(European Respiratory Monograph) A. Bush, K-H. Carlsen, M.S. Zach-Growing Up With Lung Disease - The Lung in Transition To Adult Life-European Respiratory Society Journals Ltd. (2002)

Diagnosis, Prevention and Treatment of
Exercise-Related Asthma, Respiratory

and Allergic Disorders in Sports
INTRODUCTION
K-H. Carlsen*, J. Cummiskey#, L. Delgado}, S. Del Giaccoz

*Voksentoppen BKL, Rikshospitalet University Clinic, University of Oslo, Oslo, Norway. #Blackrock Clinic,
Blackrock, County Dublin, Ireland. }Servico de Imunologia, Faculdade de Medicina, da Universidade do
Porto, Hospital S. Joao, Porto, Portugal. zDipartimento di Medicina 2, University of Cagliari, Cagliari,
Italy.
Asthma and allergy represent increasing problems for the actively competing athlete.
The prevalence of exercise-induced asthma (EIA) has increased over the last two decades,
especially amongst elite endurance athletes [13]; it has been reported that high-level
endurance training in particular may increase bronchial hyperresponsiveness (BHR) [4]
and cause inflammation in the airways [5]. Intensive endurance training and competition,
together with environmental influences, are thought to be causative factors. For winter
sports, inhaled cold air represents such an environmental factor; moreover, exposure of
competing swimmers to organic chlorine products released from indoor swimming pools
is another example of a harsh environment. Furthermore, the increased amount of
training and increased level of physical fitness and maximum oxygen uptake reached by
present-day elite athletes may, in some cases, make it difficult to discriminate between
limitations to maximum exercise set by normal airways and EIA. This underlines the
need for developing good diagnostic criteria for EIA and BHR in relation to sports.
It has become a concern that the use of inhaled asthma drugs, especially inhaled b2agonists, has become increasingly wide-spread amongst elite athletes and that high-level
endurance training in particular may increase BHR [4] and cause inflammation in the
airways [5]. In 1993, the Medical Commission of the International Olympic Committee
(MC-IOC) restricted the use of inhaled b2-agonists, even in asthmatic athletes, and only
allowed inhalation of the short-acting b2-agonists (SABA) salbutamol and terbutaline
for use in relation to sports by asthmatic athletes. All drugs should be prescribed by a
doctor with confirmation of an asthma diagnosis.
Several studies were performed on the effect on performance of both inhaled SABA
and long-acting b2-agonists (LABA), regarding endurance performance and maximal
strength, speed and power functions; however, none of these studies could confirm any
improvement in performance. Thus, from 1996, the MC-IOC also allowed the use of
salmeterol, a LABA, by inhalation; later (2001), inhaled formoterol was allowed by both
the MC-IOC and the newly formed World Anti-Doping Agency (WADA) in relationship
to participation in sports by asthmatic athletes.
However, due to the frequent use of both SABA and LABA by inhalation, and the fear
that b2-agonsts in high systemic doses might increase muscle mass, as indicated by some
animal studies [6, 7], further regulations were introduced by the MC-IOC in December
2001, shortly before the Winter Olympic Games in Salt Lake City (UT, USA) 2002. In
order to be allowed to use inhaled b2-agonists, the team doctor had to make a prior
application to the commission, together with documentation of increased reversibility to
bronchodilators, bronchial hyperresponsiveness and/or exercise-induced bronchoconstriction (EIB). Anderson et al. [8], who suggested these regulations, described
their experiences during the Winter Olympics in 2002.
Many respiratory physicians caring for top athletes felt that the regulations were too
strict and the procedures required for documentation were too demanding on resources,
Eur Respir Mon, 2005, 33, viiix. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
vii
K-H. CARLSEN ET AL.
particularly as no improvement in performance has been demonstrated when using

inhaled b2-agonists or anti-inflammatory drugs. In contrast, there is general agreement
that the use of inhaled b2-agonists should be limited amongst athletes and not permitted
in healthy subjects [9]. From January 1, 2004, the WADA has also restricted the use of
inhaled steroids, thereby also limiting the availability of anti-inflammatory treatment.
There is concern that overly strict criterion for the diagnosis of asthma, which in clinical
practice is a clinical diagnosis, could lead to underdiagnosis and undertreatment of
asthma amongst athletes. Recommendations for diagnosis and treatment should be in
accordance with general clinical guidelines, such as the Global Initiative for Asthma
guidelines.
Amongst the aims that the MC-IOC has set up for Sports Medicine, there is the aim
that all participants should have equal conditions, and that care should be taken to
ensure that sports should not cause any long-lasting harm or disease to the participants
[10]. Therefore, asthmatic athletes should receive optimal treatment both symptomatically and prophylactically for their asthma.
Due to these concerns, the European Academy of Allergy and Clinical Immunology
and the European Respiratory Society have established a joint Task Force to outline the
problem of asthma and allergy in sports, establish definitions for asthma, EIA and EIB in
relation to sports. The primary objective of the present Monograph (written by the Task
Force) is to outline the problem of allergy and asthma related to sports, establish
diagnostic criteria for the diagnosis of asthma and EIA in relation to sports and, finally,
to set up guidelines for the treatment of asthma and EIA and other exercise-related
respiratory problems in relation to sports. The diagnostic criteria and treatment
guidelines should be set up from recognised evidence-based methods, as given by
Harbour and Miller [11], taking into account the quality of the cited studies and
assessing existing levels of evidence as the basis for the grading of the recommendations
given [11].
It should be remembered that athletes are examples and idols to the children and
adolescents in our communities. The proper use of asthma medications, without the
danger of being accused of doping, is important for the asthmatic athlete, but it also has
an effect upon the general view of asthma treatment in the community. Furthermore,
knowledge obtained from studies performed on elite competitive athletes may influence
future treatment of asthmatic children and adolescents.
References
1.
2.
3.
4.
5.
6.
Larsson K, Ohlsen P, Larsson L, Malmberg P, Rydstrom PO, Ulriksen H. High prevalence of

asthma in cross country skiers. BMJ 1993; 307: 13261329.
Heir T, Oseid S. Self-reported asthma and exercise-induced asthma symptoms in high-level
competetive cross-country skiers. Scand J Med Sci Sports 1994; 4: 128133.
Helenius IJ, Tikkanen HO, Haahtela T. Occurrence of exercise induced bronchospasm in elite
runners: dependence on atopy and exposure to cold air and pollen. Br J Sports Med 1998; 32: 125
129.
Carlsen KH, Oseid S, Odden H, Mellbye E. The response to heavy swimming exercise in children
with and without bronchial asthma. In: Oseid S, Carlsen K-H, eds. Children and Exercise XIII.
Champaign, IL, USA, Human Kinetics Publishers, Inc., 1989; pp. 351360.
Sue-Chu M, Karjalainen EM, Altraja A, et al. Lymphoid aggregates in endobronchial biopsies
from young elite cross-country skiers. Am J Respir Crit Care Med 1998; 158: 597601.
Dodd SL, Powers SK, Vrabas IS, Criswell D, Stetson S, Hussain R. Effects of clenbuterol on
contractile and biochemical properties of skeletal muscle. Med Sci Sports Exerc 1996; 28: 669676.
viii
INTRODUCTION
7.
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11.
Suzuki J, Gao M, Xie Z, Koyama T. Effects of the beta(2)-adrenergic agonist clenbuterol on

capillary geometry in cardiac and skeletal muscles in young and middle-aged rats. Acta Physiol
Scand 1997; 161: 317326.
Anderson SD, Fitch K, Perry CP, et al. Responses to bronchial challenge submitted for approval
to use inhaled beta2-agonists before an event at the 2002 Winter Olympics. J Allergy Clin Immunol
2003; 111: 4550.
Bonini S, Brusasco V, Carlsen K-H, et al. Diagnosis of asthma and permitted use of inhaled beta2agonists in athletes. Allergy 2004; 59: 3336.
Samaranch JA. The Olympic Book of Sports Medicine. London, Blackwell Scientific Publications,
1988; pp. vivii.
Harbour R, Miller J. A new system for grading recommendations in evidence based guidelines.
BMJ 2001; 323: 334336.
ix
CHAPTER 1
Epidemiology of asthma, allergy and

bronchial hyperresponsiveness in sports
T. Haahtela*, K. Larsson#, S. Bonini}
*Dept of Allergy, Skin and Allergy Hospital, Helsinki University Central Hospital, Helsinki, Finland, #Unit
of Lung and Allergy Research, National Institute of Environmental Medicine, IMM Karolinska Insitituet,
Stockholm, Sweden. }IRCCS San Raffaele, Rome, and Second University of Naples, Naples, Italy.
Correspondence: T. Haahtela, Dept of Allergy, Skin and Allergy Hospital, Helsinki University Central
Hospital, FIN-00250 Helsinki, Finland. Fax: 385 947186500; E-mail: tari.haahtela@hus.fi
Asthma has a higher prevalence in athletes compared with the general population. In
summer sport events, the prevalence ranges 3.722.8%, as reviewed by Helenius and
Haahtela [1]. In winter sport events, the occurrence is even higher, ranging 2.854.8%
(table 1) [28]. A total of 17% of 253 Finnish elite summer sport athletes used asthma
medication, most commonly inhaled b2-agonists [1]. Also, 17% of the USA Winter
Olympic Team (Nagano, Japan) were current users of asthma medication [5], while the
figure was twice as high (36%) amongst Swedish cross-country skiers [2]. In a Swedish
study in upper secondary schools for young skiers, 15% had phsysician-diagnosed
asthma and 18% were treated with anti-asthma drugs compared with 6% and 7%,
respectively, amongst the controls [9].
Occurrence of bronchial hyperresponsiveness

Bronchial hyperresponsiveness (BHR) is correlated with clinical asthma symptoms,
but the relationship is not straight forward. Larsson et al. [2] observed that 23 out of 42
(54.8%) cross-country skiers had BHR and asthma symptoms. Two skiers had BHR
without symptoms and 17 had symptoms, but no BHR. Leuppi et al. [7] found that 35%
of Swiss ice hockey players had BHR, but clinical asthma was diagnosed in 19% and
exercise-induced bronchospasm (EIB) in 11% of them. The respective figures for BHR,
clinical asthma and EIB were lower in floor ball players: 21%, 4.2% and 4.2%.
Sue-Chu et al. [3] reported that in cross-country skiers the figures for BHR and clinical
asthma were closer to each other: 14% and 12% in Norway, and 43% and 42% in Sweden,
respectively. Karjalainen et al. [10] studied 40 young elite skiers and 12 healthy control
subjects. BHR to methacholine was found in 30 (75%) of the skiers, and one-third of
them had symptoms suggestive of asthma.
BHR is also prevalent in swimmers. Zwick et al. [11] found competitive swimmers to
have BHR significantly more often than control subjects (78% versus 36%). In another
study, BHR was detected in 60% of swimmers and in 12% of nonswimming athletes [12].
The prevalence of BHR was higher in swimmers (36%) than in speed and power athletes
(18%) and in long-distance runners (9%) [13]. A "healthy runner effect" certainly takes
place, especially in long-distance runners. BHR was significantly associated with atopy.
Conclusions of the associations are problematic in cross-sectional studies because
dynamic variables fluctuate over time depending on various factors. Heir et al. [14]
observed that acute respiratory tract infections were associated with a transient increase
Eur Respir Mon, 2005, 33, 14. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
T. HAAHTELA ET AL.
Table 1. Prevalence of asthma amongst highly trained winter sports athletes

Group of athletes
Subjects n
Method
Prevalence %
First author [Ref.]
Cross-country skiers
42
54.8
LARSSON [2]
171
124
12 (Norway)
42 (Sweden)
35 (exercise-induced
bronchospasm)
19.2
11.5 (exercise-induced
bronchospasm)
22 (total asthma)
13 (current asthma)
21.9
60.7 (cross-country, etc.)
24 (alpine, etc.)
2.8 (bobsleigh, etc.)
23 (all, exercise-induced
bronchospasm)
50 (cross-country)
SUE-CHU [3]
Figure skaters
Questionnaire, spirometry,
methacholine challenge
methacholine challenge
Exercise test
Ice hockey players
Ice hockey players
88
1998 USA Winter

Olympic team
196
1998 USA Winter

Olympic team
methacholine challenge,
exercise test
histamine challenge
Questionnaire
Exercise challenge,
spirometry
MANNIX [4]
LEUPPI [7]
LUMME [8]
WEILER [5]
WILBER [6]
: Source population n=196.
in BHR in athletes performing physical training, but not in nonactive control subjects.
Exercise and breathing cold air causes transient BHR even in asthmatic nonathletes [15, 16].
Occurrence of eosinophilic airway inflammation

Asthma symptoms and lung function abnormalities, including BHR, are a
consequence of airway inflammation, which in asthma is predominately of an
eosinophilic type. However, in athletes a mixed type of eosinophilic and neutrophilic
airway inflammation has been shown to affect ice hockey players, cross-country skiers
and elite swimmers [8, 10, 17].
Sputum eosinophilia (w2% of the differential cell count) affected one-fifth of highly
trained swimmers [17, 18] and one-tenth of ice hockey players [8]. Those swimmers with
exercise-induced bronchial symptoms had significantly higher sputum eosinophil cell
counts (mean 7.6%) than the symptom-free swimmers (mean 0.7%) [17]. After 5-yr
follow-up, sputum eosinophilia was detected in 38% (6% at baseline) of those swimmers
who continued their active career, and in 8% (19% at baseline) of those who had stopped
intensive training [18].
Karjalainen et al. [10] showed that the number of activated eosinophils, Tlymphocytes and macrophages in the subepithelial tissue are much higher in crosscountry skiers than in sedentary control subjects. Elite swimmers have shown increased
concentrations of eosinophil peroxidase (EPO) and human neutrophil lipocaline (HNL)
in the supernatant of induced sputum samples as compared with control subjects, which
suggests that both eosinophils and neutrophils are more activated in swimmers than in
controls [17].
Type of training as a risk factor

Highly trained athletes are repeatedly and strongly exposed to cold air during winter
training and to many inhalant irritants and allergens all year long. The type of training
has been associated with the occurrence of bronchial symptoms, BHR and asthma in elite
athletes [13, 19].
2
ASTHMA, ALLERGY AND BHR IN SPORTS
Asthma is most commonly found in athletes performing endurance events, such as

cross-country skiing, swimming or long-distance running. Mild asthma (defined usually
as increased BHR and asthma symptoms) is most common in endurance athletes, such
as cross-country skiers (1455%) [2, 3], swimmers (1344%) [13, 17, 18, 20] and longdistance runners (1524%) [13, 21]. Also, speed and power athletes, e.g. ice hockey
players (1519%) [6, 7, 8], and track and field athletes (16%) [13, 19], have a somewhat
increased risk of asthma.
Atopy as a risk factor

Evidence for an increase in immunoglobulin E-mediated allergy has been shown in the
general population [22, 23]. It seems that an increasing proportion of young athletes are
atopic [8, 13] and suffer from symptoms caused by inhalant allergens. Hay fever, the most
clear-cut atopic condition, is more common in summer sports athletes than in control
subjects [13, 24].
Atopic disposition is a major risk factor along with the type of training. Risk of asthma
is closely associated with atopy and its severity amongst athletes. When the risk factors
"sporting event" and "atopy" were combined in a logistic regression model, the relative
risk of asthma was surprisingly large: 25 fold in atopic speed and power athletes, 42 fold
in atopic long-distance runners, and 97 fold in atopic swimmers compared with
nonatopic control subjects [13].
Outcome of asthma and asthma-like symptoms

Outcome of asthma in athletes has not been widely studied. In swimmers who stopped
intensive training, BHR and asthma attenuated or even disappeared, whilst symptoms
increased and eosinophilic airway inflammation was aggravated in swimmers who
remained active during the 5-yr follow-up, irrespective of asthma treatment [18]. Thus,
asthma in athletes is at least partly reversible, and intensive training seems to cause
airway inflammation and asthmatic symptoms in susceptible individuals.
Summary
Clinical asthma, exercise-induced bronchospasm and bronchial hyperresponsiveness are
more common in competitive athletes compared with the general population. Various
atopic conditions (e.g. pollen allergy) seem to be more common in summer sports athletes
than in control subjects. Type of training and atopy are major risk factors for lower airway
symptoms. Asthma is most commonly found in athletes performing endurance events,
such as cross-country skiing, swimming or long-distance running. These athletes are
repeatedly and strongly exposed to cold air and many inhalant irritants and allergens all
year long. In symptomatic athletes, a mixed type of eosinophilic and neutrophilic airway
inflammation often occurs leading in some individuals to functional abnormalities.
Asthmatic symptoms in athletes are usually mild and at least partly reversible as they may
disappear in those who stop intensive training.
Keywords: Allergy, asthma, bronchospasm, bronchial hyperresponsiveness, epidemiology, exercise.
3
T. HAAHTELA ET AL.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
Helenius I, Haahtela T. Allergy and asthma in elite summer sports athletes. J Allergy Clin Immunol
2000; 106: 444452.
Larsson K, Ohlsen P, Larsson L, Malmberg P, Rydstrom P, Ulriksen H. High prevalence of
asthma in cross-country skiers. BMJ 1993; 307: 13261329.
Sue-Chu M, Larsson L, Bjermer L. Prevalence of asthma in young cross-country skiers in central
Scandinavia: differences between Norway and Sweden. Respir Med 1996; 90: 99105.
Mannix ET, Farber MO, Palange P, Galassetti P, Manfredi F. Exercise-induced asthma in figure
skaters. Chest 1996; 109: 312315.
Weiler JM, Ryan EJ 3rd. Asthma in United States Olympic athletes who participated in 1998
Olympic Winter Games. J Allergy Clin Immunol 2000; 106: 267271.
Wilber RL, Rundell KW, Szmedra L, Jenkinson DM, Im J. Incidence of exercise-induced
bronchospasm in Olympic Winter sport athletes. Med Sci Sports Exerc 2000; 32: 732737.
Leuppi JD, Kuhn M, Comminot C, Rheinhart WH. High prevalence of bronchial
hyperresponsivness and asthma in ice hockey players. Eur Resp J 1998; 12: 1316.
unap J, et al. Airway inflammation, bronchial hyperresponsiveness, and
Lumme A, Haahtela T, O
asthma in elite ice hockey players. Eur Respir J 2003; 22: 113117.
Larsson L, Hemmingsson P, Boethius G. Self-reported obstructive airway symptoms are common
in young cross-country skiers. Scan J Med Sci Sports 1999; 4: 124127.
Karjalainen EM, Laitinen A, Sue-Chu M, Altraja A, Bjermer L, Laitinen LA. Evidence of airway
inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to
methacholine. Am J Respir Crit Care Med 2000; 161: 20862091.
Zwick H, Popp W, Budik G, Wanke T, Rauscher H. Increased sensitization to aeroallergens in
competitive swimmers. Lung 1990; 168: 111115.
Potts J. Factors associated with respiratory problems in swimmers. Sports Med 1996; 21: 256261.
Helenius IJ, Tikkanen HO, Sarna S, Haahtela T. Asthma and increased bronchial responsiveness
in elite athletes: atopy and sport event as risk factors. J Allergy Clin Immunol 1998; 101: 646652.
Heir T, Aanestad G, Carlsen KH, Larsen S. Respiratory tract infection and bronchial responsiveness
in elite athletes and sedentary control subjects. Scand J Med Sci Sports 1995; 5: 9499.
Suzuki S, Chonan T, Sasaki H, Takishima T. Bronchial hyperresponsiveness to methacholine after
exercise in asthmatics. Ann Allergy 1985; 54: 136141.
Dosman JA, Hodgson WC, Cockcroft DW. Effect of cold air on the bronchial response to inhaled
histamine in patients with asthma. Am Rev Respir Dis 1991; 144: 4550.
Helenius IJ, Rytila P, Metso T, Haahtela T, Venge P, Tikkanen HO. Respiratory symptoms,
bronchial responsiveness and cellular characteristics of induced sputum in elite swimmers. Allergy
1998; 53: 346352.
Helenius I, Rytila P, Sarna S, et al. Effect of continuing or finishing high-level sports on airway
inflammation, bronchial hyperresponsiveness, and asthma. A prospective follow-up study of 42
elite swimmers. J Allergy Clin Immunol 2002; 109: 962968.
Helenius IJ, Tikkanen HO, Haahtela T. Association between type of training and risk of asthma in
elite athletes. Thorax 1997; 52: 157160.
Langdeau JB, Turcotte H, Bowie DM, Jobin J, Desgagne P, Boulet LP. Airway
hyperresponsiveness in elite athletes. Am J Respir Crit Care Med 2000; 161: 14791484.
Tikkanen HO, Helenius I. Asthma in runners. BMJ 1994; 309: 1087.
Kosunen TU, Hook-Nikanne J, Salomaa A, Sarna S, Aromaa A, Haahtela T. Increase of allergenspecific immunoglobulin E antibodies from 1973 to 1994 in a Finnish population and a possible
relationship to helicobacter pylori infections. Clin Exp Allergy 2002; 32: 373378.
Krause T, Koch A, Friborg J, Poulsen LK, Kristensen B, Melbye M. Frequency of atopy in the
arctic in 1987 and 1998. Lancet 2002; 360: 691692.
Katelaris CH, Carrozzi FM, Burke TV, Byth K. A springtime Olympics demands special
consideration for allergic athletes. J Allergy Clin Immunol 2000; 106: 260266.
CHAPTER 2
Epidemiology of rhinitis and conjunctivitis

in athletes
S. Bonini*, G.W. Canonica#, T. Haahtela}, L. Delgadoz
*IRCCS San Raffaele, Rome, and Second University of Naples, Naples, Italy. #Dept of Internal Medicine,
University of Genoa, Genoa, Italy. }Dept of Allergy, Skin and Allergy Hospital, Helsinki University Central
Hospital, Helsinki, Finland. zServico de Imunologia, Faculdade de Medicina, da Universidade do Porto,
Hospital S. Joao, Porto, Portugal.
Correspondence: S. Bonini, IRCCS San Raffaele, Via Ugo de Carolis 59, IT-00136 Rome, Italy. Fax: 39
0635403017; E-mail: se.bonini-cnr@flashnet.it
Rhinitis occurs very frequently in athletes, with its prevalence in various studies being
dependant on the criteria used for diagnosis.
Helbling et al. [1] found that 16.8% of 2,060 active Swiss athletes (from 68 different
sports) suffered from hay fever, most of them (59%) needing medication during the
pollen season. Athletes with hay fever had exercise-related airway symptoms significantly
more often, but received inadequate treatment.
In the study by Katelaris et al. [2] on 214 athletes, 56% gave a symptom history
consistent with allergic rhinoconjunctivitis, with 41% also having a positive skin-prick
test response to any one allergen and 29% seasonal allergic rhinoconjunctivitis (a positive
seasonal history and at least one positive skin-prick test response to a seasonal allergen).
In another series of 265 athletes selected for the Sydney Olympic Games (Sydney,
Australia), the prevalence of positive skin-prick tests was 32.6%, and 25.3% of athletes
had clinical rhinitis [3].
Like asthma, the prevalence of allergic rhinitis seems to be on the increase, as the
reported prevalence of y8.0% in the 1980s doubled in 1996 (to 16.9%) [4].
Allergic rhinitis was shown to have negative effects on performance scores (ability to
train and compete) over the spring season. Athletes from aquatic sports were more likely
to have symptoms than those from other sports. Athletes who were treated in season with
intranasal steroids (once daily, for 8 weeks) had statistically significant improvements in
symptoms, quality of life (QoL) and performance scores [5, 6].
In a study of 83 high-level training athletes referred for respiratory symptoms, the
reported nasal symptoms in the responses to the USA Olympic Committee questionnaire
(n=67) were as follows: obstruction 55%, rhinorrhoea 54%, sneezing 50% and pruritus
43%. A total of 52% of rhinitis athletes were treated with oral antihistamines and 60%
with nasal corticosteroids [7].
However, clinical presentation (and pathophysiological mechanisms) of rhinitis may
vary depending on the type of sports practiced. Accordingly, rhinitis in swimmers, skiers,
boxers and in runners are often considered as distinct clinical entities [8].
Epidemiological data indicate that asthma and allergic rhinitis frequently coexist [9
14], even in the absence of atopy [15], with rhinitis symptoms being reported in 8090% of
asthma patients, and asthma symptoms in 1938% of those with allergic rhinitis. A
European survey [16] of 1,412 subjects with perennial rhinitis and 5,198 control subjects
found asthma present in 16.2% of subjects with rhinitis and 1% of controls.
Epidemiological studies indicate that up to 40% of patients with allergic rhinitis may
ISSN 1025-448x. ISBN 1-904097-22-7.
S. BONINI ET AL
have asthma [17], and prospective studies suggest that rhinitis frequently precedes the
development of asthma [18]. Moreover, many patients with rhinitis alone demonstrate
nonspecific bronchial hyperresponsiveness (BHR) and this may be a risk factor for
developing asthma [19].
Severity of allergic rhinitis and asthma has also been shown to be correlated. Patients
with allergic rhinitis exhibit increased eosinophil activity in both upper and lower airways
[20, 21]. In these patients, nasal allergen challenge can induce increased BHR [22, 23]
suggesting that upper and lower airway disorders share common inflammatory features.
Proper management of allergic rhinitis also improves asthma control, reinforcing the link
between both diseases. In fact, intranasal steroids prevent the seasonal increase in
nonspecific bronchial hyperreactivity and asthma symptoms associated with pollen
exposure [24]. In patients with perennial rhinitis, intranasal corticosteroids were also
shown to reduce asthma symptoms, exercise-induced bronchospasm and bronchial
responsiveness to methacholine [25, 26]. In addition to being safe and effective, inhaled
corticosteroids are permitted by the World Anti-Doping Agency (WADA) and the
International Olympic Committee Medical Commission following notification.
The pathophysiological connections between the upper and lower airways are not
completely understood and different mechanisms have been proposed [27].
Exercise-induced asthma (EIA) occurs in a high percentage of patients with allergic
rhinitis depending on the type of exercise and outcome measure considered. Moreover,
EIA frequently goes undiagnosed in children and athletes [28] because of normal baseline
spirometry and a negative history of asthma and EIA [29, 30].
On the basis of the data described above, every rhinitic athlete should be screened for
asthma and EIA [8] according to the Allergic Rhinitis and its Impact on Asthma (ARIA)
guidelines [27].
Standard asthma diagnosis procedures for the athlete with rhinitis should include a
resting spirometry bronchodilator test, bronchial provocation with methacholine and
field exercise challenge in the usual sporting environment or in a controlled environment
in the laboratory. Nasal peak inspiratory flow monitoring in the field and/or laboratory
exercise challenge with specific nasal evaluation (functional rhinomanometry and
morphological acoustic rhinometry) may be especially useful in the diagnosis of exerciseinduced rhinitis. Ideally, as in other occupational diseases, these tests should be
performed and recorded before therapeutical interventions.
Athletes practicing and competing outdoors should also be screened for the possibility
of intermittent rhinitis and/or asthma associated with pollen allergy, which will have a
negative impact on their expected peak performances. In major national and
international competitions, local pollen counts and forecasts (www.polleninfo.org)
should be made available in advance to allergic athletes, their coaches and medical teams.
Conjunctivitis in athletes
The lack of common nomenclature and of standardised diagnostic procedures and
flow charts [31] makes it particularly difficult to determine the prevalence of
conjunctivitis in elite athletes. In fact, most of the studies refer to hay fever or allergic
rhinoconjunctivitis or seasonal rhinoconjunctivitis, without differentiating between nasal
and eye symptoms and, therefore, they do not give any information on different forms
and severity of allergic conjunctivitis in individual cases. Data about nonallergic
conjunctivitis are even more scarce and anecdotic.
In the study by Katelaris et al. [2], 29% of 214 athletes had seasonal allergic rhinitis,
defined as a positive seasonal history and at least one positive skin-prick test to a seasonal
allergen. In a study by Labucci et al. [3] of 265 Italian Olympic athletes, conjunctivitis
6
RHINITIS AND CONJUNCTIVITIS IN ATHLETES
was found in 18.8% of athletes. Certainly, data from epidemiological studies of

allergic diseases in the general population suggests allergic conjunctivitis is widely
underdiagnosed, since conjunctival symptoms are often considered of minor importance
versus lung and eye symptoms, both by patient and doctor. On the contrary, allergic
conjunctivitis has a significant effect on the athletes well-being and sports activity.
Moreover, oral antihistamines, often used to control symptoms, may significantly affect
vigilance, further impairing the quality of performances.
Atopic conjunctivitis and contact ocular allergy (contact dermatitis of the eyelids) also
frequently occur in athletes, in whom increased sweating and use of detergents modify
the hydrolipid film of the skin and reduce its defensive capacity.
In a study of professional football players, a diagnosis of atopic conjunctivitis or
contact dermatitis was made in 5.8% of cases, with thiourans and mercaptobenzothiazole
the prevalent haptens responsible for positive patch tests in contact dermatitis of the
eyelids [32]. The study also showed the increasing relevance of sensitisation to latex,
favoured by the many rubber items in sports equipment (eyeglasses, masks, gloves,
clothes, shoes, etc.) [32].
Summary
Rhinitis has a very high and increasing prevalence in athletes. Symptoms and
mechanisms of rhinitis in athletes may differ in relation to the type of sports (e.g.
swimming, running, skiing and boxing). Certainly, symptoms (and treatments) may
affect performances, particularly in some environments (allergen content, quality of
the air, etc.).
Since rhinitis and asthma often coexist, even in the absence of allergy, all rhinitic
athletes should be screened for asthma and exercise-induced bronchoconstriction
according to the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines.
The lack of common nomenclature and of standardised diagnostic procedures and
flow charts makes it difficult to determine the prevalence of conjunctivitis in athletes.
In fact, most of the studies refer to allergic rhinoconjunctivitis while data on vernal,
atopic and contact lens conjunctivitis, as well as on contact ocular allergy, are very
limited, although these conditions may significantly affect the well-being, vision and
performances of athletes.
Keywords: Conjunctivitis, contact dermatitis, exercise-induced asthma, pollen allergy,
provocation tests, rhinitis.
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Wright AL, Holberg CJ, Martinez FD, Halonen M, Morgan W, Taussig LM. Epidemiology of
physician-diagnosed allergic rhinitis in childhood. Pediatrics 1994; 94: 895901.
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cities. Respir Med 1995; 89: 685692.
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adult Finnish men and women of the Finnish Twin Cohort from 1975 to 1990, and their relation to
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Greisner Wr, Settipane RJ, Settipane GA. Co-existence of asthma and allergic rhinitis: a 23-year
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Leynaert B, Bousquet J, Neukirch C, Liard R, Neukirch F. Perennial rhinitis: An independent risk
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Ventura MT, Dagnello M, Matino MG, Di Corato R, Giuliano G, Tursi A. Contact dermatitis in
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CHAPTER 3
Exercise and airway physiology:

interactions with immune and allergic
responses
P. Palange*, V. Brusasco#, L. Delgado}, S. Del Giaccoz
*Dipartimento di Medicina Clinica, University of Rome "La Sapienza", Rome, #Dipartimento di Medicina
Interna, University of Genoa, Genoa, and zDipartimento di Medicina 2, University of Cagliari, Cagliari,
Italy. }Servico de Imunologia, Faculdade de Medicina, da Universidade do Porto, Hospital S. Joao,
Porto, Portugal.
Correspondence: P. Palange, Dipartimento di Medicina Clinica, Servizio di Fisiopatologia Respiratoria,
Universita` of Rome "La Sapienza", Viale Universita` 37, 00185 Rome, Italy. Fax: 39 064940421; E-mail:
paolo.palange@uniroma1.it
Pulmonary ventilation (V9E) increases during exercise to meet metabolic needs [1]. In
particular, V9E increases proportionally to the CO2 produced at muscular level, up to the
point where lactic threshold (LT) is achieved. Above LT, V9E increases in excess to the
CO2 produced by the working muscles, because additional CO2 is generated from the
bicarbonate component of lactate isocapnic buffering. At higher work loads, a further
increase in V9E occurs with a decrease in CO2 in order to compensate for metabolic
acidosis. In most normal individuals, exercise is terminated well below the maximum
ventilation a subject can achieve voluntarily. This may not be the case in pulmonary
disorders (either obstructive or restrictive) and in highly trained athletes, who may reach
a V9E w200 L?min-1 at high-intensity exercise. The usual ventilatory response to exercise
is for V9E to be dominated by an increase in tidal volume (VT) at low-to-moderate work
loads, with respiratory frequency increasing only at high levels of exercise. This pattern,
however, may vary among subjects and types of exercise, but it is also affected by lung
size [2] or airway calibre or both.
This chapter will first examine how changes in airway physiology may affect the
pattern of the ventilatory response to exercise and performance. Therefore, the effects of
exercise on airway calibre and their relationships to airway inflammation will be
reviewed.
Airway physiology and exercise

Changes in airway calibre during exercise
Airway calibre is a major determinant of the pattern of response to exercise, as it sets
the limits within which airflow can be increased during hyperpnoea. In normal subjects,
the maximal flow is not achieved during exercise, which is generally terminated because
of peripheral muscle fatigue. The large flow reserve, i.e. the difference between maximal
and resting tidal flows, allows the generation of hyperpnoea by using both inspiratory
and expiratory reserve volumes. In airway obstruction, the flow reserve is reduced and
hyperpnoea can only be generated by breathing at increased lung volumes (dynamic lung
ISSN 1025-448x. ISBN 1-904097-22-7.
10
EXERCISE AND AIRWAY PHYSIOLOGY
hyperinflation). Therefore, any change occurring in the airway during exercise may also
affect the pattern of response to exercise and performance. Studies on changes in airway
calibre in exercising normal subjects gave inconsistent results, which may depend on
method of measurement and type of exercise. Pulmonary resistance was found to be
decreased on exercise when it was measured during panting [3, 4] but not during
spontaneous breathing [58]. As the decrease in pulmonary resistance during exercise was
not observed after anticholinergic treatment [4], it has been suggested that exercise may
act by blunting an increase of vagal tone. Interpretation of changes in pulmonary
resistance is, however, complicated by the fact that its components, airway and tissue
resistances, may change differently with changes in breathing pattern; airway resistance
decreases with the increase of mean lung volume but slightly increases with flow [9].
Tissue resistance decreases with breathing frequency for any given VT [10], but it may
also be altered during exercise because of an increase in lung elastic recoil, possibly
associated with increments of blood flow and surface tension. Finally, the contribution of
possible changes in upper airway resistance, a major determinant of total airway
resistance remains to be determined. Changes in airway calibre can be inferred from
spirometry, but there are some problems connected with its use during exercise. Tidal
flow on exercise has been occasionally found to exceed the flow measured during a
maximal forced expiratory manoeuvre. This seemingly paradoxical effect may be due to a
wrong alignment of tidal and forced flow-volume curves on the volume axis, to different
gas compression during tidal and forced expirations, to inhomogeneous distribution of
time constants, to the bronchodilator effect of volume history, but also to real
bronchodilatation. There are some mechanisms that may cause effective bronchodilatation during exercise by reducing airway smooth muscle tone. Adrenaline levels increase
during exercise [11], but there is no evidence that it has a great influence on
bronchomotor tone in normal subjects. Other bronchodilator mediators that may
influence airway physiology during exercise include prostaglandin (PG) E2 and nitric
oxide (NO) [12].
Studies in asthmatic subjects also gave inconsistent results. Pulmonary resistance was
found to be decreased for the whole duration of a 12-min exercise in one study [5], but
only transiently in another [7]. However, in another study [13], inspiratory pulmonary
resistance increased during a 20-min exercise, but not isocapnic hyperventilation. More
recently, Crimi et al. [14] documented a potent bronchodilator effect of exercise by use of
partial flow-volume curves in asthmatic subjects during episodes of induced or
spontaneous bronchoconstriction. It has been proposed that the increase in VT during
exercise may reduce the ability of airway smooth muscle to generate force either because
tidal stretching suppresses the contractile machinery at the level cross-bridge number and
cycling rate [15] or a plastic adaptation of the contractile filaments occurs within the
muscle cell [16]. Other mechanisms by which stretching may exert its bronchodilator
effect include the release of PGE2 and PGI2 [17, 18], activation of neural pathways that
could lead to inhibition of cholinergic tonic activity [19], nonadrenergic-noncholinergic
bronchodilatation [20], or even release of NO from non-neural sources [21]. No
experimental evidence exists for or against the above mentioned mechanisms on exercise,
and, therefore, they remain purely speculative.
Exercise-induced bronchoconstriction
In a number of asthmatic subjects, a transient increase in airways resistance develops
early after exercise; this phenomenon has been called exercise-induced bronchocostriction (EIB). Cold, but particularly, dry inspired air amplifies this effect, while warm and
humidified air usually blunts or even abolishes it [22]. Although originally described as
11
P. PALANGE ET AL.
typically occurring after exercise, EIB has recently been shown to already appear during
exercise if this is sufficiently prolonged [13]. This has practical implications as it may
influence exercise performance, particularly in endurance activities.
Water loss and cellular shrinkage

The main pathogenetic theory on EIB is that exercise hyperventilation causes drying of
the airways and increases the osmolarity of the fluid lining the airways surface, which
causes bronchial epithelial cells to "shrink" and release inflammatory mediators. All these
alterations are believed to cause airway smooth muscle contraction [23]. The evidence
that hypertonic aerosol challenge is capable of inducing airway obstruction in asthmatic
subjects, a phenomenon called hypertonic aereosol-induced bronchocostriction, supports
the theory that hyperosmolality induced by hyperpnoea initiates EIB [24, 25].
Bronchoalveolar lavage (BAL) studies on animals and humans suggest that EIB is
associated with some mucosal damage [26] and that this effect is reduced by breathing
warm and wet air [27]. Mast cell degranulation has also been shown to be involved in the
pathogenesis of EIB, as suggested by increased numbers of degranulating mast cells in
bronchial biopsies from humans after exercise [28] and from animals during or
immediately after hyperpnoea with dry air [29], by the capacity of hypertonic stimulus to
cause mast cell mediator release [30], and by the inhibiting efficacy of mast cell-stabilising
drugs [22, 31]. Endothelin, produced by bronchial epithelium and endothelium, may also
contribute to EIB, through an increase in smooth muscle tone and an increase in the
permeability of microvasculature [32]. Other potential contributors include numerous
cytokines which are involved in the acute-phase response to injury [33]. NO has been
shown to attenuate methacoline-induced bronchoconstriction in man [34], but the data
on EIB are conflicting with some studies suggesting a protective role [35], some an
enhancing effect [36] and some little or no effect [37, 38]. It was also observed that the
increase in vasoactive intestinal peptide (VIP) induced by exercise is associated with an
increase in peak expiratory flow [39] and a reduction of airway responsiveness to
histamine [40]. These observations, in conjunction with the fact that exogenous VIP
inhibits dry air-induced broncoconstriction in dogs [41], suggest that VIP may prevent
bronchoconstriction during exercise.
The efficacy of b2-agonists in protecting against EIB, and the speed at which it
develops and subsides, have convinced many investigators that mediator-induced
smooth muscle contraction is the primary cause of EIB [42]. In contrast, it is not known if
bronchovascular leakage may also causally relate to EIB; the fact that hyperpnoea with
dry air causes bronchovascular hyperpermeability and bronchoconstriction in animal
models [22, 27, 29] suggests that this association is also likely to occur in humans.
Cooling and rewarming

Another theory proposed to explain EIB involves airway rewarming after cooling as
the initiating mechanism. In asthmatic patients and in animal models, it has been
demonstrated that when airway cooling continues after hyperpnoea ceases, airway
obstruction is significantly reduced [43]. This could mean that airway cooling per se
inhibits EIB during exercise, possibly by decreasing neuronal activity or the production
of inflammatory mediators [43, 44]. This may suggest that both cooling and rewarming
are necessary for the initiation of EIB [43]. However, EIB does not develop in canine
airways when cooling and rewarming occur in the absence of hyperpnoea-induced airway
drying [44].
It was also proposed that EIB may result from vasoconstriction of the bronchial
12
vasculature induced by cooling. This hypothesis is based on the assumption that airway
cooling transiently decreases bronchial blood flow and that a rewarming-induced
hyperaemia results in bronchovascular engorgement and airway oedema with bronchial
narrowing [45]. Studies conducted on animals using radiolabelled microspheres to
measure airway blood flow demonstrated that bronchial flow increases during
hyperpnoea with dry air [4648]. Also, hyperventilation with warm dry air produces a
greater increase in airway blood flow than hyperventilation with cold, dry air, indicating
that airway drying is the primary stimulus for increasing blood flow [46]. The release of
vasodilator PGs and neuropeptides has also been highlighted as the possible factor
modulating vascular response to dry air [47]. Although these studies do not support the
original hypothesis that cooling induces airway vasoconstriction, they also do not rule
out the possibility that bronchovascular hyperaemia and oedema formation contributes
to the development of EIB.
Interestingly, volume expansion with saline before hyperpnoea blunts EIB in
asthmatics, suggesting that intravascular plasma expansion before challenge contributes
to the maintenance of airway fluid balance during hyperventilation [49]. On the contrary,
saline infusion late in the challenge enhanced EIB, suggesting that volume loading may
contribute to airway oedema caused by a dry air-induced increase in microvascular
permeability [49]. Studies conducted on animal models suggest that the increase in
bronchial blood flow induced by dry air breathing is accompanied by an increase in
bronchovascular permeability and a concomitant fluid exudation into the airway wall
with oedema formation [50, 51]. However, there is evidence to suggest that vascular
engorgement and mucosal oedema are not the primary effectors of EIB. Bronchovascular hyperpermeability in dogs persists for i24 h after hyperpnoea [29]. Also, b2receptor agonists significantly attenuate EIB in dogs without altering vascular
permeability [5254]. Finally, ligation of the bronchial artery in dogs during hyperpnoea
abolishes bronchovascular leakage without altering hyperpnoea-induced bronchoconstriction. All these observations led to the hypothesis that airway and vascular responses
to dehydratation may actually protect the bronchial mucosa from acute injury, and that
the increase in smooth muscle tone would narrow the airway lumen not only reducing the
penetration of cool, dry air but also reducing the mucosal surface area exposed to this
insult [22]. With regard to airway dehydration, bronchovascular leakage may replace the
evaporative water lost from the mucosa during and immediately after exertion.
Alternatively, the movement of fluid towards the airway lumen may increase the
clearance of mediators released even during and after hyperpnoea [22].
Finally, it has been shown that inflammation developing in patients with mild asthma,
with leakage of plasma proteins into the airway lumen, compromises the surfactant
ability to maintain the patency of terminal conducting airways [55, 56]. Recently, it has
been demonstrated that this ability decreases with cooling [57].
Exercise and airway inflammation

It has been shown that repeated hyperventilation challenges may cause epithelial
damage with eosinophil and neutrophil influx and increased peptidoleukotriene
concentrations in BAL fluid [58]. In cultured human bronchial epithelial cells, exposure
to a hyperosmolar medium or the coolingrewarming process is capable of triggering an
inflammatory cascade by increasing the expression of chemokines, such as interleukin-8
(IL-8) and regulated on activation normal T-cell expressed and secreted (RANTES) [59,
60]. Therefore, both hyperventilation and hyperosmolarity seem capable of causing
an inflammatory response, involving common pathways of allergic and asthmatic
13
P. PALANGE ET AL.
inflammation. Although few studies are available, all of them reported an increased
number of inflammatory cells in bronchial biopsies, BAL fluid or induced sputum of
endurance athletes of different sports measured at rest. However, the increase in number
of inflammatory cells in the airway of athletes does not always correlate with exerciserelated respiratory symptoms and bronchial hyperresponsiveness, so the link between
EIB and airway inflammation in humans, either healthy or asthmatic, remains elusive
[61].
Elite athletes of summer [6264] or winter [65, 66] sports show a high prevalence of
exercise-induced respiratory symptoms and/or spirometric alterations. Nowadays, the
increased risk for EIB in athletes is believed to be linked to exercise hyperventilation,
through enhanced airway exposure to allergens and pollutants in summer sports and dry
and cold air in winter sports [67]. At baseline, cross-country skiers show, compared with
sedentary controls, increased total cell and lymphocyte counts in BAL [68], lymphoid
aggregates [69] and increased T-lymphocytes, macrophage, eosinophils, neutrophils in
endobronchial biopsies [61]. Also, runners show increased cellularity and marked
neutrophilia but no increase in eosinophils or lymphocytes in induced sputum [70]. Elite
swimmers show increased neutrophil and eosinophil counts in induced sputum [62]; in
contrast, swimmers trained outdoors showed increased numbers of neutrophils in
induced sputum, not associated with eosinophilia. Due to it being observed in all the
above studies, irrespective of sample type or sport activity, the increase in neutrophils is
considered the result of endurance training. In contrast, the increase in eosinophil and
lymphocyte 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-country skiers [58].
Only few studies are available on the acute effect of exercise on airway inflammation.
Normal subjects exercising at a moderate intensity for 2 h in a dry and cold environment
showed an increase in granulocyte and macrophage counts in BAL fluid, compared with
indoor conditions [71]. After a marathon race, an increase in airway neutrophils,
accounting for 90% of cells in induced sputum, has been reported in the absence of postrace respiratory symptoms or spirometric changes [70]. Indoor swimmers did not show
changes in airway cell counts and composition, as reflected by measurements in induced
sputum, after prolonged exercise [72]; interestingly, the same swimmers after prolonged
exercise in sea water showed a slight increase in eosinophil and lymphocyte differential
counts [72]. It is noteworthy that endurance exercise causes a systemic response
characterised by plasmatic increase of inflammatory cells, mainly neutrophils, and
markers, mainly neutrophil elastase and tumour necrosis factor-a [73]. This
inflammatory response is regulated by a complex pattern of pro- and anti-inflammatory
cytokines release, probably related to muscle damage and intense stress [74]. The
intensity of exercise-induced inflammation progressively decreased in sedentary subjects
undergoing training [75]. Interestingly, some studies found consistently that the increase
in airway inflammatory cells was not associated with an increase of inflammatory
markers in the BAL fluid or in the induced sputum of normal subjects exposed to dry and
cold air after exercise [71], cross-country skiers at rest [69], and runners at rest and after a
marathon race [70]. This may mean that endurance exercise determines a "frustrated"
airway inflammation that some authors believe could be explained by the shedding of Lselectin induced by exercise hyperventilation. Bronchial epithelial cells were shown to
release IL-8 and RANTES upon exposure to a hyperosmolar medium or the cooling
rewarming process [59, 60], suggesting a possible mechanism for exercise-induced
leukocyte migration into the airways. In both runners [70] and swimmers [72], the
expression of L-selectin by airway neutrophils decreased after exercise and no increase in
the expression of CD11b/CD18 was seen, indicating the absence of neutrophil activation.
Hypertonic exposure of neutrophils in vitro caused cell shrinkage and shedding of Lselectin [76] and neutrophils exposed to hypertonic environment became resistant to
14
activation by endotoxin, with adhesion-independent shedding of L-selectin and

inhibition of CD11b upregulation [77]. In the light of the above mentioned observations,
it is reasonable to hypothesise that neutrophil function might be modulated by exercise
hyperventilation through the ensuing airway hyperosmolarity.
Summary
In this chapter, the relationships between exercise and lung function are analysed. The
presence of airflow obstruction may impede an efficient ventilatory response to
exercise because of the occurrence of dynamic hyperinflation. In normal subjects,
bronchodilation may occur during exercise and this may also be true in asthmatics that
are bronchoconstricted at rest. However, in a number of asthmatics with normal lung
function at rest, bronchoconstriction may occur after a short submaximal exercise or
even during it if the bout is prolonged. The mechanisms by which exercise-induced
bronchoconstriction develop are triggered by thermodynamic events and involve
inflammatory cells present in the airways at the time of exercise. Furthermore, recent
data suggest that exercise may prime airway inflammation, thus leading to airway
hyperresponsiveness in elite athletes.
Keywords: Airway inflammation, airway resistance, exercise-induced bronchoconstriction.
Acknowledgements. The authors would like to thank P. Paoletti for help in the preparation
of the manuscript.
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18
CHAPTER 4
Bronchial hyperresponsiveness in athletes:

mechanisms for development
L. Bjermer*, S.D. Anderson#
*Dept of Respiratory Medicine and Allergology, University Hospital, Lund, Sweden. #Dept of Respiratory
Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
Correspondence: L. Bjermer, Dept of Respiratory Medicine and Allergology, University Hospital, 221 85
Lund, Sweden. Fax: 46 46146793; E-mail: Leif.bjermer@med.lu.se
Bronchial hyperresponsiveness (BHR) is an abnormal increase in airflow limitation

following exposure to a nonallergenic stimulus [1]. A high prevalence of BHR, relative to
the general population, has been reported in athletes. It is now thought that strenuous
activity itself may be a contributing factor for the development of BHR in young athletes
[2]. However, the airway response to the different provoking stimuli used to measure
BHR is not uniform in athletes and the presence or absence of BHR is seldom simply a
"yes" or "no" answer. Furthermore, there is normally a substantial overlap in bronchial
responsiveness between health and disease. This is demonstrated well in epidemiological
studies where a significant percentage of people with BHR have never had any symptoms
of asthma [3, 4]. This is probably explained by the high cut-off points (e.g. 16 mg?mL-1)
used to define BHR when a pharmacological agent, such as methacholine or histamine, is
used. Before discussing the development of BHR in athletes, it is important to look at the
phenomenon of BHR itself.
BHR is a characteristic feature in asthma but is also commonly found in chronic
obstructive pulmonary disease (COPD) [5]. Moreover, a high prevalence of BHR has
also been documented in other lung disorders, such as sarcoidosis [6], Sjogrens syndrome
[7] and rheumatoid arthritis [8]. BHR appears to be a consequence of many different
pathophysiological phenomena and its presence only confirms abnormality not cause. In
untreated asthmatics with recent disease, BHR in response to direct stimuli, such as
methacholine or histamine, seem to be fairly well linked to underlying inflammation in
the lower airways. BHR is known to increase after allergen challenge [9]. Moreover, in
steroid-naive asthmatics, there is a significant relationship between BHR and induced
sputum eosinophils [10]. The severity of BHR also seems to predict the response to
inhaled corticosteroids in asthma [1113]. Moreover, it was shown that adjustment of
treatment according to BHR provides better long-term asthma control then adjusting
treatment using standard clinical parameters, such as symptoms and lung function [14].
Whilst BHR to stimuli that act directly to cause smooth muscle contraction seems to
relate fairly well to underlying disease activity in previously untreated asthma, the
relationship is less impressive in chronic asthmatics treated with inhaled steroids. Despite
the absence of inflammation in bronchial biopsies from patients treated with inhaled
corticosteroids for years, BHR to histamine was still a prominent feature [15]. Thus,
BHR is only partly related to airway inflammation in people with chronic asthma. BHR
may be explained in part by lower than normal forced expiratory volume in one second
(FEV1) as demonstrated in patients with moderate-to-severe airflow limitation. The
resistance in the peripheral or "small airways" [16] is also likely to contribute to BHR.
Airway calibre is important because narrowing serves to amplify bronchial smooth
ISSN 1025-448x. ISBN 1-904097-22-7.
19
L. BJERMER, S.D. ANDERSON
muscle contraction (fig. 1). There are other factors, including airway remodelling, altered
contractile properties of smooth muscle [17, 18] and thickening of the reticular basement
membrane [19], which potentially contribute to BHR in the absence of active
inflammation. These changes may result from inflammation, but remain after the
inflammation has ceased to be active. In patients with COPD, BHR is related to the
degree of airway obstruction as measured by FEV1 [20, 21]. In asthma, evidence of
peripheral airway obstruction measured by forced expiratory flow through the midportion of the vital capacity (FEF2575) predicts the BHR response to methacholine [22,
23]. Although some suggest FEF2575 predicts exercise-induced bronchoconstriction [24],
this was not demonstrated in a formal study [25]. Difference in baseline airway calibre is
also thought to partly explain the sex difference, with females having a slightly higher
prevalence of BHR to methacholine [26, 27]. In keeping with the concept that baseline
calibre could be an important determinant of response to direct stimuli is the finding that
a low sensitivity to detect BHR with a direct stimulus occurred in athletes with good lung
function and BHR to indirect stimuli [28].
The direct stimuli commonly used are the pharmacological agonists methacholine or
histamine. The indirect physical stimuli that are commonly used include exercise,
isocapnic hyperventilation, hypertonic saline, mannitol or distilled water (table 1). There
are examples of pharmacological agents that act indirectly to stimuli and the most
common one is adenosine monophosphate (AMP).
MCh provocation test
FEV1
Normal
Mucosal
thickening
Mucosal
thickening +
inflammation
Dose
Fig. 1. Schematic illustration of the mechanisms explaining the degree and slope of bronchial hyperresponsiveness in health and disease. The same degree of muscle contraction (#: 30% narrowing illustrated) induces a
different slope response, which is dependent on the degree of mucosal thickening and inflammation. MCh:
methacholine.
20
DEVELOPMENT OF BHR IN ATHLETES
Table 1. Direct and

hyperresponsiveness
Direct stimuli
Indirect stimuli
indirect
stimuli
for
identifying
bronchial
Methacholine, histamine, propanolol

Exercise, eucapnic voluntary hyperpnoea,
mannitol, hypertonic saline
Although referred to as the presence or absence of BHR, the airway response to the
various indirect and direct stimuli varies considerably, and the relationship between the
responses is usually poor [29, 30]. In contrast, the responses to histamine and
methacholine are more comparable. The reason for this may be that these agents are
administered and the response is mediated via receptors on the smooth muscle, whereas
responses to indirect acting stimuli are dependent on the presence of inflammatory cells
and their mediators, in addition to smooth muscle responsiveness. Importantly, the
various indirect stimuli share many common characteristics [1]. The response to indirect
stimuli can, for example, be inhibited by inhaling sodium cromoglycate and nedocromil
sodium, heparin and furosemide [3133]. Another common characteristic of indirect
stimuli is the refractoriness that follows the initial challenge such that the response is less
than half following a second challenge. This refractoriness, sometimes called
tachyphylaxis, occurs in y50% of subjects. Cross refractoriness to the indirect stimuli
has also been documented [34].
Bronchial hyperresponsiveness in athletes

The prevalence of BHR has been reported to be higher in athletes than in the general
population. Most of the studies have been performed using methacholine or histamine
and the prevalence of BHR amongst athletes has been reported to be between 1.52-times
higher than matched controls. The prevalence of exercise-induced bronchospasm (EIB) is
also increased relative to the general population, with reported prevalence rates of 11
50% depending on sport activity and the cut-off values used for fall in FEV1 (15 or 10%)
[35, 36]. However, these studies have been limited by failure to include control subjects.
Langdeau et al. [37] investigated the Canadian Olympic Team and found that nearly
50% were positive to methacholine compared with 18% of the healthy controls. However,
there was no defined border between the presence and absence of BHR, but more a
continuous distribution with a tendency for the athletes to be more responsive [37]
(fig. 2).
There are some common risk factors to all athletes and also some risk factors that are
specific for the individual sporting activity (table 2). While hyperpnoea of dry, cold air
may be a dominating risk factor in cross-country skiers, cyclists are exposed to road dust.
As with marathon runners, cyclists are exposed to airborne allergens. Swimmers are
exposed to chlorine gas and skaters to ozone and oxides of nitrogen (table 2).
Risk factors for development of BHR in athletes: possible

mechanisms
Immune suppression: respiratory tract infections
One common risk factor is the increased vulnerability to respiratory tract infections in
all athletes who perform strenuous physical activity. Of nearly 1,300 marathon runners
attending the Los Angeles (CA, USA) marathon in 1987, 12.9% reported that they had a
respiratory tract infection within 1 week after the run! This value compared with only
21
80
Cumulative % of subjects
70
60
50
40
30
20
10
0
<2
<8
<16
PC20 methacholine mgmL-1
16
Fig. 2. Methacholine provocation test amongst 100 high-level athletes from Canada (&) compared with 50
healthy non-athletic controls (h). A general trend towards increased hyperresponsiveness was seen amongst the
athletes. PC20: provocative concentration of methacholine causing a 20% reduction in forced expiratory volume
in one second. Reproduced with permission from [37].
Table 2. Risk factors for development of

bronchial hyperresponsiveness in athletes
Irritants
Cyclists (e.g. road dust, diesel exhaust)
Swimmers (e.g. chloramines)
Skaters (e.g. N2O, ozone)
Cold, dry air
Skaters
Allergens
Marathon runners
Cyclists
Viral infections
All strenuous sport activities
2.2% for the control group [38]. There is evidence that immunosuppression occurs in
relation to strenuous activity and is greatest in the hours immediately following
strenuous activity. The term "open window theory" is used to refer to this period of
suppressed immunity and it occurs between 372 h after heavy exercise. During this time
there is an increased susceptibility for viral or bacterial infections that might be clinical or
subclinical [39]. Potential important immunological features are decreases in: T-cellmediated immune responses (including reduced proliferative response to lectins [40]);
delayed type hypersensitivity reactions [41]; phagocytic activity and oxidative burst
amongst macrophages and neutrophils [42]; and NK cell activity [43] (fig. 3).
Another important immunological feature is the decreased humoral response
documented after strenuous exercise. A decrease in immunoglobulin (Ig)A concentration
in nasal secretions by 70% was observed for i18 h after racing 31 km [44]. Following
strenuous prolonged exercise, salivary secretion rates fall, decreasing the level of IgAmediated immune protection at the mucosal surface [45, 46]. Moreover, nasal
mucociliary transit time is significantly prolonged for several days after a marathon
22
NK cell activity, total lytic units
350
300
250
200
150
100
50
0
Pre-run
Post-run
1.5 h post-run 3 h post-run 6 h post-run
Fig. 3. Natural killer (NK) cell activity response to 2.5 h of intensive running in 62 marathon runners. Data
reproduced with permission from [43]. *: pv0.05.
and is caused in part by abnormally functioning ciliated cells [47]. This is presumably due
to dehydration of the nasal surface fluid layer making the cilia less efficient. In a recent
study of marathon runners competing in the Western States Endurance Run, 26% of
those completing the run reported an upper respiratory tract infection (URTI) within 2
weeks of the race. The best predictor of getting an infection was a low serum IgA
secretion rate at mid-race after 90 km [48]. Interestingly, lymphoid aggregates mimicking
bronchus associated lymphoid tissue (BALT) is commonly found in cross-country skiers
with BHR [49] (fig. 4). Even though the pathogenesis is unclear, the present authors can
speculate that these changes are an indication of immune response to repeated clinical or
subclinical infections [50, 51]. In keeping with this speculation is the finding that training
with an URTI induces a long-lasting (i6 weeks), increased BHR to histamine [52]. Thus,
immune suppression may play a role in the development of BHR, at least in endurance
athletes.
Influence by (cold) dry air hyperventilation

Airway injury following hyperpnoea of cold, dry air is also likely to be an important
risk factor for the development of BHR in cross-country skiers. Repeated dry, cold air
hyperpnoea in dogs has been shown to increase resistance in the peripheral airways [53].
This increased resistance is associated with increased production of pro-inflammatory
mediators (leukotriene (LT)B4 and LTC4) and an increased number of inflammatory cells
(neutrophils and eosinophils) in bronchoalveolar lavage (BAL) fluid [53]. The same
increase in peripheral airway response has been reported in humans breathing cold, dry
air [54]. Dry air represents an osmotic stress to the respiratory mucosa with dehydration
[55] leading to shrinkage and sloughing of epithelial cells [56]. Epithelial cells and mast
cells are believed to be of special importance, releasing inflammatory mediators, such as
histamine, leukotrienes and prostaglandins (PGs), in response to the osmotic effects of
dehydration [57, 58]. Elevated levels of urinary LTE4 have been documented after EIB
[59] and increased concentrations of leukotrienes have also been measured in BAL fluid
after dry air hyperpnoea [60]. The role of leukotrienes is to sustain the airway narrowing
provoked by exercise and this has been demonstrated by pre-medication with a
leukotriene receptor antagonist enhancing recovery from EIB [61]. In particular, PGD2
(measured as the metabolite 9a,11bPGF2) is also an important mediator and significant
23
a)
b)
c)
Fig. 4. Lymphoid aggregates in bronchial mucosa from a skier with asthma symptoms and bronchial
hyperresponsiveness. Haematoxylin-eosin staining (a). CD3 stains all T-cells and CD20 all B-cells (b and c).
Adapted with permission from [49].
24
increases in this metabolite have been noted in the urine after exercise [57, 62]. The
cyclooxygenase inhibitors, such as flurbiprofen [63] and indomethacin [64], have been
shown to partly inhibit the exercise-induced airway response. However, total inhibition
of PG synthesis is not necessarily positive because some PGs are protective. For example,
epithelial cells synthesise PGE2 and this plays an important role in refractoriness to
exercise, preventing EIB after repeated challenges [65]. Osmotic stimulus to epithelial
cells in vitro induces release of interleukin (IL)-8 [66]. IL-8 promotes neutrophil
chemotaxis, an event that has been reported in vivo during EIB [67].
Indeed, it may be the loss of protective PGs that makes the difference in the airway
response to exercise between asthmatic and healthy subjects who have BHR. There are
several important pieces of information that have come together recently that may help
to explain how an athlete may become responsive to exercise. The first is the finding of
mast cells in healthy subjects close to the airway surface [68, 69]. The second is the finding
that healthy subjects do release mediators, such as PGD2 and LTs, in response to
dehydration stress. Thus, Mickleborough et al. [57] and Caillaud et al. [58] found
strenuous exercise, and Brannan [70] found inhalation of mannitol in healthy fit
subjects, was associated with increased urinary excretion of the metabolite of PGD2 and
LTC4. If the mediators are present in sufficient concentrations then it only remains for
the airway smooth muscle to become responsive for the airways of otherwise healthy
people to respond. It is the events that might make the airway smooth muscle of the elite
athletes sensitive that are of interest. Several mechanisms suggested by different
investigators are illustrated in figure 5 [2]. They include airway injury in response to
excessive dehydration stress causing exudation of plasma and repeated exposure to
circulating substances in the repair process.
Studies in skiers. Skiers from mid-Norway and Sweden aspiring to be elite were
investigated with methacholine provocation test, bronchoscopy and BAL. While the
skiers in Sweden had their training in a cold, dry climate, the Norwegian skiers trained in a
coastal climate that was less cold. The difference in temperature (usually -20 versus -5uC) is
a possible reason why the prevalence of BHR was higher in Sweden versus Norway (45
versus 15%). Bronchoscopy and BAL of these skiers revealed evidence of airway
remodelling, shown by increased deposition of tenascin and collagen close to the
basement membrane. Interestingly, the thickening was the same for both those with and
without current BHR to methacholine, indicating that the structural changes were a
general consequence of chronic hyperpnoea of cold, dry air [71]. Bronchoscopy and BAL
also revealed a pattern of inflammation different from the one usually seen in non-athletic
asthmatics. With the exception of a few atopic subjects there was no evidence of
eosinophil activation. A slight increase of neutrophils, tumour necrosis factor (TNF)-a
and myeloperoxidase was measured in the skiers, as well as increased numbers of mast
cells and lymphocytes [72]. However, no significant differences could be seen in the
inflammatory pattern between those with or without current BHR. The subjects were also
investigated using noninvasive markers of inflammation, which included bronchial
provocation with AMP [73] and the measurement of exhaled nitric oxide (eNO). Slightly
elevated levels of eNO and increased responsiveness to AMP were measured, but only in a
few subjects, all of whom were atopic [74].
A trial of 3 months treatment with the inhaled corticosteroid budesonide in skiers with
exercise-induced "asthma" symptoms and BHR was also conducted. Interestingly, with
the exception of a slight improvement in FEV1 in the budesonide treatment group, no
beneficial effect could be measured. Thus, there was no effect of treatment on BHR,
airway remodelling or inflammatory indices measured in the biopsies or BAL. In
contrast, most of the changes seem to be related to intensity of "dehydration" stress to the
25
Heat loss
Water loss from humidifying inspired air
Recruitment of small
airways (<1 mm) into
humidifying process
Dehydration of the ASL

Airway cooling
Increase in [Na+], [Cl-], [Ca2+], [K+]
Glandular secretion
Increase in osmolarity of ASL

Water moves from all cells to restore ASL
Cell shrinkage
followed by release of mediators
Sensory
nerves
Mucus
Cough
breathlessness
Symptoms
Airway smooth muscle contractionoedema

Microvascular leak
and exudation
of plasma
Cells
Amplification of
normal FEV1
response to
exercise
Repeated exposure to plasma

products alters properties
of airway smooth muscle
rgic
Alle ct
je
Sub
e.g. Histamine, prostaglandins,

leukotrienespeptides
Epithelial damage,
loss of protective
mediator PGE2
AHR to
pharmacological
agents
Sensitisation
of airway
smooth muscle
Increased response to
acute increase of
leukotrienes, prostaglandins, etc.
Fig. 5. Schematic presentation of mechanisms related to hyperpnoea of cold, dry air and effect on the airway
mucosa. ASL: airway surface liquid; FEV1: forced expiratory volume in one second; PGE2: prostaglandin E2;
AHR: airway hyperresponsivenes. Reproduced with permission from [2].
airways. For example, there was a clear improvement documented in the placebo group
when the skiers went from a high intensity to a less intense period of training [75]. This is
in keeping with other observations in skiers [76]. A recent report in elite swimmers shows
similar findings, with spontaneous recovery occurring in those reducing their exposure
following retirement from high-level sport activities [77].
Thus, it seems as if cold, air hyperpnoea in humans produces asthma-like symptoms
that in many circumstances differ from those usually seen in asthmatics who are not elite
athletes. The role of sensory nerve stimulation in response to increased osmolarity may
serve to explain some of these symptoms in the absence of airway narrowing [78, 79].
For winter athletes, chronic dehydration or other stress to the airways may result in
exposure to circulating substances with the potential to induce airway remodelling and
an increase in contractility of the smooth muscle leading to BHR [2]. In contrast, in
summer athletes, the inflammatory response is more characterised by increased numbers
of lymphocytes, mast cells and neutrophils, while eosinophils are only seen in those who
are also atopic.
Allergen exposure
The hyperpnoea of exercise, especially during the summer, increases the allergen load
and thereby the risk of being sensitised to airborne allergens. Under resting conditions,
pollen allergens (w10 mm) are usually filtered out by the nose and have the potential to
26
cause allergic rhinitis. During hyperpnoea, there is a shift from nose to mouth breathing
so that there is an increased amount of allergen that enters the lower airways, despite the
relatively large size. Many patients with rhinitis have BHR to methacholine or histamine
[80]. Bronchoscopies and studies of induced sputum have indicated asymptomatic
inflammation in the lower airways in people with allergic rhinitis. This suggests that
rhinitis is an intermediate stage and indicates a high risk of developing asthma later. In
the 2000 Olympic and Paralympic Games in Sydney (Australia) 56% gave a symptom
history consistent with allergic rhinoconjunctivitis, 41% had symptoms of allergic
rhinoconjunctivitis and a positive test response to any one allergen, and 29% had
seasonal allergic rhinoconjunctivitis (a positive history and at least one positive skinprick test response to a seasonal allergen) [81]. In elite athletes from Finland, the highest
prevalence of asthma was found in swimmers. However, in elite runners, asthma
symptoms were closely related to those sensitised to airborne allergens [82]. This finding
contrasts with the reported low prevalence of allergy in skiers [83] who are less likely to be
exposed to massive amounts of airborne allergens compared with summer athletes.
Influence by irritants
Several studies report a high prevalence of BHR to methacholine or histamine in
swimmers [8487]. However, while 60% had a provocative concentration of methacholine
causing a 20% reduction in FEV1 v8 mg?mL-1, only 20% of the swimmers in the
Canadian Olympic Team had exercise-induced wheeze or dyspnoea [37]. The same
discrepancy between BHR and prevalence of symptoms has been reported by other
investigators [88]. In a study on Finnish swimmers, active elite swimmers were compared
with those who had retired from active swimming. The group was followed for 5 yrs. The
prevalence of atopy in the group that were actively swimming was 56% at baseline and
increased to 69% at follow-up. Among the retired swimmers, the atopy prevalence was
46% on both occasions. The prevalence of BHR to histamine was 44% in the active
group, increasing to 50% at follow-up, compared with 31% amongst the retired
swimmers, decreasing to 12% (pv0.05) at follow-up. The change in BHR was associated
with evidence of airway inflammation as measured by a slight increase in sputum
lymphocytes and eosinophils [77, 89].
Chlorinated pools and asthma development

Chloramine is formed when chlorine from the water reacts with protein from the
airways. Increased exposure to chlorine is thought to contribute to the development of
BHR in swimmers. Although the concentration of chlorine in the air may not be high, the
high ventilation rates of exercise mean that the actual amount of chlorine inhaled during
periods of intense training may result in a high total load of chlorine [90].
Further prolonged stays in swimming halls may also induce problems in non-athletes
[91]. Reduced plasma Clara cell protein (CC16) levels have not only been reported in
swimmers but also in pool attendants who are repeatedly exposed to the chlorine in
swimming pools. CC16 is a protein important for mucosal defence and is produced by
the Clara cells in the airways. CC16 has been found to be related to BHR in asthmatic
children [92], and induction of allergic inflammation in the lower airway in asthmatics is
associated with reduced serum CC16 levels [93]. The important role of CC16 in mucosal
defence was further explored in a recent study, which indicated an interaction between
chlorine and ozone exposure on Clara cell function measured as expression of CC16 [94].
The degree of exposure to natural ozone was measured in children spending 4 h
27
outdoors. The children were divided in two groups according to those who frequently
visited indoor pools and those who seldom visited indoor pools. In the group who
frequently visited indoor pools, significantly lower plasma CC16 levels were found.
Moreover, during outdoor stay and ozone exposure, there was a tendency of further
decrease in CC16 levels in this same group while those who infrequently visited the pool
showed an opposite pattern.
Skating and asthma

Increased prevalence of BHR is also reported in skaters [88, 9597], as well as in ice
hockey players [98, 99]. Levy et al. [100] measured levels of nitrogen dioxide (NO2) in
different ice halls and found mean daily concentrations of 37206 parts per billion (ppb)
[100]. Exposure to 4 parts per million of NO2 for 20 min is known to induce
inflammation in the lower airways [101]. Exercising at high ventilation for hours in ice
halls, with NO2 concentrations w100 ppb, could result in a cumulative dose above the
level that is known to induce inflammation in previously healthy subjects. Interestingly,
treatment with montelukast in these ice hockey players with asthma symptoms and
presence of BHR did not prove to be beneficial. This is in contrast to what is known from
treating exercise-induced asthma in nonatopic subjects and indicates that the
phenomenon seen in ice hockey players represents a different pathophysiology.
However, a recent study reports a benefit from montelukast when exercise is performed
in an environment where there is a high concentration of particles [102]. What is of great
concern is the report of a faster than normal decline in FEV1 in young female skaters
training in facilities where the ice resurfacing machines are driven by diesel fuel [103].
Cycling and asthma

Cyclists are repeatedly exposed to irritants, as well as allergens, and this group had the
highest frequency of recorded use of asthma medication (50%) amongst 1996 USA
summer Olympians [95]. Road dust and diesel exhaust are two important trigger factors
for airway inflammation, and motor vehicle emissions, especially from diesel engines, are
a major source of airborne pollutants. The combustion of fossil fuels produces a number
of unhealthy substances, including carbon monoxide, nitrogen oxides, benzene, sulphur
dioxides and particulate matter [102, 104]. Experimental studies exposing healthy
humans to diesel exhaust particles (DEP), in concentrations that can be expected in daily
life situations, has shown increased airway resistance and increased numbers of
inflammatory cells, mainly lymphocytes and neutrophils, in the airways. Similar
exposure of mild asthmatics also induced increased airway resistance. Exposure to DEP
has also been shown to increase responsiveness to methacholine and to increase the IL-6
concentration in sputum [105]. In addition, DEPs can interact with allergen to augment
allergen-induced responses, so that allergen-specific IgE levels are up to 50-fold greater in
allergic subjects challenged with DEPs plus allergen than in those receiving allergen
alone. There is also evidence that DEP exposure can drive the allergen-induced response
towards the T-helper cell type-2 pathway, possibly through direct stimulation of mast
cells and basophils in the airways [106, 107].
28
Summary
Development of bronchial hyperresponsiveness (BHR) is complex, although there are
common risk factors for all athletes. These include: 1) effort-induced immunosuppression with increased vulnerability to respiratory tract infections and 2) exercise-induced
hyperpnoea causing the airways to be exposed to higher than normal levels of
allergens, fine particles and gases, and to be subjected to dehydration stress from
conditioning of large volumes of cold and dry air.
Whilst exposure to airborne allergens is important in cyclists and runners, it is the
irritants and gases that are important in swimmers and skaters. The bronchoscopy
findings in skiers suggest that airway injury can occur simply from the dehydration
stress. One potential outcome of dehydration stress is exudation of bulk plasma to
restore the airway surface liquid. If the smooth muscle is repeatedly exposed to plasma
products that have the potential to alter its contractile properties, then it is likely to
become more sensitive to circulating mediators, such as leukotrienes and prostaglandins. In a winter athlete, this could lead to nonspecific BHR and in an atopic athlete
the smooth muscle could become passively sensitised and develop BHR to allergens.
Nonspecific BHR in athletes should not be necessarily interpreted as an indicator of
asthma. Skiers and skaters have failed to benefit from treatment with either inhaled
corticosteroids or leukotriene antagonists. Other strategies are required and these
should include a reduction in environmental levels of potentially offending agents e.g.
chloride content in swimming pools, fine particles and nitrogen dioxide in ice hockey
halls.
Winter athletes may benefit from using heat-exchange devices and summer athletes
from masks that capture allergens. Due to the increased vulnerability to respiratory
tract infections, hard training and competition in close relation to a recent upper
respiratory tract infectious episode should be discouraged. These interventions may
lead to a reduction in the prevalence of BHR in elite athletes.
Keywords: Aeroallergens, bronchial hyperresponsiveness, fine particles, gases,
infection, injury.
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34
CHAPTER 5
The role of the environment and climate in

relation to outdoor and indoor sports
F. Drobnic*,#, T. Haahtela}
*Dept of Sports Physiology, Olympic Training Center - CAR, Sant Cugat del Valles, and #Medical
Services, FC Barcelona, Barcelona, Spain. }Dept of Allergy, Skin and Allergy Hospital, Helsinki University
Central Hospital, Helsinki, Finland.
Correspondence: F. Drobnic, Dept of Sports Physiology, Olympic Training Center CAR, Avda Alcalde
Barnils 3-5, 08173 Sant Cugat del Valles, Spain. Fax: 34 936754106; E-mail: drobnic@car.edu
Outdoor and indoor environment

The number of hours spent in training at high intensity levels by athletes is
progressively increasing. At the same time, a growing number of recreational athletes are
more concerned about the intensity of their training schedules. Physical exercise imposes
a stress on the respiratory tract as it eliminates carbon dioxide and supplies the muscles
with oxygen for energy production. Increased ventilation may go as high as 1015 times
above the normal resting frequency. For the asthma patient, this represents the most
important stimulus for the onset of exercise-induced asthma (EIA).
Increased ventilation rate and oral breathing displaces pulmonary uptake of pollutants
to more distal sites in the lung, thereby further increasing the deposition of ambient air
pollutants in the distal airways. This may affect the athlete who suffers from asthma or
bronchial hypersensitivity. Cross-sectional studies have demonstrated that competitive
athletes have a high prevalence of asthma and EIA or bronchial hyperreactivity.
Mechanisms include increased inhalation of cold air, allergens and pollutants,
respiratory infections, and increased parasympatethic tone [18]. This chapter provides
a review of the outdoor and indoor environmental factors that may affect the airways of
the asthmatic athlete.
Cold and dry air

It is assumed that drying of the lining of the airway wall during exercise is the main
factor in the early EIA reaction, modulated by the inspired air temperature [9].
Hyperpnoea induces EIA by causing loss of water from the respiratory mucus [10, 11].
Evaporative water loss causes increases in the osmolarity of the airway surface liquid of
the respiratory tract due to a concentration of ions [12]. The osmolarity change, due to
the dry air, may be more important than heat loss for determining EIA [13]. Even in the
healthy athlete the combined effect of the drying and temperature stimuli to the airways,
stimulating vagal nerve activity, can provoke minor bronchoconstriction [14]. The effect
of cold and dry air has also been evaluated in animals practicing sports, such as Alaskan
sled dogs [15, 16], showing that 81% of the dogs have intraluminal debris, indicating
significant accumulation of exudate. In cold environments, the hotter it is when
asthmatic patients stop exercising the more intense the bronchoconstriction [17]. This
emphasises the importance to the athlete of "cooling down" slowly after ending an
ISSN 1025-448x. ISBN 1-904097-22-7.
35
F. DROBNIC, T. HAAHTELA
exercise session, which allows the airways to gradually recover the initial temperature.
Individuals sensitive to temperature changes may experience dyspnoea when entering a
hot environment following moderately intense exercise in cold surroundings.
Air pollutants
There are a large number of chemical compounds present in the polluted ambient air
that, alone or in combination, have the potential to affect the respiratory system and
athletic performance [18]. Many of these substances may induce inflammatory responses
in the asthmatic athletes respiratory tract. A number of factors can contribute to it,
including: 1) concentration of pollutants; 2) ventilation level; 3) previous state of the
airways; and 4) other atmospheric factors, such as temperature or humidity. There is an
estimated mean increase of 3% in the prevalence of lower respiratory symptoms with
each 10 mg?m-3 increase in the daily mean concentrations of airborne particulate matter, a
0.7% increase in the prevalence of upper respiratory symptoms for each 10 mg?m-3
increase in airborne particulate matter v1 mm [19].
Polluting agents can be classified as primary or secondary. The primary agents, e.g.
CO, CO2, Sulphur dioxide (SO2), nitric oxide, and metals, such as lead, graphite or coal,
originate from a source and do not undergo significant chemical changes. Even if changes
take place, these are irrelevant from the clinical point of view. Secondary agents are
produced through chemical reactions from natural precursors or are emitted by artificial
sources, such as ozone (O3), nitric acid, sulphuric acid, nitrate peroxiacetyl and a great
number of inorganic compounds, which can exist in gas or particulate form. The most
important source of both types of agents is oil combustion in cities and industrial areas.
For athletes suffering from asthma, the risk environments are the big industrial cities
with heavy car traffic.
There is some evidence that the incidence of new diagnoses of asthma is associated
with heavy exercise in communities with high concentrations of O3. Air pollution and
outdoor exercise may contribute to the development of asthma in children [20]. Although
no effect of sports on asthma has been seen in communities with high concentrations of
pollutants (other than O3), it is difficult to evaluate the real power of other pollutants
alone, in terms of the development of newly diagnosed asthma, or to identify the
interaction between sports and other pollutants, other than O3 [20]. Nitrogen dioxide
(NO2) may increase the risk for asthma exacerbation in adults [21].
The role of atopy in sports-related asthma is unclear. For example, atopy did not
modify the risk of asthma associated with nordic skiing [1], but those children with
bronchial hyperresponsiveness and relatively high concentrations of serum Immunoglobulin E are susceptible to air pollution [22].
Ozone. O3 is a gas that is produced by electric or a photochemical reactions of ultraviolet

radiation of a certain wavelength. At high concentrations, O3 can be very harmful due to
its oxidative power. This is the most potent oxidative gas found in ambient air and is the
most significant component of photochemical smog.
Exposure to O3 provokes nose and throat irritation, shortness of breath, and shallow,
rapid breathing, as well as alteration of the breathing function at low intensity training
[23]. Some long-term adaption to O3 exposure may occur [24, 25]. After 2 days of O3
exposure, symptoms and respiratory function stabilise [26]. However, this adaptation
disappears after 1 week if the exposure is stopped or when the O3 concentration increases
[27]. Although O3 can affect the lung tissue, the alveolar gas exchange is not affected.
Diffusion and transport of oxygen and CO2 is not altered [28]. The inflammatory and
lung function responses to O3 differ between individuals and are usually reproducible,
36
ENVIRONMENT AND CLIMATE IN RELATION TO SPORTS
and are similar in healthy or asthmatics subjects. Therefore, these responses appear to
represent two independent factors underlying the airway response to O3 [29].
Athletes, even if well trained and in good health, when exposed to high levels of
environmental pollutants and when breathing high volumes of air, as is required when
exercising, are at risk for the problems mentioned above. The need for a high ventilation
volume contributes to disconnection of the nose as a filtering air barrier. This increases
the amount of toxic substances penetrating into the lower airways. In healthy people,
airway reactivity is increased after 5 h of exercise, which is equivalent to a day of
moderate-to-heavy work or play during exposure to 0.08 ppm of O3 [30]. O3 also
increases responses to allergens in ambient air [31]. In communities with high O3
concentrations, the relative risk of developing asthma in children playing three or more
sports is 3.3-times higher compared with children not playing any sports. Also, the time
spent outside was associated with a higher incidence of asthma in those areas [20]. The
increased pulmonary dose of ambient O3 resulting from heavy exercise, combined with
exposure to outdoor and indoor allergens, is one possible mechanism for inducing newonset asthma or for exacerbating existing disease [20]. Fortunately for asthmatic athletes,
response to O3 is similar to that of healthy adults, and the bronchoconstriction caused by
subsequent exercise after exposure to O3 has not increased [32]. However, it does increase
the response to subsequently encountered allergens, and this is of special importance to
those athletes who may encounter both airborne allergens and O3 during exercise [33].
The vasoconstriction produced by O3 seems to diminish after administration of
topical atropine [34] and a cyclooxygenase inhibitor [35]. The efficacy of b-agonists is
unclear [36].
Sulphur dioxide. Coal and oil combustion produce SO2, which is a common
environmental pollutant produced mainly from oil derivatives and also from the
paper, varnish and enamel manufacturing industries and products containing sulphur. It
is readily absorbed by epithelial fluid and bronchial mucus forming the acidic compounds
involved in inflammation. As a consequence, basal pulmonary function may deteriorate
and bronchial hyperreactivity may increase [37]. Exercise increases the effect of this gas
[38]. These physiological effects are responsive to treatment with b-agonists, cromolyn
and atropine but are unresponsive to theophylline and steroids [39]. Spontaneous
recovery has been reported after 30 min of challenge, with a refractory period of up to 4 h.
Repeated exposures to a low concentration of SO2 over a short period can induce
tolerance to the bronchomotor effect of SO2 [40, 41]. However, responsiveness is restored
within 6 h.
The response of the asthmatic athlete to SO2 depends more on the concentration of the
gas than the humidity and temperature of ambient air [42]. However, previous exposure
to cold or dry air has exacerbated the bronchospastic effect of SO2 in asthmatics [43].
Other symptoms include nasal irritation, conjunctivitis, pharyngitis and an unpleasant
sulphur smell. Serious symptoms in nonreactive subjects are rarely produced if the
concentrations are not very high.
Nitrogen dioxide. Nitrogen oxide is a precursor of photochemical smog, and is found in

ambient outdoor air in urban and industrial regions. NO2 is formed by oil combustion
and from its derivatives, which are used by cars. There are two daily concentration peaks
in cities: one early in the morning and the other in the afternoon. Other places where NO2
is found are smoking areas and areas heated with kerosene and gas stoves. Like O3, NO2
produces oxidation of cell membranes of the respiratory airways and free radicals with an
inflammatory response [44], but the mechanism by which NO2 alters airway function is
unclear.
37
In asthmatic subjects exposure to NO2 increases bronchial reactivity to other stimuli,

such as cold or exercise [45], despite the fact that response to methacholine is not affected
[46]. The high prevalence of asthma in competitive figure skaters might be related to NO2
generated by ice-grooming equipment [6]. However, controlled chamber studies reveal no
consistent effect of NO2 on airway function of either normal subjects or those with
asthma [47].
Chlorine. Chlorine is a greenish-yellow gas used in the sterilisation of water supplies and
in swimming pools. It is a potent irritant to the mucous membranes, eyes and skin, and its
exposure causes pulmonary irritation [48]. Accidental exposures of humans to high
concentrations during work and sports activities have been reported [4951]. There is
insufficient evidence to conclude that there is chronic impairment of pulmonary function
after acute or chronic exposure in athletes, but some observations indicate effects of
chlorine on the airways. Swimmers inhale high amounts of chlorine during training and
competition throughout their sporting season [52]. The sudden onset of reversible airway
obstruction in young swimmers [53], increased sensitisation to aeroallergens [54], high rate
of bronchial responsiveness to methacholine [55], increased lung epithelium permeability
[56] or epithelial integrity [57], or change in the antioxidant status of the respiratory
airways [58] suggest that high exposure to chlorinated products in indoor pools might be
an important cause in the respiratory problems in the athletes.
Cigarette smoke. Parental tobacco smoking worsens airway function and increases the
incidence of wheezy respiratory illnesses in infants [59]. Increased bronchial reactivity [60],
even from prenatal cigarette smoke [61], increases upper respiratory infections, induces
small airway damage [62], and may even induce exercise-induced narrowing in children
[63]. Cigarette smoking produces a 10% increase of the basal metabolic rate and an almost
inverse relationship between the levels of carboxyhaemoglobin (COHb) and the capacity
to achieve maximal oxygen consumption, influencing not only the work capacity of the
athletes but also the recovery from exercise.
Cannabis. Cannabis was banned by the World Anti-Doping Agency in 1986. Its
consumption by athletes is inexcusable [64]. Tetrahydrocannabinol (THC) in cannabis
has been shown to have a short-term bronchodilator effect [65]. This has lead to
suggestions that THC may have therapeutic benefits in asthma. However, the noxious
gases, chronic airway irritation or risk of cancer after long-term use, associated with
smoking, negate the possible benefits [66]. Other noxious effects of the cannabis smoking
habit include: 1) an increase in the fixation of COHb (more than five times that obtained
from tobacco); 2) a suppression of the inmune system; 3) increased deposits of tar; and 4)
increases in cellular abnormalities, indicating a cumulative effect of smoking [67, 68].
Effect on psyche and social behaviour are no less important [69, 70].
Eradicating drug usage in sport is only possible by developing strict policies to deal
with those athletes who use banned substances, refinement of drug testing procedures
and enhancement of athlete education [71, 72].
Aeroallergens. Subjects suffering from allergy to certain aeroallergens will be more

exposed if their sport requires them to run long distances, travel frequently to diverse
places or exercise during certain times of the year [5, 73]. Moreover, if their sport requires
an important respiratory debt, the aeroallergens will perhaps reach the respiratory tract
through unusual channels. This will produce a positive skin-prick test result in atopic
athletes who will be prone to EIA. With one or two positive responses, the risk is 3.1, and
with five or more, the risk is 4.7 compared with skin-prick test negative subjects [2]. The
38
practice of a sports activity combined with sustained allergenic inhalation, as occurs in

diving, is unfortunate and at the same time avoidable [74]. This situation should bring us
to reconsider the control mechanisms of this sport and the environment in which it is
carried out.
Upper respiratory airway infection. Upper respiratory tract infection (URTI),

pollution, exercise and asthma are increasingly being related. Intensive training is
associated with an increased risk of URTIs, and elite athletes are at a greater risk than
those undertaking more moderate training regimes [75]. The most frequent precipitating
factor associated with acute asthma is respiratory virus infection [76]. This has been
shown by case reports [77], time series studies [78], identification of viruses during
exacerbations of asthma [79] or following prospective longitudinal studies of individual
asthma [80].
Exercise can induce significant and measurable immunological changes involving a
transient immune suppression (changes in the number and activity of neutrophils,
lymphocytes and macrophages, and the secretion of cytokines) [81]. Johnston et al. [82]
confirmed the high incidence of viral infection in acute exacerbation of asthma, especially
enteroviruses or rhinoviruses. Persistent clinical features are more frequently associated
with atypical bacterial infections, suggesting these infections should be investigated and
treated in cases of persistent asthmatic symptoms [83]. Respiratory tract infection and
bronchial responsiveness has been observed in elite athletes and sedentary control
subjects, and when it is related to environmental conditions, seasonal variations and
training intensity [7, 8]. Sport can be important in the development of URTIs, and not
just in elite athletes; for example, baby swimming increases the risk of recurrent
respiratory tract infections and otitis media [84]. In fact, Chlamydia pneumoniae infection
has been reported as a possible aetiological agent in asthma, which in primary care
settings often appears to be initiated by acute respiratory infections [7, 8]. Serological
markers of C. pneumoniae infection were associated with acute bronchitis and with
asthma (which first became symptomatic following respiratory illness). Serological
responses to C. pneumoniae may be useful in the classification and diagnosis of asthma
[85], mostly in those who have a variant of the mannose-binding lectin alleles, who seem
to have a susceptibility to asthma when infected with C. pneumoniae [86]. Some attempts
to identify any relationship between C. pneumoniae and Mycoplasma pneumoniae
infection in athletes has been made [87], and its impact on incidence of EIA symptoms,
but a low correlation was found [84, 88].
Impact of the sport activity

The prevalence of asthma and bronchial responsiveness is greater amongst elite
athletes than in the general population [89]. This prevalence is even higher amongst
certain groups of athletes (e.g. long distance runners, cyclists, cross-country skiers and
swimmers) than amongst athletes in general. The underlying inflammation in such
athletes is often a mixed type of eosinophilic and neutrophilic response, and has been
related to the presence of atopy, type of sport, seasonal activity and duration of training
[90]. The characteristics of the inflammation indicate a strong irritative component (high
number of neutrophils) as well as more of an allergic type component (high number of
eosinophils). Inflammation can be reversed, at least partially, when an athletes period of
active training comes to an end [91], suggesting that it is at least partly caused by
participating in heavy training (table 1).
39
Table 1. Recommendations for athletic competition in polluted environments

Organisers of the sport event
Investigate the characteristics and needs for the sport
Evaluation of training areas
Establish the time of day for the sport event on the basis of lowest pollution levels
Establish measures to limit pollution during physical activities (factories, cars, etc.)
Assess the ventilation of indoor sport facilities
Assess the temperature for outdoor events
Athletes team (technical personnel, athletes)
Plan the arrival of the athletes i3 days before competition
Use a preventive medication for cough post-exercise in sensitive subjects
Evaluate the presence of other possible contaminants and establish preventive measures in hyperreactive
subjects (asthmatics or nonasthmatics)
If the sports area is highly contaminated consider cancelling the events mainly in those sports of high intensity and
long duration
Check the accommodation and living conditions for athletes
Check pollen charts for the competitive area for the season for the competition
Indoor practice
Swimming and other water sports. Water sports are indicated in asthmatics. The
adaptation to the effort of heavy swimming in children with asthma is basically the same
as that observed in nonasthmatics [92]. There is no satisfactory explanation for the
advantage of exercising in water for asthmatic patients. In contrast, an increase in
bronchial sensitivity in asthmatic and nonasthmatic swimmers has been reported when
compared with a reference population and with other athletes [93, 94]. If EIA is triggered
by dry air and intensive ventilation, asthmatic subjects may use indoor pools where the
temperature and humidity is 2430uC and 6070%, respectively.
Even by changing the air composition [95] it is suggested that, unlike running,
swimming is of low asthmogenicity, even when the inspired air is dried to 2530% at
neutral temperatures [96]. The reason for this beneficial effect [97] is difficult to explain as
body posture on land has no meaningful effect on the severity of bronchoconstriction in
asthmatic children [98]. Also, airway hyperactivity is not alleviated by whole-body prone
immersion [99]. Therefore, there is no satisfactory explanation for the advantage of
exercising in water. Respiratory and other health-related complaints also become evident
when swimmers exercise for long periods of time at high intense or minute ventilation [93,
100]. This situation can be maintained with an alteration of the cellular and inflammatory
response of these athletes [57], probably modulated by excess of chorine inhalation
throughout the sporting life of the athlete [52]. Elite athletes who practice water sports
have mild neutrophilic inflammation, whether they have asthma or not, which is related
to the degree of bronchial reactivity and the duration of training in the swimming pool [4,
101]. In contrast, if the possible infectious influences in the development of asthma are
considered, asthma may be triggered in this particular type of sport [55, 102]. Differential
diagnosis has to be made with swimming-induced pulmonary oedema (observed in some
swimmers and divers), which can masquerade as EIA.
Ice hockey players and skaters. In a study by Lumme et al. [103], the presence of a
positive histamine challenge test and atopy (determined by skin-prick test), was 24% and
58%, respectively, in a total of 88 ice hockey players. Similar results were obtained for
methacholine tests (34.6%) and prevalence of asthma (19.2%) in this sport by other
authors [104], and in those related with ice arenas [105]. A mixed neutrophilic and
eosinophilic airway inflammation was shown in these athletes and is associated with
40
exposure to cool air and indoor inhaled pollutants, such as NO2, during intensive training
[103, 106].
Cycling. Indoor cycling is a strenous exercise practiced by a lot of athletes in the Nordic
countries, mostly during the winter season. However, indoor cyclists usually perform part
of their season and training outdoors. Respiratory problems were mostly related to those
observed in other outdoor endurance athletes, as explained below. Even though the places
of competition and training are large and spacious, ventilation and smoke exits have to be
taken into account in acute cases.
Outdoor practice
Endurance sports. Endurance sports are usually performed outdoors, although there are
competitions throughout the year which are performed indoors. This situation allows for
some mechanisms that contribute to an inflammatory state of the airways e.g. chemical
contamination, aeroallergens, respiratory infection, etc. Moreover, this happens with
high respiratory ventilation. This is the reason why the prevalence of asthma in endurance
athletes isy17% as compared with that of power and speed sports, where it isy8% [107].
Further research by the same investigators demonstrated that the risk of asthma was 6times higher in endurance athletes and 3.5-times higher in power sport athletes compared
with control subjects [3]. In cyclists and long distance runners, the asthma prevalence has
varied from 2050% [94, 108]. In this regard, the diagnosis of asthma is based on the
criteria of bronchial hyperreactivity, as assessed by any positive test, which complies with
drug testing rules. In this way, hyperreactive subjects with symptomatology during
exercise are allowed to continue their treatment and compete under the same conditions as
their nonhyperreactive competitors. As a matter of fact, hyperreactive subjects of
endurance sports can modify the prevalence and intensity of their complaints according to
environmental conditions, season of the year and triggers of asthma [109].
Power sports. Asthmatics that practice speed and power sports, such as weightlifting,
throws in track and field, or even gymnastics, seem not to be significantly influenced by
their activity. Other power sports that are combined with outdoor activity and with
running as the basis of their physical fitness condition (e.g. speed running, wrestling,
jumps, etc.) can develop symptoms related to asthma, as their ventilation increases and/or
environmental and climactic conditions change.
Winter sports. Asthma prevalence in athletes participating in winter sports was higher
compared with that of summer endurance athletes, being 517% in the Barcelona (Spain,
1992) and Atlanta (USA, 1996) Summer Olympic Games and 22% in the Nagano (Japan,
1998) Winter Olympic Games [108, 110, 111]. The intense cold and dry atmosphere and
high hyperventilation during lengthy training and competition contributes to the high
figures. In the bronchoalveolar lavage of skiers, an increase in the total number of cells
was seen with a very marked increase in lymphocytes and mastocytes [112], and with
bronchial remodeling defined by an increase in neutrophils [114], as occurs in other sports
(such as swimming, cycling, ice hockey) [101, 103]. Approximately 80% of Swedish elite
skiers suffer from respiratory symptoms [115]. The prevalence of asthma between two
countries with a great tradition in cross-country skiing is somewhat different, with
Norway at 12% and Sweden at 40% [1]. According to the Sue-Chu et al. [1], the probable
reason for this difference is the fact that one country is located along the coast and the
other is located inland.
41
Conclusion
After reviewing these concepts, the present authors believe that there is a need for
further studies to better define the aetiological factors and mechanisms involved in the
development of asthma, AHR or pathophysiological processes masquerading as asthma
in athletes. Moreover, the authors propose that other relevant preventive and therapeutic
measures are found for EIA in athletes. Also, official regulations incorporating the
ranges of optimal climate and air contamination conditions (including poor or dangerous
conditions) in which to play sport have to be created. At this moment, only cross-country
skiing has one officially regulated body, the Federation Internationale de Ski (http://
www.fis-ski.com)
Summary
Physical exercise imposes a certain level of stress on the respiratory tract to eliminate
carbon dioxide and to supply the muscles with oxygen for energy production. This
process requires increased airways ventilation above the normal resting frequency. The
number of hours spent in training at high intensity levels by athletes is progressively
increasing, and the number of recreational athletes is also growing and they are more
concerned about their training schedules and intensities. Increased ventilation rate and
oral breathing displaces pulmonary uptake of pollutants to more distal sites in the
lung, depositing ambient air pollutants in the distal airways. This will affect the
athlete, whether recreational or professional, who suffers from asthma or bronchial
hypersensitivity. In contrast, it is known that competitive athletes have a high
prevalence of asthma, exercise-induced asthma or bronchial hyperreactivity.
Mechanisms for this association include increased inhalation of cold air, air
pollutants, allergens, an increased response to respiratory infections, and increased
parasympathetic tone. This chapter provides a review of outdoor and indoor sports
practice and the environmental and climatological factors that can affect the airways
of the asthmatic athlete.
Keywords: Asthma, aeroallergens, chlorine, doping, exercise, pollution.
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47
CHAPTER 6
Criteria for diagnosis of asthma,

EIB and AHR for athletes: lessons
from the Olympic Games
S.D. Anderson*, V. Brusasco#, T. Haahtela}, T. Popovz
*Dept of Respiratory Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
#
Internal Medicine, University of Genoa, Genova, Italy. }Dept of Allergy, Skin and Allergy Hospital,
Helsinki University Central Hospital, Helsinki, Finland. zClinical Centre of Allergology, Sofia, Bulgaria.
Correspondence: S.D. Anderson, Dept of Respiratory Medicine, 11 West, Royal Prince Alfred Hospital,
Missenden Road, Camperdown, New South Wales, Australia 2050. Fax: 61 295158195; E-mail:
sandya@med.usyd.edu.au
Clinically, the diagnosis of asthma and exercise-induced bronchoconstriction (EIB) in

athletes is usually made on the basis of symptoms and allergies. This is particularly true
for athletes with normal spirometry in whom a significant bronchodilator response
cannot be documented. The symptomatic approach to prescribing treatment has been
associated with an increase in the percentage of athletes using inhaled b2-adrenoceptor
agonists (IBAs) prior to a sporting competition [1]. Daily use of this class of drug for
prevention of EIB is not ideal [24], and an alternative approach to treatment of EIB is
encouraged [2, 5]. Formal studies in athletes have now shown that respiratory symptoms
do not predict hyperresponsive airways [6, 7]. Furthermore, many athletes with no
respiratory symptoms can have significant airway narrowing in response to exercise and
would benefit from treatment for asthma [8, 9]. For these reasons, there has been a move
to objective testing to demonstrate asthma or EIB in athletes. Objective testing permits
rational decisions to be made with respect to dose and type of medication that can be
used to prevent EIB and the airway inflammation related to asthma.
The background to the selection of current criteria

"In May 2001 a workshop was convened in Lausanne by the International Olympic
Committee Medical Commission (IOC-MC) to examine the use of IBAs at the Olympic
games. This revealed a trend towards an increasing frequency of notification of use of
IBAs, from 1.7% of athletes at the Los Angeles Games (1984), 3.6% at Atlanta (1996),
and 5.6% in Nagano (1998) and 5.7% Sydney (2000). Furthermore, the use of IBAs was
more common in athletes competing in endurance sports with, for example, notification
of 17.9% by cross-country skiers in Nagano and by 17% of cyclists and 24% of triathletes
in Sydney. The frequency of notification correlated well with the reported prevalence of
asthma symptoms in the various nations [10], and is consistent with studies reporting a
high prevalence of asthma symptoms in elite athletes. The workshop recommended that,
in addition to notification, the IOC-MC seek objective evidence to justify, on medical
grounds, the use of IBAs before an event" [1]. This established a need to identify the best
and most appropriate physiological tests to identify asthma and EIB, two indications for
which an IBA is indicated. The primary measurement recommended was forced
expiratory volume in one second (FEV1) and its change in response to a stimulus. For
ISSN 1025-448x. ISBN 1-904097-22-7.
48
AIRWAY HYPERRESPONSIVENESS AND ELITE ATHLETES
measurement, readers were referred to guidelines and these have been recently updated
[11, 12]. The report discusses the criteria used for approval and why they were chosen,
and the possibilities for simplifying cut-off points to define an abnormal response on the
basis of a 12% change in FEV1.
The criteria and why they were chosen for Salt Lake City
(UT, USA) and Athens (Greece)
Exercise
At the time of the decisions for Salt Lake City (SLC) there were only two medical
indications for the use of IBAs, asthma and EIB [13]. For the Winter Games, it seemed
reasonable to suggest that athletes seeking approval to use a b2-agonist prior to an event
could either: 1) demonstrate a significant increase in FEV1 in response to a
bronchodilator or 2) demonstrate EIB simply by performing their usual exercise in
the field with measurements of FEV1 pre- and post-exercise at 5-min intervals up to
30 min. Wilber et al. [14] had reported a prevalence of EIB of 23% in USA Olympic
Winter Sports Athletes and a prevalence of 50% EIB in cross-country skiers performing
in competitions or simulated competitions. Thus, exercise in the field was recommended
for SLC because it is an effective [14, 15] and more sensitive way to identify EIB in cold
weather athletes when compared with exercise performed under laboratory conditions of
temperature and humidity (fig. 1) [16]. By performing the usual exercise in the field, the
athlete would be in the best position to reproduce the problem for which they were
requesting approval to use a b2-agonist.
A positive response to exercise was a fall in FEV1 of i10% in accordance with the
suggestions in the European Respiratory Society and American Thoracic Society (ATS)
guidelines [17, 18]. A cut-off point of i10% also seemed justified based on the coefficient
of variation of 6% for the repeated manoeuvres of FEV1 [19]. The request by the panel to
have the FEV1 reduced at more than one time point was based on the possibility that
40
Maximum fall %
30
20
10
FEV1
FEF2575
FVC
Fig. 1. Exercise in elite athletes. The maximum fall, expressed as a percentage of the baseline value, in forced
expiratory volume in one second (FEV1), forced expiratory flow over the mid portion of the vital capacity
(FEF2575) and forced vital capacity (FVC) in 18 athletes who performed field (h) and laboratory-based (60%
relative humidity, 25uC; &) exercise. Figure produced using data from [16] with permission.
49
S.D. ANDERSON ET AL.
respiratory muscle fatigue could reduce the maximum effort needed to perform an FEV1
after exercise. It would not be valid for poor effort to be misinterpreted as EIB. It was
recognised that respiratory muscle fatigue is only likely to occur in athletes performing
endurance events.
Several investigators have suggested that the value to define an abnormal fall in FEV1
after exercise should bev10%. Helenius et al. [20] have suggested an abnormal value for
% fall in FEV1 of 6.5% that represented the mean % fall in FEV1 plus 2 sd in 19
nonatopic symptom-free runners [20]. A similar value was suggested after a study of elite
winter athletes where the mean % fall in FEV1 plus 2 sd was 7.0% for 48 healthy subjects
without EIB or symptoms [6].
The value of 10% fall in FEV1 is probably justified on the basis of it being a potential
factor for limiting exercise performance. A 10% reduction in FEV1 is usually associated,
but not always, with the 26% reduction in the flow rates through the mid portion of the
flowvolume curve [21]. The change in forced expiratory flow over the mid portion of
the vital capacity (FEF2575) after exercise is not used to quantify EIB because of the
dependence of the measurement on an unchanged vital capacity. Furthermore, a
surrogate measure of FEF2575, the forced expiratory volume at 50% of forced vital
capacity (FEF50) [22], has recently been shown to be insensitive to identify EIB in elite
athletes [9]. Nevertheless, reduced mid-flow rates can, theoretically, decrease performance by limiting tidal volume, particularly if end-expiratory reserve volume is
unchanged.
A cut-off value of 12% could be supported on the basis of being twice the coefficient of
variation for the measurement of the FEV1 manoeuvres. This would also be supported
by the findings of Koskela and Tukiainen [23] who demonstrated that facial cooling
alone could lead to significant falls in FEV1 independently of exercise. Furthermore, a
value of 13% has been suggested to define EIB in children [24]. A 12% fall in FEV1 would
not be supported by the data in elite athletes [6, 20] and would have decreased the
possibility of a person with a borderline response being approved to use a b2-agonist in
Athens. A total of 25% of the applications for SLC and 16% for Athens were the results
of an exercise test (table 1) [25].
Although exercise in the field was the primary recommendation for identifying EIB, it
can be inconvenient for logistical and environmental reasons. Exercise testing for EIB in
elite athletes in the laboratory is usually a challenge in itself. Few laboratories are
equipped with appropriate ergometers to test winter athletes and few have treadmills that
can be safely used at high speeds. For those with a long-term history of asthma it is
possible to perform 8 min of vigorous exercise by cycling or running in accordance with
published protocols [18, 2628]. However, the sensitivity of these laboratory-based tests
to identify airway hyperresponsiveness (AHR) to exercise, even when the inspired air is
cool and dry, is onlyy65% in treated adult asthmatics [26] and 50% in asthmatic children
who inhale air of temperate climatic conditions [29]. The sensitivity of laboratory-based
exercise to identify EIB in athletes that occurs in the field is even less at 25% [16]. For
these reasons, other bronchial provocation tests have been used as surrogate tests for
exercise to identify EIB, and these are recommended to test athletes in the laboratory
environment.
Eucapnic voluntary hyperpnoea

The best known of the surrogate tests to identify exercise-induced asthma is eucapnic
voluntary hyperpnoea (EVH). The test is well standardised [3034]. Briefly, the subject
ventilates dry air containing 5% CO2 for 6 min. The target ventilation for 6 min is
306FEV1 and this is close to 85% of the predicted maximum voluntary ventilation [35].
50
Table 1. The total number of tests and the number of tests for each challenge is shown for each National
Olympic Committee with three or more submissions
Country
Australia
Great Britain
USA
France
Germany
Italy
Spain
Switzerland
Denmark
Hungary
The Netherlands
Canada
New Zealand
Finland
Cuba
Sweden
Japan
RSA
Austria
Czech Republic
Ireland
Barbados
Estonia
Greece
Argentina
Belgium
Brazil
Croatia
Norway
Subjects n
BD
MCh
EVH
Exer.
NaCl
67
54
53
27
22
21
21
16
14
14
14
13
11
10
9
7
6
6
5
5
5
4
4
4
3
3
3
3
3
15
2
13
4
2
13
1
1
2
9
2
5
7
2
26
31
3
12
31
4
1
15
9
9
14
18
3
15
13
1
11
10
6
2
2
2
2
1
2
3
6
2
1
3
1
5
5
2
5
9
1
2
3
5
4
1
2
1
2
1
1
1
1
3
3
3
3
1
2
2
1
BD: bronchodilator response; MCh: methacholine; EVH: eucapnic voluntary hyperpnoea; Exer.: exercise
(laboratory or field); NaCl: 4.5% saline; RSA: Republic of South Africa. Note that the numbers for each country do
not include the 39 applications by track and field athletes approved by the International Association of Athletics
Federations for the World Championships in Paris, 2003.
This level of ventilation would rarely be achieved during exercise in asthmatics and
healthy subjects [26], making EVH at this ventilation unlikely to result in false-negative
tests. The major advantage of EVH is that, if necessary, the time, ventilation and inspired
air conditions can all be adjusted to simulate the conditions under which the athlete is
competing [35, 36].
The same cut-off value for the % fall in FEV1 is used for EVH as for exercise, i.e. 10%.
This was based on the findings of Hurwitz et al. [33] who found a 10% fall in FEV1 to
have a specificity of 90% for identifying those with asthma. It was also in keeping with the
value for exercise and, therefore, seems to be consistent for the stimulus of hyperpnoea.
An argument for a cut-off point of 12% could not be supported by the finding reported
by Hurwitz et al. [33] of a mean plus 2 sd being 6.2%, although a value of 11% had a
specificity of 100% in the study by Eliasson et al. [31]. A 12% fall in FEV1 would have
decreased the possibility of a person with a borderline response being approved to use a
b2-agonist at the Summer Games in Athens. Had a cut-off value of 12% been applied for
SLC, seven athletes who submitted results of an exercise or EVH test would not have
been approved to use a b2-agonist at SLC. This represents a 20% reduction in positive
responses, from 36 to 29. Undoubtedly, this higher value would be perceived as
underdiagnosis of a problem (i.e. EIB) that is preventable with treatment.
Mannix et al. [37] were the first to report a comparison between EVH and exercise in
51
athletes and did so in a group of figure skaters. In brief, they concluded that 5 min of
EVH was able to identify most skaters who suffered from EIB and was better than on-ice
skating. It is likely that the outcome of the EVH tests would have been even better if
Mannix et al. [37] had used the standard time (6 min) and ventilation (85% of maximum)
rather than 5 min at a ventilation of 60% maximum voluntary ventilation.
Holzer et al. [38] reported the responses to EVH in a group of summer elite athletes
unselected for respiratory symptoms. The mean ventilation achieved over 6 min of EVH
was 126.821.9 L?min-1 and this represented 93.8%4.5 of the maximum voluntary
ventilation and confirms the ability of athletes to reach and maintain high levels of
ventilation independently of exercise (fig. 2). A total of 25 of the subjects documented a
fall in FEV1 i10% (meansd 25.415%) and 25 had a maximum fall in FEV1 v10%
(meansd 32%). Moreover, 27 had a previous clinical diagnosis of asthma and 21 were
currently receiving treatment for asthma or EIB.
The utility of using EVH as a surrogate for exercise in elite athletes performing exercise
in the cold has now also been confirmed [39]. The results of a group of unselected athletes
who volunteered for testing in the field (2uC) and the laboratory (19uC) are given in
figure 3. In brief, 11 subjects were positive to exercise and 19 to EVH. Two subjects who
performed exercise for 8 min in the field had a fall v10% in response to 6 min of EVH.
The ventilation during EVH was 28 times the measured FEV1, confirming that 30 times
the FEV1 is close to an appropriate target ventilation for elite athletes. Rundell et al.
[39] concluded that EVH had a greater chance of identifying AHR compared with 6
8 min exercise in the cold. They suggested that testing in the field need only be performed
as a secondary test in the event of a negative response to EVH.
A recent study from the same group found little effect of temperature between exercise
and EVH [40], suggesting that cooling the inspired air for EVH testing is not important
when a high ventilation is used for 6 min. Their finding supports the concept that a
60
% Fall in FEV1
50
l
ll
40
ll
30
Severe
Moderate
20
l
l
10
0
l
l
l
80
l
l
l
l
l
l
l
Mild
l
l
l
ll
l
l
l l
l l l ll l
l
l
l
l
l
l
85
90
95
VE % maximum voluntary ventilation (FEV135)
Normal
l
100
Fig. 2. The fall in forced expiratory volume in one second (FEV1; expressed as a percentage of the baseline
value) in relation to the average ventilation over 6 min (expressed as a percentage of maximum voluntary
ventilation) in 50 elite summer sports athletes. VE: ventilation. Figure produced using the data from HOLZER
et al. [38].
52
30
% Fall in FEV1 following EVH
20
ll
l
l
l ll
l
ll
10
l
l
ll
l
l
l
l l
l l
l l
l l
10
20
30
% Fall in FEV1 following exercise
40
Fig. 3. The maximum fall in forced expiratory volume in one second (FEV1; expressed as a percentage of the
baseline value) documented in the 15 min after 6 min of eucapnic voluntary hyperpnoea (EVH) of dry air
(containing 5% carbon dioxide) at a target ventilation rate equivalent to 30 times the FEV1, in relation to the
fall in FEV1 after exercising in cold air (25.6uC) for 6 or 8 min in a group of unselected elite athletes
(n=38). Reproduced with permission from [39].
plateau can be reached in the airway response to hyperpnoea, providing the intensity of
the stimulus is sufficient to recruit the small airways into the air conditioning process [41].
The findings in the studies by Mannix et al. [37] and Holzer et al. [38] contributed to
the recommendations of EVH as the optimal bronchial provocation test to identify EIB
in the laboratory for SLC. The additional findings of Rundell et al. [39] contributed to
this same recommendation going on to the Summer Games in Athens. The EVH test was
available in Athens and 24.4% (n=104) of applications submitted results of an EVH test
(table 1) [25].
Hyperosmolar aerosols
One of the mechanisms proposed for dry air hyperpnoea to cause the airways of
asthmatics to narrow is an increase in the osmolarity of the airway surface in response to
loss of water by evaporation in conditioning the inspired air [4143]. In the 1980s, many
studies were carried out comparing the effects of exercise and eucapnic hyperpnoea to
nonisotonic aerosols. These studies clearly showed that asthmatics were similarly
sensitive to these stimuli [4450].
Hyperosmolar aerosols are well established for assessing AHR and for collecting
secretions in people with asthma [5153]. Hyperosmolar saline has been used to identify
prevalence of currently active asthma in epidemiological studies, particularly in Europe
and Australia [5456]. These aerosols have also been used in an occupational setting [57].
The severity of the response to 4.5% saline has been shown to relate to mast cell number
in brush biopsies [58]. A positive response to exercise is 4.3 times more likely in a child
who has AHR to 4.5% saline [54]. The 4.5% saline test identified AHR in 17% of 180
people wishing to dive with self-contained underwater breathing apparatus (SCUBA)
who had a past history of asthma but no current symptoms, were not using medication
and were approved "otherwise" fit to dive on medical grounds [59]. A questionnaire has
also been developed to help predict the likelihood of a positive response to saline [60].
53
The hyperosmolar challenge tests

The wet aerosol of 4.5% saline is usually generated by a large-volume (200 mL)
ultrasonic nebuliser (DeVilbiss 99, 2000; DeVilbiss Healthcare, Somerset, Pennsylvania,
USA) and delivered to the inspiratory port of a large two-way breathing valve between
1.2 and 1.5 mL?min-1. Details of the challenge can be found elsewhere [51, 6163].
Relative to the equipment required to perform exercise or EVH, the equipment needed
for challenge with hypertonic saline is less expensive and more portable. There is a good
relationship between the sensitivity to 4.5% saline and EVH [44, 64] (fig. 4). Many
pulmonary function laboratories have access to a suitable ultrasonic nebuliser as this
equipment is also used to deliver drugs and to induce sputum.
Measurements of FEV1 are made before challenge and 60 s after each exposure to the
aerosol hyperosmolar saline (4.5%). The exposure times are 1, 2, 4 and 8 min. Initially, a
20% cut-off point was used to be consistent with the pharmacological challenges [51, 65].
However, this was reduced to 15% as more healthy subjects were studied, particularly in
epidemiological studies. Dutoit et al. [66] reported a mean plus 2 sd of 11.2% for 55
healthy adult subjects with normal lung volumes and normal values for spirometry when
performing a bronchial provocation test (BPT) with 4.5% saline. It would seem logical
that a 10% cut off could be used for hyperosmolar challenge as this has been shown to
identify athletes with EIB [38].
A cut-off value of 12% would be supported by the findings of Dutoit et al. [66]. A
value of 12% would also be supported by an occupational study [57] and two
epidemiological studies [54, 56]. A 12% fall in FEV1 would have increased the possibility
of a subject with a borderline response being approved to use a b2-agonist at Athens,
where 24 (5.6%) applications were made on the basis of this test (table 1).
A new osmotic challenge involving the inhalation of progressively increasing doses of
dry powder mannitol has been developed for use as a BPT in asthma [67] and to identify
EIB [38, 68]. The mannitol, which is specially prepared for inhalation, is delivered from a
capsule using a dry powder inhaler (Cyclohaler; PlastiapeTM, Osnago-Lecco, Italy)
21
Rank order of sensitivity to EVH
l
l
l
14
l
l
l
l
7
14
Rank order of sensitivity to 4.5% saline
21
Fig. 4. Spearmans rank order correlation showing the relationship between the maximum percentage fall in
forced expiratory volume in one second (FEV1) after 6 min of eucapnic voluntary hyperpnoea (EVH) with dry
air and the provoking dose of 4.5% saline to cause a 15% fall in FEV1 in asthmatics (r=0.9; pv0.001).
Reproduced with permission from [64].
54
similar to those used to deliver asthma medications. Mannitol is given in progressively

increasing doses (5, 10, 20, 40, 80 and 160 mg) and the FEV1 is measured 60 s later. The
test takes 1025 min depending on the sensitivity of the subject. The mannitol test has
completed phase 3 trials [69, 70] and a submission for registration was made to the
regulatory authorities in Europe and Australia in 2005. Should the mannitol test kits
become commercially available, they will fulfil the need for a common operating
standard to assess AHR at the point of care. The other items required for testing include
a spirometer and a bronchodilator. A fall in FEV1 of 10% to mannitol has been shown to
be consistent with EIB [38] and a fall of 15% consistent with currently active asthma
responsive to treatment with inhaled corticosteroids [71, 72].
A study of responses to inhaled mannitol has been made in elite summer athletes; these
are illustrated in figure 5. All but one athlete responsive to EVH responded to mannitol
with a 10% fall in FEV1. A further two athletes were identified with potential for EIB
using mannitol. Inhaled mannitol causing at 10% fall in FEV1 had a sensitivity of 96%
and a specificity of 92% for identifying elite athletes responsive to EVH. The geometric
mean provocative dose (PD) causing a 10% fall in FEV1 was 202 mg (95% confidence
interval 134300) and the mean maximum fall in FEV1 after challenge was 20.47.9%
[38].
Why hyperosmolar aerosols

The argument to recommend challenge by hyperosmolar aerosols to establish a
diagnosis of asthma, EIB or AHR in athletes was originally based on observations in
people with clinically recognised asthma. It is now also based on experience with testing
in elite athletes [38]. There are a number of advantages to using hyperosmolar aerosols
for the assessment of an athlete.
First, hyperosmolar aerosols can simulate some of the symptoms reported on exercise
and demonstrate whether they are associated with bronchoconstriction. For example,
60
l
EVH % fall in FEV1
50
40
l l
l
l
30
20
l
l
10
l
l
l
l
l
ll
100
200
l
l
l
400
300
500
PD10 mannitol mg
600
No
PD10
Fig. 5. Relationship between the maximum percentage fall in forced expiratory volume in one second (FEV1)
after 6 min of eucapnic voluntary hyperpnoea (EVH) of dry air in relation to the provocative dose of mannitol
required to induce a 10% fall in FEV1 (PD10 mannitol) in elite summer sports athletes (r=-0.61; pv0.001; n=26).
Reproduced with permission from [38].
55
cough is a common occurrence in both healthy and asthmatic subjects in response to a

hyperosmolar challenge [73]. The cough can occur without bronchoconstriction and this
is documented for both hyperosmolar saline and mannitol [73, 74]. Hyperosmolar
aerosols stimulate release and clearance of mucus [75, 76]. Mucus production is a
problem for many cold weather athletes [6] but is usually cleared by cough. The second
advantage is that a positive response to a hyperosmolar aerosol (i.e. a fall in FEV1 w15%)
identifies a person who has currently active airway inflammation consistent with asthma
and indicates that they would benefit from treatment with inhaled corticosteroids [71, 72,
77]. The third advantage is that people positive to hyperosmolar aerosols have been
shown to have AHR to EVH and exercise (fig. 4) [44, 45, 48, 49]. The fourth advantage is
that a number of inflammatory mediators are released in response to an increase in
airway surface osmolarity [78]. Finally, while the airways of asthmatics are sensitive to
changes in airway osmolarity [79, 80], the airways of healthy nonasthmatic subjects
generally are not [54, 55, 57, 69, 70, 81].
The airway response to a hyperosmolar aerosol is also inhibited by drugs used in the
treatment of asthma and EIB. This makes hyperosmolar aerosol challenge different to
the pharmacological challenges. The airway response to hyperosmolar aerosols is
markedly reduced or even inhibited by acute administration of nedocromil sodium [82,
83], sodium cromoglycate [77, 84], montelukast [85] and b2-agonists [84, 86]. The
response to these aerosols is reduced following chronic treatment with inhaled
corticosteroids [71, 72, 87]. The response to those aerosols is increased following
back-titration of steroid dose in well-controlled asthmatics [88]. All these features
indicate good specificity for identifying asthma or EIB.
The role of pharmacological challenge in the assessment of AHR in elite athletes

with asthma
Measuring AHR by pharmacological challenge has been very common in people
suspected of having asthma. Guidelines for challenge have been available for many years
[18, 51, 89, 90]. Methacholine (Provocholine; Methapharm Inc., ON, Canada) is most
commonly used and it is the only pharmacological agent approved by regulatory
authorities for use by inhalation in humans.
In 1983, the recommendations of the European Society for Clinical Physiology
Working Group on Bronchial Hyperreactivity stated: "bronchial hyperresponsiveness
denotes an increased bronchial response to inhaled substances which produce airways
obstruction in normal subjects if given in adequate doses" [89]. This definition
acknowledges the capacity of the airways of healthy people to narrow in response to
pharmacological agonists, and demands selection of an "adequate dose" to distinguish
normal subjects from those who have asthma. That healthy nonasthmatic subjects can
respond to pharmacological agents is well documented in epidemiological studies [91
93], and can simply occur after exposure to rhinovirus [94], even if the virus has not
caused an infection. It also occurs in healthy subjects when the airway response is
measured without a preceding inspiration [95, 96], but this is not usually a problem as the
FEV1 manoeuvere requires a deep inspiration. Indeed, the difference between the
response of asthmatic and healthy subjects when deep inspirations are prevented is
reduced, although not completely abolished [96]. This suggests that both airway smooth
muscle contractility and lack of ability to dilate constricted airways contribute to AHR in
asthma. This has re-focused peoples attention back on the smooth muscle with respect to
primary abnormality of asthma [97].
The dose or concentration of agent that is used to identify AHR can vary between
laboratories and doctors depending on the expected or desired outcome and the
56
repeatability of the airway response. It should be noted that the AHR reported in athletes
by many investigators occurs only at very high doses or high concentrations, a feature
highlighted by the data of Langdeau et al. [98] (fig. 6). The pharmacological challenge
test cut-off points to define abnormality have been more difficult to select than the other
tests because of overlap in responses with athletes with no respiratory symptoms (fig. 6).
Furthermore, there are two different techniques used to deliver the aerosol and two
different ways of expressing the response. Briefly, the 2-min tidal breathing technique
exposes the subject to y8590 mL for each concentration and the dosimeter technique
that uses five breaths to total lung capacity (TLC) exposes the subject to 45 mL for each
concentration. Although the doses are different, similarities were found with the
provocative concentration, causing a 20% fall in FEV1 when the two techniques were
originally compared [99]. The major problem is that unless the output of the nebuliser is
precisely known, then a PD value cannot be reported. This is presumably the reason that
the ATS guidelines do not make reference to dose but only to concentration [18]. The
cut-off values suggested by the ATS guidelines [18] are normal w16 mg?mL-1,
borderline 416 mg?mL-1, mild 14 mg?mL-1, moderate 0.251.0 mg?mL-1 and marked
v0.25 mg?mL-1. For the dosimeter technique, assuming the recommended output of 45
mL per concentration (0.0625, 0.25, 1, 4 and 16 mg?mL-1) is used and that the dose is
cumulative, it is estimated that the equivalent cumulative PD20 for those concentrations
is 3, 15, 60, 240 and 960 mg. These doses are consistent with the cut-off point of PD20
v1,000 mg used in the European Health survey to define AHR [100]. In a recent study
that compared responses using the tidal volume and dosimeter technique, differences in
the provocative concentration causing a 20% fall in FEV1 (PC20) were reported for the
first time [101]. This was in part attributed to the bronchoprotective effect [102] of the five
inspiratory manoeuvres to TLC used for the dosimeter technique [101]. This new
information suggests that the two cut-off points recommended by the IOC-MC for SLC
and Athens may need to be revised upwards for the dosimeter technique and that
applicants be requested to cite the methodology used.
Over time, and from the findings of epidemiological studies, it has become clear that
there is an overlap between responses in healthy, asthmatic and rhinitis subjects [103].
80
Cumulative % of subjects
70
60
50
40
30
20
10
0
<2
<8
<16
PC20 methacholine mgmL-1
16
Fig. 6. Methacholine provocation test amongst 100 high-level athletes from Canada (&) compared with 50
healthy non-athletic controls (h). A general trend towards increased hyperresponsiveness was seen amongst the
athletes. PC20: provocative concentration of methacholine causing a 20% reduction in forced expiratory volume
in one second. Reproduced with permission from [98].
57
There is an overlap between athletes with and without respiratory symptoms (fig. 6) [98].
Further, it is possible that in elite athletes, particularly cold weather athletes, AHR to
methacholine could result from airway injury and not reflect the classic inflammation of
asthma [104]. To overcome the problem of overlap and to encourage treatment of asthma
with inhaled steroids, the criteria for methacholine for SLC was set at PD20 of 200 mg,
1 mmol or PC20 2 mg?mL-1 for those not taking inhaled steroids, and PD20 1,320 mg,
6.6 mmol or PC20 13.2 mg?mL-1 for those taking inhaled steroids. Interestingly, for SLC
there were only 14 submissions reporting a PC20 and all but one was v3 mg?mL-1.
However, there were a significant number of rejected applications reporting methacholine PD20 values w2,000 mg. The cut-off values recommended for SLC continued to
Athens 2004 when 30.8% of the applicants submitted the results of a methacholine test
(table 1). The median value for the PD20 for those approved applications for Athens was
147 mg. For those athletes taking inhaled steroids, it was 168 mg and this value was
not significantly different from those recorded for people not taking inhaled
corticosteroids for whom it was 96 mg. Thus, it would not appear that high doses of
methacholine are required to identify the majority of athletes with asthma taking inhaled
steroids.
In order to use a 12% fall in FEV1 to methacholine as the cut-off point, re-analysis of
many studies would be needed to find out what dose or concentration would provide the
same specificity for asthma as the other challenge tests. The reason this analysis is
required is that healthy people are known to respond but plateau in their response to
these agents [105]. The plateau may occur well after a fall of 12% [105].
Sovijarvi et al. [106] used histamine as the provoking agent and suggested a 15% fall at
v400 mg (0.4 mg) is specific for the diagnosis of asthma, as patients with chronic cough
and chronic rhinitis had values between 400 mg and 1,600 mg, and no healthy subject
responded to values v400 mg. In a study on children, a PC12 of 2.4 mg?mL-1 had a
sensitivity of 75% and specificity of 93% to identify asthma [107]. Cockcroft [108] has
recently suggested that a value of 1 mg?mL-1 for PC20 gives the same specificity and
sensitivity as the indirect challenges to identify those with active asthma and could be
used to make the same decisions.
The study in elite athletes by Holzer et al. [38] demonstrated that, of the 25 summer
athletes with a positive response to EVH (meansd % fall in FEV1 of 25.4%14.9), only
nine had a 20% fall in FEV1 with a geometric mean PD20 of 1.692.05 mmol at the top
dose of methacholine (cumulative dose of 9.47 mmol, equivalent toy18 mg?mL-1) [7]. For
the 25 athletes who were negative to EVH, none recorded a positive response to
methacholine. In the athletes who were negative to methacholine, the mean maximum
fall in FEV1 was 5.1%4.4 at the top dose of 9.47 mmol. For the 16 athletes who were
positive to EVH and negative to methacholine, the mean % fall in FEV1 at the top dose
was 7.64.9% so these were not "near miss" cases. The finding of a low sensitivity for a
pharmacological challenge to identify EVH positive athletes confirmed the earlier ones
for exercise [109, 110]. Haby et al. [110] reported that only 18 out of 40 children with a
w15% fall in FEV1 had a positive result to the top dose of histamine. These findings
confirmed the earlier observations of Backer et al. [109] and have also themselves been
reproduced in adult athletes [38]. This seemingly paradoxical finding on AHR may be
explained by the greater potency of some of the mediators implicated in EIB (e.g.
prostaglandin D2 and leukotriene C4) compared with methacholine or histamine. The
same is not apparent in winter athletes, where a high percentage can be positive to
methacholine and negative to EVH and hyperosmolar aerosols [111]. This AHR in cold
weather athletes, which is not changed by treatment with inhaled steroids [112], has
recently been attributed to airway injury [104].
There are two aspects to consider when looking at the sensitivity of the test. First, from
an epidemiological viewpoint, methacholine and histamine are no more sensitive for
58
identifying people with asthma [91] than hypertonic saline [54, 57] or exercise [113].
Secondly, from a laboratory viewpoint and with selective referral, the sensitivity
increases as one may expect according to the Bayesian approach [114, 115]. However, the
findings of Holzer et al. [7] clearly demonstrate low sensitivity to identify EIB in athletes
and this does not simply relate to a 10% versus 20% cut-off point. In contrast, the socalled "direct stimuli" have the advantage of being positive in asthmatic subjects, even in
the absence of inflammatory cells in their airways [116]. Therefore, a positive response to
a methacholine challenge can allow the identification of asthmatic subjects who do not
exhibit EIB, because of little airway inflammation at the time of study, but may become
eventually ill if exposed to sensitising allergens or after virus infection.
Response to bronchodilator
Quanjer et al. [117] have also suggested an FEV1 value of 12 % of predicted (% pred)
to define a positive response and this was the criterion chosen for SLC. It was
recommended because it was considered fair to athletes, many of whom may have an
FEV1 w100 % pred at baseline. This value is still recommended. However, the mean %
pred FEV1 pre-bronchodilator for those submitting a positive test with a bronchodilator
was 9311.1% (n=13), and for those with a negative one, 95.7%13.8% (n=15) [1]. For
Athens, it was altered to be 15% of baseline and 23.2% of submissions were for
bronchodilator (table 1) [25]. Also, the recommendation for a significant response (an
increase of i12% of baseline FEV1), is supported by previous submissions and is in
keeping with the recommendations for new ATS/ERS consensus guidelines [12]. It is also
appropriate for athletes who tend to have volumes close to the normal predicted values.
Using a value of 12% of baseline would have increased by three, from 13 to 16, the
number approved for SLC. Thus, a criteria with an FEV1 increase w12% baseline or
predicted appears to be fair to all athletes, whatever their baseline value.
Conclusion
Objective testing to identify AHR is recommended in athletes with symptoms of
asthma. The simplest test for AHR is to document a significant response to
bronchodilator but many athletes have normal lung function at rest, necessitating the
use of other tests for AHR. Preference would be given to using a nonpharmacological
stimulus to provoke the airways because the AHR to these stimuli can be treated
effectively. Whilst exercise in the field is most likely to reproduce the symptoms of the
athletes it can be inconvenient for logistical reasons. The best laboratory-based test to
identify EIB is EVH. Methacholine is used to identify asthma, but there is an overlap in
responses for athletes with and without symptoms above a PC20 of 2 mg?mL-1.
Furthermore, neither EIB nor response to inhaled corticosteroids is predicted or
excluded by PC20 to methacholine. The different techniques used for delivering the
aerosol and the different expression of the response have limited the usefulness of
methacholine for comparing results between laboratories. Hyperosmolar aerosols are
useful in that they only identify subjects whose asthma is currently active who are likely
to have an attack provoked by exercise and would benefit from treatment. There is also
future potential for these tests to be performed with a common standard operating
procedure.
59
Summary
A history of symptoms of asthma in an elite athlete is not a reliable indicator of the
need for treatment with a b2-agonist. Requesting an athlete to demonstrate either a
response to a bronchodilator or an exercise test that reproduced the reason for use of a
b2-agonist seemed the best approach to approve the use of a b2-agonist. For the
Winter Games in Salt Lake City (UT, USA), laboratory-based tests were also
suggested by the independent panel of the International Olympic Committee Medical
Commission and included exercise, eucapnic voluntary hyperpnoea and methacholine
challenge, and for Athens (Greece), hypertonic saline. Selecting realistic cut-off points
to physical and pharmacological challenges, whilst permitting both types of test to be
used, aimed at a high specificity for the diagnosis of asthma or exercise-induced
bronchoconstriction. This approach meant the athlete could have confidence that
asthma treatment was either appropriate or insufficient.
Many athletes had only a past history (not current) of asthma. There was no evidence
that athletes being treated with asthma drugs not requiring approval (inhaled
corticosteroids, cromoglycate, nedocromil sodium, leukotriene antagonist), but whose
application to use a b2-agonist was rejected, had any difficulties at either Salt Lake
City or Athens. The submissions did not suggest that the athletes were at risk of
inadequate management of asthma. Simplifying the challenges to a single cut-off point
of a 12% fall in forced expiratory volume in one second for all the tests would have
advantages and disadvantages. The major disadvantage is that procedures and
guidelines for asthma are built on years of practice and data collection, and to move
away from them is not advisable. More importantly, it would be a disadvantage to
those who have exercise-related changes in lung function, which is the most important
indication to seek approval to use a b2-agonist before a sporting event. In contrast, an
increase w12% of either baseline or predicted seems appropriate to define a positive
bronchodilator response in athletes.
Keywords: Bronchial provocation, hyperosmolar aerosols, hyperpnoea, methacholine.
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66
CHAPTER 7
Asthma-like conditions in athletes

L. Delgado*, K-H. Carlsen#, K. Larsson}
*Servico de Imunologia, Faculdade de Medicina, da Universidade do Porto, Hospital S. Joao, Porto,
Portugal. #Voksentoppen BKL, Rikshospitalet University Clinic, University of Oslo, Oslo, Norway.
}
University of Lung and Allergy Research, National Institute of Environmental Medicine, Karolinska
Institute, Stockholm, Sweden.
Correspondence: L. Delgado, Servico de Imunologia, Faculdade de Medicina, da Universidade do Porto,
Hospital S. Joao, PT-4200-319 Porto, Portugal. Fax: 35 1225510119; E-mail: ldelgado@med.up.pt
There are several differential diagnoses for exercise-induced asthma (EIA) in athletes,
including exercise-induced laryngeal dysfunction (EILD; vocal cord dysfunction (VCD),
laryngeal prolapse, or laryngomalacia with inspiratory stridor (IS)) and hyperventilation
during exercise [15]. Other chronic disorders, including heart diseases, may have an
effect upon physical performance and thus may be a possible differential diagnosis
related to EIA. Also, poor physical fitness or overtraining may represent possible
differential diagnoses to EIA. This is especially the case when the physical fitness and
exercise performance are not up to the expectations of the athlete or possibly their
parents and trainers; lack of success in sports may be explained by often minor
respiratory complaints that may be mistaken for asthma. Other specific conditions,
especially those occurring in highly trained athletes, are exercise-induced arterial
hypoxaemia and swimming-induced pulmonary oedema.
All these conditions should be considered and ruled out with a thorough examination,
as many such patients receive unnecessary treatment for asthma, including both inhaled
steroids and b2-agonists, which characteristically do not improve the exercise-induced
respiratory symptoms (EIRS) [4, 5].
EILD is an abnormal laryngeal response to exercise that encompasses different, but
closely related, entities: exercise-induced (paradoxical) VCD (PVCD) [1], exerciseinduced laryngeal prolapse (EILP) [2] and/or exercise-induced laryngomalacia (EIL) [3,
6]. All these conditions present as exercise-induced IS and are more common amongst
highly trained adolescent female athletes [4, 5]. During maximal exercise, an IS with a
typical pattern of variable extrathoracic obstruction, flattening of the maximal
inspiratory flowvolume curve [2, 4, 6], contrasts with EIA, in which the dyspnoea
occurs after exercise and is expiratory due to the lower airways obstruction [5, 7]. In
table 1, the major distinctive characteristics of both conditions are shown.
VCD is a well-recognised cause of dyspnoea, wheezing and IS [9], frequently mistaken
for the wheeze of EIA [4, 14]. McFadden and Zawadski [14] first reported VCD in seven
elite athletes referred for EIA, with a diagnosis based on the observation of a marked IS
during exercise, lack of resolution with a b2-agonist, and a normal response to exercise
provocation; three cases were confirmed with laryngoscopy.
Direct observation of vocal cord adduction by laryngoscopy is considered the "gold
standard" for VCD diagnosis, being usually positive while the patient is symptomatic
[12]. However, the inconsistent occurrence of IS (e.g. only with the stress of competition)
makes laryngoscopy less practical and successful [4, 12, 14]. Flowvolume loop testing
during spirometry can reveal a flattening/truncation of the inspiratory limb characteristic
ISSN 1025-448x. ISBN 1-904097-22-7.
67
L. DELGADO ET AL.
Table 1. Distinctive clinical characteristics of exercise-induced laryngeal dysfunction (EILD) and exerciseinduced asthma (EIA)
Respiratory cycle
Symptoms
Relation to exercise
Responsive to b2-agonists
Exercise challenge
Spirometry after exercise
Laryngoscopy
EILD
EIA
Ref.
Inspiration, laryngeal
Throat tightness, stridor,
dyspnoea
Immediately with maximal exercise;
resolves within 5 min of stopping
No
Inconsistent response
Expiration, bronchial
Breathing troubles, wheezing,
dyspnoea
510 min after maximal exercise;
peaks 520 min after stopping
Yes
Reproducible (also with surrogate
challenges)
Consistent decrease of expiratory
flowvolume loop
Normal
[4]
[811]
Variable; possible flattening of

inspiratory flowvolume loop
Abnormal during episodes
(sometimes resting)
[1113]
[4, 11, 14]
[1416]
[4, 8]
[8, 17]
of a variable extrathoracic obstruction, but this finding is generally absent unless patients
are symptomatic at the time of testing [12].
Rundell et al. [16] recently reported that VCD might be identified in athletes if they
have IS after exercise; this was identified by careful larynx and lung auscultation
performed by an experienced investigator. The overall prevalence of IS in their cohort of
370 developmental and elite athletes was 5.1%, with an 8.3% prevalence in the outdoor
athlete group, significantly higher than the 2.5% observed in indoor athletes and the 2.5%
estimate for the general population [11]. Moreover, they also found that VCD overlaps
with exercise-induced bronchospasm (EIB): 53% of the IS-positive athletes had comorbid
EIB (representing 9% of the 111 athletes identified as EIB positive). This number is
similar to other VCD patients, as a study by Newman et al. [12] reported 56% of 95
laryngoscopically confirmed cases as also having asthma.
VCD may also overlap with airway hyperresponsiveness to methacholine. Not only
will some patients with VCD develop acute symptoms after methacholine challenge, but
6070% may also have a positive response (w20% decline in forced expiratory volume in
one second (FEV1)) to methacholine [8, 18]. This highlights the difficulties in
differentiating VCD and asthma based solely on symptoms or bronchoprovocation
testing. However, in patients with exercise-induced IS, post-exercise spirometry can be
evocative; in cases negative for EIB, a post-exercise fall in forced vital capacity (FVC; 9
14%) with no concomitant fall in FEV1 (v5%) and, in cases with comorbid EIB, higher
forced expiratory flow at 50% of FVC/forced inspiratory flow at 50% of FVC ratios
(w1.52.0) than control subjects (v1.0) are usually seen after, but not before, exercise [14].
Another condition that may be associated with IS during exercise is laryngomalacia.
Congenital laryngomalacia is recognised as the most common cause of IS in infants [19],
with peak symptoms at 6 months of age and complete resolution in most children by the
age of 24 yrs [17]. Although of unknown aetiology, it is thought to be due to deficient
neurological control, redundant laryngeal soft tissue, laryngeal hypotonia, and/or weak
cartilaginous support [19]. In a subset of patients laryngomalacia presents [6] or recurs
later in childhood [17] as exertional activities increase, typically after engagement in
competitive sports. This syndrome has been called EIL [3, 6] and, as with other causes of
EILD, is characterised by severe dyspnoea, stridor, and mild wheezing during exercise
that fails to respond to inhaled b2-agonists, rapidly resolving as the degree of exertion is
decreased or stopped. These cases are often misdiagnosed as EIA [17], and the
endoscopic findings [6, 17, 19] are similar to the pattern described by some authors as
EILP [2].
EILP has been found in otherwise healthy athletes [2], where extreme exertion and
68
ASTHMA-LIKE CONDITIONS IN ATHLETES
inspiratory forces cause an abnormal movement of the arytenoid region, with the
collapse of the aryepiglottic folds anteriorly and medially into the endolarynx, resulting
in a subtotal glottic closure. Fibreoptic rhinolaryngoscopy during exercise shows oedema
with prolapse of the aryepiglottic folds [20]. These changes have been attributed to
mechanical trauma of the arytenoids area; during maximal exertion, a breathing pattern
generating high inspiratory flows increases the negative pressure gradient in the
hypopharynx, collapsing the upper airways [2].
Gastro-oesophageal reflux disease (GERD) is also another possible cause of EIRS [21]
and a comorbid factor with VCD [1]. Chronic cough and dyspnoea are common extraoesophageal symptoms of GERD. In the evaluation of videolaryngoscopic tapes from a
cases series of 22 adolescents with VCD, Powell et al. [1] noted that 19 out of 22 (86%)
had glottic changes (arytenoid and interarytenoid oedema) commonly found in GERD.
In another recent case series of PVCD, laryngoscopic findings suggestive of GERD were
also seen in 19 out of 30 cases (63%) [22].
Among 189 patients investigated for EIRS, TurzIkovA et al. [21] identified 14
(7%) patients involved in sports activities with negative exercise challenge, no
gastro-oesophageal symptoms, but with cough hand dyspnoea during exercise
correlating with gastro-oesophageal reflux episodes, by pH monitoring. Exercise is a
risk factor that can induce gastro-oesophageal reflux [23] through a low thoracic pressure
during forced respiration, combined with an increased abdominal pressure during
exercise.
Exercise-induced hyperventilation
Although the pathophysiological mechanisms that underline EIA are not fully
understood, the two major hypotheses that have been put forward link water loss and/or
cooling of the airways to the increased ventilation during exercise [5, 7]. In this context,
voluntary hyperventilation with dry air has been used as a surrogate laboratory test to
identify EIA in athletes [24, 25]. However, hyperventilation during exercise may also be
linked to other EIRS not directly related to bronchial obstruction [9, 26, 27].
Hammo and Weinberger [26] evaluated 32 children and adolescents (aged 818 yrs)
with exertional dyspnoea, previously diagnosed as EIA, who had a poor response to
inhaled b2-agonists. Monitoring end-tidal CO2 during a standardised exercise test, they
were able to identify a group of 11 patients whose EIRS were associated with hypocapnia
rather than bronchospasm. These patients, wrongly diagnosed and treated for EIA,
complained of dyspnoea and chest tightness by the end of the exercise challenge, with no
wheeze or cough, and had a post-exercise decrease of FEV1 v15% and a significant endtidal CO2 drop of 23.2% (versus 9.8% in controls). The authors also made the clinical
observation that this group included individuals that were highly competitive athletically,
with symptoms typically occurring when they attempted peak performances in athletic
competitions. Although they could not exclude a physiological mechanism (respiratory
compensation for the metabolic lactic acidosis of high level exercise), wrongly perceived
as pathological by those patients (and their physicians), they raised the hypothesis of an
abnormal ventilatory homeostasis during exercise, also suspected in other hyperventilation syndromes [27, 28]. Interestingly, chest pain associated with hyperventilation has
also been described in adults with negative cardiac stress testing by treadmill, and
reproduced by the induction of hypocapnia with voluntary hyperventilation [26, 29].
Lowhagen et al. [9], studying 88 adults with EIRS with a maximal exercise test, found
that the most common reason for stopping exercise in the nonasthmatic group (n=40)
69
L. DELGADO ET AL.
was chest pain and discomfort (35%), followed by dizziness and/or pricking sensations in
the arms or legs (20%), symptoms often seen with profound hyperventilation [27, 28].
Other conditions
Swimming-induced pulmonary oedema occurs in well-trained swimmers after a heavy
swimming session. This condition was recently reported in 70 previously healthy
swimmers, who developed typical symptoms of pulmonary oedema together with a
restrictive pattern in pulmonary function, which remained for up to 1 week after the
swimming event [30]. Finally, reports have been made concerning exercise-induced
arterial hypoxaemia [31]. This occurs especially in highly trained athletes and is thought
to be primarily due to diffusion limitations and ventilation-perfusion inequality. It is
postulated that incomplete diffusion in the healthy lung may be due to a rapid red blood
cell transit time through the pulmonary capillary. Physical training will improve muscle
strength and endurance, and in the cardiovascular system the ionotropic and
chronotropic capacities increase. However, in the respiratory tract no such effects of
training occur. The lungs diffusion capacity and pulmonary capillary blood volume
remain unaltered in the highly trained athlete, whereas maximum pulmonary blood flow
increases with enhanced maximum oxygen uptake. Ventilatory requirement rises with no
alteration in the capability of the airways and the lungs to produce higher flow rates or
higher tidal volumes, and little or no change in the pressure-generating capability of
inspiratory muscles [32]. The result is exercise-induced arterial hypoxaemia, which may
occur in up to 50% of highly trained athletes [3335]. This reduction in arterial oxygen
saturation may be confused with EIA.
Summary
Differential diagnoses of exercise-induced asthma in athletes include exercise-induced
laryngeal dysfunction and abnormal laryngeal response to exercise in different, but
closely related, entities, i.e. exercise-induced (paradoxical) vocal cord dysfunction,
laryngeal prolapse and/or laryngomalacia. All these conditions present as exerciseinduced inspiratory stridor with maximal exercise, usually resolving within 5 min of
stopping. Gastro-oesophageal reflux disease is another possible diagnosis and/or
comorbid factor in laryngeal dysfunction. Exercise-induced hyperventilation, swimming-induced pulmonary oedema and exercise-induced arterial hypoxaemia have all
been reported in highly trained athletes and are linked to respiratory symptoms not
directly related to bronchial obstruction. All of these conditions should be considered
and ruled out with a thorough examination, as many athletes receive unnecessary
treatment for asthma, which characteristically does not improve the exercise-induced
respiratory symptoms.
Keywords: Exercise-induced asthma, gastro-oesophageal refux, laryngeal dysfunction.
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72
CHAPTER 8
Anti-asthmatic drugs: treatment of athletes

and exercise-induced bronchoconstriction
K. Larsson*, K-H. Carlsen#, S. Bonini}
*Unit of Lung and Allergy Research, National Institute of Environmental Medicine, Karolinska Institutet,
Stockholm, Sweden. #Voksentoppen BKL, Rikshospitalet University Clinic, University of Oslo, Oslo,
Norway. }Allergology, University of Rome, Rome, Italy.
Correspondence: K-H. Carlsen, Voksentoppen BKL, Rikshospitalet (National Hospital) University Clinic,
University of Oslo, Ullveien 14, NO 0791 Oslo, Norway. Fax: 47 22136505; E-mail: k.h.carlsen@medisin.
uio.no
In recent decades it has become obvious that anti-asthma drugs are frequently used in
elite athletes in many kinds of sports and in cross-country skiers in particular. Amongst
the athletes who joined the USA Olympic Winter Sports Team in 1998, one out of four
had exercise-induced bronchoconstriction (EIB) and cross-country skiers were the most
affected [1]. In a Swedish study of 42 elite cross-country skiers, more than half fulfilled
strict criteria for asthma [2], and, in an epidemiological investigation conducted at
Swedish upper secondary schools, in which pupils were accepted based on merit as skiers,
15% of the skiers had physician-diagnosed asthma and 18% were treated with antiasthma drugs compared with 6% and 7%, respectively, amongst the controls [3]. Heir
et al. [4] found that 14% of Norwegian cross-country skiers had self-reported asthma and
22% used anti-asthma drugs. During the last decade it has also been convincingly shown
that athletes, other than skiers, have a higher prevalence of asthma compared with the
normal population. Thus, runners (long-distance runners in particular), figure skaters,
swimmers and athletes practicing other kinds of sport have an increased prevalence of
asthma.
It is highly unlikely that the asthmatic condition, which develops in athletes during
their career as elite athletes, is identical to what is usually considered to be asthma in
clinical practice, i.e. allergic asthma. Although the clinical appearance is similar in
athletes and those with "classical" asthma, there are differences between the two groups.
Thus, the skiers seem to have a weaker bronchial response to adenosine, lower levels of
exhaled nitric oxide (NO), less airway eosinophilia and a reduced number of mast cells
compared to a group of other asthmatic subjects [5, 6]. Whether subjects with "sports
asthma" respond to anti-asthmatic drugs in a similar manner as subjects with "classical"
allergic and nonallergic asthma has not been extensively studied. There are no clear data
indicating a different response to anti-asthmatic drugs between athletes who have
developed asthma during their career as athletes and nonathletic asthmatic subjects.
Thus, there is no evidence supporting different treatment for EIB in asthmatic athletes
and nonathletes.
Treatment of exercise-induced bronchoconstriction

The effect of drugs on EIB has been thoroughly studied in asthmatic subjects during
the last 30 yrs. In this review, studies have only been considered if they have fulfilled
certain criteria. Only controlled (placebo, and in a few cases comparisons between active
ISSN 1025-448x. ISBN 1-904097-22-7.
73
K. LARSSON ET AL.
drugs) trials based on eight or more subjects have been considered. In addition, the trials
have only been included if post-exercise values have been compared with pre-exercise,
post-drug values. The number of studies focusing on anti-asthmatic drugs in EIB is listed
in table 1.
b-Agonists
The class of drugs that have been shown to be most effective in protecting against EIB
are the b-adrenoceptor agonists, administered by inhalation. In earlier studies, it was
convincingly demonstrated that orally administered b-agonists (terbutaline, salbutamol,
orciprenaline, hexoprenaline) offered a very poor protective effect against EIB [710].
However, it was also demonstrated that inhaled b-agonists protected against EIB. Thus,
inhaled fenoterol completely abolished the response immediately after inhalation
whereas the effect wore off and did not differ from placebo 46 h after inhalation [7]. In
an early study, complete protection against EIB was demonstrated in asthmatic children
20 min after inhalation of salbutamol and salmefamol [11]. In a large number of studies it
has been demonstrated that short-acting b2-agonists protect against EIB and that the
effect is almost complete immediately and up to 20 min after inhalation. The effect is
short lasting and wears off with time. In most studies the effect is still detected up to 3 h
after inhalation [12] but is not different from placebo 4 h after inhalation.
Formoterol (a long-acting b2-agonist) offered similar protection to salbutamol 2 h
after inhalation, while the effect of formoterol, but not of salbutamol, remained 4 h after
inhalation [13]. In a study by Anderson et al. [14], salbutamol (a short-acting b2-agonist)
and salmeterol (a long-acting b2-agonist) offered a similar protective effect 30 min after
inhalation whereas salmeterol (but not salbutamol) was still protective, compared with
placebo, 2.5, 4.5 and 6.5 h after inhalation [14]. In a study of 13 asthmatic children,
Green and Price [15] found a post-exercise forced expiratory volume in one second
(FEV1) fall of 22.726.6% after inhalation of placebo and 2.75.3% after inhalation of
salmeterol, 1, 5 and 9 h after inhalation. Carlsen et al. [16] found a remaining partial
protection against EIB of inhaled salmeterol 10 and 12 h (overnight) after inhalation in
children. In that study, the post-exercise reduction of FEV1 was 1819% after inhalation
of salmeterol and 30% after placebo.
Certain studies have shown that the protection against EIB, offered by a long-acting
b2-agonist (salmeterol), has been found to be reduced during continuous treatment with
the drug. Thus, Simons et al. [17] found a weaker protection after 4 weeks of treatment
than on day 1 in 14 young asthmatic subjects and, in accordance with this, Nelson et al.
[18] demonstrated a weaker protection by salmeterol after 4 weeks treatment than after 1
week and 14 days of treatment. This tolerance towards the protective effect mainly seems
to affect the duration of action whereas the protective effect 1 h after inhalation seems to
be unaffected.
In conclusion, the protective effect of inhaled b2-agonists against EIB is very good or
even complete when exercise is performed a few hours after inhalation of short-acting
b2-agonists and somewhat longer after inhalation of one dose of a long-acting b2-agonist.
Continuous treatment with a long-acting b2-agonist reduces the protective effect, mainly
regarding the duration of protection, offered by the same b2-agonist given prior to
exercise.
Inhaled glucocorticosteroids
The effect of inhaled steroids on EIB has been studied in adults and even more in
asthmatic children. The duration of steroid treatment in these studies has been from 3
74
ASTHMA TREATMENT FOR ATHLETES AND EIA
Table 1. Studies of pharmacological treatment of exercise-induced bronchcoconstriction

Class of drug
Trials n
Drugs in the trials (n)
Comments
Inhaled steroids
Budesonide (4)
Fluticasone (2)
Triamcinolone (1)
Betamethasone (1)
Comparisons between
inhaled steroids and placebo
b-agonists
39
Salbutamol (19)
Terbutaline (8)
Fenoterol (6)
Orciprenaline (3)
Procaterol (2)
Clenbuterol (2)
Hexoprenaline, isoprenaline,
rimiterol, salmefamol,
biltolterol, tulobuterol (1)
Salmeterol (8)
Formoterol (5)
Comparisons between
b-agonists and placebo
and other b-agonists
Antileukotrienes
12
Montelukast (3)
Zafirlukast (3)
Verlukast (1)
Cinalukast (1)
Piriprost (1)
Zieluton (1)
ABT-761 (1)
Comparisons between
antileukotrienes and placebo
Cromones
31
Cromoglycate (24)
Nedocromil (15)
Minocromil (1)
FPL 57787 (1)
Comparisons between
cromones and placebo
and other cromones. Includes
one systematic review and
one meta-analysis.
Xanthines
Theophylline (3)
Aminophylline (1)
Enprofylline (1)
M&B 22,948 (1)
Comparisons between
xanthines and placebo
and other xanthines.
Antihistamines
11
Cetririzine (2)
Loratadine (1)
Ketotifen (2)
Astemizole (2)
Azelastine (1)
Clemastine (1)
Cimetidine (2)
Ranitidine (1)
Comparisons between
antihistamines and placebo
and other antihistamines.
Anticholinergics
Ipratropium (4)
Oxitropium (1)
Comparisons between
anticholinergics and placebo
Ca2z blockers
12
Nifedipine n=6)
Verapamil (3)
Diltiazem (3)
Gallopamil (1)
Felodipine (1)
Comparisons between Ca2z

blockers and placebo and
other Ca2z blockers
Furosemide
Furosemide
Comparisons between
furosemide and placebo
Local anaesthesia
Lidocaine (1)
Lignocoine (1)
75
K. LARSSON ET AL.
Table 1. Continued
Class of drug
Trials n
Drugs in the trials (n)
Comments
Furosemide
Furosemide
Comparisons between
furosemide and placebo
Local anaesthesia
Lidocaine (1)
Lignocoine (1)
a-agonists
Methoxamine (1)
Prasozin (1)
Other mediator blockers
TP1-antagonists (2)
Indomethacin (1)
Other drugs
Heparin (1)
b-Carotene (1)
Lycopene (1)
Roflumilast (1)
Multiple drug treatment
29
Comparisons between
classes of drugs and effect
of combination therapy
weeks to 22 months, mostly in a parallel group design. Four weeks of betamethasone

inhalation gave a 50% reduction of EIB in a study of 18 adult asthmatics [19]. In a 6-week
study of 40 adult subjects with asthma, the post-exercise fall in FEV1 was 22% after
6 weeks of placebo and 7% after inhalation of 0.8 mg b.i.d. budesonide [20], i.e. an almost
70% reduction of the airway response. The effect of budesonide on EIB has been studied
in children. Waalkens et al. [21] found a 45% reduction of EIB when pre- and postexercise response was compared and a reduction of 51% when inhaled budesonide
(0.2 mg b.i.d.) was compared with placebo after 22 months of treatment in 55 children.
Jonasson et al. [22] found a 1316% improvement of EIB after 12 weeks of budesonide
inhalation (0.1 and 0.2 mg q.d. and 0.1 mg b.i.d.) while the improvement offered by
placebo was 4.2% in a parallel group study of 57 asthmatic children [22].
One single dose of inhaled fluticasone (1 mg) reduced EIB by y50% compared with
placebo in nine asthmatic children [23] and 6 weeks of fluticasone inhalation (0.1 mg
b.i.d. and 0.25 mg b.i.d.) in a parallel group study reduced EIB by 60% (no difference
between the two doses) in 37 asthmatic children [24].
Antileukotrienes
In a parallel group study of 110 adult asthmatic subjects, montelukast reduced EIB by
45% compared with placebo in a 3-month study [25]. In a study by Peroni et al. [26], one
single oral dose of montelukast protected against EIB for 12 h after administration (EIB
reduced by 52%) whereas no effect was found 2 h and 24 h after administration in
children with asthma. Treatment for 2 days with oral montekulast (5 mg q.d.) yielded a
30% reduction of EIB in a cross-over study of 27 asthmatic children [27].
Inhalation of a single dose of zafirlukast (0.4 mg) reduced EIB by 49% compared with
placebo in a cross-over study of nine asthmatic subjects [28]. One single oral dose of
zafirlukast reduced EIB by 40% in a cross-over study of nine asthmatics [29] and 2 weeks
of treatment (20 mg b.i.d. and 80 mg b.i.d.) yielded a reduction of EIB by 35% (low dose)
76
and 49% (high dose) 2 h after last dosing and 23% (low dose) and 27% (high dose) 8 h
after last dosing [30].
In a dose-response study, a single dose of oral cinalukast (10, 50 and 200 mg) reduced
EIB by 3743% 2 h after administration and by 1845% 8 h after administration. A doseresponse relationship was found 8 h, but not 2 h, after ingestion of the drug [31].
Two days of treatment with oral zileuton (0.6 mg q.i.d.), a leukotriene synthesis
inhibitor, reduced EIB by 40% in 24 asthmatic subjects [32], and intravenously
administrated verlukast (160 mg) reduced EIB by 63% in 12 asthmatics [33].
Cromones
The effect of disodium cromoglycate (DSCG) and nedcromil sodium on EIB has been
extensively studied and more than 30 randomised, controlled, cross-over clinical trials
were identified. In addition, one meta-analysis and one systematic review have been
conducted. The meta-analysis evaluates the effect of nedocromil sodium on EIB and is
based on 20 studies [34]. The mean post-exercise fall (95% confidence interval) was 32%
(2836%) following placebo treatment and 16% (1318%) after inhalation of nedocromil,
implying a protection (reduction of FEV1 fall) of y50% by the drug.
In a systematic review based on 8 studies, DSCG was compared with nedocromil
sodium [35]. No difference was found between the two drugs with regard to the capability
to protect against EIB.
Xanthines
Oral aminophylline, aiming at a target plasma concentration of 1020 mg?mL-1, in
nine asthmatic subjects offered a w50% reduction in post-exercise fall in FEV1 [36]. In a
study by Laursen et al. [37], intravenously administered theophylline (5 mg?kg-1)
reduced post-exercise FEV1 fall by 50% whereas enprofylline (5 mg?kg-1) did not offer
significant protection [37].
Antihistamines
Antihistamines have, in most studies, not been shown to give beneficial protection
against EIB. In three studies of ketotifen no protection was found [3840]. Cetirizine has
been studied following oral intake and inhalation. No effect on EIB was found after
orally administered cetirizine [41, 42] while inhalation offered significant protection with
a 33% reduction of post-exercise FEV1 fall compared with placebo [42]. In a study by
Baki et al. [43], loratadine (10 mg q.d. for 3 days prior to the exercise test) offered a
significant protection against EIB with a 42% reduction of post-exercise FEV1 fall in 11
asthmatic children [43]. Selective H2-blockers (cimetidine, ranitidine) do not seem to
influence EIB [44, 45]. Magnussen et al. [46] found that orally administered azelastine
offered a 50% protection against EIB in 10 asthmatic subjects.
Anticholinergics
In most studies, anticholinergics do not offer any protection against EIB [4750]. In
two studies, post-exercise increase in airway resistance (Raw) has been compared after
inhalation of an anticholinergic agent and placebo. Thus, Taytard et al. [51] found a
109% increase in Raw following inhalation of oxitropium bromide (0.3 mg) compared
with 266% increase after placebo [51], and Magnussen et al. [52] found a 173% increase
77
K. LARSSON ET AL.
in specific Raw after inhalation of ipratropium bromide (0.08 mg) compared with 231%
increase after placebo.
Other drugs
A substantial number of studies have been conducted on the protective effect against
EIB of calcium blockers. In almost all these studies calcium blockers (verapamil,
nifedipine, gallopramil, diltiazem, felodipine) have been demonstrated to protect against
EIB. The effect of nifedipine was investigated after sublingual administration [5358] and
was found to inhibit post-exercsie fall in FEV1 by 25100% compared with placebo.
Inhaled verapmil reduced EIB by 5065% in two studies by Patel et al. [59, 60] but did
not provide the same effect in a more recent investigation [61]. Diltiazem seems to
provide a moderate but significant protection against EIB [62, 63] whereas felodipine
reduced post-exercise fall in FEV1 by 50% [64].
The protection against EIB by furosemide has been studied in adults and children with
asthma. Inhalation of furosemide reduces post-exercise bronchoconstriction, measured
as fall in FEV1, by 4560% [6567].
Comparisons between active drugs

b2-Agonists compared with other drugs. In an early study by Seale et al. [68], no effect
on EIB and no difference were found between orally administered salbutamol,
theophylline and placebo with regard to the protective effect against EIB. The effect
of inhaled isoetharine and DSCG was similar and provided 62% protection against EIB
compared with placebo in a study of 10 asthmatic subjects [69]. Larsson et al. [70]
demonstrated better protection against EIB by fenoterol than by ipratropium and
oxitropium, the latter two being no better than placebo. Agostini et al. [71] were not able
to demonstrate an additive effect between fenoterol and ipratropium in 15 asthmatic
children. Obata et al. [72] showed that procaterol provided a better protection against
EIB than did DSCG, which in turn was better than placebo up to 8 h after inhalation in
asthmatic children.
In an acute study of protection against EIB, offered by a single dose of salmeterol
(0.042 mg by inhalation), montelukast (10 mg orally) and zafirlukast (20 mg orally), no
difference was found between the drugs when exercise tests were performed up to 12 h
after dosing [73]. The leukotriene synthesis inhibitor zileuton (600 mg orally) was equal
to the other drugs up to 8 h after administration but the protection was attenuated after
12 h. In that study, all four drugs provided better protection than placebo. In a
comparison between salmeterol and montelukast, no difference as regards protection
against EIB was observed after 3 days of treatment while montelukast offered a small but
significantly better protection after 4 and 8 weeks of treatment [74]. In that study, which
was not placebo controlled, the exercise tests were performed 12 h after the last dosing of
salmeterol and the results were interpreted as a development of tachyphylaxis of the
protective effect of the long-acting b2-agonist. This is in accordance with previous studies
in which tolerance to the protection by b2-agonists is observed in particular regard to the
duration of action [17, 18]. Edelmann et al. [75] showed a better protection by
montelukast (10 mg orally q.d.) than by salmeterol (0.05 mg b.i.d.) after 4 and 8 weeks of
treatment while no difference between the drugs was found after 3 days of treatment.
Salmeterol offered an almost 40% protection and montelukast y50% protection against
EIB. Also, in that study, which was not placebo controlled, the effect of salmeterol
against EIB was assessed 12 h after last dosing.
In a 1 week comparison between salmeterol (0.05 mg b.i.d.) and inhaled DSCG (2 mg
78
q.i.d.) in asthmatic children, salmeterol offered a better protection against EIB than did
DSCG when inhaled 30 min prior to the exercise test [76]. The study was not placebo
controlled.
Disodium cromoglycate compared with other drugs. Tullett et al. [77] showed a 50%
protection against EIB by ipratropium and almost 75% protection by DSCG in eight
asthmatic subjects; however, the difference between ipratropium and DSCG was not
significant. In a study by Tan et al. [78], DSCG offered better protection against EIB than
did ketotifen, the latter being no different compared with placebo. In the study by Tan
et al. [78], in which 10 asthmatic subjects were included, the post-exercise fall in FEV1 was
38% after placebo, 24% after DSCG (20 mg q.i.d.) and 45% after ketotifen (1 mg b.i.d.)
after 1 week of treatment. In a single dose study of 15 asthmatic children, Boner et al. [79]
found a significant protection by ipratropium and DSCG but not by verapamil when
compared with placebo. In a single dose comparison between inhaled probilukast
(0.8 mg) and DSCG (20 mg), both drugs offered a 33% protection against EIB with no
difference between the drugs [80]. Nedocromil and DSCG have been compared with
furosemide in two studies in asthmatic children [81, 82]. In neither study was a difference
found between DSCG/nedocromil and furosemide.
Influence of anti-asthma drugs on physical performance

There is no doubt that treatment with anti-asthmatic drugs improves physical capacity
in asthmatic subjects who, without these drugs, would suffer from EIB leading to
impaired physical performance. The increased use of anti-asthma drugs among elite
athletes has raised the question of whether anti-asthma drugs improve physical
performance in subjects who do not suffer from asthma. If this was the case, these drugs
should be included on the doping list.
b2-Agonists
Of the drugs that have been used as a remedy for asthma the b2-agonists have been the
most extensively studied with regard to the capability to improve physical performance.
The decision to include b-agonists on the doping list was not based on the finding that
those drugs had actually been shown to improve physical performance but rather that the
b2-agonists have similarities to endogenously produced and released catecholamines. At
present, the use of oral b-agonists is forbidden in connection with sport whereas some
inhaled b2-agonists are allowed after special examination of the athlete.
Effect on endurance physical capacity. A literature search on PubMed (2004) on the

effect of inhaled b2-agonists on physical endurance performance in nonasthmatic subjects,
including only placebo-controlled, randomised, blinded (single or double-blind) studies
with a cross-over design gave 13 hits (table 2). A total of 12 of these studies were
performed on healthy, highly trained athletes and one in healthy young males with normal
physical fitness. These studies have, in general, been conducted on small samples (n=724)
and the power calculation of the primary outcome variable has not been done in any of
these trials. The studies were mostly performed on cyclists, runners, skiers and triathletes
and the exercise tests were performed by ergometer cycling (n=5) or treadmill running
(n=8). One important aim has been to find out whether endurance time/time to exhaustion
is improved by pre-exercise inhalation of a b2-agonist. The design of the trials to achieve
this information differs and in three of the studies exercise tests were performed at low
79
80
24
CARLSEN [95]
Skiers, Runners,
others
Triathletes
Skiers
Skiers
Skiers, runners
Cyclists, Skiers,
runners
Cyclists
Skiers, runners
Males
Cyclists
Cyclists
Runners
Cyclists
Type of sport
Exercise test
Treadmill running
Ergometer cycle
Treadmill running
Treadmill running
Treadmill running
Treadmill running
Ergometer cycle
Treadmill running
Treadmill running
Ergometer cycle
Ergometer cycle
Treadmill running
Ergometer cycle
Drug/blind
Formoterol 0.09 mg DB
Salbutamol 0.2 mg and

0.8 mg DB
Salmeterol 0.05 mg DB
Salbutamol 1.2 mg DB
Salbutamol 0.8 mg,

salmeterol 0.05 mg DB
Terbutaline 3.0 mg SB
Salbutamol 0.05 mg?kg /DB
-1
Terbutaline 1.0 mg SB
Outcome measures
Time to exhaustion, VO2,max,

VE,max, HR, LA,max
VE,max, HR, LA,max
VE,max, HR,
psychometric
tests, dyspnoea, LA,max,
Ser-Kz, FFA, Gly, Glu
VE,max

VE,max, HR, AT
1 h enduranceztime to
exhaustion, VO2,max,
VE,max, HR
Time to exhaustion,
VO2,max, RPE, HR, VE,max,
MaxLA,
45 min enduranceztime
to exhaustion, VO2,max, HR
Maximal work load, VO2,max,
RPE, HR, LA,max
HR, VE,max, RER
HR, VE,max O2 saturation
Time to exhaustion, maximal
work load, VO2,max, HR
VE,max, HR, LA,max, Ser-Kz
b-agonist effect
Formoterol=placebo
Salbutamol=placebo
Salmeterol=placebo
LA,max and post-exercise Ser-Kz fall:

Terbutaline w placebo, otherwise
terbutaline=placebo
Time to exhaustion,
Salbutamol=salmeterol v placebo,
otherwise salbutamol=
salmeterol=placebo
Salbutamol=placebo
Salbutamol=placebo
RER: terbutaline w placebo,

otherwise terbutaline=placebo
Salbutamol=placebo
Salbutamol=placebo
Salbutamol=placebo
Time to exhaustion:
salbutamol w placebo,
otherwise salbutamol=placebo
Salbutamol=placebo
DB: double blind; VO2,max: oxygen uptake at maximal exercise; VE,max: ventilation at maximal exercise; HR: heart rate during exercise; RPE: rating of perceived exertion;
LA,max: post-exercise maximal blood lactic acid level; SB: single blind; RER: respiratory exchange ratio; Ser-Kz: serum potassium concentration; AT: anaerobic threshold;
FFA: plasma concentration of free fatty acids; Gly: plasma concentration of glycerol; Glu: plasma concentration of glucose. #: Eleven randomised, placebo-controlled, crossover studies are summarised.
12
20
LARSSON [83]
GOUBAULT [93]
15
NORRIS [93]
17
HEIR [92]
SUE-CHU [85]
10
UNNITHAN [91]
21
FLECK [90]
SANDSUND [84]
MEEUWISSE [89]
18
17
MORTON [88]
CARLSEN [87]
15
Subjects n
BEDI [86]
First author [ref.]
Table 2. The effect of b2-agonists on physical endurance performance in healthy athletes#
K. LARSSON ET AL.
81
16
11
MORTON [98]
MCDOWELL [99]
Cyclists
Cyclists,
triathletes
Cyclists
Cyclists
Power athletes
Cyclists
Healthy
nonathletes
Runners
Type of sport
Exercise test
Ergometer cycle
Ergometer cycle
Ergometer cycle
Ergometer cycle
Ergometer cycle
Ergometer cycle
Ergometer cycle
Treadmill running
Drug/blind
Outcome measures
Wingate test 30 s, PP, TW,

TTPP, PF, HR
Sprint test 10 s and 30s,

reaction time, hand steadiness,
strength/power leg test
Wingate test 30 s, PP, TW,

TTPP, HR, Ser-LA
Wingate test 60 s, PP
Sprint test 10 s, PP, TW,

strength/power leg test
Wingate test 30 s, PP, TW
Supramax effort 15 s PP, TW,

TTPP, PF
Sprint test 10 s and 30 s, PP
b-agonist effect
Salmeterol=placebo
Salmeterol=placebo
Salbutamol=placebo
Salbutamol=placebo
Salbutamol=placebo
Salbutamol=placebo
PP and PF: Salbutamol w

placebo, otherwise salbutamol=placebo
Salbutamol=placebo
DB: double blind; PP: peak power; TW: total work; TTPP: time to peak power; HR: heart rate during exercise; PF: percent fatigue; Ser-LA: serum lactate concentration.
#
: Eight randomised, double-blind, placebo-controlled, cross-over studies are summarised.
14
17
MORTON [96]
LEMMER [97]
MEEUWISSE [88]
15
15
SIGNORILE [100]
NORRIS [92]
17
Subjects n
MORTON [87]
First author [ref.]
Table 3. The effect of b2-agonists on physical performance and power output#
K. LARSSON ET AL.
temperatures (-10uC and -15uC) [8385]. In only one study was a beneficial effect of
salbutamol on endurance time found [86], but, in a study by Carlsen et al. [87], a shorter
time to exhaustion was found after inhalation of salbutamol and salmeterol compared
with placebo. In all the other nine studies no difference in time to exhaustion was found
between the b2-agonist (salbutamol and terbutaline) compared with placebo [83, 84, 88
94]. Maximal heart rate during exercise and maximal oxygen uptake were measured in all
11 trials and maximal ventilation in seven trials. All three parameters were unaffected by
the b2-agonist in all studies. Oxygen saturation was measured in one study and no
difference between salbutamol and placebo was found [92]. In one study, a high dose of
terbutaline (3.0 mg) increased the plasma level of lactate and enhanced the post-exercise
fall in the serum potassium concentration significantly more than did placebo [83]. Blood
lactate concentration was not found to be affected by the b2-agonist in the other four
studies in which it was measured [84, 88, 90, 94]. Neither were plasma levels of free fatty
acids, glycerol and glucose influenced by salbutamol with a low (0.2 mg) or a high
(0.8 mg) dose [94]. In a study by Goubault et al. [94], measurements of dyspnoea and
psychometric tests, and psychomotor and sensory motor performance, were performed.
Neither of these outcomes was influenced by salbutamol. Although no difference in
maximal oxygen uptake was found between formoterol and placebo in a study by
Carlsen et al. [95], the estimated difference was statistically significant in favour of
placebo.
Effect on power output. A search for randomised, placebo-controlled, blinded studies

with a cross-over design regarding the effect of b2-agonist on power output in healthy
subjects yielded eight trials (table 3). Seven of those studies were performed on athletes
[88, 89, 94, 9699] and one on healthy nonathletes [100]. Similar to the trials of endurance
performance, the trials of b2-agonist effect on power output were made on small sample
sizes (n=717). In all studies of athletes no influence of b2-agonists (salbutamol, n=5;
salmeterol, n=2) on peak power, time to peak power, total work, fatigue or leg strength
was demonstrated (table 2). In the study of healthy nonathletes [100], inhalation of
0.18 mg salbutamol was found to enhance peak power and fatigue rate, the latter being a
consequence of the former. The effect of salbutamol on peak power in that study is minor
but it remains unclear why the results by Signorile et al. [100] are not supported by results
from any of the other trials.
Other anti-asthmatic drugs

There are no indications that inhaled DSCG, nedocromil sodium or inhaled
glucocorticosteroids improve physical performance but the effect of these drugs has
not been studied in healthy, nonasthmatic individuals in this context. In a study by SueChu et al. [101], montelukast was not found to influence physical performance in highly
trained endurance male athletes.
82
Summary
Controlled studies of the protective effect of pharmacological treatment of exerciseinduced bronchoconstriction (EIB( were reviewed. The studies were accepted only if
they fulfilled certain criteria. In total, 164 studies were included in this review. It was
found that inhaled b2-agonists offer a partial or complete (during the first 30 min after
inhalation) protection against EIB, whereas the protection of oral b2-agonists was
poor. Continuous treatment with b2-agonists induces tolerance of the protective effect,
which seems to influence the duration rather than the magnitude of the protection.
Treatment with inhaled steroids, xanthines and anti-leukotrienes offer a partial
protection against EIB, while antihistamines and anticholinergic drugs are of less
value in this context. Cromones offer a partial protection against EIB with no
difference between cromoglycate and nedocromil. Furthermore, frusemide and
calcium blockers have been shown to protect against EIB.
A total of 13 controlled, randomised studies with a cross-over design of the effect of
b2-agonists on physical endurance performance in healthy athletes or healthy young
males were identified. In one study, a favourable effect of the drug was found (time to
exhaustion), while in another study the placebo was favoured in this respect. In the
other 11 studies no beneficial effect on endurance performance was found by b2agonists. Of the eight studies examining the effect of b2-agonists on power output in
athletes or non-athletes, one study favoured the active drug while the other seven
studies did not find a difference between the active drug and the placebo. In one study,
montelukast was not found to alter physical performance. There are reasons to believe
that other anti-asthmatic drugs do not influence physical performance, but there are
no studies supporting this assumption.
Keywords: Anti-asthma drugs, athletes, beta-agonists, controlled trials, corticosteroids, exercise-induced bronchoconstriction.
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physical performance in high-performance nonasthmatic athletes. Clin J Sport Med 1992; 2: 9397.
Meeuwisse WH, McKenzie DC, Hopkins SR, Road JD. The effect of salbutamol on performance
in elite nonasthmatic athletes. Med Sci Sports Exerc 1992; 24: 11611166.
Fleck SJ, Lucia A, Storms WW, Wallach JM, Vint PF, Zimmerman SD. Effects of acute
inhalation of albuterol on submaximal and maximal VO2 and blood lactate. Int J Sports Med
1993; 14: 239243.
Unnithan VB, Thomson KJ, Aitchison TC, Paton JY. Beta 2-agonists and running economy in
prepubertal boys. Pediatr Pulmonol 1994; 17: 378382.
Heir T, Stemshaug H. Salbutamol and high-intensity treadmill running in nonasthmatic highly
conditioned athletes. Scand J Med Sci Sports 1995; 5: 231236.
Norris SR, Petersen SR, Jones RL. The effect of salbutamol on performance in endurance cyclists.
Eur J Appl Physiol Occup Physiol 1996; 73: 364368.
Goubault C, Perault MC, Leleu E, et al. Effects of inhaled salbutamol in exercising non-asthmatic
athletes. Thorax 2001; 56: 675679.
Carlsen K-H, Hem E, Stensrud T, Held T, Herland K, Mowinckel P. Can asthma treatment in
sports be doping? The effect of the rapid onset, long-acting inhaled beta2-agonist formoterol upon
endurance performance in healthy well-trained athletes. Respir Med 2001; 95: 571576.
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K. LARSSON ET AL.
96.
Morton AR, Papalia SM, Fitch KD. Changes in anaerobic power and strength performance after
inhalation of salbutamol in nonasthmatic athletes. Clin J Sport Med 1993; 3: 1419.
97. Lemmer JT, Fleck SJ, Wallach JM, et al. The effects of albuterol on power output in nonasthmatic athletes. Int J Sports Med 1995; 16: 243249.
98. Morton AR, Joyce K, Papalia SM, Carroll NG, Fitch KD. Is salmeterol ergogenic? Clin J Sport
Med 1996; 6: 220225.
99. McDowell SL, Fleck SJ, Storms WW. The effects of salmeterol on power output in nonasthmatic
athletes. J Allergy Clin Immunol 1997; 99: 443449.
100. Signorile JF, Kaplan TA, Applegate B, Perry AC. Effects of acute inhalation of the
bronchodilator, albuterol, on power output. Med Sci Sports Exerc 1992; 24: 638642.
101. Sue-Chu M, Sandsund M, Holand B, Bjermer L. Montelukast does not affect exercise
performance at subfreezing temterature in highly trained non-asthmatic endurance athletes.
Int J Sports Med 2000; 21: 424428.
88
CHAPTER 9
Prevention: educational issues and

recommendations for early recognition
P. van Cauwenberge*, P. Palange#, G.W. Canonica}
*Dept of Oto-rhino-laryngology, Ghent University, Belgium. #Dipartimento di Medicina Clinica, University
of Rome "La Sapienza", Rome, and }Dipartimento di Medicina Interna, University of Genoa, Genoa,
Italy.
Correspondence: P. van Cauwenberge, Dept of Oto-rhino-laryngology, Ghent University Hospital, De
Pintelaan 185, 9000 Ghent, Belgium. Fax: 32 92404993; Email: paul.vancauwenberge@Ugent.be
Allergic rhinitis/conjunctivitis and asthma are the most common allergic and
respiratory disorders in athletes. Allergic rhinitis/conjunctivitis has a peak incidence
between 10 and 25 yrs, the age range of most elite athletes.
Asthma is especially problematic in athletes if it is triggered by exercise. This condition
is described as exercise-induced asthma (EIA). It can occur at any age, but is clinically
more apparent in the younger population because of their inherently greater degree of
activity. In most patients with chronic asthma, exercise is a potent stimulus for
bronchoconstriction and EIA is usually part of an overall asthmatic diathesis in which
exercise is but one of many stimuli inducing airflow limitation. In some cases, however,
EIA is the only manifestation of asthma.
Both allergic rhinitis/conjunctivitis and asthma can cause serious morbidity, have a
significant impact on quality of life and a compromising effect on the athletes ability to
obtain maximal performance. The management of allergic and respiratory disorders
undoubtedly poses some specific challenges in athletes, especially in professional athletes.
Environmental control is unpractical and often impossible in elite athletes exposed to
the offending allergen(s), pollutants and irritants during training and/or competition. In
addition, increased ventilation rate during exercise augments the inhaled air volumes
and, therefore, the amount of airborne triggering particles in contact with the nasal and
bronchial mucosa [1].
Pharmacological treatment must comply with the anti-doping rules, should provide
optimal symptom control and minimal detrimental influences from adverse effects on
performance. In contrast, elite athletes have a great reluctance to take any medication.
They avoid even prescribed, permitted medication. Many have an itinerant and irregular
lifestyle, which complicates compliance with the proposed preventive and therapeutic
measures [2].
In all patients (including elite athletes) suffering from asthma and/or allergic rhinitis,
early recognition, profound education, preventive strategy and, if necessary, pharmacological measures are the cornerstones of appropriate management.
In this chapter the authors will focus on prevention, educational issues and early
recognition. Other allergic and respiratory disorders, such as exercise-induced
anaphylaxis and contact dermatitis, have been described in sports, but these conditions
are rare and will not be discussed here.
ISSN 1025-448x. ISBN 1-904097-22-7.
89
P. VAN CAUWENBERGE ET AL.
Prevention of allergic and respiratory disorders in sports

There is an increasing interest in primary and secondary prophylaxis in the
management of asthma and allergic rhinitis. Primary prophylaxis includes interventions
made before any evidence of disease, in an attempt to prevent its onset. Secondary
prophylaxis tries to avoid symptom aggravation and to reduce disease impact after the
onset of the disease, but does not include therapeutic measures taken during symptom
worsening.
Primary prevention
Potential strategies for the primary prevention of allergic and respiratory disorders will
only be discussed briefly as this has no specific implications for athletes.
In the past, primary prevention strategies for allergic diseases (atopic dermatitis,
allergic rhinitis/conjunctivitis and allergic asthma) focussed on allergen avoidance
measures early in life, which were supposed to prevent primary sensitisation to both food
and inhalant allergens. This was based on the concept of the "atopic march", claiming
that this march starts with early atopic sensitisation to food allergens, which was
understood to be a risk factor for subsequent sensitisation to inhalant allergens, which in
turn was regarded as a risk factor for the development of allergic rhinitis and allergic
asthma [3].
However, more recent studies suggest a careful re-examination of this proposed
concept and some even suggest a protective role of certain exposures [47].
The complex interplay among different environmental factors, timing of the exposure
and genetic factors all need to be considered and this might allow the development of
individualised prevention strategies in the future [8].
The "hygiene hypothesis" suggests that early exposure to microbial products switches
off allergic responses and prevents the development of allergic diseases [9]. This
hypothesis is supported by epidemiological studies comparing large populations who
have and have not had such exposures [10]. However, due to the absence of good quality
intervention studies no recommendations can be made at present.
Three observational studies, in w8,000 patients, have shown that immunotherapy in
individuals with a single allergy reduces the subsequent development of new allergies
over a 34-yr follow up compared to contemporaneous untreated controls [1113]. No
double-blind, placebo-controlled trials of immunotherapy as a primary preventative
treatment have been conducted until now, so it is still uncertain how well immunotherapy
works as a primary prevention tool.
Other suggested strategies for the primary prevention of asthma (both allergic and
nonallergic) are campaigns to reduce smoking, the promotion of breastfeeding and other
dietary modifications.
The effects of environmental tobacco smoke (the most common indoor pollutant) on
the respiratory health of children have been extensively reviewed. Smoking in pregnancy
is associated with a dose-dependent decrease in an infants lung function [14, 15].
Exposing a child to tobacco during pregnancy and early childhood increases the risk of
infant wheeze [16] and approximately doubles the risk of that child having a serious
respiratory infection requiring hospitalisation or treatment by a doctor [17].
Concerning outdoor air pollutants, there is no evidence that exposure to air pollution
plays a role in the acquisition of asthma. Comparison of highly and lesser polluted cities
in Europe even demonstrates more cough and bronchitis symptoms in the highly polluted
cities, but more allergy and asthma in the lesser polluted cities [18].
A systematic review and meta-analysis involving 8,183 subjects, followed for a mean of
90
PREVENTION: EDUCATION FOR EARLY RECOGNITION
4 yrs, revealed a significant protective effect of breastfeeding against the development of

asthma. The effect was greatest in children with a family history of atopy [19]. In
contrast, in a more recent study in 1,246 patients, breastfeeding was associated with a
reduced risk of infant wheeze but also with an increased risk of asthma at 6 yrs [20].
There is limited epidemiological evidence suggesting a beneficial effect on the risk of
getting asthma for other dietary modifications e.g. reducing salt intake and increasing the
consumption of fresh food, vegetables and fish oil [17].
Secondary prevention
Nonpharmacological measures. Environmental control in allergic athletes. In
sensitised patients, avoidance of the triggering allergens is usually recommended to
prevent symptom aggravation. For athletes, this applies both to the athletes home
environment and exercise environment. Recreational athletes are able to adjust their
exercise activities to minimise exposure to the offending allergens; however, for
competitive athletes, options are much more limited. Additionally, exercise worsens
allergen exposure because of the higher inhalation of airborne allergens [1].
In outdoor sports, such as soccer, football, baseball and track events, seasonal
allergens can cause serious problems in athletes sensitised to pollen.
Organising major sporting events, such as the Olympics, during the pollen season can
be a dramatic problem for pollen-sensitive athletes hoping to obtain peak performance
[21].
No practical interventions have been identified for controlling common outdoor
allergens. Exposure whilst exercising in the open air can only be prevented by not joining
in the training or competition, especially on days with a high pollen count. However,
although pollen levels can be easily monitored, there is no firm dose-response curve and
the inhaled pollen dose required to cause symptoms varies widely and depends on
individual sensitivity and the progression of the pollen season (as the pollen season
progresses, decreasing quantities are required to elicit symptoms) [21, 22]. Ventilation
systems can be equipped with appropriate filters to avoid drawing pollen allergens into
indoor sporting facilities during the pollen season.
Indoor allergens, in particular house dust mite (HDM), are potential hazards, not only
in the indoor sport facilities, but also in the training camps and the homes of athletes.
There are a number of specific interventions that have been advocated as methods to
reduce or prevent exposure to HDM allergen.
Application of physical barriers to bedding, washing to remove allergens and
interventions to lower indoor humidity are central components of any HDM avoidance
strategy. To assess the benefit and harm of measures designed to reduce HDM exposure
in the management of HDM-sensitive allergic rhinitis, published and unpublished
randomised, controlled trials were systematically reviewed. A methodological assessment
of trial quality was conducted using the Cochrane approach. The results indicate that,
when compared with controls, significant reductions of allergen load can be achieved by
physical and chemical means, but there is little evidence at present that these reductions
translate into a sustained improvement in clinical outcome [23]. No specific measures
have been described for athletes allergic to HDM.
Sensitisation to animals is especially problematic for athletes exposed to these allergens
during exercise, e.g. in equestrian sport. For athletes sensitised to their own pet(s), the
same preventive strategy as that used in the general population should be followed.
Usually, the removal of the pet is advised. The feasibility of this measure is limited by the
often strong affinity people have for their pets.
The present authors conclude that, in the domestic environment, allergic athletes
91
should take the same measures as all other sensitised patients to avoid or decrease
allergen exposure. However, in the training or competitive environment, this is often
impossible or impractical.
Often a type of "natural selection" occurs. Atopic individuals are most unlikely to
continue in highly allergenic environments, such as horse stables, where they are exposed
to hay, dust and horse hair. This explains why equestrians are a group of athletes with a
low incidence of atopic tendencies. On the contrary, in swimmers the incidence of atopy
is much higher. This is undoubtedly partly due to the low allergenicity of this
environment and the tradition of encouraging atopic children to participate in water
sports, particularly swimming [1].
Along with exposure to allergens, exposure to irritants, chemicals and air pollutants
can exacerbate allergic rhinitis, conjunctivitis and asthma. Inhalation of chlorine for
example, which is used to disinfect pools, has been shown to produce nasal congestion,
which is more pronounced amongst patients with seasonal allergic rhinitis compared
with nonallergic patients [24].
Nonpharmacological prophylactic management of exercise-induced asthma. In

patients with EIA, the airway response and the severity of obstruction varies with both the
exercise task and the environment in which it is occurring.
Intense exercise requires greater ventilation to meet the metabolic demands and this
increased ventilation is a key element in the pathophysiology of exercise-induced airway
narrowing. Therefore, EIA definitely depends on the exercise-load [25, 26].
The airway reaction during exercise is also influenced by environmental temperature
and humidity. Cold, dry air inhalation maximises airway obstruction, whereas warm,
humid air minimises obstruction [2729]. Differences between airway temperature during
and after exercise also seem to play a role in the severity of obstruction. Inhaling warm
air after exercise in cold air has been shown to worsen bronchoconstriction, whereas cold
air has been shown to lessen it [30].
Most patients with EIA also have an airway hyperresponsiveness to other direct and
indirect airway challenges. Hyperventilation during exercise increases exposure of the
airways to several possible triggering substances, such as allergens, outdoor air pollutants
(e.g. particulates, tobacco smoke, sulphur dioxide, nitrogen oxide and ozone), indoor air
pollutants (e.g. carbon monoxide, nitric oxide, nitrogen dioxide and a variety of organic
volatile compounds) and these potential triggers can certainly worsen EIA.
The observation that certain activities produce greater airflow limitation (e.g. running)
than other activities (e.g. swimming) is only caused by differences in absolute ventilation
level and by differences in characteristics of the inhaled air content. The idea that there
are inherently unique aspects of specific exercise tasks is outdated [31].
What are the implications of this information for the prophylactic approach to EIA?
Recreational athletes may be able to adjust their exercise intensity level and the
ambient conditions to minimise exposure to environmental triggering factors. For elite
athletes the situation is totally different. The fact that swimming is the least asthmogenic
of all sports and that sports that are of lower intensity and shorter duration are less likely
to cause EIA will not usually convince a competitive athlete to change sports.
Apart from changing sports (environment), some other strategies have been suggested
to control the characteristics of the inhaled air. As the nose is important in humidification
and temperature adjustment of the inhaled air, nasal breathing is often recommended in
sports [32]. Some authors report a beneficial effect on EIA by covering the nose and
mouth with a (surgical) mask or scarf, especially in a dry, cold environment [3335].
Exercise is the only natural precipitant of asthma that induces tachyphylaxis [36].
Clinically, this means that a warm-up period can be effective in decreasing the airway
92
response to subsequent exercise. This phenomenon is called the refractory period. The
athlete should warm up to y80% of the maximal output before any formal exercise; the
refractory period to bronchoconstriction after exercise may last from 40 min up to 3 h
[37]. It is important to mention that during the refractory period the airways are only
refractory to exercise but are still vulnerable to other stimuli [38]. The exact mechanism
underlying the phenomenon of the refractory period is still unknown.
Cooling down or slowly lowering the intensity of exercise, instead of stopping
abruptly, also has a beneficial effect by making airway rewarming and the resulting
vascular dilatation and oedema more gradual and less intense [39].
A double-blind, cross-over study compared the response to exercise challenge after a 2week diet of high, normal or low salt intake and found that a low salt diet might improve
and a high salt diet might worsen EIA [40]. The mechanism of this potentially beneficial
effect is unclear.
The intensity of EIA also depends on the degree of underlying baseline bronchial
reactivity. In patients with persistent asthma, baseline bronchial reactivity is increased,
especially after recurrent exposure to allergens, pollutants and other airway challenges.
Appropriate treatment of underlying persistent asthma is very important in the
prevention of EIA and exercise should be avoided when chronic asthma is not well
controlled. Viral airway infections also increase the baseline bronchial reactivity and,
therefore, the severity of EIA [41].
Most authors believe that a regular regimen of moderate exercise tailored to a patients
asthma severity has physical, social and emotional benefits. Whether or not training
programmes improve EIA is more difficult to assess. Apparently, improving fitness
lowers the minute ventilation required for a given workload. Lower minute ventilation
equals a less intense EIA stimulus. However, in the case of equal minute ventilation, most
studies have shown no differences in EIA responses in fit versus unfit subjects. This
implicates that exercise conditioning is good for asthma patients as it lowers the required
minute ventilation during exercise, but it probably does not lead to a decreased
underlying airway reactivity [42].
Prophylactic pharmacological management. Environmental control measures and

practical advice are often not sufficient to control allergic and respiratory disorders. In
this case, pharmacological intervention is required. As cited before, athletes are a patient
population where environmental control is especially difficult. As a consequence,
medication will often be an important part of their treatment. In this chapter, only
prophylactic pharmacological management will be discussed.
Prophylactic medication. Several drugs have been developed to prevent symptom

aggravation in patients with asthma and allergic rhinitis/conjunctivitis. For athletes, it is
important to select the products that provide optimal symptom control, with minimal
detrimental influences on performance caused by adverse effects. Additionally,
pharmacological treatment must comply with the anti-doping rules (tables 1 and 2).
On January 1, 2004, the new World Anti-doping Agency list replaced the previous
International Olympic Committee list. This new list is an important step forward in the
harmonisation of anti-doping rules across all sports and continents.
Regular use of intranasal corticosteroids is the most effective prophylactic
pharmacological treatment for allergic rhinitis/conjunctivitis. Adequate prophylactic
use of intranasal corticosteroids is effective in reducing nasal blockage, rhinorrhoea,
sneezing and itching in children and adults. Studies have demonstrated that they are
more effective than systemic and topical antihistamines and topical disodium
cromoglycate. A meta-analysis confirmed the superiority of intranasal corticosteroids
93
Table 1. Drugs used for allergic rhinitis/conjunctivitis and whether they are legal or banned for international
competition#
Drug
Glucocorticosteroids
Antihistamines
Cromones
Decongestants
Route of administration
Legal or banned
Oral
Topical
Oral
Topical
Topical
Oral
Topical
Banned
}
Legal
Legal
Legal
z
Legal
: Based on the World Anti-Doping Agency 2004 prohibited list (came into effect on January 1, 2004);
: glucocorticosteroids are prohibited when administered orally, rectally, intravenously or intramuscularly. All
other administration routes require a medical certificate, in accordance with section 8 of the International
Standard for Therapeutic Use Exemptions; z: ephedrine and methylephedrine are prohibited when the
concentration in urine is w10 mg?mL-1. Phenylephrine, phenylpropanolamine and pseudo-ephedrine are
permitted.
}
to antihistamines in the treatment of allergic rhinitis/conjunctivitis [43]. In a controlled

clinical trial in elite athletes with allergic rhinoconjunctivitis, statistically significant
improvement in symptoms, quality of life and performance scores were found in athletes
who used intranasal budesonide [2].
Antihistamines are effective in decreasing symptoms of allergic rhinitis/conjunctivitis
(except nasal obstruction). Topical antihistamines have an even more rapid onset of
action. Due to their ability to rapidly resolve symptoms, antihistamines are particularly
useful for "treatment on demand", rather than on a regular, prophylactic basis. However,
for patients suffering from seasonal allergic rhinitis/conjunctivitis, regular and
prophylactic use of the newer nonsedating antihistamines is often recommended
during the offending period.
Cromones are prophylactic agents, acting by inhibiting mast cell degranulation. Their
inferior efficacy compared to other available medication, and the need for frequent
administration, classify them as an unhelpful option.
EIA can be prevented with the prophylactic use of medication just before exercise. If
EIA is only one manifestation of an overall asthmatic diathesis, exertional pre-treatment
should be added to the basic therapy, which is usually anti-inflammatory.
Short-acting inhaled b2-agonists are the medication of choice for prophylaxis of EIA.
Two to four puffs of a short-acting b2-agonist, 560 min before exercise, preferably as
close to exercise as possible, are recommended. The effects of this treatment last 23 h
[41, 44].
Long-acting inhaled b2-agonists also provide excellent protection against EIA. They
should be taken i30 min before exercise and their effects last 1012 h. Unfortunately, it
has been found that regular, prolonged use of long-acting inhaled b2-agonists is
associated with a reduction of its protective effect, a phenomenon known as
tachyphylaxis or tolerance [41, 44].
Inhaled cromolyn and nedocromil are the next most commonly used prophylactic
agents for EIA. Although not as effective as inhaled b2-agonists, they have been shown to
block or attenuate EIA for a duration of 12 h, when taken 1020 min before exercise
[41, 44].
Oral antileukotrienes have also been demonstrated to be effective in protecting
patients against EIA [45, 46]. Single doses of montelukast (10 mg) and zafirlukast
(20 mg) have been shown to provide protection within 1 h and for up to 12 h after
ingestion [47]. When compared to the long-acting inhaled b2-agonist salmeterol,
leukotriene receptor antagonists appear equally effective for acute prophylaxis [48]. For
94
Table 2. Drugs used for exercise-induced asthma and whether they are legal or banned for international
competition#
Drug
Cromolyn sodium
Nedocromil Sodium
Montelukast
b2-agonists
Glucocorticosteroids
Theophylline
Ipratropium bromide
Route of administration
Legal or banned
Aerosol
Aerosol
Oral
Oral
Inhaled
Oral
Aerosol
Oral
Aerosol
Legal
Legal
Legal
Banned
}
Banned
z
Legal
Legal
: Based on the World Anti-Doping Agency 2004 prohibited list (came into effect on January 1, 2004); }: all b2agonists, including their D- and L-isomers, are prohibited; however, formoterol, salbutamol, salmeterol and
terbutaline are permitted but only by inhalation to prevent and/or treat asthma and exercise-induced asthma/
bronchoconstriction. A medical certificate, in accordance with section 8 of the International Standard for
Therapeutic Use Exemptions, is required; z: glucocorticosteroids are prohibited when administered orally,
rectally, intravenously or intramuscularly. All other administration routes require a medical certificate, in
accordance with section 8 of the International Standard for Therapeutic Use Exemptions.
long-term protection over weeks and months, no tachyphylaxis [47] has been described
and montelukast may even be more effective than salmeterol [48]. However, at this time,
oral antileukotrienes do not have a Food and Drug Administration-approved specific
indication for the prevention of EIA, while long-acting inhaled b2-agonists do.
Immunotherapy. The clinical effectiveness of allergen immunotherapy in allergic rhinitis

has largely been proven in well-selected patients. A meta-analysis was performed on 16
prospective blinded, placebo-controlled studies of immunotherapy for allergic rhinitis
published between 1966 and 1996. Seven used grass extracts, six ragweed, two
Dermatophagoides pteronyssinus, two mountain cedar and one alternaria. In 15 out
of 16 studies, specific immunotherapy (SIT) was effective. Symptoms of allergic rhinitis
were more likely to improve in patients receiving SIT than in control patients; moreover,
symptom medication scores were significantly lower in SIT patients than in control
patients [49].
As the effects of immunotherapy are long lasting, immunotherapy may be a very
practical option for the allergic athlete, where avoidance of allergen is impossible and
where severity of symptoms has a negative effect on training and performance.
Immunotherapy for specific allergens should be considered, especially in athletes with
pollen, mold, mite and dander allergies, if the nasal symptoms are significant and cannot
be controlled with environmental measures or acceptable drug therapy [1, 50].
The risk-to-benefit ratio should be considered in all cases and athletes should be
warned not to train vigorously in the hours following the immunotherapy injection.
Whereas few persons will dispute the clinical effectiveness of allergen immunotherapy
in allergic rhinitis/conjunctivitis, some have reservations regarding its use in patients with
asthma [51]. However, there are a number of adequate controlled studies that have
established the effectiveness of allergen immunotherapy in carefully selected patients
with asthma caused by grass pollen, cats and HDM [5254]. A meta-analysis of 20
randomised, controlled trials, published between 1977 and 1997, concluded that the odds
ratio for symptom improvement was 3.2 with all allergens and 4.2 for reduction in
medication with HDM immunotherapy [55]. In an update of this meta-analysis, these
results were confirmed [56]. However, other carefully conducted studies of seasonal [57]
or perennial [58] asthma have only provided limited [57] or no [58] evidence for clinical
improvement of asthma.
95
Due to the disputable efficacy of immunotherapy in asthma and because of the lack of
specific studies in the athlete population, no specific recommendations for the
prophylactic use of allergen immunotherapy in athletes suffering from allergic asthma
can be made.
Early recognition of allergic and respiratory disorders in sports

Early recognition of allergic rhinitis/conjunctivitis
Athletes seem to be very bad at recognising upper respiratory symptoms as being
caused by allergic rhinitis/rhinoconjunctivitis [22]. Better education of coaches and
athletes should make them aware of symptoms of nasal congestion, rhinorrhoea,
sneezing, nasal itchiness, postnasal drip, itching of the throat and ears, and redness and
itching of the eyes.
If an athlete is suspected as having allergic rhinitis/rhinoconjunctivitis, a thorough
history and a careful clinical examination, concentrating on the nose, chest and skin,
should be performed. Allergy testing, preferentially by highly sensitive, specific skin-prick
testing, is required to have objective proof, allowing athletes to have medical
programmes tailored to meet their needs and comply with the anti-doping rules.
Objective identification of the triggering factors is also important in the assessment of an
appropriate avoidance strategy [1].
Some authors claim that all potential Olympic athletes, hoping for peak performance
at the Olympics during the pollen season, should be screened for the possibility of pollen
allergy. However, higher levels of evidence are required to make specific recommendations for allergy screening in elite athletes [22].
In patients with allergic rhinitis/rhinoconjunctivitis and, in particular, asthma, EIA is a
frequent problem, but many athletes do not recognise breathing difficulties or do not
spontaneously report them. Due to the serious implications of unrecognised (exerciseinduced) asthma, pulmonary function tests and assessment of EIA should be considered
in allergic athletes [1].
Early recognition of EIA and screening procedures

EIA is a prevalent condition in both recreational and elite athletes. The highest
incidences are found in cold weather athletes.
The usual presenting symptoms of EIA include coughing, shortness of breath, chest
pain, chest tightness, and wheezing during or after exercise. In some cases, the symptoms
can be more atypical. Patients can present with cramps, stomach pain, headache or
fatigue. Many people are unaware of these abnormal symptoms and just think they are
"out of shape".
It is very important that physicians, athletic trainers, coaches and athletes are
knowledgeable of, and alert for, these symptoms. If there is any suspicion of EIA, the
athlete must seek proper medical attention and has to be subjected to a thorough medical
evaluation [59]. Further diagnostic procedures are described in chapter 6 of this
Monograph.
Although many studies suggest that EIA is often unrecognised in athletes, screening
for EIA is not routinely part of the pre-participation physical examination of athletes.
Due to the serious health risk of unrecognised EIA (including hypoxaemia and cyanosis
during exercise) and its significant impact on quality of life and performance level, many
authors claim that pre-sports EIA screening should be performed.
96
The World Health Organization describes screening as "the presumptive identification

of an unrecognised disease or defect by the application of tests, examinations, or other
procedures that can be applied rapidly. Screening tests sort out apparently well persons
who probably do not have disease from those who do have the disease. A screening test is
not intended to be diagnostic. Persons with a positive or suspicious finding must be
referred to their physician for diagnosis and necessary treatment" [60].
Hammerman et al. [61] examined various EIA screening methods in high school
athletes and found that: 1) a questionnaire may be a good negative screening tool; 2) the
peak expiratory flow rate meter is not a good screening tool; and 3) the use of a free
running exercise challenge is a good test for identifying and assessing the athlete with
EIA. Hallstrand et al. [62] compared EIA screening by phys`cal examination and
medical history with the "gold standard" test, consisting of a 7-min challenge test
followed by serial spirometry. Screening by physical examination and medical history did
not accurately detect EIA [62]. Rundell et al. [63] compared a laboratory-based exercise
challenge (LBC) to a field-based exercise challenge (FBC) for pulmonary function test
(PFT) EIA screening in elite athletes. Before PFT, athletes completed a medical history
questionnaire for EIA. Self-reported symptoms by elite athletes were unreliable in
identifying EIA. As 78% of the FBC PFT positives were PFT normal after LBC, this
suggests that a large number of false negatives may occur in this population if EIA
screening is performed with inadequate exercise and environmental stress [63].
Randomised, controlled, large-scale studies are required to make evidence-based and
cost-effective recommendations about screening techniques for EIA in sports.
Knowledge of, and awareness for, the symptoms of allergic rhinitis/rhinoconjunctivitis
and EIA are the main elements in the early recognition of both conditions. Early
recognition is the first step towards an appropriate, preventive management and this can
allow children, adolescents and adults to fully participate in physical activities and
sports.
Conclusion
Better education of athletes, coaches, athletic trainers and physicians must make them
more aware of upper and lower respiratory symptoms. If there is any suspicion of allergic
rhinitis/rhinoconjunctivitis, asthma, EIA or other allergic respiratory disorders, the
athlete needs to be subjected to thorough diagnostic procedures. Early recognition and
correct diagnosis are the first step towards an appropriate management. This includes
education of the athlete and support team on the nature of the condition and how to
control it with or without medication.
Prophylaxis is a very important part of the therapeutic strategy. It includes individual
environmental control measures, exercise advice and, if necessary, prophylactic medical
treatment. For pharmacological treatment with drugs, complying with the anti-doping
rules and providing optimal symptom control and minimal detrimental influences on
performance must be selected.
Finally, allergic and/or asthmatic athletes should understand that they suffer from a
common disease and that appropriate management will ensure that they can safely
perform to the maximum of their ability. Allergic rhinitis, asthma and EIA do not have
to be a restricting factor in sports and does not preclude successful competition at the
highest level of sport.
97
Summary
Education of athletes, coaches, athletic trainers and physicians must make them more
aware of upper and lower respiratory symptoms. If there is any suspicion of allergic
rhinitis/conjunctivitis, asthma, exercise-induced asthma or other allergic respiratory
disorders, the athlete needs to be subjected to thorough diagnostic procedures. Early
recognition and correct diagnosis are the first step towards appropriate management.
This includes education of the athlete on the nature of the condition and how to
control it with or without medication.
Prevention is a very important part of the therapeutic strategy. Individual
environmental control measures and exercise advice have gained increasing interest,
but are often impractical or even impossible in elite athletes. Consequently,
pharmacological interventions and, in selected cases, immunotherapy have become
an essential part of the prophylactic management. This also poses specific challenges in
athletes, as only drugs complying with the anti-doping rules and providing optimal
symptom control and minimal detrimental influences on performance can be selected.
Finally, the allergic and/or asthmatic athlete should understand that they suffer from a
common disease and that appropriate management will ensure that they can safely
perform to the maximum of their ability. Allergic rhinitis, asthma and exerciseinduced asthma do not have to be a restricting factor in sports and does not preclude
successful competition at the highest level of sport.
Keywords: Allergen avoidance, early recognition, education, environment, immunotherapy, prevention.
Acknowledgements
The authors would like to thank H. Van Hoecke and L. Sys (Dept of
Otorhinolaryngology, Ghent University, Belgium) for their invaluable help in the
writing of this chapter.
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101
CHAPTER 10
Evidence-based recommendations for

the diagnosis of exercise-induced asthma
in athletes
Task Force on Recognizing and Diagnosing Exercise-Related Asthma, Respiratory and Allergic Disorders in
Sports
Correspondence: K-H. Carlsen, Voksentoppen BKL, Rikshospitalet (National Hospital) University Clinic,
University of Oslo, Ullveien 14, NO 0791 Oslo, Norway. Fax: 47 22136505; E-mail: k.h.carlsen@medisin.
uio.no
Recommendations for the diagnosis of asthma, exercise-induced

bronchoconstriction and bronchial responsiveness in athletes
1. The report of recurrent symptoms of bronchial obstruction as chest tightness,
wheeze and cough provoked by different stimuli, and in particular by exercise, is a
prerequisite for the diagnosis of asthma or exercise-induced asthma (EIA) in athletes.
Laboratory tests alone are not sufficient for the diagnosis.
2. The report of such symptoms should be verified by the demonstration of airways
reversibility, exercise-induced bronchoconstriction (EIB) or other methods of diagnosing
either indirect or direct bronchial hyperresponsiveness (BHR).
3. Possible differential diagnoses should be investigated by a combination of patient
history, clinical examination and judgement, along with adequate laboratory and field
tests and examinations.
4. When demonstrable objective symptoms and signs of bronchial obstruction occur,
either spontaneously or due to physical exercise in athletes, treatment may be necessary
or advisable even when objective measurements have not been performed. However, the
presence of such symptoms should lead to a follow-up with adequate objective measures.
5. When prescribing treatment to an athlete for asthma or symptoms suggesting
asthma, the athlete should be followed to assess the effect of treatment. With lack of
treatment effect, the treatment should be modified if it is considered inadequate, or the
diagnosis reconsidered. The athlete should always be treated at the lowest possible
medication level necessary to control the symptoms.
6. When participating in international sports, a combination of medical history and
laboratory tests should be documented, as the basis for the diagnosis of asthma and the
possibility of using asthma medication in an athlete. The laboratory test could either be
the demonstration of EIB, reversibility to inhaled b2-agonists or the demonstration of
BHR to direct or indirect stimuli.
a) EIB:
A standardised exercise test taking into consideration a high enough and standardised
exercise load, as well as stable environmental conditions regarding temperature and
humidity of inhaled air, should be employed, either in a laboratory or as a field test,
demonstrating a reduction in forced expiratory volume in one second (FEV1) of i10%
from baseline after exercise. Type of exercise may be varied in accordance with the type
of sport practised, although running is generally best suited for provoking EIB.
ISSN 1025-448x. ISBN 1-904097-22-7.
102
RECOMMENDATIONS
b) Responsiveness to inhaled bronchodilators:

This is demonstrated by an increase in FEV1 of 12% (as a percentage of baseline or a
percentage of the predicted value) after inhalation of a bronchodilator, preferably an
inhaled b2-agonist, administered by a metered dose inhaler, powder inhaler or
nebuliser.
c) Direct bronchial responsiveness:
In athletes who have received inhaled steroids for a period of i3 months, a
provocative concentration causing a 20% fall in FEV1 (PC20) to either histamine or
metacholine v16 mg?mL-1 or a PD20 v3.2 mg (16 mmol) should be documented. In
athletes who have not received such medication, the levels should be: PC20
4 mg?mL-1 or PD20 0.8 mg (4 mmol). In laboratories that have developed their
own reference values for bronchial responsiveness, these could be employed after the
references levels of the laboratory have been scientifically documented.
d) Other measures of indirect bronchial responsiveness:
A reduction in FEV1 of 10% from baseline after the provocative agent is considered as
an adequate and comparable stimulus to exercise. The test can be inhalation of cold,
dry air or dry air, as in the eucapnic hyperventilation test, or the inhalation of
hyperosmolar aerosols, such as hypertonic saline or mannitol.
Differential diagnosis of exercise-induced bronchoconstriction

There are several important differential diagnoses to EIA and EIB in an athlete.
Studies have demonstrated that most of the elite athletes referred for respiratory
problems do not suffer from asthma or EIA [1].
One frequent differential diagnosis is exercise-induced inspiratory stridor (IS) or vocal
cord dysfunction [2]. The symptoms of this are inspiratory stridor occurring during
maximum exercise and stopping when exercise is terminated, unless hyperventilation is
maintained. There are audible inspiratory sounds from the laryngeal area and there is no
help from bronchodilators or other asthma medication. The condition most often occurs
in young well-trained athletic females aged 1516 yrs. Symptoms only occur during
maximum exercise. The symptoms are thought to be due to the relatively small crosssectional area of the laryngeal orifice, which may be even further reduced through the
negative pressure created during inspiration during heavy exercise. One possible
differential diagnosis to this syndrome is paradoxical movement of the vocal cords with
adduction during inspiration. There is gradual overlap to functional disorders such as
hyperventilation. This may also occur without exercise. The diagnoses is made by direct
fibreoptic laryngoscopy during exercise.
Swimming-induced pulmonary oedema (SIPE) is another possible differential
diagnosis to EIA. SIPE occurs in well-trained swimmers after a heavy swimming
session. This condition was recently reported in 70 previously healthy swimmers who
developed typical symptoms of pulmonary oedema together with a restrictive pattern in
pulmonary function, which remained for up to 1 week after the swimming incident [3].
Other chronic disorders, including heart diseases, may have an effect upon physical
performance and thus be a possible differential diagnosis related to EIA.
Also, poor physical fitness or overtraining may represent another possible differential
diagnosis to EIA. This is especially the case when the physical fitness and exercise
performance are not up to the expectations of the athletes or possible parents or trainers.
Lack of success in sports may be explained by often minor respiratory complaints, which
may be mistaken for asthma.
Finally, reports have been made concerning exercise-induced arterial hypoxaemia [4].
103
TASK FORCE
This occurs especially in highly trained athletes and is thought to be primarily due to
diffusion limitations and ventilation-perfusion inequality. It is postulated that
incomplete diffusion in the healthy lung may be due to a rapid red blood cell transit
time through the pulmonary capillary. Physical training will improve muscle strength
and endurance, and in the cardiovascular system the ionotropic and chronotropic
capacities increase. However, in the respiratory tract no such effects of training occur.
The lungs diffusion capacity and pulmonary capillary blood volume remain unaltered in
the highly trained athlete, whereas maximum pulmonary blood flow increases with
enhanced maximum oxygen uptake. Ventilatory requirement rises with no alteration in
the capability of the airways and the lungs to produce higher flow rates or higher tidal
volumes, and little or no change in the pressure-generating capability of inspiratory
muscles [5]. The result is exercise-induced arterial hypoxaemia which may occur in up to
50% of highly trained athletes [68]. This reduction in arterial oxygen saturation may be
confused with EIA.
Thus, several different diagnoses to EIA exist. Whatever the cause for the respiratory
difficulties, it is important to make a thorough examination and rule out possible
differential diagnoses. The different diagnoses require different approaches and different
treatment.
Acknowledgements. This chapter was contributed to by all the members of the Task Force
on Recognising and Diagnosing Exercise-Related Asthma, Respiratory and Allergic Disorders
in Sports (Diagnosis, Treatment and the Relationship to Dosing). This Task Force is a joint
collaboration of the European Respiratory Society and European Academy of Allergy and
Clinical Immunology. The members are as follows: S.D. Anderson (Camperdown, Australia),
L. Bjermer (Lund, Sweden), S. Bonini (Rome, Italy), V. Brusasco (Genova, Italy), K-H.
Carlsen (Oslo, Norway), T. Haahtela (Helsinki, Finland), G.W. Canonica (Genova, Italy),
J. Cummiskey (Blackrock, Ireland), L. Delgado (Porto, Portugal), S.R. Del Giacco (Cagliari,
Italy), F. Drobnic (Barcelona, Spain), K. Larsson (Stockholm, Sweden), P. Palange (Rome,
Italy), T.A. Popov (Sofia, Bulgaria) and P. van Cauwenberge (Ghent, Belgium).
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104
APPENDIX
Members of the Task Force on Recognizing

and Diagnosing Exercise-Related Asthma,
Respiratory and Allergic Disorders in Sports
S.D. Anderson
Dept of Respiratory Medicine
11 West, Royal Prince Alfred Hospital
Missenden Road, Camperdown, NSW 2050
Australia
Tel: 02 95156120
Fax: 02 95158196
E-mail: sandya@mail.med.usyd.edu.au
L. Bjermer
Dept of Respiratory Medicine and Allergology
gon B
bld O
University Hospital
S-22185 Lund
Sweden
Tel: 46 46172325
Fax: 46 702126845
E-mail: Leif.bjermer@med.lu.se
S. Bonini
Via Ugo de Carolis 59
IT-00136 Rome
Italy
Tel: 39 0635346840
Fax: 39 0635403017
E-mail: se.bonini-cnr@flashnet.it
V. Brusasco
Dipartimento di Medicina Interna
Faculta di Medicina e Chirurgia
Universita di Genova
viale Benedetto xv, 6
16132 Genova
Italy
Tel: 39 0103537690
Fax: 39 0103537690
E-mail: vito.brusasco@unige.it
K-H. Carlsen
Voksentoppen BKL
Rikshospitalet (National Hospital)
University Clinic, University of Oslo
ISSN 1025-448x. ISBN 1-904097-22-7.
105
Ullveien 14
NO 0791 Oslo
Norway
Tel: 47 22136500 (16, direct)
Fax: 47 22136505
E-mail: k.h.carlsen@medisin.uio.no
G.W. Canonica
Allergy and Respiratory Diseases
Dept of Internal Medicine
University of Genova
Pad. Maragliano, Largo Rosanna Benzi 10
16132 Genova
Italy
Tel: 39 0103538931
Fax: 39 0103538904
E-mail: canonica@unige.it
J. Cummiskey
Suite 35 Blackrock Clinic
Rock Road
Blackrock
County Dublin
Ireland
Tel: 353 12064256
Fax: 353 12783018
E-mail: joecummiskey@eircom.net
L. Delgado
Servico de Imunologia
Faculdade de Medicina
da Universidade do Porto
Hospital S. Joao
PT-4200-319 Porto
Portugal
Tel: 351 225020674
Fax: 351 225510119
E-mail: ldelgado@med.up.it
S.R. Del Giacco
Medicina 2
Policlinico Univer. di Cagliari
presidio di Monserrato
Monserrato
Cagliari, IT-09042
Italy. Tel: 39 070510289
Fax: 39 07060286227
E-mail: delgiac@tiscali.it
F. Drobnic
Head Sports Physiology Dept
Olympic Training Center CAR
Alcalde Barnils 3-5
08173 Sant Cugat del Valles
106
Barcelona
Spain
Tel: 34 935891572
Fax: 34 936754106
E-mail: drobnic@car.edu
T. Haahtela
Dept of Allergy
Skin and Allergy Hospital
Helsinki University Central Hospital
FIN-00250
Helsinki
Finland
Fax: 385 947186500
E-mail: tari.haahtela@hus.fi
K. Larsson
Unit of Lung and Allergy Research
Division of Physiology
IMM Karolinska Institutet
171 77 Stockholm
Sweden
Tel: 46 87287433
Fax: 46 8300619
E-mail: kjell.larsson@imm.ki.se
P. Palange
Dipartimento di Medicina Clinica
v.le Universita` 37
00185 Rome
Italy
Tel: 39 0649972082
Fax: 39 064940421
E-mail: paolo.palange@uniroma1.it
T.A. Popov
Clinical Centre of Allergology
Medical University
1, Sv. Georgi Sofiyski St.
BG-1431 Sofia
Bulgaria
Tel: 359 29230397
Fax: 359 29230715
E-mail: tedpop@rtb-mu.com
P. van Cauwenberge
Dept of Otorhinolaryngology
Ghent University
De Pintelaan, 185
B-9000 Ghent
Belgium
Tel: 32 92402328
Fax: 32 92404993
E-mail: paul.vancauwenberge@Ugent.be
107

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Diagnosis, Prevention and Treatment of

Exercise-Related Asthma, Respiratory

K-H. Carlsen*, J. Cummiskey#, L. Delgado}, S. Del Giaccoz

K-H. CARLSEN ET AL.

particularly as no improvement in performance has been demonstrated when using

Larsson K, Ohlsen P, Larsson L, Malmberg P, Rydstrom PO, Ulriksen H. High prevalence of

Suzuki J, Gao M, Xie Z, Koyama T. Effects of the beta(2)-adrenergic agonist clenbuterol on

Epidemiology of asthma, allergy and

Occurrence of bronchial hyperresponsiveness

Table 1. Prevalence of asthma amongst highly trained winter sports athletes

First author [Ref.]

Ice hockey players

Ice hockey players

1998 USA Winter

1998 USA Winter

: Source population n=196.

Occurrence of eosinophilic airway inflammation

Type of training as a risk factor

ASTHMA, ALLERGY AND BHR IN SPORTS

Asthma is most commonly found in athletes performing endurance events, such as

Atopy as a risk factor

Outcome of asthma and asthma-like symptoms

Epidemiology of rhinitis and conjunctivitis

RHINITIS AND CONJUNCTIVITIS IN ATHLETES

was found in 18.8% of athletes. Certainly, data from epidemiological studies of

Helbling A, Muller U. [Bronchial asthma in high-performance athletes]. Schweiz Z Sportmed 1991;

RHINITIS AND CONJUNCTIVITIS IN ATHLETES

Exercise and airway physiology:

Airway physiology and exercise

EXERCISE AND AIRWAY PHYSIOLOGY

Water loss and cellular shrinkage

Cooling and rewarming

EXERCISE AND AIRWAY PHYSIOLOGY

Exercise and airway inflammation

EXERCISE AND AIRWAY PHYSIOLOGY

activation by endotoxin, with adhesion-independent shedding of L-selectin and

EXERCISE AND AIRWAY PHYSIOLOGY

Bronchial hyperresponsiveness in athletes:

Bronchial hyperresponsiveness (BHR) is an abnormal increase in airflow limitation

L. BJERMER, S.D. ANDERSON

MCh provocation test

DEVELOPMENT OF BHR IN ATHLETES

Table 1. Direct and

Methacholine, histamine, propanolol

Bronchial hyperresponsiveness in athletes

Risk factors for development of BHR in athletes: possible

L. BJERMER, S.D. ANDERSON

Table 2. Risk factors for development of

DEVELOPMENT OF BHR IN ATHLETES

NK cell activity, total lytic units

1.5 h post-run 3 h post-run 6 h post-run

Influence by (cold) dry air hyperventilation

L. BJERMER, S.D. ANDERSON

DEVELOPMENT OF BHR IN ATHLETES

L. BJERMER, S.D. ANDERSON

Water loss from humidifying inspired air

Dehydration of the ASL

Increase in [Na+], [Cl-], [Ca2+], [K+]

Increase in osmolarity of ASL

Airway smooth muscle contractionoedema

Repeated exposure to plasma

e.g. Histamine, prostaglandins,

DEVELOPMENT OF BHR IN ATHLETES