4
Addressing the Threats: Conclusions and Recommendations

Ten years after the 1992 Institute of Medicine report Emerging Infections: Microbial Threats to Health in the United States was issued, it has become even more apparent that infectious diseases continue to have a dramatic impact on the United States and the world. The response to microbial threats—from detection to prevention and control—requires a multidisciplinary effort involving all sectors of the public health, clinical medicine, and veterinary medicine communities. The committee’s recommendations, which emerged from focused deliberations and the application of the criteria of urgency, priority, and amenability to immediate action, are presented in this chapter. Given that infectious diseases are a significant threat to the health of the world’s population, several of the committee’s recommendations could be justified solely on the basis of humanitarian need; all are justified as being in the best interest of the United States to protect the health of its own citizens.

ENHANCING GLOBAL RESPONSE CAPACITY

The emergence of infectious diseases reflects complex social, economic, political, environmental, ecological, and microbiological factors that are globally linked. A number of forces operating in developing countries in particular, including urbanization, deforestation, changes in land use and climate, population growth, poverty, malnutrition, political instability, and even terrorism, have created the conditions for several infectious diseases to become new or recurrent threats. To devise and implement effective preven-



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4 Addressing the Threats: Conclusions and Recommendations Ten years after the 1992 Institute of Medicine report Emerging Infections: Microbial Threats to Health in the United States was issued, it has become even more apparent that infectious diseases continue to have a dramatic impact on the United States and the world. The response to microbial threats—from detection to prevention and control—requires a multidisciplinary effort involving all sectors of the public health, clinical medicine, and veterinary medicine communities. The committee’s recommendations, which emerged from focused deliberations and the application of the criteria of urgency, priority, and amenability to immediate action, are presented in this chapter. Given that infectious diseases are a significant threat to the health of the world’s population, several of the committee’s recommendations could be justified solely on the basis of humanitarian need; all are justified as being in the best interest of the United States to protect the health of its own citizens. ENHANCING GLOBAL RESPONSE CAPACITY The emergence of infectious diseases reflects complex social, economic, political, environmental, ecological, and microbiological factors that are globally linked. A number of forces operating in developing countries in particular, including urbanization, deforestation, changes in land use and climate, population growth, poverty, malnutrition, political instability, and even terrorism, have created the conditions for several infectious diseases to become new or recurrent threats. To devise and implement effective preven-

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tion and control strategies, therefore, the factors influencing the emergence of infectious disease must be recognized and addressed at a global level. Disease burdens—such as those incurred as a result of HIV, tuberculosis, and malaria—can contribute to the destabilization of nations, damaging their social and political infrastructures (National Intelligence Council, 2000; Denver Summit of the Eight, 1997). The past decade has seen the HIV epidemic besieged but entrenched in the United States, and spread globally with a catastrophic social and economic impact on many developing countries. Affecting adults in their productive years disproportionately, HIV has led to a grievous decrease in per capita gross domestic product (GDP) across Africa, resulting in a vicious spiral of decreased investment in public health and worsening of the epidemic. The resurgence of tuberculosis is devastating many countries, particularly Russia and other former Soviet republics, where tuberculosis rates have increased an astounding 70 percent in less than a decade. Antimicrobial resistance has become a major barrier to treatment of tuberculosis and malaria worldwide, threatens the effectiveness of antiretroviral therapy in persons with AIDS, and has made treatment of common bacterial infections more difficult in the United States and elsewhere. Infectious diseases are appearing abruptly in new locations and claiming hundreds of lives; a case in point is West Nile encephalitis, which spread to most parts of the United States within 3 years following its sudden appearance in the Northeast. Certain risks to health, such as contamination of food products, have resulted in enormous economic consequences, along with implications for human disease. Infectious diseases have even been used to intentionally terrorize populations, further dramatizing the need for a comprehensive assessment of and response to microbial threats. Amelioration of major health risks and problems in any country, therefore, is a global good that may indirectly benefit the United States. Moreover, in an era of heightened concern regarding international networks of terrorism and nations with weapons of mass destruction, leadership in addressing the infectious disease problems of other countries can build trust and goodwill toward the United States. Repeatedly, U.S. efforts to monitor and address infectious disease threats in other countries have been welcomed and have increased understanding and improved relationships between countries. The need for an adequate global response to infectious disease threats, therefore, derives from the United States’ humanitarian, economic, and national security interests. According to a recent analysis by the National Intelligence Council (2000), newly emerging infectious diseases, including the intentional use of a biological agent, will pose an increasing global health threat and will complicate U.S. and global security over the next 20 years. As outlined in that report, the future impact of infectious diseases will be heavily influ-

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enced by three sets of variables: (1) the relationship between increasing antimicrobial resistance and the success of research to develop new antibiotics and vaccines; (2) the trajectory of developing and transitional economies, especially concerning the basic quality of life of the poorest groups among the population; and (3) the degree of success of global and national efforts to create public health infrastructure with effective systems of surveillance and response. The interplay among these variables will determine the overall outlook regarding the impact of infectious diseases. In this context, it is clear that the response to emerging infectious diseases at a global level requires an investment in the capacity of developing countries to address these diseases as they arise. Such investments should take the form of financial and technical assistance, operational research, enhanced surveillance, and efforts to share both knowledge and best public health practices across national boundaries. For example, the World Health Organization (WHO) has developed a program for ensuring global health security by strengthening country capacity in microbiology and epidemiology to improve national preparedness (see Box 4-1). Financial and technical assistance to international agencies, governments, and nongovernmental organizations has already proven to be an effective means of addressing global disease threats. The Centers for Disease Control and Prevention (CDC) continues to support reference laboratories and provide technical assistance for disease outbreaks. Likewise, the National Institutes of Health (NIH) has expanded the number of international research and treatment centers. Financial and technical support has also come from private foundations and other U.S. agencies and organizations, and has been particularly effective in supporting efforts to combat HIV, tuberculosis, malaria, and polio. The United States should seek to enhance the global capacity for response to infectious disease threats, focusing in particular on threats in the developing world. Efforts to improve the global capacity to address microbial threats should be coordinated with key international agencies such as the World Health Organization (WHO) and based in the appropriate U.S. federal agencies (e.g., the Centers for Disease Control and Prevention [CDC], the Department of Defense [DOD], the National Institutes of Health [NIH], the Agency for International Development [USAID], the Department of Agriculture [USDA]), with active communication and coordination among these agencies and in collaboration with private organizations and foundations. Investments should take the form of financial and technical assistance, operational research, enhanced surveillance, and efforts to share both knowledge and best public health practices across national boundaries.

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BOX 4-1 The World Health Organization Office in Lyon Epidemics and emerging infections continue to threaten human health worldwide, and many developing countries lack the capacity and expertise necessary to address these threats effectively. The World Health Organization (WHO), head-quartered in Geneva, Switzerland, is working to ensure global health security. In 2001, WHO’s Department of Communicable Diseases, Surveillance, and Response opened an office in Lyon, France. To strengthen country capacity in microbiology and epidemiology, this new office provides a training program focused on enhancing the capacity of national public health laboratories, supporting field epidemiology training programs, and improving the capacity to detect and respond to disease outbreaks. The overall objective of the program is to strengthen diagnostic and surveillance capabilities at all levels. This goal can be achieved through an increase in reference diagnostic capabilities for communicable diseases; the development of appropriate core public health administrative practices; the development of rapid, sustainable national and international laboratory communications networks; the development of rapid, efficient, and safe means for shipment of diagnostic materials and laboratory specimens; and the establishment of appropriate quality control principles and practices. The 2-year training program is designed for senior laboratory staff. Throughout the course of the program, participants receive training in essential laboratory diagnostic practices and techniques, biosafety, data collection and management, statistical analysis, basic disease epidemiology, and personnel management and administration. Following an initial 8-week session in Lyon, the trainees return to their home organizations. Over the course of the next 2 years, they are followed up in their home countries and return to Lyon for two shorter visits. Upon completion of the program, participants should be able to contribute effectively to the rapid detection of epidemic and emerging diseases in their countries. Each year the program enrolls 15 participants for two sessions. It is estimated that after 5 years, the program will have trained 150 specialists from 45 countries. The first training cohort consisted of participants from 7 African countries who were selected for their senior roles in the management of their country’s national public health reference laboratory. The first training session consisted of three modules: laboratory, surveillance, and information technology; laboratory response; and laboratory management. The second group of trainees was selected from Middle Eastern and North African countries and began training in 2002. SOURCE: World Health Organization, 2001h. Improving the global capacity to respond to microbial threats will require sustained efforts over time. Given the imminent nature of many infectious disease threats, however, it is critical that immediate action be taken toward achieving this capacity. Mobilization of young graduates in the health sciences has proven to be a successful strategy for meeting the

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goals identified by government agencies responsible for improving health domestically. For example, the National Health Service Corps, administered by the Health Resources and Services Administration (HRSA), has created a mechanism for dedicated health professionals to work in underserved communities where they are most needed nationwide. A similar mechanism could be used to established a Global Health Services Corps, offering loan forgiveness in exchange for service in areas of global public health need. Such a program could provide the stimulus for an immediate U.S. workforce to serve as a means of increasing global response capacity by assisting developing countries in creating the infrastructure, knowledge, and skills necessary to sustain long-term independent success. In addition to building developing-country capacity to respond, the program could enable U.S. public health agencies (e.g., CDC, NIH) to maintain expertise in epidemiology and laboratory issues related to diseases no longer endemic in the United States through training of U.S. scientists within countries where these diseases remain endemic. The same is true for diseases that are potential bioterrorist agents, particularly since the cadre of U.S. experts in rare diseases has declined (see the later discussion of educating and training the microbial threats workforce). Expansion of programs in infectious disease research and training for health professionals from other countries is also needed. Notable successes in this area include the NIH Fogarty International Center for Advanced Study in the Health Sciences (FIC) that sponsors U.S. schools of medicine and public health in providing training for foreign scientists from developing countries through its AIDS International Training and Research Program (NIH, 1999). Since the center’s inception, more than 2,000 scientists from more than 100 countries and territories have received training. In addition, over 46,000 students and health professionals have been provided short-term training through courses conducted in 65 countries. FIC also supplies funding for competitive supplemental awards under the Tuberculosis International Training and Research Program, a collaborative program with the National Institute of Allergy and Infectious Diseases (NIAID), CDC, and USAID. An aim of this funding is to foster global health research efforts and public health capacity to better respond to the threat posed by tuberculosis and multidrug-resistant tuberculosis. In yet another collaborative program, FIC and NIAID provide awards to U.S. universities under the International Training and Research Program in Emerging Infectious Diseases, which expands NIH research training efforts in the study of microbial threats. The long-term objective is to train teams of scientists in regions of the world that offer unique opportunities to understand the fundamental biology, epidemiology, and control of emerging microbial diseases.

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IMPROVING GLOBAL INFECTIOUS DISEASE SURVEILLANCE The need to strengthen global infectious disease surveillance is vital. As noted earlier, in addition to the United States’ humanitarian objective of aiding countries in crisis, it is critical to U.S. national security that quality population-based data on disease burden and trends in the developing world be obtained through global surveillance (Hyder and Morrow, 2000). Yet disease burden estimates and projections are often based on only fragmentary data (Murray and Lopez, 1997). The reality in many developing societies is that deaths and births are not recorded, and a formal system of medical care is unavailable to most of the population (Cooper et al., 1998). Health care infrastructures that lack simple diagnostic tests for diseases such as tuberculosis or that have insufficient resources to perform diagnostic tests add to the lack of knowledge of disease burden. Developing countries in which high proportions of the population experience morbidity and/ or mortality from infectious diseases may be the least likely to be encompassed by official statistics because of this lack of resources. Basic health indices, such as death rates or causes of death, are unknown in such contexts. Health ministries may generate health reports, but the data are generally unreliable. Such numbers have been used as the basis for broad policy recommendations; if the numbers are incorrect, however, the resulting policies can be damaging. In addition to monitoring disease burden, surveillance efforts should be expanded and diversified to include the capacity to recognize previously unknown illnesses or unusual outbreaks of disease that may have global significance. With today’s rapid and often mass global movements of people, animals, and goods, the transnational spread of infectious diseases can occur quickly and easily. Global surveillance, especially for newly recognized infectious diseases, is therefore crucial in responding to and containing microbial threats before isolated outbreaks develop into regional or worldwide epidemics. U.S. agencies have been working with WHO and other partners to achieve the goal of a comprehensive global surveillance system, and efforts to date are aptly described as creating a “network of networks” (see Figure 4-1). In Europe, countries have made significant progress through the development of networks such as those for travel-related Legionnaires’ disease, enteric organisms (Enter-net), and drug resistance. The United States has also supported efforts to establish regional networks. An example is DOD’s support for laboratory-based surveillance in the 21 countries of the Caribbean Epidemiology Center, in collaboration with the Pan American Health Organization and CDC. Likewise, CDC and others have worked in many areas to assist regional surveillance networks. Examples include the Amazon and Southern Cone networks, which encompass eight laboratories

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FIGURE 4-1 Global surveillance of communicable diseases: a network of networks. SOURCE: WHO, Communicable Diseases. in six countries of South America (CDC, 2002r), and the MeKong Delta Surveillance Network, which includes five countries of Asia, as well as the province of Yunan in China. In 1996, DOD was mandated to use its long-standing and well-respected overseas research laboratories in Egypt, Indonesia, Kenya, Peru, and Thailand to establish the Global Emerging Infections Surveillance (GEIS) program. GEIS is a critical and unique resource for the United States in the context of global infectious disease surveillance; it is the only U.S. entity with broad-based laboratory capacity in overseas settings. GEIS has already demonstrated its excellent potential to detect the emergence of disease in those and surrounding countries (IOM, 2001e). CDC has assigned several epidemiologists to GEIS to provide increased epidemiologic capacity at these overseas sites. CDC plans to establish multiple international programs to address emerging infections, the first of which was established in Thailand in 2001 (CDC, 2002r). As more DOD overseas laboratories and CDC Emerging Infections Programs are established, increased collaboration between the two agencies will be beneficial, and serious consideration must be given to which geographic sites will fill the most critical gaps in surveillance worldwide. Also important for global surveillance are novel training programs initiated by NIAID that provide the opportunity for field training in Asia, Africa, and South America, along with laboratory-based training in the United States, with incentives to return trainees to their home countries. Such programs require expansion in particular in the “hot zones” of Africa and Asia that are recognized as epicenters for the emergence of such agents

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as Ebola, HIV, Nipah, and influenza. NIAID initiatives on pandemic preparedness for influenza in Asia, which promote zoonotic surveillance and preparation of the necessary reagents, are prototypes for the programs necessary for global surveillance. The WHO Global Influenza Surveillance Program, now 50 years old, was responsible for the early identification of the H5N1 influenza A virus, as well as the H9N2 virus that occurred later—viruses that had previously been detected only in birds. The reagents necessary for identification of these viruses were developed by NIAID and were made available to the WHO program. Because WHO must issue recommendations for the composition of influenza vaccines twice a year—once for the Northern Hemisphere in February and once for the Southern Hemisphere in September— data must be gathered throughout the year. The infrastructure in place allows the identification of new variants, whether they are new epidemic variants or new variants with pandemic potential. The infrastructure rests on a number of national influenza centers that serve as the key laboratories for the isolation and identification of influenza viruses, using a kit of reagents produced by CDC and distributed globally. The laboratories also collect epidemiological information for transmittal to WHO headquarters in Geneva. International collaborating centers, including CDC, conduct comparative analyses of influenza viruses from around the world. Collaboration with industry is essential because the strains that are identified as vaccine candidates are provided free of charge to the pharmaceutical industry for vaccine production. Globally, advances in information technology have also allowed novel uses of the Internet in disease surveillance. The Program for Monitoring Infectious Diseases (Pro-Med) uses electronic communications to provide up-to-date news on disease outbreaks and is open to all users. A team of experts in human, animal, and plant diseases screens, reviews, and investigates reports before posting notices. The system was designed to promote communication among the international infectious disease community, and to provide for the exchange of information about outbreaks and other matters of interest regarding emerging infectious diseases (International Society for Infectious Diseases, 2001). PacNet, an Asian network of health professionals on 20 Pacific Islands, is another such network, established to allow the exchange of information among health professionals regarding epidemics in that region. An even more innovative system, established by Health Canada in collaboration with WHO, is the Global Public Health Intelligence Network (GPHIN), an Internet-based application that continuously scans global electronic media (news wires, websites) for information on global public health risks, including infectious disease outbreaks (WHO, 1998b) (see Box 4-2). In line with the growth of electronic media, approximately 65 percent of the world’s first news about infectious disease events

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BOX 4-2 Global Outbreak Alert and Response Network The Global Outbreak Alert and Response Network enables WHO to monitor disease outbreaks continuously. This network was formally launched in 2000 and links over 72 existing networks around the world, some of which are able to diagnose and detect unusual agents and handle dangerous pathogens. The four critical tasks of the network are epidemic intelligence and detection, verification of rumors and reports, immediate alert, and rapid response. The Global Outbreak Alert and Response Network gathers global disease intelligence using a number of sources, such as ministries of health, WHO country offices and collaborating centers, laboratories, academic institutes, and nongovernment organizations. The Global Public Health Intelligence Network (GPHIN), an electronic system that constantly performs surveillance of worldwide communications for disease events, is one of the most important informal sources from which the network gathers data. GPHIN was developed for WHO through a collaboration with Health Canada in 1996. The intelligence gathered is converted by the WHO Outbreak Alert and Response team, which then determines whether a reported disease event constitutes cause for international concern. The team meets each morning to review reports and rumors, assess their epidemiological significance, and determine actions needed. The team creates a detailed report that is distributed electronically each day to specific WHO staff around the world. From 1998 to 2001, WHO verified 578 outbreaks in 132 countries. The network electronically connects WHO member countries, disease experts, institutions, agencies, and laboratories to keep them constantly informed of outbreak events, rumored and confirmed. The network also provides real-time alerts through an outbreak verification list, offering detailed information on current outbreaks that is regularly updated and maintained. In addition, WHO posts information on outbreaks on its Disease Outbreak News website. Rapid response is a critical task of the Global Outbreak Alert and Response Network. Once an outbreak has been verified, the Outbreak Alert and Response team determines whether an international response is needed to contain it. When an international response is necessary, partners in the global health network are called upon to provide specific support, from investigations and patient management to logistics, including the provision of necessary staff and supplies. WHO and the Nuclear Threat Initiative recently partnered to create an Emergency Outbreak Response Fund to ensure that the rapid response teams can be at a designated site within 24 hours of a detected outbreak. Since 2000, WHO and the network have launched effective international responses to outbreaks in Afghanistan, Cote d’Ivoire, Egypt, Ethiopia, and other countries. SOURCE: World Health Organization, 2003b.

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during the past 4 years has come not from official country notifications, but from informal sources, including press reports and the Internet (Heymann, 2001). Recent efforts to increase capacity for translation to the six official United Nations languages will further enhance the GPHIN system. As described earlier, surveillance of and response to emerging infectious disease threats in other parts of the world can directly benefit the United States as well as the country in which an occurrence is detected. For example, the investigation of hantavirus in Korea in the 1970s and the development of a diagnostic test were useful in the identification of and response to the epidemic of hantavirus infection in the southwestern United States in 1993. Similarly, the investigation of the H5N1 influenza virus in Hong Kong in 1997 alerted the United States and the world to the threat posed by influenza viruses in avian species as sources of pandemic influenza viruses in humans, and highlighted the urgency of influenza pandemic planning globally. The rapid measures taken to control H5N1 influenza in Hong Kong exemplify increasing global cooperation in disease surveillance. WHO, together with experts from the United States, Europe, and the Pacific region, provided information to the Hong Kong authorities on the virological and epidemiological properties of the H5N1 threat, and as a consequence, the local authorities decided to slaughter all poultry in Hong Kong. This decision resulted in a dramatic cessation of human cases of H5N1, providing a direct benefit to Hong Kong, China, and the global community. Similar steps to stamp out the epidemic of Nipah viruses among livestock and humans in Malaysia provide yet another example of the importance of global disease surveillance and the benefits to global health. Likewise, liaisons between the U.S. and European sentinel surveillance networks have led to the identification and removal of products being marketed in numerous countries, including the United States, that were contaminated with bacterial pathogens. Several national and international groups, including the National Science and Technology Council (1995) and the Denver Summit of the Eight (1997), have echoed the 1992 IOM recommendation to establish a global disease and outbreak surveillance system. Significant efforts have been made to enhance global surveillance, but the system remains skeletal and is inadequate to monitor disease incidence and prevalence in most parts of the world. The United States should take a leadership role in promoting the implementation of a comprehensive system of surveillance for global infectious diseases that builds on the current global capacity of infectious disease monitoring. This effort, of necessity, will be multinational and will require regional and global coordination, advice, and resources from participating nations. A comprehensive

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system is needed to accurately assess the burden of infectious diseases in developing countries, detect the emergence of new microbial threats, and direct prevention and control efforts. To this end, CDC should enhance its regional infectious disease surveillance; DOD should expand and increase in number its Global Emerging Infections Surveillance (GEIS) overseas program sites; and NIH should increase its global surveillance research. In addition, CDC, DOD, and NIH should increase efforts to develop and arrange for the distribution of laboratory diagnostic reagents needed for global surveillance, transferring technology to other nations where feasible to ensure self-sufficiency and sustainable surveillance capacity. The overseas disease surveillance activities of the relevant U.S. agencies (e.g., CDC, DOD, NIH, USAID, USDA) should be coordinated by a single federal agency, such as CDC. Sustainable progress and ultimate success in these efforts will require health agencies to broaden partnerships to include nonhealth agencies and institutions, such as the World Bank. REBUILDING DOMESTIC PUBLIC HEALTH CAPACITY The U.S. capacity to respond to microbial threats to health is contingent on a public health infrastructure that has suffered years of neglect. Upgrading current public health capacities will require considerably increased investments across differing levels of government. Most important, this support will have to be sustained over time. Such an investment will have lasting and measurable benefits for all humankind. With recent increased funding for bioterrorism preparedness, the United States has an opportunity to develop programs and policies that will both protect against acts of bioterrorism and improve the U.S. public health response to all microbial threats. However, it is alarming that some of these funds have been diverted from multipurpose infrastructure building to single-agent preparedness. The threat of bioterrorism is intimately related to that of naturally occurring infectious diseases. The response to bioterrorism is much like the response to any microbial threat to health, and the necessary resources for building the public health infrastructure are, in essence, the same as those needed to respond to bioterrorism. It would be counterproductive to develop an ancillary system for bioterrorist threats. Rather, such efforts must be integrated with those addressing the continuum of infectious disease concerns and potential disasters to which public health agencies are already charged to respond. While preparedness for bioterrorist-inflicted outbreaks will require certain specialized program elements and policies (related, e.g., to law enforcement, evidence collection), the human health aspects of this

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Need to Increase the Armamentarium for Vector Control Expanded research into the biological and ecological determinants of vector maintenance and transmission of pathogens, together with the explosion of information that will occur in the mosquito post-genomics era (Holt et al., 2002) are likely to result in new and unforeseen approaches and targets to control vector-borne diseases. Examples of research areas with the potential to increase the armamentarium for control of vector-borne diseases and to augment currently available control approaches are described below. For the foreseeable future, traditional approaches to reducing vector populations or repelling vectors will remain the first lines of defense against emerging and resurging vector-borne diseases. Clearly, the development of new, environmentally acceptable pesticides will be critical to mitigate the potential for dramatic increases in such diseases (Sina and Aultman, 2001). Improved Pesticides Discontinuance of DDT usage has exacerbated the burden of vector-borne diseases in many parts of the world (Attaran et al., 2000). The resurgence of vector-borne diseases and resistance to alternative pesticides, therefore, has forced some countries to resume DDT usage. Since domicile treatment with DDT has not been associated with major adverse environmental consequences, this practice should be allowed for vector control in public health emergencies until equally effective and inexpensive substitutes for DDT are developed. DDT may help control vector-borne diseases, such as dengue and malaria, not only by killing vectors, but also by repelling them (Roberts et al., 2000). Residual DDT in homes may repel mosquitoes, thereby disrupting the close association between the human host and anthropophilic and endophilic vectors and dramatically reducing opportunities for pathogen transmission. At the same time, care will be needed to ensure that the availability of DDT for public health uses does not result in its use in agricultural applications. The development of efficacious and environmentally sensitive alternatives to DDT needs to become a major research objective. Novel Strategies to Prolong Pesticide Usage Pesticide usage in integrated pest management programs, which incorporate established agricultural practices for mitigating the evolution of resistance (e.g., rotation of pesticides used, inclusion of refugia with no pesticide applications), would extend the useful life of existing pesticides. Incorporating new molecular tools for diagnosing pesticide resistance into

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control programs could also result in more effective and efficient pesticide usage. Moreover, the development of novel strategies for prolonging pesticide efficacy, such as negative cross-resistance, should be possible in this era of high-throughput screening (Pittendrigh and Gaffney, 2001). More information on the effect of the prevalence of resistance to pesticides on the control of vector-borne diseases would be of great value for risk assessment. New Repellents As noted, repellents remain a first line of defense against emerging or resurging vector-borne diseases. DEET is the most efficacious repellent currently available commercially; however, its relicensing has been problematic because of adverse effects associated with its overuse in children, presumably due to its lipophilic nature (Qiu et al., 1998). Modern high-throughput and genomic approaches may permit the identification of new molecules with repellent activity similar to that of DEET (and DDT), but without adverse effects. Understanding of the molecular basis of vector olfaction and host seeking (Hill et al., 2002) could lead to the development of new repellents and attractants to control vectors (Day et al., 2001). New Biopesticides and Biocontrol Agents to Augment Chemical Pesticides The increase in pesticide resistance necessitates new investigations into biocontrol agents, such as viruses and bacteria, that could be incorporated into integrated pest management approaches for vector control. New formulations of Bacillus thruringiensis and Bacillus sphaericus show promise for control of vectors, even in tropical regions (Thiery et al., 1997; Regis et al., 2001). Baculoviruses from mosquitoes may be useful for vector control (Afonso et al., 2001). Other biopesticide agents could be improved using molecular genetic approaches to make them more efficacious control agents. For example, viruses could be used to transduce effector molecules in order to enhance vector knockdown or manipulate vector phenotypes. Novel Strategies to Interrupt Pathogen Transmission Strategies for vector-borne disease control remain focused on approaches that involve immunizing humans, using pesticides to reduce vector populations, or repellents to reduce contact with vectors. If pesticide resistance and parasite resistance to drugs continue to increase, if public health infrastructure cannot be rebuilt, and if mortality rates from vector-borne diseases persist or increase, novel approaches now emerging from

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investigations of vector molecular biology and pathogen–vector–host interactions may be necessary to control these diseases. Insights into the molecular basis of pathogen–vector–host interactions suggest new strategies for controlling vector-borne diseases (Foy et al., in press; Willadsen, 2001). Immunizing hosts to vector-specific determinants of pathogen transmission (e.g., salivary effector proteins that enhance pathogen infection; see Titus and Ribeiro, 1988) could provide broad-spectrum protection against multiple pathogens or strains (Kamhawi et al., 2000, Valenzuela et al., 2001). Other critical determinants of pathogen infection of and transmission by vectors (e.g., vector proteolytic enzymes, which process arbovirus proteins and condition vector infection) could be targeted for transmission-blocking vaccines (Carter, 2001). Immunizing vertebrate hosts to immunologically privileged antigens of vectors could kill or impair blood-feeding mosquitoes, a strategy that works for ticks (Willadsen and Billingsley, 1996) and may also be useful against mosquito vectors, which frequently feed on humans (Foy et al., in press). Theoretically, these vectors would feed on other hosts (zooprophylaxis), thereby reducing pathogen transmission. Genetic approaches in which vector populations are manipulated to become incompetent vectors are being investigated for their potential to interrupt pathogen transmission. Such approaches could minimize potential environmental issues associated with pesticide usage and prevent an ecological vacuum that other vectors could occupy. The vector population could theoretically be genetically immunized to make it nonpermissive to pathogen transmission. The “immunogens” could be driven into vector populations by harnessing naturally occurring arthropod systems, such as transposable elements, symbionts, or transducing viruses, which would be vector-specific (Beaty, 2000). RNAi, which was recently documented in vectors (Adelman et al., 2001), could be exploited in such programs. Proof of principle has been provided that vectors can be molecularly manipulated to make them refractory to arboviruses and trypanosome and malaria parasites (Beard et al., 2002; Olson et al., 1996, Ito et al., 2002). Recent progress in vector molecular biology suggests that continued research in these areas may provide new approaches for the control of vector-borne diseases, although the success of genetic manipulation in control programs is by no means certain (Boete and Koella, 2003). Research utilizing genetically manipulated vectors would require ecological studies (Scott et al., 2002) to determine the feasibility of such an approach to vector control and would require addressing the benefits, risks, and social and political issues associated with such a control strategy (Alphey et al., 2002).

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DOD and NIH should develop new and expand upon current research efforts to enhance the armamentarium for vector control. The development of safe and effective pesticides and repellents, as well as novel strategies for prolonging the use of existing pesticides by mitigating the evolution of resistance, is paramount in the absence of vaccines to prevent most vector-borne diseases. In addition, newer methods of vector control—such as biopesticides and biocontrol agents to augment chemical pesticides, and novel strategies for interrupting vector-borne pathogen transmission to humans—should be developed and evaluated for effectiveness. Geographic Information Systems and Robust Models for Predicting and Preventing Vector-borne and Zoonotic Diseases Also complicating the control of vector-borne and zoonotic diseases has been a lack of knowledge of fundamental epidemiologic, genetic, biologic, and environmental determinants that condition potential increased transmission to humans by the respective nonhuman vectors or reservoirs. Because biological and ecological factors condition the transmission of pathogens by vectors and from animal reservoirs to humans, GIS and robust models (see Appendix E for a discussion of modeling) offer the potential to provide predictive capability for the emergence of vector-borne and zoonotic diseases. The ecological and quantitative capabilities of GIS make it possible to identify some of the determinants of endemicity and emergence. The developing hantavirus GIS models are promising in this regard (Boone et al., 1998; Glass et al., 2000; Hjelle and Glass, 2000; Yates et al., 2002b). The inclusion of genetic information concerning vector competence and rodent permissiveness, as well as other epidemiologically important information, such as gene flow in vector and reservoir populations (e.g., Black et al., 2001; Gorrochotequi-Escalante et al., 2002), may improve surveillance and risk assessment strategies for zoonoses and enhance the predictive capability of GIS and model systems. New GIS and robust models could revolutionize surveillance, risk assessment, and prevention strategies for zoonoses and permit the focusing of resources and talent on prevention efforts in areas of greatest risk, an especially important capability in resource-limited environments. CDC, DOD, and NIH should work with state and local public health agencies and academia to expand efforts to exploit geographic information systems (GIS) and robust models for predicting and preventing the emergence of vector-borne and zoonotic diseases.

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COMPREHENSIVE INFECTIOUS DISEASE RESEARCH AGENDA Research remains an essential underpinning of the capacity to prevent and control infectious diseases. Despite recommendations made in the 1992 IOM report Emerging Infections: Microbial Threats to Health in the United States, calling for increased research on factors underlying the emergence of infectious diseases and an extramural grant program for research on surveillance and applied control methods, significant gaps remain in the overall infectious disease research agenda of the United States. To ensure that the nation is strategically poised to protect itself against the threat of infectious diseases and to maximize its assistance to developing countries in their efforts to combat these diseases, further investments must be made to support a diverse array of multidisciplinary research domains. These new investments must be part of an overall strategy for improved public health preparedness and protection against infectious disease threats, and a comprehensive system of accountability must be in place to ensure that no critical areas are neglected. The considerable amount of new resources now becoming available for biodefense research makes this a critical time to develop a comprehensive research agenda. The most effective use of these new funds will involve integration of the evolving threat posed by the intentional use of biological agents as weapons into the broader context of infectious disease research. As previously noted, bioterrorism represents but the extreme end of a continuum of serious infectious disease threats, including the emergence of new infectious diseases, the resurgence of old ones, the appearance of new antimicrobial-resistant forms of old diseases, recognition of the infectious etiology of chronic diseases, and the creation of bioengineered organisms that produce disease in unforeseen ways. For such an integrated agenda to be effective, it must address both long- and short-term needs, involve both basic science and applied public health research, be multidisciplinary in nature, and utilize modern and robust molecular and quantitative tools. Scientific research can yield a greater understanding of the biology and pathogenesis of organisms that cause disease, the biology of disease-spreading vectors, and the ways in which the human immune system responds to infection and disease. Several factors beyond these traditional foci of infectious disease research, however, play significant roles in the emergence of infectious disease threats (see Chapter 3). For example, malnutrition has long been known to play a role in susceptibility to death from diarrhea, respiratory infection, and malaria. Not as well understood are the roles of famine, war, crowding, urbanization, and population growth. Risky behaviors, such as illicit drug use and unprotected sex, are closely linked to several emerging infectious diseases. Ecological factors surrounding a lack of clean water and poor sanitation have also been linked to diseases such as

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cholera and plague. Additional ecological factors (e.g., deforestation or other forms of land use change) are associated with many emerging vector-borne and zoonotic diseases, such as dengue, malaria, yellow fever, Lassa fever, Lyme disease, and West Nile encephalitis, but remain poorly understood. New grounds for mosquito breeding have developed in waste dumps, threatening vector control efforts that have traditionally focused on vector breeding in swamps and marshes. As previously noted, agricultural practices have been closely linked to the spread of antibiotic resistance, influenza outbreaks, and diseases of food crops and animals. Migration, travel, and commerce have been associated with several microbial threats to health. Human development and large-scale social phenomena are closely connected to infectious disease threats at a global level. National security and an enlightened self-interest require that countries recognize the direct impact of social, economic, political, and ecological factors, especially in developing countries. In additional to technical and financial support, a research program focused on the global social and ecological factors affecting infectious disease emergence should be established. Only recently have studies been conducted within the traditional biomedical, social epidemiology, and medical anthropology research arenas to begin to address these factors and the interventions necessary to combat them. Inferences about the etiology of disease are typically drawn through statistical association of natural observations or experiments. Recognizing, however, that the emergence of infectious disease is usually not attributable to any single factor, but the result of complex interactions among numerous and often unknown physical, biological, ecological, and socioeconomic variables, it is clear that multidisciplinary studies, including dynamic analyses of such interactions, are needed. NIH should develop a comprehensive research agenda for infectious disease prevention and control in collaboration with other federal research institutions and laboratories (e.g., CDC, DOD, the U.S. Department of Energy, the National Science Foundation), academia, and industry. This agenda should be designed to investigate the role of genetic, biological, social, economic, political, ecological, and physical environmental factors in the emergence of infectious diseases in the United States and worldwide. This agenda should also include the development and assessment of public health measures to address microbial threats. A sustained commitment to a robust research agenda must be a high priority if the United States is to dramatically reduce the threat of naturally occurring infectious diseases and intentional uses of biological agents. The research agenda should be flexible to permit rapid assessment of new and emerging threats, and should be rigorously reevaluated

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on a 5-year basis to ensure that it is addressing areas of highest priority. Successfully carrying out such an integrated, comprehensive research agenda will entail collaboration among multiple government agencies, academia, and the private sector. Collaborations between the academic research and public health communities are essential to ensure that priority research areas are addressed in a timely manner and that findings can be readily applied. Research driven by grants in the infectious disease arena rarely includes the kind of practical research, such as evaluations of programs and interventions, that is of value to public health workers in the field. Even within schools of public health, applied public health research has not been a priority. This problem can be addressed, in part, by creating faculty positions that are accountable to both academic centers and health departments. A coordinated approach must extend from fundamental laboratory science through operation, evaluation, and intervention research. In addition, the full support and engagement of a range of professional disciplines, including such often-overlooked fields as entomology, ecology, and anthropology, are needed. INTERDISCIPLINARY INFECTIOUS DISEASE CENTERS As previously noted, addressing the highly complex nature of infectious disease emergence requires the involvement of experts from a broad range of disciplines and health sectors. Collaborative links within and between universities and among international, federal, and state governments currently exist. The present structure of academic and public health institutions, however, requires that most of these arenas operate independently of each other. Opportunities for convergence and synergism are often lost unless experts convene under the same roof (or on the same campus) to discuss a problem. Not only are opportunities lost for collaboration, but there are often unnecessary redundancies of effort and expense. Furthermore, the absence of an interdisciplinary collaborative approach results in failure to adequately train the workforce needed to address the emerging microbial threats facing the world today. While federally proposed Research Centers of Excellence in Biodefense and Emerging Infections may provide some of the infrastructure needed to address specific emerging disease threats (e.g., basic research, vaccine and antimicrobial drug development), they do not meet the need for such an approach. Many types of infectious disease problems—including the search for infectious triggers of chronic disease, the emergence of antibiotic resistance, nosocomial infections, and zoonotic infections—could be addressed through an interdisciplinary approach. The majority of emerging diseases that

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threaten humans are of zoonotic origin. In the past 10 years, the world has had to respond to Sin Nombre virus and other hantaviruses from rodents, Nipah virus from bats via pigs, influenza viruses from aquatic birds, and West Nile virus from birds via mosquitoes. Zoonotic diseases have also emerged when domestic animals have served as reservoirs. As discussed earlier, antimicrobial-resistant organisms have emerged in part as a result of the agricultural use of antimicrobials for disease prevention and growth promotion in chickens, pigs, cattle, and even fish and shellfish. Indeed anthrax, used as an agent of bioterrorism in 2001, is a naturally occurring zoonotic disease. The vulnerability of the United States and the developed world to agroterrorism attack using agents such as foot and mouth disease virus and the high socioeconomic cost of diseases of livestock could be better addressed through an interdisciplinary approach to microbial threats. It is imperative that those in the human, animal, agricultural, and environmental sciences come together to examine such threats. Our understanding of many recent emerging disease threats has come mostly from a cadre of scientists who are at home in the laboratory, in the clinic, or in the field. These scientists have usually been formally trained in one medical/biomedical/veterinary discipline, but have gained additional training and experience in other disciplines pertinent to disease prevention and control. The disciplinary base of this cadre of scientists has been remarkably diverse, including clinical medicine, veterinary medicine, microbiology, virology, molecular biology, pathology, immunology, toxicology, epidemiology, public health, mammalogy, wildlife biology, medical entomology, and ecology. Some of these scientists have had valuable tertiary expertise as well, in such areas as epidemiologic modeling, GIS and remote sensing technologies, health education, administration and management, and public policy. Other relevant disciplines include economics, anthropology, and ethics. This cadre of scientists has provided invaluable knowledge and skills to address the multidisciplinary nature of infectious disease control. Younger counterparts rely increasingly on molecular approaches and computer-based tools, and often lack training and experience in the basic disciplines most pertinent to infectious disease prevention and control, such as epidemiologic field observations and investigations. Unfortunately, today there are too few scientists who can bring to bear all the various tools and approaches that may be of use in the detection, diagnosis, investigation, prevention, and control of emerging infectious diseases. These problems are not unique to infectious diseases. In the past, one solution has been to create centers of interdisciplinary excellence, perhaps best exemplified by the cancer research centers that have proven invaluable to advances in cancer prevention ansd treatment. Denmark has met the need for an interdisciplinary perspective in addressing emerging infectious dis-

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eases by developing a zoonosis center as an element of its national public health institution, the Statens Serum Institut, uniting veterinary and human health professionals. The committee believes much could be gained if the United States were to create similar interdisciplinary infectious disease centers for research, education, training, and public service. Given the nation’s lack of infrastructure in this area, such centers would have to be established with bricks and mortar, not as completely virtual centers. Interdisciplinary infectious disease centers should be developed to promote a multidisciplinary approach to addressing microbial threats to health. These centers should be based within academic institutions and link (both physically and virtually) the relevant disciplines necessary to support such an approach. They would collaborate with the larger network of public agencies addressing emerging infectious diseases (e.g., local and state health agencies, CDC, DOD, the U.S. Department of Energy, FDA, the Food Safety and Inspection Service, NIH, the National Science Foundation, USAID, USDA), interested foundations, private organizations, and industry. The training, education, and research that these centers would provide are a much-needed resource not only for the United States, but also for the entire world. The proposed centers would provide space to bring people together so that their proximity would generate work across intellectual discipline– driven boundaries on a research agenda that requires a cross-disciplinary approach. This is exactly what comprehensive cancer centers have done so well, bringing together clinicians (pediatricians, internists, oncologists, radiologists, and surgeons), basic scientists, epidemiologists, pharmacologists, immunologists, virologists, cell biologists, structural biologists, radiation biologists, and radiation therapists. Interdisciplinary work requires that those involved have not only good will toward and awareness of each other, but also a means of actually talking to each other frequently, often casually—contacts that in time lead to new kinds of work that bridge multiple disciplines. Seminars on various arenas of work given regularly in a center help bring people and ideas together. Economists, sociologists, medical anthropologists, epidemiologists, medical geographers, and others might need to pool their talents with those of immunologists, vaccine developers, and infectious disease clinicians and health care workers to solve persistent problems of community- or regionally-based outbreaks of infection. A center would help unite faculty of schools of public health, medical school basic and clinical faculty, and local and state public health officials. Nowhere is the opportunity for interdisciplinary work greater than in the global infectious diseases arena. To make such work a reality, we need to create space and support for people from multiple disciplines to work

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A Vision for Interdisciplinary Infectious Disease Centers Interdisciplinary, multidisciplinary research projects. The centers would foster interactions among university faculty in public health, clinical medicine, veterinary medicine, and the relevant basic and social sciences, as well as among those working in local, state, and national public health systems. The centers would focus on high-priority public health problems and leverage expertise across multiple organizations. A training venue. The aim would be to develop future scientists and leaders with the kind of broad perspective needed to work across boundaries in their efforts to control new and reemerging microbial threats to health. A venue providing a point of entry or primary exposure for young scientists might take the form of summer fellowship programs, internships, and other training opportunities. A link to primary and reference laboratory diagnostic systems. No common ground for developing a proper national reference diagnostic system and communal repository of infectious agent stocks and other diagnostic reagents currently exists. The centers would also provide an ideal venue for creating such a system and for training in laboratory technologies. Information/database systems. Databases would provide pertinent epidemiological, diagnostic, and other important information for all members of the scientific community. Some aspects of this information/database system might be made available via the Internet, and an e-mail network (perhaps as a subunit of the highly successful Pro-Med system) might also be provided. together. Emerging infectious diseases and persistent infections create an urgent need for such centers. In addition to helping to meet national and even international needs in addressing emerging infectious diseases, the proposed centers would play a critical role in improving our national capacity to deal with nosocomial infections, drug resistance, socioeconomic issues in the emergence and transmission of infection, and the infectious etiologies of cancer and chronic inflammatory and degenerative diseases. Individual centers would be expected to have different foci of interest, so as to provide the nation with a broad-based ability to deal with infections of all kinds. A case in point to suggest the value of such centers is the importance of addressing the zoonotic aspects of influenza. While WHO oversees global surveillance of human influenza through centers in London, Atlanta, Tokyo, and Melbourne, there is little interaction between this program and animal influenza surveillance programs. Influenza viruses that have been

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transmitted from wild aquatic bird reservoirs through domestic poultry and pigs and then on to humans represent the most significant threat of influenza to humans. Although the Office International des Epizooties (OIE) deals with the reportable diseases of animals, only certain influenza virus types that are highly pathogenic for poultry are of concern—those viruses that are found to be rather nonpathogenic in poultry, but for which a potential threat to humans exists, are ignored. Given the remarkable mutability of influenza viruses, it might be expected that there would be strong links between WHO and its human influenza tracking system and OIE and its still-primitive animal influenza tracking system. It can be argued that such linkage will be effected only through the development of several interdisciplinary infectious disease centers focused on zoonoses.