Download Chronic Cough Due to Gastroesophageal Reflux

Chronic Cough Due to
Gastroesophageal Reflux Disease
ACCP Evidence-Based Clinical Practice Guidelines
Richard S. Irwin, MD, FCCP
Objectives: To critically review and summarize the literature on cough and gastroesophageal
reflux disease (GERD), and to make evidence-based recommendations regarding the diagnosis
and treatment of chronic cough due to GERD.
Design/methodology: Ovid MEDLINE literature review (through March 2004) for all studies
published in the English language and selected articles published in other languages such as
French since 1963 using the medical subject heading terms “cough,” “gastroesophageal reflux,”
and “gastroesophageal reflux disease.”
Results: GERD, singly or in combination with other conditions, is one of the most common causes
of chronic cough. In patients with normal chest radiographic findings, GERD most likely causes
cough by stimulation of an esophageal-bronchial reflex. When GERD causes cough, there may be
no GI symptoms up to 75% of the time. While 24-h esophageal pH monitoring is the most sensitive
and specific test in linking GERD and cough in a cause-effect relationship, it has its limitations.
In addition, there is no general agreement on how to best interpret the test, and it cannot detect
non-acid reflux events. Therefore, when patients fit the clinical profile that has a high likelihood
of predicting that GERD is the cause of cough, antireflux medical therapy should be empirically
instituted. While some patients improve with minimal medical therapy, others require more
intensive regimens. When empiric treatment fails, it cannot be assumed that GERD has been
ruled out as a cause of chronic cough. Rather, an objective investigation for GERD is then
recommended because the empiric therapy may not have been intensive enough or medical
therapy may have failed. Surgery may be efficacious when intensive medical therapy has failed in
selected patients who have undergone an extensive objective GERD evaluation.
Conclusions: Accurately diagnosing and successfully treating chronic cough due to GERD can be
a major challenge.
(CHEST 2006; 129:80S–94S)
Key words: acid reflux disease; clinical profile of cough due to gastroesophageal reflux disease; cough due to
gastroesophageal reflux disease; esophageal-bronchial cough reflex; gastroesophageal reflux; gastroesophageal reflux
disease; macroaspiration; microaspiration; nonacid reflux disease; silent reflux disease
Abbreviations: GER ⫽ gastroesophageal reflux; GERD ⫽ gastroesophageal reflux disease; PPI ⫽ proton pump inhibitor; BAL ⫽ bronchoalveolar lavage
he origin of the terms gastroesophageal reflux
T (GER)
and gastroesophageal reflux disease
(GERD) is Latin.1 Reflux literally means backflow,
coming from the two Latin words (re meaning
“back,” plus fluere meaning “to flow”). It follows that
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Richard S. Irwin, MD, FCCP, University of
Massachusetts Medical School, Room S6-842, 55 Lake Ave North,
Worcester, MA; e-mail address: [email protected]
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GER is a term that refers to the backflow of stomach
contents into the esophagus. Because GER episodes
can occur up to 50 times a day, usually during meals
and the postprandial state in healthy individuals, and
not produce any symptoms, GER events can be
physiologic in nature.2 On the other hand, GERD is
a term that refers to a disease that is caused by GER
manifested by either symptoms and/or tissue damage.
GERD is a term that encompasses a spectrum of
common clinical manifestations from localized
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esophageal manifestations with typical and prominent GI symptoms, such as heartburn and regurgitation, to extraesophageal problems, such as cough or
hoarseness, without any GI complaints. For example,
in a population-based study in Olmsted County, MN,
Locke et al,3 using a validated GER questionnaire,
identified a prevalence rate of 59% for occasional
episodes of GER-related symptoms such as heartburn, regurgitation, and dysphagia; 20% of the respondents reported weekly symptoms. In a prospective before-and-after intervention trial, Irwin et al4
found that when GERD was the cause of chronic
cough, it could be silent from a GI standpoint up to
75% of the time. In a study in which the symptoms
and findings of GERD were specifically sought and
prospectively compared in otolaryngology and gastroenterology patients, Ossakow et al5 found that
hoarseness was present in 100% of the otolaryngology patients and 0% of the gastroenterology patients,
while heartburn was present in 89% of the gastroenterology patients and in only 6% of the otolaryngology patients. When otolaryngologists diagnose laryngeal or pharyngeal disease due to the backflow of
stomach contents into the laryngopharynx, they refer
to it as laryngopharyngeal reflux disease.1
It is now clear that the spectrum of clinical
manifestations of GERD as evaluated by different
specialists can vary.1,4,6 It is also becoming increasingly more likely that the management of a variety of
extraesophageal manifestations of GERD cannot
only differ in clinical and diagnostic ways from the
classic GERD seen by gastroenterologists, but also
perhaps in pathogenetic and therapeutic aspects as
well. Physicians who manage patients with cough
should be aware of these differences. While there is
much that has been learned about a variety of
esophageal and extraesophageal manifestations of
GERD, this section will focus solely on chronic
cough. Literature on screening for and managing
complications of esophageal GERD, such as Barrett
epithelium and esophageal cancer, can be found
elsewhere.7,8 This section reflects an Ovid MEDLINE literature review (through March 2004) for all
studies published in the English language and selected articles published in other languages such as
French since 1963 using the medical subject heading
terms “cough,” “gastroesophageal reflux,” and “gastroesophageal reflux disease.”
Prevalence of GERD as a Cause of Cough
When the diagnosis of chronic cough due to
GERD is based on a favorable response (eg, elimination of or improvement in cough) to specific
GERD treatment, prospective before-and-after inwww.chestjournal.org
tervention studies9 –14 have revealed that GERD,
singly or in combination with other conditions, is one
of the most common causes of chronic cough in
adults in the world. The prevalence in these studies
ranged from 5 to 41%. While it is not clear what
accounts for the variation in prevalence, multiple
factors likely contribute to it, such as differences in
the populations referred and studied. For example,
in three prospective studies published by Irwin et
al9,15,16 over a period of 17 years, the prevalence and
relative commonness of GERD as the cause of
chronic cough increased from a low of 10% and
being the fourth most common cause in 1981,15 to
21% and the third most common cause in 1990,9 to
36% and the second most common cause in 1998.16
Pathophysiology
Knowledge of what is known about where and how
GERD can cause cough provides a framework for
understanding what has been learned about diagnosis and treatment.17 Although GERD can stimulate
the afferent limb of the cough reflex by irritating the
upper respiratory tract without aspiration (eg, the
larynx) and by irritating the lower respiratory tract by
microaspiration or macroaspiration, there is evidence from a randomized and controlled study by
Ing and colleagues18 that strongly suggests that
GERD also can cause chronic cough by stimulating
an esophageal-bronchial cough reflex. By this neural
reflex mechanism, refluxate into the distal esophagus
alone is thought to be a sufficient stimulus to cause
cough.19
When GERD causes cough by irritating the larynx, laryngoscopy has the potential to demonstrate
signs consistent with “reflux laryngitis” (eg, posterior
laryngitis with red arytenoids and piled-up interarytenoid mucosa).20 Bronchoscopy and chest-imaging
studies have the potential to detect abnormalities
consistent with aspiration. Bronchoscopy may reveal
airway signs consistent with aspiration (eg, subglottic
stenosis,2 hemorrhagic tracheobronchitis, and erythema of subsegmental bronchi);21 chest-imaging
studies may demonstrate a wide spectrum of parenchymal abnormalities.22 While laryngoscopic and
bronchoscopic signs are consistent with reflux-induced injury, one must be cautious and not assume
that merely observing changes consistent with inflammation and edema of the larynx and lower
airways is specific for GERD because they may also
potentially be due to the act of coughing itself that is
provoked by other diseases.23 When laryngoscopy,
bronchoscopy, and chest-imaging studies are normal,
it is assumed that GERD has caused cough by
stimulating the esophageal-bronchial reflex. Multiple
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prospective clinical studies17 have suggested this
latter pathophysiologic scenario to be the most common.
Evidence is mounting (eg, prospective before-andafter, successful antireflux surgery intervention trial
in patients who had previously failed to improve
despite total/near-total elimination of esophageal
acid24; prospective, randomized, controlled pharmacologic studies18; and randomized, controlled intraesophageal acid/saline solution challenge studies4,18)
that there are likely to be multiple potential triggers
of cough including, but not limited to, acid in the
gastric refluxate, and the triggers of cough may differ
among patients. While it is not known what the
nonacid factors are, they may include4,24 alkaline pH,
pancreatic enzymes, bile, and esophageal dysmotility.25,26 Because esophageal dysmotility can be commonly demonstrated in patients with GERD, it is not
clear whether or when esophageal dysmotility is an
adverse occurrence due to GERD or contributing to
GERD. Because the term acid reflux disease when
applied to chronic cough due to GERD can be a
misnomer and may mislead clinicians into thinking
that all patients with cough due to GERD should
improve with acid-suppression therapy, it is recommended that the term acid reflux disease no longer
be used in the context of cough unless it can be
definitively shown to apply. Unless acid reflux disease can be definitively proven, the more general
term reflux disease should be used.
Because coughing can induce GER episodes,27 a
cough-GER self-perpetuating cycle may be involved
in the pathophysiology of a patient’s chronic
cough.18,28 While cough-induced GER episodes are
often observed in 24-h esophageal pH-monitoring
tracings, the mechanisms by which these GER episodes are triggered by coughing is not known.
Based on inhaled tussigenic cough challenges,
there is little evidence to support the theory that an
increased sensitivity of the cough reflex is the sole
explanation why some patients with GERD complain
only or predominantly of cough, while others primarily have GI complaints. An increased sensitivity has
been observed in patients with GERD who do not
cough29 as well as in those who do cough.30
Recommendation
1. In patients with chronic cough due to
GERD, the term acid reflux disease, unless it
can be definitively shown to apply, should be
replaced by the more general term reflux disease so as not to mislead the clinicians into
thinking that all patients with cough due to
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GERD should improve with acid-suppression
therapy. Level of evidence, expert opinion; benefit,
substantial; grade of recommendation, E/A
Diagnosis
Clinical Presentation
There is nothing about the character and timing of
the cough due to GERD that distinguishes it from
other causes of cough.31 It can present as a coughphlegm (ie, productive cough) syndrome, just like
chronic bronchitis from cigarette smoking, as well as
a dry cough. It occurs nocturnally in only a minority
of patients,31 and it can be “silent” from a GI
standpoint up to 75% of the time.4
On the other hand, GERD should always be
considered as a possible cause of chronic cough
when patients also complain of typical and frequent
GI symptoms such as daily heartburn and regurgitation, especially when the chest-imaging studies
and/or clinical syndrome are consistent with an
aspiration syndrome.22 Aspiration syndromes associated with cough due to GERD include Mendelson
syndrome, bacterial pneumonia and lung abscess,
chemical pneumonitis, exogenous lipoid pneumonia,
recurrent bacterial pneumonias, chronic interstitial
fibrosis, bronchiectasis, Mycobacterium fortuitum or
Mycobacterium chelonei pneumonia, diffuse aspiration bronchiolitis, and tracheobronchitis.22
While the character and timing of cough are not
predictive of when GERD is likely to be the cause of
chronic cough, there is a clinical profile that has been
highly predictive (approximately 91%) that the patient’s cough will respond to antireflux treatment,
even when there are no GI complaints. This clinical
profile, which appears in Table 1, was initially sug-
Table 1—Clinical Profile That Predicts That Chronic
Cough Is Likely Due to GERD
Chronic cough
Not exposed to environmental irritants nor a present smoker
Not taking an angiotensin-converting enzyme inhibitor
Chest radiograph is normal or shows nothing more than stable,
inconsequential scarring
Symptomatic asthma has been ruled out:
Cough has not improved with asthma therapy, or
Methacholine inhalation challenge is negative
Upper airway cough syndrome due to rhinosinus diseases has been
ruled out:
First-generation H1-antagonist has been used and cough failed
to improve, and
“Silent” sinusitis has been ruled out
Nonasthmatic eosinophilic bronchitis has been ruled out:
Properly performed sputum studies are negative, or
Cough has not improved with inhaled/systemic corticosteroids
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gested by post hoc analyses of four prospective,
before-and-after intervention studies9,15,31,32 of patients with chronic cough due to a variety of diseases,
and was prospectively assessed in two small, beforeand-after intervention studies4,33 of patients with
chronic cough due to GERD. In one of these
prospective studies,4 cough disappeared in 12 of 12
patients receiving intensive medical therapy; in the
other study,33 cough disappeared or significantly
improved in 18 of 21 patients who had undergone
antireflux surgery after they had not responded to
intensive medical therapy.
The results of a prospective, before-and-after intervention trial24 have suggested that GERD cannot
be excluded on clinical grounds as the potential
cause of cough. This study suggested that there can
be a dissociation in improvement in cough and GI
complaints. Chronic cough due to GERD in some
patients remained unchanged, while GI symptoms
improved or disappeared with medical antireflux
therapy. Moreover, because prior antireflux surgery
failed to control GERD in some of the patients,
perhaps for technical reasons, this study also suggested that it cannot be assumed that GERD has
been definitively ruled out as a cause of cough
because there is a history of prior antireflux surgery.
A number of potential risk factors for GERD
have been identified. These include the following:
drugs such as alendronate,34 oral corticosteroids,35
bronchodilators such as inhaled ␤2-adrenergic
agonists36 and theophylline in some studies,37
progesterone,37
calcium
channel-blocking
agents,37anticholinergic agents,37 morphine,37 and
meperidine37; obesity38; smoking37; vigorous exercise39,40; alcohol41; caffeine in some studies37; fatty
foods, chocolate, carminatives, and irritating foods
such as citrus juices and tomato products37; prolonged gastric intubation42,43; lung transplantation44; following pneumonectomy45 and peritoneal
dialysis46,47; and a variety of respiratory diseases
such as asthma48 and obstructive sleep apnea.49 –51
While it is not known what their presence means
from a diagnostic standpoint in the evaluation of
cough, the failure to correct or eliminate risk
factors may assume importance during treatment.
This will be discussed in the “Treatment” section.
Based on a small genome-wide scan52 of families
affected by severe pediatric GERD, followed by
haplotying and by pairwise and multipoint linkage
analyses based on epidemiologic studies, it is
possible that GERD, in the future, may one day be
found to be a genetically determined disease, and
that genetic testing may be able to predict who is
at risk for GERD and its varied presentations.52
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Laboratory Testing
Depending on the information that is sought,
there are a variety of laboratory tests from which to
choose. For example, the results of esophageal manometry to assess for a hypotensive lower esophageal
sphincter and barium esophagography to assess for
the presence of a hiatus hernia may suggest that
there is the potential for GERD. While barium
esophagography results may suggest that there is
mucosal injury, esophagoscopy with mucosal biopsy
can confirm it. Intraesophageal hydrochloric acid
infusion while monitoring symptoms (ie, the Bernstein test) may reveal esophageal mucosal acid sensitivity. Barium esophagography, radionuclide
esophageal scintigraphy, and esophageal pH monitoring can assess for GER events. Dual esophageal
and pharyngeal simultaneous pH monitoring can
evaluate for gastropharyngeal GER events and their
potential to cause laryngopharyngeal injury, and the
risk of aspiration. A radionuclide gastric-emptying
study with solids has the potential to assess for
GERD that may be contributed to by delayed gastric
emptying. Last, 24-h esophageal pH monitoring,
lung scintiscanning after intragastric 99mTc-sulfur
colloid infusion, investigating for lipid-laden alveolar
macrophages in induced sputum or BAL fluid and
observing the gross appearance of airway mucosal
surfaces during laryngoscopy and bronchoscopy, and
lung biopsy have been utilized to link GER with a
variety of pulmonary diseases as well as cough.
While tests that link GER with cough suggest a
potential cause-effect relationship, a definitive diagnosis of cough due to GERD requires that cough
nearly or completely disappear with antireflux treatment.28 Utilizing a favorable response to specific
antitussive therapy as the “gold standard” test for
comparison, and following previously published evidence-based guidelines for interpreting 24-h esophageal pH monitoring and treating GERD in the
context of chronic cough,28 three prospective beforeand-after intervention trials4,9,32 have revealed the
following.17 Although the standard catheter-based
24-h esophageal pH monitoring has been shown to
be the single best test to link GERD and cough in a
cause-effect relationship, because it is the most
sensitive and specific test, it is important to be aware
that conventionally utilized diagnostic indexes of
GERD (eg, percentage of time that pH is ⬍ 4) can
be misleadingly normal and that observing GERinduced coughs can more often be helpful. Consequently, the sensitivity of the test can depend on how
it is interpreted. Until future studies provide better
guidelines, it is recommended that the test be interpreted as normal only when conventional indexes for
acid reflux are within the normal range and no
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reflux-induced coughs appear during the monitoring
study. For example, in three prospective studies,4,33,53 a cough was considered to be induced by
acid reflux only when cough occurred simultaneously
with or within 3 min following a drop in pH to ⬍ 4.
These criteria were empirically established and will
need to be validated by future prospective studies.
When cough is due to GERD, it should not be
expected that there will necessarily be a high percentage of coughs that appear to be induced by GER
events in the 24-h esophageal pH tracing. In two
prospective, before-and-after intervention trials in
which it was determined that chronic cough was due
to GERD, GER events in the distal esophagus
appeared to induce an average of 29% of the patients’ coughs (range, 0 to 100 coughs)4 and 35% of
the patients’ coughs (range, 0 to 89 coughs).53 It is
also important to stress that the degree of abnormality noted in the esophageal pH-monitoring variables
does not directly correlate with the severity of the
patients’ cough.54
The standard, catheter-based 24-h esophageal pHmonitoring study has its own inherent limitations.17
For example, because it cannot detect reflux events
with a pH similar to that of the normal esophagus,
the monitoring study can be entirely normal at a time
when nonacid GERD is the cause of cough. In this
situation, barium esophagography may be the only
available test to reveal GER of potential pathologic
significance (see the discussion below regarding
esophageal impedance monitoring). Barium esophagography has revealed reflux to the mid-esophagus
or higher when refluxate from the stomach had a pH
value similar to that of the normal esophagus.4
Because the majority of patients with cough due to
GERD do not have esophagitis or Barrett epithelium,4 a normal esophagoscopy finding does not rule
out GERD as the cause of cough. While pilot
studies55 have shown that ambulatory esophageal pH
monitoring using a wireless recording system is a
viable option for patients who are unwilling or
unable to undergo conventional ambulatory pHmonitoring studies using a transnasally positioned
pH catheter, it is likely that future studies will show
that the wireless system will have the same limitations as the standard catheter-based systems, which
were summarized above.
Because 24-h esophageal pH monitoring in the
context of prospectively evaluating chronic cough has
a sensitivity of ⬍ 100% (approximately 90%) and its
specificity has ranged between 66% and 100%,4,9,32
even when interpreted according to the guidelines
described above, and because these ranges have
been confirmed in a retrospective study,56 it is
recommended that treatment be initially started in
lieu of testing for patients who fit the clinical profile
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for cough due to GERD (Table 1). This recommendation is supported by a retrospective, before-andafter intervention study57 in which GERD was diagnosed as the cause of chronic cough in 79% of
patients (44 of 56 patients) by the empiric trial of
therapy, thus obviating the need to perform 24-h
esophageal pH monitoring. The performance of 24-h
esophageal pH monitoring is recommended during
therapy when cough does not improve or resolve to
assist in determining whether the therapy needs to
be intensified or medical therapy has failed. The
usefulness of this recommendation was shown in a
small prospective before-and-after intervention trial.24 Hopefully, in the near future, it will be determined whether simultaneous 24-h monitoring of
intraesophageal impedance and pH will allow us to
more easily determine when acid reflux disease
and/or nonacid reflux disease are the causes of
chronic cough.58,59
While impedance monitoring allows for the detection of air and liquid reflux without requiring a pH
shift to detect the liquid reflux, the simultaneous
monitoring of pH helps to determine whether the
liquid reflux observed by impedance was acidic in
nature. Dual-impedance pH monitoring may also
help to determine the roles of esophageal manometry in diagnosing cough and esophageal dysmotility
in causing cough due to GERD.25,26,60 While a high
prevalence of abnormal esophageal manometric
measurements have been reported in a group of
patients with chronic cough thought to be due to
GERD, and manometry was the only abnormal test
result in 32% of patients,60 a randomized, prospective study utilizing a control group of patients with
cough due to conditions other than GERD will be
required to determine whether manometry is a
useful diagnostic test for distinguishing cough due to
GERD from cough due to other diseases. Moreover,
a randomized, prospective, double-blind, placebocontrolled trial will be required to determine
whether esophageal dysmotility is pathogenetically
linked to cough due to GERD.
As stated above, the findings of chest-imaging
studies, laryngoscopy, and bronchoscopy can be entirely normal when GERD is the cause of cough. In
this context, GERD most likely has caused cough via
stimulation of an esophageal-bronchial reflex pathway.28 While laryngoscopic findings61 and bronchoscopic findings,2,21 putatively due to GERD, have
been published, it is not known how specific any of
the findings are for injury due to GERD because
they may also be potentially caused by the trauma of
coughing itself23 (also see the “Complications” section elsewhere in this Supplement).
Lipid-laden alveolar macrophages have been prospectively evaluated as a marker of aspiration by
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BAL in patients with pulmonary parenchymal lung
diseases62 and by induced sputum in patients with
either GI symptoms without respiratory complaints
or patients with mild asthma in the context of normal
chest radiographs.63 In the first study,62 the mere
presence of lipid-laden alveolar macrophages in
lower respiratory tract secretions was found to be a
nonspecific marker of parenchymal lung disease
because the presence and/or appearance of intracellular lipid in these cells was not helpful in differentiating aspiration from nonaspiration as the cause of
the lung disease. A post hoc analysis of the data
revealed that observing few or no lipid-laden alveolar
macrophages might be helpful in ruling out aspiration as the cause of the parenchymal lung disease.
This conclusion was reached on the basis of the
following information: a lipid cellular index of ⱖ 100,
which was computed by multiplying the observed
amount of intracellular lipid in 100 cells, graded
from 0 to 4, had a specificity of 57%, and sensitivity
and negative predictive values of 100%. In the
second study,63 while it was found that the presence
of an increased number of lipid-laden macrophages
in induced sputum predicted the presence of oropharyngeal reflux by dual-channel 24-h esophageal
and pharyngeal pH monitoring, it was not determined that these same patients actually had aspirated. Most relevant to the discussion in this section,
the diagnostic usefulness of the presence of lipidladen macrophages in induced sputum was not
assessed in patients with chronic cough. On the basis
of these studies, assessing for lipid-laden macrophages in BAL fluid and induced sputum does not
appear, at this time, to have a role to play in
diagnosing cough due to GERD.
Because inhaled tussigenic challenges with capsaicin have revealed the increased sensitivity of the
cough reflex in a variety of diseases (eg, asthma, viral
upper respiratory tract infections, and angiotensinconverting enzyme inhibitors) in addition to
GERD30 and even in patients with GERD without
cough,29 inhaled tussigenic challenges with capsaicin
at this time do not appear to have a role to play in
diagnosing cough due to GERD. Because exhaled
nitric oxide can be a marker of airway inflammation
in patients with asthma, its measurement may be of
potential benefit in diagnosing the cause of chronic
cough. However, preliminary studies64,65 to date
have not shown exhaled nitric oxide measurements
to be particularly helpful in diagnosing cough due to
GERD. In a cross-sectional prospective study65 utilizing exhaled nitric oxide as well as induced sputum,
it was determined that GERD, when associated with
cough or mildly symptomatic asthma, did not cause
or aggravate existing airway inflammation as meawww.chestjournal.org
sured by exhaled nitric oxide or other indexes of
airway inflammation (eg, cell counts and fibrinogen
level).
Because two prospective studies4,18 in subjects
with chronic cough due to GERD have produced
divergent results during intraesophageal infusions of
hydrochloric acid to provoke cough, a negative Bernstein test cannot be used to exclude the diagnosis of
cough due to GERD. While a radioisotope scintiscan
that documents pulmonary aspiration of gastric contents is definitive, it is not routinely performed
because it may be positive in not ⬎ 50% of subjects
with suspected aspiration, and it has a much lower
sensitivity.
Empiric Trial of Therapy
The first consensus panel report28 in 1998 recommended that, when 24-h esophageal pH monitoring
cannot be performed or is not available, a diagnostic,
empiric trial of medical antireflux therapy be performed in patients who meet the clinical profile
(Table 1) predicting that silent GERD is the likely
cause of chronic cough or in patients with chronic
cough who also have prominent upper GI symptoms
that are consistent with GERD. The first consensus
panel report28 also recommended that if empiric
treatment fails, it cannot be assumed that GERD has
been ruled out as a cause of chronic cough; rather,
objective investigation for GERD is then recommended because the empiric therapy may not have
been intensive enough or medical therapy may have
failed.
Since 1998, a number of articles have been published that support the above two recommendations.
Poe and Kallay,57 in a retrospective before-and-after
empirical medical intervention trial, provided data
suggesting that an empiric trial of therapy can be
successful; they were able to avoid the performance
of 24-h esophageal pH monitoring in 44 of 56
patients in whom cough due to GERD had been
determined. Others have provided data that support
the contention that a negative finding in an empiric
trial of therapy does not rule out GERD as a cause of
cough. Peghini et al,66 in a controlled investigation
that assessed for nocturnal acid breakthrough in
patients with GI complaints who were receiving
omeprazole (20 mg bid) or lansoprazole (30 mg bid)
and in healthy volunteers, showed that nocturnal
acid breakthrough occurred in the majority of all
subjects. This study underscores the importance of
being aware that a fixed dose of medication may not
be adequate in all patients. Allen and Anvari,67 in a
prospective before-and-after antireflux surgery intervention trial in patients who had failed to improve
with intensive medical therapy, showed that laparoCHEST / 129 / 1 / JANUARY, 2006 SUPPLEMENT
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scopic reflux surgery had improved or cured cough
in 85% of chronic coughers 6 months after surgery.
Novitsky et al,33 in a prospective before-and-after
antireflux surgery intervention trial in patients with
chronic cough who had failed to respond to intensive
medical therapy, reported an 86% improvement of
chronic cough 12 months following surgery. Irwin et
al,24 in a small, prospective, before-and-after intervention trial in patients with chronic cough who had
failed to respond to very intensive medical therapy,
reported the improvement or elimination of cough in
all subjects 12 months following surgery. In this
study, cough persisted prior to surgery even though
the antireflux medical regimen was serially intensified until there was total or near-total elimination of
esophageal acid on repeated 24-h esophageal pH
monitoring. This finding supported the diagnosis of
nonacid reflux disease.
The results of a metaanalysis68 of 15 trials (openlabel, 2 trials; randomized, controlled, 10 trials;
randomized, controlled, crossover, 3 trials) that did
not involve extraesophageal symptoms such as cough
showed that the short-term treatment (ie, 1 to 4
weeks) of GERD with normal-dose or high-dose
proton pump inhibition (ie, the so-called PPI test) in
patients who were suspected of having GERD did
not confidently establish or exclude the diagnosis
when GERD was defined by objective reference
standards. In patients with GI symptoms suggestive
of GERD in which the clinical response to a short
course of proton pump inhibition was compared with
24-h esophageal pH monitoring, the positive likelihood of a symptomatic response detecting GERD
ranged from 1.63 to 1.87. The sensitivity was 0.78
(95% confidence interval, 0.66 to 0.86) and specificity 0.54 (95% confidence interval, 0.44 to 0.65).
While Ours et al69 concluded from their prospective, double-blind, randomized, placebo-controlled
study that the best diagnostic and therapeutic approach to chronic cough is a fixed dose of omeprazole, 40 mg bid for 2 weeks, there are many methodological concerns about this study that make the
results uninterpretable.70 With respect to concerns
about GERD, there were 17 patients with chronic
cough who had abnormal findings of 24-h esophageal
pH-monitoring studies, and only 6 patients improved
with omeprazole therapy for a response rate of 35%.
Because the authors assumed that the dose and
duration of omeprazole therapy that they used would
cure all patients with cough due to GERD, they
reasoned that the other patients with abnormal
findings of 24-h esophageal pH-monitoring studies
could not have GERD. In the patients who did not
respond, the authors did not (1) determine whether
their medical therapy was maximal, (2) consider that
their subjects might have had nonacid reflux disease
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and therefore required more than acid suppression
therapy, and (3) did not find another cause for the
chronic coughs of the patients.
On the basis of the above considerations, the panel
recommends that an empiric trial of medical antireflux therapy be performed in patients who meet the
clinical profile (Table 1) predicting that silent GERD
is the likely cause of chronic cough or in patients
with chronic cough who also have prominent upper
GI symptoms (eg, heartburn, sour taste, and regurgitation) that are consistent with GERD. The panel
does not think that it is necessary to order tests to
assess for the potential of GERD before observing
the response to empiric therapy. While it is not
known what constitutes the minimum effective medical therapy for treating the majority of patients with
chronic cough due to GERD, the panel, by expert
opinion, recommends (1) dietary and lifestyle modifications, (2) acid suppression therapy, (3) the addition of prokinetic therapy (ie, to enhance gut motility) either initially or if there is no response to the
therapy stated in steps 1 and 257 (see section on
Treatment), and (4) that the response to therapy be
assessed within 1 to 3 months. In some patients,
there can be a delay of 2 to 3 months in improvement
with therapy that will eventually eliminate the
cough.53 If empiric treatment fails, it cannot be
assumed that GERD has been ruled out as a cause of
chronic cough; rather, the objective investigation for
GERD is then recommended because the empiric
therapy may not have been intensive enough or
medical therapy may have failed.
Recommendations
2. In patients with chronic cough who also
complain of typical and frequent GI complaints
such as daily heartburn and regurgitation, especially when the findings of chest-imaging
studies and/or clinical syndrome are consistent
with an aspiration syndrome, the diagnostic
evaluation should always include GERD as a
possible cause. Level of evidence, low; benefit,
substantial; grade of recommendation, B
3. Patients with chronic cough who have GI
symptoms that are consistent with GERD or
who fit the clinical profile described in Table 1,
should be considered to have a high likelihood
of having GERD and should be prescribed
antireflux treatment even when they have no GI
symptoms. Level of evidence, low; benefit, substantial; grade of recommendation, B
4. In patients with chronic cough, it should
not be assumed that GERD has been definitively ruled out as a cause of cough simply
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because there is a history of antireflux surgery.
Level of evidence, low; benefit, substantial; grade of
recommendation, B
5. In patients with chronic cough, while tests
that link GERD with cough suggest a potential
cause-effect relationship, a definitive diagnosis
of cough due to GERD requires that cough
nearly or completely disappear with antireflux
treatment. Level of evidence, low; benefit, substantial; grade of recommendation, B
6. In patients with chronic cough being evaluated for GERD, the 24-h esophageal pH-monitoring test is the most sensitive and specific
test; however, it is recommended that the test
results be interpreted as normal only when
conventional indexes for acid reflux are within
the normal range and no reflux-induced coughs
appear during the monitoring study. Level of
evidence, low; benefit, substantial; grade of recommendation, B
7. In patients with cough who are undergoing 24-h monitoring, a low percentage of
coughs associated with (or induced by) reflux
does not exclude a diagnosis of cough due to
GERD. Level of evidence, low; benefit, substantial;
grade of recommendation, B
8. In patients with cough due to GERD, the
degree of abnormality noted in the esophageal
pH-monitoring variables, such as the frequency
and duration of reflux events, does not directly
correlate with the severity of the patients’
cough. Level of evidence, low; benefit, substantial;
grade of recommendation, B
9. In diagnosing nonacid GERD as the cause
of cough, barium esophagography may be the
only available test to reveal GER of potential
pathologic significance in this setting (see the
discussion regarding esophageal impedance
monitoring in the “Laboratory Testing” section). When this is the case, barium esophagography is the test of choice to reveal GER of
potential pathologic significance. Level of evidence, low; benefit, substantial; grade of recommendation, B
10. In patients with cough due to GERD,
normal esophagoscopy findings do not rule out
GERD as the cause of cough. Level of evidence,
low; benefit, substantial; grade of recommendation,
B
11. For patients fitting the clinical profile for
cough due to GERD, it is recommended that
treatment be initially started in lieu of testing.
Level of evidence, low; benefit, substantial; grade of
recommendation, B
12. For patients fitting the clinical profile for
cough due to GERD, the performance of 24-h
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esophageal pH monitoring is recommended on
therapy when cough does not improve or resolve to assist in determining whether the therapy needs to be intensified or if medical therapy
has failed. Level of evidence, low; benefit, substantial; grade of recommendation, B
13. For patients with chronic cough, the following tests are not routinely recommended to
link cough with GERD: (a) assessing for lipidladen macrophages in BAL fluid and induced
sputum, because this test has not been studied
in patients with chronic cough and because a
positive test result is not specific for aspiration;
(b) exhaled nitric oxide measurements, because
they do not appear to be helpful in diagnosing
cough due to GERD; (c) a Bernstein test, because a negative Bernstein test result cannot be
used to exclude the diagnosis of cough due to
GERD; and (d) inhaled tussigenic challenges
with capsaicin, because they are not specific for
coughs due to GERD and because the test
result can be positive in patients with GERD
without cough. Level of evidence, low; benefit,
conflicting; grade of recommendation, I
Treatment
Based on the apparent heterogeneity of patient
populations with differing pathogenetic mechanisms
and differing risk factors that can adversely affect
GERD, it is not likely that all patients will theoretically respond to the same treatment. A review of the
literature on the treatment of cough due to GERD,
which is summarized in Table 2, supports this statement. The review suggests the following: that when
medical therapy is effective, some patients with
cough due to GERD will favorably respond to acid
suppression therapy alone69,71; that proton pump
inhibition may be effective when H2-antagonism has
been ineffective57; that prokinetic therapy and diet,
when added to proton pump inhibition, may be
effective when proton pump inhibition alone has
been ineffective57; that while medial therapy may
eliminate cough within 8 weeks in some patients,71 it
may still lead to a favorable outcome despite taking
months before it starts to work9,53; and that cough in
other patients will only improve or be eliminated
with antireflux surgery, after cough in these patients
has failed to improve with maximal medical therapy
that includes an intensive antireflux diet, maximum
acid suppression, and prokinetic therapy.24 These
findings have come from prospective and retrospective before-and-after intervention trials, and from
two imperfectly designed (see Table 2), prospective,
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Table 2—Evidence for the Treatment of Chronic Cough Due to GERD*
Treatment
Diet ⫹ LS, antacids,
cimetidine
Diet ⫹ LS,
metoclopramide and/
or H2-blockers
Diet ⫹ LS,
metoclopramide and/
or H2-blockers
Diet ⫹ LS, antacids,
metoclopramide,
cimetidine, surgery
Diet ⫹ LS, omeprazole
or surgery
Dosing
qid
300 mg hs
Not stated
Not stated
Not stated
Not stated
Not stated,
10 mg tid
300, mg qid
20–40 mg/d
Cisapride,†
domperidone
0.2 mg/kg tid
0.2 mg/kg tid
Domperidone
2 mg/kg/d
divided qid
Diet Prokinetic and/or
H2-blockers
Not stated
Not stated
Surgery
Surgery
Surgery
Study ID
Prospective, before/after
intervention, uncontrolled,
unblinded15
Prospective, before/after
intervention, uncontrolled,
unblinded53
Prospective, before/after
intervention, uncontrolled,
unblinded9
Retrospective, before/after
intervention, uncontrolled,
unblinded82
Prospective, before/after
intervention, uncontrolled,
unblinded83
Prospective, before/after
intervention, uncontrolled,
unblinded84
Prospective, before/after
intervention, uncontrolled,
unblinded85
Prospective, before/after
intervention, uncontrolled,
unblinded32
Prospective, before/after
intervention, uncontrolled,
unblinded86
Prospective, before/after
intervention, uncontrolled,
unblinded87
Prospective, before/after
intervention, uncontrolled,
unblinded88
Retrospective, before/after
intervention, uncontrolled,
unblinded57
Diet, prokinetics and/or Cisapride or metoclopraPPIs
pramide 10 mg qid,
omeprazole up to 40
mg and lansoprazole,
30 mg bid
Omeprazole
Omeprazole, 40 mg/d, or Prospective, double-blind,
placebo for 8 wk
randomized, placebocontrolled, cross-over
trial71
Omeprazole
Omeprazole, 40 mg bid, Prospective, double-blind,
or placebo for 12 wk
randomized, placebocontrolled trial69
Patients,
No.
Age
Results
5
67.2 yr
9
52 ⫾ 11 yr
Cough cured 100%; time to cure, 161 ⫾ 74 d
28
56 ⫾ 12 yr
Cough cured 100%; time to cure, 179 ⫾ 205 d
20
Adult
Cough cured 90%; 70% cured with medication in 3
mo, 20% with surgery
25
Adult
Cough or hoarseness improved in 80%; only patients
without heartburn had full resolution of cough
55
Infants
Cough improved 64.5%; no significant difference
between drugs
18
Cough cured 100%
1 mo to 12.7 yr Cough improved 100% (p ⬍ 0.05)
20
58 ⫾ 17 yr
17
Adult
100% cure if esophageal motility was normal
5
Adult
13
Adult
100% cured in highly selected patients who were
thought to be aspirators; only 5/100 patients were
suitable
Cough cured in 84.6%; only 13/140 patients
considered suitable
56
57 yr
29
Adults
23
Adults
Surgery
Prospective, before/after
intervention, uncontrolled,
unblinded67
119
Adults
Surgery
Prospective before/after
intervention, uncontrolled,
unblinded89
35
Adults
Surgery
Prospective before/after
intervention, uncontrolled,
unblinded33
21
Adults
Surgery
Prospective before/after
intervention, uncontrolled,
unblinded24
8
54.2 ⫾ 10.8 yr
Cough cured in 97%; productive coughs in all patients
Cough cured or improved in 86%; 17/56 had not
responded to H2-blockers; 5/56 required up to 8
weeks to improve, and 1/55 up to 12 weeks; 24/56
only required PPIs, 18/56 required PPIs plus
prokinetics
Cough improved (p ⫽ 0.02) with omeprazole
compared to placebo; proper statistics were not
utilized to analyze crossover design
Of 17 patients with abnormal findings of 24-h
esophageal pH monitoring studies, 6 significantly
improved after drug therapy compared to placebo; it
is not known whether the remaining patients also
had GERD because no further testing was
performed and treatment was not intensified
Of 119 patients with inadequate control of respiratory
symptoms with medical therapy, 42 had chronic
cough as chief complaint; surgery cured or
improved cough in 85% at 6 mo after surgery
Of 35 patients with chronic cough, cough improved or
was cured in 56% at 12 mo; patients did not appear
to have been selected based upon lack of response
to medical treatment
At 1 yr following surgery, cough had significantly
improved (p ⬍ 0.01); improvement was reported by
86% of patients, with complete resolution in 62%;
prior to surgery, cough had failed to improve with
intensive medical therapy
At 1 yr following surgery, cough had significantly
improved (p ⬍ 0.001); all patients reported
improvement in cough; prior to surgery, patients
had failed to respond to maximal medical therapy
even though there was total/near-total elimination of
esophageal acid
*LS ⫽ lifestyle changes (such as not wearing constricting clothing and head of bed elevation). Diets were not well-described in any study and were
not consistently described between studies.
†Cisapride is off the market in the United States but is available in other countries.
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double-blind, randomized placebo-controlled trials69,71 that have compared the effects of omeprazole
with placebo.
While the optimal way to treat all patients with
cough due to GERD has yet to be determined,
medical therapy in adults, based on the results of
prospective and retrospective before-and-after intervention trials, when not limited to acid suppression
therapy alone, has improved cough in 70 to 100% of
patients. When cough in adults has not improved
with medical therapy, surgery has improved cough 6
to 12 months following surgery in prospective, before-and-after intervention trials33,67 in approximately 85% of patients.
Until multiple randomized controlled clinical trials
provide guidance on which treatment regimens will
be successful in which groups of subjects, the panel
by consensus recommends that clinicians must be
aware of the spectrum of treatment options that may
favorably affect GERD (Table 3) and that an intensive medical treatment regimen that includes all
medical therapeutic options listed in Table 3 be
instituted before considering antireflux surgery.17
While there has been an anecdotal report72 suggesting that one patient may have developed an intractable cough due to receiving omeprazole therapy,
the patient was not rechallenged with the drug to
solidify the association. Nevertheless, if drug-induced cough is considered to be a clinical possibility,
the agent should be discontinued to determine
whether it might be playing a role before recommending surgery.
An intensive medical treatment regimen includes
the following: (1) an antireflux diet that includes no
⬎ 45 g of fat in 24 h and no coffee, tea, soda,
chocolate, mints, citrus products, including toma-
Table 3—Spectrum of Options for Treating Chronic
Cough Due to GERD
Treatment
Options
Antireflux medical therapy
Diet
Lifestyle changes
Smoking
Exercising
Consuming alcohol
Medications
Acid suppression
Prokinetic
Address risk factors
Treat other causes of cough
Treat comorbid conditions
Obesity
Obstructive sleep apnea
Consider changing medications for
comorbid conditions
Antireflux surgery
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toes37,73 or alcohol,41 no smoking,37 and limiting
vigorous exercise that will increase intraabdominal
pressure39,40; (2) acid suppression with a proton
pump inhibitor (PPI); and (3) prokinetic therapy.
Even though nocturnal breakthrough gastric acid
production has been noted in healthy control subjects and patients with GERD who are receiving
PPIs, the addition of a nocturnal H2-antagonist has
not been shown to improve clinical outcomes.66,74,75
Because comorbid diseases such as obstructive sleep
apnea51,76 or therapy for comorbid conditions (eg,
nitrates, progesterone, and calcium channel blockers)37,77 can potentially make GERD more difficult
to control, routinely consider trying to mitigate the
influences of these factors whenever possible. Because coughing can induce GER events, it should be
appreciated that less than optimal results may occur
due to a cough-GER self-perpetuating cycle unless
all causes of cough are adequately treated.28 Reliance on acid suppression alone may not only fail to
adequately control the cough but also potentially
place the patient at increased risk of communityacquired pneumonia. According to a retrospective
case-control analysis, which was nested in a cohort of
incident users of acid-suppressive drugs for at least 1
year,78 the adjusted risk for pneumonia among persons currently using PPIs compared with those who
stopped receiving the PPIs was 1.89. Current users
of histamine-2 receptor antagonists had a 1.63-fold
increased risk of pneumonia compared with those
patients who had stopped using them. These data
translated into approximately one case of pneumonia
for every 100 years of patient exposure.79 A prospective, randomized, controlled clinical trial will be
necessary to confirm the accuracy of these results.
While the role of antireflux surgery has not been
clearly defined, it appears that antireflux surgery has
been able to effectively eliminate or significantly
improve cough that is unresponsive to intensive
antireflux medical therapy. The panel by consensus
recommends that antireflux surgery be considered in
patients who meet the following criteria: (1) the
findings of a 24-h esophageal pH-monitoring study
before treatment are positive, as defined above; (2)
patients fit the clinical profile suggesting that GERD
is the likely cause of their cough (Table 1); (3) cough
has not improved after a minimum of 3 months of
intensive therapy (Table 3), and serial esophageal
pH-monitoring studies or other objective studies (eg,
barium esophagography, esophagoscopy, or gastricemptying study with solids) performed on therapy
show that intensive medical therapy has failed to
control the reflux disease and GERD is still the likely
cause of cough; and (4) patients express the opinion
that their persisting cough does not allow them a
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tive, uncontrolled and unblinded, descriptive study80
suggested that an assessment of gastric emptying
would not assist in patient management, another
small, prospective, before-and-after intervention trial24 found that a gastric-emptying study with solids
provided the only insight as to why prior antireflux
surgery had failed to control cough. Redo antireflux
surgery that included a gastric-emptying procedure
in three of four patients was successful.24 While a
variety of endoscopically assisted interventional techniques have been developed and performed in patients with classic GI GERD symptoms,81 these
procedures should be considered experimental at
this time in the population of patients with cough.
Recommendations
14. In patients who meet the clinical profile
predicting that silent GERD is the likely cause
of chronic cough or in patients with chronic
cough who also have prominent upper GI symptoms consistent with GERD, an empiric trial of
medical antireflux therapy is recommended.
Level of evidence, low; benefit, substantial; grade of
recommendation, B
15. For treating the majority of patients with
chronic cough due to GERD, the following
medical therapies are recommended: (a) dietary and lifestyle modifications; (b) acid suppression therapy; and (c) the addition of prokinetic therapy either initially or if there is no
response to the first two therapies. The response to these therapies should be assessed
within 1 to 3 months. Level of evidence, expert
opinion; benefit, substantial; grade of recommendation, E/A
16. In patients in which this empiric treatment fails, it cannot be assumed that GERD has
been ruled out as a cause of chronic cough;
rather, the objective investigation for GERD is
then recommended because the empiric therapy may not have been intensive enough or
medical therapy may have failed. Level of evidence, expert opinion; benefit, substantial; grade of
recommendation, E/A
17. In some patients, cough due to GERD
will favorably respond to acid suppression therapy alone; proton pump inhibition may be effective when H2-antagonism has been ineffective; prokinetic therapy and diet, when added to
proton pump inhibition, may be effective when
proton pump inhibition alone has been ineffective. Level of evidence, low; benefit, substantial;
grade of recommendation, B
18. Patients requiring an intensive medical
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treatment regimen should be treated with the
following: (a) antireflux diet that includes no
> 45 g of fat in 24 h and no coffee, tea, soda,
chocolate, mints, citrus products, including tomatoes, or alcohol, no smoking, and limiting
vigorous exercise that will increase intra-abdominal pressure; (b) acid suppression with a
PPI; (c) prokinetic therapy; and (d) efforts to
mitigate the influences of comorbid diseases
such as obstructive sleep apnea or therapy for
comorbid conditions (eg, nitrates, progesterone, and calcium channel blockers) whenever
possible. Level of evidence, expert opinion; benefit,
substantial; grade of recommendation, E/A
19. In patients with chronic cough due to
GERD that has failed to improve with the most
maximal medical therapy, which includes an
intensive antireflux diet and lifestyle modification, maximum acid suppression, and prokinetic
therapy, and the rest of the spectrum of treatment options in Table 3, cough may only improve or be eliminated with antireflux surgery.
Level of evidence, low; benefit, substantial; grade of
recommendation, B
20. In patients who meet the following criteria, antireflux surgery is the recommended
treatment: (a) findings of a 24-h esophageal
pH-monitoring study before treatment is positive, as defined above; (b) patients fit the clinical profile suggesting that GERD is the likely
cause of their cough (Table 1); (c) cough has not
improved after a minimum of 3 months of
intensive therapy (Table 3), and serial esophageal pH-monitoring studies or other objective
studies (eg, barium esophagography, esophagoscopy, and gastric-emptying study with solids) performed while the patient receives therapy show that intensive medical therapy has
failed to control the reflux disease and that
GERD is still the likely cause of cough; and (d)
patients express the opinion that their persisting cough does not allow them a satisfactory
quality of life. Level of evidence, expert opinion;
benefit, substantial; grade of recommendation, E/A
Summary of Recommendations
1. In patients with chronic cough due to
GERD, the term acid reflux disease, unless
it can be definitively shown to apply, should
be replaced by the more general term reflux
disease so as not to mislead the clinicians
into thinking that all patients with cough
due to GERD should improve with acidDiagnosis and Management of Cough: ACCP Guidelines
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suppression therapy. Level of evidence, expert
opinion; benefit, substantial; grade of recommendation, E/A
2. In patients with chronic cough who
also complain of typical and frequent GI
complaints such as daily heartburn and regurgitation, especially when the findings of
chest-imaging studies and/or clinical syndrome are consistent with an aspiration
syndrome, the diagnostic evaluation should
always include GERD as a possible cause.
Level of evidence, low; benefit, substantial;
grade of recommendation, B
3. Patients with chronic cough who have
GI symptoms that are consistent with
GERD or who fit the clinical profile described in Table 1, should be considered to
have a high likelihood of having GERD and
should be prescribed antireflux treatment
even when they have no GI symptoms. Level
of evidence, low; benefit, substantial; grade of
recommendation, B
4. In patients with chronic cough, it
should not be assumed that GERD has been
definitively ruled out as a cause of cough
simply because there is a history of antireflux surgery. Level of evidence, low; benefit,
substantial; grade of recommendation, B
5. In patients with chronic cough, while
tests that link GERD with cough suggest a
potential cause-effect relationship, a definitive diagnosis of cough due to GERD requires that cough nearly or completely disappear with antireflux treatment. Level of
evidence, low; benefit, substantial; grade of recommendation, B
6. In patients with chronic cough being
evaluated for GERD, the 24-h esophageal
pH-monitoring test is the most sensitive and
specific test; however, it is recommended
that the test results be interpreted as normal only when conventional indexes for acid
reflux are within the normal range and no
reflux-induced coughs appear during the
monitoring study. Level of evidence, low; benefit, substantial; grade of recommendation, B
7. In patients with cough who are undergoing 24-h monitoring, a low percentage of
coughs associated with (or induced by) reflux does not exclude a diagnosis of cough
due to GERD. Level of evidence, low; benefit,
substantial; grade of recommendation, B
8. In patients with cough due to GERD,
the degree of abnormality noted in the
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esophageal pH-monitoring variables, such
as the frequency and duration of reflux
events, does not directly correlate with the
severity of the patients’ cough. Level of
evidence, low; benefit, substantial; grade of recommendation, B
9. In diagnosing nonacid GERD as the
cause of cough, barium esophagography
may be the only available test to reveal GER
of potential pathologic significance in this
setting (see the discussion regarding esophageal impedance monitoring in the “Laboratory Testing” section). When this is the
case, barium esophagography is the test of
choice to reveal GER of potential pathologic significance. Level of evidence, low; benefit, substantial; grade of recommendation, B
10. In patients with cough due to GERD,
normal esophagoscopy findings do not rule
out GERD as the cause of cough. Level of
evidence, low; benefit, substantial; grade of recommendation, B
11. For patients fitting the clinical profile
for cough due to GERD, it is recommended
that treatment be initially started in lieu of
testing. Level of evidence, low; benefit, substantial; grade of recommendation, B
12. For patients fitting the clinical profile
for cough due to GERD, the performance of
24-h esophageal pH monitoring is recommended on therapy when cough does not
improve or resolve to assist in determining
whether the therapy needs to be intensified
or if medical therapy has failed. Level of
evidence, low; benefit, substantial; grade of recommendation, B
13. For patients with chronic cough, the
following tests are not routinely recommended to link cough with GERD: (a) assessing for lipid-laden macrophages in BAL
fluid and induced sputum, because this test
has not been studied in patients with
chronic cough and because a positive test
result is not specific for aspiration; (b) exhaled nitric oxide measurements, because
they do not appear to be helpful in diagnosing cough due to GERD; (c) a Bernstein
test, because a negative Bernstein test result cannot be used to exclude the diagnosis
of cough due to GERD; and (d) inhaled
tussigenic challenges with capsaicin, because they are not specific for coughs due to
GERD and because the test result can be
positive in patients with GERD without
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cough. Level of evidence, low; benefit, conflicting; grade of recommendation, I
14. In patients who meet the clinical profile predicting that silent GERD is the likely
cause of chronic cough or in patients with
chronic cough who also have prominent
upper GI symptoms consistent with GERD,
an empiric trial of medical antireflux therapy is recommended. Level of evidence, low;
benefit, substantial; grade of recommendation, B
15. For treating the majority of patients
with chronic cough due to GERD, the following medical therapies are recommended: (a) dietary and lifestyle modifications;
(b) acid suppression therapy; and (c) the
addition of prokinetic therapy either initially or if there is no response to the first
two therapies. The response to these therapies should be assessed within 1 to 3
months. Level of evidence, expert opinion; benefit, substantial; grade of recommendation, E/A
16. In patients in which this empiric
treatment fails, it cannot be assumed that
GERD has been ruled out as a cause of
chronic cough; rather, the objective investigation for GERD is then recommended because the empiric therapy may not have
been intensive enough or medical therapy
may have failed. Level of evidence, expert
opinion; benefit, substantial; grade of recommendation, E/A
17. In some patients, cough due to GERD
will favorably respond to acid suppression
therapy alone; proton pump inhibition may
be effective when H2-antagonism has been
ineffective; prokinetic therapy and diet,
when added to proton pump inhibition, may
be effective when proton pump inhibition
alone has been ineffective. Level of evidence,
low; benefit, substantial; grade of recommendation, B
18. Patients requiring an intensive medical treatment regimen should be treated
with the following: (a) antireflux diet that
includes no > 45 g of fat in 24 h and no
coffee, tea, soda, chocolate, mints, citrus
products, including tomatoes, or alcohol, no
smoking, and limiting vigorous exercise that
will increase intraabdominal pressure; (b)
acid suppression with a PPI; (c) prokinetic
therapy; and (d) efforts to mitigate the influences of comorbid diseases such as obstructive sleep apnea or therapy for comorbid conditions (eg, nitrates, progesterone,
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and calcium channel blockers) whenever
possible. Level of evidence, expert opinion;
benefit, substantial; grade of recommendation,
E/A
19. In patients with chronic cough due to
GERD that has failed to improve with the
most maximal medical therapy, which includes an intensive antireflux diet and lifestyle modification, maximum acid suppression, and prokinetic therapy, and the rest of
the spectrum of treatment options in Table
3, cough may only improve or be eliminated
with antireflux surgery. Level of evidence,
low; benefit, substantial; grade of recommendation, B
20. In patients who meet the following
criteria, antireflux surgery is the recommended treatment: (a) findings of a 24-h
esophageal pH-monitoring study before
treatment is positive, as defined above; (b)
patients fit the clinical profile suggesting
that GERD is the likely cause of their cough
(Table 1); (c) cough has not improved after a
minimum of 3 months of intensive therapy
(Table 3), and serial esophageal pH-monitoring studies or other objective studies (eg,
barium esophagography, esophagoscopy,
and gastric-emptying study with solids) performed while the patient receives therapy
show that intensive medical therapy has
failed to control the reflux disease and that
GERD is still the likely cause of cough; and
(d) patients express the opinion that their
persisting cough does not allow them a
satisfactory quality of life. Level of evidence,
expert opinion; benefit, substantial; grade of
recommendation, E/A
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Diagnosis and Management of Cough: ACCP Guidelines
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