There is a general perception among top athletes, coaches, and sport physicians that athletes are at increased risk of upper respiratory tract infection (URTI; e.g., common cold, sore throat) during periods of intense exercise training and after major competition (reviewed by 30,55). At the same time, “recreational” or noncompetitive athletes believe that, compared with the average sedentary population, their physically active lifestyle affords protection against URTI. Over the past decade, this perceived dual effect of exercise has been supported by empirical study of the incidence of URTI symptoms among competitive and recreational athletes (23,43,52–54). A “J curve” hypothesis has been proposed suggesting that, whereas intense exercise increases risk, moderate exercise may decrease risk of URTI (41).
The apparently high incidence of URTI among athletes has prompted an interest in whether chronic exercise training suppresses immune function. As will be discussed in this paper, recent evidence suggests that chronic mild suppression of some immune parameters occurs during periods of intense training or overtraining in athletes (11,12,16,18,21,22,33,34,56,63). Whereas athletes may exhibit evidence of mild immune suppression, however, it must be noted that they would not be considered clinically immune deficient. That is, athletes do not develop illnesses commonly associated with immune deficiency; moreover, URTI is a relatively mild illness and appears to be the only illness to which athletes are more susceptible.
EXPERIMENTAL APPROACHES TO STUDY CHRONIC TRAINING EFFECTS ON IMMUNE FUNCTION
Both cross-sectional and longitudinal (intervention) approaches have been used to study the immune response to chronic exercise training. In cross-sectional studies, immune variables (e.g., rates of illness, immune cell number or function) are compared between athletes and matched nonathletes or clinical reference values. The implication is that any differences between groups result from exercise training. The weakness of this approach is that there is great individual variability in any immune parameter that may not be revealed by a single measurement at only one particular point in time. In the second approach, immune parameters may be measured in athletes repeatedly over a designated time such as a training season, and values compared between different phases of the training cycle (e.g., moderate vs intense training, training vs competition periods). This model provides useful information about the effects of exercise training volume and/or intensity on immune function in the athlete’s “natural” environment. On the other hand, it is often difficult to control for possible confounding variables such as competition, travel, diet, and psychological stress, each of which may independently influence immune function. In another type of exercise intervention model, previously sedentary individuals undergo a training program, usually of moderate intensity because of their initial untrained state. Immune function is compared from before to after the training program. In the two latter models, nonexercising control groups should be included to account for possible seasonal variability. Although no single approach is best, combining data from these models provides complementary information to help understand chronic adaptations of the immune system to exercise training.
INCIDENCE OF URTI IN EXERCISE-TRAINED GROUPS
As discussed in detail in David Nieman’s paper in this Supplement, in endurance athletes such as distance runners the incidence of URTI appears to be highest after major competition or during periods of intense training. Between 50 and 70% of athletes report symptoms of URTI during the 2 wk after a major event such as a marathon or ultramarathon (43,52–54). In addition, the incidence of URTI after a race has been correlated with race time and prerace training distance (43,52). After a major event such as a marathon, URTI risk is elevated between 2 and 6 times in runners compared with matched nonparticipants (43,52). In contrast, shorter duration or less competitive events such as half-marathons or “fun runs” are not associated with an elevated risk of URTI (42).
Athletes also experience a high incidence of URTI during intense training, even for relatively short periods. For example, the incidence of URTI was more than 40% in the following groups of athletes: competitive swimmers followed over 4 wk intense training (34), elite hockey players assessed during a 10-d training camp (32), and elite squash athletes followed over 10-wk training (32). Over the longer term, risk of URTI appears to be related to training volume in distance runners (23,42,43). For example, Heath et al. (23) reported a dose-response relationship between yearly training distance and risk of URTI in >500 distance runners. Compared with athletes running < 778 km·yr−1, the odds ratio of URTI was 2 times higher in those running 778-1384 km and 3.5 times higher for those running > 1384 km·yr−1. The frequency rather than severity of URTI appears to increase in endurance athletes compared with nonathletes (28).
In contrast to the increased risk of URTI associated with intense prolonged exercise training, URTI risk does not appear to be elevated, and may even be reduced, by moderate training. For example, in a randomized trial of 15-wk moderate exercise (brisk walking) in 36 mildly obese women, the number of symptom days with URTI was 50% lower in women who walked compared with sedentary controls (44). Moreover, the number of symptom days was significantly correlated with the increase in cardiorespiratory fitness in exercising subjects. Taken together, the data from these studies are consistent with the hypothesized “dual effect” of exercise, that moderate exercise enhances or has little effect on, whereas intense exercise suppresses, immune function (30,41).
RESPONSES OF IMMUNE PARAMETERS TO CHRONIC EXERCISE TRAINING
The immune system response to any challenge is complex, involving coordinated activity by many different types of cells and messenger molecules. A physical stressor such as exercise may thus act at any number of points along a complex sequence of events (called the “immune response”). As will be discussed below, immune parameters do not all respond similarly to the same exercise stimulus. Moreover, the magnitude and direction of change of any immune parameter may depend on exercise dose (i.e., duration, intensity) and the subject’s fitness level. Table 1 summarizes the major effects of moderate and intense exercise training on various aspects of immune function.
Effects of Chronic Exercise on Immune Cell Number and Function
Leukocytes (white blood cells) are a heterogeneous group of immune cells that circulate continuously between various lymphoid tissues and organs, and the blood and lymph. The major leukocyte subsets are polymorphonuclear granulocytes (mainly neutrophils) comprising about 60–70% of circulating leukocytes; lymphocytes [including T, B, and natural killer (NK) cells] comprising about 20–25% of circulating leukocytes; and monocytes comprising about 15% of circulating leukocytes. Each cell exerts particular functions in the complex sequence of the immune response; the effects of exercise on each cell subset number and function are discussed in the following sections.
Effects of Chronic Exercise on Immune Cell Number
Whereas acute exercise causes profound changes in the number and relative distribution of leukocyte subsets in the circulation (discussed in the previous paper in this symposium), these changes are generally transitory and resting levels are usually restored within 24 h after exercise. Provided the subject is truly rested (i.e., blood is sampled > 24 h after the last exercise session), leukocyte number is clinically normal and usually remains unchanged during exercise training (16,24,46,48). There are a few possible exceptions, however. For example, in a study on overtraining, leukocyte count declined progressively toward the low end of the clinically normal range (4 × 109·L−1) in distance runners who underwent 4 wk intensified running training (27). NK cell number has also been shown to decline during periods of intense training including 10-d interval running in military personnel (12), 7 months’ swim training in elite swimmers (16), and 4-wk intensified training in competitive swimmers (14). These changes in NK cell number occurred despite no changes in other cell counts (14,16). Thus, although the majority of published studies report normal resting values for most cell counts (reviewed by 30), total leukocyte and NK cell numbers may decline during prolonged periods of intense exercise training. Reduced cell number may result from migration of cells out of the circulation, or increased turnover of cells, or some combination of the two. The mechanisms responsible and biological significance, if any, of such changes are unknown at present.
Effects of Chronic Exercise Training on Immune Cell Function
Although circulating cell number may remain relatively constant, there is consistent evidence that chronic intense training alters several aspects of immune cell function, including neutrophil priming (21,56,62,63), NK cell cytotoxicity (14), and lymphocyte activation (2,11,22). On the other hand, moderate exercise training appears to have little or no effect on these immune parameters (6,21,38,40,67).
NK cell cytotoxic activity.
NK cells comprise a distinct, but heterogeneous, subset of lymphocytes capable of recognizing and killing certain tumor and virally-infected cells without prior exposure. Cytotoxicity (cell killing) by NK cells is important in the body’s early response to tumor cell growth and viral infection. At present, the long-term effects of exercise training on NK cytotoxic activity (NKCA) are subject to considerable debate. Several studies show no differences in resting NKCA in athletes compared with nonathletes (1,46,67). On the other hand, other studies suggest that NKCA may be elevated by up to 50% in resting blood sampled from athletes compared with nonathletes (45,47,51). In studies showing differences in NKCA between trained and untrained individuals, these differences remain after adjusting for any differences in NK cell number in the circulation, suggesting that chronic exercise may possibly stimulate each NK cell to kill more targets. In most studies, however, athletes were rested for only 24–36 h before blood sampling, and a possible long-lasting stimulation from the last bout of exercise before blood sampling cannot be completely discounted (30). A recent study showed no differences in the proportion or number of activated NK (CD69+) cells in resting blood sampled from trained cyclists and untrained individuals (15), suggesting that exercise training has little effect on the activation state of NK cells in rested athletes.
Long-term intervention studies suggest that in previously sedentary individuals moderate exercise training may either have no effect or may slightly enhance NKCA. In one intervention study on mildly obese women, NKCA increased significantly by 55% after 6 wk of moderate training (brisk walking at 60% heart rate reserve), but there were no further increases when the program was extended to 15 wk (44). In another study from the same laboratory, a similar walking program for 12 wk had no effect on NKCA in older (65–84 yr) previously sedentary women (45). As mentioned above, several cross-sectional reports suggest that NKCA may be higher in athletes compared with nonathletes. The lack of effect of short-term moderate training on NKCA suggests that more intense exercise over a longer period of time (i.e., years) may be needed to influence NKCA.
Neutrophils comprise the majority of circulating leukocytes and are important to the body’s early response to bacterial and fungal infection. Neutrophils are also the first cell localizing to sites of injury and inflammation where they are involved in degradation and repair of damaged tissue. Resting and postexercise neutrophil function appears to be attenuated in athletes compared with nonathletes, and in athletes during periods of intense compared with moderate training (5,6,21,56,63). For example, reduced neutrophil activation was shown in cells sampled at rest and 6 h after 60 min cycling in cyclists compared with nonathletes (63). In another study, neutrophil phagocytic activity was lower at rest and 24 h after a standard exercise session in distance runners during intense compared with moderate training, and compared with nonathletes (21). In a study on elite swimmers, neutrophil activation declined as training intensity increased during 12 wk preparation for major competition; this occurred despite maintenance of neutrophil number (56). Since neutrophils are involved in the inflammatory process, it has been suggested that, in athletes, this apparent downregulation of neutrophil function may reflect the body’s attempt to limit inflammation caused by intense daily exercise (30,62,65). After intense acute exercise, neutrophils may infiltrate tissues throughout the body (e.g., heart, skeletal muscle, nasal mucosa) (3,8,39), where they may release toxic reactive oxygen and nitrogen molecules. It is possible that downregulation of neutrophil function in athletes may be protective by limiting chronic inflammation during periods of intense training.
Lymphocyte activation and proliferation.
Upon exposure to antigen or other challenge, lymphocytes become activated to enter the cell cycle and proliferate. When activated, lymphocytes express specific cell-surface activation markers that may be quantified with flow cytometry. Although there are few, if any, chronic changes in circulating lymphocyte counts, lymphocyte activation and proliferation may be altered by exercise training. For example, compared with nonathletes, resting lymphocytes obtained from athletes (track and distance runners) show greater expression of activation markers such as the low and high affinity interleukin-2 (IL-2) receptor subunits (CD25 and CD122, respectively) and HLA-DR antigen (2,57). In physically active compared with inactive older women (ages 60–98 yr), a higher percentage of lymphocytes expressed CD25 upon exposure to mitogenic challenge (20). Increased expression of CD25 was also observed after 10-d intense interval running training (12) and after a competitive season in track runners (2).
In contrast, other studies have failed to find increased expression of the activation marker HLA-DR in distance runners compared with nonathletes (46), and in elite swimmers after compared with before 7 months intense training (16). There are no readily apparent reasons for discrepancies between studies, although the specific activation marker(s) used, time of blood sampling, and type or intensity of training may be involved. Taken together, these data suggest that lymphocyte activation may occur in some but not all instances of intense exercise training. The significance, if any, of such changes in lymphocyte activation are not clear at present. Most studies show normal (38,47) or slightly enhanced (1) lymphocyte activation and proliferation during moderate to intense exercise training; proliferation may decline during prolonged periods of very intense training (22). It is possible that the enhanced lymphocyte proliferative capacity observed after moderate, and decreased capacity after intense, exercise training may reflect corresponding changes in lymphocyte activation.
EFFECTS OF CHRONIC EXERCISE ON SOLUBLE FACTORS
An effective immune response requires many soluble factors that act as messenger molecules, growth factors, and effectors of various immune cell functions. Soluble factors include diverse substances such as cytokines (growth factors produced by leukocytes and other cells), antibody and immunoglobulin (produced by mature B lymphocytes), and glutamine (required as a substrate for energy production and cell division in lymphocytes).
Immunoglobulin (Ig) and Antibody
Ig is a generic term to describe a class of glycoproteins produced by B cells that appear in serum and bodily secretions such as tears and saliva. Antibody refers to an Ig that reacts with a specific antigen (foreign protein). Antibody serves many functions, most importantly to bind to the surface antigens of pathogens and thus stimulate activation and differentiation of other immune cells. There are five classes of Ig (related to their basic structure). The major Ig class found in serum is IgG, and IgA is most prevalent in mucosal secretions (e.g., tears, saliva, respiratory fluids), where it is an important effector of early defense against viruses.
Moderate exercise training exerts little, if any, effect on serum and mucosal Ig and antibody levels (reviewed by 29,30). In contrast, both serum and mucosal Ig levels may be reduced during periods of intense exercise training in athletes. For example, compared with matched nonathletes, significantly lower concentrations of serum IgA, IgG, and IgM were reported in swimmers followed throughout a 7-month season; values in swimmers were in the lowest 10th percentile relative to clinical norms (16). Although serum Ig levels were clinically low, however, these athletes were able to mount a clinically appropriate specific antibody response when immunized with a novel antigen (17). It is unclear whether there is any biological significance to these clinically low serum Ig concentrations in athletes.
Because of the relatively high incidence of URTI symptoms among endurance athletes and the importance of mucosal IgA to resistance to viral infection, several research groups have focused on the IgA response to exercise. Salivary IgA concentration has been shown to decline acutely after intense exercise (reviewed by 29,30). Resting salivary IgA concentration is either normal (16,31) or low (66) in competitive athletes compared with nonathletes. Although still within the clinically normal range, salivary IgA levels were significantly lower in overtrained compared with well-trained swimmers followed over a 6-month season (33). Salivary IgA concentration does not change during moderate exercise training (37). In contrast, IgA concentrations measured at rest and after exercise declined progressively as training intensity increased over a 7-month season in elite swimmers (16) and over a 4-month season in collegiate swimmers (64). Two studies suggest a relationship between declining salivary IgA concentration and the appearance of URTI in elite athletes (18,32). In one study of elite squash and field hockey athletes, declines in salivary IgA during acute intense exercise predicted the appearance of URTI within the following 2 d (32). In the other study, low resting and postexercise IgA levels were predictive of development of URTI over a season in elite swimmers (18). To date, salivary IgA concentration is the only immune parameter to be correlated with the appearance of URTI in athletes. Interestingly, IgA output and the number of IgA producing cells are normal or slightly elevated in duodenum biopsies from marathon runners compared with nonathletes (49), suggesting that the effects of intense exercise training may be specific to the respiratory tract.
Glutamine is the most abundant amino acid in the body; skeletal muscle is the major source of glutamine appearing in the blood. Proliferating lymphocytes require glutamine for metabolism and nucleotide synthesis. Plasma glutamine concentration declines acutely for up to 4 h after intense exercise, and resting levels may be low in overtrained athletes (reviewed by 60,69). It has been proposed that low plasma glutamine concentration may compromise immune function in athletes.
Plasma glutamine concentration declined progressively after 10-d intense interval training in well-trained military personnel (25) and 8-wk intense interval training (22). Significantly lower resting plasma glutamine concentration has been reported in overtrained compared with nonovertrained athletes from various sports (50) and in overtrained compared with well-trained swimmers (34). In athletes showing symptoms of chronic fatigue, plasma and skeletal muscle glutamine concentrations were the only biochemical and immunological variables that distinguished athletes with symptoms from those without (59,61). These data suggest that prolonged periods of intense training may lower plasma glutamine levels, possibly by altering skeletal muscle output into the circulation and/or lymphocyte uptake and oxidation. Whether such alterations in plasma glutamine concentration directly influence immune function in athletes is unclear at present. Greig et al. (19) reported a significant inverse relationship between plasma glutamine concentration and the appearance of viral illness in nonathletes. A recent report suggested that glutamine supplementation reduced the incidence of URTI symptoms after endurance competition in distance runners (7). On the other hand, during a 4-wk period of intensified training there was no difference in plasma glutamine concentration between swimmers who developed URTI and those who remained healthy (34). Moreover, glutamine supplementation after a marathon run had no effect on exercise-induced changes in immune parameters such as NK cytotoxic activity and lymphocyte proliferation (58). The topic of glutamine supplementation and immunity is addressed in detail in Catherine Field’s paper in this supplement.
OVERTRAINING AND IMMUNE FUNCTION
Overtraining is a process of excessive training with inadequate recovery that may lead to the overtraining syndrome, a stress response characterized by poor performance, persistent fatigue, decreased catecholamine production, and alterations in mood state (reviewed by 26). Although there are few empirical studies on overtraining and immune function (10,13,24,33–35,59), overtraining is associated with frequent URTI (9). The data supporting this concept, however, are few and equivocal. For example, a study following 24 competitive swimmers over 4-wk intensified training found a lower incidence of URTI in athletes diagnosed as overtrained compared with those considered not overtrained (12.5% vs 56%, respectively) (34). On the other hand, a recent study of 25 athletes found that athletes were susceptible to minor illness such as URTI when they exceeded “individually identifiable training thresholds” (10). These data suggest that the overtraining syndrome itself may not necessarily cause or contribute to frequent illness, rather that high training load (volume and intensity) may be the major determinant of susceptibility.
The few studies attempting to compare immune function in overtrained and nonovertrained athletes have generally found little or no effect of overtraining on circulating immune cell counts, lymphocyte proliferation and lymphocyte activation (13,35,59). The possible exceptions are concentrations of plasma glutamine (34,59) and mucosal IgA (33), which may be lower, and expression of lymphocyte activation markers, which may be marginally higher (13), in overtrained athletes. However, the biological significance, if any, of such small changes in specific immune parameters remains unclear. Certainly, such differences have not been consistently observed enough to warrant their use as markers of overtraining syndrome.
MECHANISMS UNDERLYING THE APPARENT SUPPRESSION OF IMMUNE FUNCTION DURING INTENSE TRAINING IN ATHLETES
Given the complexity and overlapping functions of the many arms of the immune system, it is unlikely that a single mechanism is responsible for the apparent suppression of immune function during periods of intense training in athletes. As discussed in the previous paper in this supplement, the acute response to a single bout of intense exercise may persist for several hours after the end of exercise. Because competitive athletes train at least daily, and often twice per day, it is possible that chronic suppression of immune function may result from the cumulative long-lasting acute effects of each successive exercise bout. For example, prolonged exercise (90-min running at 75% V̇O2max) repeated on 3 consecutive days exerted a cumulative suppressive effect on salivary IgA concentration (33). In another study, NKCA was suppressed more after intense prolonged exercise (60 min at 80% V̇O2max) when such exercise was preceded by a similar exercise bout 12 h before (36).
Many acute effects of exercise on immune function appear to relate to neuroendocrine changes, in particular release of stress hormones such as catecholamines and corticosteroids. It is possible that chronic changes in immune function also result from neuroendocrine changes such as alterations in the amount of hormone released during exercise, hormone receptor number or receptor sensitivity. Depletion of catecholamines and/or downregulation of hormone receptors may occur during prolonged periods of intense exercise training (27,35,68). Training is also associated with reduced blood levels of stress hormones at the same relative exercise intensity. Stress hormones act as mediators of a host of immune responses including release of cytokines (which in turn influence many immune cell activities), neutrophil function, NKCA, redistribution of immune cells within the body, and Ig synthesis. In addition, intense exercise training and competition are associated with significant psychological stress. Psychological stress is a well-known modulator of immune function, and the combined effects of physical and psychological stress are likely to influence immune function in the competitive athlete.
The clinical implications of the chronic changes in immune function described above are not clearly known at present. Certainly, physicians treating athletes should be aware of both the acute and chronic effects of intense exercise on immune cell number and function if these variables are to be used in clinical diagnosis. Because there may be long-lasting effects of intense exercise on immune parameters, the athlete should be well-rested (at least 24 and preferably 48 h since the last session) before blood is taken for clinical measurements of immune function. As mentioned above, athletes are not generally clinically immune deficient and URTI seems to be the main illness to which they are more susceptible, suggesting only mild effects on immunity. Changes in the risk of URTI and selected immune parameters seem to be related to training volume and intensity (16,22,23,52,56), suggesting that careful monitoring of these variables by the coach, physician, and athlete may help prevent illness. It is likely that the same guidelines recommended to help athletes avoid overtraining would also apply to preventing illness—that is, ensuring adequate nutrition and sleep, programming rest and recovery into the training cycle and after competition, and counseling athletes in effective stress management techniques. Moderate doses of vitamin C may be helpful. For example, in runners, vitamin C supplementation (600 mg·d−1 for 3 wk) reduced by half the incidence of URTI during the 2 wk after an ultramarathon (53–55). The long-term effectiveness of vitamin C in preventing URTI in endurance and other athletes has yet to be documented.
Athletes tend to experience more frequent but not necessarily more severe URTI than the general public (28). In the physically active individual, mild URTI may not require a break from regular exercise. For example, in healthy young adults moderate exercise training (40 min at 70% V̇O2max 3 times per week) did not influence the severity or duration of a mild experimentally induced URTI (70). On the other hand, as discussed in Holger Gabriel’s paper in this supplement, during systemic viral illness the athlete may need to alter exercise training or competition to avoid possible deleterious consequences such as viral myocarditis. Coaches and physicians who treat athletes should be aware of the need to alter training and closely follow the athlete’s health during recovery after viral illness. Use of simple tools, such as an athlete’s daily log of indicators of “well-being,” such as fatigue, perceived stress, quality of sleep, and muscle soreness (24), may help in monitoring the athlete’s recovery and progression back to the normal training regime after illness.
SUMMARY AND CONCLUSIONS
Athletes appear to experience a high incidence of symptoms of upper respiratory tract infection during intense training and after major competition. Although athletes would not be considered clinically immune deficient, recent evidence suggests that athletes experience mild suppression of immune function during periods of intense training. Whereas circulating immune cell numbers are generally maintained during intense training, slight impairments have been observed in neutrophil function, serum and mucosal immunoglobulin concentrations, plasma glutamine levels, and natural killer cell number and cytotoxic activity. It is possible that, in athletes, the combined effects of small changes in several immune parameters may compromise resistance to minor infectious agents. In contrast, moderate exercise training appears to have either no effect on, or to enhance resistance to, upper respiratory infection, possibly by stimulating immune function. Although competitive athletes must train intensely on a regular basis, monitoring athletes’ adaptation to training, allowing adequate recovery between sessions and after major competition, and attention to other factors such as proper nutrition and stress management may help athletes avoid immune suppression and associated illness.
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