Avian Flu Diary: EID Journal: New Introductions Of EV-71 Subtype C4 To France

Photo Credit University of Iowa

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Human Enterovirus 71 (EV-71) – which is most often reported in Asia and the Western Pacific region - is one of more than 60 non-polio enteroviruses (NPEVs) known to cause cause human illness, and that primarily affect children under the age of 10.

While EV-71 is most frequently linked to severe outbreaks of HFMD (Hand, Foot, & Mouth Disease), it is also capable of producing serious neurological illnesses – including poliomyelitis-like paralysis (AFD or Acute Flaccid Paralysis), encephalitis, and sometimes death.

It should be noted that HFMD can be caused by a variety of viruses, and most of the time, it is generally mild and only rarely requires medical attention. It is, however, highly contagious and spreads via close personal contact, droplets (through coughing or sneezing), the fecal-oral route, or contact with contaminated objects and surfaces (fomites).

The most common cause of HFMD in North America and Europe is the Coxsackie A16 virus, and more rarely the Coxsackie A10 virus. In recent years, we’ve also seen the emergence of the Coxsackie A6 virus which has been linked to somewhat more severe HFMD cases (see MMWR: Coxsackievirus A6 Notes From The Field).

But it is Enterovirus 71 that has been linked to the most severe cases of HFMD – particularly across Asia - with serious outbreaks recorded over the past 18 years in places like China, Taiwan, Malaysia, Hong Kong and Cambodia.

Like other RNA viruses we monitor, EV71 is constantly evolving, creating new strains or lineages, and as a result we’ve seen repeated outbreaks over the years. During the late 1990s and early 2000s, genotypes C1, C2, B3, and B4 were most commonly reported as sparking outbreaks in Malaysia, Singapore, and Taiwan.

But by 2005, emerging genotype C4 had replaced B4 in Taiwan, while in China C4 (which had split into 2 distinct lineages, C4a and C4b) caused major HFMD outbreaks in 2007–2009 (see Phylogenetic analysis of Enterovirus 71 circulating in Beijing, China from 2007 to 2009.)

The spread and diversity of EV71 – Credit WHO

As shown in the chart above, the more aggressive C4 genotype – which first appeared in China in 1998 - has made significant inroads across much of Asia and the Western Pacific over the past 15 years.

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), while last year, in Australia: Acute Flaccid Paralysis & EV71, we looked at a report that described 5 recent cases of acute flaccid paralysis (AFP) in children who tested positive for the EV71 virus.

Although EV-71 was first described in a California infection in 1969, and outbreaks of EV-71 associated HFMD were recorded in Europe, North America, and Australia back in the 1970s (see BMJ article on Challenges of EV-71) the genotypes circulating in Asia today have evolved to become more virulent than those of 40 years ago.

As with many other infectious diseases, there are genuine concerns that EV-71 may, through repeated introductions via international travel, spread beyond Asia and the Pacific to get a foothold in Europe and North America. While large outbreaks have not occurred outside of Asia yet, there is no good reason known why they couldn’t in the future.

All of which serves as prelude to a new Dispatch from the EID Journal, which documents recent introductions of the EV-71 C4 subtype to France. The bottom line – which comes from the author’s conclusions – reads: The phylogenetic data are consistent with 3 independent virus introductions, presumably from China, and are compatible with a more global circulation of subgenogroup C4 enteroviruses

Volume 20, Number 8—August 2014

Dispatch

New Introductions of Enterovirus 71 Subgenogroup C4 Strains, France, 2012

Abstract

In France during 2012, human enterovirus 71 (EV-A71) subgenogroup C4 strains were detected in 4 children hospitalized for neonatal fever or meningitis. Phylogenetic analysis showed novel and independent EV-A71 introductions, presumably from China, and suggested circulation of C4 strains throughout France. This observation emphasizes the need for monitoring EV-A71 infections in Europe.

Conclusions

In 2012, EV-A71 C4 strains were detected in France in 4 children hospitalized for neonatal fever or meningitis. Although EV-A71 C4 strains have circulated extensively in China since 2008, this virus has rarely been detected in Europe. In France, 133 cases of EV-A71 infections were reported during January 2000–May 2013 (9) (I. Schuffenecker, unpub. data). EV-A71 C2 infections have been predominant since 2007; however, only 5 cases of EV-A71 C4 infection have been identified in the country since 2004. Our Bayesian analyses excluded a direct evolution of the 2012 EV-A71 C4 strains from the earlier 2004 European virus lineage. The phylogenetic data are consistent with 3 independent virus introductions, presumably from China, and are compatible with a more global circulation of subgenogroup C4 enteroviruses. In 2013, the C4 subgenogroup also emerged in Russia, where it was associated with an outbreak of 78 reported cases, including 1 fatal case of meningoencephalitis (14).

Many cases of fatal encephalitis have been associated with EV-A71 C4 infection outbreaks in China (6), which highlights the neurovirulence of EV-A71 strains. Rare acute flaccid paralysis cases have also been reported in Australia through the national poliomyelitis surveillance program (15).

Although the prevalence of neurologic cases associated with EV-A71 infection is currently low in Europe, the recent circulation of EV-A71 C4 in France and in Rostov, Russia (along the eastern border with Europe), underscores the need for improved surveillance of neurologic manifestations associated with EV infection and of the incidence of HFMD within communities. In addition, careful monitoring for the possible introduction and circulation of new EV-A71 genogroups and subgenogroups should be conducted.

Among the challenges of controlling EV71 outbreaks are:

Although at least three vaccine candidates have recently completed Phase III trials, none are currently commercially available.
A moving viral target, with new strains evolving and emerging over time
Many children can carry (and shed) the virus asymptomatically (see Incidence Rates of Enterovirus 71 Infections in Young Children during a Nationwide Epidemic in Taiwan, 2008–09)
Patients may shed virus for month or longer (see Long persistence of EV71 specific nucleotides in respiratory and feces samples of the patients with Hand-Foot-Mouth Disease after recovery)

For now, control and prevention are limited to promoting good hygiene, and removing children with signs of the disease from child care or school environments. For more on HFMD, including the more severe Enterovirus-71 (EV-71), you may wish to revisit the following blogs: