Signature: Med Sci Monit, 2002; 8(3): RA64-71 WWW.MEDSCI MONIT.

COM
PMID: 11887043 Review Article

Received: 2001.06.11
Accepted: 2002.01.04 Asthma and gastroesophageal reflux in children
Published: 2002.03.11

Krystyna Wąsowska-Królikowska, Ewa Toporowska-Kowalska, Aneta Krogulska

Clinic of Pediatric Gastroenterology and Allergology, Institute of Pediatrics, Medical University of Łódź, Poland

Summary
Gastroesophageal reflux (GER) is a factor often neglected in the etiopathogenesis of asthma.
The estimated incidence of GER in asthmatic children reaches 50–60% and is higher than in
the general population. GER may accompany typical symptoms: hoarsness, sore throat, tho-
racic pain, cough or wheezing. GER may not only aggravate the course of bronchial obstruc-
tion, but may also cause it, or trigger obstruction due to other factors. Asthma and GER coin-
cidence has been acknowledged for many years. The paper presents a current review of stud-
ies concerning the relations between asthma and GER and attempts to establish, which is the
cause and which is the result. The hypotheses how GER can lead to bronchial obstruction,
and how obstruction can aggravate GER, are also presented. GER is believed to be a factor
causing obstruction by: 1. an indirect mechanism – reflex theory, 2. a direct mechanism –
reflux theory, and 3. a neuropeptide-mediated mechanism. The paper also presents diagnos-
tic methods allowing to detect GER in asthmatics. A review of recent studies concerning the
treatment of GER in asthmatics, both with pharmacological and surgical methods, is also
included. Beneficial effect of antireflux therapy on the course of asthma has been emphasized.
Therefore, antireflux therapy is recommended in all patients with concurrent asthma and
GER, irrespective of severity of clinical GER symptoms, even in those with silent GER. The
essential drugs used in the treatment of GER are proton pump inhibitors. Appropriately high
dose level and appropriately long duration of the therapy should be taken into consideration.

key words: asthma • gastroesophageal reflux • child

Full-text PDF: http://www.MedSciMonit.com/pub/vol_8/no_3/2009.pdf

File size: 89 kB
Word count: 4700
Tables: —
Figures: —
References: 45

Author’s address: Aneta Krogulska, Clinic of Pediatric Gastroenterology and Allergology, Institute of Pediatrics,
Medical University of Łódź, ul. Sporna 36/50, Łódź, Poland

RA64
Med Sci Monit, 2002; 8(3): RA64-71
BACKGROUND
Gradual increase of the incidence of asthma, as well as
aggravation of the course of the disease, was observed
during the last century. Intensive research aimed at elu-
cidation of the reasons of this phenomenon are under
way. Asthma is known to be a multifactor disease char-
acterized by bronchial hyperreactivity, mucosal constric-
tion, increased mucus production and development of
an inflammation as a result of released inflammatory
mediators.
Gastroesophageal reflux (GER) is a factor often neglected
in the etiopathogenesis of asthma. GER may not only
aggravate the course of bronchial obstruction, but may also
cause it, or trigger obstruction due to other factors [1].
On the other hand, sthma and its treatment may aggra-
vate, and even induce GER. The relations between asth-
ma and GER have been extensively investigated. How-
ever, it is still difficult to determine, which of them is the
result, and which is the cause [2–4].
Asthma and GER coincidence has been acknowledged
for a long time. As early as the 12th century, Moses Mai-
monides wrote in his treatise that horizontal position
was dangerous during dyspnea. Then, Nicholas Rosen
von Rosenstein was the first to use the term ‘stomachic
cough’ in the 18th century. In 1802, William Heberden
wrote that ‘In many people respiration becomes more
rapid and forced after meals’. In 1892, Sir William
Osler emphasized the necessity to avoid excessive eat-
ing, and Bray in 1934 – the tendency to develop
bronchial obstruction in subjects who had eaten a meal
immediately after going to bed. In turn, Kennedy sug-
gested in 1962 the possibility of influence of silent reflux
on respiratory disorders. Bronchial obstruction as a
cause of GER was first observed by Barr in 1970 [2,5].
About 200 studies concerned with the concurrence of
asthma and GER have been published to date. Howev-
er, only 18 of them can provide the basis for assessment
of the frequency of this concurrence [2]. Most studies
were aimed at elucidation of the mechanism of asthma
provocation by GER. The estimation of actual frequency
of asthma and GER concurrence is difficult because,
although there is a well-established definition of asthma,
the applied definitions of GER differ considerably, and,
what is more, the methods of its confirmetion in the
reviewed studies were different. According to many
publications, It was enough to observe characteristic
clinical symptoms to diagnose GER, in others the diag-
nosis was based on abnormal pH values in pHmetry,
inflammation of esophageal mucosa, or presence of
esophageal hiatus hernia. Moreover, the studies were
carried out in selected groups of patients, so it was diffi-
cult to estimate the actual incidence of GER in the gen-
eral population of asthmatic patients.
GER occurs both in children and in adults with the
overall incidence of ca. 8%. In asthmatics, this incidence
is higher than in the general population [4]. GER is esti-
mated to occur in 60–80% of asthmatic adults and
Wąsowska-Królikowska K et al – Asthma and gastroesophageal reflux in children
50–60% of children [2,3,6–9]. According to Tucci, reflux
is observed in 60–80% children with asthma, including
75% of asthmatic children with inappropriately con-
trolled disease [10]. According to Andze, 75% children
with asthma have GER [11]. It is estimated that 50% of
children with chronic respiratory disorders [12] and
25–30% of adults have so-called silent GER [1,13]. In
turn, 30–75% of these patients suffer from esophagitis.
Sontag reports that 40% of asthmatics have erosive
esophagitis, 58% hiatus hernia, and over 80% pathologic
GER [9,14]. GER is regarded as the third most frequent
cause of chronic cough after asthma and sinobronchial
syndrome. GER is diagnosed in 10–20% of patients
seeking doctor's advice because of chronic cough. To
sum up, mean incidence of GER in asthmatic children
RA
reaches ca. 56% and is similar to that observed in adults
[2]. If the incidence of GER concurrent with asthma is
similar to general incidence of GER among children,
the question can be asked what the size of morbidity is.
Two hypothetical answers are possible – all children
with asthma and GER carry on their disorders into
adult age (GER morbidity = 0), or some children with
asthma and GER ‘grow out’ of their diseases and GER
develops in some asthmatic adults, or conversely, some
adults with GER develop asthma. It is possible that
some children apparently cured of asthma will become
adults with asthma and GER in future [2].
According to the current views, diagnosis of gastroe-
sophageal reflux disease (GERD) may be based both on
the basis of symptoms traditionally associated with the
presence of gastroesophageal reflux and on so-called
‘atypical’ ones. The typical symptoms include heart-
burn, eructation nausea and vomiting, acid taste in the
pharynx, dysphagia. The atypical symptoms include
hoarseness, pharyngeal dryness sensation, excessive sali-
vation, pains in the neck, otalgia, sore throat, loss of
voice, sinusitis, choking, breathlessness. The possibility
of asymptomatic, so-called ‘silent’ reflux should be also
taken into consideration.
Generally, two types of reflux has been distinguished:
primary reflux due to disturbances of the so-called
reflux barrier and secondary reflux, caused by the fac-
tors associated both with gastrointestinal (inflammatory
conditions, gastroparesis, impatency) and systemic
pathology (infections, metabolic disturbances, activation
of the vomitus center in the CNS by various impulses –
visual, auditory and vagal stimuli, as well as those origi-
nating from the pharynx, gastrointestinal tract, urinary
tract or testes) [12].
A characteristic feature of reflux i8s aggravation of the
complaints after meals, alcohol consumption, in
horisontal position, on exertion and at night (due to
lower esophageal clearance than during the day).
Cough, dyspnea, wheezing belong to the respiratory
symptoms associated with gastroesophageal reflux
(RARS – reflux-associated respiratory syndrome)
[1–3,5,15]. They may occur in asthma concurrent with
gastroesophageal reflux, or as pulmonary manifesta-
tions of gastroesophageal reflux disease.
RA65
Review Article
GER should be suspected in asthmatic patients in the
following cases:
1. aggravating course of asthma or resistance to treat-
ment
2. presence of typical or atypical GER symptoms
3. aggravation of asthma during sleep, after large meals,
in horizontal position
4. onset of endogenous asthma in adult age
5. aggravation of respratory symptoms after administra-
tion of bronchodilators
Does reflux cause asthma? Does asthma cause reflux?
Do they aggravate the course of each other? Or do both
processes coincide but are not connected with each
other? We are trying to review the opinions on these
issues below.
REFLUX AS A CAUSAL FACTORS FOR ASTHMA ATTACKS
Under physiologic conditions, the respiratory tract does
not come in direct contact with the gastrointestinal con-
tent owing to the efficient function of protective mecha-
nisms, including [5]:
1. swallowing reflex
2. reflexive closing of the larynx at the moment of sud-
den esophageal dilatation
3. cough reflex
4. efficient function of the ‘antireflux barrier’
In case of GER, the above mechanisms are impaired,
which, consequently may induce bronchial obstruction.
Indirect evidence of the effect of reflux on asthma is
provided by its remission after pharmacological or sur-
gical cure of reflux [10]. Another piece of evidence for
the association of asthma with GER is remission of
chronic wheezing as a result of pharmacological or sur-
gical treatment of GER in infants, observed by Eid [16].
It cannot be, however, unequivocally assumed on the
basis of the cited studies that the respiratory symptoms
observed in the patients allowed the diagnosis of asth-
ma, although antireflux therapy led to improvement of
the patients' complaints associated with the respiratory
tract.
Ineffective esophageal motility (IEM) belongs to the
most common GERD-related esophageal function dis-
turbances. This abnormality, manifested by chronic
cough, is reported in 41% of patients with GERD and
53% of patients with concurrent GER and asthma
[5,15]. Coincidence of IEM and GER increases the risk
of respiratory disturbances because of prolonged
esophageal clearance time observed in such motility
impairment [15]. Gustafsson, investigating esophageal
motility in 55 children with mild and severe forms of
asthma, observed in 60% of them disturbances involving
decreased amplitude of peristaltic waves [17]. Another
study reported abnormal peristaltic wave propagation
with so-called secondary peristalsis present in asthmatic
patients [18].
The problem of the mechanisms leading to bronchitis,
pneumonia, pulmonary fibrosis or asthma as a result of
RA66
Med Sci Monit, 2002; 8(3): RA64-71
GER has been extensively considered. GER is currently
regarded as a potential factor inducing bronchial
smooth muscle contraction by the following mechanisms
[1–3,5,7,19–23]:
1. indirect – a reflex mechanism induced by the effect
of acid gastric content getting to the esophagus on
vagal nerve terminals in the mucous membrane
(vago-vagal reflex). Reflex theory.
2. direct – epithelial damage due to aspiration of gastric
content getting to the esophagus ‘Reflux’ theory.
3. changes in bronchial reactivity due to the effect of
neuropeptides.
Ad. 1. The esophagus and the bronchial tree are known
to have common origin from the primary alimentary
tract and common innervation by the vagal nerve.
Bronchial contraction is believed to occur in response to
a vagal reflex initiated by the stimulation of receptors
located in the esophagus by a decrease of pH and dilata-
tion of its lumen. Lodi demonstrated some hyperreac-
tivity of the vagal nerve in subjects with asthma and
GER [6].
Administration of acid into the esophagus in dogs
proved to induce an increase of bronchial resistance.
This response could be abolished by vagotomy [22].
Esophageal acid provocation (Bernstein test) in patients
with asthma also causes a decrease of MEF 25 and MEF
50 values (MEF-maximal expiratory flow, MEF 25 and
MEF 50 stand for mean air flow velocity in the middle
phase of expiration). No reactions of this type were
observed in healthy subjects and in patients with chron-
ic bronchitis [1]. After acidification of the esophagus in
asthmatic, bronchial hyperreactivity after metacholin
was also noted. Metacholin-induced bronchial hyperre-
activity is more pronounced in patients with than in
those without GER symptoms. According to Wilson,
intraesophageal administration of acid in children with
atopic asthma did not cause PEF (peak expiratory flow)
changes, but increased bronchial hyperreactivity to hist-
amine and metacholin was observed [24]. Mansfield
suggests, that induction of vagal reflex by intrae-
sophageal pH changes or increased pressure in its
lumen may cause bronchospasm in patients with GER
and asthma [22]. According to Schan, intraesophageal
administration of hydrochloric acid causes a decrease of
PEF and increased airway resistance in healthy subjects,
asthmatics with and without GER and in isolated GER,
which suggests the presence of vagal reflex [7].
Using 24h-pHmetry, Herbst demonstrated in infants
that GER was the cause of apnea, which was eliminated
by antireflux surgery and pharmacological treatment
[25].
The role of vagal reflex was confirmed by Harding, who
demonstrated that administration of atropine b oth to
healthy subjects and to asthmatics with GER prevented
bronchospasm [26}.
Med Sci Monit, 2002; 8(3): RA64-71
Harding investigated PEF and pH using a two-channel
probe during intraesophageal administration of
hydrochloric acid and did not observe the expected cor-
relation between the decrease of pH in the upper seg-
ment of the esophagus and the decrease of PEF, which
may confirm the ‘reflex theory’ [26].
The study by Gastal also seems to confirm the above
hypothesis [19]. On investigation of intraesophageal pH
with a two-channel probe, he observed, firstly, frequent
occurrence of reflux in the distal portion of the esopha-
gus in patients with asthma (44%), chronic cough (50%)
and thoracic pains (54%), and, secondly, significantly
more frequent frequent proximal reflux occurring in
patients with thoracic pains withough respiratory disor-
ders (44%), than in those with asthma (24%) or chronic
cough (11%).
Davis reports that GER-induced bronchial obstruction
requires a coincidence of various factors, such as [23]:
1. presence of gastroespohageal reflux
2. ‘acid-sensitive’ esophagus (positive Bernstein test)
3. low-threshold nocturnal sensitivity to bronchocon-
stricting stimuli.
According to Schan, bronchial obstruction due to esoph-
agus acidification does not depend on esophagitis (inde-
pendently of Bernstein test) [7]. Therefore, esophago-
pulmonary reflex associated with the vagal nerve is
believed to be present in everyone and may serve as a
physiological protective reflex, limiting airway exposure
to acid. On the other hand, in case of pathologic reflux,
it may be induced too frequently.
Ad. 2. By simultaneous pH monitoring in the trachea
and esophagus, Jack demonstrated in asthmatic falling
pH in those with GER – which was considered to pro-
vide evidence for microaspirations [27]. Aspiration of
the gastric content leads to inflammatory conditions
within the airways, which may result in bronchial hyper-
reactivity.
Food allergens present in the aspirated content sensitize
T cells of the peribronchial lymphoid tissue and induce
specific IgE production. Another exposure to the same
allergens may cause IgE-dependent mediator release
from mast cells and activation of T lymphocytes and
eosinophils, leading to the development of an inflamma-
tion in the respiratory tract. Meer points to frequent
occurrence of food allergy in patients with bronchopul-
monary dysplasia, asthma, and GER [28]. In his opin-
ion, a patient with asthma and GER should be evaluated
for food allergy.
Additionally, it has been observed that the more fre-
quent the aspirations are, the more pronounced
bronchial hyperreactivity to different stimuli becomes.
Finally, hyperreactivity develops, which does not
require the decrease of intraesophageal [2]. Other evi-
dence for the important role of microaspiration in
bronchial obstruction are the studies carried out by
Tuchman [29]. He demonstrated that acidification of
the airways in cats caused more pronounced obstruction
Wąsowska-Królikowska K et al – Asthma and gastroesophageal reflux in children
of the bronchial tree than acidification of the distal
esophagus.
Although numerous studies indicate the probability of
both reflux and reflex theory, it is currently believed
that the role of reflexive bronchospasm is more impor-
tant with respect to microaspiration [7,19,26].
Ad. 3. A stimulus damaging esophageal mucosa acti-
vates the sensory fibers leading to the CNS, but may
also activate an antidromic efferent conduction path-
way. Such an impulse may induce the release of neu-
ropeptides from peripheral sensory nerve terminals.
Numerous neuropeptides are distributed within the
autonomic nervous system at the same sites as classic
RA
neurotransmitters [6]. Neuropeptides are produced also
outside the nervous system. They play different and
opposite roles in the respiratory tract – some of them
cause contraction and other ones relaxation of the
bronchial muscles. They also regulate vascular tone and
permeability, as well as the activity of immune cells. The
neuropeptide active withing the respiratory system is
substance P, which:
– decreases the tone and increases the permeability of
blood vessels.
– modulates the activity of immunocompetent cells,
– increases bronchial smooth muscle tone,
– stimulates the release of mediators by mast cells, hista-
min, leukotriens, and chemotactic factors.
– enhances T lymphocyte proliferation and cytokine
receptor (IL 1, IL 2, IL 6) expression as well as that of
inflammatory mediators.
As a result, the reactivity of bronchial smooth muscles is
altered.
ASTHMA AS A REFLUX-INDUCING FACTOR
Asthma and its treatment may aggravate reflux by
decreasing the tone of lower esophageal sphincter and
increasing intraabdominal pressure due to the cough
reflex.
Sontag and Harper demonstrated that the pressure in
the lower esophageal sphincter (LES) in asthmatics is
lower than in healthy subjects [9,20]. Then, Mitsuhashi
sobserved in asthmatic children a positive correlation
between low LES tone and asthma attacks [30]. Reflux is
known to be aggravated by:
– decrease of LES tone due to the descent of the
diaphragm associated with the trapping of air as a
result of bronchospasm.
– gradient increase due to more negative intrathoracic
pressure as opposed to more positive intraabdominal
pressure.
The literature contains contradictory views concerning
the role of UES (upper esophageal sphincter) in the
pathogenesis of pulmonary symptoms accompanying
gastroesophageal reflux disease. According to Patti,
patients with GER and chronic lung diseases have sig-
nificantly lower pressure in UES, LES and reduced
RA67
Review Article
peristaltic amplitude both in LES and in UES, which
may favor aspiration [31].
Recent studies indicate that GER may be the cause ra-
ther than the result of obstruction.
According to Sontag, the neverending debate whether
asthma is the result of reflux or vice versa leads to the
conclusion that it is not important to establish whether
GER occurs in asthmatics, or whether pulmonary symp-
toms are observed in subjects with GER. Instead, find-
ing the methods of management allowing to curb these
disorders is important [2]. The author also suggests that
the asthma – GER relation is based on feedback, where
reflux aggravates the course of asthma and asthma, in
turn, enhances reflux.
POTENTIAL GER PROMOTERS
Provocation of a GER-related asthma episode is favored
by many coincident factors, previously described by
Davis [23]. In turn, all the factors favoring GER will also
favor the above relation [23,30]. Such factors include:
– bronchodilators
– horizontal position
– overeating
– hiatus hernia.
Bronchodilators
Earlier studies, including those carried out by Mitsuha-
shi, indicated decreasing the LES tone by bronchodila-
tors [30]. Then, Sontag observed that reflux parameters
were identical in the groups of asthmatic patients treat-
ed and not treated with bronchodilators [9]. Thus, these
studies clearly indicate that GER is an important, intrin-
sic abnormality in asthma rather than the result of LES
tone decrease by drugs [2,9].
According to current views, administration of such
preparations does not contribute significantly to the
development of pathologic GER [1]. Assuming that the
reflux symptoms are favored by transient LES relax-
ation and not its low baseline tone, there are no impor-
tant gastrological contraindications for the use of these
drugs [2,18].
Systemic administration of theophylline and beta-2-
mimetics decrease the LES tone and stimulate
hydrochloric acid secretion [5,30]. Inhalant beta-2-
mimetics, as well as inhalant and systemic GCS do not
alter the LES tone [1]. According to Hubert, theo-
phylline does not enhance GER [32], whereas other
investigators observed a 24% increase of GER after
theophylline and over 100% increase of GER-related
symptoms.
Because of the possible effect of drugs, despite some of
the findings to the contrary, they were usually discon-
tinued before the investigations of the relationship
between asthma and reflux: theophylline and oral beta-
2-mimetics 72 h before the tests, short-acting beta-2-
RA68
Med Sci Monit, 2002; 8(3): RA64-71
mimetics and ipratropium bromide 8 hours before,
antireflux agents 72 h, and omeprazole 7 days [6].
In patients with sthma and GER, the reflux symptoms
were observed more frequently and were characterized
by longer duration of reflux episodes than in GERD
patients [1].
Horizontal position
Frequency of nocturnal wheezing episodes or cough is
higher in asthmatic patients with GER than in those
without GER. Additionally it has been observed that,
independently of bronchodilator therapy, night reflux is
more pronounced in patients with asthma than in non-
asthmatic patients [9].
Diet
After abundant meals, when the stomach is full, hori-
zontal position increases the risk of GER and obstruc-
tion, probably due to aspiration [30]. Similarly, the com-
position of diet significantly influences the LES function
(decreasing its tone after products rich in fat, protein,
beverages).
Hiatus hernia
Hiatus hernia seems to be the most important factor
inducing esophagitis. It is observed with 7-fold higher
frequency in patients with asthma and esophagitis than
in those without esophagitis [14]. It still remains unclear
whether the presence of hiatus hernia and esophagitis
are the indicators of asthma induced by, or coincident
with reflux.
DIAGNOSTICS OF GER IN ASTHMATIC PATIENTS
GERD should be suspected as the cause for asthmatic
symptoms in patients with:
• asthma and typical or atypical symptoms of GERD;
• asthma and negative family history, no signs of atopy,
normal IgE and eosinophil level, signs of treatment-
resistant asthma, aggravation of symptoms after theo-
phylline.
In order to establish the correlation of the respiratory
disorder with the presence of pathologic reflux, various
research methods of different clinical value are used,
including [1,2,21]:
1. methods documenting the presence of pathologic
GER
• 24-hour pHmetry [9,21,33]. Many investigators employ
pHmetry both to confirm and to exclude the relation-
ship between GER and asthma. z astmà. Confirmation
of reflux by pHmetry can only suggest its role as a
causal factor for wheezing. It is not, however, direct
evidence for the correlation between intraesophageal
pH decrease and clinical manifestation in the form of
respiratory disorders [2]. Documenting such correla-
tion would require a technique involving simultane-
Med Sci Monit, 2002; 8(3): RA64-71
ous evaluation of the respiratory function and reflux
recording. Therefore, Wiener proposed an index for
assessment whether the respiratory symptoms are relat-
ed to GER; if respiratory symptoms coincide with GER
in less than 25% or more than 75% of time, the causal
relationship seems to be low or high, respectively. The
index, however, does not account for the total number
of respiratory episodes. Consequently, a significant
causal relationship may be demonstrated both in a child
who had one respiratory episode coincident with one
episode of GER and in a child who had 50 respiratory
episodes coincident with GER [34].
RARS occurring during GER or within 10 min after it
seem to point to GER as a factor provoking asthmatic
symptoms [35]. According to Sontag, RARS symptoms
are observed during GER in 15.5% of patients, after
GER in 9.9% before GER in 20.4% and are unrelated to
GER in 54.2% of cases [35].
• endoscopy with collection of bioptate for histopatho-
logic investigation;
• scintigraphy with isotope-labeled test meal;
• radiological imaging in order to exclude hiatus hernia.
2. methods confirming the role of gastric content
microaspiration into the lungs
• sputum analysis for lipid-laden alveolar macrophages
– lipids present in the lungs due to aspiration. Low
practical value because of very low specificity of the
test [36]
• lung scintigraphy after technetium-labeled meal –
aspiration of gastric content into the lungs – low sensi-
tivity [33].
The diagnostic methods used include also acidification
of the esophagus to confirm the role of the vagal nerve
in the development of bronchial obstruction [24] and
patient questionnaire assessing GER correlation with
pulmonary symptoms.
None of these methods allows to establish which
patients have GER-induced asthma, and in whom asth-
ma is accompanied by GER.
Yellon reports that esophageal biopsy is a quick and safe
method of GER diagnostics in children with reflux
symptoms [37]. On endoscopy, Harding observed
esophagitis in 60–72% of asthmatic children [38] and
Sontag in 42% of asthmatic adults [9].
EFFECTS OF GER TREATMENT IN ASTHMATIC PATIENTS
Although the causal relationship between asthma and
GER often remains unclear, the fact of marked
improvement after surgical or pharmacological treat-
ment of GER is evident [2,10]. Unfortunately, most of
these studies were not controlled and did not assess the
pulmonary function before and after the surgery [2].
Wąsowska-Królikowska K et al – Asthma and gastroesophageal reflux in children
It is known that GER can cause dyspnea in healthy sub-
jects, which disappears after antireflux therapy.
The treatment of asthmatic patients with reflux utilizes
standard drugs such as neutralizing agents, H2 block-
ers, proton pump inhibitors, prokinetic drugs or
surgery [39]. It should be remembered that in GERD
H2 blocker doses should be 2-4-fold higher than the
standard ones, and the treatment should be continued
for 3 months [1].
Many studies indicate that neutralizing agents and H2
blockers, even used at standard doses, may cause in
asthmatics with GERD either improvement of both
reflux and pulmonary symptoms, or improvement of
RA
reflux symptoms only, or no improvement [20,32,40].
Godall demonstrated by DBPCS (Double Blind Placebo
Control Study) method a clinical improvement in asth-
matic patients treated with cimethidine. Such an effect
was not observed after placebo treatment [41]. Harper
observed statistically significant improvement of FEV1
(forced expiratory volume in one sec) after ranitidine
treatment [20].
It currently seems that prokinetics and proton pump
inhibitors (PPI) are more effective. Harding demon-
strated alleviation of asthmatic symptoms in 62% of the
examined patients with parallel PEF increase and
reduction of drug consumption among patients treated
with Omeprazole [8].
In view of chronic character of the disease, considering
the use of prokinetics one should always take into
account the potential benefits and risk associated with
their long-term administration. Tucci demonstrated a
beneficial effect of such treatment in children with poor-
ly controlled asthma [10].
The possibility of surgical treatment (classic or laparo-
scopic fundoplication) should be taken into considera-
tion in patients demonstrating improvement after phar-
macological treatment [1]. Four independent studies of
children with GER and pulmonary symptoms who
underwent surgery, although involving no comparison
with controls, demonstrated evident improvement mea-
sured by disappearance of respiratory symptoms in
70–100% of cases [2,16]. However, it is difficult to estab-
lish the diagnosis of asthma in infants if recurrent aspi-
rations and pneumonias are primary symptoms, but
surgical elimination of GER evidently leads to marked
improvement in most children.
Sontag demonstrated in 5-year follow-up a significant
improvement of pulmonary function, reduction of drug
consumption and disappearance of asthmatic symptoms
only in patients who had undergone surgery in compar-
ison with pharmacologically treated patients [42]. It is
worth emphasizing that marked improvement due to
the surgery results not only from the prevention of acid
reflux, but also of any other reflux, e. g. biliary [2].
In contrast, Field reports that the effectiveness of long-
term pharmacotherapy is comparable with that of surgi-
RA69
Review Article
cal treatment. He observed reduction of GERD symp-
toms in 90% of patients after surgery, alleviation of asth-
matic symptoms in 79%, reduction of antiasthmatic
drug consumption in 88%, and in 22% improvement of
spirometric parameters [3].
After antireflux surgery, Harding observed remission of
asthmatic symptoms in 34% of patients, clinical
improvement in 42% and no improvement in 24% [38].
Then, Sontag demonstrated, after 5-year follow-up,
improvement of clinical asthmatic symptoms in 74.9% of
patients subjected to antireflux surgery, 9% of those
treated with Ranitidine, 4% receiving placebo, and
aggravation in 47.8% of patients receiving placebo,
36.2% of those using H2 blockers and only in 6.2% of
patients after the surgery. Inprovement of PEF and pos-
sibility of GCS discontinuation was observed in 33% of
operated patients, only in 11% of patients treated with
Ranitidine, leczonych Ranitydynà and none of the con-
trol group [42]. Contrary to Field's findings, Sontag
demonstrates much better effects of antireflux surgery
as compared with pharmacotherapy [42]. Bittner
emphasizes that laparoscopic fundoplication may prove
not only to be a very effective, but also a cheap method
of treatment [43]. As a result of longitudinal studies car-
ried out in a group of 243 children, Snajdauf observed
remission of GER symptoms in 83% and recommended
Nissen fundoplication as the most effective surgical
method [44].
Although the correlation between asthma and reflux has
been clearly confirmed, the background of this correla-
tion still remains controversial. GER symptoms occur in
asthmatic patients 4-5-fold more frequently than in
other subjects. Many asthmatics experiencing RARS
(reflux-associated respiratory symptoms) use beta-ago-
nists during symptomatic GER.
Antireflux therapy, although it alleviates the symptoms
of asthma and reduces drug consumption, paradoxically
does not improve pulmonary function in objective
assessment [3,7,45]. There are attempts to explain this
by the positive effect of antireflux therapy attainable
only in some patients with asthma and GER, despite the
lack of data concerning the factors predisposing for
cure. The situation is compared to another aspect asso-
ciated with asthma, i. e. that not all asthmatics react to
exertion, tobacco smoke or cold air [3].
The elucidation of this paradox is a challenge for future
research, similarly as selection of patients likely to
respond positively to treatment.
If antireflux therapy allows to control asthma better, it
should be instituted in all patients, irrespective of the
severity of GER symptoms, and even in those with silent
reflux. It should be remembered that esophagitis devel-
oped in the course of GER may result from reflux of
bile acids and trypsin. Then the patients will not
respond to treatment inhibiting hydrochloric acid secre-
tion.
RA70
Med Sci Monit, 2002; 8(3): RA64-71
CONCLUSIONS
1. Most of asthmatic patients have GER and it is a well-
documented fact that GER plays an important role in
patients with asthma.
2. Despite sophisticated methods and advanced diag-
nostic techniques, no tests allowing the differentia-
tion of patients with GER-induced asthma or vice
versa or the identifications of patients likely to
respond well to antireflux therapy are available.
3. It is difficult to establish the cause-and-effect relation-
ship between asthma and GER.
4. Even positive results of diagnostic tests such as sputum
analysis or scintigraphy do not allow to establish the
cause or result and predict the course of the disease.
5. Ambulatory pHmetry can suggest, but not confirm,
the presence of GER-induced asthma and clinical
decision cannot rely on findings concerning the
esoophageal content ph only.
6. Provocations during PPI medication are recom-
mended to assess subjective or objective improve-
ment, the doses must be sufficiently high and the
duration of treatment sufficiently long (3 months) to
observe even slight improvement, both objective and
subjective.
7. Antireflux surgery should be taken into considera-
tion if GER is regarded as the cause of asthma exa-
cerbations.
8. Positive response to PPI treatment does not necessar-
ily predict good response to antireflux surgery, and,
conversely, poor response to PPI does not predict
poor response to surgical treatment.
9. The ultimate antireflux therapy, which has proved
effective over time, involves:
• avoiding eating later than 3 hours before going to
bed;
• avoiding abundant and fatty meals, which delay
gastric clearance;
• raising the head of the bed;
• H2 blockers, e.g. Ranitidine 300 mg b.i.d.;
• PPI;
• antireflux surgery.
Positive results of GER treatment in asthmatic pa-
tients lead to:
• reduced frequency of hospitalizations;
• reduced pulmonary morbidity and mortality;
• reduced demand for pulmonary drugs;
• lower absenteeism due to diseases;
• reduced frequency of visits at the doctor's;
• lower incidence of GCS-related complications.
REFERENCES:
1. Simpson WG: Gastroesophageal reflux disease and asthma. Arch
Intern Med, 1995; 155: 798-803
Med Sci Monit, 2002; 8(3): RA64-71
2. Sontag SJ: Gastroesophageal reflux disease and asthma. J Clin Gas-
troenterol, 2000; 30(3 Suppl): 9-30
3. Field SK, Sutherland LR: Does medical antireflux therapy improve
asthma in asthmatics with gastroesophageal reflux? Chest, 1998;
114: 275-283
4. Sontag SJ: Why do the published data fail to clarify the relationship
between gastroesophageal reflux and asthma? Am. J Med, 2000;
6(suppl 4a): 159-169
5. Chazan R: Asthma and gastroesophageal reflux (in Polish). Alergia
Astma Immunologia, 2000; 5(suppl 2): 93-96
6. Lodi U, Harding SM, Coghlan C et al: Autonomic regulation in
asthmatics with gastroesophageal reflux, Chest, 1997; 111: 65-70
7. Schan CA, Harding SM, Haile JM et al: Gastroesophageal reflux-
induced bronchoconstriction. Chest, 1994; 106: 731-37
8. Harding SM, Schan CA, Guzzo MR et al: Asthma and GERD: Acid
suppression with Omeprazole improves asthma in selected patients.
Gastroenterology, 1993; 104a-95
9. Sontag SJ, O’Connel S, Khandelwal S: Most asthmatics have GER
with or without bronchodilator therapy, Gastroenterol, 1990; 99:
613-20
10. Tucci F, Resti M, Fontana R et al: Gastroesophageal reflux and
bronchial asthma: prevalence and effect of cisapride therapy. J
Pediatr Gastroenterol Nutr, 1993; 17:265-270
11. Andze GO, Brandt ML, St Vil D et al: Diagnosis and treatment of
gastroesophageal reflux in 500 children with respiratory symptoms:
the value of pH monitoring, J Pediatr Surg, 1991; 26: 295-300
12. Vandeplas Y: Asthma and gastroesophageal reflux. Gastrol Inter
Ped Nutrition, 1997; 24: 89-99
13. Harding SM, Guzzo MR, Richter JE: 24-h esophageal pH testing in
asthmatics. Respiratory symptom correlation with esophageal acid
events. Chest, 1999; 115: 654-9
14. Sontag SJ, Schnell TG, Miller TQ et al: Prevalence of oesophagitis
in asthmatics, Gut, 1992; 33: 872-876
15. Fouad YM, Katz PO, Hatlebakk JG, Castell DO: Ineffective
Esophageal Motility: The most common motility abnormality in
patients with GERD-associated respiratory symptoms, Am J Gas-
troenterol, 1999; 94(6): 1464-1467
16. Eid NS, Shepherd RW, Thomson MA: Persistent wheezing and gas-
troesophageal reflux in infants. Pediatr Pulmonol, 1994; 18(1): 39-44
17. Gustafsson PM, Kjellman N, Tibbling L: Oesophageal function and
symptoms in moderate and severe asthma. Acta Paediatr Scand,
1986; 75: 729-736
18. Fyderek K: Gastroesophageal reflux disease and other abnormali-
ties of esophageal motility in children Cracow, Medycyna Praktycz-
na, 1998; 21-70
19. Gastal OL, Castell JA, Castell DO: Frequency and site of gastroe-
sophageal reflux in patients with chest symptoms. Chest, 1994; 106:
1793-96
20. Harper PC, Bergner A, Kaye MD: Antireflux treatment for asthma:
improvement in patients with associated gastroesophageal reflux.
Arch Intern Med, 1987; 147: 56-60
21. Fonkalsrud EW, Ament ME: Gastroesophageal reflux in childhood,
Curr Probl Surg, 1996; 33(1): 1-70
22. Mansfield LE, Hameister HH, Spanlding HS: The role of the vagus
nerve in airway narrowing caused by intraesophageal hydrochloric
acid provocation and esophageal distention, Ann Alergy, 1981; 47:
431-46
23. Davis RS, Larsen GL, Grunstein MM: Respiratory response to
intraesophageal acid infusion in asthmatic children during sleep, J
Allergy Clin Immunol, 1983; 72: 393-8
24. Wilson NM, Charette L, Thomson AH, Silverman M: Gastroe-
sophageal reflux and childhood asthma: the acid test. Thorax,
1985; 40: 592-597
Wąsowska-Królikowska K et al – Asthma and gastroesophageal reflux in children
25. Herbst JJ, Minton SD, Book LS: Gastroesophageal reflux causing
respiratory distress and apnea in newborn infants. J. Pediatr, 1979;
95: 763-8
26. Harding SM, Schan CA, Guzzo MR et al: Gastroesophageal reflux-
induced bronchoconstriction. Chest, 1995; 108: 1220-1227
27. Jack CI, Calverley DM, Donnelly RJ et al: Simultaneous tracheal
and oesophageal pH measurements in asthmatic patients with gas-
trooesophageal reflux, Thorax, 1995; 50: 201-204
28. Meer S, Groothuis JR, Harbeck R et al: The potential role of gas-
troesophageal reflux in the pathogenesis of food-induced wheez-
ing, Pediatr Allergy Immunol, 1996; 7(4): 167-70
29. Tuchman DN, Boyle JT, Pack AL: Comparison of airway responses
following tracheal or oesophageal acidification in the cat. Gastroen-
terology, 1984; 87: 872-81
30. Mitsuhashi M, Tomomasa T, TokuyamaK et al: The evaluation of
gastroesophageal reflux symptoms in patients with bronchial asth-
ma. Ann Allergy, 1985; 54: 317-20
31. Patti MG, Debas HT, Pellegrini CA: Esophageal manometry and
RA
24-hour pH monitoring in the diagnosis of pulmonary aspiration
secondary to gastroesophageal reflux. Am J Surg, 1992; 163: 401-
406
32. Hubert D, Gaudric M, Guerre J: Effect of theophylline on gastroe-
sophageal reflux in patients with asthma. J Allergy Clin Immunol,
1988; 81: 1168-1174
33. Reich SB, Earley WC, Rawin TH, Goodman M: Evaluation of gas-
tropulmonary aspiration of gastric contents in asthmatics with gas-
troesophageal reflux, Ann Allergy, 1979; 42: 306-308
34. Wiener GJ, Richter JE, Cooper JB et al: The symptom index: a
clinically important parameter of ambulatory 24-hour esophageal
pH monitoring, Am J Gastroenterol, 1988; 83: 358-61
35. Sontag S, O’Connell S, Khandelwal S et al: Does wheezing occur in
association with an episode of gastroesophageal reflux? Gastroen-
terology, 1989; 96: A482
36. Nussbaum E, Maggi JC, Mathis R, Galant SP: Association of lipid-
laden alveolar macrophages and gastroesophageal reflux in chil-
dren, J Pediatr, 1987; 110: 190-4
37. Yellon RF, Coticchia J, Dixit S: Esophageal biopsy for the diagnosis
of gastroesophageal reflux associated otolaryngologic problems in
children, Am J Med, 2000; 6, 108(Suppl 4a): 131-138
38. Harding SM, Richter JE: Gastroesophageal reflux disease and asth-
ma. Semin Gastrointest Dis, 1992: 3: 139-150
39. Wallner G, Misiuna P: Principles of conservative menegement of
gastroesophageal reflux disease, Gastroenterol Pol, 1997; 4(2): 193-
200
40. Gustaffson PM, Kjellman NTM, Tibbling L: A trial of ranitidine in
asthmatic children and adolescents with or without pathological
gastroesophageal reflux. Eur Respir J, 1992; 5: 201-206
41. Goodall RJR, Earis JE, Cooper DN et al: Relationship between
asthma and gastroesophageal reflux, Thorax, 1981; 36: 116-21
42. Sontag SJ, O’Connel S, Khandelwal S: Antireflux surgery in asth-
matics with reflux improves pulmonary symptoms and function.
Gastroenterology, 1990; 98(2): A128
43. Bittner HB, Pappa TN: Laparoscopic approaches to symptomatic
gastroesophageal reflux, Semin Gastrointest Dis, 1994; 5: 113-119
44. Snajdauf J, Vyhnanek M, Vondrakova L et al: Late results after
surgical treatment of gastroesophageal reflux in chilhood, Rozhl
Chir, 1997; 76(8): 370-3
45. Sheikh S, Stephen T, Howell L, Eid N:Gastroesophageal reflux in
infants with wheezing, Pediatr Pulmonol, 1999; 28(3): 181-186
RA71
Index Copernicus
Global Scientific Information Systems
for Scientists by Scientists

www. IndexCopernicus.com

EVALUATION & BENCHMARKING

PROFILED INFORMATION
NETWORKING & COOPERATION
VIRTUAL RESEARCH GROUPS
GRANTS
PATENTS
CLINICAL TRIALS
JOBS
STRATEGIC & FINANCIAL DECISIONS

Index IC Scientists IC Virtual Research Groups [VRG]

Copernicus
integrates
IC Journal Master List
Scientific literature database,
including abstracts, full text,
and journal ranking.
Instructions for authors
available from selected journals.
Effective search tool for
collaborators worldwide.
Provides easy global
networking for scientists.
C.V.'s and dossiers on selected
scientists available. Increase
your professional visibility.
IC Patents
Provides information on patent
registration process, patent offices
and other legal issues. Provides
links to companies that may want
to license or purchase a patent.
Web-based complete research
environment which enables researchers
to work on one project from distant
locations. VRG provides:
customizable
 and individually
self-tailored electronic research
protocols and data capture tools,
statistical
 analysis and report
creation tools,
profiled information on literature,

publications, grants and patents
related to the research project,
administration
 tools.

IC Conferences
Effective search tool for
worldwide medical conferences
and local meetings.
IC Grant Awareness
Need grant assistance?
Step-by-step information on
how to apply for a grant. Provides
a list of grant institutions and
their requirements.
IC Lab & Clinical Trial Register
Provides list of on-going laboratory
or clinical trials, including
research summaries and calls for
co-investigators.