PEDIA TOPIC COXSACKIE

Etiology
Enteroviruses are nonenveloped, single-stranded, positive-sense viruses in the
Picornaviridae (“small RNA virus”) family, which also includes the rhinoviruses,
hepatitis A virus, and parechoviruses. The original human enterovirus subgroups
—polioviruses (see Chapter 276 ), coxsackieviruses, and echoviruses—were
differentiated by their replication patterns in tissue culture and animals (Table
277.1 ). Enteroviruses have been reclassified on the basis of genetic similarity
into 4 species, human enteroviruses A-D. Specific enterovirus types are
distinguished by antigenic and genetic sequence differences, with enteroviruses
discovered after 1970 classified by species and number (e.g., enterovirus D68
and A71). Although more than 100 types have been described, 10-15 account for
the majority of disease. No disease is uniquely associated with any specific
serotype, although certain manifestations are preferentially associated with
specific serotypes. The closely related human parechoviruses can cause clinical
presentations similar to those associated with enteroviruses.

Epidemiology
Enterovirus infections are common, with a worldwide distribution. In temperate
climates, annual epidemic peaks occur in summer/fall, although some
transmission occurs year-round. Enteroviruses are responsible for 33–65% of
acute febrile illnesses and 55–65% of hospitalizations for suspected sepsis in
infants during the summer and fall in the United States. In tropical and
semitropical areas, enteroviruses typically circulate year-round. In general, only
a few serotypes circulate simultaneously. Infections by different serotypes can
occur within the same season. Factors associated with increased incidence and/or
severity include young age, male sex, exposure to children, poor hygiene,
overcrowding, and low socioeconomic status. More than 25% of symptomatic
infections occur in children younger than 1 yr of age. Breastfeeding reduces the
risk for infection, likely via enterovirus-specific antibodies.
Humans are the only known natural reservoir for human enteroviruses. Virus
is primarily spread person to person, by the fecal-oral and respiratory routes,
although types causing acute hemorrhagic conjunctivitis may be spread via
airborne transmission. Virus can be transmitted vertically prenatally or in the
peripartum period, or, possibly, via breastfeeding. Enteroviruses can survive on
environmental surfaces, permitting transmission via fomites. Enteroviruses also
can frequently be isolated from water sources, sewage, and wet soil. Although
contamination of drinking water, swimming pools and ponds, and hospital water
reservoirs may occasionally be responsible for transmission, such contamination
is often considered the result rather than the cause of human infection.
Transmission is common within families (≥50% risk of spread to nonimmune
household contacts), daycare centers, playgrounds, summer camps, orphanages,
and hospital nurseries; severe secondary infections may occur in nursery
outbreaks. Transmission risk is increased by diaper changing and decreased by handwashing.
Tickborne transmission has been suggested.
Large enterovirus outbreaks have included meningitis epidemics (echoviruses
4, 6, 9, 13, and 30 commonly); epidemics of hand-foot-and-mouth disease with
severe central nervous system (CNS) and/or cardiopulmonary disease caused by
enterovirus A71 in Asia and Australia; outbreaks of atypical, severe hand-foot-
and-mouth disease caused by coxsackievirus A6 in the United States and United
Kingdom; outbreaks of human enterovirus D68 respiratory illness associated
with acute flaccid myelitis in the United States and Europe; outbreaks of acute
hemorrhagic conjunctivitis caused by enterovirus D70, coxsackievirus A24, and
coxsackievirus A24 variant in tropical and temperate regions; and community
outbreaks of uveitis. Reverse transcription polymerase chain reaction (RT-PCR)
and genomic sequencing help identify outbreaks and demonstrate, depending on
the outbreak, commonality of outbreak strains, differences among epidemic
strains and older prototype strains, changes in circulating viral subgroups over
time, cocirculation of multiple genetic lineages, coinfections with different
enterovirus serotypes, and associations between specific genogroups and/or
genetic substitutions and epidemiologic and clinical characteristics. Genetic
analyses have demonstrated recombination and genetic drift that lead to
evolutionary changes in genomic sequence and antigenicity and extensive
genetic diversity. For example, emergence of new subgenotypes and genetic
lineages of enterovirus A71 may contribute to sequential outbreaks and increases
in circulation.
The incubation period is typically 3-6 days, except for a 1-3 day incubation
period for acute hemorrhagic conjunctivitis. Infected children, both symptomatic
and asymptomatic, frequently shed cultivable enteroviruses from the respiratory
tract for <1-3 wk, whereas fecal shedding continues for as long as 7-11 wk.
Enterovirus RNA can be shed from mucosal sites for comparable, and, possibly,
longer periods.

Pathogenesis
Cell surface macromolecules, including poliovirus receptor, integrin very-late-
activation antigen (VLA)-2, decay-accelerating factor/complement regulatory
protein (DAF/CD55), intercellular adhesion molecule-1 (ICAM-1), ICAM-5,
and coxsackievirus-adenovirus receptor, serve as viral receptors. In addition,
respiratory epithelial cell sialic acids serve as receptors for enterovirus D68,
enterovirus D70, and coxsackievirus A24 variants, and human scavenger receptor class B2
(SCARB2), human P-selectin glycoprotein ligand-1, and DC-
SIGN are receptors for enterovirus A71. After virus attaches to a cell surface
receptor, a conformational change in surface capsid proteins expels a
hydrophobic pocket factor, facilitating penetration and uncoating with release of
viral RNA in the cytoplasm. Translation of the positive-sense RNA produces a
polyprotein that undergoes cleavage by proteases encoded in the polyprotein.
Several proteins produced guide synthesis of negative-sense RNA that serves as
a template for replication of new positive-sense RNA. The genome is
approximately 7,500 nucleotides long and includes a highly conserved 5′
noncoding region important for replication efficiency and a highly conserved 3′
polyA region; these flank a continuous region encoding viral proteins. The 5′ end
is covalently linked to a small viral protein (VPg) necessary for initiation of
RNA synthesis. There is significant variation within genomic regions encoding
the structural proteins, leading to variability in antigenicity. Replication is
followed by further cleavage of proteins and assembly into 30 nm icosahedral
virions. Of the 4 structural proteins (VP1-VP4) in the capsid, VP1 is the most
important determinant of serotype specificity. Additional regulatory proteins
such as an RNA-dependent RNA polymerase and proteases are also present in
the virion. Approximately 10
4
-10
5 virions are released from an infected cell by
lysis within 5-10 hr of infection.
Following oral or respiratory acquisition, initial replication for most
enteroviruses occurs in the pharynx and intestine, possibly within mucosal M
cells. The acid stability of most enteroviruses favors survival in the
gastrointestinal tract. Two or more enteroviruses may invade and replicate in the
gastrointestinal tract simultaneously, but interference due to replication of 1 type
often hinders growth of the heterologous type. Initial replication of most
enteroviruses in the pharynx and intestine is followed within days by
multiplication in lymphoid tissue such as tonsils, Peyer patches, and regional
lymph nodes. A primary, transient viremia (minor viremia ) results in spread to
distant parts of the reticuloendothelial system, including the liver, spleen, bone
marrow, and distant lymph nodes. Host immune responses may limit replication
and progression beyond the reticuloendothelial system, resulting in subclinical
infection. Clinical infection occurs if replication proceeds in the
reticuloendothelial system and virus spreads via a secondary, sustained viremia
(major viremia ) to target organs such as the CNS, heart, and skin. Tropism to
target organs is determined in part by the infecting serotype. Some
enteroviruses, such as enterovirus D68, can be acid-labile and bind sialic acid receptors on
respiratory epithelial cells in the upper and lower respiratory tract
and primarily produce respiratory illness. Cytokine responses may contribute to
development of respiratory disease by these viruses. Transient early viremia
following respiratory enterovirus D68 infection has also been demonstrated.
Enteroviruses can damage a wide variety of organs and systems, including the
CNS, heart, liver, lungs, pancreas, kidneys, muscle, and skin. Damage is
mediated by necrosis and the inflammatory response. CNS infections are often
associated with pleocytosis of the cerebrospinal fluid (CSF), composed of
macrophages and activated T lymphocytes, and a mixed meningeal
inflammatory response. Parenchymal involvement may affect the cerebral white
and gray matter, cerebellum, basal ganglia, brainstem, and spinal cord with
perivascular and parenchymal mixed or lymphocytic inflammation, gliosis,
cellular degeneration, and neuronophagocytosis. Encephalitis during enterovirus
A71 epidemics has been characterized by severe involvement of the brainstem,
spinal cord gray matter, hypothalamus, and subthalamic and dentate nuclei, and
can be complicated by pulmonary edema, pulmonary hemorrhage, and/or
interstitial pneumonitis, presumed secondary to brainstem damage, sympathetic
hyperactivity, myoclonus, ataxia, autonomic dysfunction, and CNS and systemic
inflammatory responses (including cytokine and chemokine overexpression).
Immunologic cross-reactivity with brain tissue has been postulated as 1
mechanism responsible for neurologic damage and sequelae following
enterovirus A71 infection.
Enterovirus myocarditis is characterized by perivascular and interstitial
mixed inflammatory infiltrates and myocyte damage, possibly mediated by viral
cytolytic (e.g., cleavage of dystrophin or serum response factor) and innate and
adaptive immune-mediated mechanisms. Chronic inflammation may persist after
viral clearance.
The potential for enteroviruses to cause persistent infection is controversial.
Persistent infection in dilated cardiomyopathy and in myocardial infarction has
been suggested, but enterovirus RNA sequences and/or antigens have been
demonstrated in cardiac tissues in some, but not other, series. Infections with
enteroviruses such as coxsackievirus B4, during gestation or subsequently, have
been implicated as a trigger for development of β-cell autoantibodies and/or type
1 diabetes in genetically susceptible hosts. Persistent infection in the pancreas,
intestine, or peripheral blood mononuclear cells, with downstream
immunomodulatory effects, has been suggested, but data are inconsistent.
Similarly, persistent infection has been implicated in a variety of conditions, including
amyotrophic lateral sclerosis, Sjögren syndrome, chronic fatigue
syndrome, and gastrointestinal tumors. Early enterovirus infection was
associated with reduced risk of developing lymphocytic and myeloid leukemia in
1 large retrospective Taiwanese cohort study.
Severe neonatal infections can produce hepatic necrosis, hemorrhage,
inflammation, endotheliitis, and venoocclusive disease; myocardial mixed
inflammatory infiltrates, edema, and necrosis; meningeal and brain
inflammation, hemorrhage, gliosis, necrosis, and white matter damage;
inflammation, hemorrhage, thrombosis, and necrosis in the lungs, pancreas, and
adrenal glands; and disseminated intravascular coagulation. In utero infections
are characterized by placentitis and infection of multiple fetal organs such as
heart, lung, and brain.
Development of type-specific neutralizing antibodies appears to be the most
important immune defense, mediating prevention against and recovery from
infection. Immunoglobulin (Ig) M antibodies, followed by long-lasting IgA and
IgG antibodies, and secretory IgA, mediating mucosal immunity, are produced.
Although local reinfection of the gastrointestinal tract can occur, replication is
usually limited and not associated with disease. In vitro and animal experiments
suggest that heterotypic antibody may enhance disease caused by a different
serotype. Evidence also suggests that subneutralizing concentrations of serotype-
specific antibody may lead to antibody-dependent enhancement of enterovirus
A71 infection. Innate and cellular defenses (macrophages and cytotoxic T
lymphocytes) may play important roles in recovery from infection. Altered
cellular responses to enterovirus A71, including T lymphocyte and natural killer
cell depletion, were associated with severe meningoencephalitis and pulmonary
edema.
Hypogammaglobulinemia and agammaglobulinemia predispose to severe,
often chronic enterovirus infections. Similarly, perinatally infected neonates
lacking maternal type-specific antibody to the infecting virus are at risk for
severe disease. Enterovirus A71 disease increases after 6 mo of age, when
maternal serotype-specific antibody levels have declined. Other risk factors for
significant illness include young age, immune suppression (posttransplantation
and lymphoid malignancy), and, according to animal models and/or
epidemiologic observations, exercise, cold exposure, malnutrition, and
pregnancy. Specific human leukocyte antigen genes, immune response gene
(e.g., interleukin-10 and interferon-γ) polymorphisms, and low vitamin A levels
have been linked to enterovirus A71 susceptibility and severe disease.

Clinical Manifestations
Manifestations are protean, ranging from asymptomatic infection to
undifferentiated febrile or respiratory illnesses in the majority, to, less frequently,
severe diseases such as meningoencephalitis, myocarditis, and neonatal sepsis. A
majority of individuals are asymptomatic or have very mild illness, yet may
serve as important sources for spread of infection. Symptomatic disease is
generally more common in young children.

Hand-Foot-and-Mouth Disease
Hand-foot-and-mouth disease, one of the more distinctive rash syndromes, is
most frequently caused by coxsackievirus A16, sometimes in large outbreaks,
and can also be caused by enterovirus A71; coxsackie A viruses 5, 6, 7, 9, and
10; coxsackie B viruses 2 and 5; and some echoviruses. It is usually a mild
illness, with or without low-grade fever. When the mouth is involved, the
oropharynx is inflamed and often contains scattered, painful vesicles on the
tongue, buccal mucosa, posterior pharynx, palate, gingiva, and/or lips (Fig.
277.1 ). These may ulcerate, leaving 4-8 mm shallow lesions with surrounding
erythema. Maculopapular, vesicular, and/or pustular lesions may occur on the
hands and fingers, feet, and buttocks and groin (see Figs. 277.1 and 277.2 ). Skin
lesions occur more commonly on the hands than feet and are more common on
dorsal surfaces, but frequently also affect palms and soles. Hand and feet lesions
are usually tender, 3-7 mm vesicles that resolve in about 1 wk. Buttock lesions
do not usually progress to vesiculation. Disseminated vesicular rashes described
as eczema coxsackium may complicate preexisting eczema. Coxsackievirus A6,
in particular, is responsible for relatively severe, atypical hand-foot-and-mouth
disease (and herpangina) affecting adults and children that is characterized by
fever, generalized rash (face, proximal extremities, and trunk, in addition to
hands, feet, and buttocks), pain, dehydration, and desquamation of palms and
soles (Fig. 277.2 ). Onychomadesis (nail shedding) has been observed following
coxsackievirus A6 and other coxsackievirus infections. Hand-foot-and-mouth
disease caused by enterovirus A71 can be associated with neurologic and
cardiopulmonary involvement, especially in young children (see Neurologic
Manifestations below). Hand-foot-and-mouth disease caused by coxsackievirus
A16 also can occasionally be associated with complications such as encephalitis,
acute flaccid paralysis, myocarditis, pericarditis, and shock.

Diagnosis
Clues to enterovirus infection include characteristic findings such as hand-foot-
and-mouth disease or herpangina lesions, consistent seasonality, known
community outbreak, and exposure to enterovirus-compatible disease. In the
neonate, history of maternal fever, malaise, and/or abdominal pain near delivery
during enterovirus season is suggestive.
Traditionally, enterovirus infection has been confirmed with viral culture
using a combination of cell lines. Sensitivity of culture ranges from 50% to 75%
and can be increased by sampling of multiple sites (e.g., CSF plus oropharnyx
and rectum in children with meningitis). In neonates, yields of 30–70% are
achieved when blood, urine, CSF, and mucosal swabs are cultured. A major
limitation is the inability of most coxsackie A viruses to grow in culture. Yield
may also be limited by neutralizing antibody in patient specimens, improper
specimen handling, or insensitivity of the cell lines used. Culture is relatively
slow, with 3-8 days usually required to detect growth. Although cultivation of an
enterovirus from any site can generally be considered evidence of recent
infection, isolation from the rectum or stool can reflect more remote shedding.
Similarly, recovery from a mucosal site may suggest an association with an
illness, whereas recovery from a normally sterile site (e.g., CSF, blood, or tissue)
is more conclusive evidence of causation. Serotype identification by type-
specific antibody staining or neutralization of a viral isolate is generally required
only for investigation of an outbreak or an unusual disease manifestation,
surveillance, or to distinguish nonpoliovirus enteroviruses from vaccine or wild-
type polioviruses.
Direct testing for nucleic acid has replaced culture due to increased sensitivity
and more rapid turnaround. RT-PCR detection of highly conserved areas of the
enterovirus genome can detect the majority of enteroviruses in CSF; serum;
urine; conjunctival, nasopharyngeal, oropharyngeal, tracheal, rectal, and stool specimens; dried
blood spots; and tissues such as myocardium, liver, and brain.
However, the closely related parechoviruses are not detected by most enterovirus
RT-PCR primers. Sensitivity and specificity of RT-PCR are high, with results
available in as short as 1 hr. Real-time, quantitative PCR assays and nested PCR
assays with enhanced sensitivity have been developed, as have enterovirus-
containing multiplex PCR assays, nucleic acid sequence–based amplification
assays, reverse transcription-loop-mediated isothermal amplification, culture-
enhanced PCR assays, and PCR-based microarray assays. PCR testing of CSF
from children with meningitis and from hypogammaglobulinemic patients with
chronic meningoencephalitis is frequently positive despite negative cultures.
Routine PCR testing of CSF in infants and young children with suspected
meningitis during enterovirus season decreases the number of diagnostic tests,
duration of hospital stay, antibiotic use, and overall costs. PCR testing of tracheal
aspirates of children with myocarditis has good concordance with testing of
myocardial specimens. In ill neonates and young infants, PCR testing of serum
and urine has higher yields than culture. Viral load in blood of neonates is
correlated with disease severity; viral nucleic acid may persist in blood of
severely ill newborns for up to 2 mo.
Sequence analysis of amplified nucleic acid can be used for serotype
identification and phylogenetic analysis and to establish a transmission link
among cases. Serotype-specific (e.g., enterovirus A71, enterovirus D68, and
coxsackievirus A16) PCR assays have been developed. For enterovirus A71, the
yield of specimens other than CSF and blood (oropharyngeal, nasopharyngeal,
rectal, vesicle swabs, and CNS tissue) is greater than the yield of CSF and blood,
which are infrequently positive. Enterovirus D68 is more readily detected in
respiratory specimens (i.e., nasal wash or nasopharyngeal swab) compared to
stool/rectal or CSF specimens. Of note, commercially available multiplex
respiratory PCR assays generally are unable to distinguish enteroviruses
(including enterovirus D68) from rhinoviruses. Antigen detection assays that
target specific serotypes such as enterovirus A71 with monoclonal antibodies
have also been developed.
Enterovirus infections can be detected serologically by a rise in serum or CSF
of neutralizing, complement fixation, enzyme-linked immunosorbent assay, or
other type-specific antibody or by detection of serotype-specific IgM antibody.
However, serologic testing requires presumptive knowledge of the infecting
serotype or an assay with sufficiently broad cross-reactivity. Sensitivity and
specificity may be limiting, and cross-reactivity among serotypes may occur.

Treatment
In the absence of a proven antiviral agent for enterovirus infections, supportive
care is the mainstay of treatment. Newborns and young infants with nonspecific
febrile illnesses and children with meningitis frequently require diagnostic
evaluation and hospitalization for presumptive treatment of bacterial and herpes
simplex virus infection. Neonates with severe disease and infants and children
with concerning disease manifestations (e.g., myocarditis, enterovirus A71
neurologic and cardiopulmonary disease, enterovirus D68 respiratory failure,
and acute flaccid myelitis) may require intensive cardiorespiratory support.
Milrinone has been suggested as a useful agent in severe enterovirus A71
cardiopulmonary disease. Liver and cardiac transplantation have been performed
for neonates with progressive end-organ failure.
Immunoglobulin has been utilized to treat enterovirus infections based on the
importance of the humoral immune response to enterovirus infection and the
observation that absence of neutralizing antibody is a risk factor for symptomatic
infection. Immunoglobulin products contain neutralizing antibodies to many
commonly circulating serotypes, although titers vary with serotype and among
products and lots. Anecdotal and retrospective, uncontrolled use of intravenous
immunoglobulin or infusion of maternal convalescent plasma to treat newborns with severe
disease has been associated with varying outcomes. The 1
randomized, controlled trial was too small to demonstrate significant clinical
benefits, although neonates who received immunoglobulin containing high
neutralizing titers to their own isolates had shorter periods of viremia and
viruria. Immunoglobulin has been administered intravenously and
intraventricularly to treat hypogammaglobulinemic patients with chronic
enterovirus meningoencephalitis and intravenously in transplant and oncology
patients with severe infections, with variable success. Intravenous
immunoglobulin and corticosteroids have been used for patients with neurologic
disease caused by enterovirus A71, enterovirus D68, and other enteroviruses.
Modulation of cytokine profiles after administration of intravenous
immunoglobulin for enterovirus A71–associated brainstem encephalitis has been
demonstrated. High-titer enterovirus A71 immunoglobulin appeared promising
in animal models, and clinical trials in regions with epidemic enterovirus A71
disease are ongoing. Anti–enterovirus A71 monoclonal antibodies have also
been generated and evaluated in vitro and in animal models. A retrospective
study suggested that treatment of presumed viral myocarditis with
immunoglobulin was associated with improved outcome; however, virologic
diagnoses were not made. Evaluation of corticosteroids and cyclosporine and
other immunosuppressive therapy for myocarditis has been inconclusive.
Successful treatment of enterovirus myocarditis with interferon-α has been
reported anecdotally, and interferon-β treatment was associated with viral
clearance, improved cardiac function, and survival in chronic cardiomyopathy
associated with persistence of enterovirus (or adenovirus) genome. Activity of
interferon-α against enterovirus 71 has been demonstrated in in vitro and animal
models, but potency varies with interferon-α type.
Antiviral agents that act at various steps in the enterovirus life cycle—
attachment, penetration, uncoating, translation, polyprotein processing, protease
activity, replication, and assembly—are being evaluated. Candidates include
pharmacologically active chemical compounds, small interfering RNAs and
DNA-like antisense agents, purine nucleoside analogs, synthetic peptides,
enzyme inhibitors of signal transduction pathways, interferon-inducers, and
herbal compounds. Pleconaril, an inhibitor of attachment and uncoating, was
associated with benefit in some controlled studies of enterovirus meningitis and
picornavirus upper respiratory tract infections, and uncontrolled experience
suggested possible benefits in high-risk infections. A randomized, controlled
trial of pleconaril in neonates with severe hepatitis, coagulopathy, and/or myocarditis suggested
possible virologic and clinical benefits of treatment.
Pocapavir, an agent with a similar mechanism of action that is in development
for treatment of poliovirus infections, has been used in a small number of cases
of severe neonatal enterovirus sepsis. Vapendavir is another attachment inhibitor
that is in clinical trials for rhinovirus infections and has in vitro activity against
enteroviruses (including enterovirus A71) but has not entered clinical trials for
enterovirus infections. Pleconaril, pocapavir, and vapendavir are not currently
available for clinical use.
Design and evaluation of candidate agents active against enterovirus A71 and
enterovirus D68 are high priorities. Challenges for therapies of enterovirus A71
include limited cross-genotypic activity of candidate compounds and high viral
mutagenicity that favors emergence of resistance. Lactoferrin and ribavirin have
demonstrated activity in in vitro and/or animal models. The investigational
agents rupintrivir and V-7404, which inhibit the 3C-protease conserved among
many enteroviruses and essential for infectivity, have broad activity in vitro,
including against both enterovirus A71 and enterovirus D68. DAS181 is an
investigational, inhaled drug with sialidase activity that has in vitro activity
against recently circulating strains of enterovirus D68. The antidepressant
fluoxetine interacts with the enterovirus 2C protein and has in vitro activity
against group B and D enteroviruses; it has been used anecdotally for chronic
enterovirus encephalitis associated with agammaglobulinemia and enterovirus
D68-associated acute flaccid myelitis. A retrospective study did not demonstrate
a signal of efficacy in the latter condition

Complications and Prognosis

The prognosis in the majority of enterovirus infections is excellent. Morbidity
and mortality are associated primarily with myocarditis, neurologic disease,
severe neonatal infections, and infections in immune compromised hosts.
Prevention
The first line of defense is prevention of transmission through good hygiene,
such as handwashing, avoidance of sharing utensils and drinking containers and
other potential fomites, disinfection of contaminated surfaces, and avoiding
community settings where exposures are likely to occur. Chlorination of
drinking water and swimming pools may be important. Contact precautions should be used for
all patients with enterovirus infections in the hospital setting;
droplet precautions should also be included for patients with respiratory
syndromes and, possibly, enterovirus A71 infection. Infection control techniques
such as cohorting have proven effective in limiting nursery outbreaks.
Prophylactic administration of immunoglobulin or convalescent plasma has been
used in nursery epidemics; simultaneous use of infection control interventions
makes it difficult to determine efficacy.
Pregnant women near term should avoid contact with individuals ill with
possible enterovirus infections. If a pregnant woman experiences a suggestive
illness, it is advisable not to proceed with emergency delivery unless there is
concern for fetal compromise or obstetric emergencies cannot be excluded.
Rather, it may be advantageous to extend pregnancy, allowing the fetus to
passively acquire protective antibodies. A strategy of prophylactically
administering immunoglobulin (or maternal convalescent plasma) to neonates
born to mothers with enterovirus infections is untested.
Maintenance antibody replacement with high-dose intravenous
immunoglobulin for patients with hypogammaglobulinemia has reduced the
incidence of chronic enterovirus meningoencephalitis, although breakthrough
infections occur. Inactivated vaccines to prevent enterovirus A71 infections have
been demonstrated to be safe and effective (>90% against enterovirus A71 hand-
foot-and-mouth disease and >80% against enterovirus A71 serious disease) in
phase 3 clinical trials. Inactivated enterovirus A71 vaccines have been approved
for prevention of severe hand-foot-and-mouth disease in China and are being
studied in other Asian countries. Other vaccine strategies for enterovirus A71,
including VP1 capsid protein-based subunit, DNA, and vector vaccines;
combined peptide vaccines; live-attenuated vaccines; virus-like particles; breast
milk enriched with VP1 capsid protein or lactoferrin; and interferon-γ–
expressing recombinant viral vectors, are also under investigation. Circulation of
multiple enterovirus A71 types, antigenic drift, viral recombination, and
potential immunologic cross-reactivity with brain tissue may pose challenges to
development of enterovirus A71 vaccines.