Thursday, May 25, 2006

Clusters, sequences, trust

If there is more upset than WHO feels appropriate about the large cluster of cases in Indonesia with apparent human to human spread within an extended family, they have no one to blame but themselves. With financial markets spooked and currencies in Asia falling, WHO is saying this may not be as unusual an event as appeared at first:
But Firdosi Mehta, acting representative of the WHO in Indonesia, urged against any over-reaction, saying this was not the first cluster that the world has known.

Limited transmissions between people are caused by close and prolonged contact when the sick person is coughing and probably infectious. (Reuters)
It is certainly true this appears more serious. One reason for this is WHO's habit of reassuring the world that whatever is happening at the moment is no big deal but what could happen in the future is a big deal. Whenever their prognostications elicit too much concern they ratchet them back. There has been evidence of human to human transmission right along -- sporadic but fairly clear -- but WHO has chosen to ignore it in their public pronouncements, instead electing to emphasize (falsely) that all the evidence to date has been it required close contact with sick or dead birds to put a person at risk. It has been clear to WHO and many others that close contact with sick and dead poultry is neither a sufficient nor necessary condition for contracting the illness. Had WHO been more accurate about this, the reaction to the Indonesian cluster might not be so great.

Lack of clarity from WHO remains troublesome, particularly regarding the viral sequences from this cluster and more generally. They have the sequence information in hand. They can deposit it immediately in GenBank so others can look at it and decide whether their claims of "no change" are correct. This needs to be done with the other Indonesian isolates as well, not just human isolates but those from birds and any other animals. Here is the WHO statement from yesterday concerning the sequencing:
Full genetic sequencing of two viruses isolated from cases in this cluster has been completed by WHO H5 reference laboratories in Hong Kong and the USA. Sequencing of all eight gene segments found no evidence of genetic reassortment with human or pig influenza viruses and no evidence of significant mutations. The viruses showed no mutations associated with resistance to the neuraminidase inhibitors, including oseltamivir (Tamiflu).

The human viruses from this cluster are genetically similar to viruses isolated from poultry in North Sumatra during a previous outbreak. (WHO)
WHO spokesperson Peter Cordingley said yesterday, "There is no change in the virus whatsoever. This virus has not developed the ability to jump more easily from chickens to humans, nor spread among humans more easily." (CNN)

We assume Cordingley isn't speaking literally ("no change whatsoever") since this is improbable and different than the WHO statement there was no "significant" mutation. A quibble, perhaps, but it raises the question what WHO considers a "significant" mutation. Does the statement the virus is "genetically similar" to poultry viruses imply the cleavage site is the same as the avian one and not the one seen in humans in Indonesia? Would WHO consider an anomalous cleavage site be considered "significant" because it wouldn't be expected to affect transmissibility? What is the WHO criterion for a "significant" mutation, anyway?

Even the statement there is no reassortment with human or pig viruses is ambiguous. Was it meant to leave open the possibility there was reassortment with other bird viruses? For example, if you were to draw phylogenetic trees for each of the eight segments, would you find there has been a swapping of some of the internal gene segments from one avian clade to another in the new isolates (i.e., the isolates are a new avian genotype)? This has been advanced as an explanation for the switch from one predominant strain to another in seasonal flu, but is visible only when you consider the whole viral genome, not just the HA and NA genes. Since no one else has the sequences for the many other Indonesian viruses, no one else can draw these trees. Have they done so?

The certainty with which WHO says there is no significant change in the genetics of the virus gives the false impression they will know such a change when they see it. We have an inkling of some things that might worry us, and presumably the statement means they haven't seen any of these. But our area of ignorance is much larger than our area of knowledge, so reassurances about the lack of change of the virus are premature. It is a melancholy truth that we will know a pandemic is coming our way when we see cases piling up somewhere, not before.

WHO has brought these suspicions on themselves. Let us be as clear as we can. Unlike some others, we don't view WHO as the enemy. Without it the world would be much worse off. WHO is not a monolith or a single person. There are many hard working and dedicated people giving their "all" at WHO and we would be ungrateful not to acknowledge this. If you want to battle an emerging pandemic, this is where the action is and it is going to attract the best, the bravest and the most dedicated. But WHO is also a lot of other people working in a complicated bureaucracy that has become ever more politicized since the days Director General Marcolino Candau ruled so effectively with an iron fist (and wasn't renewed for his trouble). Many countries, including the US, mess around politically with WHO, to everyone's detriment.

With bird flu, WHO's lack of transparency, titrating public reaction and attempts to avoid offending any of its member states have resulted in a serious loss of trust. We shouldn't have to raise any questions about the genetics of the isolates. WHO should release the new sequences (and many others). And so should CDC, St. Jude's, Weybridge and the other stellar flu scientists around the world who are sitting on sequences. If isolates come to a scientist with strings attached, they should tell the source they will not be party to suppressing scientific information. They run a risk that somone else will get the isolate or that no one will. But it is the right thing to do and will change behavior of sources if legitimate scientists cooperate. Scientists who don't should be held up to censure and their papers refused publication just as with any other ethical lapse.

We wish we could take WHO's statements about the genetics of the virus at face value. It is a sad commentary that we and many others no longer do this.