Aspirin-Exacerbated Respiratory Disease

Humans

To the Editor

Figure 1. Figure 1. The Prostaglandin Metabolic Pathway.

PGH2 is an unstable intermediary produced by the cyclooxygenase enzymes. PGH2 is then converted into the five primary prostanoids (prostaglandin D2 [PGD2], prostaglandin E2 [PGE2], prostaglandin F [PGF], prostaglandin I2 [PGI2], and thromboxane A2 [TXA2]) by their respective synthases.

In Figure 1 of the review article by White and Stevenson (Sept. 13 issue),1 there was an unfortunate, but important, misrepresentation of the prostaglandin E2 (PGE2) synthesis pathway. The figure incorrectly shows PGE2 as a downstream product of the sequential metabolism of prostaglandin I2 (PGI2), prostaglandin F2 (PGF2), and prostaglandin D2 (PGD2). Instead, PGE2, PGD2, prostaglandin F, and PGI2 are each independently synthesized from prostaglandin H2 (PGH2) through different enzymes (Figure 1).2 The synthesis of PGE2 from PGH2 is catalyzed by four distinct PGE synthase enzymes: microsomal PGE synthase-1 (mPGES-1), cytosolic PGE synthase (cPGES), microsomal PGE synthase-2 (mPGES-2), and glutathione-S-transferase μ (GSTμ).3

The figure correctly shows that the generation of the cysteinyl leukotrienes is sequential from the immediate upstream product (leukotriene E4 [LTE4] from leukotriene D4 [LTD4] and LTD4 from leukotriene C4 [LTC4]), so the arrows are accurate in this part of the figure. However, there should be individual arrows from PGH2 to PGD2, PGE2, PGF, and PGI2 — similar to the arrow from PGH2 to thromboxane A2 (TXA2) (Figure 1). This is important because the figure in the article by White and Stevenson implies that inhibition of PGI synthase, PGF synthase, or the prostaglandin D synthases (hematopoietic PGD synthase or lipocalin PGD synthase) will block production of PGE2.

Mark Rusznak, B.A.
Stokes Peebles, M.D.
Vanderbilt University Medical Center, Nashville, TN

No potential conflict of interest relevant to this letter was reported.

  1. 1. White AA, Stevenson DD. Aspirin-exacerbated respiratory disease. N Engl J Med 2018;379:10601070.

  2. 2. Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 2004;56:387437.

  3. 3. Murakami M, Kudo I. Recent advances in molecular biology and physiology of the prostaglandin E2-biosynthetic pathway. Prog Lipid Res 2004;43:335.

To the Editor

As a practicing pulmonologist who sees many patients with aspirin-exacerbated respiratory disease (AERD), I would raise two points about the article by White and Stevenson. First, it seems questionable that tests to detect sensitivity to acetylsalicylic acid (aspirin) are in fact necessary to confirm the diagnosis of AERD in most patients as the authors implied. Many patients have such a classic presentation of “Samter’s triad” (nasal polyps, asthma, and sensitivity to aspirin) that formal testing appears to be both unnecessary and unduly burdensome.1 Second, it would have been helpful to include a discussion of the role of newer biologic agents such as omalizumab (Xolair) (a monoclonal antibody against IgE) or mepolizumab (Nucala) (an anti–interleukin-5 monoclonal antibody) in the management of this disease.2,3 In particular, my colleagues and I have noted substantial success with the use of omalizumab, specifically in patients with persistently active asthma or with poor compliance that was thought to preclude safe, effective, or lasting desensitization.

Duncan M. Kuhn, M.D.
Cambridge Health Alliance, Cambridge, MA

No potential conflict of interest relevant to this letter was reported.

  1. 1. Laidlaw TM, Israel E. Aspirin-exacerbated respiratory disease. UpToDate. Waltham, MA: UpToDate, 2018.

  2. 2. Le Pham D, Lee JH, Park HS. Aspirin-exacerbated respiratory disease: an update. Curr Opin Pulm Med 2017;23:8996.

  3. 3. Tuttle KL, Buchheit KM, Laidlaw TM, Cahill KN. A retrospective analysis of mepolizumab in subjects with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol Pract 2018;6:10451047.

Response

The authors reply: We appreciate the proper depiction of the prostaglandin metabolic pathway in the figure provided by Rusznak and Peebles.

In reply to Kuhn: although some patients have a classic presentation and history of AERD, we disagree that it is unnecessary to clarify the diagnosis of AERD through an aspirin challenge in most patients. An oral aspirin challenge or desensitization should be considered in all patients with rhinosinusitis and asthma who report any history of respiratory symptoms after ingesting nonsteroidal antiinflammatory drugs (NSAIDs), since 15 to 20% of patients with asthma who have pansinusitis and who report a history of respiratory symptoms after ingesting NSAIDs will have a negative aspirin challenge.1 Also, approximately one eighth of patients with rhinosinusitis and asthma who have not recognized respiratory symptoms after ingestion of NSAIDs or might not take NSAIDs at all actually have AERD.2 Finally, in most clinics, the aspirin challenge and aspirin desensitization occur simultaneously. In patients with suspected AERD, desensitization is planned, and thus the initial part of the challenge confirms the diagnosis and the rest of the process successfully desensitizes the patient. Treatment with aspirin after desensitization is now recognized as the standard of care for patients with AERD; therefore, aspirin desensitization is usually planned. However, in cases in which the history is unclear, the patient does not wish to receive daily aspirin, or the use of aspirin is contradicted, a challenge should still be considered to make a proper diagnosis and determination of the phenotype. The aspirin challenge plus desensitization is now streamlined to be completed in 1 or 2 days. Kuhn also mentions the exciting topic of new biologic agents for patients with asthma. Although it is likely that in the future these agents will play a therapeutic role in the treatment of patients with AERD, studies of biologic therapy for AERD are scant. Currently, the role of biologic agents in AERD is limited to the Food and Drug Administration–approved indications for poorly controlled asthma.

Andrew A. White, M.D.
Donald D. Stevenson, M.D.
Scripps Clinic, San Diego, CA

Since publication of their article, Dr. White reports receiving lecture fees from Regeneron. No further potential conflict of interest relevant to this letter was reported.

  1. 1. Dursun AB, Woessner KA, Simon RA, Karasoy D, Stevenson DD. Predicting outcomes of oral aspirin challenges in patients with asthma, nasal polyps, and chronic sinusitis. Ann Allergy Asthma Immunol 2008;100:420425.

  2. 2. Szczeklik A, Nizankowska E, Duplaga M. Natural history of aspirin-induced asthma. Eur Respir J 2000;16:432436.

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