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MICROBIAL THREATS TO HEALTH

THE THREAT OF PANDEMIC INFLUENZA

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
www.nap.edu



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Microbial Threats to Health: The Threat of Pandemic Influenza MICROBIAL THREATS TO HEALTH THE THREAT OF PANDEMIC INFLUENZA INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Microbial Threats to Health: The Threat of Pandemic Influenza THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The materials in this document draw from the 2003 Institute of Medicine publication, Microbial Threats to Health: Emergence, Detection, and Response, and have been updated with a new Preface by the committee chairs and study director. Additional copies are available from the Institute of Medicine, 500 Fifth Street, NW, Washington, DC 20001. Copies of the full report, Microbial Threats to Health: Emergence, Detection, and Response, are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2005 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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Microbial Threats to Health: The Threat of Pandemic Influenza “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Adviser to the Nation to Improve Health

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Microbial Threats to Health: The Threat of Pandemic Influenza THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Microbial Threats to Health: The Threat of Pandemic Influenza Preface In 2003, the Institute of Medicine of the National Academies published a report, Microbial Threats to Health: Emergence, Detection, and Response, that addressed global emerging infectious diseases and provided a set of recommendations for responding to the threat. The recommendations called for enhancing global public health and medical response capacities, improving global infectious disease surveillance, rebuilding domestic public health capacity, encouraging better disease reporting, exploring innovative systems of surveillance, developing and using diagnostics, educating and training the public health and medical workforces, developing new vaccines and antimicrobial drugs, ending the inappropriate use of antimicrobials, improving vector and zoonotic disease control, and developing a comprehensive and interdisciplinary approach for addressing microbial threats to health. It was no coincidence that the committee that authored the report chose to illustrate the report’s cover with an artist’s rendition of the ecology of influenza. The committee unanimously agreed that an influenza pandemic represented a significant threat to the world at the time of publication. Unfortunately, a mere two years later, we are indeed at the precipice of realizing the imminence of this threat. The World Health Organization has warned that mankind may never have faced a greater risk of a deadly epidemic than it is currently facing with influenza. Unless we take aggressive action now, an influenza pandemic will cause massive loss of life and economic disruption to any country and the world, either through the natural emergence of this threat or by the hands of man-made terror.

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Microbial Threats to Health: The Threat of Pandemic Influenza Influenza pandemics have appeared at irregular intervals during the last century, with the most devastating being the 1918 influenza pandemic that claimed more than 40 million lives worldwide in less than a year’s time. The pandemic was especially brutal for those in early adulthood, something we do not routinely see with the annual influenza epidemics that tend to strike the very young or the very old. Scientists have been intrigued as to why the 1918 influenza strain was so lethal to those in the prime of their life, and the modern wonders of medical technology have made available the entire genomic sequence of that strain for research. Reverse genetic technology can remake this virus in the laboratory. While the advance of science may certainly provide insight to virulence factors of this historical strain and open new possibilities for antivirals and vaccines, we could put ourselves at risk from an inadvertent laboratory accident or even an intentional misappropriated use of this deadly strain as an agent of bioterrorism. While such apprehensions are the new reality of research in the biosciences, nature itself may be providing our greatest threat from a potentially virulent strain of influenza A, known as the H5N1 virus. Influenza A (H5N1) is a subtype of the type A influenza virus. The virus is maintained in the environment by wild birds as the natural hosts, hence the name avian influenza or bird flu. The virus circulates among birds worldwide, is very contagious among them, and avian influenza epidemics can be deadly, particularly to domesticated birds like chickens. The world is witnessing such an event with the emergence of the H5N1 virus as the highly pathogenic strain that is responsible for the wide outbreak of avian influenza in the poultry populations of Asia. The avian influenza virus does not typically infect humans with great efficiency; however, exposure to sick birds, uncooked poultry, or contaminated surfaces has been linked to the transmission of the H5N1 virus to humans. In 1997, the first direct bird-to-human transmission of influenza A (H5N1) virus was documented during an outbreak of avian influenza among poultry in Hong Kong. The H5N1 virus was responsible for at least 18 human cases of influenza disease and resulted in 6 deaths. This particular H5N1 virus was eradicated by culling all of the poultry in Hong Kong and was therefore not able to adapt to humans. Since 1997, the world has witnessed highly pathogenic avian influenza, H5N1, in eight different countries simultaneously. Outbreaks of avian influenza occurred among poultry in Cambodia, China, Indonesia, Japan, Lao, South Korea, Thailand and Vietnam in 2003 and early 2004. At that time, more than 100 million birds either died from the disease or were culled. The massive culling of chickens is an important public health measure to prevent the spread of virus to humans. With increased incidence of sporadic bird-human transmission there is an elevated potential that avian and human influenza viruses will undergo genetic reassortment and poten-

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Microbial Threats to Health: The Threat of Pandemic Influenza tially emerge as a highly virulent strain that can be passed from human-to-human. An avian influenza epidemic also increases the possibility that this gene reassortment will occur in pigs, since they possess receptors for both avian and human influenza viruses. According to the CDC, new research suggests that H5N1 viruses are becoming more capable of causing disease for mammals than earlier H5 viruses and are becoming more widespread in birds in the region. Other findings have documented H5 virus infection among pigs in China and Indonesia, and also in cats. These finding are particularly worrisome in light of the fact that reassortment of avian influenza genomes is most likely to occur when these viruses demonstrate a capacity to infect multiple species, as is now the case in Asia. In early 2004, 35 confirmed human cases of H5N1 virus infection were reported in Thailand and Vietnam, resulting in 23 deaths. Beginning in late June 2004, new lethal outbreaks of H5N1 virus infection among poultry were reported in Cambodia, China, Indonesia, and for the first time, Malaysia. The new outbreaks in poultry were followed by renewed sporadic reporting of human cases of H5N1 virus infection in Vietnam and Thailand beginning in August 2004 and continuing into 2005. According to the World Health Organization, since January 2004, 97 cases and 53 deaths have been reported (as of May 12, 2005) in Viet Nam, Thailand and Cambodia. Viet Nam, with 76 cases and 37 deaths, has been the most severely affected country. It is important to note that no human cases have been isolated in Thailand in 2005. It is now likely that H5N1 virus infection among birds has become endemic to Asia and human infections will continue to be reported. So far, no sustained human-to-human transmission of the H5N1 virus has been identified and no evidence for genetic reassortment between human and avian influenza virus genes has been detected. One instance of probable limited human-to-human transmission of H5N1 virus was reported in Thailand between a child and her mother and aunt in September 2004. In 2005, reports have been made of new family clusters of H5N1 virus infection in separate parts of Vietnam. If these H5N1 viruses gain the ability for efficient and sustained transmission between humans, an influenza pandemic could result with high rates of illness and deaths. It has been conservatively estimated that two to seven million deaths could occur worldwide. The current weight of evidence now suggests a shift from the possible to the likely. In the event of an influenza pandemic of H5N1 virus, most of the world’s population will have no humoral immunity to this strain. Our only defense will be the rapid development of an effective vaccine and/or the use of antivirals effective against the strain. In 2003, the Institute of Medicine Microbial Threats Committee reported, “Our nation—and the world—face

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Microbial Threats to Health: The Threat of Pandemic Influenza a serous crisis with respect to vaccine development, production, and deployment.” This is as true for an influenza vaccine as it is for the vaccines needed to respond to the infectious diseases plaguing many parts of the globe on an annual basis. The reasons for this crisis are spelled out in the report and have been articulated in many other studies and reports from other organizations and governments. The bottom line is that the current technologies and infrastructure will require an estimated minimum of six months from the identification of the pandemic strain to the availability of a vaccine. Efforts to produce a vaccine that would be effective against the current strain of H5N1 virus are under way, but mass production and availability of such a vaccine is some time off. This, in essence, leaves us with antivirals as our first line of defense. Of concern, genetic sequencing of H5N1 virus samples from human cases in Vietnam and Thailand show resistance to the antiviral medications amantadine and rimantadine, leaving only two remaining antiviral medications (oseltamavir and zanamavir) that should still be effective against currently circulating H5N1 virus strains. Again, despite numerous calls for the stockpiling of antivirals for influenza, we do not yet have in possession the adequate volume of antivirals necessary to respond to a pandemic. The time to act is now. A number of immediate steps can be taken to prevent an inevitable influenza pandemic from reeking havoc upon the world. For years, pandemic influenza preparedness plans have been bantered around within nations and as a global plan. To answer the repeated call for a comprehensive strategy to respond to a pandemic, the political will to do so must be increased and must include governments, corporations, officials, health professionals, and the public. In the cases where action has occurred, it has not been enough or has not been of the scale that will be required to respond to the global demand that will follow a pandemic. Although we are faced with a complex challenge of preparing for an influenza pandemic, we have the knowledge and capabilities to put in place systems to reduce the threat. Such systems can have vast implications for maintaining national and international security, and for saving lives. More needs to be done now, both within countries and globally, to better prepare for the threat of pandemic influenza. Renewed and serious commitments to the public/private partnerships are necessary for developing new vaccines for influenza and for assuring their adequate production and supply, whether for routine use or in a pandemic emergency. These same partnerships are also needed to contribute to the development of new and improved antivirals, and to ensure an adequate stockpiling of such drugs. The current global system for disease detection and reporting should be strengthened and expanded upon to get the earliest warning of an emerging outbreak, which is crucial to responding to a threat. Pandemic preparedness

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Microbial Threats to Health: The Threat of Pandemic Influenza plans should be in place on a local, national, and global level, to offer an effective plan to respond and to share critical resources during an unfolding crisis. And finally, we need to continue to work closely with other countries to develop new agricultural strategies and animal management practices that are less likely to propagate the development and rapid spread of influenza among animals, and more importantly, from animals to humans. These are just some of the key issues that must be approached from a global perspective if we are to be better prepared. Surely we do not want to be in the position of looking back after such an epidemic hits, wondering why we did not act before. The public, scientific community, and policy makers must understand that the threat of an influenza pandemic is real and imminent. To this end, we have republished a section of the Microbial Threats report entitled: “Influenza: A Case in Point” in an effort to educate readers about the ecology of influenza and facilitate an informed response. In addition, we have included the executive summary of the report that has key information about the factors that lead to the emergence of microbial threats and the recommendations of the committee for implementing an effective and appropriate response. We hope all citizens of the world, and especially our scientific and political leaders, will take it upon themselves to do all they can to act now to prevent and prepare for the global threat before us. Sincerely, Margaret A. Hamburg Co-chair and editor Joshua Lederberg Co-Chair and editor Mark S. Smolinski Study Director and editor

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Microbial Threats to Health: The Threat of Pandemic Influenza Contents     Executive Summary   1     Reprinted from Microbial Threats to Health: Emergence, Detection, and Response (2003)         A Case in Point: Influenza—We Are Unprepared   19     Reprinted from Chapter 3, pages 136-147 of Microbial Threats to Health: Emergence, Detection, and Response (2003)         References   31     Appendix   33     Reviewers   35

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