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EINet Alert ~ Oct 12, 2007
*****A free service of the APEC Emerging Infections Network*****
APEC EINet News Briefs offers the latest news, journal articles, and notifications for emerging infections affecting the APEC member economies. It was created to foster transparency, communication, and collaboration in emerging infectious diseases among health professionals, international business and commerce leaders, and policy makers in the Asia-Pacific region.
In this edition:
- Global: Cumulative number of human cases of avian influenza A/(H5N1)
- Indonesia (Riau, Jakarta): New avian influenza H5N1 cases reported
- Viet Nam (Tra Vinh): New avian influenza H5N1 outbreak in poultry
- Avian/Pandemic influenza updates
- CDC EID Journal, Volume 13, Number 10--Oct 2007
- H5N1 mutation that could help spark pandemic identified
- Fresh doubts, new support for influenza shots for seniors
- Trends in influenza vaccination in Canada, 1996/1997 to 2005
- Influenza viruses and the evolution of avian influenza virus H5N1
- Development and evaluation of an influenza subtype H7N2 vaccine candidate for pandemic preparedness
- Antiviral Oseltamivir Is not Removed or Degraded in Normal Sewage Water Treatment: Implications for Development of Resistance by Influenza A Virus
- A Single Mutation in the PB1-F2 of H5N1 (HK/97) and 1918 Influenza A Viruses Contributes to Increased Virulence
- The role of oseltamivir in the treatment and prevention of influenza in children.
- Cross-Protection against H5N1 Influenza Virus Infection Is Afforded by Intranasal Inoculation with Seasonal Trivalent Inactivated Influenza Vaccine
- Progress and shortcomings in European national strategic plans for pandemic influenza
Global: Cumulative number of human cases of avian influenza A/(H5N1)
Economy / Cases (Deaths)
Total no. of confirmed human cases of avian influenza A/(H5N1), Dec 2003 to present: 330 (202).
Avian influenza age distribution data from WHO/WPRO: http://www.wpro.who.int/sites/csr/data/data_Graphs.htm.
WHO's maps showing world's areas affected by H5N1 avian influenza (last updated 10/11/07): http://gamapserver.who.int/mapLibrary/
WHO’s timeline of important H5N1-related events (last updated 9/11/07): http://www.who.int/csr/disease/avian_influenza/ai_timeline/en/index.html.
Indonesia (Riau, Jakarta): New avian influenza H5N1 cases reported
A 44-year-old Indonesian woman who died Oct 6, 2007 had H5N1 avian influenza, marking the country's 108th human H5N1 case and 87th death. The woman, from Pekan Baru city in Sumatra's Riau province, fell ill Sep 27 and was hospitalized Oct 2, said I Nyoman Kandun of the Indonesian Health Ministry. Kandun said it was unclear how the woman contracted the disease, but she often visited marketplaces and might have had contact with poultry there. He said the ministry was sending a team to Riau to conduct an investigation. The patient's contacts remain healthy but are being monitored. Riau has recorded 4 bird flu cases since 2005.
Indonesia also reported an additional H5N1 avian influenza case in a 12-year-old boy in the Jakarta area, raising the country's human case count to 109. The boy is from the Jakarta suburb of Tangerang and is being treated in a Jakarta hospital, said Muhammad Nadirin, a spokesman for the health ministry's avian flu center. Nadirin said it was not clear how the boy was exposed to the virus, but some chickens had reportedly died in his neighborhood. 87 of Indonesia's H5N1 cases have been fatal. Meanwhile, 5 people with suspected avian flu in Indonesia's North Sumatra province tested negative for the H5N1 virus. The 5 were among 7 people from the same village who were admitted to a hospital in Medan, the provincial capital, Oct 6, 2007.
Viet Nam (Tra Vinh): New avian influenza H5N1 outbreak in poultry
Avian/Pandemic influenza updates
- UN: http://www.un-influenza.org/ : latest on Indonesian avian influenza case. Also, http://www.irinnews.org/Birdflu.asp provides information on avian influenza.
- WHO: http://www.who.int/csr/disease/avian_influenza/en/index.html.
- UN FAO: http://www.fao.org/ag/againfo/subjects/en/health/diseases-cards/special_avian.html. Link to supplement to Journal of Wildlife Diseases on avian influenza.
- OIE: http://www.oie.int/eng/info_ev/en_AI_avianinfluenza.htm.
- US CDC: http://www.cdc.gov/flu/avian/index.htm.
- The US government’s web site for pandemic/avian flu: http://www.pandemicflu.gov/.
- Health Canada: information on pandemic influenza: http://www.influenza.gc.ca/index_e.html. Latest updates on Saskatchewan H7N3 outbreak.
- CIDRAP: http://www.cidrap.umn.edu/.
- PAHO: http://www.paho.org/English/AD/DPC/CD/influenza.htm. Link to National Influenza Centers in PAHO Member States.
- US Geological Survey, National Wildlife Health Center Avian Influenza Information: http://www.nwhc.usgs.gov/disease_information/avian_influenza/index.jsp. Updated 5 Oct 2007 with information on H7N3 outbreak in Canada.
(UN; WHO; FAO, OIE; CDC; Health Canada; CIDRAP; PAHO; USGS)
CDC EID Journal, Volume 13, Number 10--Oct 2007
CDC Emerging Infectious Diseases Journal Oct 2007 issue is now available at: http://www.cdc.gov/ncidod/EID/index.htm. Influenza-related articles: Preparedness for Highly Pathogenic Avian Influenza Pandemic in Africa by R.F. Breiman et al.; Influenza A and B Infection in Children in Urban Slum, Bangladesh by W.A. Brooks et al.; Confronting Potential Influenza A (H5N1) Pandemic with Better Vaccines by A. Haque et al.; Personal Protective Equipment and Antiviral Drug Use during Hospitalization for Suspected Avian or Pandemic Influenza by A. Swaminathan et al.; Chlorine Inactivation of Highly Pathogenic Avian Influenza Virus (H5N1) by E.W. Rice et al.; Multifocal Avian Influenza (H5N1) Outbreak by R.D. Balicer et al.; Super-Sentinel Chickens and Detection of Low-Pathogenicity Influenza Virus by P.I. Marcus et al.
Expedited articles can be viewed at: http://www.cdc.gov/ncidod/eid/upcoming.htm. Influenza related articles: Protection and Virus Shedding of Falcons Vaccinated against Highly Pathogenic Avian Influenza A Virus (H5N1); Role of Terrestrial Wild Birds in Ecology of Influenza A Virus (H5N1); Pandemic Influenza and Hospital Resources; Medical Students and Pandemic Influenza; Bird Flu: A Virus of Our Own Hatching.
H5N1 mutation that could help spark pandemic identified
The authors write that the hemagglutinin protein's specificity for avian- or human-type receptors on airway cells is thought to be a major factor governing the efficient transmission of H5N1 viruses. Yet the disease still doesn't spread easily among humans, though scientists have isolated from humans some H5N1 viruses that had specificity for human receptors. To determine what other amino acid substitutions are needed to make the virus more transmissible among humans, they explored the role of the amino acid at position 627 of the PB2 viral protein, one of the key proteins involved in viral replication. The scientists used two H5N1 viruses—one from the lungs and one from the upper airway—that were isolated from a single patient in Vietnam. They found that the virus from the patient's upper airway exhibited a single amino acid change at position 627 of PB2: from glutamic acid (Glu) to lysine (Lys).
The researchers then compared the growth of the two viral strains in mice and in different cell types. They found that viruses with Lys at position 627 replicated more efficiently in mammalian respiratory tracts, at temperatures as low as 33°C [91.4°F], and in a wider range of cells than those with Glu at the same amino acid position. Kawaoka said that the H5N1 viruses circulating now are more "mammalian-like" than the ones that circulated in 1997, when the first human infections were identified. "The viruses that are circulating in Africa and Europe are the ones closest to becoming a human virus," he said. However, the researchers say in their report that additional genetic changes are probably needed to equip the H5N1 virus with full pandemic potential. "Indeed, multiple amino acid changes have been identified in the so-called Spanish influenza virus, which is thought to be derived from an avian antecedent," they write. Kawaoka and his team believe it's only a matter of time before the H5N1 virus evolves into a strain that's capable of launching a pandemic. "I don't like to scare the public, because they cannot do very much," Kawaoka was quoted. "But at the same time it is important to the scientific community to understand what is happening."
Hatta M, Hatta Y, Kim J, et al. Growth of H5N1 influenza A viruses in the upper respiratory tracts of mice. PLoS Pathogens 2007 Oct 4;3(10):e133
Fresh doubts, new support for influenza shots for seniors
The Lancet Infectious Diseases authors offer several reasons for questioning the notion that flu immunization saves lives in the elderly:
Simonsen and colleagues also write that since 1968, flu has accounted for an average of about 5% of all winter deaths in older people. Yet the results of cohort studies have prompted claims that flu vaccination reduces the risk of winter death from any cause by about 50% for community-dwelling people older than 65. "That influenza vaccination can prevent ten times as many deaths as the disease itself causes is not plausible," say Simonsen et al. They argue that in view of the "slim" evidence that flu immunization prolongs elderly people's lives, it may be time to consider doing more randomized, placebo-controlled trials—even though using a placebo would be "ethically unappealing." In addition, they suggest, other options for protecting the elderly should be pursued, such as developing vaccines that are more immunogenic, using larger vaccine doses, and employing antiviral drugs more aggressively. The researchers say elderly people should continue to be vaccinated, because "even a partly effective vaccine would be better than no vaccine at all."
The review by Simonsen et al. drew praise in an editorial in The Lancet, written by 2 other vaccine experts who have reviewed the case for flu immunization in the elderly. Tom Jefferson and Carlo Di Pietrantonj of the Cochrane Vaccine Fields in Italy, write that Smonsen et al "prove that statistical methods for adjustment for residual bias used in the observational studies of influenza vaccines did not work, largely because of the difficulty of adjusting for frailty with data available in electronic records." Jefferson and Di Pietrantonj endorse the idea of doing new randomized, placebo-controlled trials of flu vaccination in older people, arguing that such studies are "the only ethical and scientific way" to settle conclusively whether the vaccines are protective. The trials must cover more than 1 flu season and be large enough to detect rare outcomes, such as deaths due to flu, the pair assert.
In an interview, a flu expert with the CDC asserted that the evidence of effectiveness remains strong enough to justify the US policy of promoting flu shots for the elderly. David K. Shay, a medical officer in the CDC's influenza division, agreed that better vaccines are needed, but he rejected the idea of doing placebo-controlled trials in the elderly as unethical. Shay said the randomized, controlled trial from the Netherlands that showed a 50% reduction in confirmed flu cases among the elderly provided "gold standard evidence" for a protective effect. The risk was reduced 57% in 60- to 69-year-olds versus 23% in those 70 and older, but because of wide confidence intervals, the difference between the two groups was not significant, he said. The Dutch findings and the high risk of flu-related hospitalization and death in the elderly provide the major underpinnings of the US policy of promoting flu vaccination in the elderly, Shay said, adding, "We're left with the fact that this study [by Simonsen et al] isn't going to change policy in the US for the use of these vaccines."
As for the suggestion that unmeasured confounding variables have inflated the effectiveness of flu vaccines in observational studies, Shay said, "We also think that's possible. The CDC is interested in working with HMOs to get a better handle on how to do vaccine effectiveness studies and mortality outcome studies." But given the existing evidence that flu shots do help protect seniors, he rejected the suggestion of doing placebo-controlled trials. On the other hand, Shay commented, "Everybody would agree that we need a vaccine with greater effectiveness and greater immunogenicity in the elderly. Manufacturers are working on adjuvanted vaccines that hopefully will be more effective."
In the NEJM study, Nichol and associates sought specifically to address the kinds of methodologic problems cited by Simonsen et al. They retrospectively gathered data on flu vaccination, hospitalization for pneumonia and flu, and death from any cause among community-dwelling elderly members of three HMOs. The study covered the flu seasons from 1990-91 through 1999-2000 for one HMO and those from 1996-97 through 1999-2000 for the other two. The HMOs were in Minnesota and Wisconsin, Washington state, and the New York City area. The study included 713,872 person-seasons of observation. Vaccinated subjects were slightly older and had slightly higher rates of most of the underlying medical conditions that were recorded. There were 4,599 hospitalizations for pneumonia or flu and 8,796 deaths. The per-season hospitalization rates for unvaccinated and vaccinated people were 0.7% and 0.6%, and the corresponding death rates were 1.6% and 1.0%. The figures translated into a 27% reduction in hospitalization rate for pneumonia and flu among the vaccinated (adjusted odds ratio, 0.73; 95% confidence interval [CI], 0.68 to 0.77) and a 48% reduction in mortality (adjusted odds ratio, 0.52; 95% CI, 0.50 to 0.55).
The vaccine was somewhat less effective in preventing death—a 37% compared with 48% reduction—in the two seasons when the vaccine was a poor match for the circulating viral strains. For the seasons in which there was a good match, the vaccine yielded a 52% reduction in mortality risk. In an effort to detect any "healthy-vaccinee bias" (better underlying health among the vaccinated than the unvaccinated), the authors compared the risk of hospitalization among vaccinated and unvaccinated subjects during the summers (noninfluenza seasons) of 1999 and 2000. They found that the risks were similar for the two groups.
The researchers went a step further by hypothesizing that an unmeasured confounding variable was influencing their findings and then estimating what that influence would be under various assumptions. They picked functional status as the unmeasured variable most likely to affect their subjects' risk of hospitalization or death. On the basis of studies of functional status, the authors estimated that subjects with poor functional status would be half as likely to get a flu shot and two to three times as likely to be hospitalized or die, compared with those with better functional status. When they plugged these estimates into their data, along with estimates of the prevalence of the confounding variable, they found that the effectiveness of vaccination was reduced but still significant.
The researchers write that their study "showed multiple benefits across multiple subgroups, a result suggesting that vaccination benefits probably extend to a broad spectrum of elderly persons." However, they acknowledge that elderly HMO members may differ from elderly nonmembers, and the study did not include the frailest elderly, such as those living in nursing homes, who are likely to have weaker immune responses.
In an accompanying NEJM editorial, John D. Treanor writes that the study by Nichol et al addresses many of the concerns raised about other observational studies "and increases our confidence in the benefits of influenza vaccination in older adults." Because the evidence of vaccine effectiveness held up well through 10 seasons, the findings "convincingly dispel concerns that the previous studies were artifacts of a specific influenza season or a specific population," states Treanor. He also comments favorably on the authors' efforts to address the concerns about unmeasured confounding variables, including the examination of summer hospitalization rates and the estimate of the effect of a hypothetical difference in functional status. "Overall, this study provides additional support for the current strategy to vaccinate elderly adults," Treanor asserts. The methodologic issues are important, and the precise magnitude of the benefits of vaccination is not yet clear, but it is clear that vaccination is beneficial and should be used widely, he adds.
However, he agrees with Shay that the development of more immunogenic and effective vaccines for the elderly is an important goal. Shay said CDC is contemplating a special initiative to help resolve the controversy over the value of flu immunization for seniors. "Sometime in 2008 the CDC hopes to get together a panel of consultants to bring about ways to move forward and find ways to resolve this controversy," he said. By assembling experts from the different camps, the agency hopes to come up with recommendations to guide the next series of studies, he said.
- Simonsen L, Taylor RJ, Viboud C, et al. Mortality benefits of influenza vaccination in elderly people: an ongoing controversy. Lancet Infect Dis 2007 Oct;7:658-66
Trends in influenza vaccination in Canada, 1996/1997 to 2005
Influenza viruses and the evolution of avian influenza virus H5N1
Development and evaluation of an influenza subtype H7N2 vaccine candidate for pandemic preparedness
Antiviral Oseltamivir Is not Removed or Degraded in Normal Sewage Water Treatment: Implications for Development of Resistance by Influenza A Virus
A Single Mutation in the PB1-F2 of H5N1 (HK/97) and 1918 Influenza A Viruses Contributes to Increased Virulence
The role of oseltamivir in the treatment and prevention of influenza in children.
Cross-Protection against H5N1 Influenza Virus Infection Is Afforded by Intranasal Inoculation with Seasonal Trivalent Inactivated Influenza Vaccine
Progress and shortcomings in European national strategic plans for pandemic influenza