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**HenryN** · January 3, 2007, 03:48 AM

Re: Stop Squawking Over Avian Flu

Originally posted by AlaskaDenise

For every 1 documented case, there are 139 others?

I'm looking forward to reading the article in Archives of Internal Medicine.

.

This is the "no data" paper that assumes flu-like symptoms equals H5N1 infection.

Nonsense on nonsense.

**sharon sanders** · January 3, 2007, 08:06 AM

Abstract

Is Exposure to Sick or Dead Poultry Associated With Flulike Illness?
A Population-Based Study From a Rural Area in Vietnam With Outbreaks of Highly Pathogenic Avian Influenza
Anna Thorson, MD, PhD; Max Petzold, PhD; Nguyen Thi Kim Chuc, PhD; Karl Ekdahl, MD, PhD

Arch Intern Med. 2006;166:119-123.
Background The verified human cases of highly pathogenic avian influenza in Vietnam may represent only a selection of the most severely ill patients. The study objective was to analyze the association between flulike illness, defined as cough and fever, and exposure to sick or dead poultry. 
Methods A population-based study was performed from April 1 to June 30, 2004, in FilaBavi, a rural Vietnamese demographic surveillance site with confirmed outbreaks of highly pathogenic avian influenza among poultry. We included 45 478 randomly selected (cluster sampling) inhabitants. Household representatives were asked screening questions about exposure to poultry and flulike illness during the preceding months; individuals with a history of disease and/or exposure were interviewed in person. 
Results A total of 8149 individuals (17.9%) reported flulike illness, 38 373 persons (84.4%) lived in households keeping poultry, and 11 755 (25.9%) resided in households reporting sick or dead poultry. A dose-response relationship between poultry exposure and flulike illness was noted: poultry in the household (odds ratio, 1.04; 95% confidence interval, 0.96-1.12), sick or dead poultry in the household but with no direct contact (odds ratio, 1.14; 95% confidence interval, 1.06-1.23), and direct contact with sick poultry (odds ratio, 1.73; 95% confidence interval, 1.58-1.89). The flulike illness attributed to direct contact with sick or dead poultry was estimated to be 650 to 750 cases. 
Conclusions Our epidemiological data are consistent with transmission of mild, highly pathogenic avian influenza to humans and suggest that transmission could be more common than anticipated, though close contact seems required. Further microbiological studies are needed to validate these findings. 

Author Affiliations: Division of International Health, Departments of Public Health Sciences (Drs Thorson, Petzold, and Chuc) and Medical Epidemiology and Biostatistics, (Dr Ekdahl), Karolinska Institutet, and Clinic of Infectious Diseases, Karolinska University Hospital (Dr Thorson), Stockholm, Sweden; Nordic School of Public Health, G?teborg, Sweden (Dr Petzold); Hanoi Medical University, Hanoi, Vietnam (Dr Chuc); European Centre for Disease Prevention and Control, Solna, Sweden (Dr Ekdahl); and Stockholm Group of Epidemic Modeling, Stockholm (Dr Ekdahl).
http://archinte.ama-assn.org/cgi/con...urcetype=HWCIT

**AlaskaDenise** · January 3, 2007, 08:25 AM

Re: Stop Squawking Over Avian Flu

Household representatives were asked screening questions about exposure to poultry and flulike illness during the preceding months; individuals with a history of disease and/or exposure were interviewed in person....

They just ASSUMED all flu-like illness was HPAI???

No testing for antibodies???

.

**sharon sanders** · January 3, 2007, 08:29 AM

Abstract from Ferret Study

BIOLOGICAL SCIENCES / MICROBIOLOGY
Lack of transmission of H5N1 avian?human reassortant influenza viruses in a ferret model
Taronna R. Maines*, Li-Mei Chen*, Yumiko Matsuoka*, Hualan Chen*,, Thomas Rowe*,, Juan Ortin, Ana Falc?n,?, Nguyen Tran Hien||, Le Quynh Mai||, Endang R. Sedyaningsih**, Syahrial Harun**, Terrence M. Tumpey*, Ruben O. Donis*, Nancy J. Cox*, Kanta Subbarao*,, and Jacqueline M. Katz*,
*Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333; Centro Nacional de Biotecnologia, Consejo Superior de Investigaciones Cient?ficas, 28049 Madrid, Spain; ||National Institute of Hygiene and Epidemiology, Hanoi, Vietnam; and **Center for Biomedical and Pharmaceutical Research and Development, Ministry of Health, Jakarta 10560, Indonesia
Communicated by Peter Palese, Mount Sinai School of Medicine, New York, NY, June 23, 2006 (received for review May 23, 2006)

Avian influenza A H5N1 viruses continue to spread globally among birds, resulting in occasional transmission of virus from infected poultry to humans. Probable human-to-human transmission has been documented rarely, but H5N1 viruses have not yet acquired the ability to transmit efficiently among humans, an essential property of a pandemic virus. The pandemics of 1957 and 1968 were caused by avian?human reassortant influenza viruses that had acquired human virus-like receptor binding properties. However, the relative contribution of human internal protein genes or other molecular changes to the efficient transmission of influenza viruses among humans remains poorly understood. Here, we report on a comparative ferret model that parallels the efficient transmission of H3N2 human viruses and the poor transmission of H5N1 avian viruses in humans. In this model, an H3N2 reassortant virus with avian virus internal protein genes exhibited efficient replication but inefficient transmission, whereas H5N1 reassortant viruses with four or six human virus internal protein genes exhibited reduced replication and no transmission. These findings indicate that the human virus H3N2 surface protein genes alone did not confer efficient transmissibility and that acquisition of human virus internal protein genes alone was insufficient for this 1997 H5N1 virus to develop pandemic capabilities, even after serial passages in a mammalian host. These results highlight the complexity of the genetic basis of influenza virus transmissibility and suggest that H5N1 viruses may require further adaptation to acquire this essential pandemic trait. 
transmissibility | pandemic virus properties | pandemic influenza | animal model | receptor specificity

http://www.pnas.org/cgi/content/abstract/103/32/12121

**sharon sanders** · January 3, 2007, 08:36 AM

Another Ferret Study that Needs to be Considered

Avian Influenza (H5N1) Viruses Isolated from Humans in Asia in 2004 Exhibit Increased Virulence in Mammals

Taronna R. Maines,1 Xui Hua Lu,1 Steven M. Erb,1 Lindsay Edwards,1 Jeannette Guarner,2 Patricia W. Greer,2 Doan C. Nguyen,1 Kristy J. Szretter,1 Li-Mei Chen,1 Pranee Thawatsupha,3 Malinee Chittaganpitch,3 Sunthareeya Waicharoen,3 Diep T. Nguyen,4 Tung Nguyen,4 Hanh H. T. Nguyen,5 Jae-Hong Kim,6 Long T. Hoang,5 Chun Kang,7 Lien S. Phuong,4 Wilina Lim,8 Sherif Zaki,2 Ruben O. Donis,1 Nancy J. Cox,1 Jacqueline M. Katz,1 and Terrence M. Tumpey1*
Influenza Branch,1 Infectious Disease Pathology Activity, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333,2 Thai National Influenza Center, National Institute of Health, Ministry of Public Health, Bangkok, Thailand 11000,3 National Center for Veterinary Diagnosis, Department of Animal Health, Ministry of Agriculture and Rural Development, Hanoi, Vietnam,4 National Institute of Hygiene and Epidemiology, Hanoi, Vietnam,5 National Veterinary Research and Quarantine Service, Anyang 430-824, Korea,6 Laboratory of Respiratory Viruses, Department of Viruses, Korean National Institute of Health, Seoul, Korea,7 Hong Kong National Influenza Center, Government Virus Unit, Kowloon, Hong Kong Special Administrative Region, China8
Received 9 April 2005/ Accepted 2 June 2005

<TABLE cellSpacing=0 cellPadding=0 width="100%" bgColor=#e1e1e1><TBODY><TR><TD vAlign=center align=left width="5%" bgColor=#ffffff></TD><TH vAlign=center align=left width="95%">ABSTRACT </TH></TR></TBODY></TABLE><TABLE cellPadding=5 align=right border=1><TBODY><TR><TH align=left>Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
</TH></TR></TBODY></TABLE>
The spread of highly pathogenic avian influenza H5N1 viruses across Asia in 2003 and 2004 devastated domestic poultry populations and resulted in the largest and most lethal H5N1 virus outbreak in humans to date. To better understand the potential of H5N1 viruses isolated during this epizootic event to cause disease in mammals, we used the mouse and ferret models to evaluate the relative virulence of selected 2003 and 2004 H5N1 viruses representing multiple genetic and geographical groups and compared them to earlier H5N1 strains isolated from humans. Four of five human isolates tested were highly lethal for both mice and ferrets and exhibited a substantially greater level of virulence in ferrets than other H5N1 viruses isolated from humans since 1997. One human isolate and all four avian isolates tested were found to be of low virulence in either animal. The highly virulent viruses replicated to high titers in the mouse and ferret respiratory tracts and spread to multiple organs, including the brain. Rapid disease progression and high lethality rates in ferrets distinguished the highly virulent 2004 H5N1 viruses from the 1997 H5N1 viruses. A pair of viruses isolated from the same patient differed by eight amino acids, including a Lys/Glu disparity at 627 of PB2, previously identified as an H5N1 virulence factor in mice. The virus possessing Glu at 627 of PB2 exhibited only a modest decrease in virulence in mice and was highly virulent in ferrets, indicating that for this virus pair, the K627E PB2 difference did not have a prevailing effect on virulence in mice or ferrets. Our results demonstrate the general equivalence of mouse and ferret models for assessment of the virulence of 2003 and 2004 H5N1 viruses. However, the apparent enhancement of virulence of these viruses in humans in 2004 was better reflected in the ferret. 

<TABLE cellSpacing=0 cellPadding=0 width="100%" bgColor=#e1e1e1><TBODY><TR><TD vAlign=center align=left width="5%" bgColor=#ffffff></TD><TH vAlign=center align=left width="95%">INTRODUCTION </TH></TR></TBODY></TABLE><TABLE cellPadding=5 align=right border=1><TBODY><TR><TH align=left>Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
</TH></TR></TBODY></TABLE>
From December 2003 to April 2005, highly pathogenic avian influenza (HPAI) H5N1 viruses caused outbreaks of disease in domestic poultry in nine Asian countries (World Organization for Animal Health [OIE] [http://www.oie.int]). This unprecedented spread of HPAI virus was associated with a total of 79 human infections and 49 deaths in Vietnam, Thailand, and Cambodia (World Health Organization [WHO; http://www.who.int/en/]). With continued H5N1 virus circulation in poultry and further human cases likely, the potential for the emergence of an H5 avian-human reassortant with pandemic potential is a clear and present threat to public health worldwide. 
HPAI viruses were first recognized to cause human respiratory infection and death in 1997, when, during outbreaks of disease in domestic poultry in Hong Kong, avian-to-human transmission of a purely avian H5N1 virus resulted in 18 human cases, of which 6 were fatal (5, 6, 35). The outbreak ended with the culling of all poultry in Hong Kong's poultry farms and markets. Although routine surveillance in Hong Kong repeatedly detected H5N1 virus in poultry between 1999 and 2003 (9, 13-15, 33), no further human cases were reported until February 2003, when H5N1 viruses were isolated from two family members with respiratory illness, one of whom died (26). 
In December 2003, South Korean authorities first reported outbreaks of HPAI H5N1 virus in poultry (OIE [http://www.oie.int]; 21). By February 2004, seven additional Asian countries announced poultry outbreaks due to HPAI H5N1 virus (OIE [http://www.oie.int]). The outbreaks in Vietnam and Thailand were widespread, with approximately 90% and 60% of provinces affected, respectively. In contrast, outbreaks in Japan, Cambodia, Laos, Indonesia, and China were reported to be more regional. In August 2004, Malaysian authorities reported outbreaks in a single district (OIE [http://www.oie.int]). 
Although the true numbers of human infections during the H5N1 outbreaks remain unknown, the 62% mortality rate among humans with documented H5N1 disease in 2004 and 2005 was markedly higher (WHO [http://www.who.int/en/]) than the 33% fatality rate among documented human H5N1 cases in 1997. Patients evaluated in Vietnam and Thailand generally presented with fever, respiratory symptoms, diarrhea, lymphopenia, and thrombocytopenia (2, 36), and although rare, presentation with fever and gastrointestinal symptoms but no respiratory symptoms was also reported (1, 7). Pneumonia with severe impairment of respiratory gas exchange was common, and despite assisted ventilation, most of these patients progressed to respiratory failure and death. 
Because there is only limited information on the biologic and molecular properties that may confer virulence on HPAI H5N1 virus in humans, studies in mammalian models are necessary. Nonhuman primates, ferrets, and mice have been used as mammalian models to study influenza virus pathogenesis. Experimental infection of cynomolgous macaques with an H5N1 virus from the index case of the 1997 outbreak reproduced the acute respiratory distress syndrome and multiple-organ dysfunction observed in humans (19, 30, 31, 39). However, additional studies with other avian H5N1 strains have not been reported, likely due in part to the practical, ethical, and economic limitations of this mammalian model. On the other hand, the ferret, a naturally susceptible host to influenza A viruses, has been effectively used to evaluate H5N1 virus virulence, as well as the safety and efficacy of H5N1 vaccine candidates (12, 22, 38, 41). We previously established criteria for the assessment of H5N1 virus virulence in ferrets and demonstrated an equivalence in virulence for two 1997 H5N1 strains studied in this model (41). In contrast, the same two 1997 H5N1 strains caused two distinct phenotypes of disease in BALB/c mice: a highly pathogenic phenotype with systemic replication, lymphopenia, and death, and a low-pathogenic phenotype with efficient respiratory viral replication but no systemic lethal infection (11, 16, 17, 23, 37). 
Here, we evaluate the relative virulence of selected H5N1 viruses isolated from humans or avian species during the 2003 and 2004 outbreak in Asia in both the mouse and ferret models and compare them to the earlier 1997 H5N1 strains isolated from humans. Our results demonstrate that, in general, the levels of virulence of H5N1 viruses in these two models are comparable. Furthermore, the ferret model demonstrates an increase in virulence of the 2004 human H5N1 isolates compared with the 1997 human isolates and with the 2003 and 2004 avian isolates studied. 


discussion and full paper at:

http://www.flutrackers.com/forum/showthread.php?t=14211

**cartski** · January 3, 2007, 10:44 AM

Re: Another Ferret Study that Needs to be Considered

Ugg.

I find this article a good thing: he actually makes his arguments clearer than the previous 2 pieces (one reported here a couple of weeks ago, and the other on his website).

I didn't notice any new arguments in my cursory read. He's probably done a lot of our work for us - comparing his last 2 pieces and listing the arguments in a relatively succinct form. If we number the arguments, or identify them with a short title, that might make discussion and debunking easier.

If it's correct that this piece is essentially a repeat, it's grandstanding.

J.

**sharon sanders** · January 3, 2007, 11:22 AM

NEJM - As to the effectiveness of Tamiflu (oseltamivir).....

<TABLE cellSpacing=0 cellPadding=0 width=640 border=0><TBODY><TR><TD vAlign=top align=middle><TABLE cellSpacing=0 cellPadding=0 border=0><TBODY><TR><TH vAlign=top noWrap align=right>Volume 353:2633-2636</TH><TD noWrap></TD><TH vAlign=top noWrap>December 22, 2005</TH><TD noWrap></TD><TH vAlign=top noWrap align=left>Number 25</TH></TR></TBODY></TABLE></TD><TD vAlign=top noWrap align=right>Next</TD></TR></TBODY></TABLE>

Oseltamivir Resistance ? Disabling Our Influenza Defenses

<CENTER>Anne Moscona, M.D. </CENTER>
<TABLE cellSpacing=0 cellPadding=0 width=200 align=right border=0><TBODY><TR><TD width=20></TD><TD bgColor=#336699><TABLE cellSpacing=1 cellPadding=0 border=0><TBODY><TR vAlign=top><TD align=middle width=200 bgColor=#e8e8d1>

</TD></TR><TR><TD><TABLE cellSpacing=0 cellPadding=2 width="100%" bgColor=#ffffff border=0><TBODY><TR vAlign=top><TD colSpan=2></TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center>PDF</TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center>PDA Full Text</TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center>Interview</TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center>Animated Figure</TD></TR><TR vAlign=top><TD colSpan=2></TD></TR></TBODY></TABLE></TD></TR><TR><TD align=middle width=200 bgColor=#e8e8d1>

</TD></TR><TR><TD><TABLE cellSpacing=0 cellPadding=2 width="100%" bgColor=#ffffff border=0><TBODY><TR vAlign=top><TD colSpan=2></TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center>Add to Personal Archive</TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center>Add to Citation Manager</TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center>Notify a Friend</TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center>E-mail When Cited</TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center>E-mail When Letters Appear</TD></TR><TR vAlign=top><TD colSpan=2></TD></TR></TBODY></TABLE></TD></TR><TR><TD align=middle width=200 bgColor=#e8e8d1>

</TD></TR><TR><TD><TABLE cellSpacing=0 cellPadding=2 width="100%" bgColor=#ffffff border=0><TBODY><TR vAlign=top><TD colSpan=2></TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center>Related Article</TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center><TABLE cellSpacing=0 cellPadding=0 border=0><TBODY><TR><TD></TD><TD vAlign=center>by Brett, A. S.</TD></TR></TBODY></TABLE></TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center>Related Article</TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center><TABLE cellSpacing=0 cellPadding=0 border=0><TBODY><TR><TD></TD><TD vAlign=center>by de Jong, M. D.</TD></TR></TBODY></TABLE></TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center>Find Similar Articles</TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center>PubMed Citation</TD></TR><TR vAlign=top><TD colSpan=2></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></TABLE>As the potential for an influenza pandemic has galvanized the medical community and the public into action, physicians and patients alike have been heartened by the availability of effective antiviral drugs. The neuraminidase inhibitors provide valuable defenses against pandemic and seasonal influenza, and physicians have been flooded with requests from patients for personal supplies of oseltamivir (Tamiflu). A benefit of having oseltamivir at home is that the sooner the drug is taken after the onset of symptoms, the better its clinical efficacy.1 And certainly, enabling ill people to stay home and out of waiting rooms and pharmacies should limit the spread of influenza. So it is not surprising that many believe there should be a supply of oseltamivir in every medicine cabinet. This scenario, however, is potentially dangerous. Misuse of the drug could rob us of the advantages that neuraminidase inhibitors provide, by favoring the emergence of oseltamivir-resistant influenza virus. The potentially serious consequences of oseltamivir resistance in patients with influenza A (H5N1) virus infections is alarmingly underscored by the report by de Jong and colleagues in this issue of the Journal (pages 2667?2672). 
One strength of the neuraminidase inhibitors oseltamivir and zanamivir (Relenza) over the older adamantanes is that they are less prone to selecting for resistant influenza viruses.2 Indeed, no virus resistant to zanamivir, which is currently available only in an inhaled form, has yet been isolated from immunocompetent patients after treatment. The recent emergence of oseltamivir-resistant variants is therefore a matter of immediate concern. 
Why is resistance developing to oseltamivir? Several years ago,structural analysis3 predicted that aspects of the chemical structure of oseltamivir (not present in zanamivir) could facilitate the development of resistance mutations that would permit neuraminidase to function, allowing drug-resistant virus to survive and propagate. This prediction is now being validated by clinical data. 
The mechanism of the development of resistance is illustrated in the diagram. The influenza neuraminidase releases newly formed viruses from infected cells, allowing them to spread from cell to cell. The inhibitor molecules mimic the natural substrate of the influenza neuraminidase (the sialic acid receptors) and bind to the active site, preventing neuraminidase from cleaving host-cell receptors and releasing new virus. All the resistant variants thus far have contained specific mutations in the neuraminidase molecule; but since neuraminidase serves an essential purpose, mutations that allow the virus to survive must not inactivate the enzyme. 
<TABLE cellSpacing=0 cellPadding=0><TBODY><TR bgColor=#e8e8d1><TD><TABLE cellSpacing=2 cellPadding=2><TBODY><TR bgColor=#e8e8d1><TD vAlign=top align=middle bgColor=#ffffff>
View larger version (42K):
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</TD><TD vAlign=top align=left>Mechanism of Resistance to Oseltamivir.
The neuraminidase active site changes shape to create a pocket for oseltamivir, whereas it accommodates zanamivir without such a change (Panel A). Any of several mutations may prevent the binding of oseltamivir by preventing the formation of this pocket (Panel B); the oseltamivir-resistant virus can nonetheless bind to the host-cell sialic acid receptor and to zanamivir. The pocket for oseltamivir, illustrated by key amino acids in Panel C, is created by the rotation of E276 and bonding of the amino acid to R224 ? events that are prevented by the mutations R292K, N294S, and H274Y and therefore result in resistance to oseltamivir. An E119V mutation may permit the binding of a water molecule in the space created by the smaller valine, also interfering with oseltamivir binding. None of these mutations prevent the binding of zanamivir or of the natural sialic acid substrate. An animated version of this figure is available with the full text of the article at www.nejm.org.

</TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE>
To accommodate the bulky side chain of oseltamivir in the active site, the neuraminidase molecule must undergo rearrangement to create a pocket (Panel A). Zanamivir, by contrast, binds to the active site without any rearrangement of the molecule. Several mutations that limit the necessary molecular rearrangement may diminish the binding of oseltamivir (Panel B). Molecular-level analysis (Panel C) shows that the amino acid termed E276 must rotate and bond with R224 to form a pocket for the side chain of oseltamivir. The mutations R292K, N294S, and H274Y inhibit this rotation and prevent the pocket from forming, resulting in resistance to oseltamivir. The mutations nonetheless allow the binding of natural sialic acid substrate, so mutated virus can survive and propagate. In contrast, the binding of zanamivir does not require any reorientation of amino acids, so these mutated viruses remain sensitive to that drug. An E119V mutation also interferes only with oseltamivir binding, possibly because a water molecule can fit between oseltamivir and valine at the active site but cannot insinuate itself between zanamivir and valine at residue 119. 
These mechanisms have clinical implications. The mutations identified in the resistant viruses have thus far all been in the amino acids mentioned above. A 2004 study in Japan found that 9 of 50 children with influenza A (H3N2) virus infection who had been treated with oseltamivir (18 percent) had a virus with a drug-resistance mutation in the neuraminidase gene (R292K, N294S, or E119V).1 A 2000?2001 Japanese study also revealed resistant influenza A (H1N1) viruses with the H274Y mutation in 7 of 43 oseltamivir-treated children (16 percent).4
The surprisingly high rate of emerging resistance in the Japanese studies may have been due to the use of insufficient doses of the drug and resultant failure to eradicate the virus. In both studies, the children were given 2 mg of oseltamivir per kilogram of body weight, and many were very young (75 percent were one to three years of age in the 2004 study, as were 43 percent of those in the 2000?2001 study). Of 147 children in a U.S. trial (including 26 younger than five years) who received the age- and weight-tailored (and therefore sometimes substantially higher) doses that have been approved outside of Japan, none shed resistant virus.1 
It is therefore worrisome that personal stockpiling of oseltamivir is likely to lead to the use of insufficient doses or inadequate courses of therapy. Shortages during a pandemic would inspire sharing of personal supplies, resulting in inadequate treatment. Such undertreatment is of particular concern in children ? the main source for the dissemination of influenza within the community, since they usually have higher viral loads than adults and excrete infectious virus for longer periods. The habit of stopping treatment prematurely when symptoms resolve (a well-established tendency with antibiotic therapy) could also lead to suboptimal treatment of influenza and promote the development of drug resistance. 
Could drug-resistant viruses then spread? Although many oseltamivir-resistant (non-H5N1) viruses that have been studied in animals have compromised biologic fitness, some resistant variants have been transmitted among ferrets, arousing concern about transmissibility among humans.5 In fact, according to recent data collected in Japan by the Neuraminidase Inhibitor Susceptibility Network, 3 of 1200 isolates from ill patients without known exposure to neuraminidase inhibitors contained resistance mutations, suggesting that these resistant viruses are transmitted at least at a low level in humans and are not severely biologically compromised. 
There have now been several reports that oseltamivir-resistant influenza A (H5N1) viruses with the H274Y mutation have been isolated from humans with avian influenza infection who were treated with oseltamivir.4 The cases described by de Jong et al. raise the worrisome prospect that even with therapeutic doses, oseltamivir resistance may develop during the course of illness and may affect clinical outcomes. Nothing is yet known about the transmissibility of oseltamivir-resistant influenza A (H5N1) viruses in humans, and it will be important to study these isolates in animals to determine how the H274Y mutation affects virulence, pathogenicity, and transmissibility. 
There is much to be learned about the clinical and virologic course of H5N1 infection in humans, as well as the response to therapy and the development of resistance. We know that the virus may have a longer incubation period than other influenza viruses, potentially increasing the period of transmissibility before symptoms appear, and that the virus frequently leads to fulminant lower respiratory tract infection.4 Interventions of any kind have failed when initiated late in the course of illness, but early therapy with neuraminidase inhibitors is probably beneficial; the cases reported by de Jong et al. suggest that even therapy initiated later in the illness may limit ongoing viral replication. H5N1 virus infections may require higher doses of oseltamivir for longer periods than do other types of influenza.5 Indeed, it is becoming clear that more medication than the currently recommended doses may be required for adequate treatment. If so, treatment with the current doses could not only fail but also select for resistant influenza A (H5N1) viruses. 
Like any successful infectious agent, influenza virus will most likely evolve to evade any single drug. By targeting several points in the viral life cycle simultaneously with different drugs, we are more likely to discourage the emergence of viruses that can resist all drugs at once. But we currently rely solely on the neuraminidase inhibitors ? and solely on oseltamivir in many situations, such as in patients who cannot use inhaled medication or in patients infected with H5N1 virus, in whom systemic drug levels may be important. We must not abrogate the usefulness of these drugs by exposing circulating influenza to them in such a way as to facilitate the selection of resistant viruses. The study by de Jong et al. confirms that oseltamivir-resistant H5N1 virus is now a reality. The need to learn more about how and when resistance to the neuraminidase inhibitors develops, while we focus on the development of new antiviral drugs, is pressing. This frightening report should inspire us to devise pandemic strategies that do not favor the development of oseltamivir-resistant strains. Improper use of personal stockpiles of oseltamivir may promote resistance, thereby lessening the usefulness of our frontline defense against influenza, and should be strongly discouraged. 


Source Information
Dr. Moscona is a professor in the Departments of Pediatrics and Microbiology and Immunology at Weill Medical College of Cornell University, New York. 

An interview with Dr. Moscona can be heard at www.nejm.org.
References

<LI value=1>Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med 2005;353:1363-1373. [Free Full Text] <LI value=2>Bright RA, Medina MJ, Xu X, et al. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet 2005;366:1175-1181. [CrossRef][Medline] <LI value=3>Varghese JN, Smith PW, Sollis SL, et al. Drug design against a shifting target: a structural basis for resistance to inhibitors in a variant of influenza virus neuraminidase. Structure 1998;6:735-746. [CrossRef][ISI][Medline] <LI value=4>The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. Avian influenza A (H5N1) infection in humans. N Engl J Med 2005;353:1374-1385. [Free Full Text]
McKimm-Breschkin JL. Management of influenza virus infections with neuraminidase inhibitors: detection, incidence, and implications of drug resistance. Treat Respir Med 2005;4:107-116. [Medline]

http://content.nejm.org/cgi/content/full/353/25/2633

**sharon sanders** · January 3, 2007, 11:45 AM

de Jong et. al. article

SUMMARY
Influenza A (H5N1) virus with an amino acid substitution in neuraminidase conferring high-level resistance to oseltamivir was isolated from two of eight 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. 

Full article:

http://www.h5n1experts.org/forum/showthread.php?t=486

**sharon sanders** · January 3, 2007, 11:59 AM

What percent of 6.5 billion is 7.5 million?

"At least one country has ordered enough for every citizen."

I believe this is Switzerland. "The United States and some other countries have been stockpiling H5N1 vaccines, despite lack of assurance that they would be effective against a pandemic strain. Switzerland recently announced plans to buy enough vaccine for the entire Swiss population."

http://www.flutrackers.com/forum/sho...ht=switzerland

The population of Switzerland is approximately 7,489,370 in 2005.

http://en.wikipedia.org/wiki/Demogra...of_Switzerland

THE WORLD IS CURRENTLY INHABITATED BY APPROXIMATELY 6.5 BILLION HUMANS

http://en.wikipedia.org/wiki/World_population

**sharon sanders** · January 3, 2007, 12:27 PM

What does this comment mean???

"Better nourishment alone would dramatically reduce the death rate -- even if we're actually quite over-nourished. That's why a recent widely misinterpreted medical journal article said that if there were a repeat of the Spanish flu that 96 percent of the deaths would be in the developing world."

I guess the developing world does not count???

Population of India:

Approx: 1.1 BILLION

http://en.wikipedia.org/wiki/Demographics_of_India

Population of Africa:

Approx: 890 MILLION

http://en.wikipedia.org/wiki/Africa

**sharon sanders** · January 3, 2007, 12:57 PM

It is not "regular" pneumonia

"...pneumonia vaccine has already been available for decades, and pneumonia is by far the greatest killer of flu victims."

It is about the cytokine storm not pneumonia.

The Lancet 2004; 363:617-619
DOI:10.1016/S0140-6736(04)15595-5
Research Letters
Re-emergence of fatal human influenza A subtype H5N1 disease

Dr JSM PeirisFRCPath a , WC YuFRCP b, CW LeungFRCPCH b, CY CheungMPhil a, WF NgFRCPath b, JM NichollsFRCPA a, TK NgFRCPath b, KH ChanPhD a, ST LaiFHKAM b, WL LimFRCPA c, KY YuenMD a and Y GuanPhD a

Summary

Human disease associated with influenza A subtype H5N1 reemerged in January, 2003, for the first time since an outbreak in Hong Kong in 1997. Patients with H5N1 disease had unusually high serum concentrations of chemokines (eg, interferon induced protein-10 [IP-10] and monokine induced by interferon γ [MIG]). Taken together with a previous report that H5N1 influenza viruses induce large amounts of proinflam-matory cytokines from macrophage cultures in vitro, our findings suggest that cytokine dysfunction contributes to the pathogenesis of H5N1 disease. Development of vaccines against influenza A (H5N1) virus should be made a priority.

Affiliations

a. Department of Microbiology and Pathology, University of Hong Kong and Queen Mary Hospital, Pokfulam, Hong Kong SAR, People's Republic of China
b. Departments of Medicine, Paediatrics, Intensive Care, and Pathology, Princess Margaret Hospital, Hong Kong
c. Government Virus Unit, Department of Health, Hong Kong

Correspondence to: Dr J S M Peiris

http://www.thelancet.com/journals/la...bstractprinter

**gsgs** · January 3, 2007, 01:05 PM

Re: What percent of 6.5 billion is 7.5 million?

also Singapore AFAIK.
And France was reported to have signed a contract, while
Britain was still negotiating ( "The Times")

But this is just one strain (Vietnam/1203/2004). You could have several prepandemic vaccines for several strains. USA has this (A/IDN/5/2005),(A/Anhui/1/2005), but not so much . (Someone fill in the numbers ?)

Originally posted by Florida1

"At least one country has ordered enough for every citizen."

I believe this is Switzerland. "The United States and some other countries have been stockpiling H5N1 vaccines, despite lack of assurance that they would be effective against a pandemic strain. Switzerland recently announced plans to buy enough vaccine for the entire Swiss population."

http://www.flutrackers.com/forum/sho...ht=switzerland

The population of Switzerland is approximately 7,489,370 in 2005.

http://en.wikipedia.org/wiki/Demogra...of_Switzerland

THE WORLD IS CURRENTLY INHABITATED BY APPROXIMATELY 6.5 BILLION HUMANS

http://en.wikipedia.org/wiki/World_population

**sharon sanders** · January 3, 2007, 01:14 PM

How about a lower death rate? I am all for it.

"How about all the talk of H5N1 having a death rate above 50 percent? This is based on a readily-dismissible artifact: The numbers come from that tiny subset of persons whose flu symptoms are so severe that go to the hospital -- Third World hospitals with Third World medicine, at that."

What is this theme with the "Third World"? I do not think that Turkey considers themselves "Third World".

From the World Bank November 30:

"The number of confirmed human deaths in 2006 reported to WHO reached 76 as of November 29, thus already nearly equaling the total for the previous three years combined. Furthermore, the fatality rate among those infected is increasing, currently standing at 60 percent versus 53 percent at the time of the <?xml:namespace prefix = st1 ns = "urn:schemas-microsoft-com:office:smarttags" /><st1:City><st1:place>Beijing</st1:place></st1:City> conference. <st1:country-region><st1:place>Indonesia</st1:place></st1:country-region>, where the disease has become endemic within the domestic poultry population, has this year seen on average one human death a week. In addition, worrying reports of possible human-to-human transmission of the virus among a family cluster of eight in North Sumatra in May this year has again highlighted the uncertainty as to when and where a possible mutation might take place, underscoring that there is no room for complacency in the global fight against AHI. Containing the threat of H5N1 thus poses a complex, multisectoral, cross-border challenge, which requires continued worldwide cooperation in terms of technical aid, coordination and financial contributions."

http://siteresources.worldbank.org/I...0-Nov-2006.doc

**sharon sanders** · January 3, 2007, 01:35 PM

New vaccines - Hooray! , Ready for mass innoculation when?

"Meanwhile, at least six different drug companies have vaccines for H5N1 in testing or even in production while awaiting regulatory approval."

US awards $1 billion for cell-based flu vaccines

Robert Roos News Editor

May 4, 2006 (CIDRAP News) ? In an effort to modernize vaccine production while preparing for an influenza pandemic, the US government today awarded five contracts totaling more than $1 billion to develop cell-based technologies for making flu vaccines.
The awards to five pharmaceutical companies are intended to help create an alternative to growing flu vaccines in eggs, the time-consuming production method used since the 1950s, and boost US production capacity. The money comes from $3.3 billion Congress appropriated last December for pandemic preparations by the Department of Health and Human Services (HHS).
"Today, we're taking a step closer to preparedness by investing more than $1 billion to develop vaccines more quickly and to produce them here in the United States," HHS Secretary Mike Leavitt said in a news release.
HHS listed the vaccine makers and their contract awards as follows: GlaxoSmithKline, $274.75 million; MedImmune, $169.6 million; Novartis Vaccines & Diagnostics, $220.51 million; DynPort Vaccine, $40.97 million; and Solvay Pharmaceuticals, $298.59 million.
The announcement comes a day after the Bush administration released a 228-page plan for implementing its flu pandemic strategy. One of the administration's goals is to develop the capacity for domestic production of enough vaccine for every American within 6 months of the emergence of a pandemic.
It takes about 6 months to grow seasonal flu vaccines in eggs, and the eggs must be ordered well in advance. Growing vaccines in laboratory cell cultures promises to be a somewhat faster and much more flexible approach. The method is already used for a number of other vaccines, such as polio, hepatitis A, and chickenpox.
"Our current capacity of egg-based influenza vaccine production is not sufficient to meet increased demands during an emergency," said Leavitt. "Accelerating the development of this vaccine technology and creating domestic capacity are critical to our preparedness efforts."
With cell-based production, companies can skip the step of adapting the virus strains to grow in eggs, the HHS statement said. In addition, the method will make it possible to meet increased needs in case of a shortage or pandemic, since cells can be frozen in advance and large volumes can be grown quickly, officials said.
Cell-based methods also sidestep the risk of loss of egg supplies because of various poultry diseases. Such methods also eliminate the drawback that people who are allergic to eggs can't receive vaccines grown in eggs.
The HHS announcement didn't give details on the contract requirements or timetables, but the companies offered some information in news releases. All said the contracts are for 5 years.
GlaxoSmithKline said it will use the award to speed the development of new cell-based seasonal and pandemic flu vaccines and to increase cell-culture manufacturing capability at the company's plant in Marietta, Pa. The company said that in addition to using the HHS funds, it will continue plans to invest more than $100 million in cell-culture production at the Pennsylvania plant.
MedImmune, maker of the intranasal vaccine FluMist, said it will use the contract to develop cell-based flu vaccines involving the same technology as FluMist, which uses a weakened live virus. The company, based in Gaithersburg, Md., said it plans to build "a cell-based facility in the Untied States that can produce at least 150 million doses within six months of notification of an influenza pandemic."
Swiss-based Novartis, like MedImmune, cited a goal of being able to produce 150 million doses of vaccine in a US facility within 6 months after declaration of a pandemic. The HHS contract will support product development and the design and testing of equipment.
Last fall Novartis launched a US phase 1-2 study of an investigational cell-culture-derived flu vaccine, the company said. The firm expects to file for European approval of that vaccine, made in Marburg, Germany, later this year.
DynPort Vaccine Corp. (DVC), a subsidiary of Computer Sciences Corp., said it is collaborating with Baxter Healthcare Corp. to develop cell-based flu vaccines. The firm said its HHS contract is worth $242.5 million, whereas the HHS announced listed the amount at $40.9 million.
HHS spokesman Marc Wolfson explained that the amount in excess of $40.9 million is conditional on additional appropriations as well as meeting the requirements of the contract. Wolfson is with the HHS Office of Public Health Emergency Preparedness in Washington.
DynPort said its contract supports, in addition to cell-based vaccine development, the pursuit of licensing for two flu vaccine candidates: "a split virus vaccine" for seasonal flu and a modified whole-virus vaccine for H5N1 avian flu.
Solvay, based in Brussels, Belgium, said its HHS contract covers the development of new cell-based flu vaccine and "the development of a master plan to manufacture, formulate, fill and package annual and pandemic influenza vaccines in a new U.S.-based facility."
"Our expertise gained from building our new commercial scale, cell-based influenza vaccine manufacturing facility in The Netherlands provides a strong foundation for the development of a similar facility in the U.S.," said Werner Cautreels, PhD, the company's CEO.
In April 2005, HHS awarded Sanofi Pasteur a $97 million contract to develop a cell-based flu vaccine. The company was the first to receive a federal contract for commercial scale use of new flu vaccine technology, the agency said.

http://www.cidrap.umn.edu/cidrap/con...6vaccines.html

Announcement

Stop Squawking Over Avian Flu

Stop Squawking Over Avian Flu

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