JSM0404Pg000ED. Introduction The most common reason for absence from training in elite sportsmen is the presence of upper respiratory tract infections, followed by acute and chronic injuries. (Berglund and Hemmingson 2) In 1983 Professor Eric Bateman and I described an increased prevalence of self-reported symptoms of upper respiratory tract ‘infections’ following participation in a 56 km ultramarathon in runners when compared with the preva- lence in matched non-running, sedentary controls during the same time period.58 Both runners and controls had reported the incidence of runny noses, sneezing, sore throats and coughs with or without accompanying fever, immediately before and during the 2 weeks following the 1982 Two Oceans Ultramarathon. The incidence of these self-reported symptoms was found to be significantly higher in runners than in controls and the post-race symptoms highest amongst the runners who ran the fastest.58 This finding has been repeated numerous times, both in South Africa and abroad.33,44,46,59 Research focus in the rapidly developing field of exercise immunology has subsequently been placed on identifying: (i) the mechanisms which possi- bly result in this high prevalence of ‘infection’ during the post- race period; and (ii) nutritional and pharmacological intervention strategies in an attempt to reduce the higher ‘infection’ risk experienced by ultradistance athletes during the 3 - 72 hour post-event ‘open-window’ period (Fig. 1) and during periods of excessive training. During the last 25 years, no less than 1 500 studies have been published in this rela- SPORTS MEDICINE VOL 16 NO.1 2004 3 REVIEW ARTICLE Postrace upper respiratory tract ‘infections’ in ultra- marathoners — infection, allergy or inflammation? E M Peters (BA (Hons), BSc(Med) Hons, MSc(Med), PhD) Department of Physiololgy, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban Abstract Despite more than 20 years of research into mechanisms which could result in the increased predisposition of ath- letes to ‘infection’ incidence following excessive and pro- longed exercise, definitive explanations are not yet available. A strong temporal relationship between the inci- dence of upper respiratory tract infection symptoms and immune system changes following excessive exercise load (EEL) have not been shown. T-helper cells are func- tionally polarised according to the cytokines which they produce. While exercise-induced upregulation of T-helper- 2 (TH2) cells and type 2 cytokines is indicative of enhanced activation of allergic responses, downregula- tion of T-helper-1 (TH1) cells and type 1 cytokines confirms suppression of cellular immune functions. The current knowledge regarding the exercise-induced kinetics of interleukin (IL)-4, a cytokine that is crucial in the activation of the TH2 cells, does, however, not appear to provide suf- ficient support for an upregulation of a type 2 response. Lowered or unchanged circulating concentrations of type1 cytokines (IL12, IL-2 and interferon γ) and short-term sup- pression of lymphocyte, natural killer cell and neutrophil function following EEL, reflect a transient, post-exercise suppression of cellular immunity. Despite a partial damp- ening thereof by the anti-inflammatory actions of IL-10, IL-1ra and IL-6, the evidence supporting a pro-inflamma- tory response to prolonged exercise and overtraining is unequivocal. At present, the data appear to support the theory that symptoms of ‘infection’ experienced by ath- letes are the manifestation of a significant pro-inflamma- tory response, combined with a modest, transient suppression of cellular immune functions which may be clinically insignificant. CORRESPONDENCE: E M Peters Department of Physiology Nelson R Mandela School of Medicine Private Bag 7 Congella 4013 South Africa Tel: 031-260 4237 Fax: 031-260 4455 E-mail: futree@nu.ac.za NK activity IgA levels Lymphocyte counts Severe exercise Post exercise Immunodepression Open Window Fig. 1. The exercise-induced open-window period (adapted from Pedersen and Ullum.52) 4 SPORTS MEDICINE VOL 16 NO.1 2004 tively new field of exercise immunology. As Noakes, however, so appropriately concludes in his most recent version of The Lore of Running,47 ‘it is my impression that a considerable amount of research has been done in this field without any practical advances being made’. In 1994 Nieman45 postulated that the relationship between exercise-load and ‘infection risk’ could be modelled in the form of a J-shaped curve, suggesting that although the risk of upper respiratory tract infection (URTI) may decrease below that of a sedentary individual undergoing moderate exercise training, risk may rise above average during periods of excessive amounts of high-intensity exercise.45 In 1999 he introduced a further dimension to this graphic model; while ‘infection risk’ increased, ‘immunsurveillance’ decreased and vice versa (Fig. 2).39 Temporary modulations of innate and adapted immune function have been alleged to be the basis for the relation- ship between the level of physical activity and susceptibility to infection. While limited evidence of enhancement of immune function has been found following moderate exer- cise exposure,4,25,30,38 it has been shown that excessive pro- longed exercise transiently suppresses markers of both cellular and humoral adaptive immunity15,26,28,35,42,70 and to a lesser degree, some aspects of non-specific immunity including neutrophil respiratory burst8,61-63,66,78 and natural killer (NK) cell activity.21,26,27 Yet a consistent correlation between this temporary ‘sup- pression’ of markers of immune function and incidence of URTI infection symptoms following excessive exercise load (EEL) has not been found. The closest link that has been shown has been in the work of exercise immunologists of the Australian Institute of Sport and University of Queensland who were able to show that a decrease in salivary immunoglobulin (IgA) concentration is associated with a cor- responding enhanced infection incidence in elite, overtrained swimmers and kayakers.12,16-19,65 However, the recent debate regarding the validity of the practise of expressing salivary IgA as a function of salivary total protein or albumin concen- trations when these have different origins,3 makes explana- tion of the results elusive and leaves exercise immunologists with little alternative but to acknowledge that the transient suppression of markers of immune function which have been reported in the last two decades may not be of clinical sig- nificance. In re-examining possible factors which could account for the higher incidence of what have primarily been self-report- ed symptoms of URTI, a number of interesting new perspec- tives and hypotheses have arisen. Broadly, these can be divided into three general categories: those supporting aller- gy, inflammation or infection. Let us examine each of these in turn. A case in favour of allergic origins? An enlightening dimension of recent immunological studies on exercising individuals has involved the analysis of the post-event cytokine milieu (Table I). It is well accepted that the CD4 lymphocyte subsets, T- helper-1 (TH1) and T-helper-2 (TH2), impact differentially on cellular and humoral lymphocyte function.14,67,77 As direct measurement of the CD 26 (TH1) and 30 (TH2) cell surface molecules is not possible due to their instability, a compre- hensive picture of the cytokine milieu created by cells of the immune system is the best evidence which we presently have of TH1:TH2 balance following EEL. Whereas the type 1 cytokines, interleukin (IL)-2, interferon gamma (IFN γ), tumour necrosis factor (TNF)α and IL-12 activate the devel- opment and activation of TH1 cells which upon recognition of antigens, stimulate cell-mediated immunity increasing CD8 and NK cell cytotoxic activity as well as activating macrophages and neutrophils to kill the bacteria they har- bour, TH2 upregulation has been shown to augment B-cell antibody production via the release of the type 2 cytokines, IL-4, IL-5, IL-6, IL-10 and IL-13. Suzuki et al.77 and Smith72 have recently proposed an hypothesis which suggests an exercise-induced shift in cytokine balance from type -1 to type-2 cytokines with an upregulation of TH2 cells (as con- firmed by substantially elevated post-exercise concentra- tions of IL-6 and IL-10) and a relative downregulation of TH1 helper cells, as expressed in elevated circulating cortisol and prostaglandin E2 concentrations73 and unchanged/slightly decreased type 1 cytokine concentrations following EEL (Table I). This exercise-induced ‘tipping’ of the TH1: TH2 bal- ance (Fig. 3) differs significantly from the cytokine milieu pre- sent in auto-immune disorders which present with elevated IL-2, IFNγ and IL-12 concentrations. The high prevalence of exercise-induced asthma, anaphaxis and systemic histamine release recently reported by Helenius et al.,13 Mucci et al.,23 Shadick et al.,69 and Sue-Chu et al.,76 has encouraged exer- cise immunologists to look more deeply into this shift in TH1:TH2 balance following exercise which appears to support upregulation of humoral immunity and allergic responses with simultaneous downregulation of cell-mediated immunity. While IL-10 plays an important role in upregulating TH2 cells and inhibiting TH1 lymphocyte development, 72 it is well accepted that IL-4 is the dominant cytokine in the upregula- tion of TH2 lymphocytes promoting their differentiation and inducing further type 2 cytokine production.67 This cytokine is therefore the ‘key player’ in supporting humoral immunity and possible allergen-derived activation of eosinophils/mast cells and IgE production. There is, however, presently little Fig. 2. The paradoxical relationship between workload, infection risk and immunosurveillance in athletes (adapted from Nieman et al. 38) SPORTS MEDICINE VOL 16 NO.1 2004 5 evidence of exercise-induced elevation of circulating IL-4 concentrations and preferential post-exercise synthesis of IgE following exercise.32,75 Although IL-6 (which rises dramat- ically during prolonged exercise24,29,31), is thought to stimulate the production of IL-4, Steensberg et al.75 were not able to show evidence of its production in CD4+ cells. Additional work on the kinetics of IL-4 is therefore required before the TH1 -TH2 hypothesis can be substantiated. The significant post-exercise elevations of IL-10, a potent suppressor of cell- mediated immunity and anti-inflammatory cytokine, as well as the multifunctional IL-6 and chemotactic IL-8 (Table I), fur- ther complicate the argument in favour of a cytokine balance which is exclusively associated with allergic-type reactions. The case for and against infectious origins Despite the above-described evidence of the presence of a type 2 post-exercise cytokine milieu which points to modest, transient downregulation of the cellular components of spe- cific and innate immunity, it would appear that, at this stage, there is little support for a truly infectious origin of the URTI symptoms experienced by athletes following an EEL. As findings of transient suppression of lymphocyte count and proliferation,34,41 NK-cell counts and cytolytic activity,21,26 sali- vary IgA concentrations11,12,20 and phagocytic oxidative burst activity8,37 have not been shown to be paralleled by increased incidence of ‘infection’, the clinical significance of these find- ings is in question. TABLE I. The cytokine milieu in the blood following prolonged exercise in excess of 2 hours Exercise-induced changes Cytokine Primary cell source Primary functions in peripheral blood Tumour necrosis factor Activated macrophages, NK, Primary mediator of SIRS; stimulation Changes inconsistent, but (TNF)∝ T-cells, B-cells of release of acute phase proteins, concentrations remain within lymphocyte proliferation & killing clinically normal range 32,48,56, 57 Interferon (IFN) ∝ & ß Epithelia, fibroblasts, macrophages Antiviral; activation of NK cells No change Interferon (IFN)γ Activated TH1 cells, NK cells Antiviral; activation of macrophages, 50% ↓ (Steensberg et al.75*) neutrophils, NK cells, inhibition of TH2 cells No change Undectectable (Nieman et al.,32 Gannon et al.9) Interleukin-1 ß (IL-1 ß) Macrophages, monocytes Mediator of SIRS; activation of 1.5 - 2-fold↑ (Nieman et al.,40 phagocytosis, B-cell proliferation; Ig Ostrowski et al.48,50) production Interleukin-2 (IL-2) Activated TH1 cells, NK cells Modulator of TH2 cell proliferation & 32% ↓ Suzuki et al.77) function; IgG expression 50 % ( (Steensberg et al. 75*) Interleukin-4 (IL-4) TH2 cells, mast cells, basophils, Downregulation of TNFα and IL- 1ß; No change (Nieman et al.32 eosinophils induction of IL-6, IL-10, IL- 1ra Malm22, Steensberg et al.75*) synthesis; B-cell proliferation and class Delayed onset secretion after 2 switching to IgE expression. hrs (Susuki et al.79) Interleukin-5 (IL-5) TH2 cells, mast cells, eosinophils Eosinophil & B-cell growth and differentiation. No consistent change (Malm 22) Interleukin-6 (IL-6) Activated TH2 cells, APCs, active Multi-functional; B-cell proliferation 30-fold ↑ (Steensberg et al,75*) skeletal muscle fibres and Ig & acute phase protein synthesis; 30-fold ↑ (Peters et al.57) inhibition of synthesis of TNFα and IL- 100-fold ↑ (Starkie et al.74) 1ß; induction of cortisol, IL-10 & IL- 1ra synthesis Interleukin-8 (IL-8) Macrophages Chemotaxis, superoxide release, 6-fold↑ (Peters et al.55) granule release 6.7-fold ↑(Ostrowski et al.49) Interleukin-10 (IL-10) Activated TH2, CD8 and B Inhibition of synthesis of TNFß, IL- 1ß, 60-fold ↑ (Peters et al.56) lymphocytes, macrophages IFNγ, IL-6, IL-8 by TH1 cells, NK cells 40-fold↑ (Nieman et al. 32) & APCs; promotion of B-cell proliferation & antibody responses, mast cell growth Interleukin 12 (IL-12) Monocytes Activation of TH1 cells Undetectable (Nieman et al, 32 NK stimulating factor Suzuki et al.79, Gannon et al.9) IFN γ production Increased† (Akimoto et al.1) Interleukin 13 (IL-13) TH2 cells B-cell growth & differentiation, inhibition of No exercise-related data available pro-inflammatory cytokine production Interleukin 15 (IL-15) Skeletal muscle cells, T and B-cell proliferation, increase of No change (Ostrowski et al.48). endothelium, monocytes. myosin heavy chain expression in skeletal muscle. Interleukin-1ra (IL-1ra) Macrophages, TH2 cells Inhibition of pro-inflammatory action of 20 fold↑ (Peters et al.56) IL-1 by blocking IL-1 α & ß receptors; 40 fold↑ (Toft et al.80) no agonist activity 214 fold↑(Suzuki et al.79) * Intracellular concentrations (CD4 + cells). †Short-term maximal exercise. APC = antigen presenting cell; TH1 = T-helper-1; TH2 = T-helper-2; Ig = immunoglobulin; SIRS = systemic inflammatory response syndrome. (Ganong,10 Janeway and Travers,14 Roitt et al.,67 Smith 72) Although the open-window hypothesis of Pedersen and Ullum52 and Pedersen et al.54 describes a period of increased susceptibility to infection which may last from 3 to 72 hours post-exercise, most exercise-induced haematological pertur- bations have returned to baseline values within 16 hours post-exercise.60 As Shepard and Shek71 point out, ‘it is diffi- cult to reconcile a 2-to 3-hour reduction of NK cell activity with the reported 2-to 6- fold increase in the incidence of URTIs in the weeks following participation in a marathon or ultramarathon run’. Furthermore, antibody responses following vaccination have not been shown to be influenced by exercise training,5 while negative bacterial throat swabs obtained by Schwellnus et al. following the Two-Oceans 56 km Ultramarathon also appear to rule out the possibility of enhanced incidence of post-race infection symptoms being of infectious origin (M Schwellnus — personal communica- tion). As false-negative bacterial throat swabs are, however, a common occurrence in clinical practice, we cannot, at this stage, consider these data as conclusive. The evidence in support of a decrease in delayed type hypersensitivity (DTH) reactions, the T-cell-dependent activation of macrophages and inflammation in response to a previously encountered antigen, is also presently conflictling; while Bruunsgaard et al.5 found decreased DTH after a one-half Ironman race, Jansen et al. (personal communication), failed to show any change following 8 weeks of training in excess of 110 km/week. The case in favour of inflammatory origins The evidence in favour of an inflammatory response both to epithelial tissue damage in the upper respiratory tract and muscle fibre damage in the contracting skeletal muscle fibres, as manifested in systemic markers of an inflammato- ry response, is, however, strong. During prolonged endurance exercise increased ventila- tory rates and volumes, with actual damage to sensitive mucous membranes in the respiratory tract, and an inflam- matory response at the sites of muscle cell damage have been linked to the development of an acute phase reaction.80 Evidence of systemic manifestation of pro and anti- inflammatory response to exercise-induced microtrauma (whether this be in the contracting muscle itself or in the res- piratory tract membranes exposed to excessive mouth 6 SPORTS MEDICINE VOL 16 NO.1 2004 IL-4 IL-5 IL-10 IL-6 IL-8 IL-13 TNF α EEL T1H cells IL-12 IL-2 IFN γ TG β TNF β TH2 cells Cell mediated immunity: Macrophages, PMNs, NK, Tc cells Pro-inflammatory response: Phagocyte mobilisation & activation EEL Humoral immuntity: allergic response Fig. 3. The exercise-induced disturbance of cytokine equilibrium: a downregulation of type 1 and upregulation of type 2 cytokines. promotion; inhibition; EEL : excessive exercise load; TH1: T-helper-1; TH2: T-helper-2; PMN : polymor- phonuclear neutrophils; TC : cytotoxic T-cells; NK cells: natural killer cells. breathing) has been confirmed by numerous studies focus- ing on exercise-induced cytokine changes. In addition to the early studies which consistently confirm the presence of increased prostaglandin E2 concentrations, 53,73 the endocrine,43,44,64,72 cytokine,36,48-51 acute phase protein,6,7,81 and enzymatic66 milieu in the circulation favours an inflam- matory response (Fig. 4). In three consecutive studies following the 90 km ultrama- rathon, we have confirmed systemic evidence of a pro- inflammatory response.55-57 Not only are markers of an acute phase reaction, CRP and amyloid A consistently elevated, peaking 24 hours after a race and reaching concentrations in excess of those reported following myocardial infarctions,55,57 but also a cascade of pro-inflammatory and chemotactic cytokines40,56 and systemic markers of phagocyte activation including myeloperoxidase, elastase and neutrophil/ mono- cyte adhesion factors.55,61,66 Our most recent research findings confirm elevated concentrations of neutrophils and mono- cytes expressing CD11 a and b integrins which control the movement of leukocytes towards areas of inflammation fol- lowing 2.5 hours of treadmill running at 70% VO2max. (Peters et al., unpublished data). The substantial elevation of circulating anti-inflammatory mediators, IL-10, IL-1ra and IL-6 (Fig. 5) do, however, point towards a partial dampening of this pro-inflammatory response. Despite this endogenous attempt to counter the exercise-induced inflammation, systemic markers of an acute phase reaction peak at 24 hours post-event. In 1997 Schwellnus et al.68 reported that administration of the local antimicrobial and anti-inflammatory agent, Fusafungine, significantly reduced post-race URTIs in 48 participants during the 9 days following the 1996 Two Oceans 56 km Ultramarathon. However as this nasobuc- copharangeal spray has both anti-inflammatory and anti- infective properties, this intervention study on its own does not provide conclusive evidence that the increased incidence of infection following EEL is solely attributable to an inflam- matory response. Perhaps we should also not ignore the early finding of Pedersen et al.53 that administration of the non-steroidal anti- inflammatory agent, indometacin, which inhibits prosta- glandin E2 release and the inflammatory response, reduces post-exercise suppression of NK cell activity and restores post-exercise neurophil chemiluminescence in peripheral blood. As the authors concluded, these findings strongly indicate that prostaglandins released from monocytes and neutrophils, are involved in the downregulation of NK cells, again pointing towards systemic manifestation of an inflam- matory response. An answer? At this stage, there is not enough evidence in favour of an exclusive contribution of allergic, inflammatory or infective origins to the incidence of post-event URTI symptoms. SPORTS MEDICINE VOL 16 NO.1 2004 7 Fig. 4. Mean (± SEM) circulating acute phase protein (CRP and amyloid A), elastase and interleukin-8 concentrations before and after a 90 km ultramarathon, which support an upregulation of inflammatory responses (data from Peters et al. 55) *P > 0.05 (N = 29). 60 50 40 30 20 10 0 Time S e ru m C P R ( m g /l) Pre 0 hrs 24 hrs 48 hrs post post post 250 200 150 100 50 0 Time S e ru m a m yl o id A ( m g /l) Pre 0 hrs 24 hrs 48 hrs post post post 200 180 160 140 120 100 80 60 40 20 0 Time P la sm a e la st a se ( µ g /l) Pre 0 hrs 24 hrs 48 hrs post post post 30 25 20 15 10 5 0 Time P la sm a I n te rl e u ki n -8 ( p g /m l) Pre 0 hrs 24 hrs 48 hrs post post post 8 SPORTS MEDICINE VOL 16 NO.1 2004 In terms of the TH1: TH2 balance hypothesis which favours an allergic response, the evidence in favour of exercise- induced production of IL-4 requires further elucidation. The exercise-induced ‘switching’ of B-cells to a preferential pro- duction of IgE and significant upregulation of IgG1 production in response to mast cell activation also requires further con- firmation. In terms of the inflammation and infection-based hypothe- ses, supportive data are undoubtedly strong. While transient- ly and modestly suppressed cellular components of immunity including cytotoxic T lymphocytes, NK cells and in the case of EEL, neutrophil function are supported by a relative down- regulation of type 1 cytokines, the post-exercise cytokine, acute phase protein and adhesion molecule milieu strongly supports an upregulation of inflammatory responses. Shephard and Shek71 have eloquently referred to the ‘active enmeshment’ of the immune system in the muscle tis- sue repair and inflammation process. 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