How Best to Measure Airway Responsiveness

Donald W. Cockcroft, F.R.C.P.(C)

Department of Medicine, Division of Respiratory Medicine, Royal University Hospital, Saskatoon, Canada

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In 1988, Pauwels and colleagues recommended that we should reassess the way we looked at airway responsiveness (1), an approach that has recently been updated and reviewed by these investigators (2). They pointed out the differences in mechanisms and potential clinical relevance between direct and indirect stimuli used to measure so-called nonspecific airway responsiveness. Direct stimuli act upon the relevant receptors on airway smooth muscle stimulating airway muscle contraction directly; direct stimuli include methacholine and other cholinergic analogues, histamine, and arachidonic acid metabolites. Indirect stimuli result in airway smooth muscle contraction through one or more intermediate mechanisms, including local or central neuronal reflexes, activation of inflammatory cells, or others. Indirect stimuli include all the physical stimuli (exercise, cold air, hyperventilation, nonisotonic aerosols, mannitol, etc.) and a number of chemical stimuli, including adenosine monophosphate (AMP), propranolol, bradykinin, and tachykinins. They reasoned that, because symptoms and bronchoconstriction occurred in clinical asthma by means of indirect mechanisms, airway hyperresponsiveness to indirect stimuli should be more relevant than responsiveness to direct stimuli to asthma. There were few data available at the time; however, they speculated that indirect airway responsiveness should correlate better with asthma severity, current asthma symptoms (1), and by extrapolation airway inflammation (2).

As had been recognized for some time, indirect airway hyperresponsiveness (e.g., to exercise, AMP) is more specific for a diagnosis of asthma (3); the corollary is that responsiveness to these stimuli is substantially less sensitive. Over the last 10 yr, more data have emerged providing evidence of superior correlation between airway responsiveness to indirect stimuli (compared with direct stimuli) and indirect markers of airway inflammation in asthma. For example, AMP PC₂₀ correlates better than methacholine PC₂₀ both with circadian variation in peak expiratory flow (PEF) in atopic asthmatics (4) and with elevated exhaled nitric oxide (NO) levels in atopic asthmatics in remission (5). Anti-inflammatory therapeutic strategies such as allergen avoidance (6) and inhaled corticosteroids (7, 8) have usually resulted in greater improvements in indirect airway responsiveness, including exercise (6), cold air (8), and AMP (6). This has not been found in all studies (9), a fact that may relate in part to the timing of measurements. A recent study has shown that inhaled corticosteroids caused a more rapid improvement in airway responsiveness to exercise than to methacholine. However, after 3 wk airway responsiveness to exercise did not improve further whereas airway responsiveness to methacholine continued to improve over several weeks (10). The choice of stimulus may also be important. AMP is an indirect stimulus that acts through release of mast cell mediators and possibly also by means of afferent nerve stimulation (2). Some feel that AMP-induced airway responses may depend on the state of mast cell priming and, therefore, that AMP responsiveness may correlate better than other indirect stimuli with airway inflammation (2).

Direct evidence of correlation with airway inflammation has only recently become available. Polosa and colleagues recently demonstrated a positive correlation between AMP PC₂₀ but not methacholine PC₂₀ and sputum eosinophils in 12 subjects with nonasthmatic allergic rhinitis (11). In the current issue of the journal (pp. 1546-1550), van den Berge and colleagues expand on these observations in a larger cohort of asthmatic subjects (12). In 120 asthmatic subjects, they provide convincing evidence of a superior correlation of AMP PC₂₀ with sputum eosinophils counts compared with the methacholine PC₂₀ correlation with sputum eosinophils. Interestingly, airway responsiveness to neither of the stimuli correlated with exhaled NO.

Thus, there is an increasing body of evidence to support Pauwels' hypotheses. Indirect airway responsiveness is both more specific for asthma and correlates better with asthma severity, asthma symptoms, and asthma airway inflammation. AMP challenge may perform better in this regard than challenges with the physical stimuli.

How then should we best measure airway responsiveness? The answer to this question is as yet uncertain. However, it depends at least in part on the reason for performing the measurement. Airway responsiveness to direct stimuli such as methacholine remains an extremely sensitive test. As such, like any sensitive test, it serves well to exclude disease. A methacholine challenge with a sensitive cutpoint (e.g., PC₂₀  16 mg/ml, PD₂₀  8 µmol), with certain caveats, is a valuable test to exclude with reasonable certainty current symptoms of asthma. By contrast, because of increased specificity, airway responsiveness to indirect stimuli may be preferred to confirm a diagnosis of asthma. In addition, indirect challenges, possibly preferentially with AMP, may be preferred for monitoring subjects with asthma, primarily to infer parallel changes in airway inflammation. This is particularly useful as an adjunct to the diagnosis of occupational asthma where work-related falls in PC₂₀ suggest exposure to a sensitizer. Serial measurements of airway responsiveness may, in the future, become of increased value in monitoring anti-inflammatory effects of asthma therapy.

Acknowledgments: The author wishes to thank Jacquie Bramley for assisting in the preparation of this manuscript.

	References

TOP ARTICLE REFERENCES

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11. Polosa R, Ciamarra I, Mangano G, Prosperini G, Pistorio MP, Vancheri C, Crimi N. Bronchial hyperresponsiveness and airway inflammation markers in nonasthmatics with allergic rhinitis. Eur Respir J 2000; 15: 30-35 [Abstract].

12. van den Berge M, Meijer RJ, Kerstjens HA, de Reus DM, Koëter GH, Kauffman HF, Postma DS. PC₂₀ Adenosine 5'-Monophosphate is more closely associated with airway inflammation in asthma than PC₂₀ methacholine. Am J Respir Crit Care Med 2001; 163: 1546-1550 [Abstract/Free Full Text].