Thanks to Mike Coston for the heads up on the WHO report resulting form the Influenza-A-team's Joint Mission to parts of China (18/24 April, 2013). They have a nice graphic on pg17 outlining the denominator issue. I've adapted for the H7N9 page.

And it would seem that the current outbreak as a whole is largely over as well. Without specific details its hard to place when the 1 new case and 4 deaths (among existing positives) occurred that were announced earlier this week in the official update from China. My own weekly numbering is from the 31st when the WHO was notified, which is slightly off kilter with the weekly report dates from China. So what can I comment on? Well, 2 provinces (Shandong and Jiangsu) and a municipality (Shanghai) have wound down the level of their emergency response. No new cases there for some time.
So we're left wondering what sparked this strange spread of human infection with a virus that is almost identical in its HA gene sequence from that found in birds and the environment during the outbreak (>99.5% amino acid identity; about 88% with H7N9s found in the US and Guatemala years earlier). The strangest part is if it spread from birds.....why weren't vendors, traders, butchers and truckers in the closest of contact with the suspected hosts more commonly infected and reporting to hospital? Are they just too young? Too healthy? H7N9 infection seems to lead to severe disease most of the time. Did they have specific or cross-reactive immunity? Was the underlying disease factor the most significant issues for severe illness? We read in the literature that contacts mostly had no severe disease.
I guess we now wait to see what wild bird testing yields. Could wild bird populations already have H7N9 in them and be circulating in the Mediterranean and Australasian flyways?

Having killed the 3 humans its infected since it was first isolated in 1996, the first recorded case of ABLV in a horse in the state of Queensland, Australia has been quickly acted upon.
Humans in contact with a horse that was put down last Saturday (11.05.13)have been offered treatment after test results on Friday 17.05.13 identified ABLV. There are 20 other horses on the property. This was the second horse euthanased from the same property although the first horse was not subjected to any testing. ABLV, 1 of 12 species of the genus Lyssavirus, family Rhabdoviridae, has been found in several bat species.
Rabies immunoglobulin can halt severe disease along with a course of rabies vaccine infections

I've added a new graphic to the H7N9 page that compares the important cleavage site in the immature HA protein among influenza A viruses, including H7N9. This shows that H7N9 is more similar to seasonal influenza viruses in this area-low-pathogenic viruses rather than high pathogenic viruses. The latter have a multiple basic amino acids at the cleavage site making them a target for proteases located throughout the body rather than just in the human respiratory system and bird gut.

Ouch. Anyway, before you finish typing or reading that coronavirus outbreak story make sure it doesn't use the names human betacoronavirus 2c EMC, human betacoronavirus 2c England-Qatar, human betacoronavirus 2C Jordan-N3, betacoronavirus England 1 or (especially the short-sighted) novel coronavirus (NCoV)-they are so, like, yesterday's name. Prof Raoul J. de Groot and a host of coronavirus (CoV) experts, comprising the CoV Study Group, have penned a scientific article that has just been accepted into theJournal of Virology. The name of the newest spiky little killer is officially Middle East Respiratory Syndrome Coronavirus or MERS-CoV for short. New variants (the same virus detected in other people/animals) will be given a name using the influenza virus naming system:
Virus name host/country of virus detection/variant identifier/year detected e.g. MERS-CoV Hu/Jordan-N3/2012).
That's as official as it gets anyway so this is how we should label it from here on in.
We're also avoiding calling it a human CoV until we know how humans get the infections. Since the virus is similar to a bat version one of many question is whether the cases all got it directly from bats (unlikely) or from human contact with another, intermediate, host. This builds on the media reports noted on 07.05.13.

The numbers rise again and "foreign specialists" have been hired(?perhaps invited) to help the Kingdom contain the spread of MERS-CoV. While human-to-human transmission is very likely occurring, sustained transmission (going beyond the immediate close contact, to their contacts and so on (see figure-circles represent a person; yellow represents spread beyond immediate and close contacts) it seems to be limited to close contact and perhaps long exposure.

I thought I might add a new bit to this bloggy thing I'm doing (6 weeks old and I'm changing it already). So, see below for the first "Stuff from the Literature" comment. I'll try and find a paper or two and break it into manageable chunks. As always, this is firstly an effort by me to learn something new, and secondly to try and communicate that to others. It won't be definably regular.

Yes, ducks do mount an immune response even to "low path" influenza virus infections. Dabbling ducks (those that feed near the surface rather than diving underwater) are the natural reservoir for Low Pathogenic Avian Influenza (LPAI).
LPAI viruses circulate among wild birds, especially Mallards, all the time. As Jourdain and colleagues pointed out in 2010, mallards are not obviously affected by experimental infection - for example they don't lose weight or cease moving around and they don't show any other clear signs of disease (very slight temperature rise for 2-days) after infection. However, the authors note other studies identifying egg production problems and also the importance of further studies on wild populations as opposed to a small number of birds.
Perkins and colleagues showed that ducks, sparrows and gulls tend to control virus replication differently from chickens suggesting that the ducks may have a better ability to mount an immune response. A weaker (less antibody and shedding) reinfection with the same H7N7 virus was still possible even in the presence of an antibody response to the first H7N7 infection. Reinfection by a different virus subtype (H5N2) seems to have been blocked by the antibodies made to initial infection by H7N7; so-called heterotypic immunity (cross-protective immunity to a different viral subtype).
Volmer and colleagues reported in 2011 that ducks infected with an LPAI mount an interferon (IFN) response in their guts. The cells (enterocytes) of the duck gut is where most flu virus replication occurs and its from here that most of the virus shedding originates. This study found the gut was inflamed and that there was some cell death. So, not at all like the respiratory disease the human host experiences. In the cells lining the intestine, the authors found lots of myxovirus-resistant (Mx) gene activity; diverse genes in birds, which may be especially well adapted in mallards to control influenza, that are key to the earliest immune response to virus infections (also important in humans) and particularly effective against influenza virus. Mx proteins trap and redirect flu virus nucleoproteins.
In particular, a Type I (antiviral) IFN response was detected. IFN-g (gamma) gene activity was up, activating important immune cells (T cells or natural killer cells), important for flu vaccines in poultry and humans.
Swayne provides an excellent review of the vaccines used in birds to moderate H5N1 disease ('fowl plague'). The formulation, use and effect of these vaccines are as varied as the influenza viruses themselves. China leads the field in the use of reverse genetics to create the contemporary flu viruses carrying the most relevant immune stimulating (antigenic) bits.

The tally rises to 36

Reports suggest 19-20 deaths now with 2 new cases, both healthcare workers, reported by the Saudi Ministry of Health. They release notes that "citizens, journalists and interested" can get information from the MOH website which is updated "first hand". Unfortunately the translator can't translate fixed graphics written in Arabic and used liberally through out the site, so look to click on the pretty coronavirus icon if you want to be updated and then go to the press releases. Apparently the translator also has some issues with Arabic numbers...or else the press reports are from 1434. [UPDATE 16.05: Please pardon my ignorance of the Islamic calendar. As DG has pointed out to me this morning, it is indeed the Hirji year (AH-anno hegirae) of 1434, part of what the Gregorian/Western/Christian calendar calls 2013. No offence was intended.]

As described by EpiVax Inc. previously and now described in a scientific paper in Human Vaccine and Immunotherapeutics, the H7N9 virus is not just stealthy in poultry, its also hard to find in humans. There is concern over whether it will be possible to produce a vaccine that will be effective against a virus with such low predicted immunogenic potential. An H7N9 vaccine, without the right concoction of boosting additives, is predicted to be a poor trigger of our immune system's response to it. This is because H7N9 doesn't have as many T cell epitopes as other flu viruses...these are the bits recognized by important white blood cells that fight infection and shorten disease. Because of this human 'stealth' capability, it may evade the human response. This has obvious implications for disease (more severe if the host cannot shut the virus down quickly) and may also have implications for the usefulness of existing serodiagnostic (virus-specific antibody-detecting) assays.

This weeks case report (May 6 to May 13) describes the discharge of 15 new existing H7N9 cases, four deaths and a new case in Jiangxi. No further details to be had in the Ministry of Health release.

Week 6 was relatively quiet although more fatalities occurred than in Week 5 (3 vs. 2). No new H7N9 cases with a date of onset in Week 6 occurred, and there were only 3 in Week 5 so confirmed case reports have dropped right back. Tomorrow is "tell-all Tuesday" (well, I'd like some more date data this time around) in which we hope to get a snapshot of cases over the past reporting week in China. No sustained human-to-human transmission, no new provinces or municipalities reporting cases. Reports suggest that with summer coming H7N9 cases will drop off. I'm not convinced given of that H1N1pdm 2009 peaked in the US during the warmer months - I think an emerging flu virus may well be able to buck the trend of seasonality. However, I suspect that seasonality is heavily influenced by virus:virus interactions in the community so it may depend on what other respiratory viruses are co-circulating now and in the coming weeks.

A belated congratulations to my fellow Group Leader here at the Qpid lab, A.Prof David Whiley on the implementation and media coverage of his sensitive real-time RT-PCR to detect H7N9 for implementation by Pathology Queensland's microbiology laboratory. It targets the matrix gene segment, which as far as we know, is unique among the H7N9 assays in use to date.

VDU has had some FTP issues with its server so no updates across the weekend. The University of Queensland quickly fixed the problem today.

As part of my crippled USS Vengeance-like crash course into the workings of influenza viruses over the past nearly 6 weeks, I've been doing some reading. A Science Policy Forum article I'm skimming through tonight, from Lipsitch and colleagues in 2012, makes a nice comment: We contend that predictions about how particular influenza strains will behave in humans or, even more important, how they will evolve, remain highly speculative. While this was written with H5N1 as the subject, it is clearly applicable to H7N9. It nicely sums up my understanding on this late Friday evening as well! And who needs a colon anyway?

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.

Sampling of the environment in a Fujian market yielded another positive. There are now 52 such samples positive according to the Ministry of Agriculture

A study by Fournié in PNAS and colleagues looks at risk and H5N1 and live bird markets (LBMs) in North Vietnam. Such sites implicated in H7N9's diverse and rapid spread in South East China, notes the interconnectivity between markets using social network analysis. Some act as hubs, spreading poultry to others. Infection in a hub will more effectively spread virus to outlying nodes. A similar, older study of Southern China LBMs provides insight into the number of sites affected by hubs and the vast distances travelled by poultry (with the help of humans and vehicles) in this area. It unfortunately doesn't cover the South East, the H7N9 hot zone, but I presume the pattern can be extrapolated. The 2011 study, by Martin and colleagues, focuses on markets in the Yunnan, Guangxi and Hunan provinces. It shows travel on one of many routes extending 2,500km (Yunnan to Shandong) and the importance of risk reduction measures (for H5N1) including daily poultry cage cleaning and disinfection and manure disposal/processing.

A translated article suggests that hospital infection control broke down and may be a factor in transmission.

A French citizen has been isolated in an intensive care unit somewhere in Paris after returning to France from the United Arab Emirates. The health website of the Ministry of Social Affairs and Health (Le site santé di Ministère des Affaires sociales et de la Santé) cites the National Reference Center at the Institute Pasteur as having confirmed the MERS-CoV (HCoV-EMC) case. This is not the Kingdom of Saudia Arabia (KSA) for the geographically challenged among us (I've added a map to the , so the virus is active in at least two sites unles sthis case visited KSA as well.

That's how it was described to me by my esteemed colleague, the Editor in Chief of FluTrackers. For the past 5 week we've had fairly detailed data coming out of China about avian influenza A(H7N9) cases; dates, places, names, deaths, discharges., All these placed into the public domain and not just reported to Health officials through less public channels. Sure, I've griped about a missing number here and there in the past, but its not like I have a right to this information. Are these the data I'd like to see? No, I'd like to have seen prospective real-time RT-PCR-based (couple of assays targeting different regions) screening hospital outpatients, the community and including asymptomatic people, of all ages. I'd like to see serology on the vendors and those who frequently visit markets versus those who do not. And I'd like it all done yesterday. But that's flippant, and easy to say from my desk in my environment of instant gratification, some 7,330km away. Are these data from every single H7N9 case? Probably not, for a number of reasons. So, for some pure speculation. It just doesn't feel right. 130 cases spread over such a wide area, steep onset curves that suddenly halt, patents like Lee from Taiwan and others who claim no bird contact, so few severe cases among market vendors, evidence for asymptomatic and suspected clusters. 130 cases seems too low. More unreported cases may exist simply because we don't have all the results yet. Those may be coming down the pipeline. The time and effort to conduct screening and sequencing, collate data, cross-check and report results for humans and animals on the scale that is necessary to answer the questions being posed, is vast. China needs to juggle many other social and political issues around the reporting of deaths, illnesses and human-to-human transmission of this new virus. It has its own way of doing that. Most states do.
Nonetheless, scientists, policy makers, healthcare officials and vaccine producers (traditional and cutting edge) already have the information they need to get started on preparing for any future H7N9 pandemic.

• Vaccine seed strains have been circulated worldwide
• WHO influenza collaboration centres have positive H7N9 RNA controls for their RT-PCRs
• More RT-PCRs have since been developed to overcome the (not unexpected) deficiencies in first-generation assays
• Serological reagents are in use in China and in preparation elsewhere
• Key global health bodies have updated their pandemic plans
• We have estimates of incubation periods, clinical signs and symptoms indicating that severe acute respiratory disease cases look like....severe acute respiratory disease cases would be expected to look
• We know transmission may be happening between humans but inefficiently
• We know closing down wholesale poultry markets seems to correlate with a decrease in severe H7N9 cases in humans
• We've dusted off (ineffective) heat sensing cameras and (pointlessly) ill-fitting face masks again
• We have a good idea of what the wild host is (a bird...like it is for all influenza A viruses) just not evidence for which one or where it all started
• We've officially named our viral nemesis.

So all in all, we're not too badly off.
However Week 6, so far, has provided confirmation that publicly available case details have almost dried up.
The data we've had have been interesting and have allowed me to plot the detailed charts and graphs you've been viewing on the H7N9 page. Half of those views are from repeat visits. Today, my last hope faded for an update on those details for the recent 6 H7N9 deaths and the missing details on about 15 discharged patients. The WHO update had no new information in it at all. Perhaps other lists will be updated soon?
Here's hoping for some new data in the future, especially if that data should signal to the rest of the world that H7N9 has changed genetically, or a return of exponential rises in new H7N9 illness onsets such as we saw in Shanghai and Zhejiang. I think we have what we need to know that an H7N9 pandemic could emerge, but that one hasn't emerged yet.

While MERS-CoV (f. HCoV-EMC) cases have been detected in the UK (3-2 fatal), Jordan (2-both fatal), the United Arab Emirates (1, fatal) and Qatar (2) since April 2012, it has been the Kingdom of Saudi Arabia (22 cases-13 fatal) that is the current hot zone. These cases are from 5 different clusters according to the FluTrackers. The latest news paints a bleak picture. According to the Wall Street Journal, Al Moosa General Hospital is not the only hospital treating patients from the current outbreak. Given that human-to-human transmission has been noted for MERS-HCoV, this may nor bode well for containment.

It was an unusual move that apparently required "a great deal of effort to find a name that all parties involved could agree on". Avian Flu Diary reports on a ScienceInsider article noting that the Coronavirus Study Group will propose an entirely new name for the latest human coronavirus type that seems to cause respiratory disease in humans and belongs to a new coronavirus species. Usually the International Committee on Taxonomy of Viruses (ICTV) doesn't fiddle around with naming below the level of species and the new human coronavirus type seems to be part of a group of viruses (including bat coronaviruses) that together will likely form a novel species. Do the bat viruses also cause respiratory syndrome in humans...or other animals? There is likely to be some (more) confusion caused by this name change, and it is very possible that the press will not strictly adhere to the new name any more than the old one (an argument that supports either side of the debate).
So far the virus has been called novel coronavirus (NCOV-a name that never should have stuck-what do we call the next one....more novel CoV?) and in the scientific, peer-reviewed literature, HCoV-EMC after the laboratory that characterized the virus (Erasmus Medical Center). Still, its only about 8 months since we learned of the first case subsequently attributed to this virus in Sept 2012 (the patient presented in June 2012). How big could the body of literature be on EMC at this point? Apparently its 23 papers strong according to PubMED.
The new name for the disease and the virus group will change to MERS-CoV (Middle East Respiratory Syndrome). It will next go before the ICTV) for ratification.

Based on the Liu et al. Lancet paper, this new graphic shows a possible series of evolutionary steps leading to the human-infecting influenza A(H7N9) virus.

Large amounts of viral RNA were detected in 2 sputa and 1 throat swab collected from the imported Taiwan cases according to a recent Lancet letter. While early throat swabs (days after fever onset)and a chest X-ray did not indicate H7N9 infection, later in the disease course (11-13-days after onset of his 3-day fever) signs and virus became more clearly detectable. This case may suggest shedding is possible well before incapacitation and not long after a clinically indistinguishable episode of fever begins.

H7N9-associated deaths now listed at being at 31 (last count 25-26). Details for 6 cases are limited but appear to have come from Anhui (1), Zhejiang (1) and Jiangsu (4). A new 9M case, apparently mild (fever, fatigue, diarrhoea), also reported in Fujian province - he's already discharged - found positive "retrospectively". Two items of interest here: (1) The delay in detecting the virus may simply reflect the lengthy average laboratory turnaround time (9d); (2) it seems the swabs were from the upper airways (throat), a site that has proven problematic for accurate testing so far. If sustained human-to-human transmission was an efficient means of spread....
Total H7N9 cases listed as 131 (likely to exclude Taiwan case [imported from mainland] and asymptomatic child case) and discharged patients now number 42.

HCoV-EMC cases have risen by three to a total of 30 (FluTrackers are running a nice tally). The latest severe acute respiratory illness (SARI) cases occur in Alhasa and comprise a cluster of 13 cases. This is becoming a rapidly developing situation given that 18 cases have died overall. The spectre of underlying disease lurks here as it does with H7N9 but the evidence for human-to-human transmission seems more clear than for the flu. No host and little patient detail are also features of this outbreak.

Esteemed virologist Professor Malik Peiris believes the drop in H7N9 cases linked to the shutdown in wet markets, underscores the impact of the large, fast-moving and diverse poultry trade in the south east of China. Wet markets have closed in all affected areas and cases have subsequently dropped. Prof Peiris noted that a study of human blood samples is underway. This will shed light on the proportion of cases, if any, that did not have severe enough disease to put them on the hospital radar or to lift them above the "noise" of normal upper respiratory tract infections, other respiratory diseases or pollution-exacerbated lung problems. This study will provide a key piece of the H7N9 puzzle.

Canadian Food Inspection Agency is not overly concerned that Canadian animals are at risk of intermingling with contaminated bird species.

The entirely confusingly named Australian Vaccination Network (next month they will face a court battle to retain their misleading name), actually a cabal of anti-vaccination advocates, has encouraged parents to avoid vaccinating their children and do not rely on your GP's opinion. You know, those experts in community ills who often have there own children and have trained and worked for over a decade to ensure the community is healthy.
Instead, consult books, especially those penned by fringe writers who may have not knowledge or expertise in the science and medicine of infectious disease whatsoever.
As Australian Medical Association president Dr Steve Hambleton suggested, you can obtain facts from the Immunise Australia website and there is an excellent publication, produced by the Australian Academy of Science, The Science of Immunisation: questions and answers. The documents on these sites are fully up front about their being some risks, its just that these risks are generally very minor things like redness, soreness and swelling - probably nothing like that bruise little Johnny is sporting from school today or that bite Jenny inflicted on herself when she bit her own cheek at dinner last night. In comparison to acquiring the unadulterated disease against which these vaccines protect, its nothing to be unusually worried about.

A new chart on the H7N9 page that puts key events on a timeline.

We start week 6 of the H7N9 outbreak with confirmation...or new test results....that H7N9 (not some other H7) is indeed among the poultry in Guangdong province, which is adjacent to Hong Kong. One sample was positive from s wholesale market in the city of Dongguan, which had previously (see post on 28.04) been positive for an H7 virus that was not H7N9. Previous testing of 542 poultry workers (method unknown) in Guangdong had not identified H7N9 infection. As ProMED noted, in "AVIAN INFLUENZA, HUMAN (71): CHINA H7N9 UPDATE", this makes animals sentinels, instead of humans, for H7N9's presence for the first time during this outbreak. Shows the benefits of screening for virus without relying on symptomatic presentations hmm?

We finished Week 5 with astonishingly few new notifications and a lot more difficulty finding key dates for hospitalization, death and discharge. For example, a 55-year old male named Jiao from Hunan province has been variously cited as being the 25th or 27th death associated with H7N9. No-one seems to have a name for the 26th death. Just 1 disease onset and 2 deaths deaths during that period (see the many charts on the H7N9 page) making it the least fatal week of the outbreak. A total of 26 cases have been discharged from hospital (see Case chart on H7N9page, with perhaps another 9 unnamed discharges from Zhejiang. No new cases reported from Shanghai, Beijing, Anhui, Jiangsu, Henan or Shandong. Lab confirmations for cases with dates of onset preceding Week 5 appeared for Jiangxi, Fujian, Hunan and Zhejiang. Considering how steep the rate of confirmations was for Zhejiang in particular, the drop off is quite remarkable. The wet market closures seem to be the most popular factor in the decline of new (severe) human cases but there is still no word on prospective PCR screening for H7N9 among non-severe cases or among those without chronic underlying conditions.
So, as far as we know, pneumonia remains the most frequent indicator of H7N9 infection and that seem to be among mostly males with a constellation of underlying disease and infection.
Week 5 saw a flurry of peer-reviewed scientific papers emerge. Some better-defined the clinical cases, other reported risks based on what we know from past influenzaviruses and others described the avian and genetic pathways for the parent and grandparent H7 and N9-containing viruses that seem to lead to the creation of H7N9. Intriguingly, there are still very few reports of H7N9 in the ducks, chickens and wild birds proposed as the hosts from which humans catch the virus.
While markets have been found to contain H7N9-positive birds, there are remarkably few human cases among market vendors or those working with the feather plucking machines (another proposed transmission route proposed during Week 5). Could vendors have pre-existing immunity?
So another curious week with plenty of questions raised, but cases and deaths declining.

FluTrackers, often the case as I've learned during the past 5 weeks, is the first to have all the info on the total 27 cases of infection by the newest human coronavirus ...to date. Nice graphic too.

The WHO has released a document about its potential candidate vaccine viruses which are expected to available shortly.

VDU's Editor asked to comment on recent WHO statement about H7N9 severity on BBC World News' Newsday show with Rico Hizon. Video currently viewable at the Australian Infectious Diseases Research Centre at The University of Queensland.

The US CDC publish a wrap-up in an early release issue of Morbidity and Mortality Weekly Report.

Anew paper in by J. Han et al. Emerging Microbes and Infection concludes that neither 2 vendors in an H7N9-positive poultry market visited by the H7N9-positive patient (our Case#10, also studied in recent Lancet article) nor his close contacts, were WHO RT-rtPCR positive. So picking up H7N9 is certainly not a frequent thing. Also supported by the few cases that have been identified considering the population in these areas that move through and interact with birds and the markets. Also, once you have it, transmitting H7N9 it seems to be an infrequent event.

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 (creating reassortants). 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.

An interesting document that compares the effectiveness of some different diagnostic PCR methods for use in H7 or N9-based flu diagnosis. It seems to show that in a couple of instances H7-specific or H9-specific molecular methods will fail (1:10,000,000 is a pretty extreme dilution) to detect H7N9 at low levels while some assay fail to amplify the intended target altogether. This sort of assay variation is pretty commonplace when you compare different PCR designs for the same target. Its a major reason why everyone prefers to design their own assay; each are convinced there's is the best. From this document, the people behind the OFFLU (FLI-H7) assay happen to be right. How these data relate to viral load in the human (and animal) samples these may be/have been used on is unknown. This sort of variance may contribute to negative throat swabs in H7N9-cases subsequently proven positive using lower respiratory tract samples (e.g. sputum) in which the viral load is presumed to be higher.
OFFLU: a network of expertise on animal influenza established jointly in 2005 by the World Organisation for Animal Health (OIE) and the Food and Agriculture Organization of the United Nations (FAO) to support and coordinate global efforts to prevent, detect and control important influenzas in animals.
CNIC: Chinese National Influenza Center

Media reports, FluTrackers and Avian Flu Diary describe five recent deaths and two other critically ill cases under close watch in the Al-Ahasa region of the Kingdom of Saudi Arabia, linked to infection with the newly identified human coronavirus HCoV-EMC. This virus was first isolated in September 2012 from a 60M (60-year-old male) with pneumonia and renal failure in Jeddah, KSA. Further evidence for bats as a major source of CoVs came in a recent study in Emerging Infectious Diseases. Yang and colleagues identified a novel CoV from each of 2 bat species. The newly identified betacoronaviruses (betaCoVs), Bat Rp-coronavirus/Shaanxi2011 and Bat Cp-coronavirus/Yunnan2011 (rolls of the tongue doesn't it?) were not that closely related to human betaCoVs but resided in the bat verison of the SARS-like COVs.

A report from the Ministry of Health describes 19 cases during the period spanning from April 25th to May 1st. There are also 2 new deaths (total now at 26)- but no details provided for any of the cases. Stay tuned next Thursday for more.

A new article just published at the Lancet describes a detailed genetic analysis of four H7N9 virus sequences, in the context of all likely contributing influenza virus sequence. The resultant virus' HA and NA genes may have been contributed by migratory birds a year prior to acquisition of internal genes from poultry influenza viruses. Since its emergence "several months ago", H7N9 has divided into at least two different groups (lineages). One strain (Shanghai/1) has signs of oseltamivir resistance.
With thanks to Prof. Ross Barnard, University of Queensland for helpful contributions.

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?

US CDC have made available their CDC H7N9 rRT-PCR for use on suspect cases (see interim guidance for defining cases) and in combination with their existing Flu rRT-PCR Dx Panel ("r"=real-time; "Dx"=Diagnosis/Diagnostic) after FDA support through an Emergency Use Authorization.

A new scientific article in the Chinese Science Bulletin talks of there being a high risk of a continuing and severe outbreak of H7N9 in the future. It extrapolates from the first 91 cases (today's case count is at 128), using a mathematical formula that could be heavily influenced by the appearance of decent numbers of mild cases - should testing find mild cases of course. Given the variation seen among many aspects of the different influenza viruses of recent years, I'm inclined to maintain my wait-and-see attitude a little longer before stocking the pantry.

No evidence for human-to-human (h2h) transmission though. No evidence against it being the cause either of course. See my comments from the 18th regarding the first reported H7N9 case and family cluster. They still apply. Incubation time being surreptitiously the same as the (presumed) incubation period means nothing. Two people completely geographically isolated could have the the same gap between onsets and the second case would obviously not have been infected by the first. Even if the sequences of the two viruses are very similar, that does not prove h2h transmission. Chances are that many of the H7N9s will have very similar sequences reflecting that they have originated form the same animal (or human) source at some point.

What does this mean? It doesn't mean the sky is falling - contacts, by their very nature share things. In a family you often share (inhale, have land in your eyes etc) aerosolized (virus-laden) droplets as well as common surfaces contaminated by with those aerosols, when you have an acute virus infection. Coughing and sneezing do that. But you also share common tasks. There is so far no clear evidence of direct Dad to Son (or Son to Dad) transmission here (there is a timing issue that is intriguing)- the father and son may have simply shared the same airspace (I think its pretty safe to say this is transmitted through the air in some form) with an animal host during contact, handling, butchery, cleaning etc. Despite testing of animals to date finding very few have detectable H7N9 infections.

crofsblogs reports on a news article quoting the Hunan Provincial Health Department will be setting up isolation wards in medical institutions to cater for fever and H7N9 influenza cases (allowing for interpretation of machine translation). This suggests to me that Hunan is expecting more cases and that they might be worried about human-to-human spread.

And what a week its been. There are now 122 H7N9 lab confirmed cases including an asymptomatic boy and an imported (to Taiwan from China) case. The numbers have risen from around 108 to 125 and the deaths from 13 to 23. More people have been discharged from hospital as well and the Case Fatality Rate/Ratio is sitting fairly steady at around 19%. A comment was made that official case reports would only appear once per week, but Provincial/Municipal numbers seem to still be coming out. Much has been made about age and sex. In the cases this past week, older males have borne the brunt of H7N9 infection.
Holes keep appearing in the amount of data coming out about each patient and as I write this (its 10pm and FluTrackers have already added more cases) there are at least 14 missing dates of onset, 54 dates of hospital admission (granted, some were not admitted, but only a small number), 2 dates of discharge, a number of occupations and the date of 1 (?Jiangsu) fatality in a state of flux. Despite that, so far no new cases have been reported, that have a date of onset in Week 4. That will probably change with newer provinces coming online and the diagnostic lag still being 9 days on average (having remained at 8-9 days since Week #2).

A 64-year old woman was the first case reported for the province of Hunan (1,km south-west of Shanghai, population >65,000,000). This province is adjacent (west) to Jiangxi, now reporting 5 cases (2 added tonight). There are now 10 provinces or municipalities having reported positive cases of H7N9 originating from within their borders.

Destruction of poultry in Guangdong province, the last province between Hong Kong and an inexorable march of H7N9-infected eastern Chinese provinces, has some FluTrackers noting that H7N9 may already be in Guangdong. UPDATE: An H7, but not H7N9.

This completes the provinces surrounding the highly active Zhejiang province.

..and I say WOO-HOO! This is an important step forward. Looking among the currently healthy for past exposure to H7N9 will tell us a lot.
These results will start to unravel how long this virus has been circulating in Shanghai (it takes a couple of weeks to "seroconvert"; show a jump in specific antibody levels in the blood; looking in any older paired sera repositories would be great too) and also how many cases, beyond the one child so far reported, of moderate, mild or asymptomatic infection there could have been. Increasing that denominator is a great way to put the ability of H7N9 to cause severe illness in much clearer perspective.

Despite contact, and some confusion over whether they were or were not wearing personal protective equipment, they are H7N9 negative. So the upper respiratory tract infections (UTRIs; acute signs and symptoms including headache, perhaps a temperature, runny nose, sneezing, cough etc) they manifested after being in contact are due to another virus. Might be interesting to know which one(s). Presumably Taiwan already screens for whatever it is as part of a standard "respiratory virus panel". Thanks to ClaireW for the link.

Well that will let the guys at FluTrackers get some more sleep. Mike at Avian Flu Diary (who could probably do with some sleep too) notes it might not have a real impact on provincial reports but time will tell. The info is nestled at the bottom of this report.
This is a real shame for the public who have been getting access to some great real-time data break-downs, assemblies and interpretations from the flublogians.
Realistically, its not like we're entitled to these detailed data from China. It all takes work (and workers) to compile, release the number and organize and hold the official press conferences etc...but in the age of "always on" and instant internet gratification...I think we feel that is how it should be.
We would feel entitled to the information if it were a story about a terrorist act or the latest comings and goings of a public figure or personality, or sports scores. Its been nice to see something as important as the emergence of a new human pathogen receiving the attention it has...at least so far.

In an excellent new article in the Lancet, Chen and colleagues explain testing (sensitive real-time RT-PCR for M, H7 and H9 targets; culture on MDCK (canine) cells to grow virus) describing result from throat and sputum samples from four patients
They associate human cases directly to epidemiologically linked chickens (also tested quail, pigeons and ducks) samples from "wet" market (traditional live animals with on-site butchery - water used to clean up).

Given its proximity to Zhejiang its not too surprising that a case has been reported here-still to be confirmed by central testing. However, I don't know of a provincial/municipal announcement that didn't get confirmed so the odds are good that a confirmation is forthcoming After a quiet yesterday, Zhejiang also has a couple more H7N9 cases to report.

Is the closure of Shanghai's wet animal markets to thank for the precipitous drop in H7N9 cases from Shanghai from around mid-April? Back in 13.04.13 I mentioned we still had a few days to see if there was any impact based on the diagnostic testing lag of 10-12 days. Dr Kelso of the WHO influenza-A team thinks the drop and the market closures could be linked.

Apparently the 53M was also hepatitis B (HepB) positive as were 2/3 cases described in detail in the recent NEJM manuscript (see H7N9 page). Is there an association between HepB virus/viral disease and H7N9 or are these co-detections just coincidence due to high prevalence of HepB infection in China (suggested here)?

The first case of H7N9, has been reported reported in Taiwan marking its first known departure from the borders of mainland China. It seems that the 53-year old businessman imported it from somewhere on the mainland - he visited Suchou city in Jiangsu province, traveling out via Shanghai. He reportedly did not have any live birds or poultry.
There is now a risk of new cases emerging from close/regular/healthcare worker (HCW) contacts (n=138) he had (also also those during travel although he was pre-symptomatic and possibly not shedding), in the 3 three days he spent in Taiwan before showing signs of illness and at the medical facilities where he visited and was eventually admitted. If human-to-human transmission can happen, this will be the first chance to see it spread under the auspices of a different government. Four HCWs have cleared the suspected 7-day incubation period without symptoms while 3 HCWs have "developed" upper respiratory infections
The patient did not seem to respond to Tamiflu but his infection was well advanced and beyond the recommended 48-hour commencement time (Tamiflu was started 16.04.13, about a week after first symptoms). His condition on 20.04.13 required intubation to manage respiratory failure
The only upside to this "release" is that we may see and hear about some prospective testing which is sorely needed. Thanks to ClaireW and Jason Gale for the heads up.

Three HCWs who looked after the first H7N9 exported case have developed upper respiratory tract(URTs) infections somewhere during the 15-days between illness onset and lab confirmation. It is well worth noting that H7N9 is not the only virus that can cause URTs.
There are over 200 endemic human "respiratory viruses" that have been associated with URTs including the rhinoviruses (160 of them alone), coronaviruses, adenoviruses, enteroviruses, parainfluenzaviruses, influenza viruses, metapneumovirus, respiratory syncytial virus and bocavirus. Working out what causes a patient's URT is a challenging task, especially when more than one of these viruses can be detected by PCR in a patients airway sample at the same time.
Differential diagnoses (testing for all the things that may cause the same clinical appearance) is interesting in times of an outbreak. Keep an eye on these HCWs - they could be an important canary in the dark H7N9 mine we've been stumbling about in so far.

Well of course that was going to be the quote picked up by the world's press from comments made by WHO Assistant-Director-General, Health Security and Environment, Dr Keiji Fukuda.

used in a couple of charts on the H7N9 page. This uses numbers based on very limited testing, publicly available data, recovered case numbers or understanding of the acquisition, transmission and clinical presentations associated with avian influenza A(H7N9) virus. It is very early days yet however I think this number gives you an idea of our understanding at the moment. It will undoubtedly change in the coming days, weeks and years. To be pedantic, the CFR relies uses the number of discharges/recovered cases as the denominator for the CFR. However, that will sensationally inflate the result. The CFR is often considered most useful at the end of an epidemic/pandemic, but less so when data-in-hand is limited such as during the early days of many outbreaks. Keeping in mind that some will take the CFR and multiply it by the world's population as an estimate of how many would die if the virus reached pandemic levels, I don't believe that approach is the best way to present the CFR metric for the emergence of a novel virus (usually first identified by the worst of the clinical presentations that will eventually be attributed to the virus). You won't see that usage on VDU, you will see the "rolling" version though. The US CDC definition is useful here.

I wrote about this on the 22.04.13 but forgot to mention that there are no accompanying descriptions of the societal roles of males and females in these areas, or in general. The skewing may reflect a bias towards the males simply because they could be more involved in activities that increase their risk of exposure to the influenza A(H7N9) virus host or its environmental source.

"The primary focus of the investigation is to determine whether this is in fact spreading at a lower level among humans. But there is no evidence for that so far except in these very rare instances," said the WHO panel.
So presumably there is no signs or symptoms of disease spreading within these clusters. It is remains unclear from this visit whether the spread of the virus can be ruled out among these cases. Realistically (and pedantically), its very likely that the virus entered the airways and eyes of close contacts during sneezing, coughing etc. It just didn't cause obvious signs or self-reported symptoms of disease as a result of that challenge. Presumably the virus lacks something when replicating in humans that it has when coming from the suspected animal source, which allows it to cause disease in humans. Or that other theory - it can infect humans and cause mild and subclinical disease.
The quickest way to resolve this question, a very important one for short-term and future containment of the virus, is to use PCR-based lab testing of contacts; look for virus in eye and upper airway swabs and, for a little bit, forget about being led by symptomatic illness alone.

We are reading much about the older than expected ages of those infected by H7N9 (current average case age of 58 years). Why? One school of thought is that the elderly have weaker, or perhaps "less experienced" immune defences. But there are many other risk factors for severe complications arising after influenzavirus infection including heart and other organ disease, things which may accumulate with age.
This shift is not uncommon among pandemic influenzaviruses - those settling in to a new host. Also worth noting: (1) seasonal influenza is commonly regarded as having its worst impact in those over 65 years of age, (2) influenza A(H5N1) virus (the other bird flu) has had its biggest impact in pre-adults and young adults (15-39)(3) the influenza A(H1N1)pdm virus (swine flu) had its greatest impact on children and young adults and(4) influenza A(H7N7) virus was confirmed in 89 people (average age 30 years among mostly workers culling chickens), mostly mild, including conjunctivitis
That' a lot of diversity. Begs the question of whether we can predict too much about H7N9 until we've lived with it a bit longer.

The H7N9 graphs highlight that cases and deaths are occurring in males more than females. We often see more males than females in hospital presentations for acute respiratory illnesses. Why this is so is not known for certain.
Published research from Prof John Upham in Queensland, Australia shows a difference in the immune response to rhinovirus, the virus responsible for triggering most asthma attacks, between males and females in that females stronger response cleans up the virus, probably related to sex hormones. This was supported by research from Dr Scotland in London, United Kingdom who found that female mice had more white blood cells and that these were more effective and less over-reactive than male cells in responding to invaders.
Perhaps this can be extended to influenzavirus infections also.

The H7N9 outbreak welcomes Shandong, about 870km north-west of Shanghai and 420km south of Beijing; population >95,000,000, of whom 1 (37M) is now confirmed as being H7N9-positive. Given the rate of case reports from Zhejiang, I'm surprised we haven't heard from provinces further south such as Jiangxi or Fujian.

avian influenza A(H7N9) cases. Nothing has changed since yesterday, apart from Zhejiang province now surpassing Shanghai municipality in the total number of cases reported and accelerating (see chart below) in case numbers at a very rapid rate. Still, but a 3-digit number tends to sound more scary to some - so expect the media to carry big banner headlines akin to "100 cases of killer virus in three weeks!"

who linked to the Cases and Deaths chart.

Three weeks since the WHO was notified of the newly emerged avian influenza A(H7N9) virus. Today the case tally sits at 97 confirmation including 18 deaths, an asymptomatic case, three family clusters, no proven or sustained human-to-human transmission, no clear host in poultry or wild birds or pigs (all things that history or H7N9 genetic sequences indicate should be hosting infection).

...have arrived in China to examine, understand and advise on the avian influenza A(H7N9) virus situation in Shanghai and Beijing. The comment that "with perhaps rare exceptions, people are not getting sick from other people. Of the many hundreds of people who were in close contact with the H7N9 patients, all the care-givers, neighbors, family members, and so on, there are only a very few cases where these contacts have become ill as well." exemplifies the search for symptomatic illness. However there is still an opportunity to test the contacts using sensitive laboratory methods. These results will be very important for ruling out (or in) the potential for stealthy H7N9 spread among people without predetermined clinical signs and symptoms.

I highly recommend this Editorial over at crofsblogs. Adds a little context to some exaggerated headlines over the past three weeks and looks at the emergence of a novel virus from a...different angle.

A collaborative report (by Dutch and Chinese contributor) published yesterday from Eurosurveillance shows that 5/7 H7N9 strains from humans, birds and the environment have an amino acid change in the HA gene called Q226L (the normal" glutamine [Q] found at amino acid position 226 has "mutated" to a Leucine[L]). In the past, this change has been associated with binding of influenzavirus to a receptor molecule called alpha(2,6,)-linked sialic acid, which is found in the human upper respiratory tract. A virus that is happy to replicate in the upper airways, one of the first ports of call for inspired virus-laded droplets, is going to have a good ability to spread by the aerosol route. [I include the eyes in here - but they may considered anatomically separate and the true first point of contact with virus-laden aerosols as they are probably open more than the mouth. Other influenza viruses have been shown, by testing of eye swabs, to cause conjunctivitis at this site and common cold viruses can enter the airways through the tear duct. More info on Q226L can be found here and here

US CDC asked local healthcare providers to keep an eye out for "signs of H7N9 flu". Rather than watch for feathers, this will entail being on the lookout for cases with influenza-like illness (ILI) among those who have themselves, or are in contact with someone who, recently traveled China who are influenzavirus-negative by standard laboratory testing methods. Rapid prescription of Tamiflu is recommended (within 48h). All commercially available influenzavirus tests on these cases should be disregarded because their ability to detect the new H7N9 is untested so the risk of false negatives is high.

...but Zhejiang has surpassed Jiangsu to take second most active spot for H7N9.

Perhaps once Prof Ron Fouchier can get the virus into his ferret model he should be able to definitively answer whether avian influenza A(H7N9) can be transmitted via the airborne route and the real impact of the much discussed mutations found in H7N9 over recent weeks. He will also look at the virus by infecting rhesus macaques and African green monkeys.

..not my interpretation, tweet from WHO's Gregory Hartl, it seems that at least one son of this outbreak's first reported H7N9 case (Case #1, 87M) has been confirmed as also being H7N9 positive. What does this mean? It doesn't mean the sky is falling - contacts, by their very nature share things. In a family you often share (inhale, have land in your eyes etc) aerosolized (virus-laden) droplets as well as common surfaces contaminated by with those aerosols, when you have an acute virus infection. Coughing and sneezing do that. But you also share common tasks. There is so far no clear evidence of direct Dad to Son (or Son to Dad) transmission here (there is a timing issue that is intriguing)- the father and son may have simply shared the same airspace (I think its pretty safe to say this is transmitted through the air in some form) with an animal host during contact, handling, butchery, cleaning etc. Despite testing of animals to date finding very few have detectable H7N9 infections.

Increasing calls to reduce paranoia and stop overstating the likelihood of pandemic. Hopefully VDU doesn't add to the blather too much - collecting only verified observations of interest is the name of its game on this page. Opinions are mine alone and I hope they don' extend beyond hard data...too much.

However, dates are scant and patchy so I have not further updated the charts yet. I'm hoping for some clear data later in the day. New retrospective test results have appeared - these comprise serological data for two cases (seroconversion to influenzavirus can take 12-21d which may vary further in the elderly or those with immunocompromise) and culture isolations for two cases as well as two deaths. Why PCR did not pick up the H7N9 in the cases from which virus was isolated? Unclear and surprising.

...to mull over: Have viral co-infections and bacterial super-infections been sought, or excluded, in the H7N9 fatalities to date (some mention the 3 cases NEJM article)? What contribution do they make, along with existing co-morbidities, in the deaths of the 14 (as of 15.04) H7N9-positive cases?

..it will also be interesting to see whether the H7N9 circulation had an unusual impact on "seasonal" respiratory viruses like parainfluenzaviruses (PIVs), enteroviruses (EVs) and rhinoviruses (HRV) which reportedly, like influenzavirus, can peak in Beijing and Shanghai around May (Ren et al., Clin Microbiol Infect 2009;p1146-; Wang et al. J Clin Virol 2010;p211-)

Over at FluTrackers, expert virology communicator (the virology blog), picornavirologist and teacher Prof Vincent Racaniello reiterates a point that hasn't been mentioned much with respect to the H7N9 emergence. "Conclusions about etiology are more difficult to determine if viral sequences are detected by PCR in the absence of clinical symptoms". In other words its important to consider the much greater sensitivity of PCR compared to old culture-based diagnostics, in the context of false positives (environmental or laboratory cross-contamination) and what a weak H7N9-positive might practically mean. A good seroconversion still can't be beat in these cases! IMHO - experienced diagnostic labs should have long ago dealt with this issue. PCR has been in use as the "gold standard" for years. In a situation like the one ongoing, I assume that all H7N9 positives are being suitably confirmed using follow-up confirmatory testing using previously established protocols.

... in an article by Jason Gale, Editor, Bloomberg News, picked up by crofsblogs and on ProMED too in the AVIAN INFLUENZA, HUMAN (47): CHINA H7N9 UPDATE update.

The latter of a 77F previously H7N9 POS. Numbers of new notifications are surprisingly low after the weekend's flurry.

Multiple reports of the first asymptomatic case in a 4-year old male (4M) living across the street from the previously H7N9-POS, 7F. This may demystify a lot of H7N9 confusion as well as seriously increase the threat level for H7N9 spread...a stealth virus not only in poultry but humans is a new game. As I've suggested earlier, the widespread use of sensitive molecular detection methods, not just on the cases with the most severe clinical signs and symptoms, is absolutely essential to detect mild or asymptomatic cases of infection. The use of PCR in this way seems to have done just that. I'll keep a close eye on this story but I suspect it will result in a drastic change to the landscape of detection numbers and epidemiology. Symptoms alone tell only a small part of the story of any respiratory virus. This may strengthen the case for H7N9 having been in the community for much longer than the pneumonia cases officially commencing back in Feb, suggest.

Just a note of sincere thanks and a fair serving of awe to the tireless (perhaps sleepless) efforts of the dedicated guys at FluTrackers (Sharon Sanders, EiC) and the Avian Flu Diary (Mike Coston), and Crofs blogs for help and generous hat tips (see #7137 and others) that have kept VDU fed over the past couple of weeks.

Today saw a remarkable 11 H7N9 confirmations added including 2 new deaths and a new province (Henan; population >94,000,000) added to the list. FluTrackers has all the details...although many cases do not have full details; the best quality data come from Shanghai, Beijing and Henan at the moment. Cases jump to 60 with 13 deaths but the Case Fatality Rate remains steady at 22%. No sustained human-to-human transmission has been identified yet.

A new format for the Cases Chart is being tried out to help me cope with the increasing analysis. Check out the other H7N9 charts of province, age, sex and mortalities all at the H7N9 page.