Tuesday, February 28, 2006

Taking stock, part II

We return to the task we set ourselves in Part I, surveying our ignorance about some important bird flu questions. Taking up where we left off, we ask what we know about what determines which species the virus infects. This is not an in-depth treatment. We just mention a few topics still being debated in each category. The extent of disagreement varies with topic.

Host range: This is being intensively studied. Paradoxically we may know less about it now than we thought we did ten years ago, as the complexity of the host range problem is being revealed by better scientific techniques. We originally thought that the determinant rested solely with the nature of the cell surface receptors in the host, with birds having one kind of receptor, humans another, and pigs having both. Pigs could thus act as a necessary "mixing vessel" where human and bird adapted viruses would exchange genetic information and produce a Frankenstein monster pandemic hybrid. We now know that the pig isn't necessary, as both the 1918 virus and the current crop of avian viruses seem to have jumped from birds directly to humans. Moreover the supposed division of cell surface receptors between humans and birds also isn't what we thought it was. The human respiratory tract has a lot of cells with the receptor we thought was characteristic of birds. (If you want to know more about this subject we treated it here in a series of four posts: here, here, here and here). Moreover the interaction between the receptor on the host cell and the HA protein on the virus that supposedly determines the specificity is quite subtle. Predicting and understanding the effects of a particular mutation is still not possible, although some relationships are known or can be inferred. It is also probably true that the ability to infect different hosts requires changes in other genes. A recent discovery that the presence of a ligand on the viru's NS1 protein that binds the PZD domain in host cells differentiates bird and human viruses raises a whole new set of possibilities. Obviously there is still a lot to learn and no guarantee we know the most important part as yet.

Becoming easily transmissible from person to person and virulence: Disease is not inherent in an organism itself but is from an interaction the between the virus, its host and the environment. We are now able to rapidly sequence viral isolates but the step from the genetic sequence to knowing its implication for disease is a big one. At the moment we don't know what makes one virus easily transmissible nor do we understand what makes one virus virulent and another likely to cause milder disease. The nasty and rapid symptoms and pathology of human H5N1 infection is still shrouded in mystery. The suspicion that "cytokine storms" -- uncontrolled inflammatory responses -- are responsible has scientific support but we remain at a loss as to the mechanism behind it. What is there about the virus that it is able to subvert the very machinery we use to defend ourselves for its own purposes and to our detriment? There is a also uncertainty about many details of the immune response, especially the cell-mediated response. The immune system is extremely complex, so our difficulty understanding its function in influenza shouldn't be a surprise, but many people assume we know all about it. We don't.

Vaccines and antivirals: We have yet to make a feasible experimental vaccine we are confident will protect people against this virus. Not only don't we yet know what the pandemic strain but existing strains have not made especially effective vaccines. For reasons still not clear the virus is not very immunogenic and efforts to date have not been able to produce potent vaccines. Nor do we have the production capacity to make much difference for years to come. For the near future vaccines do not seem to be the answer. Nor do we yet know how useful either of the two main classes of antivirals will be. Many strains of H5N1 are resistant to the older class of drugs (the adamantanes), and there is uncertainty about whether there is emerging resistance to the newer neuraminidase inhibitors like Tamiflu and Relenza. Whether Tamiflu resistant strains will be less virulent than sensitive ones, as some believe, or whether resistance will develop to any appreciable extent is still unknown. Finally, if the neuraminidase inhibitors are effective, there is now uncertainty what the proper dose regiment should be, both in daily dose and length of treatment.

How does influenza spread in human populations? Probably most surprising of all our areas of ignorance is that we are still not sure all the modes by which influenza virus spreads in human populations. The three main possibilities are via large droplets (from sneezing or coughing), which is a well established mode of spread and has a radius of about five feet; small droplet nuclei, tiny droplets that remain suspended for long periods in the air so the infecting radius is much larger; and fomites, or inanimate objects, like computer keyboards and door knobs. Handshakes, too, are still of uncertain importance. We know the virus will survive for long periods on hard surfaces but we don't know if this is an important mode of transmission compared to others. For example, there are some data the virus will only survive for minutes on human hands, so that if you touch a doorknob the amount of virus may diminish rapidly and even if you then touch your nose, eyes or mouth the amount of virus may not be sufficient in instances to infect you. We can be fairly confident, I think, that transmission via fomites happens sometimes. The question, however, is how often and how important is it in the scheme of things. A great deal of advice is being given out about how to avoid the flu, ranging from washing your hands to wearing a mask. In truth, while some of this advice is plausible and prudent, we have little idea how effective any of it is.

This has been a very cursory survey of our ignorance. There is a great deal more that could be said about all of these topics. And we will learn more, no doubt. I hope it won't be the hard way. Meanwhile, we will be forced to make our best guesses, given the uncertainties. People and nations will sometimes opt for different measures, influenced by valid considerations beyond the science (but no doubt invoking science as their rationale). That is inevitable and necessary.

All the while the virus is also learning the best way to accomplish its only task, making more copies of itself.

Part I, here.