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Worldwide Transmission of D225G
Recombinomics Commentary 06:45
November 27, 2009

The recently released sequences from patients in Ukraine provided valuable insight into the pathogenicity of H1N1 and the genetic change associated with the total destruction of both lungs in fatal cases.  The description of the patients and the spread of receptor binding domain change, D225G, to multiple genetic bakgrounds via recombination led to the prediction that D225G would be found in the lung samples from fatal cases.  The release of the sequences by Mill Hill confirmed the prediction.  Sequences from 10 isolates were released and all four fatal cases had D225G.  Moreover, all 9 cases from western Ukraine, which were from three Oblasts (Ternipol, Lviv, and Khmelnitsy) were from the same sub-clade as the fatal cases, but the samples from the upper respiratory tract did not have D225G.  The absence of D225G from the upper respiratory tract is not a surprise because the specificity of D225G included alpha 2,3 receptors which are present in the lungs.  Thus, the sub-clade with D225G can expand and cause a cytokine storm which destroys the lungs.  Moreover, sequences with D225G have been designated as low reactors by Mill Hill, raising concern that immune responses and vaccine will select for D225G.

Although D225G transmits from patient to patient, only the samples from the fatal cases, which were from  lung and throat samples were positive for D225G.  The sequences from Ukraine led other countries to more fully investigate samples.  Norway, which had seen an increase in fatalities announced the detection of D225G in two fatal and one severe case.  Although those sequences have not been released, 25 HA sequences were subsequently released and one sequence had D225G as a mixture, confirming the mixed nature of samples with D225G.

Moreover, the sequence with D225G was the same sub-clade as Ukraine, and several matching sub-clades were in subsequent samples, but those samples did not contain D225G, again pointing to a requirement for sampling of appropriate tissues.

The implication of this sub-clade in the increase in deaths in Norway was the finding that the first fatality was also linked to the same sub-clade.  The patient, 43F, was in previously good health and given a prescription for Tamiflu after visiting the hospital.  However, she was sent home and died two days later.  This type of rapid death had been noted for many of the Ukraine cases.  Full sequences were generated confirming that the NA sequence was closely related to the NA sequences from western Ukraine, but the sample was from the trachea and did not have the D225G.  However, the association of this sub-clade with the first patients death and the finding of D225G in the first isolate matching this sub-clade support D225G transmission as a mixture, with detection in appropriate sampling of the lower respiratory tract.

Phylogenetic analysis of public sequences indicate that the Norway/Ukraine is widespread, strong suggesting that D225G has sread worldwide.  However, detection of D225G, as was seen in Ukraine requires that the proper samples are tested.

The finding of D225G in four of four fatal cases in Ukraine leaves little doubt that the polymorphism is transmitting and the recent classification of Ukraine sequences carrying D225G suggests the spread will accelerate.  The finding of the same change in unlinked patients in two Oblasts in western Ukraine is similar to the finding of swine H1N1 in two counties in southern California in April.  The fact that the two California cases had no link to swine or each other, and were collected from patients over 100 miles apart conclusively demonstrated that the swine H1N1 was efficiently transmitted human-to-human and many more cases would be identified.

The data from Ukraine conclusively demonstrate that D225G is efficiently transmitting and the transmission traces back to earlier isolates from Norway of the same sub-clade with D225G.

Since D225G is frequently not detected in samples from the upper respiratory tract, another method of tracking is through phylogenetic analysis, which shows that the Norway/Ukraine sub-clade is widespread, even though all HA sequences do not have D225G, as was seen in Ukraine.

The worldwide transmission of the Norway/Ukraine sub-clade, or other sub-clades with D225G raises concerns that associate hospitalizations and fatalities will have a significant uptick as an increasing number of patients get exposed to this sub-clade linked to D225G.

More surveillance of low respiratory tract infections would be useful.

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