Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions

Abstract

Purpose: Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.

Methods: The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.

Results: More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.

Conclusions: NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.

Trial registration: ClinicalTrials.gov Identifier: NCT03849625.

Keywords: Leukotriene E4; anti-inflammatory agents; aspirin; biomarkers; desensitization; drug hypersensitivity; non-steroidal; phenotype.

Fig. 1. Schematic diagram of patient selection for this study.

A total of 158 patients with a suspected history of NSAID hypersensitivity were initially recruited into this study. Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a well-documented drug allergy history and verified by a positive drug provocation test in 25 patients with a suggestive history of NSAID reactions. NSAID, non-steroidal anti-inflammatory drug.

Fig. 2. Clinical presentations in patients with cross-reactive NSAID hypersensitivity.

A proportional Venn diagram shows that about half of patients with cross-reactive NSAID hypersensitivity in Thailand reported only cutaneous symptoms after NSAID exposure, while one-third of them experienced NSAID-induced blended reactions. NSAID, non-steroidal anti-inflammatory drug.

Fig. 3. Respiratory parameters and uLTE4 levels in different phenotypes of NSAID-sensitive subjects compared to NSAID-tolerant subjects.

Baseline FeNO in NIBR and NERD were higher than those in the NSAID-tolerant group. After aspirin provocation, % predicted FEV1 in NERD and NIBR were significantly reduced from the baseline while uLTE4 levels were much higher than those in NSAID-tolerant subjects. uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; FEV1, forced expiratory volume in 1 second. ^*P values < 0.05, ^†P values < 0.01.

Fig. 4. uLTE4 levels in NSAID-sensitive subjects after aspirin desensitization.

Our study demonstrated that uLTE4 levels (pg/mg creatinine) in 3 NERD and 3 NIBR patients were increased and remained elevated up to 3 years after aspirin desensitization even though recurrent nasal polyposis was successfully prevented in all cases. uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.