Influenza Virus Mashup

(Sat, 19 Nov 2011 14:07:00 +0000)

 

 

 

# 5969  

 

 

An intriguing study from the Journal of Virology this morning that looks at an unusual route of infection  - and resultant pathogenesis – of the H5N1 virus in cats (My thanks to Tetano on FluTrackers for posting this link).

 

The study is called:

 

Marked endotheliotropism of highly pathogenic avian influenza virus H5N1 following intestinal inoculation in cats.

November 2011, doi: 10.1128/​JVI.06375-11

Reperant LA, van de Bildt MW, van Amerongen G, Leijten LM, Watson S, Palser A, Kellam P, Eissens AC, Frijlink HW, Osterhaus AD, Kuiken T.

 

 

Endotheliotropism is simply a 12-dollar word meaning an affinity for endothelial cells which are the cells that line the interior surface of blood vessels throughout the body.

 

 

Photo Credit – Wikipedia

 

From the abstract (the entire study is behind a pay wall), we learn that researchers gave cats enteric coated capsules containing H5N1 infected chicken liver in order to deliver the virus directly to the intestine.

 

(EXCERPT)

Intestinal inoculation of HPAIV H5N1 resulted in fatal systemic disease. The spread of HPAIV H5N1 from the lumen of the intestine to other organs took place via the blood and lymphatic vascular systems but not via neuronal transmission.

 

Remarkably, the systemic spread of the virus via the vascular system was associated with massive infection of endothelial and lymphendothelial cells, resulting in widespread hemorrhages.

 

As the abstract points out, this resulted in a disease process similar to what is seen in terrestrial poultry, and differs greatly from the pathogenesis normally seen from respiratory tract infection.

 

The authors conclude that:

 

The marked endotheliotropism of the virus following intestinal inoculation indicates that the pathogenesis of systemic influenza virus infection in mammals may differ according to the portal of entry.

 

 

The surprise here isn’t that cats (and other mammals) can acquire the H5N1 virus via a non-respiratory route (we’ve known that for some time), it is the discovery of the manner in which the virus spread systemically; via massive infection of endothelial and lymph endothelial cells.

 

While anything that betters our understanding of the H5N1 virus is a good thing, this discovery may eventually have practical applications as well. 

 

Should an outbreak occur, gastrointestinal H5N1 infection (with its atypical pathogenesis) may require a different treatment regimen than is currently used with a respiratory infections.

 

An oral route of infection from the H5N1 virus has been suggested over the years, with several human cases being linked to the consumption of infected poultry.

 

One of the earliest indications that H5N1 could bind and flourish in the human gastrointestinal tract comes from this study involving the deaths of a brother and sister in Vietnam in 2004.

 

Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma.

de Jong MD, Bach VC, Phan TQ, Vo MH, Tran TT, Nguyen BH, Beld M, Le TP, Truong HK, Nguyen VV, Tran TH, Do QH, Farrar J.

 

 

In June of 2007, we got a report (see Atypical Presentations of H5N1)  out of Indonesia, of a child infected with H5N1 but that presented without respiratory symptoms.

 

A year later, in a large review of Chinese bird flu patients (see Clinical Case Review Of 26 Chinese H5N1 Patients), we find several mentions of gastrointestinal involvement as well.

 

Diarrhea was present in only two H5N1 cases at admission, but developed in a quarter of cases during hospitalization. Diarrhea was a common presenting symptom among H5N1 cases in Vietnam  and Thailand , but was reported infrequently among cases in Hong Kong SAR, China and Indonesia.

 

H5N1 virus and viral RNA have been detected in feces and intestines of human H5N1 cases. Whether the gastrointestinal tract is a primary site for H5N1 virus infection is currently unknown.

 

In 2010, we saw a study (see H5N1 Can Replicate In Human Gut) that provided even more evidence that the bird flu virus can thrive in the human gastrointestinal system.

 

We’ve also seen numerous reports over the years of cats infected with the H5N1 virus after consuming infected birds.  The following comes from a World Health Organization GAR report from 2006.

 

 

H5N1 avian influenza in domestic cats

28 February 2006

(EXCERPTS)

Several published studies have demonstrated H5N1 infection in large cats kept in captivity. In December 2003, two tigers and two leopards, fed on fresh chicken carcasses, died unexpectedly at a zoo in Thailand. Subsequent investigation identified H5N1 in tissue samples.

 

In February 2004, the virus was detected in a clouded leopard that died at a zoo near Bangkok. A white tiger died from infection with the virus at the same zoo in March 2004.

 

In October 2004, captive tigers fed on fresh chicken carcasses began dying in large numbers at a zoo in Thailand. Altogether 147 tigers out of 441 died of infection or were euthanized. Subsequent investigation determined that at least some tiger-to-tiger transmission of the virus occurred.

 

In 2006, Dr. C.A. Nidom demonstrated that of 500 cats he tested in and around Jakarta, 20% had antibodies for the bird flu virus.  

 

In 2007 the FAO warned that:

 

Avian influenza in cats should be closely monitored

So far no sustained virus transmission in cats or from cats to humans

 

For an overview of a number of other cases involving cats, see Apparently They Didn’t Get The Memo.

 

And it isn’t just the H5N1 virus which as shown some propensity for gastrointestinal involvement.

 

Seasonal A & B Influenza viruses, along with the 2009 H1N1 virus, have been looked at for exhibiting unusual gastrointestinal symptoms, albeit nowhere near as severe as described in today’s study.   

 

In January of 2010, in Influenza’s Gastrointestinal Connection, I wrote about a study that appeared in BMC Infectious Diseases, that looked at seasonal flu in pediatric patients. 

 

 

Influenza virus infection among pediatric patients reporting diarrhea and influenza-like illness

The detection of influenza viral RNA and viable influenza virus from stool suggests that influenza virus may be localized in the gastrointestinal tract of children, may be associated with pediatric diarrhea and may serve as a potential mode of transmission during seasonal and epidemic influenza outbreaks.

 

And lastly, during the 2009 pandemic, the CDC’s Interim guidance on Infection Control for the pandemic H1N1 Virus, warned:

 

Transmission of influenza through the air over longer distances, such as from one patient room to another, is thought not to occur. All respiratory secretions and bodily fluids, including diarrheal stools, of patients with 2009 H1N1 influenza are considered to be potentially infectious.

 

 

More evidence (as if we needed it) to show that influenza is a far more complex, and fascinating, virus than most people give it credit for.

Via The Poultry Site, a reminder that H5N1 isn't the only avian influenza: Highly Pathogenic Bird Flu Breaks Out in Taiwan. Excerpt:

The Taiwanese veterinary authorities have reported an outbreak of highly pathogenic avian influenza (HPAI), at Zhupei City located in Northern Taiwan's Hsinchu. 

The World Organisation for Animal Health (OIE) received an immediate notification yesterday, 17 November. The causal agent was found to be H5N2 serotype. 

The affected population consists of 2,720 native chicken breeders and 3,280 native chickens, thereby bringing the number of susceptible birds to 6000. Out of this, 20 cases were identified. No deaths were recorded, and no birds were destroyed. The report states that the notifiable avian influenza (NAI) viral infection was detected on a native chicken breeder farm in the process of active surveillance and identified as H5N2 strain on 15 November 2011. Movement restriction was implemented on the infected farm immediately when the virus was detected. 

Clinical health investigation in the infected farm was done and showed that the breeders were in healthy condition and without clinical signs. The positive results of serological and virological tests confirm this H5N2 outbreak. The clinical and epidemiological investigation of surrounding poultry farms and pathogenicity test of virus isolate are in progress.

(Fri, 18 Nov 2011 12:37:00 +0000)

 

 

# 5968

 

The World Health Organization is holding a 3-day conference this week in Mexico City called Health Risks in Human-Animal Ecosystems, attended by more than 100 experts from 30 countries.

 

Their goal is to coordinate, and improve, the global response to future outbreaks of zoonotic diseases; those that jump between animals and humans.

 

 

At this week’s conference, WHO Assistant Director-General of Health Security and Environment Keiji Fukuda warned on the inevitability of the world seeing another pandemic, calling it was a matter of when, not `if’.

 

He is further quoted by Reuters as saying:

 

"We do face the risk of another pandemic in the future. We know that the viruses which can cause influenza pandemic circulate in animals and then we don’t know when one of those viruses then becomes highly infectious for people and then spreads around the world. We also don’t know when something like that happens, which we do expect in the future someday, when something like that happens we don’t know how severe the effect will be."

 

 

Working as an alliance, the WHO, FAO, and OIE formally joined forces in 2010 with the issuance of a Tripartite Concept Note outlining their collaborative efforts.

 

Their stated goal is to `coordinate global activities to address health risks at the animal-human-ecosystems interface’.

 

The WHO webpage Zoonoses and veterinary public health (VPH)  provides a description of zoonotic pathogens for us:

 

Any disease or infection that is naturally transmissible from vertebrate animals to humans and vice-versa is classified as a zoonosis according to the PAHO publication "Zoonoses and communicable diseases common to man and animals".

Over 200 zoonoses have been described and they have been known for many centuries. They are caused by all types of agents: bacteria, parasites, fungi, viruses and unconventional agents.

 

Twice in the last decade (SARS in 2003, and Swine Flu in 2009) we saw how quickly viruses normally found in non-human hosts can evolve and adapt to humans and spread globally.

 

Which is why efforts such as Global Early Warning System for Major Animal Diseases, including Zoonoses (GLEWS) have been set up to detect, and provide early warning of animal disease threats

 

The WHO lists the criteria by which events are assessed by the GLEWS task force as:

 

Triggers and GLEWS diseases

What triggers GLEWS

A potential event is assessed according to criteria derived from the International Health Regulations (2005) and the Terrestrial Animal Health Code from OIE:

• Is the public health impact of the event serious?
  • High morbidity and/or high mortality in humans and/or animals.
  • Emerging disease with significant mortality and/or morbidity or zoonotic potential.
• Is the event unusual or unexpected?
  • First occurrence or reoccurrence of a disease/strain.
  • Unusual event for the area or season.
  • Event associated with an unknown agent.
• Is there significant risk of international spread or interference with international travel or trade?

 

You’ll find more information, including a priority list of zoonotic pathogens, on this page as well.

 

There are other efforts out there to detect or provide early warning for the next emerging pathogen, including (but not limited to):

 

• Nathan Wolfe’s Global Viral Forecasting Initiative (GVFI) (see Nathan Wolfe On Pandemic Prevention),
• The National Biological Information Infrastructure (NBII)
• Promed Mail
• The volunteer efforts of the newshounds on the flu forums (see Newshounds: They Cover The Pandemic Front).

While the 2009 H1N1 pandemic is ended, it is important to remember that the world remains at pre-pandemic phase III on the H5N1 virus. 

 

 

But as SARS showed us in 2003, sometimes a pathogen can emerge with little or no warning. Hence the need for nations, businesses, and individuals to be prepared for the unexpected.

Via CIDRAP, a must-read article by Robert Roos: H5N1 transmission experiment stirs concern. Excerpt:

A national biosecurity board that monitors "dual use" research is apparently worried about an as-yet-published study in which a mutant form of H5N1 avian influenza virus was found to be easily transmissible in ferrets, which are considered good models for flu in humans. 

A National Public Radio (NPR) report today said the National Science Advisory Board for Biosecurity (NSABB) is scrutinizing the research by Dr. Ron Fouchier of Erasmus University Medical Center in the Netherlands. The board provides guidance on biological research that has a legitimate purpose but could be misused to endanger public health. 

Dr. Paul S. Keim, acting chair of the NSABB, said today that the board is conducting a review of H5N1 virus transmission in mammals, but because of the board's confidentiality rules, he could not give any details. Keim is director of pathogen genomics in the Translational Genomics Research Institute at Northern Arizona University. 

Referring to the Office of Biotechnology Activities in the National Institutes of Health's Office of Science Policy, Keim told CIDRAP News, "We have now been directed by OBA staff that we can acknowledge that a review process on the H5N1 transmissibility in mammals is under way. We are not allowed to provide additional details." 

The H5N1 virus causes human illness relatively rarely, but it is often deadly when it does, with a case-fatality rate of about 60% among cases confirmed by the World Health Organization. Though the virus has circulated in poultry in many countries since 2003, it has not gained the ability to spread easily in humans. Scientists worry that if it did gain that ability, it could spark a fearsome pandemic. 

With the goal of identifying genetic changes that could lead to greater person-to-person transmissibility, a number of researchers have introduced mutations in the virus and studied how the mutant strains behaved in animals. 

Fouchier gave a general description of his experiments at a European meeting in September, according to a news story published in Scientific American after the meeting. He and his team introduced various mutations into the virus and watched their effects on its ability to attach to human respiratory tract cells. They found that with as few as five single mutations, the virus could bind to nasal and tracheal cells, according to the story. 

But when tested in ferrets, this mutant virus still didn't spread very easily through close contact. Fouchier and his team then undertook to let the virus evolve naturally—a project that he described as "really, really stupid," according to the story. They inoculated one ferret with the mutant virus, and after it got sick, they exposed a second ferret to infectious material from the first one. 

After they repeated this process 10 times, "H5N1 became as easily transmissible as seasonal flu," the story said. Fouchier said he concluded from this that H5N1 viruses "can become airborne" and do not need to reassort with other mammalian flu viruses to do so.

Thanks to Mike Coston at Avian Flu Diary for sending me the new link to WHO's cumulative tallies of human H5N1 cases. I've updated the link in the WHO list. 

Via The Bali Times: Rainy Season Could Exacerbate Bird Flu. Excerpt:

The start of the rainy season could see an increase in incidents of bird flu amongst humans, as the damp conditions encourage respiratory infections, health experts have said. 

Ngurah Mahardika, a flu specialist at Udayana University, said bird-to-human transmission of the disease was more likely during wet weather. 

“In high humidity, the virus is able to survive a little bit longer. Besides, in the transition period between the dry and the rainy seasons, poultry easily get sick and are therefore more vulnerable to the virus,” he said. 

However, Mahardika said that it was still only those who lived in close proximity to poultry who were at serious risk. 

“It would require proximity of less than 10 meters between a sick bird and a human for the virus to spread. A person can also easily be infected when in contact with the body fluids of sick poultry. This can also happen in the dry season, not only in the rainy season,” he said. 

“The public should not worry too much. As long as they don’t come into contact with sick poultry or with meat from sick poultry, they will not be infected,” he said, adding that people should always be careful when buying poultry, either for home consumption or as offerings for religious ceremonies.

(Thu, 17 Nov 2011 13:54:00 +0000)

 

# 5967

 

 

Constant readers may have noticed that after a lull of a couple of years, interest and concern over the H5N1 bird flu appears to be on the rise again.

 

In August the FAO issued a statement on the emergence of clade 2.3.2.1 (see FAO Warns On Bird Flu) that is not covered by currently available poultry vaccines.

 

Last month, In H5N1: An Increasingly Complex Family Tree, we looked at the continued diversification of the H5N1 virus, which has now evolved into at least least 20 genetically separate clades of the virus, with many minor variants of each clade thrown in the mix.

 

 

Last August, in Professor Peter Doherty On Bird Flu, we looked at his concerns over the possibility that the H5N1 virus might one day swap genes (reassort) with the H1N1 virus and produce an easily transmitted, highly virulent flu strain.

 

Reassorted viruses can result when two different flu strains inhabit the same host (human or otherwise) at the same time. Under the right conditions, they can swap one or more gene segments and produce a hybrid virus.

 

 

In September of this year Professor John Oxford - Scientific Director of Retroscreen Virology Ltd. and a Professor of Virology, expressed renewed concerns over the continued evolution of the H5N1 bird flu virus during a Webinar: John Oxford On Pandemic Preparedness.

 

But while nature continues to play mix and match with influenza genes – looking for a more `biologically fit’ combination - so do scientists in the laboratory.

 

Using reverse genetics, scientists are creating influenza reassortments to see exactly what genetic changes are needed to turn H5N1 (and other flu strains) into a human pandemic threat.

 

A few recent examples of this kind of research include:

 

In Study: Reassorted H1N1-H5N1 Produced Virulent Strain, we looked at work conducted by researchers at St. Jude Children’s Research Hospital who created several reassortant 2009 pH1N1 viruses with individual genes borrowed from a 1997 H5N1 virus.

 

They found that one of these lab-created viruses, with the HA gene from the H5 virus, increased replication over the parental strain and produced virulence in mice comparable to the parent H5N1 strain.

 

And last February in PNAS: Reassortment Of H1N1 And H9N2 Avian viruses we saw research from Chinese scientists that created – using reverse genetics – 128 reassorted viruses from the avian H9N2 virus and the (formerly pandemic) H1N1 virus.

 

In mouse testing, they found half of the hybrid viruses were biologically `fit’ as far as replication goes, and 8 hybrids were significantly more pathogenic than either of their parental viruses.

 

Most strikingly, last September we learned of as-yet unpublished research conducted by Ron Fouchier of the Erasmus Medical Center in the Netherlands. 

 

He basically `mutated the hell’ out of the H5N1 virus in the lab, and then passed it serially through 10 ferrets, during which time it mutated further to become both easily transmissible and highly virulent.

 

You can read about this work in Katherine Harmon’s Sci-Am article.

 

 

I wrote a follow up to this story in New Scientist: Five Easy Mutations.

 

These studies have evoked considerable controversy over what kinds of information should be published, since the details of these sorts of experiments could conceivably be used to create a bio-weapon.

 

Today NPR has a segment on their Morning Edition show that looks at the ethics of such research and their publication. 

 

You can listen to the 5 minute audio report at the link below.

 

 

 

Bird Flu Experiment Rattles Bioterrorism Experts

by Nell Greenfieldboyce

November 17, 2011

 

November 17, 2011

Scientists are worried about the deadly bird flu called H5N1 which sometimes infects people. It’s never acquired the ability to transmit easily between humans, but researchers would like to know if that could happen. Recently, they’ve essentially been altering the genes of H5N1 to make the virus spread more easily between lab animals — raising concerns about biosafety and how this research is regulated.

(Thu, 17 Nov 2011 12:35:00 +0000)

 

 

# 5966

 

 

Short of seeing a Category 5 pandemic, I can think of no health threat that has a greater potential to threaten the general public than does the global rise in antibiotic resistant bacteria.

 

As Maryn McKenna so eloquently explained in her book Superbug: The Fatal Menace Of MRSA, not only are many of our older antibiotics losing their effectiveness, the number of replacement antibiotics under development is distressingly limited.

 

While it may sound alarmist, there are many scientists who fear that one day we may find ourselves facing a post-antibiotic world, where many of the infections we can treat today will no longer respond to the antibiotics we have remaining.

 

In April of this year, Margaret Chan – Director General of the World Health Organization – in a speech for World Health Day 2011, issued this stark warning:

 

In the absence of urgent corrective and protective actions, the world is heading towards a post-antibiotic era, in which many common infections will no longer have a cure and, once again, kill unabated.

 

 

Since much of this resistance has come about from inappropriate use of antibiotics (in humans, and on the farm), the immediate focus is on ways to curb their improper use.

 

This week the CDC is promoting their GET SMART about antibiotics campaign, while countries across Europe are promoting European Antibiotic Awareness Day tomorrow, November 18th.

 

 

Today, a round up of some antibiotic resistance resources for you to explore.

 

 

First stop, a short video from the CDC on the appropriate use of antibiotics.

 

 

The CDC has also introduced a number of new fact sheets and other promotional material for 2011 on antibiotic resistance.

 

Fact Sheets New 2011

• Antibiotics: Will they work when you really need them? [412 KB, 2 ages]

                                                                 

• Delivering safe care for patients: all healthcare providers play a role [503 KB, 2 pages]
• Antibiotic stewardship – the ultimate return on investment [460 KB, 2 pages]
• Preserving antibiotics for the future [420 KB, 2 pages]
• Resistance anywhere is resistance everywhere [475 KB, 2 pages]
• Antibiotic use in long-term care facilities [600 KB, 2 pages]

 

Across the pond, the ECDC has posted a short (8 minute) documentary on antibiotic resistance, and some short PSA announcements which can be viewed at this link.

 

You’ll find additional European initiatives and information on the European Antibiotics Awareness Day website.

 

In support of the CDC & ECDC awareness campaigns, Clinical Infectious Diseases  and The Journal of Infectious Diseases  have made a number of recent articles on antibiotic resistance freely available for the month of November.

 

Clinical Infectious Diseases articles:

Editorial commentary: Outpatient Antibiotic Use in the United States: Time to "Get Smarter"

Behavior Change Strategies to Influence Antimicrobial Prescribing in Acute Care: A Systematic Review

The Interface Between Antibiotic Resistance and Virulence in Staphylococcus aureusand Its Impact Upon Clinical Outcomes

Rapid Diagnostics and Appropriate Antibiotic Use

Strategies for Reduction in Duration of Antibiotic Use in Hospitalized Patients

The Journal of Infectious Diseases articles:

Editor’s Choice: Antibiotic Choice May Not Explain Poorer Outcomes in Patients With Staphylococcus aureus Bacteremia and High Vancomycin Minimum Inhibitory Concentrations

Editorial commentary: At What Cost Echinocandin Resistance?

Acinetobacter baumannii Resistant to Colistin Alters Its Antibiotic Resistance Profile: A Case Report From Spain

The Combination of a Tumor Necrosis Factor Inhibitor and Antibiotic Alleviates Staphylococcal Arthritis and Sepsis in Mice

Divergent Mechanisms for Passive Pneumococcal Resistance to &szlig-Lactam Antibiotics in the Presence of Haemophilus influenza

 

 

And for good measure, a sampling of some of my antibiotic resistance essays from the past year.

 

India: The NDM-1 Story Continues

CDDEP: Mapping Resistance

NDM-1: One Year Later

ECDC/EMEA: Joint Report On Resistant Bacteria

Carbapenemases Rising

Via CNTV English, a report that's interesting because so little H5N1 news comes out of China these days: Bird flu virus found in poultry markets. Excerpt:

The bird flu virus, also known as H5N1, seems to exist widely in the poultry markets, particularly in South China, posing a tough challenge for the nation's epidemic intervention work, senior experts warned. 

Worse, a mutant strain of the virus called H5N1-2.3.2.1 was found spreading among live poultry, which the vaccine now in use cannot fully protect against, Guo Fusheng, technical adviser in animal health of the Food and Agriculture Organization (FAO) of the United Nation, told China Daily on Tuesday, citing information and statistics from China's Ministry of Agriculture. 

"With the arrival of autumn and winter, the country is facing an escalating risk of bird flu outbreaks among poultry as well as that of humans getting infected," he warned. 

Yu Kangzhen, the national chief veterinary officer of the Ministry of Agriculture, said previously that it would be hard to avert regional bird flu cases during autumn and winter but "the chance of large-scale outbreaks is quite slim". 

In late August, FAO warned of a possible resurgence of bird flu outbreaks around the world. According to the organization, since the virus was first detected in 2003, it has infected at least 560 people worldwide, killing 331 of them. 

Sun Yan, an official of the Bureau of Veterinary under the Ministry of Agriculture, conceded that China is at even greater risk of avian influenza, given that it produced 25 percent chicken, 87 percent goose and 65 percent duck of the world's total yield. 

In China, some 50 cases of bird flu involving poultry have been detected on the mainland since 2004, with 31 of these in 2005 alone, according to the Ministry of Agriculture. 

Forty human cases were reported, including 26 deaths, statistics from the Ministry of Health showed. 

The last human death happened in June in Hubei province and the infected woman tested positive for H5N1-2.3.2.1, said Shu Yuelong, director of the National Influenza Center of the Chinese Center for Disease Control and Prevention.

I can't confirm the numbers of cases and deaths the story cites. For some reason, WHO recently removed its very useful updated tables of H5N1 cases and deaths, which it had maintained since I started blogging H5N1 in 2005. Nor can I find anything like them in WHO's H5N1 archives. Very strange. I'll try to find out why.

China, meanwhile, has long had a reputation for concealing the true numbers of cases of politically embarrassing diseases like SARS and H5N1. Given the size of its human and poultry populations, it's remarkable that so few cases have been reported in recent years.

Via CIDRAP: FLU NEWS SCAN: H5N1 in Bangladesh, flu hybrid in Hong Kong pigs, anti-vaccine group vs AAP. Excerpt:

Hong Kong officials announced today that 15 samples from pigs were recently found to contain an H3N2 swine influenza virus with genes from 2009 pandemic H1N1 flu (pH1N1).

In a report on about 1,000 samples taken during surveillance from August to mid October, the Hong Kong Centre for Food Safety (CFS) said the virus is "unlikely to cause any major human health risk or problems in food safety." In August the agency said that 16 samples collected from May through July also tested positive for the virus. 

The report made no comparison of the hybrid virus to swine flu viruses detected in other countries, such as the H3N2-pH1N1 combination isolated from eight people in the United States since September.