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Expected Explosion Of Novel Influenza In United States
Recombinomics Commentary 23:00
December 20, 2011

· While testing of all ILI cases is encouraged as this point, there is increased emphasis on the following populations with ILI:
Children under 18 years of age, as most of the confirmed cases have been in young children;
Particularly severe or unusual cases including pediatric deaths;
Persons who were vaccinated with 2011-12 seasonal flu vaccine but present with influenza-like symptoms;
A history of swine (pig) exposure in the two weeks preceding symptom onset;
Outbreaks or clusters of ILI cases.
If your facility performs your own influenza testing, please forward ALL positive influenza specimens, regardless of testing method, to the MDCH Bureau of Laboratories.
Specimens from patients with illness highly consistent with influenza but negative by rapid testing methods can be sent to MDCH.
The above comments are from the surveillance document distributed by the Michigan Department of Community Health to its ILINet (influenza like illness network) members, which should serve as a model of all state labs in the US (and worldwide).

The above action is similar to the response in 2009, when novel influenza was detected in two cases in southern California who had no linkage to each other or swine.  At the time detection of H1N1pdm09 was signaled in samples that were influenza A positive, but unsubtypable (tested negative for seasonal H1 and seasonal H3).

The current situation in the United States has striking parallels because of the recent reports of clusters in Iowa, Minnesota, and West Virginia of novel influenza (H3N2pdm11 – A/Iowa/07/2011, A/Iowa/08/2011, A/Iowa/09/2011; trH3N2 – A/West Virginia/06/2011; trH1N2 – A/Minnesota/19/2011) which represent three different constellations of genes, signaling extreme genetic instability in novel cases circulating in humans in the US.  Although these novel cases involve at least three different constellations of the 8 influenza genes, all human 2010 and 2011 isolates either have a PB1 with H1N1pdm09 E618D or the H1N1pdm09 M gene.

Detection of these novel cases is a challenge because these viruses are detected indirectly through cross reactivity with targets in the newly approved CDC PCR test.  All of the above novel constellations have seasonal H and N genes due to swine infections in the early 1990’s for H3 and H1 or N2 due to infections in 2003.  However, evolution in swine in the past 8-15 years produced changes that reduce the sensitivity of the current seasonal H3 or H1 targets.  Similarly, the PCR kit has an NP target from H1N1pdm09, which also cross reacts with the novel cases because, like H1N1pdm09, all of the recent human novel cases are triple reassortants which include a swine NP gene related to H1N1pdm09.
However, the PCR kit can give anomalous results, including weak signals for the cross reacting targets, as well as an H3 positive, NP negative result in samples with low RNA levels.  These samples require sequence analysis for a definitive diagnosis, which leads to the request listed above, for samples from clear ILI cases or those testing positive for influenza, regardless of test.

The low levels of RNA in prior samples may be linked to the seasonal influenza origin of the various H and N genes for the above triple reassortants, leading to false negatives or weak positives which can be mis-diagnosed as seasonal H3N2, as was seen for A/Maine/07/2011 or A/Pennsylvania/40/2010.  Therefore, sequence analysis as a compliment to PCR testing is critical for an accurate diagnosis.

Compliance with the above request for samples, coupled with aggressive PCR testing, including sequence analysis, will lead to an explosion of novel influenza cases in states such as Maine and West Virginia, where all PCR confirmed cases in the 2011/2012 season were novel.

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