Summary of Avian Influenza and Pandemic related Events in

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					          Summary of Avian Influenza and
          Pandemic-related Events in 2006
         Introduction                                                                                     Figure1:
                                                                                                  World Health Organization
                                                                                                      Pandemic Phases
            The H5N1 avian influenza strain first emerged as a human                               Inter-   New animal virus,
            threat in 1997, when a poultry outbreak in Hong Kong led to 18                       pandemic   no human cases
            human infections and 6 deaths. Prompt culling of poultry                                1       Low risk of human
            appeared to have been effective in controlling the disease.                                     cases

            H5N1 infection was not reported again until 2003, when human                            2       Higher risk of
                                                                                                            human cases
            cases appeared shortly after poultry outbreaks toward the end
            of the year.1 Since then, health officials have carefully                            Pandemic   New virus causes
                                                                                                   Alert    human cases
            monitored the situation and recognized the threat of a
                                                                                                    3       No or very limited
            pandemic that may be caused by this particular avian flu                                        human-to-human
            strain. This caused the World Health Organization (WHO) to                                      transmission
            increase the WHO’s Pandemic Alert to Phase 3.2                                          4       Evidence of
                                                                                                            increased human-to-
                                                                                                            human transmission
            At the beginning of January 2007, the WHO’s Pandemic Flu
            Alert was still at Phase 3 (Figure 1). However, the annual                              5       Evidence of
                                                                                                            significant human-
            number of people infected by the highly pathogenic H5N1                                         to-human
            avian influenza increased once again. The threat of a                                           transmission

            pandemic grows with each human case, which provides an                               Pandemic
            opportunity for the virus to mutate, change and adapt to                                6       Efficient and
            become transmissible from human-to-human.                                                       sustained human-to-
                                                                                                            human transmission

                                                                                     This is a summary of
                                                                                     developments in 2006 that are
                                                                                     related to avian influenza and
                                                                                     pandemic influenza.

                                                                                     H5N1 Moves West
                                                                                     At the start of this H5N1 avian
                                                                                     influenza epidemic in
                                                                                     November 2003, we primarily
                                                                                     saw human cases and poultry
                                                                                     outbreaks in the Southeast
                                                                                     Asian countries. By the end of
                                                                                     2005, Vietnam was one of four
                                                                                     countries reporting human
                                                                                     cases and was the most
                                                                                     severely impacted country,
Figure 2: Human H5N1 cases and deaths in 2005 and 2006 reported to WHO, by country


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                   having reported 93 (63.3% of total reported) human infections and 42 (53.4% of
                   total reported) human deaths (Figure 2).3 Yet through intensive education efforts
                   and community collaboration, Vietnam was able to implement a national policy to
                   vaccinate all domestic poultry in the country, which resulted in zero human cases
                   in 2006.4 Despite this silver lining, the virus spread to other parts of the world and
                   more human cases were seen.

               Migratory Birds and Domestic Poultry

                  In 2006, the virus had spread to countries and regions other than China and
                  Southeast Asia. As seen in Figure 3, the H5N1 avian influenza was found in the
                  Middle East, Russia, parts of Africa and several European countries. Many of these
                  countries only reported wild or migratory birds affected by the virus, as infections
                  followed migratory bird paths. In every nation, surveillance was increased and the
                  risks were communicated to poultry farmers. However, the H5N1 virus still hit
                  poultry farms in Eastern Europe, Nigeria and Egypt.

                                                                                                                 The list of countries that
                                                                                                                 reported poultry outbreaks
                                                                                                                 increased from 10 to 16 just
                                                                                                                 in the first two months of
                                                                                                                 2006. By the end of the
                                                                                                                 year, 55 countries reported
                                                                                                                 H5N1 infection in domestic
                                                                                                                 poultry or wild, migratory
                                                                                                                 birds.5,6 This trend fed into
                                                                                                                 the growing concern that
                                                                                                                 migratory birds would carry
                                                                                                                 the highly pathogenic virus
                                                                                                                 around the world, causing
                                                                                                                 infections in domestic
                                                                                                                 poultry, which may
                                                                                                                 subsequently lead to human
                                                                                                                 infections.
Figure 3: Areas reporting confirmed occurrences of H5N1 avian influenza in poultry and wild birds
         from 1 January to 31 December, 2006
                                                                          In April, the United States
        http://gamapserver.who.int/mapLibrary/Files/Maps/Global_SubNat_H5N1inAnimalConfirmed_2006_20070119.png

                                                                          began the National Avian
                  Influenza Surveillance program first in Alaska, and then expanded the surveillance
                  program to the 48 contiguous states in August. Through the surveillance program,
                  several birds were identified to be infected with a type of bird flu in 2006, not the
                  specific highly pathogenic H5N1 strain. At the end of the year, both North and
                  South America have not yet reported a case of highly pathogenic H5N1.



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                             Towards the end of 2006, studies came out suggesting that avian influenza would
                             most likely enter the United States through unreported or illegal import of poultry,
                             as opposed to migratory birds as was commonly believed.7 Part of this reasoning is
                             that few birds migrate between the United States and areas currently dealing with
                             H5N1 infection. Most of the United States poultry population belong to the
                             commercial industry and are kept under stringent biosecurity requirements. Private
                             ownership and backyard poultry rearing practices are not nearly as common as
                             some of the countries severely affected by the H5N1 bird flu, such as Indonesia.
                             There was an instance in 2006 where poultry was illegally imported into the U.S.
                             from a region in China which reported H5N1 outbreaks in poultry. Thorough
                             investigation found no trace of bird flu. 8,9

                          More Countries Report Human Infections

                             The beginning of 2006 was greeted with a large outbreak of human infections in
                             Turkey, the first country outside of Southeast Asia and China to report human
                             infections (Figure 4). In January, there were 18 suspected human cases; most of
                             them (90.5%) were under the age of 19. Within this large outbreak, there were
                             several family clusters, but epidemiological investigations determined that


                                                      Total Human H5N1 Infections
                           Reported to the WHO from January 1 to December 31, 2006
                                                                   [123 cases / 77 deaths]

              15
                                                                Fatal   Djibouti   Cambodia   Iraq   Thailand   Azerbaijan   China   Egypt   Turkey   Indonesia   Vietnam   Total
              14                                                Yes        0          2        2        3           5         8       10      4          43          0        77
                                                                No         1          0        1        0           3         5        8      17         11          0        46
              13                                                Total      1          2        3        3           8         13      18      21         54          0       123

              12

              11

              10

               9
Case Number




               8

               7

               6

               5

               4

               3

               2

               1

               0
                   1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52

                                                                                      Week Number
                   Figure 4: Total Human H5N1 infections reported to the WHO from January 1 to December 31 2006
 infection was still through direct contact with sick and dead poultry rather than by
 person-to-person transmission. The month prior to this, Turkey reported wild birds
 carrying the H5N1 virus which led to numerous outbreaks in domestic poultry
 population. People who became ill reported having close and direct contact with
 sick and dead poultry.

 H5N1 infection in humans is still caused by a bird-to-human transmission in which a
 person comes into close contact with an infected bird or an infected bird’s fecal or
 nasal secretions. Yet, as more human cases occur, the concern for a pandemic
 increases. Each time a human is infected, it provides an opportunity for the
 influenza virus to mutate, change and adapt to humans, leading to a new virus that
 could be transmitted efficiently from person-to-person. Though most of the
 reported human cases were infected through close contact with sick and dead
 poultry, there was one instance of human-to-human transmission in mid-2006.

Pandemic Scare

 In May, there was a cluster of H5N1 cases involving eight members of an extended-
 family. In less than three weeks, seven of the eight family members died – six were
 positively confirmed as being infected by the H5N1 avian influenza. Through
 epidemiological investigations done by experts from the World Health Organization
 (WHO) and the U.S. Centers for Disease Control and Prevention (CDC), transmission
 of the disease was identified as person-to-person, which was verified through
 laboratory analysis. This incidence was the first laboratory confirmed human-to-
 human transmission, but it did not lead to a change in the Pandemic phase. This
 cluster still occurred in a limited manner, with only immediate family members
 who had spend extensive time together becoming ill.10,11 This example is a
 reminder (that the H5N1 virus is capable of mutating and adapting to be
 transmitted person-to-person and become the next pandemic).

 Reactions in Indonesia to the increasing number of human cases in 2006 highlighted
 social and cultural barriers faced by health officials. The lone survivor of the family
 cluster refused anti-viral treatment and left the hospital against his doctor’s
 orders. The survivor and many of the residents living in the same village where the
 family cluster occurred believed that the medication (Tamiflu®) was causing this
 illness. They did not believe in bird flu and thought it was fabricated by the
 government.

Similarities to the 1918 Spanish Flu Pandemic

 Pandemic planning has relied on the available information from the three previous
 pandemics. Based on the reported numbers of ill and dead here in the United
 States and globally, the 1918-20 Pandemic is considered the worst-case scenario we
 may face. In addition to historical data, scientists were also able to reconstruct the

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                                                                           virus that caused the Spanish flu
                                                                           pandemic. Published results from
                   Ages 20-29
                    25 (21%)
                                                                           studies on this virus have shown
                                                           Ages 40-49      similarities between the H5N1 bird
                                                             2 (2%)
                                Ages 30-39                                 flu and the 1918-20 Spanish
                                 16 (13%)
                                                           Ages 50-59      Pandemic flu (which was an H1N1
                                                             1 (1%)
                                                                           influenza strain).
      Ages 10-19
       37 (30%)                                            Ages 60-69                One similar characteristic is the
                                                             3 (3%)
                                                                                     mechanism by which severe illness
                                  Ages 0-9                                           and death is caused. During the
                                  34 (29%)                             Ages 70-79    1918-20 pandemic, a large
                                                                         1 (1%)
                                                                                     percentage of those who became
                                                                                     seriously ill or died were young and
                                                                                     healthy people between the ages
Figure 5: Age-distribution of all confirmed H5N1 human cases reported to WHO in 2006
                                                                                     of 15 to 35 years, which has also
                  been seen in the current H5N1 avian flu outbreak in humans (figure 5).12 Scientists
                  had hypothesized that an overactive immune response was the cause of
                  disproportionate deaths in young, healthy individuals. In 2006, several studies using
                  the reconstructed 1918 Pandemic flu virus confirmed this hypothesis.13,14

             Research
               In December 2005, the United States Congress approved $3.8 billion to help the
               Nation prepare for a pandemic. Almost 75% of that money was allocated for
               vaccine ($1.78 billion) and antiviral ($731 million) research.15 The focus of vaccine
               research is to increase manufacturing capacity based on current, egg-based
               technology. The government also recognized the delay in vaccine production
               following current technology. There could also be a shortage of chicken eggs that
               are used to make vaccines if this avian influenza continues to ravage the domestic
               poultry population. These conditions forced the government to look at alternate
               vaccine production methods, namely cell-based technology, which, if successful,
               could produce viable vaccines in just a few months after the pandemic flu virus is
               isolated.

               During 2006, results from several vaccine trials highlighted the effective use of
               adjuvants to increase the potential supply. Adjuvants are chemicals that enhance
               the immune response and are added to the vaccines. Trials have shown that a
               smaller amount of vaccine, used in conjunction with these adjuvants, can induce a
               protective immunity level. If further clinical trials produce similar results, the use
               of adjuvants could have a profound impact on the supply of vaccines. The
               Department of Health and Human Services recognized this success and at the end
               of 2006, provided additional research funding on this technology.17


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Pre-pandemic vaccines

 Current vaccine research is based on two different H5N1 strains that have caused
 severe illness and death in humans. The current vaccines being tested are termed
 “pre-pandemic” vaccines, and may not be effective during a pandemic. Vaccines
 target specific viruses, and the virus that may cause the pandemic may be very
 different from the H5N1 avian influenza strain that is currently causing human
 illness and death.

 The United States Department of Health and Human Services has been stockpiling
 pre-pandemic vaccines. As of November 2006, they have enough vaccine doses for
 some three million people.16

Antiviral drugs

 Antivirals are the other medical treatment being funded. There are four antiviral
 medications that have been approved by the Food and Drug Administration (FDA) to
 treat flu—amantadine (Symetrel®), rimantadine (Flumadine®), oseltamivir
 (Tamiflu®) and zanamivir (Relenza®). Unfortunately, H5N1 has been found to be
 resistant to two of the four drugs (amantadine and rimantadine)18 so the attention
 has been focused on oseltamivir and zanamivir.

 The federal government has begun stockpiling Tamiflu®, trying to reach a stockpile
 goal of 81 million treatment courses by 2008.15,16,17 There have been reports of
 reports of abnormal behavior among Japanese patients taking this medication.
 Though no causal evidence has been found, the Food and Drug Administration (FDA)
 and Roche (sole manufacturer of Tamiflu®) issued a warning, alerting healthcare
 professionals of this situation.19

Resources
World Health Organization Avian Influenza Website
 <http://www.who.int/csr/disease/avian_influenza/en/index.html>
Food and Agriculture Organization of the United Nations (FAO)
 <http://www.fao.org/ag/againfo/subjects/en/health/diseases-cards/
  special_avian.html>
National Pandemic Influenza Website
 <http://www.pandemicflu.gov>
National Avian Influenza Surveillance Program
 <http://wildlifedisease.nbii.gov/ai/>
USDA Brochure on Avian Influenza
 <http://www.usda.gov/documents/AvianFluBrochure.pdf>
Centers for Infectious Disease Research and Policy at the University of Minnesota
 <http://www.cidrap.umn.edu>

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References
1. Juckett, G. Avian Influenza: Preparing for a Pandemic. American Family Physician 2006;74: 783-
    790.
2. WHO Pandemic Phases: http://www.who.int/csr/disease/avian_influenza/phase/en/index.html
3. WHO. Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to
    WHO. 2005. Dec 30. (http://www.who.int/csr/disease/avian_influenza/country/
    cases_table_2005_12_30/en/index.html)
4. FAO. United against bird flu: Reports from the global campaign (http://www.fao.org/docs/eims/
    upload//213477/news_birdflu06_en.pdf)
5. FAO. Avian Influenza Disease Emergency news: situation update 39 (http://www.fao.org/ag/
    againfo/subjects/documents/ai/AVIbull039.pdf)
6. FAO. Avian Influenza Disease Emergency news: situation update 44 (http://www.fao.org/docs/
    eims/upload//217700/aidenews_nov06_no44.pdf)
7. Kilpatrick AM, Chmura AA, et. al. Predicting the global spread of H5N1 avian influenza. PNAS
    2006;103: 19368-19373.
8. Ashenfelter D, Rector S, Swickard J. Inspectors find no bird flu—poultry smuggled into Troy from
    China. 2006. WZZM 13 News. 15 Jul. 2006 (http://www.wzzm13.com/news/news_article.aspx?
    storyid=57870)
9. CIDRAP. Michigan officials track smuggled Chinese poultry. 2006. CIDRAP. 13 Jul. 2006 (http://
    www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/jul1306avian.html)
10. Butler D. Family tragedy spotlights flu mutations. Nature 2006;442: 114-115.
11. CIDRAP. Report: H5N1 mutated rapidly in Indonesian cluster. 2006. CIDRAP. 12 Jul. 2006 (http://
    www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/jul1206mutate.html)
12. WHO. Avian influenza: assessment the pandemic threat. 2005. (http://www.who.int/csr/disease/
    influenza/WHO_CDS_2005_29/en/index.html)
13. de Jong MD, Simmons CP, Thanh TT, et al. Fatal outcome of human influenza A(H5N1) is
    associated with high viral load and hypercytokinemia. Nature Medicine 2006; 12:1203-1207.
14. Kash JC, Trumpey TM, Proll SC, et al. Geonmic analysis of increased host immune and cell death
    responses induced by 1918 influenza virus. Nature 2006;443: 578-581.
15. Dept of Health and Human Services. Pandemic Planning Update I —A report from Secretary
    Michael O. Leavitt. 2006. (http://www.pandemicflu.gov/plan/pdf/panflu20060313.pdf)
16. Dept of Health and Human Services. Pandemic Planning Update II —A report from Secretary
    Michael O. Leavitt. 2006. (http://www.pandemicflu.gov/plan/pdf/panflureport2.pdf)
17. Dept of Health and Human Services. Pandemic Planning Update III —A report from Secretary
    Michael O. Leavitt. 2006. (http://www.pandemicflu.gov/plan/pdf/panflureport3.pdf)
18. Cheung CL, Rayner JM, Smith GJ, et al. Distribution of amantadine-resistant H5N1 avian influenza
    variants in Asia. J Infect Dis 2006; 354:1343-51.
19. FDA. Tamilfu drug infopage: http://www.fda.gov/cder/drug/infopage/tamiflu/default.htm




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