AERD and NSAID hypersensitivity

AERD/NERD and NSAIDs
hypersensitivity
Natasorn Lekuthai, MD.
Fellowship year 2

NSAIDs hypersensitivity
• It is estimated that less than 20% of reported adverse reactions to NSAIDs are consistent with a true
hypersensitivity reaction in both adult and pediatric patients
• 5 distinct clinical phenotypes based on timing of symptom onset, presence of underlying disease, and organ
systems involvement.
Current Allergy and Asthma Reports (2023) 23:181–188

Classification of NSAIDs
Pediatr Allergy Immunol. 2019;30:25–35.
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Allergo J Int (2018) 27:114–121
Classification of NSAIDs

Type of drug reactions
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OTHER PHENOTYPES BEYOND THE EAACI CLASSIFICATION
: Blended reactions
• This is the case of CRs with simultaneous involvement of skin and airways or even other organs.
• In the EAACI classification, respiratory and cutaneous reactions are exclusive and there is not a single
category for multiple-organ involvement.
• represents the second most frequent entity in NSAIDs hypersensitivity after NIUA, accounting for more
than a quarter of CRs in adults.
• Most common symptoms comprise the combination of urticaria/ angioedema plus rhinitis/asthma. BRs
show a percentage of underlying rhinitis and asthma similar to NERD, and of atopy similar to NIUA.
• Other combinations include urticaria/angioedema plus glottis oedema and other organs involvement (eg the
gastrointestinal tract), in which the percentages of underlying rhinitis, asthma and atopy are similar to NIUA.
• High rate of positive intranasal Lys-ASA-DPT, similar to NERD, independently of symptoms after NSAIDs
intake.
Allergy. 2020;75:561–575.

: Food-dependent NSAID-induced anaphylaxis
• NSAIDs have been suggested to increase intestinal barrier permeability, enhancing allergen absorption. The
effect is stronger with drugs inhibiting the two COX isoforms compared with selective COX-2 inhibitors.
Another possibility suggests a direct effect of the drug potentiating basophils and mast cells activation/
degranulation. The magnitude of the IgE response may depend on the NSAIDs class, the dose and the COX-1
inhibition potency.
• food-dependent NSAIDs-induced anaphylaxis (FDNIA) is a phenotype of anaphylaxis in which NSAIDs are the
only cofactor enhancing the reaction.
• Diagnosis of FDNIA is difficult, as clinical history does not always identify potential participating factors, apart
from NSAIDs.
• Thus, even if DPT with the culprit is performed, the reaction will not occur as the food allergen is not
present. Consequently, some patients with a history of NSAIDs hypersensitivity and negative DPT could
belong to the FDNIA group.
Allergy. 2020;75:561–575.

J Allergy Clin Immunol Pract 2023;11:1843-53

• Immediate reactions to several NSAIDs but tolerate ASA. We have recently described a patient who
presented different episodes of anaphylaxis to ibuprofen and diclofenac while tolerating ASA during DPT, and
another patient who tolerated ASA and developed hypersensitivity reactions to three chemically nonrelated
NSAIDs.
• A previous study in a pediatric population, which used DPT to the culprits and to ASA, described two
episodes of urticaria/angioedema induced by ibuprofen and paracetamol in a child who tolerated ASA.
• Another study reported four patients who, based on clinical history, suffered from anaphylaxis to several
NSAIDs and were considered as BRs; however, the possibility of being NMSIRs should not be excluded as
ASA-DPT was not performed. Assessing ASA tolerance is crucial when patients respond to nonrelated NSAIDs
to rule out CRs and consider them as NMSIRs.
• The prevalence of this phenotype is unknown.
: NSAIDs-multiple selective immediate reactions
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Phenotypes
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Pathophysiology
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Pathophysiology : Cross reactive
Inflammatory mechanism
- NSAID-induced urticaria and angioedema have reactions to all NSAIDs, which have in common their
ability to inhibit COX-1. Subjects with chronic urticaria and NSAID intolerance have increased levels of basal
urinary LTE4 compared with patients with chronic urticaria who are tolerant to aspirin. Furthermore, increases
of urinary LTE4 occur in the first group after oral aspirin challenge
- Increased cysteinyl- leukotriene production contributes to the inflammatory process, as
suggested by the ability to inhibit these reactions by leukotriene receptor antagonists.
- Patients with chronic urticaria and NSAID intolerance also exhibit, with high frequency, positive
results on autologous serum and plasma skin tests, which would suggest an association among chronic urticaria,
autoimmunity, and NSAID hypersensitivity.

• Genetic polymorphism
• focused on leukotriene synthesis or mast cell– and histamine-related genes. Neutrophil-related genes
have also been studied; regarding a neutrophil activation–related gene, the promoter polymorphism
of ADORA3 at −1050 G/T was found to be associated with the phenotype of aspirin-intolerant urticaria,
in which the ht1 [TC] haplotype transcript was found to be associated with increased basophil histamine
releasability.
• The genetic polymorphism at FCER1G −237 G was also significantly associated with atopic status and
basophil histamine releasability in patients with NECD. Although no significant associations were found
between the two histamine receptor genes, HRH1 and HRH2, the histamine N-methyl transferase
(HNMT) 939A>C polymorphism was associated with the NECD phenotype by regulation of enzymatic
activity and histamine release from peripheral basophil
Pathophysiology

Potential biomarkers
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Diagnosis

Diagnosis : NECD, NIUA
• Clinical history suggests the diagnosis of NECD and NIUA
• Patients should be classified according to whether they have underlying chronic urticaria
• Reliable in vitro tests for the diagnosis of NECD and NIUA are not available

Diagnosis
Oral provocation test
• to confirm or rule out a diagnosis, to determine cross-reactivity, or to find a safe alternative therapy
• one suggested approach is to challenge all patients first to aspirin, and then if negative, consider
performing OPT to the culprit drug.
• In our experience, most patients selected to undergo an aspirin OPT for a history of NECD, NIUA, or SNIDHR
are satisfied by performing only an aspirin OPT. In the setting of a history consistent with NECD or NIUA, a
negative OPT to aspirin supports tolerance of all COX-1 inhibitors.

Management
• For all NSAID hypersensitivity, NSAID avoidance is the mainstay of treatment
• For AERD, NECD, and NIUA, it is recommended to avoid both culprit and cross-reacting non-selective COX-1
inhibitors.
• COX-2 inhibitors are generally well tolerated by patients who have had isolated skin symptoms
whether NECD or NIUA and in those with AERD.
• This data supports a small risk of cross- reactivity for patients with urticaria and/or angioedema and good
tolerance in patients with AERD. Therefore, an oral challenge with a COX-2 inhibitor would be prudent prior
to use, particularly in those with a history of severe reactions in the setting of NECD and NIUA.
• In patients with AERD or isolated respiratory disease, however, selective COX-2 inhibitors and doses of
acetaminophen which lack COX-1 inhibitor properties (< 650 mg) are considered safe without
challenge.

• Therefore, control of the underlying CSU disease significantly decreased the risk of NSAID reaction.
• In the setting of SNIUAA, patients can safely take structurally unrelated NSAIDs. In the USA, ibuprofen
and naprosyn are the most common agents associated with single-NSAID-induced anaphylaxis. A formal
aspirin challenge confirms tolerance of a structurally unrelated agent and strongly supports a diagnosis of
SNIUAA without the need to expose the patient to the agent connected with an anaphylaxis event.
Management

Desensitization
• Desensitization may also be considered in non-AERD patients. While there is less consensus about the
timing and dosage for non-AERD patients, multiple studies indicate that aspirin desensitization is
effective and safe.
• Large amounts of data, from both a meta-analysis of 15 studies and a prospective multicenter study,
demonstrate that at least 98% of patients with coronary artery disease, including those with recent ischemic
events, who reported prior hypersensitivity reactions to NSAIDs and required antiplatelet therapy with aspirin
were successfully and safely desensitized to aspirin. These patients were able to be treated as medically
indicated with prolonged courses of aspirin. Most of these patients described AERD or NIUA symptoms
with prior aspirin use.

Delayed Hypersensitivity Reactions to
Nonsteroidal Antiinflammatory Drug
• Single NSAID-induced delayed reactions (SNIDR). Symptoms usually emerge several days to weeks after
initiation of a new drug
• Fixed drug eruption (FDE)
• Maculopapular exanthem
• Contact and photocontact dermatitis
• Severe bullous cutaneous reaction ( TEN, SJS)
• Drug induced hypersensitivity syndrome
• Acute generalized exanthematous granulomatosis( AGEP)

• Salicylic acid is found in an extracted prepared from the bark of white willow trees and has been used for
thousands of years for the relief of fever and pain.
• In 1967, Max Samter, an immunologist in the United States who was unaware of the 1922 French report,
believed that he had discovered this disease and named it “Samter’s Triad” (nasal polyps, asthma, and
sensitivity to aspirin).
N Engl J Med 2018;379:1060-70.
AERD( Aspirin Exacerbation Respiratory Disease)

/NERD (NSAID-exacerbated respiratory disease)
• characterized by eosinophilic rhinosinusitis, asthma and often nasal polyposis.
• Exposure to aspirin or other nonsteroid anti-inflammatory drugs (NSAIDs) exacerbates bronchospasms with
asthma and rhinitis
• persistent and sequential progression of the upper and lower airway inflammation resulting in
rhinosinusitis, asthma and recurrent ethmoidal polyposis.
• Infiltration of eosinophils and mast cells along with TH2 type cytokines in the bronchoalveolar lavage shows
inflammodulatory variation in local cellular abundance at least in airways.
Clinical Biochemistry 46 (2013) 566–578

• caused not by an allergic reaction but by a non-allergic hypersensitivity that produces severe respiratory
symptoms (congested nose, nasal discharge, and asthma attacks) caused by nonsteroidal anti-inflammatory
drugs (NSAIDs), such as aspirin, that inhibit cyclooxygenase (COX), a synthetic enzyme of prostaglandins
(PGs).
Allergology International 68 (2019) 289e295

Prevalence
• AERD is rare among children.
• Ratio of male and female patients is 1:2
• According to a European-wide study, the average age of AERD onset is 35 years
• about 50% of AERD cases appear after a viral respiratory infection.
• Familial AERD has been reported in 1-2% of patients with AERD.
• The type of asthma in AERD is a non-atopic or weakly atopic constitution, and their almost all asthma onset
in AERD is after adolescence.
• However, there are some (~10%) patients whose symptoms are mild and such patients only develop asthma
attacks when they take NSAIDs. The mechanisms of intractable AERD have remained unclear.
Allergology International 68 (2019) 289-295
N Engl J Med 2018;379:1060-70.

• Among the patients in whom AERD develops in the third decade of life, two thirds have a history of atopy
and the other third are free from any allergies.
• In our meta-analysis, the prevalence of AERD was 7.2% in the general population of patients with
asthma, 14.9% among patients with severe asthma, 9.7% among patients with nasal polyps, and 8.7%
among those with chronic sinusitis.
• Furthermore, oral aspirin challenges were positive in 20 to 42% of patients with nasal polyps, asthma, and
chronic rhinosinusitis but no known exposure to COX-1–inhibiting NSAIDs.
Prevalence
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Signs and symptoms
• appears within 1 h from ingestion of NSAIDs, sometimes delayed when slow-releasing tablets or transdermal
patches are used.
• Cutaneous symptoms : Itching, flushing and urticaria facial flushing and conjunctival reddening derived from
histamine overproduction.
• Upper airway symptoms : Nasal congestion, Rhinorrhea, and Sneezing
• Lower airways : laryngospasm, cough, and wheeze.
• Gastrointestinal symptoms : abdominal pain, diarrhea and nausea
• Patients with AERD have severe and often difficult-to-treat CRSwNP leading to chronic nasal congestion,
hyposmia or anosmia, rhinorrhea, and postnasal drip.
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• Nasal symptoms (particularly hyposmia) generally develop several years before the onset of AERD.
• Most patients with AERD are unable to drink alcoholic beverages without having upper- or lower-airway
hypersensitivity reactions; the underlying mechanism is unclear.
Signs and symptoms
N Engl J Med 2018;379:1060-70.

• Peripheral blood eosinophilia is more prominent in patients with moderate-severe AERD than
in those with aspirin-tolerant asthma (ATA).
• 10%-20% of patients with AERD show a hypersensitivity reaction (mainly, coughing) to several
kinds of mint and toothpaste containing them.
• It is considered that the chemical structure of mint is similar to that of salicylates.
• hypersensitivity reaction to colorings (such as tartrazine), additives, and natural salicylates contained in
fruits and vegetables
Signs and symptoms

Pathophysiology
Genetic predisposition
• Several genetic studies on aspirin hypersensitivity have been performed to detect the genetic predisposition
to AERD and to gain insight into the phenotypic diversity. However, familial AERD is rare, and no strong
genetic basis has been observed.

Genetic polymorphism
- HLA DPB1*0301 has been identified as a strong genetic marker for AERD in a Polish and a
Korean population
- HLA DRB1*1302-DQB1*0609-DPB1*0201 haplotype was found to be a marker for aspirin-
induced urticaria in a Korean population

Inhibition of COX-1 deprives inflammatory cells of the internal synthesis of
prostaglandins , particularly the protective PGE2. inhibition of prostaglandins
through increased doses of NSAIDs correlated perfectly with the same drug’s
ability to induce asthma reactions in patients with known AERD.
N Engl J Med 2018;379:1060-70.

Involvement of platelets
• Platelets are considered to be involved in the development of AERD because
• AERD is induced after the administration of 100 mg of aspirin (a small amount of aspirin that mainly
inhibits COX-1 in platelets),
• There is a refractory period of 3-7 days after the administration of aspirin (this refractory period is
specific to AERD and almost corresponds to the lifetime of platelets,
• Patients with AERD are sensitive to COX-1 inhibitors but tolerant to COX-2 inhibitors (among the cells in
the human body, only platelets contain COX-1 alone).
• The group of Laidlaw and Boyce and Mitsui et al. reported the specific activation of platelets as well as the
frequent adhesion with granulocytes and platelets in peripheral blood and the respiratory tract of patients
with AERD.

Involvement of platelet
The activated platelets and adhesion molecules such as P
selectin, lead to the adhesion of platelets and inflammatory
granulocytes or respiratory epithelium. The interaction
between platelets and granulocytes is considered to lead to
the overproduction of CysLT and severe eosinophilic
inflammation.

• The decrease in the production of PGE2 caused by the reduction in COX-2 activity, especially the
attenuation of PGE2 receptor subtype 2 (EP2) stimulation.
• The urinary concentration of leukotriene E4 (LTE4), a stable metabolic product of cysteinyl leukotriene
(CysLT), is 3-5-fold higher in patients with stable AERD than in patients with stable ATA.
• Other typical pathological conditions are an imbalance of eicosanoids and decreases in the production of
the anti-inflammatory mediator, prostaglandin E2 (PGE2) and lipoxin.
Pathophysiology

• LTE4-induced enhancement of airway responsiveness to histamine, an effect not seen with leukotriene C4
(LTC4) and leukotriene D4 (LTD4), suggesting the presence of a unique LTE4 receptor.
• After aspirin desensitization, LTE4-induced bronchospasm is markedly diminished in patients with
AERD, a response that does not occur in patients with aspirin-treated asthma who do not have AERD.
• G protein–coupled receptor 99 (GPR99), a specific LTE4 receptor, might transduce the biologic effects
previously described.
N Engl J Med 2018;379:1060-70.
Pathophysiology

Pathogenesis :
ASA-induced acute respiratory reactions
• Cyclooxygenase hypothesis
• Mediators involved in aspirin-induced respiratory reaction
- release of both mast cell– (tryptase, histamine, PGD2) and eosinophil-specific mediators such as
eosinophil cationic protein (ECP) into nasal fluid, indicating. activation of both types of cells.
- concentrations of a PGD2 metabolite, which is likely derived largely from mast cells, increase in
urine after aspirin challenge, and recent studies suggest that the extent to which PGD2 metabolites increase
may correlate with the clinical severity of the aspirin-induce reactions
- The acute clinical reaction is accompanied by release of cysteinyl leukotrienes into nasal
secretions, sputum, lung fluid, and urine.

N Engl J Med 2018;379:1060-70.

COX ( cyclooxygenase)
• COX-1 is constitutively expressed housekeeping gene product by almost all tissue involved in homeostasis
whereas COX-2 is only expressed in response to certain stimuli such as inflammation, tumorigenesis etc.
although both isoforms have similar active site.
• the substrate binding site of COX-2 is less restrictive to different substrates compared to COX-1.
• This is the result of a larger active site pocket in COX-2 mainly due to an isoleucine to valine substitution.
• COX-2 has also been shown to be more catalytically efficient and exhibits positive cooperativity upon
arachidonic acid binding.
• Both enzymes are functionally inactivated within less than 1 to 2 min when exposed to exogenous
arachidonic acid

• Aspirin mediated irreversible transacetylation of critical serine 530 residue in substrate channel cripples
catalysis of both COX-1 and COX-2 by substrate channel blockage.
• COX-1 is more susceptible to acetylation because of its small substrate binding pocket, allowing aspirin to
be placed around 5A° from serine 530 in its substrate binding site.
• Because of larger substrate binding pocket in COX-2, aspirin cannot reach so close to critical serine 530
thus lowering irreversible transacetylation efficiency of COX-2 10 to 100-fold .
• Majority of AERD subjects tolerate COX-2 inhibitors and none tolerate COX-1 inhibitors which may point
to slightly different pathological mechanisms persisting within AERD at least with respect to COX.
COX ( cyclooxygenase)

• At therapeutic doses, all cyclooxygenase 1 (COX-1) inhibitors, including aspirin, initiate respiratory reactions in
patients with AERD.
• Even low doses of aspirin acetylate COX-1, permanently inhibiting function until new enzyme is generated
(>48 hours).
• All other NSAIDs are competitive inhibitors of the COX-1 enzyme channel, with much shorter blockades of
COX-1 functions (<12 hours). The larger the doses of COX-1–inhibiting NSAIDs, including aspirin, the larger the
ensuing respiratory reactions.
• Specific cyclooxygenase 2 (COX-2) inhibitors do not cause respiratory reactions in patients with AERD.
These larger molecules cannot access the smaller COX-1 channel and can fit only into the wider COX-
2 enzymes as competitive inhibitors.
• Therefore, they cannot interfere with constitutive activity of the COX-1 enzymes in mast cells, basophils,
eosinophils, and platelets, including critical synthesis of PGE2.
N Engl J Med 2018;379:1060-70.
AERD (Aspirin Exacerbation Respiratory Disease)

Pathogenesis: chronic intractable inflammation of the lower
and upper airways
• Inflammatory cells and cytokines
- Tissue eosinophilia and mast cell infiltration are prominent features of the mucosal inflammation
in the upper and lower airways of patients with AERD
- upregulation of several cytokines related to eosinophil activation and survival (e.g., interleukin
[IL]-5, granulocyte-macrophage colony-stimulating factor [GM-CSF], RANTES [regulated on activation normal T
cell expressed], and eotaxinsin the airway mucosa in which overproduction of IL-5 might be a major factor
responsible for increased eosinophil survival, contributing to increased eosinophilic inflammation in patients
with AERD.
- During aspirin-induced reactions, both eosinophils and group 2 innate lymphoid cells (ILC2s)
increase acutely in the nasal mucosa. Levels of activated platelets and platelet-leukocyte aggregates are
also increased in the blood and nasal polyps of patients with AERD compared with aspirin-tolerant
patients.

• Arachidonic acid metabolites
• Prostaglandin E2 deficiency
• local PGE2 generation may contribute to the development of more severe eosinophilic and mast cell–
derived inflammation in ASA-sensitive patients
• reduced expression of COX-2 mRNA in nasal polyps of these patients was inversely correlated with
PGE2 generation and positively correlated with leukotriene production.
• The data with regard to COX expression in the lower airways showed decreased COX-2 mRNA levels
and diminished COX-1 expression in bronchial epithelial cells from patients with AERD.
and upper airways

• Overproduction of leukotrienes
- Basal levels of leukotriene metabolites in the urine of patients with AERD are several-fold higher
than in ASA-tolerant asthmatics
- A greater number of cells expressing leukotriene C4 synthase (LTC4s).
- Leukotrienes LTC4, LTD 4, and LTE4 and overexpression of enzymes involved in the production of
leukotrienes 5-LOX and LTC4 synthase.
- platelet granulocyte aggregates
- On the other hand, in support of a distinct role for leukotriene pathways in patients with AERD, increased
expression of type 1 cysteinyl leukotriene receptor (CysLTR1) was found in the nasal mucosa of these
patients, suggesting local hyperresponsiveness to leukotrienes.
and upper airways

• 15-lipoxygenase pathways
• decreased production of lipoxin A4 and upregulation of 15-lipoxygenase were noted in nasal polyp
tissue from patients with AERD, pointing to a distinct, but not yet understood, role for 15-LO
metabolites in this clinical entity.
• Environmental triggers
• Putative viral factors have been proposed as both primary triggers of ASA hypersensitivity and a cause
of the underlying chronic inflammation in the airways of patients with AERD. This hypothesis is
supported by the observation that human rhinovirus mRNA transcripts were detected in bronchial
epithelial cells from 100% of patients with AERD but only 73% of ASA-tolerant patients with well-
controlled asthma.
• A role for a specific immune response to Staphylococcus enterotoxin in perpetuating chronic
eosinophilic inflammation in the airways of patients with AERD also has been suggested
and upper airways

Pathophysiology
PTGS1
PTGS2

History taking
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Diagnosis
• Physician-observed graded-dose aspirin challenges are standard for diagnosis of AERD.
• If challenges are done after a sinus surgery with debulking of nasal polyp tissue, patients may not exhibit the
typical upper and lower respiratory symptoms, and the diagnosis could be missed.
Ann Allergy Asthma Immunol 131 (2023) 317−324

Diagnosis of NERD
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Diagnosis
• Hypersensitivity to aspirin is caused by the mechanism of a non- allergic reaction. Therefore, general
allergy tests (skin examination and blood tests) are not used to diagnose AERD.
• A drug lymphocyte stimulation test (DLST) using peripheral blood is also not helpful in diagnosis.
• AERD is basically diagnosed by a medical interview and aspirin challenge test.
1) History of the use of NSAIDs and any adverse events related to their use: the history of
the use of NSAIDs before the onset of asthma should not be taken into consideration because
patients develop hypersensitivity to NSAIDs after the onset of asthma.
2) Presence of hyposmia: nasal polyps tend to develop in the vicinity of the ethmoid sinus in
patients with AERD. Therefore, they tend to complain of hyposmia (~90% of patients) from an
early stage of AERD, which can be transiently recovered by the administration of systemic
steroids.
3) Histories of nasal polyps and rhinosinusitis and surgical history

Diagnosis
• Challenge tests
- There are four types of aspirin-provocation tests: oral, inhalation (bronchial), nasal, and intravenous.
- Asthma should be stable, and baseline FEV1 should be at least 70% of the predicted value.

Indication for ASA challenge test
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Drug withdrawal in ASA challenge
Allergy 2007: 62: 1111–1118

Oral challenge test
• Controlled oral challenge with aspirin is regarded as the gold standard, a definitive means by which aspirin
sensitivity can be determine
• FEV1 is measured before each aspirin dose and every 30 to 90 minutes thereafter.
• Positive reaction: The challenge is interrupted if FEV1 falls to 20% of baseline or lower.
• Negative reaction : if the maximum cumulative dose of aspirin (500 to 600 mg) is reached without a fall in
FEV1 of 15% or greater and in the absence of nasoocular symptoms
• The test result also can be regarded as positive on appearance of unequivocal extrabronchial symptoms
(e.g., severe nasal congestion, pronounced rhinorrhea).
Diagnosis

• Oral challenge is preferred for investigation of extrapulmonary or systemic symptoms of aspirin
hypersensitivity.
• The threshold dose of aspirin that provokes a 15% FEV1 fall varies among patients and depends also on
level of asthma control. In rare cases, hypersensitivity to aspirin and NSAIDs may remit over time.
Diagnosis

• During inhalational (bronchial) challenge, increasing doses of lysine aspirin (soluble synthetic aspirin analog,
available in Europe and Asia) are administered.
• Inhalation challenge involves administration of increasing doses of lysine aspirin using a dosimeter-controlled
nebulizer every 30 minutes, with FEV1 measurement every 10 minutes after each ASA administration.
• The criteria for a positive response are the same as for oral aspirin challenge (greater than 20% fall of
FEV1 from the baseline value), and a dose-response curve is constructed to calculate the provocative
concentration causing 20% fall in FEV1 (PC20).
• In cases of a positive reaction, symptoms are relieved by inhalation of 2 to 4 puffs of a short-acting β2-
agonist or by nebulization of a similar agent until FEV1 returns to the baseline value. If more severe reactions
occur, oral or intravenous corticosteroids are administered.
Diagnosis : Bronchial challenge test

Allergy 2007: 62: 1111–1118
Diagnosis : Bronchial challenge test

• . Evaluation of the response following nasal instillation of 16 mg of acetylsalicylic acid (a lysine-aspirin
solution) is based on symptom scores and/or rhinomanometry and/or acoustic rhinometry or peak nasal
inspiratory flow (PNIF).
• In a newer diagnostic test, ketorolac solution (2.26 mg of ketorolac per spray) is delivered as a nasal
spray in increasing doses every 30 minutes. This test offers an alternative to the lysine-aspirin nasal
challenge used in Europe. Unlike the oral challenge, the nasal test is very safe and rarely produces systemic
reactions.
• Patients with septal perforation or important nasal blockade secondary to nasal polyposis are not suitable
candidates for nasal provocation testing or rhinomanometry.
Diagnosis: Nasal aspirin challenge

• Intravenous tests with lysine-aspirin, with administration of increasing doses of aspirin every 30 minutes
(12.5, 25, 50, 100, 200 mg), are also an option in countries where this aspirin formulation is available.
Diagnosis: Intravenous aspirin challenge

In vitro diagnostic tests
• Several in vitro tests for confirming aspirin hypersensitivity in patients with AERD have been proposed, but
none is recommended at this time for routine diagnosis.
• The basophil activation test, which uses measurement of CD63 expression on in vitro challenge, has been
proposed for in vitro AERD diagnosis. Its reported specificity and sensitivity vary, however, and no firm
conclusions on the reliability of this test in the routine setting have been reached.
• The measurement of aspirin-triggered 15-HETE release from peripheral blood leukocytes has also been
proposed, but its clinical utility must first be confirmed by larger studies.

Treatment
• AERD is treated medically in a stepwise fashion according to established guidelines for the management
of asthma and chronic sinusitis.
• Management usually progresses through the use of controller inhaler medications and leukotriene- modifier
drugs, with the possible use of biologic agents as indicated for asthma.
• The upper aiways are similarly treated with topical glucocorticoids, and if this treatment fails, it is necessary
to add antihistamines, leukotriene modifiers, and systemic glucocorticoids.
• Zileuton, an inhibitor of 5-lipoxygenase, merits attention, since it partially blocks the formation of all
cysteinyl leukotrienes, including LTE4, and has proved to be effective in the treatment of AERD.
• LTE4 would not be markedly affected by the CysLT1 receptor antagonists montelukast, zafirlukast, and pran-
lukast.
• The only unique treatment for AERD that is currently available is aspirin desensitization.
N Engl J Med 2018;379:1060-70.

• Aspirin desensitization seems to actually increase levels of type 2 inflammatory biomarkers, including cysLTs.
• It has been hypothesized that the increase in cysLTs induced by aspirin desensitization may ultimately
decrease mast cell-derived PGD , a potent proinflammatory mediator in AERD.
• ATAD significantly improves
• nasal symptoms and sinonasal outcome test (SNOT)-20 scores
• lessens the need for intranasal and systemic corticosteroids
• mitigates the rate of nasal polyp relapse after sinus surgery.
• improves asthma control questionnaire (ACQ) scores
• significantly increases forced expiratory volume in 1 second (FEV1)
• improves health-related quality of life,.
Aspirin desensitization
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Indication for ASA desensitization
Curr Treat Options Allergy (2015) 2:124–140

Indications for treatment with ATAD in
NERD patients
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• starting at low oral doses of aspirin (approximately 40.5 mg) and gradually increasing the dose over a period
of 1 to 3 days, during which drug-induced reactions become milder and shorter and then disappear. When
the target dose of 325 mg is achieved, any additional doses of aspirin or other COX-1–inhibiting NSAIDs do
not induce hypersensitivity reaction
• a typical target dose of aspirin 325 mg daily to 650 mg by mouth twice daily.
N Engl J Med 2018;379:1060-70.

ASA desensitization
• Target dose
- Control the nasal symptoms, a subsequent decrease to 325 mg twice daily after 1 to 6 months can be tried.
- 81 mg once per day for cardiovascular disease prevention
- 325 mg once per day to maintain cross-desensitization to any dose of all NSAIDs,
- 650 mg twice daily as a starting dose for desensitization and treatment of patients with AERD who are using
the aspirin as a treatment for their respiratory disease.
- Tolerance will disappear after 2 to 5 days without aspirin intake.

• Aspirin can be discontinued for 48 hours without loss of desensitization.
• after desensitization and daily treatment with aspirin, the mean interval for sinus revision surgery was 9 years.
• Two complications of long-term aspirin desensitization treatment.
• The first is gastric pain or ulcer caused by diminished synthesis of gastric prostaglandin (PGI2) formation and inadequate
repopulation of gastric mucosal cells (occurring in <15% of patients).
• The second complication is bleeding, usually in the skin (ecchymosis) but occasionally in the nose, bronchi, bladder, or
gastrointestinal tract
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N Engl J Med 2018;379:1060-70.

Leukotrienes inhibitors
• Montelukast, pranlukast, and zafirlukas and 5-lipoxygenase (5-LO) inhibitors (zileuton). Leukotriene
inhibition has been repeatedly found to mitigate the severity of respiratory reactions experienced during
aspirin challenge and desensitization.
• Improve asthma control, asthma-specific quality of life, and FEV1, independent of baseline urinary LTE4
levels. Montelukast was also found to improve nasal function and nasal symptom scores in AERD.
• Similarly, the addition of the 5-LO inhibitor zileuton to existing therapy (either inhaled or oral glucocorticoids)
in AERD produced greater control of asthma symptoms, diminished nasal dysfunction, and inhibited aspirin-
induced bronchoconstriction.
• Subgroup analysis of the phase 3 studies for zileuton in asthma revealed that patients with aspirin-
sensitive asthma had significantly greater improvements in pulmonary function after zileuton
treatment, compared with aspirin-tolerant subjects, underscoring the unique role of leukotriene
dysregulation in AERD pathogenesis. Smaller retrospective studies also suggest that zileuton use in AERD may
reduce the number of sinus surgeries required for management

Management of Asthmatic symptoms
• Zileuton ; 6-week treatment with zileuton in 40 patients. Zileuton treatment led to improved pulmonary
function, lower use of rescue bronchodilators, and a remarkable return of the patient’s sense of smell.
• Monteluklast ; Montelukast (10 mg taken once daily for 4 weeks) in a randomized, double-blind, placebo-
controlled study improved asthma control and pulmonary function (10.2% increase in FEV1) in 80 patients.

Biologic therapy

Biologic therapy: Omalizumab
- Humanized IgG1k monoclonal antibody targeting free IgE that is currently approved in the United States and
Europe for the treatment of severe asthma, CRSwNP, and chronic spontaneous urticaria.
- Omalizumab treatment in AERD significantly reduces urinary LTE4 and the stable urinary PGD2 metabolite
(PGD- M) concentrations.
- also been found to blunt aspirin-induced respiratory reactions during aspirin desensitization
- Reduce the number of asthma exacerbations and hospitalizations, reduce daily inhaled and systemic
corticosteroid doses, and improve patient-reported asthma symptom scores.
- Efficacy and safety of omalizumab in nasal polyposis were evaluated in the POLYP1 and POLYP2 studies,
replicate phase 3, randomized, double-blind placebo-controlled studies. Patients with AERD represented
27.2% of study participants. In these studies, omalizumab therapy significantly improved mean daily
nasal congestion score (NCS) and nasal polyp score (NPS) in 24 weeks, in addition to improvements in
the SNOT-22 score, University of Pennsylvania Smell Identification Test (UPSIT) score, and total nasal
symptom score (TNSS) Ann Allergy Asthma Immunol 131 (2023) 317−324

Biologic therapy : Mepolizumab
• Humanized monoclonal antibodies targeting the IL-5 pathway, a key cytokine promoting respiratory tract
eosinophilia in AERD. Mepolizumab targets IL-5 directly,
• Mepolizumab is approved in the United States and Europe for the treatment of both severe asthma and
nasal polyps. A higher dose of mepolizumab is approved for treatment of hypereosinophilic syndrome and
eosinophilic granulomatosis with polyangiitis.
• Mepolizumab treatment in AERD has been found to mitigate IL-5−mediated signaling on multiple
immune cells (including mast cells, eosinophils, and epithelial cells), leading to significant decreases in
peripheral blood eosinophilia, urinary tetranor PGD2, and urinary LTE4 concentrations.
• a significant improvement in nasal congestion, anosmia, and asthma control.
• reduced polyp size and nasal obstruction in patients with AERD. Notably, however, mepolizumab treatment
was not found to improve sense of smell as assessed by UPSIT.

• Benralizumab is an IL-5Ra antagonist.
• Benralizumab is currently approved for the treatment of severe eosinophilic asthma, and phase 3
studies of benralizumab for treatment of CRSwNP are ongoing (NCT04157335).
• The efficacy and safety of benralizumab for the treatment of CRSwNP were evaluated in the OSTRO
study, a phase 3, randomized controlled trial in which 30% of patients in the intervention arm and
29.1% of patients in the placebo arm had AERD.
• Reduce NPS and nasal blockage score among patients with severe CRSwNP; subgroup analysis
revealed similar improvements in NPS and nasal blockage score among those patients with AERD.
• ANDHI substudy analysis also revealed that benralizumab significantly reduced annualized asthma
exacerbation rate, in addition to improving ACQ-6 scores.
Biologic therapy : Benralizumab

Dupilumab
• Fully human monoclonal antibody targeting the alpha subunit of the IL-4 receptor.
• the treatment of severe asthma and CRSwNP, including eosinophilic esophagitis, atopic dermatitis, and
prurigo nodularis.
• Decreases levels of urinary LTE4 and serum IgE and increases nasal levels of the anti-inflammatory
prostaglandin PGE2, in addition to down-regulating transcripts related to epithelial dysfunction and leu-
kocyte dysfunction in nasal inferior turbinate tissue.
• leading to significant improvements in NPS, SNOT-22 scores, total symptom scores, Lund- McKay CT scores,
and ACQ scores.

Treatment

Treatment
Molecular Biology Reports (2021) 48:2703–
2711

Surgical treatment
• Surgical debulking of nasal polyps and functional endoscopic sinus surgery provide ventilation of the sinuses
and facilitate the delivery of topical medications as well as removal of an inflammatory nidus (eosinophilic
polyps).
• Polyps recur rapidly, it is recommended that aspirin desensitization be performed shortly after sinus
surgery.
N Engl J Med 2018;379:1060-70.

Longterm clinical outcomes
• AERD patients had significantly lower FEV1%,
higher blood neutrophil counts, and higher
sputum eosinophils (%) (all p < .05) as well
as higher levels of urinary LTE4 and serum
periostin, and lower levels of serum
myeloperoxidase and surfactant protein D
(all p < .01) than those with ATA. In a 10-year
follow-up, the severe AERD group maintained
lower FEV1% with more severe AEs than the
nonsevere AERD group.
Clin Exp Allergy. 2023;53:941–950.

Longterm clinical outcomes
Clin Exp Allergy. 2023;53:941–950.

Prevention and management
• Acetaminophen (paracetamol), celecoxib, and codeine usually are safe choices for management of acute
pain in these patients, though acetaminophen may cause mild respiratory reactions at doses of 1000 mg or
more.
• Other medications like azapropazone, choline magnesium trisalicylate, and salsalate, which are very
weak inhibitors of COX-1 and COX-2, should be well tolerated by most patients with AERD.
• Nimesulide and meloxicam generally are well tolerated.

AERD and NSAID hypersensitivity

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