Clin Exp Otorhinolaryngol.  2018 Jun;11(2):71-80. 10.21053/ceo.2017.01606.

Samter's Triad: State of the Art

• Kim SD
• Cho KS

• KMID: 2412663
• DOI: http://doi.org/10.21053/ceo.2017.01606

Abstract

Samter's triad (ST) is a well-known disease characterized by the triad of bronchial asthma, nasal polyps, and aspirin intolerance. Over the past few years, a rapid development in the knowledge of the pathogenesis and clinical characteristics of ST has happened. The aim of this paper is to review the recent investigations on the pathophysiological mechanisms and genetic background, diagnosis, and different therapeutic options of ST to advance our understanding of the mechanism and the therapeutic control of ST. As concern for ST increase, more application of aspirin desensitization will be required to manage this disease successfully. There is also a need for continued research efforts in pathophysiology, treatment, and possible prevention.

Keyword

Aspirin; Asthma; Nasal Polyps; Sinusitis; Desensitization; Physiopathology

MeSH Terms

Aspirin
Asthma
Diagnosis
Genetic Background
Nasal Polyps
Sinusitis
Aspirin

Figure

• 

  Fig. 1. Metabolic pathway of arachidonic acid. Via the cyclooxygenase (COX) pathway, prostanoids (prostaglandins [PG], prostacyclins [PGI2], and thromboxanes) are formed, whereas the lipoxygenase (LO) pathway produces leukotrienes (LT). PLA2, phospholipase A2; FLAP, 5-LO activating protein; HPETE, hydroperoxyeicosatetraenoic acid; PGG2, prostaglandin G2; LTA4, leukotriene A4; PGH2, prostaglandin H2; LTC4, leukotriene C4; LTB4, leukotriene B4; Cys-LTs, cysteinyl leukotrienes; LTD4, leukotriene D4; LTE4, leukotriene E4; TXA2, thromboxane A2; PGE2, prostaglandin E2; PGD2, prostaglandin D2; PGF2, prostaglandin F2.

• 

  Fig. 2. Pathogenetic mechanism of Samter’s triad. Aspirin inhibits the cyclooxygenase (COX) pathway and diverts arachidonic acid metabolites to the lipoxygenase (LO) pathway. By inhibition of COX-1, the production of prostaglandin E2 (PGE2) decreases. Low levels of PGE2 lead to increased synthesis of cysteinyl leukotrienes (Cys-LTs). The inhibition of COX-2 might lead to a structural change in the enzyme, which results in the increase of prostaglandin D2 (PGD2). PLA2, phospholipase A2; FLAP, 5-LO activating protein; HPETE, hydroperoxyeicosatetraenoic acid; PGG2, prostaglandin G2; LTA4, leukotriene A4; PGH2, prostaglandin H2; LTC4, leukotriene C4; ASA: acetylsalicylic acid, NSAID, nonsteroidal anti-inflammatory drug; LTB4, leukotriene B4; LTD4, leukotriene D4; LTE4, leukotriene E4.

Reference

1. Widal F, Abrami P, Lermoyez J. First complete description of the aspirin idiosyncrasy-asthma-nasal polyposis syndrome (plus urticaria): 1922 (with a note on aspirin desensitization). By F. Widal, P. Abrami, J. Lermoyez. J Asthma. 1987; 24(5):297–300.

2. Samter M, Beers RF Jr. Intolerance to aspirin. clinical studies and consideration of its pathogenesis. Ann Intern Med. 1968; May. 68(5):975–83.

3. Stevenson DD, Sanchez-Borges M, Szczeklik A. Classification of allergic and pseudoallergic reactions to drugs that inhibit cyclooxygenase enzymes. Ann Allergy Asthma Immunol. 2001; Sep. 87(3):177–80.

4. Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004; May. 113(5):832–6.

5. Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol. 2003; May. 111(5):913–21.

6. Babu KS, Salvi SS. Aspirin and asthma. Chest. 2000; Nov. 118(5):1470–6.

7. Szczeklik A, Sanak M, Nizankowska-Mogilnicka E, Kiełbasa B. Aspirin intolerance and the cyclooxygenase-leukotriene pathways. Curr Opin Pulm Med. 2004; Jan. 10(1):51–6.

8. Pfaar O, Klimek L. Aspirin desensitization in aspirin intolerance: update on current standards and recent improvements. Curr Opin Allergy Clin Immunol. 2006; Jun. 6(3):161–6.

9. Stevenson DD, Szczeklik A. Clinical and pathologic perspectives on aspirin sensitivity and asthma. J Allergy Clin Immunol. 2006; Oct. 118(4):773–86.

10. Vally H, Taylor ML, Thompson PJ. The prevalence of aspirin intolerant asthma (AIA) in Australian asthmatic patients. Thorax. 2002; Jul. 57(7):569–74.

11. Jenkins C, Costello J, Hodge L. Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. BMJ. 2004; Feb. 328(7437):434.

12. Delaney JC. The diagnosis of aspirin idiosyncrasy by analgesic challenge. Clin Allergy. 1976; Mar. 6(2):177–81.

13. Weber RW, Hoffman M, Raine DA Jr, Nelson HS. Incidence of bronchoconstriction due to aspirin, azo dyes, non-azo dyes, and preservatives in a population of perennial asthmatics. J Allergy Clin Immunol. 1979; Jul. 64(1):32–7.

14. 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; May. 100(5):420–5.

15. Berges-Gimeno MP, Simon RA, Stevenson DD. The natural history and clinical characteristics of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol. 2002; Nov. 89(5):474–8.

16. Szczeklik A, Nizankowska E, Duplaga M. Natural history of aspirin-induced asthma. AIANE investigators. European Network on Aspirin-Induced Asthma. Eur Respir J. 2000; Sep. 16(3):432–6.

17. Kidon MI, Kang LW, Chin CW, Hoon LS, See Y, Goh A, et al. Early presentation with angioedema and urticaria in cross-reactive hypersensitivity to nonsteroidal antiinflammatory drugs among young, Asian, atopic children. Pediatrics. 2005; Nov. 116(5):e675–80.

18. Kim JE, Kountakis SE. The prevalence of Samter’s triad in patients undergoing functional endoscopic sinus surgery. Ear Nose Throat J. 2007; Jul. 86(7):396–9.

19. Szczeklik A, Sanak M. The role of COX-1 and COX-2 in asthma pathogenesis and its significance in the use of selective inhibitors. Clin Exp Allergy. 2002; Mar. 32(3):339–42.

20. Chavis C, Vachier I, Godard P, Bousquet J, Chanez P. Lipoxins and other arachidonate derived mediators in bronchial asthma. Thorax. 2000; Oct. 55 Suppl 2:S38–41.

21. Stevenson DD. Aspirin sensitivity and desensitization for asthma and sinusitis. Curr Allergy Asthma Rep. 2009; Mar. 9(2):155–63.

22. Cowburn AS, Sladek K, Soja J, Adamek L, Nizankowska E, Szczeklik A, et al. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest. 1998; Feb. 101(4):834–46.

23. Adamjee J, Suh YJ, Park HS, Choi JH, Penrose JF, Lam BK, et al. Expression of 5-lipoxygenase and cyclooxygenase pathway enzymes in nasal polyps of patients with aspirin-intolerant asthma. J Pathol. 2006; Jul. 209(3):392–9.

24. Steinke JW, Borish L. Factors driving the aspirin exacerbated respiratory disease phenotype. Am J Rhinol Allergy. 2015; Jan-Feb. 29(1):35–40.

25. Hamad AM, Sutcliffe AM, Knox AJ. Aspirin-induced asthma: clinical aspects, pathogenesis and management. Drugs. 2004; 64(21):2417–32.

26. Gaber F, Daham K, Higashi A, Higashi N, Gulich A, Delin I, et al. Increased levels of cysteinyl-leukotrienes in saliva, induced sputum, urine and blood from patients with aspirin-intolerant asthma. Thorax. 2008; Dec. 63(12):1076–82.

27. Capra V. Molecular and functional aspects of human cysteinyl leukotriene receptors. Pharmacol Res. 2004; Jul. 50(1):1–11.

28. Hui Y, Funk CD. Cysteinyl leukotriene receptors. Biochem Pharmacol. 2002; Dec. 64(11):1549–57.

29. Jenneck C, Juergens U, Buecheler M, Novak N. Pathogenesis, diagnosis, and treatment of aspirin intolerance. Ann Allergy Asthma Immunol. 2007; Jul. 99(1):13–21.

30. Sousa AR, Parikh A, Scadding G, Corrigan CJ, Lee TH. Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis. N Engl J Med. 2002; Nov. 347(19):1493–9.

31. Kim SH, Ye YM, Hur GY, Lee SK, Sampson AP, Lee HY, et al. CysLTR1 promoter polymorphism and requirement for leukotriene receptor antagonist in aspirin-intolerant asthma patients. Pharmacogenomics. 2007; Sep. 8(9):1143–50.

32. Peters-Golden M, Henderson WR Jr. Leukotrienes. N Engl J Med. 2007; Nov. 357(18):1841–54.

33. Szczeklik A. Prostaglandin E2 and aspirin-induced asthma. Lancet. 1995; Apr. 345(8956):1056.

34. Buchheit KM, Cahill KN, Katz HR, Murphy KC, Feng C, Lee-Sarwar K, et al. Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2016; May. 137(5):1566–76.

35. Yamashita T, Tsuji H, Maeda N, Tomoda K, Kumazawa T. Etiology of nasal polyps associated with aspirin-sensitive asthma. Rhinol Suppl. 1989; 8:15–24.

36. Sladek K, Dworski R, Soja J, Sheller JR, Nizankowska E, Oates JA, et al. Eicosanoids in bronchoalveolar lavage fluid of aspirin-intolerant patients with asthma after aspirin challenge. Am J Respir Crit Care Med. 1994; Apr. 149(4 Pt 1):940–6.

37. Dekker JW, Nizankowska E, Schmitz-Schumann M, Pile K, Bochenek G, Dyczek A, et al. Aspirin-induced asthma and HLA-DRB1 and HLA-DPB1 genotypes. Clin Exp Allergy. 1997; May. 27(5):574–7.

38. Choi JH, Lee KW, Oh HB, Lee KJ, Suh YJ, Park CS, et al. HLA association in aspirin-intolerant asthma: DPB1*0301 as a strong marker in a Korean population. J Allergy Clin Immunol. 2004; Mar. 113(3):562–4.

39. Sanak M, Simon HU, Szczeklik A. Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet. 1997; Nov. 350(9091):1599–600.

40. Choi JH, Park HS, Oh HB, Lee JH, Suh YJ, Park CS, et al. Leukotriene-related gene polymorphisms in ASA-intolerant asthma: an association with a haplotype of 5-lipoxygenase. Hum Genet. 2004; Mar. 114(4):337–44.

41. Jinnai N, Sakagami T, Sekigawa T, Kakihara M, Nakajima T, Yoshida K, et al. Polymorphisms in the prostaglandin E2 receptor subtype 2 gene confer susceptibility to aspirin-intolerant asthma: a candidate gene approach. Hum Mol Genet. 2004; Dec. 13(24):3203–17.

42. Park BL, Park SM, Park JS, Uh ST, Choi JS, Kim YH, et al. Association of PTGER gene family polymorphisms with aspirin intolerant asthma in Korean asthmatics. BMB Rep. 2010; Jun. 43(6):445–9.

43. Kim SH, Choi JH, Park HS, Holloway JW, Lee SK, Park CS, et al. Association of thromboxane A2 receptor gene polymorphism with the phenotype of acetyl salicylic acid-intolerant asthma. Clin Exp Allergy. 2005; May. 35(5):585–90.

44. Park JS, Chang HS, Park CS, Lee JH, Lee YM, Choi JH, et al. Association analysis of cysteinyl-leukotriene receptor 2 (CYSLTR2) polymorphisms with aspirin intolerance in asthmatics. Pharmacogenet Genomics. 2005; Jul. 15(7):483–92.

45. Kim SH, Yang EM, Lee HN, Cho BY, Ye YM, Park HS. Combined effect of IL-10 and TGF-beta1 promoter polymorphisms as a risk factor for aspirin-intolerant asthma and rhinosinusitis. Allergy. 2009; Aug. 64(8):1221–5.

46. Kohyama K, Abe S, Kodaira K, Yukawa T, Hozawa S, Sagara H, et al. IL-13 and IL-17A gene polymorphisms in Japanese patients with aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol. 2011; Dec. 107(6):510–6.

47. Bochenek G, Niz Ankowska E, Szczeklik A. Testing for aspirin hypersensitivity. Allergy. 2002; Jul. 57(7):562–5.

48. Nizankowska E, Bestynska-Krypel A, Cmiel A, Szczeklik A. Oral and bronchial provocation tests with aspirin for diagnosis of aspirin-induced asthma. Eur Respir J. 2000; May. 15(5):863–9.

49. Lee RU, Stevenson DD. Aspirin-exacerbated respiratory disease: evaluation and management. Allergy Asthma Immunol Res. 2011; Jan. 3(1):3–10.

50. Nizankowska-Mogilnicka E, Bochenek G, Mastalerz L, Swierczynska M, Picado C, Scadding G, et al. EAACI/GA2LEN guideline: aspirin provocation tests for diagnosis of aspirin hypersensitivity. Allergy. 2007; Oct. 62(10):1111–8.

51. Melillo G, Balzano G, Bianco S, Dahlen B, Godard P, Kowalsky ML, et al. Report of the INTERASMA Working Group on standardization of inhalation provocation tests in aspirin-induced asthma: oral and inhalation provocation tests for the diagnosis of aspirin-induced asthma. Allergy. 2001; Sep. 56(9):899–911.

52. Palikhe NS, Kim JH, Park HS. Update on recent advances in the management of aspirin exacerbated respiratory disease. Yonsei Med J. 2009; Dec. 50(6):744–50.

53. Milewski M, Mastalerz L, Nizankowska E, Szczeklik A. Nasal provocation test with lysine-aspirin for diagnosis of aspirin-sensitive asthma. J Allergy Clin Immunol. 1998; May. 101(5):581–6.

54. Alonso-Llamazares A, Martinez-Cocera C, Dominguez-Ortega J, Robledo-Echarren T, Cimarra-Alvarez M, Mesa del Castillo M. Nasal provocation test (NPT) with aspirin: a sensitive and safe method to diagnose aspirin-induced asthma (AIA). Allergy. 2002; Jul. 57(7):632–5.

55. White A, Bigby T, Stevenson D. Intranasal ketorolac challenge for the diagnosis of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol. 2006; Aug. 97(2):190–5.

56. Lee RU, White AA, Ding D, Dursun AB, Woessner KM, Simon RA, et al. Use of intranasal ketorolac and modified oral aspirin challenge for desensitization of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol. 2010; Aug. 105(2):130–5.

57. Klimek L, Pfaar O. Aspirin intolerance: does desensitization alter the course of the disease. Immunol Allergy Clin North Am. 2009; Nov. 29(4):669–75.

58. Daffern PJ, Muilenburg D, Hugli TE, Stevenson DD. Association of urinary leukotriene E4 excretion during aspirin challenges with severity of respiratory responses. J Allergy Clin Immunol. 1999; Sep. 104(3 Pt 1):559–64.

59. Jerschow E, Ren Z, Hudes G, Sanak M, Morales E, Schuster V, et al. Utility of low-dose oral aspirin challenges for diagnosis of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol. 2016; Apr. 116(4):321–8.

60. Antczak A, Montuschi P, Kharitonov S, Gorski P, Barnes PJ. Increased exhaled cysteinyl-leukotrienes and 8-isoprostane in aspirin-induced asthma. Am J Respir Crit Care Med. 2002; Aug. 166(3):301–6.

61. Cahill KN, Laidlaw TM. Aspirin exacerbated respiratory disease: the search for a biomarker. Ann Allergy Asthma Immunol. 2014; Nov. 113(5):500–1.

62. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A. 2002; Oct. 99(21):13926–31.

63. Settipane RA, Schrank PJ, Simon RA, Mathison DA, Christiansen SC, Stevenson DD. Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects. J Allergy Clin Immunol. 1995; Oct. 96(4):480–5.

64. Yoshida S, Ishizaki Y, Onuma K, Shoji T, Nakagawa H, Amayasu H. Selective cyclo-oxygenase 2 inhibitor in patients with aspirin-induced asthma. J Allergy Clin Immunol. 2000; Dec. 106(6):1201–2.

65. Szczeklik A, Nizankowska E, Bochenek G, Nagraba K, Mejza F, Swierczynska M. Safety of a specific COX-2 inhibitor in aspirin-induced asthma. Clin Exp Allergy. 2001; Feb. 31(2):219–25.

66. Stevenson DD, Simon RA. Lack of cross-reactivity between rofecoxib and aspirin in aspirin-sensitive patients with asthma. J Allergy Clin Immunol. 2001; Jul. 108(1):47–51.

67. Woessner KM, Simon RA, Stevenson DD. The safety of celecoxib in patients with aspirin-sensitive asthma. Arthritis Rheum. 2002; Aug. 46(8):2201–6.

68. Inoue K, Takano H, Kawahito Y, Sano H, Yoshikawa T. Cyclooxygenase-2 inhibitors in aspirin-induced asthma. Chest. 2003; Apr. 123(4):1317–8.

69. Gyllfors P, Bochenek G, Overholt J, Drupka D, Kumlin M, Sheller J, et al. Biochemical and clinical evidence that aspirin-intolerant asthmatic subjects tolerate the cyclooxygenase 2-selective analgetic drug celecoxib. J Allergy Clin Immunol. 2003; May. 111(5):1116–21.

70. Stevenson DD, Simon RA. Selection of patients for aspirin desensitization treatment. J Allergy Clin Immunol. 2006; Oct. 118(4):801–4.

71. Berges-Gimeno MP, Simon RA, Stevenson DD. Long-term treatment with aspirin desensitization in asthmatic patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2003; Jan. 111(1):180–6.

72. Stevenson DD, Hankammer MA, Mathison DA, Christiansen SC, Simon RA. Aspirin desensitization treatment of aspirin-sensitive patients with rhinosinusitis-asthma: long-term outcomes. J Allergy Clin Immunol. 1996; Oct. 98(4):751–8.

73. Kowalski ML, Grzelewska-Rzymowska I, Szmidt M, Rozniecki J. Clinical efficacy of aspirin in “desensitised” aspirin-sensitive asthmatics. Eur J Respir Dis. 1986; Oct. 69(4):219–25.

74. Rizk H. Role of aspirin desensitization in the management of chronic rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg. 2011; Jun. 19(3):210–7.

75. Hope AP, Woessner KA, Simon RA, Stevenson DD. Rational approach to aspirin dosing during oral challenges and desensitization of patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2009; Feb. 123(2):406–10.

76. Cho KS, Soudry E, Psaltis AJ, Nadeau KC, McGhee SA, Nayak JV, et al. Long-term sinonasal outcomes of aspirin desensitization in aspirin exacerbated respiratory disease. Otolaryngol Head Neck Surg. 2014; Oct. 151(4):575–81.

77. Swierczynska-Krepa M, Sanak M, Bochenek G, Strek P, Cmiel A, Gielicz A, et al. Aspirin desensitization in patients with aspirin-induced and aspirin-tolerant asthma: a double-blind study. J Allergy Clin Immunol. 2014; Oct. 134(4):883–90.

78. Macy E, Bernstein JA, Castells MC, Gawchik SM, Lee TH, Settipane RA, et al. Aspirin challenge and desensitization for aspirin-exacerbated respiratory disease: a practice paper. Ann Allergy Asthma Immunol. 2007; Feb. 98(2):172–4.

79. Comert S, Celebioglu E, Yucel T, Erdogan T, Karakaya G, Onerci M, et al. Aspirin 300 mg/day is effective for treating aspirin-exacerbated respiratory disease. Allergy. 2013; Nov. 68(11):1443–51.

80. Ortega-Loayza AG, Raza S, Minisi AJ, Topaz O, Heller A, Jovin IS. Aspirin desensitization/challenge in 3 patients with unstable angina. Am J Med Sci. 2010; Nov. 340(5):418–20.

81. Lee JY, Simon RA, Stevenson DD. Selection of aspirin dosages for aspirin desensitization treatment in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2007; Jan. 119(1):157–64.

82. Rozsasi A, Polzehl D, Deutschle T, Smith E, Wiesmiller K, Riechelmann H, et al. Long-term treatment with aspirin desensitization: a prospective clinical trial comparing 100 and 300 mg aspirin daily. Allergy. 2008; Sep. 63(9):1228–34.

83. Namazy JA, Simon RA. Sensitivity to nonsteroidal anti-inflammatory drugs. Ann Allergy Asthma Immunol. 2002; Dec. 89(6):542–50.

84. Arm JP, Austen KF. Leukotriene receptors and aspirin sensitivity. N Engl J Med. 2002; Nov. 347(19):1524–6.

85. Steinke JW, Culp JA, Kropf E, Borish L. 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. 2009; Oct. 124(4):724–30.

86. White AA, Stevenson DD. Does suppression of IL-4 synthesis by aspirin explain the therapeutic benefit of aspirin desensitization treatment. J Allergy Clin Immunol. 2010; Oct. 126(4):745–6.

87. Katial RK, 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; Oct. 126(4):738–44.

88. Aksu K, Kurt E, Alatas O, Gulbas Z. Effect of aspirin desensitization on T-cell cytokines and plasma lipoxins in aspirin-exacerbated respiratory disease. Allergy Asthma Proc. 2014; Mar-Apr. 35(2):148–55.

89. Dahlen SE, Malmstrom K, Nizankowska E, Dahlen B, Kuna P, Kowalski M, et al. Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med. 2002; Jan. 165(1):9–14.

90. Mastalerz L, Milewski M, Duplaga M, Nizankowska E, Szczeklik A. Intranasal fluticasone propionate for chronic eosinophilic rhinitis in patients with aspirin-induced asthma. Allergy. 1997; Sep. 52(9):895–900.

91. Lee DK, Haggart K, Robb FM, Lipworth BJ. Montelukast protects against nasal lysine-aspirin challenge in patients with aspirin-induced asthma. Eur Respir J. 2004; Aug. 24(2):226–30.

92. Ta V, White AA. Survey-defined patient experiences with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol Pract. 2015; Sep-Oct. 3(5):711–8.

93. Wenzel S, Busse W, Calhoun W, Panettieri R Jr, Peters-Golden M, Dube L, et al. The safety and efficacy of zileuton controlled-release tablets as adjunctive therapy to usual care in the treatment of moderate persistent asthma: a 6-month randomized controlled study. J Asthma. 2007; May. 44(4):305–10.

94. Hayashi H, Mitsui C, Nakatani E, Fukutomi Y, Kajiwara K, Watai K, et al. Omalizumab reduces cysteinyl leukotriene and 9α,11β-prostaglandin F2 overproduction in aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2016; May. 137(5):1585–7.

95. Kolbeck R, Kozhich A, Koike M, Peng L, Andersson CK, Damschroder MM, et al. MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010; Jun. 125(6):1344–53.

96. Varricchi G, Bagnasco D, Borriello F, Heffler E, Canonica GW. Interleukin-5 pathway inhibition in the treatment of eosinophilic respiratory disorders: evidence and unmet needs. Curr Opin Allergy Clin Immunol. 2016; Apr. 16(2):186–200.

97. Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol. 2013; Nov. 132(5):1086–96.

98. Hosemann W. Surgical treatment of nasal polyposis in patients with aspirin intolerance. Thorax. 2000; Oct. 55 Suppl 2:S87–90.

99. McMains KC, Kountakis SE. Medical and surgical considerations in patients with Samter’s triad. Am J Rhinol. 2006; Nov-Dec. 20(6):573–6.

100. Jang DW, Comer BT, Lachanas VA, Kountakis SE. Aspirin sensitivity does not compromise quality-of-life outcomes in patients with Samter’s triad. Laryngoscope. 2014; Jan. 124(1):34–7.

101. Havel M, Ertl L, Braunschweig F, Markmann S, Leunig A, Gamarra F, et al. Sinonasal outcome under aspirin desensitization following functional endoscopic sinus surgery in patients with aspirin triad. Eur Arch Otorhinolaryngol. 2013; Feb. 270(2):571–8.

102. Batra PS, Kern RC, Tripathi A, Conley DB, Ditto AM, Haines GK 3rd, et al. Outcome analysis of endoscopic sinus surgery in patients with nasal polyps and asthma. Laryngoscope. 2003; Oct. 113(10):1703–6.

103. Rotenberg BW, Zhang I, Arra I, Payton KB. Postoperative care for Samter’s triad patients undergoing endoscopic sinus surgery: a double-blinded, randomized controlled trial. Laryngoscope. 2011; Dec. 121(12):2702–5.

104. Katotomichelakis M, Riga M, Davris S, Tripsianis G, Simopoulou M, Nikolettos N, et al. Allergic rhinitis and aspirin-exacerbated respiratory disease as predictors of the olfactory outcome after endoscopic sinus surgery. Am J Rhinol Allergy. 2009; May-Jun. 23(3):348–53.

105. Adelman J, McLean C, Shaigany K, Krouse JH. The role of surgery in management of Samter’s triad: a systematic review. Otolaryngol Head Neck Surg. 2016; Aug. 155(2):220–37.

106. Loehrl TA, Ferre RM, Toohill RJ, Smith TL. Long-term asthma outcomes after endoscopic sinus surgery in aspirin triad patients. Am J Otolaryngol. 2006; May-Jun. 27(3):154–60.

107. Awad OG, Fasano MB, Lee JH, Graham SM. Asthma outcomes after endoscopic sinus surgery in aspirin-tolerant versus aspirin-induced asthmatic patients. Am J Rhinol. 2008; Mar-Apr. 22(2):197–203.