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D
Emerging Infections, Nutritional Status, and Immunity

Presentation by Stephen S. Morse, Edited by William R. Beisel

Seldom-recognized infections are likely to be encountered by U.S. troops who are deployed in unusual places (Morse, 1997). This problem has long been under investigation by the military, and as Susanna Cunningham-Rundles has said so very eloquently (see Chapter 9), one should expect the unexpected. Some of the lessons already obtained by studying the pathogenesis of newly emerged infections have been fruitful. However, there may also be some contradictory lessons to be gained from these studies.

Popularly speaking, emerging infections are the ones that suddenly appear in the news, such as the Ebola outbreak in Africa or, more recently, the Ebola—Reston virus, which appeared in monkeys in Reston, Virginia, and more recently in Alice, Texas. The most important emerging infection, which contributes to the realization that surprises will always occur, is the HIV (human immunodeficiency virus) infection that leads to AIDS. Like other emerging infections, AIDS was unknown to humans prior to the early 1980s. At that time, the major causes of death among men aged 25 to 44 years, a prime age group, did not include infectious disease death. Rather, the predominant causes of death



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--> D Emerging Infections, Nutritional Status, and Immunity Presentation by Stephen S. Morse, Edited by William R. Beisel Seldom-recognized infections are likely to be encountered by U.S. troops who are deployed in unusual places (Morse, 1997). This problem has long been under investigation by the military, and as Susanna Cunningham-Rundles has said so very eloquently (see Chapter 9), one should expect the unexpected. Some of the lessons already obtained by studying the pathogenesis of newly emerged infections have been fruitful. However, there may also be some contradictory lessons to be gained from these studies. Popularly speaking, emerging infections are the ones that suddenly appear in the news, such as the Ebola outbreak in Africa or, more recently, the Ebola—Reston virus, which appeared in monkeys in Reston, Virginia, and more recently in Alice, Texas. The most important emerging infection, which contributes to the realization that surprises will always occur, is the HIV (human immunodeficiency virus) infection that leads to AIDS. Like other emerging infections, AIDS was unknown to humans prior to the early 1980s. At that time, the major causes of death among men aged 25 to 44 years, a prime age group, did not include infectious disease death. Rather, the predominant causes of death

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--> were injuries, automobile accidents, and so on. This cohort of men was similar to those in the military—soldiers who were preparing to fight. In the last decade, AIDS has shown a remarkably steep slope of increase and is now the leading cause of death among men of prime age. In this case, expecting the unexpected is not only necessary, but also something that must be prepared for. Emerging infections are more formally defined as infections that appear suddenly in a population or that rapidly increase in prevalence or in some new geographic range. Many of these conditions will be faced by troops deployed to distant places, which is why the military has a long-standing interest in emerging infections. During the Korean War, almost 4,000 U.S. and UN troops acquired a viral disease called Korean hemorrhagic fever. The virus was not identified until the mid-1970s, and it is now known as Hantavirus, after a river in Korea near where it was first isolated. Almost 400 troops died, many more were incapacitated, and military demoralization occurred. Thus, emerging infections certainly can affect military operations, in addition to having a civilian impact. Soldiers serve as sentinels, intentionally or unintentionally, for emerging infections. Viral emergence or, in general terms, infectious disease emergence is a process that involves two steps. The first step is introduction. Where do these apparently mysterious viruses or other agents come from, and how are they introduced into the human population? This has long been the most mysterious step. Pathogen dissemination is the second step. Many infections are introduced into the human population, but most fail to make the leap to wide dissemination. Infections that are geographically localized cause problems for troops and others who are deployed in those areas, but they do not necessarily lead to a worldwide pandemic. Influenza does on occasion, and AIDS certainly has. A number of factors can be associated with the emergence of a new infection (IOM, 1992a; Morse, 1997). These factors promote either the introduction or the dissemination step, and sometimes they influence both steps. Introduction factors include ecological changes, which involve the changing relationship between humans and their environment. They typically involve land-use changes or people interposing themselves into formerly sequestered natural environments. The result is increased human contact with a natural host. For example, a rodent species carries an infection that is natural to the wild host, but not to humans. As a result of increased rodent–human contact, an apparently new zoonotic infection can be introduced into the human population and disease may occur. Other factors leading to the introduction of disease include land-use changes, such as clearing the land for agriculture, which may precipitate the introduction of a new infection. Human demographics and behavior also play a very important role. The role of human behavior is illustrated by the dissemination of HIV and AIDS. Isolated infections can be introduced from a zoonotic source in an isolated

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--> geographic setting; then, the infection becomes disseminated as people move from rural areas into cities. Such movement is occurring with increasing frequency throughout the world. The United Nations estimates that, by the year 2025, two-thirds of the world's population will live in cities. Probably a dozen cities have populations of 8 million or more, and this trend will continue, largely for economic reasons related to demographic upheavals or war. In the case of HIV, this trend transposed once localized viruses to a larger population. The population in these burgeoning Third World cities such as Bangkok, Mexico City, Cairo, and Lagos, Nigeria (all larger than New York City), is often at high density, which facilitates the spread of potentially transmissible viruses. Malnutrition is also common in these high-density areas. Soldiers who are deployed in such areas—as they have been in Haiti, Panama, and Somalia—will be at risk of disease. International travel and commerce include the rapid movement of people and goods around the world, which can allow previously isolated pathogens that have made the leap from the country into the city to disseminate even further. Such movement may be aided by advances in technology and industry such that biological products contaminating a single batch of a product become introduced to a larger final product. For example, hemolytic uremic syndrome is caused by a particular strain of E. scherichia coli that makes a toxin that contaminates hamburger. In high-density settings in which cattle are kept, the bacteria are largely disseminated by way of a small number of cattle who pick up the infection and transmit it to others. This scenario has also happened with bovine spongiform encephalopathy (BSE). Changes in rendering processes in England allowed the feeding of cattle with contaminated material very likely from sheep, although the transmission path has not been definitely identified. The oil shortage may also have influenced the transmission of BSE, in that portions of the rendering process were modified. Thus, technology and industry often create high-density settings in which biological products contaminated by an agent can flourish and spread. A highly important factor in the spread of infection involves microbial adaptation and change, sometimes resulting in antibiotic-resistant organisms. Virus evolution is not usually the engine of a new disease, simply because so many viruses exist in various zoonotic species. Reemerging diseases are also an important factor. These are infections that have reappeared in places where they were thought to be eliminated. Diphtheria, for example, is now making a massive reappearance in the former Soviet Union. Reemerging diseases are usually an indication of a breakdown in public health measures, such as sanitation, immunization, and all of the nineteenth-century control measures that were so effective in reducing infectious diseases in the past. It is important to ask where and in what manner future infections might emerge, including pathogenetic mechanisms and the extent of human

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--> susceptibility during nutritional deficiency states. Where do these infections come from? The answer is from nature. In most cases, ecological changes underlie these events. They often involve previously sequestered natural hosts—in many cases, though not always, a rodent. There is a great biodiversity of rodents throughout the world carrying their own infections, and sometimes they come in contact with humans under suitable conditions. For example, hantaviruses, named after the prototype Hantaan, the virus of Korean hemorrhagic fever, is a virus carried by a common field mouse Apodemis aggrarious. This mouse flourishes in rice fields, as well as in somewhat more pristine environments occupied by military troops. As rice planting increases throughout Asia, the incidence of Korean hemorrhagic fever in Korea and China also increases, probably 100,000 to 200,000 cases occur per year. This particular rodent consumes rice in the fields prior to harvest. With their rice harvest, humans may also accidentally reap a virus that is left behind from the urine of infected mice. After the urine dries, the virus becomes airborne. Humans can then inhale this virus and become infected. Historically, Hantavirus has been considered exotic. Although it was known to be in North America, none was associated with disease until the famous outbreak of Hantavirus pulmonary syndrome (HPS), as it is now called, in the Four-Corners region of the southwestern United States in 1993. The setting in which it occurred was not a jungle and not one where a new and unknown disease would be expected. The rodent that transmitted the virus is Peromyscus meniculatas, the common deer mouse, which is commonly found over most of North America. In fact, it appears to be the natural host of the virus that causes HPS. Probably the virus has been widespread in the United States and in North America, since there are related viruses now known in South America. It is now well-documented by ecologists in the area that a temporary change in the climate resulted in a rodent population explosion and an increase in rodent–human contact. Various human activities may also provide opportunities for larger numbers of people to come in contact with diseases and spread them—for example, international travel. Troop movements follow the same pattern. This phenomenon underscores the need to be prepared, both diagnostically and in terms of surveillance. Comparatively little is known about the role of nutrition in many of these infections, even for some that are quite familiar. Regarding pathogenesis and the effect of nutritional interventions on the pathogenesis of many of these infections, very little is known, aside from the truism that "malnutrition is bad." One of the most common of the emerging infections in the world is dengue hemorrhagic fever (Bhamarapravati, 1989; Fan et al., 1989; Halstead, 1989; Krishnamurti and Alving, 1989; LeDuc, 1989; Rosen, 1989), a severe manifestation of dengue infection in children. Dengue is a common, tropical, mosquito-borne infection that most people living in the tropics eventually experience. The more severe forms of infection lead to something not unlike

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--> septic shock, and one assumes there is an underlying mechanism. Interest has focused on cytokines in recent years, but few details have been elucidated. The pathogenesis of dengue hemorrhagic fever is probably similar to the pathogenesis of other hemorrhagic fevers and perhaps similar to the pathogenesis of septic shock. Scott Halstead working in Thailand some years ago noted clinically that he rarely saw dengue hemorrhagic fever in undernourished children. It was only the better-nourished children who seemed to mount this particular response. In 1993, an epidemiological study in Thailand confirmed this observation (Thisyakorn and Nimmannitya, 1993). The children studied were ages 3 to 15, and it was relatively uncommon, compared with the entire population, to see dengue hemorrhagic fever in those who were malnourished. Because little is understood about the pathogenesis of dengue hemorrhagic fever, one wonders about the effect of nutritional intervention on the release of cytokines. Indeed, comparatively little is known in vivo about the effects of nutrition or malnutrition on the cytokines. Indeed, this may be a double-edged sword. Why do children seem to be most susceptible to dengue hemorrhagic fever, and why are those who become clinically ill better nourished rather than malnourished? The answer is not known. However, the dangers of poor nutrition are clear and palpable. Measles in Africa, for example, appeared in unusual manifestations, causing immunosuppressive disease with much more severe manifestations than normally expected. Although the pathogenesis is not known, a widespread suspicion suggests that malnutrition may have altered the presentation of disease. Indeed, when working in places with high operational, environmental, and nutritional stresses, unusual manifestations can be expected—even of well-known infections—and we may be fooled by them. Finally, relatively little is known about the many factors affecting resistance to viral infection in humans. The macrophage is an important target for many of the infections that might be classified as emerging, including HIV and many of those causing hemorrhagic fevers. Macrophages are also important cells for releasing TNF (tumor necrosis factor) and IL-1 (interleukin-1), which may be important as a pathogenic mechanism. Finally, the role of the immune system itself in the evolution of viruses is still unknown. One expects, for example, that immunosuppression might lead to viral variation and mutation. However, in some situations, the opposite may be true. The immune response itself may help to drive variation. In contrast, there are remarkable and unexpected effects of even micronutrient malnutrition on viral evolution. Melinda Beck's work (see Chapter 16) with mice deficient in selenium or vitamin E illustrates this viral evolution—the appearance in these animals of a variant that was virulent for them and also for healthy animals. In other words, a malnourished mouse who gets this infection is a danger to itself, but also to the

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--> others next to it who now become infected. This work came out of a clinical observation of humans in China where a similar disease was seen in areas of low selenium. To understand, in sum, there are many more questions than answers, and it is important to look at biological outcomes and the relationship between nutritional factors and pathogenesis. These factors can be defined, and they can be studied. Attention to cytokines is an important research task. Certainly, military troops deployed in distant, hazardous locations and experiencing a diverse variety of stresses will always face these potential problems of emerging infections. This threat argues for the systematic study of potential infections in a combined research program that would also make intervention studies possible. References Bhamarapravati, N. 1989. Hemostatic defects in dengue hemorrhagic fever. Rev. Infect. Dis. 11(suppl. 4):S826-S829. Fan, W.F., S.R. Yu, and T.M. Cosgriff. 1989. The reemergence of dengue in China. Rev. Infect. Dis. 11(suppl. 4):S847-S853. Halstead, S.B. 1989. Antibody, macrophages, dengue virus infection, shock, and hemorrhage: A pathogenetic cascade. Rev. Infect. Dis. 11(suppl. 4):S830-S839. IOM (Institute of Medicine). 1992a. Emerging Infections: Microbial Threats to Health in the United States, J. Lederberg, R.E. Shope, and S.C. Oaks Jr., eds. Committee on Emerging Microbial Threats Health, Division of Health Sciences Policy, Division of International Health. Washington, D.C.: National Academy Press. Krishnamurti, C., and B. Alving. 1989. Effect of dengue virus on procoagulant and fibrinolytic activities of monocytes. Rev. Infect. Dis. 11(suppl. 4):S843-S846. LeDuc, J.W. 1989. Epidemiology of hemorrhagic fever viruses. Rev. Infect. Dis. 11(suppl. 4):S730-S735. Morse, S.S. 1997. The public health threat of emerging viral diseases. J. Nutr. 127(5 suppl.):951S-957S. Rosen, L. 1989. Disease exacerbation caused by sequential dengue infections: Myth or reality? Rev. Infect. Dis. 11(suppl. 4):S840-842. Thisyakorn, U., and S. Nimmannitya. 1993. Nutritional status of children with dengue hemorrhagic fever. Clin. Infect. Dis. 16(2):295-297. Discussion G. RICHARD JANSEN: Your talk reminded me so much of a book that Renee Dubose wrote like 40 or 50 years ago called The Mirage of Health. Essentially what he was saying is that we cannot keep up with it because there is always going to be something new coming along.

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--> STEPHEN MORSE: Yes. There is a great biodiversity of microbes out there that have been evolving far longer than we have. They have evolved all sorts of strategies for better evolution. I am afraid that Dubose was right. The good news though is that these factors can be studied, they can be identified, and I think we can better understand the complex interactions of these multifactorial interactions. There are a lot of surprises out there. Certainly, Melinda Beck's work is a surprise and opens up a lot of questions about how some of the things like nutrients could in fact shape evolution in ways that we had not originally expected. I think that it is an exciting time to be studying this. Perhaps we have more of an advantage. We are more vulnerable, but we also have more advantages for studying these factors than were available in Dubose's time. WILLIAM BEISEL: Talking about the possible disease effects in healthy children for dengue hemorrhagic fever earlier, Dr. Chandra showed a picture. The third man in that picture was Dr. Nevin Scrimshaw, and he introduced the concept of synergism and antagonism. I went through all of his quoted papers, and antagonism was about 50/50 in virus diseases with synergism. Microbiologists cannot grow viruses unless their cultured cells have a beautifully balanced nutritional status. So this is a possible reason as to why the healthy children developed the dengue hemorrhagic fever symptoms. They were better nourished. They could maybe grow more viruses in the body than the malnourished kids. STEPHEN MORSE: That is entirely possible. It would also be ironic, of course, if their nutritional status made children less able to mount an effective immune response and, therefore, in some sense, less able to make some of the mediators that caused the immunopathology that was really the problem. JOHANNA DWYER: Just a quick question. Richard Mung, from Harvard, says it is a big, bad world out there, but also that part of the problem lies in ourselves, that we use paradigms that are outdated and so forth. Can you suggest any that might be helpful to the committee in its deliberations? STEPHEN MORSE: In terms of ecological paradigms, or infectious disease paradigms, or nutrition paradigms? JOHANNA DWYER: Both infectious disease, which I think is what he deals with, and nutritional.

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--> STEPHEN MORSE: This is certainly a subject that one could speculate about for hours. First of all, we know relatively little about the biodiversity of organisms that we might potentially be exposed to, and we know relatively little about how we would respond to them. For example, at this point, we cannot look at a sequence of any given virus and say what effect it is going to cause in a human being. I find that not surprising. But I think that we are in a position where soon we may be able to change that. For example, Ebola-Reston is arguably less virulent than Ebola-Zaire in humans. There is some natural evidence from the monkey handlers and others who became infected. It appears to be less virulent, and yet it is fairly closely related to known virulent strains. The Hantavirus pulmonary syndrome, caused by Hantavirus Muerto Canyon, is fairly closely related to other hantaviruses that are not associated with human disease. Smallpox and vaccinia are another pair. One is not very virulent for humans by most measures. In fact, we used it as a vaccine, and one is highly virulent. One of the underlying problems is our lack of pathogenesis models. We know so little about dengue because we have no pathogenesis model. If we had better pathogenesis models, nutrition could also be studied, and the factors isolated in those models could be further tested through interventional studies. Now, on sort of the broad global scale, I would argue that the military is one of a number of components that is well positioned to be doing infectious disease surveillance and providing those data both to themselves and, when available, to others. Military operations may occur anywhere in the world. When troops are sent somewhere, they become effectively sentinels. So this requires watchfulness. We have long argued—every expert group like the Institute of Medicine Committee on Emerging Microbial Threats to Health—for the importance of surveillance, but we are not there yet. The World Health Organization, for example, is beginning to formulate effective plans for global surveillance, but it is going to take years to do that. JOHN VANDERVEEN: One of the comments we are hearing occasionally now—not only that we are concerned about public health being a major cause for disease spread, but also there is some suggestion that perhaps we made some of our environment too clean, in that we are ridding ourselves of beneficial organisms that may cut down on the possibility of the spread of more harmful organisms. What is your opinion on that? STEPHEN MORSE: We know relatively little. It is an interesting question. I cannot speak with authority on it. The impression I have is that we know relatively little about that. On sort of a macroscale, if I can get to just something a little bit larger, namely the rodents, we know that many of these outbreaks that have occurred in natural settings are very likely to be the result of an ecological change, some sort of agricultural change that favored a particular rodent. The

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--> result was that that rodent, which was best adapted to that environment, outcompeted the others who were holding it in check. It is interesting that we know relatively little about beneficial effects and about what maintains these balances in nature at the detailed level of being able to model and predict them.

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