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

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JW McCallister, JP Parsons et al.

definitions of asthma and GERD were utilized of asthma symptoms in the included studies pre-
for inclusion; variable outcome measures were vented detailed analysis of any parameter except
recorded; multiple GERD treatment regimens for nocturnal asthma symptoms which were
including histamine-2 receptor (H-2) antagonists noted to be improved by some authors in patients
and proton-pump inhibitors (PPIs) were used for treated with histamine antagonists [Ekstrom et al.
relatively short durations (<3 months) in groups 1989; Goodall et al. 1981] or omeprazole
of patients with varying degrees of asthma [Kiljander et al. 1999]. However, others failed
severity. to show improvement in nocturnal asthma symp-
toms with GERD therapy [Boeree et al. 1998;
These limitations were highlighted in a 2003 sys- Ford et al. 1994; Gustafsson et al. 1992]. From
tematic review of the currently available literature these data, the Cochrane group concluded that
by the Cochrane Collaboration examining the ‘in asthmatic subjects with gastroesophageal
utility of GERD treatment for asthma [Gibson reflux, there was no overall improvement in
et al. 2000]. The analysis included 12 random- asthma following treatment for gastroesophageal
ized controlled trials with a combined total of 432 reflux’, and the authors called upon researchers
subjects in whom the effects of GERD therapy on to develop larger randomized controlled trials
asthma outcomes were reported [Kiljander et al. using longer courses of treatment to better eval-
1999; Boeree et al. 1998; Levin et al. 1998; uate the role of antireflux therapy in these
Teichtahl et al. 1996; Ford et al. 1994; Meier patients [Gibson et al. 2000].
et al. 1994; Gustafsson et al. 1992; Larrain et al.
1991; Ekstrom et al. 1989; Nagel et al. 1988; Several larger, more recent studies have been
Goodall et al. 1981; Kjellen et al. 1981]. completed which again suffered from some limi-
Treatment with antireflux therapy did not consis- tations and demonstrated varying outcomes with
tently improve any one measure of pulmonary no definitive evidence to support or refute this
function in patients with asthma, but some stud- important clinical question (Table 1). Littner
ies did report objective improvement in single and colleagues described the effects of 24 weeks
measurements of lung function such as FEV1 of twice daily treatment with a PPI in patients
[Meier et al. 1994; Larrain et al. 1981], morning with difficult to control asthma [Littner et al.
peak expiratory flow rates (PEF) [Levin et al. 2005]. The study utilized a strict definition of
1998] and evening PEF [Teichtahl et al. 1996; asthma, with a focus on participants with moder-
Goodall et al. 1981]. The variability in reporting 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 from PPI therapy. However, these changes in
bronchodilator reversibility. However, the diag- PEF were relatively small (8.7 l/min for morning
nosis of GERD was based on clinical symptoms and 10.2 l/min for evening) and may be of limited
alone with zero of enrolled participants complet- clinical significance. Of interest, though, the
ing the optional confirmatory 24-hour esopha- improvements in PEF were most significant in
geal pH monitoring. In this study of 207 those asthmatics receiving long-acting beta-ago-
moderate-to-severe asthmatics with clinical nists. The study was limited by the short duration
symptoms of GERD, treatment with lansoprazole of therapy for GERD and the use of patient-
30 mg twice daily for 6 months did not improve reported symptoms of acid reflux as the primary
asthma symptoms, pulmonary function (includ- basis of diagnosis.
ing PEF or FEV1), rescue albuterol use, or over-
all asthma quality of life when compared with In a follow-up study, Kiljander and colleagues
placebo. However, participants receiving lanso- compared the efficacy of 40 mg once daily esome-
prazole noted an improvement in the emotional prazole with 40 mg twice daily esomeprazole in
functional domain of the asthma quality of life improving asthma control in patients with symp-
questionnaire and experienced statistically signif- tomatic GERD [Kiljander et al. 2010]. They
icantly fewer asthma exacerbations (odds ratio included 961 patients with moderate-to-severe
[OR] 2.9; 95% confidence interval [CI] asthma with demonstrated reversibility of airflow
1.2—6.9) than those receiving placebo. A post obstruction and 1 clinically important asthma
hoc analysis suggested that those participants exacerbation within the preceding 12 months
treated with more than one asthma controller with symptomatic GERD (as determined by the
medication seemed to benefit most from lanso- Reflux Disease Questionnaire [Shaw et al.
prazole therapy. However, a significant limitation 2001]). After 26 weeks of therapy, there was no
to this study is the lack of objective confirmation improvement noted in the primary endpoint of
of GERD and correlation with symptoms. It has the study, change from baseline mean morning
been well established that symptoms of GERD PEF, in either study group. In addition, no dif-
do not correlate with direct measures of acid ferences were noted in use of rescue bronchodi-
reflux [Kiljander and Laitinen, 2004; Harding lators, percentage of asthma symptom-free days,
et al. 2000; Sontag et al. 1990], the major factor or frequency of severe asthma exacerbations.
in suggesting a causal link between asthma and Treatment with esomeprazole at both doses was
GERD. associated with a statistically significant improve-
ment in FEV1 and asthma-related quality of life
Kiljander and associates assessed the effects of throughout the study period. However, the
esomeprazole 40 mg twice daily versus placebo improvement in FEV1 was small and likely of
for 16 weeks among 770 patients with moder- small clinical significance, with an increase of
ate-to-severe asthma [Kiljander et al. 2006]. 0.09 l (CI 0.03—0.15; p ¼ 0.0039) or 0.12 l (CI
The study included asthmatics with moderate- 0.06—0.18; p < 0.0001) for esomeprazole 40 mg
to-severe asthma based on FEV1 (50—80% once or twice daily, respectively. Significantly
predicted) and evidence of bronchodilator revers- more participants treated with esomeprazole
ibility. The presence of GERD was based primar- reported a significant improvement in asthma-
ily on patient reported clinical symptoms. related quality of life than those treated with pla-
Participants were classified into one of three cebo (esomeprazole once daily, n ¼ 173, 61%;
groups based on the presence or absence of p ¼ 0.016; esomeprazole twice daily, n ¼ 176,
GERD and nocturnal respiratory symptoms 62%; p ¼ 0.001). However, the clinical signifi-
(NOC): GERD with NOC, GERD without cance of this finding remains uncertain.
NOC, and NOC without GERD. Overall, there
were no improvements in daily peak expiratory Therefore, in some asthmatics with symptoms
flow rate, asthma symptoms, asthma related suggestive of GERD, the available literature
quality of life, or asthma exacerbations in those suggests that there may be a small benefit of
asthmatics treated with esomeprazole. In the sub- treatment of GERD on some aspects of asthma-
group of participants with GERD and NOC, sta- related quality of life and possibly on exacerba-
tistically significant improvements in the morning tions, but no clear evidence supports objective
and evening PEF were observed in subjects who benefits in pulmonary function or overall
received esomeprazole when compared with pla- asthma control. However, one could argue that
cebo, suggesting that this subgroup may benefit treatment for symptomatic GERD is warranted

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JW McCallister, JP Parsons et al.

in patients with asthma independent of any or an increase in the use of short-acting beta-
potential benefit on asthma outcomes if the agonists of a least four inhalations above baseline.
underlying GERD warrants treatment on its After 6 months of therapy, episodes of poor
own. The current NIH guidelines recommend asthma control occurred with similar frequency
an empiric trial of GERD therapy in poorly con- in the placebo and esomeprazole groups (2.3
trolled asthmatics even if they do not have GERD versus 2.5 events per person-year respectively;
symptoms [Busse and Lemanske, 2007]; however p ¼ 0.66). Although nighttime awakenings due
at the time of their publication, no studies had to asthma occurred on more than one occasion
been completed specifically to address this in over half of the subjects, there was no signifi-
unique clinical situation. Furthermore, these cant difference between groups. Similarly, there
guidelines were based on studies which included was no difference with respect to lung function
participants with symptomatic GERD based pri- (including PEF, FEV1, and methacholine
marily on patient-reported clinical symptoms responsiveness), asthma symptoms, or asthma
rather than more objective measurements of related quality of life when patients treated with
acid reflux such as 24-hour pH probe monitor- esomeprazole were compared with those who
ing. In these studies, no attempts to correlate epi- received placebo. Ambulatory pH monitoring
sodes of reflux with asthma symptoms were demonstrated acidic gastroesophageal reflux in
made, nor were investigators clearly able to iden- approximately 40% of both groups of partici-
tify those subgroups of patients who benefited pants, but failed to identify a subgroup of
most from PPI therapy. patients that was likely to benefit from therapy
with the PPI. From these findings, Mastronarde
The American Lung Association Asthma Clinical and colleagues concluded that the empiric use of
Research Centers conducted a multicenter, ran- acid suppression in patients with poorly con-
domized, placebo-controlled trial of esomepra- trolled asthma but minimal or no GERD symp-
zole 40 mg twice daily for 24 weeks in patients toms should not be routinely recommended
with poorly controlled asthma and minimal or [Mastronarde et al. 2009].
no symptoms of (silent) gastroesophageal reflux,
using ambulatory esophageal pH monitoring to To date, this is the only published trial evaluating
confirm the presence or absence of gastroesoph- the effects of treatment of silent GERD on
ageal reflux in participants [Mastronarde et al. asthma control. It is difficult to compare the
2009]. Four hundred and twelve patients on results of this study with those examining the
moderate or high doses of inhaled corticosteroids effects of treatment of symptomatic GERD in
with inadequately controlled asthma (defined as asthma because those trials relied on patient-
either a Juniper Asthma Control Questionnaire reported symptoms. It is possible that those sub-
[JACQ] [Juniper et al. 2006] of 1.5 or higher or jectively noted symptoms were not related to acid
the presence of more than one unscheduled in the esophagus at all and, therefore, would not
healthcare visit for asthma in the preceding be expected to change with acid suppression
12 months) underwent pH testing and were ran- therapy or be expected to alter the measured
domly assigned to treatment with esomeprazole asthma-related outcomes. Until further studies
or placebo independent of pH study results. are undertaken to objectively correlate GERD
Investigators and participants were blinded to symptoms with GERD in patients with asthma,
the results of the pH study and intervention. it remains impossible to clearly describe the
The diagnosis of asthma was based on physician potential differences between symptomatic and
diagnosis with either a positive methacholine silent GERD on asthma outcomes.
challenge test or evidence of bronchodilator
reversibility of the FEV1 with an increase of The potential importance of the location of reflux
12% after short-acting bronchodilator adminis- in the esophagus (proximal versus distal) has also
tration. The primary objective of the study was to been considered as a potential important factor in
determine whether acid suppression therapy the clinical relationship between asthma and
could improve asthma symptoms as determined GERD. In a small study (n ¼ 133) of subjects
by frequency of episodes of poor asthma control with upper airway symptoms attributed to
which were defined as any one of the following: a GERD, dual-probe esophageal pH monitoring
decrease from a patient’s best morning PEF, an demonstrated a significantly higher incidence of
unplanned healthcare visit for asthma, the need nocturnal cough in those participants with acid
for systemic corticosteroids for asthma treatment, reflux detected at both the proximal and distal

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Therapeutic Advances in Respiratory Disease 5 (2)

probe than in those in whom reflux was Funding


detected at the distal probe alone [Tomonaga This research received no specific grant from any
et al. 2002]. While the possibility that the partic- funding agency in the public, commercial, or not-
ipants’ nocturnal cough may have been related to for-profit sectors.
uncontrolled asthma was not specifically
addressed by the authors, the study still raises
the important issue that symptoms from proximal Conflict of interest statement
GERD such as cough may mimic asthma and None declared.
may confound measurements of asthma control
in the clinical and research setting. A subgroup
(n ¼ 242) of participants in the American Lung References
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