Bronchial Provocation Testing: The Future

Sandra D. Anderson; John D. Brannan

Disclosures

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

In This Article

Mediators and other Markers of Inflammation and Bronchial Hyper-responsiveness

The laboratory protocols used for exercise testing have a high failure rate to identify EIB that occurs in the field.[34] For this reason EVH and mannitol are currently being evaluated as potential surrogates for exercise to identify EIB.[4,9••,22•,24••,30••,31••,35••] Recent studies using EVH in asthmatic patients and in athletes with EIB demonstrate an increase in urinary excretion of the metabolites of prostaglandin D2 and leukotriene C4 (9α11β-PGF2 and leukotriene E4) after EVH with a similar time course to that observed following exercise and mannitol.[30••,31••] The significant relationship (r = 0.54, P < 0.001) reported between the percentage fall in FEV1 after EVH and the increase in 9α11 β-PGF2 is important because PGD2 is almost exclusively derived from the mast cell. Further, the inhibition of the increase in 9α11 β-PGF2 in response to EVH and to mannitol, immediately following inhalation of sodium cromoglycate,[31••,36] suggests that the mast cells are close to the airway surface.

Bronchial hyper-responsiveness to mannitol and to exercise is frequently being reported in those with a high fraction of exhaled nitric oxide (FeNO) and those with a high percentage of eosinophils in sputum.[17,37,38,39••] These are both surrogate markers of inflammation that are sensitive to treatment with inhaled corticosteroids (ICS). However, BHR to mannitol and exercise is also sensitive to treatment with ICS[37,40] and can occur in the absence of a high FeNO or a high percentage of eosinophils.[38,39••,41] This finding suggests that BHR to mannitol and exercise occurs early in the onset of asthma at a time when mast cell numbers increase in the airway epithelium. Mast cells are often overlooked because they are tissue bound in mucous glands, on BSM, and in the epithelium, and do not readily appear in sputum as do eosinophils. The importance of mast cells and their location is now being emphasized by the suggestion that asthma is a mast cell myositis.[42,43] Mast cells are important, both for their role in containing potent mediators of bronchoconstriction, and also for cytokines that contribute to the development of responsiveness of the BSM.[42] For this reason, BPTs that act via release of mast cell mediators are likely to become increasingly used as a surrogate for the presence of mast cells.

The advantage of the indirect BPTs over the direct tests such as methacholine is that they provide information on the interaction of the two key features of asthma: airway inflammation and BHR. In addition to a hyper-responsive BSM, a positive response to an indirect stimulus such as exercise or mannitol indicates both the presence of a sufficient number of inflammatory cells (mast cells with or without eosinophils), and a sufficient concentration of mediators to cause bronchoconstriction. A negative test result to an indirect stimulus indicates a missing element that is either insufficient numbers of inflammatory cells or insufficient concentration of mediator or an unresponsive smooth muscle. Examples of negative tests include known asthmatic patients being treated effectively with inhaled corticosteroids,[32,40] and people with eosinophilic bronchitis but no asthma,[44] or people with asymptomatic BHR to methacholine[10•,15,45] who may have airway injury.

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