49(RR-5):1-22; quiz CE1-7. [Medline]. [Full Text].
Roivainen M. Enteroviruses and myocardial infarction. Am Heart J. 1999 Nov. 138(5 Pt 2):S479-83. [Medline].
Rotbart HA, Sawyer MH, Fast S, Lewinski C, Murphy N, Keyser EF, et al. Diagnosis of enteroviral meningitis by using PCR with a colorimetric microwell detection assay. J Clin Microbiol. 1994 Oct. 32(10):2590-2. [Medline]. [Full Text].
Shechet RJ, Tanenbaum B. Preventing unnecessary hypospadias repair. Am Fam Physician. 1999 Nov 1. 60(7):1933. [Medline].
Wilfert CM, Lehrman SN, Katz SL. Enteroviruses and meningitis. Pediatr Infect Dis. 1983 Jul-Aug. 2(4):333-41. [Medline].
Yang TT, Huang LM, Lu CY, et al. Clinical features and factors of unfavorable outcomes for non-polio enterovirus infection of the central nervous system in northern Taiwan, 1994-2003. J Microbiol Immunol Infect. 2005 Dec. 38(6):417-24. [Medline].
Zaoutis T, Klein JD. Enterovirus infections. Pediatr Rev. 1998 Jun. 19(6):183-91. [Medline].
Nicholas John Bennett, MBBCh, PhD, MA(Cantab), FAAP Assistant Professor of Pediatrics, Co-Director of Antimicrobial Stewardship, Medical Director, Division of Pediatric Infectious Diseases and Immunology, Connecticut Children’s Medical Center
Disclosure: Received research grant from: Cubist<br/>Received income in an amount equal to or greater than $250 from: Horizon Pharmaceuticals, Shire<br/>Medico legal consulting for: Various.
Joseph Domachowske, MD Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York Upstate Medical University
Joseph Domachowske, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Phi Beta Kappa
Disclosure: Received research grant from: Pfizer;GlaxoSmithKline;AstraZeneca;Merck;American Academy of Pediatrics, Novavax, Regeneron, Diassess, Actelion<br/>Received income in an amount equal to or greater than $250 from: Sanofi Pasteur.
Mobeen H Rathore, MD, CPE, FAAP, FIDSA Chief of Division of Pediatric Infectious Diseases/Immunology, Associate Chairman of Department of Pediatrics, University of Florida College of Medicine at Jacksonville; Hospital Epidemiologist and Section Chief of Infectious Disease and Immunology, Wolfson Children’s Hospital; Director of University of Florida Center for HIV/aids Research, Education and Service (UF CARES)
Mobeen H Rathore, MD, CPE, FAAP, FIDSA is a member of the following medical societies: American Academy of Pediatrics, American Society for Microbiology, Florida Medical Association, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Society for Healthcare Epidemiology of America, Society for Pediatric Research, Southern Medical Association, Southern Society for Pediatric Research, Florida Chapter of The American Academy of Pediatrics, Florida Pediatric Society, European Society for Paediatric Infectious Diseases
Disclosure: Nothing to disclose.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Mark R Schleiss, MD Minnesota American Legion and Auxiliary Heart Research Foundation Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota Medical School
Mark R Schleiss, MD is a member of the following medical societies: American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Society for Pediatric Research
Disclosure: Nothing to disclose.
Russell W Steele, MD Clinical Professor, Tulane University School of Medicine; Staff Physician, Ochsner Clinic Foundation
Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, Southern Medical Association
Disclosure: Nothing to disclose.
Leonard R Krilov, MD Chief of Pediatric Infectious Diseases and International Adoption, Vice Chair, Department of Pediatrics, Winthrop University Hospital; Professor of Pediatrics, Stony Brook University School of Medicine
Leonard R Krilov, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Society for Pediatric Research
Disclosure: Nothing to disclose.
The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Michelle Mowad, MD, to the original writing and development of this article.
Figure 5 is a photograph of a case of Atypical HFMD seen by Dr Henry Feder and Dr Nicholas Bennett. Permission to use the photograph was granted by the patient’s family. The image is reprinted from The Lancet Infectious Diseases, Vol. 14(1), Feder, Bennett and Modlin, Atypical hand, foot, and mouth disease: a vesiculobullous eruption caused by Coxsackie virus A6, Pages 83-86., Copyright (2014), with permission from Elsevier.
Pediatric Enteroviral Infections
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