Unique Effect of Aspirin Therapy on Biomarkers in Aspirin-exacerbated Respiratory Disease. A Prospective Trial

Abstract

Rationale: Daily high-dose aspirin therapy benefits many patients with aspirin-exacerbated respiratory disease but provides no benefit for aspirin-tolerant patients with asthma. Type 2 inflammation characterizes aspirin-exacerbated respiratory disease.Objectives: To determine whether high-dose aspirin therapy changes biomarkers of type 2 inflammation in aspirin-exacerbated respiratory disease.Methods: Forty-two subjects with aspirin-exacerbated respiratory disease underwent an aspirin desensitization and were placed on high-dose aspirin (1,300 mg daily). Fifteen aspirin-tolerant subjects with asthma were also placed on high-dose aspirin. Biologic specimens and clinical parameters were collected at baseline and after 8 weeks on aspirin. Urinary eicosanoids, plasma tryptase and cytokine levels, platelet-leukocyte aggregates, and granulocyte transcripts were assessed.Measurements and Main Results: Eight weeks of high-dose aspirin decreased nasal symptoms and urinary prostaglandin E metabolite (P < 0.05) and increased urinary leukotriene E₄ (P < 0.01) levels in subjects with aspirin-exacerbated respiratory disease, but not in those with aspirin-tolerant asthma. Urinary prostaglandin D₂ and thromboxane metabolites decreased in both groups. Only in subjects with aspirin-exacerbated respiratory disease, exhaled nitric oxide (P < 0.05), plasma tryptase (P < 0.01), and blood eosinophil (P < 0.01) and basophil (P < 0.01) counts increased and plasma tryptase correlated with eosinophil counts (Pearson r = 0.514; P < 0.01) on aspirin. After correction for eosinophil counts, aspirin-induced changes in blood granulocyte transcripts did not differ between groups. Aspirin had no effect on platelet-leukocyte aggregates, platelet activation markers, or plasma cytokines in either group.Conclusions: High-dose aspirin therapy for 8 weeks paradoxically increases markers of type 2 inflammation in subjects with aspirin-exacerbated respiratory disease, despite reducing nasal symptoms. This effect of aspirin is unique to aspirin-exacerbated respiratory disease and not observed in subjects with aspirin-tolerant asthma.

Keywords: aspirin-exacerbated respiratory disease; aspirin-tolerant asthma; cysteinyl leukotrienes; mast cell; type 2 inflammation.

Figure 1.

Trial design. (A) Overview of the trial design and procedures. The period between screening and V1 was a minimum of 24 hours (for patients already taking montelukast) and a maximum of 4 weeks. At the baseline visit, baseline disease symptoms including asthma control questionnaire and total nasal symptom scores, lung function, and fractional exhaled nitric oxide were assessed, and blood and urine samples were collected. Most patients with aspirin-exacerbated respiratory disease (AERD) then underwent randomization to prasugrel or placebo and underwent two aspirin challenge/desensitization visits (gray font) and completed desensitization at Week 10. *The remainder completed aspirin challenge (all patients with aspirin-tolerant asthma [ATA]) and desensitization (remaining patients with AERD) at the baseline visit at Week 0. All subjects who successfully completed challenge and/or desensitization returned on high-dose aspirin 8 weeks later. (B) Summary of the numbers of patients involved in screening, randomization, and study completion for subjects with AERD and ATA. ACQ = asthma control questionnaire; BID = twice a day; CBC = complete blood count; Fe_NO = fractional exhaled nitric oxide; LFT = liver function test; LTE₄ = leukotriene E₄; TNSS = total nasal symptom scores.

Figure 2.

High-dose aspirin suppresses prostaglandin E₂ metabolite and increases cysteinyl leukotrienes in subjects with aspirin-exacerbated respiratory disease (AERD). Urinary eicosanoids were assessed at baseline and after 8 weeks of high-dose aspirin in subjects with AERD and aspirin-tolerant asthma (ATA). P values reflect a difference in change from baseline between the AERD and ATA groups. LTE₄ = leukotriene E₄ (AERD n = 40, ATA n = 13); PGD-M = prostaglandin D₂ metabolite (AERD n = 43, ATA n = 15); PGE-M = prostaglandin E₂ metabolite (AERD n = 43, ATA n = 15); TXB₂ = thromboxane B₂ (AERD n = 41, ATA n = 15). Data are expressed as means + SEM. *P < 0.05 and **P < 0.01.

Figure 3.

High-dose aspirin increases CRTH2⁺ peripheral blood cells in aspirin-exacerbated respiratory disease (AERD). Peripheral blood leukocyte counts at baseline and at 8 weeks on high-dose aspirin in subjects with AERD and aspirin-tolerant asthma (ATA). No difference in baseline eosinophil, basophil, monocyte, neutrophil, or platelet counts between ATA and AERD were observed. High-dose aspirin resulted in marked elevation of peripheral blood eosinophil (415–879/μl; P < 0.01) and basophil (43–66/μl; P < 0.01) counts, whereas no change was noted in neutrophils, monocytes, or platelets. Data are expressed as means + SEM. **P < 0.01.

Figure 4.

Platelet–leukocyte aggregates are increased in the blood of patients with aspirin-exacerbated respiratory disease (AERD) at baseline and do not change with 8 weeks of high-dose aspirin therapy. Percentages of leukocytes with adherent platelets (as determined by staining with CD61) in blood of aspirin-tolerant asthma control subjects (n = 15) and subjects with AERD (n = 36). Data are expressed as means + SEM. ATA = aspirin-tolerant asthma.

Figure 5.

Mast cell activation increases on high-dose aspirin and correlates with peripheral blood eosinophilia observed in aspirin-exacerbated respiratory disease (AERD). (A) Plasma total tryptase at baseline and on 8 weeks of high-dose aspirin in subjects with AERD and aspirin-tolerant asthma. Horizontal bars reflect group mean. **P < 0.01. (B) Plasma tryptase correlation (Pearson) with peripheral blood eosinophil counts on high-dose aspirin in subjects with AERD. ASA = aspirin; ATA = aspirin-tolerant asthma.