Chapter 297 ◆ Nonpolio Enteroviruses 1979

be provided with an International Certificate of Vaccination of Prophy-

laxis to record their polio vaccination and service proof of vaccination. Table 297.1 Classification of Human Enteroviruses
These countries have been advised to restrict at the point of departure Family Picornaviridae
the international travel of any resident lacking documentation of full
vaccination, whether by air, sea, or land. For countries infected with Genus Enterovirus
cVDPV2 with potential risk of international spread (see Fig. 296.1 and Subgroups* Poliovirus serotypes 1-3
WHO website), visitors should be encouraged to follow these recom- Coxsackie A virus serotypes 1-22, 24 (23
mendations (not mandated). reclassified as echovirus 9)
The WHO has mandated that infants in all countries still using Coxsackie B virus serotypes 1-6
bOPV should receive a dose of IPV, to offer protection against polio Echovirus serotypes 1-9, 11-27, 29-33 (echoviruses
virus type 2. These efforts have been stymied because of the global 10 and 28 reclassified as nonenteroviruses;
inability to produce IPV in a large enough volume to cover all the 128 echovirus 34 reclassified as a variant of coxsackie
million babies born annually in the world. This problem was a crisis A virus 24; echoviruses 22 and 23 reclassified
during the global synchronized introduction of bOPV, when several within the genus Parechovirus)
countries (e.g., India) had to use two fractional doses of IPV (1/5 dose) Numbered enterovirus serotypes (enterovirus 72
administered intradermally. To enhance scale-up of IPV production in reclassified as hepatitis A virus)
countries such as India, Brazil, and China, IPV using Sabin strains of *The human enteroviruses have been alternatively classified on the basis of nucleotide
poliovirus (sIPV) were developed in Japan and China. These mitigate and amino acid sequences into four species (human enteroviruses A-D).
the stringent requirements for wild-type poliovirus culture that are
normally required for IPV production. Other strategies include devel-
oping adjuvants for IPV (approved by the Danish Medicines Agency Epidemiology
in 2019) and other novel E.coli–based adjuvants that could potentially Enterovirus infections are common, with a worldwide distribution.
lower the antigen quantities needed for each dose. In temperate climates, annual epidemic peaks occur in summer/fall,
Given the ongoing spread of cVDPVs, alternative stable novel Sabin although some transmission occurs year-round. Enteroviruses are
vaccine strains that do not revert to neurovirulence (nOPVs) were responsible for 33–65% of acute febrile illnesses and 55–65% of hospital-
developed for all three strains (Bio Farma, Indonesia) and have been izations for suspected sepsis in infants during the summer and fall in the
shown to be immunogenic, stable, and safe. United States. In tropical and semitropical areas, enteroviruses typically
In countries where bOPV is included in routine immunization, it circulate year-round. In general, only a few serotypes circulate simulta-
is best if it follows at least one dose of IPV or two doses of fractional neously. Infections by different serotypes can occur within the same sea-
intradermal IPV. son. Factors associated with increased incidence and/or severity include
young age, male sex, exposure to children, poor hygiene, overcrowding,
Visit Elsevier eBooks+ at eBooks.Health.Elsevier.com for Bibliography. and low socioeconomic status. More than 25% of symptomatic infec-
tions occur in children younger than 1 year of age. Breastfeeding reduces
the risk for infection, likely via enterovirus-specific antibodies.
Humans are the only known natural reservoir for human enterovi-
ruses. Virus is primarily spread person to person, by the fecal-oral and
respiratory routes, although types causing acute hemorrhagic conjunc-
tivitis may be spread via airborne transmission. Virus can be transmit-
Chapter 297 ted vertically prenatally or in the peripartum period or possibly via
breastfeeding. Enteroviruses can survive on environmental surfaces,

Nonpolio Enteroviruses permitting transmission via fomites. Enteroviruses also can frequently
be isolated from water sources, sewage, and wet soil. Although con-
tamination of drinking water, swimming pools and ponds, and hospital
Kevin B. Messacar and Mark J. Abzug 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, play-
The genus Enterovirus contains a large number of viruses spread via grounds, summer camps, orphanages, and hospital nurseries; severe
the gastrointestinal and respiratory routes that produce a broad range secondary infections may occur in nursery outbreaks. Transmission
of illnesses in patients of all ages. Many of the manifestations predomi- risk is increased by diaper changing and decreased by handwashing.
nantly affect infants and young children. Tickborne transmission has been suggested by some authors but is not
a predominant route of transmission.
ETIOLOGY Large enterovirus outbreaks have included meningitis epidemics
Enteroviruses are nonenveloped, single-stranded, positive-sense (echoviruses 4, 6, 9, 13, and 30 commonly); epidemics of hand-foot-
viruses in the Picornaviridae (small RNA virus) family, which also and-mouth disease with severe central nervous system (CNS) and/
includes the rhinoviruses, hepatitis A virus, and parechoviruses. The or cardiopulmonary disease caused by enterovirus A71 in Asia and
original human enterovirus subgroups—polioviruses (see Chap- Australia; outbreaks of atypical, severe hand-foot-and-mouth disease
ter 296), coxsackieviruses, and echoviruses—were differentiated by caused by coxsackievirus A6 in the United States and United Kingdom;
their replication patterns in tissue culture and animals (Table 297.1). outbreaks of human enterovirus D68 respiratory illness associated
Enteroviruses have been reclassified on the basis of genetic similarity with acute flaccid myelitis in the Americas, Europe, and Asia; out-
into four species, human enteroviruses A-D. Specific enterovirus types breaks of acute hemorrhagic conjunctivitis caused by enterovirus D70,
are distinguished by antigenic and genetic sequence differences, with coxsackievirus A24, and coxsackievirus A24 variant in tropical and
enteroviruses discovered after 1970 classified by species and number temperate regions; and community outbreaks of uveitis. Reverse tran-
(e.g., enterovirus D68 and A71). Although more than 100 types have scription polymerase chain reaction (RT-PCR) and genomic sequenc-
been described, 10-15 account for the majority of disease. No disease ing help identify outbreaks and demonstrate commonality of outbreak
is uniquely associated with any specific serotype, although certain strains, differences among epidemic strains and older prototype
manifestations are associated with specific serotypes. The closely related strains, changes in circulating viral subgroups over time, cocircula-
human parechoviruses can cause clinical presentations similar to those tion of multiple genetic lineages, co-infections with different entero-
associated with enteroviruses. virus serotypes, and associations between specific genogroups and/or

E 2 @ 2 2 @ A 2 4 2 1 D @A F 0 C @ )2 @ 2 @ ) 42 . F 4 F A D @
( @ , @ @A 2 CA F @ CA A E C @ AA ) F@ A D @ 4 ( @ A @ A @D
1980 Part XV ◆ Infectious Diseases

genetic substitutions and epidemiologic and clinical characteristics. Enteroviruses can damage a wide variety of organs and systems,
Genetic analyses have demonstrated recombination and genetic drift including the CNS, heart, liver, lungs, pancreas, kidneys, muscle, and
that lead to evolutionary changes in genomic sequence and antigenicity skin. Damage is mediated by necrosis and the inflammatory response.
and extensive genetic diversity. For example, emergence of new sub- CNS infections are often associated with pleocytosis in the cerebrospi-
genotypes and genetic lineages of enterovirus A71 may contribute to nal fluid (CSF), composed of macrophages and activated T lympho-
sequential outbreaks and increases in circulation. cytes, and a mixed meningeal inflammatory response. Parenchymal
The incubation period is typically 3-6 days, except for a 1-3 day incu- involvement may affect the cerebral white and gray matter, cerebellum,
bation period for acute hemorrhagic conjunctivitis. Symptomatic and basal ganglia, brainstem, and spinal cord with perivascular and paren-
asymptomatic infected children typically shed cultivable virus from the chymal mixed or lymphocytic inflammation, gliosis, cellular degen-
respiratory tract for <1-3 weeks. In contrast, fecal shedding of cultivat- eration, and neuronophagocytosis. Encephalitis during enterovirus
able virus continues for as long as 7-11 weeks for acid stabile strains A71 epidemics has been characterized by severe involvement of the
(e.g., poliovirus, enterovirus A71). Enterovirus RNA can be shed from brainstem, spinal cord gray matter, hypothalamus, and subthalamic
mucosal sites for comparable and possibly longer periods.␣ and dentate nuclei, and can be complicated by pulmonary edema, pul-
monary hemorrhage, and/or interstitial pneumonitis, presumed sec-
PATHOGENESIS ondary to brainstem damage; sympathetic hyperactivity; myoclonus;
Cell surface macromolecules, including poliovirus receptor, integ- ataxia; autonomic dysfunction; and CNS and systemic inflammatory
rin very-late-activation antigen (VLA)-2, decay-accelerating factor/ responses (including cytokine and chemokine overexpression). Immu-
complement regulatory protein (DAF/CD55), intercellular adhesion nologic cross-reactivity with brain tissue has been postulated as one
molecule-1 (ICAM-1), ICAM-5, and coxsackievirus-adenovirus recep- mechanism responsible for neurologic damage and sequelae following
tor, serve as viral receptors. In addition, respiratory epithelial cell sialic enterovirus A71 infection.
acids serve as receptors for enterovirus D68, enterovirus D70, and Enterovirus myocarditis is characterized by perivascular and inter-
coxsackievirus A24 variants, and human scavenger receptor class B2 stitial mixed inflammatory infiltrates and myocyte damage, possi-
(SCARB2), human P-selectin glycoprotein ligand-1, and DC-SIGN bly mediated by viral cytolytic (e.g., cleavage of dystrophin or serum
are receptors for enterovirus A71. After virus attaches to a cell surface response factor) and innate and adaptive immune-mediated mecha-
receptor, a conformational change in surface capsid proteins expels a nisms. Chronic inflammation may persist after viral clearance.
hydrophobic pocket factor, facilitating penetration and uncoating with The potential for enteroviruses to cause persistent infection is contro-
release of viral RNA in the cytoplasm. Translation of the positive-sense versial. Persistent infection in dilated cardiomyopathy and in myocar-
RNA produces a polyprotein that undergoes cleavage by proteases dial infarction has been suggested, but enterovirus RNA sequences and/
encoded in the polyprotein. Several proteins resulting from cleavage or antigens have been demonstrated in cardiac tissues in some, but not
of the polyprotein guide synthesis of negative-sense RNA that serves other, series. Infections with enteroviruses such as coxsackievirus B4,
as a template for replication of new positive-sense RNA. The genome is during gestation or subsequently, have been implicated as a trigger for
approximately 7,500 nucleotides long and includes a highly conserved development of β-cell autoantibodies and/or type 1 diabetes in geneti-
5′ noncoding region important for replication efficiency and a highly cally susceptible hosts. Persistent infection in the pancreas, intestine, or
conserved 3′ polyA region; these regions flank a continuous region peripheral blood mononuclear cells, with downstream immunomodula-
encoding viral proteins. The 5′ end is covalently linked to a small tory effects, has been suggested, but data are inconsistent. Similarly, per-
viral protein (VPg) necessary for initiation of RNA synthesis. There is sistent infection has been implicated in a variety of conditions, including
significant variation within genomic regions encoding the structural amyotrophic lateral sclerosis, Sjögren syndrome, chronic fatigue syn-
proteins, leading to variability in antigenicity. Replication is followed drome, and gastrointestinal tumors. Early enterovirus infection was
by further cleavage of proteins and assembly into 30-nm icosahedral associated with reduced risk of developing lymphocytic and myeloid
virions. Of the four structural proteins (VP1-VP4) in the capsid, VP1 is leukemia in a large retrospective Taiwanese cohort study.
the most important determinant of serotype specificity. Additional reg- Severe neonatal infections can produce hepatic necrosis, hemor-
ulatory proteins such as an RNA-dependent RNA polymerase and pro- rhage, inflammation, endotheliitis, and venoocclusive disease; myocar-
teases are also present in the virion. Approximately 104-105 virions are dial mixed inflammatory infiltrates, edema, and necrosis; meningeal
released from an infected cell by lysis within 5-10 hours of infection. and brain inflammation, hemorrhage, gliosis, necrosis, and white mat-
Following oral or respiratory acquisition, initial replication for most ter damage; inflammation, hemorrhage, thrombosis, and necrosis in
enteroviruses occurs in the pharynx and intestine, possibly within the lungs, pancreas, and adrenal glands; and disseminated intravascu-
mucosal M cells. The acid stability of most enteroviruses favors survival lar coagulation. In utero infections are characterized by placentitis and
in the gastrointestinal tract. Two or more enteroviruses may invade and infection of multiple fetal organs such as heart, lung, and brain.
replicate in the gastrointestinal tract simultaneously, but interference Development of type-specific neutralizing antibodies appears to be
due to replication of one type often hinders growth of the heterolo- the most important immune defense, mediating prevention against
gous type. Initial replication of most enteroviruses in the pharynx and and recovery from infection. Immunoglobulin (Ig) M antibodies, fol-
intestine is followed within days by multiplication in lymphoid tissue, lowed by long-lasting IgA and IgG antibodies, and secretory IgA, medi-
such as tonsils, Peyer patches, and regional lymph nodes. A primary, ating mucosal immunity, are produced. Although local reinfection of
transient viremia (minor viremia) results in spread to distant parts the gastrointestinal tract can occur, replication is usually limited and
of the reticuloendothelial system, including the liver, spleen, bone not associated with disease. In vitro and animal experiments suggest
marrow, and distant lymph nodes. Host immune responses may limit that heterotypic antibody may enhance disease caused by a different
replication and progression beyond the reticuloendothelial system, serotype. Evidence also suggests that subneutralizing concentrations of
resulting in subclinical infection. Clinical infection occurs if replica- serotype-specific antibody may lead to antibody-dependent enhance-
tion proceeds in the reticuloendothelial system and virus spreads via a ment of enterovirus A71 infection. Innate and cellular defenses (mac-
secondary, sustained viremia (major viremia) to target organs such as rophages and cytotoxic T lymphocytes) may play important roles in
the CNS, heart, and skin. Tropism to target organs is determined in part recovery from infection. Altered cellular responses to enterovirus A71,
by the infecting serotype. Some enteroviruses, such as enterovirus D68, including T lymphocyte and natural killer cell depletion, have been
can be acid-labile and bind sialic acid receptors on respiratory epithe- associated with severe meningoencephalitis and pulmonary edema.
lial cells in the upper and lower respiratory tract and primarily produce Hypogammaglobulinemia and agammaglobulinemia predispose to
respiratory illness. Cytokine responses may contribute to development severe, often chronic enterovirus infections. Similarly, perinatally infected
of respiratory disease by these viruses. Enterovirus D68 RNA has also neonates lacking maternal type-specific antibody to the infecting virus
been transiently detected by PCR in the blood of young children with are at risk for severe disease. Enterovirus A71 disease increases after 6
enterovirus D68 pneumonia when drawn soon after illness onset. months of age, when maternal serotype-specific antibody levels have

E 2 @ 2 2 @ A 2 4 2 1 D @A F 0 C @ )2 @ 2 @ ) 42 . F 4 F A D @
( @ , @ @A 2 CA F @ CA A E C @ AA ) F@ A D @ 4 ( @ A @ A @D
 Chapter 297 ◆ Nonpolio Enteroviruses 1981

A B C
Fig. 297.1 A, Oval blisters of the palms in a child with hand-foot-and-mouth disease (coxsackievirus A16 infection). B, Oval blisters on the feet of a
child with hand-foot-and-mouth disease. C, Erosion of the tongue in a child with hand-foot-and-mouth disease. (From Weston WL, Lane AT, Morelli
JG. Color Textbook of Pediatric Dermatology, 3rd ed. St. Louis: Mosby; 2002:109.)

declined. Other risk factors for significant illness include young age, Hand-Foot-and-Mouth Disease
immune suppression (posttransplantation and lymphoid malignancy), Hand-foot-and-mouth disease, one of the more distinctive rash syn-
and, according to animal models and/or epidemiologic observations, dromes, is most frequently caused by coxsackievirus A16, sometimes in
exercise, cold exposure, malnutrition, and pregnancy. Specific human large outbreaks, and can also be caused by enterovirus A71; coxsackie A
leukocyte antigen genes, immune response gene (e.g., interleukin-10 viruses 5, 6, 7, 9, and 10; coxsackie B viruses 2 and 5; and some echovi-
and interferon-γ) polymorphisms, and low vitamin A levels have been ruses. It is usually a mild illness, with or without low-grade fever. When
linked to enterovirus A71 susceptibility and severe disease.␣ the mouth is involved, the oropharynx is inflamed and often contains
scattered, painful vesicles on the tongue, buccal mucosa, posterior phar-
CLINICAL MANIFESTATIONS Changes frequently ynx, palate, gingiva, and/or lips (Fig. 297.1). These lesions may ulcerate,
Manifestations are protean, ranging from asymptomatic infection to leaving 4-8 mm shallow lesions with surrounding erythema. Maculo-
undifferentiated febrile or respiratory illnesses, often in association papular, vesicular, and/or pustular lesions may occur on the hands and
with exanthems and/or enanthems, to, less frequently, severe diseases fingers, feet, and buttocks and groin (see Figs. 297.1 and 297.2). Skin
such as meningoencephalitis, myocarditis, and neonatal sepsis. A lesions occur more commonly on the hands than feet and are more com-
majority of individuals are asymptomatic or have very mild illness, yet mon on dorsal surfaces, but frequently also affect palms and soles. Hand
may serve as important sources for spread of infection. Symptomatic and foot lesions are usually tender, 3-7–mm vesicles that resolve in about
disease is generally more common in young children. 1 week. Buttock lesions do not usually progress to vesiculation. Dissemi-
nated vesicular rashes described as eczema coxsackium may complicate
Nonspecific Febrile Illness preexisting eczema. Coxsackievirus A6, in particular, is responsible for
Nonspecific febrile illnesses are the most common symptomatic mani- relatively severe, atypical hand-foot-and-mouth disease (and herpan-
festations, especially in infants and young children. These are difficult gina) affecting adults and children that is characterized by fever, general-
to differentiate clinically from serious infections such as urinary tract ized rash (face, proximal extremities, and trunk, in addition to hands,
infection, bacteremia, and bacterial meningitis, often necessitating feet, and buttocks), pain, dehydration, and desquamation of palms and
hospitalization with diagnostic testing and presumptive antibiotic soles (see Fig. 297.2). Onychomadesis (nail shedding) has been observed
therapy for suspected bacterial infection in young infants. following coxsackievirus A6 and other coxsackievirus infections. Hand-
Illness usually begins abruptly with fever of 38.5–40°C (101.3– foot-and-mouth disease caused by enterovirus A71 can be associated
104°F), malaise, and irritability. Associated symptoms may include with neurologic and cardiopulmonary involvement, especially in young
lethargy, anorexia, diarrhea, nausea, vomiting, abdominal discomfort, children (see “Neurologic Manifestations,” later). Hand-foot-and-mouth
rash, sore throat, and respiratory symptoms. Older children may have disease caused by coxsackievirus A16 also can occasionally be associated
headaches and myalgias. Findings are generally nonspecific and may with complications such as encephalitis, acute flaccid paralysis, myocar-
include mild conjunctivitis, pharyngeal injection, and cervical lymph- ditis, pericarditis, and shock.␣
adenopathy. Meningitis may be present, but specific clinical features
Pharynxxxxx
such as meningeal findings or bulging anterior fontanelle distinguish- Herpangina
ing those with meningitis are often lacking in infants. Fever lasts a mean Herpangina is characterized by sudden onset of fever, sore throat,
of 3 days and occasionally is biphasic. Duration of illness is usually 4-7 dysphagia, and painful lesions in the posterior pharynx. Tempera-
days but can range from 1 day to >1 week. White blood cell (WBC) tures range from normal to 41°C (105.8°F); fever tends to be higher in
count, inflammatory biomarkers (e.g., C-reactive protein, erythrocyte younger patients. Headache and backache may occur in older children,
sedimentation rate), and results of routine laboratory tests are gener- and vomiting and abdominal pain occur in 25% of cases. Characteristic
ally normal, although transient neutropenia can be seen. Concomitant lesions, present on the anterior tonsillar pillars, soft palate, uvula, ton-
enterovirus and bacterial infection is rare but has been observed in a sils, posterior pharyngeal wall, and, occasionally, the posterior buccal
small number of infants, most commonly with urinary tract infections. surfaces, are discrete 1-2–mm vesicles and ulcers that enlarge over 2-3
Enterovirus illnesses may be associated with a wide variety of skin days to 3-4 mm and are surrounded by erythematous rings that vary in
manifestations, including macular, maculopapular, urticarial, vesicu- size up to 10 mm. The number of lesions can range from 1 to >15 but
lar, and petechial eruptions. Rare cases of idiopathic thrombocytopenic is most commonly around 5. The remainder of the pharynx appears
purpura have been reported. Enteroviruses have also been implicated normal or minimally erythematous. Most cases are mild and have
in cases of pityriasis rosea. In general, the frequency of cutaneous man- no complications. However, dehydration as a result of decreased oral
ifestations is inversely related to age. Serotypes commonly associated intake may occur with more severe illness; meningitis can also some-
with rashes are echoviruses 9, 11, 16, and 25; coxsackie A viruses 2, 4, times occur. Fever generally lasts 1-4 days, and resolution of symptoms
6, 9, and 16; coxsackie B viruses 3-5; and enterovirus A71. Virus can occurs in 3-7 days. A variety of enteroviruses cause herpangina, includ-
occasionally be recovered from vesicular skin lesions.␣ ing enterovirus A71, but coxsackie A viruses are implicated most often.␣

E 2 @ 2 2 @ A 2 4 2 1 D @A F 0 C @ )2 @ 2 @ ) 42 . F 4 F A D @
( @ , @ @A 2 CA F @ CA A E C @ AA ) F@ A D @ 4 ( @ A @ A @D
1982 Part XV ◆ Infectious Diseases

and marked by high contagiousness, with spread mainly via eye-hand-

fomite-eye transmission. School-age children, teenagers, and adults
20-50 years of age have the highest attack rates. Sudden onset of severe
eye pain is associated with photophobia, blurred vision, lacrima-
tion, conjunctival erythema and congestion, lid edema, preauricular
lymphadenopathy, and, in some cases, subconjunctival hemorrhages
and superficial punctate keratitis. Subconjunctival hemorrhage is the
hallmark of enterovirus D70 cases (>70%) but is more rare with cox-
sackievirus infections. Eye discharge is initially serous but becomes
mucopurulent with secondary bacterial infection. Systemic symptoms,
including fever and headache, occur in up to 20% of cases; manifes-
tations suggestive of pharyngoconjunctival fever occasionally occur.
Recovery is usually complete within 1-2 weeks. Polyradiculoneu-
ropathy or acute flaccid paralysis following enterovirus D70 infection
occurs occasionally. Other enteroviruses have occasionally been impli-
cated as causes of keratoconjunctivitis.
Epidemic and sporadic uveitis in infants caused by subtypes of
enteroviruses 11 and 19 can be associated with severe complications,
including destruction of the iris, cataracts, and glaucoma. Enterovi-
ruses have been implicated in cases of chorioretinitis, uveoretinitis,
optic neuritis, and unilateral acute idiopathic maculopathy.␣

Myocarditis and Pericarditis

Enteroviruses account for approximately 25–35% of cases of myocardi-
tis and pericarditis of proven etiology (see Chapters 488 and 489). Cox-
Fig. 297.2 Atypical hand-foot-and-mouth disease. Vesiculobullous sackie B viruses are most commonly implicated, although coxsackie
rash on the right buttock and posterior thigh. (From Waldman A, Thom- A viruses and echoviruses also may be causative. Adolescents and
as L, Thacker S, et al. Vesiculobullous eruption as an atypical hand, foot, young adults (especially physically active males) are disproportionately
and mouth presentation. J Pediatr. 2016;179:273. Fig. B.) affected. Myopericarditis may be the dominant feature, or it may be one
manifestation of disseminated disease, as in neonates. Disease ranges
Respiratory Manifestations from relatively mild to severe. Upper respiratory tract symptoms fre-
Symptoms such as sore throat and coryza frequently accompany and quently precede fatigue, dyspnea, chest pain, congestive heart failure,
sometimes dominate enterovirus illnesses. Other respiratory findings and dysrhythmias. Presentations may mimic myocardial infarction;
may include wheezing, exacerbation of asthma, apnea, pneumonia, sudden death may also occur (including apparent sudden infant death
otitis media, bronchiolitis, croup, parotitis, and pharyngotonsillitis, syndrome). A pericardial friction rub indicates pericardial involve-
which may occasionally be exudative. Lower respiratory tract infec- ment. Chest radiography often demonstrates cardiac enlargement,
tion may be significant in immunocompromised patients. Clusters and and echocardiography may confirm ventricular dilation, reduced con-
outbreaks of cases of severe respiratory disease, including pneumonia tractility, and/or pericardial effusion. Electrocardiography frequently
and wheezing (both in children with a history of asthma and those reveals ST segment, T wave, and/or rhythm abnormalities, and serum
unaffected by asthma), have been increasingly recognized in associa- myocardial enzyme concentrations are often elevated. The acute
tion with multiple lineages of enterovirus D68. mortality of enterovirus myocarditis is 0–4%. Recovery is complete
Pleurodynia (Bornholm disease), caused most frequently by cox- without residual disability in the majority of patients. Occasionally,
sackie B viruses 3, 5, 1, and 2 and echoviruses 1 and 6, is an epidemic chronic cardiomyopathy, inflammatory ventricular microaneurysms,
or sporadic illness characterized by paroxysmal thoracic pain, as a or constrictive pericarditis may result. The role of persistent infection
result of myositis involving chest and abdominal wall muscles and, in chronic dilated cardiomyopathy is controversial. Enteroviruses have
possibly, pleural inflammation. In epidemics, which occur every 10-20 also been implicated in late adverse cardiac events following heart
years, children and adults are affected, but most cases occur in per- transplantation and in acute cardiac events such as myocardial infarc-
sons younger than age 30 years. Malaise, myalgias, and headache are tion, endocarditis, and peripartum cardiomyopathy. Cardiopulmonary
followed by sudden onset of fever and spasmodic, pleuritic pain in dysfunction observed in enterovirus A71 epidemics most commonly
the chest or upper abdomen aggravated by coughing, sneezing, deep occurs without evidence of myocarditis and may be of neurogenic ori-
breathing, or other movement. During spasms, which last from a few gin; however, true myocarditis has also been described.␣
minutes to several hours, pain may be severe, and respirations are usu-
ally rapid, shallow, and grunting, suggesting pneumonia or pleural Gastrointestinal and Genitourinary Manifestations
inflammation. A pleural friction rub is noted during pain episodes in Gastrointestinal symptoms such as emesis (especially with meningitis),
<10% of patients. Chest radiographs are generally normal but can dem- diarrhea (rarely severe), and abdominal pain are frequent but generally
onstrate pulmonary infiltrates or pleural effusions. Pain localized to not dominant. Diarrhea, hematochezia, pneumatosis intestinalis, and
the abdomen may suggest colic, intestinal obstruction, appendicitis, or necrotizing enterocolitis have occurred in premature infants during
peritonitis. Pain usually subsides within 3-6 days but may persist for up nursery outbreaks. Enterovirus infection has been implicated in acute
to weeks. Symptoms may occur in a biphasic or, rarely, recurrent pat- and chronic gastritis, intussusception, chronic intestinal inflamma-
tern, with less prominent fever during recurrences. Pleurodynia may tion in hypogammaglobulinemic patients, sporadic hepatitis in nor-
be associated with meningitis, orchitis, myocarditis, or pericarditis. mal children, severe hepatitis in neonates, and pancreatitis, which may
Life-threatening noncardiogenic pulmonary edema, hemorrhage, result in transient exocrine pancreatic insufficiency.
and/or interstitial pneumonitis may occur in patients with enterovirus Coxsackie B viruses are second only to mumps as causes of orchi-
A71 brainstem encephalitis.␣ tis, most commonly presenting in adolescents. The illness is fre-
quently biphasic; fever and pleurodynia or meningitis are followed
Ocular Manifestations approximately 2 weeks later by orchitis, often with epididymitis.
Epidemics of acute hemorrhagic conjunctivitis, primarily caused by Enteroviruses have also been implicated in cases of nephritis and IgA
enterovirus D70 and coxsackievirus A24/A24 variant, are explosive nephropathy.␣ Causes of ORCHITIS
1. Mumps
2. Coxsackie B

E 2 @ 2 2 @ A 2 4 2 1 D @A F 0 C @ )2 @ 2 @ ) 42 . F 4 F A D @
( @ , @ @A 2 CA F @ CA A E C @ AA ) F@ A D @ 4 ( @ A @ A @D
 Chapter 297 ◆ Nonpolio Enteroviruses 1983

Neurologic Manifestations limb weakness, and muscle atrophy have been observed among sur-
Enteroviruses are the most common cause of viral meningitis in vivors, especially those who experienced cardiopulmonary failure or
mumps-immunized populations, accounting for up to 90% or more acute flaccid paralysis during their acute illness. Although the most
of cases in which a cause is identified. Meningitis is particularly com- severe cases have been associated with enterovirus A71, similar clini-
mon in infants, especially in those younger than 3 months of age, often cal pictures have been produced by other enterovirus serotypes (e.g.,
during community epidemics. Frequently implicated serotypes include coxsackieviruses A16 and B5, echovirus 7). Increased risk
coxsackie B viruses 2-5; echoviruses 4, 6, 7, 9, 11, 13, 16, and 30; and Patients with antibody or combined immunodeficiencies (includ-
enteroviruses D70 and A71. Most cases in infants and young children ing human immunodeficiency virus infection, acute lymphocytic leu-
are mild and lack specific meningeal signs, whereas nuchal rigidity is kemia, and transplantation) and patients receiving anti-CD20 antibody
apparent in more than half of children older than 1-2 years of age. Fever therapy are at risk for acute or, more commonly, chronic enterovirus
is present in 50–100% and may be accompanied by irritability, malaise, meningoencephalitis. The latter is characterized by persistent CSF
headache, photophobia, nausea, emesis, anorexia, lethargy, hypotonia, abnormalities, viral detection in CSF or brain tissue for years, and
rash, cough, rhinorrhea, pharyngitis, diarrhea, and/or myalgia. Some recurrent encephalitis and/or progressive neurologic deterioration,
cases are biphasic, with fever and nonspecific symptoms lasting a few including insidious intellectual or personality deterioration, altered
days and followed by return of fever with meningeal signs several days mental status, seizures, motor weakness, and increased intracranial
later. Fever usually resolves in 3-5 days, and other symptoms in infants pressure. Although disease may wax and wane, deficits generally
and young children usually resolve within 1 week. In adults, symptoms become progressive and ultimately are frequently fatal or lead to long-
tend to be more severe and of longer duration. CSF findings include term sequelae. A dermatomyositis-like syndrome, hepatitis, arthritis,
pleocytosis (generally <500 but occasionally as high as 1,000-8,000 myocarditis, or disseminated infection may also occur. Chronic entero-
WBCs/µL; often predominantly polymorphonuclear cells in the first virus meningoencephalitis has become less common with prophylactic
48 hours before becoming mostly mononuclear); normal or slightly high-dose intravenous immunoglobulin replacement in agammaglob-
low glucose content (10% <40 mg/dL); and normal or mildly increased ulinemic patients.
protein content (generally <100 mg/dL). CSF parameters are normal A variety of nonpoliovirus enteroviruses, including enteroviruses
in up to half of young infants despite detection of enterovirus in CSF D68, D70, A71, coxsackie A viruses 7 and 24, coxsackie B viruses, and
and may also be normal in older children early after illness onset. Acute several echoviruses, have been associated with acute flaccid paraly-
complications occur in approximately 10% of young children, includ- sis with motor weakness as a result of spinal cord anterior horn cell
ing simple and complex seizures, obtundation, increased intracranial involvement. Acute flaccid myelitis is used to designate the clinical
pressure, syndrome of inappropriate antidiuretic hormone secretion, syndrome of acute flaccid limb weakness with longitudinal MRI abnor-
ventriculitis, transient cerebral arteriopathy, and coma. The long-term malities in the spinal cord gray matter. Neurologic abnormalities are
prognosis for most children, even in those with acute complications, commonly preceded by a febrile respiratory or gastrointestinal prodro-
is good. mal illness around 1 week before onset. Limb involvement tends to be
Enteroviruses are also responsible for ≥10–20% of cases of encepha- asymmetric and varies from one to all four limbs, with severity ranging
litis with an identified cause. Frequently implicated serotypes include from mild weakness to complete paralysis. Cranial nerve dysfunction,
echoviruses 3, 4, 6, 9, and 11; coxsackie B viruses 2, 4, and 5; coxsackie including bulbar paralysis, and respiratory failure requiring ventila-
A virus 9; and enterovirus A71. After initial nonspecific symptoms, tor support, similar to poliovirus poliomyelitis, have been described
there is progression to encephalopathy characterized by confusion, in acute flaccid myelitis cases associated with enterovirus D68 and
weakness, lethargy, and/or irritability. Symptoms are most commonly enterovirus A71. Sensory involvement, encephalopathy, seizures, and
generalized, although focal findings, including focal motor seizures, supratentorial imaging changes are uncommon with enterovirus D68
hemichorea, acute cerebellar ataxia, aphasia, extrapyramidal symp- infection. Functional improvements may be seen over time, but muscle
toms, and/or focal imaging abnormalities, may occur. Meningeal signs atrophy with limb weakness and some degree of disability persist in
and CSF indices similar to those of enteroviral meningitis are com- the vast majority of cases. A proportion of children with acute flac-
monly present, leading to characterization of most cases as meningo- cid myelitis will have a need for long-term tracheostomy, ventilation,
encephalitis. Severity ranges from mild alteration in mental status to and enteral feeding tubes as a result of persistent bulbar or respiratory
coma and decerebrate status. Long-term sequelae, including epilepsy, paralysis, and scoliosis requiring spinal fusion, limb deformity requir-
weakness, cranial nerve palsy, spasticity, psychomotor retardation, and ing orthotics and assistive devices, and low bone density predispos-
hearing loss, or death may follow severe disease. Persistent or recurrent ing to fractures are common. Nerve transfer surgical procedures that
cases have been observed rarely. involve splitting and moving functioning nerves to completely dener-
Neurologic manifestations have been prominent in epidemics in vated muscles have been used to improve functional outcomes in select
Asia and Australia of enterovirus A71, and, to a lesser extent, cox- cases.
sackievirus A16 disease. Many affected children have had hand-foot- Other neurologic syndromes include cerebellar ataxia; transverse
and-mouth disease, some have had herpangina, and others have had myelitis; Guillain-Barré syndrome (including Miller Fisher variant)
no mucocutaneous manifestations. Neurologic syndromes in a frac- and axonal polyneuropathy; acute disseminated encephalomyeli-
tion of children have included meningitis, meningoencephalomy- tis; peripheral neuritis; optic neuritis; sudden hearing loss, tinnitus,
elitis, acute flaccid paralysis, Guillain-Barré syndrome, transverse and inner ear disorders such as vestibular neuritis; and other cranial
myelitis, acute disseminated encephalomyelitis, cerebellar ataxia, neuropathies.␣
opsoclonus-myoclonus syndrome, benign intracranial hyperten-
sion, and brainstem encephalitis (rhombencephalitis involving the Myositis and Arthritis
midbrain, pons, and medulla). Enterovirus A71 rhombencephalitis is Although myalgia is common, direct evidence of muscle involvement,
characterized by altered consciousness, myoclonus, vomiting, ataxia, including rhabdomyolysis, muscle swelling, focal myositis, and poly-
nystagmus, tremor, cranial nerve abnormalities, autonomic dysfunc- myositis, has uncommonly been reported. A dermatomyositis-like syn-
tion, and MRI demonstrating lesions in the brainstem, thalamus, drome and arthritis can be seen in enterovirus-infected patients with
and cerebellum. Although the disease has been mild and reversible hypogammaglobulinemia. Enteroviruses are a rare cause of arthritis in
in some children, others have had rapid progression to noncardio- normal hosts.␣
genic (presumed neurogenic) pulmonary edema and hemorrhage,
cardiopulmonary failure, shock, and coma. High mortality rates have Neonatal Infections
been reported in children younger than 5 years of age, especially in Neonatal infections are relatively common, with a disease incidence
those younger than 1 year of age. Deficits such as central hypoven- comparable to or greater than that of symptomatic neonatal herpes
tilation, bulbar dysfunction, neurodevelopmental delay, cerebellar simplex virus, cytomegalovirus, and group B streptococcus infec-
defects, attention deficit/hyperactivity–related symptoms, persistent tions. Infection frequently is caused by coxsackie B viruses 2-5 and

E 2 @ 2 2 @ A 2 4 2 1 D @A F 0 C @ )2 @ 2 @ ) 42 . F 4 F A D @
( @ , @ @A 2 CA F @ CA A E C @ AA ) F@ A D @ 4 ( @ A @ A @D
1984 Part XV ◆ Infectious Diseases

echoviruses 6, 9, 11, and 19, although many serotypes have been impli- myocarditis have been reported in children with malignancies and
cated, including coxsackie B virus 1 and echovirus 30 in more recent patients treated with anti-CD20 monoclonal antibody. Infections in
years. Enteroviruses may be acquired vertically before, during, or after these groups are associated with high fatality rates.␣
delivery, including possibly via breast milk; horizontally from family
members; or by sporadic or epidemic transmission in nurseries. In DIAGNOSIS
utero infection can lead to fetal demise, nonimmune hydrops fetalis, Clues to enterovirus infection include characteristic findings such as
or neonatal illness. Additionally, maternal and intrauterine infections hand-foot-and-mouth disease or herpangina lesions, consistent sea-
have been speculatively linked to congenital anomalies; prematurity, sonality, known community outbreak, and exposure to enterovirus-
low birthweight, and intrauterine growth restriction; neurodevelop- compatible disease. Acute flaccid myelitis due to enterovirus should be
mental sequelae; unexplained neonatal illness and death; and increased considered in the differential diagnosis of any child presenting with
risk of type 1 diabetes and schizophrenia. acute-onset limb weakness, particularly in the summer to fall during
The majority of neonatal infections are asymptomatic, and symp- enterovirus outbreaks and when following a febrile illness. In the neo-
tomatic presentations range from benign febrile illness to severe mul- nate, history of maternal fever, malaise, and/or abdominal pain near
tisystem disease. Most affected newborns are full term and previously delivery during enterovirus season is suggestive.
well. Maternal history often reveals a recent viral illness preceding or Traditionally, enterovirus infection has been confirmed with viral cul-
immediately following delivery, which may include fever and abdomi- ture using a combination of cell lines. Sensitivity of culture ranges from
nal pain. Neonatal symptoms may occur as early as day 1 of life, with 50% to 75% and can be increased by sampling of multiple sites (e.g., CSF
onset of severe disease generally within the first 2 weeks of life. Fre- plus oropharynx and rectum in children with meningitis). In neonates,
quent findings include fever or hypothermia, irritability, lethargy, yields of 30–70% are achieved when blood, urine, CSF, and mucosal
anorexia, rash (usually maculopapular, occasionally petechial or papu- swabs are cultured. A major limitation is the inability of most coxsackie
lovesicular), jaundice, respiratory symptoms, apnea, hepatomegaly, A viruses to grow in culture. Yield may also be limited by neutralizing
abdominal distention, emesis, diarrhea, and decreased perfusion. Most antibody in patient specimens, improper specimen handling, or insensi-
patients have benign courses, with resolution of fever in an average of tivity of the cell lines used. Culture is relatively slow, with 3-8 days usually
3 days and of other symptoms in about 1 week. A biphasic course may required to detect growth. Although cultivation of an enterovirus from
occur occasionally. A minority have severe disease dominated by any any site can generally be considered evidence of recent infection, isola-
combination of sepsis, meningoencephalitis, myocarditis, hepatitis, tion from the rectum or stool can reflect more remote shedding. Simi-
coagulopathy, and/or pneumonitis. Meningoencephalitis may be man- larly, recovery from a mucosal site may suggest an association with an
ifested by focal or complex seizures, bulging fontanelle, nuchal rigidity, illness, whereas recovery from a normally sterile site (e.g., CSF, blood, or
and/or reduced level of consciousness. Myocarditis, most often associ- tissue) is more conclusive evidence of causation. Serotype identification
ated with coxsackie B virus infection, may be suggested by tachycardia, by type-specific antibody staining or neutralization of a viral isolate is
dyspnea, cyanosis, and cardiomegaly. Hepatitis and pneumonitis are generally required only for investigation of an outbreak or an unusual
most often associated with echovirus infection, although they may also disease manifestation, for surveillance, or to distinguish nonpoliovirus
occur with coxsackie B viruses. Gastrointestinal manifestations may be enteroviruses from vaccine or wild-type polioviruses.
prominent in premature neonates. Laboratory and radiographic evalu- Direct testing for nucleic acid has replaced culture because of
ation may reveal leukocytosis, thrombocytopenia, CSF pleocytosis, increased sensitivity and more rapid turnaround. RT-PCR detection
CNS white matter damage, elevations of serum transaminases and bili- of highly conserved areas of the enterovirus genome can detect the
rubin, coagulopathy, pulmonary infiltrates, and electrocardiographic majority of enteroviruses in CSF; serum; urine; conjunctival, naso-
changes. pharyngeal, oropharyngeal, tracheal, rectal, and stool specimens;
Complications of severe neonatal disease include CNS necrosis and dried blood spots; and tissues such as myocardium, liver, and brain.
generalized or focal neurologic compromise; arrhythmias, congestive However, the closely related parechoviruses are not detected by most
heart failure, myocardial infarction, and pericarditis; hepatic necrosis enterovirus RT-PCR primers. Sensitivity and specificity of RT-PCR are
and failure; coagulopathy with intracranial or other bleeding; adrenal high, with results available in as short as 1 hour. Real-time, quantita-
necrosis and hemorrhage; and rapidly progressive pneumonitis and tive PCR assays and nested PCR assays with enhanced sensitivity have
pulmonary hypertension. Myositis, arthritis, necrotizing enterocoli- been developed, as have enterovirus-containing multiplex PCR assays,
tis, inappropriate antidiuretic hormone secretion, hemophagocytic nucleic acid sequence–based amplification assays, reverse transcrip-
lymphohistiocytosis-like presentation, bone marrow failure, and sud- tion loop-mediated isothermal amplification, culture-enhanced PCR
den death are rare events. Mortality with severe disease is significant assays, and PCR-based microarray assays. PCR testing of CSF from
and is most often associated with hepatitis and bleeding complications, children with meningitis and from hypogammaglobulinemic patients
myocarditis, and/or pneumonitis. with chronic meningoencephalitis is frequently positive despite nega-
Survivors of severe neonatal disease may have gradual resolution of tive cultures. Routine PCR testing of CSF in infants and young children
hepatic and cardiac dysfunction, although persistent hepatic dysfunc- with suspected meningitis during enterovirus season decreases the
tion and residual cardiac impairment, chronic calcific myocarditis, number of diagnostic tests, duration of hospital stay, antibiotic use, and
and ventricular aneurysm may occur. Meningoencephalitis may be overall costs. Enterovirus RNA may not be detected in CSF by the time
associated with speech and language impairment; cognitive deficits; of clinical presentation with neurologic syndromes associated with cer-
spasticity, hypotonicity, or weakness; seizure disorders; microcephaly tain enteroviruses (e.g., enterovirus A71 and D68), but shedding may
or hydrocephaly; and ocular abnormalities. However, many survivors still be detectable in nonsterile sites (stool/rectal for enterovirus A71;
appear to have no long-term sequelae. Risk factors for severe disease respiratory for enterovirus D68). PCR testing of tracheal aspirates of
include illness onset in the first few days of life; maternal illness just children with myocarditis has good concordance with testing of myo-
before or after delivery; prematurity; male sex; infection by echovirus cardial specimens. In ill neonates and young infants, PCR testing of
11 or a coxsackie B virus; positive serum viral culture; absence of neu- serum and urine has higher yields than culture. Viral load in blood
tralizing antibody to the infecting virus; and evidence of severe hepati- of neonates is correlated with disease severity; viral nucleic acid may
tis, myocarditis, and/or multisystem disease.␣ persist in blood of severely ill newborns for up to 2 months.
Sequence analysis of amplified nucleic acid can be used for serotype
Transplant Recipients and Patients with Malignancies identification and phylogenetic analysis and to establish a transmission
Enterovirus infections in stem cell and solid organ transplant recipi- link among cases. Serotype-specific (e.g., enterovirus A71, enterovi-
ents may be severe and/or prolonged, causing progressive pneumonia, rus D68, and coxsackievirus A16) PCR assays have been developed.
severe diarrhea, pericarditis, heart failure, meningoencephalitis, and For enterovirus A71, the yield of specimens other than CSF and blood
disseminated disease. Enterovirus-associated hemophagocytic lym- (oropharyngeal, nasopharyngeal, rectal, vesicle swabs, and CNS tis-
phohistiocytosis, meningitis, encephalitis, acute flaccid myelitis, and sue) is greater than the yield of CSF and blood, which are infrequently

E 2 @ 2 2 @ A 2 4 2 1 D @A F 0 C @ )2 @ 2 @ ) 42 . F 4 F A D @
( @ , @ @A 2 CA F @ CA A E C @ AA ) F@ A D @ 4 ( @ A @ A @D
 Chapter 297 ◆ Nonpolio Enteroviruses 1985

positive. Enterovirus D68 is more readily detected in respiratory spec- as enterovirus infections, with a biennial pattern of circulation noted
imens (i.e., nasal wash or nasopharyngeal swab) compared to stool/ in Europe. Outbreaks have been described in the nursery setting. In
rectal or CSF specimens. Routine collection and testing of respiratory young infants, parechoviruses can cause a sepsis-like illness similar to
and stool/rectal specimens, in addition to CSF, is warranted in neuro- enterovirus illness and are a common, underrecognized cause of viral
logic presentations potentially associated with these viruses. Of note, meningoencephalitis. More frequently than with enteroviruses, infants
commercially available multiplex respiratory PCR assays generally are with parechovirus CNS infection often have no CSF pleocytosis. There
unable to distinguish enteroviruses (including enterovirus D68) from is also a higher incidence of white matter MRI abnormalities and long-
rhinoviruses. Antigen detection assays that target specific serotypes term neurodevelopmental deficits with parechovirus encephalitis com-
such as enterovirus A71 with monoclonal antibodies have also been pared with enterovirus encephalitis. Rarely, parechoviruses have been
developed. identified in cases of hepatitis or myocarditis. Infections in older chil-
Enterovirus infections can be detected serologically by a rise in dren are often unrecognized or cause acute, benign febrile, respiratory,
serum or CSF of neutralizing, complement fixation, enzyme-linked or gastrointestinal illnesses with few specific findings.
immunosorbent assay, or other type-specific antibody or by detec- Infants suspected of having an enterovirus infection should also
tion of serotype-specific IgM antibody. However, serologic testing be considered as possibly having a parechovirus infection, because
requires presumptive knowledge of the infecting serotype or an assay the two may be indistinguishable. A distinctive rash involving the
with sufficiently broad cross-reactivity. Sensitivity and specificity may extremities with palm and sole erythema or peripheral leukopenia
be limiting, and cross-reactivity among serotypes may occur. Except in the setting of high fever during the summer-fall season are clinical
for epidemiologic studies or cases characteristic of specific serotypes findings that should also prompt consideration of parechovirus infec-
(e.g., enterovirus A71 or enterovirus D68), serology is generally less tion. The diagnosis of parechovirus infection is confirmed by human
useful than culture or nucleic acid detection. Enterovirus antibodies parechovirus-specific PCR on CSF, blood, stool, and oropharyngeal or
have been detected in CSF of children with acute flaccid myelitis when nasopharyngeal specimens.␣
viral RNA was not detectable.␣
TREATMENT
DIFFERENTIAL DIAGNOSIS In the absence of a proven antiviral agent for enterovirus infections,
The differential diagnosis of enterovirus infections varies with the clin- supportive care is the mainstay of treatment. Newborns and young
ical presentation (Table 297.2). infants with nonspecific febrile illnesses and children with meningitis
Human parechoviruses, members of the Picornaviridae family, frequently require diagnostic evaluation and hospitalization for pre-
produce many manifestations similar to the nonpolio enteroviruses. sumptive treatment of bacterial and herpes simplex virus infection.
They are small RNA viruses that were originally classified as echo- Neonates with severe disease and infants and children with concerning
viruses. Nineteen parechoviruses have been identified that infect disease manifestations (e.g., myocarditis, enterovirus A71 neurologic
humans; serotypes 1 and 3 are the most common causes of symp- and cardiopulmonary disease, enterovirus D68 respiratory failure, and
tomatic infection. Parechovirus epidemics occur in the same season acute flaccid myelitis) may require intensive cardiorespiratory support.

Table 297.2 Differential Diagnosis of Nonpolio Enterovirus Infections

CLINICAL MANIFESTATION BACTERIAL PATHOGENS VIRAL PATHOGENS NONINFECTIOUS
Nonspecific febrile illness Streptococcus pneumoniae, Influenza viruses, human Rheumatologic disorders,
Haemophilus influenzae type b, herpesviruses 6 and 7, human oncologic diseases, drug
Neisseria meningitidis parechoviruses reaction
Exanthems/enanthems Group A Streptococcus, Herpes simplex virus, adenoviruses, Drug reaction, Stevens Johnson
Staphylococcus aureus, N. varicella-zoster virus, Epstein-Barr syndrome, toxic epidermal
meningitidis, T. pallidum, M. virus, measles virus, rubella virus, necrolysis, Kawasaki syndrome,
pneumoniae human herpesviruses 6 and 7, vasculitis
human parechoviruses
Respiratory illness/ S. pneumoniae, H. influenzae Adenoviruses, influenza viruses, Asthma exacerbation,
conjunctivitis (nontypeable and type b), N. respiratory syncytial virus, rheumatologic uveitis, Kawasaki
meningitidis, Mycoplasma parainfluenza viruses, rhinoviruses, syndrome
pneumoniae, Chlamydophila human metapneumovirus,
pneumoniae coronaviruses
Myocarditis/pericarditis S. aureus, H. influenzae type b, M. Adenoviruses, influenza virus, Drugs, Kawasaki syndrome,
pneumoniae parvovirus, cytomegalovirus rheumatic fever
Meningitis/encephalitis S. pneumoniae, H. influenzae Herpes simplex virus, West Nile virus, Drugs, intravenous
type b, N. meningitidis, influenza viruses, adenoviruses, immunoglobulin, Kawasaki
Mycobacterium tuberculosis, Epstein-Barr virus, mumps virus, syndrome, autoimmune
Borrelia burgdorferi, M. lymphocytic choriomeningitis virus, encephalitis (e.g., anti-NMDA
pneumoniae, Bartonella arboviruses, human parechoviruses receptor), acute disseminated
henselae, Listeria monocytogenes encephalomyelitis (ADEM),
demyelinating disorders
Acute flaccid myelitis C. botulinum Poliovirus, West Nile virus, Japanese Spinal cord infarction, antimyelin
encephalitis virus, rabies virus, oligodendrocyte glycoprotein
adenovirus (MOG) myelitis, neuromyelitis
optica (NMO), Guillain-Barré
syndrome, ADEM, transverse
myelitis, lupus, tick paralysis
Neonatal infections Group B Streptococcus, Herpes simplex virus, adenoviruses, Neonatal lupus, Aicardi-Goutières
gram-negative enteric bacilli, cytomegalovirus, rubella virus, syndrome
L. monocytogenes, Enterococcus human parechoviruses

E 2 @ 2 2 @ A 2 4 2 1 D @A F 0 C @ )2 @ 2 @ ) 42 . F 4 F A D @
( @ , @ @A 2 CA F @ CA A E C @ AA ) F@ A D @ 4 ( @ A @ A @D
1986 Part XV ◆ Infectious Diseases

Milrinone has been suggested as a useful agent in severe enterovirus has in vitro activity against recently circulating strains of enterovirus
A71 cardiopulmonary disease. Liver and cardiac transplantation have D68. The antidepressant fluoxetine interacts with the enterovirus 2C
been performed for neonates with progressive end-organ failure. protein and has in vitro activity against group B and D enteroviruses; it
Immunoglobulin has been used to treat enterovirus infections based has been used anecdotally for chronic enterovirus encephalitis associ-
on the importance of the humoral immune response to enterovirus ated with agammaglobulinemia and enterovirus D68-associated acute
infection and the observation that absence of neutralizing antibody flaccid myelitis. A retrospective study did not demonstrate a signal of
is a risk factor for symptomatic infection. Immunoglobulin products efficacy in the latter condition.␣
contain neutralizing antibodies to many commonly circulating sero-
types, although titers vary with serotype and among products and lots. COMPLICATIONS AND PROGNOSIS
Anecdotal and retrospective, uncontrolled use of intravenous immu- The prognosis in the majority of enterovirus infections is excellent.
noglobulin or infusion of maternal convalescent plasma to treat new- Morbidity and mortality are associated primarily with myocarditis,
borns with severe disease has been associated with varying outcomes. neurologic disease, severe neonatal infections, and infections in immu-
The one randomized controlled trial was too small to demonstrate nocompromised hosts.
significant clinical benefits, although neonates who received immu-
noglobulin containing high neutralizing titers to their own isolates Prevention
had shorter periods of viremia and viruria. Immunoglobulin has been The first line of defense is prevention of transmission through good
administered intravenously and intraventricularly to treat hypogam- hygiene, such as handwashing, avoidance of sharing utensils and
maglobulinemia in patients with chronic enterovirus meningoen- drinking containers and other potential fomites, disinfection of con-
cephalitis and intravenously in transplant and oncology patients with taminated surfaces, and avoiding community settings where exposures
severe infections, with variable success. Intravenous immunoglobulin are likely to occur. The paucity of enterovirus circulation and associ-
and corticosteroids have been used for patients with neurologic disease ated hand-foot-mouth disease and respiratory and neurologic disease
caused by enterovirus A71, enterovirus D68, and other enteroviruses. in 2020 during the COVID-19 pandemic provides indirect evidence of
Modulation of cytokine profiles after administration of intravenous the efficacy of nonpharmaceutical interventions targeted to decrease
immunoglobulin for enterovirus A71–associated brainstem encephali- SARS-CoV-2 spread (masking, distancing, school mitigation strate-
tis has been demonstrated. High-titer enterovirus A71 immunoglobu- gies) against enteroviruses. Chlorination of drinking water and swim-
lin appeared promising in animal models, and clinical trials in regions ming pools also may be an important preventative strategy. Contact
with epidemic enterovirus A71 disease are ongoing. Anti–enterovirus precautions should be used for all patients with enterovirus infections
A71 and D68 monoclonal antibodies have also been generated and in the hospital setting; droplet precautions should also be included for
evaluated in vitro and in animal models. A retrospective study sug- patients with respiratory syndromes and, possibly, enterovirus A71
gested that treatment of presumed viral myocarditis with immuno- and D68 infection. Infection control techniques such as cohorting have
globulin was associated with improved outcome; however, virologic proven effective in limiting nursery outbreaks. Prophylactic adminis-
diagnoses were not made. Evaluation of corticosteroids and cyclospo- tration of immunoglobulin or convalescent plasma has been used in
rine and other immunosuppressive therapy for myocarditis has been nursery epidemics; simultaneous use of infection control interventions
inconclusive. Successful treatment of enterovirus myocarditis with makes it difficult to determine efficacy.
interferon-α has been reported anecdotally, and interferon-β treat- Pregnant women near term should avoid contact with individuals ill
ment was associated with viral clearance, improved cardiac function, with possible enterovirus infections. If a pregnant woman experiences
and survival in chronic cardiomyopathy associated with persistence of a suggestive illness, it is advisable not to proceed with emergency deliv-
enterovirus (or adenovirus) genome. Activity of interferon-α against ery unless there is concern for fetal compromise or obstetric emer-
enterovirus A71 has been demonstrated with in vitro and animal mod- gencies cannot be excluded. Rather, it may be advantageous to extend
els, but potency varies with interferon-α type. pregnancy, allowing the fetus to passively acquire protective antibod-
Antiviral agents that act at various steps in the enterovirus life cycle— ies. A strategy of prophylactically administering immunoglobulin
attachment, penetration, uncoating, translation, polyprotein processing, (or maternal convalescent plasma) to neonates born to mothers with
protease activity, replication, and assembly—are being evaluated. Candi- enterovirus infections is untested.
dates include pharmacologically active chemical compounds, small inter- Maintenance antibody replacement with high-dose intravenous
fering RNAs and DNA-like antisense agents, purine nucleoside analogs, immunoglobulin for patients with hypogammaglobulinemia has
synthetic peptides, enzyme inhibitors of signal transduction pathways, reduced the incidence of chronic enterovirus meningoencephalitis,
interferon-inducers, and herbal compounds. Pleconaril, an inhibitor of although breakthrough infections occur. Inactivated vaccines to pre-
attachment and uncoating, was associated with benefit in some controlled vent enterovirus A71 infections, given to children 6-35 months of age,
studies of enterovirus meningitis and picornavirus upper respiratory tract have been demonstrated to be safe and effective (>90% against entero-
infections, and uncontrolled experience suggested possible benefits in virus A71 hand-foot-and-mouth disease and >80% against enterovirus
high-risk infections. A randomized controlled trial of pleconaril in neo- A71 serious disease) in phase 3 clinical trials. Three inactivated entero-
nates with severe hepatitis, coagulopathy, and/or myocarditis suggested virus A71 vaccines have been licensed and approved for prevention of
possible virologic and clinical benefits of treatment. Pocapavir, an agent severe hand-foot-and-mouth disease in China and are being studied
with a similar mechanism of action that is in development for treatment of in other Asian countries. Other vaccine strategies for enterovirus A71,
poliovirus infections, has been used in a small number of cases of severe including VP1 capsid protein–based subunit, DNA, and vector vac-
neonatal enterovirus sepsis. Vapendavir is another attachment inhibitor cines; combined peptide vaccines; live-attenuated vaccines; virus-like
that is in clinical trials for rhinovirus infections and has in vitro activity particles; breast milk enriched with VP1 capsid protein or lactoferrin;
against enteroviruses (including enterovirus A71) but has not entered clin- and interferon-γ–expressing recombinant viral vectors, are also under
ical trials for enterovirus infections. Pleconaril, pocapavir, and vapendavir investigation. Circulation of multiple enterovirus A71 types, antigenic
are not currently available for clinical use. drift, viral recombination, and potential immunologic cross-reactivity
Design and evaluation of candidate agents active against enterovirus with brain tissue may pose challenges to development of enterovirus
A71 and enterovirus D68 are high priorities. Challenges for therapies A71 vaccines. Vaccine candidates against EV-D68, including virus-like
of enterovirus A71 include limited cross-genotypic activity of candi- particle vaccines and inactivated whole virus vaccines, are in develop-
date compounds and high viral mutagenicity that favors emergence ment, but have not progressed beyond animal studies. Most enterovi-
of resistance. Lactoferrin and ribavirin have demonstrated activity rus vaccines do not provide cross-protection against other serotypes;
with in vitro and/or animal models. The investigational agents rupin- however, the potential to create multivalent enterovirus vaccines tar-
trivir and V-7404, which inhibit the 3C-protease conserved among geting several common strains with severe manifestations is under
many enteroviruses and essential for infectivity, have broad activity investigation.
in vitro, including against both enterovirus A71 and enterovirus D68.
DAS181 is an investigational, inhaled drug with sialidase activity that Visit Elsevier eBooks+ at eBooks.Health.Elsevier.com for Bibliography.

E 2 @ 2 2 @ A 2 4 2 1 D @A F 0 C @ )2 @ 2 @ ) 42 . F 4 F A D @
( @ , @ @A 2 CA F @ CA A E C @ AA ) F@ A D @ 4 ( @ A @ A @D