Evidence Report/Technology Assessment 

Number 189 

Exercise-Induced Bronchoconstriction and Asthma

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov 

Contract No. HHSA 290-2007-10021-I 

Prepared by: 

University of Alberta Evidence-based Practice Center, Edmonton, AB, Canada 

Investigators 

Donna M. Dryden, Ph.D. 

Carol H. Spooner, B.Sc.N., M.Sc. 

Michael K. Stickland, Ph.D. 

Ben Vandermeer, M.Sc. 

Lisa Tjosvold, B.A., M.L.I.S. 

Liza Bialy, B.Sc. 

Kai Wong, B.Sc. 

Brian H. Rowe, M.D., M.Sc., C.C.F.P. (E.M.) 

AHRQ Publication No. 10-E001 

January 2010 (Web site posting) 

Revised March 2010 
This document is in the public domain and may be used and reprinted without permission 

except those copyrighted materials noted for which further reproduction is prohibited 

without the specific permission of copyright holders. 

Suggested Citation: 

Dryden DM, Spooner CH, Stickland MK, Vandermeer B, Tjosvold L, Bialy L, Wong K, 

Rowe BH. Exercise-Induced Bronchoconstriction and Asthma. Evidence 

Report/Technology Assessment No. 189 (Prepared by the University of Alberta 

Evidence-based Practice Center under Contract No. 290-2007-10021-I) AHRQ 

Publication No. 10-E001. Rockville, MD: Agency for Healthcare Research and Quality. 

January 2010 (Web site posting); revised March 2010.

No investigators have any affiliations or financial involvement (e.g., employment, 

consultancies, honoraria, stock options, expert testimony, grants or patents received or 

pending, or royalties) that conflict with material presented in this report. 
 

Preface 

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. The reports and assessments provide organizations 

with comprehensive, science-based information on common, costly medical conditions and new 

health care technologies. The EPCs systematically review the relevant scientific literature on 

topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to 

developing their reports and assessments. 

To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

We welcome comments on this evidence report. They may be sent by mail to the Task Order 

Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, 

Rockville, MD 20850, or by e-mail to epc@ahrq.gov. 

Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H. 

Director Director, Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality 

Beth A. Collins Sharp, R.N., Ph.D. Capt. Karen Lohmann Siegel, P.T., M.A. 

Director, EPC Program EPC Program Task Order Officer 

Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality 

iii 
Acknowledgments 

We are grateful to members of the technical expert panel, Dr. Louis-Philippe Boulet 

(Université Laval, Sainte-Foy, QC), Dr. Robert Cowie (University of Calgary, AB), Dr. Andrew 

Gregory (Vanderbilt University Medical Center, Nashville, TN), Dr. Cynthia LaBella 

(Children’s Memorial Hospital, Chicago, IL), Dr. Darcy Marciniuk (University of Saskatoon, 

SK), Dr. Kenneth Rundell (Marywood University, Scranton, PA), Dr. John Weiler (American 

Academy of Asthma Allergy and Immunology) and Karen Siegel (Agency for Healthcare 

Research and Quality), who provided direction for the scope and content of the review. We thank 

the Cochrane Airways Group for their assistance and providing access to their database of 

articles. We also thank all the individuals at AHRQ, the Scientific Resource Center, and the peer 

reviewers for their comments and suggestions. 

We thank Jennifer Seida for her work in developing the protocol, Mohammad Karkhaneh and 

Kate O’Gorman for assistance with data extraction and preparation of the appendices, Ken Bond 

for copyediting, and Simon Bow and Annabritt Chisholm for their assistance with literature 

retrieval. 

iv 
Structured Abstract 

Objectives: The objectives are: (1) to assess diagnostic test characteristics of six alternative 

index tests compared with the selected reference standard–a standardized exercise challenge test 

(ECT) in patients with suspected exercise-induced bronchoconstriction or asthma (EIB/EIA); (2) 

to determine the efficacy of a single prophylactic dose of four pharmacologic and one 

nonpharmacologic interventions versus placebo to attenuate EIB/EIA in patients with diagnosed 

EIB/EIA; and (3) to determine if regular daily treatment with short-acting or long-acting betaagonists (SABA or LABA) causes patients with EIA to develop tachyphylaxis when additional 

prophylactic doses are used pre-exercise. 

Data Sources: A systematic and comprehensive literature search was conducted in 14 electronic 

databases (Diagnosis) and the Cochrane Airways Register (Therapy). 

Review Methods: Study selection, quality assessment, and data extraction were conducted 

independently by two reviewers. The primary outcome was the maximum percent fall in the 

post-exercise forced expiratory volume in 1 second (percent fall FEV1). The diagnostic threshold 

for a positive ECT was a percent fall FEV1 of 10 percent or more. Sensitivity (SN) and 

specificity (SP) were calculated. For therapy, mean differences (MD) in the percent fall FEV1 

and 95 percent confidence intervals (CI) (random effects model) were calculated. A positive MD 

indicates the intervention works better than the control. 

Results: For the diagnostic reviews, 5,318 citations yielded 28 relevant studies; for the therapy 

reviews, 1,634 citations yielded 109 relevant RCTs 

Diagnostic test results versus ECT: self-reported history (2 studies) SN=36–89 percent, 

SP=85–86 percent; methacholine challenge (16 studies) SN=0–100 percent, SP=0–100 percent; 

sport specific challenges (5 studies) SN=0–100 percent, SP=0–100 percent; eucapnic voluntary 

hyperpnea (7 studies) SN=25–90 percent, SP=0–71 percent; free running asthma screening test 

(3 studies) SN=60–67 percent, SP=47–67 percent; mannitol (3 studies) SN=58–96 percent, 

SP=65-78 percent. All SN and SP calculations indicated substantial heterogeneity that could not 

be explained by sensitivity or subgroup analyses. 

Therapy results: SABA offered greater protection than mast cell stabilizers (MCS) (12 

studies); MD=6.8 (95 percent CI: 4.5, 9.2) but combining them offered no additional benefit; 

SABA versus MCS plus SABA (5 studies) MD=1.3 (95 percent CI: -6.3, 8.9). Leukotriene 

receptor antagonists (LTRA), MCS, ipratropium bromide, and interval warmup routines 

provided statistically significant attenuation of EIA when compared with placebo; inhaled 

corticosteroids (ICS) and other warmup routines did not. Single-dose intervention versus placebo 

results are: LTRA (9 studies) MD=8.9 (95 percent CI: 6.9, 11.0); MCS (nedocromil sodium) (17 

studies) MD=15.6 (95 percent CI: 13.2, 18.2); interval warmup versus no warmup (4 studies) 

MD=10.6 (95 percent CI: 6.5, 14.7); ICS (4 studies) MD=5.0 (95 percent CI: 0.0, 9.9); 

continuous low intensity warmup versus no warmup (3 studies) MD=12.6 (95 percent CI: -1.5, 

26.7); continuous high intensity warmup versus no warmup (2 studies) MD=9.8 (95 percent CI: ­

6.4, 26.0). 

After daily LABA (salmeterol) use for 3 to 4 weeks (4 studies), the percent fall FEV1 

following an ECT at 2 and 4 weeks was greater than at day 1 in the LABA arm indicating that 

tachyphylaxis to prophylactic LABA use occurred. Daily SABA use for 1 week (1 study) also 

v 
indicated development of tachyphylaxis. However, both LABA and SABA continued to 

have an attenuating effect on EIA. 

Conclusions: Given the small number of studies comparing EIB/EIA diagnostic tests, the 

heterogeneity of the study populations, and the varied study methodologies, there is no 

clear evidence that any of the index tests are a suitable replacement for a standardized 

ECT to diagnose EIB/EIA in the general population. 

All bronchodilator agents and most anti-inflammatory agents when used as pretreatment are somewhat effective in attenuating the percent fall FEV1 associated with 

EIA. There is evidence that the protective effect of LABA and SABA decreases with the 

daily use of these drugs. There is no evidence of an attenuating benefit following singledose pre-treatment with ICS. There is a role for LTRA and MCS; however, the 

attenuation appears less than with bronchodilator agents. Finally, pre-exercise interval 

warmup appears to be effective in attenuating the FEV1 falls associated with EIA. 

UPDATE: The following section was added on 3/15/2010: 

 On February 18, 2010 the Food and Drug Administration issued a drug safety 

communication requiring changes to use of Long-Acting Beta-Agonists (LABAs) in the 

treatment of asthma. These changes are based on FDA's analyses of studies showing an 

increased risk of severe exacerbation of asthma symptoms in some patients using LABAs 

for the treatment of asthma. The FDA cautioned that LABAs should only be used longterm in patients whose asthma cannot be adequately controlled on asthma controller 

medications and then, LABAs should be used only in combination with these other 

medications. 

 The Exercise-Induced Bronchoconstriction and Asthma (EIB/EIA) Evidence Report 

was conducted prior to the FDA warning and focused on studies that examined whether 

individuals using LABAs develop a tolerance (tachyphylaxis) to long term regular use of 

the drugs. The evidence suggests that the protective effect of LABA drugs decrease if 

they are used daily rather than “as needed” before exercising. These conclusions reflect a 

different focus than the FDA analysis; however, the conclusions for EIB/EIA do not 

conflict with the FDA concerns about daily use of LABAs. 

vi 
Contents 

Executive Summary.............................................................................................1 
 

Evidence Report................................................................................................21 
 

Chapter 1. Introduction ...................................................................................................................23 
 

What is Exercise-Induced Bronchoconstriction and Asthma?.........................................................23 
 

Magnitude and Importance of the Condition...................................................................................25 
 

Diagnosis of Exercise-Induced Bronchoconstriction and Asthma ..................................................26 
 

Treatment of Exercise-Induced Bronchoconstriction and Asthma..................................................27 
 

Objective of this Evidence Report ...................................................................................................27 
 

The Key Questions...........................................................................................................................28 
 

Chapter 2. Methods.........................................................................................................................29 
 

Literature Search and Retrieval .......................................................................................................29 
 

Study Selection ................................................................................................................................30 
 

Assessment of Methodological Quality...........................................................................................31 
 

Grading the Body of Evidence.........................................................................................................32 
 

Data Extraction ................................................................................................................................32 
 

Data Analysis...................................................................................................................................32 
 

Diagnostic Test Accuracy Review...................................................................................................33 
 

Therapy Review...............................................................................................................................33 
 

Peer Review .....................................................................................................................................33 
 

Chapter 3. Results ...........................................................................................................................35 
 

Diagnostic Test Accuracy Review...................................................................................................35 
 

Literature Search..............................................................................................................................35 
 

Key Question D–1: Self-Reported History or Symptoms Diary .....................................................37 
 

Description of Included Studies.......................................................................................................37 
 

Methodological Quality of the Included Studies .............................................................................37 
 

Quantitative Results.........................................................................................................................37 
 

Key Question D–2: Methacholine Challenge ..................................................................................40 
 

Description of Included Studies.......................................................................................................40 
 

Methodological Quality of Included Studies ...................................................................................40
 


Quantitative Results.........................................................................................................................40 
 

Key Question D–3: Sport or Venue Specific Exercise Challenges .................................................51 
 

Description of Included Studies.......................................................................................................51 
 

Methodological Quality of the Included Studies .............................................................................52 
 

Quantitative Results.........................................................................................................................52 
 

Key Question D–4: Eucapnic Voluntary Hyperpnea.......................................................................56 
 

Description of Included Studies.......................................................................................................56 
 

Methodological Quality of Included Studies ...................................................................................56
 


Quantitative Results.........................................................................................................................56 
 

Key Question D–5: Free Running Asthma Screening Test .............................................................63 
 

Description of Included Studies.......................................................................................................63 
 

vii 
Methodological Quality of the Included Studies .............................................................................63 
 

Quantitative Results.........................................................................................................................63 
 

Key Question D–6: Mannitol Challenge..........................................................................................67 
 

Description of Included Studies.......................................................................................................67 
 

Methodological Quality of Included Studies ...................................................................................67
 


Quantitative Results.........................................................................................................................67 
 

Therapy Review...............................................................................................................................72 
 

Literature Search..............................................................................................................................72 
 

Key Question T–1: Tachyphylaxis to Short-Acting or Long-Acting Beta-Agonists................. 74 
 

Description of Included Studies.......................................................................................................74 
 

Methodological Quality of Included Studies ...................................................................................74
 


Quantitative Results: SABA ............................................................................................................74 
 

Quantitative Results: LABA............................................................................................................76 
 

Key Question T–2: Leukotriene Receptor Antagonist Therapy ......................................................87 
 

Description of Included Studies.......................................................................................................87 
 

Methodological Quality of Included Studies ...................................................................................87
 


Quantitative Results.........................................................................................................................87 
 

Key Question T–3: Inhaled Corticosteroid Therapy........................................................................95 
 

Description of Included Studies.......................................................................................................95 
 

Methodological Quality of Included Studies ...................................................................................95
 


Quantitative Results.........................................................................................................................95 
 

Key Question T–4: Mast Cell Stabilizers ........................................................................................99 
 

Background......................................................................................................................................99 
 

NCS versus Placebo Review............................................................................................................99 
 

NCS versus SCG Review...............................................................................................................100 
 

MCS to Prevent EIA Review.........................................................................................................102 
 

Key Question T–5: Anticholinergic Agents ..................................................................................107 
 

Description of Included Studies.....................................................................................................107 
 

Methodological Quality of Included Studies .................................................................................107 
 

Quantitative Results.......................................................................................................................107 
 

Key Question T–6: Refractory Period (10 to 15 Minute Warmup and/or Cooldown) ..................118 
 

Description of Included Studies.....................................................................................................118 
 

Methodological Quality of Included Studies .................................................................................118 
 

Quantitative Results.......................................................................................................................118 
 

Chapter 4. Discussion ...................................................................................................................127 
 

Diagnostic Test Accuracy Review.................................................................................................127 
 

Limitations .....................................................................................................................................133 
 

Conclusions....................................................................................................................................133 
 

Therapy Review.............................................................................................................................135 
 

Pharmacologic Interventions .........................................................................................................137 
 

Bronchodialating Agents ...............................................................................................................137 
 

Anti-inflammatory Agents.............................................................................................................138 
 

Nonpharmacologic Interventions...................................................................................................140 
 

Limitations .....................................................................................................................................141 
 

Conclusions....................................................................................................................................142 
 

viii 
Reccomendations for Future Research ..........................................................................................143 
 

References and Included Studies ...................................................................................................145 
 

Abbreviations.................................................................................................................................152 
 

Tables 

Table 1. Summary of sensitivity and specificity for the diagnostic test accuracy review............ 20 
 

Table 2. Prophylactic therapy for EIA: Pulmonary function results ............................................ 21 
 

Table 3. Factors that may influence the severity of EIB/EIA....................................................... 24 
 

Table 4. Inclusion and exclusion criteria for the diagnostic test accuracy review ....................... 30 
 

Table 5. Inclusion and exclusion criteria for the therapy review.................................................. 31 
 

Table 6. Description of studies in the diagnostic test accuracy review: Self-report vs. ECT....... 38 
 

Table 7. Description of participants in the diagnostic test accuracy review: Self-report vs. 
 

ECT............................................................................................................................................... 38 
 

Table 8. Methodological quality of the studies in the diagnostic test accuracy review: 
 

Self-report vs. ECT ....................................................................................................................... 39 
 

Table 9. Description of studies in the diagnostic test accuracy review: Methacholine vs. ECT .. 44 
 

Table 10. Description of participants in the diagnostic test accuracy review: Methacholine vs. 
 

ECT............................................................................................................................................... 47 
 

Table 11. Methodological quality of studies in the diagnostic test accuracy review: 
 

Methacholine vs. ECT .................................................................................................................. 50 
 

Table 12. Description of studies in the diagnostic test accuracy review: Sport specific vs. 
 

ECT............................................................................................................................................... 53 
 

Table 13. Description of participants in the diagnostic test accuracy review: Sport specific vs. 
 

ECT............................................................................................................................................... 54 
 

Table 14. Methodological quality of studies in the diagnostic test accuracy review: Sport 
 

specific vs. ECT............................................................................................................................ 55 
 

Table 15. Description of studies in the diagnostic test accuracy review: Eucapnic voluntary 
 

hyperpnea vs. ECT........................................................................................................................ 59 
 

Table 16. Description of participants in the diagnostic test accuracy review: Eucapnic 
 

voluntary hyperpnea vs. ECT ....................................................................................................... 61 
 

Table 17. Methodological quality of studies in the diagnostic test accuracy review: Eucapnic 
 

voluntary hyperpnea vs. ECT ....................................................................................................... 62 
 

Table 18. Description of studies in the diagnostic test accuracy review: FRAST vs. ECT.......... 65 
 

Table 19. Description of participants in the diagnostic test accuracy review: FRAST vs. ECT .. 66 
 

Table 20. Methodological quality of studies in the diagnostic test accuracy review: FRAST 
 

vs. ECT ......................................................................................................................................... 66 
 

Table 21. Description of studies in the diagnostic test accuracy review: Mannitol vs. ECT ....... 69 
 

Table 22. Description of participants in the diagnostic test accuracy review: Mannitol vs. 
 

ECT............................................................................................................................................... 70 
 

Table 23. Methodological quality of studies in the diagnostic test accuracy review: Mannitol 
 

vs. ECT ......................................................................................................................................... 71 
 

Table 24a. Description of trials in the therapy review: Tachyphylaxis to LABA ........................ 81 
 

Table 24b. Description of trials in the therapy review: Tachyphylaxis to SABA ........................ 83 
 

ix 
 

 

Table 25a. Baseline characteristics of patients in trials in the therapy review: Tachyphylaxis 
 

to LABA........................................................................................................................................ 84 
 

Table 25b. Baseline characteristics of patients in trials in the therapy review: Tachyphylaxis 
 

to SABA........................................................................................................................................ 85 
 

Table 26. Quality assessment of trials in the therapy review: Tachyphylaxis to LABA and 
 

SABA............................................................................................................................................ 86 
 

Table 27. Description of trials in the therapy review: LTRA....................................................... 90 
 

Table 28. Baseline characteristics of patients in trials in the therapy review: LTRA .................. 93 
 

Table 29. Quality assessment of trials in the therapy review: LTRA........................................... 94 
 

Table 30. Description of trials in the therapy review: Inhaled corticosteroids............................. 97 
 

Table 31. Baseline characteristics of patients in trials in the therapy review: Inhaled 
 

corticosteroids............................................................................................................................... 98 
 

Table 32. Quality assessment of trials in the therapy review: Inhaled corticosteroids................. 98 
 

Table 33. Description of trials included in the Cochrane reviews of mast cell stabilizers......... 104 
 

Table 34. Baseline characteristics of patients in trials included in the Cochrane reviews of 
 

mast cell stabilizers..................................................................................................................... 106 
 

Table 35. Description of trials in the therapy review: Anticholinergic therapy ......................... 111 
 

Table 36. Baseline characteristics of patients in trials in the therapy review: Anticholinergic 
 

therapy......................................................................................................................................... 115 
 

Table 37. Quality assessment of trials in the therapy review: Anticholinergic therapy ............. 117 
 

Table 38. Description of trials in the therapy review: Refractory period ................................... 121 
 

Table 39. Baseline characteristics of patients in trials in the therapy review: Refractory 
 

period .......................................................................................................................................... 124 
 

Table 40. Quality assessment of trials in the therapy review: Refractory period....................... 125 
 

Table 41. Summary of sensitivity and specificity for the diagnostic test accuracy review........ 132 
 

Table 42. Prophylactic therapy for EIA: Pulmonary function results ........................................ 136 
 

Figures

Figure 1. Diagnosis of EIB/EIA: Flow diagram for study retrieval and selection ....................... 36 
 

Figure 2. Forest plot of sensitivity and specificity: Methacholine challenge vs. ECT 
 

(PC20 MCH less than 8 mg/ml; FEV1 fall index 10 percent or more for ECT) ............................ 41 
 

Figure 3. Forest plot of sensitivity and specificity: Methacholine challenge vs. ECT 
 

(PC20 MCH less than 16 mg/ml; FEV1 fall index 10 percent or more for ECT) .......................... 41 
 

Figure 4. ROC curve plotting sensitivity vs. specificity: Methacholine challenge vs. ECT 
 

(PC20 MCH less than 8 mg/ml; FEV1 fall index 10 percent or more for ECT) ............................ 42 
 

Figure 5. Forest plot of sensitivity and specificity: Methacholine challenge vs. ECT in studies 
 

in which all patients had asthma (PC20 MCH less than 8 mg/ml; FEV1 fall index 10 percent 
 

or more for ECT) .......................................................................................................................... 42 
 

Figure 6. Forest plot of sensitivity and specificity: Methacholine challenge vs. ECT in studies 
 

in which less than 50 percent of patients had asthma (PC20 MCH less than 8mg/ml; FEV1
 

fall index 10 percent or more for ECT) ........................................................................................ 43 
 

Figure 7. Forest plot of sensitivity and specificity: Sport specific challenges vs. ECT (FEV1
 

fall index 10 percent or more)....................................................................................................... 52 
 

Figure 8. Forest plot of sensitivity and specificity: Eucapnic voluntary hyperpnea vs. ECT 
 

(participants with no history of EIB/EIA; FEV1 fall index 10 percent or more for ECT and 
 

EVH)............................................................................................................................................. 57 
 

x 
Figure 9. Forest plot of sensitivity and specificity: Eucapnic voluntary hyperpnea vs. ECT 
 

(participants with a history of EIB/EIA; FEV1 fall index 10 percent or more for ECT and 
 

EVH)............................................................................................................................................. 57 
 

Figure 10. Forest plot of sensitivity and specificity: Eucapnic voluntary hyperpnea vs. ECT 
 

(all participants; threshold for a positive test is a FEV1 fall index 10 percent or more for ECT 
 

and 15 percent or more for EVH) ................................................................................................. 58 
 

Figure 11. Forest plot of sensitivity and specificity: FRAST vs. ECT (FEV1 fall index ≥10%).. 64 
 

Figure 12. Forest plot of sensitivity and specificity: Mannitol vs. ECT (FEV1 fall index ≥10% 
 

for ECT and ≥15% for mannitol).................................................................................................. 68 
 

Figure 13. Therapy for EIB/EIA: Flow diagram for study retrieval and selection....................... 73 
 

Figure 14. Effectiveness of LABA vs. placebo: Change from day 1 to week 3–4 weeks after 
 

the first ECT (MD in the maximum percent fall FEV1) ............................................................... 77 
 

Figure 15. Effects over time of LABA and placebo on the maximum percent fall in FEV1 for 
 

the first ECT.................................................................................................................................. 78 
 

Figure 16. Effectiveness of LABA vs. placebo: Change from day 1 after the second ECT (MD 
 

in the maximum percent fall FEV1).............................................................................................. 79 
 

Figure 17. Effectiveness of LABA vs. LTRA: Change from day 1 to week 8 (MD in the 
 

maximum percent fall FEV1)........................................................................................................ 80 
 

Figure 18. LTRA vs. placebo in pre-exercise treatment of EIB/EIA: Maximum decrease in 
 

FEV1.............................................................................................................................................. 88 
 

Figure 19. LTRA vs. placebo in pre-exercise treatment of EIB/EIA: Achievement of 
 

complete protection (maximum percent fall FEV1 is less than 10 percent) ................................. 89 
 

Figure 20. Inhaled corticosteroids vs. placebo in pre-exercise treatment of EIA: MD in 
 

maximum percent fall in FEV1 or peak expiratory flow............................................................... 96 
 

Figure 21. Ipratropium vs. placebo in pre-exercise treatment of EIA: Mean difference in 
 

maximum percent fall in FEV1 or peak expiratory flow............................................................. 108 
 

Figure 22. Atropine vs. placebo in pre-exercise treatment of EIA: Mean difference in 
 

maximum percent fall in FEV1 or peak expiratory flow............................................................. 108 
 

Figure 23. Oxitropium vs. placebo in pre-exercise treatment of EIA: Mean difference in
 

maximum percent fall in FEV1 or peak expiratory flow............................................................. 108 
 

Figure 24. Ipratropium vs. placebo in pre-exercise treatment of EIA: Achievement of 
 

complete protection (maximum fall FEV1 less than 10 percent)................................................ 109 
 

Figure 25. Oxitropium bromide vs. placebo in pre-exercise treatment of EIA: Achievement 
 

of complete protection (maximum fall FEV1 is less than 10 percent)........................................ 109 
 

Figure 26. Ipratropium vs. placebo in pre-exercise treatment of EIA: Achievement of clinical 
 

protection (50 percent or greater improvement over placebo in FEV1)...................................... 110 
 

Figure 27. Warmup vs. no warmup in pre-exercise treatment of EIB/EIA: maximum percent 
 

decrease in FEV1 or peak expiratory flow .................................................................................. 120 
 

Figure 28. Mean difference in the maximum percent decrease in FEV1 following ECT with 
 

prophylactic therapy relative to placebo..................................................................................... 140 
 

xi 
 

Appendixes 

Appendix A. Technical Expert Panel and Peer Reviewers 

Appendix B. Literature Search Strings 

Appendix C. Forms 

Appendix D. Excluded Studies 

Appendix E. Studies Investigating Mast Cell Stabilizing Agents 

Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/eibeia/eibeia.pdf 

xii 
 

 

Executive Summary 

Introduction 

Vigorous physical exercise can be followed by transient clinical signs and symptoms similar 

to an asthma attack and are due to post-exercise bronchoconstriction (i.e., a narrowing of the 

airways). Clinical symptoms include coughing, wheezing, shortness of breath, excessive mucus 

production, chest tightness, chest pain, or an ‘itching or scratching sensation’ in the chest. 

Though it is more common in people with asthma, it also occurs in people without asthma. 

For the purposes of this evidence report, we defined exercise-induced bronchoconstriction 

(EIB) as “the airway obstruction that occurs in association with exercise without regard to the 

presence of chronic asthma”1 and we defined exercise-induced asthma (EIA) as “the condition in 

which exercise induces symptoms of asthma in patients who have asthma.”1 Research is ongoing 

to determine if the pathogenesis of the phenomenon is the same in non-asthmatics and 

asthmatics. In this report EIB and EIA were analyzed and discussed separately when the 

populations and data were specifically identified by authors of the primary studies as one or the 

other. When it was not clear or studies included patients with and without asthma, we referred to 

them as EIB/EIA. 

The acute bronchoconstriction associated with EIB/EIA peaks rapidly, 3 to 15 minutes after 

exercise stops, then remits spontaneously within 20 to 60 minutes.2

 It does not cause a persistent 

deterioration in lung function. Following recovery, a refractory period of 40 minutes to 3 hours 

has been reported. During this time repeat exercise causes less bronchoconstriction.3 

Two of the most common pulmonary function measures used to quantify the degree of 

bronchoconstriction are the forced expiratory volume in 1 second (FEV1) and the peak expiratory 

flow (PEF), with FEV1 considered the more reliable and valid. Both measures will decrease from 

baseline pre-exercise values in susceptible individuals. It is proposed that the increase in minute 

ventilation caused by vigorous exercise triggers the airway narrowing.3,4 Some episodes are 

severe enough that the person will require an inhaled bronchodilator agent to reverse the 

bronchoconstriction. 

Approximately 20.5 million people in the United States (7 percent) have asthma.5 Between 

60 and 90 percent of people with asthma experience EIA and consider exercise a major trigger of 

asthma symptoms.6,7 Prevalence of EIB is lower (6 to 13 percent) in populations with no history 

of asthma or allergy.8,9 Among elite athletes the prevalence is reported to range from 10 to 50 

percent.7 

The signs and symptoms of EIB/EIA often go unrecognized or are blamed on lack of 

conditioning. Some people will avoid exercise and some parents, teachers, and coaches of 

children with asthma may impose restrictions on which activities will be allowed.10 With a 

proper diagnosis and treatment, children and adults have successfully competed at all levels of 

physical activity. 

Key Questions 

The objective of this report was to synthesize the evidence for six key questions on 

diagnostic test accuracy for EIB/EIA and six key questions on therapy for EIB/EIA (five 

involving pharmaceutical interventions and one on a nonpharmacologic intervention). 

1
 

D–1. In patients with suspected EIB/EIA, what are the diagnostic test characteristics of a selfreported history/symptoms diary for diagnosing EIB/EIA compared with a standardized 

exercise challenge? 

D–2. In patients with suspected EIB/EIA, what are the diagnostic test characteristics of a 

methacholine challenge (MCH) for diagnosing EIB/EIA compared with a standardized 

exercise challenge? 

D–3. In patients with suspected EIB/EIA, what are the diagnostic test characteristics of 

sport/venue specific exercise challenges for diagnosing EIB/EIA compared with a 

standardized exercise challenge? 

D–4. In patients with suspected EIB/EIA, what are the diagnostic test characteristics of eucapnic 

voluntary hyperpnea (EVH) for diagnosing EIB/EIA compared with a standardized exercise 

challenge? 

D–5. In patients with suspected EIB/EIA, what are the diagnostic test characteristics of a free 

running asthma screening test (FRAST) for diagnosing EIB/EIA compared with a 

standardized exercise challenge? 

D–6. In patients with suspected EIB/EIA, what are the diagnostic test characteristics of mannitol 

for diagnosing EIB/EIA compared with a standardized exercise challenge? 

T–1. In patients with confirmed EIB/EIA, do patients using short- or long-acting beta-agonists 

(SABA or LABA) therapy develop tachyphylaxis to treatment and, if so, at what frequency, 

compared with standard comparator treatments and/or placebo? 

T–2. In patients with confirmed EIB/EIA, does pre-exercise treatment with leukotriene receptor 

antagonist therapy (LTRA) reduce symptoms and prevent a 10 percent or more drop in 

FEV1 compared with no treatment/placebo? 

T–3. In patients with confirmed EIB/EIA, does pre-exercise treatment with inhaled corticosteroid 

therapy (ICS) reduce symptoms and prevent a 10 percent or more drop in FEV1 compared 

with no treatment/placebo? 

T–4. In patients with confirmed EIB/EIA, does pre-exercise treatment with mast cell stabilizers 

(sodium cromoglycate or nedocromil; MCS) therapy reduce symptoms and prevent a 10 

percent or more drop in FEV1 compared with no treatment/placebo? 

T–5. In patients with confirmed EIB/EIA, does pre-exercise treatment with anticholinergic 

therapy (SAAC) reduce symptoms and prevent a 10 percent or more drop in FEV1 

compared with no treatment/placebo? 

T–6. In patients with confirmed EIB/EIA, does a refractory period (10 to 15 minute warmup 

and/or cooldown) reduce symptoms and prevent a 10 percent or more drop in FEV1 

compared with no treatment/placebo? 

Methods 

For questions involving diagnostic test accuracy, we searched MEDLINE®, EMBASE, EBM 

Reviews - Cochrane Central Register of Controlled Trials, AMED, PsycINFO, PASCAL, 

CINAHL®, SPORTDiscus with Full Text, Academic Search Elite, Web of Science®, BIOSIS 

Previews®, PubMed, Scopus®, the Medion Database of Diagnostic Reviews - University of 

Maastricht, and Proquest Dissertations and Theses. For questions involving EIB/EIA therapy we 

searched the Cochrane Airways Register. This Register contains references to randomized 

controlled trials (RCTs) from the Cochrane Central Register of Controlled Trials, MEDLINE®, 

EMBASE, CINAHL®, AMED, PsycINFO, as well as results from handsearches of respiratory 

2
 

 

journals and meeting abstracts. For all questions, we handsearched conference proceedings from 

key scientific meetings and reference lists of included studies. 

Two reviewers independently screened the search results (titles and abstracts) to determine if 

an article met broad inclusion criteria. The full-text of potentially relevant articles was retrieved 

and two reviewers independently assessed each study using a standard inclusion/exclusion form. 

Disagreements were resolved by discussion or through third party adjudication, as needed. 

Two reviewers independently assessed the methodological quality of individual diagnostic 

test accuracy studies using the Quality Assessment of Studies of Diagnostic Accuracy 

(QUADAS) tool11 and the methodological quality of RCTs in the therapy reviews using the 

Jadad12 scale and Schulz’s criteria to assess allocation concealment.13,14 

Two reviewers also independently assessed the strength of evidence for each key question. 

For the diagnostic test reviews, we used the GRADE system for rating the quality of evidence 

and strength of recommendations for diagnostic tests.15 We assessed the strength of the study 

designs, the quantity and quality of individual studies, the indirectness of evidence, and the 

consistency and precision of the results. For all studies, the outcomes were measures of test 

accuracy (i.e., true positive, true negative, false positive, false negative), which are surrogates for 

patient-important outcomes. For each key question the quality of evidence was graded as high, 

moderate, low or very low. For therapy reviews, the strength of evidence for the primary 

outcome (maximum percent fall in FEV1) was assessed using the EPC approach to grading the 

strength of a body of evidence.16 A grade of high, moderate, low, or insufficient was based on 

four domains: risk of bias, consistency, directness, and precision. Disagreements were resolved 

by discussion or through third party adjudication, as needed. 

Data analysis 

The primary outcome used to determine the presence or absence of EIB/EIA was the 

maximum percent fall in FEV1 post-exercise challenge calculated using the following formula: 

FEV1 / PEFpre−exercise − minimum FEV1 / PEFpost −exercise ×100

FEV1 / PEFpre−exercise 

The peak expiratory flow (PEF) was used if that was the only pulmonary function measure 

reported. In the case of missing data, some assumptions and imputations were necessary to 

transform reported data into the form required for analysis. Data from graphs were extracted 

using CorelDRAW® 9.0 (Corel Corp., Ottawa, Canada). Means were approximated by medians, 

and 95 percent empirical intervals were used to calculate approximate standard deviations. In the 

therapy reviews the majority of studies used a crossover design, therefore, standard errors of 

mean differences were either computed exactly using individual patient data, or imputed using an 

estimated within-patient correlation of 0.5. Meta-analyses were conducted using the random 

effects model where appropriate. The I2 statistic was used to assess heterogeneity.17 Planned 

subgroup analyses included age (children [less than 18 years old] versus adult [18 years and 

older]), severity of EIB/EIA as defined by the percent fall index on placebo (mild [less than 30 

percent] versus moderate-severe [30 percent or more]), and patients with EIB versus EIA. All 

data pooling was performed using Review Manager 5.0 (The Cochrane Collaboration, 

Copenhagen, Denmark). 

3
 

 

 

 

Therapy reviews 

For each study the maximum percent fall in FEV1 on the placebo ECT was subtracted from 

the maximum percent fall on the treatment ECT to obtain the difference. For each comparison a 

mean difference (MD) and 95 percent confidence interval (CI) were calculated using all included 

studies weighted according to sample size. There were two secondary outcomes of interest: (1) 

the proportion of people who received complete protection from EIB/EIA with treatment 

compared with placebo, for which a risk ratio (RR) and 95percent CI were calculated; and (2) the 

degree of protection received over placebo, known as the “clinical protection index,” which was 

calculated using the following formula: 

maximum % fall FEV 1(placebo) − maximum % fall FEV1(treatment) ×100 

maximum % fall FEV1(placebo) 

Results – Diagnostic Test Accuracy Review 

In addition to a history of symptoms suggesting EIB/EIA following exercise, objective 

diagnostic testing is necessary to confirm a diagnosis. A fall in the FEV1 of 10 percent or more 

after a challenge test is the recommended diagnostic threshold to objectively diagnose 

EIB/EIA.18 Testing can be done using either direct or indirect methods. Currently, there is no 

universally accepted gold standard test to confirm a diagnosis of EIB or EIA. In the absence of a 

gold standard, a standardized exercise challenge test (ECT) on a treadmill or bicycle ergometer 

conducted according to the American Thoracic Society guidelines18 is the best defined reference 

standard that is available and was used as the reference test in this report. The index tests that 

were assessed included a self reported history/symptoms diary, one direct challenge, and four 

indirect challenge tests. Methacholine (MCH) is considered a direct challenge as it acts directly 

on smooth muscle receptors to cause constriction independent of airway inflammation.19 The 

indirect challenges included two alternative exercise protocols (sport/venue-specific and free 

running asthma screening test [FRAST]), eucapnic voluntary hyperpnea (EVH), and inhaled 

mannitol. The indirect challenges are thought to cause inflammatory cells to release mediators 

such as leukotrienes, prostaglandin, and histamine which provoke smooth muscle constriction.20 

Sensitivity and specificity are two measures of diagnostic test characteristics. Sensitivity is 

the probability of testing positive if EIB/EIA is really present. Specificity is the probability of 

testing negative if EIB/EIA is truly absent. As the sensitivity of the test under investigation 

(index test) increases, the number of persons with EIB/EIA who are missed (false negatives) will 

decrease. As the specificity of the index test increases, the number of persons without EIB/EIA 

who are incorrectly classified (false positives) will decrease. To avoid the risk of spectrum bias, 

diagnostic test accuracy studies should include a broad spectrum of participants who range from 

high to low likelihood of EIB/EIA. 

Twenty-eight studies met the inclusion criteria for the questions relating to diagnostic test 

accuracy: self-reported history/symptoms diary21,22 (n=2), MCH23-37 (n=15), sport or venue 

specific challenges34,38-41 (n=5), EVH34,38,39,42-45 (n=7), FRAST36,40,46 (n=3), and mannitol23,47 

(n=2). 

Table 1 and the following summaries provide an overview of the results of the diagnostic test 

accuracy review. Sensitivity and specificity are reported for individual studies but data were not 

pooled due to substantial heterogeneity. 

4
 
 

 

Key Question D–1. Self-Reported History or Symptoms Diary 

Many people with potential EIB/EIA present with complaints of symptoms such as shortness 

of breath, cough, wheeze, and chest pain, associated with exercise18 and these symptoms have 

been used to diagnose EIB/EIA. There is a concern that self-report alone leads to an 

unacceptably high rate of false positive and false negative decisions.4 

Results. Two studies21,22 met the inclusion criteria for the diagnostic test accuracy of selfreported history/symptoms diary compared with a standardized ECT. 

Frobase et al.21 matched 20 teenage athletes who answered “yes” to the question “do you 

experience cough after exercise” to 20 who responded “no.” All participants performed a 

treadmill ECT. The authors used a fall in FEV1 of 10 percent or more to define a positive ECT. 

They reported a sensitivity of 89 percent (95 percent CI: 67, 99); a specificity of 86 percent (95 

percent CI: 64, 97). 

Rupp et al.,22 gave 166 teenage athletes a questionnaire with two questions relevant to 

EIB/EIA (“Do you have trouble breathing after running 1 mile and resting?” “Do you have to 

stop when running for 1⁄2 mile?”). Twenty-nine percent were identified as being at risk of 

EIB/EIA. All took a treadmill ECT. At a threshold of 15 percent or more, the authors reported a 

sensitivity of 36 percent (95 percent CI: 17, 59); a specificity of 85 percent (95 percent CI: 78, 

90). 

Methodological quality. Neither study included a representative spectrum of participants or 

defined their selection criteria and neither study blinded assessors to the results of the other 

challenge. It is unclear whether the ECTs met the ATS guideline recommendations.18 

Furthermore, the number of “unclear” responses for both studies using the QUADAS tool raises 

questions regarding bias and generalizability. 

Discussion. Despite extensive searching, only two studies addressed this question. The 

results of one study21 suggest that exercise-induced cough may be a predictor of EIB/EIA. Selfreported history and symptoms may be a starting point for further investigations but on their own 

are not sufficient to confirm a diagnosis of EIB/EIA. 

Conclusion: There is insufficient evidence to conclude that self-report of symptoms is a 

reliable diagnostic tool for EIB/EIA. The quality of evidence is classified as “very low.” The 

initial grade based on study design was low and there are serious limitations related to study 

quality. The diagnostic thresholds differed and the sensitivity estimates are inconsistent and 

imprecise. 

Key Question D–2. Methacholine Challenge 

MCH is considered a direct challenge. Once inhaled into the lungs, it acts on smooth muscle 

acetylcholine receptors causing contraction and airway narrowing.23 It has been noted that 

airway responsiveness to pharmacological agents such as MCH is different from hyperresponsiveness to osmotic agents or to hyper-responsiveness following exercise.18 

The threshold for a positive ECT was a maximum fall in FEV1 of 10 percent or more from a 

pre-exercise baseline.18 The threshold for a positive MCH challenge was a fall in FEV1 of 20 

percent or more at a provocative concentration of less than 8 mg/ml (PC20).18 We also looked at a 

threshold PC20 of less than 16 mg/ml. 

Results. Fifteen studies23-37 met the inclusion criteria for the diagnostic test accuracy review 

of a MCH challenge compared with a standardized ECT. The number of participants ranged 

5
 

 

from 12 to 375. Considerable heterogeneity was observed across the studies. Overall, 331 

participants (57 percent) had a positive ECT and 416 (71 percent) had a positive MCH at the 8 

mg/ml threshold. Both sensitivity and specificity ranged from 0 to 100 percent. Using the 16 

mg/ml threshold, 420 participants (53 percent) had a positive ECT and 498 (63 percent) had a 

positive MCH. Sensitivity ranged from 55 to 100 percent and specificity 0 to 100 percent. To 

explore heterogeneity, we conducted a post hoc subgroup analysis on studies where all 

participants had mild to moderate stable asthma24-26,28,29,32,33,35,36 and studies27,30,34,37 that reported 

fewer than 50 percent of participants had confirmed asthma. The heterogeneity was reduced 

somewhat. Among studies in which all participants had asthma, the sensitivity ranged from 66 to 

100, specificity 0 to 100 percent; in 4 studies reporting fewer than 50 percent had asthma 

sensitivity ranged from 0 to 50 percent and specificity 42 to 84 percent. 

There was no reduction in heterogeneity when we explored the effects of age (child versus 

adult), MCH method (5 breath dosimeter versus 2 minute tidal breathing), or ECT parameters 

(air temperature and humidity, or treadmill versus bicycle ergometer). 

Methodological quality. There are several methodological issues in this group of studies. Of 

concern is the risk of spectrum bias. Most studies did not report how participants were recruited 

into the study, nor did they describe the inclusion criteria; three studies recruited 

volunteers.26,30,34 Blinding of the ECT results to the results of the MCH challenge was not 

reported. It is unclear whether eight of the ECTs met the ATS guideline recommendations.18 

Discussion. Across these 15 studies, there was considerable heterogeneity in estimates for 

sensitivity and specificity although sensitivity estimates varied less when examining patients 

with a confirmed diagnosis of asthma. Unlike ECTs, a positive airway response to MCH does 

not imply the presence of inflammatory cells or their mediators that are known to be present in 

EIB/EIA;20 therefore, it is not surprising that MCH shows variable sensitivity and specificity to 

detect EIB/EIA. It has been suggested18 that a positive MCH test should not be used to infer 

EIB/EIA and likewise, a negative MCH should not be used to exclude EIB/EIA. 

Conclusion. Based on the available evidence we cannot conclude that the MCH challenge is 

a reliable test to diagnose EIB/EIA in those with confirmed asthma or in populations with mixed 

asthma prevalence. The quality of evidence is classified as “moderate.” The initial grading based 

on study design was high; however, there are serious limitations to quality of individual studies. 

Sensitivity estimates are reasonably consistent but are imprecise in the participants with EIA. 

Specificity estimates are inconsistent and imprecise. 

Key Question D–3. Sport or Venue Specific Exercise Challenge 

Sport/venue specific challenges are advantageous in that the athlete can exercise in the 

conditions where they become symptomatic and the tests are reasonably inexpensive. In 

comparing sport/venue specific challenges with an ECT, coordinating the timing of the two tests 

and ensuring good quality control on the sport challenges can be problematic. The environmental 

conditions, level of intensity, and increase in minute ventilation reached during both challenges 

may be hard to match. 

The threshold for a positive ECT or a sport specific challenge was a maximum fall in FEV1 

of 10 percent or more from a pre-exercise baseline.18 

Results. Five studies34,38-41 met inclusion criteria for the diagnostic test accuracy review of 

sport or venue specific exercise challenges compared with a standardized ECT. Three focused on 

swimming challenges34,38,40 and two assessed cold weather sport challenges.39,41 Rundell et al.41 

6
 

 

 

only included athletes who tested positive on a sport specific challenge. The sensitivity of the 

swimming challenge tests ranged from 0 to 50 percent; specificity from 83 to 100 percent. In 

total 11 (19 percent) participants were positive on the ECT and 5 (9 percent) were positive on the 

swim challenge. In the two studies involving winter athletes, Dickensen et al.39 had no true 

positives but a specificity of 79 percent, and Rundell et al.41 sensitivity of 100 percent but had no 

true negatives and a specificity of 0 percent. 

Methodological quality. In these five studies there are some methodological weaknesses. 

None of the studies had a representative patient spectrum which suggests the possibility of 

spectrum bias. Blinding of ECT results to the results of the index test was not reported. It is 

unclear whether two of the ECTs met the ATS guideline recommendations.18 

Discussion. These studies compared challenges in the specific sport the athletes practiced 

(e.g., biathlon) or at the venue of activity (e.g., skating arena, swimming pool) to a laboratory 

ECT. The estimates of sensitivity and specificity both, ranged from 0 to 100 percent. Sport 

specific challenges are one of the recommended challenges for diagnosing EIB/EIA in elite 

athletes;34 however, in total only seven athletes were positive in their own field of competition 

while 16 were positive on a standardized ECT. It is not clear why this occurred, although it is 

possible that the level of minute ventilation and differences in environmental conditions played a 

role. 

Conclusion. Sport specific challenges may be useful in identifying athletes who do not have 

EIB/EIA but other testing such as a standardized ECT may also be required. The quality of 

evidence is classified as “low.” The initial grading based on study design was high; however, 

there are serious limitations related to study quality. The sensitivity estimates are inconsistent 

and imprecise. Specificity estimates are also inconsistent and imprecise. 

Key Question D–4. Eucapnic Voluntary Hyperpnea 

Eucapnic voluntary hyperpnea (EVH) is a test based on the premise that the increased 

minute ventilation with exercise is responsible for bronchoconstriction in susceptible subjects.48 

The EVH challenge requires the person to increase their minute ventilation up to 80-85 percent 

of the maximum minute ventilation for 5-6 minutes, which approximates the minute ventilation 

obtained during vigorous exercise. EVH was developed as a surrogate for exercise to identify 

EIB49 and currently, it is the challenge recommended by the International Olympic Committee 

Medical Commission to identify EIB/EIA among Olympic athletes.19 

The threshold for a positive ECT or EVH challenge was a maximum fall in FEV1 of 10 

percent or more from a pre-exercise baseline.18 

Results. Seven studies34,38,39,42-45 met inclusion criteria for the diagnostic test accuracy 

review of EVH compared with a standardized ECT. The number of participants ranged from 10 

to 33. Substantial heterogeneity was identified. Forty-two (30 percent) participants had a positive 

ECT and 74 (54 percent) had a positive EVH. Sensitivity estimates ranged from 25 to 90 percent 

and specificity from 0 to 71. A post hoc subgroup analysis of studies in which participants did 

not have known EIB/EIA34,38,39,42 explained some of the heterogeneity. In this population, the 

sensitivity ranged from 25 to 75 percent and specificity from 29 to 71 percent. Among studies in 

which all participants had EIB/EIA,42-45 the sensitivity of EVH was high, ranging from 71 to 90 

percent; however, one study had no true positive cases

42 and three had no true negative cases. 

Methodological quality. As a group, there are methodological weaknesses that limit the 

interpretation and generalizability of the results. Of greatest concern is the risk of spectrum bias 

7
 

in all studies. Either the participants recruited into the studies were volunteers,34,38,39,42,44 or the 

recruitment source and methods were not reported.43,45 In some studies all participants had a 

history of EIB/EIA43-45 and therefore are not representative of the spectrum of patients who 

might be tested for EIB/EIA. Blinding of the ECT results to the results of the EVH challenge was 

not reported. It is unclear whether the ECTs met the ATS guideline recommendations.18 

Discussion. Overall, both the sensitivity and specificity of EVH compared to an ECT 

showed substantial heterogeneity and no trend was observed. It is unclear whether an EVH 

challenge is identifying the same people that experience a fall in FEV1 of 10 percent or more on 

an ECT, particularly in a population of athletes with an unclear history of asthma. The EVH 

challenge resulted in a higher proportion of false positives (FP) (i.e., negative on the ECT but 

positive on EVH) among participants with no or unknown history of EIB/EIA. The proportion of 

FP ranged from 25 to 71 percent. The participants included both elite athletes (n=63) and those 

with unknown activity levels (n=20). Based on the available evidence, it is unclear if the EVH 

challenge is more sensitive to EIB/EIA, or if the mechanism that triggers the bronchoconstriction 

is different from that for the ECT, or if level of minute ventilation achieved on an ECT according 

to ATS recommendations is less than the level achieved in an EVH challenge particularly in 

athletes. Among participants with a history of EIB/EIA, the proportion of FPs ranged from 0 to 5 

percent in participants with unknown activity levels. Among athletes, the proportion with a FP 

result was 27 percent. Further research is needed to determine if the EVH challenge would be an 

appropriate add-on test to an ECT in athletes with symptoms of EIB/EIA. 

Conclusion. Based on the available data, we cannot conclude that an EVH challenge is a 

reliable diagnostic test for EIB/EIA. The quality of evidence is classified as “low.” The initial 

grading based on study design was high; however, there are serious limitations related to study 

quality. Furthermore, the sensitivity and specificity estimates are inconsistent and imprecise. 

Key Question D–5. Free Running Asthma Screening Test (FRAST) 

Free running has often been used in screening large groups for EIB/EIA because the test is 

relatively easy to perform, requires limited equipment, and multiple subjects can be tested at the 

same time.48 The threshold for a positive ECT or FRAST was a maximum fall in FEV1 of 10 

percent or more from a pre-exercise baseline.18 

Results. Three studies36,40,46 met inclusion criteria for the diagnostic test accuracy review of 

FRAST compared with a standardized ECT. Participants were children under 15 years, and all 

free running tests took place indoors. In two studies36,40 the threshold for a positive FRAST was 

a fall in FEV1 of 10 percent or more. In these 34 participants, 13 (38 percent) had a positive ECT 

and 18 (41 percent) had a positive FRAST. The sensitivities were 60 and 67 percent; specificities 

were 47 and 67 percent. The remaining study46 used a threshold of a fall in FEV1 of 16.5 percent 

or more for the FRAST and 20 percent or more for the ECT. Based on these thresholds the 

sensitivity was 53 percent (95 percent CI: 34, 72); specificity was 100 percent (94 percent CI: 88, 

100). 

Methodological quality. Overall, there were concerns about the methodological quality of 

the studies. Generalizing the results to a target population of people with suspected EIB/EIA may 

be limited as none of the studies had representative spectrum of participants. Blinding of results 

of the ECT to the results of the FRAST was not reported. It is unclear whether two of the ECTs 

met the ATS guideline recommendations.18 

8
 

Discussion. Sensitivity and specificity of FRAST were modest (60 to 67 percent and 47 to 67 

percent, respectively). While the FRAST may be easy to perform, there is insufficient evidence 

to conclude that it accurately identifies people with EIB/EIA compared with a standardized ECT. 

Furthermore, in a FRAST challenge there is an overall lack of control in terms of exercise 

intensity and therefore stimulus (i.e., minute ventilation). 

Conclusion. There is insufficient evidence to conclude that FRAST is a reliable diagnostic 

test for EIB/EIA. The quality of evidence is classified as “very low.” The initial grading based on 

study design was moderate; however, there are serious limitations related to study quality. The 

sensitivity and specificity estimates are consistent but imprecise. 

Key Questions D–6. Mannitol Challenge 

Recently, a mannitol provocation test has been developed to examine airway hyperresponsiveness. Like exercise, mannitol is thought to cause airway narrowing indirectly through 

increasing the osmolarity of the airway surface, leading to the release of endogenous mediators 

such as prostaglandin, leukotrienes and histamine, and resulting in smooth muscle 

contraction.50,51 Mannitol has the advantage that it can be performed with minimal equipment 

(i.e., a metered-dose inhaler and spirometer). 

The threshold for a positive ECT was a maximum fall in FEV1 of 10 percent or more. The 

threshold for a positive mannitol challenge was a 15 percent drop in FEV1 at less than 635mg or 

a drop of 10 percent between consecutive doses.23 

Results. Three studies23,47,52 met the inclusion criteria for the diagnostic test accuracy review 

of mannitol compared with a standardized ECT. All participants in Brannan et al.47 and Kersten 

et al.52 had diagnosed asthma. In these 58 participants, 39 (67 percent) had a positive ECT test, 

35 (67 percent) had a positive mannitol challenge. The sensitivity was 69 and 96 percent, 

respectively. Specificity was 78 percent in the Kersten et al.52 study. Anderson et al.23 included 

those with suspected but not confirmed asthma and reported a sensitivity of 58 percent (95 

percent CI: 50, 66) and a specificity of 65 percent (95 percent CI: 58, 72). 

Methodological quality. Concern regarding the risk of spectrum bias in the studies by 

Brannan et al.47 and Kersten et al. limits the conclusions that can be drawn.52 Participants were 

volunteers who had a history of EIA and are not representative of the spectrum of patients who 

might be tested for EIB/EIA. Blinding of the results of the ECT and the index test was not 

reported. All three of the ECTs met the ATS guideline recommendations.18 

Discussion. Both mannitol and ECT are considered indirect tests, acting through a similar 

mechanism of increasing osmolarity of the airway surface. The advantage of mannitol is that 

exercise is not a requirement, and the test can be conducted in a physician’s office with minimal 

equipment. Among adults and children with a history of EIA or suspected asthma, the diagnostic 

test characteristics for mannitol compared to an ECT hold promise. Its role as a screening or 

diagnostic tool requires further study. 

Conclusion. Based on these data, it is difficult to conclude that the mannitol provocation test 

is a reliable diagnostic test for EIB/EIA. The quality of evidence is classified as “moderate.” The 

initial grading based on study design was high; however, there are concerns regarding the 

limitations related to study quality. The sensitivity and specificity estimates are reasonably 

consistent but are imprecise. 

9
 
Results – Therapy Reviews 
 

The primary objective of therapy is to prevent EIB/EIA from occurring or, short of that, to at 

least attenuate the degree of bronchoconstriction. Pharmacologic effect is assessed by taking a 

single dose of an inhaled agent prior to an ECT that meets intensity and ventilation standards. 

FEV1 or PEF is measured immediately following the challenge and at 5 minute intervals until 

lung function begins to improve. The maximum fall in FEV1 is expressed as a percent of the 

baseline measure taken immediately prior to the ECT. The greater the percent fall, the worse the 

EIB/EIA or, conversely, the less the percent fall the more effective the therapy. This report 

conducted systematic reviews of randomized controlled trials (RCTs) involving four categories 

of prophylactic agents compared with a placebo: inhaled corticosteroids (ICS), leukotriene 

receptor antagonists (LTRA), mast-cell stabilizers (MCS), and short-acting anticholinergics 

(SAAC). We conducted two additional reviews. The first was to determine if using short- or 

long-acting beta agonists (SABA or LABA) on a daily basis caused people to develop a 

tolerance, or tachyphylaxis, to these agents thus reducing the prophylactic effect on EIB/EIA. If 

the post-exercise drop in FEV1 increases after prolonged use of SABA or LABA, it is an 

indication of tachyphylaxis. The second review investigated whether engaging in a specific 

warmup routine prior to an ECT caused a refractory period during which time the EIB/EIA 

response was prevented or attenuated on a subsequent ECT. 

The primary outcome for these six reviews was the mean difference (MD) between the mean 

maximum percent fall in FEV1 on drug or warmup and the mean maximum percent fall in FEV1 

with placebo or no warmup. In this executive summary, we report the absolute MD in order to 

phrase the results using positive numbers. In the forest plots in the main report, a negative MD 

that falls to the left of the null line indicates the drug performed better than the placebo and, by 

extension, a larger difference indicates a greater drug effect. The 95 percent CIs relate to whether 

or not the result represents a statistically significant improvement. 

Overall, 109 studies were included in the therapy reviews. The included studies addressed the 

following research questions: tachyphylaxis to SABA and LABA53-63 (n=11), LTRA44,64-71 (n=9), 

ICS72-75 (n=4), MCS (n=3 Cochrane reviews and publications76-78), SAAC79-96 (n=18), and a 

refractory period97-103 (n=7). 

Table 2 and the following summaries provide an overview of the results. The 

pharmacological treatments were further divided into bronchodilating and anti-inflammatory 

agents. 

Pharmacological Interventions: Bronchodilating Agents 

T–1. Tachyphylaxis to SABA or LABA Therapy 

β2-Receptors on the airway smooth muscle are responsible for bronchodilation; beta-agonist 

agents attach to these receptors and are effective bronchodilators and improve breathing. SABA 

agents have been the mainstay of EIB/EIA treatment for many years. With the development and 

availability of LABA agents, more research has been applied to the effectiveness of these agents 

in preventing EIB/EIA. It has been reported in the literature that some people develop a tolerance 

10
 

 

(tachyphylaxis) to long term regular use of beta-agonist drugs and they lose some of their 

effectiveness and protective effect.57,59 

Seven studies met inclusion criteria to address the question of whether people with EIB/EIA 

develop tachyphylaxis to LABA agents53-61 and two met the inclusion criteria for SABA 

agents.62,63 Overall, the quality of the trials was high. All were randomized, double-blind trials 

that described the withdrawals and dropouts. Five described an adequate process to ensure 

double-blinding. 

SABA. Data from the two SABA crossover studies could not be combined and are therefore 

described individually. Both studies involved asthmatics who took 1 week of regular (four times 

per day) SABA or placebo prior to exercise challenges and measured the baseline FEV1 at the 

end of the treatment weeks. In one study63 there was a statistically significant 230 ml difference 

(p=0.02) in the measure of FEV1 after the treatment weeks that favored placebo. In the second 

study,62 there was no significant difference between the mean FEV1 after the placebo week 

compared with the salbutamol week (2.8L versus 2.8L). 

Only the study by Inman and O’Byrne63 assessed prophylaxis. When the 10 adults took a 

single dose of placebo prior to an ECT on day 8, the mean fall in FEV1 was positive for EIA in 

both groups; however, the fall was slightly greater after the SABA week (29.4 ± 4.7 percent 

versus 24.9 ± 4.4; p=0.12). On day 9 following pre-treatment with a SABA, all received total 

protection from EIA; however, the fall in FEV1 was greater after the SABA week (5.1 ± 2.0 

percent versus 1.1 ± 0.8; p=0.05) and remained lower throughout the recovery period. Adverse 

events were not reported. Hancox62 randomized 8 women with EIA and following a week of 

study drug performed an ECT with no pretreatment but gave SABA 5, 10, and 15 minutes post 

ECT. The fall in FEV1 was greater in the SABA treated group (p=0.001). 

LABA. Four crossover trials55,57-59 randomized groups to 3 to 4 weeks of salmeterol55,57 once 

a day,59 or every other day58 or to a matching placebo. The average fall in FEV1 after the first 

ECT on day 1 was 3.7 percent in the LABA arms compared with 26.9 percent in the placebo 

arms. The absolute MD was 25.1 percent (95 percent CI: 18.0, 32.3) In the individual studies the 

percent fall in FEV1 following an ECT at both 2 weeks and 4 weeks was of a greater magnitude 

in the LABA arms than at day 1, indicating a greater degree of EIA and less protection from 

salmeterol. The fall in FEV1 in the placebo arms remained unchanged or showed a small 

decrease. After 4 weeks of daily LABA use, the average fall in FEV1 after an ECT (3 studies) 

increased to 11.4 percent in the LABA arms compared with a decrease to 21.3 percent in the 

placebo arms. The pooled MD was 10.5 percent (95 percent CI: 14.7, 6.4. Three headaches were 

attributed to salmeterol; one exacerbation and one complaint of chest tightness were attributed to 

placebo. 

The study by Garcia et al.54 compared daily formoterol with placebo and also concluded that 

twice daily LABA over 4 weeks caused a significant reduction in bronchoprotection against EIA. 

Though the LABA was still effective, tachyphylaxis was evident by day 14. Adverse events were 

not reported. 

Two studies compared regular use of salmeterol versus a LTRA (montelukast) once in the 

evening for 8 weeks.53,60 Both drugs attenuated the EIA response after 3 days of treatment to a 

similar degree. The mean fall in FEV1 on LABA was 19.8 percent compared with 18.2 percent 

on LTRA (MD=1.01; 95 percent CI: -2.2, 4.2). Montelukast maintained its effectiveness at 4 and 

8 weeks compared with a slight decrease in effect with regular use of salmeterol. At 8 weeks the 

mean fall in FEV1 on LABA increased to 23.0 percent compared with a slight decrease to 17.1 

percent on LTRA. The pooled MD was 5.4 (95 percent CI: 2.2, 8.7). This evidence, although 

11
 

indirect, provides additional support for the concept of tachyphylaxis following regular use of 

LABA agents in patients with EIA. Adverse events were infrequent, mild and occurred more or 

less equally between therapies. 

Discussion. Based on the results of one study,63 SABA agents were found to have a 

prophylactic effect on EIA. The day 1 data from the LABA tachyphylaxis review also show that 

LABA is effective for attenuating the drop in FEV1 post exercise. However, the evidence 

indicates tachyphylaxis is associated with the regular use of both SABA and LABA agents. The 

results of this review demonstrated that the percent fall in FEV1 following an ECT after 1 to 4 

weeks of use was greater (i.e., drugs were becoming less effective) in the SABA and LABA 

arms than in the placebo arms. Notwithstanding the tachyphylaxis, a prophylactic effect for 

SABA and LABA was still observed. 

Conclusion. Given the consistency of results, the magnitude of effect and concordance with 

clinical consensus, the evidence indicates that prophylactic use of SABA and LABA agents is 

safe and effective for episodic prophylaxis of EIA. The evidence suggests that tachyphylaxis 

develops if these agents are used daily. The body of evidence comparing SABA/LABA to 

placebo was graded as “moderate”; evidence comparing LABA to LTRA was graded as “low.” 

Pharmacological Interventions: Anti-Inflammatory Agents 

T–2. Leukotriene Receptor Antagonist Therapy 

Leukotrienes are produced by the cysteinyl leukotriene pathway and are implicated in both 

bronchoconstriction and in the inflammatory cascade leading to worsening asthma. LTRAs are 

relatively new agents available for the management of chronic and acute asthma which block this 

pathway. 

Nine crossover trials44,64-71 met the inclusion criteria for the single prophylactic use of LTRA 

compared with placebo in the pre-treatment of EIA. Overall, the methodological quality of the 

trials was good. All were randomized, eight were double-blind trials and six described an 

adequate process to ensure double-blinding. Seven described the withdrawals and dropouts; 

however, none described the method of randomization and only one had adequate allocation 

concealment. All trials recruited people with asthma and confirmed EIA and all recorded the 

mean fall in FEV1 up to 2 hours after drug administration. The pooled results showed that LTRA 

was more effective than placebo in preventing EIA. The average fall in FEV1 in the LTRA arms 

after the first ECT ranged from 7.6 to 13.3 percent (average 10.9) compared with 15.0 to 23.2 

percent (average 18.5) on the placebo challenges. The absolute MD was 8.3 percent (95 percent 

CI: 6.9, 11.0; I2

=65 percent) and represented clinical protection of approximately 45 percent over 

placebo. Three trials68,70,71 recorded the mean maximum fall in FEV1 24 hours after drug 

administration. The average fall in the placebo arms was 13.8 percent (range 10.7 to 16.9) 

compared with 8.7 percent (range 8.3 to 10) in the LTRA arms. The pooled results showed that 

LTRA remained more effective than placebo in preventing EIA (MD=4.9; 95 percent CI: 1.8 to 

8.0; I2

=76 percent). Adverse events were infrequent, mild and occurred more or less equally 

between LTRA and placebo groups. 

Discussion. We identified nine trials of LTRA compared with placebo in the pre-treatment of 

EIA. The methodological quality of the studies was high and the pooled results demonstrated a 

consistent benefit associated with prophylactic use. LTRAs reduced the maximum percent fall in 

12
 

FEV1 at the earliest measurement by approximately nine percent compared with placebo (Table 

2). 

Conclusion. From the available evidence, it appears that LTRAs are effective and safe as 

pre-exercise treatment for patients with mild to moderate stable asthma and EIA. The strength of 

the body of evidence is “moderate.” 

T–3. Inhaled Corticosteroid Therapy 

The main inhaled anti-inflammatory agents used for chronic and acute asthma are ICS 

agents. The search and selection methods employed for this review identified trials involving 

single prophylactic ICS use compared with placebo in the pre-treatment of EIA. 

Four crossover trials72-75 met the inclusion criteria. Overall the quality of the trials was 

good. All were randomized and double-blind; two described an adequate process to ensure 

double-blinding. All described the withdrawals and dropouts; however, none described the 

method of randomization and one had inadequate allocation concealment. All trials recruited 

people with stable asthma and confirmed EIA. The pooled results showed no significant 

difference between ICS and placebo (absolute MD=5.0 percent; 95 percent CI 0.0, 10.0; I2=0 

percent). None of the studies reported adverse events. 

Discussion. The pooled results failed to produce a statistically significant or clinically 

important reduction in the percent fall in FEV1 compared with placebo. 

Conclusion. From the available evidence, we cannot concude that a pre-exercise singledose of an ICS agent will attenuate EIA. The strength of the body of evidence is “moderate.” 

T–4. Mast Cell Stabilizers 

Three systematic reviews were identifed that synthesized the evidence for MCS. One review 

compared nedocromil sodium (NCS) versus placebo for preventing EIA76,104 and one compared 

NCS versus sodium cromoglycate (SCG).77 The third review78 compared the effects of a 

prophylactic dose of either NCS or SCG (collectively called MCS) to that of atropine, 

ipratropium or oxitropium bromide (collectively called SAAC agents) and to SABA. The review 

also compared the effects of a combination of a SABA plus a MCS to a SABA alone. Our search 

strategy located no additional RCTs that would add to these reviews. In the three reviews, all 

trials recruited people with stable asthma and confirmed EIA. 

Twenty-one RCTs were included in the NCS versus placebo review.76,104 NCS provided a 

statistically and clinically significant attenuation of EIA. The average fall in FEV1/PEF was 15.2 

percent (range 10.0 to 29.8) in the NCS arms compared with 31.5 percent (range 17.5 to 47.2) in 

the placebo arms (absolute MD=15.6 percent; 95 percent CI: 13.2, 18.1; I2

=20 percent). This 

represents a clinical protection index of approximately 51 percent over placebo. In those that had 

more severe EIA (i.e., a percent fall index 30 percent or more), the effect of NCS appeared more 

pronounced (absolute MD=21.4 percent; 95 percent CI: 25.5, 17.2). 

There were nine RCTs included in the NCS versus SCG review.77 No significant differences 

between NCS and SCG were identified (absolute MD=0.88; CI: -4.5, 2.7; I2=0 percent). 

There were 24 RCTs included in the review comparing MCS to other agents. Overall, the 

maximum fall on MCS was reduced to 7.1 percent compared with 13.8 percent on SAAC agents 

(MD=6.7 percent; 95 percent CI: 3.3, 10.0; I2

=0 percent). When compared with SABA, MCS 

were not as effective at preventing EIA. The mean percent fall in FEV1 using MCS was 11.2 

13
 

percent compared with 4.3 percent on SABA (MD=6.8 percent; 95 percent CI: 4.5, 9.2; I2

=0 

percent). Combining MCS with a SABA did not produce significant advantages to pulmonary 

function over SABA alone (MD=1.8 percent; 95 percent CI: -1.1, 4.6; I2

=0 percent). Few trials 

reported adverse events due to MCS; those that did reported bad taste, throat irritation and 

cough. 

Discussion. MCS stabilize the mast cell membranes and prevent the release of inflammatory 

mediators; they are used as weak anti-inflammatory agents in mild to moderate chronic asthma. 

Examining existing Cochrane reviews, this report highlights the efficacy (approximately 51 

percent improvement in the post-exercise FEV1 compared with placebo) for NCS. An analysis 

failed to demonstrate a difference between NCS and SCG and further comparative analyses 

suggest that MCS are more effective than SAAC agents but less effective than SABA agents 

(Table 2). 

Conclusion. From the available evidence, it appears that MCS agents are effective and safe 

as pre-exercise treatment for patients with stable asthma and EIA. No significant differences 

were identified between NCS and SCG on pulmonary function or degree of protection afforded 

to patients. MCS agents were somewhat more effective than SAAC agents but not as effective as 

SABA agents. The combination of SABA and MCS agents did not provide significant 

advantages over a SABA alone. The strength of the body of evidence is “moderate.” 

T–5. Anticholinergic Therapy 

SAAC agents are used in respiratory conditions to decrease mucus production and as weak 

bronchodilators. The original anticholinergic agent used in asthma was atropine; however, 

ipratropium bromide (IB) is now the most commonly used agent in this class. Long-acting 

anticholinergic agents such as titropium bromide are also now available. The search and 

selection methods employed for this review trials involving single prophylactic SAAC use 

compared with placebo in the pre-treatment of EIA. 

Eighteen crossover trials79-96 met the inclusion criteria. Overall, the methodological quality 

was low. Though all were randomized, seven were not double-blind trials and only one described 

an adequate process to ensure double-blinding. Seventeen trials described the withdrawals and 

dropouts; however, none described the method of randomization and all had unclear allocation 

concealment. 

All trials recruited people with stable asthma and confirmed EIA. The mean fall in FEV1/PEF 

on the placebo challenges ranged from 14 to 41 percent (average 32). Seven of the placebo 

groups79,83,85,88,90,93,96 had a mean fall in FEV1/PEF greater than 30 percent indicating moderate to 

severe EIA. The average fall in FEV1/PEF in the SAAC arms ranged from 10 to 33 percent 

(average 21). The pooled results showed that IB was more effective than placebo in preventing 

EIA (absolute MD=8.8 percent; 95 percent CI: 5.0, 14.6; I2

=76 percent). Four trials compared 

atropine to placebo.80,84,86,91 The pooled results showed that atropine was more effective than 

placebo in preventing EIA (absolute MD=16.0; 95 percent CI: 10.2, 21.7; I2

=0 percent). Two 

trials compared oxitropium bromide to placebo.88,89 The pooled results showed that oxitropium 

bromide was more effective than placebo in preventing EIA (absolute MD=13.8; 95 percent CI: 

6.0, 21.6; I2

=0 percent). Few trials reported adverse events; those that did reported dry mouth or 

thirst, bitter taste, and slight tremor. 

Discussion. The pooled results demonstrated a modest but consistent benefit associated with 

the pre-exercise use of IB in EIA. IB reduced airway narrowing at the earliest measurement by 

14
 

34 percent over placebo; however, the results should be viewed cautiously due to the presence of 

heterogeneity. Complete protection was achieved 4.5 times more often with IB than placebo. 

Conclusion. The evidence suggests that when used as a pre-treatment, SAAC agents are 

effective and safe for patients with EIA and can offer a clinically relevant protective effect to 

some people. The strength of the body of evidence is “moderate.” 

Nonpharmacologic Interventions 

T–6. Refractory Period (10 to 15 Minute Warmup and/or Cooldown) 

As an alternative, or in addition to using medications to attenuate EIB/EIA, many athletes, 

trainers and researchers advocate specific warmup routines as a method to trigger a refractory 

period. A refractory period is the time after the warmup routine during which further vigorous 

exercise will evoke significantly less severe or no EIB/EIA. 

Seven trials97-103 met the inclusion criteria. Overall, the methodological quality was low. All 

were randomized, but none were double-blind trials. Six described the withdrawals and dropouts; 

however, none described the method of randomization and all had unclear allocation 

concealment. Six of the seven trials reported participants had stable asthma and confirmed EIA. 

The effect of a warmup routine on EIA prior to a standard exercise challenge was examined 

for the following subgroups. 

Interval protocol. Four trials compared an interval warmup to no warmup97,99,100,103 prior to 

an ECT. The MD in the percent fall FEV1 on the ECT ranged from an improvement of 4.8 to 

16.1 percent over the fall after no warmup. The pooled results showed that a series of short 

intense sprints attenuated the EIA response by a mean of 10.6 percent (95 percent CI: 6.5, 14.7; 

I

2

=15 percent). 

Continuous low intensity protocol. Three trials compared a continuous low intensity warmup 

that ranged from 3 minutes101 to 30 minutes102 to no warmup prior to an ECT. The mean 

difference in the percent fall in FEV1 on the ECT ranged from an improvement of 0 to 20.6 

percent over the fall after no warmup. The pooled results failed to demonstrate statistically 

significant evidence that the low intensity warmup attenuated the EIA response (absolute 

MD=12.6 percent; 95 percent CI: -1.5, 26.7; I2

=90 percent). 

Continuous high intensity protocol. Two trials compared a continuous high intensity warmup 

that was identical to the ECT with no warmup prior to the ECT.102,103 The mean difference in the 

maximum percent fall in FEV1 on the ECT ranged from an improvement of 1.0 to 17.6 percent 

over the fall after no warmup. The pooled results failed to demonstrate statistically significant 

evidence that a continuous high intensity warmup attenuated the EIA response. (absolute 

MD=9.8 percent; 95 percent CI: -6.4, 26.0; I2

=89 percent). 

Discussion. Seven RCTs compared either different warmup routines with each other or with 

no warmup prior to an ECT. The evidence suggests that compared with no warmup, pretreatment of EIA with interval warmup exercise offers a statistically significant and 

homogeneous attenuating benefit of approximately 11 percent improvement in the percent fall 

FEV1 index (Table 2). For both high and low intensity continuous warmup protocols, the 

evidence is less clear. Combinations of interval and continuous warmup protocols compared 

within one study identified no differences and all protocols provided similar protection against 

EIA in the 10 to 11 percent range. 

15
 
Conclusion. From the available evidence, it appears that certain warmup protocols are 

effective in reducing the degree of airway obstruction associated with EIA. Combination 

warmups show promise; however, it is unclear whether continuous warmups are effective in this 

condition. The strength of the body of evidence is “low.” 

Gaps in Evidence and Recommendations for Future 
 

Research 
 

Methodological Limitations of the Reviews 

This review has methodological and logistic limitations. Some of the important limitations 

are listed below. 

Diagnostic test accuracy reviews. Since there is no universally accepted gold standard to 

diagnose EIB/EIA, we used the standardized ECT based on ATS guidelines as our reference 

standard. Not all studies performed the ECT according to the ATS guidelines, however, and the 

variations in ECT protocol among studies may have affected the pulmonary response to the 

challenge and underestimated the number of positive results. Specifically, there were variations 

in environmental conditions (percent humidity and temperature of inspired air); restrictions on 

nose breathing; speed, grade, intensity and duration of the challenge; and target heart rate and 

minute ventilation achieved during the ECT. All of these have the potential to influence the 

stimulus for triggering EIB/EIA. These variations may have contributed to the heterogeneity in 

sensitivity and specificity observed with all the index tests. 

Another concern is that many studies suffered from a potential spectrum bias. Ideally, studies 

should have a sample of participants who are representative of the population being examined for 

EIB/EIA. That is, studies should have sufficient subjects that span the range from high to low 

likelihood of EIB/EIA. In this review, many studies purposely recruited volunteers who either 

had known EIB/EIA, or definitely did not have it. In several studies no information on baseline 

likelihood was reported. The lack of a representative patient spectrum limits the generalizability 

of the results to a target population of people with suspected EIB/EIA and makes estimates of 

sensitivity and specificity unreliable. 

A further limitation is that not all potentially relevant studies reported sufficient data to 

generate a 2x2 table comparing the reference standard result with an index test result based on 

one or more diagnostic thresholds. 

Finally, poor reporting of study methods, challenge criteria, or participant characteristics 

meant we were not able to perform important subgroup analyses to provide more useful evidence 

summaries. 

Therapy reviews. A double-blind RCT is considered the highest quality study design for 

assessing drug therapy. A short-coming of many of the included trials was a lack of disclosure on 

the methods used to generate and conceal the randomization code from investigators and 

participants as well as the adequacy of the blinding process. 

Concerns regarding crossover trials, even though randomized, center on three factors: drug 

carryover effects, period effects, and statistical issues. Ideally, results should be reported for each 

treatment period and the test sequence reported so analyses can confirm the presence or absence 

of a carryover or period effect. No study reported data in such a manner and all merged the 

results from the treatment and placebo periods as though it were a parallel study. 

16
 
Studies did not always provide sufficient quantitative data (e.g., measures of variance, mean 

endpoint estimates, statistical test results) needed to pool the individual trial results and to judge 

the treatment-related between group outcome differences. 

In studies assessing the effect of a refractory period, the warmup protocols were not 

standardized. We categorized the warmup interventions into three groups, but still within each 

group the warmup approaches varied from each other. 

Studies varied in the presentation of FEV1 and PEF data. Our primary outcome was the 

maximum percent fall in FEV1 from baseline. When possible we transformed data to this 

measure. The ATS convention is to accept a 10 percent maximum fall in FEV1 following ECT as 

the diagnostic cutpoint for EIB/EIA and the majority of studies used this. However, other 

cutpoints were used and it was not always possible to obtain data at the 10 percent level. The 

review provided data on 15 and 20 percent cutpoints when available. While outcome reporting 

mainly included detailed pulmonary function measures, data on the proportion obtaining clinical 

and complete protection were not always reported nor was it standardized (Table 2). 

Side effect profiles were also poorly reported. While side effects were likely uncommon, 

better reporting and the use of patient treatment preference may have provided more robust 

assessments of the effectiveness of various treatment options. Finally, most studies relied 

exclusively on pulmonary function outcomes to assess effectiveness; symptom control and 

exercise performance data were not available. 

Recommendations for Future Research 

Efforts are needed to improve the overall quality of reporting of primary studies of diagnostic 

test accuracy. The STARD checklist105 details 25 items that address the level of detail that should 

be specified within such studies including descriptions of participants, tests methods, statistical 

methods, and results. This could be considered as a guide for authors reporting studies that 

evaluate diagnostic tests and for journals that publish EIB/EIA-related research. 

Studies designed to more carefully examine the methodology of the standard ATS ECT test 

are needed. Specifically, guidelines state that the inspired air temperature must be less than 25o

C, 

and less than 50 percent relative humidity. Studies have used inspired air as cold as -18oC and 

many have used medical compressed air, which has a relative humidity of 0 percent as the air 

leaves the tank. Colder, drier air would result in the greatest increase in osmolarity of the airway 

surface and thus most likely cause EIB/EIA. Additional studies are needed to more thoroughly 

examine how inspired air affects EIB/EIA so that a more standardized ECT guideline can be 

developed. 

Future purposely designed studies to compare the diagnostic characteristics of different 

diagnostic methods are needed. New tests such as mannitol are encouraging; however, currently 

there are insufficient data to allow for a strong recommendation of this test. Particular attention 

in future studies must be given to including a representative sample of participants with 

suspected EIB/EIA. Studies that prospectively recruit participants and blind the reference 

standard results to those who interpret the index test results are needed. 

To determine if the response to diagnostic tests differs in those with EIB versus EIA, those 

with atopy or no atopy, or other potentially defining characteristics, appropriate populations need 

to be included, adequate baseline data reported, and comparative analyses by the characteristics 

of interest performed and reported. 

17
 
With regard to the systematic review of therapy for EIA, there are several issues with respect 

to methodological quality, populations, interventions, outcome assessments, and controls that 

require discussion. 

Efforts are needed to improve the quality of reporting primary studies (i.e., randomized 

controlled trials). The CONSORT Statement106 could be considered as a guide for authors 

reporting trials and journals that publish EIB/EIA-related research. Most trials in this review 

used a crossover design. Concerns regarding crossover trials center on three factors: drug 

carryover effects, period effects, and statistical issues. Data should be reported in a manner that 

allows analyses to confirm the presence or absence of a carryover effect. Future studies should 

focus on complete reporting of results by period and sequence to assure readers that these 

concerns have been accounted for. 

Population: The populations involved in the therapy trials all had stable asthma and 

confirmed EIA. Athletic status was not reported. This finding, coupled with the small number of 

studies investigating some interventions, precluded more detailed subgroup analysis of the issue 

of EIB/EIA in elite athletes. Additional investigations of treatment effects in patient subgroups 

defined by asthma severity, age, and activity level are clearly indicated. 

More trials in clinically homogenous groups of patients with EIB and patients with EIA are 

needed to better explore and characterize differences in the efficacy of interventions between 

these two conditions. 

Intervention: The nonpharmacologic interventions were not standardized. Although the 

warmup interventions were divided into similar groups, each warmup approach varied from the 

others. Future research exploring different standardized warmup approaches is clearly indicated. 

Control: Many of the patients in the pharmacological studies were administered placebo 

agents as the control treatment. These agents were often similar in appearance or delivered in 

similar appearing devices (inhaler agents) to the active treatment; however, it may have been 

possible for patients to detect differences among treatments, especially the bronchodilators such 

as SABA, LABA and SAAC agents. It is impossible to determine how frequently this occurred 

since most studies did not report the patient’s perception of treatment received. In addition, it 

was not possible to blind the participants to the warmup programs in the refractory studies. When 

the participant cannot be blinded, it is particularly important that the outcome assessor be blinded 

to all information that could bias the outcome measure or assessment (e.g., other test results, 

intervention given, challenge performed). 

Outcome: The pulmonary function outcomes reported varied and studies used different 

diagnostic cutpoints ranging from a fall index of 10 to 20 percent. The ATS convention is to 

accept a 10 percent maximum fall in FEV1. While outcome reporting included detailed 

pulmonary function measures, the format was not standardized. Data on the proportion obtaining 

clinical and complete protection were often missing (Table 2). 

Side effect profiles were also poorly reported. While there is evidence for the safety of many 

of these agents from the chronic asthma literature, it would be prudent for future research to 

capture adverse effects in the EIB/EIA population. Future trials of interventions to prevent or 

attenuate EIB/EIA should include clinically relevant secondary outcomes such as patient 

preferences, symptom scores, and sport performance effects (e.g., changes in athletic 

performance or endurance). More robust outcome reporting would further inform decisionmaking by athletes, physicians, and sporting bodies. 

18
 

Conclusion 
 

Despite exhaustive efforts to identify evidence regarding the diagnostic test characteristics of 

self-reported history, MCH, sport or venue specific challenges, EVH, FRAST, or mannitol to 

diagnose patients with EIB/EIA, few studies were found that compared these diagnostic tests to a 

standardized ECT. The studies that were identified suffered from spectrum bias and considerable 

variability in test methodology and reported data. 

Based on the available data as summarized in this review, none of the six tests provide the 

diagnostic test characteristics to make them individually attractive as an exclusive alternative to a 

standardized ECT. There is no clear evidence to suggest that any are equivalent to, or better than, 

a standardized ECT to diagnose EIB/EIA. More important, given the difference in response by a 

single individual to multiple challenges, a single negative test should not be used to exclude 

EIB/EIA. A specificity ranging from 79 to 100 percent in sport specific challenges may indicate 

they are useful in identifying athletes who do not have EIB/EIA. 

Despite exhaustive efforts to locate randomized trials that compared the therapeutic 

effectiveness of six different interventions for EIB/EIA against placebo, only a small number of 

studies were identified for each question. The studies that were included suffered from several 

potential biases; however, this summary represents the most comprehensive review of therapies 

for EIB/EIA ever reported. 

On the basis of this review, we can conclude that the bronchodilator agents examined 

(SABA, LABA, LTRA, and SAAC) are effective to varying degrees at attenuating or eliminating 

the drop in FEV1 associated with EIA. There is evidence of the development of tachyphylaxis 

associated with 1 to 4 weeks of regular use of SABA and LABA agents but it was not enough to 

negate their usefulness altogether. 

On the basis of this review, we can conclude that the anti-inflammatory agents examined 

provide mixed results. The evidence suggests that MCS agents are effective in attenuating or 

eliminating the FEV1 drop associated with EIA. There is some role for LTRA agents in the 

treatment of EIA; however, the attenuation appears less than with other bronchodilator agents. 

There is limited evidence that a single prophylactic dose of ICS is of clinical benefit in 

preventing EIA. The long-term benefit of ICS agents in asthma is well known, and it is possible 

that better control of chronic airway inflammation may benefit patients with EIA specifically.107 

Finally, from the available evidence, it appears that certain warmup protocols are effective at 

reducing the degree of airway obstruction associated with EIA. Combination warmups show 

promise; however, it is unclear whether continuous warmups are effective for this condition. 

19
 

Table 1. Summary of sensitivity and specificity for the diagnostic test accuracy review 

20
 


Index test 

# studies, 

sample size 

ECT type (# studies) Definition of EIB/EIA (# studies) 

Sensitivity point estimate or range mean % (95% CI) 

Specificity point estimate or range mean % (95% CI) 

ECT +ve (≥10% 

fall FEV1) 

N (%) 

Self-report 2, N=206 Treadmill (2) 

≥10% fall FEV1 (1) 

≥15% fall FEV1 (1) 

89% (67, 99) 36% (17, 59) 

86% (64, 97) 85% (78, 90) 

19 (48) 20 (13) 

Methacholine 16, N=1,048 Treadmill (10) 

Bicycle ergometer (6) ECT: ≥8% fall FEV1 (1), 

≥10% fall FEV1 (6), 

≥15% fall FEV1 (2), ≥18% fall FEV1 (1), ≥20% fall FEV1 (5) 

MCH: ≥20% fall FEV1 at 

≥10% fall FEV1 

0-100%; 

(MCHPC20 <8mg/ml) 

55-100% 

(MCHPC20 <16mg/ml) 

0-100% 0-100% 

331 (57) 420 (53) 

various doses MCH 

Sport specific 

challenge 

5, N=95 Treadmill (3), bicycle 

ergometer (2) 

≥10% fall FEV1 (4) 

≥20% fall FEV1 (1) 

≥10% fall FEV1 

Swim challenge 0-50% Winter sports n=37 100% (48, 100) (1 study) 

83-100% 79% (49, 95) (1 study) 

11 (19) 5 (14) 

Eucapnic 

voluntary hyperpnea 

7, N=138 Treadmill (4), bicycle 

ergometer (3) 

ECT: ≥10% fall FEV1 

(4), ≥20% fall FEV1 (1) 

≥10% fall FEV1 

25-90% 0-71% 42 (30) 

NR (2) EVH: ≥10% fall FEV1 

(4), NR (3) 

FRAST 3, N=99 Treadmill (1), bicycle 

ergometer (2) 

≥10% fall FEV1 (1) 

≥20% fall FEV1 (2) 

≥10% fall FEV1 : 60-67% ≥20% fall FEV1: 53% 

47-67% 100% 

13 (38) 30 (50) 

Mannitol 3, N=423 Treadmill (2), bicycle 

ergometer (1) 

ECT: ≥10% fall FEV1 (3) 

Mannitol: ≥15% fall 

≥10% fall FEV1 58-96% 

(≥10% fall FEV1) 65-78% 202 (48) 

FEV1 (3) 

ECT = exercise challenge test; EVH = eucapnic voluntary hyperpnea; FEV1 = forced expiratory volume in 1 second; FRAST = free running asthma scmethacholine; PC = provocative concentration; +ve=positive 
Table 2. Prophylactic therapy for EIA: Pulmonary function results 

Comparisons Intervention vs. control 

N trials (SSi vs. SSc) 

MD % fall FEV1/PEF 

(95% CI)* 

Clinical protection ≥50% 

N trials (SSi vs. SSc) 

RR (95% CI) † 

Mean % protection of 

intervention over control (95% CI) 

Complete protection N trials (SSi vs. SSc) 

RR (95% CI) † 

Leukotriene receptor N=9 (267 vs.267) NR NR ≤10% fall FEV1 

antagonists vs. 8.9 (6.9, 11.0) N=4 (124 vs. 123) placebo 1.87 (0.77, 4.56) 

Inhaled corticosteroids N=4 (50 vs. 50) NR BV 6%; BUD 17%; NR 

vs. placebo 5.0 0.0, 9.9) FP 49% 

MCS (Nedocromil N=17 (240 vs. 240) NR 51 (46, 55) NR 

sodium) vs. placebo 15.6 (13.2, 18.2) 

Nedocromil sodium N=7 (97 vs. 97) N=6 (78 vs. 78) NR ≤10% fall FEV1 

vs. sodium cromoglycate 0.9 (-2.7, 4.5) 1.12 (0.89, 1.40) N=6 (78 vs. 78) 

1.0 (0.7, 1.4) 

MCS vs. anticholinergics N=8 (183 vs. 175) N=5 (56 vs. 48) 11.2 (2.4, 20.0) ≤15% fall FEV1 

6.7 (3.3, 10.0) 1.35 (1.00, 1.83) N=8 (177 vs. 169) 

1.3 (1.1, 1.6) 

SABA vs. MCS N=12 (271 vs. 272) N=6 (77 vs. 77) 22.7 (11.9, 33.4) ≤15% fall FEV1 

6.8 (4.5, 9.2) 1.4 (1.1, 1.7) N=9 (225 vs. 226) 

1.4 (1.2, 1.8) 

SABA + MCS vs. SABA N=5 (40 vs. 40) N=3 (37 vs. 37) 10.3 (-27.0, 6.5) ≤15% fall FEV1 

1.3 (-6.3, 8.9) 0.9 (0.7, 1.1) N=4 (44 vs. 44) 

0.9 (0.5, 1.4) 

LABA vs. placebo N=4 (55 vs. 55) NR 86% NR 

25.1 (18.0, 32.3) 

Anticholinergics N=11 (142 vs. 142) N=6 NR ≤10% fall FEV1 

(Ipratropium bromide) 9.8 (5.0, 19.5) % achieved=60 (48, 72) N=7 (74 vs. 74) vs. placebo 4.5 (1.2, 10.9) 

Interval warmup vs. no N=4 (56 vs. 56) NR NR ≤15% fall FEV1 

warmup 10.6 (6.5, 14.7) N=1 

1/12 (8.3%) 

Continuous low intensity N=3 (37 vs. 37) NR NR ≤15% fall FEV1 

warmup vs. no warmup 12.6 (-1.5, 26.7) N=1 

6/12 (50%) 

Continuous high intensity N=2 (13 vs. 13) NR NR NR 

warmup vs. no warmup 9.8 (-6.4, 26.0) 

21
 


BUD = budesonide; BV =Betamethasone valerate; FEV1 = forced expiratory flow in 1 second; FP=fluticasone ICS = Inhaled corticosteroid; LTRA = 

antagonist; MCS = mast cell stabilizers; MD = mean difference; NR = not reported; PEF = peak expiratory flow; RR = risk ratio; SABA = short-acting 

size intervention; SSc = sample size comparison. *a positive MD indicates intervention is better; † RR>1 indicates intervention is better 

Evidence Report 
 
Chapter 1. Introduction 

What is Exercise-induced Bronchoconstriction and Asthma? 

Vigorous physical exercise can be followed by transient clinical signs and symptoms of 

asthma due to airway narrowing. The phenomenon was first recorded around 150 AD by 

Aretaeus of Cappodocia.108 Airway obstruction following exercise was first observed among 

individuals with underlying asthma from which the term exercise-induced asthma (EIA) was 

derived. Asthma is a chronic inflammatory disorder of the airways in which many cells and 

cellular elements play a role, and it is associated with bronchial (or airway) hyperresponsiveness.109 Similar post-exercise asthma-like symptoms have been observed in persons 

without the presence of co-existing asthma, particularly in athletes. In this population the 

phenomenon has been referred to as exercise-induced bronchoconstriction (EIB).1 In this report 

we define EIB as “the airway obstruction that occurs in association with exercise without regard 

to the presence of chronic asthma.” We define EIA as “the condition in which exercise induces 

symptoms of asthma in patients who have asthma.”1

 (The two conditions will be discussed 

separately when the populations are specifically identified; otherwise, for the sake of brevity, 

they are collectively referred to as EIB/EIA. 

The underlying mechanisms of EIB and EIA are multifactorial and complex. Whether the 

two phenomena have the same pathogenesis is still unknown and continues to be explored.110,111 

In the early 1970s, Chan-Yeung et al.112 recognized that the severity of the airway constriction 

was associated with the level of ventilation. In normal nasal breathing, inspired air is heated to 

body temperature and is completely saturated with water in the first few generations of the 

airways. There is a marked increase in minute ventilation during and following strenuous 

exercise and, as a result, the nose is unable to condition the increased volume of air. The added 

burden on the lower airways, down to the tenth generation and beyond, to warm and humidify 

the large volume of air triggers osmotic and thermal changes.20,113,114 Loss of water in the 

periciliary fluid layer of the airway produces a hyperosmotic environment that may stimulate 

degranulation of pulmonary mucosa mast cells with subsequent release of several inflammatory 

mediators such as histamine, leukotrienes, prostaglandin, platelet activating factors, and 

neuropeptides from sensory nerves.115 Theorists propose that the released mediators stimulate 

bronchial smooth muscle spasm116 and rapid rewarming leads to increased bronchial circulation 

and engorged capillary beds (or airway edema) that may intensify the obstruction.114,117,118 

The hallmark of EIB/EIA is that the acute airflow obstruction (measured by the forced 

expiratory volume in 1 second [FEV1]) peaks rapidly 3 to 15 minutes after exercise stops and 

then remits spontaneously within 20 to 60 minutes.2 It does not cause a prolonged deterioration 

in lung function. The nature and severity of episodes vary widely within and among individuals 

and can be influenced by multiple factors (Table 3). Common clinical symptoms include 

coughing, wheezing, shortness of breath, excessive mucus production, chest tightness, chest pain 

or an itching or scratching sensation in the chest. Less common symptoms include stomach pain, 

nausea;119 and near-death experiences.120 EIB/EIA has been shown to appear during prolonged 

exercise causing a lack of endurance despite conditioning. It may influence athletic performance 

120,121 and often results in a prolonged recovery time following exercise.119 A small subset of 

individuals experience a second, late-phase constriction 4 to 12 hours after the initial activity. 

This constriction is generally less severe than the first, but the magnitude of the two episodes are 

Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/eibeia/eibeia.pdf 

23
 
 

significantly correlated.108 No single factor predicts who will experience a late response, and 

these responses do not happen consistently in the same individuals.108,122 

Approximately 40 to 50 percent of individuals who have an initial episode of EIB/EIA 

experience a refractory period that is defined as “a period of diminished responsiveness when a 

second period of exercise follows in 1 to 4 hours.”8

 During this time the magnitude of the 

EIB/EIA response to an identical exercise task may be less than 50 percent of the initial 

response.123 This phenomenon is somewhat elusive as it can be present at some times but not at 

others. The cause is not fully understood but it has been suggested that depletion of 

catecholamines, increased circulation of prostaglandin, and degranulation of mast cell mediators 

play a role. 

Table 3. Factors that may influence the severity of EIB/EIA 

Factor Decrease EIB/EIA Increase EIB/EIA 

Environmental conditions Warm temperatures (34-37° C)124 

High humidity (100%) 

Absence of allergens 

Low air pollution 

Cold temperatures, dry air124,125 

Airborne particles and pollutants, 

allergens, moulds, dust 

Irritants: automobile exhaust, sulphur 

dioxide, nitrogen dioxide, smoke, 

ozone,126 chlorine127 

Type, intensity, duration of 

exercise 

Short episodes of fast/slow running 

with brief rests128 

VO2 max <40% predicted129 

<3 minutes continuous exercise 

Continuous activities that require 

near maximum aerobic capacity 

VO2 max ≥60% predicted 

6-8 minutes continuous exercise 

Overall control of 

underlying asthma and 

BHR 

Good control: FEV1 >70% predicted 

Fall in BHR130 Poor control: FEV1 <65% predicted Increase in BHR130 

Physical conditioning Good physical conditioning 

Warmup and cooldown sessions 

Poor physical conditioning 

Sudden burst of activity 

Fatigue126 

Emotional stress126 

Athletic overtraining126 

Respiratory tract infections, 

especially viral 

No respiratory tract infections Presence of respiratory tract 

infections126 

Sinusitis130 

Rhinitis 

Time since last exercise 

Concurrent medications 

If within 40-90 min may benefit from 

refractory period130 

Maintenance anti-inflammatory 

bronchodilator medication 

>2-3 hr 

Salicylates, NSAIDS, ß-blockers130 

Pre-exercise foods eaten None Peanuts, celery, shrimp, grain, 

carrots, bananas130 

BHR = bronchial hyperresponsiveness 

24
 

Magnitude and Importance of the Condition 
 

According to National Center for Health Statistics estimates, approximately 20.5 million 

Americans (seven percent) have asthma.5 Asthma is reported to have resulted in 4,099 deaths in 

2003 and 1.8 million emergency department visits in 2004.5,131,132 Between 60 to 90 percent of 

people with asthma experience EIA and consider exercise a major trigger of their asthma 

symptoms.133 Some claim that all asthmatics will experience EIA if ventilation is sufficiently 

high.6 Prevalence of EIB is lower (six to 13 percent) in a population with no history of asthma or 

allergy.8,9 

EIB/EIA gained considerable attention following the 1972 Olympic Games when a gold 

medalist swimmer, Rick Demont, had his medal rescinded because he took oral ephedrine prior 

to the race to control his EIB/EIA. Since then, several studies conducted among athletes have 

reported the prevalence of EIB/EIA to range from 11 to 50 percent.7

 Helenius and Haahtela9 

estimated that the prevalence in summer sport athletes was between 3.7 to 22.8 percent, whereas 

among winter sport athletes the estimate ranged from 2.8 to 54.8 percent.134 High level endurance 

training in sports such as cross-country skiing, swimming, and long distance running may 

increase bronchial hyper-responsiveness (BHR) and cause inflammation in the airways because 

these athletes are repeatedly exposed to cold air, inhaled irritants, and allergens.135 

Asthma is known to have a negative impact on health-related quality of life.136 The threat of 

an asthma attack may result in withdrawal from physical and social activities, which can lead to 

deconditioning, weight gain, and to an altered sense of self-esteem.137 Both recreational and elite 

athletes tend to minimize or deny symptoms due to embarrassment, fear of repercussions, or lack 

of understanding of what they are experiencing.8,138 EIB/EIA and asthma have an impact on 

quality of life. The fear of sudden breathlessness creates a sense of panic, which may prevent 

children and adults from participating in sports and cause parents of children with asthma to 

impose restrictions.10 Fear of failure and sub-optimal performance in sports may lead many 

individuals suffering from EIB/EIA to opt for sedentary activities.120 

Unrecognized EIB/EIA can result in serious public health consequences. Data compiled from 

coroners reports for deaths between 1993 to 2000 indicated that, among 61 asthma-related deaths 

occurring in close relation to physical activity, about 80 percent occurred in individuals younger 

than 21 years of age. More than half of all asthma-related deaths occurred in individuals who 

were considered to be elite or competitive athletes, nearly 10 percent of which occurred in 

individuals with no known history of asthma.139 

25 
 
 

 

Diagnosis of Exercise-Induced Bronchoconstriction and 

Asthma 

Potential EIB/EIA can be detected by taking a thorough medical history. EIB/EIA is 

suspected when individuals, who otherwise have good lung function, complain of recurrent 

shortness of breath and symptoms of cough, wheeze, chest pain, or prolonged recovery time 

following exercise. These symptoms are independent of a person’s conditioning level. If 

symptoms are relieved by inhaling a short-acting beta-agonist (SABA) or if symptoms are 

prevented by taking a SABA before exercise, a diagnosis of EIB/EIA is strongly supported.118 

The degree of airway constriction can be measured objectively by a spectrum of pulmonary 

function tests; however, most clinicians and laboratories use the FEV1

7

 or, very occasionally, the 

peak expiratory flow (PEF). 

When a patient’s history suggests EIB/EIA, measuring the change in FEV1 before and after a 

standardized exercise challenge test (ECT) on a treadmill or bicycle ergometer can assist in 

making the diagnosis. The American Thoracic Society (ATS) has published guidelines for 

conducting a standardized ECT,18 which include recommendations for environmental control, as 

well as the level and duration of intensity required to ensure a sufficiently vigorous challenge. 

Minute ventilation must reach the target level in the first 4 minutes of the challenge. 

The standardized laboratory ECT has not always demonstrated sufficient sensitivity to 

identify EIB/EIA in elite athletes who perform in many venues and with widely varying intensity 

and duration, therefore, other surrogate tests have been recommended.140 Some of the current 

options include sport specific challenges, the free running asthma screening test (FRAST), 

measures of direct bronchial responsiveness to methacholine (MCH) and indirect responsiveness 

to eucapnic voluntary hyperpnea (EVH) or mannitol. 

In the general population, vigorous exercise should cause little to no prolonged decrease in 

airflow following exercise. A decrease of 10 percent from baseline has been shown to be a 

change greater than two standard deviations from the normal response.141 In 2001, prior to the 

Salt Lake City Olympics, the International Olympic Committee Medical Commission met to 

determine the parameters for EIB/EIA. They accepted a cutpoint of a fall of 10 percent or more 

in FEV1, as suggested by the European Respiratory Society and ATS guidelines.18,142 This 

decision was supported by a study indicating a coefficient of variation of six percent for repeated 

maneuvers of FEV1.

143 However, the cutpoint value is a subject of ongoing debate. Two 

investigators have suggested that a fall in FEV1 of only 6.5 percent is appropriate.144,145 

Anderson et al. claim that the 10 percent value is justified as this level of constriction could 

potentially limit exercise performance.140,145 A 10 percent fall is also supported by Hurwitz et al. 

who found this degree of constriction to have a specificity of 90 percent for identifying those 

with asthma.146 

By convention EIB/EIA is quantified using the maximum percent fall index, which is the 

maximum reduction in lung function post-exercise, expressed as a percent of the pre-exercise 

value. The index is calculated using the formula: 

FEV1 / PEFpre−exercise − minimum FEV1 / PEFpost −exercise ×100

FEV1 / PEFpre−exercise 

A fall of 10 percent or greater on an ECT indicates that the individual has EIB/EIA. The 

greater the reduction in FEV1, the more severe the EIB/EIA episode is. If a person takes a 

26 
 
 

 

 

 

prophylactic dose of a medication to control EIB/EIA, “complete protection” is achieved if the 

percent fall index is less than 10 percent.147 

A significant placebo effect has been observed in randomized trials comparing an active preexercise treatment to placebo. Some participants have obtained either complete protection from 

EIB/EIA or significant attenuation of it with the placebo alone. Therefore, it is customary to 

subtract the fall in FEV1 on the active drug from the fall experienced on placebo and calculate 

the “clinical protection index” (the degree of protection afforded by a drug expressed as a 

percent of that offered by placebo) using the following formula: 

maximum % fall FEV 1(placebo) − maximum % fall FEV1(treatment) ×100 

maximum % fall FEV1(placebo) 

A result of 50 percent or more is regarded as clinically significant.122 

Treatment of Exercise-Induced Bronchoconstriction and 

Asthma 

The goal of treatment is to prevent or, at least, to reduce the severity of the 

bronchoconstriction and symptoms so that an individual can participate in any activity, 

regardless of its intensity and duration, without serious respiratory limitations. Through a 

combination of education, a commitment to fitness, pharmacologic intervention, and use of 

nonpharmacologic strategies, EIB/EIA can be successfully managed in the majority of cases. 

Different pharmaceutical agents that appear to operate on different phases of the response can 

provide at least partial relief from EIB/EIA.125 The most commonly used agents are inhaled 

SABA and long-acting beta-agonist (LABA) agents. Other agents include mast cell stabilizing 

agents (MCS), short-acting anticholinergics (SAAC), leukotriene receptor antagonists (LTRA), 

and inhaled corticosteroids (ICS). Theophyllines,148-150 antihistamines,151-153 calcium channel 

blockers,79,154 heparin,155 and furosemide155-158 have also been shown to have some degree of 

effectiveness. 

There are many unresolved issues with respect to the treatment of EIB/EIA with 

pharmaceutical agents. There is concern that the continuous use of the SABA and LABA agents 

to control asthma over the long term could lead to a decrease in efficacy when also used 

prophylactically to control EIA. A development of tolerance, or tachyphylaxis, to SABA or 

LABA agents may not only decrease their protective effect, but also shorten their duration of 

action.62 In the case of SABAs, a serious concern is that continuous use will decrease its impact 

as a rescue medication in the case of severe EIA. 

Objective of this Evidence Report 

The objective of this report was to synthesize the evidence to answer six key questions on 

diagnostic testing for EIB/EIA and six key questions on therapy for EIB/EIA (five involving 

pharmaceutical interventions and one a nonpharmacologic intervention). 

27 
 
The Key Questions 

The key questions for the diagnostic test accuracy review were as follows: 

D–1. In patients with suspected EIB/EIA, what are the diagnostic test characteristics of a selfreported history/symptoms diary for diagnosing EIB/EIA compared with a standardized 

exercise challenge? 

D–2. In patients with suspected EIB/EIA, what are the diagnostic test characteristics of a 

methacholine challenge for diagnosing EIB/EIA compared with a standardized exercise 

challenge? 

D–3. In patients with suspected EIB/EIA, what are the diagnostic test characteristics of 

sport/venue specific exercise challenges for diagnosing EIB/EIA compared with a 

standardized exercise challenge? 

D–4. In patients with suspected EIB/EIA, what are the diagnostic test characteristics of eucapnic 

voluntary hyperpnea for diagnosing EIB/EIA compared with a standardized exercise 

challenge? 

D–5. In patients with suspected EIB/EIA, what are the diagnostic test characteristics of a free 

running asthma screening test (FRAST) for diagnosing EIB/EIA compared with a 

standardized exercise challenge? 

D–6. In patients with suspected EIB/EIA, what are the diagnostic test characteristics of mannitol 

for diagnosing EIB/EIA compared with a standardized exercise challenge? 

The key questions for the therapy review were as follows: 

T–1. In patients with confirmed EIB/EIA, do patients using SABA or LABA therapy develop 

tachyphylaxis to treatment and, if so, at what frequency, compared with standard 

comparator treatments and/or placebo? 

T–2. In patients with confirmed EIB/EIA, does pre-exercise treatment with leukotriene receptor 

antagonists therapy reduce symptoms and prevent a 10 percent or more drop in FEV1 

compared with no treatment/placebo? 

T–3. In patients with confirmed EIB/EIA, does pre-exercise treatment with inhaled corticosteroid 

therapy reduce symptoms and prevent a 10 percent or more drop in FEV1 compared with no 

treatment/placebo? 

T–4. In patients with confirmed EIB/EIA, does pre-exercise treatment with mast cell stabilizers 

(sodium cromoglycate or nedocromil) therapy reduce symptoms and prevent a 10 percent or 

more drop in FEV1 compared with no treatment/placebo? 

T–5. In patients with confirmed EIB/EIA, does pre-exercise treatment with anticholinergics 

(ipratropium) therapy reduce symptoms and prevent a 10 percent or more drop in FEV1 

compared with no treatment/placebo? 

T–6. In patients with confirmed EIB/EIA, does a refractory period (10 to 15 minute warmup 

and/or cooldown) reduce symptoms and prevent a 10 percent or more drop in FEV1 

compared with no treatment/placebo? 

28 
 
Chapter 2. Methods 

In this chapter we document a prospectively developed protocol that was used to conduct this 

evidence report. A core research team was assembled by the University of Alberta Evidencebased Practice Center (UAEPC). In consultation with the Agency for Healthcare Research and 

Quality (AHRQ) Task Order Officer (TOO) and the American Academy of Asthma Allergy and 

Immunology (AAAAI) representative, a Technical Expert Panel (TEP) was assembled to provide 

content and methodological expertise in the development of this report (Appendix A). 

Literature Search and Retrieval 

The research librarian, in collaboration with the core research team and TEP, developed 

search strategies designed to identify evidence relevant to each key question of the report. 

For questions relating to the diagnostic test accuracy reviews (Key Questions D–1 to D–6), 

we systematically searched the following electronic resources: MEDLINE®, EMBASE, EBM 

Reviews - Cochrane Central Register of Controlled Trials, AMED, PsycINFO, PASCAL, 

CINAHL®, SPORTDiscus with Full Text, Academic Search Elite, Web of Science®, BIOSIS 

Previews®, PubMed, Scopus®, the Medion Database of Diagnostic Reviews - University of 

Maastricht, and Proquest Dissertations and Theses. The original searches were performed 

between November 5 and 28, 2008. On July 31, 2009, the, the searches were updated using the 

original search strategies in MEDLINE®, EMBASE, Cochrane Central Register of Controlled 

Trials, PASCAL, SPORTDiscus with Full Text, Web of Science®, BIOSIS Previews®, PubMed, 

and Scopus®. 

Search terms were identified by reviewing search strategies of systematic reviews on similar 

topics and by looking at how potentially relevant studies were indexed in various databases. A 

combination of subject headings and text words was adapted for each electronic resource: 

(exerc* OR train* OR fitness OR physical OR athlete* OR sport*) AND (bronchoconstrict* OR 

asthma* OR antiasthma* OR wheez* OR “Respiratory Sounds” OR “Bronchial Spasm” OR 

bronchospas* OR “Bronchial Hyperreactivity” OR “Respiratory Hypersensitivity” OR (bronch* 

AND spasm*) OR (bronch* AND constrict*) OR (bronchial* OR respiratory OR airway* OR 

lung*) AND (hypersensitiv* OR hyperreactiv* OR allerg* OR insufficiency)) OR EIB OR EIA. 

Terms used to limit the searches to diagnostic studies included: diagnos* or predict* or 

probability or accuracy or sensitivity or specificity. Searches were limited to English language. 

Date restrictions were not applied. (See Appendix B for exact search strings). 

Handsearches were conducted to identify literature from symposia proceedings from the 

following scientific meetings: AAAAI Annual Meeting (2007–2008), American Thoracic 

Society (ATS) International Conference (2008), British Thoracic Society (BTS) Winter Meeting 

(2008), Chest Meeting (2008), and the European Respiratory Society (ERS) Annual Congress 

(2008). We also searched the last 3 years (2006–2008) of conference proceedings of the 

American College of Sports Medicine (ACSM) and the Canadian Society for Exercise 

Physiology (CSEP). 

For questions relating to the therapy reviews (Key Questions T–1 to T–6), a comprehensive 

search was run in the Cochrane Airways Register. The Register contains references to 

randomized controlled trials (RCTs) from systematic searches of bibliographic databases 

including Cochrane Central Register of Controlled Trials, Medline®, Embase, Cinahl®, AMED, 

Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/eibeia/eibeia.pdf 

29 
 
PsycINFO, as well as handsearching of respiratory journals and meeting abstracts. The original 

search was performed on November 5, 2008. On August 4, 2009, the, the search was updated 

using the original search strategy. 

Search terms were identified by reviewing search strategies of systematic reviews on similar 

topics and by looking at how potentially relevant studies were indexed in various databases. A 

combination of subject headings and textwords were used: (exerc* OR train* OR fitness OR 

physical OR athlete* OR sport*) AND (bronchoconstrict* OR asthma* OR antiasthma* OR 

wheez* OR “Respiratory Sounds” OR “Bronchial Spasm” OR bronchospas* OR “Bronchial 

Hyperreactivity” OR “Respiratory Hypersensitivity” OR (bronch* AND spasm*) OR (bronch* 

AND constrict*) OR (bronchial* OR respiratory OR airway* OR lung*) AND (hypersensitiv* 

OR hyperreactiv* OR allerg* OR insufficiency)) OR EIB OR EIA. We did not apply language or 

date restrictions. A study design filter was not required as all references in this database are 

RCTs. (Appendix B). The results from the literature searches were entered into a Reference 

Manager for Windows bibliographic database version 11.0 (© 2004-2005 Thomson 

ResearchSoft). 

We handsearched abstracts for those years not yet available in the Cochrane Airways 

Register for the following conference proceedings: AAAAI (2007–2008), ATS International 

Conference (2008), BTS Winter Meeting (2008), Chest Meeting (2008), ERS Annual Congress 

(2008). We also searched the last 3 years (2006–2008) of conference proceedings of the ACSM 

and the CSEP. 

To identify ongoing studies we searched ClinicalTrials.gov and ClinicalStudyResults.org. 

Studies were also identified by checking reference lists of included studies. 

Study Selection 

Our inclusion/exclusion criteria (Tables 4 and 5) were developed in consultation with the 

TEP. 

Table 4. Inclusion and exclusion criteria for the diagnostic test accuracy review 

Study design Prospective or retrospective studies 

Participants Adults and children aged 6 years and older with suspected EIB/EIA. Recreational and 

elite athletes are eligible for inclusion. 

Index tests Self-reported history/symptoms diary; methacholine challenge; sport/venue specific 

exercise challenges; eucapnic voluntary hyperpnea; FRAST; mannitol 

Reference Standardized exercise challenge test (treadmill or cycle ergometer) with a drop in FEV1 

standard of 10% or more from baseline 

Outcomes Studies should provide numeric data for the calculation of diagnostic test 

characteristics (sensitivity, specificity) 

30 
 
Table 5. Inclusion and exclusion criteria for the therapy review 

Study design Randomized controlled trials (parallel or crossover) 

Participants Adults and children aged 6 years and older with confirmed EIB/EIA. Recreational and 

elite athletes are eligible for inclusion. 

Interventions Pre-exercise pharmacologic therapy: For Key Question T-1: regular use (≥1 wk) SABA 

or LABA. For Key Questions T-2 to T-5: single-dose prophylactic use of leukotriene 

receptor antagonists, inhaled corticosteroids, mast cell stabilizers, short-acting 

anticholinergics 

Nonpharmacologic therapy: refractory period (pre-exercise warmup and/or cooldown) 

Comparator For Key Question T-1, any standard comparator treatments and/or placebo. For Key 

Questions T-2 to T-6, no treatment or placebo. 

Outcomes Maximum percent fall in FEV1 or PEF from pre-exercise baseline, symptoms, presence 

or absence of EIB/EIA (complete protection), clinical protection, adverse effects 

We used a two-step process for article screening. First, two reviewers independently screened 

the titles and abstracts (when available) to determine if an article met broad inclusion criteria. 

Each article was rated as “include,” “exclude,” or “unclear.” The full-text of all articles classified 

as “include” or “unclear” were retrieved for formal review. Second, two reviewers independently 

assessed each study using a standard inclusion/exclusion form (Appendix C). Disagreements 

were resolved through discussion between the two reviewers or third party adjudication, as 

needed. 

Assessment of Methodological Quality 

We assessed the methodological quality of the diagnostic test accuracy studies using the 

Quality Assessment of Studies of Diagnostic Accuracy (QUADAS) tool.11 This tool comprises 

14 items that assess several common sources of bias in diagnostic studies, including spectrum 

bias, selection bias, information bias, verification bias, misclassification bias, disease progression 

bias, and excluded data. For the purpose of this review, we chose to include only 13 of the 

QUADAS items. A priori, we determined that the question regarding incorporation bias did not 

apply because none of the index tests under review were incorporated in the reference standard. 

Each item in the QUADAS tool is scored as “yes,” “no,” or “unclear.” In addition, the source of 

funding (e.g., industry, government, other) for each study was recorded.159 Results of the quality 

assessment are presented in the text and a table for each of the individual key questions (D–1 to 

D–6). 

We assessed the methodological quality of RCTs included in the therapy review using the 

Jadad12 scale and Schulz’s criteria to assess allocation concealment.13,14 Components of the 5­

point Jadad scale include randomization, double blinding, and reporting of withdrawals and 

dropouts. Allocation concealment was assessed and scored as “adequate,” “inadequate,” or 

“unclear.” In addition, the source of funding for each study (e.g., industry, government, other) 

was recorded.159 Results are presented in the text and a table for each of the individual key 

questions (T–1 to T–6). 

The methodological quality of included studies was assessed independently by two 

reviewers. Decision rules regarding application of the quality assessment tools were developed a 

priori (Appendix C). Discrepancies were resolved through discussion between the two reviewers 

or third party adjudication, as needed. 

31 
 
Grading the Body of Evidence 

For the diagnostic test accuracy reviews, we graded the available evidence for each key 

question using the GRADE system for rating the quality of evidence and strength of 

recommendations for diagnostic tests.15 We assessed the strength of the study designs, the 

quantity and quality of individual studies, and the consistency and precision of the results. We 

also assessed the indirectness of evidence. For all studies, the outcomes were measures of test 

accuracy (i.e., true positive, true negative, false positive, false negative), which are surrogates for 

patient-important outcomes. We determined that true positive and true negative results would 

improve outcomes that are important to patients. True positive results will lead to administration 

of effective, safe prophylactic treatment for EIB/EIA; true negative results will spare patients 

unnecessary treatment or further testing for EIB/EIA. We identified uncertainty about the 

consequences of false positive results which could lead to unnecessary treatment for EIB/EIA 

and the potential exclusion of individuals from participating in sports or working in occupations 

requiring heavy physical demands. We also determined that there was uncertainty about 

directness for false negative results related to delayed access to prophylactic and/or rescue 

treatments, ongoing symptoms of EIB/EIA, underperformance in physical activity, and reduced 

quality of life leading to avoidance of physical activities and sports. This uncertainty about 

directness resulted in a reduction in the quality of evidence. For each key question the quality of 

evidence was graded as high, moderate, low or very low. 

For the therapy reviews, the strength of evidence for the primary outcome (maximum percent 

fall in FEV1 from baseline) was assessed for each key question using the EPC approach to 

grading the strength of a body of evidence.16 This approach assesses the evidence based on four 

domains: risk of bias, consistency, directness, and precision. We classified the strength of 

evidence as high, moderate, low, or insufficient. 

Data Extraction 

Data were extracted using standard forms (Appendix C) by one reviewer and checked for 

accuracy and completeness by a second reviewer. Data extracted for each study included details 

of study design and inclusion/exclusion criteria, details of the population, details of the index test 

and reference standard (for the diagnostic test accuracy reviews), intervention and comparator 

(for the therapy reviews), and results obtained for various outcomes. Reviewers resolved 

discrepancies in data extraction by consensus or in consultation with a third party. 

Data Analysis 

The following data assumptions were made and imputations performed to transform reported 

data into the form required for this report. Graph extraction was performed using CorelDRAW® 

9.0 (Corel Corp., Ottawa, Canada). Means were approximated by medians, and 95 percent 

empirical intervals were used to calculate approximate standard deviations (SD). Because the 

majority of the included studies in the therapy reviews used a crossover design, standard errors 

of mean differences were either computed exactly using individual patient data (IPD) or imputed 

using an estimated within-patient correlation of 0.5. 

32 
 
Diagnostic Test Accuracy Review 

Our reference standard was a standardized ECT- either using a treadmill or bicycle 

ergometer. Our threshold for a positive test on the ECT was a fall in FEV1 of 10 percent or more 

from a pre-exercise baseline.18 Thresholds of 15 percent and 20 percent were examined in 

sensitivity analyses. The threshold for a positive test for the methacholine challenge was a 20 

percent or more drop in FEV1 at a provocative concentration of less than 8 mg/ml (PC20).18 For 

mannitol the threshold was a 15 percent drop in FEV1 at less than 635mg or a drop of 10 percent 

between consecutive doses.23 The threshold for a positive test for EVH, FRAST and sport/venue 

specific challenges was a fall in FEV1 of 10 percent or more. Where data were available we 

conducted sensitivity analyses using a different threshold dose for methacholine (less than 16 

mg/ml). True positives, false positives, true negatives, and false negatives were recorded for each 

of the six index tests. These data were used to calculate sensitivity and specificity for each study. 

We present individual study results graphically by plotting the estimates of sensitivity and 

specificity and their 95 percent confidence intervals (95 percent CI) in forest plots. Where there 

were more than five studies, we plotted the sensitivity and specificity in receiver operating 

characteristic (ROC) space and present a summary ROC curve. Area under the curve (AUC) was 

estimated. 

Because many of the studies presented IPD, we were able to use our thresholds for both 

reference and index tests for our primary and sensitivity analyses. Where no IPD were available 

and a different threshold was used by the study authors, we presented a qualitative summary of 

the results of the study. 

Planned subgroup analyses included age (children [less than 18 years old] versus adult [18 

years and older]), different thresholds for positive results, and patients with EIB versus EIA. 

Therapy Review 

For studies assessing therapy of the five treatments compared with a control or placebo, a 

mean difference (MD) was calculated for continuous variables and a risk ratio (RR) was 

calculated for dichotomous variables. Results are reported with accompanying 95 percent CI. 

Meta-analyses were conducted using the random effects model where appropriate. The I2 

statistic was used to assess heterogeneity.17 Planned subgroup analyses included age (children 

[less than 18 years old] versus adult [18 years and older]), severity of EIB/EIA as defined by the 

percent fall index on placebo (mild [less than 30 percent] versus moderate-severe [30 percent or 

more]), and patients with EIB versus EIA. 

 Sensitivity analyses were conducted to assess the robustness of the findings across study 

quality.160 When meta-analyses had sufficient studies, publication bias was tested visually using 

the funnel plot. All data pooling was performed using Review Manager 5.0 (The Cochrane 

Collaboration, Copenhagen, Denmark). 

Peer Review 

Eight experts in the field (Appendix A) agreed to peer review the draft report and provide 

comments. Reviewer comments were considered by the UAEPC in preparation of the final 

report. All peer reviewer comments and the UAEPC disposition of comments were submitted to 

AHRQ for assessment and approval. 

33 
 

 

Chapter 3. Results 

Diagnostic Test Accuracy Review 

Literature Search 

The search strategy for the diagnosis of EIB/EIA identified 5,318 citations from electronic 

databases and six additional references by handsearching (Figure 1). Screening these titles and 

abstracts identified 434 potentially relevant references. Ten studies could not be retrieved 

(Appendix D). Most of these were abstracts that were only available in supplementary issues of 

journals; they were requested through interlibrary loan but did not arrive by the time this report 

was written. The search update identified an additional six studies for further evaluation. Overall 

28 studies met the inclusion criteria for this report; 412 studies were excluded. The included 

studies addressed the following research questions: self-report (n=2),21,22 methacholine (MCH) 

challenge (n=15),23-37 sport/venue specific challenges (n=54),34,38-41 eucapnic voluntary 

hyperpnea (EVH; n=7),34,38,39,42-45 FRAST (n=3),36,40,46 and mannitol (n=3).23,47 

The main reasons for excluding studies were (1) the diagnostic technique did not assess 

EIB/EIA (n=158), (2) inappropriate study design (n=116), (3) there was no comparison group 

(n=46), (4) there were insufficient data to construct a 2x2 table (n=26), (5) the study assessed 

other diagnostic tests that were not included in this report (n=24), and (6) there was an 

inappropriate reference standard (n=21). Eleven studies were excluded for other reasons. The list 

of excluded studies and reasons for exclusion are identified in Appendix D. 

Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/eibeia/eibeia.pdf 

35 
 
Figure 1. Diagnosis of EIB/EIA: Flow diagram for study retrieval and selection 

Records identified through 

database searches for screening 

n = 5,318 

Potentially relevant studies 

assessed for eligibility 

n = 434 

Studies identified through 

handsearching 

n = 6 

Primary studies 

included in the review 

n = 28 

FRAST 

n = 3 

Eucapnic 

voluntary 

hyperpnea 

n = 7 

Mannitol 

n = 3 

Methacoline 

n = 15 

Self report 

n = 2 

Sport/Venue 

n = 5 

Excluded studies n = 412 

- Not dx EIB/EIA = 158 

- Study design = 116 

- Comparison = 46 

- Insufficient data = 26 

- Other dx test = 24 

- No reference standard = 21 

- Population = 8 

- Duplicate publications = 2 

- Language = 1 

- Reports pending retrieval = 10 

Search update (July 2009) 264 

records retrieved; potentially 

relevant n = 6 

* Some studies address more than one research question 

Records excluded 

n = 4,890 

36 
 
 

Key Question D–1: Self-Reported History or Symptoms Diary 

Description of Included Studies 

Two studies21,22 met the inclusion criteria for the diagnostic test accuracy review of selfreported history/symptoms diary compared with a standardized exercise challenge test (ECT). 

Tables 6 and 7 summarize the study and participant characteristics. 

In the study by Frobase et al.21 20 junior high school athletes (11 to 15 years) who responded 

“yes” to the question “do you experience cough after exercise?” were included. They were 

matched to 20 controls who responded “no” to the same question. All participants underwent a 

treadmill ECT. They ran for 6 minutes at an intensity of 85 to 90 percent of predicted maximum 

heart rate. No information about a history of asthma was provided. 

In the study by Rupp et al.22 166 high school athletes (12 to 18 years) completed a self-report 

questionnaire that included two questions relevant to EIB/EIA (“do you have trouble breathing 

after running 1 mile and resting?” and “do you have to stop when running for 1⁄2 mile?”). Fortyeight students (29 percent) were identified as being at risk for EIB/EIA based on baseline 

spirometry or by clinical history. All participants underwent a treadmill ECT. They ran for 6 

minutes after reaching 80 percent of their predicted maximum heart rate. 

Methodological Quality of the Included Studies 

Table 8 summarizes the methodological quality of the included studies. The number of 

“unclear” responses for both studies raises questions regarding bias and generalizability. Neither 

study had a representative patient spectrum which suggests the possibility of spectrum bias. 

Blinding to the results of the ECT and the index test was not reported. There were no details 

about uninterpretable or indeterminate index test results. One study22 did not report their source 

of funding; one21 was supported by government grants. The body of evidence is classified as 

“low.” 

Quantitative Results 

The two studies used different thresholds to define a positive result on the ECT. Using a 

threshold of a maximum percent fall in FEV1 of 10 percent or more, Frobase et al.21 reported a 

sensitivity of 89 percent (95 percent CI: 67, 99) and a specificity of 86 percent (95 percent CI: 

64, 97). In the study group, 17 (85 percent) participants had a positive ECT; in the control group 

2 (10 percent) had a positive ECT. 

Using a threshold of 15 percent or more, Rupp et al.22 reported a sensitivity of 36 (95 percent 

CI: 17, 59) and specificity of 85 percent (95 percent CI: 78, 90). Twenty participants (13 percent) 

had a positive ECT; 30 (18 percent) were at risk of EIB/EIA based on the questionnaire. 

37 
 
38
 


Table 6. Description of studies in the diagnostic test accuracy review: Self-report vs. ECT Author Year Study design; Order of tests REFERENCE STANDARD (ECT) INDEX TEST (Self-re

Study days; Challenges per day [N]; Type; Duration (min) Type; Description 

Time between challenges Load; Environmental conditions 

Concomitant treatment for asthma Follow-up time points 

Author definition of EIB 

Frobase21 1992 Case control (prospective); self-report first Treadmill; 6 Do you experience co

NR; NR 85-90% max HR; NR NR PEF at 3 min intervals up to 15 min NR ≥10% fall FEV1 

Rupp22 1993 Cross sectional (prospective); self-report Treadmill; 6 Determination of risk 

first 6 mph, 10% grade after HR reached 170 bpm; components of pre-

NR; NR; all ECT completed in 1 mo 45-55% RH, air conditioned 22-25oC questionnaire, phys

period Aug-Sept 1990; back to back After 1 min cooldown, 1, 10, 20, 30 min participants catego

NR ≥15% fall FEV1 ≤80% of predicted v

≤0.80 

bpm = beats per minute; C = Celsius; ECT = exercise challenge test; EIB/EIA = exercise-induced bronchoconstriction/asthma; FEV1 = forced expirato

= forced vital capacity; HR = heart rate; max = maximum; min = minute(s); mph = miles per hour; NR = not reported; PFT = pulmonary function testTable 7. Description of participants in the diagnostic test accuracy review: Self-report vs. ECT Author Year Frobase21 1992 

Participants enrolled (N); 

analyzed (N) 

Age (range) Males: N (%) 

20; 20 

Recruitment Country Index of activity (fitness level) Junior high school students answering yes 

History of asthma N (%); Asthma 

severity; Atopic status N (%); History of ICS 

History of EIB/EIA NR; NR 

11-15 to "Do you cough after exercise?" NR 

NR U.S. NR 

NR NR 

Rupp22 1993 166; 166 High school (students in athletic program) NR; NR 

12-18 U.S. NR 

121 (72.8) High school athletes NR 

NR 

EIB/EIA = exercise-induced bronchoconstriction/asthma; FEV1 = forced expiratory volume in 1 second; ICS = inhaled corticosteroids; NR = not repo
Table 8. Methodological quality of the studies in the diagnostic test accuracy review: Self-report vs. ECT 

Author Year 

Representative spectrum 

Selection criteria defined 

Acceptable reference 

standard

Timing bias avoided 

Partial verification avoided

Differential verification

avoided

Clear reporting of index test

Clear reporting of reference 

standard

Index test blinded 

Reference standard blinded

Clinical data

Uninterpretable results 

reported 

Frobase21 1992 No No Yes Yes Yes Yes Yes U U U U U 

Rupp22 1993 U U Yes Yes Yes Yes U Yes U U U U 

U = unclear 

39 
 

Key Question D–2: Methacholine Challenge 
 

Description of Included Studies 

Fifteen studies23-37 met the inclusion criteria for the diagnostic test accuracy review of a 

methacholine (MCH) challenge compared with a standardized exercise challenge test (ECT). All 

studies were conducted prospectively. Twelve used a cross sectional study design,23-25,27-32,34-36 

three26,33,37 used a case-control design. One was published as a meeting abstract;24 fourteen were 

published in peer reviewed journals. The median year of publication was 1994 and ranged from 

1973 to 2009. Studies were conducted in Europe,27,29-31,34,35,37 the United States,23,26,28 the Middle 

East,24,25 Asia,32,33 and South America.36 

The characteristics of the studies are summarized in Table 9. The standardized ECT was 

performed on a treadmill23-28,30,32-34 or a bicycle ergometer.29,31,35-37 A positive test was defined at 

five different cutpoints using the maximum percent fall in FEV1 of 8 percent or greater,25 10 

percent or greater,23,24,30,34,36,37 15 percent or greater,27,31 18 percent or greater,28 and 20 percent 

or greater.26,29,32,33,35 Most studies reported the target workload as between 80 to 90 percent of 

maximum predicted heart rate. In one study the target workload was described as “to 

exhaustion”34 and in another “target ventilation output of more than 60 percent of predicted 

maximum voluntary ventilation.”37 For two studies, the target workload was not reported.24,25 

MCH challenges were based on the 2 minute tidal breathing method25,27,29,30,35 or the five 

breath dosimeter method.23,26,28,32-34,36,37 For the remaining studies, the protocol was either 

specific to the particular study group or was not clearly described.24,31 

The baseline characteristics of the participants are presented in Table 10. The number of 

participants in each study ranged from 12 to 375 (median=52; IQR 28, 59). Six studies involved 

adults,26,28,31,33,34,37 seven involved children,24,27,29,30,32,35,36 and two included both adults and 

children.23,25 One study focused on elite female swimmers34 and one on endurance athletes.37 The 

remaining studies did not report on the level of fitness or sports participation. Most studies 

included participants who had a history of asthma.23-26,28,29,31-33,35,36 Generally, asthma was mild 

to moderate and stable. For the studies that used a case-control design,26,33,37 the control group 

comprised healthy controls who had no history of asthma. 

Methodological Quality of Included Studies 

Table 11 summarizes the methodological quality of the included studies. There are several 

methodological issues in this group of studies. Of concern is the risk of spectrum bias. Most 

studies did not report how participants were recruited into the study, nor did they describe the 

inclusion criteria; three studies recruited volunteers.26,30,34 Blinding of results of the ECT to the 

results of the MCH challenge was not reported. Seven studies did not report their sources of 

funding.24,25,27-29,35,36 Four studies received funding support from industry,23,30-32 and six were 

supported by government and/or institution grants.26,30,31,33,34,37 The body of evidence is classified 

as “moderate.” 

Quantitative Results 

We analyzed the data using two concentration thresholds for MCH: PC20 MCH less than 8 

mg/ml and PC20 MCH less than 16 mg/ml. Regardless of the threshold, there was considerable 

heterogeneity across the studies. Using the PC20 MCH less than 8 mg/ml threshold 331 (57 

40 
 
 

0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1 

percent) tested positive for EIB/EIA on the ECT; 416 (71 percent) were positive on the MCH 

challenge. Sensitivity and specificity both ranged from 0 to 100 percent. (Figure 2) 

Figure 2. Forest plot of sensitivity and specificity: Methacholine challenge vs. ECT (PC20 MCH less than 8 

mg/ml; FEV1 fall index 10 percent or more for ECT) 

Study TP FP FN TN Sensitivity Specificity Sensitivity Specificity 

Avital 1989 49 19 0 2 1.00 [0.93, 1.00] 0.10 [0.01, 0.30] 

Avital 2000 80 45 1 2 0.99 [0.93, 1.00] 0.04 [0.01, 0.15] 

Chatham 1982 9 6 0 0 1.00 [0.66, 1.00] 0.00 [0.00, 0.46] 

Clough 1990 11 9 11 29 0.50 [0.28, 0.72] 0.76 [0.60, 0.89] 

Eggleston 1979 27 0 14 2 0.66 [0.49, 0.80] 1.00 [0.16, 1.00] 

Foresi 1986 21 4 0 0 1.00 [0.84, 1.00] 0.00 [0.00, 0.60] 

Henriksen 2002 8 22 12 16 0.40 [0.19, 0.64] 0.42 [0.26, 0.59] 

Koh 1996 27 7 11 8 0.71 [0.54, 0.85] 0.53 [0.27, 0.79] 

Lin 1991 14 7 0 1 1.00 [0.77, 1.00] 0.13 [0.00, 0.53] 

Pedersen 2008 0 6 4 6 0.00 [0.00, 0.60] 0.50 [0.21, 0.79] 

Sekerel 1997 11 1 0 0 1.00 [0.72, 1.00] 0.00 [0.00, 0.97] 

Souza 2005 12 11 1 6 0.92 [0.64, 1.00] 0.35 [0.14, 0.62] 

Verges 2005 3 7 5 37 0.38 [0.09, 0.76] 0.84 [0.70, 0.93] 

Using the PC20 MCH less than 16 mg/ml threshold 420 (53 percent) tested positive for EIB/EIA 

on the ECT; 498 (63 percent) were positive on the MCH challenge. Heterogeneity in sensitivity 

estimates was reduced somewhat (range 55 to 100); specificity still ranged from 0 to 100 percent 

(Figure 3). 

Figure 3. Forest plot of sensitivity and specificity: Methacholine challenge vs. ECT (PC20 MCH less than 16 

mg/ml; FEV1 fall index 10 percent or more for ECT) 

Study TP FP FN TN Sensitivity Specificity Sensitivity Specificity 

Anderson 2009 90 66 73 146 0.55 [0.47, 0.63] 0.69 [0.62, 0.75] 

Avital 2000 80 47 1 0 0.99 [0.93, 1.00] 0.00 [0.00, 0.08] 

Chatham 1982 9 6 0 0 1.00 [0.66, 1.00] 0.00 [0.00, 0.46] 

Clough 1990 14 12 8 26 0.64 [0.41, 0.83] 0.68 [0.51, 0.82] 

Eggleston 1979 32 0 9 2 0.78 [0.62, 0.89] 1.00 [0.16, 1.00] 

Foresi 1986 21 4 0 0 1.00 [0.84, 1.00] 0.00 [0.00, 0.60] 

Henriksen 2002 13 30 7 8 0.65 [0.41, 0.85] 0.21 [0.10, 0.37] 

Koh 1996 32 9 6 6 0.84 [0.69, 0.94] 0.40 [0.16, 0.68] 

Lin 1991 14 7 0 1 1.00 [0.77, 1.00] 0.13 [0.00, 0.53] 

Sekerel 1997 11 1 0 0 1.00 [0.72, 1.00] 0.00 [0.00, 0.97] 

0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1 

The area under the curve (AUC) of the ROC curve was marginally more than 0.5 using a 10 

percent fall in FEV1 for a positive ECT and a PC20 MCH of less than 8 mg/ml (Figure 4) for a 

positive MCH. There was no improvement in the AUCs for any of the FEV1 cutpoints (10, 15 or 

20 percent) or the MCH threshold (data not shown). 

41 
 
 

Figure 4. ROC curve plotting sensitivity vs. specificity: Methacholine challenge vs. ECT (PC20 MCH less than 

8 mg/ml; FEV1 fall index 10 percent or more for ECT) 

Sensitivity 1 

0.9 

0.8 

0.7 

0.6 

0.5 

0.4 

0.3 

0.2 

0.1 

0 

1	 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
 

Specificity
 

To explore heterogeneity, we performed a subgroup analysis on studies in which all 

participants had a diagnosis of asthma.24-26,28,29,32,33,35,36 This analysis (Figure 5) reduced the 

heterogeneity in sensitivity somewhat (range from 66 to 100); however, specificities ranged from 

0 to 100 percent. Among this group of participants, 277 (70 percent) tested positive for EIA on 

the ECT; 350 (88 percent) were positive to the MCH challenge. 

Figure 5. Forest plot of sensitivity and specificity: Methacholine challenge vs. ECT in studies in which all 

patients had asthma (PC20 MCH less than 8 mg/ml; FEV1 fall index 10 percent or more for ECT) 

Study TP FP FN TN Sensitivity Specificity Sensitivity Specificity 

Avital 1989 49 19 0 2 1.00 [0.93, 1.00] 0.10 [0.01, 0.30] 

Avital 2000 80 45 1 2 0.99 [0.93, 1.00] 0.04 [0.01, 0.15] 

Chatham 1982 9 6 0 0 1.00 [0.66, 1.00] 0.00 [0.00, 0.46] 

Eggleston 1979 27 0 14 2 0.66 [0.49, 0.80] 1.00 [0.16, 1.00] 

Foresi 1986 21 4 0 0 1.00 [0.84, 1.00] 0.00 [0.00, 0.60] 

Koh 1996 27 7 11 8 0.71 [0.54, 0.85] 0.53 [0.27, 0.79] 

Lin 1991 14 7 0 1 1.00 [0.77, 1.00] 0.13 [0.00, 0.53] 

Sekerel 1997 11 1 0 0 1.00 [0.72, 1.00] 0.00 [0.00, 0.97] 

Souza 2005 12 11 1 6 0.92 [0.64, 1.00] 0.35 [0.14, 0.62] 

0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1 

In the subgroup of four studies in which fewer than 50 percent of participants had 

asthma27,30,34,37 heterogeneity remained (Figure 6). Sensitivity ranged from 0 to 50 percent and 

42 
 
specificity from 42 to 84 percent. Among this group of participants, 54 (29 percent) tested 

positive for EIB/EIA on the ECT; 66 (35 percent) were positive to the MCH challenge. Of note, 

the study by Pedersen et al.34 focused on elite swimmers; when this study was excluded, 

sensitivity ranged from 38 to 50 percent and specificity from 42 to 76 percent. 

Figure 6. Forest plot of sensitivity and specificity: Methacholine challenge vs. ECT in studies in which less 

than 50 percent of patients had asthma (PC20 MCH less than 8mg/ml; FEV1 fall index 10 percent or more for 

ECT) 

Study TP FP FN TN Sensitivity Specificity Sensitivity Specificity 

Clough 1990 

Henriksen 2002 

Pedersen 2008 

Verges 2005 

11 

8 

0 

3 

9 

22 

6 

7 

11 

12 

4 

5 

29 

16 

6 

37 

0.50 [0.28, 0.72] 0.76 [0.60, 0.89] 

0.40 [0.19, 0.64] 0.42 [0.26, 0.59] 

0.00 [0.00, 0.60] 0.50 [0.21, 0.79] 

0.38 [0.09, 0.76] 0.84 [0.70, 0.93] 

0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1 

We also explored the following possible sources of heterogeneity: adults versus children, 

treadmill versus bicycle ergometer ECT, the five breath dosimeter versus 2 minute tidal 

breathing method for the MCH challenge, and cold/dry air versus other conditions during the 

ECT. There was no improvement in heterogeneity for any of these subgroups. 

43 
 
Table 9. Description of studies in the diagnostic test accuracy review: Methacholine vs. ECT 

Author Year Study design; Order of tests REFERENCE STANDARD (ECT) INDEX TEST (M

Study days; Challenges per day [N]; Type; Duration (min) Type; DescriptioTime between challenges Load; Environmental conditions Follow-up time Concomitant treatment for asthma Follow-up time points Author definitio

Author definition of EIB 

Anderson23 Cross sectional (prospective); ECT first Treadmill; 6 5 breath dosimet

2009 5 visits; 1; 80-90% max H; concentrations 

ECT - MCH: 1-2 d; ECT - Mannitol: 1-2 d; medical grade dry air from Douglas bag; 20-25oC measured within 

MCH - Mannitol: 1 d Pre-ECT, 5, 10, 15, 30 min post ECT NR 

NR ≥10% fall FEV1 PC20 MCH ≤16 m

Avital24 1989 Cross sectional (prospective); NR Treadmill; 6 Steady state tida

2; 1; 6 km/hr at 10% slope concentrations a2 within a 2 mo period RH and temp NR NR NR NR PC20 MCH <8 mg

≥10% fall FEV1 

Cross sectional (prospective); MCH first Treadmill; 6 (5 km/h, 10% slope) 2 min tidal breath

Varied; 3; NR concentrations 

85% within 7 d; 15% within 30 d RH 48-56%; 22-26oC measurements a

Withheld: Bronchodilators ≥12 hr; SCG Pre-ECT, 1, 3, 5, 10, 15 min post ECT inhalation 

Avital25 2000 

≥20 hr; ICS continued unchanged ≥8% fall FEV1 	 NR 

PC20 MCH <8 mg

Chatham26 1982 Case-control (prospective); MCH first Treadmill; 6 5 breath dosimet

2; all within 48 hr; 24 hr 

90 max HR RH 40.1±13.3%; 22.3±1oC 

concentrations increments 

Withheld: bronchodilators, Pre-ECT, 5, 15, 30, 60 min post ECT NR 

methylxanthines, antihistamines x 72 hr ≥20% fall FEV1 	 PC20 MCH 

Clough27 1991 Cross sectional (prospective); Treadmill; 6 2 min tidal breath

Randomized order: half MCH first, half 4.8 km/hr, 15% slope; 90% max HR concentrations 

ECT first RH NR; air conditioned room NR 

2; 1; Pre-ECT, 3, 5, 10 min post ECT PC20 MCH <6.4 μ

24 hr ≥15% fall FEV1 

Withheld: beta2-agonists x 6 hr; all other 

med. x 24 hr 

bpm = beats per minute; C = Celsius; d = day(s); ECT = exercise challenge test; EIB/EIA = exercise-induced bronchoconstriction/asthma; hr = hour(s

kilometers per hour; ICS = inhaled corticosteroids; m = meters; μmol = micromole; max = maximum; mcg = microgram; MCH = methacholine; med milligram per milliliter; min = minute(s); mo = month(s); mph = miles per hour; NR = not reported; PC20 = provocative concentration causing a 20% f

expiratory flow; PSI = pounds per square inch; RH = relative humidity; rpm = revolutions per minute; SABA = short-acting beta-agonist; SCG = sodiu

standard deviation; sec = seconds; temp = temperature; wk = week(s) 

44
 

Table 9. Description of studies in the diagnostic test accuracy review: Methacholine vs. ECT (continued) 

Author Year Study design; Order of tests REFERENCE STANDARD (ECT) INDEX TEST 

Study days; Challenges per day [N]; Type; Duration (minutes) Type; DescriptioTime between challenges Load; Environmental conditions Follow-up time Concomitant treatment for asthma Follow-up time points Author definitio

Author definition of EIB 

Eggleston28 Cross sectional (prospective); ECT first Treadmill; 5 5 breath dosimet

	 

1979 NR; NR; 90% max HR 1.5 and 3 min aft

<3 mo 


 

RH and temp NR NR 
 

Withheld: SABA x 8 hr; LABA x 12 hr; Pre-ECT, 1, 5, 10, 15, 20 min post ECT PC20 MCH 

SCG x 2 wk 	 

≥18% fall FEV1

Foresi29 1986 Cross sectional (prospective); MCH first Bicycle ergometer; 6 2 min tidal breath

3; 1; Resistance of 2.0 - 3.5 watts/kg; workload=90% concentrations 

48 hr max HR 1.5, 3 min after 19 on no drugs or SABA as necessary; 2 RH ≤50%; 22oC PC20 MCH 

on SABA (200 mcg 4 /d); Pre-ECT, immediately after, 5 min intervals x 30
 

min post ECT 3 on IB 80 mcg + SABA 200 mcg 4 /d Withheld: all x 12 hr >20% fall FEV1 


 
 

Henriksen30 

2002 

Cross sectional (prospective); ECT first 2; 1; 2-7 d after d 1 NR 

Treadmill; 6 to 8 5.5% incline; load increased during 1st 2 min by 

increasing speed to HR of 180 bpm; load further increased to 90% max HR of 220 bpm minus age during last 4 min 

RH mean 34%, range 33-35%; mean 22oC, range 

20-24oC 

2 min tidal breath

mg MCH in 5 in

NR PC20.MCH 

Pre-ECT immediately after, 3, 6, 10, 15 min post 

ECT 

≥10% fall FEV1 

Kiviloog31 1973 Coss sectional (prospective); MCH first 

1; 2 (MCH in am; ECT in pm); at least 4 hr Withheld: steroids x 8 hr; bronchodilators, 

coffee, tea, antihistamines, anticholinergics x 24 hr 

Bicycle ergometer; load increased every 6 min by 

49 (males) or 33 watts (females) to exhaustion (80-102%); RH mean 41, range 15-66%; mean 19oC, range 18-25.5oC, no fan used 

2, 6, 10, 15, 30 min post-exercise ≥15% fall in PEF for ECT within 10 min of 

termination 

Concentrations o

0.25 (x15), 2.5 breath 

NR Decrease in PEF 

min of terminat

response decre

45
 

Table 9. Description of studies in the diagnostic test accuracy review: Methacholine vs. ECT (continued) 

Author Year Study design; Order of tests REFERENCE STANDARD (ECT) INDEX TEST 

Study days; Challenges per day [N]; Type; Duration (min) Type; DescriptioTime between challenges Load; Environmental conditions Follow-up time Concomitant treatment for asthma Follow-up time points Author definitio

Author definition of EIB 

Koh32 1996 Coss sectional (prospective); ECT first Treadmill; 6 5 breath dosimet

2 consecutive d; 1; 80-90% max HR (slope/speed adjusted) concentrations 

17 hr (d1=MCH test at 4 pm; d2=ECT at 9 RH NR; no variations in environmental temp, air increments; me

am) conditioned, NR 

Withheld: no meds or caffine on test day; 

ICS x 24 hr; cromolyn sodium x 7d 

3-10 min apart until 60 min post-ECT ≥20% fall FEV1 

PC20 MCH 

Lin33 1991 Case-control (prospective); ECT first 

2; 1, then 4; MCH then ECT 1-3 wk later NR 

Treadmill; 6 3 mph at 10% incline, adjusted until HR reached 

90% predicted age max for 4 min 

RH and temp NR Pre-ECT, 5, 10, 15, 20, 25, 30 min post ECT ≥20% fall FEV1 

5 breath dosimet

concentrations 

NR PC20.MCH 

Pedersen34 	 

2008 

46
 

Cross sectional (prospective); NR 4 visits; NR; at least 24 hr apart NA 

Treadmill; 5±1.1 Ran until exhausted at constant speed with 

gradiant increasing 2% every 2 min 

RH and temp NR Pre-ECT, 1, 3, 5, 10, 15, 20 min post ECT ≥10% fall FEV1 

5 breath dosimet

measured afte

NR 
 PC20.MCH ≤2μm

Sekerel35 1997 Cross sectional (prospective); randomized Bicycle ergometer; 6 2 min tidal breath

order of tests 90% max HR concentrations 

3; 1; RH and temp NR 0.5 and 1.5 min 

within 1 wk at same time of d 1, 5, 10, 15, 20 min post ECT NR Withheld: oral med x 24 hr; inhaled med x ≥20% fall FEV1 PC20.MCH 

12 hr 

Cross sectional (prospective); randomized Bicycle ergometer; 6 (nose clips) 5 breath dosimet

order of tests 80-90% max HR after 1-2 min warmup (target concentrations 

3; 1 (all 8-10 am); min 24 h to 10 d 178±7 bpm) NR Withheld: coffee, tea, drinks with caffine x compressed air RH ~50%; 21.1±1oC PC20 MCH ≤6.6μ 

	 

Souza36 2005 

2 hr; SABA x 12 h; antihistamines x 48 3, 6, 10, 15, 20, 30 min post ECT
 

hr (short-acting) x 5 d (long-acting) ≥10% fall FEV1 
 

Verges37 2005 Case-control (prospective); MCH Bicycle ergometer; 12 at >60% max HR, voluntary 5 breath dosimet

first ventilation (35 x FEV1) concentrations 

1; 6; RH dry medical air; NR measured 2 m

mean interval of 6.2±1.5 hr (range=4-10 Pre-ECT, 1, 3, 5, 7, 10, 15 min post ECT NR 

hr) between MCH and ECT ≥10% fall FEV1 PC20 MCH <4 mg 

Withheld: SABA x 48 hr; ICS x 3 wk 
Table 10. Description of participants in the diagnostic test accuracy review: Methacholine vs. ECT 

47
 


Author Year Participants enrolled (N); 

analyzed (N) 

Age (mean±SD) Males: N (%) 

Recruitment Country Index of activity (fitness level) 

History of asthma N (%); Asthma 

severity; 

Atopic status N (%); History of ICS N (%) History of EIB/EIA 

Bas

Bas

% p

Anderson23 510; 375 (performed all tests) Clinic (referred for investigation of Suspected asthma at ≥step 1 3.3

2009 24.3±10.2; range 6-50 asthma-type symptoms) NAEPPII asthma severity 93.

182 (48.2) U.S. grading; mild to stable NAEPPII 

NR score 1.2±0.5 

293 (78) none within 4 wk prior to study NR 

Avital24 1989 70; 70 NR Severe=14; moderate=22; mild=34 NR 

11.3; range 5-19 Israel NR NR NR NR NR 

NR 

Avital25 2000 135; 128 Clinic (pediatric pulmonology) ATS criteria; mild=85 (63.0), NR 

12.4±3.9; range 6-25 Israel moderate=50 (37.0) 86.NR NR NR All 

38 (28.1) inhaled beclomethasone p

dipropionate F

NR 

Chatham26 1982 25; 25 Clinic and newspaper advertising 15 (60); mild (all asymptomatic) NR 

All: 26.4±4.7, asthmatics: U.S. 15 (60) All: 

26.5±4.6 NR 12/15 (80); none for 4 wk 7

All: 15 (60), asthmatics: 9 (60) History of EIA in asthmatics 11/15 

(73.3) 

Clough27 1991 60; 60 Clinic (all registered to 86 general 24 (40) physician Dx or receiving NR 

Range 7-8 practitioner offices were sent anti-asthma med or parent NR 38 (63.3) questionnaire) thought child had asthma 

United Kingdom NR 

NR All taking beta-agonists: 21 

inhalation, 3 orally; 3 SCG; 1 oral theophylline 

Atopy 30 (50); ICS 2 (3.3) NR 

ATS = American Thoracic Society; BHR = bronchial hyper-responsiveness; CI = confidence interval; d = day(s); Dx = diagnosis; ECT = exercise chaexercise-induced bronchoconstriction/asthma; FEV1 = forced expiratory volume in 1 second; hr = hour(s); Hx = history; ICS = inhaled corticosteroids

methacholine; NAEPPII = National Asthma Education and Prevention Program; NR = not reported; prn = as needed; SABA = short-acting beta-agoni

cromoglycate; SD = standard deviation; Tx = treatment; wk = week(s) 
Table 10. Description of participants in the diagnostic test accuracy review: Methacholine vs. ECT (continued) 

48
 


Author Year Participants enrolled (N); 

analyzed (N) 

Age (mean±SD) Males: N (%) 

Recruitment Country Index of activity (fitness level) 

History of asthma N (%); Asthma 

severity; 

Atopic status N (%); History of ICS History of EIB/EIA 

Bas

Bas

Eggleston28 45; 45 NR 45 (100) defined by ATS; NR NR 

1979 21.1±3.1; range 16-30 U.S. 42 (93.3) 94.

27 (60) NR 5 (11.1) 

Most had history of EIA 

Foresi29 1986 25; 25 NR 25 (100) clinical Hx of asthma; all NR 

12.5±2.8; range 9-19 Italy FEV1 >70% predicted, all stable 91.

19(76) NR in previous month; 

25 (100) none on ICS NR 

Henriksen30 74; 58 Adolescents with wheeze from NR; beta-agonist=11(19) NR 

2002 mean 17.9 (95% CI: 17.6, 18.3) previous phase of study NR Me

16 (25.4) Norway ICS=4(6.6) 

Physical activity hr/wk, mean (95% NR 

CI)=3.1 (2.8-3.5) 

Kiviloog31 1973 57; 57 Clinic (lung clinic outpatients) 57 (100) defined by ATS, NR NR 

31; range 15-61 Sweden extrinsic asthma 32 (56.1%) NR 26(45.6) NR NR 

47 (82.5%) 

Koh32 1996 56; 53 NR 53 (100); mild, stable; beta-agonist NR 

9.9±2.5; range 6-15 South Korea prn, SCG 11/56 97.41(73.2) NR 43 (76.8) 

NR NR 

Lin33 1991 42 (22 asymptomatic asthma, 20 Authors selected subjects 22 asthma patients; stable Bef

matched controls); 22 (only China medicated basthma pts analyzed) NR NR NR 

Range 20-40 NR 12(60) NR 
Table 10. Description of participants in the diagnostic test accuracy review: Methacholine vs. ECT (continued) 

49
 


Author Year Participants enrolled (N); 

analyzed (N) 

Age (mean±SD) Males: N (%) 

Recruitment Country Index of activity (fitness level) 

History of asthma N (%); Asthma 

severity; 

Atopic status N (%); History of ICS History of EIB/EIA 

Bas

Bas

% p

Pedersen34 21; 16 Elite swimmers (invited to None 4.3

2008 18.3±2.7 participate) 1 (6.3) 110

0 Denmark NA 

Athletic (4+ d per wk activity); elite NR 

swimmers 22.2±4 hr/wk 

Sekerel35 1997 12; 12 Clinic (allergy outpatient) 12 (100) confirmed by ATS criteria; NR 

9.83±1.8 Turkey stable, varying severity NR 

7(58.3) NR NR 

6 (50) Baseline EIB median fall 

FEV1=22% (range 4.0–35.0) 

Souza36 2005 43; 30 Clinic (pulmonary outpatient) Hx of ≥2 episodes dyspnea and/or 2.3

11±3; range 6-15 Brazil wheezing relieved with 98±14 (46.7) NR bronchodilators; other Dx ruled 

out; stable at testing 

NR None NR 

Verges37 2005 39=competitive athletes, Competitive athletes and healthy NR; NR Ath

13=controls sedentary subjects none had allergic asthma c

Athletes=22.4±4.8, France ICS: 2 athletes Ath

controls=27±7 13 <2 hr physical activity per wk, EIB: 4 athletes c

Athletes=26(66.7), 39 >12 hr/wk during 4 mo 

controls=7(53.8) preceeding study 
Table 11. Methodological quality of studies in the diagnostic test accuracy review: Methacholine vs. ECT 

Author Year 

Anderson23 2009 Yes Yes Yes Yes Yes Yes Yes Yes U Yes 

Avital24 1989 U No U U Yes Yes No No U U 

Avital25 2000 U U Yes No Yes Yes Yes Yes U U 

Chatham26 1982 No U Yes Yes Yes Yes Yes Yes U U 

Clough27 1991 U U Yes Yes Yes Yes Yes Yes U U 

Eggleston28 1979 U No Yes U Yes Yes Yes U U U 

Foresi29 1986 U U Yes Yes Yes Yes Yes Yes U U 

Henriksen30 2002 No No Yes Yes U U U Yes U U 

Kiviloog31 1973 U No Yes No Yes Yes Yes Yes U U Koh32 1996 U No U U Yes Yes Yes Yes U U 

Lin33 1991 No No Yes Yes U U Yes U U U 

Pedersen34 2008 No No U Yes Yes Yes Yes U U U 

Sekerel35 1997 U U U Yes Yes Yes Yes U U U 

De Souza36 2005 U No Yes Yes U Yes Yes Yes U U 

Verges37 2005 U No U No Yes Yes Yes Yes U U 

Representative

spectrum 

Selection criteria 

defined 

Acceptable reference 

standard

Timing bias avoided 

Partial verification

avoided

Differential

verification

avoided

Clear reporting of 

index test 

Clear reporting of 

reference standard 

Index test blinded 

Reference standard

blinded 

U = unclear 

50
 

Key Question D–3: Sport or Venue Specific Exercise 
 

Challenges 
 

Description of Included Studies 

Five studies34,38-41 met the inclusion criteria for the diagnostic test accuracy review of sport or 

venue specific exercise challenges compared with a standardized exercise challenge test (ECT). 

Three studies focused on swimming challenges,34,38,40 one assessed short track speed skating and 

biathlon field challenges,39 and one assessed five cold weather sport challenges.41 Tables 12 and 

13 summarize the study and participant characteristics. 

Dickinson et al.39 included elite winter athletes who were members of Great Britain’s 

national teams for short track speed skating (n=10) and biathlon (n=4). The sport specific 

challenge for speed skaters involved indoor skating for 6 minutes at an 11 to 12 second pace per 

250 meter lap. The sport specific challenge for biathletes was a 20 minute simulated race in 

Finland. The standardized ECT was performed on a treadmill for 8 minutes; the intensity level 

was more than 90 percent of maximum heart rate for the final 4 minutes. As part of this study, 

participants also completed an EVH challenge test (see Key Question D-4 for details). Two (14 

percent) participants had a previous diagnosis of asthma and were taking asthma medication. 

Rundell et al.41 included 23 elite winter athletes who competed in a race or race simulation at 

their regular sport (biathlon, short-track speed skating, Nordic combined, cross country skiing, or 

kayaking) and demonstrated a drop in FEV1 of 10 percent or more. Seven of the participants had 

been diagnosed with EIA as children but took no medications at the time of the study. 

Castricum et al.38 included 33 elite swimmers who were members of Australia’s state, 

national or international teams. The swim challenge required participants to swim for 8 minutes 

at more than 85 percent of their predicted maximum heart rate in an indoor 50 meter pool. The 

standardized ECT was a bicycle ergometer test; participants cycled at more than 90 percent of 

their predicted maximum heart rate. As part of this study, participants also completed an EVH 

challenge test (see Key Question D-4 for details). Thirteen (39 percent) participants had a 

previous diagnosis of asthma; of these, 11 were taking asthma medication. 

In the study by Pedersen et al.34 16 elite (national or international caliber) female swimmers 

from Denmark underwent four different challenge tests: swimming, MCH, EVH, and a 

standardized ECT performed on a treadmill (see also Key Questions D-2 and D-4). The swim 

challenge was carried out under race conditions at the National Danish Swimming 

Championships. The distances were 200 meters (n=11), 400 meters (n=3) and 800 meters (n=2). 

For the treadmill test, the participants were instructed to run until exhaustion. None of the 

swimmers had a previous diagnosis of asthma. 

Reggiani et al.40 assessed nine competitive swimmers from Italy; all had been involved in 

competitive swimming for at least 5 years. The swim challenge required participants to swim for 

8 minutes at 80 percent of their maximum heart rate in an indoor 25 meter pool. The 

standardized ECT was a bicycle ergometer test; participants cycled at 80 percent of their 

maximum heart rate for 8 minutes. As part of this study, participants also completed a FRAST 

(see Key Question D-5 for details). All participants had a history of atopic diseases; they were 

asymptomatic at the time of the challenge tests. 

51 
 
Methodological Quality of the Included Studies 

Table 14 summarizes the methodological quality of the included studies. There are several 

methodological issues. None had a representative patient spectrum which suggests the possibility 

of spectrum bias. Blinding of assessment of the ECT to the results of the index test was not 

reported. Two studies38,40 did not report their source of funding; one reported industry funding;39 

one was supported by government grants,34 and one by the United States Olympic Committee.41 

The body of evidence is classified as “low.” 

Quantitative Results 

In the study by Dickinson et al.39 three (21 percent) athletes had a positive test on the sport 

specific challenge using a FEV1 fall index of 10 percent or more. None of the participants had a 

positive test on the ECT; therefore, sensitivity could not be calculated. Specificity of the sport 

specific challenge was 79 percent (95 percent CI: 49, 95) indicating an 80 percent probability 

that for participants who do not have EIB/EIA, the sport challenge would correctly identify them 

as not having EIB/EIA. All of the athletes in the study by Rundell et al.41 were positive on a 

sport specific challenge. Five were also positive on an ECT at 95 percent of peak heart rate for 8 

minutes. Sensitivity was 100 percent (95 percent CI: 48, 100). Overall, 5 (14 percent) of the cold 

weather athletes were positive for EIB/EIA on the ECT; 21 (57 percent) were positive for 

EIB/EIA on cold air challenges. None of the participants had a negative test on the sport specific 

challenge. 

The sensitivity of the swimming challenge tests ranged from 040 to 50 percent34 (Figure 7). 

The specificity ranged from 83 to 100 percent. Overall, 11 (19 percent) of the swimmers were 

positive for EIB/EIA on the ECT; 5 (9 percent) were positive for EIB/EIA on the swimming 

challenge. 

Figure 7. Forest plot of sensitivity and specificity: Sport specific challenges vs. ECT (FEV1 fall index 10 

percent or more) 

Study TP FP FN TN Sensitivity Specificity Sensitivity Specificity 

Casticrum 2008 1 0 3 29 0.25 [0.01, 0.81] 1.00 [0.88, 1.00] 

Dickinson 2006 0 3 0 11 Not estimable 0.79 [0.49, 0.95] 

Pedersen 2008 2 2 2 10 0.50 [0.07, 0.93] 0.83 [0.52, 0.98] 

Reggiani 1988 0 0 3 6 0.00 [0.00, 0.71] 1.00 [0.54, 1.00] 

Rundell 2000 5 18 0 0 1.00 [0.48, 1.00] 0.00 [0.00, 0.19] 

0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1 

52 
 
Table 12. Description of studies in the diagnostic test accuracy review: Sport specific vs. ECT 

Author Year Study design; Order of tests REFERENCE STANDARD (ECT) INDEX TEST (Sport spec

Study days; Challenges per day Type; Duration (min) Type; Description 

[N]; Load; Environmental conditions Follow-up time points 

Time between challenges Follow-up time points Author definition of EIB Concomitant treatment for asthma Author definition of EIB 

Castricum38 Cross sectional (prospective); Bicycle ergometer; 8 Swimming: 50 m chlorine 

randomized order of tests 91±4.8% max HR; 30±2.7oC; pool temp: 27

	 

2008 

3; 1; 

between 1 and 7 d Asthma med withheld for designated 

time 

RH 60.5±2.1%; 21±0.8oC 

1, 3, 5, 7, 10 min post ECT ≥10% fall FEV1 

min to maintain >85% m

1, 3, 5, 7, 10 min post cha

≥10% fall FEV1 

Cross sectional (prospective); 

randomized order of tests 

Treadmill; 8 90% max HR; 

Skating: indoor speed ska

Biathlon: simulated outdoo

Dickinson39 	 

2006 

NR RH 56%; 18oC 34% 

Asthma med withheld: ICS and LABA 3, 5, 10, 15 min post ECT 3, 5, 10, 15 min post chall

x 3 d; SABA x 1 d ≥10% fall FEV1 	 ≥10% fall FEV1 

Pedersen34 Cross sectional (prospective); NR Treadmill: constant speed, incline increased Swimming: Race condition

	 

2008 4 visits; NR; every 2 min; 5±1.1 min; ran to exhaustion; swimmers chose favorit

at least 24 hr apart RH and temp NR min at highest possible 

NA 0, 1, 3, 5, 10, 15, 20 min post ECT 1, 3, 5, 10, 15, 20 min pos

≥10% fall FEV1 	 ≥10% fall FEV1 

Reggiani40 1988 Cross sectional (prospective); NR Bicycle ergometer; 8 Swimming: 25 m indoor po

3; 1; 80% max HR; max HR ≥3 d to <1 wk RH 76%; 22oC, in environmental chamber 5, 10, 15 min post challen

None on ICS 5, 10, 15, min post ECT ≥20% fall FEV1 

≥20% fall FEV1 

Cross sectional (prospective); Treadmill: 8 (no warmup) Biathlon, short-track spee

Sport specific first 2; 1 

95% peak HR RH 60%; 21oC 

Nordic combined, kyakinthen performed in comp

Different days 5, 10, 15, min post ECT for speed skaters to >1h 

None on asthma med ≥10% fall FEV1 5, 10, 15 min post compet

≥10% fall FEV1 

Rundell 2000 C = Celsius; d = day(s); ECT = exercise challenge test; EIB/EIA = exercise-induced bronchoconstriction/asthma; FEV1 = forced expiratory volume in 

heart rate; ICS = inhaled corticosteroids; LABA = long-acting beta-agonist; m = meters; max = maximum; med = medication(s); min = minute(s); NA reported; RH = relative humidity; SABA = short-acting beta-agonist; temp = temperature; wk = week(s) 

53
 

Table 13. Description of participants in the diagnostic test accuracy review: Sport specific vs. ECT 

54
 


Author Year Participants enrolled (N); 

analyzed (N) 

Age (mean±SD) Males: N (%) 

Recruitment Country Index of activity (fitness level) 

History of asthma N (%); Asthma 

severity; 

Atopic status N (%); History of ICS History of EIB/EIA 

Castricum38 33; 33 Competative athletes (swimmers; 13 (39.4); NR 

2008 18.2±4.9 volunteers) Australia NR 

23 (69.7) Athletic 3 ICS; 3 ICS+LABA; 1 MSC; 4 SABA 

prn; 2 no med; 

No 

Dickinson39 14; 14 Competative athletes (speed 2 (14); NR 

2006 22.6±5.7 skating, biathalon; volunteers) NR 

NR United Kingdom 2 (14) ICS or SABA 

Athletic No 

Pedersen34 21; 16; Competative athletes (swimmers; None 

2008 18.3±2.7; range 15–25 invited) 1 (6.3) 

0 Denmark NA 

Athletic (4+ days per wk activity); NR 

elite swimmers 22.2±4 hr/wk 

Reggiani40 1988 9; 9 Competitive athletes (swimmers; NR; stable and asymptomatic at testing 

15.1±2.0 volunteers) 9 (100) 7 (77.8) Italy NR 

Athletic average 40 km/wk NR 

Rundell41 2000 23; 23 Competitive athletes (biathlon, 7 (30) EIA as children; 

20.0±4.5 short-track speed skating, cross- NR 14 (61) country skiing, Nordic combined, None on oral/inhaled med 

kyaking; invited) United States 23 (100) 

Elite cold weather athletes 

Dx = diagnosis; EIB/EIA = exercise-induced bronchoconstriction/asthma; FEV1 = forced expiratory volume in 1 second; hr = hour(s); Hx = history; IC

km = kilometers; LABA = long-acting beta-agonist; L = liters; MCS= mast cell stabilizers; NA = not applicable; NR = not reported; prn = as needed; 

agonist; SD = standard deviation; wk = week(s) 
Table 14. Methodological quality of studies in the diagnostic test accuracy review: Sport specific vs. ECT 

Author Year 

Representative

spectrum 

Selection criteria 

defined 

Acceptable reference 

standard

Timing bias avoided 

Partial verification

avoided

Differential

verification

avoided

Clear reporting of 

index test 

Clear reporting of 

reference standard 

Index test blinded 

Reference standard

blinded 

Uninterpretable

results reported

Castricum38 2008 No Yes Yes Yes Yes Yes Yes Yes U U Yes 

Dickinson39 2006 No No Yes U Yes Yes Yes Yes U U Yes 

Pedersen34 2008 No No U Yes Yes Yes Yes U U U Yes 

Reggiani40 1988 No U Yes Yes Yes Yes Yes Yes U U Yes 

Rundell41 2000 No U Yes Yes Yes Yes No Yes No No Yes 

U = unclear 

55 
Key Question D–4: Eucapnic Voluntary Hyperpnea 

Description of Included Studies 

Seven studies34,38,39,42-45 met the inclusion criteria for the diagnostic test accuracy review of 

eucapnic voluntary hyperpnea (EVH) compared with a standardized ECT. All seven studies were 

conducted prospectively. Six 34,38,39,43-45 used a cross sectional design, and one42 used a casecontrol design with healthy controls. They were all published in peer reviewed journals. The 

median year of publication was 2005 and ranged from 1984 to 2008. Studies were conducted in 

Europe,34,39,45 Australia,38 and the United States.42-44 

The characteristics of the studies are summarized in Table 15. The standardized ECT was 

performed on a treadmill34,39,43,45 or a bicycle ergometer.38,42,44 A positive test was defined as a 

FEV1 fall index of 10 percent or more,34,38,39,44 or 15 percent or more.

45 Two studies did not 

report their definitions of a positive ECT.42,43 The target workload was reported as 90 percent of 

maximum heart rate,38,39 pulse rate of greater than 170 after 2 minutes of running (equivalent to 

80 percent of predicted maximum heart rate),45 “until exhaustion,”34 “until a symptom limited 

maximum exercise capacity,”42 and “highest intensity.”44 One study43 did not report the criteria 

for target workload. 

Most studies used five percent CO2 air content for the EVH challenge at room temperature. 

One study42 also tested participants with cold air. The duration of hyperpnea was either 5 

minutes42 or 6 minutes.34,38,39,44,45 One study43 did not report duration. During the EVH 

challenge, the target ventilation rate was set at 80 percent maximum voluntary ventilation 

(MVV),42 85 percent MVV,38,44 a minimum ventilation of 30 times FEV1 equivalent to MVV,34 

or 40 or more liters per minute.43 Two studies39,45 did not specify the rate of target ventilation. 

The baseline characteristics of the participants are presented in Table 16. The number of 

participants in each study ranged from 10 to 33. Three studies included adults only,39,42,44one 

included children only,45 two included both adults and children,34,38 and one43 did not report the 

age of participants. Four studies34,38,39,44 focused on elite athletes; three42,43,45 did not report the 

level of fitness or sports participation. Fourteen39 to 100 percent of participants43,45 had a 

diagnosis of asthma in the five studies that reported this. In three studies43-45 100 percent of 

participants had a history of EIB/EIA. 

Methodological Quality of Included Studies 

Table 17 summarizes the methodological quality of the included studies. As a group, there 

are methodological issues that limit interpretation and generalizability of the results. Of concern 

is the risk of spectrum bias in all studies. Either the participants recruited into the studies were 

volunteers,34,38,39,42,44 or the recruitment source and methods were not reported.43,45 In some 

studies all participants had a history of EIB/EIA43-45 and therefore are not representative of the 

spectrum of patients who might be tested for EIB/EIA. Blinding of results of the ECT to the 

results of the EVH challenge was not reported. Four studies did not report their sources of 

funding.38,42,43,45 Two studies received funding support from industry,39,44 and one was supported 

by government and institution grants.34 The body of evidence is classified as “low.” 

Quantitative Results 

A total of 138 participants were studied; 42 (30 percent) tested positive for EIB/EIA on the 

ECT and 74 (54 percent) were positive using EVH. Overall, the sensitivity and specificity of the 

56 
 
 

seven studies were heterogeneous with values ranging from 25 to 90 percent for sensitivity and 0 

to 71 percent for specificity (data not shown). 

To explore the heterogeneity, we conducted a post hoc subgroup analysis of participants who 

did not have a history of EIB/EIA. This included all participants from three studies34,38,39 and one 

group of participants from a fourth study.42 Among these 83 individuals, 10 (12 percent) tested 

positive on the ECT while 44 (53 percent) tested positive using EVH. Heterogeneity was 

somewhat reduced and the range of sensitivity and specificity was narrowed—25 to 75 percent 

and 29 to 67 percent, respectively (Figure 8). Of note, the studies by Castricum et al.,38 

Dickinson et al.,39 and Pedersen et al.34 focused on elite athletes (proportion with asthma 39, 14 

and 0 percent, respectively). 

Figure 8. Forest plot of sensitivity and specificity: Eucapnic voluntary hyperpnea vs. ECT (participants with 

no history of EIB/EIA; FEV1 fall index 10 percent or more for ECT and EVH) 

Study TP FP FN TN Sensitivity Specificity Sensitivity Specificity 

Casticrum 2008 3 15 1 14 0.75 [0.19, 0.99] 0.48 [0.29, 0.67] 

Dickinson 2006 0 10 0 4 Not estimable 0.29 [0.08, 0.58] 

Eliasson 1992 1 10 1 8 0.50 [0.01, 0.99] 0.44 [0.22, 0.69] 

Pedersen 2008 1 4 3 8 0.25 [0.01, 0.81] 0.67 [0.35, 0.90] 

0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1 

For the three studies43-45 and one group42 in which all participants had a history of EIB/EIA 

the sensitivity of EVH was higher, ranging from 71 to 90 percent43 (Figure 9). Among these 55 

people, 32 (58 percent) tested positive for EIB/EIA using the ECT and 30 (55 percent) tested 

positive using EVH. 

Figure 9. Forest plot of sensitivity and specificity: Eucapnic voluntary hyperpnea vs. ECT (participants with a 

history of EIB/EIA; FEV1 fall index 10 percent or more for ECT and EVH) 

Study TP FP FN TN Sensitivity Specificity Sensitivity Specificity 

Eliasson 1992 0 1 0 19 Not estimable 0.95 [0.75, 1.00] 

Rosenthal 1984 9 0 1 0 0.90 [0.55, 1.00] Not estimable 

Rundell 2004 7 3 1 0 0.88 [0.47, 1.00] 0.00 [0.00, 0.71] 

Schmidt 1983 10 0 4 0 0.71 [0.42, 0.92] Not estimable 

0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1 

Subgroup and sensitivity analyses. Sensitivity analyses were performed using different 

thresholds for a positive EVH challenge. Using a threshold of a FEV1 fall index of 15 percent or 

more for a positive EVH challenge, the sensitivity improved; however, there was still 

considerable heterogeneity (Figure 10). The results of the analyses using a threshold of 20 

percent or more were not substantially different (data not shown). In a subgroup analysis on 

studies enrolling athletes the sensitivity ranged 25 to 88 percent; specificity ranged 0 to 67 

percent (data not shown). 

57 
 
 

 

Study TP FP FN TN Sensitivity Specificity 

Casticrum 2008 2 16 0 15 1.00 [0.16, 1.00] 0.48 [0.30, 0.67] 

Dickinson 2006 0 10 0 4 Not estimable 0.29 [0.08, 0.58] 

Eliasson 1992 1 11 0 28 1.00 [0.03, 1.00] 0.72 [0.55, 0.85] 

Pedersen 2008 0 5 2 9 0.00 [0.00, 0.84] 0.64 [0.35, 0.87] 

Rosenthal 1984 9 0 1 0 0.90 [0.55, 1.00] Not estimable 

Schmidt 1983 9 1 4 0 0.69 [0.39, 0.91] 0.00 [0.00, 0.97] 

Sensitivity Specificity 

0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1 

Figure 10. Forest plot of sensitivity and specificity: Eucapnic voluntary hyperpnea vs. ECT (all participants; 

threshold for a positive test is a FEV1 fall index 10 percent or more for ECT and 15 percent or more for EVH) 

Cold air versus warm air. In the study by Eliasson et al.42 participants performed EVH tests 

while inspiring air at room temperature or inspiring air cooled to minus 18°C to minus 26°C. 

Despite the increased conditioning of the air required during the cold air trial, there was no 

difference in post-EVH FEV1 response between the cold versus room temperature challenges 

(data not shown). 

58 
 
59
 


Table 15. Description of studies in the diagnostic test accuracy review: Eucapnic voluntary hyperpnea vs. ECT 

Author Year Study design; Order of tests REFERENCE STANDARD (ECT) INDEX TEST (EVH

Study days; Challenges per day [N]; Type; Duration (min) Type; Description Time between challenges Load; Environmental conditions Follow-up time poConcomitant treatment for asthma Follow-up time points Author definition 

Author definition of EIB 

Castricum38 Cross sectional (prospective); Bicycle ergometer; 8 Gas (dry) 5% CO2, 

2008 randomized order of tests 91±4.8% max HR RH 60.5±2.1%; L

3; 1; RH 60.5±2.1%, 21±0.8oC 1, 3, 5, 7, 10 min po

between 1 and 7 d 1, 3, 5, 7, 10 min post ECT ≥10% fall FEV1 

Asthma med withheld ≥10% fall FEV1 

Dickinson39 Cross sectional (prospective); Treadmill; 8 Gas (dry) 5% CO2, 

2006 randomized order of tests 

NR 

90% max HR RH 56%, 18oC 

RH <2%; Load: h

1, 3, 5, 7, 10 min po

Asthma med withheld before tests (ICS 3, 5, 10, 15 min post ECT ≥10% fall FEV1 

x 3 d; LABA x 2 d, SABA x 1 d) ≥10% fall FEV1 

Eliasson42 1992 Case-control (prospective); randomized 

order of tests 

Bicycle ergometer at 60 rpm with resistance 

increased by 25 watts/min; NR 

1) Gas (dry) compr

80% MVV; 2) Ga

At least 4; 1; Symptom-limited max exercise capacity CO2 x 5 min at 80

all challenges between 7-9 am ambient indoor conditions 1 then 5 min intervaNo caffine x 12 hr prior to tests 0, 5, 10, 15 min post ECT NR 

SABA/LABA discontinued NR 

Pedersen34 Cross sectional (prospective); NR Treadmill at constant speed; incline increased 2% Gas (dry) 5% CO2, 

2008 4 visits; NR; every 2 min; 5±1.1 until exhaustion x 6 min; Load: 85

at least 24 hr apart NR 0, 1, 3, 5, 10, 15, 2NA 0, 1, 3, 5, 10, 15, 20 min post ECT ≥10% fall FEV1 

≥10% fall FEV1 

Rosenthal43 Cross sectional (prospective); NR Treadmill; NR; NR Gas (dry) 5% C02, 

1984 2; 1; dry air, room temperature Load: hyperventi

>24 hr otherwise unspecified NR NR NR NR NR 

Rundell44 2005 Cross sectional (prospective); Bicycle ergometer; 6 Gas (dry) 5% CO2, 

randomized order of tests 

4; 1; 

Highest intensity RH 50%, -3oC 

40%; Load: 85% 

5, 10, 15 min post c

48-72 hr 5, 10, 15 min post ECT ≥10% fall FEV1 

NR ≥10% fall FEV1 

bpm = beats per minute; C = Celsius; d = day(s); ECT = exercise challenge test; EIB/EIA = exercise-induced bronchoconstriction/asthma; FEV1 = for

second; hr = hour(s); HR = heart rate; ICS = inhaled corticosteroids; L/min = liters per minute; LABA = long-acting beta-agonist; m = meters; μmol = maximum; med = medication(s); mg/ml = milligram per milliliter; min = minute(s); MMV = maximal voluntary ventilation; NR = not reported; RH = peak expiratory flow; rpm = revolutions per minute; SABA = short-acting beta-agonist; temp = temperature 
Table 15. Description of studies in the diagnostic test accuracy review: Eucapnic voluntary hyperpnea vs. ECT (continued) 

Author Year Study design; Order of tests REFERENCE STANDARD (ECT) INDEX TEST (EVH

Study days; Challenges per day [N]; Type; Duration (min) Type; Description Time between challenges Load; Environmental conditions Follow-up time poConcomitant treatment for asthma Follow-up time points Author definition 

Author definition of EIB 

Schmidt45 1983 Cross sectional (prospective); Treadmill; 6; HR >170 bpm after 2 min running Gas 5% CO2, 21% 

randomized order of tests 

2; 1; 

(~80% max HR) 

RH 40%, 21oC 

Load: hyperventi

NR 

24 hr 0, 1, 3, 5, 10, 15 min post ECT >15% fall in PEF froAll med x 8 hr prior to tests ≥15% fall in PEF 

60 
Table 16. Description of participants in the diagnostic test accuracy review: Eucapnic voluntary hyperpnea vs. ECT 

61
 


Author Year Participants enrolled (N); 

analyzed (N) 

Age (mean±SD) Males: N (%) 

Recruitment Country Index of activity (fitness level) 

History of asthma N (%); Asthma severity; Atopic status N (%) History of ICS History of EIB/EIA 

Castricum38 33; 33 Athlete volunteers at state level or 13 (39.4); NR 

2008 18.2±4.9 above NR 

23 (69.7) Australia 3 ICS; 3 ICS+LABA; 1 mast; 4 SABA as neede

Athletic no med 

NR 

Dickinson39 14; 14 Athlete volunteers from Great 2 (14) Hx of asthma; NR 

2006 22.6±5.7 Britain short track speed skating NR 

NR and biathlon teams 2 (14) treated with ICS or SABA 

United Kingdom NR Athletic 

Eliasson42 1992 40; 40 Clinic (from pulmonary clinic with 9 (23) family Hx of asthma; NR; 20 (50) self-re

Range 22–42 suspected EIB; healthy controls post-exercise wheeze=13; dyspnea out of 33 (82.5) with no symptoms of EIB), proportion to level of exertion=11; chest 

volunteers tightness=8 

U.S. 16 (40) seasonal allergies; 5 (13) food allergies 

NR None on ICS or NSAIDs 

20 had EIB; 20 did not 

Pedersen34 21; 16 Athletic team of elite swimmers None; NA 

2008 18.3±2.7 (invited to participate) 1 (6.3) 

0 Denmark NA 

Athletic (4+ d/wk activity), elite NR 

swimmers 22.2±4 hr/wk 

Rosenthal43 10; 10 NR 10 (100); NR 

1984 NR U.S. NR 

NR NR NR 

10 (100) 

Rundell44 2005 11; 11 11 volunteers, EIB positive, 4 (36); 4 mild 

22.8±6.8 recreational and college athletes NR 

8 (72.7) U.S. NR 

Athletic 11 (100) 

Schmidt45 1983 14; 14 NR 14 (100); NR 

11.6; range 8-14 Denmark NR NR NR NR 

14 (100) 

Dx = diagnosis; EIB/EIA = exercise-induced bronchoconstriction/asthma; FEV1 = forced expiratory volume in 1 second; Hx = history; ICS = inhaled 

long-acting beta-agonist; L = liters; med = medication(s); min = minute(s); NA = not applicable; NSAID=non-steroidal anti-inflammatory; NR = not rexpiratory flow; SABA = short-acting beta-agonist; SD = standard deviation; wk = week(s); y = year 
Table 17. Methodological quality of studies in the diagnostic test accuracy review: Eucapnic voluntary hyperpnea vs. ECT 

Author Year 

Representative

spectrum 

Selection criteria 

defined 

Acceptable reference 

standard

Timing bias avoided 

Partial verification

avoided

Differential

verification

avoided

Clear reporting of 

index test 

Clear reporting of 

reference standard 

Index test blinded 

Reference standard

blinded 

Uninterpretable

Castricum38 2008 No Yes Yes Yes Yes Yes Yes Yes U U Ye

Dickinson39 2006 No No Yes U Yes Yes Yes Yes U U Ye

Eliasson42 1992 U Yes U Yes Yes Yes U Yes U U Ye

Pedersen34 2008 No No U Yes Yes Yes Yes U U U YeRosenthal43 1984 No No U Yes Yes Yes No No U U Ye

Rundell44 2005 No No U Yes Yes Yes Yes U U U Ye

Schmidt45 1983 No No U Yes Yes Yes Yes Yes U U Ye

U = Unclear 

62 
 

Key Question D–5: Free Running Asthma Screening Test 

Description of Included Studies 

Three studies36,40,46 met the inclusion criteria for the diagnostic test accuracy review of a free 

running asthma screening test (FRAST) compared with a standardized exercise challenge test 

(ECT). All studies were conducted prospectively; two used a cross sectional design36,40 and one 

used a case-control design with healthy controls.46 The studies were published in peer reviewed 

journals in 1988,40 200536 and 2008.46 The studies were conducted in Europe40,46 and South 

America.36 

The standardized ECT was performed on a treadmill46 and a bicycle ergometer.36,40 All free 

running tests took place indoors. Garcia de la Rubia et al.46 defined a positive test as a FEV1 fall 

index of 20 percent or more on the treadmill and a 16.5 percent or more for the FRAST. Among 

children with asthma the maximum heart rate ranged from 70 to 90 percent in treadmill running 

and 82 to 93 percent in free running. Results were not reported for the control group. Reggiani et 

al.40 defined a positive test as a FEV1 fall index of 20 percent or greater on the bicycle ergometer 

and the FRAST. The target workload was 80 percent of maximum heart rate for both tests. As 

part of the study the authors also assessed the diagnostic characteristics of a sport specific 

(swimming) challenge (see Key Question D-3 for details). Souza et al.36 defined a positive test as 

a FEV1 fall index of 10 percent or greater for both the ECT and FRAST. The target workload 

was between 80 and 90 percent of maximum heart rate for both tests. The characteristics of the 

studies are summarized in Table 18. 

The baseline characteristics of the participants are presented in Table 19. Sixty people were 

enrolled in the study by Garcia de la Rubia et al.,46 30 had extrinsic asthma but were 

asymptomatic at testing. The 30 healthy controls had never presented with symptoms of asthma 

and had no history of allergy. The nine competitive swimmers who participated in the study by 

Reggiani et al.40 all had a history of atopy but were asymptomatic at the time of testing. In the 

study by Souza et al.36 the 30 participants analyzed had intermittent asthma defined as at least 

two episodes of dyspnea and/or wheezing relieved with the use of bronchodilators. 

Methodological Quality of the Included Studies 

Table 20 summarizes the methodological quality of the included studies. Overall there were 

concerns with the methodological quality of the studies. Generalizing the results to a target 

population of people with suspected EIB/EIA may be limited as none of the studies had 

representative spectrum of participants. Blinding of assessment of the ECT to the results of the 

FRAST was not reported. None of the studies reported their source of funding. The body of 

evidence is classified as “very low.” 

Quantitative Results 

For two studies36,40 the sensitivity and specificity could be calculated using a FEV1 fall index 

of 10 percent or more on both challenges. The sensitivity of FRAST was 60 and 67 percent; 

specificity was 47 and 67 percent (Figure 11). Overall, 13 (38 percent) participants had a positive 

ECT; 18 (53 percent) had a positive FRAST. 

63 
 
Figure 11. Forest plot of sensitivity and specificity: FRAST vs. ECT (FEV1 fall index ≥10%) 

Study TP FP FN TN Sensitivity Specificity Sensitivity Specificity 

Reggiani 1988 2 2 1 4 0.67 [0.09, 0.99] 0.67 [0.22, 0.96] 

Souza 2005 6 8 4 7 0.60 [0.26, 0.88] 0.47 [0.21, 0.73] 

0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1 

Garcia de la Rubia et al.46 used a FEV1 fall index of 20 percent or more as the threshold for a 

positive test for the ECT and 16.5 percent or more for the FRAST. Based on these thresholds the 

sensitivity was 53 percent (95 percent CI: 34, 72) and the specificity was 100 percent (94 percent 

CI: 88, 100). Thirty (50 percent) participants had a positive ECT; 16 (27 percent) had a positive 

FRAST. 

64 
 
Table 18. Description of studies in the diagnostic test accuracy review: FRAST vs. ECT 

Author Year Study design; Order of tests REFERENCE STANDARD (ECT) INDEX TEST (FRA

Study days; Type; Duration (min) Type; Description Challenges per day [N]; Load; Environmental conditions Follow-up time poTime between challenges Follow-up time points Author definition Concomitant treatment for asthma Author definition of EIB 

Garcia de la 

Rubia46 1998 Case-control (prospective); NR Treadmill; 6-8 Indoor sports cente

2; 1; Variable speed/incline 5%; 70-90% max HR; RH 54.73±3.41%, 1within 7 d RH 53.69±5.34%, 19.06±1.39oC NR 
 NR 2, 5, 10, 15, 20 min post ECT 

≥20% fall FEV1 

≥16.5% fall FEV1 
 

Reggiani40 1988 Cross sectional (prospective); NR 

3; 1; ≥3 d to <1 wk None on ICS 

Bicycle ergometer; 8 80% max HR; RH 76%, 22oC; in environmental chamber 

5, 10, 15 min post ECT ≥20% fall FEV1 

25 m indoor pool, 8 RH NR; pool temp 

5, 10, 15 min post c≥20% fall FEV1 

Souza36 2005 Cross sectional (prospective); 

Randomized order of tests 

3; 1 (all 8-10 am); min 24 hr to 10 d None; asthma med stopped based on 

guidelines 

Bicycle ergometer; 6 90-100% max HR; RH 50%, 21.1±1oC, 

3, 6, 10, 15, 20, 30 min post ECT ≥10% fall FEV1 

Indoors along 50 m 

RH 50%, 22±2oC

3, 6, 10, 15, 20, 30 ≥10% fall FEV1 

d = day(s); ECT = exercise challenge test; EIB/EIA = exercise-induced bronchoconstriction/asthma; FEV1 = forced expiratory volume in 1 second; hr 

ICS = inhaled corticosteroids; m = meters; max = maximum; MCH = methacholine; med = medication(s); mg/ml = milligram per milliliter; min = minRH = relative humidity; temp = temperature 

65
 

 

 

Table 19. Description of participants in the diagnostic test accuracy review: FRAST vs. ECT 

66
 


Author Year Participants enrolled (N); 

analyzed (N) 

Age (mean±SD) Males: N (%) 

Recruitment Country Index of activity (fitness level) 

History of asthma N (%); Asthma 

severity; 

Atopic status N (%); History of ICS History of EIB/EIA 

Bas

Bas

% p

Garcia de la 

Rubia46 1998 

60; 60 Asthma: 9.8±1.9, Control: 10.7±2.0 

University medical sports center Spain NR 

Asthma group: 30 (100); stable 30 (100) NR 

Ast

p

NR 

NR NR 

Reggiani40 1988 9; 9 

15.1±2.0 7 (77.8) 

Competitive swimmers (volunteers) Italy Athletic average 40 km/wk 

NR 9 (100); stable and asymptomatic 

at testing 

NR 

4.1NR 

NR 

Souza36 2005 43; 30 

11±3; range 6-15 14 (46.7) 

Pulmonary outpatient clinic Brazil NR 

30 (100); Intermittant NR 0 (0) NR 

2.398±

EIB/EIA = exercise-induced bronchoconstriction/asthma; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; ICS = inhaled c

kilometers per week; L = liters; NR = not reported; SD = standard deviation Table 20. Methodological quality of studies in the diagnostic test accuracy review: FRAST vs. ECT 

Author Year 

Representative spectrum 

Selection criteria defined 

Acceptable reference 

standard

Timing bias avoided 

Partial verification avoided

Differential verification

avoided

Clear reporting of index test

Clear reporting of reference 

standard

Index test blinded 

Reference standard blinded

Uninterpretable results 

Garcia de la Rubia46 U No U Yes Yes Yes Yes Yes U U Y

1998 

Reggiani40 1988 No U Yes Yes Yes Yes Yes Yes U U Y

Souza36 2005 U No Yes Yes U Yes Yes Yes U U U U = unclear 
Key Question D–6: Mannitol Challenge 
 

Description of Included Studies 

Three studies23,47,52 met the inclusion criteria for the diagnostic test accuracy review of 

Mannitol compared with a standardized exercise challenge test (ECT). All studies used a cross 

sectional design and all were conducted prospectively. The characteristics of the studies and the 

participants are summarized in Tables 21 and 22. 

In the study by Anderson et al.23 the standardized ECT was performed on a treadmill. The 

target workload was between 80 and 90 percent of maximum heart rate. A positive test was 

defined as a FEV1 fall index of 10 percent or greater. A positive test for the mannitol challenge 

was defined as a FEV1 fall index of 15 percent or more or a fall of 10 percent or more between 

consecutive doses. As part of the study the authors also compared the ECT to a MCH challenge 

(See Key Question D-2). In total, there were 510 participants enrolled, 375 underwent all three 

challenge tests and were included in the final analyses. Both children (26 percent) and adults (74 

percent) were included in the study. Participants had symptoms suggestive of asthma but none 

had a confirmed diagnosis. Symptoms suggested mild, persistent asthma (i.e., symptoms two or 

more times per week; asymptomatic between exacerbations; exacerbations of only a few hours to 

a few days; night time symptoms two or more times per month).109 Seventy-eight percent of 

participants were atopic. 

Brannan et al.47 used a standardized bicycle ergometer challenge. The target workload was 

between 90 and 100 percent of maximum heart rate. A positive test was defined as a FEV1 fall 

index of 10 percent or greater. A positive test for the mannitol challenge was defined as a FEV1 

fall index of 15 percent or more. As part of the study the authors also compared the ECT to an 

EVH challenge (See Key Question D-4). In total 36 adults were enrolled in the study; however, 

only 23 (64 percent) completed both the mannitol challenge and the ECT. All participants had 

atopic asthma, were taking asthma medications, and had a self-reported history of EIA. 

In the study by Kersten et al.52 the ECT was performed on a treadmill. The target workload 

was approximately 90 percent of predicted maximum heart rate for 6 minutes. A positive test for 

both the ECT and the mannitol challenge was defined as a FEV1 fall index of 15 percent or 

greater. In total, 33 children were enrolled; 25 underwent both challenge tests and were included 

in the final analyses. All children had a history of allergic asthma and EIA. 

Methodological Quality of Included Studies 

Table 23 summarizes the methodological quality of the three studies. Of concern is the risk 

of spectrum bias in the studies by Brannan et al.47 and Kersten et al.52 Participants were 

volunteers who had a history of EIA and are not representative of the spectrum of patients who 

might be tested for EIB/EIA. Blinding of the results of the ECT and the index test was not 

reported. There were no details about uninterpretable or indeterminate index test results in two of 

the three trials. All studies reported their sources of funding: Anderson et al.23 received funding 

support from industry; Brannan et al.47 and Kersten et al.52 were supported by government 

grants. The body of evidence is classified as “moderate.” 

Quantitative Results 

Using the threshold of a FEV1 fall index of 10 percent or more for the ECT, 23 (100 percent) 

participants in the Brannan et al.47 study were diagnosed with EIA; 22 (96 percent) were positive 

67
 

on the mannitol challenge. The sensitivity was 96 percent (95 percent CI: 78, 100). Specificity 

could not be calculated as none of the participants tested negative on the ECT (Figure 12). 

Anderson et al.23 reported a sensitivity of 58 percent (95 percent CI: 50, 66) and a specificity 

of 65 percent (95 percent CI: 58, 72) (Figure 12). The ECT diagnosed 163 (44 percent) 

participants with EIA; 168 (45 percent) were positive on the mannitol challenge. 

In the study by Kersten et al.52 sensitivity was 69 percent (95 percent CI: 41, 89) and 

specificity was 78 percent (95 percent CI: 40, 97) (Figure 12). The ECT diagnosed 16 (64 

percent) participants with EIA; 13 (52 percent) were positive on the mannitol challenge. Three 

participants had to terminate the mannitol challenge due to persistent cough and were excluded 

from analysis. 

Figure 12. Forest plot of sensitivity and specificity: Mannitol vs. ECT (FEV1 fall index ≥10% for ECT and ≥15% 

for mannitol) 

Study 

Anderson 2009 

Brannan 1998 

Kersten 2009 

TP 

95 

22 

11 

FP 

73 

0 

2 

FN 

68 

1 

5 

TN Sensitivity Specificity 

136 0.58 [0.50, 0.66] 0.65 [0.58, 0.72] 

0 0.96 [0.78, 1.00] Not estimable 

7 0.69 [0.41, 0.89] 0.78 [0.40, 0.97] 

0 

Sensitivity 

0.2 0.4 0.6 0.8 1 0 

Specificity 

0.2 0.4 0.6 0.8 1 

68
 

Table 21. Description of studies in the diagnostic test accuracy review: Mannitol vs. ECT 

Author Year Study design; Order of tests REFERENCE STANDARD (ECT) INDEX TEST (Mannitol) 

Study days; Challenges per day [N]; Type; Duration (minutes) Type; Description Time between challenges Load; Environmental conditions Follow-up time points Concomitant treatment for asthma Follow-up time points Author definition of EIB/EI

Author definition of EIB/EIA 

Anderson23 Cross sectional (prospective); ECT first Treadmill; 6 Dose: 0, 5, 10, 20, 40, 80, 16

2009 5 visits; 1; 

ECT – MCH: 1-2 d; 

80-90% max HR; RH dry (compressed) air; 20-25oC 

exhale completely, take de

through mouth, remove no

ECT – mannitol: 1-2 d; 0, 5, 10, 15, 30 min post ECT Measured 60 sec after each MCH – mannitol: 1 day ≥10% fall FEV1 ≥15% fall FEV1 or a ≥10% fa

Asthma medications withheld according to doses 

guidelines 

Cross sectional (prospective); ECT or Bicycle ergometer; 8 Dose: 0, 5, 10, 20, 40, 80, 16

EVH first except for 3 participants 90-100% max HR; inhalation; test stopped if ≥

1 screening, 2-3 test d; 1; NR dose of 635 mg administeall completed in 35 d period 3, 5, 7, 10, 15, 30 min post ECT FEV1 measured at 60 sec af

NR ≥10% fall FEV1 30 min 

≥15% fall FEV1 

Cross sectional (prospective); ECT first Treadmill; 6 Dose: 0, 5, 10, 20, 40, 80, 16

2 visits; 1; within 4 wk 

90% max HR; RH dry air in a skating rink; 1oC, 

inhalation; Process: with nfrom near functional residu

Asthma medication withheld according to 1, 3, 6, 9, 12, 15, 20 min post ECT capacity, held for 5 sec, ex

guidelines ≥15% fall FEV1 nose clip, repeat for each 

Measured 60 sec after each 

cough noted 

≥15% fall FEV1 or ended wh

mannitol reached 

Brannan47 1998 Kersten52 2009 	 C = Celsius; d = day(s); ECT = exercise challenge test; EIB/EIA = exercise-induced bronchoconstriction/asthma; EVH = eucapnic voluntary hyperpne

volume in 1 second; HR = heart rate; max = maximum; MCH = methacholine; mg/ml = milligram per milliliter; MVV = maximal voluntary ventilatiosecond(s) 

69
 

Table 22. Description of participants in the diagnostic test accuracy review: Mannitol vs. ECT 

Author Year Participants enrolled (N); 

analyzed (N) 

Age (mean±SD) Males: N (%) 

Recruitment Country Index of activity (fitness level) 

History of asthma N (%); Asthma 

severity; 

Atopic status N (%); History of ICS History of EIB/EIA 

B

B

Anderson23 510; 375 (performed all tests) Participants referred to clinic for 0 (0); all had symptoms suggestive 3

2009 24.3±10.2, range 6-50 investigation of asthma-type of asthma but no confirmed Dx; 9

182 (48.2) symptoms NAEPPII score 1.2±0.5 

U.S. 293 (78) NR NR 

NR 

Brannan47 1998 36; 23 Volunteers recruited through 36 (100); stable; N

24.5±6.4, range 18-40 advertisement in local community 36 (100) atopic; 816/36 (44.4) Australia 16 (44.4) 

NR 36 (100) self-report 

Kersten52 2009 33; 25 Volunteers from outpatient clinic 25 (100); clinically stable; N

12.4±2.0 The Netherlands 25 (100) allergic asthma; 917/25 (68.0) NR 15 (60) ICS; 

25 (100) 

EIB/EIA = exercise-induced bronchoconstriction/asthma; Dx = diagnosis; FEV1 = forced expiratory volume in 1 second; ICS = inhaled corticosteroid

National Asthma Education and Prevention Program; NR = not reported; SD = standard deviation 

70 
Table 23. Methodological quality of studies in the diagnostic test accuracy review: Mannitol vs. ECT 

Author Year 

Representative spectrum 

Selection criteria defined 

Acceptable reference 

standard

Timing bias avoided 

Partial verification avoided

Differential verification

avoided

Clear reporting of index

test

Clear reporting of 

reference standard 

Index test blinded 

Reference standard

blinded 

Uninterpretable index 

test results reported

Withdrawals explained 

Anderson23 2009 Yes Yes Yes Yes Yes Yes Yes Yes U Yes U Ye

Brannan47 1998 No Yes Yes Yes Yes Yes Yes U U U Yes Ye

Kersten52 2009 No Yes Yes Yes Yes Yes Yes Yes U U U Ye

U = unclear 

71 
 

Therapy Review 
 

Literature Search 

The search for controlled trials of the interventions targeted in this report identified 1,634 

citations from electronic databases and eight by handsearching (Figure 13). Through screening of 

titles and abstracts, 490 references were selected for further examination. The full manuscripts of 

13 citations could not be retrieved (Appendix D). Most of these were abstracts only available in 

supplementary conference proceedings. They were requested through interlibrary loan but did 

not arrive by the time this report was written. The search update identified an additional 19 

citations; none met the screening criteria. We retrieved and evaluated the full-text of 477 

potentially relevant articles. The application of the selection criteria resulted in 109 RCTs and 

CCTs being included; 368 studies were excluded. 

During preliminary searches of the literature on mast cell stabilizing agents (MCS) three 

systematic reviews were identified. All three were published in the Cochrane Library76-78 and 

two were also published in journal format.104,161 Our search strategy included terms to identify 

new or additional trials that would update the existing reviews but none were identified. In 

consultation with AHRQ and the TEP, we made the decision to present a summary of these 

existing reviews (Appendix E). 

The included articles addressed the following research questions: tachyphylaxis (n=9),53-55,57­

60,62,63 leukotriene receptor agonists (n=9),44,64-71 inhaled corticosteroids (n=4),72-75 MCS 

(n=62),76-78,104,161anticholinergics (n=18),79-96 and a refractory period (warmup/cooldown; 

n=7).97-103 

The main reasons for excluding studies were (1) the intervention did not address one of the 

research questions (n=214), (2) the study was not an RCT or CCT (n=60), (3) the study was not 

published in English (n=38), (4) the study population did not have a confirmed a diagnosis of 

EIB/EIA or included only children under the age of 6 (n=32). There were 24 studies excluded for 

other reasons. The list of excluded studies and reasons for exclusion are identified in Appendix 

D. 

72 
 
Figure 13. Therapy for EIB/EIA: Flow diagram for study retrieval and selection 

73 
 
 

 

Key Question T–1: Tachyphylaxis to Short-Acting Beta-
 

Agonists or Long-Acting Beta-Agonists 
 

Description of Included Studies 

Nine RCTs met the inclusion criteria for the review on whether people with EIB/EIA develop 

tachyphylaxis to long-acting beta-agonists (LABA)53-55,57-60 or to short-acting beta-agonists 

(SABA).62,63 Tachyphylaxis is defined as a waning or a diminishing response to prophylactic 

doses of a beta-agonist to attenuate or prevent EIB/EIA when these agents are also used on a 

continuous basis. In the case of continuous SABA use, tachyphylaxis is also defined as a 

diminished ability to cause bronchodilation when needed to reverse bronchoconstriction. Six 

trials used a crossover design55,57-59,62,63 and three were parallel trials.53,54,60 The LABA agents 

studied were formoterol,54 and salmeterol.53,55,57-60 The duration of LABA use was every other 

day for 3 weeks,58 daily use for 4 weeks,54,55,57,59 or daily use for 8 weeks.53,60 

The studies were published in peer reviewed journals between 1994 and 2009. Five were 

conducted in North America,53,55,59,62,63 three in Europe,54,57,58 and one in 12 different countries.60 

EIA was defined using different cutpoints of the maximum FEV1 fall index: 15 percent or 

greater,54,55,62,63 18 percent or greater,60 and 20 percent or greater.57 The exercise challenge test 

(ECT) was performed on a treadmill53,57,59,60 or bicycle ergometer.54,55,62,63 The characteristics of 

the trials are summarized in Tables 24a and 24b. 

The baseline characteristics of the participants are presented in Tables 25a and 25b. The 

number of patients enrolled ranged from 9 to 248. Two studies58,59 included children only, 

two62,63 included adults only, and five53-55,57,60 included both adults and children. All participants 

had confirmed asthma; for most, their asthma was mild and stable. 

Methodological Quality of Included Studies 

Table 26 summarizes the methodological quality of included studies. Overall the quality of 

individual trials was high with a median Jadad score of 4 (IQR: 3, 4). Concealment of allocation 

was unclear in six trials54,55,57-60 and adequately reported in one.53 Two trials did not report their 

source of funding,57,58 three had industry support,53,59,60 three had government support,54,62,63 and 

one had a combination of institution, government and private industry support.55 

Quantitative Results: SABA 

Two crossover trials that involved 1 week of regular (four times daily) SABA or placebo use 

prior to ECTs looked for evidence of tachyphylaxis to SABA.62,63 The SABA agent studied was 

albuterol (salbutamol). Both studies compared baseline FEV1 at the end of 1 week of use. Inman 

and O’Byrne63 assessed the prophylactic effect on EIA of an additional prophylactic dose of 

SABA. Hancox et al.62 did not address prophylaxis; however, did assess the bronchodilator effect 

of SABA following the ECT. Methodological differences precluded combining the data and the 

two studies are described separately. 

Inman and O’Byrne63 randomized 10 adults with asthma and EIA (maximum percent fall 

FEV1 on pre-study ECTs ranged 15 to 45 percent) to 1 week of SABA 200μg or placebo four 

times per day. The washout period ranged from 7 to 21 days. Additional SABA use was allowed 

as needed throughout study weeks and the washout period. Baseline SABA use was less than 

200μg per day and no other asthma medications had been taken in the previous month. No ECT 

was performed on day one of treatment and no baseline lung function measures were reported. 

74 
 
On day 8 of each treatment week, participants performed an ECT following a dose of placebo; 

on day 9, all performed an ECT following 200μg SABA (participants only were blinded to the 

prophylactic treatment taken). 

Baseline FEV1 after 1 week of treatment. The mean (±SE) pre-challenge FEV1 on day 8 of 

the placebo week was 3.58±0.18L compared with 3.36±0.19L on day 8 of the SABA week; the 

pre-challenge FEV1 on day 9 of the placebo week was 3.58±0.17L compared with 3.34±0.20L 

after the SABA week. The mean difference of 230 ml between treatment weeks was statistically 

significant (p=0.02). 

Post bronchodilator FEV1. On day 9, all participants received pre-challenge SABA 200μg. 

There was no significant difference between the placebo and SABA groups on the post-SABA 

FEV1 prior to the ECT (3.94 ±0.18L versus 3.83 ±0.18L; p=0.06). No comparison on the degree 

of bronchodilation that occurred was reported. 

Effect on EIA. On day 8 after pre-treatment with placebo, both groups experienced EIA 

following the ECT. The mean maximum percent fall in FEV1 after the placebo week was 

24.9±4.36 percent compared with a slightly greater fall of 29.4±4.71 percent after the SABA 

week. The difference of 4.5 percent was not statistically significant (p=0.12). 

On day 9 following pre-challenge SABA, both groups experienced total protection from EIA. 

The mean maximum percent fall in FEV1 in the placebo group was 1.1±0.76 percent compared 

with a slightly greater fall of 5.1±2.03 percent in the SABA group. The difference of 4 percent 

was statistically significant (p=0.05). The post-exercise FEV1 measures were significantly lower 

at all time points over the recovery period after 1 week of continuous SABA use on both the day 

8 placebo challenge (p=0.02) and the day 9 SABA challenge (p=0.01). 

Other outcomes. Self-reported use of additional SABA for rescue during the placebo week 

was lower than during the SABA week (p>0.05). 

The authors concluded that 1 week of regular SABA use resulted in a decrease in baseline 

FEV1, a decreased prophylactic effect on EIA, and more pronounced EIA. 

Hancox et al.62 randomized eight, stable asthmatic women with EIA (maximum percent fall 

FEV1 of 15 percent or more) to 6 to 10 days of SABA 200μg or placebo four times per day. 

There was no washout period. Baseline SABA use was not reported. All bronchodilating drugs 

were withheld for 8 to 36 hours pre-ECT and no prophylactic treatment was given prior to the 

ECT at the end of the treatment week. SABA 100 μg, 100 μg, and 200 μg were given at 5, 10, 

and 15 minutes post-ECT following FEV1 measurements. 

Baseline FEV1 after 1 week of treatment. There was no significant difference between the 

mean pre-challenge FEV1 after the SABA week compared with the placebo week (2.76L versus 

2.80L). 

Effect on EIA with no pre-treatment. At 5 minutes post-ECT the fall in FEV1 was greater 

in the SABA arm and the group as a whole experienced EIA. The mean minimum absolute FEV1 

post-ECT after the SABA week was 2.28L (95 percent CI: 2.21, 2.35) compared with 2.55L (95 

percent CI: 2.48, 2.62) after the placebo week (p=0.001). The percent fall in FEV1 was not 

reported and could not be calculated. The authors reported that the magnitude of the 

bronchodilator response to SABA in both arms was similar (no data); however, the FEV1 

remained significantly lower in the SABA arm over the 25 minute recovery period despite 

administration of SABA at 5, 10, and 15 minutes. 

The authors concluded that 1 week of regular SABA use results in more pronounced EIA and 

a suboptimal response to rescue medication. 

75 
 
Conclusions. The results from these two studies are equivocal on whether regular SABA use 

affects the baseline FEV1 over time. The studies are consistent in presenting data that indicates 

that regular SABA use may lead to a greater degree of EIA. It is important to note that pretreatment with SABA still offered complete protection to both groups in the one study.63 There is 

some evidence to indicate tachyphylaxis develops to the bronchodilating effect of SABA as 

rescue medication.62 The body of evidence is classified as “low.” 

Quantitative Results: LABA 

Five studies compared regular LABA use to placebo,54,55,58,59 four to salmeterol,55,57-59 and 

one to formoterol.54 Four studies reported regular LABA use for 4 weeks,54,55,57,59 and one58 used 

LABA treatment every other day for 21 days. Four studies were crossover trials55,57-59 and one 

used a parallel group design.54 

Formoterol versus placebo. Garcia et al.54 randomized 19 stable asthmatics with EIA 

(maximum percent fall FEV1 of 15 percent or more) to 28 days of formoterol 12μg twice daily 

(n=10) or to a matching placebo (n=9) in a parallel group design. In the month prior to the study, 

SABA use was less than two doses per week and other asthma treatment remained unchanged. 

The primary outcome was the change in the bronchoprotection index (BI) defined as the 

reduction in the maximum percent fall in FEV1 after formoterol compared with no pre-treatment 

on the three test days. 

On days 1, 14 and 28, participants refrained from taking all asthma medications and study 

drugs for 12 hours and performed two bicycle ECTs, 3 hours apart. The first took place with no 

prophylactic treatment; the second 30 minutes after taking formoterol. 

Bronchoprotection index. The BI on day 1 was similar in the formoterol and placebo groups 

(71.3±32.6 percent versus 69.3±30.1 percent). During the study there was a significant decrease 

in the degree of protection offered by formoterol as the BI dropped to 52.3±31.7 percent on day 

14 (p=0.012) and then to (27.8±32.6 percent) on day 28 (p=0.06). In the placebo group, the BI 

increased to 88.6±19.5 percent and 84.8±21.2 percent over the test days. The authors reported 

that these differences were not significant. 

Complete protection (maximum percent fall FEV1 less than 10 percent). On study days 1, 14 

and 28, a prophylactic dose of formoterol conferred complete protection to 9 of 10, 5 of 8, and 5 

of 10 patients in the formoterol group, respectively (p=0.28). On days 1 and 14, a prophylactic 

dose of formoterol conferred complete protection to 8 of 9 patients, and on day 28 to 7 of 9 

patients in the placebo group. 

The authors concluded that twice daily formoterol over 4 weeks caused a significant 

reduction in bronchoprotection against EIA. Tachyphylaxis was evident by day 14 but did not 

progress. A single pre-exercise LABA dose in non-regular users (i.e., placebo group) maintained 

its efficacy. 

Salmeterol versus placebo. Four crossover studies55,57-59 randomized groups to 3 or 4 weeks 

of salmeterol (50μg twice a day,55,57 once a day,59 or every other day for 3 weeks58) or to a 

matching placebo. Throughout the studies, the ECT was performed at 30 minutes,55 1 hour,59 6 

hours,57 and 9 hours58 following administration of a study drug. The average fall in FEV1 after 

the first ECT on day 1 in the four studies was 3.7 percent (range 5.0 to 11.9) in the LABA arms 

compared with 26.9 percent (range 20.5 to 36.6) in the placebo arms. The pooled difference 

favored the salmeterol (MD = 25.1 percent [95 percent CI: 32.3, 18.0) (Figure 14). The pooled 

results are presented as the MD between salmeterol and placebo at day 1, week 2 or 3, and week 

4. The decreasing MD between salmeterol and placebo from day 1 to week 4 reflects the 

76 
 
 

-20 -10 0 10 20 

Favors LABA Favors placebo 

in the maximum percent fall FEV1) 

Study or Subgroup Mean Difference 

LABA Placebo Mean Difference 

4.1.1 1 Day 

SE Total Total Weight IV, Random, 95% CI 

Nelson 1998 -15.7 3.12 20 20 25.1% -15.70 [-21.82, -9.58] 

Ramage 1994 -22.9 4.26 12 12 22.8% -22.90 [-31.25, -14.55] 

Selvaggio 2003 -29.9 2.34 9 9 26.4% -29.90 [-34.49, -25.31] 

Simons 1997 -31 2.78 14 14 25.7% -31.00 [-36.45, -25.55] 

Subtotal (95% CI) 55 55 100.0% -25.11 [-32.25, -17.98] 

Heterogeneity: Tau2 = 43.09; Chi2 = 17.40, df =

Test for overall effect: Z = 6.90 (P < 0.00001) 

 3 (P = 0.0006); I2 = 83% 

4.1.2 2 weeks 

Nelson 1998 -7.84 3.42 20 20 48.1% -7.84 [-14.54, -1.14] 

Selvaggio 2003 -18.1 2.34 9 9 51.9% -18.10 [-22.69, -13.51] 

Subtotal (95% CI) 29 29 100.0% -13.27 [-23.31, -3.24] 

Heterogeneity: Tau2 = 44.05; Chi2 = 6.13, df = 1

Test for overall effect: Z = 2.59 (P = 0.010) 

 (P = 0.01); I2 = 84% 

4.1.3 4 weeks 

Nelson 1998 -9.36 3.6 20 20 34.2% -9.36 [-16.42, -2.30] 

Ramage 1994 -8.9 4.91 12 12 30.3% -8.90 [-18.52, 0.72] 

Simons 1997 

Subtotal (95% CI) 

-12 3.08 14 14 35.6% -12.00 [-18.04, -5.96] 

46 46 100.0% -10.52 [-14.66, -6.38] 

Heterogeneity: Tau2 = 0.00; Chi2 = 0.44, df = 2 (P = 0.80); I2 = 0% 

Test for overall effect: Z = 4.98 (P < 0.00001) 

decreasing effect of the LABA as a prophylactic EIA agent; over the same time period the 

placebo effect remained constant. 

Figure 14. Effectiveness of LABA vs. placebo: Change from day 1 to week 3–4 weeks after the first ECT (MD 

Maximum percent fall in FEV1. The mean maximum fall in FEV1 following an ECT after 2 

and 4 weeks of continuous salmeterol use plus a pre-exercise dose was greater at week 4 than at 

day 1 (Figure 15). In contrast, the placebo arms showed a small decrease in the degree of EIA 

over the same time period. At the 4 week ECT, 30 minutes post-study drug, the average fall in 

FEV1 was 11.4 percent (range 4.0 to 24.0) in the LABA arms compared with 21.3 percent (range 

16.0 to 32.9) in the placebo arms; however, the pooled difference still favored the LABA (MD = 

10.5 percent; 95 percent CI: 14.7, 6.4) (Figure 14). The timing of the ECT following 

administration of the study drug (30 minutes to 9 hours) was not a factor. Onset of the 

bronchodilator effect of salmeterol occurs in 10 to 20 minutes and lasts for at least 12 hours.162 

Mean Difference 

IV, Random, 95% CI 

77 
 
Figure 15. Effects over time of LABA and placebo on the maximum percent fall in FEV1 for the first ECT % Fall in FEV1 

-10 

0 

10 

20 

30 

40 

50 

LABA 

PLACEBO 

↓ EIB/EIA prevention 

0 5 10 15 20 25 30
 

Days of Treatment 

Duration of action (maximum percent fall in FEV1). Three studies55,57,59 investigated the 

duration of action of salmeterol. Participants underwent a second ECT on the same day; the ECT 

was given 9 to 12 hours after administration of the study drug. The pooled results (Figure 16) 

show that salmeterol continued to have a greater protective effect than placebo at 4 weeks (MD = 

4.4 percent; 95 percent CI: 7.6, 1.2). However, the protective effect had decreased from day 1 
 

when the absolute MD was 11.5 percent (95 percent CI: 14.3, 8.7). 
 

78 
 
 

 

Figure 16. Effectiveness of LABA vs. placebo: Change from day 1 after the second ECT (MD in the maximum 

percent fall FEV1) 

LABA Placebo Mean Difference Mean Difference
 


Study or Subgroup Mean Difference SE Total Total Weight IV, Random, 95% CI IV, Random, 95% CI
 


4.5.1 1 Day 

Nelson 1998 -11.77 2 20 20 39.5% -11.77 [-15.69, -7.85] 

Ramage 1994 -9.9 3.17 12 12 27.7% -9.90 [-16.11, -3.69] 

Simons 1997 -12 2.63 14 14 32.8% -12.00 [-17.15, -6.85] 

Subtotal (95% CI) 46 46 100.0% -11.46 [-14.25, -8.67] 

Heterogeneity: Tau2 = 0.00; Chi2 = 0.31, df = 2 (P = 0.86); I2 = 0% 

Test for overall effect: Z = 8.06 (P < 0.00001) 

4.5.2 2 weeks 

Nelson 1998 -3.39 2.78 20 20 100.0% -3.39 [-8.84, 2.06] 

Subtotal (95% CI) 20 20 100.0% -3.39 [-8.84, 2.06] 

Heterogeneity: Not applicable
 


Test for overall effect: Z = 1.22 (P = 0.22)
 


4.5.3 4 weeks 

Nelson 1998 -2.23 3.6 20 20 31.0% -2.23 [-9.29, 4.83] 

Ramage 1994 -4.8 5.57 12 12 17.4% -4.80 [-15.72, 6.12] 

Simons 1997 -5 1.93 14 14 51.6% -5.00 [-8.78, -1.22] 

Subtotal (95% CI) 46 46 100.0% -4.42 [-7.61, -1.23] 

Heterogeneity: Tau2 = 0.00; Chi2 = 0.47, df = 2 (P = 0.79); I2 = 0% 

Test for overall effect: Z = 2.72 (P = 0.007) 

-20 -10 0 10 20 

Favors LABA Favors placebo 

Conclusions. Three to 4 weeks of regular LABA use results in a decreased prophylactic 

effect on EIA and more pronounced EIA. In studies that included a second ECT given 9 to 12 

hours after the first ECT, the duration of the beneficial effects of LABA waned. The body of 

evidence is classified as “moderate.” 

LABA compared to other agents. Two studies compared regular use of salmeterol 50μg, 

two puffs twice daily versus a leukotriene receptor antagonist (LTRA) (montelukast 10mg) once 

in the evening for 8 weeks. The studies included 360 participants with stable asthma and 

confirmed EIA.53,60 Both studies were funded by industry partners. The ECTs were performed 

near the end of the dosing interval for each drug (Table 24A). The pooled baseline fall in FEV1 

in both groups in both studies (34.9 percent for LABA and 33.9 percent for LTRA) indicated that 

the participants experienced moderate to severe EIA. Both agents attenuated the EIA response 

after 3 days of treatment to a similar degree. The mean fall in the LABA group was reduced to 

19.8 percent compared with 18.2 percent in the LTRA group; this difference was not significant 

(MD = 1.0 percent; 95 percent CI: -2.2, 4.2) (Figure 17). Both agents continued to be effective; 

however, montelukast maintained the same level of effectiveness at 4 and 8 weeks compared 

with a slight decrease in effect with regular use of salmeterol. At 8 weeks, the mean fall in the 

LABA group was 23.0 percent compared with 17.1 percent in the LTRA group; this difference 

was significant (MD = 5.4 percent; 95 percent CI: 2.2, 8.7). The studies also reported that a 

combined 52 percent of LABA participants compared with 65 percent of LTRA participants 

experienced falls in FEV1 of less than 20 percent at 8 weeks. 

Although indirect evidence, these results lend support to other results that indicate some 

degree of tachyphylaxis develops early on with regular daily use of LABA. Furthermore, regular 

daily use of LABA lessens its ability to attenuate EIA when prophylactic doses are taken before 

exercise. 

79 
 
 

Figure 17. Effectiveness of LABA vs. LTRA: Change from day 1 to week 8 (MD in the maximum percent fall 

FEV1) 

LABA LTRA Mean Difference Mean Difference
 


Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI
 


5.1.1 1 day 

Edelman 2000 21.5 25.09 91 18.84 12.15 86 37.7% 2.66 [-3.10, 8.42] 

Villaran 1999 18 12.9 88 17.7 13.5 98 62.3% 0.30 [-3.50, 4.10] 

Subtotal (95% CI) 179 184 100.0% 1.01 [-2.15, 4.18] 

Heterogeneity: Tau2 = 0.00; Chi2 = 0.45, df = 1 (P = 0.50); I2 = 0% 

Test for overall effect: Z = 0.63 (P = 0.53) 

5.1.2 4 weeks 

Edelman 2000 25.64 21.27 91 17.44 18.18 86 39.8% 8.20 [2.38, 14.02] 

Villaran 1999 23.5 14.7 83 17.3 13.8 97 60.2% 6.20 [2.01, 10.39] 

Subtotal (95% CI) 174 183 100.0% 6.88 [3.48, 10.28] 

Heterogeneity: Tau2 = 0.00; Chi2 = 0.30, df = 1 (P = 0.58); I2 = 0% 

Test for overall effect: Z = 3.97 (P < 0.0001) 

5.1.3 8 weeks 

Edelman 2000 25.64 21.27 91 18.36 14.37 86 42.6% 7.28 [1.96, 12.60] 

Villaran 1999 20.2 14.3 86 15.9 14.3 97 57.4% 4.30 [0.15, 8.45] 

Subtotal (95% CI) 177 183 100.0% 5.43 [2.15, 8.70] 

Heterogeneity: Tau2 = 0.00; Chi2 = 0.75, df = 1 (P = 0.39); I2 = 0% 

Test for overall effect: Z = 3.25 (P = 0.001) 

-10 -5 0 5 10 

Favors LABA Favors LTRA 

80 
 
Table 24a. Description of trials in the therapy review: Tachyphylaxis to LABA 

Author Year Publication Randomized Treatment Groups: ECT: type; duration; predicted HR; Definition ECountry status [R] drug; dose; delivery temp; RH; % Outcomes: 

Source 

Funding Analyzed [A] device; time pre- Study days; challenges/day [N]; Primary Trial design Withdrawals ECT time between challenges Secondary 

[W] Withheld asthma med; class; time Adverse eve

Formoterol vs. placebo Garcia54 2001 Journal article F: 10; P: 9 F: 12 μg/bid x 28 d; Bicycle ergometer; 6 min; 85% ≥15% 

21.2oC; 48.30% RH Primary: ma


 

Spain Fondo de F: 10; P: 9 MDI; 
 Clinic Investigación 0 no pre-Tx and 30 min 
 4 [1 screen then days 1, 14, 28] bronchopr

Sanitaria P: 2 puffs bid x 28 d; 2; 3 hr Secondary: 

Parallel MDI; 30 min SABA, NCS, SCG, calcium clinical pro

antagonists, antihistamines, FEV1 measu

ipratropium bromide and study 20, 30, 40medication x 12 hr NR 

Salmeterol vs. placebo Nelson55 

1998 

U.S. Clinic 

Journal article 20 National Heart, 20 

Lung, and 0 Blood Institute; NIH; Glaxo Wellcome Corp. 

Crossover 

Salm: 50 μg bid x 30 d; 

MDI; 30 and 9.5 hr 

P: 2 puffs bid x 30 d; 

MDI; 30 min and 9.5 hr 

Bicycle ergometer; 4 min; 740±246 

kilopond meters/min 

cold air (-8.5±1.3oC); NR 

7 [1 screen then 1, 14 and 29 d of 

each study mo] 

2; 9 hr ICS, methylxanthines, SABA, NS x 

12 hr; methylxanthines x 24 hr 

≥15% Primary: me

post-ECT; 

Secondary: 

protection 

FEV1 measu

NR 

81
 


Ramage57 Journal article 12 Salm: 50 μg bid x 4 wk; Treadmill; 6 min; 85% ≥20% 

1994 NR 12 MDI; 6 and 12 hr dry air; NR Primary: ma

United Crossover 0 P: 1 puff bid x 4 wk; 5 [1 screen, and first and last day of difference 

Kingdom MDI; 6 and 12 hr each Tx period] dosing 

Clinic 2; 6 hr Secondary: 

SABA, SCG, methylxanthines x 8 hr; complete p

24 hr and 24 hr protection 

FEV1 measu

min post E

NR 

Ach = anticholinergic; AE = adverse events; AUC = area under curve; bid = twice/day; C = Celsius; d = day(s); ECT = exercise challenge test; EIB/EIbronchoconstriction/asthma; F=formoterol; FEV1 = forced expiratory volume in 1 second; hr = hour(s); HR = heart rate; ICS = inhaled corticosteroid; 

acting beta-agonist; LTRA = leukotriene receptor antagonist; μg = microgram; max = maximum; m = meters; M=montelukast; MDI = metered dose in

milligram; mo = month(s); NR = not reported; NS=nedocromil sodium; P = placebo; PEF = peak expiratory flow; RH = relative humidity; SABA = sh

SALM=salmeterol; SCG = sodium cromoglycate; temp = temperature; Tx = treatment; URTI = upper respiratory tract infection; wk = week(s) 
Table 24a. Description of trials in the therapy review: Tachyphylaxis to LABA (continued) 

Author Year Publication Randomized Treatment Groups: ECT: type; duration; % predicted Definition ECountry status [R] drug; dose; delivery HR temp; RH; Outcomes: Source Funding Analyzed [A] device; time pre- Study days; challenges/day [N]; Primary 


 

Trial design Withdrawals ECT time between challenges Secondary 

[W] Withheld asthma med; class; time Adverse eve

Salmeterol vs. placebo Selvaggio58 Abstract 9 Salm: 50 μg every other NR NR 

2003 NR 9 d x 21 d; diskus; 9 hr 4 [day 1 and 21 of each Tx period]; 1 Primary: max 

Italy Crossover 0 P: 1 puff every other d x 20 d Secondary: bNR 21 d; diskus; 9 hr NR NR 

Simons59 Journal article 16 Salm: 50 μg/d x 28 d; Treadmill; 8 min; 90% NR 

1997 Glaxo Wellcome 14 MDI with nebulizer; 21.7-22.4oC; 46.5-53.9% RH Primary: max 

Canada Inc. 2 chronolog; 1 and 9 hr 4; 2 of action 

Clinic Crossover P: 2 puffs/d x 28 d; MDI 8 hr Secondary: 

with nebulizer SABA, pseudoephedrine x 8 hr P: exacerbatchronolog; 1 and 9 hr tightness=

Salmeterol vs. montelukast Edelman53 Journal article Salm: 94; M: Salm: 50 μg/bid x 8 wk; Treadmill; 6 min; 80-90% ≥20% 
 

2000 Merck 97 MDI; 9 hr room temp; dry air Primary: max 

U.S. [17 sites] Parallel Salm: 86; M: M:10 mg/d x 8 wk; 3; 1 Secondary: cClinic 91 tablet; 21 hr day 1-3, wk 4, wk 8 FEV1 L; co

82

Salm: 8; M: 6 SABA x 6 hr FEV1 measu

45, 60 min 

Salm vs. M: 

headache vs. 14%; to40% vs. 4

Villaran60 Journal article R=Salm: 95; Salm: 50 μg bid x 8 wk; Treadmill; 8 min; 80-90% 

1999 

25 centers in 

Merck Parallel 

M: 102; 

A=Salm: 88; 

MDI; 8-12 hr 

M: 10 mg OD; tablet; 

room temp; compressed dry air 5 [2 screen, 3rd d, wk 4 and 8]; 1 in 

12 countries M: 100 20-24 hr evening 

Clinic W=Salm: 7; M: 25-28 d 

2 SABA; antihistamines x 8 hr; 48 hr; all 

others 1-2 wk 

≥18% Primary: max 

AUC 

Secondary: c

FEV1; FEVbaseline; % 

FEV1 measu

60 min pos

Salm vs. M: 

32% vs. 2410%; pharURTI 8% v
Table 24b. Description of trials in the therapy review: Tachyphylaxis to SABA 

Author Year Country Source Hancox62 

2002 

Canada Clinic 

Publication 

status 

Funding Trial design Journal article Father Sean 

O'Sullivan Research Centre; Ont Thoracic Society 

Crossover 

Randomized 

[R] Analyzed [A] 

Withdrawals 

[W] 

9 8 1 

Treatment Groups: 

drug; dose; delivery device; time preECT 

Sal: 200 μg qid x 7 d; 

MDI; 

8 hr P: 2 puffs qid x 7 d; 

MDI; 

8 hr 

ECT: type; duration; temp; RH; % 

predicted HR 

Study days; challenges/day [N]; 

time between challenges 

Withheld asthma med; class; time Bicycle ergometer; incremental over 

7 min; 80% 

NR; dry air 1; 1 NA LABA 36 hr; SABA 8 hr; IB 12 hr IB 20 μg/puff allowed for relief 

Definition EOutcomes: Primary Secondary Adverse eve≥15% Primary: cha

response 

Secondary: 

L; 

FEV1 measu

20, 25, 30 

Exacerbation

Inman63 1996 

Canada Clinic 

Journal article Ontario Thoracic 

Society 

Crossover 

10 10 0 

Alb: 200 μg qid x 7 d; 

MDI; immediate 

P: 2 puffs qid x 7 d; 

MDI; immediate 

Bicycle ergometer; 5 min; 

67.2±10.8% of max work rate 

21.5oC; <10% RH 

4; 1 24 hrs SABA x 8 hr; caffeine x 24 hr 

≥15% Primary: ma

Secondary: 

FEV1 measu

NR 

83
 Alb=albuterol; d = day(s); ECT = exercise challenge test; EIB/EIA = exercise-induced bronchoconstriction/asthma; FEV1 = forced expiratory volume 

= heart rate; IB = ipratropium bromide; L = liter; LABA = long-acting beta-agonist; μg = microgram; max = maximum; MDI = metered dose inhaler; reported; qid = four times a day; RH = relative humidity; P=placebo; SABA = short-acting beta-agonist; sal=salbuterol; temp = temperature; wk = wee
Table 25a. Baseline characteristics of patients in trials in the therapy review: Tachyphylaxis to LABA 

Author Year Age (mean±SD) Asthma status Pulmonary Max % fall Smoking Atopic 

Males: N (%) function (% FEV1 status: N status: N 

predicted FEV1 / (mean±SD) (%) (%) 

mean±SD) 

Formoterol vs. placebo Garcia54 2001 F: 22.8±6.1 Stable x 1 mo F: 104.4±19.4 Control ECT NR NR 

P: 25.4±5.2 and P: 97.7±13.4 F: 21.5±10.0 

F: 3/10 (30) throughout trial P: 18.11±10.0 P: 5/9 (56) 

Salmeterol vs. placebo Nelson55 1998 

Ramage57 1994 

Selvaggio58 

2003 

29±8.9 

9/20 (45) 

25.8±5.0 

8/12 (66.7) Range 6-16 NR 

Stable but with 

mixed severity 

Stable mild NR 

93±13.4 

105.7±20.5 

NR 

Control ECT 

24±8.9 

Placebo ECT 

34.8±17.0 

Placebo ECT 

36.6±7.6 

Non-smokers Non-smokers NR 

Mixed 

7/12 (58.3) NR 

Edelman53 2000 

Villaran60 1999 

Salm: 26; range 15­

46 

M: 26.5, range 15-46 Salm: 54/94 (57) M: 46/97 (47) 

All: 27±5.4 

Salm: 45/95 (47) M: 53/102 (52) 

Stable with 

range of severity 

Stable mild 

Salm: 88.0±13.5 M: 87.1±11.2 

Salm: 87.2±14 

M: 86.6±13.7 

Control ECT Salm: 36.6±12.3 M: 37.0±11.5 Control ECT Salm: 30.5±10.5 M: 33.3±12.1 

Non-smokers 

≥1yr 

Past: 

170/197 (86) 

Never 27/197 

(13.7) 

NR NR 

Simons59 1997 13.1±1.3 Stable 93.4±12.7 Placebo ECT NR 16/16 (100) 

7/16 (43.8) 24±12 

Salmeterol vs. montelukast ECT = exercise challenge test; F = formoterol; FEV1 = forced expiratory volume in 1 second; M = montelukast; mo = month(s); NR = not reported; P 

salmeterol; SD = standard deviation 

84
 

Table 25b. Baseline characteristics of patients in trials in the therapy review: Tachyphylaxis to SABA 

Author Year Age (mean±SD) 

Males: N (%) 

Asthma status Pulmonary 

function (% predicted FEV1 / 

mean±SD) 

Max % fall 

FEV1 (mean±SD) 

Smoking 

status: N (%) 

Atopic 

status: N (%) 

Hancox62 2002 26, range 18-44 Stable FEV1/FVC=83±10 Placebo ECT NR NR 

1/9 (11.1) % 10% 

FEV1 =2.8 L 

Inman63 1996 24.5, range 19-37 Stable 85.4±6.3 Control ECT 15­ Non-smokers 10/10 (100) 

7/10 (70) 45% 

ECT = exercise challenge test; FEV1 = forced expiratory volume in 1 second; ICS = inhaled corticosteroids; NR = not reported; SD = standard deviati

85 
 

Table 26. Quality assessment of trials in the therapy review: Tachyphylaxis to LABA and SABA 

86
 


Author Year 

Described as randomized? 

Described as double-blind?

Description of withdrawals/ 

dropouts?

Method of randomization

described and appropriate? 

Method of double-blinding

described and appropriate? 

Method of randomization

described but inappropriate?

Method of double-blinding

described but inappropriate?

Overall Score: Jadad

Concealment of allocation 

Edelman53 2000 Yes Yes Yes Yes Yes No No 5 Adequate 

Garcia54 2001 Yes Yes Yes No Yes No No 4 Unclear 

Hancox62 2002 Yes Yes Yes No Yes No No 4 Unclear 

Inman63 1996 Yes Yes Yes No No No No 3 Unclear 

Nelson55 1998 Yes Yes Yes No Yes No No 4 Unclear 

Ramage57 1994 Yes Yes Yes No No No No 3 Unclear 

Selvaggio58 2003 Yes Yes Yes No No No No 3 Unclear 

Simons59 1999 Yes Yes Yes Yes No No No 4 Unclear 

Villaran60 1999 Yes Yes Yes Yes Yes No No 5 Unclear 
Key Question T–2: Leukotriene Receptor Antagonist Therapy 

Description of Included Studies 

Nine randomized crossover trials44,64-71 met the inclusion criteria for the review comparing a 

single dose of leukotriene receptor antagonist (LTRA) with no treatment or placebo to prevent a 

10 percent or greater drop in FEV1 compared with no treatment or placebo. The studies were 

published between 1999 and 2007. Six trials were conducted in North America,44,64,65,67,68,71 two 

in Europe,66,69 and one70 involved multiple sites in North and South America. 

The drugs studied were montelukast,44,64-66,68-71 zafirlukast,65,67 and zileuton.65 They were 

administered between 2 and 24 hours prior to an ECT. The thresholds for EIB/EIA measured by 

the FEV1 fall index were 10 percent or greater,44,66 15 percent or greater,64,65,69 and 20 percent or 

greater.67,68,70,71 The ECT was performed on a treadmill,64,66-71 or bicycle ergometer.44,65 The 

characteristics of the trials are summarized in Table 27. 

The baseline characteristics of the participants are presented in Table 28. The number of 

patients enrolled ranged from 10 to 62 (total 267). Three studies64,67,69 included children only, 

four65,66,68,70 included adults only, and two44,71 included both children and adults. In eight 

trials44,64-71 all participants had a confirmed diagnosis of asthma; in the remaining trial44 36 

percent of the participants had confirmed asthma. Participants had stable asthma with lung 

function greater than 85 percent predicted. 

Methodological Quality of Included Studies 

Table 29 summarizes the methodological quality of the included studies. Overall, the quality 

of the nine trials was good; the median Jadad score was 3 (IQR: 3, 5). Concealment of allocation 

was unclear in eight trials,44,64-69,71 and adequately reported in one.70 Two trials66,69 did not report 

their source of funding, five44,67,68,70,71 reported pharmaceutical industry support, and two64,65 had 

government/institutional support. The body of evidence is classified as “moderate.” 

Quantitative Results 

Pulmonary function measures. All nine trials recorded the maximum percent fall in FEV1 

on an ECT performed 2 hours or less following drug administration. The times at which later 

ECTs were performed varied across studies thus data were categorized into two groups: 8 to 12 

hours and 24 hours. 

The mean fall in FEV1 on the placebo challenges ranged from 15.0 to 23.2 percent (average 

18.5) indicative of mild EIA. The average fall in FEV1 in the LTRA arms after the first ECT 

ranged from 7.6 to 13.3 percent (average 10.9). The absolute MD = 8.3 percent (95 percent CI: 

6.9, 11.0) and represents clinical protection of approximately 41 percent over placebo. 

Substantial heterogeneity (I2

=65 percent) was identified (Figure 18). 

Six of the trials64,65,68-71 recorded the mean maximum percent fall in FEV1 on an ECT 8 to 12 

hours after drug administration. The difference between groups ranged from 1.8 to 13.3 percent 

and all favored LTRA. The absolute MD = 6.8 percent (95 percent CI: 3.9, 9.6). Substantial 

heterogeneity (I2=70 percent) was identified (Figure 18). 

The difference in the mean fall in FEV1 on an ECT 24 hours following drug administration 

was reported in three trials68,70,71 and ranged from 4 to 8.6 percent in favor of LTRA. The average 

fall in the placebo arms was 13.8 percent (range 10.7 to 16.9) compared with 8.7 percent (range 

8.3 to 10) in the LTRA arms. The pooled results indicate that LTRA remained significantly more 

87 
 
 

 

effective than placebo in attenuating EIA (MD = 4.9 percent; 95 percent CI: 8.0, 1.8). Substantial 

heterogeneity (I2

=76 percent) was identified (Figure 18). 

The source of the heterogeneity could not be explained by subgroup analyses based on age, 

dose of study medication, or funding source. Other subgroup analyses (e.g., ICS use, atopic 

status) could not be performed due to lack of data. 

Figure 18. LTRA vs. placebo in pre-exercise treatment of EIB/EIA: Maximum decrease in FEV1 

LTRA Placebo Mean Difference Mean Difference
 


Study or Subgroup Mean Difference SE Total Total Weight IV, Random, 95% CI IV, Random, 95% CI
 


1.1.1 2 hours or earliest measurement 

Becker 2002 -9.9 2.78 19 19 8.9% -9.90 [-15.35, -4.45] 

Coreno 2000 -15.62 4.37 10 10 5.2% -15.62 [-24.19, -7.05] 

Mastalerz 2002 -12.3 2.84 19 19 8.7% -12.30 [-17.87, -6.73] 

Pearlman 1999 -7.01 1.278 39 39 14.1% -7.01 [-9.51, -4.51] 

Pearlman 2005 -11.5 1.63 49 49 12.8% -11.50 [-14.69, -8.31] 

Peroni 2002 -2 2.6 19 19 9.4% -2.00 [-7.10, 3.10] 

Philip 2007 (i) -5.8 1.58 54 54 13.0% -5.80 [-8.90, -2.70] 

Philip 2007 (ii) -8.6 1.2 47 47 14.4% -8.60 [-10.95, -6.25] 

Rundell 2005 -11.61 1.44 11 11 13.5% -11.61 [-14.43, -8.79] 

Subtotal (95% CI) 267 267 100.0% -8.93 [-11.00, -6.85] 

Heterogeneity: Tau2 = 5.94; Chi2 = 23.09, df = 8 (P = 0.003); I2 = 65% 

Test for overall effect: Z = 8.42 (P < 0.00001) 

1.1.2 8 to 12 hours 

Becker 2002 -10.6 3.9 19 19 9.6% -10.60 [-18.24, -2.96] 

Coreno 2000 -13.33 4.22 10 10 8.7% -13.33 [-21.60, -5.06] 

Pearlman 2005 -7.7 1.31 49 49 22.2% -7.70 [-10.27, -5.13] 

Peroni 2002 -8.91 2.49 19 19 15.5% -8.91 [-13.79, -4.03] 

Philip 2007 (i) -1.8 1.405 52 52 21.6% -1.80 [-4.55, 0.95] 

Philip 2007 (ii) -5.1 1.25 47 47 22.5% -5.10 [-7.55, -2.65] 

Subtotal (95% CI) 196 196 100.0% -6.75 [-9.62, -3.87] 

Heterogeneity: Tau2 = 7.87; Chi2 = 16.77, df = 5 (P = 0.005); I2 = 70% 

Test for overall effect: Z = 4.60 (P < 0.00001) 

1.1.3 24 hours 

Pearlman 2005 -8.6 1.63 49 49 30.9% -8.60 [-11.79, -5.41] 

Philip 2007 (i) -2.7 1.3 52 52 33.7% -2.70 [-5.25, -0.15] 

Philip 2007 (ii) -4 1.1 47 47 35.4% -4.00 [-6.16, -1.84] 

Subtotal (95% CI) 148 148 100.0% -4.94 [-8.03, -1.84] 

Heterogeneity: Tau2 = 5.66; Chi2 = 8.45, df = 2 (P = 0.01); I2 = 76% 

Test for overall effect: Z = 3.13 (P = 0.002) 

-20 -10 0 10 20 

Favors LTRA Favors placebo 

Complete protection. Four trials66-69 reported the proportion of participants who received 

complete protection as an outcome measure. Using less than a 10 percent fall in FEV1 as the 

cutpoint, the pooled estimate indicated that there was no significant difference in the number 

who achieved complete protection with LTRA (RR = 1.9; 95 percent CI: 0.8 to 4.6) compared 

with placebo. Substantial heterogeneity (I2

=72 percent) was identified (Figure 19). 

88 
 
Figure 19. LTRA vs. placebo in pre-exercise treatment of EIB/EIA: Achievemen t of complete protection 

(maximum percent fall FEV1 is less than 10 percent) 

LATRA Placebo Risk Ratio 

Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI

Mastalerz 2002 12 19 0 19 8.6% 25.00 [1.59, 394.17] 

Pearlman 1999 21 37 12 36 40.4% 1.70 [0.99, 2.92] 

Pearlman 2005 23 49 24 49 43.1% 0.96 [0.63, 1.45] 

Peroni 2002 3 19 0 19 7.9% 7.00 [0.39, 126.92] 

Total (95% CI) 124 123 100.0% 1.87 [0.77, 4.56] 

Total events 59 36 

Heterogeneity: Tau2 = 0.44; Chi2 = 10.86, df = 3 (P = 0.01); I2 = 72% 

Test for overall effect: Z = 1.38 (P = 0.17) 

Risk Ratio 

M-H, Random, 95% CI 

0.02 0.1 1 10 50 

Favors placebo Favors LATRA 

Adverse effects. One study69 reported that there were no adverse effects using a 5 mg dose 

of montelukast. Using 10 mg of montelukast, three trials reported non-serious adverse effects 

that included mild headache,68,70,71 nausea,68 nervousness,68 arthralgia,71 and myalgia.71 One 

study67 reported dizziness, pharyngitis, fatigue and headache at a dose ranging from 5 to 40 mg 

of zafirlukast. The occurrence of side effects, however, was not markedly different between the 

treatment and placebo groups (Table 27). 

89 
 
Table 27. Description of trials in the therapy review: LTRA 

Author Year Country Source 

Publication status Funding Trial design 

Randomize 

d [R] 

Analyzed 

[A] 

Withdrawal 

s [W] 

Treatment Groups: drug; 

dose; delivery device; time pre-ECT (min) 

ECT: type; duration (min); % 

predicted HR 

temp; RH; Study days; challenges/day 

[N]; 

time between challenges Withheld asthma med; class; 

Definition 

OutcomesPrimary Secondary Adverse e

time 

Becker64 2002 Abstract 19 M: 5 mg; chewable tablet Treadmill; 8; 50% ≥15% 

Canada Industry/Institution 19 1, 2, 4, 8 hr 20°C; NR Primary: m

Clinic Crossover 0 P: NA; chewable tablet 3; 4 Secondary

1, 2, 4, 8 hr 1, 2, 4 hr FEV1 meas

NR post ECT 

NR 

Coreno65 2000 Journal article 10 M: 10 mg; oral Bicycle ergometer; 4; 790±7 ≥15% 

U.S. Government/iInstitute 10 1, 4, 8, 12 hr kilopound m/min Primary: m

Clinic Crossover 0 Za: 20 mg; oral frigid air -5 to -16°C; NR Seconda

1, 4, 8, 12 hr 5 (1/wk); 4 FEV1 meas

ZI: 600 mg; oral; 4 hr each of 4 1, 4, 8, 12 hr ICS continued; BD x 24 hr; NR 

P: NA; oral antihistamine x 72 hr 1, 4, 8, 12 hr

90
 


Mastalerz66 

2002 

Poland NR 

Journal article NR Crossover 

19 19 0 

M: 10 mg; tablet 1 hr P: NA; tablet 1 hr 

Treadmill; 6-8; 80-90% 20-25°C; ≤50% 3 d intervals; 1 3 d 

≥10% Primary: m

SecondaryFEV1 meas

No; BD; NR 30 min p

NR 

Pearlman67 

1999 

U.S. Clinic 

Journal article Zeneca 

Pharmaceuticals 

3 way crossover; 2 

independent groups; 2 doses Za, 1 P 

39 36 3 

G1: Za:, 5 mg; 20 mg; oral, 4 hr G2: Za: 10 mg; 40 mg; oral 4 hr G1: P: NA; oral G2: P: NA; oral 4 hr 

Treadmill; 6-8; 80-90% room temp; NR 4; 1 4-14 d ICS, SCG x 4wk; astemizole x 

3 mo, LABA x 48 hr 

≥20% Primary: m

Secondary

(at 20%) 

FEV1 meas

min post 

Za: dizzine

fatigue=4

P: dizzines

fatigue=2

AE = adverse events; BD = bronchodilator; d = day(s); ECT = exercise challenge test; EIB/EIA = exercise-induced bronchoconstriction/asthma; FEV1 in 1 second; hr = hour(s); HR = heart rate; ICS = inhaled corticosteroid; L = liter; LABA = long-acting beta-agonist; M=montelukast; m = meter; max medication; min = minute(s); mg = milligram; NA = not applicable; NR = not reported; P = placebo; RH = relative humidity; SABA = short-acting betemperature; wk = week(s); za= zafirlukast; zi=zileuton 
Table 27. Description of trials in the therapy review: LTRA (continued) 

Author Year Publication status Randomized Treatment Groups: drug; ECT: type; duration (min); % Definition Country Funding [R] dose; delivery device; predicted HR OutcomesSource 


 

Trial design Analyzed [A] time pre-ECT temp; RH; Primary 

Withdrawals Study days; challenges/day Secondary 

[W] [N]; Adverse e

time between challenges Withheld asthma med; class; 

time 

Pearlman68 Journal article 51 M: 10 mg; oral Treadmill; 6; 80-90% ≥20% 

2005 Merck Research 49 2, 12, 14 hr NR; NR Primary: m

U.S. Laboratories 2 P: NA; oral 4 (3-7 d between ECTs) 12 hr, 24 

Clinic (9 	 Crossover 2, 12, 24 hr. 3/24 hr; 10, 12 hr Secondary

centers) ICS allowed; SABA x 8 hr % protec

protectioclinical p

FEV1 meas

30, 45, 6

No serious 

nausea, exacerba

91

(these 2 


 

Peroni69 2002 Journal article 19 M: 5 mg; NR Treadmill; 6; 80% ≥15% 

Italy NR 19 2, 12 hr 21°C; 40-50% RH Primary: m

Lived in Italian Crossover 0 P: NA; NR 4 (3-5 d apart); 2 Secondary

Alps at high 2, 12 hr 10 hr protectio

altitude Meds continued; BD x 12 hr FEV1 meas

20, 30 m

No AE wer

Philip70 2007a Journal article 47 M: 10 mg; oral Treadmill; 6; 80-90% ≥20% 
 

U.S., South Merck Research 45 2, 8.5 and 24 hr room temp; dry air 

America Laboratories 1 P: NA; oral 5 (3-7 d between ECTs); 3/24 (Peru) Crossover 2, 8.5 and 24 hr hr 

Clinic (5 2, 8.5, 12 hr 

centers) ICS allowed, all others 

excluded; SABA x 8 hr 

Primary: m

8.5 hr, 24 

Secondary

max chaFEV1 

FEV1 meas

30, 45, 6

No serious 

(2/7 were 
Table 27. Description of trials in the therapy review: LTRA (continued) 

Author Year Publication status Randomized Treatment Groups: drug; ECT: type; duration (min); % Definition Country Funding [R] dose; delivery device; predicted HR OutcomesSource 


 

Trial design Analyzed [A] time pre-ECT temp; RH; Primary 

Withdrawals 

[W] 

Study days; challenges/day Secondary 

[N]; Adverse e

time between challenges Withheld asthma med; class; 

time 

Philip71 2007b Journal article 62 M: 10 mg; oral Treadmill; 6; 80-90% ≥20% 

U.S. Merck Research 53 2, 12, 24 hr room temp; dry air Primary: m

NR Laboratories 9 P: NA; oral 2; 3/24 hr Secondary

Crossover 2, 12, 24 hr 10, 12 hr (at 20%) 

Meds continued; BD x 8 hr FEV 1 mea

30, 45, 6

AE=7 (non

arthralgia flushing adiarrhea=nausea=

Rundell44 2005 Journal article 11 M: 10 mg; oral Bicycle ergometer; 6; NR ≥10% 

U.S. Merck Research 11 6-8 hr -3°C; 50% RH Primary: m

College athletes Laboratories 0 P: NA; oral 4; 1 Secondary

(volunteers) Crossover 6-8 hr 2-3 d % protec

None on asthma med protectio

protectio

FEV1 meas

post ECT 

NR 

92
 

Table 28. Baseline characteristics of patients in trials in the therapy review: LTRA 

93
 


Author Year Becker64 2002 

Age (mean±SD) Males: N (%) 

11.0±2.7 

Asthma status Stable 

Pulmonary function % predicted FEV1 

(mean±SD) 

88.6±14.4 

Max % fall FEV1 

(mean±SD) 

Control ECT 

Smoking 

status: N (%) 

NR 

Atop

staN (

NR 

NR 21.1±9.6 

Coreno65 2000 29±9.5 

4/10 (40) 

Stable 93±12.6 Placebo ECT 

21±15.8 to 26±15.8 

Non-smokers NR 

Mastalerz66 2002 

Pearlman67 1999 

36.2 

10/19 (52.6) 

10.5±2.0 

Stable Stable 

84.3 ±13.5 89.5±11.4 

Placebo ECT 

22.5±10.2 

Placebo ECT 

NR Non-smokers 

11/19 

(57

NR 

Pearlman68 2005 

Peroni69 2002 

Philip70 2007a 

22/39 (56.4) 

24.5±5.9 

24/51 (47) 

11.1±1.8 

13/19 (68) 

26.0±7.9 

23/47 (48.9) 

Stable; mild to 

moderate 

Stable Mild 

86.4±11.9 

87.7±8.7 

87.8±11.4 

16.7±10.8 

Placebo ECT 

22.3±13.1 

Placebo ECT 

15.3±12.8 

Placebo ECT 

27.8±6.2 

NR NR Non-smokers 

NR 

19 (1

38/47 

allerhi

Philip71 2007b 

Rundell44 2005 

24.4±6.9 

33/62 (53.2) 

22.8±6.8 

Stable; mild to 

moderate 

Mild 

88.9±12.4 

98.4±14.2 

Placebo ECT 

17.5±13.8 

Placebo ECT 

NR NR 

NR 

NR 

8/11 (72.7) 22.4±18.0 

ECT = exercise challenge test; EIB/EIA = exercise-induced bronchoconstriction/asthma; FEV1 = forced expiratory volume in 1 second; ICS = inhaled 

reported; SD = standard deviation 
 

Table 29. Quality assessment of trials in the therapy review: LTRA 

94
 


Author Year 

Described as randomized? 

Described as double-blind?

Description of withdrawals/ 

dropouts?

Method of randomization

described and appropriate? 

Method of double-blinding

described and appropriate? 

Method of randomization

described but

inappropriate? 

Method of double-blinding

described but

inappropriate? 

Overall Score: Jadad

Concealment of allocation 

Becker64 2002 Yes Yes No No Yes No No 3 Unclea

Coreno65 2000 Yes No No No Yes No No 2 Unclea

Mastalerz66 2002 Yes Yes Yes No No No No 3 Unclea

Pearlman67 1999 Yes Yes Yes No Yes No No 5 Unclea

Pearlman68 2005 Yes Yes Yes Yes Yes No No 5 Unclea

Peroni69 2002 Yes Yes Yes No No No No 3 Unclea

Philip70 2007a Yes Yes Yes Yes Yes No No 5 Unclea

Philip71 2007b Yes Yes Yes Yes Yes No No 5 Adequa

Rundell44 2005 Yes Yes Yes No No No No 3 Unclea
Key Question T–3: Inhaled Corticosteroid Therapy 

Description of Included Studies 

Four randomized crossover trials72-75 met the inclusion criteria for the review on the 

prophylactic use of a single dose of inhaled corticosteroid therapy (ICS) prior to an ECT. The 

studies were published in peer reviewed journals between 1974 and 2001 and all were conducted 

in Europe. The definitions of EIA as measured by the FEV1 percent fall index were 10 percent or 

greater,73 15 percent or greater,74,75 and 20 percent or greater.72 The ECT was performed on a 

treadmill,73,74 bicycle ergometer,75 or by having participants run or exercise hard.72 The 

characteristics of the trials are summarized in Table 30. 

The drugs studied were betamethasone valerate,72,73 budesonide,75 and fluticasone 

propionate.74 The number of patients enrolled ranged from 9 to 20 (total=50). Two studies73,74 

included children only, one included adults only,75 and one included both adults and children.72 

All participants had confirmed asthma; for most, their asthma was mild to moderate and stable. 

The baseline characteristics of the participants are presented in Table 31. 

Methodological Quality of Included Studies 

Table 32 summarizes the methodological quality of the included studies. Overall, the quality 

of the four trials was good with a median Jadad score of 3.5 (IQR: 3, 4). Concealment of 

allocation was unclear in three trials72,74,75 and inadequately reported in one.73 One trial did not 

report their source of funding,73 two had private industry support,72,74 and one was supported by 

a government grant.75 The body of evidence is classified as “moderate.” 

Quantitative Results 

Pulmonary function measures. Two trials72,74 reported the maximum percent fall in FEV1 

and two73,75 reported the maximum percent fall in peak expiratory flow (PEF) post-ECT. The 

mean fall in FEV1/PEF on the placebo challenges ranged from 19.2 to 36.2 percent (average 

30.5). Three of the placebo groups72,73,75 had a mean fall in FEV1/PEF greater than 30 percent 

indicating moderate to severe EIA. The average fall in FEV1/PEF in the ICS arms ranged from 

9.7 to 31.9 percent (average 25.5). The pooled MD was 5.0 percent (95 percent CI: 0.0, 9.9). The 

differences were not statistically significant and the results failed to identify important 

heterogeneity (I2

=0) (Figure 20). 

95 
 
 

 

Figure 20. Inhaled corticosteroids vs. placebo in pre-exercise treatment of EIA: MD in maximum percent fall 

in FEV1

ICS Placebo Mean Difference 

Study or Subgroup Mean Difference SE Total Total Weight IV, Random, 95% CI 

2.1.1 Measured in FEV1 

Hills 1974 -1.77 3.35 18 18 57.1% -1.77 [-8.34, 4.80] 

Thio 2001 

Subtotal (95% CI) 

-9.5 4.74 9 9 28.5% -9.50 [-18.79, -0.21] 

27 27 85.7% -4.91 [-12.35, 2.53] 

Heterogeneity: Tau2 = 13.03; Chi2 = 1.77, df = 1 (P = 0.18); I2 = 44% 

Test for overall effect: Z = 1.29 (P = 0.20) 

2.1.2 Measured in PEF 

Hodgson 1974 -6.75 10.54 10 10 5.8% -6.75 [-27.41, 13.91] 

Venge 1990 -9.97 8.67 13 13 8.5% -9.97 [-26.96, 7.02] 

Subtotal (95% CI) 23 23 14.3% -8.67 [-21.79, 4.45] 

Heterogeneity: Tau2 = 0.00; Chi2 = 0.06, df = 1 (P = 0.81); I2 = 0% 

Test for overall effect: Z = 1.29 (P = 0.20) 

Total (95% CI) 50 50 100.0% -4.96 [-9.93, -0.00] 

Heterogeneity: Tau2 = 0.00; Chi2 = 2.19, df = 3 (P = 0.53); I2 = 0% 

Test for overall effect: Z = 1.96 (P = 0.05) 

 or peak expiratory flow 

Mean Difference 

IV, Random, 95% CI 

-20 -10 0 10 20 

Favors ICS Favors placebo 

Clinical protection. The mean clinical protection over placebo for participants was either 

reported as an outcome measure or we were able to calculate it from the data. The protection 

index in children was 49 percent after a high dose of fluticasone,74 and 19.6 percent after 

betamethasone.73 A combined population of children and adults who received betamethasone72 

did better on the placebo (clinical protection was –5.9 percent). The clinical protection index for 

adults who received budesonide75 was 27.5 percent. 

Complete protection. Thio et al74 provided IPD from which we could determine that 6 of 9 

participants using high dose fluticasone obtained complete protection (maximum percent fall 

FEV1 less than 10 percent) compared with 4 of 9 on placebo (RR=1.5; 95 percent CI: 0.6, 3.6). 

This outcome was not reported in any of the other trials. 

Adverse effects. None of the studies reported on adverse events. 

Conclusions. We cannot conclude that ICS taken prior to exercise provides a clinical benefit 

to people with stable asthma who experience EIA. 

96 
 
Table 30. Description of trials in the therapy review: Inhaled corticosteroids 

97
 


Author Year Country Source 

Publication 

status 

Funding Trial design 

Randomized 

[R] 

Analyzed [A] Withdrawals 

[W] 

Treatment Groups: 

drug; dose; delivery device; time pre-ECT (min) 

ECT: type; duration; % 

predicted HR 

temp; RH; Study days; challenges/day 

[N]; time between challenges 

Withheld asthma med; class; 

Definition E

Outcomes: Primary Secondary Adverse eve

time 

Hills72 1974 Journal article 20 BV: 0.2 mg; MDI; 15 min Ran or exercised sufficiently to ≥20% 

United Kingdom Glaxo Ltd. 18 P: NA; MDI; 15 min maintain a steady level of Primary: FEV

Clinic Crossover 2 dyspnoea; NR Secondary: 

NR; NR fall FEV1; 

3; 1 FEV1 measu

1-2 d post ECT BD x 6-9 hr NR 

Hodgson73 1974 Journal article 10 BV: 0.2 mg; MDI; Treadmill; HR ≥160 bpm ≥10% 

United Kingdom NR 10 immediately before NR; NR Primary: me

Clinic Crossover 0 P: NA; MDI; immediately 4; 1 Secondary: 

before NR but all at same time of d PEF measur

All x 12 hr 20, 25, 30

NR 

Thio74 2001 Journal article 9 FP: 1 mg; MDI with Treadmill; 90% of predicted ≥15% 

Netherlands GlaxoWellcome 9 spacer maximum Primary: me

Clinic Netherlands 0 4 hr NR; NR Secondary: 

Crossover P: NA; MDI with spacer; 2; 1 protection 

4 hr 7-14 d FEV1 measu

BD x 12 hr; cromoglycates x 2 20, 25, 30 

wk NR 

Venge75 1990 Journal article 13 BUD: 1 mg; MDI; 15 min Bicycle ergometer; 80% >15% 

Sweden Government 13 P: 5 puffs; MDI; 15 min NR; absolute Primary: maClinic Crossover 0 humidity=5.85±1.72; Secondary: 

2; 1 PEF measurNR 25, 30, 60 CS x 3 mo; BD/SCG; oral BD x 8 NR 

hr and 24 hr 

BD = bronchodilator; bpm = beats per minute; BUD= budesonide; BV= betamethasone valerate;CS=corticosteroids; d = day(s); ECT = exercise challe

exercise-induced bronchoconstriction/asthma; FEV1 = forced expiratory volume in 1 second; FP= fluticasone propionate; hr = hour(s); HR = heart rate

dose inhaler; min = minute(s); mg = milligram; mo = month(s); NR = not reported; P = placebo; PEF = peak expiratory flow; RH = relative humidity; cromoglycate; temp = temperature; wk = week(s) 
 

Table 31. Baseline characteristics of patients in trials in the therapy review: Inhaled corticosteroids Author Year Age yr (mean±SD) Asthma status Pulmonary function Max % fall FEV1 Smoking Atopi

Males: N (%) (% predicted FEV1 (mean±SD) status: sta

(mean±SD) N (%) N (%

98
 


Hills72 1974 Range 5-30 5=mild; 2=normal; 3=76-90%; Control ECT 49% NR 16/18 

9/18 (50) 10=moderate; 10=51-75%; 3 >50% 

3=severe 

Hodgson73 1974 Children Stable >50% predicted PEF Control ECT 35% NR NR 

NR (PEF) 

Thio74 2001 11.2±2.5 Mild to moderate 102 ±11.8 Placebo ECT NR NR 

6 (67) (ATS) 19.2±17.3 

Venge75 1990 29.2±8.3 Stable 84.8±11.9 (PEF) Control ECT NR 9/13 (

7 (53.8) 36.2±13.6 

ATS = American Thoracic Society; ECT = exercise challenge test; EIB/EIA = exercise-induced bronchoconstriction/asthma; FEV1 = forced expiratory 

inhaled corticosteroids; NR = not reported; PEF = peak expiratory flow; SD = standard deviation; yr = year Table 32. Quality assessment of trials in the therapy review: Inhaled corticosteroids 

Author Year 

Described as randomized? 

Described as double-blind?

Description of withdrawals/ 

dropouts?

Method of randomization

described and appropriate? 

Method of double-blinding

described and appropriate? 

Method of randomization

described but inappropriate?

Method of double-blinding

described but inappropriate?

Overall Score: Jadad

Concealment of treatment
 

allocation
 

Hills72 1974 Yes Yes Yes No Yes No No 4 Unclear 

Hodgson73 1974 Yes Yes Yes No Yes No No 4 Inadequate 

Thio74 2001 Yes Yes Yes No No No No 3 Unclear 

Venge75 1990 Yes Yes Yes No No No No 3 Unclear 
Key Question T–4: Mast Cell Stabilizers 
 

Background 

With better understanding of the possible role of inflammatory mediators and mast cell 

degranulation in the pathogenesis of EIB/EIA, a variety of mast cell degranulation drugs have 

been investigated for their potential to protect against bronchoconstriction caused by exercise. 

Sodium cromoglycate (SCG; also referred to as "cromolyn sodium") and nedocromil sodium 

(NCS) are mast cell stabilizer (MCS) agents introduced in the late 1960s and early 1980s, 

respectively. Both are reportedly effective on a single-use basis for inhibiting 

bronchoconstriction due to antigens, fog, cold air, sulphur dioxide, and exercise. If effective and 

safe in EIB/EIA, these properties would make them attractive therapeutic options for active 

people. 

During preliminary searches of the literature on MCS, three systematic reviews were 

identified. All three were published in the Cochrane Library and two were subsequently 

published in peer-reviewed journals. The reviews addressed the following topics: NCS to prevent 

EIA,76,104 NCS versus SCG to prevent EIA,77 and MCS versus an anticholinergic agent, a SABA 

agent, or a combination of MCS and SABA agents to prevent EIA.78 Our search strategy 

included terms to locate any new or additional RCTs that would add to the existing reviews. 

None were identified (Appendix E). 

SCG is no longer available in a dry-powdered inhaler in North America; the only remaining 

formulations for asthma are solutions for nebulization. The evidence related to these drugs in 

EIB/EIA are summarized from the existing reviews. 

NCS versus Placebo Review 

Design issues. All the studies included in this review were randomized crossover trials.76,104 

The ECTs were conducted on separate days and the researchers adhered to the recommended 

washout time of 5 to 10 times the half-life of a drug between challenges. 

Objective. The objective of the review was to compare the effects of a prophylactic dose of 

inhaled NCS with placebo in persons with confirmed EIA. The primary outcome was a measure 

of the change in the percent fall index pre- or post-exercise. Secondary outcomes were the mean 

percent fall in FEV1 at varying time points up to 1 hour post-ECT and the degree of clinical 

protection afforded by NCS over placebo. A mean protection index of 50 percent or more was 

considered clinically significant. The review also investigated subgroups based on dose, delivery 

device, timing of pre-treatment, severity of EIA, and age. 

Populations. Recruitment procedures were not often described but generally seemed to be 

volunteers from asthma clinics or schools for asthmatic children. All had documented asthma 

and demonstrated reproducible EIA. All were described as having stable asthma at testing, were 

otherwise healthy, non pregnant, and had no respiratory comorbidity. 

Exercise challenge tests. All ECTs were conducted indoors on an inclined treadmill (n=18), 

a bicycle ergometer (n=1), FRAST (n=1), or sport specific (n=1) (3 sprinters ran outdoors). 

Room temperatures ranged from 17 to 24 degrees Celsius and relative humidity ranged from 35 

to 60 percent. One trial163 conducted a trial using cold air (-18 degrees Celsius). Regardless of 

the challenge format, the intensity and duration demanded was sufficient to induce EIA. 

Results. Description of studies. There were 21 RCTs included in the review (20 peer 

reviewed articles and one unpublished thesis). The trials all used the crossover design but did not 

report data by period and only one reported the treatment sequence. The reviewers analyzed the 

99 
 
data as though from parallel studies determining that this approach would provide a more 

conservative estimate of treatment effect. Data on continuous measures were pooled and reported 

as MD with 95 percent CI using a random effects model. In the subgroup analyses examining the 

effect of treatment based on baseline severity, mild EIA was defined a priori as a mean 

maximum percent fall in FEV1/PEF less than 30 percent on the placebo challenge. Moderate to 

severe EIA was defined as a mean maximum percent fall greater than 30 percent. 

Methodological quality. Using the Jadad scale for RCTs, two studies were rated “strong” (5 

points), nine “very good” (4 points), with the remaining 10 studies rated as “good” (3 points). All 

studies were double-blinded. Two studies were rated as “adequate” concealment of allocation; 

the remaining studies were rated “unclear.” The body of evidence is classified as “moderate.” 

Pulmonary function results. Seventeen trials measured the FEV1 to determine the response to 

treatment following an ECT (total sample size=240; 11 children and 6 adult studies); seven 

measured the PEF (total sample size=115; 4 children and 3 adult studies). Three trials assessed 

the duration of effect over two or three challenges given 2 to 4 hours apart on the same day. 

The maximum percent fall in either FEV1 or PEF improved significantly following NCS 

indicating a statistically and clinically significant attenuation of the EIA response over placebo 

(MD =15.6 percent; 95 percent CI: 13.2, 18.1) (Table 33). Subgroup analyses indicated no 

significant differences: age (children less than 18 years; n=11), dose (low less than 4 mg, n=3; 

standard 4 mg, n=16; high more than 4mg, n=1), delivery system (metered dose inhaler [MDI], 

n=12 versus MDI with spacer device, n=5), and timing of pre-treatment (less than 30 minutes, 

n=10 versus 30 minutes or more, n=7). The effect of NCS appeared more pronounced in those 

that experienced moderate to severe EIA (i.e., a fall index 30 percent or more). In this the MD 

increased to 21.36 percent (95 percent CI: 25.52, 17.20). 

Other outcomes. Thirteen studies compared lung function up to 30 minutes post-challenge. 

At each of seven time points pre-treatment with NCS resulted in significant improvements in 

FEV1 and a return to within 10 percent of baseline function occurred in 10 minutes compared 

with 30 minutes with placebo. 

In three trials that examined the duration of action on subsequent ECTs within 4.5 hours on 

the same day with no further medication, NCS appeared to offer benefit but of a lesser 

magnitude (MD=5.7 percent; 95 percent CI: 2.8, 14.2). 

The trials provided no data on symptom scores, performance measures or participant 

preference. Subgroup comparisons by sex and corticosteroid use were not performed due to lack 

of data. Sensitivity analyses based on study quality, fixed versus random models, and publication 

status were all nonsignificant. 

Adverse events. Twelve studies mentioned side effects. Seven stated that no adverse effects 

or symptoms attributable to NCS were observed. Minor effects reported were bad taste, throat 

irritation, and cough, and in one study a clinically insignificant increase in heart rate of four beats 

per minute. 

Conclusions. In people with stable asthma that experience EIA, NCS taken 15 to 60 minutes 

prior to exercise reduces the severity and duration of EIA in both children and adults. The benefit 

appears more pronounced in those with more severe EIA. 

NCS versus SCG Review 

Design issues. Only crossover trials were included in this revew.

77,161 To ensure drug 

clearance, the challenges within each study were conducted with a minimum 24 hour break. 

100 
 
Objective. The objective of the review was to compare the effects on post-exercise lung 

function following prophylactic doses of NCS and SCG by MDI, in persons with confirmed EIA. 

The primary outcome was the maximum percent fall index. The review also reported the odds 

ratio (OR) and 95 percent CIs of not obtaining complete protection and clinical protection over 

placebo. Complete protection was not obtained if the post-exercise fall in FEV1 exceeded either 

the 10 or 15 percent diagnostic cutpoints. Clinical protection was not obtained if the postexercise fall in FEV1 after NCS or SCG was less than 50 percent of the drop following placebo. 

Population. Recruitment procedures were not well described but appeared to be healthy 

volunteers from either asthma clinics or schools for asthmatic children. Five studies involved 

children (6.5 to 15 years), three involved adults (17 to 38 years), and one study enrolled a mixed 

population (13 to 30 years). The majority recruited stable asthmatics with a reproducible postexercise fall in FEV1 of either 15 percent or 20 percent. 

Exercise challenge tests. All ECTs were performed indoors on either an inclined treadmill 

(n=8) or a bicycle ergometer (n=1) for a duration of 6 to 8 minutes. Intensity required was 

reported as either a heart rate of 170 to 180 or 85 percent of predicted maximum for age. ECTs 

were conducted in controlled environments; however, room temperature and humidity were not 

reported. In all studies, the ECTs were conducted at the same time of day on different days. 

Results. Description of studies. The review included nine RCTs (eight peer-reviewed articles 

and one conference abstract). As in the previous review, the data were analyzed as though they 

were from parallel studies. Data on continuous measures were pooled and reported as a MD with 

95 percent CI, using a random effects model. Dichotomous variables for individual and pooled 

statistics were calculated as OR with 95 percent CI, using a random effects model. We have 

converted the OR of not obtaining complete or clinical protection to the RR of obtaining 

complete or clinical protection to allow comparisons to the key questions from the current 

review. 

Subgroup analyses were performed on adults (18 years and older) versus children (under 18 

years), baseline asthma severity (mild versus moderate-severe), different doses of NCS and SCG, 

and the timing of ECT post-treatment. 

Methodological quality. Using the Jadad scale one study was rated “strong” (5 points), one 

“very good” (4 points), with the remaining studies rated as “good” (3 points). All studies except 

one were double-blinded. One study was rated as “adequate” concealment of allocation; the 

remaining studies were rated “unclear.” The body of evidence is classified as “moderate.” 

Pulmonary function results. Seven trials reported the maximum percent fall in FEV1 (sample 

size=97; 5 children, 2 adult studies). No significant differences between NCS and SCG were 

identified (MD=-0.88; CI: -4.50, 2.74; I2=0 percent). Subgroup analyses based on dose (NCS 4 

mg versus SCG 10 mg, n=5; NCS 4 mg versus SCG 20 mg, n=1; NCS 8 mg versus SCG 4 mg, 

n=1) and timing of the ECT (30 minutes or less, n=7; 120 to 140 minutes, n=2; 240 minutes, 

n=1) failed to identify significant differences (Table 33). 

Other outcomes. Six trials reported complete protection using a fall in FEV1 of less than 10 

percent and six used less than 15 percent; six also reported clinical protection over placebo. 

There were no significant differences between NCS and SCG by diagnostic cutpoint in providing 

complete or clinical protection (Table 33). The trials provided no data on symptom scores, 

performance measures or participant preference. 

Adverse events. Three trials reported on treatment side effects (unpleasant taste N=3; sore 

throat N=2). No significant differences were found between NCS and SCG with respect to 

101 
 
unpleasant taste (RR=3.77; 95 percent CI: 1.29, 10.97) or sore throat (RR=4.96; 95 percent CI: 

20.1, 9.1). Overall, the trend in both cases was for fewer side effects in the SCG group. 

Conclusions. In people with stable asthma who experience EIA, both NCS and SCG provide 

a significant protective effect against EIA. No significant differences were evident between the 

two drugs on pulmonary function; however, more people experienced a sore throat or an 

unpleasant taste from NCS. 

MCS to Prevent EIA Review 

Design issues. This review78 was restricted to full manuscripts regardless of publication 

status and three foreign language studies were included. All but two studies used a crossover 

design. 

Objective. The objective of the review was to compare the effects of a prophylactic dose of 

either NCS or SCG (collectively called MCS) to that of atropine, ipratropium or oxitropium 

bromide (collectively called anticholinergics), and SABA. The review also compared the effects 

of a combination of SABA plus MCS to a SABA alone. The primary outcome was the percent 

fall in FEV1 post-exercise. The review also reported the OR and 95 percent CIs of obtaining 

complete protection and clinical protection. Complete protection was obtained if the postexercise fall in FEV1 was less than either the 10 or 15 percent diagnostic cutpoints. Clinical 

protection was obtained if the post-exercise fall in FEV1 after drug intervention was at least 50 

percent less than that with placebo. 

Population. Recruitment procedures were not well described but appeared to be healthy 

volunteers from either asthma clinics or schools for asthmatic children. Thirteen trials recruited 

children (6 to 13 years) and 11 recruited adults (18 years and older). Most studies documented 

recruiting healthy, stable, asthmatics and all of the trials required at least a 15 percent fall in 

FEV1 to diagnose EIA. The populations in seven trials were considered to have mild EIA defined 

as a percent fall index less than 30 percent on placebo; 16 were classified moderate to severe; 

one did not report baseline data. 

Exercise challenge tests. The ECTs involved an inclined treadmill (n=19), FRAST (n=1), 

bicycle ergometer (n=3), and stair climbing (n=1). Most studies reported an exercise challenge 

time of between 5 to 8 minutes with a target heart rate ranging from 150 to 180 beats per minute. 

Results. Description of studies. The 24 RCTs included in the review reported data on 518 

participants. The studies compared the following drug combinations: MCS versus 

anticholinergics (8 studies), MCS versus SABA (20 studies), and SABA versus a combination of 

SCG plus SABA (10 studies). The method of delivery varied across studies (8 nebulizer, 5 MDI, 

3 spinhaler, and 2 not described), with six studies comparing two or more devices. All studies 

required participants to abstain from taking any bronchodilator for at least 8 hours prior to a 

challenge; other medications were withheld for longer periods of time. 

Methodological quality. Using the Jadad score, two studies were rated “strong” (5 points), 

five rated “very good” (4 points), nine rated “good” (3 points), and eight rated “poor” (2 points 

or less). Four studies were rated to have “adequate” concealment of allocation; the rest were 

rated “unclear.” The body of evidence is classified as “moderate.” 

Pulmonary function results. Sixteen studies (9 children, 7 adult) reported the response to 

treatment using different FEV1 measures (maximum percent fall FEV1=14 studies; percent 

predicted=1 study; change=1 study); 8 studies (5 children, 3 adult) reported maximum percent 

fall PEF. 

102 
 
MCS versus anticholinergics: MCS provided a modest but significant advantage in postexercise lung function over anticholinergics. Pooled results indicate MCS attenuated the fall in 

FEV1 to 7.1 percent compared with 13.8 percent on anticholinergics (MD=6.7 percent; 95 

percent CI: 3.3, 10.0; I2=0 percent). MCS provided more individuals with complete protection 

(OR=2.2; 95 percent CI: 1.3, 3.7) and clinical protection (OR=2.7; 95 percent CI: 1.1, 6.4). 

There were no subgroup differences based on age, severity, or study quality. No adverse effects 

were reported for either agent group. 

MCS versus SABA: When compared with SABA, MCS were not as effective at preventing 

EIA. The mean maximum percent fall in FEV1 using MCS was 11.2 percent compared with 4.3 

percent on SABA (MD=6.8 percent; 95 percent CI: 4.5, 9.2; I2

=20 percent).). MCS provided 

fewer individuals with complete protection (OR=0.3; 95 percent CI: 0.2, 0.5) or clinical 

protection (OR=0.4; 95 percent CI: 0.2, 0.8). There were no significant subgroup differences 

based on age, severity, drug, delivery, or study quality. 

SABA versus combination of SCG plus SABA: Combining a MCS with a SABA did not 

indicate significant advantages to pulmonary function over SABA alone. On average the 

maximum fall in FEV1 on SABA alone was reduced to 5.3 percent compared with 3.5 percent 

using a combination (MD=1.3 percent; 95 percent CI: -6.3, 8.9). There were no significant 

differences in the number achieving complete protection (OR=0.5; 95 percent CI: 0.2, 1.4) or 

clinical protection (OR=0.4; 95 percent CI: 0.1 to 1.2). There were no subgroup differences. 

Overall, every comparison favored the combination; however, none reached statistical 

significance. 

Other outcomes. One study measured the work effort involved during exercise. This 

analysis showed that SCG and SABA significantly decreased the energy cost of running, 

ventilation, oxygen consumption, and tidal volume which significantly increased running 

duration. The trials provided no data on symptom scores, performance measures or participant 

preference. 

Adverse events. A nonsignificant difference in side effects was demonstrated with 11 

percent of SABA patients experiencing side effects compared with 3 percent of those receiving 

MCS (OR=0.2; 95 percent CI: 0.0, 8.2). No adverse events were reported for MCS versus 

anticholinergics or SABA versus combinations of MCS and SABA. 

Conclusions. In people with stable asthma who experience EIA, SABA, MCS, and 

anticholinergic agents can provide a significant protective effect against EIA with few adverse 

effects. On average, SABA agents were more effective than MCS, and MCS agents were more 

effective than anticholinergics. The combination of SABA and MCS agents did not provide 

significant advantages over a SABA alone; however, this approach may be appropriate for some 

people. 

103 
 
Table 33. Description of trials included in the Cochrane reviews of mast cell stabilizers 

Author Year Publication Randomized Inclusion Intervention: drug; ECT: type Definiti

104
 


Number of trials 

included 

Country Dates published 

(range) 

status 

# of trials 

Children [C], Adults [A] 

Funding Trial design 

[R] 

Sample size 

range [SS] 

Analyzed [A] 

Withdrawals 

[W] 

criteria dose; delivery 

device 

Time pre-ECT Comparison 

Withheld asthma 

med 

(% faFEV1) 

Spooner76,104 20 journal R=280 Reproducible NCS: Inclined treadmill Max % f

2002 articles; 1 SS=8-24 (mean EIA 1 mg, N=1; 2 mg, N=3; N=17; FRAST FEV1 

N=21 unpublished 14) Stable asthma 4 mg, N=20; 8 mg, N=1; Bicycle ≥15% 

(20 in the MA) thesis A=279 Lung function N=2 ergometer N=1; ≥20%

North C: N=11 W=1 >70% MDI, N=21; MDI plus Sport specific 

America=1, A: N=10 predicted; spacer, N=5 N=1 

Europe=18, Funding NR variability Time pre-ECT All asthma meds Australia=2 All crossover between 15 min, N=3; 20 min, stopped 

1987-1995 trials challenges N=8; 30 min, N=9; 60 appropriately 

<10-15% min, N=1; 120-150 for 6 h to 1 wk; 

N=1 Olympic min, N=3; 240-270 some allowed 

athletes min, N=2 ICS to continue 

N=20 physical Placebo 

conditioning NR 

Kelly77,161 2000 8 journal articles; R=162 Hx EIA NCS: Inclined treadmill: Max % f

N=9 (8 in the MA) 1 abstract SS=8-45 Stable asthma 4 mg, N=7; 8 mg, N=1 N=8 FEV1 

North C: N=5 A=162 Atopic SCG: Most meds ≥15% N

America=1; A: N=3 W=unclear Baseline FEV1 4 mg, N=1; 10 mg, N=6; stopped ≥20% N

Europe=7; Mixed N=1 >70% 20 mg, N=1; dose appropriately NR N=1 

Australia=1 Funding NR predicted, NR, N=1 for 4 hr to 1 wk; 

1987-1995 All crossover and vary MDI N=8; some allowed 

trials <10% from MDI plus spacer N=4 ICS to continue 

previous Time pre-ECT 

study day 15 min, N=1; 20 min, 

No URIs in last N=5; 30 min, N=2; 

3 wk 120 min, N=1;140 

Non-smokers min, N=1; 240 min, 

N=1 

AC = anticholinergic; AE = adverse events; BD = bronchodilator; ECT = exercise challenge test; EIA = exercise-induced asthma; Fen = fenoterol; FE

volume in 1 second; FRAST = free running asthma screening test; hr = hour(s); Hx = history; MA = meta analysis; max = maximum; MCS = mast cel

dose inhaler; min = minute(s); mg = milligram; NCS = nedocromil sodium; NR = not reported; PEF = peak expiratory flow; SABA = short-acting betaSCG = sodium cromoglycate; URI = upper respiratory infection; wk = week(s) 
Table 33. Description of trials included in the Cochrane reviews of mast cell stabilizers (continued) 

Author Year Publication Randomized Inclusion criteria Intervention: drug; dose; ECT: type Defini

Number of trials status [R] delivery device 

included Children [C], Sample size Time pre-ECT 

Country Adults [A] range [SS] Comparison 

Dates published Funding Analyzed [A] 

Withheld 

asthma med 

EIA FEV

(range) Trial design Withdrawals 

[W] 

Spooner78 2003 24 journal R=518 Hx of asthma MCS N=24 Inclined Max % 

24 articles SS=7-100 and/or EIA SCG N=23, 2-40 mg treadmill: FEV

North America C: N=13 A=505 CS oral and NCS: N=1, 4 mg N=19 PEF 

=3; Europe A: N=11 W=5 trials inhaled use AC N=11 FRAST: N=1 ≥10% =17; Asia=2; Funding NR reported total varied (never, IB: N=8, 0.12–2 mg Bicycle ≥15% Australia=2 Crossover: of 13 none in past 2 Atropine: N=2, 0.2% ergometer: ≥20% 

1976-1998 N=22; withdrawals mo., or OB: N=1, 0.02 mg N=3 ≥25% 

Parallel: N=2 currently taking) MCS vs. AC N=11 Stair climbing: ≥30% 

Lung function SCG vs. SABA N=20; N=1 NR=3 

>50% Fen N=6, 0.1–2 mg Most meds 

predicted; Sal N=10, 0.2-2.5mg stopped for 8 variability Terbutaline N=2 h to 1 wk; between Reproterol, procaterol, some allowed challenges <10­ isoproterenol N=1 each ICS to 15% SCG vs. SCG plus SABA continue; 1 

N=10 did not permit 

Combination doses any meds 

SCG 1–20mg; throughout the Fen N=4, 0.05–0.4 mg trial Sal N=3, 0.2–2.5mg Terbutaline N=1, 

0.5mg 

Reproterol N=1, 

1.0mg 

Device 

Nebulizer N=8; MDI 

N=5; spinhaler N=3; NR N=2; ≥2 devices N=6 

Time pre-ECT 

10 min N=4; 15 min 

N=6; 15-45 min N=1; 20 min N=3; 30 min N=6; 30-45 min N=1; 60 min N=2; 120 min oral N=1 

105
 

Table 34. Baseline characteristics of patients in trials included in the Cochrane reviews of mast cell stabilizers 

Author Year Age yr (mean±SD) 

Males: N (%) 

Asthma 

status 

Pulmonary function 

(% predicted FEV1 / mean±SD) 

Max % fall FEV1 (mean±SD) Smoking 

status: N (%) 

Ato

ss

Spooner76 C: 11.3±2.2 All stable at FEV1 >70% Mean range of EIA severity on Nonsmokers All 

2002 A: 26.5±5.0 time of predicted; control or placebo ECT N=3; NR N

M ~ 64% ECT variability <10-15% C: 28.7 to 50.0% N=17 MNot all reported between A: 15.00 to 40.6% N

male/female mix challenges Mean fall <30% N=16 

Mean fall ≥30% N=5 

Kelly77 2002 C:11.85±4.4; All stable at FEV1 >70% Mean range of EIA severity on Nonsmokers All 

A: 24±4.2 time of predicted; control or placebo ECT N=1; NR NM ~ 54% ECT variability <10-15% C: 27.4 to 35.9% N=8 mNot all reported between A: 15.00 to 33.2% N

male/female mix challenges Mean fall <30% N=4 

Mean fall ≥30% N=4 NR N=1 

Spooner78 C:11.49±3.99 All stable at FEV1 >70% Mean range of EIA severity on Nonsmokers 2/4

2003 A: 26.98±11.15 time of predicted; control or placebo ECT N=4; 3/18 N

M ~ 48% ECT variability <10-15% C: 14.3 to 45.2% smokers atNot all reported between A: 15 to 47% included N

male/female mix challenges Mean fall <30% N=7 N=1 ; NR 

Mean fall ≥30% N=16 N=19 NR N=1 

106
 


A = adult; C = children; ECT = exercise challenge test; EIA = exercise-induced asthma; FEV1 = forced expiratory volume in 1 second; ICS = inhaled NR = not reported; SD = standard deviation 
 

Key Question T–5: Anticholinergic Agents 
 

Description of Included Studies 

Eighteen randomized crossover trials79-96 met the inclusion criteria for the review of shortacting anticholinergic (SAAC) therapy. The studies were published between 1976 and 1989. All 

studies were conducted either in Europe79,82,85-90,92-94 or North America.80,81,83,84,91,95,96 

The drugs studied were atropine,84,86,91 ipratropium bromide (IB),79-83,85,87,88,90,93-96 and 

oxitropium bromide (OB).88,89,92 The definitions of EIA as measured by the percent fall in FEV1 

or PEF were 10 percent or greater,81,86,96 15 percent or greater,80,83,87-89,91,95 and 20 percent or 

greater.79,85,92,93 The ECT was performed on a treadmill,79,83-86,89,90,92-94,96 bicycle 

ergometer,80,81,87,88,91,95 and free running (FRAST).82 The characteristics of the trials are 

summarized in Table 35. 

The baseline characteristics of the participants are presented in Table 36. The number of 

patients enrolled ranged from 6 to 20. Seven studies79,80,84,86,89,91,96 included only children, eight 

included only adults, 81-83,87,88,90,94,95 and three included both.85,92,93 All participants in these trials 

had a confirmed asthma status; for most, the asthma was mild and stable. 

Methodological Quality of Included Studies 

Table 37 summarizes the methodological quality of the included studies. Overall the quality 

of the 18 trials was low with a median Jadad score of 2.5 (IQR: 2, 3) (Table 37). Concealment of 

allocation was unclear in all the trials. Seven trials did not report their source of 

funding,79,82,85,86,91,92,94 eight received private industry support,80,83,87-90,93,95 and three were 

supported by government grants.81,84,96 The body of evidence is classified as “moderate.” 

Quantitative Results 

Pulmonary function measures. Eleven trials compared IB to placebo79,80,83,85,87,88,90,93-96 and 

reported the maximum percent fall in FEV1 as the outcome measure; one82 reported the 

maximum percent fall in peak expiratory flow (PEF). The mean fall in FEV1/PEF on the placebo 

challenges ranged from 14 to 41 percent (average 32). Seven of the placebo groups79,83,85,88,90,93,96 

had a mean fall in FEV1/PEF greater than 30 percent indicating they experienced moderate to 

severe EIA. The average fall in FEV1/PEF in the SAAC arms ranged from 10 to 33 percent 

(average 21). The pooled difference favored IB over placebo (MD = 9.8 percent; 95 percent CI: 

5.0, 14.6) was statistically significant (Figure 21); however, substantial heterogeneity (I2

=76 

percent) was identified. 

107 
 
 

Figure 21. Ipratropium vs. placebo in pre-exercise treatment of EIA: Mean difference in maximum percent fall 

in FEV1 or peak expiratory flow 

Ipratropium Placebo Mean Difference Mean Difference 

Study or Subgroup Mean Difference SE Total Total Weight IV, Random, 95% CI IV, Random, 95% CI 

Boner 1987 -19.1 3.04 15 15 11.0% -19.10 [-25.06, -13.14] 

Borut 1977 -8.49 4.35 20 20 9.3% -8.49 [-17.02, 0.04] 

Bundgaard 1980 1.4 2.68 18 18 11.5% 1.40 [-3.85, 6.65] 

Chan-Yeung 1977 -24.44 8.75 9 9 4.9% -24.44 [-41.59, -7.29] 

Dorward 1982 -24 8.04 7 7 5.4% -24.00 [-39.76, -8.24] 

Hartley 1980 -9.8 1.94 10 10 12.3% -9.80 [-13.60, -6.00] 

Larsson 1982 -3.1 12.12 8 8 3.1% -3.10 [-26.85, 20.65] 

Poppius 1986 1.33 7.09 9 9 6.3% 1.33 [-12.57, 15.23] 

Thomson 1978 -11.69 4.61 13 13 9.0% -11.69 [-20.73, -2.65] 

Tullett 1982 -18.11 6.42 8 8 6.9% -18.11 [-30.69, -5.53] 

Wolkove 1981 -2.4 2.08 8 8 12.1% -2.40 [-6.48, 1.68] 

Yeung 1980 -9.1 5.31 17 17 8.2% -9.10 [-19.51, 1.31] 

Total (95% CI) 142 142 100.0% -9.80 [-14.57, -5.02] 

Heterogeneity: Tau2 = 44.67; Chi2 = 46.27, df = 11 (P < 0.00001); I2 = 76% -20 -10 0 10 20 Test for overall effect: Z = 4.02 (P < 0.0001) Favors Ipratropium Favors placebo 

Four trials compared atropine to placebo80,84,86,91 and all reported the maximum percent fall 

in FEV1 as the outcome measure. The mean difference in the percent fall in FEV1 ranged from 

11.9 to 22.7 percent. The pooled estimate indicated that atropine was significantly more effective 

than placebo in attenuating EIA (MD=16.0; 95 percent CI: 10.2, 21.7) (Figure 22). Negligible 

heterogeneity was identified (I2=0 percent). 

Figure 22. Atropine vs. placebo in pre-exercise treatment of EIA: Mean difference in maximum percent fall in 

FEV1 or peak expiratory flow 

Atropine Placebo Mean Difference Mean Difference 

Study or Subgroup Mean Difference SE Total Total Weight IV, Random, 95% CI IV, Random, 95% CI 

Borut 1977 -11.92 5.38 20 20 29.8% -11.92 [-22.46, -1.38] 

Chen 1981 -14.5 5.29 6 6 30.9% -14.50 [-24.87, -4.13] 

Godfrey 1976 -14.57 8.36 7 7 12.4% -14.57 [-30.96, 1.82] 

Tashkin 1977 -22.73 5.66 15 15 27.0% -22.73 [-33.82, -11.64] 

Total (95% CI) 48 48 100.0% -15.96 [-21.72, -10.20] 

Heterogeneity: Tau2 = 0.00; Chi2 = 2.10, df = 3 (P = 0.55); I2 = 0% -20 -10 0 10 20 Test for overall effect: Z = 5.43 (P < 0.00001) Favors Atropine Favors placebo 

Two trials compared OB to placebo88,89 and both reported the maximum percent fall in FEV1 

as the outcome measure. The pooled results showed that OB was significantly more effective 

than placebo in attenuating EIA (MD=13.8; 95 percent CI: 6.0, 21.6) (Figure 23). Negligible 

heterogeneity was identified (I2=0 percent). 

Figure 23. Oxitropium vs. placebo in pre-exercise treatment of EIA: Mean difference in maximum percent fall 

in FEV1 or peak expiratory flow 

Oxitropium Placebo Mean Difference Mean Difference 

Study or Subgroup Mean Difference SE Total Total Weight IV, Random, 95% CI IV, Random, 95% CI 

Larsson 1982 

Neijens 1981 

-1.3 

-15 

13.4 

4.16 

8 

13 

8 

13 

8.8% 

91.2% 

-1.30 [-27.56, 24.96] 

-15.00 [-23.15, -6.85] 

Total (95% CI) 

Heterogeneity: Tau2 = 0.00; Chi2 = 0.95, df = 1 (P = 0.33); I2 = 0% 

Test for overall effect: Z = 3.47 (P = 0.0005) 

21 21 100.0% -13.80 [-21.58, -6.01] 

-20 -10 

Favors Oxitropium 

0 10 20 

Favors placebo 

108 
 
 

 

Complete protection. Seven trials involving IB reported complete protection as an outcome 

measure.79,83,85,87,88,94,96 The proportion of patients who achieved complete protection ranged 

from 0 to 13 percent. The pooled estimate showed that patients are 4.5 times more likely to 

achieve complete protection with IB compared with placebo (RR=4.5; 95 percent CI: 1.9, 10.9) 

(Figure 24). Negligible heterogeneity was identified (I2

=0 percent). 

Figure 24. Ipratropium vs. placebo in pre-exercise treatment of EIA: Achievement of complete protection 

(maximum fall FEV1 less than 10 percent) 

Ipratropium Placebo Risk Ratio Risk Ratio 

Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 

Boner 1987 6 15 0 15 9.9% 13.00 [0.80, 212.02]
 

Chan-Yeung 1977 5 9 0 9 10.1% 11.00 [0.70, 173.66]
 

Dorward 1982 2 7 0 7 9.3% 5.00 [0.28, 88.53]
 

Hartley 1980 6 10 1 10 20.7% 6.00 [0.87, 41.21]
 

Larsson 1982 4 8 2 8 40.0% 2.00 [0.50, 8.00]
 

Tullett 1982 4 8 0 8 10.0% 9.00 [0.56, 143.89]
 

Yeung 1980 0 17 0 17 Not estimable
 

Total (95% CI) 74 74 100.0% 4.54 [1.89, 10.91] 

Total events 27 3
 

Heterogeneity: Tau2 = 0.00; Chi2 = 2.90, df = 5 (P = 0.71); I2 = 0%
 0.005 0.1 1 10 200 Test for overall effect: Z = 3.38 (P = 0.0007)
 Favors placebo Favors Ipratropium 

Godfrey et al.86 found no significant difference in achieving complete protection in patients 

who received atropine versus placebo (RR=5.0; 95 percent CI: 0.3, 88.5). The remaining studies 

on atropine did not report this outcome. 

The pooled estimate of RR for complete protection from the three studies88,89,92 comparing 

OB with placebo was nonsignificant (RR=4.7; 95 percent CI: 0.4, 60.3) (Figure 25). There was 

substantial heterogeneity (I2

=67 percent). 

Figure 25. Oxitropium bromide vs. placebo in pre-exercise treatment of EIA: Achievement of complete 

protection (maximum fall FEV1 is less than 10 percent) 

Oxitropium Placebo Risk Ratio Risk Ratio 

Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 

Larsson 1982 1 8 2 8 36.5% 0.50 [0.06, 4.47] 

Neijens 1981 9 13 0 13 31.7% 19.00 [1.22, 295.91] 

Taytard 1987 7 10 0 10 31.8% 15.00 [0.97, 231.84] 

Total (95% CI) 31 31 100.0% 4.67 [0.36, 60.33] 

Total events 17 2 

Heterogeneity: Tau2 = 3.42; Chi2 = 6.05, df = 2 (P = 0.05); I2 = 67% 0.005 0.1 1 10 200 Test for overall effect: Z = 1.18 (P = 0.24) Favors placebo Favors Oxitropium 

Clinical protection. Six trials that examined IB reported clinical protection as an outcome 

measure.79,81,83,85,87,94 The pooled estimate showed that 60 percent (95 percent CI: 48, 72) of 

patients achieved clinical protection when defined as at least a 50 percent improvement in FEV1 

over placebo (Figure 26). There was negligible heterogeneity (I2=0 percent). 

109 
 
 

 

Figure 26. Ipratropium vs. placebo in pre-exercise treatment of EIA: Achievement of clinical protection (50 

percent or greater improvement over placebo in FEV1) 

Number with protection Proportion Proportion 

Study or Subgroup Proportion SE Total Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI 

Boner 1987 0.6667 0.122 10 15 25.1% 0.67 [0.43, 0.91]
 


Boulet 1989 0.4545 0.15 5 11 16.6% 0.45 [0.16, 0.75]
 


Chan-Yeung 1977 0.7778 0.139 7 9 19.3% 0.78 [0.51, 1.05]
 


Dorward 1982 0.5714 0.187 4 7 10.7% 0.57 [0.20, 0.94]
 


Hartley 1980 0.4 0.155 4 10 15.5% 0.40 [0.10, 0.70]
 


Tullett 1982 0.625 0.171 5 8 12.8% 0.63 [0.29, 0.96]
 


Total (95% CI) 35 60 100.0% 0.60 [0.48, 0.72] 

Heterogeneity: Chi2 = 4.58, df = 5 (P = 0.47); I2 = 0% -1 0 0.5 1 0.5 Test for overall effect: Z = 9.75 (P < 0.00001) Favors placebo Favors Ipratropium 

In the study by Godfrey et al.86 29 percent (95 percent CI: 8, 64) of patients achieved clinical 

protection when taking atropine. The remaining studies did not report on this outcome or provide 

data for calculation. 

Adverse effects. Overall, IB was well tolerated with seven studies reporting no adverse 

effects.79,82,87,88,93-95 Dry mouth or thirst was reported in three studies: 16 percent of patients in 

two studies in which the dose was 0.04 mg of IB,80,96 and 20 percent at a dose of 0.2 mg and 60 

percent at a dose of 2 mg in the third study.90 Other side effects included bitter taste90 and slight 

tremor.96 

Larsson et al. reported no side effects with oxitropium.88 The remaining two studies did not 

report on adverse effects. None of the studies that examined atropine reported on adverse effects. 

Subgroup/sensitivity analyses. Subgroup analyses based on age suggest similar results for 

children and adults for maximum percent decrease in FEV1. Analyses based on asthma severity 

did not reduce heterogeneity. Sensitivity analysis on high versus low quality studies did not 

reduce the heterogeneity. 

110 
 
Table 35. Description of trials in the therapy review: Anticholinergic therapy 

111
 


Author Year Publication Randomized [R] Intervention: drug; ECT: type; duration (min); % Definition 

Country status Analyzed [A] dose; delivery device; predicted HR OutcomesSource Funding Withdrawals time pre-ECT Temp; RH; Primary 

Trial design [W] Study days; challenges/day [N]; Secondary 

Time between challenges Adverse eWithheld asthma med; class; 

time 

Boner79 1987 Journal article 15 IB; 0.5 mg in 2 ml saline; Treadmill; 6; 90±4% ≥20% 

Italy NR 15 nebulizer; 30 min NR; NR Primary: m

Residential Crossover 0 P: Saline; 2 ml; nebulizer; 4; 1 Secondary

home for 30 min 24 hr protectioasthmatics BD x12 hr; SCG x 24 hr; FEV1 meas

theophylline x 1 wk min or un

No AE for a

Borut80 1977 Journal article 20 IB; 0.04 mg; MDI; 45 min Bicycle ergometer; 6-8; workload >15% 

U.S. Foundation 20 IB; 0.08 mg; MDI; 45 min that caused the requisite degree Primary: S

Clinic and 0 P: NA; MDI; 45 min of bronchoconstriction Secondary

Boehringer NR; NR FEV1 meas

Ingelheim 6 [1 control, 5 test]; 1 Yes 

Crossover 1 wk 

All med x 12 hr 

Boulet81 1989 Journal article 12 IB; 0.08 mg; MDI with Bicycle ergometer; 6; NR ≥10% 

Canada Government 11 aerochamber; 30 min NR; NR Primary: mClinic Crossover 1 P; NA; MDI with 4; 1 Secondary

aerochamber; 30 min ≥48 hr protectio

Theophyllines x 24 hr; BD x 8 hr FEV1 meas

FEV1 sta

NR 

AE = adverse events; BD = bronchodilators; bpm = beats per minute; C = Celsius; cc = cubic centimeter; d = day(s); DSCG = disodium cromoglycatetest; EIB/EIA = exercise-induced bronchoconstriction/asthma; FEV1 = forced expiratory volume in 1 second; g/L = grams per liter; hr = hour(s); HR = 

bromide; BD= bronchodilator; IM = intra muscular; L = liter; max = maximum; med = medication; MDI = metered dose inhaler; min = minute(s); mg 

NA = not applicable; NR = not reported; OB = oxytropium bromide; P = placebo; PEF = peak expiratory flow; RAW = airway resistance; RH = relat

revolutions per minute; SCG = sodium cromoglycate; SGaw = specific airways conductance; temp = temperature; Tx = treatment; wk = week(s) 
Table 35. Description of trials in the therapy review: Anticholinergic therapy (continued) 

Author Year Country Source 

Publication 

status 

Funding Trial design 

Randomized [R] Analyzed [A] Withdrawals 

[W] 

Intervention: drug; 

dose; delivery device 

time pre-ECT 

ECT: type; duration (min); % 

predicted HR 

Temp; RH; Study days; challenges/day [N]; Time between challenges Withheld asthma med; class; time 

Defin

OutcoPrimaSecoAdve

Bundgaard82 Journal article 18 IB: 0.5 mg + 2 ml isotonic Free running test; 6; 160 bpm after 2 NR 

1980 NR 18 saline; nebulizer; 30-45 min running Prima

Denmark Crossover 0 min NR; NR SeconClinic P: saline; 4 ml; nebulizer; 6 [1 no-Tx, 5 test]; 1 PEF m

30-45 min 24 hr No AE 

All med x 24 hr 

ChanYeung83 

1977 

Canada Clinic 

Journal article Drugs supplied 

by Boehringer Ingelheim 

Crossover 

9 9 0 

IB: 0.08 mg; freonpropelled inhaler; 15 

min 

P: lactose powder; NR; 

spinhaler; 15 min 

Treadmill (n=6), jogging outside (n=3); 

2.5-6; NR 

NR; NR 3; 1 3-7 d at same time of d All except oral prednisone x 6 hr 

≥15% Prima

Secon

pro

FEV1 

min 

NR 

Chen84 1981 

U.S. NR 

Journal article Government Crossover 

6 6 0 

a) atropine plus 1ml IM 

saline; individual dosing to achieve max bronchodilation; 

Treadmill; 10; 180 bpm NR; NR 5; 1 5 ECT in 3 wk at same time of d 

NR Prima

SeconFEV1 

nebulizer; 60 min Theodur, BD, SCG, ICS and NR 

b) atropine plus 1ml IM 

saline; double dose of a; nebulizer; 60 min 

prednisone every other d unchanged; testing done on d when prednisone not taken; BD x 4 hr 

P: distilled water plus 1ml 

IM saline; 1 ml; nebulizer; 60 min 

112
 


Dorward85 Journal article 7 IB: 0.12 mg; nebulizer; 60 Inclined treadmill; 8; 170-180 bpm ≥25% 

1982 NR 7 min 20-22°C; 30-50% RH Prima

United Crossover 0 P: saline; 9 g/L; nebulizer; 5; 1 Secon

Kingdom 60 min on different d pro

Clinic SCG and BD x 24 hr pro

FEV1 

NR 
Table 35. Description of trials in the therapy review: Anticholinergic therapy (continued) 

Author Year Country Source 

Publication 

status 

Funding Trial design 

Randomized [R] Analyzed [A] Withdrawals 

[W] 

Intervention: drug; 

dose; delivery device; time pre-ECT 

ECT: type; duration (min); % 

predicted HR 

Temp; RH; Study days; challenges/day [N]; Time between challenges Withheld asthma med; class; time 

Defin

OutcoPrimaSecoAdve

Godfrey86 Journal article 7 Atropine; 0.2%; nebulizer; Treadmill; 6; 170-180 bpm ≥10% 

1976 NR 7 5-10 min NR; NR Prima

United Crossover 0 P: saline; NA; nebulizer; 1; 2 Secon

Kingdom 5-10 min 2 hr pro

Clinic All med x 12 hr PEF m

NR 

Hartley87 Journal article 10 a) IB: 0.1 mg; nebulizer; Bicycle ergometer; 8; 80% ≥15% 

1980 Drugs supplied 10 90 min 20-24°C; not controlled Prima

United by Boehringer 0 b) IB:1.0 mg; nebulizer; 3; 2 Secon

Kingdom Ingelheim 90 min 2-3 hr pro

Clinic Crossover P: saline; NA; nebulizer; ICS allowed; SCG x 24 hr; BD x 12 hr pro

90 min FEV1/

25, 

No AE 

Larsson88 Journal article 8 OB; 0.1 mg; MDI; 60 min Bicycle ergometer; 6-9; load increased >15% 

1982 Boehringer 8 IB: 0.04 mg; MDI; 60 min every min until exhaustion Prima

Sweden Ingelheim 0 P: NA; MDI; 10 min NR; NR Secon

Clinic Crossover 4; 1 pro

24 hr FEV1 

All med x 12 hr No AE 

113
 


Neijens89 

1981 

Netherlands Clinic 

Journal article Foundation; 

Drugs supplied by Boehringer Ingelheim 

Crossover 

13 13 0 

OB: 0.02 mg; MDI; 20 min P: NA; MDI; 20 min 

Treadmill; 6; 175 bpm 22°C; 70% RH 4 consecutive d; 2 2 hr All med x 3 d 

≥15% Prima

Secon

FEV1 

NR 

Poppius90 

1986 

Finland Clinic 

Journal article Drugs supplied 

by Boehringer Ingelheim; Sigrid Juselius Foundation 

Crossover 

10 10 0 

a) IB: 0.2 mg; powder 

capsule; 60 min 

b) IB 1 mg; powder 

capsule; 60 min 

c) IB: 2 mg; powder 

capsule; 60 min 

P: Powder capsule; NA; 

60 min 

Treadmill; 8; workload chosen to induce 

slight bronchoconstriction 

Cold air -9±7°C; water content 1.5 mg/L 4; 1 1 to 3 d All antiasthmatic meds during the trial 

Not cPrima

Secon

FEV1 

Yes 
Table 35. Description of trials in the therapy review: Anticholinergic therapy (continued) 

114
 


Author Year Country Source 

Publication 

status 

Funding Trial design 

Randomized [R] Analyzed [A] Withdrawals 

[W] 

Intervention: drug; 

dose; delivery device; time pre-ECT 

ECT: type; duration (min); % 

predicted HR 

Temp; RH; Study days; challenges/day [N]; Time between challenges Withheld asthma med; class; time 

Defin

OutcoPrimaSecoAdve

Tashkin91 Journal article 15 Atropine: 1 mg; nebulizer; Bicycle ergometer; 6-8; 25-watt >15% 

1977 NR 15 10 min workload at 60 rpm Prima

U.S. Crossover 0 P: saline; 0.25 cc; NR; NR SeconClinic nebulizer; 10 min 7 [2 screen, 5 test]; 1 FEV1 

≤1 wk at same time of d NR DSCG x 2 wk; oral/inhaled BD x 12 hr 

Taytard92 Journal article 10 OB: 0.3 mg; MDI; 25 min Treadmill; ≤8; 80% ≥20% 

1987 NR 10 P: NA; MDI; 25 min NR; NR Prima

France Crossover 0 2; 1 SeconClinic 48 hr FEV1 

Oral/inhaled BD 48 and 12 hr NR 

Thomson93 Journal article 13 IB: 2 mg; nebulizer; 20 Treadmill; 5-8; ≥170-180 bpm ≥20% 

1978 Fison's 13 min NR; NR Prima

United LtdIndustry 0 P: saline; 9 g/L; nebulizer; 4; 1 Secon

Kingdom Crossover 20 min 4 ECT within 10 d FEV1 

Clinic SCG and BD x 24 hr No AE Tullett94 1982 Journal article 12 IB 0.12 mg; nebulizer; 30 Treadmill; 8; 160 bpm NR 

United NR 8 min 20-22°C; 20-40% RH Prima

Kingdom Crossover 0 P: saline; 9 g/L; nebulizer; 4; 1 Secon

Clinic 30 min 2-3 d com

SCG and BD x 24 hr FEV1 

Yes 

Wolkove95 Journal article 8 IB: 0.04 mg; MDI; 60 min Bicycle ergometer; 8; 300, 600, or 900 ≥15% 

1981 Sigrid Juselius 8 P: 2 puffs; MDI; 60 min km/min Prima

Canada Foundation; 0 indoors 23.3±0.4°C, cold air -9.8±0.6°C; temClinic Drugs from indoors=35±4%; outdoors=65±7% Secon

Boehringer 4; 1 FEV

Ingelheim NR FEV1 

Crossover All med x 12 hr No AE 

Yeung96 1980 Journal article 17 IB: 0.04 mg; MDI; 45 min Treadmill; effort to cause a 25% fall in ≥10% 

Canada Foundation 17 P: NA; MDI; 45 min FEV1 pre-study; 170-180 bpm Prima

Clinic Cross-over 0 NR; NR Secon

3; 1 pro1 to 2 d FEV1 

All med x 12 hrs Yes 
Table 36. Baseline characteristics of patients in trials in the therapy review: Anticholinergic therapy 

115
 


Author Year Age (mean±SD) 

Males: N (%) 

Asthma status Pulmonary function: 

baseline FEV1 % 

predicted (mean±SD) 

Max % fall 

FEV1 

(mean±SD) 

Smoking 

status: N (%) 

Atopic 

statusN (%) 

Boner79 1987 11.7±1.4 Stable >80 Placebo ECT NR 15/15 (1

10/15 (66.7) 40.9±17.2 

Borut80 1977 13.1±2.15 Stable mild­ 77.9±16.01 Control ECT NR 20/20 (1

18/20 (90) moderate 20-25 

Boulet81 1989 30±10.9 Stable 90.5±13.1 NR NR 9/11 (81

4/11 (57.1) 

Bundgaard82 1980 30.5±7.6 Stable NR Placebo ECT Never 10/18 17/18 (9

7/18 (38.9) 33.5 (56); current 

3/18 (17) <5/d 

Chan-Yeung83 33.1±13.8 Stable 90.2±12.2 Control ECT All non-smokers 4/9 (44.

1977 5/9 (55.6) 36±15 

Chen84 1981 13.5±1.76 Stable 85±10 Placebo ECT NR NR 

5/6 (83.3) 28±14.69 

Dorward85 1982 24±9.5 Stable 2.8±0.87 L Control ECT All non-smokers 7/7 (100

2/7 (28.6) 47±18.4 

Godfrey86 1976 8.7±2.9 Stable 70.3±15.1 Placebo ECT NR NR 

13/15 (86.7) 45.2±15.5 

Hartley87 1980 32; range 21-48 Stable 77.6 (53-113) Placebo ECT NR 8/10 (80

4/12 (40) 29.2±12.3 

Larsson88 1982 44.8±10.5 Stable 78.61±27.32 All ≥15 NR 4/8 (50) 

5/8 (62.5) 

Neijens89 1981 12.5±3.13 Stable mild­ ≥60 Control ECT NR NR 

9/13 (69.2) moderate 32.4±10.8 

Poppius90 1986 27.7±7.21 Mild 94.6±15.6 Placebo ECT All non-smokers 5/10 (50

5/10 (50) 14 

Tashkin91 1977 11.7±1.7 Stable (mild 79±11 Placebo ECT NR 15/15 (1

14/15 (93.3) airway 18-28 

obstruction) 

ECT = exercise challenge test; EIB/EIA = exercise-induced bronchoconstriction/asthma; FEV1 = forced expiratory volume in 1 second; ICS = inhaled NR = not reported; SD = standard deviation 
Table 36. Baseline characteristics of patients in trials in the therapy review: Anticholinergic therapy (continued) 

Author Year Age (mean±SD) 

Males: N (%) 

Asthma status Pulmonary function: 

baseline FEV1 % 

predicted (mean±SD) 

Max % fall 

FEV1 

(mean±SD) 

Smoking 

status: N (%) 

Atopic 

statusN (%) 

Taytard92 1987 19±4 Stable 88±16 NR None or <5 NR 

4/10 (40) cigarettes/d 

Thomson93 1978 17-3 Stable 87±22.3 Control ECT All non-smokers 13/13 (1

7/13 (53.8) 38.1±15.2 

Tullett94 1982 31.2±11.3 Stable 3.43±0.54 L Placebo ECT All non-smokers 12/12 (1

5/8 (62.5) 38.1±14.1 

Wolkove95 1981 28.7±5.4 Stable 62.0±16.4 to All ≥15 NR NR 

Yeung96 1980 

4/8 (50) 

13; range 9-18 Stable 

69.8±16.7 

77.1±21.85 Placebo ECT NR NR 

14/27 (51.9) 35.8±18.1 

116
 

 

Table 37. Quality assessment of trials in the therapy review: Anticholinergic therapy 

117
 


Author Year 

Described as randomized? 

Described as double-blind?

Description of withdrawals/ 

dropouts?

Method of randomization

described and appropriate? 

Method of double-blinding

described and appropriate? 

Method of randomization

described but

inappropriate? 

Method of double-blinding

described but

inappropriate? 

Overall Score: Jadad

Concealment of allocation 

Boner79 1987 Yes Yes Yes No No No No 3 Unclear 

Borut80 1977 Yes Yes Yes No No No No 3 Unclear 

Boulet81 1989 Yes Yes Yes No No No No 3 Unclear 

Bundgaard82 1980 Yes Yes Yes No No No No 3 Unclear 

Chan-Yeung83 1977 Yes No Yes No No No No 2 Unclear Chen84 1981 Yes No Yes No No No No 2 Unclear Dorward85 1982 Yes No Yes No No No No 2 Unclear 

Godfrey86 1976 Yes No Yes No No No No 2 Unclear 

Hartley87 1980 Yes No Yes No No No No 2 Unclear 

Larsson88 1982 Yes Yes Yes No Yes No No 4 Unclear 

Neijens89 1981 Yes Yes Yes No No No No 3 Unclear 

Poppius90 1986 Yes Yes Yes No No No Yes 2 Unclear 

Tashkin91 1977 Yes Yes Yes No No No No 3 Unclear 

Taytard92 1987 Yes Yes Yes No No No No 3 Unclear 

Thomson93 1978 Yes Yes Yes No No No No 3 Unclear 

Tullett94 1982 Yes No Yes No No No No 2 Unclear 

Wolkove95 1981 Yes Yes No No No No No 2 Unclear 

Yeung96 1980 Yes No Yes No No No No 2 Unclear 
Key Question T–6: Refractory Period (10 to 15 Minute 
 

Warmup and/or Cooldown) 
 

Description of Included Studies 

Seven trials97-103 met the inclusion criteria for the review investigating whether a defined 

exercise warmup protocol induces a refractory period that attenuates or prevents the EIB/EIA 

phenomenon within 2 hours of a subsequent ECT. Six trials used a crossover design;97,99-103 for 

one abstract the specific design could not be determined.98 The studies were published between 

1979 and 2007. Four trials were conducted in Europe,97,98,101,102 two in Australia101,103 and two in 

North America.99,100 The definition of EIB/EIA was measured by at least a 1098,100,101 or 

1597,99,102 percent fall in FEV1. 

In three trials97,98,102 it was not clear if the ECT following the warmup met the ATS criterion 

of a work rate equal to 80 to 90 percent of an individually calculated maximum.164 The time 

between warmup and ECT ranged from 1 to 49 minutes. The characteristics of the trials are 

summarized in Table 38. 

The baseline characteristics of the participants are presented in Table 39. The number of 

patients enrolled ranged from 6 to 46. One study97 included children only, three included adults 

only,99,100,102 and three included both children and adults.98,101,103 All participants in these trials 

except for one98 had confirmed asthma; for most, their asthma was mild and stable. 

Five of the seven studies investigated two or more warmup protocols. In order to capture all 

comparisons the protocols were categorized into three subgroups based on the intensity of the 

routine. Four routines involved several short sprints and are designated “interval” 

warmups;97,99,100,103 two studies involved two standardized challenges 45 minutes apart and are 

designated “continuous high intensity” warmups;102,103 three involved treadmill runs at work 

rates of 60 percent and are designated as “continuous low intensity” warmups.99,101,102 Study 

arms that involved drug therapy with or without a warmup are not included in this analysis.100 

Finally, the study by Eck et al.,98 and one arm of the study by Schnall et al.103 that used a 

continuous routine followed by an interval routine are reported separately. 

Methodological Quality of Included Studies 

Table 40 summarizes the methodological quality of the included studies. Overall the seven 

trials received low Jadad scores ranging from 1 to 2. No study described the randomization 

method. None stated that the assessors were blind; it was not possible to blind the participants to 

the type of warmup. Concealment of allocation was unclear in all the trials. The body of 

evidence is classified as “low.” 

Quantitative Results 

In all studies the mean maximum percent fall in FEV1 or PEF was measured after a control 

ECT of 5 to 10 minutes and compared with the percent fall in an identical challenge after a 

designated warmup routine. The pooled results are presented as a MD in the maximum percent 

fall in FEV1 or PEF between the two challenges. Because studies are included in more than one 

group, only subgroup pooled estimates were calculated. 

Interval protocol. Four trials compared an interval warmup to a control challenge with no 

warmup.97,99,100,103 The protocols involved repetitive sprints of 26 to 30 seconds at 100 percent 

maximal oxygen consumption (VO2max) or higher. The mean difference in the maximum percent 

118 
 
fall in FEV1 ranged from an improvement of 4.8 to 16.1 percent over the control challenge. The 

pooled results showed that a series of short intense sprints attenuated the EIB/EIA response by a 

mean of 10.6 percent (95 percent CI: -14.7, -6.5; I2

=15 percent) (Figure 27). One study reported 

that one of the 12 participants had falls in FEV1 of less than 15 percent99 and would be classified 

as having obtained complete protection from EIB/EIA following the interval warmup. 

Continuous low intensity protocol. Three trials compared a continuous low intensity 

warmup that ranged from 3 minutes101 to 30 minutes102 to a control challenge with no warmup. 

Exercise intensity for the warmup was 60 percent of maximum heart rate,101 60 percent of 

VO2max,

99 and reported as low intensity in the third study.102 The mean difference in the 

maximum percent fall in FEV1 ranged from no improvement to 20.6 percent over the control 

challenge. The pooled results showed that this type of warmup attenuated the EIB/EIA response 

by a mean of 12.6 percent (95 percent CI: -26.7, 1.5; I2=90 percent) (Figure 27). One study also 

reported that 6 of the 12 participants had falls in FEV1 of less than 15 percent and classified them 

as having obtained complete protection from EIB.99 

Continuous high intensity protocol. Two trials compared a continuous high intensity 

warmup102,103 to a control challenge with no warmup. Exercise intensity for the warmup was a 

heart rate equal to180 beats per minute103 and 98±2 percent of predicted maximum.102 The mean 

difference in the maximum percent fall in FEV1 ranged from very little improvement (0.99) to 

17.6 percent over the control challenge. The pooled results showed that this type of warmup 

attenuated the EIB/EIA response by a mean of 9.8 percent (95 percent CI: -26.0, 6.4) (Figure 

27). Substantial heterogeneity was identified (I2=89 percent). 

Combination protocols. Eck et al.98 reported that there was no significant difference among 

the three protocols they investigated—one each of continuous 10 minutes of low intensity 

running, 10 minutes of running in intervals, and 10 minutes of exercising with increasing 

intensity. No data on the intensity of each warmup were reported. When combined, the three 

protected 79 percent (36/46) of participants from EIB/EIA (cutpoint not reported). The combined 

mean maximum percent fall in FEV1 on the challenge following all warmup protocols was 

compared with no warmup and indicated a mean improvement of 11.0 percent (95 percent CI: 

7.5, 14.6) (Figure 27). 

One of three protocols in the Schnall and Landau103 trial involved a combination of 

continuous and interval segments—a 6 minute treadmill run (heart rate 180 beats per minute), a 

10 minute rest followed by 7 x 30 second sprints (treadmill speed increased 120 to 130 percent 

over first run), then a 20 minute rest before the final challenge of the same intensity as the 

original 6 minute run. The mean difference in the maximum percent fall in FEV1 compared with 

no warmup was 10.4 percent (95 percent CI: 0.2, 21.1). 

Other comparisons: One study reported no significant changes among three formats of 

warmup in measures of respiratory heat and water loss.99 

119 
 
Figure 27. Warmup vs. no warmup in pre-exercise treatment of EIB/EIA: maximum percent decrease in FEV1 

or peak expiratory flow 

Warmup No warmup Mean Difference Mean Difference 

Study or Subgroup Mean Difference SE Total Total Weight IV, Random, 95% CI IV, Random, 95% CI 

10.6.1 Interval 

de Bisschop 1999 -12 3.04 30 30 29.0% -12.00 [-17.96, -6.04] 

McKenzie 1994 -4.8 4.41 12 12 22.9% -4.80 [-13.44, 3.84] 

Mickleborough 2006 -9.15 3.74 8 8 25.8% -9.15 [-16.48, -1.82] 

Schnall 1980 -16.1 4.56 6 6 22.3% -16.10 [-25.04, -7.16] 

Subtotal (95% CI) 56 56 100.0% -10.61 [-14.69, -6.53] 

Heterogeneity: Tau2 = 2.71; Chi2 = 3.55, df = 3 (P = 0.31); I2 = 15% 

Test for overall effect: Z = 5.10 (P < 0.00001) 

10.6.2 Continuous: High Intensity 

Reiff 1989 -17.57 2.64 7 7 59.5% -17.57 [-22.74, -12.40] 

Schnall 1980 -0.99 4.89 6 6 40.5% -0.99 [-10.57, 8.59] 

Subtotal (95% CI) 13 13 100.0% -9.79 [-26.01, 6.43] 

Heterogeneity: Tau2 = 122.01; Chi2 = 8.90, df = 1 (P = 0.003); I2 = 89% 

Test for overall effect: Z = 1.18 (P = 0.24) 

10.6.3 Continuous: Low Intensity 

McKenzie 1994 -18.25 4.26 12 12 31.6% -18.25 [-26.60, -9.90] 

Morton 1979 0 2.96 18 18 39.5% 0.00 [-5.80, 5.80] 

Reiff 1989 -20.57 4.74 7 7 28.9% -20.57 [-29.86, -11.28] 

Subtotal (95% CI) 37 37 100.0% -12.60 [-26.68, 1.48] 

Heterogeneity: Tau2 = 138.54; Chi2 = 19.92, df = 2 (P < 0.0001); I2 = 90% 

Test for overall effect: Z = 1.75 (P = 0.08) 

10.6.4 Progressive 

Eck 2002 -11 1.85 46 46 64.4% -11.00 [-14.63, -7.37] 

Schnall 1980 -10.42 5.44 6 6 35.6% -10.42 [-21.08, 0.24] 

Subtotal (95% CI) 52 52 100.0% -10.94 [-14.37, -7.51] 

Heterogeneity: Tau2 = 0.00; Chi2 = 0.01, df = 1 (P = 0.92); I2 = 0% 

Test for overall effect: Z = 6.25 (P < 0.00001) 

-20 -10 0 10 20 

Favors warmup Favors no warmup 

120 
 
Table 38. Description of trials in the therapy review: Refractory period 

Author Year Publication Randomized Warmup protocol ECT ECT: temp; RH DefCountry status [R] Description; Rest type/duration Number of protocols; F

Source Funding Analyzed (min) protocols per day [N]; 

Ou

Trial design [A] following no time between protocols Pri

Withdrawals warmup or Withheld asthma med; Sec

[W] warmup class; time Adv

de Bisschop97 

1999 

France Treatment center 

Journal 

article 

NR Crossover 

30 30 0 

No warmup or Protocol 1: interval: 2 sets 

of 5 x 26 sec sprints, 1.5 min between, 5 min between sets (7.5% of the distance and 120% of the speed of FRAST) 

10 min rest 

FRAST: running 

as fast as possible x 7 min (mean distance =1,171±142 m) 

4±5°C; 1.5±0.5 mmHg 2; 1; 24 hr, at mid-day SABA x 12 hr 

≥15PrimSec

% 

PE

s1

NR 

Eck98 2002 

Germany, 

Switzerland 

Clinic 

Abstract NR Not clear 

46 NR NR 

No warmup or 5 min stretching, no rest, 

plus 

Protocol 1: continuous: 10 

min steady training 

Protocol 2: interval: 10 min 

Treadmill x 10 

min steady running 

NR; NR 4; not clear; not clear NR 

≥10Prim

Sec

p

NR 

interval running 

Protocol 3: progressive: 10 

min exercises with increasing intensity 

AE = adverse events; AUC = area under the curve; bpm = beats per minute; C = Celsius; ECT = exercise challenge test; EIB/EIA = exercise-induced b

FEV1 = forced expiratory volume in 1 second; FRAST = free running asthma screening test; hr = hour(s); HR = heart rate; ICS = inhaled corticosteroi

hour; L = liter; max = maximum; μg = microgram; min = minute(s); mmHg = millimeter of mercury; NR = not reported; PEF = peak expiratory flow; 

SABA = short-acting beta-agonist; Sal = salbutamol; SCG = sodium cromoglycate; sec = second(s); temp = temperature; V02 = oxygen consumption; 

121 
 
Table 38. Description of trials in the therapy review: Refractory period (continued) 

Author, Year Publication Randomized Warmup Protocol ECT type/duration ECT: temp; RH DCountry status [R] Description; Rest (min) following Number of protocols; 

Source Funding Analyzed no warmup or protocols per day [N]; 

O

Trial design [A] warmup Time between protocols P

Withdrawals Withheld asthma med; Se

[W] class; time A

McKenzie99 1994 

Canada Volunteers Mickleborough100 

2007 

U.S., United 

Kingdom 

University and 

local community 

Journal 

article 

NR Crossover Journal 

article 

NR Crossover 

12 12 0 8 8 0 

No warmup or Protocol 1: continuous 

low intensity: treadmill x 15 min at 60% VO2max; 2 min rest; 

Protocol 2: interval: 8 x 

30 sec sprints at 100% VO2max 

separated by 1.5 min rest; 2 min rest 

No warmup or Protocol 1: Interval: 8 x 30 sec sprints with 

45 sec recovery between; 15 min rest (interval intensity equal to VO2max) 

Protocol 2: Sal 200 μg 

plus 8 x 30 sec sprints with 45 sec recovery between sprints; 15 min rest; 

Protocol 3: Sal 200 μg; 

15 min rest 

Treadmill x 6 min at 

90% VO2max 

Treadmill x 8 min at 

85-90% predicted max HR; wore a noseclip 

20.7±1.2°C; ambient room 

humidity 

3; not clear (3 sessions); not clear Caffeine and exercise x 4 

hr. 

23°C; 50% 4; 1; ≥96 hr SABA x 12 hr, 

caffeine/alcohol x 8 hr, exercise x 24 hr 

≥1P

SF

N≥1P

SF

N

Morton101 1979 

Australia Local volunteer 

Journal 

article 

Foundation Crossover 

19 18 1 

No warmup or Protocol 1: continuous 

low intensity: treadmill x 3 min at 60% predicted max HR; 1 min rest; 

Treadmill x 5 min at 

85% predicted max HR 

Room temp; NR 2; 1; 

≥8 day 

All med and exercise x 12 

hr 

≥1P

SF

 1 

122 
 
Table 38. Description of trials in the therapy review: Refractory period (continued) 

Author Year Publication Randomized Warmup Protocol ECT type/duration ECT: temp; RH DCountry status [R] Description; Rest (min) following Number of protocols; OSource Funding Analyzed no warmup or protocols per day [N]; P

Trial design [A] warmup Time between protocols Se

Withdrawals Withheld asthma med; A

[W] class; time 

Reiff102 1989 Journal 7 Protocol 1: continuous Treadmill x 6 min at 19.9±0.7°C; 39-50±4.0% ≥1

United Kingdom article 7 high intensity: 15% incline; 6 2; 1; P

Clinic Volunteers NR 0 treadmill at 15% km/h; HR=97±3% 2 sessions within 1 wk at 

Crossover incline; 6 km/h x 6 predicted max same time of d S

min; 45 min rest ICS x 24 hr; SABA x 8 hr 

HR=98±2% predicted F

max 

Protocol 2: continuous N

low intensity: treadmill at 3% incline, 6 km/h x 30 min; 21 min rest HR=88±32% predicted max 

Schnall103 1980 Journal 6 Protocol 1: continuous 

Australia article 6 high intensity: 

NR Government 0 Treadmill x 6 min at 

Crossover 10% incline (HR 180 

bpm), 49 min rest 

Protocol 2: Progressive: 

Treadmill x 6 min at 

10% incline (HR 180 bpm); 10 min rest; 7 x 30 sec sprints with 2.5 min between (speed 120-130% of 1st run); 20 min rest 

Protocol 3: Interval: 7 x 

30 sec sprints with 2.5 min between (speed 120-130% of 1st run) 

20 min rest 

Treadmill x 6 min at 21-23.5±1.2°C; 0.55 N

10% incline; HR 3; 1; P

180 bpm 3 sessions in 4 wk 

SABA and SCG x 8 hr S

F

Y

123 
 
Table 39. Baseline characteristics of patients in trials in the therapy review: Refractory period 

Author Year Age (mean±SD) 

Males: N (%) 

Asthma status Pulmonary function: 

baseline FEV1 % 

predicted (mean±SD) 

Max % fall FEV1 

(mean±SD) 

Smoking 

status: N (%) 

A

de Bisschop97 1999 12; range 8-15 Stable, mixed PEF: 99±15% PEF: 37±14.5 NR 

21/30 (70) severity 

Eck98 2002 Range 6-19 NR NR NR NR 

NR 

McKenzie99 1994 26.5±7.8 Stable 3.42±1.05 L >30 Non-smokers 

3/12 (33.3) 

Mickleborough100 

2007 

19.5±1.2 

NR 

Mild-persistent 92.4±6.12 (3.5±0.82 L) 18.25±4.01 Never smoked 

Morton101 1979 19.7; range 11-33 Stable 100 38.1 NR 

10/18 (55.6%) 

Reiff102 1989 25.4±6.6 Stable, mild­ 80.6±20.7 FEV1: 46±6.9; PEF: NR 

5/7 (71.4) persistent 51±10.6 

Schnall103 1980 Range 12-31 Stable 84.1 (2.7±0.71 L) 22.8±8.08 NR 

4/6 (66.7) 

FEV1 = forced expiratory volume in 1 second; L = liters; NR = not reported; PEF = peak expiratory flow; SD = standard deviation 

124 
 
 

Table 40. Quality assessment of trials in the therapy review: Refractory period 

Author Year 

de Bisschop97 1999 Yes No Yes No No No No 2 Unclear 

Eck98 2002 Yes No No No No No No 1 Unclear 

McKenzie99 1994 No No Yes No No No No 1 Unclear 

Mickleborough100 2007 Yes No Yes No No No No 2 Unclear 

Morton101 1979 Yes No Yes No No No No 2 Unclear 

Reiff102 1989 Yes No Yes No No No No 2 Unclear 

Schnall103 1980 Yes No Yes No No No No 2 Unclear 

Described as randomized? 

Described as double-blind?

Description of withdrawals/ 

dropouts?

Method of randomization

described and appropriate? 

Method of double-blinding

described and appropriate? 

Method of randomization

described but inappropriate?

Method of double-blinding

described but inappropriate?

Overall Score: Jadad

Concealment of allocation 

125 
 

Chapter 4. Discussion 

Diagnostic Test Accuracy Review 

A valid test to determine if EIB or EIA is present must involve a standardized measure of 

effort (heart rate or ventilation rate) or dose of inhalant and be of sufficient duration to produce a 

response in susceptible subjects. Airway response measures must also be standardized. Testing 

protocols for airway constriction can be classified into direct or indirect tests. Indirect challenges 

such as exercise, eucapnic voluntary hyperpnea (EVH), and inhaled mannitol are thought to 

cause inflammatory cells to release mediators such as leukotrienes, prostaglandin, and histamine 

which provoke smooth muscle constriction.20 In contrast, direct tests such as methacholine or 

histamine act directly on smooth muscle receptors to cause constriction independent of airway 

inflammation.19 

Using a comprehensive search strategy and concerted efforts to avoid publication and 

selection bias, this review identified all the available evidence to assess the diagnostic test 

characteristics of six tests for the diagnosis of EIB/EIA. In total, we identified 27 studies that met 

our inclusion criteria. The number of studies available to address each of the six key questions 

ranged from 2 to 16. 

There are many methodological considerations when undertaking a systematic review of the 

diagnostic literature. To determine the accuracy of a diagnostic test, a reference standard must be 

available for comparison. The reference test used for this report was the exercise challenge test 

(ECT) as detailed by the ATS.18 The guidelines cover water content and temperature of the 

inspired air plus work effort required for either treadmill or bicycle ergometer testing. According 

to the ATS criteria,18 during the ECT participants should inspire dry air at a temperature of less 

than 25°C with a noseclip in place to force mouth breathing. Nasal breathing decreases the water 

loss from the airways. Temperature and relative humidity (RH) during testing should be 

documented, and RH should be low (50 percent or less). It is unclear if the ambient humidity in 

the typical air conditioned laboratory (30 to 50 percent water vapor saturation) is less likely to 

induce airway narrowing as compared with perfectly dry air obtained from compressed gas (i.e., 

RH ~0 percent).18 However, as airway drying is the primary trigger for EIB/EIA,19 it would seem 

logical that tests completed with compressed air would be more sensitive for detecting EIB/EIA. 

In this review, many studies had the participants inspire room air as detailed in ATS guidelines, 

while others used compressed air during their ECT. 

Among the included studies, detailed reporting of the ECT protocol varied, and in several 

cases it was not clear if the challenge met ATS recommendations particularly when it came to 

nose versus mouth breathing, effort required, and duration. Treadmill grade and speed must be 

individually chosen and progressively increased in the first minutes to produce 6 to 8 minutes of 

near maximum target heart rates (i.e., 80 to 90 percent of the predicted rate for age). Ventilation 

should reach 40 to 60 percent of the predicted maximum voluntary ventilation. In a bicycle 

ergometer challenge a target work rate is determined to achieve target ventilation and the work 

rate is gradually increased until the target exercise intensity is maintained for 4 to 6 minutes. 

With either method, the subject must reach the target heart or ventilation rate in the first 4 

minutes as water loss and airway drying determine the development of EIB/EIA.18 Since the 

specifics of the ECTs were not consistently reported in full, some exercise challenges may not 

have met these standards. Furthermore, a number of studies used higher diagnostic cutpoints of a 

15 or 20 percent fall in FEV1 post-exercise instead of the ATS guideline of a 10 percent drop. 

Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/eibeia/eibeia.pdf 

127 
We could not always extract results for the 10 percent cutpoint. We suspect that the variability in 

methodology used for the reference standard ECT may be the cause of some heterogeneity in 

comparisons with other EIB/EIA diagnostic methods. 

A key concern, which may also have contributed to the heterogeneity observed across all the 

diagnostic comparisons, was that of a spectrum bias. Ideally, studies should have a sample of 

participants who are representative of the population being examined for EIB/EIA. That is, 

studies should have participants that span the range from high to low likelihood of EIB/EIA so 

that the true positive and true negative numbers are approximately the same. Many studies 

included in these reviews purposely recruited participants who either had or did not have a 

history of EIB/EIA or asthma (asthma increases the likelihood of having EIA) or they did not 

mention clinical history or provide baseline data. Cumulatively, only 6 percent of studies had a 

representative sample and only 21 percent stated their inclusion criteria. Virtually all studies 

recruited volunteers who were willing to undergo the tests being compared. The lack of a 

representative patient spectrum limits the generalizability of the results to the target population 

of people with suspected EIB/EIA and therefore a pooled estimate of sensitivity and specificity is 

not reliable. 

Table 41 and the following sections review the individual tests examined in the review. 

Self-report. Since many patients present to clinicians with simply their story of breathing 

difficulties following exercise, the first question in this diagnostic review examined the accuracy 

of self-reported history or symptoms. EIB/EIA may be associated with symptoms such as 

shortness of breath, cough, wheeze and chest pain,18 and therefore these symptoms may lead 

clinicians to suspect EIB/EIA. For clinicians and patients, the diagnostic test characteristics of 

self-report are important to understand. 

Despite extensive searching, only two studies addressed this question. While the results of 

one of the studies21 comparing post-exercise cough to an ECT are encouraging (89 percent 

sensitivity, 86 percent specificity), this is not sufficient evidence to conclude that self-report of 

symptoms is a reliable diagnostic tool for EIB/EIA (Table 41). There were too few studies to 

produce reliable ROC curves. Furthermore, given the complexity and variability of respiratory 

symptoms, recent research in chronic asthma has shown that objective lung testing is vital for a 

valid diagnosis165 and there is no reason not to apply this to a diagnosis of EIB/EIA. 

Quality of evidence. The evidence from this group of two studies was graded as “very low”. 

Both study designs were rated low and there are serious limitations due to the lack of a 

representative spectrum of participants and uncertainty whether the ECTs met the ATS guideline 

recommendations.18 The diagnostic thresholds differed and the sensitivity estimates are 

inconsistent and imprecise. 

Methacholine (MCH) challenge. MCH is considered a direct challenge as it acts on smooth 

muscle acetylcholine receptors, causing contraction and airway narrowing.23 It has been noted 

that airway responsiveness to pharmacologic agents such as MCH differs from hyperresponsiveness in response to physical stimuli such as exercise and osmotic agents.18 

The review identified 16 studies that met the inclusion criteria for the diagnostic test 

accuracy review of the MCH challenge. Overall, the study quality varied, and there was a 

concern of spectrum bias in all but one study.23 Regardless of the threshold level for MCH (8 

mg/ml or 16 mg/ml), there was considerable heterogeneity across individual study estimates for 

sensitivity (66 to 100 percent at 8 mg/ml; 0 to 100 percent at 16 mg/ml) and specificity 0 to 100 

percent at either threshold. (Table 41) Moreover, the area under the curve (AUC) of the ROC 

was marginally more than 0.5 for any of the FEV1 cutpoints (10, 15, or 20 percent) or MCH 

128 
 
thresholds. Based on these results we cannot conclude that the MCH challenge is a valid test to 

diagnose EIB/EIA. 

Unlike exercise challenges, a positive airway response to MCH does not infer the presence of 

inflammatory cells or their mediators;20 therefore, it is not surprising that MCH shows variable 

sensitivity and specificity to detect EIB/EIA. It has been suggested18 that a positive MCH test 

should not be used to infer EIB/EIA and likewise, a negative MCH should not be used to exclude 

EIB/EIA. 

Quality of evidence. The evidence from this group of 15 studies was graded as “moderate”. 

The study designs were rated high; however, there are serious limitations to the body of evidence 

as a whole. Only one study had a representative spectrum of participants and blinded the 

assessors to test results. It is unclear whether eight of the ECTs met the ATS guideline 

recommendations.18 The sensitivity estimates are reasonably consistent but are imprecise in the 

EIA participants. Specificity estimates are inconsistent and imprecise. 

Sport or venue specific challenges. Sport or venue specific challenges refer to challenges in 

the specific sport (e.g., basketball, soccer) or at the venue of activity (e.g., hockey arena, 

swimming pool). They are advantageous in that the athlete can exercise in the conditions where 

they become symptomatic and the tests are reasonably inexpensive; however, coordinating the 

two tests and ensuring good quality control on both can be problematic. 

Five studies addressed the key question of sport or venue specific exercise challenges (Table 

41). Three studies focused on swim challenges and two assessed cold weather challenges. All 

studies involved elite athletes. The sensitivity of the field tests ranged from 0 to 100 percent. 

Specifity also ranged from 0 to 100 percent; however, in one study,41 all participants had a 

history of EIB/EIA and therefore had a high pre-test probability of testing positive on both tests. 

In the studies that did not have this select population, the specificity ranged from 79 to 100 

percent. There were too few studies to produce reliable ROC curves. Althought sport specific 

challenges are one of the recommended challenges for diagnosing EIB/EIA in elite athletes,34 in 

total, only seven athletes tested positive in their own field of competition while 16 were positive 

on a standardized ECT. It is not clear why this occurred, although it is possible that the level of 

minute ventilation and differences in environmental conditions played a role. Sport specific 

challenges may be useful in identifying athletes who do not have EIB/EIA but additional testing 

such as a standardized ECT may be required to confirm a diagnosis. 

Quality of evidence. The evidence from this group of five studies was graded as “low”. The 

study designs were rated high; however, there are serious limitations to the body of evidence as a 

whole. No study had a representative spectrum of participants or blinded the assessors to test 

results. It is unclear whether two of the ECTs met the ATS guideline recommendations.18 Both 

the sensitivity and specificity estimates are inconsistent and imprecise. 

Eucapnic voluntary hyperpnea (EVH) challenge. EVH challenge is a test based on the 

premise that the increased minute ventilation with exercise is responsible for airway constriction 

in susceptible participants.19 Currently, EVH is the challenge recommended by the International 

Olympic Committee Medical Commission to identify EIB/EIA among Olympic athletes.48 

The stimulus for the airways to narrow in response to exercise is the water lost by 

evaporation from the airway surface and the osmotic and thermal effects arising from this.18 

Theoretically, conditioning large volumes of cold inspired air places a greater burden on the 

airways to reheat and rehumidify it quickly as compared with inspiring warmer, humid air. 

Therefore, it is likely that additional (i.e., small) airways would be recruited to achieve the task 

and this would increase airway dehydration. Similarly, inspiration of cold air during EVH would 

129 
 
increase the likelihood of bronchoconstriction compared with EVH using room temperature air. 

In the study by Eliasson et al.42 participants performed EVH tests while inspiring air at room 

temperature or inspiring air cooled to between minus 18°C and minus 26°C. Despite the 

increased conditioning of the air required during the cold air trial, there was no difference in 

post-EVH FEV1 response between the cold versus room temperature challenges. 

It is worth noting that EVH challenges are likely the most technically difficult of all the 

EIB/EIA diagnostic tests to perform for a variety of reasons. First, minute ventilation must be 

measured accurately in real-time and displayed so that participants can receive feedback on their 

target minute ventilation. The substantial increase in minute ventilation with the challenge will 

cause hypocapnea, which can cause bronchoconstriction166 as well as nausea and fainting. It is 

for this reason that EVH trials are performed with participants rebreathing a gas mixture of 

approximately five percent CO2 so that arterial CO2 levels can be maintained at resting eupneic 

levels. Importantly, rebreathing a gas mixture for 5 to 6 minutes may also cause hypoxemia if the 

gas mixture does not contain an elevated oxygen concentration. Thus, additional monitoring 

equipment as well as well-trained respiratory or exercise physiology staff are required to 

maintain CO2 and O2 levels within normal physiological ranges during EVH challenges. 

Seven studies met the inclusion criteria to assess the diagnostic accuracy of EVH (Table 41). 

In general study quality raised questions of bias, in particular, there was a concern of spectrum 

bias in all studies. Overall, the sensitivity and specificity was heterogeneous with values ranging 

25 to 100 percent, and 0 to 74 percent, respectively. It is unclear whether an EVH challenge is 

identifying the same people that experience a fall in FEV1 of 10 percent or more on an ECT, 

particularly in a population of athletes with an unclear history of asthma. The EVH challenge 

resulted in a higher proportion of false positives (FP) (i.e., negative on the ECT but positive on 

EVH) among participants with no or unknown history of EIB/EIA. The proportion of FP ranged 

from 25 to 71 percent. The participants included both elite athletes (n=63) and those with 

unknown activity levels (n=20). Based on the available evidence, it is unclear if the EVH 

challenge is more sensitive to EIB/EIA, or if the mechanism that triggers the bronchoconstriction 

is different from that for the ECT, or if level of minute ventilation achieved on an ECT according 

to ATS recommendations is less than the level achieved in an EVH challenge particularly in 

athletes. Among participants with a history of EIB/EIA, the proportion of FPs ranged from 0 to 5 

percent in participants with unknown activity levels. Among athletes, the proportion with a FP 

result was 27 percent. Further research is needed to determine if the EVH challenge would be an 

appropriate add-on test to a standardized ECT in athletes with symptoms of EIB/EIA. Based on 

this evidence, it is unclear whether EVH challenge is more accurate diagnostic test for EIB/EIA 

compared with a standardized ECT. 

Quality of evidence. The evidence from this group of seven studies was graded as “low”. The 

study designs were rated high; however, there are serious limitations to the body of evidence as a 

whole. No study had a representative spectrum of participants or blinded the assessors to test 

results. It is unclear whether the ECTs met the ATS guideline recommendations.18 Furthermore, 

the sensitivity and specificity estimates are inconsistent and imprecise. 

Free running asthma screening test (FRAST). Free running has often been used in 

screening large groups for EIB/EIA because of the ease in performing such challenges.19 Three 

studies met the inclusion criteria for assessing the diagnostic accuracy of the FRAST (Table 41). 

Participants in all the studies were children (younger than 15 years), and all tests took place 

indoors. Despite being able to run freely during the FRAST, the reported average heart rate 

during the challenge for each group was 80 percent or greater of maximum and was comparable 

130 
 
to the ECT. None of the studies had a representative patient spectrum. Sensitivity and specificity 

were modest (60 to 67 percent and 47 to 67 percent, respectively). There were too few studies to 

produce reliable ROC curves. While the FRAST is easy to perform, there is insufficient evidence 

to conclude that it accurately identifies people with EIB/EIA compared to a standardized ECT. 

Quality of evidence. The evidence from this group of three studies was graded as “very low”. 

The study designs were rated medium; however, there are serious limitations to the body of 

evidence as a whole. No study had a representative spectrum of participants or blinded the 

assessors to test results. It is unclear whether two of the ECTs met the ATS guideline 

recommendations.18 The sensitivity and specificity estimates are consistent but imprecise. 

Mannitol provocation test. Recently, a mannitol provocation test has been developed to 

examine airway hyper-responsiveness. Like exercise, mannitol is considered an indirect 

bronchial provocation test. Mannitol increases osmolarity, which causes the release of 

endogenous mediators such as prostaglandin, leukotrienes and histamine, and results in smooth 

muscle contraction.50,51 Mannitol has the advantage that it can be performed with minimal 

equipment (i.e., a metered-dose inhaler and spirometer). 

Three studies met the inclusion criteria for the diagnostic test accuracy review of mannitol 

(Table 41). Sensitivity ranged from 58 to 96 percent; specificity ranged 65 to 78 percent. At this 

time there is insufficient evidence to conclude that the mannitol provocation test is a reliable test 

to diagnose EIB/EIA. 

Quality of evidence. The evidence from this group of 3 studies was graded as “moderate”. 

The study designs were rated high; however, there is reasonable concern regarding the 

limitations to the body of evidence as a whole. Only one study had a representative spectrum of 

participants and blinded the assessors to test results. All three of the ECTs met the ATS guideline 

recommendations.18 The sensitivity and specificity estimates are reasonably consistent but are 

imprecise. 

131 
 
Table 41. Summary of sensitivity and specificity for the diagnostic test accuracy review 

132
 


Index test 

# studies, 

sample size 

ECT type (# studies) Definition of EIB/EIA (# studies) 

Sensitivity point estimate or range mean % (95% CI) 

Specificity point estimate or 

range 

mean % (95% CI) 

ECT +ve 

(≥10% faFEV1) 

N (%) 

Self-report 2, N=206 Treadmill (2) 

≥10% fall FEV1 (1) 

≥15% fall FEV1 (1) 

89% (67, 99) 36% (17, 59) 

86% (64, 97) 85% (78, 90) 

19 (48) 20 (13) 

Methacholine 16, N=1,048 Treadmill (10) 

Bicycle ergometer (6) ECT: ≥8% fall FEV1 (1), ≥10% fall 

FEV1 (6), ≥15% fall FEV1 (2), 

≥18% fall FEV1 (1), ≥20% fall 

FEV1 (5) 

MCH: ≥20% fall FEV1 at various 

doses MCH 

≥10% fall FEV1 

0-100%; 

(MCHPC20 <8mg/ml) 

55-100% 

(MCHPC20 <16mg/ml) 

0-100% 0-100% 

331 (57) 420 (53) 

Sport specific 

challenge 

5, N=95 Treadmill (3), bicycle ergometer 

(2) 

≥10% fall FEV1 (4) 

≥20% fall FEV1 (1) 

≥10% fall FEV1 

Swim challenge 0-50% Winter sports n=37 100% ( 48-100) (1 study) 

83-100% 79% (49, 95) (1 study) 

11 (19) 5 (14) 

Eucapnic 

voluntary hyperpnea 

7, N=138 Treadmill (4), bicycle ergometer 

(3) 

ECT: ≥10% fall FEV1 (4), ≥20% 

fall FEV1 (1), 

≥10% fall FEV1 25-90% 0-71% 42 (30) 

NR (2) EVH: ≥10% fall FEV1 (4), NR (3) 

FRAST 3, N=99 Treadmill (1), bicycle ergometer 

(2) 

≥10% fall FEV1 (1) 

≥20% fall FEV1 (2) 

≥10% fall FEV1: 60-67% 

≥20% fall FEV1: 53% 

47-67% 100% 

13 (38) 30 (50) 

Mannitol 3, N=423 Treadmill (2), bicycle ergometer 

(1) 

ECT: ≥10% fall FEV1 (3) 

Mannitol: ≥15% fall FEV1 (3) 

≥10% fall FEV1 58-96% 65-78% 202 (48) 

ECT = exercise challenge test; EVH = eucapnic voluntary hyperpnea; FEV1 = forced expiratory volume in 1 second; FRAST = free running asthma sc

methacholine; PC = provocative concentration 
Limitations 

In addition to the issues identified regarding ECT and index test performance, there are 

several limitations that need to be discussed regarding systematic reviews of diagnostic test 

accuracy. First, there is a possibility of publication bias. The impact of publication bias on the 

results of diagnostic test accuracy reviews is not well understood nor have the tools to investigate 

publication bias in these reviews been developed.167 However, we conducted a comprehensive 

and systematic search of the published literature for potentially relevant studies. Search strategies 

included combinations of subject headings and free text words. These searches were 

supplemented by handsearching for gray literature (i.e., unpublished or difficult to find studies). 

Despite these efforts, we recognize that we may have missed some studies. 

Overall, EIB/EIA literature is not indexed well and authors are not consistent in using the 

terms in titles or abstracts that clearly describe the scope of their research. There are also a 

variety of activities and sports that can potentially cause EIB/EIA. It is impossible to account for 

every variation and term within the search strategy. Knowing this, the search strategy was 

designed to be highly sensitive in order to avoid missing any potentially relevant articles and 18 

electronic databases were searched in order to retrieve as many pertinent studies as possible. 

There is also a possibility of study selection bias. We employed at least two independent 

reviewers to identify potentially relevant studies, and feel confident that the studies that were 

excluded from this report were done so for consistent and appropriate reasons. 

A further limitation was that not all studies that seemed potentially relevant were designed as 

diagnostic test accuracy studies but they did compare two test methods of interest; however, the 

data presented were not in a useful form to evaluate the diagnostic accuracy of the comparison. 

In order to be included, a study had to report sufficient data to generate a 2x2 table of the 

reference standard and index test results based on one or more diagnostic thresholds. 

Finally, we did not pool the sensitivity and specificity data in this report. A decision was 

made that the populations, tests, and study designs were sufficiently heterogeneous for each of 

the key questions that pooling would be invalid. Where appropriate we wanted to produce AUC 

results for ROC curves; however, given the small number of studies that addressed each of the 

key questions, an ROC curve was possible only for MCH versus ECT. 

Conclusions 

Despite exhaustive efforts to identify evidence regarding the diagnostic test characteristics of 

tests used to identify patients with EIB/EIA, few studies were identified. Moreover, the studies 

that were identified suffered from considerable test variability and spectrum bias. In all included 

studies, the participants were volunteers and varied from exclusively elite athletes with or 

without documented or suspected EIB/EIA to patients with or without documented or suspected 

EIB/EIA who were not trained athletes. In the many of studies physical fitness was not addressed 

at all. The diversity in included populations and the fact that there were not many studies 

comparing the same diagnostic tests precluded more detailed subgroup analysis of the issue of 

EIB versus EIA. However, we do not believe these limitations invalidate the results presented in 

the review as the reviewers analyzed the data as vigorously as it allowed. The results of this 

report apply to patients being screened for EIB/EIA as well as the clinicians caring for them. 

133
 

On the basis of this review, there is no clear evidence to support that any of the six index 

tests studied are equivalent to, or better than, the standardized ECT to diagnose EIB/EIA. At this 

time none can be recommended to replace the ECT for diagnosing EIB/EIA in the general 

population. EIB/EIA remains a complex phenomenon that does not always occur in the same 

individual every time they under go a challenge. Combining history, symptoms, objective testing 

plus trial and error therapy may still be the preferred path to an active life in those that have 

EIB/EIA. 

134
 

Therapy Review 

Using a comprehensive search strategy and concerted efforts to avoid publication and 

selection bias, this review identified all the available evidence to assess the effectiveness of six 

interventions (five pharmacologic and one nonpharmacologic) to treat EIB/EIA. Overall, we 

identified 109 studies that met our inclusion criteria. The number of studies available to address 

each of the six key questions ranged from 4 to 17 involving between 40 and 272 participants. 

There are many methodological considerations when undertaking a systematic review of the 

therapeutic literature. When determining the effectiveness of a therapy, the highest level of 

evidence arises from well-conducted RCTs. EIB/EIA is a unique condition. It would not exist if 

not triggered by vigorous exercise and, although the bronchoconstriction can be severe; it 

generally resolves spontaneously over the course of an hour and leaves no permanent sequelae. 

The therapeutic drugs used for EIB/EIA are short-acting and are rapidly cleared from the body. 

As a result, therapy trials for this condition lend themselves to crossover RCT methodology and 

the majority of trials in these reviews employed this design. The advantage of a crossover 

compared with a parallel group design is that all participants receive all interventions and, 

therefore serve as their own control. This reduces sample size requirements. However, concerns 

with washout periods, carryover effects, and changes over time mean trialists must design the 

timing and frequency of ECTs with this in mind. 

Since asthma is a common chronic condition, in most countries guidelines exist for the 

treatment of this disease. Not surprisingly, the treatment options for EIB/EIA mirror those for 

symptoms in chronic asthma—mainly, bronchodilators and anti-inflammatory agents. Like an 

asthma attack, an EIB/EIA attack can produce symptoms such as shortness of breath, cough, 

wheeze and chest pain,143 and, as in asthma, these symptoms are amenable to treatment with 

bronchodilators. Since many of the anti-inflammatory agents improve asthma control, clinicians 

and researchers have been curious to know if they also have an effect on EIB/EIA. 

The following sections summarize the pharmacologic and nonpharmacologic treatments 

addressed in this report (Table 42 and Figure 28). The pharmacologic interventions are further 

divided into bronchodilating and anti-inflammatory agents. 

135
 

Table 42. Prophylactic therapy for EIA: Pulmonary function results 

Comparisons Intervention vs. control 

N trials (SSi vs. SSc) 

MD % fall FEV1/PEF 

(95% CI)* 

Clinical protection ≥50% 

N trials (SSi vs. SSc) 

RR (95% CI) † 

Mean % protection of 

intervention over control (95% CI) 

Complete protectN trials (SSi vs. S

RR (95% CI) † 

Leukotriene receptor N=9 (267 vs.267) NR NR ≤10% fall FEV1 

antagonists vs. placebo 8.9 (6.9, 11.0) N=4 (124 vs. 123) 

1.87 (0.77, 4.56) 

Inhaled corticosteroids vs. N=4 (50 vs. 50) NR BV 6%; BUD 17%; NR 

placebo 5.0 0.0, 9.9) FP 49% 

MCS (Nedocromil sodium) N=17 (240 vs. 240) NR 51 (46, 55) NR 

vs. placebo 15.6 (13.2, 18.2) 

Nedocromil sodium N=7 (97 vs. 97) N=6 (78 vs. 78) NR ≤10% fall FEV1 vs. Sodium cromoglycate 0.9 (-2.7, 4.5) 1.12 (0.89, 1.40) N=6 (78 vs. 78) 

1.0 (0.7, 1.4) 

MCS vs. Anticholinergics N=8 (183 vs. 175) N=5 (56 vs. 48) 11.2 (2.4, 20.0) ≤15% fall FEV1 

6.7 (3.3, 10.0) 1.35 (1.00, 1.83) N=8 (177 vs. 169) 

1.3 (1.1, 1.6) 

SABA vs. MCS N=12 (271 vs. 272) N=6 (77 vs. 77) 22.7 (11.9, 33.4) ≤15% fall FEV1 

6.8 (4.5, 9.2) 1.4 (1.1, 1.7) N=9 (225 vs. 226) 

1.4 (1.2, 1.8) 

SABA + MCS vs. SABA N=5 (40 vs. 40) N=3 (37 vs. 37) 10.3 (-27.0, 6.5) ≤15% fall FEV1 

1.3 (-6.3, 8.9) 0.9 (0.7, 1.1) N=4 (44 vs. 44) 

0.9 (0.5, 1.4) 

LABA vs. Placebo N=4 (55 vs. 55) NR 86% NR 

25.1 (18.0, 32.3) 

Anticholinergics (Ipratropium N=11 (142 vs. 142) N=6 NR ≤10% fall FEV1 

bromide) vs. placebo 9.8 (5.0, 19.5) % achieved=60 (48, 72) N=7 (74 vs. 74) 

4.5 (1.2, 10.9) 

Interval warmup vs. no N=4 (56 vs. 56) NR NR ≤15% fall FEV1 

warmup 10.6 (6.5, 14.7) N=1 

1/12 (8.3%) 

Continuous low intensity N=3 (37 vs. 37) NR NR ≤15% fall FEV1 

warmup vs. no warmup 12.6 (-1.5, 26.7) N=1 

6/12 (50%) 

Continuous high intensity N=2 (13 vs. 13) NR NR NR 

warmup vs. no warmup 9.8 (-6.4, 26.0) 

136
 


BUD = budesonide; BV =Betamethasone valerate; FEV1 = forced expiratory flow in 1 second; FP=fluticasone ICS = Inhaled corticosteroid; LTRA = 

antagonist; MCS = mast cell stabilizers; MD = mean difference; NR = not reported; PEF = peak expiratory flow; RR = risk ratio; SABA = short-acting 

size intervention; SSc = sample size comparison *a positive MD indicates intervention is better; † RR>1 indicates intervention is better. 
Pharmacologic Interventions 
 

Bronchodilating Agents 

SABA/LABA. Beta2-receptors on the airway smooth muscle are responsible for 

bronchodilation; beta2-agonist agents attach to these receptors and are effective bronchodilators. 

SABA agents have been the mainstay of EIB/EIA prevention and treatment for many years. With 

the development and availability of LABA agents, more research has been applied to their 

effectiveness in EIB/EIA. 

Although the evaluation of SABA or LABA versus placebo for prophylactic EIB/EIA use 

was not the focus of this review, results were available in some comparisons on which to base a 

reasonable conclusion. In the mast cell stabilizer (MCS) review78 SABA agents were 

approximately 7.0 percent more effective than MCS. Using data from the SABA groups in the 12 

studies in the comparison with MCS,78 SABA reduced the maximum percent fall in FEV1 to an 

average of 4.3 percent (SD±14.1; range 1.0 to 15.5) whereas as the MCS groups averaged a 

maximum percent fall in FEV1 of 11.0 percent (SD±17.7; range 4.2 to 27.2).78 The day 1 data for 

the four LABA groups in the tachyphylaxis review showed that LABA reduced the fall in FEV1 

to an average of 3.7 percent (SD±8.7). This indicates that LABA is also an effective agent for 

attenuating the bronchoconstriction that is characteristic of EIB/EIA (Figure 28). 

While SABA and LABA treatments are effective, caution is advised. The data from this 

review support that a degree of tachyphylaxis is associated with the regular use of both betaagonist agents. The pooled results from four LABA trials demonstrated the maximum percent 

fall in FEV1 following an ECT after 4 weeks of regular LABA use was of a greater magnitude in 

the LABA arm than the placebo arm. Similar results were shown in the two studies that 

investigated SABA after only 1 week of regular use. While the results were statistically 

significant, there was no discussion on whether this was clinically significant or important to the 

participants. These data do not imply that SABA or LABA agents lose their effectiveness 

altogether following regular use; however, the magnitude of their effectiveness is reduced. There 

are no data on whether the tolerance to these agents continues to increase as duration of regular 

use increases to several months. 

Short-acting anticholinergic (SAAC) agents. Anticholinergic agents are used in respiratory 

conditions to decrease mucus production and as weak bronchodilators. The original SAAC agent 

used in asthma was atropine; however, ipratropium bromide (IB; AtroventTM) and oxitropium 

bromide (OB; OxiventTM) are more commonly used. Long-acting anticholinergics such as 

tiotropium (Spiriva®) are available; however, they are more commonly used in the management 

of chronic obstructive pulmonary disease. SAAC agents are an intuitive addition to the treatment 

regimen given the concerns regarding the potential for tachyphylaxis with regular use of SABA 

and LABA agents. 

We identified 18 trials (211 patients enrolled) that compared SAAC agents with placebo in 

single-dose prophylactic treatment of EIB/EIA. Twelve of the 18 researched IB and, given the 

worldwide availability and use of this drug, the discussion focuses on this agent. 

The pooled results demonstrated a consistent benefit attributable to IB (Table 42 and Figure 

28). The maximum percent fall in FEV1 at an ECT less than 2 hours following treatment was 

reduced by approximately 12 percent (17 percent in PEF) compared with placebo. These 

clinically relevant results, however, are tempered by the presence of moderate heterogeneity. 

137
 

Complete protection was achieved 4.5 times more often with IB than placebo. This conclusion is 

strengthened by the negligible heterogeneity (I2

=0 percent). Only four of 18 studies reported side 

effects; there were no differences identified between IB and placebo. Despite the theoretical 

autonomic nervous system risks associated with use of SAAC agents (e.g., dry mouth, glaucoma, 

confusion), there is sufficient evidence from the acute respiratory literature to suggest that a 

single dose of IB is safe in patients with EIA.168,169 

From the available evidence, it appears that when used as a pre-exercise treatment IB can be 

effective and safe for patients with EIB/EIA. The strength of the body of evidence is moderate. 

Anti-inflammatory Agents 

Mast cell stabilizers (MCS). Mast cells are important cellular contributors to the 

inflammatory cascade seen in asthma. MCS are asthma agents that stabilize the mast cell and 

prevent the release of inflammatory mediators. They are used as weak anti-inflammatory agents 

in mild to moderate chronic asthma. We identified three existing Cochrane reviews that 

addressed MCS as prophylactic treatment for EIA (Table 42 and Figure 28). The first review76 

included 21 trials that studied a single prophylactic dose of nedocromil sodium (NCS) in doses 

ranging from 1 mg to 8 mg, compared with a placebo. The second review77 (9 trials) compared 

the effects of a single prophylactic dose of NCS, in doses ranging from 2 mg to 8 mg, to one of 

sodium cromoglycate (SCG), in doses ranging from 10 mg to 20 mg. The summary data from 

this review failed to identify differences with respect to the maximum percent decrease in FEV1, 

complete protection, or the degree of clinical protection between the two drugs. Given this result, 

the third review78 included trials that compared either NCS or SCG (collectively called MCS) to 

an anticholinergic agent (n=11), a SABA alone (n=20), or a combination of a SABA and MCS 

(n=10). 

All studies in these three reviews included RCTs conducted on children (6 to 17 years) and 

adults (18 years and older) with stable asthma who experienced EIA. The majority of studies 

employed a crossover design with adequate time between ECTs to eliminate carryover effects 

but avoid period effects. 

In people with stable asthma that experience EIA, NCS taken 15 to 60 minutes prior to 

exercise significantly reduced the severity of EIA in both children and adults. Regardless of 

dose, timing, delivery method, or age, NCS provided a clinically significant benefit that was 51 

percent greater than placebo. The average post-exercise percent fall in FEV1 across the 16 

studies after NCS was 15.6 percent (range 10 to 29.8) compared with a fall of 30.2 (range 20.8 to 

48.1) on placebo (MD=15.6 percent; 95 percent CI: 13.2, 18.1). There was substantial 

heterogeneity in this result that was eliminated when subgroups based on severity of EIA were 

compared. The benefit from NCS was more pronounced in those with severe EIA (fall in FEV1 

of 30 percent or greater). 

When either NCS or SCG was compared to anticholinergics the data indicated MCS agents 

were somewhat more effective than anticholinergics but not as effective as SABA agents. The 

combination of SABA and MCS agents did not provide significant advantages over a SABA 

alone. Data on the safety of these agents were not routinely reported, but when it was, no serious 

side effects were observed. The strength of the body of evidence is moderate. 

Inhaled corticosteroids (ICS). The main anti-inflammatory agents used for chronic and 

acute asthma management are ICS, either alone or in combination with LABA agents. ICS 

agents are used in respiratory conditions to decrease inflammation and reduce mucus production; 

138
 

they have no direct bronchodilating effects. Contrary to systemic corticosteroids, ICS are inhaled 

and exert their effects locally; little of the available drug is absorbed into the systemic 

circulation. There are a large number of ICS agents available on the North American market (in 

alphabetical order): beclomethasone (QVARTM), budesonide (PulmicortTM), flunisolide 

(AerobidTM), fluticasone (FloventTM), and triamcinolone (AzmacortTM). Agents also exist that 

combine ICS with LABA in one inhaler (in alphabetical order): budesonide and formoterol 

(SymbicortTM) and fluticasone and salmeterol (AdvairTM). Koh et al.107 published a systematic 

review involving six studies comparing 4 to 12 weeks of daily ICS use with placebo for 

prevention of EIB/EIA. The reviewers concluded that 4 or more weeks of daily ICS use 

attenuated the fall in FEV1 in ranges of 7 to 14 percent over placebo. There was not enough data 

at that time to assess ICS used as a single-dose prophylactic for EIB/EIA. We identified four 

trials involving 50 children and adults that did so. Though the methodological quality of the 

studies was moderately good, questions remain on how adequately they were randomized and 

double blinded. 

Although the pooled results presented here favor ICS, they failed to demonstrate a 

statistically or clinically beneficial reduction in the maximum percent fall in FEV1 or PEF 

compared with placebo (Table 42 and Figure 28). No sound conclusions could be drawn on the 

complete or clinical protection provided by ICS either. None of the studies reported adverse 

effects. Despite the theoretical risks associated with ICS use, there is sufficient evidence from the 

acute respiratory literature to suggest that a single dose of ICS is safe in patients with EIB/EIA. 

Adverse effects such as cataracts,170 adrenal suppression, osteoporosis and fractures,171 occur 

with long-term use; they are not likely an issue of concern with episodic use. 

From the available evidence we cannot conclude that pre-treatment with ICS agents is an 

effective and safe strategy for patients with EIB/EIA. The strength of the body of evidence is 

moderate. 

Leukotriene receptor antagonists (LTRA). Leukotrienes are produced by the cysteinyl 

leukotriene pathway and are implicated in both bronchoconstriction and in the inflammatory 

cascade leading to worsening asthma. LTRAs, which block this pathway, are available for the 

management of chronic and acute asthma. 

We identified nine trials involving 535 patients and 10 comparisons of prophylactic treatment 

of EIA with LTRA compared with placebo. The methodological quality of the studies was 

reasonably strong. The pooled results demonstrated a consistent though modest benefit in favor 

of LTRAs. LTRAs were superior to placebo and reduced (i.e., improved) the percent fall in 

FEV1 at the earliest measurement (usually less than 2 hours) by approximately 9 percent 

compared with placebo (Table 42 and Figure 28). The protective effect of this pre-treatment 

extended up to the 8 and 24 hour measurements of FEV1 when there was a 7 and 5 percent 

improvement over placebo, respectively. It is likely that the weak anti-inflammatory effect of 

LTRAs is responsible for this extended action. These results are tempered by the presence of 

moderate heterogeneity (50 to 70 percent) in all meta-analyses. Few studies reported side effects 

and the data that were reported identified no differences between LTRAs and placebo; however, 

there is sufficient evidence from the chronic asthma literature to suggest that LTRAs are safe.172 

From the available evidence, it appears that LTRAs can be somewhat useful and safe as preexercise treatment for patients with EIB/EIA. The strength of the body of evidence is moderate. 

139
 

 

Nonpharmacologic Interventions 

As an alternative to drug interventions to attenuate and/or prevent EIB/EIA, many athletes, 

trainers and researchers advocate specific warmup exercises as a method to achieve similar 

results. We identified seven trials involving 128 patients that compared various forms of warmup 

activities to no warmup in the pre-exercise treatment of EIB/EIA. Convincing conclusions 

cannot be made regarding warmups because results are tempered by the methodologically poor 

quality of the studies and the variability in the warmup protocols studied. 

Three general approaches were examined: interval, continuous high intensity (two 

standardized exercise challenges 45 minutes apart), and continuous low intensity (treadmill runs 

at work rates of 60 percent). The pooled results varied (Table 42 and Figure 28). Compared with 

no warmup, interval warmups attenuated the fall in FEV1 following a subsequent ECT by a 

statistically significant 11 percent. For both high and low intensity continuous warmups, there 

was a 10 to 12 percent improvement in FEV1 but it was not statistically significant and it was 

associated with substantial heterogeneity. Combinations of various warmup protocols within 

studies also demonstrated protection against EIB/EIA with an attenuating factor between 10 and 

11 percent. Eck et al.98 reported that 79 percent of participants achieved protection (but did not 

designate a cutpoint for this) when a combination of warmup activities was used as a pretreatment for EIB/EIA. Pooling the study data was not possible due to the heterogeneity of the 

warmup protocols. 

From this evidence, it appears that certain warmup protocols are effective at reducing the 

degree of airway obstruction associated with EIB/EIA. Combination warmups show promise; 

however, it is unclear whether continuous warmups are effective in this condition. The strength 

of the body of evidence is low. 

Figure 28. Mean difference in the maximum percent decrease in FEV1 following ECT with prophylactic 

therapy relative to placebo 

Mean Difference Mean Difference 

Study or Subgroup Mean Difference SE IV, Random, 95% CI 

LABA -25.11 3.643 -25.11 [-32.25, -17.97] 

Atropine -15.96 2.939 -15.96 [-21.72, -10.20] 

MCS -15.64 1.276 -15.64 [-18.14, -13.14] 

Oxotropium -13.8 3.969 -13.80 [-21.58, -6.02] 

Ipratropium -13.11 2.01 -13.11 [-17.05, -9.17] 

Cont. low intens warmup -12.6 7.184 -12.60 [-26.68, 1.48] 

Interval warmup -10.61 2.082 -10.61 [-14.69, -6.53] 

Cont high intens warmup -9.79 8.276 -9.79 [-26.01, 6.43] 

LTRA -8.93 1.056 -8.93 [-11.00, -6.86] 

ICS -4.44 2.531 -4.44 [-9.40, 0.52] 

IV, Random, 95% CI 

-20 -10 0 10 20 

Favors Intervention Favors Placebo 

NOTE: The reduction in FEV1 post-exercise challenge with prophylactic therapy was compared with FEV1 post-exercise 

challenge with placebo (i.e. placebo response - prophylactic response), and therefore negative values favor the prophylactic pretreatment. 

140
 

Limitations 

In addition to the methodological issues identified previously regarding trial designs in 

EIB/EIA, there are several limitations that need to be discussed regarding systematic reviews. 

First, there is a possibility of publication bias in this systematic review. By missing unpublished 

and/or negative therapy studies, we may be overestimating the therapeutic benefits of certain 

interventions. A comprehensive and systematic search of the published literature for potentially 

relevant studies was conducted to avoid publication bias. This was supplemented by searching 

for gray literature (i.e., unpublished or difficult to find studies. Despite these efforts, we 

recognize that we may have missed some of these types of studies. 

There is also a possibility of study selection bias. However, we employed at least two 

independent reviewers and feel confident that the studies that were excluded from this report 

were done so for consistent and appropriate reasons. Our search was comprehensive, so it is 

unlikely that there are many studies in press or publication that were missed. 

There are several other issues with respect to populations, interventions, outcome 

assessments, and controls that require discussion. 

Population. In general the populations involved in the therapy trials were volunteer recruits 

from hospital and outpatient clinics or schools for asthmatic children. All had confirmed asthma 

and documented EIA. The lack of reporting certain baseline data precluded more detailed 

subgroup analysis that would be of interest to the medical community. Larger sample sizes 

would help to provide more conclusive results. Overall, we do not believe these limitations 

invalidate the results presented in the therapy review as the reviewers analyzed the data as 

vigorously as was possible. 

Intervention. Despite the variation in dose, delivery method, and timing of prophylactic 

drug treatment, these studies employed RCT methodology and standardized the drug 

interventions that were investigated. The major limitations are the small sample sizes and small 

number of trials that investigated each drug category. The interventions investigating warmup 

protocols were not standardized across trials. While we divided the warmup interventions into 

three groups based on the level of intensity required, each warmup approach varied considerably 

from study to study. Overall, we do not believe these limitations invalidate the results presented 

in the review; however, they do limit robust interpretation, drawing firm conclusions, and 

generalization of results. 

Control. Many of the patients in the pharmacologic studies were administered placebo 

agents as the control treatment. These agents were often similar in appearance or delivery; 

however, it may have been possible for patients to detect differences among treatments, 

especially the bronchodilators such as SABA, LABA and SAAC agents. Also, the studies used a 

range of placebo devices and propellants, some of which provided significant protection to a 

large proportion of participants in the study. It was not possible to blind the participants to the 

warmup protocols in the refractory studies and it was not reported if the purpose of the 

intervention was known to them. Furthermore, blinding of the person conducting and assessing 

spirometry following the intervention and the ECT was rarely reported. It is impossible to 

determine how this might have affected the results. None of the included studies reported the 

patient’s perception of treatment received. Overall, we do not believe these limitations invalidate 

the results presented in the review; however, they do raise questions surrounding the lack of 

blinding and how that may affect estimates of the overall treatment effect.13 

141
 

Outcome. The pulmonary function outcomes reported were not standardized and comprised 

various forms of FEV1 and PEF measures. Some could not be transformed or calculated from 

individual patient data and therefore were not included in a pooled analyses. Also, the maximum 

percent fall in FEV1 cutpoints to confirm EIB/EIA ranged from a fall of 10 to 20 percent. The 

ATS convention is to accept a 10 percent fall in FEV1, and that was what was employed in the 

majority of studies. 

Outcome reporting always included a pulmonary function measure following the intervention 

and ECT. However, reporting other useful outcomes such as clinical and complete protection 

data was not consistent (Table 42). Wherever possible, we calculated these results from IPD. 

Few secondary outcomes were reported. For example, patient preference for the intervention, 

effect on performance, effect on signs and symptoms were absent. Side effect profiles were also 

poorly reported; however, sufficient evidence exists for the safety of many of these agents from 

the chronic asthma literature. Overall, we do not believe these limitations invalidate the results of 

the therapy review. 

Finally, the comparative effectiveness of these treatments is difficult to determine. There are 

few direct comparisons among specific interventions for EIB/EIA treatments and this makes 

decisionmaking for patients and clinicians problematic. The indirect comparisons provided in 

Figure 28 are to be used with caution. 

Conclusions 

Despite exhaustive efforts to identify evidence regarding therapeutic effectiveness of various 

interventions used to treat people with EIB/EIA, only a small number of studies met the 

inclusion criteria for each key question. All of the studies recruited people with asthma and 

reproducible EIA. Evaluation of therapeutic effect on EIB was not possible. Many of the studies 

suffered from potential biases. Nonetheless, this summary represents the most comprehensive 

review of therapies for EIA published to date. 

On the basis of this review, we can conclude that all bronchodilators that were examined are 

effective at attenuating and even preventing the FEV1 drop associated with EIA (Figure 28). 

There is emerging evidence of the development of tachyphylaxis associated with daily use of 

SABA and LABA agents. This suggests that SABA and LABA agents should be used only “as 

required,” rather than regularly, in order to preserve their use as prophylactic agents for EIA. 

SAAC agents were found to be effective pre-EIA bronchodilator agents. 

We can conclude that the anti-inflammatory agents examined provide mixed results. For 

example, MCS agents are very effective in attenuating or eliminating the FEV1 drop associated 

with EIA. There is some role for LTRA in the treatment of EIA; however, the attenuation of EIA 

appears less than with other anti-inflammatory agents. There is limited evidence of a benefit 

associated with pre-treatment with ICS compounds. The long-term benefit of ICS agents in 

asthma is no longer questioned,107 and it is possible that better control of chronic airway 

inflammation may benefit patients with EIA specifically. 

Finally, pre-exercise interval warmup appears to be useful in significantly attenuating or 

eliminating the FEV1 falls associated with EIA. This set of interventions requires further research 

on the relative effectiveness of various types of warmup. 

142
 

Recommendations for Future Research 
 

Efforts are needed to improve the overall quality of reporting of primary studies of diagnostic 

test accuracy. The STARD checklist105 details 25 items that address the level of detail that should 

be specified within such studies including descriptions of participants, tests methods, statistical 

methods, and results. This could be considered as a guide for authors reporting studies that 

evaluate diagnostic tests and for journals that publish EIB/EIA-related research. 

Studies designed to more carefully examine the methodology of the standard ATS ECT test 

are needed. Specifically, guidelines state that the inspired air temperature must be less than 25o

C, 

and less than 50 percent relative humidity. Studies have used inspired air as cold as -18o

C and 

many have used medical compressed air, which has a relative humidity of 0 percent as the air 

leaves the tank. Colder, drier air would result in the greatest increase in osmolarity of the airway 

surface and thus most likely cause EIB/EIA. Additional studies are needed to more thoroughly 

examine how inspired air affects EIB/EIA so that a more standardized ECT guideline can be 

developed. 

Future purposely designed studies to compare the diagnostic characteristics of different 

diagnostic methods are needed. New tests such as mannitol are encouraging; however, currently 

there are insufficient data to allow for a strong recommendation of this test. Particular attention 

in future studies must be given to including a representative sample of participants with 

suspected EIB/EIA. Studies that prospectively recruit participants and blind the reference 

standard results to those who interpret the index test results are needed. 

To determine if the response to diagnostic tests differs in those with EIB versus EIA, those 

with atopy or no atopy, or other potentially defining characteristics, appropriate populations need 

to be included, adequate baseline data reported, and comparative analyses by the characteristics 

of interest performed and reported. 

With regard to the systematic review of therapy for EIA, there are several issues with respect 

to methodological quality, populations, interventions, outcome assessments, and controls that 

require discussion. 

Efforts are needed to improve the quality of reporting primary studies (i.e., randomized 

controlled trials). The CONSORT Statement106 could be considered as a guide for authors 

reporting trials and journals that publish EIB/EIA-related research. Most trials in this review 

used a crossover design. Concerns regarding crossover trials center on three factors: drug 

carryover effects, period effects, and statistical issues. Data should be reported in a manner that 

allows analyses to confirm the presence or absence of a carryover effect. Future studies should 

focus on complete reporting of results by period and sequence to assure readers that these 

concerns have been accounted for. 

Population: The populations involved in the therapy trials all had stable asthma and 

confirmed EIA. Athletic status was not reported. This finding, coupled with the small number of 

studies investigating some interventions, precluded more detailed subgroup analysis of the issue 

of EIB/EIA in elite athletes. Additional investigations of treatment effects in patient subgroups 

defined by asthma severity, age, and activity level are clearly indicated. 

More trials in clinically homogenous groups of patients with EIB and patients with EIA are 

needed to better explore and characterize differences in the efficacy of interventions between 

these two conditions. 

143
 

Intervention: The nonpharmacologic interventions were not standardized. Although the 

warmup interventions were divided into similar groups, each warmup approach varied from the 

others. Future research exploring different standardized warmup approaches is clearly indicated. 

Control: Many of the patients in the pharmacological studies were administered placebo 

agents as the control treatment. These agents were often similar in appearance or delivered in 

similar appearing devices (inhaler agents) to the active treatment; however, it may have been 

possible for patients to detect differences among treatments, especially the bronchodilators such 

as SABA, LABA and SAAC agents. It is impossible to determine how frequently this occurred 

since most studies did not report the patient’s perception of treatment received. In addition, it 

was not possible to blind the participants to the warmup programs in the refractory studies. When 

the participant cannot be blinded, it is particularly important that the outcome assessor be blinded 

to all information that could bias the outcome measure or assessment (e.g., other test results, 

intervention given, challenge performed). 

Outcome: The pulmonary function outcomes reported varied and studies used different 

diagnostic cutpoints ranging from a fall index of 10 to 20 percent. The ATS convention is to 

accept a 10 percent maximum fall in FEV1. While outcome reporting included detailed 

pulmonary function measures, the format was not standardized. Data on the proportion obtaining 

clinical and complete protection were often missing (Table 2). 

Side effect profiles were also poorly reported. While there is evidence for the safety of many 

of these agents from the chronic asthma literature, it would be prudent for future research to 

capture adverse effects in the EIB/EIA population. Future trials of interventions to prevent or 

attenuate EIB/EIA should include clinically relevant secondary outcomes such as patient 

preferences, symptom scores, and sport performance effects (e.g., changes in athletic 

performance or endurance). More robust outcome reporting would further inform decisionmaking by athletes, physicians, and sporting bodies. 

144
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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1995;96(6 Pt 1):906-9. 

157. Novembre E, Frongia G, Lombardi E, et al. The 

preventive effect of nedocromil or furosemide 

alone or in combination on exercise-induced 

asthma in children. J Allergy Clin Immunol 

1994;94(2 Pt 1):201-6. 

158. Melo RE, Sole D, Naspitz CK. Comparative 

efficacy of inhaled furosemide and disodium 

cromoglycate in the treatment of exerciseinduced asthma in children. J Allergy Clin 

Immunol 1997;99(2):204-9. 

159. Cho MK, Bero LA. The quality of drug studies in 

symposium proceedings. Ann Int Med 

1996;124:485-9. 

160. Deeks JJ, Altman DG, Bradburn MJ. Statistical 

methods for examining heterogeneity and 

combining results from several studies in meta

analysis. In: Egger M, Davey Smith G, Altman 

DG, eds. Systematic reviews in health care: metaanalysis in context. 2nd ed. London: BMJ 

Publishing Group; 2001:285-312. 

161. Kelly K, Spooner CH, Rowe BH. Nedocromil 

sodium versus sodium cromoglycate in treatment 

of exercise-induced bronchoconstriction: a 

systematic review. Eur Respir J 2001;17(1):39­

45. 

162. Compendium of pharmaceuticals and specialties. 

9th ed. Ottawa, ON: Canadian Pharmacists 

Association; 2008. 

163. Oseid S, Mellbye E, Hem E. Effect of nedocromil 

sodium on exercise-induced bronchoconstriction 

exacerbated by inhalation of cold air. Scand J 

Med Sci Sports 1995;5(2):88-93. 

164. Palange P, Ward SA, Carlsen K-H, et al. 

Recommendations on the use of exercise testing 

in clinical practice. Eur Respir J 2007;29:185­

209. 

165. Aaron SD, Vandemheen KL, Boulet LP, et al. 

Overdiagnosis of asthma in obese and nonobese 

adults. CMAJ 2008;179(11):1121-31. 

166. Sterling GM. The mechanism of 

bronchoconstriction due to hypocapnia in man. 

Clin Sci 1968;34(2):277-85. 

167. Leeflang MM, Deeks JJ, Gatsonis C, et al. 

Systematic reviews of diagnostic test accuracy. 

Ann Intern Med 2008;149(12):889-97. 

168. McDonald NJ, Bara AI. Anticholinergic therapy 

for chronic asthma in children over two years of 

age. Cochrane Database Syst Rev 

2003;3:CD003535. 

169. Westby M, Benson M, Gibson P. Anticholinergic 

agents for chronic asthma in adults. Cochrane 

Database Syst Rev 2004;3:CD003269. 

170. Uboweja A, Malhotra S, Pandhi P. Effect of 

inhaled corticosteroids on risk of development of 

cataracts: a meta-analysis. Fundam Clin 

Pharmacol 2006;20(3):305-9. 

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171. 	 Halpern MT, Schmier JK, Van Kerkhove MD, et 

al. Impact of long-term inhaled corticosteroid 

therapy on bone mineral density: results of a 

meta-analysis. Ann Allergy Asthma Immunol 

2004;92:201-7. 

172. 	 Ducharme FM, Lasserson TJ, Cates CJ. Longacting beta2-agonists versus antileukotrienes as 

add-on therapy to inhaled corticosteroids for 

chronic asthma. Cochrane Database Syst Rev 

2006;4:CD003137. 

151
 

 

Abbreviations
 


95% CI 95 percent confidence interval 

ATS American Thoracic Society 

AUC Area under the curve 

BI Bronchoprotection index 
 

C Centigrade 
 

CCT Clinical controlled trial 
 

CO2 Carbon dioxide 

ECT Exercise challenge test 

EIA Exercise induced asthma 

EIB Exercise induced bronchoconstriction 

EVH Eucapnic voluntary hyperpnea 

FEV1 Forced expiratory volume in 1 second 

FRAST Free running asthma screening test 

GRADE Grading of Recommendation, Assessment, Development, and Evaluation 

IB Ipratropium bromide 

ICS Inhaled corticosteroid 

IPD Individual patient data 

IQR Inter-quartile range 

LABA Long-acting beta-agonist 

LTRA Leukotriene receptor antagonist 

MCH Methacholine challenge 

MCS Mast cell stabilizer 

MD Mean difference 

MDI Metered-dose inhaler 

Mg/ml Milligrams per millilitre 

mg Milligram 

MVV Maximum voluntary ventilation 

NCS Nedocromil sodium 

NSAIDS Nonsteroidal anti-inflammatory drugs 

O2 Oxygen 

OB Oxitropium bromide 

PC20 Provocative concentration causing a 20 percent fall in FEV1 

PEF Peak expiratory flow 

QUADAS Quality Assessment of Studies of Diagnostic Accuracy 

RCT Randomized controlled trial 

RH Relative humidity 

ROC Receiver operating characteristic 

RR Risk ratio 

SAAC Short-acting anticholinergic 

SABA Short-acting beta-agonist 

SCG Sodium cromoglycate 

SD Standard deviation 

SE Standard error 

STARD Standard of Reporting of Diagnostic Accuracy 

152
 
TEP Technical expert panel 

VATAP Veterans Affairs Technology Assessment Program 

VO2max Maximum oxygen consumption 

153
 

154
 

 

Appendix A. Technical Expert Panel and Peer 

Reviewers 

Technical Expert Panel 

In designing the study questions and methodology, the EPC consulted several technical and 

content experts. Broad expertise and perspectives were sought. Divergent and conflicting 

opinions are common and perceived as healthy scientific discourse that results in a thoughtful, 

relevant systematic review. Due to these differences in opinion, the study questions, design, 

and/or methodologic approaches do not necessarily represent the views of individual technical 

and content experts. 

Technical Expert Affiliations/Location 

Louis-Philippe Boulet, M.D., F.R.C.P.C. Université Laval and Hôpital Laval 

Sainte-Foy, QC 

Robert Cowie, M.D., F.C.P.(S.A.), M.Sc. University of Calgary 

Calgary, AB 

Andrew Gregory, M.D., F.A.A.P., F.A.C.S.M. Vanderbilt University Medical Center 

Nashville, TN 

Cynthia LaBella, M.D. Children's Memorial Hospital 

Chicago, IL 

Darcy Marciniuk, M.D., F.R.C.P.C. University of Saskatchewan 

Saskatoon, SK 

Kenneth Rundell, Ph.D. Marywood University 

Scranton, PA 

A-1 
 
 

 

 

Peer Reviewers 

Peer reviewer comments on a preliminary draft of this report were considered by the EPC in 

preparation of the final report. The synthesis presented in this report does not necessarily 

represent the views of individual reviewers. 

Peer Reviewer Affiliations/Location 

Louis-Philippe Boulet, M.D., F.R.C.P.(C.) Université Laval and Hôpital Laval 

Sainte-Foy, QC 

Robert Cowie, M.D., F.C.P.(S.A.), M.Sc. University of Calgary 

Calgary, AB 

Andrew Gregory, M.D., F.A.A.P., F.A.C.S.M. Vanderbilt University Medical Center 

Nashville, TN 

Kenneth Rundell, Ph.D. Marywood University 

Scranton, PA 

Jeannette May Representative, Disease Management Association of America 

Washington, DC 

H. William Kelly, Pharm.D. University of New Mexico 

Albuquerque, NM 

Sheldon Spector, M.D. & Ricardo Tan, M.D. California Allergy & Asthma Medical Group 

Los Angeles, CA 

John Weiler, M.D. American Academy of Asthma Allergy and Immunology 

Iowa City, IA 

A-2 
 
 

Appendix B. Literature Search Strings 

Table B1. Diagnosis of EIB/EIA review – OVID Databases 

Search Date: November 20, 2008 

Number of Results: 3640 

Database Years Searched Number of Results 

AMED (Allied and Complementary Medicine) 1985 to November 2008 21 

PsycINFO 1806 to November Week 3 2008 14 

MEDLINE® 1950 to November Week 2 2008 2321 

EMBASE 1988 to 2008 Week 46) 1006 

PASCAL 1987 to October 2008 179 

EBM Reviews - Cochrane Central Register of 

Controlled Trials 

4th Quarter 2008 99 

MULTIFILE STRATEGY 

1. exp "Exercise Induced Asthma"/ or exp Asthma, Exercise-Induced/ 

2. ("induced bronchoconstriction" or "induced asthma" or "induced bronchospasm").kw,ie,id,sh. and 

(exercise* or (train* and (military or army)) or fitness or "physical activity" or exertion or athlet* or 

sport*).mp. 

3. (bronchoconstrict* or asthma* or antiasthma* or wheez* or (respiratory adj sound?) or (bronchial 

adj5 (spasm* or constrict*)) or bronchospas* or "bronchial hyperreactivity" or "respiratory 

hypersensitivity").mp. 

4. ((bronchial* or respiratory or airway* or lung*) adj5 (hypersensitiv* or hyperreactiv* or allerg* or 

insufficiency)).mp. 

5. or/3-4 

6. (EIB or EIA).ti,ab. 

7. ((exercise adj5 induced) or "exercised-induced" or (exercise adj5 challenge) or "exercise 

tolerance" or "physical exercise" or (train* and (military or army)) or fitness or "physical activity" 

or exertion or athlet* or sport*).mp,jn. or exp Sports/ or Exercise/ 

8. or/6-7 

9. and/5,8 

10. or/1-2,9 

11. (sensitiv* or diagnos* or predictive value* or probability).mp. 

12. (accurac* or specificity).tw. 

13. ((pre-test or post-test) adj probability).mp. 

14. likelihood ratio*.mp. 

15. di.fs. 

16. *Diagnostic Accuracy/ 

17. (mannitol or methacholine or MCT or EVH or eucapnic or hyperpnea* or FRAST or provocation 

or marker* or screen* or test*).mp. 

18. or/11-17 

19. 18 and 10 

20. limit 19 to english language 

21. limit 20 to human 

22. remove duplicates from 21 

B-1 
 
 

Table B2. Diagnosis of EIB/EIA review – EBSCO Databases 

Search Date: November 17, 2008 

Number of Results: 905 

Database Years Searched Number of Results 

CINAHL®

 (Cumulative Index to Nursing & Allied 

Health Literature) 

1937 to 2008 280 

SPORTDiscus with Full Text 1800 to 2008 246 

Academic Search Elite 1985 to 2008 379 

MULTIFILE STRATEGY 

S1 (DE "EXERCISE" OR DE "ABDOMINAL exercises" OR DE "AEROBIC exercises" OR DE 

"AQUATIC exercises" OR DE "ARM exercises" OR DE "BACK exercises" OR DE "BREATHING 

exercises" OR DE "BREEMA" OR DE "BUTTOCKS exercises" OR DE "CALLISTHENICS" OR DE 

"CHAIR exercises" OR DE "CIRCUIT training" OR DE "EXERCISE therapy" OR DE "FACIAL 

exercises" OR DE "FALUN gong exercises" OR DE "GYMNASTICS" OR DE "HAND exercises" OR 

DE "HATHA yoga" OR DE "ISOKINETIC exercise" OR DE "ISOMETRIC exercise" OR DE "LEG 

exercises" OR DE "LIANGONG" OR DE "METABOLIC equivalent" OR DE "MU-lan chuan" OR DE 

"MUSCLE strength" OR DE "PHYSICAL fitness" OR DE "PHYSICAL fitness for men" OR DE 

"PILATES method" OR DE "PLYOMETRICS" OR DE "QI gong" OR DE "REDUCING exercises" 

OR DE "RUNNING" OR DE "SCHOOLS -- Exercises & recreations" OR DE "SEXUAL exercises" 

OR DE "SHOULDER exercises" OR DE "STRETCHING exercises" OR DE "TAI chi chuan" OR DE 

"TREADMILL exercise") or (DE "SPORTS" OR DE "AERONAUTICAL sports" OR DE "AGE & 

sports" OR DE "AQUATIC sports" OR DE "BALL games" OR DE "BASEBALL" OR DE 

"BASKETBALL" OR DE "CHARITY sports events" OR DE "COLLEGE sports" OR DE 

"DISCRIMINATION in sports" OR DE "DOPING in sports" OR DE "ENDURANCE sports" OR DE 

"EXTREME sports" OR DE "FASCISM & sports" OR DE "FEMINISM & sports" OR DE 

"FOOTBALL" OR DE "GAELIC games" OR DE "GAY Games" OR DE "GAYS & sports" OR DE 

"GLBT people & sports" OR DE "GLBT rodeos" OR DE "GOLF" OR DE "GOODWILL Games" OR 

DE "GROUP games" OR DE "GYMNASTICS" OR DE "HOCKEY" OR DE "HOMOPHOBIA in 

sports" OR DE "INDIVIDUAL sports" OR DE "KNIFE throwing" OR DE "LESBIANS & sports" OR 

DE "LOG-chopping (Sports)" OR DE "MASCULINITY in sports" OR DE "MASS media & sports" OR 

DE "MILITARY sports" OR DE "MINORITIES in sports" OR DE "MOTION pictures in sports" OR 

DE "MOTORSPORTS" OR DE "NATIONAL socialism & sports" OR DE "NATIONALISM & sports" 

OR DE "OLYMPICS" OR DE "PARKOUR" OR DE "PRESIDENTS -- Sports" OR DE 

"PRESIDENTS -- United States -- Sports" OR DE "PROFESSIONAL sports" OR DE 

"PROFESSIONALISM in sports" OR DE "RACING" OR DE "RACISM in sports" OR DE "RACKET 

games" OR DE "ROBOTICS in sports" OR DE "RODEOS" OR DE "ROLLER skating" OR DE 

"SCHOOL sports" OR DE "SENIOR Olympics" OR DE "SEX discrimination in sports" OR DE 

"SEXUAL harassment in sports" OR DE "SHOOTING" OR DE "SHUTOUTS (Sports)" OR DE 

"SOCCER" OR DE "SOCIALISM & sports" OR DE "SPORT for All" OR DE "SPORTS & tourism" 

OR DE "SPORTS -- Collectibles" OR DE "SPORTS -- Corrupt practices" OR DE "SPORTS -- 

Economic aspects" OR DE "SPORTS -- Finance" OR DE "SPORTS -- Songs & music" OR DE 

"SPORTS for children" OR DE "SPORTS for people with disabilities" OR DE "SPORTS for women" 

OR DE "SPORTS forecasting" OR DE "SPORTS rivalries" OR DE "SPORTS teams" OR DE 

"STEREOTYPES (Social psychology) in sports" OR DE "TARGETS (Sports)" OR DE 

"TEAMWORK (Sports)" OR DE "TELEVISION & sports" OR DE "TOMAHAWK throwing" OR DE 

"TRACEURS" OR DE "VIDEO tapes in sports" OR DE "VIOLENCE in sports" OR DE "WINTER 

sports") 

S2 (MH "Sports+") or (MH "Physical Fitness") or (MH "Exercise+") 

S3 exerc* OR train* OR fitness OR physical OR athlet* OR sport* 

S4 S3 or S2 or S1 

S5 ( bronchial* OR respiratory OR airway* OR lung* ) and ( hypersensitiv* OR hyperreactiv* OR allerg* 

OR insufficiency ) 

S6 bronchoconstrict* OR asthma* OR antiasthma* OR wheez* OR "Respiratory Sounds" OR 

"Bronchial Spasm" OR bronchospas* OR "Bronchial Hyperactivity" OR "Respiratory 

B-2 
 
 

 

 

Hypersensitivity" 

S7 DE "BRONCHIAL spasm" 

S8 (MH "Bronchoconstriction") 

S9 (MH "Asthma") 

S10 ( bronch* AND spasm* ) or ( bronch* AND constrict* ) 

S11 S10 or S9 or S8 or S7 or S6 or S5 

S12 S11 and S4 

S13 DE "EXERCISE-induced asthma" 

S14 (MH "Asthma, Exercise-Induced") 

S15 S14 or S13 or S12 

S16 diagnos* OR specificity OR accurac* OR predictive OR sensitiv* OR probability OR likelihood 

S17 S16 and S15 

S18 

S16 and S15 

Limiters - Exclude MEDLINE records; Language: English 

Table B3. Diagnosis of EIB/EIA review – Web of Science® - Institute for Scientific Information – Thomson 

Reuters 

Years/issue searched: 1900 to 2008 

Search date: November 17, 2008 

Number of Results: 984 

TS=((exerc* OR train* OR fitness OR "physical activity" OR athlet* OR sport*) AND (bronchoconstrict* 

OR asthma* OR antiasthma* OR wheez* OR "Respiratory Sounds" OR "Bronchial Spasm" OR 

bronchospas* OR "Bronchial Hyperreactivity" OR "Respiratory Hypersensitivity" OR (bronch* AND 

spasm*) OR (bronch* AND constrict*) OR (bronchial* OR respiratory OR airway* OR lung*) AND 

(hypersensitiv* OR hyperreactiv* OR allerg* OR insufficiency))) AND TS=(diagnos* OR sensitiv* or 

predictive OR accurac* OR specificity OR probability OR likelihood) AND Language=(English) AND 

Document Type=(Article OR Meeting Abstract OR Meeting-Abstract OR Proceedings Paper) 

Table B4. Diagnosis of EIB/EIA review – BIOSIS PREVIEWS® - Institute for Scientific Information – Thomson 

Reuters 

Years/issue searched: 1926 to 2008 

Search date: November 17, 2008 

Number of Results: 1317 

#1 Topic=(diagnos* OR sensitiv* or predictive OR accurac* OR specificity OR likelihood OR probability) 

#2 Topic=(exerc* OR train* OR fitness OR "physical activity" OR athlet* OR sport*) 

#3 TS=(bronchial* OR respiratory OR airway* OR lung*) SAME TS=(hypersensitiv* OR hyperreactiv* OR 

allerg* OR insufficiency) 

#4 TS=(bronchoconstrict* OR asthma* OR antiasthma* OR wheez* OR "Respiratory Sounds" OR 

"Bronchial Spasm" OR bronchospas* OR "Bronchial Hyperreactivity" OR "Respiratory Hypersensitivity" 

OR (bronch* SAME spasm*) OR (bronch* SAME constrict*)) 

#5 #3 OR #4 

#6 #1 AND #2 AND #5 AND Language=(English) AND Document Type=(Article OR Book Chapter OR 

Meeting OR Meeting Paper OR Technical Report OR Thesis Dissertation) AND Taxa Notes=(Humans) 

#7 TI=COPD NOT TI=asthma* 

#8 #6 NOT #7 

B-3 
 
Table B5. Diagnosis of EIB/EIA review – PubMed: National Library of Medicine 

Years/issue searched: 1950 to 2008 

Search date: November 25, 2008 

Number of Results: 138 

("diagnosis"[MeSH Subheading] OR diagnos* OR sensitiv* OR predictive OR accurac* OR specificity OR 

probability OR likelihood OR mannitol OR methacholine) AND ((((bronchoconstrict* OR asthma* OR 

antiasthma* OR wheez* OR "Respiratory Sounds" OR "Bronchial Spasm" OR bronchospas* OR 

"Bronchial Hyperreactivity" OR "Respiratory Hypersensitivity") OR (bronch* AND (spasm* OR constrict*)) 

OR ((bronchial* OR respiratory OR airway* OR lung*) AND (hypersensitiv* OR hyperreactiv* OR allerg* 

OR insufficiency))) AND (exerc* OR train* OR fitness OR "physical activity" OR athlet* OR sport*)) OR 

((EIB OR EIA) AND (asthma* OR bronch*))) Limits: added to PubMed in the last 1 year, English 

Table B6. Diagnosis of EIB/EIA review – Scopus®

: Elsevier 

Years/issue searched: 1823 to 2008 

Search date: November 14, 2008 

Number of Results: 1466 

TITLE-ABS-KEY(diagnos* OR sensitiv* OR predictive OR accurac* OR specificity OR probability OR 

likelihood OR methacholine OR mannitol OR screen* OR test*) AND TITLE-ABS-KEY-AUTH(exercise 

induced asthma) AND (LIMIT-TO(LANGUAGE, "English")) AND (LIMIT-TO(DOCTYPE, "ar") OR LIMIT

TO(DOCTYPE, "cp") OR LIMIT-TO(DOCTYPE, "ip")) 

­

Table B7. Diagnosis of EIB/EIA review – Medion database of diagnostic reviews - University of Maastricht 

Years/issue searched: 1967 to 2008 

Search date: November 28, 2008 

Number of Results: 0 

Asthma , eia, eib, exercise 

Table B8. Diagnosis of EIB/EIA review – Proquest Dissertations and Theses 

Years/issue searched: 1861 to 2008 

Search date: November 13, 2008 

Number of Results: 25 

(bronchoconstrict* OR asthma* OR antiasthma* OR wheez* OR "Respiratory Sounds" OR "Bronchial 

Spasm" OR bronchospas* OR "Bronchial Hyperreactivity" OR "Respiratory Hypersensitivity" OR (bronch* 

AND (spasm* OR constrict*))) AND TITLE(exerc* OR train* OR fitness OR "physical activity" OR athlet* 

OR sport*) AND (diagnos* OR sensitiv* OR predictive OR accurac* OR specificity OR probability OR 

likelihood OR methacholine OR mannitol OR EVH OR screen* OR test*) AND LN(EN) 

Look for terms in: Citation and abstract 

Publication type: All publication types 

B-4 
 
Table B9. Therapy for EIB/EIA review – Cochrane Airways Register 

Years/issue searched: 1900 to 2008 

Search date: November 5, 2008 

Number of Results: 1601 

The following databases are searched systematically for the Cochrane Airways Register: Cochrane 

Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO, 

and hand searching of respiratory journals and meeting abstracts. 

(exerc* OR train* OR fitness OR physical OR athlete* OR sport*) AND (bronchoconstrict* OR asthma* 

OR antiasthma* OR wheez* OR “Respiratory Sounds” OR “Bronchial Spasm” OR bronchospas* OR 

“Bronchial Hyperreactivity” OR “Respiratory Hypersensitivity” OR (bronch* AND spasm*) OR (bronch* 

AND constrict*).OR (bronchial* OR respiratory OR airway* OR lung*) AND (hypersensitiv* OR 

hyperreactiv* OR allerg* OR insufficiency)) OR EIB OR EIA 

Table B10. Therapy for EIB/EIA review – ClinicalTrials.Gov: National Institutes of Health 

Search date: November 28, 2008 

Number of Results: 31 

asthma OR eia OR eib OR exercise-induced 

Table B11. Therapy for EIB/EIA review – ClinicalStudyResults.Org: PhRMA Clinical Study Results Database 

Search date: November 28, 2008 

Number of Results: 2 

Browsed by trade and generic drug names 

B-5 
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

e Exclude Unsure 

e said “NO” for at least one of 1-8. 

 

Appendix C. Forms 

Inclusion Criteria Worksheet: Diagnosis of EIB/EIA review 

Reviewer ID: Date: / /2009 Record ID: 

Criteria Yes No Unclear 

1. ENGLISH LANGUAGE 

2. PUBLICATION TYPE 

a. Report of primary research 

3. STUDY OBJECTIVE 

a. Must be to diagnose or confirm diagnosis of EIB 

4. STUDY DESIGN 

a. Comparative study or... 

b. Single arm study (but results are compared to a previous standardized test (i.e. 

cannot just be a prevalence study) 

5. POPULATION 

a. >80% patients ≥6 years who are otherwise healthy (i.e., do not have bronchitis, 

COPD, cystic fibrosis, bronchiectasis, etc.) NOTE: participants may have asthma or 

suspected EIA/EIB 

6. INDEX TEST (circle the test) 

a. One of the following diagnostic tests: 

i. Self-reported history 

ii. Self-reported symptoms diary 

iii. Methacholine challenge 

iv. Sport or venue specific exercise challenges 

v. Eucapnic (or normocapnic) voluntary hyperpnea 

vi. Free running asthma screening test (FRAST) 

vii. Mannitol 

NOTE: if another testing method not listed above is used please flag as an ‘other’ below 

and keep separate from excluded pile 

7. REFERENCE STANDARD 

a. Standardized exercise challenge test (treadmill or Cycle ergometry) that 

resulted in a drop in FEV1 ≥ 10% from baseline 

8. OUTCOME 

a. Numeric data sufficient to create a 2 x 2 table and/or calculation of sensitivity, 

specificity, positive and negative likelihood ratios. 

Comments: 

REVIEWER’S DECISION : Include Exclude Unsure Other 

FINAL DECISION: Includ

NOTE: To exclude must hav

C-1 
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Inclusion Criteria Worksheet: Therapy for EIB/EIA review 

Reviewer ID: 	 Date: / /2009 Record ID: 

Criteria Yes No Unclear 

1. ENGLISH LANGUAGE 

2. PUBLICATION TYPE 

a. Report of primary research 

3. STUDY DESIGN 

a. Randomized controlled trial (parallel or cross-over) 

4. POPULATION 

a. >80% patients ≥6 years who are otherwise healthy (i.e., do not have bronchitis, 

COPD, cystic fibrosis, bronchiectisis) 

b. Confirmed diagnosis of EIB or EIA (defined as drop in FEV1 or peak flow ≥10%) 

[EXCLUDE self-report diagnosis] 

5. INTERVENTION (circle the intervention) 

Q1. One of the following regular dose therapies for ≥1 week before a standard exercise 

challenge (focus - testing for tachyphylaxis) 

a. SABA (see separate list of SABA agents) 

b. LABA (formoterol or salmeterol) 

OR 

One of the following single dose pre-exercise therapies tested by standard exercise 

challenge 

Q2. Leukotriene receptor antagonists (LTRA) (montelukast or zafirlukast) 
 

Q3. Inhaled corticosteroid (ICS) (see separate list of ICS agents) 
 

Q4. Mast cell stabilizers (sodium cromoglycate or nedocromil)
 


Q5. Anti-cholinergics (ipratropium, oxitropium, atropine) 
 

OR 

Q6. A 10-15 min warmup and/or cool down prior to a standard exercise challenge 

(focus: checking for the effect of a refractory period) 

6. COMPARATOR 

a.	 For SABA or LABA: placebo or any standard comparator treatments for ≥1 

week 

OR 
 

For other therapies: A single dose of placebo or no treatment 
 

7. OUTCOME 

Study reports numeric data on at least one outcome of interest (e.g., max % fall FEV1 

from pre-exercise baseline, symptoms, presence/absence of EIA/EIB, % protection over 

placebo, recovery time, adverse effects). 

Comments: 

REVIEWER’S DECISION : Include Exclude Unsure 

FINAL DECISION: Include Exclude Unsure 

NOTE: To exclude must have said “NO” for at least one of 1-7. 

RELEVANT TO QUESTION(S): 

1. In patients with confirmed EIB/EIA, do patients using SABA and/or LABA develop tachyphylaxis to treatment and, if so, 

at what frequency compared to standard comparator treatments and/or placebo? 

2 - 5. In patients with confirmed EIA/EIB, does pre-exercise treatment with
 


2) leukotriene receptor antagonists (LTRA) therapy OR 
 

3) mast cell stabilizers (sodium cromoglycate or nedocromil) therapy OR 
 

4) inhaled corticosteroid (ICS) therapy OR 
 

5) anti-cholinergics (ipratropium) therapy 
 

reduce symptoms and prevent a ≥ 10% drop in FEV1 compared to no treatment/placebo. 

6. In patients with confirmed EIA/EIB, does a refractory period (10-15 min warmup and/or cool down) reduce symptoms 

and prevent a ≥ 10% drop in FEV1 compared to no treatment/placebo. 

C-2 
 
 

 

 

 

 

 

 

Data Extraction Form: Diagnosis of EIB/EIA review 

I. CODER INFORMATION 

1. Reviewer initials: 2. Time to extract (to nearest minute): 

Applies to question: 1 self-reported hx/symptoms diary 2 methacholine challenge 3 sport/venue-specific 

exercise 4 eucapnic voluntary hyperpnea (EVH) 5 free running asthma 

screening test (FRAST) 6 mannitol 

II. PUBLICATION 
 

3. Author: 4. Year of publication: 

5. Country trial conducted in (n=___ and complete list if 

>1): 

NR 

6. Number of centres:

 single 

 multi: n= 

NR 

7. Publication Type: 

journal article 

industry reported trial 

abstract 

other (describe) 

8. Funding

 Government 

Institution 

 Industry (describe) 

 No funding 

 Other (describe) 

NR 

9. Type of study: 

Trial 

Observational 

other (specify) _______________________ 

10. Design attributes

 prospective 

retrospective 

III. STUDY CHARACTERISTICS
 


11. Study objective: 

12. Recruitment dates (mm/yy–mm/yy): 

NR 

13. Source of participants:

 clinic/office 

school 

athletic team (sport/level) ___________________________ 

 other (describe) 

NR 

14. No. of study days (i.e # screening/testing days) 15. No. of challenges per day 

16. Time between challenges: 

24 hours 

≥2 days 

Other: ____________________________ 

NR 

17. Inclusion criteria:

 NR 

18. Exclusion criteria:

 NR 

19. Definition of bronchial hyper reactivity (BHR) according to EVH or methacholine or mannitol (i.e. cut point for diagnosis): 

Report the reference or comments to support the cut point. 

20. Definition of EIA/EIB: ≥ 10% fall in FEV1 or PEF 

≥ 15% fall in FEV1 or PEF 

≥ 20 % fall in FEV1 or PEF 

 Reproducible EIA/EIB (no definition given) 

 Other (describe) e.g. self-report; physician diagnosed; symptoms etc. 

NR 

21. Please report the reference or comments made that supported the EIA/EIB definition they used (if any). 

C-3 
 
IV. DIAGNOSTIC TESTS 
 

Treadmill 

22. Duration of challenge: 6 minutes 

8 minutes 

Other (describe) 

_________________________________________________________ 

NR 

23. % of maximal heart rate / workload: 

24. Relative humidity: ≤50% 

Other (describe) 

_________________________________________________________ 

NR 

25. Air temperature: Air conditioned (ambient temp. 20-25 ̊ C) 

Other (describe) 

_________________________________________________________ 

NR 

26. Referenced standardized protocol: Yes 

No 

If yes, supply reference ID (if given): 

_________________________________________ 

27. Follow-up time points:

 (i.e. 1, 3, 5, 7, 30 min post challenge) 

Cycle ergometry 

28. Duration of challenge: 6 minutes 

8 minutes 

Other (describe) 

_________________________________________________________ 

NR 

29. % of maximal heart rate / workload: 

30. Relative humidity: ≤50% 

Other (describe) 

_________________________________________________________ 

NR 

31. Air temperature: Air conditioned (ambient temp. 20-25 ̊ C) 

Other (describe) 

_________________________________________________________ 

NR 

32. Referenced standardized protocol: Yes 

No 

If yes, supply reference ID (if given): 

_________________________________________ 

33. Follow-up time points:

 (i.e. 1, 3, 5, 7, 30 min post challenge) 

Self reported history/Questionnaire 

34. Summary of comments from study: 

C-4 
 
 

 

 

 

 

Methacholine challenge 

35. Dosing protcol 2 min tidal breathing method 

 10 doubling concentrations of MCH (0.03, 0.06, 0.125, 0.25, 0.50, 1, 2, 4, 8, 

16 mg/ml)

 Nebulizer using dry compressed air for power 

 Perform baseline spirometry 

 Noseclip should be worn 

 Breathe quietly for 2 min. 

 Measure FEV1 30 – 90s after nebulization of each dose 

 Commence subsequent concentrations with ≤5 min interval 

5 breath dosimeter method 

 5 quadrupling concentrations of MCH (0.0625, 0.25, 1,4,16 mg/ml) 

 Perform baseline spirometry 

 Noseclip should be worn 

 Inhale slowly & deeply from nebulizer and exhale; repeat for 5 inhalations 

 Measure FEV1 30 – 90s after 5th inhalation 

 Commence subsequent concentrations with ≤5 min interval 

Other (specify) 

36. Follow-up time points:

 (i.e. 1, 3, 5, 7, 30 min post challenge) 

Sport/venue-specific exercise 

37. Sport: 

38. Venue: 

39. Duration: 

40. Follow-up time points:

 (i.e. 1, 3, 5, 7, 30 min post challenge) 

41. Other: 

EVH 

42. Description: 

FRAST 

43. Standard test: YES NO 

If no, describe: 

Mannitol 

44. Description: 

Resources used for diagnosis challenges 

45. Time: 

46. Personnel (who, how many?): 

47. Cost(s) (if given): 

48. Patient safety: 

49. Other (e.g. ease of administration): 

C-5 
 
 

 

 

 

 

 

 

 

 

V. BASELINE CHARACTERISTICS (when possible report data post run-in/pre-test) *Circle or describe units 

Indicate if no variance measure reported 

50. Age: years mean±SD; mean±SE; median 

(range); IQR 

51. Males: n (%) 

52. Ethnicity: 

53. Height: 

54. Weight: 

55. BMI: 

56. Number of participants enrolled/randomized: 

(n) 

57. Number of participants analyzed: (n) 

58. Number of dropouts/withdrawals: (n) 

59. Reasons for dropout/withdrawal: 

60. History of asthma/BHR: YES NO NR 

If yes, how confirmed? 

61. Proven EIA/EIB: YES NO NR 

If yes, how confirmed? 

62. Baseline severity of asthma: mild/mod/severe 

or stable 

(Report authors words) 

NR 

63. Index of activity/fitness level: Sedentary (no activity per week) 

Normally active (1-3 days per week activity) 

Athletic (competitive athlete, 4+ days per week activity) 

Other 

NR 

64. Atopic status: 

YES = to at least one allergen; 

NO=none were atopic 

Mix of atopy/no atopy (x%=yes; X%=no) 

(a positive skin prick test=atopic to at least 1) 

65. Baseline ICS history: 

NO = none on ICS 

YES = all on maintenance ICS 

mixed ICS use (x%= yes; X%= no) 

NR 

66. Which asthma medications were 

discontinued pre challenge and how long 

before challenge 

67. Baseline FEV1 (L): (mean±SD; mean±SE; 

median (range); IQR) 

68. Baseline FEV1 (% predicted): (mean±SD; 

mean±SE; median (range); IQR) 

69. Baseline PEF: (mean±SD; mean±SE; 

median (range); IQR) 

70. PC20 (mg/ml): 

71. Smoking Hx: never/past/current 

C-6 
 
 

 

 

 

 

 

 

 

72. Other (describe) 

VI. REPORTED OUTCOMES 
 

Exercise Standard Totals 

EIB (+) EIB (-) 

Comparator 1 EIB (+) 

EIB (-) 

Totals 

OTHER OUTCOMES REPORTED 

73. Sensitivity: 

74. Specificity: 

VII. ADVERSE EVENTS/SIDE EFFECTS NR Statement re: no AE observed in study 

Exercise Standard Comparator 1 Comparator 2 Comparator 3 

Total reported 

ADDITIONAL COMMENTS 
 

75. 

C-7 
 
 

 

 

 

 

 

 

Data Extraction Form: Therapy for EIB/EIA review 

I. CODER INFORMATION 

1. Reviewer initials: 2. Time to extract (to nearest minute): 

3. Applies to question: 1 tachyphylaxis SABA or LABA 

2 i [LTRA] 2 ii] [ICS 2 iii] [SCG / NCS 2 iv [anti-cholinergic] 

6 refractory period 

II. PUBLICATION 
 

4. Author: 5. Year of publication (last two digits): 

6. Country trial conducted in (n=___ and complete list if 

>1): 

NR 

7. Number of 

centres:

 single 

 multi: n= 

NR 

8. Publication Type: 

journal article 

industry reported trial 

abstract 

 other (describe) 

9. Funding 

government 

institution 

 Industry (describe) 

 No funding 

 other (describe) 

NR 

10. Type of trial:

 parallel 

 cross-over 

11. Blinding

 open label 

 single blind 

 dble blind 

NR 

12. Other design attributes

 double-dummy 

placebo-controlled 

III. STUDY CHARACTERISTICS
 


13. Recruitment dates (mm/yy–mm/yy): 

NR 

14. Source of participants:

 clinic/office 

school 

 athletic team 

 other (describe) 

NR 

15. Run-in period? Yes NO [describe] 

16. No. of study days (i.e # screening/testing days) 17. No. of challenges per day 

18. Time between challenges:

 NR 

19. Exclusion criteria:

 NR 

20. Definition of EIA/EIB: ≥ 10% fall in FEV1 or PEF 

≥ 15% fall in FEV1 or PEF 

≥ 20 % fall in FEV1 or PEF 

 Reproducible EIA/EIB (no definition given) 

 Other (describe) e.g. self-report; physician diagnosed; symptoms etc. 

NR 

21. Please report the reference or comments made that supported the EIA/EIB definition they used (if any) we need to 

report this in a table for the funders. 

22. Exercise challenge: Inclined treadmill 

Bicycle ergometer 

 FRAST (Free Running Asthma 

Screening Test)

 Sport-specific challenge 

Other (describe) 

23. Duration of challenge 

6 minutes 

8 minutes 

 Other (describe) 

24. Temperature

 Room/ambient temperature 

25. Relative humidity 26. % of maximal heart rate / 

workload 

C-8 
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 Cold air 

 Other (describe) 

27. Other conditions reported 

IV. TREATMENT GROUPS 
 

Group A Group B Group C Group D Total 

28. Number of participants 

enrolled/randomized (n) 

29. Number of participants 

analyzed (n) 

30. Number of 

dropouts/withdrawals (n) 

31. Reasons for 

dropout/withdrawal 

INTERVENTIONS 

32. Drug 1: name 

33. Dose 1 

34. Delivery device 1: 

 Diskhaler (diskus)

 pMDI (MDI) 

Turbuhaler 

Spinhaler 

Nebulizer 

 Other (describe) 

35. Time 1: time med taken pre 

exercise (minutes) 

36. Drug 2: name 

37. Dose 2 

38. Delivery device 2:

 Diskhaler (diskus)

 pMDI (MDI) 

Turbuhaler 

Spinhaler 

Nebulizer 

 Other (describe) 

39. Time 2: time med taken pre 

exercise (minutes) 

40. Current asthma medications 

allowed to continue during 

testing: YES NO 

41. Which asthma medications 

were allowed 

42. Which asthma medications 

were discontinued pre 

challenge and how long 

before challenge 

V. BASELINE CHARACTERISTICS (when possible report data post run-in/pre-treatment) *Circle or describe units 

Indicate if no variance measure 

reported 

Group A Group B Group C Group D Total 

43. Age: years mean±SD; 

C-9 
 
 

 

 

 

 

 

mean±SE; median (range); 

IQR 

44. Males n (%) 

45. Participants had confirmed 

asthma: 

YES NO 

46. Baseline severity of asthma: 

mild/mod/severe or stable 

(Report authors words later we will convert to 

GINA guideline category) 

NR 

47. Atopic status: 

YES = to at least one allergen; 

NO=none were atopic 

Mix of atopy/no atopy 

(x%=yes; X%=no) 

(a positive skin prick test=atopic to 

at least 1) 

48. Baseline ICS history: 

NO=none on ICS 

YES=all on maintenance ICS 

mixed ICS use (x%= yes; 

X%= no) 

NR 

49. Baseline FEV1: L 

50. Baseline FEV1 % predicted 

51. mea/max % fall FEV1 

control / screening challenge 

mean±SD / SE; median(range); IQR 

52. Severity of EIB 

(mild/mod/severe) 

53. mean / max % fall PEF 

control / screening challenge 

mean±SD / SE; median(range); IQR 

54. Smoking Hx: 

never/past/current 

55. Other (describe) 

VI. REPORTED OUTCOMES (outcomes with data reported) circle or check outcome reported 

56. Primary outcome: 

OTHER OUTCOMES REPORTED 

57. FEV1: L 58. Individual patient data 

59. FEV1: Max % fall 60. Adverse events (I.e.) anaphylaxis. Had to d/c challenge 

etc. 

61. FEV1: change 62. Side effects 

63. FEV1: times measured 64. Time course of EIB (graph) 

65. PEF: L/min 66. Repeat tests on same day 

67. PEF: max % fall 68. Symptoms 

69. PEF: change 70. Rescue medication use 

71. PEF: times measured 72. Other (describe) 

73. % protection 74. Other (describe) 

75. Complete protection: 76. Other (describe) 

77. Clinical protection 78. Other (describe) 

C-10 
 
 

 

 

VII. ADVERSE EVENTS/SIDE EFFECTS 
 

Group A Group B Group C Group D Total 

Total reported 

VIII. CONCLUSIONS 

Describe conclusions: (Please, also describe such as: “Compared to B and C, A-----was-superior/inferior in ----”, or “There were 

no differences between A and B in -----, but B was superior/inferior to C”) 

ADDITIONAL COMMENTS 
 

79. 

C-11 
 
 

Quality Assessment Form: Diagnosis of EIB/EIA review, QUADAS 

1 The spectrum of patients was representative of the patients who 

would receive the test in practice. 

YES NO UNCLEAR 

2 Were selection criteria clearly defined? YES NO UNCLEAR 

3 Is the reference standard likely to classify the condition correctly? 

(Reference standard was specified as part of inclusion criteria) 

YES NO UNCLEAR 

4 Is the time period between reference standard and index test 

appropriate to be reasonably sure that the target condition did not 

change between the two tests? 

YES NO UNCLEAR 

5 Did the whole sample or a random selection of the sample, receive 

verification using a reference standard (partial verification bias)? 

YES NO UNCLEAR 

6 Did patients receive the same reference standard regardless of the 

index test results (differential verification bias)? 

YES NO UNCLEAR 

7 Was the execution of the index test described in sufficient detail to 

permit replication of the test? 

YES NO UNCLEAR 

8 Was the execution of the reference test described in sufficient detail 

to permit replication of the test? 

YES NO UNCLEAR 

9 Were the index test results interpreted without knowledge of the 

results of the reference standard? 

YES NO UNCLEAR 

10 Were the reference standard results interpreted without knowledge of 

the results of the index test? 

YES NO UNCLEAR 

11 Were the same clinical data available when index test results were 

interpreted as would be available when the test is used in practice? 

(Only applicable to self-reported history and self-reported symptoms 

diary) 

YES NO UNCLEAR 

12 Were uninterpretable/intermediate test results reported? YES NO UNCLEAR 

13 Were withdrawals from the study explained? YES NO UNCLEAR 

Guidelines for interpretation of QUADAS questions for EIB/EIA 

1. 	 Was the spectrum of participants representative of the patients who would receive the test in practice? 

Answer YES if 

- Unbiased recruitment methods: consecutively or randomly selected in a prospective way 

- Characteristics of participants are presented: Age, comorbidity (e.g., asthma), where they were 

recruited from (e.g., school, clinic, sport team, etc.), all have suspected EIB 

Answer NO if 
 

- Biased recruitment methods: volunteers, retrospective selection 
 

- Participants include those with confirmed (not suspected) EIB 
 

- Characteristics of participants are not reported
 


Answer UNCLEAR if 
 

- There is not enough relevant information to score either a Yes or No. 
 

2. 	 Were selection criteria clearly defined? 

Answer YES if 

- There is information on how participants were selected for inclusion including recruitment methods and 

inclusion/exclusion criteria (e.g., age, EIB status, setting (i.e., high school), recruitment method) 

Answer NO if 

- There is no information regarding recruitment methods and inclusion/exclusion criteria 

Answer UNCLEAR if 
 

- There is not enough relevant information to score either a Yes or No. 
 

3. 	 Is the reference standard likely to classify the condition correctly? 

Answer YES 

- Standardized exercise challenge (treadmill or cycle ergometry) that resulted in a drop of ≥ 10% in FEV1 

as being acceptable. 

- Age-specific heart rate achieved during exercise (>80% of predicted) 

- Exercise duration ≥ 6 min 

C-12 
 
-	 Post exercise measure interval is approximately 2 min (i.e., 1, 3, 5, 7min) 

Answer UNCLEAR if 
 

- The achieved age-specific HR or exercise duration are not mentioned 
 

- The achieved age-specific HR is mentioned but less than 80% 
 

- The exercise duration is mentioned but less than 6 min 
 

- Post exercise measure interval is longer than 2 min (i.e, 1, 4, 8m post exercise) 
 

4. 	 Is the time period between reference standard and index test appropriate to be reasonably sure that the target 

condition did not change between the 2 tests? 

Answer YES if 

- There was an acceptable delay between the 2 tests; doesn’t apply to self report and a 2nd test (mark as 

NA where self report is the comparison test) 

- We judged a time interval of at least 24 hours between tests as appropriate. 

Answer NO if 

- If the period between the 2 tests does not fall within the time interval 

Answer UNCLEAR if 

- There is not enough relevant information to score either a Yes or No. 

5. 	 Did the whole sample or a random selection of the sample, receive verification using a reference standard 

(partial verification bias)? 

Answer YES if 

- All participants received the reference test before receiving the index test; or 

- In cases where the index test is given prior to the reference test, either all participants go on to receive 

the reference test or a random sample of participants receive the reference test 

Answer NO if 

- Less than 90% of the participants who received the index test also received the reference test and the 

selection of this smaller group is based on a non-random method (such as results from the index test) 

Answer UNCLEAR if 

- There is not enough relevant information to score either a Yes or No 

6. 	 Did patients receive the same reference standard regardless of the index test results (differential verification)? 

Answer YES if 

- All participants received the same reference test 

Answer NO if 

- Some participants received verification of EIB using a different reference standard or some of the 

participants who received the index test did not have their true disease state verified. 

Answer UNCLEAR if 

- There is not enough relevant information to score either a Yes or No 

7. 	 Was the execution of the index test described in sufficient detail to permit replication of the test? 

Answer YES if ... 

- Details are provided about duration, dose, load, environmental conditions and other items relevant to 

the specific index test 

Answer NO if 

- There are no details about the execution of the index test. 

Answer UNCLEAR if 

- There is not enough relevant information to score either a Yes or No 

C-13 
 
8. Was the reference standard described in sufficient detail to permit replication of the test? 

Answer YES if 

- Information is reported on duration of challenge, % of maximal heart rate / workload, relative humidity, 

air temperature, or if a standardized protocol is referenced (i.e., AAS or similar). 

Answer NO if 

- There is no information about how the exercise challenge was conducted. 

Answer UNCLEAR if 

- There is not enough relevant information to score either a Yes or No 

9. Were the index test results interpreted without knowledge of the results of the reference standard? 

10.	 Were the reference standard results interpreted without knowledge of the results of the index test? 

Answer YES if 

- The authors stated explicitly that the results of the index test were interpreted blind to the results of the 

exercise challenge, and vice versa 

Answer NO if 

- If it does not seem likely that the test results were interpreted blind to the results of the other test 

Answer UNCLEAR if 

- It is not reported in the study 

11.	 Were the same clinical data available when test results were interpreted as would be available when the test is 

used in practice?(Applicable only to Self reported history and Self reported symptoms diary) 

Answer YES if 

- If the interpretation of the index test is fully automated and involves no interpretation 

- If the index test is interpreted with additional clinical data in the study, while these same clinical data will 

also be available when the index test is performed in practice 

- If the index test is interpreted without additional clinical data, and additional clinical data will also be 

unavailable when the index test is performed in practice 

Answer NO if 

- If the interpretation of the index test is not fully automated and involves interpretation components which 

can be influenced by additional clinical data 

- If the index test is interpreted with additional clinical data in the study, however, these clinical data will 

not be available when the index test is performed in practice 

- If the index test is interpreted without additional clinical data, however, additional clinical data will be 

available when the index test is performed in practice 

Answer UNCLEAR if 

- Not enough relevant information to score either a Yes or No 

12.	 Were uninterpretable/intermediate test results reported? 

Answer YES if 

- It is clear that all test results are reported 

Answer NO if 

- You suspect that uninterpretable/indeterminate/intermediate results occur but are not reported 

Answer UNCLEAR if 
 

- There is no mention of whether such results occurred or how they were handled
 


13.	 Were withdrawals from the study explained? 

Answer YES if 

- All the participants enrolled are accounted for (i.e., a flow chart or description of reasons for dropouts or 

withdrawals) 

Answer NO if 

- Some participants did not receive both tests and are not accounted for 

Answer UNCLEAR if 

- It is not clear whether all participants who entered the study were accounted for 

Note: We did not apply Item 7 (incorporation bias) from the original QUADAS tool as it does not apply to this review. 

C-14 
 
Quality Assessment Form: Therapy for EIB/EIA review (RCTs) 

Jadad scale 

YES NO 

1. Was the study described as randomized (this includes the use of words such as 1 0 

randomly, random and randomization)? 

2. Was the study described as double-blind? 1 0 

3. Was there a description of withdrawals and drop-outs? 1 0 

4. Method to generate the sequence of randomization was described and was appropriate 1 0 

(e.g. table of random numbers, computer generated, coin tossing, etc.) 

5. Method of double-blinding described and appropriate (identical placebo, active placebo, 1 0 

dummy) 

6. Method of randomization described and it was inappropriate (allocated alternately, -1 0 

according to date of birth, hospital number, etc.) 

7. Method of double-blinding described but it was inappropriate (comparison of tablet vs. -1 0 

injection with no double dummy) 

OVERALL SCORE (Maximum 5) 

Concealment of treatment allocation – Schulz 

Concealment of treatment allocation  Adequate 

 Inadequate 

 Unclear 

Adequate: e.g. central randomization; numbered/coded containers; drugs prepared by pharmacy; serially 

numbered, opaque, sealed envelopes 

Inadequate: e.g. alternation, use of case record numbers, dates of birth or day of week; open lists 

Unclear: Allocation concealment approach not reported or fits neither above category 

C-15 
 
 

 

 

 

 

 

 

 

Appendix D. Excluded Studies 

Diagnosis of EIB/EIA reviews 

402 studies were excluded from the diagnostic test accuray reviews. Reasons for exclusion 

include: study design (n=116), population (n=8), no reference standard (n=21), no comparison 

(n=46), did not diagnose EIA/EIB (n=158), insufficient data (n=26), other diagnostic tests 

(n=24), duplicate publication (n=2), and language (n=1). In addition, we were unable to obtain 

copies of 10 studies. 

Study Design (n = 116) 

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4. 	 Amirav I. Airway response to methacholine during 

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5. 	 Anderson SD, Argyros GJ, Magnussen H, Holzer 

K. Provocation by eucapnic voluntary hyperpnoea 

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D-1 
 
 

 

 

 

 

 

 

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30.	 D'Urzo AD. Hypercapnia during exercise in 

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41.	 Gerhard H, Schachter EN. Exercise-induced 

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42. 	 Godfrey S, Konig P. Exercise-induced bronchial 

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43. 	 Godfrey S, Koenig P. Exercise induced bronchial 

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44. 	 Godfrey S, Silverman M, Anderson SD. Problems 

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45. 	 Godfrey S. Proceedings: the clinical value of 

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46. 	 Godfrey S, Silverman M, Anderson SD. The use of 

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and the effect of varying the severity and duration 

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47.	 Goldberg S, Schwartz S, Izbicki G, et al. Sensitivity 

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48. 	 Gordon BR. Asthma history and presentation. 

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58. 	 Hurwitz KM, Argyros GJ, Roach JM, Eliasson AH, 

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Insufficient Data (n = 26) 

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6. 

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14
 

 

 

 

 

 

 

 

 

 

26. Wiens L, Sabath R, Scagliotti D, et al. The chest pain in children. J Allergy Clin Immunol 

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. 

D-15 
 
 

 

 

 

 

 

Duplicate Publication (n = 2)

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Suppl):908-9. 

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D-16 
 
 

 

 

 

 

 

 

 

Therapy for EIB/EIA review 

368 studies were excluded from the review. Reasons for exclusion include: study design (n=60), 

population (n=32), intervention (n=214), no comparison (n=2), outcome (n=1), language (n=38), 

insufficient data (n=12), and duplicate publication (n=9). We were not able to retrieve the reports 

of 15 studies. 

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D-17 
 

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D-19 
 
 

 

 

 

 

 

 

 

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9.	 Boye NP. Disodium cromoglycate and exercise 

induced airway obstruction. Tidsskr Nor 

Laegeforen 1973;93(12):840-2. 

10.	 Corrias A, Pelosi U, Corona GB, et al. [Efficacy of 

broxaterol vs salbutamol in asthma induced by 

physical exercise in children]. Pediatr Med Chir 

1989;11:161-3. Norwegian. 

11. 	 Cropp GJ, A. [Relative effectivity of inhalation of 

Isoprenalin and Disodium Chromoglycicum on 

exercise-induced asthma]. Monatsschr Kinderheilkd 

1976;124:234-7. German. 

12. 	 Dal CG, Martinati L, Mingoni S, et al. [Salbutamol 

powder, administered via a multidose and a singledose powder inhaler, in the prevention of exerciseinduced asthma in children]. Rev Bras Med 

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13. 	 Debelic M, Stechert R. [Exercise-induced asthma— 

protection with disodium cromoglycate alone and in 

combination with fenoterol]. Monatsschr 

Kinderheilkd 1988;136(8):448-52. German. 

14.	 Delnitz D, Rozniecki J, Grabski W. [Comparative 

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15.	 Delnitz D, Rozniecki J. [Pharmacological 

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16. 	 Fu YX, Ye ST, Xia LY. [The effect of sodium 

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17. 	 Gehrke I, Bohm E, Sybrecht GW. [Stress-induced 

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18. 	 Gmur H, Scherrer M. [Protection from exertioninduced bronchial asthma with disodium 

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with ketotifen zaditen. Doubly crossed double-blind 

study]. Schweiz Med Wochenschr 1979;109:881-4. 

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19. 	 Guerin JC, Flandrois R. [A study of berodual 

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D-30 
 
 

 

 

20.	 Guerin JC, Brambilla C, Godard P, et al. [Prolonged 

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21. 	 Hertz B, Fuglsang G, Holm EB. [Exercise-induced 

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1994;156(39):5693-5. Danish. 

22. 	 Jenssen AO. [Broncholytic effects of salbutamol 

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exercise]. Tidsskr Nor Laegeforen 

1972;92(16):1104-7. Norwegian. 

23. 	 Joppich R. [Comparison of the effects of reproterol, 

oxitropium bromide, disodium cromoglycate and 

theophylline in the prevention of exercise-induced 

asthma in children]. Atemwegs- und 

Lungenkrankheiten 1987;13(9):453-6. German. 

24. 	 Koenig P, Abramov A, Godfrey S. [Exerciseinduced asthma as an objective criterion for
 


assessing response to disodium cromoglycate]. 
 

Harefuah 1971;81(3):127-30. Hebrew. 
 

25.	 Lecheler J, Biberger A, Seligmann C, et al. [Sports 

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training]. Prax Klin Pneumol 1988;42(7):475-8. 

German. 

26. 	 Magnussen H, Reuss G. [Blockade of exercise-
 

induced bronchial asthma by fenoterol]. Klin
 


Wochenschr 1984;62(4):168-74. German. 
 

27. 	 Negele K, Stein D, Grubl A, Bauer CP. [Value of 

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28. 	 Petrov VI, Smolenov IV, Alikova OA, et al. [Stepby-step management of bronchial asthma children: 

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Russian. 

29. 	 Rampulla C, Bruschi C, Zoia MC. [Calciumantagonists and exercise-induced 

bronchoconstriction (EIB): immediate and late 

effects of nifedipine, in comparison with salbuamol 

and DSCG]. Folia Allergologica et Immunologica 

Clinica 1985;32(4):271-7. Italy. 

Insufficient Data (n = 12) 

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30. 	 Scherrer M, Zeller C, Kyd K, Geiser M. 

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31. 	 Sienra Monge JJ, Bermejo Guevara MA, Espinola 

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32. 	 Sin HL, Jae JS, Sang YL, et al. [The protective 

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and furosemide on exercise-induced asthma]. 

Zhonghua Jie He He Hu Xi Za Zhi 

1998;45(6):1188-98. Korean. 

33. 	 Spada EL, Donner CF, Meriggi A, Vecchio C. 

[Pharmacologic prevention of exercise-induced 

asthma]. Minerva Pneumol 1985;24(2):159-64. 

Italy. 

34. 	 Stemmann EA, Weihermann D, Schachoff R. 

[Prophylactic treatment of exercise-induced 

asthma]. Med Welt 1981;32(24):981-4. German. 

35. 	 Todaro A, Rossi A. [Formoterol for the treatment of 

the asthmatic athletes]. Med Sport (Roma) 

2002;55(3):189-94. Italian. 

36. 	 Vazquez C, Fidalgo I, Virto MC, et al. 

[Effectiveness of disodium cromoglycate, 

salbutamol, and ipratropium bromide in the 

inhibition of exercise-induced bronchospasm]. An 

Esp Pediatr 1984;20(8):756-62. Spanish. 

37. 	 Viallat JR, Razzouk H, Boutin C. [A double-blind 

study of sodium chromoglycate preventive effect of 

sodium chromoglycate on children with postexercise asthma]. Rev Mal Respir 1985;2(2):111. 

French. 

38. 	 von Berg A, Albrecht B, Darlath W, et al. 

[Intraindividual randomised double-blind 

comparison between sodium cromoglycate and 

reproterol to assess the protective effect of the 

single drugs and their combination in children with 

exercise induced asthma]. Allergologie 

2002;25(11):557-64. German. 

2. 	 Coreno AJ, Skowronski ME, Kotaru C, et al. 

Comparative effects of single doses of antileukotrienes and long acting b2- agonists on 

exercise induced asthma (EIA) [abstract]. Am J 

Respir Crit Care Med 2000;161(3 Suppl):A613. 

D-31 
 
 

 

3. 	 Filipovic M, Kamenov S, Kamenov B, et al. 

Comparative efficacy of cromolyn and salbutamol 

in exercise induced asthma. Eur Respir J Suppl 

1999;14(Suppl 30):1385. 

4. 	 Hartley JPR, Davies BH, Nogrady SG. The effect of 

anticholinergic and H1 receptor blockade on 

exercise-induced asthma. Br J Dis Chest 

1980;74:315-6. 

5. 	 Johnson CE, Belfield PW, Davis S, et al. Platelet 

activation during exercise induced asthma: effect of 

prophylaxis with cromoglycate and salbutamol. 

Thorax 1986;41(4):290-4. 

6. 	 Kendall MJ. The Problem of salmeterol. University 

Hospital Birmingham NHS Trust 2001 Mar 

14;14/03/2002 End date(Unknown):Complete. 

7. 	 Lee T, Mant T, Amin D, et al. A single dose (4 mg) 

of CFC-free nedocromil sodium is effective against 

exercise-induced bronchoconstriction (EIB) in 

asthmatic volunteers [abstract]. Eur Respir J Suppl 

1997;10(Suppl 25):128S. 

8.	 Ostrom N, Bronsky E, Pearlman D, et al. Effects of 

the leukotriene-receptor antagonist zafirlukast on 

exercise-induced asthma in pediatric subjects 

[abstract]. Eur Respir J Suppl 1997;10(Suppl 

25):276S. 

9. 	 Pearlman D, Greos L, Olson G, et al. A single-dose 

efficacy comparison of albuterol-HFA-BOI and 

albuterol-HFA-MDI in adolescents and adults with 

exercise-induced bronchospasm (EIB) [abstract]. 

American Thoracic Society 2005 International 

Conference; May 20-25; San Diego, California 

2005;B36. 

10.	 Pearlman DS, Ostrom NK, Bronsky EA, et al. 

Efficacy and safety of zafirlukast (Accolate®) in 

pediatric patients with exercise-induced asthma. 

Ann Allergy Asthma Immunol 1997;78:113. 

11. 	 Shapiro GG, DuHamel TR, Wighton TG, et al. The 

childhood asthma management program (CAMP): 

design, rationale, and methods. Control Clin Trials 

1999;20(1):91-120. 

12. 	 Weiner P, Greif J, Fireman E, et al. Bronchodilating 

effect of cromolyn sodium in asthmatic patients at 

rest and following exercise. Ann Allergy 

1984;53(2):186-8. 

D-32 
 
 

 

 

 

 

 

 

 

 

Duplicate Publication (n = 9)

 1.	 De Benedictis FM, Tuteri G, Niccoli A, et al. The 

protective effect and the duration of action of 

cromolyn and nedocromil sodium on exercise-induced 

asthma in children [abstract]. Eur Respir J Suppl 

1994;7(Suppl 18):140S. 

2. 	 Godfrey S, Konig P. Suppression of exercise-induced 

asthma by salbutamol, theophylline, atropine, 

cromolyn, and placebo in a group of asthmatic 

children. Pediatrics 1975;56(5 suppl):930-4. 

3. 	 Hancox RJ, Subbarao P, Kamada D, et al. Betaagonist tolerance and exercise-induced bronchospasm. 

Am J Respir Crit Care Med 2002;165(Suppl 8):A185. 

4. 	 Hancox RJ, Subbarao P, Kamada D, et al. Beta2­

agonist tolerance and exercise-induced bronchospasm. 

Am J Respir Crit Care Med 2002;165(8 Suppl):A185. 

5. 	 Johnson O, van Adelsberg J, Pearlman DS, et al. 

Onset and duration of single-dose protection of 

montelukast against exercise-induced bronchospasm 

[abstract]. J Allergy Clin Immunol 2005;115(2 

Suppl):S11. 

Unable to Retrieve (n = 13) 

1. Bach-Mortensen N, Bundgaard A, Schmidt A. 

Ipratropium (Atrovent) treatment (alone and in 

combination) in children with exercise-induced 

asthma. Postgrad Med J 1987;63(Suppl 1):11A. 

2. 	 Cooper DM, Atlas AB. Effectiveness of single dose 

pre-exercise treatment with montelukast in children 

with exercise induced asthma [abstract]. American 

Thoracic Society 100th International Conference, 

May 21-26, 2004, Orlando 2004;A53. 

3. 	 Dinh Xuan AT, Campagnon A, Summerton L, et al. 

Attenuation of exercise-induced asthma but not 

exercise induced increases in exhaled oxide output 

by zafirlukast (AccolateTM) [abstract]. Am J Respir 

Crit Care Med 1998;157(3 Suppl):A624. 

4. 	 Flynn D. Proposal for a series of n of 1 trials of the 

bronchodilator effect of the Leucotriene receptor 

antagonist (LTRA) montelukast (ML) in childhood 

asthma. Barking, Havering and Redbridge Hospitals 

NHS Trust 2003. 

5.	 GlaxoSmithKline. A study to determine the 

duration of action of inhaled salmeterol during 

exercise challenge tests in asthmatic children. 

[Internet] 2005 July. [Cited 2009 Sept 3]. Available 

from: http://www.clinicaltrials.gov/ 

ct2/show/NCT00118690. 

6.	 Patel KR, Tullett WM, Neale MG, et al. Plasma 

concentrations of sodium cromoglycate given by 

nebulisation and metered dose inhalers in patients with 

exercise-induced asthma: relationship to protective 

effect. Br J Clin Pharmacol 1986;21(2):231-3. 

7. 	 Pearlman DS, Philip G, Johnson O, et al. Protection 

against exercise-induced bronchospasm by a single 

dose of montelukast [abstract]. American Thoracic 

Society 2005 International Conference; May 20-25; 

San Diego, California 2005;B36. 

8.	 Peroni DG, Piacentini GL, Ress M, et al. Time 

efficacy of a single dose of montelukast on exerciseinduced asthma in children. Pediatr Allergy Immunol 

2002;13(6):434-7. 

9.	 Rachelefsky GS, Tashkin DP, Katz RM, et al. A 

Comparison of aerosolized atropine, isoproterenol, 

atropine plus isoproterenol, disodium cromoglycate 

and placebo in the prevention of exercise-induced 

asthma. Chest 1978;73(6 Suppl):1017-9. 

6. 	 Gronnerod TA, Hamre HS, Oepen G, et al. 

Protective effect of single doses of formoterol 

turbuhaler® 4.5 microgramm and 9 microgramm in 

children with exercise-induced bronchoconstriction. 

Eur Respir J Suppl 1999;14(Suppl 30):352. 

7.	 Kim JH, Kim BS, Choi SO, et al. Clinical and 

bronchoprotective effects of montelukast in children 

with exercise-induced asthma [abstract]. American 

Thoracic Society 99th International Conference 

2003;B036. 

8.	 Morgan M. A comparison of the efficiency of 

Salmeterol xinofoate with oral salbutamol 

controlled release against exercise induced asthma 

in adult asthmatics. University Hospitals of 

Leicester NHS Trust 1994. 

9.	 Pearlman DS, Rees W, Huang H, et al. An 

evaluation of levalbuterol HFA in the prevention of 

exercise-induced brochospasm [abstract]. Chest 

2006;130(4):163S. 

10. 	 Richter K, Jorres RA, Janicki S, et al. Protection 

against exercise-induced asthma by the inhaled 

luekotriene D4-receptor antagonist bay X7195 

[abstract]. Am J Respir Crit Care Med 1998;157(3 

Suppl):A409. 

D-33 
 
 

 

11. 	 Silverman M. Management of asthma in 

schoolchildren: role of montelukast and salmeterol 

at step 3 of the BTS guidelines: a double blind 

randomised controlled trial using exercise induced 

asthma as outcome. To compare the efficacy of two 

medications currently used for persistent exercise 

induced asthma in school children 2000. 

12. 	 Thio BJ, Slingerland GLM, Nagelkerke AF, et al. 

Single high dose inhaled fluticasone propionate 

(FP) reduces exercise induced bronchial obstruction 

(EIB). Am J Respir Crit Care Med 1998;157(3 

Suppl):A710. 

13. 	 West J. A secondary care based study to examine 

the effect of salmeterol vs. salbutamol in exercise 

induced asthma in children 1998. 

D-34 
 
 

 

 

 

 

Appendix E. Studies Investigating Mast Cell 

Stabilizing Agents 

The following 44 studies were included in three systematic reviews and two subsequent 

publications that investigated mast cell stabilizing agents.72-75 Six of the studies in this list 

addressed one or more of the other key questions of this current report; they have been marked 

with an asterisk (*). Nine studies did not meet the inclusion criteria for this current report; most 

were excluded because they were not published in English or were not randomized controlled 

trials. These studies have been marked with a †. 

1. 	 Boner AL, Vallone G, Bennati D. Nedocromil 11. 	 Comis A, Valletta EA, Sette L, et al. Comparison of 

sodium in exercise-induced bronchoconstriction in nedocromil sodium and sodium cromoglycate 

children. Ann Allergy 1989;62(1):38-41. administered by pressurized aerosol, with and 

without a spacer device in exercise-induced asthma 2.	 Boner AL, Miglioranzi P, Piacentini G, et al. in children. Eur Respir J 1993;6(4):523-6. Effects of nedocromil sodium pressurized aerosol 

on exercise challenge using a spacer device and the 12. 	 De Benedictis FM, Tuteri G, Niccoli A, et al. The 

normal adapter. Pediatr Asthma Allergy Immunol effect of cromolyn sodium and nedocromil sodium 

1988;2(3):207-15. administered by a pressurized aerosol with a spacer 

device on exercise-induced asthma in children. *3. 	 Boulet LP, Turcotte H, Tennina S. Comparative Mediators Inflamm 1994;3(Suppl 1):S35-7. efficacy of salbutamol, ipratropium, and 

cromoglycate in the prevention of bronchospasm 13.	 De Benedictis FM, Tuteri G, Bertotto A, et al. 

induced by exercise and hyperosmolar challenges. J Comparison of the protective effects of cromolyn 

Allergy Clin Immunol 1989;83(5):882-7. sodium and nedocromil sodium in the treatment of 

exercise-induced asthma in children. J Allergy Clin 4. 	 Bundgaard A, Enehjelm SD, Schmidt A. A Immunol 1994;94(4):684-8. comparative study of the effects of two different 

doses of nedocromil sodium and placebo given by 14.	 De Benedictis FM, Tuteri G, Pazzelli P, et al. 

pressurised aerosol in exercise-induced Cromolyn versus nedocromil: duration of action in 

bronchoconstriction. Allergy 1988;43(7):493-6. exercise-induced asthma in children. J Allergy Clin 

Immunol 1995;96(4):510-4. *5. 	 Bundgaard A, Rasmussen FV, Madsen L. 

† Pretreatment of exercise-induced asthma in adults 15.	 De Benedictis FM, Tuteri G, Pazzelli P, et al. 

with aerosols and pulverized tablets. Allergy Combination drug therapy for the prevention of 1980;35(8):639-45. exercise-induced bronchoconstriction in children. 

Ann Allergy Asthma Immunol1998;80(4):352-6. 6. 	 Bundgaard A, Buch D, Schmidt A, et al. 

Pretreatment of exercise-induced asthma in children 16. 	 Debelic M. Nedocromil sodium and exerciseusing disodium cromoglycate and fenoterol induced asthma in adolescents. Eur J Respir Dis inhalation powder. Eur J Respir Dis Suppl 1986;69(Suppl 147):266-7. 1983;130:36-41. 

17. 	 Debelic M, Hertel G, Konig J. Double-blind 7. 	 Bundgaard A, Schmidt A. Pretreatment of exercise- crossover study comparing sodium cromoglycate, induced asthma by disodium cromoglycate and reproterol, reproterol plus sodium cromoglycate, fenoterol. Eur J Respir Dis Suppl 1983;128(Pt and placebo in exercise-induced asthma. Ann 2):521-5. Allergy 1988;61(1):25-9. 

8. 	 Bundgaard A. Exercise-induced asthma. Eur J 
 *18. 	 Dorward AJ, Patel KR. A comparison of ketotifen Respir Dis 1980;68(Suppl 143):51-6. 
 with clemastine, ipratropium bromide and sodium 

cromoglycate in exercise-induced asthma. Clin 9. 	 Chudry N, Correa F, Silverman M. Nedocromil 
 Allergy 1982;12(4):355-61. sodium and exercise induced asthma. Arch Dis
 


Child 1987;62(4):412-4. 
 †

19. Gehrke I, Bohm E, Sybrecht GW. [Stress-induced 

10. 	 Clarke PS, Ratowsky DA. Effect of fenoterol asthma--placebo-controlled double-blind 

hydrobromide and sodium cromoglycate comparison of prevention using fenoterol, disodium 

individually and in combination on postexercise cromoglycate and a combination of the two]. Prax 

asthma. Ann Allergy 1990;64(2 Pt 2):187-90. Klin Pneumol 1986;40(4):129-34. German. 

E-1 
 
 

 

 

 

 

†

20. Godfrey S, Konig P. Suppression of exerciseinduced asthma by salbutamol, theophylline, 

atropine, cromolyn, and placebo in a group of 

asthmatic children. Pediatrics 1975;56(5 

Suppl):930-4. 

*21. 	 Godfrey S, Konig P. Inhibition of exercise-induced 

asthma by different pharmacological pathways. 

Thorax 1976;31(2):137-43. 

22. Henriksen JM. Effect of nedocromil sodium on 
 

exercise-induced bronchoconstriction in children.
 

Allergy 1988;43(6):449-53. 
 

23. 	 Konig P, Hordvik NL, Kreutz C. The preventive 

effect and duration of action of nedocromil sodium 

and cromolyn sodium on exercise-induced asthma 

EIA in adults. J Allergy Clin Immunol 

1987;79(1):64-8. 

24. 	 Morton AR, Ogle SL, Fitch KD. Effects of 
 

nedocromil sodium, cromolyn sodium, and a 
 

placebo in exercise-induced asthma. Ann Allergy 
 

1992;68(2):143-8. 
 

*25. 	 Neijens HJ, Wesselius T, Kerrebijn KF. Exerciseinduced bronchoconstriction as an expression of 

bronchial hyperreactivity: a study of its mechanisms 

in children. Thorax 1981;36(7):517-22. 

26. 	 Novembre E, Frongia G, Lombardi E, et al. The 

preventive effect of nedocromil or furosemide alone 

or in combination on exercise-induced asthma in 

children. J Allergy Clin Immunol 1994;94(2 Pt 

1):201-6. 

27. 	 Novembre E, Frongia GF, Veneruso G, et al. 

Inhibition of exercise-induced-asthma EIA by 

nedocromil sodium and sodium cromoglycate in 

children. Pediatr Allergy Immunol 1994;5(2):107­

10. 

28.	 Obata T, Matsuda S, Akasawa A, et al. Preventive 

effect and duration of action of disodium 

cromoglycate and procaterol on exercise-induced 

asthma in asthmatic children. Ann Allergy 

1993;70(2):123-6. 

29. 	 Oseid S, Mellbye E, Hem E. Effect of nedocromil 

sodium on exercise-induced bronchoconstriction 

exacerbated by inhalation of cold air. Scand J Med 

Sci Sports 1995;5(2):88-93. 

†

30. Pichaipat V, Tongpenyai Y, Nerntong T, et al. The 

protective effect of inhaled terbutaline, sodium 

cromoglycate and budesonide on exercise-induced 

asthma in children. J Med Assoc Thai 

1995;78(10):505-8. 

31. 	 Roberts JA, Thomson NC. Attenuation of exerciseinduced asthma by pretreatment with nedocromil 

sodium and minocromil. Clin Allergy 

1985;15(4):377-81. 

†

32. 

33.	 

34.	 

†

35. 

†

36. 

37. 	 

*38. 	 

39. 	 

*40. 	 

†

41. 

42. 	 

43. 	 

44. 	 

E-2 
 

Rohr AS, Siegel SC, Katz RM, et al. A comparison 

of inhaled albuterol and cromolyn in the 

prophylaxis of exercise-induced bronchospasm. 

Ann Allergy 1987;59(2):107-9. 

Shaw RJ, Kay AB. Nedocromil, a mucosal and 
 

connective tissue mast cell stabilizer, inhibits
 

exercise-induced asthma. Br J Dis Chest 
 

1985;79(4):385-9. 
 

Sinclair DG, Winfield CR. Attenuation of exercise 

induced asthma by nedocromil sodium and sodium 

cromoglycate. J R Army Med Corps 

1990;136(2):105-6. 

Spada EL, Donner CF, Meriggi A, et al. 
 

[Pharmacologic prevention of exercise-induced
 

asthma]. Minerva Pneumol 1985;24(2):159-64. 
 

Italian. 
 

Svenonius E, Arborelius M, Wiberg R, et al. A 

comparison of terbutaline inhaled by Turbuhaler 

and by a chlorofluorocarbon CFC inhaler in 

children with exercise-induced asthma. Allergy 

1994;49(6):408-12. 

Thomson NC, Roberts JA. Nedocromil sodium 

attenuates exercise-induced asthma. Eur J Respir 

Dis 1986;69(Suppl 147):297-8.

Thomson NC, Patel KR, Kerr JW. Sodium 

cromoglycate and ipratropium bromide in exerciseinduced asthma. Thorax 1978;33(6):694-9. 

Todaro A, Faina M, Alippi B, et al. Nedocromil
 

sodium in the prevention of exercise-induced 
 

bronchospasm in athletes with asthma. J Sports 
 

Med Phys Fitness 1993;33(2):137-45. 
 

Tullett WM, Patel KR, Berkin KE, et al. Effect of 

lignocaine, sodium cromoglycate, and ipratropium 

bromide in exercise-induced asthma. Thorax 

1982;37(10):737-40. 

Vazquez C, Fidalgo I, Virto MC, et al. 

[Effectiveness of disodium cromoglycate, 

salbutamol, and ipratropium bromide in the 

inhibition of exercise-induced bronchospasm]. An 

Esp Pediatr 1984;20(8):756-62. Spanish. 

Vilsvik J, Schaanning J. A comparative study of the 

effect of three doses of nedocromil sodium and 

placebo given by pressurized aerosol to asthmatics 

with exercise-induced bronchoconstriction. Ann 

Allergy 1988;61(5):367-70. 

Woolley M, Anderson SD, Quigley BM. Duration 

of protective effect of terbutaline sulfate and 

cromolyn sodium alone and in combination on 

exercise-induced asthma. Chest 1990;97(1):39-45. 

Zanconato S, Baraldi E, Santuz P, et al. Effect of 

inhaled disodium cromoglycate and albuterol on 

energy cost of running in asthmatic children. 

Pediatr Pulmonol 1990;8:240-4. 
 

 

 

 

 

 

 

The following 33 studies investigated mast cell stabilizing agents but were not included 

in three previous systematic reviews. 

1. 	 Bar-Yishay E, Gur I, Levy M, et al. Duration 

of action of sodium cromoglycate on exercise 

induced asthma: comparison of 2 formulations. 

Arch Dis Child 1983;58(8):624-7. 

2. 	 Bauer CP. The protective effect of nedocromil 

sodium in exercise-induced asthma. Eur J 

Respir Dis 1986;69(Suppl 147):252-4. 

3. 	 Ben-Dov I, Bar-Yishay E, Godfrey S. 

Heterogeneity in the response of asthmatic 

patients to pre-exercise treatment with 

cromolyn sodium. Am Rev Respir Dis 

1983;127(1):113-6. 

4. 	 Bianco S, Moavero E, Robuschi M, et al. 

Prevention of PGF2alpha induced 

bronchoconstriction by disodium cromoglycate 

in asthmatic patients. IRCS Med Sci Clin Med 

1976;4(4):147. 

5. 	 Brooks CD, Nelson AL, Metzler C. 

Attenuation of protection with repeated 

cromolyn dosing before exercise challenge in 

subjects with asthma. J Clin Pharmacol 

1986;26(2):91-6. 

6. 	 Bundgaard A, Bach-Mortensen N, Schmidt A. 

The effect of sodium cromoglycate delivered 

by Spinhaler and by pressurized aerosol on 

exercise-induced asthma in children. Clin 

Allergy 1982;12(6):601-5. 

7. 	 Calvayrac P, Leophonte P, Fuseiller A, et al. 

Reduction of bronchial hyperreactivity and 

exercise-induced bronchospasm in children 

treated for one month with a pressurized 

sodium cromoglycate aerosol. Curr Ther Res 

Clin Exp 1991;49(3):422-35. 

8. 	 Corkey C, Mindorff C, Levison H, et al. 

Comparison of three different preparations of 

disodium cromoglycate in the prevention of 

exercise-induced bronchospasm: a doubleblind study. Am Rev Respir Dis 

1982;125(6):623-6. 

9. 	 Dahl R, Henriksen JM. Effect of oral and 

inhaled sodium cromoglycate in exerciseinduced asthma. Allergy 1980;35(4):363-5. 

10.	 Dahl R, Henriksen JM. Inhibition of exerciseinduced bronchoconstriction by nebulised 

sodium cromoglycate in patients with 

bronchial asthma. Scand J Respir Dis 

1979;60(2):51-5. 

11. 	 De Cree J, Verhaegen H, Geukens H, et al. 
 

Exercise-induced asthma. The comparative 
 

acute effects of oxatomide, placebo and
 

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