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H5N1 Bird Flu False Negatives In Indonesia
September 29, 2005
As a result of intensified surveillance and heightened public concern, growing numbers of people with respiratory symptoms or possible exposure to the virus are being admitted to hospital for observation and, when appropriate, treatment. Until a conclusive diagnosis is made, these patients are classified by the Ministry of Health as suspect cases. While many do not have symptoms compatible with a diagnosis of H5N1 infection, screening of patient samples is being undertaken in national laboratories as part of efforts to ensure that no new cases are missed.
Laboratory testing to confirm human infection with H5N1 avian influenza is technically difficult; some tests produce inconclusive or unreliable results. To ensure a reliable assessment of the situation in Indonesia, authorities are, after initial screening, continuing to send samples from people considered likely to have H5N1 infection to WHO reference laboratories for diagnostic confirmation.
The above comments by WHO announcing the fourth confirmed H5N1 case in Indonesia fails to address the false negatives in Indonesia due to improper sample collection. Although this problem is obvious to the most casual observer, the WHO continues to battle H5N1 via press release. Sample collection and testing remain scandalously poor. The samples are clearly improperly collected, but the WHO comments on the unreliability of the testing and fails to address the issue.
The problem can be easily identified in the first few cases, which clearly show human-to-human transmission and false negatives.
The initial familial cluster involved three fatalities. All three fatalities were clearly due to H5N1 infection, but only one tested positive for H5N1 by PCR. The failure to detect H5N1 in the other two fatalities was simply due to the improper collection of samples.
The index case, an 8 year-old girl, was hospitalized for almost 3 weeks before she died, but never tested positive for H5N1. This is because no early samples were collected. The same was true for her 1 year old sister. However, her father was admitted after his two daughters were clearly dying, so a sample was collected from him shortly after admission, and he was PCR positive for H5N1. Eventually serum was collected from the index case and both samples were also strongly H5N1 positive by testing in Hong Kong and Atlanta leaving little doubt that all three fatalities were due to H5N1. However, because the serum samples were collected just 3 days apart, and the initial sample was strongly positive, the second sample was not four fold higher than the first, so the index case was excluded from confirmed cases.
Thus, although there was strong evidence for human-to-human transmission, only one of the three fatalities was included in the WHO list of confirmed cases in Indonesia. The one positive was a 38 year old government auditor, with no history of contact with infected birds. The birdcage across the street was H5N1 positive, raising the possibility of infection of the 8 year old by a pet bird leading to three fatalities in the suburban Tangerang family.
The second confirmed case was another office worker who worked for immigration at the airport. She was PCR positive, as was her nephew, who was the third confirmed case in Indonesia. The time between symptoms of the index case and the family member again points to human-to-human transmission. Because of the screening of relatives of the index case, a sample was collected early and he tested positive for H5N1. However, in contrast to the fatal outcome in the first four cases, he had a relatively mild case and has been discharged. His outcome indicates that H5N1 can be transmitted human-to-human and such transmissions can produce mild disease, raising the real possibility of silent spread of H5N1 in humans.
The casual spread of H5N1 was highlighted by analysis of workers and visitors at the Ragunan Zoo. They had bird flu symptoms and tested positive for H5N1 antibody. However most of the visitors initially went to primary hospitals, where no samples were collected. When the patients did not improve, they were transferred to the infectious disease hospital. Sample collection at this time produced negative PCR tests because by this time the patient was transferred to the infectious disease hospital, the H5N1 was no longer in the nose or throat, so swabs of those sites were negative.
The testing of zoo visitors with symptoms has been far from ideal. When 115 arrived at the infectious disease hospital, they were turned away because their symptoms were too mild. However, as seen by the nephew of the second index case, H5N1 infections can produce mild disease, and it is at the time of initial symptoms that H5N1 is most easily collected from swabs of the nose or throat.
The screening of patients also reduces the likelihood of detecting human to human transmissions. Patients not recovering were transferred if they had been to the zoo. More recent transfers have been linked to dying poultry. Thus, the screening would screen out those that were H5N1 infected by other people or casual contact not involving dying poultry or zoo visits.
The ability to test and treat these patients is limited. There are only four beds set aside for patients requiring ventilators, but one ventilator is not functioning and a monitor is broken, so there are only two ventilators available at the infectious disease hospital.
There is also an effort to quickly discharge patients to make room for more patients. One was scheduled to be discharged today, but when her 14 month-old baby was admitted, she was not released.
The resource shortage also applies to individual families. In Demak two children died without being admitted because the family could not afford the medical expenses. Now a third sibling has symptoms, suggesting more human-to-human transmission and more missed patients and samples.
The larger clusters and clusters of clusters (see map) indicates that the pandemic in Indonesia has moved to phase 5, yet WHO maintains a phase 3 level.
The number of false negatives in Indonesia is a cause for concern and WHO's efforts of battling H5N1 by press release become more remarkable by the hour.
The time for collection and testing of samples at primary sites is long overdue.
WHO's failure to address this obvious problem remains scandalous.