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H5N1 Genetic Diversity Producing False Negatives?
Recombinomics Commentary

August 15, 2006

The case occurred in a 62-year-old male farmer from the north-western province of Xinjiang. He developed symptoms on 19 June and died on 12 July. Initial tests on patient specimens produced negative results. As a precautionary measure, tests were repeated during July and August and eventually produced positive results, which were confirmed today by the Ministry of Health.

The above comments from the most recent WHO update again highlight concerns over false negatives.  Media reports indicated that the patient was positive at the national center, even though the same sample had tested negative at the regional center.  These data suggest H5N1 may be evolving away from some of the testing procedure used in testing birds or people.

The above case is the first reported in northwestern China.  Prior human cases have been reported in eastern or southeastern China.  Xingjian, in western China has reported positives for H5N1 in birds, including an outbreak in June, but the above patient has no link to birds and China has a least two distinct major strains of H5N1 co-circulating.  The Fujian stain has been reported for all human cases in 2005 and 2006.  However, the Qinghai strain was first identified in central China last year and has been detected in many outbreaks, including central and western China this year

The Fujian strain has spread to Laos, Malaysia and Hong Kong and isolates from this year have Qinghai polymorphism.  Similarly, Qinghai isolates have Fujian polymorphism.  These two major stains have been recombining to produce new versions of H5N1.

Similarly, Fujian H5N1, which is Clade 2, has been found in southeast Asia, which previously had been endemic for Clade 1.  Clade 1 polymorphisms from Vietnam and Thailand have been found in the newly released Indonesian sequences, which are distinct from the Fujian and Qinghai sequences in China, but are also Clade 2.  At least one Indonesian bird sequence has also acquired the Qinghai HA cleavage site.

Similarly, the recent Qinghai isolates from Russia have at least one polymorphism from the wild bird H5N2 in Canada.  It is likely that this change is also in the recent H5N1 isolates in Michigan.

Thus, H5N1 has been actively recombining and evolving. This evolution may produce false negatives.  The H5 PCR positive result on Prince Edward Island was said to have been a weak positive.  Similarly, most of the human samples in Thailand are said to be H5N1 negative, although there are reports of 300 fatalities in 6000 seasonal flu patients in Thailand.  The 5% case fatality rate is extremely high, even if the 6000 flu patients were limited to those hospitalized.

H5N1 is dramatically increasing its geographical reach and genetic diversity.  There are already at least four versions that have caused human fatalities and are currently circulating (Clade 1 in Southeast Asia, Fujian in China and southeast Asia, Indonesian in Indonesia, and Qinghai worldwide).

This H5N1 genetic diversity is without precedent and leads to rapid evolution.  It is unclear that the H5N1 testing has kept pace with these changes.

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