The boiling cauldron – transmission, virulence, resistance

When shall we three meet again.
In thunder, lightning or rain?
Opening lines of Macbeth, by William Shakespeare

Many virologists have a recurring nightmare: a virus arises which is easily transmissible, highly lethal and resistant to antiviral drugs. It spreads before an effective vaccine can be developed and deployed. Bodies pile up faster than they can be disposed of. Civilisation cracks under the strain.

Such a virus does not yet exist, but the ingredients to make this nightmare real exist, today.


The novel H1N1 virus has spread to nearly every corner of the world since it was first reported in April 2009. The vast majority of outbreaks have occurred among children. There have been very few examples of large scale outbreaks among adults. There are several reasons why this may be so (discussed here). However, it is possible at any time for H1N1 to become even more transmissible – through mutation, recombination or reassortment. The virus is now under intense selection for increased ability to transmit from one human host to another.


A mutation associated with very severe symptoms and deaths has recently been identified.

From The New York Times, November 21,2009

Norway reported finding a mutated virus in three people who died or were severely ill. The mutation, known as D222G on the receptor binding domain, allow the virus to grow deeper in the lungs.


The D222G mutation allows the virus to bind to receptors on cells lining the lungs, which are slightly different from those in the nose and throat. Henry L. Niman, a flu tracker in Pittsburgh, has been warning for a week that D225G — the same mutation under a different numbering system — has been repeatedly found in Ukraine, which is in the grips of a severe outbreak and where surprising numbers of people have died with lung hemorrhages.

Dr. Schuchat of the CDC suggests that the same mutation has been found in mild cases. If so, she should provide the accession numbers of the relevant sequences along with the case history of the patients. It is especially important to note whether these “mild” cases involved patients who received antiviral medication. If so, then such cases would not constitute evidence against the idea that the D225G mutation causes severe symptoms and death. A virus may be highly virulent, but still susceptible to Tamiflu.

One might also ask Dr. Schuchat why the CDC is looking for clusters of hemorrhagic pneumonia in the US?


What was the lethal mutation that killed two Americans?


Having tracked patient deaths in countries all over the world, I have become convinced that the antiviral drug Tamiflu makes a huge difference in the case fatality rates (CFR) from pandemic H1N1. Simply put, countries with lots of Tamiflu have lower CFRs than countries without much Tamiflu. Tamiflu may also be slowing down the transmission of the virus by breaking chains of infection. Without antivirals, we would be defenseless against a new, more virulent virus. And, unfortunately, the cracks in our antiviral defense are getting bigger.

From Mail Online, November 20, 2009

A strain of swine flu resistant to Tamiflu has spread between patients in a British hospital.

Five patients on a unit at the University Hospital of Wales in Cardiff were diagnosed with swine flu resistant to the drug.

The infection is believed to be the first confirmed case of a person-to-person transmission of a resistant strain in the world.

From, November 20, 2009

State health officials annouced late Friday that three of four people infected with drug-resistant H1N1 have died at Duke University Hospital.

The four patients tested positive for what officials said is a mutation of H1N1 that is resistant to Tamiflu, one of two medications used to help fight the virus. The patients were diagnosed with the flu during October and November and all were hospitalized in the same unit at Duke University Medical Center.

Some strains of influenza that are resistant to Tamiflu are still susceptible to another antiviral called Relenza. But supplies of Relenza are even more limited than stocks of Tamiflu.

How fast could pandemic H1N1 convert from a virus that is almost always susceptible to Tamiflu to one that is almost always resistant to Tamiflu? Very fast indeed. “Regular” H1N1 made this transition in a few months.

From Dharan, et al. (2009) Infections With Oseltamivir-Resistant Influenza A(H1N1) Virus in the United States. JAMA. 301: 1034-1041.

Although oseltamivir-resistant A(H1N1) viruses circulated widely in the United States, during the 2007-2008 influenza season, the national adjusted overall proportion of oseltamivir-resistance among all influenza viruses was low (2%), and national recommendations for use of antiviral agents were not changed during 2007-2008. However, early surveillance data from 2008-2009 suggest that the prevalence of oseltamivir resistance among A(H1N1) viruses will most likely be higher (>90%) during the 2008-2009 season.

The Witches Brew

The worst case scenario would be for the new pandemic H1N1 virus to develop greater transmissibility, greater virulence and resistance to Tamiflu. Today, all the ingredients for this to happen exist. Whether they will come together remains to be seen. But each passing day that the virus is allowed to spread unchecked, the probability of this catastrophe will increase.

I hope that the people who are supposed to plan for a worst case scenario are paying attention.

Because sometimes nightmares come true.


5 thoughts on “The boiling cauldron – transmission, virulence, resistance

  1. Thank you for this analysis. It is very troubling to read the response of the CDC and WHO on both the spread of Tamiflu resistance and the D225G mutation. The public health villains of 1918 have been reborn in Margaret Chan and Thomas Friedan. We have already seen how their meme of “mild” flu plus the vaccine delay fiasco has discouraged people from getting vaccinated. Why take the risk of a new vaccine when the peak has already been reached. I wonder how many people will die when the winter wave arrives?

  2. Dark Horse, I agree. The parallels between 1918 and today are striking. The same attempts to minimise the lethality of the virus, the same disorganised response, the same premature “all clear” signals.

  3. I think this is one of your best, Monotreme; although they are all excellent – clear and understandable to the layman, yet scientifically accurate.

    The insistence in the last couple of days that we have nothing at all to “worry” or be “concerned” about regarding the spread of Tamiflu resistance, or a more lethal strain of flu – is sickening me. I keep thinking that my contempt and disgust towards these public spokespeople couldn’t get worse, and then they make even worse statements designed to make the pandemic seem perfectly harmless. Heck, it might as well be a furry squeeze toy!

  4. Thanks, BeWell.

    The public spokespeople really have no idea of the science. They just repeat to a reporter what they’ve been told to say. Management,ie, Frieden decides what they are told.

    What is remarkable is the almost total silence from people like Dr. Webster. Hard to believe that he doesn’t have an opinion about what is going on.

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