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Silence On Novel Flu Cases Raises Concerns
The above comments from the latest WHO update on influenza are similar to the latest update from PAHO, which also attempted to link these two novel human cases to prior swine isolates. Both of the above cases were from suspect clusters without swine exposure, and follow a confirmed cluster which also had no swine exposure linkage. Now the West Virginia cluster has been confirmed. Moreover, the five sets of sequence represent three different reassortants, signaling extreme genetic instability in human isolates, which have H1N1pdm11 linked adaptations.
This alarming development has been met with stunning silence from WHO, in contrast to a pager alert issued just over a year ago, which cited two novel trH3N2 cases (A/Wisconsin/12/2010 and A/Pennsylvania/14/2010), which increased the number of confirmed trH3N2 cases from 3 to 5. The alert generate concern, especially in Eastern Europe, which the CDC addressed by noting sequences difference between the two cases indicating they did not come from a common source. However, a second case from Pennsylvania, A/Pennsylvania/40/2010, was under investigation. Confirmation was announced in 2011, and the sequence was released on Sunday, April 17, 2011, which had the same constellation as the Wisconsin isolate, suggesting human trH3N2 transmission, which was confirmed in a cluster in Minnesota, which was also confirmed in 2011, raising the number of confirmed cases due to 2010 infections to six, which shared a number of similarities, including a closely related H3 for 5 of the 6 isolates.
However, of greater concern was the acquisition of H1N1pdm09 PB1 E618D, which was in the first US case, A/Kansas/13/2009, as well as all six 2010 human cases, raising concerns that the novel US cases were adapting to humans via acquisitions from H1N1pdm09. These concerns were increased when the sequence from the first 2011 case, A/Indiana/08/2011, were released, which was followed by a CDC early released MMWR which noted that the Indiana case, as well as the first 2011 case from Pennsylvania, A/Pennsylvania/09/2011, which had acquired the H1N1pdm09 M gene. This concern was increased by the two additional cases from Pennsylvania, A/Pennsylvania/10/2011 and A/Pennsylvania/11/2011, which were almost identical to the Indiana case. Thus, the same constellation of flu genes was in all four of the 2011 human cases. Five of the gene segments (PB2, PA, HA, NP, NS) matched the 2010 isolates, while the NA gene matched the Pennsylvania isolate described in the WHO pager alert. These four cases were then followed by three more cases, A/Maine/06/2011, A/Maine/07/2011, and A/Indiana/10/2011, which all had the same constellation of genes, which was not reported for swine isolates.
These cases were followed by the announcement of the first swine isolate with a matching constellation, but the isolate date of Sept 13, 2011 was after the confirmed cases in Indiana and Pennsylvania suggesting the swine infection signal the movement of the novel constellation, H3N2pdm11, from humans to swine, as was seen for H1N1pdm09, which has now been reported in swine worldwide.
Although the first seven cases in the US were directly or indirectly linked to swine exposure, the linkage was due to the CDC program which targets such cases during the off season. Detection of the novel cases requires sophisticated PCR testing, which is indirect, so confirmation relies on sequencing of the suspect samples. Thus, the majority of sequences for those under the age of 10 is largely limited to “swine exposure” cases, and since the H and N from these novel cases links back to seasonal flu circulating in the 1990’s or 2003, the younger cases are those most likely to have higher levels of RNA, leading to medical attention and sample collection.
The first seven cases were followed by a cluster in Iowa, which had 3 epidemiologically confirmed cases (A/Iowa/07/2011, A/Iowa/08/2011, A/Iowa/09/2011). as well as two suspect cases (brother and father of index case), as described in an early release MMWR and a WHO alert. The sequences of all three confirmed cases were virtually identical, and had the same constellation of genes amd lineages seen in the first seven confirmed cases.
These ten H3N2pdm11 cases were then followed by the release of a full set of sequences from a 2010 trH1N2 swine isolate from Ohio, A/swine/Ohio/FAH10-1/2010, which had the three gene segments (PB1, NA, MP) acquired by the H3N2pdm11 sequences.
The two most recent sequences were reassortants that had evolved from the human cases in 2010 and 2011. The isolate(s) from West Virginia had acquired another NA gene, which was common in trH3N2 swine, but also linked to human H3N2 cases from 2003. A symptomatic contact is under invesigation. The Minnesota case, A/Minnesota/19/2011, (symptomatic contact was not tested) involved the same parental sequences which created H3N2pdm11, except only the H1 and N2 were acquired from the Ohio parent, A/swine/Ohio/FAH10-1/2010. Thus, the serotype was new, but the internal genes matched the human sequences, and the closest match for N2, NP, and NS were A/Pennsylvania/09/2011.
Thus, all 18 human cases in 2010 and 2011 were related and all either had a PB1 with H1N1pdm09 E618D, or an H1N1pdm09 M gene, signal human adaptation and efficient transmission. The finding of three distinct reassortants in confirmed or suspect clusters with no swine exposure is without precedent, but instead of addressing this alarming development, the WHO puts out false and misleading statements attempting to link the two most recent cases to swine, instead of early adapted human cases.