Eir_broschuere_2007_neues format

6 • airway inflammation and upper respiratory tract infection Airway inflammation and upper respiratory tract
infection in athletes: is there a link?
Stéphane BERMON
Monaco Institute of Sports Medicine and Surgery, 98000 Monaco
ABSTRACT
Upper Respiratory Tract Infection (URTI) is regarded as the most common med-ical condition affecting both highly trained and elite athletes, in particular thoseparticipating in endurance events. The causes of these disturbances, also occur-ring during training, remain unclear. Viruses such as rhinovirus, adenovirus andpara-influenza virus are frequently reported as the source of URTI. However, in afew comprehensive laboratory and epidemiological studies which reported atleast a 30% incidence of URTI, no identifiable pathogens were either reported orstudied. A recent, longitudinal study investigated symptomatology and pathogenicetiology in sedentary controls, recreational and elite athletes. The highest inci-dence of URTI occurred in elite athletes. However, only 11 out of 37 illnessepisodes overall had pathogenic origins, and most of the unidentified upper respi-ratory illnesses were shorter in duration and less severe than infectious ones. Thisconcept of inflammation without infection in athletes is quite new and leads us toconsider other explanatory pathophysiological conditions. Increases in airwayneutrophils, eosinophils and lymphocytes have been described under resting con-ditions in endurance sports, swimmers and cross-country skiers. These inflamma-tory patterns may be due to pollutants or chlorine-related compounds in swim-mers. After intense exercise similar airways cellular profiles have been reported,with a high amount of bronchial epithelial cells. This increase in airway inflam-matory cells in athletes can result from a hyperventilation-induced increase inairway osmolarity stimulating bronchial epithelial cells to release chemotacticfactors. Fortunately, in most cases, these inflammatory cells express rather lowlevel of adhesion molecules, explaining why airway inflammation may appearblunted in athletes despite numerous inflammatory cellular elements. However, itcan be hypothesized that a transient loss of control of this local inflammation, dueto various external physico-chemical strains, might occur. This might account forsome of the unidentified upper respiratory illnesses. Keywords: airway inflammation, environment, sports, upper respiratory tract
infection
Address Correspondence to: Stéphane BERMON, MD, PhD,Institut Monégasque de Médecine et Chirurgie du Sport,11 avenue d’Ostende, 98000 Monaco, phone : +377 99 99 10 24,e-mail: [email protected] airway inflammation and upper respiratory tract infection • 7 The aim of this short review is to provide an up-to-date summary of the known effects of exercise on airway inflammation and upper respiratory tractinfections. Although additional research is needed, there are some consistent datain the existing literature allowing these two topics to be tentatively linked.
1. Airway inflammation in athletes: cellular aspects
Many studies about airway inflammation in athletes reported an increased num-ber of inflammatory cells in bronchial biopsies, bronchioalveolar lavage fluid(BALF) or induced sputum of endurance athletes of different sports measured atrest (see ref 5 for review).
When compared with sedentary controls, cross-country skiers show increased total cell and lymphocyte counts in BALF (39), lymphoid aggregates(37) and increased T-lymphocytes, macrophage, eosinophils, neutrophils in endo-bronchial biopsies (21). Similarly, runners show increased cellularity and markedneutrophilia but no increase in eosinophils or lymphocytes in induced sputum (3).
Elite swimmers show increased neutrophil and eosinophil counts in induced spu-tum (20). Interestingly, swimmers training outdoors have increased numbers ofneutrophils in induced sputum, but no associated eosinophilia (25). Because theincrease in neutrophils is observed in all the above sports, this may be a directconsequence of endurance training. In contrast, the increase in eosinophil andlymphocyte counts is likely to be related to the exposure to environmental factors,such as chlorine compounds in swimmers or dry air and cold air in cross-countryskiers (5). The mixed type eosinophilic and neutrophilic airway inflammationshown by ice-hockey players is peculiar and more complex since these athletesare chronically exposed to both cold and dry air and carbon and nitrogen oxidesfrom ice resurfacing machine in indoor ice arenas (18) Airway inflammation and asthmatic symptoms improve in swimmers quit- ting competitive training, but tend to worsen in those who continue their sportcareer (19).
Very few studies about effect of acute exercise on airway cell changes are available. Bronchial cell counts are unaffected by 5-km swimming in an openswimming pool whereas the same distance swum in the sea slightly increases air-way eosinophil differential counts (4). The same group reported increased neu-trophils in sputum after a marathon and an all-out rowing test in non asthmaticathletes (3, 24). High counts of airway macrophages are also reported post-exer-cise in rowers (24).
2. The concept of blunted airway inflammation
In spite of elevated numbers of inflammatory cells in the BALF, sputum orbronchial biopsies, markers of inflammation such as eosinophil peroxidase, neu-trophil lipocain or elastase were generally found at normal or very slightlyincreased concentrations at rest or after exercise in cross-country skiers, runnersor outdoor swimmers (3, 5, 25). Exercise-induced hyperventilation is responsible for both cooling–rewarm- ing process (15, 16) and epithelial cell dehydration (especially if exercise is per-formed in cold and dry air) and subsequent hyperosmolar cellular stress (2).
8 • airway inflammation and upper respiratory tract infection These two conditions induce a release of IL-8 and RANTES (Regulated on Acti-vation, Normal T-Expressed and Secreted), two potent chemotactic agents, by thebronchial epithelial cells, suggesting a possible mechanism for exercise-inducedleukocyte migration into the airways.
At this point, the airway neutrophil plays a pivotal role. Indeed, it has been shown in runners, swimmers, and rowers that expression of L-selectin by airwayneutrophils decreases after exercise and no increase in the expression ofCD11b/CD18 is observed (3, 4, 24). This attests to an absence of neutrophil acti-vation. Airway macrophages and eosinophils also decrease their surface expres-sion of the adhesion molecules LFA-1, L-selectin and MAC-1 respectively, fol-lowing an all-out rowing test (24).
Considering the central role of neutrophil in potential airway inflammation, it is suggested that there is a modulation of neutrophil function by exercise hyper-ventilation, through airway hyperosmolarity and a shedding of L-selectin.
Therefore, the concept of “blunted inflammation” (13, 35) originally devel- oped to characterize the low-grade systemic inflammatory status after regulartraining (40) might be applicable to the upper respiratory tract as well.
Little is known about airway cytokine expression during or after exercise.
However, Cox et al. (6) recently conducted an interesting study, comparing plas-ma cytokine levels at rest and post exercise, in healthy (less than 2 URI per year)and illness-prone (more than 4 URI per year) athletes. In illness-prone athletesthey observed lower absolute concentrations of IL-10, IL-1ra, and IL-8, at restcombined with a greater post-exercise elevation in IL-6: this highlighted a poten-tial for excessive inflammatory responses. The altered state of inflammatory con-trol observed in this group might explain the increased rate of URI in these indi-viduals. It is important to confirm with additional experiments whether or notthese altered plasma cytokine profiles also exist at the airway level. Such researchwould help in understanding whether or not illness-prone athletes show differentlocal cytokine profiles compared with healthy athletes within and without upperrespiratory episodes.
3. Airway inflammation: environmental aspects
Swimmers may represent the most interesting population when studying upperrespiratory symptoms, inflammation and environmental aspects (31). Whenswimming for up to 30 hours per week, competitive swimmers inhale largeamounts of air immediately above the water surface and are exposed to largequantities of chlorine derivatives from swimming pool disinfectants (32). Whencompared to sedentary and healthy controls, elite swimmers demonstrated higherlevels of exhaled leukotriene B4, attesting to a neutrophilic and eosinophilicinflammation, possibly accounting for airway tissue damage. Such chronic expo-sure is frequently (36% to 79% in competitive swimmers), associated withbronchial hyperresponsiveness (22) and asthma (33%; 41). However, in swim-mers who stop high-level training, bronchial hyperresponsiveness and asthmamay attenuate or even disappear, whereas mild eosinophilic airway inflammationis aggravated among highly trained swimmers who keep on training hard (19).
Competitive Nordic skiers are also regularly exposed to environmental ther- mal and hygrometric stress. Karjalainen et al. (21) submitted elite nordic skiers to airway inflammation and upper respiratory tract infection • 9 methacholine provocation test, bronchoscopy and bronchoalveolar lavage. Bron-choscopy and bronchoalveolar lavage of these skiers revealed evidences of airwayremodelling and thickening which were the same for both those with and withoutbronchial hyperresponsiveness to methacholine. This clearly indicated that theobserved structural changes were a general consequence of chronic hyperpnoeaof cold, dry air. This specific pattern of inflammation independent bronchialhyperresponsiveness, so-called “skier’s lung”, included a slight increase of neu-trophils, tumour necrosis factor alpha and myeloperoxidase, as well as increasednumbers of mast cells and lymphocytes (39). This pattern was much less influ-enced by budesonide treatment than by the hydration and osmotic status of therespiratory mucosa (38). Interestingly, Davis et al (9), using a canine model of dryair challenge, showed that a single hyperventilation challenge induced extensivebut reversible mucosal injury and neutrophilic inflammation that was not com-pletely resolved one week after the challenge. Since the trigger factors, the clini-cal features, and the time course are similar, it is thus tempting to associate suchphenomenon with the unidentified-URI (36), at least for endurance athletes exer-cising in cold environments.
4. Upper Respiratory Tract Infection in Athletes
Numerous studies have shown an inverse relationship between decreased immunefunction and augmented exercise workloads (7, 8, 17, 23, 27). Very few studieshave actually been able to show a direct link between exercise-induced immunedepression and increased incidence of confirmed illness in athletes. Nevertheless,it is important to note that acute URTI is the most frequent reason for consultationin sports medicine clinics (11), and is the most common medical condition affect-ing athletes attending both summer and winter Olympics (14, 34).
This relationship between training status and susceptibility to infection has been modelled in the form of a “J”-shaped curve (28). This suggests that, whileengaging in moderate activity may reduce the incidence of illness sedentary lev-els, excessive amounts of prolonged and high-intensity exercise may result in anincreased incidence of illness. Some epidemiological studies confirmed that ath-letes engaged in intensive endurance training appear to be more susceptible toURTI than their moderately active peers. Examining illness patterns in a cohort of530 male and female runners who completed a monthly log for 12 months, Heathet al. (17) reported [that the odds of getting a URTI was] 2.00, 3.50, and 2.96 forrunning mileage between 486-865 miles, 866-1388 miles, and greater than 1388miles, respectively. These results suggested that high running mileage is a signifi-cant risk factor for URTI.
Many concepts and some experimental data are now available to explain how intense regular physical training may increase the susceptibility to URTI(most of them virally-induced). In terms of immune function, intense exercise isknown to decrease the expression of toll-like receptors and to increase cortisol,epinephrine, and IL-6 production. This leads to an impaired cell-mediated immu-nity and inflammation, via a decreased macrophage and Th-1 cell cytokine pro-duction (13).
Acute and exhaustive exercise (lasting more than three hours) also appears being a risk factor for increased URTI incidence.
10 • airway inflammation and upper respiratory tract infection For instance, Peters and Bateman (29) reported for the first time an increased URTI risk during the two weeks following the Capetown or Pretoriaultramarathons. This was later confirmed by other studies (26, 30) which reporteda 100–500% increase in risk of picking up an infection in the weeks following acompetitive ultra-endurance running event.
A more recent study (10) failed to confirm these findings in a large cohort of marathon runners where there was no difference in infection incidence in the 3weeks after the race compared with the 3 weeks before. These authors reportedthat the post-race URTI incidence in runners without URTI symptoms in the 3 wkpreceding the race was 16% and not statistically different from the 17% preraceURTI incidence. However, among the group of runners who experienced an URTIepisode in the 3 weeks before the race, 33% experienced an URTI episode afterthe race also. This suggests that the stress of the exercise may have allowed areactivation of the virus responsible for the pre-race infection or an extendedduration of the infection when the latter occurred within the few days before themarathon.
However, most of the above cited studies did not clinically confirm infec- tions. In view of this, it cannot be ruled out that some of the reported symptoms(e.g., sore throat) were caused by non-infectious airway inflammation due to dry-ing of the mucosal surfaces and/or the inhalation of dry air, pollutants, orbronchial hyperresponsiveness. 5. The non-infectious hypothesis
Recently, Spence et al. (36) conducted a surveillance study over a 5-month sum-mer/autumn competition season to identify the pathogenic etiology and sympto-matology of upper respiratory illness (URI) in highly trained elite athletes (n =32), recreationally competitive athletes (n = 31), and untrained sedentary controls(n = 20). These authors preferred to use the term “upper respiratory illness” ratherthan “upper respiratory infection”; the first definition being more general makingthus possible the inclusion in such a definition of non-infectious episodes. Whensubjects presented two or more defined URI symptoms, they were administeredthe Wisconsin Upper Respiratory Symptom Survey (WURSS-44) questionnaire(1) to assess the daily symptomatology and functional impairment. Nasopharyn-geal and throat swabs were collected on these subjects and analyzed usingmicroscopy, culture, and polymerase chain reaction testing for bacterial, viral,chlamydial, and mycoplasmal respiratory pathogens. A total of 37 URI episodesin 28 subjects were reported (9 controls, 7 recreationally competitive exercisers,and 21 elite athletes). Although the overall distribution mimicked the “J”-shapedcurve, with rate ratios for illness higher in both the control and elite cohorts com-pared with the recreationally competitive athlete cohort, only 11 infectious agentsout of these 37 episodes (30%), were identified (2 control, 3 recreationally com-petitive exercisers, and 6 elite athletes). No pathogens were identified in 26episodes of URI, leading to the non-infectious hypothesis drawn by these authors.
This ratio is also confirmed by other similar studies (33) which have reported over55% of illnesses without an identifiable pathogen.
However, the fact that no identifiable pathogen was observed does not nec- essarily mean that the URI is not infectious. Indeed, pathogens may not be detect- airway inflammation and upper respiratory tract infection • 11 ed in a relatively large proportion of patients with respiratory disease, because oflimitations of current diagnostic assays, non-optimal timing of the detection peri-od, or simply because some infections are caused by as yet unknown pathogens.
For instance, systematic Epstein-Barr virus or other herpes viridae DNA analysisshould systematically be undertaken in such study protocols since some of theunidentified URI symptoms might be associated with latent viral shedding (12).
Comparing the WURSS-44 specific global symptom, total symptom, and functional impairment severity scores in URI and unidentified URI (no identifi-able pathogen) groups, Spence et al (36) reported similar scores within the firsttwo days but higher in subjects of the URI group, particularly on illness days 3–5.
Moreover, the episode duration was about 3 days longer in the URI group (9.6 +/-2.4 d vs 6.5 +/- 3.2 d; p < 0.006). These findings suggest that there may have beena higher degree of immunological and inflammatory activation in those caseswhere a pathogen was identified.
Measuring systemic and local (upper respiratory tract) biological indices of inflammation or immune activation in future studies is important. Indeed, thismay help to differentiate symptoms caused by pathogen agents from those causedby inflammatory, allergic, cold dry air inhalation, vasomotor, and other idiopathicupper respiratory disorders seen in athletes.
Conclusion and future developments
Cellular components of airway inflammation exist in high-level athletes airways,particularly those involved in endurance events. These airway cellular patternsmay differ according to: a) the type of sports, b) the environmental conditions, c)the duration of sports career, and d) the existence of allergy. However, despitethese numerous inflammatory components, airway inflammation usually appearsas a tightly regulated and blunted process, as it can be seen with the low gradesystemic inflammation encountered after regular training. The most attractivehypothesis includes a modulation of the high amount of airway neutrophils byexercise hyperventilation, through an airway hyperosmolarity. This hyperosmo-larity would trigger both release of neutrophilic chemotactic factors and sheddingof adhesion molecules. This antagonism would maintain a low level of localinflammation and preserving athlete’s respiratory health.
Whether or not a transient imbalance in these opposed influences may explain some of the so called “non infectious upper respiratory episodes”deserves more investigations. Moreover, the respective contribution of regularcold dry air inhalation, cellular lineage dehydration, pollutants (especially chlo-rine-related compounds) exposure to these non-infectious episodes should bestudied in more detail. In order to obtain a better diagnosis, treatment, and man-agement strategies of upper respiratory episodes in athletes, the followingresearch axes should be considered:- Confirm the existence of infectious or non-infectious upper respiratory episodes, by improving i) pathogen detection methods (including systematicEBV DNA quantification in order to identify serological reactivation) and tim-ing of these detections when a supposed URTI occurs, ii) clinical monitoring(e.g. pulse, temperature, symptom scores, and clinical examination) of theseepisodes, iii) characterisation of the studied population:- e.g. type of sports, 12 • airway inflammation and upper respiratory tract infection environmental factors, training parameters, allergic and immunological sta-tus,).
- Develop an airway osmotic stress test and use it routinely, especially when investigating endurance athletes exposed to cold and dry environments - Look for more indices of systemic inflammation (e.g., cytokine profiles, ultra sensitive measurement of C-reactive protein), especially in the case of suspect-ed non-infectious upper respiratory episodes. This would help understandingwhether or not unidentified URI could have an echo at the systemic level and towhich extent this could influence scores of respiratory symptom questionnaire.
- Conduct more studies at the airway level, in order to compare: i) cell popula- tion and distribution, ii) chemotactic and cytokine factors, iii) adhesion mole-cule expression, in illness-prone versus healthy athletes, or infectious versusnon infectious episodes. - Test the hypothesis of exercise-induced airway inflammation as a risk factor of viral infection. Expression of dysfunctional adhesion molecules and ICAM-1(Intercellular Adhesion Molecule-1) in the post-exercise situation could theo-retically lead to a higher risk of URTI, with ICAM-1 being the major rhi-novirus receptor.
REFERENCES
Barrett B, Locken K, Maberry R, Schwamman J, Brown R, Bobula J, StauffacherEA. The Wisconsin Upper Respiratory Symptom Survey (WURSS): a new researchinstrument for assessing the common cold. J Fam Pract 1: 265, 2002.
Bjermer L, Anderson SD. Bronchial hyperresponsiveness in athletes: mechanismsfor development Eur Respir Mon, 2005, 33, 19–34. Bonsignore MR, Morici G, Riccobono L, Insalaco G, Bonanno A, Profita M, Pater-nò A, Vassalle C, Mirabella A, Vignola AM. Airway inflammation in nonasthmaticamateur runners. Am J Physiol Lung Cell Mol Physiol 281: L668-76, 2001.
Bonsignore MR, Morici G, Riccobono L, Profita M, Bonanno A, Paternò A, DiGiorgi R, Chimenti L, Abate P, Mirabella F, Maurizio Vignola A, Bonsignore G. Air-way cells after swimming outdoors or in the sea in nonasthmatic athletes. Med SciSports Exerc35: 1146-1152, 2003.
Bonsignore MR, Morici G, Vignola AM, Riccobono L, Bonanno A, Profita M, AbateP, Scichilone N, Amato G, Bellia V, Bonsignore G. Increased airway inflammatorycells in endurance athletes: what do they mean? Clin Exp Allergy 33: 14-21, 2003.
Cox AJ, Pyne DB, Saunders PU, Callister R, Gleeson M. Cytokine responses totreadmill running in healthy and illness-prone athletes. Med Sci Sports Exerc;39:1918-26, 2007.
Davis JM, Kohut ML, Colbert LH, Jackson DA, Ghaffar A, Mayer EP. Exercise,alveolar macrophage function, and susceptibility to respiratory infection. J ApplPhysiol 83: 1461–1466, 1997.
Davis JM, Murphy EA, Brown AS, Carmichael MD, Ghaffar A, Mayer EP. Effectsof moderate exercise and oat beta-glucan on innate immune function and suscepti-bility to respiratory infection. Am J Physiol Regul Integr Comp Physiol 286:R366–R372, 2004.
Davis MS, Schofield B, Freed AN. Repeated peripheral airway hyperpnea causesinflammation and remodeling in dogs. Med Sci Sports Exerc 35: 608–616, 2003.
airway inflammation and upper respiratory tract infection • 13 Ekblom B, Ekblom O, Malm C. Infectious episodes before and after a marathonrace. Scand J Med Sci Sports 16: 287–293, 2006.
Fricker PA, Infectious problems in athletes: an overview. In: Medical Problems inAthletes, KB. Fields and PA. Fricker (Eds.). Malden, MA: Blackwell Science, pp.
3–5, 1997.
Gleeson M, Pyne DB, Austin JP, Lynn Francis J, Clancy RL, McDonald WA, FrickerPA. Epstein-Barr virus reactivation and upper-respiratory illness in elite swimmers.
Med Sci Sports Exerc 34: 411-7, 2002.
Gleeson M. Immune function in sport and exercise. J Appl Physiol 103: 693-699,2007 Hanley DF. Medical care of the US Olympic Team. JAMA 236: 147–148, 1976.
Hashimoto S, Matsumoto K, Gon Y, Maruoka S, Kujime K, Hayashi S, Takeshita I,Horie T. p38 MAP kinase regulates TNF alpha-, IL-1 alpha- and PAF-inducedRANTES and GM-CSF production by human bronchial epithelial cells. Clin ExpAllergy 30: 48-55, 2000.
Hashimoto S, Matsumoto K, Gon Y, Nakayama T, Takeshita I, Horie T. Hyperosmo-larity-induced interleukin-8 expression in human bronchial epithelial cells throughp38 mitogen-activated protein kinase. Am J Respir Crit Care Med 159: 634-640,1999.
Heath GW, Ford ES, Craven TE, Macera CA, Jackson KL, Pate RR. Exercise andthe incidence of upper respiratory tract infections. Med Sci Sports Exerc 23:152–157, 1991.
Helenius I, Lumme A, Ounap J, Obase Y, Rytilä P, Sarna S, Alaranta A, Remes V,Haahtela T. No effect of montelukast on asthma-like symptoms in elite ice hockeyplayers. Allergy 59: 39-44, 2004.
Helenius I, Rytilä P, Sarna S, Lumme A, Helenius M, Remes V, Haahtela T. Effect ofcontinuing or finishing high-level sports on airway inflammation, bronchial hyperre-sponsiveness, and asthma: a 5-year prospective follow-up study of 42 highly trainedswimmers. J Allergy Clin Immunol 109: 962-968, 2002.
Helenius IJ, Rytila P, Metso T, Haahtela T, Venge P, Tikkanen HO. Respiratorysymptoms, bronchial responsiveness and cellular characteristics of induced sputumin elite swimmers. Allergy 53: 346–352. 1998 Karjalainen EM, Laitinen A, Sue-Chu M, Altraja A, Bjermer L, Laitinen LA. Evi-dence of airway inflammation and remodeling in ski athletes with and withoutbronchial hyperresponsiveness to methacholine. Am J Respir Crit Care Med 161:2086–2091, 2000.
Langdeau JB, Turcotte H, Bowie DM, Jobin J, Desgagne P, Boulet LP. Airwayhyperresponsiveness in elite athletes. Am J Respir Crit Care Med 161: 1479-84,2000.
Matthews CE, Ockene IS, Freedson PS, Rosal MC, Merriam PA, Hebert JR. Moder-ate to vigorous physical activity and risk of upper-respiratory tract infection. MedSci Sports Exerc 34: 1242–1248, 2002.
Morici G, Bonsignore MR, Zangla D, Riccobono L, Profita M, Bonanno A, PaternòA, Di Giorgi R, Mirabella F, Chimenti L, Benigno A, Vignola AM, Bellia V, AmatoG, Bonsignore G. Airway cell composition at rest and after an all-out test in compet-itive rowers. Med Sci Sports Exerc 36 :1723-9, 2004.
Morici GBM, Riccobono L, Insalaco G. Markers of airway inflammation in non-asth-matic swimmers at rest and after exercise (Abstract). Eur Respir J; 18: 491S, 2001.
14 • airway inflammation and upper respiratory tract infection Nieman DC, Johansen LM, Lee JW, Arabatzis K. Infectious episodes in runners beforeand after the Los Angeles Marathon. J Sports Med Phys Fitness 30: 316–328, 1990.
Nieman DC, Nehlsen-Cannarella SL, Markoff PA, Balk-Lamberton AJ, Yang H,Chritton DB, Lee JW, Arabatzis K. The effects of moderate exercise training on nat-ural killer cells and acute upper respiratory tract infections. Int J Sports Med 11:467-73, 1990.
Nieman DC. Exercise, infection and immunity. Int J Sports Med 15: S131–S141,1994.
Peters EM, Bateman ED. Ultramarathon running and URTI: an epidemiological sur-vey. S Afr Med J 64: 582–584, 1983.
Peters EM, Goetzsche JM, Grobbelaar B, Noakes TD. Vitamin C supplementationreduces the incidence of post-race symptoms of upper respiratory tract infection inultramarathon runners. Am J Clin Nutr 57: 170–174, 1993.
Piacentini GL, Rigotti E, Bodini A, Peroni D, Boner AL. Airway inflammation inelite swimmers. J Allergy Clin Immunol 119: 1559-60, 2007.
Potts J. Factors associated with respiratory problems in swimmers. Sports Med 21:256-261, 1996.
Pyrc K, Berkhout B, van der Hoek L. Identification of new human coronaviruses.
Expert Rev Anti Infect Ther 5: 245-53. 2007.
Reeser JC, Willick S, M. Elstad M. Medical services provided at the Olympic Villagepolyclinic during the 2002 Salt Lake City Winter Games. WMJ 102: 20–25, 2003.
Shek PN, Shephard RJ. Physical exercise as a human model of limited inflammatoryresponse. Can J Physiol Pharmacol ;76: 589-97. 1998.
Spence L, Brown WJ, Pyne DB, Nissen MD, Sloots TP, McCormack JG, Locke AS,Fricker PA. Incidence, etiology, and symptomatology of upper respiratory illness inelite athletes. Med Sci Sports Exerc 39: 577-86, 2007.
Sue-Chu M, Karjalainen EM, Altraja A, Laitinen A, Laitinen LA, Naess AB, LarssonL, Bjermer L. Lymphoid aggregates in endobronchial biopsies from young elitecross-country skiers. Am J Respir Crit Care Med 158: 597-601. 1998.
Sue-Chu M, Karjalainen E-M, Laitinen A, Larsson L, Laitinen LA, Bjermer L.
Placebo-controlled study of inhaled budesonide on indices of airways inflammationin bronchoalveolar lavage fluid and bronchial biopsies in cross country skiers. Res-piration 67: 417–425, 2000.
Sue-Chu M, Larsson L, Moen T, Rennard SI, Bjermer L. Bronchoscopy and bron-choalveolar lavage findings in cross-country skiers with and without “ski asthma”.
Eur Respir J 13: 626– 632, 1999.
Suzuki K, Totsuka M, Nakaji S, Yamada M, Kudoh S, Liu Q, Sugawara K, YamayaK, Sato K. Endurance exercise causes interaction among stress hormones, cytokines,neutrophil dynamics, and muscle damage. J Appl Physiol 87: 1360-1367, 1999.
Weiler JM, Layton T, Hunt M. Asthma in United States Olympic athletes who partic-ipated in the 1996 Summer Games. J Allergy Clin Immunol 102: 722-726, 1998.

Source: http://www.aimec.it/tm/pdf/pubblicazioni/free4.pdf