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Table 1. Randomized Trials on Medical Management of Extraesophageal Manifestations of GERD
Source
Cough
Shaheen 2011
Faruqi 2011
Sample
Size
Intervention
Primary Outcome(s)
Main Finding(s)
P-value
40
Esomeprazole 40 mg bid for
12 weeks versus placebo
Change in Cough Specific
Quality of Life
Questionnaire score
Mean improvement in CSQLQ of
9.8 in treatment group vs 5.9 in
placebo group.
0.3
Mean improvement in Fisman
Cough Severity score of 1 in the
treatment group vs 0.8 in the
placebo group.
0.7
Mean improvement in Fisman
Cough Frequency score of 3.2 in
the treatment group vs 2.3 in the
placebo group.
Change in cough frequency was 1.6
in the treatment group and 1.5 in
the placebo group.
0.3
49
Esomeprazole 20 mg bid for
8 weeks
Change in integral
response score for cough,
change in Leicester Cough
Questionnaire, change in
Hull Airway Reflux
Questionnaire, Reflux
Finding Score, citric acid
cough challenge
Change in cough severity was 1.2
in the treatment group and 1.7 in
the placebo group.
Change in the Leicester Cough
Questionnaire was 2.6 in the
treatment group and 0.7 in the
placebo group.
Change in the RFS was 0.72 in the
treatment group and 2.4 in the
placebo group.
Change in the Hull Airway Reflux
Questionnaire was 7.3 in the
0.92
0.8
0.25
0.94
0.61
treatment group and 7.1 in the
placebo group.
Change in log of inhaled citric acid
concentration to produce 2 coughs
was -0.15 in the treatment group
and -0.04 in the placebo group.
Baldi 2006
Kiljander 2000
(randomized
case-crossover
trial)
LPR
Lam 2010
35
Lansoprazole 30 mg qd and Changes in cough scoring
placebo dose in PM (control) system and VAS
versus lansoprazole 30 mg
bid for 12 weeks.
21
Omeprazole 40 mg qd for 8
weeks
Changes in cough
symptom score in the last
3 weeks of each study
period.
82
Rabeprazole 20 mg bid for
12 weeks
Change in RSI and RFS
Change in log of inhaled citric acid
concentration to produce 5 coughs
was 0.02 in the treatment group
and -0.09 in the placebo group.
Median change in VAS was 1 in
both the treatment and control
groups.
Median change in cough scoring
system was 1 in the treatment
group and 0.5 in the control group.
10 of 17 (59%) patients in the
treatment group and 11 of 18
(61%) in the control group had
complete resolution of their
symptoms.
Cough symptom score decreased
1.5 in patients who received
omeprazole, and increased 0.7 in
patients who received placebo.
At week 12, RSI decreased 2.8 in
the treatment group and increased
0.93 in the placebo group.
At week 12, RFS decreased 2.21 in
the treatment group and 2.75 in
the placebo group.
0.66
0.57
> 0.05
> 0.05
> 0.05
< 0.05
0.002
0.017
At week 18 RSI decreased 0.9 in
the treatment group and increased
0.58 in the placebo group.
At week 18 RFS decreased 3.2 in
the treatment group and 3 in the
placebo group.
McGlashan
2009
Reichel 2008
45
58
10 mL liquid dose of sodium
alginate 1000 mg and
potassium bicarbonate 200
mg after meals and at
bedtime
Esomeprazole 20 mg bid for
3 months
Change in RSI and RFS
from baseline to 2 month
and 6 month follow up
Change in RSI and RFS at
6 weeks and 3 months
follow up, and subjective
report of being symptomfree at 3 months.
RSI from baseline to 2 month
follow up decreased 12.7 in the
treatment group and 7.8 in the no
treatment group.
0.12
0.68
0.005
RSI from baseline to 6 month
follow up decreased 12.7 in the
treatment group and 6.3 in the no
treatment group.
0.008
RFS from baseline to 2 month
follow up decreased 2.2 in the
treatment group and 0.6 in the no
treatment group.
0.08
RFS from baseline to 6 months
follow up decreased 3.2 in the
treatment group and 0.7 in the no
treatment group.
RSI from baseline to 6 weeks
decreased 9.87 in the treatment
group and 6.93 in the placebo
group.
0.005
RSI from baseline to 3 months
decreased 14.27 in the treatment
group and 7.79 in the placebo
group.
< 0.05
RSI from baseline to 6 weeks
Not significant
Not significant
(value
unreported
Wo 2006
Vaezi 2006
Steward 2004
35
145
37
Pantoprazole 40 mg daily
for 12 weeks
Esomeprazole 40 mg bid for
16 weeks
Rapeprazole 20 mg bid for 8
weeks
Change in RFS, and
subjective “adequate
relief” of laryngeal
symptoms.
Resolution of primary
symptom, change in
chronic posterior
laryngitis index, and
change in LPR-HRQL
score.
Change in reflux symptom
score, subjective report of
“significant global
improvement”, change in
decreased 3.47 in the treatment
group and 2.46 in the placebo
group.
(value
unreported)
RSI from baseline to 3 months
decreased 4.6 in the treatment
group and 2.32 in the placebo
group.
< 0.05
At 3 months 78.6% of patients in
the treatment group and 42.3% of
patients in the placebo group
reported being symptom-free.
Median RFS decreased 1 in the
treatment group and 3 in the
placebo group.
0.006
Adequate relief of laryngeal
symptoms was reported by 40% of
patients in the treatment group
and 42% of patients in the placebo
group.
Resolution of primary symptom
was reported in 14.7% of patients
in the treatment group and 16% of
patients in the placebo group.
0.89
CPLI decreased 1.6 in the
treatment group and 2 in the
placebo group.
LPR-HRQL score decreased 11.6 in
the treatment group and 7.8 in the
placebo group.
Mean reflux symptom score
decreased 9.7 in the treatment
group and 6.6 in the control group.
Not significant
(value
unreported)
0.799
0.446
0.424
0.44
laryngeal grading of
video-recorded strobelaryngoscopy signs
scoring system
Ehrer 2003
(placebocontrolled
case-crossover
trial)
14
Noordzij 2001
30
El-Serag 2001
Asthma
Kiljander 2010
20
828
Pantoprazole 40 mg bid for
3 months
Omeprazole 40 mg bid for 8
weeks
Lansoprazole 30 mg bid for
3 months
Three randomization
Change in symptom score,
change in laryngoscopic
signs score
Change in symptom score,
change in laryngoscopic
scores for vocal fold
edema, arytenoid
erythema, arytenoid
edema, interarytenoid
irregularity, and mucus
accumulation.
Resolution of all
presenting laryngeal
symptoms, complete or
partial resolution of all
presenting laryngoscopic
signs
Changes in lung function
Significant global improvement
was reported in 53.3% of
treatment patients and 50% of
control patients.
Laryngoscopic grade increased 0.6
in the treatment group and 0.5 in
the control group.
No statistically significant
difference in mean symptom
scores between groups (values
unreported).
1
0.69
Not significant
(value
unreported)
Mean laryngoscopic signs score
decreased 8 in the treatment-first
group and 5.6 in the placebo-first
group.
Laryngeal symptom score
decreased 1078.6 in the treatment
group and 1944.9 in the placebo
group.
Not significant
(value
unreported)
No significant difference was found
in the change in laryngoscopic sign
scores between the two groups.
Resolution of all presenting
laryngeal symptoms was reported
in 55% of patients in the treatment
group and 11% of patients in the
placebo group.
Not significant
(values
unreported)
0.04
Complete or partial resolution of
laryngeal signs was found in 58%
of patients in the treatment group
and 30% of patients in the control
group.
Mean morning PEF improved 3.5L
0.098
0.123
Not significant
groups: esomeprazole 40
mg daily and placebo daily,
esomeprazole 40 mg bid, or
placebo bid for 26 weeks
tests, change in asthma
quality of life
questionnaire score, and
experiencing a severe
asthma exacerbation
and 5.5L more in patients receiving (values
esomeprazole daily and bid,
unreported)
respectively, compared to placebo.
Mean FEV1 improved 0.07L more
in patients receiving esomeprazole
bid compared to placebo.
Esomeprazole once daily was not
statistically significantly better
than placebo.
Mean AQLQ score increased 0.2 in
patients receiving esomeprazole
40 mg daily, 0.3 in patients
receiving esomeprazole bid, and
0.1 in patients receiving placebo.
Severe asthma exacerbations were
experienced by 10%, 7.5%, and
10% of patients receiving
esomeprazole once daily, bid, and
placebo, respectively.
Peterson 2009
30
Three randomization
groups: rabeprazole 20 mg
daily and placebo daily,
rabeprazole 20 mg bid, or
placebo bid
Subjective determination
by subjects of improved
exercise symptoms,
changes in pulmonary
function test, spirometry,
SF-36 score, and miniAQLQ score
Subjectively improved exercise
tolerance was reported by 70% of
patients receiving rabeprazole and
25% of patients receiving placebo
bid.
There was no statistically
significant difference in change in
FEV1, FVC, or FEV1/FVC between
the rabeprazole groups and
placebo (values unreported).
There were no statistically
significant difference in change in
< 0.0042
Not significant
(value
unreported)
< 0.001
Not significant
(values
unreported)
0.03
Not significant
(values
unreported)
SF-36 or mini-AQLQ scores (values
unreported).
Mastronarde
2009
393
Esomeprazole 40 mg bid
Rate of episodes of poor
asthma control, change in
PFTs, asthma symptoms,
or asthma control
No of episodes of poor asthma
control per person-year was 2.5 in
the treatment group and 2.3 in the
placebo group.
Change in FEV1 was 0L in the
treatment group and -0.02L in the
placebo group.
0.36
Change in FVC was 0 in the
treatment group and -0.03 in the
placebo group.
0.3
Change in PEF was 9.2 L/min in
the treatment group and 3.2 L/min
in the placebo group.
0.24
Change in PC20 was 0.3 mg/mL in
the treatment group and 1.5
mg/mL in the placebo group.
Sharma 2007
198
Omeprazole 20 mg bid and
domperidone 10 mg tid for
16 weeks
Not significant
(values
unreported)
0.66
Change in JACQ, ASUI, mini-AQLQ,
and SF-36 scores were not
statistically significantly different
between the treatment and
placebo groups.
Changes in asthma
Daytime asthma symptom score
symptom score, rescue
decreased 0.48 in the treatment
albuterol use, daytime and group and 0.22 in the placebo
nighttime PEF, postgroup.
bronchodilator FEV1, and
FVC
Nighttime asthma score decreased
0.51 in the treatment group and
0.14 in the placebo group.
0.04
0.11-0.56
0.0001
0.0001
Rescue albuterol puffs/week
decreased 0.76 in the treatment
<0.0001
group and 0.1 in the placebo group.
Morning PEF increased 22.78
L/min in the treatment group and
decreased 0.76 L/min in the
placebo group.
Evening PEF increased 27.76
L/min in the treatment group and
decreased 1.43 L/min in the
placebo group.
FEV1 increased 0.21L in the
treatment group and 0.07L in the
placebo group.
Kiljander 2006
624
Esomeprazole 40 mg bid for
16 weeks
Change in morning and
evening PEF
FVC increased 0.18L in the
treatment group and decreased
0.03L in the placebo group.
Morning PEF increased 22.3 L/min
in the treatment group and 16
L/min in the placebo group from
baseline to the last 28d of the
study.
Morning PEF increased 5.6 L/min
more in the treatment group than
in the placebo group after
treatment was completed.
In patients with GERD and
nocturnal respiratory symptoms
morning PEF increased 8.7 L/min
more in the treatment than the
placebo group.
<0.004
0.002
0.0013
0.0023
0.061
0.042
0.03
Evening PEF increased 5.9 L/min
more in the treatment group than
in the placebo group.
Littner 2005
173
Lansoprazole 30 mg bid for
24 weeks
24-week average of
asthma symptom score
calculated from patient
diaries, albuterol use,
changes in PEF, postbronchodilator FVC and
FEV1, AQLQ score, and
asthma exacerbations.
In patients with GERD and
nocturnal respiratory symptoms
evening PEF increased 11.2 L/min
more in the treatment group than
in the placebo group.
Asthma symptom scores decreased
0.36 in the treatment group and
0.21 in the placebo group.
Morning PEF increased 5 L/min in
the treatment group and 10 L/min
in the placebo group.
Evening PEF increased 4 L/min in
the treatment group and 12 L/min
in the placebo group.
0.053
0.02
Not significant
(value
unreported)
Not significant
(value
unreported)
< 0.05
Post-bronchodilator FEV1 changed
0L in both groups.
Post-bronchodilator FVC changed
0L in the treatment group and
decreased 0.1L in the placebo
group.
AQLQ score increased 0.9 in the
treatment group and 0.7 in the
placebo group.
Albuterol use decreased 1 puff/day
in the treatment group and 0.9
puffs per day in the placebo group.
Asthma exacerbations were
Not significant
(value
unreported)
Not significant
(value
unreported)
< 0.05
Not significant
(value
experienced by 8.1% of patients in
the treatment group and 20.4% of
patients in the placebo group.
Moderate or severe asthma
exacerbations were experienced by
4% of patients in the treatment
group and 13.9% of patients in the
placebo group.
Sontag 2003
62
Three randomization
groups: lifestyle
Cont
modifications and prn
24
medications only (control),
Med 22 lifestyle modificaitons and
Surg
ranitidine 150 mg tid, and
16
lifestyle modificaitons and
Nissen fundoplication,
followed for 2 years
Change in asthma
symptom score,
requirement for
pulmonary medications,
and overall clinical
response
Mean asthma symptom score
improved significantly in 75% of
surgical patients, 20% of control
patients, and 0% of medical
treatment patients.
The requirement for pulmonary
medications decreased in 9.1% of
patients in the medical group but
increased in 18.2% of these
patients. Pulmonary medication
requirement decreased in 50% of
patients in the surgical group. Zero
patients in the control group
changed their need for pulmonary
medications.
Overall improvement occurred in
9.1% of patients in the medical
group, 75% of the surgical group,
and 4.2% of the control group.
Jiang 2003
30
Two randomization arms:
asthma treatment only,
versus asthma treatment
plus omeprazole 20 mg qd
Change in PFTs and
histamine-induced
bronchial sensitivity.
FVC increased 0.8L in the
treatment group vs decreased 0.2L
in the no-treatment group.
unreported)
0.017
0.016
0.008 (surgery
versus control
and medical
groups
combined)
Not significant
(value
unreported)
< 0.001
(surgery versus
control and
medical groups
combined)
< 0.05
and domperidone 10 mg tid
for six weeks
FEV1 increased 0.6L in the
treatment group and 0.1 L in the
no-treatment group.
< 0.05
PEF increased 1.3 L/s in the
treatment group versus 0.4 L/s in
the no-treatment group.
< 0.05
Bronchial sensitivity improved
0.51 g/L in the treatment group
versus worsened 0.03 g/L in the
no-treatment group.
< 0.05
Table 2. Level of Recommendation for Systematic Review of Recent Literature Compared to Current Practice Guidelines for
Management of Extraesophageal Manifestations of GERD
Intervention
Current Evidence Review and Guidelines
Cough
Treating chronic cough with medical antisecretory therapy.
Evidence review
Randomized controlled trials on treating suspected cough due to reflux with
PPIs have had mixed results. Shaheen 2011 (patients with chronic cough and
without typical GERD symptoms) and Faruqi 2011 (patients with chronic cough
and with or without typical GERD symptoms) showed no improvement in
cough-related quality of life, cough severity, cough frequency, induced cough
threshold compared to placebo. However, Kiljander 2000 (patients with chronic
cough and abnormal esophageal pH monitoring) showed greater improvement
in cough symptoms with omeprazole compared to placebo. No randomized trial
has directly addressed the question of medical treatment of reflux in patients
with persistent chronic cough and non-acid reflux.
Patients with persistent chronic cough who do not smoke and are not taking an
ACE inhibitor, after ruling out or treating for upper airway cough syndrome,
asthma, and non-asthmatic eosinophilic bronchitis should undergo medical
treatment for GERD. (ACCP)
Treating patients with chronic cough and typical symptoms of GERD with medical antisecretory therapy.
Evidence review
Two randomized controlled trials have enrolled patients with chronic cough and
a diagnosis of GERD, Baldi 2006 and Kiljander 2000. Baldi 2006 compared daily
to twice daily lansoprazole, and found that bid therapy was not significantly
better than daily therapy. Kiljander 2000 showed greater improvement in cough
symptoms with omeprazole compared to placebo. While patients with typical
symptoms of GERD should be treated for GERD regardless of what
extraesophageal manifestations of GERD they may have, whether or not treating
their GERD has a positive impact on their chronic cough is not clear.
Recommendation
Level
Class
A
IIb
B
IIb
B
IIa
Practice guidelines
Practice guidelines
Patients with chronic cough and typical symptoms of GERD should undergo
medical treatment for GERD (ACCP).
Using esophageal monitoring to diagnose cough due to reflux.
Evidence review
Studies have sought to evaluate the utility of esophageal monitoring – pH and
MII-pH monitoring, on and off antisecretory therapy, with subjective and
objective reporting of cough – in diagnosing cough due to reflux. A prospective
case-control study found that weakly acidic gas reflux was unique to patients
with cough due to reflux compared to patients with GERD and healthy controls.
(Kawamura 2011) Retrospective studies found esophageal pH monitoring with
SAP analysis with self-reported cough off antisecretory therapy was found to
have a positive and negative predictive value of 0.28 and 0.72, respectively
(Hersh 2010), and that 26% of patients with cough due to reflux had a positive
SI for non-acid reflux during esophageal MII-pH monitoring with self-reported
cough on antisecretory therapy (Tutuian 2006). A prospective cohort study on
esophageal MII-pH monitoring off antisecretory therapy with SAP analysis and
cough recorded with concurrent manometry found 77% of patients with cough
due to reflux were SAP positive, while 44% of patients without cough due to
reflux were SAP positive. This study also reported that only 39% of cough bursts
were not recorded by patients, and those that were recorded were delayed by
28 seconds. (Sifrim 2005) These studies were all small (n ≤ 61) and some had
significant methodological flaws. Overall, no strong recommendations about
patient selection, whether monitoring should be conducted on or off
antisecretory therapy, or the true diagnostic yield of esophageal monitoring can
be made with the data currently available. Still, it is reasonable to conclude that
patients with chronic cough and typical GERD symptoms should undergo an
empiric trial of antisecretory therapy before being subjected to esophageal
monitoring. Furthermore, if at all possible, esophageal pH/MII-pH monitoring
should be accompanied by concurrent manometry in order to gather superior
objective data on cough bursts and their timing. The evidence does not support
the guidelines’ assertion that esophageal pH monitoring is the most sensitive
and specific test available for cough due to reflux: MII-pH monitoring with
objective cough recording and SAP analysis may be superior to esophageal pH
monitoring to diagnose GERD in patients with chronic cough.
Practice guidelines
Patients with typical symptoms of GERD whose cough does not resolve with
antisecretory therapy should undergo esophageal pH monitoring while on
antisecretory therapy to determine whether medical therapy has failed (ACCP).
Antireflux surgery for the treatment of cough due to reflux.
Evidence review
No randomized controlled trial has compared medical to surgical treatment of
cough due to reflux in any patient population. Two prospective cohort studies
have observed patients who underwent antireflux surgery after a negative
workup for other causes of chronic cough. Allen 2004 reported on 79 patients
who had a negative workup for UACS and asthma and complained primarily of
respiratory symptoms before undergoing laparoscopic Nissen fundoplication. At
B
IIb
5-years follow-up patients subjectively reported 36% were cured of cough, 35%
were improved, 24% were unchanged, and in 5% cough was worse. Mean cough
score decreased 3.9 on a 12-point scale. Brouwer 2003 reported on 28 patients
who underwent laparoscopic Nissen fundoplication for predominantly
respiratory symptoms. Mean cough score decreased from 4.7 to 0.4 at mean 650
days follow-up. 19 patients had cough or “aspiration-type symptoms”: 53%
reported resolution of their symptoms (symptom score of 0/5), 32% had
marked improvement (symptom score of 1/5), 11% reported some
improvement, and 5% were unchanged. Antireflux surgery for cough due to
reflux is promising for cases refractory to medical management. However
patient selection to maximize successful resolution of cough is uncertain. In
patients who have been ruled out or treated for the three other most common
causes of chronic cough and MII-pH monitoring shows acid or non-acid reflux on
maximal antisecretory therapy, it may be reasonable to refer for evaluation for
antireflux surgery. However, patients should be counseled that success is not
guaranteed, and surgery is not without risks.
Practice guidelines
Antireflux surgery is recommended in patients who have positive esophageal pH
monitoring in whom cough has not improved after a minimum of 3 months of
maximal medical therapy and lifestyle modifications and esophageal monitoring
studies show continued reflux while on maximal medical therapy (ACCP).
LPR
Use of the Reflux Symptom Index to diagnose LPR
B
Evidence review
One prospective study has evaluated the Reflux Symptom Index (Belafsky 2002).
The authors reported mean RSI of patients with LPR was 19.9, of healthy
controls was 11.6. They considered RSI > 13 abnormal and indicative of LPR.
Patients with suspected LPR should be evaluated with the Reflux Symptom
Index and Reflux Finding Score. If > 13 and > 7, respectively, patients should
undergo an empiric trial of antisecretory therapy (Ford).
Use of the Reflux Finding Score to diagnose LPR
Evidence review
Belafsky 2001: mean RFS of patients with LPR was 11.5. Interrater reliability
was 0.9.
IIb
Practice guidelines
Patients with suspected LPR should be evaluated with the Reflux Symptom
Index and Reflux Finding Score. If > 13 and > 7, respectively, patients should
undergo an empiric trial of antisecretory therapy (Ford).
Use of the Laryngoscopic Reflux Index score to diagnose LPR
B
IIb
C
IIb
Practice guidelines
Evidence review
Jonaitis 2006: LRI significantly higher in patients with LPR versus healthy
controls. LRI > 5 significantly more common in cases than controls, but test
characteristics unreported.
Practice guidelines
Not addressed.
Use of laryngoscopy to diagnose LPR
Evidence review
Three prospective studies have examined the use of laryngoscopy to diagnose
LPR. In one case-control study (Vavricka 2007), only posterior pharyngeal wall
cobblestoning was more common in cases than controls (66% vs 55%).
Agreement between blinded observers on laryngeal findings ranged from good
to poor. Another prospective study found that only interarytenoid mucosal
inflammation and inflammation of the true vocal cords were significant
predictors of response to antisecretory therapy (Park 2005). Yet another
prospective study compared transnasal flexible fiberoptic laryngoscopy to
transoral rigid laryngoscopy, finding fiberoptic laryngoscopy superior in
detecting laryngeal findings. However even with flexible fiberoptic laryngoscopy
interrater reliability for findings ranged from poor to moderate.
B
Laryngoscopic findings are highly suggestive of LPR: posterior laryngitis, contact
granuloma, and pseudosulcus (Ford).
Esophageal pH or MII-pH monitoring to diagnose LPR
B
Evidence review
Two prospective studies have examined esophageal or pharyngoesophageal pH
monitoring to diagnose LPR. One found increased laryngopharyngeal bolus
exposure time and increased distal AET were only two significant predictors of
response to PPI therapy (Wang 2012), while the other found that 52% of
patients with laryngeal symptoms and 38% of patients with typical GERD
symptoms had laryngopharyngeal acid reflux episodes during monitoring
(Yorulamz 2003).
IIa
Practice guidelines
In patients whose symptoms do not resolve after 6 months or improve after 3
months patients should be evaluated with pharyngoesophageal MII-pH
monitoring to demonstrate reflux (Ford).
Empiric PPI trial to diagnose LPR
Evidence review
One prospective trial examined the sensitivity and specificity of an empiric trial
of twice daily PPIs to diagnose LPR, reporting positive and negative predictive
values of 86% and 25%, respectively (Masaany 2011).
IIb
Practice guidelines
Practice guidelines
If patients have RSI > 13 and RFS > 7, initiate 3-6 months of anti-reflux diet,
B
IIb
lifestyle modifications, and twice daily PPI therapy.
Treatment of LPR with PPIs
Evidence review
Eight randomized trials have compared twice daily PPI therapy with placebo.
Some followed changes in the RSI and RFS. Six of these trials reported no
differences between the placebo and treatment groups (or in the case of Lam
2010, only a transient difference), while 2 did report significant differences.
Reichel 2008 showed RSI and RFS both improved at 3 months in patients
treated with esomeprazole 20 mg bid for 3 months compared to placebo, while
El-Serag 2001 reported a greater percentage of patients in the treatment group
reporting complete resolution of their symptoms than in the placebo group
(55% vs 11%), but no difference in change in laryngeal signs of inflammation
between the two groups (Lam 2010, Reichel 2008, Wo 2006, Vaezi 2006,
Steward 2004, Ehrer 2003, Noordzij 2001, El-Serag 2001). Overall, there is little
evidence from randomized trials that PPIs are an effective treatment for LPR.
This may be due to poor patient selection for randomized trials of LPR.
Practice guidelines
Recommends treating patients with 3-6 months of twice daily PPI therapy.
Treatment of LPR with sodium alginate and potassium bicarbonate.
Evidence review
One randomized non-placebo controlled trial has evaluated the effect of treating
LPR with sodium alginate and potassium bicarbonate found RSI and RFS
improved significantly from baseline to 2 months (RSI only) and baseline to 6
months (RSI and RFS both) (McGlashan 2009).
Practice guidelines
Not addressed.
Antireflux surgery for LPR
Evidence review
No randomized trials have compared medical to surgical therapy for LPR.
Swoger 2006 reported a prospective cohort of 25 patients who were
unresponsive to PPI therapy. 10 chose to have surgery. At 1 year follow up, 1
patient in the surgery group and 1 patient in the medical groups reported
resolved symptoms. Given the paucity of prospective data surgical intervention
must be undertaken with the greatest caution, and only in patients whom
studies have shown have a reasonable chance of achieving cure.
Practice guidelines
A
IIb
B
IIa
C
IIb
C
IIb
In patients whose pharyngoesophageal MII-pH monitoring demonstrates reflux,
referral should be made for surgery.
Asthma
Use of esophageal acidification to diagnose asthma due to reflux
Evidence review
One prospective case-control study used an increase of 100 μg in PD20 FEV1 of a
methacholine inhalation test after esophageal acidification to diagnose asthma
due to reflux. Positive and negative predictive values were reported as 86% and
82%, respectively. (Dal Negro 2009)
Practice guidelines
Not addressed
Use of esophageal pH monitoring to diagnose asthma due to reflux
Evidence review
One randomized case-crossover trial (Kiljander 2001) studied using esophageal
pH monitoring to diagnose asthma due to reflux. The authors found that mean
distal esophageal acid exposure time (11% vs 8%) and supine distal esophageal
acid exposure time (12% vs 8%) were statistically significantly higher in
patients whose asthma responded to therapy with omeprazole than in patients
whose asthma did not respond to omeprazole.
B
The Expert Panel recommends that patients with poorly controlled asthma
despite maximal medical therapy should be evaluated for GERD with esophageal
pH monitoring. (NIH-EPR3)
Use of antisecretory therapy in patients with typical GERD symptoms.
A
Evidence review
Three placebo-controlled randomized trials and 1 uncontrolled randomized trial
have evaluated the effect of twice daily PPI therapy on asthma symptoms and
pulmonary function tests in patients with GERD, diagnosed either by symptoms
or esophageal pH monitoring. Three (Kiljander 2010, Sharma 2007, Jiang 2003)
found improvement in PFTs, while 1 (Littler 2005) did not. Kiljander 2010 found
decreased time to asthma exacerbation, greater asthma-free days, and less
bronchodilator use in the treatment group, and Sharma 2007 found decreased
bronchodilator use, while Littler 2005 found fewer asthma exacerbations and
moderate-severe asthma exacerbations in the treatment group but no difference
in bronchodilator use. Jiang 2003 found decreased inhaled histamine sensitivity
in the treatment group. Kiljander 2010 found improvement in the Asthma
Quality of Life Questionnaire score, while Littler 2005 did not. Overall,
symptomatic GERD should be treated regardless of whether or not a patient has
asthma, and the evidence indicates that treating GERD with twice daily PPI
therapy in patients with asthma improves subjective symptoms and PFTs, and
may decrease rescue bronchodilator use and increase asthma-related quality of
life.
IIb
Practice guidelines
Practice guidelines
The Expert Panel recommended that patients with asthma and GERD symptoms
should be treated for GERD. (NIH-EPR3).
I
Use of antisecretory therapy in patients without typical GERD symptoms but with positive esophageal pH
monitoring.
Evidence review
One randomized trial evaluated the effect of twice-daily PPI therapy on asthma
symptoms and PFTs in patients without typical GERD symptoms. Mastronarde
2009 found no difference in episodes of poor asthma control, PFTs, or asthma
symptoms in patients without typical GERD symptoms, including patients with
silent GERD discovered on esophageal pH monitoring. Kiljander 2006 studied
patients without moderate or severe GERD symptoms and found significantly
greater improvement in morning PEF in the treatment group, but no significant
difference in asthma exacerbations or median time to asthma exacerbation. In a
subgroup of patients with mild GERD symptoms and nocturnal asthma
symptoms morning and evening PEF increased significantly more in the
treatment group.
Practice guidelines
Not addressed.
Antireflux surgery for asthma due to reflux.
Evidence review
One randomized controlled trial compared antireflux surgery to H2 blocker
therapy for asthma due to reflux (Sontag 2003). It found that at 2 years asthma
symptom scores decreased significantly more in the surgical group than in the
H2 blocker and placebo groups combined. 75% of surgical patients had
improvement, marked improvement, or cure of asthma after 2 years follow up.
However pulmonary function tests and asthma medication requirements were
not significantly different between the groups. Rakita 2006 found mean asthma
symptom scores decreased from 4.7 to 1.7 after antireflux surgery (laparoscopic
Nissen fundoplication) in patients who presented with a mean asthma symptom
score of at least 4.
Practice guidelines
Surgical treatment has been reported to reduce the symptoms of asthma and
medication requirements (NIH-EPR3)
B
IIb
B
IIb
Q1a: How is reflux cough diagnosed?
Source
Study participants
Xu 2014
126 patients with either: chronic
cough and typical reflux
symptoms, persistence of
chronic cough after prior workup
failed to identify a cause, or
persistence of chronic cough
after attempted interventions
failed to resolve a chronic cough
Diagnostic
studies evaluated
GerdQ
Vs
MII-pH off
antisecretory
therapy
Gold standard
Study design
Main finding(s)
Complete resolution or
cough symptom score
decreased by at least two
points after 8-weeks of
omeprazole 20 mg bid and
domperidone 10 mg tid, and
further treatment with
omeprazole 80 mg/day or
replacement of domperidone
with baclofen 20 mg tid if
unresponsive after initial 8
weeks
Response to empiric therapy
with PPIs
Prospective
cohort
GerdQ vs MII-pH
 sensitivity: 66.7% vs 97.1% (p <
0.001)
 specificity: 91.7% vs 62.5% (p <
0.001)
 PPV: 97.1% vs 91.7% (p = 0.121)
 NPV: 42.9% vs 83.3% (p < 0.001)
Prospective
cohort
Simultaneous
measurement
with both
modalities
Prospective
cohort
The presence of heartburn had a
sensitivity of 72% and a specificity of
68% for GERD as the cause of chronic
cough. The presence of an acid taste in
the mouth had a sensitivity of 50% and
a specificity of 80%.
No correlation between reflux events or
positive-SAP for cough and reflux
between MII-pH and oropharyngeal pH
monitor
Only patients with GERD-cough had
weakly acidic gaseous
esophagopharyngeal reflux, which was
eliminated on PPI therapy.
21 (40%) patients reported cough
without typical GERD symptoms.
Ojoo 2013
112 patients with chronic cough
Symptoms
Ummarino
2013
10 patients with unexplained
chronic cough referred for
suspected reflux cough
Oropharyngeal
monitoring
MII-pH
Kawamura
2011
10 patients with GERD-cough,
10 with GERD alone, and 10
healthy controls
MII-pH
Resolution of cough on PPI
therapy and recurrence off
PPI therapy
Hersh
2010
53 patients with a primary
complaint of chronic cough who
underwent ambulatory pH
monitoring off antisecretory
therapy
pH monitoring and
SAP
SI, SAP, acid-exposure time
High degree of
response to
treatment
A high degree of response to treatment
(either submaximal or maximal
antisecretory therapy, or antireflux
surgery) was predicted by female sex (p
= 0.02) and positive SAP (p = 0.03) in
univariate and multivariable analysis.
Positive-predictive value of a positive
SAP predicting high degree of response
to treatment was 0.28, while negative
predictive value was 0.72.
PPV and NPV of elevated acidexposure time was 0.47 and 0.53,
respectively.
Patterson
2009
19 patients with asthma, 17 with
chronic cough
Oropharyngeal
monitoring
MII-pH
Prospective
cohort
Combining AET, SAP, and SI yielded
greater negative predictive value.
142/144 pharyngeal reflux episodes
were non-acidic.
There was a significant correlation
between the number of reflux episodes
reaching the pharynx and the total
number reaching the distal (r = 0.59, p <
0.002) and mid-esophagus (r = 0.53, p <
0.001).
There was no significant difference
between asthma and cough patients for
any impedence or pH parameter.
Songur
2008
Everett
2007
55 patients with chronic cough
and reflux symptoms, thought to
have reflux cough by Montreal
definition, having all of the
following: complaint of heartburn
or regurgitation, upper GI
endoscopic findings and
histology of reflux esophagitis,
normal CXR, nonsmoker, not
using ACE inhibitors, normal
PEF rate variability, and failure of
cough to resolve after treatment
for postnasal drip, asthma and/or
nonasthmatic bronchitis. And, 12
healthy volunteers.
47 patients referred for chronic
cough without respiratory
disease or history of GERD
Gastroesophageal
scintigraphy
Montreal definition of reflux
cough
Prospective
cohort
History and
symptomatology
Chronic cough and any two
of: esophageal acid reflux on
pH probe, esophageal
dysmotility on manometry, or
low LES pressure on
manometry
Retrospective
cohort
SAP-positive cough patients
experienced more reflux episodes
crossing the UES over 24h (5 vs 2, p <
0.05), and had a higher percentage of
reflux episodes cross the UES (25% vs
6.7%, p < 0.02) than SAP-negative
cough patients.
GES showed pathologic reflux in 51 of
55 (92.7%) patients with reflux cough,
19 (37%) of whom had proximal reflux
and 32 (63%) of whom had distal reflux.
After treatment with omeprazole 20 mg
bid for 8 weeks, cough had resolved
completely in 19 (37%) patients, and
sleep and daytime quality of life had
improved in another 22 (43%). Of the 10
patients who did not improve, 9 (90%)
had proximal reflux and grade B or C
esophagitis.
Cough on phonation, on rising from bed,
after throat clearing, with certain foods,
and with eating generally were the
symptoms most commonly associated
with reflux cough (90%, 86.7%, 82.5%,
76.5%, and 74.4% respectively).
Mainine
2006
144 patients referred for
symptoms refractory to PPI
therapy
MII-pH
Positive SI during MII-pH
Prospective
cohort
Tutuian
2006
50 patients with persistent cough
despite twice daily PPI therapy
MII-pH on PPI
therapy
Positive SI during MII-pH
Retrospective
cohort
Sifrim 2005
22 patients with chronic cough
and a normal CXR, negative
workup for asthma and postnasal
drip syndrome, and not on ACEi,
who had more than 5 cough
bursts during monitoring
MII-pH and
manometry and
SAP
Esophageal pH monitoring
Prospective
cohort
For patients with atypical symptoms
(cough, hoarseness, abdominal
discomfort, nausea, belching, throat
discomfort, throat mucous, globus
sensation, hiccups, wheezing, or sour
taste), 3% had a positive SI for acid
reflux, 19% had a positive SI for nonacid reflux while on twice-daily PPI
therapy.
13 (26%) patients had a positive SI for
non-acid reflux. 6 of 13 underwent
laparoscopic Nissen, 1 of whom was
lost to follow-up. At median follow-up of
17 months, the 5 laparoscopic Nissen
patients were asymptomatic and off PPI
therapy.
966 reflux events were detected, and
647 cough bursts. 198 of 647 (30.6%)
cough busts occurred within 2 minutes
of a reflux episode. In 49% of these 198,
reflux proceeded cough.
13 of 22 (59%) patients had abnormal
pH findings and/or typical GERD
symptoms. 10 (77%) were SAP positive
(77%), 3 (23%) were SAP negative.
9 of 22 (41%) patients had normal pH
findings and no typical GERD
symptoms. 5 (56%) were SAP negative,
4 (44%) were SAP positive.
Of the 4 patients with normal pH
findings and no typical GERD symptoms
but positive SAP, 3 had a positive SAP
with weakly acidic reflux.
Overall, inclusion of SAP changed the
diagnosis from reflux cough to idiopathic
cough in 3 of 22 patients, and from
idiopathic cough to reflux cough in 4 of
22 patients.
9 patients recorded cough as occurring
after reflux episodes, while manometry
recorded coughs prior to the patient
Wunderlich
2003
Avidan
2001
61 patients referred for chronic
cough, 23 on and 38 not on
antisecretory medications
128 asthmatic patients not on
antisecretory therapy
Esophageal pH
monitoring SAP
Esophageal pH
monitoring and
SAP
Esophageal pH monitoring
with SI and SSI
None
Retrospective
cohort
Prospective
cohort
recording, changing these events from
reflux-cough to cough-reflux.
SAP detected significantly more
temporal associations than SI/SSI in
patients on and off PPIs (p < 0.002).
SAP and SI/SSI had moderate
agreement (κ = 0.41)
Cough and reflux were temporally
associated in 46% of patients using a 2minute window (p < 0.001) and in 62%
of patients using a 5-minute time
window (p < 0.001). In a 2-minute
window, reflux preceded cough in 40%
of coughs (p < 0.001), while cough
preceded reflux in 6% of coughs (p =
0.043). In a 5-minute time window,
reflux preceded cough in 50% of coughs
(p < 0.001), while cough preceded reflux
in 12% of coughs (p = 0.014).
Q1b How is reflux laryngitis/LPR diagnosed?
Source
Study participants
Wang
2012
92 patients with chronic laryngitis
diagnosed with laryngoscopy
Masaany
2011
55 patients with either Reflux
Symptom Index > 13 or Reflux
Finding Score > 7
132 patients with esophagoscopic
findings of GERD, and 132 sexand age-matched controls
Vavricka
2007
Jonaitis
2006
Ylitalo
2005
108 patients with hoarseness
lasting more than 3 months,
chronic throat clearing, or throat
itching, had laryngitis on
laryngoscopy, and esophagitis on
endoscopy or biopsy pathology;
and 90 healthy controls
50 patients with chronic heartburn,
25 of whom had GERD diagnosed
on pH monitoring
Diagnostic studies
evaluated
Laryngoscopy, EGD, MII-pH
Gold standard
Study design
Main finding(s)
Decrease of 50% in
laryngeal symptom
score after
rabeprazole 10 mg
bid therapy
Prospective
cohort
Response to empiric
treatment with pantoprazole
40 mg bid
Structured examination of
the laryngopharyngeal area
during upper
gastrointestinal endoscopy
Symptoms of LPR
and positive pH
monitoring
None
Prospective
double-blind
cohort
Matched casecontrol
On multivariate analysis, increased
distal esophageal acid exposure time
(hazard ratio 2.6, p = 0.011) and
increased laryngopharyngeal bolus
exposure time (hazard ratio 2.6, p =
0.004) were associated with response
to rabeprazole therapy.
Sensitivity of empiric treatment was
92.5%, specificity 14.2%. PPV 86%,
NPV 25%.
No significant difference between
cases and controls in prevalence of
abnormal interarytenoid bar findings
(32% vs 32%), arytenoid medial wall
erythema (47% vs 43%), posterior
commissure changes (36% vs 34%), or
posterior cricoid wall edema (1 vs 3%).
Posterior pharyngeal wall
cobblestoning was more common in
cases than controls (65.5% vs 49.7%, p
= 0.004).
A novel laryngoscopic reflux
index scoring findings on
the arytenoids,
intraarytenoid notch,
vestibular folds, and vocal
cords, calculated after
examination by a single
laryngoscopist
Laryngoscopy
Definition of LPR as
patient with consistent
complaints, laryngitis
on laryngoscopy, and
esophagitis on
endoscopy or biopsy
pathology
Oropharyngeal reflux
on pH monitoring
Case-control
Prospective
cohort
Agreement between four blinded
observers (3 gastroenterologists and 1
otolaryngologist) on laryngopharyngeal
findings ranged from fair/good to poor.
Erythema and edema of the whole
laryngeal mucosa, reduced mucosal
light reflex on the aryetnoids,
interaretynoid notch, vocal folds, vocal
cords, hypertrophy, roughness, and
granulomas were all significantly more
common in LPR patients than in
controls (p ranging from < 0.001 to
0.01).
Both the laryngoscopic reflux index and
its individual components were
significantly different between cases
and controls (p < 0.001).
No laryngoscopic sign was statistically
significantly different between patients
with and without GERD, or those with
Park
2005
72 patients with signs and
symptoms of LPR who underwent
adequate video-recorded
laryngoscopy
Laryngoscopy
Response to therapy
Prospective
cohort
Qadeer
2005
10 patients who underwent
laparoscopic Nissen fundoplication
after failure (< 50% symptomatic
improvement) of laryngeal
symptoms (cough, throat clearing,
sore/burning throat, hoarseness, or
globus sensation) to respond to 4
months of omeprazole 40 bid or
lansoprazole 60 bid
Laryngoscopy by one
otolaryngologist at 6 and 12
months after surgical
fundoplication
Symptomatic
improvement
Prospective
cohort
Milstein
2005
52 healthy volunteers, 26% of
whom were former smokers and
none of whom were current
smokers, with mild or no
complaints of cough, hoarseness,
throat clearing, sore throat, globus
sensation, heartburn, regurgitation,
dysphagia, chest pain,
odynophonia.
Transoral laryngoscopy with
rigid telescopic
laryngoscope
None
Crosssectional
Vs
Transnasal laryngoscopy
with flexible fiberoptic
laryngoscope
and without oropharyngeal reflux on pH
monitoring
Pretherapy presence of abnormal
laryngoscopic findings in the
interarytenoid mucosa and the true
vocal folds was associated with
response to PPI therapy (OR 2, p =
0.02).
Sore/burning throat, hoarseness, and
chronic cough were the most common
persistent complaints (70%, 50%, 30%,
respectively). At 12-month follow-up,
heartburn had resolved in all patients,
while laryngeal symptoms had
improved in 1 of 10 (10%) patients.
Laryngoscopic signs improved in 80%
of patients: 5 of 10 (50%) had a
normalized laryngoscopic exam at 6month follow-up, another 3 (30%) had a
normalized exam at 12-month followup. 2 patients (20%) had improvement
in laryngeal symptoms after treatment
for asthma and allergies after
completion of the study.
Patients complained of mild cough,
hoarseness, throat clearing, sore
throat, globus sensation, heartburn,
and regurgitation (13%, 4%, 27%, 4%,
2%, 4%, 2%, respectively). None
complained of odynophagia, chest
pain, or odynophonia. 71% consumed
alcohol 2-3 times per month or less.
Video of laryngoscopic examination
was reviewed by three independent
otolaryngologists.
With the flexible and rigid
laryngoscopes, 145 of 156
observations (93%) and 130 of 156
observations (83%), respectively,
detected at least 1 sign of laryngeal
irritation.
In 7 of 13 common laryngoscopic
findings, the flexible laryngoscopic
examination discovered the sign
significantly more often (p < 0.01 for
all).
Hicks
2002
105 healthy volunteers without
heartburn more than three times
per month, or chronic throat
clearing, sore throat, coughing,
hoarseness, or globus sensation,
or with known GERD, and not on
antisecretory medications.
Flexible laryngoscopic
examination by one
licensed speech-language
pathologist
None
Crosssectional
Interrater reliability was calculated for
11 signs. 2 signs had poor, 2 slight, 5
fair, and 2 moderate agreement. On
rigid laryngoscopy interrater reliability
was calculated for 8 signs. 1 sign had
slight, 4 fair, and 3 moderate
agreement.
Patients most commonly complained of
throat clearing, heartburn, cough, thick
drainage, and throat tickle (33%, 24%,
14%, 13%, and 13%, respectively).
86% of patients had at least 1
laryngoscopic finding, while 64% had 2
or more. 12% had 4 or 5 signs, and 3%
had more than 5 signs.
Intrarater reliability was calculated for 5
signs with the same reviewer observing
the recorded examination 5 months
apart, with substantial agreement (κ =
0.63, 0.7, 0.78, 0.68) between the 2
observers for posterior pharyngeal wall
cobblestoning, arytenoid medial wall
erythema, interarytenoid bar presence,
and true vocal cord edema,
respectively, and fair agreement for
interarytenoid bar erythema (κ = 0.26).
Yorulmaz
2003
139 patients who underwent
esophageal pH monitoring, 97 with
primarily laryngopharyngeal
symptoms (chronic or intermittent
Esophageal and
laryngopharyngeal pH
monitoring
None
Retrospective
cohort
Interrater reliability between two
independent observers was calculated
for 3 signs, with interarytenoid bar
presence showing moderate
agreement (κ = 0.58), and posterior
pharyngeal wall cobblestoning and
arytenoid medial wall erythema
showing fair agreement (κ = 0.33 and
0.32, respectively).
50 of 97 (52%) patients with primarily
laryngopharyngeal symptoms and 16 of
42 (38%) patients with primarily typical
symptoms had laryngopharyngeal acid
hoarseness, frequent throat
clearing, chronic cough,
laryngospasm, globus sensation,
or sore throat), 42 with primarily
typical symptoms (heartburn or
regurgitation)
Branski
2002
100 patients with primary
complaint of dysphonia
Transoral rigid laryngoscopy
None
Prospective
cohort
reflux episodes (p < 0.005). Supine
acid reflux episodes were more
frequent in patients with typical
symptoms than patients with
laryngopharyngeal symptoms (p <
0.005). There were no significant
differences in acid clearance
parameters or esophageal acid
exposure times between the groups.
6 independent otolaryngologists
evaluated video recordings of each
patient’s laryngoscopic examination.
Intrarater reliability from 20 repeated
recording observations was calculated.
1 of 5 observers had consistent
intrarater reliability for across multiple
laryngoscopic signs.
Belafsky
2002
25 patients with LPR and 25 ageand gender-matched controls
Reflux symptom index (RSI)
pH monitoring
Prospective
matched
cohort
Single measure interclass correlation
coefficients for 7 laryngoscopic signs,
for otolaryngologist’s opinion of the
severity of GERD, and for the likelihood
of GERD contributing to patient
dysphonia were calculated, and ranged
from 0.161 to 0.461, corresponding to
poor agreement for all but one
measure, which had fair agreement.
Mean RSI on 2 different days
correlated well in LPR patients
(Pearson correlation coefficient = 0.81,
p < 0.001). Mean RSI after 6 mo of PPI
therapy decreased from 20.9 to 12.8 (p
< 0.001). Mean RSI in controls was
11.6, not statistically significantly
different from LPR patients after 6 mo
of PPI therapy.
Q1c: How is reflux asthma diagnosed?
Source
Study participants
Komatsu
2013
31 patients with adult-onset
asthma
Dal
Negro
2009
Kiljander
2001
27 patients non-atopic patients
with mild asthma and
symptomatic GERD confirmed
on esophageal pH monitoring,
and 29 atopic asthmatics without
symptoms of heartburn or
regurgitation and no diagnosis of
GERD after esophageal pH
monitoring
52 asthmatic patients with GERD
on pH monitoring
Diagnostic
studies evaluated
MII-pH off
antisecretory
therapy
Gold standard
Study design
Main finding(s)
Retrospective
cohort
Abnormal proximal esophageal exposure in 19
(70%) patients. 9 (33%) also had
laryngopharyngeal reflux. 20% of
laryngopharyngeal reflux episodes and 36% of
proximal esophageal acid exposures were nonacidic.
LFTs and bronchial
response to
methacholine
before and after
esophageal acid
infusion
Defined reflux asthma
as asthmatic patients
without atopy and with
symptomatic GERD
confirmed on
esophageal pH
monitoring
Case-control
pH probe findings
Increase > 20% in
symptom scores, PEF,
or FEV1 on
omeprazole compared
to placebo
Randomized
placebocontrolled casecrossover
18 of 19 patients with laryngopharyngeal or
high esophageal exposure underwent antireflux
surgery, as did 2 patients without these reflux
events but with type III paraesophageal hernias.
18 of 20 (90%) patients undergoing antireflux
surgery had complete (2) or significant (18)
improvement in asthma symptoms. 6 reduced
or discontinued pulmonary medications at mean
follow-up of 4.6 months. Response to antireflux
surgery did not differ by DeMeester scores.
 Sensitivity: 82.8% (72.9-92.7%)
 Specificity: 85.2% (75.9%-94.5%
 PPV: 85.7% (76.6%-94.9%)
 NPV: 82.1% (72.1%-92.2%)
Total distal acid exposure time was the
strongest predictor of response to omeprazole
therapy (OR 1.8, p = 0.04), and the only
significant predictor on multivariable analysis.
Q2a: What effect does treating GERD medically have on reflux cough?
Source
Sample
size
Study design
Diagnosis of reflux
cough/selection of patients
Xu 2013
16
Prospective
cohort
All 4 of: 1) chronic cough, 2) MII-pH
confirmed reflux with DeMeester
score >= 14.72 and/or SAP >= 95%,
3) failure of cough to improve on
omeprazole 20 mg bid and
domperidone 10 mg tid for 8 weeks,
and 4) exclusion of upper airway
cough syndrome, cough variant
asthma, and esoinophilic bronchitis
excluded
Length
of
follow
up
8
weeks
Intervention
Outcome(s)
Main finding(s)
Discontinuation of
domperidone and
initiation of
baclofen 20 mg tid
for 8 weeks
1) Relief from cough
by changes in cough
symptom score
(controlled if resolved
completely, improved
if cough symptom
score decreased by
at least 1, or failed),
2) capsaicin cough
threshold causing 2
and 5 coughs
4 of 16 (25%) patients
withdrew due to nausea
and diarrhea (1) and
worsened or unimproved
symptoms (3). Cough
was controlled in 7 of
remaining 12 (58%)
patients, improved in 2
(16%), and failed to
improve in 3 (25%).
Of the 9 controlled or
resolved patients, 6
(67%) had acid refluxinduced cough, while 3
(33%) had non-acid
reflux-induced cough.
In the same 9 patients,
capsaicin cough
threshold for 2 coughs
increased from 0.98
umol/L to 1.95 umol/L (p
= 0.024), for 5 coughs
increased from 1.95
umol/L to 7.8 umol/L (p =
0.014).
Shaheen
2011
40
Randomized
double-blind
placebocontrolled
All 5 of: 1) chronic cough > 8 weeks
duration, 2) symptom severity criteria
>= 2 on Fisman Cough Severity
Questionnaire, 3) >= 3 on Fisman
Cough Frequency Questionnaire, 4)
failure of cough to respond to
postnasal drip therapy, 5) heartburn
no more than 2 times per month
12
weeks
Omeprazole 40
bid for 12 weeks
Change in CoughSpecific Quality of
Life Questionnaire
score, change in
Fisman Cough
Severity and Cough
Frequency scores,
and Reflux Finding
Score.
5 patients (31%)
No significant difference
in change in Cough
Specific Quality of Life
Questionnaire score (p =
0.3), Fisman Cough
Severity score (p = 0.7),
Fisman Cough
Frequency score (p =
0.3), or Reflux Finding
Score (p = 0.5).
Faruqi
2011
49
Randomized
double-blind
placebocontrolled
1) clinical features consistent with
reflux cough, with or without
dyspepsia, 2) chronic cough > 8
weeks duration, 3) normal CXR, 4)
not on ACEi, 5) with cough score >= 3
Esomeprazole 20
mg bid for 8
weeks
Hersh
2010
53
Retrospective
cohort
1) patients referred for ambulatory pH
monitoring with chronic cough as a
dominant symptom, 2) not taking
ACEi
Mean of 3 years
Baldi
2006
35
Randomized
double-blind
comparative
effectiveness
1) cough >= 3 days per week for >= 3
months, 2) diagnosis of GERD with
either EGD, esophageal pH
monitoring, or resolution of
improvement >= 5 on VAS after
empiric trial of lansoprazole 30 mg bid
for 4 weeks
12
weeks
Lansoprazole 30
mg qd (placebo
dose qPM) and
lansoprazole 30
mg bid for 12
weeks
Change in integral
response score for
cough, change in
Leicester Cough
Questionnaire,
change in Hull Airway
Reflux Questionnaire,
Reflux Finding Score,
citric acid cough
challenge
High degree
response, defined as
> 3 months without
cough on stable PPI
doses, or
discontinuation of
PPIs after antireflux
surgery
Changes in cough
scoring system, VAS,
from baseline to end
of 4 week
lansoprazole trial,
and at end of 12week lansoprazole
treatment
In subgroup analysis of
patients with positive
esophageal pH study, still
no significant differences
in these outcomes (p =
0.2, 0.4, 0.8, and 0.8).
No significant difference
between the treatment
and placebo groups in
any measured parameter.
High degree response
was achieved by 19 of 53
(35.8%) of patients.
Independent predictors of
high degree response
included female sex,
positive SAP, and
undergoing maximal
antireflux therapy (high
dose PPI or antireflux
surgery) (p = 0.02, 0.03,
and 0.02, respectively).
No significant difference
between two treatment
groups in changes in
cough scoring system,
VAS, complete resolution
of cough after 12-week
treatment.
18 of 22 (82%) patients
with positive response to
empiric PPI trial and 3 of
13 (23%) patients with
negative response to PPI
trial had complete
symptom relief at the end
of the 12 week treatment
period.
El
Hennawi
2004
80
Prospective
cohort
1) cough for >= 4 weeks, 2) normal
CXR, 3) no ACEi
3
months
Famotidine 40 mg
qPM and
dompridon 10 mg
tid for 6 weeks; or
omeprazole 20 mg
qd; or omeprazole
20 mg bid
Various
combinations of
PPI, H2 blocker,
and/or prokinetic
agents
?
?
Poe
2003
183
Retrospective
cohort
1) chronic cough >= 3 weeks, 2)
normal CXR, 3) no ACEi, 4) negative
workup for post-nasal drip syndrome
(empiric trial of
antihistamine/decongestant) and
asthma (methacholine challenge)
3
months
Resolution of cough
symptoms
18
weeks
Omeprazole 40
mg qd for 8 weeks
Change in asthma
symptom score in last
3 weeks of each
study period
60 days
Omeprazole 40
mg qd for 5 days
and for 60 days
Change in inhaled
methacholine and
capsaicin sensitivity
Of 183 patients 67 were
diagnosed with cough
caused by PNDS (37%),
59 with cough caused by
asthma (32%), and 56
with suspected reflux
cough (31%), based on
response to empiric
medical therapy or
esophageal pH
monitoring if no response
to empiric therapy was
observed. Of the 56
suspected reflux cough,
44 (79%) resolved cough
symptoms after 12 weeks
of medical therapy.
Cough score decreased
1.5 in patients who
received omeprazole and
increased 0.7 in patients
who received placebo (p
< 0.05).
Inhaled capsaicin
sensitivity decreased
significantly after 5d (p =
0.001) and further after
60 days (p = 0.002).
Kiljander
2000
21
Prospective
cohort
(designed as
casecrossover)
Benini
2000
21
Prospective
cohort
(designed as
casecrossover)
1) chronic persistent cough >= 2
months, 2) negative sinus XR, CXR,
methacoline inhalation challenge,
physical exam findings for PNDS, 3)
no diagnosis of asthma or bronchitis,
4) no ACEi
1) endoscopic findings of erosive
esophagitis, 2) increased esophageal
acid exposure on pH monitoring, 3)
without other chronic respiratory or
ENT conditions, 4) non-smokers, 5)
not on ACEi, 6) not on antisecretory
medications
No significant difference
in change in cough
sensitivity between
patients with grade 1 and
grade 2 esophagitis.
Patients without posterior
laryngitis on
laryngoscopy had
decreased capsaicin
sensitivity after 5d (p =
0.014) but not after 60d
(p = 0.64). Patients with
posterior laryngitis had
decreased capsaicin
sensitivity after 5d (p =
0.002) and after 60d
(0.001). After 5d of
treatment a direct
correlation between
grade of laryngitis and
capsaicin sensitivity was
found (r = 0.67, p <
0.001).
Q2b: What effect does treating GERD medically have on chronic laryngitis/LPR?
Source
Sample
size
Study
design
Diagnosis of
LPR/selection of
patients
Masaany
2011
47
Prospective
double-blind
cohort
1) presenting with globus
sensation, hoarseness,
cough, excess mucus in
throat, choking, or
dysphagia, and 2) with
either Reflux Symptom
Index > 13 or Reflux
Finding Score > 7
Lam 2010
Karoui
2010
82
33
Prospective
double-blind
placebocontrolled
Prospective
cohort
1) presenting with
hoarseness, globus
sensation, persistent
throat discomfort, or
frequent throat clearing
for at least 1 month in
preceding 1 year, and 2)
Reflux Finding Score > 7
1) clinical diagnosis of
chronic pharyngitis
(symptoms of parasthesia
of the pharynx, scraping,
sore throat, or globus
sensation) and/or
laryngitis (symptoms of
hoarseness, chronic
cough, wheezing, stridor)
suspected due to GERD,
2) proximal esophageal
acid reflux on pH
monitoring
Length
of
follow
up
4
months
18
weeks
9
weeks
Intervention
Outcome(s)
Main finding(s)
Pantoprazole 40
mg bid for four
months
Improvement in Reflux
Symptom Index or Reflux
Finding Score at 2, 3, and 4
months
Reflux Symptom Index
improved from baseline (19.87)
after 2 months (10.87),
improved at 3 months (6.78),
and improved at 4 months
(4.27, p < 0.001 for all).
Rabeprazole 20
mg bid for 12
weeks
Pantoprazole 40
mg bid for 8
weeks
Reflux Symptom Index
Clinical improvement in
laryngeal or pharyngeal
symptoms appreciated by
the patient, and
improvement in
laryngopharyngoscopic
signs of inflammation.
Reflux Finding Score improved
from baseline 12.79 after 2
months (7.61), 3 months (4.09),
and 4 months (2.77, p < 0.001
for all).
Change in Reflux Symptom
Index was significantly greater
in the treatment group
compared to the placebo group
at week 6 (-3.03, p = 0.003) and
week 12 (-3.73, p = 0.002), not
significantly reduced at week
18.
Change in Reflux Finding Score
was not significantly different at
week 6, 12, or 18 between
treatment and placebo groups.
After treatment the proportion of
patients complaining of
pharyngeal discomfort,
pharyngeal parasthesia,
scraping, globus sensation,
hoarseness, and dry cough all
significantly improved (p <
0.0001 – 0.02), while the
proportion of patients
complaining of sore throat was
not statistically significantly
different.
The proportion of patients with
signs of pharyngeal wall
erythema and posterior
laryngitis significantly
decreased after treatment (p =
0.003 and 0.001, respectively),
while the proportion of patients
with five other
laryngopharyngoscopic findings
did not significantly change
after treatment.
McGlashan
2009
Reichel
2008
45
58
Randomized
assesor-blind
non-placebo
controlled
Randomized
double-blind
placebo
controlled
1) RSI > 10, 2) RFS > 5,
3) not on antisecretory
therapy, 4) without
significant dysphagia,
pain, or hemoptysis
1) complaint of chronic
cough, dysphagia, throat
clearing, globus
sensation, hoarseness,
sore throat, and
heartburn, 2) RFS > 7, 3)
RSI > 13
2-6
months
3
months
Change in RSI
and RFS from
baseline to 2
month follow up
and from 0
month to 6
month follow up
Change in RSI
and RFS at 6
weeks and 3
months follow
up, and
subjective report
of being
1000 mg sodium alginate
and 200 mg potassium
bicarbonate liquid
(Gaviscon® Advance),
delivered in 10 mL qid
Symptom improvement was
seen in 15 of 22 (68%) patients
without proximal acid reflux on
esophageal pH monitoring after
treatment and in 2 of 11 (18%)
patients with persistent proximal
acid reflux (p = 0.006).
RSI from baseline to 2 month
follow up decreased 12.7 in the
treatment group and 7.8 in the
no treatment group (p = 0.005).
RSI from baseline to 6 month
follow up decreased 12.7 in the
treatment group and 6.3 in the
no treatment group (p = 0.008).
The decrease in the treatment
group from baseline to 2
months and baseline to 6
months follow up was identical
(12.7).
Esomeprazole 20 mg bid for
3 months
There was no significant
difference in change in RFS
from 0 to 2 months follow up.
RFS from baseline to 6 months
follow up decreased 3.3 in the
treatment group and 0.5 in the
no treatment group (p = 0.005).
At 6 weeks follow up changes in
RSI and RFS between
treatment and placebo groups
were not statistically significant.
Diffuse laryngeal edema on
laryngoscopic exam improved
significantly more in the
symptom free at
3 months.
Oridate
2008
45
Prospective
cohort
Qua 2007
32
Prospective
cohort
Wo 2006
35
Randomized
double-blind
placebo-
Complaint of throat
clearing, annoying cough,
hoarseness, problem with
voice, globus sensation,
or dysphagia
1) persistent symptoms of
cough, sore throat, throat
clearing, globus
sensation, or hoarseness
for >= 3 months, 2)
laryngoscopically proven
laryngitis, 3) no allergic
causes for laryngitis
1) chief complaint of
hoarseness, sore throat,
throat buring or pain,
Up to 6
months
8
weeks
16
weeks
Change
symptom score
and in modified
Reflux Finding
Score
Change in 1week laryngeal
symptom score
from before
initiation of
treatment to last
week of
treatment
Pantoprazole 40
mg qd
treatment than the placebo
group (p < 0.05), but change no
other RFS component sign was
significantly different between
the two groups.
Rabeprazole 20 mg qd or
lansoprazole 30 mg qd for
up to six months
Lansoprazole 30 mg bid for
8 weeks
At 3 months follow up, RSI
improved 14.27 in the treatment
group and 7.79 in the placebo
group (p < 0.0001). RFS
improved 4.6 in the treatment
group and 2.32 in the placebo
group (p < 0.05). 22 of 28
(79%) patients in the treatment
group and 11 of 26 (42%)
patients in the placebo group
felt themselves to be free of
symptoms (p = 0.006).
Laryngopharyngeal symptoms
resolved more slowly than
heartburn in patients after
initiation of PPI therapy (p =
0.003).
21 of 32 (66%) patients had
GERD diagnosed on
esophageal pH monitoring.
LSS significantly improved from
29 to 20 (p < 0.001) in patients
with positive pH monitoring, but
not in patients without positive
pH monitoring (26 to 20, p =
0.134). Change in LSS was
significantly greater in patients
with positive pH monitoring than
in patients without (p = 0.01).
Change in laryngeal
symptom score based on
weekly diaries of symptom
14 of 21 (67%) patients with
positive pH monitoring and 2 of
11 (18.2%) without positive pH
monitoring had marked or
moderate improvement in
symptoms (p = 0.026).
No significant difference
between groups in change in
laryngeal symptom score.
controlled
Vaezi 2006
145
Multicenter
prospective
double-blind
placebocontrolled
Park 2005
85
Prospective
cohort
throat clearing, voice loss,
cough, excessive throat
mucus, globus sensation,
or choking for > 3 days
per week in past 2
months, 2) LPR signs on
laryngoscopic exam, 3)
positive pH monitoring of
hypopharynx or distal
esophagus
1) complaint of throat
clearing, cough, globus
sensation, sore throat, or
hoarseness for >= 3
months, 2) moderate-tosevere heartburn for no
more than 3 or more days
per week for 3 months, 3)
no allergic causes of
laryngitis, 4) chronic
posterior laryngitis index
score >= 5
1) chronic symptoms of
hoarseness, throat
clearing, sore throat,
cough, globus sensation,
or dysphagia, 2)
laryngoscopic signs
suspicious for LPR
assessment for globus
sensation, cough, sore
throat, hoarseness, throat
clearing, and excessive
mucus, and change in RFS
16
weeks
Omeprazole 40
mg bid for 16
weeks
Proportion of patients with
resolution of their primary
symptom (score of 0 for the
last 7 days of treatment or
score of 1 for up to 3 days),
resolution of laryngoscopic
signs, and change in LPRHRQL score
16
weeks
Lansoprazole 30
mg bid;
omeprazole 20
mg bid and
ranitidine 300
mg at bedtime;
esomeprazole
40 mg qd for 8
weeks
Self-reported improvement,
changes in laryngoscopic
signs
In nonresponders to 8week therapy,
PPI dose was
doubled
Williams
2004
19
Prospective
cohort
1) laryngeal symptoms for
>= 3 months, 2)
laryngoscopic signs of
laryngitis, 3) without
chronic cough
12
weeks
Omeprazole 20
mg tid for 12
weeks
Improvement of at least one
point on 4-point
laryngoscopic score at 12
week follow-up,
improvement in symptoms
on symptom questionnaire
No significant difference in
change in RFS between
treatment and placebo groups.
In subgroup analysis of patients
with heartburn > 2 days per
week, no significant differences
between treatment and
placebo.
No difference in resolution of
primary symptom at 16 weeks
follow-up (p = 0.799), patient
diary card assessments (p =
0.621-1), complete resolution of
laryngoscopic signs (no p-value
reported), or change in LPRHRQL score (p = 0.424)
between treatment and placebo
groups.
At 8-week follow-up 50% of the
lansoprazole group, 50% of the
omeprazole group, and 28% of
the esomeprazole group
reported >= 50% improvement.
The lansoprazole and
omeprazole groups combined
had significantly higher >= 50%
improvement than the
esomeprazole group (p = 0.03).
At 16-week follow-up (with
increased PPI dose in nonresponders) 63% of the
lansoprazole group, 80% of the
omeprazole group, and 65% of
the esomeprazole group
reported >= 50% improvement.
At 12 weeks 12 of 19 (63%)
patients improved at least one
point on the laryngoscopic
score (p < 0.0001). Of 4
patients with GERD diagnosed
on esophageal pH monitoring,
Steward
2004
37
Randomized
double-blind
placebocontrolled
1) complaint of
hoarseness, throat
clearing, nonproductive
cough, globus sensation,
or sore throat > 4 weeks,
2) laryngoscopic findings
of edema, erythema, or
pachydermia
8
weeks
Rabeprazole 20
mg bid
Change in reflux symptom
score from GERD
questionnaire modified to
include laryngopharyngeal
symptoms, change in
laryngoscopic signs by
scoring system
Ehrer 2003
14
Placebocontrolled
casecrossover
26
weeks
Pantoprazole 40
mg bid for 3
months
Changes in symptom score
and laryngoscopic signs
score
Noordzij
2001
30
Randomized
double-blind
placebocontrolled
1) hoarseness >= 2
months, other laryngeal
symptoms, and
laryngoscopic signs of
laryngitis, 2) GERD
diagnosed with
esophageal pH monitoring
1) hoarseness, excessive
phlegm, throat clearing,
throat pain, lump in throat,
or cough >= 3 months, 2)
no strong history of
seasonal allergies, 3) >=
4 episodes of
laryngopharyngeal reflux
on esophageal/OP ph
monitoring
8
weeks
Omeprazole 40
mg bid for 8
weeks
Change in symptom score,
laryngoscopic sign score,
1) hoarseness, frequent
clearing of the throat, dry
cough, globus sensation,
or persistent sore throat
for >= 3 weeks, 2)
laryngoscopic signs of
posterior laryngitis, 3) no
allergic causes of
laryngitis
3
months
El-Serag
2001
20
Randomized
double-blind
placebo
Lansoprazole 30
mg bid for 3
months
Resolution of all presenting
laryngeal symptoms,
resolution of all laryngeal
signs, partial resolution of
laryngeal signs
all had improvement in the
laryngoscopic score. In 16
patients without positive
esophageal monitoring, 8 (50%)
improved on the laryngoscopic
score.
No significant differences were
found in change in total reflux
symptom score or individual
score components for typical,
laryngeal, or pharyngeal
symptoms between treatment
and placebo groups. No
significant difference in change
in laryngoscopic signs scoring
system between treatment or
placebo groups.
No significant difference in
changes in symptom or
laryngoscopic scores between
treatment and placebo groups.
Changes in total symptom
scores and laryngoscopic sign
scores were not significantly
different between the
omeprazole and placebo
groups.
Mean throat clearing score
decreased 197.4 in the
omeprazole group and 79.6 in
the placebo group (p = 0.043).
6 of 12 patients (50%) in the
lansoprazole group and 1 in 10
patients (10%) in the placebo
group had complete resolution
of laryngeal symptoms (p =
0.04).
There was no significant
difference in complete or partial
resolution of laryngoscopic
signs.
Eubanks
2001
14
Prospective
cohort
?
3
months
Double-dose PPI
therapy
Resolution of symptoms
Esophageal pH monitoring
parameters did not differ
between patients with complete
resolution of symptoms and
those with persistent symptoms.
7 patients reported cough. 5
reported improvement after
treatment and had elimination
or > 70% reduction in
pharyngeal acid reflux
episodes. 1 patient reported
consistent cough and only 33%
reduction in pharyngeal acid
reflux episodes. 1 patient did
not have pharyngeal acid reflux
at baseline.
7 patients reported hoarseness.
4 reported elimination or
reduction after treatment. 2
patients without pharyngeal
acid reflux at baseline reported
no improvement. 1 patient had
persistent hoarseness despite
elimination of pharyngeal acid
reflux.
Q2c: What effect does treating GERD medically have on reflux asthma?
Source
Sample
size
Study design
Diagnosis of reflux
asthma/selection of
patients
Kiljander
2013
12
Prospective
cohort
1) scheduled to undergo
antireflux surgery for
GERD, 2) diagnosis of
asthma
Kiljander
2010
828
Multicenter
international
randomized
double-blind
placebocontrolled
Peterson
2009
30
Randomized
double-blind
placebocontrolled
Length
of
follow
up
3
months
Intervention
Outcome(s)
Main finding(s)
Esomeprazole 40 mg bid
Change in doseresponse slope in
methacholine inhalation
challenge, exhaled
nitric oxide, and FEV1
1) clinical diagnosis of
asthma >= 6 months
duration, 2) FEV1
reversibility >= 12% with
inhaled short-acting betaagonists, 3) receiving
inhaled corticosteroids
and LABA treatment for
>= 3 months, 4) >= 1
clinically important asthma
exacerbation in past 12
months, 5) >= 3 month
history of heartburn,
regurgitation, or abnormal
esophageal pH monitoring
26
weeks
Esomeprazole 40 mg qd
or esomeprazole 40 mg
bid
Changes morning PEF,
evening PEF, FEV1,
use of rescue
bronchodilators,
percent asthma-free
days, time to first
asthma exacerbation,
number of severe
asthma exacerbations,
and Asthma Quality of
Life Questionnaire,
No significant change in
methacholine inhalation
sensitivity, exhaled nitric
oxide, or FEV1 in
asthmatic patients after
treatment.
Improvement in morning
PEF, FEV1, and Asthma
Quality of Life
Questionnaire was
significantly greater in
the treatment groups
compared to placebo.
1) complaint of cough,
shortness of breath, or
chest tightness occurring
during or directly after
moderate exercise, 2) selfreported reflux symptoms
less than twice weekly, 3)
not on antisecretory
therapy, 4) not
hospitalized in preceding 6
months
10-12
weeks
Rabeprazole 20 mg qd
(with placebo qPM),
rabeprazole 20 mg bid, or
placebo bid
Subjective
determination by
subjects (yes or no) on
improved exercise
symptoms, pre- and
post-exercise PFTs,
spirometry, SF-36
score, and mini-AQLQ
score.
There was no significant
difference in changes in
evening PEF, time to
first asthma
exacerbation, number of
severe asthma
exacerbations, use of
rescue bronchodilators,
or asthma-free days.
16 of 23 (70%) patients
receiving rabeprazole
and 2 of 8 (25%)
patients receiving
placebo reported
subjectively improved
exercise symptoms (p =
0.03).
In subgroup analysis for
those with GERD seen
on 24h esophageal pH
probe, 15 of 17 (88%)
patients receiving
rabeprazole and 1 of 5
(20%) patients receiving
placebo reported
subjectively improved
exercise symptoms (p =
0.009).
In subgroup analysis for
those who had
esophageal acid reflux
during tredmill test, 15
of 19 (79%) patients
receiving rabeprazole
and 1 of 5 (20%)
receiving placebo
reported subjectively
improved exercise
symptoms (p = 0.03).
Mastronarde
2009
393
Multicenter
randomized
double-blind
placebocontrolled
Bucknall
2009
51
Prospective
cohort
1) diagnosis of asthma
supported by
methacholine challenge
test or >= 12% increase in
FEV1 after
bronchodilation, 2) >= 8
weeks stable inhaled
corticosteroid use at doseequivalent of 400 ug
fluticasone/day or greater,
3) JACQ >= 1.5 or >= 1
acute episode of asthma
requiring medical attention
in previous year, 4) < 2
episodes per week of
heartburn, 5) not taking
antisecretory mediations
Patients with diagnosis of
asthma confirmed
objectively and therapy
optimized but with
24
weeks
Esomeprazole 40 mg bid
Rate of episodes of
poor asthma control
(decrease of 30% or
more in morning PEF
on 2 consecutive days,
an unscheduled
healthcare visit for
asthma symptoms, or
need for course of oral
prednisone, PFTs,
asthma symptoms,
asthma control
Unclear
Low-dose PPI therapy,
increased stepwise after
serial esophageal pH
monitoring studies
Reduction in required
asthma therapy
There was no significant
difference in subjectively
improved exercise
symptoms between the
rabeprazole qd and bid
groups, or in PFTs,
spirometry, SF-36
score, or mini-AQLQ
score.
There were no
significant differences in
change in any of the
parameters measured
between the treatment
and placebo groups.
Subgroup analysis of
patients with GERD on
esophageal pH
monitoring also
revealed no differences
between changes in
treatment and placebo
groups.
32 of 51 (63%) patients
had negative
esophageal pH
monitoring. 19 of 32
persistent symptoms
Sharma
2007
198
Randomized
double-blind
placebo
controlled
1) > 12% improvement in
FEV1 with
bronchodilators, 2) mildto-moderate persistent
asthma, 3) no acute
exacerbations or changes
in asthma medications in
past weeks, 4) GERD on
esophageal pH monitoring
16
weeks
Omeprazole 20 mg bid
and domperidone 10 mg
tid for 16 weeks
Asthma symptom
score, rescue albuterol
use, daytime and
nighttime PEF,
postbronchodilator
FEV1 and FVC
Wong 2006
27
Prospective
cohort
1) asthma meeting the
American Thoracic
Society diagnostic criteria
or with typical history of
asthma in past 12 months,
2) moderate-to-severe
asthma as defined by
8
weeks
Lansoprazole 30 mg qd
for 8 weeks
Patient-assessed global
improvement of asthma
symptoms, changes in
1-week PSS, PEF,
FEV1
(59%) patients
underwent repeated pH
monitoring up to 3
episodes, increasing
PPI dose until
monitoring parameters
normalized. 8 of 11
(73%) patients whose
esophageal acid
exposure normalized on
pH monitoring reduced
their required asthma
therapy, while 0 of 8
patients without
normalized esophageal
acid exposure reduced
their required asthma
therapy (p = 0.0034).
In the treatment and
placebo groups,
respectively, mean
daytime asthma
symptom score
decreased 0.48 and
0.22, mean nighttime
asthma score
decreased 0.51 and
0.14, albuterol
puffs/week decreased
0.76 and 0.1, morning
PEF increased 22.78
and decreased 0.56,
evening PEF increased
27.76 and decreased
1.43, FEV1 increased
0.21L and 0.07 L, FVC
increased 0.18 L and
decreased 0.03 L (p =
0.0001-0.0023)
16 of 27 (59%) patients
were diagnosed with
GERD based on weekly
symptoms for 6 months,
findings of erosive
esophagitis on EGD, or
positive esophageal pH
GINA guidelines and with
poor asthma control, 3)
optimized asthma
treatment medications
Shimzu
2006
30
Prospective
parallel
comparative
effectiveness
cohort
1) diagnosis of asthma
based on American
Thoracic Society
definition, 2) meeting
GINA guidelines for
asthma medications, 3)
with endoscopically
diagnosed GERD or
QUEST score >= 4
Kiljander
2006
624
Multicenter
international
randomized
double-blind
placebocontrolled trial
1) asthma treated with
inhaled corticosteroids
and.or leukotriene
pathway modifiers for >= 3
months before study entry
and with no medication
changes in previous 30
days, 2) FEV1 50-80%
predicted and >= 12%
reversibility with
bronchodilators and mean
morning PEF < 80%
monitoring. 12 of these
16 (75%) reported
global improvement in
asthma symptoms.
Median PSS decreased
from 35 to 21 (p =
0.002). 11 of 27 (41%)
patients were not
diagnosed with GERD.
1 of these 11 (9%)
reported global
improvement. Median
PSS did not decrease
significantly (p = 0.18).
16
weeks
Roxatidine 150 mg qd or
lansoprazole 30 mg qd for
2 months
Changes in ACQ, PEF,
FEV1
Esomeprazole 40 mg bid
for 16 weeks
Change in morning PEF
Median PSS, median
PEF, and median FEV1
improved significantly
more in GERD than in
non-GERD patients (p =
0.01, 0.04, and 0.017,
respectively).
Morning PEF
significantly increased in
the lansoprazole group
(p = 0.002) but not in
the roxatidine group (p =
0.08). ACQ scores
significantly improved in
the lansoprazole group
but not in the roxatidine
group. FEV1 did not
significantly improve in
either group.
Change in morning PEF
observed over the
treatment period was
5.6 L/min greater in the
treatment than placebo
groups (p = 0.042).
Change in evening PEF
was 5.4 L/min greater in
the treatment than the
placebo groups (p =
0.053).
predicted, 2) no recurrent
moderate or severe GERD
symptoms in previous
year in patients > 40 years
old
No significant difference
in asthma exacerbations
or median time to
asthma exacerbation
between treatment and
placebo groups.
In subjects with GERD
(diagnosed as >= 2
episodes per week of
heartburn, or 1 episode
per week of acid
regurgitation in 3
months before
enrollment) and
nocturnal asthma
symptoms morning PEF
increased 8.7 L/min
more in the treatment
than the placebo groups
(p = 0.03), and evening
PEF increased 10.2
L/min more in the
treatment than the
placebo groups (p =
0.012).
Littner 2005
173
Multicenter
double-blind
randomized
placebocontrolled
1) investigator-determined
history of or currently
symptomatic GERD, 2)
moderate-to-severe
persistent asthma, 3)
FEV1 50-85% predicted,
4) >= 12% improvement in
FEV1 with
bronchodilators, 5) on
inhaled corticosteroids, 6)
without marked seasonal
24
weeks
Lansoprazole 30 big bid
24-week average of
asthma symptom score
by diary, albuterol use,
changes in PEF, postbronchodilator FVC and
FEV1, AQLQS, asthma
exacerbations
In subjects who did not
have both GERD and
nocturnal asthma
symptoms did not have
significantly greater
improvement in morning
PEF or evening PEF
compared to placebo.
No significant difference
between treatment and
placebo groups in daily
asthma symptoms by
patient diary, rescue
albuterol use, morning
PEF, evening PEF,
FEV1, FVC, or AQLQS
score.
8.1% of patients in the
variability or allergy
symptoms, 7) reporting >=
5 nocturnal asthma
awakenings in prior 4
weeks, 8) on stable doses
of asthma medications for
past 4 weeks
Calabrese
2005
Bocskei
2005
34
126
Prospective
cohort
Prospective
cohort
Intrinsic mild persistent
asthma by diagnostic
criteria of American
Thoracic Society
1) mild to moderate
asthma diagnosed by
American Throacic
Society criteria >= 12
months before enrollment,
2) chronic dry cough for
>= 3 months, 3) low to
moderate dose inhaled
corticosteroids, 4) no
changes in asthma
medications in prior 6
weeks
6
months
12
weeks
Pantoprazole 80 mg qd
for 6 months
Esomeprazole 40 mg qd
for 3 months
FEV1, patient-reported
asthma symptom score,
of rescue inhalers
FEV1, PEF, symptom
score
treatment group and
20.4% in the placebo
group experienced an
asthma exacerbation
(OR = 2.9, p = 0.017).
4% of patients in the
treatment group and
13.9% in the placebo
group experienced a
moderate to severe
exacerbation (OR = 3.8,
p = 0.016).
27 of 34 (21%) patients
had GERD diagnosed
endoscopically either by
interstitial space on
biopsy > 0.74 um or by
reflux esophagitis.
23 of 27 (85%) patients
with GERD had
improved mean asthma
symptom score from
4.37 to 0.33 (p < 0.001)
and FEV1 increased 2.8
L (p < 0.01).
94 of 126 (75%)
patients were diagnosed
with GERD by report of
heartburn and/or
regurgitation or
esophageal pH
monitoring. Mean FEV1
increased from 79.21%
predicted to 82.92%
predicted (p < 0.001),
and PEF increased from
73.7% predicted to
78.42% predicted (p <
0.001) before and after
treatment in patients
with GERD. Mean 2week use of rescue
inhalers also decreased
from 20.24 to 4.56 (p <
0.001). Mean symptom
score decreased from
6.46 to 2 (p-value not
reported).
26 of 126 (21%)
patients were not
diagnosed with GERD.
These patients had no
significant change in
FEV1, PEF, or rescue
inhaler use from
baseline to 12-week
follow-up.
Tsugeno
2003
49
Prospective
cohort
1) bronchial asthma
diagnosed according to
American Thoracic
Society guidelines
8
weeks
Rabeprazole 20 mg qd for
8 weeks (for all patients),
followed by ranitidine 300
mg bid (for GERD
patients only)
Changes in morning
PEF, evening PEF,
FEV1, FVC
FEV1 and PEF
increased significantly
more in GERD patients
treated for GERD than
in non-GERD patients (p
< 0.0001 for both).
Rescue inhaler use was
significantly lower in
GERD patients treated
for GERD than in nonGERD patients (p <
0.0001).
21 of 53 (42%) patients
were diagnosed with
GERD based on
endoscopy or QUEST
score > 4. Among
patients with GERD,
morning and evening
PEF improved from 286
L/min to 323 L/min and
304 L/min to 334 L/min,
respectively (p < 0.0001
for both). FEV1 and
FVC did not significantly
change.
Among patients without
GERD, morning and
evening PEF, FEV1,
and FVC did not
signifincalty change.
Sontag 2003
Jiang 2003
62
30
Randomized
trial, no
placebo
Randomized
no placebo
1) mild asthma causing no
impairment of in activities,
defined as both a) history
of wheezing, coughing, or
dyspnea and b) either
increase in FEV1 >= 20%
with bronchodilators or
decrease FEV1 >= 20%
on methacholine
challenge, 2) GERD
defined as both a) positive
esophageal pH
monitoring, and b)
esophagoscopic findings
or biopsy pathology
consistent with reflux
esophagitis, 3) FEV1 >=
50% predicted and >=
1.5L
1) asthma according to
GINA criteria, 2) GERD
diagnosed as postprandial
chest pain, sour
regurgitation, signs of
erosive esophagitis on
barium esophagram, or
lower esophageal
erosions on
2 years
Ranitidine 150 mg tid vs
Nissen fundoplication vs
aluminum
hydroxide/magnesium
hydroxide/simethicone
and H2 blockers prn
(control)
Change in asthma
symptom score, mean
PEF, mean PEF %
variation, PFTs,
requirement for
pulmonary medications,
overall clinical response
of asthma
Mean asthma symptom
score at 2 years
decreased significantly
in the surgical group (p
< 0.05) but not in the
medical or control
groups. The surgical
group’s mean asthma
symptom score
improved significantly
more than the ranitidne
and control groups
combined (p = 0.0009).
Overall clinical response
of asthma reached
improvement, marked
improvement, or cure in
74.9% of surgical
patients, 9.1% of
ranitidine patients, and
4.2% in the control
group. The improvement
was significant in the
surgical group
compared to the
combined ranitidine and
control groups (p <
0.001).
6
weeks
Salbutamol 200 ug qid
and budesonide 400 bid
for six weeks (control)
versus same asthma
regimen plus omeprazole
20 mg qd and
domperidone 10 mg tid
for six weeks
Change in PFTs and
histamine-induced
bronchial sensitivity
Change in mean PEF,
mean PEF % variation,
PFTs, and asthma
medication
requirements were not
significantly different
between groups.
In the control and
treatment groups,
changes in FVC (-0.2 vs
+0.8 L), FEV1 (0.1 vs
0.6 L), PEF (0.4 vs 1.3
L/s), and bronchial
sensitivity (-0.03 vs 0.51
g/L inhaled histamine
causing 20% decrease
esophagoscopy and
mucosal biopsy
in FEV1) were
significantly better in
patients receiving
GERD therapy (p < 0.05
for all).
Q3a: What effect does treating GERD surgically have on reflux cough?
Source
Sample
size
Study design
Diagnosis of reflux
cough/selection of
patients
Hoppo 2013
36
Retrospective
cohort
1) persistent cough >= 8
weeks, 2) no ACEi or
seasonal allergies, 3) no
known pulmonary disease
Zhang 2012
198
Retrospective
cohort
Koch 2012
100
Randomized
comparative
effectiveness
1) coughing, asthma,
wheezing, shortness of
breath, or choking, 2)
GERD diagnosed on
esophageal pH monitoring
with DeMeester score >=
14.7
1) persistent or recurrent
GERD despite medical
treatment and a)
DeMeester score >= 14.7
and b) symptom correlation
>= 50% or reflux episodes
> 73 during MII-pH
Length
of
follow
up
0.5-13
months
Intervention
Outcome(s)
Main finding(s)
Nissen (10), Dor (2),
Toupet (1),
esophagojejunostomy
(3)
Improvement in
cough symptoms
12
months
Laparoscopic Nissen
(197), laparoscopic
converted to open
Nissen (1)
Improvement in
Reflux Diagnostic
Questionnaire
13 of 16 (81%) patients with
abnormal proximal refluxate
exposure on MII-pH had
resolution of cough, while the
other 3 had significant
improvement (19%)
Mean cough scores
improved from 7.23 to 2.79
(p < 0.01) after ARS.
1 year
Laparoscopic floppy
Nissen (50) or Toupet
fundoplication (50)
Change in
symptom
questionnaire
score
98 patients were available at
3-month follow-up. Mean
cough score improved 2.46
in the Nissen group and 1.77
in the Toupet group, both of
which were significant
changes from baseline (p <
0.001 and p = 0.001,
respectively).
89 patients were available at
1 year follow-up. Mean
cough score improved 1.74
in the Nissen group and 2.14
in the Toupet group, both of
which were significant
changes from baseline (p =
0.007 and 0.004,
respectively).
There were no statistically
van der
Westhuizen
2011
244
Retrospective
cohort
Patients who underwent
antireflux surgery for reflux
Unclear
Nissen
Reported change
in symptom
intensity
Brown 2011
113
Prospective
cohort
Mean
28
months
Laparoscopic Nissen
Change in VAS
symptom score
Francis 2011
27
Retrospective
cohort
1) GERD diagnosed on
esophageal pH monitoring,
2) underwent laparoscopic
Nissen
1) chief complaint of
atypical symptom, 2)
without improvement after
12 weeks of bid PPI
therapy, 3) with abnormal
esophageal acid exposure
on bid PPI therapy, 4) who
underwent antireflux
surgery
Median
33
months
Antireflux surgery
Resolution or >
50% improvement
in primary atypical
symptom
significant differences in
improvement of cough
scores between the two
procedures.
> 50% improvement in
symptom intensity was
reported by 84 of 135 (62%)
patients who reported
chronic cough
preoperatively.
Mean cough score
decreased from 3.78 to 0.95
(p < 0.0001) after surgery.
12 patients presented with
cough and 7 with
asthma/wheezing. No
significant difference in
response to surgery was
found according to the
specific presenting atypical
complaint.
After 1 year of follow-up,
59% of patients reported
improvement (11%) or
complete resolution (48%) of
their presenting atypical
symptom.
Patients with concomitant
heartburn or with > 12% acid
exposure time had greater
likelihood of symptom
resolution after
fundoplication than patients
without heartburn (OR 6.6, p
= 0.05; OR 10.5, p = 0.02).
Patients without concomitant
heartburn and acid exposure
time < 12% resolved their
symptoms after
fundoplication 8.5% of the
time, while patients with both
factors resolved their
Iqbal 2009
Retrospective
cohort
1) underwent ARS, 2)
predominance of
extraesophageal symptoms
before surgery
Mean
53.3
months
Open (9) or
laparoscopic (31)
Nissen (33) or partial
(7) fundoplication
Change in cough
symptoms
Oelschlager
2008 (same
cohort as
Oelschlager
2002)
288
Retrospective
cross-section
Underwent ARS between
1993 and 1999 for reflux
indication
Median
69
months
Laparoscopic Nissen
Reported
resolution or
improvement in
cough symptoms
Ranson 2007
69
Prospective
cohort
Underwent ARS after
GERD diagnosis by empiric
PPI trial or esophageal pH
monitoring
Mean
24.6
months
Laparoscopic Nissen
Improvement in
modified Allen
symptom score
Tutuian 2006
50
Retrospective
review
Patients with persistent
cough on day of MII-pH
monitoring while on bid PPI
therapy with or without
nighttime H2 blocker
therapy
Median
17
months
Laparoscopic Nissen
Resolution of
cough
Rakita 2006
813
Prospective
cohort
Mean
50
months
Laparoscopic Nissen
Improvement of
symptoms
Kaufman
128
Retrospective
1) underwent laparoscopic
Nissen, 2) had preoperative
symptom scores of 4 or 5
on 5 point scale for
extraesophageal symptoms
(asthma [diagnosed by
having symptoms of
asthma and having been
cared for by a physician for
asthma], cough, gas/bloat,
chest pain, odynophagia)
1) Underwent laparoscopic
Median
Laparoscopic Nissen
Improvement of
symptoms 90.7% of the time.
32 of 40 (80%) patients
reported cough
preoperatively. 17 (53%)
reported their cough cured,
10 (32%) reported it
improved, 4 (13%) reported
no change, and 1 (3%)
reported worsened cough.
88 of 288 (31%) of patients
reported cough
preoperatively. 40% reported
symptom resolution, another
29% reported symptom
improvement.
55 of 69 (80%) patients
reported cough
preoperatively. Their mean
cough symptom score
decreased from 1.2 to 0.5 (p
< 0.01) after ARS. 35 (64%)
reported their cough
resolved, another 7 (10%)
reported their cough
improved, 6 (10%) reported
no change, and 7 (13%)
reported worsened cough.
13 of 50 patients had positive
non-acid SI for reflux-cough.
6 of these 13 underwent
laparoscopic Nissen (1 lost
to follow up). All patients
reported complete resolution
of cough at follow-up.
132 patients presented with
cough scores of 4-5. Mean
cough score decreased from
4.3 to 2 (p < 0.0001).
108 patients presented with
2006
cohort
Nissen, 2) experienced
cough, hoarseness, or
wheezing > once per week
53
months
(123) and Toupet (5)
symptoms
1) underwent laparoscopic
Nissen for GERD, 2)
without evidence of postnasal drip or having
received treatment for it, 3)
with negative methacholine
inhalation challenge, 4)
with primarily respiratory
complaints
1) underwent laparoscopic
Nissen, 2) predominantly
respiratory symptoms
(cough, aspiration, voice
changes)
1) underwent laparoscopic
ARS
5-years
Laparoscopic Nissen
Mean
650
days
Laparoscopic Nissen
Symptoms cured
(score = 0), better
(score improved >
2), no significant
change (score
change <= 2), or
worse (score
decreased 2 or
more)
Symptom score
Unclear
Laparoscopic Nissen or
Toupet
Patient-reported
resolution or
significant
improvement in
cough symptoms
1) cough > 8 weeks, normal
CXR, non-smoker, no
ACEi, no relief with
treatment of post-nasal
drip, no asthma, 2) failure
of intensive medical
therapy, 3) underwent ARS
1) underwent ARS, 2)
reported wheezing, sputum
production, cough, choking,
hoarseness, or pneumonia
Underwent laparoscopic
Nissen
1 year
Laparoscopic Nissen
(18), open Nissen (3)
Patient report of
improvement,
ACOS, SIP
Median
65
months
Wide variety of open
and laparoscopic
antireflux operations
Patient-reported
improvement in
symptoms
6
months
Laparoscopic Nissen
Change in cough
score
Allen 2004
209
Prospective
cohort
Brouwer
2003
28
Prospective
cohort
Thoman
2002
129
Retrospective
cohort
Novitsky
2002
21
Retrospective
cohort
Greason
2002
62
Retrospective
cohort
Allen 2002
483
Prospective
cohort
cough. 80 (74%) patients
reported improved cough.
There was a statistically
significant decrease in the
frequency of cough (p <
0.001).
79 of 209 (38%) patients with
primarily respiratory
complaints were available for
5-year follow-up. Mean
cough score decreased 3.9.
36% of patients were cured,
35% were better, 24% had
no significant change, and
5% were worse.
Mean cough score
decreased after ARS from
4.7 to 0.36 (p < 0.001)
37 of 129 patients
complained of cough
preoperatively. 24 (65%)
patients reported their cough
completely resolved (p =
0.002), while another 10
(27%) reported significant
improvement.
18 of 21 (86%) reported
improved cough at 1-year
follow-up, with 13 (62%)
having complete resolution.
ACOS improved from 15.1 to
5.8 (p < 0.01), SIP improved
from 15 to 4.2 (p < 0.01).
30 patients reported cough
preoperatively, 10 after ARS.
287 of 483 patients
presented with cough. Mean
cough score decreased from
35.1 to 13.2 (p < 0.0001).
Patients with a positive
esophageal acid infusion test
were significantly more likely
Patti 2000
340
Prospective
cohort
1) underwent laparoscopic
Nissen, 2) complaint of
heartburn and/or
regurgitation
Median
28
months
Laparoscopic NIssen
Patient-reported
resolution of
symptoms
Ekstrom
2000
24
Prospective
cohort
1) severe GERD refractory
to maximal medical
therapy, 2) simultaneous
asthma (according to
American Thoracic Society
criteria) or chronic cough
12
months
Open (20) or
laparoscopic (4) Nissen
Improvement in
symptoms by
patient diary,
FEV1, FVC,
to respond to ARS (p = 0.02).
39 of 340 (11%) patients had
cough or wheezing attributed
to GERD on clinical grounds.
All 39 complained of cough
preoperatively. Cough
resolved in 74%.
11 patients had chronic
cough. 12 months postoperatively all had significant
improvement in FEV1, FVC,
cough day score, cough
night score, hoarseness
score, and expectoration
score (p < 0.01 - < 0.05).
Q3b: What effect does treating GERD surgically have on chronic laryngitis/LPR?
Source
Sample
size
Study design
Diagnosis of LPR/selection
of patients
Koch 2012
100
Randomized
comparative
effectiveness
1) persistent or recurrent
GERD despite medical
treatment and a) DeMeester
score >= 14.7 and b)
symptom correlation >= 50%
or reflux episodes > 73
during MII-pH
Length
of
follow
up
1 year
Intervention
Outcome(s)
Main finding(s)
Laparoscopic
floppy Nissen
(50) or Toupet
fundoplication
(50)
Change in symptom
questionnaire score
98 patients were available at
3-month follow-up. Mean
hoarseness score improved
0.76 (p = 0.004) in the Nissen
group and nonsignificantly in
the Toupet group.
89 patients were available at
1-year follow-up. Mean
hoarseness score improved
1.35 (p = 0.034) in the Nissen
group and 1.11 (p = 0.003) in
the Toupet group.
Johannessen
2012
243
van der
Westhuizen
2011
244
Matched (age,
sex, geographic
location, follow-up
time, degree of
esophagitis,
presence of hiatal
hernia, and
presence of
Barrett
esophagus) crosssectional
Retrospective
cohort
GERD diagnosed
endoscopically or on
esophageal pH monitoring
Mean
6-6.3
years
Laparoscopic
or open
fundoplication
versus medical
therapy
Mean RASQ items
and subscale for
laryngopharyngitis
Patients who underwent
antireflux surgery for reflux
Unclear
Nissen
Reported change in
symptom intensity
There were no statistically
significant differences in
improvement of asthma
scores between the two
procedures.
Mean score for globus
sensation (0.76 vs 1.11, p =
0.01) and sore throat (0.86 vs
1.13, p = 0.04) and the
laryngopharyngitis subscale
(1.06 vs 1.27, p = 0.04) were
significantly lower in the ARS
group than the medically
treated group.
> 50% improvement in
symptom intensity was
reported by 99 of 140 (71%)
patients who reported sore
throat preoperatively, 86 of
124 (69%) who reported lump
in throat preoperatively, 96 of
139 (69%) who reported
dysphagia preoperatively, and
89 of 162 (55%) who reported
Brown 2011
113
Iqbal 2009
Ranson 2007
Prospective cohort
Retrospective
cohort
69
Prospective cohort
1) GERD diagnosed on
esophageal pH monitoring,
2) underwent laparoscopic
Nissen
1) underwent ARS, 2)
predominance of
extraesophageal symptoms
before surgery
Underwent ARS after GERD
diagnosis by empiric PPI trial
or esophageal pH monitoring
Mean
28
months
Laparoscopic
Nissen
Change in VAS
symptom score
Mean
53.3
months
Open (9) or
laparoscopic
(31) Nissen
(33) or partial
(7)
fundoplication
Change in globus
sensation
symptoms
Mean
24.6
months
Laparoscopic
Nissen
Improvement in
modified Allen
symptom score
repetitive throat clearing
preoperatively.
Mean hoarseness score
decreased from 3.16 to 0.82
(p < 0.0001) after surgery.
29 of 40 (73%) patients
reported globus sensation
preoperatively. 12 (41%)
reported globus cured, 7
(24%) reported it improved, 7
(24%) reported no change,
and 3 (10%) reported
worsened globus.
31 of 40 (78%) reported throat
clearing, mucous, or postnasal drip. 16 (51%) reported
these symptoms cured, 10
(32%) reported them
improved, 4 (13%) reported no
change, and 1 (3%) reported
worsened symptoms.
47 (68%), 41 (59%), and 60
(87%) of 69 patients
preoperatively reported
hoarseness, sore throat, and
throat clearing, respectively.
Their mean hoarseness
symptom score decreased
from 1.2 to 0.6 (p < 0.01) after
ARS. 22 (47%) reported their
hoarseness resolved, another
11 (23%) reported their
hoarseness improved, 6
(13%) reported no change,
and 8 (17%) reported
worsened hoarseness. Their
mean sore throat symptom
score decreased from 0.9 to
0.4 (p < 0.01) after ARS. 25
(61%) reported their sore
throat resolved, another 6
(15%) reported their sore
throat improved, 2 (5%)
reported no change, and 8
Swoger 2006
Kaufman
2006
72
128
Prospective cohort
Retrospective
cohort
1) chronic laryngeal signs
and symptoms (cough,
throat clearing, sore/burning
throat, hoarseness, or
globus sensation), 2) treated
with omeprazole 40 mg bid
or lansoprazole 60 mg bid
for 4 months with < 50%
symptomatic improvement,
3) abnormal esophageal pH
monitoring or evidence of
reflux on barium
esophagram off PPI therapy,
4) with normal esophageal
acid exposure parameters
on bid PPI therapy
1) Underwent laparoscopic
Nissen, 2) experienced
cough, hoarseness, or
wheezing > once per week
1 year
Laparoscopic
Nissen
Symptom resolution
or improvement on
symptom score
questioinnaire
(20%) reported their sore
throat worsened. 26 (43%)
reported their throat clearing
resolved, another 14 (23%)
reported their throat clearing
improved, 12 (20%) reported
no change, and 8 (13%)
reported worsened throat
clearing.
25 of 75 (35%) patients were
unresponsive to bid PPI
therapy. 10 chose to have
surgery while 15 refused.
At 1 year follow-up, 1 of 10
(10%) ARS patients and 1 of
15 (7%) medical patients had
resolved laryngeal symptoms.
Median
53
months
Laparoscopic
Nissen (123)
and Toupet (5)
Improvement of
symptoms
82 patients presented with
hoarseness. 54 (66%) patients
reported improved
hoarseness. There was a
statistically significant
decrease in the frequency of
hoarseness (p < 0.001).
41 patients presented with
sore throat. 29 (70%) patients
reported improved sore throat.
There was a statistically
significant decrease in the
frequency of sore throat (p =
0.001).
Fernando
2005
74
Prospective cohort
1) primary complaint of
heartburn, regurgitation, or
water brash, 2) pulmonary
symptoms of
bronchospasam,
Median
12
months
Laparoscopic
fundoplication
Resolution of
laryngeal symptoms
46 patients complained of
hoarseness before the
operation. 33 (72%) had
complete resolution after the
operation (p < 0.01). Patients
hoarseness, aspiration, or
laryngitis, 3) underwent
laparoscopic Nissen
1) underwent ARS, 2)
reported wheezing, sputum
production, cough, choking,
hoarseness, or pneumonia
did not report significantly less
laryngitis after ARS.
Greason
2002
62
Retrospective
cohort
Median
65
months
Patti 2000
340
Prospective cohort
1) underwent laparoscopic
Nissen, 2) complaint of
heartburn and/or
regurgitation
Median
28
months
Lindstrom
2002
29
Retrospective
cohort
Underwent Nissen for
extraesophageal
manifestations of GERD
6-108
months
Wide variety of
open and
laparoscopic
antireflux
operations
Laparoscopic
Nissen
Patient-reported
improvement in
symptoms
17 patients reported
hoarseness preoperatively, 11
after ARS.
Patient-reported
resolution of
symptoms
Laparoscopic
Nissen (n = 28)
or open Nissen
(n = 1)
Reported resolution
of symptoms on
chart review?
13 of 340 (4%) patients had
hoarseness attributed to
GERD on clinical grounds.
Hoarseness resolved in 82%
of patients.
27 of 29 patients reported
near-total relief of
extraesophageal symptoms.
2 patients had wrap
breakdown after 2 years, 1
from abdominal trauma.
1 patient with persistent
symptoms had both typical
and atypical manifestations of
GERD: typical symptoms
resolved while atypical
symptoms persisted. Was
diagnosed with
cricopharyngeal muscle
myositis caused by Lyme
disease.
1 patient with chronic cough
did not improve after Nissen.
Q3c: What effect does treating GERD surgically have on reflux asthma?
Source
Sample
size
Study design
Diagnosis of reflux
asthma/selection of
patients
Kiljander
2013
12
Prospective
cohort
1) scheduled to undergo
antireflux surgery for
GERD, 2) diagnosis of
asthma
Komatsu
2013
27
Retrospective
review
1) diagnosed adult onset
asthma adult onset
wheezing, coughing, or
shortness of breath and
using at least 1
bronchodilator or
corticosteroid, 2) no
additional pulmonary
diagnoses
Zhang
2012
198
Retrospective
cohort
Koch
2012
100
Randomized
comparative
effectiveness
1) coughing, asthma,
wheezing, shortness of
breath, or choking, 2)
GERD diagnosed on
esophageal pH monitoring
with DeMeester score >=
14.7
1) persistent or recurrent
GERD despite medical
treatment and a)
DeMeester score >= 14.7
and b) symptom
correlation >= 50% or
reflux episodes > 73 during
MII-pH
Length
of
follow
up
3
months
Intervention
Outcome(s)
Main finding(s)
Antireflux surgery
No significant change in
methacholine inhalation
sensitivity, exhaled nitric oxide,
or FEV1 in asthmatic patients
after treatment.
0.615.2
months
Nissen (15), Dor (2),
roux-en-Y
esophagojejunostomy (1)
(together, ARS)
Change in doseresponse slope in
methacholine
inhalation
challenge, exhaled
nitric oxide, and
FEV1
Symptomatic
improvement,
reduction or
discontinuation of
asthma
medications,
change in PFTs
19 of 27 patients (70%) had
abnormal proximal reflux
exposure on MII-pH, 18 of whom
underwent ARS. 8 of 27 patients
(30%) had no abnormal proximal
exposure, 2 of whom underwent
ARS.
2 of 20 patients who underwent
ARS had complete resolution of
asthmas symptoms, 16 had
significant improvement.
12
months
Laparoscopic Nissen
(197), laparoscopic
converted to open
Nissen (1)
Improvement in
Reflux Diagnostic
Questionnaire
1 year
Laparoscopic floppy
Nissen (50) or Toupet
fundoplication (50)
Change in
symptom
questionnaire
score
No significant difference in ARS
patients with symptomatic
improvement by DeMeester
score > 14.7.
Mean wheezing scores
decreased from 7.5 to 2.53, and
mean shortness of breath scores
decreased from 5.83 to 1.37 (p <
0.01 for both).
98 patients were available at 3month follow-up. Mean asthma
score improved 0.63 (p = 0.004)
in the Nissen group and
nonsignificantly in the Toupet
group.
89 patients were available at 1year follow-up. Mean asthma
score improved 0.62 (p = 0.048)
in the Nissen group and
nonsignificantly in the Toupet
group.
Brown
2011
113
Prospective
cohort
Francis
2011
27
Retrospective
cohort
1) GERD diagnosed on
esophageal pH monitoring,
2) underwent laparoscopic
Nissen
1) chief complaint of
atypical symptom, 2)
without improvement after
12 weeks of bid PPI
therapy, 3) with abnormal
esophageal acid exposure
on bid PPI therapy, 4) who
underwent antireflux
surgery
Mean
28
months
Laparoscopic Nissen
Change in VAS
symptom score
Median
33
months
Antireflux surgery
Resolution or >
50% improvement
in primary atypical
symptom
There were no statistically
significant differences in
improvement of asthma scores
between the two procedures.
Mean wheeze score decreased
from 2.03 to 0.56 (p < 0.0001)
after surgery.
12 patients presented with cough
and 7 with asthma/wheezing. No
significant difference in response
to surgery was found according
to the specific presenting atypical
complaint.
After 1 year of follow-up, 59% of
patients reported improvement
(11%) or complete resolution
(48%) of their presenting atypical
symptom.
Patients with concomitant
heartburn or with > 12% acid
exposure time had greater
likelihood of symptom resolution
after fundoplication than patients
without heartburn (OR 6.6, p =
0.05; OR 10.5, p = 0.02).
Rakita
2006
813
Prospective
cohort
1) underwent laparoscopic
Nissen, 2) had
preoperative symptom
scores of 4 or 5 on 5 point
scale for extraesophageal
Mean
50
months
Laparoscopic Nissen
Improvement of
symptoms
Patients without concomitant
heartburn and acid exposure
time < 12% resolved their
symptoms after fundoplication
8.5% of the time, while patients
with both factors resolved their
symptoms 90.7% of the time.
135 patients presented with
asthma scores 4-5. Mean asthma
score decreased from 4.7 to 1.7
(p < 0.0001).
Kaufman
2006
128
Retrospective
cohort
Sontag
2003
62
Randomized
trial, no
placebo
Brouwer
2003
28
Prospective
cohort
Kiljander
15
Prospective
symptoms (asthma
[diagnosed by having
symptoms of asthma and
having been cared for by a
physician for asthma],
cough, gas/bloat, chest
pain, odynophagia)
1) Underwent laparoscopic
Nissen, 2) experienced
cough, hoarseness, or
wheezing > once per week
1) mild asthma causing no
impairment of in activities,
defined as both a) history
of wheezing, coughing, or
dyspnea and b) either
increase in FEV1 >= 20%
with bronchodilators or
decrease FEV1 >= 20% on
methacholine challenge, 2)
GERD defined as both a)
positive esophageal pH
monitoring, and b)
esophagoscopic findings
or biopsy pathology
consistent with reflux
esophagitis, 3) FEV1 >=
50% predicted and >= 1.5L
1) underwent laparoscopic
Nissen, 2) predominantly
respiratory symptoms
(cough, aspiration, voice
changes)
Underwent laparoscopic
Median
53
months
Laparoscopic Nissen
(123) and Toupet (5)
Improvement of
symptoms
2 years
Ranitidine 150 mg tid vs
Nissen fundoplication vs
aluminum
hydroxide/magnesium
hydroxide/simethicone
and H2 blockers prn
(control)
Change in asthma
symptom score,
mean PEF, mean
PEF % variation,
PFTs, requirement
for pulmonary
medications,
overall clinical
response of
asthma
37 patients presented with
hoarseness. 25 (69%) patients
reported improved hoarseness.
There was a statistically
significant decrease in the
frequency of wheezing (p <
0.001).
Mean asthma symptom score at
2 years decreased significantly in
the surgical group (p < 0.05) but
not in the medical or control
groups. The surgical group’s
mean asthma symptom score
improved significantly more than
the ranitidne and control groups
combined (p = 0.0009).
Overall clinical response of
asthma reached improvement,
marked improvement, or cure in
74.9% of surgical patients, 9.1%
of ranitidine patients, and 4.2% in
the control group. The
improvement was significant in
the surgical group compared to
the combined ranitidine and
control groups (p < 0.001).
Mean
650
days
Laparoscopic Nissen
Symptom score
5
Laparoscopic Nissen
Airway
Change in mean PEF, mean PEF
% variation, PFTs, and asthma
medication requirements were
not significantly different between
groups.
Mean wheezing/bronchospasam
score decreased after ARS from
2.8 to 0.8 (p < 0.05)
5 months after laparoscopic
2002
cohort
Nissen
months
1) underwent ARS, 2)
reported wheezing, sputum
production, cough,
choking, hoarseness, or
pneumonia
1) underwent laparoscopic
Nissen, 2) complaint of
heartburn and/or
regurgitation
1) severe GERD refractory
to maximal medical
therapy, 2) simultaneous
asthma (according to
American Thoracic Society
criteria) or chronic cough
Median
65
months
Wide variety of open and
laparoscopic antireflux
operations
Median
28
months
12
months
Greason
2002
62
Retrospective
cohort
Patti
2000
340
Prospective
cohort
Ekstrom
2000
24
Prospective
cohort
responsiveness
during
methacholine
inhalation
challenge,
changes in PFTs
Patient-reported
improvement in
symptoms
Nissen patients had a
significantly improved FEV1/FVC
(p = 0.03) and FEV1 (p = 0.03).
Laparoscopic NIssen
Patient-reported
resolution of
symptoms
Open (20) or
laparoscopic (4) Nissen
Improvement in
symptoms by
patient diary,
FEV1, FVC,
14 of 340 (4%) patients had
wheezing attributed to GERD on
clinical grounds. Wheezing
resolved in 64% of patients.
13 patients had asthma. 12
months post-operatively there
was no significant change in
FEV1, FVC, cough day score,
cough night score, hoarseness
score, or expectoration score.
43 patients reported wheezing
preoperatively, 21 after ARS.
PubMed Search Terms/Strategies
Q1 Search. What is the pathophysiology of pulmonary diseases in those w/GERD?
Terms/Concepts: Pulmonary Diseases AND (pathophysiology OR etiology OR pathogenesis) AND GERD n=765
(Chronic Bronchitis[title] OR COPD[title] OR chronic cough[title] OR pulmonary disease[title] OR asthma*[title] OR hoarseness[title] OR
hoarse[title] OR “idiopathic pulmonary fibrosis”[title] OR “end stage pulmonary disease”[title] OR “chronic laryngitis”[title] OR “throat
clearing”[title] OR “sore throat” [title] OR “Globus pharyngeus”[title] OR “excessive phlegm”[title]) AND (pp[sh] OR
pathophysiolog*[tiab] OR physiopathology*[tiab] OR etiology[sh] OR etiolog*[tiab] OR pathogenesis[tiab] OR causality[tiab]) OR
(“Asthma/physiopathology"[Majr] OR "Cough/physiopathology"[Majr] OR "Pulmonary Disease, Chronic
Obstructive/physiopathology"[Mesh] OR "Lung Diseases, Obstructive/physiopathology"[Majr] OR “Asthma/etiology"[Majr] OR
"Cough/etiology"[Majr] OR "Pulmonary Disease, Chronic Obstructive/etiology"[Mesh] OR "Lung Diseases, Obstructive/etiology"[Majr])
AND ("Gastroesophageal Reflux"[Majr] OR respiratory aspiration of gastric contents[majr] OR Laryngopharyngeal Reflux[majr]) OR
(“oesophageal Reflux”[title] OR “acid reflux”[title] OR “gastroesophageal reflux”[title] OR GERD[title] OR “Esophageal Reflux”[title] OR
“gastro oesophageal Reflux”[title] OR “Gastric Acid Reflux”[title] OR “laryngopharyngeal reflux”[title] OR “Gastric Acid Reflux
Disease”[title])
With application of limits to years and English language: 1/1/2000 to 9/1/2014; n=458
Q2 Search. What is the natural history of pulmonary diseases in those w/GERD?
Terms/Concepts: ("natural history"[tiab] OR outcome[tiab] OR outcomes[tiab] OR prognosis[tiab] OR "clinical epidemiology"[tiab] OR
“end stage”) AND Pulmonary Diseases AND GERD n=16633
("natural history"[tiab] OR outcome[tiab] OR outcomes[tiab] OR prognosis[tiab] OR "clinical epidemiology"[tiab] OR “end stage”) AND
(Chronic Bronchitis[title] OR COPD[title] OR chronic cough[title] OR pulmonary disease[title] OR asthma*[title] OR hoarseness[title] OR
hoarse[title] OR “idiopathic pulmonary fibrosis”[title] OR “end stage pulmonary disease”[title] OR “chronic laryngitis”[title] OR “throat
clearing”[title] OR “sore throat” [title] OR “Globus pharyngeus”[title] OR “excessive phlegm”[title] OR “Asthma"[Majr] OR "Cough"[Majr]
OR "Pulmonary Disease, Chronic Obstructive"[Mesh] OR "Lung Diseases, Obstructive"[Mesh]) AND (("Gastroesophageal Reflux"[Majr]
OR respiratory aspiration of gastric contents[majr] OR Laryngopharyngeal Reflux[majr]) OR (“oesophageal Reflux”[title] OR “acid
reflux”[title] OR “gastroesophageal reflux”[title] OR GERD[title] OR “Esophageal Reflux”[title] OR “gastro oesophageal Reflux”[title] OR
“Gastric Acid Reflux”[title] OR “laryngopharyngeal reflux”[title] OR “Gastric Acid Reflux Disease”[title]))
Combined Results n=103 with application of limits to years and English language: 1/1/2000 to 9/1/2014 n=94
Q3 Search. What is the outcome of treating GERD medically, on pulmonary diseases in patients with GERD?
Terms/Concepts: (Medical therapy of GERD AND Pulmonary OR Lung Diseases) with years applied; n=334
GERD Therapy MESH and Free Text search
(("Respiratory Aspiration of Gastric Contents/therapy"[Mesh]) OR ( "Laryngopharyngeal Reflux/drug therapy"[Mesh] OR
"Laryngopharyngeal Reflux/therapy"[Mesh] OR "Gastroesophageal Reflux/drug therapy"[Majr]) OR ("Gastroesophageal Reflux"[Majr]
AND ("Proton Pump Inhibitors/therapeutic use"[Majr] OR "Proton Pump Inhibitors"[Pharmacological Action] OR PPI[tiab] OR proton
pump*[tiab] OR medical therap*[tiab] OR drugs[title] OR drug[title] OR medical manag*[tiab] OR TU[sh] OR "drug therapy*”[subheading]
OR acid blocker*[tiab])) OR (“oesophageal Reflux”[title] OR “acid reflux”[title] OR “gastroesophageal reflux”[title] OR GERD[title] OR
“Esophageal Reflux”[title] OR “gastro oesophageal Reflux”[title] OR “Gastric Acid Reflux”[title] OR “laryngopharyngeal reflux”[title] OR
“Gastric Acid Reflux Disease”[tiab])) AND ((PPI[tiab] OR proton pump*[tiab] OR medical therap*[tiab] OR drugs[title] OR drug[title] OR
medical manag*[tiab] OR TU[sh] OR "drug therapy*”[subheading] OR acid blocker*[tiab] OR drug therapies*[tiab] OR “non
surgical*”[tiab] OR drug therapy[tiab]) AND
(Chronic Bronchitis[title] OR COPD[title] OR chronic cough[title] OR pulmonary disease[title] OR asthma*[title] OR hoarseness[title] OR
hoarse[title] OR “idiopathic pulmonary fibrosis”[title] OR “end stage pulmonary disease”[title] OR “chronic laryngitis”[title] OR “throat
clearing”[title] OR “sore throat” [title] OR “Globus pharyngeus”[title] OR “excessive phlegm”[title] OR “Asthma"[Majr] OR "Cough"[Majr])
OR ("Pulmonary Disease, Chronic Obstructive"[Mesh] OR "Lung Diseases, Obstructive"[Mesh]))
With application of study filters: Medline study type filters below, plus the PubMed McMaster created filters (RCTs OR placebo OR
case series OR systematic [tiab] OR meta analy* OR metaanalys* OR randomise* OR randomize* OR clinical trial* OR clinical stud*
OR RCTs OR clinical trials OR clinical studies OR case series OR systematic review OR meta-analysis OR comparative study OR
controlled clinical trial OR evaluation study OR multicenter study OR pragmatic clinical trial OR practice guideline; with application of
limits to years and English language: 1/1/2000 to 9/1/2014; n=89
Q4 Search. What is the outcome of treating GERD surgically (fundoplication) on pulmonary diseases in patients with GERD?
Terms/Concepts: (surgical therapy of GERD) AND (Pulmonary OR Lung Diseases) Combined Search Results n=1890
(("Laryngopharyngeal Reflux/surgery"[Mesh] OR "Gastroesophageal Reflux/surgery"[Majr]) OR ("Gastroesophageal Reflux"[Majr] AND
(surgery*[subheading] OR “antireflux*”[tiab] OR “reflux*”[tiab] OR fundoplication*[tiab] OR fundoplication[mesh])) OR (“oesophageal
Reflux”[tiab] OR “acid reflux”[tiab] OR “gastroesophageal reflux”[tiab] OR GERD[tiab] OR “Esophageal Reflux”[tiab] OR “gastro
oesophageal Reflux”[tiab] OR “Gastric Acid Reflux”[tiab] OR “laryngopharyngeal reflux”[tiab] OR “Gastric Acid Reflux Disease”[tiab])
AND (fundoplication OR anti reflux surg* OR antireflux surg* OR reflux surg* OR surgical therap* OR (surgical[tiab] AND treat*[tiab]))
OR (surgical*[title] OR surgery[title] OR surgeon*[title] OR non medical* manag*[tiab] OR nonmedical* manag*[tiab])) AND (Chronic
Bronchitis OR COPD OR cough OR coughing OR pulmonary disease OR asthma* OR hoarseness OR hoarse OR “idiopathic
pulmonary fibrosis” OR “end stage pulmonary disease” OR “chronic laryngitis” OR “throat clearing” OR “sore throat” OR “Globus
pharyngeus” OR “excessive phlegm” OR “Asthma"[Majr] OR "Cough"[Majr] OR "Pulmonary Disease, Chronic Obstructive"[Mesh] OR
"Lung Diseases, Obstructive"[Mesh])
With application of limits to years and English language: 1/1/2000 to 9/1/2014 n=1215. With application of Medline study type filters,
plus the PubMed McMaster created filters (RCTs OR placebo OR case series OR systematic [tiab] OR meta analy* OR metaanalys*
OR randomise* OR randomize* OR clinical trial* OR clinical stud* OR RCTs OR clinical trials OR clinical studies OR case series OR
systematic review OR meta-analysis OR comparative study OR controlled clinical trial OR evaluation study OR multicenter study OR
pragmatic clinical trial OR practice guideline n=407.
Q5 SEARCH. What are the current best practices for diagnosing pulmonary diseases (cough, hoarseness, asthma) caused by GERD
or LPR, Laryngo-pharyngeal Reflux?
Terms/Concepts: (pulmonary diseases or cough or hoarseness or asthma) and diagnosis and (reflux or LPR or GERD) n=389
((chronic cough[title] OR cough[title] OR asthma*[title] OR hoarse[title] OR hoarseness[title]) AND (diagnos*[title]OR evaluat *[title]
OR assess*[title] OR consensus[title]) OR ("Cough/diagnosis"[Majr] OR "Hoarseness/diagnosis"[Majr] OR "Lung Diseases,
Obstructive/diagnosis"[Majr] OR "Asthma/diagnosis"[Majr])) AND (Laryngopharyngeal reflux OR gastroesophageal reflux OR
reflux[title] OR gerd[title] OR esophageal reflux[title] OR gastro-oesophagealreflux[title] OR laryngo-pharyngealreflux[title] OR
"Respiratory Aspiration of Gastric Contents"[Mesh] OR "Laryngopharyngeal Reflux"[Mesh] OR "Laryngopharyngeal Reflux"[Mesh] OR
"Gastroesophageal Reflux"[Majr] OR "Gastroesophageal Reflux"[Majr])
With application of limits to years and English language: 1/1/2000 to 9/1/2014, and application of Medline study type filters, plus the
PubMed McMaster created filters (RCTs OR placebo OR case series OR systematic [tiab] OR meta analy* OR metaanalys* OR
randomise* OR randomize* OR clinical trial* OR clinical stud* OR RCTs OR clinical trials OR clinical studies OR case series OR
systematic review OR meta-analysis OR comparative study OR controlled clinical trial OR evaluation study OR multicenter study OR
pragmatic clinical trial OR practice guideline n=86.
Total PubMed n=728
PRISMA TABLE