SSE #69: Immunity in Athletes: Current Issues

David C. Nieman, DrPH, FACSM

SPORTS SCIENCE EXCHANGE

 

Immunity in Athletes: Current Issues

SSE#69, Volume 11 (1998), Number 2


David C. Nieman, DrPH, FACSM
Department of Health and Exercise Science
Appalachian State University, Boone, NC 28608

Key Points

1. The immune systems of athletes and nonathletes when measured in the resting state are more similar than disparate. Even when significant reductions in resting immune function have been observed in athletes, investigators have had little success in linking these to a higher incidence of infection and illness.

2. Many components of the immune system exhibit change after prolonged, heavy exertion. During this “open window” of altered immunity (which may last between 3 and 72 hours, depending on the measure of immune function), viruses and bacteria may gain a foothold, increasing the risk of subclinical and clinical infection.

3. The influence of some nutritional supplements on acute immune response to prolonged exercise has been evaluated in endurance athletes. Though vitamin C and glutamine have received the most attention, the data thus far are inconclusive as to a beneficial effect.

4. In contrast to micronutrient and amino acid supplementation, the ingestion of fluids that contain carbohydrate reduce perturbations in the immune system (less disturbance in blood immune cell counts, lower granulocyte and monocyte phagocytosis and oxidative burst activity; diminished pro- and anti-inflammatory cytokine response).

5. By maintaining higher plasma glucose levels and attenuating the cortisol and growth hormone responses during heavy exercise, carbohydrate-beverage ingestion may reduce stress to the immune system of athletes.

INTRODUCTION

Publications on the topic of exercise immunology date from late in the 19th century, but it was not until the mid-1980s that a significant number of investigators worldwide devoted their resources to this area of research endeavor. From 1900 to 1997, just under 900 papers on exercise immunology were published, with 75% of these appearing in the 1990s.

Despite growing attention to the relationship between exercise, the immune system, and host protection, many questions and unexplored issues remain. This article reviews four topics that have received much attention by exercise immunologists and have practical application to athletes:
(1) the contrast in immune function between athletes and nonathletes,
(2) acute immune changes that occur following prolonged and intensive exercise,
(3) the role of nutritional supplements in attenuating exercise-induced changes in immunity,
(4) practical recommendations for athletes.

Immune Function in Athletes and non-athletes: more similar than disparate

Among elite athletes and their coaches, a common perception is that heavy exertion lowers resistance and is a predisposing factor to upper respiratory tract infection (URTI)(Nieman, 1997a). In a 1996 survey by the Gatorade Sports Science Institute of 2,700 high school and college coaches and athletic trainers, 89% answered “yes” to the question, “Do you believe overtraining can compromise the immune system and make athletes sick?” (personal communication, Gatorade Sports Science Institute, Barrington, IL). Several studies using epidemiological designs have verified that URTI risk is elevated during periods of heavy training and for 1-2 weeks following competitive endurance race events (Nieman 1997a; Peters-Futre, 1997).

Conversely, there is also a common belief among fitness enthusiasts that regular exercise confers resistance against infection. In a survey of 170 non-elite marathon runners (average personal best time of 3 h 25 min) who had been training for and participating in marathons for an average of 12 years, 90% reported that they definitely or mostly agreed with the statement that they “rarely get sick” (unpublished observations).

Figure 1. Near-daily brisk walking for 45 minutes per session is associated with significantly fewer days with URTI symptoms (Mean ±SE). This figure combines the results from two studies of 126 overweight women randomized to exercise and nonexercise groups. Data from Nieman et al.(1993) and Nieman et al.(1998).  

A survey of 750 masters athletes (ranging in age from 40 to 81 years) showed that 76% perceived themselves as less vulnerable to viral illnesses than were their sedentary peers (Shephard et al., 1995). Three randomized exercise training studies have demonstrated that near-daily exercise is associated with a significant reduction in URTI (Nieman et al., 1990, 1993, 1998b). Figure 1 combines the results of two studies of 126 women randomized to exercise (5 days per week, 45 minutes/session, brisk walking) and nonexercise groups (Nieman et al., 1990,1998b). The results indicate that the number of days with URTI was reduced by nearly half in the exercise group.

Do the immune systems of athletes and nonathletes function differently? Although the URTI risk data suggest that disparities should exist, attempts thus far to compare resting immune function in athletes and nonathletes have failed to provide compelling evidence that athletic endeavor is linked to clinically important changes in immunity (Nieman 1997a, 1997b).

In the resting state, the adaptive immune system (i.e., the function of T and B cells that produce specific reactions and immunological memory to each infectious agent when activated) appears to be largely unaffected by intensive and prolonged exercise training. The innate immune system (i.e., immune cells that act as a first line of defense against infectious agents) appears to respond differentially to the chronic stress of intensive exercise, with natural killer cell activity tending to be enhanced, whereas neutrophil function is suppressed.

Even when significant changes in the concentrations and functional activities of immune variables have been observed in athletes, investigators have had little success in linking these changes to a higher incidence of infection and illness. In one report, elite swimmers undertaking intensive training had significantly lower neutrophil oxidative activity at rest than did age-and sex-matched sedentary individuals, with function further suppressed during the period of strenuous training prior to national-level competition (Pyne et al., 1995) (See Figure 2). Nonetheless, URTI rates did not differ between the swimmers and sedentary controls.

Figure 2. Elite swimmers (line graph) undertaking intensive training had a significantly lower neutrophil oxidative activity at rest than did age- and sex-matched sedentary individuals (histogram blocks). Function was further suppressed during the period of strenuous training prior to national-level competition. Data {means (+SE)} from Pyne et al.(1995). Brackets represent mean ±SE.   

Two studies indicate that salivary immunoglobulin A (IgA) concentration warrants further research as a marker of potential infection risk in athletes. Mackinnon et al. (1993) demonstrated that elite squash and hockey athletes with low salivary IgA concentrations experienced higher rates of URTI. This was later confirmed in a study of elite swimmers (Gleeson et al., 1996). Salivary IgA levels measured in swimmers before training sessions showed significant correlations with infection rates, and the number of infections observed in the swimmers was predicted by the pre-season and the mean pre-training salivary IgA levels.

In general, when analyzed in resting subjects, the immune systems of athletes and nonathletes appear to be more similar than disparate. Of the various immune function tests that show some change with athletic endeavor, only salivary IgA has emerged as a potential marker of infection risk. Future research should concentrate on this immune measure using large groups of athletes and nonathletes to clarify its potential clinical usefulness.

The Acute immune response to heavy exertion: Update on the "Open Window" theory

 

In light of the mixed results regarding the effect of chronic, intensive training on resting immune function and host protection, several authors have theorized that each bout of prolonged exercise leads to transient but clinically significant changes in immune function (Hoffman-Goetz & Pedersen, 1994; Nieman, 1997b). During this “open window” of altered immunity (which may last between 3 and 72 hours, depending on the immune measure), viruses and bacteria may gain a foothold, increasing the risk of subclinical and clinical infection.

Although this is an attractive hypothesis, no serious attempt has been made by investigators to establish that athletes showing the most extreme immunosuppression following heavy exertion are those who contract an infection during the following 1-2 weeks. This link must be established before the “open window” theory can be wholly accepted.

Compared to rest, many components of the immune system exhibit change after prolonged, heavy exertion, including the following (Nieman 1997b, 1998):

High neutrophil and low lymphocyte blood counts, induced by high concentrations of plasma cortisol.
Increase in blood granulocyte and monocyte phagocytosis (engulfing of infectious agents and of breakdown products of muscle fiber) but a decrease in nasal neutrophil phagocytosis.
Decrease in granulocyte oxidative-burst activity (killing activity).
Decrease in nasal mucociliary clearance (sweeping movement of cilia).
Decrease in natural-killer-cell cytotoxic activity (the ability to kill infected cells or cancer cells).
Decrease in mitogen-induced lymphocyte proliferation (a measure of T cell function).
Decrease in the delayed-type hypersensitivity skin response (the ability of the immune system to produce hard red lumps after the skin is pricked with antigens).
Increase in plasma concentrations of pro- and anti-inflammatory cytokines (e.g., interleukin-6 and interleukin-1 receptor antagonist).
Decrease in ex vivo production of cytokines (interferon-'o', interleukin-1, and interleukin-6) in response to mitogens and endotoxin.
Decrease in nasal and salivary IgA concentration (an important antibody).
— 
Blunted expression of major histocompatibility complex (MHC) II in macrophages (an important step in recognition of foreign agents by the immune system).

Increase in phagocytic activities of blood granulocytes and monocytes and in blood levels of interleukin-6 suggests a strong pro-inflammatory response to damage of muscle induced by heavy exertion, whereas the rise in cortisol and interleukin-1 receptor antagonist shows that anti-inflammatory forces are also at work. The interleukin response to strenuous exercise is similar to that of sepsis and trauma. The immune system’s involvement in the inflammatory response following heavy exertion has been hypothesized to divert attention and resources away from host protection against URTI (Nehlsen-Cannarella, 1997; Nieman, 1997a).

Taken together, these data suggest that the immune system is suppressed and stressed, albeit transiently, following prolonged endurance exercise. Thus, it makes sense (but still remains unproven) that URTI risk may be increased when the endurance athlete goes through repeated cycles of heavy exertion, has been exposed to novel pathogens, and has experienced other stressors to the immune system, including lack of sleep, severe mental stress, malnutrition, or weight loss.

Figure 3. A reduced delayed-type hypersensitivity skin-test response was measured in 22 male triathletes 48 hours after competing in a half-Ironman triathlon competition, compared to controls (11 non-exercising triathletes and 22 moderately trained males).Data from Bruunsgaard et al.(1997).Mean ±SE.   

Several studies have shown that despite altered immunity following prolonged and intensive exercise, the ability of the immune system to mount an antibody response to vaccination over the 2-4 week postexercise period is not affected. In a study by Bruunsgaard et al. (1997), male triathletes, when compared to sedentary controls, had normal antibody production to pneumococcal, tetanus, and diphtheria vaccines following a half-Ironman triathlon competitive event. However, the skin test response to seven recall antigens applied after the race and measured 48 hours later was suppressed when compared to control subjects. (Figure 3). These data suggest that the short-term but complex immunological reaction to the delayed-type hypersensitivity skin test is negatively affected by prolonged and intensive exercise, whereas the longer-term, antibody-titer response to vaccination is not affected. While these data lend support to the “open window” theory, additional research is needed to establish a link with infection risk.

Role of Nutritional supplements in attenuating exercise-induced Immunosuppression

Although endurance athletes may be at increased risk for URTIs during heavy training cycles, they must exercise intensively to compete successfully. Athletes appear less interested in reducing training workloads and more receptive to ingesting nutrient supplements that have the potential to counter exercise-induced immunosuppression.

Investigators have measured the influence of nutritional supplements, primarily zinc, vitamin C, glutamine, and carbohydrate, on the immune response to intense and prolonged exercise (Shephard & Shek, 1995). Several double-blind placebo-controlled studies of South African ultramarathon runners have demonstrated an association between vitamin C supplementation (about 600 mg/day for 3 weeks) and fewer reports of URTI symptoms (Peters-Futre, 1997). This has not been replicated, however, by other research teams, and the method of reporting URTI symptoms resulted in unrealistically high incidence rates. A double-blind, placebo-controlled study was unable to establish that vitamin C supplementation (1,000 mg/day for 8 days) had any significant effect in altering the immune response to 2.5 hours of intensive running (Nieman et al., 1997b).

Glutamine, a nonessential amino acid, has attracted much attention from investigators (Mackinnon et al., 1996). Glutamine and glucose are important fuels for lymphocytes and monocytes, and decreased amounts of these nutrients have a direct effect in lowering proliferation rates of lymphocytes. Reduced plasma glutamine levels have been observed in response to various stressors, including prolonged exercise. Whether exercise-induced reductions in plasma glutamine levels are linked to impaired immunity and host protection against viruses in athletes is still unsettled, but most studies have not favored such a relationship.

Figure 4. This model suggests that carbohydrate supplementation during prolonged and intensive exercise maintains or elevates plasma glucose concentrations, attenuates the normal rise in stress hormones, and thereby counters negative immune changes.

The most impressive results have been reported in the carbohydrate supplementation studies (Nieman, 1998). Earlier research had established that a reduction in blood glucose concentration is linked to hypothalamic-pituitary-adrenal activation, an increased release of adrenocorticotrophic hormone and cortisol, increased plasma growth hormone, decreased insulin, and a variable effect on blood epinephrine levels. Given the link between stress hormones and immune responses to prolonged and intensive exercise, carbohydrate compared to placebo ingestion should maintain plasma glucose concentrations, attenuate increases in stress hormones, and thereby diminish changes in immunity (See Figure 4).

This hypothesis was first tested in a group of 30 experienced marathon runners (Nehlsen-Cannarella, et al., 1997; Nieman et al., 1997a). A double-blind, placebo-controlled randomized study was designed to investigate the effect of drinking fluids containing carbohydrate on the immune response to 2.5 hours of running. In a subsequent study of 10 triathletes, carbohydrate ingestion was studied for its effect on the immune response to 2.5 hours of running and cycling (Nieman et al., 1998a, 1998c). During four sessions, subjects ran on treadmills or cycled using their own bicycles on electromagnetically braked tripod trainers for 2.5 hours at ~75% VO2 max.

In both studies, carbohydrate beverage ingestion before, during (about 1 liter/hour), and after 2.5 hours of exercise was associated with higher plasma glucose levels, an attenuated rise in plasma levels of cortisol and growth hormone, fewer perturbations in blood immune-cell counts, lower granulocyte and monocyte phagocytosis and oxidative burst activity, and a diminished pro- and anti-inflammatory cytokine response. Overall, the hormonal and immune responses to carbohydrate compared to placebo ingestion suggest that physiologic stress was diminished. Some immune variables were affected slightly by carbohydrate ingestion (for example, granulocyte and monocyte function), while others were strongly influenced (e.g., plasma cytokine concentrations and blood cell counts).

The clinical significance of these carbohydrate-induced effects on the endocrine and immune systems awaits further research. At this point, the data indicate that athletes ingesting carbohydrate beverages before, during, and after prolonged and intensive exercise should experience lowered physiologic stress. Research to determine whether carbohydrate ingestion will improve host protection against viruses in endurance athletes during periods of intensified training or following competitive endurance events is warranted.

Practical Recommendations

Although public health recommendations must be considered tentative, the data on the relationship between moderate exercise and lowered risk of URTI are consistent with guidelines urging the general public to engage in near-daily brisk walking. There is reason to believe that endurance athletes engaging in normal training cycles also experience a reduced URTI risk.

For athletes undergoing intensified training or engaging in long-endurance race events, the risk of immune suppression and sickness is increased. Several lifestyle practices may help serve as countermeasures. Considerable evidence indicates that improper nutrition and psychological stress can compound the negative influence that heavy exertion has on the immune system. Based on current understanding, the athlete is urged to eat a well-balanced diet, keep other life stresses to a minimum, avoid overtraining and chronic fatigue, obtain adequate sleep, and space vigorous workouts and race events as far apart as possible. The new research data on carbohydrate supplementation suggest that drinking carbohydrate beverages before, during, and after prolonged and intensive training bouts or competitive race events may lessen physiologic stress to the immune system.

Immune system function appears to be suppressed during periods of low caloric intake and weight reduction, so when necessary, the athlete is advised to lose weight slowly during noncompetitive training phases. Cold viruses are spread by both personal contact and breathing the air near sick people. Therefore, if at all possible, athletes should avoid being around sick people before and after important events. If the athlete is competing during the winter months, a flu shot is recommended.
Possible indicators of overtraining include immunosuppression with loss of motivation for training and competition, depression, poor performance, and muscle soreness. However, at this time, there are no practical markers of immunosuppression (other than infection) that coaches and clinicians can use to indicate that the athlete is overtrained.

Summary

There is growing evidence that prolonged intensive exercise is associated with altered immune function and an increased risk of URTI. Attempts have been made to alter these negative changes through nutritional means, with carbohydrate supplementation offering the most promising results thus far reported. Further research is needed to establish the relationship of carbohydrate supplementation to changes in both immune function and host protection against URTI pathogens.

References

Bruunsgaard, H., A. Hartkopp, T. Mohr, H. Konradsen, I. Heron, C.H. Mordhorst, and B.K. Pedersen (1997). In vivo cell-mediated immunity and vaccination response following prolonged, intense exercise. Med. Sci. Sports Exerc. 29:1176-1181.

Gleeson, M., D.B. Pyne, W.A. McDonald, R.L. Clancy, A.W. Cripps, P.L. Horn, and P.A. Fricker (1996). Pneumococcal antibody responses in elite swimmers. Clin. Exp. Immunol. 105:238-244.

Hoffman-Goetz, L., and B.K. Pedersen (1994). Exercise and the immune system: a model of the stress response? Immunol. Today. 15:382-387.

Mackinnon, L.T., E.M. Ginn, and G.J. Seymour (1993). Temporal relationship between decreased salivary IgA and URTI in elite athletes. Aust. J. Sci. Med. Sport. 25:94-99.

Mackinnon, L.T., and S.L. Hooper (1996). Plasma glutamine and URTI during intensified training in swimmers. Med. Sci. Sports Exerc. 28:285-290.

Nehlsen-Cannarella, S.L., O.R. Fagoaga, D.C. Nieman, D.A. Henson, D.E. Butterworth, R.L. Schmitt, E.M. Bailey, B.J. Warren, and J.M. Davis (1997). Carbohydrate and the cytokine response to 2.5 hours of running. J. Appl. Physiol. 82:1662-1667.

Nieman, D.C. (1998). Influence of carbohydrate on the immune response to intensive, prolonged exercise. Exerc. Immunol. Rev. 4:64-76

Nieman, D.C. (1997a). Exercise immunology: practical applications. Int. J. Sports Med. 18(suppl. 1):S91-S100.

Nieman, D.C. (1997b). Immune response to heavy exertion. J. Appl. Physiol. 82:1385-1394.

Nieman, D.C., O.R. Fagoaga, D.E. Butterworth, B.J. Warren, A. Utter, J.M. Davis, D.A. Henson, and S.L. Nehlsen-Cannarella (1997a). Carbohydrate supplementation affects blood granulocyte and monocyte trafficking but not function following 2.5 hours of running. Am. J. Clin. Nutr. 66:153-159.

Nieman, D.C., D.A. Henson, D.E. Butterworth, B.J. Warren, J.M. Davis, O.R. Fagoaga, and S.L. Nehlsen-Cannarella (1997b). Vitamin C supplementation does not alter the immune response to 2.5 hours of running. Int. J. Sports Nutr. 7:174-184.

Nieman, D.C., D.A. Henson, G. Gusewitch, B.J. Warren, R.C. Dotson, D.E. Butterworth, and S.L. Nehlsen-Cannarella (1993). Physical activity and immune function in elderly women. Med. Sci. Sports Exerc. 25:823-831.

Nieman, D.C., S.L. Nehlsen-Cannarella, O.R. Fagoaga, D.A Henson, A. Utter, J.M. Davis, F. Williams, and D.E. Butterworth (1998a). Influence of mode and carbohydrate on the cytokine response to heavy exertion. Med. Sci. Sports Exerc. 30:671-678.

Nieman, D.C., S.L. Nehlsen-Cannarella, D.A. Henson, A. J. Koch, D.E. Butterworth, O.R. Fagoaga, and A. Utter (1998b). Immune response to exercise training and/or energy restriction in obese women. Med. Sci. Sports Exerc. 30:679-686.

Nieman, D.C., S.L. Nehlsen-Cannarella, O.R. Fagoaga, D.A. Henson, A. Utter, J.M. Davis, F. Williams, and D.E. Butterworth (1998c). Effects of mode and carbohydrate on the granulocyte and monocyte response to intensive prolonged exercise. J. Appl. Physiol. 84:1252-1259.

Nieman, D.C., S.L. Nehlsen-Cannarella, P.A. Markoff, A.J. Balk-Lamberton, H. Yang, D.B.W. Chritton, J.W. Lee, and K. Arabatzis (1990). The effects of moderate exercise training on natural killer cells and acute URTIs. Int. J. Sports Med. 11:467-473.

Peters-Futre, E.M. (1997). Vitamin C, neutrophil function, and URTI risk in distance runners: the missing link. Exerc. Immunol. Rev. 3:32-52.

Pyne, D.B., M.S. Baker, P.A. Fricker, W.A. McDonald, and W.J. Nelson (1995). Effects of an intensive 12-wk training program by elite swimmers on neutrophil oxidative activity. Med. Sci. Sports Exerc. 27:536-542.

Shephard, R.J., T. Kavanagh, D.J. Mertens, S. Qureshi, and M. Clark (1995). Personal health benefits of Masters athletics competition. Br. J. Sports Med. 29:35-40.

Shephard, R.J., and P.N. Shek (1995). Heavy exercise, nutrition and immune function: Is there a connection? Int. J. Sports Med. 16:491-497.

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