2
Factors in Emergence

Emerging infectious diseases are clinically distinct conditions whose incidence in humans has increased. For the purposes of this study, the committee has focused on diseases that have emerged in the United States within the past two decades. Emergence may be due to the introduction of a new agent, to the recognition of an existing disease that has gone undetected, or to a change in the environment that provides an epidemiologic "bridge." (For an example of an emerging disease, see Box 2-1.) Emergence, or, more specifically, reemergence, may also be used to describe the reappearance of a known disease after a decline in incidence. Although an infectious agent plays a role in any emerging infectious disease, other causative factors may be important as well.

BOX 2-1 A Deadly Form of Strep

It was a shock to many when renowned puppeteer Jim Henson died suddenly in May 1990. How could a healthy man in his early 50s be so easily felled by a case of pneumonia? Since his death, attention has focused on a deadly "new" form of streptococcal bacteria. This new bacterium belongs to a category of strep bacteria called "Group A," a subset of organisms familiar to many as the cause of acute pharyngitis (strep throat). The new strep A has been killing otherwise healthy people (like Henson), and doing so in a frighteningly rapid fashion. This was true for a 30-year-old Canadian man who got a splinter in his finger, which later became infected. Within six days he had become so ill that he was admitted to an intensive care unit and placed on a respirator. He died six weeks later of sepsis (disseminated infection) (Goldman, 1991).



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Emerging Infections: Microbial Threats to Health in the United States 2 Factors in Emergence Emerging infectious diseases are clinically distinct conditions whose incidence in humans has increased. For the purposes of this study, the committee has focused on diseases that have emerged in the United States within the past two decades. Emergence may be due to the introduction of a new agent, to the recognition of an existing disease that has gone undetected, or to a change in the environment that provides an epidemiologic "bridge." (For an example of an emerging disease, see Box 2-1.) Emergence, or, more specifically, reemergence, may also be used to describe the reappearance of a known disease after a decline in incidence. Although an infectious agent plays a role in any emerging infectious disease, other causative factors may be important as well. BOX 2-1 A Deadly Form of Strep It was a shock to many when renowned puppeteer Jim Henson died suddenly in May 1990. How could a healthy man in his early 50s be so easily felled by a case of pneumonia? Since his death, attention has focused on a deadly "new" form of streptococcal bacteria. This new bacterium belongs to a category of strep bacteria called "Group A," a subset of organisms familiar to many as the cause of acute pharyngitis (strep throat). The new strep A has been killing otherwise healthy people (like Henson), and doing so in a frighteningly rapid fashion. This was true for a 30-year-old Canadian man who got a splinter in his finger, which later became infected. Within six days he had become so ill that he was admitted to an intensive care unit and placed on a respirator. He died six weeks later of sepsis (disseminated infection) (Goldman, 1991).

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Emerging Infections: Microbial Threats to Health in the United States The new strep A bacteria, like all streptococcal organisms, are typically inhaled, but they can also enter the body through a cut or scrape. The infection they provoke once inside the body is especially insidious: its early symptoms are easily mistaken for signs of the flu. In several cases, the bacteria have overwhelmed their host with pneumonia, and in others, with kidney and liver damage before the infected person has sought treatment. So advanced, the infection is extremely difficult to treat. Even if massive doses of penicillin succeed in killing the bacteria, there are no means available to counter the effects of the deadly toxin they produce—which actually causes the pneumonia and tissue damage. Although reports of the first cases of fatal infection with the new strep A appeared in the medical literature in 1989 (Stevens et al., 1989), health problems associated with the streptococcus family of bacteria are not new. In the days before antibiotics, they were responsible for widespread outbreaks of scarlet fever and rheumatic fever. Nor are these bacteria rare. Strep throat is so common an ailment among children that it could almost be considered a rite of passage. Much about the new strep A remains a mystery. Some scientists—noting the similarity between the toxin secreted by the new strep A and the toxin once seen with scarlet fever—believe that this bacterium is an old microbe making a comeback. Others consider this highly virulent form of strep the result of a recent bacterial mutation. Whatever its origin, the new strep A deserves attention. Experts strongly encourage people to seek immediate medical care if they become very ill (high fever, sore throat) in a sudden fashion, especially if they have recently suffered a cut or burn. Although cases of infection with this new, deadly microbe remain quite rare, their increasing incidence in the past two years is cause for concern. A vaccine for streptococcal infections is in development, but researchers estimate that it will not be ready for public use for at least another three years. In the meantime, the Centers for Disease Control is working to track the new strep A more closely, with the hope of learning more about the bacterium and how to stop it. Table 2-1 is a list of emerging infectious agents, categorized by type of organism. Appendix B provides more detailed information on each of these agents. The committee recognizes that this list is continually expanding, mainly as a result of the growing numbers of immunocompromised individuals. Therefore, it may not contain all organisms that fit the definition above. Once a new pathogen has been introduced into a human population, its ability to spread becomes a critical factor in emergence. The same is true for agents that are already present in a limited or isolated human population:

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Emerging Infections: Microbial Threats to Health in the United States TABLE 2-1 Part 1: Examples of Emergent Bacteria, Rickettsiae, and Chlamydiae Agent Related Diseases/Symptoms Mode of Transmission Cause(s) of Emergence Aeromonas species Aeromonad gastroenteritis, cellulitis, wound infection, septicemia Ingestion of contaminated water or food; entry of organism through a break in the skin Immunosuppression; improved technology for detection and differentiation Borrelia burgdorferi Lyme disease: rash, fever, neurologic and cardiac abnormalities, arthritis Bite of infective Ixodes tick Increase in deer and human populations in wooded areas Campylobacter jejuni Campylobacter enteritis: abdominal pain, diarrhea, fever Ingestion of contaminated food, water, or milk; fecal-oral spread from infected person or animal Increased recognition; consumption of uncooked poultry Chlamydia pneumoniae (TWAR strain) TWAR infection: fever, myalgias, cough, sore throat, pneumonia Inhalation of infective organisms; possibly by direct contact with secretions of an infected person Increased recognition Chlamydia trachomatis Trachoma, genital infections, conjunctivitis; infection during pregnancy can result in infant pneumonia Sexual intercourse Increased sexual activity; changes in sanitation Clostridium difficile Colitis: abdominal pain, watery diarrhea, bloody diarrhea Fecal-oral transmission; contact with the organism in the environment Increased recognition; immunosuppression Ehrlichia chaffeensis Ehrlichiosis: febrile illness (fever, headache, nausea, vomiting, myalgia) Unknown; tick is suspected vector Increased recognition; possibly increase in host and vector populations Escherichia coli O157:H7 Hemorrhagic colitis; thrombocytopenia; hemolytic uremic syndrome Ingestion of contaminated food, esp. undercooked beef and raw milk Likely due to the development of a new pathogen Haemophilus influenzae biogroup aegyptius Brazilian purpuric fever: purulent conjunctivitis, high fever, vomiting, and purpura Contact with discharges of infected persons; eye flies are suspected vectors Possibly an increase in virulence due to mutation

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Emerging Infections: Microbial Threats to Health in the United States Agent Related Diseases/Symptoms Mode of Transmission Cause(s) of Emergence Helicobacter pylori Gastritis, peptic ulcer, possibly stomach cancer Ingestion of contaminated food or water, esp. unpasteurized milk; contact with infected pets Increased recognition Legionella pneumophila Legionnaires' disease: malaise, myalgia, fever, headache, respiratory illness Air-cooling systems, water supplies Recognition in an epidemic situation Listeria monocytogenes Listeriosis: meningoencephalitis and/or septicemia Ingestion of contaminated foods; contact with soil contaminated with infected animal feces; inhalation of organism Probably increased awareness, recognition, and reporting Mycobacterium tuberculosis Tuberculosis: cough, weight loss, lung lesions; infection can spread to other organ systems Exposure to sputum droplets (exhaled through a cough or sneeze) of a person with active disease Immunosuppression Staphylococcus aureus Abscesses, pneumonia, endocarditis, toxic shock Contact with the organism in a purulent lesion or on the hands Recognition in an epidemic situation; possibly mutation Streptococcus pyogenes (Group A) Scarlet fever, rheumatic fever, toxic shock Direct contact with infected persons or carriers; sometimes ingestion of contaminated foods Change in virulence of the bacteria; possibly mutation Vibrio cholerae Cholera: severe diarrhea, rapid dehydration Ingestion of water contaminated with the feces of infected persons; ingestion of food exposed to contaminated water Poor sanitation/hygiene; possibly introduced via bilge-water from cargo ships Vibrio vulnificus Cellulitis; fatal bacteremia; diarrheal illness (occasionally) Contact of superficial wounds with seawater or with contaminated (raw or undercooked) seafood; ingestion (occasionally) Increased recognition

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Emerging Infections: Microbial Threats to Health in the United States TABLE 2-1 Part 2: Examples of Emergent Viruses Agent Related Diseases/Symptoms Mode of Transmission Cause(s) of Emergence Bovine spongiform encephalopathy (BSE) agent Bovine spongiform encephalopathy in cows Ingestion of feed containing infected sheep tissue Changes in the rendering process Chikungunya Fever, arthritis, hemorrhagic fever Bite of infected mosquito Unknown Crimean-Congo hemorrhagic fever Hemorrhagic fever Bite of an infected adult tick Ecological changes favoring increased human exposure to ticks on sheep and small wild animals Dengue Hemorrhagic fever Bite of an infected mosquito (primarily Aedes aegypti) Poor mosquito control; increased urbanization in tropics; increased air travel Filoviruses (Marburg, Ebola) Fulminant, high-mortality hemorrhagic fever Direct contact with infected blood, organs, secretions, and semen Unknown; in Europe and the United States, virus-infected monkeys shipped from developing countries via air Hantaviruses Abdominal pain, vomiting, hemorrhagic fever Inhalation of aerosolized rodent urine and feces Human invasion of virus ecologic niche Hepatitis B Nausea, vomiting, jaundice; chronic infection leads to hepatocellular carcinoma and cirrhosis Contact with saliva, semen, blood, or vaginal fluids of an infected person; mode of transmission to children not known Probably increased sexual activity and intravenous drug abuse; transfusion (before 1978) Hepatitis C Nausea, vomiting, jaundice; chronic infection leads to hepatocellular carcinoma and cirrhosis Exposure (percutaneous) to contaminated blood or plasma; sexual transmission Recognition through molecular virology applications; blood transfusion practices following World War II (esp. in Japan) Hepatitis E Fever, abdominal pain, jaundice Contaminated water Newly recognized Human herpesvirus 6 (HHV-6) Roseola in children, syndrome resembling mononucleosis Unknown; possibly respiratory spread Newly recognized

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Emerging Infections: Microbial Threats to Health in the United States Agent Related Diseases/Symptoms Mode of Transmission Cause(s) of Emergence Human immunodeficiency viruses  HIV-1 HIV disease, including AIDS: severe immune system dysfunction, opportunistic infections Sexual contact with or exposure to blood or tissues of an infected person; vertical transmission Urbanization; changes in lifestyles/mores; increased intravenous drug use; international travel; medical technology (transfusions/transplants) HIV-2 Similar to above Same as above Same as above, esp. international travel Human papillomavirus Skin and mucous membrane lesions (often, warts); strongly linked to cancer of the cervix and penis Direct contact (sexual contact/contact with contaminated surfaces) Newly recognized; perhaps changes in sexual lifestyle Human parvovirus B19 Erythema infectiosum: erythema on face, rash on trunk; aplastic anemia Contact with respiratory secretions of an infected person; vertical transmission Newly recognized Human T-cell lymphotropic viruses (HTLV-I and HTLV-II) Leukemias and lymphomas Vertical transmission through blood/breast milk; exposure to contaminated blood products; sexual transmission Increased intravenous drug abuse; medical technology (transfusion) Influenza  Pandemic Fever, headache, cough, pneumonia Airborne (esp. in crowded, enclosed spaces) Animal-human virus reassortment; antigenic shift Drift Same as above Same as above Antigenic drift Japanese encephalitis Encephalitis Bite of an infective mosquito Changing agricultural practices La Crosse and California Group viruses Encephalitis Bite of an infective mosquito Increasing interface between human activity and endemic areas; discarded tires as mosquito breeding sites

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Emerging Infections: Microbial Threats to Health in the United States Agent Related Diseases/Symptoms Mode of Transmission Cause(s) of Emergence Lassa Fever, headache, sore throat, nausea Contact with urine or feces of infected rodents Urbanization/conditions favoring infestation by rodents Measles Fever, conjunctivitis, cough, red blotchy rash Airborne; direct contact with respiratory secretions of infected persons Deterioration of public health infrastructure supporting immunization Norwalk and Norwalk-like agents Gastroenteritis; epidemic diarrhea Most likely fecal-oral; alleged vehicles of transmission include drinking and swimming water, and uncooked foods Increased recognition Rabies Acute viral encephalomyelitis Bite of a rabid animal Introduction of infected reservoir host to new areas Rift Valley Febrile illness Bite of an infective mosquito Importation of infected mosquitoes and/or animals; development (dams, irrigation) Ross River Arthritis, rash Bite of an infective mosquito Movement of infected mosquitoes or people Rotavirus Enteritis; diarrhea, vomiting, dehydration, and low-grade fever Primarily fecal-oral; fecal-respiratory transmission can also occur Increased recognition Venezuelan equine encephalitis Encephalitis Bite of an infective mosquito Movement of mosquitoes and amplification hosts (horses) Yellow fever Fever, headache, muscle pain, nausea, vomiting Bite of an infective (Aedes aegypti) mosquito Lack of effective mosquito control and widespread vaccination; urbanization in tropics; increased air travel TABLE 2-1 Part 3: Examples of Emergent Protozoans, Helminths, and Fungi Agent Related Diseases/Symptoms Mode of Transmission Cause(s) of Emergence Anisakis Anisakiasis: abdominal pain, vomiting Ingestion of larvae-infected fish (undercooked) Changes in dietary habits (eating of raw fish)

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Emerging Infections: Microbial Threats to Health in the United States Agent Related Diseases/Symptoms Mode of Transmission Cause(s) of Emergence Babesia Babesiosis: fever, fatigue, hemolytic anemia Bite of an Ixodes tick (carried by mice in the presence of deer) Reforestation; increase in deer population; changes in outdoor recreational activity Candida Candidiasis: fungal infections of the gastrointestinal tract, vagina, and oral cavity Endogenous flora; contact with secretions or excretions from infected persons Immunosuppression; medical management (catheters); antibiotic use Cryptococcus Meningitis; sometimes infections of the lungs, kidneys, prostate, liver Inhalation Immunosuppression Cryptosporidium Cryptosporidiosis: infection of epithelial cells in the gastrointestinal and respiratory tracts Fecal-oral, person-to-person, waterborne Development near watershed areas; immunosuppression Giardia lamblia Giardiasis: infection of the upper small intestine, diarrhea, bloating Ingestion of fecally contaminated food or water Inadequate control in some water supply systems; immunosuppression; international travel Microsporidia Gastrointestinal illness, diarrhea; wasting in immunosuppressed persons Unknown; probably ingestion of fecally contaminated food or water Immunosuppression; recognition Plasmodium Malaria Bite of an infective Anopheles mosquito Urbanization; changing parasite biology; environmental changes; drug resistance; air travel Pneumocystis carinii Acute pneumonia Unknown; possibly reactivation of latent infection Immunosuppression Strongyloides stercoralis Strongyloidiasis: rash and cough followed by diarrhea; wasting, pulmonary involvement, and death in immunosuppressed persons Penetration of skin or mucous membrane by larvae (usually from fecally-contaminated soil); oral-anal sexual activities Immunosuppression; international travel Toxoplasma gondii Toxoplasmosis: fever, lymphadenopathy, lymphocytosis Exposure to feces of cats carrying the protozoan; sometimes foodborne Immunosuppression; increase in cats as pets

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Emerging Infections: Microbial Threats to Health in the United States those agents best adapted to human transmission are likely to be those that will emerge. Introduction of a disease-causing agent into a new host population and dissemination of the agent within the new host species can occur almost simultaneously, but they are more commonly separated by considerable periods of time. Changes in the environment and in human behavior, as well as other factors, may increase the chances that dissemination will occur. For familiar, "old" agents, whose spread has been successfully controlled, reemergence is often the result of lapses in public health measures owing to complacency, changes in human behavior that increase person-to-person transmission of an infectious agent, or changes in the ways humans interact with their environment. The return of dengue fever into areas of South and Central America where previously Ae. aegypti had been eradicated and the resurgence of yellow fever in Nigeria, where more than 400 persons were estimated to have died between April 1 and July 14, 1991 (Centers for Disease Control, unpublished data, 1992), reflect the operation of these mechanisms. THE CONCEPT OF EMERGENCE Although specific agents are usually associated with individual diseases, historically it is the diseases that usually have been recognized first. With improved techniques for the identification of microbes, however, this situation is changing. The causative agents for many newly emergent diseases are often discovered virtually simultaneously with (or in some cases before) their associated disease syndromes. For this reason, the term emerging microbial threat as used in this report includes both the agent and the disease. It is important to understand the difference between infection and disease. Infection implies that an agent, such as a virus, has taken up residence in a host and is multiplying within that host—perhaps with no outward signs of disease. Thus, it is possible to be infected with an agent but not have the disease commonly associated with that agent (although disease may develop at a later time). In discussions about the emergence of "new" diseases, considerable debate has centered on the relative importance of de novo evolution of agents versus the transfer of existing agents to new host populations (so-called microbial traffic). It is sometimes presumed that the appearance of a novel, disease-causing microorganism results from a change in its genetic properties. This is sometimes the case, but there are many instances in which emergence is due to changes in the environment or in human ecology. In fact, environmental changes probably account for most emerging diseases. For example, despite the fact that many viruses have naturally high rates of mutation, the significance of new variants as a source of new viral

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Emerging Infections: Microbial Threats to Health in the United States diseases has been hard to demonstrate, and there appear to be relatively few documented examples in nature. Influenza is probably the best example of a virus for which the importance of new variants (i.e., antigenic drift) can clearly be shown. Variants of the hepatitis B virus also have been shown recently to cause disease. However, cases like these are greatly outnumbered by instances of new diseases or outbreaks resulting from microbial traffic between species. Cross-species transfer of infectious agents is often the result of human activities. The evolution of viruses is constrained by their requirement for being maintained in a host. It would therefore seem that new variants of nonviral pathogens, such as bacteria, would be more common than new forms of viral pathogens since nonviral organisms are less constrained by host requirements. However, most nonviral pathogens usually show a clonal origin (Selander and Musser, 1990; Musser et al., 1991; Tibayrenc et al., 1991a,b). That is, they appear to be derived from a single ancestor, suggesting that the evolution of a successful new pathogen is a relatively rare event. When it does occur, the new microbe probably originates in a single geographic area and is disseminated through channels of microbial traffic. One implication of this model is that the control of ''new" diseases may be more likely if the new variant is identified early (e.g., by worldwide infectious disease surveillance) and steps are taken to prevent its further dissemination. It is likely that emerging pathogens generally are not newly evolved. Rather, it appears that they already exist in nature. Some may have existed in isolated human populations for some time; others, including many of the most novel, are well established in animals. Infections in animals that are transmissable to humans are termed zoonoses. As discussed in Chapter 1, throughout history rodents have been particularly important natural reservoirs of many infectious diseases. The significance of zoonoses in the emergence of human infections cannot be overstated. The introduction of viruses into human populations, for example, is often the result of human activities, such as agriculture, that cause changes in natural environments. These changes may place humans in contact with infected animals or with arthropod vectors of animal diseases, thereby increasing the chances of human infection. Argentine hemorrhagic fever, a natural infection of rodents, emerged as a result of an agricultural practice placing humans in close proximity to the rodents. Marburg, Machupo, Hantaan, and Rift Valley fever viruses are also of zoonotic origin, as, arguably, is human immunodeficiency virus (HIV). Yellow fever, whose natural cycle of infection takes place in a jungle habitat and involves monkeys and mosquitoes in tropical areas of Africa and South America, is probably an ancient zoonosis. Jungle yellow fever occurs when humans interpose themselves in the natural cycle and are bitten by infected mosquitoes. Yet there is also urban yellow fever, in which the same virus is transmitted among

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Emerging Infections: Microbial Threats to Health in the United States humans by other mosquitoes (e.g., Aedes aegypti) that have adapted to living in cities. It is generally believed that the movement of people through the slave trade and maritime commerce disseminated yellow fever, dengue, and chikungunya viruses, as well as Ae. aegypti , from Africa to other tropical areas. Ae. aegypti is still widespread in many urban areas of the southeastern United States, although the last yellow fever epidemic in a major U.S. city was in New Orleans in 1905. Although the odds are low that a randomly chosen organism will become a successful human pathogen, the great variety of microorganisms in nature increases those odds. For example, field sampling and disease surveillance efforts have now identified more than 520 arthropod-borne viruses, or arboviruses (Karabatsos, 1985). The disease potential of most of these viruses is unknown, but nearly 100 have been shown to cause human disease (Benenson, 1990). In spite of the demise of the Rockefeller Foundation arbovirus program in 1971, and although only a few laboratories are actively searching for new pathogens in animals and arthropods, new viruses are being discovered every year (see Box 2-2). One example of a recently discovered zoonotic virus is Guanarito, the cause of Venezuelan hemorrhagic fever. In the fall of 1989, an outbreak of an unusually severe and sometimes fatal disease was detected in the state of Portuguesa in central Venezuela. Patients presented for treatment with prolonged fever, headache, arthralgia, diarrhea, cough, sore throat, prostration, leucopenia, thrombocytopenia, and hemorrhagic manifestations. Physicians in the region initially diagnosed the disease as dengue hemorrhagic fever (DHF). During one period, from early May 1990 through late March 1991, 104 cases of the disease were recorded. Slightly more than a quarter of these patients, most of them adults, died (Salas et al., 1991). All of the cases of the DHF-like illness occurred in the Municipio of Guanarito in Portuguesa State, or in adjoining areas in Barinas State. The Municipio of Guanarito, population 20,000, is located in the central plains of Venezuela, a major food-producing region. The outbreak was confined to the municipio's roughly 12,000 rural inhabitants, who either farm or raise cattle (Salas et al., 1991). In the fall of 1990, a virologist from the Venezuelan Ministry of Health sent serum samples from several patients who were suspected to have DHF to the Yale Arbovirus Research Unit (YARU) at Yale University School of Medicine. No virus could be isolated after routine culture of the sera in mosquito cells (the standard method for recovery of dengue viruses). In early 1991, a member of the YARU staff visited Venezuela while on a trip to South America collecting dengue virus isolates for an ongoing research project. In Caracas, the YARU staff member was given spleen cultures from two fatal cases of suspected DHF from the Guanarito area. Upon inoculation into newborn mice and Vero (monkey kidney) cell cultures at

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Emerging Infections: Microbial Threats to Health in the United States VECTOR RESISTANCE TO PESTICIDES Agriculture accounts for about 75 percent of the pesticides used in the United States. In 1987, approximately 407,000 tons of pesticides were applied in agricultural settings throughout the nation, of which about 89,500 tons were insecticides. About 10 percent of the pesticides used worldwide are applied for public health purposes, mainly to control malaria, filariasis, schistosomiasis, onchocerciasis, and trypanosomiasis (Moses, 1992). This high volume of pesticide use for agricultural purposes has contributed to the development of resistance in infectious disease vectors, particularly mosquitoes. Public health use of insecticides has also played a role in the emergence of resistance, although not in the United States, where public health use of insecticides is not sufficiently regular to elicit the development of resistance. Resistance, in the field, to a number of pesticides belonging to organochlorine, organophosphate, and other insecticide groups has developed in vector arthropods. In addition, recent evidence from laboratory studies points to the emergence of resistance in mosquito larvae to the delta endotoxins of the commercialized microbial control agents Bacillus thuringiensis israeliensis (Georghiou, 1990) and B. sphaericus (Rodcharoen and Mulla, in press). Although resistance to these agents has not yet been demonstrated in a field situation, the laboratory finding illustrates the strong potential for the development of such resistance. New Understandings: Microbes as Cofactors in Chronic Disease Although medical science has been able to discern the causes of many diseases, the etiology of some that have a significant impact on the health of the U.S. population is still speculative, even after decades or more of research. The recognition that an ''old" disease, with heretofore unknown causes, is associated with an infectious agent is one of the more interesting ways infectious diseases emerge. A number of diseases are now thought to be caused by microbial infection or to involve microbes as cofactors in pathogenesis. These include, but are not limited to, atherosclerosis, rheumatoid arthritis, insulin-dependent diabetes mellitus, Reye's syndrome, Kawasaki disease, systemic lupus erythematosis, and Alzheimer's disease. The final chapters on these diseases have not been written; it remains to be seen which, if any, will be determined with certainty to involve microbial agents. The examples below illustrate the relationships between some of these diseases and the infectious agents associated with them.

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Emerging Infections: Microbial Threats to Health in the United States HUMAN T-CELL LEUKEMIA VIRUS TYPES I AND II Isolation of the first pathogenic human retrovirus was reported in 1980 (Poiesz et al., 1980) and was soon followed by the isolation of a second, closely related but distinct virus (Kalyanaraman et al., 1982). These viruses subsequently became known as human T-cell leukemia virus types I and II (HTLV-I, HTLV-II); they are sometimes referred to as human T-lymphotropic viruses. Multiple isolates of the HTLVs have now been obtained, novel regulatory properties identified, and areas of endemicity throughout the world defined by seroepidemiological studies. Although HTLV-II has not been linked definitively to a specific disease, HTLV-I has been shown to be etiologically associated with two very different diseases. The first, adult T-cell leukemia/lymphoma (ATLL), for which the virus is named, was first described in southern Japan (Uchiyama et al., 1977), where the virus is endemic. ATLL is a malignancy primarily of CD4+ (T-helper/inducer) lymphocytes, and in the leukemic phase, the HTLV-I provirus is monoclonally integrated into the DNA of neoplastic cells. The onset of disease occurs many years after the initial infection, and the most severe forms of the disease are characterized by generalized lymphadenopathy, visceral and cutaneous involvement, and bone lesions (Kuefler and Bunn, 1986). Effective treatment is not available, and death usually occurs within one year of diagnosis. Fortunately, only 2 to 5 percent of HTLV-I-infected persons develop ATLL (Murphy et al., 1989). The second HTLV-I-associated disease is a neurological condition called tropical spastic paraparesis (TSP), which was first described in the Caribbean (Gessain et al., 1985). The same syndrome was subsequently described by doctors in Japan, who called it HTLV-I-associated myelopathy (HAM) (Osame et al., 1986). This disease, which is now usually referred to as TSP/HAM, begins with difficulties in walking and weakness and spasticity in the legs; it can also include back pain, sensory disturbances, urinary incontinence, and impotence in men. Disability progresses over several years, and eventually victims may become confined to a wheelchair. Because afflicted individuals have high concentrations of HTLV-I-specific antibodies in serum and spinal fluid (Osame et al., 1990), sometimes in association with an human leukocyte antigen (HLA)-linked high immune responsiveness to HTLV-I (Usuku et al., 1988), some investigators feel that TSP/HAM is an immunological disease triggered by the virus. As with ATLL, TSP/HAM occurs in a small percentage (about 1 percent) of HTLV-I-infected persons (Kaplan et al., 1990). Interest in HTLV-I increased with the in vitro observation of several investigators that the efficiency of replication of HIV, the virus that causes

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Emerging Infections: Microbial Threats to Health in the United States HIV disease and AIDS, increased in cells transformed by HTLV-I. The subsequent identification of persons in endemic areas, many with AIDS, who were infected with both HIV and HTLV-I (Cortes et al., 1989; Hattori et al., 1989) led to the speculation that interaction of these two viruses may potentiate disease progression. The prevalence of infection with both HIV and HTLV-I or HTLV-II is increasing in populations of intravenous drug abusers in the United States (Lee et al., 1991). This increase offers the possibility of a study group, albeit an unwanted one, in which to assess this additional risk for disease. HTLV-I has also been implicated as a factor in other disease syndromes, including polymyositis, arthritis, infective dermatitis, mycosis fungoides, and multiple sclerosis (although the latter is controversial). In addition, HTLV-II was recently linked to chronic fatigue syndrome (DeFreitas et al., 1991). It is probable that the full spectrum of diseases and immunological abnormalities associated with the human retroviruses has yet to be delineated. It is also probable that additional human retroviruses exist but have not yet been discovered. ATHEROSCLEROSIS Atherosclerosis, commonly known as hardening of the arteries, is the result of an uncontrolled proliferation of arterial smooth muscle cells, which eventually can block the flow of blood through the vessel. This disease is the underlying cause of strokes and myocardial infarctions and results in more deaths in the United States (and in other industrialized countries) than any other single disease. The burden on the U.S. health care system is estimated to be in excess of $60 billion per year (Levi and Moskovitz, 1982; Kannel et al., 1984). Although it is well known that smoking, high cholesterol levels, and elevated blood pressure are major risk factors for atherosclerosis, viruses can generate the pathologic events—cell destruction, metabolic changes within cells, and cell transformation—that precede the appearance of atherosclerotic lesions. This observation has led some researchers to conclude that a virus or viruses may play some role in the disease. Supporting this theory are reports that chickens can develop atherosclerotic lesions as a result of infection with an avian herpesvirus (Fabricant et al., 1978, 1980; Minick et al., 1979). In humans, two similar viruses, herpes simplex virus (HSV-1 and HSV-2) and cytomegalovirus (CMV), infect infants and young children worldwide. During infection, the viruses are often found in the blood vessels, potentially exposing the smooth muscle cells to their effects. In one recent study, CMV infection was demonstrated in patients with atherosclerosis; there was no evidence of either HSV-1 or HSV-2 infection in the same individuals (Melnick et al., 1990). Other studies have implicated

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Emerging Infections: Microbial Threats to Health in the United States CMV, as well as HSV-1 and HSV-2 in human atherosclerotic disease (Benditt et al., 1983; Yamashiroya et al., 1988; Hendrix et al., 1989, 1990). Recently, a bacterium, Chlamydia pneumoniae, was reported to play a potential role in the pathogenesis of atherosclerotic disease. The investigators examined the consequences of human infection with C. pneumoniae and found evidence, in the form of persistently elevated levels of anti-C. pneumoniae antibodies and immune complexes containing chlamydial lipopolysaccharide, that chronic infection with this bacterium was associated with increased risk for coronary heart disease. This risk was shown to be independent of those factors—age, smoking, total cholesterol to high-density-lipoprotein-cholesterol ratios, and hypertension—most often associated with atherosclerosis (Saikku et al., 1992). Because C. pneumoniae infection is fairly common and can be treated with antibiotics, a proven association of this organism with atherosclerosis and subsequent myocardial infarction could have a significant public health impact. HUMAN PAPILLOMAVIRUS Papillomaviruses were described and associated with disease in the early to mid-1900s. Research on these viruses, however, suffered from the inability to grow them in cells in the laboratory. It was not until the 1980s that techniques to identify and characterize human papillomavirus (HPV) became readily available (deVilliers, 1989). In the past 10 years, more than 67 HPV types have been defined; the molecular biology of the virus has been developed in exquisite detail; and knowledge concerning molecular mechanisms of infection and disease has emerged (Reeves et al., 1989). Epidemiological studies have shown that HPV infection (with HPV types 16 and 18) is the major risk factor for cervical cancer (Reeves et al., 1989), an important public health problem in the United States and the developing world. The American Cancer Society estimated that 13,000 new cases would occur in the United States in 1991, resulting in about 4,500 deaths (American Cancer Society, 1991). Most of these cases and deaths could have been prevented by appropriate screening and control programs. Cervical cancer is uniquely amenable to secondary prevention by screening and early treatment since it evolves through surgically curable premalignant stages to invasive disease over a 10- to 20-year period (Tabbara et al., 1992). Other factors besides HPV infection, however, play a role in the development of cervical cancer. For example, a woman's risk of cervical cancer is directly related to the number of sexual partners she has had (the greater the number of partners the greater her risk) and inversely related to age at first intercourse (the younger her age, the greater the risk). It has only recently been recognized that male sexual behavior also influences cervical cancer risk. Spouses of women with cervical cancer are more likely to

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Emerging Infections: Microbial Threats to Health in the United States exhibit high-risk sexual behavior than spouses of women without the disease (Brinton et al., 1989). These behaviors undoubtedly increase the chance that the men will be exposed to sexually transmitted agents such as HPV. There is growing evidence that other venereal disease agents, such as HSV-2 and HIV, interact with HPV in a multiplicative fashion to boost the risks for cervical cancer (Hildesheim et al., 1991). Women infected with HIV have at least a 10-fold increased risk for active HPV infection and a 12-fold increase in risk of cervical neoplasia (Laga et al., 1992). HPV infection and cervical disease also progress more rapidly and are more refractory to treatment in women with HIV infection. As the prevalence of heterosexually transmitted HIV increases among women, HPV infection and cervical disease will continue to emerge as major opportunistic complications. The strong association between HIV and HPV infection may involve interactions between the proteins of HPV and HIV, in addition to general immunosuppression. For all of the apparent links between HPV infection and cervical disease, the relationship is not a simple one of cause and effect. For example, no study has found HPV in all cervical cancers, and a variety of studies have shown that 10 to 50 percent of healthy women are infected with HPV (Burk et al., 1986; Cox et al., 1986; Toorn et al., 1986; and Reeves et al., 1987). HPV infection can only be estimated by detecting viral DNA, and there is no single accepted criterion for judging the results of such testing. In addition, there is no clinically useful serological assay that can independently estimate past HPV infection. Well-standardized commercial kits can be used to diagnose HPV infection, but infection alone is neither sufficient nor necessary for cervical cancer. The condition appears to be brought on by a complex interaction of infections and demographic, behavioral, and hormonal risk factors. The only currently efficacious cervical cancer control strategy is secondary prevention—detecting and ablating preinvasive cervical intraepithelial neoplasia (CIN) lesions. New strategies based on HPV detection and Pap smear screening may be possible. BREAKDOWN OF PUBLIC HEALTH MEASURES The control of many infectious illnesses has occurred as societies themselves have become more advanced. Improvements in medicine, science, and public health have come only as a result of the complex growth and maturation of modern civilization. Many of the protections now in place, such as vaccination, proper hygiene, water and sewage treatment, and safe food-handling and distribution practices have vastly improved our ability to control infectious disease outbreaks. Despite the appearance of security, however, there is only a thin veneer protecting humankind from potentially devastating infectious disease epidemics.

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Emerging Infections: Microbial Threats to Health in the United States Alone or in combination, economic collapse, war, and natural disasters, among other societal disruptions, have caused (and could again cause) the breakdown of public health measures and the emergence or reemergence of a number of deadly diseases. Inadequate Sanitation: Cholera Cholera, a sometimes rapidly fatal diarrheal disease caused by the bacterium Vibrio cholerae, reached epidemic levels in South America in January 1991 for the first time in almost a century. Inadequate sanitation played a role in its reappearance, which occurred initially in several coastal cities in Peru; then the disease spread through much of the continent. A scattering of epidemic-related cases were reported later in the year in Central America and the United States. As of December 1991, there had been 366,056 reported cases of the disease and 3,894 deaths in these three regions (Pan American Health Organization, 1991). It is believed that V. cholerae was first introduced into the harbor at Lima, Peru, through the dumping of bilge water by a ship arriving from the Far East. Once in the water, the bacteria rapidly contaminated the fish and shellfish, which were then consumed (often in the form of ceviche, a dish made with raw seafood that is popular in that part of the world). Following the initial seafood-related cases in humans, the organisms are thought to have been spread by fecal contamination of the water supply. Epidemiologic investigations in Peru have implicated such contaminated municipal water supplies as the principal means by which the disease is now being transmitted. Based on a study by the U.S. Environmental Protection Agency (EPA) that showed a possible link between chlorination and cancer, Peruvian officials apparently ceased treating much of the country's drinking water in the early 1980s (C. Anderson, 1991). A paucity of hygienic food preparation practices also appears to have played a role. The epidemic is traveling northward at a rapid rate; several cases have already been reported in the United States, originating from contaminated foodstuffs. U.S. public health authorities are maintaining a close watch on foods imported from South and Central America (the majority of fresh fruits and vegetables imported into the United States during the winter come from Mexico). In February 1992, at least 31 of 356 passengers and crew aboard a flight from Buenos Aires, Argentina, to Los Angeles, California (with a brief stopover in Lima) were diagnosed with cholera (18 in California, 9 in Nevada, 3 in Japan, and 1 in Argentina—1 person died). At least 54 other passengers reported having diarrhea of unknown etiology. This illustration demonstrates the ease with which this disease can be transported worldwide (Centers for Disease Control, 1992c).

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Emerging Infections: Microbial Threats to Health in the United States Cholera can almost always be treated successfully with oral rehydration therapy, which replaces fluids and essential salts lost in diarrheal stools. Disease surveillance and maintenance of a clean water supply are the most effective methods of preventing disease spread. Currently available vaccines are of limited effectiveness. Extensive transmission of cholera and other waterborne infectious diseases in the United States is highly unlikely, owing to the generally high standards required of U.S. municipal water and sewage treatment facilities. Outbreaks could occur, however, in areas with substandard water supplies and inadequate sewage disposal. Occasional cholera outbreaks in the United States are most often caused by fecal contamination of estuarine waters. Inadequately treated sewage can be taken up by the fin fish and shellfish harvested from these waters; their consumption can infect humans if the fish are prepared improperly. As coastal areas become increasingly crowded and water treatment facilities are overwhelmed or poorly maintained, a rise in cases of Vibrio infection is likely. Complacency There can be a delicate balance between maintaining control of a disease and the initiation of an epidemic. It is one thing to have this balance disrupted by essentially uncontrollable elements; it is quite another to have it go awry as a result of individual or organizational complacency. Sometime in the 1950s, the attention given to acute infectious diseases by public health and medical officials, physicians, researchers, and others began to wane, and a shift in focus to chronic, degenerative diseases occurred. Much of the reason for this shift was the notion that infectious disease problems were becoming a thing of the past—science, medicine, public health, and an improved standard of living had brought most of these diseases under control. People were living longer and developing more chronic illnesses as a result. The emergence of HIV disease and AIDS swung the pendulum back to infectious diseases. HIV disease and the host of opportunistic infections that accompany it have severely challenged the scientific, medical, and public health communities, as well as politicians. Infectious diseases clearly are not a problem of the past. Measles is highlighted here as an example of complacency regarding the control of infectious diseases. Tuberculosis is yet another example that has already been discussed in other sections of this report. There are certainly other diseases, however (including typhoid, diphtheria, whooping cough, tetanus, and louse-borne typhus) that may pose significant threats to health when complacency sets in.

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Emerging Infections: Microbial Threats to Health in the United States INADEQUATE LEVELS OF IMMUNIZATION: MEASLES Immunization against infectious diseases is one of the most effective ways of improving overall public health. Medical researchers have developed dozens of vaccines, a number of which have been incorporated into childhood vaccination programs. These programs have greatly reduced the health-related and financial impacts of a number of previously devastating diseases. However, if such programs falter or are carried out incompletely, diseases that are now relatively rare can reemerge as the killers they once were. This phenomenon is a danger to all countries, particularly those with poor or inactive immunization programs (see Table 2-7). The incidence of measles, a highly communicable viral disease, declined rapidly in the United States after the introduction of an effective vaccine in 1963. There were some 500,000 reported cases each year during the 1950s, a number that had dropped to less than 2,000 by the early 1980s. In 1989, however, the number of measles cases began to climb, and by 1990, more than 26,000 cases were reported, the largest number since 1977 (Atkinson and Markowitz, 1991). What happened? TABLE 2-7 Percentage of 1-Year-Olds Immunized Against Measles in the Americas in 1990 Country Percentage Country Percentage Panama 99 Belize 81 Anguilla 99 Nicaragua 81 British Virgin Islands 99 Turks and Caicos 81 Montserrat 99 Brazil 77 St. Kitts/Nevis 99 Paraguay 77 Chile 98 El Salvador 75 Dominican Republic 96 Jamaica 74 Argentina 94 Suriname 74 Cuba 94 United Statesa 70 Honduras 91 Guatemala 68 Antigua 89 Mexico 66 Barbados 87 Peru 64 Bahamas 86 Venezuela 64 Costa Rica 85 Grenada 63 Colombia 82 Ecuador 62 St. Lucia 82 Bolivia 53 Uruguay 82 Haiti 31 a Data are for 2-year-olds. SOURCE: Bernier, 1991.

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Emerging Infections: Microbial Threats to Health in the United States Measles vaccine induces immunity in more than 95 percent of individuals over one year of age (R. M. Davis et al., 1987). The requirement that school-age children in the United States present evidence of measles vaccination in order to be admitted to school was largely responsible for the dramatic reduction in the incidence of measles in the 1960s, 1970s, and early 1980s. Vaccination levels in preschool-age children, however, were lower than for those attending school (Orenstein et al., 1990; Atkinson and Markowitz, 1991). In 1990, there were large outbreaks of measles in Dallas, San Diego, and Los Angeles; each city reported more than 1,000 cases. In New York City, an outbreak that started in March 1990 continued through 1991, with more than 2,000 cases reported in the first five months of 1991. Epidemiologic data from the New York outbreak revealed that a majority of cases were among preschool-age black and Hispanic children who had not been immunized. Vaccination goals in this population were not being met (Centers for Disease Control, 1991d). There have also been additional outbreaks among vaccinated school-age groups, indicating that in some cases the one-time vaccination was insufficient to prevent disease. In response, the American Academy of Family Physicians, the American Academy of Pediatrics, and the Immunization Practices Advisory Committee (ACIP; a committee of experts convened by the CDC) recommended, in 1989, that a second dose of measles vaccine (as part of the trivalent measles, mumps, and rubella vaccine) be given (Atkinson, 1991). In early 1991, the National Vaccine Advisory Committee issued recommendations to improve the availability of childhood vaccines and urged a two-dose schedule for the measles-mumps-rubella (MMR) immunization (National Vaccine Advisory Committee, 1991). Available data for 1991 indicate that the trend of rising measles incidence is reversing itself. As of November 1991, there were 60 percent fewer cases than had been reported during the same period in 1990 (Cotton, 1991). Although efforts have been made over the past several years to reduce the number of people, particularly children, who have not been vaccinated against measles, the present decline in cases is too great to be attributable to better vaccine coverage alone (Cotton, 1991). At this time, however, a full explanation is not available. War When deployed outside of this country, U.S. military forces are at high risk of being exposed to a variety of infectious disease agents. In past conflicts, infectious diseases have produced higher hospital admission rates among U.S. troops and, until World War II, higher mortality rates, than battle injuries (Gordon, 1958; Reister, N.d.; Washington Headquarters Service

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Emerging Infections: Microbial Threats to Health in the United States Directorate for Information, Operations, and Reports, 1985). Table 2-8 shows the types of infectious diseases that have accounted for the greatest morbidity among American soldiers. The relative importance to deployed forces of any particular infectious disease depends on a number of environmental factors and operational circumstances, including, principally, the geographic area of deployment, the time of year, the mission and composition of the force, and the intensity of the conflict. For example, military operations generally result in large numbers of susceptible individuals living in close proximity, circumstances that can facilitate the transmission of respiratory diseases. Under field conditions, food and water sanitation services may be rudimentary and subject to disruptions, opportunities to exercise good personal hygiene are diminished, and there may be exposure to the bites of infected arthropod vectors of both human and zoonotic diseases. In addition, warfare usually creates some degree of social disruption, which can produce refugee populations that are frequently subject to epidemics of infectious disease. Troops may be at added risk of infection to the extent that they become involved in the supervision and care of the refugees. Because troops are frequently living under relatively primitive field conditions, there is also the potential for accidental transmission of previously unknown zoonotic diseases. The return of TABLE 2-8 Infectious Diseases Causing High Morbidity in U.S. Forces in Past Conflicts: World War II, Korea, Vietnam, and Operation Desert Storm Disease Category Conflict Acute respiratory diseases and influenza All Acute diarrheal diseases All Malaria WWII, Korea, Vietnam Hepatitis WWII, Korea, Vietnam Sexually transmitted diseases WWII, Korea, Vietnam Arthropod-borne diseasesa WWII, Vietnam Rickettsial diseasesb WWII, Vietnam Leptospirosis WWII, Vietnam Leishmaniasis WWII, Desert Storm Schistosomiasis WWIIc NOTE: WWII=World War II. a Especially dengue fever, sandfly fever, hemorrhagic fevers, and encephalitides. b Principally scrub typhus, whose distribution is limited to parts of Asia and northern Australia. c Principally in engineer bridge-building units in Luzon, Philippines. SOURCE: L. J. Legters, Department of Preventive Medicine, Division of Tropical Public Health, Uniformed Services University of the Health Sciences, Bethesda, Maryland.

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Emerging Infections: Microbial Threats to Health in the United States U.S. troops from foreign soils offers a unique opportunity for the introduction or reintroduction of infectious diseases into the United States. The following examples describe infectious diseases that have emerged in association with military operations, some of which involved U.S. Troops. Epidemic typhus, caused by Rickettsia prowazekii, has been a frequent accompaniment of warfare in Europe, dating back to the siege of Naples by the French in 1528 (Zinsser, 1935). The disease, which is acquired by contact with the feces of infected body lice, was a major problem in World War II. Trench fever, caused by Rochalimaea quintana (Rickettsia quintana) , which are transmitted by body lice, made its first appearance in troops during World War I (Fuller, 1964). Epidemic hemorrhagic fever, now known to be due to a zoonotic infection caused by Hantaan virus, was reported in Japanese and Soviet troops in Manchuria before the onset of World War II and was later (1951) recognized in United Nations troops in Korea (Benenson, 1990). Scrub typhus, caused by a rickettsia transmitted by the bite of an infected larval mite of the genus Leptotrombidium, was a major medical problem (surpassed only by malaria in some areas) in the Pacific Theater in both World War II (Philip, 1948) and the Vietnam conflict (Berman et al., 1973). A massive outbreak (involving 30,000 to 50,000 cases) of acute schistosomiasis, caused by Schistosoma japonicum, is reputed to have occurred in Chinese troops in 1950. The troops were being taught to swim in infected canals in southern China in preparation for what, because of the outbreak, became an aborted invasion of Taiwan in 1950 (Kiernan, 1959). Leptospirosis, caused by Leptospira interrogans, was first identified as an important military disease in British troops during jungle operations against Communist terrorists in what was then Malaya in the late 1950s (U.S. Army Medical Research Unit, Malaya, 1962). Leishmaniasis, due to Leishmania tropica, was known to be endemic in the Persian Gulf region before U.S. troops were committed in Operation Desert Shield. Known to cause cutaneous lesions, the capacity of L. tropica to ''visceralize" (i.e., invade bone marrow, liver, and spleen) was not well documented before its discovery in returning U.S. troops. The apparently atypical visceral expression of the disease may not be unusual at all but merely a natural consequence of the exposure of more than 500,000 susceptible troops to infected sand fly vectors in an endemic area. A total of 26 cases of leishmaniasis in U.S. troops—17 cutaneous and 9 visceral—had been diagnosed as of April 1992 (M. Grogl, Chief, Leishmania Section, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, D.C., personal communication, 1992).