Factors associated with hyperresponsiveness to adenosine 5’‐monophosphate in healthy subjects

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Factors associated with hyperresponsiveness to adenosine 5'-monophosphate in healthy subjects LETTER  We expected a relation with allergies based on a skin prick test (P = 0.59) and self-reported allergic rhinitis (P = 0.91), but this relation was absent. Two samples had sputum eosinophils above the commonly used threshold of 3%. Therefore, we analyzed the percentage of sputum eosinophils categorized as <1%, ≥1%, and missing (only 74 subjects were able to expectorate sputum). AHR was significantly associated with sputum eosinophils ( Table 1). The multivariate model (Table 2) shows that AHR is more likely in subjects with ≥1% sputum eosinophils compared to subjects with <1% sputum eosinophils, but equally likely in subjects with a missing sputum sample compared to those with <1% sputum eosinophils. This indicates that ≥1% sputum eosinophils in a healthy subject associates with AHR to AMP. This aligns with earlier observations in asthma and allergic rhinitis that sputum eosinophils predict AHR to AMP. 2 We now show the association in healthy subjects.
Strikingly, all subjects with AHR to AMP were current smokers.
Smoking status was significantly different (P < 0.01) between subjects with and without AHR and smokers with AHR smoked more cigarettes per day than smokers without AHR (P < 0.01). Previously reported healthy subjects with AHR to AMP were also all current smokers. 3 Furthermore, smoking is associated with AMP sensitivity in patients with chronic obstructive pulmonary disease (COPD), 3 as COPD smokers had a significantly lower PC 20 AMP compared to COPD nonsmokers. Based on these findings, we speculate that AHR to AMP in healthy subjects is affected by cigarette smoke-induced presence of mast cells, the primary target for AMP. Cigarette smoke irritates epithelial cells, initiating the release of pro-inflammatory cytokines. 4 These trigger mast cell infiltration and proliferation, resulting in increased numbers of mast cells in the airway's submucosa. 5 Cigarette smoke also causes the reduction of epithelial integrity which facilitates the cigarette smoke to reach the mast cells. 6 As AMP provocation initiates bronchoconstriction through mediators released by mast cells, 7 healthy smokers may have AHR to AMP.
Multivariately, small airways function, in terms of R 5 -R 20 , was independently associated with AHR ( Finally, AHR to AMP associated with a lower quality of life.
Univariately, hyperresponsive subjects scored higher on the St.
Nevertheless, all scores were below the clinically used thresholds of ≤25, ≤1.5, and ≤1, respectively, indicating that our subjects have few symptoms. Multivariately, the SGRQ was independently associated with AHR to AMP ( subjects may be an early predictor for development of pulmonary complaints. In conclusion, in a group of healthy never and current smokers, eight subjects (7.4%) expressed AHR to AMP (PC 20 AMP ≤160 mg/ mL). These subjects were current smokers with a higher cigarette consumption compared to subjects without AHR. Furthermore, AHR to AMP associated with a reduced small airways function, higher sputum eosinophil levels, and a lower quality of life. Further research should concentrate on whether AHR to AMP in healthy smokers indicates the onset of respiratory disease development.

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Additional supporting information may be found online in the Supporting Information section at the end of the article.