The Laryngoscope

© 2023 The Authors. The Laryngoscope

published by Wiley Periodicals LLC on
behalf of The American Laryngological,
Rhinological and Otological Society, Inc.

Non-Type 2 and Mixed Inflammation in Chronic Rhinosinusitis and

Lower Airway Disease

Austin Heffernan, BMSc ; Amir Shafiee, BSc; Teffran Chan, MD; Sydney Sparanese, BSc;
Andrew Thamboo, MD, MHSc, FRCSC

Objective: The aim was to discuss the role of non-type 2 inflammation in patients diagnosed with chronic rhinosinusitis
(CRS) and comorbid lower airway disease.
Data Sources: Medline, Embase, National Institute for Health and Care Excellence, TRIP Database, ProQuest, Clinicaltrials.
gov, Cochrane Central Registry of Controlled Trials, Web of Science, government and health organizations, and graduate-level
theses.
Review Methods: This scoping review followed PRISMA-ScR guidelines. Search strategy was peer-reviewed by medical
librarians. Studies were included if they utilized airway sampling, non-type 2 cytokines, and patients with CRS and lower air-
way disease.
Results: Twenty-seven from 7060 articles were included. In patients with CRS and comorbid asthma, aspirin-exacerbated
respiratory disease (AERD), and chronic obstructive pulmonary disease (COPD)/bronchiectasis, 60% (n = 12), 33% (n = 2),
and 100% (n = 1), respectively, demonstrated mixed or non-type 2 endotypes. Comorbid CRS and asthma produced type
1 (n = 1.5), type 2 (n = 8), type 3 (n = 1), mixed type 1/2 (n = 1), and mixed type 1/2/3 (n = 8.5) endotype shifts. AERD
demonstrated type 2 (n = 4), mixed type 2/3 (n = 1), and mixed type 1/2/3 (n = 1) endotype shifts. CRS with COPD or bron-
chiectasis demonstrated a mixed 1/2 (n = 1) endotype shift.
Conclusion: Type 2 disease has been extensively reviewed due to advent biologics targeting type 2 inflammation, but out-
comes may be suboptimal due to the presence of non-type 2 inflammation. A proportion of patients with CRS and comorbid
lower airway disease demonstrated mixed and non-type 2 endotype shifts. This emphasizes that patients with unified airway
disease may have forms of inflammation beyond classical type 2 disease which could inform biologic development.
Key Words: chronic rhinosinusitis, endotypes, mixed inflammation, non-type 2 inflammation, unified airway disease.
Laryngoscope, 134:1005–1013, 2024

INTRODUCTION 2 inflammation. The former is defined by serum

The unified airway concept (UAC) is a theory that
proposes shared pathophysiological mechanisms among
pathologies in the respiratory tract that span from the
paranasal sinuses to the distal bronchioles. These patho-
physiological mechanisms define endotypes which have
become more prominent in the management of upper and
lower airways over recent years. Currently, chronic
rhinosinusitis (CRS) inflammatory endotypes are predom-
inantly classified into type 2 inflammatory and non-type
This is an open access article under the terms of the Creative
Commons Attribution-NonCommercial License, which permits use, distri-
bution and reproduction in any medium, provided the original work is
properly cited and is not used for commercial purposes.
From the Division of Otolaryngology – Head and Neck Surgery,
Department of Surgery (A.H., A.S., T.C., S.S., A.T.), University of British
Columbia, Vancouver, Canada.
Additional supporting information may be found in the online
version of this article.
Editor’s Note: This Manuscript was accepted for publication on
August 03, 2023.
AAO-HNSF 2022 Annual Meeting-OTO Experience, Philadelphia,
PA, September 10–14.
The authors have no funding, financial relationships, or conflicts of
interest to disclose.
Send correspondence to Andrew Thamboo, Division of
Otolaryngology – Head and Neck Surgery, Department of Surgery,
University of British Columbia, 2775 Laurel Street, 4th floor, Vancouver,
British Columbia V5Z 1M9, Canada. Email: andrew.thamboo@gmail.com
DOI: 10.1002/lary.30992
eosinophilia (≥300 cells/uL) and elevated IgE levels (≥250
ug/L), while the latter can be further subdivided into type
1 and type 3 inflammatory endotypes.1–3 The majority of
literature defines type 1 biomarkers as IFN-γ and TNF-α,
while type 3 biomarkers mainly include IL-17A and
IL-22.3–11 Similarly, asthma can be subdivided into two end-
otypes: T2 high and non-T2 asthma. The T2-high endotype
has been well delineated based on biomarkers including air-
way eosinophilia, blood periostin, FeNO, and allergen-specific
IgE levels.12 On a pathophysiological basis, there has been
significant discussion on a shared type-2 inflammatory mech-
anism in CRS and lower airway diseases.13–15 One review by
Li et al. stated that “IL-5 high” CRS is the upper airway
counterpart to “Th2-high” asthma in the lower airway.15 This
assertion is supported by biomarkers of Th2 inflammation in
nasal polyps being significantly correlated with Th2 bio-
markers of asthma and bronchial inflammation.16
Understanding the UAC and its inflammatory mech-
anisms could have a significant impact on the manage-
ment of patients with these comorbid conditions.17
However, our understanding of the UAC is incomplete, as
there is a lack of literature discussing non-type 2 inflam-
mation in the setting of the UAC. The current literature
lacks consensus on a shared non-type 2 inflammatory
mechanism within the upper airway and lower airway.
Understanding this relationship could better inform

Laryngoscope 134: March 2024 Heffernan et al.: Unified Airway and Non-Type 2 Endotypes
1005

biologic development which could ultimately make care
more personalized for patients with chronic rhinosinusitis
and lower airway disease. Therefore, the aim of this
review was to explore the presence of non-type 2 inflam-
mation in patients diagnosed with CRS and comorbid
lower airway disease.
METHODS
Research Question
Do patients diagnosed with CRS and a comorbid lower air-
way disease have higher levels of non-type 2 inflammatory bio-
markers compared with patients diagnosed with CRS or lower
airway disease alone.
Preliminary Search
A preliminary search on non-type 2 inflammation in the
UAC was conducted in Embase and Medline databases which
yielded a small number of articles and no review articles on the
topic. For this reason, a scoping review was conducted, and find-
ings were reported using the PRISMA-ScR reporting guidelines
(Preferred Reporting Items for Scoping Reviews and Meta-
analyses Extension for Scoping Reviews). The protocol was regis-
tered on the Open Science Framework (OSF) (registration DOI:
10.17605/OSF.IO/JG3C8).
Data Sources and Search Strategy
The search strategy consisted of CRS, lower airway dis-
ease, biomarkers, and their related terms combined with rele-
vant Boolean operators (Fig. S1). Lower airway diseases
included asthma, AERD, COPD, and bronchiectasis. This was
peer-reviewed by two medical librarians. Search strategy was
made public on OSF. Databases searched included Medline,
Embase, National Institute for Health and Care Excellence,
TRIP Database, ProQuest, Clinicaltrials.gov, Cochrane Cen-
tral Registry of Controlled Trials, Web of Science Core Collec-
tion, websites of government and health organizations
(i.e., Health Canada) and libraries of graduate-level theses.
The search was conducted in January 2022 and repeated in
July 2022.
Study Selection
All studies were stored on the Covidence systematic review
management software, which removed duplicates. No restrictions
were placed on publication date. Inclusion criteria included
(1) human participants, (2) experimental group participants diag-
nosed with CRS and a lower airway disease, (3) control group diag-
nosed with an upper or lower lung disease alone, (4) airway
biological sampling in upper airway and or lower airway, and
(5) studied type 1, 2, and 3 cytokines. Endotypes were defined as
the following: type 2 cytokines and cells included IL-4, IL-5, IL-13,
IgE, and eosinophils.3 Type 1 biomarkers consist of IL-6, IL-8, IL-
1B, myeloperoxidase (MPO), TNF, IFN-gamma, and macro-
phages.3 Type 3 cytokines included IL-17A, IL-17F, and IL-22.3
Additionally, neutrophils may play a role in both type 1 and type
3 inflammations.14 Articles were excluded if they were in vitro or
if they did not meet inclusion criteria. These articles were
reviewed independently by two authors (AH and SS), and all dis-
crepancies were resolved by the senior author (AT). After title and
abstract screening, the full texts of shortlisted articles were
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reviewed by AH and SS, and a final list was presented to AT for
approval.
Main Outcomes and Data extraction
Data were extracted by three authors (AH, SS, and AS) using
a predefined template. The data were collected, combined, and
stored on a password protected spreadsheet. All discrepancies in
data extraction were resolved by the AT. Data included study objec-
tive, design, number of participants, demographic information, sam-
pling location, lower airway pathology, CRS phenotype, cytokines
studied, and change in cytokine expression with presence or absence
of lower airway or CRS pathology. This allowed authors to comment
on the impact of non-type 2 inflammation on UAC in patients diag-
nosed with CRS and a lower airway pathology.
RESULTS
Characteristics of Included Studies
The search strategy yielded 7060 articles, and 27 arti-
cles met inclusion criteria (Fig. S2). More than 80% of
included articles were published between 2015 and 2022.
The mean age of these participants ranged from 9 to 72, with
96.6% (n = 30) of articles focusing on the adult population.
Five studies did not provide age information.18–22 These
studies obtained biological samples from the airway, 77.7%
(n = 21) from the upper airway, 11.1% (n = 3) from the
lower airway, and 11.1% (n = 3) from both the upper and
lower airways. Among upper airway samples, material
included sinonasal mucosa (n = 15), nasal polyps (n = 3),
nasal secretions (n = 2), and rhinonasal lavage (n = 1). All
lower airway samples were sputum (n = 3), and combined
upper and lower airway samples were sinonasal mucosa and
bronchial biopsy (n = 1), nasal secretion and sputum (n = 1),
and rhinonasal lavage and bronchoalveolar lavage (n = 1).
These journal articles studied CRS comorbid with asthma
(74.1%, n = 20), AERD (22.2%, n = 6), COPD, and or bron-
chiectasis (3.7%, n = 1).
Levels of Evidence
The included studies were given a level of
evidence based on the rating scale published by Oxford
Centre for Evidence Based Medicine.23 The level of evi-
dence ranged from 3 (n = 4) to 4 (n = 23) throughout
included studies.
Non-Type 2 Inflammation and the Unified Airway
Patients with comorbid CRS and lower airway disease
showed increased mixed or non-type 2 inflammation on bio-
logic sampling in 56% of studies assessing type 1, 2, and
3 markers. In patients with CRS and comorbid asthma,
AERD, and COPD/bronchiectasis, 60% (n = 12), 33%
(n = 2), and 100% (n = 1), respectively, demonstrated mixed
or non-type 2 inflammation (Fig. 1). Isolated non-type
2 inflammation was more prevalent in patients with CRS
and asthma. Populations studied in Asian, western, or
Russian countries with CRS and asthma demonstrated dis-
tinct mixed and non-type 2 inflammatory endotypes (Fig. 2).
Heffernan et al.: Unified Airway and Non-Type 2 Endotypes
 15314995, 2024, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/lary.30992 by Nat Prov Indonesia, Wiley Online Library on [17/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Fig. 1. Predominant cytokine endotypes in upper and lower airway diseases from studies that investigated type 1, 2, and 3 biomarkers.
(A) CRS + asthma: type 1 n = 1.5, type 2 n = 8, type 3 n = 1, mixed types 1 and 2 (Type 1/2) n = 0, mixed types 2 and 3 (Type T2/3) n = 0,
mixed types 1, 2, and 3 (type 1/2/3) n = 9.5. (B) AERD: type 1 n = 0, type 2 n = 4, type 3 n = 0, mixed types 1 and 2 (type 1/2) n = 0, mixed
types 2 and 3 (Type 2/3) n = 1, mixed types 1, 2, and 3 (type 1/2/3) n = 1. (C) CRS + COPD/bronchiectasis. Mixed types 1 and 2 (type 1/2)
n = 1. The “0.5” values refer to one study where there were two clusters of patients, each with a different endotype. [Color figure can be
viewed in the online issue, which is available at www.laryngoscope.com.]

Endotypes in Comorbid Chronic Rhinosinusitis
and Lower Airway Pathologies
Patients diagnosed with both CRS and asthma dem-
onstrated type 2 (40.0%, n = 8),10,20,24–29 type 1 (7.5%,
n = 1.5),30,31 type 3 (5.0%, n = 1),32 mixed types 1 and
2 (T1/2) (5.0%, n = 1),33 and mixed type 1, 2, and
3 (T1/2/3) (42.5%, n = 8.5)11,14,18,19,30,34–37 endotype shifts
in upper and lower airway samples (Table I) (Fig. 1). The
“0.5” describes inflammatory endotypes of two clusters of
patients studied by Hoggard et al.30 Zhang et al.30 and
Hoggard et al.31 depicted a type 1 endotype; however, dif-
ferent cytokines were elevated in the sinonasal mucosa of
patients with CRSwNP and asthma. Zhang et al.31 dem-
onstrated a significant elevation in TGFβ while Hoggard

Fig. 2. Predominant endotype in patients with asthma and CRS based on geographical location from studies that investigated type 1, 2, and
3 biomarkers. (A) West: type 1 n = 0.5, type 2 n = 5, mixed types 1, 2, and 3 (type 1/2/3) n = 3.5. (B) Asia: type 1 n = 1, type 2 n = 3, type
3 n = 1, mixed types 1, 2, and 3 (type 1/2/3) n = 4. (C) Russia: Mixed types 1 and 2 (type 1/2) n = 2. The “0.5” values refer to one study where
there were two clusters of patients, each with a different endotype. [Color figure can be viewed in the online issue, which is available at www.
laryngoscope.com.]

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TABLE I.
Studies Examining for Cytokine Endotypes in CRS and Asthma.
Biomarkers different from Predominant
Author, year n UA Phenotype (s) Sampling controls Summary of findings endotype LOE

Saitoh, 2010 51 CRSwNP UA: SM IL-17A, eosinophils, IL-17A correlated with eosinophils Mixed (1–3) 4
neutrophils but not neutrophils. All three
biomarkers were significantly
elevated in CRS and asthma.
Hoggard, 2018 110 CRSwNP UA: SM • SC5: IL-8, CD68+ Type 1 and mixed endotypes seen Type 1 4
macrophages in subject clusters diagnosed
CRSsNP Mixed (1–3)
with CRS and asthma
• SC6: IL-5, IL-6,
eosinophils,
neutrophils, CD68+
macrophages
Huang, 2016 30 CRSsNP UA: SM IL-17A IL-17 was elevated in smokers Type 3 4
with CRS and asthma.
Yamamoto, 2007 16 CRSwNP UA: SM Eosinophils, IL-4, IL-5, IL- Eosinophils, IL-4, IL-5, and IL-13 Type 2 4
13 were elevated in CRS and
asthma compared with CRS
without asthma.
Ryu, 2019 179 CRSwNP UA: SM ECP, MPO, IFN-γ, IL-17A Refractory CRSwNP with asthma Mixed (1–3) 4
is more likely to have elevated
ECP. MPO, IFN-γ, and IL-17A
were also elevated.
Chen, 2017 53 CRSwNP UA: SM • Increased: IL-25, IL-5, Patients with asthma + NP: type 1 Type 2 4
CRSsNP and eotaxin 3 and 2 cytokines decreased and
increased, respectively. IL-25
• Decreased: IFN-γ
was elevated
Riccio, 2002 35 CRS UA: RL IL-4, IL-1B, IL-6, IL-8, Type 1 and 2 cytokines trended Mixed (1, 2) 4
neutrophils, and higher in patients with CRS and
monocytes/ asthma partly independent from
macrophages atopy
Tomassen, 2016 262 CRSwNP UA: SM • SC9: IL-17, TNF-a, Type 1, 2 and 3 inflammations Mixed (1–3) 4
IL-22, IL-5, ECP, IgE, developed more frequently in
MPO, IL-8 patients with comorbid asthma
• SC10: IL-5, ECP, IgE,
MPO, IL-8
Wei, 2018 69 CRSwNP UA: SM IL-5, IgE, ECP Type 2 inflammation was Type 2 3
increased in patients with
recurrent CRSwNP and asthma
Dyneva, 2019* 4 CRSwNP UA: SM IL-17F, IL-13, IFN-γ Type 1, 2, and 3 inflammations Mixed (1–3) 4
were increased in patients with
CRSwNP and allergic or non-
allergic bronchial asthma
Wu, 2017 106 CRSwNP UA: SM Eosinophils, IgE Type 2 inflammation in sinuses Type 2 3
was correlated with asthma
severity and was consistent
between UA and LA
Stevens, 2019 25 CRSwNP UA: SM CLC, ECP Type 2 inflammation occurred in Type 2 4
group with highest CRSwNP
CRSsNP
and asthma comorbidity
Dyneva, 2020* 96 CRSwNP UA: SM IL-6, TNF-alpha, TGF- Mixed type 1, 2, and 3 Mixed (1–3) 4
beta, IL-10, IL-5, IL-13, inflammations were induced in
IL-17f, IL-37 non-allergic asthma and CRS
Van Zele, 2014 36 CRSwNP UA: SM IL-5, ECP Type 2 inflammation was higher in Type 2 4
those with recurrent CRS and
asthma
Zhang, 2008 105 CRSwNP UA: SM TGFβ Among Belgian patients with CRS Type 1 4
and asthma, type 1
inflammation was increased
Paggiaro, 2019* 91 CRSwNP UA + LA: NS, Eosinophils Severe asthmatics showed higher Type 2 4
CRSsNP Sputum eosinophils in group with higher
proportion of CRS
Hakansson, 2015 33 CRSwNP UA + LA: SM BB IL-13 Type 2 inflammation was Type 2 3
significantly elevated in
bronchial biopsies in the CRS
+ asthma group. NP and
bronchial type 1/2 inflammation
were associated.

(Continues)

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TABLE I.
Continued
Biomarkers different from Predominant
Author, year n UA Phenotype (s) Sampling controls Summary of findings endotype LOE

Nishio, 2019 57 CRSwNP LA: Sputum Neutrophils, eosinophils Type 1/3 (neutrophils) and type 2 Mixed (1,2, and 3) 4
(eosinophils) cytokines increase
CRSsNP
with severity of CRS in setting
of comorbid asthma
Forster-Ruhrmann, 2022 91 CRSwNP (75%) UA: SM, NP SC5: IL-5, ECP, TARC, Type 1/2/3 mixed inflammatory Mixed (1–3) 3
PARC, eotaxin, MIP1α, endotype developed in patient
CRSsNP(25%)
MPO, IL-22 cluster with highest proportion
of asthma and CRSwNP
Huang, 2022 143 CRSwNP LA: Sputum SC3: IL-4, IL-5, IL-13, Mixed 1, 2, and 3 inflammatory Mixed (1–3) 4
CRSsNP IFN-γ, TNF-α, IL-17, cytokines were elevated in
and IL-33 patients with uncontrolled
asthma and comorbid CRS

BL = bronchoalveolar lavage; BB = bronchial biopsy CRS = chronic rhinosinusitis; LA = lower airway; LOE = level of evidence; NSAID = non-steroidal
anti-inflammatory drug; NS = nasal secretions; NP = nasal polyps; pNP = primary nasal polyps; RL = rhinonasal lavage; rNP = refractory nasal polyps;
SC = subject cluster; SM = sinonasal mucosa; UA = upper airway.
*Grey literature.

showed a significant elevation in IL-8 and CD68+ macro-
phage levels. A type 3 endotype shift was also demon-
strated in one study, with IL-17A being significantly
elevated in the sinonasal mucosa of Taiwanese patients
with both asthma and CRSsNP.32 Mixed endotype shifts
were also prevalent in this patient population. This
includes the T1/2 (n = 1) endotype demonstrated by Ric-
cio et al.33 with elevations in IL4, IL-6, IL-8, and IL-1B
from rhinonasal lavage. The T1/2/3 endotype was particu-
larly prevalent (n = 8.5), with the following biomarkers
being elevated by 3 or more T1/2/3 studies; type 2 markers
(IL-5, IL-13, and eosinophils), type 1 markers (IL-6, MPO,
TNF-alpha, and IFN-gamma) and the type 1/3 marker,
neutrophils.11,14,18,19,30–37 The T1/2/3 endotype shift was
more prevalent in patients residing in Asia or Russia, due
to 44.4% (4/9) and 100% (2/2) of studies in each respective
location demonstrating a T1/2/3 endotype shift (Fig. 2).
Only 27.7% (2.5/9) of studies conducted in western coun-
tries demonstrated a T1/2/3 shift (Fig. 2). Atopy was
reported by Huang et al.37 in patients with a T1/2/3 mixed
endotype; however, a T1/2/3 endotype shift occurred in a
study by Riccio et al.33 independent of atopy.
Patients diagnosed with AERD demonstrated type
2 (n = 4), T1/2/3 (n = 1), and mixed type 2, 3 (T2/3)
(n = 1) endotype shifts (Table II). Among patients with
type 2 endotype shifts, elevated biomarkers included
ECP, eosinophils, and periostin shown in uncinate tissue,
nasal polyps, rhinonasal lavage, and sputum samples.38–40
Upper and lower airway eosinophilia were correlated in
this patient population. Two studies on AERD described
mixed inflammatory endotype shifts, T1/2/3 and T2/3.41,42
Scott et al.41 demonstrated a shift to the T1/2/3 endotype
through significant elevations in type 1 (IFN-γ) and type
2 (IL-5 and IL-13) cytokines. San Nicolo et al.42 demon-
strated a T2/3 endotype, which shared with Scott et al.41
elevations in type 2 cytokines and the type 3 cytokine:
IL-17.
Patients diagnosed with CRS and COPD or bronchi-
ectasis demonstrated a T1/2 (n = 1) endotype shift
(Table III). Yang et al.43 demonstrated this T1/2 endotype
through elevations in type 1 (IL-6 and IL-8) and type
2 (eosinophils) biomarkers in patients diagnosed with
COPD and CRS compared with COPD alone. A similar
elevation was demonstrated in those with CRS, COPD,
and bronchiectasis; however, the elevation in IL-8 did not
reach significance.43
DISCUSSION
Endotypes in Comorbid Chronic Rhinosinusitis
and Asthma
The limited evidence in CRS and comorbid
asthma demonstrated a predominance of non-type 2 or
mixed inflammation. Zhang et al.30,31 and Hoggard
et al.31 depicted a type 1 endotype; however, different
cytokines were elevated in the sinonasal mucosa. This dif-
ference could be caused by the different array of cytokines
being studied (Table I). However, geography could play a
role as Zhang et al.31 and Hoggard et al.30 were conducted
in China and New Zealand, respectively.44 Geographical
differences in cytokine expression within the same CRS
endotype has not been comprehensively studied.
A type 3 endotype shift was also demonstrated in
the sinonasal mucosa of Taiwanese patients with asthma
and CRSsNP.32 This endotype could be related to the lack
of nasal polyps which is supported by Stevens et al., who
demonstrated a higher proportion of type 3 inflammation
in CRSsNP than CRSwNP.10,32 There was limited evi-
dence for CRSsNP (n = 1) and asthma in this review, so
it is difficult to confidently discern the impact of nasal
polyposis on non-type 2 inflammation. It is possible that
nasal polyposis plays a predictive role when placed in a
model consisting of multiple variables.30,45 Interestingly,
being in Taiwan may have influenced this study’s type 3
endotype shift, as Staudacher44 demonstrated a higher
proportion of type 3 inflammation in patients from Bei-
jing when compared with Europe, Australia, and the
United States.44
In patients that had a mixed endotype shift, there is
likely a unique unified airway inflammatory mechanism
due to Håkansson et al.29 demonstrating an association

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TABLE II.
Studies Examining for Cytokine Endotypes in AERD.
Biomarkers different from Predominant
Author, year n CRS Phenotype Sampling controls Summary of findings endotype LOE

Stevens, 2015 56 CRSwNP, CRSsNP, AERD UA:UT, RL • Increased: ECP, MCP-1, Type 2 cytokines and cytokines Type 2 4
GM-CSF potentially involved in eosinophil
survival (GM-CSF) and activation
• Decreased: IL-10, SDF-1α,
(MCP-1) were elevated in AERD
SDF-1β
Brescia, 2020 135 CRSwNP, AFRS, AERD UA: SM None (did not reach No significant differences, but cluster Type 2 4
significance) with elevated AERD was mainly
eosinophilic by histology
Scott, 2021 139 CRSwNP, AERD UA: NS IL-5, IL-6, IL-13, IFN-γ Type 1 and 2 cytokines elevations Mixed (1–3) 4
differentiate AERD from CRSwNP,
but the former also has features of
type 3 inflammation 1, 2, 3
Contro, 2020 144 CRSwNP, AERD UA: NP Eosinophils Type 2 cytokines (eosinophils) tend to Type 2 4
be elevated in AERD, but not in
non-eosinophilic CRS or asthma
alone
San Nicolo, 2020 104 CRSwNP, AERD UA: NS IL-17, eotaxin Type 3 (IL-17) and type 2 (eotaxin) Mixed (2, 3) 4
cytokines were elevated, and type 1
inflammation was downregulated in
patients with AERD compared with
healthy controls and NP alone
Jakiela, 2021 54 AERD UA + LA: Eosinophils, periostin Type 2 cytokines were more elevated Type 2 4
RL + BL in AERD than in NSAID-tolerant
asthma (NTA). UA eosinophilia was
correlated with LA levels.

AERD = aspirin-exacerbated respiratory disease; AFRS = allergic fungal rhinosinusitis; BL = bronchoalveolar lavage; C = cluster; CHES = chronic hyper-
plastic eosinophilic sinusitis; CRS = chronic rhinosinusitis; LA = lower airway; n = total sample size; NP = nasal polyps; NSAID = nonsteroidal anti-inflammatory
drug; NS = nasal secretions; RL = rhinonasal lavage; SM = sinonasal mucosa; UA = upper airway; UT = uncinate tissue.

between nasal polyp and bronchial type 1 and 2 inflamma-
tory cytokines. Additionally, all three endotypes can occur
simultaneously in the UAC with T1/2/3 endotype shifts
being depicted in sinonasal mucosa and sputum samples.
The prevalence of the T1/2/3 mixed endotype shift
could be impacted by nasal polyposis, geographical loca-
tion, and atopy. Nasal polyposis could influence the
T1/2/3 endotype due to this being the predominant
endotype in 65% of studies focusing on CRSwNP and
asthma and 0% of CRSsNP and asthma studies. Addi-
tional research is needed as there was only one study
focusing on patients with CRSsNP and asthma.32 Inter-
estingly, the T1/2/3 endotype shift was more prevalent in
patients residing in Asia or Russia than in western coun-
tries (Fig. 2). The cause for this geographical difference in
endotype proportions could be related to the unique
weather, pollen, and pollution.46,47 Lastly, atopy is com-
monly associated with type 2 inflammation, but there is
mixed evidence regarding its prevalence in patients with
a T1/2/3 mixed endotype.18,19,33,37 Furthermore, the
factors impacting non-type 2 and mixed endotypes in
patients with CRS and asthma is a novel area of study
that requires more attention.
Endotypes in Aspirin-Exacerbated Respiratory
Disease
As expected, type 2 was the predominant endotype
shift in AERD.38–40 Upper airway and lower airway eosin-
ophilia were also correlated, which provides support for a
unified inflammatory process in AERD.40 A comprehen-
sive discussion of type 2 inflammation in AERD was not
the focus of this study.
Despite AERD being a classically type 2 disease, two
studies described mixed inflammatory endotype shifts.41,42
Scott et al.41 demonstrated a shift to the T1/2/3 endotype,
while San Nicolo et al.42 demonstrated a T2/3 endotype
shift. Scott et al.41 was the only AERD study to demonstrate
elevations in the type 1 cytokine, IFN-γ, which could be
related to eosinophils expressing IFN-gamma in patients

TABLE III.
Studies Examining for Cytokine Endotypes in Comorbid CRS and COPD or Bronchiectasis.
CRS
Author, year n Phenotype Sampling Biomarkers different from controls Summary of findings Predominant endotype LOE

Yang, 2017 136 CRS LA: sputum IL-6, IL-8, MMP-9, eosinophils Type 1 and 2 cytokines are significantly Mixed (1, 2) 4
elevated in patients with CRS and COPD
and CRS, COPD, and bronchiectasis
compared to patients without CRS

AERD = CRS: chronic rhinosinusitis; COPD = chronic obstructive pulmonary disease; LA = lower airway; n = total sample size.

Laryngoscope 134: March 2024 Heffernan et al.: Unified Airway and Non-Type 2 Endotypes
1010

with AERD.22,48 The similarity in geographic location and
sampling techniques can explain the inflammatory congruen-
cies, but the differences lack an explanation.44 Understanding
that inflammatory patterns are not homogenous amongst
AERD patients could help explain discrepancies in time to
polyp recurrence and biologic initiation, but its impact on
the response to biologic agents remains controversial.49
This statement is based on one clinical communication
which emphasizes the need for additional studies.
Endotypes in Comorbid Chronic Rhinosinusitis
and COPD or Bronchiectasis
Patients diagnosed with CRS and COPD or Bronchi-
ectasis demonstrated a T1/2 endotype shift. The causes for
these cytokine elevations could be related to age, smoking
status, and nasal polyposis. The population studied by
Yang et al.43 was over 70 years of age and had a high pro-
portion of cigarette smokers which could have influenced
the inflammatory endotype. This is supported by Ryu7 who
demonstrated that smokers with eosinophilic nasal poly-
posis had age-associated increases in type 1, 2, and
3 inflammatory mediators.7 Nasal polyposis remains a
potential confounding factor; however, no conclusion can
be made due to this study’s lack of nasal endoscopy. Fur-
thermore, additional studies are needed to better under-
stand mixed inflammation in this patient population.
Implications for Practice
This review demonstrates that there is a paucity of data
on the impact of comorbid CRS and lower airway disease on
non-type 2 inflammation. Based on limited evidence, patients
with CRS and comorbid lower airway pathologies demon-
strated shifts to non-type 2, type 2, and mixed endotypes in
both the upper and lower airways. Type 1 was predominant
in a small number of articles studying upper airway samples
from patients with CRS and asthma living in the West or
Asia (Fig. 2), whilst type 3 endotype shifts were seen in
patients with CRS and asthma from Italy or Taiwan (Fig. 2).
Additionally, a large proportion (47.7%) of studies demon-
strated mixed inflammatory shifts. These mixed endotypes
were demonstrated in AERD, comorbid CRS and asthma,
and comorbid CRS and COPD. Endotyping patients with
CRS and COPD is a new practice that is based on proteo-
mics, sputum microbiome, and cytokines, with minimal
research on its impact on CRS endotypes.50–52
This demonstrates the need to conceptualize CRS
inflammation as a continuum of type 1, 2, and 3 endotype
profiles. These include type 1, type 2, type 3, T1/2, T1/3,
T2/3, and T1/2/3 inflammatory endotypes with different
inflammatory endotypes being expressed at different levels.
Utilizing this framework of a proportional endotype predom-
inance may help rhinologists explain why specific patients
do not respond optimally to targeted biologics. This classifi-
cation remains academic until we can validate these con-
cepts clinically. Standardized inflammatory endotyping for
every patient at academic institutions could help improve
the quality of future studies. Regarding clinical signs and
symptoms, our understanding is limited to type 2 inflamma-
tion being associated with allergic mucin, hyposmia, and a
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lack of rhinorrhea, while non-type 2 inflammation is defined
by pus in the nasal cavity.10,31,53,54 Additional studies are
needed to identify more clinical features that differentiate
type 1, 3, and mixed inflammatory endotypes.
The optimization of CRS endotyping could allow for bet-
ter selection of biologics. Currently approved biologics in
Canada for CRS target type 2 inflammation (e.g., dupilumab,
mepolizumab, and omalizumab). There could be some
benefit of using these drugs in patients with mixed
inflammation that includes type 2 inflammation;
however, studies on this are lacking. Biologics for
non-type 2 inflammation could also benefit patients
diagnosed with CRS and comorbid lower airway dis-
ease. These therapies include type 1 specific biologics
(Canakinumab (anti-IL-1B), Sirukumab (anti-Il-6), and
Fontolizumab (anti-IFN-gamma)) and the type 3 specific
biologic ixekizumab (anti-IL17A). 55–58 There is a lack
of literature describing their use in CRS but, there
could be a theoretical benefit to patients with non-type
2 or mixed endotypes. Currently, only tezepelumab, an
anti-thymic stromal lymphopoietin (TSLP) monoclonal
antibody approved for use in severe asthma, has the poten-
tial to treat both non-type 2 and type-2 inflammation in
CRS.59 This is under the assumption that TSLP’s role in
CRS is similar to that of asthma where it is a common
upstream regulator of type 2 and non-type 2 inflammation.60
Tezepelumab is currently not approved for use in CRS but a
phase 3 efficacy and safety study (WAYPOINT) in patients
with severe CRSwNP is in progress.61 Studies on non-type
2 biologics in CRS are needed to achieve precision medicine
in CRS management.
The results should be assessed knowing that this
study had limitations. A risk of bias analysis was not
completed, but the level of evidence was provided. Gluco-
corticoid use prior to sampling was not controlled for in a
majority of studies, which could impact inflammatory
endotypes. Most studies did not include healthy controls
which prevented this study from determining the overall
inflammatory endotype. Therefore, endotypes listed in
this study are endotype shifts relative to isolated upper
airway or lower airway disease rather than absolute end-
otypes. Lastly, most lower airway samples were sputum
which is not a pure lower airway sample due to contami-
nation by upper airway secretions.
To improve the literature on non-type 2 and mixed
inflammation in CRS, the following recommendations
should be considered. Prospective studies with larger sam-
ple sizes are needed. The location of airway sampling and
use of steroids should be controlled due to their impact on
inflammation. The remaining concomitant treatments
should be recorded to mitigate confounding. This medica-
tion choice and inflammation will be influenced by CRS
severity, which should be measured in future studies.
Patient geographical location, environmental factors (aller-
gens, pollution, weather, etc.), and ethnicity should also be
included in the discussion of patient endotypes. Addition-
ally, bronchioalveolar lavages should be used over sputum
to obtain a pure lower airway sample. Lastly, when study-
ing CRSsNP, ethmoid mucosa should be sampled as it was
the only location to yield cytokine differences when com-
pared with healthy controls.62
Heffernan et al.: Unified Airway and Non-Type 2 Endotypes
1011

CONCLUSION
Type 2 CRS has been extensively reviewed due to
the advent of biologics targeting type 2 inflammation, but
outcomes may be suboptimal due to the presence of non-
type 2 and mixed inflammation. This mixed inflammatory
picture was demonstrated by 56% of the included studies
on comorbid CRS and lower airway disease. The limited
evidence on CRS and comorbid asthma demonstrated a
predominance of non-type 2 or mixed inflammation,
which could be impacted by patient geography, polyposis,
and atopy. In AERD, which is classically thought of as a
type 2 disease; demonstrated mixed inflammation in
a third of included studies. The study on CRS and COPD
or bronchiectasis demonstrated a mixed endotype shift
that may be related to age, smoking status, and nasal
polyposis. This is evidence that CRS endotyping in the
setting of the UAC should be thought of as a continuum
of endotype profiles with mixed endotypes expressing dif-
ferent types of inflammation to various degrees. However,
additional work needs to be done in non-type 2 inflamma-
tion to optimize the management of patients who have a
mixed inflammatory picture.
ACKNOWLEDGEMENTS
We acknowledge Dr. Ximena Maul Fonseca for assistance
with administrative tasks.
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