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Paradigm Shift Intervention Monitoring
Issues trH3N2 Health Advisory
The above comments are from a North Dakota DoH Health Advisory on H3N2pdm11 / trH3N2 cases. This request is similar to one issued by the Michigan Department of Community Health (MDCH), which also asked samples per CDC request. The CDC is expected to announce a second case from West Virginia today which is epidemiologically linked to their first case, A/West Virginia/06/2011, which was closely related to the 10 prior 2011 trH3N2 cases, including an H1N1pdm11 M gene, although the West Virginia isolate is an isolate with an N2 that is from a different lineage circulating in trH3N2 swine. However, like the recent trH1N2 case from Minnesota, A/Minnesota/19/2011, and the cluster from Iowa (A/Iowa/07/2011, A/Iowa/08/2011, A/Iowa/09/2011) which had no “swine exposure”.
However, although these requests will likely lead to more novel cases, there are serious detection issues, even when samples are PCR tested by state labs. All four of the H3N2 pediatric samples reported after the CDC requested samples from patients with “swine exposure” (A/Pennsylvania/10/2011, 9F – A/Pennsylvania/11/2011, 8M – A/Maine/06/2011, 8M – A/Maine/07/2011) were designated as “inconclusive”, “unsubtypable” or weak H3 positive and negative for H1N1pdm NP gene, and confirmation was through partial sequencing by the CDC. Similarly, the trH1N2 case in Minnesota, A/Minnesota/19/2011, was identified by testing, an isolate, not direct testing of the clinical sample. The most recent trH3N2 sample from West Virginia also gave a weak signal and was initially listed as influenza A prior to confirmation by the CDC. Thus state labs from Pennsylvania, Maine, Minnesota, West Virginia, as well as the University of Pittsburgh Medical center diagnostic lab failed to PCR confirm these cases from clinical samples.
These failures are linked to low RNA levels, which are likely associated with the human origin of H (H1 and H3) and N (N2) of these novel isolates which likely creates reductions in viral load due to prior exposures to seasonal flu, as well as the PCR test targets, which rely on cross reactivity for detection since none have targets based solely on sequences from these isolates.
All of the 2010 and 2011 cases either have a PB1 gene with E618D (which is virtually all H1N1pdm09) or a H1N1pdm09 M gene, which are likely required for efficient transmission in humans. The constellation identified in the first 10 cases has only been reported in one swine isolate (from New York), and the sequences from the trH3n2 cases in West Virginia or the trH1N2 cases in Minnesota have not been reported in swine.
Moreover, none of the recent isolates (from Iowa, Minnesota, West Virginia) are from cases with swine exposure, and all are linked to confirmed (IA and WV) or suspect (MN) clusters.
Thus, the unprecedented co-circulation of three distinct novel constellations circulating in humans without swine exposure has led to the CDC requests and a WHO warning and a focus o state lab / CDC PCR testing, but a conclusive diagnosis requires sequencing, and to date the number of public influenza A sequences from seasonal influenza in under 10 cases in the 2011/2012 flu season in the United States has been limited to one, collected in early October.
This limited testing by the CDC as well as serious detection issues using the PCR test has not been noted in the state alerts, and the failure of the CDC to generate more than 8 public sequences from such cases when 7 of the 8 cases are novel, representing three different reassortant constellations remains a serious pandemic concern.