Wednesday, March 28, 2018

EID J. & Virology Reports On Emerging Coxsackievirus A6

Vesicular eruptions in A) hand, B) foot, and C) mouth
 of a 6.5-year-old boy from Turku, Finland, with 
coxsackievirus (CV) A6 infection.  Credit - CDC EID Journal


Non-polio Enteroviruses (NPEV's) - of which there are dozens - typically spread in the summer and early fall, and generally produce mild or even asymptomatic infections, mostly in children under the age of 10.
Symptomatic cases can range from a mild fever or a runny nose - to HFMD (Hand Foot Mouth Disease) - a generally mild childhood disease characterized by blisters on the hand, feet, and mouth.
For several decades - particularly in Asian and Western Pacific nations - we've monitored yearly NPEV epidemics of a much more serious nature, with the most severe illness linked to Human Enterovirus 71 (EV-71), which can cause a polio-like paralysis, and sometimes even death.
  • In 2009 China reported 1,155,525 HFMD cases, including 13,810 severe cases and 353 deaths. Among laboratory confirmed cases, EV71 was responsible for 41% of cases, 82% of severe cases, and 93% of the deaths (cite WHO HFMD Guide Pg.6).
  • In 2012, we saw an outbreak of EV-71 in Cambodia that claimed the lives of dozens of children (see Updating The Cambodian EV71 Story).
  • In 2013 in Australia: Acute Flaccid Paralysis & EV71, we looked at a report that described 5 cases of acute flaccid paralysis (AFP) in children who tested positive for the EV71 virus.
In 2014 a nationwide outbreak of EV-D68 was linked to a concurrent spike in AFP (Acute Flaccid Paralysis) cases across the United States, and since then we've seen a number of EV-D68 outbreaks around the world (see here, here & here).
While a causal link between EV-D68 and AFM hasn't been fully established, last January's Eurosurveillance Review: Association Between Acute Flaccid Myelitis (AFM) & Enterovirus D68 (EV-D68), presented a pretty good argument for causation. 
Less well known, but rapidly coming up in the ranks, is Coxsackievirus A6, which was only first described about a decade ago.

In 2008, the CDC’s EID Journal carried a dispatch regarding an outbreak of HFMD in Finland due to an unusual, and apparently emerging, viral cause; the Coxsackie A6 virus. 

Coxsackievirus A6 and Hand, Foot, and Mouth Disease, Finland

Riikka Österback, Tytti Vuorinen, Mervi Linna, Petri Susi, Timo Hyypiä, and Matti Waris

During fall 2008, an outbreak of hand, foot, and mouth disease (HFMD) with onychomadesis (nail shedding) as a common feature occurred in Finland. We identified an unusual enterovirus type, coxsackievirus A6 (CVA6), as the causative agent. CVA6 infections may be emerging as a new and major cause of epidemic HFMD.
Since then, we’ve seen a growing number of reports of HFMD outbreaks around the world attributed to this emerging coxsackievirus, including outbreaks in Europe, Asia and North America (see Nevada: HFMD Coxsackievirus A6 Outbreak).

In 2012, in EID Journal: HFMD Cluster Due To CVA6 we looked at a report on cluster of 8 patients who were treated CVA6 HFMD at Boston Children’s Hospital.

The authors cautioned:
Given the numerous CVA6 outbreaks in multiple countries in 2008 and a US population that may be relatively naïve to this serotype, CVA6 is likely to spread throughout North America.

Which brings us to two recent reports on CVA6.

First from Virology, a report that CVA6 has overtaken both EV71 and CV-A16 as the primary cause of HFMD in China, and that it continues to evolve.

An emerging and expanding clade accounts for the persistent outbreak of Coxsackievirus A6-associated hand, foot, and mouth disease in China since 2013
Shuizhen Hea, 1, ,Mengyuan Chenb, c, d, 1, ,Wenhui Wub, c, d, ,Qiang Yanc, ,Zhihao Zhuob, c, ,Xiaosong Sub, c, d, ,Shiyin Zhangb, c, d, , ,Shengxiang Geb, c, d, , ,Ningshao Xiab, c, d, rights and content


  • CV-A6 became the primary pathogen in China in 2013 and 2015.
  • D5.4 Lineage strains were responsible for CV-A6 epidemics since 2013 in China.
  • Eight VP1 candidate substitutions were identified between different CV-A6 lineage strains.

Enterovirus (EV)-A71 and Coxsackievirus (CV)-A16 have historically been the major pathogens of hand, foot, and mouth disease (HMFD) in China; however, CV-A6, which had previously received little attention, became the predominant pathogen in 2013, and has remained one of the common pathogens since then.
In this work, we conducted a molecular epidemiology study of CV-A6-associated HFMD in Xiamen from 2009 to 2015. The data showed CV-A6 pandemics had a certain periodicity rather than occurring randomly. Evolution analysis based on near-complete VP1 nucleotide sequences showed subgenotype D5 lineage 4 strains account for the persistent outbreak of CV-A6-associated HFMD in China since 2013.
Alignment analysis revealed eight candidate amino acid substitutions in VP1, which may provide useful information for the research of CV-A6 virulence enhancement. This study contributed to elucidating the circulation patterns and genetic characteristics of CV-A6 in China; however, further surveillance and intervention in CV-A6 epidemics is recommended.

And from the EID Journal, this cautionary report from Vietnam warning of the ongoing evolution and pandemic potential of CVA6.
Volume 24, Number 4—April 2018
Emerging Coxsackievirus A6 Causing Hand, Foot and Mouth Disease, Vietnam

Nguyen To Anh, Le Nguyen Truc Nhu, Hoang Minh Tu Van, Nguyen Thi Thu Hong, Tran Tan Thanh, Vu Thi Ty Hang, Nguyen Thi Han Ny, Lam Anh Nguyet, Tran Thi Lan Phuong, Le Nguyen Thanh Nhan, Nguyen Thanh Hung, Truong Huu Khanh, Ha Manh Tuan, Ho Lu Viet, Nguyen Tran Nam, Do Chau Viet, Phan Tu Qui, Bridget Wills, Sarawathy Sabanathan, Nguyen Van Vinh Chau, Louise Thwaites, H. Rogier van Doorn, Guy Thwaites, Maia A. Rabaa, and Le Van Tan


Hand, foot and mouth disease (HFMD) is a major public health issue in Asia and has global pandemic potential. Coxsackievirus A6 (CV-A6) was detected in 514/2,230 (23%) of HFMD patients admitted to 3 major hospitals in southern Vietnam during 2011–2015.
Of these patients, 93 (18%) had severe HFMD.
Phylogenetic analysis of 98 genome sequences revealed they belonged to cluster A and had been circulating in Vietnam for 2 years before emergence. CV-A6 movement among localities within Vietnam occurred frequently, whereas viral movement across international borders appeared rare.
Skyline plots identified fluctuations in the relative genetic diversity of CV-A6 corresponding to large CV-A6–associated HFMD outbreaks worldwide. These data show that CV-A6 is an emerging pathogen and emphasize the necessity of active surveillance and understanding the mechanisms that shape the pathogen evolution and emergence, which is essential for development and implementation of intervention strategies.

Hand, foot and mouth disease (HFMD) is an emerging infection that has overwhelmed countries in the Asia–Pacific region over the past 2 decades. The outbreak in Sarawak, Malaysia, in 1997 caused 2,628 reported cases and 29 deaths and marked the start of explosive regional HFMD outbreaks in subsequent years.
On average, >1 million cases have been recorded in China annually since 2008 (1). In Vietnam, the average annual incidence is ≈80,000 cases; an epidemic peak occurred during 2011–2012, resulting in >200,000 cases and >200 deaths (2).

HFMD is caused by enterovirus A (genus Enterovirus, family Picornaviridae), but the epidemic patterns until now have been punctuated by the frequent replacement of dominant pathogens between enterovirus serotypes over time.
Enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) have been regarded as the major causes of HFMD (3). CV-A6 was isolated in the United States in 1949 (4) and has steadily become one of the main viruses causing HFMD outbreaks in Europe, America, and Asia, including China, Japan, Taiwan, and Thailand (3,510).
Unlike EV-A71, for which the (sub)genogroup designation has been well established (11), but similar to other coxsackieviruses (CV-A16 and CV-A10), CV-A6 is arbitrarily divided into several phylogenetic clusters or lineages, from cluster A to F (12) or lineage A to E (E1 and E2) (3). Cluster A/lineage E2 is distributed worldwide and has frequently been detected in recent outbreaks. We use the term cluster in this article.

Despite the public health burden of HFMD, no antiviral drug has been clinically proven effective. A vaccine for EV-A71 has recently been licensed in China only (13), and CV-A16 vaccines (either monovalent or EV-A71/CV-A16 bivalent forms) are under development (14,15).

The emergence of CV-A6 has further challenged the development of intervention strategies, including vaccines, to reduce the burden of HFMD (13). It also emphasizes the need to better understand the molecular evolution of this emerging pathogen, which is essential for development of an effective CV-A6 vaccine in the future (16).
(Continue . . . )

Just as we see with influenza, these non-polio enteroviruses continue to evolve - and while not as deadly as flu - they are capable of causing large epidemics or potentially even pandemics (referring to spread, not severity). 
Some of my earlier blogs NPEVs include:
MMWR: Cluster of Acute Flaccid Myelitis in Five Pediatric Patients - Arizona, 2016

CDC Acute Flaccid Myelitis Update - January 2017

EID Journal Upsurge In EV-D68 In The Netherlands, 2016

ECDC: Rapid Risk Assessment On Recent Enterovirus Outbreaks In Europe

EID Journal: New Introductions Of EV-71 Subtype C4 To France – 2012

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