The relationship between exercise and infection has been explored since early in the 20th century (for review, see 23). Nonetheless, the number of epidemiological and exercise training experimental trials on humans is still small, limiting our understanding of this important topic.
EXERCISE WORKLOAD AND INFECTION
The link between infection and exercise immunology is based upon several lines of evidence:
▪ Studies using animal models.
▪ Humans studies:
• Anecdotal and survey data from athletes.
• Epidemiologic data.
• Cross-sectional studies comparing athletes and nonathletes.
• Human studies on the acute and chronic influence of exercise on immune function and infection.
Data from animal studies have been difficult to apply to the human condition, but in general, have supported the finding that one or two periods of exhaustive exercise after inoculation leads to a more frequent appearance of infection and a higher fatality rate (but results differ depending on the pathogen, with some more affected by exercise than others) (3,20–23). Davis et al. (3), for example, exposed mice to rest, 30 min of moderate exercise, or 2.5–3 h of exhaustive exercise after intranasal infection with the herpes simplex virus (HSV-1). Mice exercised to fatigue had a greater overall mortality during a 21-d period than did controls or moderately exercised mice.
Abundant anecdotal and survey data exist in support of the relationship between exercise workload and infection. A common perception among elite athletes and their coaches is that prolonged and intense exertion lowers resistance to upper respiratory tract infection (URTI) (20–23,49). In a 1996 survey conducted by the Gatorade Sports Science Institute, 89% of 2700 high school and college coaches and athletic trainers checked “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). On the other hand, other surveys support the common belief among fitness enthusiasts that regular exercise confers resistance against infection. In a survey of 170 nonelite marathon runners (personal best time, an average of 3 h 25 min) who had been training for and participating in marathons for an average of 12 yr, 90% reported that they definitely or mostly agreed with the statement that they “rarely get sick” (unpublished data, D. C. Nieman, 1993). A survey of 750 masters athletes (ranging in age from 40 to 81 yr) showed that 76% perceived themselves as less vulnerable to viral illnesses than their sedentary peers (47).
Three randomized exercise training studies have demonstrated that near daily exercise by previously sedentary women for 12–15 wk is associated with a significant reduction in URTI (29,34,35). These studies have been reviewed in detail elsewhere (20,21). Figure 1 summarizes this information. In general, subjects randomized to brisk walking for 40–45 min, 5 d·wk−1, report 40–50% fewer days with URTI symptoms of sedentary control subjects. Longer-term studies with larger groups of subjects is needed to verify these preliminary findings.
It is well established that various measures of physical performance capability are reduced during an infectious episode (5). Several case histories have been published demonstrating that sudden and unexplained deterioration in athletic performance can be traced to either recent URTI or subclinical viral infections that run a protracted course (5,37). In some athletes, a viral infection may lead to a debilitating state known as “postviral fatigue syndrome” (15,37). The symptoms include lethargy, easy fatigability, and myalgia, and can persist for several months. Indirectly, these data support that exercise and infection are related.
Several studies using epidemiological designs have indicated that URTI risk is elevated during periods of heavy training and in the 1- to 2-wk period after participation in competitive endurance races (11,30,40–42). Foster (4) showed that a high percentage of illnesses occurred when elite athletes exceeded individually identifiable training thresholds, mostly related to the strain of training. These studies have been reviewed in detail elsewhere (20,21). It should be emphasized, however, that the majority of endurance athletes do not experience URTI after competitive race events. For example, only one in seven marathon runners reported an episode of URTI after the March 1987 Los Angeles Marathon (30). URTI rates in marathon runners are even lower during the summer than winter. In a study of 170 experienced marathon runners, only 3% reported an URTI during the week after a July marathon race event. (unpublished data, D. C. Nieman, 1993).
Together, these data indicate that there is a relationship between exercise workload and infection, and may be modeled in the form of a “J” curve (20–23) (see Fig. 2). This model suggests that although the risk of URTI may decrease below that of a sedentary individual when one engages in moderate exercise training, risk may rise above average during periods of excessive amounts of high-intensity exercise. At present, there is more evidence, primarily epidemiological in nature, exploring the relationship between heavy exertion and infection (although even these studies are small in number). For public health reasons, the link between moderate exercise and lowered URTI risk is of great importance, and large-scale studies are sorely needed in this area of exercise immunology.
The model in Figure 2 also suggests that immunosurveillance mirrors that relationship between infection risk and exercise workload. In other words, it makes sense that if regular moderate exercise lowers infection risk, it should be accompanied by enhanced immunosurveillance. On the other hand, when an athlete engages in unusually heavy exercise workloads (e.g., overtraining or a competitive endurance race event), infection risk should be related to diminished immunosurveillance.
EXERCISE AND IMMUNOSURVEILLANCE
Do the immune systems of endurance athletes and nonathletes function differently? Although the epidemiological data on exercise and infection risk 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 (13,22,26,32,34,35,43) The few studies available suggest that the innate immune system responds differentially to the chronic stress of intensive exercise, with natural killer cell activity tending to be enhanced while neutrophil function is suppressed (but only during unusually heavy periods of training) (26,32,43,51). The adaptive immune system (resting state) in general seems to be largely unaffected by athletic endeavor.
Even when significant changes in the concentration and functional activity of immune parameters have been observed in athletes, investigators have had little success in linking these to altered rates of infection and illness (8,13,32,34,35). Of all immune cells, natural killer cells appear to be most effected by athletic endeavor, but in a positive way (55). In other words, the elevated natural killer cell function often reported in athletes should enhance host protection against certain types of viruses and cancer cells. Nonetheless, Nieman et al. (32) reported that URTI rates were similar in female elite rowers and nonathletes during a 2-month period (winter/spring) despite substantially higher natural killer function in the rowers (1.6-fold above that of controls).
Neutrophils are an important component of the innate immune system, aiding in the phagocytosis of many bacterial and viral pathogens, and the release of immunomodulatory cytokines (43,55). Neutrophils are critical in the early control of invading infectious agents. In one report, elite swimmers undertaking intensive training had significantly lower neutrophil oxidative activity at rest than age- and sex-matched sedentary individuals, and function was further suppressed during the period of strenuous training before national-level competition (43). Nonetheless, URTI rates did not differ between the swimmers and sedentary controls.
Salivary IgA concentration warrants further research as a marker of potential infection risk in athletes (although an impractical one due to the difficulty and expense in measuring this immune parameter). Gleeson et al. (8) reported that 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 preseason and the mean pretraining salivary IgA levels. Nieman et al. (32), however, were unable to establish any link between salivary IgA and infection rates in elite female rowers and nonathletes.
The “Open-Window Theory”
Several authors have theorized that comparing resting immune function in athletes and nonathletes is not as important as measuring the magnitude of change in immunity that occurs after each bout of prolonged exercise (22,23,38,49). During this “open window” of altered immunity (which may last between 3 and 72 h, 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 demonstrate that athletes showing the most extreme immunosuppression following heavy exertion are those that contract an infection during the following 1–2 wk. This link must be established before the “open window” theory can be wholly accepted.
During the past decade, a plethora of research worldwide has greatly increased our understanding of the relationship between prolonged, intensive exercise, the immune system, and host protection against viruses and bacteria (for review, see 23). Many components of the immune system exhibit change after heavy exertion, including the following (1,18,23,31,36,38):
▪ Neutrophilia (high blood neutrophil counts) and lymphopenia (low blood lymphocyte counts), induced by high plasma catecholamines, growth hormone, and cortisol.
▪ Increase in blood granulocyte and monocyte phagocytosis, but a decrease in nasal neutrophil phagocytosis.
▪ Decrease in granulocyte oxidative burst activity.
▪ Decrease in nasal mucociliary clearance.
▪ Decrease in natural killer cell cytotoxic activity (NKCA).
▪ Decrease in mitogen-induced lymphocyte proliferation (a measure of T cell function).
▪ Decrease in the delayed-type hypersensitivity response.
▪ Increase in plasma concentrations of pro- and anti-inflammatory cytokines (e.g., tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), and interleukin-1 receptor antagonist (IL-1ra)).
▪ Decrease in ex vivo production of cytokines (interferon gamma (IFN-γ), TNF-α, IL-1, IL-2, IL-6, and IL-10) in response to mitogens and endotoxin.
▪ Decrease in nasal and salivary IgA concentration.
▪ Blunted major histocompatibility complex (MHC) II expression and antigen presentation in macrophages.
Taken together, these data suggest that the immune system is suppressed and stressed, albeit transiently, after prolonged endurance exercise (23). These immune changes do not occur after moderate 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 experienced other stressors to the immune system including lack of sleep, severe mental stress, malnutrition, or weight loss. Attempts thus far, however, to link extreme perturbations in immune function following heavy exertion with an elevated infection risk have failed (31). This failure is largely due to the difficulty of measuring immunity in groups of athletes large enough to have sufficient statistical power to detect an effect.
GUIDELINES FOR ATHLETES
Endurance athletes are often uncertain of whether they should exercise or rest during an infectious episode. There are few data available in humans to provide definitive answers. Most clinical authorities in this area recommend that if the athlete has symptoms of a common cold with no constitutional involvement, then regular training may be safely resumed a few days after the resolution of symptoms (5,22,53,54). Mild exercise during sickness with a common cold does not appear to be contraindicated. Weidner et al. (53,54), for example, have shown that rhinovirus-caused upper respiratory illness does not impair short duration submaximal or maximal exercise performance. In addition, moderate exercise training did not influence URTI symptomatology. However, it should be cautioned that rhinoviruses account for only 40% of URTI, and further research is needed with other pathogens to determine their relationship to exercise. Some clinicians feel that if there are symptoms or signs of systemic involvement (fever, extreme tiredness, muscle aches, swollen lymph glands, etc.), then 2–4 wk should probably be allowed before resumption of intensive training (5). In one study of horses infected with influenza virus, exercise training during the illness phase exacerbated the severity of clinical disease (9).
For elite athletes who may be undergoing heavy exercise stress in preparation for competition, several precautions may help them reduce their risk of URTI (16,20–22):
▪ Keep other life stresses to a minimum (mental stress in and of itself has been linked to increased URTI risk).
▪ Eat a well-balanced diet to keep vitamin and mineral pools in the body at optimal levels. The use of various nutritional countermeasures can be considered, especially the use of carbohydrate before, during, and after prolonged, intensive exertion (see the next section).
▪ Avoid overtraining and chronic fatigue.
▪ Obtain adequate sleep on a regular schedule (disruption linked to suppressed immunity).
▪ Avoid rapid weight loss (linked to adverse immune changes).
▪ Avoid putting the hands to the eyes and nose (a major route of viral self-inoculation).
▪ Before important race events, avoid sick people and large crowds when possible.
▪ For athletes competing during the winter months, influenza vaccination is recommended.
▪ Upon the advise of a physician, consider the use of new antiinflammatory and antiviral agents to treat URTI.
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 drugs or nutrient supplements that have the potential to counter exercise-induced inflammation and immune alterations.
There are some preliminary data that various immunomodulator drugs may afford athletes some protection against inflammation, negative immune changes, and infection during competitive cycles, but much more research is needed before any of these can be recommended (6,12,25).
Researchers have measured the influence of nutritional supplements (48,49), primarily zinc (50), dietary fat (52), vitamin C (28,40–42), glutamine (2,14,39,44–46), and carbohydrate (7,10,19,24,27,33), on the immune and infection response to intense and prolonged exercise.
Several double-blind placebo studies of South African ultramarathon runners have demonstrated that 3 wk of vitamin C supplementation (about 600 mg·d−1) is related to fewer reports of URTI symptoms (40–42) This has not been replicated, however, by other research teams. Himmelstein et al. (11), for example, reported no alteration in URTI incidence among 44 marathon runners and 48 sedentary subjects randomly assigned to a 2-month regimen of 1000 mg·d−1 of vitamin C or placebo. A double-blind, placebo-controlled study was unable to establish that vitamin C supplementation (1000 mg·d−1 for 8 d) had any significant effect in altering the immune response to 2.5 h of intensive running (28). More research is needed to sort out these contradictory findings.
Glutamine, a nonessential amino acid, has attracted much attention by investigators because plasma levels have been observed to decrease in response to prolonged exercise (2,14,39,44–46). Glutamine is an important fuel along with glucose for lymphocytes and monocytes, and decreased amounts have a direct effect in lowering proliferation rates of lymphocytes. Whether exercise-induced reductions in plasma glutamine levels are linked to impaired immunity and host protection against viruses in athletes is still being debated, but the majority of studies have not favored such a relationship.
A reduction in blood glucose levels has been related 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 (17). Given the link between stress hormones and immune responses to prolonged and intensive exercise, a hypothesis has been proposed that carbohydrate compared to placebo ingestion should maintain plasma glucose concentrations, attenuate increases in stress hormones, and thereby diminish changes in immunity (as summarized in Fig. 3) (24).
Several studies have now verified that carbohydrate ingestion during prolonged and intensive exercise lessens hormonal and immune responses that have been related to physiological stress and inflammation (7,10,19,24,27,33). Carbohydrate beverage ingestion has been associated with higher plasma glucose levels, an attenuated cortisol and growth hormone response, 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, these data indicate that physiological stress to the immune system is reduced when endurance athletes use carbohydrate beverages before, during, and after prolonged and intense exertion. The clinical significance of these carbohydrate-induced effects on the endocrine and immune systems awaits further research.
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