The present study showed that BHR to methacholine and AMP are correlated with each other and with FEV1. Our results also indicated that BHR to AMP implicates airway inflammation more than that of BHR to methacholine. In contrast, BMI correlated with BHR to methacholine but not with BHR to AMP. Together, these findings suggest that the AMP challenge test provides a better estimate of airway inflammation, and that the methacholine challenge test provides a better measure of airway mechanics.
Several studies have reported that responsiveness to methacholine and AMP are indicators of BHR, but there are discrepancies in the reported prevalence rates of responsiveness to these tests in patients with atopic and non-atopic asthma.5,14
However, a recent study of 93 children with recurrent wheezing reported similar BHR to methacholine in children with atopic and non-atopic disease.6
Several explanations are possible for the discrepancies in these previous studies. Younger children tend to have smaller airways, and are thus more sensitive to airway stimulation and have a higher prevalence of hyper-responsiveness to methacholine even if they are non-atopic. Thus, we compared the BHR of methacholine and AMP in children with atopic asthma.
The BHR to AMP but not methacholine was significantly correlated with inflammatory markers (total eosinophil count, IgE level, and percentage of eosinophils), which is consistent with a previous study of 47 children with asthma that showed no significant correlation between the PC20 of methacholine and serum IgE levels.15
In contrast, several studies have reported positive correlations between the PC20 of AMP and inflammatory markers.3,9,10,16,17
Additionally, a study of 120 patients with asthma reported that an improvement in the AMP PC20 after steroid therapy is more closely associated with a reduction in airway inflammation,18
suggesting that BHR to the AMP challenge test may better represent airway inflammation as compared with BHR to the methacholine challenge test.
Previous studies have reported that BHR to AMP varies from 39.4%19
The methacholine challenge test is thought to be a highly sensitive method for detecting asthma.16
One study of 77 children with asthma reported that the positive response to methacholine challenge (96.1%) was greater than that of AMP challenge (85.7%).20
This is consistent with results for adults.21
However, we found higher responsiveness to the AMP challenge (94.5%) than that of the methacholine challenge (86.7%). Although the reasons for these discrepant results are unclear, it is likely that they are due to differences in study populations, such as age, sex, atopic status, and asthma severity. In particular, our study population consisted entirely of children with mild intermittent atopic asthma. This result is supported by previous studies reporting that patients with atopic asthma are significantly more responsive to AMP than to methacholine.9
Thus, although the methacholine challenge test might be sensitive for detecting asthma, it may not be useful for defining allergic inflammation of the airway or the effectiveness of steroid treatment.
Differences between the results of the methacholine and AMP challenge tests are probably due to differences in the mechanisms of these tests. Methacholine acts through a cholinergic receptor as a stimulus (direct stimulation), making the results less correlated with mechanisms of atopy. However, AMP acts by releasing inflammatory mediators; therefore, results are more correlated with atopy. It is generally accepted that airway inflammation contributes to the presence and severity of BHR.22,23
Airway inflammation and eosinophilia are key features of asthma, and an increase in eosinophils in the peripheral blood is associated with asthma severity, and is thus used as a marker of disease activity.20
IgE also has a pivotal role in asthma.24
In the present study, we observed significant differences in eosinophil percentages and counts and IgE levels between the groups with positive and negative BHR to AMP, but not in response to the methacholine test.
Additionally, BMI was significantly correlated with BHR to methacholine. Previous studies have also reported a relationship between obesity and asthma,25,26
although the underlying mechanism is unclear. Possible explanations include the following: obesity may have a mechanical effect on lung function, adipocytes may be associated with chronic low-grade inflammation, and obesity comorbidities may disrupt lung function.27
However, the link between BMI and the differences between BHR to methacholine and BHR to AMP is unclear. A previous review of 30 adult females in France reported a significant correlation between BMI and BHR to methacholine, but not to AMP.28
These results are compatible with our finding that BMI may be linked to BHR to methacholine but not BHR to AMP.
The present study had several limitations. First, this study was based on a relatively small population because we only included children with atopic asthma. Second, we did not directly measure airway inflammation biomarkers, such as sputum eosinophils or exhaled nitric oxide from the airway. However, because children with asthma include those with atopic asthma, our study showed that indirect stimulation with the AMP challenge test could be as useful as a methacholine challenge test for assessing airway hyperresponsiveness in children with atopic asthma. Furthermore, the BHR to methacholine decreases with age in children with asthma, so the AMP challenge test appears to be an effective method for measuring airway hyperresponsiveness in children and adolescents with atopic asthma. Additionally, the AMP challenge test, which reflects airway inflammation, could be a valuable method to monitor the effectiveness of steroid treatment.
In summary, our results in children with atopic asthma indicate that airway inflammation is better correlated with BHR to AMP than to methacholine. Thus, the AMP challenge test, which implicates airway inflammation, could be a useful method for diagnosing asthma. We suggest future investigations to examine BHR after steroid treatment in children with atopic asthma.