H7N9 is off the mainland; Case reported in Taiwan

A Taiwanese man has been confirmed to have H7N9. The 53 year-old business man had returned from Suzhou, China three days prior to the onset of symptoms on April 9th. He is listed as being in serious condition. Suzhou is about 70 miles from Shanghai, the center of the H7N9 outbreak.

Vector for H7N9

 Since the first confirmed cases was reported in late March, between 104 and 109 cases have been confirmed with either 21 or 22 deaths, depending on the source of info. Regardless of the actual number, there have been about as many human cases of H7N9 in the last 24 days as there have been human cases of H5N1 in the last 3 years, although there have been only a third the number of deaths attributed to the current outbreak.

New paper suggests H7N9 has high rate of mutation

Jonges M, Meijer A, Fouchier RA, Koch G, Li J, Pan JC, Chen H, Shu YL, Koopmans MP. Guiding outbreak management by the use of influenza A(H7Nx) virus sequence analysis. Euro Surveill. 2013;18(16):pii=20460. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20460  

Also had high mutation rates

 


The author compare the genetics of isolates from 3 H7 outbreaks fromt he last 15 years: 2003 Netherlands outbreak of high path H7N7, 99/00 low path H7N1 in Italy, and the current Chinese H7N9 outbreak. They note that all four of the Chinese isolates have the E627K humanization marker in the PB1, but no bird or environmental sample does. They give two possible explanations for this:

"1. the mammalian adaptation markers are selected during replication in humans following exposure to viruses that do not have this mutation, which are circulating in animals;
2. the mammalian adaptation markers result from virus replication in animals from which humans become infected.
The relatively protracted disease course in the current outbreak of A(H7N9) virus infection, with relatively mild symptoms at first, followed by exacerbation in the course of a week or longer, is suggestive of the first hypothesis, similar to the outbreak in the Netherlands."

Comparing the human markers in viruses from the NL outbreak and this one shows some discrepancies. Namely, 1/61 human H7N7 cases had the 627 mutation, while 4/4 H7N9 did (no bird or environmental isolate in the current outbreak carries the mutation).  They go on to conclude that this is due to a higher mutation rate in the Chinese viruses based on the comparison of the maximum genetic distance of isolates from different outbreaks of H7s.

"The maximum genetic distance generated during the three months of the Dutch HPAI A(H7N7) outbreak in concatenated HA, NA and PB2 segments of A(H7N7) viruses was 25 nucleotide substitutions. For the Italian LPAI A(H7N1) epidemic, the distance generated during a nine-month period was 66 nucleotide substitutions. For the A(H7N9) outbreak strains, this genetic distance is 35 substitutions"

New mutations arise randomly. However, the rate of mutations is relatively constant over time given equal rates of replication (the number of infections). Over three months and hundreds of samples the most genetically dissimilar isolates from the Netherlands outbreak were 25 nucleotides. The Italian outbreak lasted three times a long and the genetic diversity was slightly less than three times greater.  The Chinese H7N9 shows a roughly equal amount of mutations as the NL outbreak in 1/6th the time over presumably far fewer infections. The caveat here is that we are looking at only 7 H7N9 samples. As we get more and more data on these viruses we may see less diversity... or we may see more.
Those two points combine point to a non-humanized virus transmitting into humans from birds and then picking up humanization markers as the replicate. It could very well be the case as (at least the first three) isolates show a lot of genetic differences.  Depending on high mutation rates and still ending up with the same markers is surprising and indicates that these markers are not just "A" way the virus becomes humanized, but "THE" way it happens. Additionally, all the isolates recovered so far show a deletion in the NA stalk that is a hallmark of replication in chickens and other gallinaceous birds. This suggests that the virus spent time in these birds and became adapted and then transmitted to humans from there.

Common galliforms: Turkey, chicken, pheasant, guinea fowl, quail, etc.

One other option that they did not discuss is sub-populations. Flu as an RNA virus exists as a quasi-species. The birds could be carrying a version of the virus with some human markers at very low levels that are undetectable with standard sequencing methods (I don't think deep sequencing, limiting dilutions, or plaque isolations have been done yet). These minority populations could be the ones that transmit to humans. I would still lean towards their model based on the evidence available, but its something to think about.
So far the sequencing has not revealed any H2H transmission. If the model they propose in the paper is correct, then this is surprising. If the viruses are mutating at such a high rate, still arriving at the same set of mutations independently and showing no H2H transmission, then maybe there is no set of mutations that will allow it (maybe that is why there has not been an H7 pandemic before). This would also raise the question of why is the virus mutating so much faster.

A comparison of the 1997 H5N1 outbreak and the H7N9 outbreak

Late in 1997 a novel influenza virus began infecting people in Hong Kong and was associated with several deaths. The pathogen was quickly identified as a highly pathogenic H5N1 influenza virus that was crossing the species barrier from chickens into humans.  The response from health officials and specialists was quick and decisive. 1.3 million chickens were slaughtered in the city. Quail, guinea fowl, pigeons and pet birds were also abandoned or slaughter. Over three days the city was depopulated of domestic birds.
The result was no new human cases of H5N1 in the city over the next month. Eventually, the bird markets reopened and life continued on as before. H5N1 was eradicated from the city (for the next 5 years at least). The drastic actions undoubtedly saved many lives and possibly prevented a human pandemic. In total, 18 human cases resulted in 6 deaths.
Fast forward 16 years and we are now looking at a similar situation with the H7N9 virus. Sixteen human infections and 5 deaths from a virus that came from poultry, lead to the shut down of bird markets, and the initiated the slaughter of thousands of birds in an effort to stymie the spread of the virus. This time something is different.
As of this morning (4/16/2013), there are 72 confirmed human cases and 14 deaths. The the cessation of live bird markets and the culling of thousands of birds has not slowed the spread of this virus to humans. Case rates in Shanghai were steadily increasing for the three weeks prior to the closure of bird markets and a week after the closure the rates were drastically reduced (11 cases reported the week prior, 2 reported the week following). However, case rates in other cities seemed to be climbing still, including the spread of the virus to Beijing some 700+ miles away.

Shanghai

Hong Kong

Hong Kong is an island city of 7,000,000 people. Quarantine and poultry depopulation are relatively easy to accomplished when compared to a main land city with more than three times the population and 6 times the land area. The initial outbreak of H7N9 was spread out across several different cities and the spread was facilitated by ground transportation from city to city. The physically isolated nature of Hong Kong probably prevented that and helped keep the H5N1 contained long enough for human intervention to stamp it out.
Differences in the viruses also make the current situation far more difficult to control. The H5N1 was highly pathogenic in chickens. This made finding the source of the virus fairly easy (hint: its the severely diseased birds). The H7N9 shows no signs of disease in the birds that have tested positive so far. To identify an H5N1 infected chicken you need a basic understanding of what a healthy bird looks like and a functioning set of eyes. To ID an H7N9 positive bird you need serology tests, virus isolation, and genetic sequencing. Additionally, the H5N1 virus was not as infectious to humans as the H7N9 appears to be. If the current case rate identification continues, there will be more human cases of H7N9 over three months than there have been H5N1 human cases in the last 10 years.

 Healthy birds.

Not so much.

The good news for now is that the virus still does not appear to transmit from human to human and seems to be sensitive to available drugs (although more tests are needed to confirm this). The demographics of the cases so far are also pointing to a more promising conclusion. Age breakdowns of cases show a skewing towards the elderly, which is typical of influenza outbreaks. The most troubling human outbreaks (H5N1, 1918 H1N1) show a trend of infecting and killing young to middle aged adults as well as the very young and very old. So far H7N9 does not appear to be especially infectious or deadly to the 20-50 year-old age range suggesting a more moderate phenotype.

A recently published article in the New England Journal of Medicine reviews the first three fatal cases in great detail (http://www.nejm.org/doi/full/10.1056/NEJMoa1304459#t=article). They have a potential lineage origin for the genesis of this virus as well as most virulence, receptor specificity, and drug resistance markers. It is a good overview of the early infections (and I think free to read for all). Basic overview: these viruses probably have partial human like receptor specificity, have some markers for drug resistance (but not all), and are positive for most virulence markers in mice. Most of these markers were established in other subtypes of viruses. Some are more broadly established across subtypes (like receptor specificity markers), while others have only been established in certain lineages. This raises the question of how relevant they are, but based on the observations of the natural infection thus far, I would conclude that they are fairly accurate.
One final update: H7N9 was isolated from an apparently healthy 4 year old. This is potentially bad news. On one hand, silent or mild infections that have not been reported would lower the perceived virulence of the virus (14 deaths in 72 cases is terrifying. 14 deaths in 200(?) cases is significantly less terrifying). However, far more concerning is the possibility that silent or mild infections would make quarantining infected individuals nearly impossible. That would also allow the virus ample hosts to further adapt to humans and gain transmission and infectivity functions that it currently lacks and are currently preventing massive outbreaks on the potential pandemic scale.

Don't need to break out the masks yet.

My original feeling on this virus was that it would be a typical avian influenza outbreak in humans. Cause a few to several dozen cases with high morbidity and mortality (due to only severe cases being reported) and then peter out over a couple of weeks.  However, the case rate does not appear to be slowing down and the identification of silent and mild infections  coupled with the geographic spread is very troubling.   It is still too early for the doomsday preppers to start screaming "Told you so!", but I am far more nervous about this virus than I was two weeks ago.

Pigeon is Shanghai test positive for H7N9

Chinese authorities have announced more human infections and another death associated with H7N9.  The news brings the totals up to 14 human infections and 5 deaths - 6 cases and 4 deaths in Shanghai alone.
The Chinese Ministry of Agriculture also announced that H7N9 has been isolated from pigeons found in a Shanghai market place.  Sequencing analysis indicates a positive match for the viruses recovered from the human cases.

 Are skyrats spreading H7N9?

Pigeons do not typically spread influenza viruses. Most experimental studies have focused on highly pathogenic avian influenza (HPAI) viruses. A 1996 USDA study found that pigeons were not readily infected by an HPAI H5N2 virus and never shed any virus (thus no transmission). However, as the HPAI H5N1 outbreak continued over the last decade and the virus began accruing mutations that gave it human like receptor binding ability, a few pigeons were reported to have been infected with the virus.

I assume there have been a lot of birds swabbed in China over the last week. I suspect as data comes in there will be more species turning up positive. The positive birds came from a market place that likely contained chickens, ducks and other poultry species. Given the historically low prevalence of flu in pigeons, it would be surprising if the virus was not found in the more commonly infected poultry species.

Case overview and map of H7N9 human infection locations.

Update: H7N9

China has reported a four more cases of H7N9 in humans.  A 45 year-old woman slaughters poultry in a local bird market. She began showing symptoms early last week and quickly deteriorated to critical condition.  She is still in the hospital in Nanjing. The other cases involved an 83 year-old retired man, 48 year-old woman who worked in a sheet metal factory, and a 32 year-old unemployed woman. Their close contacts are being monitored and there is no sign of spread of the virus to others. All four people are in critical condition. 

Further details about the first three cases have also come to light. The woman who is recovering apparently had contact with poultry prior to the onset of symptoms. The 27 year-old man worked in a swine slaughtering facility.  The 87 year-old man had no known contact with any swine or poultry. The first three cases all presented with typical viral pneumonia with fever and coughing. By 5-7 days after symptom onset patients had difficulty breathing. The two fatally infected men died from acute respiratory distress syndrome.

None of the 88 close contacts o the first three cases have tested positive and surveillance of those individuals is ongoing.

UPDATE: Two more cases were announced today. A 38 year-old male chef died on March 27th 20 days after becoming ill and 9 days after being admitted to the hospital.

A retired 67 year-old man was admitted to the hospital on March 25th and remains hospitalized.

Total cases: 9
Total deaths: 3

3 human infections with H7N9 avian influenza, two fatal

Three people have been infected with an H7N9 subtype of influenza virus in the last two month in central China. Two, an 87 year-old man and a 27 year-old man, became infected in February and died within a week.  A third case, a 35 year-old woman, became infected March 9th and is recovering in the hospital.
88 close contacts of these three individuals have been sampled and monitored for influenza and influenza like illness. To date, it does not appear that these viruses have been able to transmit from human to human. The source of all three infections is currently unknown.
Initial fears were that a new highly pathogenic avian influenza (HPAI) strain of H7 was the culprit. However, recent information from the CDC indicates that these viruses lack the polybasic cleavage site that defines a highly pathogenic strain.  Additionally, the virus seems to be a reassortant with internal genes that are very similar to H9N2 viruses.
This marks the second time that a virus containing genes from an H9N2 via reassortment has caused deaths in humans. The HPAI H5 virus isolated in the Hong Kong outbreak of 1997 also contained internal gene segments that matched H9N2 viruses.
My own personal research has focused on the threat that H9N2 viruses could pose to the human population. Our research has focused on reassortant viruses of the H9 subtype, and we have found that H9 viruses can gain infectivity, pathogenicity, and aerosol transmissiblity in ferrets and swine via reassortment, especially in regards to the 2009 pandemic H1N1.
The results we have gathered from lab and the recent outbreak once again highlight the potential dangers of H9N2 influenza viruses to humans. The viruses can infect humans, readily reassort with other viruses, and twice now have created viruses with significant effects in a human host.

Update: http://bkviroblog.blogspot.com/2013/04/update-h7n9.html