Original ResearchLaryngology and Neurolaryngology

Narrow-Band Imaging of Laryngeal

Images and Endoscopically Proven Reflux
Esophagitis

Otolaryngology
Head and Neck Surgery
2015, Vol. 152(5) 874880
American Academy of
OtolaryngologyHead and Neck
Surgery Foundation 2015
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/0194599814568285
http://otojournal.org

Wen-Hung Wang, MD, PhD1,2,3, and Kai-Yu Tsai, MD1

No sponsorships or competing interests have been disclosed for this article.

Abstract
Objective. To compare the difference between white light
(WL) and narrow-band imaging (NBI) endoscopy in evaluating patients who had reflux laryngitis and esophagitis.
Study Design. Retrospective review of medical records and
endoscopic images.
Setting. Outpatient clinic.
Subjects and Methods. There were 102 consecutive patients
with reflux esophagitis (mean age, 48 6 11 years) who had
office-based transnasal esophagoscopy (TNE) with WL and
NBI views, including 60 men (59%) and 42 women (41%).
We compared WL and NBI endoscopy in observing the laryngeal and esophageal epithelium. The nasopharynx, base of
the tongue, epiglottis, hypopharynx, larynx, esophagus, gastroesophageal junction, and stomach were examined, and all
procedures were digitally recorded. All patients were evaluated with WL and NBI views to determine the reflux finding
score (RFS) in the larynx and Los Angeles (LA) classification
grade in the esophagus.
Results. The NBI views were more sensitive than the WL
views in the erythema/hyperemia, vocal cord edema, and
global RFS scores. The NBI view facilitated the identification
of the erythema/hyperemia change representing dilation or
proliferation of microvessels caused by epithelial inflammation. The global RFS score was significantly associated with
severity of LA grade only with the NBI view.
Conclusion. The endoscopic findings with the NBI view
permit an easier identification of the RFS parameters of laryngeal erythema/vocal cord edema, which have a stronger
correlation with the severity of reflux esophagitis, than the
WL view. The importance of NBI in the evaluation of reflux
laryngitis and gastroesophageal reflux disease deserves further study.

Keywords
endoscopy, gastroesophageal reflux disease, outpatient,
reflux laryngitis

Received August 25, 2014; revised December 5, 2014; accepted

December 23, 2014.

ar, nose, and throat physicians often encounter

patients complaining of the sensation of a foreign
body in the throat. This may be caused by diseases,
including acute laryngitis, hypopharyngeal cancer, sinusitis,
tonsillar hyperplasia, cervical abnormalities, and globus hystericus or pharyngeus. Globus hystericus or pharyngeus may
be related to acid reflux disease, which may cause inflammation of the esophagus, termed reflux esophagitis.1
Gastroesophageal reflux disease (GERD) is a prevalent
chronic disorder caused by the reflux of gastric contents
into the esophagus. The reported incidence is 10% to 20%
in Western countries and 5% in Asia.2,3 The most common
symptoms include regurgitation and heartburn. Moreover,
GERD may cause pulmonary problems, including asthma,
bronchitis, microaspiration, and pulmonary fibrosis.4 The
main findings of reflux esophagitis on endoscopy are mucosal breaks in the esophagus.3 The severity of esophagitis
may be graded with the Los Angeles (LA) classification:
grade A, 1 mucosal break (length 5 mm) that does not
extend between the tops of 2 mucosal folds; grade B, 1
mucosal break (length .5 mm) that does not extend
between the tops of 2 mucosal folds; grade C, 1 mucosal
break that is continuous between the tops of 2 mucosal
folds but involves \75% esophageal circumference; or
grade D, 1 mucosal break that involves 75% esophageal
circumference.5
Laryngopharyngeal reflux occurs when the height of the
reflux exceeds the hypopharynx or larynx. Laryngeal
inflammation is caused by stomach acid, and the patient
1
Department of Otolaryngology, Cathay General Hospital, Taipei, Taiwan,
Republic of China
2
Department of Otolaryngology, Sijhih Cathay General Hospital, New
Taipei City, Taiwan, Republic of China
3
School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan,
Republic of China

Corresponding Author:
Wen-Hung Wang, MD, PhD, Department of OtolaryngologyHead and
Neck Surgery, Cathay General Hospital and School of Medicine, Fu-Jen
Catholic University, No. 280, Jen-Ai Road, Sec. 4, Taipei 10630, Taiwan.
Email: evan_travel@hotmail.com

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875

may experience a sensation of a foreign body in the throat,

difficulty with swallowing, throat clearing, coughing, fatigue with talking, and hoarse voice. Esophageal inflammation caused by acid reflux may cause complaints of
heartburn. Patients with laryngopharyngeal reflux do not
necessarily experience heartburn, but they may have hoarseness, cough, laryngitis, subglottic stenosis, laryngeal cancer,
sinusitis, pharyngitis, or sleep apnea.4 The reflux finding
score (RFS) that is based on laryngoscopy is a clinical severity scale that standardizes the laryngeal findings of laryngopharyngeal reflux for better diagnosis and evaluation of
therapeutic efficacy.6 The RFS, which is highly reproducible
between different observers, involves 8 items: subglottic
edema with pseudosulcus, ventricular obliteration, erythema/
hyperemia, vocal cord edema, diffuse laryngeal edema, posterior commissure hypertrophy, granuloma/granulation, and
thick endolaryngeal mucus. The RFS may range from 0 (no
abnormal findings) to 26 (worst), and RFS .7 predicts laryngopharyngeal reflux with 95% confidence.6
Conventional white light (WL) endoscopy for GERD has
low sensitivity but excellent specificity (90%-95%).3 Major
limitations of WL endoscopy in GERD include difficulties
in visibly distinguishing and diagnosing nonerosive reflux
disease (NERD) and Barrett esophagus.7 Laryngeal and esophageal mucosa may be observed with endoscopic techniques that use a full spectrum of visible light. Narrow-band
imaging (NBI) endoscopy equipment, developed during the
past decade, has better depth of penetration and increases
the diagnostic sensitivity of endoscopy to characterize tissues. The NBI endoscopy uses narrow-bandwidth filters in a
sequential red-green-blue illumination system and may
detect superficial pharyngeal mucosal lesions.8-10 The red
wavelength (540 nm) may penetrate the deepest layers and
reveal dark larger vessels. The blue wavelength (415 nm) in
the superficial layer shows microvascular red. The green
wavelength (440 nm) is displayed between the red and blue
colors. Light filtering through the filter palate controls the
intensity of the 3 colors and adjusts color contrast.
Therefore, the system reduces the unnecessary intermediate
colors to increase the contrast of blood vessels.
Angiogenesis, the formation of new blood vessels from preexisting vessels, is an important phenomenon in various physiological processes, including acute and chronic inflammation.11
Superficial mucosal lesions that usually cannot be detected by
regular WL endoscopy can be identified with blue light in NBI
endoscopy because of the vasculature pattern of neoangiogenesis. The inflammatory response involves dilation of capillaries
to increase blood flow and microvascular structural changes.12
Vascular damage is common to inflammatory lesions following
a wide variety of sublethal insults and is associated with characteristic changes in the inflamed tissues.13 Inflamed mucosa may
be accompanied by dilation or proliferation of microvessels, and
we may easily observe the severity of epithelial inflammation
with NBI endoscopy.
The relation between laryngeal findings with NBI endoscopy and reflux esophagitis is not well established. The
purpose of this study was to compare the difference between

WL and NBI endoscopy in evaluating patients who had

reflux laryngitis and esophagitis.

Methods
Participants
Consecutive patients (102 patients; mean age, 48 6 11
years) with reflux esophagitis who had office-based transnasal esophagoscopy (TNE) with WL and NBI views were
included in this retrospective study. There were 60 men
(59%) (mean age, 48 6 11 years) and 42 women (41%)
(mean age, 47 6 11 years). We compared WL and NBI
endoscopy in observing the laryngeal and esophageal
epithelium. Included subjects were outpatient adult patients
(age range, 21-65 years) who had endoscopically proven
reflux esophagitis. Patients were excluded because of acute
laryngitis, hypopharyngeal cancer, sinusitis, tonsillar hyperplasia, autoimmune diseases (xerostomia), or cervical
abnormalities. The institutional ethics committee approved
this study (Chang Gung Memorial Hospital Internal Review
Board no. 100-1237B).

Narrow-Band Imaging System and Endoscopy

The TNE with NBI system was equipped with a light source
and central video system (CLV-180; Olympus Medical
Systems, Tokyo, Japan). The system switched between conventional and NBI views with a button on the control section
of the videoscope. All endoscopic examinations were performed in an outpatient clinic by 1 experienced otolaryngologist (W.-H.W.) who was blinded to the subjects prior
evaluation or diagnosis. The patient received simethicone (20
mg/mL; dose, 20 mL) 30 minutes before endoscopy, and the
nasal cavity was anesthetized with lidocaine spray (2%). The
TNE was performed with the patient in the seated position,
first in the WL mode and then using the NBI system. The
nasopharynx, base of the tongue, epiglottis, hypopharynx,
larynx, esophagus, gastroesophageal junction, and stomach
were examined, and all procedures were digitally recorded.
All patients were evaluated to determine the RFS in the
larynx (both using WL and NBI), the LA classification grade
in the esophagus (both using WL and NBI), and the presence
of a brownish area (using NBI).
The TNE examinations were performed by 1 physician
who was blinded to the subjects prior diagnosis. We retrospectively reviewed the medical records of all 102 patients.
A blinded reviewer read the TNE images and determined
the RFS in all patients. The LA classification was used in
the esophagus to avoid subjective differences and interobserver variability in image interpretation. In addition, we
compared the severity of the image interpretation and association between both WL and NBI views.

Statistical Analysis
We compared the outcome differences between the WL and
NBI views in the larynx and esophagus using a paired t test.
Spearman rank correlation was used to determine comparative relevance of laryngeal and esophageal images. Several
conditions (inflammation, trauma, or infection) could cause

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OtolaryngologyHead and Neck Surgery 152(5)

Figure 1. Endoscopic finding showed negative reflux (control) under white light (WL) (A) and narrow-band imaging (NBI) views (B). A
patient with arytenoid erythema and diffuse edema under WL (C) and NBI views (D). A patient with a more apparent brownish area and
edema (arrows) under the NBI view (F) than the WL view (E).

Table 1. Comparison of RFS under WL and NBI Views.a

RFS Variable
Subglottic edema with
pseudosulcus
Ventricular obliteration
Erythema/hyperemia
Vocal cord edema
Diffuse laryngeal edema
Posterior commissure
hypertrophy
Granuloma/granulation
Thick endolaryngeal mucus
Global RFS score

WL View

NBI View

161

0.9 6 1

P Valueb
.158

2.9 6 1
2.6 6 0.9
1.760.6
2.1 6 0.6
2.2 6 0.6

2.9 6 1
3.161
1.8 6 0.6
2.2 6 0.5
2.2 6 0.6

1.000
\.001
\.001
.014
1.000

0.4 6 0.8
0.4 6 0.8
13.2 6 3.7

0.4 6 0.8
0.4 6 0.8
13.5 6 3.8

1.000
1.000
\0.001

Abbreviations: NBI, narrow-band image; RFS, reflux finding score; WL,

white light.
a
The RFS scores are reported as mean 6 standard deviation. The figures in
boldface represent a significant difference between WL and NBI.
b
Paired t test.

similar laryngeal reflux findings such as erythema, hyperemia, or vocal cord edema; therefore, statistical significance
was defined by P  .001.

Results
RFS from WL and NBI Views
We examined the 8 items of RFS in the larynx. In 1 patient,
there was arytenoid erythema and diffuse edema noted with

WL and NBI views, in contrast with image findings of negative reflux (control) with WL and NBI views (Figure 1).
We could identify the brownish area over bilateral arytenoid
and interarytenoid folds. The inflamed mucosa often was
accompanied by dilation or proliferation of microvessels,
and we could easily observe the range and severity of
epithelial inflammation with NBI views. Another patient
had a brownish area and edema over bilateral arytenoids
and the posterior part of the false vocal cords that were
more apparent with the NBI than the WL view (Figure 1).
The NBI views were more sensitive than the WL views in
erythema/hyperemia, vocal cord edema, and global RFS
scores (Table 1). The NBI view facilitated the identification
of the erythema/hyperemia change representing dilation or
proliferation of microvessels caused by epithelial inflammation. However, there was no significant advantage of the
NBI compared with the WL view in detecting subglottic
edema with pseudosulcus, ventricular obliteration, posterior
commissure hypertrophy, granuloma/granulation, or thick
endolaryngeal mucus.

Laryngeal RFS with WL and NMI Views and the LA

Classification
We compared the laryngeal signs of RFS between the WL
and NBI views and the LA classification in the esophagus
using Spearman correlation. The endoscopic images of granuloma/granulation and thick endolaryngeal mucus in the
larynx with both WL and NBI views had higher correlations
with the severity of LA grade (Table 2). When granuloma/
granulation and thick mucus in the larynx were identified

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877

Table 2. Correlation between Laryngeal Signs of RFS under

WL and NBI Views and LA Classification.a
RFS Parameter vs
LA Classification
Subglottic edema with
pseudosulcus
Ventricular obliteration
Erythema/hyperemia
Vocal cord edema
Diffuse laryngeal edema
Posterior commissure
hypertrophy
Granuloma/granulation
Thick endolaryngeal mucus
Global RFS score

WL View
P Valueb

NBI View
P Valueb

0.087 (.383)

0.112 (.2860)

0.063
0.123
0.195
0.124
0.279

0.063 (.531)
0.151 (.130)
0.166 (.096)
0.150 (.132)
0.279 (.005)

(.531)
(.217)
(.049)
(.213)
(.005)

0.440 (\.001)
0.513 (\.001)
0.168 (.092)

0.440 (\.001)
0.513 (\.001)
0.382 (\.001)

Abbreviations: LA, Los Angeles; NBI, narrow-band image; RFS, reflux finding
score; WL, white light.
a
The values reported are the Spearman correlation coefficients (Spearman
r values). The figures in boldface represent a significant association with the
LA classification.
b
Spearman correlation test.

on endoscopy (WL or NBI views), a higher grade of esophagitis was more likely. Patients who had endoscopic findings of posterior commissure hypertrophy and granuloma
with WL and NBI views typically had a higher grade of
reflux esophagitis such as LA grade C with WL and NBI
views (Figure 2). However, the global RFS score was significantly associated with severity of LA grade only with
the NBI view (Table 2 and Figure 3).

Discussion
The TNE used in this study included a flexible endoscope that
was passed transnasally under topical anesthesia.14 The advantages of TNE compared with conventional esophagoscopy
under general anesthesia included increased patient safety,
increased practice efficiency, cost savings, and early detection
of esophageal cancer.15 The use of office-based TNE by otolaryngologists is available for patients who are at risk for
Barrett esophagus, esophageal adenocarcinoma, hypopharyngeal cancer extended to the esophagus, and GERD.16 The
TNE can be safely performed with topical anesthesia in an
office setting for diagnostic and therapeutic procedures.
Previous studies showed that TNE had no major complications
such as esophageal perforation, and the minor complications
included epistaxis (most common), vasovagal reaction, and laryngospasm.14,17 Most patients tolerate TNE well, and patient
tolerance to TNE on a 10-point scale (1, no discomfort; 10,
severe discomfort) is 2.0 6 1.2 (range, 1-4).17
Acute laryngitis usually is caused by infection, but
chronic laryngitis may result from acid reflux, smoking,
muscular imbalance, or dehydration.18 Most (50%-60%)
chronic laryngitis and chronic pharyngitis may be related to
GERD.19 The most common symptoms associated with

Figure 2. Endoscopic finding for a patient showing posterior commissure hypertrophy with granuloma and Los Angeles grade C esophagitis under white light (A and C) and narrow-band imaging
views (B and D).

laryngopharyngeal reflux include throat cleaning (98.3%),

chronic cough (96.6%), heartburn (95.7%), and hoarseness
(94.9%).20 Animal studies have shown that small amounts
of gastric acid may cause marked laryngeal mucosal inflammation and edema.21 Extraesophageal gastric acid may
cause vagal-mediated reflexes such as bronchospasm, laryngospasm, and cough and may cause chronic laryngitis.22 In
addition to detailed medical history and laryngeal observations, diagnosis of these diseases may require a 24-hour pH
recording, but this study may be limited because of high
cost and reluctance of patients to perform the study.
Furthermore, a negative pH study does not exclude extraesophageal reflux because reflux episodes may be intermittent.23 Therefore, we sought to improve general outpatient
techniques to facilitate examination and diagnosis.
Most patients with GERD have no evidence of esophageal damage with standard WL endoscopy. Nonerosive subtypes of GERD (NERD) account for 70% patients with
GERD.24 Standard WL endoscopy fails to detect GERD
endoscopically in 60% to 70% patients. The sensitivity of
standard WL endoscopy for the diagnosis is low.25,26 A previous study showed that NBI may increase the sensitivity
for the diagnosis of GERD.27
In a previous study of patients with and without GERD
symptoms who completed 2 validated GERD questionnaires, the distal esophagus was examined by standard WL
and NBI endoscopy, and the features observed only with
NBI were compared between patients with GERD and control subjects. On multivariate analysis, increased number

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OtolaryngologyHead and Neck Surgery 152(5)

Figure 3. A visual representation of the data presented in Table 2. LA, Los Angeles; NBI, narrow-band image; RFS, reflux finding score;
WL, white light.

and dilation of intrapapillary capillary loops were the best

predictors for diagnosing GERD.28 The maximum, minimum, and average numbers of intrapapillary capillary loops/
field were significantly greater in the GERD group than in
control subjects (P \ .0001). Although the interobserver
agreement for the various NBI findings was very good, the
intraobserver agreement was modest.28 Another study of 3
subtypes of GERD (NERD, reflux esophagitis, and Barrett
esophagus) using NBI magnifying endoscopy showed that
a significantly higher proportion of patients with GERD
had an increased number of intrapapillary capillary loops,
microerosions, and nonround pit patterns below the squamocolumnar junction than did healthy control subjects, and
the numbers of intrapapillary capillary loops/field were significantly greater in patients with GERD.29
Another comparative study of NBI and convention endoscopy in the diagnosis of GERD (107 subjects: NERD, 36
subjects; erosive reflux disease, 41 subjects; controls, 30
subjects) showed that microerosions, increased vascularity,
and pit patterns at the squamocolumnar junction not seen on
conventional endoscopy were well seen with NBI; interobserver agreement was good for increased vascularity (k =
0.95) and microerosions (k = 0.89) but lower for pit patterns
(k = 0.59).30 Therefore, NBI views improved the endoscopic
diagnosis of mucosal morphology at the squamocolumnar
junction and GERD.30 A study that evaluated intra- and
interobserver variations in the endoscopic scoring of esophagitis with conventional imaging with and without NBI
showed that intra- and interobserver reproducibility in grading esophagitis could be improved when NBI was applied
with conventional imaging because of improved depictions
of small erosive foci.31 These previous studies examined the
lining of the esophagus with NBI magnifying endoscopy
(esophagogastroduodenoscopy with 80-fold optical magnification) to easily observe pit patterns and intrapapillary
capillary loops, but these were not easily performed with
TNE because of the absence of a magnification function.
In a study of 111 patients with laryngopharyngeal
reflux who underwent TNE by the same otolaryngologist,

biopsy-proven Barrett esophagus was observed in 13.5%

patients, including 7 of 58 patients (12.1%) with WL and
8 of 53 patients (15.1%) with NBI; 3 patients (2.7%) had
dysplasia on biopsy, and all 3 cases were detected with NBI
(5.7%).32 It was concluded that NBI may be a useful adjunct
to increase the diagnostic sensitivity of TNE by the otolaryngologist.32 Our preliminary results (data not shown) for diagnosis of GERD by TNE also showed that we could easily
observe microerosions and Barrett esophagus, except pit patterns, number, and dilation of intrapapillary capillary loops,
with the NBI view better than the WL view.
Several studies have shown the benefit of NBI in the early
detection of recurrent laryngeal and hypopharyngeal cancer
and early diagnosis of laryngeal cancer.33-35 A previous study
showed that the NBI laryngoscope is highly valuable for the
diagnosis and treatment of laryngopharyngeal reflux disease
and that laryngopharyngeal reflux disease has characteristic
findings on NBI laryngoscopy, including erythema and
edema between the arytenoid cartilages (71.7%); epiglottis
congestion
(67.4%);
pharyngeal
isolation/integration
erythema (65.2%); pharyngeal pebble-like changes (65.2%);
hypertrophy of the posterior commissure (52.2%); vocal cord
erythema and edema (47.8%); vocal nodules or vocal polyps
with erythema or edema (39.1%), arytenoid cartilage edema
and erythema (21.7%); ventricular edema, erythema, and laryngeal ventricle disappearance (17.4%); granuloma (6.5%);
ulcers (4.3%); and false vocal cord pitch (4.3%).36
Several studies have investigated the association between
laryngopharyngeal reflux and GERD. In 1 study, the prevalence rate of laryngopharyngeal reflux in subjects with reflux
esophagitis was 23.9%.37 Another study showed that 24-hour
multichannel intraluminal impedance and pH esophageal
monitoring analysis confirmed GERD diagnosis in \40%
patients with a previous diagnosis of laryngopharyngeal
reflux, most likely because of the low specificity of the laryngoscopic findings.38 However, the expression of Helicobacter
pylori positivity and the degree of GERD correlate with laryngopharyngeal reflux, and Helicobacter pylori positivity and
the degree of GERD are higher in patients with RFS 7.39

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879

Another study showed that the severity of laryngeal

mucosal lesions in patients with GERD is significantly
greater than in control patients, and a higher degree of laryngeal mucosal injury may be documented in patients for
whom GERD is associated with more advanced esophageal
lesions.40 Both the global RFS score and scores of all RFS
parameters (except for presence of granulomatous tissue)
were significantly higher in patients with GERD than in
control subjects; patients in whom GERD was associated
with more severe esophageal lesions (LA group B) had a
significantly higher global RFS score and scores of all analyzed parameters of laryngeal injury (except subglottic
edema) than individuals in whom the degree of esophageal
involvement was classified as group A.40
In our study, when the RFS parameters of granuloma/granulation and thick endolaryngeal mucus were identified in the
larynx with either WL or NBI endoscopy, a higher grade of esophagitis was present. The granulation and thick mucus were
important predictors for GERD and erosive esophagitis. In contrast with the previous study, we observed that the global RFS
score was significantly associated with severity of the LA grade
only with NBI, and traditional WL endoscopy was not sufficiently reliable to reflect the severity of reflux esophagitis.40
Differences between the studies include the fewer patients with
GERD in the previous (46 patients with GERD and 46 controls)
than in present study (GERD, 102 patients), and the grading
interpretation of GERD may be inconsistent between WL and
NBI views, which may affect the calculation of the correlation
with laryngopharyngeal reflux.40
The mean global RFS scores in our study were 13.2 6
3.7 in WL and 13.5 6 3.8 in NBI views, consistent with
previous findings.6 The endoscopic findings in the larynx
showed that NBI has higher sensitivity for detecting
erythema, hyperemia, and edema in the mucosa, possibly
because of the ability of NBI to increase the contrast of
blood vessels and improve the identification of the neoangiogenic vasculature in inflamed mucosa.
Limitations of the present study include the lack of a
standard 24-hour pH recorder for the definite diagnosis of
GERD. There was a lack of a patient reflux symptom
index41 measurement to determine laryngeal signs and
symptoms that most significantly correlated. There were no
treatment data for patients who had higher scores based on
NBI and who did better with antireflux treatment.
Therefore, further studies with longer follow-up are required
to determine the usefulness of NBI in evaluating laryngopharyngeal reflux and identifying correlations with GERD.

Conclusion
Literature review showed no previous comparison of the
endoscopic images of laryngopharyngeal reflux and GERD
with WL and NBI views. Although previous studies showed
that NBI with and without magnification may increase the
sensitivity for the diagnosis of GERD and observation of
microerosions and Barrett esophagus, there was limited previous study to investigate the association between reflux laryngitis and esophagitis with NBI.

In addition, the imaging technology for the improved detection of laryngopharyngeal reflux appears promising. The
endoscopic findings with the NBI view permit an easier identification of the RFS parameters of laryngeal erythema/vocal
cord edema, which have a stronger correlation with the severity of reflux esophagitis, than the WL view. Among the RFS
variables, granuloma/granulation and thick endolaryngeal
mucus might be 2 important laryngeal imaging signs for predicting the severity of reflux esophagitis with either the WL
or NBI view. The importance of NBI in the relation between
reflux laryngitis and GERD deserves further study. A large
prospective study with more patients, reflux symptom index,
and outcome data about antireflux treatment are needed for
the future study of NBI in reflux esophagitis.
Author Contributions
Wen-Hung Wang, study concept and design, acquisition of data,
analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content,
statistical analysis; Kai-Yu Tsai, acquisition of data, analysis and
interpretation of data, drafting of the manuscript, critical revision
of the manuscript for important intellectual content, statistical
analysis.

Disclosures
Competing interests: None.
Sponsorships: None.
Funding source: None.

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