Prostaglandin D₂: a dominant mediator of aspirin-exacerbated respiratory disease

Abstract

Background: Aspirin desensitization followed by high-dose aspirin therapy is routinely performed for patients with aspirin-exacerbated respiratory disease (AERD). Little is known about the contributions of mediators other than cysteinyl leukotrienes to aspirin reactions and to the therapeutic benefit of high-dose aspirin therapy.

Objective: We investigated differences in urinary eicosanoid metabolite levels and blood eosinophil counts in patients with AERD who tolerate and those who fail aspirin desensitization and also in patients with AERD who were successfully treated with high-dose aspirin therapy.

Methods: Twenty-nine patients with AERD were stratified into those who tolerated aspirin desensitization (group I) and those who did not (group II). Urine was analyzed for eicosanoid metabolites at baseline, during aspirin reactions, and during high-dose aspirin therapy. Blood was analyzed for cell differentials at baseline and during aspirin therapy.

Results: Basal prostaglandin D2 metabolite (PGD-M; 13.6 ± 2.7 vs 7.0 ± 0.8 pmol/mg creatinine [Cr], P < .05) and thromboxane metabolite (TX-M; 1.4 ± 0.3 vs 0.9 ± 0.1 pmol/mg Cr, P < .01) levels were higher in group II than in group I. During aspirin reactions, PGD-M levels remained unchanged, whereas TX-M levels (0.7 ± 0.1 pmol/mg Cr, P = .07) tended to decrease in group I. In contrast, PGD-M levels increased dramatically in group II (61.3 ± 19.9 pmol/mg Cr, P < .05), whereas TX-M levels did not change. The decrease in FEV1 inversely correlated with basal urinary levels of both leukotriene E4 and PGD-M. Blood eosinophil and basophil levels increased and urinary PGD-M levels (2.2 ± 0.8 pmol/mg Cr, P < .001) decreased on 2 months of high-dose aspirin therapy in group I.

Conclusion: Failure to tolerate aspirin desensitization in a subset of patients with AERD is associated with prostaglandin D2 overproduction. The increase in blood eosinophil and basophil counts during high-dose aspirin therapy might reflect the functional consequences of decreased prostaglandin D2 release and the therapeutic benefit of aspirin.

Keywords: Aspirin-exacerbated respiratory disease; Samter triad; aspirin desensitization; asthma; cysteinyl leukotrienes; eosinophils; nasal polyps; prostaglandin D(2); thromboxane; urinary eicosanoids.

Figure 1

Rash observed following provocative dose of aspirin in 3 Group II AERD patients.

Figure 2. Basal and post-aspirin (ASA) urinary LTE₄ levels

Basal and aspirin-induced urinary LTE₄ levels analyzed by GC-MS from ATA controls (basal n=10, post-aspirin n=5), Group I AERD subjects (n=23) and Group II AERD subjects (n=6) are shown. Data are expressed as mean +SEM (٭P<.05, ٭٭P<.01).

Figure 3. Basal and post-aspirin (ASA) PG levels

(A) Basal (left panel) and post-aspirin administration (right panel) urinary PG levels in subjects with ATA (basal n=10, post-aspirin n=5), Group I (n=23) and Group II (n=6) are shown. (B) Log₂ of change from basal levels in urinary PGs induced by aspirin administration is shown for the three patient groups. Data are expressed as mean +SEM (٭P<.05, ٭٭P<.01, ٭٭٭P<.001).

Figure 3. Basal and post-aspirin (ASA) PG levels

(A) Basal (left panel) and post-aspirin administration (right panel) urinary PG levels in subjects with ATA (basal n=10, post-aspirin n=5), Group I (n=23) and Group II (n=6) are shown. (B) Log₂ of change from basal levels in urinary PGs induced by aspirin administration is shown for the three patient groups. Data are expressed as mean +SEM (٭P<.05, ٭٭P<.01, ٭٭٭P<.001).

Figure 4. Basal urinary eicosanoid levels correlate with change in FEV₁ during aspirin desensitization

Basal urinary (A) LTE₄ and (B) PGD-M levels plotted against the corresponding percent change in FEV₁ during aspirin reaction for each subject with AERD. Effect size, determined with Pearson correlation coefficient, is denoted as an r value.

Figure 4. Basal urinary eicosanoid levels correlate with change in FEV₁ during aspirin desensitization

Basal urinary (A) LTE₄ and (B) PGD-M levels plotted against the corresponding percent change in FEV₁ during aspirin reaction for each subject with AERD. Effect size, determined with Pearson correlation coefficient, is denoted as an r value.

Figure 5. Effect of high-dose aspirin therapy on urinary eicosanoid levels in AERD

Urinary eicosanoid levels of Group I AERD subjects (n=14) are shown at baseline pre-aspirin and after 650mg twice-daily aspirin therapy for 8 weeks. Data are expressed as mean +SEM (٭٭P<.01, ٭٭٭P<.001).

Figure 6. Peripheral blood eosinophils increase on high-dose aspirin therapy

Blood eosinophil, basophil, and neutrophil counts (K/μL) for Group I AERD subjects (n=11) at baseline and on high-dose aspirin. Data are expressed as mean +SEM (٭٭P<.01).