Link between pharyngeal acid reflux episodes and the effectiveness of proton pump inhibitor therapy

Table 1 Baseline characteristics of the study populations

Characteristic	PAR1 alone (n = 11)	EAR2 alone (n = 68)	Both pH (+) (n = 18)	Both pH (-) (n = 93)	P value (4-group comparison)
Demographics
Age in years, n (%)	47.2 (16.4)	53.9 (10.8)9	54.8 (15.5)	49.7 (12.1)	0.1
Male sex, n (%)	4 (36)11	50 (74)9	11 (61)	50 (54)	0.03
BMI in kg/m2, (n (%)	22.7 (2.7)12	24.7 (3.8)9	25.0 (2.9)	23.5 (3.5)	0.08
ENT first visit, n (%)	9 (82)	50 (74)	9 (50)10	76 (82)	0.03
Clinical presentations
Major laryngeal symptom, n (%)
Globus sensation, n (%)	1 (9)	17 (25)	6 (33)	26 (28)	0.5
Throat pain, n (%)	2 (18)	18 (26)	4 (22)	18 (19)	0.7
Hoarseness, n (%)	3 (27)	18 (26)	5 (28)	30 (32)	0.9
Cough, n (%)	5 (45)8	11 (16)	2 (11)	8 (9)	0.008
Throat clearing, n (%)	0 (0)	3 (4)	1 (6)	11 (12)	0.2
Symptom duration in months, median (IQR)	13 (4, 24)12	18 (7, 48)13	30 (13, 90)10	12 (6, 36)	0.03
Typical reflux symptoms3, n (%)	5 (45)	34 (50)	13 (72)	47 (51)	0.4
Previous acid suppressive therapy use, n (%)	5 (45)	43 (63)	13 (72)	52 (57)	0.3
Diabetes mellitus, n (%)	1 (9)	2 (3)	1 (6)	5 (5)	0.8
Hypertension, n (%)	1 (9)	16 (24)	3 (17)	17 (18)	0.5
Post nasal drip, n (%)	4 (36)	29 (43)	9 (50)	39 (42)	0.9
Endoscopic findings
Reflux esophagitis, n (%)					< 0.0001
No reflux esophagitis, n (%)	4 (36)	15 (22)	4 (22)	28 (30)
Grade A, n (%)	4 (36)	36 (53)	11 (61)	65 (70)
Grade B, n (%)	3 (27)	11 (16)	3 (17)	0 (0.0)
Grade C, n (%)	0 (0)	6 (9)	0 (0)	0 (0)
Grade D, n (%)	0 (0)	0 (0)	0 (0)	0 (0)
Barrett’s esophagus, n (%)	0 (0)	5 (7)9	2 (11)10	0 (0)	0.03
Hiatus hernia, n (%)	1 (9)	11 (16)	5 (28)10	7 (8)	0.08
Peptic ulcer, n (%)	3 (27)	5 (7)	2 (11)	13 (14)	0.2
Helicobacter pylori, n (%)	3 (27)	12 (18)	5 (28)	14 (15)	0.6
Reflux finding score4, median (IQR)	6 (3, 11)	7 (5, 9)	5 (3, 7)	7 (4, 10)	0.4
Patient report outcome, median (IQR)
Reflux symptom index total score5, median (IQR)	16 (11, 20)	16 (12, 21)	20 (10, 28)	16 (11, 22)	0.5
GERDyzer total score6, median (IQR)	45 (31, 49)	38 (19, 49)	35 (20, 50)	36 (25, 50)	0.7
Heartburn frequency7, median (IQR)	1 (0, 4)	2 (0, 4)	3 (1, 4)10	1 (0, 3)	0.1
Heartburn severity7, median (IQR)	2 (0, 3)	2 (0, 3)	3 (1, 4)	2 (0, 3)	0.2
Acid regurgitation frequency7, median (IQR)	3 (1, 4)	2 (0, 4)	3 (1, 4)	2 (1, 4)	0.8
Acid regurgitation severity7, median (IQR)	2 (1, 4)	2 (0, 4)	3 (1, 4)	3 (1, 3)	0.8

¹Excessive pharyngeal acid reflux is defined as pharyngeal acid reflux ≥ 2 episodes.

²Excessive distal esophageal acid reflux is defined as distal esophageal acid reflux total time ≥ 4.2% of 24-hour, or ≥ 6.3% of upright position, or ≥ 1.2% of supine position.

³Typical reflux symptoms is defined as regurgitation or heartburn at least twice a week with mild symptom, or once a week with moderate/severe symptom.

⁴Score range from 0 to 26, with higher scores suggesting more severe laryngitis.

⁵Score range from 0 to 45, with higher scores suggesting more severe symptoms.

⁶Score range from 0 to 70, with higher scores suggesting worse quality of life.

⁷Score range from 0 to 5 for symptom frequency or severity, with higher scores suggesting worse quality of life.

⁸P < 0.05 for pharyngeal acid reflux alone vs both pH (-).

⁹P < 0.05 for esophageal acid reflux alone vs both pH (-).

¹⁰P < 0.05 for both pH (+) vs both pH (-).

¹¹P < 0.05 for pharyngeal acid reflux alone vs esophageal acid reflux alone.

¹²P < 0.05 for pharyngeal acid reflux alone vs both pH (+).

¹³P < 0.05 for esophageal acid reflux alone vs both pH (+).

BMI: Body mass index; EAR: Esophageal acid reflux; ENT: Ear-nose-throat specialists; GERD: Gastroesophageal reflux disease; IQR: Interquartile range; PAR: Pharyngeal acid reflux; pH: Potential of hydrogen.

Table 2 Primary and secondary outcomes

Outcome	PAR1 alone (n = 11)	EAR2 alone (n = 68)	Both pH (+) (n = 18)	Both pH (-) (n = 93)	P value (4-group comparison)
Week 4
Symptom improvement, median (IQR)	40 (5, 70)3	30 (0, 60)4	30 (0, 40)5	0 (0, 30)	0.001
≥ 50% improvement, n (%)	5 (45)	28 (41)4	4 (22)	19 (20)	0.02
Change of the GERDyzer total score, median (IQR)	-11 (-21, -3)	-14 (-26, -1)4	-9 (-19, -4)	-5 (-12, 0)	0.02
Week 8
Symptom improvement, median (IQR)	70 (20, 80)3	50 (30, 80)4	35 (0, 60)	20 (0, 50)	0.0007
≥ 50% improvement, n (%)	8 (73)3	40 (59)4	7 (39)	31 (33)	0.003
Change of the GERDyzer total score, median (IQR)	-23 (-39, -13)3	-18 (-28, -1)4	-18 (-23, -10)	-8 (-16, 0)	0.006
Week 12
Symptom improvement, median (IQR)	85 (20, 99)3	60 (10, 85)4	50 (0, 90)	30 (0, 60)	0.002
≥ 50% improvement, n (%)	8 (73)3	40 (59)4	10 (56)	31 (33)	0.003
Change of the GERDyzer total score, median (IQR)	-26 (-28, -19)3	-20 (-30, -3)4	-16 (-26, -8)	-9 (-18, -1)	0.01

¹Excessive pharyngeal acid reflux is defined as pharyngeal acid reflux ≥ 2 episodes.

²Excessive distal esophageal acid reflux is defined as distal esophageal acid reflux total time ≥ 4.2% of 24-hour, or ≥ 6.3% of upright position, or ≥ 1.2% of supine position.

³P < 0.05 for pharyngeal acid reflux alone vs both pH (-).

⁴P < 0.05 for esophageal acid reflux alone vs both pH (-).

⁵P < 0.05 for both pH (+) vs both pH (-).

EAR: Esophageal acid reflux; GERD: Gastroesophageal reflux disease; IQR: Interquartile range; PAR: Pharyngeal acid reflux; pH: Potential of hydrogen.

Table 3 Manometric and 24-hour potential of hydrogen findings

Finding	PAR1 alone (n = 11)	EAR2 alone (n = 68)	Both pH (+) (n = 18)	Both pH (-) (n = 93)	P value (4-group comparison)
24-hour pH findings
Distal esophagus
Total time pH < 4, median (IQR)	1.2 (0.9, 2.1)6,7	6.1 (4.5, 8.5)4	7.6 (4.7, 11.9)5	0.6 (0.1, 1.5)	< 0.0001
Upright time pH < 4, median (IQR)	2.2 (1.3, 3.4)6,7	8.1 (6.1, 12.1)4	9.1 (7.4, 14.3)5	0.9 (0.2, 2.3)	< 0.0001
Supine time pH < 4, median (IQR)	0.0 (0.0, 0.2)3,6,7	1.3 (0.0, 4.5)4	1.4 (0.2, 10.1)5	0.0 (0.0, 0.0)	< 0.0001
Pharynx
Number of PAR event, total, median (IQR)	5 (2, 10)3,6	0 (0, 0)4,8	3 (2, 6)5	0 (0, 0)	< 0.0001
Number of PAR event, upright, median (IQR)	5 (2, 9)3,6	0 (0, 0)4,8	3 (2, 5)5	0 (0, 0)	< 0.0001
Number of PAR event, supine, median (IQR)	0 (0, 1)3,6	0 (0, 0)4,8	0 (0, 0)5	0 (0, 0)	0.0002
Manometric findings
Lower esophageal sphincter, median (IQR), mmHg	19 (15, 27)6,7	13 (10, 20)8	9 (7, 11)5	16 (10, 27)	0.0002
Upper esophageal sphincter, median (IQR), mmHg	32 (22, 87)	30 (18, 48)4,8	15 (7, 28)5	38 (25, 54)	0.0002
Ineffective esophageal motility, n (%)	1 (14)	14 (33)	3 (27)	13 (24)	0.6
Esophageal sensation
Bernstein test, n (%)	4 (36)	21 (31)4	9 (50)5	14 (15)	0.01
Symptom index, n (%)	3 (27)	24 (35)4,8	12 (67)5	17 (18)	0.0003

¹Excessive pharyngeal acid reflux is defined as pharyngeal acid reflux ≥ 2 episodes.

²Excessive distal esophageal acid reflux is defined as distal esophageal acid reflux total time ≥ 4.2% of 24-hour, or ≥ 6.3% of upright position, or ≥ 1.2% of supine position.

³P < 0.05 for pharyngeal acid reflux alone vs both pH (-).

⁴P < 0.05 for esophageal acid reflux alone vs both pH (-).

⁵P < 0.05 for both pH (+) vs both pH (-).

⁶P < 0.05 for pharyngeal acid reflux alone vs esophageal acid reflux alone.

⁷P < 0.05 for pharyngeal acid reflux alone vs both pH (+).

⁸P < 0.05 for esophageal acid reflux alone vs both pH (+).

EAR: Esophageal acid reflux; IQR: Interquartile range; PAR: Pharyngeal acid reflux; pH: Potential of hydrogen.