H5N1 versus H7N9...

Data from the World Health Organization (2).

Green bars include surviving and fatal H5N1 laboratory-

confirmed cases in humans. The green "mountain" (area 

under the curve) is the accumulating tally of total cases. 

The red area-under-the-curve is the accumulating tally of 

fatal cases. The current total H7N9 cases is shown as a 

horizontal dashed blue line.

Click on image to enlarge.

This remains a kind of a pointless exercise. As I noted when I posted this first time back in February, but since I'm preparing some lectures I thought I'd post the latest version anyway.

These avian influenza A(H5N1) virus numbers have been curated since 2003 when the World Health Organization started an official tally. To that chart I've added where the current total number of laboratory confirmed human cases of infection by avian influenza A(H7N9) virus sits on the accumulating case tally (the green area-under-the-curve line). This blue dashed line highlights what we've heard before; H7N9 cases are piling up faster than H5N1 cases did. 

From 2003 it took H5N1 human cases nearly 6-years to reach the 430'ish mark; it's taken H7N9 about 61 weeks.

Sources...

1. Monthly risk assessment summary |  Influenza at the Human-Animal Interface
   http://www.who.int/influenza/human_animal_interface/HAI_Risk_Assessment/en/

Watching zoonoses evolve...

Special guest writer: @influenza_bio

For the first time in human history, we are watching diseases jump from animals to humans on a large scale. We've seen diseases appear for the first time in humans before; that's not new. We've seen HIV and several new strains of influenza emerge over the past century or so, for example. What is new is that we can now watch this process as it happens. We are able to watch animal diseases trickle case by case into humans, and we wonder whether any of these diseases might some day become human diseases. We wonder whether we might be watching pandemics develop in real time.

A disease that jumps from a non-human animal to a human (or the other way around) is called a "zoonotic" disease or a "zoonosis." Individual cases are called "zoonotic" cases. When a zoonotic disease is trying to make the jump to us permanent, we call this disease an "emerging infectious disease."

We have certainly been watching a lot of zoonotic MERS coronavirus and bird flu (e.g., H7N9 and H5N1) cases develop in people lately, along with Ebola virus cases. Zoonotic cases of other diseases, including infections with various strains of bird and swine flu, occasionally develop, as well, and are watched closely.

When the 2009 H1N1 flu pandemic started, we had no clue much beforehand that it was on its way.  We didn't even have surveillance data about swine flu strains that were even particularly close to the strain that emerged in us. A large animal flu surveillance gap blindsided us that year.

And we will undoubtedly be blindsided again by other emerging infectious diseases that we won't even see coming, although people are doing their best to see what's out there.

When an emerging infectious disease jumps to humans, it can cause either a relatively local outbreak or a worldwide outbreak, called a "pandemic." If a disease becomes a pandemic, that just means that it's spreading worldwide; the word "pandemic" doesn't imply anything about how bad the disease might or might not be. In some sense, the worst case can be when a disease jumps to humans and becomes "endemic" in humans, meaning that it gets established in people and regularly infects people, year after year. Endemic diseases can circulate worldwide (e.g., influenza) or in more restricted geographical regions (e.g., malaria).

Our knowledge and resources have grown to the extent that we are currently able to monitor some significant zoonotic outbreaks of disease. We are currently watching the MERS coronavirus and the influenza A(H7N9) virus both try to become human viruses.

Will either one succeed? We can't say. We've never watched this process happen before. We don't know how long such a process "usually" takes, or whether there even is a "usual" amount of time that it takes. We don't know how long it might take, or how quickly it has happened before. We do know that the process is "stochastic," meaning that it involves a lot of chance. A pathogen that in one situation might cause a pandemic might just die out in another situation. Everything depends on the specific changes in a pathogen that get a chance to develop and on whether those changes end up getting passed on. We don't know how often pathogens "fail" when they "try" to make the jump to humans.

A lot of us have watched the recent surge in MERS coronavirus cases with some amount of concern. As of April 19, 2014, there are two large clusters of cases in the Middle East, and at least one of them is still growing. One cluster, in Jeddah, Saudi Arabia, now has 60 cases; 7 cases were added to this cluster today, and 6 were added yesterday. There are perhaps over a dozen cases in another cluster in the UAE. One patient who became ill with MERS in Jeddah at the end of March flew to his home country of Malaysia while ill and subsequently died in Malaysia; 79 of his contacts are now being watched closely in Malaysia. Test results are starting to come in for a number of these contacts, and thankfully all are negative for MERS so far. An asymptomatically infected Filipino health care worker traveled on an airplane back to the Philippines a few days ago. Yesterday, a MERS case was announced in Greece; a Greek man who had been living in Saudi Arabia was recently in Jeddah and presumably became infected there before flying back to Greece. He arrived in Greece with a fever; his contacts are now being monitored. In other words, MERS case numbers are growing quickly right now, at least in part through human-to-human transmission, and infected – and potentially infectious – patients are getting on airplanes to travel around the globe.

Does what we're seeing now represent changes in the virus that are making it more transmissible among humans? Or are we seeing a random fluctuation in the numbers of cases? Or, are we seeing more cases simply as a result of improved surveillance? I would argue that what we're seeing likely reflects one or more changes in the virus, simply because

1. We've been seeing so many more symptomatic cases recently, 
2. We've been seeing significantly larger clusters than we've ever observed before,
3. A greater number of health care workers appear to be getting infected than ever before, and
4. A greater proportion of cases are in health care workers than ever before. 

It's not that we've been seeing a rise only in the number of asymptomatic cases detected, which could suggest that we're only seeing the effects of improved surveillance. Moreover, while surveillance does seem to be picking up more mild and asymptomatic cases, it is difficult to know whether we are seeing more of these cases because of improved surveillance or because there simply are more such cases now. A lot of variables are being changed at the same time, and we don't have perfect information.

Nonetheless, the sheer numbers of recent cases suggest to me, at least, that the virus is changing and becoming more transmissible among humans. Until recently, we rarely saw evidence for human-to-human transmission of MERS; most cases may have been zoonotic. Now, however, large clusters involving roughly 1 to 4 dozen people are being seen, with single infected individuals infecting possibly up to a dozen or more other people. This is new. I don't think that we're seeing these clusters just as a result of improved surveillance, although I would be very happy to be wrong.

What does the future hold for MERS? We can't know. We might be watching MERS become a pandemic, and we might not. We might be watching the current relatively small MERS outbreak develop into a larger outbreak that eventually gets contained, as was seen with SARS. Or, the whole outbreak might all just simmer down or go away. Even if the virus were currently changing to become more transmissible, the current spate of cases could still simmer down or go away, just stochastically, just through sheer chance.

Prudence would dictate that we remain concerned and vigilant, however, especially as symptomatic MERS cases have had an approximately 40% case fatality rate (CFR). If MERS did cause one or more wider outbreaks in humans, that CFR might or might not change. Even if the CFR dropped to 10% of what it is now, it would still be on the same scale as the CFR for the 1918-19 influenza pandemic.

As a global society, we have an obligation to do everything in our power to prevent the MERS coronavirus from causing larger disease outbreaks in humans. We need more surveillance in affected countries, including much more genetic sequence data. And in countries of the Arabian Peninsula that are currently detecting MERS cases, infection control procedures need to be improved to the point where nosocomial cases in health care workers and patients are prevented. Health care workers in other countries should be educated about the possibility of MERS patients arriving from afar and about how to treat such patients safely. If this virus becomes more transmissible, we should not be caught unprepared. We can see this one coming.

H7N9 versus H5N1

Click on image to enlarge.
Data from the World Health Organization (2).
Green bars include surviving and fatal H5N1 laboratory-
confirmed cases in humans. The green "mountain" (area 
under the curve) is the accumulating tally of total cases. 
The red area-under-the-curve is the accumulating tally of  
fatal cases. The current total H7N9 cases is shown as a 
horizontal dashed blue line.

This is kind of a pointless exercise.

I admit it.

Every flu is different, just like every person is different and comparisons at the interface of the two is probably of little value beyond water-cooler conversation and blogging. But this is a blog. 

I've been wanting to visualize human case numbers for avian influenza A(H5N1) virus for a while. These numbers have been curated since 2003 when the World Health Organization started an official tally. To that chart I've added where the current total number of laboratory confirmed human cases of infection by avian influenza A(H7N9) virus sits on the accumulating case tally (the green area-under-the-curve line). This blue dashed line highlights what we've heard before; H7N9 cases are piling up faster than H5N1 cases did. 

From 2003 it took 4-years to reach the 330'ish human H5N1 case mark; it took H7N9 51 weeks.

H5N1 was first noted in humans in 1997, and there were at least 18 other cases between then and 2003 (1). That is in the early days of PCR methods and the early days for global communication of things like "hey everyone, I have this bird-killing, human-killing virus breaking out in my back yard". 


References..

1. H5N1 in humans
   http://www.nejm.org/doi/full/10.1056/NEJMra052211
2. WHO H5N1 data
   http://www.who.int/influenza/human_animal_interface/EN_GIP_20140124CumulativeNumberH5N1cases.pdf

Why have a case definition that seems designed to miss transmission events? [UPDATED]

v2 24APR2015. Modified figure to exclude erroneous "uninfected" person

FluTrackers just tweeted a link to a story they have posted from Korea which I've excerpted below. 

I don't usually excerpt, so take it as a measure of my complete dismay about this.

Asymptomatic Carriers of AI Confirmed in S. Korea 2014-02-04

..The Korea Centers for Disease Control and Prevention confirmed that ten people who had participated in culling birds during the outbreaks of bird flu in 2003 and 2006 had antibodies for the H5N1 strain of avian influenza....

...The agency said that it had announced before that there were no human infection cases as asymptomatic carriers are not regarded as patients under the World Health Organization standards.

What? Seriously? You cannot be listed as a Case unless you are symptomatic?! 

I can understand that a symptomatic Case will require medical care and resources and is a priority in counting the true human toll from an infectious agent spreading among people, but to be excluded from any Case counts when you are still a viable piece in the transmission chain puzzle (see image below)? That makes no sense to me at all. Unless there is concern that the laboratory is at fault or that the test is untrustworthy. But there are no mentions of those issues.

I've pasted below the most up-to-date H5N1 Case Definition (CD) I could locate on the World Health Organizations's (WHO) website. It's from 2006 but there does not seem to be anything more contemporary (at least on H5N1 CDs) at WHO.

Confirmed H5N1 case (notify WHO)

A person meeting the criteria for a suspected or probable case

AND

One of the following positive results conducted in a national, regional or international influenza laboratory whose H5N1 test results are accepted by WHO as confirmatory:

a. Isolation of an H5N1 virus;

b. Positive H5 PCR results from tests using two different PCR targets, e.g. primers specific for influenza A and H5 HA;

c. A fourfold or greater rise in neutralization antibody titer for H5N1 based on testing of an acute serum specimen (collected 7 days or less after symptom onset) and a convalescent serum specimen. The convalescent neutralizing antibody titer must also be 1:80 or higher;

d. A microneutralization antibody titer for H5N1 of 1:80 or greater in a single serum specimen collected at day 14 or later after symptom onset and a positive result using a different serological assay, for example, a horse red blood cell haemagglutination inhibition titer of 1:160 or greater or an H5-specific western blot positive result.

So Korea's CDC had lab results (the stuff after the "AND"). What else does a person "meeting the criteria for a suspected or probable case" have to be diagnosed with for them to be a confirmed case? See the relevant section below with my highlighting (read the entire thing, in its intended order here)

Suspected H5N1 case

A person presenting with unexplained acute lower respiratory illness with fever (>38 ºC ) and cough, shortness of breath or difficulty breathing.

AND

One or more of the following exposures in the 7 days prior to symptom onset:

a. Close contact (within 1 metre) with a person (e.g. caring for, speaking with, or touching) who is a suspected, probable, or confirmed H5N1 case;

b. Exposure (e.g. handling, slaughtering, defeathering, butchering, preparation for consumption) to poultry or wild birds or their remains or to environments contaminated by their faeces in an area where H5N1 infections in animals or humans have been suspected or confirmed in the last month;

c. Consumption of raw or undercooked poultry products in an area where H5N1 infections in animals or humans have been suspected or confirmed in the last month;

d. Close contact with a confirmed H5N1 infected animal other than poultry or wild birds (e.g. cat or pig);

e. Handling samples (animal or human) suspected of containing H5N1 virus in a laboratory or other setting.

Probable definition 1:A person meeting the criteria for a suspected case

AND

One of the following additional criteria: 

a. infiltrates or evidence of an acute pneumonia on chest radiograph plus evidence of respiratory failure (hypoxemia, severe tachypnea)

OR 

b. positive laboratory confirmation of an influenza A infection but insufficient laboratory evidence for H5N1 infection. 

Probable definition 2:

A person dying of an unexplained acute respiratory illness who is considered to be epidemiologically linked by time, place, and exposure to a probable or confirmed H5N1 case.

Korea's CDC had no choice but to exclude what appear to be retrospectively confirmed, real avian influenza A(H5N1) virus cases of infection because they adhered to the letter of the CD. 

Click on image to enlarge.
Excluding cases from official reporting & tallies
because they are asymptomatic or don't meet the 
"AND" and "OR" extra criteria may make tracking
infections to their source that much more difficult. 

In doing so, they omitted reporting cases that could have held vital epidemiological information; these cases may have linked 1 severe case to another otherwise sporadic case via an asymptomatic link. The linkage might explain how a case "popped up" or it might better define person-to-person spread. They may not have done any of this too. I have no idea of the history of these 10 cases nor any of their contacts nor any H5N1 cases that may have occurred around the same time. 

But the possibility exists that they could have had a role in improving understanding of the spread of a new or newly identified virus. Could this particular CD discourage more comprehensive testing of less ill groups? That would be unfortunate. There  is already far too much that we don't know about the spread of influenza, let alone all the other respiratory viruses.

Take a look at the US Center for Disease Control and Prevention's CD advice for H5N1 and for H7N9; it leaves out the need for symptomatic illness in defining a confirmed case. However it does retain "illness compatible with influenza", which clearly implies a symptomatic event, as a prerequisite for a "case under investigation".

What is also very informative to this debate though, is that the WHO's much more contemporary CD for reporting MERS-CoV infection does take into account asymptomatic cases..

Asymptomatic cases: The demonstration of asymptomatic infection is useful for epidemiological investigations and should be pursued as part of case investigations, however, the burden of proof must be higher due to the risk misclassification because of false positive tests due to laboratory contamination. Generally, in most viral infections, an immunological response such as development of specific antibodies would be expected even with mild or asymptomatic infection and as such serological testing may be useful as additional confirmation of the diagnosis. Additional steps to reconfirm asymptomatic cases, or any case in which the diagnosis is suspect, could include re-extraction of RNA from the original clinical specimen and testing for different virus target genes, ideally in an independent laboratory.

This may mean that the H5N1 definition was just out of date and is in dire need of modernisation. 

One implication from the Korean statement, to my mind at least, is that an absence of symptoms has been taken to mean an absence of importance in the chain of transmission because that person was not registered as a Case. I suspect that the simple act of listing a person carries significant weight. I just can't see how leaving even 1 lab-confirmed but asymptomatic person off such a list benefits the search for an answer to how an emerging virus is spreads. At least, I haven't read a convincing case for any such benefit (pun intended).

[UPDATE] Reply from WHO's Gregory Härtl (@HaertlG)

.@MackayIM @FluTrackers @GertvanderHoek @WHO Concerning the #H5N1 cases, asymptomatic cases with positive serotests were not required to 1/2
— Gregory Härtl (@HaertlG) February 4, 2014

.@MackayIM @FluTrackers @GertvanderHoek @WHO to b reported before revised #IHR came into force in '07. Concerning #H7N9 case, am asking. 2/2
— Gregory Härtl (@HaertlG) February 4, 2014

H7N9 snapdate: new charts for sex and age distribution and region of acquisition...

Two new charts.

Click on image to enlarge.

Firstly, the "age pyramid", a revised and combined version of the age and sex distribution charts for 265/267 H7N9 cases to date. This one comes with many thanks to Shane Granger for helping me learn a new trick. Please follow him @gmggranger or visit his chart-tacular blog, Random Analytics at http://gmggranger.wordpress.com/.

Secondly, we have the latest map of the H7N9 hotzone; adjusted to account for Zhejiang tipping over the 100 cases mark (new colours!), and for the addition of a new province into the world of H7N9 human infections; Guangxi. This marks the first new region and 13th to generate cases overall, since 9-Aug-2013. 

H7N9 has thus crept sideways towards the west and as FluTrackers noted, Guangxi shares a border with Vietnam. An entire other country. The first shared land border since we learned of H7N9 I think. I'm no expert in this topic, but trade in poultry and tourists between these two regions seems commonplace, as noted here, here and to the extent that research such as this study (and its references) indicate H5N1 sequences are shared between the regions.

Do we know if Vietnam actively employs laboratory methods to screen poultry for H7N9, H9N2, H10N8 screening of their birds? I suspect we'll learn soon if not.

Things I did not know #125,326...H5N1 is enzootic (=endemic in animals) in some countries...

Makes perfect sense of course, I just hadn't seen that in print in my short time looking at flu.

Helen Branswell has a piece on CTVnews about the Canadian H5N1 cases, noting that the genome will be deduced and submitted to the GISAID database.

So officially, H5N1 is considered enzootic in poultry (endemic for animals) in at least 6 countries (circulating, or epizootic, in at least 9 others):

1. Bangladesh
2. China (since 2003) 
3. Egypt
4. India
5. Indonesia
6. Vietnam

Further reading and references...

1. http://www.cdc.gov/flu/news/first-human-h5n1-americas.htm
2. http://www.cdc.gov/flu/avianflu/h5n1-animals.htm

H5N1 case in Canada had been diagnosed with pneumonia...testing at the source would have been helpful

And now, from a fantastically detailed post onto ProMED by Fonseca and colleagues, we see that the H5N1 case was diagnosed with pneumonia.

On 28-Dec, the patient presented to a local emergency department.

"A chest X-ray and CT scan revealed a right apical infiltrate. A diagnosis of pneumonia was made; the patient was prescribed levofloxacin and discharged home."

One sad point made in the ProMED post which supports the need for constant viral vigilance the world over, coupled with the dissemination of those surveillance data, so that patient management anywhere in the world can be armed with the best possible decision-making information...

"The index of suspicion was low as travel was to an area in China where there have been no recent reports of the circulation of this virus, and coupled with no obvious exposure to poultry, the diagnostic work-up and consideration for A(H5N1) infection was very low"

As a recent J Virology article by Yu and colleagues highlights, when a sensitive testing method like the polymerase chain reaction (PCR; in this case RT-PCR because influenza viruses all have an RNA genome, not a DNA one) is applied to the search for a virus, it yields the kind of data that can:

1. Explain from where a virus emerges
2. Inform the search for disease aetiology - where are human cases getting infected from and if a zoonotic infection (from animals to humans), which animal(s) is the culprit?
3. Alert the world to any risks of infection when travelling to a certain area(s)
4. Allow the local health departments to mitigate the risk of their population acquiring infection by instigating controls (like live bird market closures). This has implications for the world since respiratory viruses have the potential (thankfully not realized for H7N9 or H5N1 to date) to spread more rapidly and efficiently that blood-borne or mosquito-borne or sexually transmitted viruses.
5. Permit understanding of how widespread (over what geographic area is it detected) a novel or emerging virus may be and how entrenched (is the same site repeatedly positive) it is

Not doing such testing, or using less sensitive methods will not yield this information. 

In Yu's study, testing of 12 poultry markets, mostly urban, and local farms linked to 10 human infections in Hangzhou, Zhejiang province around 4th to 20th April 2013 yielded signs of H9N2, H7N9 and/or H5N1 viruses in all markets. Poultry were often positive for H7N9 and H9N2 (this finding from individual RT-PCRs was confirmed using next generation sequencing), whereas human specimens were not. These levels hadn't been turned up when 899,000 bird were tested in 2013 using (perhaps) less sensitive methods.

I think with influenza, it may be safer to presume its everywhere until that presumption can be discounted. Clearly the conditions for influenza viruses to swap gene segments and sort themselves into new subtypes and variants are commonplace and frequent; these aren't just chance occurrences of different birds passing in the night via overlapping flyways. These feathered vectors are co-infected by 2 or more viruses at a time. Luck and the constraints of viral fitness are presumably the only things keeping H7N1, H5N9, H7N2 cases from dialing up in humans? What seems to be lacking is more molecular testing at the farms supplying the markets. Not just in Zhejiang, but all over the region.

As the authors noted, 100,000s of people visit these live bird markets each day and very few influenza cases seem to be due to them. Long may that last. But it's a tinderbox for which matches are already being struck; if the viruses should bud of that one-in-a-million variant that is enabled to readily spread from person-to-person, whooshka. 

More testing guys, keep testing.

Why one watches the webs for the worst of the woes...

In an article on BAYTODAY.CA,written by @HelenBranswell, there is a fantastic quote that really defines why infectious disease bloggers, and public health professionals working through more official channels, get all fired up when they cannot have or find, information that could be used to help monitor or understand disease outbreaks. 

"We breathe the same air. We drink the same water. We fly on the same planes. And an infectious disease outbreak anywhere is a potential risk and threat to all of us," said Dr. Martin Cetron, director of the center for global immigration and quarantine at the U.S. Centers for Disease Control in Atlanta.

"And we just have to constantly pay attention and stay vigilant."

The influenza H5N1 death in Canada has and continues to generate a huge amount of interest. It's also generating no small amount of confusion over how the infection was acquired by this late 20-something East Asian female who worked in healthcare at Red Deer Regional Hospital. Apart from that, this infection also highlighted that when many eyes focus on a case, it is very difficult to keep a patient's details, work, travel routes and trip details, secret for long. 

Does intentionally withholding any or all of age, sex, date of onset, date of hospitalization, and perhaps a few other deidentified details truly hinder a globally connected world's efforts to uncover these details? Seems not. Whether those details hinder a patient's ability to remain anonymous I cannot say; I said other things about that recently though.

In the meantime, interested and involved professionals and amateurs alike use what information they have to hand to bend their minds towards seeking answers and making comments that might help solve mysteries like this. Because they try to help. For the benefit of all of us. I suspect, regardless of the communicative devices available to them and the extent of the interconnectedness in which they abided at the time, they always have and they always will.

H5N1: 1st fatal case in North America...[UPDATED x4-FINAL]

An otherwise healthy resident of Alberta, Canada, died 3-Jan after contracting influenza A(H5N1) virus during a visit to Beijing ,China. The person did not leave the Beijing area and did not visit live bird market. The victim returned on Air Canada flights (according to a Tweet from @HelenBranswell), showing signs and symptoms on admission to hospital 1-Jan which included high fever and lethargy without cough or other signs of acute respiratory tract illness. The patent died of meningoencephalitis. The lab confirmed H5N1 7-Jan. 

Canadian officials will not be describing the patients age, sex or occupation. Giving the region would be enough to identify the patient given there is only 1 case.

A highly pathogenic avian influenzavirus (HPAI or "high-path) that can kill the birds it infects, H5N1 has been confirmed in 648 people across 15 countries since its identification in a 3-year old boy in Hong Kong in May 1997 (first identified in a goose in 1996). There were 38 cases identified globally in 2013, with 24 deaths. A slow-burn that seems comparable to H7N9's current spread. How often H5N1 is considered in the screening of influenza-like illness I do not know; another similarity might be under-reporting/limited prospective PCR-based screening.

As ever, these sporadic imported cases also serve to highlight that the pathogen is circulating at the source. The route of acquisition for this case is unclear at this stage. H5N1 does not readily transmit among humans requiring close contact with birds and there has been no sustained human-to-human transmission.

When a human does become infected by the virus, severe acute respiratory distress syndrome can result. This is ascribed to the availability of receptors in the deeper airways and lungs, which bind the virus and trigger the person's own immune-mediated disease via a "cytokine storm"; a large scale release of the chemicals our bodies usually employ to keep virus infections in check, but on a larger scale with more severe consequences to the host. Such a storm does not commonly occur following infection by a seasonal influenza virus (e.g. H3N2) infection, 

The WHO does not list any H5N1 cases in the area around Beijing on its 2013 map (18-Dec-2013). An out-of-date timeline of "major" H5N1 events lists human cases in Beijing in Nov-2003 and Dec-2008. Major outbreaks among birds in China have centered around Qinghai lake.

There is no H5N1 component in the current seasonal influenza vaccine, but then there is no significant risk to the Canadian public health from H5N1.

The current WHO phase of pandemic alert for H5N1 is ALERT:

This is the phase when influenza caused by a new subtype has been identified in humans. Increased vigilance and careful risk assessment, at local, national and global levels, are characteristic of this phase. If the risk assessments indicate that the new virus is not developing into a pandemic strain, a de-escalation of activities towards those in the interpandemic phase may occur.

As the Public Heath Agency Canada recommend, Think-Tell-Test....

THINK

• query travel

• implement best practices for triage, infection control and patient management as indicated

TELL

• Consult your local Public Health for assistance in SRI/severe ILI patients with the following:

• Recent travel or contact with travelers to an affected area with confirmed H5N1 activity in humans and/or domestic poultry

TEST

• Consult your local Public Health for guidance on appropriate testing, recommended procedures and prioritization for H5N1 investigation IF significant exposure history has been established which may include:

• Close contact (within 1 metre, i.e. touching distance) with a confirmed human case of H5N1 or

• Close contact with sick or dead domestic poultry or wild birds

Other news and related information sources include...

• http://www.cbc.ca/news/politics/h5n1-bird-flu-death-confirmed-in-alberta-1st-in-north-america-1.2489160
• http://www.edmontonjournal.com/health/Fatal+case+H5N1+bird+reported+Alberta+first+North+American+case/9364388/story.html
• http://crofsblogs.typepad.com/h5n1/2014/01/more-on-the-fatal-canadian-h5n1-case.html
• http://vir.sgmjournals.org/content/89/3/697.full.pdf+html
• http://gamapserver.who.int/mapLibrary/app/searchResults.aspx
• http://www.sciencedirect.com/science/article/pii/S0140673697112120#
• http://www.sciencedirect.com/science/article/pii/S0264410X9800005X#
• http://edmonton.ctvnews.ca/video?playlistId=1.1618959
• http://www.theglobeandmail.com/news/national/canadian-first-to-die-from-h5n1-bird-flu-in-north-america/article16244697/
• http://www.cbc.ca/news/health/bird-flu-questions-and-answers-1.2489341
• http://www.who.int/influenza/human_animal_interface/H5N1_cumulative_table_archives/en/index.html

Age and sex morbidity and mortality from avian influenza A(H7N9) virus

Click to enlarge. The majority of cases of H7N9 that occurred
worldwide earlier in 2013. Taken from Virology Down Under's
H7N9 page.

In a study co-written by yours truly using a lot of data collected for Virology Down Under, Dr Joseph Dudley and I have just described, in the Journal of Clinical Virology, the age-specific and sex-specific morbidity and mortality from the avian influenza A(H7N9) virus outbreak earlier in the year.

We sought to highlight differences between H7N9 and another zoonotic influenza A virus, H5N1. The distribution of age and sex is notably different between cases of each virus in more distant countries (Saudi Arabia vs Egypt) as it is within the same country (see Cowling et al reference in the article's discussion). Such differences and patterns may be instructive for identifying specific risk factors for an outbreak and also serve to highlight that there are differences between outbreaks which, on the surface, might be expected to have very similar courses. 

Intriguingly, there were marked similarities between H7N9 and Middle East respiratory syndrome coronavirus age and sex case distribution.

We also published the term created here on VDU, the Proportion of Fatal Cases (PFC). A percentage defined as the number of currently known fatalities divided by the number of total lab-confirmed cases including fatalities, regardless of whether they are inpatients (hospitalized) or outpatients. It was created to avoid the need for a gauge of recovered cases (released from hospital) which is linked with use of the term Case Fatality Ratio.

Taihu lake & influenza viruses Part II: people, pigs, poultry and migratory birds

Source of H5N1/H7N9 spatial overlap figure: Many thanks to Dr Ricardo J. Soares Magalhaes, The Univeristy of Queensland.

The figure below, from the Letter I talked about yesterday, published by Wang and colleagues in Emerging Infectious Diseases, Vol 19(11) shows the Lake Tai region.

To clarify, the paper talked about an area of high risk of infection. It did not specify whether the risk was due to exposure to poultry or wild birds. The issue of visiting LBMs and exposure to poultry and their excrement was secondary to the finding of overlapping regions of human cases and proposed region of greater risk.

Having said that, it appears (and these are all web sources so take them with a grain of chicken salt) that a domestic breed of pig and poultry may be farmed around this lake, one of China's largest fresh water bodies containing dozens of islands. Water quality and its levels algae and contaminating animal and human waster have also been issue for the lake, which supplies drinking water to approximately 30-million people in cities within Jiangsu and Zhejiang provinces. 

Expansion of poultry farm seems to have been stopped, if not contracted, and better management of aquaculture and livestock and poultry wastes has been recommended.

However, wild waterfowl as well as duck and goose farms seem to remain around the lake according to at China Travel and the maps at the bottom of this post. There seem to be monkeys and caves (bats?) too and as you would expect, this is also a thoroughfare and winter stopover for wild birds. It's also about 380km north-east of Poyang lake, another important wintering ground for wild waterbirds and one that is known to harbour influenza viruses.

• A study by Duan and colleagues  of >11,500 cloacal swabs from migratory ducks and >36,400 swabs from sentinel ducks identified 90 and 1,681 influenza isolates, respectively during 2002-2007. he sentinel duck seasonal influenza peak overlapped with the migratory duck over-wintering period. Major haemagglutinin (HA) types included H3, H4, H6 and H10. H5N1 was detected during 2005. H7 was also found. The major neuraminidase (NA) type was N6. N9 was not identified. These combined to form 27 HA/NA antigenic combinations.

You can see the overlap between areas of human infections with influenza A(H7N9) virus (green circles; area bounded in blue and green) and H5N1 (red triangles; area bounded in pink).

Below, I have excerpted 2 maps from William Wint and Timothy Robinson's document, Gridded Livestock of the World 2007 written for the Food and Agriculture Organization (FAO) of the United Nations¹. They show using livestock data modelling (which is described in the full document) that there were certainly lots of pigs and poultry in that region in 2007. 

So, the 3-Ps are in place: People, Pigs, Poultry probably kept freshly supplied with out-of-town influenza by migratory birds. 

1. FAO. 2007. Gridded livestock of the world 2007, by G.R.W. Wint and T.P. Robinson. Rome, pp 131.

H5N1 did not transmit easily between humans in the wild...

Hat tip to @Laurie_Garrett and CIDRAP

Despite wearing next to no personal protective equipment (5% of 419 contacts used a mask, face shield, gown or gloves) and coming into contact with sick or dead poultry (12% of contacts), 85/87 household members and 332 "less close" contacts of 23 influenza A(H5N1) virus cases did not show any significant sign of antibodies to the virus, a study published in PLOS|ONE by Bai and colleagues noted.

Only 2 (0.4% of all contacts tested) were defined as infected by H5N1  during the study period of 2005-2008, on mainland China. 

The study used both haemagglutination test (antibodies in the patients sera bind horse red blood cells together giving a distinctive pattern) and micro-neutralization (presence of specific antibodies in a sample prevents a lab stock of virus from infecting a cell line-amount of virus can be determine by making dilutions of  the sample and comparing to a sample with no antibodies to the virus). When they had a single serum, the authors used:

• A neutralizing antibody cut-off titre of ≥40 children (<14-years of age)  with a haemagglutination titre ≥40.
• A neutralizing antibody cut-off titre ≥80 for those aged 15-59-years with a haemagglutination titre ≥40.

For acute and convalescent sera pairs positivity to H5N1 was defined as:

• A ≥4-fold rise in neutralizing antibody titre between acute and convalescent sera
• Convalescent sera needed a neutralizing titre of ≥40 for children and ≥80 for adults, or a haemagglutination titre ≥40

There were a few more positives below these cut-offs.

While genetically altered H5N1 can be made to spread among ferrets in the lab, it seems that some years ago in the wild, H5N1 had a ways to go before it could spread efficiently between humans. That's a good thing.

Resp virus causing gastro but little respiratory symptoms...

Hat tip to Secret Squirrel D for this.

To add to my first two post's today,this paper by de Jong and colleagues in the New England Journal of Medicine details a 4-year old male (4M) who presented with a 2-day history of fever, headache and diarrhoea which after admission progressed; cough, then to coma and death.

4M was found to have systemic influenza A(H5N1) virus infection (viable virus was isolated from cerebrospinal fluid, throat and rectal swabs and were RT-PCR positive).4M and his sister (9F who died 2-weeks previously but had no diagnostic specimens collected) were diagnosed with acute encephalitis.

Chest X-rays were normal and 4M exhibited some lung sounds suggestive of infection after transfer to a paediatric referral hospital and he went on to respiratory failure.

This highlight my earlier points: respiratory viruses could spread from gastrointestinal disease and encephalitis has a lot of causes in addition to the usual suspects.

H7N9 more transmissible than H5N1.

A comment in BMJ by Jane Parry stresses the use of closing live bird markets (LBMs)to halt human H7N9 cases and adds that this virus is more transmissible to/between humans than is H5N1 (45 human cases confirmed in China since 2001 vs H7N9's 132 but in only 5 weeks). 

I wonder how related this is to H7N9 being a low pathogenic avian influenza (LPAI) in birds compared to H5N1's highly pathogenic course in birds. H7N9 can, in theory, stealthily sweep through flocks without setting off veterinary alarm bells (human cases acting as the "sleeping" canary in the mine) whereas H5N1 triggers alarm and can be better controlled by early culling. 

So far 47,8000 samples from 1,000 farms and poultry markets have been been tested and only 39 have been H7N9 positive.

Swapping H1N1's PA and NS into H5N1 flu helps H5N1 spread.

A new study by Hualan Chen's group at Harbin Veterinary Research Institute published in Science reveals that avian influenza A(H5N1) can acquire mammalian transmissibility if it acquires the right segments of human influenza A(H1N1). This was not a mutation study, but a whole gene segment-swapping study (creatingreassortants). 

This work was conducted in mice (for lethality studies) and guinea pigs (for transmission) and yielded different results compared to similar studies using ferret models, which did spread via aerosols or droplets.

Some have expressed their dismay at the study itself. It seemed to fly in the face of the many concerned scientists who wrote at length after similar studies, classified as 'gain of function' virus research, were described using mutations in flu genes, instead of entire gene segments. "Play" was pressed on the voluntary pause in highly pathogenic avian influenzavirus H5N1 research in Feb 2013 after a list of uber-expert flu researchers declared that sufficient time had passed, explanations, debates, reviews and revisions had occurred. 

Those scientists suitably supported and qualified to do so should get back to the bench in order to better prepare humanity for pandemic influenzas of the future. Timely. There were 3 Chinese affiliations as signatories on this article including Harbin Veterinary Research Institute's Prof Hualan Chen.

Whatever you think of this study, the outcome is a very sobering reminder of what chance could be capable of in those locations where animal and human flu viruses co-circulate. 

Fit and better-transmitting viruses can result.

Influenza virus transmission.

An interesting blog post from 2006 by Revere on some aspects of what H5N1 virulence (in terms of disease severity), transmission and preconceptions. 

Do we put too much stock in believing that recently emerged viruses eventually settle in to their new hosts, seeking a perfect balance between virus replication, transmission and host mortality? 

In other words, do viruses adapt over time so that originally severe infection outcomes (like pneumonia) become mild illnesses (like the common cold or just feeling a it crook). 

There may be some parallels to be drawn with H7N9 as we continue down its path. 

Or perhaps H7N9 has been adapting to humans for longer than we think?