INTRODUCTION — Aspirin-exacerbated respiratory disease (AERD), which is commonly called nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) in Europe, refers to the combination of asthma, chronic rhinosinusitis (CRS) with nasal polyposis, and NSAID intolerance. NSAID intolerance presents as acute upper and/or lower respiratory tract symptoms following the ingestion of aspirin (acetylsalicylic acid [ASA]) or other cyclooxygenase 1 (COX-1)-inhibiting NSAIDs.
The first case of aspirin sensitivity in a patient with asthma was described in 1902, a few years after the introduction of aspirin into clinical use. In 1968, Samter and Beers described a triad consisting of asthma, aspirin sensitivity, and nasal polyps , which came to be known as Samter's triad. The modern name for this triad is AERD.
An overview of AERD with emphasis on pathophysiology and the management of asthma will be presented here. Other types of hypersensitivity reactions to NSAIDs and the treatment of CRS with nasal polyposis are discussed separately:
NSAIDs — The primary effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is to inhibit cyclooxygenase (COX; also called prostaglandin synthase), thereby impairing the transformation of arachidonic acid (AA) to prostaglandins, prostacyclin, and thromboxanes and enhancing production of leukotrienes (figure 1). Two related isoforms of the COX enzyme have been described, COX-1 and COX-2. Some NSAIDs have a greater inhibitory effect on COX-1 and others on COX-2 (table 1). COX-1 inhibition is the stimulus for acute reactions to NSAIDs in aspirin-exacerbated respiratory disease (AERD). In this topic review, the term "NSAID" includes aspirin (acetylsalicylic acid [ASA]). However, in some clearly marked sections, aspirin is discussed exclusive of other NSAIDs.
AERD — Aspirin-exacerbated respiratory disease refers to the combination of:
●Chronic rhinosinusitis (CRS) with nasal polyposis
●Reactions to aspirin and other COX-1-inhibiting NSAIDs, in which symptoms of nasal congestion and bronchoconstriction typically begin 20 minutes to 3 hours after administration
Patients with AERD are also described as having aspirin-sensitive asthma or aspirin-intolerant asthma, although these terms refer to just one component of the disorder. The term "AERD" places emphasis on the chronic upper and lower respiratory disease as the fundamental disorder and a reaction to NSAIDs as an exacerbating factor [2,3]. Because NSAID exposure is not the cause of the disorder, avoidance of NSAIDs by these patients does not result in resolution of asthma or CRS.
Pseudoallergy — Reactions to NSAIDs in patients with AERD are classified as "pseudoallergic" because they are not immunoglobulin E (IgE)-mediated. These reactions represent an abnormal biochemical response to the pharmacologic actions of NSAIDs. In contrast, IgE-mediated "allergic" reactions result from the formation of antibodies against a specific drug, haptenated drug, or a group of structurally similar drugs. Pseudoallergic reactions are triggered by a wide range of structurally distinct NSAIDs that have in common the ability to inhibit the COX-1 enzyme.
Reactions to aspirin in patients with AERD are characterized as type 1 pseudoallergic reactions. The other types of pseudoallergic reactions to NSAIDs are discussed separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on 'Pseudoallergic reactions'.)
EPIDEMIOLOGY — Fully developed AERD (asthma, polyposis, and nonsteroidal anti-inflammatory drug [NSAID] sensitivity) is usually diagnosed in adults. It is rare in children and adolescents . The three component disorders of AERD tend to develop serially over a period of years, although some patients may present with rapid progression of sinonasal symptoms to asthma [2,5]. Many patients report a history of progressive rhinosinusitis, which gradually worsens and begins to involve inflammation in the lower airway. The diagnosis of asthma then follows, although, in some series, asthma was the first component to be diagnosed . At some point during this progression, nasal polyposis and aspirin/NSAID sensitivity appears, although the latter may not be recognized if the patient rarely takes NSAIDs.
The prevalence of AERD is approximately 7 percent among adults with asthma, based on a 2014 metaanalysis of clinical trial data . Among patients with severe asthma, the prevalence is twice as high, at approximately 14 percent. Among patients with chronic rhinosinusitis (CRS) with nasal polyposis, the prevalence is about 16 percent . However, some patients may not be aware that they are sensitive to NSAIDs. In a prospective study of 80 adults presenting consecutively to an allergy and immunology clinic with CRS and nasal polyps, 36 percent reported sensitivity to NSAIDs, but 49 percent reacted to aspirin upon challenge .
The asthma and chronic sinusitis of AERD usually become more severe over time, even with NSAID avoidance [3,10-12]. However, not all patients have severe asthma, and, for many patients, the symptoms related to nasal polyposis and CRS are more troubling on a day-to-day basis .
PATHOPHYSIOLOGY — The pathophysiology of AERD is not fully understood. There appears to be a dysregulation of arachidonic acid (AA) metabolism, particularly with an overproduction of leukotrienes, which may result from decreased inhibition of the 5-lipoxygenase (5-LO) pathway of AA metabolism by prostaglandin E2 (PGE2). The overproduction of leukotrienes is further exacerbated by the action of cyclooxygenase 1 (COX-1) inhibitors (which block production of PGE2). In addition, patients with AERD may have decreased elaboration of downregulatory fatty acid products, such as lipoxins. Collectively, these abnormalities result in an imbalance between proinflammatory and anti-inflammatory mediators.
Normal arachidonic acid metabolism — AA is derived from the membrane phospholipids of many cell types and is metabolized along different pathways to yield various lipid mediators. Some of these mediators are proinflammatory and some are anti-inflammatory. A few can act in both capacities, depending upon the target cell. A simplified overview of AA metabolism is provided (figure 2).
5-lipoxygenase pathway — The metabolism of AA by the enzyme 5-LO generates the leukotrienes (LTs), as depicted in the figure (figure 2). The cysteinyl leukotrienes (cysLTs), LTC4, LTD4, and LTE4, are potent inducers of bronchoconstriction, mucus secretion, nasal mucosal swelling, and airway edema and also attract eosinophils into the airways [13-15]. These are the major LTs synthesized by eosinophils and mast cells, cell types that are abundant in inflamed airways.
Leukotriene B4 (a non-cysLT) is also proinflammatory but with effects on neutrophils and monocytes. Yet another 5-LO product, 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), is a very potent eosinophil chemoattractant (figure 2).
Cyclooxygenase pathway — The metabolism of AA by the two cyclooxygenase isoforms (COX-1 and COX-2, also known as cycloendoperoxidase H synthases or prostaglandin synthases) yields prostaglandins and thromboxanes (figure 1) . One of the prostaglandins, prostaglandin D2 (PGD2), is predominantly produced by mast cells and has a bronchoconstrictor effect. Production of PGD2 and its metabolite, PGD2S, is relatively aspirin resistant and may be more dependent upon COX-2 than COX-1. In contrast, PGE2 is a bronchodilator with potent anti-inflammatory effects. It is expressed in a broad range of cells and is decreased after COX-1 inhibition [16-18]. PGE2 is believed to act as a "brake" on the production of the proinflammatory LTs. (See "NSAIDs: Pharmacology and mechanism of action".)
Abnormalities in AERD — Studies of patients with AERD demonstrate a baseline dysregulation of AA metabolism with greatly increased production of the proinflammatory and underproduction of the anti-inflammatory products compared with patients with asthma but without AERD [19-23]. The proinflammatory leukotrienes promote airway inflammation and edema. The baseline dysregulation is acutely exaggerated by ingestion of COX-1 inhibitors, perhaps because the synthesis of PGE2 is reduced and the "brake" on leukotrienes is released [24-27]. While mast cells have traditionally been thought to be the major source of cysLTs, accumulating evidence suggests that platelets may play a role in this process by providing the enzymes needed for leukocytes to produce leukotrienes [28,29].
The following abnormalities, which support this model of AERD pathophysiology, have been identified in patients with AERD [30-41]:
●The primary cellular source of leukotriene LTC4 in patients with AERD appears to be mast cells in the nasal polyp tissue and bronchi, although eosinophils are also capable of producing large amounts [32,42]. Both cell types are increased and activated in the respiratory tracts of patients with AERD [33-35].
●The enzyme LTC4 synthase, which mediates the formation of LTC4, is overexpressed by eosinophils and other leukocytes in both nasal and pulmonary tissues of some patients with AERD (figure 2) [33,36].
●Abnormal aggregations of platelets and leukocytes (specifically, neutrophils, eosinophils, and monocytes) were demonstrated in nasal polyp tissue and peripheral blood from patients with AERD . When closely associated, platelets and leukocytes can share metabolic processes (ie, transcellular synthesis) to produce enhanced amounts of proinflammatory leukotrienes. In patients with AERD, the percentages of platelet-leukocyte aggregates correlated with markers of systemic cysLT production, suggesting that these aggregates play a role in the enhanced production of leukotrienes.
●Levels of PGE2 in polyp tissue and lower airway fibroblasts of AERD patients are reduced at baseline and fall further after aspirin challenge [48-50]. PGE2 is believed to act as a brake on leukotriene production, as mentioned previously. The inhalation of PGE2 has been shown to prevent the reaction to inhaled forms of acetylsalicylic acid (ie, lysine-aspirin), as well as the rise in cysLTs , suggesting that altered PGE2 homeostasis may be key to this disorder. PGE2 suppresses leukotriene production through the activity of protein kinase A (PKA), and PKA activity was shown to be abnormally low in granulocytes in the blood of patients with AERD, compared with controls . Additionally, several isoforms of the PGE receptors are reduced on the inflammatory cells in nasal polyp and bronchial tissues of AERD patients, further suggesting that altered PGE homeostasis may contribute to AERD [25,52].
●Additional evidence of a role for PGE2 in AERD comes from laboratory studies. PGE2-synthase-1-deficient mice demonstrate sustained increases in airway resistance, mast cell activation, and cysLT overproduction following inhalation of lysine-aspirin, similar to AERD in humans . These effects were blocked by pretreatment with leukotriene antagonists.
Involvement of mast cells — Mast cells, especially those in the nasal and bronchial epithelium, may represent an important source of lipid mediators in patients with AERD. Evidence for mast cell activation and degranulation during aspirin challenge in patients with AERD includes demonstrable elevations in mast cell tryptase, histamine, and PGD2 [35,46,54]. In addition, H1 receptor antagonists (antihistamines) may reduce the extent of nasal and ocular reactions to aspirin to varying degrees.
Other areas of investigation — Differences in complement proteins between asthmatics with and without aspirin sensitivity were detected using proteomics . A small case-control study examined changes in expression of plasma proteins in six aspirin-sensitive and six aspirin-tolerant asthmatics at baseline and after aspirin challenge, compared with control patients without asthma. Baseline differences were detected in complement proteins, apolipoproteins, and albumin complexed with myristic acid, with significant up- and downregulation of these proteins after aspirin challenge. In particular, patients with AERD had higher levels of C3a and C4a than tolerant patients at baseline, with levels that correlated to changes in forced expiratory volume in one second (FEV1) during challenge.
SIGNS AND SYMPTOMS — Patients with AERD typically have asthma and chronic rhinosinusitis with nasal polyposis and experience acute exacerbations of upper and lower respiratory symptoms after the ingestion of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) . In most patients, the three component disorders develop sequentially over a period of years.
Asthma — Asthma usually develops in adulthood in patients who ultimately prove to have AERD . Patients with AERD are more likely to have severe asthma, to have been intubated, and to require systemic glucocorticoids to control their symptoms compared with patients with aspirin-tolerant asthma . However, a small percentage of those with AERD (estimated about less than 5 percent) have very mild asthma or are not aware that they have asthma. The inflammation in the lungs of patients with AERD is nearly always eosinophilic and more driven by cysteinyl leukotrienes compared with that in patients with aspirin-tolerant asthma [58,59].
Chronic rhinosinusitis with nasal polyposis — The majority of patients initially develop refractory rhinitis, which is usually established by their early 30s. This is followed by the development of chronic hypertrophic eosinophilic rhinosinusitis, characterized by nasal congestion, anosmia, and nasal polyposis (picture 1 and picture 2). On computed tomography (CT), mucosal thickening typically affects most, if not all, of the paranasal sinuses, and polyps may appear as rounded mucosal protrusions in the nasal or sinus cavities. Hearing loss and eustachian tube dysfunction are also common . Some patients have repeated sinus surgeries and polypectomies before the disorder is recognized. Sinus disease is a significant burden for many patients. In a survey of 190 patients, the majority reported that AERD adversely affected their quality of life and identified chronic nasal symptoms and decreased sense of smell as important factors . Hyposmia and anosmia are even more common and severe in patients with AERD compared with aspirin-tolerant patients with CRS with nasal polyps [62,63]. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis".)
Acute reactions to NSAIDs — Acute reactions to NSAIDs in patients with AERD typically begin 30 minutes to 3 hours after NSAID ingestion, peak at one to two hours after onset, and generally resolve by three hours from onset [64,65]. The symptoms are dose related (ie, small doses of NSAIDs may produce minimal symptoms, such as isolated nasal congestion), whereas larger doses may induce severe bronchospasm requiring intubation. Rare fatal reactions have been reported following full NSAID doses .
When patients with AERD are challenged with aspirin on an escalating dose schedule, most bronchoconstrictive reactions occur with low doses of 30 to 120 mg, although a few patients require 325 mg or more to elicit a reaction . Thus, when an unknowing patient with AERD ingests 650 mg of aspirin or its equivalent of ibuprofen (400 mg), naproxen (440 mg), or indomethacin (50 mg), reactions may be quite severe.
The classic reaction following NSAID ingestion consists of one or more of the following:
●Nasal and ocular symptoms, including nasal congestion/obstruction, watery rhinorrhea, periorbital edema, and/or injection of the conjunctiva – These symptoms are often the first manifestation of the reaction. However, patients may not recognize the association if the NSAID is taken at the time of an upper respiratory infection or at a time when their baseline sinus disease symptoms are severe and uncontrolled.
●Asthmatic symptoms, including wheezing, dyspnea, cough, and chest tightness – These symptoms can be accompanied by a marked fall in forced expiratory volume in one second (FEV1). Bronchoconstriction is typically reversible with an inhaled beta-agonist bronchodilator, or it slowly reverses without treatment within several hours.
Additional symptoms may occur in patients with severe respiratory reactions. These include facial flushing/erythema, laryngospasm, abdominal cramps, epigastric pain, and hypotension. Severe reactions may be difficult or impossible to distinguish from immunoglobulin (Ig)E-mediated anaphylaxis.
A pruritic urticarial-like macular rash occurs in approximately 15 percent of AERD patients during these acute reactions (picture 3A-B). However, true urticaria and angioedema (without respiratory symptoms) are more characteristic of other distinct types of NSAID sensitivity without asthma, called NSAID-induced urticaria/angioedema (type 2 and 3 pseudoallergic reactions) (table 2). Of note, macular rashes have been noted during these reactions as well . (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on 'Pseudoallergic reactions'.)
Other clinical manifestations — Other clinical manifestations seen in some patients with AERD include reactions to alcoholic beverages, nonexertional chest pain, and otologic complications.
Reactions to alcoholic beverages — Patients with AERD often report that alcoholic beverages induce symptoms in the upper (nasal congestion and rhinorrhea) and lower (wheezing, shortness of breath) respiratory tract . In a questionnaire study of 59 patients with aspirin challenge-confirmed AERD, 83 percent reported respiratory reactions to a variety of alcoholic drinks, with symptoms usually developing within an hour of ingestion .
Chest pain — Patients with AERD may report a nonexertional angina-like chest pain. In a retrospective review of 153 individuals with AERD, 10 reported episodes of chest pain, which was associated in several cases with a peripheral blood eosinophilia . The pain was retrosternal, heavy, or squeezing in nature and radiated into the jaw, neck, or arms, with accompanying diaphoresis, nausea, or lightheadedness. It did not improve acutely with nitrates or longer-term with antihypertensives or statins. Of the 10 patients, 8 had initiated high-dose aspirin therapy after undergoing an aspirin desensitization, and 6 of those patients reported that the chest pain began or worsened while they were on high-dose aspirin. Patients who underwent cardiac catheterization either had normal coronary arteries (without significant atherosclerosis) or showed evidence of coronary vasospasm. A course of glucocorticoids resulted in improvement or resolution in several patients. Until more is known about this entity, clinicians should be aware that patients with AERD may have angina-like chest pain in association with peripheral blood eosinophilia if no other cause can be identified. It has been speculated that the vasospasm may be related to eosinophils as indicated by the case report of resolution with steroid therapy, although further study is needed. The evaluation of coronary vasospasm is discussed separately. (See "Vasospastic angina".)
Otologic complications — Some patients also report hearing loss as well as middle ear symptoms, including effusions, chronic ear drainage, otitis media requiring antibiotics as an adult, and, rarely, possible aural polyps . In a survey of 660 patients with AERD, 28 percent reported a physician-diagnosed hearing loss that was unexplained by other identifiable causes .
Laboratory findings — Variable laboratory findings include a peripheral eosinophilia and elevated levels of IgE.
Peripheral blood eosinophilia is common in AERD patients and correlates with severity of sinus disease in most studies [69-72]. In a series of 81 AERD patients, 51 percent had absolute eosinophil counts (AECs) >450 cells/microliter . In another cohort, absolute eosinophil counts (AECs) were between 1000 and 1500 in 10 percent of patients, and >1500 in three percent . However, an AEC >1500 should prompt an evaluation for other causes of hypereosinophilia, the extent of which can be determined by the patient's clinical status.
Total serum IgE levels in patients with AERD are variable and do not tend to correlate with the severity of sinus disease . The prevalence of atopic diseases, such as allergic rhinitis, is not clearly higher in patients with AERD [74,75]. However, some patients are sensitized to inhalant allergens, particularly perennial allergens such as dust mite . Other patients have elevated total serum IgE in the absence of any discernable allergic disorders .
DIAGNOSIS — The diagnosis of AERD can often be made clinically when all three of the conditions that characterize AERD are present: asthma, visible nasal polyposis (or a history of nasal polypectomy), and a history of typical upper and lower respiratory symptoms after exposure to a nonsteroidal anti-inflammatory drug (NSAID). (See 'Signs and symptoms' above.)
A clinical diagnosis may be more difficult in patients with isolated asthma or isolated chronic rhinosinusitis (CRS) with nasal polyposis. In this case, a careful clinical history of symptoms following NSAID ingestion is required, possibly followed by diagnostic aspirin challenge, as discussed in the following sections.
The differentiation of pseudoallergic reactions, such as AERD, from allergic reactions to an individual NSAID is discussed in greater detail separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)
Clinical diagnosis of NSAID intolerance — When trying to determine whether a patient with asthma and/or nasal polyposis has had an adverse reaction to NSAIDs, it is helpful first to describe the symptoms of pseudoallergic reactions, as patients may not have previously recognized the association. NSAID sensitivity is an acquired condition, and the symptoms following NSAID ingestion are similar to flares in the underlying asthma and rhinosinusitis, so patients who were accustomed to taking these medications without difficulty often do not recognize the connection for some time. Clarifying the association with NSAID ingestion can be complicated, as the reason for NSAID ingestion, such as a respiratory infection or menstruation, may itself be a potential asthma trigger.
The absence of a history of an NSAID reaction does not exclude NSAID sensitivity. Studies in which NSAID intolerance was diagnosed by challenge have reported higher rates among the general asthmatic population compared with those that rely on history alone .
●Some patients have empirically avoided aspirin and NSAIDs for many years at the advice of providers.
●A small number of patients with NSAID intolerance may not recognize it because they are taking low daily doses of aspirin without obvious symptoms. This was observed in 7 patients in a series of 163 patients with AERD at one referral center . Patients were taking 81 mg of aspirin daily. After stopping aspirin for at least 10 days, these patients had typical reactions to aspirin upon challenge, although with smaller decreases in forced expiratory volume in one second (FEV1) compared with other AERD patients. Four were subsequently desensitized to aspirin and responded to higher-dose therapy with improvements in nasal and asthma symptoms. Thus, the ability to tolerate low-dose aspirin therapy does not exclude the possibility of NSAID intolerance.
If the clinical history suggests a reaction to an NSAID, the clinician should then attempt to determine if the patient has reacted to more than one cyclooxygenase 1 (COX-1)-inhibiting NSAID, to exclude the possibility of an immunoglobulin (Ig)E-mediated reaction to a single NSAID. The patient should be questioned about any NSAID use SUBSEQUENT TO the first recognized reaction. NSAID ingestions BEFORE the first reaction are not relevant, since NSAID sensitivity is acquired, as reviewed previously. However, there is no evidence that previous NSAID use is required in order to develop NSAID sensitivity.
Among patients with asthma and significant rhinosinusitis after a careful history, there is an 80 percent likelihood of having a positive oral aspirin challenge with a history of a single NSAID reaction . This increases to 90 percent with a history of reactions to two different NSAIDs.
Cutaneous symptoms to NSAIDs usually signify a different type of NSAID reaction (eg, NSAID-induced urticaria/angioedema). However, occasional patients with AERD have blended reactions (mixed respiratory and cutaneous). Thus, the presence of urticaria/angioedema does not exclude the possibility of AERD. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on 'Type 4: Blended reactions in otherwise asymptomatic individuals'.)
While the majority of NSAIDs are administered orally, reactions can occur with ketorolac given via intravenous or intramuscular injection or ophthalmic application.
Diagnostic aspirin challenge — Aspirin challenge is the only way to definitively diagnose type 1 pseudoallergy to NSAIDs and thus AERD. Definitive diagnosis is important for research protocols involving AERD patients. Outside of research protocols, we typically reserve aspirin challenge for use as the first step in aspirin desensitization for patients with a specific need for regular NSAID therapy (ie, NSAIDs for rheumatologic disease, aspirin for cardiovascular disease, or aspirin for treatment of AERD).
●Types of challenge – Aspirin challenges are generally performed orally in the United States. In other areas (eg, Europe), a liquid lysyl-acetylsalicylic acid derivative is available for intranasal or bronchial challenge. Intranasal ketorolac is used in some research centers. However, inhaled challenges are purely diagnostic and not adequate for desensitization unless followed by oral aspirin. Protocols for aspirin challenge in patients with AERD are reviewed separately. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Challenge protocols and procedures'.)
●Premedication – In preparation for oral aspirin challenge or desensitization, patients with suspected AERD are usually pretreated with leukotriene-modifying agents (LTMAs), as these medications have been shown to dramatically reduce the severity of pulmonary reactions during the procedure. Despite the reduction in pulmonary symptoms, nasal and ocular symptoms still occur in most patients, such that the outcome of challenge should be apparent to the experienced clinician. Antihistamines are withheld for a week prior to the procedure, as they tend to blunt the nasal symptoms. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Premedication for oral protocols'.)
Nasal or inhaled glucocorticoids (eg, intranasal, inhaled, or in combination with a long-acting beta-agonist) that are part of the patient's usual regimen should be continued up to and during the procedure. These medications decrease the likelihood of a serious episode of bronchoconstriction, but enough of the manifestations are not suppressed to enable a diagnosis of aspirin sensitivity. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Provocation of symptoms'.)
●Staffing and location of challenge – Aspirin challenges are usually performed by allergy or pulmonary specialists with the expertise to manage any resultant symptoms and in settings equipped with the necessary medications, equipment, and support staff to manage acute bronchoconstriction or anaphylaxis.
●Challenge procedure – Oral aspirin challenge procedures vary among institutions but generally start with a low dose of aspirin, such as 30 to 41.5 mg, and advance by doubling doses approximately every 90 minutes to 3 hours . The details of aspirin challenge are provided separately. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Oral aspirin challenge'.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of each of the components of AERD is reviewed separately:
Goals of therapy — The main goals of therapy are to control asthma and chronic rhinosinusitis (CRS) symptoms and to prevent the regrowth of nasal polyps. Most patients will require lifelong therapy, so it is important to use shared decision making to create a long-term plan that the patient understands and supports. The approach to different patient groups is described here and is consistent with, but not identical to, guidelines for CRS with nasal polyposis and advice on AERD from expert panels [84-86]. (See 'Society guideline links' below.)
The important components of therapy for AERD are:
●Treatment of the patient's asthma, including a trial of leukotriene-modifying agents. (See 'Asthma therapies' below.)
●Medical and surgical management of CRS with nasal polyposis. (See 'Management of sinus disease' below.)
●Avoidance of cyclooxygenase 1 (COX-1)-inhibiting NSAIDs, unless the patient is a candidate for aspirin desensitization followed by daily nonsteroidal anti-inflammatory drug (NSAID) therapy. (See 'NSAID avoidance' below.)
NSAID avoidance — Patients with AERD should avoid all NSAIDs that inhibit COX-1 (table 1), unless they have been desensitized to aspirin. The following alternatives are usually tolerated and can be given for the treatment of pain and/or inflammation, although exquisitely sensitive patients may react to higher doses of nonacetylated salicylates or acetaminophen:
●NSAIDs with very weak COX-1 inhibitory properties (eg, nonacetylated salicylates, such as salsalate and others)
The optimal use of these alternative agents in patients with AERD is reviewed separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on 'Types 1 to 4: Treatment options'.)
Initial therapies — For the majority of patients who present with all the manifestations of AERD, we attempt to optimize asthma management according to guideline-based care and administer a trial of antileukotriene drugs if not done previously (see 'Leukotriene-modifying agents' below). For nasal polyps, if not already tried, we initiate daily nasal washes with budesonide solution (eg, respules intended for use in nebulizers) mixed with normal saline. Sometimes these interventions are enough to control symptoms adequately.
Asthma therapies — Guideline-based asthma management utilizing a step-wise approach is the same for patients with and without AERD, except that patients with AERD sometimes experience more dramatic improvement in asthma symptoms with leukotriene-modifying agents, compared with those without AERD. Guidelines for asthma therapy are discussed in detail elsewhere (table 3). (See "An overview of asthma management" and "Treatment of moderate persistent asthma in adolescents and adults" and "Treatment of severe asthma in adolescents and adults".)
Leukotriene-modifying agents — For patients with AERD and moderate-to-severe asthma, we recommend adding a leukotriene-modifying agent (LTMA) to their other asthma therapy if symptoms are not fully controlled. To varying degrees, these medications address the underlying dysregulation of leukotriene production in AERD and also protect patients from severe exacerbations due to accidental NSAID exposure [43-45,89-91]. (See "Antileukotriene agents in the management of asthma".)
Leukotriene modifying agents (LTMAs) provide significant benefit to a subset of patients. Specific agents include (table 4):
●Zileuton, which inhibits 5-lipoxygenase (5-LO) and blocks the synthesis of leukotrienes. Zileuton can be especially helpful for blunting reactions to NSAIDs and alcoholic beverages.
For patients who have not been treated with LTMAs in the past, we usually begin with an LTRA (eg, montelukast, zafirlukast) because they are straightforward to administer. If there is no clinical improvement after four to six weeks, we add or substitute zileuton. Zileuton works quickly and if there is no improvement within a week or two, it can also be stopped. For patients who improve on a LTMA, we continue that agent long term. In our experience, zileuton is more effective, and, in a survey of patients with AERD, respondents identified zileuton as "extremely effective" more often than LTRAs . However, zileuton requires twice-daily administration, periodic monitoring of liver function tests, and has some potential drug interactions.
While the simultaneous use of zileuton and a LTRA has not been formally studied, it has been described in case series and reviews [92-94]. Combination therapy may be advantageous in patients who do not achieve disease control with either of the individual agents. The rationale for combination therapy is based upon studies demonstrating that patients with AERD have elevated cysteinyl leukotriene (cysLT) levels and receptor numbers, as well as upregulation of 5-LO. Thus, combination therapy may address these abnormalities more completely.
Management of sinus disease — Medical management for all patients begins with intranasal corticosteroids in the form of nasal sprays or irrigations, if these have not already been tried. However, patients with extensive polyposis may not be able to use these therapies because their nasal passages are completely obstructed. The medical and surgical management of CRS with nasal polyposis are presented separately. (See "Chronic rhinosinusitis with nasal polyposis: Management and prognosis".)
Advanced therapies: Our approach — If the interventions above do not control symptoms or have already been tried without success in the past, we then either pursue aspirin desensitization followed by daily aspirin therapy or we begin a biologic (usually dupilumab).
Choosing between biologics and aspirin — We consider multiple factors, as well as patient preferences, when choosing between these two therapies.
●Aspirin desensitization and daily aspirin therapy improves asthma and CRS symptoms in 80 to 90 percent of patients [95,96] (see 'Aspirin desensitization and daily therapy' below). We prefer aspirin therapy for the following types of patients:
•Those who prefer the idea of using an inexpensive, readily-available medication that has well-known side effects and benefits. It is also important that patients choosing aspirin are amenable to undergoing sinus surgery to remove existing polyps, because clinical experience suggests that aspirin effectively slows the regrowth of polyps but only minimally shrinks existing polyps. For this reason, we recommend sinus surgery prior to aspirin desensitization and daily aspirin therapy.
•Patients who are interested in taking aspirin or another NSAID either daily or intermittently for other reasons (eg, pain, rheumatologic diseases, or cardiac disease).
•Those who wish to avoid sinus surgery, because dupilumab does shrink existing polyps to varying degrees.
•Those for whom severe asthma is the most significant problem, despite Global Initiative for Asthma (GINA) step 4 to 5 therapy (table 3), since aspirin challenge and desensitization can induce significant pulmonary symptoms in patients with low baseline lung function, and a prebronchodilator forced expiratory volume in one second (FEV1) of ≤70 percent of the patient's best or ≤1.5 L is usually considered a contraindication to aspirin challenge. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Contraindications to challenge'.)
•Patients with a history of gastric ulcers or gastrointestinal bleeding, as daily aspirin is likely to aggravate these problems. Similarly, patients whose occupations involve risk of trauma, in whom bleeding would be potentially serious problem, or older adult patients in whom bleeding risk is higher.
•Those who have already tried daily aspirin therapy and experienced regrowth of nasal polyps despite it.
•Patients who are younger than 18 years of age, because aspirin use is discouraged in children due to the risk of Reye syndrome, and polyposis at this age should raise a concern of possible cystic fibrosis.
•Patients who do not have access to a clinician or center that can perform aspirin desensitization.
Relative efficacy — Studies directly comparing biologic agents to each other and to aspirin desensitization and daily aspirin therapy for CRS with nasal polyposis are lacking. A network meta-analysis (NMA) indirectly compared the findings of 29 randomized trials for six patient-important outcomes: health-related quality of life, symptoms, smell, need for rescue oral glucocorticoids, and need for rescue polyp surgery . Dupilumab showed the most benefit overall. Aspirin reduced symptoms but was associated with the highest rate of adverse effects. However, there were several important limitations to this NMA. In the studies evaluating the effects of aspirin therapy, all patients had AERD, which is generally more difficult to treat, whereas in the studies of biologics, the number of patients with AERD was highly variable and sometimes not reported. In addition, aspirin is most helpful when it is started immediately after sinus surgery, as soon as the patient has been cleared by the otolaryngologist, as it appears to prevent regrowth of polyps more consistently than shrinking existing polyps, and not all the studies of aspirin involved patients who had preceding surgery. Finally, at least one of the five studies of aspirin used a low dose that has not been proven effective. Thus, this meta-analysis was helpful in comparing biologics to each other but did not clarify the efficacy of aspirin therapy relative to the biologics for patients with AERD specifically.
Aspirin desensitization and daily therapy — Nearly all AERD patients can be successfully desensitized to aspirin. Uncommon exceptions include patients with type 4 or blended reactions with a history of urticaria occurring as part of a respiratory reaction to NSAIDs (particularly more than one NSAID). Patients with type 4 reactions are less likely to experience successful desensitization. Another small subset of patients will not be able to complete the aspirin desensitization procedure because of refractory nausea, abdominal pain, and diarrhea, and these patients often also develop other extra-pulmonary symptoms during their reactions, specifically the appearance of an erythematous, pruritic, macular dermatitis (picture 3A and picture 3B) [17,23]. Urticaria that persists can also be a reason for failure (picture 4). Rarely, a patient may develop lower respiratory symptoms that do not resolve between doses, and we may abort the protocol if the patient's symptoms cannot be controlled within a few hours.
The protocol for desensitization is essentially a continuation of the challenge procedure, which is described in detail separately. (See 'Diagnostic aspirin challenge' above and "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization".)
Prerequisite surgery — Aspirin therapy is best initiated shortly after surgical polypectomy because aspirin prevents the regrowth of polyps but has minimal effect on existing polyps, and reactions to aspirin during desensitization are usually more severe if there is a heavy polyp burden present at the time.
Dosing and monitoring — We aim to perform aspirin desensitization within three months of surgical polypectomy. We begin daily therapy with high-dose aspirin (650 mg twice daily) and reassess in three months. At this dose, benefit was seen in 65 to 87 percent of 126 patients treated for 6 to 12 months in a prospective, uncontrolled study . An analysis of 137 patients with AERD referred to the Scripps Clinic and treated with aspirin for at least one year found that approximately one-half could successfully decrease the dose from 650 mg twice daily to 325 mg twice daily without a relapse of symptoms . However, the other one-half required the higher dose to maintain improvement long term. Because approximately equal percentages of patients tolerated each of these doses but one-half clearly benefit only from the higher dose, it is logical to begin therapy at the higher dose, though some centers prefer to being at 325 mg twice daily to assess for side effects and then increase to 650 mg twice daily if the patient is tolerating the aspirin well. Only occasional patients derived lasting benefit from 325 mg once daily, so this dose is considered too low for maintenance for most patients.
Some patients will notice improvement within a week, while others may report slow, steady progress over weeks to months. If the patient is tolerating high-dose aspirin, we continue it for 6 to 12 months. After this initial period, if the patient is improving and/or if their nasal polyps have not recurred, we usually try lowering the dose to 325 mg twice daily, but if the patient subsequently notices any increase in asthma or nasal symptoms, we resume 650 mg twice daily. If their nasal polyps grow back within 12 to 24 months while on high-dose aspirin, we consider aspirin therapy to have failed and try dupilumab next. When effective, daily aspirin therapy is continued indefinitely or until the patient develops an adverse effect that requires discontinuation. The evidence in support of the recommended dosing of aspirin is reviewed elsewhere. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Optimal aspirin dose for AERD'.)
Once patients are on daily aspirin therapy, they are generally also able to tolerate other NSAIDs (ibuprofen, etc) and can take those medicines if needed for pain, fever, or inflammatory conditions. However, there is no evidence that taking another NSAID daily prevents the regrowth of polyps in the same way that aspirin can.
Efficacy — Daily aspirin therapy can reduce upper and lower airway symptoms in patients with AERD, slow progression of nasal polyps, reduce patients' need for intranasal and systemic glucocorticoids, and improve quality of life. It is the authors' clinical impression that improvements in sinus symptoms tend to be more dramatic than improvements in asthma symptoms in many patients. The benefits of aspirin therapy on AERD have been demonstrated in a small number of randomized trials and several uncontrolled studies [95,96,98-108].
●In a small randomized crossover trial involving 25 patients with AERD, subjects were desensitized to aspirin, then treated with daily aspirin or placebo for three months, and then crossed over to the other intervention . Patients receiving aspirin had significant improvement in nasal symptoms and use of nasal medications. Approximately one-half experienced improvements in asthma symptoms, although these changes did not reach statistical significance.
●In another small randomized trial, the impact of daily aspirin therapy (624 mg once daily for six months) was compared with placebo in 20 patients with AERD (with aspirin intolerance) and 14 patients with asthma and chronic rhinosinusitis with nasal polyposis but without aspirin intolerance . Primary outcomes included nasal symptoms, Sino-Nasal Outcomes Test (SNOT-20) scores, peak nasal inspiratory flows, Asthma Control Test (ACT) scores, and spirometric parameters. Only patients with AERD who received aspirin therapy showed significant improvements in these measures. Maintenance dose of inhaled glucocorticoids also decreased in the AERD group receiving aspirin. These findings also support the clinical observation that patients without aspirin intolerance do not benefit from aspirin therapy. Of note, the dose of aspirin used in this trial was relatively low, as some centers use 650 mg twice daily or even higher doses. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Optimal aspirin dose for AERD'.)
●An uncontrolled study examined 65 patients with AERD already receiving optimal medical management who were desensitized to aspirin and received daily treatment for one to six years (mean of three years) . Doses ranged from 325 mg once daily to 650 mg three times daily, with a mean dose of about 1200 mg daily. Clinical outcomes before desensitization and after varying periods of aspirin treatment were compared. Those taking aspirin experienced significant reductions in the numbers of sinus infections per year (median reduction was from six episodes to two), hospitalizations for treatment of asthma per year, improvement in olfaction, and reduction in use of systemic glucocorticoids. The need for sinus surgery/polypectomy decreased from an average of one surgery every 3 years to one every 10 years. In contrast, emergency department visits for asthma and use of inhaled glucocorticoids were unchanged.
●Another study followed 172 patients with AERD who were desensitized to and treated with aspirin at a referral center and then discharged back to their original providers and followed with interviews . The mean daily dose of aspirin was 1138 mg daily. By the first six months of aspirin treatment, there were significant reductions in the number of sinus infections and need for oral glucocorticoids and improvements in both nasal/sinus and asthma symptoms. Of the 126 patients who completed one year or more of aspirin treatment, 87 percent experienced a good to excellent response. Mean prednisone doses decreased at six months and one year.
The remaining 13 percent of patients did not experience noticeable improvement . Most of these patients had concomitant forms of chronic rhinosinusitis in addition to AERD. For example, some were sensitized to perennial allergens and were generally not being treated for concomitant allergic rhinitis. Others had severe gastroesophageal reflux disease, allergic fungal rhinosinusitis, or other coexisting conditions that would not be altered by aspirin. Fourteen percent of patients discontinued aspirin because of various known side effects (mostly gastrointestinal intolerance).
Mechanism — The mechanism by which daily aspirin therapy reduces asthma and sinus symptoms in patients with AERD remains unclear. An initial hypothesis was that chronic aspirin therapy somehow corrected the underlying perturbations observed in the disorder, but a prospective study of 42 patients with AERD showed that eight weeks of high-dose aspirin (650 mg twice daily) paradoxically increased markers of type 2 inflammation, an effect that was unique to these patients and not seen in subjects with aspirin-tolerant asthma . Specifically, aspirin therapy increased the already constitutively high cysLT production and further reduced abnormally low prostaglandin E2 (PGE2) levels in the urine. A subsequent explanation for the ability of aspirin to improve symptoms while worsening the abnormalities often measured in AERD is the drug's ability to impair the production of PGD2 by mast cells . PGD2 can be pro-inflammatory and drive recruitment and activation of various inflammatory cells . Thus, these findings suggest that overproduction of PGD2 may contribute to the pathobiology of AERD, although further study of this mediator and the receptors through which it acts is needed.
Avoiding gastrointestinal toxicity — The development of gastric irritation from daily aspirin is reported by up to one-half of patients, although not all these patients have symptoms severe enough to cause them to stop therapy. The risk of gastrointestinal (GI) toxicity should be assessed and reviewed with the patient prior to choosing aspirin therapy and at follow-up visits. We generally avoid aspirin in patients with past peptic ulcer disease or severe gastritis. For patients with a history of mild gastritis that has resolved, we empirically coadminister a proton pump inhibitor (PPI). We prefer PPIs (eg, lansoprazole [15 or 30 mg daily] or esomeprazole [20 or 40 mg daily]) over H2 receptor antagonists or misoprostol because H2 antagonists are less effective than PPIs, and misoprostol is difficult to tolerate due to gastrointestinal side effects (see "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity"). We also advise desensitized patients to take their daily aspirin doses after a meal and to use enteric-coated tablets, although the impact of these precautions may be limited. Tolerance of daily aspirin in patients with AERD is reviewed separately. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Reasons for discontinuation'.)
Biologic agents — Dupilumab, omalizumab, and mepolizumab have been available for the treatment of moderate-to-severe asthma (table 5). In the United States, these three agents are also approved by the US Food and Drug Administration (FDA) for treatment of CRS with nasal polyposis. Based on a network meta-analysis indirectly comparing these three biologics, dupilumab showed the most benefit overall .
While aspirin desensitization can be particularly effective for reducing nasal symptoms in AERD and is significantly less expensive, the use of biologics is evolving to take on a more prominent role, especially in those with severe asthma. In addition, not all centers have the expertise or experience to perform aspirin desensitizations, and biologics may be more practical for this reason.
A 2020 European position paper on rhinosinusitis (not specifically addressing those with AERD) proposed criteria to identify appropriate candidates for biologic therapies. Among patients with bilateral nasal polyposis who had previously undergone sinus surgery or who were not surgical candidates, the position paper suggested that three of the following five criteria should be met :
●Evidence of type 2 disease (tissue eosinophils ≥10 per high power field or blood eosinophils ≥250/microliter or total IgE ≥100 IU/mL)
●The need for at least two courses of systemic corticosteroids per year or >3 months of low-dose systemic corticosteroids or who had a contraindication to systemic corticosteroids
●Significantly impaired quality of life, as defined by a SNOT-22 score ≥40
●Anosmia on a smell test
●Comorbid asthma needing regular inhaled corticosteroids
Also relevant are the GINA guidelines for asthma, which suggest that patients with GINA steps 4 to 5 asthma, with peripheral eosinophils >150/microliter (others contend >300) and two steroid-requiring exacerbations in the past year, are appropriate for therapy with a biologic agent (table 3). The choice between sinus surgery followed by aspirin desensitization versus initiating a biologic should be made with the patient through shared decision-making.
Dupilumab — Dupilumab is a monoclonal antibody that blocks the shared interleukin (IL-) 4/IL-13 receptor. The approved dose of dupilumab for CRS with nasal polyposis is 300 mg given subcutaneously every other week (without a loading dose). If the primary indication is severe asthma, we give a 600 mg loading dose followed by 300 mg every 2 weeks. Patients should have an absolute eosinophil count ≥150/mcL unless they are receiving chronic oral corticosteroids.
In two multicenter randomized trials including 724 patients with CRS with nasal polyposis, 204 of whom had AERD, dupilumab therapy for 24 or 52 weeks resulted in significant improvements in the primary endpoints of nasal polyp scores, nasal congestion/obstruction, and sinus Lund-MacKay CT scores compared with placebo and was well tolerated . Dupilumab-treated patients also experienced greater improvements in olfaction and in overall CRS symptoms as measured by SNOT-22. Patients with AERD or asthma experienced improvements in lung function as well, a finding that was also noted in AERD patients in previous smaller studies . A post-hoc analysis evaluated the safety and efficacy of dupilumab in the 28 percent of patients with AERD and CRS with nasal polyposis and found significantly greater benefit compared to similar patients without AERD . Dupilumab is generally well tolerated by patients with AERD, although several conditions, including seronegative arthritis, enthesitis/enthesopathy, psoriasis, and iridocyclitis have been linked to its use [115,116]. Longer term safety will require time to assess.
Omalizumab — Omalizumab is approved by the FDA for inadequately controlled moderate-to-severe asthma and for CRS with nasal polyposis. In our allergy clinic, we have used omalizumab in a small number of patients with severe AERD with mixed results. Most of these individuals either could not take aspirin or did not improve sufficiently with aspirin therapy.
A small trial suggested that omalizumab (an anti-IgE monoclonal antibody) may be helpful in patients with nasal polyps . In 24 patients with CRS with nasal polyposis and concomitant asthma, approximately one-half of whom had AERD, subjects received four to eight subcutaneous doses of omalizumab or placebo, consistent with omalizumab dosing guidelines for asthma (based on serum IgE level and body mass) . Omalizumab treatment was associated with improved airway symptoms and quality of life and with a significant decrease in total endoscopic nasal polyposis scores after 16 weeks compared with placebo. Changes in polyposis scores were confirmed by means of sinus CT scoring (Lund-MacKay score) and were independent of the presence of allergy. However, in the subset of patients with AERD, sinus CT did not show clear improvement. Thus, it is unclear whether this agent is as beneficial for patients with AERD.
In several case reports of patients with AERD and severe asthma, omalizumab was associated with clinical improvement in asthma and loss of sensitivity to oral aspirin challenge [81,118,119]. The dosing and administration of omalizumab for asthma are described separately. (See "Anti-IgE therapy", section on 'Administration'.)
Mepolizumab — Mepolizumab is an anti-IL-5 monoclonal antibody that is beneficial in patients with severe asthma and blood or sputum eosinophilia and also those with CRS and nasal polyposis, as reviewed elsewhere. (See "Treatment of severe asthma in adolescents and adults", section on 'Anti-IL-5 therapy' and "Chronic rhinosinusitis with nasal polyposis: Management and prognosis", section on 'Anti-IL-5 (mepolizumab)'.)
In a randomized, phase 3, multinational SYNAPSE trial of over 400 adults with recurrent, severe bilateral nasal polyps and at least one polyp surgery in the past 10 years, patients received either 100 mg mepolizumab subcutaneously or placebo every 4 weeks for 52 weeks . All patients also received standard care: saline nasal irrigations, mometasone furoate intranasal spray for at least 8 weeks, and systemic corticosteroids or antibiotics or both as required. Mepolizumab therapy improved nasal polyp size (adjusted difference in median endoscopic nasal polyp score -0.73, 95% CI -1.11 to -0.34) and nasal obstruction scores (-3.14, 95% CI -4.09 to -2.18) compared with placebo and was well-tolerated. However, olfaction did not improve.
PROGNOSIS — AERD is a persistent condition that does not resolve spontaneously. Once a patient has found an effective therapy that they tolerate, treatment is continued indefinitely.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic rhinosinusitis".)
SUMMARY AND RECOMMENDATIONS
●Clinical manifestations – Aspirin-exacerbated respiratory disease (AERD; also called nonsteroidal anti-inflammatory drug [NSAID]-exacerbated respiratory disease, or NERD) describes patients with the triad of asthma, chronic rhinosinusitis (CRS) with nasal polyposis, and intolerance to aspirin or other NSAIDs. Within 30 minutes to 3 hours after ingesting an NSAID, patients develop a sudden worsening of asthma and nasal congestion, sometimes accompanied by other symptoms. AERD affects 5 to 20 percent of all patients with asthma and typically presents in adulthood. (See 'Signs and symptoms' above and 'Terminology' above and 'Epidemiology' above.)
●Pathophysiology – The pathophysiology of AERD involves acquired perturbations in arachidonic acid (AA) metabolism and a resulting imbalance between proinflammatory and anti-inflammatory mediators, leading to chronic upper and lower airway inflammation. The pharmacologic action of cyclooxygenase 1 (COX-1)-inhibiting NSAIDs acutely exacerbates this imbalance and also results in mast cell activation. (See 'Pathophysiology' above.)
●Diagnosis – A working diagnosis of AERD is usually made clinically based upon the presence of the three characteristic component disorders (ie, asthma, CRS with nasal polyposis, and a history of NSAID reactions). Definitive diagnosis requires aspirin challenge, although this degree of diagnostic precision is rarely needed outside of research protocols. (See 'Diagnosis' above and "Diagnostic challenge and desensitization protocols for NSAID reactions".)
●Initial management – Patients with AERD should initially be managed according to guideline-based therapy for asthma and medical and surgical management of CRS with nasal polyposis. (See "An overview of asthma management" and "Chronic rhinosinusitis with nasal polyposis: Management and prognosis".)
•Intranasal corticosteroids – Nasal congestion and anosmia due to nasal polyposis are initially managed with corticosteroid nasal sprays or irrigations. Endoscopic sinus surgery is often required if nasal polyposis is extensive. The management of CRS with nasal polyposis is reviewed separately. (See "Chronic rhinosinusitis with nasal polyposis: Management and prognosis".)
•Leukotriene-modifying agents – For patients with AERD and moderate-to-severe asthma, we recommend adding a leukotriene-modifying agent (LTMA) to their other asthma therapy, if symptoms are not fully controlled (Grade 1B). We usually begin with a leukotriene-receptor antagonist (LTRA; eg, montelukast, zafirlukast). If there is no clinical improvement after four to six weeks, we add or substitute the 5-lipoxygenase (5-LO) inhibitor zileuton. If there is no improvement in response to zileuton, it can also be stopped. (See 'Leukotriene-modifying agents' above.)
●Therapy for persistent disease – For patients with AERD and chronic rhinosinusitis with nasal polyposis who have symptoms that persist despite LTMAs and intranasal corticosteroids, we recommend adding either an asthma biologic or performing aspirin desensitization followed by daily aspirin therapy, rather than resorting to intermittent oral corticosteroids (Grade 2C). Of the available asthma biologics, we prefer dupilumab.
•Dupilumab – We prefer dupilumab for patients with severe or unstable asthma, patients who cannot tolerate aspirin or have potential contraindications, and/or patients who have failed aspirin therapy previously. The dose for CRS with nasal polyposis is 300 mg given subcutaneously every other week. Other biologics may also be effective but have not been as extensively studied. (See 'Biologic agents' above.)
•Aspirin desensitization and daily therapy – We prefer aspirin desensitization and daily aspirin therapy for patients who wish to take aspirin (or other NSAIDs) for other reasons (eg, rheumatologic disease, cardiovascular risk) and patients who prefer to take a drug that is inexpensive and well-studied. For patients with significant polyposis, aspirin therapy is best initiated shortly after polyp surgery, because aspirin slows the regrowth of polyps but has minimal effect on existing polyps. Therefore, patients choosing aspirin therapy should be amenable to polypectomy before undergoing desensitization. (See 'Aspirin desensitization and daily therapy' above.)
Aspirin desensitization should be performed by clinicians (usually allergists or pulmonologists) with expertise in the technique and in a setting that is equipped to treat the range of reactions that may result. We suggest an initial aspirin dose of 650 mg orally twice daily rather than lower doses (Grade 2C). We evaluate the patient's response to therapy after three months. If symptoms have improved, the dose may be lowered to 325 mg twice daily. If symptoms have stabilized, we continue for a longer period and reassess. If symptoms have worsened, we stop aspirin and change to dupilumab. (See 'Dosing and monitoring' above.)
●Prognosis – AERD is a persistent disorder that requires lifelong management. Therapies that are effective and well-tolerated for an individual patient are continued indefinitely. (See 'Prognosis' above.)
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