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Hong Kong D225G Limited To Severe and Fatal pH1N1

Recombinomics Commentary 16:50
April 8, 2010

D225G was detected in 7 patients with severe disease, including 3 who died. Mixed 225D/G (4 cases) or 225D/G/N (1 case) quasispecies was found in 5 patients with severe disease, including 2 who died. The D225E mutation was identified in only 1 patient with severe disease. Of the 3 patients with mild disease for whom a mutation was identified at position 225, 2 had D225E and 1 had D225N. Comparison of the frequency of the D225G mutation between patients with severe disease (7/57 [12.5%]) and patients with mild disease (0/60 [0%]) showed that the difference was statistically significant.

To examine whether 225G variants may be more adaptable to replication in the lower respiratory tract, we conducted quasispecies population analysis by cloning and sequencing RT‐PCR products from specimens from 1 patient with severe disease. Notably, the patient (patient 1) had a low level of D225G quasispecies in the NPA specimen (11.1%), but the variant comprised the entire population in the concomitantly obtained ETA specimen

The above comments from the paper, “Quasispecies of the D225G Substitution in the Hemagglutinin of Pandemic Influenza A(H1N1) 2009 Virus from Patients with Severe Disease in Hong Kong, China” provide additional detail on the linkage of D225G with severe and fatal pH1n1 infections, as well as the frequency of mixtures.  Media reports had noted that 3 of 7 Hong Kong patients with D225G had died, which was among the lower frequencies reported to date.  The recent publication from Norway noted that 8/11 patients with D225G were fatal, and the numbers were near 100% for Ukraine.  However, the Hong Kong paper notes that like Norway, all cases with D225G were severe.  The paper also notes that most (5/7) samples had mixtures of D225G with wild type or D225N, and providing tracings for two samples from the same patient, showing that D225G in the nasopharyngeal swab was at 11%, which would not appear in a consensus sequence, but was at 100% in an endotracheal wash.  Thus, a nasopharygeal swab would generate a wild type sequence, even though D225G was at 100% in the lower respiratory tract.

These data provide additional evidence that the level of D225G in circulation is grossly under-estimated in sequence databases, because minor species would not be indicated in the published sequence.  Moreover, the discounting of D225G in egg isolates is not warranted, because D225G is frequently present as a mixture, and the same selection in a human lung (which has gal 2.3 receptors), would also be active in eggs, which also have al 2,3 receptors.

The CDC has discounted the linkage between D225G and severe/fatal infections, and has noted instances where D225G was not found in a direct sequence, but was found in lab isolates.  The data from Hong Kong indicates that such results are expected and are not evidence of lab artifact.  The CDC comments were included in the WHO working hypothesis on D225G, which maintained that it was spontaneous and not clustered in time and space and was due to random mutations generated by copy errors.

The CDC/WHO working hypothesis remains hazardous to the world’s health, and is inconsistence with the high frequency of D225G in fatal cases, including 2 of 5 sequences from 1918/1919.

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