Exercise, immunity, and infection

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dable bank of scientific, clinical, and epidemiolog- ic data supporting this belief.l ...... gination in the human lung and its response to strenuous exer- cise. Clin Sci ..... Paffenbarger RS, Hyde RT, Wing AL, Hsieh CC: Physi- cal activity, all cause ...
~l Exercise, immunity, and infection LEONARD H . CALABRESE, DO DAVID C. NIEMAN, PhD

The conviction that exercise is an effective means to improve health is widespread in contemporary culture and, indeed, there is a formidable bank of scientific, clinical, and epidemiologic data supporting this belief.l The potential for exercise to modifY host defenses (that is, immune responsiveness) is a more recent concept and one Dr Calabrese is Vice Chairman, Department of Rheumatic and Immunologic Disease, Cleveland Clinic Foundation, Cleveland, Ohio, and Dr Nieman is at Appalachian State University, Boone, NC. Correspondence to Leonard H. Calabrese, DO, Vice Chairman, Department of Rheumatic and Immunologic Disease, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.

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Although further research is n~_v ed with larger study groups and improved study designs, a review of the literature indicates that there are some scientific bases to suggest that heavy or exhaustive exercise may be predisposing to upper respiratory tract illness while moderate amounts may be protective. There exists no convincing evidence suggesting that moderate exercise poses a demonstrable negative influence on the frequency of common respiratory tract infections or adversely influences the course of certalli chronic viral illnesses, including viral hepatitis and human immunodeficiency virus infection. Constitutional symptoms secondary to infectious diseases appear to compromise human performance. Exhaustive exercise appears to be a predisposing factor for the development of common respiratory tract infections and may potentially adversely affect the course of certain infectious diseases. Very limited data suggest an enhancement of resistance to respiratory tract infections from moderate exercise training. Although biologically plausible, data to support unequivocal exercise-induced enhancement or suppression of immunologic function are inconclusive at this time. (Key words: Exercise, immunity, infection)

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not as generally accepted. Dedicated recreational runners and other athletes believe that they have increased resistance to infection, presumably as a result of bolstered host defenses. Alternatively, physicians caring for elite athletes have noted increasing susceptibilities to respiratory tract illnesses that are also ascribed to the effects of exercise on host defenses. Five years ago, the highly publicized case of Earvin "Magic" Johnson raised numerous questions among members of the general public and medical communities concerning the advisability of rigorous exercise by individuals infected with the human immunodeficiency virus (RIV). Given the current interest in the effects of acute and chronic exercise on immunity, it is important for physicians to be aware of recent advances in the field of exercise and immunity. It now appears that there exist sufficient data to give reasonable guidance in answering a series of important questions commonly asked of clinicians: o Does exercise predispose to, or protect from, infectious diseases? o What are the effects of exercise on the natural history of infectious diseases, including RIV? o What are the effects of infection on athletic performance? o Are there clear guidelines for recreational athletes regarding exercise during infections? This review will address these issues and, in addition, will begin with a brief overview of the effects of exercise on immunity. Effects of exercise on immunity Exercise is the leisure-time application of physical activity. Training is the result of repetitive bouts of exercise over weeks or months, with the resulting development of physical or physiologic fitness (or both). Fitness not only applies to cardiovascular and musculoskeletal conditioning, but also extends to other physiologic systems as well and may effect changes in blood pressure, blood lipid levels, glucose tolerance, and insulin sensitivity. In this context, it is reasonable to ask whether exercise and training can induce immunologic fitness

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and influence the host's response to infectious diseases. Over the past decade, numerous investigations have shown that both acute and chronic exercise can modifY, at times profoundly, numerous classic in vitro tests ofthe human immune response. These studies were reviewed in considerable detail. 2·6 Among more recent investigations, many methodologic problems that plagued earlier work have been resolved but uncertainties persist regarding the relevance of these largely in vitro studies to health and disease. Despite such limitations, sufficient data exist to draw certain limited conclusions.

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Effects of acute exercise on immunity Acute exercise can be quantified by its intensity and duration and is capable of briefly perturbing a host of physiologic systems, including the immune system. Questions of whether postexercise immunologic perturbations merely represent circadian influences or methodologic epiphenomena have been addressed by increasing numbers of carefully designed and well-controlled experiments measuring a variety of immunologic parameters. Acute exercise alters the number and relative distribution of peripheral blood leukocytes, including lymphocyte subpopulations.7-11 Functional studies of peripheral blood mononuclear cells have demonstrated changes in polymorphonuclear cells,12,13 monocytes,13 natural killer (NK) cells,n,14 antibodydependent cellular cytotoxicity-mediating cells,15,16 and T cells.17 -19 Alteration of cytokine production, as assessed by concentrations in plasma or production in vitro, has been demonstrated for interleukin (IL)-1,20-22 IL_2,21,22 IL-6,22 tumor necrosis factor, 21,22 and interferon alfa,23 and varies depending on the nature, intensity, and duration of the exercise. In general, the acute response of the immune system to exercise is transient and highly variable, depending on the nature and intensity of exercise, the state of fitness of the subjects, the methods of immunologic assessment used, and the timing of sampling. Despite the variability in postexercise immune responsiveness, numerous studies have established that vigorous physical exercise (5 to 60 minutes at 70 % to 80% aerobic capacity) is associated with a biphasic alteration of peripheral blood mononuclear cell number and distribution. 8,15,17,24,25 Immediately after exercise, circulating lymphocytes increase by 70 % to 130%, followed by a 30% to 50% lymphopenia beginning 30 minutes postexercise and lasting close to 4 hours. Moderate-intensity exercise (40% to 60% aerobic capacity) is associated with similar changes, but of smaller magnitude 10,l1,17,26-28 (Figure 1). The biologic implications of this exercise-associated alteration of leukocyte traffic is unknown, and

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transient increases or decreases in peripheral blood mononuclear cell number may not reflect integrity of host defenses because this change represents only a small percentage of total cell number. Functional studies of mononuclear proliferative capacity have generally demonstrated a postexercise suppression lasting 2 to 4 hours. 17,19,25,29-31 Some investigations have documented postexercise hyporesponsiveness, independent of exercise intensity,19 whereas others have recorded little change after exercise of moderate intensity.1 7,26 Interpretation of this exercise-related immunosuppression must be made with caution, for it may merely reflect a dilutional effect created by lower numbers of mitogen responsive T cells secondary to the influx ofNK cells. Thus, the drop in T-cell function has been challenged as not being clinically important.30 ,31 Further investigation of this issue is clearly warranted. The mechanism ofpostexertional panleukocytosis followed by a relatively sustained neutrophilia and lymphopenia, as well as a suppressed lymphocyte proliferation after high-intensity exercise, is incompletely understood. The changes may be due to the release of a variety of mediators, the best studied being epinephrine and cortisol. Epinephrine is capable of inducing 13 2-adrenergic receptor expression on lymphocytes,32,33 and shifts of lymphocyte subsets after epinephrine infusion studies are similar to those seen after rigorous exercise. 24 ,34,35 I3-Adrenergic receptor expression is also influenced by cortisol and training.32 ,33,36-39 Cortisol is known to induce a polymorphonuclear leukocytosis as well as peripheral lymphopenia. 40 Both epinephrine and cortisol are capable of inhibiting lymphocyte proliferation in physiologic concentrations in vitro. 40-42 Other factors contributing to these perturbations may include alterations in body temperature,43 changes in glutamine availability,44 and release of neuroendocrine mediators, such as l3-endorphins 45 and growth hormone. 14 The physiologic significance of these observations is at present unproved. Gabriel and coUeagues 8 postulated that after intensive exercise, shifts in leukocytes to injured muscle result in a brief window of susceptibility to viral infections. Another possible explanation of these findings, particularly the postexertional suppression of lymphocyte proliferation, is that they merely represent a physiologic response analogous to acute stress, such as that precipitated by myocardial infarction, burns, severe psychiatric illness, and other stressors. 46 -48 Nieman and associates 49 suggested that the acute immunologic changes after particularly heavy exercise may predispose to upper respiratory tract infections (URTIs) via the aforementioned immunosuppressive mechanisms, whereas moderate levels of exercise may be somewhat protective. They pos-

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tulated that because moderate-intensity exercise does not increase the concentration of epinephrine and cortisol as does high-intensity exercise, the smaller, but significant, increase in circulating immunocompetent cells will be favorable to host defenses. In 1993, Cannon3 cautioned against biologic interpretations of in vitro immunologic data. 3

Effects of training on the immune response The experimental demonstration of a "training effect" on the immune response is difficult for a variety of reasons. Animal studies are technically challenging from the perspective of separating training effect from other associated stressors (that is, electric shocks, sleeplessness, handling, etcetera) and thus difficult to interpret. Human investigations are limited by the fact that the immune system is highly redundant and our ability to analyze only isolated phenomena does not readily permit a direct assessment of integrated host defenses. Most longitudinal studies performed to date have rarely controlled for such variables as seasonal variation in immune parameters or included appropriately matched controls in terms of such factors as psychologic stress, which may influence immune response. 3

Although animal studies during the past 10 years have consistently revealed that intense endurance training is associated with suppression of several immunologic parameters,50,51.52 this association has not been clearly demonstrated in humans. Methodologically, human investigations have taken several forms. Some have attempted to compare cross-sectional studies in trained and untrained subjects at rest, whereas others have compared post-acute exercise responses in similar groups. Finally, several studies of exercise effects on immunity have used matched parallel control groups. Cross-sectional investigations ofleukocyte function and numbers in trained and untrained populations have been unrevealing. 16,53 Resting mitogen-stimulated lymphocyte proliferation is not appreciably altered by exercise training.l 9 Findings of investigations into phagocytic cell function have been conflicting, making strong conclusions impossible.l 2,13,54,55 Serum immunoglobulin concentrations appear similar in trained and untrained individuals56,57; however, some elite athletes may develop low levels of secretory IgA. 58 Natural killer activity has generally been found to be elevated in both physically active individuals 59-61 and trained athletes 62 relative to sedentary controls. The mech-

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anism for enhanced NK activity in such studies has not yet been established. With the possible exception of NK activity, there is no convincing immunologic evidence that exercise training enhances host defenses in healthy persons. Perhaps one methodologic reason for failing to demonstrate an immunoenhancing effect of training has been the use of study populations consisting of healthy young adults with well-functioning host defenses. Given the redundancy of the human immun3 system and the limitations of in vitro testing, it is possible that we are limited in our capacity to demonstrate immunoenhancement. Given these limitations, it may be more logical to study populations with some degree of immunocompromise. Elderly people represent such a group with clear evidence of immune dysfunction that advances with age.63,64 The immunologic dysfunction associated with aging involves multiple limbs of the immune response, with T cell-dependent functions most drastically affected. The elderly also have greater morbidity and mortality from infectious diseases and have higher rates for many forms of cancer. Two reviews in 1994 analyzed the relationships between exercise, aging, and immune function. 65,66 A limited number of animal investigations have demonstrated either an absence 67 ,68 or a positive protective effect from exercise training on certain ce11mediated immune functions, including the restoration of age-associated loss of IL-2 production.69 Christ and coworkers 70 demonstrated that a program of modest exercise training in elderly women increa sed resting and postexercise NK responses. In 1993, Nieman and co11eagues71 found that NK function and lymphocyte proliferative response to phytohemagglutinin are significantly higher in highly trained elderly women compared with that in age-matched sedentary control subjects. Immune function correlated with the level of aerobic conditioning as well as body leanness. A modest 12-week cardiorespiratory fitness program failed to alter immune function in the sedentary women. The authors concluded that higher levels of training capable of effecting both fitness and fatness may be necessary before improvements in immune functions can be expected in the elderly. The mechanisms responsible for age-related deterioration in immune function are poorly understood but may include alterations in a variety of systems, including neuroendocrine function and body composition as well as environmental factors, such as nutritional status and physical activity. Does exercise predispose or protect from infectious diseases? A common belief among the general and athletic populations alike is that regular exercise training decreases the risk of acquiring a cold or flu, while

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severe exertion may increase the risk. 49,73,74 For example, in the January 1989 Runner's World survey, 60.7% of 700 subscribers reported that they had fewer colds since beginning to run, whereas only 4.9% claimed that they had more. Some athletes think that although regular training promotes resistance to URTI, the actual competitive event itself increases their risk. 7 There is considerable anecdotal information from coaches and physicians of athletic teams in support of the belief that severe exertion, especially when coupled with mental stress, places athletes at increased risk for URTLll Daniel Hanley, MD, who has assisted in the medical care of US Olympic athletes, reported that respiratory tract infections were the most common medical problems experienced, postulating that overcrowding, fatigue, and jet lag were responsible.74 It has been reported that at the 1994 winter and 1992 Olympic Games, some of the world's best athletes were unable to compete or had subpar performances because of infectious illness. The Centers for Disease Control and Prevention estimates that more than 425 million colds and episodes of influenza occur annually in the United States, resulting in $2.5 billion in lost school and work days, and medical costS.75 The National Center for Health Statistics reports that acute respiratory conditions (primarily the common cold and influenza) have an annual incidence rate of 90 per 100 persons 76 Understanding the relationship between exercise and URTI has potential public health implications, and, for the athlete, may mean the difference between being able to compete or missing the event because of illness. 49

Exercise and upp er respiratory tract infection The relationship between exercise and URTI may be modeled in the form of a J-shaped cu rve 49 ,73 (Fig ure 2). This model suggests that while the risk of URTI may decrease below that of a sedentary individual when engaging in moderate exercise training, risk may rise above average during prolonged periods of high-intensity exercise. Relatively few studies have explored this relationship.28,77 One of the first reviews on this topic was published in 1932, with the reviewer concluding that there was little "evidence to show that muscular fatigue lowers the resistance of man to infectious diseases."78 Although some of the early studies suggested that heavy exertion and fatigue from industrial labor were associated with lowered resistance to infectious diseases , study designs and methodologies were weak at best. Eight selected studies using improved designs and methods have been published since 1983 . Although there have been other published reports on the relationship between exercise or sports par-

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ticipation and URTI, the methods used in these investigations make it difficult to draw conclusions or make comparisons with other studies.74 ,77 Of these studies, six are epidemiologic in design (two prospective and four retrospective ), and only two used a randomized, controlled experimental design.

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Heavy exertion and upper respiratory tract infection Several epidemiologic reports suggest that athletes engaging in marathon-type events or very heavy training (or both) are at Below increased risk of URTJ.79·85 The average first published report was in 1983 by Peters and Bateman,83 Moderate Very high Sedentary who studied the incidence of URTI in 150 South African runAmount and intensity of exercise ners; they compared those participating in a 56-km ultrama- Figure 2. J·shaped curve demonstrating relationship between exercise and risk of upper rathon race with matched respiratory tract infection. This model implies diminished risk with m oderate exercise and controls who did not run. Symp- increased risk with excessive exercise. toms of URTI occurred during the 2 weeks after the race in 33.3% of runners comthe control group (NS). The control group had the pared with 15.3% of control subjects, and were expected seasonal variation, with the peak incidence in winter and relatively few cases in summost common in those runners who achieved the faster race times. Two subsequent studies from mer, whereas the orienteers tended to show a more this group of researchers confirmed this finding. 82,84 even distribution. In their 1993 publication, this group noted that The Run Through Redlands race in Redlands, 68% of runners reported the development of sympCalif, is conducted every March, drawing nearly toms ofURTI within 2 weeks after the 90-km Com1200 runners to its 5-km, 10-km, and 21.1-km events (run the same morning). Nieman and colrades Ultramarathon. 84 The incidence of URTI was greatest among the runners who trained the hardleagues81 studied the incidence of URTI in these est coming into the race (85% versus 45% of the runners during the 2 winter months before the low- or medium-training-status runners). By use race, evaluating the impact of varying levels of of a double-blind, placebo-controlled research design, training. In addition, they studied the effect of the it was detennined that only 33% of runners taking race experience on URTI. In this group of recreational runners, 25% of those running 25 km/wk or a 600-mg vitamin C supplement daily for 3 weeks more (mean, 42 km/wk) reported at least one URTI before the race reported respiratory symptoms. episode during January and February, as opposed The authors suggest that because heavy exertion to 34.3% training less than 25 kmlwk (mean, 12 enhances the production of free oxygen radicals, km/wk) (X 2 2.83, P= .092). During the week after the vitamin C, which has antioxidant properties, may be required in increased quantities. road race, runners did not report an increase in Linde80 studied URTI in a group of 44 elite oriURTI episodes as compared with the week before enteers and 44 nonathletes of the same age, sex, and the race. These findings suggest that running an occupational distribution during a 1-year period. average of 42 kmlwk versus 12 kmlwk is associatThe orienteers had significantly more infectious ed with a slight reduction in URTI incidence, and episodes during the year in comparison to the conracing 5 km to 21.1 km is not related to an increased trol group (2.5 vs 1.7 episodes, respectively). Whererisk of sickness during the ensuing week. Nieman and coworkers85 next researched the incias a third of the control subjects reported no URTI during the year-long study period, such absence dence of URTI in a group of 2311 marathon runners who varied widely in running ability and training of URTI applied to only 10% of the orienteers. The average duration of symptoms in the group of orihabits. For the entire sample, the average runner enteers was 7.9 days compared with 6.4 days in had 7 years of experience, ran 61 km/wk, trained

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5 d/wk, and ran the 1987 Los Angeles Marathon (LAM) in 256 minutes. Using a pilot-tested questionnaire, runners retrospectively self-reported demographic, training, and URTI episode and symptom data for the 2 months (January and February) before and the 1 week immediately after the March 1987 race. An important finding was that 12.9% of LAM participants reported an infectious episode during the week after the race in comparison to only 2.2% (odds ratio 5.9 [CI 1.9-18.8] ) of similarly experienced runners who had applied but did not participate (for reasons other than sickness). Controlling for important demographic and training data by using logistic regression, the researchers determined that the' odds were 6 to 1 in favor of sickness for the LAM participants versus the nonparticipating runners. It is still possible that other variables, such as crowded race conditions-including participants and fansas well as other competition-associated variables, could serve as unaccounted confounders. Forty percent of the runners reported at least one URTI during the 2 winter months before the LAM. Controlling for important confounders, it was determined that runners training more than 96 kmlwk doubled their odds for sickness compared with those training less than 32 kmlwk. Although the lowest odds of sickness were in the less-than2 kmlwk group, the odds ratio did not increase significantly until 96 kmlwk was exceeded. The researchers concluded that runners may have increased risk for URTI during heavy training or after a marathon race event. Heath and associates 79 followed up a cohort of 530 runners who self-reported URTI symptoms daily for 1 year. The average runner in the study was about 40 years old, ran 32 kmlweek, and had 1.2 URTI episodes per year. Controlling for various confounding variables using logistic regression, these investigators found the lowest odds ratio for URTI in those running less than 16 kmlwk. The odds ratio more than doubled for those running more than 27 kmlwk, demonstrating that total running distance for a year is a significant risk factor for URTI among recreational runners, with risk increasing as the running distance lengthens. These epidemiologic studies suggest that heavy acute or chronic exercise is associated with an increased risk ofURTI. The risk appears to be especially high during the 1 or 2 weeks after marathontype race events. Among runners varying widely in training habits, the risk for URTI is slightly elevated for the longest-distance runners, but only when controlling several confounding factors. As Cannon3 emphasized, multiple factors are involved in the complex relationship between pathogens, host defense mechanisms, and exercise, and further research is needed, with special attention to confounders to interpret results correctly.

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Moderate exercise and upper respiratory tract infection What about the common belief that moderate physical activity is beneficial in decreasing risk of URTI and improving immune function? Very few studies have been done in this area, and more research is certainly warranted to investigate this interesting question. At present, there are no published epidemiologic reports that have retrospectively or prospectively compared incidence of URTI in large groups of moderately active and sedentary individuals. Several epidemiologic studies have compared URTI incidence rates among runners training varying distances, but these studies are more useful for determining whether heavy training has a negative effect. 79 ,81,85 Two randomized experimental trials using small numbers of subjects have provided important preliminary data in support of the viewpoint that moderate physical activity may reduce URTI symptoms. In one randomized, controlled study of 36 women (mean age, 35 years), exercise subjects (45 minutes of walking, 5 d/wk) experienced onehalf the days with URTI symptoms during the 15week period compared with that of the sedentary control group (5. I ::±: 1.2 vs 10.8::±: 2.3 days, P = .039).60 In a 1993 study of elderly women, the incidence of the common cold during 12 weeks in the fall was measured to be lowest in highly conditioned subjects who exercised moderately each day for about 1.5 hours (8%). Elderly subjects who walked 40 minutes, 5 times per week, had an incidence of 21 %, as compared with 50% for the sedentary control groUp.71 Effects of exercise on established infectious diseases An important clinical question, apart from whether exercise modifies risk of developing infectious diseases, is the impact of exercise and training on the pathogenesis and natural history of infection once established. This question may be particularly relevant for individuals infected with viral pathogens with long clinical latencies (such as HIV, which frequently affords many years of preserved health during which exercise and training remain viable options). In 1984, Cannon and Kluger 86 reviewed the animal literature on the subject and concluded that moderate exercise training before bacterial infection provided some measure of protection, whereas exhaustive exercise after infection was often detrimental in infection with Mycobacterium tuberculosis, Pasteurella multocida, and Salmonella typhimurium. The effect of exercise in viral infections in animals has shown similar patterns, demonstrating the deleterious effects of exhaustive exer-

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cise in certain diseases. Perhaps the best studied model exploring this relationship is that of murine coxsackievirus B myocarditis. 87.91 The seminal studies of Lerner and Wilson92 demonstrated that forced exercise after inoculation increased viral load, myocyte necrosis, and lethality. More recent investigations have demonstrated the importance of immune mechanisms in the mediation of tissue damage.93 Limited data in humans reveal sudden death in a small percentage of athletes and physically active individuals linked to myocarditis, suggesting at least circumstantially an adverse effect of exercise on the course of certain infections. 94.98 The relative frequency of myocarditis as a cause of sudden death in this group is unknown, but, in one series, it was 12%.99 The reported frequency of febrile states preceding sudden death related to exercise of 10% in one series further suggests an adverse effect of physical activity on certain infectious processes. lOO Infectious agents that have been identified in such circumstances include coxsackievirus BIOI and Chlamydia pneumoniae. I 02 The hypothesis that physical activity during acute viral illness can at times lead to severe clinical sequelae is supported by numerous anecdotal reports. I03,104 A study by Montague and associates l05 of cardiac function, using echocardiography and recording of body surface potential mapping in patients during acute flulike illnesses, revealed frequent subtle and clinically benign cardiac abnormalities compared with healthy controls. These authors concluded that viral illness may at times serve as a substrate or a trigger factor for clinically important cardiac disease. Unfortunately, it is difficult to extrapolate from these data any quantification of cardiac risk for physically active individuals with clinical signs and symptoms of acute viral illness. Experimental studies in animals and limited observations in man have also suggested that increased physical activity adversely affects infection with poliomyelitis by predisposing toward more extensive and severe paralysis.I06-108 Despite the rare reports of the adverse effect of strenuous exercise and the tradition of bed rest for acute viral hepatitis,I09 there are substantial data supporting the safety of modest amounts of physical activity and exercise training in the convalescent phase of the disease.llo Several studies of military recruits allowed physical activity in the form of camp work have documented the short- and longterm safety of physical activity during recovery from hepatitis.l 1l-1l3 More recently, several studies using modern training principles found no adverse effects on the biochemical or histologic recovery from acute hepatitis.l14,1l5 A similar tradition of rest therapy for acute infectious mononucleosis also appears unfounded, on the basis oflim-

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ited data comparing bed rest to ad libitum activity.lll For athletes recovering from acute EpsteinBarr virus infection, return to training is limited solely by symptoms, particularly fatigue , and the risk of splenic rupture. Some have suggested a minimum of 4 weeks as a rough guideline to return to athletic activity. Others have suggested that imaging the spleen can assist in guiding athletes' return to contact-and-collision sports.l17 Finally, given the influence of exercise and training on the immune system, it would appear clinically important that this interaction may influence the natural history of infection with HIV. Anecdotal testimonies by some long-term survivors have emphasized the importance of exercise as well as other factors in their longevity.l18 Given the hypothesis that modest exercise may enhance certain aspects of immune responsiveness, there is at least the potential for benefit in patients with HIV infection. Several late 1980 and early 1990 studies demonstrated the safety and physiologic benefit of exercise and training in HIV-infected individuals with a wide spectrum of symptoms ranging from asymptomatic to advanced disease .1l9-123 In one of the most detailed of these studies, Rigsby and his as sociates l23 reported on the physiologic and immunologic effects of a combined aerobic, strength, and flexibility program in a cohort of patients with a spectrum of HIV illness. Improvement was noted in cardiorespiratory fitness and strength, and no adverse effects were found during this 20-week investigation. Immunologic parameters, including CD4 cell count, were unchanged. An important series of investigations by LaPerriere and colleaguesl24-126 beginning in 1986 have addressed the questions of whether exercise training can attenuate both psychologic stress and immunologic deterioration and ultimately slow disease progression in HIV-infected subjects.l24-126 In a carefully designed trial of moderate-exercise training in a cohort of healthy homosexual men at high risk for HIV infection, subjects were randomly assigned to exercise training or a contact-control limb. Mter 5 weeks of aerobic fitness training, subjects were tested for HIV and given their results. Mter receiving the news of a positive test, those in the control group had dramatic increases in levels of psy. chic stress and decreases in their NK cells. Those in the exercise arm of the study h ad no increase in psychic stress and no decrease in NK cells. After 10 weeks of training, both seropositive and seronegative exercising groups demonstrated modest rises in CD4 cell counts. Thus, it appears that exercise training may provide some "buffer ing" capacity against acute psychic stress and its immunologic sequelae. Long-term investigations are now under way to determine whether these exercise-induced

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changes are capable of slowing the onset and advancement of HN-related symptoms and complications . These investigators proposed a psychoneuroimmunologic model whereby exercise can improve the psychologic and immunologic sequelae of certain chronic diseases. 126 A conservative interpretation of these preliminary data suggests that moderate exercise training is safe and may be a useful lifestyle modification in the management of HIV disease. A common question asked by exercising patients is whether it is safe to exercise with symptoms of common infections, particularly those afflicting the upper or lower respiratory tract (or both). Aside from the aforecited studies describing the rare occurrence of sudden death secondary to infectious myocarditis, there are little data on which to base strong recommendations. However, a large practical experience generated by physicians with long interest and experience in such issues has been published in both medica1l27-I3I and consumer publications I32 that, although not directly supported, is clearly not refuted by available data. In the presence of upper respiratory tract symptoms unaccompanied by significant fever, myalgia, or lower respiratory tract symptoms, moderate amounts of exercise-if well-tolerated-would appear safe; exhaustive exercise should be avoided in these situations. Alternatively, in the presence of significant fever, myalgia, or lower respiratory tract symptoms, even moderate exercise may carry some increased risk of disease progression or development of an infectious myocarditis, suggesting that relative rest until the acute symptoms subside may be prudent. Effects of infection on athletic performance Anecdotes of reduced athletic performance secondary to viral illness are familiar to physicians involved in sports medicine.124-I26 Alternatively, reports of heroic performances by athletes afflicted with illness or injury abound as well. 123 Whether infection with common viral pathogens impedes athletic performance is unknown, but it is well established that various measures of physical and mental performance are reduced during certain infectious diseases.130-I32 GrimbyI33 demonstrated that patients with pyrogen-induced fever were unable to perform prolonged exercise, particularly during the "chill" phase. Friman and colleaguesl 34,135 found decreased muscular strength in patients hospitalized for acute viral or mycoplasmal infections. In a controlled investigation of the effects of viral infection on human performance, Daniels and colleagues I36 experimentally infected nine subjects with sandfly fever virus, which causes a self-limiting syndrome characterized by fever, photophobia, arthralgia, and myalgia. Their findings demon-

strated diminished isometric strength and reduced ability or willingness (or both) to perform exercise at gradually increasing intensity. Comment Evidence exists that regular exercise during leisure time offers some protection from death from any cause. 137 Yet, apart from known benefits on coronary artery disease, weight control, and functional work capacity, little evidence exists demonstrating biologically significant enhancement of other systems, including the immune system. Current epidemiologic findings suggest that heavy exertion is associated with an increased risk of respiratory tract infections but that moderate activity may lower such risk. The biologic basis for these findings has not been proved. Although considerable data on the adaptation of the immune response to exercise and training have been reported during the past decade, it would be unwise to draw strong conclusions regarding the biologic significance of these changes . Acute exercise is capable of reproducibly perturbing numerous phases of the immune response, but these changes are of relatively small magnitude and of brief duration. Training may be capable of altering some in vitro parameters of the resting immune response , but such changes are of uncertain clinical significance. Despite such limitations, physicians are routinely asked to discuss and advise their patients on the health risks and benefits of exercise and training. A growing segment of the population has been inundated with such information from nonscientific sources. Accordingly, it is reasonable for physicians-even in the absence of conclusive scientific data-to be knowledgeable on current developments in such areas (that is, exercise and immunity) and offer counsel on the basis of current information. References 1. Astrand P : 'Why exercise?' Med S ci Sports Exerc 1992;24:153162. 2. Keast D, Cameron K, Morton AR: Exercise and the immune respon se. Sports Med 1988;5:248-267 . 3. Ca nnon JG: Exerci se and resist ance t o infec tion. J Appl Physiol 1993;74:973-98 l. 4. Peder son BK: Influence of physical activity on the cellular immune sys t em: Mecha nis m s of action . I nt J S po rts M ed 1991;12:23-29. 5. Nieman DC: Exer cise, upper respiratory tract infection and the immune system. Med S ci Sports Exerc 1994;26:586-592. 6. Shepard RJ, Verde TJ, Thom as SG, Shek P : Physical activity and the immune system . Can J Sports S ci 1991;16:169-185 . 7. Nieman DC, Berk LS, Simpson-Westerberg M, et al: Effect oflong endurance r unning on immune system parameter s and lymphocyte function in experienced mara thoners. Int J Sports Med 1989;10:317- 323. 8. Gabriel H , Urhausen A, Kinderman W: Circulating leuco-

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