EINet Alert ~ Dec 23, 2005

*****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:
- Romania: New suspected avian influenza in poultry
- East Asia: Cumulative number of human cases of avian influenza A/(H5N1)
- Indonesia: 2 more confirmed human cases of avian influenza
- Viet Nam: Avian influenza update
- China: Avian Influenza H5N1 human case isolates sent to WHO
- South Korea: Migratory bird surveillance
- USA: Agents seize shipments of fake Tamiflu

1. Updates
- Influenza

2. Articles
- Viet Nam: Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection
- Human-to-human transmission of avian influenza A/H7N7, The Netherlands, 2003
- Glycan microarray analysis of the hemagglutinins from modern and pandemic influenza viruses reveals different receptor specificities

Romania: New suspected avian influenza in poultry
Romania has found new suspected bird flu in hens in a village 160 km east of Bucharest and began culling domestic fowl there, officials said 21 Dec 2005. The H5 type virus was confirmed last week in 2 villages in the Ialomita County, 100 km east of the capital, indicating the disease could be spreading towards Bucharest. The 2 outbreaks in Ialomita, one in the village of Marsilieni (Albesti district) and another in the village Rovine (Reviga district) were officially reported to the OIE 19 Dec 2005. Since Oct 2005, the Balkan country has found avian flu in 22 villages in and around the Danube delta on the Black Sea. 9 cases have been confirmed as the highly pathogenic H5N1 strain, but the disease has not appeared close to large cities. "Rapid tests on samples taken from hens in the village of Stelnica, on a Danube river tributary, raised suspicion of the H5 type," Nicolae Stefan, head of the Animal Health and Diagnosis Institute, said. He said the village will be quarantined and all domestic fowl culled as a precaution. He also said that more samples from hens in the village of Traian 100 km east of the capital showed signs of the H5 type. About 50 birds have already been destroyed since 19 Dec 2005 when authorities first suspected the virus there.

An official notification on an additional infected village has been sent to the OIE, 21 Dec 2005: http://oie.int/downld/AVIAN%20INFLUENZA/Romania%20Follow%20up%20report%20No15.pdf . This notification refers to 2 different backyard premises, 500 m apart, in the village of Chichinetu. There are 136 backyard premises in the village, including a total of 3350 fowl. The distance from the previous outbreak in Ciocile is 3.5 km. Veterinary and local authorities decided to apply a partial stamping-out, culling 329 poultry from 22 backyard premises, since the first cases appeared (14 Dec 2005). Disinfecting was performed, also the installing of "sanitary filters" at the entrance to the infected area. Quarantine, zoning and screening was also performed.

An interactive map, showing the affected provinces in Romania in a chronological display, is available at: http://poultrymed.com/files/index.html. Romania has set aside around USD 700 000 for compensation for farmers affected by the virus. Farmers are banned from selling live poultry anywhere in the country. Farm ministers from Germany, Ukraine, Bulgaria and Moldova plan to meet in Bucharest in early February 2006 to discuss joining forces to fight the disease, agriculture minister Gheorghe Flutur said. The Danube delta is Europe's largest wetlands and lies on a major migratory route for wild birds which travel south each winter from Scandinavia and Russia to northern Africa. (Promed 12/16/05, 12/20/05, 12/22/05)


East Asia: Cumulative number of human cases of avian influenza A/(H5N1)
Cumulative number of confirmed human cases of avian influenza A/(H5N1), 2005:
Economy / Cases (Deaths)
Indonesia / 16 (11)
Cambodia / 4 (4)
Thailand / 5 (2)
Viet Nam / 61 (19)
China / 6 (2)
Total / 92 (38)

Total number of confirmed human cases of avian influenza A/(H5N1), 26 Dec 2003 to present: 141 (73)
(WHO 12/23/05 http://www.who.int/csr/disease/avian_influenza/country/en/index.html )


Indonesia: 2 more confirmed human cases of avian influenza
2 more human deaths from avian influenza in Indonesia have been confirmed by the U.S. CDC, a Health Ministry official said 22 Dec 2005, bringing total known Indonesian deaths to 11. "We have received confirmation from CDC Atlanta that the 2, designated N and M, are positive," said Hariadi Wibisono, director of the department charged with control of animal-borne diseases. He was referring to the cases of a 39-year-old man and an 8-year-old boy who had previously tested positive locally for the H5N1 strain of avian influenza. Local tests are not considered definitive. Both victims died in earlier in Dec 2005. In addition to the 11 deaths, 5 individuals in Indonesia have been confirmed as having the disease but are still alive. Wibisono had said earlier that it was unclear if the boy had contact with infected chickens. In the case of the 39-year-old, a WHO official has said there were reports of sick and dying poultry in the neighbourhood. Indonesia will launch house-to-house surveillance of poultry in Jakarta in a bid to halt the spread of the flu, a minister reportedly said. Local communities, student volunteers and military forces will be deployed to inspect poultry across the sprawling capital. Several of the victims so far have come from the Jakarta area. Since August 2003, 10 million poultry have died from the disease in Indonesia or been killed to prevent its spread.

Indonesia, with 220 million people, has millions of chickens and ducks, the majority in the yards of rural or urban homes, including many in Jakarta. Such a close relationship between people and livestock has helped spread the disease in humans and the virus has been found in poultry in 2/3 of the nation's 33 provinces. The Food and Agriculture Organisation has launched its own grass roots scheme covering the island of Java. The U.N. agency says Indonesian efforts to control bird flu should be stepped up and the government needs to draft an effective national strategy. “It is a very nasty bird flu virus," David Nabarro, the U.N. coordinator for avian influenza, said. "Act as though a pandemic influenza will start tomorrow. Don't think we can wait around and not worry it won't start for 6 months or one year," Nabarro said. "Once it starts, it is too late to prepare." Children would be the most vulnerable group, he said. Indonesia is also preparing an early bird flu warning system that will involve local governments setting up health posts in all villages, where doctors and nurses would be on the lookout for flu cases in birds and humans. (Promed 12/19/05, 12/22/05)


Viet Nam: Avian influenza update
Central Quang Tri Province and northern Bac Ninh Province announced that they were free of bird flu after 21 days with no cases reported. So far, 9 provinces have met conditions set by local health authorities to qualify as free of the virus, including Bac Giang, Hoa Binh, Thai Binh, Hung Yen, Long An, Hai Duong, Phu Tho, Quang Tri, and Bac Ninh. 67 communes of 37 districts in 12 provinces still officially have animals infected with bird flu: Cao Bang, Ninh Binh, Son La, Thai Nguyen, Hai Phong, Vinh Phuc, Quang Ninh, Yen Bai, Ha Giang and Bac Kan in the north and Thanh Hoa and Nghe An in the central region. Since 1 Oct 2005, nearly 3.65 million fowl have been culled. By 19 Dec 2005, 15 provinces had completed the second cycle of vaccinations for 71.5 million fowl, 28 are preparing for the second round and the remaining provinces are vaccinating their poultry for the first time. Vietnam switched its policy of HPAI control in poultry into mass vaccination since 1 Aug 2005. For a map showing Vietnam's outbreaks reported to the OIE, see "maps" in http://poultrymed.com/files/index.html. (Promed 12/20/05)


China: Avian Influenza H5N1 human case isolates sent to WHO
The Chinese CDC on 20 Dec 2005 handed over H5N1 human case isolates to WHO. 2 strains of avian influenza virus isolated from human infections in China were forwarded to Dr. Shigeru Omi, WHO Western Pacific Regional Director, by Wang Yu, Director of the Chinese CDC, along with relevant virus information on Chinese human cases. Offered to the organization for further research, the strains will help trace the virus' mutation and develop anti-influenza virus drugs. It is a major contribution made by China to the global fight against the epidemic, said Omi. Omi said good collaboration in the international community will be crucial in dealing with the immense challenge posed by H5N1 avian influenza, and China, as one of the centers of the global fight, can play an important role in this regard. Chinese experts will join in the WHO's research of these isolates. On his visit to the Chinese National Influenza Center, Omi was introduced to the monitoring, lab testing and control of human cases of avian influenza. China has announced 6 human cases of bird flu since 16 Nov 2005, including at least 2 fatalities. Lab tests show that the genotype of H5N1 seen in human bird flu infections in China is different from those observed in humans in Viet Nam. The observation that the genotypes of the H5N1 avian influenza virus isolated from patients in China and Viet Nam are not identical is not surprising, as all RNA viruses exhibit high mutation rates. This observation by itself does not confirm that the virus is evolving towards a form capable of person-to-person transmissibility. (Promed 12/20/05)


South Korea: Migratory bird surveillance
A report titled: "Special Preventive Measures to Block the Spread of Avian Flu," was published by the Ministry of Agriculture and Forestry. According to the report, 50 cases of low-pathogenic Avian influenza infections were discovered in 8 areas between 1 Oct and 11 Dec 2005. The H5 subtype was in one of 50 samples to test positive for low-pathogenic avian influenza The discoveries were made after researchers collected and analyzed about 3000 bird fecal samples from 24 habitats of migratory birds across the country and the off-limits area near the inter-Korean border. Professor of veterinary medicine Kim Seon-jung, at Seoul National University, also warned, "Even if the H5 and H7 viruses are defined as low-pathogenic, they are much more likely to mutate into highly pathogenic varieties. So the government must publicly announce the discovery of those viruses and inform people of the danger of them." Authorities will continue to take preventive measures in rural areas until the end of February 2005, as some low-pathogenic strains could mutate into highly-pathogenic forms. The H5 virus was in a migratory bird's dropping found at a lake in Ansan, a city west of Seoul, and the government will take no particular action, Yang said. "We will act if chickens and geese are infected with H5 or H7 subtypes," he said.

In late 2004, the government culled all the ducks at a duck farm in Gwangju, where the low-pathogenic H5 strain appeared. An Agriculture Ministry official promised that the ministry would let the public know in case the highly pathogenic H5N1 and the low-pathogenic H5 or H7 are detected during a presentation of its special preventive measures against AI in early October 2005. But the ministry has yet to publicize the discovery of the H5 virus around the Sihwa Lake area. (Promed 12/19/05)


USA: Agents seize shipments of fake Tamiflu
US customs agents have reportedly seized more than 50 shipments of fake oseltamivir (Tamiflu), the antiviral drug being stockpiled in preparation for a possible influenza pandemic. Customs officials said the first package was intercepted Nov 26, 2005 at a mail facility near San Francisco International Airport. Agents have seized 51 more packages since then, each containing up to 50 counterfeit capsules labeled as "generic Tamiflu," the report said. Since Roche is the only manufacturer of the drug, generic Tamiflu doesn't exist, said David Elder, head of the Food and Drug Adminstration's Office of Enforcement. The capsules contained none of oseltamivir's active ingredients, and officials were running tests to learn what they did contain. Elder said initial tests pointed to vitamin C.

"At this point, we haven't found anything harmful," Elder said. "The harm comes from people believing they are being protected from the flu. They are not getting the benefit they expect." Information on the packages was in Chinese, but it was unclear where the drugs came from, Elder reported. Asian suppliers sent them to individuals who ordered them online, Roxanne Hercules of US Customs and Border Protection said. In related news, WHO's top flu expert warned Dec 16 that governments are counting too heavily on Tamiflu to protect their populations from a flu pandemic. Nations are investing far more in stockpiling Tamiflu than in developing vaccines that might offer protection from a pandemic virus, said Klaus Stohr, head of the WHO's global influenza program. He said, "There's been so much excitement about stockpiling of antivirals, that this is going to be the silver bullet, this is going to be the solution to the whole problem. There are uncertainties we have to start communicating, and we haven't done that." Stohr said studies show the drug protects about 70% of people from the flu if they take it before being infected, but only about 40% benefit it they take the drug within 48 hours after infection. In November President Bush asked Congress for $1 billion to spend on antiviral drugs, as part of his $7.1 billion request for pandemic preparedness. This week the House voted to appropriate $3.8 billion for pandemic preparations, but left it to the administration to decide how much of that to spend on antivirals. The House-passed bill was awaiting action by the Senate. (CIDRAP 12/20/05 http://www.cidrap.umn.edu/index.html )


1. Updates
Seasonal influenza activity for the Asia Pacific and APEC Economies
A slight increase of influenza activity was observed for the first time so far this season in several countries in the northern hemisphere during week 49. Overall activity remains low.

Canada. Localized activity of influenza continued to be reported in Alberta (B) and British Columbia (A). Activity remained low in the rest of the country.

Japan. Influenza activity increased and was reported as regional. Both influenza A(H1) and A(H3) viruses were isolated.

Others. During week 49, low influenza activity was detected in Hong Kong (H1, H3, A and B), Mexico (H3 and A), and Russia (H1 and B). Philippines reported no influenza activity. (WHO 12/22/05 http://www.who.int/csr/disease/influenza/update/en/ )

USA. During week 50 (Dec 11 – Dec 17, 2005), influenza activity continued to increase mostly in the southwestern USA. 169 (8.9%) specimens tested by U.S. WHO and National Respiratory and Enteric Virus Surveillance System (NREVSS) collaborating laboratories were positive for influenza. The proportion of patient visits to sentinel providers for influenza-like illness (ILI) was above the national baseline. The proportion of deaths attributed to pneumonia and influenza was below the baseline level. 1 state reported widespread influenza activity; 5 states reported regional influenza activity; 2 states reported local influenza activity; 33 states, New York City and the District of Columbia reported sporadic influenza activity; and 9 states reported no influenza activity. (CDC 12/22/05 http://www.cdc.gov/flu/weekly/ )

Avian/Pandemic influenza updates
- Comprehensive information on the avian influenza: http://www.who.int/csr/disease/avian_influenza/en/index.html. WPRO website on avian influenza: http://www.wpro.who.int/health_topics/avian_influenza/overview.htm
- Latest FAO updates on avian influenza: http://www.fao.org/ag/againfo/subjects/en/health/diseases-cards/special_avian.html. Includes maps documenting the latest avian flu outbreaks and an interactive timeline of the outbreaks. Documents from the avian influenza meeting (7-9 Nov 2005) are also available.
- OIE updates on avian influenza: http://www.oie.int/eng/en_index.htm. Includes documents from the 7-9 Nov 2005 meeting and the 15-18 Nov 2005 Conference of the OIE Regional Commission for Asia, the Far East and Oceania.
- CDC website on pandemic influenza: http://www.cdc.gov/flu/pandemic.htm (includes the new Business Pandemic Plan Checklist and the State and Local Pandemic Influenza Planning Checklist). For avian influenza (available in Chinese, Vietnamese, and Spanish): http://www.cdc.gov/flu/avian/.
- The US government’s official Web site for pandemic flu: http://www.pandemicflu.gov/.
- Influenza information from the US Food and Drug Administration: http://www.fda.gov/oc/opacom/hottopics/flu.html. Q & A on Using PPE During Influenza Outbreaks, Including Bird Flu: http://www.fda.gov/cdrh/emergency/flu_qa.html.
- Latest CIDRAP updates on avian/pandemic influenza: http://www.cidrap.umn.edu/index.html. A comprehensive overview on avian influenza, updated Dec 20, 2005, is available: http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/biofacts/avflu_human.html.
- PAHO’s latest updates on avian influenza: http://www.paho.org/. Includes the press release (20 Dec 2005): Avian vs. Pandemic Flu: Understanding the Threat.
- American Public Health Association (APHA) information on Influenza (http://www.apha.org/preparedness/influenza.htm) and Avian Influenza (http://www.apha.org/preparedness/avian.htm).
- The American Veterinary Medical Association information on avian influenza: http://www.avma.org/public_health/influenza/default.asp


2. Articles
Viet Nam: Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection
Doctors in Viet Nam reported 21 Dec 2005 that they had found more evidence that the H5N1 avian influenza virus can mutate into a form that resists the effect of Roche AG's drug Tamiflu. 4 of 8 patients treated in Viet Nam for avian influenza infection died despite the use of Tamiflu, Dr. Menno de Jong of the Oxford University Clinical Research Unit at the Hospital for Tropical Diseases in Ho Chi Minh and colleagues wrote in the New England Journal of Medicine. Tests showed that in 2 of the patients, the virus had become resistant to Tamiflu. And in 1 patient, the drug was used very early on, as is recommended. "It is becoming clear that to treat avian influenza with neuraminidase inhibitors (such as Tamiflu) we are going to need higher doses and a longer course of treatment for it to work," said Dr. Anne Moscona, an expert in pediatric viral diseases at Weill Medical College of Cornell University. The researchers said the report concerned only a few people and stressed that more study is needed. Of the 138 people known to have been infected with H5N1, 31 have been treated with Tamiflu, Roche said.

The findings add to a report published in October 2005 about a 14-year-old Vietnamese girl who survived an H5N1 infection after being treated with Tamiflu, but who had a drug-resistant virus strain in her body. 4 drugs can be used to treat influenza, but H5N1 already resists 2 older drugs, amantadine and rimantadine. Countries have been stockpiling the newer drugs, known as neuraminidase inhibitors -- Roche and Gilead Science's Tamiflu (oseltamivir), and GlaxoSmithKline and Biota's Relenza, known generically as zanamivir. De Jong and Moscona agreed that Relenza is a good alternative to Tamiflu. "Furthermore, Relenza is active against Tamiflu-resistant virus," De Jong said. But Relenza currently must be inhaled and may not be useful in patients with respiratory conditions, and it might not spread past the lungs to protect other organs. There is not enough of either drug to treat more than a fraction of patients should a bird flu pandemic erupt this year. Roche is trying to license a generic process and step up its own production to 600 million treatment courses by 2007. There is an H5N1 vaccine but it is experimental and is unlikely to work well against whatever pandemic strain may eventually emerge. De Jong said Tamiflu must be used early on in infection to do any good against any type of influenza.

Signs that the H5N1 avian influenza virus may be developing resistance to Tamiflu in some patients are not necessarily a cause for alarm, said Keiji Fukuda, a scientist at the WHO's global influenza program. He said some resistance was inevitable with any kind of drug. "It just points out the need for more information. . .What really is critical is understanding whether the way we are using the drugs contributes to that (resistance)," he added. Tamiflu remained an "excellent choice" among a limited number of antivirals available against the deadly virus, Fukuda said.

The article can be found at: http://content.nejm.org/cgi/content/full/353/25/2667 NEJM (Volume 353:2667-2672, 2005) by Menno D. de Jong et al.
Summary: "Influenza A (H5N1) virus with an amino acid substitution in neuraminidase conferring high-level resistance to oseltamivir was isolated from 2 of 8 Vietnamese patients during oseltamivir treatment. Both patients died of influenza A (H5N1) virus infection, despite early initiation of treatment in one patient. Surviving patients had rapid declines in the viral load to undetectable levels during treatment. These observations suggest that resistance can emerge during the currently recommended regimen of oseltamivir therapy and may be associated with clinical deterioration and that the strategy for the treatment of influenza A (H5N1) virus infection should include additional antiviral agents."

***For additional discussion, please read, “Tamiflu resistance in avian flu victims sparks concern”: http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/dec2205tamiflu.html.

2 Perspectives on “Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection” article:
- “The Run on Tamiflu — Should Physicians Prescribe on Demand?”, by Allan S. Brett, M.D., and Abigail Zuger, M.D. (Volume 353:2636-2637; December 22, 2005; Number 25). http://content.nejm.org/cgi/content/full/353/25/2636.
- “Oseltamivir Resistance — Disabling Our Influenza Defenses”, by Anne Moscona, M.D. (Volume 353:2633-2636; December 22, 2005; Number 25). http://content.nejm.org/cgi/content/full/353/25/2633.
(Promed 12/22/05)


Human-to-human transmission of avian influenza A/H7N7, The Netherlands, 2003
Eurosurveillance Monthly Release, December 2005, Vol. 10, Issue 12
Abstract: “An outbreak of highly pathogenic avian influenza A virus subtype H7N7 began in poultry farms in the Netherlands in 2003. Virus infection was detected by RT-PCR in 86 poultry workers and 3 household contacts of PCR-positive poultry workers, mainly associated with conjunctivitis. To determine the magnitude of and risk factors for human-to-human transmission of influenza A/H7N7 in the Netherlands, a retrospective cohort study among household members of infected poultry workers was undertaken. In total, 33 (58.9 percent) of 56 (among 62) participants who provided blood samples had positive H7 serology, using single convalescent serum samples obtained at least 3 weeks after onset of symptoms of the index case. 8 household members (12.9 percent) reported symptoms (conjunctivitis and/or ILI), of which 4 of 5 (80.0 percent) tested seropositive. On univariate analysis, significant risk factors for seropositivity included having at least 2 toilets, a pet bird, and using cloth handkerchiefs. It was not possible to obtain a stable model for binomial regression for the outcome of A/H7N7 infection. Further seroprevalence studies among contacts of asymptomatic H7 cases should be conducted.”

The significant conclusion applicable to other situations, such as the A/H5N5 outbreaks in East Asia is that: Current outbreak control measures did not take transmission to household contacts into account. This also raises the question of whether or not subclinical A/H7N7 cases can transmit the virus efficiently to other close contacts, which would imply that outbreak control strategy for A/H7N7 should be thoroughly revised. Consideration may be given to early isolation of cases and quarantine of contacts. Prophylactic treatment with oseltamivir should be considered for all household contacts of poultry workers during outbreaks of avian influenza, although its role must be further assessed in order to determine the risk of developing antiviral resistance. (Promed 12/21/05)


Glycan microarray analysis of the hemagglutinins from modern and pandemic influenza viruses reveals different receptor specificities
Stevens J, Blixt O, Glaser L, Taubenberger JK, Palese P, Paulson JC, Wilson IA. J Mol Biol. 2005 Nov 18
Abstract: “Influenza A virus specificity for the host is mediated by the viral surface glycoprotein hemagglutinin (HA), which binds to receptors containing glycans with terminal sialic acids. Avian viruses preferentially bind to a2-3-linked sialic acids on receptors of intestinal epithelial cells, whereas human viruses are specific for the a2-6 linkage on epithelial cells of the lungs and upper respiratory tract. To define the receptor preferences of a number of human and avian H1 and H3 viruses, including the 1918 H1N1 pandemic strains, their hemagglutinins were analyzed using a recently described glycan array. The array, which contains 200 carbohydrates and glycoproteins, not only revealed clear differentiation of receptor preferences for a2-3 and/or a2-6 sialic acid linkage, but could also detect fine differences in HA specificity, such as preferences for fucosylation, sulfation and sialylation at positions 2 (Gal) and 3 (GlcNAc, GalNAc) of the terminal trisaccharide. For the two 1918 HA variants, the South Carolina (SC) HA (with Asp190, Asp225) bound exclusively a2-6 receptors, while the New York (NY) variant, which differed only by one residue (Gly225), had mixed a2-6/a2-3 specificity, especially for sulfated oligosaccharides. Only one mutation of the NY variant (Asp190Glu) was sufficient to revert the HA receptor preference to that of classical avian strains. Thus, the species barrier, as defined by the receptor specificity preferences of 1918 human viruses compared to likely avian virus progenitors, can be circumvented by changes at only 2 positions in the HA receptor binding site. The glycan array thus provides highly detailed profiles of influenza receptor specificity that can be used to map the evolution of new human pathogenic strains, such as the H5N1 avian influenza.” (Promed 12/22/05)