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The D222G Mutation and Severe Influenza

By Amesh A. Adalja, MD, FACP, January 25, 2013

During the 2009 H1N1 influenza pandemic, a variety of clinical presentations occurred, ranging from asymptomatic infection to fulminant respiratory failure that required extra-corporeal membrane oxygenation (ECMO). An interplay between host and viral factors is the likely answer to the question of why some but not all patients developed severe illness. Early in the pandemic, one viral factor postulated as having a role in disease severity was the D222G mutation on the HA1 subunit of the viral hemagglutinin. This mutation, which was present in the 1918 H1N1 virus, is known to alter binding properties by permitting replication of the virus in the lower respiratory tract. In 2009, officials from Norway announced that the mutation was found in isolates from 3 patients, at which point the need for case control studies to confirm the severity of associated clinical disease was noted. A new article by authors from the Norwegian Institute of Public Health provides this information.1

Characteristics of the D222G Mutation

Rykkvin and colleagues analyzed 462 respiratory samples from pandemic patients with ordinary and severe cases of influenza, including 52 samples from severe nonfatal cases and 26 from fatal cases. Severe cases included those with lower respiratory tract disease or other end organ complications of influenza.

Through pyrosequencing, the D222G mutation was found in 13 samples—in 31% of fatal cases, 10% of severe cases, and none of the mild cases. The mutation was more likely to be present in specimens collected 8 days or more after symptom onset. In samples collected from the upper and lower respiratory tracts of the same patient, the mutation was found in both.

Of samples that underwent full genetic sequencing, phylogenetic analysis revealed that the isolates did not form a distinct cluster. Instead, each was on a separate genetic branch, indicating that sporadic development occurred rather than transmission of the mutated virus. Most of the D222G-containing viruses existed as quasi-species—or minor variants—that represented less than 50% of the proportion of the circulating virus. In serial samples, the wild type allele preceded detection of D222G in 80%, implying the mutation arose after infection.

Incorporating D222G into Clinical Practice?

The results of this study are important because they offer another clue to the etiology of severe influenza. By changing its binding preference via the D222G mutation, the influenza virus is able to access deeper sites of replication (via targeting of type II pneumocytes and alpha 2,3 linked sialic acid residues) and cause more severe disease. However, the implications for clinical decision making are not clear. The mutation was not found in initially infecting viruses (likely because of known inefficient transmission of alpha 2,3 binding preference viruses); instead it occurs during infection. Since serial sampling is not typically performed with influenza patients, it would be difficult to track development of the mutation.

Because viruses with this mutation are sporadic mutants and do not form one lineage, D222G-containing virus is not likely to become widespread in the population unless further mutations occur. Nonetheless, given its association with severe disease, D222G screening should become part of influenza surveillance. This would allow for tracking of the mutation’s prevalence and identification of other mutations that may render the virus more transmissible.

References

  1. Rykkvin R, Kilander A, Dudman SG, et al. Within-patient emergence of the influenza A(H1N1)PDM09 HA1 222G variant and clear association with severe disease, Norway. Eurosurveillance. 2013;18(3):pii-20369. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20369. Accessed January 22, 2013.