A summary of Influenza A(H7N9) virus findings in birds and humans [UPDATED, AMENDED FIGURE]

An article from Bloomberg news highlights some interesting studies, how they present opposing conclusions and why we can expect to see more H7N9 activity, perhaps peaking at Chinese New Year.

Click on image to enlarge.
H7N9-positive birds and humans (see MOA report) in 
April 2013. 17x more humans were virus-positive 
than humans were PCR/symptom positive. Based on 
Li et al's April 24th New England Journal of Medicine 
article from a similar time period which uses observation 
for signs of disease among 1,251 followed contacts of 81 cases and
sentinel surveillance PCR data from 5,551 humans to
identify H7N9 cases).

The authors (Khan and Loo) remind us that earlier in the year, China's Ministry of Agriculture reported 46 positive poultry samples among 68,060 tested positive using viral culture, for H7N9 (0.07% or about 1:1,500). 

In a more detailed report from MOA from 30th May 2013, 88 of 899,758 [0.009%] duck, pigeon, chicken (722,380 or 80% of all the samples tested), wild bird, pig, geese, "other" animal or environmental samples were virus [197,389 of the samples tested this way] &/or antibody [702,369 of the samples] positive (chicken, duck and pigeons were the positives; 3 were positive for both). The report presented by Zhang Zhongqiu does not make clear how many swabs and bloods were tested per animal so I'll just talk about sample numbers. The report notes that there were no clinical cases reported from 44 million farming households and no positives from 51,876 samples of 746,212 samples (?chickens) sent to Hong Kong; monitored by the General Administration of Quality Supervision, Inspection and Quarantine, China) nor among the 120/samples being tested per day in Hong Kong. In 1,874 samples collected from Henan and Jiangxi provinces, none were positive. Transmission among chickens was possible but was not efficient among ducks.

• Lam and colleagues (previously reviewed) identified 8 avian H7N9 strains from 1,308 (0.6%) chickens (95% of samples), ducks, pigeon and geese samples collected from live bird markets (LBMs) in Rizhao, Shandong province (about 9 times more than the 1st MOA study above, if they can be compared directly). 
• Yang and colleagues (previously reviewed) found H7N9 antibodies in 25 (6%) of 396 humans poultry workers (none prior to 2013) but only 9 of 1,129 (0.8%) members of the general community showed some weak sign of past exposure (or cross-reaction with another influenza). No viral RNA was found in these poultry workers.
• Wang and colleagues, writing in the Journal of Infectious diseases,  recently traced the source of some cases in the Hangzhou region of Zhejiang, to LBMs. 95 samples from chickens (n=47 samples), ducks (n=9), quails (n=2), pigeons (n=3) and poultry handlers and 4 from water were inoculated into eggs and were tested by real-time RT-PCR, within the first 2-weeks of April 2013. H7N9 RNA was found in 41/85 (48%) of samples. 40% of the chicken samples, 89% of the duck samples and a third of the pigeon samples. No human or environmental samples were positive. The authors concluded that migratory birds would continue the spread of H7N9 viruses and that their findings highlight LBMs as the major source of infection an as such control measures are needed.
• Shi and colleagues reached a similar conclusion in April in the Chinese Science Bulletin. "Strong measures" were needed to control the spread of H7N9 in order to prevent more infections. This followed the testing of 970 samples of drinking water, soil, cloacal and tracheal swabs from LBM poultry in Shanghai and Anhui province using egg inoculation. All 20 (10 from chickens) of the H7N9 isolates came from LBMs in Shanghai, confirming high genetic homology across the H7N9 genome from human H7N9 cases.

Today's Bloomberg article quotes researchers' concerns that the cooler weather will drive the re-appearance of H7N9, since influenza usually reaches epidemic levels during cooler months. In other words they believe this particular strain of H7N9 (the one infecting humans) was never removed from the ecosystem.

Re-opening of the LBMs has been ongoing since June in Shanghai municipality and Zhejiang and Jiangsu provinces, albeit in a more regulated fashion. The cleansing of the markets after culling more than 560,000 poultry from LBMs as of May 2013 combined to precede the precipitous decline in what had been an alarming rate of new cases in those regions. Is testing of these markets an ongoing process?

With the markets refilling from farms located in rural regions with exposure to mobile wild bird populations that may (albeit infrequently) carry H7N9 (and many other influenza viruses including its components), the risk of fresh outbreaks among humans is also growing. 

It's a numbers game. 

Even 1 human case, like the one we saw infected this week could signal an even wider level of circulation of H7N9. Let's hope testing will make sure our number's not up this time around.

Editor's Note - the figure was altered 01.02.14 to correct an error in the proportions and to adjust down the number of contacts since not all had been followed.

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3 in 50 mostly asymptomatic workers handling live poultry have H7N9 antibodies...

Earlier in the week Yang and colleagues, publishing in the Journal of Infectious Diseases, found that among 1570 people from Zhejiang province tested for antibodies towards influenza A(H7N9) virus, 25 of 396 (6.3%) poultry handlers from live poultry markets had antibodies detected. Only 9 (0.8%; statistically significantly fewer) of the 1129 community members showed signs of an immune response to H7N9 infection while 33 of 45 (73%) laboratory confirmed H7N9 cases had significant levels of antibody.

No poultry handlers (mostly exposed through slaughtering) had H7N9 in nasal swabs collected at the time of blood sampling, probably reflecting that collection had occurred after the infection that elicited antibody had resolved. Less than 4% of poultry handlers or the general community had fever or respiratory symptoms at sampling compared to 100% of the lab-confirmed group.

This partially answers one of my questions from earlier in the year - but leaves the part which asks: if the main H7N9 host is poultry (and not wild birds), why don't we see the majority of ill people coming from the poultry worker population? While aerosol transmission has been described as low among ferrets, H7N9 transmission might be effective enough to explain the other human H7N9 cases not due to slaughtering of poultry.

Now we can say that poultry handlers are getting exposed and 3 in every 50 are getting infected (or mounting an immune response, to be pedantic). Only 3% of this population and 10% of the general community had underlying diseases compared to 64% of the lab confirmed cases. Sex of the groups did not seem to play a role but those aged =60-years were over-represented among the lab-confirmed H7N9 cases (53% of them) compared to poultry handlers (1%-a much younger population) or the general community (19%).

As for MERS-CoV, underlying conditions and older age are clearly important risk factors for more severe disease.

The authors also noted that higher antibody levels were found in survivors that in fatalities, perhaps suggesting (a) the fatalities did not have time to mount a suitable response before they succumbed or (b) the antibodies protected against worse outcomes. Poultry workers do not always have serious disease, which probably means lower viral loads and thus reduced likelihood that they are major sources of human-to-human transmission.

In a previous study by Bai et al, using one of same sort of antibody detection techniques (haemagglutination inhibition), no poultry handlers from were found to be positive prior to late 2013. So this new article proves the emergence of H7N9 human infections is a recent event. And this provides Chapter 2 on that earlier post. 

Some questions still remain in my mind:

• Are these 3/50 poultry handlers also getting moderately or severely ill? 
• How often does infection in this group result in asymptomatic or mild disease?
• If disease is mild or asymptomatic in poultry handlers, is it because these workers are exposed to poultry with other influenza viruses comprised of proteins that are or are sufficiently related to H7 and so they already have some protective immunity to moderate their disease after H7N9 infection? 

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Poultry workers had no prior exposure to H7N9 [UPDATED]

Bai and colleagues report in NEJM that 1,544 samples collected from young adult poultry workers between Jan-Nov 2012 in 4 key provinces/municipalities of China (municipality of Shanghai, Zhejiang province, Jiangsu province and Anhui province) were tested using a haemagglutinin-inhibition (HAI) assay and a microneutralization (MN) assay. 

The HAI assay found some weak reactivity (antibody was positive when diluted as far as 1:40), but no neutralizing antibodies were found by MN test. 

This is chapter 1 of a story that next needs to include more contemporary testing. 

The first part reveals no assay-specific antibodies present in these close contacts of poultry, prior to late 2012; before the H7N9 outbreak.

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