Aspirin-exacerbated respiratory disease (AERD) is characterized by the triad of asthma, sinonasal polyposis, and aspirin intolerance. The hallmark of the disease is baseline overproduction of cysteinyl leukotrienes via the 5-lipoxygenase pathway, exacerbated by ingestion of aspirin. Patients with AERD have high rates of recidivistic polyposis following sinus surgery, although the improvement in quality of life following surgery is similar to aspirin-tolerant patients. The diagnosis is secured by a positive aspirin provocation test, usually administered by a medical allergist. Aspirin therapy is a unique treatment consideration for patients with AERD.
Key points
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AERD is a well-recognized subtype of difficult-to-control CRS. It has specific biomarkers and disease-specific treatment considerations.
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The clinical hallmark of AERD is an acquired sensitivity to ingestion of aspirin and other cyclooxygenase-1 (COX-1) inhibitors.
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Familiarity with aspirin desensitization is essential for sinus surgeons, although it is often performed by medical allergists.
Introduction
Aspirin-exacerbated respiratory disease (AERD) is an inflammatory condition characterized by the triad of asthma, rhinosinusitis, and sensitivity to aspirin. AERD is also referred to as Samter triad, and beyond these two designations, the literature has used several others including aspirin triad, aspirin-sensitive asthma, aspirin-induced asthma, and aspirin-intolerant asthma. For this article, AERD is the preferred nomenclature.
AERD is one of the best characterized subtypes of rhinosinusitis. Disordered eicosanoid metabolism, the pathophysiologic mechanism underlying AERD, is unique to this disorder. The rhinosinusitis of AERD is typically severe and, among currently defined subtypes, one of the more difficult to control. Fortunately, there are specific treatment options available to patients with aspirin sensitivity, including aspirin desensitization, which may ameliorate the severity of upper and lower airway inflammatory disease. In this sense AERD is a prototype for the application of precision medicine principles; it is a well-defined subtype of chronic rhinosinusitis (CRS) with individualized treatment strategies tailored to the underlying pathophysiologic mechanism. With a proliferation of novel biologic agents to address specific components of the inflammatory cascade, AERD may serve as a model for how other types of difficult-to-control CRS are treated in the future.
Introduction
Aspirin-exacerbated respiratory disease (AERD) is an inflammatory condition characterized by the triad of asthma, rhinosinusitis, and sensitivity to aspirin. AERD is also referred to as Samter triad, and beyond these two designations, the literature has used several others including aspirin triad, aspirin-sensitive asthma, aspirin-induced asthma, and aspirin-intolerant asthma. For this article, AERD is the preferred nomenclature.
AERD is one of the best characterized subtypes of rhinosinusitis. Disordered eicosanoid metabolism, the pathophysiologic mechanism underlying AERD, is unique to this disorder. The rhinosinusitis of AERD is typically severe and, among currently defined subtypes, one of the more difficult to control. Fortunately, there are specific treatment options available to patients with aspirin sensitivity, including aspirin desensitization, which may ameliorate the severity of upper and lower airway inflammatory disease. In this sense AERD is a prototype for the application of precision medicine principles; it is a well-defined subtype of chronic rhinosinusitis (CRS) with individualized treatment strategies tailored to the underlying pathophysiologic mechanism. With a proliferation of novel biologic agents to address specific components of the inflammatory cascade, AERD may serve as a model for how other types of difficult-to-control CRS are treated in the future.
Clinical presentation
AERD is an acquired disorder that typically presents in the third or fourth decade. Patients usually do not report a previous history of atopy, rhinitis, or asthma, and may offer a history of tolerating aspirin or nonsteroidal anti-inflammatory drugs well into adulthood. This disorder affects approximately 0.5% of the population, and females twice as often as males. Obesity and smoking are risk factors that are more associated with AERD than aspirin-tolerant asthma.
The hallmark of AERD is an acquired sensitivity to ingestion of aspirin and other cyclooxygenase (COX)-1 inhibitors. Patients with AERD develop symptoms 30 to 120 minutes after ingestion of aspirin, resulting from proinflammatory effects of dysregulated cysteinyl leukotrienes on the upper and lower respiratory tracts (increased vascular permeability, bronchoconstriction, and eosinophil chemotaxis and activation). Patients typically experience acute onset of nasal congestion, conjunctivitis, throat tightness, and exacerbation of asthma. There can also be an associated anaphylactic-like reaction characterized by urticaria, gastrointestinal disturbance, or hypotension. Because the drug reaction is not IgE-mediated, it is not considered true anaphylaxis. The severity of symptoms is variable, from minimal wheezing to severe respiratory compromise.
In the absence of an acute exposure to aspirin, patients who develop AERD still experience progressive upper and lower respiratory inflammatory symptoms because of abnormally elevated circulating levels of cysteinyl leukotrienes. The syndrome may unfold over a few years, with the first symptom to present usually being rhinitis. The rhinitis is often reported to have originated as a “cold that never went away.” It is associated with a clear discharge and may be resistant to standard therapies. Rhinitis progresses to CRS in 60% to 90% of cases. CRS associated with AERD is characterized by hyperplastic mucosal remodeling with prominent eosinophilia, and ultimately, nasal polyposis.
An average of 2 years later, patients develop asthma. Patients frequently have no prior history of childhood asthma or any prior problems with reactive airway disease. The asthma of AERD is typically moderate-severe to severe, by current classification standards. It is often difficult to control; compared with patients with aspirin-tolerant asthma, patients with AERD are more likely to have severe asthma, to require intensive care unit admission for asthma, to need oral steroids for asthma exacerbation, and to receive high-dose inhaled steroids for asthma control. However, sometimes asthma is absent.
Aspirin intolerance can develop at any point during this time course but frequently is the last part of the triad to develop. This happens on average 4 years after the onset of asthma. Because most patients with CRS and comorbid asthma do not have aspirin sensitivity, taking a careful history regarding aspirin tolerance is important to discern patients with AERD from those without AERD. Still, in patients with asthmatic rhinosinusitis who have no history of adverse reaction to aspirin, 15% have a positive oral aspirin challenge. Conversely, for patients with asthmatic rhinosinusitis who do report a history of adverse reaction to aspirin, 14% have a negative oral aspirin challenge. Patients who report recurrent adverse reactions to aspirin, or who had a previous severe reaction to aspirin, have fewer negative oral aspirin challenges.
Pathophysiology
AERD is an acquired disorder of arachidonic acid metabolism. The salient finding is a marked baseline overproduction of cysteinyl leukotriene metabolites, most notably LTE4, which is a potent proinflammatory lipid. Leukotrienes are produced by the metabolism of arachidonic acid via the 5-lipoxygenase (5-LO) pathway. Because LTE4 is constitutively overexpressed, irrespective of aspirin exposure, patient avoidance of aspirin does not modify the natural history of the asthmatic and sinonasal manifestations of the disease.
Aspirin is a potent COX-1 inhibitor. COX-1 modulates an alternative route for the metabolism of arachidonic acid, resulting in the synthesis of prostaglandins, including prostaglandin E 2 (PGE2), an anti-inflammatory prostaglandin. PGE2 provides negative feedback to the 5-LO pathway, reducing the burden of LTE4. For patients with AERD, the ingestion of aspirin or other COX-1 inhibitors blocks PGE2 production, which in turn bolsters the 5-LO pathway, causing a surge of proinflammatory leukotrienes. During oral aspirin challenge, PGE2 levels are decreased, and LTE4 levels are increased. The resulting surge of serum leukotrienes results in acute bronchoconstriction, vascular permeability, and eosinophil migration, manifesting clinically as acute rhinitis and asthma. Notably, the reaction that occurs after ingestion of aspirin is pseudoallergic, because it is not IgE-mediated. Furthermore, sensitivity to ingested aspirin is a marker of disease, not the cause of the disease.
In the clinical setting, LTE4 is measured by urine collection, and serves as a marker of overall production of proinflammatory leukotrienes. At baseline, without exposure to aspirin, patients with AERD have elevated LTE4 levels three to five times that of those with aspirin-tolerant asthma. The magnitude of the surge in urinary LTE4 after aspirin challenge has been shown to correlate with the severity of the clinical reaction observed. In patients with a positive oral aspirin challenge, testing of urinary LTE4 is not routinely necessary. But in patients with a negative oral aspirin challenge for whom there is still strong suspicion for AERD, an elevated urinary LTE4 may predict a therapeutic benefit for aspirin therapy.
Leukotrienes seem to play a dominant role in the pathophysiology of patients with AERD relative to aspirin-tolerant patients with asthma and CRS. After aspirin desensitization and continued aspirin therapy, sensitivity to inhaled LTE4 was noted to decrease 33-fold from the predesensitization state in patients with AERD, although there was no observed change in sensitivity in aspirin-tolerant patients. In a double-blind placebo-controlled trial of patients with AERD, oral challenge with aspirin produced a six-fold increase in urinary LTE4 compared with placebo. In patients with asthma who were tolerant to aspirin during oral aspirin challenge, this phenomenon was observed to a lesser degree. The observed differences in leukotriene sensitivity and production, at baseline and during aspirin challenge, support the primary relevance of leukotrienes in patients with AERD compared with those without AERD.
Platelets have also been implicated in the overproduction of leukotrienes observed in patients with AERD. Transcellular synthesis of LTE4 occurs when leukocytes adhere to platelets to appropriate their cellular machinery for leukotriene production. These platelet-leukocyte aggregates are measurable in the research setting and have been correlated with the increase in urinary LTE4 seen in patients with AERD during oral aspirin challenge. The inhibition of platelets by aspirin, and thus of the requisite machinery for leukotriene production, may be one mechanism by which aspirin therapy improves symptoms in patients with AERD.
There are differences in cytokine expression that distinguish AERD-related CRS from aspirin-tolerant CRS. Compared with aspirin-tolerant CRS with nasal polyposis, polyp tissue from patients with AERD contain higher levels of eosinophilic cationic protein, a marker of eosinophilia, elevated expression of interleukin-5, and interferon-γ. In addition to 5-LO, leukotriene C4 synthetase is another enzyme that is upregulated in AERD, which drives not only LTE4 production, but also precursor leukotrienes types C4 and D4.
Asthma in aspirin-exacerbated respiratory disease
Approximately 7% of all people with asthma are aspirin intolerant. In the subgroup of those with severe asthma, this proportion doubles to 14%. Of people with asthma with nasal polyposis, 10% to 42% are aspirin intolerant. Patients with AERD typically have moderate-severe to severe asthma and thus, by current guidelines recommendations, usually require regular use of inhaled corticosteroid in addition to long-term inhaled β-agonists.
Chronic rhinosinusitis in aspirin-exacerbated respiratory disease
AERD is a severe subtype of CRS, characterized by chronic eosinophilic hyperplastic inflammation of the sinonasal mucosa. Nasal polyps are typically present. A total of 8% to 26% of all patients with CRS with polyps have AERD. Thus, for all patients who have CRS with polyps, it is important to elicit if there is a history of asthma, particularly adult-onset, or a history of adverse reaction to aspirin. Patients with AERD have worse sinonasal disease by computed tomography (CT) evaluation and are more likely to require revision surgery than aspirin-tolerant patients with CRS.
Treatment options for aspirin-exacerbated respiratory disease–related chronic rhinosinusitis
Like all other patients with CRS, patients with AERD with symptomatic nasal polyposis should undergo a trial of medical therapy before pursuing surgical therapy. This usually includes saline irrigations, topical steroids, oral antibiotics, and judicious use of oral steroids. Specifically for AERD, zileuton (see later) may be used preoperatively to reduce polyp burden, but this is not routine practice. It should be noted that as a subtype of CRS with nasal polyposis, AERD-related CRS is treated with standard therapies that are generally used for all subtypes of CRS with nasal polyposis. This discussion highlights specific strategies for management of AERD-related CRS, namely aspirin desensitization, and also reviews strategies for managing CRS with nasal polyposis generally, which are widely applied in clinical practice.
Antileukotriene Therapy
Two classes of drugs are available: leukotriene receptor competitive antagonists, which block the CysLT1 receptor; and 5-LO inhibitors, which block the rate-limiting step of arachidonic metabolism in the leukotriene pathway. To date, despite a plausible pathophysiologic rationale, there is no evidence that leukotriene receptor antagonists are beneficial for the treatment of CRS in the setting of AERD. However, leukotriene receptor antagonists may benefit some patients with AERD in control of asthma and/or allergic rhinitis (independent of aspirin tolerance).
Drugs in the CysLT1 receptor antagonist class include montelukast, zafirlukast, and pranlukast. These drugs are indicated for asthma and are sometimes used in the treatment of allergic rhinitis. Some researchers have postulated that leukotriene receptor antagonists might have a role in preventing polyp regrowth after endoscopic sinus surgery, but studies of patients with nasal polyps, which included aspirin-tolerant CRS, have not shown leukotriene receptor antagonists to be effective as monotherapy when compared with topical mometasone. In addition, there is no durable benefit for using montelukast as an additional therapy for symptom control in CRS with polyposis in patients already using topical nasal steroids. These studies evaluated montelukast in the treatment of all CRS with nasal polyposis, not specifically AERD-associated CRS. A separate leukotriene receptor, CysLT2, has been shown to be upregulated in nasal polyp tissue, but the current leukotriene receptor antagonists do not affect these receptors.
The only drug available in the 5-LO inhibitor class is zileuton, which is indicated for asthma. Ex vivo studies of nasal polyp tissue have shown increased inhibition of mast cell activation with the combination of zileuton plus montelukast compared with montelukast alone. Currently no clinical studies directly evaluate use of this medication in patients with CRS. A study of patients with asthma and AERD showed improved sense of smell and nasal peak inspiratory flow in the zileuton group compared with placebo to be a significant secondary outcome. Use of this medication carries a small risk of hepatotoxicity and requires monitoring of liver function throughout its course.
For both classes of leukotriene-modifying medications, a rare but concerning potential side effect is psychiatric disturbance including suicidal ideation, particularly in adolescents, for which the Food and Drug Administration has issued warnings.
Antibiotic Therapy
Antibiotic therapy for AERD-associated rhinosinusitis is not an intuitive proposition given that the understood cause of AERD is inflammatory, not infectious. However, there is evidence that in all subtypes of CRS with nasal polyposis, the addition of 3 weeks of doxycycline to prednisone results in more durable reduction of disease by objective and subjective measures in patients with nasal polyps compared with prednisone alone. The proposed mechanism of action of doxycycline is reduction of staphylococcal enterotoxin, to which nasal polyposis is associated with an IgE-mediated hypersensitivity. In patients with AERD, levels of antistaphylococcal enterotoxin IgE are elevated compared with aspirin-tolerant CRS with nasal polyposis, and may be responsible for the observed elevation of total IgE seen in patients with AERD without atopy.
Omalizumab
Omalizumab, an anti-IgE monoclonal antibody, has been reported to be beneficial in the treatment of patients with AERD, even though the primary pathophysiologic disturbance of leukotriene overproduction and the adverse reaction to aspirin ingestion are not thought to be IgE-mediated. Omalizumab is currently indicated for use in severe asthma. Aside from case reports, to date there are no large studies that have specifically addressed CRS and asthma in the setting of AERD. In patients with severe asthma who also have nasal polyposis, use of this medication is associated with improved control of CRS symptoms. This effect seems to be independent of atopy status. In a prospective, uncontrolled study evaluating CRS and asthma symptoms in patients with severe asthma, patients receiving omalizumab had improved CRS symptom scores, decreased objective disease as measured on CT, improved asthma symptom scores, and reduced polyp burden.
Oral Corticosteroids
No studies have specifically addressed oral steroid use in patients with AERD, but they are commonly used in clinical practice for AERD and for other subtypes of CRS with nasal polyposis. Oral corticosteroids are an effective short-term treatment of nasal polyps. The maximum effect is reached by approximately 2 to 3 weeks of therapy. Although at times necessary, the short-term side effects of corticosteroid use include insomnia, anxiety, hyperglycemia, dyspepsia, and exacerbation of closed-angle glaucoma, if present. Long-term side effects include diabetes, osteoporosis, Cushing syndrome, adrenal insufficiency, and avascular necrosis of the femur. The prescribing of oral steroids for patients with CRS requires careful consideration, because of the potentially devastating adverse effects associated with their use. Furthermore, use of oral steroid bursts even once yearly results in significant increase in the rate of diabetes and osteoporosis in patients with allergic rhinitis compared with those who do not receive systemic steroids. Therefore, repeated use of steroids is not judicious as first-line therapy for most patients suffering from CRS.
Surgical Management
Endoscopic sinus surgery for patients with AERD with nasal polyps adheres to similar principles as with other types of CRS with nasal polyps. Surgery for AERD-associated rhinosinusitis is not minimally invasive in the sense that the goal is not merely to ventilate the sinuses at the ostiomeatal complex, considering that AERD and other forms of eosinophilic CRS are not caused by ostiomeatal obstruction of the sinuses. Surgery should aim to remove polyps, remove any eosinophilic mucin that might stimulate ongoing inflammation, and yet preserve the mucosal lining of the surgical cavities. It should also facilitate access for postoperative irrigations. Thus, meticulous postoperative debridement is necessary to maintain widely patent sinuses.
Patients with AERD are more likely to have recurrence of nasal polyposis following surgery than patients with other forms of nasal polyposis. In one study, patients with AERD had an average of 10 times the number of sinus surgeries compared with aspirin-tolerant patients. However, postoperative quality-of-life outcomes may actually be comparable between patients with and without AERD. Although patients with AERD have a higher preoperative disease burden by CT imaging, and worse postoperative endoscopy scores, there is no measurable difference in postoperative quality of life compared with patients with aspirin-tolerant CRS. Surgical benefits seem to be preserved when performed in conjunction with aspirin desensitization (see next section). Patients with AERD with asthma and CRS who undergo sinus surgery have improved asthma control following surgery compared with the previous year. Compared with the previous year before surgery, in the first postoperative year patients have fewer emergency room visits and improved asthma symptom scores.
Because patients with AERD have adverse reactions to COX-1 inhibitors, the management of postoperative pain must accommodate for drug intolerances. Aspirin cannot be used for pain control, and as for other strong COX-1 inhibitors, there is a 41% rate of cross-reactivity to ibuprofen, 4% cross-reactivity to naproxen, and 1% cross-reactivity to ketorolac. Acetaminophen, commonly used in combination with narcotic medications, is actually a weak COX-1 inhibitor. At oral doses greater than 1000 mg of acetaminophen, one-third of patients with AERD experience an adverse reaction. Doses less than 500 mg are generally well tolerated. COX-2 inhibitors, such as celecoxib, are generally tolerated but are not typically used in the postoperative period.
Aspirin desensitization is usually performed 1 month after surgery, so as to avoid the risk of postoperative epistaxis from platelet inhibition and yet also to preempt early polyp regrowth. Aspirin therapy is not known to shrink the existing polyp burden, but it does seem to prevent polyp regrowth. Thus it is not recommended to pursue aspirin desensitization unless a thorough surgical removal of polyps has occurred first. When patients who are already desensitized to aspirin require revision sinus surgery, the surgeon may elect to proceed with surgery with the patient on a reduced daily dose of 81 mg of aspirin, which maintains the desensitized state. The patient can then be re-escalated to therapeutic doses at home postoperatively without clinical supervision. Otherwise, if aspirin has been completely discontinued for more than 72 hours, the patient will likely need to repeat the complete process of desensitization from the beginning.
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