Mechanisms of allergy and clinical immunology
Prostaglandin D2: A dominant mediator of aspirin-exacerbated respiratory disease

https://doi.org/10.1016/j.jaci.2014.07.031Get rights and content

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.

Section snippets

Patient selection and stratification

Patients with AERD who underwent aspirin desensitization at Brigham and Women's Hospital (Boston, Massachusetts) between 2009 and 2014 and signed informed consent forms to have urine samples, blood samples, or both collected were included in the study. All subjects had a history of asthma, nasal polyposis, and characteristic respiratory reactions upon ingestion of COX-1 inhibitors. All were offered desensitization because of refractory rhinosinusitis, nasal polyposis, or both, as specified in

Clinical characteristics of patients and reactions

Between 2009 and 2014, 111 patients with AERD underwent aspirin desensitizations at our institution and agreed to participate in clinical research. Of these, 29 patients provided urine for eicosanoid analysis, and 11 provided blood for complete blood counts before desensitization and after 2 months of aspirin treatment. Twenty-three (group I) completed the desensitization and successfully initiated treatment with high-dose aspirin, while 6 (group II) were unable to tolerate the desensitization

Discussion

AERD involves complex dysregulation of proinflammatory (cysLTs and PGD2) and anti-inflammatory (PGE2) eicosanoid mediators. Clinical reactions to drugs that block COX-1 are characterized by increases in urinary LTE4 levels and have been thought to be largely driven by the effector functions of cysLTs.32 To our knowledge, ours is the first comprehensive examination of PG generation in patients with AERD undergoing a therapeutic desensitization procedure. Unexpectedly, subjects unable to tolerate

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    Supported by National Institutes of Health grants (National Institute of Allergy and Infectious Diseases: AI007306-27, U19 AI095219-01, and 5U19AI070412-06 with Opportunity Fund Subaward No. 153556/153044; and National Heart, Lung, Blood Institute: K23HL111113-02) and by generous contributions from the Vinik Family and the Kaye Family.

    Disclosure of potential conflict of interest: The authors have received research support from the National Institutes of Health/National Institute of Allergy and Infectious Diseases.

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