Bruiih Mtdual BulUlm (1992) VoL 48. No. 3, pp. 518-533 © The Brituh Coundl 1992

Sport and the overtraining syndrome: Immunological aspects N C C Sharp British Olympic Medical Centre, Northtuick Park Hospital, Harrow, UK

Y Koutedakis School of Health Sciences Wolverhampton Polytechnic, UK

Acute exercise of varying severity and corresponding levels of long term competition and training have been found to affect various components of the immune system including lymphocyte subsets, immunoglobulin levels, the mononuclear phagocytic system, polymorphonuclear leukocytes and cytokines, especially IL-1, IL-2, IL-6 and TNF. A tentative trend may be discerned whereby light to moderate exercise may increase immune responsiveness but high-level competition sport, especially if it involves extensive endurance training, may lead to a degree of immunosuppression. Such immune malfunction may be a component of the overtraining syndrome, in which recurrent infections during periods of maximum training or competition stress may form part of the syndrome. Evidence is presented that such overworked muscle may fail to supply adequate glutamine for normal lymphocyte function. Principles of an overtraining treatment strategy are suggested.

For 14 years the senior author worked within the field of immunology,1""3 but since 1971 his work has been entirely in sports physiology. Originally the two disciplines seemed to have very little in common, but now there are extensive reviews on exercise and immunity,4"8 as well as work linking muscle metabolism and the immune system,9 and overtraining and the immune system.10 The topic of overtraining is also the subject of an increasing review literature.11"13

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THE IMMUNE SYSTEM A brief reminder of the immune system may be useful. It probably originated with the formation of the metazoa from single-celled life-forms in order to keep cell clusters together as organisms became more complex. The basic binding and recognition molecules were copied in an array of different forms within the Ig superfamily, which now serves three main functions: antigen recognition, e.g. IgM; cell function regulation, e.g. CD4 and CD8 molecules as markers for helper and suppressor T-lymphocytes respectively; and CNS structuring, e.g. the neurone organiser contactin. Cells of the immune system originate from a multipotential stem cell, which develops either through the thymus to form T-lymphocytes, or through bone marrow as B-lymphocytes. In human peripheral blood, T-cells account for some 75% and B-cells approximately 10% of mononuclear leukocytes. T-cells provide a cell-mediated response to micro-organisms and parasites, together with delayed hypersensitivity reactions. They also form helper, cytotoxic and suppressor subsets, are important in immunological surveillance, and secrete a number of regulatory proteins within the class of the cytokines. B-lymphocytes can be triggered to differentiate into plasma cells, which produce the five Ig subclasses. Immunoglobulin provides defence against micro-organisms and parasites and may assist the 15% of 'null' or 'non-T non-B' mononuclear cells, almost all of which are lymphocytes. If appropriate antibody is present, null cells may serve a direct cytotoxic function, inducing cell membrane lysis via perforins, or pore-forming proteins. Antibody may also activate the complement system, the 20protein cascade which may augment the effects of antigenantibody combination and produce cellular lysis through the membrane-attack-pathway, as well as attracting and activating neutrophils, and mediating mast cell degranulation. The non-phagocytic null cells, together with the non-T natural killer (NK) cells and large-granule lymphocytes are all part of a cell killing population. Much of this killing may be activated by cytokines, and may be of particular importance against neoplasia.16 The mononuclear phagocytic system, including tissue macrophages, monocytes, Kupffer cells and osteoclasts, not only scavenges but also presents antigen to T-cells, thus initiating immune responses. It also secretes, and reacts to, cytokines, and produces prostaglandins.

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IMMUNE RESPONSES TO EXERCISE AND TRAINING Lymphocytes A mild lymphocytosis occurs during and after bouts of acute exercise. 17~19 However, the T-suppressor population has been found 20 to be very resistant to change on exercise either of high intensity (75% of VO2 max) or of long duration (120 minutes) and the Ts response was not related to levels of aerobic fitness, whether low (i.e. mean VOj max of 44.9 ml O2/kg/min), moderate (mean VOl max of 55.2 ml O2/kg/min) or reasonably high (mean V02 max of 63.3 ml O2/kg/min in male subjects. It was also found that the percentages of T-4 helper lymphocytes were reduced immediately after the exercise, with the highest intensity of exercise (75% of VOj max for 60 min) producing the largest Th drop, closely followed by the group who worked longer at the lower intensity (65% VOl max for 75 min). The lowest intensity exercise (30% VOj max for 60 min) resulted in some reduction in Th lymphocytes, but not as markedly or consistently as in the higher work sessions. Finally, marked rises in the percentages of NK cells were noted, with the greatest increases occurring at the highest work intensity. These results were independent of the fitness levels of the subjects. No clinical histories of the 3 fitness groups were recorded, so disease incidences could not be matched. Resting lymphocyte counts have been found to be low (< 1500/mm3) in marathon runners, especially in those faster than 2 h 25 min.21 Apart from numbers, a vital attribute of lymphocytes is their degree of responsiveness, for example to the mitogen concanavalin A as studied by the incorporation of radiolabelled thymidine. By this technique, a consistent depression in mitogenesis was found22 2 h post-exercise in 3 groups with a trend towards greater reduction on highest exercise intensity in the fittest group. The subjects used were of the same fitness levels as above,20 and were exercised by the same 4 randomly ordered cycle ergometer tests (30 min at 65% of VO2 max; 60 min at 30%; 60 min at 75% and 120 min at 65%). Exercise duration did not affect the degree of reduction in mitogenesis, and all values had returned to preexercise baselines by 24 hours. Interestingly, the group with the lowest level of fitness showed the lowest pre-exercise lymphocyte proliferation rate, but their T-cell response was not as severely depressed by the high-intensity exercise as the other 2 fitter groups.

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In the above studies it is noteworthy that, although lymphocyte subset numbers have returned to normal by 2 h after exercise, lymphocyte function, as assessed by mitogenesis, may then be at its lowest level. Lymphocyte function in vitro has also been found to be markedly reduced in elite runners after a fast marathon,23 whereas lymphocytes from moderate but not elite runners in the same study showed no reduction in responsiveness after a training run. Similarly, depressions of from 30% to 70% in lymphocyte responsiveness to concanavalin A have been found2* in 7 moderate marathon runners sampled between 4 and 6 min after the race finish, with results similar to those of Sky lab and Space-Shuttle astronauts, who showed comparable depressions of responsiveness. The investigators believed that cortisol may have been responsible for such depression in lymphocyte function of the runners, as 6 of them had immediate post-race plasma cortisol levels of 1000 to 1250 nmol/l, compared to their pre-race levels of from 276 to 690 nmol/l. However, the effect of cortisol on lymphocyte function may depend on its local concentration, as it has been indicated25 that small increases locally may act as an immune stimulant, rather than a depressant. Nearly 50 years ago there was demonstrated26 a reduction in the growth of transplanted tumours in vigorously exercised rats, compared to controls, and now there is a growing body of data 67 to suggest that exercise may lessen the risk of some neoplasms, especially mammary and colon carcinomata, mainly for reasons unconnected with immunity. Nevertheless, it is quite possible that exercise-associated increases in NK cells may contribute to this resistance, as they are part of the effector series against neoplastic cells. It has been stated, for example that, apart from numerous other factors; 'The potential for physical activity to influence the immune response and possibly enhance tumour surveillance is an hypothesis that deserves serious consideration.'6 Complement and Immunoglobulin Levels of IgG, IgA and IgM, and the complement factors C3 and C4 were compared between 11 marathon runners and sedentary controls before, during and after a maximal treadmill test.27 The complement factors, but not the immunoglobulins, were significantly lower throughout in the marathon runners, before, during and after the test (from 11 blood samples from indwelling cath-

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eters), suggesting that complement depression may also follow long term endurance exercise. However, within the running group, no significant correlations were found between training mileage, body fat percentage, or the level of competition performance, and resting C3 and C4 levels. The runners were only of moderate standard, as indicated by a group mean VOj max of 54.2 ml O2/ kg/min and a mean body fat percentage of 12.5% (specified skinfold regression formula).26 IgA and IgG have been reported to be significantly increased, by 11.8% and 14.4% respectively, following maximal exercise in 28 Olympic competitors, i.e. more than could be accounted for by a decreasing plasma volume,29 while a significant 7% increase in IgG has been found following a 100 km run, despite no change in plasma volume.27 Resting levels of salivary IgA have been found to be depressed in elite cross-country skiers, with further depressions after racing.30 IgG levels in the latter were unaffected, although low resting levels of IgG have been found in elite distance runners5 possibly due to a cumulative effect of repeated training and racing as they were end-of-season findings. Cytokines A number of regulatory proteins, synthesized and secreted by lymphocytes and other cells, have a role in orchestrating immune activity, under the generic name of cytokines. Their 4 main groups comprise; at least 10 interleukins (IL1-10); tumour necrosis factors (TNF); 3 interferons; and colony stimulating factors. Probably all cytokines have multiple biological activities. Collectively, they stimulate T and B lymphocytes, e.g. IL-1 enhances T-cell activation; IL-2 stimulates cytotoxic T-cells and NK cells; and IL-6 contributes to the differentiation of B-cells into plasma cells. Cytokines also promote haemopoiesis, and contribute to the inflammatory process including the stimulation of fibroblasts while, more specifically, interferons and TNF may inhibit cellular replication. Cytokines tend to function in networks and cascades and, although they may show only a modest rise in blood levels, this may indicate much higher local concentrations in the cellular milieu. Eleven elite road cyclists (mean VOj max 76 ml O2/kg/min) were studied31 after a bout of maximum exercise, and in vitro IL-1 production was found to rise from 27.4 units/ml before exercise to 48.7 units/ml during and to 57.2 units/ml 2 h after stopping the work. IL-2 production, however, fell from a resting 68.9 units/ml

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to 49.6 units/ml during the exercise, and to 41.4 units/ml 2 h after. On the other hand, NK activity increased by 100% in the same subjects. By contrast, in 11 runners (mean VO2 max 72 ml O2/kg/ min) after a moderate 5000 m run, it was found that IL-2 levels were significantly decreased immediately after the run, compared to resting values. Rest levels were restored 2 h later and they were significantly increased 24 h after. TNF values in plasma were significantly elevated 2 h after, but nearly normal at 24 h. In both these runners and cyclists the T-helper/T-suppressor ratio dropped immediately post-exercise, but increased above rest values 2 h later, dropping back to normal at 24 h. Interestingly, the Th/Ts ratio at rest was higher in the competitors than their matched controls at 1.7 compared to 1.4. The former may be a critical ratio at which susceptibility to infection may increase due to a lowering of appropriate lymphocyte response.33 The increase in IL-2 has been explained32 by the increase in numbers of HLA-DR or 'activated' lymphocytes, which are known to express an increased number of IL-2 receptors. Possibly, muscle micro-trauma with resulting micro-foci of inflammation and cytokine release may explain the higher IL-2 levels found 24 h after exercise. IL-2 receptor concentration was found to be significantly raised 24 and 48 h after a 2.5 h race in moderate runners in a study34 which also showed an increase in plasma elastase-alpha-1-antitrypsin complex to twice resting values after 1 h of the run, with a threefold increase at the end. This rise in elastase is indicative of lysosomal enzyme release from polymorphonuclear leukocytes, suggesting an exercise-induced proteolysis in muscle. IL-6 levels, in a study on 16 marathon runners,35 showed a significant systemic increase 2 h after a race, with a return to normal by 24 h. Most authors working on cytokines and exercise remark on the striking similarities between the response to strenuous acute exercise and the acute inflammatory response to infection, including marked leukocytosis, moderate fever and an increase in cytokines influencing leukocyte function. Polymorphonuclear leukocytes Although not strictly part of the immune system, this cell type is included because of close links with it, especially the acute inflammatory response and the defence against pyogenic and other

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bacterial infections. Regular moderate exercise (e.g. 1 h at 60% VO2 max) has been shown36 to increase non-specific resistance to infection by priming the 'killing capacity' of neutrophils to produce hydrogen peroxide, for example. Such priming may last for up to 6 h after exercise. However, prolonged periods of intensive training may curtail this activity by up to 50% , 36 Similarly, macrophage chemotactic and phagocytic activities have been shown37'38 to increase after a bout of strenuous exercise, but to be diminished by long-term endurance training. Finally, it has been shown39 in cyclists, studied longitudinally, that the resting neutrophil count was significantly lower after 5 months of intensive training, than before. EFFECTS OF TRAINING AND SPORT ON CLINICAL ASPECTS OF IMMUNITY There is little doubt that frequent moderately strenuous aerobic exercise is beneficial to health, especially regarding cardiovascular pathology as shown by major studies. 4041 However, there is a general feeling among team doctors, coaches and competitors that more severe competition and training schedules render athletes more liable to illness and infection, on a spectrum the upper end of which may encompass the overtraining syndrome. There is also an increasing necessity for the elite competitor to become a virtually full-time sportsperson. For example, in gymnastics about 35 h of training per week are required to challenge seriously for a place in an individual apparatus final at Olympic or world championship level. Swimmers spend 2-4 h daily in the water, and canoeists, cyclists, distance runners and cross-country skiers more than that on the water, road, track or trail. Squash, badminton and tennis players may play and practise for 5 h daily most days per week, and triathletes, pentathletes, heptathletes and decathletes may spend even longer. Yet there exist very few clinical data charting disease prevalence in such competitors. Clinical data Outbreaks of mainly viral disease have been reported in sporting groups, usually in educational institutions. Some workers suggest an increased susceptibility to infection among competitors, others indicate that training or competing within the incubation period may exacerbate the illness.

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An outbreak of poliomyelitis was reported42 in a school at which, through religious conviction, there was a non-vaccination policy. All nine boys who contracted the disease suffered paralysis, attributed to the fact that they were active sportsmen. Exercise during incubation is known to worsen polio, and paresis tends to affect muscles specific to the exercise. An outbreak of infectious hepatitis was reported43 which affected 90 out of 97 college footballers, during which no other students or staff became ill, and an outbreak of echoviral meningitis occurred44 in which 43 of 61 footballers were affected, while non team members suffered half the morbidity and less severe symptoms. Gastro-intestinal infections, respiratory disease and skin conditions seem more frequent in sports competitors45 while the common occurrence of tracheitis and tracheobronchitis in American Olympic distance runners, rowers and speed skaters has been noted,46 with speculation however that the combination of cold air and high ventilation rates might have been more important in aetiology than alterations in immune status. Nevertheless, a more recent report47 specifies an increased incidence of disease in elite competitors which 'may have to do with an impairment of the body immune response caused by physical exercise'. At high levels of competition, especially associated with high expectations of success, the contribution of psychological stress may be added to any effect of exercise stress on the immune system. Many studies have implied that various forms of psychological stress, including life stress, bereavement and examination stress, affect immune function.*8 High-level competition stress would seem likely to produce similar effects, although the modern elite competitor receives ever-increasing help from good sports psychologists. The author49 of a comprehensive review of viral illness and sports performance specifically indicates that 'recent evidence has shown that people undergoing severe mental or physical stress may have reduced immunity to viral infections'. THE IMMUNE SYSTEM AND THE OVERTRAINING SYNDROME The British Olympic Medical Centre, (BOMC)12 defines the overtraining syndrome as prolonged fatigue and underperformance, following a period of heavy training or competition, lasting at least 2 weeks and possibly much longer, and confirmed by physiological

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monitoring on appropriate ergometry, or by comparing training times or results in previous competition. A primary medical cause must be excluded, but recurrent infections during periods of maximum training or competition stress may be part of the syndrome, possibly indicating that the stress has initiated immune dysfunction, and increased vulnerability to infection. Based on empirical, scientific and medical evidence there would seem to be 2 forms of the syndrome,14 'monotonous programme overtraining' and 'chronic overwork overtraining'. The first may, for example, occur in weightlifters, and could be a central nervous adaptation to repetitious movement routines; the second arises from overwork which lasts too long or is repeated too frequently,14 or from too much competition as may occur in track and road running, football, rugby, squash and tennis when competitors are faced with overcrowded fixture lists. Various combinations of physical signs may be present,12 including raised morning pulse, increased postural hypotension, decreased maximal power output, diarrhoea, upper respiratory tract infections, lymphadenopathy and delay in minor wound healing. Evidence is increasing to suggest that immunosuppression forms at least a component of the overtraining syndrome of the 'chronic overwork' type.50 Also, Newsholme, Parry-Billings and other members of the Cellular Nutrition Group at the University of Oxford are providing an increasing rationale for its pathogenesis, partly in conjunction with ourselves at the British Olympic Medical Centre.10-13-15 A summary of this rationale is as follows. Lymphoid tissue utilizes glutamine at rates similar to those at which glucose is used by skeletal or cardiac muscle, and as there is over 1.0 kg of human lymphoid tissue, this creates a very high requirement for glutamine. The glutamine is used both as a fuel, supplying approximately 35% of the energy, and more relevantly it has a vital role in biosynthetic regulation in lymphoid cells. Thus glutamine may be said to act both as a lymphoid substrate and as a lymphoid stimulator.10 The main source of plasma glutamine is skeletal muscle, as most dietary glutamine is utilized by the highly metabolically active intestinal epithelium. In vitro, lowered concentrations of glutamine adversely affect lymphocyte proliferation and macrophage function, even in the presence of alternative fuels.51-52 Plasma glutamine has been found10 to be chronically depressed in overtrained competitors, with levels of 503 ± 12 uM in 40 overtrained subjects compared to 550 ± 14 uM in 36 matched controls

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Sport and the overtraining syndrome: immunological aspects.

Acute exercise of varying severity and corresponding levels of long term competition and training have been found to affect various components of the ...
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