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EINet Alert ~ Jul 17, 2009


*****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:
- ***This bulletin was supplemented with information provided by Veratect***

1. Influenza News
- Weekly APEC update of pandemic influenza H1N1
- Cumulative number of human cases of avian influenza A/H5N1
- Global: WHO suspends reporting of pandemic influenza H1N1 case counts
- Global: WHO says healthcare workers should get first pandemic H1N1 vaccine
- Global: Obesity emerges as new risk factor for severe pandemic influenza H1N1 infection
- Global: Another study suggests greater pandemic influenza H1N1 pathogenicity
- Global: Vaccine contracts could be broken in severe pandemic, experts say
- UK: Prepares to launch phone service to supply antivirals
- Australia: Vaccine manufacturer announces launch of human trial for pandemic H1N1 vaccine
- China (Hunan): China confirms 27th H5N1 avian influenza fatality
- South America: Ministers meet to coordinate response to pandemic influenza H1N1
- USA: An additional $1 billion will be used to procure pandemic H1N1 influenza vaccine
- USA (California): Nurses file complaint alleging lack of protective gear

2. Updates
- INFLUENZA A/H1N1
- AVIAN INFLUENZA

3. Articles
- Dating the emergence of pandemic influenza viruses

4. Notifications
- Pandemic influenza response: CDC guidance for medical offices and outpatient facilities
- CDC Health Alert Network Info Service Message: Three Reports of Oseltamivir Resistant Novel Influenza A (H1N1) Viruses
- Influenza in the Asia-Pacific

***This bulletin was supplemented with information provided by Veratect***

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1. Influenza News

Global
Weekly APEC update of pandemic influenza H1N1
Australia and Chile exceed 10,000 cases of pandemic H1N1 influenza. Five thousand surgeries were postponed in Chile last week to free up hospital beds for patients with H1N1 influenza. The number of delayed procedures could rise to over 20,000 over the next few weeks. Thailand reports continued spread of pandemic H1N1 infection with over 3800 cases and 21 deaths as of 13 July 2009.
(AP 7/13/09; CIDRAP 7/14/09, 7/15/09)

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Cumulative number of human cases of avian influenza A/H5N1
Economy / Cases (Deaths)

2009
China/ 7 (4)
Egypt/ 30 (4)
Viet Nam/ 4 (4)
Total/ 41 (12)

***For data on human cases of avian influenza prior to 2009, go to:
http://depts.washington.edu/einet/humanh5n1.html

Total no. of confirmed human cases of avian influenza A/(H5N1), Dec 2003 to present: 436 (262)
(WHO 7/1/09 http://www.who.int/csr/disease/avian_influenza/en/index.html )

Avian influenza age distribution data from WHO/WPRO:
http://www.wpro.who.int/sites/csr/data/data_Graphs.htm (WHO/WPRO 6/30/09)

WHO's maps showing world's areas affected by H5N1 avian influenza (last updated 5/10/09): http://gamapserver.who.int/mapLibrary/

WHO’s timeline of important H5N1-related events (last updated 3/23/09):
http://www.who.int/csr/disease/avian_influenza/ai_timeline/en/index.html

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Global: WHO suspends reporting of pandemic influenza H1N1 case counts
Citing the questionable usefulness of reporting pandemic H1N1 case counts and the burden it puts on countries experiencing widespread transmission, the World Health Organization (WHO) announced 16 Jul 2009 that it will no longer issue regular reports of confirmed global case totals. The WHO has issued 58 such reports since the start of the novel H1N1 outbreak, the last one on 6 Jul 2009.

In a 16 Jul 2009 statement, the WHO said countries with sustained community transmission are having an extremely difficult time confirming cases through laboratory testing. In addition, counting individual cases isn't essential for monitoring the level or nature of risk posed by the virus or implementing response measures. Detecting and confirming all possible cases is highly resource-intensive, the WHO said. "In some countries, this strategy is absorbing most national laboratory and resource capacity, leaving little capacity for the monitoring and investigation of severe cases and other exceptional events."

For these reasons, the WHO said it will no longer issue reports of confirmed cases. However, it said it will provide regular updates on the spread of pandemic flu in newly affected countries. The focus of surveillance activities in countries where the virus is already established will shift to existing systems for monitoring seasonal flu, the WHO said. Countries are no longer required to submit regular reports of individual confirmed cases and deaths to the WHO. Monitoring for unusual events such as clusters of severe or fatal cases or changes in clinical patterns is important and should continue, the agency said. It added that countries should maintain vigilance for changes in transmission patterns, such as rising rates of school or work absenteeism, and also surges in emergency department visits, which could foreshadow increasing numbers of severe cases.

US CDC says change is no surprise
Tom Skinner, a spokesman for the US Centers for Disease Control and Prevention (CDC), said the change in the WHO's case-reporting policy is not unexpected, because the WHO and CDC have been emphasizing over the past several weeks that the number of lab-confirmed cases is just the tip of the iceberg of the true number of people who are or were sick with the novel H1N1 virus.

Specific case counts were once needed to help characterize the early spread of the disease, he said. Now that the virus is widespread and poised for a potential surge in the fall, "specific case counts are no longer needed, and since they don't represent the true picture of the situation, they are not necessary," Skinner said. The CDC will likely make a similar move to downplay the number of confirmed cases, but it will maintain, if not expand, surveillance to gauge the health impact of the pandemic and the severity of the illness, he said.

Case counts give wrong impression
Peter Sandman, a New Jersey-based consultant and risk-communication expert, said that early on in the novel H1N1 outbreak the WHO had a good technical reason to urge countries to track the number of confirmed cases—to help assess community transmission—but the usefulness of the numbers quickly waned. "The big problem is that almost everyone has used the number of confirmed cases as if it were the true number of cases," he said. "Everyone was pouncing on those numbers."

The downside of the focus on the confirmed case numbers has been that the public perceives the pandemic as less pervasive than experts know it to be, Sandman said. When a public health official makes a reasonable extrapolation of the burden of disease, the number of confirmed cases seems puny by comparison. "Reputable experts are dismissed as nuts," he added.

Sandman said another problem is that an emphasis on the number of confirmed cases, along with the number of deaths, gives the public—and even some government and public health officials—an inflated impression of the case fatality rate.

"The pandemic H1N1 virus could get more deadly at any time," Sandman said. "But if you compare the number of pandemic deaths in the US to the CDC estimates of how many people have already had the disease, it calculates out that the pandemic is less deadly than seasonal flu so far." However, most people don't do that calculation, he said. "People compare the number of deaths to the number of confirmed cases, and that makes the pandemic look much more deadly, because all the cases that never got confirmatory testing are missing from the denominator."
(CIDRAP 7/16/09)

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Global: WHO says healthcare workers should get first pandemic H1N1 vaccine
The World Health Organization (WHO) recommended on 13 Jul 2009 that governments put healthcare workers first in line for pandemic H1N1 vaccine when it becomes available and that countries should choose other priority groups on the basis of their own situations.

The agency said it's important to vaccinate health workers first in order to keep health systems functioning. After that, governments should consider other groups that are most vulnerable to severe H1N1 infections, such as pregnant women, people with chronic health problems, and young adults. At the same time, the WHO reported that vaccine manufacturers growing the candidate H1N1 vaccine viruses are getting relatively poor yields—only about 25% to 50% as much antigen as with seasonal H1N1 vaccine viruses. That suggests it may take longer for manufacturers to fulfill their existing vaccine contracts and to begin making vaccine for countries that have not yet ordered doses.

Dr. Marie-Paule Kieny, director of the WHO's initiative for vaccine research, said the low yields are not yet considered a major concern and that the agency's collaborating laboratories are working to develop better-yielding strains.

SAGE advice
The recommendations released emerged from a meeting on 7 Jul 2009 of the WHO's Strategic Advisory Group of Experts on Immunization (SAGE), the agency's top advisory body on vaccines. After healthcare workers, governments should consider the following groups for vaccination, depending on local conditions: pregnant women, people (over 6 months old) with chronic medical conditions, healthy people between 15 and 49 years old, healthy children, healthy adults aged 50 to 64, and healthy older adults.

Last week, US Health and Human Services Secretary (HHS) Kathleen Sebelius said priority groups for H1N1 vaccine would include schoolchildren, non-elderly adults with health problems, pregnant women, and healthcare and emergency workers, but she did not put any one of those ahead of the others. Elderly adults are believed to have some protection from the novel virus because of past exposure to H1N1 viruses and vaccines.

Kieny said vaccine allocation plans will depend on how countries balance the three major objectives of immunization: reducing transmission, reducing sickness and death, and protecting the healthcare system. If a country's primary aim is to limit spread of the virus, authorities might put children ahead of other groups, she observed.

Seasonal vaccine nearly all made
In other deliberations, SAGE determined that production of seasonal flu vaccine for the northern hemisphere will be more than 90% complete by the end of July 2009, Kieny reported. Therefore, manufacturers will not need to curtail seasonal vaccine production in order to start making pandemic vaccine, she said.

Further, because some pandemic vaccines involve new technologies, the best possible post-marketing surveillance will be important, SAGE said. The group said findings should be shared with the world quickly so that countries can adjust their immunization strategies. The advisory panel also said that the production and use of vaccines containing oil-in-water adjuvants and of live attenuated vaccines should be encouraged, since initial vaccine supplies will be limited and there is a potential for drifted strains of the H1N1 virus.

Low yields with current candidates
The problem of low production yields was revealed in SAGE meeting documents that the WHO recently posted online. Kieny said, "It's not known what's happening, but the output they have at the end is 25% to 50% of normal yield."

"For the first series of [vaccine] strains that were generated, we unfortunately didn't come up with a good yielder," she said. "In order to remedy that, the WHO laboratory network is trying to generate new vaccine viruses from wild type viruses generated from patients."

Kieny asserted that the low yields are not a big problem for the timing of vaccine production now. Using the current strains, manufacturers are harvesting enough antigen for clinical trials, she said. Also, regulatory authorities have said that when new candidate strains become available, it won't be necessary to conduct "bridging studies" to compare them with the current strains, because they will differ only in yield, not in antigenicity, she said.

However, in slides that Kieny presented at the SAGE meeting, she stated that a lower-yielding vaccine "would considerably push back the timelines." The presentation, which is available online, suggests that poor yields could delay manufacturers' fulfillment of current vaccine orders by two to six months.

The presentation says existing government orders for H1N1 vaccines total 850 million to 900 million doses. On average, governments have ordered one dose per person, but most have options for, or are considering ordering, two doses per person, which would increase total orders to about 1.8 billion doses. If vaccine yields are normal, if a relatively low dose of 8 micrograms (mcg) is sufficient, and if governments order an average of one dose person, vaccine manufacturers in the wealthy countries could fulfill their current vaccine orders in November, according to Kieny's estimate.

But if vaccine yield is only half of normal, with other conditions the same, it would take until January 2010 for the manufacturers to fulfill their vaccine orders, she projects. An even lower yield, such as one third of normal, could delay the completion of production until April 2010, according to her presentation. Other factors could also slow production, according to Kieny's estimates. For example, using a dose of 15 mcg instead of 8 mcg could delay the fulfillment of vaccine orders from November 2009 until February 2010 (still assuming one dose per person).

In other comments at the press conference, Kieny said the manufacturers of live attenuated H1N1 vaccines have not had a problem with yield so far. The appropriate dose for these vaccines is not yet known, but "in terms of growth they seem to be behaving normally," she said.

SAGE meeting documents are available at http://www.who.int/immunization/sage/previous_july2009/en/index.html. In addition, Kieny’s slide presentation can be accessed at http://www.who.int/immunization/sage/3.MPK-SAGE_7_July.pdf.
(CIDRAP 7/13/09)

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Global: Obesity emerges as new risk factor for severe pandemic influenza H1N1 infection
People who are obese but otherwise healthy may be at special risk of severe complications and death from the new influenza pandemic H1N1 2009 virus, US researchers reported on 10 Jul 2009. They described the cases of 10 patients at a Michigan hospital who were so ill they had to be put on ventilators. Three died. Nine of the 10 were obese, seven were severely obese, including two of the three who died.

The study, published in advance in the Centers for Disease Control and Prevention's (CDC) weekly report on death and disease, also suggests doctors can safely double the usual dose of oseltamivir, the antiviral drug sold under the Tamiflu brand name.

"What this suggests is that there can be severe complications associated with this virus infection, especially in severely obese patients," said CDC virus expert Dr. Tim Uyeki. "And five of these patients had. . .evidence of blood clots in the lungs. This has not been previously known to occur in patients with severe influenza virus infections," Uyeki said.

Dr. Lena Napolitano of the University of Michigan Medical Center and colleagues studied the cases of 10 patients admitted to the university's intensive care unit with severe acute respiratory distress syndrome caused by infection with H1N1.

Their study was not designed to see if obesity or anything else poses a special risk factor for flu. But the researchers were surprised to see that seven of the 10 patients were extremely obese. Nine had multiple organ failure, which can be seen in influenza, but five had blood clots in the lungs, and six had kidney failure. None has fully recovered, the researchers said.

"The high prevalence of obesity in this case series is striking," the CDC's commentary accompanying the researchers’ report reads. "Whether obesity is an independent risk factor for severe complications of novel influenza A (H1N1) virus infection is unknown. Obesity has not been identified previously as a risk factor for severe complications of seasonal influenza."
(ProMED 7/11/09)

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Global: Another study suggests greater pandemic influenza H1N1 pathogenicity
The pandemic H1N1 virus in different animal models causes more lung damage and can replicate efficiently in the trachea and deep in the lungs when compared with its seasonal flu counterpart—a pattern seen in the 1918 pandemic virus—according to a study published on 13 Jul 2009. Though the new report appears to confirm the pathogenicity findings of two studies that appeared 2 Jul 2009 in Science, the more severe disease that researchers are seeing in animal experiments runs counter to the mild-to-moderate infection profile in humans.

In a multifaceted study that appears in an early online edition of Nature, the group, from Japan and the University of Wisconsin, conducted a host of other experiments—both in vitro and in vivo—to better characterize the risks of the new virus.

Yoshihiro Kawaoka, PhD, a researcher from the University of Wisconsin-Madison who led the Nature study, said that the study may help clear up misunderstandings people have about the new virus. "People think this pathogen may be similar to seasonal influenza," he said. "This study shows that is not the case. There is clear evidence the virus is different than seasonal influenza."

Animal models show pathogenicity trends
The research group evaluated pathogenicity in four animal models: mice, ferrets, macaques, and pigs. They used pandemic H1N1 viruses obtained this year from patients in California, Wisconsin, the Netherlands, and Japan, as well as a seasonal H1N1 virus from Japan. They found that the pandemic H1N1 virus replicated more efficiently in the lungs and that it exhibits a different pro-inflammatory cytokine response pattern in infected animals. However, they wrote that more study is needed to understand the relevance of the cytokine findings.

In macaques, animals infected with the pandemic H1N1 virus had greater body temperature increases, but body weight loss wasn't different from animals that were infected with the seasonal flu virus. The new virus replicated efficiently in the lungs and other respiratory organs, similar to highly pathogenic influenza viruses. Pathological examination revealed that the novel virus caused more severe lung lesions that contained type 2 pneumocytes—a finding that has been reported with H5N1 avian influenza viruses.

In the ferret model, the group found more severe bronchopneumonia in the animals infected with the pandemic H1N1 virus. Researchers also used ferrets to test transmission, a key factor in human-to-human spread of the virus. They placed ferrets infected with either the pandemic or seasonal flu virus in perforated cages next to, but not touching, cages housing uninfected ferrets.

Experts say animal models have limits
Vincent Racaniello, PhD, professor of microbiology at Columbia University and author of Virology Blog, said that the two recent studies in Science both showed that the new H1N1 strain replicates more extensively than the seasonal strain in the lower respiratory tracts of ferrets. However, the replication pattern with the new virus was not associated with significantly higher morbidity. He said the Kawaoka study in Nature had similar conclusions, but it's not clear what that means for humans.

"We have already had over a million—probably several million—human infections with the new strain, and all agree the symptoms are mild, similar to those of seasonal flu," Racaniello said. "So it's not clear to me why these results should suddenly make us all fear that the new virus is in fact more virulent than we think." Perhaps the results underscore the point that animal models are just models and don't reveal much about human infections, he added.

Racaniello cautioned against thinking of serious infections in patients with no known underlying conditions as evidence of pandemic H1N1's pathogenic potential. Subtle defects that can impair immune response, especially early in infection, can lead to lethal disease in otherwise healthy people, he said. "In other words, you don't have to have heart disease to have a bad outcome with influenza."

"I don't think the results of any of the three papers should be interpreted to mean that 2009 H1N1 is more virulent than we think it is," he said, pointing out that there are enough differences among the three studys' results to cast doubt on any virulence extrapolations in humans.

The article “In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses” by Itoh Y, Shinya K, Kiso M, et al. can be found in Nature early online edition 13 July 2009 at http://www.nature.com/nature/journal/vnfv/ncurrent/abs/nature08260.html.
(CIDRAP 7/13/09)

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Global: Vaccine contracts could be broken in severe pandemic, experts say
Experts warn that if the H1N1 flu pandemic turns severe, countries that have vaccine factories might seize vaccine supplies, rendering contracts that promise doses to other countries meaningless, the Associated Press reports. Many vaccine contracts that countries have signed involve doses made outside their borders. In a severe pandemic, countries with vaccine plants might decide to seize all doses and ban their export, said David Fidler, a law professor at Indiana University, and other experts. About 70 percent of the world's flu vaccines are made in Europe, and only a handful of countries are self-sufficient in vaccines. And because factories can't be built overnight, there is no quick fix to boost vaccine supplies.
(CIDRAP 7/16/09; AP 7/16/09)

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Europe/Near East
UK: Prepares to launch phone service to supply antivirals
Following a surge of flu-like illnesses, a British system that will allow people to report symptoms by phone and obtain antiviral drugs will be launched very soon. Data from general practitioners indicated that the rate of people reporting flu-like illnesses rose to 73 per 100,000 last week, from 50 per 100,000 the week before. Using the phone service, people will get reference numbers that friends can use to collect antivirals for them.

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Asia
Australia: Vaccine manufacturer announces launch of human trial for pandemic H1N1 vaccine
Australia-based flu vaccine maker CSL Ltd said on 13 Jul 2009 that it expects to launch a human trial of its novel H1N1 vaccine on 22 Jul 2009, Bloomberg News reported. In a Jun 29 press release, CSL said it would undertake the trial with a research group in Adelaide and was seeking healthy adults aged 18 to 64 to enroll in the study to compare two injections of a standard dose, administered three weeks apart, with a higher dosage. The Australian government has ordered enough vaccine to immunize 10 million people.
(CIDRAP 7/13/09)

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China (Hunan): China confirms 27th H5N1 avian influenza fatality
Highly pathogenic H5N1 avian influenza claimed its second human fatality in China since February 2009 when the Ministry of Health confirmed the death of a Guangxi Zhuang Autonomous Region man. The 41-year-old man in Nanning City developed fever and headache symptoms on 12 Feb 2009 and died at on 20 Feb 2009 after all rescue measures proved ineffectual. Tests of the man were H5N1 positive, said China's Center for Disease Control and Prevention.

On 18 Feb 2009, the Health Ministry confirmed a 22-year-old man in the central Hunan Province had tested positive for H5N1. He had died on 24 Jan 2009.
(ProMED 7/16/09)

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Americas
South America: Ministers meet to coordinate response to pandemic influenza H1N1
Health ministers from six South American countries met 15 Jul 2009 in Buenos Aires, Argentina, to coordinate responses to the H1N1 pandemic. Besides Argentina, the meeting included Bolivia, Brazil, Chile, Paraguay, and Uruguay. Ministers said the countries need to share medicine and supplies, and they voiced concern about access to vaccines. Argentina has had 137 deaths, second highest toll after the United States.
(CIDRAP 7/16/09)

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USA: An additional $1 billion will be used to procure pandemic H1N1 influenza vaccine
The United States will order another $1 billion worth of pandemic H1N1 influenza vaccine, Health and Human Services (HHS) Secretary Kathleen Sebelius said on 12 Jul 2009. "There'll be another $1 billion worth of orders placed to get the bulk ingredients for an H1N1 vaccination," Sebelius said, without naming the suppliers. Sebelius announced on 22 May 2009 that HHS would spend about $1 billion to buy vaccine antigen and adjuvant and fund clinical studies.
(CIDRAP 7/13/09)

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USA (California): Nurses file complaint alleging lack of protective gear
Nurses at a hospital in Vallejo, CA, filed a complaint on 14 Jul 2009 with the state's Division of Occupational Safety and Health alleging that their facility has not supplied them with adequate masks for caring for patients with pandemic H1N1 influenza. Ten nurses reportedly got sick after treating three patients with novel flu infections.
(CIDRAP 7/14/09)

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2. Updates
INFLUENZA A/H1N1
The following websites provide the most current information and advice.

- WHO
Influenza A/H1N1: http://www.who.int/csr/disease/swineflu/en/index.html
Influenza A/H1N1 frequently asked questions: http://www.who.int/csr/swine_flu/swine_flu_faq_26april.pdf
Map of the spread of influenza A/H1N1: http://www.who.int/csr/don/GlobalSubnationalMaster_20090507_1800.png.

- North America
US CDC: http://www.cdc.gov/flu/swine/investigation.htm
US pandemic emergency plan: www.pandemicflu.gov
MOH Mexico: http://portal.salud.gob.mx/index_eng.html
PHAC Canada: http://www.phac-aspc.gc.ca/media/nr-rp/index-eng.php
PAHO: http://www.paho.org/English/AD/DPC/CD/influenza.htm

- Other useful sources
CIDRAP: Influenza A/H1N1 page: http://www.cidrap.umn.edu/cidrap/content/influenza/swineflu/biofacts/swinefluoverview.html
ProMED: http://www.promed.org
(WHO; US CDC; MOH Mexico; PHAC; PAHO; CIDRAP; ProMED)

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AVIAN INFLUENZA
- UN: http://www.undp.org/mdtf/influenza/overview.shtml UNDP’s web site for information on fund management and administrative services and includes the website of the Central Fund for Influenza Action. This site also includes a list of useful links.
- WHO: http://www.who.int/csr/disease/avian_influenza/en/index.html. The (interim) Influenza Virus Tracking System can be accessed at: www.who.int/fluvirus_tracker.
- UN FAO: http://www.fao.org/avianflu/en/index.html. View the latest avian influenza outbreak maps, upcoming events, and key documents on avian influenza.
- OIE: http://www.oie.int/eng/info_ev/en_AI_avianinfluenza.htm. Link to the Communication Portal gives latest facts, updates, timeline, and more.
- US CDC: Visit "Pandemic Influenza Preparedness Tools for Professionals" at: http://www.cdc.gov/flu/pandemic/preparednesstools.htm. This site contains resources to help hospital administrators and state and local health officials prepare for the next influenza pandemic.
- The US government’s website for pandemic/avian flu: http://www.pandemicflu.gov/. View archived Webcasts on influenza pandemic planning.
- CIDRAP: http://www.cidrap.umn.edu/ Access their Swine Influenza website at http://www.cidrap.umn.edu/cidrap/content/influenza/swineflu/index.html.
- PAHO: http://www.paho.org/English/AD/DPC/CD/influenza.htm Link to the Avian Influenza Portal at: http://influenza.bvsalud.org/php/index.php?lang=en The Virtual Health Library’s Portal is a developing project for the operation of product networks and information services related to avian influenza.
- US National Wildlife Health Center: http://www.nwhc.usgs.gov/disease_information/avian_influenza/index.jsp Read about the latest news on H5N1 in wild birds and poultry.
(UN; WHO; FAO, OIE; CDC; CIDRAP; PAHO; USGS)

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3. Articles
Dating the emergence of pandemic influenza viruses
Smith GJD et al. PNAS. 13 July 2009. Available at http://www.pnas.org/content/early/2009/07/10/0904991106.abstract?etoc.

Abstract
Pandemic influenza viruses cause significant mortality in humans. In the 20th century, 3 influenza viruses caused major pandemics: the 1918 H1N1 virus, the 1957 H2N2 virus, and the 1968 H3N2 virus. These pandemics were initiated by the introduction and successful adaptation of a novel hemagglutinin subtype to humans from an animal source, resulting in antigenic shift. Despite global concern regarding a new pandemic influenza, the emergence pathway of pandemic strains remains unknown. Here we estimated the evolutionary history and inferred date of introduction to humans of each of the genes for all 20th century pandemic influenza strains. Our results indicate that genetic components of the 1918 H1N1 pandemic virus circulated in mammalian hosts, i.e., swine and humans, as early as 1911 and was not likely to be a recently introduced avian virus. Phylogenetic relationships suggest that the A/Brevig Mission/1/1918 virus (BM/1918) was generated by reassortment between mammalian viruses and a previously circulating human strain, either in swine or, possibly, in humans. Furthermore, seasonal and classic swine H1N1 viruses were not derived directly from BM/1918, but their precursors co-circulated during the pandemic. Mean estimates of the time of most recent common ancestor also suggest that the H2N2 and H3N2 pandemic strains may have been generated through reassortment events in unknown mammalian hosts and involved multiple avian viruses preceding pandemic recognition. The possible generation of pandemic strains through a series of reassortment events in mammals over a period of years before pandemic recognition suggests that appropriate surveillance strategies for detection of precursor viruses may abort future pandemics.

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4. Notifications
Pandemic influenza response: CDC guidance for medical offices and outpatient facilities
Available at http://www.cdc.gov/h1n1flu/10steps.htm.

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CDC Health Alert Network Info Service Message: Three Reports of Oseltamivir Resistant Novel Influenza A (H1N1) Viruses
An alert regarding the previously reported pandemic H1N1 cases resistant to antiviral treatment in Hong Kong, Denmark, and Japan available at http://www.cdc.gov/h1n1flu/HAN/070909.htm.

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Influenza in the Asia-Pacific
The Lancet Conferences
Date: August 21-23, 2009; Location: Qingdao, China

The Lancet and The Lancet Infectious Diseases have joined forces to develop a conference that will enable leaders in their fields to present and discuss management of influenza with key health administrators, experts from the medical and scientific communities, and industry representatives. We hope the meeting will provide valuable insight into fundamental public health and operation strategies to bring about change within the Asia-Pacific.

To register, go to http://mail.elsevier-alerts.com/go.asp?/bELA001/qUQEAS8/x8BATS8

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 apecein@u.washington.edu