Abstract
Aspirin-exacerbated respiratory disease (AERD) refers to the combination of asthma, chronic rhinosinusitis with nasal polyposis, and acute upper and lower respiratory tract reactions to the ingestion of aspirin (acetylsalicylic acid, ASA) and other cyclooxygenase-1 inhibiting non-steroidal anti-inflammatory drugs. AERD affects 0.3–0.9 % of the general population. AERD generally occurs due to abnormalities in mediators and expression of arachidonic acid biosynthesis. Local IgE responses to staphylococcal enterotoxins may also be responsible for eosinophilic activation in the nasal polyp tissues of AERD patients. Clinical features of AERD include the onset of nasal congestion with anosmia, progressing to chronic pansinusitis and nasal polyps that regrow rapidly after surgery. Aspirin desensitization, Leukotriene-modifying agents, biologic agents, management of asthma, chronic rhinosinusitis, and nasal polyposis are recommended as treatment modalities. Immunotherapy is prescribed only to those AERD patients who experience clear seasonal or perennial allergy symptoms in addition to the symptoms attributable to chronic nasal polyposis. There are also investigational and dietary therapies. In this review, the important aspects of AERD will be presented, along with a literature survey.
Similar content being viewed by others
References
Laidlaw TM, Israel E (2016) Aspirin-exacerbated respiratory disease. In: Bochner BS (ed) UpToDate. http://www.uptodate.com/contents/aspirin-exacerbated-respiratory-disease. Accessed 2 May 2016
Lee RU, Stevenson DD (2011) Aspirin-exacerbated respiratory disease: evaluation and management. Allergy Asthma Immunol Res 3(1):3–10. doi:10.4168/aair.2011.3.1.3 (Epub 2010 Aug 20)
Choi JH, Kim JH, Park HS (2015) Upper airways in aspirin-exacerbated respiratory disease. Curr Opin Allergy Clin Immunol 15(1):21–26. doi:10.1097/ACI.0000000000000122
Berges-Gimeno MP, Simon RA, Stevenson DD (2002) The natural history and clinical characteristics of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol 89:474–478
Fahrenholz JM (2003) Natural history and clinical features of aspirin-exacerbated respiratory disease. Clin Rev Allergy Immunol 24(2):113–124
Szczeklik A, Nizankowska-Mogilnicka E, Sanak M (2009) Hypersensitivity to aspirin and non-steroidal anti-inflammatory drugs. In: Adkinson NF Jr, Bochner BS, Busse WW, Holgate ST, Lemanske RF Jr, Simons FER (eds) Middleton’s allergy: principles and practice, 7th edn. Mosby, New York, pp 1227–1240
Stevenson DD (2009) Aspirin sensitivity and desensitization for asthma and sinusitis. Curr Allergy Asthma Rep 9:155–163
Mullol J, Picado C (2013) Rhinosinusitis and nasal polyps in aspirin-exacerbated respiratory disease. Immunol Allergy Clin N Am 33:163–176
Jenkins C, Costello J, Hodge L (2004) Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. BMJ 328(7437):434
McDonald JR, Mathison DA, Stevenson DD (1972) Aspirin intolerance in asthma. Detection by oral challenge. J Allergy Clin Immunol 50(4):198–207
Weber RW, Hoffman M, Raine DA Jr, Nelson HS (1979) Incidence of bronchoconstriction due to aspirin, azo dyes, non-azo dyes, and preservatives in a population of perennial asthmatics. J Allergy Clin Immunol 64(1):32–37
Delaney JC (1976) The diagnosis of aspirin idiosyncrasy by analgesic challenge. Clin Allergy 6(2):177–181
Berges-Gimeno MP, Simon RA, Stevenson DD (2002) The natural history and clinical characteristics of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol 89(5):474–478
Rajan JP, Wineinger NE, Stevenson DD, White AA (2015) Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: a meta-analysis of the literature. J Allergy Clin Immunol 135(3):676–681
Szczeklik A, Nizankowska E, Duplaga M (2000) Natural history of aspirin-induced asthma. AIANE Investigators. European network on aspirin-induced asthma. Eur Respir J 16:432–436
Hamad AM, Sutcliffe AM, Knox AJ (2004) Aspirin-induced asthma: clinical aspects, pathogenesis and management. Drugs 64(21):2417–2432
Kanaoka Y, Boyce JA (2014) Cysteinyl leukotrienes and their receptors; emerging concepts. Allergy Asthma Immunol Res 6(4):288–295
Higashi N, Taniguchi M, Mita H, Kawagishi Y, Ishii T, Higashi A et al (2004) Clinical features of asthmatic patients with increased urinary leukotriene E4 excretion (hyperleukotrienuria): involvement of chronic hyperplastic rhinosinusitis with nasal polyposis. J Allergy Clin Immunol 113(2):277–283
Cai Y, Bjermer L, Halstensen TS (2003) Bronchial mast cells are the dominating LTC4S-expressing cells in aspirin-tolerant asthma. Am J Respir Cell Mol Biol 29(6):683–693
Cowburn AS, Sladek K, Soja J, Adamek L, Nizankowska E, Szczeklik A et al (1998) Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest 101(4):834–846
Nasser S, Christie PE, Pfister R, Sousa AR, Walls A, Schmitz-Schumann M et al (1996) Effect of endobronchial aspirin challenge on inflammatory cells in bronchial biopsy samples from aspirin-sensitive asthmatic subjects. Thorax 51(1):64–70
Fischer AR, Rosenberg MA, Lilly CM, Callery JC, Rubin P, Cohn J et al (1994) Direct evidence for a role of the mast cell in the nasal response to aspirin in aspirin-sensitive asthma. J Allergy Clin Immunol 94(6 Pt 1):1046–1056
Perez-Novo CA, Watelet JB, Claeys C, Van Cauwenberge P, Bachert C (2005) Prostaglandin, leukotriene, and lipoxin balance in chronic rhinosinusitis with and without nasal polyposis. J Allergy Clin Immunol 115(6):1189–1196
Choi GS, Kim JH, Shin YS, Ye YM, Kim SH, Park HS (2013) Eosinophil activation and novel mediators in the aspirin-induced nasal response in AERD. Clin Exp Allergy 43(7):730–740
Steinke JW, Liu L, Huyett P, Negri J, Payne SC, Borish L (2013) Prominent role of IFN-[gamma] in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 132:856–865
Suh Y, Yoon S, Sampson A, Kim HJ, Kim SH, Nahm DH et al (2004) Specific immunoglobulin E for staphylococcal enterotoxins in nasal polyps from patients with aspirin-intolerant asthma. Clin Exp Allergy 34(8):1270–1275
Pérez-Novo CA, Kowalski ML, Kuna P, Ptasinska A, Holtappels G, van Cauwenberge P et al (2004) Aspirin sensitivity and IgE antibodies to Staphylococcus aureus enterotoxins in nasal polyposis: studies on the relationship. Int Arch Allergy Immunol 133(3):255–260
Conley DB, Tripathi A, Seiberling KA, Schleimer RP, Suh LA, Harris K et al (2006) Superantigens and chronic rhinosinusitis: skewing of T-cell receptor V beta-distributions in polyp-derived CD4+ and CD8+ T cells. Am J Rhinol 20(5):534–539
Dursun AB, Woessner KA, Simon RA, Karasoy D, Stevenson DD (2008) Predicting outcomes of oral aspirin challenges in patients with asthma, nasal polyps, and chronic sinusitis. Ann Allergy Asthma Immunol 100(5):420–425
Stevenson DD, Szczeklik A (2006) Clinical and pathologic perspectives on aspirin sensitivity and asthma. J Allergy Clin Immunol 118(4):773–786
Pfaar O, Klimek L (2006) Eicosanoids, aspirin-intolerance and the upper airways—current standards and recent improvements of the desensitization therapy. J Physiol Pharmacol 57(Suppl 12):5–13
Milewski M, Mastalerz L, Nizankowska E, Szczeklik A (1998) Nasal provocation test with lysine-aspirin for diagnosis of aspirin-sensitive asthma. J Allergy Clin Immunol 101(5):581–586
Nizankowska E, Bestynska-Krypel A, Cmiel A, Szczeklik A (2000) Oral and bronchial provocation tests with aspirin for diagnosis of aspirin-induced asthma. Eur Respir J 15:863–869
Parikh AA, Scadding GK (2005) Intranasal lysine-aspirin in aspirin-sensitive nasal polyposis: a controlled trial. Laryngoscope 115(8):1385–1390
Graefe H, Roebke C, Schäfer D, Meyer JE (2012) Aspirin sensitivity and chronic rhinosinusitis with polyps: a fatal combination. J Allergy (Cairo) 2012:817910. doi:10.1155/2012/817910
Schäfer D, Maune S (2012) Pathogenic mechanisms and in vitro diagnosis of AERD. J Allergy (Cairo) 2012:789232
De Weck AL, Sanz ML, Gamboa PM, Aberer W, Blanca M, Correia S et al (2009) Nonsteroidal anti-inflammatory drug hypersensitivity syndrome. A multicenter study. I. Clinical findings and in vitro diagnosis. J Investig Allergol Clin Immunol 5:355–369
Kowalski M (2016) Aspirin exacerbated respiratory disease (AERD). http://www.worldallergy.org/professional/allergic_diseases_center/aspirin/. Accessed 5 May 2016
Gaber F, Daham K, Higashi A, Higashi N, Gülich A, Delin I et al (2008) Increased levels of cysteinyl-leukotrienes in saliva, induced sputum, urine and blood from patients with aspirin-intolerant asthma. Thorax 63:1076–1082
Corey EJ, Niwa H, Falck JR, Mioskowski C, Arai Y, Marfat A (1980) Recent studies on the chemical synthesis of eicosanoids. Adv Prostaglandin Thromboxane Res 6:19–25
Smith DL, Willis AL (1987) A suggested shorthand nomenclature for the eicosanoids. Lipids 22(12):983–986
Chilton FH, Fonteh AN, Surette ME, Triggiani M, Winkler JD (1996) Control of arachidonate levels within inflammatory cells. Biochim Biophys Acta 1299(1):1–15
Laneuville O, Breuer DK, Xu N, Huang ZH, Gage DA, Watson JT et al (1995) Fatty acid substrate specificities of human prostaglandin-endoperoxide H synthase-1 and -2. Formation of 12-hydroxy-(9Z, 13E/Z, 15Z)- octadecatrienoic acids from alpha-linolenic acid. J Biol Chem 270(33):19330–19336
Nizankowska-Mogilnicka E, Bochenek G, Mastalerz L, Swierczyńska M, Picado C, Scadding G et al (2007) EAACI/GA2LEN guideline: aspirin provocation tests for diagnosis of aspirin hypersensitivity. Allergy 62(10):1111–1118
Miller B, Mirakian R, Gane S, Larco J, Sannah AA, Darby Y et al (2013) Nasal lysine aspirin challenge in the diagnosis of aspirin: exacerbated respiratory disease: asthma and rhinitis. Clin Exp Allergy 43(8):874–880
Hopkins C, Browne JP, Slack R, Lund V, Brown P (2007) The Lund-Mackay staging system for chronic rhinosinusitis: how is it used and what does it predict? Otolaryngol Head Neck Surg 137(4):555–561
Samter M, Beers RF Jr (1968) Intolerance to aspirin. Clinical studies and consideration of its pathogenesis. Ann Intern Med 68(5):975–983
Widal MF, Abrami P, Lermeyez J (1922) Idiosyncratic anaphylaxis. Presse Med 30:189–192
Mascia K, Borish L, Patrie J, Hunt J, Phillips CD, Steinke JW (2005) Chronic hyperplastic eosinophilic sinusitis as a predictor of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol 94(6):652–657
Buchheit KM, Laidlaw TM (2016) Update on the management of aspirin-exacerbated respiratory disease. Allergy Asthma Immunol Res 8(4):298–304. doi:10.4168/aair.2016.8.4.298
Woessner KM, White AA (2014) Evidence-based approach to aspirin desensitization in aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 133(1):286.e1–9–287.e1–9
Kim YJ, Lim KH, Kim MY, Jo EJ, Lee SY, Lee SE et al (2014) Cross-reactivity to acetaminophen and celecoxib according to the type of nonsteroidal anti-inflammatory drug hypersensitivity. Allergy Asthma Immunol Res 6(2):156–162
Christie PE, Smith CM, Lee TH (1991) The potent and selective sulfidopeptide leukotriene antagonist, SK&F 104353, inhibits aspirin-induced asthma. Am Rev Respir Dis 144(4):957–958
Nasser SM, Bell GS, Foster S, Spruce KE, MacMillan R, Williams AJ et al (1994) Effect of the 5-lipoxygenase inhibitor ZD2138 on aspirin-induced asthma. Thorax 49(8):749–756
Dahlén SE, Malmström K, Nizankowska E, Dahlén B, Kuna P, Kowalski M et al (2002) Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med 165(1):9–14
Lee DK, Haggart K, Robb FM, Lipworth BJ (2004) Montelukast protects against nasal lysine-aspirin challenge in patients with aspirin-induced asthma. Eur Respir J 24(2):226–230
Israel E, Fischer AR, Rosenberg MA, Lilly CM, Callery JC, Shapiro J et al (1993) The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am Rev Respir Dis 148(6 Pt):1447–1451
Dahlén B, Nizankowska E, Szczeklik A, Zetterström O, Bochenek G, Kumlin M et al (1998) Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am J Respir Crit Care Med 157(4 Pt 1):1187–1194
Ta V, White AA (2015) Survey-defined patient experiences with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol Pract 3(5):711–718
Settipane RA, Schrank PJ, Simon RA, Mathison DA, Christiansen SC, Stevenson DD (1995) Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects. J Allergy Clin Immunol 96(4):480–485
Morales DR, Lipworth BJ, Guthrie B, Jackson C, Donnan PT, Santiago VH (2014) Safety risks for patients with aspirin-exacerbated respiratory disease after acute exposure to selective nonsteroidal anti-inflammatory drugs and COX-2 inhibitors: meta-analysis of controlled clinical trials. J Allergy Clin Immunol 134(1):40–45
Steinke JW, Culp JA, Kropf E, Borish L (2009) Modulation by aspirin of nuclear phospho-signal transducer and activator of transcription 6 expression: possible role in therapeutic benefit associated with aspirin desensitization. J Allergy Clin Immunol 124(4):724–730
Katial RK, Strand M, Prasertsuntarasai T, Leung R, Zheng W, Alam R (2010) The effect of aspirin desensitization on novel biomarkers in aspirin-exacerbated respiratory diseases. J Allergy Clin Immunol 126(4):738–744
Lee JY, Simon RA, Stevenson DD (2007) Selection of aspirin dosages for aspirin desensitization treatment in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 119:157–164
Berges-Gimeno MP, Simon RA, Stevenson DD (2003) Long-term treatment with aspirin desensitization in asthmatic patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 111:180–186
Gevaert P, Calus L, Van Zele T, Blomme K, De Ruyck N, Bauters W et al (2013) Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol 131(1):110.e1–116.e1
Gevaert P, Van Bruaene N, Cattaert T, Van Steen K, Van Zele T, Acke F et al (2011) Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal olyposis. J Allergy Clin Immunol 128(5):989.e1–8–995.e1–8
Menzella F, Lusuardi M, Galeone C, Taddei S, Zucchi L (2015) Profile of anti-IL-5 mAb mepolizumab in the treatment of severe refractory asthma and hypereosinophilic diseases. J Asthma Allergy 8:105–114
Bafadhel M, McCormick M, Saha S, McKenna S, Shelley M, Hargadon B et al (2012) Profiling of sputum inflammatory mediators in asthma and chronic obstructive pulmonary disease. Respiration 83(1):36–44
Menzella F, Lusuardi M, Galeone C, Zucchi L (2015) Tailored therapy for severe asthma. Multidiscip Respir Med 10(1):1
Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F et al (2012) EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 50(1):1–12
Ragab S, Parikh A, Darby YC, Scadding GK (2001) An open audit of montelukast, a leukotriene receptor antagonist, in nasal polyposis associated with asthma. Clin Exp Allergy 31(9):1385–1391
Awad OG, Lee JH, Fasano MB, Graham SM (2008) Sinonasal outcomes after endoscopic sinus surgery in asthmatic patients with nasal polyps: a difference between aspirin-tolerant and aspirin-induced asthma? Laryngoscope 118(7):1282–1286
Morrissey DK, Bassiouni A, Psaltis AJ, Naidoo Y, Wormald PJ (2016) Outcomes of modified endoscopic Lothrop in aspirin-exacerbated respiratory disease with nasal polyposis. Int Forum Allergy Rhinol. doi:10.1002/alr.21739 (Epub ahead of print)
Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F et al (2012) European position paper on rhinosinusitis and nasal polyps 2012. Rhinol Suppl 23:3 p preceding table of contents: 1–298
Klinkhardt U, Bauersachs R, Adams J, Graff J, Lindhoff-Last E, Harder S (2003) Clopidogrel but not aspirin reduces P-selectin expression and formation of platelet-leukocyte aggregates in patients with atherosclerotic vascular disease. Clin Pharmacol Ther 73:232–241
Laidlaw TM, Kidder MS, Bhattacharyya N, Xing W, Shen S, Milne GL et al (2012) Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes. Blood 119:3790–3798
Paruchuri S, Tashimo H, Feng C, Maekawa A, Xing W, Jiang Y et al (2009) Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor. J Exp Med 206:2543–2555
Cummings HE, Liu T, Feng C, Laidlaw TM, Conley PB, Kanaoka Y et al (2013) Cutting edge: Leukotriene C4 activates mouse platelets in plasma exclusively through the type 2 cysteinyl leukotriene receptor. J Immunol 191:5807–5810
Liu T, Laidlaw TM, Katz HR, Boyce JA (2013) Prostaglandin E2 deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes. Proc Natl Acad Sci USA 110:16987–16992
Kim SH, Choi JH, Park HS, Holloway JW, Lee SK, Park CS et al (2005) Association of thromboxane A2 receptor gene polymorphism with the phenotype of acetyl salicylic acid-intolerant asthma. Clin Exp Allergy 35:585–590
Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F et al (2013) Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 368:2455–2466
Beck LA, Thaçi D, Hamilton JD, Graham NM, Bieber T, Rocklin R et al (2014) Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med 371:130–139
Chudwin DS, Strub M, Golden HE, Frey C, Richmond GW, Luskin AT (1986) Sensitivity to non-acetylated salicylates in a patient with asthma, nasal polyps, and rheumatoid arthritis. Ann Allergy 57:133–134
Park HS, Lim YS, Suh JE, Rhu NS, Cho DI, Kim JW (1991) Sodium salicylate sensitivity in an asthmatic patient with aspirin sensitivity. J Korean Med Sci 6:113–117
Sommer DD, Hoffbauer S, Au M, Sowerby LJ, Gupta MK, Nayan S (2015) Treatment of aspirin exacerbated respiratory disease with a low salicylate diet: a pilot crossover study. Otolaryngol Head Neck Surg 152:42–47
Wood A, Baxter G, Thies F, Kyle J, Duthie G (2011) A systematic review of salicylates in food: estimated daily intake of a Scottish population. Mol Nutr Food Res suppl 1:S7–S14
Baxter GJ, Graham AB, Lawrence JR, Wiles D, Paterson JR (2001) Salicylic acid in soups prepared from organically and nonorganically grown vegetables. Eur J Nutr 40:289–292
Mitchell J, Skypala I (2013) Aspirin and salicylate in respiratory disease. Rhinology 51:195–205
Acknowledgments
The preparation of this paper (including design and planning) was supported by the Continuous Education and Scientific Research Association.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that there is no conflict of interest.
Ethical approval
This is a review, therefore there is no need for ethical approval.
Informed consent
This is a review, therefore there is no need for Informed consent.
There is no funding source for this manuscript
Rights and permissions
About this article
Cite this article
Sakalar, E.G., Muluk, N.B., Kar, M. et al. Aspirin-exacerbated respiratory disease and current treatment modalities. Eur Arch Otorhinolaryngol 274, 1291–1300 (2017). https://doi.org/10.1007/s00405-016-4273-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00405-016-4273-1