Bronchial Provocation Testing: The Future

Sandra D. Anderson; John D. Brannan


Curr Opin Allergy Clin Immunol. 2011;11(1):46-52. 

In This Article

Stimuli Used for Bronchial Provocation Test Act Either Directly or Indirectly

The terms 'direct' or 'indirect' refer to the mechanism by which a BPT causes bronchoconstriction. For example, the pharmacological agent methacholine chloride acts directly on bronchial smooth muscle (BSM) receptors causing it to contract and the airways to narrow. The indirect stimuli (e.g. exercise) cause the release of mediators (prostaglandins, leukotrienes and histamine) locally in the airways and these mediators act on BSM receptors to cause contraction.

Methacholine is considered to be such a highly sensitive agent to identify bronchial hyper-responsiveness (BHR) that currently a negative test result at 16 mg/ml is promoted as a rule-out test for clinically current asthma.[5,6••] However, reliance on a negative methacholine test would frequently result in under-diagnosis of asthma and exercise-induced bronchoconstriction (EIB).[7,8,9••,10•] EIB is an early sign of asthma[11] and is unwanted in many occupational and recreational settings.

In stark contrast, a high prevalence of positive methacholine tests is being reported in elite skiers without EIB[10•,12] and frequently in those without symptoms of asthma.[10•] These findings raise the possibility that 'BHR to methacholine' in this group may reflect airway injury from breathing vast volumes of cold dry air rather than the pathophysiology consistent with asthma and associated with EIB.[13] If this is the case, then asthma may be being over-diagnosed on the basis of a positive methacholine test. Caution in interpreting a positive methacholine test as diagnostic of asthma has recently been recommended.[6••,14] The reason for this recommendation is that there are many technical factors and disease states or transient influences of viruses, smoking, or allergen exposure that can cause BHR to methacholine.[6••,14] These transient influences may account for the relatively high prevalence of BHR to methacholine reported in healthy children. For example, at the 'best' cut point reported to diagnose asthma, the specificity for a PC20 less than 4 mg/ml was 64%, indicating a high rate (36%) of false-positive tests.[15] Further, response to methacholine is complicated by the fact that there is a 'variable' and 'fixed component', the former being susceptible to treatment and the latter due to airway remodelling.[16]

The stimuli being commonly reported that act indirectly to identify BHR include exercise, adenosine monophosphate (AMP), dry powder mannitol, and hyperpnoea of cold or dry air [often referred to as eucapnic voluntary hyperpnoea (EVH) or isocapnic hyperventilation]. BPTs that act indirectly are considered more specific for identifying the presence of inflammation that is consistent with a diagnosis of asthma than methacholine. It follows that indirect stimuli are promoted to confirm a diagnosis of asthma[5,6••,17,18] and to follow response to therapy.[18,19] Further most stimuli that provoke an attack of asthma in daily life act indirectly so it seems appropriate that indirect BPT are now being commonly reported to identify BHR.

Indirect stimuli are now being used to assess athletes,[4,10•,20,21,22•] fire fighters,[2] defence force personnel,[3•] smokers,[23] children,[9••,24••] to evaluate cough,[25] to confirm asthma,[26] for assessment of new methods for measuring airway narrowing,[27•] to investigate two different BPTs on 1 day,[28] and to assess drugs.[29,30••,31••] This increase in use of indirect tests may, in part, be accounted for by the recent and wide commercial availability of a standardized test kit for mannitol inhalation and in part by the need to identify EIB. The increase may also be driven by the physician's need to confirm the presence of asthma or EIB in order to justify making changes to treatment[32] or to demonstrate the need for treatment.[33]


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