3
Addressing the Threats

The process by which an infectious disease emerges and is recognized and responded to can be complex. Chapter 2 dealt with the many factors involved in emergence. This chapter addresses disease recognition and intervention and provides specific recommendations for improving the ability of the United States and the global community to respond to future microbial threats to health. The relationships between and among recognition activities and interventions are diagrammed in Figure 3-1.

Chapter 3 is divided into two sections. The first, on recognition, addresses domestic and international surveillance. The recommendations in this section, if implemented, would strengthen U.S. surveillance activities and encourage efforts to develop a global infectious disease surveillance network. The second section, on interventions, is divided into subsections that address the U.S. public health system, research and training, vaccine and drug development, vector control, and public education and behavioral change. Each subsection includes one or more recommendations directed at improving the current U.S. capability to respond to outbreaks of emerging infectious diseases.

RECOGNITION

The key to recognizing new or emerging infectious diseases, and to tracking the prevalence of more established infectious diseases, is surveillance. Surveillance and rapid response to identified disease threats are at the core of preventive medicine. A well-designed and well-implemented infectious disease surveillance program can provide a means to detect unusual clusters of disease, document the geographic and demographic spread of an outbreak,



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Emerging Infections: Microbial Threats to Health in the United States 3 Addressing the Threats The process by which an infectious disease emerges and is recognized and responded to can be complex. Chapter 2 dealt with the many factors involved in emergence. This chapter addresses disease recognition and intervention and provides specific recommendations for improving the ability of the United States and the global community to respond to future microbial threats to health. The relationships between and among recognition activities and interventions are diagrammed in Figure 3-1. Chapter 3 is divided into two sections. The first, on recognition, addresses domestic and international surveillance. The recommendations in this section, if implemented, would strengthen U.S. surveillance activities and encourage efforts to develop a global infectious disease surveillance network. The second section, on interventions, is divided into subsections that address the U.S. public health system, research and training, vaccine and drug development, vector control, and public education and behavioral change. Each subsection includes one or more recommendations directed at improving the current U.S. capability to respond to outbreaks of emerging infectious diseases. RECOGNITION The key to recognizing new or emerging infectious diseases, and to tracking the prevalence of more established infectious diseases, is surveillance. Surveillance and rapid response to identified disease threats are at the core of preventive medicine. A well-designed and well-implemented infectious disease surveillance program can provide a means to detect unusual clusters of disease, document the geographic and demographic spread of an outbreak,

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Emerging Infections: Microbial Threats to Health in the United States FIGURE 3-1 Recognition of and interventions for emerging infectious diseases.

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Emerging Infections: Microbial Threats to Health in the United States estimate the magnitude of the problem, describe the natural history of the disease, identify factors responsible for emergence, facilitate laboratory and epidemiological research, and assess the success of specific intervention efforts. Unfortunately, there is insufficient awareness of and appreciation for the value of comprehensive surveillance programs. Even among public health personnel, involvement in surveillance activities is often limited to collecting and transmitting disease-related data, a viewpoint that can mask the objectives and significance of the overall effort. Some health care and public health professionals are unfamiliar with surveillance methods, mainly because the topic is covered inadequately in medical schools and even in schools of public health (Thacker and Berkelman, 1988). The result is incomplete, underrepresentative, and untimely disease reporting. Poor surveillance leaves policymakers and practitioners without a basis for developing and implementing policies for controlling the spread of infectious diseases. Surveillance can take many forms, from complex international networks involving sophisticated laboratory and epidemiological investigations, to small, community-based programs or a single astute clinician. Disease surveillance often is a passive process that is based on individual health care workers who report instances of unusual or particularly contagious human illnesses, usually to a government health agency. In other instances, more formal surveillance can take place, in which public health workers actively seek out cases of disease and report their findings regularly to a central data collection point. The importance of surveillance to the detection and control of emerging microbial threats cannot be overemphasized. Active monitoring of such factors as population growth and migration, vector abundance, development projects that disturb the environment, and natural environmental factors (especially temperature and precipitation) is an essential component of surveillance and can influence the spread of emerging infectious diseases and the effectiveness of efforts to control them. Surveillance is important to any disease control effort; it is absolutely essential if that effort's goal is eradication. Without the information obtained through disease surveillance, it is not possible to know how and where disease control efforts should be focused or to analyze the impact of ongoing efforts. The smallpox eradication program, discussed below, is an excellent example of the use of surveillance for case finding and program monitoring. Surveillance in Action: The World Health Organization's Smallpox Eradication Program An often overlooked but very significant contributor to the success of global smallpox eradication was disease surveillance. Of course, smallpox eradication would have been impossible had there not been an effective

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Emerging Infections: Microbial Threats to Health in the United States vaccine and a simple, inexpensive means of delivering it—the bifurcated needle. The fact that humans were the only known reservoir for the smallpox virus also simplified the task of eradication, since no insect vector or nonhuman animal hosts were involved in disease transmission. Smallpox is transmitted by the respiratory route, by contact with pox lesions, or by infective material, such as bed linens, recently contaminated with discharge from lesions. A distinctive rash and skin lesions develop within 10 to 14 days in virtually all who are infected by the smallpox virus. Because those infected are contagious only from the time the rash appears to the time the resulting scabs fall off, and because subclinical cases play no role in disease spread, tracing the chain of transmission is fairly straightforward. During the eradication period, when a case of disease was located, the affected individual was isolated and potential contacts were vaccinated. At the same time, an effort was made to find the person from whom the patient had presumably contracted the disease, and that individual's contacts were similarly vaccinated. Perhaps the most difficult part of the eradication effort was the development of adequate national surveillance programs, since they were either nonexistent or nearly so in all participating countries when the program began. At the outset, it was evident that most smallpox cases were not being reported even though smallpox was, by international treaty, a reportable disease. It has been estimated that less than 1 percent of cases were being reported when the World Health Organization's (WHO) global smallpox eradication program got under way in 1967 (Henderson, 1976a,b). Thus, one of the early steps in the eradication campaign was to establish disease reporting systems in countries that did not have them and to upgrade the quality of reporting systems in countries that did. It was a formidable task. In African countries and in Brazil, this was often done by assigning teams of two to four persons to an administrative area that encompassed a population of from 2 million to 5 million. The teams were charged with regularly visiting health centers and hospitals to encourage health personnel to report cases (or the absence of cases) each week, with investigating and containing outbreaks, and with distributing vaccine and vaccination supplies. These teams played a vital role in the development and success of the reporting system. Not only did they discover unreported cases, but their prompt response to smallpox outbreaks also served to encourage case-reporting by health workers. As the incidence of the disease fell, periodic searches were conducted on a house-by-house basis. In some countries, such as India, Pakistan, and Bangladesh, rewards were offered for reporting cases. Another key feature of the smallpox surveillance effort, and one that is common to all effective surveillance initiatives, was information dissemination.

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Emerging Infections: Microbial Threats to Health in the United States Those taking part directly in the eradication effort, as well as others with a "need to know," were regularly supplied with surveillance reports. The reports contained weekly tallies of cases from each reporting unit, comments, and other items of interest, such as specimen collection procedures or information about other smallpox programs. In 1971, four years after the global campaign had begun, the number of countries reporting smallpox cases had fallen from 44 to 16 (Henderson, 1976a,b). By 1975, only one country, Ethiopia, remained endemic for the disease; two years later, the last known case of naturally occurring smallpox was diagnosed. Finally, in 1979, after long and careful review, the WHO certified the world free of smallpox. LESSONS FROM THE SMALLPOX EXPERIENCE Because every disease is different, in terms of how it is diagnosed, whom it affects, and where it occurs, surveillance efforts must be individually tailored. The experience with smallpox eradication was unique in several respects. Most important, eradication is not the goal of most public health activities that use surveillance. The fact that vaccination was the primary tool used to combat the disease also sets smallpox apart from most other situations in which surveillance plays a role. Nevertheless, the eradication campaign illustrated a number of important principles about surveillance that might be applied to other efforts to monitor and control the spread of infectious diseases. One of the most fundamental is that a reduction in disease incidence is the ultimate measure of success in disease control. In the case of smallpox, for example, tallying the number of vaccinations performed in order to gauge the campaign's success would have been of little value because the immune response to the vaccine was not the same for all who were vaccinated. Not everyone to whom vaccine was administered was effectively vaccinated in terms of protection from contracting smallpox.1 In addition, as the eradication campaign developed, it became clear that special efforts to vaccinate those at high risk, particularly contacts of infected individuals, were the most effective strategy. By focusing on disease incidence, it was possible to identify the epidemiological factors responsible for cases of disease that occurred despite ongoing efforts to prevent them. Once these 1   Failures might be attributed to substandard vaccine (prior to 1970, when all vaccine used in the eradication program met international standards for potency and stability) or to poor (or absent) host immune response. Many other vaccines are likely to be somewhat less effective than smallpox vaccine (vaccinia); nevertheless, they may be important and useful tools for disease control.

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Emerging Infections: Microbial Threats to Health in the United States factors had been identified, disease control efforts could be modified accordingly. The importance of flexibility in surveillance activities was underscored early in the eradication campaign. The initial strategy had been to conduct mass vaccinations in every endemic country and at the same time improve surveillance capabilities. It was felt that once 80 percent of a country's population was immunized, any remaining foci of infection could be rapidly identified, contained, and eliminated. Once the campaign was under way, however, it became clear that achieving the 80 percent immunization goal might not be necessary. A more targeted approach, called surveillance-containment, was tried. Infected individuals were located and isolated, and known or suspected contacts were vaccinated, thus preventing the disease from spreading to others. The new strategy worked because smallpox infection is never silent, because it spreads slowly compared with many other infectious diseases, and because vaccination could produce immunity within the incubation period for the disease. Current U.S.-Supported Surveillance Efforts Current U.S. surveillance efforts include both domestic and international components. Although the domestic program, in which a number of federal government agencies participate independently, is fairly comprehensive, U.S. international surveillance activities at this time are fragmented and inadequate to detect emerging infectious disease threats on a timely basis. DOMESTIC EFFORTS Surveillance of infectious diseases in the United States is a passive process. It relies on physicians, hospitals, and other health care providers to report cases to state and local organizations that are responsible for disease surveillance. The Centers for Disease Control (CDC) works in cooperation with the states in monitoring the domestic incidence of specific infectious diseases (such as measles, mumps, rubella, pertussis, diphtheria, and hepatitis B). Each state has its own regulations regarding the reporting of specific diseases. These "notifiable" diseases may duplicate or expand on the list of 49 diseases that are reportable to the CDC (see Table 3-1). Notifiable Diseases Surveillance The bulk of the federal reporting requirements are implemented through the National Notifiable Diseases Surveillance System (NNDSS), established in 1961. The list of nationally notifiable diseases is maintained and revised as needed by the Council of State and Territorial Epidemiologists in collaboration

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Emerging Infections: Microbial Threats to Health in the United States TABLE 3-1 Diseases Currently Reportable to the Center for Disease Control Acquired immunodeficiency syndrome Amebiasis Anthrax Aseptic meningitis Botulism, food borne Botulism, infant Botulism, wound Botulism, unspecified Brucellosis Chancroid Cholera Congenital rubella syndrome Diphtheria Encephalitis, post chickenpox Encephalitis, post mumps Encephalitis, post other Encephalitis, primary Gonorrhea Granuloma inguinale Hansen disease Hepatitis A Hepatitis B Hepatitis, non-A, non-B Hepatitis, unspecified Legionellosis Leptospirosis Lyme disease Lymphogranuloma venereum Malaria Measles Meningococcal infections Mumps Pertussis Plague Poliomyelitis, paralytic Psittacosis Rabies, animal Rabies, human Rheumatic fever Rocky Mountain spotted fever Rubella Salmonellosis Shigellosis Syphilis, all stages Syphilis, primary and secondary Syphilis, congenital Tetanus Toxic shock syndrome Trichinosis Tuberculosis Tularemia Typhoid fever Yellow fever     SOURCE: Wharton et al., 1990. with the CDC. Reporting of diseases on the list is voluntary, with the exception of the diseases that require quarantine: yellow fever, cholera, diphtheria, infectious tuberculosis, plague, suspected smallpox, and viral hemorrhagic fevers. Regulatory authority for disease surveillance in the United States is provided through state legislation. Reportable disease data are provided to the CDC on a weekly basis by state health departments, New York City, the District of Columbia, Puerto Rico, the Virgin Islands, Guam, American Samoa, and the Commonwealth of the Northern Mariana Islands. Since 1984, disease reporting has been accomplished through a computer-based telecommunications system, the National Electronic Telecommunications System for Surveillance (NETSS). The CDC analyzes the data and disseminates it in its Morbidity and Mortality Weekly Report. As of June 1990, aggregate or case-specific data for a total of 49 infectious diseases were being reported to the CDC by all

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Emerging Infections: Microbial Threats to Health in the United States U.S. states and territories. Individual states require reporting on more than 100 additional infectious diseases or infectious disease-related conditions (Centers for Disease Control, 1991k). Data on disease incidence obtained through the NNDSS are important for public health decision making. Data supplied by private physicians and laboratories, the points of contact within the health care system for individuals who become ill, are critical elements in this process. In those instances in which a patient is diagnosed with a reportable disease, this information is supposed to be transmitted to the local or state health department. Unfortunately, this does not always happen. Laboratories may not have sufficient resources for reporting or may decide that reporting is unimportant. (Some states, however, require laboratories to report specific diseases.) Some physicians may be unaware of the requirement to report the occurrence of a specific disease or may not appreciate the importance of such a requirement. Outbreaks of any disease that is not on CDC's current list of notifiable illnesses may go undetected altogether or may be detected only after an outbreak is well under way. In fact, except for food-borne and waterborne diseases, the United States has no comprehensive national system for detecting outbreaks of infectious disease. Emerging infectious diseases also are not usually detected and reported through established surveillance activities. Instead, private physicians who see small clusters of unusual cases may report them in the medical literature. What is needed is a way to bring these small clusters to the attention of the appropriate agencies in a timely manner. The committee recommends the development and implementation of strategies that would strengthen state and federal efforts in U.S. surveillance. Strategy development could be a function of the Centers for Disease Control (CDC). Alternatively, the strategy development and coordination functions could be assigned to a federal coordinating body (e.g., a subcommittee of the Federal Coordinating Council for Science, Engineering, and Technology's [FCCSET] Committee on Life Sciences and Health,2 specifically constituted to address this issue. Implementation of the strategies would be assigned to the appropriate federal agencies 2   The FCCSET is a federally appointed body of experts that serve on seven standing committees and act as a mechanism for coordinating science, engineering, technology, and related activities of the federal government that involve more than one agency. In addition to conducting cross-cutting analyses of programs and budgets, the various committees and their subcommittees (interagency working groups) examine wide-ranging topics with the goal of reaching consensus on fundamental assumptions and procedures that can guide the actions of the participating agencies in achieving their mission objectives more effectively.

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Emerging Infections: Microbial Threats to Health in the United States (e.g., CDC, National Institutes of Health, U.S. Department of Agriculture). Approaches for consideration could include simplifying current reporting forms and procedures, establishing a telephone hotline by which physicians could report unusual syndromes, and using electronic patient data collected by insurance companies to assist in infectious disease surveillance. The committee believes that an excellent example of appropriate coordination of surveillance (and other) activities related to the emergence of a microbial threat to the U.S. population is the recent effort spearheaded by the CDC. Recognizing the seriousness of the emerging multidrug-resistant TB (MDRTB) epidemic, the CDC convened a federal task force in December 1991 at the request of James Mason, the Assistant Secretary for Health. This effort resulted in the National Action Plan to Combat Multidrug-Resistant Tuberculosis (National MDR-TB Task Force, 1992). The plan lays out a series of objectives, in the areas of epidemiology and surveillance, laboratory diagnosis, patient management, screening and preventive therapy, infection control, outbreak control, program evaluation, information dissemination/training and education, and research. These objectives are based on specific problems identified by the task force to meet these objectives. The plan specifies a series of activities, responsible organizations, and time frames for implementation. The committee feels that a similar task force could be convened to implement the above recommendation, as well as the one presented later in this chapter on U.S. international efforts in surveillance. Nosocomial Infections Surveillance A second major domestic disease surveillance effort is the National Nosocomial Infections Surveillance System (NNISS), which gathers data from approximately 120 sentinel hospitals. The NNISS is operated by the CDC's Hospital Infections Program (HIP); it is the nation's only database devoted to tracking nosocomial infections, which annually affect some 2 million hospitalized patients. The system allows estimates to be made about the incidence of nosocomial infections in the United States, and it provides data that help to detect changes in patterns of incidence, distribution, antibiotic drug resistance, sites of infection, outcomes of infection, and risk factors for nosocomial infections. Each year, the HIP receives more than 5,000 inquiries about nosocomial infections, including a small number that involve the management of acute outbreaks. In the past 10 years, HIP staff have investigated approximately 120 hospital outbreaks of infectious disease (Centers for Disease Control, 1991b).

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Emerging Infections: Microbial Threats to Health in the United States Hospitals must apply for membership in the NNISS, and their identity remains confidential. Membership is approved based on adequacy of personnel support for infection control, availability of a computer compatible with the NNISS software, and agreement of the hospital administration. The system has several limitations. For example, it cannot correct for differences among participating hospitals in diagnostic testing, intensity of surveillance, and provisions for post discharge surveillance. The requirement that NNISS member hospitals have at least 100 beds and the fact that a relatively small sample of hospitals is included in the system are potential sources of bias (Gaynes et al., 1991). Even so, the NNISS is the only national database for nosocomial infections, and it is a critical element in the CDC's program to monitor disease incidence. The system is still evolving. Current plans call for improvements in the dissemination of NNISS data, the inclusion of a surveillance component for immunosuppressed patients, and the addition of more sentinel hospitals, among other efforts (Gaynes et al., 1991). These improvements should lead to better detection of outbreaks and widespread trends in the emergence of resistance among nosocomial pathogens. The limited participation of hospitals in the NNISS, however, remains a problem; as a result, little improvement will occur in nosocomial surveillance in the more than 6,000 hospitals that are not NNISS participants. Since hospital surveillance activities are not income generating, there is little financial motivation for hospitals to become involved. It is likely that accrediting agencies will have to mandate greater full-time-equivalents before the surveillance and control of these pathogens will improve in the majority of hospitals. The committee recommends that additional resources be allocated to the Centers for Disease Control to enhance the National Nosocomial Infections Surveillance System (NNISS) in the following ways: Include data on antiviral drug resistance. Include information on morbidity and mortality from nosocomial infections. Increase the number of NNISS member hospitals. Strive to make NNISS member hospitals more representative of all U.S. hospitals. Evaluate the sensitivity the specificity of nosocomial infection surveillance activities performed in NNISS member hospitals. Determine the reliability of antimicrobial susceptibility testing performed in NNISS member hospitals.

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Emerging Infections: Microbial Threats to Health in the United States Outbreak Surveillance Since 1988, the CDC has participated with a number of states in a pilot project to develop a system for computerized surveillance of outbreaks of diseases that are not currently notifiable. For food-borne or waterborne outbreaks, reporting is required when two or more cases occur; for other outbreaks, the threshold for reporting is three cases. During a five-month period in 1990, nine participating states reported 233 outbreaks involving 6,241 individual cases of disease (Centers for Disease Control, 1991k). This initiative should also provide data to help identify factors that increase the risks of outbreaks and make it easier to assess the effectiveness of outbreak prevention and control measures. Influenza Surveillance To monitor influenza incidence and the prevalence of particular virus strains in this country, the CDC, in addition to participating in the WHO's global influenza surveillance network (see the later discussion), operates a domestic influenza surveillance program. Data for the program come from state and territorial health departments, U.S.-based WHO collaborating laboratories (see Figure 3-2), 121 key U.S. cities, and ''sentinel" U.S. physicians. The epidemiological information these sources gather is analyzed and released to public health officials, physicians, the media, and the public. Access to Surveillance Information Considerable effort and resources are being expended on the various surveillance activities in which U.S. government agencies and the private sector participate. Much of this information, however, is not readily accessible. There is currently no single database from which a physician, researcher, health care worker, public health official, or other interested party can obtain information on disease incidence, antibiotic drug resistance, drug and vaccine availability, or other topics that might be relevant to infectious disease surveillance, prevention, treatment, and control. The need for such a database is strong; given the current communications capabilities of personal computers and the relative ease with information on a multitude of topics can be accessed, a database is not only technologically feasible but could be a valuable addition to U.S. surveillance efforts. The committee recommends that the U.S. Public Health Service develop a comprehensive, computerized infectious disease database. Such a database

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Emerging Infections: Microbial Threats to Health in the United States would require development of an integrated national process, as described above. The committee offers two options for implementation of this recommendation: Develop an integrated management structure within the federal government and provide purchase guarantees, analogous to farm commodity loans, to vaccine manufacturers that are willing to develop the needed capacity. Build government-supported research and development and production facilities, analogous to the National Cancer Institute's program for cancer therapeutics and the federal space, energy, and defense laboratories. The assigned mission of these new facilities would be vaccine development for future infectious disease contingencies. ANTIMICROBIAL DRUGS Since the 1940s, antimicrobial agents have served to control many previously life-threatening infections. Antimicrobials have the unique ability to cure certain diseases, to provide prophylaxis for others, and to reduce sources of infection. The usefulness of these drugs must be protected by careful and responsible use, and by continuing to encourage the development of new antimicrobial drugs. The development of resistance by microorganisms (see Chapter 2), as well as the emergence of new organisms, will require replacement drugs to be in the pipeline even while existing drugs are still effective. Success depends on the alertness of the clinical community in identifying resistant organisms through surveillance and in reaching consensus on the need for new drugs. Data from the CDC's NNISS will be crucial to surveillance efforts and for developing guidelines for the rational use of antimicrobial drugs, as a means to delay the development of resistance. Should a global infectious disease surveillance system be put in place, such as the one suggested in this report, tracking antimicrobial resistance worldwide may be possible. The development of public/private sector alliances, along the lines of the National Cooperative Drug Development Groups at the NIH (similar to the vaccine groups discussed above), may be desirable. There may also be circumstances similar to the current shortage of antituberculosis drugs in which the active involvement of the FDA may be necessary to encourage manufacturers to produce specific drugs or to pursue the development of drugs for a specific purpose. The committee recommends that clinicians, the research and development community, and the U.S. government (Centers for Disease Control, Food and Drug Administration, U.S. Department of Agriculture,

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Emerging Infections: Microbial Threats to Health in the United States and Department of Defense) introduce measures to ensure the availability and usefulness of antimicrobials and to prevent the emergence of resistance. These measures should include the education of health care personnel, veterinarians, and users in the agricultural sector regarding the importance of rational use of antimicrobials (to preclude their unwarranted use), a peer review process to monitor the use of antimicrobials, and surveillance of newly resistant organisms. Where required, there should be a commitment to publicly financed rapid development and expedited approval of new antimicrobials. Vector Control The United States and other developed countries have been able to free themselves to a remarkable degree from the burden of vector-borne diseases using a variety of methods of vector control. If that level of vigilance is maintained, there is a chance of minimizing new outbreaks of vector-borne disease. The potential for vector-borne disease to emerge in the United States still exists, however, because of the abundance of certain vectors, such as Aedes albopictus mosquitoes. And even in Lyme disease, a vector-borne illness with a known vector—the Ixodes tick—there is currently no agreement on intervention strategies. Vector control generally includes the use of one or more measures to reduce vector abundance, vector longevity, and human-vector contact. Depending on the type of vector, common control measures include, but are not limited to, indoor and outdoor spraying of chemical pesticides, application of biological control agents, destruction or treatment of larval development sites, and personal protective measures, such as covering exposed areas of the body, application of repellents, sleeping under bednets, or reducing human contact with infective insects by remaining away from areas inhabited by the vectors. Innovative methods of vector control, such as genetic modification of vectors, the development of antivector vaccines, and the use of biological control techniques are currently being examined, particularly for use in the control of mosquito vectors of malaria (Institute of Medicine, 1991a). The transovarial transmission (from infected female vectors through their eggs to succeeding generations) of pathogens, such as arboviruses, poses some unique problems for the development of control programs. A transovarially infected adult mosquito vector can transmit infection immediately after it emerges. In the case of the LaCrosse virus, for example, it is important to preclude adult emergence and/or reduce the abundance of adult vectors that emerge in the spring or early summer. Any reduction in vector-control efforts is likely to be followed by a resurgence of the vector population. For a disease agent that is known or suspected to be transmitted by an

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Emerging Infections: Microbial Threats to Health in the United States arthropod vector, efforts to control the vector can be crucial in containing or halting an outbreak. This is true even for those vector-borne diseases, such as yellow fever or malaria, for which there is or may eventually be an effective vaccine. To be effective, a vaccine must have time—often several weeks—to elicit an immune response in recipients. Vector control may provide this opportunity (see Box 3-5). BOX 3-5 Vector Control in Action Venezuelan equine encephalomyelitis was introduced into Texas in 1971. This was not a new virus but a highly pathogenic (in both equines and people) strain that had emerged in Central America in 1969. The disease advanced from Guatemala through Mexico and into Texas, a distance of more than 4,000 kilometers, in two years. The virus produced high-titer viremias in equines and was isolated from many species of mosquitoes that fed on equines and people. Most of these mosquito species previously had been considered to be pests rather than vectors of disease (Sudia et al., 1975). The initial approach to containing the epidemic was to immunize equine populations (horses, mules, donkeys, and burros) across extensive areas of Central America and Mexico. The objective was to create an immunological barrier to prevent further spread. Fortunately, a vaccine developed by U.S. Army researchers (Berge et al., 1961) had been stockpiled, and additional doses were rapidly prepared. Although more than 4 million equines were vaccinated in Mexico in a two-year period, the virus continued to spread. There were tens of thousands of equine cases and 8,000 to 10,000 equine deaths in Mexico alone. Almost 17,000 cases (but no deaths) were reported in humans (Sudia et al., 1975). Once it was recognized that the disease had invaded Texas, a massive campaign to eliminate the virus was initiated (Pan American Health Organization, 1972). A total of 2.25 million equines were vaccinated over an 11-state area, and a quarantine was established to prevent movement of the equines out of infected areas. Malathion and dibrom pesticides were applied over 8 million acres in Texas and Louisiana to control mosquito populations. With completion of these activities in 1972 and the onset of winter, the pathogenic strain of the virus disappeared from Texas, Mexico, and Central America. The program's cost exceeded $30 million (Sudia et al., 1975). The virus has not reappeared, and it must be assumed that the vaccinated equine population has, after 20 years, been replaced by susceptible animals. Thus, this region is now receptive to the reintroduction of a pathogenic virus from South America or to the reemergence of a virulent strain from the Venezuelan equine encephalomyelitis viruses endemic in Central America and Florida.

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Emerging Infections: Microbial Threats to Health in the United States In temperate zones, epidemic onset of a newly emergent vector-borne disease occurs most often in the spring or summer, since both vector and pathogen depend on higher temperatures to maintain a rapid rate of reproduction. The spread of infection during the summer months may be rapid, particularly if humans are an effective source of vector infection or if the agent has become widespread in a nonhuman reservoir population. Thus, to be effective, vector control efforts must be launched shortly after the disease is first recognized or, ideally, before the disease is apparent. For most vector-borne infectious diseases, the onset of winter dampens transmission or can even eliminate the vector or infectious agent. The exception is pathogens that can survive in humans for long periods and produce chronic infection (e.g., malaria and typhus). Vectors native to temperate areas, if introduced into new regions, may be able to survive at low temperatures, while those native to the tropics may not. In much of North America, cold weather is a second line of defense against most newly emerged or introduced pathogens that depend on vectors to be transmitted to humans. A sudden decrease in incidence of an unidentified disease at the start of winter may be the first epidemiological evidence that the disease is vectorborne. VECTOR-CONTROL RESOURCES North America has extensive vector-control resources. In fact, vector control is an essential part of environmental health programs in many communities. California's mosquito control, for example, covers most of the state and involves some 72 agencies with a 1991 budget of more than $48.9 million for an area with a population of more than 20 million (California Mosquito and Vector Control Association, Inc., 1991). Statewide surveillance for mosquito-borne encephalitis, plague, malaria, and Lyme disease is coordinated by the California Department of Health Services. There are approximately 1,000 additional regional and community vector-control and vector-surveillance programs in the United States and Canada (American Mosquito Control Association, 1991). Most of these programs are geared to protecting local populations from indigenous vector-borne diseases and arthropod pests. They may also provide an early line of defense against newly introduced or resurgent vector-borne diseases. In the United States, responsibility for organizing surveillance data and investigating epidemics of emerging vector-borne diseases, such as encephalitis, plague, and Lyme disease, rests with the CDC's Division of Vector-Borne Infectious Diseases in Fort Collins, Colorado. The control methods used in a particular region depend on the vectors that are present and on what is known about their biology and behavior. Chemical and biological agents and environmental modification can be

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Emerging Infections: Microbial Threats to Health in the United States used individually or together in an integrated control effort. Although many local and regional vector-control programs can effectively combat local and even regional outbreaks of vector-borne disease, they are not equipped to deal with outbreaks that are national in scope. For example, regional vector-control programs cannot declare a health emergency or bypass the many legal restrictions that now limit the use of certain pesticides that are potentially useful for vector-control efforts. That authority rests with health and environmental agencies at the state and federal levels. PESTICIDES FOR VECTOR CONTROL A growing problem in controlling vector-borne diseases is the diminishing supply of effective pesticides. Federal and state regulations increasingly restrict the use and supply of such chemicals, largely as a result of concerns over human health or environmental safety. All pesticides must be registered with the U.S. Environmental Protection Agency (EPA) before they can be offered for sale in the United States. A 1972 amendment to the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), called for all pesticides to be re-registered by 1975 in order to meet new health and safety standards (Public Law No. 92-516). By 1986, only one of approximately 1,200 previously registered pesticides had met all of the re-registration requirements. A 1988 amendment to FIFRA moved the re-registration deadline to 1997, giving manufacturers additional time to locate or develop scientific data necessary for re-registration that were not in the original registration materials for their products. If adequate data are not submitted by the cut-off date, pesticide makers face the loss of registration (Moses, 1992). Some manufacturers have chosen not to re-register their products because of the expense of gathering the required safety data. Partly as a result, many effective pesticides developed over the past 40 years to control agricultural pests and vectors of human disease are no longer available because their registrations have been canceled or suspended in the United States. For example, malathion, a pesticide used worldwide for both agricultural and public health purposes, is currently registered in the United States but must be re-registered in accordance with the provisions of FIFRA. The manufacturer (American Cyanamid Corporation) has sold the rights to malathion to a Danish company, which may or may not apply for re-registration in the United States. Because malathion is an effective, relatively inexpensive broad-spectrum pesticide, a failure to re-register would be considerable cause for concern. Pyrethrum, a plant product that has been used successfully to control adult vectors for many years, is currently being reviewed for its potential environmental and health hazards. This product is not produced in the

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Emerging Infections: Microbial Threats to Health in the United States United States, and supply is often a problem. Nevertheless, its failure to be re-registered would be a serious loss to the vector-control armamentarium in this country. In addition, the new registration frequently limits the circumstances under which products may be applied. In many instances, compounds that were once approved for pest-control applications are now restricted to certain narrow agricultural uses, such as for pest control in a single crop. The result is that many pesticides that might have been used to control emerging vector-borne diseases are either no longer registered or are not available in sufficient quantity. In accordance with federal endangered species legislation, the EPA further restricts pesticide use through its Endangered Species Protection Plan. The plan prohibits the use of a wide range of pesticides within the habitat of any endangered species. Prohibitions extend in some cases to urban and suburban environments, in which outbreaks of vector-borne disease pose a particular threat. Efforts have been made to develop a workable, legal strategy for vector control in the event of a public health emergency. Specifically, EPA has developed an emergency exemption procedure in collaboration with the California Mosquito and Vector Control Association and the American Mosquito Control Association. The plan calls for specific steps to be followed when surveillance data suggest that the possibility of an outbreak of a vector-borne disease is great. After the local vector-control agency has determined a need to invoke the exemption, it must follow a 12-step procedure that includes review of the area for endangered species, consultation with the U.S. Fish and Wildlife Service (FWS), submission of a request for a public health exemption to the state public health agency or the CDC, a review and determination by the state agency or the CDC (which must be performed within 10 days if an emergency is anticipated or within 24 hours if the emergency is in progress), review and revision (if necessary) of the original plan and submission of a final plan to the state or the CDC, submission (within 15 days) by the CDC of a request to the EPA for an exemption, EPA consultation with the FWS, EPA approval or denial of the request (within 15 days), and, finally, implementation of the plan (B. Eldridge, Director, Mosquito Research Program, Department of Entomology, University of California at Davis, personal communication, 1992). The committee recommends that the Environmental Protection Agency develop and implement alternative, expedited procedures for the licensing of pesticides for use in vector-borne infectious disease emergencies. These procedures would include a means for stockpiling designated pesticides for such use. As with vaccines, there is little economic incentive for firms to develop new pesticides for public health use because such use makes up a very

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Emerging Infections: Microbial Threats to Health in the United States small part of the pesticide market. The committee feels strongly, however, that pesticide development in this area needs to be given some priority. Pesticide development is now driven mainly by the demands of agriculture. Moreover, as pesticide development has become ever more specialized, there are fewer compounds available that have both agricultural and public health uses. Agricultural applications account for about 75 percent of pesticide use in the United States. Approximately 407,000 tons of pesticide were used in 1987, of which about 89,500 tons were insecticides. Public health use accounts for about 10 percent of all pesticides globally; the major public health uses are for control of malaria, filariasis, schistosomiasis, onchocerciasis, and trypanosomiasis (Moses, 1992). Dichlorodiphenyl trichloroethane (DDT), one of the most effective and economical pesticides ever developed, was first marketed in 1942, three years after Swiss chemist Paul Mueller discovered that the compound had insecticidal properties. In 1972, all agricultural use of DDT in the United States was banned because of its adverse environmental effects. Its use is now restricted by the EPA to public health emergencies, as defined under FIFRA. DDT is still used in many developing countries for public health purposes, particularly malaria control. Currently, aldrin, benzene hexachloride, chlordane, chlordimeform, DBCP, diazinon, dieldrin, dinogeb, ethylene dibromide, andrin, EPN, heptachlor, lindane, mirox, nitrofen (TOK), 2,4,5-T/silvex, and toxaphene also are banned, suspended, or severely restricted in their use as pesticides within the United States (Moses, 1992). The use of insect growth regulators (so-called biorational or third-generation pesticides) to control vector populations is being investigated. These compounds affect certain biological processes of insects, such as metamorphosis, that are not present in mammals and other vertebrates. Biological control agents (the use of one organism to control another) are also considered biorational pesticides. Once licensed, many such materials will be used to control the immature stages of a number of insect vectors. They are likely to be of limited value as adulticides, however, since compounds used to control adult insects usually must produce mortality quickly. So far, only conventional broad-spectrum pesticides possess this characteristic. Resistance to biorational pesticides has recently been demonstrated in laboratory settings, even in the case of microbial pesticides. The lack of a sufficient stockpile of effective pesticides, which might be required in the event of a major epidemic, continues to be a serious problem. The public health community has played a minor role in the formulation of pesticide use policy, which is mainly influenced by agricultural and environmental lobbying efforts. Until there are adequate alternative means for controlling disease-carrying vectors, it is critical that public health requirements for pesticides be considered when pesticide policy is being

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Emerging Infections: Microbial Threats to Health in the United States debated. There may well be instances in which the limited application of pesticides, such as DDT, to deal with a public health emergency may be acceptable—as long as the overall burden on the environment is not excessive. The committee believes that the current EPA contingency plan that addresses this issue is ineffective: the approval process for emergency use of pesticides is so cumbersome that approval would likely come after the critical period in which application of the pesticide could avert the outbreak. Under emergency circumstances, a tradeoff must be made, so that the process can be more expedient. Several arboviruses (St. Louis, western, and eastern equine encephalitis) are examples of diseases that could erupt suddenly into emergency proportions that might require pesticide use. These arboviruses are enzootic in North America and are maintained in a cycle of infection between wild birds and vector mosquitoes, with little or no transmission to humans. Periodically, however, excessive rain or snow, followed by high summer temperatures, favors the emergence of increased vector populations, which may lead to the rapid spread of infection to humans. These events can occur in both urban and rural communities, and when they do, there is an immediate need to implement a control program. The primary goal at the onset of mosquito-borne disease epidemics is to eliminate the infective mosquitoes as quickly as possible. Transmission can only be stopped by the effective application of a pesticide that kills adult mosquitoes. A control program directed against the preadult aquatic and adult stages of the vector would not have an immediate effect on virus transmission but might be valuable for preventing a prolonged epidemic. St. Louis encephalitis (SLE) exemplifies the above scenario. It has frequently reemerged as an epidemic infection in the United States (Monath, 1980), most recently in Florida and Texas in 1990 (Centers for Disease Control, 1990d). In 1966, an effort was made, in the middle of an epidemic in Dallas, Texas, to evaluate the effectiveness of controlling populations of adult mosquitoes that transmit this disease. There were 545 suspected and 145 confirmed cases of SLE in a period of a few weeks (Hopkins et al., 1975). In an eight-day period, 475,000 acres of the area were aerially sprayed with 12,000 gallons of malathion in an ultra-low-volume, high-concentration mist. Observations made before and after the application indicated that there was a significant reduction in the vector population and its infection rate. Few new cases were detected during the two to three weeks after the spraying. This is one of the few epidemics of a reemerging infection for which a study was conducted on its economic impact. It was estimated that the SLE outbreak cost the community $796,500, of which almost $200,000 was spent on vector control (Schwab, 1968). The economic and public health consequences would certainly have been greater had pesticides not been available.

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Emerging Infections: Microbial Threats to Health in the United States Alternative strategies for the control of epidemics of SLE and western equine encephalitis are considered in detail elsewhere (Reeves and Milby, 1990). In the event of an epidemic caused by one of these enzootic viruses, the control of adult vectors is probably the best approach for stopping the spread of disease. To be successful, it has been estimated that pesticide application should achieve a 90 percent or greater reduction in the infected vector population (W. Reeves, Professor of Epidemiology Emeritus, School of Public Health, University of California at Berkeley, personal communication, 1992). As in the drug arena, resistance to pesticides can present serious problems to disease control. Mosquitoes, flies, and other disease-carrying insects have relatively short life cycles and produce many generations per year. This is a major factor in the development of pesticide resistance, and it is usually in these groups that resistance to a given chemical is seen. There are many strategies that can be used to delay or prevent pesticide resistance. So-called pesticide resistance management can include the rotation of chemicals, avoidance of sublethal doses, and the use of biodegradable materials. More research is needed, however, to hone the usefulness of these approaches. The committee recommends that additional priority and funding be afforded efforts to develop pesticides (and effective modes of application) and other measures for public health use in suppressing vector-borne infectious diseases. Public Education and Behavioral Change The areas of public education and behavioral change in relation to emerging infectious diseases currently show visible activity; the media, for example, have been presenting information to the public about the control of Lyme disease and HIV transmission. The committee was not constituted to address these two issues; however, because the topics represent potentially important aspects of emerging infectious disease prevention and control, it was considered appropriate to address them briefly here. Public policy discussions and scientific efforts sometimes focus on vaccine and drug development and fail to give appropriate consideration to education and behavioral change as means for preventing and controlling infectious diseases. This is unfortunate, since it is often only by changing patterns of human activity—from travel and personal hygiene to sexual behavior and drug abuse—that the spread of disease can be halted. For many infectious disease problems, however, particularly those that result from emerging microbes, the use of vaccines and drugs is not practical. Often, for newly recognized diseases, the causative agent is unknown,

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Emerging Infections: Microbial Threats to Health in the United States making vaccine and drug development essentially impossible. Because of the long development process, vaccines and drugs can contribute little to disease control at the onset of an outbreak of a newly emergent disease. Only in a case in which an effective drug has already been developed for use against another organism and is found be efficacious against the newly discovered agent will drugs be of use in such circumstances. HIV disease illustrates these problems quite clearly. It has been almost a decade since HIV was isolated, yet there is no vaccine and few drugs that have been shown to slow the disease process. Since the major modes of transmission of HIV are behaviorally based, the pandemic offered a unique opportunity to put public education and behavior modification to use. Initially, officials were highly reluctant to provide candid information to the public on how to prevent the spread of HIV. Recently, however, efforts at education on HIV and AIDS, much of it from nongovernmental organizations, have been more straightforward. Among the more visible of the federal government efforts were the mailing of an AIDS information pamphlet to every household in the country in 1988 and the current television spots that provide a toll-free number to call to learn more about HIV disease. The concern of the committee is that these efforts are targeted to a general audience rather than to specific risk groups, and do not use the terminology that is most understandable to these populations. Nevertheless, despite a disappointing beginning, the experience with HIV demonstrates that human behavior can be modified in part through education. Condom use has increased and numbers of sexual partners have decreased in most male homosexual populations that have been studied (National Commission on Acquired Immune Deficiency Syndrome, 1991). Evidence for similar behavioral change among those using intravenous drugs or crack cocaine is less encouraging. Even when scientists and public health officials rely on education and encourage behavioral change to prevent or limit the spread of infectious disease, the public may not be convinced. Although scientists may see emerging microbes as a very real threat to public health, the average citizen may be unaware of the potential danger or may consider those dangers to be less important than other health risks, for example heart disease or cancer. In such instances, carefully conceived media campaigns may have a beneficial effect on behavior in relation to disease transmission. The committee recommends that the National Institutes of Health give increased priority to research on personal and community health practices relevant to disease transmission. Attention should also be focused on developing more effective ways to use education to enhance the health-promoting behavior of diverse target groups. * * * *

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Emerging Infections: Microbial Threats to Health in the United States It is the committee's hope that this report will be an important first step in highlighting the growing problem of emerging microbial threats to health and focus attention on ways in which the United States and the global community will attempt to address such threats, now and in the future. The major emphasis in the American health care system has always been on curing rather than prevention. The committee strongly believes that the best way to prepare for the future is by developing and implementing preventive strategies that can meet the challenges offered by emerging and reemerging microbes. It is infinitely less costly, in every dimension, to attack an emerging disease at an early stage and prevent its spread than to rely on treatment to control the disease. In some instances, what this report proposes will require additional funds. The committee recognizes and has wrestled with the discomforts that such recommendations can bring—for example, the awareness that there are other compelling needs that also justify—and require—increased expenditures. But everyone must realize and understand the potential magnitude of future epidemics in terms of human lives and monetary costs. The 1957 and 1968 influenza pandemics killed 90,000 people in the United States alone. The direct cost of medical care was $3.4 billion (more than three times the NIAID budget for fiscal year 1992), and the total economic burden was $26.8 billion 3—almost three times the total NIH budget for fiscal year 1992 (Kavet, 1972). A more current example offers a similar lesson. The recent resurgence of TB (from 22,201 cases in 1985 to 26,283 cases in 1991, or 10.4 per 100,000 population) (Centers for Disease Control, 1992g), after a steady decline over the past several decades, will be costly. Every dollar spent on TB prevention and control in the United States produces an estimated $3 to $4 in savings; these savings increase dramatically when the cost of treating multidrug-resistant tuberculosis is factored in. We also have a recent example of what results when early prevention and control efforts are lacking. The costs of AIDS/HIV disease—in human lives as well as dollars—have been staggering, and the end is not yet in sight. The objective in the future should be earlier detection of such emerging diseases, coupled with a timely effort to inform the population about how to lower their risk of becoming infected. Obviously, even with unlimited funds, no guarantees can be offered that an emerging microbe will not spread disease and cause devastation. Instead, this committee cautiously advocates increased funding and proposes some more effective ways for organizations—domestic and international, public and private—as well as individuals—both health professionals and the lay public—to work together and, in some cases, combine their resources. These efforts will help to ensure that we will be better prepared to respond to emerging infectious disease threats of the future. 3   Study staff converted the figures in the original publication (Kavet, 1972) to 1992 dollars using the NIH Biomedical Research and Development Price Index (BRDPI).