REVIEW

CURRENT
OPINION Aspirin-exacerbated respiratory disease: an update
Duy Le Pham a,b,c, Ji-Ho Lee a, and Hae-Sim Park a,b

Purpose of review
The pathophysiology of aspirin-exacerbated respiratory disease (AERD) is not fully understood and
diagnostic methods and so far, treatments for AERD have not been standardized. We summarize recent
research into the pathological mechanisms of AERD, diagnostic methods, and treatments for AERD patients.
Recent findings
In AERD pathophysiology, not only the reduced expression of E prostanoid 2 but also the dysfunction of its
pathway could be involved. Moreover, eosinophils of AERD patients could be directly activated by aspirin
to produce prostaglandin D2. Platelet activations are well known to be involved in AERD; however, plasma
markers do not change during aspirin challenge tests. Additionally, novel genetic polymorphisms, such as
P2RY12 and dipeptidyl peptidase 10 gene, and epigenetic predispositions of AERD were found. In AERD
diagnosis, bronchial and nasal aspirin challenges have been applied in addition to oral challenge. Serum
periostin has been suggested as a potential biomarker for AERD. Apart from standard pharmacological
treatment and aspirin desensitization, biologics, including omalizumab and mepolizumab, as well as
CRTH2 antagonists have been suggested as promising therapies for AERD treatment.
Summary
AERD is usually associated with severe asthma phenotypes. AERD pathophysiology mainly involves the
dysregulation of eicosanoid metabolisms, activations of effector cells, which could be influenced by
genetic/epigenetic factors. Understanding the pathophysiology of AERD is key to improve the diagnostic
methods and proper management of AERD patients.
Keywords
aspirin-exacerbated respiratory disease, asthma, diagnosis, pathophysiology, treatment

INTRODUCTION based on aspirin challenges; however, biomarkers

Aspirin-exacerbated respiratory disease (AERD) is a
major clinical phenotype of NSAID hypersensitivity
that involves upper and lower airway mucosa [1 ].
&&
Several studies demonstrated that AERD affects
7–20% of asthmatic patients [2,3]. AERD is charac-
terized by Samter’s triad that includes asthma,
chronic rhinosinusitis, and nasal polyps, which
are exacerbated upon ingestion of cyclooxygenase
(COX)-1 inhibitors such as aspirin and nonselective
NSAIDs [4]. Patients with AERD typically have a
higher prevalence of severe asthma phenotype with
a requirement for high-dose corticosteroids com-
pared with those with aspirin-tolerant asthma
(ATA) [5]. Although the pathogenic mechanisms
of AERD are not fully understood, numerous studies
provided insight into AERD pathophysiology,
which includes dysregulated eicosanoid metab-
olism, activated effector cells such as eosinophils,
mast cells, and platelets. In addition, various genetic
predispositions in AERD have also been found and
offer information for personalized management of
AERD patients. Presently, AERD diagnosis is mainly
for increased diagnostic and prognostic values have
also been investigated. The safety and effectiveness
of aspirin desensitization in AERD patients have
also been investigated providing promising
methods for the management of refractory AERD.
Furthermore, some existing and novel biologics may
offer promising treatment options for AERD. This
review summarizes recent insights into the patho-
physiology, diagnostic methods, and advances in
AERD management.
a
Department of Allergy and Clinical Immunology, Ajou University School
of Medicine, bDepartment of Biomedical Sciences, Ajou University
School of Medicine, Suwon, South Korea and cFaculty of Medicine,
University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam
Correspondence to Hae-Sim Park, MD, PhD, Department of Allergy and
Clinical Immunology, Ajou University School of Medicine, Worldcup-ro
164, Youngtong-gu, Suwon-si 443-380, South Korea. Tel: +82 31 219
5150; fax: +82 31 219 5154; e-mail: hspark@ajou.ac.kr
Curr Opin Pulm Med 2017, 23:89–96
DOI:10.1097/MCP.0000000000000328

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Asthma
KEY POINTS
 AERD pathophysiology mainly involves dysregulation of
the eicosanoid metabolism, where not only reduced
expression of EP2 but also the dysfunction of its
pathway may be involved.
 Novel AERD-associated genetic (e.g., P2RY12, DPP10)
and epigenetic polymorphisms have been found.
 AERD diagnosis can be established with aspirin
challenges via oral, bronchial, or nasal routes; in
addition, biomarkers such as eosinophilia, serum
periostin, LTE4 in EBC, and BAT are
potential candidates.
 Biologics including antibodies against IgE
(omalizumab) and IL-5 (mepolizumab) as well as
CRTH2 antagonists may offer potential in future
treatment of AERD.
PATHOPHYSIOLOGY OF ASPIRIN-
EXACERBATED RESPIRATORY DISEASE
Dysregulated eicosanoid metabolism
The most well known underlying pathomechanism
of AERD is the dysregulation of arachidonic acid
metabolism [6]. COX inhibitors that shift arachi-
donic acid metabolism from COX to 5-lipoxygenase
(5-LO) pathway are known to increase the pro-
duction of cysteinyl leukotrienes (CysLTs), produc-
ing bronchoconstriction and airway inflammation
&
[7,8 ]. However, this cannot fully explain why COX
inhibitors do not induce symptoms in ATA despite
similar acting mechanisms. Recent evidence
suggests different expression levels of metabolic
enzymes and eicosanoids in the two arachidonic
acid metabolism pathways between AERD and
ATA patients [4].
In COX pathway, arachidonic acid is converted
into prostaglandins (PG) E2, PGF2, PGI2, and PGD2
by corresponding prostaglandin synthases or into
thromboxane (TBX) A2 by TBX synthase. Among the
prostaglandins, PGD2 can induce bronchoconstric-
tion, vasodilation and recruit eosinophils, baso-
phils, and T-helper cells by interaction with its
receptor D prostanoid 2 or the G-protein-coupled
chemokine receptor homologous molecule
expressed on Th2 lymphocytes (CRTH2). AERD
patients had an elevated PGD2 generation that fur-
ther increased in a subgroup of AERD patients intol-
erant to high-dose aspirin desensitization but
decreased in the tolerant subgroup [9,10]. In con-
trast, PGE2 has a protective effect against broncho-
constriction, allergic inflammation, mast cell
degranulation, and eosinophil recruitment when
binding to its receptor, termed E prostanoid 2
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(EP2) [11–13]. Lower PGE2 expressions in peripheral
blood leukocytes, nasal epithelial cells, and nasal
fibroblasts (NF) of AERD compared with ATA
&&
patients were reported [14 ,15]. Additionally,
reduced EP2 expression was observed in nasal polyps
and NF of AERD patients [9,16]. The activation of
EP2 by PGE2 or EP2 agonists induces the accumu-
lation of cyclic AMP (cAMP), which subsequently
activates protein kinase A (PKA) to phosphorylate 5-
LO and prevents the production of CysLTs [17,18 ].
&&
In AERD patients, a lower level of PGE2-induced
cAMP accumulation was noted in NF compared with
control study participants, consistent with the
reduced EP2 expression in those cells [16]. In con-
trast, another study demonstrated comparable
levels of PGE2-induced cAMP accumulation and
EP2 expression in granulocytes of AERD and ATA
&&
patients as well as control study participants [18 ].
The latter study identified PKA dysfunction in gra-
nulocytes as a mechanism of PGE2 resistance found
&&
in AERD patients [18 ]. These findings suggest that
a downregulation of EP2 as well as a malfunction of
its signaling pathway may contribute to AERD
pathogenesis. However, altered PGE2 –EP2 expres-
sion level can vary among cell types and should
be further studied.
Leukotriene (LT) A4, produced from arachidonic
acid via the 5-LO pathway, is unstable and rapidly
converted into LTC4, and subsequently into LTD4
and LTE4. CysLTs bind to CysLT type 1 receptor
(CysLTR1) and/or CysLTR2. CysLTR1 expressions
on inflammatory cells are upregulated in AERD
patients compared with ATA patients [4]. Increased
activity of 5-LO and LTC4 synthase as well as
increased production of LTE4 and other CysLTs in
AERD have also been widely reported [6,15]. LTE4
was found to bind weakly to CysLTR1 and CysLTR2
in vitro and in vivo; however, it could interact with
ADP-reactive purinergic receptor (P2Y12) or G-
protein-coupled receptor 99 [4]. However, a recent
study found that LTE4 can fully activate CysLTR1 on
human mast cells (LAD-2), which may explain its
potent proinflammatory activity observed in asth-
&
matic patients [19 ].
Lipoxins (LX) are produced by 15-LO pathway
and have been found to inhibit CysLTs production
and eosinophilic infiltration into the lung of mice
with pulmonary inflammation [15]. An epimer of
LXA4 (15-epi-LXA4) is also produced by COX-2,
&
which is acetylated in the presence of aspirin [8 ].
Several studies [20–22] demonstrated lower levels of
LXA4 in nasal lavage fluid (NLF) and 15-epi-LXA4
(an epimer of LXA2) in urine of AERD patients
compared with those of ATA patients, suggesting
a protective role of these metabolites in AERD
pathogenesis.
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 Aspirin-exacerbated respiratory disease: an update Le Pham et al.

Cells involved in aspirin-exacerbated CD63, and CD69 on platelets of AERD patients,

respiratory disease
Increased eosinophil infiltration, degranulated mast
cells in tissues, and platelet activation have been
characterized in AERD (Fig. 1). A higher level of
eosinophilic cationic protein (ECP) in NLF as well
as an increased serum level of eosinophil-derived
which correlated with CysLTs overproduction and
persistent airflow limitation. Adherence of platelets
to leukocytes (e.g., eosinophils, neutrophils, and
monocytes) mediated by P-selectin also facilitates
leukocyte adhesion and transmigration into
inflamed airway tissues that contribute to AERD
&&

neurotoxin were also found in AERD patients com-
pared with those with ATA, which supports the
involvement of eosinophil activation in AERD path-
ophysiology [23,24]. Increased IL-5 production was
pathogenesis [15,29,30 ]. However, plasma markers
of platelet activation remained unchanged during
aspirin challenge suggesting that plasma markers do
not reflect platelet activation within the airways
&&

found in nasal polyp tissue of AERD patients induc-
ing eosinophil infiltration and activation [25].
Aspirin has been found to directly induce a higher
production of PGD2 from the eosinophils of AERD
compared with ATA patients and implicates eosino-
phil as another source of PGD2 in AERD apart from
mast cell [26]. Mast cell activation in AERD is evi-
denced by the release of histamine, tryptase, and
PGD2 in NLF. A recent study [7] found an elevated
epithelial IL-33 expression in AERD patients, which
is induced by LTE4 to activate mast cells. The role of
mast cells in AERD has been widely reported; how-
ever, basophil activation levels at baseline and after
aspirin stimulation were not different between
AERD and ATA patients [27,28]. Recent studies
&&
[29,30 ] on the role of platelet activation in AERD
have shown elevated expressions of P-selectin,
[30 ]. Although these findings suggest potential
therapeutic options targeting platelet activation
and their interaction with leukocytes, factors that
enhance platelet activation in AERD remain to
be elucidated.
Genetic mechanisms
Numerous studies have identified genetic single-
nucleotide polymorphisms (SNPs) associated with
&
AERD (Table 1) [8 ]. SNPs in CysLTR1 ( 634 C>T,
475 A>C, 336 A>G) and CysLTR2 ( 189 T>C) are
shown to associate with AERD and could influence
gene transcriptional activity [31–33]. COX-2 765
G>C SNP could also affect gene transcriptional
activity and contribute to PGD2 production in AERD
patients [34]. AERD susceptibility is also associated

Airway epithelial cells

Aspirin
?
Periostin IL-33
IL-5 Omalizumab

IgE
Mepolizumab
Platelet activation
Eosinophil activation Mast cell activation platelet adherent leukocyte

5-LO inhibitor

EDN ECP PGD2 Histamine CysLTs

tryptase

CRTH2
CRTH2 (DP2) CysLTRs LTRA
antagonist
GPR99
P2Y12

FIGURE 1. Cells involved in the pathophysiology of aspirin-exacerbated respiratory disease (AERD) and potential treatments
for AERD. CRTH2, chemokine receptor homologous molecule expressed on Th2 lymphocytes; CysLTs, cysteinyl leukotrienes;
CysLTR, CysLT receptors; DP2, receptor D prostanoid 2; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin;
GPR99, G-protein-coupled receptor 99; IL, interleukin; LO, lipoxygenase; LTRA, leukotriene receptor antagonist; P2Y12, ADP-
reactive purinergic receptor; PGD2, prostaglandin D2.

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Asthma
with the SNPs on TBXA2 receptor gene (TBXA2R
4684 C>T, 795 T>C) [35,36], PGE receptor
(PTGER)2 ( 616 C>G, 166 G>A), PTGER3
( 1709 T>A, rs7543182, rs959), PTGER4 ( 1254
A>G) [37–39]. SNPs on genes involved in acti-
vations of eosinophil [IL-5 receptor a (IL-5Ra
5993G>A)] [40], basophil and mast cell [Fc-epsilon
receptor 1 (FCER1G 237 A>G, FCER1A 344 T>A)]
[41,42], and histamine N-methyltransferase (HNMT
939 A>G)] [43] were also associated with AERD
susceptibility. Genome-wide association studies
&&
with large cohorts of Korean populations [44,45 ]
reported associations of HLA (human leukocyte
antigen)-DPB1 polymorphisms such as rs1042151,
rs3128965 as well as Met105Val, with AERD
susceptibility and implicate HLA-DBP1 as having a
crucial role in AERD development.
Two SNPs on P2Y12 receptor gene (P2RY12 742
T>C and 18 C>T) have been found to be associated
with increased ECP level in NLF and P2Y12 expres-
sion level on platelets of AERD patients [46]. Our
group demonstrated the associations of the
rs17048175 (TT genotype) in dipeptidyl peptidase
10 gene (DPP10) with AERD susceptibility as well as
increased total serum IgE and serum DPP10 levels in
&
asthmatic patients [47 ]. The different DNA meth-
ylation levels of 490 loci found in 437 genes among
AERD and ATA patients also suggest an involvement
of epigenetic factors in AERD pathogenesis [48].
However, these studies need to be replicated and
further investigations are required to assess the
role of genetic/epigenetic factors in the disease
pathomechanism.
DIAGNOSIS OF ASPIRIN-EXACERBATED
RESPIRATORY DISEASE
Thorough history taking is fundamental to diagnose
&&
AERD. Kowalski and Makowska [1 ] suggested a step-
wise approach for a careful history taking and diag-
nostic work-up based on the new classification in the
guidelines. Oral aspirin challenge (OAC) remains the
gold standard for AERD diagnosis; however, other
tests with a reduced risk of adverse reactions and
increased diagnostic yield have been investigated.
They include other routes of aspirin challenge (e.g.,
bronchial or nasal challenge), biomarkers such as
fractional exhaled nitric oxide (FeNO), eosinophilia,
serum periostin, urine LTE4 level, and basophil
activation test (BAT) to diagnose AERD.
Bronchial aspirin challenge (BAC) has become
widespread because of its safety and a shorter
duration compared with OAC. However, BAC may
have a lower sensitivity and cannot replace OAC
when patients only have upper airway symptoms
[49]. A recent study suggested a combination of fall
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in peak expiratory flow within 4–11 h after BAC
(late-phase reaction) and at least 20% fall in forced
expiratory volume in 1 s (FEV1) to yield a sensitivity
of 91% and a specificity of 100% for AERD diagnosis
[50]. Additionally, when extrabronchial symptoms
(cutaneous and nasal symptoms), late-phase reac-
tion, and the fall in FEV1 were taken into account,
the BAC sensitivity reached 94% compared with
80.5% when only using spirometry criteria [50].
Nasal lysine-aspirin challenge is an alternative
method, especially in patients with severe asthma
because it seldom triggers a bronchial response [49].
A recent study [51] indicated 88% of patients had a
positive nasal challenge and 12% of the remaining
patients had positive responses following OAC.
OAC provides sensitivity up to 90% and is pres-
ently the most sensitive diagnostic test for AERD.
The test usually starts with 20–30 mg of aspirin
followed by a gradually increasing dose every 3 h
until a cumulative dose of 1000 mg has been reached
[52]. In a meta-analysis, the mean provocative dose
of aspirin that triggered respiratory symptoms was
85.8 mg, which varied from 61.7 to 197.7 mg accord-
&
ing to different FEV1 thresholds [53 ]. Previously,
FeNO was found to be higher in AERD than in ATA
patients after a BAC, suggesting FeNO as a potential
biomarker for AERD [54]. Recently, a low oral dose
(40 mg) of aspirin challenge in combination with
FeNO has been suggested to distinguish AERD from
&
ATA patients [55 ]. However, clinicians should note
that a small portion of AERD patients could tolerate
&
a low aspirin dose [56 ].
Diagnostic biomarkers are presently under
investigation. As AERD mainly involves eosino-
philic inflammation and the dysregulation of
CysLTs, eosinophilia is a suggestive diagnostic
marker in suspected AERD [57]. Although increased
numbers of activated eosinophils in bronchial biop-
sies of AERD patients were documented [58], some
studies have reported an insignificant difference in
blood and sputum eosinophil counts between AERD
and ATA patients even though the values tended to
be higher in the AERD group [23,59]. In comparison
with ATA patients, AERD patients had a higher
serum periostin level, which is considered a predic-
&&
tor for eosinophilic airway inflammation [60 ,61].
Serum periostin levels in AERD patients were sig-
nificantly higher in patients with severe chronic
rhinosinusitis (CRS) compared with those with less
&&
severe CRS [60 ]. Urinary CysLTs and LTE4 metab-
olites were significantly higher in AERD patients
compared with ATA, which increased further after
an aspirin challenge test and indicated that urine
LTE4 metabolite can be a potential biomarker to
diagnose AERD [59]. However, data of exhaled
breath condensate (EBC) LTE4 levels are inconsistent
Volume 23  Number 1  January 2017
 Aspirin-exacerbated respiratory disease: an update Le Pham et al.

Table 1. Genetic polymorphisms associated with aspirin-exacerbated respiratory disease

Pathway/gene SNP Suggested functions Reference

Eicosanoid metabolism
CYSLTR1 634 C>T, 475 A>C, 336 A>G These SNPs affected gene transcriptional [31–33]
activity
CYSLTR2 189 T>C
COX-2 765 G>C This SNP affected gene transcriptional activity [34]
and PGD2 production
TBXA2R 4684 C>T This SNP affected gene transcriptional activity [35,36]
795 T>C This SNP associated with percentage fall in
FEV1 after aspirin challenge
PTGER2 616 C>G, 166 G>A ND [37]
PTGER3 1709 T>A, rs7543182, rs959 ND [37,38]
PTGER4 1254 A>G This SNP affected gene transcriptional activity [37,39]
Effector cell activations
IL-5RA 5993 G>A This SNP affected gene transcriptional activity [40]
associated with serum level of specific IgE
antibody to SEA and may affect eosinophil
activation
FCER1G 237 A>G This SNP associated with increased total IgE [41]
serum level in AERD patients
FCER1A 344 T>A This SNP associated with serum levels of total [41,42]
IgE and specific IgE to SEA
HNMT 939 A>G This SNP affected HNMT mRNA stability, [43]
protein expression, and enzymatic activity of
HNMT
P2RY12 742 T>C, 18 C>T These SNPs were associated with eosinophil [46]
cationic protein level in nasal secretion and
P2Y12 expression level on platelet
DPP10 rs17048175 The TT genotype could contribute to [47 ]
&

eosinophilic inflammation in AERD

HLA system
HLA-DBP1 rs1042151, rs3128965, Met105Val ND [44,45 ]
&&

AERD, aspirin-exacerbated respiratory disease; COX, cyclooxygenase; CYSLTR, cysteinyl leukotriene receptor; DPP10, dipeptidyl peptidase 10; FCER, Fc-epsilon-
receptor; FEV1, forced expiratory volume in 1 s; HLA, human leukocyte antigen; HNMT, histamine N-methyltransferase; IL-5RA, IL-5 receptor a; ND, no data;
PGD, prostaglandin; PTGER, prostaglandin E receptor; SEA, staphylococcal enterotoxin A; SNP, single-nucleotide polymorphism; TBXA2R, thromboxane A2
receptor.

among studies [52,62]. Following BAC, EBC-LTE4
levels were more increased in AERD patients
but not statistically different from patients with
ATA [62].
The value of BAT in AERD diagnosis has also
been investigated. However, levels of basophil acti-
vation at baseline and after aspirin stimulation
showed inconsistent results yielding a low sensi-
tivity, ranging from 30 to 67% [27,28]. Therefore,
the diagnostic value of BAT and its protocol should
be further studied to apply to AERD diagnosis.
Considering the heterogeneity of AERD, a recent
study has classified 201 AERD patients into four
subphenotypes (latent classes) using an advanced
biostatistical analysis, which includes class 1, mod-
erate asthma with intensive upper airway symptoms
and blood eosinophilia (18.9% of patients); class 2,
mild asthma, relatively controlled with low health-
care use (34.8% of patients); class 3, severe asthma,
poorly controlled with severe exacerbation and air-
way obstruction (41.3% of patients); and class 4,
poorly controlled asthma with frequent and severe
exacerbation in female patients (5.0% of patients)
&&
[63 ]. This novel classification may facilitate the
diagnosis and precision medicine for AERD patients,
although its practical approach needs to be further
investigated in larger cohorts.
ASPIRIN-EXACERBATED RESPIRATORY
DISEASE TREATMENT
Treatment for AERD patients includes pharmaco-
logical therapies and desensitization, and presently
novel treatment options with biologics are being

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Asthma
explored (Fig. 1). Leukotriene modulators, including
leukotriene receptor antagonists (LTRAs) and 5-LO
inhibitors, are widely used in AERD treatment.
Aspirin desensitization may be considered when
patients are refractory to conventional medications
or need aspirin/NSAID maintenance [64]. Further-
more, specific antibodies against IgE (omalizumab)
and IL-5 (mepolizumab), as well as CRTH2
antagonists have shown promising effects in
patients with asthma and/or nasal polyps.
LTRA (e.g., montelukast) and 5-LO inhibitor
(e.g., zileuton) are being prescribed as mono or
add-on therapy to standard treatment based on
the pathogenesis of AERD. Consequently, LTRA is
the most widely used drug in clinics for treatment
&
modality [65 ]. AERD patients treated with an LTRA
or 5-LO inhibitor showed improvement in symp-
toms, lung function, quality of life, exacerbations,
and less bronchodilator use [66,67]. In addition,
LTRA has a protective effect on nasal response
during nasal lysine-aspirin challenge as well as asth-
matic response during OAC in patients with AERD
&&
[68 ]. The therapeutic effects of LTRAs and 5-LO
inhibitors for CRS with nasal polyposis (CRSwNP),
regardless the coexistence of asthma or AERD, were
also established [69].
Aspirin desensitization has shown therapeutic
effectiveness in the treatment of AERD [70]. In a
recent survey with 190 AERD patients, 85 out of 93
patients (91%) who had undergone desensitization
found the therapy to be effective in symptom con-
trol, whereas smaller groups of patients had their
symptoms improved by LTRAs (50%), 5-LO inhibi-
&
tors (52%), or omalizumab (57%) [65 ]. Another
study [71] also reported that AERD patients who
received 624 mg of aspirin once daily for 6 months
showed improvements in nasal symptoms, asthma
control scores, and decreased use of inhaled cortico-
steroids. In addition, desensitization was shown to
significantly improve lung function and sinusitis as
estimated by sinus computed tomography scan [72].
In AERD patients who had nasal polypectomy,
desensitization could improve both nasal symptoms
and nasal polyp scores, as well as the requirement for
& &
recurrent surgery [73 ]. There is no standardized
protocol for aspirin desensitization; however, main-
tenance aspirin dose of 650 mg twice daily for the
first month and a lower dose of 325 mg twice daily,
&&
as symptom controlled, are recommended [68 ].
Omalizumab has been investigated in the treat-
ment of moderate-to-severe allergic asthma [74]. In
a small randomized, double-blind, placebo-con-
trolled study, omalizumab effectively improved
upper and lower airway symptoms, quality of life,
and nasal polyp score in asthma patients; 12 of the
24 study participants in this study were sensitive to
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aspirin [75]. Local IgE in airway tissue was con-
sidered to have a pathogenic role in the disease
[76]. Moreover, several case reports testified of oma-
&
lizumab’s beneficial effects in AERD [64,65 ]. Hence,
omalizumab could be an add-on treatment for AERD
patients with CRSwNP, although more clinical trials
should be conducted.
Mepolizumab had a beneficial effect in a small
randomized double-blind study with 20 patients
with CRSwNP that included five patients with
aspirin intolerance [77]. In total, 60% of patients
who received two single intravenous injections of
mepolizumab (750 mg) with 28-day interval had
improved nasal polyp score and polyp size. More-
over, blood eosinophil count, serum ECP, and serum
IL-5Ra subunit levels also significantly decreased in
the mepolizumab-treated group [77]. A phase 2
clinical trial (NCT01362244) reported the benefit
of mepolizumab in reducing the need for surgery
in patients with severe bilateral nasal polyp, includ-
ing those with aspirin hypersensitivity. Although
the effectiveness and safety of mepolizumab in
AERD has not yet been systematically investigated,
anti-IL-5 antibodies may offer a promising treat-
ment option because of the crucial role of IL-5
and eosinophil in AERD pathophysiology.
Given the role of PGD2 and its receptor CRTH2
in the AERD pathophysiology, CRTH2 antagonists
could be another potential treatment option. A
multiple dose, randomized, double-blind, placebo-
controlled study with approximately 440 asthmatic
patients demonstrated a beneficial effect of the
CRTH2 antagonist (OC000459) on lung function
and incidence of exacerbation in patients with
uncontrolled eosinophilic asthma. Nevertheless,
effectiveness of CRTH2 antagonist in AERD treat-
ment needs to be established [78].
In addition to pharmacological therapies,
dietary factors may also influence AERD control
status. A low-salicylate diet was reported to reduce
AERD symptoms in 24 of 71 (34%) AERD patients in
&
a survey-based study [65 ]. In another prospective,
crossover single-blind multicenter study with 30
AERD patients, a 6-week low-salicylate diet signifi-
cantly improved the disease scores [79 ]. These find-
ings suggest that controlling the diet of AERD
patients could be of additional benefit to the current
management of the disease.
CONCLUSION
AERD is a major manifestation of NSAID hypersen-
sitivity and usually associated with severe asthma
and CRS. The pathophysiology of AERD is compli-
cated and involves dysregulation of the arachidonic
acid metabolism, activated eosinophils, mast cells,
Volume 23  Number 1  January 2017
 Aspirin-exacerbated respiratory disease: an update Le Pham et al.
and platelets with genetic/epigenetic alternations.
Aspirin challenges by different routes such as oral,
bronchial, and nasal challenges are confirmative
methods for AERD diagnosis; in addition, novel
biomarkers for AERD such as serum periostin are
under investigation to increase diagnostic value. In
addition to standard pharmacological treatment
and desensitization, specific antibodies against IgE
(omalizumab) and IL-5 (mepolizumab), as well as
CRTH2 antagonists may offer future treatment
options for AERD.
Acknowledgements
We thank Dr Phap N.H. Tran (Faculty of Public Health,
University of Medicine and Pharmacy, Ho Chi Minh
City, Vietnam) for his technical support.
Financial support and sponsorship
This research was supported by a grant of the Korea
Health Technology R&D Project through the Korea
Health Industry Development Institute (KHIDI), funded
by the Ministry of Health & Welfare, Republic of Korea
(grant number: HI16C0992).
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Kowalski ML, Makowska JS. Seven steps to the diagnosis of NSAIDs
&& hypersensitivity: how to apply a new classification in real practice? Allergy
Asthma Immunol Res 2015; 7:312–320.
The article suggested a stepwise approach to careful history taking and diagnostic
work-up for AERD.
2. Rajan JP, Wineinger NE, Stevenson DD, et al. Prevalence of aspirin-exacer-
bated respiratory disease among asthmatic patients: a meta-analysis of the
literature. J Allergy Clin Immunol 2015; 135:676.e1–681.e1.
3. Choi JH, Kim MA, Park HS. An update on the pathogenesis of the upper
airways in aspirin-exacerbated respiratory disease. Curr Opin Allergy Clin
Immunol 2014; 14:1–6.
4. Steinke JW, Wilson JM. Aspirin-exacerbated respiratory disease: pathophy-
siological insights and clinical advances. J Asthma Allergy 2016; 9:37–43.
5. Mascia K, Haselkorn T, Deniz YM, et al. Aspirin sensitivity and severity of
asthma: evidence for irreversible airway obstruction in patients with severe or
difficult-to-treat asthma. J Allergy Clin Immunol 2005; 116:970–975.
6. Narayanankutty A, Resendiz-Hernandez JM, Falfan-Valencia R, et al. Bio-
chemical pathogenesis of aspirin exacerbated respiratory disease (AERD).
Clin Biochem 2013; 46:566–578.
7. Liu T, Kanaoka Y, Barrett NA, et al. Aspirin-exacerbated respiratory disease
involves a cysteinyl leukotriene-driven IL-33-mediated mast cell activation
pathway. J Immunol 2015; 195:3537–3545.
8. Pham DL, Kim JH, Trinh TH, et al. What we know about nonsteroidal
& anti-inflammatory drug hypersensitivity. Korean J Intern Med 2016;
31:417–432.
This is the most recent review article to summarize the current knowledge
regarding NSAID hypersensitivity.
9. Cahill KN, Bensko JC, Boyce JA, et al. Prostaglandin D2: a dominant mediator
of aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 2015;
135:245–252.
10. Laidlaw TM, Boyce JA. Aspirin-exacerbated respiratory disease: new prime
suspects. N Engl J Med 2016; 374:484–488.
1070-5287 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
11. Feng C, Beller EM, Bagga S, et al. Human mast cells express multiple EP
receptors for prostaglandin E2 that differentially modulate activation
responses. Blood 2006; 107:3243–3250.
12. Sturm EM, Schratl P, Schuligoi R, et al. Prostaglandin E2 inhibits eosinophil
trafficking through E-prostanoid 2 receptors. J Immunol 2008; 181:7273–
7283.
13. Zaslona Z, Okunishi K, Bourdonnay E, et al. Prostaglandin E2 suppresses
allergic sensitization and lung inflammation by targeting the E prostanoid 2
receptor on T cells. J Allergy Clin Immunol 2014; 133:379–387.
14. Cahill KN, Raby BA, Zhou X, et al. Impaired E prostanoid2 expression and
&& resistance to prostaglandin E2 in nasal polyp fibroblasts from subjects with
aspirin-exacerbated respiratory disease. Am J Respir Cell Mol Biol 2016;
54:34–40.
This is the most recent study that reported a reduced expression of EP2 receptor,
under epigenetic control, in fibroblasts isolated from nasal polyps of AERD
patients. This finding supports the role of EP2 signaling pathway in growth of
nasal polyp in AERD.
15. Laidlaw TM, Boyce JA. Pathogenesis of aspirin-exacerbated respiratory
disease and reactions. Immunol Allergy Clin North Am 2013; 33:195–210.
16. Machado-Carvalho L, Torres R, Perez-Gonzalez M, et al. Altered expression
and signalling of EP2 receptor in nasal polyps of AERD patients: role in
inflammation and remodelling. Rhinology 2016; 54:254–265.
17. Flamand N, Surette ME, Picard S, et al. Cyclic AMP-mediated inhibition of 5-
lipoxygenase translocation and leukotriene biosynthesis in human neutrophils.
Mol Pharmacol 2002; 62:250–256.
18. Laidlaw TM, Cutler AJ, Kidder MS, et al. Prostaglandin E2 resistance in
&& granulocytes from patients with aspirin-exacerbated respiratory disease.
J Allergy Clin Immunol 2014; 133:1692–1701.
This is the first study to describe the impaired PKA function in granulocytes of
AERD patients, which leaded to dysregulated control of 5-LO activity by PGE2.
This findings suggest that the malfunction of EP2 signalling pathway could be
involved in PGE2 resistance in AERD.
19. Foster HR, Fuerst E, Branchett W, et al. Leukotriene E4 is a full functional
& agonist for human cysteinyl leukotriene type 1 receptor-dependent gene
expression. Sci Rep 2016; 6:20461.
The study demonstrated that leukotriene E4 fully activates CysLTR1 to induce
related gene expressions.
20. Kupczyk M, Antczak A, Kuprys-Lipinska I, et al. Lipoxin A4 generation is
decreased in aspirin-sensitive patients in lysine-aspirin nasal challenge in vivo
model. Allergy 2009; 64:1746–1752.
21. Yamaguchi H, Higashi N, Mita H, et al. Urinary concentrations of 15-epimer of
lipoxin A4 are lower in patients with aspirin-intolerant compared with aspirin-
tolerant asthma. Clin Exp Allergy 2011; 41:1711–1718.
22. Sanak M, Levy BD, Clish CB, et al. Aspirin-tolerant asthmatics generate more
lipoxins than aspirin-intolerant asthmatics. Eur Respir J 2000; 16:44–49.
23. Choi GS, Kim JH, Shin YS, et al. Eosinophil activation and novel mediators
in the aspirin-induced nasal response in AERD. Clin Exp Allergy 2013;
43:730–740.
24. Shin SW, Park JS, Park CS. Elevation of eosinophil-derived neurotoxin in
plasma of the subjects with aspirin-exacerbated respiratory disease: a pos-
sible peripheral blood protein biomarker. PLoS One 2013; 8:e66644.
25. De Schryver E, Devuyst L, Derycke L, et al. Local immunoglobulin E in the
nasal mucosa: clinical implications. Allergy Asthma Immunol Res 2015;
7:321–331.
26. Steinke JW, Negri J, Baker MG, et al. Eosinophil production of PGD2 in
aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 2016;
137:AB187.
27. Mitsui C, Ono E, Kajiwara K, et al. Is there any basophil activation in peripheral
blood in AERD patients? J Allergy Clin Immunol 2016; 137:AB107.
28. Celik GE, Schroeder JT, Hamilton RG, et al. Effect of in vitro aspirin stimulation
on basophils in patients with aspirin-exacerbated respiratory disease. Clin Exp
Allergy 2009; 39:1522–1531.
29. Laidlaw TM, Kidder MS, Bhattacharyya N, et al. Cysteinyl leukotriene over-
production in aspirin-exacerbated respiratory disease is driven by platelet-
adherent leukocytes. Blood 2012; 119:3790–3798.
30. Mitsui C, Kajiwara K, Hayashi H, et al. Platelet activation markers over-
&& expressed specifically in patients with aspirin-exacerbated respiratory dis-
ease. J Allergy Clin Immunol 2016; 137:400–411.
The study described the elevated expressions of platelet activation markers in
AERD patients compared with ATA patients. Moreover, this is the first study to
demonstrate the lack of change in platelet activation markers during aspirin
challenge test and suggest that plasma markers do not reflect platelet activation
in the airways.
31. Kim SH, Oh JM, Kim YS, et al. Cysteinyl leukotriene receptor 1 promoter
polymorphism is associated with aspirin-intolerant asthma in males. Clin Exp
Allergy 2006; 36:433–439.
32. Kim SH, Ye YM, Hur GY, et al. CysLTR1 promoter polymorphism and
requirement for leukotriene receptor antagonist in aspirin-intolerant asthma
patients. Pharmacogenomics 2007; 8:1143–1150.
33. Park JS, Chang HS, Park CS, et al. Association analysis of cysteinyl-leuko-
triene receptor 2 (CYSLTR2) polymorphisms with aspirin intolerance in
asthmatics. Pharmacogenet Genomics 2005; 15:483–492.
www.co-pulmonarymedicine.com 95
Asthma
34. Szczeklik W, Sanak M, Szczeklik A. Functional effects and gender association
of COX-2 gene polymorphism G-765C in bronchial asthma. J Allergy Clin
Immunol 2004; 114:248–253.
35. Kim SH, Choi JH, Park HS, et al. Association of thromboxane A2 receptor
gene polymorphism with the phenotype of acetyl salicylic acid-intolerant
asthma. Clin Exp Allergy 2005; 35:585–590.
36. Palikhe NS, Kim SH, Lee HY, et al. Association of thromboxane A2 receptor
(TBXA2R) gene polymorphism in patients with aspirin-intolerant acute urti-
caria. Clin Exp Allergy 2011; 41:179–185.
37. Kim SH, Kim YK, Park HW, et al. Association between polymorphisms in
prostanoid receptor genes and aspirin-intolerant asthma. Pharmacogenet
Genomics 2007; 17:295–304.
38. Park BL, Park SM, Park JS, et al. Association of PTGER gene family poly-
morphisms with aspirin intolerant asthma in Korean asthmatics. BMB Rep
2010; 43:445–449.
39. Palikhe NS, Sin HJ, Kim SH, et al. Genetic variability of prostaglandin E2
receptor subtype EP4 gene in aspirin-intolerant chronic urticaria. J Hum
Genet 2012; 57:494–499.
40. Losol P, Kim SH, Shin YS, et al. A genetic effect of IL-5 receptor a
polymorphism in patients with aspirin-exacerbated respiratory disease. Exp
Mol Med 2013; 45:e14.
41. Palikhe NS, Kim SH, Cho BY, et al. Association of three sets of high-affinity
IgE receptor (FcepsilonR1) polymorphisms with aspirin-intolerant asthma.
Respir Med 2008; 102:1132–1139.
42. Bae JS, Kim SH, Ye YM, et al. Significant association of FcepsilonRIalpha
promoter polymorphisms with aspirin-intolerant chronic urticaria. J Allergy Clin
Immunol 2007; 119:449–456.
43. Kim SH, Kang YM, Kim SH, et al. Histamine N-methyltransferase 939A>G
polymorphism affects mRNA stability in patients with acetylsalicylic acid-
intolerant chronic urticaria. Allergy 2009; 64:213–221.
44. Kim SH, Cho BY, Choi H, et al. The SNP rs3128965 of HLA-DPB1 as a
genetic marker of the AERD phenotype. PLoS One 2014; 9:e111220.
45. Park BL, Kim TH, Kim JH, et al. Genome-wide association study of aspirin-
&& exacerbated respiratory disease in a Korean population. Hum Genet 2013;
132:313–321.
The study used a high-density BeadChip to find that HLA-DBP1 genetic poly-
morphisms are the most susceptible genetic factor for AERD in a Korean
population.
46. Losol P, Palikhe NS, Lee JW, et al. Association of P2RY12 polymorphisms
with eosinophil and platelet activation in patients with aspirin-exacerbated
respiratory disease. Ann Allergy Asthma Immunol 2015; 114:423.e1–
424.e1.
47. Kim SH, Choi H, Yoon MG, et al. Dipeptidyl-peptidase 10 as a genetic
& biomarker for the aspirin-exacerbated respiratory disease phenotype. Ann
Allergy Asthma Immunol 2015; 114:208–213.
This is the first study to demonstrate an association of DPP10 gene polymorph-
isms with eosinophilic inflammation in AERD patients.
48. Cheong HS, Park SM, Kim MO, et al. Genome-wide methylation profile of
nasal polyps: relation to aspirin hypersensitivity in asthmatics. Allergy 2011;
66:637–644.
49. Makowska J, Lewandowska-Polak A, Kowalski ML. Hypersensitivity to aspirin
and other NSAIDs: diagnostic approach in patients with chronic rhinosinu-
sitis. Curr Allergy Asthma Rep 2015; 15:47.
50. Tworek D, Zielińska-Wyderkiewicz E, Górski P, et al. Extrabronchial symptoms
and late phase reaction enhance the diagnostic value of aspirin bronchial
challenge. Adv Dermatol Allergol 2015; 6:431–436.
51. Miller B, Mirakian R, Gane S, et al. Nasal lysine aspirin challenge in the
diagnosis of aspirin: exacerbated respiratory disease: asthma and rhinitis. Clin
Exp Allergy 2013; 43:874–880.
52. Kowalski ML, Asero R, Bavbek S, et al. Classification and practical approach
to the diagnosis and management of hypersensitivity to nonsteroidal anti-
inflammatory drugs. Allergy 2013; 68:1219–1232.
53. Morales DR, Guthrie B, Lipworth BJ, et al. NSAID-exacerbated respiratory
& disease: a meta-analysis evaluating prevalence, mean provocative dose of
aspirin and increased asthma morbidity. Allergy 2015; 70:828–835.
This is the first meta-analysis study to describe the mean aspirin dose used during
an oral provocation test.
54. Rolla G, Di Emanuele A, Dutto L, et al. Effect of inhalation aspirin challenge on
exhaled nitric oxide in patients with aspirin-inducible asthma. Allergy 2004;
59:827–832.
55. Jerschow E, Ren Z, Hudes G, et al. Utility of low-dose oral aspirin challenges
& for diagnosis of aspirin-exacerbated respiratory disease. Ann Allergy Asthma
Immunol 2016; 116:321.e1–328.e1.
The study suggested a decrease in FeNO as a useful marker for diagnosis of AERD
after a low-dose aspirin challenge test.
56. Lee-Sarwar K, Johns C, Laidlaw TM, et al. Tolerance of daily low-dose aspirin
& does not preclude aspirin-exacerbated respiratory disease. J Allergy Clin
Immunol Pract 2015; 3:449–451.
The study highlighted the value of provocation test to confirm AERD in patients
tolerant to low-dose aspirin.
96 www.co-pulmonarymedicine.com
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
57. Ledford DK, Wenzel SE, Lockey RF. Aspirin or other nonsteroidal inflammatory
agent exacerbated asthma. J Allergy Clin Immunol Pract 2014; 2:653–657.
58. Nasser S, Christie PE, Pfister R, et al. Effect of endobronchial aspirin
challenge on inflammatory cells in bronchial biopsy samples from aspirin-
sensitive asthmatic subjects. Thorax 1996; 51:64–70.
59. Celejewska-Wojcik N, Mastalerz L, Wojcik K, et al. Incidence of aspirin
hypersensitivity in patients with chronic rhinosinusitis and diagnostic value
of urinary leukotriene E4. Pol Arch Med Wewn 2012; 122:422–427.
60. Kim MA, Izuhara K, Ohta S, et al. Association of serum periostin with aspirin-
&& exacerbated respiratory disease. Ann Allergy Asthma Immunol 2014;
113:314–320.
This is the first study to demonstrate the associations of increased serum periostin
level with AERD, severe asthma as well as eosinophilic asthma. This finding
suggests serum periostin level as a novel biomarker for AERD.
61. Bae Y, Izuhara K, Ohta S, et al. Periostin and interleukin-13 are independently
related to chronic spontaneous urticaria. Allergy Asthma Immunol Res 2016;
8:457–460.
62. Mastalerz L, Sanak M, Kumik J, et al. Exhaled eicosanoids following bronchial
aspirin challenge in asthma patients with and without aspirin hypersensitivity:
the pilot study. J Allergy (Cairo) 2012; 2012:696792.
63. Bochenek G, Kuschill-Dziurda J, Szafraniec K, et al. Certain subphenotypes of
&& aspirin-exacerbated respiratory disease distinguished by latent class analysis.
J Allergy Clin Immunol 2014; 133:98.e1-6–103.e1-6.
The study suggested a novel classification for AERD using an advanced biosta-
tistical analysis method. The finding in this study may facilitate personalized
medicine for AERD treatment.
64. Buchheit KM, Laidlaw TM. Update on the management of aspirin-exacerbated
respiratory disease. Allergy Asthma Immunol Res 2016; 8:298–304.
65. Ta V, White AA. Survey-defined patient experiences with aspirin-exacerbated
& respiratory disease. J Allergy Clin Immunol Pract 2015; 3:711–718.
The survey provided detailed information about the clinical status of AERD
patients, uses and effectiveness of medications in AERD treatment.
66. Dahlen SE, Malmstrom K, Nizankowska E, et al. Improvement of aspirin-
intolerant asthma by montelukast, a leukotriene antagonist: a randomized,
double-blind, placebo-controlled trial. Am J Respir Crit Care Med 2002;
165:9–14.
67. Dahlen B, Nizankowska E, Szczeklik A, et al. Benefits from adding the 5-
lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant
asthmatics. Am J Respir Crit Care Med 1998; 157:1187–1194.
68. Simon RA, Dazy KM, Waldram JD. Aspirin-exacerbated respiratory disease:
&& characteristics and management strategies. Expert Rev Clin Immunol 2015;
11:805–817.
A recent review providing updated information in AERD management. This review
focused on the method and safety of aspirin desensitization in AERD.
69. Wentzel JL, Soler ZM, DeYoung K, et al. Leukotriene antagonists in nasal
polyposis: a meta-analysis and systematic review. Am J Rhinol Allergy 2013;
27:482–489.
70. Stevenson DD, Pleskow WW, Simon RA, et al. Aspirin-sensitive rhinosinusitis
asthma: a double-blind crossover study of treatment with aspirin. J Allergy Clin
Immunol 1984; 73:500–507.
71. Swierczynska-Krepa M, Sanak M, Bochenek G, et al. Aspirin desensitization in
patients with aspirin-induced and aspirin-tolerant asthma: a double-blind
study. J Allergy Clin Immunol 2014; 134:883–890.
72. Esmaeilzadeh H, Nabavi M, Aryan Z, et al. Aspirin desensitization for patients
with aspirin-exacerbated respiratory disease: a randomized double-blind
placebo-controlled trial. Clin Immunol 2015; 160:349–357.
73. Cho KS, Soudry E, Psaltis AJ, et al. Long-term sinonasal outcomes of aspirin
& desensitization in aspirin exacerbated respiratory disease. Otolaryngol Head
Neck Surg 2014; 151:575–581.
The study reported the effect of aspirin desensitization on nasal symptom and nasal
polyp after sinus surgery.
74. Li J, Kang J, Wang C, et al. Omalizumab improves quality of life and asthma
control in Chinese patients with moderate to severe asthma: a randomized
phase III study. Allergy Asthma Immunol Res 2016; 8:319–328.
75. Gevaert P, Calus L, Van Zele T, et al. Omalizumab is effective in allergic and
nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol
2013; 131:110.e1–116.e1.
76. Kern RC. Biologics and the treatment of chronic rhinosinusitis. J Allergy Clin
Immunol 2013; 131:117–118.
77. Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a humanized anti-
IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin
Immunol 2011; 128:989.e1–995.e1.
78. Pettipher R, Hunter MG, Perkins CM, et al. Heightened response of eosino-
philic asthmatic patients to the CRTH2 antagonist OC000459. Allergy 2014;
69:1223–1232.
79. Sommer DD, Rotenberg BW, Sowerby LJ, et al. A novel treatment adjunct for
& aspirin exacerbated respiratory disease: the low-salicylate diet: a multicenter
randomized control crossover trial. Int Forum Allergy Rhinol 2016; 6:385–391.
This is the first randomized study showing that low-salicylate diet is effective in
AERD control.
Volume 23  Number 1  January 2017