H5N1: The Only Constant is Change

#17,482

The avian flu situation has changed markedly in the 7 months since we first looked at a Preprint: Rapid Evolution of A(H5N1) Influenza Viruses After Intercontinental Spread to North America, which described the detection of multiple new genotypes of H5N1 - some with increased virulence - which evolved after the H5N1 virus crossed the Atlantic Ocean and arrived in Canada in late 2021.

At the time, the authors wrote:

From a public health perspective, the increased pathogenicity of the reassortant A(H5N1) viruses is of significant concern. However, this is tempered by the avian virus–like characteristics of the viruses with respect to their receptor binding preference and their pH of HA activation. These characteristics probably need to change to enable sustained human-to-human transmission, although only a few amino acid changes among various influenza proteins are needed to switch these properties during adaptation in mammals.

Within weeks of its publication we saw the H5 virus spread southward for the first time along the South American Pacific coast, followed by reports of hundreds (then thousands) of marine mammal deaths from Peru to Chile. 

As we've seen in North America and Europe, new genotypes have emerged in South America as well (see Preprint: Highly Pathogenic Avian Influenza A (H5N1) in Marine Mammals and Seabirds in Peru).

Also in the fall of 2022, Spain reported an Avian H5N1 Spillover Into Farmed Mink, which we would later learn (see Eurosurveillance: HPAI A(H5N1) Virus Infection in Farmed Minks, Spain, October 2022) not only suggested possible mammal-to-mammal transmission of the virus, but it also produced a rare `mammalian' mutation (T271A), which `enhances the polymerase activity of influenza A viruses in mammalian host cells and mice'.

Reports of H5Nx spillover into mammalian wildlife species have increased markedly over the past year (see Avian influenza overview March – April 2023). Surveillance and reporting from many regions of the world being limited, these likely represent only a fraction of the actual number of spillover events.

Somewhat ominously, H5N1 appears to be becoming increasingly neurotropic in mammals. A few (of many) studies we've seen on this changing aspect of H5N1 infection include:

UK Reports 2 Dolphins With HPAI H5N1 & EID Report On Infected Harbor Porpoise in Sweden

PLoS Pathogens: Evolution of Highly Pathogenic H5N1 Influenza A Virus in the Central Nervous System of Ferrets

Preprint: Pathology Of HPAI H5N1 clade 2.3.4.4b in Wild Terrestrial Mammals in the United States in 2022

Emerging Microbes & Inf.: Neurotropic HPAI H5N1 Viruses with Mammalian Adaptive Mutations in Free-living Mesocarnivores in Canada 

These spillovers have also impacted household pets (see Nebraska Veterinary Diagnostic Center (NVDC) Report: 2 Domestic Cats Infected With HPAI H5N1  and  PHAC: Domestic Dog Tests Positive for Avian Influenza in Canada), prompting warnings about protecting animals from undo exposure (see CDC Bird Flu in Pets and Other Animals).

 

This proclivity for spilling over into mammals has generated warnings that swine might serve as efficient `mixing vessels' for avian influenza.  A concern that was validated less than a month ago when we saw a report of Seroconversion of a Swine Herd at a `mixed species' farm (poultry & swine) in Italy.

Human infections with this new H5 virus have been rare, but have increased and have ranged from mild or asymptomatic to life threatening.  Since testing and surveillance is sporadic at best (see UK Novel Flu Surveillance: Quantifying TTD), it is likely some cases have been missed.

A week rarely goes by without a new revelation, or study, suggesting that H5N1 continues to evolve towards a potential pandemic threat. Just over a week ago, we saw the announcement from Japan's MOH of their intention to Stockpile 10 Million Doses of H5N1 Vaccine, and they are far from alone in their concern.

This week Nature published the final version of the preprint mentioned at the top of this blog (see below), which has generated a good deal of buzz in the media this week (see Experts warn bird flu virus changing rapidly in largest ever outbreak).

 

If you missed it the first time around, or simply desire a valuable refresher, it is well worth reading in its entirety.  I'll have a bit more after you return.

Rapid evolution of A(H5N1) influenza viruses after intercontinental spread to North America

Ahmed Kandeil, Christopher Patton, Jeremy C. Jones, ,Trushar Jeevan, Walter N. Harrington, Sanja Trifkovic, Jon P. Seiler, Thomas Fabrizio, Karlie Woodard, Jasmine C. Turner, Jeri-Carol Crumpton, Lance Miller, Adam Rubrum, Jennifer DeBeauchamp, Charles J. Russell, Elena A. Govorkova, Peter Vogel, Mia Kim-Torchetti, Yohannes Berhane, David Stallknecht, Rebecca Poulson, Lisa Kercher & Richard J. Webby

Nature Communications volume 14, Article number: 3082 (2023) Cite this article

Abstract

Highly pathogenic avian influenza A(H5N1) viruses of clade 2.3.4.4b underwent an explosive geographic expansion in 2021 among wild birds and domestic poultry across Asia, Europe, and Africa. By the end of 2021, 2.3.4.4b viruses were detected in North America, signifying further intercontinental spread. Here we show that the western movement of clade 2.3.4.4b was quickly followed by reassortment with viruses circulating in wild birds in North America, resulting in the acquisition of different combinations of ribonucleoprotein genes.

These reassortant A(H5N1) viruses are genotypically and phenotypically diverse, with many causing severe disease with dramatic neurologic involvement in mammals. The proclivity of the current A(H5N1) 2.3.4.4b virus lineage to reassort and target the central nervous system warrants concerted planning to combat the spread and evolution of the virus within the continent and to mitigate the impact of a potential influenza pandemic that could originate from similar A(H5N1) reassortants.

          (Continue . . . )

While H5N1 has threatened unsuccessfully before, one can't help but feel that this time things are different. The virus is far more widespread than ever, not only in terms of geography, but also in the number of species (avian and mammalian) it is affecting. 

H5N1 is also a blanket term for scores of similar - but genetically distinct - genotypes, all of which continue to evolve and diversify.  We aren't just facing one wayward H5N1 virus with pandemic potential, we are potentially facing dozens. 

Although we'd seen some hints of neurological impacts from H5N1 in the past (see 2015's CJ ID & MM: Case Study Of A Neurotropic H5N1 Infection - Canada), it was considered a rare presentation. The authors of that report did warn, however:

These reports suggest the H5N1 virus is becoming more neurologically virulent and adapting to mammals. 

In a 2015 Scientific Reports study on the genetics of the H5N1 clade 2.3.2.1c virus - Highly Pathogenic Avian Influenza A(H5N1) Virus Struck Migratory Birds in China in 2015 – the authors warned of its neurotropic effects, and that it could pose a ` . . . significant threat to humans if these viruses develop the ability to bind human-type receptors more effectively.'

Although the name is the same, the H5N1 virus of today is a far cry from the virus that emerged in Southeast Asia two decades ago.  

HPAI H5 was initially limited to Southern China and parts of Southeast Asia, where it smoldered in poultry and wild birds until it evolved into clade 2.2 at Qinghai Lake - and then quickly spread to Europe, the Middle East, and Africa - in 2005-2007.

For the next decade it set up housekeeping in places like Egypt, Cambodia, and Indonesia - forming geographically distinct clades and variants - but by 2012 H5 appeared to be declining globally. 

A new H5N8 clade 2.3.4.4 emerged in South Korea in 2014, breathing new life into the H5 subtype, spreading with unexpected vigor around the globe, and reassorting readily with other LPAI viruses. In 2016, a reassortment event in Russia or China further increased its ability to be carried by migratory birds. 

Since then HPAI H5Nx viruses have undergone numerous and rapid evolutionary changes, morphing from H5N8, to H5N6, and more recently to H5N1 and H5N5 subtypes.

Not surprisingly, H5's evolutionary rate has increased as the number and variety of H5 viruses in circulation has grown.  Exactly where this uncontrolled global field experiment will lead remains to be seen, but additional changes to the virus are inevitable. 

We need to be prepared for surprises ahead.  And time is not our friend. 

UK HAIRS Risk Assessment: Avian Influenza in A(H5N1) in Non-Avian UK Wildlife

Credit HAIRS Report

#17,481

With the double caveat that avian H5N1 is continually evolving, and anything we can say about the virus is based on limited evidence gathered weeks or even months ago, the UK HAIRS (Human Animal Infections and Risk Surveillance group) has published an updated risk assessment on avian flu in non-avian UK wildlife.

Unlike South America - which has reported thousands of marine mammals killed by avian flu over the past 6 months - the UK has only reported a couple of dozen confirmed non-avian wildlife infections.  

Their numbers, like those reported in the United States and elsewhere, are thought to represent only a fraction of the true number of infections in the wild. Most dead terrestrial animals are never recovered (or tested), and marine mammal losses are even harder to assess. 

Despite these limitations - and the reluctance of many countries around the world to report on avian flu (and other emerging threats) at all - it is pretty safe to assume that the H5N1 virus hasn't yet acquired the ability to spread efficiently in humans or other mammalian species. 

And as we've discussed often, there may be some as-yet undefined species barrier that protects us.  Or, the virus may simply not have stumbled upon the right combination of genetic changes that would allow it to spread as a pandemic virus. 

Time, as they say, will tell.  

Due to it length, I've only posted some excerpts from the HAIRS report.  Follow the link to read it in its entirety.   I'll have a bit more after the break. 

Research and analysis
HAIRS risk assessment: avian influenza A(H5N1) in non-avian UK wildlife

Published 2 June 2023

Summary

Avian influenza (AI) is an infectious disease of birds caused by the influenza A virus. Birds are the hosts for most AI viruses (AIV), and a variety of influenza subtypes, including AI A(H5N1), can be found in birds, particularly in waterfowl and shore birds. Domestic poultry are especially vulnerable, and the   (Continue . . . )virus can rapidly cause epidemics in flocks. In October 2020, highly pathogenic AI A(H5N1) clade 2.3.4.4b was detected in Europe, after re-assortment of AI A(H5N8) with wild bird lineage N1 viruses. Since October 2021, AI A(H5N1) clade 2.3.4.4b has become the dominant AI subtype detected in wild and captive birds across Europe and the UK, with a relatively stable genotype.

The virus has now been reported from wild birds and poultry across Africa, Asia, North and South America, Europe and the Middle East. Globally, there has been an increased spillover to non-avian species including wild terrestrial and marine mammals, likely as a result of the increased environmental pressure from the thousands of wild birds infected, rather than as a result of increased viral affinity for mammalian cells.

Positive detections of AI A(H5N1) have been identified in a range of animals, mostly from the Carnivora family. In the UK, and as of March 2023, retrospective testing of samples collected since 2021 revealed positive detections in red foxes, Eurasian otters, common and grey seals, harbour porpoises and common dolphins. These were the first detections of AI A(H5N1) in non-avian UK wildlife. Although these findings appear sporadic and isolated incidents, potential mammal-to-mammal transmission of AI A(H5N1) has recently been described in farmed mink in Spain, with genetic analysis revealing an uncommon mutation (T271A) in the PB2 gene which may enhance influenza A viral activity in mammalian host cells.

Where AI A(H5) subtypes circulate in poultry or wild birds, then sporadic human cases should not be unexpected in people with close contact or high levels of exposure. This is particularly evident for Asian lineage AI A(H5N1), with 868 human cases, including 457 deaths, being reported from 21 countries between January 2003 and January 2023. Where Eurasian lineage AI A(H1N1) clade 2.3.4.4b is concerned, from 2020 to the end of December 2022, 6 human cases were reported, globally. All these cases had exposure to infected poultry. To date, there are no reported transmission events of AI A(H5N1) from non-avian infected wildlife to humans.

This risk assessment will focus predominantly on AI A(H5N1) clade 2.3.4.4b as this is the dominant subtype detected in wild and captive birds across Europe and the UK at the time of writing.          

Assessment of the risk of infection in the UK

Probability

General UK population: Very Low

The probability of infection would be considered Low for those exposed to infected live or dead non-avian wildlife.

Impact

The impact on the general UK population would be considered Very Low, while it would be considered Low for high risk groups (for example individuals with occupational exposure to infected wildlife and/or immunocompromised or paediatric cases).

 

Level of confidence in assessment of risk

Satisfactory.

The majority of mammal cases are of the order Carnivora. While they may not all be recognised as commonly predating live or dead avian species, direct contact with a contaminated environment is also a possible transmission route. Without direct observational studies or environmental sampling in areas in the vicinity of known infection, it cannot be proven that mammal-to-mammal transmission is not occurring.

Given human detections of AI A(H5N1) clade 2.3.4.4b are rare, there is a paucity of evidence on what risk factors may increase disease susceptibility, severity and poorer clinical outcomes in human cases. For those cases reported, clinical disease has ranged from mild to severe. There is possible under-ascertainment of cases, particularly in instances where mild disease manifests.

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Admittedly, the UK ranks pretty far down the list of countries where we would expect pandemic H5N1 to take off, but it has the virtue of better surveillance and more open reporting than many places around the world. 

Even so, they cite a number of instances in today's report where there is a `paucity' of evidence or data available.  Risk assessments on emerging threats are always hindered by incomplete or inconsistent information.

Complicating matters, as the H5 virus spreads geographically it continues to diversify into new genotypes (see Novel Highly Pathogenic Avian Influenza A(H5N1) Clade 2.3.4.4b Virus in Wild Birds, South Korea) and new subtypes (see CIDRAP Canada reports first H5N5 avian flu in a mammal; US reports more H5N1 in animals). 

Most of this evolution goes on out of our sight.  Just as what is happening in the high latitude summer roosting areas right now won't be apparent until migratory birds make their return in the fall. 

A month ago, in Netherlands: Zoonoses Experts Council (DB-Z) Risk Assessment & Warning of Swine As `Mixing Vessels' For Avian Flu, we looked at concerns that avian H5N1 could increase its pandemic threat by spreading (and evolving) in farmed swine.

Which was followed a week later by a report (see Study: Seroconversion of a Swine Herd in a Free-Range Rural Multi-Species Farm against HPAI H5N1 2.3.4.4b Clade Virus) at a `mixed species' farm (poultry & swine) in Italy.

But the testing of swine herds is only rarely done, and some countries are not inclined to share results for political, economic, or societal reasons.  It is just one of many blind spots we have. 

Despite all of these concerns, there are no guarantees that H5N1 will spark the next pandemic.  It is just one of many plausible contenders, but it appears to have the most momentum now, which is why we focus on it so much. 

Six months from now, we could easily be looking at a completely different threat.  The only thing guaranteed is that - ready or not - there will be another pandemic in our future. 

(Pathogens Review) SARS-CoV-2: Companion Animal Transmission and Variants Classification

 

#17,480

Last night Stephanie Soucheray of CIDRAP News reported on a Study: Cats can transmit COVID-19 to each other, conducted by Wageningen University and Research, in the Netherlands. In a press release, tudy coauthor Wim van der Poel DVM, Ph.D., Professor of Emerging and Zoonotic Viruses, stated:

“SARS-CoV-2 transmission between cats is efficient and can be sustained. Infections of cats via exposure to a SARS-CoV-2-contaminated environment cannot be discounted if cats are exposed shortly after contamination."

Aside from concerns over the health and safety of our companion animals, the ability of the SARS-CoV-2 virus to infect and spread within non-human hosts is a serious concern.  It not only provides the virus  additional reservoir hosts, it may also provide the virus with new and unpredictable evolutionary paths to follow. 

Famously, in November of 2020 SARS-CoV-2 jumped from humans to mink in Denmark, spread like wildfire, mutating into new mink-variants (see Denmark Orders Culling Of All Mink Following Discovery Of Mutated Coronavirus), several of which spilled back into the community.

This emergency was short-lived as the Alpha variant emerged in Europe in late 2020 and quickly supplanted these mink variants.

We saw a more recent example of this kind of parallel evolution a couple of months ago in Eurosurveillance: Cryptic SARS-CoV-2 Lineage Identified on Two Mink Farms In Poland, when we looked at the detection of two closely related COVID variants that turned up - 3 months apart - at two mink farms in Poland.

Cats and dogs - because they often live in close proximity to humans - are not only at high risk of exposure (see EID Journal: SARS-CoV-2 Seroprevalence Studies in Pets, Spain) they may also serve as a conduit for the virus to infect other peridomestic animals.  

Already we've seen dozens of examples of SARS-CoV-2 spilling over into wildlife, including:

Viruses: Detection of SARS-CoV-2 in Terrestrial Animals in Southern Nigeria

Wildlife Exposure to SARS-CoV-2 Across a Human Use Gradient

SARS-CoV-2 Exposure in Norway Rats in New York City 

PNAS: White-Tailed Deer as a Wildlife Reservoir for Nearly Extinct SARS-CoV-2 Variants

All of which brings us to a lengthy, and highly detailed, review - published this week in the journal Pathogens - on the spillover of SARS-CoV-2 to companion animals, and the challenges this may present.  

Due to its length I've only posted the link and a few short excerpts, so follow the link to read it in its entirety.  I'll have a postscript after the break.

A SARS-CoV-2: Companion Animal Transmission and Variants Classification

by Rachana Pandit 1 andQiana L. Matthews 1,2,*

Pathogens 2023, 12(6), 775; https://doi.org/10.3390/pathogens12060775

Abstract

The continuous emergence of novel viruses and their diseases are a threat to global public health as there have been three outbreaks of coronaviruses that are highly pathogenic to humans in the span of the last two decades, severe acute respiratory syndrome (SARS)-CoV in 2002, Middle East respiratory syndrome (MERS)-CoV in 2012, and novel SARS-CoV-2 which emerged in 2019. The unprecedented spread of SARS-CoV-2 worldwide has given rise to multiple SARS-CoV-2 variants that have either altered transmissibility, infectivity, or immune escaping ability, causing diseases in a broad range of animals including human and non-human hosts such as companion, farm, zoo, or wild animals.

In this review, we have discussed the recent SARS-CoV-2 outbreak, potential animal reservoirs, and natural infections in companion and farm animals, with a particular focus on SARS-CoV-2 variants. The expeditious development of COVID-19 vaccines and the advancements in antiviral therapeutics have contained the COVID-19 pandemic to some extent; however, extensive research and surveillance concerning viral epidemiology, animal transmission, variants, or seroprevalence in diverse hosts are essential for the future eradication of COVID-19.

(SNIP)

4. Potential Animal Reservoirs of SARS-CoV-2

As the world is amid a COVID-19 pandemic, the exact source of the SARS-CoV-2 origin and its intermediate host for crossing the species barrier to infect humans is still unknown. SARS-CoV-2 is most likely zoonotic in origin, and infections have been documented in human and non-human hosts such as companion, farm, zoo, or wild animals, indicative of its expanded host range compared to SARS-CoV and MERS-CoV.

As of the 31 of December 2022, 36 countries have reported a total of 699 outbreaks in 26 different animals species, such as cats, dogs, minks, pet ferrets, otters, tigers, white-tailed deer, lynx, hamsters, monkeys, snow leopards, gorillas, and others, indicative of gradual host range expansion [31]. Correspondingly, it is imperative to review the potential animal reservoirs and naturally susceptible infections to companion animals and farm animals that are in prolonged contact with humans as probable reservoirs or hosts that can further lead to the emergence of new variants with spillback capacity to humans (Figure 3).

 

(SNIP)

7. Conclusions

The emergence of SARS-CoV-2 variants and their rapid spread has posed a great need for research into viruses, their diseases, and infections in animals and humans. SARS-CoV-2 is the third highly pathogenic human CoV to emerge in the 21st century, which has crossed species barriers to infect humans and animals such as companion, farm, zoo, or wild animals.

Correspondingly, new variants of SARS-CoV-2 are continuously evolving, and monitoring each variant is essential to control the rapid spread, even more so when SARS-CoV-2 infection can affect multiple human and animal hosts. The advent of effective therapeutics and vaccines provides hope for controlling the ongoing COVID-19 pandemic; however, the susceptibility of the virus to a broad range of hosts and the continuous evolution of SARS-CoV-2 variants is very daunting.

Hence, to fully eradicate COVID-19 in the future, an extensive understanding and surveillance of SARS-CoV-2 epidemiology, reservoir species, animal host susceptibility, variants, and vaccine efficacy is needed, along with effective vaccination and booster immunization to humans and animals.

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While there are hopeful signs that our current COVID crisis may be waning, we inhabit a far different world today than we did 4 years ago.  In 2019, the SARS-CoV-2 virus was so rare in the wild it was unknown to science, and to this day we aren't 100% sure from what species it sprang. 

Today, variants of SARS-CoV-2 now circulate - alongside MERS-CoV, and other coronaviruses - in dozens of species (see Nature: Comparative Susceptibility of SARS-CoV-2, SARS-CoV, and MERS-CoV Across Mammals).

Not only is there the very real potential for a spillback of a mutated COVID virus from another species into humans, some scientists worry that a recombinant SARS/MERS virus might someday emerge (see Nature: CoV Recombination Potential & The Need For the Development of Pan-CoV Vaccines). 

For the past 500 years (probably longer) influenza viruses have been our primary pandemic concern.

Credit Pandemic Influenza's 500th Anniversary

 

Today a growing array of coronaviruses provide influenza A with some serious competition.  All of which means that pandemics are likely to become more frequent going forward, and we need to be actively preparing for whatever comes next.

Eurosurveillance: Severe and fatal neonatal infections linked to a new variant of echovirus 11, France, July 2022 to April 2023

#17,479

Earlier today, in WHO: DON On Enterovirus (Echovirus-11 (E-11)) Uptick In France, we looked at report from the World Health Organization on an apparent new lineage of Echovirus-11 affecting neonates in France. 

In the past hour, the ECDC journal Eurosurveillance has published a detailed Rapid Communications on this emerging viral threat.  I've only reproduced the abstract, discussion, and conclusion below. 

Follow the link to read the full report. 

Severe and fatal neonatal infections linked to a new variant of echovirus 11, France, July 2022 to April 2023

Mathilde Grapin1,* , Audrey Mirand2,3,* , Didier Pinquier4 , Aurélie Basset5 , Matthieu Bendavid1 , Maxime Bisseux2,3 , Marion Jeannoël6 , Bérengère Kireche7 , Manoelle Kossorotoff8 , Anne-Sophie L’Honneur9 , Lila Robin7 , Yves Ville10 , Sylvain Renolleau1 , Véronique Lemee11 , Pierre-Henri Jarreau5 , Isabelle Desguerre8 , Florence Lacaille12 , Marianne Leruez-Ville13 , Clémence Guillaume14 , Cécile Henquell2,3 , Alexandre Lapillonne15 , Isabelle Schuffenecker6,** , Mélodie Aubart8,16,** 

Enteroviruses (EV) are a common cause of neonatal infections with clinical manifestations ranging from asymptomatic to severe and sometimes fatal disease [1–3]. Between July 2022 and April 2023, nine cases of severe neonatal infection with a liver failure were reported in France. Seven of these children died. All were associated with a new variant of echovirus 11 (E-11). We describe the clinical and virological characteristics of this upsurge of highly severe neonatal EV infections.

Discussion

We report a cluster of severe neonatal cases with liver failure and a high mortality rate associated with a new variant of E-11, leading to an alert in the European Union Early Warning and Response System on 4 May 2023, and inclusion in the ECDC Communicable Disease Threat Report [9]. Enterovirus infections in neonates may be associated with severe clinical illness and mortality depending on (i) the infecting EV type, of which the group B coxsackieviruses and E-11 are the most commonly EVs associated with neonatal sepsis [10] and (ii) the clinical infection phenotype, where the mortality rate is the highest for severe hepatitis or myocarditis manifestations [11].

Fulminant hepatitis associated with E-11 has already been described, but the high fatality rate within a nine-month period and the high proportion of twin cases were striking in this cluster. All patients presented with one or more well-known risk factors for severe neonatal EV infection, which are maternal evidence of a recent EV infection (four of the five mothers in this report), prematurity and onset of illness within the first few days of life [1,11].

The emergence of a new E-11 variant of recombinant origin in 2022, after a period of a low-level circulation of this type since 2008 may have led to a higher proportion of women susceptible to E-11 infection and subsequently to the higher proportion of E-11 associated neonatal infections observed in 2022–2023. Recombination, which frequently occurs in enteroviruses, is considered a factor driving viral emergence. Whether the genetic changes of the predominant circulating E-11 lineage have influenced the pathogenicity needs further investigation. Host genetic factors affecting immunity might also have influenced the clinical severity observed in the nine cases (by comparison with other patients infected with the same E-11 variant during their first week of life) as previously described in EV rhombencephalitis cases [12]. High prevalence of boys in severe neonatal EV infection might speak for a predisposition associated with X-chromosome.

Therapeutic options for neonatal EV infections are limited and include intravenous immunoglobulins or investigational/compassionated specific antiviral therapy consisting of pleconaril or pocapavir [13–15]. We used pocapavir for three patients, of whom two survived, but the efficacy of the treatment cannot be concluded from our data.

Conclusion

This report suggests that a new variant of E-11 is currently circulating and associated with a high risk of severe neonatal infection and death at least in France. Clinicians should be aware of potential involvement of EV in severe clinical presentations in neonates, as they are at the frontline to detect such cases. Enterovirus surveillance in France, as in most European country, is a voluntary system reporting EV-positive cases which could lead to an underestimation of the number of severe cases if EV genome detection is not considered. As a reminder, symptomatic neonatal EV disease initially presents as a neonatal sepsis, which is clinically indistinguishable from bacterial or herpes simplex virus infections.

Neonates with an unexplained sepsis who present with signs of myocarditis or liver failure with cytolysis should be rapidly evaluated for EV infection, especially if the mother has had acute symptoms of gastroenteritis in the days before birth. Blood, as well as respiratory, cerebrospinal fluid and stool samples should be collected for initial testing and further sequencing. Therapeutic options as IVIg or pocapavir should be considered.

          (Continue . . . )

 

WHO: DON On Enterovirus (Echovirus-11 (E-11)) Uptick In France

 Credit CDC NESS

#17,478

While `big-ticket' viruses like Influenza A and (now) a handful of Coronaviruses (SARS, SARS-CoV-2, MERS-CoV) get the bulk of our attention, the world is filled with literally hundreds of `lesser' seasonal virus threats that can have significant public health impacts. 

Over the past year we've looked at a number of outbreaks of RSV (see here, here, here), Adenoviruses (see here, and here), Parechoviruses (see here), and enteroviruses (see here).

These viruses are of particular concern because they tend to impact young children the hardest, and while they don't tend to mutate as rapidly as influenza or COVID, they can and do evolve over time.  

Prior to 2014, EV-D68 was considered both rare and mild, but over the past decade it has evolved into a more pathogenic (and neurotropic) virus (see mBio: Contemporary EV-D68 Strains Have Acquired The Ability To Infect Human Neuronal Cells).

Although they are generally not reportable diseases, the CDC's The National Respiratory and Enteric Virus Surveillance System (NREVSS) and the National Enterovirus Surveillance System (NESS) monitor reports that are voluntarily submitted by laboratories across the nation, as do other countries. 

Yesterday the WHO published a DON (Disease Outbreak News) report on an increase in an Enterovirus (Echovirus-11) in France over the past year, resulting in at least 9 severe infections in neonatal patients including 7 deaths. 

Of note, France is reporting two new recombinant lineages of E-11, and all of the identified samples since the first of the year belong to the lineage linked to these severe cases.  That said, only about 4% of known infections have proved severe. 

First some excerpts from yesterday's report, then I'll return with a postscript. 

Enterovirus Infection - France
31 May 2023

Situation at a glance

On 5 May 2023, France reported an increase in cases of severe neonatal sepsis associated with Enterovirus (Echovirus-11 (E-11)). A total of nine cases of neonatal sepsis with hepatic impairment and multi-organ failure were reported between July 2022 and April 2023 from four hospitals in three regions of France. As of 5 May 2023, seven cases have died and two were still hospitalized in neonatal unit.

The current increase in incidence and severity in neonates, associated with a recombinant lineage of E-11 that previously was not detected in France, and is considered unusual due to the extremely rapid deterioration and associated case fatality rate amongst the affected babies.

Based on the limited information available, WHO assesses the public health risk for the general population to be low, despite the concerning nature of the increase.

(SNIP)

Epidemiology of disease

Enteroviruses are a group of viruses that can cause various infectious illnesses and are responsible for annual epidemics. Illness is usually mild but has been found to affect neonates differently and sometimes more severely than older children and adults. There are multiple transmission routes, particularly in the neonatal period, including intrapartum by exposure to maternal blood, secretions, and/or stool, or postnatally from close contacts with infected caregivers. Echovirus 11 (E-11) is a positive-strand RNA virus belonging to the genus Enterovirus of the family Picornaviridae.

The infections can cause severe inflammatory illnesses in neonates, including severe acute hepatitis with coagulopathy.

WHO risk assessment

A review of the epidemiological data collected from 2016 to 2022 in France through routine surveillance of enterovirus infections among hospitalized patients showed a significant increase in incidence and mortality for all severe neonatal infections associated with E-11, defined as infections with at least one organ failure and/or requiring admission to intensive care.

A total of 443 enterovirus neonatal infections (severe and non-severe types) including seven deaths (case fatality rate, (CFR) 1.6%) were reported in France in 2022. Of these, 72% (n=317) had a known enterovirus type. E-11 was the predominant circulating enterovirus type (all ages included) and was identified in 30.3% (96 of 317) of neonatal infections (severe and non-severe) with known enterovirus type. It has been continuously detected since June 2022.

Of the reported neonatal infections in 2022, 4.5% (22 of 443) were classified as severe. Of these 20 had known enterovirus types. E-11 represented 55% (11 of 20) of these cases as compared to 6.2% (3 of 48) of cases with known enterovirus type out of the total reported severe neonatal infections (n=62) between 2016 to 2021.

In 2022, there were seven deaths (case fatality rate, (CFR) 1.6%) out of the cumulative 443 enterovirus neonatal infections recorded in 2022 (six associated with E-11), compared to seven deaths (CFR 0.4%), out of 1774 neonatal infections from 2016 to 2021(none associated with E-11). As mentioned above, there have also been seven deaths so far in 2023.

Sequence analyses showed the circulation of at least two lineages of recombinant origin, of which the predominant one included all the sequences associated with the nine severe cases together with sequences associated with non-neonatal or non-severe neonatal infections. This new variant of E-11 had not been observed in France before July 2022, nor elsewhere based on available sequences on Genbank, as of 28 April 2023. As of 5 May 2023, E-11 sequences retrieved from samples collected in 2023 all belong to this predominant lineage.

Although higher pathogenicity of this new lineage cannot be excluded, the severity of infections may also be explained by the young age, prematurity, and the absence of maternal immunity. Further analyses are warranted to delineate the characteristics of this recombinant virus.

Based on the limited information available, WHO assesses the public health risk for the general population to be low. However, asymptomatic carriage and shedding of infectious viruses are a feature of enterovirus infection. Echovirus infection was confirmed in four out of five mothers by analyzing blood samples three days before or at delivery. There have been previous reports of severe E-11 infection in twin neonates, however, the observation of four sets of twins amongst nine cases is more than expected. As non-polio enterovirus infection is often not a notifiable disease in Member States, additional cases of severe neonatal enterovirus infection may have gone undiagnosed and/or unreported.

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While it doesn't tend to grab headlines, E-11 is of considerable interest to researchers. Over the past year a number of studies have been published on the evolution and severity of Echovirus-11, including:

Detection of recombinant breakpoint in the genome of human enterovirus E11 strain associated with a fatal nosocomial outbreak

Martina Rueca, Simone Lanini, Emanuela Giombini, Francesco Messina, Concetta Castilletti, Giuseppe Ippolito, Maria Rosaria Capobianchi & Maria Beatrice Valli

Echovirus 11 infection induces pyroptotic cell death by facilitating NLRP3 inflammasome activation

Chong Wang ,Ruyi Yang ,Fengxia Yang,Yang Han,Yujie Ren,Xiaobei Xiong,Xingyun Wang,Yidan Bi,Lijun Li,Yang Qiu ,Yi Xu ,Xi Zhou 

Risk factors and early markers for echovirus type 11 associated haemorrhage-hepatitis syndrome in neonates, a retrospective cohort study

Ping Wang, 1 , † Yi Xu, 2 , † Ming Liu, 3 , † Huixian Li, 4 Hui Wang, 5 Yumei Liu, 6 Bin Wang, 7 Shiwen Xia, 5 Heng Su, 1 Mou Wei, 1 Li Tao, 1 Xiaowen Chen, 1 Bingtai Lu, 8 Xiaoqiong Gu, 9 Hui Lyu, 3 Wei Zhou, 1 ,* Huayan Zhang, 1 , 10 ,* and Sitang Gong 11 ,*

Last year, after the UK reported an unusual increase in acute pediatric hepatitis with unknown etiology it led to dozens of other countries looking at their epidemiological data, and finding similar patterns of infection (see CDC HAN Advisory On Adenovirus Testing and Reporting Of Children With Acute Hepatitis).

Hopefully, if today's report is more than a transient, localized, outbreak we'll hear from other countries in the days and weeks ahead.

WHO DON & Risk Assessment On Two Asymptomatic H5N1 Cases In the UK

 

#17,477

Two weeks ago the UK reported the detection of a pair of H5N1 positive nasal/throat swabs collected from two asymptomatic poultry workers, although it wasn't immediately clear whether these were genuine infections, or merely the detection of contaminated `dust' in these worker's respiratory tract.

Viable avian viruses can be spread via dried feces, feathers, and other airborne contaminants that are generated by wet markets and poultry farms (see Zoonoses & Public Health: Aerosol Exposure of Live Bird Market Workers to Viable Influenza A/H5N1 and A/H9N2 Viruses, Cambodia). 

Which means that it would not be unexpected to see H5N1 positive nasal and throat swabs from poultry workers, even if they aren't truly infected. Last year Spain detected viral fragments in the throat swabs of two asymptomatic poultry workers, and a similar case was reported by the United States, but actual evidence of infection was lacking. 

For now, the jury is still out on whether these latest cases from the UK were actually infected. Serology testing over the next few weeks may provide additional clues.  

Yesterday the WHO published their a new DON (Disease Outbreak News) and Risk Assessment on this event, where they deem the risk of spread as low.   I've only posted some excerpts, so follow the link to read it in its entirety. 

Avian Influenza A(H5N1) - United Kingdom of Great Britain and Northern Ireland
30 May 2023

Situation at a glance

In mid-May, the United Kingdom of Great Britain and Northern Ireland reported to the World Health Organization (WHO) the detection of avian influenza A(H5) virus in a poultry worker at a farm in England where poultry was infected with high pathogenicity avian influenza (HPAI) A(H5N1) viruses. Another detection was reported in a second individual performing culling operations on the farm. Both detections were later confirmed by additional testing as A(H5N1). Both cases were asymptomatic and detected as part of an ongoing enhanced surveillance study of asymptomatic workers exposed to poultry infected with avian influenza.

All the workers at this farm and their contacts have been identified; none of the contacts have reported symptoms, and no other influenza cases have been identified. The United Kingdom Health Security Agency (UKHSA) has not detected evidence of human-to-human transmission.

Based on the available information, WHO considers these as sporadic detections of avian influenza viruses among humans with no evidence of person-to-person transmission to date. Thus, the likelihood of international disease spread through humans is considered to be low.

Given the widespread circulation in birds and the constantly evolving nature of influenza viruses, WHO stresses the importance of global surveillance to detect virological, epidemiological and clinical changes associated with circulating influenza viruses which may affect human (or animal) health.

Description of the situation

In late April, the UKHSA was notified by the Animal and Plant Health Protection Agency (APHA) of an outbreak of HPAI (H5N1) on a poultry farm in England, United Kingdom. The human cases were detected through an ongoing enhanced surveillance study of asymptomatic workers exposed to poultry infected with avian influenza.

The UKHSA Rapid Investigation Team were deployed to the farm in early May 2023 to recruit exposed participants for the study. Of the 24 eligible persons, one tested positive for influenza A (with no detection of human seasonal subtypes H1 or H3) on the first sample self-taken at the premises. Two further nasopharyngeal samples collected from the same person tested negative for influenza A by a UKHSA regional laboratory and by the UKHSA national influenza reference laboratory. The participant remained clinically asymptomatic throughout.

An update from the United Kingdom authorities to WHO in mid-May 2023, notified of an additional case from the same farm as influenza A(H5) positive on two separate samples. This second person was a poultry culler exposed to infected birds at the same farm. The poultry culler worked on the farm in early May using personal protective equipment (PPE). The case was clinically assessed and remains asymptomatic. The case was treated with oseltamivir and was negative on respiratory sampling taken on the last day of isolation.

Sequencing later confirmed the virus detected in both individuals as A(H5N1). All samples from these two individuals were negative for seasonal influenza viruses. All other study participants remain well and have tested negative for influenza A on their samples to date. Follow-up of contacts has been completed. The affected farm is one of the first recruited in the ongoing enhanced surveillance study of asymptomatic workers exposed to poultry infected with avian influenza.

Work to determine whether these are infections or not (i.e., could instead be due to transient mucosal contamination of the nose with virus particles) is underway, though it may be difficult to reach a conclusion.

(SNIP)

WHO risk assessment

The two reported individuals with influenza A(H5N1) detection in their samples have remained asymptomatic and tested negative for influenza in their most recent samples to date. Their close contacts were asymptomatic and the follow-up period has been completed. 

Both cases were detected as part of an ongoing enhanced surveillance study of asymptomatic workers exposed to poultry infected with avian influenza. In these cases, detections may have resulted from either transient respiratory tract contamination (with no virus replication) or asymptomatic infection. Further testing (e.g., serology) is needed to confirm infection.

Whenever avian influenza viruses are circulating in birds, humans who are exposed to these birds or their environments are at risk of infection.

Sporadic human cases and transient contaminations of humans are rare, but not unexpected in such contexts. Thus far, there is no evidence of person-to-person transmission in this incident.

Although both reported cases were asymptomatic in this instance, previous A(H5N1) infections have resulted in severe infections in humans.

Based on the available information, WHO assesses that the risk for the general population posed by this virus is low, and for occupationally exposed persons it is low to moderate.

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