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False Negatives Raise H5N1 Surveillance Concerns In Indonesia

Recombinomics Commentary

June 16, 2006

According to news agency reports quoting health officials, the 7-year-old had tested negative for avian flu in nose and throat swabs taken when she was alive, but then tested positive when lung tissue was taken after her death.

Nose and throat swabs - the routine way of diagnosing regular flu - may give false negatives because the bird flu virus attaches to cells deep in the lungs, not to the upper respiratory tract. In January, according to the World Health Organization, the same error caused the first human cases in Turkey's outbreak to be misdiagnosed.

There have been several reports of Indonesian nurses' falling sick after tending avian flu victims, which could indicate that the virus was spreading more easily between humans. On June 6, the World Health Organization reported that tests on four such nurses had convincingly ruled out A(H5N1), the avian flu, and indicated that one had a seasonal flu, A(H1N1), instead.

Dr. Niman said convincing evidence could be obtained only from blood tests.

Mr. Thompson, who recently returned from Indonesia, said that he did not know how the nurses had been tested, but that he thought that Indonesian health authorities "are really on top of the human cases, investigating them aggressively," even though animal cases were spiraling out of control.

The above comments in today's Donald McNeil article in the New York Times has more curious comments by WHO and health officials.  Testing in Jakarta is generally quite reliable, so it was surprising that WHO failed to confirm an 18 year old brother who had tested positive in Jakarta and his sister had tested positive in both Jakarta and Hong Kong.  It was highly unlikely that a sibling of an H5N1 bird flu confirmed patient would falsely test positive in Jakarta.  The Hong Kong lab ran additional tests and confirmed the Bandung cluster.

The repeated false negatives by Hong Kong in the latest cluster from Bandung raises serious questions about the "definitive" negative results on the nurses in Bandung.  As noted on the media reports, the false negatives were generated by nose and throat swabs.  This type of testing has previously been called Goldilocks testing because it is too late to detect H5N1 in the nose and throat, but too early to detect H5N1 antibodies in the blood, but just right to generate false negatives.

The testing of the nurses was clearly in the Goldilocks category because the antibody levels peak 3-4 weeks after symptoms, and at least two of the four nurses were tested about a week after symptoms.  Since the time for collecting samples is fast approaching, it is surprising that the WHO spokesperson did not know of plans to due further testing to truly rule up H5N1 infections in the nurses.

Moreover, the H5N1 isolated from patients in Western Java, including Tangerang, Jakarta, and Bandung, have a novel cleavage site that does not match reported bird isolates but do match and isolate from a cat.  Therefore, the source of the H5N1 in these cases remains unclear.

As the number of human cases and poultry outbreaks continue to increase, the surveillance failures become more clear.  New sequences at Genbank from birds in Indonesia identify one isolate with a cleavage site that matches the Qinghai strain.  This isolate is cause for concern because all Qinghai isolates reported to date have PB2 E627K, which is associated with a poor outcome and was detected in the second reported Indonesian case.  Thee has also been speculation that the higher levels of H5N1 in the nose and throat of members of the Sumatra cluster was due to E627K.

Thus, release of the human sequences, as well as more data on H5N1 in animals in Indonesia is urgently needed.

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