Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5226_Библиотеки_им_академика_М_И_Перельмана.pdf
264
rhinosinusitis without nasal polyps who have not undergone sinus surgery. Int Forum Allergy
Rhinol. 2020;10(8):936–43.
37. Harvey RJ, Snidvongs K, Kalish LH, Oakley GM, Sacks R.Corticosteroid nasal irrigations
are more effective than simple sprays in a randomized double-blinded placebo-controlled trial
for chronic rhinosinusitis after sinus surgery. Int Forum Allergy Rhinol. 2018;8(4):461–70.
38. Tait S, Kallogjeri D, Suko J, Kukuljan S, Schneider J, Piccirillo JF.Effect of budesonide
added to large-volume, low-pressure saline sinus irrigation for chronic rhinosinusitis: a randomized clinical trial. JAMA Otolaryngol Head Neck Surg. 2018;144(7):605–12.
39. Rawal RB, Deal AM, Ebert CS, Dhandha VH, Mitchell CA, Hang AX, etal. Post-operative
budesonide irrigations for patients with polyposis: a blinded, randomized controlled trial.
Rhinology. 2015;53(3):227–34.
40. 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;121(12):2702–5.
41. Dawson B, Gutteridge I, Cervin A, Robinson D.The effects of nasal lavage with betamethasone cream post-endoscopic sinus surgery: clinical trial. J Laryngol Otol. 2018;132(2):143–9.
42. Kang TW, Chung JH, Cho SH, Lee SH, Kim KR, Jeong JH.The effectiveness of budesonide
nasal irrigation after endoscopic sinus surgery in chronic rhinosinusitis with asthma. Clin
Exp Otorhinolaryngol. 2017;10(1):91–6.
43. Kosugi EM, Moussalem GF, Simões JC, de Paula e Silva Felici de Souza R, Chen VG, Neto
PS, etal. Topical therapy with high-volume budesonide nasal irrigations in difcult-to-treat
chronic rhinosinusitis. Braz J Otorhinolaryngol. 2016;82(2):191–7.
44. Sachanandani NS, Piccirillo JF, Kramper MA, Thawley SE, Vlahiotis A.The effect of nasally
administered budesonide respules on adrenal cortex function in patients with chronic rhinosinusitis. Arch Otolaryngol Head Neck Surg. 2009;135(3):303–7.
45. Snidvongs K, Pratt E, Chin D, Sacks R, Earls P, Harvey RJ. Corticosteroid nasal irrigations after endoscopic sinus surgery in the management of chronic rhinosinusitis. Int Forum
Allergy Rhinol. 2012;2(5):415–21.
46. Pipaliya RM, Duckett KA, Monaghan NP, Miller EM, Young G, Brennan EA, etal. The placebo effect in randomized-controlled trials of medical treatments for chronic rhinosinusitis: a
systematic review and meta-analysis. Int Forum Allergy Rhinol. 2024;14(3):695–710.
47. Park DY, Choi JH, Kim DK, Jung YG, Mun SJ, Min HJ, etal. Clinical practice guideline: nasal
irrigation for chronic rhinosinusitis in adults. Clin Exp Otorhinolaryngol. 2022;15(1):5–23.
48. Gutierrez JA, Shannon CM, Chapurin N, Schlosser RJ, Soler ZM. Challenges to medication adherence with intranasal corticosteroid irrigations. Int Forum Allergy Rhinol.
2024;14(1):32–40.
49. Eschenbacher WH.Nasal saline irrigation with steroids: reviewing a common practice carefully. Ann Allergy Asthma Immunol. 2023;130(1):2–3.
50. Barham HP, Ramakrishnan VR, Knisely A, Do TQ, Chan LS, Gunaratne DA, et al.
Frontal sinus surgery and sinus distribution of nasal irrigation. Int Forum Allergy Rhinol.
2016;6(3):238–42.
51. Beule A, Athanasiadis T, Athanasiadis E, Field J, Wormald PJ. Efcacy of different techniques of sinonasal irrigation after modied Lothrop procedure. Am J Rhinol Allergy.
2009;23(1):85–90.
52. Mozzanica F, Preti A, Bandi F, Fazio E, Cardella A, Gallo S, etal. Effect of surgery, delivery
device and head position on sinus irrigant penetration in a cadaver model. J Laryngol Otol.
2021;135(3):234–40.
53. Singhal D, Weitzel EK, Lin E, Feldt B, Kriete B, McMains KC, etal. Effect of head position and surgical dissection on sinus irrigant penetration in cadavers. Laryngoscope.
2010;120(12):2528–31.
54. Sumaily I, Jomaah M, Alari I, Alromaih S, Aloulah M, Ajlan A, etal. Extent of nasal irrigation in non-operated sinuses: a cadaveric trial. Ear Nose Throat J. 2022;1455613221081567
D. R. Romano et al.
22 Topical Corticosteroid Therapy inRecalcitrant Chronic Rhinosinusitis
55. Barham HP, Hall CA, Hernandez SC, Zylicz HE, Stevenson MM, Zito BA, etal. Impact of
Draf III, Draf IIb, and Draf IIa frontal sinus surgery on nasal irrigation distribution. Int Forum
Allergy Rhinol. 2020;10(1):49–52.
56. Grayson JW, Cavada M, Wong E, Lien B, Duvnjak M, Campbell R, etal. Effects of sphenoid
surgery on nasal irrigation delivery. Int Forum Allergy Rhinol. 2019;9(9):971–6.
57. Wong E, Sansoni ER, Do TQ, Matchett I, Kalish LH, Sacks R, etal. Cadaveric assessment
of the efcacy of sinus irrigation after staged clearance of the medial maxillary wall. Am J
Rhinol Allergy. 2020;34(2):290–6.
58. Hansen FS, Djupesland PG, Fokkens WJ.Preliminary efcacy of uticasone delivered by a
novel device in recalcitrant chronic rhinosinusitis. Rhinology. 2010;48(3):292–9.
59. Vlckova I, Navrátil P, Kana R, Pavlicek P, Chrbolka P, Djupesland PG.Effective treatment
of mild-to-moderate nasal polyposis with uticasone delivered by a novel device. Rhinology.
2009;47(4):419–26.
60. Leopold DA, Elkayam D, Messina JC, Kosik-Gonzalez C, Djupesland PG, Mahmoud
RA.NAVIGATE II: randomized, double-blind trial of the exhalation delivery system with
uticasone for nasal polyposis. J Allergy Clin Immunol. 2019;143(1):126–34.e5
61. Palmer JN, Jacobson KW, Messina JC, Kosik-Gonzalez C, Djupesland PG, Mahmoud
RA.EXHANCE-12: 1-year study of the exhalation delivery system with uticasone (EDSFLU) in chronic rhinosinusitis. Int Forum Allergy Rhinol. 2018;8(8):869–76.
62. Sher MR, Steven GC, Romett JL, Pien G, LeBenger K, Messina JC, etal. EXHANCE-3: a
cohort study of the exhalation delivery system with uticasone for chronic sinusitis with or
without nasal polyps. Rhinology. 2020;58(1):25–35.
63. Palmer JN, Adappa ND, Chandra RK, Davis GE, Mahdavinia M, Messina J, etal. Efcacy
of EDS-FLU for chronic rhinosinusitis: two randomized controlled trials (ReOpen1 and
ReOpen2). J Allergy Clin Immunol Pract. 2024;12(4):1049–61.
64. Sindwani R, Han JK, Soteres DF, Messina JC, Carothers JL, Mahmoud RA, et al.
NAVIGATE I: randomized, placebo-controlled, double-blind trial of the exhalation delivery
system with uticasone for chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy.
2019;33(1):69–82.
65. Messina JC, Offman E, Carothers JL, Mahmoud RA.A randomized comparison of the pharmacokinetics and bioavailability of uticasone propionate delivered via Xhance exhalation
delivery system versus Flonase nasal spray and Flovent HFA inhalational aerosol. Clin Ther.
2019;41(11):2343–56.
66. Senior BA, Schlosser RJ, Bosso J, Soler ZM.Efcacy of the exhalation delivery system with
uticasone in patients who remain symptomatic on standard nasal steroid sprays. Int Forum
Allergy Rhinol. 2021;11(5):837–45.
67. Yao WC, Ramakrishnan VR, Luong AU, Citardi MJ.VISUALIZE: a 24-week, open-label
study using nasal endoscopy video to evaluate the efcacy and safety of EDS-FLU 186 μg
twice daily in adults with bilateral nasal polyps. Rhinology Online. 2020;3:58–66.
68. Ow RA, Soler ZM, Sindwani R, Leopold DA, Lee JT, Mahmoud RA, et al. Efcacy of
the exhalation delivery system with uticasone in patients with chronic rhinosinusitis
with nasal polyps whose symptoms recur after sinus surgery. Int Forum Allergy Rhinol.
2023;13(1):31–41.
69. Wise SK, Adappa ND, Chandra RK, Davis GE, Mahdavinia M, Mahmoud R, etal. EDSFLU efcacy in patients with chronic rhinosinusitis with or without prior sinus surgery in
ReOpen1 and ReOpen2 randomized controlled trials. Int Forum Allergy Rhinol. 2024;
70. Li PM, Downie D, Hwang PH.Controlled steroid delivery via bioabsorbable stent: safety and
performance in a rabbit model. Am J Rhinol Allergy. 2009;23(6):591–6.
71. Forwith KD, Chandra RK, Yun PT, Miller SK, Jampel HD.ADVANCE: a multisite trial of
bioabsorbable steroid-eluting sinus implants. Laryngoscope. 2011;121(11):2473–80.
72. Murr AH, Smith TL, Hwang PH, Bhattacharyya N, Lanier BJ, Stambaugh JW, etal. Safety
and efcacy of a novel bioabsorbable, steroid-eluting sinus stent. Int Forum Allergy Rhinol.
2011;1(1):23–32.
265
266
73. Marple BF, Smith TL, Han JK, Gould AR, Jampel HD, Stambaugh JW, etal. Advance II:
a prospective, randomized study assessing safety and efcacy of bioabsorbable steroidreleasing sinus implants. Otolaryngol Head Neck Surg. 2012;146(6):1004–11.
74. Luong A, Ow RA, Singh A, Weiss RL, Han JK, Gerencer R, etal. Safety and effectiveness of
a bioabsorbable steroid-releasing implant for the paranasal sinus ostia: a randomized clinical
trial. JAMA Otolaryngol Head Neck Surg. 2018;144(1):28–35.
75. Smith TL, Singh A, Luong A, Ow RA, Shotts SD, Sautter NB, etal. Randomized controlled
trial of a bioabsorbable steroid-releasing implant in the frontal sinus opening. Laryngoscope.
2016;126(12):2659–64.
76. Wang C, Yu L, Chu X, Wang K, Li J, Lai Y, etal. Short-term postoperative efcacy of steroideluting stents for eosinophilic chronic rhinosinusitis with nasal polyps: a randomized clinical
trial. Int Forum Allergy Rhinol. 2023;13(5):899–909.
77. Huang Z, Zhou B, Wang D, Zang H, Zhang H, Wang H, etal. Comparison of bioabsorbable
steroid-eluting sinus stents versus nasopore after endoscopic sinus surgery: a multicenter,
randomized, controlled, single-blinded clinical trial. Ear Nose Throat J. 2022;101(4):260–7.
78. Sow YL, Tang IP, Kho JP, Prepageran N. Pilot study comparing steroid-impregnated and
non-steroid-impregnated absorbable nasal dressing following endoscopic sinus surgery. Med
J Malaysia. 2018;73(4):244–8.
79. Adriaensen GF, Lim KH, Fokkens WJ.Safety and efcacy of a bioabsorbable uticasone
propionate-eluting sinus dressing in postoperative management of endoscopic sinus surgery:
a randomized clinical trial. Int Forum Allergy Rhinol. 2017;7(8):813–20.
80. Côté DW, Wright ED. Triamcinolone-impregnated nasal dressing following endoscopic
sinus surgery: a randomized, double-blind, placebo-controlled study. Laryngoscope.
2010;120(6):1269–73.
81. Grzeskowiak B, Wierzchowska M, Walorek R, Seredyka-Burduk M, Wawrzyniak K, Burduk
PK. Steroid vs. antibiotic impregnated absorbable nasal packing for wound healing after
endoscopic sinus surgery: a randomized, double blind, placebo-controlled study. Braz J
Otorhinolaryngol. 2019;85(4):473–80.
82. Promentilla SM, Onofre RD, Campomanes BS. Effects of dexamethasone versus salineimpregnated nasal packing on the postoperative outcome of patients with chronic rhinosinusitis and nasal polyps after endoscopic sinus surgery: a randomized controlled trial. Philipp J
Otolaryngol Head Neck Surg. 2016;31(1):10–3.
83. Zhao KQ, Yu YQ, Yu HM. Effects of mometasone furoate-impregnated biodegradable
nasal dressing on endoscopic appearance in healing process following endoscopic sinus
surgery: a randomized, double-blind, placebo-controlled study. Int Forum Allergy Rhinol.
2018;8(11):1233–41.
84. Rudmik L, Mace J, Mechor B.Effect of a dexamethasone Sinu-Foam™ middle meatal spacer
on endoscopic sinus surgery outcomes: a randomized, double-blind, placebo-controlled trial.
Int Forum Allergy Rhinol. 2012;2(3):248–51.
85. Hwang CS, Al Sharhan SS, Kim BR, Kim SI, Kim JW, Cho HJ, etal. Randomized controlled
trial of steroid-soaked absorbable calcium alginate nasal packing following endoscopic sinus
surgery. Laryngoscope. 2018;128(2):311–6.
86. Lavigne F, Miller SK, Gould AR, Lanier BJ, Romett JL. Steroid-eluting sinus implant for
in-ofce treatment of recurrent nasal polyposis: a prospective, multicenter study. Int Forum
Allergy Rhinol. 2014;4(5):381–9.
87. Matheny KE, Carter KB, Tseng EY, Fong KJ.Safety, feasibility, and efcacy of placement
of steroid-eluting bioabsorbable sinus implants in the ofce setting: a prospective case series.
Int Forum Allergy Rhinol. 2014;4(10):808–15.
88. Kern RC, Stolovitzky JP, Silvers SL, Singh A, Lee JT, Yen DM, etal. A phase 3 trial of
mometasone furoate sinus implants for chronic sinusitis with recurrent nasal polyps. Int
Forum Allergy Rhinol. 2018;8(4):471–81.
89. Forwith KD, Han JK, Stolovitzky JP, Yen DM, Chandra RK, Karanlov B, etal. RESOLVE:
bioabsorbable steroid-eluting sinus implants for in-ofce treatment of recurrent sinonasal
D. R. Romano et al.
22 Topical Corticosteroid Therapy inRecalcitrant Chronic Rhinosinusitis
polyposis after sinus surgery: 6-month outcomes from a randomized, controlled, blinded
study. Int Forum Allergy Rhinol. 2016;6(6):573–81.
90. Han JK, Forwith KD, Smith TL, Kern RC, Brown WJ, Miller SK, etal. RESOLVE: a randomized, controlled, blinded study of bioabsorbable steroid-eluting sinus implants for in-ofce
treatment of recurrent sinonasal polyposis. Int Forum Allergy Rhinol. 2014;4(11):861–70.
91. Cervin A, Rimmer J, Wrobel A, Abelak Y, Brayton L, Kuang Y.Long-acting implantable
corticosteroid matrix for chronic rhinosinusitis: results of LANTERN Phase 2 randomized
controlled study. Int Forum Allergy Rhinol. 2022;12(2):147–59.
92. Tang DM, Roxbury CR, Sindwani R, Kshettry VR, Recinos P, Woodard TD. Multiple
bioabsorbable corticosteroid-eluting stent placement with associated skull base injury.
Laryngoscope. 2019;129(7):1494–6.
93. Shah VN, Pasick LJ, Benito DA, Ghiam MK, D’Aguillo C.Complications associated with
PROPEL Mometasone Furoate bioabsorbable drug-eluting sinus stents from 2012 to 2020.
Am J Rhinol Allergy. 2022;36(2):185–90.
94. Lee JT, DelGaudio J, Orlandi RR.Practice patterns in ofce-based rhinology: survey of the
American Rhinologic Society. Am J Rhinol Allergy. 2019;33(1):26–35.
95. Rudmik L, Smith TL. Economic evaluation of a steroid-eluting sinus implant following endoscopic sinus surgery for chronic rhinosinusitis. Otolaryngol Head Neck Surg.
2014;151(2):359–66.
96. Han JK, Marple BF, Smith TL, Murr AH, Lanier BJ, Stambaugh JW, etal. Effect of steroidreleasing sinus implants on postoperative medical and surgical interventions: an efcacy
meta-analysis. Int Forum Allergy Rhinol. 2012;2(4):271–9.
97. Singh A, Luong AU, Fong KJ, Ow RA, Han JK, Gerencer R, etal. Bioabsorbable steroidreleasing implants in the frontal sinus ostia: a pooled analysis. Int Forum Allergy Rhinol.
2019;9(2):131–9.
98. Stolovitzky JP, Kern RC, Han JK, Forwith KD, Ow RA, Wright SK, etal. In-ofce placement
of mometasone furoate sinus implants for recurrent nasal polyps: a pooled analysis. Am J
Rhinol Allergy. 2019;33(5):545–58.
99. Lee VS, Patel P, O’Brien D, Scangas GA, Campbell RG, Chandra R, etal. Indications for
absorbable steroid-eluting sinus implants: viewpoint via the Delphi method. Int Forum
Allergy Rhinol. 2022;12(10):1225–31.
100. Wu C, Fang F, Zhan X, Wei Y.The association between glucocorticoid receptor (NR3C1)
gene polymorphism and difcult-to-treat rhinosinusitis. Eur Arch Otorrinolaringol.
2022;279(8):3981–7.
101. Milara J, Morell A, Ballester B, Armengot M, Morcillo E, Cortijo J. MUC4 impairs the
anti-inammatory effects of corticosteroids in patients with chronic rhinosinusitis with nasal
polyps. J Allergy Clin Immunol. 2017;139(3):855–862.e13.
102. Milara J, Peiró T, Armengot M, Frias S, Morell A, Serrano A, etal. Mucin 1 downregulation
associates with corticosteroid resistance in chronic rhinosinusitis with nasal polyps. J Allergy
Clin Immunol. 2015;135(2):470–6.
103. Kocharyan A, Feldman R, Singleton A, Han X, Bleier BS. P-glycoprotein inhibition promotes prednisone retention in human sinonasal polyp explants. Int Forum Allergy Rhinol.
2014;4(9):734–8.
104. An YH, Hong SL, Han DH, Lee CH, Min YG, Rhee CS.Expression of the cysteinyl leukotriene 1 receptor and glucocorticoid receptor-β in nasal polyps. Eur Arch Otorrinolaringol.
2013;270(4):1373–8.
105. Choi BR, Kwon JH, Gong SJ, Kwon MS, Cho JH, Kim JH, etal. Expression of glucocorticoid
receptor mRNAs in glucocorticoid-resistant nasal polyps. Exp Mol Med. 2006;38(5):466–73.
106. Hamilos DL, Leung DY, Muro S, Kahn AM, Hamilos SS, Thawley SE, etal. GRbeta expression in nasal polyp inammatory cells and its relationship to the anti-inammatory effects of
intranasal uticasone. J Allergy Clin Immunol. 2001;108(1):59–68.
107. Li P, Li Y, Li YQ, Yang QT, Zhang GH.Glucocorticoid receptor expression and glucocorticoid therapeutic effect in nasal polyps. Clin Invest Med. 2010;33(3):E181–8.
267
268
108. Pujols L, Alobid I, Benítez P, Martínez-Antón A, Roca-Ferrer J, Fokkens WJ, etal. Regulation
of glucocorticoid receptor in nasal polyps by systemic and intranasal glucocorticoids. Allergy.
2008;63(10):1377–86.
109. Pujols L, Mullol J, Benítez P, Torrego A, Xaubet A, de Haro J, etal. Expression of the glucocorticoid receptor alpha and beta isoforms in human nasal mucosa and polyp epithelial cells.
Respir Med. 2003;97(1):90–6.
110. Valera FC, Scrideli C, Queinoz, Tone LG, Anselmo-Lima. NF-kappaB expression predicts
clinical outcome for nasal polyposis. Rhinology. 2010;48(4):408–41.
111. Wang SB, Chen SM, Zhu KS, Zhou B, Chen L, Zou XY.Increased lipopolysaccharide content is positively correlated with glucocorticoid receptor-beta expression in chronic rhinosinusitis with nasal polyps. Immun Inamm Dis. 2020;8(4):605–14.
112. Wang M, Shi P, Chen B, Shi G, Li H, Wang H.Superantigen-induced glucocorticoid insensitivity in the recurrence of chronic rhinosinusitis with nasal polyps. Otolaryngol Head Neck
Surg. 2011;145(5):717–22.
113. Watanabe S, Suzaki H.Changes of glucocorticoid receptor expression in the nasal polyps of patients with chronic sinusitis following treatment with glucocorticoid. In Vivo.
2008;22(1):37–42.
114. Rawl JW, McQuitty RA, Khan MH, Reichert LK, Kuo YF, Chaaban MR.Comparison of
steroid- releasing stents vs nonabsorbable packing as middle meatal spacers. Int Forum
Allergy Rhinol. 2020;10(3):328–33.
D. R. Romano et al.
Aspirin Desensitization forRecalcitrant
Chronic Rhinosinusitis withNasal
23
Polyposis
AnthonyF.LaCava andJohnV.Bosso
Key Points
• Aspirin-exacerbated respiratory disease (AERD) consists of the triad of asthma,
chronic rhinosinusitis with nasal polyposis, and respiratory reactions to COX-1
inhibitors/allergy to nonsteroidal anti-inammatory drugs.
• Aspirin desensitization in patients with AERD is an effective means to control
inammatory symptoms.
• Aspirin therapy after desensitization improves sinus and respiratory symptoms,
reduces polyp formation, and reduces the need for oral and inhaled corticosteroids and revision sinus surgery.
• Aspirin therapy is affordable and cost-effective as rst-line therapy after com-
plete endoscopic sinus surgery.
Background
Pseudonyms, Prevalence, andClinical Manifestations
Aspirin-exacerbated respiratory disease (AERD), also known as Samter’s triad,
aspirin-sensitive rhinosinusitis asthma, aspirin triad, aspirin idiosyncrasy, and nonsteroidal anti-inammatory drug (NSAID)-exacerbated respiratory disease, is an
A. F. LaCava
Section of Allergy & Immunology, Division of Pulmonary, Allergy, & Critical Care Medicine,
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
J. V. Bosso (
Division of Rhinology, Department of Otolaryngology, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, PA, USA
e-mail: john.bosso@pennmedicine.upenn.edu
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2025
J. T. Lee et al. (eds.), Advances in Surgical and Medical Interventions for
Recalcitrant Chronic Rhinosinusitis,
https://doi.org/10.1007/978-3-031-89191-5_23
*)
269
270
A. F. LaCava and J. V. Bosso
Table 23.1
Highly selective COX-1 inhibitors
Acetylsalicylic acid Flurbiprofen Dipyrone
Antipyrine-benzocaine Ibuprofen Mefenamic acid
Benoxaprofen Indomethacin Naproxen
Diclofenac Ketoprofen Oxaprozin
Etodolac Ketorolac Piroxicam
Fenoprofen Meclofenamate Tolmetin
Weakly selective COX-1 inhibitors
Acetaminophen Diunisal
Choline magnesium trisalicylate Salsalate
Highly selective COX-2 inhibitors
Celecoxib Lumiracoxib
Etoricoxib Parecoxib
Preferentially selective COX-2 inhibitors
Meloxicam
Nabumetone
Nimesulide
Medications that inhibit COX-1 and COX-2
inammatory syndrome characterized by the combination of asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), and acute respiratory reactions following
exposure to cyclooxygenase (COX)-1 inhibitors. Table23.1 lists the medications
that are known to inhibit COX-1 and COX-2 enzymes. In AERD patients, challenges with highly selective COX-2 inhibitors have demonstrated that these medications are well tolerated [1]. There is variable cross-reactivity among the weakly
selective COX-1 inhibitors, and these reactions tend to be less severe. Settipane
demonstrated 34% cross-reactivity in AERD patients with acetaminophen doses at
or above 1000mg [2]. Lower doses did not seem to trigger respiratory reactions.
AERD is often rst noted following an upper respiratory infection in early adulthood, with progression to chronic rhinosinusitis and recurrent nasal polyposis. As
the sinus disease develops, lower respiratory tract symptoms also begin, and asthma
is diagnosed. In some cases, respiratory symptoms are more notable, and asthma
may be diagnosed before nasal polyposis. Respiratory sensitivity to COX-1inhibiting NSAIDs often manifests after the establishment of upper and lower respiratory disease. The syndrome can take 2–4years to clinically manifest its full triad,
thereby leading to diagnostic confusion and delays [3]. Rarely, a patient with AERD
does not demonstrate clinical asthma, the so-called upper airway variant. When
patients with AERD ingest aspirin or an NSAID, they develop acute upper and/or
lower respiratory symptoms. Other clinical associations include anosmia or hyposmia, respiratory reactions to alcoholic beverages especially beer and wine, atopic
disorders, and peripheral blood eosinophilia. AERD affects between 7% and 15% of
patients with asthma and up to 16% of patients with CRSwNP [4, 5]. Atopy is present in a higher-than-expected number of AERD patients; however, the clinical signicance of this nding is still unclear [6]. Exposure to passive cigarette smoke in
early life and a personal history of smoking have been associated with more than a
threefold increase in the odds of developing AERD [7]. Atopy, cigarette smoke, and
• Eosinophil chemotaxis
23 Aspirin Desensitization forRecalcitrant Chronic Rhinosinusitis withNasal Polyposis
271
viral or bacterial insults to the sinonasal epithelium could be initial catalysts in
igniting the dysregulated inammation seen in AERD.Unfortunately, despite an
avalanche of recent publications, AERD is often underdiagnosed due to a lack of
physician recognition [8].
Pathophysiology
Arachidonic acid metabolism is chronically dysregulated in AERD (Fig. 23.1).
There is overproduction of cysteinyl leukotrienes (LTC4, LTD4, LTE4) and PGD2,
which leads to the development of bronchospasm, increased mucus production,
increased vascular permeability, and recruitment of inammatory cells [9–11].
Levels of PGE2, which has anti-inammatory effects and suppresses leukotriene
production, are reduced in AERD [11]. Abnormal aggregates of platelets and leukocytes (i.e., neutrophils, eosinophils, and monocytes) can share metabolic processes
(i.e., through transcellular transfer of metabolic intermediates) to produce high
amounts of inammatory leukotrienes [12]. Eosinophils and mast cells have been
Membrane
Phospholipids
Lipoxin LXA
Leukotriene production
Pulmonary eosinophils
CysLT-R antagonism
LTB
4
4
5-LO
LTA
4
S
LTC
4
LTC
4
LTD
4
LTE
4
CysLT1R
CysLT2R
LTE4R
•Bronchoconstriction
•Airway mucus production
•Eosinophil migration
LO Pathway
Phospholipase A
Arachidonic
Acid
PGE
2
5-LO activity
Leukotriene production
Eosinophil migration
• Bronchoconstriction
• ICAM-1
• VCAM-1
• LT C4S activity
COX
Pathway
COX-1
COX-2
PGH
TXA
2
2
2
PGD
2
• Bronchoconstriction
Fig. 23.1 Pathways of arachidonic acid metabolism involved in the pathogenesis of AERD
Italicized words represent enzymes involved in this pathway. Signaling effects are listed in bullet
points. Red arrows represent mediators that are either increased or decreased in AERD patients
272
shown to be primary sources of excess leukotrienes in patients with AERD [13–15].
Basophils have also been demonstrated to contribute to AERD pathogenesis,
although their involvement in AERD pathophysiology remains unclear [16].
Recently, it has been demonstrated that there may be inammatory heterogeneity
within AERD, which can be differentiated into three inammatory sub-endotypes:
(1) low inammatory burden, (2) very high type 2 cytokines (IL-4, IL-5, IL-13), and
(3) low type 2 cytokines with high levels of type 1 (IFN-γ) and type 3 cytokines
(IL-17A). The concept of sub-endotypes within AERD may explain some of the
differential responses to treatments.
A. F. LaCava and J. V. Bosso
Radiographic andHistologic Findings
CT imaging of the sinuses reveals pan-sinus opacication in most AERD patients
secondary to diffuse mucosal inammation [6]. Bony thickening of the intersinus
septum and sphenoid bone is also seen in increased frequency [17]. The evolution
of sinus polypoid opacication typically starts in the ethmoid and frontal sinuses
[18]. Normal preoperative imaging of the sinuses rules out the diagnosis of
AERD.Histologically, AERD is characterized by increased inammation within
the upper and lower respiratory tracts. Bronchial and nasal/sinus tissue examination
reveals an increased number of eosinophils and degranulated mast cells [13, 19].
Diagnosis
A clinical diagnosis of AERD can be made based on a history of asthma and nasal
polyposis, in addition to adverse reactions caused by aspirin, NSAIDs, or other
COX-1 inhibitors. Many patients do not have a clear history of adverse reactions to
COX-1 inhibitors or other NSAIDs. In patients without a clear history, aspirin challenge can conrm or exclude hypersensitivity and is considered the gold standard
for diagnosing AERD [20]. Urinary leukotriene E4 measurements are poorly predictive of AERD [21]. Diagnostic aspirin challenges should be offered to patients
with suspected AERD prior to endoscopic sinus surgery to increase diagnostic accuracy and to minimize the risk of false-negative aspirin challenges, which are sometimes seen in the early postoperative period [22].
Aspirin Challenge
Indications forAspirin Challenge
An aspirin challenge should be considered in all chronic rhinosinusitis with nasal
polyposis patients with an unclear clinical presentation. A list of clinical scenarios
where an aspirin challenge should be considered is shown in Table23.2.
23 Aspirin Desensitization forRecalcitrant Chronic Rhinosinusitis withNasal Polyposis
273
Table 23.2
Clinical indications for aspirin challenge
CRSwNP, asthma without prior exposure to aspirin or COX-1 inhibitor during the time of the
inammatory disease
CRSwNP, asthma receiving a leukotriene receptor antagonist (i.e., montelukast, zarlukast) or
5-lipooxygenase inhibitor (i.e., zileuton)
CRSwNP, asthma on daily low-dose aspirin
CRSwNP, asthma and is a poor perceiver of nasal or respiratory symptoms
CRSwNP, asthma with suggestive radiographic (pansinusitis, intersphenoid septal thickening)
or histopathologic ndings (intense eosinophilic inltration on structured histopathologic
examination)
CRSwNP, asthma requiring frequent bursts of systemic corticosteroids to control respiratory or
sinus symptoms
CRSwNP, asthma with one reaction associated with aspirin or COX-1 inhibitor which was
atypical in nature and not serious
Uncontrolled chronic rhinosinusitis with nasal polyposis despite the use of standard medical
therapy
Recurrent nasal polyposis requiring repeat endoscopic sinus surgery
Any patient with pansinusitis
Abbreviations: CRSwNP chronic rhinosinusitis with nasal polyposis, COX-1 cyclooxygenase-1
Indications for aspirin challenge
A common clinical scenario that would warrant an aspirin challenge includes
patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma
without a previous exposure to aspirin or COX-1 inhibitor during the time of the
inammatory disease. Leukotriene receptor antagonists can modify upper airway
symptoms in AERD and can decrease nasal symptoms with aspirin exposure, which
can potentially mask an underlying hypersensitivity. Therefore, an aspirin challenge
can be considered in patients with CRSwNP and asthma who have tolerated aspirin
or COX-1 inhibitors while receiving concomitant leukotriene or 5-lipoxygenase
inhibitor treatment [23]. There is also a subset of patients who are desensitized to
aspirin through low-dose daily use; these patients would also benet from an aspirin
challenge after holding their daily aspirin for 10days [24]. An aspirin challenge
may also be considered in patients who are poor perceivers of symptoms, patients
with suggestive radiographic or histopathologic ndings, and patients with refractory sinus disease. It is possible to have AERD without asthma; therefore, aspirin
challenge can be considered in carefully selected patients with a history of chronic
pansinusitis alone.
A study by Dursun etal. evaluated 243 consecutive referrals for aspirin challenges and desensitization. They found that patients with at least two prior aspirinand NSAID-associated respiratory reactions had an 89% chance of having a positive
oral aspirin challenge [25]. Therefore, aspirin challenge is typically unnecessary in
patients with CRSwNP and asthma who report a history of two previous hypersensitivity reactions to aspirin or COX-1 inhibitors. In this same study, patients who
had one serious respiratory reaction associated with aspirin/NSAID ingestion had a
100% likelihood of a positive challenge, thereby eliminating the need to challenge
patients with this history.