Immunology Today, Vol. 9, No. 11, 1988

vivre remains so vivid; yet.he is no longer here to passionately discuss, criticize, joke and share his vision with us. As much as any human geneticistlimmunologist, he has left us a living inheritance. He has joined that very exclusive club of the great teachers of medicine described by Lord Moynihan.

So it has often been in medicine. The great teacher leaves behind

him the written word or the mem- ory of the spoken word. Those who have learned from a great master must surely not be content to imitate his methods, but rather they must strive to capture his authentic spirit and in that spirit to seek for new ,-'--~'~,~ and so to discover still further truths.

Through his insistence on excellence, his clarity of thought, and most of all

his extravagantly productive imagin- ation, Ceppellini leaves a rich inheritance - a vibrant and living spirit. For all that, Ruggero, we say arriverderci with fondness and gratitude.

F.H. Bach is in the Universiiy of ?viinnesota, Irnmunobioiuyy ~e~arch Ce~r, D~#a~tllen~ of Laboratory Medicine and Pathology, Medi- cal School, Minneapolis, MN 55455, USA.

Exercise and the immune system The recent Olympic Games in Seoul featured most of the world's best athletes. To compete at this level, athletes have to adhere to intensive training schedules, and in this article, Lynn Fitzgerald discusses how such rigorous training induces an immunodeficiency state in some athletes, resulting in an

increased susceptibility to infection.

At the recent Olympic Games, some of the world's best athletes were unable to compete due to illness or injury through overtraining: for example, the respiratory infec- tion that struck UK Olympic gold medallist Sebastian Coe during the UK Olympic trials in August so affected his running that he failed even to qualify for the team to go to Seoul. The immune system may be a limiting factor in human performance. While some individuals can with- stand rigorous training and competition schedules with- out missing a day, others are very susceptible to colds and infections. A robust immune system will allow an athlete to stay free of infection in the same way that a robust physique will allow him to remain free of injury.

Overtraining is blamed by top athletes and their coaches for the illnesses that afflict them with increasing frequency as the competitive season progresses. These illnesses range from frequent persistent colds, sore throats and flu-like illnesses to severely debilitating states resembling post-viral fatigue syndrome, which can cause the athlete to miss an entire season, or even force him to give up competitive sport completely. Athletes are often reported to be suffering from glandular fever, but this is a convenient term to fit vague clinical symptoms, and only rarely is the diagnosis of infectious mononucleosis confirmed. For example, Sebastian Coe's so-called glandular fever was eventually diagnosed as a Toxoplas- ma infection some five years ago. Earlier this year the UK 800 metre runner Diane Edwards was also diagnosed as having toxoplasmosis. The incidence of opportunistic and other infections among top athletes raises the question: can too much exercise have a damaging effect on the immune system?

Although moderate excercise appears to stimulate the immune system, there is good evidence that intense exercise can cause immune deficiency. We still do not really know why.

Department of Medicine One, St George's Hospital Medical School, London SW17 ORE, UK. ~) 1988, Elsevier Science Publishers Lid, UK 0167 4919/88/50200

Lynn Fitzgerald Moderate exercise boosts the immune system

Many recreational runners claim a state of physical well-being in which they are less susceptible to respir- atory infections; consequently, some studies have set out to examine the possibility that regular exercise augments some aspect of host immunity 1.

None of the research in man has monitored immune function before and after a regular exercise programme, but two such studies in laboratory mice show clear evidence of immune enhancement. But laboratory mice are chronically under-exercised compared with wild mice; perhaps being unfit impairs the immune system and the moderate exercise schedules boosted their im- mune responses. If human volunteers who take little or no regular exercise were monitored during an exercise programme, there might also be evidence of immune enhancement.

Liu and Wang in Nanning, China, found increased antibody responses in exercising mice compared with controls 2. BALB/c mice were divided into two groups and kept in identical conditions except that half were trained to run on a rolling drum for ten minutes twice daily. After 23 days all the mice received two injections, ten days apart, of Salmonella typhi. Antibody levels in serum samples at two week intervals from 1-13 weeks later were all significantly higher in exercising mice than in sedentary controls, with a mean titre 2.7 times that of controls. Liu and Wang conclude that long-term running can significantly enhance humoral immunity.

An earlier study by Good and Fernandes also demon- strated enhanced immunity in exercising mice 3. Mice were trained to run daily on a treadmill to avoid mild electric shock. One control group was subjected to the shock w~thout exercise and the other controls were not subjected to shock or exercise. The exercised mice had an increased plaque-forming cell response to sheep red blood cells, and showed a significant delay in tumour growth following immunization with syngeneic turnour cells.

Epidemiological studies of illness in athletes Several studies indicate that intense training increases

susceptibility to illness. Some of the reports of infectious 337

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disease outbreaks among athletes emphasize their in- creased susceptibility to infection, while otl~ers show that exercise during the incubation period may worsen the disease.

In an outbreak of polio at a Connecticut school in which none of the pupils or staff had been vaccinated, all nine boys who contracted the disease were actively partici_nating i:. ~-:.;cr, uo~ is ~lJur i.~ ~. 'il ,,w, AJ,,~, IL.oJ, coii~y~ outbreak of infectious hepatitis, 90 out of 97 members of the football team were affected, whereas no other students or staff became ill s . Furthermore, in an out- break of aseptic meningitis in a US high school the incidence of illness was twice as high and symptoms were more severe among members of the football team than other students 6.

Top runners are more than usually susceptible to upper respiratory tract infections. Of 150 runners questioned about respiratory symptoms after a 56 km ultra-marathon race, symptoms were most common in those who achieved the fastest race times, and who as a group had the highest weekly training mileagesL

Exercising during the incubation period of polio substantially worsens the disease 8. Similar findings have been reported in experimental animals. Monkeys exer- cised during the incubation of poliomyelitis had a higher incidence of more severe paralysis than controls 9. In mice infected with Coxsackie B virus, enforced swimming increased mortality from 5% to 50%, and virus repli- cation in the heart was markedly augmented lo.

Transient effects of intense exercise Most of the research on the effect of exercise on the

immune system has measured changes following a single exercise session. Dramatic changes in the numbers and functional capacities of lymphocytes have been observed after exhausting exercise. These effect~ may reflect a transient suppression of cell-mediated immunity suf- fici~nttn allnw rnirrnnrn~nicnnc n.~rfiriil:lrhnlnlriic,'.c "l-lrt'~ to-evad-e-e-arlyimmunologTcal "recognition" and:' {'i~'us establish infection in the athlete.

Exercising to exhaustion results in a temporary reduc- tion in the in-vi t ro response to T- and B-cell mitogens, a reduction in the CD4:CD8 ratio 11, and changes in natu- ral killer (NK) cell activity. These data come from testing after a single bGut of maximal exercise in healthy un- trained volunteers and in sportsmen. Maximal exercise overcomes the problem of any differences in training and fitness levels, since each subject exercises to his own limit. When trained and untrained volunteers exercised to exhaustion, no significant differences in the effects on lymphocytes were observed between the groups. Maximal NK cell activity seen immediately after exercise dropped to a minimum two hours later and did not return to pre-exercise levels for 20 hours 12. CD4 ÷ cell numbers were reduced, but the numbers of CD8 ÷ or NK cells did not change. In another study of maximal exercise in which seven athletes and five non-athletes exercised to exhaustion on a treadmill 13, the percentage of helper T cells and the helper/suppressor ratio were reduced in both groups 15 minutes after exercising was stopped.

In-vitro lymphocyte function was dramatically reduced in elite Finnish marathon runners after a fast marathon 14. The runners' lymphocytes were markedly less responsive to stimulation by phytohaemagglutinin (PHA), concan-

avalin A (Con A) and purified protein derivative (PPD) when sampled at 30 minutes and at three hours after the race In contrast, lymphocytes from trained but not elite lunners tested in the same study after a training run showed no reduction in responsiveness. The depression in responsiveness correlated with increased cortisol levels in the marathon runners, and was equivalent to reduc- {iOi-i~ seeii a[{ei ....... ,i idx.'l~iai' e^haus{ir'.~ ....... ; . . . . . . . . . +;~,,. &7.1%,t~11.I..l~.., ~l.dit,~:~i~,,,ilill I ~

that the elite runners pushed themselves to exhaustion in the race, whereas the exercising control subjects did not.

Immune deficiency in elite athletes Studies on elite endurance athletes suggest that reg-

ular intense training can have longer-term damaging effects on the immune system.

Members of the US National cross country ski team were found to have significantly lower resting salivary IgA levels than control subjects, and these decreased further after a 50 kilometre race (2-3 hours of exhaustive exercise) 15. To determine whether this decrease in IgA levels might be due to the exercise itself, or might be due to the effects of cold, to the stress of competition, or to a combination of factors, Tomasi and his colleagues con- ducted a study of competitive cyclists 16. No differences were found between resting salivary IgA levels in cyclists and controls. However a 70% decrease in salivary IgA levels was observed immediately after intense endurance exercise. This was not due to the effects of cold, nor to the stress of competition, since they cycled for two hours in the laboratory, in a controlled temperature and a non-competitive setting. There was also a significant reduction in NK cell activity. The reduction in IgA and NK cell activity was transitory, returning to pre-exercise levels 24 hours after this single bout of severe exercise. The authors conclude that prolonged intense exercise alters parameters of mucosal and natural immunity, and suggest that severe exercise may itself be a form of stress

changes occurred in the absence of cold or competition. The authors comment that th~ suppressive effects of intense exercise may be cumulative, which would explain the low resting IgA levels in their study of skiers who were tested at the end of the competitive season, yet normal levels in the cyclists tested earlier in the season. Low resting serum IgG levels in elite ultra-distance runners tested at the end of the season have also been found (Lynn Fitzgerald, unpublished).

Other defects noted in marathon runners at rest include low total lymphocyte counts (less than 1500 per cubic mm) particularly in those with marathon times of less than 2 hours 25 minutes 1.

Non-specific immunity is also suppressed by regular intense exercise. Twenty conditior,ed competitive cyclists and 19 untrained control subjects exercised to exhaus- tion in the laboratory and even at rest, neutrophil adherence was lower in sportsmen than in controls, and maximal exercise revealed further differences between the two groups 17. Adherence of neutrophils and mono- cytes, and neutrophil bactericidal activity, all decreased significantly in the sportsmen following exercise, but did not change significantly in untrained men. Neutrophil phagocytic activity did not change in the sportsmen following exercise, but was significantly increased in untrained men. The authors conclude that long-term physical exercise depresses non-specific immunity,

Immunology Today, Vol. 9, No. 11, 1988

possibly rendering sportsmen more susceptible to infec- tions.

Further evidence of immune suppression comes from Petrova and co-workers in Moscow ~8. They reported a comparative study of 91 sportsmen undertaking physical exercise of different intensities and 30 healthy adults not active in sport. They found a decrease in the functional activity of neutrophils in response to increasing physical strain which coincided with a drop in the levels of normal serum and secretory antibodies, immunoglobulins and lysozyme in the sportsmen.

The studies on elite sportsmen have, therefore, all revealed some immune abnormalities in the resting state, any or all of which could account for the increased susceptibility to infection seen among these athletes. No studies have specifically tested elite athletes before and after specific training schedules, even though it is those who push themselves to the limits necessary to compete at top level who are most at risk of exercise-induced immune suppression.

Possible mechanisms A variety of hormones and chemicals are released

during exercise. Cortisol and catecholamines are known to cause redistribution of lymphocytes and both are generally immunosuppressive. Less is known about the effects of neuropeptides on lymphocytes. Plasma levels of interferon alpha, interleukin 1 (IL-1), [3 endorphin and met-enkephalin all increase during exercise. The mechanisms responsible for exercise-induced enhance- ment and suppression may involve one or more of these.

Intense training inevitably results in muscle damage, and overtraining results in increased muscle damage. It has been suggested that cortisol, by suppressing the immune response to the damaged tissue, actually serves to reduce the tissue damage which could otherwise result from autoimmune disease and hypersensitivity 19.

Elite athletes are obviously subject to greater psycho- logical stress than the average sportsman. Many of the hormones and chemicals released during exercise are also released as a result of psychological or emotional stress, and a great deal of research has been published on the links between stress and the immune system. While two of the exercise studies cited ls,16 reported reduction in salivary IgA levels, it should be noted that significantly lowered salivary IgA levels were found in a prospective study of dental students during periods of high stress coinciding with major examinations 2°. However, the reduced IgA levels in the cyclists' study described earlier ~6 were the result of exercise alone.

From the research carried out to date, all that can be said is that a combination of intense training and the stress of competition makes some athletes immunosuppressed and more susceptible to infection. Studies to date, however, have been limited by the small number of elite athletes examined, or have been based on a random sample of student volunteers. Athletes have traditionally been wary of scientists keen to use them as guinea-pigs, and it is difficult to draw conclusions from the small number who have been studied because of their highly individual training schedules, diets and lifestyles. Ideally, immunological counselling should be provided to athletes, but reliable markers of altered immunocompetence among them must first be identified.

Future research must include prospective studies of top athletes in a variety of sports throughout the year, recording details of their health and infections, and monitoring physiological, hormonal and psychological changes in relation to changes in immune parameters. A study of recruits to the armed forces who will be undergoing a vigorous training programme under controlled conditions, starting from a baseline of fitness and subject to similar diet and lifestyle, is now being planned. In addition, more extensive studies of animals undergoing intense exercise schedules may yield more information on the factors contributing to immuno- deficiency among top athletes. Animal studies have the advantage that any changes found in the immune system can be directly related to susceptibility to infection by challenging the animals with infectious agents.

Hopefully these types of study will elucidate the mechanisms underlying these apparent immuno- deficiencies, possibly highlighting which aspects of train- ing are most damaging to the immune system and which predispose to infection. They may also indicate the amount of rest required for the immune system to recover following the physical and psychological stresses of intense training and competition. It may then be possible to determine the point at which exercise ceases to enhance, and begins to diminish the immune respon- siveness of athletes.

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