Age-related prevalence of chronic rhinosinusitis and nasal polyps and their relationships with asthma onset

Accepted Manuscript Title: Age-related prevalence of chronic rhinosinusitis and nasal polyps and their relationships with asthma onset Author: Ha-Kyeong Won, Young-Chan Kim, Min-Gyu Kang, Han-Ki Park, Seung-Eun Lee, Min-Hye Kim, Min-Suk Yang, Yoon-Seok Chang, Sang-Heon Cho, Woo-Jung Song PII: DOI: Reference:

S1081-1206(18)30114-5 https://doi.org/10.1016/j.anai.2018.02.005 ANAI 2460

To appear in:

Annals of Allergy, Asthma & Immunology

Received date: Revised date: Accepted date:

25-10-2017 2-2-2018 5-2-2018

Please cite this article as: Ha-Kyeong Won, Young-Chan Kim, Min-Gyu Kang, Han-Ki Park, Seung-Eun Lee, Min-Hye Kim, Min-Suk Yang, Yoon-Seok Chang, Sang-Heon Cho, Woo-Jung Song, Age-related prevalence of chronic rhinosinusitis and nasal polyps and their relationships with asthma onset, Annals of Allergy, Asthma & Immunology (2018), https://doi.org/10.1016/j.anai.2018.02.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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TITLE PAGE

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Age-related prevalence of chronic rhinosinusitis and nasal polyps and their

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relationships with asthma onset

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Ha-Kyeong Won, MDa,b, Young-Chan Kim, MD a,b, Min-Gyu Kang, MDc, Han-Ki Park, MDd,

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Seung-Eun Lee, MDe, Min-Hye Kim, MD, PhDf , Min-Suk Yang, MD, PhDa,g, Yoon-Seok

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Chang, MD, PhDa,h, Sang-Heon Cho, MD, PhDa,b, Woo-Jung Song, MD, PhDa,b

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a

Department of Internal Medicine, Seoul National University College of Medicine, Seoul,

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Korea

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b

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c

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d

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Korea

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e

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Korea Department of Internal Medicine, College of Medicine, Ewha Womans University,

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Seoul, Korea

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g

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h

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Korea

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea Department of Internal Medicine, Kyungpook National University Chilgok Hospital, Deagu,

Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan,

Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul, Korea Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam,

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Corresponding Author:

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Woo-Jung Song, MD, PhD

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Department of Internal Medicine, Seoul National University College of Medicine, 101

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Daehak-ro, Jongno-gu, Seoul, 03080, Seoul, Korea

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Mobile: 82-10-2721-9386

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Fax: 82-2-742-3291

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E-mail: [email protected]

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Key words: Chronic rhinosinusitis, nasal polyp, asthma, onset, epidemiology

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Abbreviations used:

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CRS: Chronic rhinosinusitis

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CRSsNP: Chronic rhinosinusitis without nasal polyps

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CRSwNP: Chronic rhinosinusitis with nasal polyps

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KNHANES: Korean National Health and Nutritional Examination Survey

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Source of Funding: None

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Conflict of Interest: None to declare

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Word count: 2773

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Figures: 3

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Tables: 3

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Abstract: Background: Chronic rhinosinusitis (CRS) is a major disease condition with high

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morbidity, and may influence lower airway disease status in adults. However, its associations

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with adult asthma onset and activity have not been examined in detail in a general adult

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population.

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Objective: To investigate the relationships between CRS with nasal polyps and asthma

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characteristics.

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Methods: A cross-sectional dataset from 17,506 adult participants (age≥18 years) in the

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Korean National Health and Nutrition Examination Survey 2010-2012 was analyzed. CRS

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was defined using structured questionnaires according to the international guideline, and

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presence of nasal polyps was objectively assessed using nasal endoscope. Presence of asthma

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and its onset and current activity were asked using structured questionnaires.

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Results: CRS was significantly related with asthma, but the relationships were distinct by

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CRS and asthma status. CRS with nasal polyps (CRSwNP) was significantly associated with

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adult-onset asthma (onset after 18 years) or late-onset asthma (onset after 40 years), whereas

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CRS without nasal polyps (CRSsNP) were related to childhood-onset asthma (onset before 18

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years) or early-onset asthma (onset before 40 years) in adults. Both CRS subgroups showed

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significant associations with current asthma but not with past asthma. However, comorbid

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asthma rate was less than 10% among subjects with CRS.

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Conclusion: This study found distinct age-related patterns of CRSwNP and asthma and

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demonstrated their significant associations in a general population. However, low prevalence

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of asthma in CRSwNP is in sharp contrast to the findings in Western populations, which

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warrants further investigation for ethnic or regional difference in CRSwNP-asthma

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relationships.

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INTRODUCTION

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Chronic rhinosinusitis (CRS) is a major disease affecting 5–10% of the general adult

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population worldwide.1 It significantly impacts broad aspects of quality of life and poses a

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considerable socioeconomic cost.1, 2 The disease burden is attributable not only to the direct

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effects of nasal symptoms, but also to asthma comorbidity.1, 3 Thus, the relationship between

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CRS and asthma has been a major topic of interest.4,5

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The clinical implications for comorbid asthma and CRS are complex but significant. Patients

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with comorbid asthma and CRS not only suffer from both conditions, but their CRS is more

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likely to be accompanied by nasal polyps (CRSwNP) and is more resistant to conventional

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treatment.1 In a recent cluster analysis of CRS patients, the rate of asthma comorbidity varied

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widely between CRS clusters, ranging from 7 to 71%; however, asthma comorbidity was

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strongly correlated with the presence of nasal polyps (NP).6 CRSwNP comorbidity is also

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clinically relevant to asthma, because the asthma is significantly more severe and persistent,

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compared to asthma in CRS without nasal polyps (CRSsNP) subjects.7, 8

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Comorbid CRSwNP and asthma are increasingly prevalent with age5, 9, 10, which implies that

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the disease burden will increase due to the aging population.11 However, in previous studies

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the participants were recruited from specialist clinics5, 9 or primary healthcare databases.10 To

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our knowledge, the age-related prevalence and relationship between CRSwNP and asthma

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have not been investigated using a nationwide community population survey.

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Another notable possibility is that the specific variety of asthma that is comorbid with CRS is

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a late-onset disease. Asthma is a heterogeneous syndrome rather than a single disease. In

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particular, the pathophysiology of typical adult-onset asthma is distinct from that of

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childhood-onset asthma.12, 13 Among various parameters that characterize asthma, age of

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onset is particularly important.14 The pathophysiology of late-onset asthma remains largely

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elusive, but it may be related to chronic upper airway diseases, even in the absence of atopy.

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In a recent series of asthma phenotyping studies (based in specialist clinics), CRSwNP was

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associated with the late-onset, non-atopic severe asthma phenotype.7, 13, 15 However, studies

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based in specialist clinics are subject to selection bias.

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In a large-scale general population study among European adults conducted by the GA2LEN

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network, late-onset asthma (defined as asthma onset at age ≥ 16 years) was significantly

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associated with CRS.16 Even in the absence of allergic rhinitis, the relative risk ratio (RRR)

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of late-onset asthma with CRS was 3.09 (95% confidence interval [CI] 2.51–3.81).16

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Considering the clinical relevance of NP in late-onset asthma7, 13, 15, the association between

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CRS and asthma according to the presence of NP warrants further investigation.

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This study examined the age-related prevalence of CRSwNP, CRSsNP, and asthma, as well

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as trends in asthma onset age, in a Korean general adult population.

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METHODS

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Study population

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This analysis was performed using the cross-sectional database of the 5th Korean National

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Health and Nutrition Examination Survey (KNHANES V) 2010–2012, which has been

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previously described.17 Briefly, the KNHANES V was a nationwide survey investigating

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health and disease status among the Korean general population. The details of the survey can

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be accessed online at https://knhanes.cdc.go.kr/knhnes. We selected this survey database

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because CRS and NP were assessed in this random population sample. Of the original 25,534

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participants, our study included a total of 17,506 who were at least 18 years old at the time of

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the survey and were not missing any relevant data. Participant selection is summarized in

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Figure 1. The Institutional Review Board at the Korea Centers for Disease Control and

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Prevention approved the study protocol, and all participants signed informed consent forms.

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Parameters

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The presence of CRS was assessed using criteria from the European Position Paper on

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Rhinosinusitis and Nasal Polyps (EP3OS) 201218, based on structured questionnaires and

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nasal endoscopic findings. A subject was considered positive for CRS if two or more of the

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following symptoms were present for longer than 3 months: anterior/posterior nasal drip,

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nasal obstruction, facial pain, and olfactory dysfunction. The presence of NP was objectively

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determined by trained otolaryngology residents using a nasal endoscope.19 CRS was

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classified accordingly as CRSsNP or CRSwNP.

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Asthma was defined by the following questionnaire items:

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Self-reported asthma: positive response to “Have you ever had asthma?”

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Never asthma: negative response to “Have you ever had asthma?”

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have asthma?”

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Past asthma: positive response to “Have you ever had asthma?”, but negative response to “Do you still have asthma?”

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Current asthma: positive responses to “Have you ever had asthma?” and “Do you still

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Physician-diagnosed asthma: positive response to “Have you ever had asthma diagnosed by a physician?”

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For those with physician-diagnosed asthma, the age at diagnosis was also requested. As there

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is no consensus on the criteria for adult-onset or late-onset adult asthma14, we arbitrarily

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classified subjects by the following age criteria:

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Using cutoff age ≥ 18 years: adult-onset vs. childhood-onset asthma

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Using cutoff age ≥ 40 years: late-onset vs. early-onset adult asthma

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Among a wide range of demographic parameters, we examined age, sex, body mass index

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(BMI), smoking status, and household income. Height and weight were measured and BMI

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was calculated as weight divided by height squared (kg/m2). Smoking status was classified as

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“never” for subjects who had never smoked or had smoked fewer than 100 cigarettes, as

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“former” for those who had stopped smoking for 6 months or more but who had smoked

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more than 100 cigarettes, and as “current” for those who currently smoked or had quit within

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the past 6 months. Household income was categorized as “low” or “high” at the 50th

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percentile of the entire survey population. History of allergic rhinitis was assessed using the

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question “Have you ever been diagnosed with allergic rhinitis by a doctor?”

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Statistics analyses

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For descriptive analyses, we calculated mean ± standard error (SE), or proportion ± SE. The

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chi-squared test for likelihood ratio was used to examine the relationships among categorical

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parameters. Multinomial logistic regression analyses were performed to investigate the

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relationship between CRS and asthma, with “no CRS” and “never asthma” as controls. The

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multivariate analyses were adjusted for basic demographic parameters that were significantly

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related to CRS status in univariate analyses (age, sex, smoking status, and BMI) and also for

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history of allergic rhinitis.

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To obtain unbiased national estimates representing the Korean general adult population, we

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applied the KNHANES sampling weights to account for the complex sample design. The

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sampling was adjusted for strata at the level of primary sampling units and households. As the

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proportion of missing data was near or below 5%, missing data was assumed to be missing at

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random and considered valid in all analyses. All statistical analyses were performed using

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Stata version 14.2 (Stata Corp, College Station, TX, USA). A two-sided p value less than 0.05

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was considered statistically significant.

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RESULTS

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Prevalence of CRS, asthma, and baseline characteristics

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Prevalence of CRSsNP and CRSwNP was 3.5 ± 0.2% and 2.5 ± 0.2% (mean ± SE),

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respectively. When classified by age group, the prevalence of CRSwNP increased with age

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among adults (≥ 18 years of age), which was particularly evident after the age of 40 years

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(see Figure 2). Current asthma and physician-diagnosed asthma also increased with age.

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However, CRSsNP was more prevalent in subjects aged < 40 years. The prevalence of

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allergic rhinitis was three times greater in CRSsNP compared to compared to CRSwNP and

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no CRS groups. Those with CRSwNP were significantly more likely to be male, to have

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higher BMI, to smoke cigarettes and to have asthma than the CRSsNP or no CRS groups (see

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Table 1).

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Relationship between CRS and asthma

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Self-reported asthma was more prevalent in the CRS groups compared to those without CRS

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(see Table 1). This association was noted irrespective of NP. However, current asthma was

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more prevalent in CRSwNP than in CRSsNP. In multinomial logistic regression analyses,

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both CRSsNP and CRSwNP retained statistically significant positive associations with

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current asthma (see Table 2). However, CRSwNP had a stronger association with current

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asthma than did CRSsNP, reflected in both RRR and p value (see Table 2). Past asthma was

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associated with neither CRS subgroups. Finally, in multivariate analyses, CRSsNP was only

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marginally related to physician-diagnosed asthma (RRR 1.57 [95% CI 0.97–2.55]; p = 0.067),

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while CRSwNP was significantly related (RRR 2.45 [95% CI 1.50–4.00]; p < 0.001).

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Relationship between CRSwNP and asthma onset

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Age at asthma onset was significantly greater in subjects with CRSwNP (51.9 ± 2.7 years)

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than in those with CRSsNP (31.7 ± 3.1 years) or without CRS (36.7 ± 1.0 years; Table 1).

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Figure 4 provides histograms showing the age of asthma onset is typically greater than 40

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years of age in CRSwNP in contrast to younger onset in CRSsNP and in those without CRS.

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The association between CRSwNP and adult-onset asthma was examined in multinomial

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logistic regression analyses, using two different cutoff ages (18 and 40 years; Table 3). Using

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the cutoff age of 18 years (adult-onset vs. childhood-onset asthma), CRSwNP was

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significantly related to adult-onset asthma (onset ≥ 18 years; RRR 2.40 [95% CI 1.37–4.18];

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p = 0.002), but was only marginally related to childhood-onset asthma (onset < 18 years;

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RRR 2.58 [95% CI 1.37–4.18]; p = 0.064). However, CRSsNP was not significantly

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associated with either adult-onset or childhood-onset asthma (see Table 3). History of allergic

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rhinitis was similarly related to both childhood-onset and adult-onset asthma (RRR 2.43

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[95% CI 1.53–3.87], p < 0.001 and RRR 2.35 [95% CI 1.63–3.39], p < 0.001, respectively;

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not shown).

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Using the cutoff age of 40 years (late-onset vs. early-onset asthma among adults), the

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associations were only significant between CRSwNP and late-onset asthma (onset ≥ 40 years;

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RRR 3.18 [95% CI 1.80–5.62], p < 0.001; Table 3). History of allergic rhinitis was more

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strongly associated with early-onset than late-onset asthma among adults (RRR 2.91 [95% CI

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2.00–4.22], p < 0.001 and RRR 1.77 [95% CI 1.09–2.89], p = 0.021, respectively; not shown).

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DISCUSSION

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This study examined age-related prevalence of CRSsNP, CRSwNP, and asthma, as well as the

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relationships among them, in a nationally representative, adult population sample in Korea.

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CRSwNP and asthma were both more prevalent in older adults, and CRSwNP is significantly

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related to current asthma and physician-diagnosed asthma but not to past asthma. The age of

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onset of asthma was significantly older in subjects with CRSwNP than in subjects with

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CRSsNP (51.9 vs. 31.7 years old). The relationships between CRSwNP and adult-onset (or

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late-onset) asthma were validated in multivariate analyses. In contrast, CRSsNP was more

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prevalent in younger adults and more closely related to history of allergic rhinitis. CRSsNP

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was significantly associated with current asthma but did not have any significant associations

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with either asthma onset phenotype.

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The predominance of CRSwNP in older adults has been reported from hospital-based studies.

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In a previous analysis of asthma patients, the frequency of NP was three to four times higher

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among those older than 40 years than their younger counterparts (12.4% vs. 3.1%; p < 0.01).5

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In a study of patients with CRS visiting a specialist clinic, elderly patients (older than 65

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years) had significantly more frequent asthma than non-elderly patients (younger than 65

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years) (51% vs. 32%; p < 0.01).9 In a large electronic healthcare database analysis of primary

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care patients, patients with CRSwNP had a significantly older age distribution than did those

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with CRSsNP. 10 Our findings from a general population sample support these previous

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observations that CRSwNP is a disease related to aging.

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The reasons for the differences in age-related prevalence are currently unclear. Considering

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the heterogeneity of CRS6, the explanation is unlikely to be simple. However, based on our

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observation that the CRSsNP group had a frequent history of allergic rhinitis (52%), we

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speculate that high prevalence of CRSsNP during early adulthood (age 18–39 years) is

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primarily attributable to persistent nasal allergies.

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Our findings that CRSwNP, but not CRSsNP, was significantly related to late-onset (or adult-

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onset) asthma, further complement the findings of the European GA2LEN survey which first

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demonstrated that CRS is significantly associated with late-onset asthma (onset age ≥ 16

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years) in a general adult population.16 In our study, CRSwNP was more specifically related to

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asthma onset at ≥ 40 years (Table 3).

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There is still no clear explanation for the association between CRSwNP and asthma. Several

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markers for Th2 inflammation, such as eosinophils, interleukin-5, total IgE, or IgE specific to

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staphylococcal enterotoxins (SE-IgE), are commonly observed in the nasal tissues of

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CRSwNP subjects with comorbid asthma.6, 20, 21 Our group has reported that elderly asthma

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patients with elevated serum SE-IgE levels have significantly more severe asthma and are

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also more likely to have CRSwNP. 13 Unlike atopic sensitization, SE-IgE sensitization

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increases or remains constant with increasing age, as reported in general adult population

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samples of two distinct ethnicities.22, 23 Serum SE-IgE levels were independently associated

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with the risk of current asthma and asthma severity in two adult patient cohort studies.13, 24

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Staphylococcus aureus frequently colonizes the nasal mucosa and is more prevalent in

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subjects with CRSwNP and asthma.20 Bacterial proteins, including staphylococcal

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enterotoxins and serine protease-like proteins, can promote the development of allergic

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sensitization and airway inflammation.25, 26 Thus, we speculate that an inflammatory process

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involving S. aureus links CRSwNP and asthma.

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We found an asthma prevalence of less than 10% among subjects with CRSwNP. This was

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lower than expected, as the prevalence of comorbid asthma has previously been reported to

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be as high as 60% among patients with CRSwNP at specialist clinics.6 We speculate that this

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gap in asthma comorbidity rates is related to differences in the study populations. Although it

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is still higher than our findings, the comorbid asthma rate was previously reported to be lower

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among CRSwNP patients visiting primary clinics than among those referred to specialist

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clinics for sinus surgery in Denmark (44% vs. 65%; p = 0.04).27 It is also possible that our

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findings reflect the nature of CRSwNP in Asians. There is a considerable variability of NP

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endotypes by region.28 NP in Chinese patients are much less likely to be the Th2-type and

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comorbid asthma is also less likely, compared to Europeans.28, 29 However, interestingly, the

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strength of association (RRR or odds ratio) between CRSwNP and asthma appears to be

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similar for Koreans and Europeans.16 In addition, the demographic characteristics of our

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CRSwNP subjects (predominantly male and older) are consistent with studies of Western

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populations which used insurance or claims databases (where CRSwNP was defined by

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practitioner-coded ICD-9 codes).10, 30 As no other epidemiological surveys have investigated

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the relationship between CRSwNP and asthma in a community-based general adult

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population, our findings warrant further validation in different ethnic or regional populations.

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Our study has several limitations. First, it is a cross-sectional study, and thus temporal or

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causal relationships cannot be established. Second, there was no objective assessment of

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asthma, such as methacholine challenge testing. Asthma diagnosis was self-reported, which is

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subject to recall bias and invites questions of validity. However, the questions for defining

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asthma adopted a standardized methodology that has been used in other nationally

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representative surveys like the US National Health and Nutrition Examination Survey.31

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Objective assessment of asthma is difficult in large-scale nationwide surveys. Given this

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limitation, we examined several different indicators for asthma in relation to CRSwNP. The

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higher prevalence of asthma in older adults is in line with previous Korean community

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population surveys using methacholine challenge testing.22, 32 Third, age of onset of asthma

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was also self-reported. However, the patterns for age distribution observed for CRSwNP and

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CRSsNP were distinctive, while recall bias would presumably be random and show no

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distinct pattern. Fourth, our definition of CRS was followed the consensus criteria for large-

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scale epidemiologic surveys18, 33 but lacked imaging like sinus computed tomography (CT).

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The EP3OS 2012 criteria recommends the symptomatic definition of CRS to be supported by

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either imaging or nasal endoscopic findings.18 CT scanning of paranasal sinuses would

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improve the accuracy of the diagnosis.34 Finally, biomarkers for atopy and Th2 inflammation

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(i.e., blood eosinophils or serum total and specific IgE levels) were not assessed in this study.

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Such measurements would provide additional details to improve our unbiased understanding

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of the CRSwNP–asthma relationship.

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In conclusion, this study found distinct age-related patterns of CRSwNP and asthma in a

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general population. CRSwNP showed increasing prevalence with age and a significant

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relationship with late-onset asthma, validating previous hospital-based observations and

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providing additional details to previous community-based studies. These findings suggest a

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possible unique common pathogenic mechanism of CRSwNP and late-onset asthma, which

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warrants further investigation. Comorbid asthma rate was much lower in Korean subjects

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with CRSwNP than in Western populations, which warrants further investigation for ethnic or

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regional difference in the relationships between CRSwNP and late-onset asthma.

303 304

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Figure legends

399

Figure 1. Flowchart showing the selection of study population.

400

Figure 2. Prevalence of chronic rhinosinusitis, nasal polyps and asthma according to age

401

groups. Each symbol and error bar indicates mean ± standard error of prevalence.

402

Figure 3. Histograms showing the distribution of asthma onset age among the subjects

403

with physician-diagnosed asthma according to chronic rhinosinusitis status.

404

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405

Table I. Baseline characteristics of chronic rhinosinusitis in the KNHANES 2010-2012

406

survey p Characteristics

No CRS

CRSsNP

CRSwNP value

Age (years)

45.3±0.2

41.8±0.9

52.7±0.9

<0.001

Male sex (%)

49.7±0.4

54.3±2.9

60.7±2.7

<0.001

Never (%)

56.5±0.7

53.5±2.8

44.4±3.0

0.003

Former (%)

17.2±0.3

18.8±2.3

23.7±2.5

Current (%)

26.4±0.5

27.7±2.4

32.0±2.8

23.7±0.0

23.5±0.2

24.4±0.2

0.013

56.5±0.8

53.6±3.3

53.4±2.8

0.386

3.8±0.2

8.3±1.6

9.3±1.6

<0.001

2.5±0.2

4.7±1.2

3.9±1.0

<0.001

1.3±0.1

3.6±1.0

5.4±1.4

Smoking status

2

BMI (kg/m ) High household income (%) Self-reported asthma (%) Past asthma (%) Current

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asthma (%) Current asthma/past

0.52

0.77

1.38

2.8±0.2

5.7±1.2

6.7±1.5

<0.001

36.7±1.0

31.7±3.1

51.9±2.7

<0.001

13.3±0.4

52.0±2.8

17.4±2.3

<0.001

asthma ratio Physiciandiagnosed asthma (%) Age of asthma onset (years) History of allergic rhinitis (%) 407

BMI: body mass index; CRS: chronic rhinosinusitis; CRSsNP: CRS without nasal polyp;

408

CRSwNP: CRS with nasal polyp; KNHANES: Korean National Health and Nutritional

409

Examination Surveys

410

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411

Table II. Multinomial logistic regression analyses for relationships between chronic

412

rhinosinusitis, nasal polyps, and asthma CRSsNP Adjusted RRR*

CRSwNP p value

Adjusted RRR*

p value

Self-reported asthma by status Never asthma Past asthma

Reference 1.59 (0.90-

Reference 0.109

1.49 (0.87-2.55)

0.148

0.003

3.91 (2.18-7.00)

<0.001

2.83) Current asthma

2.48 (1.374.48)

Physiciandiagnosed asthma No

Reference

Yes

1.57 (0.97-

Reference 0.067

2.45 (1.50-4.00)

<0.001

2.55) 413

*Adjusted for age, sex, smoking status, body mass index, and history of allergic rhinitis

414

CRSsNP: CRS without nasal polyp; CRSwNP: CRS with nasal polyp; RRR: relative risk

415

ratio

416

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417

Table III. Multinomial logistic regression analyses for relationships between chronic

418

rhinosinusitis, nasal polyps, and asthma onset age CRSsNP Asthma onset

Adjusted RRR*

CRSwNP p value

Adjusted RRR*

p value

age Using cut-off of 18 years Never asthma

Reference

Reference

Asthma onset

1.91 (0.83-4.39)

0.127

2.58 (0.95-7.03)

0.064

1.41 (0.80-2.49)

0.236

2.40 (1.37-4.18)

0.002

age <18 years Asthma onset age ≥18 years Using cut-off of 40 years Never asthma

Reference

Reference

Asthma onset

1.48 (0.78-2.82)

0.234

1.54 (0.56-4.19)

0.399

1.75 (0.89-3.44)

0.105

3.18 (1.80-5.62)

<0.001

age <40 years Asthma onset age ≥40 years 419

*Adjusted for age, sex, smoking status, body mass index, and history of allergic rhinitis

420

CRSsNP: CRS without nasal polyp; CRSwNP: CRS with nasal polyp RRR: relative risk ratio

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421

422

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423 424

Figure 2.tif

425

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426 427

Figure 3.tif

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