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Human Transmission of Multiple Novel Influenza Constellations
Recombinomics Commentary 12:00
December 12, 2011

An investigation by the Iowa Department of Public Health (IDPH) determined that the families of patients A, B, and C reported no recent travel or attendance at community events. To date, the only epidemiologic link among patients A, B, and C that has been identified is attendance at a gathering of children on patient A's illness day one. No illnesses were reported among adults or among the five other children who were present at this gathering on that day. No swine exposures have been identified among adults or children attending this gathering.

Two human infections with novel influenza A viruses were detected in children from two states (Minnesota and West Virginia). One patient was infected with a novel influenza A (H1N2) virus and one patient was infected with a novel influenza A (H3N2) virus. Both patients have recovered from their illnesses. While both viruses are known to circulate in U.S. swine, there was no close contact with pigs reported preceding illness onset in either case.

The above comments from the early release MMWR on the Iowa cluster (H3N2pdm11 – A/Iowa/07/2011, A/Iowa/08/2011, A/Iowa/09/2011), and the week 48 FluView on the novel cases from Minnesota (trH1N2 – A/Minnesota/19/2011) and West Virginia (trH3N2 – A/West Virginia/06/2011), note that none of the five cases had a swine exposure, and the MMWR cites two additional contacts with the confirmed cases in Iowa who became symptomatic within 1-2 days of the index case (brother and father), and this linkage to an untested symptomatic contact was also noted for the case in Minnesota, which has similarities with the initial confirmed cases in 2009 because those two cases had no swine linkage, and untested relatives / contacts were also symptomatic, signaling efficient and sustained human transmission.

The efficient and sustained human transmission is also seen in the frequency of the novel cases in patients under 10, which is alarming because the above cases represent three different versions of the same virus transmitting in this population.  These cases are all rooted in the 2010 human trH3N2  sequences most completely represented by the two cases with the same lineages for all eight gene segments (A/Pennsylvania/40/2010 and A/Wisconsin/12/2010) which were altered by reassortment.  The first 10 cases in 2011 had the same constellation of genes, which had 5 genes from the two 2010 human cases cited above, as well as three genes from a swine H1N2 parent from Ohio, A/
swine/Ohio/FAH10-1/2010, which contributed PB1, NA, and the M gene which was from H1N1pdm09.  The trH3N2 described above exchanged the N2 for another swine trH3N2, so it matches the above cases in 7 of the 8 gene segments, including the H1N1pdm09 M gene.  The trH1N2 was generated by the same two parents which formed the H3N2pdm11 constellation, except the H1N2 just swapped the H and N genes.  Therefore, the N2 matches the 10 H3N2pdm11 cases and is most closely related to A/Pennsylvania/09/2011 (which is also true for the MP and NS genes).  Thus, all 12 of the novel isolates in 2011 are reassortant versions of the same H3N2  and trH1N2 parents, and 11/12 match trH3N2 cases match in 7 of the 8 gene segments, while the trH1N2 has the same N2 found in 11/12 cases (as well as four other genes (PB2, PA, NP, NS) that have the same lineage for all 12 isolates.  Moreover, the H and N genes trace back to human isolates for all 12 cases.  H3 is linked to seasonal H3N2 from the mid 1990’s, while the N2 is linked to seasonal H3N2 from 2003, while the H1 is linked to seasonal H1N2 from 2003.

Consequently, the age group under 10 is most vulnerable because of a lack of exposure to the earlier seasonal influenza’s which is reflected in the age of the five confirmed cases cites above (all under 5 years of age) as well as the chronology of the cases for the 2011/2012 season, which indicates the first case was seasonal H3N2, and all 7 of the most recent cases have been novel (the five cases above, as well as the two cases from Maine (A/Maine/06/2011 and A/Maine/07/2011).  The second Maine case like the 2010 Pennsylvania case, tested as seasonal H3N2 because of low levels of RNA.  However both were tested further because of a “swine exposure”.  Thus, the number of novel cases in the 2010/2011 season, as well as the current season, is markedly higher than the confirmed cases, which require sequencing, since none of the PCR targets use sequences from these novel isolate (the H3 test is directed at seasonal H3, while the NP target is based on H1N1pdm09).

Thus, sequencing of influenza A positives from patients under 10 years-of-age would create a more accurate tally of novel influenza infections in this age group, as well as a more complete description of the number of different reassortants transmitting in this age group.
Moreover, as the viral loads increase, the detection of severe cases in this age group, as well as detection of adult cases, are also likely to increase.

Therefore, aggressive testing of influenza A positive cases is long overdue, to more accurately characterize the nature and extent of the 2011 pandemic.

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