2006 05 26 1

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Travel-Nature

Published on March 27, 2008

Author: aksu

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Slide1:  Avian influenza Slide2:  Why is it important ? Slide3:  Avian Influenza: Mortality Slide4:  N Engl J Med 2005;353:1374-85. Slide6:  Consequences of H5N1 Poultry Epidemic, Thailand ~62 million birds were culled ≈5,300 million Thai baht (US $132.5 million) for direct compensation to affected farmers. an estimated effect on the national GDP of 0.39% (25,240 millionThai baht (US $631 million)). National Economic and Social Development Board. Analysis of avian influenza epidemics’ impacts on the Thai economy in 2004. [cited 2005 Feb 15]. Available from http: // www.nesdb.go.th/ econSocial/macro/ Outlook_data/ econ_outlook_q4_46/03.pdf Slide7:  Pandemics are severe outbreaks that rapidly progress to involve all parts of the world. They are usually associated with the emergence of a new virus to which the overall population possess no immunity. Slide8:  Pandemics? the three important criteria for a new pandemic influenza virus—ie, the ability to replicate in human beings and the absence of antibodies to the virus in the human population at large. The third criterium is the potential to rapidly spread from man to man. Slide9:  Hong Kong H5N1 Avian Influenza : ?Pandemic The influenza A (H5N1) virus meets two of the three important criteria for a new pandemic influenza virus—ie, the ability to replicate in human beings and the absence of antibodies to the virus in the human population at large. The third criterium is the potential to rapidly spread from man to man, which has so far not been observed. Slide12:  a sequence of 709 bases (nucleotides 480 to 1189) of the hemagglutinin gene was the same in the viruses from the mother and aunt, except for one synonymous substitution at nucleotide 936. Slide13:  Sequencing of RT-PCR products from the mother and the aunt revealed that all the viral genes were avian and were closely related to other H5N1 sequences in Thailand Slide14:  The previous influenza pandemics “There were three influenza pandemics during the last century (1918, 1957, 1968). The greatest pandemic in recorded history occurred in 1918–1919 when, during three “waves” of H1N1- influenza, a fifth of the world's population was infected and 21 million deaths were recorded worldwide in less than 1 year, more deaths than from any war or famine in an equivalent period.” Slide15:  The influenza pandemic of 1918-1919 -Known as"Spanish Flu” (BMJ,10/19/1918) -Killed more people than the Great World War I – -Has been cited as the most devastating epidemic in recorded world history. More people died of this influenza in a single year than in four-years of the Black Death Bubonic Plague from 1347 to 1351. . Slide17:  The influenza pandemic of 1918-1919: USA “The first wave of influenza appeared early in the spring of 1918 in Kansas and in military camps throughout the US. Of the U.S. soldiers who died in Europe, half of them fell to the influenza virus and not to the enemy. In the fall and winter of 1918, the war brought the virus back into the US for the second wave of the epidemic. The flu that winter was beyond imagination as millions were infected and thousands died.The virus killed almost 200,000 in October of 1918 alone….. Slide20:  ….With the military patients coming home from the war with battle wounds, hospital facilities and staff were taxed to the limit. Since the medical practitioners were away with the troops and many had been lost for service with the military,this created a shortage of physicians, especially in the civilian sector. The shortage was further confounded by the added loss of physicians to the epidemic. In some hospitals only the medical students were left to care for the sick. Third and forth year classes were closed and the students assigned jobs as interns or nurses…. Slide22:  …The public health departments distributed gauze masks to be worn in public. Stores could not hold sales, funerals were limited to 15 minutes. Some towns required a signed certificate to enter and railroads would not accept passengers without them. Those who ignored the flu ordinances had to pay steep fines enforced by extra officers. Bodies piled up as the massive deaths of the epidemic ensued. Besides the lack of health care workers and medical supplies, there was a shortage of coffins, morticians and gravediggers. The conditions in 1918 were not so far removed from the Black Death in the era of the bubonic plague of the Middle Ages. Slide23:  One-quarter of the US were infected with this H1N1-influenza. An estimated 675,000 Americans died during the pandemic, ten times as many as in the world war. Slide24:  Crude Death Rate for Infectious Diseases,USA Slide25:  "The 1918 has gone…….unfortunately a year in which developed a most fatal infectious disease causing the death of hundreds of thousands of human beings.” Journal of the American Medical Association, December Edition,1918: Slide26:  Influenza ?Gone 1957-58, "Asian flu," [A (H2N2)], caused about 70,000 deaths in the United States. First identified in China in late February 1957, the Asian flu spread to the United States by June 1957. 1968-69, "Hong Kong flu," [A (H3N2)], caused approximately 34,000 deaths in the United States. This virus was first detected in Hong Kong in early 1968 and spread to the United States later that year. Type A (H3N2) viruses still circulate today. Slide27:  The previous influenza pandemics How did they occur? Slide28:  Avian and human HAs differ in their ability to bind to different forms of sialic acids and avianHAs bind poorly to the sialic acid receptors prevalent in the human respiratory tract. These different receptor affinities act as a barrier to cross-species infection. Before a virus with an avian HA can replicate and spread efficiently in humans, some adaptation of the HA binding affinity is necessary. Slide29:  A pandemic virus faces the twin challenges of being antigenically ‘new’ to its host, while being supremely well adapted to it. This challenge was met in 1957 and 1968 by reassortment: combining surface proteins novel to humans with human-adapted internal proteins. Slide30:  Sequencing of an avian H3 HA gene (A/duck/Ukraine/1/63) isolated in 1963 demonstrated its close molecular similarity to the HA gene of A/Aichi/2/68, the latter being an example of the 1968 pandemic virus. 1605 of 1765 nucleotides (91%) are identical between the two viruses, while 542 of 566 amino acids (96%) are identical. Ref.:Reid AN & Taubenberger JK Journal of General Virology 2003;84, 2285–2292 Slide31:  Like the 1968 H3 pandemic strain, the HA of the 1957 pandemic is closely related also to avian H2 sequences. When the 1957 H2 sequences are compared as a group to avian HA sequences, only four amino acids differ consistently between the human and avian groups. Phylogenetic analyses indicate that the gene was acquired from an avian source shortly before 1957.It appears that the avian source was Eurasian. Ref.:Reid AN & Taubenberger JK Journal of General Virology 2003;84, 2285–2292 Slide32:  Reassortment Slide33:  The influenza A virus is capable of enormous genetic variability, both by continuous, gradual mutation and by reassortment of gene segments between viruses. Ref.:Reid AN & Taubenberger JK Journal of General Virology 2003;84, 2285–2292 Slide34:  Reassortment in Pigs:?Evidence? In 1993, reassortant viruses presenting the internal viral protein genes of H1N1 avian virus and the surface glycoprotein genes of H3N2 human virus were isolated in pigs ; thereafter, this reassortant was isolated from children in the Netherlands.Tollis M & di Trani L. The Veterinary Journal 2002;164:202 Slide35:  H5N1 in pigs?: Hong Kong “…in 4 years each of virus surveillance of pigs before and after 1997, no H5N1 virus was isolated raising the question of the susceptibility of the pig to infection by avian H5 subtype virus.” Shortridge et al. J Applied Microbiol 2003, 94, 70S–79S Slide36:  H5N1 in pigs? - China More recently, as part of an ongoing epidemiological surveillance programme, 1.1 million samples including 4447 from pigs in China have been collected and analysed between April and August 2004 from 10 provinces including Fujian, and no infection from H5N1 has been detected in pigs. ---ProMED-mail Slide37:  AVIAN INFLUENZA - EASTERN ASIA (56): INDONESIA, PIGS The 1st survey was conducted on 23 Feb 2005 in a farm in Babat village, Legok subdistrict, where 5 out of 10 nasal swabs were positive and the subtype involved was identified as H5N1. Not a single pig has shown clinical signs of avian influenza. A ProMED-mail post :1 Jun 2005 Slide38:  H5N1: ?Cats In Feb 2004, Veterinarian Teeraphon Sirinaruemit announced in Bangkok that H5N1 bird flu had been found in at least 2 domestic cats and a white tiger. Autopsies and virus tests were performed on 3 cats at Kasetsart University's animal hospital. 2 cats tested positive for the H5N1 virus. They were among 15 cats owned by a Thai man living near an infected chicken farm in Nakorn Pathom. The white tiger affected by H5N1 was housed at the Khao Khiew private zoo in Chonburi. Tests confirmed that H5N1 had killed a rare Thai clouded leopard from the same zoo in January 2004. Slide39:  Science 2004:306:241 Slide40:  Three cats which were inoculated with H5N1 viruses developed fever on day 1 post inoculation. They had protrusion of the third eyelids, conjunctivitis and labored breathing on day 2. One cat died at day 6 from H5N1 pneumonia. The illness also developed in 2 sentinel cats placed in the same cage as these 3 cats. In contrast, 3 cats inoculated with H3N2 viruses showed no signs of infection or disease. Slide41:  In addition, 3 cats fed on H5N1 infected chicks also developed clinical signs, excreted H5N1 viruses and had pulmonary pathologic changes similar to cats inoculated intra-tracheally with H5N1 viruses. Slide43:  In an unpublished study carried out last year by the National Institute of Animal Health in Bangkok, researchers led by virologist Sudarat Damrongwatanapokin tested 629 village dogs and 111 cats in the Suphan Buri district of central Thailand. Out of these, 160 dogs and 8 cats had antibodies to H5N1. Slide44:  H5N1: Do they need reassortment? Slide46:  Phylogenetic analysis of the 1918 virus genome sequence indicates that, unlike what occurred for the viruses that caused the 1957 and 1968 pandemics, the 1918 H1N1 virus was derived entirely from an avian source. Slide49:  Science 7 October 2005: Vol. 310. no. 5745, pp. 77 - 80 DOI: 10.1126/science.1119392 Characterization of the Reconstructed 1918 Spanish Influenza Pandemic Virus Terrence M. Tumpey, Christopher F. Basler, Patricia V. Aguilar, Hui Zeng, Alicia Solórzano, David E. Swayne, Nancy J. Cox, Jacqueline M. Katz, Jeffery K. Taubenberger, Peter Palese, Adolfo García-Sastre Slide51:  Until recently, there was no evidence that humans could be infected by a wholly avian influenza virus. However, in the 1997 HongKong outbreak, although these H5N1 viruses were very poorly transmissible, if at all, their detection indicates that humans can be infected with wholly avian influenza virus strains. Slide54:  a sequence of 709 bases (nucleotides 480 to 1189) of the hemagglutinin gene was the same in the viruses from the mother and aunt, except for one synonymous substitution at nucleotide 936. Slide55:  Sequencing of RT-PCR products from the mother and the aunt revealed that all the viral genes were avian and were closely related to other H5N1 sequences in Thailand Slide56:  “.the picture emerged that the H5 haemagglutinin gene was derived from a precursor H5N1 virus from geese, A/Goose/Guangdong/1/96, the genes encoding the internal proteins were from an A/Quail/HK/G1/97-like H9N2 or A/Teal/HK/W312/97-like H6N1 virus each from quail and the N1 gene was also of quail H6N1 origin, the quail possibly being an avian mixing vessel for the necessary re-assortment events. Thus the H5N1/97 virus was a triple avian virus re-assortant that had become highly pathogenic for chicken and humans in the process of its generation Ref.:Shortridge et al J Applied Microbiol 2003,94,70S–79S Slide57:  H5N1 changes From 1997 through 2001, the HA on the various H5N1 genotypes remained antigenically homogeneous, but in 2002 it underwent marked antigenic drift to be highly pathogenic for ducks and other aquatic birds, a property rarely found in nature. In early February 2003, H5N1 virus reemerged in a family in Hong Kong. The father died and the son recovered. the strain was antigenically and molecularly similar to the antigenically drifted strain that was highly pathogenic for ducks and chickens. Ref.:Guan, Y et al. Proc. Natl. Acad. Sci. USA 2004;101:8156–8161. Slide58:  H5N1 changes The H5N1 virus currently circulating in Asia is genetically similar to the Z genotype that became dominant in Hong Kong in 2003, but it has drifted antigenically. Ref.:Lipatov AS et al. J Virol 2004; 78:8951-8959 Slide59:  Fatal Avian Influenza A (H5N1) in a Child Presenting with Diarrhea Followed by Coma de Jong M. D. et al. NEJM 2005;352:686-691 a fatal case of influenza H5N1, diagnosed by isolating the virus from cerebrospinal fluid, fecal, throat, and serum specimens, in a 4-year old boy who presented with severe diarrhea but no apparent respiratory illness. The CXR became abnormal on day 6 of his illness. Two weeks earlier his 9- year old sister had died of a similar illness.Epidemiologic, investigations did not reveal exposure to ill poultry except that his sister swam regularly in the nearby canal. Slide60:  The currently circulating strain of H5N1 has also been shown to cause encephalitis in ducks, mice, tigers and leopards. Slide61:  EID 2004;10:1322-4 39 yr. old woman with Hx of dead chicken exposure, had symptoms of fever, diarrhea and n/v without respiratory illness for 1 week. Pneumonia developed on hospital day 5. At that time her WBC was 2200 with normal platelet count. She died on the next day. Slide62:  ? Influenza should be included in the D/Dx for patients with diarrhea, particularly if they have a history of exposure to sick or dead poultry. Slide63:  Is the influenza pandemic inevitable? Slide64:  H5N1 changes:?Leading to pandemics? It is unknown whether these changes will result in the establishment of an H5N1 lineage in humans, but the very large number of infected poultry in many countries and the rising number of infected humans increase this likelihood. Slide65:  “Based on historical patterns, influenza pandemics can be expected to occur, on average, three to four times each century. In the 20th century, the great influenza pandemic of 1918–1919, which caused an estimated 40 to 50 million deaths worldwide, was followed by pandemics in 1957–1958 and 1968–1969. Experts agree that another influenza pandemic is inevitable and possibly imminent.” WHO. Slide66:  It is sobering to realize that in 1968, when the most recent influenza pandemic occurred, the virus emerged in a China that had a human population of 790 million, a pig population of 5.2 million, and a poultry population of 12.3 million; today, these populations number 1.3 billion, 508 million, and 13 billion, respectively. Similar changes have occurred in the human and animal populations of other Asian countries, creating an incredible mixing vessel for viruses. Given this reality, as well as the exponential growth in foreign travel during the past 50 years, we must accept that a pandemic is coming. - Osterholm M. T. Slide67:  http://www.fao.org/ag/againfo/foto/poultry-south-asia.gif Slide68:  http://europa.eu.int/comm/health/ph_threats/com/Influenza/ai_jan_mar_en.htm Slide69:  EID 2005;11:1164-1672 Before 2004, Thailand produced ≈1 billion chickens per year. >400,000 persons were employed in the poultry industry Slide72:  During the 1st phase of epidemic(P1), >100,000 tubes of swab samples were tested for avian influenza virus. During P2, ≈130,000 tubes of swab samples and 72,000 serum samples were collected for diagnosis. Slide74:  Type of Poultry infected Backyard chickens (56%) Ducks (27%) Broilers (6%) Layers (5%) Quails (2%) Other birds (3%). ลักษณะฟาร์ม รอบ 1 และรอบ 2:  ลักษณะฟาร์ม รอบ 1 และรอบ 2 รอบ 1 : 23 ม.ค.- 21 เม.ย. 47, รอบ 2 : 3 ก.ค. - 11 ส.ค. 2547 Methods by which virus was transmitted among the 19 cases in the Republic of Korea :  Methods by which virus was transmitted among the 19 cases in the Republic of Korea สพ.ญ. อุษา เชษฐานนท์ Slide86:  Early detection of the epidemic:?Possible? Slide87:  Lancet 2004; 363: 587–93 Slide89:  “Based on the virology update of March 14, 2003, when 19 confirmed cases of A/H7 were discussed, as well as the first confirmed contact transmission, preventive measures were stepped up. Immediate treatment with oseltamivir was recommended for all new conjunctivitis cases, and a prophylactic regimen of oseltamivir (75 mg daily) was started for all people handling potentially infected poultry, to be continued for 2 days after last exposure.” Slide90:  “Despite decisions being made very quickly, a sobering conclusion is that by the time full prophylactic measures were reinforced (1 week after the first confirmation of human infection), more than 1000 people from all over the Netherlands and from abroad had been exposed. Therefore, if a variant with more effective spreading capabilities had arisen, containment would have been very difficult.” Slide91:  “We see this outbreak as providing strong support for the need for pretested pandemic preparedness plans, including the stockpiling of essential control components such as vaccines and antivirals.” Koopman M et al. Lancet 2004;363: 587 Slide92:  EID 2003;9:531-538 The nonintervention scenario of an influenza pandemic with a gross attack rate of 30% and no interventions available could lead to as many as 10,000 influenza-related hospitalizations and >4,000 deaths. Slide93:  Influenza Vaccination Scenario: Two possible strategies are considered: 1) vaccination of risk groups including persons >65 years of age and healthcare workers and 2) vaccination of the total population. Pneumococcal Vaccination Scenario: 3) vaccination of influenza risk groups (including those >65 years of age) Neuraminidase Inhibitors Scenario Slide96:  “Production of an egg-based vaccine would take a minimum of six months, and given the capacity of all the current international vaccine manufacturers, supplies during those next six months would be limited to fewer than a billion monovalent doses. Since two doses may be required for protection, we could vaccinate fewer than 500 million people — approximately 14 percent of the world's population .” Osterholm M. T. Preparing for the next pandemic NEJM 2005;352:1839-1842 Slide106:  Scenario of the epidemic Slide107:  When? Slide111:  Where did they begin? Slide112:  Poultry Farms Slide115:  Lancet 2004; 363: 587–93 Slide116:  Three outbreaks of influenza A (H5N1)disease had occurred among chicken flocks on 3 poultry farms in the New Territories of Hong Kong during March–May 1997 and preceded illness in the child which occurred in May 1997. Investigations could not establish a direct link between the index case and exposure to the infected poultry. –JID 1999; 180: 505–8 Slide117:  From June–October 1997, no new poultry outbreaks or infections were identified, despite active serosurveys of local poultry farms. However, in November and December, new human H5N1 cases were detected during the same time period when influenza A (H5N1) viruses were cultured from both live chickens and chicken feces obtained from retail poultry stalls and wholesale poultry markets in Hong Kong. -–JID 1999; 180: 505–8 Slide118:  Poultry Markets Slide119:  Risk Factors for H5N1- Influenza A OR (95% CI) Exposed to live poultry in market* 4.5 (1.2–21.7) Consumed poultry in restaurant 2.9 (0.6-14.9) Consumed poultry organs or poultry 0.6 (0.0-7.5) Live birds in home 1.4 (0.3-6.4) Anyone in flat had influenza-like illness 0.8 (0.2-2.8) Contact with known H5N1 case 1/13 vs. 0/35 P=NS Ref.:JID 1999; 180: 505–8 Slide120:  Birds that survive infection excrete virus for at least 10 days, orally and in faeces, thus facilitating further spread at live poultry markets and by migratory birds. The virus can survive, at cool temperatures, in contaminated manure for at least three months. (WHO: Avian influenza FAQs) Slide121:  A retrospective cohort study of risk of H5N1- influenza infection among 1525 poultry workers (PWs) and among 293 government workers (GWs) involved in the 4 days -poultry slaughter. -Among GWs, 3% were seropositive, and 1 seroconversion was documented. -Among PWs, 10% had anti–H5 antibody. JID 2002;185:1005–10 Slide122:  Risk factors for H5 antibody among poultry workers Odd ratio (95% CI) Touching poultry 5.8 (0.9-113.6) Butchering poultry* 3.1 (1.6-5.9) Feeding poultry* 2.4 (1.4-4.1) Collecting eggs 1.2 (0.6-2.2) Cleaning poultry stalls 1.6 (0.9-2.7) Touching poultry intestines 1.7 (0.9-2.9) Ref.: JID 2002;185:1005–10 Slide124:  Live poultry for sale, That Khe market. Northest Vietnam Slide125:  Management of wet market: HongKong Experience Slide126:  “Ducks and geese (the original source of influenza viruses), were eliminated from the markets and sold chilled. Subsequently, quails, the newly recognised host susceptible to all subtypes of influenza and a potential intermediate host,were removed. A clean day every month when all markets are emptied simultaneously and cleaned was introduced. Despite these additional changes H5N1 viruses reappeared in 2002 and 2003. Slide127:  ....Introduction of a second clean day every month in live poultry markets and the use of inactivated H5N1 vaccine on poultry farms in Hong Kong are further measures being taken to keep H5N1 out of live-poultry markets” Per cent isolations of H5N1 from aquatic and terrestrial poultry samples in Hong Kong SAR and southern China from 2000 to 2004 :  Per cent isolations of H5N1 from aquatic and terrestrial poultry samples in Hong Kong SAR and southern China from 2000 to 2004 Li, K. S., Y. Guan, et al. (2004). "Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia." Nature 430(6996): 209-213. เริ่มนโยบายใช้วัคซีน สพ.ญ. อุษา เชษฐานนท์ Slide131:  The spreading of influenza into the communities Slide133:  The influenza pandemic of 1918-1919: USA “The first wave of influenza appeared early in the spring of 1918 in Kansas and in military camps throughout the US. ......” Slide135:  EID 2004;10:210-216 Slide136:  During March 8–April 3, 2003, almost all (96%) probable SARS patients reported close contact with a known SARS patient. However, during the peak of the epidemic (April 4–May 4), the percentage of probable SARS patients who reported no contact with another SARS patient and who were not healthcare workers rose to 42%. Slide137:  Second Wave of Epidemic: in the Hospitals Slide138:  Nosocomial transmission was the primary acceleration of SARS infections accounting for 72% of cases in Toronto and 55% of probable cases in Taiwan. Ref.: Booth CM et al. JAMA 2003;289:2801-9 CDC. MMWR 2003;52:461-6 Slide139:  Where in the hospital did the outbreak occur? Slide140:  EID 2004;10:782-788 Thirty- one cases of SARS occurred after exposure in the emergency room of the National Taiwan University Hospital. Slide141:  Crit Care Med 2005;33:S53-S60 Four hospitals had major nosocomial outbreaks of SARS. Three of these outbreaks occurred in ICUs. Slide142:  “Within 18 hrs of presentation, the patient was admitted to the ICU and 3 hrs later was placed in an isolation room.This 21-hr period of unprotected contact led to128 cases of SARS resulted from transmission of the virus within this hospital. (42% HCWs, 28% patients or visitors, and 30% household contacts).” Slide143:  “Another patient was transferred to the ICU of a second community hospital.He was treated with noninvasive ventilation for 2 days and then mechanically ventilated for 11 days before the recognition of SARS.In addition to the patient’s wife, 14 further cases of SARS resulted from transmission within this ICU (10 hospital staff and four patients). Slide144:  “Mass voluntary quarantine of people exposed to the hospital included more than 5,000 people.” Slide145:  73 ICU beds were closed during various phases of the SARS outbreak, representing 38% of the tertiary-care university medical–surgical ICU beds and 33% of the community ICU beds in Toronto. Ref.: Booth CM & Stewart TE. Crit Care Med 2005;33:S53-S60 Slide146:  EID 2004;10:25-31 Through June 2003, a total of 2,521 patients with probable cases of SARS were hospitalized in Beijing. The outbreak peaked during the 3rd and 4th weeks in April, when hospitalizations for probable SARS exceeded 100 cases for several days, Slide147:  SARS occurred in healthcare workers in >70 hospitals throughout Beijing, and clusters of >20 probable SARS cases among healthcare workers occurred in four Beijing hospitals. Slide148:  Schools were closed, travel was restricted, the community was educated about seeking care at designated sites, and temperatures were monitored at frequent check points. More than 60 fever clinics were established. Slide149:  By June 19, 2003, a total of 30,172 people who had had close contact with probable or suspected SARS case-patients had been quarantined. Slide150:  Local shortages of isolation rooms, intensive care facilities, and hospital beds were addressed by dispatching specially equipped ambulances to transfer SARS patients to designated facilities. An anticipated shortage of hospital beds for care and isolation of SARS patients prompted authorities to construct a new 1,000-bed hospital in 8 days. Slide151:  EID 2005;11:278-282 Slide152:  Pandemics: Social effects “What if the next pandemic were to start tonight? If it were determined that several cities in Vietnam had major outbreaks of H5N1 infection associated with high mortality, there would be a scramble to stop the virus from entering other countries by greatly reducing or even prohibiting foreign travel and trade. The global economy would come to a halt.... Slide153:  ....We have no detailed plans for staffing the temporary hospitals that would have to be set up in high-school gymnasiums and community centers — and that might need to remain in operation for one or two years. Health care workers would become ill and die at rates similar to, or even higher than, those in the general public. Judging by our experience with the severe acute respiratory syndrome (SARS), some health care workers would not show up for duty.” Osterholm M. T. Preparing for the next pandemic NEJM 2005;352:1839-1842 Slide161:  What can we do with the poultry? Slide162:  Conceptual Framework Slide163:  Animals H5N1 Water Poultry Man infection Slide164:  Animals H5N1 Water Poultry Man infection Culling Slide165:  The culling of infected poultry is the time-honored method of achieving this goal. This strategy was successful in Hong Kong in 1997 and in The Netherlands in 2003, and time will tell whether it will be successful in Asia in 2004- 2005. Slide166:  EID 2005;11:1164-1672 Before 2004, Thailand produced ≈1 billion chickens per year. >400,000 persons were employed in the poultry industry Slide167:  According to the Thai Broiler Processing Exporters Association, approximately 800 millions chicken are produced every year in Thailand with more than 400,000 people employed in this industry. Ref.:Sirimongkolkasem. Proceedings of the 28th annual conference of the Thai Medical Veterinary Association,Bangkok 2003 Slide172:  “ in 1968, when the most recent influenza pandemic occurred, the virus emerged in a China that had a human population of 790 million, a pig population of 5.2 million, and a poultry population of 12.3 million; today, these populations number 1.3 billion, 508 million, and 13 billion, respectively.” - Osterholm M. T. Slide173:  http://www.fao.org/ag/againfo/foto/poultry-south-asia.gif Slide174:  http://europa.eu.int/comm/health/ph_threats/com/Influenza/ai_jan_mar_en.htm Slide175:  Animals H5N1 Water Poultry Man infection ?Vaccine Slide176:  Poultry Vaccine??? Slide177:  Major limitations to vaccine use include interference with eradication efforts (inability of distinguishing vaccinated from infected birds).and inadequate quality of vaccines . Moreover, it has been proven that chickens immunized against HPAI viruses may excrete virulent variants following challenge with live virus (Hinshaw et al., 1990). Slide182:  “The risk of generating antigenic variants possessing a selective advantage in the presence of low levels of antibodies can very likely be the consequence of the use in the field of poorly immunogenic vaccines.” Slide184:  One of the puzzling aspects of the avian influenza virus H5N1 outbreak in Hong Kong in 1997 was that most chickens in the poultry markets appeared to be healthy, despite the presence of lethal H5N1 virus in 20% of the birds. Slide185:  Seo and Webster showed that prior infection with H9N2 virus before chickens were transferred to the Hong Kong markets protected them from lethal infection with H5N1 influenza viruses in the Hong Kong markets in 1997 but permitted virus shedding in the feces,thus created conditions that masked the lethal effects of the H5N1 virus and permitted transmission to humans. Slide188:  VIRUS WAS RECOVERED LESS FREQUENTLY FROM THE CLOACA OF VACCINATED CHICKEN (<20%) WHEN COMPARED TO THE SHAM AND H7 GROUPS (60%).THIS SUGGESTED THAT VACCINATION HAD THE POTENTIAL TO REDUCE ENVIRONMENTAL CONTAMINATION WITH VIRUS AND PREVENT SUBSEQUENT BIRD TO BIRD TRANSMISSION.PREVIOUSLY, THE RECOMBINANT FOWLPOX VIRUS VACCINE WAS SHOWN TO REDUCE CONTACT TRANSMISSION OF A HPAI H5 VIRUS FROM MEXICO. Slide190:  A recombinant fowlpox virus vaccine (Vector-HA) containing a cDNA copy of the hemagglutinin gene of A/turkey/Ireland/ 1378/83 (H5N3) (vFP89, Merial-Select Inc., Gainesville, GA) was used. Slide193:  Poultry Vaccination: Mexico Slide194:  In Mexico, an vaccination program with over 1.3 billion doses of inactivated vaccine and 850 million doses of recombinant fowlpox has been used since January 1995 . Highly pathogenic avian influenza H5N2 has been eradicated (last isolate was in June 1995), but low pathogenic avian influenza H5N2 still circulates in central Mexico. Similarly, the vaccination policy pursued in Pakistan does not appear to have resulted in eradication of the causative agent. David Swayne http://www.promedmail.org 7 Mar 2005 Slide195:  Poultry Vaccination: Hong Kong Slide196:  “Ducks and geese (the original source of influenza viruses), were eliminated from the markets and sold chilled. Subsequently, quails, the newly recognised host susceptible to all subtypes of influenza and a potential intermediate host,were removed. A clean day every month when all markets are emptied simultaneously and cleaned was introduced. Despite these additional changes H5N1 viruses reappeared in 2002 and 2003. Slide197:  ....Introduction of a second clean day every month in live poultry markets and the use of inactivated H5N1 vaccine on poultry farms in Hong Kong are further measures being taken to keep H5N1 out of live-poultry markets” Per cent isolations of H5N1 from aquatic and terrestrial poultry samples in Hong Kong SAR and southern China from 2000 to 2004 :  Per cent isolations of H5N1 from aquatic and terrestrial poultry samples in Hong Kong SAR and southern China from 2000 to 2004 Li, K. S., Y. Guan, et al. (2004). "Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia." Nature 430(6996): 209-213. เริ่มนโยบายใช้วัคซีน สพ.ญ. อุษา เชษฐานนท์ Slide199:  Despite the widespread emergence of H5N1 influenza virusesin poultry in many countries in Asia in early 2004, there were no outbreaks of H5N1 influenza in poultry or humans in Hong Kong during this time. This lack of outbreaks probably reflects changes in live poultry marketing practices since 1997 in Hong Kong , improvement in biosecurity, and the use of inactivated H5N1 vaccine on poultry farms in the region . Ref.:Lipatov AS et al. J Virol 2004; 78:8951-8959 Slide200:  These farms also utilize unvaccinated sentinel birds in each flock to ensure that vaccinated birds are not shedding transmissible levels of H5N1 virus. While the optimal method of eradication of H5N1 influenza is the culling of poultry when the outbreak is widespread, this course of action may not be possible and the alternative strategy is culling plus vaccination. Ref.:Lipatov AS et al. J Virol 2004; 78:8951-8959 Slide201:  Poultry Vaccination: China Slide202:  Based on the national emergency plan against highly pathogenic avian influenza (HPAI), China has inoculated a total of 2.68 billion birds -- mainly chickens, ducks and geese during February 2004 to January 2005. The objective of China's poultry vaccine is to inactivate the highly pathogenic avian influenza (HPAI) virus H5N2. Explanation on Using Vaccines for the Prevention of Avian Influenza in China (Ministry of Agriculture, March 2005) , unofficial translation by Casey Bean & Zhang Jianping <http://www.promedmail.org> 2 Apr 2005 Slide203:  “the Ministry of Agriculture has carried out regular inoculation supervision and evaluation through sampling serum and pathogen tests among inoculated poultry flocks. Up to now, we have not isolated any H5N1 virus from our inoculated poultry flocks.” Explanation on Using Vaccines for the Prevention of Avian Influenza in China (Ministry of Agriculture, March 2005) , unofficial translation by Casey Bean & Zhang Jianping <http://www.promedmail.org> 2 Apr 2005 Slide204:  3 avian influenza vaccines were approved for use by the Chinese Ministry of Agriculture between Dec 2003 and Jan 2005. (a H5N28 inactivated vaccine , a reverse genetic produced recombinant H5N1 inactivated vaccine and a recombinant fowl pox H5N1 virus live vaccine.) <http://www.promedmail.org> 2 Apr 2005 Slide205:  In the United States,vaccines have been used in some programs to control mildly pathogenic avian influenza during sporadic outbreaks in turkeys. From 1979 to 1997, 22 million doses of inactivated vaccine were used in Minnesota, the major geographic location of mildly pathogenic avian influenza outbreaks within the U.S.. Slide206:  A few inactivated whole avian influenza vaccines and a recombinant fowlpox-avian influenza H5 hemagglutinin vaccine have been licensed by the US Department of Agriculture (USDA). Use of the H5 and H7 vaccines requires approval by the federal government and can only be part of an offcial USDA avian influenza disease control program. Individually, avian influenza vaccines are licensed by the USDA and any changes, such as replacing the virus strain in the vaccine, requires a new license application. Slide207:  In addition, live recombinant vaccines are required to have a risk analysis and environmental assessment, in accordance with the National Environmental Policy Act, prior to licensure. Therefore, the initial development or the changing of avian influenza vaccines for poultry is a costly, 2-3 year process. Slide208:  WHO: China Denies Reports of Human Cases of H5N1 Influenza Infection . "Up to 26 May 2005, total of over 1000 birds at a nature reserve in the western province of Qinghai. have been found dead." Jia Youling, director of the Ministry of Agriculture's veterinary bureau, said at a press conference. The dead birds include wild geese, gulls and cormorants and wild ducks. A ProMED-mail post: 28 and 25 May 2005 Slide216:  ?Human vaccine vs. ?Pre-exposure anti-viral prophylaxis Slide217:  Conceptual Framework Slide218:  Organisms Infection Disease Death . . . 1 2 3 Slide219:  Organisms Infection Disease Death . . . 1 2 3 ?Vaccine? Slide220:  EID 2003;9:531-538 The nonintervention scenario of an influenza pandemic with a gross attack rate of 30% and no interventions available could lead to as many as 10,000 influenza-related hospitalizations and >4,000 deaths. Slide221:  Influenza Vaccination Scenario: Two possible strategies are considered: 1) vaccination of risk groups including persons >65 years of age and healthcare workers and 2) vaccination of the total population. Pneumococcal Vaccination Scenario: 3) vaqccination of influenza risk groups (including those >65 years of age) Neuraminidase Inhibitors Scenario Slide224:  “Production of an egg-based vaccine would take a minimum of six months, and given the capacity of all the current international vaccine manufacturers, supplies during those next six months would be limited to fewer than a billion monovalent doses. Since two doses may be required for protection, we could vaccinate fewer than 500 million people — approximately 14 percent of the world's population .” Osterholm M. T. Preparing for the next pandemic NEJM 2005;352:1839-1842 Slide225:  Organisms Infection Disease Death . . . 1 2 3 Pre-exposure Prophylaxis? Slide226:  What shall we do in case that an outbreak occurs? Giving Tamiflu? Slide227:  JAMA 2001;285:748 Slide228:  Participants: Three hundred seventy-seven index cases(ICs), 163 (43%) of whom had laboratory confirmed influenza infection, and 955 household contacts (aged >12 years) of all ICs (415 contacts of influenza-positive ICs). Slide229:  Interventions: Household contacts were randomly assigned by household cluster to take 75 mg of oseltamivir (n=493) or placebo (n=462) once daily for 7 days within 48 hours of symptom onset in the index case. The index cases did not receive antiviral treatment. Slide231:  Results: In contacts of an influenza-positive index case, the overall protective efficacy of oseltamivir against clinical influenza was 89% for individuals (95% CI, 67%-97%; P<001) . Slide232:  NEJM 1999;341:1336 Slide233:  Design:Placebo controlled, double-blind trials at different U.S. sites during the winter of 1997–1998. Methods:1559 healthy, nonimmunized adults were randomly assigned to receive either oral oseltamivir (75 mg given once or twice daily, for a total daily dose of 75 or 150 mg) or placebo for six weeks during a peak period of local influenza virus activity. The primary end point with respect to efficacy was laboratory-confirmed influenza-like illness. Slide234:  Results:For culture-proved influenza, the rate of protective efficacy in the two oseltamivir groups combined was 87 percent (95 percent confidence interval, 65 to 96 percent). The rate of laboratory-confirmed influenza infection was lower with oseltamivir than with placebo (5.3 percent vs. 10.6 percent, P<0.001). Slide236:  Lancet 2004; 364: 759–65 Slide237:  “We identified a neuraminidase mutation in viruses isolated from nine (18%) of the 50 oseltamivir-treated patients. On day 5 or 6, the level of virus shedding was reduced in 18 of 19 patients without resistant viruses and in four of six with resistant viruses.” Slide238:  “Are the oseltamivir-resistant viruses transmissible and pathogenic?.. Generally, neuraminidase mutations have led to viruses with reduced pathogenicity in animal models because the mutations cause defects in an important enzyme. There is no documented transmission of anoseltamivir-resistant virus in human beings, but the frequent emergence of resistance mutations in Kiso’s study suggests that this is only a matter of time.” Anne Moscona. Lancet 2004; 364: 733-734 Slide246:  How to Dx Avianflu? Clinical Clues? Slide247:  Conceptual Framework Slide248:  Organisms Infection Disease Death . . . 1 2 3 Slide249:  Organisms Infection Disease Death . . . 1 2 3 Diagnosis Treatment Slide250:  Hx of exposure to sick or dead poultry. Slide251:  The H5N1virus is highly pathogenic for chickens: all eight chickens inoculated intratracheally with this virus died within 3 days of infection. Ref.: Class ECJ et al. Lancet 1998;351:472 Studies have shown that a single gram of contaminated manure can contain enough virus to infect 1 million birds. WHO:Avian influenza FAQs. Slide252:  N Engl J Med 2005;353:1374-85. Slide254:  Type of Poultry infected Backyard chickens (56%) Ducks (27%) Broilers (6%) Layers (5%) Quails (2%) Other birds (3%). Slide257:  ลักษณะอาการของสัตว์ปีกที่สงสัยว่าเป็นโรคไข้หวัดนก ๑. ตายกะทันหันมากกว่า ๑๐ เปอร์เซ็นต์ ภายใน ๑ วัน ๒. แสดงอาการระบบทางเดินหายใจ เช่น หายใจลำบาก มีน้ำมูก ไซนัสบวม น้ำตาไหล ทยอยตาย ๓.  แสดงอาการระบบประสาท เช่น ชัก คอบิด ทยอยตาย ๔.  ท้องเสีย หรือขนยุ่ง ซึม ไม่กินอาหาร ไข่ลด ไข่ผิดปกติ หงอน เหนียงคล้ำ หรือหน้าแข้งมีจุดเลือดออก ทยอยตาย สพ.ญ. อุษา เชษฐานนท์ Slide258:  ภาพ: ดร.ทวีศักดิ์ ส่งเสริม Slide259:  ภาพ: ดร.ทวีศักดิ์ ส่งเสริม อาการที่พบ รอบที่ 1 และรอบที่ 2:  อาการที่พบ รอบที่ 1 และรอบที่ 2 รอบ 1 : 23 ม.ค.- 21 เม.ย. 47, รอบ 2 : 3 ก.ค. - 11 ส.ค. 2547 ชนิดสัตว์ป่วยรอบ 1 และรอบ 2 :  ชนิดสัตว์ป่วยรอบ 1 และรอบ 2 รอบ 1 : 23 ม.ค.- 21 เม.ย. 47, รอบ 2 : 3 ก.ค. - 11 ส.ค. 2547 Slide262:  ลักษณะอาการของสัตว์ปีกที่สงสัยว่าเป็นโรคไข้หวัดนก 5 กรณีเป็ด / ห่าน มีอาการซึม เบื่ออาหาร ขนยุ่ง หัวบวม หรือตาขุ่น ภาพ: ดร.ทวีศักดิ์ ส่งเสริม Slide263:  ภาพ: ดร.ทวีศักดิ์ ส่งเสริม Slide264:  Jan- Mar = 12 Cases, Central=7, NE=3, North=2 Children=7M:F=8:4 Mean age= 10 (Range=2-58 ) Case fatality= 8/12 (67%) Slide265:  Contact with sick chicken= 7, Odd ratio=11 (95%CI= 2.7-45.4) Contact with dead chicken= 8 Oddratio=9.2(95%CI= 2.3-37.2) Butchered sick chicken= 2 Prepared chicken meat= 3 Stored chicken meat in house=6 Odd ratio=16.7(95%CI= 33.3-84.6) Ref.:Areechokechai D et al. Slide266:  Darin Areechokchai, C. Jiraphongsa, Y. Laosiritaworn, W. Hanshaoworakul, M. O'Reilly Investigation of Avian Influenza (H5N1) Outbreak in Humans --- Thailand, 2004 MMWR Morb Mortal Wkly Rep. 2006;55 Suppl 1:3-6. Slide268:  Avian Influenza: Incubation Period Slide273:  Darin Areechokchai, C. Jiraphongsa, Y. Laosiritaworn, W. Hanshaoworakul, M. O'Reilly Investigation of Avian Influenza (H5N1) Outbreak in Humans --- Thailand, 2004 MMWR Morb Mortal Wkly Rep. 2006;55 Suppl 1:3-6. Slide275:  Uncomplicated Severe cases WBC count 12·5 +/-4·34 3+/-1·58 Presence of lymphopenia 0 7 Impaired liver function test 1 5 Impaired renal function test 0 3 Death 0 5 Lancet 1998; 351: 467–71 Slide277:  MMWR 2004;53:100 “On admission, clinically apparent pneumonia with chest radiograph changes was observed in all 5 patients, with patchy infiltrates in four and interstitial infiltrates in one.” . Slide278:  Fatal Avian Influenza A (H5N1) in a Child Presenting with Diarrhea Followed by Coma de Jong M. D. et al. NEJM 2005;352:686-691 a fatal case of influenza H5N1, diagnosed by isolating the virus from cerebrospinal fluid, fecal, throat, and serum specimens, in a 4-year old boy who presented with severe diarrhea but no apparent respiratory illness. The CXR became abnormal on day 6 of his illness. Two weeks earlier his 9- year old sister had died of a similar illness. Epidemiologic, investigations did not reveal exposure to ill poultry except that his sister swam regularly in the nearby canal. Slide279:  The currently circulating strain of H5N1 has also been shown to cause encephalitis in ducks, mice, tigers and leopards. Slide280:  EID 2004;10:1322-4 39 yr. old woman with Hx of dead chicken exposure, had symptoms of fever, diarrhea and n/v without respiratory illness for 1 week. Pneumonia developed on hospital day 5. At that time her WBC was 2200 with normal platelet count. She died on the next day. Slide281:  ? Influenza should be included in the D/Dx for patients with diarrhea, particularly if they have a history of exposure to sick or dead poultry. Slide282:  How to Dx Avianflu? Laboratory Tests Slide283:  Influenza Antigen Tests Direct immunofluorescence with the DAKO influenza A -specific reagent was positive for 7/13 specimens and led to rapid diagnosis in 5/8 patients examined. 74 of 81 specimens culture-positive for non-H5 influenza A were also positive . Enzyme immunomembranefilter assay (Directigen Flu A) was positive in the initial specimens of 6/7 patients and in 9/11 specimens. Both assays were not subtype,specific. Lancet 1998; 351: 467–71 Slide284:  H5N1- Virus RT-PCR The RT-PCR assay was positive for the initial specimens of all seven patients tested and in 10 of 11 specimens overall. None of the 44 specimens culture-positive for other subtypes of influenza A or the 145 specimens from patients culture-negative for influenza A were reactive in the RT-PCR. Lancet 1998; 351: 467–71 Slide285:  Darin Areechokchai, C. Jiraphongsa, Y. Laosiritaworn, W. Hanshaoworakul, M. O'Reilly Investigation of Avian Influenza (H5N1) Outbreak in Humans --- Thailand, 2004 MMWR Morb Mortal Wkly Rep. 2006;55 Suppl 1:3-6. Slide296:  How to Rx Avianflu? Slide297:  Conceptual Framework Slide298:  Organisms Infection Disease Death . . . 1 2 3 Slide299:  Organisms Infection Disease Death . . . 1 2 3 Diagnosis Treatment Slide300:  Avian Influenza: Mortality As of February 9, 2004, a total of 23 laboratory-confirmed human cases of influenza A (H5N1)had been reported in Thailand and Vietnam. In 18 (78%) of these cases, the patients died.. MMWR 2004,53:100 Slide301:  Amantadine was given to eight patients between 1 and 7 days (median 3) after admission. Despite intensive-care support, five patients developed multiple organ dysfunction syndrome and died. Lancet 1998; 351: 467–71 Genetic sequencing of A(H5N1) virus samples from human cases in Vietnam show antiviral resistance to amantadine and rimantadine, The remaining two antivirals (oseltamavir and zanamavir) should still be effective against this strain of H5N1. CDC: Avian Influenza (Bird Flu) Outbreak . Jan 30, 2004 Slide303:  Influenza neuraminidase is essential for viral replication. Through cleaving of terminal sialic-acid residues from glycoproteins, this enzyme facilitates the release of new virus particles from infected cells, prevents virus aggregation, and promotes viral passage through respiratory mucus. Inhibition of neuraminidase enzymatic action by antibody, mutation, or chemicals causes virus particles to aggregate at the cell surface and with each other. Slide304:  Use of the Oral Neuraminidase Inhibitor Oseltamivir in Experimental Human Influenza Randomized Controlled Trials for Prevention and Treatment Heyden FG et al JAMA 1999;282:1240 Slide305:  The subjects were isolated in individual hotel rooms 1 day before inoculation until 8 days after inoculation. They were inoculated by intranasal drops with influenzaA /Texas /36/91(H1N1) virus. In the prophylaxis study,Oseltamivir administration began 26 hours prior to viral inoculation and continued for 5 days. In the treatment study, administration began at 28 hours after inoculation and continued for 5 days Slide306:  Results:  In the prophylaxis study, 8 (67%) of 12 placebo and 8 (38%) of 21 oseltamivir recipients became infected (P=.16; efficacy, 61%); 6 (50%) placebo compared with 0 oseltamivir recipients shed virus (P<.001; efficacy, 100%), and 33% of placebo but no oseltamivir recipient had infection-related respiratory illness (P<.01). Slide307:  Results :In the treatment study (n=69), the median (IQR) duration of viral shedding with therapy was reduced from 107 (83-131) to 58 (35-59) hours (P=.003). Oseltamivir treatment also reduced symptom scores (median [IQR] score-hours, 225 [97-349] vs 400 [189-645]; P=.05), Slide310:  Results: Duration of illness was significantly shorter by 29 h (25% reduction, median duration 87·4 h [95% CI 73·3–104·7], p=0·02) with oseltamivir 75 mg and by 35 h (30%, 81·8 h [68·2–100·0], p=0·01) with oseltamivir 150 mg than with placebo (116·5 h [101·5–137·8]). Slide311:  Results: Cough resolved a median of 24 h and 37 h earlier in the oseltamivir 75 mg and 150 mg groups, respectively, compared with placebo. The time to become afebrile (temperature <37·2ºC) was also significantly shorter. Slide312:  Efficacy and Safety of the Oral Neuraminidase Inhibitor Oseltamivir in Treating Acute Influenza: A Randomized Controlled Trial Treanor JJ et al JAMA 2000;283:1016 Participants:  A total of 629 healthy nonimmunized adults aged 18 to 65 years with febrile respiratory illness of no more than 36 hours' duration. Slide313:  The duration of illness was reduced by more than 30% with oseltamivir, 75 mg twice daily (median, 71.5 hours; P<.001), compared with placebo (median, 103.3 hours). Severity of illness was reduced by 38% (median score, 597 score-hours; P<.001) with oseltamivir, 75 mg twice daily, vs placebo (median score, 963 score-hours). Slide314:  Oseltamivir recipients returned to usual activities 2 to 3 days earlier than placebo recipients (P=<05). Secondary complications such as bronchitis and sinusitis occurred in 15% of placebo recipients compared with 7% of combined oseltamivir recipients (P = .03). Slide315:  Nausea and vomiting occurred more frequently in both oseltamivir groups (combined, 18.0% and 14.1%, respectively; P = .002) than in the placebo group (7.4% and 3.4%; P<.001). Slide316:  A double- blind, randomized, placebo- controlled multicenter study of oseltamivir phosphate for treatment of influenza infection in China. Longyun L et al. Chin Med J 2003;116(1):44-48  134 oseltamivir(75 mg. bid x 5d. ) vs. 139 placebo (within 36 hrs. after onset of illness) Slide317:  The median durations of fever and myalgia was 27. 9 h and 35. 5 h in the oseltamivir group, which were significantly shorter than the 51. 5 h and 36. 0 h in placebo group (P=0. 0001 and 0. 0361, respectively) Slide318:  The incidence of secondary complications (predefined as bronchitis, pneumonia, sinusitis, tonsillitis, and otitis media) occurred at similar rates in the oseltamivir and placebo groups, 5. 2% (7/134) and 5. 0% (7/139), respectively (P=0. 944) Slide320:  Oseltamivir was administered to five of the patients, four of whom died. Treatment with the drug may have been started too late to be effective. There seemed to be no benefit from the oral administration of ribavirin (in Patients 3 and 4). Slide321:  MMWR 2004;53:100 “All 5 patients had respiratory failure and required intubation a median of 7 days (range: 4–10 days) after onset of illness. Two patients had a pneumothorax. Three patients required inotropic support for decreased cardiac function; two patientshad renal impairment as a later manifestation.. . Slide324:  Influence of delay of treatment with GS 4104 on virus infection in mice. In our experiments, twice-daily treatment of mice infected with 10 MLD50 of A:HK:156:97 (H5N1) virus began at 24, 36, 48, 60, and 72 h after infection. GS4104 was efficacious in mice when therapy was initiated 24 or 36 h after infection.When treatment was delayed until 48 h after virus exposure all of the mice died. Slide327:  NEJM 2005;353:2667-72 Slide332:  Oseltamivir: Dosage & Duration of Rx Murine studies indicate that as compared with an influenza A (H5N1) strain from 1997, the strain isolated in 2004 requires higher oseltamivir doses and more prolonged administration (eight days) to induce similar antiviral effects and survival rates. Yen HL et al. Virulence may determine the necessary duration and dosage of oseltamivir treatment for highly pathogenic A/Vietnam/ 1203/04 influenza virus in mice. J Infect Dis 2005; 192:665-72. Slide333:  In 1997, virus could be detected in nasopharyngeal isolates for a median of 6.5 days (range, 1 to 16). In Thailand, the interval from the onset of illness to the first positive culture ranged from 3 to 16 days. Slide334:  The duration of viral shedding in children younger than 12 years of age who have human influenza can last up to 21 days and also may be protracted in children and adults with avian influenza A (H5N1), so that infection-control precautions should be maintained for at least 7 days after the resolution of fever or possibly up to 21 days. Slide341:  How much is the risk of getting avian flu from the patients? Slide342:  Conceptual Framework Slide343:  Organisms Infection Disease Death . . . 1 2 3 Slide344:  Organisms Infection Disease Death . . . 1 2 3 ? Slide345:  How much is the risk of getting avian flu from the patients? Slide346:  Epidemiologic investigation of the first case of human influenza A(H5N1) infection. MMWR 1998;46:1245 Serum samples were obtained from 54 healthcare workers who have had contact with the child. One (2%) was positive. Seropositivity was not associated with reported influenza-like illness. Slide347:  Nosocomial Transmission of Avian Influenza -a retrospective cohort study comparing the prevalence of H5N1 antibody among 217 health care workers(HCWs) exposed to H5N1 case-patients with the prevalence among 309 nonexposed HCWs. -Eight (3.7%) of 217 exposed and 2 (0.7%) of 309 nonexposed HCWs were H5N1 seropositive . The difference remained significant after controlling for poultry exposure (P = .01 ). Ref.: JID 2000;181:344–8 Slide350:  CID 2005;40: Slide351:  CID 2005;40: Slide352:  “Plucking and preparing of diseased birds; handling fighting cocks; playing with poultry, particularly asymptomatic infected ducks; and consumption of duck’s blood or possibly undercooked poultry have all been implicated.” Slide354:  “The absence of any report to date of a similar illness among the health care workers who cared for these patients, despite the lack of full droplet and respiratory infection-control measures early in the outbreak, is reassuring.” Slide356:  How much is the risk? Household&Neighbors,?School Slide357:  Epidemiologic investigation of the first case of human influenza A(H5N1) infection. MMWR 1998;46:1245 Of the 328 persons tested who may have had contact with the child, elevated neutralization antibody titers to influenza A(H5N1) virus were present in 2 (0.6%). One (2%) of 63 neighbors, and one (0.4%) of 261 child-care center contacts.Specimens were negative for the four family members,,and the 419 controls. Seropositivity was not associated with reported influenza-like illness. Slide366:  How to prevent getting Avianflu? Slide367:  Conceptual Framework Slide368:  Organisms Infection Disease Death . . . 1 2 3 ? Transmission: How?:  Transmission: How? Possible Modes of Spread Slide370:  Hand-to-hand transmission of rhinovirus colds. Gwaltney JM Jr et al. Ann Intern Med 1978 Apr;88(4):463-7 Virus on donors' hands was transferred to recipients' fingers during 20 of 28 (71%) 10-second hand-contact exposures. These findings support the concept that hand contact/self-inoculation may be an important natural route of rhinovirus transmission. Slide371:  Aerosol transmission of rhinovirus colds. Dick EC et al. J Infect Dis 1987; 156:442-448 “(donors) and susceptible men (recipients) who played cards together for 12 hr. In three experiments the infection rate of restrained recipients (10 [56%] of 18), who could not touch their faces and could only have been infected by aerosols, and that of unrestrained recipients (12[67%] of 18), who could have been infected by aerosol, by direct contact, or by indirect fomite contact, was not significantly different (chi 2 = 0.468, P = .494). …These results suggest that contrary to current opinion, rhinovirus transmission, at least in adults, occurs chiefly by the aerosol route.” Slide372:  Modes of transmission of respiratory syncytial virus. Hall C:J. Pediatr 1981;99:100-103 The first group, called "cuddlers".These staff wore gowns but no mask or gloves. The second group, called "touchers," touched with ungloved hand surfaces likely to be contaminated with the baby's secretions when the infant was out of the room. They then gently rubbed the mucous membranes of their nose or eye, The third group, called "sitters," was exposed to an infected baby by sitting at a distance of >1.8 m from the bed. They wore gowns and gloves, but no masks. Only the cuddlers and touchers became infected, which suggests that routes that require close or direct contact with infectious secretions and self-inoculation were the major or most effective means of transmission. 3 Possible Modes of Spread :  3 Possible Modes of Spread 1. small-particle aerosols <10 m mass median diameter generated by coughing or sneezing traverse distances > 1.8 m such as occur with measles, varicella, and sometimes influenza 3 possible mechanisms:  3 possible mechanisms 2. Droplets or large particles close person-to-person contact at a distance of < 0.9 m 3. Fomites self-inoculation after touching contaminated surfaces Slide375:  Organisms Infection Disease Death . . . 1 2 3 Mask? Gown? Gloves? Goggles? Handwashing? Slide376:  Standard droplet precautions Wearing masks, gloves, and gowns when within 3 feet of the patient. Garner JS, Hospital Infection Control Practices Advisory Committee.Guidelinefor isolation precautions in hospitals. Infect Control Hosp Epidemiol 1996;17:53–80. Slide377:  Goggles ? Avian influenza viruses of the H7 subtype have been isolated from eye swabs of human beings in two cases of clinical conjunctivitis. Ref.: Kurtz J, et al. Lancet 1996; 348:901–02. Slide378:  Viral Shedding in Man Influenza infection generally results in viral shedding for <7 days. Frank Let al.. Patterns of shedding of myxoviruses and paramyxoviruses in children. J Infect Dis1981;144:433–41. Slide379:  Infectious period. An H5N1-infected patient was considered to be potentially infectious to HCWs from the day of admission through 14 days after illness onset or until a repeat viral culture was negative. Frank Let al.. Patterns of shedding of myxoviruses and paramyxoviruses in children. J Infect Dis1981;144:433–41. Slide380:  In 1997,H5N1 virus could be detected in nasopharyngeal isolates for a median of 6.5 days (range, 1 to 16). In Thailand, the interval from the onset of illness to the first positive culture ranged from 3 to 16 days. Slide381:  The duration of viral shedding in children younger than 12 years of age who have human influenza can last up to 21 days and also may be protracted in children and adults with avian influenza A (H5N1), so that infection-control precautions should be maintained for at least 7 days after the resolution of fever or possibly up to 21 days. Slide382:  Studies have shown that infected birds can shed large amounts of the virus in their faeces. The

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