Chronic rhinosinusitis with nasal polyps and

allergic rhinitis as different multimorbid

treatable traits in asthma

Antonio Castillo, MD, PhD,a,b,c Vicente Plaza, MD, PhD,d Gustavo Rodrigo, MD, PhD,e Berta Julia
Jose
, MD, PhD,f

sar Picado, MD, PhD, Cristina Ferna
Ce b,g

ndez, MD, PhD, and Joaquim Mullol, MD, PhD, FAAAAI
h b,c,i
Barcelona,
Madrid, and Santiago de Compostela, Spain, and Montevideo, Uruguay

Background: Respiratory multimorbidities are linked to identified 2 main different upper airway treatable traits, AR
asthma, such as allergic rhinitis (AR) with early allergic asthma and CRSwNP, which need further evaluation to improve
and chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) management and control of patients with asthma. (J Allergy
with late nonallergic asthma. Clin Immunol Global 2023;2:100134.)
Objective: Our aim was to investigate the association of asthma
severity and control with specific upper airway phenotypes. Key words: Asthma, allergic rhinitis, chronic rhinosinusitis with
Method: Patients with asthma were prospectively recruited nasal polyps, united airway disease, asthma severity, asthma control
from 23 pulmonology and ear, nose, and throat clinics. Asthma
severity and control, as well as upper airway comorbidities (AR
and non-AR [NAR], CRSwNP, and CRS without nasal polyps Asthma is a heterogeneous condition with many different
[CRSsNP]) were assessed according to international consensus subphenotpyes with differences in severity, natural history,
guidelines definitions. multimorbidity, and response to treatment. Although most pa-
Results: A total of 492 asthmatic patients were included. Half of the tients with asthma can be controlled with optimal therapy,1 a
asthmatic patients (49.6%) had associated rhinitis (37.0% had AR number of asthmatic patients show severe uncontrolled asthma.1,2
and 12.6% had NAR) and 36.2% had CRS (16.7% had CRSsNP These patients are at risk for increased burden, such as frequent
and 19.5% had CRSwNP), whereas 14.2% had no sinonasal and severe exacerbations, and they account for a significant
symptoms. Most cases of AR (78%) and NAR (84%) were present in amount of health care costs.1,3
patients with mild-to-moderate asthma, whereas CRSwNP was The synergic and concurrent interactions between upper and
more frequent in patients with severe asthma (35% [P < .001]), lower airways is now well recognized, thus supporting use of the
mainly nonatopic asthma (44% [P < .001]). Patients with severe term united (also known as "unified airway disease"4 or ‘‘1
asthma with CRSwNP had worse asthma control, which was airway, 1 disease’’). Rhinitis and chronic rhinosinusitis (CRS)
correlated (r 5 0.249 [P 5 .034]) with sinus occupancy. Multiple constitute common multimorbidities with asthma, influencing
logistic regression analysis showed that late-onset asthma, the disease progression from nose to bronchi.5 There appears to
intolerance of aspirin and/or nonsteroidal anti-inflammatory drugs, be a clear correlation between asthma severity and control and
and CRSwNP were independently associated with severe asthma. the presence and severity of rhinitis or CRS,6 this being more
Conclusion: Severe asthma is associated with CRSwNP, with evident in CRS with nasal polyps (CRSwNP). Airway inflamma-
sinus occupancy affecting asthma control. This study has tion in severe chronic upper airway diseases is likely to contribute
to the worsening of asthma severity and control.7,8
To better understand the origin and evolution of asthma,
From athe Pneumology Department, Hospital Universitari Dexeus, Barcelona; bthe especially in cases of severe asthma, there is a need to characterize
CIBER of Respiratory Diseases; cthe Group of Rhinitis, Rhinosinusitis, and Nasal asthma9,10 and CRS11 phenotypes and endotypes. Important clin-
Polyps, Area of Asthma, SEPAR; dthe Pneumology Department, Hospital Santa
Creu i Sant Pau, Barcelona; ethe Emergency Departament, Hospital Central de las
ical features in phenotyping asthma12,13 are age at disease onset,
Fuerzas Armadas, Montevideo; fthe Medical Department, MSD Madrid; gthe Pneu- presence of concomitant allergy, and frequency of exacerbations
mology Department, Hospital Clinic, Universitat de Barcelona; hthe Preventive Med- and airflow limitation. Several other clinical phenotypes and coex-
icine Department, Complejo Hospitalario Universitario de Santiago de Compostela, isting conditions, such as sex, smoking, and obesity,14 have also
Instituto de Investigaci
on Sanitaria Santiago de Compostela, Fundaci
on IMAS, San-
tiago de Compostela; and ithe Clinical and Experimental Respiratory Immunoallergy,
been described. In addition, aspirin-exacerbated respiratory disease
IDIBAPS & Rhinology Unite and Smell Clinic, ENT Department, Hospital Cl
ınic Bar- (AERD) or nonsteroidal anti-inflammatory drug (NSAID)-exacer-
celona, Universitat de Barcelona. bated respiratory disease15,16 (N-ERD) has been analyzed.17,18
Received for publication November 30, 2022; revised March 23, 2023; accepted for pub- Recent ‘‘cluster’’ analysis, based on inflammatory cells (eosinophils
lication April 10, 2023. and neutrophils) and biomarkers (IgE and IL-5) in sputum from pa-
Available online July 3, 2023.
Corresponding author: Jos
e Antonio Castillo, MD, PhD, Sant Joan 10, 08870 Sitges, Bar-
tients with asthma or integration of the transcriptomic19,20 signa-
celona, Spain. E-mail: [email protected]. Or: Joaquim Mullol, MD, PhD, tures into the analysis21,22 and nasal secretions from CRSwNP,23
FAAAAI, Entença 64, 38 1a, 08015 Barcelona, Spain. E-mail: [email protected]. have identified a number of potential endotypes to study upper
The CrossMark symbol notifies online readers when updates have been made to the and lower airway multimorbidity. Recently, patients with asthma
article such as errata or minor corrections
2772-8293
have been broadly split into 2 distinct endotypes—type 2 asthma
Ó 2023 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, and non–type 2 asthma—depending on the degree of type 2 inflam-
USA and The Author(s). Published by Elsevier Inc. on behalf of American Academy mation. The fact that patients with asthma can present with many
of Allergy, Asthma & Immunology This is an open access article under the CC BY li- clinical phenoptypes has justified the need for a precision medicine
cense (http://creativecommons.org/licenses/by/4.0/). strategy based on the presence of treatable traits.
https://doi.org/10.1016/j.jacig.2023.100134

1
2 CASTILLO ET AL J ALLERGY CLIN IMMUNOL GLOBAL
NOVEMBER 2023

Study design
Abbreviations used In this cross-sectional multicenter study with a prospective
AIA: Aspirin intolerance asthma protocol, all patients attended 1 visit at which clinical and
AR: Allergic rhinitis questionnaire characterization was undertaken.
CRS: Chronic rhinosinusitis
Asthma characteristic severity and control. Consecu-
CRSsNP: Chronic rhinosinusitis without nasal polyps
CRSwNP: Chronic rhinosinusitis with nasal polyps
tive asthmatic patients attending pulmonologist and allergy
CT: Computed tomography outpatient clinics using a multidisciplinary approach with ENT
FENO: Fraction of exhaled nitric oxide specialists were included. Asthma was diagnosed on the basis of
GINA: Global Iniciative for Asthma clinical history and lung function. Asthma severity was stratified
IQR: Interquartile range according to GINA25 and control was stratified according to
LMS: Lund-Mackay score Asthma Control Test score.27 Number of exacerbations was
LoS: Loss of smell defined as the number of prednisone bursts needed to control
NAR: Nonallergic rhinitis increased asthma symptoms in the past 12 months.
N-ERD: Nonsteroidal anti-inflammatory drug–exacerbated respi- Lung function. Spirometry with a bronchodilator test was
ratory disease
performed according to the European Respiratory Society
NSAID: Nonsteroidal anti-inflammatory drug
OR: Odds ratio
recommendations.1 FEV1 and forced vital capacity values were
SPT: Skin prick test obtained from flow-volume curves and expressed as absolute
VAS: Visual Analog Scale values, percentage of predicted normal values, and ratio of
FEV1 value to forced vital capacity (Tiffeneau index).
Atopic status. Atopic status was assessed on the basis of
serum-specific and total IgE levels (RASTand CAP) in response to a
In this direction and from a clinical point of view, involvement panel of common aeroallergens by means of Inmuno-CAP (Phadia,
of upper airway disease should also be considered in every patient Uppsala, Sweden) or a positive result of a skin prick test (SPT) to
with asthma in the light of a precision medicine approach, as it has common aeroallergens. Sensitization to the most common aero-
been identified as a treatable trait that needs to be assessed and allergens was tested according to SPT practical guide in allergy.29
treated to improve outcome.24 Inflammatory status. Inflammatory status was assessed
The aim of this study was to investigate, first, the prevalence through exhaled nitric oxide (FENO) levels and blood count of pe-
of sinonasal diseases such as rhinitis (allergic or nonallergic) ripheral eosinophils. FENO level measured with a Niox Mino
and CRS (CRSwNP and CRS without nasal polyps [CRSsNP]) (Model 03-1100; Aerocrine, Solna, Sweden) was preferentially
in patients with asthma, and second, the phenotype characteristics used. Intolerance of aspirin (AIA) or NSAIDs was assessed by
that are significantly associated with asthma severity and control. clinical history and/or aspirin challenge.
Sinonasal phenotypes. Allergic rhinitis (AR) and non-AR
(NAR) were diagnosed according to the Allergic Rhinitis and Its
Impact on Asthma (ARIA)28 definitions by using nasal symptoms
METHODS
and a positive result of an SPT to clinically relevant aeroaller-
Ethics approval
gens.29 AR severity was rated according to the m-ARIA severity
This study was registered at ClinicalTrials.gov under the iden-
classification.30
tifier NCT01513837 and given the title ‘‘IRIS-Asthma’’ (an
CRSwNP and CRSsNP were diagnosed according to the
acronym for Prevalence, Severity, and Impact of Rhinitis and Rhi-
European Position Paper on Rhinosinusitis and Nasal Polyps.31
nosinusitis by Asthma Severity and Control). The study was
Symptoms for AR and CRS were self-evaluated separately by us-
approved by the Hospital Santa Creu i Sant Pau ethics committee,
ing Visual Analog Scale (VAS) score (0-100 mm). Loss of smell
and all subjects provided written informed consent.
(LoS) was classified as normal or normosmia (VAS score 0-10
mm), partial loss or hyposmia (VAS score > 10-70 mm), or total
loss or anosmia (VAS score > 70 mm).
Study population Nasal endoscopy and sinonasal computed tomography (CT)
Adult patients (aged 18-70 years) who had a physician
s diagnosis were also performed, and the results were categorized according
of asthma (according to the Global Iniciative for Asthma [GINA]25 to international scores.32
and the Spanish guideline for asthma management26) that had been
evolving for at least 1 year and who had visited outpatients clinics at
23 centers (19 in Spain and 4 in Latin America) between 2012 and Analysis
2013 were consecutively screened and selected for the participation Sample size. Approximately 450 patients with asthma
in this study. Patients with nonrelated major comorbidities (eg. needed to be enrolled in the study. This number was achieved
emphysema, congestive heart failure, and anemia) and pregnancy by assuming the participation of 18 centers, with each of them
were excluded. Current smokers and former smokers (>10 pack recruiting 25 patients on average and losses somewhat higher than
years) were allowed for inclusion only if the patient had at least a 10%. To estimate the precision provided by such a number, a 50%
12% improvement in FEV1 value and FEV1 percent predicted after rhinitis/rhinosinusitis comorbidity rate was assumed. On the basis
inhalation of 400 mg of salbutamol, as well as a normal diffusion ca- of these data, precision would be less than 5% (very close to
pacity of greater than 90% of the predicted value. All patients had to 4.6%). If another prevalence rate (probably more realistic) for
have had stable disease for at least 4 weeks before entering the study. rhinitis/rhinosinusitis comorbidity were assumed (eg, a rate close
J ALLERGY CLIN IMMUNOL GLOBAL CASTILLO ET AL 3
VOLUME 2, NUMBER 4

TABLE I. Demographic, clinical, and functional characteristics of patients with asthma according to the GINA severity
classification
Mild Moderate Severe
Asthma characteristic Global Intermittent persistent persistent persistent P value

Severity, no. (%) 492 (100) 86 (17.3) 121 (24.6) 154 (31.4) 131 (26.7)
Age (y), median (25-75 IQR) 46 (33-58) 39 (28-53) 42 (29-56) 45 (35-57) 51 (41-61)*** <.001
Time since asthma onset (y), 13 (5-25) 11 (4-19) 11 (3-21) 12 (5-25) 20 (10-31)*** <.001
median (25-75 IQR)
BMI (kg/m2), median (25-75 IQR) 26 (23-30) 26 (23-28) 25 (23-30) 26 (24-30) 27 (24-30)* .142
Female sex, no. (%) 347 (70.5) 57 (66.3) 89 (73.6) 108 (70.1) 93 (71.0) .728
Sinonasal comorbidity, no. (%)
None 70 (14.2) 10 (11.6) 24 (19.8) 21 (13.6) 15 (11.5) <.001
NAR 62 (12.6) 14 (16.3) 17 (14.0) 21 (13.6) 10 (7.6) —
AR 182 (37.0) 35 (40.7) 45 (37.2) 62 (40.3) 40 (30.5) —
CRSsNP 82 16.7 16 (18.6) 24 (19.8) 22 (14.3) 20 (15.3) —
CRSwNP 96 19.5 11 (12.8) 11 (9.1) 28 (18.2) 46 (35.1)*** —
ACT score (pts), median (25-75 IQR) 21 (16-24) 23 (20-25) 22 (18-25) 20 (17-23) 17 (12-21)*** <.001
Asthma exacerbations, no. (%)
0 310 (63.0) 73 (84.9) 95 (78.5) 91 (59.1) 51 (38.9) <.001
1-3 165 (33.5) 12 (14.0) 24 (19.8) 58 (37.7) 71 (54.2)*** —
>
_4 17 (3.5) 1 (1.2) 2 (1.7) 5 (3.2) 9 (6.9) —
Sinonasal CT score (pts), median (25-75 IQR) 4 (0-11) 4 (0-9) 2 (0-5) 4 (0-12) 8 (1-15)* .014
LoSss of smell (VAS score), no. (%)
Normosmia 167 (43.6) 36 (51.4) 45 (53.6) 54 (43.9) 32 (30.2) .001
Hyposmia (10-70 mm) 159 (41.5) 28 (40.0) 30 (35.7) 55 (44.7) 46 (43.4) —
Anosmia (>70 mm) 57 (14.9) 6 (8.6) 9 (10.7) 14 (11.4) 28 (26.4)*** —
Blood eosinophil count (cell/mL), 250 (112-415) 225 (126-400) 230 (117-428) 250 (100-400) 300 (110-590) .024
median (25-75 IQR)
FENO level (ppb), median (25-75 IQR) 26 (15-45) 24 (14-47) 27 (17-43) 24 (15-44) 30 (16-46) .495
FEV1 (%), median (25-75 IQR) 91 (75-103) 102 (91-110) 95 (88-108) 90 (75-100) 65 (53-86)*** <.001
IgE (IU/mL), median (25-75 IQR) 150 (56-377) 125 (29-276) 124 (47-311) 130 (61-293) 193 (77-539)* .088
Oral steroid intake, no. (%) 55 (11.2) 0 (0.0) 2 (1.7) 7 (4.5) 46 (35.1)*** <.001
Positive SPT result, no. (%) 298 (71.1) 50 (70.4) 78 (76.5) 90 (69.2) 80 (69.0) .588
AERD/N-ERD, no. (%) 72 (15.2) 3 (3.8) 17 (14.4) 21 (14.5) 31 (23.7)** .002
Smoking habit, no. (%) 47 (9.6) 12 (14.0) 13 (10.7) 18 (11.7) 4 (3.1)** .025
Packs/y, (25-75 IQR) 5 (2-20) 9 (3-28) 2 (1-9) 7 (2-15) 6 (2-24) .173
ACT, Asthma Control Test; BMI, body mass index; pts, points.
Severe versus nonsevere asthma.
*P < .05.
**P < .01.
***P < .001.

to 80%), the precision would be on the order of 3.7%. In addition, RESULTS

because losses have been overestimated, the total number of Population and demographic characteristics
patients to be recruited for the study appears more than adequate In all, 492 patients with asthma, mean age 46 (33-58) years old,
to answer the research question. 70.5% being females, who met the inclusion and exclusion
Statistical analysis. The number of available subjects (N5 criteria participated in this study. Two patients were excluded for
492) was greater than that required according to sample size calcu- lack of essential demographic data. The characteristics of the
lations from the total of 23 centers. Data values are given as means study population by descriptive analysis of demographics,
with SDs, medians (interquartile ranges [IQR]), or percentages. clinical, and functional characteristics, are shown in Table I.
The means of the quantitative outcomes tested were compared be-
tween groups by using ANOVA or a median test, whereas a chi-
square test was used for qualitative outcomes. In the case of quan- Atopy
titative outcomes, their association with the Pearson correlation co- Most of the asthmatic patients (71.1%) showed a positive result
efficient was evaluated. Multivariate logistic regression was used to of an SPT to common aeroallergens, with more patients with
estimate an association of independent outcomes. We included CRSsNP presenting a positive SPT result than did patients with
those that were significant (P <.05) in the univariate analysis. Com- CRSwNP (76.8% vs 67.8% [P < .001]) (see Table E1 in this
plete hierarchic models were estimated, and confusion was as- article’s Online Repository at www.jaci-global.org).
sessed by comparing the change in effect greater than 10%.
Adjusted odds ratios (ORs) and their 95% CI are presented. P
values less than .05 were considered statistically significant. Inflammatory biomarkers
SPSS software, version 16.0 (2008) (SPSS for Windows, Chicago, Only blood eosinophilia (but not FENO or total serum IgE
Ill) was used for all statistical analyses. levels) was higher in patients with severe asthma (Table I).
4 CASTILLO ET AL J ALLERGY CLIN IMMUNOL GLOBAL
NOVEMBER 2023

Finally, on the basis of nasal endoscopy and sinus computed

tomography (CT) scan, patients with asthma and CRS were
classified as having CRSwNP (19.5%) or CRSsNP (16.7%).

Asthma severity and control

Asthma severity. According to the GINA asthma severity
classification, the distribution of the study population was as
follows: 17.3% had intermittent asthma and 82.7% had persistent
asthma (24.6% mild, 31.4% moderate, and 26.7% severe).
According to patients’ Asthma Control Test score, 58.5% of
cases were controlled, 20.3% were partially controlled, and
21.1% were uncontrolled. Body mass index increased with
asthma severity. Patients with severe asthma (mean age 51 years)
and those with CRSwNP (mean age 50 years) were among the
oldest patients, whereas patients with intermittent asthma (mean
age 39 years) and those with AR (mean age 43 years) were among
the youngest. Time since onset of asthma was significantly higher
in the case of patients with severe asthma (mean age 20 years) and
patients with asthma and CRSwNP (mean age 16 years), (see
Table E1 in this article’s Online Repository at www.jaci-global.
org).
Asthma exacerbations, intake of oral steroids in the past 3
months, and lower FEV1 predicted values were predominantly
also observed in patients with severe asthma and those with
asthma and CRSwNP. The level of serum total IgE increased
with asthma severity despite allergy condition and was highest
in patients with severe asthma and CRSwNP.
Impact of rhinitis and CRS in asthma severity and
FIG 1. Frequency of sinonasal phenotypes in asthma (N 5 492). Percentage control. Most patients with AR (78%) or NAR (84%) had
of patients using nasal symptoms (86%) (A); using ARIA and European intermittent or mild-to-moderate asthma. A similar frequency of
Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) guideline defini-
tions (50% had rhinitis whereas 36% had CRS) (B); and using allergy testing,
CRSsNP (from 15% to 20%) was found in all levels of asthma
nasal endoscopy, and sinus CT scan (14.2% were without sinonasal severity, whereas CRSwNP was clearly associated with severe
disease, 13% had NAR, 37% had AR, 16% had CRSsNP, and 20% had asthma (35% [P <.001]; OR 5 3.4 [95% CI 5 1.68-6.78]) (Fig 2).
CRSwNP) (C). The prevalence of CRSwNP was significantly higher in patients
with nonatopic asthma than in patients with severe atopic asthma
(44% vs 32% [P < .01]).
Despite atopy, patients with asthma and CRSwNP showed higher LoS was present in 54.5% of asthmatic patients (hyposmia
blood eosinophilia (P 5 .024), FENO levels (P < .001), and total 41.5%, anosmia 14.9%). LoS severity was greater (22 mm
serum levels IgE (P < .001) than those with other sinonasal phe- [IQR 5 0-75 (P < .001)]) and anosmia more frequent (26.4%
notypes (see Table E1 in this article’s Online Repository at [P < .001]) in patients with severe persistent asthma than in those
www.jaci-global.org). with moderate (10 mm [IQR 5 0-50]) (11.4%), mild (0 mm
[IQR 5 0-28]) (10.7%), or intermittent asthma (0 mm [IQR 5
0-45]) (8.6%). In addition, LoS was more severe (38 mm
NSAID sensitivity [IQR 5 2-76] vs 0 mm [IQR 5 0-20], P < .001) and anosmia
The asthmatic patients with a history of AIA or AERD/N- was more frequent (28.1% vs 3.9% [P < .001]) in patients with
ERD22,23 had a prevalence of 15% (72 of 473). AERD/N-ERD was CRS than in those with rhinitis, and even more severe (50 mm
strongly associated with severe asthma (OR 5 7.85 [P 5.001]) and [IQR 5 11-89] vs 20 mm [IQR 0-56] [P < .001]) and anosmia
with CRSwNP phenotype (OR 5 9.05 [P < .001]) (Table I). more frequent (40.6% vs 13.4% [P < .001]) in patients with
CRSwNP than in those with CRSsNP (see Table E1 in this
article’s Online Repository at www.jaci-global.org).
Sinonasal phenotypes Futhermore, LoS was more severe in patients with asthma and
Prevalence of rhinitis and CRS in asthma is shown in Fig 1 and AERD/N-ERD than in those without asthma and AERD/N-ERD
Fig E1 (see this article’s Online Repository at www.jaci-global. (33 mm [IQR 5 2-81] vs 3 mm [IQR 5 0-48]) [P < .001]).
org). Most of the asthmatic patients (86%) reported nasal symp- Nasal endoscopy was performed in all of the patients, and sinus
toms and, according to the ARIA and European Position Paper CT scan was performed in 181 asthmatic patients, mainly in those
on Rhinosinusitis and Nasal Polyps definitions, 49.6% of asth- with CRS symptoms (CRSwNP [n 5 73 (76%)], CRSsNP [n 5 42
matic patients had rhinitis whereas 36.2% had CRS. On the basis (51.2%)], AR [n 5 43 (23%)], NAR [n 5 19 (30.6%)], and those
of a positive result of an SPT to clinically relevant aeroallergens, without sinonasal symptoms [n 5 4 (5%)]), and according to
patients with asthma and rhinitis were classified as having AR asthma severity, in patients with intermittent (n 5 25 [13.8%]),
(37.0%) or NAR (12.6%). mild (n 5 39 [21.5%]), moderate (n 5 57 [31.5%]), and severe
J ALLERGY CLIN IMMUNOL GLOBAL CASTILLO ET AL 5
VOLUME 2, NUMBER 4

FIG 2. Frequency (A) and association (B) of sinonasal diseases according to asthma severity. CRSwNP
shows an increased frequency of (35.1% [P < .001]) and association with (OR 5 3.37 [95% CI 5 1.69-6.78]
[P < .001]) severe persistent asthma. The frequency and association of AR and NAR and CRSsNP are similar
in all asthma severity groups. Frequency is expressed as a percentage, and association is expressed as an
OR (95% CI).

FIG 3. Sinonasal CT LMS scores in patients with CRSwNP and CRSsNP according to asthma severity. A, Pa-
tients with severe asthma shows higher LMS scores than patients with nonsevere asthma do (P 5 .014). B,
LMS scores in patients with CRSwNP (r 5 –0.249; P 5 .034), but not in patients with CRSsNP (r 5 0.091;
P 5 .567), were negatively correlated with Asthma Control Test (ACT) score. The Pearson correlation
coefficient (r) was used for the correlation. Quantitative variables are expressed as medians and IQRs.

(n 5 60 [33.1%]) persistent asthma. Lund-Mackay score (LMS), severe asthma, as were high symptom score, poor lung function
as determined by CT scan, was significantly higher in patients (P < .001), need for intense treatment (use of oral corticosteroids)
with severe asthma (8 [IQR 5 1-15] [P 5 .014]) than in patients (P < .001), and exacerbation rate (P < .001). Patients with severe
with intermittent (4 [IQR5 0-9]), mild (2 [IQR 5 0-5]), and mod- asthma were older (P < .001), had late-onset asthma (P < .001),
erate (4 [IQR 0-12]) persistent asthma. LMS was also signifi- and showed a higher sinus occupancy (P <.001), which was corre-
cantly higher in patients with CRSwNP (10 [IQR 6-18] [P < lated with poor asthma control. Multiple logistic regression anal-
.001]) than in patients with CRSsNP (5 [IQR 1-7]) and ysis showed that CRSwNP, AIA, and late-onset asthma were
moderate-to-severe asthma (Fig 3, A) and in patients with asthma independently associated with severe asthma (Fig 4).
and AERD/N-ERD than in those without AERD/N-ERD (8 [IQR
0-17] vs 3 [IQR 0-10] [P 5 .027]).
LMS was associated with LoS in patients with hyposmia Factors associated with severe and uncontrolled
(OR 5 2.66 [95% CI 5 1.27-5.53] [P 5.009]) but mainly in those asthma
with anosmia (OR 5 16.67 [95% CI 5 4.43-62.67] [P < .0001]) Multiple logistic analysis by univariate (see Table E2 in this ar-
(area under the curve 5 0.70 [95% CI 5 0.62-0.77]). ticle’s Online Repository at www.jaci-global.org) and multivar-
Finally, LMS score showed a negative correlation with asthma iate regression analysis (Table II), showed that FEV1 (%) and
control (determined according to Asthma Control Test score) in use of oral corticosteroids were associated with both severe and
patients with CRSwNP (r5 –0.249; P 5 .034) but not in patients uncontrolled asthma. CRSwNP, AERD/N-ERD, and late-onset
with CRSsNP (Fig 3, B). asthma were independently associated with only severe asthma,
and hyposmia was associated only with poor asthma control.

Factors associated with severe asthma DISCUSSION

(multivariate analysis) To our knowledge, this is the first study to show the combined
As already mentioned, CRSwNP (OR 5 3.4 [P < .001]) and prevalence of rhinitis and CRS in patients with asthma by using a
AERD/N-ERD (OR 5 7.8; [P < .001]) were associated with systematic approach based on definitions and classifications of the
6 CASTILLO ET AL J ALLERGY CLIN IMMUNOL GLOBAL
NOVEMBER 2023

The relationship between severe asthma and CRS has been

acknowledged, with more recent studies showing the relationship
of severe asthma with CRSwNP.6,43,44
The present study, which is based on the upper airway multi-
morbidity in patients with asthma and their relationship with
asthma severity and control, provides a useful method to phenotype
asthma. Importantly, it finds that asthma associated with CRSwNP
is the most severe type of asthma, conditioning its severity and
control, which is clearly in alignment with the recent publication
of Laidlaw et al45 identifying CRSwNP with comorbid
AERD/N-ERD and asthma as a most severe and difficult-to-treat
disease that may be the main target for type 2 biologic treatments.
Association of asthma with CRSwNP has a high clinical,
social, and economic burden,3,17 especially in patients with
AERD/N-ERD.46
Like the data of other studies9,22 reporting phenotypic charac-
terization of population with severe asthma, our data fit the obser-
FIG 4. Age, sex, age of asthma onset, prevalence of nasal polyps, AIA, and
vation that patients with nonsevere asthma, patients with severe
atopy in patients with severe asthma and patients with mild-to-moderate asthma are characterized by a higher proportion of negative re-
persistent asthma. **P < .01; ***P < .001. sults of SPTs to aeroallergens, higher prevalence of comorbid
CRS, and late onset.35,36,43
In addition, patients with CRSwNP are more likely to have an
international consensus guidelines and their relationship with altered microbiome in nasal mucosa colonization by Staphylo-
asthma severity and control, as well as to define them as different coccus aureus and, through the accumulation of associated im-
treatable traits in asthmatic patients. mune cells, tissue injury leading to loss of the mucosal barrier.
The IRIS-Asthma study shows that CRSwNP is associated with S aureus enterotoxins act as superantigens and induce subsequent
severe asthma, whereas CRSwNP severity is associated with local production of polyclonal IgE that enhances mast cell
worse asthma control. degranulation contributing to chronic inflammation. In people
CRSwNP, together with AERD/N-ERD and late-onset asthma, with asthma, IgE to S aureus enterotoxins is associated with
appear as independent factors associated with severe asthma in greater severity of asthma47,48 and serves to predict the severity
contrast to mild-to-moderate asthma. Sinonasal occupancy (as and occurrence of asthma exacerbations. Functions of IgE in
indicated by LMS) and anosmia are associated with worse asthma may be similar to those in nasal polyposis.
control, thus supporting the role of LoS as a clinical marker of In our study, we observed that CRSwNP occurs with similar
severity.33,34 frequency in patients with atopic asthma and patients with
Our data also support a frequent late-onset asthma disease nonatopic asthma and that total IgE, which is correlated with
pattern35,36 in the intrinsic severe asthma subgroup, thus differen- eosinophil and type 2 biomarkers,23 is significantly higher in pa-
tiating these patients from atopic patients with early-onset tients with severe asthma with CRSwNP independently of their
asthma.10 In consequence, there are 2 major sinonasal phenotypes allergic status. This finding agrees with previous findings
or ‘‘traitable traits’’ in patients with asthma: AR, which is associ- regarding the role of IgE in patients with intrinsic asthma and pa-
ated with mild-to-moderate asthma, and CRSwNP which is tients with CRSwNP and the possible role of bacterial superanti-
mainly associated with nonatopic severe asthma, reaffirming gens in the pathophysiology of patients with severe asthma and
other studies.37-40 high IgE levels47,48 differing from that of patients with AR in
The need for a better understanding of asthma heterogeneity terms of polyclonal IgE while indicating the importance of assess-
prompted implementation of the ENFUMOSA41 study, which ing upper airway disease when phenotyping asthma. This finding
described the clinical characteristics of a cohort of asthmatic pa- may also help to explain the effect of anti-IgE biologics (omalizu-
tients from several European countries, showing female sex, mab)49 in patients with nonatopic asthma with CRSwNP.
neutrophilic inflammation, and lower atopy as the key findings Although a significant correlation between sinus occupancy
in severe asthma. Despite being a hallmark study regarding phe- (LMS) and symptom scores and asthma severity has been
notyping of asthmatic patients, the ENFUMOSA study did not described,6,50 our study has interestingly found a relationship be-
consider the evaluation of upper airways in patients with asthma. tween poor asthma control and high LMS only in asthmatic patients
Similarly, Haldar et al42 proposed a mathematic cluster analysis to with comorbid CRSwNP, which was not described previously.
provide a framework for identifying distinct phenotypes, with In the present study, we found a prevalence of AERD/N-ERD
specific pathophysiologic abnormalities predicting the therapeu- of 15% among patients with asthma. In addition, AERD/N-ERD
tic response and identifying the early-onset atopic and late- was clearly associated with severe asthma,16,51 high sinus occu-
onset nonatopic asthma as 2 different phenotypes. That study pancy in patients with CRSwNP, and greater LoS than in asth-
also did not mention the impact of upper airway diseases (rhinitis matic patients with no AERD/N-ERD.52
or CRS) in the phenotyping of asthma. Since then, multiple ap- The finding of anosmia being much more prevalent in patients
proaches have been made to identify different types or phenotypes with severe asthma supports the idea of this symptom serving as a
of patients with asthma with different characteristics and their clinical marker of severe asthma while reinforcing its assessment
evolution, management, and prognosis that need to be considered in daily clinical asthma practice. Overall, our results are
to precisely treat to target. consistent with those of other studies44 reporting that CRSwP,
J ALLERGY CLIN IMMUNOL GLOBAL CASTILLO ET AL 7
VOLUME 2, NUMBER 4

TABLE II. Factors associated with severe and uncontrolled asthma by backward multivariate regression analysis
Severe asthma (GINA) Uncontrolled asthma (ACT score < 20)
Factor Adjusted OR 95% CI P value Adjusted OR 95% CI P value

Time since asthma onset 1.02 1.00 1.05 .022

Sinonasal comorbidity .001
No 1
NAR 4.98 0.65 38.12 .122
AR 11.81 1.73 80.74 .012
CRSsNP 8.07 1.15 56.49 .035
CRSwNP 25.16 3.64 173.86 .001
LoS .014
Normosmia 1
Hyposmia 2.29 1.17 4.46 .015
Anosmia 0.65 0.21 2.03 .457
FEV1 (%) 0.36 0.24 0.52 .000 0.69 0.49 0.97 .032
Oral steroid intake 14.56 5.67 37.38 .000 4.11 1.69 10.00 .002
AERD/N-ERD 2.13 1.04 4.36 .039
ACT, Asthma Control Test.

aspirin/NSAID sensitivity, and late onset of asthma are indepen- DISCLOSURE STATEMENT
dent and crucial factors linked to severe asthma. This study was designed and conducted by the Rhinitis,
With regard to body mass index, in our study patients with severe Rhinosinusitis and Polyposis Group of the Spanish SEPAR
asthma did not differ significantly from patients with nonsevere Asthma Area and partially funded by MSD, Spain and the
asthma, whereas other studies have associated severe asthma with Integral Research Program (PII) of SEPAR. The funders had no
obesity.53 Although the cohort had more female participants (70%), role in design and conduct of the study; collection, analysis, and
female sex was not related to asthma severity in our patients. This is interpretation of the data; or preparation, review, or approval of
in contrast with the findings of other studies previous.41,54 the article. The actual sponsor is the Integral Research Program
The strengths of our study are (1) the large sample of patients (PII) of SEPAR.
with asthma who have been included prospectively in this multi- Disclosure of potential conflict of interest: J. A. Castillo has
centric study that is strictly phenotyped for upper airway diseases; received research grants from AstraZeneca, Boehringer Ingel-
(2) the fact that this study reflects a real-life multidisciplinary heim, GSK, MSD, and Uriach and attended speaker bureaus
approach with pulmonologists and ENT specialists, which implies and/or advisory boards for ALK, AstraZeneca, GSK, Novartis,
a high external validity to be implemented in clinical practice; and and Sanofi-Genzyme. In the last 3 years, V. Plaza has received
(3) the fact that this study describes the existence of different honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi, Ge-
‘‘treatable traits’’ within a group of asthmatic patients with upper bro, GSK, and Sanofi for speaking at sponsored meetings;
airway disease, either rhinitis or CRS, that may have an impact received assistance from AstraZeneca and Chiesi for travel to
on asthma severity and control and hence need to be considered meetings; acted as consultant for AstraZeneca, GSK, and Sanofi;
when diagnosing and treating patients with asthma. and received funding and/or grant support for research projects
On the other hand, the limitations of this multicenter prospec- from a variety of government agencies and not-for-profit founda-
tive study include an information bias during recruitment that tions, as well as from AstraZeneca, Chiesi, and Menarini. B. Juli
a
cannot be excluded as an important challenge to recruitment of is a full-time employee of MSD. J. Mullol has received research
patients with intermittent asthma in most participating centers. grants, attended speaker bureaus and/or advisory boards, and
In addition, the study results are not intended to reflect the real received consulting fees from AstraZeneca, Genentech, Glen-
prevalence of the different levels of asthma severity, as its aim was mark, GSK, Menarini, Mitsubishi-Tanabe Pharma, MSD, Nou-
to describe the association of upper airway multimorbidity in cor/Uriach Group, Novartis, Proctor & Gamble, Regeneron
patients with asthma with different levels of severity. Pharmaceuticals Inc, and Sanofi-Genzyme, UCB Pharma, and
In conclusion, our IRIS-Asthma study reports that compared Viatris. The rest of the authors declare that they have no relevant
with patients with mild-to-moderate persistent asthma, patients conflicts of interest.
with severe asthma have a predominant nonatopic airway inflam-
mation with CRSwNP, whereas sinus occupancy and anosmia,
which are 2 main characteristics of CRSwNP, impair asthma We acknowledge the services of the Prevalence, Severity, and Impact of
control. Furthermore, the presence of CRSwNP, late-onset asthma, Rhinitis and Rhinosinusitis by Asthma Severity and Control (IRIS-Asma
and AERD/N-ERD are crucial clinical features that are indepen- Group), including the group members from Spain (C. Almonacid and E. M.
dently associated with severe asthma. Overall, the present findings Dom
ınguez [H.U. de Toledo]; A. P. Arenas, C. Bujalance, and J. Guti
errez [H.
Reina Sof
ıa, C
ordoba]; F. J. G. Barcala, I. Ar
an I, and E. R. Cabanas [H.C.U.
support the relevance of evaluating the upper airway while giving
Santiago de Compostela y Hospital de Pontevedra]; J. A. Castillo, S. Vila, and
high importance to an integral multidisciplinary approach in the B. de Fr
ıas B [Hospital Universitario Quir
on Dexeus, Barcelona]; C. Cisneros
management of multimorbid asthma and sinonasal diseases, either and I. Fern
andez [H. de la Princesa, Madrid]; M. V. Gonz
alez, S. Bardag
ı S,
rhinitis or CRS, under the united airway disease umbrella. Future and J. Chamizo J [H. de Matar
o]; R. Hernando, X. Casas, L. Lores, and R.
clinical guidelines should put additional effort into the presence of Vera [H. de Sant Boi de Llobrega]; J. M. Ignacio, C. O’Connor, and F. P
erez
upper and lower airway multimorbidity as more common ‘‘treat- [H. USP Marbella]; E L
opez and J. Chac
on [H. Virgen de la Salud, Toledo]; N.
able traits’’ to improve their management and follow-up. Marina and J. G
omez [H. Cruces, Baracaldo]; E. Mart
ınez and B. P
erez del
8 CASTILLO ET AL J ALLERGY CLIN IMMUNOL GLOBAL
NOVEMBER 2023

Valle [H. de Sagunto]; C. Mart
ınez Rivera and C. Pollan [H. U. Germans Tr
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Badalona]; J. Mullol , M. C. Vennera and I. Alobid [H. Cl
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Sant Pau, Barcelona]) and the group members from Latin America (I. Carra- phil counts are associated with more severe asthma phenotypes using cluster anal-
sco, G. Cukier, A. Mel
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notypes and IgE responses. Eur Respir J 2016;47:304-19.
the patients who participated in the study for their generosity.
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