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H1N1 D225G D225N H274Y Mixtures in Duke Death Cluster
Recombinomics Commentary 15:58
February 05, 2010

4 oseltamivir-resistant pandemic (H1N1) 2009 viruses emerged at Duke University Hospital in Durham, North Carolina, United States. One male and 3 female patients, ranging in age from 43 years to 67 years, with severely immunocompromised status, were admitted to the same ward. The onset of influenza illness occurred in a 2-week period between mid-October and early November.

While 3 of the cases were fatal, the role of H1N1 infection in contributing to the deaths is uncertain.

In 3 of the 4 cases, the H275Y mutation was identified before oseltamivir was administered.

The above comments from today’s WER still fail to comment on D225G and D225N in the sequences from the above cluster and still maintain that the role of the H1N1 in the deaths is still unclear.  However, the demographics help sort out the sequences from five isolates placed on deposit at GISAID by the CDC.  All five isolates match the demographics and timeframe detailed above.  Two of the isolates, A/North Carolina/39/2009 and A/North Carolina/49/2009, have the same demographic information (43F) and are likely to have been collected from the same patient. The sequence from the earlier collection is a mixture with D225G and wild type, while the later collection is D225G only. 

However, the sequences from other samples collected in mid-October are also mixtures. One sequence has a mixture of D225N with wild type, while the other isolate was cloned and one clone has H274Y, while the second clone is wild type at NA position 274.

Since all of the samples have NA with H274Y and HA with Y233H, it is likely that all three patients linked to the October collections had all three markers (D225G, D225N, and H274Y) and the collection site and time, as well as virus cloning and growth conditions, determined which combinations were in the sequences placed on deposit.

These data raise concerns that the levels of D225G/N and H274Y in the sequence databases under-represents these polymorphism in patients.  Moreover, host factors, including immunological status may influence which sequences become dominant to impact the clinical picture.

The low reactor status published by Mill Hill raises concerns that immune response to wild type may select these variants, leading to more severe and fatal cases in the new wave which is beginning to emerge in the northern hemisphere.

Detailed sequence data on recent H1N1 is schools and hospitals in North Carolina would be useful.

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