Updated Treatment of Non‐Steroidal Anti‐Inflammatory Drug‐Exacerbated Respiratory Disease: How to Decide on Aspirin Therapy After Desensitization or Biologics? When? How? An EAACI Task Force Report

ABSTRACT

Nonsteroidal anti‐inflammatory drug (NSAID)‐exacerbated respiratory disease (NSAID‐ERD) is a heterogeneous condition characterized by chronic eosinophilic airway inflammation in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma whose symptoms are aggravated after ingestion of aspirin and other NSAIDs. As a unique treatment, aspirin treatment after desensitization (ATAD) has been in use for several years after showing the inhibitory effect on CRS symptoms and nasal polyp growth as well as severe asthma. However, in recent years, biologics have also shown to cause a decrease in polyp size as well as associated outcomes such as quality of life. In this manuscript, considerations on choosing the best treatment of NSAID–ERD are laid out based on current literature.

Short abstract

1. Introduction

Nonsteroidal anti‐inflammatory drug (NSAID)‐exacerbated respiratory disease (NSAID‐ERD) is a heterogeneous condition characterized by chronic eosinophilic airway inflammation in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma whose symptoms are aggravated after ingestion of aspirin and other NSAIDs [1, 2]. It is also known as Aspirin/NSAID‐exacerbated respiratory disease (AERD/NSAID‐ERD), formerly known as Widal's or Samter's triad [1, 3]. The prevalence of NSAID‐ERD is about 10% in CRSwNP and 7.1% in asthmatic adults, reaching up to 24% in patients with severe asthma and up to 30% of severe CRSwNP [4, 5].

NSAID‐ERD is a distinct endotype of asthma with a complex pathophysiology that is not yet fully understood. It involves consequences of NSAID‐induced inhibition of the cyclooxygenase (COX)‐1 enzyme and dysregulated arachidonic acid (AA) metabolism with overproduction of cysteinyl leukotrienes (CysLTs) and PGD₂ as well as underproduction and under‐responsiveness to prostaglandin (PG) E₂ [6, 7]. In addition to lipid mediator dysregulation, there is chronic and extensive type 2 eosinophilic inflammation and increase in Th2 cytokines [1, 8] and interactions among mast cells, basophils, epithelial cells, platelets, and other components of the innate immune system [9, 10] (Figure 1a). Recent studies indicate that lower and upper airway inflammation in N‐ERD patients is heterogeneous. Inflammation in N‐ERD may extend beyond classical type 2 disease [11, 12].

FIGURE 1.

(a) Pathogenesis of NSAIDs exacerbated respiratory disease. (b) Effect of ATAD on mechanisms of NSAID‐ERD.

Most patients with NSAID‐ERD present with more severe and persistent symptoms of both asthma and CRSwNP than do NSAID‐tolerant asthmatics with a tendency for frequent exacerbations and a high recurrence rate of nasal polyps after polypectomy [2, 8]. Having both asthma and intractable nasal polyps requires strong collaborations of ENT physicians and allergist and pulmonologist. For many years, Aspirin Therapy After Desensitization (ATAD) (formerly aspirin desensitization) had been the primary option for preventing nasal polyp regrowth and improving the associated underlying severe asthma. However, growing evidence demonstrates the effectiveness of biologics, which are used for treating T2 respiratory diseases and are also effective in treating CRSwNP. The limited amount of data in an area with increased needs and expanding treatment options makes it challenging to know when to recommend one treatment over another. This position paper presents details of each treatment modality, and the advantages and limitations of each are discussed.

2. Aspirin Treatment After Desensitization (ATAD)

ATAD is the administration of daily aspirin doses to NSAID‐ERD patients who have undergone a formal aspirin desensitization procedure that allows for developing tolerance to aspirin [1]. Successful ATAD results in cross‐tolerance to all COX‐1 inhibiting NSAIDs.

ATAD was discovered serendipitously when two NSAID‐ERD patients who were challenged to and desensitized with aspirin refused to stop taking aspirin as they had noticed an almost immediate improvement in nasal symptoms following their desensitization [13]. Since then, multiple studies have shown the benefits of ATAD, including the reduction of symptoms and the need for oral corticosteroids, improvement in quality of life, delay in regrowth of nasal polyps, and reduction in the need for additional sinus surgery [14, 15, 16, 17, 18, 19, 20]. ATAD has shown to be effective over 10 years of treatment, in which the treatment was effective in controlling sinonasal disease and improving quality of life in 85% of NSAID‐ERD patients who were still taking daily aspirin [16, 21]. Some studies showed high drop‐out rate [22]. There are also some studies showing conflicting results. However, it should be noted that the dose of aspirin used was quite low and likely subtherapeutic [23].

2.1. ATAD: Results From Randomized Controlled Studies

Conducting randomized, double‐blind, placebo‐controlled trials in NSAID‐ERD is challenging because patients experience respiratory symptoms during acute aspirin desensitization. This limits the ability to blind the study drug properly. In addition, the study drug, aspirin, is available over the counter [24]. Despite these challenges, there are six randomized controlled trials to date, of which five have also demonstrated the effectiveness of ATAD [18, 25, 26, 27, 28, 29] (Table 1). The trial that failed to show benefit used intranasal lysine aspirin [29].

TABLE 1.

Randomized clinical trials for aspirin therapy after desensitization.

Study	Methods	Duration	Maintenance dose of ASA	Participants	Study outcomes	Results (Asthma)	Results (CRS)	Safety
Stevenson et al., 1984 [27]	Prospective double blind crossover study with Po ASA	7 months, consisted of two separate 3‐month treatment phases (ASA/placebo treatment), separated by a l‐month washout period	325 mg ASA once or four times or eight times daily	38 patients with RS and asthma 25 completed the study	Upper and lower airway symptoms, FEV1, anti‐asthmatic and nasal medications	No significant change in lower respiratory tract symptoms, FEV, and anti‐asthmatic medications Only half of the patients had improvement in asthma symptoms during ASA treatment	Improvement in nasal symptoms and a reduction in use of nasal beclomethasone during ASA treatment	Drop‐outs due to adverse effects: Gastritis (3 patients) Increased asthma symptoms (3 patients) Uterine bleeding (1 patient) Increased nasal congestion (1 patient‐during placebo therapy)
Parikh et al., 2005 [29]	Prospective, randomized, DBPC crossover study with In LAS	13 months, consisted of two separate 6‐month treatment phases (LAS/placebo), separated by a 1‐month washout period	16 mg In LAS every other day	22 patients with aspirin sensitive nasal polyposis and asthma 11 patients completed the study	Acoustic rhinometry, NIPF, PEFR, daily diary of symptom scores IHC in biopsy specimen from nasal turbinate tissue	No significant clinical difference between the changes during the placebo or intranasal LAS phase.	No clinical benefit in nasal clinical parameters Significant reduction in the number of cells expressing CystLT1 receptor	Not indicated
Lee et al., 2007 [18]	Prospective, randomized cohort study of two groups of patients either receiving 625 or 325 mg twice daily	12 months	625 mg ASA twice daily 325 mg ASA twice daily	137 patients with AERD	Asthma/ nasal/sinus symptoms systemic CS, hospitalizations	Improvements in asthma symptoms/scores and hospitalizations Decrease in systemic CS by 3‐ to 4‐fold in both groups	Improvements in numbers of sinus infections, sinus and nasal symptoms, smell scores, sinus operations	Adverse effects in 44%–56% of cases Dyspepsia was the most common adverse effect, followed by bleeding/ecchymosis and urticarial/angioedema. 22 patients discontinued and 10 patients decreased ASA due to adverse effects
Fruth et al., 2013 [26]	Prospective, randomized, DBPC study	36 months	100 mg ASA once daily	70 patients with AERD who had sinus surgery before 31 patients completed the study	Polyp relapse	—	In the ASA group: Nasal polyp relapse was less frequent. Polyposis score was lower. QoL and sense of smell improved Clinical complaints were reduced	No severe aspirin‐related side‐effects
Swierczynska‐Krepa et al., 2014 [28]	Prospective randomized DBPC study	6 months	624 mg ASA once daily	20 patients with AIA, CRSwNP 14 patients with ATA, CRS and nasal polyposis 28 patients completed the study	Diary of nasal/bronchial symptom VAS scores, SNOT20 scores, NIPF, ACQ scores, PEFR, FEV1, Lund‐Mackay CT scores, blood eosinophil, CS dose, urinary LTE4, plasma PG metabolite levels	ACQ scores decreased in AIA patients ICS dosages decreased in AIA patients	Improvement in smell, sneezing, nasal blockage, SNOT20 scores and NIPF in AIA patients No change in LTE4 and PG levels	Drop‐outs due to adverse effects: Dyspepsia (4 AIA patients, 1 ATA patient) Transient skin rash (1 AIA patient)
Esmaeilzadeh et al., 2015 [25]	Randomized DBPC study	7 months	650 mg ASA twice daily for one month, 325 mg ASA twice daily in the following 6 months	34 patients with CRSwNP and AIA	FEV1, SNOT‐22 score, symptom score, medication score, Lund‐MacKay CT score Serum cytokine levels	FEV1	Improvements in FEV1, symptom medication and QoL scores, SNOT‐22 and Lund‐MacKay score No change in serum IL‐10, IFN‐γ, and TGF‐β levels	Drop outs due to adverse effects: Gastrointestinal bleeding (1 patient) Skin rash (1patient)

Abbreviations: ACQ, asthma control questionnaire; AERD, aspirin‐exacerbated respiratory disease; AIA, aspirin‐induced/induced asthma; ASA, acetylsalicylic acid; ATA, aspirin‐tolerant asthma; CRS, chronic rhinosinusitis; CRSwNP, chronic rhinosinusitis with nasal polyposis; CS, corticosteroid; CT, computed tomography; CystLT1 receptor, cysteinyl leukotriene receptor 1; DBPC study, double blind placebo controlled study; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; IFN‐γ, Interferon‐γ; IHC, immunohistochemistry; IL‐10, Interleukin‐10; In, intranasal; LAS, lysine aspirin; LTE4, leukotriene E4; NIPF, nasal inspiratory peak flow; PEFR, peak expiratory flow rate; PG, prostaglandin; Po, peroral; QoL, quality of life; RS, rhinosinusitis; SNOT20, Sino‐nasal outcome test; TGF‐β, transforming growth factor‐β; VAS, visual analog scale.

2.2. ATAD: How Does It Work?

ATAD is associated with rapid downregulation of CysLT₁ receptors and reduced sensitivity to inhaled leukotriene E₄ (LTE₄) [30, 31] (Figure 1b). Despite the therapeutic benefit of aspirin therapy, urinary LTE₄ and serum tryptase levels remain elevated while PGE₂ metabolites remain low or below baseline [32, 33]. A recent study showed that although basophils are active during the first 3 months of ATAD, no releases of CysLT, tryptase, or LXA₄ exist, suggesting that despite active basophils, inhibition of mediators can at least partly explain the underlying mechanism in the first three months of ATAD [34]. However, more data are needed to confirm this finding. ATAD leads to beneficial changes in PGD₂ levels, a known driver of IL‐4, IL‐5, IL‐9, and IL‐13 production by ILC2s [35, 36]. PGD₂ levels, which are elevated at baseline and increase during aspirin‐induced reactions, drop dramatically with continued aspirin therapy [36, 37], potentially leading to decreased type 2 inflammation.

2.3. ATAD: Steps (Figure 2)

FIGURE 2.

Steps to be taken on ATAD.

2.3.1. Assess the Indication for ATAD

The indication for ATAD is having NSAID‐ERD, for which standard medical treatment is failing to control both the upper and lower airway disease. This would include patients who need daily or frequent courses of oral corticosteroids to control respiratory or sinus‐related symptoms, rapid regrowth of nasal polyps following sinus surgery despite medical therapy (according to EPOS2020), and individuals who may require aspirin/NSAID for other medical indications [1, 38]. It should also be noted that Black and Latino patients tend to have poorer responses to ATAD, as evidenced by higher rates of desensitization failure and worsening of asthma symptoms during therapy [39].

2.3.2. Assess the Contraindication for ATAD

Pregnancy (or plans for pregnancy), poorly controlled asthma, history of gastric/peptic ulcer disease, known bleeding disorder or coagulopathy, significant CRSwNP burden at the time of aspirin desensitization, and history of eosinophilic esophagitis are contraindications for ATAD [1]. All comorbidities should be carefully considered when selecting ATAD, including those that favor long‐term aspirin use (such as concomitant cardiovascular indications for antiplatelet therapy) and those that increase the risk of bleeding or other aspirin‐related complications.

2.3.3. Preparing for ATAD

2.3.3.1. Perform Functional Endoscopic Sinus Surgery

Ideally, ATAD should be performed within 1–2 months after a polyp debulking procedure. ATAD is more effective at preventing the regrowth of nasal polyps than clearing established CRSwNP [27]. Functional endoscopic sinus surgery (ESS) prior to ATAD reduces the severity of or occasionally completely prevents aspirin‐induced respiratory reactions [19, 40].

2.3.3.2. Optimize Asthma Management

Due to the risk of severe bronchospasm, asthma should be well controlled prior to the aspirin challenge. This may require a course of oral corticosteroids. It is generally recommended that FEV₁ be at least 70% of the predicted value, and that asthma be stable [41]. It is recommended that patients continue their baseline asthma medications (inhaled corticosteroids (ICSs) and long‐acting beta‐agonists (LABA)) during ATAD.

2.3.3.3. Consider Premedication

The pretreatment strategy is to make the procedure as safe as possible. Using leukotriene modifying drugs (LTMD) has been shown to decrease the severity of bronchospasm, with one study showing a 90% reduction in asthma exacerbations during aspirin challenge with montelukast pretreatment [42]. Prior to pre‐medicating with LTMD, very severe bronchospasm resulting in a 50% drop in FEV₁ or more could be seen during the aspirin challenge [43]. It is standard in most US centers performing large numbers of aspirin desensitizations to start montelukast or zafirlukast at least 1–3 days prior and continue for the duration of the procedure. Systemic corticosteroids do not block the respiratory reactions. As such, pretreatment with oral corticosteroids is not usually recommended [43]. Less data exist regarding the use of antihistamines. Antihistamines may alleviate some of the naso‐ocular symptoms.

2.3.4. ATAD: How to Perform?

2.3.4.1. Setting and Requirements

ATAD can be safely performed in an outpatient setting for many patient groups. Still, an inpatient setting for desensitization should be strongly considered for patients with underlying comorbidities that would make the management of severe reactions more difficult. Such co‐morbidities and co‐factors include the concurrent use of a beta blocker, recent myocardial infarction, or unstable asthma [38, 42]. Emergency equipment and trained staff are necessary for the safe introduction of ATAD.

2.3.4.2. Protocols

Multiple protocols exist for aspirin challenge and desensitization in NSAID‐ERD, differing in terms of dosing intervals (60 min, 90 min, 3 h), starting dose (20.5, 40.5 mg), and route of provocation (oral aspirin, intranasal ketorolac, intranasal lysine‐aspirin, or a combination) [38, 44, 45, 46] (Tables 2 and 3). Intravenous aspirin desensitization using lysine‐aspirin is used in some European and Asian centers. However, since lysine‐aspirin is not accessible worldwide, it is not included here.

TABLE 2.

Examples of aspirin challenge and desensitization protocols and management of breakthrough reactions during acute phase of ATAD.

2 Day ASA desensitization [23]			1 Day ASA desensitization [2]
Time	Day 1	Day 2
8:00 a.m.	20–40 mg	100–160 mg	40.5 mg
9:30 a.m.			81 mg
11:00 a.m.	40–60 mg	160–325 mg	162 mg
12:30 p.m.			325 mg
2:00 p.m.	60–100 mg	325 mg	Desensitization complete
5 p.m.		Desensitization complete
Confirm that patient's baseline FEV1 is the same as their prior best value (stable PFTs) Using a pill cutter, 81 mg ASA tablet can be cut into a half or a fourth Measure FEV1 every hour. Follow clinical condition of the patient.

In case of reactions	Dose modification during ASA desensitization
Bronchospasm: Nebulized bronchodilator Naso‐ocular reactions: nasal oxymetazolone, nasal or ocular antihistamines. Laryngospasm: nebulized racemic/IM epinephrine Gastrointestinal: H2 Blockers Cutaneous: H1 antihistamines *Consider systemic corticosteroids for severe reactions	If there is a reaction first treat and got to step A. Repeat the provoking dose of ASA If no reaction, continue to escalate the dose every 3 h (2 d protocol) or 1.5 h (1 d protocol) At 325 mg ASA, desensitization is complete Instruct patient to start 650 mg ASA that night as their first dose and continue with 650 mg BID

Source: Stevenson et al. [27]; DeGregorio et al. [47].

TABLE 3.

Nasal ketorolac + oral aspirin challenge/desensitization.

Time	Intranasal ketorolac and oral aspirin
Day 1		To prepare ketorolac
8:00 a.m.	1 spray (1.26 mg)	Ketorolac 60 mg/2 mL mix with 2.75 mL saline. Use meter‐dose nasal spray bottle. Each spray delivers 0.1 mL of solution (1.26 mg ketorolac)
8:30 a.m.	2 sprays (1 each nostril)
9:00 a.m.	4 sprays (2 each nostril)	Contraindications: complete nasal obstruction
9:30 a.m.	6 sprays (3 each nostril)	Treat Reactions and continue: Bronchospasm: nebulized bronchodilator Nasal‐ocular reactions: nasal oxymetazolone spray. Nasal/ocular antihistamines Laryngospasm: racemic epinephrine Gastrointestinal: H2 blockers Cutaneous: H1 antihistamines
10:30 a.m.	60 mg ASA
12:00 p.m.	60 mg ASA
15:00 PM	Discharge instructions
Day 2
8:00 a.m.	150 mg ASA
11:00 a.m.	325 mg ASA
2:00 p.m.	Discharge instructions

Source: Lee et al. [48].

2.3.4.3. Adverse Effects During Aspirin Challenges/Desensitization and Their Management

During the aspirin challenge/desensitization, hypersensitivity reactions such as developing upper and lower airway symptoms, a decrease in FEV₁ > 15%, and/or a reduction in peak nasal inspiratory flow by > 20% are common [46]. Most reactions are provoked at a dose between 45 and 100 mg of aspirin [46]. And with an average time to reaction from provocation dose of aspirin of 102 min [46].

In addition to nasal‐ocular and respiratory reactions, cutaneous symptoms, including flushing, urticaria, maculopapular eruptions, and angioedema [36, 49], and gastrointestinal symptoms, including severe gastrointestinal pain, dyspepsia, nausea, vomiting, and diarrhea, can occur. Rarer reactions are laryngeal edema and hypotension [14, 16, 49].

After initiating the aspirin provocation, if at any time a reaction occurs in the bronchi or larynx, reactions are treated before continuation, and the provocation dose is repeated [50] (Table 2). In severe reactions, the decision on continuing ATAD is reconsidered. In case of risk of severe reaction, slower protocols can be adapted.

2.3.4.4. Maintenance Doses of ATAD

The optimal dosing of ATAD is not known. The benefits of high‐dose aspirin 650 mg twice daily in controlling airway disease in patients with NSAID‐ERD are well established [15, 18, 25]. A study comparing twice daily dosing of aspirin 325 vs. 650 mg aspirin found that approximately half of the patients did as well on the lower dose, whereas the rest required 1300 mg/day aspirin for benefit [18]. Data on lower doses of aspirin is limited. A study comparing 300 mg versus 100 mg aspirin daily found that the 100 mg/day dose showed no improvement in symptoms or CRSwNP recurrence. In contrast, the 300 mg/day dose demonstrated a decrease in CRSwNP and some symptom improvement [20]. A second study also found benefits with 300 mg aspirin daily, but the number of patients in both studies was small [51]. A comparison of 300 versus 600 mg of aspirin in the maintenance of ATAD provided similar sinonasal outcomes [52]. It is recommended to start with aspirin 650 mg twice a day for 1 to 6 months, and then the dose could be titrated down as tolerated [18]. However, the decision should be on an individual basis.

2.3.4.5. Duration of ATAD

The duration of therapy depends on the patient's response to the intervention. After an initial 6‐month trial of ATAD, patients who have responded with improved clinical outcomes can be maintained on aspirin indefinitely [16, 53]. For non‐responders, aspirin therapy may be discontinued at 6 months with instructions to avoid all COX‐1‐inhibiting NSAIDs. Non‐responders who wish to remain cross‐desensitized to all COX‐1‐inhibiting NSAIDs should continue at least 325 mg of aspirin daily [54].

2.3.4.6. Safety

The most important concern with long‐term ATAD is the gastrointestinal adverse effects of aspirin (Table 1). These adverse effects are mostly seen at higher doses of aspirin. The other adverse events are urticaria and eosinophilia [42, 55].

2.4. ATAD in Special Conditions

2.4.1. Pregnancy

ATAD has been successfully performed in two pregnant women, one with antiphospholipid syndrome and another at high risk of coronary stent thrombosis. Both patients tolerated a 10‐step desensitization to reach an aspirin dose of 100 mg [56, 57]. With a very limited number of cases, we suggest that during pregnancy, patients with NSAID‐ERD who require aspirin should be discussed by a multidisciplinary team to determine the benefit–risk for the mother and fetus. If done, the desensitization procedure should be strictly monitored.

2.4.2. Childhood and Adolescence

ATAD is not used often in pediatric patients because of the risk of Reye's syndrome [58].

2.4.3. The Patients on ATAD Undergoing Surgery

NSAIDs are routinely used as analgesics both pre, peri, and postoperatively, and avoidance may be challenging; instead, COX 2‐specific inhibitors and paracetamol/acetaminophen can be used [59]. For patients on ATAD, the risk of needing a repeat aspirin desensitization makes stopping aspirin a challenge. Unvalidated protocols suggest preoperative dose decrease or bridging with an NSAID as alternatives. A recent questionnaire study found that of 191 patients undergoing a procedure requiring stopping or decreasing aspirin, 100 continued treatments (pausing only a few days around surgery); 32 stayed on a regular dose of aspirin, 56 used a reduced dose regimen, 8 used bridging with ibuprofen, and 4 used a different regimen. None experienced adverse effects, and none needed repeat desensitization [59, 60].

2.4.4. Patients Requiring Antithrombotic Therapy

Aspirin has been a cornerstone of antithrombotic therapy in cardiovascular disease [61, 62]. In patients with either acute or chronic coronary syndromes undergoing percutaneous coronary intervention, aspirin is mandatory in a dual antiplatelet therapy regimen for prevention of stent thrombosis and/or new ischemic events. Aspirin is also currently a first‐option antithrombotic therapy after an aortic prosthetic valve replacement. Although infrequent, when encountered in clinical practice, aspirin hypersensitivity poses for cardiologists a clinical dilemma. In these cases, taking history helps for determining hypersensitivity reactions to aspirin. ATAD seems to be an important option for these cases. Although different ATAD protocols may be applied, the fast desensitization protocols could be favorable concerning the similar safety profile [63].

3. Biologic Treatments

Following dramatic clinical improvements seen with the introduction of biologics in allergic disorders such as severe asthma, atopic dermatitis, and urticarial [64], recent studies also showed promising outcomes in CRSwNP, particularly by Dupilumab, Mepolizumab, and Omalizumab. Although currently, no specific data for patients with NSAIDs‐ERD exist, subgroup analyses provide important data related to the effect of biologics in NSAID‐ERD. To date, Dupilumab, Omalizumab, and Mepolizumab have been approved by the FDA and EMA to treat recurrent CRSwNP for mainly recurrent nasal polyps (Table 4).

TABLE 4.

Indications for nasal polyps (revised recommendations of EPOS) for biologics.

In patients with bilateral nasal polyps who had ESS if at least 3 criteria presented below existed biologic treatment is required
Variable	Proof
Evidence of Type 2 inflammation	Blood eosinophil ≥ 150 OR Total IgE ≥ 100 OR Tissue eosinophil ≥ 10 hpf
Ned for systemic corticosteroids or contraindication to systemic corticosteroids	≥ 2 courses per year OR Long term (3 months) low dose steroids
Significantly impaired quality of life	SNOT 22 ≥ 40
Significant loss of smell	Anosmic on smell test (score depending on test)
Diagnosis of comorbid asthma	With regular use of inhaled corticosteroids

3.1. Dupilumab

Dupilumab is a humanized IgG₄ antibody that inhibits the IL‐4Rα subunit shared by IL‐4 and IL‐13 [64, 65]. In NSAID‐ERD, after 3 month treatment with Dupilumab the main biomarkers become normalized (PGE₂, PGD₂, LTE₂, total IgE) in correlation with symptom (mainly loss of smell) improvement [59]. It also normalizes the altered eicosanoid metabolism, increasing PGE₂, and reducing CysLT production [65, 66].

Initial clinical studies suggested that within 16 weeks of treatment, Dupilumab improves upper and lower respiratory tract symptoms in NSAID‐ERD patients, including improved sense of smell, reduction in nasal polyp size, and improvements in lung function [67, 68]. Additional observation studies of Dupilumab in NSAID‐ERD have shown clinical improvement as early as 1 month after starting treatment [65]. In the phase 3 trials of Dupilumab for the treatment of CRSwNP (SINUS 24 and SINUS 52), sub‐group analysis of the patients with NSAID‐ERD showed a Dupilumab‐induced improvement from baseline to week 24 and also a Dupilumab‐induced improvement in sense of smell at week 24 with a mean difference in UPSIT of 10.52 points between Dupilumab and placebo [69]. A sub‐group analysis of pooled SINUS 24 and SINUS 52 data showed that the NSAID‐ERD patients experienced significantly greater Dupilumab‐induced improvements in nasal congestion and SNOT‐22 scores than did the aspirin‐tolerant CRSwNP patients in the study [70]. Of further clinical relevance for patients with NSAID‐ERD, Dupilumab has also been found to have an abrogating effect on the severity of aspirin‐induced reactions. It can either increase the threshold for the provoking dose of aspirin or completely prevent all symptoms of aspirin reactions [71, 72]. Finally, in addition to reducing the burden of existing CRSwP, a recent series of NSAID‐ERD patients found that Dupilumab can also successfully be used as an adjunct to ESS to prevent or delay the time to regrowth of CRS and nasal polyps post‐operatively [73]. In an open‐label observational study of 22 adult patients with NSAID‐ERD who were treated with Dupilumab for eosinophilic asthma or CRSwNP, 8 underwent aspirin desensitization prior to the start of Dupilumab and continued ATAD throughout the study. Compared to the pre‐Dupilumab phase, participants on ATAD and Dupilumab treatment had a 4‐fold reduction in nasal ECP levels after 1 month of Dupilumab treatment, which was sustained after 3 months of treatment. However, clinical endpoints, including upper and lower airway symptoms, FEV1, and the rate of adverse events, did not differ between the two groups [74]. Although there are no head‐to‐head comparison studies, a large network meta‐analysis [55] found that among available therapies for CRSwNP‐including aspirin desensitization and several biologics‐dupilumab provided the greatest overall clinical benefit across all evaluated outcomes, while other biologics and aspirin therapy also improved symptoms but to a lesser extent.

3.2. Anti‐IL‐5/IL5Rα Drugs (Mepolizumab, Benralizumab, Reslizumab)

IL‐5Rα is expressed on many relevant cells, including mast cells, basophils, ciliated epithelial cells, and some B cells, T cells, and plasma cells. The polyp tissue from NSAID‐ERD patients harbors increased numbers of IL‐5Rα⁺ plasma cells compared to tissue from aspirin‐tolerant CRSwNP patients [75, 76, 77]. Mepolizumab is a humanized IgG1κ anti‐IL‐5 antibody [78], and Benralizumab is a humanized IgG1κ antibody that binds to and inhibits extracellular IL‐5Rα, preventing IL‐5 signaling [78]. It also binds to FcRγIIIa on NK cells and macrophages [79] that promote apoptosis of eosinophils and basophils through antibody‐dependent cell‐mediated cytotoxicity [64, 78]. In NSAID‐ERD, Mepolizumab reduces both tissue and blood eosinophils, decreases CysLT production, and improves the respiratory epithelial barrier via an upregulation of tight‐junction protein expression [64, 80, 81].

Mepolizumab has recently been approved for treating CRSwNP based on data showing its beneficial effects on nasal obstruction and nasal polyp size [82]. About 22% of the mepolizumab‐treated group had comorbid NSAID‐ERD, and an exploratory analysis indicated that mepolizumab's efficacy was irrespective of the presence or absence of comorbid NSAID‐ERD [83]. Mepolizumab treatment has been associated with a significant reduction of blood eosinophils as well as a reduction in nasal and urinary levels of inflammatory eicosanoids in patients with NSAID‐ERD [84]. Observational data from several real‐life studies indicate that a subset of NSAID‐ERD patients do not respond adequately to Mepolizumab. The lack of response likely occurs in patients with high blood eosinophil counts or high IgE serum levels [68, 85]. In one retrospective single‐center study, which followed 26 patients with NSAID‐ERD who received an anti‐IL5/IL‐5Rα therapy (3 Reslizumab, 13 Benralizumab, 10 Mepolizumab), 50% of patients were considered non‐responders as they showed no improvement or worsening of symptoms while on therapy [86]. However, failure to respond to one biologic does not necessarily mean that all targeted respiratory biologics will fail. In a separate study, NSAID‐ERD patients with an inadequate response to anti‐IL‐5 or anti‐IL‐5Rα therapy who were switched to Dupilumab displayed a good clinical response to anti‐IL4Rα therapy [68]. Case series suggest that Mepolizumab does not consistently prevent aspirin reactivity [87]. A case report suggests a positive effect of Mepolizumab treatment on aspirin‐induced reaction symptoms [88].

3.3. Omalizumab

Humanized IgG₁ MoAb binds circulating IgE, causing FcεRI downregulation on inflammatory and structural cells [64, 78]. Omalizumab has demonstrated effectiveness by suppressing free IgE [89] and downregulating FcεRI expression, thereby stabilizing mast cells [90, 91], basophils, and dendritic cells in patients with NSAID‐ERD, even though NSAID‐ERD is not considered to be specifically IgE mediated [92]. The Omalizumab‐induced improvement is thought to be due to its suppression of CysLT production [93, 94], decrease in eosinophils in the blood, sputum, and bronchial submucosa [89, 90, 91, 94], and decrease in IL‐33, IL‐25, and TSLP [95].

In the large trials of Omalizumab for the treatment of CRSwNP, 17%–39% of the total study participants had comorbid NSAID‐ERD. After 24 weeks of Omalizumab, the improvement in nasal polyp score in the patients with NSAID‐ERD was slightly greater but not statistically different than in the NSAID‐tolerant CRSwNP study patients [96]. Omalizumab pre‐treatment has also been shown to decrease the severity of, or occasionally ultimately prevent, aspirin‐induced reactions, likely due to its ability to lower the production of CysLTs. Still, studies show that omalizumab does not always improve reaction severity [94, 97].

3.4. Tezepelumab

Tezepelumab is a human monoclonal antibody (immunoglobulin G2λ) which binds specifically to thymic stromal lymphopoietin (TSLP) for the treatment of severe asthma, without any phenotype or biomarker restrictions. TSLP, an epithelial cytokine, plays an important role in the initiation and persistence of asthma pathophysiology, including allergic inflammation, eosinophilic inflammation, and type 2 (T2)‐independent effects on mast cells, airway smooth muscle, and airway hyperresponsiveness. Tezepelumab has been shown to act upstream of all currently clinically used biomarkers.

Concerning use of tezepelumab in nasal polyps, recent analysis showed greater improvement in nasal symptoms such as olfactory functions and smell test scores in patients using Tezepelumab and dupilumab in patients in comparison to other biologicals [98].

A recent study also showed that use of Tezepelumab therapy for 52 weeks was shown to significantly decrease the size of nasal polyps, the severity of nasal congestion and sinonasal symptoms, and the use of nasal‐polyp surgery and systemic glucocorticoids in 203 patients than placebo in adults with severe, uncontrolled chronic rhinosinusitis with nasal polyps [99].

Importantly, a very recent study highlighted that the patients with aspirin or NSAID sensitivity had been shown to have the greatest reductions in annualized asthma exacerbation rate with tezepelumab compared with placebo (83%; 95% CI: 66, 91) [100].

4. Surgical Treatment

Concerning the severity of CRSwNP in patients with NSAID‐ERD, a retrospective hospital cohort showed that patients with NSAID‐ERD had a higher risk of uncontrolled CRSwNP than the patient group without NSAID‐ERD [101]. There is a high polyp recurrence risk of NSAID‐ERD patients who undergo endoscopic sinus surgery (ESS) as a single treatment.

4.1. Which Type of Surgery?

ESS is a procedure designed to remove CRS and nasal polyp inflammatory tissue and to open the natural drainage pathways of the sinuses to restore their function and health [102]. ESS is an effective, safe, and widely accepted surgical approach.

For CRSwNP patients, the extent of ESS may vary from a simple polypectomy to extended ESS, such as removal of the nasal middle turbinate and/or total ethmoidectomy and/or opening of all other nasal sinuses. However, there is still a lack of knowledge and consensus regarding the optimal extent of ESS in recalcitrant CRSwNP with or without NSAID‐ERD [97].

Extended surgery may be needed due to the aggressive inflammatory process in the mucosa, as this reduces the need for revision surgery compared with partial ESS [103, 104]. A retrospective cohort of Finnish CRSwNP patients with NSAID‐ERD has shown that partial ethmoidectomy in patients with NSAID‐ERD increased the risk of revision surgery [104]. NSAID‐ERD is a risk factor for revision ESS of CRSwNP patients [105]. The short‐term effects of ESS in patients with NSAID‐ERD are comparable to patients with CRSwNP overall, but patients with NSAID‐ERD tend to need revision surgery earlier in the post‐operative period [106], and these patients undergo two‐fold more sinus surgeries and at a younger age compared to NSAID‐tolerant patients with CRSwNP [107]. ESS is individually tailored based on the clinical situation and the surgeon's opinion, as well as published evidence and recommendations [108].

4.2. When to Perform ESS?

4.2.1. ESS in the Context of ATAD

ESS is used as primary treatment or an “adjuvant” treatment prior to ATAD (4–6 weeks prior to ATAD) for medically recalcitrant CRSwNP with NSAID‐ERD. Patients who underwent ESS and then aspirin therapy were less likely to require daily prednisolone treatment at all time points and upon long‐term follow‐up, and their average daily prednisolone dose decreased significantly [109] compared to initiating aspirin desensitization and ATAD pre‐operatively. Another study reported that patients who had ESS with subsequent ATAD had fewer CRSwNP relapses compared to ESS alone [110].

4.2.2. ESS in the Context of Biologics

Unlike the decision for ATAD, the decision for ESS is based on the patient's clinical condition, grade of nasal polyps, and the decision of the physician in patients with NSAID‐ERD who have recurrent CRSwNP.

5. Evaluation of Patients' Response

Evaluation of the patient's responses to either treatment choice is particularly based on the indication of the treatment. In this sense, if the indication is recurrent CRSwNP only the main outcome, then the main follow‐up criteria should be sinonasal outcomes. On the other hand, some patients may have both severe asthma and recurrent CRSwNP, both of which are indications for the introduction of biological treatments. In this case, follow‐up of both clinical conditions is necessary (Figure 3). Criteria for evaluation of responses to a biologic in a clinical trial have been evaluated. However, to compare treatment options from data in separate trials, it is necessary to follow the cases in a standardized way regardless of the treatment selected. The data that is going to be discussed below is mainly derived from the studies related to the use of biologics in NSAID‐ERD; the same criteria should be followed for ATAD as well. Below, both clinical parameters and biomarkers will be discussed.

FIGURE 3.

Tools to assess the response to biologicals and ATAD.

5.1. Asssement of Clinical Parameters

5.1.1. Assesment of Asthma

Assessment of response to biologics has not been standardized and different domains (clinical, functional, biological, patient's related outcomes) can be evaluated [111, 112, 113, 114, 115, 116, 117]. The use of biologics in treating severe asthma patients has identified a subgroup of patients with a remarkable clinical benefit, usually higher than those reported in registered trials and defined as super‐responders [118]. However, the current definition of super‐response includes only clinical features without considering lung function and inflammatory biomarkers.

Currently, using a combination of parameters represents the most important response criteria. Such parameters include symptom control (evaluated by ACT and/or ACQ5 scores), the reduction of exacerbations (according to ATS/ERS definition), the OCS‐sparing effect, and lung function improvement [112, 113, 114, 115, 116, 117, 119] (Figure 3).

Quantifying improvement may be difficult, but in the last two years, different scores have been presented to evaluate the response to biological treatment in severe asthma, such as the FEOS score (FEV₁, Exacerbations, Oral corticosteroids, and Symptoms) and the Biologics Asthma Response Score (BARS) score [112, 113, 114]. FEOS and BARS scores combine clinical and functional outcomes (symptoms, OCS use, exacerbations, and bronchial obstruction) and give a score according to the improvement of each outcome, thus representing a tool to measure the clinical response to biologics. The range of responses in FEOS runs from 0 (worse response) to 100 (best possible response): the higher the score, the larger the response. A correlation between super‐responders and FEOS has been described, and a cut‐off of 75.5 was found to identify super‐responders, with a good sensitivity and specificity.

The concept of remission was also introduced last year, but the definition is still being discussed [115]. Of note, the same criteria are used for both the definition of clinical response and clinical remission, leaving room for possible misclassifications (Figure 4).

FIGURE 4.

Evaluation of the responses for asthma.

Response in terms of symptoms, lung function, or reducing the corticosteroid dose can be estimated 4–6 months after starting treatment with a biologic. For ATAD, a 6‐month evaluation is recommended to assess efficacy. A 12‐month period seems feasible for both treatments to assess the effect on exacerbations.

5.1.2. Assesment of CRSwNP

So far, no single definition of treatment response in CRSwNP has been internationally accepted. However, there are recommendations from National Allergy/ENT Societies and an International Expert group [116, 117] that treatment response should assess the presence of different domains such as olfactory disorders, nasal blockage, QoL impairment, response to basic therapy, resistance to and/or dependence on oral corticosteroids, and cumulative annual dose of systemic corticosteroids.

Five evaluation criteria (EUFOREA/EPOS) seem to characterize the response to treatment best: (1) Reduced nasal polyp size, (2) reduced need for systemic corticosteroids, (3) improved quality of life, (4) improved sense of smell (using smell tests or VAS), and (5) reduced impact of comorbidities while five levels of response at one year of treatment were proposed, ranging from no response (0 criteria fulfilled) to excellent response (5 criteria fulfilled) [103]. In 2023, the grade of response for these 5 criteria was simplified to 3 levels (from the original 5 ones) [120] (Figure 5).

FIGURE 5.

Evaluation of the response for CRS with or without nasal polyps.

Subsequently, these criteria have been implemented based on the data obtained in phase 3 trials with Dupilumab and Omalizumab, showing that most patients reach a significant NPS and sinonasal symptom reduction within the first 12 weeks of therapy [69, 96].

The proposed management strategy requires improvement of at least one symptom/score (loss of smell, NCS, NPS, SNOT‐22, total symptom score VAS) at a 6‐month assessment and patient satisfaction with the outcomes. At the 12‐month assessment, the improvement of all outcomes with no need for surgery or systemic steroids would be considered an adequate response [117].

5.2. Assesment of Biomarkers

Biological therapies may lead to the decrease of some NSAID‐ERD biomarkers. Omalizumab decreases urinary LTE₄ induced by oral aspirin challenge [94]; the anti‐IL‐5 strategy is associated with the reduction of blood eosinophils, serum EDN, and urinary LTE₄ concentration, with no effect on periostin, TGF‐beta₁, or tryptase [84, 121]. Dupilumab treatment in NSAID‐ERD patients showed that improved FeNO, total serum IgE, and urinary LTE₄ levels are associated with increased anti‐inflammatory eicosanoid PDE₂ [65, 122]. The effects of biologics on PGD₂ metabolites are not conclusive. A decrease in PGD₂ induced by mepolizumab has been shown in some studies [84]. Buchheit et al. showed that after 3 months the main biomarkers normalized (PGE₂, PGD₂, LTE₂, total IgE) under Dupilumab treatment. This is correlated with symptom improvement (mainly loss of smell) [65].

6. Conclusions and Future Perspectives

The old belief that management of NSAID‐ERD has limited effective treatments has significantly changed with current increased experience and knowledge of ATAD and early promising results derived by biologics. Both ATAD and biologicals seem effective in reducing CRSwNP recurrence and controlling asthma. On the other hand, although ATAD is on a limited scale in many countries, it remains a valuable option for patients with NSAIDs‐ERD with recurrent nasal polyps due to its low cost and availability in every country as there are patients who benefit from this treatment. By contrast, biologics are not available in all countries or reimbursement policies of the governments make this treatment inaccessible for at least some patients, thereby contributing to health inequalities.

The treatment approach thus should be based on shared decision‐making, considering the patient's clinical characteristics, the likelihood of patient adherence, the availability of endoscopic sinus surgery options, the cost of the medications, and access to biologic therapies (Figure 6). From an economic and efficacy perspective, ESS and/or ATAD as initial treatment for patients with NSAID‐ERD should be performed in experienced centres if there are no contraindications (Figure 7). For patients with contraindications to ATAD and/or ESS, a biologic treatment can be given depending on the availability and reimbursement policy in the country. However, it should be noted that safety issues related to the long‐term use of ATAD are a concern in many countries. Whichever approach is chosen, the patients should be followed up with standardized criteria to evaluate the response. Importantly, the key to success comes from a multidisciplinary approach by the involvement of allergists and immunologists, ENT physicians, and pulmonologists. The key to success is to evaluate the case in detail, especially the evaluation of comorbid asthma and nasal polyps.

FIGURE 6.

Comparison of ATAD and Biological treatments in the management of NSAID‐ERD.

FIGURE 7.

How to decide? ATAD or biological treatments in the management of NSAID‐ERD.

Author Contributions

All authors contributed equally to their parts, revised the manuscript, and approved the final version. Gülfem E. Çelik and Joanna S. Makowska revised and organized the draft manuscript.

Funding

This work was supported by the European Academy of Allergy and Clinical Immunology.

Conflicts of Interest

Professor Ludger Klimek has received research grants from Allergy Therapeutics/Bencard, Great Britain/Germany; ALK‐Abelló, Denmark; Allergopharma, Germany; Aimmune, USA; ASIT Biotech, Belgium; AstraZeneca, Sweden; Bionorica, Germany; BioNTech, Germany; Biomay, Austria; Blueprint, USA; Boehringer Ingelheim, Germany; Celltrion, South Korea; Circassia, USA; Chiesi, Italy; Cytos, Switzerland; Curalogic, Denmark; HAL, Netherlands; Lofarma, Italy; Menarini, Italy; Viatris/Mylan, USA; Novartis, Switzerland; Leti, Spain; ROXALL, Germany; GlaxoSmithKline (GSK), Great Britain; Sanofi, France; Stallergenes, France; Thermofisher, USA and/or has served on the speaker's bureau or was consulting for the above mentioned pharmaceutical companies. Ludger Klimek is the current President of German Society of Allergology AeDA, Governance Committee Board Member and ENT Section Board Member of the European Academy for Allergy and Clinical Immunology (EAACI), Vice‐President of German Academy for Allergy and Environmental Medicine and Editor‐in‐Chief of AllergoJournal and AllergoJournal International. Other authors reported no COI related to this manuscript.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.