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D225G / D225N H1N1 Fatal Cluster in San Lois Potosi Mexico
Recombinomics Commentary 23:54
December 24, 2009

The recently released HA sequences from fatal cases in Mexico has identified a cluster(25M and 40M) with D225G and D225N.  Both isolates, A/Mexico/InDRE50625/2009 and A/Mexico/InDRE50617/2009) have mixed signals and were collected within a day of each other from San Lois Potosi, Mexico.  They are the first two isolates from patients in Mexico with both receptor binding domain changes, D225G and D225N, although the same combination was found in a swine sequence, A/swine/4/Mexico/2009, from an outbreak in the adjacent province of Queretaro in April.  The only other reported human sequence with D225G and D225N was from a fatal case in Utah, A/Utah/42/2009, who died July 28.

Concern about the association of receptor binding domain changes D225G and D225N began to emerge when sequences from cases in Brazil were released.  Two Sao Paulo sequences had D225G and both were from fatal cases.  Two more Sao Paulo sequences had D225N and both cases were also fatal.  Moreover, D225G was also found in fatal cases from 1918 and 1919, and the sequence change led to receptor binding changes that targeted receptor with gal 2,3 linkages, such as cells in the lung.

Reports of large number of fatal lung cases in Ukraine led to predictions that receptor binding domain changes at position 225 would be found.  The prediction was confirmed when Mill Hill released sequences from nine patients in western Ukraine.  Five HA sequences from survivors had no receptor binding domain changes, while all four fatal cases had D225G.  Subsequently the CDC released five HA sequence.  Three matched the demographics and sample number for the Mill Hill survivors.  The other two were unique and were likely fatal cases.  Both of these cases had D225N.

The data from Ukraine led other countries to look more closely at sequences from past cases.  In Norway, 3 sequences were identified.  Two were fatal and one severe.  In France there were two cases and both were fatal, including one that also had H274Y.  Similarly, a case from Illinois also had D225G and H274Y.

However, a fatal case from Utah had mixed signals for both D225G and D225N.  This combination was then found in a swine isolated from Queretaro, Mexico and two fatal cases in the adjacent province, San Luis Potosi also had the same combination.  In all cases the same mixed signals were found at the adjacent positions, strongly suggesting that these sequences were transmitting.  This transmission was further supported by collection dates, which were one day apart.

Transmission of these sequences was also supported by cluster in western Ukraine.  The sequences with D225G or D225N were collected from the same general area in Ukraine at the same time.  The initial spike in cases in Ukraine was followed by school closings and warmer weather.  Cases declined but recently began to surge again as the weather cooled and school re-opened.  There were 20 deaths reported in the past 24 hours, raising concerns of another spike in fatalities (see map).

These data continue to support the linkage between D225G and D225N.  Three more recent cases with these changes (one with D225G and two with D225N) were identified in Mexico, and all three were fatal (and the changes were present as mixtures with wild type).  These ratios may vary by tissue type and isolation procedure and the increasing detection may signal changes in circulating virus.

More details and collections from affected organs in severe and fatal cases would be useful.

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