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Delays In trH3N2 Testing and Reports
Recombinomics Commentary 16:45
September 13, 2011

The recent cluster of trH3N2 cases in Pennsylvania and identity with the cases in Indiana raises concerns that more such cases will be reported in the near term.  Multiple public sites allow for monitoring of developments, although delays inn report can be significant, even for important samples.  Human infections with a novel influenza, like trH3N2 are reportable in the US and worldwide in accordance with International Health Regulations signed by all member nations of the UN.

Consequently, these cases appear in the CDC’s weekly MMWR on the reportable diseases page.  Although this page should be an early indicator, delays due to testing issues can be significant.

These delays include two important trH3N2 cases.  One, A/Pennsylvania/40/2010 was from a case (36M) who developed symptoms on Sept 6, 2010.  However, the sample initially tested as seasonal H3N2.  More advanced testing, such as an antigen characterization test or sequencing usually involves isolation of the virus, and technical problems led to a five month reporting delay.  Consequently, this case was not reported until week 4 in MMWR as well as FluView and the sequence was released April 17, 2011 at GISAID, more than seven months after the infection.

Similar delays were seen for confirmation of the daughter of the index case in Minnesota, A/Minnesota/11/2010.  The index case was reported in late 2010 and the sequence was released at GISAID on December 08, 2010.  However, in 2010 contacts of the case were under investigation and in the week 21 MMWR influenza update it was announced that the daughter was serologically trH3N2 confirmed and the case was added to the MMWR notifiable disease page on week 30, more than 8 months after the infection.

Thus, prior to the latest cluster, the MMWR notifiable disease table had two trH3N2 cases reported in 2011, but both cases were due to infections in 2010.  However, in the week 34 MMWR, the page was updated with the case (2M) in Indiana, A/Indiana/08/2011 (IN/08/11), and index case (2F) for Washington County, A/Pennsylvania/09/2011, bringing the total number reported in 2011 to four.  The week 35 MMWR did not include the two later cases (both 9F), who were initially reported by the Pennsylvania Department of Health on September 5, 2011, followed by a CDC “have you heard” on September 6.

Public data on this cluster however, began with the release of the full sequence for IN/08/11 at GISAID on August 25, 2011.  The sequence clearly demonstrated that the isolate was related to the earlier trH3N2 sequences for 5 of the 8 gene segments (PB2, PA, HA, NP, NS), but the other three gene segments were acquired via reassortment.  The most striking result was the acquisition of the MP gene segment from pandemic H1N1, since this gene segment was critical for the aerosolization of the virus and efficient transmission to humans.  The PB1 was closely related to human isolates from the Huron County fair (A/Ohio/01/2007 and A/Ohio/02/2007) prior to acquisition of E618D by recent trH3N2 isolates, and the NA was closely related to another Pennsylvania case, A/Pennsylvania/14/2010.  Thus, IN/08/11 had a unique constellation of gene segments, including the m gene segment from pandemic H1N1.

The acquisition of the M gene from pandemic H1N1 raised concerns that the new reassortant would transmit it humans, which was supported when details of the index case were reported in the Sept 2 MMWR early release, which noted that the Pennsylvania sequence, A/Pennsylvania/09/2011, also had the M gene segment from pandemic H1N1, although the MMWR and FluView noted that the Pennsylvania sequence was slight different than the Indiana sequence.  However, further support for human transmission came on Sep 5 when the Pennsylvania announced two additional trH3N2 confirmations which also had the H1N1 M gene acquisitions.

The CDC’s prompt release of Pennsylvania sequences on Sep 7 at GISAID and Sep 8 at Genbank raised additional concerns because all three Pennsylvania isolates had the same constellation of genes as the Indiana case, and the two most recent collections from Pennsylvania (August 25 and 26 from A/Pennsylvania/11/2011 and A/Pennsylvania/10/2011, respectively) generated sequences that were virtually identical to the Indiana sequences, strongly supporting human transmission.

In addition, the CDC updated the underlying data for the subtyping table, showing an unsubtypable for week 33, which was almost certainly PA/09/11 based on the Aug 20 collection, which was followed by an unsubtypable for week 34, which almost certainly was from PA/10/11 or PA/11/11 based on collection dates.

However, the reporting on the cluster remains uneven.  The MMWR notifiable diseases page still only lists two of the four trH3N2 confirmed cases for 2011, and the FluView still only list two of the four as unsubtypable.  Moreover, the reporting delays for the 2010 cases raise concerns that additional cases are under investigation, including more unsubtypable cases.

Comments on the cases under investigation, including additional unsubtypables, would be useful.

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