The Late Asthmatic Reaction Is in Part Independent from the Early Asthmatic Reactions

Abstract

House dust mites (HDM) are the world's most important cause of allergic asthma. It is unclear why some patients with HDM allergy develop an early asthmatic reaction (EAR) only, whereas others react with a dual asthmatic reaction-EAR plus late asthmatic reaction (LAR). In patients with LAR, the symptoms and bronchial inflammation are more severe, and the current knowledge suggests that the EAR always precedes the LAR. The aim of the present study was to investigate whether a LAR can occur separately even without a significant EAR. In a pilot study of 20 patients with asthma and HDM allergy, a bronchial allergen challenge (BAC) was performed on three separate occasions with a tapered allergen dose. Before and 24 h later, exhaled NO (eNO), eosinophils and miRNAs were measured as markers of bronchial inflammation. Compared to BAC1, at BAC2 there was a significant decrease in the EAR from mean 39.25 ± 13.37% to mean 33.55 ± 5.25% (p < 0.01), whereas the LAR remained unchanged: mean 28.10 ± 10.95% to mean 30.31 ± 7.77% (n.s.). At BAC3, both the EAR and the LAR were significantly attenuated compared to the first and second BAC. In 3 (15%) patients, even the tapered allergen dose induced a dual asthmatic reaction. In 10 (50%) patients, the allergen dose was too low to trigger a significant EAR and LAR. In 7 (35%) patients, there was no EAR, but a significant LAR (mean max fall FEV1 20.5 + 4.7%) recorded. Significant correlations (p < 0.05) were found between distinct miRNAs (miR-15a-5p, miR-15b-5p and miR-374a-p5), eNO, and the decline in lung function and the presence of a LAR (p < 0.01). We can demonstrate that a LAR is induced in some patients without an EAR to low allergen exposure. This leads to a strong inflammatory reaction with an increase in eNO and a decrease in FEV1 and distinct miRNAs. Accordingly, these individuals are at greater risk of asthmatic symptoms and remodeling with loss of lung function than patients who do not have a LAR.

Keywords: bronchial allergen challenge; early asthmatic and late asthmatic reaction; epigenetic regulation; house dust allergy; microRNAs.

Figure 1

Change of EAR and LAR in response to the allergen reduction.

Figure 2

eNo (a) and eosinophils (b) before and 24 h after BACC. For statistical analysis, BAC pre- was compared to BAC post using the Wilcoxon test. ** p < 0.01, *** p < 0.001.

Figure 3

Time course of mRNA expression. Changes in the expression of (a) miR-15a-5p, (b) miR-15b-5p and (c) miR-374a-5p were analyzed in the peripheral blood of patients with asthma and HDM allergy before (t0), 7 (t7) and 24 h (t24) after BAC by RT-PCR. ** p < 0.01, *** p < 0.001, **** p < 0.0001.

Figure 4

Correlations of miRNA expression with eNO, eosinophilia and max fall LAR. Correlations of miR-15a-5p, miR-15b-5p and miR-374a-5p with (a–c) eNO, (d–f) eosinophils and (g–i) max fall LAR are shown.