This report, Military Strategies for Sustainment of Nutrition and Immune Function in the Field, is a review of nutrition and immune function and its application to military operational missions. It is the latest in a series of reports by the Institute of Medicine's Committee on Military Nutrition Research (CMNR) and was requested by Army scientists from the U.S. Army Medical Research and Materiel Command (USAMRMC) and the Military Nutrition Division (currently the Military Nutrition and Biochemical Division) of the U.S. Army Research Institute of Environmental Medicine (USARIEM).

Specifically, the committee was charged with reviewing the current state of knowledge about immune function, assessing how it may be impacted unfavorably by military stresses (including food deprivation), and with

evaluating ongoing research efforts by USARIEM scientists to study immune status in Special Forces troops.

In order to accomplish this task, the CMNR held a workshop, reviewed the literature, and deliberated on its findings to provide responses to the following task questions:

1. What are the significant military hazards or operational settings most likely to compromise immune function in soldiers?
2. What methods for assessment of immune function are most appropriate in military nutrition laboratory research, and what methods are most appropriate for field research?
3. The proinflammatory cytokines have been proposed to decrease lean body mass, mediate thermoregulatory mechanisms, and increase resistance to infectious disease by reducing metabolic activity in a way that is similar to the reduction seen in malnutrition and other catabolic conditions. Interventions to sustain immune function can alter the actions, nutritional costs, and potential changes in the levels of proinflammatory cytokines. What are the benefits and risks to soldiers of such interventions?
4. What are the important safety and regulatory considerations in the testing and use of nutrients or dietary supplements to sustain immune function under field conditions?
5. Are there areas of investigation for the military nutrition research program that are likely to be fruitful in the sustainment of immune function in stressful conditions? Specifically, is there likely to be enough value added to justify adding to operational rations or including an additional component?

6. This report focuses on the many stresses encountered by military personnel and the complexity of their immune responses.

   Overview of Nutritional Status and Immune Function

   Immunity, if defined broadly, encompasses all mechanisms and responses used by the body to defend itself against foreign substances, microorganisms, toxins, and incompatible living cells. Such responses may be conferred by the immune system itself or by the protective role of other generalized host defensive mechanisms.

   The immune system resides in no single organ but depends on the interactions and secretions of various organs and white blood cells. The physiologic function of the immune system may be viewed simplistically as a mechanism by which the human body responds to and eliminates an initiating antigen. This process is mediated by a myriad of specialized cells and depends on a pathway involving recognition, activation, differentiation, and response to

lymphocytes. Thus, this simplistic view becomes significantly more complicated when one is examining the biological nature of these responses in greater detail.

Every aspect of immunity and host defense is dependent upon a proper supply and balance of nutrients (Chandra, 1988; Cunningham-Rundles, 1993; Forse, 1994; Gershwin et al., 1985; Watson, 1984). Severe protein-energy malnutrition can cause significant alterations in the immune response, but even subclinical deficits may be associated with a catabolic response, an impaired immune response, and an altered risk of infection (Beisel, 1982; Keusch and Farthing, 1986). Research using laboratory animals and work with human subjects has extended these observations to the recognition that nutritional deficiencies are associated with a large number of alterations in cell-mediated immunity and the cytokine-initiated acute-phase response. Fever and other hypermetabolic components of acute-phase reactions can deplete the body of essential nutrients. Deficiencies of many individual nutrients, including protein, essential fatty acids, vitamin A, vitamin B₆, folic acid, zinc, iron, copper, and selenium, have been associated with altered immune function. An overview of the nutrients that support immune function is presented in Table S-1, which is a summary of data presented in Chapter 1. Cytokine-induced changes in metabolism can become severe and lead to malnutrition, as seen clinically in many victims of trauma, infections, or other wasting illnesses.

The stresses experienced by military personnel are numerous and varied, encompassing changes in temperature, altitude, humidity, and the availability of food and water; limited or nonrestful sleep; prolonged moderate-to-heavy physical activities; increased susceptibility to infection and injury; and other psychological stresses associated with training or battlefield combat. Military personnel frequently face simultaneous (and often varying) combinations of these diverse stresses for weeks or months at a time. Very little is currently known about the possible additive immunological consequences of these combined stresses. However, much has been learned about the immunological consequences of several of these stresses on an individual basis (for example, malnutrition, semistarvation, severe exercise, infection, and trauma). The primary goal of the Army Operational Medicine Program is to develop physiologic strategies to protect and sustain deployed soldiers, thereby enhancing readiness by maintaining their ability to accomplish assigned missions. One program with a critical need to enhance and maintain readiness is the U.S. Army Special Operations Training Program, which includes the U.S. Army Ranger Training Courses.

At the conclusion of the 1990 U.S. Army Ranger Training Course (Moore et al., 1992), an unusually high incidence of infection was documented in the Rangers. This promoted an extensive investigation by a military epidemiology team. An increased incidence of upper respiratory infection, cellulitis, and pneumococcal pneumonia was reported. In addition to the increased infection rates noted in the Rangers, laboratory tests of immune function, showed decreased proliferative activity of both T- and B-lymphocytes in response to an applied mitogenic stimulus (phytohemagglutinin) in cultures of whole blood samples. Other significant findings included marked deficits in energy intake resulting in an average weight loss of 15.9 percent over the eight-week training period; significant losses in body fat from an average of 14.6 percent at entry to 6.9 percent at the end of training. Therefore, the team of epidemiologists recommended that further studies be conducted by military researchers to evaluate the effects of multiple stresses on host defense mechanisms.

After discussions between military research personnel and the Ranger Training School officials, it was decided to perform an additional field study, a nutritional intervention study using a modified ration (Long-Life Ration Packet, LLRP) containing approximately 15 percent more energy on a per-ration basis than the previously supplied Meal, Ready-to-Eat (MRE) ration.

The Ranger II study, which was conducted between the months of August and September 1992, was a collaborative effort among investigators and resources from USARIEM; the Walter Reed Army Institute of Research; the U.S. Department of Agriculture Human Nutrition Research Center in Beltsville, Maryland; and the Pennington Biomedical Research Center at Louisiana State University, Baton Rouge (Shippee et al., 1994). In Ranger II, two significant training stresses were changed after the Ranger I course: (1) the order of the geographically different testing phases was changed (military base field training, desert, mountain, and jungle, to military base field training, mountain, jungle, and desert) because significant immune depression was noted in the Ranger I training course at the end of the mountain and jungle phases; and (2) energy intake was increased by approximately 15 percent (220 kcal/d). In the first two training phases, the MRE was supplemented with a carbohydrate-containing drink and fruit, and in the last two training phases, the MRE was replaced with the LLRP.

A major finding from the Ranger II study was a less dramatic weight loss, which averaged 12.5 percent of initial body weight compared to 15.9 percent in Ranger I. This resulted in an average body fat content at the end of training of 8.4 percent compared to 6.9 percent in Ranger I. Researchers found that with the increased energy intake, there was less suppression of T-lymphocyte cell proliferation in response to an applied mitogenic stimulus, indicating an improvement in immune response. The depression in T-cell proliferative response that was demonstrated at the midpoint of the training phases of Ranger I was found to occur in the later testing phases of Ranger II. Although there was

a reduction in the absolute number of circulating T-lymphocytes (CD3), T-helper lymphocytes (CD4), and T-suppressor lymphocytes (CD8) in response to stress during Ranger II, this reduction was less severe than that observed in Ranger I.

Although significant improvements were noted in the maintenance of normal nutritional status of the Ranger trainees with the Ranger II intervention study many questions remained regarding the impact and intensity of Ranger training with respect to body composition changes and host defense mechanisms. In order to delineate further some of the mechanisms and stresses contributing to these alterations, the CMNR conducted a focused review of current information pertaining to: (1) the combined effects of health, exercise, and stress on immune function; (2) the impact of nutritional status on immune function; (3) the role of nutritional supplements and biotechnology in enhancement of immune function; and (4) the assessment of immune status under field conditions. The CMNR then used this review to identify and recommend future research needs and directions for the military in the area of nutrition and immune function.

Many stressful conditions encountered by military personnel have immunological consequences. Undoubtedly, food deprivation is one of the most common and important of these stresses. Total energy intake appears to play the greatest role in nutritional modulation of immune function. Since it has been demonstrated that prolonged energy deficits resulting in significant weight loss have an adverse effect on immune function, emphasis should be placed on the importance of adequate ration intake during military operations to minimize weight loss.

The military's use of prophylactic immunization provides sufficient benefits beyond risk to warrant continued development. This is supported by a recent decision by the Secretary of Defense to begin systematic immunization of all U.S. military personnel against the biological warfare agent anthrax.

Pharmacologic agents such as aspirin, ibuprofen, and glucocorticoids, which modulate the effects of cytokines, can be used to minimize signs and symptoms of cytokine-induced acute-phase reactions and the nutrient losses that accompany them. Future investigations into the changing immunological status of troops in the field must obviously be based upon available current knowledge about the immunological impact of individual stresses. However, because multiple stresses (including food deprivation) are expected, these wil l have to be studied using experimental designs and methods that have been validated by pilot studies prior to their use in large field studies.

Evidence to suggest that the administration of recombinant cytokines can modulate immune function in a desirable manner is limited. Their effectiveness has not been demonstrated in healthy subjects.

Field studies must be based on the results of prior experiments conducted in controlled laboratory and clinical settings. Experimental designs and methods must be validated by pilot tests prior to use.

Total energy intake appears to play the greatest role in nutritional modulation of immune function. Since it has been demonstrated that prolonged energy deficits resulting in significant weight loss have an adverse effect on immune function, emphasis should be placed on the importance of adequate ration intake during military operations to minimize weight loss. Weight loss in the range of 10 percent in operations extending over 4 weeks raisee the concern of reduced physical and cognitive performance and has potential health consequences for some individuals (IOM, 1995).

The nutritional status of soldiers should be optimized prior to deployment, engagement in any exercise or training course, or even brief encounters with anything that would present a potential immune challenge (disease, toxic agent, or environmental stress). When consumed as recommended, operational rations provide adequate energy and macronutrients.

Nutrients that appear to play a role in immune function include protein, iron, zinc, copper, and selenium; the B-group vitamins, especially B₆, B₁₂, and folate; vitamin A and its precursor, β-carotene, vitamins C and E; the amino acids glutamine and arginine; and the polyunsaturated fatty acids. It is difficult, however, to consider the role of one nutrient in isolation. Evidence for a distinct role for vitamin C in immunomodulation remains controversial, and the role of vitamin E has been demonstrated chiefly in the elderly. There is no evidence at this time to indicate that the levels of vitamins A, C and E, or trace elements including zinc, copper, or selenium, are inadequate in operational rations. Increasing or decreasing the consumption of n-6 or n-3 PUFAs or altering their intake ratios may impact immunological function.

The effects of providing supplements of vitamins A, C and E, as well as certain polyunsaturated fatty acids and amino acids, prior to, during, or following infections are virtually unknown in young, healthy adult men. Many questions remain regarding the efficacy of these nutrients in amounts that exceed Military Recommended Dietary Allowance (MRDA) levels. However,

during protracted infections, nutritional supplements (multivitamin and/or multimineral pills, antioxidants, and amino acids such as glutamine and arginine) may provide valuable immunological support. Further, the consumption of high-quality diets should be encouraged early in convalescence to restore body nutrient pools and lost weight.

Excess iron as well as iron deficiency may compromise immune status. The problem of compromised iron status in female personnel is a matter of concern because it may impact immune function, physical performance, and cognitive function. It is important to maintain adequate iron status in female soldiers and to do so without causing excess iron intake by males.

Glutamine has demonstrated potential for improving immune function in critical illness, but its usefulness in healthy populations is unknown. Parenteral and enteral administration of glutamine has been observed to improve recovery following gastrointestinal surgery. Thus far, the effect of glutamine has been observed only in supraphysiological amounts and only in patients undergoing bone marrow transplantation or major operations and those who sustain life-threatening sepsis. Studies to evaluate the effects of supplemental glutamine on the immune function of soldiers have shown no demonstrable effects. An effect of glutamine deficiency also has not been demonstrated.

Risks associated with excess consumption of supplements are much more likely for some nutrients than for others. Toxicity and the potential for nutrient—nutrient interactions must be considered individually. Excess vitamin A may be toxic, whereas vitamins C and E are relatively nontoxic and have been shown to enhance the immune response in some individuals. Trace elements are particularly problematic since requirements may be increased during periods of illness, but at the same time, excessive intakes of some trace elements may be immunosuppressive. Very little is yet known about the immunological effects of short-term food deprivation when accompanied by varying combinations of other military stresses.

• The CMNR recommends the use of medically appropriate and directed prophylactic medications and procedures to minimize the adverse effects of infectious agents. However, the CMNR sees no potential value at this time in administering cytokines or anti-cytokines to healthy military personnel. It is generally assumed that the body's production of endogenous cytokines during stressful situations is beneficial to the host. However, if endogenous proinflammatory cytokines accumulate in large excesses or are given in large doses, they may have noxious or even dangerous consequences.

• The military should remain cognizant of the very active civilian-sector research concerning cytokines, their complex control mechanisms, and their functions, and should apply any pertinent new findings to the management of militarily relevant infectious diseases, trauma, or other stresses.
• In light of the importance of military immunization programs for achieving and maintaining immune status at optimal levels, the CMNR reiterates its previous recommendations (IOM, 1997) that vigorous research efforts be undertaken to create and evaluate militarily relevant oral vaccines. These should include optimization of administration schedules and elucidation of the influence of nutritional status on vaccine efficacy. Immunological responses to vaccines may be altered by the stresses of mobilization and/or overseas deployments. Antibody responses to vaccines are known to be depressed by protein-energy malnutrition. The potential problem of reduced responsiveness to military vaccines given during periods of mobilization and deployment stresses (in comparison to normal responses, as measured in control studies) also deserves future study.
• It is recommended that soldiers maintain good physical fitness via a regular, moderate exercise program as a means of sustaining optimum immune function. Since the intensity and duration of physical activity can affect immune function, training regimens that achieve high levels of physical fitness without adverse effects on immune status should be established.
• Additionally, the CMNR recommends the use of methods to minimize psychological stresses, including training, conditioning, and structured briefing and debriefing.

• In view of the compromised immune function noted in studies of Ranger trainees, the CMNR recommends that, where possible, individuals who have lost significant lean body mass should not be redeployed until this lean mass is regained. Although data showing an effect of weight loss on immune function may be limited, it is reasonable to suggest that the maintenance of body weight within 10 percent of ideal weight should increase the likelihood that adequate immune function will be maintained. Thus, the committee recommends that soldiers be advised to achieve an energy intake sufficient to maintain normal weight. The energy intakes required to maintain body weight will vary with the intensity and duration of physical activity; therefore, the best field guide for individual soldiers and commanders is to monitor body weight changes and to emphasize, through a ''field-feeding doctrine,'' the importance of ration intake as the fuel for the soldier to maintain health and performance.

• The CMNR recommends that nutritional anemias be treated prior to deployment and that individuals classified as anemic¹ and requiring iron supplements not be deployed. With the reduced personnel in today's Army and the potential for frequent deployment, it is important that soldiers be in good nutritional health at the time of deployment and that an effort be made to correct any compromise in status that may have resulted from previous deployment. Some scientists believe that iron supplements, if given during the course of bacterial or parasitic infections, may increase the severity of these illnesses. Because this topic is a controversial one, it requires further investigation. Nevertheless, it is recommended that if supplemental iron is required (for prophylactic purposes), it should be in the form of an optional ration component, and the iron content of operational rations themselves should not exceed MRDA levels.
• As a means of reducing the number of stresses encountered by military personnel, the committee encourages the development and implementation of nutrition education programs targeted at high-risk military groups, such as Special Forces troops and female soldiers, to communicate information regarding healthy eating habits and supplement use.

Supplementation with certain nutrients may be of value for sustaining host defense mechanisms (including those conferred by the immune system) at normal levels during periods of extreme physiological and physical stress. It is unlikely, however, that nutritional supplements can produce a state of superimmunity in military personnel.

• At this time, the CMNR cannot recommend general supplementation of military rations above MRDA levels for the purpose of enhancing immune function. There are no definitive studies that demonstrate positive benefits to young, healthy, active individuals of nutrient supplements at levels significantly in excess of those recommended by the MRDAs and commonly provided by foods. Soldiers should be cautioned regarding the indiscriminate use of individual supplements.
• The CMNR recommends that, when needed, the preferred method of providing supplemental nutrients is through a ration component. This would reduce both the potential for excessive intake by those individuals whom do not need the nutrient and the misuse that may occur when supplemental nutrients are provided in single nutrient form. Because energy is one nutrient

• that has been identified as playing a role in immune function, provision of supplemental energy in the form of a food bar would allow soldiers to increase their nutrient intake as needed according to activity levels.
• The CMNR recommends that the military gain a better understanding of the prevalence of supplement use and abuse by personnel and make strong recommendations for their appropriate use or nonuse. The emphasis should be on education and wise choices. A better understanding of supplement use will provide information on the prevalence and frequency of use, its impact on an individual's nutritional status, and the likelihood of reckless or dangerous nutrition practices. Such information will help provide for the delivery of targeted and focused nutritional education messages. As more information is gained on supplement use and misuse and the risks and benefits of supplements, the Army may want to consider formulating a "supplement doctrine" to address these concerns and add a component to nutrition education programs.

• The CMNR recommends that research be conducted to determine the appropriate field measures (see Table S-2) for monitoring nutritionally induced immune responses, particularly for determining the presence of acute-phase reactions and changes in immune function of the type and degree that are likely to occur as a result of the nutritional insults suffered by soldiers in typical deployment situations. This will require basing field study design and methodology on appropriate clinical investigations, piloting experimental designs, and using a simple panel of standard tests that have been validated for the field. Particular attention must be paid to the timing of sample collection; the conditions under which samples are transported, stored and handled; and the use of proper controls.
  
  

  A rapid assessment of immune functions for use in the field includes clinical evaluations of local lesions, sites of inflammation, and signs and symptoms of generalized infectious illness. The C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and white cell counts are the most rapid and least expensive lab tests.

• multistress environments. Developmental efforts should be focused on one or two measurements that could be standardized with sufficient accuracy to serve as marker replacements for an entire (and complex) cytokine battery and would have some clinical correlate in immune function; some examples are skin test response or peak titer following vaccination. Civilian research efforts in this area should be followed carefully, and collaborative relationships should be formed.
• The CMNR recommends that if research is conducted on the ability of nutrients to influence immune status, priority should be placed on the antioxidant nutrients β-carotene and vitamins C and E. The committee acknowledges that insufficient data are available to identify any specific nutrient or combination of nutrients as having adequately demonstrated the ability to enhance immune function under the military operational conditions investigated. This would include vitamins C and E, as well as the amino acids glutamine and arginine.
• It is recommended that the military keep apprised of research being conducted in the civilian sector on immune function in physically active women and consider conducting studies on military women in situations of deployment to augment the findings of civilian studies. At present, there are few studies on immune function in women.
• The influence of iron status on the risk of infection requires further investigation. This is also an area of interest to the civilian medical community.

The Committee on Military Nutrition Research is pleased to participate with the Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine, and the U.S. Army Medical Research and Materiel Command in progress relating to the nutrition, performance, and health of U.S. military personnel.

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