REVIEW

published: 28 July 2020

doi: 10.3389/fphar.2020.01147

NSAID-Exacerbated Respiratory
Disease (NERD): From Pathogenesis
to Improved Care
Seong-Dae Woo 1, Quoc Quang Luu 1,2 and Hae-Sim Park 1,2*
1 Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, South Korea, 2 Department of

Biomedical Sciences, Ajou University School of Medicine, Suwon, South Korea

Nonsteroidal antiinflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is

characterized by moderate-to-severe asthma and a higher prevalence of chronic
rhinosinusitis/nasal polyps, but is a highly heterogeneous disorder with various clinical
manifestations. Two major pathogenic mechanisms are: (1) overproduction of cysteinyl
leukotrienes with dysregulation of arachidonic acid metabolism and (2) increased type 2
eosinophilic inflammation affected by genetic mechanisms. Aspirin challenge is the gold
standard to diagnose NERD, whereas reliable in vitro biomarkers have yet not been
identified. Therapeutic approaches have been done on the basis of disease severity with
Edited by: the avoidance of culprit and cross-reacting NSAIDs, and when indicated, aspirin
Tahia Diana Fernández,
University of Málaga, Spain desensitization is an effective treatment option. Biologic approaches targeting Type 2
Reviewed by: cytokines are emerging as potential therapeutic options. Here, we summarize the up-to-
Craig R. Lee, date evidence of pathophysiologic mechanisms and diagnosis/management approaches
University of North Carolina
at Chapel Hill, United States
to the patients with NERD with its phenotypic classification.
M. Isabel Lucena,
Keywords: nonsteroidal antiinflammatory drugs, hypersensitivity, asthma, rhinitis, eosinophil, leukotrienes,
University of Malaga, Spain
diagnosis, treatment
*Correspondence:
Hae-Sim Park
hspark@ajou.ac.kr
orcid.org/0000-0003-2614-0303 INTRODUCTION
Specialty section: Aspirin (acetylsalicylic acid, ASA) and nonsteroidal antiinflammatory drugs (NSAIDs) are the most
This article was submitted to commonly prescribed drugs in the world (Doña et al., 2012); however, they are considered the most
Pharmaceutical Medicine common causes of hypersensitivity reactions to drugs (Blanca-Lopez et al., 2018). Hypersensitivity
and Outcomes Research, reactions to NSAIDs have recently been classified by the European Academy of Allergy and Clinical
a section of the journal Immunology (EAACI) and European Network of Drug Allergy (ENDA): 1) pharmacologic
Frontiers in Pharmacology
reactions (mediated by cyclooxygenase [COX]-1 inhibitions) include NSAID-exacerbated
Received: 24 May 2020 respiratory disease (NERD), NSAID-exacerbated cutaneous disease (NECD) and NSAID-induced
Accepted: 14 July 2020 urticarial/angioedema (NIUA), and present cross-intolerance to various COX-1 inhibitors; 2)
Published: 28 July 2020
selective responses (mediated by immunologic mechanisms) include single NSAIDs-induced
Citation: urticaria, angioedema and/or anaphylaxis (SNIUAA) and single NSAIDs-induced delayed
Woo S-D, Luu QQ and Park H-S
hypersensitivity reactions (SNIDHR) (Kowalski and Stevenson, 2013). NERD is a major
(2020) NSAID-Exacerbated
Respiratory Disease (NERD): From
phenotype among cross-intolerant categories of NSAID hypersensitivity and had been called
Pathogenesis to Improved Care. ASA-induced asthma, ASA-intolerant asthma, ASA-sensitive asthma; however, NERD and ASA-
Front. Pharmacol. 11:1147. exacerbated respiratory disease (AERD) are commonly used (Sá nchez-Borges, 2019). The
doi: 10.3389/fphar.2020.01147 prevalence of NERD is reported to be 5.5% to 12.4% in the general population (Lee et al., 2018a;

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Woo et al. Management of NERD

Chu et al., 2019; Taniguchi et al., 2019), 7.1% among adult eosinophilia, leukotriene (LT) E4 metabolite levels, the frequency
asthmatics and 14.9% among severe asthmatics (Rajan et al., of asthma exacerbation, medication requirements (high-dose ICS-
2015), while it rarely occurs in children (Taniguchi et al., 2019). LABA or systemic corticosteroids) and asthma severity, suggesting
No relationships were found with family history or NSAID that stratified strategies according to subtype classification may help
administration history (Kowalski et al., 2011; Taniguchi achieve better clinical outcomes in the management of NERD.
et al., 2019).
NERD is characterized by moderate-to-severe asthma and a
higher prevalence of chronic rhinosinusitis (CRS) nasal polyps
(NPs) with persistent eosinophilic inflammation in the upper
PATHOPHYSIOLOGY
and lower airways (Taniguchi et al., 2019) as well as NSAID The major upper and lower airway symptoms of NERD are
hypersensitivity where cysteinyl leukotrienes (CysLTs) over- mediated by increased levels of CysLTs with dysregulation of
production and chronic type 2 airway inflammation are key arachidonic acid (AA) metabolism and intense type 2/
findings (Taniguchi et al., 2019). The diagnosis of NERD is eosinophilic inflammation (Cingi and Bayar Muluk, 2020).
confirmed by ASA challenge (via orally, bronchially or nasally
route) and supported by potential biomarkers (Pham et al., 2017; CysLTs Overproduction
Cingi and Bayar Muluk, 2020). In addition, in vitro cell activation In the COX and LOX pathways, AA is metabolized to CysLTs
tests and radiological imaging with nasal endoscopy can aid in (mostly LTE4, via 5-lipoxygenase [5-LO] and LTC4 synthase
NERD diagnosis (Taniguchi et al., 2019). This review updates the [LTC4S]), prostaglandin (PG) pathway (PGE2, PGF2, PGI2 and
current knowledge on pathophysiologic mechanisms including PGD2) and thromboxanes (TBX) A2 by PG synthase and TBX
molecular genetic mechanisms as well as the diagnosis and synthase (Szczeklik, 1990), where enhanced synthesis of CysLTs
treatment of NERD. synthesis with reduced level of PGE2 is a major finding in NERD
(Pham et al., 2016; Pham et al., 2017; Lee et al., 2018a; Yin et al.,
2020). NERD patients have higher levels of CysLTs (especially
CLINICAL FEATURES LTE4) mainly derived from various inflammatory cells, including
neutrophils, monocytes, and basophils, eosinophils and mast
NERD is characterized by chronic type 2 inflammation in the upper cells, which further increases after ASA/NSAID exposure
and lower airways; therefore, patients suffer from chronic persistent compared to asthmatic patients with ASA/NSAID tolerance
asthmatic symptoms and CRS with/without NPs, which are (ATA). Moreover, the increased expression of 5-LO and
exacerbated by ASA/NSAID exposure and refractory to LTC4S was noted in NERD patients with overproduction of
conventional medical or surgical treatment. Some patients are CysLTs; increased CysLTs bind to CysLT receptor 1/2,
accompanied by cutaneous symptoms such as urticaria, subsequently inducing bronchoconstriction and amplifying
angioedema, flushing or gastrointestinal symptoms (Buchheit and inflammatory signal pathways (Jonsson, 1998; Yonetomi et al.,
Laidlaw, 2016). Previous studies suggested that NERD is more 2015; Steinke and Wilson, 2016; Sekioka et al., 2017). Among
common in females (middle-age onset) and non-atopics (Choi et al., PGs, PGE2/PGD2 play a major role in the pathogenesis of NERD.
2015; Trinh et al., 2018). It was reported that rhinitis symptoms Increased PGD2 (released from mast cells and eosinophils) binds
appear and then evolve into CRS which worsens asthmatic to prostanoid receptors to induce bronchoconstriction (Säfholm
symptoms, subsequently followed by ASA intolerance (Szczeklik et al., 2015), and also binds to chemoattractant receptor-
et al., 2000). However, their clinical presentations and courses have homologous molecule expressed on TH2 cells (CRTH2) to
been found to be heterogeneous. It has been increasingly required to induce chemotaxis and activate eosinophils/basophils/Th2
classify the subphenotypes of NERD according to its clinical cells/innate lymphoid cells (ILC2) (Hirai et al., 2001;
features. One study demonstrated 4 subphenotypes by applying a Woessner, 2017), accelerating type 2 airway inflammation
latent class analysis in a Polish cohort: class 1 patients showing (Chang et al., 2014). The down-regulation of PGE 2
moderate asthma with upper airway symptoms and blood biosynthesis, especially in peripheral blood leukocytes, nasal
eosinophilia; class 2 patients showing mild asthma with low epithelial cells and nasal fibroblasts, was noted in patients with
healthcare use; class 3 patients showing severe asthma with severe NERD (Laidlaw and Boyce, 2013; Cahill et al., 2016; Pham et al.,
exacerbation and airway obstruction; and class 4 patients showing 2017). PGE2 has protective effects against bronchoconstriction,
poorly controlled asthma with frequent and severe exacerbation recruitment of eosinophils and degranulation of mast cells after
(Bochenek et al., 2014). Another study showed 4 subtypes binding to E prostanoid 2 (EP2) receptors (Feng et al., 2006;
presenting distinct clinical/biochemical findings in a Korean Sturm et al., 2008); therefore, reduced levels of PGE2 in NERD
cohort using a 2-step cluster analysis based on 3 clinical cannot suppress the signal of 5-LO pathways through IL-10-
phenotypes (urticaria, CRS and atopy status): subtype 1 (NERD dependent mechanisms (Harizi et al., 2003). Furthermore, the
with CRS/atopy and no urticaria), subtype 2 (NERD with CRS and lower expression of EP2 receptors is closely associated with
no urticaria/atopy), subtype 3 (NERD without CRS/urticaria), and abnormal regulation of the autocrine loop involved in COX
subtype 4 (NERD with acute/chronic urticaria exacerbated by pathways (IL-1R1, COX-2, mPGES) in NERD patients (Cahill
NSAID exposure) (Lee et al., 2017). Each subtype had distinct et al., 2015; Machado-Carvalho et al., 2016). This can be
features in the aspect of female proportion, the degree of explained that COX-2 could not sufficiently produce PGH2

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Woo et al. Management of NERD

(the first unstable precursors of PG products from AA evidenced through the decreased level of antiinflammatory PG/
metabolism) without COX-1 (Uematsu et al., 2002). Therefore, LX (LXA4, 15-epi-LXA4, PGE2) and increased levels of the pro-
reduction in PGE2 and its receptor levels could contribute to inflammatory CysLTs (Christie et al., 1992; Sanak et al., 2000;
CysLTs overproduction in NERD patients. Lipoxin (LX) A4 and Harizi et al., 2003; Kupczyk et al., 2009; Yamaguchi et al., 2011).
its epimer (15-epi-LXA4) are also called as the ASA-triggered
lipoxins, and have antiinflammatory effects in airway Enhanced Type 2 Airway Inflammation
inflammation (Pham et al., 2017; Sokolowska et al., 2020). NERD is characterized by persistent eosinophil activation
Their receptor termed formyl peptide receptor 2 (FPR2) is (presenting severe asthma, CRS and NPs) and CysLTs
expressed on human neutrophils, eosinophils, macrophages, T overproduction in which increased CysLTs contributes to
cells, ILCs (ILC2 and NK cells) and epithelial cells of the driving type 2 inflammatory responses (Lee et al., 2018a;
respiratory tract. After binding their receptors, it leads to the Rusznak and Peebles, 2019; Taniguchi et al., 2019). The key
restoration of epithelial barrier function and resolution of allergic inflammatory cells in NERD are eosinophils and mast cells,
inflammation through down-regulation of chemotaxis and cell which are closely interacting with other inflammatory and
activation (Barnig et al., 2013; Sokolowska et al., 2020). In the structural cells including basophils, platelets, neutrophils and
context of NERD, the concentration of LXA4 in the whole blood, epithelial cells. Regarding the activation mechanisms of
sputum and bronchoalveolar lavage fluid, and 15-epi-LXA4 in eosinophils, both Th2 cells and ILC2 could activate eosinophils
the urine from NERD patients were lower than those in ATA via release of IL-4, IL-5 and IL-13; moreover, activated
patients. Additionally, their level has a negative correlation with eosinophils release the eosinophil extracellular traps (EETs),
worsening of airflow obstruction in patients with severe asthma enhancing type 2 inflammation via interacting with epithelial
(Christie et al., 1992; Sanak et al., 2000; Kupczyk et al., 2009; cells and autocrine functions of eosinophils in the asthmatic
Yamaguchi et al., 2011). There was a significant increase in the airway (Pham et al., 2017; Choi et al., 2019b; Yin et al., 2020).
FPR2 expression of NK cells and ILC2s from patients with severe There have been some data demonstrating epithelial dysfunction
asthma compared with those with milder asthma (Barnig et al., related to type 2 inflammation in NERD: 1) lower levels of SPD
2013). All of the studies suggested that LXA4 and its epimer can (protective function against eosinophilia) (Choi et al., 2019a), 2)
be considered the potential therapeutics in the treatment of increased epithelial folliculin and periostin levels (Kim M. A.
NERD (Figure 1). NSAID-induced inhibition of the COX et al., 2014; Trinh et al., 2018; Choi et al., 2019b), 3) increased
pathway leads to shunting of AA metabolism down the 5-LO CysLT-induced signaling (binding to CysLT2R or CysLT3R) in
arm (Palikhe et al., 2009; Dominas et al., 2020). This is indirectly airway epithelial cells to induce the release of pro-inflammatory

FIGURE 1 | Mechanisms of airway inflammation in NERD. Increased levels of CysLTs and PGD2 as well as a decrease in the PGE2 level caused by the AA
metabolism dysregulation are the main mechanism for promoting the severity of NERD. Released CysLTs, PGD2, and PGE2 regulate inflammatory cells via receptors
expressed on individual cells (eosinophils, ILC2, mast cells, smooth muscle cells, granulocyte-adherent platelet, and neutrophils). These activated cells release
cytokines, histamine, CysLTs, and PGD2, contributing to airway inflammation and remodeling in airway mucosa of NERD patients. 5-LO, 5-lipoxygenase; COX,
cyclooxygenase; CysLTs, cysteinyl leukotrienes; PGs, prostaglandins; TBX, thromboxane; LT, leukotrienes; 15-HETE, 15-hydroeicosatetraenoic acid; FPR2, formyl
peptide receptor 2; CysLTR, cysteinyl leukotrienes receptors; LTC4S, LTC4 synthase; EP2, E prostanoid 2; CRTH2, chemoattractant receptor-homologous molecule
expressed on TH2 cells; TP receptors, T prostanoid receptors; IL, interleukin; TSLP, thymic stromal lymphopoietin; TSLPR, TSLP receptor; ILC2, innate lymphoid
type 2 cells; Th2: T helper 2; ECP, eosinophil cationic protein; EDN: eosinophil-derived neurotoxin; IL5R, interleukin 5 receptor.

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Woo et al. Management of NERD

cytokines including IL-33, TSLP and IL-25 (Corrigan et al., NSAIDs and other stimuli, be also revealed to contribute to the
2005), leading to type 2/eosinophilic inflammation and development of NERD (Pham et al., 2017; Yin et al., 2020); DNA
remodeling in NERD (Ulambayar et al., 2019). methylation associated with some SNPs (PGE synthesis, PGS,
Recent studies suggested that the activation of neutrophils ALOX4AP, LTC4S, etc.) may contribute to presenting more
may be related to the severity of airway inflammation in NERD severe phenotypes of NERD (Lee et al., 2019). Further
(Kim et al., 2019), although the exact mechanism is still not fully replication studies in diverse ethnic groups are needed to
elucidated. Increased LTB4 levels (mostly formed from clarify their functional roles in parallel with other omics
neutrophils) and reactive oxygen species release after N-formyl- markers with subphenotype classification.
methionyl-leucyl-phenylalanine stimulation were noted in
patients with NERD compared to ATA patients (Mita et al.,
2004; Kim et al., 2019). In addition, platelets are activated by DIAGNOSIS
CysLTR2 on their surfaces to release IL33 and to interact with
leukocytes through binding P-selectin (CD62P)–P-selectin A diagnosis of NERD is fundamentally based on the patient’s
glycoprotein ligand 1, GPIIb/IIIa-Mac-1 and CD40 history. NERD is suspected in patients having a history of upper/
ligand (CD40L)–CD40 (Laidlaw et al., 2012; Mitsui et al., 2016; lower respiratory reactions after ingestion of ASA/NSAIDs or
Liu et al., 2019; Taniguchi et al., 2019). The activation of platelets suffering from asthma along with CRS and NPs, (Choi et al.,
and adherent leukocytes with platelets leads to the transmigration 2015). Some patients have a definitive history of adverse reactions
of leukocytes into inflammatory airway tissue with increased to ASA/NSAIDs: however, many patients have not experienced
CysLTs, suggesting that platelet-aggregated granulocytes hypersensitivity reactions (Palikhe et al., 2009). One study showed
promote severe and persistent airway inflammation in NERD that 14% of patients who thought they had NERD based on
patients (Laidlaw and Boyce, 2013; Laidlaw et al., 2014; Mitsui symptoms were negative for oral aspirin challenge (Dursun et al.,
et al., 2016). 2008). Thus, ASA challenge, as the gold standard for diagnosing
NERD, is required to confirm or exclude hypersensitivity in patients
Genetic Mechanisms with unclear history of adverse reactions.
Many genetic studies have focused on CysLTs-related and There are 3 types of the ASA challenge test via the oral,
eosinophil activating genes (major pathogenic mechanisms) bronchial and nasal routes. The oral challenge test is a more
according to single nucleotide polymorphisms (SNPs) and commonly used and convenient approach compared to other
genome-wide association studies (GWASs) (Pavó n-Romero challenge tests in that it mimics natural exposure (Adkinson
et al., 2017). (Table 1) HLA DPB1*0301 has been regarded as et al., 2013). It may be more suitable for investigating systemic
a strong genetic marker and replicated in the 2 ethnic groups adverse reactions to NSAIDs. Bronchial challenge with lysine-
Polish and Korean populations (Dekker et al., 1997; Choi et al., aspirin is safer and quicker, but shows lower sensitivity than the
2004a). Patients suffering from this allele manifested the typical oral test. Nasal challenge is recommended for patients with
clinical characteristics of NERD, and had lower FEV1 levels and predominant nasal symptoms, but the sensitivity is lower (Lee
a higher prevalence of CRS and/or NPs (Choi et al., 2004a). The et al., 2018a; Kowalski et al., 2019). The EAACI recommended
GWAS demonstrated several significant SNPs (HLA-DPB1, the oral challenge protocol with starting 20-40 mg of aspirin and
rs3128965, DPP10 rs17048175 in a Korean population, TSLP gradually increasing the dose at 2 hour intervals. When no
rs1837253 in a Japanese population, etc.) which were associated reactions occur within 3 hours after 325 mg of aspirin, the
with the phenotypes of NERD (Park et al., 2013; Kim S. H. et al., challenge is considered to be negative (Kowalski et al., 2019).
2014; Kim et al., 2015). The genetic polymorphism studies Patients with lower FEV1 (<70% of the predicted value) or
identifying the SNPs related to CysLTs synthesis demonstrated unstable asthma status are not recommended, and the test
several significant SNPs: the promoter polymorphisms at the should be performed in a hospital with resuscitative equipment
LTC4S -444 A>C in a Polish population (Sanak et al., 1997), under the supervision of special training physicians (Adkinson
although it was not replicated in the other populations as the US, et al., 2013). These tests may be influenced by bronchial
Japanese and Korean (Van Sambeek et al., 2000; Kawagishi et al., hypersensitivity, ASA dosage, and the concurrent use of
2002; Choi et al., 2004b). The SNPs of G-coupled receptors leukotriene modifier drugs and antihistamines (White et al.,
(CysLTR1 -634C>T, -475 A>C, -336 A>G, CysLTR2 -819 T>G, 2005; White et al., 2006). When patients are false-negative for
2078 C>T, 2534 A>G) lead to amplify the biological activity of ASA challenge, subsequent confirmatory challenges are
CysLTs, the SNPs of prostanoid receptor genes (PTGER2 -616 recommended for holding leukotriene modifier drugs,
C>G, -166 G>A, PTGER3 -1709 T>A, PTGER4 -1254 A>G, antihistamines and oral corticosteroids for at least 1 week and
PTGIR 1915 T>A, TBXA2R -4684 C>T, 795 T>C) were employing high-dose ASA challenges (White et al., 2013).
associated with the development of NERD (Park et al., 2005; There is no in vitro test available for the diagnosis of NERD.
Kim et al., 2006; Kim et al., 2007). Regarding the SNPs related to LTE4 (especially in urine) is suggested to be the most reliable
eosinophil activation, including those of the chemokine CC biomarker for the diagnosis of NERD. Several studies
motif receptor (CCR3 −520 T>C), chemoattractant receptor demonstrated that patients with NERD had higher baseline
molecular expressed in Th2 cells (CRTH2 −466 T>C) and IL5R concentrations of urinary LTE4 as well as greater increase after
(-5993 G>A), were reported (Kim et al., 2008; Palikhe et al., 2010; aspirin/NSAID exposure than in patients with ATA, suggesting
Losol et al., 2013). Epigenetic factors, including exposure to that urine LTE4 level could be used as a clinical diagnostic test

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Woo et al. Management of NERD

TABLE 1 | Genetic polymorphisms associated with NERD.

Gene SNP Analysis methods Ethnic Patients OR P-value Reference

group (95% CI) (compared
with ATA)

CysLTs LTC4S −444 A>C Amplified-fragment single- Polish NERD: 47, ATA: 3.89 <0.001 (Sanak et al.,
overexpression strand conformation 64, NC: 42 (1.57–8.98) 1997)
polymorphism
CysLTR1 −634 C>T, Direct sequencing method Korean NERD: 105, ATA: 2.71 0.020 (Kim et al.,
−475 A<C, 110, NC: 125 (1.10–6.68) 2006)
−336 A<G 2.89
(1.14–7.28)
CysLTR2 −819 T>G ABI PRISM 3700 DNA Korean NERD: 134, ATA: 2.04 0.031 (Park et al.,
2,078 C>T analyzer 66, NC: 152 (1.06–3.85) 0.013 2005)
2,534 A>G 2.28 0.031
(1.19–4.40)
2.02
(1.07–3.84)
PTGER2 −616 C>G Direct sequencing Korean NERD: 108, ATA: 0.64 0.038 (Kim et al.,
−166 G>A 93, NC: 140 (0.42–0.98) 0.023 2007)
2.60
(1.14–5.92)
PTGER3 −1,709 T>A 3.02 0.043
(1.04–8.80)
PTGER4 −1,254 1.77 0.024
A>G (1.08–2.90)
PTGIR 1,915 T>A 0.41 0.018
(0.20–0.86)
TBXA2R −4,684 0.42 0.032
C>T (0.19–0.91)
795 T>C 0.67 0.049
(0.45–1.00) 0.032
2.57
(1.09–6.09)
Enhancement of CCR3 −520 T>C MDR method Korean NERD: 94, ATA: ND ND (Kim et al.,
type 2 inflammation 152 2008)
CRTH2 −466 T>C Primer extension methods Korean NERD: 107, ATA: ND 0.044 (TT) (Palikhe
115, NC: 133 0.037 (CC) et al., 2010)
IL5R −5,993 Primer extension method Korean NERD: 139, ATA: ND 0.685 (GG) (Losol et al.,
G>A 171, NC: 160 0.495 (AG) 2013)
0.408 (AA)
Others HLA DPB1*0301 DNA methods Polish NERD: 59, ATA: 5.3 <0.001 (Dekker
57, NC: 48 (1.90–14.40) et al., 1997)
ABI 3100 Genetic analyzer Korean NERD: 76, ATA: 5.2 0.004 (Choi et al.,
73, NC: 91 (1.80–14.70) 2004a)
HLA- rs3128965 Affymetrix Genome-Wide Korean NERD: 264, ATA: 1.8 0.098 (AG) (Kim S. H.
DPB1 Human SNP array 387, NC: 238 (1.22–2.68) 0.001 (AA) et al., 2014)
3.1
(094–10.70)
HLA- rs104215 GoldenGate assay with Korean NERD: 117, ATA: 2.40 <0.001 (fine- (Park et al.,
DPB1 the VeraCode microbead 685 (1.68–3.42) mapping study) 2013)
DPP10 rs17048175 Affymetrix Genome-Wide Korean NERD: 139, ATA: ND 0.083 (TT) (Kim et al.,
Human SNP array 171, NC: 160 0.072 (CT) 2015)
0.022 (CC)

NERD, NSAID-exacerbated respiratory disease; ATA, aspirin-tolerant asthma; CysLTR, cysteinyl leukotriene receptor; LT, leukotriene; PG, prostaglandin; TX, thromboxane; CRTH2,
chemoattractant receptor homolog expressed by type 2 helper T cells; CCR, chemokine receptor; HLA, human leukocyte antigen; DPP, dipeptidyl peptidase; IL, interleukin; ND, no data.

(Hagan et al., 2017; Bochenek et al., 2018). Recent studies activation test (BAT) has been investigated for in vitro diagnosis of
demonstrated higher levels of serum periostin, and folliculin as NERD, variable values of sensitivity and specificity were reported
potential biomarkers of NERD, however, further validation studies depending on the protocols used, remaining limitations of the
are needed in other cohorts (Kim M. A. et al., 2014; Trinh et al., clinical use (Schafer and Maune, 2012). More efforts are needed to
2018). The Polish group proposed the Aspirin-Sensitive Patients establish in vitro diagnostic tests for reducing the risks of challenge
Identification Test (ASPI Test), however, it was not replicated in tests with identifying reliable biomarkers for the diagnosis of
other centers (Kowalski et al., 2005). Despite the basophil NERD and the classification of its subphenotypes.

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Woo et al. Management of NERD

MANAGEMENT NSAIDs therapy is required for other medical conditions, such

as coronary artery disease or chronic inflammatory disease
The standard management of NERD involves the guidelines (Stevenson and Simon, 2006). Multiple studies have
established for the management of asthma and CRS with ASA/ demonstrated the effectiveness of ASA desensitization in
NSAID avoidance. The complete avoidance of culprit agents and reducing NP size and the need for sinus surgery as well as in
cross-reacting NSAIDs with use of alternative agents (highly improving nasal and bronchial symptoms with decrease in the
selective COX-2 inhibitors such as celecoxib, and partial doses of topical and oral corticosteroids (Swierczynska-Krepa
inhibitors such as acetaminophen, meloxicam or nimesulide) is et al., 2014; Waldram et al., 2018). A recent study showed the
essential. ASA desensitization can be beneficial for NERD long-term safety and efficacy of ASA desensitization in patients
patients when indicated. who underwent continuous daily ASA therapy for more than 10
years (Walters et al., 2018). ASA desensitization is a provocative
Pharmacologic Treatment procedure by starting at low doses of ASA and gradually
Treatment strategies for asthma should follow stepwise increasing to the dose of 650 to 1300 mg over a period of 1 to
management guidelines with maintaining inhaled corticosteroids 3 days, which can induce hypersensitivity reactions (White and
with or without long-acting beta 2 agonists, leukotriene modifier Stevenson, 2018). Thus, as safety is an important issue, ASA
drugs and/or biologic agents on the basis of disease severity and desensitization should be carried out in a well-equipped hospital
rescue medications (GINA-guideline, 2020). Because the under the supervision of special training physicians. The
overproduction of CysLTs is a key feature in the pathogenic protocol with gradually increasing the dose over 2 days was
mechanisms, targeting the leukotriene pathway with CysLT1 suggested by the EAACI to secure safety and efficacy of aspirin
receptor antagonists (montelukast, zafirlukast and pranlukast) desensitization (Kowalski et al., 2019).
and 5-LO inhibitors (zileuton) should be considered to improve
upper and lower airway symptoms. Several studies have shown
that these leukotriene modifiers lead to improvement in asthma Biologics
symptoms, pulmonary function, quality of life, nasal function and The emergence of biologics in the management of asthma and
lower use of bronchodilators (Rodriguez-Jimenez et al., 2018). CRSwNP has represented potential and promising therapy for
Initial treatment for CRS includes intranasal corticosteroids NERD. New biologics targeting type 2 cytokines, such as IL-4,
with intranasal saline irrigation. Intranasal corticosteroids have IL-5 and IL-13 as well as IgE, have been reported in clinical trials,
shown to be highly effective in reducing nasal inflammation and which could reduce asthma exacerbation and oral corticosteroid
in shrinking NPs, which are recommended as a first-line use, and improve lung function (Kim and Jee, 2018; McGregor
treatment in patients with CRSwNP (Choi et al., 2015; Simon et al., 2019). In addition, they have been shown to improve nasal
et al., 2015; Rodriguez-Jimenez et al., 2018). Because rinsing the symptom severity and reduce NP size in patients with CRSwNP,
nasal cavities with saline is helpful in removing secretions and leading to a significant increase in quality of life (Bachert et al.,
washing away allergens and irritants, nasal irrigation prior to 2020). Because NERD is strongly associated with mast cell
administration of topical medications can improve the response activation and eosinophilic airway inflammation, the efficacy of
to the medications (Simon et al., 2015; Rodriguez-Jimenez et al., biologics may be different from those usually observed in severe
2018). Systemic corticosteroids and broad-spectrum antibiotics asthma (Hayashi et al., 2016). Here, we summarized the available
can be additionally required according to the severity of nasal studies for these biologics in patients with NERD (Table 2).
symptoms. Adding antihistamines or oral/nasal decongestants Omalizumab, a humanized recombinant monoclonal anti-IgE
may provide symptom relief (Adkinson et al., 2013). antibody, prevents IgE from binding to its high-affinity receptor and
Despite the heterogeneity of NERD, therapeutic approaches reduces Fc receptor expression on mast cells and basophils,
have been proposed according to symptom severity. However, subsequently suppressing their activation (Chang et al., 2015).
these different phenotypes contribute to the variability in Several studies have suggested the efficacy of omalizumab in the
response to treatment. A recent study found that clinical management of NERD, demonstrating a reduction in asthma
severity and courses differ among the 4 subtypes of NERD, exacerbation and the need for systemic steroids and short acting
which affect antiasthmatic medications required (Lee et al., beta-2 agonist (SABA) as well as an improvement in upper and
2017). Subtype 1/2 patients had severe clinical courses, lower airway symptoms (Hayashi et al., 2016; (Lee et al., 2018b; Jean
requiring higher-dose of antiasthmatic medications including et al., 2019). Furthermore, there are some studies suggesting that
higher dose of ICS and systemic corticosteroids, while subtype 3 omalizumab treatment can be beneficial for reducing respiratory
patients required low doses of these drugs with less frequent symptoms during ASA desensitization and even can restore ASA
asthma exacerbation. These results suggest that a personalized tolerance without the need for ASA desensitization (Phillips-Angles
approach according to subtype classification is needed to achieve et al., 2017; Lang et al., 2018; Hayashi et al., 2020). Omalizumab
better outcomes in the management of NERD. could improve upper and lower airway symptoms with suppression
in urinary markers of mast cell activation, LTE4 and PGD2
ASA Desensitization metabolites, in patients with NERD and lead to the development
ASA desensitization is an effective treatment option when of ASA tolerance with a reduction in urinary LTE4 concentrations
standard medical treatments are not effective or daily ASA/ d u ri n g o ra l A S A c h al l e n g e (Hayashi e t a l., 2016;

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Woo et al. Management of NERD

Hayashi et al., 2020), suggesting that omalizumab has inhibitory biologic therapies, unmet needs remain in NERD patients to be
effects on mast cell activation in NERD. understood with regard to their comparative efficacy and long-
Dupilumab is a human monoclonal antibody that targets the IL- term safety. Further studies are needed to answer questions on
4a receptor and inhibits signaling of both IL-4 and IL-13. Although the selection of right patients and targets with right safety.
the study was conducted in a small number of patients with NERD,
dupilumab could improve nasal and asthma-related symptom Dietary Interventions
scores and lung functions (Laidlaw et al., 2019), although studies Dietary intervention may be beneficial for controlling symptoms in
with a larger sample size are needed to confirm its effectiveness. patients with NERD. Some studies demonstrated that restricting
Mepolizumab and reslizumab are both monoclonal antibodies that dietary salicylates, including fruits, vegetables, berries, herbs, and
prevent IL-5 from binding to its receptor on eosinophils, and spices, improves nasal and asthmatic symptoms, which can be
benralizumab is a monoclonal antibody that targets the alpha explained by the known contribution of salicylates in the
subunit of the IL-5 receptor. The respiratory tract of NERD pathogenesis (Ta and White, 2015; Sommer et al., 2016). A previous
patients is characterized by intense eosinophilic inflammation, studyshowedthatalcoholingestioncanmorecommonlyleadtoupper
with higher levels of eosinophils in NPs and bronchial mucosa and lower respiratory reactions in NERD patients, although the
biopsies than in ATA patients (Tuttle et al., 2018; Eid et al., 2020). underlying mechanism is not clear (Cardet et al., 2014). Thus,
These biologics inhibiting IL-5, eosinophilic maturation and restricting the diet, when experienced respiratory symptoms after
differentiation factor could be effective in the management of the ingestion, can be additionally effective.
patients with NERD (Choi et al., 2004b). In addition, based on
recent study results on the pathogenic mechanisms, P2Y12 receptor
antagonists, CRTH2 antagonists and anti-TSLP/IL-33 antibodies CONCLUSION
could be potential options in the management of NERD patients
(Rodriguez-Jimenez et al., 2018). Patients with NERD present with a variety of clinical features
Considering the heterogeneity of NERD phenotypes/ affected by chronic type 2 eosinophilic inflammation with the
endotypes, selecting right patients and right targets (biologics) overproduction of CysLTs in the upper and lower airways.
are essential in the management of NERD. In phenotypic clusters Although NERD tend to be associated with severe asthma and
of NERD, subtype 4 patients (NERD with urticaria) would need CRSwNP, an improved understanding of clinical features and
omalizumab as an effective option, which can inhibit activated underlying pathogenesis of NERD will aid in diagnostic
basophils and mast cells, the key elements of NERD and urticaria evaluations and new therapeutic strategies for improving
(Lee et al., 2017); subtype 2 patients with severe eosinophilia may clinical outcomes. With the increasing recognition of
need anti-IL-5 as a first option. Despite the development of phenotypic heterogeneity of NERD, efforts are needed to

TABLE 2 | Biologics in NERD patients: Summary of available studies.

Biologics Study design Route, Dose and Study period Efficacy outcomes Reference
(Target) (Number of
participants)

Omalizumab Double-blind, Subcutaneous injection every 2 or 4 weeks Improvement in ACT, ACQ-6, SNOT-22 and VAS scores in (Hayashi
(IgE) randomized, placebo- based on total IgE level and body weight foromalizumab group compared with placebo group after 3-month et al.,
controlled trial 3 months treatment. (All, P<.001) 2020)
(16 Omalizumab vs. Improvement in FEV1 (%) in omalizumab group compared with
16 Placebo) placebo group after 3-month treatment (P=.003)
Omalizumab Retrospective analysis Subcutaneous injection for 1 year Reduction in use of OCS and SABA during 1 year on omalizumab (Jean
(IgE) (29 Omalizumab) treatment compared with 1 year before initiating omalizumab. (All, et al.,
P=.001) 2019)
Dupilumab Post hoc analysis Subcutaneous injection of 300 mg weekly for Improvement in NPS, ACQ-5 and SNOT-22 total scores in (Laidlaw
(IL-4Ra) (8 Dupilumab vs. 11 16 weeks dupilumab group compared with placebo group after 16-week et al.,
Placebo) treatment (All, P<.005) 2019)
Changes in FEV1 (L) from baseline in dupilumab group compared
with placebo group after 16-week treatment. (P<.05)
Mepolizumab Retrospective analysis Subcutaneous injection of 100 mg every 4 Reduction in absolute eosinophil count from baseline after 3-month (Tuttle
(IL-5) (14 Mepolizumab) weeks for 3 months treatment. (P=.001) et al.,
Improvement in SNOT-22 and ACT scores from baseline after 3- 2018)
month treatment. (P=.005 and P=.002, respectively)
No significant improvement in FEV1 (%) from baseline (P=.16)
Reslizumab Post hoc analysis Intravenous injection of 3 mg/kg every 4 Difference in frequency of asthma exacerbation in reslizumab, 0.29 (Weinstein
(IL-5) (28 Reslizumab vs. 28 weeks for 52 weeks vs placebo, 1.95 (P=.001) during 52-week treatment. et al.,
Placebo) Changes in FEV1 (L) from baseline in reslizumab, 0.327L vs 2019)
placebo, 0.002L (P<.001) after 52-week treatment.

IL, interleukin; IL-4Ra, interleukin-4 receptor alpha subunit; ACT, asthma control test; ACQ-6, 6-item asthma control questionnaire; SNOT-22, 22-item sino-nasal outcome Test; VAS,
visual analog scale; OCS, oral corticosteroid; SABA, short-acting b2 agonist; NPS, nasal polyp score; ACQ-5, 5-item asthma control questionnaire.

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Woo et al. Management of NERD

establish precision medicine strategies tailored to individual corresponding author, performed the overall design and review
phenotypes/endotypes with potential biomarkers. of this article.

AUTHOR CONTRIBUTIONS FUNDING

The clinical features, diagnosis and treatment of NERD were This study was supported by a grant of the Korea Health
described by S-DW and the pathophysiologic mechanisms Technology R&D Project through the Korea Health Industry
including molecular genetic mechanisms were described by Development Institute, funded by the Ministry of Health &
QL. This article was written under supervision of H-SP. She, as Welfare, Republic of Korea (H116C0992).

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Asthma Immunol. 97, 688–693. doi: 10.1016/s1081-1206(10)61101-5 Conflict of Interest: The authors declare that the research was conducted in the
White, A. A., Bosso, J. V., and Stevenson, D. D. (2013). The clinical dilemma of absence of any commercial or financial relationships that could be construed as a
“silent desensitization” in aspirin-exacerbated respiratory disease. Allergy potential conflict of interest.
Asthma Proc. 34, 378–382. doi: 10.2500/aap.2013.34.3670
Woessner, K. M. (2017). Update on Aspirin-Exacerbated Respiratory Disease. Copyright © 2020 Woo, Luu and Park. This is an open-access article distributed under
Curr. Allergy Asthma Rep. 17, 1–9. doi: 10.1007/s11882-017-0673-6 the terms of the Creative Commons Attribution License (CC BY). The use, distribution
Yamaguchi, H., Higashi, N., Mita, H., Ono, E., Komase, Y., Nakagawa, T., et al. or reproduction in other forums is permitted, provided the original author(s) and the
(2011). Urinary concentrations of 15-epimer of lipoxin A 4 are lower in copyright owner(s) are credited and that the original publication in this journal is
patients with aspirin-intolerant compared with aspirin-tolerant asthma. Clin. cited, in accordance with accepted academic practice. No use, distribution or
Exp. Allergy 41 (12), 1711–1718. doi: 10.1111/j.1365-2222.2011.03839.x reproduction is permitted which does not comply with these terms.

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