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Confirmed H1N1 D225G Transmission in Italian Family Recombinomics Commentary 20:42
January 17, 2010

Following retrospective examination of the sequences of strains of influenza virus pandemic A/H1N1v by the National Influenza Center of the Department of Infectious Diseases, Parasitic and immune-mediated, we have identified two cases in total, bound together, in which a mutation was present that led to the replacement of an amino acid in hemagglutinin (D222G). The infection was transmitted from a patient suffering from a severe viral pneumonia in a family, but he has since developed a flu syndrome with benign course.

The above translation from the Italian Ministry of Health describes the transmission of D225G (aka D222G) within a family in Italy.  Media reports indicate the index case (24M) was on an ECMO machine and in an induced coma for 15 days.  He eventually recovered as did a family member, who had a milder course. Sequences from both patients had D225G, confirming trasmission within the family, or transmission to the family from a common souce.

Although some initial comments from Norway suggested D225G was spontaneous and did not transmit, there was no scientific basis for such a statement. Norway re-evaluated samples because of sequences from Ukraine, which had D225G in multiple fatal fatal cases from multiple locations in western Ukraine, providing the georgraphical and temporal data supporting transmission.  Although an ECDC report also cited spontaneus mutations, the WHO document on D225G merely said that the detection was sporatic.  D225G or D225N had already been found in 8 cases in Ukraine and all 8 appeared to be fatal including two cases which had both changes.  In Ukraine all sequences were on the same general genetic background, which contained two markers on PB2, one of which was K340D.  However, within Ukraine there were well define subclades and D225G had crossed sub-clades, supporting jumps via recombination.

In the Italian cluster above, both family members survived and one case was mild, even thogh both cases had D225G.  However, influenza is a heterogeneous disease and results can vary, even when the same virus infects two family members, because of host factors as well as viral levels in the initial infection.

This differential response was also seen in a familial cluster in Romainia which likely involved D225G.  One family mmeber (46M) had a mild course, while two other family members (42F and 19F), and the fiancee (21M) of the daughter were hospitalized, and two cluster members died (42F and 21M) creating a CFR of 50% within the cluster and an attack rate of 100%.

Thus, highly lethal H1N1 variants can be both lethal and transmissible.

The case fatality rate in several countries is 100% for D225G/N isolates raising concerns that the spread of such variants would be catastrophic if such variants become dominant.  Sequence data on these familial clusters as well as additional fatalities in Ukraine and surrounding countries would be useful.

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