Sputum Metabolomic Signature and Dynamic Change of Cough Variant Asthma

Cough variant asthma (CVA), a common reason for chronic cough, is a globally prevalent and burdensome condition. The heterogeneity of CVA and a lack of knowledge concerning the exact molecular pathogenesis has hampered its clinical management. This study presents the first sputum metabolome of patients with CVA, revealing the dynamic change during treatment and exploring biomarkers related to the occurrence and treatment response of CVA. We found that arginine biosynthesis, purine metabolism, and pyrimidine metabolism pathways were enriched in CVA compared with healthy controls. Part of the metabolic disturbances could be reversed by antiasthmatic medication. The levels of dipeptides/tripeptides (alanyl tyrosine, Gly-Tyr-Ala, Ala-Leu, and Thr-Leu) were significantly associated with sputum neutrophil or eosinophil percentages in patients with CVA. Differential metabolites before treatment between effective and ineffective treatment groups were enriched in purine metabolism, thiamine metabolism, and arginine metabolism. 2-Isopropylmalate was downregulated in CVA and increased after treatment, and the effective treatment group had a lower 2-isopropylmalate level before treatment. Random forest and logistic regression models identified glutathione, thiamine phosphate, alanyl tyrosine, and 2'-deoxyadenosine as markers for distinguishing CVA from healthy controls (all areas under the curve >0.8). Thiamine phosphate might also be promising for predicting therapy responsiveness (area under the curve, 0.684). These findings imply that disturbed mitochondrial energy metabolism and imbalanced oxidation-reduction homeostasis probably underlay the metabolic pathogenesis of CVA.