Influenza A (H7N9) virus update...

Xinhuanet has the latest H7N9 figures from China's National Health and Family Planning Commission. With no new cases reported this month, and just one from July reported in last month's update, the 12 provinces or municipalities that have hosted infections resulted in:

• 134 cases (I have 136; presumably the Taiwan case and asymptomatic Beijing boy)
• 45 deaths, up form from last month
• 87 discharged cases leaving 2 still in hospital
• PFC at 33.1%

I've updated by VDU H7N9 page with these numbers also.

Thanks to Crawford Kilian's Tweet for making me aware of this report.

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Concise overview of MERS from mid-2013...

Publishing in the Oman Medical Journal, Blakhair and colleagues summarized the state of play for MERS back in July 2013.

While the numbers may have changed since then, the article is as relevant now as it was. Not much new data has been accrued to address the knowledge gaps listed in July despite 3-months and about 50 papers having passed.

The final summary is particularity useful I thought...

The fact that our current knowledge on this virus is sparse should not induce unnecessary panic or fear, instead it should promote vigilance and a state of preparedness. Over reaction to the current situation may lead to significant clinical, economic and epidemiological impacts among others.

The article also provides VDU's first ever citation in the scientific literature. Cool.

Reference...

1. The Struggle Against MERS-CoV (The Novel Coronavirus). Oman Medical Journal. 2013. 28(4):226-7
   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725253/pdf/OMJ-D-13-00242.pdf

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The tip of the VirusBerg...

The VirusBerg.
Click to enlarge. If there are more cases with mild/less
 symptomatic disease then the denominator grows
and the proportion of deaths to survivors, the PFC,
shrinks. At the start of an outbreak or emergence of
a new pathogen, it is usually the most severely ill or
those ill with a specifically identifiable disease
that attract the attention of specimen collectors &
testers. Later in the event as resources are freed up
and panic reduces, testing of other population
groups may find more cases of less severe disease.
 This may not eventuate though and the PFC may
 remain high confirming a serious threat to human
health. Feel free to use graphic. Cite this blog
and Ian M. Mackay.

I've talked about the Denominator problem over on my "main" site, Virology Down Under's H7N9 page, but I thought it worth revisiting for 2 reasons: (1) our understanding of Middle East respiratory syndrome (MERS-CoV)  fatalities may still affected by a possible bias in our understanding of MERS-CoV transmission because of a continued focus on testing just the "tip" of the VirusBerg and (2), I made a new graphic that I like more than the old one!

We see a high PFC for MERS for 2 reasons that spring to my mind:

1. There are no, or very few, mild cases of MERS. Cases are usually severe and most are being caught. We know there are some mild cases and we know that contacts of confirmed cases are infrequently MERS-CoV positive. I'm assuming contacts are tested with the same rigour as those in hospital due severe MERS (e.g. lower airway sampling with follow-up testing). 
2. Although we don't see much transmission from cases to contacts we do see some and this may be enough to maintain a small number of community transmission events. The second reason then is that we are only testing cases with severe disease, many of whom die as a result of complications due to the initial infection. Prospective screening of a sample of the well general community and those with "common colds" might identify more cases that would reduce the PFC.

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+1 to HA and NA numbering-new fruity bat flu

Now I need to remake this tree!

Thanks to a new study in PLoS Pathogens by Tong and colleagues (they who brought us the last new influenza numbers from bats), we have a new haemagglutinin (HA) and a new neuraminidase (NA) to add to the list. These are also from a fruit bat (flat faced (Artibeus planirostris) in fact.

That makes 18 HAs and 11 NAs to play mix-and-match with. I wonder if we'll one day see the avian and bat genes mix up?

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Mycophenolic acid added to the study list of anti-MERS-CoV therapeutics?

In a recent online release from the Journal of Infection, Chan, colleagues from Kwok-Yung Yuen's group and collaborators describe their search for compounds with broad-spectrum activity against both influenza viruses and coronaviruses (CoVs); the latter being especially rare.

Testing a pre-existing 1,280 compound panel of potential drugs yielded 10 hits with activity against MERS-CoV  (EMC strain). Only mycophenolic acid (an inhibitor of T and B lymphocyte and antibody production) fit the bill for a likely compound from this panel. It is also active against other viruses and is used clinically to prevent solid organ transplant rejection. 

Mycophenolic acid is available, can be given orally or parenterally, dosage is convenient, serum concentrations exceed those needed to be active against MERS-CoV and most tertiary care facilities can monitor drug levels. The risk of immunosuppression is of concern however.

Other agents showed some anti-MERS-CoV/EMC activity in the Vero cell culture assays. Ribavirin, interferon (IFN)-a, and IFN-� were active

Combining mycophenolic acid with  (IFN)-� produced an additive effect.

Further studies sound likely.

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Does MERS-CoV delay the antiviral response against it?

Lau and colleagues from the University of Hong King recently wrote about MERS-CoV's ability to delay the induction of proinflammatory cytokines in human cells. These are potent defensive chemicals that cause and accelerate an inflammatory response to viral infection.

While inflammation is part of kicking out the virus, it can get out of control, especially with more "foreign" viruses, like those that are still zoonotic and not as co-evolved with humans. Excessive inflammation can lead to tissue remodelling and damage.

In their paper in the Journal of General Virology, the authors compared the results of growing viruses in 2 different cell systems, which was need to account for differences in tropism by the different viruses. Key findings include:

• The lower airway cell-line, CaLu-3 was used for MERS-CoV and SARS-CoV because they produce good titres
• IL-1�, IL-6, IL-8, TNF-a, IFN-� & IP-10 mRNA levels were increased by MERS-CoV and SARS-CoV compared to uninfected cells
• Proinflammatory cytokines shown in bold above were induced more by MERS-CoV infection than by SARS-CoV
• Innate antiviral cytokines TNF-a, IFN-� & IP-10  were induced more by SARS-CoV infection
• MCP-1 (a chemokine) and TGF-� (anti-inflammatory cytokine) remained unimpressed by infection
• At 48-hours, MERS-CoV infection induced less IL-8 or IFN-� protein than did SARS-CoV

• Embryonal lung fibroblasts (HFL) to grow MERS-CoV and compare it to HCoV-229E (which does not grow well in CaLu-3 cells), an infrequently identified but well characterised "common cold" CoV.

• The CaLu-3 results suggested MERS-CoV generates an attenuated innate immune response  the response which induces inflammation. SO HCoV-229E was added as it produces a strong innate response through IFN-�
• IL-1�, IL-6, IL-8, TNF-a, IFN-� & IP-10 mRNA levels were increased by MERS-CoV and HCoV-229E
• HCoV-229E was a stronger inducer than MERS-CoV of all but TNF-a, which triggered more by MERS-CoV
• MCP-1 and TGF-� again remained unchanged

The authors conclude a delayed innate immune response by MERS-CoV infection compared to SARS-CoV. 

This study contrasted with that by Kindler and colleagues which I reviewed earlier. The reason may be because Kindler only sampled for immune analyses up to 12-hours, rather than the 30-hours used by Lau. This would certainly lend weight to claims of a "delayed" induction by MERS-CoV infection since in this study no IFN-� was produced either virus at 12-hour, the first rise in mRNA was apparent at 24-hour post-infection (Lau's protein data suggest there may have been a tiny amount of IFN-� translation at 12-hours, but Kindler did not measure protein). 

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