RESPIRATORY MANIFESTATIONS OF GASTROESOPHAGEAL REFLUX IN CHILDREN

Fernando Maria de Benedictis,1 Andrew Bush2

1
Salesi Children’s Hospital Foundation, Ancona, Italy
2
Department of Paediatric Respiratory Medicine, Royal Brampton Hospital, and National Heart and Lung
Institute, Imperial School of Medicine, London, UK

Word count: 2556

Key words: Gastroesophageal reflux, Asthma, Cough, Laryngitis

Contributors
FMdB wrote the initial draft of the manuscript. Both authors participated in the critical revision for
intellectual content and accepted the final version of the manuscript.

Declaration of interests
None declared.
AB was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and
Hare field NHS Foundation Trust and Imperial College, London.

Correspondence to:
Fernando Maria de Benedictis, MD
Salesi Children’s Hospital Foundation
11, via Corridoni, I-60123 Ancona, Italy
Tel: ++39 071 5962234
Fax ++39 071 5962234
Email: pediatria@fmdebenedictis.it

1
Abstract
Gastrooesophageal reflux disease (GORD) is a complex problem in children. Suspected respiratory
manifestations of GORD, such as asthma, chronic cough and laryngitis, are commonly encountered in the
pediatric practice, but continue to be entities with more questions than answers. The accuracy of
diagnostic tests (ie, pH- or pH-impedance monitoring, laryngoscopy, endoscopy) for patients with
suspected extraesophageal manifestations of GORD is suboptimal and therefore whether there is a causal
relationship between these conditions remains largely undetermined. An empiric trial of proton pump
inhibitors can help individual children with undiagnosed respiratory symptoms and suspicion of GORD, but
the response to therapy is unpredictable, and in any case what may be being observed is spontaneous
improvement. Furthermore, the safety of these agents has been called into question. Poor response to
anti-reflux therapy is an important trigger to search for non-gastroesophageal reflux causes for patients’
symptoms. Evidence for the assessment of children with suspected extraesophageal manifestations of
GORD is scanty and longitudinal studies with long-term follow-up are urgently required.

2
Gastrooesophageal reflux (GOR), the intermittent ascent of gastric acid and/or non-acid contents into the
esophagus, is a normal physiological process, which is common, and may be harmless or pathological.
Gastrooesophageal reflux disease (GORD) is present when reflux of acid/non-acid contents causes
symptoms and/or complications,1 which may be oesophageal (vomiting, dysphagia) and extraesophageal
(respiratory, otolaryngological, neurological, haematological – iron deficiency anemia, not discussed
further). However, the lack of objective standards has led to non-evidence based practice including over-
medication. The expense of managing patients with suspected extraoesophageal reflux symptoms has been
estimated as over 5 times that of patients with symptoms typical of GORD.2
Extraesophageal manifestations of GORD in adults but not children have been recently reviewed.3,4,5,6 Here
we review the clinical presentation of respiratory reflux manifestations in children, and the current
recommendations on diagnosis and treatment. GORD respiratory manifestations include asthma, cough
and laryngopharyngitis. Aspiration pneumonia is not discussed.
A literature search identified articles with the Medical Subject Heading (MeSH) and free-text terms
(“reflux”, “esophageal”, “extraesophageal”, “asthma”, “cough”, “laryngopharyngitis”). Searching included
the Cochrane library, Medline (PubMed) and Embase (Scopus), filtered by study type (reviews, randomised
controlled trials and other types of experimental research) and by age range (0–18 years). No date limits
were applied. We also consulted reference lists in evidence-based reviews and our personal archives.

Reflux related asthma

The possible relationships between reflux and respiratory symptoms are complex. Asthma may lead to
reflux, and reflux could exacerbate asthma or cause asthma-like symptoms. The two may coexist, with
reflux being an irrelevant finding.7,8 Finally, the association may be an example of Berkson’s fallacy. Just
because reflux is demonstrated in a child with asthma does not mean treatment of reflux is either
necessary or desirable.
Many studies have reported an association between asthma and GORD. In an unselected birth cohort,
heartburn and acid regurgitation symptoms were significantly associated with asthma (Odd Ratio, OR, 3.2),
wheeze (OR, 3.5) and nocturnal cough (OR, 4.3). Persistent wheezing, asthma, and airway
hyperresponsiveness were associated with a significantly increased risk of heartburn and acid regurgitation
in adult life.9 In controlled studies, the pooled OR for the association between GORD and asthma in children
was 5.6.10 However, symptoms of asthma are difficult to distinguish from those of GORD.11 Furthermore,
symptoms are not reliable for a GORD diagnosis especially in young children.12, 13 Whether "silent' reflux
worsens asthma is even more controversial. There is no evidence of worse "silent" reflux in asthma
compared with controls, and reflux may occur independent of respiratory symptoms or alteration in
pulmonary function in asthma.14
The reported prevalence of GORD in children with asthma varies widely (from 19.6% to 80.0%). The
differences are significantly affected by diagnostic criteria for GORD (symptoms versus esophageal pH
monitoring), the severity of asthma and the study design (prospective versus retrospective).
The potential pathways of the relationships between asthma and GOR are shown in table 1,15,16,17,18 but
which is important is unknown. Obese asthmatic children had seven times higher odds of reporting GOR
symptoms than lean children. Paradoxically, worse GOR symptoms were associated with better lung
function, suggesting misattribution of GOR symptoms to asthma in obese children.19 Taken together, these
data suggest that GOR neither causes nor results from asthma.

The role of anti-GOR treatment

3
GORD is described as a comorbidity in severe asthma, and untreated GORD has been postulated to be the
cause of inadequate asthma control despite intensive treatment.20 Observational studies suggested that
treatment with proton pump inhibitors (PPIs) was beneficial,21 leading to inappropriate prescribing
Furthermore, the safety of these agents has recently been called into question.22 A systematic review of 12
randomized placebo-controlled trials reported that GORD treatment was ineffective in improving
respiratory symptoms, lung function or the use of asthma medications in uncontrolled asthma.23 This
review suggested that some subgroups may unpredictably respond to antireflux therapy. Importantly, trials
that are not double blind must be discounted in conditions like asthma and GORD which fluctuate
spontaneously.
Placebo-controlled studies in adults with documented GOR reported some slightly improved asthma
outcomes, but only in patients who were symptomatic.24,25 In 38 children with uncontrolled asthma and
symptomatic GER omepraxole did not improve asthma outcomes.26 In A large study on school-age children
with poorly controlled asthma and asymptomatic GER showed that the addition of lansoprazole to anti-
asthma medications for 24 weeks did not improve outcomes but was associated with increased adverse
events,13 irrespective of whether the pH study was positive.13 There are no large controlled trials of PPIs in
asthmatic children with symptomatic GORD, and it is unknown if treatment benefits outweigh risks.
We cannot identify any subgroup of asthmatics who may benefit from anti-GOR treatment, if indeed such
exist. Exhaled breath condensate pH did not predict response to lansoprazole treatment.27 Theoretically,
patients with a clear association of gastrointestinal and respiratory symptoms may benefit, but this
hypothesis is unproven, and any treatment trials should be focused with clearly defined and objective end-
points.

The role of nonacid reflux

The ineffectiveness of acid-suppressive treatments led to the hypothesis that GOR can exert its effects
through mechanisms other than acidic refluxate (although the alternative, more plausible hypothesis is that
reflux is irrelevant!). Acid suppression can change acid reflux to non-acid reflux, thus persisting reflux may
still produce extraesophageal symptoms.
Animal studies have demonstrated that tissue injury may be initiated by gastric or duodenal contents
(pepsinogen, trypsin, pancreatic enzymes, and bile acids/salts), even if pH is not acid.28 Experimental data
suggest that gastric contents from patients prescribed acid suppressive therapy can still provoke a
significant inflammatory reaction from human bronchial epithelial cells.29 Pepsin can induce secretion of
inflammatory mediators in hypopharyngeal tissues under non-acidic conditions, and inhibition may prevent
at least some of these changes.30
Although more reflux events are detected if combined multichannel intraluminal impedance and pH (MII-
pH) monitoring —a technique that can detect non-acid reflux— is used, there is no evidence that these
cause asthma symptoms,31,32. The improvement of extraesophageal symptoms in patients refractory to
medical treatment with laparoscopic fundoplication suggests that reflux may have some role, a placebo
effect of surgery cannot be excluded.33

Recommendations
The Problematic Severe Asthma in Childhood Initiative group recommended that GORD should be excluded
when asthma is poorly controlled on maximal medical therapy,34 but the document is not evidence based.
If there are no reflux symptoms, PPIs should not be prescribed. If symptomatic reflux is present, a 3-month
therapeutic trial with PPIs may be reasonable, and medication should be titrated down if symptoms

4
improve.35 Surgery is currently the anti-reflux procedure of choice in patients with persistent or severe
respiratory symptoms refractory to medical treatment. In a recent systematic review, fundoplication was
effective in improving asthma outcomes in children, but conclusions are limited by patient heterogeneity
and the absence of a sham operated control group.36

Reflux related cough

Cough is common in childhood; most often the child is normal. Pathological cough may be due to a number
of different conditions. Reflux related cough can theoretically be caused by direct irritation of the
tracheobronchial tree after aspiration of gastric contents into the airway, or by stimulation of the
oesophageal-bronchial neural cough reflex.37 Pressure gradient changes between the abdominal and
thoracic cavities during the act of coughing may also lead to a cycle of cough and reflux.
The largest study systematically investigating children with chronic cough in a hospital setting showed that
the ‘‘big three’’ causes of adult chronic cough (asthma, GERD, and upper airway disease) are uncommon in
children.38 GORD accounted for less than 10% of diagnoses. In a unique study involving multiple disciplines
for evaluating children with chronic cough, reflux and asthma were present in nearly half the patients and a
quarter had multiple underlying conditions, although again, causality cannot be inferred.39
The diagnosis of reflux related cough may be challenging, as many children do not exhibit typical reflux
symptoms. Empiric therapy with anti-GOR drugs is limited by the large placebo effect Acid reflux in a child
with chronic cough does not necessarily mean causality. A recent study showed that nearly 90% of cough
spells in children did not correspond with a reflux event documented by pH probe.40 Weakly acid and non-
acid reflux has been proposed as causal. There was a temporal relationship between acid or weakly acidic
reflux and cough in only 15% of the episodes in adults,41 thus suggesting that aspiration and vagally
mediated cough reflex are relevant only in a minority. The presence of an intrinsic abnormality of the cough
reflex (chronic sensory neuropathic cough),42 or a reduction in cough threshold related to the cumulated
effect of repeated oesophageal acid exposures43 have been proposed as alternative mechanisms for adults.
Indeed, higher cough sensitivity following acid perfusion into the distal esophagus was found in patients
with GORD and chronic cough than in those with GORD and no cough.44 Whether these mechanisms are
active in children with chronic cough is unknown.
To draw inferences on causality between cough and reflux, investigators have combined esophageal (or
pharyngo-esophageal) MII-pH monitoring with a method of statistical analysis known as symptom
association probability (SAP). SAP analysis means conducting a statistical test of association between reflux
events (measured by the intraluminal pH or MII-pH monitoring) and cough (which is usually self-reported).
If a cough event is recorded within 2 minutes of a reflux event, then the two are considered associated. A
Borrelli et al.45 reported that only 16 out of 45 children with unexplained chronic cough had a positive SAP,
and asymptomatic and non-acid GOR may be important. As underreporting of symptoms may lead to false
negative results, manometry was used for precise cough recognition in 26 children with chronic
unexplained cough: only 6 out of 10 with positive SAP using manometry had a positive SAP using the event
marker.46 In another study in 20 children, 94% of all coughs were detected by intraesophageal pressure
recording, while only 48% of cough episodes were reported by patients/parents.47 These studies confirm
that parental and patient symptom recording in children is unreliable, and objective recording should be
gold standard.
A recent meta-analysis that included 19 studies (13 in adults, 6 in children) concluded that PPIs are not
efficacious for cough associated with GORD symptoms in young children and in adults, and should
therefore not be used; there are insufficient data in older children to draw any valid conclusion.48 These
studies are biased by possible enrolment of subjects with cough due to other causes, use of different
outcomes for evaluation of cough, and the large placebo effect. Most patients with chronic cough do not
5
benefit from acid inhibitory treatment alone suggesting that factors other than the acid reflux are
important, or reflux is irrelevant.

Recommendations
The BTS guidelines state that in otherwise well children with non-specific cough, empirical
gastroesophageal reflux therapy is unlikely to be beneficial and is generally not recommended. Children
with chronic cough and typical symptoms of GORD should undergo medical treatment— dietary, lifestyle
modifications, and acid suppression therapy.37 Here we suggest that a three-stage therapeutic trial should
be completed before diagnosing reflux related cough: 1) clear-cut response to a 4-8 week treatment with
PPI; 2) relapse on stopping medication; 3) new response to recommencing medication, with weaning down
therapy as appropriate to the child’s symptoms. MII-pH monitoring should be reserved for those with
refractory symptoms and those considered for antireflux surgery.
The role of surgical treatment of reflux related cough is hampered by the difficulty of performing controlled
trials. Most studies in adults reported success rates of 65% to 74%, but a placebo effect cannot be
excluded. Antireflux surgery should be considered in children who are refractory to maximal medical
therapy and who have positive (acid or non-acid reflux) MII-pH monitoring.49 Since the demonstration of
reflux in a child with chronic cough does not prove causality, alternative causes need to be carefully
excluded before recommending surgery.

Reflux related laryngopharyngitis

The reflux of either gastric acid or refluxate into the larynx and/or oropharynx has been claimed to be
responsible for a large spectrum of non-specific clinical manifestations, commonly called laryngopharyngeal
reflux disease (LPRD).50 Manifestations such as laryngeal edema, laryngomalacia, subglottic stenosis, vocal
cord granulomas/nodules are the province of otolaryngologists and will not be discussed here.
There is no a standard criterion for diagnosing LPRD. There are anecdotal claims of response to GORD
therapy, but there is a high (about 40%) placebo effect. Visual examination of the larynx as a diagnostic tool
for respiratory manifestations of GORD is non-specific and poorly reproducible. A recent study in children
with chronic cough undergoing direct laryngoscopy, bronchoscopy, esophagogastroscopy, and pH-MII
testing found that the Reflux Finding Score, a validated 8-items visual score for airway inflammation
(subglottic edema, ventricular obliteration, erythema/hyperemia, vocal fold edema, diffuse laryngeal
edema, posterior commissure hypertrophy, granuloma/granulation tissue, thick endolaryngeal mucus) did
not identify pathologic GOR.51 The main role of laryngoscopy is to exclude other pathologies rather than
help to prescribe anti-GOR therapies.52 Combining the Reflux Symptom Index and the Reflux Finding Score -
which incorporates both laryngeal symptoms and laryngoscopic findings - improved the diagnostic yield in a
randomized placebo-controlled trial in adults with symptoms and signs associated with LPRD.53
Unfortunately, here are no studies in children.

Recommendations
Otolaryngologists usually recommend evaluating adults with suspected LPRD with both the Reflux
Symptom Index and the Reflux Finding Score. If they are positive, treatment with PPIs is recommended.54
LPRD is an undefined clinical entity in childhood. Many of the symptoms attributed to LPRD in adults are
non-specific or caused by other conditions in children. Laryngoscopy should be reserved in chidren to
exclude specific pathologies. In the absence of placebo-controlled, double-blind randomised controlled
trials, reflux treatment for supposed LPRD in children cannot be recommended.
6
Conclusions
There is a possible association between GORD and asthma or chronic cough, but there is not enough
evidence to support causality. There is no evidence that GOR induces laryngeal symptoms in children. There
is experimental evidence indicating the role of weak acid and non-acid gastric components in airway and
pulmonary inflammation, but the role of reflux in triggering respiratory symptom is inconclusive. Diagnostic
as well as therapeutic management of extraesophageal reflux in these settings is non-evidence based.
Combined pH-MII monitoring should be reserved for patients with suspected extraesophageal
manifestation of GORD with poor response to the initial treatment with PPIs or those being considered for
fundoplication. Anti-GOR medications should not be routinely used for treatment of poorly controlled
asthma, chronic cough and laryngitis. If these medications are used, and there is no response, rather than
escalating therapy uncritically, a second specialist opinion is recommended.

Unmeet needs and areas for future research

The evidence base on the respiratory manifestations of GOR in children is poor. Inclusion criteria and
outcome measures should be better standardized. We need more stringent criteria for causality; ideally a
double blind, N of 1 study, or at the very least that symptoms disappear with treatment and recur when
treatment is stopped. The presence and composition of any gastric contents should be investigated in the
airway of patients with GORD and respiratory problems, especially in those refractory to medical
treatment, for example bronchoalveolar lavage or induced sputum pepsin.55 Finally, for that tiny minority
with significant GORD, new therapeutic strategies are needed, that target both acid and non-acid reflux. A
new approach is to target transient lower esophageal sphincter relaxation (ie, gammaaminobutyric acid
agonists such as Baclofen) which is the basic underlying cause of reflux. Newer gammaaminobutyric acid
agonists with fewer adverse effects will be studied.

7
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10
 Table 1

Pathophysiologic mechanisms underlying the relationship between gastrooesophageal reflux and asthma

Mechanisms that can explain the increased prevalence of GER in asthmatic patients
− Increased gastro-esophageal pressure gradient due to increased negative intrathoracic pressure
during inspiration, induced by airflow obstruction
− Positive intra-abdominal pressure induced by cough
− Anatomic disconnection of the gastro-esophageal junction through the crural diaphragm due to
lung hyperinflation
−
Possible relaxation of the lower esophageal sphincter induced by asthma medication (ie, beta2-
agonists, aminophylline)

Mechanisms that can explain how GER may exacerbate asthma

− Airway injury due to microaspiration of gastric content (aspiration theory)
− Vagal-mediated bronchospasm and increased airway hyperresponsiveness due to stimulation of
irritant receptors in the distal esophagus (reflex theory)
−
Airway edema, mucus secretion, vasodilation, and smooth muscle contraction due to the gastric-
induced release of neurotransmitters (substance P and neurokinin A) into the lungs (neurogenic
theory)

11