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WHO Revisions of Pandemic Phases

Recombinomics Commentary

May 29, 2006

The difference between stages three and four hinges on how easily the virus can be passed between humans -- a subjective call that in some cases may prove very difficult to make.

Examples of close contact include "staying close to the ill persons for hours or holding, touching, wiping the face, or kissing or speaking with the ill person at a close distance," according to Paul R. Gully, a senior advisor at the WHO in Geneva. "By contrast, casual contact refers to a lesser degree of contact between the infected person and others -- for example, being [within] a few to several feet away for shorter periods of time, but long enough for common respiratory infections such as regular flu or colds to be passed on through coughing or sneezing."

New guidelines that distinguish between close contact and casual contact may eliminate some of the confusion over pandemic phases, but there are several sources of confusion.  WHO comments used the subtle approach to distinguish the types of transmission by introducing the word "easily" into human-to-human transmissions (H2H) descriptions.  Thus, comments indicted that H5N1 was not EASILY transmitted to humans.  However, this subtle change was not widely noticed and was left out of many media reports,  However, even when included, readers would not necessarily notice the subtle change.

Several months ago, when the public profile of bird flu increased, the difference of transmission was linked to the failure to identify examples of H2H2H transmission, as opposed to just H2H.  However, the recent cluster in Sumatra appeared to be H2H2H or H2H2H2H, so the failure to increase the phase from 3 to 4 caused additional confusion.

However, this confusion was due to the failure of WHO to be more transparent on prior H2H clusters.  WHO knows that the key to distinguishing H2H from a common source is the disease onset dates.  The WHO and CDC wrote a paper on the first 15 clusters, which were largely clusters that has a 5-10 day gap between disease onset dates of the index case and additional family members.  These frequent gaps left little doubt that the vast majority of familial clusters were H2H or longer chains.  As noted above, there are many types of transmission due to close contact and these types of close contact would be common among family members.  Although possible, common source transmission by two or more independent events would be highly unlikely because H5N1 transmission from birds to humans is extremely rare.  In contrast, familial clusters are increasingly common, especially in Indonesia.

The majority of cases in Indonesia is linked to family clusters and are examples of H2H.  Thus, the extended chain in Sumatra was the largest and most deadly reported cluster in Indonesia, but it was only incrementally greater than the  large number of earlier cases.

Moreover, WHO officials know that most cases in West Java have a novel cleavage site that has not been reported in bird sources in the area.  The lack of an avian source for the human infections raised the question of H2H in Indonesia as soon as the first sequences was generated in July of 2005.  The cleavage site RESRRRKKR was not in any public sequence and as the number of bird and human sequences in Indonesia increased, the difference between the human cases and bird cases remained.  Only one human case in the West Java area had the wild type H5N1 sequence, RERRRKKR, although the cases in Sumatra probably change the number of human sequences with the wild type sequence.  However, this new data clearly demonstrates that two distinct sequences are circulating in Indonesia that can cause H2H transmissions.

H5N1 has been evolving incrementally via recombination.  In many instances single nucleotide changes are acquired.  However, even a single nucleotide change like S227N in HA or E627K in PB2, can cause a dramatic change in transmission or virulence. The only viable human Indonesia sequence of HA and NA has a large number of polymorphisms found in a wide range of H5N1 sequences in Asia, indicating recombination is frequent and involves many hosts, including mammals.

Therefore changes in key areas such as the receptor binding domain can be sudden, and changes in transmission, even if limited to close contact can be instructive and offer intervention targets. 

Once H5N1 is easily transmitted by casual contact, the time between that change and phase six may be hours or days.

Therefore the small changes may provide more useful intervention opportunities than a declaration that transmission has become easy, because at that time options may be very limited.

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