Therapeutic Advances in Respiratory Disease

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The relationship between gastroesophageal reflux and asthma: an update

Jennifer W. McCallister, Jonathan P. Parsons and John G. Mastronarde
Ther Adv Respir Dis 2011 5: 143 originally published online 6 October 2010
DOI: 10.1177/1753465810384606

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 Therapeutic Advances in Respiratory Disease Review

Ther Adv Respir Dis

The relationship between gastroesophageal (2011) 5(2) 143—150
DOI: 10.1177/
reflux and asthma: an update 1753465810384606
! The Author(s), 2010.
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Abstract: Asthma and gastroesophageal reflux disease (GERD) are both common conditions
and, hence, they often coexist. However, asthmatics have been found to have a much greater
prevalence of GERD symptoms than the general population. There remains debate regarding
the underlying physiologic mechanism(s) of this relationship and whether treatment of GERD
actually translates into improved asthma outcomes. Based on smaller trials with somewhat
conflicting results regarding improved asthma control with treatment of GERD, current
guidelines recommend a trial of GERD treatment for symptomatic asthmatics even without
symptoms of GERD. However, recently a large multicenter trial demonstrated that the
treatment of asymptomatic GERD with proton-pump inhibitors did not improve asthma control
in terms of pulmonary function, rate of asthma exacerbations, asthma-related quality of life, or
asthma symptom frequency. These data suggest empiric treatment of asymptomatic GERD in
asthmatics is not a useful practice. This review article provides an overview of the epidemiology
and pathophysiologic relationships between asthma and GERD as well as a summary of current
data regarding links between treatment of GERD with asthma outcomes.

Keywords: asthma, gastroesophageal reflux disease, treatment

Introduction et al. 2005; Kiljander and Laitinen, 2004; Correspondence to:

John G. Mastronarde, MD,
Asthma and gastroesophageal reflux disease Harding et al. 1999; Sontag et al. 1990]. Thus, MSc
(GERD) are very common conditions that it appears that no matter which definition of The Ohio State University
Medical Center, Division of
affect millions of patients. The prevalence of GERD one uses, symptom based or objective Pulmonary, Allergy,
asthma is estimated to be approximately 20—25 testing, there is an increased prevalence of Critical Care, and Sleep
Medicine, 201 Davis Heart/
million people in the United States [National GERD among asthmatics. This has raised the Lung Research Institute,
Heart Lung and Blood Institute Expert Panel, question of whether GERD and asthma are just 473 West 12th Avenue,
Columbus, OH 43210, USA
2007] and gastroesophageal reflux symptoms common diseases that overlap in patients or john.mastronarde@
occur daily in approximately 10—20% of the US whether there is a pathophysiologic link between osumc.edu

adult population [Dent et al. 2005]. Owing to the the two disease states.
Jennifer W. McCallister,
high prevalence rates of both diseases, one would MD
expect many asthmatics would also have GERD. Pathogenesis Jonathan P. Parsons, MD,
MSc
However, asthmatics have been found to have a There have been several theories put forth in an The Ohio State University
much greater prevalence of GERD symptoms attempt to explain how GERD and asthma may Medical Center, Division of
Pulmonary, Allergy,
than the general population. Some studies that be linked in a causal fashion. Critical Care, and Sleep
have utilized symptoms questionnaires have Medicine, Columbus, Ohio,
USA
found nearly 80% of asthmatics may experience Asthmatic patients often have lung hyperinfla-
GERD symptoms such as heartburn, regurgita- tion. Descent of the diaphragm in the setting of
tion, and/or swallowing difficulties. [Field et al. lung hyperinflation and increased work of breath-
1996] A large Veterans Administration study of ing increases the pressure gradient between the
over 100,000 veterans found that veterans with abdomen and chest and may cause the lower
GERD were 1.15 times more likely to have esophageal sphincter (LES) to herniate into the
asthma than veterans without GERD and several chest where its barrier function is impaired
studies utilizing pH probe testing have found a [Zerbib et al. 2002; Choy and Leung, 1997].
prevalence of GERD among asthmatics of This could therefore allow more reflux of gastric
30—65% [Mastronarde et al. 2009; Leggett contents among asthmatics with hyperinflation.

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Therapeutic Advances in Respiratory Disease 5 (2)
Some asthma medications aimed at reducing
hyperinflation may promote acid reflux. Both
beta-agonists and theophylline may decrease
LES tone, which again potentially could foster
acid reflux. One study of theophylline showed
that symptoms of GERD increased by 170% in
the theophylline group compared with placebo
[Ekstrom and Tibbling, 1988]. Beta-agonists
have been shown to cause reductions of LES
tone in a dose-dependent fashion [Crowell et al.
2001]. This suggests the potential for a vicious
cycle of GERD-induced asthma symptoms
resulting in increased use of bronchodilators,
which in turn promotes more GERD.
There are also some GERD-related pathogenic
factors which could worsen asthma.
The parasympathetic nervous system, specifically
the vagus nerve, highly innervates both the
esophagus and the tracheobronchial tree and
may be a common pathogenic pathway for
GERD and asthma. In animal studies, instillation
of acid into the esophagus was shown to increase
respiratory resistance with effects ablated by
bilateral vagotomy [Mansfield et al. 1981].
In humans, instillation of acid in the esophagus
has been shown to decrease peak expiratory flow
rates and increase overall airway resistance
[Harding et al. 1995]. Both of these conse-
quences are blunted by pretreatment with atro-
pine. In contrast, others have found no
relationship between the instillation of acid and
methacholine reactivity or lung function [Araujo
et al. 2008]. Some data seem to suggest that acid
refluxed from the stomach into the esophagus
may ‘prime’ the lung to have subsequent and
more severe episodes of bronchospasm when
exposed to another trigger. Vincent and col-
leagues showed that the dose of methacholine
which caused the forced expiratory volume in
one second (FEV1) to fall by 20% (PD20) was
significantly correlated with the number of acid
reflux events as documented by pH-probe analy-
sis over a 24-hour period [Vincent et al. 1997].
The dose of methacholine required to provoke
the patients with more significant reflux tended
to be a lot lower, suggesting an increase in airway
hyper-responsiveness.
Another question raised has been whether
GERD-induced aspiration or microaspiration
could worsen asthma, as tracheal microaspiration
of acid has been found to be a very potent
144
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stimulus for bronchospasm [Jack et al. 1995]. In
addition, microaspiration may trigger broncho-
spasm indirectly by inducing chronic inflamma-
tory changes which subsequently can lead to
increased airway reactivity. Animal models have
shown that instillation of acid into the esophagus
can trigger an inflammatory cascade. One study
showed that esophageal acid led to significantly
increased levels of Substance P, a tachykinin that
leads to smooth muscle contraction and
increased vascular permeability [Hamamoto
et al. 1997]. Acid provocation has also been
shown to lead to increased lung resistance in a
dose-dependent fashion which is mediated by
release of tachykinins from peripheral nerves
[Ricciardolo et al. 2004]. Aspiration of acid may
also cause injury directly to the epithelial lining of
the upper airway which has been shown to result
in a release of cytokines and increased inflamma-
tion [Stein, 1999].
All of these data afford biologic plausibility to the
theory that asthma and medications used for
treatment may increase GERD and GERD may
subsequently induce asthma symptoms either by
direct effects on airway hyperresponsiveness or
via increases in airway inflammation. The ques-
tion then becomes is there any outcome data
demonstrating that these theories have clinical
relevance?
Relationship between treatment of GERD and
asthma outcomes
Initial studies focused on the effects of treatment
of GERD on asthma outcomes revealed inconsis-
tent results, but in general seemed to suggest an
overall improvement in some asthma symptoms
[Kiljander et al. 1999; Boeree et al. 1998; Levin
et al. 1998; Teichtahl et al. 1996; Ford et al. 1994;
Meier et al. 1994; Gustafsson et al. 1992; Larrain
et al. 1991; Ekstrom et al. 1989; Nagel et al.
1988; Goodall et al. 1981; Kjellen et al. 1981].
These data resulted in recommendations by the
National Asthma Education and Prevention
Program’s Expert Panel Report 3 (EPR-3) that
‘gastroesophageal reflux treatment may benefit
patients who have asthma and complain of fre-
quent heartburn or pyrosis, particularly those
who have frequent nighttime asthma symptoms.
Even in the absence of suggestive GERD symp-
toms, consider evaluation for GERD in patients
with poorly controlled asthma’ [Busse and
Lemanske, 2007]. However, these initial studies
all had significant limitations: the sample sizes of
the populations were small; inconsistent
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 JW McCallister, JP Parsons et al.

definitions of asthma and GERD were utilized
for inclusion; variable outcome measures were
recorded; multiple GERD treatment regimens
including histamine-2 receptor (H-2) antagonists
and proton-pump inhibitors (PPIs) were used for
relatively short durations (<3 months) in groups
of patients with varying degrees of asthma
severity.
These limitations were highlighted in a 2003 sys-
tematic review of the currently available literature
by the Cochrane Collaboration examining the
utility of GERD treatment for asthma [Gibson
et al. 2000]. The analysis included 12 random-
ized controlled trials with a combined total of 432
subjects in whom the effects of GERD therapy on
asthma outcomes were reported [Kiljander et al.
1999; Boeree et al. 1998; Levin et al. 1998;
Teichtahl et al. 1996; Ford et al. 1994; Meier
et al. 1994; Gustafsson et al. 1992; Larrain et al.
1991; Ekstrom et al. 1989; Nagel et al. 1988;
Goodall et al. 1981; Kjellen et al. 1981].
Treatment with antireflux therapy did not consis-
tently improve any one measure of pulmonary
function in patients with asthma, but some stud-
ies did report objective improvement in single
measurements of lung function such as FEV1
[Meier et al. 1994; Larrain et al. 1981], morning
peak expiratory flow rates (PEF) [Levin et al.
1998] and evening PEF [Teichtahl et al. 1996;
Goodall et al. 1981]. The variability in reporting
of asthma symptoms in the included studies pre-
vented detailed analysis of any parameter except
for nocturnal asthma symptoms which were
noted to be improved by some authors in patients
treated with histamine antagonists [Ekstrom et al.
1989; Goodall et al. 1981] or omeprazole
[Kiljander et al. 1999]. However, others failed
to show improvement in nocturnal asthma symp-
toms with GERD therapy [Boeree et al. 1998;
Ford et al. 1994; Gustafsson et al. 1992]. From
these data, the Cochrane group concluded that
‘in asthmatic subjects with gastroesophageal
reflux, there was no overall improvement in
asthma following treatment for gastroesophageal
reflux’, and the authors called upon researchers
to develop larger randomized controlled trials
using longer courses of treatment to better eval-
uate the role of antireflux therapy in these
patients [Gibson et al. 2000].
Several larger, more recent studies have been
completed which again suffered from some limi-
tations and demonstrated varying outcomes with
no definitive evidence to support or refute this
important clinical question (Table 1). Littner
and colleagues described the effects of 24 weeks
of twice daily treatment with a PPI in patients
with difficult to control asthma [Littner et al.
2005]. The study utilized a strict definition of
asthma, with a focus on participants with moder-
ate-to-severe disease as determined by degree of

Table 1. Select randomized, placebo-controlled studies of proton-pump inhibitor therapy and asthma control.
Study Number (n) GERD diagnosis PPI regimen Duration Result (asthma outcome)
Symptomatic GERD
Littner et al. [2005] 207 Patient symptoms, Lansoprazole 24 weeks Improved emotional func-
clinician diagno- 30 mg twice tional domain of asthma
sis, pH probe daily quality of life question-
optional naire, decreased
exacerbations
Kiljander et al. [2006] 770 Patient symptoms, Esomeprazole 16 weeks Improved PEF in partici-
history of abnor- 40 mg twice pants with GERD and
mal pH probe, or daily nocturnal asthma
history of esopha-
gitis on endoscopy
Kiljander et al. [2010] 961 Patient symptoms or Esomeprazole 26 weeks Improved FEV1 and
history of abnor- 40 mg once asthma-related quality
mal pH within past daily or twice of life*
3 years daily
Asymptomatic GERD
Mastronarde et al. [2009] 412 pH probe monitoring Esomeprazole 24 weeks No treatment effect
40 mg twice
daily

GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor; PEF, peak expiratory flow; FEV1, forced expiratory volume in one second.
*Limited clinical significance (see the discussion in the text).

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Therapeutic Advances in Respiratory Disease 5 (2)
airflow obstruction and documented evidence of
bronchodilator reversibility. However, the diag-
nosis of GERD was based on clinical symptoms
alone with zero of enrolled participants complet-
ing the optional confirmatory 24-hour esopha-
geal pH monitoring. In this study of 207
moderate-to-severe asthmatics with clinical
symptoms of GERD, treatment with lansoprazole
30 mg twice daily for 6 months did not improve
asthma symptoms, pulmonary function (includ-
ing PEF or FEV1), rescue albuterol use, or over-
all asthma quality of life when compared with
placebo. However, participants receiving lanso-
prazole noted an improvement in the emotional
functional domain of the asthma quality of life
questionnaire and experienced statistically signif-
icantly fewer asthma exacerbations (odds ratio
[OR] 2.9; 95% confidence interval [CI]
1.2—6.9) than those receiving placebo. A post
hoc analysis suggested that those participants
treated with more than one asthma controller
medication seemed to benefit most from lanso-
prazole therapy. However, a significant limitation
to this study is the lack of objective confirmation
of GERD and correlation with symptoms. It has
been well established that symptoms of GERD
do not correlate with direct measures of acid
reflux [Kiljander and Laitinen, 2004; Harding
et al. 2000; Sontag et al. 1990], the major factor
in suggesting a causal link between asthma and
GERD.
Kiljander and associates assessed the effects of
esomeprazole 40 mg twice daily versus placebo
for 16 weeks among 770 patients with moder-
ate-to-severe asthma [Kiljander et al. 2006].
The study included asthmatics with moderate-
to-severe asthma based on FEV1 (50—80%
predicted) and evidence of bronchodilator revers-
ibility. The presence of GERD was based primar-
ily on patient reported clinical symptoms.
Participants were classified into one of three
groups based on the presence or absence of
GERD and nocturnal respiratory symptoms
(NOC): GERD with NOC, GERD without
NOC, and NOC without GERD. Overall, there
were no improvements in daily peak expiratory
flow rate, asthma symptoms, asthma related
quality of life, or asthma exacerbations in those
asthmatics treated with esomeprazole. In the sub-
group of participants with GERD and NOC, sta-
tistically significant improvements in the morning
and evening PEF were observed in subjects who
received esomeprazole when compared with pla-
cebo, suggesting that this subgroup may benefit
146
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from PPI therapy. However, these changes in
PEF were relatively small (8.7 l/min for morning
and 10.2 l/min for evening) and may be of limited
clinical significance. Of interest, though, the
improvements in PEF were most significant in
those asthmatics receiving long-acting beta-ago-
nists. The study was limited by the short duration
of therapy for GERD and the use of patient-
reported symptoms of acid reflux as the primary
basis of diagnosis.
In a follow-up study, Kiljander and colleagues
compared the efficacy of 40 mg once daily esome-
prazole with 40 mg twice daily esomeprazole in
improving asthma control in patients with symp-
tomatic GERD [Kiljander et al. 2010]. They
included 961 patients with moderate-to-severe
asthma with demonstrated reversibility of airflow
obstruction and 1 clinically important asthma
exacerbation within the preceding 12 months
with symptomatic GERD (as determined by the
Reflux Disease Questionnaire [Shaw et al.
2001]). After 26 weeks of therapy, there was no
improvement noted in the primary endpoint of
the study, change from baseline mean morning
PEF, in either study group. In addition, no dif-
ferences were noted in use of rescue bronchodi-
lators, percentage of asthma symptom-free days,
or frequency of severe asthma exacerbations.
Treatment with esomeprazole at both doses was
associated with a statistically significant improve-
ment in FEV1 and asthma-related quality of life
throughout the study period. However, the
improvement in FEV1 was small and likely of
small clinical significance, with an increase of
0.09 l (CI 0.03—0.15; p ¼ 0.0039) or 0.12 l (CI
0.06—0.18; p < 0.0001) for esomeprazole 40 mg
once or twice daily, respectively. Significantly
more participants treated with esomeprazole
reported a significant improvement in asthma-
related quality of life than those treated with pla-
cebo (esomeprazole once daily, n ¼ 173, 61%;
p ¼ 0.016; esomeprazole twice daily, n ¼ 176,
62%; p ¼ 0.001). However, the clinical signifi-
cance of this finding remains uncertain.
Therefore, in some asthmatics with symptoms
suggestive of GERD, the available literature
suggests that there may be a small benefit of
treatment of GERD on some aspects of asthma-
related quality of life and possibly on exacerba-
tions, but no clear evidence supports objective
benefits in pulmonary function or overall
asthma control. However, one could argue that
treatment for symptomatic GERD is warranted
http://tar.sagepub.com

in patients with asthma independent of any
potential benefit on asthma outcomes if the
underlying GERD warrants treatment on its
own. The current NIH guidelines recommend
an empiric trial of GERD therapy in poorly con-
trolled asthmatics even if they do not have GERD
symptoms [Busse and Lemanske, 2007]; however
at the time of their publication, no studies had
been completed specifically to address this
unique clinical situation. Furthermore, these
guidelines were based on studies which included
participants with symptomatic GERD based pri-
marily on patient-reported clinical symptoms
rather than more objective measurements of
acid reflux such as 24-hour pH probe monitor-
ing. In these studies, no attempts to correlate epi-
sodes of reflux with asthma symptoms were
made, nor were investigators clearly able to iden-
tify those subgroups of patients who benefited
most from PPI therapy.
The American Lung Association Asthma Clinical
Research Centers conducted a multicenter, ran-
domized, placebo-controlled trial of esomepra-
zole 40 mg twice daily for 24 weeks in patients
with poorly controlled asthma and minimal or
no symptoms of (silent) gastroesophageal reflux,
using ambulatory esophageal pH monitoring to
confirm the presence or absence of gastroesoph-
ageal reflux in participants [Mastronarde et al.
2009]. Four hundred and twelve patients on
moderate or high doses of inhaled corticosteroids
with inadequately controlled asthma (defined as
either a Juniper Asthma Control Questionnaire
[JACQ] [Juniper et al. 2006] of 1.5 or higher or
the presence of more than one unscheduled
healthcare visit for asthma in the preceding
12 months) underwent pH testing and were ran-
domly assigned to treatment with esomeprazole
or placebo independent of pH study results.
Investigators and participants were blinded to
the results of the pH study and intervention.
The diagnosis of asthma was based on physician
diagnosis with either a positive methacholine
challenge test or evidence of bronchodilator
reversibility of the FEV1 with an increase of
12% after short-acting bronchodilator adminis-
tration. The primary objective of the study was to
determine whether acid suppression therapy
could improve asthma symptoms as determined
by frequency of episodes of poor asthma control
which were defined as any one of the following: a
decrease from a patient’s best morning PEF, an
unplanned healthcare visit for asthma, the need
for systemic corticosteroids for asthma treatment,
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JW McCallister, JP Parsons et al.
or an increase in the use of short-acting beta-
agonists of a least four inhalations above baseline.
After 6 months of therapy, episodes of poor
asthma control occurred with similar frequency
in the placebo and esomeprazole groups (2.3
versus 2.5 events per person-year respectively;
p ¼ 0.66). Although nighttime awakenings due
to asthma occurred on more than one occasion
in over half of the subjects, there was no signifi-
cant difference between groups. Similarly, there
was no difference with respect to lung function
(including PEF, FEV1, and methacholine
responsiveness), asthma symptoms, or asthma
related quality of life when patients treated with
esomeprazole were compared with those who
received placebo. Ambulatory pH monitoring
demonstrated acidic gastroesophageal reflux in
approximately 40% of both groups of partici-
pants, but failed to identify a subgroup of
patients that was likely to benefit from therapy
with the PPI. From these findings, Mastronarde
and colleagues concluded that the empiric use of
acid suppression in patients with poorly con-
trolled asthma but minimal or no GERD symp-
toms should not be routinely recommended
[Mastronarde et al. 2009].
To date, this is the only published trial evaluating
the effects of treatment of silent GERD on
asthma control. It is difficult to compare the
results of this study with those examining the
effects of treatment of symptomatic GERD in
asthma because those trials relied on patient-
reported symptoms. It is possible that those sub-
jectively noted symptoms were not related to acid
in the esophagus at all and, therefore, would not
be expected to change with acid suppression
therapy or be expected to alter the measured
asthma-related outcomes. Until further studies
are undertaken to objectively correlate GERD
symptoms with GERD in patients with asthma,
it remains impossible to clearly describe the
potential differences between symptomatic and
silent GERD on asthma outcomes.
The potential importance of the location of reflux
in the esophagus (proximal versus distal) has also
been considered as a potential important factor in
the clinical relationship between asthma and
GERD. In a small study (n ¼ 133) of subjects
with upper airway symptoms attributed to
GERD, dual-probe esophageal pH monitoring
demonstrated a significantly higher incidence of
nocturnal cough in those participants with acid
reflux detected at both the proximal and distal
147
Therapeutic Advances in Respiratory Disease 5 (2)
probe than in those in whom reflux was
detected at the distal probe alone [Tomonaga
et al. 2002]. While the possibility that the partic-
ipants’ nocturnal cough may have been related to
uncontrolled asthma was not specifically
addressed by the authors, the study still raises
the important issue that symptoms from proximal
GERD such as cough may mimic asthma and
may confound measurements of asthma control
in the clinical and research setting. A subgroup
(n ¼ 242) of participants in the American Lung
Association’s Study of Acid Reflux and Asthma
[Mastronarde et al. 2009] underwent dual-probe
pH esophageal monitoring [DiMango et al.
2009]. Thirty-eight percent of participants dem-
onstrated proximal GERD, but concordance
between proximal and distal GERD on pH
probe was poor. While the presence of proximal
GERD was associated with worse asthma-related
quality of life, no differences were noted in other
the asthma-related clinical outcomes measures
described above. It has been hypothesized
that nonacidic or alkali reflux may affect asthma
control parameters [Asano and Suzuki, 2009],
but, to date, this interesting theory remains
untested.
Summary and conclusions
The relationship between GERD and asthma
control remains unclear. The clinical prevalence
of the two conditions in many patients cannot be
ignored, and multiple theories highlighting plau-
sible pathogenic explanations for these associa-
tions have been described. The treatment of
symptomatic GERD in patients with asthma is
important to control the underlying GERD and
should be undertaken based upon current guide-
lines for treatment of the GERD. Currently avail-
able data have shown limited benefits of
treatment of symptomatic GERD on asthma out-
comes and no clear benefit on asthma control.
However, in a significant percentage of asth-
matics, GERD is clinically silent or associated
with only mild symptoms. Empiric treatment of
clinically silent GERD in patients with uncon-
trolled asthma does not seem to be an effective
therapy for asthma and is not supported by cur-
rent data. Instead, the clinician should focus on
other factors which can affect asthma control
such as use of adequate controller medications,
patient compliance, proper inhaler technique,
and control of other significant comorbid
conditions.
148
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Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
Conflict of interest statement
None declared.
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