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VOLUME 108 . No.4 . AUGUST 2017
350 MINERVA MEDICA August 2017
allergen or irritant exposure, change in weath-
er, or viral respiratory infections.1
Clinical manifestations may be silent for
weeks or months, but sometimes the trend
may be interposed by episodic exacerbations
of asthma, sometimes life-threatening. The
features of asthma usually persist, even when
symptoms are absent or lung function is nor-
mal, but may be responsive to appropriate
treatment.1
Among factors triggering asthma, several
studies have focused on the possible associa-
Asthma is a chronic respiratory disease,
usually associated with airway hyper-re-
sponsiveness to direct or indirect stimuli, and
with chronic airway inammation, affecting
1-18% of the general population. This condi-
tion is characterized by the presence of vari-
able expiratory airow limitation and intermit-
tent symptoms, including wheeze, shortness of
breath, chest tightness and/or cough. Symp-
toms and airow limitation characteristically
vary within and between individuals over time
and are triggered by factors such as exercise,
REVIEW
Asthma and gastroesophageal reux disease:
a multidisciplinary point of view
Paolo SOLIDORO 1, Filippo PATRUCCO 1 *, Sharmila FAGOONEE 2 , Rinaldo PELLICANO 3
1Division of Pulmonology, Cardiothoracic and Vascular Department, AOU Città della Salute e della Scienza
di Torino, Turin, Italy; 2 Institute for Biostructures and Bioimages (CNR) c/o Molecular Biotechnology Center,
University of Turin, Turin, Italy; 3Unit of Gastroenterology, Molinette Hospital, Turin, Italy
*Corresponding author: Filippo Patrucco, C.so Bramante 88/90, Città della Salute e della Scienza, Turin, Italy.
E-mail: lippo_patrucco@hotmail.it
Anno: 2017
Mese: August
Volume: 108
No: 4
Rivista: Minerva Medica
Cod Rivista: Minerva Med
Lavoro: 5181-MM
titolo breve: ASTHMA AND GASTROESOPHAGEAL REFLUX DISEASE
primo autore: SOLIDORO
pagine: 350-6
citazione: Minerva Med 2017;108:350-6
ABSTRACT
Asthma and gastroesophageal reux (GORD) are widespread and potentially coexisting diseases. Incidence and preva-
lence of concomitant asthma and GORD are highly variable among studies. This is mainly due to the heterogeneity of
study designs. To explain a potential link, some pathophysiological anomaly has been proposed such as the altered pres-
sure gradient between thorax and abdomen, the parasympathetic reex, the heightened bronchial reactivity and chemical
effects of microaspired gastric juice. An accurate diagnosis of asthma and GORD is pivotal in order to lead effective
treatment and to reach a signicant positive outcome, in terms of quality of life and respiratory function amelioration.
Gastroenterological evaluation of GORD includes the empiric proton pump-inhibitors (PPIs) trial, the esophageal pH
monitoring and endoscopic evaluation. Besides spirometric investigations, pulmonologist have more specic examens
such as bronchoalveolar lavage and exhaled breath condensate. Actually, international recommendations regarding the
management of asthma suggest the assessment of potential comorbidities, including the presence of GORD, mostly in
children, only in patients with normal pulmonary functional tests with frequent respiratory symptoms, and in case of un-
controlled asthma. Symptomatic gastro-esophageal reux patients should be treated, but those with uncontrolled asthma
should not be treated with anti-reux drugs unless they are symptomatic for reux. This review explores the state of the
art about the pathogenesis and the management of the relationship between asthma and GORD.
(Cite this article as: Solidoro P, Patrucco F, Fagoonee S, Pellicano R. Asthma and gastroesophageal re ux disease: a multidis-Solidoro P, Patrucco F, Fagoonee S, Pellicano R. Asthma and gastroesophageal reux disease: a multidis-
ciplinary point of view. Minerva Med 2017;108:350-6. DOI: 10.23736/S0026-4806.17.05181-3)
Key words: Asthma - Gastroesophageal reux - Esophagitis - Respiration disorders.
Minerva Medica 2017 August;108(4):350-6
DOI: 10.23736/S0026-4806.17.05181-3
© 2017 EDIZIONI MINERVA MEDICA
Online version at http://www.minervamedica.it
ASTHMA AND GASTROESOPHAGEAL REFLUX DISEASE SOLIDORO
Vol. 108 - No. 4 MINERVA MEDICA 351
ly involved in the pathogenesis of esophageal
acid-induced bronchoconstriction: vagally me-
diated reex, heightened bronchial reactivity,
and microaspiration of gastric juice.
For the demonstration of the rst mecha-
nism, authors provided the infusion of acid in
esophagi of normal control patients, asthmatics
with GORD and asthmatics without GORD;
esophageal acid caused a decrease in peak ex-
piratory ow rate and an increase in specic
airway resistance in asthmatics with GORD,
which did not improve after acid clearance;11
asthmatics patients had also a partial response
after infusion of vagolytics, suggesting a role
of parasympathetic system.
The bronchial reactivity was studied com-
paring results of methacholine tests of asth-
matics with GORD and normal control sub-
jects. Authors found that the dose for induce
a response was lower when esophageal acid
was infused versus normal saline solution,
and this response was abolished when atro-
pine pre-medication was performed. This sug-
gested that GORD could aggravate asthma by
increasing bronchomotor responsiveness to
other stimuli.12
Microaspiration role has been investigated
performing simultaneous tracheal and esopha-
geal pH testing in patients with severe asthma.
Authors found that peak expiratory ow rate
had higher decrease when a concomitant drop
of pH was present. Episodes of tracheal mi-
croaspiration were associated with signicant
deterioration in pulmonary function.13
In summary, there is a parasympathetic va-
gally mediated reex present so that the acid
in the esophagus causes bronchoconstriction;
however, if microaspiration is present, there is
further augmentation of this bronchoconstric-
tor response.
A critical aspect is that the studies about the
effects of acid perfusion of the esophagus in
case of asthma were designed to maximize the
likelihood that the effects on pulmonary func-
tion would be identied. The wide majority of
studies described small changes in one or two
of the more sensitive and less specic ow-
volume loop or resistance parameters,14 with a
probably low clinical signicance.
tion between this pulmonary disease and gas-
troesophageal reux disease (GORD), with
conicting conclusions and failing to clarify a
potential cause-effect interaction generally due
to their heterogeneity.2-4
Asthma and GORD: basic principles
Both asthma and GORD are listed among
the most prevalent diagnosed chronic condi-
tions in Western Countries.5
The belief that GORD could trigger or
worsen asthma (in a context of several extra-
esophageal manifestations) originated from
the observation that asthmatic patients often
have GORD and that esophageal acidication
promotes increasing of airway resistances.6, 7
However a lot of critical issues persist and im-
pede to clarify this relationship.
There are 4 points of discussion in investi-
gating the relationship between asthma and
gastroesophageal reux: 1) frequently, studies
did not characterize asthma, both in terms of
spirometric diagnosis and classication of its
severity; 2) inaccurate denitions of GORD; 3)
inability of current methods to identify not only
the different types of GORD (acid, slightly acid,
and alkaline) but also their magnitude; 4) lack
of well-established criteria for determining the
value of a diagnosis of asymptomatic GORD.8
Actually, international recommendations
regarding the management of asthma, suggest
the assessment of comorbidities, including the
presence of GORD, mostly in children, in pa-
tients with normal pulmonary functional tests
with frequent respiratory symptoms, and in
case of uncontrolled asthma.1, 3
Pathogenesis
There is a pathophysiological bidirectional
link between asthma and GORD.9 On one side
the altered respiratory physiology, in asthma
patients, may predispose to a pathological pat-
tern of gastro-esophageal reux. In this con-
text, there is an increased pressure gradient
between the thorax and abdominal cavity and
this promotes gastro-esophageal reux.10 On
the other side three mechanisms are potential-
SOLIDORO ASTHMA AND GASTROESOPHAGEAL REFLUX DISEASE
352 MINERVA MEDICA August 2017
GORD in nocturnal asthma. For this reason
International guidelines recommend that pa-
tients who present a difcult to control asthma
should be investigated for GORD.3, 20, 21 Ad-
ditionally, a cross-sectional study assessing
over 2600 persons concluded that those with
GORD had signicantly more nocturnal asth-
ma symptoms than those without.22 However, a
randomized, placebo-controlled, double-blind
trial, demonstrated that even in those patients
with a esophageal pH monitoring positive for
GORD, a trial with PPIs did not improve asth-
ma control.23
Prevalence and incidence
The prevalence of both concomitant condi-
tions, reported in literature, is extremely vari-
able and depends on the criteria used to dene
GORD and the population studied.24, 25 A sys-
tematic review on GORD symptom assessment
in asthmatics provided a realistic estimate of
the strength and direction of the association
between GORD and asthma in adults. In pa-
tients with asthma, the prevalence of abnormal
esophageal pH, esophagitis and hiatal hernia
were 50.9%, 37.3% and 51.2% respectively.
The prevalence of asthmatics with GORD was
4.6% but this increases to 12.3% when weekly
heartburn and/or acid regurgitation were in-
cluded in evaluation. The nal odds ratio was
2.27 (95% CI: 1.8-2.8).26
The incidence was evaluated in two large
retrospective studies. The rst demonstrated
that incidence rate of hospitalization for asth-
ma in patients who had a previous hospitaliza-
tion for hernia or esophagitis was 2.6 cases per
1000 person/year.27 The second described an
incidence rate of new asthma diagnosis among
patients suffering from GORD of 6.0 cases per
1000 person/years.28
These studies suggest a signicant associa-
tion between GORD and asthma. The preva-
lence of GORD symptoms in asthmatics and
the prevalence of asthmatics in patients with
GORD is generally higher than controls. How-
ever, the majority of studies performed in
this eld are cross-sectional or case-control
and they could not give us a clear indication
Rather than promoting asthma, GORD
might facilitate the triggering of asthma in-
volving other irritant factors. One of these
could be cough and increased respiratory ef-
fort accompanying asthma; this could facilitate
GORD increasing pressure gradient across the
lower esophageal sphincter (LES).15 Pulmo-
nary hyperination could affect the relation-
ship between the low resistance portion of
diaphragm and the gastroesophageal junction
compromising LES function too.16
Another potential factor inuencing the ap-
parent strict relationship between bronchial
tree and LES is the role played by relaxing ef-
fect of β2-agonists on bronchial smooth muscle
for asthma treatment. The effects of inhaled β2-
agonists on LES function are not so clear. One
study demonstrated that oral β2-agonist therapy
decreases LES tone. This mechanism could be
signicant with inhalers’ devices because part
of the drug dose is swallowed. Authors have
shown that inhaled albuterol therapy reduced
LES basal tone and contractile amplitudes in
the smooth muscle of esophageal body in a
dose-dependent manner, increasing esopha-
geal acidication in susceptible patients. This
could lead to further bronchoconstriction and
persistence of asthmatic symptoms triggering
a vicious cycle.17
Bronchial hyper-responsiveness (BHR) is
the relative ease of bronchi to constrict in re-
sponse of physical or chemical stimuli such as
methacholine. It is assumed that patients with
BHR, without respiratory symptoms, may be
in a latent phase of asthma that may become
clinically evident over the course of life.18 The
association between reux and asymptomatic
BHR (hyper-responsiveness without asthma
symptoms) has been sparked off, promoting
discussions about the cause-and-effect relation-
ship between asthma and GORD.19 Bagnato et
al. found that 36% of patients with GORD and
without respiratory symptoms had BHR sug-
gesting that GORD was associated with the in-
crease in asymptomatic BHR.18 Similar results
were found by Lapa et al. with a prevalence of
BHR of 50% in adults with GORD, compared
with 27% in the control group.8
Some study suggested a role played by
ASTHMA AND GASTROESOPHAGEAL REFLUX DISEASE SOLIDORO
Vol. 108 - No. 4 MINERVA MEDICA 353
antisecretory therapy. In this latter case it has
been suggested that symptoms may be due to
reux having pH≥4.0 (i.e. non-acid reux), a
type of reux that is difcult to identify with
conventional pH-metry. Hence, it has been
introduced a new technique named intralumi-
nal impedance depending on changes in resis-
tance to alternating current (i.e. impedance)
between two metal electrodes (i.e. impedance
measuring segment) produced by the presence
of bolus inside the esophageal lumen. Elec-
tric conductivity (the opposite of resistance
or impedance) is directly related to the ionic
concentration of the intraluminal content. En-
doscopy is superior to radiology to identify
erosive esophagitis and allows the grading of
the severity of lesions.
Laryngopharynx examination provides di-
agnostic information about symptoms and may
reveal signs of reux. It is performed with a
exible laryngoscope and the most common
ndings of reux being erythema, posterior
commissure hypertrophy, granulomas, vocal
cord dysfunction, pseudosulcus, edema, ven-
tricular obliteration, erythematous mucosa in
the nasopharynx and red mucosa of the lingual
tonsil.31
Bronchoalveolar lavage (BAL) is an inva-
sive bronchoscopic technique for the sampling
of lung epithelial lining uid. It is performed
inserting a bronchoscope through the bron-
chial tree, where it is wedged to occlude the
airway. Saline is introduced through the op-
erating channel of the bronchoscope and re-
covered for the examination. Direct proof of
aspiration requires the recovery of substances
from the lungs that are produced in the gas-
trointestinal tract, such as pepsin and bile
acids.32 However, the detection of pepsin on
BAL may not necessarily be an abnormal nd-
ing because also healthy individuals aspirate
nasopharyngeal secretions during sleep due to
drop of the upper esophageal sphincter tone.
Nevertheless, in case of bronchial asthma the
nding of pepsin in the brocholaveolar uid
has been shown in 100% of cases in a recent
study.33 The microaspiration of bile acids from
duodenal gastroesophageal reux and their
pathogenic potential to induce severe lung
of the temporal sequence of these conditions.
The severity-response relation for the evalu-
ation of casual association was inconsistent
among studies but tended to a positive corre-
lation when the increased severity of GORD
was associated with an increased prevalence
of asthma (considering increased frequency of
symptoms and severity of esophagitis).26
Diagnosis
In patients with conrmed asthma, GORD
should be considered as a possible cause of a
dry cough. Guidelines suggest an assessment
of comorbidities in patients with uncontrolled
asthma for GORD, however there is no value
in screening (evidence A).1 A prompt diagno-
sis of GORD in patients with asthma is crucial
for the management of lung disease, improv-
ing quality of life and lung function.
The main strategies involved in the inves-
tigation of this potential relationship are de-
scribed below. From a gastroenterological
point of view the 3 potential approaches are
the empiric proton pump-inhibitors (PPIs) tri-
al, the esophageal pH monitoring and endos-
copy.29, 30
A rapid symptomatic response to PPIs,
in patients with a presumptive diagnosis of
GORD, is commonly considered to validate
the diagnosis (the so-called “PPIs test”). How-
ever, the accuracy of a symptomatic response
to PPIs compared with objective measures of
GORD (such as ambulatory pH monitoring)
is unclear. Studies addressing this issue have
produced variable estimates of test accuracy.
Since its introduction ambulatory, esophageal
pH monitoring is the current “gold standard”
for GORD testing, a method based on detec-
tion of changes in content in the esophageal
lumen. Monitoring of esophageal pH allows
not only the detection of acid exposure but
also the assessment of the relationship between
acid reuxate and symptoms. It is useful to test
patients with typical or atypical reux symp-
toms who did not respond to empirical therapy
with a PPI, and for assessment of the level
of acid suppression in patients with refractory
symptoms or esophagitis despite appropriate
SOLIDORO ASTHMA AND GASTROESOPHAGEAL REFLUX DISEASE
354 MINERVA MEDICA August 2017
asthma (most of whom with GORD), but no
effect on asthma outcomes.47 Benets of PPIs
in asthmatics seem to be limited to those pa-
tients affected by symptomatic reux and night
respiratory symptoms.48
Severe asthma is dened as asthma that re-
quires treatment with high dose ICS plus a sec-
ond controller and/or systemic corticosteroids
to prevent it from becoming ‘‘uncontrolled’’ or
that remains ‘‘uncontrolled’’ despite this ther-
apy.49, 50 Symptoms originating from GORD
may mask those due to asthma. The role of
GORD treatment in patients with severe asth-
ma is not clear but International guidelines
suggest that GORD should be treated in order
to minimize its potential effects. In a recent
study, Yii et al. have shown in 177 problematic
asthma patients, that gastro-esophageal reux
was a risk of severe exacerbation. Hence, it
was included in a clinical risk score to accu-
rately identify patients at risk for future fre-
quent severe exacerbations.51
One of the potential effects of severe asth-
ma treatment on GORD symptoms may be
played by oral corticosteroids. Strickland et
al. noted in healthy subjects that 1 month of
treatment with 20 mg/day of prednisolone had
an increased stimulation of gastric acid secre-
tion that could promote GORD.52 Lazenby et
al. evaluated the role of oral prednisone in pa-
tients with stable moderate persistent asthma:
they found an increased esophageal acid con-
tact times at pH esophageal testing, not cor-
related with respiratory functional parameters,
nor with LES or upper esophageal sphincter
(UES) pressure, peristaltic contractions, trans-
diaphragmatic pressure gradient, or diaphrag-
matic pinch pressure. Thus, the mechanism for
the increase of esophageal acid contact times
remains unclear.53
Conclusions
In addition to the strength of evidence
on relationship between gastroesophageal
acid reux and asthma, the spectrum of un-
certainty encompasses other aspects of the
problem. The paradoxical observations that
asthma symptoms but not pulmonary function
damage was suggested in animal studies and
some clinical studies of rare diseases.34, 35
Exhaled breath condensate (EBC) is the
breath water vapor that has been condensed,
typically via cooling using a collection de-
vice (commonly to 4 °C or sub-zero tempera-
tures).31, 36 Pepsin has been found in EBC of
patients with clinical suspect of GORD associ-
ated with cough.37 EBC pH decreases in case
of active inammation of airways such as in
asthmatic exacerbations.38
Treatment of asthmatic patients with
GORD: pulmonologist point of view
The cornerstones of asthma treatment are
inhaled corticosteroids (ICS) and β2-agonists.
The treatment with regular daily dose of ICS
is associated to a reduction of asthma symp-
toms, asthma-related exacerbations, hospi-
talization and death.39-44 International recom-
mendations suggested their usage in STEP 1
asthma treatment as alternative to short acting
β2-agonists, and alone or in association with
short and long acting β2-agonists (respectively
SABA and LABA) in STEP 2, 3, 4 and 5.1 The
fraction of ICS that is deposited in the mouth
during inhalation will be swallowed, and oral
bioavailability is determined by its absorption
from the gastrointestinal tract and the degree
of rst-pass metabolism in the liver.45
Due to their rapid effect SABA are used
in all steps of asthma treatment, to reduce
symptoms.1 Adding LABA to ICS provides
additional improvements in symptoms and
lung function with a reduced risk of exacerba-
tions.46 Potential effects of inhaled short and
long acting β2-agonists have been previously
described.
In literature there are no studies that inves-
tigate the effect of swallowed ICS on develop-
ment or worsen of GORD.
International recommendations suggest that
symptomatic gastroesophageal reux should
be treated, but patients with uncontrolled
asthma should not be treated with anti-reux
drugs unless they are symptomatic for reux.1
A review showed a small signicant benet of
PPIs on peak expiratory ow of patient with
ASTHMA AND GASTROESOPHAGEAL REFLUX DISEASE SOLIDORO
Vol. 108 - No. 4 MINERVA MEDICA 355
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Conicts of interest.—The authors certify that there is no conict of interest with any nancial organization regarding the material
discussed in the manuscript.
Article rst published online: April 4, 2017.
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