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6
Immune Function Studies During the Ranger Training Course of the Norwegian Military Academy

Pål Wiik1

Introduction

Several reports have noted increased frequency of infectious disease especially in the respiratory system in athletes during high-intensity training (Fitzgerald, 1988; Hoffman-Goetz and Pedersen, 1994; Sharp and Koutedakis, 1992) and also during sustained military operations (Bernton et al., 1994; Kramer, 1994). From the substantial number of reports addressing this topic, the general view seems to be that light to moderate physical activities for up to a few hours stimulate immunity, while high-intensity acute exercise and chronic high-intensity training may suppress immune functions.

However, most of the published data on physical exercise consider duration of exercise of only up to a few hours. Because the strenuous physical exercise during military operations may last for weeks, sometimes with very little sleep and energy intake, the civilian data are inappropriate for purposes of

1  

Pål Wiik, Norwegian Defence Research Establishment, N-2007 Kjeller, Norway



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--> 6 Immune Function Studies During the Ranger Training Course of the Norwegian Military Academy Pål Wiik1 Introduction Several reports have noted increased frequency of infectious disease especially in the respiratory system in athletes during high-intensity training (Fitzgerald, 1988; Hoffman-Goetz and Pedersen, 1994; Sharp and Koutedakis, 1992) and also during sustained military operations (Bernton et al., 1994; Kramer, 1994). From the substantial number of reports addressing this topic, the general view seems to be that light to moderate physical activities for up to a few hours stimulate immunity, while high-intensity acute exercise and chronic high-intensity training may suppress immune functions. However, most of the published data on physical exercise consider duration of exercise of only up to a few hours. Because the strenuous physical exercise during military operations may last for weeks, sometimes with very little sleep and energy intake, the civilian data are inappropriate for purposes of 1   Pål Wiik, Norwegian Defence Research Establishment, N-2007 Kjeller, Norway

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--> comparison, and studies conducted under military conditions are necessary. In this chapter, findings from this laboratory documenting specific and nonspecific immune changes during 7 days of continuous Norwegian Ranger training will be summarized. Results of studies involving neuroendocrine modulators of immune functions will also be given. The Ranger Training Course of the Norwegian Military Academy The cadets of the Norwegian Military Academy take part in a Ranger training course lasting for 7 days as a part of their training program. During this course, cadets engage in continuous, physical, military activities of moderate intensity, day and night, such as marching with a rucksack, digging, and climbing. In a typical training course, activities have been found to correspond to an average of 32 percent of maximum oxygen uptake (O2max) around the clock or about 8,500 kcal/24 h. This estimate is derived from continuous heart rate recordings, data on maximum heart rate and O2max, and workload calculations and assumes a linear relationship between mean heart rate and the workload. However, increased heart rate due to dehydration or psychological stress, for example, may lead to an overestimation of the workload. The energy supplied to each cadet during the actual training course was 0 kcal on days 1 and 2; about 700 and 950 kcal on days 3 and 4, respectively; 0 kcal on day 5; about 1,300 kcal on day 6; and 0 kcal on day 7. In one course, one group was given an extra 1,200 kcal per day per cadet in order to study the influence of reducing the calorie deficiency from about 95 to about 80 percent. No drugs, minerals, or vitamins were allowed. Cadets were allowed no formal sleep time during the training course but got short periods of sleep between activities. On the basis of continuous heart rate recordings of individuals in a similar training course, total sleep time for Norwegian Ranger cadets was estimated to be less than 3 hours. Immune Changes During Norwegian Ranger Training Changes in Parameters of Immune Function Leukocyte Numbers The total number of blood leukocytes in cadets increased during the Norwegian Ranger training course. Maximum numbers were observed in the first blood test administered to cadets, after 12 to 18 hours of activities, and submaximal numbers were observed on the following days (Bøyum et al., 1996). Of the various blood cells, granulocytes increased about two- to threefold, with maximum numbers reached after 1 to 2 days. Monocytes increased more gradually up to twofold, with maximum numbers reached after 4

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--> to 5 days. In contrast, a reduction of 30 to 40 percent was observed in the number of the T-lymphocytes studied such as the natural killer (NK) cells, helper and suppressor cells, as well as B-lymphocytes, and a maximum reduction of these was observed already after 12 to 18 hours of activities. The same pattern was observed for eosinophils in peripheral blood, which were strongly reduced by 80 to 90 percent (Bøyum et al., 1996; Wiik et al., 1996). Plasma Levels of Immunoglobulins Serum concentrations of immunoglobulins in cadets decreased significantly throughout the course. IgG was reduced by 10 to 15 percent, IgA by 10 to 20 percent, and IgM by 20 to 35 percent (Bøyum et al., 1996). Interleukins No change in plasma levels of interleukin (IL)-1, IL-12, and IL-4 was found in cadets, but a 10 to 20 percent decrease of IL-6 (minimum after 5–7 days) and an approximately fourfold increase in granulocyte macrophage-colony stimulating factor (GM-CSF) has been demonstrated with maximum levels measured in cadets after 1 to 2 days (Bøyum et al., 1996). Lymphocyte Mitogenic Response For the lymphocyte mitogenic response, quite variable results were observed in cadets during the Norwegian Ranger training (Bøyum et al., 1996). In one course, a stimulation was observed, while in another course a suppression was observed. Changes in Phagocyte Function Granulocyte Functions An accentuated chemiluminescence2 response of the granulocytes (priming) to serum opsonized zymosan (SOZ)3 was observed during the first few days of the course with a maximum increase in cadets on days 1 to 3 (+12 to +35%) (Wiik et al., 1996). Thereafter, a reduced response to SOZ below control values (-21 to -28%) was found during the final few days of the course. Extra supplementation of cadets with 1,200 kcal/24 h resulted in a more pronounced 2   Chemiluminescence is used to measure the production of reactive oxygen molecules. 3   SOZ is produced by incubating zymosan, a particulate extract from yeast, with human plasma. SOZ is commonly used as a stimulator of phagocyte function in vitro; it stimulates phagocytosis and production of reactive oxygen molecules.

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--> priming (+57% vs. +21% of control response) during the first few days. The chemotactic response to the formylated bacterial tripeptide (fMLP) was also primed during the early days of the course, while a reduction toward control values was observed toward the end of the course (Bøyum et al., 1996). These data indicate that moderate, continuous, predominantly aerobic physical activity of individuals for 1 to 3 days, continuously, primes the production of reactive oxygen species in granulocytes, while longer, continuous military activities may also suppress granulocyte functions. Monocytes For the activated monocyte chemiluminescence production, a different pattern was observed from that of the granulocytes. A reduction was observed after 12 to 18 hours, followed by increasing values during the rest of the course, with the highest levels at the end (Wiik et al., 1989). Although no change in plasma levels of IL-1 and tumor necrosis factor was observed in cadets, increased secretion was observed in vitro after stimulation with endotoxin A (Personal communication, A. Bøyum, Norwegian Defence Research Establishment, Kjeller, Norway, 1996). These data support a long-lasting monocyte activation that is often associated with suppression of other immune functions (Tilz et al., 1993). Effect of Reducing the Calorie Deficiency Extra supplementing cadets with 1,200 kcal/24 h reduced the calorie deficiency from about 95 to 80 percent during the 7-d Norwegian Ranger training course, a rather small effect. A more significant priming was, however, observed in cadets' granulocytes, while a lower chemotactic response was observed. No significant difference was observed in leukocyte numbers (or lymphocyte subgroups), immunoglobulins, or interleukins (Bøyum et al., 1996; Wiik et al., 1996). Neuropeptide Effect During Norwegian Ranger Training Vasoactive Intestinal Peptide The effect on leukocytes of the neuropeptide vasoactive intestinal peptide (VIP), which is released from autonomic nerve terminals in peripheral organs, including spleen, lymph nodes, and Peyer's patches in the gut, has been studied in this laboratory (Ottaway, 1991). VIP inhibits lymphocyte mitogenic response and monocyte production of oxygen radicals by stimulating adenylate cyclase in lymphocytes and monocytes, respectively (Ottaway, 1991; Wiik, 1989; Wiik et al., 1985). Increased plasma concentrations of VIP were observed during the

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--> Ranger training course, which suggests an increased secretion or reduced degradation of the peptide (Øktedalen et al., 1984). It was also observed that the number of VIP receptors on leukocytes was upregulated (Wiik et al., 1988) and that a stronger inhibitory effect of VIP on monocytes occurred during the Norwegian Ranger training course (Wiik et al., 1989). In vitro studies have indicated that cortisol upregulates the VIP receptor (Wiik, 1991), which suggests that some of the inhibitory effects of glucocorticoids on phagocytes may be mediated by upregulation of receptors for inhibitory signal molecules like VIP (Wiik et al., 1988). Furthermore, the effects of β-endorphins, enkephalins, and substance P on lymphocyte mitogenic response have been studied. The usual stimulatory effect of these peptides on the lymphocyte mitogenic response was inhibited during the Ranger training course (Unpublished data, P. Wiik, Norwegian Defence Research Establishment, Kjeller, Norway, 1995). Catecholamines Catecholamines may inhibit leukocyte function (Gibson-Berry et al., 1993), and catecholamine B2 receptors and cyclic AMP response also were studied in leukocytes during the Norwegian Ranger training course. Receptor downregulation (Opstad et al., 1994a) reduced cyclic AMP response (Opstad et al., 1994b), and an impaired effect of catecholamines ex vivo were found (Unpublished data, P. Wiik, Norwegian Defence Research Establishment, Kjeller, Norway, 1995). Adrenoglucocorticoid Regulation of Phagocyte Function in Animal Studies It has generally been assumed that cortisol inhibits lymphocyte function and that it affects phagocyte function to a lesser extent. However, a strong correlation was observed between cortisol and a granulocyte respiratory burst in cadets during the Norwegian Ranger training course (Wiik et al., 1996). In contrast, further in vitro incubation of rat phagocytes with pharmacological concentrations of glucocorticoids for up to 24 hours induced no significant effect, while incubation for up to 5 days strongly inhibited a monocyte respiratory burst (Hauger and Wiik, 1997). Exposing rats to corticosterone or fasting them for 48 hours reduced phagocyte production of reactive oxygen metabolites measured in peritoneal phagocyte preparations by luminol-amplified chemiluminescence after activation by SOZ (Wiik et al., 1995). Administration of corticosterone in the drinking water led to an increase in plasma corticosterone from 31 (control level) to 46 ng/ml, reducing chemiluminescence (per cell) by 31 percent. Fasting, which did not change plasma corticosterone or plasma ACTH

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--> concentrations, also had an inhibitory effect on chemiluminescence (-25%). Corticosterone administration and fasting when imposed concurrently strongly inhibited the chemiluminescence (-89%), which indicates that plasma corticosterone and fasting reduces chemiluminescence in a synergistic way (Wiik et al., 1995). Similar effects were observed on total leukocyte number; corticosterone administration, fasting, and the combined intervention reduced macrophage numbers -13, -19.7, and -55 percent respectively. Adrenalectomy induced no significant change in peritoneal leukocyte number or composition, while cells from adrenalectomized animals had significantly higher chemiluminescence reactions than cells from sham-operated (control) animals. Administration of corticosterone to adrenalectomized animals reduced chemiluminescence by 30 percent, while sham-operated animals had 49 percent lower chemiluminescence than adrenalectomized rats. The data from adrenalectomized rats also suggest that endogenous levels of corticosterone are inhibitory for chemiluminescence. These results are inconclusive for evaluating the effects of very low doses of corticosterone, since mechanisms other than the elimination of corticosterone could prime the chemiluminescence reaction after surgical adrenalectomy. Further studies with synthetic glucocorticoids given to rats in vivo have confirmed and substantiated a strong negative effect on monocyte-macrophage function in nanomolar concentrations (Røshol et al., 1995). Studies of experimental inflammation in rats indicate that glucocorticoids in vivo strongly inhibit the chemotaxis of monocytes to the peritoneum but not the chemotaxis of granulocytes (Unpublished results, T. Haugedal, Norwegian Defence Research Establishment, Kjeller, Norway, 1995). However, the chemiluminescence responses of granulocytes as well as monocytes ex vivo were strongly inhibited by glucocorticoid administration. Author's Summary and Recommendations During and after the Ranger training course of the Norwegian Military Academy, cadets had no significant increase in infectious disease (Bøyum et al., 1996). However, during a U.S. Army Ranger training course lasting for 62 days, a high rate of infections was observed in trainees including upper-respiratory infections, cellulitis, and even an epidemic of pneumococcal pneumonia (Bernton et al., 1994; Kramer, 1994). These results are supported by studies of infections in athletes during intense training (Fitzgerald, 1988; Hoffman-Goetz and Pedersen, 1994; Sharp and Koutedakis, 1992). During the 7-d Norwegian Ranger training, cadets had increased numbers of granulocytes and monocytes in peripheral blood and a strong reduction of eosinophils and B- and T-lymphocytes, including helper, suppressor, and NK cells. A reduction in serum concentrations of immunoglobulins was also reported. However, no conclusion can be drawn from these data regarding lymphocyte mitogenic response since variable results were found. For

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--> granulocytes, a biphasic response pattern was observed, characterized by primed chemotactic and chemiluminescence responses at the beginning of the course and a normalization (chemotactic response) or a reduction to below control values (chemiluminescence) at the end of the 7-d course. Monocytes, however, remained activated during the entire course, with the highest chemiluminescence response toward the end. Other studies have reported that sustained monocyte activation is associated with suppression of other immune functions (Tilz et al., 1993). Observed immune changes in Norwegian and U.S. Ranger training courses are largely in agreement. However, in contrast to the variable changes observed in lymphocyte mitogenic response during the Norwegian Ranger training, a significant reduction in lymphocyte mitogenic response was reported during the U.S. Army Ranger training (Kramer, 1994). This discrepancy may be due to the more acute stress observed in the Norwegian Ranger training. Moreover, methodological differences may have influenced the results; studies during Norwegian Ranger training were done in cell-adjusted preparations of mononuclear leukocytes, while whole-blood preparations were used in the U.S. Army studies (Kramer, 1994). Data from the U.S. Army and Norwegian Ranger training courses comprise a complex picture of immune changes. Nonspecific granulocyte functions seem to be stimulated at the beginning of the course, followed by a period of suppression wherein the number of lymphocytes and several specific immune functions seem to be suppressed. Because these various immune parameters affect host defense against various infections differently, theoretically, these observed changes may affect the pathogenicity of different types of microorganisms differently. The priming of the phagocytic response at the beginning of Ranger training could indicate an increased resistance in soldiers' important ''first line'' of defense against invading microorganisms, and this may be one reason why no significant increase in infections during or after the 7-d Norwegian course was observed. However, it is also theoretically possible that this priming may contribute to inflammation associated with exercise-induced muscle fiber injury, ischemia-reperfusion injury of joints during exercise, and tendinitis (Armstrong et al., 1991). Reduced caloric intake for several weeks seems to be of importance for impaired immunity, and with only a small increase in caloric intake during the U.S. Army Ranger training, infections were reduced and immune function improved (Shippee et al., 1994). However, during the Norwegian training, acute energy deprivation (by up to 95 percent of energy expenditure) during 7 days seems to have only moderately affected immunity, and by supplementing 1,200 kcal/24 h to reduce the caloric deficiency to 80 percent, only minor effects in cadets were observed. Furthermore, in a battlefield environment where the level of psychological stress is also high, such stress is known to cause immune suppression (Khansari et al., 1990; Kiecolt-Glaser and Glaser, 1991). It is difficult to determine the significance of each of these factors when combined,

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--> but the results from animal studies in this laboratory suggest that simultaneous fasting and high levels of glucocorticoids may synergistically inhibit immunity (Wiik et al., 1995). No single test appears to predict immune competence, and since the immune changes observed in the Ranger studies are not indicative of a consistent change in immune function, the pathogenicity of different types of infectious agents may be differently affected by the changes in immune function. Leukocyte counts, which can be readily performed in the field, may give a simple although rough indication of the impact of the experienced stresses on immune status. In the laboratory, nonspecific phagocyte functions as well as lymphocyte subgrouping and different types of lymphocyte functions need to be studied. To evaluate immune competence, more complex immune functional studies, like skin reactions to antigens and vaccine responses, should be performed. Understanding infectious disease and immune competence are of utmost importance for promoting peak military performance on the battlefield. Results from the Norwegian and U.S. Army Ranger training studies indicate that an association exists among the duration and intensity of physical activity, lack of nutrition, and immune competence. Even extreme military activities for up to 1 week with almost no sleep or food seem to be of little consequence to well-trained military personnel, while problems with immune competence seem to be of significance with deprivation of longer duration. It appears that a research program addressing the complex changes in immune system function during military challenges, including frequency of infections, and a systematic study of the influence of altering nutrient intakes and requirements of vitamins and minerals would be of utmost importance to military medicine. References Armstrong, R.B., G.L. Warren, and J.A. Warren. 1991. Mechanisms of exercise-induced muscle fibre injury. Sports Med. 12:184-207. Bernton, E., R. Galloway, and D. Hoover. 1994. Immune function II: Monocyte and granulocyte function. Chapter 10 in Nutritional and Immunological Assessment of Ranger Students with Increased Caloric Intake. Technical Report T95-5. Natick, Mass.: U.S. Army Research Institute of Environmental Medicine. Bøyum, A., P. Wiik, E. Gustavsson, O.P. Veiby, J. Reseland, A.H. Haugen, and P.K. Opstad. 1996. The effect of strenuous exercise, calorie deficiency and sleep deprivation on white cells, plasma immunoglobulins and cytokines. Scand. J. Immunol. 43:228-235. Fitzgerald, L. 1988. Exercise and the immune system. Immunol. Today 9:337-339. Gibson-Berry, K.L., J.C. Whitin, and H.J. Cohen. 1993. Modulation of the respiratory burst in human neutrophils by isoproterenol and dibutyryl cyclic AMP. J. Neuroimmunol. 43:59-68. Hauger, S.E., and P. Wiik. 1997. Glucocorticoid and ACTH regulation of rat peritoneal phagocyte chemiluminescence and nitric oxide production in culture. Acta Physiol. Scand. 161:93-101.

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--> Hoffman-Goetz, L., and B.K. Pedersen. 1994. Exercise and the immune system: A model of the stress response? Immunol. Today 8:382-387. Khansari, D.N., A.J. Murgo, and R.E. Faith. 1990. Effects of stress on the immune system. Immunol. Today 11:170-175. Kiecolt-Glaser, J.K., and R. Glaser. 1991. Stress and immune function in humans . Pp. 849-864 in Psychoneuroimmunology, R. Ader, D.L. Felten, and N. Cohen, eds. Boston: Academic Press. Kramer, T.R. 1994. Immune function I: Lymphocyte proliferation and subset analysis; Interleukin production. Chapter 9 in Nutritional and Immunological Assessment of Ranger Students with Increased Caloric Intake. Technical Report T95-5. Natick, Mass.: U.S. Army Research Institute of Environmental Medicine. Øktedalen, O., P.K. Opstad, J. Fahrenkrug, and F. Fonnum. 1984. Plasma concentration of vasocative intestinal peptide during prolonged physical exercise, calorie supply deficiency and sleep deprivation. Scand. J. Gastroenterol. 19:59-64. Opstad, P.K., M. Bårtveit, P. Wiik, and A. Bøyum. 1994a. The dynamic response of β2- and α2-adrenoceptors in human blood cells to prolonged exhausting exercise, sleep and energy deficiency. Biogenic Amines 10:329-344. Opstad, P.K., P. Wiik, A.H. Haugen, and K.K. Skrede. 1994b. Adrenaline stimulated cyclic adenosine monophosphate response in leucocytes is reduced after prolonged physical activity combined with sleep and energy deprivation. Eur. J. Appl. Physiol. 69:371-375. Ottaway, C.A. 1991. Vasoactive intestinal peptide and immune function. Pp. 225-262 in Psychoneuroimmunology, R. Ader, D.L. Felten, and N. Cohen, eds. Boston: Academic Press. Røshol, H., K.K. Skrede, C.E. Ærø, and P. Wiik. 1995. Dexamethasone and methylprednisolone effect on peritoneal phagocyte chemiluminescence after administration in vivo. Eur. J. Pharmacol. 286:9-17. Sharp, N.C., and Y. Koutedakis. 1992. Sport and the overtraining syndrome: Immunological aspects. Br. Med. Bull. 48:518-533. Shippee, R., K. Friedl, T. Kramer, M. Mays, K. Popp, E.W. Askew, B. Fairbrother, R. Hoyt, J. Vogel, L. Marchitelli, P. Frykman, L. Martinez-Lopez, E. Bernton, M. Kramer, R. Tulley, J. Rood, J. DeLany, D. Jezior, and J. Arsenault. 1994. Nutritional and immunological assessment of Ranger students with increased caloric intake. Report No. T95-5. Natick, Mass.: U.S. Army Research Institute of Environmental Medicine . Tilz, G.P., W. Domej, A. Diez-Ruiz, G. Weiss, R. Brezinschek, H. P. Brezinschek, E. Hüttl, H. Pristautz, H. Wachter, and D. Fuchs. 1993. Increased immune activation during and after physical exercise. Immunobiology 188:194-202. Wiik, P. 1989. Vasoactive intestinal peptide (VIP) inhibits the respiratory burst in monocytes by a cyclic AMP mediated mechanism. Regul. Pept. 25:187-97. Wiik, P. 1991. Glucocorticoids upregulate the high affinity receptor for VIP on human mononuclear leucocytes in vitro. Regul. Pept. 35:19-30. Wiik, P., P.K. Opstad, and A. Bøyum. 1985. Binding of vasoactive intestinal polypeptide (VIP) by human blood monocytes: Demonstration of specific binding sites. Regul. Pept. 12:145-163. Wiik, P., P.K. Opstad, and A. Bøyum. 1996. Granulocyte chemiluminescence response to serum opsonized particles ex vivo during long-term strenuous exercise, energy, and sleep deprivation in humans. Eur. J. Appl. Physiol. 73:251-258. Wiik, P., A.H. Haugen, D. Lovhaug, A. Bøyum, and P.K. Opstad. 1989. Effect of VIP on the respiratory burst in human monocytes ex vivo during prolonged strain and energy deficiency. Peptides 10:819-823.

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--> Wiik, P., P.K. Opstad, S. Knardahl, and A. Bøyum. 1988. Receptors for vasoactive intestinal peptide (VIP) on human mononuclear luecocytes are upregulated during prolonged strain and energy deficiency. Peptides 9(1):181-186. Wiik, P., K.K. Skrede, S. Knardahl, A.H. Haugen, C.E. Ærø, P.K. Opstad, and A. Bøyum. 1995. Effect of in vivo corticosterone and acute food deprivation on rat resident peritoneal cell chemiluminescence after activation ex vivo. Acta. Physiol. Scand. 154:407-416. Discussion DONNA RYAN: You did not say much about how these Rangers did clinically. PÅL WIIK: No, I did not. I just mentioned the infections. DONNA RYAN: Is it a secret? PÅL WIIK: No, it is not a secret. Of course, when they have not slept for 7 days, they hallucinate. They do not know where they are and what they are doing. They have problems with their balance, they have ataxia, and they have problems focusing. They are really in a bad state at the end of the course. DONNA RYAN: Were there any problems with infection? PÅL WIIK: No. As I mentioned, there was a small increase in the frequency of upper-respiratory infections during the weeks of the course, but it was not significant. RONALD SHIPPEE: One of the reasons we are asked to study Ranger training was that the commander was very concerned about any lasting effects. They want to stress the soldiers, but not hurt them permanently. One aspect of the study was follow-up. The soldiers cannot control their body weight or their fat afterward. Soldiers continue to come up to me after they participate in the studies and complain that they cannot control their body weight. I was wondering whether you see any lasting effects with just this short 7-d stress? PÅL WIIK: No, I do not think we have found that really. During the month after the training, some of them have hallucinatory flashbacks. They may have them while they are driving their cars so that they have to pull over and wait for

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--> the hallucinations to end. It is like an LSD flashback. But there is not, as far as I know, any documented permanent damage to the participants. RONALD SHIPPEE: With the work I have done, one of the long-term effects that is observed is that because the Ranger trainees are allowed to use tobacco products to help them stay awake, most of the U.S. Rangers keep that habit. It is a big problem; in fact, the Regimental Command has asked us to take a look at it. Do you allow your folks to use tobacco products? PÅL WIIK: In principle, they should not use tobacco, but some of them do. I must admit that we have a big problem with performing studies of the recovery period. We would love to explore that much more thoroughly than we have had a chance to do. When the soldiers are free, they go home to their families. They do not want to have any restrictions of their lives and their diets, including alcohol. It is very difficult for us to be able to look at this recovery phase both in the short and the long term because trainees are not motivated for it. As I told you, they are volunteers for the scientific part. During the course, it is easy to because they have half an hour of rest before a blood test. After the course, their motivation is gone. GAIL BUTTERFIELD: I have asked this question of the Americans, and I will ask it of you. What is the justification for Ranger training in terms of real military experience? Are there real circumstances into which the troops are placed that warrant this type of training? PÅL WIIK: I think that the important thing is that you hope that trainees can learn something from it. When the trainees have been put through this, you want them to remember what happens when they go too far, and you hope that as leaders, they won't take their men that far. You hope that they will permit the men food and sleep, plan their missions well, and not be "Rambos." Sometimes, if you do not remind the trainees how badly they did, their endorphins make them forget it, everything is rosy, they feel that they performed very well, and they feel that everybody should perform as well as they did themselves. So, in a way, they become supermen if you do not show them videos, talk to them afterwards, and have their comrades tell them how badly they behaved. I think that is a very important thing. Because, if you do not do that, there is absolutely no advantage going through a course like this. GAIL BUTTERFIELD: Do the Ranger training commanders in the United States do that?

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--> KARL FRIEDL: The debriefing? GAIL BUTTERFIELD: Making the video? KARL FRIEDL: Not to the extent the Norwegians do. I do not think we have ever tried doing anything like that. It sounds very interesting. They do this intense briefing in which the commanders show the trainees the videos. GAIL BUTTERFIELD: It sounds like a good idea. SCOTT MONTAIN: How many people participate in the course at any one time? Can you fail? If you can fail or get tossed out of the course, how many are failing because they cannot follow the rules of the game, in the sense of performing without sleep? PÅL WIIK: About 60 every year in the military participate in this training course lasting 7 days. We take 10 or 15 or 20 for our studies. They are very well trained and selected before the course. It is in the second year of their education, so fewer than 10 percent fail. SCOTT MONTAIN: So, if you are one of these people who is hallucinating quite badly, does your buddy just drag you along even though you are totally incoherent so you can pass? Do they slow down to the pace of the weakest man? What do they do? PÅL WIIK: Well, if you have made the hallucinating person the leader, then you remove him from the leadership position. [Laughter.] If you are the leader, then you have a responsibility that is stimulatory to performance. As to your question, the trainees get some individual treatment in order to pass the course and still explore their individual limits. SCOTT MONTAIN: With the sleep deprivation, if you give them montonous tasks to do, they cannot do them, but if you give them tasks that are mentally stimulating, they can. So, if you put them into a leadership role, that is stimulating them. PÅL WIIK: But if you see that an individual has a really bad tolerance for sleep deprivation, he will be told this, but he does not fail. You have to decide what

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--> these men will do after the military academy. A soldier with poor tolerance for sleep deprivation will not be able to choose positions where you have to have a decent tolerance for sleep deprivation. This is one of the experiences, or advantages, to derive from the course. You can tell people what they are suited for. TIM KRAMER: I think, if I recall right from looking at your lymphocyte counts, that you had a U-shaped curve. You had your normal level at the beginning. It decreased. And then, if I am not mistaken, it began going back to baseline at day 7 or so. PÅL WIIK: Yes, the lymphocyte number was found to be almost normalized on the last day. And in most of our functional studies, we find that on the last day or two there is a pattern of normalization. I always wonder why. After the soldiers have been able to keep up their high intensity training for all this time, they know that this is the last day, and perhaps this will give them a little relief. I had that same thought when you showed your data. I think that this relief can be a reason for this normalization pattern during the last days of training. TIM KRAMER: That was the reason I brought that up. It is basically taking, I think, what you see in the Ranger I and Ranger II studies where you see a similar pattern but over a much longer period . . . PÅL WIIK: . . . but it is always in the end. TIM KRAMER: Yes, that is right. That is why I am wondering if really you are getting into a psychological effect, resulting in this slight increase. I guess the other question I have is, if I was reading your numbers right on the number of lymphocytes you had per what I reduced it to, which was microliters, you made the comment that the whole-blood assay system would not work on that. Is that because you do have a decrease? Or do you have an insufficient number of cells to observe any kind of a response? PÅL WIIK: I think that with this kind of lymphopenia there is an obvious need for correction of the number of cells. TIM KRAMER: You could do that, but I guess that does not mean you cannot do the assay, but you may want to express the results both ways. Your activity per volume, which would be circulating through your body, but also your

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--> activity per cell. Because, from the numbers that I was seeing there, you should get a very, very good level of activity, unless a functional capacity was impaired. PÅL WIIK: I do not completely agree with you. Doing it both the traditional way and your way would be the best. But, if you do these whole-blood cultures, I would see it as an advantage also to have the ability to correct for lymphocyte numbers. Of course, you get very interesting information from the blood cultures that reflects the hormones, the interleukins, and the functional capacity of the cells in the blood, which we do not do with our method. We get the functional capacity of the cells in a culture medium with fetal bovine serum (in the culture). TIM KRAMER: So you are really talking about a natural milieu versus an unnatural milieu? PÅL WIIK: That is right. It is a natural milieu versus a standardized milieu. JEFF KENNEDY: It brings me back to Gerald Keusch's comment earlier in the day. Your lymphocyte counts went down 80 percent. So 80 percent of your circulating lymphocytes disappeared from the blood. That means you are left with 20 percent of the original lymphocyte level. Now the question I have is, do those lymphocytes that are remaining show a decreased proliferative response; is that indicative of the lymphocyte pool in your body? Are you measuring the 20 percent that are remaining that nobody cares about or is not going to be needed or has not been honed? Or is nonproliferative, which is somehow selected against being very proliferative? PÅL WIIK: That is a very important question when you are trying to evaluate the immune competence. When we work on peripheral blood cells, and you do not know anything about the rest of the body, and the blood is actually only a transport route for these cells. It is easily accessible so everybody uses it, but of course, we should have all of the other compartments also. Of course, it would be very interesting, for instance, to do some prominent labeling of cells, injecting them and see—trying to estimate how the total pool of these cells are behaving. I have the same feeling as you that for lymphocytes there is a significant reduction. But I do not think the reduction is as big as you estimated, since the sum of CD3, CD4, CD19, and CD16 cells was approximately 120 percent in the beginning and 77 percent towards the end of the course. Because some cells in the beginning appear to have more than one of these determinants and lose these at the end of the course.

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--> DAVID NIEMAN: I have just a quick question on the timing of your samples relative to the last exertion of the trainees. Many of the changes that you were showing on day one are very similar to what we see during the one and a half to 3-h time period immediately following heavy exertion. When did you take those samples? PÅL WIIK: Blood samples are taken at 8:00 in the morning every day. DAVID NIEMAN: On day one after they have been exercising at 5:00 a.m. or 6:00 a.m.? PÅL WIIK: They started in the afternoon the day before. So this first blood sample during the course is taken 12 hours after they started. In that time period, they have been exercising continuously at low impact, approximately 30 percent of maximum work capacity. DAVID NIEMAN: So when they came at 8:00, what had they been doing for the couple of hours before? PÅL WIIK: They had been running. DAVID NIEMAN: What this looks like to me is an acute immune response to heavy exertion. PÅL WIIK: It looks much like that. But it keeps up for most of the week. DAVID NIEMAN: That is because they are exercising all of the time. PÅL WIIK: At low impact, but for a long time. ARTHUR ANDERSON: I have a question related to the answer to your first question. Would you say that vasoactive peptide intestinal receptors and liposomes were elevated during this stressful time? PÅL WIIK: Yes, vasoactive intestinal peptide receptors are elevated.

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--> ARTHUR ANDERSON: One of the vasoactive intestinal peptides does attract lymphocytes into the lymphatic tissue. It is not that common or customary attracting of lymphocytes during normal recirculation. The total circulating lymphocyte pool turns over 10 to 48 times in a 24-h period of time. An advanced mass of lymphatic pools is in lymphatic tissue. If you upregulated one of the signals for entering into lymphatic tissue because of this effect of stress, then you would change the rate of entry into lymphatic tissue without perhaps changing the rate of exit from the lymphatic tissue. So this is just a kinetic problem of turnover and not necessarily destruction or marginalization or, in any way, injury to the human body. PÅL WIIK: I agree with you. But we do not know exactly what is going on. DAVID NIEMAN: They are still there. PARTICIPANT: How would you look at that? PÅL WIIK: Actually, this is a very difficult problem to address, since no good antagonist exists to VIP. However, I personally think that catecholamines and cortisol are much more important. JOHN FERNSTROM: Am I to suppose that these guys would have an increased susceptibility to disease because of these changes? If so, given all you have done with the guys, why not expose them to a standard cold, if you will, and get the question answered as to whether there is some increased susceptibility to infection, whether it is an upper-respiratory tract infection or some other thing. Because, to me, everybody is talking about this measurement and that measurement, but they are not really trying to make any connection that I can see to the physiology. The changes are dramatic, but I do not see the connection to reality. Maybe a functional-type test would be that additional step. PÅL WIIK: It sounds logical that perhaps we should expose them to something like that. We have tried to evaluate the frequency of infections during the course. But doing a functional type test would, of course, be an ethical problem. STEVE GAFFIN: Related to the reduction in IgM and IgA, do you see this as a general turning off of the production of antibodies, and that this is the expected disappearance of IgG, given its half-life? If so, I notice the IgM was still very high, at 60 percent of so. Yet IgM half-life is only a couple of days. So it looks

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--> like the body, on the face of it, appears still to be making IgM but maybe has turned off IgA production. Is that what you see? Do you have a different explanation? PÅL WIIK: I really do not know. But Dr. Nieman told us today that IgA depletes very rapidly. STEVE GAFFIN: From the nasal lavage. PÅL WIIK: Yes. You observe a decrease very rapidly for IgM and more rapidly than the half-life. STEVE GAFFIN: No, it is less rapidly. The half-life, as I recall, is a couple of days. Yet, after a week, you still have very high levels, 60 percent. PÅL WIIK: But after 12 hours, a reduction of 20 or 30 percent was observed in IgM. If you shut off all of the new production, the primary response to antigens should be at a very low level. DAVID NIEMAN: This has been found in the blood compartment after ultramarathons and marathons as well, almost the same percentage as you found. RANJIT CHANDRA: I think that this is probably a reflection of leakage, for example, a huge stress like that and total energy deprivation within 24 hours could cause a leakage of proteins. I think it is a reflection of the size of the immunoglobulins. Those which are relatively smaller would show more leakage. PÅL WIIK: But it is the opposite. RANJIT CHANDRA: The IgM is higher. PÅL WIIK: The IgM was reduced in our data more rapidly than IgG. LEONARD KAPCALA: I just had a comment on your animal studies where your conclusions with the results of the adrenalectomy were kind of confusing. I

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--> would just comment on a couple of variables that may be contributing to that confusing picture, and that is that some cytokine systems may be differentially upregulated, playing a role that you do not know, and also adrenalectomized animals would have very high ACTH levels. ACTH is an immune modulator independent of glucocorticoids. β-endorphin would be high, and that is also an immune modulator. So you have several little variables that you do not know about, and those could then be partially responsible for some of the confusion of the results you are seeing with the adrenalectomy. BRUCE BISTRIAN: There is a wide range of physiological function between what our daily lives are and what extreme stresses are. Are we really looking at normal variabilities? Unless there is some serious consequence, unless there is some serious [change in] infection rate, or some serious change in the quality of life, or unless there is some serious problem with this, is there any problem? Are we just investigating what is a normal variant when you put a human organism to another range? PÅL WIIK: It is certain that what we are observing is a physiological response to exercise with no sleep and almost no food for 7 days. And we really have no problem during this period of time. However, if you are trying to make them go through this for a long period of time, you would have problems with immunity and consequently infections are demonstrated for the U.S. Ranger studies.