Enterovirus Infections

Asif Noor, MD,* Leonard R. Krilov, MD*†

*Department of Pediatrics, Children’s Medical Center, Winthrop University Hospital, Mineola, NY.
†
Department of Pediatrics, State University of New York, Stony Brook School of Medicine, Stony Brook, NY.

Education Gap
Clinicians must learn to recognize the spectrum of clinical syndromes
associated with enteroviruses. Examples include the association of
asthma exacerbation with enterovirus D68 and the association of acute
eczema flare-up with coxsackievirus A16.

Objectives After completing this article, readers should be able to:

1. Understand the epidemiology of enterovirus infections.

2. Recognize the wide spectrum of clinical presentations with enterovirus
infection.
3. Plan appropriate laboratory evaluation for enterovirus infection.

CASE SCENARIO

During Monday morning clinic in mid-July, you refer 2 cases to the emergency
department (ED). The first is a 2-week-old neonate who has had 1 day of decrea-
sed oral intake and a temperature of 102°F (38.9°C) at your clinic. The baby
appears alert with normal findings on physical examination. Later in the morning
you receive an update call from the ED attending physician. Examination of the
cerebrospinal fluid (CSF) shows pleocytosis with 55 white blood cells/mL but
normal glucose (68 mg/dL) and protein (90 mg/dL) measurements. The Gram
stain is negative. The CSF is positive for enterovirus (EV) by polymerase chain
reaction (PCR) assay.
The second case is a 5-year-old boy with a history of asthma who has had a
cough for 3 days and difficulty breathing for 1 day. He does not respond to 2 back-
to-back treatments with inhaled albuterol, so you refer him to the ED. He is
subsequently admitted to the pediatric intensive care unit for management of
status asthmaticus. A nasopharyngeal multiplex film array assay is positive for
EV/rhinovirus.
AUTHOR DISCLOSURE Dr Noor has disclosed
no financial relationships relevant to this
article. Dr Krilov has disclosed that he is site INTRODUCTION
principal investigator for instituted contract
research for Regeneron Pharmaceuticals, Inc, EV infections peak in the summer months; the pathogen remains one of the
and AstraZeneca. This commentary does
most common causes of community outbreaks encountered by pediatricians. The
contain a discussion of an unapproved/
investigative use of a commercial product/ prevalence is determined by weather, with most EV infections seen in summer
device. and fall in the temperate northern hemisphere and the virus circulating

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 throughout the year in the tropics. EVs are highly conta- CLASSIFICATION
gious, spreading through fecal-oral and respiratory secre-
Original Classification
tions. The organs affected and the severity of the illnesses
The original classification of EVs was based on differences
are largely determined by virulence of the virus and immu-
in their effects in tissue culture and pattern of disease in
nity of the host. Molecular technology has helped in iso-
experimentally infected animals. Human EVs were grouped
lation of many newer serotypes. For example, EV D68 was
as polioviruses and nonpolio EVs (echo-, coxsackie-, and
responsible for a large outbreak of severe respiratory illness
other numbered EVs). At first, researchers believed that
in children with asthma across the United States (initial
the human alimentary tract was a natural habitat for these
reports from Missouri and Illinois) in 2014. (1) The testing
viruses, hence, the name enterovirus. As more viruses were
strategy for EVs has evolved over the years, and widespread
identified, the association of some of these viruses with
availability of PCR assays has provided clinicians with the
human diseases was not known and they were grouped as
ability to diagnose such infections rapidly.
enteric cytopathogenic human orphan or ECHO viruses.
The coxsackie groups of viruses were named after a small
HISTORY town, Coxsackie, near the Hudson River in New York, where
Dalldorf and Sickles isolated the virus in mice in 1948 from
Poliovirus is the most famous EV of the 20th century.
fecal specimens.
President Franklin Roosevelt, who himself was affected by
the virus, founded the National Foundation for Infantile
Paralysis in 1938 to combat polio. As a result of the success- Reclassification
ful worldwide campaign for polio vaccination, the last case Many EV strains have been isolated that do not fit into these
of confirmed wild-type paralytic poliomyelitis in the west- categories, leading to the presently used revised classifica-
ern hemisphere was reported in 1991. tion. (4) This newer classification is based on molecular
Poliovirus has a long history. (2) The earliest descriptions serotyping, which includes determination of the nucleotide
of infection are found on an Egyptian stone (1580 BC) (RNA) sequence encoding the viral polypeptide capsid
showing a man with a shrunken short leg, depicting char- (Table 1).
acteristic effects of the infection. In 1908, Landsteiner and Recently, 2 echoviruses (E22 and E23) were reclassified
Popper isolated poliovirus in monkeys. It was not until 1949 as the initial members of the new genus Parechovirus as PV
that Enders and colleagues described virus growth in tissue types 1 and 2 because they differ in terms of their genomics
culture. Ultimately their techniques led to recovery of many and proteomics from other EVs. Similarly, hepatitis A virus
other EVs and enabled the development of polio vaccines initially was assigned the designation EV72, but it was
over subsequent decades. reclassified as the sole member of the Hepatovirus genus
within the Picornavirus family (Table 2).
Recently, the Cardiovirus genus of the Picornaviridae
VIRUS CHARACTERISTICS family has been expanded by identification of the Saffold
EVs belong to the family Picornaviridae (pico ¼ small). viruses (SVs). Beginning with a strain isolated in 2007, 8
Parechoviruses (PVs) and Saffold viruses (SVs) are now genetically distinct SVs have been identified. SVs have been
grouped with EVs because they share certain morphologic recognized as a cause of mild human disease in children.
and functional properties. Recombination between circulating picornaviruses is a
The virion is nonenveloped, spherical, and about 30 nm frequent event and is likely to increase genetic diversity and
in diameter. The genome is a positive sense RNA, with an pose future challenges in classification.
approximate length of 7.4 kb. Infections occur with adsorp-
tion of the virus to cellular receptors, primarily integrins and
EPIDEMIOLOGY
immunoglobulin-like proteins. (3) After penetration, there is
rapid replication (5-10 hours) inside the cytoplasm of the cell. Transmission
EVs are relatively stable viruses that can retain activity for EVs are spread from person to person via fecal-oral and
several days at room temperature and can be stored indef- respiratory routes. Most of the EVs are shed in the respira-
initely at freezer temperatures (4°F [20°C]). They are also tory secretions for 1 to 3 weeks and in the feces for 2 to 8
stable at the low pH of stomach acid. EVs grow rapidly when weeks after primary infection. EV 71, the cause of hemor-
adapted to susceptible host systems and can cause cytopa- rhagic conjunctivitis, is spread via fingers, fomites, and
thologic features within 2 to 7 days. tears. Infants, particularly those in diapers, are effective

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TABLE 1. Traditional Versus Newer Enterovirus Classification
TRADITIONAL CLASSIFICATION NEWER CLASSIFICATION
Host disease pattern and tissue culture effects Molecular serotyping (RNA sequence)
in infected animal models
Groups & Serotype Coxsackieviruses A Group A
1–22, 24* Coxsackievirus A serotypes 2–8, 10, 12, 14, 16; Enterovirus
serotypes 71, 76, 89–92
Coxsackieviruses B Group B
1–6 Coxsackievirus A serotype 9; B serotypes 1–6
Echoviruses
1–9, 11–27, 29–33 Echovirus serotypes 1–7, 9, 11–21, 24–27, 29–33; Enterovirus
serotypes 69, 73–75, 77–88, 93, 97, 98, 100, 101, 106, 107
Polioviruses Group C
1–3 Poliovirus serotypes 1–3; Coxsackievirus A serotypes 1, 11,
13, 17, 19–22, 24
Enterovirus Group D
68–72 Enterovirus D68, D70, D94, D111

*Coxsackievirus A23 was reclassified as echovirus 9.

Adapted from http://www.picornastudygroup.com/taxa/taxa.htm.

vehicles of transmission. Virus shedding by symptomatic Prevention (CDC) has increased understanding of the epi-
and asymptomatic persons may contribute to transmission demiology and nature of outbreaks. Between 1970 and
of these agents. 2005, 15 serotypes represented 83.5% of all EV isolates sub-
The incubation period for brief febrile illness due to EVs mitted from state and local public health laboratories. (6) EV
is 1 to 3 days and for poliovirus is 9 to 12 days. detections were found to have remarkable seasonality, with
the number of cases increasing sharply during summer and
Distribution and Season fall months and peaking in August. This summer-fall sea-
EVs have worldwide distribution. Neutralizing antibodies sonality was more prominent for EV detections from CSF
for specific viral types have been noted in serologic surveys specimens (81.3%) in contrast to fecal (77.6%) or respi-
throughout the world (71 serotypes to date). In any given ratory specimens (69.8%).
area, frequent fluctuations occur in the predominant types.
Epidemics may be localized and sporadic, and they may
PATHOGENESIS
vary in origin from place to place in the same year. (5) The
prevalence of unrecognized infection far exceeds that of Human EVs are acquired directly or indirectly by ingestion
clinical disease. of a virus shed in the feces or upper respiratory tract of
infected contacts. Initial viral replication occurs in the upper
Surveillance of Outbreaks respiratory tract and distal small bowel. Infectious virus is
Data collected by the National Enterovirus Surveillance detectable in the ileal lymphoid tissue 1 to 3 days after
System (NESS) of the Centers for Disease Control and ingestion of the virus, and fecal shedding can be detectable
for 6 or more weeks (Fig 1).
Viral replication in the submucosal lymphoid tissue re-
TABLE 2. Classification of Human Picornavirus sults in brief primary viremia that distributes virus to retic-
Family uloendothelial tissue in distant lymph nodes, liver, spleen,
and bone marrow. Further replication in these organs leads to
GENUS SPECIES
continued secondary viremia and dissemination of virus to
Enterovirus Human enterovirus A-D, Human target organs such as the central nervous system (CNS), heart,
rhinovirus A-C
and skin. Organ-specific disease (ie, poliomyelitis, myocardi-
Parechovirus Parechovirus tis) results from virus-induced cell necrosis and the accom-
Hepatovirus Hepatitis A virus panying inflammatory response. Many infected persons clear
the infection before the secondary viremia and experience
Cardiovirus Saffold virus
only transient symptoms or have an asymptomatic infection.

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 Figure 1. Timeline of events in enterovirus
infection: pathogenesis. CNS¼central
nervous system, GI¼gastrointestinal,
PCR¼polymerase chain reaction.

CLINICAL PRESENTATION commonly with CV B5 as well as echoviruses 4, 6, 9, 13, and

30 through 33. In general, aseptic meningitis is seen in
EVs other than poliovirus are not reportable; therefore, the
young children, but adolescents and adults can also be af-
actual burden of symptomatic infection is not available. EVs
fected during outbreaks.
are believed to account for an estimated 10 to 15 million
The clinical course typically involves an initial episode
symptomatic infections in the United States every year.
of nonspecific fevers and follows a biphasic pattern, with
Symptomatic infections range from a minor illness such
fever recurrence in conjunction with CNS symptoms. Initial
as a common cold to fulminant sepsis and meningitis. The
symptoms may also include headache, malaise, nausea, and
variation in presentation represents the wide variety of
vomiting. The headache usually is frontal or generalized and
serotypes and the host’s immunity. NESS has provided
can be accompanied by photophobia. Physical examination
valuable data since 1961 on the clinical association with
typically demonstrates generalized muscle stiffness or
specific serotypes and nature of community outbreaks
spasm. The Kernig and Brudzinski signs are positive in
(Table 3).
fewer than 50% of cases. Pharyngitis occurs frequently, as
does a maculopapular skin rash. The rash can have a
Asymptomatic Infection
petechial component, as seen in infections due to echovirus
An estimated 50% of EV infections are asymptomatic.
9. Aseptic meningitis caused by EV 71 can have associated
Young age is associated with higher frequency of symptom-
hand-foot-and-mouth (HFM) disease.
atic infection. Asymptomatic infection from CV A16 occurs
Examination of CSF reveals considerable variation
in only approximately 10% of children younger than age 5
among patients and even in the same patient on repeated
years, whereas rates are reported to be higher in older
examination. CSF leukocyte counts vary from a few cells to a
children and adults. (7)
few thousand per cubic millimeter; the median is in the
range of 100 to 500 cells/mm3. The percentage of neutro-
Nonspecific Febrile Illness phils also varies greatly. Initial examinations frequently
Most of the EVs cause a brief febrile illness with no other reveal a predominance of neutrophils. Repeated evaluations
symptom or sign. Usually, there is a sudden-onset fever that of CSF demonstrate an increasing percentage of mono-
can last up to 3 days. However, biphasic illness, character- nuclear cells. (8) CSF protein values are mildly elevated,
ized by an initial day of fever and a recurrence 2 to 3 days and glucose concentrations usually are within normal
later for 2 to 4 days, can also be seen. Younger children can ranges. Most patients have normal neurologic and cognitive
have malaise and older children can experience headache or outcomes.
a sore throat without pharyngeal injection. The physical Encephalitis. EVs are an uncommon (2%) cause of
examination and the white blood cell count usually yield encephalitis in the United States. Echovirus 9 is most often
unremarkable findings. the cause. Since the mid-1970s, epidemics of HFM disease
associated with encephalitis have been reported in Asian-
CNS Infections Pacific countries.
Aseptic Meningitis. EVs are the most common cause of Nonpolio Paralysis. In contrast to polioviruses, which
aseptic meningitis. Epidemic disease has occurred most led to epidemic paralytic disease, the nonpolio EVs cause

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TABLE 3. Clinical Syndromes Associated With Enteroviruses
SYNDROME VIRAL TYPE CLINICAL FEATURES

Nonspecific febrile illness All viral types Fevers for 3-4 days; can be biphasic. Minimal respiratory or GI
symptoms.
Aseptic meningitis CV B5; echoviruses 4, 6, 9, 13, and 30-33 Fever with meningeal signs. Mild CSF pleocytosis; normal
protein and glucose.
Acute hemorrhagic conjunctivitis EV 70; CV A24 (rare) Sudden onset of eye pain with subconjunctival hemorrhage.
Herpangina CV A & B; PV 1 & 6; EV 71; SV 2 & 3 Fevers with painful vesicles or ulcers over posterior palate and/
or tonsils.
Hand-foot-mouth CV A (6, 16) & B; EV 71; echovirus Fever with enanthem (vesicles in the mouth) and exanthem
(vesicles on hands and feet).
Carditis CV B1-5 Myopericarditis presenting with heart failure or arrhythmias.
Nonspecific exanthem CV A16 (most common), A6, A9; echovirus 9 Variable rash (vesicular, maculopapular, urticarial, petechial,
purpuric) after fevers (þ/-) for 1-2 days.
Newly Described Syndromes
Eczema coxsackium CV A6 Acute onset of vesicles or erosions in children with atopic
dermatitis. Milder and shorter course of illness.
Acute flaccid paralysis EV 71; CV A7 Paralysis, but less severe illness and less bulbar involvement
than poliovirus.
Acute respiratory illness EV D68 Acute onset of cough, dyspnea, wheezing, and hypoxemia
in children with history of asthma or wheezing.

CSF¼cerebrospinal fluid, CV¼Coxsackievirus, EV¼enterovirus, GI¼gastrointestinal, PV¼Parechovirus, SV¼Saffold virus.

sporadic paralytic disease. Paralytic disease has been re- temperatures (103°-104°F [39.4-40°C]). Higher tempera-
ported in outbreaks due to CV A7 and EV 71. In 2014, a tures (106°F [41.1°C]) and seizures may occur at disease
cluster of pediatric cases of acute flaccid myelitis was onset. Young children may be irritable, occasionally listless,
identified in the midst of an outbreak of EV D68 causing and anorexic for a few hours before the fevers appear. Older
severe respiratory distress, although no direct link between children frequently complain of headache and backache.
EV D68 and paralytic disease was confirmed. (9) The oropharyngeal lesions usually erupt around the time
Guillain-Barré syndrome, transverse myelitis, and of first fever. The characteristic lesions are small (1 to 2 mm)
cerebral ataxia have also been associated with EVs and vesicles and ulcers (Fig 2). These lesions start as papules,
echoviruses. become vesicular, and ulcerate in a short period of time. The
lesions are discrete and surrounded by an erythematous
Ocular Infections ring, with an average of 5 to 6 lesions (range, 1-14). The most
Outbreaks of acute hemorrhagic conjunctivitis are typically common site of the lesions is the anterior tonsillar pillars.
due to EV 70 or CV A24. Presentation is characterized by The duration of illness is 3 to 6 days.
a sudden onset of severe eye pain and associated photopho- Acute Lymphonodular Pharyngitis. This variant of her-
bia. Subconjunctival hemorrhages are frequently present. pangina has a similar distribution of mouth lesions. How-
Systemic symptoms, including fever, are rare. ever, the lesions are white to yellow and may persist for 6 to
10 days.
Skin and Mucous Membrane Infections Hand-foot-and-mouth Disease. This common clinical
Herpangina. This is an enanthematous (mucous mem- syndrome manifests as a vesicular skin rash on the hands
brane) disease that presents with painful vesicles of the oral and feet along with vesicles in the oral cavity. It most
mucosa along with fever and sore throat. All age groups are commonly affects toddlers and school-age children. The
affected, but it is most common in children ages 3 to 10 frequent etiologic agents are CVs A6 and A16, CV B, EV
years. CVs A and B, PVs 1 and 6, EV 71, and SVs 2 and 3 are 71, and echovirus. The presentation includes fevers, rash, and
known causes of herpangina. The onset is sudden, with high the characteristic exanthema and enanthem. Temperatures

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 range from 100.4° to 102.2°F (38°-39°C) and last for 1 to 2 Heart Infections
days. The oral vesicles usually are located on the buccal Pathologic studies have shown that both the myocar-
mucosa and tongue and are only mildly painful. The exan- dium and the pericardium are involved in myopericarditis,
them involves vesicles on the palms, soles, and the inter- which is why that term is preferred. CV B5 has been
digital surfaces of the hands and feet. Onychomadesis implicated as the most common causative agent, but types
(separation of the fingernail from the nail bed) has been 2, 3, and 4 as well as echovirus type 6 can also cause
reported 2 to 3 weeks after HFM disease (Fig 3). myopericarditis.
The differential diagnosis for HFM disease includes Myopericarditis affects all ages, but physically active
varicella-zoster virus infection, herpes simplex virus infec- adolescents and adults are at higher risk. The usual pre-
tion, or aphthous ulcers. Unlike HFM, varicella lesions are sentation is fever, fatigue, and dyspnea on exertion, but
more extensive, located more centrally, and in different more fulminant symptoms, including heart failure or
stages simultaneously, and they usually spare the palms dysrhythmia, can occur. Echocardiography may confirm
and soles. In herpetic gingivostomatitis, the lesions are diminished cardiac ejection fraction or show acute ven-
primarily anterior in the mouth, and the child has a higher tricular dilation. Serum concentrations of troponins are
temperature, prominent cervical lymphadenopathy, and frequently elevated. The mortality rate for acute CV and
no rash. Aphthous ulcers are large, ulcerative lesions of echoviral heart disease is less than 5%. Children who
the lips, tongue, and buccal mucosa that are extremely survive acute CV myocarditis usually recover completely
painful. In comparison to HFM disease, such ulcers are without any residual disability. An association between
seen most commonly in older children and adults, involve idiopathic dilated cardiomyopathy and group B CV has
multiple recurrences, have no rash, and typically are not been suggested.
associated with constitutional symptoms.

NEWLY RECOGNIZED CLINICAL SYNDROMES

Skeletal Muscle Infection
Pleurodynia (Bornholm disease) is characterized by an acute Asthma Exacerbation and EV D68
onset of severe muscular pain in the chest and abdomen EV D68 was first identified in 1962 during sporadic
accompanied by fever. It is more common in older children outbreaks of respiratory infections, but it emerged as a
and adolescents. CV B3 and B5 are the major causes of significant pathogen in 2014 when the United States
epidemic presentations. The muscular pain is sharp and experienced a nationwide outbreak. It was associated with
spasmodic, with episodes typically lasting 15 to 30 minutes. severe respiratory illness in children with asthma or a
During spasms, patients can have signs of respiratory history of wheezing. From mid-August 2014 to January
distress or appear in shock, with diaphoresis and pallor. 15, 2015, the CDC confirmed a total of 1,153 people in 49
The illness usually lasts 1 to 2 days, but frequently a biphasic states and the District of Columbia with respiratory illness
pattern is seen, with recurrences possible several weeks caused by EV D68. (1)
after the initial episode.
Eczema Coxsackium
An atypical skin rash was reported in children with atopic
dermatitis during the 2011 to 2012 outbreak of HFM
disease associated with CV A6. This rash was characterized
by accentuation of vesicles and erosions within areas of
eczema and was termed “eczema coxsackium.” (10) This
morphology was strikingly similar to eczema herpeticum
caused by herpes simplex virus 1. However, eczema cox-
sackium is generally less painful and the child remains
reasonably well.
EV infections, particularly CV A6, should be considered
in the differential diagnosis of patients presenting with
new-onset vesicles and extensive erosions in preexisting
Figure 2. Herpangina (Coxsackievirus) lesions on the posterior palate of areas of eczema (Fig 4). EV PCR on the vesicle fluid allows
a young adult male. Coxsackievirus lesions typically are found in the
for early diagnosis, thus potentially avoiding antibiotics or
posterior aspect of the oropharynx and may progress rapidly to painful
ulceration. Source: AAP Red Book, 2015. acyclovir.

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Figure 3. Vesicular eruptions in hand (A), foot
(B), and mouth (C) of a 6-year-old boy with
coxsackievirus A6 infection. Several of his
fingernails shed (D) 2 months after the
pictures were taken. Courtesy of Centers for
Disease Control and Prevention/Emerging
Infectious Diseases. Source: AAP Red Book,
2015.

SPECIAL HOST INFECTIONS outcome of neonatal infection is strongly influenced by

the presence or absence of passively acquired maternal
Neonatal Infection
antibody specific for the infecting EV serotype. EV
Neonates are at high risk of disseminated disease result-
infection should be considered in cases of neonatal
ing from EV infections acquired during the perinatal period.
sepsis when neither bacteria nor herpes simplex virus
Most of the infections are due to echoviruses (serotypes
is isolated.
6, 9, and 11), group B CVs (serotypes 1 to 5), and PVs
(serotype 3). Infection in Immunocompromised Hosts
EV infections acquired perinatally present within the EVs are known to cause serious as well as persistent
first postnatal week. Onset of serious EV infection beyond infections in patients with congenital or acquired defects
10 days of age is uncommon. A wide range of clinical in B-lymphocyte function. Persistent infections are seen
disease has been reported in neonates, including non- in children with X-linked agammaglobulinemia or severe
specific febrile illnesses, exanthems, and aseptic menin- combined immunodeficiency syndrome or in adolescents
gitis. The most severe manifestations are myocarditis with with common variable immunodeficiency. Chronic infec-
or without encephalitis, hepatitis, and pneumonia. The tions also occur in bone marrow transplant recipients.

Figure 4. Eczema coxsackium on the hands

(A) and back (B) of a 6-month-old infant with
underlying atopic dermatitis and acute onset
of vesicles and erosive rash.

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 Echoviruses (particularly serotype 11) are responsible for In the United States, 4 doses of inactivated polio vaccine
most of these infections, but individual cases caused by are recommended for routine immunization of all infants
group A and group B CVs have been reported. and children. In most countries, OPV remains the vaccine
Chronic meningoencephalitis, the most common clin- of choice. The original trivalent OPV induces humoral
ical syndrome in these immunodeficient patients, typically immunity to all types of poliovirus (1–3) in addition to
presents with insidious headache, fatigue, mild meningi- local gastrointestinal mucosal immunity, which prevents
smus, or seizures. The symptoms fluctuate in severity, spread of infection. In April and May 2016, a global switch
disappear, or slowly progress. Persistent CSF pleocytosis from trivalent to bivalent OPV(1,3) was made because the
and a high CSF protein concentration are characteristic only cases of type 2 paralytic polio were due to vaccine-
of chronic EV meningoencephalitis. The prognosis for related strains. To maintain immunity levels to type 2
immunodeficient children who are persistently infected is polio, high-risk countries introduced inactivated polio
poor. vaccine (1–3) into routine immunization programs before
the switch.
Polio was virtually eradicated from the western hemi-
INFECTION WITH POLIOVIRUS
sphere by 1991. Four of the 6 regions of the World Health
Poliovirus infection occurs only in humans. Transmission is Organization have been certified polio-free: the Americas
primary through the fecal-oral and respiratory routes. The (1994), Western Pacific (2000), Europe (2002), and South
virus is present in the throat for 1 to 2 days before the onset East Asia (2014). Pakistan and Afghanistan continue to have
of illness and is shed in feces for 3 to 6 weeks, rendering it ongoing polio transmission. In 2015, 74 cases of wild
contagious for this duration. Most poliovirus infections are poliovirus were reported: 54 from Pakistan and 20 from
asymptomatic (74%) or mild (4%). Acute paralytic disease Afghanistan.
may be caused by naturally occurring wild polioviruses or
by mutated vaccine-derived polioviruses. In addition, rare
LABORATORY DIAGNOSIS
cases of vaccine-associated paralytic poliomyelitis occur in
recipients of oral poliovirus vaccine (OPV) or their close The 3 common methods used to aid in the diagnosis of an EV
contacts. infection are PCR, viral culture, and serology (Table 4).
In classic paralytic polio, the rapid onset of paralysis
occurs 1 to 3 days after a minor febrile illness with sore Polymerase Chain Reaction
throat, headache, and myalgias. The paralysis is asymmetric PCR is more sensitive (86%) than culture (30%) for iden-
and affects the proximal muscles more than the distal tification of EVs in CSF and respiratory tract secretions. PCR
muscles. Lower limbs are more frequently affected and has been most useful in detecting EV in CSF. (11) Four
sensation is usually intact except in severe cases. CSF commercially available multiplex PCR panels are available
analysis suggests aseptic meningitis, and the virus can be in the United States that detect EVs in a swab from a
readily isolated from the throat or stool of an affected child. nasopharyngeal specimen. Some of these assays report
Postpolio syndrome is characterized by new onset of muscle enterovirus together with rhinovirus (both are picornavi-
weakness and atrophy occurring about 14 to 25 years after ruses). PCR testing of fecal specimens has been less suc-
the initial infection. The affected muscle groups are usually cessful because of the presence of substances that inhibit
the same as in the original illness. the polymerization step.

TABLE 4. Laboratory Diagnosis of Enteroviruses

TEST METHOD SENSITIVITY SPECIFICITY

Viral culture (3-8 days) Cell culture 0% to 80% 100%

PCR assay (1-2 hours) -CSF PCR 100% Variable 97% Variable
-Respiratory multiplex PCR (picornavirus: EVs/rhinovirus)
Serology (weeks) Microneutralization Limited use

CSF¼cerebrospinal fluid, EV¼enterovirus, PCR¼polymerase chain reaction.

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Virus Isolation INFECTION CONTROL AND PREVENTION
EVs can be isolated in cell culture from CSF, pericardial
Transmission can be reduced with simple measures such
fluid, tissue, blood, or stool, with cytopathic effects usually
as handwashing and careful disposal of soiled diapers.
seen between 2 and 5 days after inoculation in cell culture.
When a child becomes ill with an EV infection, he or she
Once isolated, the virus serotype can be identified for most
should be kept out of school, swimming pools, and child
of the common EVs with use of RNA sequencing. The
care settings for the first few days until the fevers defervesce.
chances of recovering a virus in cell culture are optimized
In the health care setting, contact precautions are indicated
by sampling multiple sites. Isolation of virus from stool is
for the duration of EV illness, particularly conjunctivitis.
less definitive because unrelated intercurrent asymptomatic
Immunocompromised children and pregnant women
infections can occur.
should be advised to avoid contact with a patient who has sus-
pected EV infection.
Serology
Serology is of limited use in acute infections due to the need
for acute and convalescent titers, cross-reactivity among
different serotypes, and lack of sensitivity of immunoglob- Summary
ulin M assays. • On the basis of strong research evidence, (6) enteroviruses (EVs)
cause a wide range of clinical diseases with peak prevalence in
The microneutralization test is the method used most
the summer months. They are the most common cause of aseptic
widely for determining EV antibodies. This serotype-specific meningitis in children and are responsible for community
assay has limited usefulness in the routine diagnosis of EV outbreaks of hand-foot-and-mouth disease.
infections because it is not feasible to incorporate all rele- • On the basis of strong research, (4) the nomenclature of these EVs
vant live viral antigens into the assay. The methods based on has changed with the discovery of new serotypes and is based on
neutralization are relatively insensitive, poorly standard- RNA sequencing.
ized, and labor-intensive. • On the basis of some evidence, (11) polymerase chain reaction
has a higher sensitivity for detecting EVs with a much shorter
turnaround time than culture.
TREATMENT • On the basis of some evidence, (12) treatment is symptomatic, with
no presently available antiviral therapy. Intravenous
No specific treatment for EV infections exists to date. The
immunoglobulin can be considered in neonatal infections, cases of
mainstay of management is supportive care whether the meningoencephalitis in immunocompromised patients, or life-
presentation is a mild cold or a life-threatening viremia. threatening infections in immunocompetent children.

Intravenous Immunoglobulin (IVIG)

Some evidence suggests that administering IVIG in neo-
natal EV infections can result in faster cessation of To view PowerPoint slides that accompany this article,
viremia. (12) IVIG treatment has been used in cases of visit http://pedsinreview.aappublications.org
chronic EV meningoencephalitis in immunodeficient and click on the Supplemental tab for this article.
patients. In addition, in cases of life-threatening EV in-
fection, IVIG can be considered for older immunocom-
petent children, specifically for myocarditis and EV 71
neurologic disease, although supportive data comprise
only anecdotal reports. A specific recommended dose is
not known, but 400 mg/kg per day for 4 days or 2 g/kg in
1 dose has been used.

Pleconaril
Pleconaril is an antiviral agent with demonstrated activity
against EVs. In a study comparing enteroviral meningitis
treatment with pleconaril and control, the duration of
disease was shortened from 9.5 days in controls to 4.0 days
in drug recipients. (12) However, the drug is not licensed or References for this article are at http://pedsinreview.aappubli-
available in United States at this time. cations.org/content/37/12/505.

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1. A previously healthy 15-year-old boy is admitted to the pediatric intensive care unit in July REQUIREMENTS: Learners
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2016 Pediatrics in Review
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514 Pediatrics in Review

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5. A 2-month-old girl is admitted to the hospital for decreased feeding and temperature to
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findings on physical examination. A complete blood cell count and urinalysis yield
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C. Contact precautions.
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E. Only standard precautions.

Vol. 37 No. 12 DECEMBER 2016 515

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 Enterovirus Infections
Asif Noor and Leonard R. Krilov
Pediatrics in Review 2016;37;505
DOI: 10.1542/pir.2016-0103

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 Enterovirus Infections
Asif Noor and Leonard R. Krilov
Pediatrics in Review 2016;37;505
DOI: 10.1542/pir.2016-0103

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/content/37/12/505

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