Sunday, 28 February 2016

Avian influenza A(H7N9 virus...a primer...

Influenzavirus taxonomy
OrderUnassigned
FamilyOrthomyxoviridae
GeneraInfluenzavirus A, Influenzavirus B, Influenzavirus C
SpeciesInfluenza A virus, Influenza B virus, Influenza C virus
Genome(-)ssRNA, 7 (IFCV)- 8 (IFAV/IFBV) segments (~14kb total length)
GenesPB2, PB1, PA, HA, NP, NA, M, NS
VirionEnveloped, approximately spherical, 80-120nm
NB-this has just been transferred from my old VDU website to this blog and so is out of date. I'll update in the future

One of the most recent avian influenzavirus strain added to the list of agents causing "bird flu" is called avian influenza A(H7N9) virus - a colourfully exciting reference to its key surface proteins (see influenza background). H7N9 is considered a low pathogenic avian influenza virus (LPAIV)...at least in its feathered hosts. Avian influenza A(H7N9) virus (which I may shorten to H7N9 to save my fingers) was once considered a relatively rare cause of infection although how extensively and routinely it was looked for in the past is unclear. Avian influenza A(H7N9) virus is similar to its closer cousins, H7N2, H7N3 and H7N7 and its more distant cousin H5N1 in that they are all IFAVs and they usually infect birds. However, they are each quite distinct and made up of different genes.

Avian influenza A(H7N9) virus is an IFAV (see the adjacent schematic) that has evolved in birds. The virus has 8 single-stranded RNA segments that encode 11 proteins. However, when cases of infection by it were reported for the first time in humans (China, March 2013; very general locations of confirmed cases to date are shown in the map), it was linked to its first two deaths in this host (an 87 year old male [87M, sick 19.02, died 04.03; 2 family member(s) also reported ill with pneumonia but H7N9 negative] and a 27 year old male butcher [27M, sick 27.02 and died 10.03], both in Shanghai, China) or critical illness (35F in Chuzhou city). 


Since 2013, cases have slowly but continuously climbed.

Because there is a delay between illness onset and laboratory confirmation of 10-13 days, the newest cases started have illness onset dates some way back making it is still hard to judge the impact of control measures like live animal market closures and animal culling, on interrupting transmission. A timeline of the early events shown below. 


Use images freely but please cite this blog and Dr. Ian M Mackay as their source.
Click on image to enlarge.









The chart to the left divides the H7N9 outbreak into its 2 Waves based on laboratory notifications made public starting from March 31st (Chinese CDC notified WHO). 


In the graph of the accumulating confirmed cases to the right (blue mountain), fatalities (red) and the rolling proportion of fatal cases (grey-PFC calculated using public data, yellow using media reports of totals), we can see that the total proportion of fatal cases (PFC) sits around 30%. Please don't go nuts and draw any major conclusions based on extrapolating the PFC to the global population - this figure is solely meant to show you the numbers and trends at the site of the outbreak among those people being affected. It cannot be translated widely. What it does show us is how the outbreak came to be noticed - fatalities. The PFC remained fairly steady though 2013, although its calculation is at the mercy of the availability and extent of public data. For an update on the most recent epidemiology, please visit my blog, virologydownunder.blogspot.com.au  and use the search box to find recent “H7N9” posts. 


H7N9 Fataliaties by week. Use images freely but please cite
this blog 
and Dr. Ian M Mackay as their source. Click on image to enlarge.


The various H7N9-positive municipalities (Shanghai and Beijing) and provinces (e.g. Henan, Anhui, Zhejiang, Guangdong, Jiangxi, Hebei, Fujian, Hunan and Jiangsu) in southeastern China have had different numbers of cases reported and the reports started at different times. The first cases were confirmed from Shanghai on March 30th and included the first case who showed signs darting back to February 19th. Jiangsu's first confirmed cases occurred 30-March-2013 (although they were not announced until 2-April-2013) then Anhui province followed (confirmed on 31-March-2013) then Zhejiang province (1st April-2013), Henan province (11-April-2013) and Beijing reported its first case 13- April-2013. Guangdong province confirmed its first case 6-August-2013; Fujian province, 26-April-2013; Hebei province, 20-Jul-2013; Shandong province, 22-Apr-2013; Guangxi province 29-Jan-2014; Jilin reported its first detection, 21-Feb-2014. Most cases in Wave 1 were from Zhejiang province which was also a major site of virus activity in Wave 2, along with Guangdong province.


The denominator problem...


You may remember from your early maths classes that fractions have both a numerator (the number on on top or before a slash/line, that represents a portion of the whole) and a denominator (the non-zero number on the bottom or after the line that represents all the parts of the whole).  avian influenza H7N9 flu cases by area of China The avian influenza A(H7N9) virus outbreak in March-May 2013 mostly manifested as severe disease - those people being admitted to hospital needing help to breathe (requiring oxygen or mechanical ventilation) - and we did not see many mild or asymptomatic cases (virus positive but no obvious feelings of signs of illness). This might be because there were no mild cases (although a couple popped up in children and adults) or because only the worst cases were tested. In favour of the former hypothesis, enhanced surveillance in China found few H7N9-positive cases of mild disease - the most notable being children. 

Many milder respiratory diseases look the same based on signs and symptoms but can be caused (and I use that word with caution) by many, many different respiratory viruses. There may be cases of respiratory infection going around in China that are H7N9-positive but not severe enough to warrant a admission to hospital or even a trip to the Doctor. Until we know more about this part of the H7N9 story, we won't know the total number of avian influenza A(H7N9) virus infections that are occurring, so we can't calculate the true denominator. More info on this in a recent article.

If the denominator is small (like it is now with so few H7N9-positive cases and those being from mostly severe illness or deaths, then we see a high proportion (percentage) as our Proportion of Fatal Cases  (x severe cases over a small number of total cases is a high proportion). If there are mild cases of avian influenza A(H7N9) virus infection out there (as we saw early examples of 15-Apr-13) and they are in large numbers, that denominator could be much larger and the severe disease cases will be "diluted" down to a smaller proportion (x severe cases over a large number of mild and severe total cases is a low proportion).