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An Essay on Avian Flu Pandemic Risk and Global Preparedness
by sharpe
31 May 2006
by sharpe
31 May 2006
Throughout history, epidemics have played a prominent role in the success and failure of civilizations. For instance, in Guns, Germs, and Steel, Jared Diamond puts forward the theory that diseases such as measles and smallpox that Europeans had become exposed and more resistant to by their intensive livestock farming methods played an extremely important role in the victories they won elsewhere in the world. Tens of millions of the Native American population died from such diseases before the Europeans even physically encountered them, leading them to think that the Native Americans had never had a significant presence on the continent.<!--[if !supportFootnotes]-->[i]<!--[endif]--> Similarly, in the 14<sup>th</sup> century, the Old World experienced a rapidly spreading, fatal disease termed the Black Death for the black spots that appeared on the skin. In just five years, between 1347-1352, an estimated 25 million people died in Europe, or an incredible 1/3 of the population. In the late 19<sup>th</sup> century, scientists concluded that mentions of bullae in some accounts meant that the Black Death was attributable to Yersinia pestis, carried by rat fleas, and hence it was known afterwards as the Bubonic Plague. Recent epidemiological studies of European accounts as well as DNA analyses of teeth from graveyards in France have so far made the diagnosis of bubonic plague look like a hasty and unlikely one, however.<!--[if !supportFootnotes]-->[ii]<!--[endif]--> The rapid spread, the symptomatology, the lethality, and other facts such as the absence of a single mention of rats, dead or alive, in any of the accounts, are much more consistent with a hemorrhagic fever-causing, long-incubating human-human virus, possibly a filovirus.<!--[if !supportFootnotes]-->[iii]<!--[endif]--> In more modern times, slower-spreading but equally deadly pandemics of HIV and Tuberculosis have devastated communities throughout Africa and Asia. Finally, a consistent but less discussed killer is the influenza virus—the subject of this paper. In 1917-18, three waves of a disease spread rapidly across the world, with each wave being significantly worse than the previous one. When all was said and done, an estimated 50-100 million people perished from the disease, which about ten years later was determined to have been caused by the H1N1 influenza virus, a virus which has now been sequenced using Alaskan permafrost-encased corpses from the time-period.<!--[if !supportFootnotes]-->[iv]<!--[endif]--> In 1957 and 1968, millions more died from pandemics of the respective H2H2 and H3N2 Influenza strains. Further research has identified dozens of other likely influenza pandemics over the last thousand years, with the two most 1918-like pandemics occurring in 1781 and 1890.
With the recent advances in epidemiology, microbiology and genetics, scientists have been discovering the underlying mechanisms by which viruses attach to and invade cells, multiply, and infect other cells, as well as spread from one creature to another. Viral molecules responsible for cell control, damage, and death are gradually being identified and drugs being developed to inhibit them. Some viruses such as HIV win the struggle simply by directly targeting and invading cells of the immune system. The human influenza virus appears to primarily infect cells of the respiratory tract, thus irritating it and causing the person to cough the virus on to other people. The resulting inflammatory response also results in the cytokine-caused fever and muscle aches associated with the disease. Avian influenza strains however primarily infect the GI tract, usually infecting birds asymptomatically or at least subclinically, with reduction in brood size. When, however, they convert to highly pathogenic strains via the increase in size and basicity of their cleavage site and other changes, they spread rapidly, causing severe diarrhea and death. HP H5N1 is such a virus, and has now been shown to not only cause significant diarrhea, but also acute respiratory distress syndrome (ARDS) as well as multi-organ failure and encephalitis. For an unknown reason, though possibly via acute respiratory inflammation, it also results in significant and rapid leukopenia and thrombocytopenia<!--[if !supportFootnotes]-->[v]<!--[endif]--><sup>,<!--[if !supportFootnotes]-->[vi]<!--[endif]--></sup>, thus producing almost characteristic mucosal bleeding from the nose and mouth, a physical finding that was also often noted in the 1918 pandemic<!--[if !supportFootnotes]-->[vii]<!--[endif]-->.
The existence of a threat from H5N1 became evident when in 1997, an outbreak of avian influenza occurred among poultry in Hong Kong, and proceeded to infect people as well, ultimately killing 6 out of the 18 people it infected.<!--[if !supportFootnotes]-->[viii]<!--[endif]--> This was the first known time that an influenza strain thought to be restricted to birds proceeded to infect and kill people. Since then, H9N2, H7N7 and H5N2 human infections have also been identified. Even with the massive culling and decontamination efforts that China subsequently made, it proceeded to spread rapidly among poultry in Southeast Asia, and increasingly infecting people in contact with infected birds. Additionally at a Thai zoo in May 2004, 147 out of 441 tigers died or had to be put down because of an H5N1 outbreak that was later determined to be likely tiger-tiger transmitted.<!--[if !supportFootnotes]-->[ix]<!--[endif]--> The existence of frequent feline infections is concerning too because of the recent discovery that of all tested animals, the respiratory tracts of cats are so similar to human respiratory tracts that they have been proposed as the best model of human influenza infection.<!--[if !supportFootnotes]-->[x]<!--[endif]--> Since 2004, anecdotal and published reports of infected pigs<!--[if !supportFootnotes]-->[xi]<!--[endif]-->, cats<!--[if !supportFootnotes]-->[xii]<!--[endif]-->, ferrets, and dogs<!--[if !supportFootnotes]-->[xiii]<!--[endif]--> have been made in various countries. Anecdotal reports from scientists studying the sequences of H5N1 isolated from Indonesian victims have stated that they are more closely related to those found in infected Indonesian cats than they are to any of the strains found in Indonesian poultry.<!--[if !supportFootnotes]-->[xiv]<!--[endif]--> Only a handful of Indonesian sequences have been released over the last two years so far. Particularly concerning to scientists is the existence of infections of swine with bird flu, because they harbor receptors for both human and avian influenza viruses, giving H5N1 the ability to reassort and gain human receptor binding sites that it would otherwise have a hard time obtaining. The fact that the Qinghai strain has already gained several swine polymorphisms including PB2 E627K may indicate that co-infections in swine have already been a lot more widespread than they have been thought to be.
In February 2005, wild birds returning to Qinghai Lake in northern China from their wintering grounds in India began dying in large numbers along with numerous other bird species, a die-off that continued through May, at which time it was widely reported. This was quite astonishing because of the supposed resistance of wild birds to influenza.<!--[if !supportFootnotes]-->[xv]<!--[endif]--> When the Qinghai H5N1 virus sequence was sequenced, it was discovered that it had acquired several swine influenza-derived polymorphisms including PB2 E627K, that were likely causing the increase in virulence in wild birds.<!--[if !supportFootnotes]-->[xvi]<!--[endif]--> Migratory birds from Qinghai Lake presumably then proceeded to carry this strain to their wintering grounds in Asia, Africa and Europe over the summer and fall. Countries with the biggest outbreaks in the last nine months were therefore predictably those sitting on the deltas and major rivers of the region such as those parts of Russia on the Volga, Romania on the Danube, Turkey and Iraq on the Tigris and Euphrates Rivers, Egypt on the Nile, Nigeria and Niger on the Niger River, the Democratic Republic of the Congo on the Congo River, and India and Pakistan on the Indus River. There is however a vigorous debate going on that the spread has been attributed wrongly to migratory birds and that the blame should be placed squarely on the shoulders of the vast poultry industries.<!--[if !supportFootnotes]-->[xvii]<!--[endif]--> Regardless of the mechanism of spread, there has been a concomitant increase in the distribution and number of human infections, now officially numbering 224 with 127 deaths.<!--[if !supportFootnotes]-->[xviii]<!--[endif]--> These numbers may grossly underestimate the real tally however—due to a complete lack of surveillance in vast parts of the world, attribution of disease or death to other causes, and often a fear that revealing the presence of the disease will only serve to cause panic and may cause the community and even the nation to be ostracized and cut off and people’s livelihoods suffer in the process, a fear that is often confirmed. Just to give one example, in just the past week, a family of five in the town of Kermanshah, Iran were suspected to have fallen ill from H5N1 and indeed tested positive by tests done at Kermanshah’s Medical University, which were then reported to the media by health officials and parliament members. The national government has however denied the reports and, as of this writing, also denied the WHO’s request to investigate this outbreak in which three of the five family members have now died.<!--[if !supportFootnotes]-->[xix]
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As a result of the increased risk that H5N1 will at some point achieve the ability to efficiently transmit from person to person, international bodies and national governments have been forging ahead with plans to prevent or at least mitigate another pandemic. One such plan involves setting up an international alert system in which countries promptly report any human cases of bird flu. This alert system had previously been planned to begin functioning in June 2007, but due to the perception that the threat is becoming increasingly imminent, by a unanimous resolution by the world’s 192 nations this past week, it was pushed forward to this summer.<!--[if !supportFootnotes]-->[xx]<!--[endif]--> Another aspect of the plan is for the world health community headed by the WHO to respond quickly to outbreaks of H5N1 anywhere in the world, to ensure that testing and sequencing is done, that animals are efficiently culled and safely disposed of, infected people are treated appropriately and all possible contacts are traced and quarantined. The international preparatory response involves the education of physicians and public health officials, the encouragement of governments, businesses and institutions to make contingency plans for the resulting possible disruptions involved when people everywhere are sick or dying, and the creation of a reserve of drugs to treat the disease. Those approved anti-influenza drugs consist of Amantadine, Rimantadine, Oseltimivir and Zanamivir, with other possible drugs being tested including Peramivir. Originally, it was thought that Amantadine and Rimantadine would not be useful as compared to the other two, but further sequencing of the most prevalent strains has shown that most are susceptible.<!--[if !supportFootnotes]-->[xxi]<!--[endif]--> So, aside from Tamiflu (Oseltimivir), the other three drugs are increasingly being stockpiled for a pandemic, in addition to supplies of masks, gloves, and antibiotics. Whether or not Tamiflu actually reduces symptoms or even death by H5N1 is still not clear however, though it does reduce morbidity in regular influenza and in experimental animals. The NIH is therefore funding a 2-year study to assess whether Tamiflu is actually effective in treating bird flu-infected patients.<!--[if !supportFootnotes]-->[xxii]<!--[endif]--> Nevertheless, a large stockpile of the drug has been stored by the WHO for the purpose of “fire-blanketing” any area that experiences a H2H outbreak of H5N1, in an attempt to prevent it from spreading beyond the affected area. This principle has been confirmed as effective by two computer models<!--[if !supportFootnotes]-->[xxiii]<!--[endif]-->—if the response is rapid and effective, but in practice it is a lot harder than it sounds, example in point being an outbreak among an extended family in eastern Turkey in January that ultimately killed four and infected many others.<!--[if !supportFootnotes]-->[xxiv]<!--[endif]--> It was days before the WHO was even given permission by the Turkish government and able to reach the town situated deep in the mountains, and when it did, snow and ice only served to block the roads. Fortunately, nothing further came of that outbreak, though had it been efficiently transmissible, it would have quickly spread out of control by the time the area was even reached. Additionally, this past week, seven of eight family members died of H5N1 in a remote village in western Indonesia, an outbreak that is now thought by experts to have been “effective human-to-human transmission to a very close group of people, but beyond that, not”.<!--[if !supportFootnotes]-->[xxv]<!--[endif]--> Again, in this case, several of the family members involved proceeded to escape the primary hospital and die (or live) elsewhere, and when investigators arrived on the scene, they were rebuffed at every step by villagers, who were frightened and unwilling to help in any way, believing either that the deaths had been caused by black magic or by Tamiflu, as all of the patients were treated with the drug (though this might be attributable to it’s administration being too late in the course of the disease).<!--[if !supportFootnotes]-->[xxvi]
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One of the reasons that H5N1 is thought to have such a high lethality rate is the complete lack of human immunity to the virus. This idea is probably not altogether accurate, because unlike regular human influenza strains, H5N1 has the ability to infect and kill almost all cell types causing almost violent necrosis at times<!--[if !supportFootnotes]-->[xxvii]<!--[endif]-->, and has other virulence factors such as the NS1 protein.<!--[if !supportFootnotes]-->[xxviii]<!--[endif]--> Additionally, though the actual sequences are different, the structures of the proteins it encodes are much more similar to the predicted 1918 H1N1 structures than they are to normal human influenza protein structures.<!--[if !supportFootnotes]-->[xxix]<!--[endif]--> In spite of this, the most efficient defense against high mortality and morbidity rates from a pandemic is probably vaccination-induced immunity, and so the international health community has spent a large proportion of their efforts on this avenue. One of the main problems they have encountered, however, is that the chicken eggs that are normally used to produce large quantities of influenza virus are killed by this H5N1 strain.<!--[if !supportFootnotes]-->[xxx]<!--[endif]--> As a result, it has to be transformed into a much less potent strain in order to produce enough of the virus. Early NIH vaccine trials have been so far somewhat disheartening however, as it was discovered that only the highest levels and number of doses allowed for sufficient antibody production, and even this level was much lower than what is produced in response to yearly human influenza vaccines, and so adjuvant research is being actively pursued too.<!--[if !supportFootnotes]-->[xxxi]<!--[endif]--> For an unknown reason, the H5N1 virus may not be very antigenic, thus hampering efforts. As a result of logistical problems such as these, other technologies are being developed, with the most promising being cell-based culturing technologies, which also allow for great scalability. Fortunately, large amounts of money and effort are being invested by governments and pharmaceuticals in creating a wide range of vaccines, but because H5N1 is diversifying rapidly as it enters new environments and infects new populations of birds and other animals, it will be impossible to know if any specific vaccine will be protective until the actual pandemic strain is on hand and a vaccine can be made from it. Finally, the possibility that vaccination against H5N1 may serve to lengthen the subclinical phase during which the virus is being shed—without grossly affecting morbidity or mortality—has not been posed.
As one quickly realizes, even the best laid plans can be hard to put into practice. Due to the fears that people and nations have regarding sovereignty, economics, panicked populations, and the often dramatic and unnecessary responses of other nations to their outbreaks, they often do not wish to publicize outbreaks among poultry and people. By hiding outbreaks and therefore not dealing with them appropriately, people often find that things can get out of control quite rapidly, and far more austere measures have to be made and much more suffering caused. This story has repeated itself over and over again all over the world. The best example is India, ironic because it has only had a couple of confirmed outbreaks in western India. Just to list the local newspaper reports published on the Internet of mass die-offs of poultry with the characteristically associated dead dogs and cats that had eaten them, in just February and March of this year, would literally take another paper. To this day, officials in India reassure their people that the Himalayas protect the country from ‘sick’ migratory birds, with a favorite quote of mine being “dead ducks don’t fly”<!--[if !supportFootnotes]-->[xxxii]<!--[endif]-->, while the poultry industry hosts enormous free chicken banquets for the public to allay concerns and promote continued consumption. No matter how many poultry farmers suffering one of these outbreaks die from ‘mysterious diseases’, India remains, like China did until late 2005, completely free of human H5N1 infections and sadly unwilling at this time to send samples for independent testing. Meanwhile, throughout the State of Madhya Pradesh, with a confirmed bird flu outbreak in it’s south, hundreds of villages have experienced unprecedented die-offs of swine from viral pneumonia since the beginning of the year.<!--[if !supportFootnotes]-->[xxxiii]
Other obvious examples include the Ukraine and Nigeria, where local farmers reported that their poultry had been dying in increasingly larger numbers for months before the now massive and uncontrollable outbreaks were confirmed by authorities to be caused by H5N1. This story is repeating itself again in Romania, where bird flu has broken out in at least 115 areas as of this writing and is thought to have done so because one poultry farm was able to successfully hide it’s dead chickens for a couple months, though it can also be said that migratory birds from Africa are now returning to their breeding grounds in Europe and Asia, with Romania being a particularly favorite spot.<!--[if !supportFootnotes]-->[xxxiv]<!--[endif]--> As one can see from these, there is much work to be done in the fields of international public health cooperation, as well as awareness. As a US News article on the Indonesian cluster this week points out in their final paragraph,
“All of this hand-wringing about whether or not it’s a pandemic is a distraction, says Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota. “We are woefully unprepared.” The world lacks a pandemic flu vaccine, hospitals in the United States have enough oxygen to treat patients for only two or three days, and the global community hasn’t figured out how people will get food, water, and medical supplies during a pandemic that could disrupt economies for months. A report from the University of Pittsburgh’s Center for Biosecurity says it would cost the average hospital $1 million to gear up, not counting buying more ventilators and antiviral drugs. Says Osterholm: “We're nibbling at the edges of the things we need to do.”<!--[if !supportFootnotes]-->[xxxv]<!--[endif]-->
It is a huge and difficult endeavor, with sometimes seemingly insurmountable obstacles in our way, but no matter how much or how little is done, if an avian flu pandemic occurs, no effort will be wasted, and if, by some miracle, H5N1 decides to leave the human race alone, and if history is anything to judge, it will still be a very valuable lesson for our ever-shrinking planet in the mitigation of the inevitable and periodic pandemics to come.-------------------------------------------------------
<!--[endif]--> <!--[if !supportFootnotes]--> [i]<!--[endif]--> Diamond, Jared. Guns, Germs, and Steel. WH Norton: 1999.<!--[if !supportFootnotes]--> [ii]<!--[endif]--> Gilbert, MT et al. Absence of Yersinia pestis-specific DNA in human teeth from five European excavations of putative plague victims. Microbiology. 2004 Feb;150(Pt 2):341-54.
<!--[if !supportFootnotes]--> [iii]<!--[endif]--> Duncan CJ and Scott S. What Caused the Black Death? PMJ. 2005; 81:315-320.
<!--[if !supportFootnotes]--> [iv]<!--[endif]--> Tumpey TM et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science. 2005 Oct 7;310(5745):77-80.
<!--[if !supportFootnotes]--> [v]<!--[endif]--> Chokephaibulkit K et al. A child with avian influenza A (H5N1) infection. Pediatr Infect Dis J. 2005 Feb;24(2):162-6.
<!--[if !supportFootnotes]--> [vi]<!--[endif]--> Areechokchai D et al. Investigation of avian influenza (H5N1) outbreak in humans--Thailand, 2004. MMWR Morb Mortal Wkly Rep. 2006 Apr 28;55 Suppl 1:3-6.
<!--[if !supportFootnotes]--> [vii]<!--[endif]--> Knobler SL et al. The Threat of Pandemic Influenza: Are We Ready? Workshop Summary. Page 60.
<!--[if !supportFootnotes]--> [viii]<!--[endif]--> Claas EC et al. Human influenza virus A/HongKong/156/97 (H5N1) infection. Vaccine. 1998 May-Jun;16(9-10):977-8.
<!--[if !supportFootnotes]--> [ix]<!--[endif]--> Thanawongnuwech R et al. Probable tiger-to-tiger transmission of avian influenza H5N1. Emerg Infect Dis. 2005 May;11(5):699-701.
<!--[if !supportFootnotes]--> [x]<!--[endif]--> Van Riel D et al. H5N1 Virus Attachment to Lower Respiratory Tract. Science. 2006 Apr 21;312(5772):399.
<!--[if !supportFootnotes]--> [xi]<!--[endif]--> Choi YK et al. Studies of H5N1 influenza virus infection of pigs by using viruses isolated in Vietnam and Thailand in 2004. J Virol. 2005 Aug;79(16):10821-5.
<!--[if !supportFootnotes]--> [xii]<!--[endif]--> Kuiken T et al. Avian H5N1 influenza in cats. Science. 2004 Oct 8;306(5694):241.
<!--[if !supportFootnotes]--> [xiii]<!--[endif]--> Butler D. Thai dogs carry bird-flu virus, but will they spread it? Nature. 2006 Feb 16;439(7078):773.
<!--[if !supportFootnotes]--> [xiv]<!--[endif]--> Butler D. Can cats spread avian flu? Nature. 9 March 2006. 440, 135.
<!--[if !supportFootnotes]--> [xv]<!--[endif]--> Liu J et al. Highly Pathogenic H5N1 Influenza Virus Infection in Migratory Birds. Science. 19 August 2005:309 (5738), 1206.
<!--[if !supportFootnotes]--> [xvi]<!--[endif]--> Gillis JS. An avian influenza vaccine for humans targeting the polymerase B2 protein inside the capsid instead of hemagglutinin or neuramidase on the virus surface. Med Hypotheses. 2006;66(5):975-7.
<!--[if !supportFootnotes]--> [xvii]<!--[endif]--> http://www.birdlife.org/action/scien...ies/avian_flu/
<!--[if !supportFootnotes]--> [xviii]<!--[endif]--> http://www.who.int/csr/disease/avian.../en/index.html
<!--[if !supportFootnotes]--> [xix]<!--[endif]--> http://www.alertnet.org/thenews/newsdesk/L27586620.htm
<!--[if !supportFootnotes]--> [xx]<!--[endif]--> http://www.alertnet.org/thenews/newsdesk/L26494082.htm
<!--[if !supportFootnotes]--> [xxi]<!--[endif]--> Cheung CL et al. Distribution of Amantadine-Resistant H5N1 Avian Influenza Variants in Asia. J Infect Dis. 2006 Jun 15;193(12):1626-9.
<!--[if !supportFootnotes]--> [xxii]<!--[endif]--> http://news.ft.com/cms/s/753787dc-ef...0779e2340.html
<!--[if !supportFootnotes]--> [xxiii]<!--[endif]--> Ferguson NM et al. Strategies for containing an emerging influenza pandemic in Southeast Asia. Nature. 2005 Sep 8;437(7056):209-14.
<!--[if !supportFootnotes]--> [xxiv]<!--[endif]--> http://www.recombinomics.com/News/01..._Timeline.html
<!--[if !supportFootnotes]--> [xxv]<!--[endif]--> http://www.abc.net.au/news/newsitems...5/s1648827.htm
<!--[if !supportFootnotes]--> [xxvi]<!--[endif]--> http://www.cbsnews.com/stories/2006/...8HSUU3O0.shtml
<!--[if !supportFootnotes]--> [xxvii]<!--[endif]--> Rimmelzwaan GF et al. Influenza A virus (H5N1) infection in cats causes systemic disease with potential novel routes of virus spread within and between hosts. Am J Pathol. 2006 Jan;168(1):176-83
<!--[if !supportFootnotes]--> [xxviii]<!--[endif]--> Seo SH et al. The NS1 gene of H5N1 influenza viruses circumvents the host anti-viral cytokine responses. Virus Res. 2004 Jul;103(1-2):107-13.
<!--[if !supportFootnotes]--> [xxix]<!--[endif]--> Stevens J et al. Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science. 2006 Apr 21;312(5772):404-10.
<!--[if !supportFootnotes]--> [xxx]<!--[endif]--> Hampton T. Mixed success found for avian flu vaccine. JAMA. 2006 Apr 26;295(16):1886.
<!--[if !supportFootnotes]--> [xxxi]<!--[endif]--> http://www3.niaid.nih.gov/news/newsr.../H5N1QandA.htm
<!--[if !supportFootnotes]--> [xxxii]<!--[endif]--> http://www.telegraphindia.com/105112...ry_5485091.asp
<!--[if !supportFootnotes]--> [xxxiii]<!--[endif]--> Examples include: http://www.dnaindia.com/report.asp?N...018456&CatID=2
http://www.thepigsite.com/swinenews/...rk-virus-fears
http://www.deccanherald.com/deccanhe...2352006322.asp
<!--[if !supportFootnotes]--> [xxxiv]<!--[endif]--> http://www.daily-news.ro/article_det...darticle=26828
<!--[if !supportFootnotes]--> [xxxv]<!--[endif]--> Shute N. A World of Worry. US News & World Report. 5 June 2006.
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