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Paradigm Shift Intervention Monitoring
Explosion Of Novel Influenza Clusters In United States
CDC is taking this situation very seriously, and surveillance surrounding reported cases is being further enhanced.
The above comments are from the Michigan Department of Community Health background document on 2011 trH3N2 cases with an M gene from H1N1pdm09. The 11 cases listed above do not include the recently confirmed trH1N2 cases in Minnesota (A/Minnesota/19/2011) which is part of a suspect cluster, or the expected confirmation of the second West Virginia case that is epidemiologically linked to A/West Virginia/06/2011. The expected CDC confirmation would increase the number of confirmed clusters to two, and both involved constellations with an H1N1pdm09 M gene (H3N2pdm11 and trH3N2).
The presence of three distinct novel clusters in cases without a swine linkage is without precedent. Prior to the 2009 pandemic, 13 human novel (triple reassortant) cases had been reported, and only one outbreak was linked to the isolation of two triple reassortants (trH1N1) which were from a Huron County fair exhibitor, and her father (A/Ohio/01/2007 and A/Ohio/02/2007). Although identical sequences had been isolated from swine at the fair, the outbreak was of concern because two dozen fair attendees had ILI (influenza-like illness), which is unusual in August in Ohio.
The first US trH3N2 case, A/Kansas/13/2009, was from another county fair (Riley County) two years later, and most of the internal genes were linked to the isolates from Ohio, but the PB1 gene had acquired E618D from H1N1pdm09. E618D was in virtually all H1N1pdm09 sequences, but not in earlier human or swine sequences, other than those with an H1N1pdm09 PB1. E618D was also in all six of the 2010 human trH3N2 isolates, signaling human adaptation. Subsequent swine sequences with E618D were on Pennsylvania isolates that evolved from the human sequence from A/Pennsylvania/14/2010, and a trH1N1 Minnesota swine evolved from the human cluster represented by A/Minnesota/11/2010.
The Minnesota cluster was the first confirmed trH3N2 cluster based on the isolation of A/Minnesota/11/2010 from the index case, and serological confirmation in the daughter, who had no swine exposure. Moreover, other family members were symptomatic, but serological tests were “inconclusive” suggesting multiple family members had been infected with A/Minnesota/11/2010.
In addition to the lab confirmed cluster, two other 2010 human isolates (A/Pennsylvania/40/2010 and A/Wisconsin12/2010) had a constellation of flu genes that matched each other, and most matched the two confirmed Minnesota cluster members, and were also related to the first trH3N2 isolate from Minnesota, A/Minnesota/09/2010. Thus, the sequences from 2010 cases also suggested that the number of cases and clusters was markedly higher than the reported cases, due in part to mis=diagnosis as seasonal H3N2, which led to a five month delay in the reporting of A/Pennsylvanai/40/2010 as another novel influenza case.
The 2010 cases were followed by 2011 case that evolved via reassortment with a swine trH1N2 parent, A/swine/Ohio/FAH10-1/2010, which contributed three gene segments (PB1, NA, MP). The PB1 did not have the H1N1pdm09 E618D, but the M gene was from H1N1pdm09, while the NA gene matched A/Pennsylvania/14/2010. This constellation was found in the first 10 cases in 2011, and designated as H3N2pdm11 because the same constellation in 10 isolates from four states (Indiana, Pennsylvania, Maine, Iowa) signaled efficient and sustained transmission. The two Maine cases had virtually identical sequences even though the cases were not epidemiologically linked and disease onset dates were two weeks apart.
The cluster in Iowa was epidemiologically linked, and two family members of the index case (father and brother) were symptomatic but not tested. None of the cluster members had a swine linkage. This cluster led to a WHO warning and an ECDC risk assessment.
This confirmed cluster, with no swine linkage, was followed by two suspect clusters, which had no swine linkage, and represented two more gene constellations. The trH1N2 in Minnesota was formed by the same two parental sequences, with H1 and N2 coming from the Ohio sequence, and the internal genes from the 2010 sequences (A/Pennsylvania/40/2010 or A/Wisconsin/12/2010). Consequently, the isolate has a new serotype, but the same N2 as seen in the first 10 isolates from 2011 (H3N2pdm11). A symptomatic contact was not tested because the Minnesota sequence was delayed because it was from an isolate generated in Minnesota during routine surveillance. The West Virginia trH3N2 cluster was recently confirmed by the CDC, and the case should be announced this week. This cluster is made of sequences which match the first 10 cases in 2011, but the N2 was replaced with a different lineage, that is found in trH3N2 swine.
Thus, the number of confirmed or suspect clusters in cases not linked to swine has increased to three, which is without precedent, but increased surveillance will lead to an explosion of confirmed novel cases and clusters driven by extreme genetic instability and sustained human transmission.