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H5N1 Bird Flu Pandemic Phase Evolution

Recombinomics Commentary

June 5, 2006

Dr. Niman contends that the largest human-to-human cluster so far was not in Indonesia, but in Dogubayazit, Turkey, in January. W.H.O. updates recorded 12 infected in three clusters, and quoted the Turkish Health Ministry blaming chickens and ducks. Dr. Niman counted 30 hospitalized with symptoms and said the three clusters were all cousins with the last names of Kocyigit and Ozcan, and that most fell sick after a big family party on Dec. 24 that was attended by a teenager who fell sick on Dec. 18 and died Jan. 1.

A patriarch, Dr. Niman said, told local papers that the two branches had had dinner together six days after the 14-year-old, Mehmet Ali Kocyigit, had shown mild symptoms. He died on Jan. 1, and several other young members of the two families died shortly after, with other relatives showing symptoms until Jan. 16. No scientific study of that outbreak has been released.

Dr. Niman also said clusters were becoming more frequent, especially in Indonesia.

Level 4 means the virus has mutated until it moves between some people who have been only in brief contact, as a cold does. Right now, Dr. Nabarro said, any human transmission is "very inefficient."

Level 6, meaning a pandemic has begun, is defined as "efficient and sustained" human transmission.

Ms. Cheng of the W.H.O. said that even if there were more clusters, the alert would remain at Level 3 as long as the virus dies out by itself.

"A lot of this is subjective, a judgment on how efficiently the virus is infecting people," she said. "If it becomes more common, we'd convene a task force to raise the alert level."

The above comments are from Donald McNeil Jr's article in the New York Times on human-to-human transmission of H5N1 bird flu.  Described above is the largest human H5N1 cluster, which was in Turkey and involved three families with confirmed H5N1 and one or two more related families which have hospitalized patients, but tested negative for H5N1.  In addition, frequent cluster are being reported in Indonesia, including the large cluster in north Sumatra.

The comments by WHO officials on the phases and change of phases is also include, and those remarks suggest that phase 4 and 5 have been phased out because the requirements for convening a task force are those that define the pandemic phase 6, which is efficient and sustained.

The two phases that are not being discussed are 4 and 5 which are defined by small localized clusters of cases number less than 25 people for phase 4 and over 25 for phase 5.  These phases are designed to identify increases in transmission frequencies, that are somewhat controlled.

Although movement to these levels was not formally announced, WHO statements in updates as well as methodology of responses indicate the level has already been raised to four and possibly five.

The most cited cluster of human-to-human transmission was in September of 2004.  The index case was staying with her aunt, 100's of miles from her both, an office worker in Bangkok.  The mother visited her daughter hospitalized in northern Bangkok.  The index case died and the mother and aunt developed symptoms after her death.

The September 28, 2004 WHO update indicated:

While the investigation of this family cluster provides evidence that human-to-human transmission may have occurred, evidence to date indicates that transmission of the virus among humans has been limited to family members and that no wider transmission in the community has occurred.

Thus, WHO indicated limited transmission within the family as defined for phase 3.

The number of clusters increase in northern Vietnam at the beginning of 2005, but it was the second cluster in Indonesia that led to WHO modifying its wording in its updates.  The first two confirmed cases in Indonesia were part of clear human-to-human clusters.  The first involved a government worker and his two daughters.  This cluster produced the only public sequence of human H5N1 from Indonesia.  It was related to Indonesian poultry sequences, but had a novel HA cleavage site and glycosylation site and contain bits of genetic information from H5N1 from southeast Asia and China.

The cluster was followed by another cluster, involving an airline worker and her nephew.  It was another case of human-to-human transmission and the H5N1 was distinct from the first cluster and had PB2 E627K as well as the wild type HA cleavage site.  In the past, E627K was associated with the ability of H5N1 to replicate at lower temperatures and was associated with poor outcomes in humans.

The September 22, 2005 WHO update indicated

In a few instances, limited human-to-human transmission of the virus may have occurred following close contact with a patient during the acute phase of illness. In all known instances, such transmission has been limited and has not led to larger outbreaks in the general community, indicating that the virus does not spread easily among people at this time.

Now the human-to-human spread was being described as not being EASILY transmitted.  The number of examples of human-to-human transmission was becoming too large to deny, so the term "easily" was introduced into descriptions of human transmissions.  This signal the move to phase 4 which was defined by limited human-to-human transmission.

The limited transmission expanded in Turkey at the beginning of 2006.  As noted in the quote above, the clusters were getting significantly larger and disease onset dates indicated that the transmission was now going from cluster to cluster.  The clusters involved relatives and close contacts, but the language in the WHO update changed.

The January 12, 2006 WHO update indicated

All available evidence indicates that no sustained human-to-human transmission has occurred

Now the WHO update include the term "sustained" human-to-human transmission.  Sustained transmission defines the final phase 6, signaling the pandemic start and inability to contain it.  Thus, the update was signaling a move toward phase 5. 

The number of cases and clusters was still developing.  WHO media reports indicated the initial cases involved two large families.  However, WHO failed to indicate that the two large families were related to each other.  As the patients were confirmed, WHO updates withheld disease onset dates.  In additional, the updates failed to disclose the relationship between the index family, Kocyigit, and cousins from the Ozcan who were together at a family gathering on December 24, 2005. The four Kocyigit siblings were transferred to Van at the end of December.  The index case had seen a local doctor when symptoms were mild and was given cough syrup.  After the family gathering the condition of the index case and siblings were deteriorating.  The three oldest arrived at Van unconscious and all three died.  Although they were initial said to be negative for H5N1, H5N1 was detected in the lungs of the three fatalities and H5N1 was isolated from the two oldest siblings.  The Ozcans began arriving at Van in early January. 10 Ozcan family members were admitted over several days.  Two admitted initial were placed in the ICU and eventually were positive for H5N1.  This cluster was followed by infections in Ozcan cousins from another family.  The index case for that family died and her bother recovered. Both were H5N1 confirmed.

The H5N1 for the index case for the Kocygit cluster was found to have a genetic alteration, S227N, in the receptor biding domain.  This change had been predicted because the H9N2 in poultry in the Middle East had donor sequences which would allow S227N to be formed in the Qinghai strain of H5N1.  This was a concern because all bird isolates from the Qinghai strain had PB2 E627K.  Although infections in humans by the Qinghai strain had not been confirmed prior to the Turkey cluster, addition of S227N would create two genetic changes which targeted humans.

The WHO update on the H5N1 in Turkey indicated

Virus from one of the patients shows mutations at the receptor-binding site. One of the mutations has been seen previously in viruses isolated from a small outbreak in Hong Kong in 2003 (two cases, one of which was fatal) and from the 2005 outbreak in Viet Nam. Research has indicated that the Hong Kong 2003 viruses bind preferentially to human cell receptors more so than to avian cell receptors. Researchers at the Mill Hill laboratory anticipate that the Turkish virus will also have this characteristic.

Thus, the clusters were growing and the H5N1 was genetically changing.  However, as noted in the same report, the H5N1 was susceptible to both classes of anti-virals, neuraminidase inhibitors such as Tamiflu, and M2 ion channel blockers such as the amantadanes.

The Turkey outbreak in January was followed by the Azerbaiian outbreak in February, which also had the characteristic gap in disease onset dates.  This outbreak was also due to the Qinghai strain, but the sequence has not been released.

The most recent large cluster was in Indonesia again.  The north Sumatra cluster involved 8 family members and 7 died.  The WHO update indicated that the H5N1 was sensitive to Tamflu, but failed to indicate that the isolates were amantadine resistant.  The description of the H5N1 suggested it had a wild type HA cleavage site.  Third party reports indicated the level of H5N1 was elevated in the nose and throat, suggesting the isolates also had PB2 E627K.

As noted above, WHO is now talking about raising the pandemic level when H5N1 is easily transmitted and is sustained, which is the definition of phase 6.

Although WHO has not acknowledge the increases in the clusters which define phase 4 and phase 5, actions have been consistent with the higher levels.  Tamiflu ahs been used to flood the area in Turkey, Azerbaijan, and now Indonesia.  The United States has begun to deploy its stockpile to a "country in Asia" and Roche, the maker of Tamiflu, as been put on notice to prepare to ship its reserves.

Thus. although WHO has maintained phase 3, their language in updates, and actions signal pandemic evolution well beyond phase 3, and recent comments indicate the level will not be raised until the pandemic has reached the final phase 6.

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