Review and Feature Article
Airway Hyperresponsiveness in Asthma: Measurement and Clinical Relevance

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Airway hyperresponsiveness is a characteristic feature of asthma, and its measurement is an important tool in its diagnosis. With a few caveats, methacholine bronchial provocation by a 2-minute tidal breathing method is highly sensitive; a negative test result (PC20 > 16 mg/mL, PD20 > 400 μg) rules out current asthma with reasonable certainty. A PC20 value of less than 1 mg/mL/PD20 value of less than 25 μg is highly specific (ie, diagnostic) but quite insensitive for asthma. For accurate interpretation of the test results, it is important to control and standardize technical factors that have an impact on nebulizer performance. In addition to its utility to relate symptoms such as cough, wheeze, and shortness of breath to variable airflow obstruction (ie, to diagnose current asthma), the test is useful to make a number of other clinical assessments. These include (1) evaluation of patients with occupational asthma, (2) evaluation of patients with exercise-induced respiratory symptoms, (3) evaluation of novel asthma medications, (4) evaluation of relative potency of inhaled bronchodilators, (5) as a biomarker to adjust anti-inflammatory therapy to improve clinical outcomes, and (6) in the evaluation of patients with severe asthma to rule out masqueraders such as laryngeal dysfunction. The actual mechanism of altered smooth muscle behavior in asthma that is assessed by direct (eg, methacholine) or indirect (eg, allergen) bronchial provocation remains one of the most fundamental questions related to asthma that needs to be determined. The test is underutilized in clinical practice.

Section snippets

Introduction (by Paul M. O'BYRNE and Parameswaran Nair)

In 1945, Tiffeneau and Beauvallet1 reported, for the first time, the use of inhaled acetylcholine to measure airway responsiveness in patients with asthma. Subsequently, Curry2 demonstrated that patients with asthma developed bronchoconstriction after administration of intramuscular, intravenous, or nebulized histamine. This increased bronchoconstrictor response in patients with asthma was labeled “airway reactivity,” which was described as nonspecific, because the increased responses occurred

The Contributions of Airway Smooth Muscle to Airway Responsiveness (by James G. Martin)

Airway smooth muscle is the principal tissue mediating airway narrowing and not surprisingly has been a target of pharmacological therapy since the earliest times. Inhaled methacholine acts principally to cause airway narrowing by activation of muscarinic receptors on the smooth muscle of the airways. The degree of airway narrowing in response to stimulation of smooth muscle by methacholine and other bronchoconstrictive substances is a function of the force generated by the contracting muscle

Measurement of AHR (by Donald W. Cockcroft)

Airway hyperresponsiveness (AHR), an objective measure of variable airflow obstruction, is measured using provocation tests with chemical (histamine, methacholine, adenosine monophosphate [AMP], mannitol, etc) or physical (exercise or its surrogate eucapnic voluntary hyperpnea [EVH]) stimuli.21 Bronchoprovocation is recommended as a diagnostic investigation in subjects with symptoms (possibly asthmatic) and normal flow rates. Stimuli used to measure AHR have been categorized as direct or

Technical Factors in the Assessment of AHR (by Myrna Dolovich)

The assessment of AHR involves the inhalation of a challenge aerosol produced via liquid nebulization with a specific breathing pattern to administer the drug.41 These components are influenced by a number of technical factors that can alter the generation and delivery of aerosol to the lung. Although liquid aerosols of histamine and methacholine have been the choice pharmaceutic, recent developments have produced and successfully tested a dry powder formulation of methacholine, inhaled via a

Assessment of Airway Responsiveness to Manage Occupational Asthma (by Catherine Lemiere)

The diagnosis of occupational asthma (OA) requires a comprehensive investigation involving the performance of different and complementary tests. The assessment of airway responsiveness is crucial in the evaluation of a patient suspected of having OA. It should be performed at different stages of the investigation of OA: at the beginning of the investigation to confirm the diagnostic of asthma; during the investigation to confirm the relationship between the onset of asthma and the exposure to a

Assessment of AHR to Evaluate Exercise-induced Respiratory Symptoms (by Louis-Philippe Boulet)

Most subjects with asthma may experience a fall in expiratory flows after exercise, usually associated with respiratory symptoms.61 This may occur more frequently when asthma is not optimally controlled, or after exposure to sensitizing agents or respiratory infections. EIB results from smooth muscle contraction, associated with the release of mediators such as histamine, prostaglandins, and cys-leukotrienes and possibly neural (eg, cholinergic) influences.62, 63 The main trigger of EIB is

Assessment of AHR to Evaluate New Medications (by Paul M. O'BYRNE)

Measurements of methacholine AHR have been extensively used to evaluate the efficacy and duration of effect of functional antagonists, such as inhaled β2-agonists. Early studies compared functional antagonists with different mechanisms of action, such as theophylline and inhaled β2-agonists,83 different formulations of short-acting inhaled β2-agonists,84 and more recently short-acting β2-agonists compared with long-acting β2-agonists.85

Another important contribution of measuring methacholine

Assessment of AHR in a Severe Asthma Clinical Practice (by Parameswaran Nair)

AHR is a characteristic feature of asthma, and its measurement is an important tool in its diagnosis. As already discussed in this symposium, in addition to its utility to relate symptoms such as cough, wheeze, and shortness of breath to variable airflow obstruction (ie, to diagnose current asthma), the test is useful to make a number of other clinical assessments. These include (1) evaluation of patients with OA, (2) evaluation of patients with exercise-induced respiratory symptoms, (3)

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  • Cited by (0)

    The symposium was organized with an unrestricted educational grant from Methapharm Inc, Brantford, Ontario, Canada. P. Nair is supported by the Frederick E. Hargreave Teva Innovation Chair in Airway Diseases.

    Conflicts of interest: P. Nair declares that the report was based on a symposium that was supported by an unrestricted grant from Methapharm Inc; has received consultancy fees from AstraZeneca, Roche, Sanofi, Knopp, and Teva; has received research support from AstraZeneca, Teva, Novartis, Roche, Sanofi, Boehringer-Ingelheim, and GlaxoSmithKline; and has received lecture fees from AstraZeneca, Novartis, and Teva. J. G. Martin has received travel support from Methapharm and has received lecture fees from AstraZenenca. D. C. Cockcroft has received consultancy fees and travel support from Methapharm; is on the Methapharm Canada advisory board; is employed by the University of Saskatchewan; and has received research support from AllerGen and AstraZeneca. M. Dolovich has received consultancy fees from Methapharm and Teva and has received research support from Boehringer-Ingelheim. C. Lemiere has received fees for participation in Metafarm, GlaxoSmithKline, Teva, and AstraZeneca advisory boards and is a member of the Canadian Thoracic Society Asthma Clinical Assembly. L.-P. Boulet is on the advisory boards for and has received consultancy fees from AstraZeenca, Novartis, and Methapharm; has received research support from Altair, Amgen, Asmacure, AstraZeneca, Boehringer-Ingelheim, Boston Scientific, Genentech, GlaxoSmithKline, Novartis, Ono Pharma, Schering, and Wyeth; has received lecture fees from AstraZeneca, GlaxoSmithKline, Merck, and Novartis; received royalties from UpToDate; has received payment for the development of educational presentations from AstraZeneca, GlaxoSmithKline, Merck Frosst, Boehringer-Ingelheim, and Novartis; has received travel support from Novartis and Takeda; is a member of the Canadian Thoracic Society Respiratory Guidelines Committee; is Chair of GINA Guidelines Dissemination and Implementation Committee; and is Laval University Chair on Knowledge Transfer, Prevention and Education in Respiratory and Cardiovascular Health. P. M. O'Byrne is on the Joint Oversight Board for Long-Acting β2-Agonists Safety Study; has received consultancy fees from AstraZenena, GlaxoSmithKline, Merck, and Boehringer-Ingelheim; and has received research support from AstraZeneca, Amgen, Genentech, and Axikin.

    Report of the Frederick E. Hargreave Symposium on Airway Hyperresponsiveness, Hamilton, Ontario, Canada, August 6, 2016.

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