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Outcomes and Interpretation of Results

Generally, a methacholine PC20 of <8 mg/mL provides a rationale to use asthma therapy but is not in itself diagnostic of asthma. Methacholine-responsive patients have a significantly lower % predicted FEV1 and higher dose of ICSs, and thus the response to methacholine has indeed been related to asthma severity (Fowler et al. 2000).

While the methacholine test has some limitations for asthma diagnosis, it is extremely useful for evaluating the effects of asthma triggers and/or asthma therapy on airway hyperresponsiveness (Inman et al. 1998). The methacholine test is used to track responses to environmental triggers, such as occupational sensitizers, inhaled allergen, and respiratory viral infections, which significantly reduce the methacholine PC20 (Gauvreau et al. 1999a).

Studies have shown that airway hyperresponsiveness to both histamine and methacholine is associated with the presence and magnitude of atopy (Crockcroft et al. 1984; Fowler and Lipworth 2003). The early asthmatic response (EAR) to allergen described as the allergen PC20 (provocation concentration causing a 20% FEVj fall) is dependent on the levels of the patients’ allergic sensitization and airway smooth muscle hyperresponsiveness (Killian et al. 1976; Cockcroft et al. 1979; Hill et al. 1982). The allergen PC20 can be predicted within 2-3 doubling concentrations, from the skin prick test end point and the histamine PC20 (Cockcroft et al. 2005). The relationship between the skin test end point and the methacholine PC20 can provide value in safely determining a starting inhalation concentration for allergen, thereby avoiding long allergen challenge protocols.

The effect of corticosteroid treatment in symptomatic asthmatic subjects improves the PC20 of methacholine by shifting the PC20 up to four doubling doses (i.e., from 1 to 16 mg/mL) (Woolcock et al. 1988) (Figure 10.3), suggesting that at least some of the response to methacholine is related to inflammation. The magnitude of shift in the methacholine/histamine PC20 to corticosteroids is variable (Koskela et al. 2003) and dependent upon factors such as steroid dose, duration of treatment, and severity of asthma.

Percent change in forced expiratory volume in 1 s

FIGURE 10.3 Percent change in forced expiratory volume in 1 s (FEVj) at doubling concentrations of methacholine (mg/mL) in patients with asthma without treatment (left) and following treatment with inhaled corticosteroids (ICSs) (right). The provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) shifts approximately 4 doubling concentrations higher with ICS treatment.

Methacholine challenges are most useful for assessing functional antagonism of beta-2 agonists on airway smooth muscle (Parameswaran et al. 1999). Shifts in the provocative concentration of methacholine can be used to establish optimum drug doses and to evaluate the onset and offset of drug activity in the airways. In a more recent study by O’Byrne et al., administration of a novel long-acting beta agonist (BI 1744 CL) at varying doses (2, 5, 10, 20 mcg) significantly increased the methacholine PC20 in a dose-dependent manner. In addition, the PC20 was elevated by a 30 min postdosing and remained elevated over a 32 h period (O’Byrne et al. 2009b). In contrast, leukotriene antagonist and mast cell stabilizers have no effect on AHR to direct stimuli (O’Byrne et al. 2009a).

It is important to note that the effectiveness of using the methacholine challenge to monitor drug activity within the airways is limited by prior administration of muscarinic antagonists. For example, the compound ipratropium bromide is a potent antagonist of muscarinic agonists, including methacholine (Crimi et al. 1992; Crapo et al. 2000). Inhaled ipratropium bromide has been shown to significantly inhibit metha- choline-induced airway hyperrepsonsiveness; however, its duration of action is still unclear. There have been conflicting results as to the duration of bronchoprotection that ipratropium bromide may provide against methacholine. It is recommended by the American Thoracic Society to withhold the use of inhaled ipratropium bromide 24 h prior to a methacholine challenge (Crapo et al. 2000). Conversely, Illamperuma et al. demonstrated that ipratropium bromide promotes bronchoprotection for up to 6 h but none by 12 h (Illamperuma et al. 2009). This lends support to conducting methacholine inhalation challenges 12 h after the last dose of ipratropium bromide as opposed to 24 h. Interestingly, other compounds such as leukotriene modifiers are to be withheld for a recommended 24 h prior to methacholine challenge testing. However, Davis et al. demonstrated that montelukast sodium administered orally at either 1 or 25 h before methacholine challenge testing did not affect the outcomes of the test. These findings demonstrate that while some compounds can negatively affect methacholine outcomes, others have little to none effect (Davis and Cockcroft 2005).

The histamine challenge has also been used to assess the efficacy of various biological agents for the treatment of asthma. For example, Purokivi et al. used histamine challenge-induced cough to assess the efficacy of ICS treatment in asthmatics (Purokivi et al. 2010). Treatment with corticosteroids showed improvements in histamine PC20 and histamine challenge-induced couch, thereby demonstrating that these outcome measurements can be used as sensitive markers to assess treatment with corticosteroids. On the other hand, Leckie et al. monitored the effects of an IL-5 blocking monoclonal antibody to treat asthma and reported that although the mean blood eosinophil count was lowered following treatment, there was no effect on airway hyperresponsiveness to histamine (Leckie et al. 2000). Bryan and colleagues carried out a double-blind, randomized parallel group study, in which patients with mild allergic asthma were given subcutaneous recombinant IL-12 or placebo. They then assessed airway hyperresponsiveness using the histamine challenge. They found a decrease in peripheral blood eosinophil counts 24 h postinjection compared to the placebo but no change in the airway hyperresponsiveness to histamine (Bryan et al. 2000).

Last, Salome et al. determined the effect of aerosol and oral fenoterol as both a histamine and methacholine challenge in asthmatic subjects. They found that the dose-response curves to both histamine and methacholine shifted to the right with aerosol fenoterol; however, no significant change was seen with oral administration. Thus, this study used airway hyperresponsiveness challenges to determine that aerosol administration of fenoterol was more effective than oral. These studies highlight that both histamine and methacholine challenges can be used to assess drug treatment and pathogenesis of asthma.

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