EINet Alert ~ Nov 17, 2006

2003
Viet Nam / 3 (3)
Total / 3 (3)

2004
Thailand / 17 (12)
Viet Nam / 29 (20)
Total / 46 (32)

2005
Cambodia / 4 (4)
China / 8 (5)
Indonesia / 17 (11)
Thailand / 5 (2)
Viet Nam / 61 (19)
Total / 95 (41)

2006
Azerbaijan / 8 (5)
Cambodia / 2 (2)
China / 12 (8)
Djibouti / 1 (0)
Egypt / 15 (7)
Indonesia / 55 (44)
Iraq / 3 (2)
Thailand / 3 (3)
Turkey / 12 (4)
Total / 111 (75)

Total no. of confirmed human cases of avian influenza A/(H5N1), Dec 2003 to present: 258 (153).
(WHO 11/13/06 http://www.who.int/csr/disease/avianinfluenza/en/ )

Avian influenza age & sex distribution data from WHO/WPRO: http://www.wpro.who.int/sites/csr/data/data_Graphs.htm.
(WHO/WPRO 11/13/06)

WHO's maps showing world's areas reporting confirmed cases of H5N1 avian influenza in humans, poultry and wild birds: http://gamapserver.who.int/mapLibrary/
(Promed 11/11/06)

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Indonesia: 2 new cases of avian influenza H5N1 infection
2 new human cases of H5N1 avian influenza, one of them fatal, were reported in Indonesia, raising the country's toll to 74 cases with 56 deaths. A 30-month-old boy from Karawang in West Java province died of the illness, WHO reported, citing information from the Indonesian health ministry. The boy became ill Nov 5 and was hospitalized Nov 10. An initial investigation turned up reports of chicken deaths near the boy's home in the days before he got sick, WHO said.

The other new case is in a 35-year-old woman from Tangerang in Banten province, also on Java, the WHO said. Her illness began Nov 7, and she has been hospitalized at Jakarta's Sulianti Saroso hospital since Nov 10. Officials are trying to learn how she was exposed to the virus. The 2 H5N1 cases are the first reported in Indonesia since Oct 16, 2006, when WHO reported 3 fatal cases, all on Java. The 17 year old suspected avian influenza case (reported in the EINet’s 10 Nov 2006 Newsbrief) remains unresolved. Indonesia has the most deaths of any country, but Vietnam still has the most cases with 93. The huge territory of Indonesia, the extent of back yard farming and the relatively sparse budget have hampered Indonesia in fighting avian influenza.
(Promed 11/13/06; CIDRAP 11/13/06 http://www.cidrap.umn.edu/ )

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Seasonal Influenza
Seasonal influenza activity in APEC economies
During weeks 41–44, overall influenza activity remained low in both hemispheres. Low influenza activity was reported in Australia (A), Hong Kong (H1, H3 and B), Mexico (H1 and H3), the Russian Federation (H1, H3 and B), and the United States (H1, H3 and B). Philippines, reported no influenza activity.
(WHO http://www.who.int/csr/disease/influenza/update/en/ 11/14/06)

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L.J. Tan, director of infectious diseases for the American Medical Association (AMA), said many patients mistakenly believe that the only time to get vaccinated is before Thanksgiving. Administering the flu vaccine in Nov - Jan and beyond is consistent with federal Advisory Committee on Immunization Practices recommendations. Gerberding said that though distributors try to provide at least partial fulfillment of all vaccine orders early in the season so that all providers can begin their vaccination activities, some providers are still having trouble getting their doses. Because flu vaccine sales and distribution are handled by private companies, CDC can't control the flow of the product to customers.

Tan said that smaller providers are most likely to have been affected by distribution delays. "The biggest challenges are the chronically ill, high-risk patients that seek the vaccine from their family doctors in early October," he said. "If they can't get it, they go somewhere else. We want to encourage them to go back to their physicians." Gerberding said that despite the record number of doses this year, officials worry about supplies going unused. According to CDC tracking through Nov 4, Florida and Louisiana have local activity, and North Carolina is the only state showing regional activity. Federal health officials have recommended that toddlers aged 2 - 4 years be immunized against influenza each year, adding millions of people to the groups included in vaccination recommendations.
(CIDRAP 11/13/06 http://www.cidrap.umn.edu/ )

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Compliance with the recommendations for two doses of trivalent inactivated influenza vaccine in children less than 9 years of age receiving influenza vaccine for the first time: a Vaccine Safety Datalink study
Jackson LA, Neuzil KM, Baggs J, et al. Pediatrics 2006;118(5)
http://pediatrics.aappublications.org/cgi/content/abstract/118/5/2032
Abstract: “OBJECTIVES. Children <9 years of age do not respond optimally to a first dose of trivalent inactivated influenza vaccine, and so 2 doses of trivalent inactivated influenza vaccine are recommended for children <9 years of age who are being vaccinated for the first time. We conducted a population-based retrospective cohort study to evaluate compliance with the 2-dose trivalent inactivated influenza vaccine recommendations. POPULATION AND SETTING. We evaluated 125928 children 6 months through 8 years of age who were enrolled in health maintenance organizations in the United States participating in the Vaccine Safety Datalink project and who received their first dose of trivalent inactivated influenza vaccine in the 2001–2002, 2002–2003, or 2003–2004 influenza seasons. RESULTS. Compliance with the 2 dose recommendations varied by age group and influenza season. Among children 6 to 23 months of age, the proportion of first-vaccinated children who received a second vaccination was 44% in 2001–2002, 54% in 2002–2003, and 29% in 2003–2004. Among children 2 to 8 years of age, the corresponding proportions were 15%, 24%, and 12%, respectively. In all seasons, compliance with the second vaccination was highest in children first vaccinated by mid-November. CONCLUSIONS. The majority of children who received their first dose of trivalent inactivated influenza vaccine did not complete the 2-dose series. The recently expanded recommendation for universal vaccination of children 6 to 59 months of age and their household contacts will substantially increase the number of children targeted for a first influenza vaccination. Noncompliance with the 2-dose trivalent inactivated influenza vaccine series may be associated with suboptimal protection against infection, which may impact the magnitude of the direct and indirect benefits achieved by the vaccination program.”
(CIDRAP http://www.cidrap.umn.edu/ )

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Study: Flu vaccine slightly raises Guillain-Barré risk
Adults may have a slightly higher risk for hospitalization with Guillain-Barré syndrome (GBS) within a few weeks after influenza vaccination than at other times, though their overall risk of the disorder remains very low, Canadian researchers reported. Researchers from the University of Toronto, who published their findings in the Nov 13 issue of Archives of Internal Medicine, studied residents of Ontario, where everyone older than 6 months can receive a free annual flu shot. GBS causes weakness or tingling that can worsen to paralysis. The syndrome affects roughly 1 in 100,000 people each year. Some previous studies have linked flu vaccination with a slightly increased risk of GBS, but uncertainty remains about the association.

The researchers performed 2 analyses. In the first, they identified all hospitalizations for GBS among Ontario residents aged 18 and older from Apr 1993 - Mar 2004. Then they identified which patients received flu shots and compared their risk for hospitalization for GBS for two time intervals: 2 to 7 weeks and 20 to 43 weeks after vaccination. In a second analysis, the researchers examined the number of hospitalizations for GBS in Ontario 1991 - 2004 and compared the number of cases before and after the universal flu immunization program began in 2000.

The results of the first analysis revealed there were 1,601 hospitalizations for GBS between 1993 - 2004, 269 of which occurred within 43 weeks after the patient received a vaccine, presumably for influenza, in Oct or Nov. Patients were 1.45 times as likely to be hospitalized for GBS from 2 - 7 weeks after vaccination as they were between 20 - 43 weeks after vaccination. In the second analysis, the authors identified 2,173 hospitalizations for GBS between 1991 - 2004 and found no significant difference between hospitalization rates before and after the universal immunization program took effect. The authors say the results should be interpreted carefully. “The increase in relative risk we observed corresponds to a very low absolute risk for Guillain-Barré syndrome, given the low baseline incidence of the disease (approximately 1 in 100,000 population),” they write. “Furthermore, the lack of association on a population level is consistent with the assumption that the influenza vaccine is one of many potential causes of GBS." They also note that the US Institute of Medicine in 2003 reviewed studies from the preceding 26 years and concluded there was inadequate evidence to either confirm or reject a link between flu immunization and GBS.

A recent study of the safety of the influenza vaccine in thousands of children aged 6 to 23 months found only 2 instances of GBS, and neither of the patients was diagnosed with the condition within a few weeks after vaccination. However, the researchers say that people who receive flu shots should be advised of the possible risk for GBS and that active surveillance should be included in any mass vaccination program for pandemic flu. Julie Gerberding, director of the US CDC, said the study is consistent with other research findings that have shown people who get the flu vaccine have a negligible risk of developing GBS. She said the study has not prompted the CDC to change its recommendations about flu vaccination, and added that the health risks related to flu far outweigh any risk of developing GBS from the vaccine.

Reference: Juurlink DN, Stukel TA, Kwong J, et al. Guillain-Barré syndrome after influenza vaccination in adults: a population-based study. Arch Intern Med 2006;166(20):2217-21. To read the abstract, go to:
http://archinte.ama-assn.org/cgi/content/abstract/166/20/2217
(CIDRAP 11/14/06 http://www.cidrap.umn.edu/ )

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Tamiflu may pose risk of mental side effects
Drug manufacturer Roche and US regulators are warning that influenza patients treated with oseltamivir (Tamiflu) may have an increased risk of self-injury and delirium. "People with the flu, particularly children, may be at increased risk of self-injury and confusion shortly after taking Tamiflu and should be closely monitored for signs of unusual behavior," says a warning that Roche has added to its official product information. Oseltamivir is used both to prevent and to treat flu and is regarded as the best available drug for dealing with a potential pandemic strain of flu. The US and many other countries are stockpiling it because of the pandemic threat.

The warning follows an FDA review of 103 reports of neuropsychiatric adverse events associated with oseltamivir use between Aug 29, 2005, and Jul 6, 2006, of which 95 came from Japan. That compares with 126 such adverse events reported between 1999 and Aug 2005. About two thirds of the problems were in children and youth younger than 17 years. The adverse events included 3 fatal falls. Most of the events (60/103) were described as delirium with disturbed behavior. Other problems included suicidal events, panic attacks, delusions, convulsions, depressed consciousness, and loss of consciousness.

FDA and Roche both say the contribution of the drug to the adverse events is not known. FDA says influenza by itself can lead to neuropsychiatric disorders, but many of the problems reported (e.g. suicide attempts), were not typical of those associated with flu alone. Citing factors that seem to implicate oseltamivir in the events, FDA said most of the problems occurred within a day after the start of treatment, and in many cases the physician suspected the drug was the cause. In addition, many of the patients recovered quickly after they stopped taking oseltamivir. "It is still unclear whether these neuropsychiatric events are drug-related only, disease manifestations alone, or a combination" of the two, the report states.

The analysis notes that oseltamivir is used much more widely in Japan, with 24.5 million prescriptions from 2001 - 2005, than in the US, with 6.5 million prescriptions in the same period. In Japan the product information already includes a warning about possible psychoneurological problems. The FDA report expresses concern that if oseltamivir use in the US increases to the levels seen in Japan, the number of adverse events will increase as well. "Therefore, it would be prudent to update the U.S. labeling to be similar in scope with the current Japanese labeling," it says. The Japanese origin of most of the adverse event reports might suggest that the problems are related to genetic characteristics common in Japan. But given the much greater use of the drug in Japan and the possibility of different surveillance practices there, the lack of cases reported in the US doesn't constitute good evidence for that hypothesis, it states.
(CIDRAP 11/14/06 http://www.cidrap.umn.edu/ )

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'Gene chip' test could speed H5N1 diagnosis
Scientists say they have developed an inexpensive "gene chip" test that can quickly identify a variety of influenza A viruses and is less apt to be confused by viral mutations than other tests are. A research team from the University of Colorado in Boulder and CDC developed the test and will report their results in the Dec 15 issue of Analytical Chemistry. The test involves a microarray of genetic material—short sequences of known RNA deposited on a microscope slide. The team says the test has a key advantage over other available tests in that it is based on a single gene segment that mutates less often than the gene segments used in other tests, meaning it may not have to be updated as frequently as viruses evolve.

Researchers examined the test's ability to identify 24 H5N1 viral isolates and distinguish them from 7 non-H5N1 isolates. They found that the "MChip" provided complete information about virus type and subtype for 21 of 24 H5N1 isolates and gave no false-positives, according to the National Institute of Allergy and Infectious Diseases (NIAID), which funded the research. The samples were collected from 2003-2006 from people and animals in places as widely separated as Vietnam, Nigeria, Indonesia, and Kazakhstan. 6 of the human isolates were taken from an Indonesian family in which human-to-human transmission was suspected. Analysis of 47 samples consisting of influenza A viruses (subtypes H5N1, H3N2, and H1N1) and negative controls revealed the test's sensitivity was 97% and its specificity was 100%.

Nancy J. Cox, director of the CDC's influenza division and a coauthor of the report, said, "The MChip could enable more scientists and physicians, possibly even those working in remote places, to more quickly test for H5N1 and to accurately identify the specific strain and its features." Kathy L. Rowlen, who led the research team, said that the MChip is an improvement over its predecessor, the FluChip. The latter uses 3 influenza genes—hemagglutinin (HA), neuraminidase (NA), and matrix (M)—whereas the MChip uses only the M gene. Rowlen said HA and NA are difficult to use in flu diagnostic tests because they mutate constantly. "The M segment is much less of a moving target than the HA and NA gene. . ." she said.

Rowlen said that a private company is negotiating with the University of Colorado to manufacture the test for commercial use. If approved by the Food and Drug Administration, the MChip system could be in great demand in a flu pandemic. Rowlen said foreign supply-chain disruptions in the event of a pandemic would probably not seriously affect MChip production. She said most of the raw materials used to make the test, such as glass slides and reagents, are supplied by US companies. The cost of the raw materials is about $10.

Article reference: Dawson E, Moore CL, Dankbar DM, et al. Identification of A/H5N1 influenza viruses using a single gene diagnostic microarray. Anal Chem 2006 Dec 15, in press.
(CIDRAP 11/15/06 http://www.cidrap.umn.edu/ )

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Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors
Shinya Yamada et al. Nature 444, 378-382 (16 November 2006)
http://www.nature.com/nature/journal/v444/n7117/abs/nature05264.html (references removed)
Abstract: “H5N1 influenza A viruses have spread to numerous countries in Asia, Europe and Africa, infecting not only large numbers of poultry, but also an increasing number of humans, often with lethal effects. Human and avian influenza A viruses differ in their recognition of host cell receptors: the former preferentially recognize receptors with saccharides terminating in sialic acid- 2,6-galactose (SA 2,6Gal), whereas the latter prefer those ending in SA 2,3Gal. A conversion from SA 2,3Gal to SA 2,6Gal recognition is thought to be one of the changes that must occur before avian influenza viruses can replicate efficiently in humans and acquire the potential to cause a pandemic. By identifying mutations in the receptor-binding haemagglutinin (HA) molecule that would enable avian H5N1 viruses to recognize human-type host cell receptors, it may be possible to predict (and thus to increase preparedness for) the emergence of pandemic viruses. Here we show that some H5N1 viruses isolated from humans can bind to both human and avian receptors, in contrast to those isolated from chickens and ducks, which recognize the avian receptors exclusively. Mutations at positions 182 and 192 independently convert the HAs of H5N1 viruses known to recognize the avian receptor to ones that recognize the human receptor. Analysis of the crystal structure of the HA from an H5N1 virus used in our genetic experiments shows that the locations of these amino acids in the HA molecule are compatible with an effect on receptor binding. The amino acid changes that we identify might serve as molecular markers for assessing the pandemic potential of H5N1 field isolates.”

The significance of this paper is that 2 independent mutations in the HA protein of avian influenza A(H5N1) virus, conferring recognition of human cell receptors, are located in the crystal structure of the HA molecule compatible with their inferred effect on receptor binding. Not all H5N1 viruses isolated from human patients, however, exhibited these mutations and other factors are likely to be involved in the host range phenotype and pandemic potential of avian influenza viruses. Yoshihiro Kawaoka, one of the authors, warned, "It is very important that we shouldn't only focus on these 2. The virus can become human-like by many mutations, these 2 are important but they are not the only ones," he said. "But these 2 will give indication when a virus has changed receptor specificity."
(CIDRAP http://www.cidrap.umn.edu/ ; Promed 11/16/06)

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USA: Pandemic planning update III
Nov 13 release from Department of Health and Human Services: Sections include: Message from the secretary; Monitoring and surveillance; Research; Vaccines and vaccine production capacity; Antiviral drugs; State and local preparedness; Communications.
http://pandemicflu.gov/plan/pdf/panflureport3.pdf

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USA: OSHA updates guidance on avian flu
The US Department of Labor released revised Occupational Safety and Health Administration (OSHA) guidance to help employers protect their workers from job-related exposure to H5N1 avian influenza. The OSHA guidance, last updated 2004, gives separate recommendations for several specific employee groups that may be most likely to encounter animals or people infected with the H5N1 virus. The groups include poultry workers, animal handlers, laboratory personnel, healthcare workers, food handlers, travelers, and Americans living abroad. The main thrust is on proper hygiene techniques, such as use of gloves and handwashing, along with respiratory protection. For many of these groups, OSHA's guidance incorporates interim recommendations from other agencies and groups (e.g. National Institute for Occupational Safety and Health, CDC). The longest set of recommendations is the one for poultry workers. It instructs employees on signs of possible avian flu in poultry, reviews basic infection control measures, and gives a protocol for proper protective equipment use. It includes the CDC recommendation that all unvaccinated employees receive seasonal influenza vaccine and that all workers who have direct contact with infected poultry or contaminated surfaces receive a prophylactic dose of antiviral medication on each day of exposure and for 1 week following their last exposure. In the food-handler recommendations, the OSHA guidance says that the 2 groups most at risk are restaurant cooks and those grocery store employees who handle raw chicken. Updated OSHA guidance on protecting employees from avian flu: http://www.osha.gov/dsg/guidance/avian-flu.html
(CIDRAP 11/15/06 http://www.cidrap.umn.edu/ )

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