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Iowa Novel Influenza Testing Paradox
Recombinomics Commentary 20:45
December 22, 2011

A new flu virus that cropped up in north-central Iowa in November has dropped out of sight, a state expert says.

The H3N2 virus sickened three children in Webster and Hamilton Counties, but apparently failed to continue spreading, Dr. Patricia Quinlisk, medical director for the Iowa Department of Public Health, said today.

About a dozen cases of infection with the H3N2 flu virus have been reported nationally. Most of those cases involved people with direct exposure to pigs, who are known to carry the virus. However, the three Iowa children and their families had no such exposure, Quinlisk said.

The above comments use limited data to claim the novel H3N2pdm11 has “dropped out of sight” based on the report of a small number of seasonal H3N2 cases in Iowa, which have not been sequenced, a requirement for claiming that the cases are not trH3N2 misdiagnosed as seasonal H3N2, which has been reported for several of the prior trH3N2 cases.

Moreover, the report tries to support this negative data with statements that are demonstrably false, centering on claims that most earlier 2011 cases were due to swine exposure.  The trH3N2 clade identified in Iowa, which has acquired the H1N1pdm09 M gene, is not widespread in swine.  In spite of enhanced surveillance by the USDA, only one match has been reported in public sequences, a Sept 13, 2011 isolate from New York,
A/swine/NY/A01104005/2011.  Another example is rumored to be from a swine in the Midwest, but sequences have not been made public, and the collection date is likely to be after the July and August cases in Indiana and Pennsylvania. 

Moreover, the earlier cases with “swine exposure” no longer constitute a majority of the 2011 cases.  The latest confirmed case is epidemiologically linked to the recent trH3N2 case from West Virginia (A/West Virginia/06/2011), which had no swine exposure linkage.  Thus, six of the twelve trH3N2 cases with an H1N1pdm09 M gene have no swine exposure.  Moreover, of the six with swine exposure, most were detected because sequencing due to the reported “swine exposure”.  Without the sequence data, these cases would be reported as seasonal H3N2 or unsubtypable/negative.

The false readings are linked to the absence of a sequence from the trH3N2 in the PCR test kit.  The cases are identified through cross reactivity with a seasonal H3 and an H1N1pdm09 NP sequence.  In cases such as the three in Iowa (A/Iowa/07/2011, A/Iowa/08/2011, A/Iowa/09/2011) where the RNA levels were high, the PCR test clearly identifies the case as a suspect trH3N2 case, which is then confirmed by sequencing by the CDC.  The three cases in Iowa are the exception, rather than the rule.  They represent the largest confirmed cluster reported to date, and may have created an expectation that future cases will be easily identified with the PCR test.

However, the most recent case from West Virginia was initially reported as influenza A, because the signal was low and the PCR result did not create a clear trH3N2 pattern.  However, because the case was epidemiologically linked to the confirmed trH3N2, it was sent to the CDC where the trH3N2 was confirmed by sequencing.
These events were strikingly similar to the second case in Maine, A/Maine/07/2011, which gave a seasonal H3N2 result on the PCR test (positive for seasonal H3, but negative for swine NP).  However, the case had a “swine exposure” and attended the same fair as the first trH3N2 case in Maine, A/Maine/06/2011, so the sample was sent to the CDC and partial sequences from four gene segments confirmed that it was another trH3N2 case.  Moreover, the sequence was virtually identical to the earlier case, signaling human transmission, because the second case developed symptoms 2 weeks after the fair closed, so the infection was not linked to swine exposures at the fair.

Similarly, A/Pennsylvania/40/2011 was also initially characterized as seasonal H3N2, but sequencing demonstrated that it was trH3N2 and closely related to A/Wisconsin/12/2011.

Thus, the sequence data is used to conclusively diagnose cases that are H3 positive by PCR, and this confirmation has not been done for the cases in Iowa, based on public sequences, which only include one seasonal H3N2 sequence from a US case under the age of 10 collected in the 2011/2012 season.

Moreover, the seasonal H3N2 case was the first case of the season.  The five subsequent cases under the age of 10 have all been novel, (the three cases from Iowa, the first case from West Virginia, and the trH1N2 case from Minnesota, A/Minnesota/19/2011, which is a different serotype but is a reassortant that was created by the same parental sequences,
A/swine/Ohio/FAH10-1/2010 and human trH3N2 cases (A/Pennsylvania/40/2010 and A/Wisconsin/12/2010), which generated the trH3N2 sequences in the Iowa cluster.

In addition, the Minnesota case, like the Iowa and West Virginia cases had no swine exposure and confirmed or suspect cluster members.
Thus, the trend in clusters without swine exposure is clear, and applies to all six of the most recent confirmed cases.  The Iowa paradox is the expectation that PCR detection of these cases will be clear, based on the data generated by the Iowa cluster, and the diagnosis will not require sequence analysis.

However, the data to date strongly suggests that seasonal H3n2 cases, especially in children under the age of 10, should be confirmed through sequence analysis, which creates an unambiguous result, which is clearly lacking for the recent cases in Iowa and the entire country, where none of the recent sequences are seasonal H3N2.

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