REVIEW

CURRENT
OPINION Enteroviruses in the early 21st century: new
manifestations and challenges
Debra Lugo a and Paul Krogstad a,b

Purpose of review
Enteroviruses cause a wide variety of diseases with neurologic, respiratory, skin, and gastrointestinal
findings. The purpose of this review is to clarify changes in the classification of enteroviruses, provide
information about recent disease outbreaks, and to summarize progress toward the treatment and
prevention of these infections.
Recent findings
Enteroviruses are now classified into four distinct species. New variants of coxsackievirus B1, enterovirus-
A71, and enterovirus-D68 (EV-D68) have emerged as causes of recent outbreaks in the United States and
other countries, including more severe disease manifestations than previously described. EV-D68 now
commonly circulates in the United States, and has been linked to severe respiratory disease and associated
with acute flaccid myelitis (AFM). Overcoming enormous political and logistical challenges, fewer than 100
cases of polio have been reported in 2015, and the initiation of ‘endgame’ strategies appears imminent.
Unfortunately, treatment for enterovirus infections remains supportive, although the recently completed
pleconaril trial in newborns suggests that antiviral therapy may reduce mortality in neonatal disease.
Summary
Clinicians should be aware of the respiratory and neurological manifestations associated with EV-D68 and
the potential for severe disease seen with other recently described enterovirus variants. Healthcare
professionals should recognize the utility of rapid diagnostic methods and progress toward prevention and
treatment of enterovirus infections.
Keywords
enterovirus-D68, enterovirus treatment, hand foot and mouth disease, pleconaril, poliovirus eradication

INTRODUCTION CURRENT TAXONOMY

Enteroviruses usually cause mild infections but also Enteroviruses are members of the picornavirus fam-
cause encephalitis, myocarditis, poliomyelitis, acute ily, a collection of small nonenveloped viruses with
heart failure, and sepsis. Disease activity is typically a simple message sense RNA genome. Serologically
seasonal, and infections occur in the summer and distinct enteroviruses were originally distributed
early fall in temperate parts of the world. Enter- into four groups based on their different effects in
oviruses are subject to significant change over time tissue culture and patterns of disease in experimen-
because of errors introduced during genome repli- tally infected animals: polioviruses (causal agents of
cation. Recombination between enteroviruses is also poliomyelitis in humans and nonhuman primates),
common, further promoting genetic diversity. This coxsackie A viruses (associated with herpangina,
genetic plasticity allows for widespread epidemics
and sporadic outbreaks to occur. In this article, we a
Department of Pediatrics and bMolecular and Medical Pharmacology,
will review recent changes in the classification and
David Geffen School of Medicine at UCLA, University of California, Los
epidemiology of enteroviruses and describe clinical Angeles, California, USA
manifestations of emerging strains of members of Correspondence to Paul Krogstad, Department of Pediatrics, David
all four species of enterovirus that infect humans. Geffen School of Medicine at UCLA, 615 Charles E. Young Drive South,
We will also outline progress toward the elimination BSRB 173, CA 90095, USA. Tel: +1 310 825 5235; fax: +1 310 206
of polio, and prevention and treatment options 4764; e-mail: [email protected]
for other enteroviruses, and highlight research Curr Opin Pediatr 2016, 28:107–113
priorities. DOI:10.1097/MOP.0000000000000303

1040-8703 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved. www.co-pediatrics.com

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Infectious diseases and immunization

(HFMD), especially in Southeast Asia. EV-B is the

KEY POINTS largest enterovirus species, consisting of 63 viruses,
 Recent outbreaks of EV-A71 demonstrate the magnitude including coxsackievirus B1–B6, many of the
and significant morbidity associated with enteroviruses, original echoviruses, and 50 other serotypes. EV-C
and emphasize the need for vaccine development. includes the three polioviruses and 20 other sero-
types, including EV-C105, which has been linked to
 EV-D68 has previously caused respiratory disease but
recent pediatric cases of AFM. EV-D includes enter-
recently has been isolated in several epidemics causing
severe disease in children, and has been suspected of ovirus-D68 (EV-D68), EV-D70, EV-D94, EV-D111,
causing neurologic disease in some cases, but the link and EV-D120. EV-D68, originally identified in
is unclear. 1962, caused recent outbreaks of severe respiratory
disease and possible neurologic disease.
 There has been significant progress in the effort to
eradicate polio, but challenges remain in areas where
the political climate impairs vaccination efforts.
RECENT OUTBREAKS
 Treatments for enterovirus are mainly supportive, but
antivirals are currently being investigated. Epidemic hand foot and mouth disease
HFMD was originally identified as a specific mani-
festation of enterovirus infections in 1956 [1,2]. It is
caused by many enteroviruses, but most often by
human central nervous system disease, and flaccid several members of the EV-A species: CVA6 and
paralysis in suckling mice), coxsackie B viruses CVA16, and EV-A71. Outbreaks of EV-A71 HFMD
(human central nervous system and cardiac disease, have been frequently reported since 1969, but a
spastic paralysis in mice), and the echoviruses (non- series of EV-A71 epidemics in the Asia-Pacific region
pathogenic in mice, and not initially linked to (Australia, Japan, Malaysia, Taiwan, Vietnam, and
human disease). China) between 1997 and 2010 have raised parti-
Enteroviruses are now assigned sequential num- cular concern about the potential emergence of
bers and grouped based on genetic and phenotypic EV-A71 as a worldwide health threat [3–5]. In the
similarity. To date, more than 110 genetically dis- largest of these, thousands of Taiwanese infants and
tinct enteroviruses that infect humans and non- children in 1998 developed the characteristic HFMD
human primates have been identified and placed seen with EV-A71 (and CVA16) in which small fluid-
into four species (Table 1). The enterovirus-A (EV-A) filled lesions appear on the hands, feet, buttocks,
group includes coxsackievirus A6 (CVA6), coxsack- and in the mouth [6–8]. Brain stem encephalitis and
ievirus A16 (CVA16), enterovirus A71 (EV-A71), and noncardiogenic pulmonary edema were commonly
22 other serotypes. CVA16 and EV-A71 are the most encountered in these recent outbreaks, and were
common causes of hand foot and mouth disease associated with a high mortality rate [4,6,7,9].

Table 1. Human enteroviruses: current taxonomy and associated diseases in recent outbreaks

Enterovirus species Types Recent outbreaks

A Coxsackievirus A2–8, 10, 12, 14, 16 Severe hand foot and mouth disease because of
CVA6, CVA16, and A71 in many countries
Enterovirus A71, A76, A89, A90, A91, A114, A119,
A120, A121
B Coxsackie B1–6, A9, echovirus 1–7, 9,11–21, Neonatal sepsis because of CVB1
24–27, 29–33
Enterovirus B69, 73–75, 77–88, 93, 97, 98, 100,
101, 106, 107, and 111
C Coxsackievirus A1, 11, 13, 17, 19, 20, 21, 22, 24, Small outbreaks of cVDPV and paralytic disease to
newer EV-C viruses
Enterovirus C95, 96, 99, 102, 104, 105, 109, 113,
116–118
Poliovirus 1–3
D EV-D68, D70, D94, D111 Worldwide reports of EV-D68 respiratory diseases.
Association with acute flaccid myelitis

cVDPV, circulating vaccine-derived polioviruses; CV, coxsackievirus; EV, enterovirus.

108 www.co-pediatrics.com Volume 28  Number 1  February 2016

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

 Enteroviruses in the early 21st century Lugo and Krogstad

Neurologic and neuropsychiatric sequelae appear to Nigeria [21]. Of these, Nigeria appears to be closest
be common in children who survive EV-A71 central to fully interrupting poliovirus circulation and
nervous system infection [3,10]. HFMD outbreaks elimination of polio, but events there have demon-
represent a perennial threat in China, resulting in an strated the fragile nature of progress. In 2000,
estimated 7.2 million cases between 2008 and 2012 rumors that the vaccine could produce sterility
&&
[11 ]. EV-A71 was responsible for about 80% of led to a prolonged ban on immunization by the
approximately 82 000 severe cases and 93% of the Sharia council of Nigeria [21]. Over the 16-month
&&
2457 deaths during this period [11 ]. period of interruption caused by this ban, polio cases
By contrast, recent outbreaks of severe HFMD in rose from less than 50 in 2000 to more than 250 in
the United States were caused by CVA6, mirroring 2003, and poliovirus was exported to 25 other
similar outbreaks in Finland and other countries countries that had previously been declared polio
&
[12,13 ]. These cases occurred in late fall and winter free [21]. Fortunately, these setbacks were reversed,
of 2011–2012. Hospitalization occurred in 19% of and no cases of paralysis because of wild poliovirus
total cases, and 24% of cases were seen in adults. In have been identified in Nigeria since July, 2014.
some infants and children with CVA6 infections, Efforts to eliminate poliovirus circulation con-
impetiginous and remarkably large bullous lesions tinue in Afghanistan and Pakistan, but progress has
were seen, leading to the descriptive title of ‘eczema been delayed by factors that have made vaccination
coxsackium’ [14]. Onychomadesis (loss of finger- unavailable for approximately 5–25% of children in
nails and toenails) occurred in some individuals. the region. In Afghanistan, these barriers include
The average severity of illness, identification of limited healthcare, poverty, and religious restric-
CVA6, and seasonality, each were unusual for HFMD tions on interactions between caregivers and vacci-
&
in the United States [13 ,14]. nators, and threats of violence. Mirroring attacks on
vaccinators in Nigeria in 2013, threats and killings of
vaccinators have also occurred in both Pakistan and
Coxsackievirus B1 myocarditis in newborns Afghanistan [22].
A recent outbreak of coxsackievirus B1 (CVB1) (a Oral poliovirus vaccine (OPV) has been an essen-
member of the EV-B species) also demonstrated the tial tool in the effort to eliminate polio, but its use is
epidemic potential of enteroviruses. In mid-2007, not risk free. Vaccine-associated paralytic poliomye-
cases of severe neonatal disease because of CVB1 litis may occur after OPV administration, and cases
were recognized nearly simultaneously in Chicago, have been reported since 1960. These events are rare,
Illinois; Los Angeles, California; and Kotzebue, and more likely to occur after the first dose or in
Alaska. Three deaths occurred among 21 confirmed persons with a primary immunodeficiency. Paralysis
cases (14%) [15]. Additional cases were identified in may also occur with infection with vaccine-derived
22 other states over the next 18 months [16,17], and polioviruses; these are OPV-like isolates, which are
CVB1, not previously associated with infant distinguished from vaccine strains by genetic
mortality, transiently became the predominant analysis of viral protein 1 capsid-encoding sequen-
enterovirus serotype identified in the United States ces. By definition, circulating vaccine-derived polio-
[18]. Reports of CVB1 disease to Centers for Disease viruses (cVDPV) differ from the OPV strains by more
Control and Prevention’s National Enterovirus than 0.6% [poliovirus (PV)2] or more than 1%
Surveillance System (NESS) have waned since (PV1 and PV3); these changes indicate persistent
2009, but it remained among the most commonly replication after administration of OPV [23]. In
circulating enteroviruses between 2009 and 2013 Afghanistan, the first case of disease caused by
&
[19 ]. cVDPV was reported in 2009–2010, and 11 cases
were reported in 2012. These cases had a median age
of 18 months, and vaccination history of two OPV
Poliomyelitis eradication: progress and perils doses, suggesting that inadequate vaccination may
Significant progress has been made in the global propagate the risk of spreading wild poliovirus from
effort to interrupt poliovirus transmission and erad- OPV [22] Better adherence to vaccination schedules
icate polio. Wild poliovirus type 2 circulation has and increased vaccination campaigns with complete
not been detected since 1999, and no cases of para- penetration into at-risk populations are crucial.
lysis caused by wild poliovirus 3 have been ident- Strategies to decrease poliomyelitis in Afghanistan
ified since 2012. Moreover, no cases of polio have include identifying high-risk areas, and focusing
occurred in India since 2011 and the country is now special efforts on these areas [22]. Transit vaccina-
considered polio free [20]. These successes reaffirm tion teams at border crossings into Pakistan and
the technical possibility of the eradication of polio, Iran have been successful in vaccinating more than
but challenges remain in Pakistan, Afghanistan, and 1 million children/year [22]. These efforts may be

1040-8703 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved. www.co-pediatrics.com 109

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Infectious diseases and immunization

bearing fruit, as no cases of paralysis caused by children hospitalized with severe respiratory illness
cVDPV have been reported in Afghanistan or in the Philippines, seven of 20 (35%) of those with
Pakistan between January and October of 2015. EV-D68 infection developed wheezing [33]. More-
The existence of circulating cVDPV has shaped over, EV-D68 viruses detected after October 2013
plans for the polio eradication ‘endgame’. In 2015, represented a distinct genetic sublineage compared
15 cases of polio have been caused by cVDPV, and 51 with EV-D68 collected between 2011 and 2013 [33].
by wild poliovirus type 1. A shift from use of triva- During the summer of 2014, EV-D68 was
lent OPV in favor of bivalent OPV (types 1 and 3), detected in every US state, excluding Alaska [34].
introduction of inactivated poliovirus vaccine, and Beginning with reports from Kansas City, Missouri,
prompt efforts to extinguish cVDPV outbreaks are in 2014, EV-D68 was linked to clusters of severe
key elements of the plan to eradicate polio. Accurate respiratory illness. Symptoms often included short-
and consistent environmental surveillance to detect ness of breath, wheezing, and respiratory failure
ongoing circulation of poliovirus will be essential in requiring mechanical ventilation. EV-D68 caused
&&
these efforts [24 ]. more severe disease in patients with a history of
asthma and reactive airway disease. Less than 50%
of patients were febrile, and it is possible that milder
EMERGING ENTEROVIRUSES AND cases of respiratory illness caused by EV-D68 were
ASSOCIATIONS WITH ACUTE FLACCID &&
being underreported [35 ]. Codetection of other
MYELITIS pathogens was rare. These outbreaks were eventu-
ally detected because of the striking severity of dis-
Evaluation of recent causes of acute flaccid ease. More outpatient surveillance data are needed
myelitis to determine the full spectrum of disease of EV-D68,
EV-C includes the emerging strains EV-C105, C109, which may include a majority of patients with
and C116, which have been detected throughout milder disease.
the world. EV-C105 was first reported in the Dem- EV-D68 was also detected in respiratory speci-
ocratic Republic of Congo in late 2010 from a fecal mens of a few patients with AFM, and in some
sample of a patient with acute flaccid paralysis. It patients with aseptic meningitis or encephalitis. It
was initially misclassified as EV-C109, but was has been reported in at least two patients with
reclassified in 2012 as EV-C105 [25]. EV-C105 was enterovirus-associated encephalitis, suggestive of
also reported in New Zealand in a man with respir- neurotropism. There was an outbreak of EV-D68
atory symptoms, including cough and wheezing respiratory illness in Colorado, described as a
[26]. Five circulating EV-C105 strains were com- defined cluster of AFM and cranial nerve dysfunc-
pared from Europe and Africa in 2015. This com- tion in a small population of patients. EV-D68 was
parison showed that EV-C105 was closely related to isolated from the respiratory tract of five of 11
EV-C109 and EV-C118, but that the strains circulat- &
patients in this outbreak [36 ], but causality was
ing in Africa were distinct from the strains circulat- not clearly demonstrated. The virus has not yet been
ing in Europe [27]. Tracking other nonpolio detected in the spinal fluid of any patients with
enterovirus causes of AFM, including EV-C105, AFM. Additional investigation is needed to deter-
remains an important step in poliovirus elimination mine if there is a direct link between EV-D68 infec-
[28,29]. tion and AFM, including the possibility that the
virus is a trigger of immunologic gray matter injury
[34].
Enterovirus D68 respiratory and neurologic
disease
EV-D68 was first isolated in 1962 [30] from children TREATMENT OF ENTEROVIRUSES: RECENT
with respiratory illness, but had limited circulation PROGRESS
in the United States for the next 4 decades, with only Treatment of enteroviruses is supportive, focusing
26 reports to the NESS between 1970 and 2005 [31]. on the management of the most severe physio-
EV-D68 has been increasingly reported worldwide logical derangements. For example, in 2014,
since 2004, with reports from Thailand, the Nether- approximately 51% of patients hospitalized with
lands, New Zealand, Kenya, and a cluster of 120 EV-D68 infections at one center required ventilator
patients in Japan in 2010 [32]. In the United States, assistance (noninvasive or mechanical ventilation)
4.3% of specimens sent to NESS between 2009 and &&
[35 ]. In cases of neonatal sepsis and meningitis,
&
2013 were positive for EV-D68 [19 ]. Between 2013 administration of intravenous immunoglobulin
and 2014, EV-D68 was detected in 1% of nasophar- (IGIV) or hyperimmune plasma has been used,
yngeal swabs performed in a surveillance study of based on case reports and small clinical studies

110 www.co-pediatrics.com Volume 28  Number 1  February 2016

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

 Enteroviruses in the early 21st century Lugo and Krogstad

suggesting amelioration of disease. However, high activity, poor bioavailability, intrinsic resistance
concentrations of antibody to neutralize the specific by some circulating strains, and pharmacoeconomic
&
virus found in the infected individual are needed to considerations [38 ].
&
alter the disease course [37,38 ]. After the 2014 out- Repurposing of existing medications would
break of EV-D68, commercial IGIV lots were tested facilitate the development of antiviral therapy for
for levels of antibody to D68 and were shown to enteroviruses. For example, the antimalarial drug
have high titers of neutralizing antibodies [39]. mefloquine, the antidepressant fluoxetine, and the
Passive immunization with IGIV could be attempted diuretic amiloride, all exhibit in-vitro activity
&
in EV-D68 disease as an adjunct to supportive care. against one or more enteroviruses [38 ]. Similarly,
The enterovirus outbreaks described above high- fluoxetine was found to inhibit EV-B and EV-D
light the ongoing, unmet need for antiviral medi- enteroviruses, including EV-D68, and group B cox-
cations with activity against enteroviruses. Further sackieviruses [44–46]. Unfortunately, achievable
impetus for the development of antienteroviral serum concentrations of fluoxetine and its active
medications comes from the threat represented by metabolite norfluoxetine are lower than inhibitory
the cVDPVs and the persistent replication of OPV thresholds likely to be required to treat systemic
strains in immunocompromised hosts [40]. disease [45]; cerebrospinal fluid concentrations
A variety of molecules have been identified that are higher and hypothetically therapeutic [47].
bind to enterovirus capsids or that interfere with Similarly, mefloquine exhibits little activity at
viral proteins involved in enterovirus replication; achievable concentrations. At present, specific anti-
several of these have made it into clinical trials. viral therapy for enteroviruses remains beyond the
Pleconaril is a viral capsid inhibitor with broad horizon.
antiviral activity against enteroviruses and rhinovi-
ruses. It binds to the viral capsid and prevents
attachment, uncoating, and subsequent release of VACCINE DEVELOPMENT
intracellular viral RNA. Pleconaril has modest anti- Based on prior experience with poliovirus, it is
viral activity in the treatment of common colds assumed that an effective vaccine could play an
because of rhinoviruses and enteroviruses, but was important role in reducing the disease burden
not granted Food and Drug Administration approval associated with enteroviruses. There has been
because of concerns about drug–drug interactions, ongoing research in this area, with significant study
evolution of drug resistance, and other concerns of vaccines for EV-A71. Immunization of pregnant
[41]. However, the results of a lengthy double-blind, mice with virus-like particles demonstrated protec-
placebo-controlled trial of pleconaril for the treat- tion of neonatal mice challenged with EV-A71 [48].
ment of neonates with enterovirus sepsis were A live attenuated strain of EV-A71 was derived from
&&
recently published [42 ]. In intent to treat analysis, the prototype strain BrCr, and inoculation of mon-
deaths were less common in pleconaril-treated keys led to the production of antibodies that dem-
infants than placebo recipients [10/43 (23%) versus onstrated cross reactivity with many enterovirus
8/18 (44%), P ¼ 0.02]; in contrast, the differences in strains. However, in this study, it also led to neuro-
mortality rates of children with proven enterovirus logic symptoms and was found to enter the spinal
infection were not significantly different [7/31 cord [49,50]. More recently, large-scale clinical trials
(23%) versus 5/12 (42%), P ¼ 0.26] [42 ]. The small
&& &
tested an inactivated alum-adjuvant vaccine [51 ].
study size of the study, low serum concentrations of This vaccine was 95.1% effective in preventing
pleconaril in the first 24 h of treatment, and other HFMD in recipients of two doses. High levels of
factors make it difficult to assess the therapeutic neutralizing antibodies were demonstrated and no
potential of pleconaril in neonates. The authors vaccine-attributable adverse events were reported
&
called for additional studies based on evidence of during the study [51 ]. More follow-up is needed
viral suppression and other statistical signals to determine long-term protection.
&&
suggesting drug efficacy [42 ].
Other capsid-binding agents exist, including
pirodavir and vapendavir, and these exhibit activity CONCLUSION
against EV-A71 and poliovirus strains [43]. However, Recent outbreaks have highlighted the public health
clinical experience with these is very limited, and impact of enteroviruses; recurrences of known
none had significant antiviral activity against the pathogens and the evolution of additional new
strains of EV-D68 that circulated in 2014 [44]. Other variants should be anticipated. Continued surveil-
novel specific inhibitors of enterovirus have been lance of circulating strains is essential, and clini-
identified. However, progress toward clinical studies cians should utilize rapid molecular diagnostic
has been impeded because of limited antiviral methods to recognize enteroviral disease. The

1040-8703 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved. www.co-pediatrics.com 111

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Infectious diseases and immunization

18. Centers for Disease Control and Prevention. Nonpolio enterovirus and human
morbidity and mortality associated with recent parechovirus surveillance: United States, 2006–2008. MMWR Morb Mortal
enterovirus outbreaks demonstrate the urgent need Wkly Rep 2010; 59:1577–1580.
19. Abedi GR, Watson JT, Pham H, et al. Enterovirus and human parechovirus
for antiviral therapies for enteroviruses. Research to & surveillance: United States. MMWR Morb Mortal Wkly Rep 2015; 64:940–
develop vaccines and antiviral agents should be 943.
The article details the changing epidemiology of enteroviruses, including a shift
prioritized. from parechoviruses and EV-A strains, and the rise of EV-D68.
20. Wassilak SG, Oberste MS, Tangermann RH, et al. Progress toward global
interruption of wild poliovirus transmission, 2010-2013, and tackling the
Acknowledgements challenges to complete eradication. J Infect Dis 2014; 210 (Suppl 1):S5–
None. S15.
21. Michael CA, Ogbuanu IU, Storms AD, et al. An assessment of the reasons for
oral poliovirus vaccine refusals in northern Nigeria. J Infect Dis 2014; 210
Financial support and sponsorship (Suppl 1):S125–S130.
22. Simpson DM, Sadr-Azodi N, Mashal T, et al. Polio eradication initiative in
D.L. received financial support from NIH training grant Afghanistan. J Infect Dis 2014; 210 (Suppl 1):S162–S172.
23. Burns CC, Shaw J, Jorba J, et al. Multiple independent emergences of type 2
T32 AI089398. vaccine-derived polioviruses during a large outbreak in northern Nigeria.
J Virol 2013; 87:4907–4922.
24. Polio Eradication & Endgame Midterm Review 2015. Edited by; 2015. Polio
Conflicts of interest && Eradication & Endgame Midterm Review.
There are no conflicts of interest. This online article from July 2015 describes the current status of efforts to
eradicate poliovirus and the initiation of endgame strategies.
25. Tokarz R, Hirschberg DL, Sameroff S, et al. Genomic analysis of two novel
human enterovirus C genotypes found in respiratory samples from Peru. J Gen
REFERENCES AND RECOMMENDED Virol 2013; 94:120–127.
READING 26. Todd A, Taylor S, Huang QS. Identification of Enterovirus C105 for the first
Papers of particular interest, published within the annual period of review, have time in New Zealand. Western Pac Surveill Response J 2015; 6:60–62.
been highlighted as: 27. Piralla A, Daleno C, Girello A, et al. Circulation of two Enterovirus C105 (EV-
& of special interest C105) lineages in Europe and Africa. J Gen Virol 2015; 96:1374–1379.
&& of outstanding interest 28. Bassey BE, Gasasira A, Mitula P, et al. Surveillance of acute flaccid paralysis
in Akwa Ibom State, Nigeria 2004-2009. Pan Afr Med J 2011; 9:32.
1. Enders JF. Observations on certain viruses causing exanthematous diseases 29. Bingjun T, Yoshida H, Yan W, et al. Molecular typing and epidemiology of
in man. Am J Med Sci 1956; 231:622–637. nonpolio enteroviruses isolated from Yunnan Province, the People’s Republic
2. Neva FA, Feemster RF, Gorbach IJ. Clinical and epidemiological features of an of China. J Med Virol 2008; 80:670–679.
usual epidemic exanthem. J Am Med Assoc 1954; 155:544–548. 30. Schieble JH, Fox VL, Lennette EH. A probable new human picornavirus
3. McMinn P, Stratov I, Nagarajan L, et al. Neurological manifestations of associated with respiratory diseases. Am J Epidemiol 1967; 85:297–310.
enterovirus 71 infection in children during an outbreak of hand, foot, and 31. Khetsuriani N, Lamonte-Fowlkes A, Oberst S, et al. Enterovirus surveillance:
mouth disease in Western Australia. Clin Infect Dis 2001; 32:236–242. United States, 1970-2005. MMWR Surveill Summ 2006; 55:1–20.
4. McMinn PC. An overview of the evolution of enterovirus 71 and its clinical and 32. Centers for Disease Control and Prevention (CDC). Clusters of acute respira-
public health significance. FEMS Microbiol Rev 2002; 26:91–107. tory illness associated with human enterovirus 68: Asia, Europe, and United
5. Ma E, Chan KC, Cheng P, et al. The enterovirus 71 epidemic in 2008: public States, 2008-2010. MMWR Morb Mortal Wkly Rep 2011; 60:1301–1304.
health implications for Hong Kong. Int J Infect Dis 2010; 14:e775–780. 33. Furuse Y, Chaimongkol N, Okamoto M, et al. Molecular epidemiology of
6. Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection in enterovirus d68 from 2013 to 2014 in Philippines. J Clin Microbiol 2015;
Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med 1999; 53:1015–1018.
341:929–935. 34. Messacar K, Abzug MJ, Dominguez SR. 2014 outbreak of enterovirus D68 in
7. Huang CC, Liu CC, Chang YC, et al. Neurologic complications in children North America. J Med Virol 2015; doi: 10.1002/jmv.24410. [Epub ahead of
with enterovirus 71 infection. N Engl J Med 1999; 341:936–942. print]
8. Chen KT, Chang HL, Wang ST, et al. Epidemiologic features of hand-foot- 35. Schuster JE, Miller JO, Selvarangan R, et al. Severe enterovirus 68 respiratory
mouth disease and herpangina caused by enterovirus 71 in Taiwan. Pediatrics && illness in children requiring intensive care management. J Clin Virol 2015;
2007; 120:e244–e252. 70:77–82.
9. Lu CY, Lee CY, Kao CL, et al. Incidence and case-fatality rates resulting from Provides detail about the magnitude and difficulty of managing an epidemic of
the 1998 enterovirus 71 outbreak in Taiwan. J Med Virol 2002; 67:217–223. patients with enterovirus D68, including a high volume of patients with virus-
10. Gau SS, Chang LY, Huang LM, et al. Attention-deficit/hyperactivity-related induced bronchospasm requiring intensive care management.
symptoms among children with enterovirus 71 infection of the central nervous 36. Messacar K, Schreiner TL, Maloney JA, et al. A cluster of acute flaccid
system. Pediatrics 2008; 122:e452–e458. & paralysis and cranial nerve dysfunction temporally associated with an out-
11. Xing W, Liao Q, Viboud C, et al. Hand, foot, and mouth disease in China, break of enterovirus D68 in children in Colorado, USA. Lancet 2015;
&& 2008-12: an epidemiological study. Lancet Infect Dis 2014; 14:308–318. 385:1662–1671.
The study demonstrates the magnitude of the problem in Asia with HFMD. This The temporal association of EV-D68 with acute flaccid paralysis is detailed in this
article highlights the importance of EV-A71 causing a majority of cases there and article, expanding the ongoing debate regarding the neurotropism of this virus.
significant mortality. 37. Abzug MJ, Keyserling HL, Lee ML, et al. Neonatal enterovirus infection:
12. Centers for Disease Control and Prevention. Notes from the field: severe virology, serology, and effects of intravenous immune globulin. Clin Infect
hand, foot, and mouth disease associated with coxsackievirus A6-Alabama, Dis 1995; 20:1201–1206.
Connecticut, California, and Nevada, November 2011-February 2012. 38. Abzug MJ. The enteroviruses: problems in need of treatments. J Infect 2014;
MMWR Morb Mortal Wkly Rep 2012; 61:213–214. & 68 (Suppl 1):S108–S114.
13. Bian L, Wang Y, Yao X, et al. Coxsackievirus A6: a new emerging pathogen The state of development of enteroviral treatments is discussed in this article. It
& causing hand, foot and mouth disease outbreaks worldwide. Expert Rev Anti also describes the difficulties in developing new antiviral medications.
Infect Ther 2015; 13:1061–1071. 39. Zhang Y, Moore DD, Nix WA, et al. Neutralization of Enterovirus D68 isolated
Describes the worldwide emergence of CVA6 as a cause of HFMD and the from the 2014 US outbreak by commercial intravenous immune globulin
genetic evolution of the virus, epidemic characteristics, and disease manifesta- products. J Clin Virol 2015; 69:172–175.
tions. It also highlights the need for vaccine development for both EV-A71 and 40. McKinlay MA, Collett MS, Hincks JR, et al. Progress in the development of
CVA6. poliovirus antiviral agents and their essential role in reducing risks that
14. Mathes EF, Oza V, Frieden IJ, et al. ‘Eczema coxsackium’ and unusual threaten eradication. J Infect Dis 2014; 210 (Suppl 1):S447–S453.
cutaneous findings in an enterovirus outbreak. Pediatrics 2013; 132:e149– 41. Hayden FG, Herrington DT, Coats TL, et al. Efficacy and safety of oral
e157. pleconaril for treatment of colds due to picornaviruses in adults: results of
15. Khetsuriani N, Lamonte A, Oberste MS, et al. Neonatal enterovirus infections 2 double-blind, randomized, placebo-controlled trials. Clin Infect Dis 2003;
reported to the national enterovirus surveillance system in the United States. 36:1523–1532.
Pediatr Infect Dis J 2006; 25:889–893. 42. Abzug MJ, Michaels MG, Wald E, et al. A Randomized, double-blind, placebo-
16. Verma NA, Zheng XT, Harris MU, et al. Outbreak of life-threatening coxsack- && controlled trial of pleconaril for the treatment of neonates with enterovirus
ievirus B1 myocarditis in neonates. Clin Infect Dis 2009; 49:759–763. sepsis. J Pediatric Infect Dis Soc 2015; doi: 10.1093/jpids/piv015. [Epub
17. Wikswo ME, Khetsuriani N, Fowlkes AL, et al. Increased activity of Coxsack- ahead of print]
ievirus B1 strains associated with severe disease among young infants in the The article detailing the randomized long-awaited results of a clinical trial of the
United States. Clin Infect Dis 2009; 49:e44–e51. antiviral drug pleconaril for treatment of neonatal enteroviral sepsis.

112 www.co-pediatrics.com Volume 28  Number 1  February 2016

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

 Enteroviruses in the early 21st century Lugo and Krogstad

43. Bernard A, Lacroix C, Cabiddu MG, et al. Exploration of the antienterovirus 48. Chung YC, Ho MS, Wu JC, et al. Immunization with virus-like particles of
activity of a series of pleconaril/pirodavir-like compounds. Antivir Chem enterovirus 71 elicits potent immune responses and protects mice against
Chemother 2015; doi: 10.1177/2040206615589035. [Epub ahead of print] lethal challenge. Vaccine 2008; 26:1855–1862.
44. Rhoden E, Zhang M, Nix WA, et al. In vitro efficacy of antiviral compounds 49. Arita M, Nagata N, Iwata N, et al. An attenuated strain of enterovirus 71
against enterovirus D68. Antimicrob Agents Chemother 2015; 59:7779– belonging to genotype a showed a broad spectrum of antigenicity with
7781. attenuated neurovirulence in cynomolgus monkeys. J Virol 2007; 81:9386–
45. Ulferts R, van der Linden L, Thibaut HJ, et al. Selective serotonin reuptake 9395.
inhibitor fluoxetine inhibits replication of human enteroviruses B and D by 50. Solomon T, Lewthwaite P, Perera D, et al. Virology, epidemiology, patho-
targeting viral protein 2C. Antimicrob Agents Chemother 2013; 57:1952– genesis, and control of enterovirus 71. Lancet Infect Dis 2010; 10:778–
1956. 790.
46. Zuo J, Quinn KK, Kye S, et al. Fluoxetine is a potent inhibitor of coxsackievirus 51. Li JX, Song YF, Wang L, et al. Two-year efficacy and immunogenicity of
replication. Antimicrob Agents Chemother 2012; 56:4838–4844. & Sinovac Enterovirus 71 vaccine against hand, foot and mouth disease in
47. Tyler KL. Rationale for the evaluation of fluoxetine in the treatment of children. Expert Rev Vaccines 2016; 15:129–137.
enterovirus D68-associated acute flaccid myelitis. JAMA Neurol 2015; Results of EV-A71 vaccine trial in Chinese children, studying immunogenicity and
72:493–494. efficacy in preventing HFMD.

1040-8703 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved. www.co-pediatrics.com 113

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.