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Frequent D225G in 1918 H1N1 Autopsy Lung
Recombinomics Commentary 11:30
September 21, 2011

The recent paper, “Autopsy series of 68 cases dying before and during the 1918 influenza pandemic peak” included release of partial HA sequences from 12 fatal cases in the United States (largely military bases), increasing the number of 1918/1919 autopsy lung sequences to 17. 

The paper noted that three of the four cases collected prior to the pandemic peak had D225G (Camp Dodge - A/Iowa/1/1918, A/Iowa/2/1918 and Camp Jackson - A/South Carolina/2/1918), while only one of the eight samples collected post peak (Camp Upton - A/New York/3a/1918) had D225G.  However, the five previously released sequences were collected post peak, and two (A/New York/1/18 and A/London/1/1919) had D225G.  Thus, although 75% of the four pre-peak samples is higher than the initial frequency of 40% for the five post peak samples or the 23% for the new total of 13 samples collected post peak, the significance of these differences is far from clear.

The role of D225G has attracted significant interest in the 2009 H1N1 pandemic because of its linkage to severe and fatal cases, and the current version of pandemic H1N1 also has had D225N and D225E at high frequencies.  The finding of D225N in fatal cases in Mexico led to a 2011 pandemic alert, and D225N has also been detected in association with D225G in multiple clusters on multiple genetic backbones (Ukraine, United States, Mexico).

D225G allows for binding to gal 2,3 receptors which are at high levels in human lung, so detection in lung samples is generally higher than samples collected from the upper respiratory tract, and there can be variation in samples collected at different time points. However, the frequent detection of D225G in pre- and post- 1918 pandemic cases indicates it efficiently transmits.

This variation was seen in the fatal cluster at Duke Medical Center in late 2009 when four patients from the same floor died.  All four were infected with the same sub-clade, which had H274Y in NA and had the rare HA marker Y233H.  Three of the four died within a day of each other, and sequences from each patient were slightly different at position 225.  Two samples were collected from the index case.  Direct sequencing of the initial sample from the index case was wild type at position 225 (D was detected), but virus isolated from that sample was a mixture of wild type and D225G.  Moreover, virus isolated from the second sample yielded a sequence with D225G alone.  The sample from a second patient was wild type when sequenced directly, but virus isolated from that sample was a mixture of wild type and D225N.  The sequence from the third fatal case was wild type as seen in direct sequencing or sequencing of the isolated virus.  Thus, although all isolates had the same characteristic markers (Y233H in HA and H274Y in NA) there was considerable variation at position 225, even in multiple sequences from the same patient or sequential collections.

This type of variation was also seen direct sequencing of autopsy lung samples from Ukraine, which would be more analogous to the 1918 results.  In the Ukraine series, the majority of samples had D225G, D225N, or both and phylogenetic analysis identified this heterogeneity in multiple samples on the same branch of phylogenetic trees, signaling the appending of these changes onto identical genetic backbones.
This variation at this position limits the interpretation of the significance of the frequency of D225G in pre and post-pandemic peak samples. 

However, it is clear that D225G was common in autopsy lung samples collected in pre- and post- 1918 pandemic peak collections, and the association of D225G with severe and fatal cases in the current outbreak is cause for concern, as is the presence of D225G in all trH3N2 cases.

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