The Laryngoscope
Lippincott Williams & Wilkins, Inc.
© 2005 The American Laryngological,
Rhinological and Otological Society, Inc.
Direct Nasopharyngeal Reflux of Gastric
Acid is a Contributing Factor in Refractory
Chronic Rhinosinusitis
John M. DelGaudio, MD
Objectives/Hypothesis: To determine whether
there is a difference in the prevalence of reflux in
patients with refractory chronic rhinosinusitis (CRS)
compared with control patients, including whether
direct nasopharyngeal reflux (NPR) occurs in CRS
patients. It is hypothesized that refractory CRS pa-
tients have a greater incidence of laryngopharyngeal
reflux and NPR events and that NPR is a significant
etiologic factor for CRS in these patients. Study De-
sign: Prospective study. Methods: The study group
consisted of 38 patients with a history of at least one
endoscopic sinus surgery (ESS) with continued CRS
symptoms and mucosal inflammation on endoscopy.
The first control group consisted of 10 patients who
had at least one ESS procedure and had no symptoms
of CRS or mucosal inflammation a minimum of 1 year
postoperatively. The second control group consisted
of 20 subjects with no history of CRS or sinus surgery.
All patients completed reflux symptom scales, a 20
item sinonasal outcome test, and a sinusitis symptom
scale and underwent nasal endoscopy to grade the
nasal mucosal findings. Patients underwent a 24 hour
pH study with a specially designed probe with sen-
sors located in the nasopharynx, 1 cm above the up-
per esophageal sphincter (UES), and the distal esoph-
agus. The pH recordings were evaluated for NPR
events less than pH 4 and 5. Reflux at the UES probe
was considered pathologic if there were more than 6.9
episodes for the entire study or the reflux area index
(RAI) exceeded 6.3. Esophageal reflux was defined as
abnormal if greater than 4% of the study time was
spent at pH less than 4. Statistical analysis was per-
From the Department of Otolaryngology—Head and Neck Surgery,
Emory University School of Medicine, Atlanta, Georgia, U.S.A.
This research was supported by a grant from the Investigator-
Sponsored Studies Program of AstraZeneca.
Editor’s Note: This Manuscript was accepted for publication March
3, 2005.
Send Correspondence to Dr. John M. DelGaudio, Department of
Otolaryngology—Head and Neck Surgery, Emory University School of
Medicine, 1365 Clifton Road NE, Room A2313, Atlanta, GA 30322, U.S.A.
E-mail: john_delgaudio@emoryhealthcare.org
DOI: 10.1097/01.MLG.0000163751.00885.63
Laryngoscope 115: June 2005
946
formed with Fisher’s exact test to compare the reflux
parameters and with analysis of variance and Tukey’s
post hoc analysis for the symptom and examination
scores. Results: No statistical difference was found
between the two control groups for any parameters at
any sites. When a single outlier was dropped from the
nonCRS control group, less NPR was found in the
nonCRS group compared with the successful ESS
control group (P ⴝ .03). Because these groups were
statistically homogenous, they were collapsed into a
single control group. Compared with the control
group, the study group had significantly more pa-
tients with NPR events pH less than 4 (39% vs. 7%, P ⴝ
.004) and an even greater difference in the number of
patients with NPR events pH less than 5 (76% vs. 24%,
P ⴝ .00003). At the UES, 74% of the study group had
greater than 6.9 reflux episodes, compared with 38%
of control patients (P ⴝ .006). The UES RAI was ab-
normal for 58% of the study group compared with 21%
of the control group (P ⴝ .007). The study group also
had more gastroesophageal reflux (66% vs. 31%, P ⴝ
.007). For nasopharynx and UES reflux parameters,
the differences between study and control groups in-
creased when the patients with isolated frontal recess
disease were removed from the dataset. The study
group also had higher scores on all symptom and ex-
amination scores (P ⴝ .001 for each scale). Conclu-
sions: Patients with persistent CRS after ESS have
more reflux at the nasopharynx, UES, and distal
esophagus than controls. The greatest difference is in
NPR, especially pH less than 5. This is the first study
to document NPR in CRS patients, and it is likely to
represent an important causative factor of refractory
CRS in adults. Key Words: Chronic sinusitis, reflux,
nasopharyngeal reflux, laryngopharyngeal reflux.
Laryngoscope, 115:946 –957, 2005
INTRODUCTION
Chronic rhinosinusitis (CRS) is a significant health
problem, estimated to be one of the most common chronic
diseases affecting adults in the United States.1 The patho-
physiology of CRS involves inflammatory changes in the
nasal and sinus mucosa, resulting in mucosal edema, os-
DelGaudio: Direct Nasopharyngeal Reflux of Gastric Acid
tial obstruction, mucus stasis, and subsequent infection sistence of CRS in patients who have previously under-
with worsening of the edema. The underlying initial insult gone ESS but continue to have sinusitis symptoms and
to the mucosa may be a viral infection, an immune- mucosal inflammation. No previous studies have looked at
mediated process such as environmental allergy or aller- the existence of direct NPR events as a contributing etio-
gic fungal sinusitis (AFS), environmental pollutants, an- logic factor of CRS in adults. It is hypothesized that LPR
atomic causes, or a combination of these factors. and NPR play a significant role in the pathogenesis of
Adequate medical treatment of CRS involves a pro- CRS in some patients.
longed course of antibiotics directed at upper respiratory
flora along with medications to reduce inflammation. En- METHODS
doscopic sinus surgery (ESS) is the preferred treatment The institutional review board approved this study protocol.
for patients with CRS who have failed to resolve with Patients were evaluated prospectively. Only adults over 18 years
maximal medical treatment. ESS has been found to be of age were asked to participate in the study. Participants were
effective in up to 89.7% of patients, with long-term symp- divided into three groups. The study group consisted of patients
who had previously undergone one or more ESS procedures but
tomatic improvement in up to 98% of patients.2–7 Multiple
continued to have CRS complaints with endoscopic evidence of
factors have been implicated for failure of ESS, including sinonasal mucosal inflammation. The first control group con-
irreversible mucosal disease, inadequate surgery, scarring sisted of individuals who had undergone ESS at least 1 year
and synechiae, allergy, tobacco use, and gastroesophageal earlier and had no complaints of CRS and minimal or no abnor-
reflux (GER) disease.2,3,8 Patients who fail ESS can malities on nasal endoscopy. The second control group consisted
present difficult management problems. of individuals who had no history of CRS and had not undergone
Recently, GER, or more accurately laryngopharyn- previous sinus surgery. Contraindications to participation in-
geal reflux (LPR), has been implicated as a contributing cluded the inability to tolerate pH probe testing and the inability
factor in a multitude of disease processes in the head and or refusal to stop antireflux medication 1 week before the pH
neck, including dysphonia, benign vocal cord lesions, vocal study. Patients with a history of reflux disease were included, but
those who were actively being treated were required to stop all
process granulomas, laryngospasm, subglottic stenosis,
antireflux medications 1 week before the day of the pH study.
and rhinosinusitis.9 –21 In children, LPR has been impli- Previous antireflux surgery was not an exclusion criterion for
cated as a reason for failure of CRS to respond to appro- participation.
priate antiinfective therapy, with resultant improvement On the day of the pH study, patients signed a written
with acid-suppression therapy.22–28 In adults, CRS has informed consent document. Height and weight were obtained,
been found to occur with greater frequency in patients along with smoking history, a list of medications, sinus surgery
with GER or LPR than in those without reflux.29,30 Med-
ically refractory CRS in adults has also been found to be
associated with a higher likelihood of LPR.30 –32
The mechanism by which reflux disease may contrib-
ute to CRS is unknown, but three mechanisms are possi-
ble. The first mechanism involves nasopharyngeal reflux
(NPR), with direct exposure of the nasopharynx and nose
to gastric acid, with resultant mucosal inflammation and
impaired mucociliary clearance. Variations in pH have
been demonstrated to affect ciliary motility and morphol-
ogy in respiratory mucosa.33 In children, NPR has been
demonstrated to occur in CRS patients by using nasopha-
ryngeal pH monitoring.24,34 NPR has been implicated as a
factor complicating choanal atresia repair.35 NPR has also
been reported to occur in children with serous otitis media
with the detection of high levels of pepsin in middle ear
effusions.36 Direct NPR events are the most likely mech-
anism in which reflux would contribute to CRS. Nasopha-
ryngeal pH monitoring for reflux has not been reported in
adults.
The second possible mechanism is a vagus nerve-
mediated reflex inflammatory response involving the na-
sal mucosa. This has been described in the lower air-
way37,38 and in patients with rhinitis39 but has not been
shown in CRS patients.
The third possible mechanism relates to the role of
Helicobacter pylori. In two previous studies, H. pylori was
found in only 3 of 19 and 4 of 12 sinonasal mucosal biopsy
specimens by polymerase chain reaction in patients un-
dergoing ESS for CRS.40,41
This study was undertaken to determine whether
NPR of gastric acid was a contributing factor to the per- Fig. 1. Patient reflux symptom scale.

Laryngoscope 115: June 2005 DelGaudio: Direct Nasopharyngeal Reflux of Gastric Acid
947
Fig. 2. Sinusitis symptom score.

and allergy history, and comorbidities. All patients filled out the
following questionnaires: a reflux symptom questionnaire that
rated 13 laryngopharyngeal and esophageal symptoms on a
4-point scale from none to severe (Fig. 1);42 a sinusitis symptom
score that rated 9 symptoms using a visual analogue scale (Fig.
2);43 and a 20 item sinonasal outcome test (SNOT-20) (Fig. 3).44
Patients then underwent rigid nasal endoscopy using a 4 mm
30-degree telescope to rate the following sinonasal characteristics Fig. 4. PH probe being placed in the pharynx under endoscopic
on a 0 to 2 scale: polyps, edema, discharge, crusting, and scar- guidance. The visual marker on the probe is 1 cm above the upper
ring.45 Each side of the nose was graded separately. No topical esophageal sphincter sensor. The probe is advanced until the top of
anesthesia or decongestant was used before the nasal endoscopy. the marker disappears.
All endoscopies and grading were performed by the author.
All patients then underwent a 24 hour pH study using the
pH-Response system (Medtronic-Xomed, Jacksonville, FL). The sphincter (UES) sensor. A visual marker was located 1 cm proximal
catheter used was custom designed with three pH sensors. The to the UES sensor to allow endoscopic positioning of the UES sensor
esophageal sensor was located 18 cm distal to the upper esophageal (Fig. 4). The nasopharyngeal sensor was located 8.5 cm proximal to
the UES sensor and, after appropriate positioning of the catheter,
was located behind the soft palate (Fig. 5). Before placement, the

Fig. 5. Position of the nasopharyngeal sensor in the nasopharynx.

The sensor is 1 cm distal to the visual marker and positioned behind
Fig. 3. Sinonasal outcome test. the soft palate.

Laryngoscope 115: June 2005 DelGaudio: Direct Nasopharyngeal Reflux of Gastric Acid
948
probes were calibrated in buffer solution at pH 7 and pH 1. Only
after all three sensors were successfully calibrated was a catheter
determined to be acceptable for use. No auto-calibration or default
settings were used.
Topical nasal decongestant and anesthetic was applied to
the nose with a mixture of neosynephrine and pontocaine. Some
patients also underwent topical anesthesia with pharyngeal ben-
zocaine spray and lidocaine gargles. The pH catheter was placed
under flexible laryngoscopic guidance and secured to the patient’s
nose with adhesive. The pH monitors were programmed to record
for a continuous 24 hours before shutting off. Patients were
instructed on how to record symptom events (heartburn, regur-
gitation, cough, etc.) on the pH monitor and in a written diary.
The patient was then discharged from the clinic and instructed to
resume his or her normal daily activities as much as tolerable.
Patients returned to the clinic the following day for removal of the
catheter. All pH probes were placed by the author.
Recordings were downloaded from the pH monitor to a lap-
top computer using an infrared port and were analyzed by the
pH-Response software (Medtronic-Xomed, Jacksonville, FL). A
reflux episode was considered to occur when the pH dropped
below 4.0 at the esophageal, UES, and nasopharyngeal sensors
and below pH 5.0 at the nasopharyngeal sensor. A positive read-
ing of a reflux episode at the UES sensor required a preceding or
simultaneous distal esophageal reflux episode to an equivalent or
lower pH, and a NPR event required a preceding distal esopha-
geal and UES event. Meal times were excluded from the analysis
of results because of the possible artifact created in the proximal
sensors with ingestion of various foods and liquids. Short snacks
of nonacidic foods and liquids were not eliminated from the re-
cordings. All pH recordings were manually evaluated by the
author to exclude artifacts. Recordings were compared with writ-
ten diaries to assure accuracy of the recordings with respect to
meal times. Data collected from each recording included the total
number of reflux episodes below pH of 4 and 5 at the nasopha-
ryngeal sensor and the number of reflux episodes and the reflux
area index (RAI) at the UES sensor. The RAI is a measurement of
the area under the pH curve below a specified cutoff for a study,
therefore taking into account the number and duration of reflux
events in addition to the degree to which these events drop below
the specified pH level.46 The amount of reflux at the UES probe
was considered abnormal if there were more than 6.9 reflux
episodes for the entire study or the RAI was greater than 6.3.46
The recordings at the esophageal sensor were evaluated for the
total time of the study spent at pH less than 4.0. In the distal
esophagus, the study was considered abnormal if greater than
4.0% of the study time was spent below a pH of 4.0.
Data were compared between the groups for the values
described above. pH study values between groups were compared
TABLE I.
Demographics.
Age BMI Comorbidities
(mean) (mean) per Patient
CRS study group (n ⫽ 38) 53.7 28.4 1.0
Successful ESS controls 41.6 25.8 0.1
(n ⫽ 10)
NonCRS controls (n ⫽ 20) 38.3 26.6 0.4
P value ⬍.001 NS .001
Significant differences were found between the study group and the
control groups for age and comorbidities. No difference was found in basal
metabolic index (BMI).
CRS ⫽ chronic rhinosinusitis; ESS ⫽ endoscopic sinus surgery; NS ⫽
no significant difference.
Laryngoscope 115: June 2005
using a Fisher’s exact test. Results of the reflux symptom scale,
SNOT-20, sinusitis symptom scale, and endoscopic examination
score were compared between groups using a multiple analysis of
variance test. Also, data from the study group were looked at as
a whole (38 patients) and without the five patients with isolated
frontal recess disease (33 patients) versus the control groups.
RESULTS
Forty-one study patients were enrolled, and 39 com-
pleted the 24 hour pH study. Two patients were unable to
complete the study because of intractable gagging, and
one patient completed the study but was determined to
have had malfunctioning of the pH probe. Therefore, 38
studies were available for evaluation. Twenty-one pa-
tients were female, and 17 were male, with a mean age
53.7 (28 –78) years. Patients had undergone an average of
3.2 previous surgeries, with a range of 1 to 10. The under-
lying cause of CRS in this group was nasal polyps in 9
patients, AFS in 7 patients, nonpolypoid CRS in 22 pa-
tients. Five of these patients had sinus disease limited to
the frontal recess. To determine whether the frontal re-
cess patients had less reflux than the rest of the study
group, the statistical calculations were also performed
without these patients. There were not enough patients
with isolated frontal recess disease to allow statistical
comparisons between this subgroup and the rest of the
study group or the controls.
In this group, 16 of 38 patients previously had a
diagnosis of GER or LPR, with most having been treated
with medical therapy at some time before the pH study.
Two patients had undergone a fundoplication approxi-
mately 7 and 8 years earlier. All patients were nonsmok-
ers. Nineteen had undergone allergy testing; four were
found to be atopic. Twenty-three patients had one or more
comorbid conditions: 16 with a history of asthma or reac-
tive airway disease, 8 with hypertension, 3 with depres-
sion, 2 with coronary artery disease, 4 with headache
syndromes, 1 with hypercholesterolemia, 1 with sarcoid-
osis, 1 with gout, and 1 with classic hemophilia and HIV.
This group averaged one (range 0 –3) comorbidity per pa-
tient. Only two patients were on oral steroid therapy at
the time of the pH study, with one being on long-term
prednisone at 10 mg daily and the other being on a 2 week
prednisone taper.
The first control group, the successful ESS group,
consisted of 10 patients. There were six females and four
males with a mean age of 41.6 (22–72) years. All were
nonsmokers. The underlying cause of CRS was nonpol-
ypoid CRS in six, AFS in two, nasal polyps in one, and a
sphenoid mycetoma in one. Patients had undergone an
average of 1.4 (1–3) surgeries. Three patients had under-
gone allergy testing, with two being found to be atopic.
One patient was asthmatic. No other comorbid conditions
were found in this group. None of these patients had a
previous diagnosis of reflux disease.
The second control group, individuals without a his-
tory of CRS or sinus surgery, consisted of 20 subjects.
There were 10 females and 10 males, with a mean age of
38.3 (25– 62) years. All were nonsmokers. Five had a pre-
vious diagnosis of reflux disease. Two subjects had under-
gone allergy testing and were found to be atopic. Seven
DelGaudio: Direct Nasopharyngeal Reflux of Gastric Acid
949
subjects had comorbid conditions: six with obstructive The pH study results for all study patients and con-
sleep apnea (1 also with hypertension) and one with hy- trols are shown in Tables II to IV. Table V summarizes all
percholesterolemia. This group averaged 0.4 (range 0 –2) of the data for the study group and control groups. The
comorbidities per patient. data for the two control groups were very similar for all
Table I compares the study and two control groups parameters, and statistical evaluation revealed no signif-
with regards to demographic data. The mean age of the icant differences between the control groups for any pa-
patients in the study group was higher than either of the rameters. Because of this lack of a difference between the
control groups (P ⬍ .001). The study group also had more control groups, the two groups were collapsed into a single
comorbidities compared with the control groups (P ⫽ control group of 30 subjects for statistical comparisons
.001). There was no difference in basal metabolic index with the study group. The lack of any statistically signif-
between the groups. icant difference may be caused by the small number of
subjects in the successful ESS control group.
One control subject in the nonCRS group (#20 in
TABLE II.
Study Group pH Study Results (n ⫽ 38). Table IV) was found to have significant reflux and to be an
outlier when the control group data were evaluated. This
NPR NPR UES Percent of Study
Events Events Reflux UES pH ⬍ 4,
subject was one of only two patients in the nonCRS control
Patient pH ⬍ 4 pH ⬍ 5 Episodes RAI Esophagus group with any NPR episodes below pH of 4. This subject
had 46 and 57 NPR events below pH 4 and 5, respectively,
1 18 104 65 73.3 9.4
in addition to abnormal UES and esophageal reflux pa-
2 15 28 60 306 38
rameters. All of the NPR events occurred in a 2 hour
3 0 10 17 35.5 6.9 period of time while eating popcorn in a semirecumbent
4 3 11 10 4.8 10.4 position. These episodes could not be explained by food
5 0 52 6 0.8 5.7 ingestion because no acidic food was eaten at this time.
6 1 8 16 32 8.2 When this subject is eliminated from the nonCRS control
7 0 2 2 0 8.4 group, a significant difference is found in the prevalence of
8 2 6 61 135 11.5 NPR at pH less than 5, when compared with the success-
9 0 0 2 0.7 3.4 ful ESS group (P ⫽ .03) (Table VI). None of the other
10 0 0 1 0.1 2.3 parameters reach statistical significance between the two
11 6 10 7 3.2 5.1
control groups when this outlier is dropped from the data-
set. Table V also shows that there is no statistically sig-
12 9 2 7 1.4 2.5
nificant difference between the successful ESS control
13 0 119 88 54.7 4.4
group and the study group (P ⫽ .09) for NPR at pH less
14 0 26 60 97.8 8.1 than 5. There is a significant difference between the study
15 0 37 7 10.6 2.7 group and the nonCRS control group with respect to NPR
16 17 12 21 72.2 4.6 with and without the outlier (P ⫽ .000008 and P ⫽
17 5 31 22 15.9 8 .0000008, respectively). All comparisons between the col-
18 0 0 28 5.6 3.5 lapsed control group and the study group are calculated
19 4 48 17 31.9 5.9 with and without the outlier, as seen in Tables VII to IX.
20 18 23 28 34.1 13.1 The elimination of the outlier increases the statistical
21 2 17 8 7.7 3 significance of the differences between these groups (Ta-
22 0 19 47 28.5 12.1
23 0 0 53 8.1 11.4
24 2 16 11 2.9 3.5 TABLE III.
pH Study Results for Control Group 1, Successful ESS
25 147 220 205 355 20.5 Patients (n ⫽ 10).
26 0 0 9 16.7 5.5
NPR NPR UES Percent of Study
27 0 25 0 0 0.4 Events Events Reflux pH ⬍ 4,
28 0 42 56 43.1 6.8 Patient pH ⬍ 4 pH ⬍ 5 Episodes UES RAI Esophagus

29 0 9 0 0 0.1 1 7 28 45 26.7 4.1

30 0 0 7 5.2 0.6 2 0 13 38 7.1 2.5
31 0 2 19 11.4 8.2 3 0 0 1 0.1 0.3
32 0 0 0 0 0.5 4 0 0 2 1.4 3.8
33 0 11 1 0.1 10.7 5 0 0 5 0.8 3.5
34 0 0 0 0 0.8 6 0 0 2 0.1 2.7
35 0 87 75 97.2 26.6 7 0 7 0 0 1.4
36 0 0 7 17.7 7.8 8 0 114 17 3.2 14.6
37 9 43 41 10.8 4.6 9 0 3 10 1.3 1.1
38 0 1 0 0 0.1 10 0 0 116 22.3 4.4
NPR ⫽ nasopharyngeal reflux; UES ⫽ upper esophageal sphincter; NPR ⫽ nasopharyngeal reflux; UES ⫽ upper esophageal sphincter;
RAI ⫽ reflux area index. RAI ⫽ reflux area index; ESS ⫽ endoscopic sinus surgery.

Laryngoscope 115: June 2005 DelGaudio: Direct Nasopharyngeal Reflux of Gastric Acid
950
 TABLE V.
Overview of Results.
UES pH ⬍4 over 4%
NPR Events NPR Events ⬎6.9 UES RAI ⬎ of Study,
pH ⬍ 4 (%) pH ⬍ 5 (%) Events 6.3 (%) Esophagus (%)

Study group (n ⫽ 38) 15 (39) 29 (76) 28 (74) 22 (58) 25 (66)

Study group minus frontal recess 15 (45) 27 (82) 26 (79) 20 (61) 22 (67)
disease only pts (n ⫽ 33)
Successful ESS controls (n ⫽ 10) 1 (10) 5 (50) 5 (50) 2 (20) 3 (30)
NonCRS controls (n ⫽ 20) 2 (10) 3 (15) 7 (35) 5 (25) 7 (35)
NonCRS controls minus outlier (n ⫽ 19) 1 (5) 2 (10) 6 (32) 4 (21) 6 (32)
Each cell represents the number of patients that had abnormal values for each listed parameter. A single nasopharyngeal reflux event was considered
abnormal (below pH 4 or 5).
NPR ⫽ nasopharyngeal reflux; UES ⫽ upper esophageal sphincter; RAI ⫽ reflux area index; ESS ⫽ endoscopic sinus surgery; CRS ⫽ chronic rhinosinusitis.

bles VII to IX). For the remainder of this section, the recess disease are removed form the dataset, the differ-
results will be reported using the collapsed control group ence increases further (P ⫽ .000008).
without the outlier. At the UES, there is a statistically significant differ-
One or more NPR events below pH of 4 are found in ence in the percentage of study patients with pathologic
39% of study patients compared with 10% of the control reflux by both parameters evaluated (⬎6.9 reflux episodes
groups (Table V). The differences are statistically signifi- for the entire study and UES RAI ⬎ 6.3) when compared
cant at P ⬍ .004. When patients with isolated frontal with control patients, with P ⫽ .006 and P ⫽ .007, respec-
recess disease are removed from the dataset, 45% of the tively. Again, these differences increase when the patients
study group have NPR events, with an increase in the with isolated frontal recess disease are removed from the
statistical difference (P ⫽ .002) (Table VII). When evalu- dataset (P ⫽ .00005 and P ⫽ .005, respectively) (Tables V
ating NPR events with pH less than 5, the difference is and VIII).
even greater. Seventy-six percent of the study group have In the esophagus, there is also a significantly higher
NPR events below pH of 5 compared with 24% of controls percentage of pathologic reflux in the study group than in
(P ⫽ .00003). When the patients with isolated frontal the control group when looking at the number of patients
with pH less than 4 for greater than 4% of the study time
(66 vs. 31%, P ⫽ .007). The elimination of the isolated
TABLE IV. frontal recess disease patients from the dataset does not
pH Study Results for NonCRS Controls (n ⫽ 20). increase this difference, unlike for the other sites (Tables
NPR NPR UES Percent of Study V and IX).
Events Events Reflux pH ⬍ 4, The patients in the study group had multiple under-
Patient pH ⬍ 4 pH ⬍ 5 Episodes UES RAI Esophagus lying causes of their refractory sinusitis, such as polyps,
1 0 0 0 0 1.5 AFS, or nonpolypoid CRS. Because of the small numbers
2 0 14 1 0.1 2.9 of patients in each of these subgroups, statistical analysis
3 0 0 25 26.9 13.2 was not performed for each individual underlying diagno-
4 0 0 3 6.4 10.1 sis. Eliminating individual diagnostic categories, such as
AFS patients, from the study group data did not signifi-
5 0 0 10 2 23.2
cantly alter the statistical data. Reflux scores, sinusitis
6 0 0 3 0.6 3
symptom scores, SNOT-20 scores, and endoscopic exami-
7 0 0 0 0 1.3
8 0 0 5 0.6 3.6
9 0 0 7 23 8.5
TABLE VI.
10 0 0 7 4.6 3.1 Comparison of Study Group and Control Groups for NPR Events
11 0 0 0 0 2 below pH 5.
12 2 15 20 16.4 1.8 Study Group Successful
13 0 0 0 0 0.2 (n ⫽ 38) ESS

14 0 0 2 0.1 1.6 Successful ESS (n ⫽ 10) P ⫽ .09 (NS) N/A

15 0 0 19 6.2 9.1 NonCRS control (n ⫽ 20) P ⫽ .000008 NS
16 0 0 0 0 2.3 NonCRS control minus P ⫽ .0000008 P ⫽ .03
outlier (n ⫽ 19)
17 0 0 1 0.1 5.7
18 0 0 0 0 0.2 Eliminating the outlier in the normal control group reveals a significant
difference between the nonCRS control group and the successful ESS control
19 0 0 0 0 0.4 group (P ⫽ .03). For no other parameter was there a significant difference
20 46 57 62 41.6 8.2 between the two control groups. Therefore, the control groups are collapsed
into a single control group for all subsequent analyses.
NPR ⫽ nasopharyngeal reflux; UES ⫽ upper esophageal sphincter; NPR ⫽ nasopharyngeal reflux; ESS ⫽ endoscopic sinus surgery;
RAI ⫽ reflux area index; CRS ⫽ chronic rhinosinusitis. CRS ⫽ chronic rhinosinusitis.

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951
 TABLE VII.
Statistical Evaluation for Nasopharyngeal Reflux (NPR) Events.
NPR ⬍ 4 NPR ⬍ 5

Controls Controls Controls Controls

(n ⫽ 30) (n ⫽ 29) (n ⫽ 30) (n ⫽ 29)

Study group (n ⫽ 38) P ⫽ .01 P ⫽ .004 P ⫽ .00007 P ⫽ .00003

Study group minus isolated frontal recess P ⫽ .002 P ⫽ .002 P ⫽ .00001 P ⫽ .000008
disease patients (n ⫽ 33)
Comparing the complete study group (n ⫽ 38) and the study group without the isolated frontal recess disease patients (n ⫽ 33) with the collapsed control
group (n ⫽ 30) and the collapsed control group minus the one outlier (n ⫽ 29). P values demonstrate the significant differences between the study groups and the
control groups with regards to the percentage of patients with NPR. Statistical significance increases further with elimination of the one outlier in the control group
and with the elimination of the isolated frontal recess disease patients in the study group.

nation scores were significantly higher for the study group
than the control groups (P ⫽ .001 for all scales) (Table X).
Two patients had a previous fundoplication 7 and 8
years before the pH study. Of these patients, one had no
evidence of reflux at any site (patient 38), whereas the
other (37) had pathologic reflux at all sites (Table II).
DISCUSSION
CRS is a condition that results from mucosal inflam-
mation and impaired mucociliary clearance. Multiple
causes of this inflammatory process are known, and it is
likely that the disease is multifactorial in many patients.
The notion that a single etiology is responsible for all CRS
is not plausible.
Reflux disease has been implicated to be associated
with CRS, but whether it is a coexistent disease process or
a cause of CRS has yet to be determined. The mechanism
of involvement of LPR in CRS is also unknown.
Multiple studies have found a higher incidence of
GER and LPR in patients with CRS than in patients
without CRS. Using pH studies with a sensor above the
UES, Ulualp et al.14 found a statistically higher incidence
of pharyngeal acid reflux events in patients with both CRS
(persistent after sinus surgery) and posterior laryngitis (4
of 6 patients, 67%) compared with healthy controls (7 of
34, 21%) or with patients with CRS without posterior
laryngitis (4 of 12, 33%). There was no difference between
the distal and proximal esophageal reflux parameters be-
tween these groups. They conclude that LPR may play a
role in a subset of patients with CRS, and posterior lar-
yngitis may be the common thread among reflux-induced
aerodigestive tract disorders. The small number of sinus-
itis patients included is a drawback of this study.
Ulualp and Toohill21 compared 11 patients with med-
ically refractory CRS with 11 healthy controls. They re-
ported a higher prevalence of pharyngeal acid reflux in
CRS patients (7 of 11, 64%) compared with control pa-
tients (2 of 11, 18%) and a greater number of pharyngeal
acid reflux events in the CRS patients. Both differences
were statistically significant (P ⬍ .05).
Chambers et al.3 retrospectively reviewed 182 pa-
tients who had undergone ESS to determine prognostic
factors for poor outcome. They found that a history of GER
was the only historic factor that was a predictor of poor
symptom outcome after ESS. A history of GER was deter-
mined to be present if the chart or the patient interview
revealed the presence of heartburn or regurgitation that
required medication for reflux. Because of the retrospec-
tive nature of this study, no pH studies or other diagnostic
tests for reflux disease were performed.
DiBiase et al.,32 in a retrospective case series, re-
ported on 18 patients with refractory CRS. Seventy-eight
percent of patients were found to have GER based on
pH-probe testing. All 18 patients had their reflux treated
medically or surgically, with 67% having improvement of
sinus symptoms at a mean follow-up of 5.8 months. Dra-
matic improvement was confined to patients with an ab-
normal pH study. No control group was used in this study.
A prospective study by DiBiase et al.31 compared 11
patients with CRS with 19 GER disease control patients.

TABLE VIII.
Statistical Evaluation for UES Reflux Events.
⬎6.9 UES Reflux Episodes UES RAI ⬎ 6.3

Controls Controls Controls Controls

(n ⫽ 30) (n ⫽ 29) (n ⫽ 30) (n ⫽ 29)

Study group (n ⫽ 38) P ⫽ .01 P ⫽ .006 P ⫽ .01 P ⫽ .007

Study group minus isolated frontal recess P ⫽ .002 P ⫽ .00005 P ⫽ .01 P ⫽ .005
disease patients (n ⫽ 33)
Comparing the complete study group (n ⫽ 38) and the study group without the isolated frontal recess disease patients (n ⫽ 33) with the collapsed control
group (n ⫽ 30) and the collapsed control group minus the one outlier (n ⫽ 29). P values demonstrate the significant differences between the study groups and the
control groups with regards to the percentage of patients with pharyngeal reflux events. Statistical significance increases further with elimination of the one outlier
in the control group. With the elimination of the isolated frontal recess disease patients in the study group, there are bigger differences in the number of patients
with greater than 6.9 reflux episodes, but not much change in the differences in reflux area index (RAI), compared with the full study group.
UES ⫽ upper esophageal sphincter.

Laryngoscope 115: June 2005 DelGaudio: Direct Nasopharyngeal Reflux of Gastric Acid
952
 TABLE IX.
Statistical Evaluation for Esophageal Reflux.
Greater than 4% of Study with
pH ⬍ 4, Esophagus
Controls Controls
(n ⫽ 30) (n ⫽ 29)
Study group (n ⫽ 38) P ⫽ .01 P ⫽ .007
Study group minus isolated P ⫽ .01 P ⫽ .01
frontal recess disease
patients (n ⫽ 33)
Comparing the complete study group (n ⫽ 38) and the study group
without the isolated frontal recess disease patients (n ⫽ 33) with the collapsed
control group (n ⫽ 30) and the collapsed control group minus the one outlier
(n ⫽ 29). P values demonstrate the significant differences between the study
groups and the control groups with regards to the percentage of patients with
abnormal esophageal reflux. Statistical significance increases further with
elimination of the one outlier in the control group only when evaluating the full
study group.
All patients underwent a dual sensor pH study for pha-
ryngeal and esophageal acid testing. There was no differ-
ence in the percentage of abnormal pH results in the CRS
group (9 of 11, 82%) compared with the GER group (15 of
19, 79%). Only the supine acid exposure time in the distal
esophagus was significantly different, being greater in the
GER patients. All CRS patients were treated with 3
months of omeprazole 20 mg twice daily. Patients had
partial symptomatic improvement of their sinus symp-
toms after treatment, but dramatic improvement occurred
infrequently.
In the pediatric population, a relationship between
GER and CRS has been suggested. In a retrospective
review of 28 patients who had failed medical treatment for
sinusitis, Bothwell et al.22 found that treatment of GER
resulted in 89% of children having improvement of their
CRS and thus avoiding sinus surgery.
Carr et al.,47 in a retrospective study of children less
than 2 years old, reported a history of reflux in 42% of
children undergoing adenoidectomy compared with 7% of
children undergoing tympanostomy tube placement alone.
This study used multiple criteria for the diagnosis of GER,
and very few patients underwent a pH study.
pH testing in the nasopharynx for evaluation of a
relationship between CRS and GER has been used in two
studies in the pediatric population. Contencin and
Narcy34 evaluated 31 children aged 1 month to 12 years
for the presence of NPR by performing a 24 hour nasopha-
TABLE X.
Symptom and Examination Scores.
Reflux Symptom
Score
CRS study group (n ⫽ 38) 13.26 (6.75)
Successful ESS controls (n ⫽ 10) 5.20 (5.09)
NonCRS controls (n ⫽ 20) 4.40 (6.19)
P value ⬍.001
Mean values are reported followed by standard deviation in parentheses. Significant differences were found between the study group and the collapsed
control group for all scores.
ESS ⫽ endoscopic sinus surgery; CRS ⫽ chronic rhinosinusitis; SNOT ⫽ sinonasal outcome test.
Laryngoscope 115: June 2005
ryngeal pH study. The study group consisted of 13 chil-
dren with recurrent or chronic rhinitis or rhinopharyngi-
tis. The 18 control subjects were children who had upper
aerodigestive tract pathology but no evidence of rhinitis or
rhinopharyngitis, with 12 having a history of confirmed
GER and 6 being actively treated for GER at the time of
the pH study. They defined an NPR episode to be a pH
drop below 6.0 and found the total time spent below pH 6.0
to be the most significant item. The study group was found
to have significantly more NPR episodes and percentage of
the study time below pH 6.0 compared with the controls (P
⬍ .00005). Unfortunately, the study used only a nasopha-
ryngeal sensor without an esophageal sensor. This does
not allow confirmation that a drop in the esophageal pH
preceded the nasopharyngeal pH drops rather than an
artifact related to pseudoreflux, meals, or nasal or naso-
pharyngeal secretions. Also, they hypothesize that a pH
drop below 6.0 in the nasopharynx to be the equivalent to
an esophageal pH drop below 4.0. There is no evidence to
support this hypothesis.
Phipps et al.24 evaluated 30 children aged 2 to 18
with a history of CRS that was refractory to standard
medical treatment. All patients underwent a dual sensor
24 hour pH study with separate probes in the distal esoph-
agus and the nasopharynx. Reflux episodes were defined
as a drop below pH 4.0. Nineteen of 30 (63%) patients had
pathologic GER. Nine of 30 (30%) patients were found to
have at least one NPR event, including 3 patients without
pathologic GER. Of the 19 patients with pathologic GER,
15 (79%) had improvement of their CRS symptoms after
treatment of GER. This study does not include any control
patients, instead using historic controls for the incidence
of GER. Unfortunately, there are no historic controls for
the incidence of NPR in healthy individuals. Also, the
authors evaluated the esophageal and nasopharyngeal
sensors individually for reflux episodes. They do not com-
ment on comparing the recording sites to confirm that an
esophageal pH drop of an equal or greater degree preceded
the NPR episodes. This does not allow the differentiation
of a true nasopharyngeal pH drop from artifact.
In the present study, it has been demonstrated that
patients with refractory CRS have a greater amount of
reflux than control patients, both distally and proximally
in the aerodigestive tract. This is reflected in higher reflux
parameters at the distal esophagus (greater percentage of
patients with pH less 4.0 for ⬎ 4% of the study [P ⫽ .007])
and at the UES (greater percentage of patients with ⬎ 6.9
Sinusitis Severity
SNOT-20 Score Examination Score
45.08 (18.19) 42.13 (18.58) 7.79 (3.77)
20.30 (18.76) 14.50 (16.23) 1.80 (2.82)
14.15 (20.80) 9.15 (14.74) .15 (0.49)
⬍.001 ⬍.001 ⬍.001
DelGaudio: Direct Nasopharyngeal Reflux of Gastric Acid
953
 reflux episodes for the entire study [P ⫽ .006] and a RAI ⬎
6.3 [P ⫽ .007]).
The most striking difference is in the amount of NPR
in the study group compared with the controls. NPR
events below pH 4 were much more common in the study
group (39% of patients), compared with either the success-
ful ESS control group (10%) and the nonCRS control group
(5%) (P ⫽ .01 for collapsed control groups). The difference
between the study (76%) and control group (24%) for the
percentage of patients with NPR events with pH less than
5 is much greater (P ⬍ .00003). The difference in the
amount of NPR between the study group and the collapsed
control group is attributable to the nonCRS control sub-
group. There is not a significant difference in the fre-
quency of NPR events below pH 5 between the study
group and the successful ESS control group (P ⫽ .09),
whereas the difference in the incidence of NPR events
between the study group and the nonCRS control group is
highly significant (P ⬍ .0000008). There is a significant
difference between the numbers of patients with NPR
below pH 5 in the successful ESS control group (50%)
compared with the nonCRS group (5%) (P ⫽ .03). The lack
of a statistical difference between the successful ESS con-
trol group and the study group for NPR events pH less
than 4 or 5 may be caused by the small number of subjects
in this control group because it appears that a greater
number of CRS patients (76%) have NPR events less than
pH 5 compared with successful ESS controls (50%). Re-
moval of the patients with isolated frontal recess disease
from the study group dataset further increases the statis-
tical difference with the control group, indicating that
NPR events are less likely to be a contributing factor to
CRS in patients with isolated frontal recess disease.
In this study, a greater incidence of reflux at the UES
was seen in the study group compared with the control
group. This is similar to what has been found in other
studies looking at reflux episodes above the UES.14,21 This
difference is statistically significant and is larger when
patients with isolated frontal recess disease are elimi-
nated from the dataset. This appears to indicate that
reflux is more of a contributing factor in patients with
diffuse sinus disease and less of a factor in patients with
frontal recess findings only. Because the majority of our
study and control patients had at least one reflux episode
above the UES, a single episode was not considered patho-
logic. In evaluating the pH study data at the UES, the
criteria used was that proposed by Vincent et al.46 to
determine what is a normal amount of reflux at the UES.
In their evaluation of normal healthy controls without a
history of reflux, they determined that the 95% confidence
interval for a normal amount of reflux at the UES is less

Fig. 6. Study patient 25. (A) Endoscopic appearance of right si-

nonasal cavity at the time of the pH study. (B) Endoscopic appear-
ance after 4 months of once-daily esomeprazole therapy. There is
improvement but not resolution of the mucosal edema and dis-
charge. (C) Endoscopic appearance after an additional 4 months of
twice-daily esomeprazole therapy and 1 month of nasal nebulized
Betamethasone treatments. There has been dramatic improvement
of the nasal mucosal edema and drainage.

Laryngoscope 115: June 2005 DelGaudio: Direct Nasopharyngeal Reflux of Gastric Acid
954
than 6.9 reflux episodes for a 24 hour study or an RAI less
than 6.3.
Esophageal reflux was more common in the study
group compared with the controls, as reflected in the num-
ber of patients with greater than 4% of the study below pH
4 (P ⫽ .007). When the patients with isolated frontal
recess disease were eliminated from the dataset, the dif-
ferences between the study group and the control group
increased for all of the nasopharyngeal and UES values
but not for the esophageal data. It is most likely that
proximal reflux is less of a contributing factor to frontal
recess disease than to diffuse sinus disease, but the inci-
dence of distal esophageal reflux is no different between
these patients. All of the pH studies were performed with
pH probes with a fixed 18 cm distance between the UES
and esophageal sensors. As a result, the position of the
esophageal sensor may not have been located 5 cm proxi-
mal to the lower esophageal sphincter in all patients, as is
the accepted position for esophageal pH monitoring. Be-
cause both the study and control patients were studied
with the same probes, the esophageal data should be com-
parable between groups even if the probes are not uni-
formly positioned at 5 cm above the lower esophageal
sphincter. It was more important to have accurate place-
ment of the nasopharyngeal and UES sensors than the
esophageal sensor in this evaluation of the role of reflux in
CRS, and therefore the esophageal sensor location was felt
not to be as critical.
The present study also found significant differences
between the study group and the control group with re-
gard to the reflux symptom score (P ⫽ .001), the SNOT-20
(P ⫽ .001), the sinusitis symptom scale (P ⫽ .001), and the
endoscopic examination score (P ⫽ .001), with the study
group having consistently higher scores. It is not surpris-
ing that the sinusitis symptom scale and SNOT-20 scores
are higher for the study group because all study patients
were required to have persistent CRS symptoms for inclu-
sion in the study group. The reflux scores were also sig-
nificantly higher for the study group, which corresponds to
the higher incidence of reflux identified in this group.
In the present study, all NPR events were confirmed
to have been preceded by a more distal reflux event. Also,
meal times were eliminated from the evaluation of the
recordings to eliminate any artifact that may have oc-
curred from eating acidic foods. These factors confirm that
the NPR events could not have represented artifact. None
of these previous studies have definitively confirmed that
the NPR events were preceded by more distal reflux
events at the UES and distal esophagus.
This study is the first to demonstrate that direct NPR
of gastric acid is found in adults with refractory CRS at a
significantly higher frequency than in control patients.
The likely mechanism of effect on the nasal mucosa is
mucosal edema and impaired mucociliary clearance. As
acid travels up the digestive tract, it reaches areas with
less ability to protect against the acid and digestive en-
zymes present in the refluxate. Just as the parameters for
abnormal reflux at the UES are different from the distal
esophagus, it is likely that the nasopharyngeal and nasal
mucosa have a lower threshold for injury from gastric
contents. Because of the lack of acid protective mecha-
Laryngoscope 115: June 2005
nisms in the nasopharynx and nose, it is likely that a
small amount of acid reaching this area can cause signif-
icant problems. The finding of a dramatically higher inci-
dence of NPR events below pH of 5 in refractory CRS
patients supports this hypothesis. It is also important to
appreciate that pepsin remains stable at pH levels up to
7.36 These results support the possibility that even more
minor pH drops can cause harmful effects in the upper
aerodigestive tract as a result of acid or pepsin exposure.
Treatment of extraesophageal manifestations of re-
flux is more difficult than treating classic GER. For areas
with little protective mechanisms against gastric acid,
complete acid suppression may be necessary to achieve
symptom relief. This is hard to achieve. Only approxi-
mately two thirds of patients with LPR have significant
improvement of symptoms after 8 weeks of once-daily
esomeprazole.42 Proton pump inhibitor (PPI) resistance
has also been reported in patients with LPR.48,49 In light
of these facts, it is likely that reflux treatment alone is
inadequate to resolve sinusitis in which reflux may be a
contributing factor. In this series, only two study patients
had dramatic improvement of their CRS after adequate
reflux treatment with PPIs was begun. One patient re-
solved completely, and the other had significant improve-
ment but required nebulized nasal steroids for complete
response (Fig. 6). Others had mild to moderate improve-
ment. This is consistent with the findings of DiBiase et
al.31,32 It is likely that reflux is one contributing factor to
a multifactorial disease in these CRS patients. Only by
addressing all of the contributing factors can the CRS be
adequately controlled. Aggressive reflux treatment should
be considered in refractory CRS patients and may be an
integral part of the treatment in a subgroup of patients.
This proof of direct NPR in refractory CRS patients
raises many more questions about the possible role of
reflux in other diseases of the proximal aerodigestive
tract. Further studies should evaluate the role of direct
NPR in pathology affecting the middle ear such as serous
otitis media, eustachian tube dysfunction, and adenoid
hypertrophy. The role of direct oropharyngeal reflux in
patients with oral and oropharyngeal pathology, such as
lingual tonsil hypertrophy, chronic tonsillitis, and burning
mouth syndrome, also needs to be evaluated.
None of the patients in the study or control groups
used tobacco, therefore eliminating this as a confounding
factor. One weakness of this study is that the study and
control groups are not controlled for age and comorbidi-
ties. The study group is older than the control group by
approximately 10 years. Also, the study group patients
have more comorbid conditions, especially asthma, com-
pared with the control group. It is possible that some of
the comorbidities, such as asthma, may also be risk factors
for reflux.
CONCLUSIONS
The present study is the first to evaluate for the
presence of NPR episodes in adult patients with refractory
CRS. The results reported here confirm that there is a
statistically significant difference in the frequency of NPR
events below pH of 4 and pH of 5 in CRS patients as
compared with those patients who have done well after
DelGaudio: Direct Nasopharyngeal Reflux of Gastric Acid
955
ESS and control patients without a history of CRS. It is
likely that NPR plays a role in refractory sinusitis. In
addition, these results show that CRS patients have a
statistically greater amount of reflux at the UES and
lower esophagus than controls. Furthermore, there is a
statistically significantly higher incidence of NPR below
pH of 5 in the control group of successful ESS compared
with the nonCRS control group. This indicates that NPR
episodes may also have been a contributing factor to CRS
in this group of patients. On the basis of these findings,
aggressive reflux therapy is recommended as part of the
treatment of refractory CRS after ESS.
Acknowledgment
The author thanks Justin C. Wise, PhD, for his help
with the statistical analysis.
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