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Evidence on H1N1 D225G in Lung Cases in Norway and Ukraine
Recombinomics Commentary 11:29
November 21, 2009

The WHO said the mutation does not appear to spread and the public health significance of the finding is unclear.

"Although further investigation is under way, no evidence currently suggests that these mutations are leading to an unusual increase in the number of H1N1 infections or a greater number of severe or fatal cases," the agency said.

The above WHO comments on the receptor binding domain change D225G (cited as position 222 in some reports using H1 numbering) is curious.  Although WHO claimed that there were no significant changes in the sequences from Ukraine, none of the Ukraine situation updates excluded a receptor binding domain change, and when 10 HA sequences were published at GISAID by WHO regional lab Mill Hill, there was clear evidence of an association of D225G with fatal cases.  Of the 10 sequences released, four were listed as deceased, and all four had D225G.  None of the six samples which came from patients that were labeled with age and gender but had no deceased designation had D225G.  Moreover, three of the four samples from deceased patients were lung samples and all three lung samples had D225G.  The samples which had closely related sequences but lacking D225G were predominantly nasal washes, which also presented concerns that the swine H1N1 was differentially detected, due in part to changes in receptor binding specificity.

This concern was based on published data on sequences from samples from 1918 patients.  In 1918 the same change occurred.  Most samples had a D at position 225, while two samples had D225G (from 1918 and 1919).  The tested sample with D225G had a different binding specificity, which would be expected to show differential binding to various tissue types.

Moreover, the D225G identified from Ukraine was in both of the hard hit areas, Ternopil and Lviv.  Two samples from each area were positive, indicating the change had spread.  Ukraine has already acknowledged over 350 dead patients and initial reports described hemorrhagic lungs that were totally destroyed.  This destruction was in multiple media reports as well as an agency report describing 90 fatal cases.

Moreover, the evidence was not limited to Ukraine.  Earlier samples from lung tissues from deceased patients in Sao Paulo also had D225G, as did patients in multiple countries.  Most cases were not described in detail, but the case from China was from the first severe case in Zheijiang Province and although the patient survived, she was hospitalized for several weeks.

In addition, the presence of the same change on multiple backgrounds indicated the polymorphism was being acquired via recombination.  The sudden appearance of the same polymorphisms on multiple backgrounds has been described previously, including a silent change in H5N1 and H274Y in seasonal flu.  These changes allowed for the prediction of D225G in the Ukraine patients prior to release of the sequences.

The above comments were made after D225G was found in samples from deceased or severe cases in Norway, which provided further evidence of spread and association with lung samples.

Thus, there was and is ample evidence of D225G in severe and fatal cases.  Like 1918, it is not in all samples from fatal cases, and as with all infectious disease, not all infections are fatal.  If the initial dose is low, or the hosts mounts and effective early defense, the clinical course may be mild, as has been seen with virtually all influenza infections, including H5N1 infections such as those in Egypt.

Thus, the presence of the 1918 receptor binding domain change in an H1N1 swine virus that has  jumped to humans is cause for concern, and a more comprehensive survey of lung samples is useful, as well as release of  new receptor binding data.

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