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4
Why Is the Army Interested in Nutrition and Immune Function?

LTC Karl E. Friedl1

Introduction

The primary goal of the Army Operational Medicine Research Program is to develop physiological strategies to protect and sustain deployed soldiers. This research is valuable to the Army if it leads to a decisive improvement in the ability to accomplish the mission (i.e., enhanced readiness). One aspect of readiness is resistance to disease, and this may be compromised in soldiers when immune function is suppressed by operational stressors and other battlefield hazards. Combined stressors may reduce the normal ability of soldiers to resist pathogens, increase susceptibility to biological threat agents employed against them, and reduce effectiveness of vaccines intended to protect them.

Some immunological impairments may be prevented by ensuring adequate nutrition (e.g., preventing substantial energy or protein deficits) and by providing specific nutritional supplements to restore deficiencies (e.g., retinol). However, this report is focused primarily on approaches to enhance disease resistance in young men and women with an adequate baseline nutritional status. The main questions to consider is ''Do intakes of specific nutrients or vitamins,

1  

Karl E. Friedl, Army Operational Medicine Research Program, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702-5012



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--> 4 Why Is the Army Interested in Nutrition and Immune Function? LTC Karl E. Friedl1 Introduction The primary goal of the Army Operational Medicine Research Program is to develop physiological strategies to protect and sustain deployed soldiers. This research is valuable to the Army if it leads to a decisive improvement in the ability to accomplish the mission (i.e., enhanced readiness). One aspect of readiness is resistance to disease, and this may be compromised in soldiers when immune function is suppressed by operational stressors and other battlefield hazards. Combined stressors may reduce the normal ability of soldiers to resist pathogens, increase susceptibility to biological threat agents employed against them, and reduce effectiveness of vaccines intended to protect them. Some immunological impairments may be prevented by ensuring adequate nutrition (e.g., preventing substantial energy or protein deficits) and by providing specific nutritional supplements to restore deficiencies (e.g., retinol). However, this report is focused primarily on approaches to enhance disease resistance in young men and women with an adequate baseline nutritional status. The main questions to consider is ''Do intakes of specific nutrients or vitamins, 1   Karl E. Friedl, Army Operational Medicine Research Program, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702-5012

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--> above normal levels, counter immunological impairments caused by operational stressors?'' Background The infectious disease threats facing soldiers vary with geography, but disease has usually accounted for more noneffective days than has combat or even nonbattle injury. In World War II, Rommel and his troops were seriously hampered by diarrheal disease (shigella) in North Africa, and the elite Merrill's Marauders and other units in the China-Burma theater were rendered ineffective by malaria (Reister, 1975). Malaria and diarrheal diseases remain high-priority research targets because of the consequences to the military mission and their widespread occurrence. Emerging infectious diseases and unexpected disease threats have occurred in recent conflicts (Heppner et al., 1993), presenting new challenges for which there may be no specific protection. This may also be true in the defense against some biological threat agents (Liu et al., 1996), for which physiological enhancements of immune protection may present one of the few options for protection. Enhancements of physiological defenses and the responsiveness to vaccines may center on nutritional strategies. Even in military training, infectious diseases are a threat. For example, in 1990, half of the high attrition from Ranger school was attributed to medical problems, with one class decimated by pneumonia (Riedo et al,. 1991), and cellulitis continues to be a problem of Ranger students (Martinez-Lopez et al., 1993). The infectious disease problem in Ranger students appears largely to have been corrected through a nutritional intervention. Immune function deficits were attenuated with increased feeding, and dramatic reductions in infection (25% prevalence reduced to 2%) paralleled the changes in immune function tests (Kramer et al., 1997). The interaction of nutrition and infection has been investigated extensively by military researchers in previous work. Most of this research centered on the consequences of infection to nutrition. COL William Beisel defined an entire field of research in the 1970s at the U.S. Army Medical Research Institute of Infectious Diseases with his work on cytokine-induced malnutrition (Beisel, 1995). His early work also described the physiological effects of lymphocytic endogenous mediator, properties of the cytokine now identified as interleukin-1 (IL-1). Beisel demonstrated that a variety of diseases produced hypermetabolism, loss of protein and vitamins, and wasting of the muscle mass. These effects were mediated through cytokines. More recently, cytokines have been implicated in responses to inflammation as well as immunological responses to a wide variety of stressors (Roubenoff, 1993). These responses are largely responsible for modified immune function and, in some settings, suboptimal resistance to disease, which is a consequence of the accumulated stressors. With this common cytokine pathway, the effect on immune status may represent a generalized stress response to a diversity of stressors. These

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--> generalized cytokine responses to stress may be modified by specific nutrients. The focus of the Army's current research program is in this direction, examining the effect of nutrition on sustainment or enhancement of immune status in healthy individuals. Immune Suppression and Inflammatory Responses to Operational Stressors A current objective of Army operational medicine research is to identify the effect of operational stressors and other battlefield hazards on soldiers' immunological and/or inflammatory host defenses. Problems must be defined in relevant models of operational stress and in terms of actual disease susceptibility (Kusnecov and Rabin, 1994); research to develop nutritional countermeasures is appropriate after problems have been clearly identified. Stressors that are being investigated in military studies include chronic anxiety (referred to in the remainder of this chapter as "psychological stress"), inadequate restorative sleep, physical exertion, inadequate energy intake, industrial toxicological hazards, and mechanical/physical stresses (e.g., blast and laser injuries). Psychological stressors are the best documented in terms of stress effects on immunological impairment, and an entire interdisciplinary field of psychoneuroimmunology is founded on studies linking the immune and central nervous systems (Ader and Cohen, 1993). The Department of Medical Neurosciences at the Walter Reed Army Institute of Research (WRAIR) has investigated acute and chronic rodent stress models actively (e.g., footshock in mice, learned helplessness in defeat-conditioned hamsters2), helping to define mechanisms of stress effects on the brain (Huhman et al., 1991, 1992). Footshock as well as chronic anxiety stress reliably suppresses T-cell proliferation and lymphocyte IL-2 production in rodents (hardy et al., 1990). While adrenocorticoids suppress potentially maladaptive overresponses of immune function (Kapcala et al., 1995), LTC Ned Bernton has demonstrated that their effect is counterbalanced by other factors, such as dehydroepiandrosterone (DHEA) and some of the lactogens, that may reverse corticotropin-releasing factor-mediated decrements in immune function (Bernton et al., 1988, 1992; Rassnick et al., 1994). Studies of combat veterans with posttraumatic stress disorder suggest that, even with adrenal adaptation, anxiety may increase glucocorticoid receptors on lymphocytes (Yehuda et al., 1990, 1991); thus, circulating levels of cortisol may be low and still significantly affect immunogenic tissues (Dhabhar et al., 1995). These basic studies help to explain and verify observed links between psychological stress and illness (Cohen et al., 1991; Lee et al., 1995; Rubin et al., 1970, 1971), 2   A model of stress in which the male hamster, accustomed to attacking unfamiliar hamsters introduced into his cage, is repeatedly defeated by larger, more aggressive intruders until his normal territorial aggression is replaced by defensive behavior and flight.

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--> wound healing (Faist et al., 1996; Kiecolt-Glaser et al., 1995), and responses to vaccines (Kiecolt-Glaser et al., 1996; Moynihan et al., 1990). Deployed soldiers suffer a wide variety of psychological stressors, including mission-related factors (e.g., ambiguity of the return date), family separation issues, and unit level issues (e.g., lack of time off); this was documented by Human Dimensions Teams (HDT) from the Army's research program in the Gulf War, Somalia, Haiti, and most recently Bosnia (Bliese and Wright, 1995; Gifford et al., 1996; Halvorsen et al., 1995; Rosen et al., 1993). Sixteen percent of soldiers in Bosnia indicated that they were coping poorly with stress in their life. This research is primarily centered on rapid identification of significant stress issues so that military leaders can pursue immediate interventions. Future HDT studies will include more comprehensive assessment of somatic complaints, including infections, as capabilities improve for quick turnaround of data acquisition and interpretation. This will also provide new information on the actual consequences of psychological stress in deployed forces. At least part of the reason for high distress scores in soldiers in Bosnia is related to self-reported inadequate sleep (Gifford et al., 1996), and this has an impact on immune function that may be distinctly different from anxiety stress effects. Acute sleep restriction produces a reduction in natural immune responses (e.g., natural killer [NK] activity) and T-cell cytokine production (Irwin et al., 1996), but after more prolonged sleep deprivation, leukocytosis (an increase in the number of leukocytes) is observed and NK activity increases (Dinges et al., 1994). The immunosupportive function of sleep has been suggested on the basis of interactions between sleep and immunological challenges, mediated through cytokines such as IL-1 (Krueger et al., 1994; Pollmacher et al., 1995). For example, low-dose challenges with endotoxin suppress rapid eye movement (REM) sleep (Pollmacher et al., 1995). Sleep deprivation does not appear to affect mitogen-stimulated proliferative responses (Dinges et al., 1994), indicating a different effect on immune function than observed with energy deficit (Christadoss et al., 1984) or with an overlay of a substantial energy deficit even with a large sleep deficit (Kramer et al., 1997). In both of these latter examples, lymphocyte proliferation is suppressed. Immune function indices reflect a complex interrelationship among immune function, psychological stress, and sleep disruption (Kant et al., 1995), which is further complicated by physical work and energy deficit stressors. For example in rats, treadmill running can reduce some of the immune suppression produced by footshock stress (Dishman et al., 1995). Physical exertion produces inflammatory changes as well as transient immunological responses. Moderate exercise is associated with enhanced immune function, but prolonged exercise, or exercise of very high intensity, causes at least transient suppression of immune function indices (Gray et al., 1992; Nieman et al., 1992; Shephard et al., 1994; Tvede et al., 1993). Thus, in female recruits participating in Army basic training involving a modest 2,800

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--> kcal/d energy expenditure, T-cell proliferative responses to phytohemagglutinin (PHA, a mitogen) were increased (Westphal et al., 1995a). In a study of prolonged exhaustive exercise at the Defense and Civil Institute of Environmental Medicine, lymphocytosis (an increase in the number of lymphocytes) was produced, with reductions in the number of T-cells to 60 percent of pre-exercise levels by 2 hours post-exercise and marked suppression of NK cell counts even 7 days after the exercise challenge (Shek et al., 1995). These results are consistent with the field studies conducted at the Norwegian Defense Research Establishment (Bøyum et al., 1996), in a multistressor paradigm that includes strenuous exercise, followed by dramatic changes in immunological indices (see Wiik, Chapter 6). However, this stressful training does not result in a significant increase in infection rates (Bøyum et al., 1996). Thus, theorized connections between physical stress and disease susceptibility in athletes engaged in prolonged intensive training (Pedersen and Bruunsgaard, 1995) remain to be evaluated. It also remains to be established if it is always desirable to block some of the observed changes. For example, there may be adaptive value in obtaining some inflammatory responses if these are linked to muscle and bone remodeling responses to a change in habitual activity. Deployed soldiers face higher health and performance risks from toxicological hazards than ever before. The modern battlefield includes unquantified but widespread agricultural and industrial toxins in developing and former Eastern bloc countries. Among the likely environmental pollutants are immunomodulators such as polychlorinated biphenyls, chlorinated dibenzo-p-dioxins, pesticides, and heavy metals. Although some immunotoxins may cause immune depression, the better known consequence of many of these is immunoenhancement, with potential health risks for autoimmune or allergic reactions (Krzystyniak et al., 1995). If the primary risk from these xenobiotics is via the disruption of brain and immune function interactions instead of through a direct effect on immunocompetent tissues (Fuchs and Sanders, 1994), conventional assays are unlikely to detect the hazard. Assessment of these deployment hazards may be difficult by conventional in vitro methods for other reasons as well: techniques have not been developed for identification of many toxins; even after a chemical is identified, health risks may be unstudied; and the effects of specific mixtures of chemicals will almost certainly be undefined. For these reasons, biosentinel species3 and nonmammalian bioassays for the identification of environmental toxin risks are being actively investigated in the Center for Environmental Health Research (CEHR) at Fort Detrick, Maryland. Fish have been explored as biosentinels of immunotoxicity (Wester et al., 1994) and are part of the current program in the CEHR. 3   Species of organisms used to detect and warn for presence of a toxin because of their sensitivity to the substance (e.g., canaries in coal mines) and/or because of their chronic contact with the environment.

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--> Conceivably, a variety of stressors cause tissue damage and decrease healing capacity through oxidative stress, which could be countered with antioxidant feeding. For example, wound healing is accelerated with vitamin E treatment (Simon et al., 1994). Hypobaric hypoxia stress in the Operation Everest II experiment produced alterations in the indices of immune function (Meehan et al., 1988), and it was suggested in a previous CMNR workshop that increased antioxidant intakes could be beneficial to soldiers operating at altitude (Simon-Schnass, 1996). However, the issue must not be oversimplified. Blast overpressure from big weapons systems produces mechanical trauma to human airways, the gastrointestinal tract, and the musculoskeletal system. Basic research in the Department of Respiratory Research at WRAIR has demonstrated an interesting paradox, wherein antioxidants may increase oxidative stress following tissue damage due to blast overpressure through redox cycling of heme proteins and nonheme iron (Elsayed et al., 1996). In vitro studies also indicate that nitric oxide reactions may play an important role in the protection of tissues from oxidative damage (Gorbunov et al., 1996). These data highlight the importance of clarifying the basic mechanisms and problems associated with operational stressors before attempting to field solutions. Military Models to Study Operational Stressors The models of operational stress that are appropriate to the military's research on immune function present some special challenges. Ideally, these should model actual deployments or realistic training scenarios in order to include stressors typical of military operations. Psychological stress and inadequate rest are probably the most important of these stressors to include because of their consistent appearance in current deployments. Significant rates of infectious disease problems should also be a key feature of the model. Ethical concerns limit the design of experimental models with these features; thus, much of the military's stress research involves opportunistic field studies where the investigators do not impose the stressors but are able to study the consequences. It is also likely that investigators will provide recommendations that will fix the problem, which, if incorporated, will reduce the future utility of the model. Thus, some of the best models are moving targets. Some limited opportunities have existed for research during actual combat service. For example, during the Vietnam War, John Mason and his colleagues examined endocrine stress responses of helicopter air ambulance crews and Special Forces A-teams under attack (Bourne et al., 1967; Rose et al., 1969); also a Navy aeromedical research team studied stress responses of carrier pilots in combat (Lewis et al., 1967). Unfortunately, these studies preceded the recent advances in immune function testing and current understanding of the associations between stress and disease susceptibility. More recently, the Ranger course provided the Army with a very stressful training model, perhaps even exceeding the combined stress effects observed in actual combat but lacking the

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--> psychological components expected in a real deployment (Johnson et al., 1976; Moore et al., 1992; Pleban et al., 1990). Unfortunately for researchers, the participants in this test model are competitively evaluated against each other, making placebo-controlled studies difficult within a single course (i.e., no advantage can be ethically withheld from a portion of the participants). Administering an infectious challenge is necessary to evaluate the efficacy of prospective interventions. For example, a study conducted in Panama demonstrated the efficacy of doxocycline prophylaxis in protection against leptospirosis infection (Takafuji et al., 1984). This placebo-controlled study took advantage of a known significant infectious hazard to which soldiers were exposed as a matter of course in jungle training and probably even in previous military nutrition studies (e.g., Consolazio et al., 1979). However, such studies tend to be one-time opportunities; if effective in demonstrating a solution to the problem, the model is no longer available for other intervention studies. In the absence of such opportunities, a safer infectious challenge may have to be considered such as respiratory tract viruses employed in the stress dose-response study of Cohen et al. (1991). Development of immunity in response to vaccines (e.g., hepatitis A vaccine) could also be evaluated in naive subjects in operationally relevant stress models. Bernton tried unsuccessfully to include such a trial in the 1992 Ranger studies; this would be invaluable in defining the practical consequences of the observed immune suppression and would offer information vital to the questions being posed in this report.4 One problem with studies of relatively short duration is that some of the changes noted may reflect acute-phase responses that could be triggered by a variety of novel stressors rather than identifying specific immune axis lesions. The Ranger training studies afforded a unique opportunity because of the duration of the course. In fact, by the end of the first study, immune function indices were returning to normal levels despite continued exposure to the course stressors (Kramer et al., 1997). This finding may indicate a recovery from acutephase responses, an adaptation to the stressors, or a reduced energy deficit in the final phase of the course as behavioral and metabolic efficiencies decreased requirements to match intakes more accurately (Friedl et al., 1995a). The many shorter-term models of operational stress range in length from 1 to 3 weeks, most typically about 1 week, as summarized elsewhere (Friedl, 1997). The Norwegian Ranger course is the best-defined model and is easily characterized for nutrition intakes because of the nearly total restriction on intakes (Opstad, 1995). Navy SEAL training "hell week" has also been characterized in nutrition studies (Singh et al. 1991; Smoak et al. 1988). A primary recommendation, which came out of the North Atlantic Treaty Organization workshop on "The Effect of Prolonged Exhaustive Military 4   Since this workshop, a study involving hepatitis A vaccine administered to Ranger students has been designed and started (October 1997) by MAJ Jeffrey Kennedy (USARIEM, Natick, Mass.).

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--> Activities on Man" (NATO, 1995), was to establish a multinational competition modeled along the lines of the 72-h Best Ranger competition to study efficacy of various interventions for enhancement of health and performance of elite soldiers. Buddy teams could be paired with both intervention and placebo members and the benefits of dietary supplements could be tested effectively in an acute operational stress scenario in motivated top performers. Mechanisms of Increased Infection Susceptibility: Army-USDA Cooperative Research Data In 1990, 14 Ranger students were hospitalized with pneumonia at Dugway Proving Ground, Utah; this unusual outbreak was investigated by a team from the Centers for Disease Control and Prevention (Riedo et al., 1991). The high level of stress and/or severity of disease was marked by negligible concentrations of testosterone in serum samples from nearly every student (Unpublished data, K. E. Friedl and L. J. Marchitelli, USARIEM, Natick, Mass., 1991). This outbreak prompted the commander of the Ranger Training Brigade to request help in determining if more sleep and changes in nutrition were necessary to ensure the health and safety of his trainees. This led to two Ranger studies in 1991 (Bernton et al., 1995; Moore et al., 1992) reviewed in a previous Committee on Military Nutrition Research workshop (IOM, 1992), which rekindled interest in the relationship between nutritional status and resistance to disease. Measurement of immune function indices were included in these studies to provide sensitive markers of nutritional status (Sauberlich, 1984) and to address the primary concern of increased susceptibility to infection. A cooperative agreement with the U.S. Department of Agriculture (USDA) enabled Tim R. Kramer to contribute experience he gained from field immunology studies in China and Thailand (Kramer et al., 1993; Zhang et al., 1995). This exchange was an opportunity to address questions of importance to both agencies under a longstanding agreement (DoD, 1983; Kramer, 1992). Since the first Ranger study, a series of studies between Kramer and U.S. Army Research Institute of Environmental Medicine investigators has led to an improved understanding of the role of energy deficit in immune function. The combined data from four separate studies involving methodology controlled by the same laboratory investigators in a consistent manner are summarized in Table 4-1. The methodology, including a whole blood method of lymphocyte proliferation measurement, and the challenges to carefully control field sample collection and handling are reviewed later in this report by Kramer (see Chapter 10). These data suggest that the degree of immune function suppression, as indicated by stimulated lymphocyte proliferative response, is proportional to the degree of energy deficit. Although reliable energy expenditure data are available only for the two Ranger studies, body weight loss is a reasonable indicator of the scale of energy

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--> TABLE 4-1 Energy Deficit and Its Relation to Stress Indices and PHA-Stimulated T-lymphocyte Proliferation Study N Wks %BW %FFM %IL-6 %PHA-T %T RGR-I 49 4 -9.2 — -17 -52 -69     8 -15.9 -6.9 -63 -21 -74 RGR-II 41 4 -7.0 — +15 -32 -60     8 -12.8 -6.1 -84 -5 -83 SFAS 37 3 -4.0 -1.0 -46 -20 -15 BCT 48 4 — — -37 +165 —     8 -1.4 +5.0 +220 +144 — NOTE: Values represent percent change from baseline measurements. BW, body weight; FFM, fat-free mass; IL-6, interleukin-6; PHA-T, phytohemagglutinin-stimulated T-cell proliferation; T, Testosterone. SOURCE: Adapted from RGR-I, Ranger course, 1991 (Kramer et al., 1997); RGR-II, Ranger course, 1992 (Kramer et al., 1997); SFAS, Special Forces and Assessment course, 1993 (Unpublished data, B. Fairbrother and T. R. Kramer, USARIEM, Natick, Mass., 1993); BCT, Army Basic Combat Training, 1993 (Westphal et al., 1995a). requirement supplied from body energy stores. The Special Forces Assessment and Selection (SFAS) course was only 3 weeks long, compared with 8 weeks for Ranger training and for Army basic training, and energy density of weight loss is likely to vary over time within a protracted energy deficit. Thus, the 4 percent weight loss figure in SFAS should be compared with 9 and 7 percent in the two Ranger classes at 4 weeks, confirming a substantially larger gap between intakes and requirements for Ranger students (Kramer et al., 1995). IL-6 was used in all of these studies as a stress marker integrally related to activation of the hypothalamo-pituitary-adrenal axis as well as being produced by cells of immune origin (Zhou et al., 1993). After initial stress responses, the IL-6 response moves in the opposite direction. The lowest levels of IL-6 were found in soldiers with the highest stress conditions, including the very lowest level of IL-6 (along with the highest level of cortisol) in the individual soldier with the greatest relative weight loss (-23% of initial body weight). Because of the hypermetabolic effects of IL-6 (Stouthard et al., 1995), a decline in the levels of this cytokine is clearly adaptive during a continued energy deficit. This decline in IL-6 may also be important to stimulation of IL-1 and other cytokines involved in immune regulation (Zhou et al., 1996). The gonadal steroids were also used as stress markers, but these steroids tend to reflect more specifically the energy deficit stressor as mediated through the hypothalamic control of the pituitary-gonadal axis. For women, progesterone was used as the female analog of the testosterone response. Mean levels of progesterone remained unchanged through the basic training studies,

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--> indicating not only the continuation of eumenorrheic cycles but also the absence of stress-induced deficient luteal phases (Friedl et al., 1995b). Other indices of immune function measured in all of these studies, such as changes in IL-2 receptor, need further investigation. Changes in IL-2 receptor may reflect an increased activation of T-lymphocytes, causing increased release of receptor into circulation. Whether this increase indicates that the immune system is functioning better than the in vitro tests indicate, or that some immunopathological process is occurring, is unknown (Kramer et al., 1995). Comprehensive vitamin and mineral analyses were performed in each of these four studies by the clinical laboratory at the Pennington Biomedical Research Center. No specific vitamin or mineral deficiencies could be identified, except for a small mid-study decline in serum retinol in the first Ranger study, probably related to a significant decline in measured retinol binding protein (Moore et al., 1992). Delayed-type hypersensitivity (DTH) test results did not correspond to suppressed lymphocyte responsiveness in vitro. In vivo tests of immunocompetence using the Merieux multitine tests were applied at the beginning, at 6 weeks, and at the end (8 weeks) of the first Ranger study (after blood samples had been drawn for in vitro tests). There was no change in 72-h response rates across the course, except for a significant increase in the tuberculin responses (based on indurations > 2 mm) (Martinez-Lopez et al., 1993). Thus, DTH testing was not performed in subsequent studies involving lower stress levels than in the first Ranger study. A modest increase in caloric intake and a 20 percent reduction in energy deficit across the course may have been responsible for the marked reduction in infection rates noted between the first and the second Ranger study (Table 4-2). It is also possible that the attenuation of the immune function deficits observed in the in vitro tests offers a mechanism for the reduction in infection rates (Kramer et al., 1997). Infectious disease was negligible in the SFAS and basic training studies. These very tentative relationships suggest directions for more controlled laboratory studies. Specific Nutritional Fixes and the Promise of Immune Sustainment and Potential Superimmunity Specific nutrients or dietary supplements may improve host immune response in trauma or malnourished patients (Gallagher and Daly, 1993; Morgan, 1966); however, there are still few data to substantiate a role for dietary supplements (e.g., arginine, glutamine, antioxidant mixtures) in the enhancement of immune function in healthy individuals. This may be due to (1) the use of inadequate study models where infection is not an important problem or the effects of the stressors were not as profound as anticipated, and (2) the location of studies in difficult-to-control field settings that do not permit definitive conclusions.

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--> TABLE 4-2 Infection Rates in Ranger Studies Study Phase 2 Wk 2–4 Phase 3 Wk 4–6 Phase 4 Wk 6–8 RGR-I (1991) 9/109 (8%) 19/75 (25%) 14/58 (24%) RGR-II (1992) 14/121 (12%) 7/85 (8%) 1/58 (2%) NOTE: These rates were determined by review of all recorded sick call visits by and medical treatments to students in the Ranger course. Cellulitis was the most common type of infection classified in both courses. The common diagnosis of ''cellulitis of the knee" was not definitively distinguished from the noninfectious injury (bursitis) produced by frequently dropping to one knee during stops in patrolling operations; greater awareness of the need for knee protection in Ranger II (Caravalho, 1992; Kragh, 1993) may have contributed to the apparent differences in "infection" rates. RGR, Ranger training course. SOURCE: Adapted from IOM (1993). One study at the SFAS course tested a dose of oral glutamine (15 g/d) compared with an isonitrogenous dose of glycine and found no differences between treatments on any tests of immune function (Shippee et al., 1995). In LTC Barry Fairbrother's original SFAS study (Fairbrother et al., 1993), there was a suppression of immune function indices, although smaller than in the Ranger studies (Table 4-1). The in vitro lymphocyte responses cannot be compared directly between the glutamine study and the original study because of the timing of a DTH test at the end of the glutamine study; however, similar results were obtained for both treatment and control groups in the glutamine study. No statistically significant difference was obtained between the groups for the DTH test even when results were classified as positive for indurations greater than 5 mm diameter only (Shippee et al., 1995). Since infection is not a medical problem in the SFAS course, the most useful end point of modified infection rates is not testable in this setting. Eric Newsholme and others have suggested on theoretical grounds that glutamine may be an important link between immune function and exhaustive exercise because of the shared requirement for glutamine by both immune cells and skeletal muscle (Newsholme, 1994); however, a benefit from glutamine supplementation in these circumstances remains to be demonstrated. Another study considered the effect of a carbohydrate beverage as a means of improving hydration status and energy balance. No differences in immune function outcomes were observed in this 3-d exercise by Ranger instructors, but there was also no change in any in vitro tests in the control group. The aspartame sweetener used in the control group beverage may have had an unexpected effect on immune indices (Montain et al., 1995). New data from antioxidant studies in the field involving a mixture of vitamins and minerals (vitamin A, E, and selenium), will be presented later in

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--> (found in alfalfa sprouts) and excessive vitamin E use and makes the recommendation that such immunomodulatory supplements should have warning labels (Herbert and Kasdan, 1994). Certainly, this points to the need for a new review of upper safe limits of nutrients and vitamins, including antioxidants. Because the military is a performance-oriented subject population that is especially likely to be lured into use of dietary supplements, it becomes important for the military to counter misinformation with substantiated nutrition facts and guidance. There is currently no reliable information clearinghouse to which a soldier, dietitian, or physician can turn to identify bogus claims. Examples of how information might be better disseminated include Carol J. Baker-Fulco's ''Performance Nutrition"/"Eat to Win" videotape instructional series, and general nutrition education centered on balanced and healthful diets (e.g., menu modification research efforts in collaboration with the Pennington Biomedical Research Center to develop good meals that will appeal to young soldiers). It is also important to publicize research findings on new supplements, including what does, and particularly what does not, appear to provide a benefit to soldiers. Author's Conclusions Military operational medicine research is necessarily problem oriented. This does not preclude the need for basic research or the use of the best state-of-the-art science to overcome technological barriers and develop solutions that will make a difference to the deployed warfighter. Key technological barriers in nutritional immunology include an understanding of the relationship between immune function indices and disease susceptibility, a better understanding of the central role of cytokines in stress-induced suppression of immunological function, and a more complete understanding of the biological effects and modulation of oxidative stress. Practical limitations include diminishing resources and limited available expertise in the multiple disciplines required to accomplish this research. This further increases the need for efficient interlaboratory and interagency collaborations. An Army nutritional immunology research program should include the following target objectives: (1) define the importance of nutritional status to effectiveness of immunizations and natural disease resistance in deployed soldiers, (2) identify a dietary supplement or feeding strategy that substantially reduces susceptibility of soldiers to infection in stressful operational settings, and (3) assess hazards to military readiness associated with dietary supplements commonly used by soldiers.

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--> KARL FRIEDL: That is not remarkable? DOUGLAS WILMORE: Yes. Some of my learned colleagues can comment more about that. But we clearly see levels much, much lower, and we set ranges for normal that are broader than that. What I am concerned about, however, are figures that look at dropout rates with 121 entrants, 85 subjects looked at in the next go-round, and 58 subjects looked at in the last analyses. What may be of more interest would be what happened to the people who are not being measured. KARL FRIEDL: We certainly tried to capture that. We captured it in those infection rates. When we looked at why people dropped out, the dropouts were not people who were having problems with infections. For the most part, the dropouts were the ones who were failing on peer reviews, that is, the subjective evaluation of their leadership capabilities and how well they could lead. DOUGLAS WILMORE: It is not physical performance, as a general rule? KARL FRIEDL: By and large, it is because they received a poor score in their leadership capabilities. Now, what goes into that though? Physical capabilities certainly do. These guys were fatigued and simply stopped performing because they couldn't think clearly anymore. I think that is the main reason they are dropping out. We looked very carefully for that because we were concerned about dropouts as well. RONALD SHIPPEE: Karl and I have talked about this a lot. You have got to be extremely careful interpreting the attrition rates from these studies. I will give you an example. We do a lot of work with SFAS. SFAS is unique because we have complete access to the students. If a guy drops out academically, he gets out and we thank him for being in the course. If you go down to the building where the dropouts are waiting to be taken back to the post, there is a lot of hacking and coughing going on in there. So I know in my heart, when I look at these guys, a lot of the attrition that occurs when a guy says he failed to perform is probably due to illness. I was going to bring this up in my presentation. We do all of these little immunological tests, and they are fine, and they give us some direction; but the true proof is going to be observing high infection rates at these schools. I will show you one approach to get at that. So, you are right. Be very careful when you look at attrition rates in these courses. They do not tell the whole story. I am sure that Karl will agree with that.

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--> DOUGLAS WILMORE: I do not want to monopolize this at all; but just for the committee to realize, I have talked to some of the people who are getting ready to go on the Ranger courses. If you talk to them about the supplements that they are taking, the pictures that Karl showed do not do them justice. When I talked to them about doses, I found that they are really dosing. And the issue is, as I understand it, that they are withdrawing themselves from the supplements as they go out on the Ranger course. There is a classic example of withdrawal from high-dose vitamin C down to normal RDA [Recommended Dietary Allowance] vitamin C intake levels, and the functional effects of vitamin C deficiency are observed. That is an issue that I think really we have to come to grips with and address. ROBERT NESHEIM: Any other questions? Yes. JOSEPH CANNON: I have a question and comment. The question relates to the infection rates in the women who were undergoing basic training. Was that similar to the infection rates in the men? KARL FRIEDL: No. I do not think we had any infection in the women. There was no significant problem with infection ratio. In fact, most of the sick call visits were for musculoskeletal injury. JOSEPH CANNON: Just a comment. I would like to follow-up on what Doug Wilmore was saying about PHA. In 1992, when we looked at U.S. Air Force cadets, they showed a similar falloff in PHA-induced lymphocyte proliferation. When we looked at the cadets who became ill, and compared them with those who remained perfectly healthy, there was no difference in those two groups in terms of their PHA response. So that certainly may not in itself tell the whole story. KARL FRIEDL: But, in addition, you have got to consider what they are exposed to. They still have to come in contact with some kind of pathogen, unless there is some endogenous problem that will take over. In the case of the Ranger students, in the last phase or towards the end of the course, when they are in this sort of suppressed stage, they are immersed in the Yellow River, and they spend a lot of time in water immersion in this fairly polluted river. At that point, they have a lot of knee abrasions. Every time they stop they drop down to one knee. So commonly we get these soft-tissue infections of the knee, cellulitis. It is because of exposure. I think that we have to have that piece of it. We have to have exposure on top of susceptibility.

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--> ROBERT NESHEIM: Last comment? ARTHUR ANDERSON: You mentioned that, with the first Ranger group study, you had an increase in positivity for T.B. [as demonstrated by the tine test] at the end of the study compared with the beginning of the study, but not in the second Ranger study, where individuals were knocked out early in the trial because of medical problems. KARL FRIEDL: No. In the second study we did not do the tine study. ARTHUR ANDERSON: Oh, you did not do the test? KARL FRIEDL: No. We just saw that it did not show us much in the first study, so we did not repeat it. ROBERT NESHEIM: Good. Well, thank you very much. I think that sets a real stage for the rest of this workshop.

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