Disclosures: Tanya M Laidlaw, MD Nothing to disclose. Elliot Israel, MD Speaker's Bureau: Merck & Co [Pharmacogenetics, leukotrienes and asthma, asthma phenotype (Montelukast)]. Consultant/Advisory Boards: Merck & Co [Pharmacogenetics, leukotrienes and asthma, asthma phenotype (Montelukast)]. Peter J Barnes, DM, DSc, FRCP, FRS Grant/Research/Clinical Trial Support: AstraZeneca [Asthma, COPD (Budesonide and formoterol)]; GSK [Asthma, COPD (Fluticasone and salmeterol, fluticasone, furoate, vilanterol)]; Pfizer [COPD (Tiotropium)]; Novartis [COPD (Indacaterol)]; Boehringer [COPD (Tiotropium)]; Chiesi [Asthma, COPD (Beclomethasone and formoterol)]; Takeda [COPD (Roflumilast)]; Sun Pharma [Asthma]. Speaker's Bureau: AstraZeneca [Asthma (Budesonide and formoterol)]; Pfizer [COPD (Titropium)]; Novartis [COPD (Indacaterol)]; Boehringer [COPD (Tiotropium)]; Chiesi [Asthma (Beclomethasone and formoterol)]; Takeda [COPD (Roflumilast)]. Consultant/Advisory Boards: AstraZeneca [Asthma]; GSK [Asthma]; Novartis [COPD]; Boehringer [COPD]; Chiesi [COPD]; Teva [COPD]; Glenmark [COPD]; Sun Pharma [COPD]; Prosonix [COPD]; Daiichi-Sankyo [COPD]. Bruce S Bochner, MD Grant/Research/Clinical Trial Support: NIAID; NHLBI; GSK [Siglec-8, Siglec-9, asthma, COPD, anaphylaxis, imaging; eosinophilic granulomatosis with polyangiitis]. Consultant/Advisory Boards: TEVA; Sanofi; Merck; Glycomimetics; Allakos; Biogen Idec; Svelte Medical Systems. Patent Holder: Siglec-8 and its ligand; anti-Siglec-8 antibodies [held by Johns Hopkins University]. Employment: Northwestern University Feinberg School of Medicine. Equity Ownership/Stock Options: Glycomimetics; Allakos. Other Financial Interest: Elsevier [publication royalties]. Anna M Feldweg, MD Employee of UpToDate, Inc. Helen Hollingsworth, MD Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — Aspirin-exacerbated respiratory disease (AERD) refers to the combination of asthma, chronic rhinosinusitis (CRS) with nasal polyposis, and acute upper and lower respiratory tract reactions to ingestion of aspirin (acetylsalicylic acid, ASA) and other cyclooxygenase-1 (COX-1) inhibiting nonsteroidal antiinflammatory drugs (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.
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 patients with asthma, CRS, and nasal polyposis are discussed separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions" and "Diagnostic challenge and desensitization protocols for NSAID reactions" and "An overview of asthma management" and "Management of chronic rhinosinusitis".)
NSAIDs — The primary effect of nonsteroidal antiinflammatory drugs (NSAIDs) is to inhibit cyclooxygenase (also called prostaglandin synthase), thereby impairing the ultimate transformation of arachidonic acid (AA) to prostaglandins, prostacyclin, and thromboxanes and enhancing production of leukotrienes. Two related isoforms of the cyclooxygenase (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. COX-1 inhibition is the stimulus for acute reactions to aspirin (ASA)/NSAIDs in AERD.
In this topic review, the term NSAID includes aspirin (ASA). However, in some clearly marked sections, aspirin is discussed exclusive of other NSAIDs.
Aspirin-exacerbated respiratory disease — Aspirin-exacerbated respiratory disease (AERD) refers to the combination of:
●Chronic rhinosinusitis (CRS) with nasal polyposis
●Reactions to aspirin (acetylsalicylic acid, ASA) and other COX-1 inhibiting NSAIDs, in which symptoms of nasal congestion and bronchoconstriction typically begin 20 minutes to three hours after ingestion
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 reactions to NSAIDs as an exacerbating factor [2,3]. In keeping with this, 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. Pseudoallergic reactions are triggered by a wide range of structurally distinct medications that have in common the ability to inhibit the COX-1 enzyme and 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.
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'.)
PREVALENCE — The prevalence of nonsteroidal antiinflammatory drug (NSAID) sensitivity among the general asthmatic population is probably less than 5 percent [4,5], although studies of variable rigor have reported higher rates [6-8]. Among patients with glucocorticoid-dependent asthma or with chronic rhinosinusitis (CRS) and nasal polyps, NSAID sensitivity may affect 20 to 40 percent [6,8]. 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 .
PATHOPHYSIOLOGY — The pathophysiology of aspirin-exacerbated respiratory disease (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 the 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 antiinflammatory mediators. AA metabolism, the role of mast cells, and other identified abnormalities in patients with AERD are reviewed in this section.
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 antiinflammatory. A few can act in both capacities, depending upon the target cell. A simplified overview of AA metabolism is provided here.
5-lipoxygenase pathway — The metabolism of AA by the enzyme 5-LO generates the leukotrienes (LTs), as depicted in the figure (figure 1). 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 [10-12]. 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 1).
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 2) . One of the prostaglandins, PGD2, is predominantly produced by mast cells and has a bronchoconstrictor effect. It appears to be overproduced at baseline in AERD and further increased after aspirin challenge [13-15]. 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 antiinflammatory effects. It is expressed in a broad range of cells and is decreased after COX-1 inhibition [13,16]. PGE2 is believed to act as a "brake" on the production of the proinflammatory LTs. (See "NSAIDs: Mechanism of action".)
Abnormalities in AERD — Studies of AERD patients demonstrate a baseline dysregulation of AA metabolism with greatly increased production of the proinflammatory and underproduction of the antiinflammatory products compared with non-AERD asthmatics [17-21]. The proinflammatory leukotrienes promote persistent airway inflammation. 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 [22-25]. 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 [26,27].
The following abnormalities, which support this model of AERD pathophysiology, have been identified in patients with AERD [28-39]:
●The primary cellular source of leukotriene LTC4 in patients with AERD appears to be the bronchial mast cell, although eosinophils are also capable of producing large amounts . Both cell types are increased and activated in the respiratory tracts of patients with AERD [31-33].
●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 1) [31,34].
●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 [43-45]. 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, lysyl-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 [23,47].
●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. When added to cultures of mast cells from patients with AERD, PGE2 suppresses anti-IgE induced release of cysLTs .
Involvement of mast cells — Mast cells 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 [14,33]. In addition, H1 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 revealed 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.
CLINICAL PRESENTATION — Patients with aspirin-exacerbated respiratory disease (AERD) typically have chronic asthma and rhinosinusitis and experience acute exacerbations of upper and lower respiratory symptoms after the ingestion of aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs). The interrelationship between nasal polyposis, asthma, and NSAID intolerance is shown in the table (table 1).
Time course of symptoms and signs — AERD is usually diagnosed in adulthood, although children and adolescents may be affected. The three component disorders of AERD tend to develop serially over a period of years [2,51], although some patients may present with rapid progression of sinonasal symptoms to asthma.
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). Some patients report repeated sinus surgeries and polypectomies. 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. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis".)
As the rhinosinusitis worsens, the patient typically develops inflammation in the lower airway and is diagnosed with asthma. At some point during this progression, aspirin/NSAID sensitivity appears. The asthma and chronic sinusitis of AERD usually become more severe over time, even with NSAID avoidance [3,4,6,52]. However, not all patients have severe asthma, and for many patients, the symptoms related to nasal polyposis and chronic rhinosinusitis (CRS) are more troubling on a day to day basis . (See "Diagnosis of asthma in adolescents and adults".)
In rare cases, the NSAID sensitivity develops first, and NSAID intolerance is an independent risk factor for developing asthma [4,6,52].
Acute reactions to NSAIDs — Acute reactions to NSAIDs in patients with AERD typically begin 30 minutes to three hours after NSAID ingestion, and may be slow to resolve (figure 4) . 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. Fatal reactions have rarely occurred 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, while few patients require 325 mg or more . 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.
●Asthmatic symptoms, including wheezing, dyspnea, cough, and chest tightness – These symptoms are accompanied by a marked fall in forced expiratory volume in one second (FEV1). Bronchoconstriction is typically reversible with an inhaled beta-agonist bronchodilator.
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 to distinguish from anaphylaxis.
Urticaria and/or angioedema occur in approximately 15 percent of AERD patients during these acute reactions. However, isolated 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). In addition, macular rashes have been noted during these reactions as well. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on 'Pseudoallergic reactions'.)
Atopy and eosinophilia — Depending on the case series, between 30 and 70 percent of patients with AERD are atopic [2,54], and a portion of these patients have high levels of specific immunoglobulin E (IgE) antibodies to inhalant allergens [55,56]. Typically, perennial allergens, such as dust mites, are implicated . However, total serum IgE levels are variable and do not tend to correlate with severity of sinus disease .
Peripheral blood eosinophilia is present in approximately 50 percent of AERD patients and appears to correlate with severity of CRS [58-61]. In a series of 81 AERD patients, 51 percent had peripheral blood eosinophilia .
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 .
DIAGNOSIS — The diagnosis of aspirin-exacerbated respiratory disease (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 a typical reaction to a nonsteroidal antiinflammatory drug (NSAID). 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 reactions — When trying to determine whether a patient with asthma and/or nasal polyposis has had an adverse reaction to NSAIDs, it is helpful 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.
Some patients may not report NSAID-associated symptoms as they have empirically avoided aspirin and NSAIDs for many years. 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 . Thus, the absence of a history of a reaction does not exclude NSAID sensitivity.
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 IgE-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 two NSAID reactions by history.
While cutaneous reactions to NSAIDs usually signify a different type of NSAID reaction (eg, NSAID-induced urticaria/angioedema), 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 are still apparent 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'.)
Topical 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 three hours. The details of aspirin challenge are provided separately. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Oral aspirin challenge and desensitization'.)
MANAGEMENT — The management of aspirin-exacerbated respiratory disease (AERD) involves guideline-based treatment of the patient's asthma and chronic rhinosinusitis (CRS), in addition to suppression of the consequences of abnormal leukotriene metabolism. Patients must avoid all cyclooxygenase-1 (COX-1) inhibiting nonsteroidal antiinflammatory drugs (NSAIDS) or, in selected cases, undergo aspirin desensitization followed by daily NSAID therapy.
Asthma — National and international guidelines for asthma management apply to patients with AERD, except that leukotriene-modifying agents (LTMAs) are administered in most cases to improve both pulmonary and sinonasal symptoms. (See 'Leukotriene-modifying agents' below.)
Asthma management utilizing a step-wise approach is discussed elsewhere. (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".)
Chronic rhinosinusitis with nasal polyposis — The medical and surgical management of CRS with nasal polyposis are presented separately. (See "Management of chronic rhinosinusitis".)
Leukotriene-modifying agents — LTMAs should be part of the management of all patients with AERD to address the underlying dysregulation of leukotriene production and also protect patients from severe exacerbations due to accidental NSAID exposure. Both leukotriene receptor antagonists (LTRAs) (eg, montelukast, zafirlukast) [41,42,64,65] and inhibitors of leukotriene synthesis (eg, zileuton) [40,66] are effective in AERD. The general use of LTMAs in asthma is reviewed separately (figure 3 and table 3). (See "Agents affecting the 5-lipoxygenase pathway in the treatment of asthma".)
As a practical matter, most clinicians select an oral LTRA (montelukast, zafirlukast) for initial therapy, rather than the 5-lipoxygenase (5-LO) inhibitor zileuton, as zileuton requires twice daily administration and periodic monitoring of liver function tests. If patients do not improve with the LTRA after four to six weeks, then zileuton may be added or substituted.
The following studies demonstrate that the addition of a LTMA to preexisting therapy improves respiratory tract symptoms in patients with AERD [17,64,66]:
●A randomized trial compared montelukast with placebo in 80 patients with asthma and NSAID intolerance, the majority of whom required inhaled or oral glucocorticoids to control their symptoms . Four weeks of treatment with montelukast was associated with a 10 percent increase in forced expiratory volume in one second (FEV1), higher morning peak flow rates, decreased use of rescue medication, and a significant improvement in asthma quality of life scores. The montelukast group also experienced 54 percent fewer asthma exacerbations.
●A randomized trial evaluated the effect of six weeks of treatment with the 5-LO inhibitor zileuton (600 mg, four times daily) in 40 patients with AERD . Existing therapy was continued, which included medium to high doses of inhaled (average daily dose >1000 micrograms of beclomethasone or budesonide) or oral glucocorticoids (4 to 25 mg daily) for all but one patient. The addition of zileuton, compared with placebo, resulted in both immediate and ongoing improvement in pulmonary function and lower use of short-acting beta-agonists for symptom relief. Zileuton also alleviated nasal symptoms, including rhinorrhea, congestion, and impaired sense of smell. Furthermore, zileuton produced a small reduction of bronchial hyperresponsiveness to histamine.
While the simultaneous use of zileuton and a LTRA has not been formally studied, it has been mentioned in case series and reviews [67-69]. It is thought that 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.
NSAID avoidance — Patients with AERD should avoid all NSAIDs that inhibit COX-1 (table 4), unless they have been desensitized to aspirin. Patients with AERD usually tolerate the following alternatives 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 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'.)
Aspirin desensitization — Nearly all AERD patients can be successfully desensitized to aspirin (acetylsalicylic acid, ASA). The mechanism through which ASA desensitization alters a patient's response to NSAIDs is not completely understood. One theory proposes that desensitization and subsequent daily aspirin treatment reduces interleukin-4 (IL-4)-induced expression of leukotrienes by inhibiting the transcription factor, signal transducer and activator of transcription (STAT)-6 [72,73].
The protocol for desensitization is essentially a continuation of the challenge procedure. (See 'Diagnostic aspirin challenge' above and "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization".)
Indications — The indications for aspirin desensitization in AERD include the following:
●Nasal polyposis that is worsening or recurring after surgery despite LTMAs, topical glucocorticoids, and other appropriate therapies
●Inflammatory conditions requiring daily NSAID therapy (eg, arthritis)
●Atherosclerotic heart/vascular disease requiring the antiplatelet effects of aspirin
●Recurrent headaches or other conditions requiring intermittent use of NSAIDs after failure of other options
In each of these settings, an individualized approach is needed to determine the likelihood that the patient will benefit and adhere to the maintenance program of daily ASA/NSAID. The risk for gastrointestinal toxicity should be assessed and reviewed with the patient.
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) are less likely to experience successful desensitization.
Efficacy of aspirin desensitization for AERD treatment — Daily aspirin therapy can reduce upper and lower airway symptoms in patients with AERD, although the effects on rhinosinusitis symptoms are typically more dramatic than the effects on asthma. Of note, there are no data to suggest aspirin is of benefit in the treatment of airway disease in patients with asthma and nasal polyposis, but without aspirin intolerance. The efficacy of daily aspirin therapy in treating upper and lower airway disease in patients with AERD and the dosing of aspirin in this setting are reviewed in greater detail elsewhere. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Efficacy of aspirin therapy in AERD'.)
Maintenance of desensitization — Patients who are successfully desensitized to ASA must continue to take aspirin or another COX-1 inhibiting NSAID daily in order to maintain the desensitized state. However, only aspirin (not other NSAIDS) has been shown to be useful in slowing the regrowth of nasal polyps and improving asthma symptoms over time.
●For patients with AERD and difficult to control asthma or nasal polyposis that is worsening or recurring despite LTMAs, topical glucocorticoids, and other appropriate therapies, aspirin desensitization is followed by daily aspirin (325 mg twice daily or 650 mg twice daily). Optimal dosing is reviewed separately. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Optimal aspirin dose for AERD'.)
●Aspirin desensitization followed by daily aspirin can be used in patients with atherosclerotic heart/vascular disease requiring the antiplatelet effects of aspirin. Patients who take 81 mg of aspirin daily for cardioprotection will remain tolerant of this low dose of aspirin, although they will almost always NOT be able to tolerate larger doses of aspirin or be cross-desensitized to other NSAIDs. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Other issues of aspirin dosing after desensitization'.)
●Aspirin desensitization followed by a daily NSAID (other than aspirin) can be used by patients with inflammatory conditions requiring daily NSAID therapy. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Cross-desensitization to other NSAIDs'.)
●Patients who have undergone aspirin desensitization and wish to use other NSAIDs intermittently (eg, for musculoskeletal pain, headaches, or dysmenorrhea) should take at least 325 mg of aspirin daily to maintain the desensitized state. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Cross-desensitization to other NSAIDs'.)
●When aspirin therapy is interrupted, there is a "refractory period" of at least two to three days, but not more than five days, before and the patient becomes reactive again. The management of missed doses is discussed separately. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Missed doses'.)
SUMMARY AND RECOMMENDATIONS
●Aspirin-exacerbated respiratory disease (AERD) describes patients with asthma and chronic rhinosinusitis (CRS) with nasal polyposis, who experience acute upper and lower respiratory tract symptoms following the ingestion of aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs). AERD affects 5 to 20 percent of all patients with asthma. Reactions to NSAIDs typically begin 30 minutes to three hours after ingestion and present as a sudden worsening of asthma and nasal congestion, sometimes accompanied by other symptoms. (See 'Clinical presentation' above.)
●The pathophysiology of AERD involves acquired perturbations in arachidonic acid (AA) metabolism and a resulting imbalance between proinflammatory and antiinflammatory mediators, leading to chronic 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.)
●A working diagnosis of AERD is usually made clinically based upon the presence of the 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".)
●Patients with AERD require guideline-based therapy for asthma and medical and surgical management of CRS with nasal polyposis. (See "An overview of asthma management" and "Management of chronic rhinosinusitis".)
●For patients with AERD and moderate to severe asthma, we recommend adding a leukotriene-modifying agent (LTMA) to their other asthma therapy (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. (See 'Leukotriene-modifying agents' above.)
●Aspirin desensitization followed by daily aspirin (or sometimes daily NSAID) therapy may be beneficial in carefully selected patients with AERD and one of the following disorders (See 'Aspirin desensitization' above.):
•Nasal polyposis that is worsening or recurring despite intranasal glucocorticoids and other appropriate therapies.
•Inflammatory conditions requiring daily NSAID therapy that cannot be treated with selective COX-2 inhibitors.
•Atherosclerotic heart/vascular disease requiring the antiplatelet effects of aspirin.
•Recurrent headaches or other conditions requiring intermittent use of NSAIDs.
●Aspirin desensitization is usually performed by allergists or pulmonologists with expertise in the technique and in a setting that is equipped to treat the range of reactions that may result. Following desensitization, patients must ingest aspirin or an NSAID daily to maintain the desensitized state. The choice and dose of aspirin or NSAID for ongoing therapy depends on the indication for desensitization. As long as the desensitized state is maintained, the patients can tolerate different COX-1-inhibiting NSAIDs interchangeably. (See 'Aspirin desensitization' above and "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization".)
- Samter M, Beers RF Jr. Intolerance to aspirin. Clinical studies and consideration of its pathogenesis. Ann Intern Med 1968; 68:975.
- Fahrenholz JM. Natural history and clinical features of aspirin-exacerbated respiratory disease. Clin Rev Allergy Immunol 2003; 24:113.
- Berges-Gimeno MP, Simon RA, Stevenson DD. The natural history and clinical characteristics of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol 2002; 89:474.
- Hedman J, Kaprio J, Poussa T, Nieminen MM. Prevalence of asthma, aspirin intolerance, nasal polyposis and chronic obstructive pulmonary disease in a population-based study. Int J Epidemiol 1999; 28:717.
- Schiavino D, Nucera E, Milani A, et al. The aspirin disease. Thorax 2000; 55 Suppl 2:S66.
- Jenkins C, Costello J, Hodge L. Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. BMJ 2004; 328:434.
- Vally H, Taylor ML, Thompson PJ. The prevalence of aspirin intolerant asthma (AIA) in Australian asthmatic patients. Thorax 2002; 57:569.
- Weber RW, Hoffman M, Raine DA Jr, Nelson HS. Incidence of bronchoconstriction due to aspirin, azo dyes, non-azo dyes, and preservatives in a population of perennial asthmatics. J Allergy Clin Immunol 1979; 64:32.
- Nabavi M, Esmaeilzadeh H, Arshi S, et al. Aspirin hypersensitivity in patients with chronic rhinosinusitis and nasal polyposis: frequency and contributing factors. Am J Rhinol Allergy 2014; 28:239.
- Shore SA, Austen KF, Drazen JM. Lung biology in health and disease: Lung cell biology. In: Eicosanoids and the lung, L'Enfant C, Massaro D (Eds), Marcel Dekker, New York 1989.
- Laitinen LA, Laitinen A, Haahtela T, et al. Leukotriene E4 and granulocytic infiltration into asthmatic airways. Lancet 1993; 341:989.
- Dahlén B. Treatment of aspirin-intolerant asthma with antileukotrienes. Am J Respir Crit Care Med 2000; 161:S137.
- Narayanankutty A, Reséndiz-Hernández JM, Falfán-Valencia R, Teran LM. Biochemical pathogenesis of aspirin exacerbated respiratory disease (AERD). Clin Biochem 2013; 46:566.
- Bochenek G, Nagraba K, Nizankowska E, Szczeklik A. A controlled study of 9alpha,11beta-PGF2 (a prostaglandin D2 metabolite) in plasma and urine of patients with bronchial asthma and healthy controls after aspirin challenge. J Allergy Clin Immunol 2003; 111:743.
- Campo P, Ayuso P, Salas M, et al. Mediator release after nasal aspirin provocation supports different phenotypes in subjects with hypersensitivity reactions to NSAIDs. Allergy 2013; 68:1001.
- Sladek K, Dworski R, Soja J, et al. Eicosanoids in bronchoalveolar lavage fluid of aspirin-intolerant patients with asthma after aspirin challenge. Am J Respir Crit Care Med 1994; 149:940.
- Antczak A, Montuschi P, Kharitonov S, et al. Increased exhaled cysteinyl-leukotrienes and 8-isoprostane in aspirin-induced asthma. Am J Respir Crit Care Med 2002; 166:301.
- Knapp HR, Sladek K, Fitzgerald GA. Increased excretion of leukotriene E4 during aspirin-induced asthma. J Lab Clin Med 1992; 119:48.
- Ferreri NR, Howland WC, Stevenson DD, Spiegelberg HL. Release of leukotrienes, prostaglandins, and histamine into nasal secretions of aspirin-sensitive asthmatics during reaction to aspirin. Am Rev Respir Dis 1988; 137:847.
- Daffern PJ, Muilenburg D, Hugli TE, Stevenson DD. Association of urinary leukotriene E4 excretion during aspirin challenges with severity of respiratory responses. J Allergy Clin Immunol 1999; 104:559.
- Lee TH, Woszczek G, Farooque SP. Leukotriene E4: perspective on the forgotten mediator. J Allergy Clin Immunol 2009; 124:417.
- Sestini P, Armetti L, Gambaro G, et al. Inhaled PGE2 prevents aspirin-induced bronchoconstriction and urinary LTE4 excretion in aspirin-sensitive asthma. Am J Respir Crit Care Med 1996; 153:572.
- Ying S, Meng Q, Scadding G, et al. Aspirin-sensitive rhinosinusitis is associated with reduced E-prostanoid 2 receptor expression on nasal mucosal inflammatory cells. J Allergy Clin Immunol 2006; 117:312.
- Babu KS, Salvi SS. Aspirin and asthma. Chest 2000; 118:1470.
- Mastalerz L, Sanak M, Gawlewicz-Mroczka A, et al. Prostaglandin E2 systemic production in patients with asthma with and without aspirin hypersensitivity. Thorax 2008; 63:27.
- Laidlaw TM, Kidder MS, Bhattacharyya N, et al. Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes. Blood 2012; 119:3790.
- Maclouf JA, Murphy RC. Transcellular metabolism of neutrophil-derived leukotriene A4 by human platelets. A potential cellular source of leukotriene C4. J Biol Chem 1988; 263:174.
- Guilemany JM, Roca-Ferrer J, Mullol J. Cyclooxygenases and the pathogenesis of chronic rhinosinusitis and nasal polyposis. Curr Allergy Asthma Rep 2008; 8:219.
- Stevenson DD, Zuraw BL. Pathogenesis of aspirin-exacerbated respiratory disease. Clin Rev Allergy Immunol 2003; 24:169.
- Cai Y, Bjermer L, Halstensen TS. Bronchial mast cells are the dominating LTC4S-expressing cells in aspirin-tolerant asthma. Am J Respir Cell Mol Biol 2003; 29:683.
- Cowburn AS, Sladek K, Soja J, et al. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest 1998; 101:834.
- Nasser S, Christie PE, Pfister R, et al. Effect of endobronchial aspirin challenge on inflammatory cells in bronchial biopsy samples from aspirin-sensitive asthmatic subjects. Thorax 1996; 51:64.
- Fischer AR, Rosenberg MA, Lilly CM, et al. Direct evidence for a role of the mast cell in the nasal response to aspirin in aspirin-sensitive asthma. J Allergy Clin Immunol 1994; 94:1046.
- Adamjee J, Suh YJ, Park HS, et al. Expression of 5-lipoxygenase and cyclooxygenase pathway enzymes in nasal polyps of patients with aspirin-intolerant asthma. J Pathol 2006; 209:392.
- Sanak M, Simon HU, Szczeklik A. Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet 1997; 350:1599.
- Sanak M, Pierzchalska M, Bazan-Socha S, Szczeklik A. Enhanced expression of the leukotriene C(4) synthase due to overactive transcription of an allelic variant associated with aspirin-intolerant asthma. Am J Respir Cell Mol Biol 2000; 23:290.
- Sousa AR, Parikh A, Scadding G, et al. Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis. N Engl J Med 2002; 347:1493.
- Sanak M, Levy BD, Clish CB, et al. Aspirin-tolerant asthmatics generate more lipoxins than aspirin-intolerant asthmatics. Eur Respir J 2000; 16:44.
- Gaber F, Daham K, Higashi A, et al. Increased levels of cysteinyl-leukotrienes in saliva, induced sputum, urine and blood from patients with aspirin-intolerant asthma. Thorax 2008; 63:1076.
- Israel E, Fischer AR, Rosenberg MA, et al. The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am Rev Respir Dis 1993; 148:1447.
- Christie PE, Smith CM, Lee TH. The potent and selective sulfidopeptide leukotriene antagonist, SK&F 104353, inhibits aspirin-induced asthma. Am Rev Respir Dis 1991; 144:957.
- Nasser SM, Bell GS, Foster S, et al. Effect of the 5-lipoxygenase inhibitor ZD2138 on aspirin-induced asthma. Thorax 1994; 49:749.
- Picado C, Fernandez-Morata JC, Juan M, et al. Cyclooxygenase-2 mRNA is downexpressed in nasal polyps from aspirin-sensitive asthmatics. Am J Respir Crit Care Med 1999; 160:291.
- Kowalski ML, Pawliczak R, Wozniak J, et al. Differential metabolism of arachidonic acid in nasal polyp epithelial cells cultured from aspirin-sensitive and aspirin-tolerant patients. Am J Respir Crit Care Med 2000; 161:391.
- Pierzchalska M, Szabó Z, Sanak M, et al. Deficient prostaglandin E2 production by bronchial fibroblasts of asthmatic patients, with special reference to aspirin-induced asthma. J Allergy Clin Immunol 2003; 111:1041.
- Laidlaw TM, Cutler AJ, Kidder MS, et al. Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 2014; 133:1692.
- Corrigan CJ, Napoli RL, Meng Q, et al. Reduced expression of the prostaglandin E2 receptor E-prostanoid 2 on bronchial mucosal leukocytes in patients with aspirin-sensitive asthma. J Allergy Clin Immunol 2012; 129:1636.
- Liu T, Laidlaw TM, Katz HR, Boyce JA. Prostaglandin E2 deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes. Proc Natl Acad Sci U S A 2013; 110:16987.
- Wang XS, Wu AY, Leung PS, Lau HY. PGE suppresses excessive anti-IgE induced cysteinyl leucotrienes production in mast cells of patients with aspirin exacerbated respiratory disease. Allergy 2007; 62:620.
- Lee SH, Rhim T, Choi YS, et al. Complement C3a and C4a increased in plasma of patients with aspirin-induced asthma. Am J Respir Crit Care Med 2006; 173:370.
- Szczeklik A, Nizankowska E, Duplaga M. Natural history of aspirin-induced asthma. AIANE Investigators. European Network on Aspirin-Induced Asthma. Eur Respir J 2000; 16:432.
- Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol 2003; 111:913.
- Hope AP, Woessner KA, Simon RA, Stevenson DD. Rational approach to aspirin dosing during oral challenges and desensitization of patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 2009; 123:406.
- Dursun AB, Woessner KA, Simon RA, et al. Predicting outcomes of oral aspirin challenges in patients with asthma, nasal polyps, and chronic sinusitis. Ann Allergy Asthma Immunol 2008; 100:420.
- Shi J, Misso NL, Duffy DL, et al. Cyclooxygenase-1 gene polymorphisms in patients with different asthma phenotypes and atopy. Eur Respir J 2005; 26:249.
- Barranco P, Bobolea I, Larco JI, et al. Diagnosis of aspirin-induced asthma combining the bronchial and the oral challenge tests: a pilot study. J Investig Allergol Clin Immunol 2009; 19:446.
- Emanuel IA, Shah SB. Chronic rhinosinusitis: allergy and sinus computed tomography relationships. Otolaryngol Head Neck Surg 2000; 123:687.
- Poznanovic SA, Kingdom TT. Total IgE levels and peripheral eosinophilia: correlation with mucosal disease based on computed tomographic imaging of the paranasal sinus. Arch Otolaryngol Head Neck Surg 2007; 133:701.
- Fountain CR, Mudd PA, Ramakrishnan VR, et al. Characterization and treatment of patients with chronic rhinosinusitis and nasal polyps. Ann Allergy Asthma Immunol 2013; 111:337.
- Newman LJ, Platts-Mills TA, Phillips CD, et al. Chronic sinusitis. Relationship of computed tomographic findings to allergy, asthma, and eosinophilia. JAMA 1994; 271:363.
- Bryson JM, Tasca RA, Rowe-Jones JM. Local and systemic eosinophilia in patients undergoing endoscopic sinus surgery for chronic rhinosinusitis with and without polyposis. Clin Otolaryngol Allied Sci 2003; 28:55.
- Cardet JC, White AA, Barrett NA, et al. Alcohol-induced respiratory symptoms are common in patients with aspirin exacerbated respiratory disease. J Allergy Clin Immunol Pract 2014; 2:208.
- Williams AN, Simon RA, Woessner KM, Stevenson DD. The relationship between historical aspirin-induced asthma and severity of asthma induced during oral aspirin challenges. J Allergy Clin Immunol 2007; 120:273.
- Dahlén SE, Malmström K, Nizankowska E, et al. Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med 2002; 165:9.
- Lee DK, Haggart K, Robb FM, Lipworth BJ. Montelukast protects against nasal lysine-aspirin challenge in patients with aspirin-induced asthma. Eur Respir J 2004; 24:226.
- Dahlén B, Nizankowska E, Szczeklik A, et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am J Respir Crit Care Med 1998; 157:1187.
- White A, Ludington E, Mehra P, et al. Effect of leukotriene modifier drugs on the safety of oral aspirin challenges. Ann Allergy Asthma Immunol 2006; 97:688.
- Lee RU, Stevenson DD. Aspirin-exacerbated respiratory disease: evaluation and management. Allergy Asthma Immunol Res 2011; 3:3.
- Lee RU, White AA, Ding D, et al. Use of intranasal ketorolac and modified oral aspirin challenge for desensitization of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol 2010; 105:130.
- Settipane RA, Schrank PJ, Simon RA, et al. Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects. J Allergy Clin Immunol 1995; 96:480.
- Morales DR, Lipworth BJ, Guthrie B, et al. Safety risks for patients with aspirin-exacerbated respiratory disease after acute exposure to selective nonsteroidal anti-inflammatory drugs and COX-2 inhibitors: Meta-analysis of controlled clinical trials. J Allergy Clin Immunol 2014; 134:40.
- Steinke JW, Culp JA, Kropf E, Borish L. Modulation by aspirin of nuclear phospho-signal transducer and activator of transcription 6 expression: Possible role in therapeutic benefit associated with aspirin desensitization. J Allergy Clin Immunol 2009; 124:724.
- Katial RK, Strand M, Prasertsuntarasai T, et al. The effect of aspirin desensitization on novel biomarkers in aspirin-exacerbated respiratory diseases. J Allergy Clin Immunol 2010; 126:738.