Recombinomics Commentary 16:50
April 21, 2009

That would be an alarming development, but other experts, including those at the World Health Organization, say such fears are exaggerated. Although thousands of Egyptians have rushed their children to hospitals this flu season, there is no evidence yet of asymptomatic avian flu cases or any significant mutation in the H5N1 virus.

“Right now, it’s all hot air,” said Dr. Robert G. Webster, a flu expert at St. Jude Children’s Research Hospital in Memphis. “I hope to hell it’s not happening, because it would mean the virus is adapting to humans. But there’s not a shred of data.”

The above comments from Donald McNeil’s New York Times piece, “Avian Flu Cases in Egypt Raise Alarms,” include the control data that provides more than a “shred of data” for enhanced H5N1 transmisison because the confirmed cases are focused in toddlers between the ages of 1 ½ and 2 ½. The other children “rushed” to hospitals this year have tested negative.  

There have been 15 confirmed H5N1 cases this year and 12 were children.  However, only one of the 12 was not a toddler.  Moreover, the 11 confirmed toddlers are almost double the 6 toddler confirmed in the past three years.  Thus, the frequency in each of the past three years was about 12%, while this year its 67% of confirmed cases. In addition, all have survived and most have had mild cases that did not produce pneumonia nor require ventilators.  Only one of the 11 toddlers had been in critical condition, and even when osletamivir treatment begins three to four days after the start of symptoms, as seen in the latest case, the case is still mild.

These mild cases raise concerns that they may represents a small tip of a very large iceberg.  In the spring of 2007 there were also mild cases, when 16/17 patients survived.  However, the demographic was different.  16/17 of the cases were children between the ages of 3-10.  Thus, the change in demographic from children in the spring of 2007 to toddlers in 2009 is significant and represents real data.

The concern of significant spread is also supported by the clustering of clusters.  The two cases (#61 and #62) identified at the beginning of this month were cousins and next door neighbors in Kom Hadash in Beheira.  The four day spread in disease onset date indicated the index case #61 infected his cousin, #62.  

That cluster was followed by the formation of a similar cluster (case #64 and #66) in Kafr el Sheikh in a small district, Kellin. It remains unclear if these two cases were related or neighbors, but the two cases had disease onset dates separated by 8 days, and the cluster signals for efficient transmission of H5N1 to humans.  

In addition, the other two cases this month (case #63 and #65) were from northern Cairo and admitted to the same hospital.  Treatment was delayed after admission, suggesting the patients denied poultry contact.

Thus, the six most recent confirmed cases form three geographic clusters, signaling more efficient transmission of H5N1 to patients.  Moreover, none of the patients have died, although three were initially in critical condition, but none were toddlers.  The three toddlers in these cluster have mild cases and only the most recent case is still hospitalized.

In addition to the epidemiological data, suggesting H5N1 infections are significantly higher than the confirmed cases, is the evidence for a genetic change.  Although there is no data supporting reassortment between human and avian flu genes, there is little reason to expect such data since there have been no prior reports, including dozens of H5N1 clusters signaling human to human transmission.

Instead there is evidence of a genetic change at position 129, which is in contact with the receptor binding domain.  Most clusters involving clade 2.2 have receptor binding domain changes.  The deletion of position 129, S129del, has been reported in 13 public H5N1 sequences in Egypt, including human and avian isolates in 2007 and 2008.  In 2007, the cluster from Qena had this change in H5N1 from two siblings.  The hospital admission dates for the siblings were four days apart, supporting the infection of one sibling (4M) by his sister (6F).  The deletion is also associated with a downstream change, A152T, found in H5N1 escape mutants isolated by the Webster lab.  This additional change signals the origin of the deletion.  
In addition, another change at position 129 (S129L) is associated with human H5N1 isolates in Asia, signaling a role for this position in the adaptation to humans.  Moreover, this change is also associated with changes that creates similarities between H5N1 and H1N1, human seasonal flu.

This genetic data is some obscured in the 2009 cases because NAMRU-3 has not released any H5N1 sequences from poultry or human isolates from the 2008/2009 season.  However the first two cases of 2009 (toddlers from Cairo and Suez) was included in a WHO phylogenetic tree on vaccine target for 2009.  Bother toddler sequences were similar, and the branch on the tree suggested that the 2009 isolates belonged to the sub-clade with S129del. In prior trees from 2007 and 2008 WHO reports on vaccine targets, at least one public sequence with S129del was included.  The absence of such a marker in the 2009 reports leaves some ambiguity, but it is likely that the two isolates from the toddlers has S129del.

Thus, the data on the genetic changes in H5N1 in 2009 in Egypt has been withheld by NAMRU-3, although WHO clearly has the data because it was required to contrauct the WHO tree.

Media reports indicate the WHO team is in route to Egypt to investigate the H5N1 cases and clusters.  

Release of the withheld sequence data is long overdue.