NSAIDs hypersensitivity - AERD

NSAIDs Hypersensitivity:
NERD/AERD
Tharida Khongcharoensombat, MD
Division of Pediatric Allergy and Immunology
Department of Pediatrics, Faculty of Medicine
King Chulalongkorn Memorial Hospital
26 October 2021

Content
• Introduction and overview of NSAIDs hypersensitivity
• Adverse reaction of NSAIDS
• Definition and classification
• Underlying mechanism
• AERD
• Epidemiology
• Pathogenesis
• Clinical features
• Diagnosis
• Treatment

Introduction
• Salicylic acid is found in an extract prepared
from the bark of white willow trees and has
been used for thousands of years for the relief
of fever and pain.
• In 1897, Felix Hoffmann, a young chemist
employed by Friedrich Bayer and Company,
acetylated salicylic acid to produce
acetylsalicylic acid.
• By 1899, Bayer had patented the drug, named
it “aspirin,” and begun selling it around the
world
• In 1922, a case report by Widal et al., (French)
that respiratory disease exacerbated by
aspirin was first described.
White AA, Stevenson DD. Aspirin-Exacerbated Respiratory Disease. N Engl J Med. 2018 Sep

• In 1968, Samter and Beers defining an “aspirin triad”/ “Samter’s
Triad” now referred to as aspirin-exacerbated respiratory disease
(AERD).
• Nasal polyps, asthma, and sensitivity to aspirin
• Although AERD is the preferred term in the United States and other
countries around the world, many parts of Europe and the Middle
East prefer NSAID-exacerbated respiratory disease.
• Various forms of NSAID hypersensitivity may affect 1% to 2% of the
general population, and in a recent large survey study, which
included 65,000 respondents in 15 European countries, the mean
prevalence of NSAID-induced dyspnea was 1.9% (varying from
0.9% to 4.8% among countries)
Introduction
Hae-Sim Park, et al., Middleton’s 9th edition, chapter 78
White AA, Stevenson DD. Aspirin-Exacerbated Respiratory Disease. N Engl J Med. 2018 Sep

Adverse reaction to NSAIDs
Type B adverse drug reaction
Mechanisms
• Allergic (immunologically mediated)
• Nonallergic or Non-immunologic
Classified based on
• Time of symptom onset
• Clinical manifestation
• Number of NSAIDs involved
• The presence/absence of an underlying disease
• A cross-reactivity with other cyclooxygenase (COX)-1 inhibitors
Kowalski ML, et al. Allergy. 2013 Oct;68(10):1219-32.

Classification of NSAIDs
Chemical structure Pharmacological
Kowalski ML, et al. Allergy. 2019 Jan;74(1):28-39
Doña I, et al., Allergy. 2020 Mar;75(3):561-575.

Type B
Type A
Adverse reaction to NSAIDs
Predictable, base on pharmacological mechanism
All individual if a sufficient dose is applied
• Side effect
• Drug interaction
• Overdose
Sensitivity, pseudoallergy, idiosyncrasy, and intolerance
Unpredictable, occurring in susceptible individuals
Pseudo allergy True allergy
Cox-1 inhibitor Immune-mediated
• IgE
• Non IgE
NERD
NSAIDs exacerbate
respiratory disease
NECD
NSAIDs exacerbate
cutaneous disease
NIUD
NSAIDs induced
urticaria-angioedema
SNIUAA
Single NSAIDs induced
urticaria/angioedema or
anaphylaxis
NIDHR
NSAIDs induce delay type
hypersensitivity reaciton
Williams AN.et al. Immunol Allergy Clin North Am. 2016 Nov;36(4):657-668
“ Cross reactivity”

Definition and classification of NSAIDS hypersensitivity
Non-immunologically mediated (cross-reactive) hypersensitivity
reactions to NSAIDs
• NSAIDs-exacerbated respiratory disease (NERD)
• Manifesting primarily as bronchial obstruction, dyspnea, and nasal
congestion/ rhinorrhea, occurring in patients with an underlying
chronic airway respiratory disease (asthma/rhinosinusitis/nasal
polyps).
• Previously used synonyms are as follows: aspirin triad, asthma triad,
Samter’s syndrome, Widal syndrome, aspirin induced asthma or
aspirin-sensitive rhinosinusitis/asthma syndrome, aspirin-intolerant
asthma, and aspirin-exacerbated respiratory disease (AERD).

Non-immunologically mediated (cross-reactive) hypersensitivity
reactions to NSAIDs
• NSAIDs-exacerbated cutaneous disease (NECD)
• Manifesting as wheals and/or angioedema occurring in patients with a
history of chronic spontaneous urticaria.
• Terms previously used to describe this type of reactions are aspirin-induced
urticaria and aspirin-exacerbated cutaneous disease.
• NSAIDs-induced urticaria/angioedema (NIUA)
• Manifesting as wheals and/or angioedema occurring in otherwise healthy
subjects (without history of chronic spontaneous urticaria).
• Symptoms are induced by at least two NSAIDs with different chemical
structure (not belonging to the same chemical group)

Immunologically mediated (cross-reactive) hypersensitivity
reactions to NSAIDs
• Single-NSAID-induced urticaria/angioedema or anaphylaxis
(SNIUAA)
• Manifesting as urticaria, angioedema and/or anaphylaxis.
• Immediate hypersensitivity reactions to a single NSAID or to several NSAIDs
belonging to the same chemical group
• Single-NSAID-induced delayed hypersensitivity reactions
(SNIRD)
• Hypersensitivity reactions to a single NSAID appearing usually within 24-48 h
after drug administration and manifesting by either skin symptoms
[exanthema, fixed drug eruption (FDE)], other organ-specific symptoms
(e.g., renal, pulmonary), or severe cutaneous adverse reactions (SCAR).

Doña I, et al., Allergy. 2020 Mar;75(3):561-575
Hae-Sim Park, et al., Middleton’s 9th edition, chapter 78.
Cross reactivity to
All Cox-1 inhibitor
Cross reactivity to
Similar structure

Yeung WYW, et al. Yonsei Med J. 2020 Jan;61(1):4-14.

Content
• Case presentation
• Introduction and overview of NSAIDs hypersensitivity
• Adverse reaction of NSAIDS
• Definition and classification
• Underlying mechanism
• NSAIDs-exacerbated respiratory disease (NERD)
• Overview
• Epidemiology
• Clinical features
• Pathogenesis
• Diagnosis
• Management

NERD: Overview
• NERD is a chronic eosinophilic inflammatory diseased of unknown etiology in both
the lower and upper airway mucosa.
• Occurring in patients with asthma and/or rhinosinusitis with nasal polyps, which
symptoms are exacerbated by NSAIDs, including aspirin.
• Age onset 30-40 year
• “ASA triad”
• Chronic hyperplastic, eosinophilic-rich rhinosinusitis with nasal polyps
• Moderate to severe bronchial asthma
• Hypersensitivity reactions occurring in response to aspirin and also to other cross-
reacting NSAIDs
• The term aspirin-exacerbated respiratory disease (AERD) has been used to emphasize
the chronicity of the disorder and the fact that the core issue in these patients is not ASA
hypersensitivity but the underlying chronic inflammatory respiratory disease.
Hae-Sim Park, et al., Middleton’s 9th edition, chapter 78.

• Although NERD patients were thought to be nonatopic, increasing evidence
indicates that up to two thirds have a history of atopy.
• In most patients, the first respiratory symptoms after NSAIDs intake appear
during the course of chronic airway disease (asthma and/or chronic
rhinosinusitis) however, they can also manifest before the onset of an evident
respiratory disease, labelling the beginning of the chronic airway disease
• Inflammation tends to be severe and difficult to manage
• Rates of NPs recurrence after surgery higher than in ASA‐tolerant asthmatics
• NERD may be suspected based on clinical history
• Diagnosis: The gold standard is oral acetyl salicylic acid (ASA)‐DPT
NERD: Overview
Doña I, et al., Allergy. 2020 Mar;75(3):561-575

Distinguishing the clinical triad of NERD from other phenotypes of chronic rhinosinusitis with
nasal polyps (CRSNP), asthma, and NSAID reactivity is very important for 2 main reasons
First
• Patients with NERD are at risk of experiencing very distressing and even life threatening
reactions
• In cases of uncertainty regarding tolerance of NSAIDs
• NERD: avoid
• Not NERD: allow when clinically indicated
Second
• There are treatment modalities uniquely beneficial in patients with NERD as compared with
other phenotypes of CRSNP and asthma.
• LRTA and long-term treatment with aspirin following aspirin desensitization can have
significant therapeutic benefit in NERD.
Williams AN.et al, Immunol Allergy Clin North Am. 2016 Nov;36(4):657-668
NERD: Overview

• The overall incidence of AERD among adult asthmatics is 7.2%, severe asthma 14.9%¹
• EAACI position paper²: Prevalence varies from 1.8-44% depend on population, method
of the diagnosis
• The prevalence of NERD increases with the severity of the underlying airway
disease
• 14.9% among patients with severe asthma
• up to 24% in patients admitted to the intensive care unit (ICU) with an asthma
exacerbation
• In children with asthma, the prevalence of ASA hypersensitivity is lower than in
adults
• Approximating 1% to 3% when determined by history alone
• Close to 5% in asthmatic children subjected to oral provocation
• Women : Men = 3 : 2
NERD: Epidemiology
1.Rajan JP, et al: J Allergy Clin Immunol 2015;135(3):676–81.e1.
2. Kowalski ML, et al. Allergy. 2019 Jan;74(1):28-39.

Risk factors associated with higher prevalence of aspirin and other
NSAIDS hypersensitivity
• Presence of
• chronic rhinosinusitis with nasal polyps
• Severe asthma
• Female gender
• History of autoimmune diseases
• Prior history of hypersensitivity reactions to other drugs
Risk factor of NERD
• Family history of NERD
• Present of CRSwNP and/or Asthma
• Presence of atopy
NERD: Risk factor
Kowalski ML, et al. Allergy. 2013 Oct;68(10):1219-32
Blumenthal KG, et al. J Allergy Clin Immunol Pract 2017;5:737-43.

• In a study with 59 AERD patients: 83% reported respiratory
reactions shortly after the ingestion of alcohol.
• Other worsening factors have been described in patients with
AERD like the use of toothpaste (27%), as well as spearmint
or peppermint flavored chewing gum, cow's milk (30%), and
a salicylate rich diet
NERD: Risk factor
Rodríguez-Jiménez JC, et al. Respiratory Medicine 2018;135:62–75.

Makowska J, et al., Current Allergy and Asthma Reports 2015;15(8).
NERD: Clinical Characteristic

Acute reaction to NSAIDs
• The reaction typically manifested by upper and/or lower airway symptoms, which develop
within 30‐180 min after NSAIDs intake
• Usually starts with nasal congestion and/or rhinorrhea, followed by wheezing,
coughing, and shortness of breath.
• May be accompanied by extra bronchial symptoms including nasal (rhinorrhea, nasal
congestion), ocular, cutaneous (flushing of the upper thorax, urticaria and/or
angioedema), or gastric symptoms
• Both the onset and severity of the reaction are dose‐related and the lowest dose
provoking a reaction (threshold dose) for individual patients varies between 10 and 300
mg, but 60 mg of ASA would induce symptoms in a majority of patients.
• Exacerbations are related to the dose and COX‐1 inhibition potency
• With weak COX‐1 inhibitors inducing milder respiratory symptoms
• Specific COX‐2 inhibitors rarely causing exacerbations
NERD: Clinical features
Kowalski ML, et al. Allergy. 2013 Oct;68(10):1219-32

Natural history of NERD
• NERD may develop along a distinctive timeline characterized by a
natural sequence of symptoms: first, persistent rhinosinusitis,
commonly with polyposis, followed by asthma, and then aspirin
hypersensitivity
• Symptoms of chronic rhinosinusitis and/or asthma usually precede the
development of hypersensitivity to aspirin although in some patients
ASA/NSAIDs intake may precipitate the first asthma attack
• In some, NSAID hypersensitivity may occur prior to the onset of obvious
respiratory disease, marking usually the beginning of asthma/CRSwNP
• Patients continue to suffer from chronic airway symptoms with loss of
smell and asthma and need for repeated sinus surgery

Clinical presentation of asthma
• The majority of NERD patients suffer from moderate to severe asthma.
NERD:
• Risk of uncontrolled asthma: increase 2x
• Risk of severe asthma and asthma attacks: increase by 60%
• Risk of emergency room visits: increase by 80%
• Asthma hospitalization increase by 40%
• The atopic aspirin‐sensitive group experienced impaired quality of life and more
frequent exacerbations
• History of aspirin hypersensitivity is
• A risk factor for severe chronic asthma
• Strongly associated with near fatal asthma
• Fatal outcome of asthma occurs more often than in asthmatics without NERD.

Clinical presentation of chronic rhinosinusitis
• Upper airway disease (CRSwNP) in N‐ERD patients is dominated by symptoms such as
nasal blockage, nasal congestion or stuffiness, facial pain or pressure, and nasal
discharge/postnasal drip
• Upper respiratory symptoms / severity of inflammation is more extensive and
recurrence of nasal polyps after surgery is more frequent in NERD than in
NSAIDs‐tolerant CRSwNP patients
• Investigation
• Rhinoscopy or nasal endoscopy findings of edema/mucosal obstruction, and or nasal
polyps, and/or mucopurulent discharge, primarily from the middle meatus.
• Upper CT scan, which is the gold standard for imaging, N‐ERD patients have a more
severe sinus opacification and extension than CRSwNP patients without NERD
• In children: asthma usually develops first and CRS with/without nasal polyps later.

• The “classic” adverse reaction to aspirin consists of
• Rhinitis symptoms of variable severity, usually accompanied by ocular injection
• Bronchospasm
• Some
• Concurrent pruritic rash of the extremities
• Occasionally gastrointestinal distress (nausea and stomach pain)
• Investigation
• Blood, nasal, and sputum eosinophilia
• Bronchial biopsies reveal eosinophil infiltration, increased numbers of IL-5–
positive cells
• Serum IL-5 levels remain within the normal range
• Some patients have a high serum total IgE level, apparently without concurrent
clinical atopy, increased levels of IgE specific to staphylococcal superantigens

1. Pathogenetic mechanisms of acetylsalicylic
acid/nonsteroidal antiinflammatory drug–induced acute
respiratory reactions.
• Cyclooxygenase hypothesis
2. Pathogenesis of chronic Inflammation in the Airways
• Chronic intractable inflammation of the lower and upper airways, which
is present even in the absence of exposure to NSAIDs and underlies
the chronicity of the disease
3. Other mechanism
• Environmental trigger: human rhinovirus, Staphylococcus enterotoxin
• Genetics: HLA allele DPB1*0301
NERD: Pathogenesis

Inhibit COX-1
• Deprived PGE2
• Activation of inflammatory cells
• Mast cells, basophils, eosinophils,
and potentially platelets
• Activate 5-LOX
• Release of inflammatory mediator
• Cysteinyl leukotrienes, PGD2,
histamine, tryptase
The mechanism underlying this
specific activation of inflammatory cells
is debatable.
• Increased susceptibility of COX‐1 to
inhibition with NSAIDs
• Intrinsic deficiency of PGE2
production by COX‐2, and/or
• Abnormal function of PGE2 receptors

Stevens WW, et al., J Allergy Clin Immunol. 2021 Mar;147(3):827-844

Woo SD, et al. Front Pharmacol. 2020 Jul 28;11:1147.
Acute respiratory reaction
Chronic inflmmation
Epithelial dysfuntion

White AA, Stevenson DD. N Engl J Med. 2018 Sep 13;379(11):1060-1070.

Cyclooxygenase hypothesis
• Strong COX-1 inhibitors precipitate the adverse symptoms in patients with AERD,
whereas weak (e.g., salicylic acid or acetaminophen) and selective COX-2 inhibitors usually
are well tolerated by these patients.
• Decreased PGE2 regulatory capacity that may be exaggerated after COX-1 inhibition
Mediators involved in aspirin-induced respiratory reactions
• ASA-induced reactions are associated with the release of
• Mast cell– (tryptase, histamine, PGD2: Correlate with clinical severity)
• Eosinophil-specific mediators such as eosinophil cationic protein (ECP)
• Mobilization of eosinophil progenitor cells from bone marrow has been reported for up to 20
hours after aspirin bronchial challenge.
• Increase cysteinyl leukotrienes in nasal secretions, sputum, lung fluid, and urine
NERD: Pathogenesis

1. Pathogenetic mechanisms of acetylsalicylic acid/nonsteroidal
antiinflammatory drug–induced acute respiratory reactions.
• Cyclooxygenase hypothesis
2. Pathogenesis of chronic Inflammation in the Airways
• Chronic intractable inflammation of the lower and upper airways, which
is present even in the absence of exposure to NSAIDs and underlies
the chronicity of the disease
3. Other mechanism
• Environmental trigger: human rhinovirus, Staphylococcus enterotoxin
• Genetics: HLA allele DPB1*0301
NERD: Pathogenesis

Inflammatory cell and cytokines
• Tissue eosinophilia and mast cell infiltration are prominent features of
the mucosal inflammation in the upper and lower airways.
• Increased numbers of tissue eosinophils have been linked to a
distinctive profile of cytokine expression, which represents a mixed
Th1/Th2 type of inflammation
• Overproduction of IL-5, GM-CSF, RANTES in airway mucosa
• Increase ILC2, activated platelet in nasal mucosa
NERD: Pathogenesis

Arachidonic acid metabolism abnormalities
Crucial arachidonic acid metabolism abnormalities detected in
patients with NERD include
• Deficient generation of PGE2
• Accompanied by reduced expression of EP2 receptor
• Elevated levels of leukotriene E4 (LTE4)
• Increased expression of leukotriene LT1 receptors in nasal mucosa
• Lower baseline production of lipoxin A4 (LXA4)
PGE2 Cysteinyl leukotrienes
(LTs)
15-lipoxygenase
NERD: Pathogenesis

Viral factors have been proposed as
• Primary triggers of ASA hypersensitivity
• The cause of the underlying chronic inflammation in the airways
• Rhinovirus mRNA transcripts were detected in bronchial epithelial
cells from
• 100% of patients with AERD
• 73% of ASA-tolerant patients with well-controlled asthma.
Staphylococcal enterotoxins (SEAs)
• IgE antibodies to SEAs were more abundant in the nasal polyp
tissue of patients with AERD
• Concentration was correlated with ECP, eotaxin, and IL-5 levels.
NERD: Pathogenesis

Genetic Mechanisms
• The human leukocyte antigen (HLA) allele DPB1*0301 has been identified as a strong
genetic marker for AERD in a Polish and a Korean population
• Lower forced expiratory volume in 1 second (FEV1)
• Very high prevalence of rhinosinusitis with nasal polyps
Genetic polymorphism
1. Leukotriene- and prostanoid-related genes including the lipoxygenase (LOX) pathway and
CysLTR1 and CysLTR2
• G protein–coupled receptor 17 (GPR17)
2. Eosinophil-related genes, including CRTH2 and CCR3
3. COX pathway metabolite receptors, including the E prostanoids 2 and 4 (EP2 and EP4), and
thromboxane A2 receptor (TBXA2R)
NERD: Pathogenesis

• Epigenetic studies have shown that
• Reduction in PGE production is due to hypomethylation of PGE
receptors by SNP
• Overproduction of CysLT is caused by hypermethylation of CysLT
receptor 1 and 2 by SNP.
• SNPs that regulate the number of CpG sites are less frequently seen in
NERD patients compared to aspirin-tolerant asthma patients.
• The complex interplay among SNP, PG, CysLTs, and inflammatory cells
makes NERD patients suffer from more severe type 2 airway
inflammation.
NERD: Pathogenesis
Yeung WYW, Park HS. Yonsei Med J. 2020 Jan;61(1):4-14.

• A clear history of multiple reactions developed within 1‐2 hours
after ingestion of an NSAID manifesting with respiratory
symptoms in a patient with adult‐onset asthma and recurrent
nasal polyposis may be sufficient to diagnose NERD
NERD: Diagnosis

• A clear history of multiple reactions developed within 1‐2 hours
after ingestion of an NSAID manifesting with respiratory
symptoms in a patient with adult‐onset asthma and recurrent
nasal polyposis may be sufficient to diagnose NERD
• Aspirin-provocation tests
• Oral
• Inhalation (bronchial)
• Nasal
• Intravenous
NERD: Diagnosis

Williams AN. et al. Immunol Allergy Clin North Am. 2016 Nov;36(4):657-668.

- RS symptoms may accompanied by skin and GI
Increase probability of
N‐ERD diagnosis
Ask about
-Non‐respiratory
Symptoms
-Check other
potential triggers of
reported reactions
Exclude/confirm
the presence of
-CRS ENT
consultation; sinus
imaging
-Asthma (PFT,
bronchial hyper
reactivity)
Diagnosis of NERD

7b. Challenge negative
• Follow‐up the patient if necessary
• If aspirin challenge is negative, but there is concern that
concomitant medications (leukotriene modifier drugs or
monoclonal antibodies) might have led to a false negative
challenge → consider withholding concomitant
medications and repeat the challenge.
NERD: Diagnosis

• Lack of history of respiratory reactions to NSAIDs in a patient with
asthma and CRS with nasal polyposis does not exclude the presence of
hypersensitivity (Grade 3 C).
• Challenge tests (oral, inhalation, or intranasal) are reliable methods to
confirm hypersensitivity to NSAIDs in a patient with suspected NERD
(Grade 3 C)
• Indications / Contraindications
• In vitro tests that have been proposed to confirm aspirin hypersensitivity
(e.g, sulfidoleukotrienes release assay; 15-HETE generation assay
(ASPITest); or basophil activation test (BAT)) cannot substitute for aspirin
challenges and are not recommended for routine diagnosis (GRADE 3
C).
NERD: Statements and recommendations

• Oral aspirin challenge is considered to be the gold standard for diagnosing
hypersensitivity to NSAIDs, as it mimics natural exposure to the drug (Grade
4 C).
• Inhalation challenge with lysine–aspirin is as sensitive as oral one (Grade 3
C), but safer and faster to perform (Grade 4 C)
• Intranasal aspirin challenge, although less sensitive when compared with
oral (Grade 3 C), is safer, quicker and may be a good diagnostic alternative
for patients in whom oral or Inhaled challenge is contraindicated (Grade 4
D)
• Intranasal: can be used initially to diagnose the most sensitive subjects
safely, leaving the less sensitive ones to be challenged orally (Grade 3 C)
• Intranasal challenge with ketorolac is less sensitive and cannot substitute
for oral aspirin challenge (Grade 3 C)

• Asthma should be stable, and baseline FEV1 should be at
least 70% of the predicted value or more than 1.5 L
• If regular treatment with oral corticosteroids is required, the
dose should not exceed 10 mg prednisolone or equivalent
• Oral aspirin challenges are rarely preceded by placebo
challenges, but a placebo challenge is recommended before
inhalation challenges.
NERD: Challenge test

Medication Duration
Short-acting β2-agonists and ipratropium
bromide
6 hours (8 hours if possible)
Long-acting β2- agonists
Long-acting theophylline
Tiotropium bromide
24 hours (48 hours if possible)
Short-acting antihistamines 3 days
Cromolyn sodium (sodium cromoglycate) 8 hours
Nedocromil sodium 24 hours
Leukotriene modifiers At least 1 week
• Before any challenges, withdrawal of several types of antiasthma drugs
is indicated
NERD: Challenge test

Niżankowska-Mogilnicka E, et al.,EAACI/GA2LEN guideline: aspirin provocation tests for diagnosis of aspirin hypersensitivity. Allergy 2007;62(10):1111–8.

Advantages and limitations of
Aspirin provocation in patients with NERD
Oral
Bronchial
Nasal
Makowska J, et al., Current Allergy and Asthma Reports 2015;15(8).

Oral challenge test
• The oral route mimics natural exposure, and the challenge procedure
does not require special equipment, except simple spirometry.
• Various oral challenge protocols exist.
• Increasing aspirin doses, and doubling the dose administered at each
interval
• Starting with 20 to 40 mg, then 80 to 120 mg, 140 to 200 mg, and
then 300 to 325 mg (for a cumulative dose of 500 to 600 mg)
• 1.5- to 2-hour intervals
• History of a severe hypersensitivity reaction
• The test can be started with only 10 mg aspirin, and the next dose of
20 mg
• 1.5- to 2-hour intervals

• After ASA exposure, FEV1 is measured before each aspirin dose and every 30 to 90 minutes thereafter
• Positive reaction
• FEV1 drop ≥ 20%
• Presence of nasoocular symptoms: rhinorrhea, nasal congestion, sneezing
• Bronchospasm : cough, wheezing, chest tightness, dyspnea • Laryngospasm : stridor, dysphonia

• Several protocols for aspirin challenges can be used.
Oral challenge test

Bronchial challenge test
• Lysine aspirin
• Safer and faster to carry out than the oral test,
less sensitive
• Increasing doses of lysine aspirin using a
dosimeter-controlled nebulizer
• Every 30 minutes
• FEV1 measurement every 10 minutes after
each ASA administration
• Positive reaction
• Symptoms are relieved by inhalation of 2 to
4 puffs of a short-acting β2-agonist until
FEV1 returns to the baseline value.
• If more severe reactions: oral or IV
corticosteroids.

Nasal challenge
• Very safe and rarely produces systemic reactions.
• It is recommended for patients with predominantly nasal symptoms and for those in whom
oral or inhalation tests are contraindicated because of the severity of their asthma.
• Patients with septal perforation or important nasal blockade secondary to nasal polyposis
are not suitable candidates for nasal provocation testing or rhinomanometry
• Lower sensitivity than oral and bronchial challenge
• A Negative result on nasal challenge should be followed, whenever possible, by an oral or
inhalation test.
• Nasal instillation of 16 mg of acetylsalicylic acid (a lysine-aspirin solution)
• Ketorolac solution (2.26 mg of ketorolac per spray) is delivered as a nasal spray in increasing
doses every 30 minutes
• Symptom scores and/or rhinomanometry and/or acoustic rhinometry or peak nasal
inspiratory flow (PNIF) Hae-Sim Park, et al., Middleton’s 9th edition, chapter 78

Intravenous 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

• A retrospective and descriptive study in a hospital.
• January 2012 to December 2017
• Jeju National University Hospital, Jeju, Korea
• Population: patient suspected of having NSAID hypersensitivity
were asked to undergo the provocation.
• Objective: Aspirin IV provocation test were to make a
confirmative diagnosis of NSAID hypersensitivity
Seong GM, et al. Asian Pac J Allergy Immunol. 2020 Jun;38(2):124-128.

Intravenous aspirin challenge

• 43/71: test positive (60.1%)
• In the positives, the reaction
occurred at a mean
cumulative dose of aspirin
of 159.2 mg (±200.0 mg,
range 31.5–841.5 mg)
• For diagnosing NSAID
hypersensitivity
• Sensitivity: 93.5%
• Specificity 100%
• This included no false
positives and 3 false negative
cases with single-NSAID
hypersensitivity, who did not
react to the consecutive aspirin
oral challenge

• Avoidance and alternative analgesics
• Underlying disease
• Desensitization
• Adjunctive treatment
NERD: Management

• Aspirin and COX-1
inhibition
• High dose acetaminophen
(≥ 1000 mg)
• Selective COX-2 inhibit are
well tolerated
• But some (1%) with
unstable asthma may
react
NERD: Avoidance

• Acetaminophen (paracetamol), celecoxib, and codeine usually
are safe choices for management of acute pain in these patients,
• Acetaminophen may cause mild respiratory reactions at doses of 1000 mg or
more.
• > 1000 mg: can induce mild asthmatic reactions in 28%–34% of patients with AERD.
• ≥ 1500 mg: can induce mild asthmatic reactions in 34-40% of patients with AERD.
• Weak COX-1 inhibition
• Nimesulide and meloxicam generally are well tolerated.
• Higher trigger reactions in highly sensitive patients
• Administer the first dose of these drugs in the physician’s office
NERD: Alternative analgesics

Asthma and rhinosinusitis should follow guidelines.
Management of asthmatic symptoms
• Asthma: Often is severe, and high doses of inhaled corticosteroids with the addition
of a long-acting β2-agonist and bursts or daily doses of oral corticosteroids often
are necessary.
• Overexpression of 5‐LO pathways of AA and overproduction of cysteinyl
leukotrienes
• The addition of a LTMD is effective in ameliorating asthma symptoms in N-ERD
patients (Grade 1 A); thus, anti-leukotriene drugs can be considered as add-on
therapy
• Zileuton (5-LO inhibitor) and montelukast, zafirlukast, and pranlukast (CysLT1
receptor inhibitors: have been widely prescribed to control upper and lower airway
symptoms in this disorder
NERD: Management of underlying disease

Management of chronic rhinosinusitis and nasal polyposis
• Aspirin-sensitive eosinophilic nasal polyps and rhinosinusitis is particularly
difficult to treat.
• Standard treatment aims to reduce nasal inflammation and retard the
formation of nasal polyps.
Medication
• Saline irrigation
• Maximal doses of intranasal steroids is often needed.
• Antibiotics
• Occasional bursts of oral steroids
• Short courses of oral steroids are necessary when maximal doses of
intranasal corticosteroids are not able to control CRS severity

Management of chronic rhinosinusitis and nasal polyposis
Medication (continue)
• Nasal and oral decongestants and antihistamine
• LTRA
• Moderate effects in relieving nasal symptoms and nasal polyps size in
some N-ERD patients
• Macrolides (for 3 months) show a moderate effect on QoL (but not
symptoms) in patients with CRSsNP.
• There is no separate evidence for a course of macrolides to be
recommended in severe cases of CRSwNP in N-ERD.

• Biologics
• Anti-IgE (omalizumab) seems to be effective in improving asthma control in NERD
patients with severe asthma./ Relieving nasal symptoms but without evidence of
preventing polyp recurrence after surgery
• Mepolizumab was shown recently to be effective in nasal polyposis with co‐morbid
asthma in a trial in which NERD subjects were included.
• Mepolizumab and dupilumab are effective for the treatment of eosinophilic
CRSwNP, typical of NERD patients.
• Surgical procedures (polypectomy, or functional endoscopic sinus surgery)
• In NERD patients, endoscopic sinus surgery improves nasal symptoms quality of life
nasal endoscopy, and CT scores
• Patient with AERD often develop rapid regrowth of polyps following surgery
• Ocular complications are more likely in N-ERD nasal polypectomy.
• Follow-up and medications, including nasal and oral corticosteroids, are
recommended after surgery.
• Alcohol avoidance should be advised to NERD patients.
NERD: Adjunctive

Woo SD, et al. Front Pharmacol. 2020 Jul 28;11:1147

• Indication for aspirin desensitization
• AERD who require aspirin (eg, cardiovascular disease).
• Poorly controlled AERD despite use of appropriate medications or
patients who require long-term treatment with systemic corticosteroids
to control their respiratory disease
NERD: Aspirin desensitization: When?
Drug allergy: practice parameter 2010 Annals of allergy, asthma & Immunology

• ATAD is associated with
• Decrease in CRS symptoms
• Decrease in intranasal corticosteroid use
• Reduction in recurrence of nasal polyps
• Decrease in the need for revision surgery
• Decrease asthma symptoms and improved
asthma control
• The overall effect of ATAD on asthma seems to
be less favorable as compared to the effect on
the course of CRS
• Effective oral maintenance dose of aspirin:
300 to 1300 mg
• Intranasal with lysin-aspirin: 75 mg/day
• Adverse effects (mostly gastrointestinal):
0% to 34%.

Kowalski ML, et al. Immunol Allergy Clin North Am. 2016 Nov;36(4):705-717.

• The mechanism of action of aspirin desensitization has not
been fully elucidated.
• During an aspirin desensitization/high dose aspirin therapy
• Bronchial response to inhaled LTE4 ↓
• Urinary levels of PGD2 ↑ but later ↓
• Urinary levels of CysLTs ↔
• Urinary levels of LTE4 ↓
• Expression of the CysLT receptor 1 (CysLTR1) ↓
• Internalization of CysLTR1
NERD: Mechanism of aspirin desensitization

• After an acute reaction, the refractory period develops and lasts 2 to 5
days.
• Continuing administration of aspirin each day during the refractory
period and thereafter for many weeks, months, or years Tolerance
• Administering increasing doses until a reaction occurs (Same protocol
used for oral aspirin challenges), and then slowly increasing the dose,
most commonly to 650 to 1300 mg daily
• If this daily aspirin dose is helping to control the nasal symptoms, a
subsequent decrease to 325 mg twice daily after 1 to 6 months can
be tried
• Several desensitization protocols that allow for completing the
procedure within 1 to 5 days have been published.
NERD: Aspirin desensitization: How?

Aspirin challenge/Desensitization protocol

• The ASA target dose differs according to the diseases underlying the
aspirin sensitivity.
• Recommended doses are as follows:
• 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
• Once thus desensitized, the patient can take aspirin on a daily basis
indefinitely, but tolerance will disappear after 2 to 5 days without
aspirin intake.
NERD: Aspirin desensitization

• Treatment with daily high-dose (325 to 1300 mg per day) aspirin has
shown to provide
• Improvement sense of smell
• Significant reduction in
• Both upper and lower airway symptoms
• Purulent sinus infections
• The need for further polyp surgery, hospitalizations, and the
requirement for systemic corticosteroids
• During the state of desensitization to aspirin, both aspirin and most
strong NSAIDs are tolerated, so desensitization and NSAID maintenance
can also be used for treatment of rheumatic diseases or chronic pain
syndromes
NERD: Aspirin desensitization
Once patients are desensitized, universal cross reactivity with all NSAIDs is achieved.

NSAIDs hypersensitivity - AERD

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