As stated in Chapter 1, the Committee on Military Nutrition Research (CMNR) was asked to respond to five specific questions dealing with the impact of nutritional status on immune function as it pertains to soldiers deployed for military operations and Special Forces troops. The conclusions and recommendations that follow are based on the discussion of these questions appearing in Chapter 2. Recommendations for areas of future development for the U.S. Army nutrition research programs are also included in this chapter.

The study of the interaction of nutrition and immune function is an exceptionally active area of research in both the military and the civilian (academic and commercial) sectors.

A considerable number of conditions encountered by the military act as immune stressors. These stressors include operationally induced undernutrition and dehydration; alterations in biological rhythms; atmospheric conditions such as temperature, humidity, and altitude; and environmental pollutants such as dust, smoke, and chemical fumes, as well as injuries and infectious agents themselves. As a result, studies of immune function in field situations contain many uncontrollable variables, and it is often difficult to attribute observed effects to one variable such as nutritional status.

The military's use of prophylactic immunization provides sufficient benefit beyond risk to warrant continued development. Recommendations concerning research on militarily relevant vaccines are contained in an earlier CMNR report (IOM, 1997). This is supported by a recent decision of the Secretary of Defense to begin systematic immunization of all U.S. military personnel angainst the biological warfare agent anthrax.

Pharmacologic agents such as aspirin, ibuprofen, and glucocorticoids modulate the effects of cytokines and can be used to minimize signs and symptoms of cytokine-induced acute-phase reactions and the nutrient losses that accompany them. Their use in military operations for the management of minor traumas and infections is well recognized and has been shown to sustain military performance during severe training exercises and operational missions.

Evidence to suggest that the administration of recombinant cytokines can modulate immune function in a desirable manner is limited at the present time to a small number of disease states. 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. Because of the effects of circadian rhythms on immune function, samples must be collected at precisely defined times. In addition, because of the sensitivity and low levels of the molecules of interest, biological samples must be handled, transported, and stored according to recommendations for the materials in question, and appropriate controls must be included.

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 or 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.

In addition to energy intake, nutrients that appear to play a role in immune function include protein, iron, zinc, copper, and selenium; the antioxidants β-carotene and vitamins C and E; vitamin A and the B-group vitamins, especially B₆, B₁₂ and folate; the amino acids glutamine and arginine; and the polyunsaturated fatty acids (PUFAs). It is difficult to consider the role of one nutrient in isolation. Evidence for a 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, E, and C, or trace elements including zinc, copper, or selenium are inadequate in operational rations. Increasing or decreasing the consumption of n-6 or n-3 polyunsaturated fatty acids (PUFAs), or altering their intake ratios, may impact on immunological functions. Available data also suggest that altered dietary intakes of essential polyunsaturated fatty acids (PUFAs), either the n-6 or the n-3 PUFAs, may influence immune functions. Iron deficiency impairs immune system competence and depresses the bactericidal functions of phagocytic cells. Excess iron as well as iron deficiency may also compromise immune status. Selenium deficiency is associated with increased susceptibility to particular infectious pathogens and may modify the virulence of a coxsackie virus that causes heart muscle damage. The latter observation may explain the apparent prevalence of Keshan disease, an endemic juvenile cardiomyopathy thought to be caused by a coxsackie virus, in areas of China experiencing periodic selenium deficiency. Glutamine has demonstrated potential for improving immune function in critical illness, and parenteral and enteral administration of glutamine has been observed to improve recovery following gastrointestinal surgery, but its usefulness in healthy populations must yet has not been determined. Studies to evaluate the effects of supplemental glutamine on the immune function of soldiers have shown no demonstrable effects. The amounts of vitamins and trace elements (including zinc, copper, and selenium), contained in operational rations, meet all MRDAs (Military Recommended Dietary Allowances) if the diet is fully consumed. However, varying combinations of military stresses may increase the need for certain essential nutrients to values greater than the MRDA to maintain immunological competence.

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. The most prudent approach seems to be one of increasing fruit and vegetable consumption in the diet, thus maximizing the potential benefits of antioxidant nutrients.

Safety problems 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 intakes of vitamin A may be toxic, whereas vitamins C and E are relatively nontoxic and have been shown to enhance the immune response. Trace minerals are particularly problematic because requirements may be altered during periods of illness (increased), while at the same time, excessive intakes of some trace elements may be immunosuppressive.

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.

Although none of the major body nutrients lost during severe diarrheal episodes (sodium, potassium, and bicarbonate) are known to influence immune function, rehydration strategies (and in some situations, supplementation with glutamine) may be of use in the treatment of diarrhea.

Finally, it must be emphasized that the results of studies performed in deficient animals or individuals are different from those done on adequately

nourished ones and that, in many cases, an "overdose" of a nutrient, as well as a deficiency, leads to negative consequences.

• 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 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. The military should also keep apprised of advances (in the form of proven treatments) that emerge from this research.

• 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 anemia 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 additional iron is required (for prophylactic purposes), it should be in the form of an optional ration supplement, 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.

• The military should increase efforts to communicate information regarding healthy eating habits and supplement use to all personnel. Since dehydration and energy deficit have a great potential for compromising immune function, soldiers should also be educated regarding compliance with the "water doctrine."

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. Carefully controlled pilot and more extensive field studies will be necessary to investigate this possibility. It is unlikely, however, that nutritional supplements can produce a state of superimmunity in normal subjects or military personnel.

• At this time, the CMNR cannot recommend general supplementation of military rations above the MRDAs 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. Encouraging ration intake to sustain nutrient levels as described in the MRDAs appears to be the best recommendation until further research clearly can define the likely benefits of specific nutrient supplementation under defined operational conditions. Soldiers should be cautioned regarding the indiscriminate use of individual supplements and the potential effects of inadequate nutrient intake, as well as the use of single or combined supplements, since their effects on immune status are not known.

• 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 who do not need the nutrient and the potential misuse that exists when supplemental nutrients are provided in individual 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 supplement use as well as supplement abuse by personnel and make strong recommendations for the appropriate use or nonuse of nutritional supplements.

• The emphasis should be on education and wise choices. In the past, the CMNR has suggested the development of a "field-feeding doctrine" (IOM, 1995a), with the guiding principle that the energy intakes of military personnel during training and combat operations should be adequate to meet their energy expenditures and to maintain body weight and lean body mass. This field-feeding doctrine would accompany the successful "water doctrine" that resulted from a recommendation in the report Fluid Replacement in Heat Stress, (IOM, 1991; and 1993a). 4). The guiding principle of the water doctrine was to ensure that adequate fluid intake is maintained to avoid dehydration and subsequent decreased food intake. As more information is gained on supplement use and misuse and on the risks and benefits of supplements, the Army may want to consider formulating a "supplement doctrine" similar to the water and food doctrines to address these concerns and add a component to nutrition education programs. 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. The committee is aware that some information on supplement use will be obtained by the Army Food and Nutrition Survey and suggests that additional information on supplement use can best be obtained by including appropriate questions in ongoing military health surveys, such as the Survey of Health-Related Behaviors Among Military Personnel.

The CMNR strongly encourages the military to keep apprised of relevant civilian research and consider the application of selected findings and protocols to the military situation.

• The CMNR recommends that research be conducted to determine the appropriate field measures 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 studies on appropriate clinical investigations, piloting experimental designs, and using a simple panel of standard tests (such as those described in Chapter 2) 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. Skin tests are highly valuable markers of cell-mediated immunity but require 48 hours before they can be read. Other tests can be valuable if time and facilities permit. On the other hand, preliminary clinical trials may employ additional kinds of sophisticated immunological studies, along with those listed for field investigations.
• In addition, the CMNR recommends careful design of research protocols.
  
  

  Efforts should be directed towards ensuring the control of as many environmental, behavioral, and treatment variables as possible so that the effects attributed to a deficiency of a particular nutrient are not in fact the result of some other operational stress. The military nutrition research program should attempt to differentiate between nutrition-induced immune dysfunction and that caused by other forms of operational stress.

• The CMNR strongly encourages the military to increase its awareness of and consider the military applications of the findings within the civilian research community regarding nutrition and immune function. The advice of civilian and military immunologists should be sought to identify the testing methods that have proven to be most useful and field applicable for monitoring immune status and function.

Very little is yet known about the immunological effects of short-term food deprivation when accompanied by varying combinations of other military stresses. 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 to be expected, these will have to be studied using experimental designs and methods that have been validated by pilot studies prior to their use in large field studies.

• The CMNR reiterates its previous recommendations (IOM, 1997) that laboratory-based studies be performed to determine if an interleukin-6 (IL-6)–creatinine ratio (or some comparable measure) can be measured in single "spot" urine samples as an index of the 24-h excretion of IL-6 and if 24-h IL-6 excretion is, in turn, a reliable indicator of acute stress response.

• Such determinations should be made before urinary IL-6 measurements are used in field studies, where 24-h urinary collections are virtually impossible to obtain.
• The CMNR recommends the development and field testing of appropriate measurements of cytokines or their various markers in urine and blood that are reflective of ongoing acute-phase reactions and of changes in immune status in multistress environments.
  
  

  Developmental efforts should focus 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, such as skin test response and peak titer following vaccination. These may be useful in studies of the effects of nutritional status on immune function. 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 at this time should be placed on the antioxidants 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.

• 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.
• 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 very few studies on the immune function of healthy women or women in high stress situations.

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.

Anderson, A.O. 1997. New Technologies for Producing Systemic and Mucosal Immunity by Oral Immunization: Immunoprophylaxis in Meals, Ready-to-Eat. Pp. 451-500 in Emerging Technologies for Nutrition Research, Potential for Assessing Military

Performance Capability, S.J. Carlson-Newberry and R.B. Costello, eds. A report of the Committee on Military Nutrition Research, Food and Nutrition Board, Institute of Medicine. Washington, D.C.: National Academy Press .

IOM (Institute of Medicine). 1991. Fluid Replacement and Heat Stress, 3d printing., B.M. Marriott, ed. A report of the Committee on Military Nutrition Research, Food and Nutrition Board. Washington, D.C.: National Academy Press.

IOM (Institute of Medicine). 1993a. Nutritional Needs in Hot Environments, Applications for Military Personnel in Field Operations, B.M. Marriott, ed. A report of the Committee on Military Nutrition Research, Food and Nutrition Board, Washington, D.C.: National Academy Press.

IOM (Institute of Medicine). 1994. Fluid Replacement and Heat Stress, 3d ed., B.M. Marriott, ed. A report of the Committee on Military Nutrition Research, Food and Nutrition Board. Washington, D.C.: National Academy Press.

IOM (Institute of Medicine). 1995a. Not Eating Enough, Overcoming Underconsumption of Military Operational Rations, B.M. Marriott, ed. A report of the Committee on Military Nutrition Research, Food and Nutrition Board. Washington, D.C.: National Academy Press.

IOM (Institute of Medicine). 1997. Emerging Technologies for Nutrition Research, Potential for Assessing Military Performance Capability, S.J. Carson-Newberry and R.B. Costello, eds. A report of the Committee on Military Nutrition Research, Food and Nutrition Board. Washington, D.C.: National Academy Press.