Persistent Eosinophilic Inflammation in Adult Asthmatics with High Serum and Urine Levels of Leukotriene E4

Abstract

Background: Cysteinyl leukotrienes (CysLTs) are key mediators for bronchoconstriction, eosinophil recruitment and mucus production in the airways of asthmatic patients. To better understand the role of CysLTs in different asthma phenotypes, we compared the levels of arachidonic acid metabolites in relation to asthma control status and phenotypes in adult asthmatics on regular anti-asthma medications. Methods: A total of 137 adult asthmatics (47 with aspirin-exacerbated respiratory disease [AERD] and 90 asthmatics with aspirin-tolerant asthma [ATA]) and 20 healthy controls were enrolled. Arachidonic acid metabolites in serum and urine were analyzed using LC-MS/MS methods, and clinical data, including asthma control status, exhaled NO (FeNO) and lung function tests, were collected. Results: Urine LTE 4 levels were significantly higher in AERD patients on inhaled corticosteroid-long-acting β 2 -agonist plus leukotriene receptor antagonist (LTRA) treatment than in ATA patients (P=0.001). No differences were found in the serum or urine levels of 15-HETE, TXB 2, or PGF 2α. High serum LTE 4 levels were associated with lower FEV1% and uncontrolled status in AERD patients (P=0.006 and P=0.002, respectively), but not in ATA patients. Multivariate analysis demonstrated that blood eosinophil counts, FeNO levels and aspirin hypersensitivity were significant factors affecting urine LTE 4 levels. Conclusion: Despite LTRA treatment in AERD, the LTE 4 levels remained high and showed close associations with blood eosinophilia, high FeNO levels and impaired disease control. Our real-world evidence indicates that control of asthma is not fully achieved by blocking the CysLT pathway with LTRA. Thus, introduction of treatment modalities targeting eosinophilia could be a better option for patients with high CysLTs.

Association of eosinophil‐derived neurotoxin levels with asthma control status in patients with aspirin‐exacerbated respiratory disease

“… 27 , 28 Urinary LTE 4 has been extensively studied as a reproducible biomarker determining the phenotype of AERD and reported to be elevated in patients with uncontrolled AERD. 29 , 30 Elevated levels of PEC or FeNO are also known for poor asthma control and risk factor for AE. 1 , 11 , 31 The present study demonstrated that EDN levels (plasma, urine, and sputum) are the most important factor predicting UA in patients with AERD, but not in those with ATA.…”

Epithelial Autoantigen-Specific IgG Antibody Enhances Eosinophil Extracellular Trap Formation in Severe Asthma

“…These findings are comparable to those of our previous studies in patients with AERD, which are characterized by moderate-to-severe asthmatic symptoms and persistent type 2/eosinophilic inflammation in upper and lower airway mucosa. 28 29 30 The mechanism of how epithelial antigens induce autoantibody production needs to be further clarified. The present study did not confirm the presence of B-cell clusters as the source of autoantibody generation, although some studies have demonstrated this finding in chronic inflammatory diseases such as rheumatoid arthritis and allergic granulomatosis.…”

Emerging Biomarkers Beyond Leukotrienes for the Management of Nonsteroidal Anti-inflammatory Drug (NSAID)-Exacerbated Respiratory Disease

“…Serum and urine levels of LTE4/PGF2α were significantly higher in NERD patients than in ATA patients and healthy controls in a recent study. 27 Moreover, the discriminative value of NERD from ATA was slightly better in urinary LTE4/PGF2α than in urinary LTE4. Thus, cysLT/PGF2α may be a new diagnostic biomarker for NERD.…”

“…Serum and urinary levels of LTE4 and LTE4/PGF2α remained high in NERD patients treated with LTRA and were related to eosinophilic inflammation and disease severity. 27 An additional treatment is warranted for NERD patients with sustained high levels of cysLTs despite LTRA treatment.…”