Avian Influenza - What is Happening and How Should We Prepare? - - - - - - - - -

1. Avian Influenza -What is Happening and How Should We Prepare?- - - - - - - - - John M. Matsen, M.D. August 9, 2006

2. Influenza Virology • “There are three types of influenza viruses, A, B, and C. • Only Influenza A viruses are further classified by subtype on the basis of the two main surface glycoproteins hemagglutinin (HA) and neuramininidase (NA). Dx by inhibition tests. • Influenza A subtypes and B viruses are further classified by strains.” (CDC 1/06)

3. DEFINITION: • Avian influenza is an infectious disease caused by Type A influenza virus strains that commonly infect poultry and other avian species. The term is synonymous with “bird flu.” • The natural reservoir species for avian flu are ducks, shorebirds and gulls. (USDA)

4. TUFTED DUCK

5. All type A influenza viruses, including human strains: • They are genetically labile RNA viruses. • Other RNA viruses are, e.g., HIV, SARS, etc. • They lack the critical mechanisms for correcting replication errors. • The genetic composition of the viruses changes as they replicate.

6. Constant Mutation • Now with a huge new amount of genetic data, we have the ability to better understand multigenictraits for the first time. As they carry RNA instead of DNA, influenza viruses mutate constantly because the enzyme that generates RNA makes frequent mistakes during replication. (NatureMed 2006; 12(258)) • “H5N1mutates rapidly and has a documented propensity to acquire genes from viruses infecting other animal species.”

7. Avian Flu Virus Makeup • Only influenza A viruses infect birds, and all known subtypes of the A viruses can infect birds. • In the influenza A genetic makeup, there are 6 internal genes plus the HA and NA genes. • A specific gene of these 8 in the 1918 H1N1 virus had the unexpected capacity for sending the body's immune system into overdrive, causing inflammation, hemorrhagic pneumonia and death.

8. Pathotype Definition There are two primary pathotypes of Avian Influenza virus: • the most common is low pathogenic AI (LPAI) which is found in a few poultry flocks in the United States and elsewhere every year—usually spread from wild birds. • the other is the highly pathogenic AI (HPAI), which is much less common and is associated with higher mortality in poultry.

9. Pathotypes Can Change • Avian flu viruses of low pathogenicity (LPAI) can, after circulation for just short periods of time, in a poultry population, mutate into HPAI. • During a 1983–1984 poultry epidemic in the US, the H5N2 virus was of low pathogenicity initially, but within 6 months mutated to become HPAI, with a mortality approaching 90%. • During a 1999–2001 poultry epidemic in Italy, the H7N1 virus, initially of low pathogenicity, mutated within 9 months to a HPAI form. (WHO)

10. Influenza Viruses Continually Evolve • They continually manifest small changes or antigenic “drift.” • Can swap or “reassort” genetic materials and merge with other flu viruses • This occasional reassortment process is known as antigenic “shift.” • The resulting novel subtype is different from both parent viruses.(WHO & CDC)

11. Avian Flu Spread “Here, we report that genetically and antigenically distinct sub lineages of H5N1 virus have become established in poultry in different geographical regions of Southeast Asia, indicating the long-term endemicity of the virus, and the isolation of H5N1 virus from apparently healthy migratory birds in southern China.” (PNAS 02/10/06)

12. Avian Flu Spread The H5N1 bird flu in humans has evolved into two separate strains, or “clades,” a development that will complicate the search for a vaccine and the prevention of a pandemic, US researchers reported. (Garten RJ, et al. International Conference on Emerging Infectious Diseases.March 2006.Paper # 64)

13. H5N1 Presence 2006 . Nations With Confirmed Cases (070706)

14. Confirmed Human H5N1 Cases 7/20/2006

15. Highly Pathogenic Avian Influenza • The H5N1 strain has now (4/06) been reported in over 50 countries, and governments throughout the world have slaughtered the enormous number of well over 200 million chickens, ducks, other poultry and wild birds in an effort to keep the H5N1 virus from spreading.

16. PNAS 2/10/06 “Our data show that H5N1 influenza virus has continued to spread from its established source in southern China to other regions through transport of poultry and bird migration. The identification of regionally distinct sub lineages contributes to the understanding of the mechanism for the perpetuation and spread of H5N1…”

17. Nature442, 37(6 July 2006) “As the avian influenza virus H5N1 swept from Asia across Russia to Europe, Nigeria was the first country in Africa to report the emergence of this highly pathogenic virus. Here we analyze H5N1 sequences in poultry from two different farms in Lagos state and find that three H5N1 lineages were independently introduced through routes that coincide with the flight paths of migratory birds, although independent trade imports cannot be excluded.”

18. Avian Influenza A Viruses Human-to-human transmission of the H5N1 avian influenza would be cause for great concern, but WHO investigations have in the past identified only one “likely” / “probable” instance of human-to-human spread, in 2004, with one additional possible case in 2005. The increasing number of reported family clusters of H5N1 in Asia may mean human-to-human transmission. Some suspect there have been other human-to-human transmissions.

19. Critical Gene a Suspect in Lethal 1918-1919 Epidemic (1) • By recreating the influenza virus that killed 50 or more million people in 1918-19, Kobasa, et al. may have identified the gene that turned it into one of the most lethal in human history. The gene, one of eight in the virus, seems to have an unexpected capacity for sending the body's immune system into overdrive, causing inflammation, hemorrhagic pneumonia and death. • (From Kobasa, et al. Nature. 10/07/04)

20. Critical Gene a Suspect in Lethal 1918-1919 Epidemic (2) Using reverse genetics, they synthesized the hemagglutinin antigen and the neuraminidase genes based on the genetic sequences of the 1918-1919 influenza pandemic strain, and in recreating the virus, they have shown that the resulting virus is significantly more virulent than the wild-type strain in a mouse model. (From Kobasa, et al. Nature. 10/07/04; Hoft, et al. NEJM. 12/9/04)

21. Critical Gene a Suspect in Lethal 1918-1919 Epidemic (3) • “Different strains of influenza virus have different pathologic effects... These events were associated with more severe pathological features and higher mortality, suggesting that overactive host immune response...may trigger severe disease. • “Death rates in the 1918 pandemic were highest among young to middle aged adults, and lower in the elderly.” (Hoft, et al. NEJM. 12/9/04)

22. Resurrected 1918 Flu Virus The team resurrected the 1918 pandemic virus by using gene sequences obtained from formalin-preserved specimens and from preserved tissue from a 1918 Inuit flu victim exhumed from the Alaskan permafrost. The virus is as lethal as expected, killing mice more quickly than any other human flu virus known. Recreating the 1918 strain “had to be done, and it's produced some extremely interesting results.” (Tumpey, et al. Science. 2005;310(77)).

23. Chemokine Storm In 1997, avian influenza virus H5N1 was transmitted directly from chicken to human and resulted in a severe disease that had a higher mortality rate in adults than in children. The characteristic mononuclear leukocyte infiltration in the lung and the high inflammatory response in H5N1 infection prompted comparison of the chemokine responses between influenza virus–infected adult and neonatal monocyte-derived macrophages (MDMs). The demonstrated strong induction of chemokines and their receptors by avian influenza viruses, particularly in adult MDMs, may account for the severity of H5N1 disease. (Zhou, et al. J. Inf. Dis. July1, 06; 194.)

24. Pathogenicity Change • Avian flu viruses of low pathogenicity (LPAI) can, after circulation for just short periods of time, in a poultry population, mutate into HPAI. • During a 1983–1984 poultry epidemic in the US., the H5N2 virus was of low pathogenicity initially, but within 6 months mutated to become HPAI, with a mortality approaching 90%. • During a 1999–2001 poultry epidemic in Italy, the H7N1 virus, initially of low pathogenicity, mutated within 9 months to a HPAI form. (WHO)

25. “Of the 16 avian influenza virus subtypes, H5N1 is of particular concern for several reasons. • “H5N1mutates rapidly and has a documented propensity to acquire genes from viruses infecting other animal species. • “H5N1’s ability to cause severe disease in humans has now been documented. In addition, laboratory studies have demonstrated that isolates from this virus have a high pathogenicity for humans.” (WHO)

26. HOW DEADLY THE PANDEMIC ? • “Even in the best-case scenarios of the next pandemic, 2 to 7 million people will die and tens of millions will require medical attention. • “If the next pandemic virus is a very virulent strain, deaths could be dramatically higher. • “The global spread of a pandemic cannot be stopped, but preparedness will reduce its impact.” (WHO)

27. Human-to-human transmission raises demand for DNA data. • A strain of avian flu that spread through a family in Indonesia, killing seven of the eight people infected, was accumulating mutations as it spread from person to person, according to confidential sequence data seen by Nature. • The cluster of cases of the deadly H5N1 strain, which occurred earlier this year, is the first in which the World Health Organization (WHO) has admitted that human-to-human transmission was the most likely cause of spread. (See Nature 441, 554–555 and 442, 114-115; 2006).

28. Human-to-Human Transmission Sequence data show that mutations were accumulating as it spread from person to person. (Nature 442, 114-115; 2006)

29. “Something in the Airway” “The existences of a molecular barrier that may contribute to [transmissability] has now been confirmed in patients. The key is the distribution in the human airway of the different receptors preferred by avian and human derived viruses. The [H5N1] virus binds preferentially to binding molecules that are common in the lower respiratory tract but are less well represented in the upper respiratory tract. As a result, the [current H5N1] virus is not readily spread by droplet infection or cough.” (Editor’s Comment. Nature. 2006;440:436)

30. Needs Better Transmissibility “The H5 strain of avian flu has so far failed to develop a pandemic form. Some virologists fear it may need only better transmissibility. The new findings suggest that the virus could acquire such a property by switching its preference from the cell receptor found in the lower lung, known as alpha 2-3, to the receptor found on cells in the upper airways, known as alpha 2-6.” (Ibid)

31. 2-step Mutation “A team of scientists at the Scripps Research Institute reported in Science (March 17, 2006) that only a couple of mutations might be needed to enable the H5 virus to make this switch to the alpha 2-6 receptor. This is the about same number of mutations made by the H1, H2 and H3 (pandemic) viruses when they adapted to infect people. Since (RNA) viruses can mutate fast, a two-mutation step is not such a big hurdle.”

32. Dr. Anthony Fauci - 4/11/06 “It is entirely conceivable that this virus is inherently programmed that it will never be able to go efficiently from human to human,'' Fauci said. ''Hopefully the epidemic (in birds) will burn itself out, which epidemics do, before the virus evolves the capability of being more efficient in going from human to human.'‘ (NYT 4/12/06)

33. BMJ 4/15/06 David King, the UK government's chief scientific adviser, states that the chances of the virus mutating into a form that could spread between humans were "very low," and it was "totally misleading" to say that such a mutation was inevitable.

34. Current Vaccine Status • The US already has several million doses of a bird flu vaccine based on a sample of a virus taken in 2004 from Vietnam. • But researchers have noted the emergence of a second strain or clade of bird flu. • US-HHS plans to create a new vaccine targeted at the second variety. "In order to be prepared, we need to continue to develop new vaccines," HHS’s Mike Leavitt said at an immunization conference in Atlanta. (AP 3/6/06)

35. Current Vaccine Status “The second vaccine will be based on a virus sample taken from Indonesia last year, said Ruben Donis, leader of the molecular genetics team at the CDC's influenza branch. The virus circulating in Indonesia is related to the Vietnamese virus, but it is not a descendant and it causes a different immune system response, he said.” (AP 3/6/06)

36. WHO Proposed Immediate Prevention Actions • Because of uncertainties about the disease situation in poultry and the potentially severe consequences for human health, WHO has defined the following proposed actions:

37. WHO Proposed Immediate Prevention Actions • 1. Continue to work towards elimination of H5N1 in all poultry populations: small holdings as well as commercial flocks. • 2. Promptly report to relevant authorities and organizations new outbreaks in poultry.

38. WHO Proposed Immediate Prevention Actions • 3. Put in place mechanisms to verify control progress and eventually monitor freedom from the disease. • 4. Ensure close collaboration between public health and agricultural sectors and veterinary services.

39. WHO Proposed Immediate Prevention Actions 5. Strengthen communicable disease • surveillance in humans and collect and provide the data needed for an accurate assessment of risks to human health. 6. Share viruses with laboratories in • the WHO Global Influenza Surveillance Network.

40. WHO Phase of Pandemic Alert ‘ April 8, 2006

41. PANDEMIC PREPAREDNESS “Given the current threat, WHO has urged all countries to develop or update their influenza pandemic preparedness plans for responding to the widespread socioeconomic disruptions that would result from having large numbers of people unwell or dying.”(WHO)

42. CDC, DOS, FDA, NGA, USDA, WHO and all 50 States The Web sites of these and other resource and administrative units all have pertinent pandemic planning and preparation documents. Units within our purview, and, indeed, all of our family units should have copies of these. We have distributed these widely. All state governments also have such for distribution.

43. HHS and State Governors Holding Pandemic Summits ‘

44. Advanced Planning Importance "A pandemic flu outbreak in any part of the world would potentially cripple supply chains, and dramatically reduce available labor pools," the Deloite report said. "In a world where the global supply chain and real-time inventories determine most everything we do, down to the food available for purchase in our grocery stores, one begins to understand the importance of advanced planning.” (NYT 3/16/06)

45. Worst-case Scenario SYDNEY, Feb 16/06 (Reuters)—A worst-case scenario bird flu pandemic could wipe US$4.4 trillion off global economic output and kill more than 140 million people, according to an Australian Lowry Institute for International Policy report which detailed four scenarios—mild, moderate, severe and ultra pandemics—using historical data on previous influenza pandemics and the economic fallout from the SARS crisis in Asia in 2003.

46. “A Nightmare Scenario” “The havoc that would be wrought by an avian-flu pandemic is so awful that we must act now to be able to prevent such a disaster.” “. . . A pandemic could well bring global, national and regional economies to an abrupt halt. . . Imagine the chaos.” (M. Zuckerman, Editor-in-Chief. US News & World Report. June 27, 2005)

47. “On a Wing and a Prayer.” (Edit.) Nature. May 26, 2005 “This issue's focus on avian flu highlights progress and incoherence in the world's response to a potential human pandemic. But the threat is enormous, and some priorities are clear enough. Millions of people killed in highly developed countries within months, and tens of millions worldwide. The global economy in tatters. A Hollywood fantasy? No—it's now a plausible scenario.”

48. Effect and Survival • The effect of an influenza pandemic on individual communities will be relatively severe and prolonged when compared to other natural disasters, as it is expected that outbreaks will reoccur in waves. • Life or death (survival) for many will be determined by how well they and their communities are prepared.

49. TRANSPORTATION: Planes don’t fly Trains are halted Buses don’t run Travel curtailed Gasoline supplies dwindle Mobility crisis Travelers stranded COMMERCE: Services unavailable Food scarce Medicines rationed Household goods gone Supplies in general are in short supply Inventories shrink Banks are closed What Can Happen—

50. CIVIL: Safety Law enforcement Civil compromise Desperation Criminal element Utilities Water, etc. Communication PEOPLE: Social distancing 40% + could be ill Personal resources Failure to cope The sick, dying & dead Grief The vulnerable “Being alone” concerns What Can Happen—