Aspirin exacerbated respiratory disease
|Aspirin exacerbated respiratory disease|
|Synonyms||Aspirin-induced asthma, Samter's triad, Samter's syndrome, nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease (N-ERD)|
|Aspirin in coated tablets|
Aspirin exacerbated respiratory disease (AERD), also termed aspirin-induced asthma, is a medical condition initially defined as consisting of three key features: asthma, respiratory symptoms exacerbated by aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and nasal polyps. The symptoms of respiratory reactions in this syndrome are hypersensitivity reactions to NSAIDs rather than the typically described true allergic reactions that trigger other common allergen-induced asthma, rhinitis, or hives. The NSAID-induced reactions do not appear to involve the common mediators of true allergic reactions, immunoglobulin E or T cells. Rather, AERD is a type of NSAID-induced hypersensitivity syndrome. EAACI/WHO classifies the syndrome as one of five types of NSAID hypersensitivity or NSAID hypersensitivity reactions.
Signs and symptoms
The various non-allergic NSAID hypersensitivity syndromes affect 0.5–1.9% of the general population, with AERD affecting about 7% of all asthmatics and about 14% of adults with severe asthma. AERD, which is slightly more prevalent in women, usually begins in young adulthood (twenties and thirties are the most common onset times, although children are afflicted with it and present a diagnostic problem in pediatrics) and may not include any other allergies. Most commonly the first symptom is rhinitis (inflammation or irritation of the nasal mucosa), which may manifest as sneezing, runny nose, or congestion. The disorder typically progresses to asthma, then nasal polyposis, with aspirin sensitivity coming last. Anosmia (lack of smell) also is common, as inflammation within the nose and sinuses likely reaches the olfactory receptors.
The respiratory reactions to NSAIDs vary in severity, ranging from mild nasal congestion and eye watering to lower respiratory symptoms including wheezing, coughing, an asthma attack, and in rare cases, anaphylaxis. In addition to the typical respiratory reactions, about 10% of patients with AERD manifest skin symptoms such as urticaria and/or gastrointestinal symptoms such as abdominal pain or vomiting during their reactions to aspirin.
In addition to aspirin, patients also react to other NSAIDs such as ibuprofen, and to any medication that inhibits the cyclooxygenase-1 (COX-1) enzyme, although paracetamol (acetaminophen) in low doses  is generally considered safe. NSAIDs that are highly selective in blocking COX-2 and do not block its closely related paralog, COX-1, such as the COX-2 inhibitors celecoxib and rofecoxib, also are regarded as safe. Nonetheless, recent studies do find that these types of drugs, e.g. acetaminophen and celecoxib, may trigger adverse reactions in these patients; caution is recommended in using any COX inhibitors. In addition to aspirin and NSAIDs, consumption of even small amounts of alcohol also produces uncomfortable respiratory reactions in many patients.
The disorder is thought to be caused by an anomaly in the arachidonic acid metabolizing cascade that leads to increased production of pro-inflammatory cysteinyl leukotrienes, a series of chemicals involved in the body's inflammatory response. When medications such as NSAIDs or aspirin block the COX-1 enzyme, production of thromboxane and some anti-inflammatory prostaglandins is decreased, and in patients with aspirin-induced asthma, this results in the overproduction of pro-inflammatory leukotrienes, which can cause severe exacerbations of asthma and allergy-like symptoms. The underlying cause of the disorder is not fully understood, but there have been several important findings:
- Abnormally low levels of prostaglandin E2 (PGE2), which is protective for the lungs, has been found in patients with aspirin-induced asthma and may worsen their lung inflammation.
- In addition to the overproduction of cystinyl leukotrienes, overproduction of 15-lipoxygenase-derived arachidonic acid metabolites viz., 15-hydroxyicosatetraenoic acid and eoxins by the eosinophils isolated from the blood of individuals with AERD; certain of these products may help promote the inflammatory response.
- Overexpression of both the cysteinyl leukotriene receptor 1 and the leukotriene C4 synthase enzyme has been shown in respiratory tissue from patients with aspirin-induced asthma, which likely relates to the increased response to leukotrienes and increased production of leukotrienes seen in the disorder.
- The attachment of platelets to certain leukocytes in the blood of patients with aspirin-sensitive asthma also has been shown to contribute to the overproduction of leukotrienes.
- There may be a relationship between aspirin-induced asthma and TBX21, PTGER2, and LTC4S.
- Eosinophils isolated from the blood of aspirin-induced asthma subjects (as well as severe asthmatic patients) greatly overproduce 15-hydroxyicosatetraenoic acid and eoxin C4 when challenged with arachidonic acid or calcium ionophore A23187, compared to the eosinophils taken from normal or mildly asthmatic subjects; aspirin treatment of eosinophils from aspirin intolerant subjects causes the cells to mount a further increase in eoxin production. These results suggest that 15-lipoxygenase and certain of its metabolites, perhaps eoxin C4, is contributing to aspirin-induced asthma in a fashion similar to 5-lipoxygenase and its leukotriene metabolites.
Avoidance of NSAID medications will not stop the progression of the disease. The preferred treatment for many patients is desensitization to aspirin, undertaken at a clinic or hospital specializing in such treatment. Patients who are desensitized then take a maintenance dose of aspirin daily to maintain their desensitization. The recommended maintenance dose for symptom control is 650mg to 1300mg aspirin daily. While on daily aspirin, most patients have reduced need for supporting medications, fewer asthma and sinusitis symptoms than previously, and an improved sense of smell. Desensitization to aspirin reduces the chance of nasal polyp recurrence and may slow the regrowth of nasal polyps. Once desensitized to aspirin, most patients can safely take other NSAID medications again.
Even patients desensitized to aspirin may continue to need other medications including nasal steroids, inhaled steroids, and leukotriene antagonists. Leukotriene antagonists and inhibitors (montelukast, zafirlukast, and zileuton) often are helpful in treating the symptoms of AERD. In a large survey of AERD patients, it was reported that Zyflo (zileuton) was significantly more effective at controlling the symptoms of the disease than Singulair (montelukast).
Biologic medications such as mepolizumab (Nucala) may also be of benefit.
Despite optimal medical management, many patients continue to require oral steroid medications to alleviate asthma and chronic nasal congestion.
Often surgery is required to remove nasal polyps, although they typically recur, particularly if aspirin desensitization is not undertaken. 90% of patients have been shown to have recurrence of nasal polyps within five years after surgery, with 47% requiring revision surgery in the same time period. A complete endoscopic sinus surgery followed by aspirin desensitization has been shown to reduce the need for revision surgeries.
The majority of those with aspirin exacerbated respiratory disease experience respiratory reactions to alcohol. One study found that 83% reported such reactions. Of those who had reactions, 75% had a sinus reaction (runny nose, nasal congestion) and 51% had a lower respiratory reaction (wheezing, shortness of breath). The current theory on the cause of these reactions is that they may be related to polyphenols found in alcoholic beverages. A 2017 study found that alcohol sensitive patients reacted to catechins in red wine, but not to resveratrol. It has been suggested that steel fermented white wines and clear liquors may cause less of a reaction than other alcoholic beverages. Desensitization to aspirin has been found to reduce reactions to alcohol.
Some people have reported relief of symptoms by following a low-salicylate diet such as the Feingold diet. Aspirin is quickly converted in the body to salicylic acid, also known as 2-Hydroxybenzoic acid. A prospective randomized trial with 30 patients following a low-salicylate diet for six weeks demonstrated a clinically significant decrease in both subjective and objective scoring of severity of disease, but made note of the challenge for patients in following what is a fairly stringent diet. Despite these findings, experts on the disease do not believe that dietary salicylates contribute to AERD symptoms. Dietary salicylates do not significantly inhibit the COX-1 enzyme, which is the cause of AERD reactions. One confounding factor in the study that showed a benefit from avoidance of dietary salicylates is that a low salicylate diet involves eliminating wine and beer. The majority of AERD patients react to wine and beer for reasons that do not involve their salicylate content. There is also a strong placebo effect involved with any dietary intervention. In contrast to aspirin, dietary salicylates are not acetylated and therefore do not block cyclooxygenases and hence, there is no rationale why a low salicylate diet would be beneficial for AERD patients.
A diet low in omega-6 oils (precursors of arachidonic acid), and high in omega-3 oils may also be of benefit. In a small study, aspirin-sensitive asthma patients taking 10 grams of fish oil daily reported relief of most symptoms after six weeks, however, symptoms returned if the supplement was stopped. In another study, a diet low in omega 6 fatty acids and high in omega 3 fatty acids significantly reduced sinus symptoms in AERD patients.
- Aspirin-induced asthma
- Leukotriene associated hypersensitivity 
- Samter's triad
- Acetylsalicylic acid triad 
- Widal's triad
- Francis' triad
- Aspirin triad
- Aspirin-exacerbated respiratory disease (AERD).
- NSAID-exacerbated respiratory disease (NERD)
- Aspirin-induced asthma and rhinitis (AIAR) 
A person who has not yet experienced asthma or aspirin sensitivity might be diagnosed as having:
- Non-allergic rhinitis
- Non-allergic rhinitis with eosinophilia syndrome (NARES)
- Kowalski ML, Asero R, Bavbek S, Blanca M, Blanca-Lopez N, Bochenek G, et al. (October 2013). "Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs". Allergy. 68 (10): 1219–32. doi:10.1111/all.12260. PMID 24117484.
- Zeitz HJ (December 1988). "Bronchial asthma, nasal polyps, and aspirin sensitivity: Samter's syndrome". Clinics in Chest Medicine. 9 (4): 567–76. PMID 3069289.
- Kim JE, Kountakis SE (July 2007). "The prevalence of Samter's triad in patients undergoing functional endoscopic sinus surgery". Ear, Nose, & Throat Journal. 86 (7): 396–9. PMID 17702319.
- Kowalski ML, Makowska JS, Blanca M, Bavbek S, Bochenek G, Bousquet J, et al. (July 2011). "Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) - classification, diagnosis and management: review of the EAACI/ENDA(#) and GA2LEN/HANNA*". Allergy. 66 (7): 818–29. doi:10.1111/j.1398-9995.2011.02557.x. PMID 21631520.
- Rajan JP, Wineinger NE, Stevenson DD, White AA (March 2015). "Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature". The Journal of Allergy and Clinical Immunology. 135 (3): 676–81.e1. doi:10.1016/j.jaci.2014.08.020. PMID 25282015.
- Welch KC. "Aspirin Desensitization". American Rhinologic Society.
- Chen BS, Virant FS, Parikh SR, Manning SC (February 2013). "Aspirin sensitivity syndrome (Samter's Triad): an unrecognized disorder in children with nasal polyposis". International Journal of Pediatric Otorhinolaryngology. 77 (2): 281–3. doi:10.1016/j.ijporl.2012.10.017. PMID 23149179.
- Fahrenholz JM (April 2003). "Natural history and clinical features of aspirin-exacerbated respiratory disease". Clinical Reviews in Allergy & Immunology. 24 (2): 113–24. doi:10.1385/CRIAI:24:2:113. PMID 12668892.
- Settipane RA, Schrank PJ, Simon RA, Mathison DA, Christiansen SC, Stevenson DD (October 1995). "Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects". The Journal of Allergy and Clinical Immunology. 96 (4): 480–5. doi:10.1016/S0091-6749(95)70290-3. PMID 7560658.
- Kalaria RN, Maestre GE, Arizaga R, Friedland RP, Galasko D, Hall K, Luchsinger JA, Ogunniyi A, Perry EK, Potocnik F, Prince M, Stewart R, Wimo A, Zhang ZX, Antuono P (September 2008). "Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors". The Lancet. Neurology. 7 (9): 812–26. doi:10.1016/S1474-4422(08)70169-8. PMC 2860610. PMID 18667359.
- Kim YJ, Lim KH, Kim MY, Jo EJ, Lee SY, Lee SE, et al. (March 2014). "Cross-reactivity to Acetaminophen and Celecoxib According to the Type of Nonsteroidal Anti-inflammatory Drug Hypersensitivity". Allergy, Asthma & Immunology Research. 6 (2): 156–62. doi:10.4168/aair.2014.6.2.156. PMC 3936045. PMID 24587953.
- Cardet JC, White AA, Barrett NA, Feldweg AM, Wickner PG, Savage J, Bhattacharyya N, Laidlaw TM (2014). "Alcohol-induced respiratory symptoms are common in patients with aspirin exacerbated respiratory disease". The Journal of Allergy and Clinical Immunology. In Practice. 2 (2): 208–13. doi:10.1016/j.jaip.2013.12.003. PMC 4018190. PMID 24607050.
- Narayanankutty A, Reséndiz-Hernández JM, Falfán-Valencia R, Teran LM (May 2013). "Biochemical pathogenesis of aspirin exacerbated respiratory disease (AERD)". Clinical Biochemistry. 46 (7–8): 566–78. doi:10.1016/j.clinbiochem.2012.12.005. PMID 23246457.
- Claesson HE (September 2009). "On the biosynthesis and biological role of eoxins and 15-lipoxygenase-1 in airway inflammation and Hodgkin lymphoma". Prostaglandins & Other Lipid Mediators. 89 (3–4): 120–5. doi:10.1016/j.prostaglandins.2008.12.003. PMID 19130894.
- Kupczyk M, Kurmanowska Z, Kupryś-Lipińska I, Bocheńska-Marciniak M, Kuna P (October 2010). "Mediators of inflammation in nasal lavage from aspirin intolerant patients after aspirin challenge". Respiratory Medicine. 104 (10): 1404–9. doi:10.1016/j.rmed.2010.04.017. PMID 20452758.
- Ledford DK, Wenzel SE, Lockey RF (2014). "Aspirin or other nonsteroidal inflammatory agent exacerbated asthma". The Journal of Allergy and Clinical Immunology. In Practice. 2 (6): 653–7. doi:10.1016/j.jaip.2014.09.009. PMID 25439353.
- Choi JH, Kim MA, Park HS (February 2014). "An update on the pathogenesis of the upper airways in aspirin-exacerbated respiratory disease". Current Opinion in Allergy and Clinical Immunology. 14 (1): 1–6. doi:10.1097/ACI.0000000000000021. PMID 24300420.
- Picado C (2002). "Aspirin-intolerant asthma: role of cyclo-oxygenase enzymes". Allergy. 57 Suppl 72: 58–60. doi:10.1034/j.1398-9995.57.s72.14.x. PMID 12144557.
- Neighbour H (2014). "Mechanisms of aspirin-intolerant asthma: identifying inflammatory pathways in the pathogenesis of asthma". International Archives of Allergy and Immunology. 163 (1): 1–2. doi:10.1159/000355949. PMID 24247362.
- Sousa AR, Parikh A, Scadding G, Corrigan CJ, Lee TH (November 2002). "Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis". The New England Journal of Medicine. 347 (19): 1493–9. doi:10.1056/NEJMoa013508. PMID 12421891.
- Cowburn AS, Sladek K, Soja J, Adamek L, Nizankowska E, Szczeklik A, Lam BK, Penrose JF, Austen FK, Holgate ST, Sampson AP (February 1998). "Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma". The Journal of Clinical Investigation. 101 (4): 834–46. doi:10.1172/JCI620. PMC 508632. PMID 9466979.
- Laidlaw TM, Kidder MS, Bhattacharyya N, Xing W, Shen S, Milne GL, Castells MC, Chhay H, Boyce JA (April 2012). "Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes". Blood. 119 (16): 3790–8. doi:10.1182/blood-2011-10-384826. PMC 3335383. PMID 22262771.
- Online Mendelian Inheritance in Man (OMIM) Asthma, Nasal Polyps, and Aspirin Intolerance -208550
- Waldram JD, Simon RA (November 2016). "Performing Aspirin Desensitization in Aspirin-Exacerbated Respiratory Disease". Immunology and Allergy Clinics of North America. 36 (4): 693–703. doi:10.1016/j.iac.2016.06.006. PMID 27712764.
- Lee JY, Simon RA, Stevenson DD (January 2007). "Selection of Aspirin dosages for aspirin desensitization treatment in patients with aspirin-exacerbated respiratory disease". Journal of Allergy and Clinical Immunology. 119: 157–164. doi:10.1016/j.jaci.2006.09.011.
- Berges Gimeno MP, Simon RA, Stevenson DD (January 2003). "Long-term treatment with aspirin desensitization in asthmatic patients with aspirin-exacerbated respiratory disease". Journal of Allergy and Clinical Immunology. 111: 180–186. doi:10.1067/mai.2003.7.
- Pleskow WW, Stevenson DD, Mathison DA, Simon RA, Schatz M, Zeiger RS (January 1982). "Aspirin desensitization in aspirin-sensitive asthmatic patients: clinical manifestations and characterization of the refractory period". The Journal of Allergy and Clinical Immunology. 69 (1 Pt 1): 11–9. doi:10.1016/0091-6749(82)90081-1. PMID 7054250.
- Ta V, White AA (September 2015). "Survey-Defined Patient Experiences With Aspirin-Exacerbated Respiratory Disease". Journal of Allergy and Clinical Immunology: In Practice. 3 (5): 711–718. doi:10.1016/j.jaip.2015.03.001.
- Tuttle KL, Buchheit KM, Schneider T, Hsu Blatman KS, Barrett NA, Laidlaw TM, Cahill KN (February 2018). "A pragmatic analysis of mepolizumab in patients with aspirin-exacerbated respiratory disease". Journal of Allergy and Clinical Immunology. 141 (2): AB168. doi:10.1016/j.jaci.2017.12.537.
- Szczeklik, A; Nizankowska, E; Duplaga, M (2000). "Natural history of aspirin-induced asthma. AIANE Investigators. European Network on Aspirin-Induced Asthma". The European Respiratory Journal. 16 (3): 432–6. PMID 11028656.
- McMains KC, Kountakis SE (2006). "Medical and surgical considerations in patients with Samter's triad". American Journal of Rhinology. 20 (6): 573–6. doi:10.2500/ajr.2006.20.2913. PMID 17181095.
- Mendelsohn D, Jeremic G, Wright ED, Rotenberg BW (March 2011). "Revision rates after endoscopic sinus surgery: a recurrence analysis". The Annals of Otology, Rhinology, and Laryngology. 120 (3): 162–6. doi:10.1177/000348941112000304. PMID 21510141.
- Adappa ND, Ranasinghe VJ, Trope M, Brooks SG, Glicksman JT, Parasher AK, Palmer JN, Bosso JV (January 2018). "Outcomes after complete endoscopic sinus surgery and aspirin desensitization in aspirin exacerbated respiratory disease". International Forum of Allergy & Rhinology. 8: 49–53. doi:10.1002/alr.22036.
- Payne SC (September 2014). "RE: Alcohol-induced respiratory symptoms are common in patients with aspirin exacerbated respiratory disease". The Journal of Allergy and Clinical Immunology: In Practice. 2 (5): 644. doi:10.1016/j.jaip.2014.05.003.
- Payne SC, Peters RD, Negri JA, Steinke JW, Borish L (February 2017). "Activation of Basophils and Eosinophils by EtOH in Alcohol Sensitive Patients with CRS and Asthma". Journal of Allergy and Clinical Immunology. 139 (2): AB90. doi:10.1016/j.jaci.2016.12.246.
- "Wine and Beer May Make Your Lungs and Sinuses Worse". www.aaaai.org. American Academy of Allergy Asthma & Immunology. August 3, 2018.
- Glicksman JT, Parasher AK, Doghramji L, Brauer D, Waldram J, Waters K, Bulva J, Palmer JN, Addapa ND, White AA, Bosso JV (July 2018). "Alcohol-induced respiratory symptoms improve after aspirin desensitization in patients with aspirin-exacerbated respiratory disease". International Forum of Allergy & Rhinology. 3 (5): 711–718. doi:10.1016/j.jaip.2015.03.001.
- Sommer DD, Rotenberg BW, Sowerby LJ, Lee JM, Janjua A, Witterick IJ, et al. (April 2016). "A novel treatment adjunct for aspirin exacerbated respiratory disease: the low-salicylate diet: a multicenter randomized control crossover trial". International Forum of Allergy & Rhinology. 6 (4): 385–91. doi:10.1002/alr.21678. PMID 26751262.
- Modena BD, White AA (2018). "Can Diet Modification Be an Effective Treatment in Aspirin-Exacerbated Respiratory Disease?". The Journal of Allergy and Clinical Immunology. In Practice. 6 (3): 832–833. doi:10.1016/j.jaip.2017.11.043. PMID 29747986.
- "A Low Salicylate Diet for AERD (Samter's Triad)". The Samter's Society.
- Healy E, Newell L, Howarth P, Friedmann PS (December 2008). "Control of salicylate intolerance with fish oils". The British Journal of Dermatology. 159 (6): 1368–9. doi:10.1111/j.1365-2133.2008.08830.x. PMID 18795922.
- Schneider TR, Johns CB, Palumbo ML, Murphy KC, Cahill KN, Laidlaw TM (2018). "Dietary Fatty Acid Modification for the Treatment of Aspirin-Exacerbated Respiratory Disease: A Prospective Pilot Trial". The Journal of Allergy and Clinical Immunology. In Practice. 6 (3): 825–831. doi:10.1016/j.jaip.2017.10.011. PMC 5945343. PMID 29133219.
- Lewis C (2017). "Leukotriene Associated Hypersensitivity". Enteroimmunology: A Guide to the Prevention and Treatment of Chronic Inflammatory Disease. Carrabelle Florida: Psy Press. pp. 148–58. ISBN 978-1-938318-06-1.
- Amar YG, Frenkiel S, Sobol SE (February 2000). "Outcome analysis of endoscopic sinus surgery for chronic sinusitis in patients having Samter's triad". The Journal of Otolaryngology. 29 (1): 7–12. PMID 10709165.
- Williams AN, Woessner KM (May 2008). "The clinical effectiveness of aspirin desensitization in chronic rhinosinusitis". Current Allergy and Asthma Reports. 8 (3): 245–52. doi:10.1007/s11882-008-0041-7. PMID 18589844.
- Bochenek G, Bánska K, Szabó Z, Nizankowska E, Szczeklik A (March 2002). "Diagnosis, prevention and treatment of aspirin-induced asthma and rhinitis". Current Drug Targets. Inflammation and Allergy. 1 (1): 1–11. doi:10.2174/1568010023345011. PMID 14561202.
- Samter's syndrome at Who Named It?
- Widal F, Abrami P, Lermoyez J (1922). "Anaphylaxie et idiosyncraise" [Anaphylaxis and idiosyncrasy]. La Presse Médicale (in French). 30 (18): 189–93.
- Samter M, Beers RF (May 1968). "Intolerance to aspirin. Clinical studies and consideration of its pathogenesis". Annals of Internal Medicine. 68 (5): 975–83. doi:10.7326/0003-4819-68-5-975. PMID 5646829.