All screening programs do harm; some do good as well.-
Gray, J. A., and J. Austoker. Quality assurance in screening programmes. Br. Med. Bull. 54:983-992, 1998 (23).
Exercise-induced bronchoconstriction (EIB) describes the phenomenon of transient airway narrowing that occurs during or after physical exertion in susceptible individuals (7,52). It has been found to be present in nearly all asthmatics and in a significant proportion of otherwise healthy individuals (19,21). In athletes, the diagnosis is particularly important because of potential implications on performance and strict regulations concerning the use of medications (8).
Investigation during the past 20 yr has revealed two intriguing facts concerning the diagnosis of EIB in athletes. First, exercise symptoms correlate poorly with objective evidence of airway narrowing, and, as such, they limit the accuracy of a symptom-based method for diagnosis (31,51). Second, there exists a population of asymptomatic athletes who have objective evidence of EIB (19). In other words there exists a potential for both overdiagnosis and, perhaps of more concern, a real risk of underdiagnosis. Studies in elite performance teams support this suggestion and have led some authors to call for widespread screening of athletes for EIB (11,19,32,62). In the United Kingdom, those athletes who compete at the Olympic level are screened for EIB; however, there currently is no guidance for non-Olympic athletes.
The aim of this article is to examine the policy of EIB screening in athletes and to determine how practical it might be to implement a widespread screening policy for athletes. The article does not endeavor to provide a comprehensive review of EIB in athletes (for reviews, see Parsons and Mastronarde (46) and the European Task Force Document (13)) but, instead, to simply highlight issues that are pertinent to answering the question: should we screen athletes for EIB?
WHY SCREEN ATHLETES FOR EIB?
From the point of view of the elite athlete, the main reason to screen for EIB is that the condition may have detrimental effects on athletic performance. Although definitive evidence of a direct effect on performance is still lacking, it has been postulated that airway narrowing during exercise compromises ventilatory capacity and efficiency (9,26). In subjects with EIB, exercise in a cold environment was found to reduce exercise capacity, particularly peak V˙O2 and running speed (57). Furthermore, EIB may compromise not only performance during competition but capacity to train effectively (12,43).
Protagonists of screening also argue that detection of EIB has important implications for the health of athletes. A key mandate of the International Olympic Committee-Medical Commission (IOC-MC) is that all care should be taken to ensure that sports do not affect the health or welfare of the participants (56). The health implications of asthma in exercise are well described, with one study in young fit adults revealing asthma as a significant risk for unexplained death (2). In addition, a high proportion of asthma-related deaths occur in elite or competitive athletes (57%) in close association with a sporting event (10). It is possible that EIB may impart similar risks, although the health implications of EIB in otherwise asymptomatic athletes or, indeed, the natural course of this condition if untreated, are currently unknown.
EVALUATING A POLICY OF SCREENING FOR EIB
For a screening program to be effective, it has to be scientifically robust and precise in detecting the condition of interest. An ineffective program runs the potential risk of causing more harm than good by misclassifying individuals, both in terms of falsely ruling out the condition (false-negative) but also by erroneously suggesting the diagnosis (false-positive).
To this end, epidemiologists commonly employ a standardized approach when evaluating screening programs; available evidence is evaluated against a number of stringent criteria (68) (Table 1), and a decision to proceed with a program is then taken after a balanced assessment of the benefits and drawbacks (23).
The process usually begins with an evaluation of the definition of the condition, herein highlighting an immediate problem with EIB screening. The definition of EIB and its distinction from asthma, exercise-induced asthma, and bronchial hyperreactivity (BHR) remains contentious (63). Is wheeze in exercising asthmatics the same condition as EIB in nonasthmatics? How does bronchospasm in exercising asthmatics relate to EIB "diagnosed" in the asymptomatic athlete through laboratory methods? Furthermore, what degree of BHR constitutes an abnormal response in the athletic population, especially in those exposed regularly to environmental triggers (e.g., winter sports participants)?
Some have argued that distinguishing these conditions is purely a matter of semantics, given that the physiological consequences are the same (34). However, there also may be fundamental differences that could confound successful evaluation of a screening program. Indeed, there may even be two separate components to EIB: one relating to the effect of mediator release on airway smooth-muscle contraction, and the other arising as an amplification of airway edema (4). Pathological studies have already suggested that there are real differences between "classical asthma" and BHR in athletes (59), and these observations highlight the need for caution when interpreting and applying evidence for a screening policy in this population. Nevertheless, we have used the criteria in Table 1 as a framework to assess the available literature, and we acknowledge in advance that this approach may be contentious and raise more questions than provide answers.
Subsequent sections are divided according to this framework, with the aim of highlighting some of the issues central to the evaluation of a screening policy. Each section begins with a descriptor (italics) of the ideal characteristics needed for a screening policy (24).
PREVALENCE OF THE CONDITION
An accurate estimate of prevalence is needed to ensure that test results are correctly interpreted and applied.
In the evaluation of a screening program, the influence of prevalence on the efficacy of the screening test is sometimes overlooked (24). Table 2 illustrates the effect of prevalence on the interpretation of values in a hypothetical test. In the example, the hypothetical test has both a high sensitivity (98%) and specificity (97%) for detecting the condition. When the test is applied to a population with a high prevalence of the condition (30%), the positive predictive value (PPV)-that is, the percentage of positive tests that were, in fact, positive-is extremely high (93%). However, when the same test is applied to a population in which the prevalence of the condition is only 3%, the PPV plummets to 50%-essentially, tossing a coin would be as effective in predicting the condition in those who had positive tests.
This effect has important implications for EIB screening because, despite extensive investigation, the prevalence of EIB in athletes remains unclear (8). Indeed, it is not uncommon for review documents to quote prevalence values as lying within a wide range (e.g., 11-50% (46)). Differences between studies in definition, diagnostic methods (33) and techniques (32), population (54), gender and age (49), country (19,65), season (36), environment (28), and sporting discipline (19) may account for some of the discrepancies in the literature. However, it is apparent that even when strict criteria are applied, an accurate estimate of prevalence may be difficult to determine when comparing different studies and test techniques (e.g., BHR testing vs exercise testing) (Table 3). It should be acknowledged, however, that after the introduction of the IOC-MC guidelines requiring objective evidence of EIB (see later), future estimates of the prevalence of EIB may be more informed (18).
An additional factor leading to difficulties of ascertaining prevalence from previous literature may be the inclusion of studies that use symptoms for diagnosis or a combination of symptom questionnaire and provocation testing. Langdeau and Boulet (37,38) found that in studies using symptom-based criteria, the prevalence tended to be below 20%, whereas in those employing objective tests, the prevalence tended to be greater than 20%. Results from questionnaire-based studies may not be applicable in the context of screening considerations (i.e., asymptomatic athletes), although Rundell et al. do argue that estimates obtained by these methods result in prevalence estimates similar to those obtained by provocation methods (51). However, although different methodologies result in a similar prevalence, the actual composition of the populations that contribute to the prevalence is not the same between methodologies.
Regardless of the methods employed, it is apparent that for a screening program to be effective, an accurate estimate of prevalence is required, and, in the context of a widespread population of athletes, the prevalence of EIB remains unclear. Furthermore, there is also a risk of misclassification if provocation tests are validated in groups of athletes with high background prevalence and then applied to groups with lower prevalence.
A screening test should discriminate absolutely between those with and without the condition.
Unfortunately, as with other measurements of continuous variables (e.g., blood pressure), determining an appropriate screening test cutoff value is particularly difficult. The level at which the cutoff value is set influences the test sensitivity and specificity and impacts the potential for misclassification. For example, screening for the serious childhood condition phenylketonuria in newborns places a premium on the cutoff allowing high sensitivity, rather than specificity, because the "cost" of missing a case is high (24).
In EIB testing, the appropriate level for a cutoff value remains debated. Commonly, a posttesting 10% drop in forced expiratory volume in 1 s (FEV1) is employed (16). The use of this value likely arose as a compromise from findings in pediatric, military, and athletic populations. However, some authors have proposed that to increase diagnostic accuracy in athletes, the criteria should incorporate a "nonasthmatic" control group of healthy individuals of similar athletic ability (53). Employing the latter method, Helenius et al. (27,28) report a 6.5% fall in FEV1 as a more relevant cutoff value in elite runners. Similarly, Rundell et al. (53) report cutoff levels of 7% in elite winter sports athletes. Equally, others have highlighted that a cutoff point of ≥ 10% is needed, given the 6% coefficient of variation for repeated FEV1 measurements, and also considering that a fall of this magnitude (i.e., ≥ 10%) is likely to be of physiological relevance to exercise performance (3).
Despite debate over the value for the cutoff value, in sporting competition there is a consensus based on the cutoff values stipulated by the IOC-MC for therapeutic exemption (see http://www.olympic.org). The current guidelines state that the diagnostic criteria should be fulfilled at two time points after the challenge test. Table 4 shows the requirements for the 2006 Winter Games in Turin.
Diagnostic methods employed should, ideally, be validated, safe, precise, and reliable, and consensus should exist regarding the optimum approach.
There currently exists a wide variety of screening methods employed for the diagnosis of EIB. These include eucapnic voluntary hyperpnoea (EVH), pharmaceutical challenge tests (metacholine or histamine), osmotic challenge tests (hypertonic saline or mannitol), and exercise challenge tests (laboratory and field) (for a detailed review, see Holzer and Brukner (32)). Data describing the validity of each of these methods are presented in Table 5.
Currently, EVH is the provocation method favored by the IOC-MC. EVH is a potent stimulus in clinically recognized asthmatics who are responsive to exercise, has a very high specificity for identifying individuals with clinically recognized asthma, and has been safely used in many thousands of adults and children (5). EVH also offers the advantage of a measure of severity of bronchoconstriction and, hence, may be used to establish treatment response. Furthermore, it addresses the difficulties of establishing a laboratory-based protocol that appropriately "challenges" elite-level athletes.
Although most pharmacological challenge tests have been shown to have a low sensitivity and specificity for diagnosis of EIB in athletes, some osmotic challenge tests, most notably mannitol provocation, compare well with EVH and may become more widely used in the future (30).
It has been argued that a sports-specific exercise field test, simulating the training and competition environment, represents the true "gold standard" method (51). However, environmental and seasonal variations and resources and equipment requirements limit the successful application of this method of testing. Furthermore, there is evidence to suggest that exercise tests might be a poor method for detecting EIB (20,22,50). Other issues concerning diagnostic methods were recently highlighted in a working group report for the American Academy of Allergy, Asthma and Immunology (63) and include the intensity required during the exercise bout, the environmental conditions during testing, and the incidence of a false-positives.
A further issue to consider is the most appropriate screening methodology with which to detect EIB in athletes with asthma. Although not within the precise remit of this article, it is interesting to note that a recent survey suggests that physicians employ different diagnostic strategies in those presenting with exercise-related respiratory complaints depending on a history of "asthma" (47). In particular, that objective testing was far less commonly employed in those with a history of asthma. A significant proportion of these individuals will have EIB (44), and, hence, an alternative methodological approach to screening may be appropriate (25).
The ultimate aim of medical screening is to allow timely initiation of treatment that will favorably affect the condition of interest.
Pharmacological and nonpharmacological therapies have been used successfully in the treatment of EIB. Medications evaluated and shown to improve FEV1 response include inhaled β-agonists, inhaled corticosteroids, cromolyn compounds, and leukotriene modifiers (for a review, refer to Parsons and Mastronarde (46) and Larsson et al. (40)). Other studies have also highlighted the importance of dietary manipulation as an adjunctive intervention (45,60). Despite these studies, there seems to be no clear consensus as to the optimum treatment (47). Nevertheless, it is now generally acknowledged that β2-agonist medication should be accompanied by an inhaled corticosteroid (6), because this helps to prevent persistent use of β2-agonist therapy and also work against potential airway remodeling that may occur.
However, studies consistently report that the most commonly prescribed treatment for EIB is a short-acting β2-agonist alone (26,47). Anderson et al. (6) recently have highlighted several problems with use of β2-agonists in this setting. These include the potential for inadequate treatment, development of tachyphylaxis, and a potential for desensitization to repeated dosing. In elite athletes, short-acting β2-agonists were found to be ineffective in controlling EIB after a 2-yr treatment period (66). Furthermore, some studies suggest that β2-agonists may be actually impair endurance performance (14). In addition, side effects (e.g., tremor and tachycardia) and ongoing controversy concerning the apparent association with increased morbidity and mortality in asthmatics suggest a real possibility of harm (1,55).
Before the initiation of any screening program, key factors relating to the socioeconomic implications of the policy should be considered.
Measures of cost-effectiveness are not easily applied to screening programs in elite athletes (15). In the United Kingdom, it has been estimated that the cost (including equipment and staffing) for EVH testing in 100 athletes would be $10,000-20,000. Set against this financial cost is the potential benefit of improved sporting achievement, which is the ultimate objective of sporting institutes/academies. Cost implications should include consideration for establishing personnel and equipment and the ongoing costs of training/maintaining equipment. Accurate testing for EIB depends on a high level of specialized technical expertise; a number of conditions can mimic EIB and could lead to misclassification and, hence, inappropriate treatment (for review, see Delgado et al. (17)). In most developed nations, financial resources are readily available for this type of testing; however, one concern is that the adoption of screening programs may disadvantage competitors from poorly resourced countries. It should be noted that other provocation methods, such as mannitol provocation, may present a more cost-favorable method of EIB screening.
Screening for EIB-potential for more harm than good?
The aim of this review has been to examine the policy of widespread screening of athletes for EIB. For this purpose, we have used an approach commonly employed to evaluate other medical screening policies. This process has revealed that in some areas of EIB research, the conflicting evidence raises concerns over the successful implementation of a widespread EIB screening policy. These have been highlighted according to the screening policy framework and are presented in Table 6.
Despite these concerns, it could be argued that a screening program for EIB still has the potential to improve the performance and health of a number of athletes without causing any "real" harm to those who may be misclassified (i.e., it does more good than harm). A key mandate of the IOC-MC is that all care should be taken to ensure that sports do not cause any long-lasting harm to the participants, and it might, therefore, be argued that this places the onus heavily on detection of EIB (i.e., a high-sensitivity approach). However, the negative effects of misclassification need to be considered in any appraisal of a screening policy. They include
- Impairing performance, both physically and psychologically.
- Exposing an athlete to the side effects and risks of medications (including possible effects on mortality).
- Incurring costs and inconvenience, both in terms of treatment and ongoing monitoring.
It could be argued that it is inappropriate to use the term and concept of medical screening in this setting at all. Screening policy is usually concerned with the detection of progressive medical conditions and particularly those with a well-described natural history (68). This differs from EIB screening in athletes, where the principle aim of screening is to ensure optimum performance. Indeed, there is currently insufficient evidence to justify screening on the grounds of health implications-that is, there is a lack of detail on the natural course of the condition in athletes.
Furthermore, there is evidence that airway responsiveness in athletes may be influenced by infection, allergen exposure, and other environmental factors, and it may periodically fluctuate (28,36). Therefore, it could be argued that diagnosis based on a single screening evaluation may be inaccurate and, indeed, inadequate. This is highlighted by a recent longitudinal study in elite triathletes, suggesting that EIB may develop over time (35). Consequently, in the evaluation of a screening program for EIB, it is important to consider the implications of multiple screening assessments-for instance, in terms of financial cost and misclassification.
In summary, our appraisal suggests that before any widespread screening program could be introduced, there are a number of issues that would need to be addressed:
- The viability of using control group reference values.
- Interpretation of results of a provocation test based on predictive values and with due consideration for the population characteristics of the athletes in which the diagnostic test was originally validated.
- Adoption of a standardized testing procedure with the greatest efficacy. The current literature suggests EVH, but cost and staffing conditions are factors. Other techniques may become increasingly important-for instance, pharmacological challenge tests such as mannitol provocation.
- Employment of widely accepted physiological measures-currently FEV1.
- Consideration of the cost-effectiveness of policy at the local/national levels and the potential effects of misclassification. In some settings, further work would be needed to establish cost-effectiveness before initiation of a screening program. This should include consideration for the repeated screening of individuals.
- Consideration of focused screening in high-risk groups. Atopic disposition and the type of training environment are known to be important risk factors. When sporting event and atopy were applied in a regression model, the relative risk of EIB was 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 (29).
In addition, further work is needed to evaluate the natural course of the condition and to establish the degree and nature of performance limitation caused by the condition in asymptomatic athletes. We hope that the approach adopted in this paper provides for a balanced evaluation of the widespread implementation of a screening policy in athletes for EIB, highlighting the potential benefits as well as the potential harm of such a policy.
The authors thank Professor R. Anderson, professor of epidemiology and public health, and Dr P. J. Hull, primary care physician, for advice.
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