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.^[1] 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.^[2] 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.

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.

Each virus obtains its antigenicity from the capsid proteins that surround the RNA core. According to the Centers for Disease Control and Prevention (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.

Frequency

United States

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.

International

Nonpolio enteroviral infections are quite prevalent worldwide. The exact numbers are unavailable.

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.^[3] 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. The data below suggests that the outbreak continues.

Worldwide polio cases from January-March 2009 are reported as follows:^[4]

• Nigeria (endemic) – 51 (801 cases in 2008)
• India (endemic) – 17 (559 cases in 2008)
• Democratic Republic of Congo (importation) – 0 (5 cases in 2008)
• Pakistan (endemic) – 8 (118 cases in 2008)
• Niger (importation) - 3 (12 cases in 2008)
• Afghanistan (endemic) - 4 (31 cases in 2008)
• Angola (importation) - 1 (29 cases in 2008)
• Ethiopia (importation) - 0 (3 cases in 2008)
• Chad (importation) – 0 (37 case in 2008)
• Kenya (importation) - 2 (0 cases in 2008)
• Nepal (importation) - 0 (6 cases in 2008)
• Uganda (importation) - 3 (0 cases in 2008)
• Sudan (importation) - 11 (26 cases in 2008)
• Togo (importation) - 3 (3 cases in 2008)
• Benin (importation ) - 2 (6 cases in 2008)
• Burkina Faso (importation) - 4 (6 cases in 2008)
• Mali (importation) - 1 (1 case in 2008)
• Côte d'Ivoire (importation) - 0 (1 case in 2008)
• Ghana (importation) - 0 (8 cases in 2008)

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.

Mortality/Morbidity

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.^[5]

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.

Race

Enteroviruses have a worldwide distribution and are not race-specific infections.

Sex

Males and females are equally affected. Males are more likely to be symptomatic.

Age

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.