National Academy Of Sciences: Biodefense in the Age of Synthetic Biology

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Just over a month ago Johns Hopkins held a day-long pandemic table-top exercise (see CLADE X: Archived Video & Recap), with former and current government officials playing the roles of the President's National Security advisory team, as a pandemic scenario unfolded.

The virus used for this exercise was a bio-engineered parainfluenza-Nipah virus hybrid, unleashed on the world by a fictitious radical terrorist group.

A scenario not so very different from 2015's Blue Ribbon Study Panel Report on Biodefense, where a bi-partisan panel described a fictional biological attack on Washington D.C. using a genetically engineered Nipah virus as part of their presentation.

Although nature may be the most prolific bio-terrorist, the past decade has seen a huge proliferation of the type of knowledge and a dramatic drop in the cost and complexity of the kind of lab equipment that one would need to create, or enhance, a pandemic virus.  

What a few short years ago would have required the resources of a technologically advanced nation state, can be accomplished today on a far more modest budget. 

And as the costs go down for these sorts of technologies in the years ahead, the odds that some group with a radical agenda will use them to create a `better' bug will only increase.Yesterday's implausible science fiction plots have an unnerving way of becoming tomorrow's fait accompli.

With that in mind, scientists have been working for years on ways to counter the triple threats of a biological attack, an accidental release, or naturally occurring pandemic with a highly pathogenic biological agent.

Yesterday the National Academies of Sciences published a 234 page PDF on the rapidly advancing state of the science of synthetic biology and our growing vulnerability to synthetic or enhanced bio-agents.

Despite its impressive pedigree and voluminous content, anyone expecting to find easy solutions to these complex and continually changing threats will come away disappointed.

As the authors write:

`. . . because it was outside of the study’s scope to consider all of the mitigation options available to the defense enterprise, the report does not make comprehensive, explicit recommendations regarding mitigation approaches.'

The full report may be downloaded (for free) as a PDF file from www.nap.edu. While I've not had time to do more than glance at this lengthy study, a press release (below) describes the report.

June 19, 2018

FOR IMMEDIATE RELEASE

If Misused, Synthetic Biology Could Expand the Possibility of Creating New Weapons; DOD Should Continue to Monitor Advances in the Field, New Report Says

WASHINGTON – Synthetic biology expands the possibilities for creating new weapons — including making existing bacteria and viruses more harmful — while decreasing the time required to engineer such organisms, concludes a new report by the National Academies of Sciences, Engineering, and Medicine.  Although some malicious applications of synthetic biology may not seem plausible right now, they could become achievable with future advances.

Synthetic biology, a field that creates technologies for engineering or creating organisms, is being used for a variety of purposes that benefit society. Applications include treating diseases, improving agricultural yields, and remediating pollution.  Even though synthetic biology holds great promise in many areas, it is possible to imagine harmful uses that could threaten U.S. citizens and military personnel.  To better prepare for potential misuse, the National Academies were asked by the U.S. Department of Defense (DOD) to develop a framework for evaluating security concerns related to advances in synthetic biology. The task included assessing the levels of concern warranted for such advances, and recommending potential options to anticipate and respond to such threats.

“In and of itself, synthetic biology is not harmful.  The level of concern depends on the specific applications or capabilities that it may enable,” said Michael Imperiale, Arthur F. Thurnau Professor of Microbiology and Immunology at the University of Michigan and chair of the committee that conducted the study and wrote the report.  “The U.S. government should pay close attention to this rapidly progressing field, just as it did to advances in chemistry and physics during the Cold War era.”

In its interim report, the committee proposed a strategic framework to identify and prioritize potential areas of concern associated with the field and to help biodefense analysts as they consider the current and future synthetic biology capabilities.  The framework is designed for analyzing existing biotechnology tools in order to evaluate the dangers at present, understand how various technologies compare with and complement each other, and assess the implications of new experimental outcomes.

In the final report, the committee used this framework to analyze potential vulnerabilities enabled by synthetic biology.  The results were based on the availability and ease of use of the technologies, the challenges of producing an effective weapon, the expertise and resources required to carry out an attack, and both proactive and reactive measures that might be taken to help mitigate the effects of an attack.  The committee ranked the synthetic biology capabilities from highest relative level of concern to lowest in the figure below.

The report emphasizes that many of the traditional approaches of biological and chemical defense will be relevant to synthetic biology-enabled threats, but the field will also present new challenges.  DOD and its partners should continue to explore strategies that can be applied to a wide range of threats and also to account for broader capabilities enabled by the field now and in the future.  Since synthetic biology-enabled weapons might be unpredictable and hard to monitor or detect, DOD should consider evaluating how the public health infrastructure needs to be strengthened to adequately recognize a potential attack.

“It’s impossible to predict when specific enabling developments will occur; the timelines would depend on commercial developments as well as academic research, and even converging technologies that may come from outside this field,” added Imperiale.  “So it is important to continue monitoring advances in synthetic biology and other technologies that may affect current bottlenecks and barriers, opening up more possibilities.”

The study was sponsored by DOD.  The National Academies of Sciences, Engineering, and Medicine are private, nonprofit institutions that provide independent, objective analysis and advice to the nation to solve complex problems and inform public policy decisions related to science, technology, and medicine.  The National Academies operate under an 1863 congressional charter to the National Academy of Sciences, signed by President Lincoln.  For more information, visit http://national-academies.org.

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Video: Senate Subcommittee Hearing On The State of U.S. Public Health Biopreparedness

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The full name of the Energy and Commerce Subcommittee hearing, held on June 15th is:

The State of U.S. Public Health Biopreparedness: Responding to Biological Attacks, Pandemics, and Emerging Infectious Disease Outbreaks

And it features a stellar panel of experts whose names are no doubt familiar to most of my readers:

Dr. Rick A. Bright
Director, Biomedical Advanced Research and Development Authority; Deputy Assistant Secretary, Office of the Assistant Secretary for Preparedness and Response

• Witness Statement
• Witness Invitation
• Truth in Testimony and CV

Dr. Anthony Fauci
Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health

• Witness Statement
• Witness Invitation
• Truth in Testimony and CV

Rear Admiral Denise Hinton
Chief Scientist, U.S. Food and Drug Administration

• Witness Statement
• Witness Invitation
• Truth in Testimony and CV

Dr. Anne Schuchat
Principal Deputy Director, Centers for Disease Control and Prevention

• Witness Statement
• Witness Invitation
• Truth in Testimony and CV

The video is clocked at 2hrs and 12 mins, but the hearing doesn't get started until about 15 minutes in, and the opening 20 minutes are consumed by opening statements by subcommittee members, so the actual testimony doesn't begin until nearly nearly the 40 minute mark.

Much of this hearing was devoted to the handover of control of the Strategic National Stockpile (for background see Webinar: The Strategic National Stockpile) from the CDC to the HHS's Assistant Secretary for Preparedness and Response (ASPR), and progress reports on vaccine development and point of care diagnostics.

But just over an hour into the video, each of the panel members was asked what biological threat keeps them up at night.  Not surprisingly influenza - or an influenza-like pandemic virus (i.e. SARS, MERS, etc.) - was at or near the top of many of their lists. 

While more than cordial, there were some tough questions asked of the panel, and it is always good to see how the real experts are assessing the current threat environment.

The full video (and accompanying documents) may be viewed at this link.

Russia Reporting Avian Flu Outbreaks In Samara, Penza & Kursk Regions

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While it isn't all that unusual to see avian flu activity in Russia during the spring and summer, the past five months have been unusually quiet, with nothing reported out of Russia since a large HPAI H5N2 outbreak was announced last December.

That is, until last week. 

In Rosselkhoznadzor & OIE: HPAI H5 Reported In Kursk Oblast, we learned of at least two outbreaks of an HPAI H5 virus (full subtype not yet identified) in Kursk Oblast.

The first in a small backyard flock in the village of N. Grayvoronka, and the second involved carcasses of poultry (chickens), found in the forest belt Ryshkovskogo.

While the Kursk Oblast office of Rosselkhoznadzor hasn't posted an update since June 14th, Russian media continues to report continued avian flu activity in the region, including this report from TASS.

In the Kursk region registered the third hearth of bird flu In the country

June 19, 18:12 UTC + 3

The governor of the region Alexander Mikhailov signed a decree on the introduction of quarantine in the district where the identified disease foci

Kursk, 19 June. / TASS /. Experts have registered the third focus of avian influenza in the territory of Kursk region. This was reported by TASS on Tuesday in the regional veterinary administration.

"At the moment we have [the flu outbreak of bird] in the Soviet area - two personal subsidiary farms in the same locality, in the Kursk region - a waste of bird carcasses, and the third case - the village Vasilevka This is also the Soviet area, but another location." , - said the source.

Experts have identified the first influenza virus hotbed of avian type A subtype H5 in the Kursk region last week in pathological material taken from dead chickens and ducks in a private farm in the village of Lower Grayvoronke Soviet area, the second - on the territory of the village council shelterbelts Ryshkovskogo Kursk region.

(Continue . . . )

Announced in just the last couple of hours - from the Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor) of the Chelyabinsk region - are reports of fresh outbreaks of avian flu in both Samara and Penza, both of which lie several hundred miles to the west of Chelyabinsk.

Cases of bird flu in the Samara and Penza regions

Office of Rosselkhoznadzor for the Chelyabinsk region informs that on 16 and 17 June in the pathological material taken from the fallen poultry contained in private farms in Bolsheglushitsky district of the Samara region and Kolyshleysky District Penza region highlighted the genetic material of the virus avian influenza.

In Bolsheglushitsky district of the Samara region and Kolyshleysky District Penza Oblast cases poultry deaths recorded contained in private farms. Also Kolyshleysky District Penza Oblast cases deaths recorded turkey, contained in the Company 'PenzaMolInvest "at the site of rearing and fattening. Laboratory confirmed that the isolated genetic material of the virus avian influenza.

In areas all measures are taken to prevent the spread of avian influenza.

Recall that the avian influenza - a highly contagious, acute viral proceeding affecting agricultural, commensal and wild birds disease affecting the respiratory and gastrointestinal tracts. Avian influenza is able to take the form of epizootic diseases, causing massive population coverage and having widespread. In unfavorable aviary suspicious diseased and disease in poultry discarded kill bloodless manner and utilized. Apparently healthy livestock are killed for meat. In the case of visiting poultry farms (farms) bird flu, caused by the highly pathogenic virus, introduced stringent sanitary operation of the economy.

In the Chelyabinsk region avian influenza was detected in 2005. Then killed 480 birds, 500 more were killed in the village of Oktyabrsky Oktyabrsky district.

Curiously, as of this writing,  I can find no mention of these outbreaks on either the main Rosselkhoznadzor website, or on the Samara or Penza local web portals.

Since avian flu activity during the summer in Russia has previously been linked to seeing increased outbreaks in Europe later in the year (see FAO/EMPRES: H5N8 Clade 2.3.4.4 Detected Over Summer In Russia), we pay attention to these types of events.

After several months of quiescence, over the past week we've seen a bit of a surge in avian flu reports in the Northern Hemisphere; specifically in Bulgaria, Northern Ireland, and now multiple locations in Russia

A subtle reminder that with the constant migration and mixing of potentially infected birds around the globe, that avian flu viruses have the ability to pop up when and where you least expect them. 

And that biosecurity against poultry diseases is now - out of necessity - a year-round endeavor.

In the country

June 19, 18:12 UTC + 3

The governor of the region Alexander Mikhailov signed a decree on the introduction of quarantine in the district where the identified disease foci

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Kursk, 19 June. / TASS /. Experts have registered the third focus of avian influenza in the territory of Kursk region. This was reported by TASS on Tuesday in the regional veterinary administration.
"At the moment we have [the flu outbreak of bird] in the Soviet area - two personal subsidiary farms in the same locality, in the Kursk region - a waste of bird carcasses, and the third case - the village Vasilevka This is also the Soviet area, but another location." , - said the source.
Experts have identified the first influenza virus hotbed of avian type A subtype H5 in the Kursk region last week in pathological material taken from dead chickens and ducks in a private farm in the village of Lower Grayvoronke Soviet area, the second - on the territory of the village council shelterbelts Ryshkovskogo Kursk region. In connection with the incident, the governor of the region Alexander Mikhailov signed a decree on the introduction of quarantine areas in the territory, providing increased control of all poultry farms, operating in closed mode, as well as the number of poultry, which is contained in private farms.

Подробнее на ТАСС:
http://tass.ru/v-strane/5304803

n the Kursk region registered the third hearth of bird flu

In the country

June 19, 18:12 UTC + 3

The governor of the region Alexander Mikhailov signed a decree on the introduction of quarantine in the district where the identified disease foci

Share

0

Kursk, 19 June. / TASS /. Experts have registered the third focus of avian influenza in the territory of Kursk region. This was reported by TASS on Tuesday in the regional veterinary administration.
"At the moment we have [the flu outbreak of bird] in the Soviet area - two personal subsidiary farms in the same locality, in the Kursk region - a waste of bird carcasses, and the third case - the village Vasilevka This is also the Soviet area, but another location." , - said the source.
Experts have identified the first influenza virus hotbed of avian type A subtype H5 in the Kursk region last week in pathological material taken from dead chickens and ducks in a private farm in the village of Lower Grayvoronke Soviet area, the second - on the territory of the village council shelterbelts Ryshkovskogo Kursk region. In connection with the incident, the governor of the region Alexander Mikhailov signed a decree on the introduction of quarantine areas in the territory, providing increased control of all poultry farms, operating in closed mode, as well as the number of poultry, which is contained in private farms.

Подробнее на ТАСС:
http://tass.ru/v-strane/5304803

DAERA: 2nd Wild Bird Confirmed With HPAI H5N6 At Lurgan Park in Northern Ireland

2018 H5N6 Reports - Northern Ireland

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Last Friday, in DAERA: H5N6 Confirmed In Wild Bird In Northern Ireland, we learned of the recovery of a dead greylag goose from Lurgan Park in County Armagh, N.I. that has tested positive for HPAI H5N6.

This location holds some significant because earlier this month, Lurgan Park was also the site of a large agricultural show (see Crowds flock to Lurgan park as farming show celebrates 106th year), which included many animal exhibits, including poultry. 

All of which makes yesterday's announcement by DAERA of a second infected greylag goose found in that park worth noting. According to a report in Farming Life, DAERA representatives met with local poultry industry representatives after the first case was announced last week.

The OIE Report on the first bird, reported last week, gives a date of the start of the outbreak as June 14th, but it isn't entirely clear when the bird was recovered, or likely died.

While we've seen no sign of sick or infected poultry linked to this agricultural show, the Chief Veterinary Officer for Northern Ireland is urging all bird keepers to be vigilant, and to review their biosecurity.

This is only the third wild bird with HPAI H5N6 detected in Northern Ireland this year (see chart at top of blog), but it is a reminder that the virus continues to circulate in the wild, even well into summer.

Chief Vet stresses importance of biosecurity and vigilance against avian flu

Date published: 19 June 2018

The Department of Agriculture, Environment and Rural Affairs (DAERA) today confirmed that a second wild greylag goose, found in Lurgan Park, County Armagh, has tested positive for H5N6 Avian Influenza. The second goose, like the first, was reported to DAERA as part of its dead wild bird surveillance programme, and was submitted for testing at the Agri-Food and Biosciences Institute (AFBI), where initial testing has indicated avian influenza, sub-type H5N6.

The Chief Veterinary Officer for Northern Ireland, Dr Robert Huey, said: “This latest case in a wild bird further emphasises the requirement for all bird keepers to remain vigilant and to critically review their biosecurity measures, for example, feeding and watering birds under cover to help reduce the risk of their poultry coming in contact with wild birds. It is important that flock keepers report early any suspicions of disease.

“While it is not unexpected to find another case of avian flu in a wild bird in close proximity to the confirmed case of last week, and the risk to poultry remains low, it is important that flock keepers remain vigilant and it is essential that we take the necessary steps to protect our poultry industry, international trade and the wider economy.

“I continue to encourage strongly all bird keepers to register their flocks. This will ensure they receive the latest information from the Department and also allow them to be contacted in an avian disease outbreak enabling them to protect their flock at the earliest opportunity. I would also encourage bird keepers to subscribe to the Avian Influenza text service by simply texting: ‘BIRDS’ to 67300”.

Bird keepers visiting waterfowl sites such as lakes and ponds should also take measures to prevent disease spread to back yard flocks through contamination of footwear with wild bird faeces.

Advice from the Public Health Agency is that the risk to public health from the virus is very low, however, the general public is advised to take appropriate biosecurity precautions before touching or picking up birds that are dead, or appear to be sick or dying. Further advice can be found on the DAERA website.

The Food Standards Agency has confirmed that Avian Influenza does not pose a food safety risk for UK consumers. Thoroughly cooked poultry and poultry products, including eggs, are safe to eat.

Members of the public are encouraged to report dead waterfowl (swans, geese or ducks) or gulls, or five or more dead wild birds of other species in the same location, to the DAERA helpline on 0300 200 7840, Mon-Fri 9.00am to 5.00pm.

Neuroinfluenza: A Review Of Recently Published Studies

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Although primarily a self-limiting infection of the respiratory tract, for a small subset of cases - most often among children - influenza can present with a variety of subtle, and sometimes profound, neurological symptoms.
 

Credit CDC 2018 COCA Call On Severe Influenza

The exact mechanisms behind these neurological manifestations are unknown, as seasonal flu viruses are generally regarded as being non-neurotropic. But some researchers have suggested that these neurological symptoms may be due to neuroinflammation induced by the host's immune response.

That said, we have seen evidence that some influenza viruses - particularly novel flu types - can be more neuroaffective than others.

In 2009, a PNAS study (link below) found that the H5N1 virus was highly neurotropic in lab mice, and in the words of the authors `could initiate CNS disorders of protein aggregation including Parkinson's and Alzheimer's diseases’.

Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration

In 2015, after the death of the first imported H5N1 case in Canada, we saw a study (see CJ ID & MM: Case Study Of A Neurotropic H5N1 Infection - Canada), where the authors wrote: `These reports suggest the H5N1 virus is becoming more neurologically virulent and adapting to mammals'.
 
In a 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.'

Far less certain are the long-term neurological impacts of severe (or repeated) influenza infections, although we've seen studies suggesting links to Parkinson's, Schizophrenia, and even Alzheimer's  (see Nature Comms: Revisiting The Influenza-Parkinson's Link). 

We last looked this topic in February, in JNeurosci: Another Study On The Neurocognitive Impact Of Influenza Infection, where we saw a study from the Technical University of Braunschweig, which found long-term neurocognitive impairment in mice following infection with specific types (H3N2 & H7N7) of influenza viruses - but not in others (H1N1).

Obviously, not-so-good news if you are a mouse, but how relevant these results are for humans remains an open question. 

Since February several new studies have been published on this topic, and so today a brief review, with links and excerpts.  I'll return with a bit more at the end. 

(Note: Although published in February,  the first study (below) was made available online in 2017).

Neuroinfluenza: evaluation of seasonal influenza associated severe neurological complications in children (a multicenter study)

Paksu, M.S., Aslan, K., Kendirli, T. et al. Childs Nerv Syst (2018) 34: 335. https://doi.org/10.1007/s00381-017-3554-3

Abstract

Purpose

Although influenza primarily affects the respiratory system, in some cases, it can cause severe neurological complications. Younger children are especially at risk. Pediatric literature is limited on the diagnosis, treatment, and prognosis of influenza-related neurological complications. The aim of the study was to evaluate children who suffered severe neurological manifestation as a result of seasonal influenza infection.

Methods

The medical records of 14 patients from six hospitals in different regions of the country were evaluated. All of the children had a severe neurological manifestations related to laboratory-confirmed influenza infection.

Results

Median age of the patients was 59 months (6 months—15.5 years) and nine (64.3%) were male. Only 4 (28.6%) of the 14 patients had a comorbid disease. Two patients were admitted to hospital with influenza-related late complications, and the remainder had acute complication.

The most frequent complaints at admission were fever, altered mental status, vomiting, and seizure, respectively. Cerebrospinal fluid (CSF) analysis was performed in 11 cases, and pleocytosis was found in only two cases. Neuroradiological imaging was performed in 13 patients. The most frequent affected regions of nervous system were as follows: cerebellum, brainstem, thalamus, basal ganglions, periventricular white matter, and spinal cords. Nine (64.3%) patients suffered epileptic seizures. Two patients had focal seizure, and the rest had generalized seizures. Two patients developed status epilepticus. Most frequent diagnoses of patients were encephalopathy (n = 4), encephalitis (n = 3), and meningitis (n = 3), respectively.

The rate of recovery without sequelae from was found to be 50%. At discharge, three (21.4%) patients had mild symptoms, another three (21.4%) had severe neurological sequelae. One (7.1%) patient died. The clinical findings were more severe and outcome was worse in patients < 5 years old than patients > 5 years old and in patients with comorbid disease than previously healthy group.

Conclusion

Seasonal influenza infection may cause severe neurological complications, especially in children. Healthy children are also at risk such as patients with comorbid conditions. All children who are admitted with neurological findings, especially during the influenza season, should be evaluated for influenza-related neurological complications even if their respiratory complaints are mild or nonexistent.

Our next study comes from the journal Brain Development.

Influenza-associated neurological complications during 2014–2017 in Taiwan

Li-Wen Chen, Chao-Ku Teng, Yi-Shan Tsai, Jieh-Neng Wang, Yi-Fang Tu, Ching-Fen Shen,  Ching-Chuan Liu
Introduction

Seasonal influenza-associated neurological complications had high mortality and morbidity rates in recent studies. We reported influenza-associated encephalitis/encephalopathy in children during 2014–2017 in Taiwan, focusing on neurological presentations, neuroimaging correlations, and critical care managements.

Materials/Subjects

During January 1st 2014 to June 30th 2017, pediatric patients reported to the Taiwan Centers for Disease Control surveillance system for severe complicated influenza infections in the hospital were retrospectively reviewed. Children with influenza-associated encephalitis/encephalopathy were inspected for clinical presentations, laboratory data, neuroimaging studies, treatment modalities, and neurological outcomes.

Results

Ten children with median age 5.9 years were enrolled for analysis. Influenza-associated encephalitis/encephalopathy appeared in the spring and summer, with a delayed peak comparing with the occurrence of pneumonia and septic shock.

The neurological symptoms developed rapidly within median 1 day after the first fever episode. All patients had consciousness disturbance. Seven patients (70%) had seizures at initial presentation, and six of them had status epilepticus. Anti-viral treatments were applied in all patients, with median door-to-drug time 0.9 h for oseltamivir and 6.0 h for peramivir. Multi-modality treatments also included steroid pulse therapy, immunoglobulin treatment, and target temperature management, with 85.2% of the major treatments administered within 12 h after admission.

Nine of the ten patients recovered without neurological sequelae. Only one patient had epilepsy requiring long-term anticonvulsants and concomitant cognitive decline.

Conclusions

In highly prevalent area, influenza-associated encephalitis/ encephalopathy should be considered irrespective of seasons. Our study suggested the effects of timely surveillance and multi-modality treatments in influenza-associated encephalitis/encephalopathy.

While influenza-related neurological complications are most often reported in children, adults are not necessarily immune, as reported in the following two studies. 

Acute necrotizing encephalopathy in an adult with influenza A infection

Nobuaki Ochi,1 Kento Takahashi,2 Hiromichi Yamane,1 and Nagio Takigawa1

Abstract

Acute necrotizing encephalopathy following influenza infection is a rapidly progressing disease with high morbidity. Although the neurological disorder is sometimes reported in children, it is very rare in adults.

We herein describe an adult with acute necrotizing encephalopathy captured on a series of brain magnetic resonance images. A 55-year-old man had fever and impaired consciousness. He was diagnosed with influenza A (H1N1). Brain magnetic resonance imaging revealed symmetrical lesions in the cerebellum and basal nucleus, showing typical acute necrotizing encephalopathy. Physicians should know that influenza-associated acute necrotizing encephalopathy can occur even in middle-aged adults.

(Continue . . . )

And finally, this study from the Indian Journal of Critical Care Medicine.

Adult Influenza A (H1N1) Related Encephalitis: A Case Report

Devinder Midha, Arun Kumar, Pratibha Vasudev, Zafar Ahmad Iqbal, and Amit Kumar Mandal

Abstract

The year 2009–2010 saw H1N1 influenza outbreaks occurring in almost all countries of the world, causing the WHO to declare it a pandemic of an alert level of 6. In India, H1N1 influenza outbreaks were again reported in late 2014 and early 2015. Since then, sporadic cases of H1N1 influenza have been reported.

H1N1 influenza usually presents itself with respiratory tract symptoms. In a minority of patients, abdominal symptoms may occur as well. Acute influenza-associated encephalopathy/encephalitis mostly occurs in the pediatric population, whereas in adults, it is a rare complication. The incidence of neurological complications appears to have increased after the 2009 H1N1 influenza A virus pandemic.

We would like to draw attention to an adult patient case who initially presented with respiratory symptoms but then deteriorated and developed encephalitis, which is rarely reported. As per literature reviewed by Victoria Bangualid and Judith Berger on PubMed, only 21 cases of neurological complications were found in adult influenza A patients, out of whom 8 had encephalopathy.

(Continue . . . )

Despite the mounting evidence, the neurological impacts of influenza are still largely unappreciated by the public, and even by a lot of doctors, and therefore cases likely go under reported.

It may also turn out that some, if not most, of the reported behavioral problems which have been previously (and tentatively) linked to the use of oseltamivir (aka Tamiflu) may have more do to with the neurocognitive effects of influenza infection than from taking the drug. 

But most of all, these studies - along with others, like NEJM: Acute Myocardial Infarction After Laboratory-Confirmed Influenza Infection and Eur. Resp.J.: Influenza & Pneumonia Infections Increase Risk Of Heart Attack and Stroke - are reminders that influenza is a far more complex, and far more dangerous, virus than most people give it credit for.

Something to seriously consider when you are deciding whether to bother getting that flu shot next fall.

HPAI H5Nx Clade 2.3.4.4. Shedding In Cottontail Rabbits

Credit Wikipedia

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Regular readers will recall that over the past several years we've been looking into the carriage of novel (and seasonal) flu by domestic and peridomestic animals, and how they might fit into the ecology and evolution of influenza viruses.

On the domestic front, dogs and cats take center stage, as both are susceptible to at least some novel flu strains.  A few (of many) blogs include:

mBio: Novel Reassortant Influenza A Viruses in Canines in Southern China

EID Journal: Avian H7N2 Virus in Human Exposed to Sick Cats

Study: Dogs As Potential `Mixing Vessels’ For Influenza

Korean CDC Statement On H5N6 In Cats

Influenza A(H6N1) In Dogs, Taiwan

On the peridomestic front, in recent years we've seen growing evidence that small mammals - like rabbits, skunks, mink, and even small rodents - can be infected by, and potentially spread, flu viruses.

While these types of animals may not pose as much as a direct threat of transmitting flu viruses to humans, they do provide a way for viruses in the wild to gain entry into farms, or to jump to dogs and cats.  

And carriage of novel flu viruses by any mammalian host provides the virus with an opportunity to develop host adaptations, potentially making it easier to jump to other mammals. 

A few past blogs include:

H9N2 Adaptation In Minks

Sci Rpts: Characterization of Avian H7N2 in Wild Birds and Pikas in Qinghai-Tibet Plateau Area

Taking HPAI To The Bank (Vole)

EID Journal: Guinea Pigs As Reservoirs For Influenza

One of the leaders in research into flu carriage and shedding by peridomestic animals is  Dr Jeffery Root - a Research Wildlife Biologist at the National Wildlife Research Center -  whose work we've been following for several years.

• Dr. Root was one of the authors of a 2014 PLoS One study called Shedding of a Low Pathogenic Avian Influenza Virus in a Common Synanthropic Mammal – The Cottontail Rabbit, which was the first to show shedding of LPAI by cottontail rabbits.
• In 2015, this work was followed up with Virology: Experimental Infection of Peridomestic Animals With Avian H7N9 where Dr. Root et al. demonstrated H7N9’s ability to infect, and to be shed by, peridomestic animals like skunks, raccoons, and rabbits.  
• And again in 2016, in Report: Skunks and Rabbits Can Catch And Shed Avian Flu, we looked at an AP News report that quoted Dr. Root as saying that small mammals like rabbits and skunks can become infected with avian flu, and they can shed enough of the virus to pass it onto ducks (and presumably other types of birds). 

Which brings us to a new brief report (alas, mostly behind a pay wall) in the Archives of Virology, where Dr. Root et al. show that the HPAI H5 clade 2.3.4.4. virus - which sparked last year's European record setting epizootic - can infect cottontail rabbits, and that they can then shed the virus for one or more days. 

This is of particular interest since most clade 2.3.4.4. viruses - while causing huge losses in the poultry industry and among wild birds over the past four years - have shown a very limited ability to infect mammals. 

The exception (so far) being the HPAI H5N6 virus which has infected at least 17 people in China (see Human Clade 2.3.4.4 A/H5N6 Influenza Virus Lacks Mammalian Adaptation Markers and Does Not Transmit via the Airborne Route between Ferrets).

First the (very) brief abstract, then I'll return with a bit more.

Cottontail rabbits shed clade 2.3.4.4 H5 highly pathogenic avian influenza A viruses

J. Jeffrey Root, Angela M. Bosco-Lauth, Nicole L. Marlenee, Richard A. Bowen

First Online: 13 June 2018

Abstract

During 2014-2015, clade 2.3.4.4 H5Nx highly pathogenic (HP) avian influenza A viruses (IAV) were first detected in North America and subsequently caused one of the largest agricultural emergencies in U.S. history.

Recent evidence has suggested that cottontail rabbits can shed multiple IAV subtypes. We experimentally infected cottontail rabbits with three HP H5Nx IAVs. All rabbits tested shed virus on at least one day by at least one route.

Cottontail rabbits appear to be an exception to the limited capacity for replication that has been previously reported for certain other mammalian species inoculated with clade 2.3.4.4 HP H5Nx avian influenza A viruses.

While clade 2.3.4.4. H5N8, H5N5 and (European Lineage) H5N6 viruses have not been shown to infect humans, we did see early reports out of South Korea in 2014 of dogs having been infected (see MAFRA: H5N8 Antibodies Detected In South Korean Dogs (Again)) and just over a year ago we looked at J. Vet. Sci.: Experimental Canine Infection With Avian H5N8.

So we know that mammalian infection with at least some genotypes of H5N8 is at least possible.  Today's report expands that host range a bit.

Over the past two years we've looked at a number of studies that have explored the potential for H5N8 or its spin offs to evolve into a human health threat. A few include:

J Vet Sci: Evolution, Global Spread, And Pathogenicity Of HPAI H5Nx Clade 2.3.4.4 

Study: Virulence Of HPAI H5N8 Enhanced By 2 Amino Acid Substitutions

Sci Rpts: H5N8 - Rapid Acquisition of Virulence Markers After Serial Passage In Mice 

Perhaps most telling of these came last September in J. Virulence : Altered Virulence Of (HPAI) H5N8 Reassortant Viruses In Mammalian Models, which found:

Taken together, our study demonstrates that a single gene substitution from other avian influenza viruses can alter the pathogenicity of recent H5N8 viruses, and therefore emphasizes the need for intensive monitoring of reassortment events among co-circulating avian and mammalian viruses.

Last October's J. Virulence Editorial: HPAI H5N8 - Should We Be Worried? reviewed and summarized the literature, and found enough reasons to be concerned over the future evolutionary path of H5N8, stating that:

The extensive distribution of HPAI H5N8, as well as the gene reassortment with other circulating avian viruses already observed for H5N8 suggests there is a potential risk for human cases of H5N8 infections.

While expanding H5's host range is always a concern, the ability of small mammals like rabbits, raccoons, and rodents to breach farm biosecurity measures, and infect poultry populations is also troubling.

And may require the the rethinking of some farm biosecurity measures in the future to prevent a repeat of 2016/17 epizootic.