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Paradigm Shift Intervention Monitoring
Testing / Reporting Creates Physician Confusion
The above comment was published in ProMED by a physician who was clearly confused by recent CDC reports of trH3N2 cases in Indiana and Pennsylvania. This confusion was largely linked to CDC testing and reporting procedures. The vast majority of the trH3N2 cases is identified in the “off season” and almost always involves cases with a perceived swine connection, because trH3N2 testing is largely limited to such cases, even though the majority of cases subsequently do not have a direct swine contact and the sequence data signals human to human transmission. The widespread human to human transmission is not identified because of testing procedures and prior cross reactivity with seasonal H3N2. The focus on swine linkage is abundantly clear in the CDC’s request for samples from patients with a swine link, even though three of the four recent patients have no reported swine contact and sequences from three of the four patients are virtually identical (even though the patients were unlinked, in two states, and infected independently). The linkage to swine is purely driven by the heavy bias is testing, not the origin of the virus, which is being transmitted human to human.
The human to human transmission began to emerge almost a year ago, when WHO issued a pager altert because two trH3N2 cases had been identified. When recipients of the alert became alarmed, they were assured that the trH3N2 was not transmitting in humans because the two cases (from Pennsylvania and Illinois) were isolated 6 weeks apart and the sequences were similar, but did not come from a common source. However, the alert did not included a second Pennsylvania case, which was from a patient who was symptomatic in September within a week of the Illinois patient (subsequently reported by Wisconsin and designated A/Wisconsin/12/2011), and the sequences between A/Wisconsin/12/2010 (WI/12/10) and those from the second Pennsylvania case, A/Pennsylvania/40/2010 (PA/40/10), were virtually identical, nullifying both reasons for the CDC assurances on lack of transmission.
These assurances were degraded further by another case, identified in November, A/Minnesota/11/2010 (MN/11/10), which was also virtually identical to WI/12/10 and PA/40/10. Moreover, the daughter of the index case was also symptomatic and was subsequently serologically confirmed to have also been trH3N2 infected and she had no direct swine contact. The CDC acknowledged the human transmission (other family members were also symptomatic but lab results were classified as “inconclusive”) and selected MN/11/10 as a pandemic trH3N2 vaccine target (two reassortants on a PR-8 genetic background were created and sequences were released at GISAID).
The latest cases were also identified in the off season, and also had a perceived swine link and the CDC again claimed in the week 34 FluView that the Indian and Pennsylvania sequences were different and did not come from a common source. However, once again subsequent sequences nullified the CDC assurances, but the CDC did not acknowledge the identity between the Indian and Pennsylvania sequences and instead focused on the swine connection in the request to clinicians for samples from patients linked to swine, and emphasized the swine linkage on its latest “have you heard” release.
Thus, the physicians reading the CDC reports in FluView, MMWR, or “Have You Heard” are operating under the misconception of a swine linkage as well as a relative rare event, when in fact the swine linkage is due to largely limiting testing to cases with a swine link as well as serious delays in routine surveillance that requires virus isolation (antigen characterization test and sequencing) instead of widespread PCR testing for trH3N2, which was used to identify recent cases 9which was subsequently confirmed with sequence data.
However, these testing issues may become moot, because two of the recent isolates have been characterized as unsubtypable because the human H3 sequences from the 1990’s has now evolved away from human in swine, and the sub-typing reagents either fail to recognize the trH3N2 or the CDC has raised the cut-off leading to an unsubtypable result, which more easily identifies the trH3N2 cases.
However, the current focus on swine linkage will limit the number of samples tested by PCR, and significantly undercount the number of trH3N2 cases and spread.
The continued CDC focus on a swine connection in testing and reporting will continue to create unnecessary confusion and delays in the reporting of the true extent of the trH3N2 pandemic.