Exercise and other indirect challenges to demonstrate asthma or exercise-induced bronchoconstriction in athletes

Article Outline

• Abstract
• Self-reported symptoms
• Indirect versus direct challenges
• Exercise challenge
  • Field-based challenges
  • Laboratory challenges
  • Recommended exercise protocol
• Eucapnic voluntary hyperpnea
• Hypertonic saline challenge
• Inhaled powder mannitol challenge
• AMP challenge
• Conclusion
• References
• Copyright

The prevalence of exercise-induced bronchoconstriction is reported to be high among recreational and elite athletes, yet diagnosis is often symptom-based. Indirect challenges such as the laboratory exercise challenge provide objective criteria for proper diagnosis and treatment. However, a standardized protocol using appropriate exercise intensity, duration, and dry air inhalation is often not implemented, and thus a false-negative test may result. This article reviews and describes the symptom-based diagnosis, the exercise challenge, and other indirect challenges such as eucapnic voluntary hyperpnea, hypertonic saline inhalation, and inhaled powdered mannitol as methods to diagnose and evaluate exercise-induced bronchoconstriction. Advantages and disadvantages of each diagnostic procedure are presented.

Key words: Athlete, bronchoconstriction, diagnosis, EVH, exercise-induced asthma, hypertonic saline, mannitol

Abbreviations used: ATS, American Thoracic Society, EIB, Exercise-induced bronchoconstriction, EVH, Eucapnic voluntary hyperpnea, FVC, Forced vital capacity, HR_peak, Peak heart rate, ICS, Inhaled corticosteroid, IOC, International Olympic Committee, MVV, Maximal voluntary ventilation, RH, Relative humidity, V_E, Minute ventilation

Exercise-induced bronchoconstriction (EIB) is the transient airway narrowing after¹, ² or during³, ⁴, ⁵ exercise. An estimated 90% of individuals with asthma⁶, ⁷ and 10% to 50% of a given elite athlete population experience EIB.⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹², ¹³ In this review, EIB is considered synonymous to exercise-induced asthma, although some reserve the term exercise-induced asthma for individuals with known asthma who bronchoconstrict from exercise. The wide range in reported prevalence in the athlete population is in part a result of the variability of specific environmental demands.¹³ This high prevalence of EIB reported in specific elite sports brings into question whether all individuals with EIB have asthma to some degree, or whether EIB is an entity exclusive from asthma and a natural occurrence related to lung injury. The 20% to 35% prevalence of EIB in the ice rink athlete has been attributed to the inhalation of cold dry air and high-emission pollutants from fossil-fueled ice resurfacing machines.¹⁴, ¹⁵, ¹⁶ The 30% to 50% prevalence among Nordic skiers is attributed to chronic inhalation of cold, dry air during training and competition,⁵, ¹⁷, ¹⁸ and the approximate 15% prevalence among distance runners is strongly associated with atopy, allergy, and asthma.¹⁹, ²⁰ Likewise, the high prevalence of asthma and EIB reported in competitive swimmers (11% to 29%)²⁰ has been related to inhalation of chloramines in the air immediately above the water in indoor pools. Current literature suggests that the prevalence of EIB is higher in the elite athlete population than in the nonathlete population. Because of high β₂-agonist use among elite athletes, the International Olympic Committee (IOC) requires objective evidence to demonstrate asthma or EIB as an indication for therapeutic use of β₂-agonists during competition²¹; documented falls in FEV₁ from a specified indirect or direct challenge have been used since the 2002 Salt Lake City Olympic Games. This article reviews indirect challenges used to obtain an objective diagnosis of EIB.

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Self-reported symptoms 

Physician diagnosis of EIB is often based on self-reported symptoms without lung function tests.¹², ²², ²³, ²⁴ EIB in the athlete is most often accompanied by symptoms of cough, wheeze, chest tightness, dyspnea, or excess mucus production.¹² Although a clinical diagnosis of EIB based on self-reported symptoms may be marginally useful,¹², ²⁵ recent studies have shown a lack of sensitivity and specificity of a symptom-based diagnosis in athletes.¹² Rundell et al¹² found that approximately half of elite athletes reporting EIB symptoms demonstrate normal airway function, whereas half of the athletes who reported having no symptoms tested positive for EIB. This study established the necessity of objective spirometry using a standardized challenge for appropriate diagnosis of EIB. Most recently, Parsons et al²⁴ confirmed that symptoms were not predictive of EIB in a study of 107 college athletes in whom eucapnic voluntary hyperpnea (EVH) challenge was performed. They defined a fall in FEV₁ of 10% or greater as consistent with EIB and found the prevalence of EIB was 36% in athletes with no symptoms and 35% for those with symptoms of EIB. Moreover, the athletes in high-ventilation sports were significantly more symptomatic (48%) than athletes in low-ventilation sports (25%; P = .02), with no difference in EIB prevalence between the groups. It is therefore necessary to confirm a diagnosis of EIB through objective measures of lung function by using standardized testing procedures.

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Indirect versus direct challenges 

The methods used to test for EIB are critical in making the correct diagnosis and developing a treatment strategy Indirect challenges such as exercise, EVH, inhaled powdered mannitol, nebulized hypertonic saline, or AMP appear to be more effective in identifying EIB in the elite athlete population than direct challenges such as methacholine or histamine.²⁶, ²⁷ Indirect challenges may be the preferred strategy for monitoring the effectiveness of asthma therapy, because airway hyperresponsiveness is associated with inflammation,²⁸ and inflammation is reduced by inhaled corticosteroid (ICS) treatment.²⁹, ³⁰, ³¹ The indirect challenge is thought to cause inflammatory cells to release mediators such as leukotrienes, prostaglandins, and histamine that provoke airway smooth muscle constriction.¹ Thus, the indirect challenge reflects the level of inflammation in the airways,²⁸ whereas a direct challenge acts directly with airway smooth muscle receptors to cause constriction independent of airway inflammation.

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Exercise challenge 

The lack of using a standardized exercise challenge for EIB may explain the wide range in reported prevalence within specific sports, whereas the variety of exercise challenges at different intensities with no control over challenge minute ventilation (V_E) or water content of inhaled air may result in poor test-retest reliability. Therefore, diagnosis should be based on objective measurement of variable or partially reversible airflow obstruction using a standardized test with prespirometry and postspirometry.³², ³³, ³⁴

The use of spirometry to identify EIB includes baseline lung function measures followed by an EIB-provoking challenge and a series of lung function measurements after the provocation. Typical postprovocation spirometry times are at 5, 10, 15, and 30 minutes after the completion of the challenge with 2 reproducible maneuvers within 3% of each other performed at each time point, although variations with maneuvers at 1-minute, 3-minute, or 20-minute time points have been performed (Fig 1). However, IOC-Medical Commission recommendations dictate that FEV₁ should first be recorded at least 3 minutes after the challenge and should be sustained over the period of the next 5 minutes to be consistent with EIB. Postprovocation spirometry values are compared with preprovocation spirometry values to calculate a percent change from baseline. If there is a 10% or greater decrease in the FEV₁ of a FEV₁ or a forced vital capacity (FVC) maneuver at any time point, then the patient is diagnosed as being positive for EIB. If vocal cord dysfunction is suspected, a FVC maneuver should be performed immediately after completion of the challenge and may reveal a flattened inspiratory loop and a decreased FEV₁ with no change in the FEV₁/FVC ratio.³⁵, ³⁶

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• Fig 1. 

  Typical change in FEV₁ in response to an 8-minute exercise challenge in EIB-positive individuals. Note the small improvement in FEV₁ immediately after exercise followed by significant falls in FEV₁ at 5 minutes after the cessation of exercise. Spontaneous recovery is most often nearly complete by 30 minutes postchallenge. Recovery can be accelerated by administration of an inhaled β₂-agonist.

Guidelines that permit the diagnosis of EIB on the basis of pulmonary function change after an exercise challenge have been clearly defined³³ and statistically justified. However, postexercise declines in FEV₁ greater than 10% to 25% have been used.⁷, ¹² A 15% fall in FEV₁ for field exercise challenges and a 10% fall in FEV₁ for laboratory challenges have been suggested.⁶ The American Thoracic Society (ATS)³³ and the European Respiratory Society³⁴ recommend a 10% decrease in FEV₁, based on 2 SDs from the mean baseline FEV₁ in healthy people, as a criterion for EIB.

It is necessary to confirm a diagnosis of EIB through quantitative objective measures of lung function by using standardized procedures because of the lack of sensitivity and specificity of self-reported symptoms and history questionnaire. The use of an exercise test for identifying EIB can be quite sensitive and specific if the V_E and water content of the inhaled air are standardized.³⁷, ³⁸, ³⁹ Some⁴⁰, ⁴¹, ⁴², ⁴³, ⁴⁴ have performed laboratory-based EIB testing by using an exercise challenge of 6 to 8 minutes in ambient conditions (20-25°C; relative humidity [RH] <50%) at 80% to 90% of peak heart rate (HR_peak). Others⁴⁵ suggested that the exercise intensity be less than 85% of predicted HR_peak. This recommendation is based on the assumption that catecholamine release at high exercise intensity levels may cause bronchodilation, and thus affect test results, although evidence suggests that vagal tone withdrawal and not circulating catecholamines is responsible for bronchodilation during exercise. In addition, this exercise intensity may not be sufficient to trigger a response in all subjects. Although ATS guidelines³³ and studies by others⁴⁰, ⁴¹, ⁴², ⁴³, ⁴⁴ recommend that laboratory-based EIB testing include an exercise challenge of 6 to 8 minutes in ambient conditions (20-25°C; RH <50%) at 80% to 90% of predicted HR_peak with prespirometry and postspirometry, the elite athlete population may require a greater exercise intensity under dry air conditions. Carlsen et al⁴⁶ examined the role of exercise load in relationship to EIB by comparing 20 children with asthma (9-17 years old) with EIB with 2 treadmill tests at 85% and 95% of calculated maximal heart rate. The peak fall in FEV₁ was significantly greater at 95% than at 85% peak heart rate (25.11% vs 8.84% fall); only 9 of 20 subjects had falls >10% at the 85% load, whereas all 20 subjects had falls >10% at the 95% work load. This study supports the necessity to standardize the exercise protocol by using high exercise intensity; the differences in peak fall in FEV₁ were most likely related to differences in V_E during the challenge.

Field-based challenges 

Free running¹⁰, ⁴⁷ and sport-specific exercise challenges⁵, ⁸, ⁹, ¹¹, ⁴⁸ have been proven to be valid for the assessment of EIB and have been shown to be more sensitive than ambient temperature and RH laboratory challenges in elite winter athletes.¹⁰ Rundell et al¹⁰ examined sport/environment-specific field-based exercise challenges of varied duration to a standardized 8-minute-duration laboratory exercise challenge; laboratory conditions were 21°C, 60% RH, and exercise intensity for the last 6 minutes was ∼95% HR_peak. Five athletes tested positive by both challenges, whereas 18 of the 23 athletes who tested positive for EIB by field-based challenge tested normal by laboratory challenge at 21°C, 60% RH (Fig 2). The remarkable differences in postexercise lung function between the field-based and ambient condition laboratory-based challenges provided strong evidence that water content of inhaled air is the primary stimulus of EIB. For some sports, sports-specific tests have been used with success; Wilber et al¹¹ used sports-specific tests (Nordic skiing, speed skating, ice hockey, ice skating) to identify EIB in Winter Olympic athletes, and Ogston and Butcher⁴⁸ used a 15-minute ski exercise to identify EIB in Nordic skiers. Free running or a 6-minute run has often been used in screening large groups for EIB because of the ease in performing such challenges. However, because of a general lack of control in terms of stimulus and the varied environmental conditions, this type of testing may not be reliable and is not appropriate to use as a means of monitoring treatment. To monitor the efficacy of EIB treatment effectively, it is imperative to use a challenge that can reproduce the stimulus and physiologic response (eg, exercise or EVH V_E).

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• Fig 2. 

  Eighteen of 23 elite winter athletes who tested positive by a field-based sport-specific exercise challenge but tested negative by laboratory treadmill run in ambient conditions of 21°C, 60% RH. Redrawn from Rundell KW, Wilber RL, Szmedra L, Jenkinson DM, Mayers LB, Im J. Exercise-induced asthma screening of elite athletes: field versus laboratory exercise challenge. Med Sci Sports Exerc 2000;32:309-16.¹⁰ FEF_25-75, Forced expiratory flow at 25% to 75% of FVC.

Laboratory challenges 

The laboratory exercise challenge for EIB may have high specificities,⁴⁹ but the sensitivity can be low because of high water content of inspired ambient air and the level of minute ventilation achieved and maintained.¹⁰ Anderson and Schoeffel⁵⁰ proposed that the increase in osmolarity of the periciliary fluid from water loss caused by conditioning of the inspired air during exercise or hyperventilation is the primary trigger of EIB. Mathematical modeling by Daviskas et al⁵¹, ⁵² suggested that the loss of water during exercise was sufficient to increase osmolarity in the periciliary fluid to greater than 900 mOsm, a value that can cause airway narrowing. Airway water loss because of low RH inhaled air is the critical trigger that initiates the release of mediators leading to airway narrowing in susceptible individuals, and is thus a key component to the EIB challenge. The model developed calculated cumulative water loss of periciliary fluid to the 12th generation after 4 minutes of exercise or hyperventilation to be >2 mL, which exceeds the ∼1.4 mL of airway surface liquid available.

Stensrud et al⁵³ demonstrated a 50% reduction in severity of EIB when comparing exercise challenge conditions of 40% to 95% RH at ambient temperature (24% and 12% falls in FEV₁, respectively). Further studies by Evans et al³⁷, ³⁸, ³⁹ examined inhaled air temperature and the EIB response and noted that the severity of EIB was related to water content and not the coldness of inhaled air during the exercise challenge. In those studies, subjects exercised while breathing room temperature (22°C) dry air or cold (−1°C), dry air where inhaled air water content was less than 5 mg·L⁻¹ air; exercising minute ventilations were equal between conditions. No significant difference in postexercise FEV₁ was noted between inhaled room temperature and cold air conditions; likewise, no difference was noted between exercise and EVH with matched V_E (Fig 3). In another study, Beuther and Martin⁵⁴ demonstrated that a heat exchange mask was as effective as pre-exercise treatment with albuterol, supporting the role of inhaled air water content/temperature in the EIB response.

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• Fig 3. 

  EVH and exercise challenge (Exer) were performed by EIB-positive athletes at room temperature (22°C) inhaling dry medical-grade air at either room temperature (RT) or chilled (−1°C; CT). Falls in FEV₁ were not different between challenge modes or between inhaled air temperature conditions. This provides further evidence supporting the notion that inhaled air water content and not air temperature per se is the major trigger for the EIB response. Redrawn from Evans TM, Rundell KW, Beck KC, Levine AM, Baumann JM. Cold air inhalation does not affect the severity of EIB after exercise or eucapnic voluntary hyperventilation. Med Sci Sports Exerc 2005;37:544-9.³⁹

Recommended exercise protocol 

Current recommendations suggest that the optimal exercise challenge for the identification of EIB is an 8-minute exercise bout, either cycling or running, that allows the patient to achieve >90% of HR_peak by 2 minutes into the challenge and maintain it for the remaining 6 minutes of the challenge. This will, except for the very fit elite athlete, result in achieving and maintaining V_E at approximately 85% of maximal voluntary ventilation (MVV)⁵⁵; for the elite or highly fit athlete, an intensity of approximately 95% HR_peak is recommended. Inhaled air during the challenge should be dry, medical grade air (<5 mg H₂O·L^-1 air) administered via gas cylinder with a reservoir bag (Douglas bag apparatus), and 1-way mouth valve and nose clips should be worn during the test. Because airway drying is the primary trigger, it is important that the challenge is not performed in ambient conditions (eg, 22°C, 50% RH), because this increases the risk for a false-negative test.¹⁰ Heart rate, arterial oxygen saturation (via pulse oximetry), and V_E should be measured throughout the test, and heart rate and arterial oxygen saturation should be monitored through postchallenge spirometry to recovery. This will provide strict monitoring of the patient and enable tight control of test conditions that will allow high test-retest reliability and patient safety. The utility of being able to reproduce test conditions can be a valuable tool for monitoring patient treatment on subsequent visits.²⁸ Lung function tests should follow ATS standards for FVC or FEV₁ maneuvers.³³ Two reproducible maneuvers within 3% of each other should be performed before the challenge, with the best maneuver used to calculate postexercise falls in FEV₁. Two reproducible postexercise spirometry maneuvers should be performed at each time point of 5, 10, 15, and 30 minutes after the completion of the challenge. Again, if vocal cord dysfunction is suspected, a FVC procedure should be performed immediately postexercise. Otherwise, the FEV₁ procedure is preferred to decrease the likelihood of poor quality maneuvers caused by respiratory muscle fatigue. Before performing the exercise challenge, the 10% fall, 50% alert value, and 95% return value FEV₁ should be calculated from the pre-exercise baseline spirometry. Spirometry should continue through each time point unless the patient has a fall in FEV₁ greater than 50%, at which point a short-acting β₂-agonist should be administered to reverse the response. The patient should remain at the clinic or laboratory until the FEV₁ returns to 95% of baseline values.

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Eucapnic voluntary hyperpnea 

Eucapnic voluntary hyperpnea is a challenge based on the premise that increased ventilation rate causes bronchoconstriction in susceptible individuals. The mechanism is thought to occur through drying the airway surface liquid and increased osmolarity, resulting in degranulation of inflammatory cells and release of inflammatory mediators, similar to what occurs during exercise. Because EVH has demonstrated high sensitivity to identify those with EIB,⁵⁶, ⁵⁷, ⁵⁸ EVH is currently the IOC Medical Commission–recommended challenge to identify EIB among Olympic athletes.²¹

The general procedure involves voluntary breathing of hypercapnic air (4.5% to 5% CO₂, 21% O₂, balance N₂) at a predetermined rate of 60% to 85% MVV; with the elite athlete, the breathing rate should be at a minimum of 85% MVV.⁵⁵ Pre-EVH and post-EVH spirometry is performed as it is with exercise. The respiration rate for the challenge is estimated by assuming MVV to be 35 × FEV₁,⁵⁵ although this assumption has been challenged. Spiering et al⁵⁹ found high variability in using FEV₁ to standardize EVH target ventilation (range, 64% to 109% maximum minute ventilation) and suggested that underdiagnosis of low-end outliers could occur. The recommended ventilation rate is 30 × FEV₁ (estimated 85% MVV) for 6 minutes.⁵⁶ Argyros et al⁶⁰ demonstrated that EVH at 30 × FEV₁ for 6 minutes resulted in a greater fall in FEV₁ than (1) EVH at 20 × FEV₁,(2) EVH at 15 × FEV₁ for 12 minutes, or (3) EVH at 30 × FEV₁ for 2 minutes repeated 3 times (26.7% ± 11.3% vs 16.6% ± 10.9% vs 11.0% ± 8.1% vs 19.6% ± 9.9% falls in FEV₁).

The dry EVH air mixture contains 4.5% to 5% CO₂⁵⁵, ⁵⁶ to ensure eucapnia because hyperventilation-induced hypocapnia can cause bronchoconstriction in people with and without asthma.⁴, ⁶¹ As with the exercise challenge, it is important to measure V_E to assure adequate and consistent ventilation throughout the 6-minute test. A variation of the EVH challenge is to chill the inspired air, potentially causing a greater change in airway osmolarity or vascular response. However, the temperature of the inspired air has been subsequently shown to be unimportant to the degree of bronchoconstriction from this challenge.³⁸, ³⁹ Using dry ambient temperature air (22°C) and dry cold air (−1°C), Evans et al³⁹ found no difference in post-EVH falls in FEV₁ between inhaled air temperature conditions (15.2 vs 13.8 for room temperature and cold air inhalation, respectively). Because the cold temperature inhaled air did not have an additive effect to the bronchoconstrictive response in this study, Evans et al³⁸ suggested that the water content and not temperature of the inhaled air is essential to test conditions. This conclusion is in agreement with others.⁵⁰

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Hypertonic saline challenge 

Nebulized hypertonic saline is considered an indirect challenge because it acts by increasing airway surface liquid osmolarity, triggering sensitized cells (in particular, mast cells) to release inflammatory mediators.⁶² An osmotic challenge such as nebulized hypertonic saline demonstrates effectiveness similar to exercise and EVH, but is more economical and easier to administer.⁶³, ⁶⁴, ⁶⁵, ⁶⁶ An additional advantage of using this challenge is the ability to collect sputum concurrently with the measure of airway responsiveness for mediator and cellular analysis.⁶⁵, ⁶⁶, ⁶⁷

The hypertonic saline challenge consists of baseline spirometry measurements followed by nebulized hypertonic saline inhalation. Most researchers have concluded that a 4.5% hypertonic saline concentration is most appropriate to deliver quicker (usually 15-20 minute) results without severe falls in FEV₁.⁶⁵, ⁶⁶, ⁶⁷ The initial exposure to the hypertonic saline is 30 seconds.⁶⁶ If the percent fall from baseline FEV₁ is less than 10%, the exposure time is doubled (eg, 30 seconds, 60 seconds, 2 minutes, 4 minutes, 8 minutes).⁶⁶ Standard protocol indicates that FEV₁ is measured 60 seconds after every exposure. If FEV₁ fall is greater than 10%, the same exposure is administered a second time. The test is terminated after a 15% or greater fall in FEV₁ is observed or when a total minimum dose of 23 g has been administered in 15.5 minutes.⁶⁶ As with the mannitol challenge (see “Inhaled powdered mannitol challenge”), the hypertonic saline challenge produces a dose-dependent response, shown in Fig 4. This enables a classification to be made concerning the severity of the patient's asthma and level of inflammation.

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• Fig 4. 

  The hypertonic saline challenge provides a cumulative dose-response curve that can be used to define the severity of the EIB response. Redrawn from Anderson SD, Brannan JD. Methods for “indirect” challenge test including exercise, eucapnic voluntary hyperpnea, and hypertonic aerosols. Clin Rev Allergy Immunol 2003;24:27-54.⁶⁶

A disadvantage of using the hypertonic saline challenge is that it may not be useful for evaluating treatment with low doses of ICSs. Jones et al⁶⁷ treated subjects with uncontrolled asthma for 8 weeks with inhaled beclomethasone of 50, 100, 200, and 500 μg/d. A dose-dependent change in responsiveness to hypertonic saline could be attained, but only the largest dose appeared to be effective.⁶⁷ Thus, hypertonic saline may function best observing dose-dependent changes of high-dose ICS therapy, which resembles the direct challenge measures. Although hypertonic saline has some pitfalls, it can still be used to identify those with exercise-induced asthma, current active asthma, or a history of asthma but no current symptoms.⁶⁵

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Inhaled powder mannitol challenge 

Mannitol was developed as a bronchial provocation test in 1994 but has not yet received final US Food and Drug Administration approval for use as a bronchoprovocation test in the United States. Mannitol is a naturally occurring sugar alcohol found in most vegetables that resists absorption at high RH and is a stable substance. The inhalation of dry powder mannitol is thought to cause smooth muscle contraction by stimulating the release of inflammatory mediators from airway cells. Because mannitol does not act directly on the airway smooth muscle, it is thought to be a better representation of the neural and cellular contribution to airway hyperresponsiveness.²⁸, ⁶⁵, ⁶⁸

The preparation of dry powder mannitol has been previously described in depth.⁶⁵ Mannitol powder is encapsulated for administration through a dry powder inhaler device. Mannitol is delivered in progressive doubling doses of 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, 160 mg, and 160 mg, with a maximal total cumulative dose of 635 mg, depending on the specific airway response.⁶⁵ One minute after each dose, FEV₁ is measured in duplicate. The initial test dose is a 0-mg capsule; the resultant FEV₁ is used to calculate the target FEV₁ (0.85 × measured FEV₁) for a 15% fall from subsequent doses. The challenge is stopped when a ≥15% fall in FEV₁ from baseline is recorded, a between-dose fall of ≥10% in FEV₁ occurs, or a cumulative dose of 635 mg has been administered.²⁸

The inhaled powdered mannitol challenge has many advantages over other indirect challenges as well as direct challenges. It is a practical option for use as an office-based test because of ease to administer and it does not require specialized equipment such as treadmills, a dry air source, and/or patient headgear. In addition, the inhaled powder mannitol challenge takes less time than other challenges and can be provided at the point of need.

A unique advantage to the mannitol challenge is the differentiation of responses to mannitol, as shown in Fig 5. A severe response to mannitol results in a decrease in FEV₁ greater than 15% from less than or equal to 35 mg, a moderate response results in a decrease in FEV₁ greater than 15% to 155 mg, a mild response results in a decrease in FEV₁ greater than 15% to greater than 155 mg, and a normal response does not express a significant decrease in FEV₁.

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• Fig 5. 

  Similar to the hypertonic saline challenge, the cumulative dose-response curve obtained from the inhaled powder mannitol challenge can be used to define the severity of the response. Thus the efficacy of treatment can be monitored through serial challenges. Redrawn from Anderson SD, Brannan JD. Methods for “indirect” challenge test including exercise, eucapnic voluntary hyperpnea, and hypertonic aerosols. Clin Rev Allergy Immunol 2003;24:27-54.⁶⁶

Mannitol may be superior to exercise and EVH because of the built-in safety feature of a progressive dose-response challenge; the test can be stopped before severe falls in lung function (FEV₁) occur. The fall in FEV₁ can also be seen much quicker with mannitol than with other procedures, such as hyperventilation, which may take as long as 10 minutes after cessation,⁶⁵ and exercise, which may take as long as 20 minutes after cessation.⁶⁶ In a phase III, multicenter, open-label, operator-blind, crossover design, randomized trial with follow-up, strong similarities between mannitol and hypertonic saline were observed.⁶⁹ The subjects who tested positive by both mannitol and hypertonic saline demonstrated equal mean percent falls in FEV₁ (mannitol, 21.0 ± 5.9; hypertonic saline, 21.3 ± 5.9).⁶⁹ This study also demonstrated similar time to completion for a positive test (mannitol, 17.3 ± 7.1 minutes; hypertonic saline, 15.0 ± 9.1 minutes).⁶⁹

Brannan et al⁶⁹ demonstrated the safety of inhaled mannitol and its ability to identify airway hyperresponsiveness; during the phase III trial, no serious adverse events were reported, and the overall safety profile was similar to that of hypertonic saline.

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AMP challenge 

Although the results of a bronchoprovocation test using inhaled AMP will not be accepted by the IOC-MC as evidence of EIB, AMP challenge has been used to identify bronchial hyperresponsiveness in competitive cross-country skiers.⁷⁰ Unlike the previous indirect challenges mentioned, the mode of action for the inhaled AMP challenge is not osmotic. When inhaled, AMP quickly dephosphorylates into adenosine,⁷¹ causing mast cells to degranulate and release histamine and leukotrienes, which have a potent effect on bronchoconstriction.⁷², ⁷³ Adenosine is a protein signaling molecule that binds to specific G-protein–coupled receptors on cell surfaces throughout the body and are involved in multiple signaling pathways that elicit cellular responses.⁷¹

AMP is prepared for inhalation by mixing AMP with a phosphate-buffered solution.⁷⁴ Briefly, AMP is administered in progressively doubling concentration doses within the range of 0.09 to 800 mg/mL.⁷⁴ Avital et al⁷⁵ used doubling concentration doses within the range of 0.39 to 400 mg/mL, and Benckhuijsen et al⁷⁶ recommended using doubling concentrations of 0.15, 0.30, to 320 mg/mL. Generally, the AMP protocol consists of baseline spirometry measurements, with a baseline FEV₁ ≥60% of predicted being acceptable to continue the procedure.⁷⁶ The doubling concentration doses of AMP are then delivered to the subject via a nebulizer for 2 minutes until a ≥20% fall in FEV₁ is recorded, at which point the protocol is terminated.⁷⁴, ⁷⁶, ⁷⁷ Spirometry measurements are taken between nebulizer treatments in at least duplicate.⁷⁴, ⁷⁶

In a comparison study between PC₂₀ AMP and PC₂₀ methacholine, van den Berge et al⁷⁸ concluded that PC₂₀ AMP was more closely related to airway inflammation than PC₂₀ methacholine. This study also concluded that AMP provides a better representation of airway inflammation based on sputum eosinophils and exhaled nitric oxide.⁷⁸ van den Toorn et al⁷⁹ also observed a significant correlation between exhaled nitric oxide levels and AMP responsiveness but did not observe such a correlation between eNO and methacholine in adolescents 18 to 25 years of age.

Although AMP is noninvasive, has low cost, and is an excellent way to monitor inflammation, there is a pitfall associated with this challenge.⁷¹ van den Berge et al⁸⁰ demonstrated that the AMP challenge can result in the production of sputum eosinophilia within 1 hour of the challenge, which was not the case with the methacholine challenge. An inflammatory response after the AMP challenge could present a problem and needs to be considered before using the AMP challenge as a diagnostic tool.⁸⁰

Both AMP and mannitol are considered indirect challenges because they stimulate the release of inflammatory mediators from mast cells.⁷², ⁷⁷ It has been shown that mannitol produces results similar to those from the AMP challenge in terms of airway hyperresponsiveness and recovery time.⁷⁷ Studies involving the recovery time from AMP and mannitol challenges suggest that histamine is involved in initiating the response, whereas cysteinyl leukotrienes maintain the bronchoconstrictor response during recovery.⁷², ⁷⁷ Although not an osmotic challenge, these findings indicate that the AMP challenge is very similar in nature to the mannitol challenge.⁷², ⁷⁷

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Conclusion 

In conclusion, a major determinant in making the correct diagnosis and in defining the severity of the EIB response is the methodology used in the challenge. For exercise and EVH challenge, the ventilation achieved and maintained and the water content of the inspired air modify the degree of reversible bronchoconstriction and therefore must be carefully regulated during challenges. This can be accomplished by measuring V_E during hyperpnea and using dry medical-grade air supplied via a gas cylinder and reservoir system. The effect of physical conditioning on serial exercise challenges and the EIB response should also be considered. For example, if the intensity of the exercise challenge is standardized and regulated by heart rate, the minute ventilation could change dramatically in an individual who was not in peak physical condition before an initial diagnostic challenge but subsequently began an exercise program before sequential challenges. This could result in lower minute ventilation at the predetermined heart rate and skew the bronchoconstriction toward normal, causing erroneous conclusions concerning treatment. Therefore, to monitor treatment effectively by exercise challenge results, it is important to standardize to measured minute ventilation based on an initial diagnostic challenge. Only when challenge conditions are standardized and tightly controlled can the laboratory challenge be used to verify the efficacy of treatment. There is certainly an argument for the use of the standardized exercise challenge over surrogate challenges. After all, the evaluation is for EIB. However, the surrogate challenges described in this review show good sensitivity and specificity to exercise and should be considered. EVH, hypertonic saline, mannitol, and AMP are challenges that require less laboratory space and set-up equipment and can be performed in the typical clinical setting. Although not yet approved for use in the United States, the inhaled powdered mannitol challenge shows great promise as a diagnostic tool and as a tool to monitor the effectiveness of medical treatment for EIB.

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References 

1. Anderson SD, Holzer K. Exercise-induced asthma: is it the right diagnosis in elite athletes?. J Allergy Clin Immunol. 2000;106:419–428
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (178 KB)
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2. McFadden ER, Gilbert IA. Exercise-induced asthma. N Engl J Med. 1994;330:1362–1367
   • View In Article
   • MEDLINE
   • CrossRef
3. Beck KC, Offord KP, Scanlon PD. Bronchoconstriction occurring during exercise in asthmatic subjects. Am J Respir Crit Care Med. 1994;149:352–357
   • View In Article
   • MEDLINE
4. Suman OE, Beck KC, Babcock MA, Pegelow DF, Reddan AW. Airway obstruction during exercise and isocapnic hyperventilation in asthmatic subjects. J Appl Physiol. 1999;87:1107–1113
   • View In Article
   • MEDLINE
5. Rundell KW, Spiering BA, Judelson DA, Wilson MH. Bronchoconstriction during cross-country skiing: is there really a refractory period?. Med Sci Sports Exerc. 2003;35:18–26
   • View In Article
   • MEDLINE
   • CrossRef
6. Anderson SD, Connolly NM, Godfrey S. Comparison of bronchoconstriction induced by cycling and running. Thorax. 1971;26:396–401
   • View In Article
   • MEDLINE
   • CrossRef
7. Fitch KD, Morton AR. Specificity of exercise in exercise-induced asthma. BMJ. 1971;4:577–581
   • View In Article
   • CrossRef
8. Mannix ET, Farber MO, Palange P, Galassetti P, Manfredi F. Exercise-induced asthma in figure skaters. Chest. 1996;109:312–315
   • View In Article
   • MEDLINE
   • CrossRef
9. Provost-Craig MA, Arbour KS, Sestili DC, Chabalko JJ, Ekinci E. The incidence of exercise-induced bronchospasm in competitive figure skaters. J Asthma. 1996;33:67–71
   • View In Article
   • MEDLINE
   • CrossRef
10. Rundell KW, Wilber RL, Szmedra L, Jenkinson DM, Mayers LB, Im J. Exercise-induced asthma screening of elite athletes: field versus laboratory exercise challenge. Med Sci Sports Exerc. 2000;32:309–316
    • View In Article
    • MEDLINE
    • CrossRef
11. Wilber RL, Rundell KW, Szmedra L, Jenkinson DM, Im J, Drake SD. Incidence of exercise-induced bronchospasm in Olympic winter sport athletes. Med Sci Sports Exerc. 2000;32:732–737
    • View In Article
    • MEDLINE
    • CrossRef
12. Rundell KW, Im J, Mayers LB, Wilber RL, Szmedra L, Schmitz HR. Self-reported symptoms and exercise-induced asthma in the elite athlete. Med Sci Sports Exerc. 2001;33:208–213
    • View In Article
    • MEDLINE
13. Rundell KW, Jenkinson DM. Exercise-induced bronchospasm in the elite athlete. Sports Med. 2002;32:583–600
    • View In Article
    • MEDLINE
    • CrossRef
14. Rundell KW. High levels of airborne ultrafine and fine particulate matter in indoor ice arenas. Inhal Toxicol. 2003;15:237–250
    • View In Article
    • MEDLINE
    • CrossRef
15. Rundell KW, Spiering BA, Evans TM, Baumann JM. Baseline lung function, exercise-induced bronchoconstriction, and asthma-like symptoms in elite women ice hockey players. Med Sci Sports Exerc. 2004;36:405–410
    • View In Article
    • MEDLINE
    • CrossRef
16. Rundell KW. Pulmonary function decay in women ice hockey players: is there a relationship to ice rink air quality?. Inhal Toxicol. 2004;16:117–123
    • View In Article
    • MEDLINE
    • CrossRef
17. Sue-Chu M, Larsson L, Moen T, Rennard SI, Bjermer L. Bronchoscopy and bronchoalveolar lavage findings in cross-country skiers with and without “ski asthma. Eur Respir J. 1999;13:626–632
    • View In Article
    • MEDLINE
    • CrossRef
18. Sue-Chu M, Henriksen AH, Bjermer L. Non-invasive evaluation of lower airway inflammation in hyper-responsive elite cross-country skiers and asthmatics. Respir Med. 1999;93:719–725
    • View In Article
    • Abstract
    • Full-Text PDF (705 KB)
    • CrossRef
19. Helenius IJ, Tikkanen HO, Haahtela T. Association between type of training and risk of asthma in elite athletes. Thorax. 1997;52:157–160
    • View In Article
    • MEDLINE
    • CrossRef
20. Helenius I, Haahtela T. Allergy and asthma in elite summer sport athletes. J Allergy Clin Immunol. 2000;106:444–452
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (116 KB)
    • CrossRef
21. Anderson SD, Sue-Chu M, Perry CP, Gratziou C, Kippelen P, McKenzie DC, et al. Bronchial challenges in athletes applying to inhale a beta2-agonist at the 2004 Summer Olympics. J Allergy Clin Immunol. 2006;117:767–773
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (172 KB)
    • CrossRef
22. Weiler JM, Layton T, Hunt M. Asthma in United States Olympic athletes who participated in the 1996 Summer Games. J Allergy Clin Immunol. 1998;102:722–726
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (55 KB)
    • CrossRef
23. Weiler JM, Ryan EJ. Asthma in United States Olympic athletes who participated in the 1998 Olympic Winter Games. J Allergy Clin Immunol. 2000;106:267–271
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (43 KB)
    • CrossRef
24. Parsons JP, Kaeding C, Phillips G, Jarjoura D, Wadley G, Mastronarde JG. Prevalence of exercise-induced bronchospasm in a cohort of varsity college athletes. Med Sci Sports Exerc. 2007;39:1487–1492
    • View In Article
    • CrossRef
25. Weiler JM, Bonini S, Coifman R, Craig T, Delgado L, Capão-Filipe M, et al. Ad Hoc Committee of Sports Medicine Committee of American Academy of Allergy, Asthma & Immunology. American Academy of Allergy, Asthma & Immunology Work Group report: exercise-induced asthma. J Allergy Clin Immunol. 2007;119:1349–1358
    • View In Article
    • Full Text
    • Full-Text PDF (368 KB)
    • CrossRef
26. 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;161:2086–2091
    • View In Article
    • MEDLINE
27. Henriksen AH, Tveit KH, Holmen TL, Sue-Chu M, Bjermer L. A study of the association between exercise-induced wheeze and exercise versus methacholine-induced bronchoconstriction in adolescents. Pediatr Allergy Immunol. 2002;13:203–208
    • View In Article
    • MEDLINE
    • CrossRef
28. Brannan JD, Koskela H, Anderson SD, Chew N. Responsiveness to mannitol in asthmatic subjects with exercise- and hyperventilation-induced asthma. Am J Respir Crit Care Med. 1998;158:1120–1126
    • View In Article
    • MEDLINE
29. Roquet A, Dahlen B, Kumlin M, Ihre E, Anstrén G, Binks S, et al. Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics. Am J Respir Crit Care Med. 1997;155:1856–1863
    • View In Article
    • MEDLINE
30. National Heart, Lung, and Blood Institute . Expert panel report 2: guidelines for the diagnosis and management of asthma. 1st ed.. Bethesda (MD): NIH Publications; 1997;p. 1-146
    • View In Article
31. Boulet LP, Becker A, Berube A, Beveridge R, Ernst P. Canadian asthma consensus report, 1999. Can Med Assoc J. 1999;161(suppl 11):S1–S62
    • View In Article
32. Bye MR, Kerstein D, Barsh E. The importance of spirometry in the assessment of childhood asthma. Am J Dis Child. 1992;146:977–978
    • View In Article
    • MEDLINE
33. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, et al. Guidelines for methacholine and exercise challenge testing—1999: this official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med. 2000;161:309–329
    • View In Article
    • MEDLINE
34. Carlsen KH, Anderson SD, Bjermer L, Bonini S, Brusasco V, Canonica W, et al. European Respiratory Society, European Academy of Allergy and Clinical Immunology. Exercise-induced asthma, respiratory and allergic disorders in elite athletes: epidemiology, mechanisms and diagnosis: part I of the report from the Joint Task Force of the European Respiratory Society (ERS) and the European Academy of Allergy and Clinical Immunology (EAACI) in cooperation with GA2LEN. Allergy. 2008;63:387–403
    • View In Article
    • CrossRef
35. Rundell KW, Spiering BA. Inspiratory stridor in elite athletes. Chest. 2003;123:468–474
    • View In Article
    • MEDLINE
    • CrossRef
36. Newman KB, Mason UG, Schmaling KB. Clinical features of vocal cord dysfunction. Am J Respir Crit Care Med. 1995;152:1382–1386
    • View In Article
    • MEDLINE
37. Evans TM, Rundell KW, Beck KC, Levine AM, Baumann JM. Impulse oscillometry is sensitive to bronchoconstriction after eucapnic voluntary hyperventilation or exercise. J Asthma. 2006;43:49–55
    • View In Article
    • MEDLINE
    • CrossRef
38. Evans TM, Rundell KW, Beck KC, Levine AM, Baumann JM. Airway narrowing measured by spirometry and impulse oscillometry following room temperature and cold temperature exercise. Chest. 2005;128:2412–2419
    • View In Article
    • MEDLINE
    • CrossRef
39. Evans TM, Rundell KW, Beck KC, Levine AM, Baumann JM. Cold air inhalation does not affect the severity of EIB after exercise or eucapnic voluntary hyperventilation. Med Sci Sports Exerc. 2005;37:544–549
    • View In Article
    • MEDLINE
    • CrossRef
40. Anderson SD, Silverman M, Tai E, Godfrey S. Specificity of exercise in exercise-induced asthma. BMJ. 1971;4:814–815
    • View In Article
    • CrossRef
41. Eggleston PA, Rosenthal RR, Anderson SA, Anderton R, Bierman CW, Bleecker ER, et al. Guidelines for the methodology of exercise challenge testing of asthmatics. Study Group on Exercise Challenge, Bronchoprovocation Committee, American Academy of Allergy. J Allergy Clin Immunol. 1979;64:642–645
    • View In Article
    • MEDLINE
    • CrossRef
42. Godfrey S, Silverman M, Anderson SD. The use of the treadmill for assessing exercise-induced asthma and the effect of varying the severity and duration of exercise. Pediatrics. 1975;56(5 pt-2 suppl):893–898
    • View In Article
    • MEDLINE
43. König P. Exercise challenge: indications and techniques. Allergy Proc. 1989;10:345–348
    • View In Article
    • MEDLINE
44. Mahler DA. Exercise-induced asthma. Med Sci Sports Exerc. 1993;25:554–561
    • View In Article
    • MEDLINE
45. Warren JB, Jennings SJ, Clark TJ. Effect of adrenergic and vagal blockade on the normal human airway response to exercise. Clin Sci (Lond). 1984;66:79–85
    • View In Article
    • MEDLINE
46. Carlsen KH, Engh G, Mørk M. Exercise-induced bronchoconstriction depends on exercise load. Respir Med. 2000;94:750–755
    • View In Article
    • Abstract
    • Full-Text PDF (162 KB)
    • CrossRef
47. Haby MM, Anderson SD, Peat JK, Mellis CM, Toelle BG, Woolcock AJ. An exercise challenge protocol for epidemiological studies of asthma in children: comparison with histamine challenge. Eur Respir J. 1994;7:43–49
    • View In Article
    • MEDLINE
    • CrossRef
48. Ogston J, Butcher JD. A sport-specific protocol for diagnosing exercise-induced asthma in cross-country skiers. Clin J Sport Med. 2002;12:291–295
    • View In Article
    • MEDLINE
    • CrossRef
49. Anderson SD, Fitch K, Perry CP, Sue-Chu M, Crapo R, McKenzie D, 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;111:45–50
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (103 KB)
    • CrossRef
50. Anderson SD, Schoeffel RE. Respiratory heat and water loss during exercise in patients with asthma: effect of repeated exercise challenge. Eur J Respir Dis. 1982;63:472–480
    • View In Article
    • MEDLINE
51. Daviskas E, Gonda I, Anderson SD. Mathematical modeling of heat and water transport in human respiratory tract. J Appl Physiol. 1990;69:362–372
    • View In Article
    • MEDLINE
52. Daviskas E, Gonda I, Anderson SD. Local airway heat and water vapour losses. Respir Physiol. 1991;84:115–132
    • View In Article
    • MEDLINE
    • CrossRef
53. Stensrud T, Berntsen S, Carlsen KH. Humidity influences exercise capacity in subjects with exercise-induced bronchoconstriction (EIB). Respir Med. 2006;100:1633–1641
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (281 KB)
    • CrossRef
54. Beuther DA, Martin RJ. Efficacy of a heat exchanger mask in cold exercise-induced asthma. Chest. 2006;129:1188–1193
    • View In Article
    • MEDLINE
    • CrossRef
55. Anderson SD, Argyros GJ, Magnussen H, Holzer K. Provocation by eucapnic voluntary hyperpnoea to identify exercise induced bronchoconstriction. Br J Sports Med. 2001;35:344–347
    • View In Article
    • MEDLINE
    • CrossRef
56. Rundell KW, Anderson SD, Spiering BA, Judelson DA. Field exercise vs laboratory eucapnic voluntary hyperventilation to identify airway hyperresponsiveness in elite cold weather athletes. Chest. 2004;125:909–915
    • View In Article
    • MEDLINE
    • CrossRef
57. Rundell KW, Evans TM, Baumann JM, Kertesz MF. Lung function measured by impulse oscillometry and spirometry following eucapnic voluntary hyperventilation. Can Respir J. 2005;12:257–263
    • View In Article
    • MEDLINE
58. Dickinson JW, Whyte GP, McConnell AK, Harries MG. Screening elite winter athletes for exercise induced asthma: a comparison of three challenge methods. Br J Sports Med. 2006;40:179–182discussion 179-82
    • View In Article
    • CrossRef
59. Spiering BA, Judelson DA, Rundell KW. An evaluation of standardizing target ventilation for eucapnic voluntary hyperventilation using FEV1. J Asthma. 2004;41:745–749
    • View In Article
    • MEDLINE
    • CrossRef
60. Argyros GJ, Roach JM, Hurwitz KM, Eliasson AH, Phillips YY. Eucapnic voluntary hyperventilation as a bronchoprovocation technique: development of a standarized dosing schedule in asthmatics. Chest. 1996;109:1520–1524
    • View In Article
    • MEDLINE
    • CrossRef
61. Sterling GM. The mechanism of bronchoconstriction due to hypocapnia in man. Clin Sci. 1968;34:277–285
    • View In Article
    • MEDLINE
62. Finnerty JP, Wilmot C, Holgate ST. Inhibition of hypertonic saline-induced bronchoconstriction by terfenadine and flurbiprofen: evidence for the predominant role of histamine. Am Rev Respir Dis. 1989;140:593–597
    • View In Article
    • MEDLINE
63. Riedler J, Reade T, Dalton M, Holst D, Robertson C. Hypertonic saline challenge in an epidemiologic survey of asthma in children. Am J Respir Crit Care Med. 1994;150:1632–1639
    • View In Article
    • MEDLINE
64. Rabone SJ, Phoon WO, Anderson SD, Wan KC, Seneviratne M, Gutierrez L, et al. Hypertonic saline challenge in an adult epidemiologic survey. Occup Med. 1996;46:177–185
    • View In Article
65. Anderson SD, Brannan JD, Chan HK. Use of aerosols for bronchial provocation testing in the laboratory: where we have been and where we are going. J Aerosol Med. 2002;15:313–324
    • View In Article
    • MEDLINE
    • CrossRef
66. Anderson SD, Brannan JD. Methods for “indirect” challenge test including exercise, eucapnic voluntary hyperpnea, and hypertonic aerosols. Clin Rev Allergy Immunol. 2003;24:27–54
    • View In Article
    • MEDLINE
    • CrossRef
67. Jones SL, Herbison P, Cowan JO, Flannery EM, Hancox RJ, McLachlan CR, et al. Exhaled NO and assessment of anti-inflammatory effects of inhaled steroid: dose-response relationship. Eur Respir J. 2002;20:301–308
    • View In Article
68. Anderson SD, Brannan JD, Spring J, Spalding N, Rodwell LT, Chan HK, et al. A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol. Am J Respir Cri Care Med. 1997;156:758–765
    • View In Article
69. Brannan JD, Anderson SD, Perry CP, Freed-Martens R, Lassig AR, Charlton B Aridol Study Group. The safety and efficacy of inhaled dry powder mannitol as a bronchial provocation test for airway hyperresponsiveness: a phase 3 comparison study with hypertonic (4.5%) saline. Respir Res. 2005;6:144
    • View In Article
    • CrossRef
70. Sue-Chu M, Henriksen AH, Bjermer L. Non-invasive evaluation of lower airway inflammation in hyper-responsive elite cross-country skiers and asthmatics. Respir Med. 1999;93:719–725
    • View In Article
    • Abstract
    • Full-Text PDF (705 KB)
    • CrossRef
71. Mohsenin A, Blackburn M. Adenosine signaling in asthma and chronic obstructive pulmonary disease. Curr Opin Pulm Med. 2006;12:54–59
    • View In Article
    • MEDLINE
72. Currie GP, Jackson CM, Lipworth GJ. Does bronchial hyperresponsiveness in asthma matter?. J Asthma. 2004;41:247–258
    • View In Article
    • MEDLINE
    • CrossRef
73. Rorke S, Jennison S, Jeffs JA, Sampson AP, Arshad H, Holgate ST. Role of cysteinyl leukotrienes in adenosine 5'-monophosphate induced bronchoconstriction in asthma. Thorax. 2002;57:323–327
    • View In Article
    • MEDLINE
    • CrossRef
74. Avraham A, Godfrey S, Springer C. Exercise, methacholine, and adenosine 5'-monophosphate challenges in children with asthma: relation to severity of the disease. Pediatr Pulmonol. 2000;30:207–214
    • View In Article
    • MEDLINE
    • CrossRef
75. Avital A, Uwyyed K, Berkman N, Bar-Yishay E, Godfrey S, Springer C. Exhaled nitric oxide is age-dependent in asthma. Pediatr Pulmonol. 2003;36:433–438
    • View In Article
    • MEDLINE
    • CrossRef
76. Benckhuijsen J, Bos JW, Velsen E, Bruijn R, Aalbers R. Differences in the effect of allergen avoidance on bronchial hyperresponsiveness as measured by methacholine, adenosine 5'-monophosphate, and exercise in asthmatic children. Pediatr Pulmonol. 1996;22:147–153
    • View In Article
    • MEDLINE
    • CrossRef
77. Currie GP, Haggart K, Lee DKC, Fowler SJ, Wilson AM, Branna JD, et al. Effects of mediator antagonism on mannitol and adenosine monophosphate challenges. Clin Exp Allergy. 2003;33:783–788
    • View In Article
    • MEDLINE
    • CrossRef
78. van den Berge M, Maijer RJ, Kerstjens HAM, de Reus DM, Koeter GH, Kauffman HF, et al. PC20 adenosine 5'-monophosphate is more closely associated with airway inflammation in asthma than PC20 methacholine. Am J Respir Crit Care Med. 2001;163:1546–1550
    • View In Article
    • MEDLINE
79. van den Toorn LM, Prins JB, Overbeek SE, Hoogsteden HC, de Jongste JC. Adolescents in clinical remission of atopic asthma have elevated nitric oxide levels and bronchial hyperresponsiveness. Am J Respir Crit Care Med. 2000;162:953–957
    • View In Article
    • MEDLINE
80. van den Berge M, Kerstjens HA, de Reus DM, Koëter GH, Kauffman HF, Postma DS. Provocation with adenosine 5'-monophosphate, but not methacholine, induces sputum eosinophilia. Clin Exp Allergy. 2004;34:71–76
    • View In Article
    • MEDLINE
    • CrossRef