respiratory investigation xxx (xxxx) xxx

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Respiratory Investigation

journal homepage: www.elsevier.com/locate/resinv

Editorial

Redefining “one airway, one disease”: Broader

classification considering specific pathophysiology
and treatment

Keywords:
One airway, one disease
Asthma
Chronic rhinosinusitis
Allergic rhinitis

The upper and lower airways are contiguous and share
functional linkages and similar histologies. Among upper and
lower airway disorders, allergic rhinitis (AR), chronic rhinosi-
nusitis (CRS), and asthma are common, often occur concom-
itantly, and exhibit similar pathophysiological or
inflammatory profiles [1].
Approximately 20%e60% of patients with AR have asthma,
whereas up to 70% of patients with asthma have AR [2,3]. AR is
associated with asthma development [4], poorer disease
control, and more intense airway inflammation [3] in patients
with asthma. The original concept of “one airway, one dis-
ease,” referring to immunoglobulin (Ig)E-mediated asthma
and AR as a “united airway” disease, emerged in the late 1990s
[5], when pivotal roles of cysteinyl-leukotrienes as potent in-
flammatory mediators in both conditions were becoming
evident. This concept was facilitated by the emergence of
leukotriene receptor antagonists, which have clinical utility in
asthma as well as AR [5]. The Allergic Rhinitis and its Impact
on Asthma (ARIA) guidelines, originally published in 2001
followed by revisions [2], further promoted this concept. More
recently, anti-IgE omalizumab has become available, which
has indications for both severe atopic asthma and intractable
AR. The link between AR and asthma has been additionally
implicated in the following: 1) an allergen challenge in one
compartment (the nose or bronchus) causes detectable
allergic inflammation in the other compartment [6]; 2) the
intensity of inflammation in both compartments, as
examined by nasal and exhaled nitric oxide levels, are inter-
correlated in patients with asthma comorbid with AR [7], 3)
patients with severe asthma comorbid with AR are more
responsive to omalizumab than those without AR [8]; and 4)
treatment of AR with nasal corticosteroids improves lung
function, airway hyperresponsiveness, and exacerbation fre-
quency in patients with asthma who are not treated with
inhaled corticosteroids [9].
Similarly, 40%e50% of patients with asthma have comor-
bid CRS [1], which is more prevalent in patients with severe
than non-severe asthma, while asthma coexists in 20%e30%
of patients with CRS [6,10]. CRS is associated with the devel-
opment of late-onset asthma [11], exacerbations [6], poor
disease control, airflow limitations [12], and elevated blood
and sputum eosinophil counts and FeNO levels [13] in patients
with asthma. In particular, patients with CRS complicated by
nasal polyps (CRSwNP) or eosinophilic CRS [14] often have
comorbid asthma, characteristically severe eosinophilic
asthma (predominantly non-atopic), at a very high prevalence
of up to 70% [14]. The degree of eosinophilia in sinus or nasal
polyp tissue obtained in endoscopic sinus surgery, severity of
CRS as assessed using computed tomography (CT), and ol-
factory function correlate with lower airway indices, including
FeNO, sputum eosinophil, and periostin levels [10]. Removal of
upper airway inflammation (i.e., nasal polyps) through sur-
gery may improve asthma control [15] and reduce sputum
periostin levels [16]. Nasal polyp eosinophilia may help predict

Please cite this article as: Niimi A, Redefining “one airway, one disease”: Broader classification considering specific patho-
physiology and treatment, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2021.04.008
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2 respiratory investigation xxx (xxxx) xxx
Table 1 e Three subtypes of the “one airway, one disease” concept and corresponding treatment(s).
Subtype
(Classical definition as proposed by the ARIA guidelines)
✓ Allergic rhinitis & atopic asthma
(Other subtypes not mentioned in the ARIA guidelines)
✓ Eosinophilic CRS (CRSwNP) & eosinophilic asthma (typically non-atopic)
✓ Neutrophilic CRS (CRSsNP) & non-asthmatic neutrophilic lower airway disease (designated as
sinobronchial syndrome)
reduced exacerbation frequency [17] or future asthma devel-
opment [18] after endoscopic sinus surgery in patients with
CRS with [17] or without [18] asthma, respectively. Serum
periostin is a sensitive biomarker for detecting comorbid
CRSwNP in patients with asthma [13]. Taken together, asthma
and CRSwNP may be linked with each other through common
pathways such as interleukin (IL)-4/13 [10]. Dupilumab, a
monoclonal antibody directed against IL-4Ra, has indications
for both conditions. Anti-IgE omalizumab and anti-IL-5 bi-
ologics (e.g., mepolizumab and benralizumab) also have po-
tential for CRSwNP, as well as asthma, despite the former
being off-label at the moment [19].
Nasal and sinus tissue may exhibit features of either type 1
or type 2 inflammation [6], while the percentage of type 2
signature disease in patients with CRS is dramatically
increasing (“eosinophilic shift”) even in Asian countries over
the last 20 years [20]. The nature of upper and lower airway
inflammation is usually concordant [6]. Besides the afore-
mentioned combinations of “type 2” disorders, classical
neutrophilic CRS, typically uncomplicated by nasal polyps
(CRSsNP), is often comorbid with neutrophilic lower airway
disease, such as diffuse panbronchiolitis, bronchiectasis, and
chronic bronchitis. These combinations are designated as
sinobronchial syndrome (SBS), which appeared in the litera-
ture in 1966 [21], but nowadays, it is an entity almost restric-
tively used in Japan [22]. Bronchitic SBS is the most common
cause of chronic productive cough and third-leading cause of
all cases of chronic cough in Japan [22,23]. Although the me-
diators/cytokines that are involved have not been confidently
indicated as are in the aforementioned two “type 2” combi-
nations, sinobronchial involvement in SBS is commonly and
uniquely responsive to low-dose macrolides, such as eryth-
romycin [23]. It is also essential to understand that mixed
endotypes of eosinophilic and neutrophilic inflammation are
often found in patients with CRS [19]. For example, even in
patients diagnosed with eosinophilic CRS, the neutrophilic
component of CRS may partially respond to macrolides [24],
and vice versa.
The three subtypes of the “one airway, one disease”
concept and their specific treatments are summarized in
Table 1. The ARIA guidelines exclusively focus on the combi-
nation of atopic asthma and AR. However, we need to identify
other subtypes, as presented in Table 1, for appropriate,
optimal, and individualized treatment. It is also important to
note that these subtypes often overlap with each other in a
single patient, who may require more comprehensive
treatment.
Please cite this article as: Niimi A, Redefining “one airway, one disease”: Broader classification considering specific patho-
physiology and treatment, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2021.04.008
Downloaded for Fakultas Kedokteran Universitas Hasanuddin (ppds.fkuh@gmail.com) at Hasanuddin University from ClinicalKey.com by
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Common treatment(s) for “united
airways”
LTRAs, Omalizumab
Dupilumab
Macrolide antibiotics
Conflict of interest
Akio Niimi received honoraria from AstraZeneca K.K., Glax-
oSmithKline K.K., KYORIN Pharmaceutical Co., Ltd., Sanofi K.K.,
Novartis Pharma K.K., and Nippon Boehringer Ingelheim Co.,
Ltd.; research funding from MSD K.K., Boston Scientific Corpo-
ration, and Nippon Boehringer Ingelheim Co., Ltd.; and dona-
tions from KYORIN Pharmaceutical Co., Ltd., Nippon Boehringer
Ingelheim Co., Ltd., and ; ONO Pharmaceutical Co., Ltd.
references
[1] Samitas K, Carter A, Kariyawasam HH, Xanthou G. Upper and
lower airway remodelling mechanisms in asthma, allergic
rhinitis and chronic rhinosinusitis: the one airway concept
revisited. Allergy 2018;73:993e1002.
[2] Brozek JL, Bousquet J, Agache I, Agarwal A, Bachert C, Bosnic-
Anticevich S, et al. Allergic rhinitis and its Impact on asthma
(ARIA) guidelines-2016 revision. J Allergy Clin Immunol
2017;140:950e8.
[3] Tajiri T, Niimi A, Matsumoto H, Ito I, Oguma T, Otsuka K,
et al. Prevalence and clinical relevance of allergic rhinitis in
patients with classic asthma and cough variant asthma.
Respiration 2014;87:211e8. https://doi.org/10.1159/
000355706.
[4] Shaaban R, Zureik M, Soussan D, Neukirch C, Heinrich J,
Sunyer J, et al. Rhinitis and onset of asthma: a longitudinal
population-based study. Lancet 2008;372(9643):1049e57.
https://doi.org/10.1016/S0140-6736(08)61446-4.
[5] Grossman J. One airway, one disease. Chest 1997;111:11Se6S.
[6] Hew M, Heaney LG. The contribution of comorbidities,
psychosocial factors and adherence to the presentation of
severe asthma. Number 84. In: Chung KF, Israel E, Gibson PG,
editors. “Severe asthma”, ERS monograph; 2019. p. 30e47.
Chief: Hurst JR.
[7] Asano T, Takemura M, Kanemitsu Y, Yokota M, Fukumitsu K,
Takeda N, et al. Combined measurements of fractional
exhaled nitric oxide and nasal nitric oxide levels for
assessing upper airway diseases in asthmatic patients. J
Asthma 2018;55:300e9. https://doi.org/10.1080/
02770903.2017.1332203. PMID: 28513250.
[8] Adachi M, Kozawa M, Yoshisue H, Milligan KL, Nagasaki M,
Sasajima T, et al. Real-world safety and efficacy of
omalizumab in patients with severe allergic asthma: a long-
term post-marketing study in Japan. Respir Med
2018;141:56e63. https://doi.org/10.1016/j.rmed.2018.06.021.
[9] Lohia S, Schlosser RJ, Soler ZM. Impact of intranasal
corticosteroids on asthma outcomes in allergic rhinitis: a
 respiratory investigation xxx (xxxx) xxx
meta-analysis. Allergy 2013;68:569e79. https://doi.org/
10.1111/all.12124.
[10] Kanemitsu Y, Suzuki M, Fukumitsu K, Asano T, Takeda N,
Nakamura Y, et al. A novel pathophysiologic link between
upper and lower airways in patients with chronic
rhinosinusitis: association of sputum periostin levels with
upper airway inflammation and olfactory function. World
Allergy Organ J 2020;13:100094. https://doi.org/10.1016/
j.waojou.2019.100094.
[11] Jarvis D, Newson R, Lotvall J, Hastan D, Tomassen P, Keil T,
et al. Asthma in adults and its association with chronic
rhinosinusitis: the GA2LEN survey in Europe. Allergy
2012;67:91e8.
[12] Kanemitsu Y, Fukumitsu K, Kurokawa R, Takeda N,
Suzuki M, Yap J, et al. Increased capsaicin sensitivity in
severe asthmatics associated with worse clinical outcome.
Am J Respir Crit Care Med 2020;201:1068e77. https://doi.org/
10.1164/rccm.201911-2263OC.
[13] Asano T, Kanemitsu Y, Takemura M, Yokota M, Fukumitsu K,
Takeda N, et al. Serum periostin as a biomarker for comorbid
chronic rhinosinusitis in patients with asthma. Ann Am
Thorac Soc 2017;14:667e75. https://doi.org/10.1513/
AnnalsATS.201609-720OC.
[14] Tokunaga T, Sakashita M, Haruna T, Asaka D, Takeno S,
Ikeda H, et al. Novel scoring system and algorithm for
classifying chronic rhinosinusitis: the JESREC Study. Allergy
2015;70:995e1003.
[15] Tajiri T, Fujita S, Sokai A, Gotoh K, Nakamura Y, Kita H, et al.
Effect of endoscopic sinus surgery for chronic rhinosinusitis
on the state of coexisting asthma. Allergol Int
2020;69:279e80. https://doi.org/10.1016/j.alit.2019.12.001.
[16] Kanemitsu Y, Fukumitsu K, Kurokawa R, Takeda N, Ozawa Y,
Masaki A, et al. Moulds and Staphylococcus aureus
enterotoxins are relevant allergens to affect Type 2
inflammation and clinical outcomes in chronic
rhinosinusitis patients. ERJ Open Res 2020;6:265e2020.
https://doi.org/10.1183/23120541.00265-2020. eCollection
2020 Oct.
[17] Kanemitsu Y, Kurokawa R, Ono J, Fukumitsu K, Takeda N,
Fukuda S, et al. Increased serum periostin levels and
eosinophils in nasal polyps are associated with the
preventive effect of endoscopic sinus surgery for asthma
exacerbations in chronic rhinosinusitis patients. Int Arch
Allergy Immunol 2020;181:862e70. https://doi.org/10.1159/
000509253.
[18] Kurokawa R, Kanemitsu Y, Fukumitsu K, Takeda N, Yap JM,
Ozawa Y, et al. Nasal polyp eosinophilia and FeNO may
Please cite this article as: Niimi A, Redefining “one airway, one disease”: Broader classification considering specific patho-
physiology and treatment, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2021.04.008
Downloaded for Fakultas Kedokteran Universitas Hasanuddin (ppds.fkuh@gmail.com) at Hasanuddin University from ClinicalKey.com by
Elsevier on June 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.
3
predict asthma symptoms development after endoscopic
sinus surgery in CRS patients without asthma. J Asthma 2021
Mar 15:1e9. https://doi.org/10.1080/02770903.2021.1897837
[Online ahead of print].
[19] Cardell L-O, Stja€ rne P, Jonstam K, Bachert C. Endotypes of
chronic rhinosinusitis: Impact on management. J Allergy Clin
Immunol 2020;145:752e6. https://doi.org/10.1016/
j.jaci.2020.01.019.
[20] Zhang Y, Gevaert E, Lou H, Wang X, Zhang L, Bachert C, et al.
Chronic rhinosinusitis in asia. J Allergy Clin Immunol
2017;140:1230e9.
[21] Greenberg SD, Ainsworth JZ. Comparative morphology of
chronic bronchitis and chronic sinusitis with discussion of
"sinobronchial syndrome". South Med J 1966;59:64e74.
[22] Niimi A. Geography and cough aetiology. Pulm Pharmacol
Therapeut 2007;20:383e7.
[23] Mukae H, Kaneko T, Obase Y, Shinkai M, Katsunuma T,
Takeyama K, et al. JRS guidelines committee for the
management of cough and sputum. The Japanese respiratory
society guidelines for the management of cough and sputum
(digest edition). Respir Investig 2021 Feb 25;S2212-
5345(21):32e40. https://doi.org/10.1016/j.resinv.2021.01.007.
Online ahead of print. PMID: 33642231.
[24] Tamechika S, Isogai S, Maeda S, Naniwa T, Niimi A.
Improvement of chronic rhinosinusitis and reduction of the
myeloperoxidase-antineutrophil cytoplasmic antibody titer
in a patient with eosinophilic granulomatosis with
polyangiitis by additional mepolizumab. Case Rep
Rheumatol 2021 Mar 29. https://doi.org/10.1155/2021/
5561762. 2021:5561762. eCollection 2021.
Akio Niimi1
Department of Respiratory Medicine, Allergy and Clinical Immu-
nology, Nagoya City University Graduate School of Medical Sci-
ences, Japan
E-mail address: a.niimi@med.nagoya-cu.ac.jp
18 April 2021
Available online xxx
https://doi.org/10.1016/j.resinv.2021.04.008
2212-5345/© 2021 The Japanese Respiratory Society. Published by
Elsevier B.V. All rights reserved.
1
Full postal address: 1 Kawasumi, Mizuho-Cho, Muzuho-Ku,
Nagoya 467e8601 Japan