Immunologic effects of aspirin desensitization and high-dose aspirin therapy in aspirin-exacerbated respiratory disease

Abstract

Respiratory reactions occurring minutes to hours following the ingestion of a COX-1 inhibitor represent the sine qua non of aspirin-exacerbated respiratory disease (AERD). Clinicians and researchers have capitalized on these unique respiratory reactions to COX-1 inhibitors to establish the diagnosis of AERD, differentiate the unique inflammatory state of AERD from aspirin-tolerant asthma (ATA) or chronic rhinosinusitis with nasal polyposis, and achieve a state of desensitization to initiate daily aspirin therapy. The clinical benefits of high-dose (325-1300 mg daily) aspirin therapy in AERD are well established and have been recently summarized by Stevens et al.1Stevens W.W. Jerschow E. Baptist A.P. Borish L. Bosso J.V. Buchheit K.M. et al.The role of aspirin desensitization followed by oral aspirin therapy in managing patients with aspirin-exacerbated respiratory disease: a work group report from the Rhinitis, Rhinosinusitis and Ocular Allergy Committee of the American Academy of Allergy, Asthma & Immunology.J Allergy Clin Immunol. 2021; 147: 827-844Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Here, we will review our current understanding of the immunologic impact of aspirin exposure during desensitization and daily high-dose therapy in AERD. In the chronic disease state, AERD is classically characterized by 3 cardinal immunologic derangements: dysregulated lipid mediator production, chronic mast cell activation, and upper and lower respiratory tract type 2 (T2) inflammation.2Cahill K.N. Cui J. Kothari P. Murphy K. Raby B.A. Singer J. et al.Unique effect of aspirin therapy on biomarkers in aspirin-exacerbated respiratory disease. A prospective trial.Am J Respir Crit Care Med. 2019; 200: 704-711Crossref PubMed Scopus (25) Google Scholar Impairments in prostaglandin E2 (PGE2) production and/or signaling contribute to abundant cysteinyl leukotriene (cysLT) production and T2 cytokine production.3Cavagnero K.J. Doherty T.A. Lipid-mediated innate lymphoid cell recruitment and activation in aspirin-exacerbated respiratory disease.Ann Allergy Asthma Immunol. 2021; 126: 135-142Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Epithelial-derived cytokines, IL-33 and thymic stromal lymphopoietin (TSLP), and local immunoglobulin E, which are abundant in the nasal polyp tissue in AERD, cysLTs, and reduced PGE2 level drive chronic mast cell activation with further production of cysLTs and PGD2.4Boyce J.A. Aspirin sensitivity: Lessons in the regulation (and dysregulation) of mast cell function.J Allergy Clin Immunol. 2019; 144: 875-881Abstract Full Text Full Text PDF PubMed Google Scholar PGD2 in turn recruits effector cells expressing D prostanoid receptor, also known as chemoattractant receptor-homologous molecule expressed on TH2 (CRTH2) cells, such as eosinophils, basophils, group 2 innate lymphoid cells (ILC2s), and TH2 cells, to the respiratory tract, whereas cysLTs increase mucus production. Both PGD2 and cysLTs trigger bronchospasm. Together, these immunologic derangements result in a chronic disease state that is often characterized by severe asthma and aggressive nasal polyp regrowth. Aspirin challenge involves exposure to increasing doses of aspirin until the onset of classical respiratory symptoms. Aspirin desensitization is the process by which we attain tolerance of aspirin in patients with AERD. Aspirin desensitization is achieved through the administration of higher doses of aspirin after the initial respiratory reaction occurs; remarkably, the aspirin-induced reactions subside, and higher doses are tolerated. Aspirin desensitization can be successfully achieved in most patients with AERD and allows for the initiation of daily aspirin therapy for AERD treatment or other medical indication. There are multiple published challenge and desensitization protocols, all of which are effective at achieving their diagnostic or therapeutic goal.1Stevens W.W. Jerschow E. Baptist A.P. Borish L. Bosso J.V. Buchheit K.M. et al.The role of aspirin desensitization followed by oral aspirin therapy in managing patients with aspirin-exacerbated respiratory disease: a work group report from the Rhinitis, Rhinosinusitis and Ocular Allergy Committee of the American Academy of Allergy, Asthma & Immunology.J Allergy Clin Immunol. 2021; 147: 827-844Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar To maximize safety, cysLT1 receptor antagonist pretreatment is used to attenuate the aspirin-induced decline in FEV1. The collection of biospecimens during standardized aspirin challenge and/or desensitization protocols has been foundational to our current understanding of the unique immunology of AERD. During a standardized aspirin challenge and/or desensitization protocol, the 3 cardinal immunologic derangements observed in the baseline AERD state are all enhanced (Fig 1, A). Aspirin-induced reactions typically occur at low doses (20-160 mg) that preferentially suppress COX-1. Impaired COX-2 expression and induction are reported in AERD, making patients more dependent on COX-1 activity to maintain PGE2 production.4Boyce J.A. Aspirin sensitivity: Lessons in the regulation (and dysregulation) of mast cell function.J Allergy Clin Immunol. 2019; 144: 875-881Abstract Full Text Full Text PDF PubMed Google Scholar In addition to serving as a modest bronchodilator, PGE2 restrains 5-lipoxygenase (5-LO) phosphorylation and translocation to the nuclear membrane, thereby decreasing leukotriene production, and it serves as an inhibitor of mast cell activation.4Boyce J.A. Aspirin sensitivity: Lessons in the regulation (and dysregulation) of mast cell function.J Allergy Clin Immunol. 2019; 144: 875-881Abstract Full Text Full Text PDF PubMed Google Scholar Pretreatment with inhaled PGE2 abolished the aspirin-induced decline in FEV1 and the systemic surge in cysLTs measured by the stable end metabolite urinary LTE4 (uLTE4), demonstrating the importance of PGE2. Additionally, nasal polyp mast cells express greater amounts of COX-2 than COX-1.4Boyce J.A. Aspirin sensitivity: Lessons in the regulation (and dysregulation) of mast cell function.J Allergy Clin Immunol. 2019; 144: 875-881Abstract Full Text Full Text PDF PubMed Google Scholar The early inhibition of COX-1, before COX-2 inhibition, is believed to allow massive mast cell PGD2 production in the face of a COX inhibitor.4Boyce J.A. Aspirin sensitivity: Lessons in the regulation (and dysregulation) of mast cell function.J Allergy Clin Immunol. 2019; 144: 875-881Abstract Full Text Full Text PDF PubMed Google Scholar Both local respiratory tract and systemic mast cell activation, as measured by histamine and tryptase levels, occur after exposure to aspirin.4Boyce J.A. Aspirin sensitivity: Lessons in the regulation (and dysregulation) of mast cell function.J Allergy Clin Immunol. 2019; 144: 875-881Abstract Full Text Full Text PDF PubMed Google Scholar,5Cahill K.N. Murphy K. Singer J. Israel E. Boyce J.A. Laidlaw T.M. Plasma tryptase elevation during aspirin-induced reactions in aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2019; 143: 799-803.e2Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar We reported that up to 50% of subjects with AERD experience systemic mast cell activation during an aspirin challenge and/or desensitization protocol.5Cahill K.N. Murphy K. Singer J. Israel E. Boyce J.A. Laidlaw T.M. Plasma tryptase elevation during aspirin-induced reactions in aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2019; 143: 799-803.e2Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Systemic mast cell activation is associated with greater uLTE4 and urinary PGD2 metabolite production and greater declines in FEV1 during the 3 hours after reaction onset.5Cahill K.N. Murphy K. Singer J. Israel E. Boyce J.A. Laidlaw T.M. Plasma tryptase elevation during aspirin-induced reactions in aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2019; 143: 799-803.e2Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Clinically, such patients report extrarespiratory symptoms involving the skin and gastrointestinal tract, both of which are associated with PGD2 production, likely reflecting synergy between IL-33 and TSLP and signaling at the DP1 receptor triggering vasodilation.4Boyce J.A. Aspirin sensitivity: Lessons in the regulation (and dysregulation) of mast cell function.J Allergy Clin Immunol. 2019; 144: 875-881Abstract Full Text Full Text PDF PubMed Google Scholar, 5Cahill K.N. Murphy K. Singer J. Israel E. Boyce J.A. Laidlaw T.M. Plasma tryptase elevation during aspirin-induced reactions in aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2019; 143: 799-803.e2Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 6Cahill K.N. Bensko J.C. Boyce J.A. Laidlaw T.M. Prostaglandin D(2): a dominant mediator of aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2015; 135: 245-252Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar Whereas mast cells are central to the chronic and acute inflammatory state in AERD, other inflammatory cells participate in aspirin-induced reactions and contribute to cysLT generation. Patients with AERD have increased circulating and tissue-resident platelet-leukocyte aggregates (PLAs) in the chronic disease state. Platelets contain the LTC4 synthase required to convert LTA4 into cysLTs and produce the potent bronchoconstrictor thromboxane A2 when activated. When bound to neutrophils, which lack LTC4 synthase but contain the 5-LO, platelets provide yet another unique source of cysLTs. The decline in PGE2 and loss of restraint on 5-LO activity is anticipated to affect PLAs and enhance cysLT generation. Laidlaw et al demonstrated that aspirin exposure does not significantly alter peripheral blood PLA numbers or platelet activation state.7Laidlaw T.M. Cahill K.N. Cardet J.C. Murphy K. Cui J. Dioneda B. et al.A trial of type 12 purinergic (P2Y12) receptor inhibition with prasugrel identifies a potentially distinct endotype of patients with aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2019; 143: 316-324.e7Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar However, they identified a subset of patients with a higher level of baseline PLAs who when pretreated with the platelet activation inhibitor prasugrel, demonstrated reduced uLTE4 and urinary PGD2 metabolite production, no increase in plasma tryptase level, and no reaction to aspirin.7Laidlaw T.M. Cahill K.N. Cardet J.C. Murphy K. Cui J. Dioneda B. et al.A trial of type 12 purinergic (P2Y12) receptor inhibition with prasugrel identifies a potentially distinct endotype of patients with aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2019; 143: 316-324.e7Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar This supports platelet activation, at least in some patients, is contributing to the inflammatory state triggered by aspirin. Mediator production from mast cells, specifically PGD2, is believed to contribute to an acute influx of inflammatory cells into the respiratory tissue. Studies have demonstrated the efflux of CRTH2+ eosinophils and ILC2 from the bloodstream and the influx of CRTH2+ ILC2s into the nasal mucosa within hours of reaction onset.3Cavagnero K.J. Doherty T.A. Lipid-mediated innate lymphoid cell recruitment and activation in aspirin-exacerbated respiratory disease.Ann Allergy Asthma Immunol. 2021; 126: 135-142Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Studies with CRTH2 antagonists, which have not yet been performed in subjects with AERD, are required to confirm this mechanism. The respiratory symptoms triggered by COX-1 inhibition classically peak and wane over a period of 3 hours, even without intervention. Once symptoms have subsided, higher doses of aspirin are generally tolerated without further respiratory symptoms, signaling that desensitization has been achieved. As daily high-dose aspirin therapy provides clinical benefit,1Stevens W.W. Jerschow E. Baptist A.P. Borish L. Bosso J.V. Buchheit K.M. et al.The role of aspirin desensitization followed by oral aspirin therapy in managing patients with aspirin-exacerbated respiratory disease: a work group report from the Rhinitis, Rhinosinusitis and Ocular Allergy Committee of the American Academy of Allergy, Asthma & Immunology.J Allergy Clin Immunol. 2021; 147: 827-844Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar the immunologic changes in patients undergoing high-dose aspirin therapy may at first seem counterintuitive (Fig 1, B). Two studies assessed the impact of 8 weeks of aspirin in a dose of 1300 mg daily in patients with AERD,2Cahill K.N. Cui J. Kothari P. Murphy K. Raby B.A. Singer J. et al.Unique effect of aspirin therapy on biomarkers in aspirin-exacerbated respiratory disease. A prospective trial.Am J Respir Crit Care Med. 2019; 200: 704-711Crossref PubMed Scopus (25) Google Scholar,6Cahill K.N. Bensko J.C. Boyce J.A. Laidlaw T.M. Prostaglandin D(2): a dominant mediator of aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2015; 135: 245-252Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar with one of these studies including important information from a cohort of patients with ATA who were also exposed to high-dose aspirin.2Cahill K.N. Cui J. Kothari P. Murphy K. Raby B.A. Singer J. et al.Unique effect of aspirin therapy on biomarkers in aspirin-exacerbated respiratory disease. A prospective trial.Am J Respir Crit Care Med. 2019; 200: 704-711Crossref PubMed Scopus (25) Google Scholar High-dose aspirin inhibits COX products, including PGE2, PGD2, prostacyclin, and thromboxane A2 in subjects with AERD.6Cahill K.N. Bensko J.C. Boyce J.A. Laidlaw T.M. Prostaglandin D(2): a dominant mediator of aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2015; 135: 245-252Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar Subjects with ATA demonstrate no appreciable change in systemic PGE2 metabolite levels, whereas systemic PGD2 metabolites decrease in subjects taking aspirin in a dose of 1300 mg daily.2Cahill K.N. Cui J. Kothari P. Murphy K. Raby B.A. Singer J. et al.Unique effect of aspirin therapy on biomarkers in aspirin-exacerbated respiratory disease. A prospective trial.Am J Respir Crit Care Med. 2019; 200: 704-711Crossref PubMed Scopus (25) Google Scholar The inability of subjects to maintain PGE2 levels when taking high-dose aspirin in AERD highlights the fundamental difference between AERD and aspirin-tolerant T2 inflammation and further cements the critical role of PGE2 as a key anti-inflammatory mediator in the respiratory tract. With the decrease in PGE2 level, it is not at all surprising that we observe a concomitant rise in cysLT levels and increased mast cell activation, as assessed by serum tryptase level in subjects taking high-dose aspirin.2Cahill K.N. Cui J. Kothari P. Murphy K. Raby B.A. Singer J. et al.Unique effect of aspirin therapy on biomarkers in aspirin-exacerbated respiratory disease. A prospective trial.Am J Respir Crit Care Med. 2019; 200: 704-711Crossref PubMed Scopus (25) Google Scholar Circulating PLAs, a possible source of increased cysLTs, are unchanged by high-dose aspirin. What is surprising is the clinical benefit derived from high-dose aspirin despite enhanced cysLT generation, which has been reported even after 52-weeks of aspirin therapy,8Tyrak K.E. Pajdzik K. Jakiela B. Kuprys-Lipinska I. Cmiel A. Kacorzyk R. et al.Biomarkers for predicting response to aspirin therapy in aspirin-exacerbated respiratory disease [e-pub ahead of print].Clin Exp Allergy. 2021; (Accessed May 5, 2021)https://doi.org/10.1111/cea.13886Crossref PubMed Scopus (4) Google Scholar and ongoing mast cell activation. Sousa et al observed that cysLT1 receptor expression on nasal biopsy specimens decreases by 2 weeks of receiving daily aspirin therapy,9Sousa A.R. Parikh A. Scadding G. Corrigan C.J. Lee T.H. Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis.N Engl J Med. 2002; 347: 1493-1499Crossref PubMed Scopus (325) Google Scholar supporting reduced end-organ reactivity to cysLTs as one mechanism by which higher cysLT production is tolerated. Additionally, aspirin has been shown to inhibit STAT6, a key transcription factor involved in T2 inflammation, and reduce sputum IL-4 levels after 6 months of high-dose aspirin therapy.10Katial R.K. Strand M. Prasertsuntarasai T. Leung R. Zheng W. Alam R. The effect of aspirin desensitization on novel biomarkers in aspirin-exacerbated respiratory diseases.J Allergy Clin Immunol. 2010; 126: 738-744Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Reductions in PGD2 levels in subjects receiving high-dose aspirin therapy also contribute to clinical benefit. A decline in tissue PGD2 level decreases the recruitment of CRTH2+ cells into the respiratory tract. We demonstrated a rise in blood eosinophil and basophil counts without a change in CRTH2– blood cells at 8 weeks of high-dose aspirin.2Cahill K.N. Cui J. Kothari P. Murphy K. Raby B.A. Singer J. et al.Unique effect of aspirin therapy on biomarkers in aspirin-exacerbated respiratory disease. A prospective trial.Am J Respir Crit Care Med. 2019; 200: 704-711Crossref PubMed Scopus (25) Google Scholar PGD2 is also a known driver of IL-4, IL-5, IL-9, and IL-13 cytokine production from ILC2s.3Cavagnero K.J. Doherty T.A. Lipid-mediated innate lymphoid cell recruitment and activation in aspirin-exacerbated respiratory disease.Ann Allergy Asthma Immunol. 2021; 126: 135-142Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar The decline in PGD2 may also reduce the capacity of remaining tissue-resident ILC2s to promote T2 inflammation. This lends further credence to the potential therapeutic benefit of suppressing PGD2 signaling with selective CRTH2+ antagonists. However, PGD2 is not the only eicosanoid to regulate ILC2 activation (recently summarized elsewhere3Cavagnero K.J. Doherty T.A. Lipid-mediated innate lymphoid cell recruitment and activation in aspirin-exacerbated respiratory disease.Ann Allergy Asthma Immunol. 2021; 126: 135-142Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). We still lack a comprehensive understanding of the impact of high-dose aspirin therapy on the balance between anti-inflammatory (PGE2 and prostacyclin) and proinflammatory (PGD2 and cysLTs) eicosanoids in the respiratory tract. Standardized aspirin challenge and desensitization protocols and high-dose aspirin therapy provide an in vivo snapshot of eicosanoid regulation of respiratory tract T2 inflammation. Selective suppression of PGD2 production and/or signaling is likely to be beneficial in patients with AERD, although this has not been studied. We and others have reported that some patients with AERD fail to tolerate aspirin desensitization and/or high-dose aspirin therapy owing to inflammatory side effects.6Cahill K.N. Bensko J.C. Boyce J.A. Laidlaw T.M. Prostaglandin D(2): a dominant mediator of aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2015; 135: 245-252Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar The significant rise in mast cell activation and cysLT generation resulting from a loss of PGE2 signaling supports the idea that abundant, unchecked mast cell activation may be responsible. Would direct inhibition of mast cells abolish aspirin-induced reactions and provide clinical benefit in AERD? If an appropriately safe and selective mast cell inhibitor were made available, I would start here. What happens to cysLT3R expression, the recently described LTE4 receptor, in the face of abundant LTE4? Why does aspirin but not other reversible COX inhibitors provide clinical benefit? Are IL-33 and TSLP affected by acute or chronic aspirin exposure? Questions remain, and future research is likely to yield mechanistic insights into both aspirin-intolerant and aspirin-tolerant T2 inflammation. I gratefully acknowledge the many patients with AERD who donated their time, blood, urine, and tissue to help unravel the mystery of aspirin desensitization and high-dose aspirin therapy in AERD, as well as the small but mighty international research community fascinated by this mystery.