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CDC Silence On trH3N2 Match Raises Pandemic Concerns

Recombinomics Commentary 15:40
April 19, 2011

Three cases of human infection with a novel influenza A virus were reported during November and December, one each from Wisconsin, Pennsylvania, and Minnesota. Onset of the illnesses occurred in September, October, and November, respectively. All three patients were infected with swine-origin influenza A (H3N2) viruses. Two of the three cases occurred in adults, and the third occurred in a child. Two of the three patients were hospitalized; all three have fully recovered from their illness. The three cases are not related, and influenza viruses recovered from each of these cases were similar but not identical, indicating that they did not come from a common source. All three patients had either contact with swine or lived in areas close to swine farms. No evidence of human-to-human transmission of these viruses was identified in the first two cases....

On January 25, 2011, a fourth case of human infection with swine origin influenza A (H3N2) was identified in a female child in Pennsylvania. She developed symptoms of fever, headache, and lethargy on September 6, 2010. She did not require hospitalization and has since fully recovered. The patient reported contact with swine in the week preceding symptom onset.

The above comments are from CDC influenza updates published in MMWR on December 24, 2010 and February 5, 2011.  The first paragraph includes a child (10 month M) from Wisconsin with a disease onset data of September 8, 2010 who was hospitalized.  This patient was described in a pager alert issue by WHO in November.  The adult case from Pennsylvania was also in the alert, which was followed by assurance that the trH3N2 infections did not transmit based on the sequence differences between the Wisconsin and Pennsylvania isolates (A/Wisconsin/12/2010 and A/Pennsylvania/14/2020, respectively).

The second paragraph describes a Pennsylvania case (3F) who developed symptoms two days earlier (September 6, 2010) and the reporting delay was detailed in the week 4 FluView.  The case was initially diagnosed as seasonal H3N2 and the sample was sent for further routine analysis.  The sample was found to be a triple reassortant (trH3N2) by PCR and the delay in reporting was attributed to a failure to grow/isolate the virus.  The report was silent on any sequence data obtained through direct sequencing of the sample. 

That silence was broken on Sunday, April 17, 2011 when the CDC deposited full or nearly full sequences for all eight gene segments on a sample collected September 13, 2010, designated A/Pennsylvania/40/2010 at GISAID.  The trH3N2 classification of the sequences was not noted, in contrast to all prior trH3N2 deposit by the CDC.  Phylogenetic analysis of all gene segments indicated the isolate was virtually identical to the Wisconsin isolate, A/Wisconsin/12/2010 from the child described above.  The silence on this match has been deafening.

The WHO alert on November was based on two trH3N2 cases isolated 6 weeks apart, which were similar but readily distinguishable.  Consequently, the alarm generated by the pager alert was blunted by a follow-up report noting the sequence differences and the absence of evidence of transmission.  However, these assurances were voided by the second Pennsylvania case, who developed symptoms 2 days prior to the Wisconsin case. 

Thus, when the pager alert was issued, the CDC had samples from at least three trH3N2 cases, and the sequences from two of the three were identical, indicating the trH3N2 was transmitting in undetected humans, as was seen in the first two confirmed US cases infected with pandemic H1N1 in April, 2009.  The detection of the same virus in two patients infected two days apart but without contract with each other signaled human to human transmission through unreported human hosts

Detection of additional trH3N2 is more challenging than pandemic H1N1 (which is also a triple reassortant), because unlike the pandemic H1N1, which has swine H1 and N1, the surface genes for trH3N2 are human, tracing back to a human infection of swine in the 1990’s.  Thus, in the above Pennsylvania sample, the initial serotyping signaled seasonal H3N2. Identification of the triple reassortant constellation of genes, as well as the characterization of H3 and N2 as human flu genes from the 1990’s required more sophisticated analysis by the CDC, which led to the detection delay.

However, when reported in FluView or MMWR there was no mention of sequence data, and when the sequences were deposited at GISAID on Sunday (the only deposit that day), there was no announcement preceding or following the released sequences.

These sequences are a game changer because they signal human to humaun transmission over long distances and nullify prior assurances by the CDC.  The 7 month delay in the release of the sequences also raises serious concerns about CDC transparency, as well as the number of similar cases known or unknown to the CDC.  The Pennsylvania case did not require hospitalization and was identified through routine surveillance.  However, only a small fraction of samples are subjected to this further characterization.  Moreover, the announcement on the Pennsylvania website requesting samples, cites the linkage to swine and heavily biases collections away from trH3N2 cases due to human to human transmission.  Thus, Pennsylvania and the CDC announcements focus on samples supporting their prior statements on transmission, which is not supported by the match between the Pennsylvania and Wisconsin cases.

The CDC silence ensures further bias in samples, which is hazardous to the world’s health.
CDC comments on the match, as well as the large number of unsubtypable samples in Pennsylvania, are long overdue.
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