10.14639/0392-100X-N1491
Objective. We determined the influence of gastro-oesophageal reflux disease (GERD) on quality of life (QOL) before and after functional-endoscopic-sinus-surgery (FESS) for chronic rhinosinusitis (CRS).Methods. Medically-recalcitrant CRS patients were recruited prior to FESS. GERD was diagnosed endoscopically. QOL was compared between patients with vs without GERD at baseline and one-year post-FESS.Results. Of 187 CRS patients receiving FESS, 40 had GERD. Pre-operative QOL was significantly worse in CRS patients with vs without GERD. Pre-operative GERD healthrelated QOL (GERD-HRQL) and reflux symptom index (RSI) scores were both correlated with pre-operative SNOT-22 scores. Compared with non-GERD CRS patients, GERD patients demonstrated larger SNOT-22 improvements after FESS, such that post-operative SNOT-22 values were no longer significantly different between GERD and non-GERD groups. However, post-FESS, in patients with CRS without nasal polyps (unlike those with nasal polyps), the GERD (vs non-GERD) group suffered from greater sleep dysfunction and otologic/facial symptoms.Conclusions. Compared to CRS patients without GERD, those with GERD experienced poorer pre-operative QOL and greater QOL improvement after FESS.
text/xml
1827-675X
1491
en
Geoffrey Liu*
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
health-related quality of life
Association of gastro-oesophageal reflux disease and quality of life in patients with chronic rhinosinusitis
Text.Serial.Journal
https://www.actaitalica.it/
41
Rhinology
2021-11-05
2021-02-18
2021-11-02
2021-11-02
450-460
1
Geoffrey Liu*
2021/11/05
10.14639/0392-100X-N1491
450
Medical Oncology and Medical Biophysics, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada; Medicine and Epidemiology Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; *G. Liu, Y. Zhao and W. Xu contributed equally to this work.
1827-675X
health-related quality of life
460
Association of gastro-oesophageal reflux disease and quality of life in patients with chronic rhinosinusitis
https://www.actaitalica.it/article/download/1491/681
41
ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41:450-460; doi: 10.14639/0392-100X-N1491




Rhinology


Association of gastro-oesophageal reflux disease
and quality of life in patients with chronic rhinosinusitis
Associazione della malattia da reflusso gastroesofageo e la qualità di vita dei pazienti
affetti da rinosinusite cronica
Yang Xu1,2, Wen Yang1, Yao Song1, Danni Cheng1, Min Cao3, Jingyue Huang4, Jianjun Ren1,2, Jong Wook Lee5,
Katrina Hueniken4, Yao Chen6, Catherine Brown2, Yuke Zhang1, Ke Qiu1, Wei Xu4,7*, Yu Zhao1*, Geoffrey Liu2,8*
1
  Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital, West China Medical School, Sichuan University,
Chengdu, Sichuan, China; 2 Medical Oncology and Medical Biophysics, Princess Margaret Cancer Centre, University of Toronto,
Toronto, Ontario, Canada; 3 General Affairs Office of Logistic Department, West China Hospital, Sichuan University, Chengdu,
Sichuan, China; 4 Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; 5 Department of
Otolaryngology Head and Neck Surgery, University of Toronto, Toronto, Ontario, Canada; 6 Department of Gastroenterology,
Chengdu First People’s Hospital, Chengdu, Sichuan, China; 7 Dalla Lana School of Public Health, University of Toronto, Toronto,
Ontario, Canada; 8 Medicine and Epidemiology Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
*
  G. Liu, Y. Zhao and W. Xu contributed equally to this work.
                                                                                                Received: February 18, 2021
                                                                                                Accepted: July 29, 2021

SUMMARY                                                                                         Correspondence
Objective. We determined the influence of gastro-oesophageal reflux disease (GERD) on           Geoffrey Liu
quality of life (QOL) before and after functional-endoscopic-sinus-surgery (FESS) for           Medical Oncology and Medical Biophysics,
chronic rhinosinusitis (CRS).                                                                   Princess Margaret Cancer Centre, University of
Methods. Medically-recalcitrant CRS patients were recruited prior to FESS. GERD was             Toronto, Toronto, Ontario, Canada; Medicine and
diagnosed endoscopically. QOL was compared between patients with vs without GERD at             Epidemiology Dalla Lana School of Public Health,
baseline and one-year post-FESS.                                                                University of Toronto, Toronto, Ontario, Canada
Results. Of 187 CRS patients receiving FESS, 40 had GERD. Pre-operative QOL was                 E-mail: Geoffrey.Liu@uhn.ca
significantly worse in CRS patients with vs without GERD. Pre-operative GERD health-
related QOL (GERD-HRQL) and reflux symptom index (RSI) scores were both correlated              Funding
with pre-operative SNOT-22 scores. Compared with non-GERD CRS patients, GERD pa-                This study was funded by International Cooperation
tients demonstrated larger SNOT-22 improvements after FESS, such that post-operative            Project of Science and Technology Department of
                                                                                                Chengdu City (Grant Number: 2018-YFYF-00123-
SNOT-22 values were no longer significantly different between GERD and non-GERD
                                                                                                SN), Fundamental Research Funds for the Central
groups. However, post-FESS, in patients with CRS without nasal polyps (unlike those with        Universities (Grant Number: 012017yjsy118),
nasal polyps), the GERD (vs non-GERD) group suffered from greater sleep dysfunction             1-3-5 Project for Disciplines of Excellence–Clinical
and otologic/facial symptoms.                                                                   Research Incubation Project of West China Hospital of
Conclusions. Compared to CRS patients without GERD, those with GERD experienced                 Sichuan University (Grant Number: 2019HXFH003).
poorer pre-operative QOL and greater QOL improvement after FESS.
                                                                                                Conflict of interest
KEY WORDS: chronic rhinosinusitis, gastroesophageal reflux disease, functional
                                                                                                The Authors declare no conflict of interest.
endoscopic sinus surgery, proton pump inhibitors, health-related quality of life

                                                                                                  How to cite this article: Xu Y, Yang W, Song Y, et
RIASSUNTO                                                                                         al. Association of gastro-oesophageal reflux disease
Obiettivo. Abbiamo determinato l’impatto della malattia da reflusso gastroesofageo                and quality of life in patients with chronic rhinosi-
(GERD) sulla qualità della vita (QOL) prima e dopo chirurgia endoscopica funzionale               nusitis. Acta Otorhinolaryngol Ital 2021;41:450-
nasosinusale (FESS) nel trattamento della rinosinusite cronica (CRS).                             460. https://doi.org/10.14639/0392-100X-N1491
Metodi. I pazienti con CRS refrattari alle terapie mediche sono stati reclutati prima della
FESS. La diagnosi di GERD è stata raggiunta endoscopicamente. La qualità della vita è           © Società Italiana di Otorinolaringoiatria
stata confrontata tra pazienti con e senza GERD al basale e a un anno dopo la FESS.             e Chirurgia Cervico-Facciale
Risultati. Dei 187 pazienti con CRS sottoposti a FESS, 40 erano affetti da GERD. La qua-
lità della vita prima dell’intervento era significativamente peggiore nei pazienti affetti da                  OPEN ACCESS
CRS e con GERD rispetto a quelli senza GERD. I punteggi preoperatori della qualità della        This is an open access article distributed in accordance with
vita in relazione alla GERD (GERD-HRQL) e dell’indice dei sintomi da reflusso (RSI) sono        the CC-BY-NC-ND (Creative Commons Attribution-Non-
stati correlati ciascuno con i punteggi SNOT-22 preoperatori. Rispetto ai pazienti con CRS      Commercial-NoDerivatives 4.0 International) license. The
                                                                                                article can be used by giving appropriate credit and mentio-
senza GERD, i pazienti con GERD hanno dimostrato miglioramenti della SNOT-22 più                ning the license, but only for non-commercial purposes and
significativi dopo trattamento FESS, i valori SNOT-22 postoperatori non erano più signifi-      only in the original version. For further information: https://
cativamente differenti tra i gruppi con GERD e senza GERD. Tuttavia, dopo la FESS, nei          creativecommons.org/licenses/by-nc-nd/4.0/deed.en




450
                                                                                                    GERD and QOL in CRS patients after FESS




pazienti con CRS senza poliposi nasale (a differenza di quelli con poliposi nasale), il gruppo GERD (contro non-GERD) ha avuto una maggiore
disfunzione del sonno e sintomi otologici/facciali.
Conclusioni. Rispetto ai pazienti con CRS senza GERD, quelli con GERD hanno beneficiato di un miglioramento della QOL maggiore dopo
trattamento FESS.
PAROLE CHIAVE: rinosinusite cronica, malattia da reflusso gastroesofageo, chirurgia endoscopica funzionale dei seni paranasali, inibitori
della pompa protonica, qualità della vita correlata alla salute



Introduction                                                           The objective of our study is to evaluate the relationship
                                                                       between the presence or absence of a concurrent confirmed
Chronic rhinosinusitis (CRS) is a common inflammatory                  GERD diagnosis in CRS patients with pre- and post-FESS
condition of the nose and paranasal sinuses, with signifi-             outcomes.
cant impact on quality of life (QOL) and productivity 1. In
mainland China, the estimated prevalence of CRS is 8%
with worldwide rates ranging from 5.5% to 10.9% 2. Pa-                 Materials and methods
tients with CRS use 152% greater healthcare services and               This prospective cohort study was approved by the Bio-
produce 139% higher healthcare costs than age-matched                  medical Research Ethics Committee of West China Hospi-
controls in the Chinese population 3.                                  tal, Sichuan University (2018 No.65), with informed con-
Gastro-oesophageal reflux disease (GERD) is one of the                 sent obtained from all patients.
most commonly encountered conditions by primary care pro-              Research involved human participants only. All procedures
viders and is frequently associated with extra-oesophageal             performed involving human participants were in accord-
conditions including dental erosions, chronic laryngitis and           ance with the ethical standards of the institutional and
laryngopharyngeal reflux (LPR). The prevalence of GERD                 national research committee and with the 1964 Helsinki
in China is approximately 3.8% with a worldwide increasing             declaration and its later amendments or comparable ethi-
trend in the past two decades 4. Like CRS, GERD is associ-             cal standards. Informed consent was obtained from all indi-
ated with lower work productivity and increased health utili-          vidual participants included in the study.
sation in those with severe and frequent symptoms.
Growing evidence has implicated a role of GERD in CRS.                 Population
A recent meta-analysis of epidemiological studies reported a           Adults diagnosed with CRS were recruited at the West Chi-
significant positive association between the two conditions 5.         na Hospital between 2016 and 2018. All participants lived
CRS patients with GERD are shown to have worse sinusitis               in Southwestern China, mainly Sichuan Province. Eligible
related-QOL compared to CRS patients without GERD.                     patients met the clinical CRS definition with symptoms
Functional endoscopic sinus surgery (FESS) is a minimally              over 12 weeks in duration, along with computed tomog-
invasive technique to recover normal sinus function and                raphy (CT) and endoscopic image documentation of CRS.
widely used in CRS patients after failure of drug treat-               Subjects had to agree to FESS after medical management
ment 1. Studies have reported that FESS results in sympto-             was unsuccessful in alleviating symptoms. Patients with
matic improvement in 76-98% of CRS patients. However,                  acute rhinosinusitis, fungal rhinosinusitis and cilia dyski-
few studies have investigated the prognostic influence of              nesia were excluded. Patients who failed to complete the
GERD on outcomes of FESS, and there is no specific study               initial clinical interview or one-year post-FESS follow up
evaluating QOL after initial FESS stratified by the presence           were excluded from the analysis. Patients receiving long-
or absence of GERD.                                                    term oral corticosteroid or nonsteroidal agents for anti-in-
Relevant studies have yielded mixed results. Some studies re-          flammatory purposes other than for CRS were also exclud-
port a higher prevalence of GERD in patients with recalcitrant         ed. CRS was confirmed secondarily at the time of FESS
CRS following FESS compared to those with resolved symp-               through histological analysis of the resected tissue.
toms 6,7. A retrospective study by Chambers et al. that col-
lected key pre-operative variables at a mean of 42.5 months            Diagnosis and management of GERD
after surgery contains potential recall bias 6. Confounders            Our institutional protocol for the diagnosis and manage-
including comorbidities were not controlled in DelGaudio’s             ment of GERD at the gastroenterology department is shown
study 7. Another study found no difference in symptoms and             in Figure 1. All study subjects were assessed for GERD
endoscopic outcomes before and after FESS between those                prior to surgery following the recruitment of this study.
with or without GERD, but used prior self-reported history or          After completion of the epidemiologic questionnaire with
anti-reflux medication as a proxy definition 8.                        CRS and GERD related QOL evaluation, all patients re-



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                                                                           and the few with refractory GERD-like symptoms but
                                                                           caused by other aetiologies (e.g. cardiac chest pain) after
                                                                           completing the extensive work-up (total of five patients).10
                                                                           The pathogenesis of eosinophilic oesophagitis (EoE) is dis-
                                                                           tinct from GERD, and EoE has been linked to CRS 11. We
                                                                           excluded EoE patients in our study.
                                                                           GERD patients were given PPIs treatment. PPIs switching,
                                                                           titration (e.g. doubling of dose) and compliance-assessment
                                                                           were used to optimise medical management of GERD 10.

                                                                           Data collection
                                                                           An epidemiologic questionnaire collected data on age, sex,
                                                                           body mass index (BMI), home address, ethnicity, smoking,
                                                                           alcohol use and previous medical history at enrollment. The
                                                                           phenotypes of CRS were recorded: CRS with nasal polyp
                                                                           (CRSwNP) and CRS without nasal polyp (CRSsNP) 1.
                                                                           Comorbidities were collected through hospital records,
                                                                           including asthma, allergic rhinitis (AR), deviated septum,
                                                                           obstructive sleep apnoea hypopnoea syndrome (OSAHS),
                                                                           diabetes and hypertension. The guidelines recommended
                                                                           by the Global Initiative for Asthma was used to define the
                                                                           diagnosis of asthma 12. AR diagnosis was based on con-
                                                                           cordance between atopy test results and a typical history of
                                                                           allergic symptoms 13. Smoking status was divided into pre-
                                                                           vious smokers, current smokers and never smoker. Alcohol
                                                                           consumption was dichotomised into less than twice a week
Figure 1. Flow diagram of how patients with chronic rhinosinusitis (CRS)   and twice a week or more.
were assessed for gastro-oesophageal reflux disease (GERD).
                                                                           FESS procedures
ceived an upper gastrointestinal endoscopy at the gastro-                  FESS was performed under general anaesthesia by the
enterology department to detect signs of GERD, those                       same set of surgeons, independent of GERD status. Sur-
with reflux oesophagitis, peptic stricturing, or Barrett’s                 gery utilised mechanical instruments with a microdebrider
oesophagus were grouped into subpopulation with GERD.                      to minimise damage to nasal mucosa. Surgery involved
GERD symptoms were inquired among patients of nega-                        removal of polyps and diseased mucosa with opening of
tive results from upper gastrointestinal endoscopy, includ-                the next anatomical compartment. The extent of the pro-
ing typical symptoms (regurgitation and heartburn) and                     cedure was tailored to individual patients, if necessary, the
extra-oesophageal symptoms (e.g. chronic throat clearing                   procedure included opening of the ethmoidal, frontal and/
or hoarseness). Twenty-four-hour pH monitoring was per-                    or sphenoidal sinuses. The surgical technique has been de-
formed to subjects with GERD symptoms, with acid expo-                     scribed by Stammberger and Kennedy 14,15.
sure time (AET) > 4.2% defined as GERD. CRS patients
without GERD symptoms and signs, or with AET < 4.2%                        Post FESS management
were classified as non-GERD patients 9.                                    All patients undergoing FESS were treated post-operative-
The four patients who had been treated with proton pump                    ly with 2-weeks of antibiotics and nasal corticosteroids.1
inhibitors (PPIs) prior to participating in this study were ex-            Intranasal corticosteroids were used to alleviate post-oper-
cluded due to heterogeneity and lack of previous supportive                ative symptoms. The Nasopore packing was used to con-
documents of GERD diagnosis. The patients who failed to                    trol post-operative bleeding 16. Routine nasal endoscopic
complete the therapy for GERD at the time of follow-up                     follow-up was at 2, 4, and 12 weeks after FESS.
were excluded. Also excluded from analyses were the rare
patients whose testing led to anti-reflux surgery or use of                QOL evaluation and objective testing
baclofen for oesophageal spasms, patients without GERD                     QOL evaluations were conducted pre-operatively prior to
but receiving anti-reflux PPIs treatment for other reasons,                GERD assessment or treatment. Post-operative QOL was



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                                                                                         GERD and QOL in CRS patients after FESS




evaluated at one-year follow up after FESS. The Sinonasal      selected by clinical judgement, including sex, age, BMI
Outcome Test-item 22 (SNOT-22), used to assess sinonasal       and smoking status. Both SNOT-22 overall and subdo-
related QOL, is a validated self-reported 22-item question-    main scores (pre-operative, post-operative and difference
naire, assessed on a Likert scale from 0 (symptom absent)      between pre- and post-operative scores) were compared
to 5 (worst symptom possible), divided into five subdo-        between GERD and non-GERD groups. Further subset
mains: rhinologic symptoms, extranasal rhinologic symp-        analyses were conducted by the presence or absence of
toms, otologic/facial symptoms, psychological dysfunc-         nasal polyps (e.g. CRSsNP patients; CRSwNP patients).
tion, and sleep dysfunction 17.                                Factors associated with post-operative QOL improvement
Gastroesophageal Reflux Disease-Health Related Quality         in CRSsNP/CRSwNP patients were tested in univariable
of Life (GERD-HRQL), pre-operatively evaluated along           and multivariable analyses. We evaluated the CRS findings
with SNOT-22, is a validated 10-item method of measuring       of different groups of sinuses involvement (frontal sinus,
GERD symptom severity, ranging from 0 (asymptomatic in         anterior ethmoid sinus, posterior ethmoid sinus, sphenoid
all items) to 50 (incapacitated in all items).                 sinus and maxillary sinus).
Reflux Symptom Index (RSI), also collected with pre-op-        All statistical tests were two-sided with statistical signifi-
erative SNOT-22, is a validated 9-item, self-administered      cance defined as p < 0.05. Wilcoxon rank-sum tests were
questionnaire designed to evaluate symptoms of extra-oe-       used to compare continuous variable. Chi-square tests were
sophageal reflux with each item ranging from 0 (absent) to
                                                               used to compare categorical variables. The difference be-
5 (severe) and a maximum score of 45.
                                                               tween pre-operative and post-operative variables was eval-
Sinus CT scan was evaluated through the 12-item Lund-
                                                               uated by paired test. All analyses were conducted in STATA
Mackay system pre-FESS, and used for radiologic stag-
                                                               (Version 14.2) and R (Version 3.6.1).
ing of CRS; the system has 24 total points, with 0-2 points
given for each sinus group: 0 point (no abnormality), 1
point (partial opacification), and 2 points (complete opaci-   Results
fication). Sinus involvement was defined as having a Lund-     Patient characteristics of GERD and non-GERD groups
Mackay score ≥ 1.                                              187 patients were enrolled and completed follow-up one
Endoscopic results were assessed by the Lund-Kenne-            year after surgery. There were 40 patients (21%) with
dy system at baseline and 12 weeks post-FESS, using a          a confirmed diagnosis of GERD who tended to be older
10-item scoring system of five items indicating severity of
                                                               (50.2 ± 1.9 years (GERD) vs 44.5 ± 1.2 years (non-GERD),
polyp, discharge, oedema, crusting and scarring, with 0-2
                                                               p = 0.02) (Tab. I). The prevalence of nasal polyposis was
points (higher scores = severe CRS signs) on each side, for
                                                               not statistically different between GERD and non-GERD
a maximum of 20 points.
                                                               CRS patients (35% vs 52%, p = 0.06). One GERD patient
                                                               was re-operated by the one-year follow-up; for the non-
Statistical analysis
                                                               GERD group, five were re-operated.
Data was double-entered and quality control steps were per-
formed using Epidata (Version 2.0). Demographic charac-
teristics were presented descriptively. Changes in SNOT-22     Pre-operative quality of life
scores from pre-operative to one-year post-operative as-       In univariable analyses, pre-operative total SNOT-22 scores
sessments and subdomain scores were presented visually         were significantly higher in CRS patients with GERD, AR,
using boxplots. Spearman correlations assessed relation-       asthma and obesity. Significance of GERD, AR and asthma
ships between GERD-HRQL, RSI, and SNOT-22 scores,              was confirmed in multivariable analysis, where female gen-
while Shapiro-Wilk test lacked normality of SNOT-22 and        der was also independently associated with higher pre-op-
Lund-Mackay scores leading to quantile normalisation           erative scores (Tab. II). Pre-operative GERD-HRQL score
prior to linear regression on transformed scores. Asso-        was significantly higher (worse symptoms) in the GERD
ciations between clinico-demographic variables including       vs non-GERD group (16.2 ± 0.6 vs 7.9 ± 0.3, p < 0.001),
presence/absence of GERD were assessed using univari-          with a moderate correlation between GERD-HRQL and
able and multivariable regression with outcomes of: pre-       total pre-operative SNOT-22 scores (r = 0.39, p < 0.001).
operative SNOT-22 score; improvement in SNOT-22 score          Pre-operative RSI of the GERD group was also signifi-
(defined as the difference between pre-operative and post-     cantly higher (worse symptoms) than the non-GERD group
operative scores); and pre-operative Lund-Mackay score.        (15.7 ± 1.4 vs 9.4 ± 0.6, p < 0.001), and demonstrated a
A multivariable linear regression model was conducted          moderate correlation with total pre-operative SNOT-22
with forward selection algorithm on plausible risk factors     score (r = 0.53, p < 0.001).



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Table I. Characteristics of GERD and Non-GERD Groups*.
 Variables                                                                        GERD                                Non-GERD                           p-value
 Clinico-demographic factors
    Sex (female/male)                                                            21/19                                  63/84                              0.28
    Age (years)                                                                50.2 ± 1.9                            44.5 ± 1.2                            0.02
    BMI (under/normal/over/obese) *                                            0/17/15/8                             3/64/61/19                            0.57
    Smoking (never/previous/current)                                             28/5/7                              107/15/25                             0.91
    Alcohol use (yes/no)                                                          7/33                                 31/116                              0.62
    Nasal polyposis (yes/no)                                                     14/26                                  76/71                              0.06
    Allergic rhinitis (yes/no)                                                   22/18                                 60/87                               0.11
    Asthma (yes/no)                                                               4/36                                 16/131                              0.87
    Deviated septum (yes/no)                                                     13/27                                 61/86                               0.30
    OSAHS (yes/no) *                                                              0/40                                 6/141                               0.19
    Diabetes (yes/no)                                                             0/40                                 3/144                               0.36
    Hypertension (yes/no)                                                         2/38                                 5/142                               0.64
 Outcomes
    Pre-operative SNOT-22                                                      44.0 ± 3.3                            29.6 ± 1.4                          < 0.001
    SNOT-22 improvement (1 year)                                               -26.2 ± 2.6                           -16.1 ± 1.4                          0.001
    Post-operative SNOT-22                                                     17.7 ± 2.7                            13.5 ± 1.1                            0.25
    Pre-operative GERD-HRQL*                                                   16.2 ± 0.6                             7.9 ± 0.3                          < 0.001
    Pre-operative RSI*                                                         15.7 ± 1.4                             9.4 ± 0.6                          < 0.001
    Pre-operative Lund-Mackay (CT)*                                             7.2 ± 1.2                            10.1 ± 0.6                            0.01
    Pre-operative Lund-Kennedy (endoscopy)                                      6.0 ± 0.5                             6.7 ± 0.2                            0.23
    Lund-Kennedy improvement (12 weeks)                                         -3.2 ± 0.6                            -3.2 ± 0.2                           0.81
    Post-operative Lund-Kennedy                                                 3.2 ± 0.3                             3.6 ± 0.2                            0.17
For continuous factors, mean and standard error were provided. The GERD group tended to be older compared to non-GERD group. Greater pre-operative SNOT-22 score and SNOT-22
improvement were found in GERD patients vs non-GERD patients. GERD: Gastroesophageal reflux disease; SNOT-22: Sinonasal outcome test-item 22; BMI: Body mass index; Under/
normal/over/obese: Underweight/ normal weight/ overweight/ obesity; OSAHS: Obstructive sleep apnoea hypopnoea syndrome; GERD-HRQL: Gastro-oesophageal reflux disease-
health related quality of life; RSI: Reflux symptom index; CT: Computed tomography.

Post-operative improvement on total quality of life                                     scores or post-operative SNOT-22 scores between GERD
Of 187 patients with one-year follow up, 40 (21%) were                                  and non-GERD groups (Tab. IV).
diagnosed with GERD pre-operatively. Regardless of
GERD status, total SNOT-22 scores improved significantly                                Analyses on QOL subdomains
post-FESS (Fig. 2). In both univariable and multivariable                               Overall, the five subdomains had similar relationship in
analyses, SNOT-22 scores in GERD patients were associ-                                  that all subdomains in both the GERD and non-GERD
ated with significantly greater improvement than SNOT-22                                groups improved substantially after FESS (p < 0.001 for
scores of non-GERD patients (Tab. III). The pre-opera-                                  each comparison; Fig. 3).
tive SNOT-22 scores were associated with post-operative                                 Pre-operatively, CRS patients with GERD had greater
SNOT-22 improvement in univariable and multivariable                                    impairment in otologic/facial symptoms, psychological
analysis (p < 0.001 for each comparison). Post-operative                                dysfunction and sleep dysfunction subdomains than non-
total SNOT-22 scores were now similar between the GERD                                  GERD CRS patients (Tab. V). All three subdomains im-
and non-GERD groups (Tab. I). Nevertheless post-opera-                                  proved substantially more after FESS in the GERD (vs the
tive SNOT-22 scores in the GERD group were significant-                                 non-GERD) group; however, there remained a smaller but
ly higher than the non-GERD group in CRSsNP patients                                    significant difference in the GERD vs non-GERD group
(17.8 ± 3.3 vs 9.8 ± 1.0, p = 0.03) (Tab. IV). This association                         post-operatively for sleep dysfunction and otologic/facial
between the presence of GERD and greater post-operative                                 symptoms. The post-operative sleep dysfunction was mod-
SNOT-22 improvement in CRSsNP patients was observed                                     erately associated with otologic/facial symptoms (r = 0.40,
in univariable and multivariable analysis (p < 0.01 for each                            p < 0.001). A similar trend was found in the subset of pa-
comparison). In contrast for CRSwNP patients, no signifi-                               tients with CRSsNP. The post-operative otologic/facial
cant differences were observed in pre-operative SNOT-22                                 symptoms subdomain scores were significantly higher in



454
                                                                                                                              GERD and QOL in CRS patients after FESS




Table II. Univariable and multivariable analysis of pre-operative SNOT-22 Score*.
 Factor                                                             Score                                Univariable analysis                  Multivariable analysis
                                                                       Mean ± SE                                p-value                                p-value
 Sex (female)                                                          33.1 ± 1.8
 Sex (male)                                                            32.3 ± 2.0                                 0.46                                   0.03
 Age                                                                        –                                     0.25                                   0.06
 BMI (normal weight)*                                                   32.4 ± 2.1
 BMI (underweight)*                                                    23.7 ± 14.3                                                                       0.06
 BMI (overweight)*                                                      30.5 ± 1.9                                                                       0.86
 BMI (obesity)*                                                         40.5 ± 3.8                                0.01                                   0.22
 Never smoker                                                           33.5 ± 1.6
 Previous smoker                                                        30.0 ± 4.4                                                                       0.39
 Current smoker                                                         31.0 ± 2.8                                0.28                                   0.75
 GERD* (no)                                                             29.6 ± 1.4
 GERD* (yes)                                                            44.0 ± 3.3                              < 0.001                                < 0.001
 Allergic rhinitis (no)                                                 29.0 ± 1.6
 Allergic rhinitis (yes)                                                37.6 ± 2.2                              < 0.001                                < 0.001
 Asthma (no)                                                            31.2 ± 1.3
 Asthma (yes)                                                           45.3 ± 5.0                               < 0.01                                 0.03
 Nasal polyposis (no)                                                   31.0 ± 1.9                                                           Not included in final model
 Nasal polyposis (yes)                                                  34.4 ± 1.9                                0.21
 Deviated septum (no)                                                   33.3 ± 1.8
 Deviated septum (yes)                                                  31.8 ± 2.0                                0.68
 OSAHS* (no)                                                            32.9 ± 1.4
 OSAHS* (yes)                                                           26.2 ± 9.7                                0.32
 Diabetes (no)                                                          32.7 ± 1.4
 Diabetes (yes)                                                        31.3 ± 12.9                                0.96
 Hypertension (no)                                                      32.8 ± 1.4
 Hypertension (yes)                                                     28.3 ± 2.7                                0.81
 Alcohol use (rare)                                                     33.5 ± 1.5
 Alcohol use (frequent)                                                 29.4 ± 2.7                                0.23
SNOT-22 scores in subgroups were presented. Global p-value was used in univariable analysis. Multiple linear regression used normalised SNOT-22 score, p-value of categorical
independent variables was compared to the reference category. The presence of GERD was associated with significant higher pre-operative SNOT-22 in both univariable analysis and
multivariable analysis. SNOT-22: Sinonasal outcome test-item 22; BMI: Body mass index; GERD: Gastro-oesophageal reflux disease; SE: Standard error; OSAHS: Obstructive sleep
apnoea hypopnoea syndrome.


CRSsNP patients with GERD than CRSsNP patients with-                                      non-GERD group compared to the GERD group (51% vs
out GERD (2.7 ± 0.5 vs 1.4 ± 0.3, p < 0.01). Compared with                                32%, p = 0.03). There was a difference in the proportion
non-GERD CRSsNP patients, the post-operative sleep dys-                                   of patients who had anterior ethmoid sinus involvement
function was significantly worse in CRSsNP patients with                                  between GERD patients and non-GERD patients (40% vs
concomitant GERD (5.4 ± 1.2 vs 2.1 ± 0.3, p = 0.02). In                                   61%, p = 0.02).
contrast, no significant differences were found in post-op-                               When evaluating the association between QOL and specif-
erative SNOT-22 subdomains between CRSwNP patients                                        ic sinus involvement, there was a significant difference in
with GERD vs without GERD.                                                                post-operative SNOT-22 scores between CRS patients with
                                                                                          vs without maxillary sinus involvement (15.1 ± 1.2, n = 161
QOL in patients with improvement in specific groups                                       vs 8.2 ± 2.0, n = 26; p < 0.01). Associations were not found
of sinuses                                                                                with other sinuses. The comparison of post-operative QOL
We compared the prevalence of specific sinus involve-                                     in GERD vs non-GERD group was further performed in
ment between GERD and non-GERD groups. The rate of                                        patients with/without involvement of individual sinuses.
frontal sinus involvement was significantly higher in the                                 There were no significant QOL differences between GERD



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Y. Xu et al.




Figure 2. Boxplot of pre-operative and post-operative total SNOT-22 scores,
comparing gastro-oesophageal reflux disease (GERD) and non-GERD groups.
Post-operative assessments were performed at 12 months after surgery.
SNOT-22: Sinonasal outcome test-item 22; CT: Computed tomography; PPIs:
Proton pump inhibitors; FESS: Functional endoscopic sinus surgery; QOL:
Quality of life.                                                              Figure 3. Boxplot of pre-operative and post-operative SNOT-22 subdomains
                                                                              of chronic rhinosinusitis (CRS) patients with and without gastro-oesophage-
and non-GERD subjects in any set of sinuses, except for a                     al reflux disease (GERD). Post-operative assessments were performed at 12
                                                                              months after surgery. SNOT-22: Sinonasal outcome test-item 22.
borderline association in patients who did not suffer from
anterior ethmoid sinus involvement (19.0 ± 3.7, n = 24,                       Summary of major findings
GERD vs 9.7 ± 1.4, n = 57, non-GERD; p = 0.04).                               CRS patients with GERD experienced significantly worse
                                                                              pre-operative QOL compared to non-GERD CRS patients,
CT and endoscopic outcomes                                                    but higher QOL improvements following FESS, result-
Compared to non-GERD patients, those with GERD                                ing in no differences in overall QOL one-year post-FESS
showed significantly lower pre-operative total Lund-Mack-                     in those with vs without GERD. In subdomain analyses,
ay CT scores (7.2 ± 1.2 vs 10.1 ± 0.6, p = 0.01; Tab. I), which               impairment in one-year post-FESS sleep dysfunction and
was confirmed by multivariable regression (p < 0.01), after                   otologic/facial symptoms were greater in GERD patients
adjustment by sex, age, BMI, smoking and comorbidities.                       (compared to non-GERD patients); these greater symptoms
The severity grade in anterior ethmoid cells (p = 0.03) and                   seemed to be driven by the subset of patients who never had
ostiomeatal complex (p = 0.01) in the Lund-Mackay sys-                        nasal polyps, as these differences by GERD-status were not
tem was significantly higher in non-GERD group vs GERD                        observed in CRS patients who did have nasal polyps.
group.
Pre-operative total Lund-Kennedy endoscopic scores were                       Discussion
similar in CRS patients with and without GERD (6.0 ± 0.5                      Comparison of results with previous studies
vs 6.7 ± 0.2, p = 0.23). Lund-Kennedy scores were signifi-                    The mechanisms of how GERD affects the sinonasal cav-
cantly decreased 12 weeks after FESS in both the GERD                         ity remain unclear. Extra-oesophageal reflux may reach the
and non-GERD group (p < 0.001 for each comparison). No                        proximal aerodigestive tract, exacerbating the symptoms of
significant differences were observed in Lund-Kennedy                         CRS. Few studies have investigated the role of GERD on
scores after FESS between GERD and non-GERD patients                          outcomes of FESS and have reported mixed results. In our
(Tab. I).                                                                     study, the presence of GERD was associated with worse



456
                                                                                                                               GERD and QOL in CRS patients after FESS




Table III. Univariable and multivariable analysis of post-operative SNOT-22 improvement*.
 Factors                                                         Improvement                              Univariable analysis                  Multivariable analysis
                                                                        Mean ± SE                                p-value                                p-value
 Sex (female)                                                           -18.2 ± 1.9
 Sex (male)                                                             -18.5 ± 1.8                                0.92                                   0.54
 Age                                                                         –                                     0.72                                   0.57
 BMI (normal weight)*                                                   -17.4 ± 1.2
 BMI (underweight)*                                                     -20.0 ± 8.1                                                                       0.69
 BMI (overweight)*                                                      -18.2 ± 1.1                                                                       0.50
 BMI (obesity)*                                                         -22.8 ± 2.7                                0.21                                   0.03
 Never smoker                                                           -18.7 ± 1.5
 Previous smoker                                                        -11.8 ± 3.8                                                                       0.18
 Current smoker                                                         -21.0 ± 3.2                                0.10                                   0.88
 GERD* (no)                                                             -16.1 ± 1.4
 GERD* (yes)                                                            -26.2 ± 2.6                               0.001                                 < 0.001
 OSAHS* (no)                                                            -19.0 ± 1.3
 OSAHS* (yes)                                                            1.5 ± 7.2                                 0.01                                < 0.001
 Nasal polyposis (no)                                                   -18.9 ± 1.6                                                           Not included in final model
 Nasal polyposis (yes)                                                  -18.3 ± 2.0                                0.82
 Allergic rhinitis (no)                                                 -17.3 ± 1.8
 Allergic rhinitis (yes)                                                -19.9 ± 1.9                                0.33
 Asthma (no)                                                            -18.1 ± 1.4
 Asthma (yes)                                                           -20.2 ± 3.1                                0.63
 Deviated septum (no)                                                   -20.0 ± 1.6
 Deviated septum (yes)                                                  -15.9 ± 2.1                                0.12
 Diabetes (no)                                                          -18.2 ± 1.3
 Diabetes (yes)                                                        -25.0 ± 11.9                                0.51
 Hypertension (no)                                                      -18.3 ± 1.3
 Hypertension (yes)                                                     -20.7 ± 4.1                                0.72
 No smoking post-surgery                                                -22.1 ± 3.4
 Smoking post-surgery                                                   -17.7 ± 1.4                                0.23
 Reoperation (no)                                                       -18.6 ± 1.3
 Reoperation (yes)                                                      -10.8 ± 6.4                                0.29
 Alcohol use (rare)                                                     -18.1 ± 3.0
 Alcohol use (frequent)                                                 -18.4 ± 1.4                                0.94
Univariable analysis used global p-value. Multivariable analysis was conducted using multiple linear regression, p-value of categorical independent variables was compared to the
reference category. SNOT-22: Sinonasal outcome test-item 22; BMI: Body mass index; GERD: Gastro-oesophageal reflux disease; SE: Standard error; OSAHS: Obstructive sleep apnoea
hypopnoea syndrome.


baseline QOL symptoms related to CRS prior to surgery                                      sult from FESS had GERD compared to 20% of patients
despite medical management for CRS. There was also a                                       with a good outcome from the surgery; however, recall bias
suggestion that CRS patients with GERD had radiologi-                                      may be a major factor as the data was collected only retro-
cally less severe CRS at presentation, despite having worse                                spectively with a mean of 42.5 months post-FESS, and was
symptoms. However, patients with GERD demonstrated                                         based on self-report without confirmation of GERD diag-
greater improvements in QOL symptoms (by SNOT-22                                           nosis 6. While DeConde et al. found no significant differ-
scores) following FESS, resulting in similar overall QOL                                   ence by GERD in SNOT-22 score improvements, the QOL
one year post-operatively.                                                                 of these patients was similar prior to surgery, and there
These findings contrast those from Chambers et al., who                                    were methodological issues with the study: this study used
reported that GERD was a prognostic predictor for FESS                                     a previous recorded diagnosis of GERD obtained from
failure. In their study, 41% of patients reporting a poor re-                              the medical record or the use of anti-GERD medication



                                                                                                                                                                           457
Y. Xu et al.




as proxy definitions 8. Although one study identified naso-                                  Potential mechanism of the association between GERD
pharyngeal reflux as being associated with recalcitrant CRS                                  and CRS
following FESS, we found no differences in re-operative                                      The presence of GERD was related to worse pre-operative
rates after initial surgery between GERD and non-GERD                                        QOL among CRS patients in our study. There are several
patients 7. Furthermore, in our population, re-operation                                     theories addressing how GERD affects the sinonasal cavity.
rates were very low, which may make it difficult to iden-                                    Firstly, reflux content may have a direct effect on the nasal
tify differences in re-operation rates, even if they existed. In                             mucosa, where the evidence lies in the response of the nasal
our results, the proportion of nasal polyposis patients was                                  mucosa that is similar to the response by the oesophageal
not significantly different between GERD vs non-GERD                                         mucosa during direct contact with gastric contents: pepsin
group, in consistence with literature before 18. Chowdhury                                   A and heat shock protein 70 expression 21. Secondly, Heli-
et al. reported pre-operative QOL as a prognostic factor for                                 cobacter pylori may be involved in mechanism of CRS by
post-operative outcomes in CRS patients 19. Pre-operative                                    promoting nasal polyp. Thirdly, dysfunction of autonomic
SNOT-22 was associated with post-operative improvement                                       nervous system attributed to GERD may result in reduction
of CRS-related QOL in our study.                                                             of PNIF, through neural reflex exists between oesophagus
                                                                                             and paranasal sinuses via the vagus nerve. The lower Lund-
Potential mechanism of greater benefit from FESS in CRS                                      Mackay scores but greater QOL impairment in CRS patients
patients with GERD                                                                           with GERD by our study is supported by a previous work
                                                                                             showing that GERD could impact CRS symptoms through
The study hypothesis is that with maximal medical man-
                                                                                             autonomic dysfunction more than sinonasal inflammatory
agement of GERD and CRS, FESS is a good method of
                                                                                             status alone.22 Because the prevalence of specific sinus in-
treating both conditions. The theory of improved peak
                                                                                             volvement varied between GERD patients and non-GERD
nasal inspiratory flow (PNIF) might explain why CRS
                                                                                             patients in our results, the anatomical underpinnings of
patients with GERD experienced greater improvement vs
                                                                                             individual paranasal sinuses might influence the effect of
non-GERD CRS patients in our study.
                                                                                             GERD on the aerodigestive tract 23. Future analyses in other
PNIF is an objective measure of nasal patency, correlated                                    datasets will be necessary to answer this question.
with QOL in post-FESS patients. Significant improvement                                      In our study, CRS QOL was positively associated with
of PNIF was found after FESS by Whitcroft et al., and                                        GERD and LPR symptoms. LPR may be an intermediary
post-FESS change of PNIF was strongly associated with                                        mechanism between GERD and CRS, and LPR may even
improvement of SNOT-22 score. PNIF was also shown to                                         play a role in the development of CRS.
be influenced by hydrochloric acid infusion, and acid infu-
sion is traditionally regarded to have an important mecha-                                   The effects of PPIs on CRS
nistic role in GERD 20. FESS might change PNIF in CRS                                        Several studies found conflicting results about effects of
patients regardless of the presence or absence of GERD,                                      PPIs therapy on symptoms improvement in CRS patients.24
resulting in QOL improvement in CRS patients with and                                        In our study, the pre-operative CRS symptoms were worse
without GERD; however, improved PNIF may have addi-                                          in patients with GERD vs patients without GERD prior to
tional secondary benefit to patients with GERD, resulting                                    initiation of PPIs treatment. Low pH and gastric enzymes
in greater improvements in QOL scores in patients with                                       of the gastric content to upper aerodigestive tract may dam-
both CRS and GERD.                                                                           age airways mucous membrane. PPIs are the most potent

Table IV. CRS QOL in CRSsNP and CRSwNP patients*.
 Variables                                                                                           GERD*                      Non-GERD*                       p-value
 CRS QOL in CRSsNP patients
   Pre-operative SNOT-22 scores*                                                                  44.7 ± 3.9                    25.9 ± 1.8                      < 0.001
   Post-operative SNOT-22 improvement                                                             -26.9 ± 3.0                   -15.7 ± 1.7                     < 0.01
   Post-operative SNOT-22 scores                                                                  17.8 ± 3.3                     9.8 ± 1.0                       0.03
 CRS QOL in CRSwNP patients
   Pre-operative SNOT-22 scores                                                                   42.5 ± 6.5                    33.0 ± 1.9                        0.21
   Post-operative SNOT-22 improvement                                                             -25.0 ± 5.2                   -17.0 ± 2.2                       0.06
   Post-operative SNOT-22 scores                                                                  17.5 ± 4.9                    16.4 ± 1.8                        0.80
For continuous factors, mean and standard error were presented. CRS: Chronic rhinosinusitis; QOL: Quality of life; CRSwNP: Chronic rhinosinusitis with nasal polyps; CRSsNP: Chronic
rhinosinusitis without nasal polyps; GERD: Gastro-oesophageal reflux disease; SNOT-22: Sinonasal outcome test-item 22.




458
                                                                                                                      GERD and QOL in CRS patients after FESS




Table V. SNOT-22 subdomain analysis*.
 Subdomains                                                                                  GERD                    Non-GERD                      p-value
 Pre-operative SNOT-22 subdomains
   Rhinologic symptoms                                                                    13.1 ± 1.2                 13.4 ± 0.6                    0.84
   Extranasal rhinologic symptoms                                                         6.0 ± 0.8                  5.2 ± 0.3                     0.48
   Otologic/facial symptoms                                                               8.1 ± 0.9                  4.8 ± 0.3                    < 0.001
   Psychological dysfunction                                                              13.8 ± 1.6                 6.9 ± 0.6                    < 0.001
   Sleep dysfunction                                                                      11.0 ± 1.4                 5.1 ± 0.5                    < 0.001
 SNOT-22 subdomains improvement
   Rhinologic symptoms                                                                    -7.0 ± 1.1                  -7.0 ± 0.6                     0.90
   Extranasal rhinologic symptoms                                                         -3.4 ± 0.8                  -3.3 ± 0.3                     0.94
   Otologic/facial symptoms                                                               -5.5 ± 0.7                  -3.1 ± 0.3                    0.001
   Psychological dysfunction                                                              -8.5 ± 1.6                  -3.5 ± 0.7                    0.001
   Sleep dysfunction                                                                      -6.0 ± 1.2                  -2.3 ± 0.5                     0.01
 Post-operative SNOT-22 subdomains
   Rhinologic symptoms                                                                     6.1 ± 1.0                  6.5 ± 0.5                     0.83
   Extranasal rhinologic symptoms                                                          2.5 ± 0.5                  2.0 ± 0.3                     0.43
   Otologic/facial symptoms                                                                2.6 ± 0.4                  1.8 ± 0.2                     0.04
   Psychological dysfunction                                                               5.3 ± 1.3                  3.3 ± 0.5                     0.14
   Sleep dysfunction                                                                       5.1 ± 0.9                  2.8 ± 0.3                     0.01
Subdomain scores were presented as mean ± standard error. P-values were generated from Wilcoxon rank-sum test. SNOT-22: Sinonasal outcome test-item 22; GERD: Gastro-
oesophageal reflux disease.


and most widely used group of drugs to treat reflux dis-                             deprivation could exacerbate GERD through enhancing
ease 24.                                                                             intra-oesophageal stimulating perception. Otologic/facial
                                                                                     pain and sleep dysfunction scores have been correlated in
GERD and CRS patients without nasal polyposis                                        CRS patients in another study, a similar relationship was
In our study, post-operative CRS-related QOL impairment                              observed in our study 25.
was greater in CRSsNP patients with GERD than those                                  This study has several strengths. Firstly, this was a prospec-
without GERD, and significantly higher SNOT-22 scores                                tive analysis with broad eligibility criteria useful as real-world
were seen in the GERD group vs the non-GERD group in                                 evidence. Secondly, we completed extensive study procedures
CRSsNP patients. The different nasal mucosal molecular                               to confirm GERD diagnosis in our patients. Thirdly, validated
characteristics between CRSsNP and CRSwNP patients                                   disease-specific instruments were used to assess and analyse
may indicate the greater mucosal damage in CRSsNP pa-                                CRS symptom-outcomes. However, there are several limita-
tients with concurrent GERD. The positive rates of pep-                              tions: (i) our patients did not receive long term PPIs prior to
sin A in turbinate mucosa of middle concha of CRSsNP                                 FESS and we were not able to collect serial QOL assessment
patients were higher than polyp tissue from CRSwNP pa-                               after PPIs initiation. Thus, we could not conclusively differen-
tients. MUC5AC, one of several mucins, demonstrated a                                tiate between improvements in QOL due to PPIs therapy for
lower expression in the nasal mucosa of CRSsNP patients                              GERD vs FESS treatment for CRS; (ii) specific GERD ques-
when compared with CRSwNP. Reflux has effects on mu-                                 tionnaires were not administered at the 12-month follow-up;
cin expression. The downregulation of MUC5AC was as-                                 (iii) information of endotypes was unavailable in this study (e.g.
sociated with mucosal damage 21.                                                     eosinophil level in CRS mucosa); accordingly, we were unable
                                                                                     to explain our findings according to the types of underlying
Sleep problems remained in post-operative CRS patients                               inflammatory response (type-2 and non-type-2); (iv) there is
with GERD                                                                            limited generalisability in this single-institution study.
As a significant difference in the SNOT-22 sleep dysfunc-
tion subdomain scores remained one year post-FESS in
our study; this difference may be explained through a bidi-
                                                                                     Conclusions
rectional relationship between GERD and sleep problems.                              In summary, we conducted a prospective study on the re-
Nocturnal reflux may lead to sleep deprivation, and sleep                            lationship between GERD and CRS related QOL before



                                                                                                                                                               459
Y. Xu et al.




and after FESS. We found greater pre-operative CRS and                     9
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