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Enterovirus D68 (EV-D68) was first identified in California in 1962 and has been associated with mild to severe respiratory illness in infants, children, and teenagers. In August 2014, clusters of disease caused by EV-D68, prominently associated with exacerbation of asthma, were noted in Kansas City, MO, and Chicago, IL, with subsequent spread through- out the country. By the end of October 2014, EV-D68 had been detected in 48 states, with more than 1,100 patients. Almost all confirmed cases were among children, many of whom had asthma or a history of wheezing. Nine children died, although the contribution of EV-D68 to the fatal outcome is unknown. Additionally, a poliolike, acute neurologic syndrome was reported in a few children with a history of recent respiratory illnesses, some of which were caused by EV-D68. Illness consisted of spinal fluid pleocytosis and acute onset of limb weakness and changes on magnetic resonance imaging of the spinal cord demonstrating non- enhancing lesions restricted to the gray matter.
As of December 2014, 94 children with acute flaccid myelitis have been reported in 33 states.
Patients with humoral and combined immune deficiencies can develop persistent central ner- vous system infections, a dermatomyositis-like syndrome, or disseminated infection. Severe neurologic or multisystem disease is reported in hematopoietic stem cell and solid organ transplant recipients, children with malig- nancies, and patients treated with anti-CD20 monoclonal antibody.
Etiology
The EVs comprise a genus in the Picornaviri- dae family of RNA viruses. The nonpolio EVs include more than 100 distinct serotypes for- merly subclassified as group A coxsackievi- ruses, group B coxsackieviruses, echoviruses, and newer numbered EVs. A more recent classification system groups these nonpolio EVs into 4 species (EV-A, -B, -C, and -D) on the basis of genetic similarity; polioviruses are members of EV-C. Echoviruses 22 and 23 have been reclassified as human parechoviruses 1 and 2, respectively.
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Enterovirus
ENTErOviruS ( NONPOLiOviruS) 161
Epidemiology
Humans are the only known reservoir for human EVs, although some primates can become infected. Enterovirus infections are common and distributed worldwide. They are spread by fecal-oral and respiratory routes and from mother to newborn prenatally, in the peripartum period, and, possibly, via breast- feeding. Enteroviruses can survive on environ- mental surfaces for periods long enough to allow transmission from fomites. Hospital nursery and other institutional outbreaks can occur. Infection incidence, clinical attack rates, and disease severity are typically greatest in young children, and infections occur more frequently in tropical areas and where poor sanitation, poor hygiene, and overcrowding are present. Most EV infections in temperate climates occur in the summer and fall (June through October in the northern hemisphere), but seasonal patterns are less evident in the tropics. Epidemics of EV meningitis, EV 71–
associated hand-foot-and-mouth disease with neurologic and cardiopulmonary complica- tions (particularly in southeastern Asia), and EV 70– and coxsackievirus A24–associated acute hemorrhagic conjunctivitis (especially in tropical regions) occur. Fecal viral shedding can persist for several weeks or months after onset of infection, but respiratory tract shed- ding is usually limited to 1 to 3 weeks or less.
Infection and viral shedding can occur without signs of clinical illness.
Incubation Period
3 to 6 days for all except acute hemorrhagic conjunctivitis, which is 24 to 72 hours.
Diagnostic Tests
Enteroviruses can be detected by reverse transcriptase-polymerase chain reaction (PCR) assay and culture from a variety of specimens, including stool, rectal, throat and conjunctival swabs, nasopharyngeal aspirates, tracheal aspi- rates, blood, urine, tissue biopsy specimens, and cerebrospinal fluid (CSF) when meningitis
is present. Patients with EV 71 neurologic dis- ease often have negative results of PCR assay and culture of CSF (even in the presence of CSF pleocytosis) and blood; PCR assay and culture of throat or rectal swab or vesicle fluid specimens are more frequently positive. Poly- merase chain reaction assays for detection of EV RNA are available at many reference and commercial laboratories for CSF, blood, and other specimens. Polymerase chain reaction assay is more rapid and more sensitive than isolation of EVs in cell culture and can detect all EVs, including serotypes that are difficult to cultivate in viral culture. Sensitivity of culture ranges from 0% to 80% depending on serotype and cell lines used. Many group A coxsackievi- ruses grow poorly or not at all in vitro. Culture usually requires 3 to 8 days to detect growth.
Acute infection with a known EV serotype can be determined at reference laboratories by demonstration of a change in neutralizing or other serotype-specific antibody titer between acute and convalescent serum specimens or detection of serotype-specific immunoglobu- lin M, but serologic assays are relatively insen- sitive and lack specificity.
Treatment
No specific antiviral therapy is available for EV infections. Intravenous immunoglobulin may be beneficial for chronic EV meningoen- cephalitis in patients who are immunodefi- cient. Intravenous immunoglobulin has also been used for life-threatening neonatal EV infections, severe EV infections in transplant recipients and people with malignancies, sus- pected viral myocarditis, and EV 71 neurologic disease, but proof of efficacy is lacking. Inter- ferons occasionally have been used for treat- ment of EV-associated myocarditis, without definitive proof of efficacy. The antiviral drug, pleconaril, has activity against EVs (but likely not parechoviruses) but is not available com- mercially. Other agents with activity against EVs are in development (eg, pocapavir).
162 ENTErOviruS ( NONPOLiOviruS)
Image 44.1
vesicular eruptions in hand (A), foot (B), and mouth (C) of a 6-year-old boy with coxsackievirus A6 infection. Several of his fingernails shed (D) 2 months after the pictures were taken. Courtesy of Centers for Disease Control and Prevention/
Emerging Infectious Diseases.
Image 44.2
Enterovirus infection in a preschool-aged girl.
Hand-foot-and-mouth disease lesions are caused by coxsackievirus A16 and enterovirus 71.
Image 44.3
Enterovirus infection (hand-foot-and-mouth disease) affecting the hands.
Image 44.4
Enterovirus infection (hand-foot-and-mouth disease) affecting the feet.
Image 44.5
Enterovirus infection (hand-foot-and-mouth disease) with typical papulovesicular lesions over the Achilles tendon area.
ENTErOviruS ( NONPOLiOviruS) 163
Image 44.6
Enterovirus infection (hand-foot-and-mouth disease) affecting the anterior buccal mucosa.
These lesions are generally less painful than herpes simplex lesions.
Image 44.7
Enterovirus infection (hand-foot-and-mouth disease). This rash, commonly seen over the buttocks, often appears macular, maculopapular, or papulovesicular and may be petechial.
Image 44.8
Enterovirus infection (hand-foot-and-mouth disease). The rash may also be seen on the trunk.
Image 44.9
Characteristic papulovesicular lesions on the palm of a 2-year-old boy with hand-foot-and- mouth disease, a coxsackievirus A infection, most often A16, or enterovirus 71. Courtesy of George Nankervis, mD.
Image 44.10
Characteristic papulovesicular lesions of hand- foot-and-mouth disease in a 2-year-old boy.
Courtesy of George Nankervis, mD.
164 ENTErOviruS ( NONPOLiOviruS)
Image 44.11
Newborn with generalized enteroviral exanthem.
Copyright michael rajnik, mD, FAAP.
Image 44.12
Herpangina (coxsackievirus) lesions on the posterior palate of a young adult male.
Coxsackievirus lesions are usually found in the posterior aspect of the oropharynx and may progress rapidly to painful ulceration.
Image 44.13
Skin lesions on the side of a young girl’s face due to echovirus 9. Courtesy of Centers for Disease Control and Prevention.
Image 44.14
Skin lesions on the neck and chest of a young girl due to echovirus 9. Echoviruses comprise 1 of 5 serotypes, which make up the genus Enterovirus, and are associated with illnesses, including aseptic meningitis, nonspecific rashes, encephalitides, and myositis. Courtesy of Centers for Disease Control and Prevention.
Image 44.15
A 4-year-old white girl with pharyngeal inflamma- tion and palatal lesions of hand-foot-and-mouth disease, a coxsackievirus A infection. Copyright Larry Frenkel, mD.
Image 44.16
This 7-year-old white girl presented with low- grade fever, malaise, sore throat, and these interesting, slightly raised oral lesions opposite the first molar. She also had approximately 10 maculopapular lesions on each buttock and a few on each foot. She had classic hand-foot-and- mouth disease. Coxsackievirus A16 was grown from throat and rectal swabs. Courtesy of Neal Halsey, mD.
EPSTEiN-BArr viruS iNFECTiONS 165
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