Vietnam - Avian Flu May
Have Been Underestimated
From Patricia Doyle, PhD
Vietnam - Deadly Avian Flu May Have Been Underestimated
BBC News Online
The spread of the deadly avian influenza virus may have been underestimated because of a misunderstanding of how it affects the body, British scientists have said. Oxford University experts studying deaths in Viet Nam suggest the disease can attack all parts of the body, not just the lungs as had been thought. They told the New England Journal of Medicine [see comment below: Engl J Med 352;7 17 Feb 2005. - Mod.CP] that they also believe humans could pass the virus on to each other. So far, there have been 42 bird flu deaths, all in Asian countries. But the Oxford University scientists say their findings suggest the number of cases of human infection with the virus may have been underestimated.
The World Health Organization said it would change its definition of what constituted an avian influenza infection. So far, the WHO says there have been 55 confirmed cases of avian influenza in humans, and 42 deaths. However, experts believe millions could be at risk if the virus acquires the ability to jump from person to person by combining with human influenza virus to make a new, mutated [reassortant] version.
The researchers examined the deaths of 2 young children -- a brother and sister -- who lived in a single room with their parents in southern Viet Nam. They were admitted to hospital suffering from gastroenteritis and acute encephalitis, which are common ailments in the country. Neither displayed respiratory problems, which have been considered typical in cases of avian influenza. But analysis revealed that the 4-year-old boy had traces of the virus in his faeces, blood, nose and in the fluid around the brain. This indicates the virus -- known as H5N1 -- can attack all parts of the body, not just the lungs. It is suspected his 9-year-old sister, who died 2 weeks earlier in February 2004, was also suffering from the virus.
The lead researcher is Dr Menno de Jong, a virologist at the Oxford University Clinical Research Unit who is based at the Hospital for Tropical Diseases in Ho Chi Minh [City]. He said: "This illustrates that when someone is suffering from any severe illness we should consider if avian influenza might be the cause. It may be possible to treat but you have to act in the early stages, so awareness of the whole spectrum of symptoms in an emerging disease like avian flu is vital. It appears this virus is progressively adapting to an increasing range of mammals in which it can cause infection, and the range of disease in humans is wide and clearly includes encephalitis."
Dr Jeremy Farrar, director of the Wellcome Trust's Viet Nam unit, said: "This latest work underlines the possibility that avian influenza can present itself in different ways. The main focus has been on patients with respiratory illnesses but clearly that's not the only thing we should be looking for. Therefore the number of cases of H5N1 may have been underestimated."
Dr Farrar said the presence of the virus in the faeces suggested that it could be spread from person to person -- especially where people are living in crowded conditions. It is not believed that either of the children passed the virus on, but it is also not clear how they contracted it. However, the girl often swam in a nearby canal which may have been contaminated by ducks carrying the virus.
Dick Thompson of the World Health Organization told the BBC the findings were significant. He said: "It means the range of illnesses we have been looking for when considering a diagnosis of avian flu will now be expanded. We will have to change the way we conduct our investigations, the management of hospital patients and even the way we deal with their bodily secretions."
-- ProMED-mail
Reference: New England Journal of Medicine brief report entitled "Fatal Avian Influenza A (H5N1) in a Child Presenting with Diarrhea Followed by Coma" by Menno D. de Jong and 12 others.
Abstract -------- In southern Viet Nam, a 4-year-old boy presented with severe diarrhea, followed by seizures, coma, and death. The cerebrospinal fluid contained 1 white cell per cubic millimeter, normal glucose levels, and increased levels of protein (0.81 g per liter). The diagnosis of avian influenza A (H5N1) was established by isolation of the virus from cerebrospinal fluid, fecal, throat, and serum specimens. The patient's 9-year-old sister had died from a similar syndrome 2 weeks earlier. In both siblings, the clinical diagnosis was acute encephalitis. Neither patient had respiratory symptoms at presentation. These cases suggest that the spectrum of influenza H5N1 is wider than previously thought. We report an additional fatal case of influenza H5N1, diagnosed by isolating the virus from cerebrospinal fluid, fecal, throat, and serum specimens, in a boy who presented with severe diarrhea but no apparent respiratory illness, followed by rapidly progressive coma, leading to a clinical diagnosis of acute encephalitis. 2 weeks earlier, his sister had died of a similar illness. These cases suggest that the clinical spectrum of influenza H5N1 is wider than previously thought, and therefore they have important implications for the clinical and public health responses to avian influenza.
We report a fatal case of influenza A (H5N1) in a child who presented with severe diarrhea, followed by convulsions and coma, and who received a diagnosis of acute encephalitis. The diagnosis of influenza H5N1 was established by isolating the virus from stored cerebrospinal fluid, serum, throat, and rectal specimens. The possibility of laboratory contamination can be ruled out, for the following reasons: all clinical specimens were cultured on separate occasions, weeks or months apart; viral RNA was subsequently detected directly in all stored specimens; and the H5N1 virus was not isolated from other patients' specimens during the same period.
Although the possibility remains unproven because of the lack of specimens from Patient 1, the temporal relationship and similarity of illnesses render it likely that the 2 patients died of the same disease. These cases have important clinical, scientific, and public health implications. In both cases, the clinical presentation led to diagnoses of gastrointestinal infection and acute encephalitis, which alone or in combination are common clinical syndromes in southern Viet Nam. Patient 1 had no respiratory symptoms and a normal chest radiograph less than 24 hours before she died. Although Patient 2 showed signs of pneumonia during the last day of his life, a respiratory illness was not considered his most relevant clinical problem. Recently, another patient with influenza H5N1 was described with an initial presentation of fever and diarrhea alone.
These cases emphasize that avian influenza A (H5N1) should be included in the differential diagnosis of a much wider clinical spectrum of disease than previously considered and that clinical surveillance of influenza H5N1 should focus not only on respiratory illnesses, but also on clusters of unexplained deaths or severe illnesses of any kind. Awareness of the full clinical spectrum is essential to appropriate management of the illness, since treatment with antiviral agents is likely to be beneficial only when it is started early in the course of illness. Encephalitis and encephalopathy are rare complications of infection with human influenza viruses, and the pathogenesis remains unclear. Although viral RNA has been detected in some cases, reports of isolation of influenza virus from cerebrospinal fluid are extremely rare. By contrast, avian influenza A (H5N1) viruses replicate systemically in poultry, affecting multiple organs, including the central nervous system. Furthermore, the H5N1 strain implicated in the 1997 Hong Kong outbreak causes encephalitis in experimentally infected mice without prior host adaptation. Recent studies in ducks and mice show that the capacity of H5N1 strains to cause systemic illness, including central nervous system involvement, is increasing.
The currently circulating strain of H5N1 has also been shown to cause encephalitis in tigers and leopards. These reports suggest that avian influenza A (H5N1) virus is progressively adapting to mammals and becoming more neurologically virulent.
In our patient, systemic infection was evidenced by the viraemia, which is rarely reported in humans with influenza, and by the isolation of virus from cerebrospinal fluid and rectal specimens. It is likely that hepatitis and metabolic acidosis were also secondary to disseminated viral infection. Since imaging of the brain or histologic analyses were not performed in either patient, we cannot be sure whether they had encephalopathy or true encephalitis. However, the presence of virus in the cerebrospinal fluid of Patient 2 strongly suggests that the virus had a causative role in his coma. The precise mechanism of this role needs to be addressed by appropriate investigations of future patients with similar presentations. Although the lumbar puncture was traumatic, the marginal increase in the protein level and the near-absence of white cells in the cerebrospinal fluid argue against blood contamination sufficient to explain the similarity of the viral loads in the serum and cerebrospinal fluid.
Assuming that the 2 children died of the same illness, why influenza H5N1 presented in this similar atypical manner in these 2 siblings remains an enigma. On the basis of the combination of influenza, elevated aminotransferase levels, and coma, a diagnosis of Reye's syndrome in Patient 2 could be considered. However, the finding of normal blood glucose levels, the absence of aspirin use, and the evidence of disseminated infection with a highly pathogenic virus as a plausible cause of the illness argue against this diagnosis.
Further research is needed to determine whether host factors, which may determine a person's susceptibility to disseminated or central nervous system infection, or a particularly neurologically virulent strain of virus is involved. The routes of transmission in our patients are unclear. Epidemiologic investigations did not reveal exposure to ill poultry. In view of recent data suggesting that ducks infected with the current H5N1 strain shed large amounts of virus, the source of transmission may have been in the canal near the children's house. Water from this canal was used for washing, and Patient 1 was reported to have swum regularly in this canal.
Direct transmission from sister to brother appears unlikely, considering the interval between their illnesses. Only if the incubation period was unusually long could sister-to-brother transmission be implicated. Nevertheless, the isolation of virus from a rectal specimen is a major source of concern, since it highlights a potential route of human-to-human transmission, especially in combination with crowded living conditions and diarrhea. In conclusion, our cases emphasize a hitherto unsuspected broad clinical spectrum of disease attributable to avian influenza A (H5N1) virus and provide important information for treatment and future clinical surveillance. The presence of viable virus in the feces of our patient has important implications for transmission, infection control, and public health.
-- ProMED-mail
A reasonable criticism of this interesting and provocative paper might be that rather much is being extrapolated from study of a single fatal case. The level of exposure and immune response of the general human population in the region is still an unknown quantity. Until more is known about the seroprevalence of avian influenza virus infection, the unpredicted disease response described in this paper could be attributed to the genetic make-up of the patent (and his sibling, presumed to have been infected with the same virus), rather than the genetic properties of the infectious agent. - Mod.CP
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