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H1N1v H1N2v H3N2v Testing Bottleneck Expected
Recombinomics Commentary 12:00
December 29, 2011

The CDC said H3N2v viruses will be positive for the nucleoprotein (NP) gene (pdmInfA), influenza A, and seasonal influenza A (H3) targets of the CDC's rRT-PCR diagnostic panel. All suspected novel influenza A and H3N2v samples should be sent to the CDC for confirmational testing, it said. "Confirmation of influenza A (H3N2)v virus is performed only at CDC at this time."

The agency urged health departments to conduct contact tracing of confirmed, probable, or suspected H3N2v cases and provided definitions for the three levels of cases in a separate document. It asked health departments to notify the CDC about all suspected and probable H3N2v infections within 24 hours of identification.

The CDC defined a suspected H3N2v case as an acute respiratory illness in a patient who has an epidemiologic link to a confirmed case or got sick within 7 days of swine exposure.

It said a probable case is in a patient whose respiratory sample tested positive on the CDC RT-PCR flu panel for influenza A, pandemic influenza A, and H3, but negative for influenza B, pandemic H1, and H1. Also, a probable case could be in a person who has an acute respiratory infection and a link to a confirmed H3N2v case and whose diagnostic test is positive for influenza A (H3) or influenza A (no subtype tested or detected).

The above comments are from a CIDRAP summary of the recent CDC early release MMWR and associated documents on sample collection, testing, case definitions, and notifications.  These documents are largely focused on H3N2v cases (trH3N2 and H3N2pdm11) but one of the documents is on international nomenclature, which uses H1N1v, H1N2v, and H3N2v for novel trH1N1, trH1N2, and trH3N2 cases. 

The focus on H3N2v cases is linked to the two recent clusters in Iowa and West Virginia.  Both clusters were large and had no swine linkage, as was seen in the initial H1N1pdm11 cases in 2009 in Southern California.  However, the H3N2v cases are more compelling because the number of confirmed cases in each cluster is larger, and the five confirmed cases in Iowa and West Virginia follow confirmed cases in Indiana, Pennsylvania, and Maine which represent independent introductions, yet have the same constellation and lineage for all 8 gene segments, which has not been found in any reported swine isolate collected prior to the July and August human cases in Indiana and Pennsylvania, and only one public sequence, A/

The clusters have also set records for novel cases.  In Iowa, three epidemiologically linked isolates (A/Iowa/07/2011, A/Iowa/08/2011, A/Iowa/09/2011) were reported, in addition to symptomatic relatives (brother and father) who were not tested.  Similarly, the West Virginia cluster involved a closely related H3N2v (with a different seasonal N2) that led to sustained transmission for almost a month within the day care center in Mineral County.  In addition to the two confirmed cases (A/West Virginia/06/2011 and A/West Virginia/07/2011), multiple symptomatic classmates were noted, but not tested.

However, as seen in the two clusters above, the number of cases is markedly higher than the 12 confirmed cases in 2011 because many cases were collected in the off season or early in the current season when RNA levels in samples are low, and PCR test interpretation is highly nuanced.  Most of the H3N2v cases were identified because a perceived swine exposure or linkage to a confirmed case led to CDC testing of samples that initially tested as negative, inconclusive, unsubtypable, or seasonal H3, including testing with the newly approved CDC PCR test.

Thus, it is likely that only a subset of H3N2v cases will be identified, but the early release MMWR, coupled with the associated documents, and last week’s 50 state conference call, will likely lead to a bottleneck in testing, as was seen in 2009 when all confirmations required CDC testing, which is the current situation for all novel cases other than H1N1pdm09.

Moreover, recent results raise concerns that novel human cases extend well beyond the 12 H3N2v cases reported in 2011.  The recently reported H1N2v case in Minnesota (A/Minnesota/19/2011) was also not linked to swine exposure, but was linked to an untested symptomatic case.  However, the Minnesota case was confirmed with an isolate tested during routine screening, leading to a delay and limited follow-up of contacts, including the symptomatic case.  Thus, the delectability of H1N2v cases in clinical samples remains unclear.  Similarly, the H1N1v sample was positive for both H1N1pdm09 targets, but the signal for H1 was markedly lower than NP, and the case had an occupational swine exposure, leading to CDC testing.  Other samples without a swine exposure may be classified as H1N1pdm09 instead of H1N1v.

Thus, the requirement of confirmation by the CDC may lead to significant confirmation delays, and limited confirmation of H1N1v and H1N2v cases, which may significant increase as conditions for the spread on influenza in the United States improve in January.

Thus, an explosion of novel cases is expected in early 2012, but the true extent of the genetic instability in human novel cases by be significantly under-represented due to testing limitations.

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