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Anomalous trH3N2 Reporting Raises Pandemic Concerns
Recombinomics Commentary 23:40
October 4, 2011

The CDC’s week 38 FluView remains confusing with regard to trH3N2 activity.  Many cities throughout the US have show recent increases in flu activity based on Google FluTrends, or ILI frequency at Emergency departments in multiple states, yet the weekly FluView is reporting activities that are barely detectable.  The initial week 37 report had only three confirmed flu cases for the entire country.  The latest report increases the number for week 37 to 10, but only one of the 10 influenza A cases has been sub-type (and was H3N2).

For the past 4 weeks, lab confirmed cases have been dominated by influenza A (only two of 43 cases were influenza B).  Of the 10 influenza A cases sub-typed, 9 have been H3N2.  However, the number of trH3N2 cases in these lab confirmed samples remains unclear.

Sub-typing of trH3N2 cases is difficult because initial swine H3N2 cases in the United States were initially linked to the infection of a swine with seasonal H3N2, giving rise to a double reassortant with human HA, NA, and PB1.  Therefore the reassortants can subtype as seasonal H3N2 as reported for A/Pennsylvania/40/2010.  Routine surveillance on that samples eventually identified the trH3N2 case, which was reported 5 months after samples collection.  These data raise concerns that many trH3N2 cases are classified as seasonal H3N2.

However, two of the recent trH3N2 cases from the Washington County fair were reported as unsubtypable in the week 35 and week 36 FluView reports.  However, these two designations were removed in week 37 without comment.  The removable of these two cases could have multiple explanations.

Although there have been 9 confirmed trH3N2 cases since September , 2010, the subtype table and graph have no designation for trH3N2.  Thus, the confirmation of trH3N2 in these two cases (by PCR or sequencing), could have led to the removal of the two cases since there was no column for trH3N2 cases. 

Alternatively, repeated testing of the samples may have yielded a weak signal for seasonal H3N2, which took the samples out of the unsubtypable column.  Similarly, the cut-off value for seasonal H3N2 may have been lowered to yield a seasonal H3N2 designation.  Alternatively, repeated influenza A testing may have led to a negative result for the samples, or the cut-off for influenza A positive may have been raised, leading to a negative result.

All of the above could lead to a reduction / absence of trH3N2 cases since the assay for influenza A and/or seasonal H3N2 has produced variable results (all four of the recent trH3N2 cases have HA sequences that are virtually identical, so it representations of the other two trH3N2 also remains unclear.

The recent trH3N2 represent a serious health risk.  About half of the cases have been hospitalized and most have no direct contact with swine.  Moreover, the detection of two cases a year ago lead to a pager alert by WHO, while the first two recent cases led to an early release MMWR, including a request for samples from symptomatic patients.  However, the request was for patients with swine contact, even though the Indiana case had no such contact, and the source of trH3N2 for all four recent cases remains unclear.  The caretaker for the Indiana case had swine contact, but the caretaker and swine were asymptomatic and no swine influenza has been identified (and trH3N2 matching the constellation of flu genes in the human cases has not been reported anywhere, in spite of increased swine surveillance and testing in 2010 and 2011).  Similarly, no symptomatic influenza infections have been reported for any of the swine at the Washington County fair in spite of an “intense” investigation.

The failure of these investigations to identify swine sources for the four independent infections involving identical trH3N2 constellations as well as virtual identity between of the Pennsylvania sequences and the sequence from Indiana strongly support human to human transmission, which is also consistent with the acquisition of the pandemic H1N1 M gene segment, by the 2011 trH3N2 isolates.

Thus, the sequence and epidemiological data support human transmission, yet the vast majority of influenza A positive samples have not been sub-typed, and the number of lab confirmed cases remain far lower than expected by recent reports of ILI activity, deaths, and flu cases throughout the country prior to the official start of the flu season in week 40.

A detailed explanation for the low number of influenza cases reported in FluView, the lack of sub-typing, the removal of unsubtypables, and the criteria used to classify samples as influenza A positive, H3N2 positive, and disposition of future unsubtypables is overdue.

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