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Hidden Novel Influenza Pandemic
Recombinomics Commentary 23:45
December 22, 2011

• As part of an ongoing investigation into the initial case of swine-origin triple reassortant influenza A (H3N2) virus infection in Pennsylvania, this child’s illness was identified and a nasopharyngeal swab specimen was collected and forwarded to the Pennsylvania Department of Health Bureau of Laboratories.
• Testing at the state laboratory was inconclusive and the specimen was sent to CDC for further characterization.
• A respiratory specimen was obtained on August 25, 2011, as part of routine care, which was identified as an un-subtypeable influenza A by the hospital laboratory. Nasopharyngeal swab and nasal wash specimens were collected.
• On September 3, 2011, the specimen was forwarded to CDC for further characterization.

HETL detected a case of influenza A virus that was inconclusive during subtyping. On October 17 Federal CDC confirmed this isolate to be the 5th recognized case of human infection with S-OtrH3N2 with the M segment gene from the pH1N1virus

On October 28, 2011, diagnostic testing at the state laboratory was weakly positive for influenza A (H3), but negative for swine-origin influenza targets. The specimen was forwarded to CDC.

The above comments describe the four adolescent samples (9F - A/Pennsylvania/10/2011, 9F – A/Pennsylvania/11/2011, 8M – A/Maine/06/2011, 8M – A/Maine/07/2011) collected after the confirmation of the first Indiana (2M – A/Indiana/08/2011) and first Pennsylvania (2F – A/Pennsylvania/09/2011) cases described in the early release MMWR, which sequenced samples for patients with “swine exposure”.  The above four cases represent the four adolescent “swine exposure” cases reported after the MMWR, although as seen in the descriptions of each case, they were inconclusive, unsubtypable, or weakly positive for seasonal H3N2.  Thus, the results at the state or university testing facilities failed to identify these cases as trH3N2, which was subsequently demonstrated by the CDC using partial sequences generated directly from the samples.

The cases demonstrate the technical difficulties associated with an accurate diagnosis, and the identification of cases with “swine exposure” was driven by the CDC request for such samples, which gave inconclusive results on various PCR tests.

The trH3N2 cluster from Iowa (A/
Iowa/07/2011, A/Iowa/08/2011, A/Iowa/09/2011) was identified with the PCR test, which was confirmed by sequencing, which indicated these samples had high levels of RNA (nearly complete full sequences were generated by each of the three samples and isolates were easily generated.  The ease in detection of trH3N2 by the PCR testing of this cluster may paradoxically lead to fewer confirmed cases, because many of the cases will produce inconclusive or seasonal H3N2 results, which may limit confirmation by CDC sequencing.

The inconclusive results are not limited to the four cases described above. The confirmation of one of the key isolates in 2010, A/Pennsylvania/40/2010, was delayed for five months because it was initially diagnosed as seasonal H3N2.  Similarly, the most recent confirmed case gave a weak signal and was listed as influenza A positive in the initial report from West Virginia.  However, it was sent to the CDC because it was epidemiologically linked to A/West Virginia/06/2011, and was confirmed to also be trH3N2.

Moreover, the trH1N2 confirmation was delayed, because it was identified as an isolate, which increased the level or RNA and the sensitivity of the PCR test.  All of these recent cases, like the cluster from Iowa lack a swine linkage, indicating this novel influenza cases (H3N2pdm11, trH3N2, trH1N2) are circulating and sustained, but the frequencies are grossly underestimated because the PCR detection is indirect and dependent on cross reactivity with probes for seasonal H3, H1, or H1N1pdm09 NP.

Thus, although the CDC and WHO have requested samples and the ECDC recognizes the technical issues associated with the detection of these novel cases, the number of cases identified by PCR will be a significant underestimate, and associated sequencing is critical.

However, currently there is only one seasonal H3N2 sequence from patients under 10 years of age this season, and novel sequences from seven cases (which may go to eight when details on the latest case from West Virginia are released).

Thus, dramatic increase in sequencing of these cases is critical, and the presence of only one seasonal sequence continues to raise pandemic concerns.

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