Chest
Volume 138, Issue 2, Supplement, August 2010, Pages 25S-30S
Journal home page for Chest

Airway Hyperresponsiveness in Asthma: Its Measurement and Clinical Significance
Indirect Challenge Tests: Airway Hyperresponsiveness in Asthma: Its Measurement and Clinical Significance

https://doi.org/10.1378/chest.10-0116Get rights and content

Indirect challenges cause the release of endogenous mediators that cause the airway smooth muscle to contract and the airways to narrow. Airway sensitivity to indirect challenges is reduced or even totally inhibited by treatment with inhaled corticosteroids (ICS), so a positive response to an indirect stimulus is believed to reflect active airway inflammation. The indirect challenges commonly used in pulmonary function laboratories include exercise, eucapnic voluntary hyperpnea, hypertonic (4.5%) saline, and mannitol. Exercise was the first test to be standardized and was used to identify exercise-induced bronchoconstriction (EIB). The inhibition of EIB in young children by sodium cromoglycate led to the concept that mast cells were important very early in the onset of asthma. All of these indirect challenges are associated with the release of mast cell mediators (eg, prostaglandins, leukotrienes, and histamine). The hypertonic saline and mannitol challenges arose from the concept that EIB was caused by an increased osmolarity of the airway surface with release of mediators. These osmotic aerosols simplified testing with indirect challenges in the laboratory, improving the potential to identify currently active asthma. Although hyperresponsiveness to indirect challenges is frequently associated with a sputum eosinophilia, it is not a prerequisite because the mast cell is the most important source of mediators. The mechanism for ICS reducing hyperresponsiveness to indirect challenges likely involves both mast cells and eosinophils. Indirect challenges are appropriate to inform further on both the pathogenesis of asthma and the role of antiinflammatory agents in its treatment.

Section snippets

Exercise as a Test of Bronchial Hyperresponsiveness

Exercise was the first indirect challenge test to be standardized.5 It was developed because the mast cell-stabilizing drug sodium cromoglycate (SCG) could not be evaluated for asthma using either a histamine or a methacholine challenge. Allergen, the indirect challenge being used at the time, was considered inappropriate because of its potential to cause a late asthmatic response. Exercise is a common stimulus for provoking bronchoconstriction, and guidelines usually include exercise tolerance

Surrogates for Identifying BHR to Inflammatory Mediators of EIB

The EVH test breathing dry air (∼5% CO2, 21% oxygen, balance nitrogen) for 6 min at a ventilation target of 30 × FEV1 was initially standardized to evaluate army recruits for asthma16 and later to identify EIB in elite athletes.17 Field exercise at 2°C was compared with EVH in the laboratory at 19.4°C and responses were found to be equivalent for most winter athletes.18 EVH can provoke severe falls in FEV1, so its use is confined to evaluate those who regularly exercise at high intensities. The

Interpretation of a Mannitol Test Result

Mannitol is used to assess BHR to aid in the diagnosis of asthma. A positive test result to mannitol is consistent with the presence of inflammatory cells (eg, eosinophils and/or mast cells) and their mediators (eg, prostaglandins, leukotrienes, and histamine). Therefore, mannitol is most useful as a test to confirm a diagnosis of currently active asthma in a treated or untreated subject.32, 33 This gives it an advantage over methacholine. Methacholine is also indicated for the diagnosis of BHR

Acknowledgments

Financial/nonfinancial disclosures: The author has reported to CHEST the following conflicts of interest: Dr Anderson is the inventor of the mannitol test. The patent is owned by her employer, Sydney South West Area Health Service (SSWAHS). SSWAHS invoiced Pharmaxis for her time until March 2009. She has not received monies from Pharmaxis other than to cover traveling expenses. Since March 2009, she has received consulting fees. She own shares in Pharmaxis that she purchased herself. She does

References (49)

  • PJ Franklin et al.

    Measuring exhaled nitric oxide levels in adults: the importance of atopy and airway responsiveness

    Chest

    (2004)
  • HO Koskela et al.

    Sensitivity and validity of three bronchial provocation tests to demonstrate the effect of inhaled corticosteroids in asthma

    Chest

    (2003)
  • GF Joos et al.

    Indirect airway challenges

    Eur Respir J

    (2003)
  • SD Anderson et al.

    Methods for “indirect” challenge tests including exercise, eucapnic voluntary hyperpnea and hypertonic aerosols

    Clin Rev Allergy Immunol

    (2003)
  • J Van Schoor et al.

    Indirect bronchial hyperresponsiveness: the coming of age of a specific group of bronchial challenges

    Clin Exp Allergy

    (2005)
  • Global Initiative for Asthma

    Global strategy for asthma and management and prevention

  • M Silverman et al.

    Standardization of exercise tests in asthmatic children

    Arch Dis Child

    (1972)
  • RO Crapo et al.

    Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999

    Am J Respir Crit Care Med

    (2000)
  • S Godfrey et al.

    Cut-off points defining normal and asthmatic bronchial reactivity to exercise and inhalation challenges in children and young adults

    Eur Respir J

    (1999)
  • MM Haby et al.

    An exercise challenge for epidemiological studies of childhood asthma: validity and repeatability

    Eur Respir J

    (1995)
  • P Ernst et al.

    Risk factors for bronchial hyperresponsiveness in late childhood and early adolescence

    Eur Respir J

    (2002)
  • S O'Sullivan et al.

    Evidence for mast cell activation during exercise-induced bronchoconstriction

    Eur Respir J

    (1998)
  • HC Haverkamp et al.

    Repeat exercise normalizes the gas-exchange impairment induced by a previous exercise bout in asthmatic subjects

    J Appl Physiol

    (2005)
  • TS Hallstrand et al.

    Inflammatory basis of exercise-induced bronchoconstriction

    Am J Respir Crit Care Med

    (2005)
  • Cited by (0)

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

    View full text