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 LTE₄ levels were significantly higher in AERD patients on inhaled corticosteroid-long-acting β₂- 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 LTE₄ 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 LTE₄ levels.

Conclusion

Despite LTRA treatment in AERD, the LTE₄ 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.

Keywords:

• asthma
• leukotrienes
• asthma control
• aspirin-exacerbated respiratory disease
• eosinophil

Abbreviations

AA, arachidonic acid; ACQ, asthma control questionnaire; ACT, asthma control test; AERD, aspirin-exacerbated respiratory disease; AQLQ, asthma quality of life; ATA, aspirin-tolerant asthma; CysLTs, Cysteinyl leukotrienes; FeNO, Fractional exhaled NO; GINA, Global Initiative for Asthma guideline; IgE, immunoglobulin E; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LTRA, leukotriene receptor antagonist; Lys-ASA BPT, lysine-aspirin bronchial provocation test; PGF2α, prostaglandin F2α; TSLP, thymic stromal lymphopoietin; TXB2, 11-dehydro thromboxane B2; 15-HETE, 15-hydroxyeicosatetraenoic acid.

Acknowledgments

We thank Fanyi Jiang, Katerina Pardali, Outi Vaarala and Joo-Youn Cho for their cooperation and contribution to this research.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interests.

Additional information

Funding

This study was supported by AstraZeneca, a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HR16C0001) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No: 2020R1I1A3051800).