case fatality ratio

The prominent lead editorial in the New York Times of Sunday, 8 January 2012 is entitled ‘An Engineered Doomsday’. It concerns recent avian influenza H5N1 research, in which scientists in the Netherlands and at the University of Wisconsin found that by passaging the virus in ferrets it could acquire aerosol transmissibility. Let’s determine if the scientific facts warrant the frightening title.

The editorial begins by rebuking the scientists who carried out the experiments on H5N1:

…the research should never have been undertaken because the potential harm is so catastrophic and the potential benefits from studying the virus so speculative.…they created a virus that could kill tens or hundreds of millions of people if it escaped confinement or was stolen by terrorists. …the new virus…ought to be destroyed.

The intent of the experiments was not to create a doomsday virus, but to answer questions about why the H5N1 virus transmits well among birds but not humans. This experiment cannot of course be done in humans, so it was carried out in ferrets, a model for influenza. The results show that aerosol transmissibility in ferrets can be achieved with just five amino acid changes, with no reduction in the virulence of the virus. That result does not mean that the same amino acid changes would have the same effect in humans – it just tells us that achieving aerosol transmissibility in an animal model is relatively easy.

Whether tens or hundreds of millions of people would be killed depends on the ability of a virus to not only transmit among humans, but to retain virulence. There is no evidence that the ferret-passaged H5N1 virus has these properties. In the unlikely event that the virus somehow escaped and began to infect people, its spread could be controlled by vaccines (candidates are under development) and antivirals (existing neuraminidase inhibitors are active against influenza H5N1).

The heart of the H5N1 controversy is encapsulated by the next passage:

Thus far the virus has infected close to 600 humans and killed more than half of them, a fatality rate that far exceeds the 2 percent rate in the 1918 influenza pandemic that killed as many as 100 million people.

This statement refers to the fact that nearly 60% of the 573 WHO-confirmed H5N1 cases have died. This death rate appears staggering until one considers how it is calculated. The WHO case definition for H5N1 influenza states that an individual must have a febrile respiratory illness, known exposure to H5N1 virus in the previous 7 days, and confirmation of infection by virus culture, polymerase chain reaction, or tests for antibodies. These conditions are highly unlikely to be fulfilled in rural populations where most H5N1 infections probably occur. The case fatality ratio can only be calculated by dividing the number of deaths by the total number of infections – and we do not know the latter number. Of ten large studies that have tested for H5N1 antibodies in rural populations, two were negative and 5 reported the presence of H5 antibodies in 0.2 – 5.6% of indiviudals. Much more work needs to be done to determine the actual fatality rate of influenza H5N1, but the WHO estimate is orders of magnitude too high.

Next the Editors weigh in on publication of the ferret results:

The Erasmus team believes that more than 100 laboratories and perhaps 1,000 scientists around the world need to know the precise mutations to look for. That would spread the information far too widely. It should suffice to have a few of the most sophisticated laboratories do the analyses.

As I have argued before, limiting the dissemination of scientific information only serves to impede progress. It is impossible to predict which laboratory is going to do the breakthrough experiment, and picking ‘sophisticated’ laboratories is meaningless.

Then the Editors argue that the research has no value:

Defenders of the research in Rotterdam claim it will provide two major benefits for protecting global health. But it is highly uncertain, even improbable, that the virus would mutate in nature along the pathways prodded in a laboratory environment, so the benefit of looking for these five mutations seems marginal.

I would like to see the studies on which this statement is based. It is well known in virology that mutations selected in laboratory experiments can be been identified in nature. For example, the mutations identified in the H5N1 influenza viruses that transmit among ferrets have indeed been observed naturally in animals. The fact is that no particular viral mutation is improbable, given the enormity of  viral diversity in nature.

The Editors write that the results of the H5N1 studies do not help determine if existing antiviral drugs and vaccines would be effective:

But genetic changes that affect transmissibility do not necessarily change the properties that make a virus susceptible to drugs or to the antibodies produced by a vaccine, so that approach may not yield much useful new information.

Two of the currently used drugs for controlling influenza, Tamiflu and Relenza, act by inhibiting the viral neuraminidase enzyme. Its function is to allow viruses to spread from cell to cell, and could very likely be involved in ferret transmission. If changes in this protein lead to aerosol transmission among ferrets, they could alter sensitivity to the drugs. Other changes in the H5N1 virus might alter its protein profile, making it less sensitive to currently proposed vaccines. These are only two of many reasons why studying this H5N1 virus would yield a great deal of useful information. As noted in A flu virus risk worth taking by Anthony Fauci, Gary Nabel, and Francis Collins in the Washington Post, “…new data provide valuable insights that can inform influenza preparedness and help delineate the principles of virus transmission between species.”

I think it is a good idea to have a public dialogue to understand the goals of influenza H5N1 research. But the discussion should be based on scientific fact, not doomsday scenarios. The Times does everyone a disservice by basing their opinion on science fiction.